Gastric cancer is one of the most common cancers and the second most common cause of cancer-related death worldwide.¹ Patients with an early-stage gastric cancer are often asymptomatic, and about 30% to 40% of patients present with distant metastases.² The most common sites of metastasis are the liver, peritoneum, and the lymph nodes. In more advanced stages, gastric cancers spread to the lungs, brain, bones, soft tissues, and other sites. Krukenberg tumors are classic but rare occurrences of gastric cancer metastasis to ovaries in females. In men, it is rare for gastric cancer to metastasize to the testes. Only a few cases of testicular metastasis from gastric cancer have been reported in the literature.^3-5

Primary testicular neoplasms typically present with unilateral testicular swelling. In rare instances, testicular swelling can be an initial presentation of a metastatic cancer. In this article, we report a man who initially presented with right testicular swelling and was eventually diagnosed with a secondary testicular cancer from an aggressive metastatic gastric adenocarcinoma.

Case Presentation

A 43-year-old male presented to his primary care physician with a 6-month history of right testicular swelling and unintentional weight loss of 33 pounds. An ultrasound of the scrotum and the testes showed a 4.5-cm hypoechoic and predominantly cystic mass in the right testis. Serum levels of β-human chorionic gonadotropin, α-feto protein and lactate dehydrogenase were within normal limits.

A primary testicular neoplasm was suspected. The patient underwent a right-sided inguinal orchiectomy. The pathology of the resected testis revealed an intestinal type adenocarcinoma with mucinous and signet-ring cell features (Figure). 

A staging Fluorine-18 fluorodeoxyglucose positron emission tomography scan revealed extensive hypermetabolic peritoneal nodules consistent with peritoneal carcinomatosis. The patient started palliative chemotherapy with 5-fluorouracil and oxaliplatin but rapidly declined with progressive abdominal symptoms after completion of 2 cycles. He discontinued chemotherapy and eventually opted for supportive care focusing on comfort.

Discussion

Testicular neoplasm is the most common solid tumor in men aged 20 to 34 years in the US.6 More than 90% of testicular neoplasms are germ-cell tumors and originate from the testes.⁶ Secondary neoplasms of the testes from solid tumors are rare. In an autopsy series, secondary neoplasms from solid tumors represented 4.6% of all testicular neoplasms.⁷ The reported frequencies of primary sites of origin vary based on the report. In a relatively large series, the most common solid tumors of origin were the prostate (35%) and lungs (20%).⁸ Among hematologic malignancies, lymphomas may originate from or secondarily involve the testes. Primary testicular lymphomas account for approximately 5% of testicular neoplasms and commonly occur in men aged > 60 years.⁹ Testicular involvement of acute myeloid or lymphoid leukemia may happen at diagnosis, but relapses of acute leukemia in a testicular site are more common and well recognized.^10,11

Our report shows a rare occurrence of a testicular swelling as an initial presentation of an aggressive metastatic gastric adenocarcinoma. When a patient presents with a testicular swelling, a testicular neoplasm is suspected based on the clinical examination, serum tumor markers, and ultrasonographic examination of the testes. Inguinal orchiectomy is the initial standard of care, and pathologic examination of a resected testis renders the confirmatory diagnosis. The overwhelming majority of these patients have primary testicular neoplasms, predominantly testicular germ-cell tumors. A small group may have atypical and rare tumors requiring additional workup to establish a diagnosis.

Metastatic spread of a solid tumor to a testicular site is rare. A testis is somewhat protected by the distinct anatomy that is offered by the blood-testis barrier. The tunica vaginalis, an external fibrous covering sheath of the testis, separates the testis from the peritoneal cavity and provides additional protection. Nevertheless, possible routes of secondary metastatic spread may include hematogenous and lymphovascular spread, cavitary dissemination and peritoneal seeding. Among gastric cancers, diffuse gastric cancer subtype is commonly associated with signet-ring cells. These cells lack adhesion and invade as single cells or small groups, leading to scattered tumor cells and a higher probability of seeding.

Our patient exhibited extensive peritoneal carcinomatosis, so peritoneal seeding likely played a dominant role in disseminating the cancer to the testis. It should be noted that possible primary sites of signet-ring cell metastatic adenocarcinomas are broad and may include the stomach and other GI and pancreaticobiliary sites, as well as the lung, bladder, breast, and gynecologic tract. Immunohistochemistry is often of limited value in establishing the primary site. Diagnosis is best established on clinical grounds, as was done in our patient.

When signet-ring cells are encountered in an orchiectomy specimen and a primary extratesticular site of origin cannot be identified, it is important to consider rare variants of primary testicular tumors in the differential diagnosis. A number of primary testicular tumors have signetring morphology. These include primary signetring cell stromal tumor of the testis (PSRST),¹² seminoma with signet-ring cell predominance,¹³ and a primary signet-ring cell germ-cell carcinoma of the testes (PSRGCT).¹⁴

Seminoma and PSRST variants generally are differentiated from adenocarcinoma by a lack of mucin production and the absence of keratin expression. PSRGCT is considered a
malignant somatic-type transformation of a testicular germ-cell tumor and germ-cell clonality is established by abnormal 12p chromosome through fluorescent in situ hybridization testing.¹³ PSRST is a benign tumor with excellent prognosis. Seminoma variants with signet-ring cell predominance and PSRGCT are managed as germ-cell tumors and are also considered to have good outcome. In contrast, testicular involvements from metastatic adenocarcinomas, including gastric cancers, are managed with multidisciplinary approach, including systemic chemotherapy. Despite this, patients have a poor outcome with a median survival of about 1 year.²

Conclusion

Advanced gastric adenocarcinoma can metastasize to the testes, and patients may present with a testicular swelling as an initial presentation. It is important to differentiate secondary testicular cancers from rare variants of primary testicular tumors because the prognosis and management vary substantially.

Gastric cancer is one of the most common cancers and the second most common cause of cancer-related death worldwide.¹ Patients with an early-stage gastric cancer are often asymptomatic, and about 30% to 40% of patients present with distant metastases.² The most common sites of metastasis are the liver, peritoneum, and the lymph nodes. In more advanced stages, gastric cancers spread to the lungs, brain, bones, soft tissues, and other sites. Krukenberg tumors are classic but rare occurrences of gastric cancer metastasis to ovaries in females. In men, it is rare for gastric cancer to metastasize to the testes. Only a few cases of testicular metastasis from gastric cancer have been reported in the literature.^3-5

Primary testicular neoplasms typically present with unilateral testicular swelling. In rare instances, testicular swelling can be an initial presentation of a metastatic cancer. In this article, we report a man who initially presented with right testicular swelling and was eventually diagnosed with a secondary testicular cancer from an aggressive metastatic gastric adenocarcinoma.

Case Presentation

A 43-year-old male presented to his primary care physician with a 6-month history of right testicular swelling and unintentional weight loss of 33 pounds. An ultrasound of the scrotum and the testes showed a 4.5-cm hypoechoic and predominantly cystic mass in the right testis. Serum levels of β-human chorionic gonadotropin, α-feto protein and lactate dehydrogenase were within normal limits.

A primary testicular neoplasm was suspected. The patient underwent a right-sided inguinal orchiectomy. The pathology of the resected testis revealed an intestinal type adenocarcinoma with mucinous and signet-ring cell features (Figure). 

A staging Fluorine-18 fluorodeoxyglucose positron emission tomography scan revealed extensive hypermetabolic peritoneal nodules consistent with peritoneal carcinomatosis. The patient started palliative chemotherapy with 5-fluorouracil and oxaliplatin but rapidly declined with progressive abdominal symptoms after completion of 2 cycles. He discontinued chemotherapy and eventually opted for supportive care focusing on comfort.

Discussion

Testicular neoplasm is the most common solid tumor in men aged 20 to 34 years in the US.6 More than 90% of testicular neoplasms are germ-cell tumors and originate from the testes.⁶ Secondary neoplasms of the testes from solid tumors are rare. In an autopsy series, secondary neoplasms from solid tumors represented 4.6% of all testicular neoplasms.⁷ The reported frequencies of primary sites of origin vary based on the report. In a relatively large series, the most common solid tumors of origin were the prostate (35%) and lungs (20%).⁸ Among hematologic malignancies, lymphomas may originate from or secondarily involve the testes. Primary testicular lymphomas account for approximately 5% of testicular neoplasms and commonly occur in men aged > 60 years.⁹ Testicular involvement of acute myeloid or lymphoid leukemia may happen at diagnosis, but relapses of acute leukemia in a testicular site are more common and well recognized.^10,11

Our report shows a rare occurrence of a testicular swelling as an initial presentation of an aggressive metastatic gastric adenocarcinoma. When a patient presents with a testicular swelling, a testicular neoplasm is suspected based on the clinical examination, serum tumor markers, and ultrasonographic examination of the testes. Inguinal orchiectomy is the initial standard of care, and pathologic examination of a resected testis renders the confirmatory diagnosis. The overwhelming majority of these patients have primary testicular neoplasms, predominantly testicular germ-cell tumors. A small group may have atypical and rare tumors requiring additional workup to establish a diagnosis.

Metastatic spread of a solid tumor to a testicular site is rare. A testis is somewhat protected by the distinct anatomy that is offered by the blood-testis barrier. The tunica vaginalis, an external fibrous covering sheath of the testis, separates the testis from the peritoneal cavity and provides additional protection. Nevertheless, possible routes of secondary metastatic spread may include hematogenous and lymphovascular spread, cavitary dissemination and peritoneal seeding. Among gastric cancers, diffuse gastric cancer subtype is commonly associated with signet-ring cells. These cells lack adhesion and invade as single cells or small groups, leading to scattered tumor cells and a higher probability of seeding.

Our patient exhibited extensive peritoneal carcinomatosis, so peritoneal seeding likely played a dominant role in disseminating the cancer to the testis. It should be noted that possible primary sites of signet-ring cell metastatic adenocarcinomas are broad and may include the stomach and other GI and pancreaticobiliary sites, as well as the lung, bladder, breast, and gynecologic tract. Immunohistochemistry is often of limited value in establishing the primary site. Diagnosis is best established on clinical grounds, as was done in our patient.

When signet-ring cells are encountered in an orchiectomy specimen and a primary extratesticular site of origin cannot be identified, it is important to consider rare variants of primary testicular tumors in the differential diagnosis. A number of primary testicular tumors have signetring morphology. These include primary signetring cell stromal tumor of the testis (PSRST),¹² seminoma with signet-ring cell predominance,¹³ and a primary signet-ring cell germ-cell carcinoma of the testes (PSRGCT).¹⁴

Seminoma and PSRST variants generally are differentiated from adenocarcinoma by a lack of mucin production and the absence of keratin expression. PSRGCT is considered a
malignant somatic-type transformation of a testicular germ-cell tumor and germ-cell clonality is established by abnormal 12p chromosome through fluorescent in situ hybridization testing.¹³ PSRST is a benign tumor with excellent prognosis. Seminoma variants with signet-ring cell predominance and PSRGCT are managed as germ-cell tumors and are also considered to have good outcome. In contrast, testicular involvements from metastatic adenocarcinomas, including gastric cancers, are managed with multidisciplinary approach, including systemic chemotherapy. Despite this, patients have a poor outcome with a median survival of about 1 year.²

Conclusion

Advanced gastric adenocarcinoma can metastasize to the testes, and patients may present with a testicular swelling as an initial presentation. It is important to differentiate secondary testicular cancers from rare variants of primary testicular tumors because the prognosis and management vary substantially.

Gastric cancer is one of the most common cancers and the second most common cause of cancer-related death worldwide.¹ Patients with an early-stage gastric cancer are often asymptomatic, and about 30% to 40% of patients present with distant metastases.² The most common sites of metastasis are the liver, peritoneum, and the lymph nodes. In more advanced stages, gastric cancers spread to the lungs, brain, bones, soft tissues, and other sites. Krukenberg tumors are classic but rare occurrences of gastric cancer metastasis to ovaries in females. In men, it is rare for gastric cancer to metastasize to the testes. Only a few cases of testicular metastasis from gastric cancer have been reported in the literature.^3-5

Primary testicular neoplasms typically present with unilateral testicular swelling. In rare instances, testicular swelling can be an initial presentation of a metastatic cancer. In this article, we report a man who initially presented with right testicular swelling and was eventually diagnosed with a secondary testicular cancer from an aggressive metastatic gastric adenocarcinoma.

Case Presentation

A 43-year-old male presented to his primary care physician with a 6-month history of right testicular swelling and unintentional weight loss of 33 pounds. An ultrasound of the scrotum and the testes showed a 4.5-cm hypoechoic and predominantly cystic mass in the right testis. Serum levels of β-human chorionic gonadotropin, α-feto protein and lactate dehydrogenase were within normal limits.

A primary testicular neoplasm was suspected. The patient underwent a right-sided inguinal orchiectomy. The pathology of the resected testis revealed an intestinal type adenocarcinoma with mucinous and signet-ring cell features (Figure). 

A staging Fluorine-18 fluorodeoxyglucose positron emission tomography scan revealed extensive hypermetabolic peritoneal nodules consistent with peritoneal carcinomatosis. The patient started palliative chemotherapy with 5-fluorouracil and oxaliplatin but rapidly declined with progressive abdominal symptoms after completion of 2 cycles. He discontinued chemotherapy and eventually opted for supportive care focusing on comfort.

Discussion

Testicular neoplasm is the most common solid tumor in men aged 20 to 34 years in the US.6 More than 90% of testicular neoplasms are germ-cell tumors and originate from the testes.⁶ Secondary neoplasms of the testes from solid tumors are rare. In an autopsy series, secondary neoplasms from solid tumors represented 4.6% of all testicular neoplasms.⁷ The reported frequencies of primary sites of origin vary based on the report. In a relatively large series, the most common solid tumors of origin were the prostate (35%) and lungs (20%).⁸ Among hematologic malignancies, lymphomas may originate from or secondarily involve the testes. Primary testicular lymphomas account for approximately 5% of testicular neoplasms and commonly occur in men aged > 60 years.⁹ Testicular involvement of acute myeloid or lymphoid leukemia may happen at diagnosis, but relapses of acute leukemia in a testicular site are more common and well recognized.^10,11

Our report shows a rare occurrence of a testicular swelling as an initial presentation of an aggressive metastatic gastric adenocarcinoma. When a patient presents with a testicular swelling, a testicular neoplasm is suspected based on the clinical examination, serum tumor markers, and ultrasonographic examination of the testes. Inguinal orchiectomy is the initial standard of care, and pathologic examination of a resected testis renders the confirmatory diagnosis. The overwhelming majority of these patients have primary testicular neoplasms, predominantly testicular germ-cell tumors. A small group may have atypical and rare tumors requiring additional workup to establish a diagnosis.

Metastatic spread of a solid tumor to a testicular site is rare. A testis is somewhat protected by the distinct anatomy that is offered by the blood-testis barrier. The tunica vaginalis, an external fibrous covering sheath of the testis, separates the testis from the peritoneal cavity and provides additional protection. Nevertheless, possible routes of secondary metastatic spread may include hematogenous and lymphovascular spread, cavitary dissemination and peritoneal seeding. Among gastric cancers, diffuse gastric cancer subtype is commonly associated with signet-ring cells. These cells lack adhesion and invade as single cells or small groups, leading to scattered tumor cells and a higher probability of seeding.

Our patient exhibited extensive peritoneal carcinomatosis, so peritoneal seeding likely played a dominant role in disseminating the cancer to the testis. It should be noted that possible primary sites of signet-ring cell metastatic adenocarcinomas are broad and may include the stomach and other GI and pancreaticobiliary sites, as well as the lung, bladder, breast, and gynecologic tract. Immunohistochemistry is often of limited value in establishing the primary site. Diagnosis is best established on clinical grounds, as was done in our patient.

When signet-ring cells are encountered in an orchiectomy specimen and a primary extratesticular site of origin cannot be identified, it is important to consider rare variants of primary testicular tumors in the differential diagnosis. A number of primary testicular tumors have signetring morphology. These include primary signetring cell stromal tumor of the testis (PSRST),¹² seminoma with signet-ring cell predominance,¹³ and a primary signet-ring cell germ-cell carcinoma of the testes (PSRGCT).¹⁴

Seminoma and PSRST variants generally are differentiated from adenocarcinoma by a lack of mucin production and the absence of keratin expression. PSRGCT is considered a
malignant somatic-type transformation of a testicular germ-cell tumor and germ-cell clonality is established by abnormal 12p chromosome through fluorescent in situ hybridization testing.¹³ PSRST is a benign tumor with excellent prognosis. Seminoma variants with signet-ring cell predominance and PSRGCT are managed as germ-cell tumors and are also considered to have good outcome. In contrast, testicular involvements from metastatic adenocarcinomas, including gastric cancers, are managed with multidisciplinary approach, including systemic chemotherapy. Despite this, patients have a poor outcome with a median survival of about 1 year.²

Conclusion

Advanced gastric adenocarcinoma can metastasize to the testes, and patients may present with a testicular swelling as an initial presentation. It is important to differentiate secondary testicular cancers from rare variants of primary testicular tumors because the prognosis and management vary substantially.

John Zic, MD. Let’s start by defining cutaneous T-cell lymphomas (CTCLs) and how they differ from other non-Hodgkin lymphomas. We also should discuss classification, which can be very confusing and epidemiology as it relates to the veteran population. Then I think we should dive into challenges with diagnosis and when should a VA or any provider consider mycosis fungoides (MF) and Sézary syndrome—the 2 most common variants of CTCLs.

I like to define the primary CTCLs as malignancies of the T-cell where the primary organ of involvement is the skin. However, this disease can spread to lymph nodes and visceral organs and the blood compartment in more advanced patients. Alejandro, could you provide some highlights about how CTCLs are classified?

Alejandro Ariel Gru, MD. Lymphomas are divided in the general hematology/oncology practice as Hodgkin and non-Hodgkin lymphomas. Traditionally all lymphomas that occur on the skin are non-Hodgkin lymphoma subtypes. That has specific connotations in terms of diagnosis, prognosis, and therapy. Because the T cells are one of the main residents of the subtypes of lymphocytes you encounter on the skin, most lymphomas that occur on the skin are derived of T-cell origin. B-cell lymphomas, in general, tend to be relatively uncommon or more infrequent.

There are 3 main subtypes of CTCL that present on the skin.¹ MF is, by far, the most common subtype of CTCL. The disease tends to present in patients who are usually aged > 60 years and is more frequent in white males. It’s a lymphoma that is particularly relevant to the veteran population. The second subtype has many similarities to MF but shows substantial peripheral blood involvement and is referred to as Sézary syndrome. The third group is encompassed under the term CD30-positive lymphoproliferative disorders. This group includes 2 main subtypes: primary cutaneous anaplastic large-cell lymphoma and lymphomatoid papulosis. Some cases of MF develop progression to what we call large cell transformation, which implies cytologic transformation to a more aggressive lymphoma.

There are other cutaneous lymphomas that are far less common. Some are indolent and others can be more aggressive, but they represent < 5% of all CTCL subtypes.

Lauren Pinter-Brown, MD. That was a great summary about these non-Hodgkin lymphomas. In the veteran population, it’s wise to remember that there are many kinds of non-Hodgkin lymphomas. Because of the action that they have seen, some people, such as Vietnam veterans, might be more susceptible to non-Hodgkin lymphomas than others.

John Zic. That’s a good point because certainly non-Hodgkin lymphomas are listed as one of the potential disease associations with exposure to Agent Orange.

I’d like to move on to epidemiology and the incidence of MF and Sézary syndrome. An article that came out of Emory University in 2013 is one of the more up-to-date articles to examine the incidence and survival patterns of CTCL.² The authors looked at patients from 2005 to 2008 and identified 2,273 patients in the Surveillance, Epidemiology, and End Results registry. They estimated that the incidence of MF in the US population is about 5.5 per 1,000,000 per year, which certainly makes it a rare disease. The incidence of Sézary syndrome was 0.1 per 1,000,000 per year, which comes out to about 1 per 10 million per year.

However, the MF incidence needs to be contrasted to the estimated incidence in the veteran population. In 2016, Larisa Geskin and colleagues from Columbia University and the Bronx US Department of Veterans Affairs (VA) Medical Center examined the VA database of patients with diagnoses of MF and Sézary syndrome.³ They combined them, but I have a feeling that the amount of Sézary syndrome patients was much less than those with MF. They estimated an incidence per million of 62 to 79 cases per 1,000,000 per year. The conclusion of Dr. Geskin’s study stated that the incidence of CTCL in the veteran population appears to be anywhere from 6 to 8 times higher. But if we use the most recent US incidence rates, it’s more than 10 times higher.

Those of you who have worked with veterans, either at the VA or in your private practice, do you have any ideas about why that might be?

Lauren Pinter-Brown. As you previously discussed, this is an illness of older people, and Vietnam veterans now are in their 60s and 70s. They may account for a lot of these diagnoses.

John Zic. That’s a good point. There’s quite a bit of talk about exposure to Agent Orange. But honestly, we really don’t know the cause of any of the CTCLs. We have not been able to identify a single cause. There are some risk factors. A 2014 article from the Journal of the National Cancer Institute looked at 324 cases of CTCL and compared it with 17,000 controls.⁴ They showed some interesting risk factors, such as body mass index (BMI) > 30 and smoking > 40 years. Similar to previous European studies, they showed that occupations like being a farmer, a painter, a woodworker, or a carpenter may carry additional risk.I wonder whether or not veterans were more likely to have some of these risk factors that this epidemiologic study picked up in addition to exposures that they may have encountered during their active-duty service. Interestingly, a decreased risk factor for developing MF was moderate physical activity. Clearly though, there are a large number of patients with CTCL in the veteran population.

I’d like to turn now to some of the challenges with diagnosis. Marianne, could you share some of your experience with early-stage disease and about how long it took them to be diagnosed?

Marianne Tawa, RN, MSN, ANP. Speaking specifically about early-stage disease, patients often share a history of waxing and waning rash that may not be particularly itchy. Confounding the picture, the distribution of early patch or plaque stage CTCL rash frequently occurs in covered areas. Many patients miss out on complete skin examinations by providers, thus early-stage CTCL may not be appreciated in a timely manner.

In certain scenarios, it may take upward of 5 to 7 years before the CTCL diagnosis is rendered. This is not because the patient delayed care. Nor is it because a skin biopsy was not performed. The progression of the disease and meeting the classic features of histology under the microscope can require clinical observation over time and repeated skin biopsies. We recommend patients refrain from topical steroid applications for 2 to 4 weeks prior to skin biopsy if we have a strong suspicion of CTCL. Many patients will report having a chronic eczematous process. Some patients may have a history of parapsoriasis, and they’re on the continuum for CTCL. That’s a common story for CTCL patients.

John Zic. What is the role of a skin biopsy in the diagnosis of CTCL? We see many patients who have had multiple skin biopsies who often wonder whether or not the diagnosis was missed by either the clinician or the pathologist.

Alejandro Ariel Gru. That is a great area of challenge in terms of pathologic diagnosis of early MF. A study led by Julia Scarisbrick, from an international registry data (PROCLIPI) on the early stages of the disease, showed a median delay of diagnosis of early MF of approximately 36 months.⁵ For all physicians involved in the diagnosis and care of patients with MF, the delay is probably significantly higher than that. We’ve seen patients who have lived without a diagnosis for a period of 10 or sometimes 15 years. That suggests that many cases are behaving in an indolent fashion, and patients are not progressing through the ‘natural’ stages of the disease and remain at the early stage. There also is the potential that other chronic inflammatory conditions, particularly psoriasis or parapsoriasis, can be confused with this entity. The diagnosis of certain types of parapsoriasis, can belong to the same spectrum of MF and can be treated in a similar way than patients with early stage MF are, such as phototherapy or methotrexate.

The diagnosis of MF relies on a combination of clinical, pathologic, and immunophenotypic findings where it is desired or preferred that at least 2 biopsies are done from different sides of the body. In addition to having a good clinical history that supports the diagnosis, a history of patches, plaques, and sometimes tumors in advanced stages in particular locations that are covered from the light (eg, trunk, buttocks, upper thighs, etc) combined with specific histopathologic criteria are capital to establish an accurate diagnosis.

In the biopsies, we look particularly for a lymphoid infiltrate that shows extension to the epidermis. We use the term epidermotropism to imply that these abnormal or neoplastic lymphocytes extend into the epidermis. They are also cytologically atypical. We see variations in the nucleus. In the size, we see a different character of the chromatin where they can be hyperchromatic. We also look for immunophenotypic aberrations, and particularly we analyze for patterns of expression of T-cell markers. Most cases of MF belong to a subset of T cells that are called CD4-positive or T-helper cells. We look for a patterned ratio of the CD4 and CD8 between the epidermis and an aberrant loss of the CD7 T-cell marker. Once we establish that we can see significant loss of these markers, we can tell where there is something wrong with that T-cell population, and likely belong to a neoplastic category.

In addition, we also rely on the molecular evaluation and search of a clonal population of T cells, by means of a T-cell receptor gene rearrangement study. Ideally, we like to see the establishment of a single clone of T cells that is matched in different biopsy sites. Proving that the same clone is present in 2 separate biopsies in 2 separate sites is the gold standard for diagnosis.⁶

John Zic. To recap, a biopsy is indicated for patients who have patches or plaques (that are slightly raised above the skin) in sun-protected areas that are fixed; rather than completely go away in the summer and come back in the winter, they are fixed if they have been present > 6 to 12 months. Many of these patients are diagnosed with eczema, psoriasis, allergic contact dermatitis, and other skin diseases before the clinician starts to think about other diagnoses, such as CTCL.

I agree that I would not rule out the diagnosis with 1 biopsy that does not show classic histologic changes. Also, I think that it’s important to alert the pathologist that you’re considering a diagnosis of T-cell lymphoma, either MF or some of the other subtypes, because that will certainly alert them to look a little closer at the infiltrating cells and perhaps do some of the other testing that was mentioned. Once we establish the MF diagnosis, staging studies may be indicated.

Lauren Pinter-Brown. Early stage would be patients with patches or plaques. Stage IA would be < 10% body surface area, and stage IB would be > 10%. I don’t perform scans for early-stage patients, but I do a very thorough physical and perform blood tests. For patients that have more advanced disease, such as tumors, erythroderma, or Sézary syndrome, I would conduct the same thorough examination and blood tests and scan the patient either with a computed tomography (CT) or a positron emission tomography (PET)/CT to detect adenopathy. We have to recognize that most of the adenopathy that is detected in these patients is peripheral, and we can feel it on physical examination.

John Zic. Do you prefer one imaging modality over the other? CT scan with IV contrast vs PET/CT?

Lauren Pinter-Brown. I tend to use PET/CT because it illuminates extranodal sites as well. I have to admit that sometimes it’s a problem to get that approved with insurance.

John Zic. In the federal system, many PET/CT scans are performed at other facilities. That would be an extra step in getting approval.

You mentioned Sézary syndrome. We should consider a diagnosis of Sézary syndrome when you have a patient with erythroderma, which means that they have > 80% of the skin covered in redness and scaling.

Lauren Pinter-Brown. The first step is to do a complete blood count (CBC) and see if there’s a lymphocytosis. Sometimes that really isn’t very sensitive, so my go-to test is flow cytometry. We are looking for an abnormal population of cells that, unlike normal T cells, often lack certain T-cell antigens. The most common would be CD7. We can confirm that this is a clone by T-cell gene rearrangement, and often in Sézary we like to compare the gene rearrangement seen in blood with what might be seen in the skin biopsy to confirm that they’re the same clone.

John Zic. That’s an excellent point. I know there are specific criteria to meet significant blood involvement. That is a topic of conversation among CTCL experts and something that might be changing over the next few years. But I think as it stands right now, having a lymphocytosis or at least an elevated CD4 count along with having a clone in the blood matching the clone in the skin are the first 2 steps in assessing blood involvement. However, the flow cytometry is very important. Not all medical centers are going to do flow cytometry—looking specifically for a drop of the CD7 or CD26 antigen among the CD4 population. But that is one of the major criteria that we look for in those patients with suspected blood involvement.

Marianne Tawa. Additionally, we would advise obtaining flow cytometry on patients that look like they have a robust skin burden with lots of patches, plaques, or tumors. We also perform lactate dehydrogenase (LDH) with staging.

John Zic. What do you usually tell patients with early-stage disease, those that have patches and plaques?

Marianne Tawa. For patients with stage IA disease, we are very optimistic about their prospects. We explain that the likelihood that early-stage disease will progress to a more advanced stage or rare variant is unlikely. This is very much a chronic disease, and the goal is to manage appropriately, palliate symptoms, and preserve quality of life (QOL).

Lauren Pinter-Brown. I often refer to a landmark paper by Youn H. Kim and colleagues that shows us that patients with IA disease who are at least treated usually have a normal lifespan.⁷ I encourage patients by sharing that data with them.

John Zic. Sean Whittaker and colleagues in the United Kingdom identified 5 risk factors for early-stage patients that may put them at higher risk for progressing: aged > 60 years; having a variant called folliculotropic MF; having palpable lymph nodes even if they’re reactive on biopsy, having plaques, and male sex.⁸ For staging of lymph nodes, what’s your usual approach when you see a patient with palpable lymph nodes?

Lauren Pinter-Brown. Many patients, particularly those with advanced skin disease, may have palpable lymph nodes that are reacting to their skin disease and on pathology would be dermatopathic. That would not change my management. I pay attention to the quality of the lymph node—if it’s very firm, if it’s > 2 cm, if it is persistent—before I biopsy. These patients have a higher incidence of wound infection after excisional biopsy. If the patient has pathologic lymph node involvement and effacement of the node with malignant cells, I would change my management. I do need to know that sort of information.

John Zic. Alejandro, as a hematopathologist can you comment on the debate about whether or not we actually do need an excisional biopsy or whether or not we can get a core lymph node biopsy to give you all the information that you need to grade it?

Alejandro Ariel Gru. There are 2 main modalities of biopsies we typically see for lymph nodes for evaluation and staging for involvement of CTCL. One is the traditional excisional biopsy that for the most part requires surgery with general anesthesia and has all the major implications that that type of procedure has. Many centers are looking at less invasive types of procedures, and needle core biopsies have become one of the most common forms of biopsy for all lymphoma subtypes. Excisional biopsies have the advantage of being able to see the whole lymph node, so you can determine and evaluate the architecture very well. Whereas needle core biopsies typically use a small needle to obtain a small piece of the tissue.

The likelihood of a successful diagnosis and accurate staging was compared recently in the British Journal of Dermatology.⁹ They were able to perform accurate staging in needle core biopsies of patients with MF. However, this is still a matter of debate; many people feel they are more likely to get enough information from an excisional biopsy. As we know, excisional biopsies sometimes can be hard, particularly if the large lymph node is located in an area that is difficult to access, for example, a retroperitoneal lymph node.

There are many staging categories that are used in the pathologic evaluation of lymph node involvement. On one hand, we could see the so-called dermatopathic changes, which is a reactive form of lymphadenopathy that typically happens in patients who have skin rashes and where there is no evidence of direct involvement by the disease (although there are some patients who can have T-cell clones by molecular methods). The patients who have clonal T cells perhaps might not do as well as the ones who do not. On the other hand, we have patients for whom the whole architecture of the lymph node is effaced or replaced by neoplastic malignant cells. Those patients are probably going to need more aggressive forms of therapy.¹⁰

John Zic. The type of lymph node biopsy has been a hot topic. If patients have palpable lymph nodes in the cervical, axillary, and inguinal area, I don’t know if it’s a consensus, but the recommendation right now is to consider performing a lymph node biopsy of the cervical lymph nodes first, axillary second, and inguinal lymph nodes third. That might have to do with the complication rates for those different areas.

I’d like to switch to a discussion to more advanced disease. CTCL tumors are defined as a dome-shaped nodule > 1 cm. They don’t have to be very big before we label it a tumor, and the disease is considered more advanced. For patients with a few tumors, what does your prognosis discussion sound like?

Marianne Tawa. Certainly, the prognosis discussion can become slightly more complicated when you move into the realm of tumor-stage development. This is especially true if a CTCL patient has lived with and managed indolent patches or plaques for several years. We approach these patients with optimism and with the goal of managing their tumors, whether it be with a skin-directed option, such as localized radiation or a host of approved systemic therapies. Patients presenting with or developing tumor-stage disease over time will require additional staging workup compared with early-stage disease staging practice. Patients are counseled on imaging use in tumor-stage disease and why flow cytometry may be requested to rule in or rule out accompanying peripheral blood involvement. Patients are exposed to a myriad of pictures, stories, and survival statistics from Internet research. It becomes our task to inform them of their unique presentation and tailored treatment plan, which thankfully may produce more favorable responses than those presented online.

Lauren Pinter-Brown. One thing that we focus on is the idea that a statistic regarding prognosis isn’t predictive for an individual patient. When patients go online, we caution them that many of the statistics are really old. There’s been a lot of new therapies in the past 10 years. Just looking at my patients, my feeling is that their prognosis has continued to improve over the decades that I’ve been involved in this area.

We have to take the statistics with a grain of salt, though certainly someone that has Sézary syndrome or someone that has nodal involvement or tumors is not going to fare as well as the patients that we talked about with stage I disease. However, if we all continue to do our jobs and have more and more treatment options for patients, that’s certainly going to change over time as it has with other non-Hodgkin lymphomas.

John Zic. We’ve all treated advanced patients with disease and some, of course, have died of the disease. When patients die of advanced CTCL, what are the things that lead to their demise?

Lauren Pinter-Brown. Probably the most common would be infections because their skin barrier has been broken. As the disease advances, their immune system also deteriorates. We may contribute to that sometimes with some of the therapies that we use, although we try and be judicious. First and foremost, the primary cause of death remains infection and sometimes inanition.

Marianne Tawa. I agree, infection or just the unfortunate progression of their lymphoma through the various armamentarium of treatments would be the 2 reasons.

John Zic. Let’s dive into therapy. I want to start with early stage. While, I don’t think there’s a role for systemic anticancer agents, certainly the IV agents for most patients with early-stage disease Marianne, you mentioned phototherapy. What are the types of phototherapy that you offer?

Marianne Tawa. We would start out with narrow band UVB therapy for patients with > 10% body surface area involvement. When applying topical corticosteroids to wider surface areas of the patient’s body is no longer feasible or effective, we recommend the initiation of narrow band UVB phototherapy. This is preferred because of its lessor adverse effect (AE) profile as far as nonmelanoma skin cancer risk. Patients commence narrow band UVB 3 times per week, with a goal of getting the patient into remission over a matter of months and then slowly tapering the phototherapy so that they get to a maintenance of once weekly.

Realizing that narrow band UVB may not penetrate deeper plaques or effectively reach folliculotropic variant of CTCL, we would employ PUVA, (psoralen and UVA). Patients are expected to protect their eyes with UVA glasses and remain out of the sun 24 hours following PUVA treatments. The cost of the methoxsalen can be an issue for some patients. Nonmelanoma skin cancer risks are increased in patients undergoing long-term PUVA treatments. Routine skin cancer surveillance is key.

There are monetary, time, and travel demands for patients receiving phototherapy. Thus, many CTCL patients are moving toward home-based narrow band UVB units supervised by their treating dermatologist. Other skin-directed treatment options, aside from topical corticosteroids and phototherapy, would include topical nitrogen mustard, imiquimod, and localized or total skin electron beam radiation.

John Zic. Here in Nashville, some of our veterans travel hundreds of miles to get to our center. It’s not practical for them to come here for the narrow band UVB phototherapy. Veterans can get approval through the VA Choice programs to have phototherapy performed by a local dermatologist closer to home. We also have had many veterans who choose to get home narrow band UVB phototherapy, which can be quite effective. Narrow band UVB phototherapy is among the most effective therapies for patients with generalized patches in particular, and maybe some with just a few plaques.

Medium potency topical steroids are not as helpful as superpotent topical steroids such as clobetasol, dipropionate ointment, or betamethasone dipropionate ointment. Usually, I tell patients to apply it twice a day for 8 weeks. You must be careful because these high-potency topical steroids can cause thinning of the skin, but it’s rarely seen, even in patients that may use them for 8 weeks if they’re applying them just to their patches and thin plaques. There are a few other topicals. There’s bexarotene gel, which is a topical retinoid, and mechlorethamine or nitrogen mustard gel that are available as topicals. Both of those can be helpful if patients have < 10% body surface area of patches or plaques because they can apply that at home.

Because of the excellent prognosis for patients in early stages, this is an area we want to try to avoid doing harm. For patients with advanced disease, what are some of the decisions that you think about in recommending a patient to get radiation therapy?
 

Lauren Pinter-Brown. I use radiation therapy sparingly and primarily for patients who either have only 1 tumor and the rest of their disease is patch and plaque or for patients who have very large tumors that are either cosmetically unacceptable or creating infection or pain. I treat people with systemic therapies primarily to prevent the formation of tumors.

John Zic. There probably is a role for total skin electron beam radiotherapy in patients who have failed multiple other skin-directed therapies and are progressing and then perhaps a role for more advanced patients who have multiple tumors where you’re trying to get some control of the disease. Are there any other situations where you might consider total skin electron beam?

Marianne Tawa. Yes, those are 2 scenarios. A third scenario would be in patients preparing for stem cell transplant. We typically do a modified 12 Gy regimen of total skin electron beam for palliation and up to 24 Gy regimen for patients who are in earnest preparing for a stem cell transplant.

John Zic. Systemic therapies also treat this disease. There are 2 oral agents. One is bexarotene capsules, a retinoid that binds to the RXR receptor and has a multitude of effects on different organ systems. It is probably the best tolerated oral agent we have. The other FDA-approved agent is vorinostat, a histone deacetylase inhibitor, but it has more gastrointestinal AEs than does bexarotene. Bexarotene has AEs as well, including hypertriglyceridemia and central hypothyroidism, which can throw a curveball to unsuspecting primary care physicians who might check thyroid function studies in these patients.

We certainly need to know about those AEs. There are many patients who have tumor-stage disease that can have radiotherapy to several tumors, then go on a drug like bexarotene capsules and may be able to maintain the remission for years. In my experience, it’s a drug that patients usually stay on. They can be weaned to a very low dose, but I’ve had several patients who come off of bexarotene only to suffer relapses.

Lauren, what are some of the things that you think about when you declare someone as having failed bexarotene or vorinostat and you’re thinking about IV therapies?

Lauren Pinter-Brown. Patient comorbidities and the particular compartment of their body that is involved are important factors. Do they have blood involvement, or not? Do they have nodal involvement, or not? Another concern is both acute and chronic toxicities that need to be discussed with the patient to determine an acceptable QOL. Finally, the schedule that you’re giving the drug. Some people may not be able to come in frequently. There are a lot of variables that go into making an individual decision at a particular time for a specific patient who will be using parenteral therapies.

John Zic. If we have a patient with advanced MF, tumors, and perhaps lymph node involvement, what are some of the systemic options that you would consider?

Lauren Pinter-Brown. With nodal involvement, an attractive option is something like IV romidepsin because we know that it treats peripheral T-cell lymphomas, which are aggressive nodal T-cell lymphomas. It’s FDA approved and also treats CTCL. Another is brentuximab vedotin if there is significant CD30 expression. It also is FDA approved for CTCL and has a long track record of treating certain peripheral T-cell lymphomas like anaplastic large cell.

John Zic. When would the stem cell transplant discussion start at your institution?

Lauren Pinter-Brown. It starts earlier for a younger patient because even though we do have lots of treatment if someone is aged 20 or30 years, I don’t really have any illusions that I have enough treatment options for them to live a normal lifespan if they have advanced disease. It’s a possibility for any patient when I see that the future options are dwindling, and that I am not going to be able to control the patient’s disease for much longer. Having said that, patients who have tumor-stage disease are among those that don’t do quite as well with allogeneic transplantation; ironically, patients with Sézary syndrome or erythroderma might do a little bit better.

John Zic. Before considering a stem cell transplant for patients with Sézary syndrome, that is erythroderma with significant blood involvement, what other treatment options would you offer?

Marianne Tawa. For low blood-burden disease, we might look at extracorporeal photopheresis as monotherapy or in combination with interferon or bexarotene. For patients with higher blood burden we might recommend low-dose alemtuzumab, especially if they have abundant CD52 expression. We also consider the newly FDA-approved anti-CCR4 antibody treatment, mogamulizumab, for patients presenting with Sézary syndrome. It is generally well tolerated but does have the potential for producing infusion reactions or drug rash.

Romidepsin has efficacy in blood, lymph node, and skin compartments. The primary considerations for patients considering romidepsin are prolonged infusion times and QOL AEs with gastrointestinal and taste disturbances and fatigue.

John Zic. Both of you have brought up an excellent point. This is a disease that while we do not have a good chance of curing, we have a pretty fair chance of controlling, especially if it’s early stage. The data from the stem cell transplant literature indicate that stem cell transplant may be one of the few modalities that we have that may offer a cure.¹¹

Lauren Pinter-Brown. There are patients who are cured with allogeneic transplants; and the very first allogeneic transplants were performed well over 20 years ago. Many patients, even some in my practice, who were among those patients and continue to do extremely well without any evidence of disease. Sometimes when people have allogeneic transplantation, their disease relapse may be in a more indolent form that’s much easier to deal with than their original disease. Even if they’re not cured, the fact that the aggressive disease seems to be at bay may make them much easier to treat.

John Zic. Those are excellent points. You brought up photopheresis as a treatment modality for patients with evolving or early Sézary syndrome and patients with erythrodermic MF can also respond. We have a lot of experience with that at the Nashville VA medical center. We’re one of the few VA hospitals in the US that has a photopheresis unit. But the modality is available at many academic medical centers because it’s a treatment for graft-vs-host disease.

We tend to also consider photopheresis in patients who may have had an excellent response to another systemic agent. There are some data that patients who received photopheresis, after total skin electron beam therapy vs those who received chemotherapy after radiation, had a longer disease-free survival.¹²

I’d like to end with a discussion of something that’s very important, which is managing QOL issues for patients with CTCL. Itch is among some of the worst symptoms that can cause suffering in patients. But it is sometimes not a problem at all for patients who have a few patches or plaques. That’s one reason why they might ignore their rash. Certainly, as the disease progresses, especially those patients with erythroderma, the itch can be intractable and can have a major impact on their life. What are some approaches to managing itch at your institutions?

Lauren Pinter-Brown. One thing to be aware of is that the itch is not usually mediated by histamine, though people will often put the patients on a lot of antihistamines. I don’t find those to be the most effective treatments. I think of the itch in these patients as more of a neuropathic condition and would tend to treat more with things that you might use for neuropathy, such as gabapentin or doxepin or antidepressants. There’s a whole host of other treatments, such as aprepitant, something that I would use as an antiemetic, that might also be helpful for pruritus in this patient population.

John Zic. That’s my experience as well. I have found gabapentin to be helpful for patients with itch, though not universally.

Marianne Tawa. I consider itch a huge QOL concern for a large majority of our patients with a CTCL diagnosis. It’s on par with pain. In early-stage disease, pruritus levels improve as the cutaneous burden is reduced with skin-directed therapies such as, topical corticosteroid or phototherapy.

SSRI agents could also be considered for select patients. The antiemetic agent, aprepitant has been useful for addressing itch in a subset of our patients with Sézary syndrome. Patients will also seek out complementary modalities such acupuncture, hypnosis, and guided imagery.

John Zic. Because the disease itself affects the skin and can lead to dryness, patients often suffer with dry skin. When I trained in Chicago, that was the foundation of our treatment, making sure that patients are using a super fatted soap such as Dove (Unilever, London, United Kingdom) or Cetaphil (Galderma Laboratories; Fort Worth, TX), making sure that they’re lubricating their skin frequently with something perhaps in the wintertime as thick as petroleum jelly. And then in the summertime perhaps with Sarna lotion (Crown Laboratories; Johnson City, TN), which has menthol. It’s important to note that when the patient’s skin is infected, the itch can skyrocket. Being aware and monitoring the skin for signs of infection such as crusting and impetigo-like findings can be helpful.

I also wanted to touch on fatigue. Patients can have fatigue for many reasons. Sometimes it’s because the itch is interfering with their sleep. How do you approach managing fatigue?
 

Lauren Pinter-Brown. There have been many studies about cancer fatigue, and it appears that one of the cheapest and easiest modalities is for patients to walk. We often suggest that our patients go on walks, however much they can do, because that has been seen over and over again in studies of cancer fatigue to be beneficial.

John Zic. Do you have any advice for nurses that might be helping to manage patients in a cutaneous lymphoma clinic?

Marianne Tawa. As this is a rare disease, nursing encounters with patients carrying a diagnosis of CTCL in both oncology and dermatology settings may be few and far between. I recommend nurses familiarize themselves with articles published on CTCL topics found in both dermatology and oncology peer review journals. Another avenue for gaining insight and education would be through continuing education courses. Resources can also be found for nurses, patients, and caregivers through advocacy foundations such as the Cutaneous Lymphoma Foundation (www.clfoundation.org) and the Lymphoma Research Foundation (LRF@lymphma.org).

John Zic. Is there anything else that anyone would like to add to our discussion?

Lauren Pinter-Brown. One thing that we touched upon, but I was concerned that we didn’t emphasize, was the use of flow cytometry as a diagnostic tool in a patient with erythroderma. Sometimes biopsies of patients with erythroderma are not diagnostic, so clinicians need to be aware that there are other ways of diagnosing patients—nodal biopsy or flow cytometry. They should not only think of it as a staging tool but sometimes as a diagnostic tool.

Alejandro Ariel Gru. I agree. Particularly in patients who have Sézary syndrome or MF with peripheral blood involvement, sometimes the findings on the biopsy show a dissociation between how impressive the clinical presentation of the patient might be and how very few findings you might encounter on the skin biopsy. Therefore, relying on flow cytometry as a diagnostic tool is capital. Lauren, you briefly mentioned the criteria, which is looking for an abnormal CD4 to CD8 ratio of > 10%, abnormal loss of CD7, > 40%, or abnormal loss of CD26 of > 30%.

In addition, there are new markers that are now undergoing validation in the diagnosis of Sézary syndrome. One is KIR3DL2, which is a natural killer receptor that has been shown to be significantly upregulated in Sézary syndrome and appears to be both more sensitive and specific. With that also comes therapies that target the KIR3DL2 molecule.

John Zic. One of the first things we teach our dermatology residents to work up patients with erythroderma is that they shouldn’t expect the skin biopsy to help them sort out the cause of the erythroderma. As you mentioned, Lauren, the flow cytometry of peripheral blood should always be accompanied by a CBC with differential and platelets. And if the patients do have lymph nodes, consider a biopsy because sometimes that’s where you can make the firmest diagnosis of a T-cell lymphoma.

Acknowledgmentszz
The participants and Federal Practitioner would like to thank Susan Thornton, CEO of the Cutaneous Lymphoma Foundation for helping to arrange this roundtable discussion.

John Zic, MD. Let’s start by defining cutaneous T-cell lymphomas (CTCLs) and how they differ from other non-Hodgkin lymphomas. We also should discuss classification, which can be very confusing and epidemiology as it relates to the veteran population. Then I think we should dive into challenges with diagnosis and when should a VA or any provider consider mycosis fungoides (MF) and Sézary syndrome—the 2 most common variants of CTCLs.

I like to define the primary CTCLs as malignancies of the T-cell where the primary organ of involvement is the skin. However, this disease can spread to lymph nodes and visceral organs and the blood compartment in more advanced patients. Alejandro, could you provide some highlights about how CTCLs are classified?

Alejandro Ariel Gru, MD. Lymphomas are divided in the general hematology/oncology practice as Hodgkin and non-Hodgkin lymphomas. Traditionally all lymphomas that occur on the skin are non-Hodgkin lymphoma subtypes. That has specific connotations in terms of diagnosis, prognosis, and therapy. Because the T cells are one of the main residents of the subtypes of lymphocytes you encounter on the skin, most lymphomas that occur on the skin are derived of T-cell origin. B-cell lymphomas, in general, tend to be relatively uncommon or more infrequent.

There are 3 main subtypes of CTCL that present on the skin.¹ MF is, by far, the most common subtype of CTCL. The disease tends to present in patients who are usually aged > 60 years and is more frequent in white males. It’s a lymphoma that is particularly relevant to the veteran population. The second subtype has many similarities to MF but shows substantial peripheral blood involvement and is referred to as Sézary syndrome. The third group is encompassed under the term CD30-positive lymphoproliferative disorders. This group includes 2 main subtypes: primary cutaneous anaplastic large-cell lymphoma and lymphomatoid papulosis. Some cases of MF develop progression to what we call large cell transformation, which implies cytologic transformation to a more aggressive lymphoma.

There are other cutaneous lymphomas that are far less common. Some are indolent and others can be more aggressive, but they represent < 5% of all CTCL subtypes.

Lauren Pinter-Brown, MD. That was a great summary about these non-Hodgkin lymphomas. In the veteran population, it’s wise to remember that there are many kinds of non-Hodgkin lymphomas. Because of the action that they have seen, some people, such as Vietnam veterans, might be more susceptible to non-Hodgkin lymphomas than others.

John Zic. That’s a good point because certainly non-Hodgkin lymphomas are listed as one of the potential disease associations with exposure to Agent Orange.

I’d like to move on to epidemiology and the incidence of MF and Sézary syndrome. An article that came out of Emory University in 2013 is one of the more up-to-date articles to examine the incidence and survival patterns of CTCL.² The authors looked at patients from 2005 to 2008 and identified 2,273 patients in the Surveillance, Epidemiology, and End Results registry. They estimated that the incidence of MF in the US population is about 5.5 per 1,000,000 per year, which certainly makes it a rare disease. The incidence of Sézary syndrome was 0.1 per 1,000,000 per year, which comes out to about 1 per 10 million per year.

However, the MF incidence needs to be contrasted to the estimated incidence in the veteran population. In 2016, Larisa Geskin and colleagues from Columbia University and the Bronx US Department of Veterans Affairs (VA) Medical Center examined the VA database of patients with diagnoses of MF and Sézary syndrome.³ They combined them, but I have a feeling that the amount of Sézary syndrome patients was much less than those with MF. They estimated an incidence per million of 62 to 79 cases per 1,000,000 per year. The conclusion of Dr. Geskin’s study stated that the incidence of CTCL in the veteran population appears to be anywhere from 6 to 8 times higher. But if we use the most recent US incidence rates, it’s more than 10 times higher.

Those of you who have worked with veterans, either at the VA or in your private practice, do you have any ideas about why that might be?

Lauren Pinter-Brown. As you previously discussed, this is an illness of older people, and Vietnam veterans now are in their 60s and 70s. They may account for a lot of these diagnoses.

John Zic. That’s a good point. There’s quite a bit of talk about exposure to Agent Orange. But honestly, we really don’t know the cause of any of the CTCLs. We have not been able to identify a single cause. There are some risk factors. A 2014 article from the Journal of the National Cancer Institute looked at 324 cases of CTCL and compared it with 17,000 controls.⁴ They showed some interesting risk factors, such as body mass index (BMI) > 30 and smoking > 40 years. Similar to previous European studies, they showed that occupations like being a farmer, a painter, a woodworker, or a carpenter may carry additional risk.I wonder whether or not veterans were more likely to have some of these risk factors that this epidemiologic study picked up in addition to exposures that they may have encountered during their active-duty service. Interestingly, a decreased risk factor for developing MF was moderate physical activity. Clearly though, there are a large number of patients with CTCL in the veteran population.

I’d like to turn now to some of the challenges with diagnosis. Marianne, could you share some of your experience with early-stage disease and about how long it took them to be diagnosed?

Marianne Tawa, RN, MSN, ANP. Speaking specifically about early-stage disease, patients often share a history of waxing and waning rash that may not be particularly itchy. Confounding the picture, the distribution of early patch or plaque stage CTCL rash frequently occurs in covered areas. Many patients miss out on complete skin examinations by providers, thus early-stage CTCL may not be appreciated in a timely manner.

In certain scenarios, it may take upward of 5 to 7 years before the CTCL diagnosis is rendered. This is not because the patient delayed care. Nor is it because a skin biopsy was not performed. The progression of the disease and meeting the classic features of histology under the microscope can require clinical observation over time and repeated skin biopsies. We recommend patients refrain from topical steroid applications for 2 to 4 weeks prior to skin biopsy if we have a strong suspicion of CTCL. Many patients will report having a chronic eczematous process. Some patients may have a history of parapsoriasis, and they’re on the continuum for CTCL. That’s a common story for CTCL patients.

John Zic. What is the role of a skin biopsy in the diagnosis of CTCL? We see many patients who have had multiple skin biopsies who often wonder whether or not the diagnosis was missed by either the clinician or the pathologist.

Alejandro Ariel Gru. That is a great area of challenge in terms of pathologic diagnosis of early MF. A study led by Julia Scarisbrick, from an international registry data (PROCLIPI) on the early stages of the disease, showed a median delay of diagnosis of early MF of approximately 36 months.⁵ For all physicians involved in the diagnosis and care of patients with MF, the delay is probably significantly higher than that. We’ve seen patients who have lived without a diagnosis for a period of 10 or sometimes 15 years. That suggests that many cases are behaving in an indolent fashion, and patients are not progressing through the ‘natural’ stages of the disease and remain at the early stage. There also is the potential that other chronic inflammatory conditions, particularly psoriasis or parapsoriasis, can be confused with this entity. The diagnosis of certain types of parapsoriasis, can belong to the same spectrum of MF and can be treated in a similar way than patients with early stage MF are, such as phototherapy or methotrexate.

The diagnosis of MF relies on a combination of clinical, pathologic, and immunophenotypic findings where it is desired or preferred that at least 2 biopsies are done from different sides of the body. In addition to having a good clinical history that supports the diagnosis, a history of patches, plaques, and sometimes tumors in advanced stages in particular locations that are covered from the light (eg, trunk, buttocks, upper thighs, etc) combined with specific histopathologic criteria are capital to establish an accurate diagnosis.

In the biopsies, we look particularly for a lymphoid infiltrate that shows extension to the epidermis. We use the term epidermotropism to imply that these abnormal or neoplastic lymphocytes extend into the epidermis. They are also cytologically atypical. We see variations in the nucleus. In the size, we see a different character of the chromatin where they can be hyperchromatic. We also look for immunophenotypic aberrations, and particularly we analyze for patterns of expression of T-cell markers. Most cases of MF belong to a subset of T cells that are called CD4-positive or T-helper cells. We look for a patterned ratio of the CD4 and CD8 between the epidermis and an aberrant loss of the CD7 T-cell marker. Once we establish that we can see significant loss of these markers, we can tell where there is something wrong with that T-cell population, and likely belong to a neoplastic category.

In addition, we also rely on the molecular evaluation and search of a clonal population of T cells, by means of a T-cell receptor gene rearrangement study. Ideally, we like to see the establishment of a single clone of T cells that is matched in different biopsy sites. Proving that the same clone is present in 2 separate biopsies in 2 separate sites is the gold standard for diagnosis.⁶

John Zic. To recap, a biopsy is indicated for patients who have patches or plaques (that are slightly raised above the skin) in sun-protected areas that are fixed; rather than completely go away in the summer and come back in the winter, they are fixed if they have been present > 6 to 12 months. Many of these patients are diagnosed with eczema, psoriasis, allergic contact dermatitis, and other skin diseases before the clinician starts to think about other diagnoses, such as CTCL.

I agree that I would not rule out the diagnosis with 1 biopsy that does not show classic histologic changes. Also, I think that it’s important to alert the pathologist that you’re considering a diagnosis of T-cell lymphoma, either MF or some of the other subtypes, because that will certainly alert them to look a little closer at the infiltrating cells and perhaps do some of the other testing that was mentioned. Once we establish the MF diagnosis, staging studies may be indicated.

Lauren Pinter-Brown. Early stage would be patients with patches or plaques. Stage IA would be < 10% body surface area, and stage IB would be > 10%. I don’t perform scans for early-stage patients, but I do a very thorough physical and perform blood tests. For patients that have more advanced disease, such as tumors, erythroderma, or Sézary syndrome, I would conduct the same thorough examination and blood tests and scan the patient either with a computed tomography (CT) or a positron emission tomography (PET)/CT to detect adenopathy. We have to recognize that most of the adenopathy that is detected in these patients is peripheral, and we can feel it on physical examination.

John Zic. Do you prefer one imaging modality over the other? CT scan with IV contrast vs PET/CT?

Lauren Pinter-Brown. I tend to use PET/CT because it illuminates extranodal sites as well. I have to admit that sometimes it’s a problem to get that approved with insurance.

John Zic. In the federal system, many PET/CT scans are performed at other facilities. That would be an extra step in getting approval.

You mentioned Sézary syndrome. We should consider a diagnosis of Sézary syndrome when you have a patient with erythroderma, which means that they have > 80% of the skin covered in redness and scaling.

Lauren Pinter-Brown. The first step is to do a complete blood count (CBC) and see if there’s a lymphocytosis. Sometimes that really isn’t very sensitive, so my go-to test is flow cytometry. We are looking for an abnormal population of cells that, unlike normal T cells, often lack certain T-cell antigens. The most common would be CD7. We can confirm that this is a clone by T-cell gene rearrangement, and often in Sézary we like to compare the gene rearrangement seen in blood with what might be seen in the skin biopsy to confirm that they’re the same clone.

John Zic. That’s an excellent point. I know there are specific criteria to meet significant blood involvement. That is a topic of conversation among CTCL experts and something that might be changing over the next few years. But I think as it stands right now, having a lymphocytosis or at least an elevated CD4 count along with having a clone in the blood matching the clone in the skin are the first 2 steps in assessing blood involvement. However, the flow cytometry is very important. Not all medical centers are going to do flow cytometry—looking specifically for a drop of the CD7 or CD26 antigen among the CD4 population. But that is one of the major criteria that we look for in those patients with suspected blood involvement.

Marianne Tawa. Additionally, we would advise obtaining flow cytometry on patients that look like they have a robust skin burden with lots of patches, plaques, or tumors. We also perform lactate dehydrogenase (LDH) with staging.

John Zic. What do you usually tell patients with early-stage disease, those that have patches and plaques?

Marianne Tawa. For patients with stage IA disease, we are very optimistic about their prospects. We explain that the likelihood that early-stage disease will progress to a more advanced stage or rare variant is unlikely. This is very much a chronic disease, and the goal is to manage appropriately, palliate symptoms, and preserve quality of life (QOL).

Lauren Pinter-Brown. I often refer to a landmark paper by Youn H. Kim and colleagues that shows us that patients with IA disease who are at least treated usually have a normal lifespan.⁷ I encourage patients by sharing that data with them.

John Zic. Sean Whittaker and colleagues in the United Kingdom identified 5 risk factors for early-stage patients that may put them at higher risk for progressing: aged > 60 years; having a variant called folliculotropic MF; having palpable lymph nodes even if they’re reactive on biopsy, having plaques, and male sex.⁸ For staging of lymph nodes, what’s your usual approach when you see a patient with palpable lymph nodes?

Lauren Pinter-Brown. Many patients, particularly those with advanced skin disease, may have palpable lymph nodes that are reacting to their skin disease and on pathology would be dermatopathic. That would not change my management. I pay attention to the quality of the lymph node—if it’s very firm, if it’s > 2 cm, if it is persistent—before I biopsy. These patients have a higher incidence of wound infection after excisional biopsy. If the patient has pathologic lymph node involvement and effacement of the node with malignant cells, I would change my management. I do need to know that sort of information.

John Zic. Alejandro, as a hematopathologist can you comment on the debate about whether or not we actually do need an excisional biopsy or whether or not we can get a core lymph node biopsy to give you all the information that you need to grade it?

Alejandro Ariel Gru. There are 2 main modalities of biopsies we typically see for lymph nodes for evaluation and staging for involvement of CTCL. One is the traditional excisional biopsy that for the most part requires surgery with general anesthesia and has all the major implications that that type of procedure has. Many centers are looking at less invasive types of procedures, and needle core biopsies have become one of the most common forms of biopsy for all lymphoma subtypes. Excisional biopsies have the advantage of being able to see the whole lymph node, so you can determine and evaluate the architecture very well. Whereas needle core biopsies typically use a small needle to obtain a small piece of the tissue.

The likelihood of a successful diagnosis and accurate staging was compared recently in the British Journal of Dermatology.⁹ They were able to perform accurate staging in needle core biopsies of patients with MF. However, this is still a matter of debate; many people feel they are more likely to get enough information from an excisional biopsy. As we know, excisional biopsies sometimes can be hard, particularly if the large lymph node is located in an area that is difficult to access, for example, a retroperitoneal lymph node.

There are many staging categories that are used in the pathologic evaluation of lymph node involvement. On one hand, we could see the so-called dermatopathic changes, which is a reactive form of lymphadenopathy that typically happens in patients who have skin rashes and where there is no evidence of direct involvement by the disease (although there are some patients who can have T-cell clones by molecular methods). The patients who have clonal T cells perhaps might not do as well as the ones who do not. On the other hand, we have patients for whom the whole architecture of the lymph node is effaced or replaced by neoplastic malignant cells. Those patients are probably going to need more aggressive forms of therapy.¹⁰

John Zic. The type of lymph node biopsy has been a hot topic. If patients have palpable lymph nodes in the cervical, axillary, and inguinal area, I don’t know if it’s a consensus, but the recommendation right now is to consider performing a lymph node biopsy of the cervical lymph nodes first, axillary second, and inguinal lymph nodes third. That might have to do with the complication rates for those different areas.

I’d like to switch to a discussion to more advanced disease. CTCL tumors are defined as a dome-shaped nodule > 1 cm. They don’t have to be very big before we label it a tumor, and the disease is considered more advanced. For patients with a few tumors, what does your prognosis discussion sound like?

Marianne Tawa. Certainly, the prognosis discussion can become slightly more complicated when you move into the realm of tumor-stage development. This is especially true if a CTCL patient has lived with and managed indolent patches or plaques for several years. We approach these patients with optimism and with the goal of managing their tumors, whether it be with a skin-directed option, such as localized radiation or a host of approved systemic therapies. Patients presenting with or developing tumor-stage disease over time will require additional staging workup compared with early-stage disease staging practice. Patients are counseled on imaging use in tumor-stage disease and why flow cytometry may be requested to rule in or rule out accompanying peripheral blood involvement. Patients are exposed to a myriad of pictures, stories, and survival statistics from Internet research. It becomes our task to inform them of their unique presentation and tailored treatment plan, which thankfully may produce more favorable responses than those presented online.

Lauren Pinter-Brown. One thing that we focus on is the idea that a statistic regarding prognosis isn’t predictive for an individual patient. When patients go online, we caution them that many of the statistics are really old. There’s been a lot of new therapies in the past 10 years. Just looking at my patients, my feeling is that their prognosis has continued to improve over the decades that I’ve been involved in this area.

We have to take the statistics with a grain of salt, though certainly someone that has Sézary syndrome or someone that has nodal involvement or tumors is not going to fare as well as the patients that we talked about with stage I disease. However, if we all continue to do our jobs and have more and more treatment options for patients, that’s certainly going to change over time as it has with other non-Hodgkin lymphomas.

John Zic. We’ve all treated advanced patients with disease and some, of course, have died of the disease. When patients die of advanced CTCL, what are the things that lead to their demise?

Lauren Pinter-Brown. Probably the most common would be infections because their skin barrier has been broken. As the disease advances, their immune system also deteriorates. We may contribute to that sometimes with some of the therapies that we use, although we try and be judicious. First and foremost, the primary cause of death remains infection and sometimes inanition.

Marianne Tawa. I agree, infection or just the unfortunate progression of their lymphoma through the various armamentarium of treatments would be the 2 reasons.

John Zic. Let’s dive into therapy. I want to start with early stage. While, I don’t think there’s a role for systemic anticancer agents, certainly the IV agents for most patients with early-stage disease Marianne, you mentioned phototherapy. What are the types of phototherapy that you offer?

Marianne Tawa. We would start out with narrow band UVB therapy for patients with > 10% body surface area involvement. When applying topical corticosteroids to wider surface areas of the patient’s body is no longer feasible or effective, we recommend the initiation of narrow band UVB phototherapy. This is preferred because of its lessor adverse effect (AE) profile as far as nonmelanoma skin cancer risk. Patients commence narrow band UVB 3 times per week, with a goal of getting the patient into remission over a matter of months and then slowly tapering the phototherapy so that they get to a maintenance of once weekly.

Realizing that narrow band UVB may not penetrate deeper plaques or effectively reach folliculotropic variant of CTCL, we would employ PUVA, (psoralen and UVA). Patients are expected to protect their eyes with UVA glasses and remain out of the sun 24 hours following PUVA treatments. The cost of the methoxsalen can be an issue for some patients. Nonmelanoma skin cancer risks are increased in patients undergoing long-term PUVA treatments. Routine skin cancer surveillance is key.

There are monetary, time, and travel demands for patients receiving phototherapy. Thus, many CTCL patients are moving toward home-based narrow band UVB units supervised by their treating dermatologist. Other skin-directed treatment options, aside from topical corticosteroids and phototherapy, would include topical nitrogen mustard, imiquimod, and localized or total skin electron beam radiation.

John Zic. Here in Nashville, some of our veterans travel hundreds of miles to get to our center. It’s not practical for them to come here for the narrow band UVB phototherapy. Veterans can get approval through the VA Choice programs to have phototherapy performed by a local dermatologist closer to home. We also have had many veterans who choose to get home narrow band UVB phototherapy, which can be quite effective. Narrow band UVB phototherapy is among the most effective therapies for patients with generalized patches in particular, and maybe some with just a few plaques.

Medium potency topical steroids are not as helpful as superpotent topical steroids such as clobetasol, dipropionate ointment, or betamethasone dipropionate ointment. Usually, I tell patients to apply it twice a day for 8 weeks. You must be careful because these high-potency topical steroids can cause thinning of the skin, but it’s rarely seen, even in patients that may use them for 8 weeks if they’re applying them just to their patches and thin plaques. There are a few other topicals. There’s bexarotene gel, which is a topical retinoid, and mechlorethamine or nitrogen mustard gel that are available as topicals. Both of those can be helpful if patients have < 10% body surface area of patches or plaques because they can apply that at home.

Because of the excellent prognosis for patients in early stages, this is an area we want to try to avoid doing harm. For patients with advanced disease, what are some of the decisions that you think about in recommending a patient to get radiation therapy?
 

Lauren Pinter-Brown. I use radiation therapy sparingly and primarily for patients who either have only 1 tumor and the rest of their disease is patch and plaque or for patients who have very large tumors that are either cosmetically unacceptable or creating infection or pain. I treat people with systemic therapies primarily to prevent the formation of tumors.

John Zic. There probably is a role for total skin electron beam radiotherapy in patients who have failed multiple other skin-directed therapies and are progressing and then perhaps a role for more advanced patients who have multiple tumors where you’re trying to get some control of the disease. Are there any other situations where you might consider total skin electron beam?

Marianne Tawa. Yes, those are 2 scenarios. A third scenario would be in patients preparing for stem cell transplant. We typically do a modified 12 Gy regimen of total skin electron beam for palliation and up to 24 Gy regimen for patients who are in earnest preparing for a stem cell transplant.

John Zic. Systemic therapies also treat this disease. There are 2 oral agents. One is bexarotene capsules, a retinoid that binds to the RXR receptor and has a multitude of effects on different organ systems. It is probably the best tolerated oral agent we have. The other FDA-approved agent is vorinostat, a histone deacetylase inhibitor, but it has more gastrointestinal AEs than does bexarotene. Bexarotene has AEs as well, including hypertriglyceridemia and central hypothyroidism, which can throw a curveball to unsuspecting primary care physicians who might check thyroid function studies in these patients.

We certainly need to know about those AEs. There are many patients who have tumor-stage disease that can have radiotherapy to several tumors, then go on a drug like bexarotene capsules and may be able to maintain the remission for years. In my experience, it’s a drug that patients usually stay on. They can be weaned to a very low dose, but I’ve had several patients who come off of bexarotene only to suffer relapses.

Lauren, what are some of the things that you think about when you declare someone as having failed bexarotene or vorinostat and you’re thinking about IV therapies?

Lauren Pinter-Brown. Patient comorbidities and the particular compartment of their body that is involved are important factors. Do they have blood involvement, or not? Do they have nodal involvement, or not? Another concern is both acute and chronic toxicities that need to be discussed with the patient to determine an acceptable QOL. Finally, the schedule that you’re giving the drug. Some people may not be able to come in frequently. There are a lot of variables that go into making an individual decision at a particular time for a specific patient who will be using parenteral therapies.

John Zic. If we have a patient with advanced MF, tumors, and perhaps lymph node involvement, what are some of the systemic options that you would consider?

Lauren Pinter-Brown. With nodal involvement, an attractive option is something like IV romidepsin because we know that it treats peripheral T-cell lymphomas, which are aggressive nodal T-cell lymphomas. It’s FDA approved and also treats CTCL. Another is brentuximab vedotin if there is significant CD30 expression. It also is FDA approved for CTCL and has a long track record of treating certain peripheral T-cell lymphomas like anaplastic large cell.

John Zic. When would the stem cell transplant discussion start at your institution?

Lauren Pinter-Brown. It starts earlier for a younger patient because even though we do have lots of treatment if someone is aged 20 or30 years, I don’t really have any illusions that I have enough treatment options for them to live a normal lifespan if they have advanced disease. It’s a possibility for any patient when I see that the future options are dwindling, and that I am not going to be able to control the patient’s disease for much longer. Having said that, patients who have tumor-stage disease are among those that don’t do quite as well with allogeneic transplantation; ironically, patients with Sézary syndrome or erythroderma might do a little bit better.

John Zic. Before considering a stem cell transplant for patients with Sézary syndrome, that is erythroderma with significant blood involvement, what other treatment options would you offer?

Marianne Tawa. For low blood-burden disease, we might look at extracorporeal photopheresis as monotherapy or in combination with interferon or bexarotene. For patients with higher blood burden we might recommend low-dose alemtuzumab, especially if they have abundant CD52 expression. We also consider the newly FDA-approved anti-CCR4 antibody treatment, mogamulizumab, for patients presenting with Sézary syndrome. It is generally well tolerated but does have the potential for producing infusion reactions or drug rash.

Romidepsin has efficacy in blood, lymph node, and skin compartments. The primary considerations for patients considering romidepsin are prolonged infusion times and QOL AEs with gastrointestinal and taste disturbances and fatigue.

John Zic. Both of you have brought up an excellent point. This is a disease that while we do not have a good chance of curing, we have a pretty fair chance of controlling, especially if it’s early stage. The data from the stem cell transplant literature indicate that stem cell transplant may be one of the few modalities that we have that may offer a cure.¹¹

Lauren Pinter-Brown. There are patients who are cured with allogeneic transplants; and the very first allogeneic transplants were performed well over 20 years ago. Many patients, even some in my practice, who were among those patients and continue to do extremely well without any evidence of disease. Sometimes when people have allogeneic transplantation, their disease relapse may be in a more indolent form that’s much easier to deal with than their original disease. Even if they’re not cured, the fact that the aggressive disease seems to be at bay may make them much easier to treat.

John Zic. Those are excellent points. You brought up photopheresis as a treatment modality for patients with evolving or early Sézary syndrome and patients with erythrodermic MF can also respond. We have a lot of experience with that at the Nashville VA medical center. We’re one of the few VA hospitals in the US that has a photopheresis unit. But the modality is available at many academic medical centers because it’s a treatment for graft-vs-host disease.

We tend to also consider photopheresis in patients who may have had an excellent response to another systemic agent. There are some data that patients who received photopheresis, after total skin electron beam therapy vs those who received chemotherapy after radiation, had a longer disease-free survival.¹²

I’d like to end with a discussion of something that’s very important, which is managing QOL issues for patients with CTCL. Itch is among some of the worst symptoms that can cause suffering in patients. But it is sometimes not a problem at all for patients who have a few patches or plaques. That’s one reason why they might ignore their rash. Certainly, as the disease progresses, especially those patients with erythroderma, the itch can be intractable and can have a major impact on their life. What are some approaches to managing itch at your institutions?

Lauren Pinter-Brown. One thing to be aware of is that the itch is not usually mediated by histamine, though people will often put the patients on a lot of antihistamines. I don’t find those to be the most effective treatments. I think of the itch in these patients as more of a neuropathic condition and would tend to treat more with things that you might use for neuropathy, such as gabapentin or doxepin or antidepressants. There’s a whole host of other treatments, such as aprepitant, something that I would use as an antiemetic, that might also be helpful for pruritus in this patient population.

John Zic. That’s my experience as well. I have found gabapentin to be helpful for patients with itch, though not universally.

Marianne Tawa. I consider itch a huge QOL concern for a large majority of our patients with a CTCL diagnosis. It’s on par with pain. In early-stage disease, pruritus levels improve as the cutaneous burden is reduced with skin-directed therapies such as, topical corticosteroid or phototherapy.

SSRI agents could also be considered for select patients. The antiemetic agent, aprepitant has been useful for addressing itch in a subset of our patients with Sézary syndrome. Patients will also seek out complementary modalities such acupuncture, hypnosis, and guided imagery.

John Zic. Because the disease itself affects the skin and can lead to dryness, patients often suffer with dry skin. When I trained in Chicago, that was the foundation of our treatment, making sure that patients are using a super fatted soap such as Dove (Unilever, London, United Kingdom) or Cetaphil (Galderma Laboratories; Fort Worth, TX), making sure that they’re lubricating their skin frequently with something perhaps in the wintertime as thick as petroleum jelly. And then in the summertime perhaps with Sarna lotion (Crown Laboratories; Johnson City, TN), which has menthol. It’s important to note that when the patient’s skin is infected, the itch can skyrocket. Being aware and monitoring the skin for signs of infection such as crusting and impetigo-like findings can be helpful.

I also wanted to touch on fatigue. Patients can have fatigue for many reasons. Sometimes it’s because the itch is interfering with their sleep. How do you approach managing fatigue?
 

Lauren Pinter-Brown. There have been many studies about cancer fatigue, and it appears that one of the cheapest and easiest modalities is for patients to walk. We often suggest that our patients go on walks, however much they can do, because that has been seen over and over again in studies of cancer fatigue to be beneficial.

John Zic. Do you have any advice for nurses that might be helping to manage patients in a cutaneous lymphoma clinic?

Marianne Tawa. As this is a rare disease, nursing encounters with patients carrying a diagnosis of CTCL in both oncology and dermatology settings may be few and far between. I recommend nurses familiarize themselves with articles published on CTCL topics found in both dermatology and oncology peer review journals. Another avenue for gaining insight and education would be through continuing education courses. Resources can also be found for nurses, patients, and caregivers through advocacy foundations such as the Cutaneous Lymphoma Foundation (www.clfoundation.org) and the Lymphoma Research Foundation (LRF@lymphma.org).

John Zic. Is there anything else that anyone would like to add to our discussion?

Lauren Pinter-Brown. One thing that we touched upon, but I was concerned that we didn’t emphasize, was the use of flow cytometry as a diagnostic tool in a patient with erythroderma. Sometimes biopsies of patients with erythroderma are not diagnostic, so clinicians need to be aware that there are other ways of diagnosing patients—nodal biopsy or flow cytometry. They should not only think of it as a staging tool but sometimes as a diagnostic tool.

Alejandro Ariel Gru. I agree. Particularly in patients who have Sézary syndrome or MF with peripheral blood involvement, sometimes the findings on the biopsy show a dissociation between how impressive the clinical presentation of the patient might be and how very few findings you might encounter on the skin biopsy. Therefore, relying on flow cytometry as a diagnostic tool is capital. Lauren, you briefly mentioned the criteria, which is looking for an abnormal CD4 to CD8 ratio of > 10%, abnormal loss of CD7, > 40%, or abnormal loss of CD26 of > 30%.

In addition, there are new markers that are now undergoing validation in the diagnosis of Sézary syndrome. One is KIR3DL2, which is a natural killer receptor that has been shown to be significantly upregulated in Sézary syndrome and appears to be both more sensitive and specific. With that also comes therapies that target the KIR3DL2 molecule.

John Zic. One of the first things we teach our dermatology residents to work up patients with erythroderma is that they shouldn’t expect the skin biopsy to help them sort out the cause of the erythroderma. As you mentioned, Lauren, the flow cytometry of peripheral blood should always be accompanied by a CBC with differential and platelets. And if the patients do have lymph nodes, consider a biopsy because sometimes that’s where you can make the firmest diagnosis of a T-cell lymphoma.

Acknowledgmentszz
The participants and Federal Practitioner would like to thank Susan Thornton, CEO of the Cutaneous Lymphoma Foundation for helping to arrange this roundtable discussion.

John Zic, MD. Let’s start by defining cutaneous T-cell lymphomas (CTCLs) and how they differ from other non-Hodgkin lymphomas. We also should discuss classification, which can be very confusing and epidemiology as it relates to the veteran population. Then I think we should dive into challenges with diagnosis and when should a VA or any provider consider mycosis fungoides (MF) and Sézary syndrome—the 2 most common variants of CTCLs.

I like to define the primary CTCLs as malignancies of the T-cell where the primary organ of involvement is the skin. However, this disease can spread to lymph nodes and visceral organs and the blood compartment in more advanced patients. Alejandro, could you provide some highlights about how CTCLs are classified?

Alejandro Ariel Gru, MD. Lymphomas are divided in the general hematology/oncology practice as Hodgkin and non-Hodgkin lymphomas. Traditionally all lymphomas that occur on the skin are non-Hodgkin lymphoma subtypes. That has specific connotations in terms of diagnosis, prognosis, and therapy. Because the T cells are one of the main residents of the subtypes of lymphocytes you encounter on the skin, most lymphomas that occur on the skin are derived of T-cell origin. B-cell lymphomas, in general, tend to be relatively uncommon or more infrequent.

There are 3 main subtypes of CTCL that present on the skin.¹ MF is, by far, the most common subtype of CTCL. The disease tends to present in patients who are usually aged > 60 years and is more frequent in white males. It’s a lymphoma that is particularly relevant to the veteran population. The second subtype has many similarities to MF but shows substantial peripheral blood involvement and is referred to as Sézary syndrome. The third group is encompassed under the term CD30-positive lymphoproliferative disorders. This group includes 2 main subtypes: primary cutaneous anaplastic large-cell lymphoma and lymphomatoid papulosis. Some cases of MF develop progression to what we call large cell transformation, which implies cytologic transformation to a more aggressive lymphoma.

There are other cutaneous lymphomas that are far less common. Some are indolent and others can be more aggressive, but they represent < 5% of all CTCL subtypes.

Lauren Pinter-Brown, MD. That was a great summary about these non-Hodgkin lymphomas. In the veteran population, it’s wise to remember that there are many kinds of non-Hodgkin lymphomas. Because of the action that they have seen, some people, such as Vietnam veterans, might be more susceptible to non-Hodgkin lymphomas than others.

John Zic. That’s a good point because certainly non-Hodgkin lymphomas are listed as one of the potential disease associations with exposure to Agent Orange.

I’d like to move on to epidemiology and the incidence of MF and Sézary syndrome. An article that came out of Emory University in 2013 is one of the more up-to-date articles to examine the incidence and survival patterns of CTCL.² The authors looked at patients from 2005 to 2008 and identified 2,273 patients in the Surveillance, Epidemiology, and End Results registry. They estimated that the incidence of MF in the US population is about 5.5 per 1,000,000 per year, which certainly makes it a rare disease. The incidence of Sézary syndrome was 0.1 per 1,000,000 per year, which comes out to about 1 per 10 million per year.

However, the MF incidence needs to be contrasted to the estimated incidence in the veteran population. In 2016, Larisa Geskin and colleagues from Columbia University and the Bronx US Department of Veterans Affairs (VA) Medical Center examined the VA database of patients with diagnoses of MF and Sézary syndrome.³ They combined them, but I have a feeling that the amount of Sézary syndrome patients was much less than those with MF. They estimated an incidence per million of 62 to 79 cases per 1,000,000 per year. The conclusion of Dr. Geskin’s study stated that the incidence of CTCL in the veteran population appears to be anywhere from 6 to 8 times higher. But if we use the most recent US incidence rates, it’s more than 10 times higher.

Those of you who have worked with veterans, either at the VA or in your private practice, do you have any ideas about why that might be?

Lauren Pinter-Brown. As you previously discussed, this is an illness of older people, and Vietnam veterans now are in their 60s and 70s. They may account for a lot of these diagnoses.

John Zic. That’s a good point. There’s quite a bit of talk about exposure to Agent Orange. But honestly, we really don’t know the cause of any of the CTCLs. We have not been able to identify a single cause. There are some risk factors. A 2014 article from the Journal of the National Cancer Institute looked at 324 cases of CTCL and compared it with 17,000 controls.⁴ They showed some interesting risk factors, such as body mass index (BMI) > 30 and smoking > 40 years. Similar to previous European studies, they showed that occupations like being a farmer, a painter, a woodworker, or a carpenter may carry additional risk.I wonder whether or not veterans were more likely to have some of these risk factors that this epidemiologic study picked up in addition to exposures that they may have encountered during their active-duty service. Interestingly, a decreased risk factor for developing MF was moderate physical activity. Clearly though, there are a large number of patients with CTCL in the veteran population.

I’d like to turn now to some of the challenges with diagnosis. Marianne, could you share some of your experience with early-stage disease and about how long it took them to be diagnosed?

Marianne Tawa, RN, MSN, ANP. Speaking specifically about early-stage disease, patients often share a history of waxing and waning rash that may not be particularly itchy. Confounding the picture, the distribution of early patch or plaque stage CTCL rash frequently occurs in covered areas. Many patients miss out on complete skin examinations by providers, thus early-stage CTCL may not be appreciated in a timely manner.

In certain scenarios, it may take upward of 5 to 7 years before the CTCL diagnosis is rendered. This is not because the patient delayed care. Nor is it because a skin biopsy was not performed. The progression of the disease and meeting the classic features of histology under the microscope can require clinical observation over time and repeated skin biopsies. We recommend patients refrain from topical steroid applications for 2 to 4 weeks prior to skin biopsy if we have a strong suspicion of CTCL. Many patients will report having a chronic eczematous process. Some patients may have a history of parapsoriasis, and they’re on the continuum for CTCL. That’s a common story for CTCL patients.

John Zic. What is the role of a skin biopsy in the diagnosis of CTCL? We see many patients who have had multiple skin biopsies who often wonder whether or not the diagnosis was missed by either the clinician or the pathologist.

Alejandro Ariel Gru. That is a great area of challenge in terms of pathologic diagnosis of early MF. A study led by Julia Scarisbrick, from an international registry data (PROCLIPI) on the early stages of the disease, showed a median delay of diagnosis of early MF of approximately 36 months.⁵ For all physicians involved in the diagnosis and care of patients with MF, the delay is probably significantly higher than that. We’ve seen patients who have lived without a diagnosis for a period of 10 or sometimes 15 years. That suggests that many cases are behaving in an indolent fashion, and patients are not progressing through the ‘natural’ stages of the disease and remain at the early stage. There also is the potential that other chronic inflammatory conditions, particularly psoriasis or parapsoriasis, can be confused with this entity. The diagnosis of certain types of parapsoriasis, can belong to the same spectrum of MF and can be treated in a similar way than patients with early stage MF are, such as phototherapy or methotrexate.

The diagnosis of MF relies on a combination of clinical, pathologic, and immunophenotypic findings where it is desired or preferred that at least 2 biopsies are done from different sides of the body. In addition to having a good clinical history that supports the diagnosis, a history of patches, plaques, and sometimes tumors in advanced stages in particular locations that are covered from the light (eg, trunk, buttocks, upper thighs, etc) combined with specific histopathologic criteria are capital to establish an accurate diagnosis.

In the biopsies, we look particularly for a lymphoid infiltrate that shows extension to the epidermis. We use the term epidermotropism to imply that these abnormal or neoplastic lymphocytes extend into the epidermis. They are also cytologically atypical. We see variations in the nucleus. In the size, we see a different character of the chromatin where they can be hyperchromatic. We also look for immunophenotypic aberrations, and particularly we analyze for patterns of expression of T-cell markers. Most cases of MF belong to a subset of T cells that are called CD4-positive or T-helper cells. We look for a patterned ratio of the CD4 and CD8 between the epidermis and an aberrant loss of the CD7 T-cell marker. Once we establish that we can see significant loss of these markers, we can tell where there is something wrong with that T-cell population, and likely belong to a neoplastic category.

In addition, we also rely on the molecular evaluation and search of a clonal population of T cells, by means of a T-cell receptor gene rearrangement study. Ideally, we like to see the establishment of a single clone of T cells that is matched in different biopsy sites. Proving that the same clone is present in 2 separate biopsies in 2 separate sites is the gold standard for diagnosis.⁶

John Zic. To recap, a biopsy is indicated for patients who have patches or plaques (that are slightly raised above the skin) in sun-protected areas that are fixed; rather than completely go away in the summer and come back in the winter, they are fixed if they have been present > 6 to 12 months. Many of these patients are diagnosed with eczema, psoriasis, allergic contact dermatitis, and other skin diseases before the clinician starts to think about other diagnoses, such as CTCL.

I agree that I would not rule out the diagnosis with 1 biopsy that does not show classic histologic changes. Also, I think that it’s important to alert the pathologist that you’re considering a diagnosis of T-cell lymphoma, either MF or some of the other subtypes, because that will certainly alert them to look a little closer at the infiltrating cells and perhaps do some of the other testing that was mentioned. Once we establish the MF diagnosis, staging studies may be indicated.

Lauren Pinter-Brown. Early stage would be patients with patches or plaques. Stage IA would be < 10% body surface area, and stage IB would be > 10%. I don’t perform scans for early-stage patients, but I do a very thorough physical and perform blood tests. For patients that have more advanced disease, such as tumors, erythroderma, or Sézary syndrome, I would conduct the same thorough examination and blood tests and scan the patient either with a computed tomography (CT) or a positron emission tomography (PET)/CT to detect adenopathy. We have to recognize that most of the adenopathy that is detected in these patients is peripheral, and we can feel it on physical examination.

John Zic. Do you prefer one imaging modality over the other? CT scan with IV contrast vs PET/CT?

Lauren Pinter-Brown. I tend to use PET/CT because it illuminates extranodal sites as well. I have to admit that sometimes it’s a problem to get that approved with insurance.

John Zic. In the federal system, many PET/CT scans are performed at other facilities. That would be an extra step in getting approval.

You mentioned Sézary syndrome. We should consider a diagnosis of Sézary syndrome when you have a patient with erythroderma, which means that they have > 80% of the skin covered in redness and scaling.

Lauren Pinter-Brown. The first step is to do a complete blood count (CBC) and see if there’s a lymphocytosis. Sometimes that really isn’t very sensitive, so my go-to test is flow cytometry. We are looking for an abnormal population of cells that, unlike normal T cells, often lack certain T-cell antigens. The most common would be CD7. We can confirm that this is a clone by T-cell gene rearrangement, and often in Sézary we like to compare the gene rearrangement seen in blood with what might be seen in the skin biopsy to confirm that they’re the same clone.

John Zic. That’s an excellent point. I know there are specific criteria to meet significant blood involvement. That is a topic of conversation among CTCL experts and something that might be changing over the next few years. But I think as it stands right now, having a lymphocytosis or at least an elevated CD4 count along with having a clone in the blood matching the clone in the skin are the first 2 steps in assessing blood involvement. However, the flow cytometry is very important. Not all medical centers are going to do flow cytometry—looking specifically for a drop of the CD7 or CD26 antigen among the CD4 population. But that is one of the major criteria that we look for in those patients with suspected blood involvement.

Marianne Tawa. Additionally, we would advise obtaining flow cytometry on patients that look like they have a robust skin burden with lots of patches, plaques, or tumors. We also perform lactate dehydrogenase (LDH) with staging.

John Zic. What do you usually tell patients with early-stage disease, those that have patches and plaques?

Marianne Tawa. For patients with stage IA disease, we are very optimistic about their prospects. We explain that the likelihood that early-stage disease will progress to a more advanced stage or rare variant is unlikely. This is very much a chronic disease, and the goal is to manage appropriately, palliate symptoms, and preserve quality of life (QOL).

Lauren Pinter-Brown. I often refer to a landmark paper by Youn H. Kim and colleagues that shows us that patients with IA disease who are at least treated usually have a normal lifespan.⁷ I encourage patients by sharing that data with them.

John Zic. Sean Whittaker and colleagues in the United Kingdom identified 5 risk factors for early-stage patients that may put them at higher risk for progressing: aged > 60 years; having a variant called folliculotropic MF; having palpable lymph nodes even if they’re reactive on biopsy, having plaques, and male sex.⁸ For staging of lymph nodes, what’s your usual approach when you see a patient with palpable lymph nodes?

Lauren Pinter-Brown. Many patients, particularly those with advanced skin disease, may have palpable lymph nodes that are reacting to their skin disease and on pathology would be dermatopathic. That would not change my management. I pay attention to the quality of the lymph node—if it’s very firm, if it’s > 2 cm, if it is persistent—before I biopsy. These patients have a higher incidence of wound infection after excisional biopsy. If the patient has pathologic lymph node involvement and effacement of the node with malignant cells, I would change my management. I do need to know that sort of information.

John Zic. Alejandro, as a hematopathologist can you comment on the debate about whether or not we actually do need an excisional biopsy or whether or not we can get a core lymph node biopsy to give you all the information that you need to grade it?

Alejandro Ariel Gru. There are 2 main modalities of biopsies we typically see for lymph nodes for evaluation and staging for involvement of CTCL. One is the traditional excisional biopsy that for the most part requires surgery with general anesthesia and has all the major implications that that type of procedure has. Many centers are looking at less invasive types of procedures, and needle core biopsies have become one of the most common forms of biopsy for all lymphoma subtypes. Excisional biopsies have the advantage of being able to see the whole lymph node, so you can determine and evaluate the architecture very well. Whereas needle core biopsies typically use a small needle to obtain a small piece of the tissue.

The likelihood of a successful diagnosis and accurate staging was compared recently in the British Journal of Dermatology.⁹ They were able to perform accurate staging in needle core biopsies of patients with MF. However, this is still a matter of debate; many people feel they are more likely to get enough information from an excisional biopsy. As we know, excisional biopsies sometimes can be hard, particularly if the large lymph node is located in an area that is difficult to access, for example, a retroperitoneal lymph node.

There are many staging categories that are used in the pathologic evaluation of lymph node involvement. On one hand, we could see the so-called dermatopathic changes, which is a reactive form of lymphadenopathy that typically happens in patients who have skin rashes and where there is no evidence of direct involvement by the disease (although there are some patients who can have T-cell clones by molecular methods). The patients who have clonal T cells perhaps might not do as well as the ones who do not. On the other hand, we have patients for whom the whole architecture of the lymph node is effaced or replaced by neoplastic malignant cells. Those patients are probably going to need more aggressive forms of therapy.¹⁰

John Zic. The type of lymph node biopsy has been a hot topic. If patients have palpable lymph nodes in the cervical, axillary, and inguinal area, I don’t know if it’s a consensus, but the recommendation right now is to consider performing a lymph node biopsy of the cervical lymph nodes first, axillary second, and inguinal lymph nodes third. That might have to do with the complication rates for those different areas.

I’d like to switch to a discussion to more advanced disease. CTCL tumors are defined as a dome-shaped nodule > 1 cm. They don’t have to be very big before we label it a tumor, and the disease is considered more advanced. For patients with a few tumors, what does your prognosis discussion sound like?

Marianne Tawa. Certainly, the prognosis discussion can become slightly more complicated when you move into the realm of tumor-stage development. This is especially true if a CTCL patient has lived with and managed indolent patches or plaques for several years. We approach these patients with optimism and with the goal of managing their tumors, whether it be with a skin-directed option, such as localized radiation or a host of approved systemic therapies. Patients presenting with or developing tumor-stage disease over time will require additional staging workup compared with early-stage disease staging practice. Patients are counseled on imaging use in tumor-stage disease and why flow cytometry may be requested to rule in or rule out accompanying peripheral blood involvement. Patients are exposed to a myriad of pictures, stories, and survival statistics from Internet research. It becomes our task to inform them of their unique presentation and tailored treatment plan, which thankfully may produce more favorable responses than those presented online.

Lauren Pinter-Brown. One thing that we focus on is the idea that a statistic regarding prognosis isn’t predictive for an individual patient. When patients go online, we caution them that many of the statistics are really old. There’s been a lot of new therapies in the past 10 years. Just looking at my patients, my feeling is that their prognosis has continued to improve over the decades that I’ve been involved in this area.

We have to take the statistics with a grain of salt, though certainly someone that has Sézary syndrome or someone that has nodal involvement or tumors is not going to fare as well as the patients that we talked about with stage I disease. However, if we all continue to do our jobs and have more and more treatment options for patients, that’s certainly going to change over time as it has with other non-Hodgkin lymphomas.

John Zic. We’ve all treated advanced patients with disease and some, of course, have died of the disease. When patients die of advanced CTCL, what are the things that lead to their demise?

Lauren Pinter-Brown. Probably the most common would be infections because their skin barrier has been broken. As the disease advances, their immune system also deteriorates. We may contribute to that sometimes with some of the therapies that we use, although we try and be judicious. First and foremost, the primary cause of death remains infection and sometimes inanition.

Marianne Tawa. I agree, infection or just the unfortunate progression of their lymphoma through the various armamentarium of treatments would be the 2 reasons.

John Zic. Let’s dive into therapy. I want to start with early stage. While, I don’t think there’s a role for systemic anticancer agents, certainly the IV agents for most patients with early-stage disease Marianne, you mentioned phototherapy. What are the types of phototherapy that you offer?

Marianne Tawa. We would start out with narrow band UVB therapy for patients with > 10% body surface area involvement. When applying topical corticosteroids to wider surface areas of the patient’s body is no longer feasible or effective, we recommend the initiation of narrow band UVB phototherapy. This is preferred because of its lessor adverse effect (AE) profile as far as nonmelanoma skin cancer risk. Patients commence narrow band UVB 3 times per week, with a goal of getting the patient into remission over a matter of months and then slowly tapering the phototherapy so that they get to a maintenance of once weekly.

Realizing that narrow band UVB may not penetrate deeper plaques or effectively reach folliculotropic variant of CTCL, we would employ PUVA, (psoralen and UVA). Patients are expected to protect their eyes with UVA glasses and remain out of the sun 24 hours following PUVA treatments. The cost of the methoxsalen can be an issue for some patients. Nonmelanoma skin cancer risks are increased in patients undergoing long-term PUVA treatments. Routine skin cancer surveillance is key.

There are monetary, time, and travel demands for patients receiving phototherapy. Thus, many CTCL patients are moving toward home-based narrow band UVB units supervised by their treating dermatologist. Other skin-directed treatment options, aside from topical corticosteroids and phototherapy, would include topical nitrogen mustard, imiquimod, and localized or total skin electron beam radiation.

John Zic. Here in Nashville, some of our veterans travel hundreds of miles to get to our center. It’s not practical for them to come here for the narrow band UVB phototherapy. Veterans can get approval through the VA Choice programs to have phototherapy performed by a local dermatologist closer to home. We also have had many veterans who choose to get home narrow band UVB phototherapy, which can be quite effective. Narrow band UVB phototherapy is among the most effective therapies for patients with generalized patches in particular, and maybe some with just a few plaques.

Medium potency topical steroids are not as helpful as superpotent topical steroids such as clobetasol, dipropionate ointment, or betamethasone dipropionate ointment. Usually, I tell patients to apply it twice a day for 8 weeks. You must be careful because these high-potency topical steroids can cause thinning of the skin, but it’s rarely seen, even in patients that may use them for 8 weeks if they’re applying them just to their patches and thin plaques. There are a few other topicals. There’s bexarotene gel, which is a topical retinoid, and mechlorethamine or nitrogen mustard gel that are available as topicals. Both of those can be helpful if patients have < 10% body surface area of patches or plaques because they can apply that at home.

Because of the excellent prognosis for patients in early stages, this is an area we want to try to avoid doing harm. For patients with advanced disease, what are some of the decisions that you think about in recommending a patient to get radiation therapy?
 

Lauren Pinter-Brown. I use radiation therapy sparingly and primarily for patients who either have only 1 tumor and the rest of their disease is patch and plaque or for patients who have very large tumors that are either cosmetically unacceptable or creating infection or pain. I treat people with systemic therapies primarily to prevent the formation of tumors.

John Zic. There probably is a role for total skin electron beam radiotherapy in patients who have failed multiple other skin-directed therapies and are progressing and then perhaps a role for more advanced patients who have multiple tumors where you’re trying to get some control of the disease. Are there any other situations where you might consider total skin electron beam?

Marianne Tawa. Yes, those are 2 scenarios. A third scenario would be in patients preparing for stem cell transplant. We typically do a modified 12 Gy regimen of total skin electron beam for palliation and up to 24 Gy regimen for patients who are in earnest preparing for a stem cell transplant.

John Zic. Systemic therapies also treat this disease. There are 2 oral agents. One is bexarotene capsules, a retinoid that binds to the RXR receptor and has a multitude of effects on different organ systems. It is probably the best tolerated oral agent we have. The other FDA-approved agent is vorinostat, a histone deacetylase inhibitor, but it has more gastrointestinal AEs than does bexarotene. Bexarotene has AEs as well, including hypertriglyceridemia and central hypothyroidism, which can throw a curveball to unsuspecting primary care physicians who might check thyroid function studies in these patients.

We certainly need to know about those AEs. There are many patients who have tumor-stage disease that can have radiotherapy to several tumors, then go on a drug like bexarotene capsules and may be able to maintain the remission for years. In my experience, it’s a drug that patients usually stay on. They can be weaned to a very low dose, but I’ve had several patients who come off of bexarotene only to suffer relapses.

Lauren, what are some of the things that you think about when you declare someone as having failed bexarotene or vorinostat and you’re thinking about IV therapies?

Lauren Pinter-Brown. Patient comorbidities and the particular compartment of their body that is involved are important factors. Do they have blood involvement, or not? Do they have nodal involvement, or not? Another concern is both acute and chronic toxicities that need to be discussed with the patient to determine an acceptable QOL. Finally, the schedule that you’re giving the drug. Some people may not be able to come in frequently. There are a lot of variables that go into making an individual decision at a particular time for a specific patient who will be using parenteral therapies.

John Zic. If we have a patient with advanced MF, tumors, and perhaps lymph node involvement, what are some of the systemic options that you would consider?

Lauren Pinter-Brown. With nodal involvement, an attractive option is something like IV romidepsin because we know that it treats peripheral T-cell lymphomas, which are aggressive nodal T-cell lymphomas. It’s FDA approved and also treats CTCL. Another is brentuximab vedotin if there is significant CD30 expression. It also is FDA approved for CTCL and has a long track record of treating certain peripheral T-cell lymphomas like anaplastic large cell.

John Zic. When would the stem cell transplant discussion start at your institution?

Lauren Pinter-Brown. It starts earlier for a younger patient because even though we do have lots of treatment if someone is aged 20 or30 years, I don’t really have any illusions that I have enough treatment options for them to live a normal lifespan if they have advanced disease. It’s a possibility for any patient when I see that the future options are dwindling, and that I am not going to be able to control the patient’s disease for much longer. Having said that, patients who have tumor-stage disease are among those that don’t do quite as well with allogeneic transplantation; ironically, patients with Sézary syndrome or erythroderma might do a little bit better.

John Zic. Before considering a stem cell transplant for patients with Sézary syndrome, that is erythroderma with significant blood involvement, what other treatment options would you offer?

Marianne Tawa. For low blood-burden disease, we might look at extracorporeal photopheresis as monotherapy or in combination with interferon or bexarotene. For patients with higher blood burden we might recommend low-dose alemtuzumab, especially if they have abundant CD52 expression. We also consider the newly FDA-approved anti-CCR4 antibody treatment, mogamulizumab, for patients presenting with Sézary syndrome. It is generally well tolerated but does have the potential for producing infusion reactions or drug rash.

Romidepsin has efficacy in blood, lymph node, and skin compartments. The primary considerations for patients considering romidepsin are prolonged infusion times and QOL AEs with gastrointestinal and taste disturbances and fatigue.

John Zic. Both of you have brought up an excellent point. This is a disease that while we do not have a good chance of curing, we have a pretty fair chance of controlling, especially if it’s early stage. The data from the stem cell transplant literature indicate that stem cell transplant may be one of the few modalities that we have that may offer a cure.¹¹

Lauren Pinter-Brown. There are patients who are cured with allogeneic transplants; and the very first allogeneic transplants were performed well over 20 years ago. Many patients, even some in my practice, who were among those patients and continue to do extremely well without any evidence of disease. Sometimes when people have allogeneic transplantation, their disease relapse may be in a more indolent form that’s much easier to deal with than their original disease. Even if they’re not cured, the fact that the aggressive disease seems to be at bay may make them much easier to treat.

John Zic. Those are excellent points. You brought up photopheresis as a treatment modality for patients with evolving or early Sézary syndrome and patients with erythrodermic MF can also respond. We have a lot of experience with that at the Nashville VA medical center. We’re one of the few VA hospitals in the US that has a photopheresis unit. But the modality is available at many academic medical centers because it’s a treatment for graft-vs-host disease.

We tend to also consider photopheresis in patients who may have had an excellent response to another systemic agent. There are some data that patients who received photopheresis, after total skin electron beam therapy vs those who received chemotherapy after radiation, had a longer disease-free survival.¹²

I’d like to end with a discussion of something that’s very important, which is managing QOL issues for patients with CTCL. Itch is among some of the worst symptoms that can cause suffering in patients. But it is sometimes not a problem at all for patients who have a few patches or plaques. That’s one reason why they might ignore their rash. Certainly, as the disease progresses, especially those patients with erythroderma, the itch can be intractable and can have a major impact on their life. What are some approaches to managing itch at your institutions?

Lauren Pinter-Brown. One thing to be aware of is that the itch is not usually mediated by histamine, though people will often put the patients on a lot of antihistamines. I don’t find those to be the most effective treatments. I think of the itch in these patients as more of a neuropathic condition and would tend to treat more with things that you might use for neuropathy, such as gabapentin or doxepin or antidepressants. There’s a whole host of other treatments, such as aprepitant, something that I would use as an antiemetic, that might also be helpful for pruritus in this patient population.

John Zic. That’s my experience as well. I have found gabapentin to be helpful for patients with itch, though not universally.

Marianne Tawa. I consider itch a huge QOL concern for a large majority of our patients with a CTCL diagnosis. It’s on par with pain. In early-stage disease, pruritus levels improve as the cutaneous burden is reduced with skin-directed therapies such as, topical corticosteroid or phototherapy.

SSRI agents could also be considered for select patients. The antiemetic agent, aprepitant has been useful for addressing itch in a subset of our patients with Sézary syndrome. Patients will also seek out complementary modalities such acupuncture, hypnosis, and guided imagery.

John Zic. Because the disease itself affects the skin and can lead to dryness, patients often suffer with dry skin. When I trained in Chicago, that was the foundation of our treatment, making sure that patients are using a super fatted soap such as Dove (Unilever, London, United Kingdom) or Cetaphil (Galderma Laboratories; Fort Worth, TX), making sure that they’re lubricating their skin frequently with something perhaps in the wintertime as thick as petroleum jelly. And then in the summertime perhaps with Sarna lotion (Crown Laboratories; Johnson City, TN), which has menthol. It’s important to note that when the patient’s skin is infected, the itch can skyrocket. Being aware and monitoring the skin for signs of infection such as crusting and impetigo-like findings can be helpful.

I also wanted to touch on fatigue. Patients can have fatigue for many reasons. Sometimes it’s because the itch is interfering with their sleep. How do you approach managing fatigue?
 

Lauren Pinter-Brown. There have been many studies about cancer fatigue, and it appears that one of the cheapest and easiest modalities is for patients to walk. We often suggest that our patients go on walks, however much they can do, because that has been seen over and over again in studies of cancer fatigue to be beneficial.

John Zic. Do you have any advice for nurses that might be helping to manage patients in a cutaneous lymphoma clinic?

Marianne Tawa. As this is a rare disease, nursing encounters with patients carrying a diagnosis of CTCL in both oncology and dermatology settings may be few and far between. I recommend nurses familiarize themselves with articles published on CTCL topics found in both dermatology and oncology peer review journals. Another avenue for gaining insight and education would be through continuing education courses. Resources can also be found for nurses, patients, and caregivers through advocacy foundations such as the Cutaneous Lymphoma Foundation (www.clfoundation.org) and the Lymphoma Research Foundation (LRF@lymphma.org).

John Zic. Is there anything else that anyone would like to add to our discussion?

Lauren Pinter-Brown. One thing that we touched upon, but I was concerned that we didn’t emphasize, was the use of flow cytometry as a diagnostic tool in a patient with erythroderma. Sometimes biopsies of patients with erythroderma are not diagnostic, so clinicians need to be aware that there are other ways of diagnosing patients—nodal biopsy or flow cytometry. They should not only think of it as a staging tool but sometimes as a diagnostic tool.

Alejandro Ariel Gru. I agree. Particularly in patients who have Sézary syndrome or MF with peripheral blood involvement, sometimes the findings on the biopsy show a dissociation between how impressive the clinical presentation of the patient might be and how very few findings you might encounter on the skin biopsy. Therefore, relying on flow cytometry as a diagnostic tool is capital. Lauren, you briefly mentioned the criteria, which is looking for an abnormal CD4 to CD8 ratio of > 10%, abnormal loss of CD7, > 40%, or abnormal loss of CD26 of > 30%.

In addition, there are new markers that are now undergoing validation in the diagnosis of Sézary syndrome. One is KIR3DL2, which is a natural killer receptor that has been shown to be significantly upregulated in Sézary syndrome and appears to be both more sensitive and specific. With that also comes therapies that target the KIR3DL2 molecule.

John Zic. One of the first things we teach our dermatology residents to work up patients with erythroderma is that they shouldn’t expect the skin biopsy to help them sort out the cause of the erythroderma. As you mentioned, Lauren, the flow cytometry of peripheral blood should always be accompanied by a CBC with differential and platelets. And if the patients do have lymph nodes, consider a biopsy because sometimes that’s where you can make the firmest diagnosis of a T-cell lymphoma.

Acknowledgmentszz
The participants and Federal Practitioner would like to thank Susan Thornton, CEO of the Cutaneous Lymphoma Foundation for helping to arrange this roundtable discussion.

Targeted therapies have transformed the treatment of many malignant diseases by inhibiting molecular pathways involved in tumor growth and oncogenesis. Although these therapies can prevent disease progression, toxicities often result. Renal cell carcinoma (RCC) is one of many cancers that responds well to these therapies.

RCC accounts for 2% to 3% of all malignancies in adults worldwide. About 30% of patients with RCC present with metastatic or advanced disease.¹ Cytokine therapy was the standard of care until multitargeted tyrosine kinase inhibitors (TKIs) were developed. Over the past 12 years, the US Food and Drug Administration (FDA) has approved 6 TKIs for the treatment of RCC: axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, and sunitinib. Vascular endothelial growth factor receptor (VEGFR) is one of many tyrosine kinase receptors targeted by these medications. This mechanism prevents angiogenesis and consequently increases the risk for hypertension, bleeding, and clot formation.

Given these risks, many patients were excluded from the initial clinical trials of these medications if they had a history of uncontrolled hypertension, advanced heart failure (HF), or a significant cardiovascular (CV) event within 6 months prior to study enrollment. Many of these studies did not report the incidence of CV events (other than hypertension) that occurred during the early trials.² The recommended monitoring for TKI therapies is focused mainly on blood pressure. For patients on pazopanib and sunitinib therapy, baseline and periodic electrocardiograms (ECGs) are recommended; echocardiograms are recommended only for patients with a history of cardiac disease.^3,4 In patients on sorafenib therapy, ECG is recommended for those at risk for corrected QT (QTc) intervalprolongation.⁵

According to a meta-analysis of the literature published between 1966 and 2013,many studies reported a CV toxicity risk associated with the TKIs used in RCC treatment.⁶ However, some studies have found modest, not clinically significant changes in cardiac function in patients with advanced disease. In 2013, Hall and colleagues found 73% of patients they studied experienced some type of CV toxicity, whereas only 33% of patients had CV toxicity when hypertension was excluded.⁷ Interestingly, Rini and colleagues found that RCC patients receiving sunitinib had better response rates and progression-free survival when they developed hypertension compared with those who did not develop hypertension.⁸

A review of several studies revealed similar numbers in patients on TKI therapy presenting with symptomatic HF, but Hall and colleagues found that 27% of patients developed asymptomatic left ventricular dysfunction.^7,9,10 These results suggest routine monitoring may allow for appropriate preventive interventions. In patients receiving TKI therapy, CV events, including QTc prolongation, left ventricular HF, myocardial infarction (MI), hypertension, pulmonary hypertension, and stroke, were commonly reported by investigators.^7,9,10 Currently, there are no studies of the incidence of CV events for the 5 TKIs (axitinib, cabozantinib, pazopanib, sorafenib, sunitinib) in this patient population.

TKI therapy may require cardiac monitoring of all patients, as studies have associated TKIs with CV toxicity in varying degrees. Therefore, the authors set out to determine the incidence of CV events as well as time to first CV event in patients with and without a history of CV disease (CVD) who received a TKI for advanced RCC. More frequent monitoring for CV toxicity may present opportunities for clinical interventions for all patients on TKI therapy—especially for those with HF or other diseases in which the goal of therapy is to prevent disease progression. As TKIs have emerged as the standard treatment option for advanced RCC, many patients will continue therapy until disease progression or intolerable toxicity. Identifying and using appropriate monitoring parameters can lead to preventive interventions that allow patients to benefit from TKI therapy longer. At the US Department of Veterans Affairs (VA) San Diego Healthcare System (VASDHS), patients undergo routine cardiac monitoring at the discretion of the provider.

In this retrospective study, the authors wanted to determine the incidence of CV events in patients with and without a history of CVD who were receiving TKIs for advanced RCC. The authors also wanted to evaluate time to CV event from start of therapy in order to determine how often monitoring may be needed. The outcomes of this study may lead to a change in practice and development of monitoring parameters to ensure appropriate and adequate management of TKI therapy in RCC.

Methods

Each year, the VASDHS oncology team diagnose 5 to 10 patients with RCC who begin TKI therapy. When sorafenib was approved by the FDA in 2005, VASDHS estimated that about 100 of its patients had an RCC diagnosis and would be treated with a TKI between December 2005 and July 2017.

The authors identified VASDHS patients with a diagnosis of advanced RCC who received axitinib, cabozantinib, pazopanib, sorafenib, or sunitinib between December 1, 2005 and July 31, 2017. Patients were included if they had been on therapy for at least 30 days. The VASDHS pharmacy informatics team assisted in extracting a list of patients with an ICD-9 or ICD-10 diagnosis of RCC and using prescription fills for any of the 5 TKIs previously noted. Medical records were reviewed for frequency of prescription fills, age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, TKI treatment duration, previous history of CVD, ethnicity, and smoking status. If documented, the incidence of CV events was reviewed for each patient at 0, 1, 3, 6, and 12 months. Patients who received medications (Appendix) for their CVD were assessed for adherence based on history of prescription refills from their medical records. Adherence was evaluated for the duration that patients were concurrently taking an oral TKI. The institutional review board at VASDHS approved the study design.

All patients included in this study started TKI therapy since the December 2005 FDA approval of sorafenib, the first oral TKI for treatment of RCC. Each new start was recorded as a separate event, regardless of previous oral TKI therapy. Albiges and colleagues found that the approximate median time from starting TKI therapy to complete response was 12.6 months, and the median duration of TKI therapy after complete response was 10.3 months.¹¹ Based on these results, the follow-up period for patients in this study was 2 years after the start of each TKI therapy. For data analysis, patients were stratified by CVD history (yes or no). In addition, composite outcomes were evaluated to identify a potential cumulative increased risk for CV events for patients who had been on multiple TKI therapies.

For this study, CV toxicities were characterized using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; severity of adverse events (AEs) was graded 1 to 5. CTCAE commonly has been used to assess AEs in oncology clinical trials. The CV AEs selected for this study included QTc prolongation, hypertension, left ventricular dysfunction, stroke, myocardial infarction (MI), and pulmonary arterial hypertension. CTCAE was not used to assess left ventricular dysfunction, as the rating is based on symptomology. Instead, worsening left ventricular ejection fraction (LVEF) was based on comparisons of ECG results at baseline with results at 1, 3, 6, and 12 months. A normal ECG result was defined as no structural change in the left ventricle, or LVEF ≥ 55%, and an abnormal result was defined as structural changes in the left ventricle, or LVEF < 55%. Given updates in blood pressure (BP) guidelines and uncertainty regarding the clinical utility of prehypertension, grade 1 hypertension was excluded as an AE.

Primary outcomes included incidence of CV events and time to first CV event after initiation of TKI therapy. Secondary outcomes included changes in ECG or echocardiogram results at 0, 1, 3, 6, and 12 months. Secondary outcomes at scheduled time points were not readily available for every patient, but any available time points were gathered to aid in identifying an optimal period for cardiac monitoring. In addition, patients with a history of CVD were evaluated for adherence to common first-line therapies for each disease.

A Fischer exact test was used to compare the incidence of CV events in patients with and without a history of CVD (significance level, α = 0.05). A subgroup analysis was used to compare the incidence of CV events in patients who experienced a CV event (significance level, α = 0.05). A Kaplan-Meier survival curve was used to determine time to first CV event. A log-rank test with significance level set at α = 0.05 also was used.

Results

An initial database search identified 134 patients who received TKI therapy at VASDHS between December 1, 2005 and July 31, 2017. According to retrospective chart review, 54 patients met the inclusion criteria for the study (Table 1).

Patients without a history of CVD (17%) did not experience any CV events while on TKI therapy. Of the patients with a history of CVD, 9 (20%) experienced ≥ 1 CV event. Fifty-five percent of the events experienced were hypertension. One patient experienced QTc prolongation, and 2 patients experienced MI. As already noted, each new start of TKI was recorded as a separate event, regardless of previous TKI therapy. Among patients with a history of CVD, 2 experienced 2 CV events. Overall, 11 CV events occurred among patients who received ≥ 1 TKI, corresponding to an overall incidence of 24% (Table 2). 

Of the 13 patients who were exposed to ≥ 2 TKI therapies, 2 experienced a CV event. Both patients were started on sunitinib and were switched to sorafenib. One of these used sunitinib for 7 months, experienced a partial response and was switched to sorafenib (with a 3-month break between therapies). The second patient was on sunitinib for 24 months, with multiple doses held because of low blood counts and diarrhea. While on sunitinib, this patient experienced a HF exacerbation, determined to be caused by the underlying disease. This event occurred 17 months after sunitinib was started, and therapy was continued for another 7 months. The patient was switched to sorafenib because of poor tolerability and disease progression. While on sorafenib, this patient experienced grade 1 QTc prolongation.

Discussion

Of the available oral TKI therapies for RCC, sunitinib and sorafenib have the most data associated with nonhypertensive CV toxicity.^2,7-10,12 Instudies, the percentage of patients who experienced CV toxicity while on sunitinib or sorafenib has ranged widely, from 2.7% to 33.8%; the variance may be attributable to differences in how institutions report CV toxicities.^7-9

According to the prescribing information for TKIs, hypertension is frequently reported as an AE for all 5 TKIs, and BP monitoring is recommended.^3,4 However, the development of hypertension with these TKIs has been associated with response to therapy.⁷ With pazopanib, sorafenib, and sunitinib, there is a higher incidence of other AEs: edema, HF, MI, and QTc prolongation. Baseline ECG is recommended for all patients started on pazopanib and sunitinib and for patients with a history of CVD who are started on sorafenib. An ECG is recommended for patients with a history of CVD who are started on pazopanib and sunitinib.

Even with the medication prescribing information recommendations, it is unclear how frequently patients should be monitored. At VASDHS, CV monitoring for any patient started on a TKI remains at the discretion of the oncologist. There are concerns that ordering cardiac monitoring tests, which might be unnecessary, will change or guide therapy. In this study, data evaluation revealed 1 patient who experienced a CV event had a CVD history that was not documented in the patient’s medical history. It is important that providers obtain a detailed clinical assessment of patients CV history during each visit to determine whether CV monitoring should be considered. Patients also may benefit from additional counseling to emphasize the importance of adherence to CV medication therapy to reduce the incidence of these events.

Data from this study indicate that routine CV monitoring should be considered in patients with CVD, in keeping with current medication prescribing information recommendations. Of the patients who had a CV event, 54% experienced hypertension, 18% MI, and 28% stroke, QTc prolongation, or congestive HF. 

Limitations

This retrospective study had several limitations. Many patients did not have a baseline cardiac monitoring test or any monitoring during therapy. Often, a cardiac test was performed only when the patient was symptomatic or experiencing a CV event. In addition, because of intolerance or nonadherence to therapy, many patients discontinued treatment early, before completing 30 days. That axitinib and cabozantinib are newer therapies and not first-line at VASDHS during the data collection period accounts for the small number of patients on these therapies. Therapy was shorter for patients started on pazopanib, axitinib, and cabozantinib than it was for patients on sunitinib and sorafenib. Duration of therapy may affect treatment-related events, but the majority of patients in this study experienced an event within 4 months of therapy. About half of the patients who experienced an event were nonadherent to their CV medication regimen. Another potential limitation is that this study was conducted at VASDHS, where most patients are male (RCC incidence is 2:1 male:female).

Conclusion

In this study, CV events occurred in 24% of patients with a history of CVD; 11% of these events were nonhypertensive. Baseline cardiac monitoring was not performed for most patients started on TKI therapy, but tests were performed once patients became symptomatic. The study results suggest that high-risk patients should undergo routine cardiac monitoring during the first 4 months of TKI therapy, in keeping with medication package insert monitoring recommendations. Cardiac monitoring of high-risk patients will allow for earlier identification of cardiac decline and offer opportunities for interventions, such as pharmacist-driven protocols to start CV medications. Implementation of this study’s recommendations should be evaluated to determine whether outcomes improve with routine cardiac monitoring in these high-risk patients.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, FrontlineMedical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects— before administering pharmacologic therapy to patients.

Targeted therapies have transformed the treatment of many malignant diseases by inhibiting molecular pathways involved in tumor growth and oncogenesis. Although these therapies can prevent disease progression, toxicities often result. Renal cell carcinoma (RCC) is one of many cancers that responds well to these therapies.

RCC accounts for 2% to 3% of all malignancies in adults worldwide. About 30% of patients with RCC present with metastatic or advanced disease.¹ Cytokine therapy was the standard of care until multitargeted tyrosine kinase inhibitors (TKIs) were developed. Over the past 12 years, the US Food and Drug Administration (FDA) has approved 6 TKIs for the treatment of RCC: axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, and sunitinib. Vascular endothelial growth factor receptor (VEGFR) is one of many tyrosine kinase receptors targeted by these medications. This mechanism prevents angiogenesis and consequently increases the risk for hypertension, bleeding, and clot formation.

Given these risks, many patients were excluded from the initial clinical trials of these medications if they had a history of uncontrolled hypertension, advanced heart failure (HF), or a significant cardiovascular (CV) event within 6 months prior to study enrollment. Many of these studies did not report the incidence of CV events (other than hypertension) that occurred during the early trials.² The recommended monitoring for TKI therapies is focused mainly on blood pressure. For patients on pazopanib and sunitinib therapy, baseline and periodic electrocardiograms (ECGs) are recommended; echocardiograms are recommended only for patients with a history of cardiac disease.^3,4 In patients on sorafenib therapy, ECG is recommended for those at risk for corrected QT (QTc) intervalprolongation.⁵

According to a meta-analysis of the literature published between 1966 and 2013,many studies reported a CV toxicity risk associated with the TKIs used in RCC treatment.⁶ However, some studies have found modest, not clinically significant changes in cardiac function in patients with advanced disease. In 2013, Hall and colleagues found 73% of patients they studied experienced some type of CV toxicity, whereas only 33% of patients had CV toxicity when hypertension was excluded.⁷ Interestingly, Rini and colleagues found that RCC patients receiving sunitinib had better response rates and progression-free survival when they developed hypertension compared with those who did not develop hypertension.⁸

A review of several studies revealed similar numbers in patients on TKI therapy presenting with symptomatic HF, but Hall and colleagues found that 27% of patients developed asymptomatic left ventricular dysfunction.^7,9,10 These results suggest routine monitoring may allow for appropriate preventive interventions. In patients receiving TKI therapy, CV events, including QTc prolongation, left ventricular HF, myocardial infarction (MI), hypertension, pulmonary hypertension, and stroke, were commonly reported by investigators.^7,9,10 Currently, there are no studies of the incidence of CV events for the 5 TKIs (axitinib, cabozantinib, pazopanib, sorafenib, sunitinib) in this patient population.

TKI therapy may require cardiac monitoring of all patients, as studies have associated TKIs with CV toxicity in varying degrees. Therefore, the authors set out to determine the incidence of CV events as well as time to first CV event in patients with and without a history of CV disease (CVD) who received a TKI for advanced RCC. More frequent monitoring for CV toxicity may present opportunities for clinical interventions for all patients on TKI therapy—especially for those with HF or other diseases in which the goal of therapy is to prevent disease progression. As TKIs have emerged as the standard treatment option for advanced RCC, many patients will continue therapy until disease progression or intolerable toxicity. Identifying and using appropriate monitoring parameters can lead to preventive interventions that allow patients to benefit from TKI therapy longer. At the US Department of Veterans Affairs (VA) San Diego Healthcare System (VASDHS), patients undergo routine cardiac monitoring at the discretion of the provider.

In this retrospective study, the authors wanted to determine the incidence of CV events in patients with and without a history of CVD who were receiving TKIs for advanced RCC. The authors also wanted to evaluate time to CV event from start of therapy in order to determine how often monitoring may be needed. The outcomes of this study may lead to a change in practice and development of monitoring parameters to ensure appropriate and adequate management of TKI therapy in RCC.

Methods

Each year, the VASDHS oncology team diagnose 5 to 10 patients with RCC who begin TKI therapy. When sorafenib was approved by the FDA in 2005, VASDHS estimated that about 100 of its patients had an RCC diagnosis and would be treated with a TKI between December 2005 and July 2017.

The authors identified VASDHS patients with a diagnosis of advanced RCC who received axitinib, cabozantinib, pazopanib, sorafenib, or sunitinib between December 1, 2005 and July 31, 2017. Patients were included if they had been on therapy for at least 30 days. The VASDHS pharmacy informatics team assisted in extracting a list of patients with an ICD-9 or ICD-10 diagnosis of RCC and using prescription fills for any of the 5 TKIs previously noted. Medical records were reviewed for frequency of prescription fills, age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, TKI treatment duration, previous history of CVD, ethnicity, and smoking status. If documented, the incidence of CV events was reviewed for each patient at 0, 1, 3, 6, and 12 months. Patients who received medications (Appendix) for their CVD were assessed for adherence based on history of prescription refills from their medical records. Adherence was evaluated for the duration that patients were concurrently taking an oral TKI. The institutional review board at VASDHS approved the study design.

All patients included in this study started TKI therapy since the December 2005 FDA approval of sorafenib, the first oral TKI for treatment of RCC. Each new start was recorded as a separate event, regardless of previous oral TKI therapy. Albiges and colleagues found that the approximate median time from starting TKI therapy to complete response was 12.6 months, and the median duration of TKI therapy after complete response was 10.3 months.¹¹ Based on these results, the follow-up period for patients in this study was 2 years after the start of each TKI therapy. For data analysis, patients were stratified by CVD history (yes or no). In addition, composite outcomes were evaluated to identify a potential cumulative increased risk for CV events for patients who had been on multiple TKI therapies.

For this study, CV toxicities were characterized using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; severity of adverse events (AEs) was graded 1 to 5. CTCAE commonly has been used to assess AEs in oncology clinical trials. The CV AEs selected for this study included QTc prolongation, hypertension, left ventricular dysfunction, stroke, myocardial infarction (MI), and pulmonary arterial hypertension. CTCAE was not used to assess left ventricular dysfunction, as the rating is based on symptomology. Instead, worsening left ventricular ejection fraction (LVEF) was based on comparisons of ECG results at baseline with results at 1, 3, 6, and 12 months. A normal ECG result was defined as no structural change in the left ventricle, or LVEF ≥ 55%, and an abnormal result was defined as structural changes in the left ventricle, or LVEF < 55%. Given updates in blood pressure (BP) guidelines and uncertainty regarding the clinical utility of prehypertension, grade 1 hypertension was excluded as an AE.

Primary outcomes included incidence of CV events and time to first CV event after initiation of TKI therapy. Secondary outcomes included changes in ECG or echocardiogram results at 0, 1, 3, 6, and 12 months. Secondary outcomes at scheduled time points were not readily available for every patient, but any available time points were gathered to aid in identifying an optimal period for cardiac monitoring. In addition, patients with a history of CVD were evaluated for adherence to common first-line therapies for each disease.

A Fischer exact test was used to compare the incidence of CV events in patients with and without a history of CVD (significance level, α = 0.05). A subgroup analysis was used to compare the incidence of CV events in patients who experienced a CV event (significance level, α = 0.05). A Kaplan-Meier survival curve was used to determine time to first CV event. A log-rank test with significance level set at α = 0.05 also was used.

Results

An initial database search identified 134 patients who received TKI therapy at VASDHS between December 1, 2005 and July 31, 2017. According to retrospective chart review, 54 patients met the inclusion criteria for the study (Table 1).

Patients without a history of CVD (17%) did not experience any CV events while on TKI therapy. Of the patients with a history of CVD, 9 (20%) experienced ≥ 1 CV event. Fifty-five percent of the events experienced were hypertension. One patient experienced QTc prolongation, and 2 patients experienced MI. As already noted, each new start of TKI was recorded as a separate event, regardless of previous TKI therapy. Among patients with a history of CVD, 2 experienced 2 CV events. Overall, 11 CV events occurred among patients who received ≥ 1 TKI, corresponding to an overall incidence of 24% (Table 2). 

Of the 13 patients who were exposed to ≥ 2 TKI therapies, 2 experienced a CV event. Both patients were started on sunitinib and were switched to sorafenib. One of these used sunitinib for 7 months, experienced a partial response and was switched to sorafenib (with a 3-month break between therapies). The second patient was on sunitinib for 24 months, with multiple doses held because of low blood counts and diarrhea. While on sunitinib, this patient experienced a HF exacerbation, determined to be caused by the underlying disease. This event occurred 17 months after sunitinib was started, and therapy was continued for another 7 months. The patient was switched to sorafenib because of poor tolerability and disease progression. While on sorafenib, this patient experienced grade 1 QTc prolongation.

Discussion

Of the available oral TKI therapies for RCC, sunitinib and sorafenib have the most data associated with nonhypertensive CV toxicity.^2,7-10,12 Instudies, the percentage of patients who experienced CV toxicity while on sunitinib or sorafenib has ranged widely, from 2.7% to 33.8%; the variance may be attributable to differences in how institutions report CV toxicities.^7-9

According to the prescribing information for TKIs, hypertension is frequently reported as an AE for all 5 TKIs, and BP monitoring is recommended.^3,4 However, the development of hypertension with these TKIs has been associated with response to therapy.⁷ With pazopanib, sorafenib, and sunitinib, there is a higher incidence of other AEs: edema, HF, MI, and QTc prolongation. Baseline ECG is recommended for all patients started on pazopanib and sunitinib and for patients with a history of CVD who are started on sorafenib. An ECG is recommended for patients with a history of CVD who are started on pazopanib and sunitinib.

Even with the medication prescribing information recommendations, it is unclear how frequently patients should be monitored. At VASDHS, CV monitoring for any patient started on a TKI remains at the discretion of the oncologist. There are concerns that ordering cardiac monitoring tests, which might be unnecessary, will change or guide therapy. In this study, data evaluation revealed 1 patient who experienced a CV event had a CVD history that was not documented in the patient’s medical history. It is important that providers obtain a detailed clinical assessment of patients CV history during each visit to determine whether CV monitoring should be considered. Patients also may benefit from additional counseling to emphasize the importance of adherence to CV medication therapy to reduce the incidence of these events.

Data from this study indicate that routine CV monitoring should be considered in patients with CVD, in keeping with current medication prescribing information recommendations. Of the patients who had a CV event, 54% experienced hypertension, 18% MI, and 28% stroke, QTc prolongation, or congestive HF. 

Limitations

This retrospective study had several limitations. Many patients did not have a baseline cardiac monitoring test or any monitoring during therapy. Often, a cardiac test was performed only when the patient was symptomatic or experiencing a CV event. In addition, because of intolerance or nonadherence to therapy, many patients discontinued treatment early, before completing 30 days. That axitinib and cabozantinib are newer therapies and not first-line at VASDHS during the data collection period accounts for the small number of patients on these therapies. Therapy was shorter for patients started on pazopanib, axitinib, and cabozantinib than it was for patients on sunitinib and sorafenib. Duration of therapy may affect treatment-related events, but the majority of patients in this study experienced an event within 4 months of therapy. About half of the patients who experienced an event were nonadherent to their CV medication regimen. Another potential limitation is that this study was conducted at VASDHS, where most patients are male (RCC incidence is 2:1 male:female).

Conclusion

In this study, CV events occurred in 24% of patients with a history of CVD; 11% of these events were nonhypertensive. Baseline cardiac monitoring was not performed for most patients started on TKI therapy, but tests were performed once patients became symptomatic. The study results suggest that high-risk patients should undergo routine cardiac monitoring during the first 4 months of TKI therapy, in keeping with medication package insert monitoring recommendations. Cardiac monitoring of high-risk patients will allow for earlier identification of cardiac decline and offer opportunities for interventions, such as pharmacist-driven protocols to start CV medications. Implementation of this study’s recommendations should be evaluated to determine whether outcomes improve with routine cardiac monitoring in these high-risk patients.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, FrontlineMedical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects— before administering pharmacologic therapy to patients.

Targeted therapies have transformed the treatment of many malignant diseases by inhibiting molecular pathways involved in tumor growth and oncogenesis. Although these therapies can prevent disease progression, toxicities often result. Renal cell carcinoma (RCC) is one of many cancers that responds well to these therapies.

RCC accounts for 2% to 3% of all malignancies in adults worldwide. About 30% of patients with RCC present with metastatic or advanced disease.¹ Cytokine therapy was the standard of care until multitargeted tyrosine kinase inhibitors (TKIs) were developed. Over the past 12 years, the US Food and Drug Administration (FDA) has approved 6 TKIs for the treatment of RCC: axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, and sunitinib. Vascular endothelial growth factor receptor (VEGFR) is one of many tyrosine kinase receptors targeted by these medications. This mechanism prevents angiogenesis and consequently increases the risk for hypertension, bleeding, and clot formation.

Given these risks, many patients were excluded from the initial clinical trials of these medications if they had a history of uncontrolled hypertension, advanced heart failure (HF), or a significant cardiovascular (CV) event within 6 months prior to study enrollment. Many of these studies did not report the incidence of CV events (other than hypertension) that occurred during the early trials.² The recommended monitoring for TKI therapies is focused mainly on blood pressure. For patients on pazopanib and sunitinib therapy, baseline and periodic electrocardiograms (ECGs) are recommended; echocardiograms are recommended only for patients with a history of cardiac disease.^3,4 In patients on sorafenib therapy, ECG is recommended for those at risk for corrected QT (QTc) intervalprolongation.⁵

According to a meta-analysis of the literature published between 1966 and 2013,many studies reported a CV toxicity risk associated with the TKIs used in RCC treatment.⁶ However, some studies have found modest, not clinically significant changes in cardiac function in patients with advanced disease. In 2013, Hall and colleagues found 73% of patients they studied experienced some type of CV toxicity, whereas only 33% of patients had CV toxicity when hypertension was excluded.⁷ Interestingly, Rini and colleagues found that RCC patients receiving sunitinib had better response rates and progression-free survival when they developed hypertension compared with those who did not develop hypertension.⁸

A review of several studies revealed similar numbers in patients on TKI therapy presenting with symptomatic HF, but Hall and colleagues found that 27% of patients developed asymptomatic left ventricular dysfunction.^7,9,10 These results suggest routine monitoring may allow for appropriate preventive interventions. In patients receiving TKI therapy, CV events, including QTc prolongation, left ventricular HF, myocardial infarction (MI), hypertension, pulmonary hypertension, and stroke, were commonly reported by investigators.^7,9,10 Currently, there are no studies of the incidence of CV events for the 5 TKIs (axitinib, cabozantinib, pazopanib, sorafenib, sunitinib) in this patient population.

TKI therapy may require cardiac monitoring of all patients, as studies have associated TKIs with CV toxicity in varying degrees. Therefore, the authors set out to determine the incidence of CV events as well as time to first CV event in patients with and without a history of CV disease (CVD) who received a TKI for advanced RCC. More frequent monitoring for CV toxicity may present opportunities for clinical interventions for all patients on TKI therapy—especially for those with HF or other diseases in which the goal of therapy is to prevent disease progression. As TKIs have emerged as the standard treatment option for advanced RCC, many patients will continue therapy until disease progression or intolerable toxicity. Identifying and using appropriate monitoring parameters can lead to preventive interventions that allow patients to benefit from TKI therapy longer. At the US Department of Veterans Affairs (VA) San Diego Healthcare System (VASDHS), patients undergo routine cardiac monitoring at the discretion of the provider.

In this retrospective study, the authors wanted to determine the incidence of CV events in patients with and without a history of CVD who were receiving TKIs for advanced RCC. The authors also wanted to evaluate time to CV event from start of therapy in order to determine how often monitoring may be needed. The outcomes of this study may lead to a change in practice and development of monitoring parameters to ensure appropriate and adequate management of TKI therapy in RCC.

Methods

Each year, the VASDHS oncology team diagnose 5 to 10 patients with RCC who begin TKI therapy. When sorafenib was approved by the FDA in 2005, VASDHS estimated that about 100 of its patients had an RCC diagnosis and would be treated with a TKI between December 2005 and July 2017.

The authors identified VASDHS patients with a diagnosis of advanced RCC who received axitinib, cabozantinib, pazopanib, sorafenib, or sunitinib between December 1, 2005 and July 31, 2017. Patients were included if they had been on therapy for at least 30 days. The VASDHS pharmacy informatics team assisted in extracting a list of patients with an ICD-9 or ICD-10 diagnosis of RCC and using prescription fills for any of the 5 TKIs previously noted. Medical records were reviewed for frequency of prescription fills, age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, TKI treatment duration, previous history of CVD, ethnicity, and smoking status. If documented, the incidence of CV events was reviewed for each patient at 0, 1, 3, 6, and 12 months. Patients who received medications (Appendix) for their CVD were assessed for adherence based on history of prescription refills from their medical records. Adherence was evaluated for the duration that patients were concurrently taking an oral TKI. The institutional review board at VASDHS approved the study design.

All patients included in this study started TKI therapy since the December 2005 FDA approval of sorafenib, the first oral TKI for treatment of RCC. Each new start was recorded as a separate event, regardless of previous oral TKI therapy. Albiges and colleagues found that the approximate median time from starting TKI therapy to complete response was 12.6 months, and the median duration of TKI therapy after complete response was 10.3 months.¹¹ Based on these results, the follow-up period for patients in this study was 2 years after the start of each TKI therapy. For data analysis, patients were stratified by CVD history (yes or no). In addition, composite outcomes were evaluated to identify a potential cumulative increased risk for CV events for patients who had been on multiple TKI therapies.

For this study, CV toxicities were characterized using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; severity of adverse events (AEs) was graded 1 to 5. CTCAE commonly has been used to assess AEs in oncology clinical trials. The CV AEs selected for this study included QTc prolongation, hypertension, left ventricular dysfunction, stroke, myocardial infarction (MI), and pulmonary arterial hypertension. CTCAE was not used to assess left ventricular dysfunction, as the rating is based on symptomology. Instead, worsening left ventricular ejection fraction (LVEF) was based on comparisons of ECG results at baseline with results at 1, 3, 6, and 12 months. A normal ECG result was defined as no structural change in the left ventricle, or LVEF ≥ 55%, and an abnormal result was defined as structural changes in the left ventricle, or LVEF < 55%. Given updates in blood pressure (BP) guidelines and uncertainty regarding the clinical utility of prehypertension, grade 1 hypertension was excluded as an AE.

Primary outcomes included incidence of CV events and time to first CV event after initiation of TKI therapy. Secondary outcomes included changes in ECG or echocardiogram results at 0, 1, 3, 6, and 12 months. Secondary outcomes at scheduled time points were not readily available for every patient, but any available time points were gathered to aid in identifying an optimal period for cardiac monitoring. In addition, patients with a history of CVD were evaluated for adherence to common first-line therapies for each disease.

A Fischer exact test was used to compare the incidence of CV events in patients with and without a history of CVD (significance level, α = 0.05). A subgroup analysis was used to compare the incidence of CV events in patients who experienced a CV event (significance level, α = 0.05). A Kaplan-Meier survival curve was used to determine time to first CV event. A log-rank test with significance level set at α = 0.05 also was used.

Results

An initial database search identified 134 patients who received TKI therapy at VASDHS between December 1, 2005 and July 31, 2017. According to retrospective chart review, 54 patients met the inclusion criteria for the study (Table 1).

Patients without a history of CVD (17%) did not experience any CV events while on TKI therapy. Of the patients with a history of CVD, 9 (20%) experienced ≥ 1 CV event. Fifty-five percent of the events experienced were hypertension. One patient experienced QTc prolongation, and 2 patients experienced MI. As already noted, each new start of TKI was recorded as a separate event, regardless of previous TKI therapy. Among patients with a history of CVD, 2 experienced 2 CV events. Overall, 11 CV events occurred among patients who received ≥ 1 TKI, corresponding to an overall incidence of 24% (Table 2). 

Of the 13 patients who were exposed to ≥ 2 TKI therapies, 2 experienced a CV event. Both patients were started on sunitinib and were switched to sorafenib. One of these used sunitinib for 7 months, experienced a partial response and was switched to sorafenib (with a 3-month break between therapies). The second patient was on sunitinib for 24 months, with multiple doses held because of low blood counts and diarrhea. While on sunitinib, this patient experienced a HF exacerbation, determined to be caused by the underlying disease. This event occurred 17 months after sunitinib was started, and therapy was continued for another 7 months. The patient was switched to sorafenib because of poor tolerability and disease progression. While on sorafenib, this patient experienced grade 1 QTc prolongation.

Discussion

Of the available oral TKI therapies for RCC, sunitinib and sorafenib have the most data associated with nonhypertensive CV toxicity.^2,7-10,12 Instudies, the percentage of patients who experienced CV toxicity while on sunitinib or sorafenib has ranged widely, from 2.7% to 33.8%; the variance may be attributable to differences in how institutions report CV toxicities.^7-9

According to the prescribing information for TKIs, hypertension is frequently reported as an AE for all 5 TKIs, and BP monitoring is recommended.^3,4 However, the development of hypertension with these TKIs has been associated with response to therapy.⁷ With pazopanib, sorafenib, and sunitinib, there is a higher incidence of other AEs: edema, HF, MI, and QTc prolongation. Baseline ECG is recommended for all patients started on pazopanib and sunitinib and for patients with a history of CVD who are started on sorafenib. An ECG is recommended for patients with a history of CVD who are started on pazopanib and sunitinib.

Even with the medication prescribing information recommendations, it is unclear how frequently patients should be monitored. At VASDHS, CV monitoring for any patient started on a TKI remains at the discretion of the oncologist. There are concerns that ordering cardiac monitoring tests, which might be unnecessary, will change or guide therapy. In this study, data evaluation revealed 1 patient who experienced a CV event had a CVD history that was not documented in the patient’s medical history. It is important that providers obtain a detailed clinical assessment of patients CV history during each visit to determine whether CV monitoring should be considered. Patients also may benefit from additional counseling to emphasize the importance of adherence to CV medication therapy to reduce the incidence of these events.

Data from this study indicate that routine CV monitoring should be considered in patients with CVD, in keeping with current medication prescribing information recommendations. Of the patients who had a CV event, 54% experienced hypertension, 18% MI, and 28% stroke, QTc prolongation, or congestive HF. 

Limitations

This retrospective study had several limitations. Many patients did not have a baseline cardiac monitoring test or any monitoring during therapy. Often, a cardiac test was performed only when the patient was symptomatic or experiencing a CV event. In addition, because of intolerance or nonadherence to therapy, many patients discontinued treatment early, before completing 30 days. That axitinib and cabozantinib are newer therapies and not first-line at VASDHS during the data collection period accounts for the small number of patients on these therapies. Therapy was shorter for patients started on pazopanib, axitinib, and cabozantinib than it was for patients on sunitinib and sorafenib. Duration of therapy may affect treatment-related events, but the majority of patients in this study experienced an event within 4 months of therapy. About half of the patients who experienced an event were nonadherent to their CV medication regimen. Another potential limitation is that this study was conducted at VASDHS, where most patients are male (RCC incidence is 2:1 male:female).

Conclusion

In this study, CV events occurred in 24% of patients with a history of CVD; 11% of these events were nonhypertensive. Baseline cardiac monitoring was not performed for most patients started on TKI therapy, but tests were performed once patients became symptomatic. The study results suggest that high-risk patients should undergo routine cardiac monitoring during the first 4 months of TKI therapy, in keeping with medication package insert monitoring recommendations. Cardiac monitoring of high-risk patients will allow for earlier identification of cardiac decline and offer opportunities for interventions, such as pharmacist-driven protocols to start CV medications. Implementation of this study’s recommendations should be evaluated to determine whether outcomes improve with routine cardiac monitoring in these high-risk patients.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, FrontlineMedical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects— before administering pharmacologic therapy to patients.

In 2016, the Cancer Care Coordinator at the US Department of Veterans Affairs (VA) Connecticut Healthcare System (VACT) in West Haven partnered with the VA New England Healthcare System to use its telementoring program. The VA Specialty Care Access Network Extension for Community Healthcare Outcomes (VA ECHO) was used to present a series of educational conferences on cancer care. This article describes our experience implementing the program and reviews participant feedback gathered from voluntary surveys.

Background

In 2011, the Veterans Health Administration (VHA) Office of Healthcare Transformation launched VA ECHO, a telementoring program for primary care providers (PCPs) and patient-aligned care team staff. VACT was selected as 1 of 7 hub sites across the US. The VA ECHO system uses video and online technology to provide PCPs with case-based specialist consultation and didactic education. The system enables providers at any VA location to participate in online and telephone conferences in real time. The presentations are recorded and made available online to VA providers through a secure site.

VA ECHO is based on the highly successful Project ECHO model established by Sanjeev Arora and the University of New Mexico in 2007.¹ The rationale for Project ECHO was that patient care could be improved by increasing the competence of PCPs in the management of complex diseases by providing access to disease specialists through a case-based learning approach that used technology, which it termed knowledge networks, to connect the PCPs to specialists.

The original model addressed management of hepatitis C in a medically underserved area where half of the population was widely geographically dispersed, making the provision of specialty care challenging. Developers identified 6 characteristics that make a disease appropriate for treatment using the Project ECHO knowledge network model:

• The disease is common;
• Management of the disease is complex;
• Treatment for the disease is evolving;
• The disease has a high societal impact;
• There are serious outcomes if the disease is not treated; and
• Disease management improves outcomes.¹

VA ECHO conferences are available to all VA personnel. Staff can subscribe to an e-mail group list to be alerted to conference times and topics. Participants can connect directly to the conference using Microsoft Outlook Lync or Skype (Redmond, WA) and see the slides in real time on their computer as they listen to the presentation. The presentations are recorded, and the slides with audio can be accessed easily on the VA ECHO SharePoint site for download, enabling VA staff to listen to conferences at their convenience (Figure).

VA Cancer ECHO

The impetus to create a series of talks related to cancer care using VA ECHO was the frequent and often time-consuming requests we received from colleagues at other VA sites for information about areas of cancer care, such as survivorship and cancer care coordination. It was felt that presenting cancer care information as a VA ECHO series would make this information available to a large group of providers at one time, making the method more time effective than sharing the information via one-on-one conversations.

The cancer care coordinator originally conceived this as a 3-part, 1-time series to present work done at VACT in the areas of survivorship, psychosocial distress monitoring, and coordination of cancer care using the VA Cancer Care Tracking System, an online tracking tool. Information about the series was disseminated via VA group e-mail lists for oncology providers and via the existing VA ECHO subscriber invitation process. The 3-presentation series garnered positive feedback and had attendance that ranged from 49 to 75 participants (mean, 60). Participants expressed enthusiasm for the format via e-mail and phone feedback directly to the West Haven staff.

Expansion

The success of this original 3-part series led to a trial of an ongoing Cancer Care Conference series (Conference) using VA ECHO. This was a novel use of VA ECHO and was outside its traditional format, which is geared to discussion of individual cases and clinical knowledge. Nevertheless, this new style of communication has been embraced by a wide range of VA cancer care professionals.

One reason we considered expanding the program was that oncology fit the framework of the original Project ECHO knowledge network model. Cancer is common at the VA, which cares for 175,000 patients with cancer annually.² The management of cancer is complex involving many disciplines working together, and treatments are constantly changing. In addition, cancer has a high societal impact; there are serious outcomes both in terms of patient survival and patient symptom burden. And lastly, outcomes are improved with proactive disease management that is informed by the most current, evidence-based medicine.

The Conference was conceived as a forum for providers across disciplines to share best practices and discuss common challenges in caring for veterans with cancer. We invited participants to submit proposals for presentations related to cancer care initiatives at their VA sites. Potential speakers across all areas of care for veterans with cancer were invited to submit possible topics for the conference. The submissions were reviewed by the moderators in an effort to create a series of talks on a variety of topics across all aspects of care for oncology patients in the VA. This process of effectively crowd-sourcing educational content inspires providers to think more creatively about their practice and quality improvement projects and has sparked an ongoing dialogue about quality initiatives among VA oncology providers across disciplines and geographic locations. As a result, this approach also has enabled participants to learn from colleagues who work at a wide range of rural and urban VA locations throughout the country and to network with colleagues who are working on similar quality initiatives and challenges related to caring for veterans with cancer.

Program

The first Conference talk was in October 2016. It encompassed ten 1-hour talks during the 2016 to 2017 academic year. Speakers were recruited from the VACT West Haven campus and from several other VA sites nationwide. Topics included survivorship, psychosocial distress, palliative care, cancer navigation, and establishing a clinical trials program.

In its first year, the Conference series had 260 unique attendees representing such disciplines as medicine, nursing, social work, pharmacy, psychology, and clinic administration and representing all 21 Veterans Integrated Services Networks (VISNs). Speakers including oncologists, hepatologists, cancer care coordinators, health psychologists, and a research coordinator gave presentations on psychosocial distress screening and issues, cognitive behavioral therapy for cancer pain, cancer navigation, cancer case tracking, VISN-based liver cancer tumor tracker and liver tumor board, starting a VA-based clinical trial, palliative care, and survivorship.

The Conference accounted for 508 continuing medical education (CME) hours, which accounted for one-third of the total CME hours generated by the VACT West Haven VA ECHO program. Highlights of the talks were presented at the 2017 Association of VA Hematology/Oncology annual meeting in Denver, Colorado.

During the second year of the Conference, speakers were recruited to address new American College of Surgeons Commission on Cancer (CoC) requirements regarding survivorship treatment summaries for a subset of cancer survivors.³ The focus on survivorship was driven by ongoing feedback from participants who were working on initiatives to implement this process at their VA sites and wanted to learn from peers involved in this process throughout the VA system. Several speakers gave talks on implementing survivorship care at their VA and specifically on the use of computerized patient record system templates to create survivorship treatment summaries for veterans in accordance with CoC standards.

Since the first Conference in 2016, the number of unique attendees grew by 20% to 327 in 2018. During its first 2 years, participants have earned a total of 1,095 CME credits through Yale University CME. Conferences are usually broadcast at noon eastern time so that providers can take advantage of sessions during lunch breaks.

Participant Surveys

Attendees were invited to participate in voluntary, anonymous surveys to obtain feedback on and to receive input on topics of interest for future talks. Participants also were asked to comment on resources that they utilized to be updated on practice changes (Table 1). 

The Conference has led to increased awareness of other continuing education opportunities available through VA ECHO-Connecticut. Of survey participants, 20% reported that they had attended other VA ECHO conferences.

The survey samples are self-selecting and may not necessarily be representative of the Conference participants or of the VA oncology interdisciplinary team as a whole; however, the relatively large number of survey participants provides some confidence that these survey results can help inform future planning for this and other continuing education opportunities for VA oncology providers.

An additional online survey was designed to elucidate whether participants were incorporating knowledge gained from the Conference in their cancer care practice. Half of the 32 participants strongly agreed with the following statement: “Participation in the VA Cancer Care Conference has added to my knowledge of information relevant to my practice,” and 13 more agreed with the statement for a total of 90.6% of those surveyed responding affirmatively. Only 3 participants neither agreed nor disagreed, and none disagreed with the statement. More than half of the participants reported that they made changes to their practice or plan to make changes as a result of the Conference.

Conculsion

The VA ECHO program established at the VACT West Haven campus in 2012 now offers regular monthly or bimonthly conferences in 9 specialties: pain, liver/hepatitis C, neurology, nephrology, cardiology, diabetes/endocrinology, mental health and addiction, nursing grand rounds, and cancer care. The VACT ECHO program is led by a medical director, and each specialty has a clinical director who conducts sessions and recruits other specialists from their department.

Teleconferencing can provide opportunities for colleagues living in distant locations to connect; share best practices, common goals, and challenges; and initiate ongoing and lasting relationships. The Conference draws the most diverse audience by discipline of all the VA ECHO conferences hosted at VACT (Table 2). 

Traditionally, the national VA ECHO program has been a forum for specialists to discuss clinical case presentations for the benefit of primary care providers and to deliver didactics about chronic clinical conditions. Our Cancer Care Management VA ECHO has explored new ground by discussing material that has helped sites set up and enhance cancer care clinics and disseminate best practices for cancer survivorship and other aspects of cancer care. As a result, this conference has attracted and provided a forum for the most diverse audience of staff among VA ECHO clinics, with participation from clinic administrators to social workers to primary care providers to tumor registrars.

Through the creation of the Conference, > 300 individuals who care for veterans with cancer have been provided with a regular forum at which to connect with colleagues, receive updates on new treatment options for their patients, and learn about and share best practices specific to VA oncology patients. The VA ECHO technology creates a resource that can be accessed by all VA staff from their desktop computer. The VA ECHO SharePoint saves the slides of the Conference presentations both with and without audio to enable staff who can’t participate in real time to access the information at their convenience.

The Conference has facilitated networking among VA oncology providers who have common interests. Conference participants also have participated in other VA ECHO conferences in disciplines beyond oncology. Participants in the Conference also are encouraged to participate as speakers by presenting quality improvement initiatives at their VA site. This novel approach to generating content for this educational series has led to a dynamic interchange of ideas and increased networking among VA providers related to their practice and quality improvement initiatives at their VA sites. The Conference provides a regular forum for VA staff across a wide range of disciplines to share personal experiences, successes, and frustrations and to get feedback from colleagues.

The Conference combines a structured approach to presenting VA-specific educational content related to cancer care and multiple mechanisms that encourage staff to participate in an ongoing dialogue related to quality initiatives both on the phone during the Conference, online using Outlook LYNC or Skype to ask questions during the Conference, and during conversations on group e-mail. The Conference promotes staff engagement at little or no extra cost to the VA. For more information about the VA ECHO Cancer Care Conference or to submit a presentation for consideration for a future session, please contact julie.beck@va.gov or pradeep.mutalik@va.gov.

In 2016, the Cancer Care Coordinator at the US Department of Veterans Affairs (VA) Connecticut Healthcare System (VACT) in West Haven partnered with the VA New England Healthcare System to use its telementoring program. The VA Specialty Care Access Network Extension for Community Healthcare Outcomes (VA ECHO) was used to present a series of educational conferences on cancer care. This article describes our experience implementing the program and reviews participant feedback gathered from voluntary surveys.

Background

In 2011, the Veterans Health Administration (VHA) Office of Healthcare Transformation launched VA ECHO, a telementoring program for primary care providers (PCPs) and patient-aligned care team staff. VACT was selected as 1 of 7 hub sites across the US. The VA ECHO system uses video and online technology to provide PCPs with case-based specialist consultation and didactic education. The system enables providers at any VA location to participate in online and telephone conferences in real time. The presentations are recorded and made available online to VA providers through a secure site.

VA ECHO is based on the highly successful Project ECHO model established by Sanjeev Arora and the University of New Mexico in 2007.¹ The rationale for Project ECHO was that patient care could be improved by increasing the competence of PCPs in the management of complex diseases by providing access to disease specialists through a case-based learning approach that used technology, which it termed knowledge networks, to connect the PCPs to specialists.

The original model addressed management of hepatitis C in a medically underserved area where half of the population was widely geographically dispersed, making the provision of specialty care challenging. Developers identified 6 characteristics that make a disease appropriate for treatment using the Project ECHO knowledge network model:

• The disease is common;
• Management of the disease is complex;
• Treatment for the disease is evolving;
• The disease has a high societal impact;
• There are serious outcomes if the disease is not treated; and
• Disease management improves outcomes.¹

VA ECHO conferences are available to all VA personnel. Staff can subscribe to an e-mail group list to be alerted to conference times and topics. Participants can connect directly to the conference using Microsoft Outlook Lync or Skype (Redmond, WA) and see the slides in real time on their computer as they listen to the presentation. The presentations are recorded, and the slides with audio can be accessed easily on the VA ECHO SharePoint site for download, enabling VA staff to listen to conferences at their convenience (Figure).

VA Cancer ECHO

The impetus to create a series of talks related to cancer care using VA ECHO was the frequent and often time-consuming requests we received from colleagues at other VA sites for information about areas of cancer care, such as survivorship and cancer care coordination. It was felt that presenting cancer care information as a VA ECHO series would make this information available to a large group of providers at one time, making the method more time effective than sharing the information via one-on-one conversations.

The cancer care coordinator originally conceived this as a 3-part, 1-time series to present work done at VACT in the areas of survivorship, psychosocial distress monitoring, and coordination of cancer care using the VA Cancer Care Tracking System, an online tracking tool. Information about the series was disseminated via VA group e-mail lists for oncology providers and via the existing VA ECHO subscriber invitation process. The 3-presentation series garnered positive feedback and had attendance that ranged from 49 to 75 participants (mean, 60). Participants expressed enthusiasm for the format via e-mail and phone feedback directly to the West Haven staff.

Expansion

The success of this original 3-part series led to a trial of an ongoing Cancer Care Conference series (Conference) using VA ECHO. This was a novel use of VA ECHO and was outside its traditional format, which is geared to discussion of individual cases and clinical knowledge. Nevertheless, this new style of communication has been embraced by a wide range of VA cancer care professionals.

One reason we considered expanding the program was that oncology fit the framework of the original Project ECHO knowledge network model. Cancer is common at the VA, which cares for 175,000 patients with cancer annually.² The management of cancer is complex involving many disciplines working together, and treatments are constantly changing. In addition, cancer has a high societal impact; there are serious outcomes both in terms of patient survival and patient symptom burden. And lastly, outcomes are improved with proactive disease management that is informed by the most current, evidence-based medicine.

The Conference was conceived as a forum for providers across disciplines to share best practices and discuss common challenges in caring for veterans with cancer. We invited participants to submit proposals for presentations related to cancer care initiatives at their VA sites. Potential speakers across all areas of care for veterans with cancer were invited to submit possible topics for the conference. The submissions were reviewed by the moderators in an effort to create a series of talks on a variety of topics across all aspects of care for oncology patients in the VA. This process of effectively crowd-sourcing educational content inspires providers to think more creatively about their practice and quality improvement projects and has sparked an ongoing dialogue about quality initiatives among VA oncology providers across disciplines and geographic locations. As a result, this approach also has enabled participants to learn from colleagues who work at a wide range of rural and urban VA locations throughout the country and to network with colleagues who are working on similar quality initiatives and challenges related to caring for veterans with cancer.

Program

The first Conference talk was in October 2016. It encompassed ten 1-hour talks during the 2016 to 2017 academic year. Speakers were recruited from the VACT West Haven campus and from several other VA sites nationwide. Topics included survivorship, psychosocial distress, palliative care, cancer navigation, and establishing a clinical trials program.

In its first year, the Conference series had 260 unique attendees representing such disciplines as medicine, nursing, social work, pharmacy, psychology, and clinic administration and representing all 21 Veterans Integrated Services Networks (VISNs). Speakers including oncologists, hepatologists, cancer care coordinators, health psychologists, and a research coordinator gave presentations on psychosocial distress screening and issues, cognitive behavioral therapy for cancer pain, cancer navigation, cancer case tracking, VISN-based liver cancer tumor tracker and liver tumor board, starting a VA-based clinical trial, palliative care, and survivorship.

The Conference accounted for 508 continuing medical education (CME) hours, which accounted for one-third of the total CME hours generated by the VACT West Haven VA ECHO program. Highlights of the talks were presented at the 2017 Association of VA Hematology/Oncology annual meeting in Denver, Colorado.

During the second year of the Conference, speakers were recruited to address new American College of Surgeons Commission on Cancer (CoC) requirements regarding survivorship treatment summaries for a subset of cancer survivors.³ The focus on survivorship was driven by ongoing feedback from participants who were working on initiatives to implement this process at their VA sites and wanted to learn from peers involved in this process throughout the VA system. Several speakers gave talks on implementing survivorship care at their VA and specifically on the use of computerized patient record system templates to create survivorship treatment summaries for veterans in accordance with CoC standards.

Since the first Conference in 2016, the number of unique attendees grew by 20% to 327 in 2018. During its first 2 years, participants have earned a total of 1,095 CME credits through Yale University CME. Conferences are usually broadcast at noon eastern time so that providers can take advantage of sessions during lunch breaks.

Participant Surveys

Attendees were invited to participate in voluntary, anonymous surveys to obtain feedback on and to receive input on topics of interest for future talks. Participants also were asked to comment on resources that they utilized to be updated on practice changes (Table 1). 

The Conference has led to increased awareness of other continuing education opportunities available through VA ECHO-Connecticut. Of survey participants, 20% reported that they had attended other VA ECHO conferences.

The survey samples are self-selecting and may not necessarily be representative of the Conference participants or of the VA oncology interdisciplinary team as a whole; however, the relatively large number of survey participants provides some confidence that these survey results can help inform future planning for this and other continuing education opportunities for VA oncology providers.

An additional online survey was designed to elucidate whether participants were incorporating knowledge gained from the Conference in their cancer care practice. Half of the 32 participants strongly agreed with the following statement: “Participation in the VA Cancer Care Conference has added to my knowledge of information relevant to my practice,” and 13 more agreed with the statement for a total of 90.6% of those surveyed responding affirmatively. Only 3 participants neither agreed nor disagreed, and none disagreed with the statement. More than half of the participants reported that they made changes to their practice or plan to make changes as a result of the Conference.

Conculsion

The VA ECHO program established at the VACT West Haven campus in 2012 now offers regular monthly or bimonthly conferences in 9 specialties: pain, liver/hepatitis C, neurology, nephrology, cardiology, diabetes/endocrinology, mental health and addiction, nursing grand rounds, and cancer care. The VACT ECHO program is led by a medical director, and each specialty has a clinical director who conducts sessions and recruits other specialists from their department.

Teleconferencing can provide opportunities for colleagues living in distant locations to connect; share best practices, common goals, and challenges; and initiate ongoing and lasting relationships. The Conference draws the most diverse audience by discipline of all the VA ECHO conferences hosted at VACT (Table 2). 

Traditionally, the national VA ECHO program has been a forum for specialists to discuss clinical case presentations for the benefit of primary care providers and to deliver didactics about chronic clinical conditions. Our Cancer Care Management VA ECHO has explored new ground by discussing material that has helped sites set up and enhance cancer care clinics and disseminate best practices for cancer survivorship and other aspects of cancer care. As a result, this conference has attracted and provided a forum for the most diverse audience of staff among VA ECHO clinics, with participation from clinic administrators to social workers to primary care providers to tumor registrars.

Through the creation of the Conference, > 300 individuals who care for veterans with cancer have been provided with a regular forum at which to connect with colleagues, receive updates on new treatment options for their patients, and learn about and share best practices specific to VA oncology patients. The VA ECHO technology creates a resource that can be accessed by all VA staff from their desktop computer. The VA ECHO SharePoint saves the slides of the Conference presentations both with and without audio to enable staff who can’t participate in real time to access the information at their convenience.

The Conference has facilitated networking among VA oncology providers who have common interests. Conference participants also have participated in other VA ECHO conferences in disciplines beyond oncology. Participants in the Conference also are encouraged to participate as speakers by presenting quality improvement initiatives at their VA site. This novel approach to generating content for this educational series has led to a dynamic interchange of ideas and increased networking among VA providers related to their practice and quality improvement initiatives at their VA sites. The Conference provides a regular forum for VA staff across a wide range of disciplines to share personal experiences, successes, and frustrations and to get feedback from colleagues.

The Conference combines a structured approach to presenting VA-specific educational content related to cancer care and multiple mechanisms that encourage staff to participate in an ongoing dialogue related to quality initiatives both on the phone during the Conference, online using Outlook LYNC or Skype to ask questions during the Conference, and during conversations on group e-mail. The Conference promotes staff engagement at little or no extra cost to the VA. For more information about the VA ECHO Cancer Care Conference or to submit a presentation for consideration for a future session, please contact julie.beck@va.gov or pradeep.mutalik@va.gov.

In 2016, the Cancer Care Coordinator at the US Department of Veterans Affairs (VA) Connecticut Healthcare System (VACT) in West Haven partnered with the VA New England Healthcare System to use its telementoring program. The VA Specialty Care Access Network Extension for Community Healthcare Outcomes (VA ECHO) was used to present a series of educational conferences on cancer care. This article describes our experience implementing the program and reviews participant feedback gathered from voluntary surveys.

Background

In 2011, the Veterans Health Administration (VHA) Office of Healthcare Transformation launched VA ECHO, a telementoring program for primary care providers (PCPs) and patient-aligned care team staff. VACT was selected as 1 of 7 hub sites across the US. The VA ECHO system uses video and online technology to provide PCPs with case-based specialist consultation and didactic education. The system enables providers at any VA location to participate in online and telephone conferences in real time. The presentations are recorded and made available online to VA providers through a secure site.

VA ECHO is based on the highly successful Project ECHO model established by Sanjeev Arora and the University of New Mexico in 2007.¹ The rationale for Project ECHO was that patient care could be improved by increasing the competence of PCPs in the management of complex diseases by providing access to disease specialists through a case-based learning approach that used technology, which it termed knowledge networks, to connect the PCPs to specialists.

The original model addressed management of hepatitis C in a medically underserved area where half of the population was widely geographically dispersed, making the provision of specialty care challenging. Developers identified 6 characteristics that make a disease appropriate for treatment using the Project ECHO knowledge network model:

• The disease is common;
• Management of the disease is complex;
• Treatment for the disease is evolving;
• The disease has a high societal impact;
• There are serious outcomes if the disease is not treated; and
• Disease management improves outcomes.¹

VA ECHO conferences are available to all VA personnel. Staff can subscribe to an e-mail group list to be alerted to conference times and topics. Participants can connect directly to the conference using Microsoft Outlook Lync or Skype (Redmond, WA) and see the slides in real time on their computer as they listen to the presentation. The presentations are recorded, and the slides with audio can be accessed easily on the VA ECHO SharePoint site for download, enabling VA staff to listen to conferences at their convenience (Figure).

VA Cancer ECHO

The impetus to create a series of talks related to cancer care using VA ECHO was the frequent and often time-consuming requests we received from colleagues at other VA sites for information about areas of cancer care, such as survivorship and cancer care coordination. It was felt that presenting cancer care information as a VA ECHO series would make this information available to a large group of providers at one time, making the method more time effective than sharing the information via one-on-one conversations.

The cancer care coordinator originally conceived this as a 3-part, 1-time series to present work done at VACT in the areas of survivorship, psychosocial distress monitoring, and coordination of cancer care using the VA Cancer Care Tracking System, an online tracking tool. Information about the series was disseminated via VA group e-mail lists for oncology providers and via the existing VA ECHO subscriber invitation process. The 3-presentation series garnered positive feedback and had attendance that ranged from 49 to 75 participants (mean, 60). Participants expressed enthusiasm for the format via e-mail and phone feedback directly to the West Haven staff.

Expansion

The success of this original 3-part series led to a trial of an ongoing Cancer Care Conference series (Conference) using VA ECHO. This was a novel use of VA ECHO and was outside its traditional format, which is geared to discussion of individual cases and clinical knowledge. Nevertheless, this new style of communication has been embraced by a wide range of VA cancer care professionals.

One reason we considered expanding the program was that oncology fit the framework of the original Project ECHO knowledge network model. Cancer is common at the VA, which cares for 175,000 patients with cancer annually.² The management of cancer is complex involving many disciplines working together, and treatments are constantly changing. In addition, cancer has a high societal impact; there are serious outcomes both in terms of patient survival and patient symptom burden. And lastly, outcomes are improved with proactive disease management that is informed by the most current, evidence-based medicine.

The Conference was conceived as a forum for providers across disciplines to share best practices and discuss common challenges in caring for veterans with cancer. We invited participants to submit proposals for presentations related to cancer care initiatives at their VA sites. Potential speakers across all areas of care for veterans with cancer were invited to submit possible topics for the conference. The submissions were reviewed by the moderators in an effort to create a series of talks on a variety of topics across all aspects of care for oncology patients in the VA. This process of effectively crowd-sourcing educational content inspires providers to think more creatively about their practice and quality improvement projects and has sparked an ongoing dialogue about quality initiatives among VA oncology providers across disciplines and geographic locations. As a result, this approach also has enabled participants to learn from colleagues who work at a wide range of rural and urban VA locations throughout the country and to network with colleagues who are working on similar quality initiatives and challenges related to caring for veterans with cancer.

Program

The first Conference talk was in October 2016. It encompassed ten 1-hour talks during the 2016 to 2017 academic year. Speakers were recruited from the VACT West Haven campus and from several other VA sites nationwide. Topics included survivorship, psychosocial distress, palliative care, cancer navigation, and establishing a clinical trials program.

In its first year, the Conference series had 260 unique attendees representing such disciplines as medicine, nursing, social work, pharmacy, psychology, and clinic administration and representing all 21 Veterans Integrated Services Networks (VISNs). Speakers including oncologists, hepatologists, cancer care coordinators, health psychologists, and a research coordinator gave presentations on psychosocial distress screening and issues, cognitive behavioral therapy for cancer pain, cancer navigation, cancer case tracking, VISN-based liver cancer tumor tracker and liver tumor board, starting a VA-based clinical trial, palliative care, and survivorship.

The Conference accounted for 508 continuing medical education (CME) hours, which accounted for one-third of the total CME hours generated by the VACT West Haven VA ECHO program. Highlights of the talks were presented at the 2017 Association of VA Hematology/Oncology annual meeting in Denver, Colorado.

During the second year of the Conference, speakers were recruited to address new American College of Surgeons Commission on Cancer (CoC) requirements regarding survivorship treatment summaries for a subset of cancer survivors.³ The focus on survivorship was driven by ongoing feedback from participants who were working on initiatives to implement this process at their VA sites and wanted to learn from peers involved in this process throughout the VA system. Several speakers gave talks on implementing survivorship care at their VA and specifically on the use of computerized patient record system templates to create survivorship treatment summaries for veterans in accordance with CoC standards.

Since the first Conference in 2016, the number of unique attendees grew by 20% to 327 in 2018. During its first 2 years, participants have earned a total of 1,095 CME credits through Yale University CME. Conferences are usually broadcast at noon eastern time so that providers can take advantage of sessions during lunch breaks.

Participant Surveys

Attendees were invited to participate in voluntary, anonymous surveys to obtain feedback on and to receive input on topics of interest for future talks. Participants also were asked to comment on resources that they utilized to be updated on practice changes (Table 1). 

The Conference has led to increased awareness of other continuing education opportunities available through VA ECHO-Connecticut. Of survey participants, 20% reported that they had attended other VA ECHO conferences.

The survey samples are self-selecting and may not necessarily be representative of the Conference participants or of the VA oncology interdisciplinary team as a whole; however, the relatively large number of survey participants provides some confidence that these survey results can help inform future planning for this and other continuing education opportunities for VA oncology providers.

An additional online survey was designed to elucidate whether participants were incorporating knowledge gained from the Conference in their cancer care practice. Half of the 32 participants strongly agreed with the following statement: “Participation in the VA Cancer Care Conference has added to my knowledge of information relevant to my practice,” and 13 more agreed with the statement for a total of 90.6% of those surveyed responding affirmatively. Only 3 participants neither agreed nor disagreed, and none disagreed with the statement. More than half of the participants reported that they made changes to their practice or plan to make changes as a result of the Conference.

Conculsion

The VA ECHO program established at the VACT West Haven campus in 2012 now offers regular monthly or bimonthly conferences in 9 specialties: pain, liver/hepatitis C, neurology, nephrology, cardiology, diabetes/endocrinology, mental health and addiction, nursing grand rounds, and cancer care. The VACT ECHO program is led by a medical director, and each specialty has a clinical director who conducts sessions and recruits other specialists from their department.

Teleconferencing can provide opportunities for colleagues living in distant locations to connect; share best practices, common goals, and challenges; and initiate ongoing and lasting relationships. The Conference draws the most diverse audience by discipline of all the VA ECHO conferences hosted at VACT (Table 2). 

Traditionally, the national VA ECHO program has been a forum for specialists to discuss clinical case presentations for the benefit of primary care providers and to deliver didactics about chronic clinical conditions. Our Cancer Care Management VA ECHO has explored new ground by discussing material that has helped sites set up and enhance cancer care clinics and disseminate best practices for cancer survivorship and other aspects of cancer care. As a result, this conference has attracted and provided a forum for the most diverse audience of staff among VA ECHO clinics, with participation from clinic administrators to social workers to primary care providers to tumor registrars.

Through the creation of the Conference, > 300 individuals who care for veterans with cancer have been provided with a regular forum at which to connect with colleagues, receive updates on new treatment options for their patients, and learn about and share best practices specific to VA oncology patients. The VA ECHO technology creates a resource that can be accessed by all VA staff from their desktop computer. The VA ECHO SharePoint saves the slides of the Conference presentations both with and without audio to enable staff who can’t participate in real time to access the information at their convenience.

The Conference has facilitated networking among VA oncology providers who have common interests. Conference participants also have participated in other VA ECHO conferences in disciplines beyond oncology. Participants in the Conference also are encouraged to participate as speakers by presenting quality improvement initiatives at their VA site. This novel approach to generating content for this educational series has led to a dynamic interchange of ideas and increased networking among VA providers related to their practice and quality improvement initiatives at their VA sites. The Conference provides a regular forum for VA staff across a wide range of disciplines to share personal experiences, successes, and frustrations and to get feedback from colleagues.

The Conference combines a structured approach to presenting VA-specific educational content related to cancer care and multiple mechanisms that encourage staff to participate in an ongoing dialogue related to quality initiatives both on the phone during the Conference, online using Outlook LYNC or Skype to ask questions during the Conference, and during conversations on group e-mail. The Conference promotes staff engagement at little or no extra cost to the VA. For more information about the VA ECHO Cancer Care Conference or to submit a presentation for consideration for a future session, please contact julie.beck@va.gov or pradeep.mutalik@va.gov.

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide.¹ Liver cancer is the fifth most common cancer in men and the seventh in women.² The highest incidence rates are in sub-Saharan Africa and Southeast Asia where hepatitis B virus is endemic. The incidence of HCC in western countries is increasing, particularly due to the rise of hepatitis C virus (HCV) as well as alcoholic liver disease and nonalcoholic fatty liver disease. The incidence of HCC has tripled in the US in the past 2 decades.^1-3

HCC can be diagnosed by radiographic images without the need for biopsy if the typical imaging features are present.³ The European Association for the Study of Liver Disease (EASL) and the American Association for the Study of Liver Diseases (AASLD) recommend screening abdominal ultrasonography at 6-month intervals for high-risk patients.^3,4 High-risk patients include patients with cirrhosis, especially those with hepatitis B or C.³

If screening ultrasonography detects a nodule, size determines whether a follow-up ultrasound is needed vs obtaining a contrast-enhanced dynamic computed tomography (CT) scan or a magnetic resonance image (MRI).³ If ultrasonography detects a nodule > 1 cm in diameter, then a dynamic CT or MRI is performed. Characteristic hyperenhancement during later arterial phase and washout during the venous or delayed phase is associated with a nearly 100% specificity for HCC diagnosis.⁵ Arterial-enhancing contrast is required when using CT and MRI because HCC is a hypervascular lesion.⁶ The portal venous blood dilutes the majority of the liver’s arterial blood; therefore, the liver does not enhance during the arterial phase, while HCC will show maximum enhancement.⁷ Furthermore, HCC should demonstrate a “washout” of contrast during the venous phase on CT and MRI.⁴ Standard imaging protocol dictates that 4 phases are needed to properly diagnose HCC including unenhanced, arterial, venous, and delayed.⁴

Regular surveillance increases the likelihood of detecting HCC before the presentation of clinical symptoms and facilitates receipt of curative therapy.^8-10 Patients with viral hepatitis and cirrhosis with HCC found on screening are more likely to have earlier-stage disease and survive longer from the time of diagnosis.¹¹ Furthermore, it has been observed that HCC detected by surveillance is significantly more likely to undergo curative therapy compared with incidental or symptomatic detection of HCC.⁹

Technical improvements in imaging techniques include advancement in contrast agents, multidetector row helical CT, and the flexibility/range of pulse sequences available in MRI.⁷ Even with technical improvements in all modalities used in HCC imaging, detecting HCC remains difficult, especially when detecting the small (< 2 cm) lesions in a cirrhotic liver.⁷ Interpretation of imaging also remains a challenge as HCC does not always fit strict criteria: lack of “washout” in a hypervascular lesion, determining small HCC lesions from benign nodules, and hypovascular/isovascular HCC.⁵ Radiologic differentials in the diagnosis of HCC include transient hepatic intensity difference (THID)/transient hepatic attenuation difference (THAD), arterio-portal shunt, and regenerative nodules.¹² In the common clinical setting, patients undergo multiple imaging studies that are interpreted by multiple radiologists, which can add to the difficulty in the diagnosis of HCC.¹³

The radiology community recognized the inconsistencies and complexities of HCC imaging. Therefore, the American College of Radiology endorsed the Liver Imaging Reporting and Data System (LI-RADS), which had the goal of reducing variability in lesion interpretation through standardization and improving communication with clinicians.¹⁴ LI-RADS uses a diagnostic algorithm for CT and MRI that categorizes observed liver findings in high-risk individuals based on the probability or relative risk of HCC without assigning a formal diagnosis.¹⁴ LI-RADS takes into account arterial phase enhancement, tumor size, washout appearance, the presence and nature of a capsule, and threshold growth.¹⁵ LI-RADS categorizes an observed liver finding on a scale of 1 to 5, with 1 corresponding to a definitely benign finding and 5 with definitive HCC.¹⁴ Furthermore, LI-RADS sought to limit the technical variabilities among institutions.

LI-RADS was launched in 2011 and has been utilized by many clinical practices while continuing to be expanded and updated.¹⁶ Recent studies examined the specificity of LI-RADS as well as interreader variability.^17,18 For nodules viewed on MRI, both LI-RADS categories 4 and 5 had high specificity for HCC.¹⁷ When looking at interreader repeatability, LI-RADS showed moderate agreement among experts using the diagnostic algorithm.¹⁹ Further studies have compared LI-RADS with the AASLD guidelines and the Organ Procurement and Transplantation Network (OPTN) guidelines.¹⁶ When compared with other guidelines, LI-RADS expands the definition of indeterminate findings into probably benign, intermediate probability of HCC, and probably HCC, which corresponds to LI-RADS categories 2, 3, and 4.¹⁶

We looked retrospectively at a group of patients previously diagnosed with HCC to see whether utilizing the LI-RADS scoring system within our screening system might have allowed an earlier prediction of HCC and a timelier intervention. Prior to this investigation the LI-RADS system was not used for HCC screening at our US Department of Veterans Affairs (VA) facility. We examined screened patients at the Memphis VA Medical Center (MVAMC) in Tennessee who were subsequently diagnosed with HCC to see which LI-RADS category the last surveillance CT prior to diagnosis would fall into, 6 months to a year prior to the diagnosis of HCC. Our control population was a group of patients screened with CT for their liver nodules who were found not to have HCC.

Methods

Patients at MVAMC with cirrhosis and patients with chronic hepatitis B are routinely screened with ultrasound, CT, or MRI in accordance with the AASLD, EASL, and VA guidelines. Of 303 patients with HCV and cirrhosis under care in 2015, 242 (81%) received imaging to screen for HCC according to the VA National Hepatitis C Registry 2015 (Personal Communication, Population Health Service, Office of Patient Care Services).The LI-RADS scoring system was not applied as a standard screening methodology.

Under an institutional review board-approved protocol, we reviewed the charts of all patients diagnosed with HCC at MVAMC from 2009 to 2014, utilizing ICD-9 code of 155.0 for HCC. We identified within these charts patients who had a surveillance CT image performed within a 6- to 13-month period prior to the CTs that diagnosed HCC (prediagnostic HCC CT). Furthermore, we reviewed the charts of all patients diagnosed with benign liver nodules at MVAMC from 2009 to 2014, utilizing the ICD-9 code of 573.8 for other specified disorders of the liver.

Within these charts, we found patients who had a surveillance CT image performed and who were followed after that image with additional imaging for ≥ 2 years or who had a liver biopsy negative for HCC (benign surveillance CT). We compared these 2 sets of CTs utilizing LI-RADS criteria. Once these patients were identified, a list of the CTs to be examined were given to 2 MVAMC radiologists who specialize in CT.

No identifying information of the patients was included, and a 13-digit number unique to each CT exam identified the CTs to be reviewed. Radiologist 1 and 2 examined the CTs on the MVAMC Picture Archiving and Communication System (PACS). Both radiologists were asked to give each nodule a score according to LI-RADS v2014 diagnostic algorithm (Figure).

We hypothesized that the prediagnostic CT images of patients eventually determined to have HCC would have a LI-RADS score of 4 (LR4) or LR5. Furthermore, we hypothesized that the CT images of the benign liver nodule patients would have a score ≤ LR3. If there was a disagreement between the radiologists in terms of a malignant score (LR4 or LR5) vs a benign score (≤ LR3), then a third radiologist (radiologist 3) provided a score for these nodules. The third, tiebreaker radiologist was given the scores of both prior radiologists and asked to choose which score was correct.

Statistical analysis was then applied to the data to determine the sensitivity, specificity, and diagnostic accuracy in diagnosing eventual HCC, as well as the false-negative and false-positive rates of radiologists 1 and 2. Raw data also were used to determine the agreement between raters by calculating the κ statistic with a 95% CI.

Results

A total of 70 nodules were examined by radiologists 1 and 2 with 42 of the nodules in the prediagnostic HCC CTs and 28 of the nodules in the benign surveillance CTs. 

Radiologist 1 identified 11 patients with LR4 and 21 patients with LR5. His scores showed a sensitivity of 64.3% and specificity of 82.1% with accuracy of 71.4% for LI-RADS in identifying eventual HCC. The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 1 was 35.7% and the false-positive rate was 17.9%. Radiologist 2 identified 17 patients LR4 and 19 patients with LR5. Radiologist 2’s scores showed a sensitivity of 69.0% and specificity of 75.0% with accuracy of 71.4% for LI-RADS in identifying eventual HCC.The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 2 was 31.0% and false-positive rate of 25.0%. The κ statistic was calculated to determine the interrater agreement. The radiologists agreed on 58 of 70 samples; 15 without HCC and 43 with HCC. The κ statistic was 0.592, which indicates moderate agreement (Table 2). 

Discussion

If HCC is diagnosed late in the disease process based on symptomatology and not on surveillance imaging, the likelihood of receiving early and potential curative therapy greatly declines as was shown in a systemic literature review.⁹ Surveillance imaging and lesion interpretation by various radiologists has been difficult to standardize as new technologic advances continue to occur in the imaging of HCC.¹⁴ LI-RADS was initiated to help standardize CT and MRI interpretation and reporting of hepatic nodules. As a dynamic algorithm, it continues to adjust with new advances in imaging techniques with the most recent updates being made to the algorithm in 2014.^14,19 LI-RADS applies to patients at high risk for HCC most often who are already enrolled in a surveillance program.¹⁹ The MVAMC has a high incidence of patients with cirrhosis who are at risk for HCC, which is why we chose it as our study population.

LI-RADS can be applied to both MRI and CT imaging. Much of the recent literature have looked at LI-RADS in terms of MRI. A group in China looked at 100 pathologically confirmed patients and assigned a LI-RADS score to the MRI at the time of diagnosis and showed that MRI LI-RADS scoring was highly sensitive and specific in the diagnosis of HCC.²⁰ This study did note a numeric difference in the specificity of LI-RADS algorithm depending on how LR3 scores were viewed. If a LR3 score was considered negative rather than positive for HCC, then the specificity increased by almost 20%.²⁰

Another study looked at patients with liver nodules ≤ 20 mm found on ultrasound and obtained MRIs and biopsies on these patients, assigning the MRI a LI-RADs score.¹⁷ Darnell and colleagues found that MRI LR4 and LR5 have a high specificity for HCC. However, 29 of the 42 LR3 lesions examined were found to be HCC.¹⁷ Furthermore, Choi and colleagues retrospectively looked at patients in a HCC surveillance program who had undergone MRI as part of the program and assigned LI-RADS scores to these MRIs.²¹ Their study showed that LR5 criteria on gadoxetate disodium-enhanced MRI has excellent positive predictive value (PPV) for diagnosing HCC, and LR4 showed good PPV.²¹

In our study, we chose to look at LI-RADS in terms of surveillance CT scans 6 to 13 months prior to the diagnosis of HCC to see whether this method would allow us to intervene earlier with more aggressive diagnostics or therapy in those suspected of having HCC. Although Choi and colleagues looked retrospectively at MRI surveillance imaging, most of the prior studies have looked at LI-RADS scoring in imaging at the time of diagnosis.^17,20,21 By looking at surveillance CT scans, we sought to determine LI-RADS sensitivity, specificity, and diagnostic accuracy as a screening tool compared with CT evaluations without LI-RADS scoring.

We also chose to look at CT scans since most of the prior studies have looked at the more detailed and often more expensive MRIs. For both radiologists 1 and 2, the sensitivity was > 60% and specificity was > 70% with a diagnostic accuracy of 71.4% in predicting a diagnosis of HCC in future scans. Although there was high false negative of > 30% for both radiologists, we did consider LR3 as negative for HCC. As Darnell and colleagues’ study of MRI LI-RADS shows, LR3 may need to be revised in the future as its ambiguity can lead to false-negatives.¹⁷ Our results also showed moderate interreader agreement, which has been seen in previous studies with LI-RADS.¹⁸

Some studies have compared MRI with CT imaging in terms of LI-RADs classification of hepatic nodules to find out whether concordance was seen.^22,23 Both studies found that there was substantial discordance between MRI and CT with CT often underscoring hepatic nodules.^22,23 In Zhang and colleagues, interclass agreement between CT and MRI varied the most in terms of arterial enhancement with CT producing false-negative findings.²² CT also underestimated LI-RADS score by 16.9% for LR3, 37.3% for LR4, and 8.5% for LR5 in this study.²² Furthermore, Corwin and colleagues found a significant upgrade in terms of LI-RADS categorization with MRI for 42.5% of observations.²³ In this study, upgraded LI-RADS scores on MRI included 2 upgraded to LR5V (Figure), 15 upgraded to LR5, and 12 upgraded to LR4.²³ 

Our study shows that the LI-RADS algorithm has a good sensitivity, specificity, and diagnostic accuracy as a screening tool, predicting HCC in scans earlier than standard CT evaluation. In our study, the patients with HCC were shown to have higher LI-RADS scores on prediagnostic imaging, while the benign liver nodule patients were shown to have lower LI-RADS scores. This data would suggest that a LI-RADS score given to surveillance CT of LR4 or higher should recommend either a biopsy or follow-up imaging after a short interval. If LI-RADS is applied to surveillance CTs in patients at risk for HCC, a diagnosis of HCC may be arrived at earlier as compared with not using the LI-RADS algorithm. Earlier detection may lead to earlier intervention and improved treatment outcomes.

Limitations

Limitations to our study occurred because radiologist 3 did not review all of the images nor score them. Radiologist 3 was limited to 12 images where there was disagreement and was limited to 2 scores to choose from for each image. Further limitations include that this study was performed at a single center. Our study focused on one imaging modality and did not include ultrasounds or MRIs. We did not compare the demographics of our patients with those of other VA hospitals. The radiologists interpreted the images individually, and their subjectivity was another limitation.

Conclusion

In the MVAMC population, LI-RADS showed a good sensitivity, specificity, and diagnostic accuracy for CT surveillance scans in patient at high risk for HCC at an earlier time point than did standard evaluation by very experienced CT radiologists. Higher LI-RADS scores on surveillance CTs had good diagnostic accuracy for the probable future diagnosis of HCC, whereas lower LI-RADS scores had a good diagnostic accuracy for probable benign nodules. Utilizing the LI-RADS algorithm on all surveillance CTs in patients at high risk for HCC may lead to obtaining MRIs or follow-up CTs sooner for suspicious nodules, leading to an earlier diagnosis of HCC and possible earlier and more effective intervention.

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide.¹ Liver cancer is the fifth most common cancer in men and the seventh in women.² The highest incidence rates are in sub-Saharan Africa and Southeast Asia where hepatitis B virus is endemic. The incidence of HCC in western countries is increasing, particularly due to the rise of hepatitis C virus (HCV) as well as alcoholic liver disease and nonalcoholic fatty liver disease. The incidence of HCC has tripled in the US in the past 2 decades.^1-3

HCC can be diagnosed by radiographic images without the need for biopsy if the typical imaging features are present.³ The European Association for the Study of Liver Disease (EASL) and the American Association for the Study of Liver Diseases (AASLD) recommend screening abdominal ultrasonography at 6-month intervals for high-risk patients.^3,4 High-risk patients include patients with cirrhosis, especially those with hepatitis B or C.³

If screening ultrasonography detects a nodule, size determines whether a follow-up ultrasound is needed vs obtaining a contrast-enhanced dynamic computed tomography (CT) scan or a magnetic resonance image (MRI).³ If ultrasonography detects a nodule > 1 cm in diameter, then a dynamic CT or MRI is performed. Characteristic hyperenhancement during later arterial phase and washout during the venous or delayed phase is associated with a nearly 100% specificity for HCC diagnosis.⁵ Arterial-enhancing contrast is required when using CT and MRI because HCC is a hypervascular lesion.⁶ The portal venous blood dilutes the majority of the liver’s arterial blood; therefore, the liver does not enhance during the arterial phase, while HCC will show maximum enhancement.⁷ Furthermore, HCC should demonstrate a “washout” of contrast during the venous phase on CT and MRI.⁴ Standard imaging protocol dictates that 4 phases are needed to properly diagnose HCC including unenhanced, arterial, venous, and delayed.⁴

Regular surveillance increases the likelihood of detecting HCC before the presentation of clinical symptoms and facilitates receipt of curative therapy.^8-10 Patients with viral hepatitis and cirrhosis with HCC found on screening are more likely to have earlier-stage disease and survive longer from the time of diagnosis.¹¹ Furthermore, it has been observed that HCC detected by surveillance is significantly more likely to undergo curative therapy compared with incidental or symptomatic detection of HCC.⁹

Technical improvements in imaging techniques include advancement in contrast agents, multidetector row helical CT, and the flexibility/range of pulse sequences available in MRI.⁷ Even with technical improvements in all modalities used in HCC imaging, detecting HCC remains difficult, especially when detecting the small (< 2 cm) lesions in a cirrhotic liver.⁷ Interpretation of imaging also remains a challenge as HCC does not always fit strict criteria: lack of “washout” in a hypervascular lesion, determining small HCC lesions from benign nodules, and hypovascular/isovascular HCC.⁵ Radiologic differentials in the diagnosis of HCC include transient hepatic intensity difference (THID)/transient hepatic attenuation difference (THAD), arterio-portal shunt, and regenerative nodules.¹² In the common clinical setting, patients undergo multiple imaging studies that are interpreted by multiple radiologists, which can add to the difficulty in the diagnosis of HCC.¹³

The radiology community recognized the inconsistencies and complexities of HCC imaging. Therefore, the American College of Radiology endorsed the Liver Imaging Reporting and Data System (LI-RADS), which had the goal of reducing variability in lesion interpretation through standardization and improving communication with clinicians.¹⁴ LI-RADS uses a diagnostic algorithm for CT and MRI that categorizes observed liver findings in high-risk individuals based on the probability or relative risk of HCC without assigning a formal diagnosis.¹⁴ LI-RADS takes into account arterial phase enhancement, tumor size, washout appearance, the presence and nature of a capsule, and threshold growth.¹⁵ LI-RADS categorizes an observed liver finding on a scale of 1 to 5, with 1 corresponding to a definitely benign finding and 5 with definitive HCC.¹⁴ Furthermore, LI-RADS sought to limit the technical variabilities among institutions.

LI-RADS was launched in 2011 and has been utilized by many clinical practices while continuing to be expanded and updated.¹⁶ Recent studies examined the specificity of LI-RADS as well as interreader variability.^17,18 For nodules viewed on MRI, both LI-RADS categories 4 and 5 had high specificity for HCC.¹⁷ When looking at interreader repeatability, LI-RADS showed moderate agreement among experts using the diagnostic algorithm.¹⁹ Further studies have compared LI-RADS with the AASLD guidelines and the Organ Procurement and Transplantation Network (OPTN) guidelines.¹⁶ When compared with other guidelines, LI-RADS expands the definition of indeterminate findings into probably benign, intermediate probability of HCC, and probably HCC, which corresponds to LI-RADS categories 2, 3, and 4.¹⁶

We looked retrospectively at a group of patients previously diagnosed with HCC to see whether utilizing the LI-RADS scoring system within our screening system might have allowed an earlier prediction of HCC and a timelier intervention. Prior to this investigation the LI-RADS system was not used for HCC screening at our US Department of Veterans Affairs (VA) facility. We examined screened patients at the Memphis VA Medical Center (MVAMC) in Tennessee who were subsequently diagnosed with HCC to see which LI-RADS category the last surveillance CT prior to diagnosis would fall into, 6 months to a year prior to the diagnosis of HCC. Our control population was a group of patients screened with CT for their liver nodules who were found not to have HCC.

Methods

Patients at MVAMC with cirrhosis and patients with chronic hepatitis B are routinely screened with ultrasound, CT, or MRI in accordance with the AASLD, EASL, and VA guidelines. Of 303 patients with HCV and cirrhosis under care in 2015, 242 (81%) received imaging to screen for HCC according to the VA National Hepatitis C Registry 2015 (Personal Communication, Population Health Service, Office of Patient Care Services).The LI-RADS scoring system was not applied as a standard screening methodology.

Under an institutional review board-approved protocol, we reviewed the charts of all patients diagnosed with HCC at MVAMC from 2009 to 2014, utilizing ICD-9 code of 155.0 for HCC. We identified within these charts patients who had a surveillance CT image performed within a 6- to 13-month period prior to the CTs that diagnosed HCC (prediagnostic HCC CT). Furthermore, we reviewed the charts of all patients diagnosed with benign liver nodules at MVAMC from 2009 to 2014, utilizing the ICD-9 code of 573.8 for other specified disorders of the liver.

Within these charts, we found patients who had a surveillance CT image performed and who were followed after that image with additional imaging for ≥ 2 years or who had a liver biopsy negative for HCC (benign surveillance CT). We compared these 2 sets of CTs utilizing LI-RADS criteria. Once these patients were identified, a list of the CTs to be examined were given to 2 MVAMC radiologists who specialize in CT.

No identifying information of the patients was included, and a 13-digit number unique to each CT exam identified the CTs to be reviewed. Radiologist 1 and 2 examined the CTs on the MVAMC Picture Archiving and Communication System (PACS). Both radiologists were asked to give each nodule a score according to LI-RADS v2014 diagnostic algorithm (Figure).

We hypothesized that the prediagnostic CT images of patients eventually determined to have HCC would have a LI-RADS score of 4 (LR4) or LR5. Furthermore, we hypothesized that the CT images of the benign liver nodule patients would have a score ≤ LR3. If there was a disagreement between the radiologists in terms of a malignant score (LR4 or LR5) vs a benign score (≤ LR3), then a third radiologist (radiologist 3) provided a score for these nodules. The third, tiebreaker radiologist was given the scores of both prior radiologists and asked to choose which score was correct.

Statistical analysis was then applied to the data to determine the sensitivity, specificity, and diagnostic accuracy in diagnosing eventual HCC, as well as the false-negative and false-positive rates of radiologists 1 and 2. Raw data also were used to determine the agreement between raters by calculating the κ statistic with a 95% CI.

Results

A total of 70 nodules were examined by radiologists 1 and 2 with 42 of the nodules in the prediagnostic HCC CTs and 28 of the nodules in the benign surveillance CTs. 

Radiologist 1 identified 11 patients with LR4 and 21 patients with LR5. His scores showed a sensitivity of 64.3% and specificity of 82.1% with accuracy of 71.4% for LI-RADS in identifying eventual HCC. The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 1 was 35.7% and the false-positive rate was 17.9%. Radiologist 2 identified 17 patients LR4 and 19 patients with LR5. Radiologist 2’s scores showed a sensitivity of 69.0% and specificity of 75.0% with accuracy of 71.4% for LI-RADS in identifying eventual HCC.The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 2 was 31.0% and false-positive rate of 25.0%. The κ statistic was calculated to determine the interrater agreement. The radiologists agreed on 58 of 70 samples; 15 without HCC and 43 with HCC. The κ statistic was 0.592, which indicates moderate agreement (Table 2). 

Discussion

If HCC is diagnosed late in the disease process based on symptomatology and not on surveillance imaging, the likelihood of receiving early and potential curative therapy greatly declines as was shown in a systemic literature review.⁹ Surveillance imaging and lesion interpretation by various radiologists has been difficult to standardize as new technologic advances continue to occur in the imaging of HCC.¹⁴ LI-RADS was initiated to help standardize CT and MRI interpretation and reporting of hepatic nodules. As a dynamic algorithm, it continues to adjust with new advances in imaging techniques with the most recent updates being made to the algorithm in 2014.^14,19 LI-RADS applies to patients at high risk for HCC most often who are already enrolled in a surveillance program.¹⁹ The MVAMC has a high incidence of patients with cirrhosis who are at risk for HCC, which is why we chose it as our study population.

LI-RADS can be applied to both MRI and CT imaging. Much of the recent literature have looked at LI-RADS in terms of MRI. A group in China looked at 100 pathologically confirmed patients and assigned a LI-RADS score to the MRI at the time of diagnosis and showed that MRI LI-RADS scoring was highly sensitive and specific in the diagnosis of HCC.²⁰ This study did note a numeric difference in the specificity of LI-RADS algorithm depending on how LR3 scores were viewed. If a LR3 score was considered negative rather than positive for HCC, then the specificity increased by almost 20%.²⁰

Another study looked at patients with liver nodules ≤ 20 mm found on ultrasound and obtained MRIs and biopsies on these patients, assigning the MRI a LI-RADs score.¹⁷ Darnell and colleagues found that MRI LR4 and LR5 have a high specificity for HCC. However, 29 of the 42 LR3 lesions examined were found to be HCC.¹⁷ Furthermore, Choi and colleagues retrospectively looked at patients in a HCC surveillance program who had undergone MRI as part of the program and assigned LI-RADS scores to these MRIs.²¹ Their study showed that LR5 criteria on gadoxetate disodium-enhanced MRI has excellent positive predictive value (PPV) for diagnosing HCC, and LR4 showed good PPV.²¹

In our study, we chose to look at LI-RADS in terms of surveillance CT scans 6 to 13 months prior to the diagnosis of HCC to see whether this method would allow us to intervene earlier with more aggressive diagnostics or therapy in those suspected of having HCC. Although Choi and colleagues looked retrospectively at MRI surveillance imaging, most of the prior studies have looked at LI-RADS scoring in imaging at the time of diagnosis.^17,20,21 By looking at surveillance CT scans, we sought to determine LI-RADS sensitivity, specificity, and diagnostic accuracy as a screening tool compared with CT evaluations without LI-RADS scoring.

We also chose to look at CT scans since most of the prior studies have looked at the more detailed and often more expensive MRIs. For both radiologists 1 and 2, the sensitivity was > 60% and specificity was > 70% with a diagnostic accuracy of 71.4% in predicting a diagnosis of HCC in future scans. Although there was high false negative of > 30% for both radiologists, we did consider LR3 as negative for HCC. As Darnell and colleagues’ study of MRI LI-RADS shows, LR3 may need to be revised in the future as its ambiguity can lead to false-negatives.¹⁷ Our results also showed moderate interreader agreement, which has been seen in previous studies with LI-RADS.¹⁸

Some studies have compared MRI with CT imaging in terms of LI-RADs classification of hepatic nodules to find out whether concordance was seen.^22,23 Both studies found that there was substantial discordance between MRI and CT with CT often underscoring hepatic nodules.^22,23 In Zhang and colleagues, interclass agreement between CT and MRI varied the most in terms of arterial enhancement with CT producing false-negative findings.²² CT also underestimated LI-RADS score by 16.9% for LR3, 37.3% for LR4, and 8.5% for LR5 in this study.²² Furthermore, Corwin and colleagues found a significant upgrade in terms of LI-RADS categorization with MRI for 42.5% of observations.²³ In this study, upgraded LI-RADS scores on MRI included 2 upgraded to LR5V (Figure), 15 upgraded to LR5, and 12 upgraded to LR4.²³ 

Our study shows that the LI-RADS algorithm has a good sensitivity, specificity, and diagnostic accuracy as a screening tool, predicting HCC in scans earlier than standard CT evaluation. In our study, the patients with HCC were shown to have higher LI-RADS scores on prediagnostic imaging, while the benign liver nodule patients were shown to have lower LI-RADS scores. This data would suggest that a LI-RADS score given to surveillance CT of LR4 or higher should recommend either a biopsy or follow-up imaging after a short interval. If LI-RADS is applied to surveillance CTs in patients at risk for HCC, a diagnosis of HCC may be arrived at earlier as compared with not using the LI-RADS algorithm. Earlier detection may lead to earlier intervention and improved treatment outcomes.

Limitations

Limitations to our study occurred because radiologist 3 did not review all of the images nor score them. Radiologist 3 was limited to 12 images where there was disagreement and was limited to 2 scores to choose from for each image. Further limitations include that this study was performed at a single center. Our study focused on one imaging modality and did not include ultrasounds or MRIs. We did not compare the demographics of our patients with those of other VA hospitals. The radiologists interpreted the images individually, and their subjectivity was another limitation.

Conclusion

In the MVAMC population, LI-RADS showed a good sensitivity, specificity, and diagnostic accuracy for CT surveillance scans in patient at high risk for HCC at an earlier time point than did standard evaluation by very experienced CT radiologists. Higher LI-RADS scores on surveillance CTs had good diagnostic accuracy for the probable future diagnosis of HCC, whereas lower LI-RADS scores had a good diagnostic accuracy for probable benign nodules. Utilizing the LI-RADS algorithm on all surveillance CTs in patients at high risk for HCC may lead to obtaining MRIs or follow-up CTs sooner for suspicious nodules, leading to an earlier diagnosis of HCC and possible earlier and more effective intervention.

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide.¹ Liver cancer is the fifth most common cancer in men and the seventh in women.² The highest incidence rates are in sub-Saharan Africa and Southeast Asia where hepatitis B virus is endemic. The incidence of HCC in western countries is increasing, particularly due to the rise of hepatitis C virus (HCV) as well as alcoholic liver disease and nonalcoholic fatty liver disease. The incidence of HCC has tripled in the US in the past 2 decades.^1-3

HCC can be diagnosed by radiographic images without the need for biopsy if the typical imaging features are present.³ The European Association for the Study of Liver Disease (EASL) and the American Association for the Study of Liver Diseases (AASLD) recommend screening abdominal ultrasonography at 6-month intervals for high-risk patients.^3,4 High-risk patients include patients with cirrhosis, especially those with hepatitis B or C.³

If screening ultrasonography detects a nodule, size determines whether a follow-up ultrasound is needed vs obtaining a contrast-enhanced dynamic computed tomography (CT) scan or a magnetic resonance image (MRI).³ If ultrasonography detects a nodule > 1 cm in diameter, then a dynamic CT or MRI is performed. Characteristic hyperenhancement during later arterial phase and washout during the venous or delayed phase is associated with a nearly 100% specificity for HCC diagnosis.⁵ Arterial-enhancing contrast is required when using CT and MRI because HCC is a hypervascular lesion.⁶ The portal venous blood dilutes the majority of the liver’s arterial blood; therefore, the liver does not enhance during the arterial phase, while HCC will show maximum enhancement.⁷ Furthermore, HCC should demonstrate a “washout” of contrast during the venous phase on CT and MRI.⁴ Standard imaging protocol dictates that 4 phases are needed to properly diagnose HCC including unenhanced, arterial, venous, and delayed.⁴

Regular surveillance increases the likelihood of detecting HCC before the presentation of clinical symptoms and facilitates receipt of curative therapy.^8-10 Patients with viral hepatitis and cirrhosis with HCC found on screening are more likely to have earlier-stage disease and survive longer from the time of diagnosis.¹¹ Furthermore, it has been observed that HCC detected by surveillance is significantly more likely to undergo curative therapy compared with incidental or symptomatic detection of HCC.⁹

Technical improvements in imaging techniques include advancement in contrast agents, multidetector row helical CT, and the flexibility/range of pulse sequences available in MRI.⁷ Even with technical improvements in all modalities used in HCC imaging, detecting HCC remains difficult, especially when detecting the small (< 2 cm) lesions in a cirrhotic liver.⁷ Interpretation of imaging also remains a challenge as HCC does not always fit strict criteria: lack of “washout” in a hypervascular lesion, determining small HCC lesions from benign nodules, and hypovascular/isovascular HCC.⁵ Radiologic differentials in the diagnosis of HCC include transient hepatic intensity difference (THID)/transient hepatic attenuation difference (THAD), arterio-portal shunt, and regenerative nodules.¹² In the common clinical setting, patients undergo multiple imaging studies that are interpreted by multiple radiologists, which can add to the difficulty in the diagnosis of HCC.¹³

The radiology community recognized the inconsistencies and complexities of HCC imaging. Therefore, the American College of Radiology endorsed the Liver Imaging Reporting and Data System (LI-RADS), which had the goal of reducing variability in lesion interpretation through standardization and improving communication with clinicians.¹⁴ LI-RADS uses a diagnostic algorithm for CT and MRI that categorizes observed liver findings in high-risk individuals based on the probability or relative risk of HCC without assigning a formal diagnosis.¹⁴ LI-RADS takes into account arterial phase enhancement, tumor size, washout appearance, the presence and nature of a capsule, and threshold growth.¹⁵ LI-RADS categorizes an observed liver finding on a scale of 1 to 5, with 1 corresponding to a definitely benign finding and 5 with definitive HCC.¹⁴ Furthermore, LI-RADS sought to limit the technical variabilities among institutions.

LI-RADS was launched in 2011 and has been utilized by many clinical practices while continuing to be expanded and updated.¹⁶ Recent studies examined the specificity of LI-RADS as well as interreader variability.^17,18 For nodules viewed on MRI, both LI-RADS categories 4 and 5 had high specificity for HCC.¹⁷ When looking at interreader repeatability, LI-RADS showed moderate agreement among experts using the diagnostic algorithm.¹⁹ Further studies have compared LI-RADS with the AASLD guidelines and the Organ Procurement and Transplantation Network (OPTN) guidelines.¹⁶ When compared with other guidelines, LI-RADS expands the definition of indeterminate findings into probably benign, intermediate probability of HCC, and probably HCC, which corresponds to LI-RADS categories 2, 3, and 4.¹⁶

We looked retrospectively at a group of patients previously diagnosed with HCC to see whether utilizing the LI-RADS scoring system within our screening system might have allowed an earlier prediction of HCC and a timelier intervention. Prior to this investigation the LI-RADS system was not used for HCC screening at our US Department of Veterans Affairs (VA) facility. We examined screened patients at the Memphis VA Medical Center (MVAMC) in Tennessee who were subsequently diagnosed with HCC to see which LI-RADS category the last surveillance CT prior to diagnosis would fall into, 6 months to a year prior to the diagnosis of HCC. Our control population was a group of patients screened with CT for their liver nodules who were found not to have HCC.

Methods

Patients at MVAMC with cirrhosis and patients with chronic hepatitis B are routinely screened with ultrasound, CT, or MRI in accordance with the AASLD, EASL, and VA guidelines. Of 303 patients with HCV and cirrhosis under care in 2015, 242 (81%) received imaging to screen for HCC according to the VA National Hepatitis C Registry 2015 (Personal Communication, Population Health Service, Office of Patient Care Services).The LI-RADS scoring system was not applied as a standard screening methodology.

Under an institutional review board-approved protocol, we reviewed the charts of all patients diagnosed with HCC at MVAMC from 2009 to 2014, utilizing ICD-9 code of 155.0 for HCC. We identified within these charts patients who had a surveillance CT image performed within a 6- to 13-month period prior to the CTs that diagnosed HCC (prediagnostic HCC CT). Furthermore, we reviewed the charts of all patients diagnosed with benign liver nodules at MVAMC from 2009 to 2014, utilizing the ICD-9 code of 573.8 for other specified disorders of the liver.

Within these charts, we found patients who had a surveillance CT image performed and who were followed after that image with additional imaging for ≥ 2 years or who had a liver biopsy negative for HCC (benign surveillance CT). We compared these 2 sets of CTs utilizing LI-RADS criteria. Once these patients were identified, a list of the CTs to be examined were given to 2 MVAMC radiologists who specialize in CT.

No identifying information of the patients was included, and a 13-digit number unique to each CT exam identified the CTs to be reviewed. Radiologist 1 and 2 examined the CTs on the MVAMC Picture Archiving and Communication System (PACS). Both radiologists were asked to give each nodule a score according to LI-RADS v2014 diagnostic algorithm (Figure).

We hypothesized that the prediagnostic CT images of patients eventually determined to have HCC would have a LI-RADS score of 4 (LR4) or LR5. Furthermore, we hypothesized that the CT images of the benign liver nodule patients would have a score ≤ LR3. If there was a disagreement between the radiologists in terms of a malignant score (LR4 or LR5) vs a benign score (≤ LR3), then a third radiologist (radiologist 3) provided a score for these nodules. The third, tiebreaker radiologist was given the scores of both prior radiologists and asked to choose which score was correct.

Statistical analysis was then applied to the data to determine the sensitivity, specificity, and diagnostic accuracy in diagnosing eventual HCC, as well as the false-negative and false-positive rates of radiologists 1 and 2. Raw data also were used to determine the agreement between raters by calculating the κ statistic with a 95% CI.

Results

A total of 70 nodules were examined by radiologists 1 and 2 with 42 of the nodules in the prediagnostic HCC CTs and 28 of the nodules in the benign surveillance CTs. 

Radiologist 1 identified 11 patients with LR4 and 21 patients with LR5. His scores showed a sensitivity of 64.3% and specificity of 82.1% with accuracy of 71.4% for LI-RADS in identifying eventual HCC. The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 1 was 35.7% and the false-positive rate was 17.9%. Radiologist 2 identified 17 patients LR4 and 19 patients with LR5. Radiologist 2’s scores showed a sensitivity of 69.0% and specificity of 75.0% with accuracy of 71.4% for LI-RADS in identifying eventual HCC.The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 2 was 31.0% and false-positive rate of 25.0%. The κ statistic was calculated to determine the interrater agreement. The radiologists agreed on 58 of 70 samples; 15 without HCC and 43 with HCC. The κ statistic was 0.592, which indicates moderate agreement (Table 2). 

Discussion

If HCC is diagnosed late in the disease process based on symptomatology and not on surveillance imaging, the likelihood of receiving early and potential curative therapy greatly declines as was shown in a systemic literature review.⁹ Surveillance imaging and lesion interpretation by various radiologists has been difficult to standardize as new technologic advances continue to occur in the imaging of HCC.¹⁴ LI-RADS was initiated to help standardize CT and MRI interpretation and reporting of hepatic nodules. As a dynamic algorithm, it continues to adjust with new advances in imaging techniques with the most recent updates being made to the algorithm in 2014.^14,19 LI-RADS applies to patients at high risk for HCC most often who are already enrolled in a surveillance program.¹⁹ The MVAMC has a high incidence of patients with cirrhosis who are at risk for HCC, which is why we chose it as our study population.

LI-RADS can be applied to both MRI and CT imaging. Much of the recent literature have looked at LI-RADS in terms of MRI. A group in China looked at 100 pathologically confirmed patients and assigned a LI-RADS score to the MRI at the time of diagnosis and showed that MRI LI-RADS scoring was highly sensitive and specific in the diagnosis of HCC.²⁰ This study did note a numeric difference in the specificity of LI-RADS algorithm depending on how LR3 scores were viewed. If a LR3 score was considered negative rather than positive for HCC, then the specificity increased by almost 20%.²⁰

Another study looked at patients with liver nodules ≤ 20 mm found on ultrasound and obtained MRIs and biopsies on these patients, assigning the MRI a LI-RADs score.¹⁷ Darnell and colleagues found that MRI LR4 and LR5 have a high specificity for HCC. However, 29 of the 42 LR3 lesions examined were found to be HCC.¹⁷ Furthermore, Choi and colleagues retrospectively looked at patients in a HCC surveillance program who had undergone MRI as part of the program and assigned LI-RADS scores to these MRIs.²¹ Their study showed that LR5 criteria on gadoxetate disodium-enhanced MRI has excellent positive predictive value (PPV) for diagnosing HCC, and LR4 showed good PPV.²¹

In our study, we chose to look at LI-RADS in terms of surveillance CT scans 6 to 13 months prior to the diagnosis of HCC to see whether this method would allow us to intervene earlier with more aggressive diagnostics or therapy in those suspected of having HCC. Although Choi and colleagues looked retrospectively at MRI surveillance imaging, most of the prior studies have looked at LI-RADS scoring in imaging at the time of diagnosis.^17,20,21 By looking at surveillance CT scans, we sought to determine LI-RADS sensitivity, specificity, and diagnostic accuracy as a screening tool compared with CT evaluations without LI-RADS scoring.

We also chose to look at CT scans since most of the prior studies have looked at the more detailed and often more expensive MRIs. For both radiologists 1 and 2, the sensitivity was > 60% and specificity was > 70% with a diagnostic accuracy of 71.4% in predicting a diagnosis of HCC in future scans. Although there was high false negative of > 30% for both radiologists, we did consider LR3 as negative for HCC. As Darnell and colleagues’ study of MRI LI-RADS shows, LR3 may need to be revised in the future as its ambiguity can lead to false-negatives.¹⁷ Our results also showed moderate interreader agreement, which has been seen in previous studies with LI-RADS.¹⁸

Some studies have compared MRI with CT imaging in terms of LI-RADs classification of hepatic nodules to find out whether concordance was seen.^22,23 Both studies found that there was substantial discordance between MRI and CT with CT often underscoring hepatic nodules.^22,23 In Zhang and colleagues, interclass agreement between CT and MRI varied the most in terms of arterial enhancement with CT producing false-negative findings.²² CT also underestimated LI-RADS score by 16.9% for LR3, 37.3% for LR4, and 8.5% for LR5 in this study.²² Furthermore, Corwin and colleagues found a significant upgrade in terms of LI-RADS categorization with MRI for 42.5% of observations.²³ In this study, upgraded LI-RADS scores on MRI included 2 upgraded to LR5V (Figure), 15 upgraded to LR5, and 12 upgraded to LR4.²³ 

Our study shows that the LI-RADS algorithm has a good sensitivity, specificity, and diagnostic accuracy as a screening tool, predicting HCC in scans earlier than standard CT evaluation. In our study, the patients with HCC were shown to have higher LI-RADS scores on prediagnostic imaging, while the benign liver nodule patients were shown to have lower LI-RADS scores. This data would suggest that a LI-RADS score given to surveillance CT of LR4 or higher should recommend either a biopsy or follow-up imaging after a short interval. If LI-RADS is applied to surveillance CTs in patients at risk for HCC, a diagnosis of HCC may be arrived at earlier as compared with not using the LI-RADS algorithm. Earlier detection may lead to earlier intervention and improved treatment outcomes.

Limitations

Limitations to our study occurred because radiologist 3 did not review all of the images nor score them. Radiologist 3 was limited to 12 images where there was disagreement and was limited to 2 scores to choose from for each image. Further limitations include that this study was performed at a single center. Our study focused on one imaging modality and did not include ultrasounds or MRIs. We did not compare the demographics of our patients with those of other VA hospitals. The radiologists interpreted the images individually, and their subjectivity was another limitation.

Conclusion

In the MVAMC population, LI-RADS showed a good sensitivity, specificity, and diagnostic accuracy for CT surveillance scans in patient at high risk for HCC at an earlier time point than did standard evaluation by very experienced CT radiologists. Higher LI-RADS scores on surveillance CTs had good diagnostic accuracy for the probable future diagnosis of HCC, whereas lower LI-RADS scores had a good diagnostic accuracy for probable benign nodules. Utilizing the LI-RADS algorithm on all surveillance CTs in patients at high risk for HCC may lead to obtaining MRIs or follow-up CTs sooner for suspicious nodules, leading to an earlier diagnosis of HCC and possible earlier and more effective intervention.

The US Food and Drug Administration (FDA) issued an emergency use authorization on May 1 for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.

The investigational antiviral drug, manufactured by Gilead Sciences Inc., was shown in a preliminary analysis of a National Institutes of Health (NIH) clinical trial to shorten recovery time in some patients, according to information presented during a White House press conference earlier this week. However, the results of the trial have not been published and little is known about how safe and effective it is in treating people in the hospital with COVID-19.

The emergency use authorization (EUA) designation means remdesivir can be distributed in the United States and administered intravenously by healthcare providers, as appropriate to treat severe disease. Those with severe disease, the FDA said in a press release, are patients with low blood oxygen levels or those who need oxygen therapy or more intensive support such as a mechanical ventilator.

“There’s tremendous interest among all parties to identify and arm ourselves with medicines to combat COVID-19, and through our Coronavirus Treatment Acceleration Program, the FDA is working around-the-clock and using every tool at our disposal to speed these efforts,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

The FDA writes, “Based on evaluation of the emergency use authorization criteria and the scientific evidence available, it was determined that it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, given there are no adequate, approved, or available alternative treatments, the known and potential benefits to treat this serious or life-threatening virus currently outweigh the known and potential risks of the drug’s use.”

The drug must be administered intravenously and the optimal dosing and duration are not yet known, the company said in a press release issued May 1.

In addition, Gilead advises that infusion-related reactions and liver transaminase elevations have been seen in patients treated with the drug.

“If signs and symptoms of a clinically significant infusion reaction occur, immediately discontinue administration of remdesivir and initiate appropriate treatment. Patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events. Monitor renal and hepatic function prior to initiating and daily during therapy with remdesivir; additionally monitor serum chemistries and hematology daily during therapy,” the company said.

Before granting the emergency use authorization, the FDA had allowed for study of the drug in clinical trials, as well as expanded access use for individual patients and through a multipatient expanded access program coordinated by Gilead.

“The EUA will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biologics for prevention and treatment of COVID-19 is terminated and may be revised or revoked if it is determined the EUA no longer meets the statutory criteria for issuance,” the FDA said.


This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) issued an emergency use authorization on May 1 for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.

The investigational antiviral drug, manufactured by Gilead Sciences Inc., was shown in a preliminary analysis of a National Institutes of Health (NIH) clinical trial to shorten recovery time in some patients, according to information presented during a White House press conference earlier this week. However, the results of the trial have not been published and little is known about how safe and effective it is in treating people in the hospital with COVID-19.

The emergency use authorization (EUA) designation means remdesivir can be distributed in the United States and administered intravenously by healthcare providers, as appropriate to treat severe disease. Those with severe disease, the FDA said in a press release, are patients with low blood oxygen levels or those who need oxygen therapy or more intensive support such as a mechanical ventilator.

“There’s tremendous interest among all parties to identify and arm ourselves with medicines to combat COVID-19, and through our Coronavirus Treatment Acceleration Program, the FDA is working around-the-clock and using every tool at our disposal to speed these efforts,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

The FDA writes, “Based on evaluation of the emergency use authorization criteria and the scientific evidence available, it was determined that it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, given there are no adequate, approved, or available alternative treatments, the known and potential benefits to treat this serious or life-threatening virus currently outweigh the known and potential risks of the drug’s use.”

The drug must be administered intravenously and the optimal dosing and duration are not yet known, the company said in a press release issued May 1.

In addition, Gilead advises that infusion-related reactions and liver transaminase elevations have been seen in patients treated with the drug.

“If signs and symptoms of a clinically significant infusion reaction occur, immediately discontinue administration of remdesivir and initiate appropriate treatment. Patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events. Monitor renal and hepatic function prior to initiating and daily during therapy with remdesivir; additionally monitor serum chemistries and hematology daily during therapy,” the company said.

Before granting the emergency use authorization, the FDA had allowed for study of the drug in clinical trials, as well as expanded access use for individual patients and through a multipatient expanded access program coordinated by Gilead.

“The EUA will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biologics for prevention and treatment of COVID-19 is terminated and may be revised or revoked if it is determined the EUA no longer meets the statutory criteria for issuance,” the FDA said.


This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) issued an emergency use authorization on May 1 for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.

The investigational antiviral drug, manufactured by Gilead Sciences Inc., was shown in a preliminary analysis of a National Institutes of Health (NIH) clinical trial to shorten recovery time in some patients, according to information presented during a White House press conference earlier this week. However, the results of the trial have not been published and little is known about how safe and effective it is in treating people in the hospital with COVID-19.

The emergency use authorization (EUA) designation means remdesivir can be distributed in the United States and administered intravenously by healthcare providers, as appropriate to treat severe disease. Those with severe disease, the FDA said in a press release, are patients with low blood oxygen levels or those who need oxygen therapy or more intensive support such as a mechanical ventilator.

“There’s tremendous interest among all parties to identify and arm ourselves with medicines to combat COVID-19, and through our Coronavirus Treatment Acceleration Program, the FDA is working around-the-clock and using every tool at our disposal to speed these efforts,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

The FDA writes, “Based on evaluation of the emergency use authorization criteria and the scientific evidence available, it was determined that it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, given there are no adequate, approved, or available alternative treatments, the known and potential benefits to treat this serious or life-threatening virus currently outweigh the known and potential risks of the drug’s use.”

The drug must be administered intravenously and the optimal dosing and duration are not yet known, the company said in a press release issued May 1.

In addition, Gilead advises that infusion-related reactions and liver transaminase elevations have been seen in patients treated with the drug.

“If signs and symptoms of a clinically significant infusion reaction occur, immediately discontinue administration of remdesivir and initiate appropriate treatment. Patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events. Monitor renal and hepatic function prior to initiating and daily during therapy with remdesivir; additionally monitor serum chemistries and hematology daily during therapy,” the company said.

Before granting the emergency use authorization, the FDA had allowed for study of the drug in clinical trials, as well as expanded access use for individual patients and through a multipatient expanded access program coordinated by Gilead.

“The EUA will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biologics for prevention and treatment of COVID-19 is terminated and may be revised or revoked if it is determined the EUA no longer meets the statutory criteria for issuance,” the FDA said.


This article first appeared on Medscape.com.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

Physicians who are conducting telephone visits during the COVID-19 pandemic will be paid at a higher rate, more closely aligning the rates with payments for face-to-face visits.

On April 30, officials at the Centers for Medicare & Medicaid Services announced the temporary telephone visit rate change and expanded the scope of services that are eligible telephone visits to include many behavioral health and patient education services.

Rates for telephone visits will jump from $14-$41 per visit to about $46-$110. The pay increase is retroactive to March 1, 2020.

The move was welcomed by the American College of Physicians, but the organization said more needs to be done in order help maintain the financial stability of physician practices.

“ACP has repeatedly requested this change from CMS as the country has been dealing with the COVID-19 national emergency, and we are heartened that they have heard our concerns,” ACP President Jacqueline Fincher, MD, said in a statement. “More still needs to be done to ensure that physician practices are able to remain operational and care for their patients, but this change in payment policy addresses one of the biggest issues facing physicians as they struggle to make up for lost revenue and provide appropriate care to patients.”

CMS also is expanding payment availability for audio-only telemedicine services by waiving the video requirement for certain evaluation and management services. The move is aimed at reaching Medicare beneficiaries who may not have access to video technology or choose not to use it.

“This is a major victory for medicine that will enable physicians to care for their patients, especially their elderly patients with chronic conditions who may not have access to audio-visual technology or high-speed Internet,” Patrice Harris, MD, president of the American Medical Association, said in a statement. “This change will help patients address their health challenges that existed before COVID-19.”

Shawn Martin, senior vice president at the American Academy of Family Physicians, said his group is pleased to see CMS roll out this change and noted that it is especially important for patients with underlying health conditions. “This is the only connectivity they may have with a health care system for their ongoing health care needs.”

Samuel Jones, MD, chair of the Health Affairs Committee at the American College of Cardiology, highlighted the expansion and coverage of audio-only telemedicine appointments as a huge plus for patient access.*

“There was a huge hunger to say, ‘Can we just have improvement in the reimbursement for telephone, which is providing a good service, our patients our asking for it,’ and we were able to get that,” Dr. Jones said in an interview. “It really was, I think, a good thing for patient care.”

Dr. Jones also suggested that the temporary policy be extended after the COVID-19 crisis is over.

“Telemedicine is here to stay,” he said. “But if all of these relaxations suddenly go away with a snap of the finger, or if the reimbursement [is lowered], if all that changes as soon as this emergency declaration is over, we are going to have a hard time.”

The pay increase for telephone services was part of a broader package of increased regulatory flexibility CMS rolled out, including expanding the types of providers who can order a COVID-19 test.

gtwachtman@mdedge.com

*Correction, 5/5/2020: An earlier version of this story misstated Dr. Samuel Jones' affiliation.  He is the chair of the Health Affairs Committee at the American College of Cardiology. 

Physicians who are conducting telephone visits during the COVID-19 pandemic will be paid at a higher rate, more closely aligning the rates with payments for face-to-face visits.

On April 30, officials at the Centers for Medicare & Medicaid Services announced the temporary telephone visit rate change and expanded the scope of services that are eligible telephone visits to include many behavioral health and patient education services.

Rates for telephone visits will jump from $14-$41 per visit to about $46-$110. The pay increase is retroactive to March 1, 2020.

The move was welcomed by the American College of Physicians, but the organization said more needs to be done in order help maintain the financial stability of physician practices.

“ACP has repeatedly requested this change from CMS as the country has been dealing with the COVID-19 national emergency, and we are heartened that they have heard our concerns,” ACP President Jacqueline Fincher, MD, said in a statement. “More still needs to be done to ensure that physician practices are able to remain operational and care for their patients, but this change in payment policy addresses one of the biggest issues facing physicians as they struggle to make up for lost revenue and provide appropriate care to patients.”

CMS also is expanding payment availability for audio-only telemedicine services by waiving the video requirement for certain evaluation and management services. The move is aimed at reaching Medicare beneficiaries who may not have access to video technology or choose not to use it.

“This is a major victory for medicine that will enable physicians to care for their patients, especially their elderly patients with chronic conditions who may not have access to audio-visual technology or high-speed Internet,” Patrice Harris, MD, president of the American Medical Association, said in a statement. “This change will help patients address their health challenges that existed before COVID-19.”

Shawn Martin, senior vice president at the American Academy of Family Physicians, said his group is pleased to see CMS roll out this change and noted that it is especially important for patients with underlying health conditions. “This is the only connectivity they may have with a health care system for their ongoing health care needs.”

Samuel Jones, MD, chair of the Health Affairs Committee at the American College of Cardiology, highlighted the expansion and coverage of audio-only telemedicine appointments as a huge plus for patient access.*

“There was a huge hunger to say, ‘Can we just have improvement in the reimbursement for telephone, which is providing a good service, our patients our asking for it,’ and we were able to get that,” Dr. Jones said in an interview. “It really was, I think, a good thing for patient care.”

Dr. Jones also suggested that the temporary policy be extended after the COVID-19 crisis is over.

“Telemedicine is here to stay,” he said. “But if all of these relaxations suddenly go away with a snap of the finger, or if the reimbursement [is lowered], if all that changes as soon as this emergency declaration is over, we are going to have a hard time.”

The pay increase for telephone services was part of a broader package of increased regulatory flexibility CMS rolled out, including expanding the types of providers who can order a COVID-19 test.

gtwachtman@mdedge.com

*Correction, 5/5/2020: An earlier version of this story misstated Dr. Samuel Jones' affiliation.  He is the chair of the Health Affairs Committee at the American College of Cardiology. 

Physicians who are conducting telephone visits during the COVID-19 pandemic will be paid at a higher rate, more closely aligning the rates with payments for face-to-face visits.

On April 30, officials at the Centers for Medicare & Medicaid Services announced the temporary telephone visit rate change and expanded the scope of services that are eligible telephone visits to include many behavioral health and patient education services.

Rates for telephone visits will jump from $14-$41 per visit to about $46-$110. The pay increase is retroactive to March 1, 2020.

The move was welcomed by the American College of Physicians, but the organization said more needs to be done in order help maintain the financial stability of physician practices.

“ACP has repeatedly requested this change from CMS as the country has been dealing with the COVID-19 national emergency, and we are heartened that they have heard our concerns,” ACP President Jacqueline Fincher, MD, said in a statement. “More still needs to be done to ensure that physician practices are able to remain operational and care for their patients, but this change in payment policy addresses one of the biggest issues facing physicians as they struggle to make up for lost revenue and provide appropriate care to patients.”

CMS also is expanding payment availability for audio-only telemedicine services by waiving the video requirement for certain evaluation and management services. The move is aimed at reaching Medicare beneficiaries who may not have access to video technology or choose not to use it.

“This is a major victory for medicine that will enable physicians to care for their patients, especially their elderly patients with chronic conditions who may not have access to audio-visual technology or high-speed Internet,” Patrice Harris, MD, president of the American Medical Association, said in a statement. “This change will help patients address their health challenges that existed before COVID-19.”

Shawn Martin, senior vice president at the American Academy of Family Physicians, said his group is pleased to see CMS roll out this change and noted that it is especially important for patients with underlying health conditions. “This is the only connectivity they may have with a health care system for their ongoing health care needs.”

Samuel Jones, MD, chair of the Health Affairs Committee at the American College of Cardiology, highlighted the expansion and coverage of audio-only telemedicine appointments as a huge plus for patient access.*

“There was a huge hunger to say, ‘Can we just have improvement in the reimbursement for telephone, which is providing a good service, our patients our asking for it,’ and we were able to get that,” Dr. Jones said in an interview. “It really was, I think, a good thing for patient care.”

Dr. Jones also suggested that the temporary policy be extended after the COVID-19 crisis is over.

“Telemedicine is here to stay,” he said. “But if all of these relaxations suddenly go away with a snap of the finger, or if the reimbursement [is lowered], if all that changes as soon as this emergency declaration is over, we are going to have a hard time.”

The pay increase for telephone services was part of a broader package of increased regulatory flexibility CMS rolled out, including expanding the types of providers who can order a COVID-19 test.

gtwachtman@mdedge.com

*Correction, 5/5/2020: An earlier version of this story misstated Dr. Samuel Jones' affiliation.  He is the chair of the Health Affairs Committee at the American College of Cardiology. 

During his shift at a COVID-19 drive-through triage screening area set up outside the University of Arkansas for Medical Sciences in Little Rock, Robert Hopkins Jr., MD, noticed a woman bowled over in the front seat of her car.

Courtesy Dr. Robert Hopkins, Jr.

A nurse practitioner had just informed her that she had met the criteria for undergoing testing for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

“She was very upset and was crying nearly inconsolably,” said Dr. Hopkins, who directs the division of general internal medicine at the University of Arkansas Medical Sciences College of Medicine. “I went over and visited with her for a few minutes. She was scared to death that we [had] told her she was going to die. In her mind, if she had COVID-19 that meant a death sentence, and if we were testing her that meant she was likely to not survive.”

Dr. Hopkins tried his best to put testing in perspective for the woman. “At least she came to a level of comfort and realized that we were doing this for her, that this was not a death sentence, that this was not her fault,” he said. “She was worried about infecting her kids and her grandkids and ending up in the hospital and being a burden. Being able to spend that few minutes with her and help to bring down her level of anxiety – I think that’s where we need to put our efforts as physicians right now, helping people understand, ‘Yes, this is serious. Yes, we need to continue to social distance. Yes, we need to be cautious. But, we will get through this if we all work together to do so.’ ”

Prior to the COVID-19 pandemic, Dr. Hopkins spent part of his time seeing patients in the university’s main hospital, but most of it in an outpatient clinic where he and about 20 other primary care physicians care for patients and precept medical residents. Now, medical residents have been deployed to other services, primarily in the hospital, and he and his physician colleagues are conducting 80%-90% of patient visits by video conferencing or by telephone. It’s a whole new world.

“We’ve gone from a relatively traditional inpatient/outpatient practice where we’re seeing patients face to face to doing some face-to-face visits, but an awful lot of what we do now is in the technology domain,” said Dr. Hopkins, who also assisted with health care relief efforts during hurricanes Rita and Katrina.

“A group of six of us has been redeployed to assist with the surge unit for the inpatient facility, so our outpatient duties are being taken on by some of our partners.”

He also pitches in at the drive-through COVID-19 screening clinic, which was set up on March 27 and operates between 8 a.m. and 8 p.m., 7 days a week. “We’re able to measure people’s temperature, take a quick screening history, decide whether their risk is such that we need to do a COVID-19 PCR [polymerase chain reaction] test,” he said. “Then we make a determination of whether they need to go home on quarantine awaiting those results, or if they don’t have anything that needs to be evaluated, or whether they need to be triaged to an urgent care setting or to the emergency department.”

To minimize his risk of acquiring COVID-19, he follows personal hygiene practices recommended by the Centers for Disease Control and Prevention. He also places his work shoes in a shoebox, which he keeps in his car. “I put them on when I get to the parking deck at work, do my work, and then I put them in the shoebox, slip on another pair of shoes and drive home so I’m not tracking in things I potentially had on me,” said Dr. Hopkins, who is married and a father to two college-aged sons and a daughter in fourth grade. “When I get home I immediately shower, and then I exercise or have dinner with my family.”

Despite the longer-than-usual work hours and upheaval to the traditional medical practice model brought on by the pandemic, Dr. Hopkins, a self-described “glass half full person,” said that he does his best to keep watch over his patients and colleagues. “I’m trying to keep an eye out on my team members – physicians, nurses, medical assistants, and folks at the front desk – trying to make sure that people are getting rest, trying to make sure that people are not overcommitting,” he said. “Because if we’re not all working together and working for the long term, we’re going to be in trouble. This is not going to be a sprint; this is going to be a marathon for us to get through.”

To keep mentally centered, he engages in at least 40 minutes of exercise each day on his bicycle or on the elliptical machine at home. Dr. Hopkins hopes that the current efforts to redeploy resources, expand clinician skill sets, and forge relationships with colleagues in other disciplines will carry over into the delivery of health care when COVID-19 is a distant memory. “I hope that some of those relationships are going to continue and result in better care for all of our patients,” he said.
 

"We are in dire need of hugs"

MaryAnn Dakkak, MD, is another primary care physician whose work week looks drastically different from how it looked before the pandemic. Typically, Dr. Dakkak, a family physician at Boston University, practices a mix of clinic-based family medicine and obstetrics, and works in inpatient medicine 6 weeks a year. Currently, she is leading a COVID-19 team full time at Boston Medical Center, a 300-bed safety-net hospital located on the campus of Boston University Medical Center.

Courtesy Dr. MaryAnn Dakkak

COVID-19 has also shaken up her life at home.

When Dr. Dakkak volunteered to take on her new role, the first thing that came to her mind was how making the switch would affect the well-being of her 8-year-old son and 10-year-old daughter.

“I thought, ‘How do I get my children somewhere where I don’t have to worry about them?’ ” Dr. Dakkak said.

She floated the idea with her husband of flying their children out to stay with her recently retired parents, who live outside of Sacramento, Calif., until the pandemic eases up. “I was thinking to myself, ‘Am I overreacting? Is the pandemic not going to be that bad?’ because the rest of the country seemed to be in some amount of denial,” she said. “So, I called my dad, who’s a retired pediatric anesthesiologist. He’s from Egypt so he’s done crisis medicine in his time. He encouraged me to send the kids.”

On the same day that Dr. Dakkak began her first 12-hour COVID-19 shift at the hospital, her husband and children boarded a plane to California, where the kids remain in the care of her parents. Her husband returned after staying there for 2 weeks. “Every day when I’m working, I validate my decision,” she said. “When I first started, I worked 5 nights in a row, had 2 days off, and then worked 6 nights in a row. I was busy so I didn’t think about [being away from my kids], but at the same time I was grateful that I didn’t have to come home and worry about homeschooling the kids or infecting them.”

She checks in with them as she can via cell phone or FaceTime. “My son has been very honest,” Dr. Dakkak said. “He says, ‘FaceTime makes me miss you more, and I don’t like it,’ which I understand. I’ll call my mom, and if they want to talk to me, they’ll talk to me. If they don’t want to talk to me, I’m okay. This is about them being healthy and safe. I sent them a care package a few days ago with cards and some workbooks. I’m optimistic that in June I can at least see them if not bring them home.”

Dr. Dakkak describes leading a COVID-19 team as a grueling experience that challenges her medical know-how nearly every day, with seemingly ever-changing algorithms. “Our knowledge of this disease is five steps behind, and changing at lightning speed,” said Dr. Dakkak, who completed a fellowship in surgical and high-risk obstetrics. “It’s hard to balance continuing to teach evidence-based medicine for everything else in medicine [with continuing] to practice minimal and ever-changing evidence-based COVID medicine. We just don’t know enough [about the virus] yet. This is nothing like we were taught in medical school. Everyone has elevated d-dimers with COVID-19, and we don’t get CT pulmonary angiograms [CTPAs] on all of them; we wouldn’t physically be able to. Some patients have d-dimers in the thousands, and only some are stable to get CTPAs. We are also finding pulmonary embolisms. Now we’re basing our algorithm on anticoagulation due to d-dimers because sometimes you can’t always do a CTPA even if you want to. On the other hand, we have people who are coming into the hospital too late. We’ve had a few who have come in after having days of stroke symptoms. I worry about our patients at home who hesitate to come in when they really should.”

Sometimes she feels sad for the medical residents on her team because their instinct is to go in and check on each patient, “but I don’t want them to get exposed,” she said. “So, we check in by phone, or if they need a physical check-in, we minimize the check-ins; only one of us goes in. I’m more willing to put myself in the room than to put them in the room. I also feel for them because they came into medicine for the humanity of medicine – not the charting or the ordering of medicine. I also worry about the acuity and sadness they’re seeing. This is a rough introduction to medicine for them.”

When interviewed for this story in late April, Dr. Dakkak had kept track of her intubated COVID-19 patients. “Most of my patients get to go home without having been intubated, but those aren’t the ones I worry about,” she said. “I have two patients I have been watching. One of them has just been extubated and I’m still worried about him, but I’m hoping he’s going to be fine. The other one is the first pregnant woman we intubated. She is now extubated, doing really well, and went home. Her fetus is doing well, never had any issues while she was intubated. Those cases make me happy. They were both under the age of 35. It is nice to follow those intubations and find that the majority are doing okay.”

The first patient she had cared for who died was a young man “who was always in good spirits,” she recalled. “We called his brother right before intubating him. After intubation, his oxygen saturation didn’t jump up, which made me worry a bit.” About a week later, the young man died. “I kept thinking, ‘We intubated him when he was still comfortable talking. Should I have put it off and had him call more people to say goodbye? Should I have known that he wasn’t going to wake up?’ ” said Dr. Dakkak, who is also women’s health director at Manet Community Health Centers. “A lot of us have worked on our end-of-life discussions in the past month, just being able to tell somebody, ‘This might be your last time to call family. Call family and talk to whoever you want.’ Guilt isn’t the right word, but it’s unsettling if I’m the last person a patient talks to. I feel that, if that’s the case, then I didn’t do a good enough job trying to get them to their family or friends. If I am worried about a patient’s clinical status declining, I tell families now, when I call them, ‘I hope I’m wrong; I hope they don’t need to be intubated, but I think this is the time to talk.’ ”

To keep herself grounded during off hours, Dr. Dakkak spends time resting, checking in with her family, journaling “to get a lot of feelings out,” gardening, hiking, and joining Zoom chats with friends. Once recentered, she draws from a sense of obligation to others as she prepares for her next shift caring for COVID-19 patients.

“I have a lot of love for the world that I get to expend by doing this hard work,” she said. “I love humanity and I love humanity in times of crisis. The interactions I have with patients and their families are still central to why I do this work. I love my medical teams, and I would never want to let them down. It is nice to feel the sense of teamwork across the hospital. The nurses that I sit with and experience this with are amazing. I keep saying that the only thing I want to do when this pandemic is over is hug everyone. I think we are in dire need of hugs.”
 

Finding light in the darkness

Internist Katie Jobbins, DO, also has worked in a professional role that was created because of COVID-19.

Shortly before Dr. Jobbins was deployed to Baystate Medical Center in Springfield, Ma., for 2 weeks in April of 2020 to help clinicians with an anticipated surge of COVID-19 cases, she encountered a patient who walked into Baystate’s High Street Health Center.

“I think I have COVID-19,” the patient proclaimed to her, at the outpatient clinic that serves mostly inner-city, Medicaid patients.

Prior to becoming an ambulatory internist, Dr. Jobbins was a surgical resident. “So I went into that mode of ‘I need to do this, this, and this,’ ” she said. “I went through a checklist in my head to make sure I was prepared to take care of the patient.”

She applied that same systems approach during her redeployment assignment in the tertiary care hospital, which typically involved 10-hour shifts overseeing internal medicine residents in a medical telemetry unit. “We would take care of people under investigation for COVID-19, but we were not assigned to the actual COVID unit,” said Dr. Jobbins, who is also associate program director for the internal medicine residency program at the University of Massachusetts Medical School–Baystate Springfield. “They tried to redeploy other people to those units who had special training, and we were trying to back fill into where those people that got moved to the COVID units or the ICU units were actually working. We were taking more of the medical side of the floors.”

Even so, one patient on the unit was suspected of having COVID-19, so Dr. Jobbins suited up with personal protective equipment and conducted a thorough exam with residents waiting outside the patient’s room, a safe distance away. “I explained everything I found on the exam to the residents, trying to give them some educational benefit, even though they couldn’t physically examine the patient because we’re trying to protect them since they’re in training,” she said. “It was anxiety provoking, on some level, knowing that there’s a potential risk of exposure [to the virus], but knowing that Baystate Health has gone to extraordinary measures to make sure we have the correct PPE and support us is reassuring. I knew I had the right equipment and the right tools to take care of the patient, which calmed my nerves and made me feel like I could do the job. That’s the most important thing as a physician during this time: knowing that you have people supporting you who have your back at all times.”

Like Dr. Dakkak, Dr. Jobbins had to make some adjustments to her interaction with her family.

Before she began the deployment, Dr. Jobbins engaged in a frank discussion with her husband and her two young boys about the risks she faced working in a hospital caring for patients with COVID-19. “My husband and I made sure our wills were up to date, and we talked about what we would do if either of us got the virus,” she said. To minimize the potential risk of transmitting the virus to her loved ones during the two-week deployment, she considered living away from her family in a nearby home owned by her father, but decided against that and to “take it day by day.” Following her hospital shifts, Dr. Jobbins changed into a fresh set of clothes before leaving the hospital. Once she arrived home, she showered to reduce the risk of possibly becoming a vector to her family.

She had to tell her kids: “You can’t kiss me right now.”

“As much as it’s hard for them to understand, we had a conversation [in which I explained] ‘This is a virus. It will go away eventually, but it’s a virus we’re fighting.’ It’s interesting to watch a 3-year-old try to process that and take his play samurai sword or Marvel toys and decide he’s going to run around the neighborhood and try to kill the virus.”

At the High Street Health Center, Dr. Jobbins and her colleagues have transitioned to conducting most patient encounters via telephone or video appointments. “We have tried to maintain as much continuity for our patients to address their chronic medical needs through these visits, such as hypertension management and diabetes care,” she said. “We have begun a rigorous screening process to triage and treat patients suspicious for COVID-19 through telehealth in hopes of keeping them safe and in their own homes. We also continue to see patients for nonrespiratory urgent care needs in person once they have screened negative for COVID-19.”

“In terms of the inpatient setting, we’ve noticed that a lot of people are choosing not to go to the hospital now, unless they’re extremely ill,” Dr. Jobbins noted. “We’re going to need to find a balance with when do people truly need to go to the hospital and when do they not? What can we manage as an outpatient versus having someone go to the emergency department? That’s really the role of the primary care physician. We need to help people understand, ‘You don’t need to go to the ED for everything, but here are the things you really need to go for.’ ”

“It will be interesting to see what health care looks like in 6 months or a year. I’m excited to see where we land,” Dr. Jobbins added.


 

Hopes for the Future of Telemedicine

When the practice of medicine enters a post–COVID-19 era, Dr. Jobbins hopes that telemedicine will be incorporated more into the delivery of patient care. “I’ve found that many of my patients who often are no-shows to the inpatient version of their visits have had a higher success rate of follow-through when we do the telephone visits,” she said. “It’s been very successful. I hope that the insurance companies and [Centers for Medicare & Medicaid] will continue to reimburse this as they see this is a benefit to our patients.

Courtesy Dr. Robert Hopkins, Jr.

Dr. Hopkins is also hopeful that physicians will be able to successfully see patients via telemedicine in the postpandemic world.

“For the ups and downs we’ve had with telemedicine, I’d love for us to be able to enhance the positives and incorporate that into our practice going forward. If we can reach our patients and help treat them where they are, rather than them having to come to us, that may be a plus,” he said.

In the meantime, Dr. Jobbins presses on as the curve of COVID-19 cases flattens in Western Massachusetts and remains grateful that she chose to practice medicine.

“The commitment I have to being an educator in addition to being a physician is part of why I keep doing this,” Dr. Jobbins said. “I find this to be one of the most fulfilling jobs and careers you could ever have: being there for people when they need you the most. That’s really what a physician’s job is: being there for people when a family member has passed away or when they just need to talk because they’re having anxiety. At the end of the day, if we can impart that to those we work with and bring in a positive attitude, it’s infectious and it makes people see this is a reason we keep doing what we’re doing.”

She’s also been heartened by the kindness of strangers during this pandemic, from those who made and donated face shields when they were in short supply, to those who delivered food to the hospital as a gesture of thanks.

“I had a patient who made homemade masks and sent them to my office,” she said. “There’s obviously good and bad during this time, but I get hope from seeing all of the good things that are coming out of this, the whole idea of finding the light in the darkness.”

dbrunk@mdedge.com

During his shift at a COVID-19 drive-through triage screening area set up outside the University of Arkansas for Medical Sciences in Little Rock, Robert Hopkins Jr., MD, noticed a woman bowled over in the front seat of her car.

Courtesy Dr. Robert Hopkins, Jr.

A nurse practitioner had just informed her that she had met the criteria for undergoing testing for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

“She was very upset and was crying nearly inconsolably,” said Dr. Hopkins, who directs the division of general internal medicine at the University of Arkansas Medical Sciences College of Medicine. “I went over and visited with her for a few minutes. She was scared to death that we [had] told her she was going to die. In her mind, if she had COVID-19 that meant a death sentence, and if we were testing her that meant she was likely to not survive.”

Dr. Hopkins tried his best to put testing in perspective for the woman. “At least she came to a level of comfort and realized that we were doing this for her, that this was not a death sentence, that this was not her fault,” he said. “She was worried about infecting her kids and her grandkids and ending up in the hospital and being a burden. Being able to spend that few minutes with her and help to bring down her level of anxiety – I think that’s where we need to put our efforts as physicians right now, helping people understand, ‘Yes, this is serious. Yes, we need to continue to social distance. Yes, we need to be cautious. But, we will get through this if we all work together to do so.’ ”

Prior to the COVID-19 pandemic, Dr. Hopkins spent part of his time seeing patients in the university’s main hospital, but most of it in an outpatient clinic where he and about 20 other primary care physicians care for patients and precept medical residents. Now, medical residents have been deployed to other services, primarily in the hospital, and he and his physician colleagues are conducting 80%-90% of patient visits by video conferencing or by telephone. It’s a whole new world.

“We’ve gone from a relatively traditional inpatient/outpatient practice where we’re seeing patients face to face to doing some face-to-face visits, but an awful lot of what we do now is in the technology domain,” said Dr. Hopkins, who also assisted with health care relief efforts during hurricanes Rita and Katrina.

“A group of six of us has been redeployed to assist with the surge unit for the inpatient facility, so our outpatient duties are being taken on by some of our partners.”

He also pitches in at the drive-through COVID-19 screening clinic, which was set up on March 27 and operates between 8 a.m. and 8 p.m., 7 days a week. “We’re able to measure people’s temperature, take a quick screening history, decide whether their risk is such that we need to do a COVID-19 PCR [polymerase chain reaction] test,” he said. “Then we make a determination of whether they need to go home on quarantine awaiting those results, or if they don’t have anything that needs to be evaluated, or whether they need to be triaged to an urgent care setting or to the emergency department.”

To minimize his risk of acquiring COVID-19, he follows personal hygiene practices recommended by the Centers for Disease Control and Prevention. He also places his work shoes in a shoebox, which he keeps in his car. “I put them on when I get to the parking deck at work, do my work, and then I put them in the shoebox, slip on another pair of shoes and drive home so I’m not tracking in things I potentially had on me,” said Dr. Hopkins, who is married and a father to two college-aged sons and a daughter in fourth grade. “When I get home I immediately shower, and then I exercise or have dinner with my family.”

Despite the longer-than-usual work hours and upheaval to the traditional medical practice model brought on by the pandemic, Dr. Hopkins, a self-described “glass half full person,” said that he does his best to keep watch over his patients and colleagues. “I’m trying to keep an eye out on my team members – physicians, nurses, medical assistants, and folks at the front desk – trying to make sure that people are getting rest, trying to make sure that people are not overcommitting,” he said. “Because if we’re not all working together and working for the long term, we’re going to be in trouble. This is not going to be a sprint; this is going to be a marathon for us to get through.”

To keep mentally centered, he engages in at least 40 minutes of exercise each day on his bicycle or on the elliptical machine at home. Dr. Hopkins hopes that the current efforts to redeploy resources, expand clinician skill sets, and forge relationships with colleagues in other disciplines will carry over into the delivery of health care when COVID-19 is a distant memory. “I hope that some of those relationships are going to continue and result in better care for all of our patients,” he said.
 

"We are in dire need of hugs"

MaryAnn Dakkak, MD, is another primary care physician whose work week looks drastically different from how it looked before the pandemic. Typically, Dr. Dakkak, a family physician at Boston University, practices a mix of clinic-based family medicine and obstetrics, and works in inpatient medicine 6 weeks a year. Currently, she is leading a COVID-19 team full time at Boston Medical Center, a 300-bed safety-net hospital located on the campus of Boston University Medical Center.

Courtesy Dr. MaryAnn Dakkak

COVID-19 has also shaken up her life at home.

When Dr. Dakkak volunteered to take on her new role, the first thing that came to her mind was how making the switch would affect the well-being of her 8-year-old son and 10-year-old daughter.

“I thought, ‘How do I get my children somewhere where I don’t have to worry about them?’ ” Dr. Dakkak said.

She floated the idea with her husband of flying their children out to stay with her recently retired parents, who live outside of Sacramento, Calif., until the pandemic eases up. “I was thinking to myself, ‘Am I overreacting? Is the pandemic not going to be that bad?’ because the rest of the country seemed to be in some amount of denial,” she said. “So, I called my dad, who’s a retired pediatric anesthesiologist. He’s from Egypt so he’s done crisis medicine in his time. He encouraged me to send the kids.”

On the same day that Dr. Dakkak began her first 12-hour COVID-19 shift at the hospital, her husband and children boarded a plane to California, where the kids remain in the care of her parents. Her husband returned after staying there for 2 weeks. “Every day when I’m working, I validate my decision,” she said. “When I first started, I worked 5 nights in a row, had 2 days off, and then worked 6 nights in a row. I was busy so I didn’t think about [being away from my kids], but at the same time I was grateful that I didn’t have to come home and worry about homeschooling the kids or infecting them.”

She checks in with them as she can via cell phone or FaceTime. “My son has been very honest,” Dr. Dakkak said. “He says, ‘FaceTime makes me miss you more, and I don’t like it,’ which I understand. I’ll call my mom, and if they want to talk to me, they’ll talk to me. If they don’t want to talk to me, I’m okay. This is about them being healthy and safe. I sent them a care package a few days ago with cards and some workbooks. I’m optimistic that in June I can at least see them if not bring them home.”

Dr. Dakkak describes leading a COVID-19 team as a grueling experience that challenges her medical know-how nearly every day, with seemingly ever-changing algorithms. “Our knowledge of this disease is five steps behind, and changing at lightning speed,” said Dr. Dakkak, who completed a fellowship in surgical and high-risk obstetrics. “It’s hard to balance continuing to teach evidence-based medicine for everything else in medicine [with continuing] to practice minimal and ever-changing evidence-based COVID medicine. We just don’t know enough [about the virus] yet. This is nothing like we were taught in medical school. Everyone has elevated d-dimers with COVID-19, and we don’t get CT pulmonary angiograms [CTPAs] on all of them; we wouldn’t physically be able to. Some patients have d-dimers in the thousands, and only some are stable to get CTPAs. We are also finding pulmonary embolisms. Now we’re basing our algorithm on anticoagulation due to d-dimers because sometimes you can’t always do a CTPA even if you want to. On the other hand, we have people who are coming into the hospital too late. We’ve had a few who have come in after having days of stroke symptoms. I worry about our patients at home who hesitate to come in when they really should.”

Sometimes she feels sad for the medical residents on her team because their instinct is to go in and check on each patient, “but I don’t want them to get exposed,” she said. “So, we check in by phone, or if they need a physical check-in, we minimize the check-ins; only one of us goes in. I’m more willing to put myself in the room than to put them in the room. I also feel for them because they came into medicine for the humanity of medicine – not the charting or the ordering of medicine. I also worry about the acuity and sadness they’re seeing. This is a rough introduction to medicine for them.”

When interviewed for this story in late April, Dr. Dakkak had kept track of her intubated COVID-19 patients. “Most of my patients get to go home without having been intubated, but those aren’t the ones I worry about,” she said. “I have two patients I have been watching. One of them has just been extubated and I’m still worried about him, but I’m hoping he’s going to be fine. The other one is the first pregnant woman we intubated. She is now extubated, doing really well, and went home. Her fetus is doing well, never had any issues while she was intubated. Those cases make me happy. They were both under the age of 35. It is nice to follow those intubations and find that the majority are doing okay.”

The first patient she had cared for who died was a young man “who was always in good spirits,” she recalled. “We called his brother right before intubating him. After intubation, his oxygen saturation didn’t jump up, which made me worry a bit.” About a week later, the young man died. “I kept thinking, ‘We intubated him when he was still comfortable talking. Should I have put it off and had him call more people to say goodbye? Should I have known that he wasn’t going to wake up?’ ” said Dr. Dakkak, who is also women’s health director at Manet Community Health Centers. “A lot of us have worked on our end-of-life discussions in the past month, just being able to tell somebody, ‘This might be your last time to call family. Call family and talk to whoever you want.’ Guilt isn’t the right word, but it’s unsettling if I’m the last person a patient talks to. I feel that, if that’s the case, then I didn’t do a good enough job trying to get them to their family or friends. If I am worried about a patient’s clinical status declining, I tell families now, when I call them, ‘I hope I’m wrong; I hope they don’t need to be intubated, but I think this is the time to talk.’ ”

To keep herself grounded during off hours, Dr. Dakkak spends time resting, checking in with her family, journaling “to get a lot of feelings out,” gardening, hiking, and joining Zoom chats with friends. Once recentered, she draws from a sense of obligation to others as she prepares for her next shift caring for COVID-19 patients.

“I have a lot of love for the world that I get to expend by doing this hard work,” she said. “I love humanity and I love humanity in times of crisis. The interactions I have with patients and their families are still central to why I do this work. I love my medical teams, and I would never want to let them down. It is nice to feel the sense of teamwork across the hospital. The nurses that I sit with and experience this with are amazing. I keep saying that the only thing I want to do when this pandemic is over is hug everyone. I think we are in dire need of hugs.”
 

Finding light in the darkness

Internist Katie Jobbins, DO, also has worked in a professional role that was created because of COVID-19.

Shortly before Dr. Jobbins was deployed to Baystate Medical Center in Springfield, Ma., for 2 weeks in April of 2020 to help clinicians with an anticipated surge of COVID-19 cases, she encountered a patient who walked into Baystate’s High Street Health Center.

“I think I have COVID-19,” the patient proclaimed to her, at the outpatient clinic that serves mostly inner-city, Medicaid patients.

Prior to becoming an ambulatory internist, Dr. Jobbins was a surgical resident. “So I went into that mode of ‘I need to do this, this, and this,’ ” she said. “I went through a checklist in my head to make sure I was prepared to take care of the patient.”

She applied that same systems approach during her redeployment assignment in the tertiary care hospital, which typically involved 10-hour shifts overseeing internal medicine residents in a medical telemetry unit. “We would take care of people under investigation for COVID-19, but we were not assigned to the actual COVID unit,” said Dr. Jobbins, who is also associate program director for the internal medicine residency program at the University of Massachusetts Medical School–Baystate Springfield. “They tried to redeploy other people to those units who had special training, and we were trying to back fill into where those people that got moved to the COVID units or the ICU units were actually working. We were taking more of the medical side of the floors.”

Even so, one patient on the unit was suspected of having COVID-19, so Dr. Jobbins suited up with personal protective equipment and conducted a thorough exam with residents waiting outside the patient’s room, a safe distance away. “I explained everything I found on the exam to the residents, trying to give them some educational benefit, even though they couldn’t physically examine the patient because we’re trying to protect them since they’re in training,” she said. “It was anxiety provoking, on some level, knowing that there’s a potential risk of exposure [to the virus], but knowing that Baystate Health has gone to extraordinary measures to make sure we have the correct PPE and support us is reassuring. I knew I had the right equipment and the right tools to take care of the patient, which calmed my nerves and made me feel like I could do the job. That’s the most important thing as a physician during this time: knowing that you have people supporting you who have your back at all times.”

Like Dr. Dakkak, Dr. Jobbins had to make some adjustments to her interaction with her family.

Before she began the deployment, Dr. Jobbins engaged in a frank discussion with her husband and her two young boys about the risks she faced working in a hospital caring for patients with COVID-19. “My husband and I made sure our wills were up to date, and we talked about what we would do if either of us got the virus,” she said. To minimize the potential risk of transmitting the virus to her loved ones during the two-week deployment, she considered living away from her family in a nearby home owned by her father, but decided against that and to “take it day by day.” Following her hospital shifts, Dr. Jobbins changed into a fresh set of clothes before leaving the hospital. Once she arrived home, she showered to reduce the risk of possibly becoming a vector to her family.

She had to tell her kids: “You can’t kiss me right now.”

“As much as it’s hard for them to understand, we had a conversation [in which I explained] ‘This is a virus. It will go away eventually, but it’s a virus we’re fighting.’ It’s interesting to watch a 3-year-old try to process that and take his play samurai sword or Marvel toys and decide he’s going to run around the neighborhood and try to kill the virus.”

At the High Street Health Center, Dr. Jobbins and her colleagues have transitioned to conducting most patient encounters via telephone or video appointments. “We have tried to maintain as much continuity for our patients to address their chronic medical needs through these visits, such as hypertension management and diabetes care,” she said. “We have begun a rigorous screening process to triage and treat patients suspicious for COVID-19 through telehealth in hopes of keeping them safe and in their own homes. We also continue to see patients for nonrespiratory urgent care needs in person once they have screened negative for COVID-19.”

“In terms of the inpatient setting, we’ve noticed that a lot of people are choosing not to go to the hospital now, unless they’re extremely ill,” Dr. Jobbins noted. “We’re going to need to find a balance with when do people truly need to go to the hospital and when do they not? What can we manage as an outpatient versus having someone go to the emergency department? That’s really the role of the primary care physician. We need to help people understand, ‘You don’t need to go to the ED for everything, but here are the things you really need to go for.’ ”

“It will be interesting to see what health care looks like in 6 months or a year. I’m excited to see where we land,” Dr. Jobbins added.


 

Hopes for the Future of Telemedicine

When the practice of medicine enters a post–COVID-19 era, Dr. Jobbins hopes that telemedicine will be incorporated more into the delivery of patient care. “I’ve found that many of my patients who often are no-shows to the inpatient version of their visits have had a higher success rate of follow-through when we do the telephone visits,” she said. “It’s been very successful. I hope that the insurance companies and [Centers for Medicare & Medicaid] will continue to reimburse this as they see this is a benefit to our patients.

Courtesy Dr. Robert Hopkins, Jr.

Dr. Hopkins is also hopeful that physicians will be able to successfully see patients via telemedicine in the postpandemic world.

“For the ups and downs we’ve had with telemedicine, I’d love for us to be able to enhance the positives and incorporate that into our practice going forward. If we can reach our patients and help treat them where they are, rather than them having to come to us, that may be a plus,” he said.

In the meantime, Dr. Jobbins presses on as the curve of COVID-19 cases flattens in Western Massachusetts and remains grateful that she chose to practice medicine.

“The commitment I have to being an educator in addition to being a physician is part of why I keep doing this,” Dr. Jobbins said. “I find this to be one of the most fulfilling jobs and careers you could ever have: being there for people when they need you the most. That’s really what a physician’s job is: being there for people when a family member has passed away or when they just need to talk because they’re having anxiety. At the end of the day, if we can impart that to those we work with and bring in a positive attitude, it’s infectious and it makes people see this is a reason we keep doing what we’re doing.”

She’s also been heartened by the kindness of strangers during this pandemic, from those who made and donated face shields when they were in short supply, to those who delivered food to the hospital as a gesture of thanks.

“I had a patient who made homemade masks and sent them to my office,” she said. “There’s obviously good and bad during this time, but I get hope from seeing all of the good things that are coming out of this, the whole idea of finding the light in the darkness.”

dbrunk@mdedge.com

During his shift at a COVID-19 drive-through triage screening area set up outside the University of Arkansas for Medical Sciences in Little Rock, Robert Hopkins Jr., MD, noticed a woman bowled over in the front seat of her car.

Courtesy Dr. Robert Hopkins, Jr.

A nurse practitioner had just informed her that she had met the criteria for undergoing testing for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

“She was very upset and was crying nearly inconsolably,” said Dr. Hopkins, who directs the division of general internal medicine at the University of Arkansas Medical Sciences College of Medicine. “I went over and visited with her for a few minutes. She was scared to death that we [had] told her she was going to die. In her mind, if she had COVID-19 that meant a death sentence, and if we were testing her that meant she was likely to not survive.”

Dr. Hopkins tried his best to put testing in perspective for the woman. “At least she came to a level of comfort and realized that we were doing this for her, that this was not a death sentence, that this was not her fault,” he said. “She was worried about infecting her kids and her grandkids and ending up in the hospital and being a burden. Being able to spend that few minutes with her and help to bring down her level of anxiety – I think that’s where we need to put our efforts as physicians right now, helping people understand, ‘Yes, this is serious. Yes, we need to continue to social distance. Yes, we need to be cautious. But, we will get through this if we all work together to do so.’ ”

Prior to the COVID-19 pandemic, Dr. Hopkins spent part of his time seeing patients in the university’s main hospital, but most of it in an outpatient clinic where he and about 20 other primary care physicians care for patients and precept medical residents. Now, medical residents have been deployed to other services, primarily in the hospital, and he and his physician colleagues are conducting 80%-90% of patient visits by video conferencing or by telephone. It’s a whole new world.

“We’ve gone from a relatively traditional inpatient/outpatient practice where we’re seeing patients face to face to doing some face-to-face visits, but an awful lot of what we do now is in the technology domain,” said Dr. Hopkins, who also assisted with health care relief efforts during hurricanes Rita and Katrina.

“A group of six of us has been redeployed to assist with the surge unit for the inpatient facility, so our outpatient duties are being taken on by some of our partners.”

He also pitches in at the drive-through COVID-19 screening clinic, which was set up on March 27 and operates between 8 a.m. and 8 p.m., 7 days a week. “We’re able to measure people’s temperature, take a quick screening history, decide whether their risk is such that we need to do a COVID-19 PCR [polymerase chain reaction] test,” he said. “Then we make a determination of whether they need to go home on quarantine awaiting those results, or if they don’t have anything that needs to be evaluated, or whether they need to be triaged to an urgent care setting or to the emergency department.”

To minimize his risk of acquiring COVID-19, he follows personal hygiene practices recommended by the Centers for Disease Control and Prevention. He also places his work shoes in a shoebox, which he keeps in his car. “I put them on when I get to the parking deck at work, do my work, and then I put them in the shoebox, slip on another pair of shoes and drive home so I’m not tracking in things I potentially had on me,” said Dr. Hopkins, who is married and a father to two college-aged sons and a daughter in fourth grade. “When I get home I immediately shower, and then I exercise or have dinner with my family.”

Despite the longer-than-usual work hours and upheaval to the traditional medical practice model brought on by the pandemic, Dr. Hopkins, a self-described “glass half full person,” said that he does his best to keep watch over his patients and colleagues. “I’m trying to keep an eye out on my team members – physicians, nurses, medical assistants, and folks at the front desk – trying to make sure that people are getting rest, trying to make sure that people are not overcommitting,” he said. “Because if we’re not all working together and working for the long term, we’re going to be in trouble. This is not going to be a sprint; this is going to be a marathon for us to get through.”

To keep mentally centered, he engages in at least 40 minutes of exercise each day on his bicycle or on the elliptical machine at home. Dr. Hopkins hopes that the current efforts to redeploy resources, expand clinician skill sets, and forge relationships with colleagues in other disciplines will carry over into the delivery of health care when COVID-19 is a distant memory. “I hope that some of those relationships are going to continue and result in better care for all of our patients,” he said.
 

"We are in dire need of hugs"

MaryAnn Dakkak, MD, is another primary care physician whose work week looks drastically different from how it looked before the pandemic. Typically, Dr. Dakkak, a family physician at Boston University, practices a mix of clinic-based family medicine and obstetrics, and works in inpatient medicine 6 weeks a year. Currently, she is leading a COVID-19 team full time at Boston Medical Center, a 300-bed safety-net hospital located on the campus of Boston University Medical Center.

Courtesy Dr. MaryAnn Dakkak

COVID-19 has also shaken up her life at home.

When Dr. Dakkak volunteered to take on her new role, the first thing that came to her mind was how making the switch would affect the well-being of her 8-year-old son and 10-year-old daughter.

“I thought, ‘How do I get my children somewhere where I don’t have to worry about them?’ ” Dr. Dakkak said.

She floated the idea with her husband of flying their children out to stay with her recently retired parents, who live outside of Sacramento, Calif., until the pandemic eases up. “I was thinking to myself, ‘Am I overreacting? Is the pandemic not going to be that bad?’ because the rest of the country seemed to be in some amount of denial,” she said. “So, I called my dad, who’s a retired pediatric anesthesiologist. He’s from Egypt so he’s done crisis medicine in his time. He encouraged me to send the kids.”

On the same day that Dr. Dakkak began her first 12-hour COVID-19 shift at the hospital, her husband and children boarded a plane to California, where the kids remain in the care of her parents. Her husband returned after staying there for 2 weeks. “Every day when I’m working, I validate my decision,” she said. “When I first started, I worked 5 nights in a row, had 2 days off, and then worked 6 nights in a row. I was busy so I didn’t think about [being away from my kids], but at the same time I was grateful that I didn’t have to come home and worry about homeschooling the kids or infecting them.”

She checks in with them as she can via cell phone or FaceTime. “My son has been very honest,” Dr. Dakkak said. “He says, ‘FaceTime makes me miss you more, and I don’t like it,’ which I understand. I’ll call my mom, and if they want to talk to me, they’ll talk to me. If they don’t want to talk to me, I’m okay. This is about them being healthy and safe. I sent them a care package a few days ago with cards and some workbooks. I’m optimistic that in June I can at least see them if not bring them home.”

Dr. Dakkak describes leading a COVID-19 team as a grueling experience that challenges her medical know-how nearly every day, with seemingly ever-changing algorithms. “Our knowledge of this disease is five steps behind, and changing at lightning speed,” said Dr. Dakkak, who completed a fellowship in surgical and high-risk obstetrics. “It’s hard to balance continuing to teach evidence-based medicine for everything else in medicine [with continuing] to practice minimal and ever-changing evidence-based COVID medicine. We just don’t know enough [about the virus] yet. This is nothing like we were taught in medical school. Everyone has elevated d-dimers with COVID-19, and we don’t get CT pulmonary angiograms [CTPAs] on all of them; we wouldn’t physically be able to. Some patients have d-dimers in the thousands, and only some are stable to get CTPAs. We are also finding pulmonary embolisms. Now we’re basing our algorithm on anticoagulation due to d-dimers because sometimes you can’t always do a CTPA even if you want to. On the other hand, we have people who are coming into the hospital too late. We’ve had a few who have come in after having days of stroke symptoms. I worry about our patients at home who hesitate to come in when they really should.”

Sometimes she feels sad for the medical residents on her team because their instinct is to go in and check on each patient, “but I don’t want them to get exposed,” she said. “So, we check in by phone, or if they need a physical check-in, we minimize the check-ins; only one of us goes in. I’m more willing to put myself in the room than to put them in the room. I also feel for them because they came into medicine for the humanity of medicine – not the charting or the ordering of medicine. I also worry about the acuity and sadness they’re seeing. This is a rough introduction to medicine for them.”

When interviewed for this story in late April, Dr. Dakkak had kept track of her intubated COVID-19 patients. “Most of my patients get to go home without having been intubated, but those aren’t the ones I worry about,” she said. “I have two patients I have been watching. One of them has just been extubated and I’m still worried about him, but I’m hoping he’s going to be fine. The other one is the first pregnant woman we intubated. She is now extubated, doing really well, and went home. Her fetus is doing well, never had any issues while she was intubated. Those cases make me happy. They were both under the age of 35. It is nice to follow those intubations and find that the majority are doing okay.”

The first patient she had cared for who died was a young man “who was always in good spirits,” she recalled. “We called his brother right before intubating him. After intubation, his oxygen saturation didn’t jump up, which made me worry a bit.” About a week later, the young man died. “I kept thinking, ‘We intubated him when he was still comfortable talking. Should I have put it off and had him call more people to say goodbye? Should I have known that he wasn’t going to wake up?’ ” said Dr. Dakkak, who is also women’s health director at Manet Community Health Centers. “A lot of us have worked on our end-of-life discussions in the past month, just being able to tell somebody, ‘This might be your last time to call family. Call family and talk to whoever you want.’ Guilt isn’t the right word, but it’s unsettling if I’m the last person a patient talks to. I feel that, if that’s the case, then I didn’t do a good enough job trying to get them to their family or friends. If I am worried about a patient’s clinical status declining, I tell families now, when I call them, ‘I hope I’m wrong; I hope they don’t need to be intubated, but I think this is the time to talk.’ ”

To keep herself grounded during off hours, Dr. Dakkak spends time resting, checking in with her family, journaling “to get a lot of feelings out,” gardening, hiking, and joining Zoom chats with friends. Once recentered, she draws from a sense of obligation to others as she prepares for her next shift caring for COVID-19 patients.

“I have a lot of love for the world that I get to expend by doing this hard work,” she said. “I love humanity and I love humanity in times of crisis. The interactions I have with patients and their families are still central to why I do this work. I love my medical teams, and I would never want to let them down. It is nice to feel the sense of teamwork across the hospital. The nurses that I sit with and experience this with are amazing. I keep saying that the only thing I want to do when this pandemic is over is hug everyone. I think we are in dire need of hugs.”
 

Finding light in the darkness

Internist Katie Jobbins, DO, also has worked in a professional role that was created because of COVID-19.

Shortly before Dr. Jobbins was deployed to Baystate Medical Center in Springfield, Ma., for 2 weeks in April of 2020 to help clinicians with an anticipated surge of COVID-19 cases, she encountered a patient who walked into Baystate’s High Street Health Center.

“I think I have COVID-19,” the patient proclaimed to her, at the outpatient clinic that serves mostly inner-city, Medicaid patients.

Prior to becoming an ambulatory internist, Dr. Jobbins was a surgical resident. “So I went into that mode of ‘I need to do this, this, and this,’ ” she said. “I went through a checklist in my head to make sure I was prepared to take care of the patient.”

She applied that same systems approach during her redeployment assignment in the tertiary care hospital, which typically involved 10-hour shifts overseeing internal medicine residents in a medical telemetry unit. “We would take care of people under investigation for COVID-19, but we were not assigned to the actual COVID unit,” said Dr. Jobbins, who is also associate program director for the internal medicine residency program at the University of Massachusetts Medical School–Baystate Springfield. “They tried to redeploy other people to those units who had special training, and we were trying to back fill into where those people that got moved to the COVID units or the ICU units were actually working. We were taking more of the medical side of the floors.”

Even so, one patient on the unit was suspected of having COVID-19, so Dr. Jobbins suited up with personal protective equipment and conducted a thorough exam with residents waiting outside the patient’s room, a safe distance away. “I explained everything I found on the exam to the residents, trying to give them some educational benefit, even though they couldn’t physically examine the patient because we’re trying to protect them since they’re in training,” she said. “It was anxiety provoking, on some level, knowing that there’s a potential risk of exposure [to the virus], but knowing that Baystate Health has gone to extraordinary measures to make sure we have the correct PPE and support us is reassuring. I knew I had the right equipment and the right tools to take care of the patient, which calmed my nerves and made me feel like I could do the job. That’s the most important thing as a physician during this time: knowing that you have people supporting you who have your back at all times.”

Like Dr. Dakkak, Dr. Jobbins had to make some adjustments to her interaction with her family.

Before she began the deployment, Dr. Jobbins engaged in a frank discussion with her husband and her two young boys about the risks she faced working in a hospital caring for patients with COVID-19. “My husband and I made sure our wills were up to date, and we talked about what we would do if either of us got the virus,” she said. To minimize the potential risk of transmitting the virus to her loved ones during the two-week deployment, she considered living away from her family in a nearby home owned by her father, but decided against that and to “take it day by day.” Following her hospital shifts, Dr. Jobbins changed into a fresh set of clothes before leaving the hospital. Once she arrived home, she showered to reduce the risk of possibly becoming a vector to her family.

She had to tell her kids: “You can’t kiss me right now.”

“As much as it’s hard for them to understand, we had a conversation [in which I explained] ‘This is a virus. It will go away eventually, but it’s a virus we’re fighting.’ It’s interesting to watch a 3-year-old try to process that and take his play samurai sword or Marvel toys and decide he’s going to run around the neighborhood and try to kill the virus.”

At the High Street Health Center, Dr. Jobbins and her colleagues have transitioned to conducting most patient encounters via telephone or video appointments. “We have tried to maintain as much continuity for our patients to address their chronic medical needs through these visits, such as hypertension management and diabetes care,” she said. “We have begun a rigorous screening process to triage and treat patients suspicious for COVID-19 through telehealth in hopes of keeping them safe and in their own homes. We also continue to see patients for nonrespiratory urgent care needs in person once they have screened negative for COVID-19.”

“In terms of the inpatient setting, we’ve noticed that a lot of people are choosing not to go to the hospital now, unless they’re extremely ill,” Dr. Jobbins noted. “We’re going to need to find a balance with when do people truly need to go to the hospital and when do they not? What can we manage as an outpatient versus having someone go to the emergency department? That’s really the role of the primary care physician. We need to help people understand, ‘You don’t need to go to the ED for everything, but here are the things you really need to go for.’ ”

“It will be interesting to see what health care looks like in 6 months or a year. I’m excited to see where we land,” Dr. Jobbins added.


 

Hopes for the Future of Telemedicine

When the practice of medicine enters a post–COVID-19 era, Dr. Jobbins hopes that telemedicine will be incorporated more into the delivery of patient care. “I’ve found that many of my patients who often are no-shows to the inpatient version of their visits have had a higher success rate of follow-through when we do the telephone visits,” she said. “It’s been very successful. I hope that the insurance companies and [Centers for Medicare & Medicaid] will continue to reimburse this as they see this is a benefit to our patients.

Courtesy Dr. Robert Hopkins, Jr.

Dr. Hopkins is also hopeful that physicians will be able to successfully see patients via telemedicine in the postpandemic world.

“For the ups and downs we’ve had with telemedicine, I’d love for us to be able to enhance the positives and incorporate that into our practice going forward. If we can reach our patients and help treat them where they are, rather than them having to come to us, that may be a plus,” he said.

In the meantime, Dr. Jobbins presses on as the curve of COVID-19 cases flattens in Western Massachusetts and remains grateful that she chose to practice medicine.

“The commitment I have to being an educator in addition to being a physician is part of why I keep doing this,” Dr. Jobbins said. “I find this to be one of the most fulfilling jobs and careers you could ever have: being there for people when they need you the most. That’s really what a physician’s job is: being there for people when a family member has passed away or when they just need to talk because they’re having anxiety. At the end of the day, if we can impart that to those we work with and bring in a positive attitude, it’s infectious and it makes people see this is a reason we keep doing what we’re doing.”

She’s also been heartened by the kindness of strangers during this pandemic, from those who made and donated face shields when they were in short supply, to those who delivered food to the hospital as a gesture of thanks.

“I had a patient who made homemade masks and sent them to my office,” she said. “There’s obviously good and bad during this time, but I get hope from seeing all of the good things that are coming out of this, the whole idea of finding the light in the darkness.”

dbrunk@mdedge.com

A minimally invasive multicancer blood test used with standard-of-care screening is safe, effective, and feasible for use in routine clinical care, according to interim findings from a large, prospective study.

The DETECT-A blood test, an early version of the CancerSEEK test currently in development, effectively guided patient management in real time, in some cases leading to diagnosis of early cancer and potentially curative surgery in asymptomatic women with no history of cancer.

Nickolas Papadopoulos, PhD, of Johns Hopkins Medicine in Baltimore, reported these findings at the AACR virtual meeting I. The findings were simultaneously published in Science.

The study enrolled 10,006 women, aged 65-75 years, with no prior cancer diagnosis. After exclusion and loss to follow-up, 9,911 women remained.

There were 26 patients who had cancer detected by the DETECT-A blood test, 15 of whom underwent follow-up PET-CT imaging and 9 of whom underwent surgical excision. An additional 24 cancers were detected by standard screening, and 46 were detected by other means.

The positive predictive value of the blood test was 19%. When the blood test was combined with imaging, the positive predictive value was 41%.
 

Improving upon standard screening

“Standard-of-care screening [was used] for three different organs: breast, lung, and colon. It was more sensitive for breast cancer,” Dr. Papadopoulos noted. “Blood testing, though, identified cancer in 10 different organs.”

In fact, the DETECT-A blood test detected 14 of 45 cancers in 7 organs for which no standard screening test is available.

In addition, 12 cancers in 3 organs (breast, lung, and colon) were first detected by DETECT-A rather than by standard screening. This increased the sensitivity of cancer detection from 47% with standard screening alone to 71% with standard screening plus blood testing.

“More important, 65% [of the cancers detected by blood test] were localized or regional, which have higher chance of successful treatment with intent to cure,” Dr. Papadopoulos said.

DETECT-A covers regions of 16 commonly mutated genes and 9 proteins known to be associated with cancer. In this study, 57% of cancers were detected by mutations.
 

Safety and additional screening

DETECT-A also proved safe, “without incurring a large number of futile invasive follow-up tests,” Dr. Papadopoulos said.

In fact, only 1% of patients without cancer underwent PET-CT imaging, and only 0.22% underwent a “futile” invasive follow-up procedure.

Three surgeries occurred in patients who were counted as false-positives, but the surgeries were determined to be indicated, Dr. Papadopoulos said. He explained that one was for large colonic polyps with high-grade dysplasia that could not be removed endoscopically, one was for an in situ carcinoma of the appendix, and one was for a 10-cm ovarian lesion that was found to be a mucinous cystadenoma.

The investigators also analyzed whether the availability of a “liquid biopsy” test like DETECT-A would inadvertently reduce patients’ use of standard screening and found that it did not. Mammography screening habits after receiving the baseline DETECT-A blood test did not differ significantly from those prior to study enrollment.

These findings are important because early detection is a key factor in reducing cancer-specific morbidity and mortality, and although minimally invasive screening tests, including liquid biopsies like DETECT-A, hold great promise, prospective clinical studies of these new methods are needed to ensure that the anticipated benefits outweigh the potential risks, Dr. Papadopoulos explained.

“The problem is that most cancers are detected at advanced stages when they are difficult to treat,” he said. “The earlier cancer is detected, the greater the chance of successful treatment.”
 

Unanswered questions and future studies

This study demonstrates that it is feasible for a minimally invasive blood test to safely detect multiple cancer types in patients without a history of cancer and to enable treatment with curative intent, at least in a subset of individuals, Dr. Papadopoulos said. He added that the findings also inform the design of future randomized trials “to establish clinical utility, cost-effectiveness, and benefit-to-risk ratio of future tests.”

Further studies will also be required to determine the clinical validity and utility of the strategy of using liquid biopsy as a complement to standard-of-care screening, Dr. Papadopoulos said.

Invited discussant David G. Huntsman, MD, of the University of British Columbia in Vancouver, applauded the investigators, saying this study serves to “move the field forward.” However, it still isn’t clear how sensitivity and negative predictive value will be determined and what the optimal testing schedule is.

“This is a prospective study that will provide the data on how this assay will be used [and] whether it should be used going forward,” Dr. Huntsman said, noting that the “much bigger and more important question” is whether it improves survival.

Cost-effectiveness will also be critical, he said.

This research was supported by The Marcus Foundation, Lustgarten Foundation for Pancreatic Cancer Research, The Virginia and D.K. Ludwig Fund for Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, Susan Wojcicki and Dennis Troper, the Rolfe Foundation, The Conrad R. Hilton Foundation, The John Templeton Foundation, Burroughs Wellcome Career Award For Medical Scientists, and grants/contracts from the National Institutes of Health.

Dr. Papadopoulos disclosed relationships with Thrive Earlier Detection Inc., PGDx Inc., NeoPhore, Cage Pharma, and other companies. Dr. Huntsman is a founder, shareholder, and chief medical officer for Contextual Genomics.

sworcester@mdedge.com

SOURCE: Papadopoulos N et al. AACR 2020, Abstract CT022; Lennon AM et al. Science. 2020 Apr 28. pii: eabb9601. doi: 10.1126/science.abb9601.

A minimally invasive multicancer blood test used with standard-of-care screening is safe, effective, and feasible for use in routine clinical care, according to interim findings from a large, prospective study.

The DETECT-A blood test, an early version of the CancerSEEK test currently in development, effectively guided patient management in real time, in some cases leading to diagnosis of early cancer and potentially curative surgery in asymptomatic women with no history of cancer.

Nickolas Papadopoulos, PhD, of Johns Hopkins Medicine in Baltimore, reported these findings at the AACR virtual meeting I. The findings were simultaneously published in Science.

The study enrolled 10,006 women, aged 65-75 years, with no prior cancer diagnosis. After exclusion and loss to follow-up, 9,911 women remained.

There were 26 patients who had cancer detected by the DETECT-A blood test, 15 of whom underwent follow-up PET-CT imaging and 9 of whom underwent surgical excision. An additional 24 cancers were detected by standard screening, and 46 were detected by other means.

The positive predictive value of the blood test was 19%. When the blood test was combined with imaging, the positive predictive value was 41%.
 

Improving upon standard screening

“Standard-of-care screening [was used] for three different organs: breast, lung, and colon. It was more sensitive for breast cancer,” Dr. Papadopoulos noted. “Blood testing, though, identified cancer in 10 different organs.”

In fact, the DETECT-A blood test detected 14 of 45 cancers in 7 organs for which no standard screening test is available.

In addition, 12 cancers in 3 organs (breast, lung, and colon) were first detected by DETECT-A rather than by standard screening. This increased the sensitivity of cancer detection from 47% with standard screening alone to 71% with standard screening plus blood testing.

“More important, 65% [of the cancers detected by blood test] were localized or regional, which have higher chance of successful treatment with intent to cure,” Dr. Papadopoulos said.

DETECT-A covers regions of 16 commonly mutated genes and 9 proteins known to be associated with cancer. In this study, 57% of cancers were detected by mutations.
 

Safety and additional screening

DETECT-A also proved safe, “without incurring a large number of futile invasive follow-up tests,” Dr. Papadopoulos said.

In fact, only 1% of patients without cancer underwent PET-CT imaging, and only 0.22% underwent a “futile” invasive follow-up procedure.

Three surgeries occurred in patients who were counted as false-positives, but the surgeries were determined to be indicated, Dr. Papadopoulos said. He explained that one was for large colonic polyps with high-grade dysplasia that could not be removed endoscopically, one was for an in situ carcinoma of the appendix, and one was for a 10-cm ovarian lesion that was found to be a mucinous cystadenoma.

The investigators also analyzed whether the availability of a “liquid biopsy” test like DETECT-A would inadvertently reduce patients’ use of standard screening and found that it did not. Mammography screening habits after receiving the baseline DETECT-A blood test did not differ significantly from those prior to study enrollment.

These findings are important because early detection is a key factor in reducing cancer-specific morbidity and mortality, and although minimally invasive screening tests, including liquid biopsies like DETECT-A, hold great promise, prospective clinical studies of these new methods are needed to ensure that the anticipated benefits outweigh the potential risks, Dr. Papadopoulos explained.

“The problem is that most cancers are detected at advanced stages when they are difficult to treat,” he said. “The earlier cancer is detected, the greater the chance of successful treatment.”
 

Unanswered questions and future studies

This study demonstrates that it is feasible for a minimally invasive blood test to safely detect multiple cancer types in patients without a history of cancer and to enable treatment with curative intent, at least in a subset of individuals, Dr. Papadopoulos said. He added that the findings also inform the design of future randomized trials “to establish clinical utility, cost-effectiveness, and benefit-to-risk ratio of future tests.”

Further studies will also be required to determine the clinical validity and utility of the strategy of using liquid biopsy as a complement to standard-of-care screening, Dr. Papadopoulos said.

Invited discussant David G. Huntsman, MD, of the University of British Columbia in Vancouver, applauded the investigators, saying this study serves to “move the field forward.” However, it still isn’t clear how sensitivity and negative predictive value will be determined and what the optimal testing schedule is.

“This is a prospective study that will provide the data on how this assay will be used [and] whether it should be used going forward,” Dr. Huntsman said, noting that the “much bigger and more important question” is whether it improves survival.

Cost-effectiveness will also be critical, he said.

This research was supported by The Marcus Foundation, Lustgarten Foundation for Pancreatic Cancer Research, The Virginia and D.K. Ludwig Fund for Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, Susan Wojcicki and Dennis Troper, the Rolfe Foundation, The Conrad R. Hilton Foundation, The John Templeton Foundation, Burroughs Wellcome Career Award For Medical Scientists, and grants/contracts from the National Institutes of Health.

Dr. Papadopoulos disclosed relationships with Thrive Earlier Detection Inc., PGDx Inc., NeoPhore, Cage Pharma, and other companies. Dr. Huntsman is a founder, shareholder, and chief medical officer for Contextual Genomics.

sworcester@mdedge.com

SOURCE: Papadopoulos N et al. AACR 2020, Abstract CT022; Lennon AM et al. Science. 2020 Apr 28. pii: eabb9601. doi: 10.1126/science.abb9601.

A minimally invasive multicancer blood test used with standard-of-care screening is safe, effective, and feasible for use in routine clinical care, according to interim findings from a large, prospective study.

The DETECT-A blood test, an early version of the CancerSEEK test currently in development, effectively guided patient management in real time, in some cases leading to diagnosis of early cancer and potentially curative surgery in asymptomatic women with no history of cancer.

Nickolas Papadopoulos, PhD, of Johns Hopkins Medicine in Baltimore, reported these findings at the AACR virtual meeting I. The findings were simultaneously published in Science.

The study enrolled 10,006 women, aged 65-75 years, with no prior cancer diagnosis. After exclusion and loss to follow-up, 9,911 women remained.

There were 26 patients who had cancer detected by the DETECT-A blood test, 15 of whom underwent follow-up PET-CT imaging and 9 of whom underwent surgical excision. An additional 24 cancers were detected by standard screening, and 46 were detected by other means.

The positive predictive value of the blood test was 19%. When the blood test was combined with imaging, the positive predictive value was 41%.
 

Improving upon standard screening

“Standard-of-care screening [was used] for three different organs: breast, lung, and colon. It was more sensitive for breast cancer,” Dr. Papadopoulos noted. “Blood testing, though, identified cancer in 10 different organs.”

In fact, the DETECT-A blood test detected 14 of 45 cancers in 7 organs for which no standard screening test is available.

In addition, 12 cancers in 3 organs (breast, lung, and colon) were first detected by DETECT-A rather than by standard screening. This increased the sensitivity of cancer detection from 47% with standard screening alone to 71% with standard screening plus blood testing.

“More important, 65% [of the cancers detected by blood test] were localized or regional, which have higher chance of successful treatment with intent to cure,” Dr. Papadopoulos said.

DETECT-A covers regions of 16 commonly mutated genes and 9 proteins known to be associated with cancer. In this study, 57% of cancers were detected by mutations.
 

Safety and additional screening

DETECT-A also proved safe, “without incurring a large number of futile invasive follow-up tests,” Dr. Papadopoulos said.

In fact, only 1% of patients without cancer underwent PET-CT imaging, and only 0.22% underwent a “futile” invasive follow-up procedure.

Three surgeries occurred in patients who were counted as false-positives, but the surgeries were determined to be indicated, Dr. Papadopoulos said. He explained that one was for large colonic polyps with high-grade dysplasia that could not be removed endoscopically, one was for an in situ carcinoma of the appendix, and one was for a 10-cm ovarian lesion that was found to be a mucinous cystadenoma.

The investigators also analyzed whether the availability of a “liquid biopsy” test like DETECT-A would inadvertently reduce patients’ use of standard screening and found that it did not. Mammography screening habits after receiving the baseline DETECT-A blood test did not differ significantly from those prior to study enrollment.

These findings are important because early detection is a key factor in reducing cancer-specific morbidity and mortality, and although minimally invasive screening tests, including liquid biopsies like DETECT-A, hold great promise, prospective clinical studies of these new methods are needed to ensure that the anticipated benefits outweigh the potential risks, Dr. Papadopoulos explained.

“The problem is that most cancers are detected at advanced stages when they are difficult to treat,” he said. “The earlier cancer is detected, the greater the chance of successful treatment.”
 

Unanswered questions and future studies

This study demonstrates that it is feasible for a minimally invasive blood test to safely detect multiple cancer types in patients without a history of cancer and to enable treatment with curative intent, at least in a subset of individuals, Dr. Papadopoulos said. He added that the findings also inform the design of future randomized trials “to establish clinical utility, cost-effectiveness, and benefit-to-risk ratio of future tests.”

Further studies will also be required to determine the clinical validity and utility of the strategy of using liquid biopsy as a complement to standard-of-care screening, Dr. Papadopoulos said.

Invited discussant David G. Huntsman, MD, of the University of British Columbia in Vancouver, applauded the investigators, saying this study serves to “move the field forward.” However, it still isn’t clear how sensitivity and negative predictive value will be determined and what the optimal testing schedule is.

“This is a prospective study that will provide the data on how this assay will be used [and] whether it should be used going forward,” Dr. Huntsman said, noting that the “much bigger and more important question” is whether it improves survival.

Cost-effectiveness will also be critical, he said.

This research was supported by The Marcus Foundation, Lustgarten Foundation for Pancreatic Cancer Research, The Virginia and D.K. Ludwig Fund for Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, Susan Wojcicki and Dennis Troper, the Rolfe Foundation, The Conrad R. Hilton Foundation, The John Templeton Foundation, Burroughs Wellcome Career Award For Medical Scientists, and grants/contracts from the National Institutes of Health.

Dr. Papadopoulos disclosed relationships with Thrive Earlier Detection Inc., PGDx Inc., NeoPhore, Cage Pharma, and other companies. Dr. Huntsman is a founder, shareholder, and chief medical officer for Contextual Genomics.

sworcester@mdedge.com

SOURCE: Papadopoulos N et al. AACR 2020, Abstract CT022; Lennon AM et al. Science. 2020 Apr 28. pii: eabb9601. doi: 10.1126/science.abb9601.