Since the early 2000s, new discoveries about GIST genomics have contributed to better, more targeted treatments. Some genomic mutations have been linked to specific gut regions,⁷ which may further help guide therapy as well.

GIST: What Is It, Who Gets It, and How Is It Diagnosed?

What, How Many, Where?

Even though GIST is considered rare—representing less than 1% of gastrointestinal tumors⁸—it is the most common sarcoma, which is a family of mesenchymal neoplasms. GISTs are thought to arise from the interstitial cells of Cajal, or the pacemaker cells of the gut that control peristalsis. In the United States, the incidence of GIST is roughly 4,000 to 6,000 new cases diagnosed per year, with most cases found in the stomach (60%) or small intestine (35%). Other gut regions in which GISTs may be identified include the rectum and esophagus.⁸

Although asymptomatic tumors are often discovered incidentally, GISTs that originate in the stomach—the most common primary tumor site—may present with nonspecific subjective symptoms such as pain, nausea, loss of appetite, early satiety, or bloating.⁹ Symptoms may vary according to tumor location (eg, stomach vs rectum vs esophagus), size, and pattern of growth. More objective signs could include anemia related to gastrointestinal bleeding, weight loss, or a palpable mass.⁹

Who?

Most cases of GIST occur in patients later in life, with a median age of 64 years at diagnosis. A slight predominance of men has been noted, along with African American and Asian individuals affected somewhat more frequently than White or Hispanic populations.¹⁰ GIST is rare in children and adolescents, and the symptoms and pathology differ from those in most adults.⁹ Previously age was considered a determining factor in the differences in GIST, with cases in children classified as “pediatric-type” GIST or “wild-type” GIST. These cases generally present in the stomach, are more likely to include lymph node involvement, and can also spread to the liver and abdominal lining. Importantly, they are usually not associated with the tyrosine-protein kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA) gene mutations found in most adults.⁹ About 80% of these cases have hereditary mutations of the succinate dehydrogenase (SDH) enzyme complex. Because some adult cases of GIST share the distinct characteristics found in most pediatric cases, distinguishing them based on age, rather than on the specific genetic characteristics of the tumor, is unwarranted.⁹

How?

When GIST is suspected or when symptoms mandate further investigation, coordination among colleagues in imaging, gastroenterology, pathology, surgery, and oncology is critical for accurate diagnosis, staging, and treatment. Abdominal imaging may be ordered using modalities such as ultrasound, computed tomography, magnetic resonance imaging, and, occasionally, positron emission tomography.¹¹ Endoscopic ultrasound is useful to identify and biopsy lesions in the stomach or rectum, as these tumors arise below the lining of the stomach or rectum. GIST diagnosis can be confirmed by biopsy during endoscopic ultrasound, which is the preferred approach, or by percutaneous biopsy when endoscopic biopsy is not feasible or safe.¹¹

According to the European Society for Medical Oncology (ESMO) and European Reference Group for Rare Adult Solid Cancers (EURACAN) Clinical Practice Guidelines, the “standard approach to tumors ≥ 2 cm in size is excision, because they are associated with a higher risk of progression if confirmed as GIST. If there is an abdominal nodule not amenable to endoscopic assessment, laparoscopic or laparotomic excision is the standard approach.”¹¹

Genetic Mutations

A diagnosis of GIST is made based on the combination of the clinical scenario, the tumor’s anatomic location, immunohistochemistry patterns, and molecular features.¹² Research has shown that genetic mutations in the KIT, PDGFRA, or SDH genes are present in most cases of GIST (70-80%,¹³ 10%,¹² and less than 10% of cases^12,14 respectively) and their presence can be used for diagnosis. A growing number of rarer mutations have also been discovered,¹³ meaning that gene-based diagnosis of GIST is becoming increasingly sensitive. In addition, antigens on the surface of cancer cells can help classify them as GIST. For example, researchers have discovered that most GIST cells have the marker CD117, the protein product of the KIT gene that is commonly mutated in GIST, on their surfaces. A different marker, DOG1 (ie, Discovered On GIST 1), is also present on the vast majority of GISTs, but not unanimously overlapping with CD117. A tumor that is positive for both CD117 and DOG1 has a high probability (> 97%) of being GIST.¹⁵

Next-generation sequencing (NGS) is considered the best tool for determining both germline and somatic mutations in patients with GIST, and NGS is recommended by both the NCCN⁶ and the ESMO¹¹ for individualizing systemic therapy. Despite these recommendations, most patients do not undergo genetic testing, both in the United States¹⁶ and internationally.¹⁷ Several barriers to genetic testing have been cited, predominately inadequate tissue and high cost. However, a study demonstrated that costs of up to $3,730 for genetic testing were ultimately cost-effective for tailoring therapy with first-line imatinib for patients with newly diagnosed metastatic GIST.¹⁸ Moreover, genetic testing also should be strongly considered for patients with nonmetastatic disease in whom systemic therapy is being considered.

Increasing evidence has emerged that gastric GIST mutations are related to tumor location within the gastrointestinal tract (Figure).⁷ The anatomic location of the GIST may provide clues for clinical decision-making and may guide selective confirmatory genomic testing when access to testing is limited.

Treatment of GIST

Surgery 

Surgery remains the main treatment for localized GIST, especially if the tumor is discovered at an early stage. Unfortunately, up to a quarter of patients present with metastatic disease at diagnosis. The goal of surgery is to resect the tumor with histologically negative margins. Every effort should be made to avoid rupturing the tumor capsule during resection. Studies have shown that laparoscopic resection is feasible and safe for gastric GISTs and is less invasive than traditional open surgery, with similar oncological outcomes.¹⁹

Debulking surgery is sometimes considered for patients with metastatic disease, especially for patients who demonstrate sensitivity to TKI and whose disease has not yet progressed.^20,21 Other interventions, such as microwave ablation or transhepatic arterial embolization, are sometimes used to control hepatic metastases.

Systemic Therapies

Whether systemic therapy is being considered in the neoadjuvant (preoperative), adjuvant (postoperative), or advanced disease setting, mutations in GIST determine the likelihood of treatment success. Both NCCN⁶ and ESMO¹¹ strongly encourage use of mutational analyses and genetic testing for patients with GIST before systemic therapy is initiated.

In some cases of locally advanced GIST, tumors may be situated in particularly challenging anatomic locations(eg, esophagus, duodenum, rectum) or may require a highly morbid, multivisceral resection. In such situations, neoadjuvant treatment with imatinib,^22,23 if deemed appropriate per mutational profiling, should be considered.

Patients who are determined to be at high risk for recurrence after surgery, based on tumor size, mitotic index determined by pathologist review of dividing cells, tumor location, and tumor rupture, may be eligible for adjuvant treatment with imatinib.²⁴ Although the ideal duration of adjuvant therapy is not yet known, the current standard is at least 3 years,²⁵ but many practitioners advocate for lifelong therapy.

Imatinib. Because chemotherapy was ineffective against GIST, prognosis was dismal for patients diagnosed with advanced disease before the approval of imatinib in the early 2000s.² A selective TKI, imatinib targets the KIT and PDGFRA receptor kinases, and most patients experience clinical benefit,²⁶ at least initially. Unfortunately, many tumors eventually develop resistance, and discontinuation of imatinib is associated with a risk for disease progression.²⁷

Sunitinib. The emergence of resistance to imatinib spurred the search for second-line agents that might be useful after disease progression. Another TKI, sunitinib, which has both antitumor and antiangiogenic activity, was approved in 2006 for management of advanced imatinib-resistant GIST.²⁸ Knowledge of a tumor’s driver mutation(s) can help optimize use of sunitinib.²⁹

Regorafenib. In 2013, the FDA approved regorafenib, another TKI, as a third-line agent for patients with advanced GIST that is refractory to imatinib and sunitinib.³⁰ Regorafenib exerts its activity against multiple targets, including VEGFR1-3, TIE2 (ie, antiangiogenic activity), PDGFR-β, FGFR (ie, stromal targets), and KIT, RET, and RAF (ie, oncogenic targets). As with other TKIs, common adverse effects associated with regorafenib treatment include hypertension, hand-foot skin reaction, rash, diarrhea, and fatigue.

Larotrectinib/entrectinib. The FDA approved larotrectinib³¹ (2018) and entrectinib³² (2019) as the first tumor-agnostic agents, whose use is based on the presence of  specific genomic alteration, in this case NTRK. If a tumor, including a GIST, harbors a specific, albeit rare, gene fusion, it may be considered for treatment with one of these small-molecule TRK family inhibitors. Although these agents are not specifically indicated for GIST, some subjects enrolled in the trials had GIST harboring the target NTRK gene fusion and their tumors responded to treatment.

Ripretinib. FDA-approved in 2020,³³ ripretinib is a novel TKI indicated for adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. A phase 3 trial demonstrated improved progression-free and overall survival when ripretinib was compared with placebo in patients who had disease progression after treatment with imatinib, sunitinib, or regorafenib.³⁴ Ripretinib is now being investigated in the second-line setting in selected patients with KIT mutations.

Avapritinib. Cases of GIST with PDGFRA D842V-mutant tumors often demonstrate primary resistance to imatinib and sunitinib. In 2020, avapritinib, a selective TKI that targets both KIT and PDGFRA, was approved³⁵ for treatment of patients with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including D842V mutations. However, it is noteworthy that many of the non-D842V mutations in PDGFRA respond to imatinib.

Dabrafenib/trametinib. In 2022, the FDA issued an approval for treatment based on a driver mutation rather than tumor type. Acknowledging that a BRAF mutation—specifically a V600E mutation—appears to be a critical target in several cancers, the FDA granted accelerated approval for the use of dabrafenib plus trametinib in adults and children 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options.³⁶

Researchers have studied additional TKIs in the setting of unresectable, metastatic disease due to the varied genomic landscape of GIST. The NCCN Guidelines include evidence of some benefit for agents such as dasatinib, cabozantinib, everolimus (plus a TKI), nilotinib, pazopanib, and sorafenib “in certain circumstances.”⁶

The Future of GIST

The most critical step toward optimal treatment decision-making when a patient has been diagnosed with GIST is identification of physicians with expertise in the care of patients with GIST. With increasing knowledge of genomic variations in GIST, patient care has become less prescripted and much more personalized. To that end, determination of the tumor’s genetic mutational profile is critical to guiding treatment. Although factors such as cost, availability/accessibility, and insufficient tissue continue to represent substantial obstacles, pursing this information may be the most important way that clinicians can advocate for their patients. Moreover, now that the anatomic location of GIST has been linked to specific driver mutations, the ability to select and refine treatments may improve significantly.

Likewise, in view of the increasing complexity and multidisciplinary management of patients with GIST, efficient coordination is paramount among surgical and medical oncologists, as well as radiologists, gastroenterologists, and pathologists.

Click to read more from 2023 Rare Diseases Report: Cancers

Since the early 2000s, new discoveries about GIST genomics have contributed to better, more targeted treatments. Some genomic mutations have been linked to specific gut regions,⁷ which may further help guide therapy as well.

GIST: What Is It, Who Gets It, and How Is It Diagnosed?

What, How Many, Where?

Even though GIST is considered rare—representing less than 1% of gastrointestinal tumors⁸—it is the most common sarcoma, which is a family of mesenchymal neoplasms. GISTs are thought to arise from the interstitial cells of Cajal, or the pacemaker cells of the gut that control peristalsis. In the United States, the incidence of GIST is roughly 4,000 to 6,000 new cases diagnosed per year, with most cases found in the stomach (60%) or small intestine (35%). Other gut regions in which GISTs may be identified include the rectum and esophagus.⁸

Although asymptomatic tumors are often discovered incidentally, GISTs that originate in the stomach—the most common primary tumor site—may present with nonspecific subjective symptoms such as pain, nausea, loss of appetite, early satiety, or bloating.⁹ Symptoms may vary according to tumor location (eg, stomach vs rectum vs esophagus), size, and pattern of growth. More objective signs could include anemia related to gastrointestinal bleeding, weight loss, or a palpable mass.⁹

Who?

Most cases of GIST occur in patients later in life, with a median age of 64 years at diagnosis. A slight predominance of men has been noted, along with African American and Asian individuals affected somewhat more frequently than White or Hispanic populations.¹⁰ GIST is rare in children and adolescents, and the symptoms and pathology differ from those in most adults.⁹ Previously age was considered a determining factor in the differences in GIST, with cases in children classified as “pediatric-type” GIST or “wild-type” GIST. These cases generally present in the stomach, are more likely to include lymph node involvement, and can also spread to the liver and abdominal lining. Importantly, they are usually not associated with the tyrosine-protein kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA) gene mutations found in most adults.⁹ About 80% of these cases have hereditary mutations of the succinate dehydrogenase (SDH) enzyme complex. Because some adult cases of GIST share the distinct characteristics found in most pediatric cases, distinguishing them based on age, rather than on the specific genetic characteristics of the tumor, is unwarranted.⁹

How?

When GIST is suspected or when symptoms mandate further investigation, coordination among colleagues in imaging, gastroenterology, pathology, surgery, and oncology is critical for accurate diagnosis, staging, and treatment. Abdominal imaging may be ordered using modalities such as ultrasound, computed tomography, magnetic resonance imaging, and, occasionally, positron emission tomography.¹¹ Endoscopic ultrasound is useful to identify and biopsy lesions in the stomach or rectum, as these tumors arise below the lining of the stomach or rectum. GIST diagnosis can be confirmed by biopsy during endoscopic ultrasound, which is the preferred approach, or by percutaneous biopsy when endoscopic biopsy is not feasible or safe.¹¹

According to the European Society for Medical Oncology (ESMO) and European Reference Group for Rare Adult Solid Cancers (EURACAN) Clinical Practice Guidelines, the “standard approach to tumors ≥ 2 cm in size is excision, because they are associated with a higher risk of progression if confirmed as GIST. If there is an abdominal nodule not amenable to endoscopic assessment, laparoscopic or laparotomic excision is the standard approach.”¹¹

Genetic Mutations

A diagnosis of GIST is made based on the combination of the clinical scenario, the tumor’s anatomic location, immunohistochemistry patterns, and molecular features.¹² Research has shown that genetic mutations in the KIT, PDGFRA, or SDH genes are present in most cases of GIST (70-80%,¹³ 10%,¹² and less than 10% of cases^12,14 respectively) and their presence can be used for diagnosis. A growing number of rarer mutations have also been discovered,¹³ meaning that gene-based diagnosis of GIST is becoming increasingly sensitive. In addition, antigens on the surface of cancer cells can help classify them as GIST. For example, researchers have discovered that most GIST cells have the marker CD117, the protein product of the KIT gene that is commonly mutated in GIST, on their surfaces. A different marker, DOG1 (ie, Discovered On GIST 1), is also present on the vast majority of GISTs, but not unanimously overlapping with CD117. A tumor that is positive for both CD117 and DOG1 has a high probability (> 97%) of being GIST.¹⁵

Next-generation sequencing (NGS) is considered the best tool for determining both germline and somatic mutations in patients with GIST, and NGS is recommended by both the NCCN⁶ and the ESMO¹¹ for individualizing systemic therapy. Despite these recommendations, most patients do not undergo genetic testing, both in the United States¹⁶ and internationally.¹⁷ Several barriers to genetic testing have been cited, predominately inadequate tissue and high cost. However, a study demonstrated that costs of up to $3,730 for genetic testing were ultimately cost-effective for tailoring therapy with first-line imatinib for patients with newly diagnosed metastatic GIST.¹⁸ Moreover, genetic testing also should be strongly considered for patients with nonmetastatic disease in whom systemic therapy is being considered.

Increasing evidence has emerged that gastric GIST mutations are related to tumor location within the gastrointestinal tract (Figure).⁷ The anatomic location of the GIST may provide clues for clinical decision-making and may guide selective confirmatory genomic testing when access to testing is limited.

Treatment of GIST

Surgery 

Surgery remains the main treatment for localized GIST, especially if the tumor is discovered at an early stage. Unfortunately, up to a quarter of patients present with metastatic disease at diagnosis. The goal of surgery is to resect the tumor with histologically negative margins. Every effort should be made to avoid rupturing the tumor capsule during resection. Studies have shown that laparoscopic resection is feasible and safe for gastric GISTs and is less invasive than traditional open surgery, with similar oncological outcomes.¹⁹

Debulking surgery is sometimes considered for patients with metastatic disease, especially for patients who demonstrate sensitivity to TKI and whose disease has not yet progressed.^20,21 Other interventions, such as microwave ablation or transhepatic arterial embolization, are sometimes used to control hepatic metastases.

Systemic Therapies

Whether systemic therapy is being considered in the neoadjuvant (preoperative), adjuvant (postoperative), or advanced disease setting, mutations in GIST determine the likelihood of treatment success. Both NCCN⁶ and ESMO¹¹ strongly encourage use of mutational analyses and genetic testing for patients with GIST before systemic therapy is initiated.

In some cases of locally advanced GIST, tumors may be situated in particularly challenging anatomic locations(eg, esophagus, duodenum, rectum) or may require a highly morbid, multivisceral resection. In such situations, neoadjuvant treatment with imatinib,^22,23 if deemed appropriate per mutational profiling, should be considered.

Patients who are determined to be at high risk for recurrence after surgery, based on tumor size, mitotic index determined by pathologist review of dividing cells, tumor location, and tumor rupture, may be eligible for adjuvant treatment with imatinib.²⁴ Although the ideal duration of adjuvant therapy is not yet known, the current standard is at least 3 years,²⁵ but many practitioners advocate for lifelong therapy.

Imatinib. Because chemotherapy was ineffective against GIST, prognosis was dismal for patients diagnosed with advanced disease before the approval of imatinib in the early 2000s.² A selective TKI, imatinib targets the KIT and PDGFRA receptor kinases, and most patients experience clinical benefit,²⁶ at least initially. Unfortunately, many tumors eventually develop resistance, and discontinuation of imatinib is associated with a risk for disease progression.²⁷

Sunitinib. The emergence of resistance to imatinib spurred the search for second-line agents that might be useful after disease progression. Another TKI, sunitinib, which has both antitumor and antiangiogenic activity, was approved in 2006 for management of advanced imatinib-resistant GIST.²⁸ Knowledge of a tumor’s driver mutation(s) can help optimize use of sunitinib.²⁹

Regorafenib. In 2013, the FDA approved regorafenib, another TKI, as a third-line agent for patients with advanced GIST that is refractory to imatinib and sunitinib.³⁰ Regorafenib exerts its activity against multiple targets, including VEGFR1-3, TIE2 (ie, antiangiogenic activity), PDGFR-β, FGFR (ie, stromal targets), and KIT, RET, and RAF (ie, oncogenic targets). As with other TKIs, common adverse effects associated with regorafenib treatment include hypertension, hand-foot skin reaction, rash, diarrhea, and fatigue.

Larotrectinib/entrectinib. The FDA approved larotrectinib³¹ (2018) and entrectinib³² (2019) as the first tumor-agnostic agents, whose use is based on the presence of  specific genomic alteration, in this case NTRK. If a tumor, including a GIST, harbors a specific, albeit rare, gene fusion, it may be considered for treatment with one of these small-molecule TRK family inhibitors. Although these agents are not specifically indicated for GIST, some subjects enrolled in the trials had GIST harboring the target NTRK gene fusion and their tumors responded to treatment.

Ripretinib. FDA-approved in 2020,³³ ripretinib is a novel TKI indicated for adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. A phase 3 trial demonstrated improved progression-free and overall survival when ripretinib was compared with placebo in patients who had disease progression after treatment with imatinib, sunitinib, or regorafenib.³⁴ Ripretinib is now being investigated in the second-line setting in selected patients with KIT mutations.

Avapritinib. Cases of GIST with PDGFRA D842V-mutant tumors often demonstrate primary resistance to imatinib and sunitinib. In 2020, avapritinib, a selective TKI that targets both KIT and PDGFRA, was approved³⁵ for treatment of patients with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including D842V mutations. However, it is noteworthy that many of the non-D842V mutations in PDGFRA respond to imatinib.

Dabrafenib/trametinib. In 2022, the FDA issued an approval for treatment based on a driver mutation rather than tumor type. Acknowledging that a BRAF mutation—specifically a V600E mutation—appears to be a critical target in several cancers, the FDA granted accelerated approval for the use of dabrafenib plus trametinib in adults and children 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options.³⁶

Researchers have studied additional TKIs in the setting of unresectable, metastatic disease due to the varied genomic landscape of GIST. The NCCN Guidelines include evidence of some benefit for agents such as dasatinib, cabozantinib, everolimus (plus a TKI), nilotinib, pazopanib, and sorafenib “in certain circumstances.”⁶

The Future of GIST

The most critical step toward optimal treatment decision-making when a patient has been diagnosed with GIST is identification of physicians with expertise in the care of patients with GIST. With increasing knowledge of genomic variations in GIST, patient care has become less prescripted and much more personalized. To that end, determination of the tumor’s genetic mutational profile is critical to guiding treatment. Although factors such as cost, availability/accessibility, and insufficient tissue continue to represent substantial obstacles, pursing this information may be the most important way that clinicians can advocate for their patients. Moreover, now that the anatomic location of GIST has been linked to specific driver mutations, the ability to select and refine treatments may improve significantly.

Likewise, in view of the increasing complexity and multidisciplinary management of patients with GIST, efficient coordination is paramount among surgical and medical oncologists, as well as radiologists, gastroenterologists, and pathologists.

Click to read more from 2023 Rare Diseases Report: Cancers

Since the early 2000s, new discoveries about GIST genomics have contributed to better, more targeted treatments. Some genomic mutations have been linked to specific gut regions,⁷ which may further help guide therapy as well.

GIST: What Is It, Who Gets It, and How Is It Diagnosed?

What, How Many, Where?

Even though GIST is considered rare—representing less than 1% of gastrointestinal tumors⁸—it is the most common sarcoma, which is a family of mesenchymal neoplasms. GISTs are thought to arise from the interstitial cells of Cajal, or the pacemaker cells of the gut that control peristalsis. In the United States, the incidence of GIST is roughly 4,000 to 6,000 new cases diagnosed per year, with most cases found in the stomach (60%) or small intestine (35%). Other gut regions in which GISTs may be identified include the rectum and esophagus.⁸

Although asymptomatic tumors are often discovered incidentally, GISTs that originate in the stomach—the most common primary tumor site—may present with nonspecific subjective symptoms such as pain, nausea, loss of appetite, early satiety, or bloating.⁹ Symptoms may vary according to tumor location (eg, stomach vs rectum vs esophagus), size, and pattern of growth. More objective signs could include anemia related to gastrointestinal bleeding, weight loss, or a palpable mass.⁹

Who?

Most cases of GIST occur in patients later in life, with a median age of 64 years at diagnosis. A slight predominance of men has been noted, along with African American and Asian individuals affected somewhat more frequently than White or Hispanic populations.¹⁰ GIST is rare in children and adolescents, and the symptoms and pathology differ from those in most adults.⁹ Previously age was considered a determining factor in the differences in GIST, with cases in children classified as “pediatric-type” GIST or “wild-type” GIST. These cases generally present in the stomach, are more likely to include lymph node involvement, and can also spread to the liver and abdominal lining. Importantly, they are usually not associated with the tyrosine-protein kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA) gene mutations found in most adults.⁹ About 80% of these cases have hereditary mutations of the succinate dehydrogenase (SDH) enzyme complex. Because some adult cases of GIST share the distinct characteristics found in most pediatric cases, distinguishing them based on age, rather than on the specific genetic characteristics of the tumor, is unwarranted.⁹

How?

When GIST is suspected or when symptoms mandate further investigation, coordination among colleagues in imaging, gastroenterology, pathology, surgery, and oncology is critical for accurate diagnosis, staging, and treatment. Abdominal imaging may be ordered using modalities such as ultrasound, computed tomography, magnetic resonance imaging, and, occasionally, positron emission tomography.¹¹ Endoscopic ultrasound is useful to identify and biopsy lesions in the stomach or rectum, as these tumors arise below the lining of the stomach or rectum. GIST diagnosis can be confirmed by biopsy during endoscopic ultrasound, which is the preferred approach, or by percutaneous biopsy when endoscopic biopsy is not feasible or safe.¹¹

According to the European Society for Medical Oncology (ESMO) and European Reference Group for Rare Adult Solid Cancers (EURACAN) Clinical Practice Guidelines, the “standard approach to tumors ≥ 2 cm in size is excision, because they are associated with a higher risk of progression if confirmed as GIST. If there is an abdominal nodule not amenable to endoscopic assessment, laparoscopic or laparotomic excision is the standard approach.”¹¹

Genetic Mutations

A diagnosis of GIST is made based on the combination of the clinical scenario, the tumor’s anatomic location, immunohistochemistry patterns, and molecular features.¹² Research has shown that genetic mutations in the KIT, PDGFRA, or SDH genes are present in most cases of GIST (70-80%,¹³ 10%,¹² and less than 10% of cases^12,14 respectively) and their presence can be used for diagnosis. A growing number of rarer mutations have also been discovered,¹³ meaning that gene-based diagnosis of GIST is becoming increasingly sensitive. In addition, antigens on the surface of cancer cells can help classify them as GIST. For example, researchers have discovered that most GIST cells have the marker CD117, the protein product of the KIT gene that is commonly mutated in GIST, on their surfaces. A different marker, DOG1 (ie, Discovered On GIST 1), is also present on the vast majority of GISTs, but not unanimously overlapping with CD117. A tumor that is positive for both CD117 and DOG1 has a high probability (> 97%) of being GIST.¹⁵

Next-generation sequencing (NGS) is considered the best tool for determining both germline and somatic mutations in patients with GIST, and NGS is recommended by both the NCCN⁶ and the ESMO¹¹ for individualizing systemic therapy. Despite these recommendations, most patients do not undergo genetic testing, both in the United States¹⁶ and internationally.¹⁷ Several barriers to genetic testing have been cited, predominately inadequate tissue and high cost. However, a study demonstrated that costs of up to $3,730 for genetic testing were ultimately cost-effective for tailoring therapy with first-line imatinib for patients with newly diagnosed metastatic GIST.¹⁸ Moreover, genetic testing also should be strongly considered for patients with nonmetastatic disease in whom systemic therapy is being considered.

Increasing evidence has emerged that gastric GIST mutations are related to tumor location within the gastrointestinal tract (Figure).⁷ The anatomic location of the GIST may provide clues for clinical decision-making and may guide selective confirmatory genomic testing when access to testing is limited.

Treatment of GIST

Surgery 

Surgery remains the main treatment for localized GIST, especially if the tumor is discovered at an early stage. Unfortunately, up to a quarter of patients present with metastatic disease at diagnosis. The goal of surgery is to resect the tumor with histologically negative margins. Every effort should be made to avoid rupturing the tumor capsule during resection. Studies have shown that laparoscopic resection is feasible and safe for gastric GISTs and is less invasive than traditional open surgery, with similar oncological outcomes.¹⁹

Debulking surgery is sometimes considered for patients with metastatic disease, especially for patients who demonstrate sensitivity to TKI and whose disease has not yet progressed.^20,21 Other interventions, such as microwave ablation or transhepatic arterial embolization, are sometimes used to control hepatic metastases.

Systemic Therapies

Whether systemic therapy is being considered in the neoadjuvant (preoperative), adjuvant (postoperative), or advanced disease setting, mutations in GIST determine the likelihood of treatment success. Both NCCN⁶ and ESMO¹¹ strongly encourage use of mutational analyses and genetic testing for patients with GIST before systemic therapy is initiated.

In some cases of locally advanced GIST, tumors may be situated in particularly challenging anatomic locations(eg, esophagus, duodenum, rectum) or may require a highly morbid, multivisceral resection. In such situations, neoadjuvant treatment with imatinib,^22,23 if deemed appropriate per mutational profiling, should be considered.

Patients who are determined to be at high risk for recurrence after surgery, based on tumor size, mitotic index determined by pathologist review of dividing cells, tumor location, and tumor rupture, may be eligible for adjuvant treatment with imatinib.²⁴ Although the ideal duration of adjuvant therapy is not yet known, the current standard is at least 3 years,²⁵ but many practitioners advocate for lifelong therapy.

Imatinib. Because chemotherapy was ineffective against GIST, prognosis was dismal for patients diagnosed with advanced disease before the approval of imatinib in the early 2000s.² A selective TKI, imatinib targets the KIT and PDGFRA receptor kinases, and most patients experience clinical benefit,²⁶ at least initially. Unfortunately, many tumors eventually develop resistance, and discontinuation of imatinib is associated with a risk for disease progression.²⁷

Sunitinib. The emergence of resistance to imatinib spurred the search for second-line agents that might be useful after disease progression. Another TKI, sunitinib, which has both antitumor and antiangiogenic activity, was approved in 2006 for management of advanced imatinib-resistant GIST.²⁸ Knowledge of a tumor’s driver mutation(s) can help optimize use of sunitinib.²⁹

Regorafenib. In 2013, the FDA approved regorafenib, another TKI, as a third-line agent for patients with advanced GIST that is refractory to imatinib and sunitinib.³⁰ Regorafenib exerts its activity against multiple targets, including VEGFR1-3, TIE2 (ie, antiangiogenic activity), PDGFR-β, FGFR (ie, stromal targets), and KIT, RET, and RAF (ie, oncogenic targets). As with other TKIs, common adverse effects associated with regorafenib treatment include hypertension, hand-foot skin reaction, rash, diarrhea, and fatigue.

Larotrectinib/entrectinib. The FDA approved larotrectinib³¹ (2018) and entrectinib³² (2019) as the first tumor-agnostic agents, whose use is based on the presence of  specific genomic alteration, in this case NTRK. If a tumor, including a GIST, harbors a specific, albeit rare, gene fusion, it may be considered for treatment with one of these small-molecule TRK family inhibitors. Although these agents are not specifically indicated for GIST, some subjects enrolled in the trials had GIST harboring the target NTRK gene fusion and their tumors responded to treatment.

Ripretinib. FDA-approved in 2020,³³ ripretinib is a novel TKI indicated for adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. A phase 3 trial demonstrated improved progression-free and overall survival when ripretinib was compared with placebo in patients who had disease progression after treatment with imatinib, sunitinib, or regorafenib.³⁴ Ripretinib is now being investigated in the second-line setting in selected patients with KIT mutations.

Avapritinib. Cases of GIST with PDGFRA D842V-mutant tumors often demonstrate primary resistance to imatinib and sunitinib. In 2020, avapritinib, a selective TKI that targets both KIT and PDGFRA, was approved³⁵ for treatment of patients with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including D842V mutations. However, it is noteworthy that many of the non-D842V mutations in PDGFRA respond to imatinib.

Dabrafenib/trametinib. In 2022, the FDA issued an approval for treatment based on a driver mutation rather than tumor type. Acknowledging that a BRAF mutation—specifically a V600E mutation—appears to be a critical target in several cancers, the FDA granted accelerated approval for the use of dabrafenib plus trametinib in adults and children 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options.³⁶

Researchers have studied additional TKIs in the setting of unresectable, metastatic disease due to the varied genomic landscape of GIST. The NCCN Guidelines include evidence of some benefit for agents such as dasatinib, cabozantinib, everolimus (plus a TKI), nilotinib, pazopanib, and sorafenib “in certain circumstances.”⁶

The Future of GIST

The most critical step toward optimal treatment decision-making when a patient has been diagnosed with GIST is identification of physicians with expertise in the care of patients with GIST. With increasing knowledge of genomic variations in GIST, patient care has become less prescripted and much more personalized. To that end, determination of the tumor’s genetic mutational profile is critical to guiding treatment. Although factors such as cost, availability/accessibility, and insufficient tissue continue to represent substantial obstacles, pursing this information may be the most important way that clinicians can advocate for their patients. Moreover, now that the anatomic location of GIST has been linked to specific driver mutations, the ability to select and refine treatments may improve significantly.

Likewise, in view of the increasing complexity and multidisciplinary management of patients with GIST, efficient coordination is paramount among surgical and medical oncologists, as well as radiologists, gastroenterologists, and pathologists.

Click to read more from 2023 Rare Diseases Report: Cancers

Adenosquamous carcinoma (ASC) of the lung is a rare, biphasic type of non-small cell lung cancer (NSCLC) that accounts for 2% to 4% of all lung cancers.¹ According to the World Health Organization (WHO) classification, the composition of ASC includes both adenocarcinoma (AC) and squamous cell carcinoma (SCC) histologies, with each subtype comprising at least 10% of the tumor.² As with other lung cancers, the average age at ASC diagnosis is about 70 years of age, it affects more men than women, and most patients are current or former smokers.^3,4 Despite these similarities, mounting evidence suggests that the molecular and genomic features of ASC are unique and they remain poorly understood.^5-8

Perhaps owing to the distinct genomics of these tumors, ASC of the lung is reported to be relatively aggressive compared to typical AC and SCC tumors. Studies indicate that ASCs at diagnosis have higher rates of lymph node invasion, metastasize rapidly, and carry a generally poor prognosis. Accordingly, the overall survival (OS) of patients with these tumors is relatively short compared to other NSCLC subtypes.^2,3,8-10 In a 2022 population-based study of the SEER database, 5-year postsurgical survival rates for early-stage cancers were reportedly 65% for ASC vs 69% for SCC P=0.003 and 77% for AC P<0.001.³ While it is clear that underlying biology driving ASC differs from more typical NSCLC subtypes, there is a lack of effective treatment options specific to ASC and a paucity of clinical research available to support therapeutic decisions for patients with ASC histology. Current management of NSCLC is based primarily on the stage of the tumor, and clinical features of the patient. In a more personalized era of targeted treatments, tumor histology is used only to predict the presence of actionable mutations in adenocarcinomas.^7,8 However, optimal treatment strategies for ASC remain a significant unmet need in lung cancer.

Diagnosis: Complex but Critically Important

Given the mixed histologies that characterize ASC of the lung, intratumoral heterogeneity often hinders and may delay diagnosis. Studies suggest that ASC is misdiagnosed as AC or SCC in at least half of biopsies prior to surgical pathology confirming an ASC diagnosis.¹¹ In one retrospective study, nearly all ASC cases (98%) were either misdiagnosed or undiagnosed preoperatively.¹² What’s more is that different types of biopsy samples may yield different results. One case report of a patient eventually diagnosed with ASC described 3 different results on workup: SCC on bronchial lavage and bronchial biopsy, AC on immunohistochemistry, and NSCLC undifferentiated on pleural effusion cytology.¹³ While a diagnosis can be made using biopsy and cytology samples, a definitive diagnosis may require larger samples (ie, several core biopsies or complete surgical resections) to fully evaluate all components of the tumor lesion.

Comprehensively evaluating entire tumor specimens can aid in further characterization ASC of the lung. ASCs may be sub-classified according to the proportions of AC and SCC histology components present. Tumors with either AC or SCC components comprising at least 60% of the tumor are referred to as AC- or SCC-predominant ASC, respectively. Those with a more even split of AC and SCC histologies (40% to 60% of each) are referred to as structure-balanced ASC and have been reported to have a better prognosis than either of the more imbalanced subtypes.^9,14

Adding to the complexity of diagnosing ASC of the lung is its unclear histologic origin and the transitional nature of these tumors over time. Some studies have pointed to possible precursor lesions, including AC with squamous metaplasia, collision tumor, and high-grade mucoepidermoid tumors.¹⁵ Reports have also shown that the molecular and histological features of the primary tumor can differ from that of metastases/recurrences.^16,17 In one case report, a patient with a resected ASC harboring an epidermal growth factor receptor (EGFR)-sensitizing mutation recurred several months later as SCC in the brain with the same EGFR mutation. A later recurrence in the lung was diagnosed as an AC and had the same EGFR mutation.¹⁶ In this example, if only the SCC component had been diagnosed, molecular testing would likely have never been ordered and the potentially actionable EGFR mutation would have been left undetected. Therefore, careful and accurate diagnosis of ASC is critically important in guiding testing for driver mutations, as well as in informing treatment choices in ASC.

Genomics

Studies indicate that ASC of the lung exhibits genomic features of both AC and SCC, with standard immunohistochemical profiles represented in each component. As expected, TTF1 positivity is common in the AC component while p63 and CK5/6 are expressed in the SCC component.¹⁸ However, evidence also indicates that ASC of the lung is a distinct entity rather than being a simple hybrid of AC and SCC histologies. That is, despite the seemingly dichotomous nature of ASC, this type of tumor is thought to have unique molecular and genomic features that have not yet been fully identified.^5-8

While the genomics of AC and SCC of the lung have been well studied, the inherent intratumoral heterogeneity that defines ASC, together with its relative rarity, complicates its analysis. There is a paucity of data available, but several groups have conducted molecular testing to better understand the genotype of ASC and potentially discover predictors about prognosis and treatment. To date, most studies on ASC lung samples have been small, and while some groups have reported overlapping results, other findings contrast with one another. In one of the most recent and comprehensive studies published on the topic, Wang et al. used next-generation sequencing (NGS) to identify a wide range of somatic mutations in 124 Chinese patients with ASC of the lung, including TP53 (66.9%), CDKN2A (21%), TERT (21%), and LRP1B (18.5%).⁶ Importantly, they found high rates of EGFR mutations (54.8%), of which 45.6% were EGFR 19del, 38.2% were EGFR L858R and 29.4% were EGFR amplifications.

Notably, not all studies have found such a strikingly increased rate of EGFR mutations in ASC versus AC of the lung.¹⁹ Other actionable mutations were found in the analysis by Wang and colleagues, including ALK and ROS1 fusions. Regarding known predictors of immunogenicity in these tumors, a subset of patients were associated with high tumor mutational burden (TMB), which was correlated with mutations in ARID2, BRCA1, and KEAP1. Immunohistochemical analyses demonstrated half of patients were positive for PD-L1 (≥ 1% tumor proportion score [TPS]).⁶ Interestingly, another study showed that PD-L1 expression in ASC differed between SCC (30% to 40%) and AC (11% to 15%) components.²⁰

Actionable mutation rates (ie, EGFR, ALK) in AC are known to vary between Asian and White patients, a finding that seems to be similar in ASC of the lung as well, although it is less clear given the limited sample size of ASC studies. Vassella et al. performed NGS and fluorescence in situ hybridization (FISH) on ASC samples from 16 White patients and found that 30% had EGFR mutations, while Tochigi et al reported an EGFR mutation rate of 13% in a study of 23 Western patients.5,12,21 In their analysis, Vassella and colleagues also found a high rate of mutations in the PI3K pathway (25%), but no KRAS mutations, which are the most common molecular driver in typical AC (30%), and thus supporting the notion that ASC has its own molecular genomic profile, distinct from AC or SCC.^5,21 Also of interest in this study was the finding that classifier miR-205 expression was intermediate between that of classical AC and SCC, suggesting that ASC of the lung may alternatively represent a transitional stage between these tumor types rather than an unrelated entity.⁵ These findings, along with others that have been reported on the genomic landscape of ASC, have advanced our understanding of the underlying biology of this malignancy, but also highlight the unmet need for more research to improve our ability to personalize treatment for ASCs.

Treatment

Owing to the heterogeneity of ASC of the lung, as well as its complex and incompletely characterized genomic landscape, treating patients with these tumors is challenging. In general, stage-based treatment approaches are used to manage ASC. The current treatment paradigm of all NSCLC has dramatically changed in recent years, with increasing incorporation of targeted treatments and immunotherapies across all stages and histologic types. Considering ASCs are composed of glandular cell components, they can contain substantial levels of relevant actionable driver mutations as described above. Therefore, if ASC is diagnosed or if a SCC has a glandular component,molecular testing is recommended and supported by guidelines, even on surgical specimens where EGFR may be targeted as adjuvant treatment.²³ However, while targeting actionable mutations and the PD1/PDL1 axis has been studied extensively in AC and SCC in all stages, the impact of these markers in ASC is unknown because patients with this histologic subtype are frequently excluded from clinical trials.

For patients with ASC and actionable mutations, EGFR inhibitors have been perhaps the best-studied targeted therapies. EGFR inhibitors have yielded responses in ASC, but the benefit has been highly variable in small case series and generally inferior to outcomes in patients with AC alone.¹⁹ Ongoing clinical trials are aiming to better understand the effects of EGFR inhibitors in ASC. As one example, first-line almonertinib is being compared to paclitaxel/carboplatin in the phase 2 ARISE clinical trial, which is specifically enrolling patients with EGFR mutation-positive locally advanced or metastatic pulmonary ASC (Clinicaltrials.gov NCT04354961). Most other reported studies are case studies or retrospective in nature.

Given that outcomes are usually reported from single patients or a group of only a few patients, contradictory findings are not uncommon. For example, crizotinib, a multi-kinase inhibitor approved for the treatment of advanced or metastatic ALK-positive and ROS1-positive NSCLC, was reported to have a clinical response in an ASC in a patient with recurrent ALK-positive disease which lasted for just over one year.²⁴ However, the response to second-line crizotinib in a case report of female non-smoking patient with ROS1-positive ASC was only 4 months.²⁵ Newer, more specific kinase inhibitors are currently in clinical practice and trials of ALK and ROS1 NSCLCs; however, their efficacy is ASC remains unclear.

In the absence of driver mutations, the optimal choice of chemotherapy (often given with immunotherapy) for neo-/adjuvant therapy or for metastatic disease has not yet been identified. While the AC component might typically be treated with pemetrexed plus a platinum agent, the SCC component may be better treated with taxane plus a platinum agent.²³ Especially in cases where neither histologic subtype is predominant, it can be difficult to decide which combination may be suitable for an individual patient. Whether the relative proportion of AC and SCC components affect treatment outcomes is not yet known. Outcomes of pemetrexed-based chemotherapy have been reported in a case study of 2 patients with relapsed disease harboring ALK and ROS1 mutations, pemetrexed alone or as part of a combination regimen (with pembrolizumab and carboplatin) was able to maintain stable disease for at least a year.²⁶

While immune checkpoint inhibitors, either as monotherapy or in combination with chemotherapy, are currently recommended for patients with NSCLC²³, few studies have reported outcomes of patients with ASC specifically. One recent real-world analysis by Li et al. evaluated the effect of immunotherapy in 46 patients with ASC, of which 18 (39%) did not contain actionable driver mutations and 18 (39%) had unknown mutational status.²⁷ In this study, 28% of the overall cohort responded to checkpoint inhibitors, the median progression-free survival was 6 months, and the median OS was 24.7 months. Notably, similar efficacy was observed in the 20 patients receiving immunotherapy monotherapy vs 26 patients who received combination immunotherapy plus chemotherapy.²⁷ Among 4 patients with EGFR mutations, 2 received immunotherapy monotherapy and progressed immediately compared to the other 2 receiving combination immunotherapy with chemotherapy achieving disease control and improved OS (18 months).

As exemplified by the select few cases summarized above, conventional treatments used in NSCLC have achieved only modest responses in ASC, most with a shorter response duration. The lack of specific treatment strategies for ASC, based on our understanding of underlying tumor biology, limits optimal treatment outcomes for this increasingly common diagnosis. Novel therapies are sorely needed. A consensus should be developed to either study novel treatments specifically in this subtype or allow for the incorporation of ASCs into future NSCLC clinical trials.

Click to read more from 2023 Rare Diseases Report: Cancers

Adenosquamous carcinoma (ASC) of the lung is a rare, biphasic type of non-small cell lung cancer (NSCLC) that accounts for 2% to 4% of all lung cancers.¹ According to the World Health Organization (WHO) classification, the composition of ASC includes both adenocarcinoma (AC) and squamous cell carcinoma (SCC) histologies, with each subtype comprising at least 10% of the tumor.² As with other lung cancers, the average age at ASC diagnosis is about 70 years of age, it affects more men than women, and most patients are current or former smokers.^3,4 Despite these similarities, mounting evidence suggests that the molecular and genomic features of ASC are unique and they remain poorly understood.^5-8

Perhaps owing to the distinct genomics of these tumors, ASC of the lung is reported to be relatively aggressive compared to typical AC and SCC tumors. Studies indicate that ASCs at diagnosis have higher rates of lymph node invasion, metastasize rapidly, and carry a generally poor prognosis. Accordingly, the overall survival (OS) of patients with these tumors is relatively short compared to other NSCLC subtypes.^2,3,8-10 In a 2022 population-based study of the SEER database, 5-year postsurgical survival rates for early-stage cancers were reportedly 65% for ASC vs 69% for SCC P=0.003 and 77% for AC P<0.001.³ While it is clear that underlying biology driving ASC differs from more typical NSCLC subtypes, there is a lack of effective treatment options specific to ASC and a paucity of clinical research available to support therapeutic decisions for patients with ASC histology. Current management of NSCLC is based primarily on the stage of the tumor, and clinical features of the patient. In a more personalized era of targeted treatments, tumor histology is used only to predict the presence of actionable mutations in adenocarcinomas.^7,8 However, optimal treatment strategies for ASC remain a significant unmet need in lung cancer.

Diagnosis: Complex but Critically Important

Given the mixed histologies that characterize ASC of the lung, intratumoral heterogeneity often hinders and may delay diagnosis. Studies suggest that ASC is misdiagnosed as AC or SCC in at least half of biopsies prior to surgical pathology confirming an ASC diagnosis.¹¹ In one retrospective study, nearly all ASC cases (98%) were either misdiagnosed or undiagnosed preoperatively.¹² What’s more is that different types of biopsy samples may yield different results. One case report of a patient eventually diagnosed with ASC described 3 different results on workup: SCC on bronchial lavage and bronchial biopsy, AC on immunohistochemistry, and NSCLC undifferentiated on pleural effusion cytology.¹³ While a diagnosis can be made using biopsy and cytology samples, a definitive diagnosis may require larger samples (ie, several core biopsies or complete surgical resections) to fully evaluate all components of the tumor lesion.

Comprehensively evaluating entire tumor specimens can aid in further characterization ASC of the lung. ASCs may be sub-classified according to the proportions of AC and SCC histology components present. Tumors with either AC or SCC components comprising at least 60% of the tumor are referred to as AC- or SCC-predominant ASC, respectively. Those with a more even split of AC and SCC histologies (40% to 60% of each) are referred to as structure-balanced ASC and have been reported to have a better prognosis than either of the more imbalanced subtypes.^9,14

Adding to the complexity of diagnosing ASC of the lung is its unclear histologic origin and the transitional nature of these tumors over time. Some studies have pointed to possible precursor lesions, including AC with squamous metaplasia, collision tumor, and high-grade mucoepidermoid tumors.¹⁵ Reports have also shown that the molecular and histological features of the primary tumor can differ from that of metastases/recurrences.^16,17 In one case report, a patient with a resected ASC harboring an epidermal growth factor receptor (EGFR)-sensitizing mutation recurred several months later as SCC in the brain with the same EGFR mutation. A later recurrence in the lung was diagnosed as an AC and had the same EGFR mutation.¹⁶ In this example, if only the SCC component had been diagnosed, molecular testing would likely have never been ordered and the potentially actionable EGFR mutation would have been left undetected. Therefore, careful and accurate diagnosis of ASC is critically important in guiding testing for driver mutations, as well as in informing treatment choices in ASC.

Genomics

Studies indicate that ASC of the lung exhibits genomic features of both AC and SCC, with standard immunohistochemical profiles represented in each component. As expected, TTF1 positivity is common in the AC component while p63 and CK5/6 are expressed in the SCC component.¹⁸ However, evidence also indicates that ASC of the lung is a distinct entity rather than being a simple hybrid of AC and SCC histologies. That is, despite the seemingly dichotomous nature of ASC, this type of tumor is thought to have unique molecular and genomic features that have not yet been fully identified.^5-8

While the genomics of AC and SCC of the lung have been well studied, the inherent intratumoral heterogeneity that defines ASC, together with its relative rarity, complicates its analysis. There is a paucity of data available, but several groups have conducted molecular testing to better understand the genotype of ASC and potentially discover predictors about prognosis and treatment. To date, most studies on ASC lung samples have been small, and while some groups have reported overlapping results, other findings contrast with one another. In one of the most recent and comprehensive studies published on the topic, Wang et al. used next-generation sequencing (NGS) to identify a wide range of somatic mutations in 124 Chinese patients with ASC of the lung, including TP53 (66.9%), CDKN2A (21%), TERT (21%), and LRP1B (18.5%).⁶ Importantly, they found high rates of EGFR mutations (54.8%), of which 45.6% were EGFR 19del, 38.2% were EGFR L858R and 29.4% were EGFR amplifications.

Notably, not all studies have found such a strikingly increased rate of EGFR mutations in ASC versus AC of the lung.¹⁹ Other actionable mutations were found in the analysis by Wang and colleagues, including ALK and ROS1 fusions. Regarding known predictors of immunogenicity in these tumors, a subset of patients were associated with high tumor mutational burden (TMB), which was correlated with mutations in ARID2, BRCA1, and KEAP1. Immunohistochemical analyses demonstrated half of patients were positive for PD-L1 (≥ 1% tumor proportion score [TPS]).⁶ Interestingly, another study showed that PD-L1 expression in ASC differed between SCC (30% to 40%) and AC (11% to 15%) components.²⁰

Actionable mutation rates (ie, EGFR, ALK) in AC are known to vary between Asian and White patients, a finding that seems to be similar in ASC of the lung as well, although it is less clear given the limited sample size of ASC studies. Vassella et al. performed NGS and fluorescence in situ hybridization (FISH) on ASC samples from 16 White patients and found that 30% had EGFR mutations, while Tochigi et al reported an EGFR mutation rate of 13% in a study of 23 Western patients.5,12,21 In their analysis, Vassella and colleagues also found a high rate of mutations in the PI3K pathway (25%), but no KRAS mutations, which are the most common molecular driver in typical AC (30%), and thus supporting the notion that ASC has its own molecular genomic profile, distinct from AC or SCC.^5,21 Also of interest in this study was the finding that classifier miR-205 expression was intermediate between that of classical AC and SCC, suggesting that ASC of the lung may alternatively represent a transitional stage between these tumor types rather than an unrelated entity.⁵ These findings, along with others that have been reported on the genomic landscape of ASC, have advanced our understanding of the underlying biology of this malignancy, but also highlight the unmet need for more research to improve our ability to personalize treatment for ASCs.

Treatment

Owing to the heterogeneity of ASC of the lung, as well as its complex and incompletely characterized genomic landscape, treating patients with these tumors is challenging. In general, stage-based treatment approaches are used to manage ASC. The current treatment paradigm of all NSCLC has dramatically changed in recent years, with increasing incorporation of targeted treatments and immunotherapies across all stages and histologic types. Considering ASCs are composed of glandular cell components, they can contain substantial levels of relevant actionable driver mutations as described above. Therefore, if ASC is diagnosed or if a SCC has a glandular component,molecular testing is recommended and supported by guidelines, even on surgical specimens where EGFR may be targeted as adjuvant treatment.²³ However, while targeting actionable mutations and the PD1/PDL1 axis has been studied extensively in AC and SCC in all stages, the impact of these markers in ASC is unknown because patients with this histologic subtype are frequently excluded from clinical trials.

For patients with ASC and actionable mutations, EGFR inhibitors have been perhaps the best-studied targeted therapies. EGFR inhibitors have yielded responses in ASC, but the benefit has been highly variable in small case series and generally inferior to outcomes in patients with AC alone.¹⁹ Ongoing clinical trials are aiming to better understand the effects of EGFR inhibitors in ASC. As one example, first-line almonertinib is being compared to paclitaxel/carboplatin in the phase 2 ARISE clinical trial, which is specifically enrolling patients with EGFR mutation-positive locally advanced or metastatic pulmonary ASC (Clinicaltrials.gov NCT04354961). Most other reported studies are case studies or retrospective in nature.

Given that outcomes are usually reported from single patients or a group of only a few patients, contradictory findings are not uncommon. For example, crizotinib, a multi-kinase inhibitor approved for the treatment of advanced or metastatic ALK-positive and ROS1-positive NSCLC, was reported to have a clinical response in an ASC in a patient with recurrent ALK-positive disease which lasted for just over one year.²⁴ However, the response to second-line crizotinib in a case report of female non-smoking patient with ROS1-positive ASC was only 4 months.²⁵ Newer, more specific kinase inhibitors are currently in clinical practice and trials of ALK and ROS1 NSCLCs; however, their efficacy is ASC remains unclear.

In the absence of driver mutations, the optimal choice of chemotherapy (often given with immunotherapy) for neo-/adjuvant therapy or for metastatic disease has not yet been identified. While the AC component might typically be treated with pemetrexed plus a platinum agent, the SCC component may be better treated with taxane plus a platinum agent.²³ Especially in cases where neither histologic subtype is predominant, it can be difficult to decide which combination may be suitable for an individual patient. Whether the relative proportion of AC and SCC components affect treatment outcomes is not yet known. Outcomes of pemetrexed-based chemotherapy have been reported in a case study of 2 patients with relapsed disease harboring ALK and ROS1 mutations, pemetrexed alone or as part of a combination regimen (with pembrolizumab and carboplatin) was able to maintain stable disease for at least a year.²⁶

While immune checkpoint inhibitors, either as monotherapy or in combination with chemotherapy, are currently recommended for patients with NSCLC²³, few studies have reported outcomes of patients with ASC specifically. One recent real-world analysis by Li et al. evaluated the effect of immunotherapy in 46 patients with ASC, of which 18 (39%) did not contain actionable driver mutations and 18 (39%) had unknown mutational status.²⁷ In this study, 28% of the overall cohort responded to checkpoint inhibitors, the median progression-free survival was 6 months, and the median OS was 24.7 months. Notably, similar efficacy was observed in the 20 patients receiving immunotherapy monotherapy vs 26 patients who received combination immunotherapy plus chemotherapy.²⁷ Among 4 patients with EGFR mutations, 2 received immunotherapy monotherapy and progressed immediately compared to the other 2 receiving combination immunotherapy with chemotherapy achieving disease control and improved OS (18 months).

As exemplified by the select few cases summarized above, conventional treatments used in NSCLC have achieved only modest responses in ASC, most with a shorter response duration. The lack of specific treatment strategies for ASC, based on our understanding of underlying tumor biology, limits optimal treatment outcomes for this increasingly common diagnosis. Novel therapies are sorely needed. A consensus should be developed to either study novel treatments specifically in this subtype or allow for the incorporation of ASCs into future NSCLC clinical trials.

Click to read more from 2023 Rare Diseases Report: Cancers

Adenosquamous carcinoma (ASC) of the lung is a rare, biphasic type of non-small cell lung cancer (NSCLC) that accounts for 2% to 4% of all lung cancers.¹ According to the World Health Organization (WHO) classification, the composition of ASC includes both adenocarcinoma (AC) and squamous cell carcinoma (SCC) histologies, with each subtype comprising at least 10% of the tumor.² As with other lung cancers, the average age at ASC diagnosis is about 70 years of age, it affects more men than women, and most patients are current or former smokers.^3,4 Despite these similarities, mounting evidence suggests that the molecular and genomic features of ASC are unique and they remain poorly understood.^5-8

Perhaps owing to the distinct genomics of these tumors, ASC of the lung is reported to be relatively aggressive compared to typical AC and SCC tumors. Studies indicate that ASCs at diagnosis have higher rates of lymph node invasion, metastasize rapidly, and carry a generally poor prognosis. Accordingly, the overall survival (OS) of patients with these tumors is relatively short compared to other NSCLC subtypes.^2,3,8-10 In a 2022 population-based study of the SEER database, 5-year postsurgical survival rates for early-stage cancers were reportedly 65% for ASC vs 69% for SCC P=0.003 and 77% for AC P<0.001.³ While it is clear that underlying biology driving ASC differs from more typical NSCLC subtypes, there is a lack of effective treatment options specific to ASC and a paucity of clinical research available to support therapeutic decisions for patients with ASC histology. Current management of NSCLC is based primarily on the stage of the tumor, and clinical features of the patient. In a more personalized era of targeted treatments, tumor histology is used only to predict the presence of actionable mutations in adenocarcinomas.^7,8 However, optimal treatment strategies for ASC remain a significant unmet need in lung cancer.

Diagnosis: Complex but Critically Important

Given the mixed histologies that characterize ASC of the lung, intratumoral heterogeneity often hinders and may delay diagnosis. Studies suggest that ASC is misdiagnosed as AC or SCC in at least half of biopsies prior to surgical pathology confirming an ASC diagnosis.¹¹ In one retrospective study, nearly all ASC cases (98%) were either misdiagnosed or undiagnosed preoperatively.¹² What’s more is that different types of biopsy samples may yield different results. One case report of a patient eventually diagnosed with ASC described 3 different results on workup: SCC on bronchial lavage and bronchial biopsy, AC on immunohistochemistry, and NSCLC undifferentiated on pleural effusion cytology.¹³ While a diagnosis can be made using biopsy and cytology samples, a definitive diagnosis may require larger samples (ie, several core biopsies or complete surgical resections) to fully evaluate all components of the tumor lesion.

Comprehensively evaluating entire tumor specimens can aid in further characterization ASC of the lung. ASCs may be sub-classified according to the proportions of AC and SCC histology components present. Tumors with either AC or SCC components comprising at least 60% of the tumor are referred to as AC- or SCC-predominant ASC, respectively. Those with a more even split of AC and SCC histologies (40% to 60% of each) are referred to as structure-balanced ASC and have been reported to have a better prognosis than either of the more imbalanced subtypes.^9,14

Adding to the complexity of diagnosing ASC of the lung is its unclear histologic origin and the transitional nature of these tumors over time. Some studies have pointed to possible precursor lesions, including AC with squamous metaplasia, collision tumor, and high-grade mucoepidermoid tumors.¹⁵ Reports have also shown that the molecular and histological features of the primary tumor can differ from that of metastases/recurrences.^16,17 In one case report, a patient with a resected ASC harboring an epidermal growth factor receptor (EGFR)-sensitizing mutation recurred several months later as SCC in the brain with the same EGFR mutation. A later recurrence in the lung was diagnosed as an AC and had the same EGFR mutation.¹⁶ In this example, if only the SCC component had been diagnosed, molecular testing would likely have never been ordered and the potentially actionable EGFR mutation would have been left undetected. Therefore, careful and accurate diagnosis of ASC is critically important in guiding testing for driver mutations, as well as in informing treatment choices in ASC.

Genomics

Studies indicate that ASC of the lung exhibits genomic features of both AC and SCC, with standard immunohistochemical profiles represented in each component. As expected, TTF1 positivity is common in the AC component while p63 and CK5/6 are expressed in the SCC component.¹⁸ However, evidence also indicates that ASC of the lung is a distinct entity rather than being a simple hybrid of AC and SCC histologies. That is, despite the seemingly dichotomous nature of ASC, this type of tumor is thought to have unique molecular and genomic features that have not yet been fully identified.^5-8

While the genomics of AC and SCC of the lung have been well studied, the inherent intratumoral heterogeneity that defines ASC, together with its relative rarity, complicates its analysis. There is a paucity of data available, but several groups have conducted molecular testing to better understand the genotype of ASC and potentially discover predictors about prognosis and treatment. To date, most studies on ASC lung samples have been small, and while some groups have reported overlapping results, other findings contrast with one another. In one of the most recent and comprehensive studies published on the topic, Wang et al. used next-generation sequencing (NGS) to identify a wide range of somatic mutations in 124 Chinese patients with ASC of the lung, including TP53 (66.9%), CDKN2A (21%), TERT (21%), and LRP1B (18.5%).⁶ Importantly, they found high rates of EGFR mutations (54.8%), of which 45.6% were EGFR 19del, 38.2% were EGFR L858R and 29.4% were EGFR amplifications.

Notably, not all studies have found such a strikingly increased rate of EGFR mutations in ASC versus AC of the lung.¹⁹ Other actionable mutations were found in the analysis by Wang and colleagues, including ALK and ROS1 fusions. Regarding known predictors of immunogenicity in these tumors, a subset of patients were associated with high tumor mutational burden (TMB), which was correlated with mutations in ARID2, BRCA1, and KEAP1. Immunohistochemical analyses demonstrated half of patients were positive for PD-L1 (≥ 1% tumor proportion score [TPS]).⁶ Interestingly, another study showed that PD-L1 expression in ASC differed between SCC (30% to 40%) and AC (11% to 15%) components.²⁰

Actionable mutation rates (ie, EGFR, ALK) in AC are known to vary between Asian and White patients, a finding that seems to be similar in ASC of the lung as well, although it is less clear given the limited sample size of ASC studies. Vassella et al. performed NGS and fluorescence in situ hybridization (FISH) on ASC samples from 16 White patients and found that 30% had EGFR mutations, while Tochigi et al reported an EGFR mutation rate of 13% in a study of 23 Western patients.5,12,21 In their analysis, Vassella and colleagues also found a high rate of mutations in the PI3K pathway (25%), but no KRAS mutations, which are the most common molecular driver in typical AC (30%), and thus supporting the notion that ASC has its own molecular genomic profile, distinct from AC or SCC.^5,21 Also of interest in this study was the finding that classifier miR-205 expression was intermediate between that of classical AC and SCC, suggesting that ASC of the lung may alternatively represent a transitional stage between these tumor types rather than an unrelated entity.⁵ These findings, along with others that have been reported on the genomic landscape of ASC, have advanced our understanding of the underlying biology of this malignancy, but also highlight the unmet need for more research to improve our ability to personalize treatment for ASCs.

Treatment

Owing to the heterogeneity of ASC of the lung, as well as its complex and incompletely characterized genomic landscape, treating patients with these tumors is challenging. In general, stage-based treatment approaches are used to manage ASC. The current treatment paradigm of all NSCLC has dramatically changed in recent years, with increasing incorporation of targeted treatments and immunotherapies across all stages and histologic types. Considering ASCs are composed of glandular cell components, they can contain substantial levels of relevant actionable driver mutations as described above. Therefore, if ASC is diagnosed or if a SCC has a glandular component,molecular testing is recommended and supported by guidelines, even on surgical specimens where EGFR may be targeted as adjuvant treatment.²³ However, while targeting actionable mutations and the PD1/PDL1 axis has been studied extensively in AC and SCC in all stages, the impact of these markers in ASC is unknown because patients with this histologic subtype are frequently excluded from clinical trials.

For patients with ASC and actionable mutations, EGFR inhibitors have been perhaps the best-studied targeted therapies. EGFR inhibitors have yielded responses in ASC, but the benefit has been highly variable in small case series and generally inferior to outcomes in patients with AC alone.¹⁹ Ongoing clinical trials are aiming to better understand the effects of EGFR inhibitors in ASC. As one example, first-line almonertinib is being compared to paclitaxel/carboplatin in the phase 2 ARISE clinical trial, which is specifically enrolling patients with EGFR mutation-positive locally advanced or metastatic pulmonary ASC (Clinicaltrials.gov NCT04354961). Most other reported studies are case studies or retrospective in nature.

Given that outcomes are usually reported from single patients or a group of only a few patients, contradictory findings are not uncommon. For example, crizotinib, a multi-kinase inhibitor approved for the treatment of advanced or metastatic ALK-positive and ROS1-positive NSCLC, was reported to have a clinical response in an ASC in a patient with recurrent ALK-positive disease which lasted for just over one year.²⁴ However, the response to second-line crizotinib in a case report of female non-smoking patient with ROS1-positive ASC was only 4 months.²⁵ Newer, more specific kinase inhibitors are currently in clinical practice and trials of ALK and ROS1 NSCLCs; however, their efficacy is ASC remains unclear.

In the absence of driver mutations, the optimal choice of chemotherapy (often given with immunotherapy) for neo-/adjuvant therapy or for metastatic disease has not yet been identified. While the AC component might typically be treated with pemetrexed plus a platinum agent, the SCC component may be better treated with taxane plus a platinum agent.²³ Especially in cases where neither histologic subtype is predominant, it can be difficult to decide which combination may be suitable for an individual patient. Whether the relative proportion of AC and SCC components affect treatment outcomes is not yet known. Outcomes of pemetrexed-based chemotherapy have been reported in a case study of 2 patients with relapsed disease harboring ALK and ROS1 mutations, pemetrexed alone or as part of a combination regimen (with pembrolizumab and carboplatin) was able to maintain stable disease for at least a year.²⁶

While immune checkpoint inhibitors, either as monotherapy or in combination with chemotherapy, are currently recommended for patients with NSCLC²³, few studies have reported outcomes of patients with ASC specifically. One recent real-world analysis by Li et al. evaluated the effect of immunotherapy in 46 patients with ASC, of which 18 (39%) did not contain actionable driver mutations and 18 (39%) had unknown mutational status.²⁷ In this study, 28% of the overall cohort responded to checkpoint inhibitors, the median progression-free survival was 6 months, and the median OS was 24.7 months. Notably, similar efficacy was observed in the 20 patients receiving immunotherapy monotherapy vs 26 patients who received combination immunotherapy plus chemotherapy.²⁷ Among 4 patients with EGFR mutations, 2 received immunotherapy monotherapy and progressed immediately compared to the other 2 receiving combination immunotherapy with chemotherapy achieving disease control and improved OS (18 months).

As exemplified by the select few cases summarized above, conventional treatments used in NSCLC have achieved only modest responses in ASC, most with a shorter response duration. The lack of specific treatment strategies for ASC, based on our understanding of underlying tumor biology, limits optimal treatment outcomes for this increasingly common diagnosis. Novel therapies are sorely needed. A consensus should be developed to either study novel treatments specifically in this subtype or allow for the incorporation of ASCs into future NSCLC clinical trials.

Click to read more from 2023 Rare Diseases Report: Cancers

Health care providers are missing opportunities to give medical treatment to high-risk individuals hospitalized for alcohol use disorder (AUD), a national analysis of Medicare beneficiaries reported.

Increasing such patients’ access to psychiatric care and addiction medicine, as well as encouraging medication prescribing by generalists and nonaddiction specialists, are remedial strategies recommended by lead author Eden Y. Bernstein, MD, of the division of general internal medicine at Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues.

“Hospitalizations for alcohol use disorder are common,” Dr. Bernstein said in an interview. “Our work shows they represent an underutilized opportunity to engage patients with appropriate treatment, including initiation of medications for alcohol use disorder.”

There is a pressing need for such treatment strategies since 29 million U.S. adults have AUD, and alcohol contributes to more than 140,000 deaths annually, the authors noted.

Rarely initiated either at hospital discharge or during follow-up care, medical therapy for AUD was more likely to be provided to younger patients and those involved with psychiatric care or addiction medicine, Dr. Bernstein’s group reported in Annals of Internal Medicine.Hospital admissions, they argued, give patients more access to clinicians and social workers and the vulnerability experienced during hospitalization may motivate behavioral change.


 

National study

The cohort included 28,601 AUD hospitalizations for 20,401 unique Medicare patients from 2015 to 2017. About 30% of admissions were for women and about 72% for non-Hispanic Blacks. Discharge initiation of medication for AUD was defined as a pharmacy claim for naltrexone, acamprosate, or disulfiram from the day before discharge to 2 days after.

Overall, just 206 patients (0.7%) initiated medication for AUD within 2 days of discharge and 364 (1.3%) started it within 30 days. Among those discharged with a primary diagnosis of AUD, only 70 (2.3%) started medical therapy within 2 days.

The most predictive demographic factor for discharge medication for AUD was younger age: 18-39 years versus 75 years and older (adjusted odds ratio, 3.87; 95% confidence interval, 1.34-11.16).

Initiation of medication for AUD should involve a long-term treatment plan, according to Dr. Bernstein’s group, and if that is not feasible during hospitalization, patients should be referred for outpatient treatment.

An accompanying editorial agrees that the results offer strong evidence of a missed opportunity to address AUD at a potential flexion point. “Hospitalization is a critical touch point for identifying and treating AUD,” wrote Michael F. Mayo-Smith, MD, MPH, of White River Junction (Vt.) VA Medical Center, and Geisel School of Medicine at Dartmouth, Hanover, N.H., and David Lawrence, MD, of the VA Greater Los Angeles Healthcare System and the University of California, Los Angeles.

An intentional discharge protocol can be effective, they noted, as evidenced by a 2014 report in which this approach increased medication-assisted treatment from 0% to 64% in tandem with a decrease in all-cause, 30-day readmission rates.

“There is also growing interest in inpatient addiction consultation services, which have shown [medication] for AUD treatment initiation rates of up to 70% as well as improved engagement in posthospital treatment,” Dr. Mayo-Smith and Dr. Lawrence wrote.

Minority populations need particular attention, they added. “Unfortunately, the availability of evidence-based treatments for AUD does not by itself lead to improved care. We need strategies for widespread adoption so that patients can realize the benefits of these treatments.”

Dr. Bernstein reported funding support from a National Research Service Award and the Massachusetts General Hospital division of general internal medicine; he disclosed fees from Alosa Health. One coauthor was supported by the Agency for Healthcare Research and Quality. Another was supported by the National Institute on Aging and reported relationships with the American College of Cardiology, Boston OIAC Pepper Center, American Heart Association, and US Deprescribing Research Network. Dr. Mayo-Smith disclosed no competing interests. Dr. Lawrence reported fees related to presentations at DDW 2023 and the California Society of Addiction Medicine 2022.

Health care providers are missing opportunities to give medical treatment to high-risk individuals hospitalized for alcohol use disorder (AUD), a national analysis of Medicare beneficiaries reported.

Increasing such patients’ access to psychiatric care and addiction medicine, as well as encouraging medication prescribing by generalists and nonaddiction specialists, are remedial strategies recommended by lead author Eden Y. Bernstein, MD, of the division of general internal medicine at Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues.

“Hospitalizations for alcohol use disorder are common,” Dr. Bernstein said in an interview. “Our work shows they represent an underutilized opportunity to engage patients with appropriate treatment, including initiation of medications for alcohol use disorder.”

There is a pressing need for such treatment strategies since 29 million U.S. adults have AUD, and alcohol contributes to more than 140,000 deaths annually, the authors noted.

Rarely initiated either at hospital discharge or during follow-up care, medical therapy for AUD was more likely to be provided to younger patients and those involved with psychiatric care or addiction medicine, Dr. Bernstein’s group reported in Annals of Internal Medicine.Hospital admissions, they argued, give patients more access to clinicians and social workers and the vulnerability experienced during hospitalization may motivate behavioral change.


 

National study

The cohort included 28,601 AUD hospitalizations for 20,401 unique Medicare patients from 2015 to 2017. About 30% of admissions were for women and about 72% for non-Hispanic Blacks. Discharge initiation of medication for AUD was defined as a pharmacy claim for naltrexone, acamprosate, or disulfiram from the day before discharge to 2 days after.

Overall, just 206 patients (0.7%) initiated medication for AUD within 2 days of discharge and 364 (1.3%) started it within 30 days. Among those discharged with a primary diagnosis of AUD, only 70 (2.3%) started medical therapy within 2 days.

The most predictive demographic factor for discharge medication for AUD was younger age: 18-39 years versus 75 years and older (adjusted odds ratio, 3.87; 95% confidence interval, 1.34-11.16).

Initiation of medication for AUD should involve a long-term treatment plan, according to Dr. Bernstein’s group, and if that is not feasible during hospitalization, patients should be referred for outpatient treatment.

An accompanying editorial agrees that the results offer strong evidence of a missed opportunity to address AUD at a potential flexion point. “Hospitalization is a critical touch point for identifying and treating AUD,” wrote Michael F. Mayo-Smith, MD, MPH, of White River Junction (Vt.) VA Medical Center, and Geisel School of Medicine at Dartmouth, Hanover, N.H., and David Lawrence, MD, of the VA Greater Los Angeles Healthcare System and the University of California, Los Angeles.

An intentional discharge protocol can be effective, they noted, as evidenced by a 2014 report in which this approach increased medication-assisted treatment from 0% to 64% in tandem with a decrease in all-cause, 30-day readmission rates.

“There is also growing interest in inpatient addiction consultation services, which have shown [medication] for AUD treatment initiation rates of up to 70% as well as improved engagement in posthospital treatment,” Dr. Mayo-Smith and Dr. Lawrence wrote.

Minority populations need particular attention, they added. “Unfortunately, the availability of evidence-based treatments for AUD does not by itself lead to improved care. We need strategies for widespread adoption so that patients can realize the benefits of these treatments.”

Dr. Bernstein reported funding support from a National Research Service Award and the Massachusetts General Hospital division of general internal medicine; he disclosed fees from Alosa Health. One coauthor was supported by the Agency for Healthcare Research and Quality. Another was supported by the National Institute on Aging and reported relationships with the American College of Cardiology, Boston OIAC Pepper Center, American Heart Association, and US Deprescribing Research Network. Dr. Mayo-Smith disclosed no competing interests. Dr. Lawrence reported fees related to presentations at DDW 2023 and the California Society of Addiction Medicine 2022.

Health care providers are missing opportunities to give medical treatment to high-risk individuals hospitalized for alcohol use disorder (AUD), a national analysis of Medicare beneficiaries reported.

Increasing such patients’ access to psychiatric care and addiction medicine, as well as encouraging medication prescribing by generalists and nonaddiction specialists, are remedial strategies recommended by lead author Eden Y. Bernstein, MD, of the division of general internal medicine at Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues.

“Hospitalizations for alcohol use disorder are common,” Dr. Bernstein said in an interview. “Our work shows they represent an underutilized opportunity to engage patients with appropriate treatment, including initiation of medications for alcohol use disorder.”

There is a pressing need for such treatment strategies since 29 million U.S. adults have AUD, and alcohol contributes to more than 140,000 deaths annually, the authors noted.

Rarely initiated either at hospital discharge or during follow-up care, medical therapy for AUD was more likely to be provided to younger patients and those involved with psychiatric care or addiction medicine, Dr. Bernstein’s group reported in Annals of Internal Medicine.Hospital admissions, they argued, give patients more access to clinicians and social workers and the vulnerability experienced during hospitalization may motivate behavioral change.


 

National study

The cohort included 28,601 AUD hospitalizations for 20,401 unique Medicare patients from 2015 to 2017. About 30% of admissions were for women and about 72% for non-Hispanic Blacks. Discharge initiation of medication for AUD was defined as a pharmacy claim for naltrexone, acamprosate, or disulfiram from the day before discharge to 2 days after.

Overall, just 206 patients (0.7%) initiated medication for AUD within 2 days of discharge and 364 (1.3%) started it within 30 days. Among those discharged with a primary diagnosis of AUD, only 70 (2.3%) started medical therapy within 2 days.

The most predictive demographic factor for discharge medication for AUD was younger age: 18-39 years versus 75 years and older (adjusted odds ratio, 3.87; 95% confidence interval, 1.34-11.16).

Initiation of medication for AUD should involve a long-term treatment plan, according to Dr. Bernstein’s group, and if that is not feasible during hospitalization, patients should be referred for outpatient treatment.

An accompanying editorial agrees that the results offer strong evidence of a missed opportunity to address AUD at a potential flexion point. “Hospitalization is a critical touch point for identifying and treating AUD,” wrote Michael F. Mayo-Smith, MD, MPH, of White River Junction (Vt.) VA Medical Center, and Geisel School of Medicine at Dartmouth, Hanover, N.H., and David Lawrence, MD, of the VA Greater Los Angeles Healthcare System and the University of California, Los Angeles.

An intentional discharge protocol can be effective, they noted, as evidenced by a 2014 report in which this approach increased medication-assisted treatment from 0% to 64% in tandem with a decrease in all-cause, 30-day readmission rates.

“There is also growing interest in inpatient addiction consultation services, which have shown [medication] for AUD treatment initiation rates of up to 70% as well as improved engagement in posthospital treatment,” Dr. Mayo-Smith and Dr. Lawrence wrote.

Minority populations need particular attention, they added. “Unfortunately, the availability of evidence-based treatments for AUD does not by itself lead to improved care. We need strategies for widespread adoption so that patients can realize the benefits of these treatments.”

Dr. Bernstein reported funding support from a National Research Service Award and the Massachusetts General Hospital division of general internal medicine; he disclosed fees from Alosa Health. One coauthor was supported by the Agency for Healthcare Research and Quality. Another was supported by the National Institute on Aging and reported relationships with the American College of Cardiology, Boston OIAC Pepper Center, American Heart Association, and US Deprescribing Research Network. Dr. Mayo-Smith disclosed no competing interests. Dr. Lawrence reported fees related to presentations at DDW 2023 and the California Society of Addiction Medicine 2022.

Incidence and Mortality

By 2040, the number of women diagnosed with ovarian cancer annually worldwide is expected to increase by 100% in low Human Development Index (HDI) countries, and by 19-28% in high HDI countries.² The causes of this increasing incidence are likely to be multifactorial, including both hereditary and modifiable risk factors.³ In addition to increasing population size, the growing prevalence of obesity, estrogen exposures, and nulliparity are particularly pertinent as potential causes of the rising incidence of ovarian cancer in younger women. The number of ovarian cancer-related deaths is also projected to rise from about 200,000 to nearly 314,000 annually, an increase of over 50% from 2020.^2,4 Although outcomes in developed regions and nations continue to improve somewhat, 5-year survival rates range from 36% to 46%.⁵ These outcomes are nevertheless dismal when compared with 5-year survival rates from other cancer types, such as breast cancer, which are approaching 90%.⁶

Principal Histotypes

The principal histotypes in ovarian cancer are epithelial in origin and include high-grade serous carcinoma, clear-cell carcinoma, endometrioid carcinoma, low-grade serous carcinoma, and mucinous carcinoma. Other rarer types are nonepithelial, ie, arising from stromal or germ cell lines.⁷ Incidence rates appear to be affected over time by trends such as birth rates, use of combination oral contraceptives, and menopausal hormone therapy.⁸ Figure 1 shows that most ovarian cancers—approximately 70%—are high-grade serous carcinoma, although in Asian countries clear cell and endometrioid carcinomas comprise a higher proportion.⁹

Into the Fallopian Tube

One of the most salient and dramatic discoveries of the last 2 decades has been the finding that high-grade, clear-cell, and endometrioid tumors appear to arise from tissues not normally present in the ovary.¹ As a result of risk-reducing efforts to prevent serous cancers in women with genetic predisposition to develop ovarian cancer (ie, those with BRCA1 or BRCA2 mutations), it became increasingly clear that many early cancers arose in the fallopian tube,^10-12 with the distal portion—the fimbria—as the most common site of origin.^13-16

Figure 2 depicts the female reproductive tract, including the location of the fimbria compared with the ovaries. Moreover, lesions observed in the fallopian tube fimbria—serous tubal intraepithelial carcinomas (STICs)—were identified as precursors of ovarian cancer, with a window of 7 years between development of STIC and the beginning of an ovarian cancer.^14,16

Early Detection

Early, localized ovarian cancer is asymptomatic; by the time a patient presents with symptoms, even with nonspecific abdominal complaints, the disease is almost invariably advanced. The concept of early detection has improved both the rate of cancer diagnoses and outcomes for some malignancies, such as cervical, colorectal, breast, and lung cancers,¹⁷ but this strategy is yet to be effectively applied in ovarian cancer. A large, population-based study, for instance, yielded negative results when multimodal screening (using both measurement of CA125 blood levels and transvaginal ultrasound imaging) failed to improve survival, even though such screening was able to detect lower stage disease.¹⁸ Emerging technologies, such as liquid biopsies and uterine lavage, which seek to detect potential biomarkers (new types of blood tests) of ovarian cancer at an early stage and closer to the site of tumor origin, are being investigated and refined but are not yet ready for clinical use, particularly at the population level for screening.¹⁹

Risk-Reducing Interventions

Use of oral contraceptives has been associated with a significant reduction in risk for ovarian cancer, but the potential risks (eg, increased risk for breast cancer, increased risk for venous thromboembolism) preclude its universal recommendation.^20-22 Simple removal of the fallopian tube, salpingectomy, was proposed as a potential intervention to “intercept” the progression of a STIC to cancer. Researchers recently compared simple salpingectomy with salpingo-oophorectomy as a risk-reduction procedure in carriers of BRCA 1/2 pathogenic variants after they had completed childbearing.²³

These investigators proposed that later removal of the ovaries would delay menopause and would contribute to fewer/less severe symptoms, such as hot flashes, disturbed sleep, and sexual issues, as well as maintain or improve overall quality of life. The hypothesis was supported by results, which showed that patients had better menopause-related quality of life after salpingectomy than after salpingo-oophorectomy, regardless of the use of hormone replacement therapy.²³ The oncologic safety of this approach was subsequently demonstrated by other studies that showed a significantly lower incidence of ovarian cancers in women who had undergone opportunistic salpingectomy.^22,24,25

An international prospective trial, TUBA-WISPII, is now underway to test the hypothesis that postponement of oophorectomy after salpingectomy is non-inferior to standard salpingo-oophorectomy in terms of ovarian cancer risk for patients at high risk.²⁶

Treatment

First-Line Therapy
Currently, there are no durable curative therapies for ovarian cancer once advanced disease has been diagnosed.

Surgery plus platinum-based chemotherapy. Most patients, even those diagnosed with advanced disease, are treated initially with debulking surgery, ideally by a gynecologic oncologist, and adjuvant chemotherapy. Most ovarian carcinomas are initially platinum-sensitive, but resistance and disease recurrence are almost inevitable. According to the National Comprehensive Cancer Network (NCCN) guidelines for ovarian cancer,²⁷ preferred chemotherapy regimens include paclitaxel and carboplatin with or without bevacizumab, docetaxel and carboplatin, or carboplatin and liposomal doxorubicin. Numerous other regimens, combinations, and agents are included in the guidelines to help providers customize treatment plans.

Neoadjuvant vs adjuvant regimens. Neoadjuvant chemotherapy has been used for other malignancies to gauge sensitivity to systemic treatments and to improve surgical margins.²⁸ Thus far, though, outcomes in ovarian cancer have been similar whether patients were given neoadjuvant or adjuvant treatment in the perioperative period. Individualizing these decisions based on ability to surgically resect, patient age, tumor histology, disease stage, and performance status is recommended.²⁹

Intraperitoneal chemotherapy. Other approaches have been explored to reduce risk for micrometastases after surgery. Hyperthermic intraperitoneal chemotherapy,³² for instance, administered immediately after cytoreductive surgery was studied as a technique that might prevent some of the risks and adverse effects associated with intraperitoneal chemotherapy.³¹ Results showed some improvement in progression-free survival and overall survival in a subgroup of patients who underwent interval cytoreductive surgery after neoadjuvant therapy, but no differences were observed for the larger population with advanced epithelial ovarian cancer. Adverse reactions to intraperitoneal chemotherapy were also observed.

Angiogenesis inhibition. Tumors need energy and oxygen to grow. Angiogenesis is the process of new blood vessel formation that provides the tumor with nutrients. Blocking angiogenesis can thwart tumor growth and improve patient outcomes. Bevacizumab is an antiangiogenic agent that has been extensively studied for 2 decades for many cancers including ovarian carcinoma. The NCCN guidelines note that bevacizumab may be considered as part of a first-line regimen with platinum agents, as maintenance in patients with wild-type or unknown BRCA mutation status and a good response to first-line therapy, or in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor in eligible patients.²⁷

PARP inhibitors. Approximately half of all high-grade serous ovarian carcinomas exhibit some defect in the ability to repair DNA damage using the homologous recombination (HR) pathway. These tumors include those with mutations in the BRCA1, BRCA2, and other HR genes. Defects in HR make tumors more dependent on back-up DNA repair systems, including the activity of PARP. PARP inhibitors were developed to specifically target HR-deficient tumors. To date, 3 PARP inhibitors have been approved for use in ovarian cancer—olaparib, rucaparib, and niraparib. Their use has expanded from later-line use in patients with BRCA1/2-mutated tumors to include frontline maintenance regimens for women with high-grade serous and high-grade endometrioid carcinomas, as well as women with recurrent disease.³² Numerous clinical trials are ongoing to develop next-generation PARP inhibitors and to explore their efficacy in combination with chemotherapy and other targeted agents.

Resistance and Disease Progression: Second-Line and Subsequent Treatment

A number of second-line and subsequent systemic treatment regimens may be considered when primary platinum-based chemotherapy and/or maintenance are no longer effective.^33,34 As emphasized by the NCCN, a clinical trial is always an appropriate option, depending on eligibility, and sometimes a second cytoreductive surgery^35,36 may be considered for patients who experience radiographic and/or clinical relapse after a long disease-free interval (6+ months). Each line of treatment is associated with progressively lower response rates and shorter durations of response. According to the NCCN guidelines, as patient performance status decreases and the toxicities of each line of therapy accumulate, assessment for palliative care should be considered and discussed.²⁷

Investigational Approaches

With the high mortality rate associated with ovarian cancer, the challenges of detecting the disease at its early stages, and the lack of therapies that can significantly extend progression-free and overall survival in patients with advanced disease, many investigators are focused on novel treatment approaches. Preclinical observations, for instance, showing synergy between ataxia telangiectasia and RAD3-related (ATR) kinase inhibitors and PARP inhibitors led researchers to initiate a phase 2 study of olaparib plus ceralasertib (an ATR inhibitor) in patients with recurrent, platinum-resistant epithelial ovarian cancer.³⁷ No objective responses were noted, but some signals of activity were seen among patients with BRCA1 mutations.

Due to success in other malignancies, immunotherapy is also being explored. Although some promising signals were reported at 6 months when nivolumab, a PD-1 (programmed cell death protein 1) inhibitor, and ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 antibody, were combined to treat patients with platinum-resistant epithelial ovarian cancer; final results are not yet available.³⁸

Ovarian cancer is sometimes characterized as immunologically “cold.” This description means that immune cells, especially T cells, are not able to enter the tumor and destroy the cancer cells. It also means that these tumors are not as responsive to immune-based treatments. Therefore, some researchers are examining novel alternative immunotherapy strategies, such as chimeric antigen receptor T-cell (CAR-T) therapy.³⁹ When a CAR T-cell encounters a tumor antigen, the CAR T-cell becomes activated. Activated CAR T-cells multiply, signal to other immune cells, and ultimately kill the tumor cells. Although CAR T-cell therapy has been tremendously successful in hematologic malignancies, to date, the benefits in solid tumors have been modest.³⁹ However, there is significant enthusiasm for novel tumor antigens that can be targeted by CAR-T therapy, including mesothelin, folate receptor, Claudin-6, B7-H3, B7-H4, HER2, CD47, and L1-CAM, among others.⁴⁰

Other investigational strategies include a p53 vaccine that would enhance the patient’s immunologic response to abnormal proteins produced by a mutated p53 gene, which is the most common finding in ovarian tumors.

Although researchers are investigating many approaches to treating advanced ovarian cancer, one strategy that has been pursued in other cancer settings—development of antibody-drug conjugates (ADCs)⁴¹—has seen promising results. In the late fall of 2022, the US Food and Drug Administration granted accelerated approval for mirvetuximab soravtansine-gynx for use in patients with a specific type of type of tumor (folate receptor alpha [FRα]-positive) when platinum resistance emerges.⁴² A companion diagnostic assay was also approved for selecting patients with FRα-positive disease. Several other clinical trials are investigating the efficacy of targeting other ovarian tumor antigens using the ADC approach. These targets include NaPi2b, mesothelin, B7-H4, Claudin-6, and Trop-2.^43,44

Progress to Come 

Progress in ovarian cancer will be made through a multipronged approach that includes interventions that may proactively “intercept” the development of cancer (eg, salpingectomy for women planning to have other simple gynecologic procedures after childbearing is complete). Although prophylactic surgeries are often undertaken by individuals at high risk for ovarian cancer because of genetic findings, such as BRCA1/2 abnormalities, even women with normal risk may consider when planning tubal ligation, removing their tubes, and other routine procedures. A substantial number of malignant tumors, and associated morbidity and mortality, may be thwarted as a result. The question of whether to treat when a STIC is detected remains to be answered.

The search for better methods of early detection continues, as local therapies for early-stage disease are invariably more effective than treatments in the advanced and/or metastatic setting.

Finally, as with certain other malignancies, even in the advanced setting, effective, often targeted, treatments can significantly prolong both progression-free and overall survival, transforming an often-lethal disease into a chronic one that allows patients to enjoy a better life expectancy with good quality of life.

Click to read more from 2023 Rare Diseases Report: Cancers

Incidence and Mortality

By 2040, the number of women diagnosed with ovarian cancer annually worldwide is expected to increase by 100% in low Human Development Index (HDI) countries, and by 19-28% in high HDI countries.² The causes of this increasing incidence are likely to be multifactorial, including both hereditary and modifiable risk factors.³ In addition to increasing population size, the growing prevalence of obesity, estrogen exposures, and nulliparity are particularly pertinent as potential causes of the rising incidence of ovarian cancer in younger women. The number of ovarian cancer-related deaths is also projected to rise from about 200,000 to nearly 314,000 annually, an increase of over 50% from 2020.^2,4 Although outcomes in developed regions and nations continue to improve somewhat, 5-year survival rates range from 36% to 46%.⁵ These outcomes are nevertheless dismal when compared with 5-year survival rates from other cancer types, such as breast cancer, which are approaching 90%.⁶

Principal Histotypes

The principal histotypes in ovarian cancer are epithelial in origin and include high-grade serous carcinoma, clear-cell carcinoma, endometrioid carcinoma, low-grade serous carcinoma, and mucinous carcinoma. Other rarer types are nonepithelial, ie, arising from stromal or germ cell lines.⁷ Incidence rates appear to be affected over time by trends such as birth rates, use of combination oral contraceptives, and menopausal hormone therapy.⁸ Figure 1 shows that most ovarian cancers—approximately 70%—are high-grade serous carcinoma, although in Asian countries clear cell and endometrioid carcinomas comprise a higher proportion.⁹

Into the Fallopian Tube

One of the most salient and dramatic discoveries of the last 2 decades has been the finding that high-grade, clear-cell, and endometrioid tumors appear to arise from tissues not normally present in the ovary.¹ As a result of risk-reducing efforts to prevent serous cancers in women with genetic predisposition to develop ovarian cancer (ie, those with BRCA1 or BRCA2 mutations), it became increasingly clear that many early cancers arose in the fallopian tube,^10-12 with the distal portion—the fimbria—as the most common site of origin.^13-16

Figure 2 depicts the female reproductive tract, including the location of the fimbria compared with the ovaries. Moreover, lesions observed in the fallopian tube fimbria—serous tubal intraepithelial carcinomas (STICs)—were identified as precursors of ovarian cancer, with a window of 7 years between development of STIC and the beginning of an ovarian cancer.^14,16

Early Detection

Early, localized ovarian cancer is asymptomatic; by the time a patient presents with symptoms, even with nonspecific abdominal complaints, the disease is almost invariably advanced. The concept of early detection has improved both the rate of cancer diagnoses and outcomes for some malignancies, such as cervical, colorectal, breast, and lung cancers,¹⁷ but this strategy is yet to be effectively applied in ovarian cancer. A large, population-based study, for instance, yielded negative results when multimodal screening (using both measurement of CA125 blood levels and transvaginal ultrasound imaging) failed to improve survival, even though such screening was able to detect lower stage disease.¹⁸ Emerging technologies, such as liquid biopsies and uterine lavage, which seek to detect potential biomarkers (new types of blood tests) of ovarian cancer at an early stage and closer to the site of tumor origin, are being investigated and refined but are not yet ready for clinical use, particularly at the population level for screening.¹⁹

Risk-Reducing Interventions

Use of oral contraceptives has been associated with a significant reduction in risk for ovarian cancer, but the potential risks (eg, increased risk for breast cancer, increased risk for venous thromboembolism) preclude its universal recommendation.^20-22 Simple removal of the fallopian tube, salpingectomy, was proposed as a potential intervention to “intercept” the progression of a STIC to cancer. Researchers recently compared simple salpingectomy with salpingo-oophorectomy as a risk-reduction procedure in carriers of BRCA 1/2 pathogenic variants after they had completed childbearing.²³

These investigators proposed that later removal of the ovaries would delay menopause and would contribute to fewer/less severe symptoms, such as hot flashes, disturbed sleep, and sexual issues, as well as maintain or improve overall quality of life. The hypothesis was supported by results, which showed that patients had better menopause-related quality of life after salpingectomy than after salpingo-oophorectomy, regardless of the use of hormone replacement therapy.²³ The oncologic safety of this approach was subsequently demonstrated by other studies that showed a significantly lower incidence of ovarian cancers in women who had undergone opportunistic salpingectomy.^22,24,25

An international prospective trial, TUBA-WISPII, is now underway to test the hypothesis that postponement of oophorectomy after salpingectomy is non-inferior to standard salpingo-oophorectomy in terms of ovarian cancer risk for patients at high risk.²⁶

Treatment

First-Line Therapy
Currently, there are no durable curative therapies for ovarian cancer once advanced disease has been diagnosed.

Surgery plus platinum-based chemotherapy. Most patients, even those diagnosed with advanced disease, are treated initially with debulking surgery, ideally by a gynecologic oncologist, and adjuvant chemotherapy. Most ovarian carcinomas are initially platinum-sensitive, but resistance and disease recurrence are almost inevitable. According to the National Comprehensive Cancer Network (NCCN) guidelines for ovarian cancer,²⁷ preferred chemotherapy regimens include paclitaxel and carboplatin with or without bevacizumab, docetaxel and carboplatin, or carboplatin and liposomal doxorubicin. Numerous other regimens, combinations, and agents are included in the guidelines to help providers customize treatment plans.

Neoadjuvant vs adjuvant regimens. Neoadjuvant chemotherapy has been used for other malignancies to gauge sensitivity to systemic treatments and to improve surgical margins.²⁸ Thus far, though, outcomes in ovarian cancer have been similar whether patients were given neoadjuvant or adjuvant treatment in the perioperative period. Individualizing these decisions based on ability to surgically resect, patient age, tumor histology, disease stage, and performance status is recommended.²⁹

Intraperitoneal chemotherapy. Other approaches have been explored to reduce risk for micrometastases after surgery. Hyperthermic intraperitoneal chemotherapy,³² for instance, administered immediately after cytoreductive surgery was studied as a technique that might prevent some of the risks and adverse effects associated with intraperitoneal chemotherapy.³¹ Results showed some improvement in progression-free survival and overall survival in a subgroup of patients who underwent interval cytoreductive surgery after neoadjuvant therapy, but no differences were observed for the larger population with advanced epithelial ovarian cancer. Adverse reactions to intraperitoneal chemotherapy were also observed.

Angiogenesis inhibition. Tumors need energy and oxygen to grow. Angiogenesis is the process of new blood vessel formation that provides the tumor with nutrients. Blocking angiogenesis can thwart tumor growth and improve patient outcomes. Bevacizumab is an antiangiogenic agent that has been extensively studied for 2 decades for many cancers including ovarian carcinoma. The NCCN guidelines note that bevacizumab may be considered as part of a first-line regimen with platinum agents, as maintenance in patients with wild-type or unknown BRCA mutation status and a good response to first-line therapy, or in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor in eligible patients.²⁷

PARP inhibitors. Approximately half of all high-grade serous ovarian carcinomas exhibit some defect in the ability to repair DNA damage using the homologous recombination (HR) pathway. These tumors include those with mutations in the BRCA1, BRCA2, and other HR genes. Defects in HR make tumors more dependent on back-up DNA repair systems, including the activity of PARP. PARP inhibitors were developed to specifically target HR-deficient tumors. To date, 3 PARP inhibitors have been approved for use in ovarian cancer—olaparib, rucaparib, and niraparib. Their use has expanded from later-line use in patients with BRCA1/2-mutated tumors to include frontline maintenance regimens for women with high-grade serous and high-grade endometrioid carcinomas, as well as women with recurrent disease.³² Numerous clinical trials are ongoing to develop next-generation PARP inhibitors and to explore their efficacy in combination with chemotherapy and other targeted agents.

Resistance and Disease Progression: Second-Line and Subsequent Treatment

A number of second-line and subsequent systemic treatment regimens may be considered when primary platinum-based chemotherapy and/or maintenance are no longer effective.^33,34 As emphasized by the NCCN, a clinical trial is always an appropriate option, depending on eligibility, and sometimes a second cytoreductive surgery^35,36 may be considered for patients who experience radiographic and/or clinical relapse after a long disease-free interval (6+ months). Each line of treatment is associated with progressively lower response rates and shorter durations of response. According to the NCCN guidelines, as patient performance status decreases and the toxicities of each line of therapy accumulate, assessment for palliative care should be considered and discussed.²⁷

Investigational Approaches

With the high mortality rate associated with ovarian cancer, the challenges of detecting the disease at its early stages, and the lack of therapies that can significantly extend progression-free and overall survival in patients with advanced disease, many investigators are focused on novel treatment approaches. Preclinical observations, for instance, showing synergy between ataxia telangiectasia and RAD3-related (ATR) kinase inhibitors and PARP inhibitors led researchers to initiate a phase 2 study of olaparib plus ceralasertib (an ATR inhibitor) in patients with recurrent, platinum-resistant epithelial ovarian cancer.³⁷ No objective responses were noted, but some signals of activity were seen among patients with BRCA1 mutations.

Due to success in other malignancies, immunotherapy is also being explored. Although some promising signals were reported at 6 months when nivolumab, a PD-1 (programmed cell death protein 1) inhibitor, and ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 antibody, were combined to treat patients with platinum-resistant epithelial ovarian cancer; final results are not yet available.³⁸

Ovarian cancer is sometimes characterized as immunologically “cold.” This description means that immune cells, especially T cells, are not able to enter the tumor and destroy the cancer cells. It also means that these tumors are not as responsive to immune-based treatments. Therefore, some researchers are examining novel alternative immunotherapy strategies, such as chimeric antigen receptor T-cell (CAR-T) therapy.³⁹ When a CAR T-cell encounters a tumor antigen, the CAR T-cell becomes activated. Activated CAR T-cells multiply, signal to other immune cells, and ultimately kill the tumor cells. Although CAR T-cell therapy has been tremendously successful in hematologic malignancies, to date, the benefits in solid tumors have been modest.³⁹ However, there is significant enthusiasm for novel tumor antigens that can be targeted by CAR-T therapy, including mesothelin, folate receptor, Claudin-6, B7-H3, B7-H4, HER2, CD47, and L1-CAM, among others.⁴⁰

Other investigational strategies include a p53 vaccine that would enhance the patient’s immunologic response to abnormal proteins produced by a mutated p53 gene, which is the most common finding in ovarian tumors.

Although researchers are investigating many approaches to treating advanced ovarian cancer, one strategy that has been pursued in other cancer settings—development of antibody-drug conjugates (ADCs)⁴¹—has seen promising results. In the late fall of 2022, the US Food and Drug Administration granted accelerated approval for mirvetuximab soravtansine-gynx for use in patients with a specific type of type of tumor (folate receptor alpha [FRα]-positive) when platinum resistance emerges.⁴² A companion diagnostic assay was also approved for selecting patients with FRα-positive disease. Several other clinical trials are investigating the efficacy of targeting other ovarian tumor antigens using the ADC approach. These targets include NaPi2b, mesothelin, B7-H4, Claudin-6, and Trop-2.^43,44

Progress to Come 

Progress in ovarian cancer will be made through a multipronged approach that includes interventions that may proactively “intercept” the development of cancer (eg, salpingectomy for women planning to have other simple gynecologic procedures after childbearing is complete). Although prophylactic surgeries are often undertaken by individuals at high risk for ovarian cancer because of genetic findings, such as BRCA1/2 abnormalities, even women with normal risk may consider when planning tubal ligation, removing their tubes, and other routine procedures. A substantial number of malignant tumors, and associated morbidity and mortality, may be thwarted as a result. The question of whether to treat when a STIC is detected remains to be answered.

The search for better methods of early detection continues, as local therapies for early-stage disease are invariably more effective than treatments in the advanced and/or metastatic setting.

Finally, as with certain other malignancies, even in the advanced setting, effective, often targeted, treatments can significantly prolong both progression-free and overall survival, transforming an often-lethal disease into a chronic one that allows patients to enjoy a better life expectancy with good quality of life.

Click to read more from 2023 Rare Diseases Report: Cancers

Incidence and Mortality

By 2040, the number of women diagnosed with ovarian cancer annually worldwide is expected to increase by 100% in low Human Development Index (HDI) countries, and by 19-28% in high HDI countries.² The causes of this increasing incidence are likely to be multifactorial, including both hereditary and modifiable risk factors.³ In addition to increasing population size, the growing prevalence of obesity, estrogen exposures, and nulliparity are particularly pertinent as potential causes of the rising incidence of ovarian cancer in younger women. The number of ovarian cancer-related deaths is also projected to rise from about 200,000 to nearly 314,000 annually, an increase of over 50% from 2020.^2,4 Although outcomes in developed regions and nations continue to improve somewhat, 5-year survival rates range from 36% to 46%.⁵ These outcomes are nevertheless dismal when compared with 5-year survival rates from other cancer types, such as breast cancer, which are approaching 90%.⁶

Principal Histotypes

The principal histotypes in ovarian cancer are epithelial in origin and include high-grade serous carcinoma, clear-cell carcinoma, endometrioid carcinoma, low-grade serous carcinoma, and mucinous carcinoma. Other rarer types are nonepithelial, ie, arising from stromal or germ cell lines.⁷ Incidence rates appear to be affected over time by trends such as birth rates, use of combination oral contraceptives, and menopausal hormone therapy.⁸ Figure 1 shows that most ovarian cancers—approximately 70%—are high-grade serous carcinoma, although in Asian countries clear cell and endometrioid carcinomas comprise a higher proportion.⁹

Into the Fallopian Tube

One of the most salient and dramatic discoveries of the last 2 decades has been the finding that high-grade, clear-cell, and endometrioid tumors appear to arise from tissues not normally present in the ovary.¹ As a result of risk-reducing efforts to prevent serous cancers in women with genetic predisposition to develop ovarian cancer (ie, those with BRCA1 or BRCA2 mutations), it became increasingly clear that many early cancers arose in the fallopian tube,^10-12 with the distal portion—the fimbria—as the most common site of origin.^13-16

Figure 2 depicts the female reproductive tract, including the location of the fimbria compared with the ovaries. Moreover, lesions observed in the fallopian tube fimbria—serous tubal intraepithelial carcinomas (STICs)—were identified as precursors of ovarian cancer, with a window of 7 years between development of STIC and the beginning of an ovarian cancer.^14,16

Early Detection

Early, localized ovarian cancer is asymptomatic; by the time a patient presents with symptoms, even with nonspecific abdominal complaints, the disease is almost invariably advanced. The concept of early detection has improved both the rate of cancer diagnoses and outcomes for some malignancies, such as cervical, colorectal, breast, and lung cancers,¹⁷ but this strategy is yet to be effectively applied in ovarian cancer. A large, population-based study, for instance, yielded negative results when multimodal screening (using both measurement of CA125 blood levels and transvaginal ultrasound imaging) failed to improve survival, even though such screening was able to detect lower stage disease.¹⁸ Emerging technologies, such as liquid biopsies and uterine lavage, which seek to detect potential biomarkers (new types of blood tests) of ovarian cancer at an early stage and closer to the site of tumor origin, are being investigated and refined but are not yet ready for clinical use, particularly at the population level for screening.¹⁹

Risk-Reducing Interventions

Use of oral contraceptives has been associated with a significant reduction in risk for ovarian cancer, but the potential risks (eg, increased risk for breast cancer, increased risk for venous thromboembolism) preclude its universal recommendation.^20-22 Simple removal of the fallopian tube, salpingectomy, was proposed as a potential intervention to “intercept” the progression of a STIC to cancer. Researchers recently compared simple salpingectomy with salpingo-oophorectomy as a risk-reduction procedure in carriers of BRCA 1/2 pathogenic variants after they had completed childbearing.²³

These investigators proposed that later removal of the ovaries would delay menopause and would contribute to fewer/less severe symptoms, such as hot flashes, disturbed sleep, and sexual issues, as well as maintain or improve overall quality of life. The hypothesis was supported by results, which showed that patients had better menopause-related quality of life after salpingectomy than after salpingo-oophorectomy, regardless of the use of hormone replacement therapy.²³ The oncologic safety of this approach was subsequently demonstrated by other studies that showed a significantly lower incidence of ovarian cancers in women who had undergone opportunistic salpingectomy.^22,24,25

An international prospective trial, TUBA-WISPII, is now underway to test the hypothesis that postponement of oophorectomy after salpingectomy is non-inferior to standard salpingo-oophorectomy in terms of ovarian cancer risk for patients at high risk.²⁶

Treatment

First-Line Therapy
Currently, there are no durable curative therapies for ovarian cancer once advanced disease has been diagnosed.

Surgery plus platinum-based chemotherapy. Most patients, even those diagnosed with advanced disease, are treated initially with debulking surgery, ideally by a gynecologic oncologist, and adjuvant chemotherapy. Most ovarian carcinomas are initially platinum-sensitive, but resistance and disease recurrence are almost inevitable. According to the National Comprehensive Cancer Network (NCCN) guidelines for ovarian cancer,²⁷ preferred chemotherapy regimens include paclitaxel and carboplatin with or without bevacizumab, docetaxel and carboplatin, or carboplatin and liposomal doxorubicin. Numerous other regimens, combinations, and agents are included in the guidelines to help providers customize treatment plans.

Neoadjuvant vs adjuvant regimens. Neoadjuvant chemotherapy has been used for other malignancies to gauge sensitivity to systemic treatments and to improve surgical margins.²⁸ Thus far, though, outcomes in ovarian cancer have been similar whether patients were given neoadjuvant or adjuvant treatment in the perioperative period. Individualizing these decisions based on ability to surgically resect, patient age, tumor histology, disease stage, and performance status is recommended.²⁹

Intraperitoneal chemotherapy. Other approaches have been explored to reduce risk for micrometastases after surgery. Hyperthermic intraperitoneal chemotherapy,³² for instance, administered immediately after cytoreductive surgery was studied as a technique that might prevent some of the risks and adverse effects associated with intraperitoneal chemotherapy.³¹ Results showed some improvement in progression-free survival and overall survival in a subgroup of patients who underwent interval cytoreductive surgery after neoadjuvant therapy, but no differences were observed for the larger population with advanced epithelial ovarian cancer. Adverse reactions to intraperitoneal chemotherapy were also observed.

Angiogenesis inhibition. Tumors need energy and oxygen to grow. Angiogenesis is the process of new blood vessel formation that provides the tumor with nutrients. Blocking angiogenesis can thwart tumor growth and improve patient outcomes. Bevacizumab is an antiangiogenic agent that has been extensively studied for 2 decades for many cancers including ovarian carcinoma. The NCCN guidelines note that bevacizumab may be considered as part of a first-line regimen with platinum agents, as maintenance in patients with wild-type or unknown BRCA mutation status and a good response to first-line therapy, or in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor in eligible patients.²⁷

PARP inhibitors. Approximately half of all high-grade serous ovarian carcinomas exhibit some defect in the ability to repair DNA damage using the homologous recombination (HR) pathway. These tumors include those with mutations in the BRCA1, BRCA2, and other HR genes. Defects in HR make tumors more dependent on back-up DNA repair systems, including the activity of PARP. PARP inhibitors were developed to specifically target HR-deficient tumors. To date, 3 PARP inhibitors have been approved for use in ovarian cancer—olaparib, rucaparib, and niraparib. Their use has expanded from later-line use in patients with BRCA1/2-mutated tumors to include frontline maintenance regimens for women with high-grade serous and high-grade endometrioid carcinomas, as well as women with recurrent disease.³² Numerous clinical trials are ongoing to develop next-generation PARP inhibitors and to explore their efficacy in combination with chemotherapy and other targeted agents.

Resistance and Disease Progression: Second-Line and Subsequent Treatment

A number of second-line and subsequent systemic treatment regimens may be considered when primary platinum-based chemotherapy and/or maintenance are no longer effective.^33,34 As emphasized by the NCCN, a clinical trial is always an appropriate option, depending on eligibility, and sometimes a second cytoreductive surgery^35,36 may be considered for patients who experience radiographic and/or clinical relapse after a long disease-free interval (6+ months). Each line of treatment is associated with progressively lower response rates and shorter durations of response. According to the NCCN guidelines, as patient performance status decreases and the toxicities of each line of therapy accumulate, assessment for palliative care should be considered and discussed.²⁷

Investigational Approaches

With the high mortality rate associated with ovarian cancer, the challenges of detecting the disease at its early stages, and the lack of therapies that can significantly extend progression-free and overall survival in patients with advanced disease, many investigators are focused on novel treatment approaches. Preclinical observations, for instance, showing synergy between ataxia telangiectasia and RAD3-related (ATR) kinase inhibitors and PARP inhibitors led researchers to initiate a phase 2 study of olaparib plus ceralasertib (an ATR inhibitor) in patients with recurrent, platinum-resistant epithelial ovarian cancer.³⁷ No objective responses were noted, but some signals of activity were seen among patients with BRCA1 mutations.

Due to success in other malignancies, immunotherapy is also being explored. Although some promising signals were reported at 6 months when nivolumab, a PD-1 (programmed cell death protein 1) inhibitor, and ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 antibody, were combined to treat patients with platinum-resistant epithelial ovarian cancer; final results are not yet available.³⁸

Ovarian cancer is sometimes characterized as immunologically “cold.” This description means that immune cells, especially T cells, are not able to enter the tumor and destroy the cancer cells. It also means that these tumors are not as responsive to immune-based treatments. Therefore, some researchers are examining novel alternative immunotherapy strategies, such as chimeric antigen receptor T-cell (CAR-T) therapy.³⁹ When a CAR T-cell encounters a tumor antigen, the CAR T-cell becomes activated. Activated CAR T-cells multiply, signal to other immune cells, and ultimately kill the tumor cells. Although CAR T-cell therapy has been tremendously successful in hematologic malignancies, to date, the benefits in solid tumors have been modest.³⁹ However, there is significant enthusiasm for novel tumor antigens that can be targeted by CAR-T therapy, including mesothelin, folate receptor, Claudin-6, B7-H3, B7-H4, HER2, CD47, and L1-CAM, among others.⁴⁰

Other investigational strategies include a p53 vaccine that would enhance the patient’s immunologic response to abnormal proteins produced by a mutated p53 gene, which is the most common finding in ovarian tumors.

Although researchers are investigating many approaches to treating advanced ovarian cancer, one strategy that has been pursued in other cancer settings—development of antibody-drug conjugates (ADCs)⁴¹—has seen promising results. In the late fall of 2022, the US Food and Drug Administration granted accelerated approval for mirvetuximab soravtansine-gynx for use in patients with a specific type of type of tumor (folate receptor alpha [FRα]-positive) when platinum resistance emerges.⁴² A companion diagnostic assay was also approved for selecting patients with FRα-positive disease. Several other clinical trials are investigating the efficacy of targeting other ovarian tumor antigens using the ADC approach. These targets include NaPi2b, mesothelin, B7-H4, Claudin-6, and Trop-2.^43,44

Progress to Come 

Progress in ovarian cancer will be made through a multipronged approach that includes interventions that may proactively “intercept” the development of cancer (eg, salpingectomy for women planning to have other simple gynecologic procedures after childbearing is complete). Although prophylactic surgeries are often undertaken by individuals at high risk for ovarian cancer because of genetic findings, such as BRCA1/2 abnormalities, even women with normal risk may consider when planning tubal ligation, removing their tubes, and other routine procedures. A substantial number of malignant tumors, and associated morbidity and mortality, may be thwarted as a result. The question of whether to treat when a STIC is detected remains to be answered.

The search for better methods of early detection continues, as local therapies for early-stage disease are invariably more effective than treatments in the advanced and/or metastatic setting.

Finally, as with certain other malignancies, even in the advanced setting, effective, often targeted, treatments can significantly prolong both progression-free and overall survival, transforming an often-lethal disease into a chronic one that allows patients to enjoy a better life expectancy with good quality of life.

Click to read more from 2023 Rare Diseases Report: Cancers

Among women with angina without obstructive coronary artery disease (ANOCA), mental stress induced a greater degree of myocardial ischemia than among those without ANOCA, new results show.

Further analysis in the small study suggested that mental stress–induced myocardial ischemia (MSIMI) was not statistically related to coronary microvascular dysfunction (CMD).

“Since the findings do not support a correlation between MSIMI and CMD, which has been a widely accepted mechanistic explanation of ANOCA, routine mental stress testing in patients with ANOCA seems necessary,” researchers led by Qingshan Geng, MD, PhD, of Shenzhen People’s Hospital, Guangdong, China, conclude in a report published online in the Journal of the American College of Cardiology.

Dr. Geng said in an interview that the use of virtual reality devices to administer mental stress tests “ensures standardized experimental procedures, with each participant receiving an objectively equivalent level of stress load.

“The immersive experience provided by VR lowers the environmental requirements for the test,” he noted. “Furthermore, the application of VR reduces the workload of personnel responsible for inducing mental stress, simplifying the experimental process.”

The team also developed a mobile app that enables remote monitoring of participants’ visual experiences during PET/CT scans and facilitates communication, he added.
 

Mental stress testing and meds?

Both ANOCA and MSIMI in patients with coronary artery disease disproportionately affect women and are associated with poor cardiovascular prognosis, the researchers write.

“However, the role of MSIMI and the exact influence of mental stress in ANOCA have not previously been studied,” they point out.

For this investigation, 84 women with ANOCA and 42 age-matched controls underwent three mental stress challenges delivered via VR.

Tests included mental arithmetic, making a public speech describing a recent emotionally upsetting event, and a task-modified Stroop test, in which participants were asked to say the color in which the word appears, not the color that the word names. For example, if the word “yellow” appears in blue type, blue would be the correct answer.

An adenosine stress test was given 5-8 minutes after the mental stress challenges started, and cardiac PET/CT was used to examine myocardial blood flow and perfusion.

The investigators report that women with ANOCA had a much higher rate of MSIMI (42.9%), compared with control participants (one patient; 2.4%). They also had a higher proportion of coronary microvascular dysfunction (CMD; 24.6% vs. 8.6%), but the occurrence of MSIMI and CMD was not related, the authors note.

Consistent with previous studies, “we observed that CMD is more prevalent in ANOCA women than the age-matched healthy individuals. MSIMI rate, however, was notably higher than the rate of CMD in our female ANOCA population,” they write. “The lack of a significant association between MSIMI and CMD indicates the mechanisms of MSIMI cannot be well explained by the adenosine-induced CMD.”

Dr. Geng suggested that ANOCA patients may benefit from treatment with escitalopram.

“Compelling evidence” from the REMIT randomized, placebo-controlled trial validates the efficacy of the drug as an MSIMI treatment, he said.
 

Sample size too small?

Asked for comment on the findings, Viola Vaccarino, MD, PhD, Wilton Looney Distinguished Professor of Cardiovascular Research at Emory University’s Rollins School of Public Health and a professor in the university’s School of Medicine, Atlanta, said she disagreed with several aspects of this study and the investigators’ conclusions.

Although the study suggests that MSIMI is prevalent among women with ANOCA, “the sample size was too small to make any definite conclusions,” she said in an interview.

“In fact,” she said, “I do not agree with the authors’ conclusions that MSIMI and CMD were not related, based on the data presented, even though the P value was not significant.”

In addition, more research is needed before screening can be recommended, she said. “The effectiveness of this testing modality in this population should be demonstrated first.”

Furthermore, she added, “an established treatment for MSIMI has yet to be tested in large, controlled trials, which limits the potential clinical benefit that may result from this [screening] test.”

For now, to ameliorate potential MSIMI in women with ANOCA, Dr. Vaccarino recommends behavioral modalities or stress-reduction management techniques, including biofeedback, meditation, breathing exercises, and “just plain regular physical activity,” rather than the use of psychotropic medications.

Dr. Vaccarino’s team has a study underway that builds on earlier work involving more than 900 participants, which showed that MSIMI was significantly associated with an increased risk of cardiovascular death or nonfatal myocardial infarction (hazard ratio, 2.5).

The ongoing study, which investigates the link between emotional stress and heart disease in men and women, should be completed in about 3 years, she said.
 

Microvascular disease or spasm?

Leslie Cho, MD, chair of the American College of Cardiology’s Cardiovascular Disease in Women Committee, director of the Cleveland Clinic’s Women’s Cardiovascular Center, and professor of medicine at Cleveland Clinic Lerner School of Medicine and Case Western Reserve Medical School, commented on the mental stress–heart connection and mental stress testing for this article.

A “very big flaw” of the JACC study, she said, is that although PET testing can detect microvascular disease, it cannot detect microvascular spasm.

PET can show the coronary flow reserve, “which is a nice way to assess microvascular dysfunction,” she acknowledged, “but it really can’t tell microvascular spasm, because adenosine works in a different pathway than acetylcholine – and I think it’s important for people to have the right diagnosis.

“We do physiologic testing to distinguish the two conditions,” she noted. “We do the gold standard, which is the cath lab.”

“The problem with women with chest pain for years is that they get a stress test, they get a cath, and everything’s normal. Then they get blown off as anxious or whatever.”

Clinicians should conduct the gold standard workup – provocative physiologic testing – for these women who continue to have chest pain when results of other tests are negative, she said. “The test used to be very cumbersome, but today, we have systems that make it super easy to use and to distinguish microvascular disease and microvascular spasm.”

Importantly, she added, physiologic testing should be performed when women are off therapy – something that doesn’t always happen in the clinic.

Regarding treatment, she added, “if you’re having emotional stress, the answer is not another medicine. The answer is cognitive-behavioral therapy or another behavioral intervention to overcome anxiety.”
 

Tune in and advocate

What can clinicians do for women with ANOCA after testing reveals no significant coronary artery disease or microvascular spasms?

“Very often, it’s a matter of the doctor listening and responding to the patient,” Johanna Contreras, MD, a cardiologist at Mount Sinai Hospital, New York, said in an intereview.

In her practice, Dr. Contreras sees highly stressed women on a daily basis. Many of her patients are women from diverse racial/ethnic groups, often of lower socioeconomic status, who are heads of households, work more than one job, and experience other major stressors.

“My message to clinicians is: don’t give up on a woman just because you looked at the arteries and couldn’t find anything specific. If she keeps coming back with the same symptom, it’s important to address it,” she said. “Maybe it isn’t the symptom. Maybe she needs to talk about her situation, about the physiological and psychosocial factors contributing to the symptom that a test alone won’t reveal.”

Regarding cardiovascular spasms that are identified through physiologic testing, she said, “I don’t know that medications such as SSRIs [selective serotonin reuptake inhibitors] are going to change anything. But many things can be changed by listening or helping the patient to stop and think about her mental health.”

Following up with a referral to a therapist can help, she said; “Take away the mental health stigma by telling the patient that the referral is simply to help her cope.”

Dr. Contreras urges clinicians to be advocates for such patients. If an insurance company says it will cover only three therapy sessions, “tell them that three appointments are not enough” to address multiple issues.

“If we invest money in helping patients identify and cope with these issues, we are likely to get better long-term outcomes, rather than having that woman come into the emergency department with chest pain over and over and doing 20,000 tests that are going to show exactly the same thing,” Dr. Contreras concluded.

Dr. Geng’s study was supported by the High-Level Hospital Construction Project of Guangdong Provincial People’s Hospital, by a grant from Guangdong Provincial Bureau of Traditional Chinese Medicine, and by a grant from Guangdong Medical Science and Technology Research Foundation. The authors, Dr. Vaccarino, Dr. Contreras, and Dr. Cho report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Among women with angina without obstructive coronary artery disease (ANOCA), mental stress induced a greater degree of myocardial ischemia than among those without ANOCA, new results show.

Further analysis in the small study suggested that mental stress–induced myocardial ischemia (MSIMI) was not statistically related to coronary microvascular dysfunction (CMD).

“Since the findings do not support a correlation between MSIMI and CMD, which has been a widely accepted mechanistic explanation of ANOCA, routine mental stress testing in patients with ANOCA seems necessary,” researchers led by Qingshan Geng, MD, PhD, of Shenzhen People’s Hospital, Guangdong, China, conclude in a report published online in the Journal of the American College of Cardiology.

Dr. Geng said in an interview that the use of virtual reality devices to administer mental stress tests “ensures standardized experimental procedures, with each participant receiving an objectively equivalent level of stress load.

“The immersive experience provided by VR lowers the environmental requirements for the test,” he noted. “Furthermore, the application of VR reduces the workload of personnel responsible for inducing mental stress, simplifying the experimental process.”

The team also developed a mobile app that enables remote monitoring of participants’ visual experiences during PET/CT scans and facilitates communication, he added.
 

Mental stress testing and meds?

Both ANOCA and MSIMI in patients with coronary artery disease disproportionately affect women and are associated with poor cardiovascular prognosis, the researchers write.

“However, the role of MSIMI and the exact influence of mental stress in ANOCA have not previously been studied,” they point out.

For this investigation, 84 women with ANOCA and 42 age-matched controls underwent three mental stress challenges delivered via VR.

Tests included mental arithmetic, making a public speech describing a recent emotionally upsetting event, and a task-modified Stroop test, in which participants were asked to say the color in which the word appears, not the color that the word names. For example, if the word “yellow” appears in blue type, blue would be the correct answer.

An adenosine stress test was given 5-8 minutes after the mental stress challenges started, and cardiac PET/CT was used to examine myocardial blood flow and perfusion.

The investigators report that women with ANOCA had a much higher rate of MSIMI (42.9%), compared with control participants (one patient; 2.4%). They also had a higher proportion of coronary microvascular dysfunction (CMD; 24.6% vs. 8.6%), but the occurrence of MSIMI and CMD was not related, the authors note.

Consistent with previous studies, “we observed that CMD is more prevalent in ANOCA women than the age-matched healthy individuals. MSIMI rate, however, was notably higher than the rate of CMD in our female ANOCA population,” they write. “The lack of a significant association between MSIMI and CMD indicates the mechanisms of MSIMI cannot be well explained by the adenosine-induced CMD.”

Dr. Geng suggested that ANOCA patients may benefit from treatment with escitalopram.

“Compelling evidence” from the REMIT randomized, placebo-controlled trial validates the efficacy of the drug as an MSIMI treatment, he said.
 

Sample size too small?

Asked for comment on the findings, Viola Vaccarino, MD, PhD, Wilton Looney Distinguished Professor of Cardiovascular Research at Emory University’s Rollins School of Public Health and a professor in the university’s School of Medicine, Atlanta, said she disagreed with several aspects of this study and the investigators’ conclusions.

Although the study suggests that MSIMI is prevalent among women with ANOCA, “the sample size was too small to make any definite conclusions,” she said in an interview.

“In fact,” she said, “I do not agree with the authors’ conclusions that MSIMI and CMD were not related, based on the data presented, even though the P value was not significant.”

In addition, more research is needed before screening can be recommended, she said. “The effectiveness of this testing modality in this population should be demonstrated first.”

Furthermore, she added, “an established treatment for MSIMI has yet to be tested in large, controlled trials, which limits the potential clinical benefit that may result from this [screening] test.”

For now, to ameliorate potential MSIMI in women with ANOCA, Dr. Vaccarino recommends behavioral modalities or stress-reduction management techniques, including biofeedback, meditation, breathing exercises, and “just plain regular physical activity,” rather than the use of psychotropic medications.

Dr. Vaccarino’s team has a study underway that builds on earlier work involving more than 900 participants, which showed that MSIMI was significantly associated with an increased risk of cardiovascular death or nonfatal myocardial infarction (hazard ratio, 2.5).

The ongoing study, which investigates the link between emotional stress and heart disease in men and women, should be completed in about 3 years, she said.
 

Microvascular disease or spasm?

Leslie Cho, MD, chair of the American College of Cardiology’s Cardiovascular Disease in Women Committee, director of the Cleveland Clinic’s Women’s Cardiovascular Center, and professor of medicine at Cleveland Clinic Lerner School of Medicine and Case Western Reserve Medical School, commented on the mental stress–heart connection and mental stress testing for this article.

A “very big flaw” of the JACC study, she said, is that although PET testing can detect microvascular disease, it cannot detect microvascular spasm.

PET can show the coronary flow reserve, “which is a nice way to assess microvascular dysfunction,” she acknowledged, “but it really can’t tell microvascular spasm, because adenosine works in a different pathway than acetylcholine – and I think it’s important for people to have the right diagnosis.

“We do physiologic testing to distinguish the two conditions,” she noted. “We do the gold standard, which is the cath lab.”

“The problem with women with chest pain for years is that they get a stress test, they get a cath, and everything’s normal. Then they get blown off as anxious or whatever.”

Clinicians should conduct the gold standard workup – provocative physiologic testing – for these women who continue to have chest pain when results of other tests are negative, she said. “The test used to be very cumbersome, but today, we have systems that make it super easy to use and to distinguish microvascular disease and microvascular spasm.”

Importantly, she added, physiologic testing should be performed when women are off therapy – something that doesn’t always happen in the clinic.

Regarding treatment, she added, “if you’re having emotional stress, the answer is not another medicine. The answer is cognitive-behavioral therapy or another behavioral intervention to overcome anxiety.”
 

Tune in and advocate

What can clinicians do for women with ANOCA after testing reveals no significant coronary artery disease or microvascular spasms?

“Very often, it’s a matter of the doctor listening and responding to the patient,” Johanna Contreras, MD, a cardiologist at Mount Sinai Hospital, New York, said in an intereview.

In her practice, Dr. Contreras sees highly stressed women on a daily basis. Many of her patients are women from diverse racial/ethnic groups, often of lower socioeconomic status, who are heads of households, work more than one job, and experience other major stressors.

“My message to clinicians is: don’t give up on a woman just because you looked at the arteries and couldn’t find anything specific. If she keeps coming back with the same symptom, it’s important to address it,” she said. “Maybe it isn’t the symptom. Maybe she needs to talk about her situation, about the physiological and psychosocial factors contributing to the symptom that a test alone won’t reveal.”

Regarding cardiovascular spasms that are identified through physiologic testing, she said, “I don’t know that medications such as SSRIs [selective serotonin reuptake inhibitors] are going to change anything. But many things can be changed by listening or helping the patient to stop and think about her mental health.”

Following up with a referral to a therapist can help, she said; “Take away the mental health stigma by telling the patient that the referral is simply to help her cope.”

Dr. Contreras urges clinicians to be advocates for such patients. If an insurance company says it will cover only three therapy sessions, “tell them that three appointments are not enough” to address multiple issues.

“If we invest money in helping patients identify and cope with these issues, we are likely to get better long-term outcomes, rather than having that woman come into the emergency department with chest pain over and over and doing 20,000 tests that are going to show exactly the same thing,” Dr. Contreras concluded.

Dr. Geng’s study was supported by the High-Level Hospital Construction Project of Guangdong Provincial People’s Hospital, by a grant from Guangdong Provincial Bureau of Traditional Chinese Medicine, and by a grant from Guangdong Medical Science and Technology Research Foundation. The authors, Dr. Vaccarino, Dr. Contreras, and Dr. Cho report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Among women with angina without obstructive coronary artery disease (ANOCA), mental stress induced a greater degree of myocardial ischemia than among those without ANOCA, new results show.

Further analysis in the small study suggested that mental stress–induced myocardial ischemia (MSIMI) was not statistically related to coronary microvascular dysfunction (CMD).

“Since the findings do not support a correlation between MSIMI and CMD, which has been a widely accepted mechanistic explanation of ANOCA, routine mental stress testing in patients with ANOCA seems necessary,” researchers led by Qingshan Geng, MD, PhD, of Shenzhen People’s Hospital, Guangdong, China, conclude in a report published online in the Journal of the American College of Cardiology.

Dr. Geng said in an interview that the use of virtual reality devices to administer mental stress tests “ensures standardized experimental procedures, with each participant receiving an objectively equivalent level of stress load.

“The immersive experience provided by VR lowers the environmental requirements for the test,” he noted. “Furthermore, the application of VR reduces the workload of personnel responsible for inducing mental stress, simplifying the experimental process.”

The team also developed a mobile app that enables remote monitoring of participants’ visual experiences during PET/CT scans and facilitates communication, he added.
 

Mental stress testing and meds?

Both ANOCA and MSIMI in patients with coronary artery disease disproportionately affect women and are associated with poor cardiovascular prognosis, the researchers write.

“However, the role of MSIMI and the exact influence of mental stress in ANOCA have not previously been studied,” they point out.

For this investigation, 84 women with ANOCA and 42 age-matched controls underwent three mental stress challenges delivered via VR.

Tests included mental arithmetic, making a public speech describing a recent emotionally upsetting event, and a task-modified Stroop test, in which participants were asked to say the color in which the word appears, not the color that the word names. For example, if the word “yellow” appears in blue type, blue would be the correct answer.

An adenosine stress test was given 5-8 minutes after the mental stress challenges started, and cardiac PET/CT was used to examine myocardial blood flow and perfusion.

The investigators report that women with ANOCA had a much higher rate of MSIMI (42.9%), compared with control participants (one patient; 2.4%). They also had a higher proportion of coronary microvascular dysfunction (CMD; 24.6% vs. 8.6%), but the occurrence of MSIMI and CMD was not related, the authors note.

Consistent with previous studies, “we observed that CMD is more prevalent in ANOCA women than the age-matched healthy individuals. MSIMI rate, however, was notably higher than the rate of CMD in our female ANOCA population,” they write. “The lack of a significant association between MSIMI and CMD indicates the mechanisms of MSIMI cannot be well explained by the adenosine-induced CMD.”

Dr. Geng suggested that ANOCA patients may benefit from treatment with escitalopram.

“Compelling evidence” from the REMIT randomized, placebo-controlled trial validates the efficacy of the drug as an MSIMI treatment, he said.
 

Sample size too small?

Asked for comment on the findings, Viola Vaccarino, MD, PhD, Wilton Looney Distinguished Professor of Cardiovascular Research at Emory University’s Rollins School of Public Health and a professor in the university’s School of Medicine, Atlanta, said she disagreed with several aspects of this study and the investigators’ conclusions.

Although the study suggests that MSIMI is prevalent among women with ANOCA, “the sample size was too small to make any definite conclusions,” she said in an interview.

“In fact,” she said, “I do not agree with the authors’ conclusions that MSIMI and CMD were not related, based on the data presented, even though the P value was not significant.”

In addition, more research is needed before screening can be recommended, she said. “The effectiveness of this testing modality in this population should be demonstrated first.”

Furthermore, she added, “an established treatment for MSIMI has yet to be tested in large, controlled trials, which limits the potential clinical benefit that may result from this [screening] test.”

For now, to ameliorate potential MSIMI in women with ANOCA, Dr. Vaccarino recommends behavioral modalities or stress-reduction management techniques, including biofeedback, meditation, breathing exercises, and “just plain regular physical activity,” rather than the use of psychotropic medications.

Dr. Vaccarino’s team has a study underway that builds on earlier work involving more than 900 participants, which showed that MSIMI was significantly associated with an increased risk of cardiovascular death or nonfatal myocardial infarction (hazard ratio, 2.5).

The ongoing study, which investigates the link between emotional stress and heart disease in men and women, should be completed in about 3 years, she said.
 

Microvascular disease or spasm?

Leslie Cho, MD, chair of the American College of Cardiology’s Cardiovascular Disease in Women Committee, director of the Cleveland Clinic’s Women’s Cardiovascular Center, and professor of medicine at Cleveland Clinic Lerner School of Medicine and Case Western Reserve Medical School, commented on the mental stress–heart connection and mental stress testing for this article.

A “very big flaw” of the JACC study, she said, is that although PET testing can detect microvascular disease, it cannot detect microvascular spasm.

PET can show the coronary flow reserve, “which is a nice way to assess microvascular dysfunction,” she acknowledged, “but it really can’t tell microvascular spasm, because adenosine works in a different pathway than acetylcholine – and I think it’s important for people to have the right diagnosis.

“We do physiologic testing to distinguish the two conditions,” she noted. “We do the gold standard, which is the cath lab.”

“The problem with women with chest pain for years is that they get a stress test, they get a cath, and everything’s normal. Then they get blown off as anxious or whatever.”

Clinicians should conduct the gold standard workup – provocative physiologic testing – for these women who continue to have chest pain when results of other tests are negative, she said. “The test used to be very cumbersome, but today, we have systems that make it super easy to use and to distinguish microvascular disease and microvascular spasm.”

Importantly, she added, physiologic testing should be performed when women are off therapy – something that doesn’t always happen in the clinic.

Regarding treatment, she added, “if you’re having emotional stress, the answer is not another medicine. The answer is cognitive-behavioral therapy or another behavioral intervention to overcome anxiety.”
 

Tune in and advocate

What can clinicians do for women with ANOCA after testing reveals no significant coronary artery disease or microvascular spasms?

“Very often, it’s a matter of the doctor listening and responding to the patient,” Johanna Contreras, MD, a cardiologist at Mount Sinai Hospital, New York, said in an intereview.

In her practice, Dr. Contreras sees highly stressed women on a daily basis. Many of her patients are women from diverse racial/ethnic groups, often of lower socioeconomic status, who are heads of households, work more than one job, and experience other major stressors.

“My message to clinicians is: don’t give up on a woman just because you looked at the arteries and couldn’t find anything specific. If she keeps coming back with the same symptom, it’s important to address it,” she said. “Maybe it isn’t the symptom. Maybe she needs to talk about her situation, about the physiological and psychosocial factors contributing to the symptom that a test alone won’t reveal.”

Regarding cardiovascular spasms that are identified through physiologic testing, she said, “I don’t know that medications such as SSRIs [selective serotonin reuptake inhibitors] are going to change anything. But many things can be changed by listening or helping the patient to stop and think about her mental health.”

Following up with a referral to a therapist can help, she said; “Take away the mental health stigma by telling the patient that the referral is simply to help her cope.”

Dr. Contreras urges clinicians to be advocates for such patients. If an insurance company says it will cover only three therapy sessions, “tell them that three appointments are not enough” to address multiple issues.

“If we invest money in helping patients identify and cope with these issues, we are likely to get better long-term outcomes, rather than having that woman come into the emergency department with chest pain over and over and doing 20,000 tests that are going to show exactly the same thing,” Dr. Contreras concluded.

Dr. Geng’s study was supported by the High-Level Hospital Construction Project of Guangdong Provincial People’s Hospital, by a grant from Guangdong Provincial Bureau of Traditional Chinese Medicine, and by a grant from Guangdong Medical Science and Technology Research Foundation. The authors, Dr. Vaccarino, Dr. Contreras, and Dr. Cho report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

VIENNA – An algorithm, the Steatosis-Associated Fibrosis Estimator (SAFE), was developed to detect clinically significant fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). It is effective at detecting chronic liver disease from all causes with or without NAFLD in the general population, according the results of a U.S. population-based study. The algorithm was designed for use in primary care to help slow the steep rise in liver disease burden.

On the basis of the SAFE score, 61.3% of participants were at low risk for clinically significant fibrosis; 11.2% were at high risk; and 27.5% were at intermediate risk. Upon validation, very few of the low-risk participants had liver fibrosis, while nearly a third of those with a high-risk score had clinically significant fibrosis. In addition, a high percentage of the patients with high-risk SAFE scores had viral hepatitis and elevations in ferritin level.

“This is the first time that there has been a test that provides a score to detect low-risk liver disease in primary care,” said Ray Kim, MD, from Stanford (Calif.) University, senior investigator, who was speaking to this news organization at the annual International Liver Congress sponsored by the European Association for the Study of the Liver

“Primary care doctors currently detect liver disease through a serendipitous abnormal finding on ultrasound or blood tests that detect elevated transaminases, and then the patient is referred to a hepatologist, who figures out what is really going on,” said Dr. Kim.

“This approach is limited, so we need to get SAFE into primary care so these doctors can automatically calculate their scores, and if the patient is over 100 [high risk of chronic liver disease], then they need help [referral to a hepatologist].”
 

Liver deaths sharply rising

Public health data show that more people are dying of liver disease today than previously. Deaths in the United States have doubled over the past 20 years, said Dr. Kim. “If our mission is to help these patients and prevent death, [things are] moving in the wrong direction.”

He stressed that in order to change the direction, “primary care doctors need to engage with the issue and have appropriate tools to identify people with liver disease.”

Most often, the reason for this rise in deaths is that cases are being diagnosed at advanced stages of disease in which reversibility is limited, he added. “We want to move upstream where people might have early-stage disease and where we can intervene and make a difference.”

In an effort to help earlier detection of liver disease, the SAFE score was developed and validated by Dr. Kim and his colleagues to detect clinically significant (greater than stage 2) fibrosis in patients with NAFLD in primary care. The score is based upon age, body mass index, diabetes, platelet level, aspartate and alanine aminotransferase levels, and globulin level. A score of less than zero signifies that a patient is at low risk for liver fibrosis, while a score greater than 100 signifies a high risk of fibrosis. A score between 0 and 99 denotes intermediate risk of fibrosis.

“Unlike other noninvasive tests that detect advanced fibrosis, this one detects early-stage fibrosis. We’ve shown that the SAFE estimator is better than all other blood-based markers,” explained Dr. Kim.
 

Applying SAFE to the general population

In the study presented here at EASL, Dr. Kim aimed to expand the horizon for SAFE testing to the U.S. general population and to assess whether SAFE was effective in screening for chronic liver disease regardless of steatosis of the liver.

Together with first author Nakia Chung, MD, also from Stanford University, Dr. Kim applied the SAFE score to data from 7,156 participants of the National Health and Nutrition Examination Survey (NHANES) for 2017-2020. NHANES is representative of the noninstitutionalized, civilian population of the United States. It includes broad demographic, clinical, and laboratory data, including transient elastography data. FibroScans were first used in 2017, so the investigators had 3 years of FibroScan data with which to validate the score.

The researchers extrapolated the NHANES sample data to the U.S. population. They found that the proportion of adults with steatosis (CAP score > 274 dB/m) and significant fibrosis (LSM > 8.0 kPa) was 42.7% (95% confidence interval, 41.0%- 44.3%) and 8.9% (7.6%-10.2%), respectively. In addition, 11.3% (10.2%-12.5%) of the adult U.S. population demonstrated a significant amount of alcohol use, 2.3% (1.4%-3.3%) showed evidence of hepatitis B or C, and 5.4% (4.6%-6.2%) had elevated serum ferritin levels.

The researchers then stratified the patients according to previously defined SAFE tiers of low, intermediate, and high risk and projected findings to the U.S. general population.

“When we applied our score to the general population, we found multiple abnormalities in the high-risk groups [SAFE >100] having Fibroscan data that are consistent with stage 2 or higher fibrosis regardless of etiology, “Dr. Kim pointed out.

Results also showed that very few patients with SAFE less than 0 had liver fibrosis (4% among those with liver stiffness measure [LSM] > 8kPa, and 0.8% with LSM > 12kPa). Among those with SAFE > 100, nearly a third (31.5%) had LSM of > 8kPa, and 16.5% had LSM > 12kPa.

In addition to fibrosis, liver abnormalities were common among patients with SAFE greater than 100, including steatosis (68.0%), viral hepatitis (7.0%), and abnormal ferritin levels (12.9%); 10.8% of these patients used alcohol.

“Right now, some patients are referred, but on examination and FibroScan, they might actually be okay, so it it’s a waste of time and money for everyone. We can preempt all of this by doing a blood test and focusing on those people who really need a scan,” said Dr. Kim.

The researcher is now working with primary care colleagues to help further develop and integrate SAFE into the primary care setting.
 

Fibrosis score in patients with metabolic dysfunction

Also presenting at the same session on population health was Willem Pieter Brouwer, MD, PhD, from Erasmus University Medical Center, Rotterdam, the Netherlands. He reported results of a validation study of a new risk score – the Metabolic Dysfunction-Associated Fibrosis–5 (MAF-5) score – for use for people with metabolic dysfunction who are recommended for screening for liver fibrosis.

“We believe the MAF-5 score may be a good alternative to the FIB-4 [a liver fibrosis biomarker] for use in the referral pathway for liver health evaluation,” remarked Dr. Brouwer. “The clinical practice guidelines recommend using FIB-4 scores, but these have a poor-moderate performance in the population setting.

“We developed and validated our score in a population of 5,500 from the NHANES 2017-2020 cycle and validated the score in populations from Rotterdam, which is a cohort of elderly participants, and in fibrosis among patients with biopsy-proven NAFLD from Colombia and Belgium,” he explained.

He also validated the score against different existing scoring systems and different methods of measuring liver stiffness and validated it for prognostic use to predict all-cause mortality in the NHANES III cohort.

Dr. Brouwer removed age as a factor of his new MAF-5 score; the score is thus stable for patients of all ages and is suitable for detecting liver disease in younger patients. “This is very important because these patients are currently underserved and have the most years of life to win.”

Referring to the SAFE score discussed by Dr. Kim, as well as other scores, he said, “The FIB-4, SAFE, and NFS [NAFLD fibrosis score] all include age in the scores, which causes problems and limitations in aging populations, as more and more patients will be referred due to an increasing score. Hence, the elderly are mostly all referred for liver checkups.”

Dr. Kim and Dr. Brouwer have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

VIENNA – An algorithm, the Steatosis-Associated Fibrosis Estimator (SAFE), was developed to detect clinically significant fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). It is effective at detecting chronic liver disease from all causes with or without NAFLD in the general population, according the results of a U.S. population-based study. The algorithm was designed for use in primary care to help slow the steep rise in liver disease burden.

On the basis of the SAFE score, 61.3% of participants were at low risk for clinically significant fibrosis; 11.2% were at high risk; and 27.5% were at intermediate risk. Upon validation, very few of the low-risk participants had liver fibrosis, while nearly a third of those with a high-risk score had clinically significant fibrosis. In addition, a high percentage of the patients with high-risk SAFE scores had viral hepatitis and elevations in ferritin level.

“This is the first time that there has been a test that provides a score to detect low-risk liver disease in primary care,” said Ray Kim, MD, from Stanford (Calif.) University, senior investigator, who was speaking to this news organization at the annual International Liver Congress sponsored by the European Association for the Study of the Liver

“Primary care doctors currently detect liver disease through a serendipitous abnormal finding on ultrasound or blood tests that detect elevated transaminases, and then the patient is referred to a hepatologist, who figures out what is really going on,” said Dr. Kim.

“This approach is limited, so we need to get SAFE into primary care so these doctors can automatically calculate their scores, and if the patient is over 100 [high risk of chronic liver disease], then they need help [referral to a hepatologist].”
 

Liver deaths sharply rising

Public health data show that more people are dying of liver disease today than previously. Deaths in the United States have doubled over the past 20 years, said Dr. Kim. “If our mission is to help these patients and prevent death, [things are] moving in the wrong direction.”

He stressed that in order to change the direction, “primary care doctors need to engage with the issue and have appropriate tools to identify people with liver disease.”

Most often, the reason for this rise in deaths is that cases are being diagnosed at advanced stages of disease in which reversibility is limited, he added. “We want to move upstream where people might have early-stage disease and where we can intervene and make a difference.”

In an effort to help earlier detection of liver disease, the SAFE score was developed and validated by Dr. Kim and his colleagues to detect clinically significant (greater than stage 2) fibrosis in patients with NAFLD in primary care. The score is based upon age, body mass index, diabetes, platelet level, aspartate and alanine aminotransferase levels, and globulin level. A score of less than zero signifies that a patient is at low risk for liver fibrosis, while a score greater than 100 signifies a high risk of fibrosis. A score between 0 and 99 denotes intermediate risk of fibrosis.

“Unlike other noninvasive tests that detect advanced fibrosis, this one detects early-stage fibrosis. We’ve shown that the SAFE estimator is better than all other blood-based markers,” explained Dr. Kim.
 

Applying SAFE to the general population

In the study presented here at EASL, Dr. Kim aimed to expand the horizon for SAFE testing to the U.S. general population and to assess whether SAFE was effective in screening for chronic liver disease regardless of steatosis of the liver.

Together with first author Nakia Chung, MD, also from Stanford University, Dr. Kim applied the SAFE score to data from 7,156 participants of the National Health and Nutrition Examination Survey (NHANES) for 2017-2020. NHANES is representative of the noninstitutionalized, civilian population of the United States. It includes broad demographic, clinical, and laboratory data, including transient elastography data. FibroScans were first used in 2017, so the investigators had 3 years of FibroScan data with which to validate the score.

The researchers extrapolated the NHANES sample data to the U.S. population. They found that the proportion of adults with steatosis (CAP score > 274 dB/m) and significant fibrosis (LSM > 8.0 kPa) was 42.7% (95% confidence interval, 41.0%- 44.3%) and 8.9% (7.6%-10.2%), respectively. In addition, 11.3% (10.2%-12.5%) of the adult U.S. population demonstrated a significant amount of alcohol use, 2.3% (1.4%-3.3%) showed evidence of hepatitis B or C, and 5.4% (4.6%-6.2%) had elevated serum ferritin levels.

The researchers then stratified the patients according to previously defined SAFE tiers of low, intermediate, and high risk and projected findings to the U.S. general population.

“When we applied our score to the general population, we found multiple abnormalities in the high-risk groups [SAFE >100] having Fibroscan data that are consistent with stage 2 or higher fibrosis regardless of etiology, “Dr. Kim pointed out.

Results also showed that very few patients with SAFE less than 0 had liver fibrosis (4% among those with liver stiffness measure [LSM] > 8kPa, and 0.8% with LSM > 12kPa). Among those with SAFE > 100, nearly a third (31.5%) had LSM of > 8kPa, and 16.5% had LSM > 12kPa.

In addition to fibrosis, liver abnormalities were common among patients with SAFE greater than 100, including steatosis (68.0%), viral hepatitis (7.0%), and abnormal ferritin levels (12.9%); 10.8% of these patients used alcohol.

“Right now, some patients are referred, but on examination and FibroScan, they might actually be okay, so it it’s a waste of time and money for everyone. We can preempt all of this by doing a blood test and focusing on those people who really need a scan,” said Dr. Kim.

The researcher is now working with primary care colleagues to help further develop and integrate SAFE into the primary care setting.
 

Fibrosis score in patients with metabolic dysfunction

Also presenting at the same session on population health was Willem Pieter Brouwer, MD, PhD, from Erasmus University Medical Center, Rotterdam, the Netherlands. He reported results of a validation study of a new risk score – the Metabolic Dysfunction-Associated Fibrosis–5 (MAF-5) score – for use for people with metabolic dysfunction who are recommended for screening for liver fibrosis.

“We believe the MAF-5 score may be a good alternative to the FIB-4 [a liver fibrosis biomarker] for use in the referral pathway for liver health evaluation,” remarked Dr. Brouwer. “The clinical practice guidelines recommend using FIB-4 scores, but these have a poor-moderate performance in the population setting.

“We developed and validated our score in a population of 5,500 from the NHANES 2017-2020 cycle and validated the score in populations from Rotterdam, which is a cohort of elderly participants, and in fibrosis among patients with biopsy-proven NAFLD from Colombia and Belgium,” he explained.

He also validated the score against different existing scoring systems and different methods of measuring liver stiffness and validated it for prognostic use to predict all-cause mortality in the NHANES III cohort.

Dr. Brouwer removed age as a factor of his new MAF-5 score; the score is thus stable for patients of all ages and is suitable for detecting liver disease in younger patients. “This is very important because these patients are currently underserved and have the most years of life to win.”

Referring to the SAFE score discussed by Dr. Kim, as well as other scores, he said, “The FIB-4, SAFE, and NFS [NAFLD fibrosis score] all include age in the scores, which causes problems and limitations in aging populations, as more and more patients will be referred due to an increasing score. Hence, the elderly are mostly all referred for liver checkups.”

Dr. Kim and Dr. Brouwer have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

VIENNA – An algorithm, the Steatosis-Associated Fibrosis Estimator (SAFE), was developed to detect clinically significant fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). It is effective at detecting chronic liver disease from all causes with or without NAFLD in the general population, according the results of a U.S. population-based study. The algorithm was designed for use in primary care to help slow the steep rise in liver disease burden.

On the basis of the SAFE score, 61.3% of participants were at low risk for clinically significant fibrosis; 11.2% were at high risk; and 27.5% were at intermediate risk. Upon validation, very few of the low-risk participants had liver fibrosis, while nearly a third of those with a high-risk score had clinically significant fibrosis. In addition, a high percentage of the patients with high-risk SAFE scores had viral hepatitis and elevations in ferritin level.

“This is the first time that there has been a test that provides a score to detect low-risk liver disease in primary care,” said Ray Kim, MD, from Stanford (Calif.) University, senior investigator, who was speaking to this news organization at the annual International Liver Congress sponsored by the European Association for the Study of the Liver

“Primary care doctors currently detect liver disease through a serendipitous abnormal finding on ultrasound or blood tests that detect elevated transaminases, and then the patient is referred to a hepatologist, who figures out what is really going on,” said Dr. Kim.

“This approach is limited, so we need to get SAFE into primary care so these doctors can automatically calculate their scores, and if the patient is over 100 [high risk of chronic liver disease], then they need help [referral to a hepatologist].”
 

Liver deaths sharply rising

Public health data show that more people are dying of liver disease today than previously. Deaths in the United States have doubled over the past 20 years, said Dr. Kim. “If our mission is to help these patients and prevent death, [things are] moving in the wrong direction.”

He stressed that in order to change the direction, “primary care doctors need to engage with the issue and have appropriate tools to identify people with liver disease.”

Most often, the reason for this rise in deaths is that cases are being diagnosed at advanced stages of disease in which reversibility is limited, he added. “We want to move upstream where people might have early-stage disease and where we can intervene and make a difference.”

In an effort to help earlier detection of liver disease, the SAFE score was developed and validated by Dr. Kim and his colleagues to detect clinically significant (greater than stage 2) fibrosis in patients with NAFLD in primary care. The score is based upon age, body mass index, diabetes, platelet level, aspartate and alanine aminotransferase levels, and globulin level. A score of less than zero signifies that a patient is at low risk for liver fibrosis, while a score greater than 100 signifies a high risk of fibrosis. A score between 0 and 99 denotes intermediate risk of fibrosis.

“Unlike other noninvasive tests that detect advanced fibrosis, this one detects early-stage fibrosis. We’ve shown that the SAFE estimator is better than all other blood-based markers,” explained Dr. Kim.
 

Applying SAFE to the general population

In the study presented here at EASL, Dr. Kim aimed to expand the horizon for SAFE testing to the U.S. general population and to assess whether SAFE was effective in screening for chronic liver disease regardless of steatosis of the liver.

Together with first author Nakia Chung, MD, also from Stanford University, Dr. Kim applied the SAFE score to data from 7,156 participants of the National Health and Nutrition Examination Survey (NHANES) for 2017-2020. NHANES is representative of the noninstitutionalized, civilian population of the United States. It includes broad demographic, clinical, and laboratory data, including transient elastography data. FibroScans were first used in 2017, so the investigators had 3 years of FibroScan data with which to validate the score.

The researchers extrapolated the NHANES sample data to the U.S. population. They found that the proportion of adults with steatosis (CAP score > 274 dB/m) and significant fibrosis (LSM > 8.0 kPa) was 42.7% (95% confidence interval, 41.0%- 44.3%) and 8.9% (7.6%-10.2%), respectively. In addition, 11.3% (10.2%-12.5%) of the adult U.S. population demonstrated a significant amount of alcohol use, 2.3% (1.4%-3.3%) showed evidence of hepatitis B or C, and 5.4% (4.6%-6.2%) had elevated serum ferritin levels.

The researchers then stratified the patients according to previously defined SAFE tiers of low, intermediate, and high risk and projected findings to the U.S. general population.

“When we applied our score to the general population, we found multiple abnormalities in the high-risk groups [SAFE >100] having Fibroscan data that are consistent with stage 2 or higher fibrosis regardless of etiology, “Dr. Kim pointed out.

Results also showed that very few patients with SAFE less than 0 had liver fibrosis (4% among those with liver stiffness measure [LSM] > 8kPa, and 0.8% with LSM > 12kPa). Among those with SAFE > 100, nearly a third (31.5%) had LSM of > 8kPa, and 16.5% had LSM > 12kPa.

In addition to fibrosis, liver abnormalities were common among patients with SAFE greater than 100, including steatosis (68.0%), viral hepatitis (7.0%), and abnormal ferritin levels (12.9%); 10.8% of these patients used alcohol.

“Right now, some patients are referred, but on examination and FibroScan, they might actually be okay, so it it’s a waste of time and money for everyone. We can preempt all of this by doing a blood test and focusing on those people who really need a scan,” said Dr. Kim.

The researcher is now working with primary care colleagues to help further develop and integrate SAFE into the primary care setting.
 

Fibrosis score in patients with metabolic dysfunction

Also presenting at the same session on population health was Willem Pieter Brouwer, MD, PhD, from Erasmus University Medical Center, Rotterdam, the Netherlands. He reported results of a validation study of a new risk score – the Metabolic Dysfunction-Associated Fibrosis–5 (MAF-5) score – for use for people with metabolic dysfunction who are recommended for screening for liver fibrosis.

“We believe the MAF-5 score may be a good alternative to the FIB-4 [a liver fibrosis biomarker] for use in the referral pathway for liver health evaluation,” remarked Dr. Brouwer. “The clinical practice guidelines recommend using FIB-4 scores, but these have a poor-moderate performance in the population setting.

“We developed and validated our score in a population of 5,500 from the NHANES 2017-2020 cycle and validated the score in populations from Rotterdam, which is a cohort of elderly participants, and in fibrosis among patients with biopsy-proven NAFLD from Colombia and Belgium,” he explained.

He also validated the score against different existing scoring systems and different methods of measuring liver stiffness and validated it for prognostic use to predict all-cause mortality in the NHANES III cohort.

Dr. Brouwer removed age as a factor of his new MAF-5 score; the score is thus stable for patients of all ages and is suitable for detecting liver disease in younger patients. “This is very important because these patients are currently underserved and have the most years of life to win.”

Referring to the SAFE score discussed by Dr. Kim, as well as other scores, he said, “The FIB-4, SAFE, and NFS [NAFLD fibrosis score] all include age in the scores, which causes problems and limitations in aging populations, as more and more patients will be referred due to an increasing score. Hence, the elderly are mostly all referred for liver checkups.”

Dr. Kim and Dr. Brouwer have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – Treatment of hyperthyroidism with surgery or radioactive iodine significantly extends survival, compared with antithyroid medication, while surgery raises the risk for obesity, new data from a large cohort study suggest.

“I think this is something we need to take into our discussions with patients because treatment for hyperthyroidism is very much individualized decision-making ... The effects on mortality are not usually one of the factors we discuss there. But now, we have strong data from a very large cohort of patients indicating that this is something that does need to be discussed,” lead author Kristien Boelaert, MD, who is the current president of the British Thyroid Association, said in an interview.

Dr. Boelaert presented the findings of the EGRET (Weight Changes, Cardio-Metabolic Risks and Mortality in Patients With Hyperthyroidism) study at the Annual Meeting of the Endocrine Society.

Other notable findings from EGRET were that the patients on antithyroid medication were thinner than expected, suggesting undertreatment, and that no differences were found for major adverse cardiac events (MACE) across the treatment options, leaving unexplained the reasons for the increased mortality in the medicated group.

Asked to comment, session moderator Spyridoula Maraka, MD, said: “I think this is very important work because so far when we counsel our patients about the different treatment modalities we focus more on risk for recurrence and other short-term outcomes.”

“But these data give us a bigger perspective on mortality and cardiovascular outcomes ... We haven’t had such good quality data to accurately counsel our patients,” added Dr. Maraka, of the University of Arkansas for Medical Sciences, Little Rock.
 

Mortality higher for medication-treated, but why?

“Hyperthyroidism or an overactive thyroid gland is common, affecting up to 3% of the population, and is associated with long-term adverse cardiac and metabolic consequences. The optimal treatment choice remains unclear,” explained Dr. Boelaert, professor of endocrinology at the University of Birmingham, England, outlining the reasons they conducted the EGRET study.

The study population was 55,318 patients (77% women) with newly diagnosed hyperthyroidism identified from a U.K. population-based primary care electronic health record database. Of those, 77.8% were treated with antithyroid medication, 14.6% with radioactive iodine, and 7.8% with surgery (total or hemithyroidectomy). The health records were linked with national mortality data and Health Survey England data on body mass index (BMI) for comparison.

Dr. Boelaert noted that the trial design “is the best we have” because a randomized clinical trial comparing hyperthyroid treatments would be extremely difficult given the need to individualize therapy and the impossibility of blinding. On the other hand, with the current study, “it’s certainly the largest patient group we’ve looked at.”

Over an average 12.1 years of follow-up, the proportion of patients who died was 14.1% in the medication group, 18.7% of those who had radioiodine therapy, and 9.2% of those who underwent surgery.

Compared with the number who would have been expected to die based on the general background population, the likelihood of reduced life expectancy for the treated groups was increased 2.10-fold for radioiodine, 2.13-fold for surgery, and 2.71-fold for medication. All were significantly higher than the general population (P < .0001).

After further adjustment for multiple confounders, mortality risk was reduced in patients treated with radioiodine (by 13%) or surgery (by 20%), compared with those treated with antithyroid medication, both significant reductions (P < .0001).

After exclusion of the 3.9% with baseline cardiovascular disease, MACE (defined as cardiovascular death or hospitalization for stroke or myocardial infarction) occurred in 9.9%, 13.4%, and 8.0% of the medication, radioiodine, and surgery groups, respectively.

After adjustments, there were no differences in MACE, compared with medications, with hazard ratios of 1.00 (P = .94) for radioactive iodine and 0.97 for surgery (P = .61).

“We were expecting to see a reduction in cardiovascular events, as previous studies suggest that radioactive iodine patients have fewer cardiovascular deaths. We did not see that but our protocol wasn’t set up to get every single specific cause of death. That will require further ongoing analysis,” said Dr. Boelaert.
 

Weight gain: Worth it for longer life

Compared with the background population, thyroidectomy was associated with an increased likelihood of developing obesity (BMI > 30 kg/m²) in both men (odds ratio, 1.56; P < .001), and women (OR, 1.27; P < .001), while radioiodine increased obesity risk in women (OR, 1.12; P < .001) but not in men (OR, 1.03; P = .55).

Among the women, those treated with antithyroid medications had an average 0.28 kg/m² lower BMI, compared with the background population, and those treated with surgery had a 0.83 kg/m² higher BMI. Both differences were significant (P < .001).

The BMI differences were not significant for radioactive iodine in women and for medications and radioactive iodine in men, although the men treated surgically also had a significantly higher BMI (1.09 kg/m²; P < .001).

“The patients on antithyroid drugs were lighter than we would expect. I think that’s ongoing hyperthyroidism. I strongly believe that ... to get rid of hyperthyroidism you have to make patients hypothyroid ... It’s really important that you get good control,” Dr. Boelaert commented.

Dr. Maraka, who is also endocrine section chief of the Arkansas Veteran’s Healthcare System, Little Rock, commented: “[Dr. Boelaert’s] concern is that the patients on antithyroid drugs are not adequately controlled, and we know very well that uncontrolled hyperthyroidism is associated with increased mortality and increased cardiovascular outcomes. This suggests that if patients are on antithyroid medications, they should at least be monitored very well.”

Regarding the possible cause of the increased mortality, if not cardiovascular, Dr. Maraka also pointed out that typically once antithyroid medications are stopped, about half of patients will stay in remission and the other half will return to hyperthyroidism.

“It might be that this kind of ‘yo-yo’ is what’s actually leading to the increased mortality, compared to patients who had definitive treatment and this problem was taken care of. This is speculation but it might be what we’re seeing,” Dr. Maraka observed.

The BMI differences worked out to a weight gain with surgery of approximately 2.1 kg (4.6 lb) for a woman with a height of 160 cm and 2.4 kg for 170 cm. Among men, those differences were 3.2 kg and 3.5 kg for heights of 170 cm and 190 cm, respectively.

Dr. Boelaert said, “I think we should discuss this with patients. They will say they don’t want to get fat, but the absolute weight gain is ... not that much.”

“I personally think that 2 kg is not a big price to pay to live longer. I hope that’s what we’ll be telling our patients in clinic in the next few years after we get this published.”

Dr. Boelaert and Dr. Maraka have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – Treatment of hyperthyroidism with surgery or radioactive iodine significantly extends survival, compared with antithyroid medication, while surgery raises the risk for obesity, new data from a large cohort study suggest.

“I think this is something we need to take into our discussions with patients because treatment for hyperthyroidism is very much individualized decision-making ... The effects on mortality are not usually one of the factors we discuss there. But now, we have strong data from a very large cohort of patients indicating that this is something that does need to be discussed,” lead author Kristien Boelaert, MD, who is the current president of the British Thyroid Association, said in an interview.

Dr. Boelaert presented the findings of the EGRET (Weight Changes, Cardio-Metabolic Risks and Mortality in Patients With Hyperthyroidism) study at the Annual Meeting of the Endocrine Society.

Other notable findings from EGRET were that the patients on antithyroid medication were thinner than expected, suggesting undertreatment, and that no differences were found for major adverse cardiac events (MACE) across the treatment options, leaving unexplained the reasons for the increased mortality in the medicated group.

Asked to comment, session moderator Spyridoula Maraka, MD, said: “I think this is very important work because so far when we counsel our patients about the different treatment modalities we focus more on risk for recurrence and other short-term outcomes.”

“But these data give us a bigger perspective on mortality and cardiovascular outcomes ... We haven’t had such good quality data to accurately counsel our patients,” added Dr. Maraka, of the University of Arkansas for Medical Sciences, Little Rock.
 

Mortality higher for medication-treated, but why?

“Hyperthyroidism or an overactive thyroid gland is common, affecting up to 3% of the population, and is associated with long-term adverse cardiac and metabolic consequences. The optimal treatment choice remains unclear,” explained Dr. Boelaert, professor of endocrinology at the University of Birmingham, England, outlining the reasons they conducted the EGRET study.

The study population was 55,318 patients (77% women) with newly diagnosed hyperthyroidism identified from a U.K. population-based primary care electronic health record database. Of those, 77.8% were treated with antithyroid medication, 14.6% with radioactive iodine, and 7.8% with surgery (total or hemithyroidectomy). The health records were linked with national mortality data and Health Survey England data on body mass index (BMI) for comparison.

Dr. Boelaert noted that the trial design “is the best we have” because a randomized clinical trial comparing hyperthyroid treatments would be extremely difficult given the need to individualize therapy and the impossibility of blinding. On the other hand, with the current study, “it’s certainly the largest patient group we’ve looked at.”

Over an average 12.1 years of follow-up, the proportion of patients who died was 14.1% in the medication group, 18.7% of those who had radioiodine therapy, and 9.2% of those who underwent surgery.

Compared with the number who would have been expected to die based on the general background population, the likelihood of reduced life expectancy for the treated groups was increased 2.10-fold for radioiodine, 2.13-fold for surgery, and 2.71-fold for medication. All were significantly higher than the general population (P < .0001).

After further adjustment for multiple confounders, mortality risk was reduced in patients treated with radioiodine (by 13%) or surgery (by 20%), compared with those treated with antithyroid medication, both significant reductions (P < .0001).

After exclusion of the 3.9% with baseline cardiovascular disease, MACE (defined as cardiovascular death or hospitalization for stroke or myocardial infarction) occurred in 9.9%, 13.4%, and 8.0% of the medication, radioiodine, and surgery groups, respectively.

After adjustments, there were no differences in MACE, compared with medications, with hazard ratios of 1.00 (P = .94) for radioactive iodine and 0.97 for surgery (P = .61).

“We were expecting to see a reduction in cardiovascular events, as previous studies suggest that radioactive iodine patients have fewer cardiovascular deaths. We did not see that but our protocol wasn’t set up to get every single specific cause of death. That will require further ongoing analysis,” said Dr. Boelaert.
 

Weight gain: Worth it for longer life

Compared with the background population, thyroidectomy was associated with an increased likelihood of developing obesity (BMI > 30 kg/m²) in both men (odds ratio, 1.56; P < .001), and women (OR, 1.27; P < .001), while radioiodine increased obesity risk in women (OR, 1.12; P < .001) but not in men (OR, 1.03; P = .55).

Among the women, those treated with antithyroid medications had an average 0.28 kg/m² lower BMI, compared with the background population, and those treated with surgery had a 0.83 kg/m² higher BMI. Both differences were significant (P < .001).

The BMI differences were not significant for radioactive iodine in women and for medications and radioactive iodine in men, although the men treated surgically also had a significantly higher BMI (1.09 kg/m²; P < .001).

“The patients on antithyroid drugs were lighter than we would expect. I think that’s ongoing hyperthyroidism. I strongly believe that ... to get rid of hyperthyroidism you have to make patients hypothyroid ... It’s really important that you get good control,” Dr. Boelaert commented.

Dr. Maraka, who is also endocrine section chief of the Arkansas Veteran’s Healthcare System, Little Rock, commented: “[Dr. Boelaert’s] concern is that the patients on antithyroid drugs are not adequately controlled, and we know very well that uncontrolled hyperthyroidism is associated with increased mortality and increased cardiovascular outcomes. This suggests that if patients are on antithyroid medications, they should at least be monitored very well.”

Regarding the possible cause of the increased mortality, if not cardiovascular, Dr. Maraka also pointed out that typically once antithyroid medications are stopped, about half of patients will stay in remission and the other half will return to hyperthyroidism.

“It might be that this kind of ‘yo-yo’ is what’s actually leading to the increased mortality, compared to patients who had definitive treatment and this problem was taken care of. This is speculation but it might be what we’re seeing,” Dr. Maraka observed.

The BMI differences worked out to a weight gain with surgery of approximately 2.1 kg (4.6 lb) for a woman with a height of 160 cm and 2.4 kg for 170 cm. Among men, those differences were 3.2 kg and 3.5 kg for heights of 170 cm and 190 cm, respectively.

Dr. Boelaert said, “I think we should discuss this with patients. They will say they don’t want to get fat, but the absolute weight gain is ... not that much.”

“I personally think that 2 kg is not a big price to pay to live longer. I hope that’s what we’ll be telling our patients in clinic in the next few years after we get this published.”

Dr. Boelaert and Dr. Maraka have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – Treatment of hyperthyroidism with surgery or radioactive iodine significantly extends survival, compared with antithyroid medication, while surgery raises the risk for obesity, new data from a large cohort study suggest.

“I think this is something we need to take into our discussions with patients because treatment for hyperthyroidism is very much individualized decision-making ... The effects on mortality are not usually one of the factors we discuss there. But now, we have strong data from a very large cohort of patients indicating that this is something that does need to be discussed,” lead author Kristien Boelaert, MD, who is the current president of the British Thyroid Association, said in an interview.

Dr. Boelaert presented the findings of the EGRET (Weight Changes, Cardio-Metabolic Risks and Mortality in Patients With Hyperthyroidism) study at the Annual Meeting of the Endocrine Society.

Other notable findings from EGRET were that the patients on antithyroid medication were thinner than expected, suggesting undertreatment, and that no differences were found for major adverse cardiac events (MACE) across the treatment options, leaving unexplained the reasons for the increased mortality in the medicated group.

Asked to comment, session moderator Spyridoula Maraka, MD, said: “I think this is very important work because so far when we counsel our patients about the different treatment modalities we focus more on risk for recurrence and other short-term outcomes.”

“But these data give us a bigger perspective on mortality and cardiovascular outcomes ... We haven’t had such good quality data to accurately counsel our patients,” added Dr. Maraka, of the University of Arkansas for Medical Sciences, Little Rock.
 

Mortality higher for medication-treated, but why?

“Hyperthyroidism or an overactive thyroid gland is common, affecting up to 3% of the population, and is associated with long-term adverse cardiac and metabolic consequences. The optimal treatment choice remains unclear,” explained Dr. Boelaert, professor of endocrinology at the University of Birmingham, England, outlining the reasons they conducted the EGRET study.

The study population was 55,318 patients (77% women) with newly diagnosed hyperthyroidism identified from a U.K. population-based primary care electronic health record database. Of those, 77.8% were treated with antithyroid medication, 14.6% with radioactive iodine, and 7.8% with surgery (total or hemithyroidectomy). The health records were linked with national mortality data and Health Survey England data on body mass index (BMI) for comparison.

Dr. Boelaert noted that the trial design “is the best we have” because a randomized clinical trial comparing hyperthyroid treatments would be extremely difficult given the need to individualize therapy and the impossibility of blinding. On the other hand, with the current study, “it’s certainly the largest patient group we’ve looked at.”

Over an average 12.1 years of follow-up, the proportion of patients who died was 14.1% in the medication group, 18.7% of those who had radioiodine therapy, and 9.2% of those who underwent surgery.

Compared with the number who would have been expected to die based on the general background population, the likelihood of reduced life expectancy for the treated groups was increased 2.10-fold for radioiodine, 2.13-fold for surgery, and 2.71-fold for medication. All were significantly higher than the general population (P < .0001).

After further adjustment for multiple confounders, mortality risk was reduced in patients treated with radioiodine (by 13%) or surgery (by 20%), compared with those treated with antithyroid medication, both significant reductions (P < .0001).

After exclusion of the 3.9% with baseline cardiovascular disease, MACE (defined as cardiovascular death or hospitalization for stroke or myocardial infarction) occurred in 9.9%, 13.4%, and 8.0% of the medication, radioiodine, and surgery groups, respectively.

After adjustments, there were no differences in MACE, compared with medications, with hazard ratios of 1.00 (P = .94) for radioactive iodine and 0.97 for surgery (P = .61).

“We were expecting to see a reduction in cardiovascular events, as previous studies suggest that radioactive iodine patients have fewer cardiovascular deaths. We did not see that but our protocol wasn’t set up to get every single specific cause of death. That will require further ongoing analysis,” said Dr. Boelaert.
 

Weight gain: Worth it for longer life

Compared with the background population, thyroidectomy was associated with an increased likelihood of developing obesity (BMI > 30 kg/m²) in both men (odds ratio, 1.56; P < .001), and women (OR, 1.27; P < .001), while radioiodine increased obesity risk in women (OR, 1.12; P < .001) but not in men (OR, 1.03; P = .55).

Among the women, those treated with antithyroid medications had an average 0.28 kg/m² lower BMI, compared with the background population, and those treated with surgery had a 0.83 kg/m² higher BMI. Both differences were significant (P < .001).

The BMI differences were not significant for radioactive iodine in women and for medications and radioactive iodine in men, although the men treated surgically also had a significantly higher BMI (1.09 kg/m²; P < .001).

“The patients on antithyroid drugs were lighter than we would expect. I think that’s ongoing hyperthyroidism. I strongly believe that ... to get rid of hyperthyroidism you have to make patients hypothyroid ... It’s really important that you get good control,” Dr. Boelaert commented.

Dr. Maraka, who is also endocrine section chief of the Arkansas Veteran’s Healthcare System, Little Rock, commented: “[Dr. Boelaert’s] concern is that the patients on antithyroid drugs are not adequately controlled, and we know very well that uncontrolled hyperthyroidism is associated with increased mortality and increased cardiovascular outcomes. This suggests that if patients are on antithyroid medications, they should at least be monitored very well.”

Regarding the possible cause of the increased mortality, if not cardiovascular, Dr. Maraka also pointed out that typically once antithyroid medications are stopped, about half of patients will stay in remission and the other half will return to hyperthyroidism.

“It might be that this kind of ‘yo-yo’ is what’s actually leading to the increased mortality, compared to patients who had definitive treatment and this problem was taken care of. This is speculation but it might be what we’re seeing,” Dr. Maraka observed.

The BMI differences worked out to a weight gain with surgery of approximately 2.1 kg (4.6 lb) for a woman with a height of 160 cm and 2.4 kg for 170 cm. Among men, those differences were 3.2 kg and 3.5 kg for heights of 170 cm and 190 cm, respectively.

Dr. Boelaert said, “I think we should discuss this with patients. They will say they don’t want to get fat, but the absolute weight gain is ... not that much.”

“I personally think that 2 kg is not a big price to pay to live longer. I hope that’s what we’ll be telling our patients in clinic in the next few years after we get this published.”

Dr. Boelaert and Dr. Maraka have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

SAN DIEGO – Children with type 2 diabetes face a strikingly high complication rate as they age into young adulthood, with an 80% incidence of at least one vascular complication during up to 15 years of follow-up, show findings from the TODAY prospective, longitudinal study of 699 U.S. children newly diagnosed with type 2 diabetes.

Arterial stiffness and worsened cardiac function often appear in these children within 2-5 years of diagnosis and seem driven in part by the development of hypertension and worsening hemoglobin A1c levels, said Rachelle G. Gandica, MD, at the annual scientific sessions of the American Diabetes Association.

Indeed, an A1c greater than 6.2% at study entry generally predicts these children will fail treatment and is a red flag, said Dr. Gandica. “I teach fellows this all the time, that if a child’s A1c is above 6.2% they will fail, and you have to watch for that,” she noted.

Mitchel L. Zoler/Medscape

The results from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed, for example, an overall cardiovascular event rate of 3.7/1,000 patient-years in a population that had just reached an average age of 26 years old, with type 2 diabetes diagnosed for an average of more than 13 years.

During follow-up, there were six cases of congestive heart failure, four myocardial infarctions, four strokes, and three cases of coronary artery disease in the cohort. Hypertension ballooned from a prevalence of 19% at study entry to 68% by the end of follow-up.

Dr. Gandica called these and other findings “sobering details” that document the toll type 2 diabetes takes on children, who averaged 14 years old at the time they entered the study – when their diabetes had been diagnosed for an average of about 8 months – and then underwent an average 12.6 years of follow-up.

Investigators also found:

• After more than 12 years of type 2 diabetes, 49% of the cohort had developed diabetic retinopathy, with 3.5% having macular edema.
• Kidney damage (diabetic nephropathy) affected 8% of the cohort at entry, and then increased to a prevalence of 55% after up to 14 years of follow-up.
• Among the 452 girls who entered the study, 141 (31%) later became pregnant, with a total of 260 pregnancies. A quarter of the pregnancies resulted in preterm deliveries (43% went to term), 25% resulted in miscarriage or fetal demise, with the remaining 8% having elective terminations or unknown outcomes.
• Complications in neonates were common, including hypoglycemia (29%), respiratory disorder (19%), and cardiac issues (10%).

Dire prognosis a reason to aggressively treat these patients

It has become apparent from this and other studies in youth with type 2 diabetes that the difference in outcomes between youth and adults is stark and could indicate that type 2 diabetes in childhood or adolescence likely has a different underlying pathology and natural history, with a more aggressive disease course.

The dire prognosis is therefore a reason to aggressively treat these patients with antidiabetic medications from drug classes with proven cardiovascular disease protection, specifically sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagonlike peptide-1 (GLP-1) agonists, said Dr. Gandica, a pediatric endocrinologist at Columbia University Medical Center in New York.

“It’s fair to say we now more aggressively use [these agents] in children,” she said in an interview, and noted the very recent approval, just last week, by the U.S. Food and Drug Administration of the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) for children as young as 10 years.

“I look forward to prescribing empagliflozin to children with type 2 diabetes to lower their blood pressure and get additional cardiovascular disease benefits,” Dr. Gandica said.

Other newer type 2 diabetes medications approved for U.S. children in the past few years include the once-weekly injectable GLP-1 agonist exenatide extended release (Bydureon/Bydureon BCise, AstraZeneca) for children with type 2 diabetes aged 10 and older, in 2021, and the daily injectable GLP-1 agonist liraglutide (Victoza, Novo Nordisk) in 2019.
 

A1c spike heralds treatment failure: ‘Watch for that’

TODAY enrolled 699 children with type 2 diabetes for an average of 8 months since diagnosis at 16 U.S. sites starting in 2004. The protocol began with a run-in phase of up to 6 months, when participating children came off any preexisting antidiabetes medications and then began a metformin-only regimen to bring A1c below 8.0%. If achieved, patients were eligible to continue to randomization.

Participants were randomized to one of three treatment groups: metformin alone, metformin plus lifestyle interventions, or metformin plus rosiglitazone (Avandia, GSK). The primary endpoint was the incidence of treatment failure, defined as A1c that rose back above 8.0% for at least 6 months or persistent metabolic decompensation during initial follow-up, for an average of just under 4 years.

The results showed that only metformin plus rosiglitazone significantly surpassed metformin alone for preventing treatment failure, reported in 2012 in the New England Journal of Medicine

More recent reports on findings from longer-term follow-up have appeared in several journals, including the cardiovascular disease results, reported in 2021 also in the New England Journal of Medicine.

Another key finding from TODAY is the importance of A1c as a risk marker for impending treatment failure. Study findingsshow that an A1c of 6.2% or higher when children entered the study best predicted loss of glycemic control during follow-up. Also, a rise in A1c of at least 0.5 percentage points was significantly associated with loss of glycemic control within the following 3-6 months.

That’s an important message for clinicians, Dr. Gandica concluded.

TODAY and TODAY2 received no commercial funding. Dr. Gandica has reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

SAN DIEGO – Children with type 2 diabetes face a strikingly high complication rate as they age into young adulthood, with an 80% incidence of at least one vascular complication during up to 15 years of follow-up, show findings from the TODAY prospective, longitudinal study of 699 U.S. children newly diagnosed with type 2 diabetes.

Arterial stiffness and worsened cardiac function often appear in these children within 2-5 years of diagnosis and seem driven in part by the development of hypertension and worsening hemoglobin A1c levels, said Rachelle G. Gandica, MD, at the annual scientific sessions of the American Diabetes Association.

Indeed, an A1c greater than 6.2% at study entry generally predicts these children will fail treatment and is a red flag, said Dr. Gandica. “I teach fellows this all the time, that if a child’s A1c is above 6.2% they will fail, and you have to watch for that,” she noted.

Mitchel L. Zoler/Medscape

The results from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed, for example, an overall cardiovascular event rate of 3.7/1,000 patient-years in a population that had just reached an average age of 26 years old, with type 2 diabetes diagnosed for an average of more than 13 years.

During follow-up, there were six cases of congestive heart failure, four myocardial infarctions, four strokes, and three cases of coronary artery disease in the cohort. Hypertension ballooned from a prevalence of 19% at study entry to 68% by the end of follow-up.

Dr. Gandica called these and other findings “sobering details” that document the toll type 2 diabetes takes on children, who averaged 14 years old at the time they entered the study – when their diabetes had been diagnosed for an average of about 8 months – and then underwent an average 12.6 years of follow-up.

Investigators also found:

• After more than 12 years of type 2 diabetes, 49% of the cohort had developed diabetic retinopathy, with 3.5% having macular edema.
• Kidney damage (diabetic nephropathy) affected 8% of the cohort at entry, and then increased to a prevalence of 55% after up to 14 years of follow-up.
• Among the 452 girls who entered the study, 141 (31%) later became pregnant, with a total of 260 pregnancies. A quarter of the pregnancies resulted in preterm deliveries (43% went to term), 25% resulted in miscarriage or fetal demise, with the remaining 8% having elective terminations or unknown outcomes.
• Complications in neonates were common, including hypoglycemia (29%), respiratory disorder (19%), and cardiac issues (10%).

Dire prognosis a reason to aggressively treat these patients

It has become apparent from this and other studies in youth with type 2 diabetes that the difference in outcomes between youth and adults is stark and could indicate that type 2 diabetes in childhood or adolescence likely has a different underlying pathology and natural history, with a more aggressive disease course.

The dire prognosis is therefore a reason to aggressively treat these patients with antidiabetic medications from drug classes with proven cardiovascular disease protection, specifically sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagonlike peptide-1 (GLP-1) agonists, said Dr. Gandica, a pediatric endocrinologist at Columbia University Medical Center in New York.

“It’s fair to say we now more aggressively use [these agents] in children,” she said in an interview, and noted the very recent approval, just last week, by the U.S. Food and Drug Administration of the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) for children as young as 10 years.

“I look forward to prescribing empagliflozin to children with type 2 diabetes to lower their blood pressure and get additional cardiovascular disease benefits,” Dr. Gandica said.

Other newer type 2 diabetes medications approved for U.S. children in the past few years include the once-weekly injectable GLP-1 agonist exenatide extended release (Bydureon/Bydureon BCise, AstraZeneca) for children with type 2 diabetes aged 10 and older, in 2021, and the daily injectable GLP-1 agonist liraglutide (Victoza, Novo Nordisk) in 2019.
 

A1c spike heralds treatment failure: ‘Watch for that’

TODAY enrolled 699 children with type 2 diabetes for an average of 8 months since diagnosis at 16 U.S. sites starting in 2004. The protocol began with a run-in phase of up to 6 months, when participating children came off any preexisting antidiabetes medications and then began a metformin-only regimen to bring A1c below 8.0%. If achieved, patients were eligible to continue to randomization.

Participants were randomized to one of three treatment groups: metformin alone, metformin plus lifestyle interventions, or metformin plus rosiglitazone (Avandia, GSK). The primary endpoint was the incidence of treatment failure, defined as A1c that rose back above 8.0% for at least 6 months or persistent metabolic decompensation during initial follow-up, for an average of just under 4 years.

The results showed that only metformin plus rosiglitazone significantly surpassed metformin alone for preventing treatment failure, reported in 2012 in the New England Journal of Medicine

More recent reports on findings from longer-term follow-up have appeared in several journals, including the cardiovascular disease results, reported in 2021 also in the New England Journal of Medicine.

Another key finding from TODAY is the importance of A1c as a risk marker for impending treatment failure. Study findingsshow that an A1c of 6.2% or higher when children entered the study best predicted loss of glycemic control during follow-up. Also, a rise in A1c of at least 0.5 percentage points was significantly associated with loss of glycemic control within the following 3-6 months.

That’s an important message for clinicians, Dr. Gandica concluded.

TODAY and TODAY2 received no commercial funding. Dr. Gandica has reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

SAN DIEGO – Children with type 2 diabetes face a strikingly high complication rate as they age into young adulthood, with an 80% incidence of at least one vascular complication during up to 15 years of follow-up, show findings from the TODAY prospective, longitudinal study of 699 U.S. children newly diagnosed with type 2 diabetes.

Arterial stiffness and worsened cardiac function often appear in these children within 2-5 years of diagnosis and seem driven in part by the development of hypertension and worsening hemoglobin A1c levels, said Rachelle G. Gandica, MD, at the annual scientific sessions of the American Diabetes Association.

Indeed, an A1c greater than 6.2% at study entry generally predicts these children will fail treatment and is a red flag, said Dr. Gandica. “I teach fellows this all the time, that if a child’s A1c is above 6.2% they will fail, and you have to watch for that,” she noted.

Mitchel L. Zoler/Medscape

The results from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed, for example, an overall cardiovascular event rate of 3.7/1,000 patient-years in a population that had just reached an average age of 26 years old, with type 2 diabetes diagnosed for an average of more than 13 years.

During follow-up, there were six cases of congestive heart failure, four myocardial infarctions, four strokes, and three cases of coronary artery disease in the cohort. Hypertension ballooned from a prevalence of 19% at study entry to 68% by the end of follow-up.

Dr. Gandica called these and other findings “sobering details” that document the toll type 2 diabetes takes on children, who averaged 14 years old at the time they entered the study – when their diabetes had been diagnosed for an average of about 8 months – and then underwent an average 12.6 years of follow-up.

Investigators also found:

• After more than 12 years of type 2 diabetes, 49% of the cohort had developed diabetic retinopathy, with 3.5% having macular edema.
• Kidney damage (diabetic nephropathy) affected 8% of the cohort at entry, and then increased to a prevalence of 55% after up to 14 years of follow-up.
• Among the 452 girls who entered the study, 141 (31%) later became pregnant, with a total of 260 pregnancies. A quarter of the pregnancies resulted in preterm deliveries (43% went to term), 25% resulted in miscarriage or fetal demise, with the remaining 8% having elective terminations or unknown outcomes.
• Complications in neonates were common, including hypoglycemia (29%), respiratory disorder (19%), and cardiac issues (10%).

Dire prognosis a reason to aggressively treat these patients

It has become apparent from this and other studies in youth with type 2 diabetes that the difference in outcomes between youth and adults is stark and could indicate that type 2 diabetes in childhood or adolescence likely has a different underlying pathology and natural history, with a more aggressive disease course.

The dire prognosis is therefore a reason to aggressively treat these patients with antidiabetic medications from drug classes with proven cardiovascular disease protection, specifically sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagonlike peptide-1 (GLP-1) agonists, said Dr. Gandica, a pediatric endocrinologist at Columbia University Medical Center in New York.

“It’s fair to say we now more aggressively use [these agents] in children,” she said in an interview, and noted the very recent approval, just last week, by the U.S. Food and Drug Administration of the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) for children as young as 10 years.

“I look forward to prescribing empagliflozin to children with type 2 diabetes to lower their blood pressure and get additional cardiovascular disease benefits,” Dr. Gandica said.

Other newer type 2 diabetes medications approved for U.S. children in the past few years include the once-weekly injectable GLP-1 agonist exenatide extended release (Bydureon/Bydureon BCise, AstraZeneca) for children with type 2 diabetes aged 10 and older, in 2021, and the daily injectable GLP-1 agonist liraglutide (Victoza, Novo Nordisk) in 2019.
 

A1c spike heralds treatment failure: ‘Watch for that’

TODAY enrolled 699 children with type 2 diabetes for an average of 8 months since diagnosis at 16 U.S. sites starting in 2004. The protocol began with a run-in phase of up to 6 months, when participating children came off any preexisting antidiabetes medications and then began a metformin-only regimen to bring A1c below 8.0%. If achieved, patients were eligible to continue to randomization.

Participants were randomized to one of three treatment groups: metformin alone, metformin plus lifestyle interventions, or metformin plus rosiglitazone (Avandia, GSK). The primary endpoint was the incidence of treatment failure, defined as A1c that rose back above 8.0% for at least 6 months or persistent metabolic decompensation during initial follow-up, for an average of just under 4 years.

The results showed that only metformin plus rosiglitazone significantly surpassed metformin alone for preventing treatment failure, reported in 2012 in the New England Journal of Medicine

More recent reports on findings from longer-term follow-up have appeared in several journals, including the cardiovascular disease results, reported in 2021 also in the New England Journal of Medicine.

Another key finding from TODAY is the importance of A1c as a risk marker for impending treatment failure. Study findingsshow that an A1c of 6.2% or higher when children entered the study best predicted loss of glycemic control during follow-up. Also, a rise in A1c of at least 0.5 percentage points was significantly associated with loss of glycemic control within the following 3-6 months.

That’s an important message for clinicians, Dr. Gandica concluded.

TODAY and TODAY2 received no commercial funding. Dr. Gandica has reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

SAN DIEGO – Coadministration of the long-acting amylin analog cagrilintide plus the glucagonlike peptide–1 (GLP-1) agonist semaglutide, dubbed CagriSema, resulted in significantly greater weight loss, along with improved measures of glucose control, than either agent alone, in a small, short phase 2 trial of patients with type 2 diabetes. 

Juan P. Frias, MD, presented the findings at the annual scientific sessions of the American Diabetes Association, which were simultaneously published in The Lancet.

“Overall, in this phase 2 trial in people with type 2 diabetes, clinically relevant improvements in glycemic control – as assessed by [hemoglobin] A1c, [time in range], and other [continuous glucose monitoring (CGM)] measures – were observed with CagriSema, as well as weight loss of a magnitude not previously reported with pharmacotherapies in this population. CagriSema also had an acceptable safety profile,” the researchers summarized.

“These data support further investigation of CagriSema in people with type 2 diabetes in longer and larger phase 3 studies,” said Dr. Frias, from Velocity Clinical Research, Los Angeles.

In reply to audience questions, he said he was “pleasantly surprised” with the low gastrointestinal adverse events, which may have been related to the slower dosing titration. He also noted that patients in the study did not receive dietary counseling, unlike in the STEP-2 trial, where weight loss with semaglutide was greater than in this study.  

Time in normal blood glucose range in the CagriSema group went from 40% at baseline to 89% at week 32, Chantal Mathieu, MD, PhD, reported during a follow-up presentation that focused on the trial’s CGM findings.

“I was extremely happy that we were allowed to include CGM measurement because it does give you more information, especially in a short-term trial,” said Dr. Mathieu, from the Katholieke Universiteit Leuven (Belgium). The CGM data were collected for 10 days preceding baseline and at weeks 20 and 32.

“At this point in time, it is difficult to make a final determination” about potential future clinical applications, session chair Elisabetta Patorno, MD, DrPH, from Harvard Medical School, Boston, said in an interview. “This was a phase 2 randomized controlled trial, so more patients are needed.

“It’s very interesting what was found with the use of CGM, which makes us think whether they should always be part of [trials] versus the more traditional A1c assessment,” Dr. Patorno added.
 

‘Synergistic effect for both glycemic control and weight loss’

“CagriSema is the next in a series of gut hormone analogs with the potential to herald a new era in treating obesity and preventing diabesity,” the coexistence of type 2 diabetes and obesity, Caroline M. Apovian, MD, and Marie E. McDonnell, MD, both also from Harvard Medical School, wrote in an accompanying editorial in The Lancet.

Cagrilintide plus semaglutide each “effectively delay gastric emptying, suppress glucagon release, and are involved in the regulation of appetite and satiety in the brain,” they noted.

The results – a substantial difference in effect size between the combination drug and each component alone – show that “there is a synergistic effect for both glycemic control and weight loss.

“The weight loss seen in this phase 2 trial of CagriSema in 32 weeks could predict a phase 3 trial result over 1 year that might surpass that of semaglutide (14.9%) and tirzepatide (20.9%) in a population without type 2 diabetes, and might equal that of bariatric surgery (23.5%-30.4%),” they speculated.

However, it’s still early days, the editorialists cautioned. Study limitations include that it was a small trial and the mean duration of type 2 diabetes at baseline was shorter in the CagriSema group (6.4 years) than in the semaglutide or cagrilintide alone groups (9.2 years and 10.7 years, respectively).

The rate of gastrointestinal adverse events was also higher in the CagriSema group (58%) than in the other two groups (about 33%). However, the adverse events “were all mild or moderate and not severe enough to lead to participant withdrawal,” they noted. “Remarkably, only one participant, from the semaglutide group, withdrew due to adverse events during the 32-week trial across all groups.

“Although bariatric surgery remains the most effective treatment for severe obesity, offering the most robust weight reduction, remission of type 2 diabetes, and reduced cardiovascular mortality,” the study suggests that “combination metabolic hormonal therapy could offer all three of these outcomes in the near future,” Dr. Apovian and Dr. McDonnell wrote.
 

92 patients randomized to three treatments

In the study, researchers randomized 92 adults with type 2 diabetes and a body mass index of at least 27 kg/m² taking metformin alone (73%) or metformin plus a sodium-glucose cotransporter 2 inhibitor (27%), at 17 sites in the United States, between August and October 2021.

Patients were a mean age of 58 years and 64% were men. Mean A1c was 8.4% and mean bodyweight was 106 kg (234 lb).

They were randomized 1:1:1 to receive up to maximal once-weekly doses of 2.4 mg semaglutide and 2.4 mg cagrilintide (CagriSema, given in two injector pens), 2.4 mg semaglutide (plus placebo), or 2.4 mg cagrilintide (plus placebo).

Both cagrilintide and semaglutide are manufactured by the Danish company Novo Nordisk. Semaglutide is already approved in the United States for type 2 diabetes, as Ozempic, and as the weight-loss drug Wegovy. Cagrilintide is not yet approved.

Treatment doses were escalated every 4 weeks from 0.25 to 0.5 to 1.0 to 1.7 mg to a maintenance dose of 2.4 mg at 16 weeks. Patients then entered a 16-week maintenance phase followed by a 5-week follow-up period.

Among the key findings, the reduction in A1c at 32 weeks, compared with baseline (primary outcome), was –2.2% with CagriSema, –1.8% with semaglutide, and –0.9% with cagrilintide, but was not significantly greater with CagriSema versus semaglutide (–0.4%; P = .07).

However, in a secondary outcome, there was a significantly greater difference in A1c at 32 weeks with CagriSema versus cagrilintide (–1.3%; P < .0001). Moreover, 89% of patients in the CagriSema group reached an A1c less than 7%.

In other secondary outcomes, there was a significantly greater reduction in body weight at 32 weeks with CagriSema versus cagrilintide or semaglutide, with 71% of patients in the CagriSema group achieving greater than 10% reduction in body weight. Patients in the CagriSema group also had clinically relevant improvements in blood pressure, lipids, and high-sensitivity C-reactive protein.

Adverse events – reported in 68% of patients with CagriSema versus 71% with semaglutide and 80% with cagrilintide – were mostly mild or moderate gastrointestinal events, consistent with those seen in these two drug classes.

At week 32, time in range was 89% with CagriSema versus 76% with semaglutide and 72% with cagrilintide.

“Our phase 2 clinical trial is the first study to report efficacy and safety data for treatment with the combination of a GLP-1 agonist and an amylin analog in participants with type 2 diabetes,” the researchers summarize. “These data support further investigation of CagriSema in this population in longer and larger phase 3 studies.”

This trial was sponsored by Novo Nordisk. Dr. Frias, Dr. Mathieu, Dr. Apovian, and Dr. McDonnell reported financial relationships with a number of companies.

A version of this article first appeared on Medscape.com.

SAN DIEGO – Coadministration of the long-acting amylin analog cagrilintide plus the glucagonlike peptide–1 (GLP-1) agonist semaglutide, dubbed CagriSema, resulted in significantly greater weight loss, along with improved measures of glucose control, than either agent alone, in a small, short phase 2 trial of patients with type 2 diabetes. 

Juan P. Frias, MD, presented the findings at the annual scientific sessions of the American Diabetes Association, which were simultaneously published in The Lancet.

“Overall, in this phase 2 trial in people with type 2 diabetes, clinically relevant improvements in glycemic control – as assessed by [hemoglobin] A1c, [time in range], and other [continuous glucose monitoring (CGM)] measures – were observed with CagriSema, as well as weight loss of a magnitude not previously reported with pharmacotherapies in this population. CagriSema also had an acceptable safety profile,” the researchers summarized.

“These data support further investigation of CagriSema in people with type 2 diabetes in longer and larger phase 3 studies,” said Dr. Frias, from Velocity Clinical Research, Los Angeles.

In reply to audience questions, he said he was “pleasantly surprised” with the low gastrointestinal adverse events, which may have been related to the slower dosing titration. He also noted that patients in the study did not receive dietary counseling, unlike in the STEP-2 trial, where weight loss with semaglutide was greater than in this study.  

Time in normal blood glucose range in the CagriSema group went from 40% at baseline to 89% at week 32, Chantal Mathieu, MD, PhD, reported during a follow-up presentation that focused on the trial’s CGM findings.

“I was extremely happy that we were allowed to include CGM measurement because it does give you more information, especially in a short-term trial,” said Dr. Mathieu, from the Katholieke Universiteit Leuven (Belgium). The CGM data were collected for 10 days preceding baseline and at weeks 20 and 32.

“At this point in time, it is difficult to make a final determination” about potential future clinical applications, session chair Elisabetta Patorno, MD, DrPH, from Harvard Medical School, Boston, said in an interview. “This was a phase 2 randomized controlled trial, so more patients are needed.

“It’s very interesting what was found with the use of CGM, which makes us think whether they should always be part of [trials] versus the more traditional A1c assessment,” Dr. Patorno added.
 

‘Synergistic effect for both glycemic control and weight loss’

“CagriSema is the next in a series of gut hormone analogs with the potential to herald a new era in treating obesity and preventing diabesity,” the coexistence of type 2 diabetes and obesity, Caroline M. Apovian, MD, and Marie E. McDonnell, MD, both also from Harvard Medical School, wrote in an accompanying editorial in The Lancet.

Cagrilintide plus semaglutide each “effectively delay gastric emptying, suppress glucagon release, and are involved in the regulation of appetite and satiety in the brain,” they noted.

The results – a substantial difference in effect size between the combination drug and each component alone – show that “there is a synergistic effect for both glycemic control and weight loss.

“The weight loss seen in this phase 2 trial of CagriSema in 32 weeks could predict a phase 3 trial result over 1 year that might surpass that of semaglutide (14.9%) and tirzepatide (20.9%) in a population without type 2 diabetes, and might equal that of bariatric surgery (23.5%-30.4%),” they speculated.

However, it’s still early days, the editorialists cautioned. Study limitations include that it was a small trial and the mean duration of type 2 diabetes at baseline was shorter in the CagriSema group (6.4 years) than in the semaglutide or cagrilintide alone groups (9.2 years and 10.7 years, respectively).

The rate of gastrointestinal adverse events was also higher in the CagriSema group (58%) than in the other two groups (about 33%). However, the adverse events “were all mild or moderate and not severe enough to lead to participant withdrawal,” they noted. “Remarkably, only one participant, from the semaglutide group, withdrew due to adverse events during the 32-week trial across all groups.

“Although bariatric surgery remains the most effective treatment for severe obesity, offering the most robust weight reduction, remission of type 2 diabetes, and reduced cardiovascular mortality,” the study suggests that “combination metabolic hormonal therapy could offer all three of these outcomes in the near future,” Dr. Apovian and Dr. McDonnell wrote.
 

92 patients randomized to three treatments

In the study, researchers randomized 92 adults with type 2 diabetes and a body mass index of at least 27 kg/m² taking metformin alone (73%) or metformin plus a sodium-glucose cotransporter 2 inhibitor (27%), at 17 sites in the United States, between August and October 2021.

Patients were a mean age of 58 years and 64% were men. Mean A1c was 8.4% and mean bodyweight was 106 kg (234 lb).

They were randomized 1:1:1 to receive up to maximal once-weekly doses of 2.4 mg semaglutide and 2.4 mg cagrilintide (CagriSema, given in two injector pens), 2.4 mg semaglutide (plus placebo), or 2.4 mg cagrilintide (plus placebo).

Both cagrilintide and semaglutide are manufactured by the Danish company Novo Nordisk. Semaglutide is already approved in the United States for type 2 diabetes, as Ozempic, and as the weight-loss drug Wegovy. Cagrilintide is not yet approved.

Treatment doses were escalated every 4 weeks from 0.25 to 0.5 to 1.0 to 1.7 mg to a maintenance dose of 2.4 mg at 16 weeks. Patients then entered a 16-week maintenance phase followed by a 5-week follow-up period.

Among the key findings, the reduction in A1c at 32 weeks, compared with baseline (primary outcome), was –2.2% with CagriSema, –1.8% with semaglutide, and –0.9% with cagrilintide, but was not significantly greater with CagriSema versus semaglutide (–0.4%; P = .07).

However, in a secondary outcome, there was a significantly greater difference in A1c at 32 weeks with CagriSema versus cagrilintide (–1.3%; P < .0001). Moreover, 89% of patients in the CagriSema group reached an A1c less than 7%.

In other secondary outcomes, there was a significantly greater reduction in body weight at 32 weeks with CagriSema versus cagrilintide or semaglutide, with 71% of patients in the CagriSema group achieving greater than 10% reduction in body weight. Patients in the CagriSema group also had clinically relevant improvements in blood pressure, lipids, and high-sensitivity C-reactive protein.

Adverse events – reported in 68% of patients with CagriSema versus 71% with semaglutide and 80% with cagrilintide – were mostly mild or moderate gastrointestinal events, consistent with those seen in these two drug classes.

At week 32, time in range was 89% with CagriSema versus 76% with semaglutide and 72% with cagrilintide.

“Our phase 2 clinical trial is the first study to report efficacy and safety data for treatment with the combination of a GLP-1 agonist and an amylin analog in participants with type 2 diabetes,” the researchers summarize. “These data support further investigation of CagriSema in this population in longer and larger phase 3 studies.”

This trial was sponsored by Novo Nordisk. Dr. Frias, Dr. Mathieu, Dr. Apovian, and Dr. McDonnell reported financial relationships with a number of companies.

A version of this article first appeared on Medscape.com.

SAN DIEGO – Coadministration of the long-acting amylin analog cagrilintide plus the glucagonlike peptide–1 (GLP-1) agonist semaglutide, dubbed CagriSema, resulted in significantly greater weight loss, along with improved measures of glucose control, than either agent alone, in a small, short phase 2 trial of patients with type 2 diabetes. 

Juan P. Frias, MD, presented the findings at the annual scientific sessions of the American Diabetes Association, which were simultaneously published in The Lancet.

“Overall, in this phase 2 trial in people with type 2 diabetes, clinically relevant improvements in glycemic control – as assessed by [hemoglobin] A1c, [time in range], and other [continuous glucose monitoring (CGM)] measures – were observed with CagriSema, as well as weight loss of a magnitude not previously reported with pharmacotherapies in this population. CagriSema also had an acceptable safety profile,” the researchers summarized.

“These data support further investigation of CagriSema in people with type 2 diabetes in longer and larger phase 3 studies,” said Dr. Frias, from Velocity Clinical Research, Los Angeles.

In reply to audience questions, he said he was “pleasantly surprised” with the low gastrointestinal adverse events, which may have been related to the slower dosing titration. He also noted that patients in the study did not receive dietary counseling, unlike in the STEP-2 trial, where weight loss with semaglutide was greater than in this study.  

Time in normal blood glucose range in the CagriSema group went from 40% at baseline to 89% at week 32, Chantal Mathieu, MD, PhD, reported during a follow-up presentation that focused on the trial’s CGM findings.

“I was extremely happy that we were allowed to include CGM measurement because it does give you more information, especially in a short-term trial,” said Dr. Mathieu, from the Katholieke Universiteit Leuven (Belgium). The CGM data were collected for 10 days preceding baseline and at weeks 20 and 32.

“At this point in time, it is difficult to make a final determination” about potential future clinical applications, session chair Elisabetta Patorno, MD, DrPH, from Harvard Medical School, Boston, said in an interview. “This was a phase 2 randomized controlled trial, so more patients are needed.

“It’s very interesting what was found with the use of CGM, which makes us think whether they should always be part of [trials] versus the more traditional A1c assessment,” Dr. Patorno added.
 

‘Synergistic effect for both glycemic control and weight loss’

“CagriSema is the next in a series of gut hormone analogs with the potential to herald a new era in treating obesity and preventing diabesity,” the coexistence of type 2 diabetes and obesity, Caroline M. Apovian, MD, and Marie E. McDonnell, MD, both also from Harvard Medical School, wrote in an accompanying editorial in The Lancet.

Cagrilintide plus semaglutide each “effectively delay gastric emptying, suppress glucagon release, and are involved in the regulation of appetite and satiety in the brain,” they noted.

The results – a substantial difference in effect size between the combination drug and each component alone – show that “there is a synergistic effect for both glycemic control and weight loss.

“The weight loss seen in this phase 2 trial of CagriSema in 32 weeks could predict a phase 3 trial result over 1 year that might surpass that of semaglutide (14.9%) and tirzepatide (20.9%) in a population without type 2 diabetes, and might equal that of bariatric surgery (23.5%-30.4%),” they speculated.

However, it’s still early days, the editorialists cautioned. Study limitations include that it was a small trial and the mean duration of type 2 diabetes at baseline was shorter in the CagriSema group (6.4 years) than in the semaglutide or cagrilintide alone groups (9.2 years and 10.7 years, respectively).

The rate of gastrointestinal adverse events was also higher in the CagriSema group (58%) than in the other two groups (about 33%). However, the adverse events “were all mild or moderate and not severe enough to lead to participant withdrawal,” they noted. “Remarkably, only one participant, from the semaglutide group, withdrew due to adverse events during the 32-week trial across all groups.

“Although bariatric surgery remains the most effective treatment for severe obesity, offering the most robust weight reduction, remission of type 2 diabetes, and reduced cardiovascular mortality,” the study suggests that “combination metabolic hormonal therapy could offer all three of these outcomes in the near future,” Dr. Apovian and Dr. McDonnell wrote.
 

92 patients randomized to three treatments

In the study, researchers randomized 92 adults with type 2 diabetes and a body mass index of at least 27 kg/m² taking metformin alone (73%) or metformin plus a sodium-glucose cotransporter 2 inhibitor (27%), at 17 sites in the United States, between August and October 2021.

Patients were a mean age of 58 years and 64% were men. Mean A1c was 8.4% and mean bodyweight was 106 kg (234 lb).

They were randomized 1:1:1 to receive up to maximal once-weekly doses of 2.4 mg semaglutide and 2.4 mg cagrilintide (CagriSema, given in two injector pens), 2.4 mg semaglutide (plus placebo), or 2.4 mg cagrilintide (plus placebo).

Both cagrilintide and semaglutide are manufactured by the Danish company Novo Nordisk. Semaglutide is already approved in the United States for type 2 diabetes, as Ozempic, and as the weight-loss drug Wegovy. Cagrilintide is not yet approved.

Treatment doses were escalated every 4 weeks from 0.25 to 0.5 to 1.0 to 1.7 mg to a maintenance dose of 2.4 mg at 16 weeks. Patients then entered a 16-week maintenance phase followed by a 5-week follow-up period.

Among the key findings, the reduction in A1c at 32 weeks, compared with baseline (primary outcome), was –2.2% with CagriSema, –1.8% with semaglutide, and –0.9% with cagrilintide, but was not significantly greater with CagriSema versus semaglutide (–0.4%; P = .07).

However, in a secondary outcome, there was a significantly greater difference in A1c at 32 weeks with CagriSema versus cagrilintide (–1.3%; P < .0001). Moreover, 89% of patients in the CagriSema group reached an A1c less than 7%.

In other secondary outcomes, there was a significantly greater reduction in body weight at 32 weeks with CagriSema versus cagrilintide or semaglutide, with 71% of patients in the CagriSema group achieving greater than 10% reduction in body weight. Patients in the CagriSema group also had clinically relevant improvements in blood pressure, lipids, and high-sensitivity C-reactive protein.

Adverse events – reported in 68% of patients with CagriSema versus 71% with semaglutide and 80% with cagrilintide – were mostly mild or moderate gastrointestinal events, consistent with those seen in these two drug classes.

At week 32, time in range was 89% with CagriSema versus 76% with semaglutide and 72% with cagrilintide.

“Our phase 2 clinical trial is the first study to report efficacy and safety data for treatment with the combination of a GLP-1 agonist and an amylin analog in participants with type 2 diabetes,” the researchers summarize. “These data support further investigation of CagriSema in this population in longer and larger phase 3 studies.”

This trial was sponsored by Novo Nordisk. Dr. Frias, Dr. Mathieu, Dr. Apovian, and Dr. McDonnell reported financial relationships with a number of companies.

A version of this article first appeared on Medscape.com.

A 65-year-old African American man presented to an Otolaryngology Head and Neck Surgery clinic at a tertiary Veterans Health Administration (VHA) facility for evaluation. The patient recalled a past diagnosis of oropharyngeal cancer (OPC), possibly associated with the human papillomavirus (HPV). After receiving the diagnosis at another VHA facility, the patient opted to seek care at a local, non-VHA facility and received approximately 7 weeks of daily radiation and weekly infusions of chemotherapy.

Six years after his initial diagnosis and treatment, the patient said he had a persistent cough with any meaningful attempts to eat or drink. He also noted he lost at least 10 lbs in the last 3 months and had been hospitalized twice during the past winter. During his second hospitalization he spent 4 days on a ventilator in the intensive care unit.

On examination, the patient appeared frail and cachectic, with significant fibrosis of the neck skin and moderate trismus. His dentition was in poor health, and an in-clinic flexible endoscopy demonstrated clear silent aspiration of oral secretions. Given his failure to thrive, the patient was urgently admitted to the hospital. A modified barium swallow study performed by the head and neck Speech Pathology team demonstrated gross aspiration with all consistencies. After extensive counseling, the patient agreed to the placement of a gastrostomy tube. He was discharged in stable condition with adequate supplies and self-care training. He was advised to continue follow-up in the Head and Neck Cancer Survivorship clinic.

Two years later, in the early phase of the COVID-19 pandemic, the patient was admitted to the hospital with COVID pneumonia. Given the damage to his lungs over the previous decade from recurrent episodes of aspiration pneumonia, the patient succumbed.

An Unexpected, Unrelenting Epidemic

Shifting population dynamics and behaviors have led to an explosion in the incidence of cancers associated with infection by oncogenic subtypes of HPV, among which cancer of the oropharynx represents the most common malignancy.^1,2 OPC now afflicts more than 30,000 new patients in the United States each year.³ Given current vaccination rates against oncogenic HPV, the overall trend of increasing incidence is not expected to stabilize until the 2040s.³ Traditional cancers of the head and neck region were previously fatal after 5 years in more than 60% of cases; however, today patients with HPV-associated OPC can expect a more than 80% chance of being alive 5 years after treatment.^4-7 Combining the increasing incidence of OPC with a high chance of oncologic cure has led to an ever-expanding cohort of OPC survivors.

Enthusiasm about a high rate of survival after an HPV-associated OPC diagnosis is now partially dampened by an increasing realization that neither oncologists nor healthcare systems are remotely prepared for this rapidly expanding cohort of OPC survivors. Their unique needs and problems have yet to be objectively defined and quantified.

Relationship Between Survival and Long-Term Toxicity in HPV-Associated OPC

Survivorship care after OPC treatment is a growing challenge in terms of the number of patients affected, the negative impact on quality of life (QOL), and the potential burden on the healthcare system. The rapidly growing number of OPC survivors who are living long enough to develop delayed adverse effects related to their past OPC treatment^1,2,8 includes many patients in whom toxicities can be truly debilitating,^9,10 generating significant unmet needs.

Tumor and Treatment Toxicity

Although HPV-associated OPC demonstrates an excellent response to conventional chemoradiotherapy (CRT), this finding cannot be interpreted to mean that reducing treatment intensity is safe for patients with this disease. Prospective trials have now demonstrated that neither replacing or eliminating conventional chemotherapy, nor significantly reducing radiation doses, can be considered safe at this time.^11-15 As a result, a patient with newly diagnosed HPV-associated OPC in 2025, and potentially even 2030, is likely to receive the same treatment as patients who were treated in the late 2010s.¹⁴

Three decades ago, the chronic effects of tumor and treatment were largely limited to a small cohort of survivors; however, today they affect more patients.^1,2,7 Chronic xerostomia, dysphagia, trismus, radiation fibrosis, and osteoradionecrosis (ORN) now confront tens of thousands of OPC survivors; over the coming decades, these treatment effects have the potential to affect millions of patients.^16-22

While most acute toxicities resolve within several months of completing CRT, late CRT sequelae tend to be dynamic and can progress silently over many years.^16,23 Adverse effects vary widely, with many toxicities (eg, dysphagia, ORN) being particularly debilitating. Many of these effects occur in a radiation dose–dependent fashion, but radiation dose does not fully predict late toxicities, pointing to a role for other, yet unidentified contributing factors.^24,25

Dysphagia in Survivors of OPC

About two-thirds of survivors of head and neck cancer (HNC) who seek follow-up care 5 years after treatment report dysphagia and at least partial dependence on a feeding tube.²⁶ The incidence of dysphagia increases proportionately with higher radiation doses delivered to the pharyngeal constrictors and supraglottic larynx.¹⁸ Dysphagia can severely reduce QOL years after treatment, necessitating substantial changes in diet and social behavior among OPC survivors. Often, patients are forced to choose between chronic malnutrition or starvation and feeding tube dependence.²⁷ Loss of a normal oral diet is frequently one of the most affected QOL measures for OPC survivors.²⁸

In addition to effects on QOL, dysphagia can have life-threatening consequences. In a recent systematic review and meta-analysis, life-threatening aspiration occurred after > 24 months at a reported incidence ranging from 3% to nearly 35%. Although a reduction in radiation dose to the pharyngeal constrictors can reduce chronic dysphagia,²⁷ whether this can be done safely in most OPC patients, particularly those with bulky primary tumors, remains unclear.

Osteoradionecrosis (ORN) in Survivors of OPC

ORN is one of the most potentially serious complications of CRT and may not manifest for years after treatment. Its median time of onset after radiotherapy is 8 years in patients with OPC.²⁴ Bone injury and impaired healing of the alveolar mucosa are signs of ORN, which occurs in ~7% of patients receiving intensity-modulated radiation therapy for OPC.¹⁷ ORN is accompanied by pain, difficulties with chewing, exacerbation of concomitant dysphagia and, in the advanced stage—gross cosmetic deformity secondary to mandibular or maxillary fracture and/or decay.²⁹ Despite the severity of this complication, we are just beginning to understand why ORN develops in a subset of patients. Although ORN is generally more common in patients with advanced-stage OPC who receive higher doses of radiation to a larger overall bone volume,^17,19,24,30 comprehensive translational research efforts focused on ORN (as well as other late toxicities of OPC treatment) are still in their infancy.

Unmet Needs in Predicting and Evaluating Late Toxicities

Predicting which patients will experience long-term treatment toxicities or which types of late toxicities they may develop is not yet possible. Whereas increased data collection and prognostic models can help inform healthcare systems as to the expected frequencies of toxicity, they are unlikely to be prognostic at the individual patient level. As such, there is a critical need for individualized biomarker strategies that can predict one’s risk of toxicity and identify normal tissue shifts in biology and function early in the process to initiate interventions before significant deterioration. Adding to the complexity of predicting late toxicities is the lack of standardization in instruments used to categorize them. Examples of tools that may be used to categorize dysphagia include the Common Terminology Criteria for Adverse Events v4.0 grading scale, the Radiation Therapy Oncology Group grading system, and the European Organization for Research and Treatment of Cancer Performance Status Scale for Head and Neck Cancer.²⁰ The MD Anderson Symptom Inventory for head and neck cancer may also be used to catalog dysphagia and other common symptoms of HNC, as well as treatment-related concerns.³¹ Magnetic resonance imaging-based techniques coupled with machine learning approaches represent emerging tools that may have a role in identifying early radiation-induced bone changes that can facilitate early detection of ORN.^32,33 Although conventional and newer tools can be used to generate objective metrics of treatment-related toxicity, consistent and appropriate deployment across the entire cohort of OPC survivors in the United States remains a distant goal.

Calibrating Treatment Intensity to Disease Intensity 

Given the risk of severe and potentially life-threatening consequences of radiation-based treatment, there is a large unmet need to better calibrate treatment intensity to the intensity of HPV-associated OPC.^14,34 In light of the good prognosis of the disease in most patients, recent efforts have focused on identifying ways to de-escalate treatment intensity while preserving the good outcomes known to be possible for patients with HPV-associated OPC. Improving tolerability and limiting the risk of late effects of radiation-based treatment is especially important with the aging population of HPV-associated OPC survivors, who would also be expected to have unrelated comorbidities.¹

Various modes of de-escalation have been studied, including adding surgery to CRT, reducing radiation dose, and modifying systemic therapy regimens. Most of these efforts have largely failed to identify a safe regimen for treatment de-escalation that applies to a majority or even a significant plurality of patients with OPC.^14,35,36 Although CheckMate 141 and KEYNOTE-048 garnered excitement when immune checkpoint inhibitors (ICIs) significantly prolonged overall survival and had a more favorable safety profile than standard systemic therapy in recurrent and metastatic OPC,^11,37,38 adding definitive frontline avelumab to CRT failed to prolong progression-free survival versus CRT alone in the phase 3 JAVELIN Head and Neck 100 trial.¹³ Combined with additional recent trial data, these findings make it unlikely that an ICI-based regimen will provide previously unavailable de-escalation options for patients with OPC in the near future.

Considering continued de-escalation efforts, it is important to remember that survival is not uniform among all patients with HPV-associated OPC. For example, patients with HPV-associated OPC and a history of current or prior heavy tobacco use have not experienced the same dramatic prolongation in overall survival as their nonsmoking counterparts.³⁶ Patients with recurrent disease also face a dismal prognosis, with failure rates of about 70% with salvage treatment with surgery, re-irradiation, or systemic therapy.^38-41 Therefore, de-escalation may not be appropriate in all patients, but identifying which patients are at risk of overtreatment is not straightforward. Better risk stratification of patients may provide part of the solution but will require rigorous testing and long-term follow-up to establish.

Discussion

There is an urgent need to carefully consider how to manage long-term survivors of HPV-associated OPC. With ever-increasing numbers of patients who are living years beyond their OPC treatment, continual reevaluation of treatment strategies in certain subsets of patients and making concerted efforts to identify and manage late toxicities early is paramount. Yet there remains a critical gap in knowledge due to insufficient metrics for both toxicity intensity and the frequency of debilitating, life-threatening toxicity. Unfortunately, the lack of tools available combined with the mismatch in disease intensity with treatment intensity likely results in excessive treatment-induced toxicity for many patients.

In the absence of clear evidence about which treatment strategy to use for individual patients, clinicians are tasked with making therapeutic choices without being fully able to predict outcomes. Patient preference is important to consider, but these conversations can be complicated. How does one talk to a patient about their willingness to risk a cancer recurrence and potentially risk late toxicities when the clinician does not know whether that individual patient will develop late toxicities, or know how severe they will be? It is a tradeoff between QOL (ie, possible feeding tube dependence) and survival—yet the magnitude of the effect on QOL remains impossible to predict at present for the individual patient.

Moreover, the needs of individual OPC survivors vary. A cross-sectional study performed at Princess Margaret Cancer Centre found that 61% of the 158 participants had unmet needs related to their cancer survivorship.⁴² Meeting the needs of survivors may require the development of better screening instruments that can manage various complications early and effectively. Continuing to follow OPC survivors with a multidisciplinary team would most certainly be beneficial and has been reported to improve QOL.⁴³ Continual Speech Pathology management and therapy from the time of diagnosis into the survivorship phase of care has been suggested as one way to improve functional outcomes.⁴⁴ Given that coordinating long-term care teams is logistically challenging, well-planned research is warranted to equip these teams to provide OPC survivors with the care they need. These efforts will be particularly important considering the large number of survivors who will need this type of care in the coming decades. The time to start is now well past.

Click to read more from 2023 Rare Diseases Report: Cancers

A 65-year-old African American man presented to an Otolaryngology Head and Neck Surgery clinic at a tertiary Veterans Health Administration (VHA) facility for evaluation. The patient recalled a past diagnosis of oropharyngeal cancer (OPC), possibly associated with the human papillomavirus (HPV). After receiving the diagnosis at another VHA facility, the patient opted to seek care at a local, non-VHA facility and received approximately 7 weeks of daily radiation and weekly infusions of chemotherapy.

Six years after his initial diagnosis and treatment, the patient said he had a persistent cough with any meaningful attempts to eat or drink. He also noted he lost at least 10 lbs in the last 3 months and had been hospitalized twice during the past winter. During his second hospitalization he spent 4 days on a ventilator in the intensive care unit.

On examination, the patient appeared frail and cachectic, with significant fibrosis of the neck skin and moderate trismus. His dentition was in poor health, and an in-clinic flexible endoscopy demonstrated clear silent aspiration of oral secretions. Given his failure to thrive, the patient was urgently admitted to the hospital. A modified barium swallow study performed by the head and neck Speech Pathology team demonstrated gross aspiration with all consistencies. After extensive counseling, the patient agreed to the placement of a gastrostomy tube. He was discharged in stable condition with adequate supplies and self-care training. He was advised to continue follow-up in the Head and Neck Cancer Survivorship clinic.

Two years later, in the early phase of the COVID-19 pandemic, the patient was admitted to the hospital with COVID pneumonia. Given the damage to his lungs over the previous decade from recurrent episodes of aspiration pneumonia, the patient succumbed.

An Unexpected, Unrelenting Epidemic

Shifting population dynamics and behaviors have led to an explosion in the incidence of cancers associated with infection by oncogenic subtypes of HPV, among which cancer of the oropharynx represents the most common malignancy.^1,2 OPC now afflicts more than 30,000 new patients in the United States each year.³ Given current vaccination rates against oncogenic HPV, the overall trend of increasing incidence is not expected to stabilize until the 2040s.³ Traditional cancers of the head and neck region were previously fatal after 5 years in more than 60% of cases; however, today patients with HPV-associated OPC can expect a more than 80% chance of being alive 5 years after treatment.^4-7 Combining the increasing incidence of OPC with a high chance of oncologic cure has led to an ever-expanding cohort of OPC survivors.

Enthusiasm about a high rate of survival after an HPV-associated OPC diagnosis is now partially dampened by an increasing realization that neither oncologists nor healthcare systems are remotely prepared for this rapidly expanding cohort of OPC survivors. Their unique needs and problems have yet to be objectively defined and quantified.

Relationship Between Survival and Long-Term Toxicity in HPV-Associated OPC

Survivorship care after OPC treatment is a growing challenge in terms of the number of patients affected, the negative impact on quality of life (QOL), and the potential burden on the healthcare system. The rapidly growing number of OPC survivors who are living long enough to develop delayed adverse effects related to their past OPC treatment^1,2,8 includes many patients in whom toxicities can be truly debilitating,^9,10 generating significant unmet needs.

Tumor and Treatment Toxicity

Although HPV-associated OPC demonstrates an excellent response to conventional chemoradiotherapy (CRT), this finding cannot be interpreted to mean that reducing treatment intensity is safe for patients with this disease. Prospective trials have now demonstrated that neither replacing or eliminating conventional chemotherapy, nor significantly reducing radiation doses, can be considered safe at this time.^11-15 As a result, a patient with newly diagnosed HPV-associated OPC in 2025, and potentially even 2030, is likely to receive the same treatment as patients who were treated in the late 2010s.¹⁴

Three decades ago, the chronic effects of tumor and treatment were largely limited to a small cohort of survivors; however, today they affect more patients.^1,2,7 Chronic xerostomia, dysphagia, trismus, radiation fibrosis, and osteoradionecrosis (ORN) now confront tens of thousands of OPC survivors; over the coming decades, these treatment effects have the potential to affect millions of patients.^16-22

While most acute toxicities resolve within several months of completing CRT, late CRT sequelae tend to be dynamic and can progress silently over many years.^16,23 Adverse effects vary widely, with many toxicities (eg, dysphagia, ORN) being particularly debilitating. Many of these effects occur in a radiation dose–dependent fashion, but radiation dose does not fully predict late toxicities, pointing to a role for other, yet unidentified contributing factors.^24,25

Dysphagia in Survivors of OPC

About two-thirds of survivors of head and neck cancer (HNC) who seek follow-up care 5 years after treatment report dysphagia and at least partial dependence on a feeding tube.²⁶ The incidence of dysphagia increases proportionately with higher radiation doses delivered to the pharyngeal constrictors and supraglottic larynx.¹⁸ Dysphagia can severely reduce QOL years after treatment, necessitating substantial changes in diet and social behavior among OPC survivors. Often, patients are forced to choose between chronic malnutrition or starvation and feeding tube dependence.²⁷ Loss of a normal oral diet is frequently one of the most affected QOL measures for OPC survivors.²⁸

In addition to effects on QOL, dysphagia can have life-threatening consequences. In a recent systematic review and meta-analysis, life-threatening aspiration occurred after > 24 months at a reported incidence ranging from 3% to nearly 35%. Although a reduction in radiation dose to the pharyngeal constrictors can reduce chronic dysphagia,²⁷ whether this can be done safely in most OPC patients, particularly those with bulky primary tumors, remains unclear.

Osteoradionecrosis (ORN) in Survivors of OPC

ORN is one of the most potentially serious complications of CRT and may not manifest for years after treatment. Its median time of onset after radiotherapy is 8 years in patients with OPC.²⁴ Bone injury and impaired healing of the alveolar mucosa are signs of ORN, which occurs in ~7% of patients receiving intensity-modulated radiation therapy for OPC.¹⁷ ORN is accompanied by pain, difficulties with chewing, exacerbation of concomitant dysphagia and, in the advanced stage—gross cosmetic deformity secondary to mandibular or maxillary fracture and/or decay.²⁹ Despite the severity of this complication, we are just beginning to understand why ORN develops in a subset of patients. Although ORN is generally more common in patients with advanced-stage OPC who receive higher doses of radiation to a larger overall bone volume,^17,19,24,30 comprehensive translational research efforts focused on ORN (as well as other late toxicities of OPC treatment) are still in their infancy.

Unmet Needs in Predicting and Evaluating Late Toxicities

Predicting which patients will experience long-term treatment toxicities or which types of late toxicities they may develop is not yet possible. Whereas increased data collection and prognostic models can help inform healthcare systems as to the expected frequencies of toxicity, they are unlikely to be prognostic at the individual patient level. As such, there is a critical need for individualized biomarker strategies that can predict one’s risk of toxicity and identify normal tissue shifts in biology and function early in the process to initiate interventions before significant deterioration. Adding to the complexity of predicting late toxicities is the lack of standardization in instruments used to categorize them. Examples of tools that may be used to categorize dysphagia include the Common Terminology Criteria for Adverse Events v4.0 grading scale, the Radiation Therapy Oncology Group grading system, and the European Organization for Research and Treatment of Cancer Performance Status Scale for Head and Neck Cancer.²⁰ The MD Anderson Symptom Inventory for head and neck cancer may also be used to catalog dysphagia and other common symptoms of HNC, as well as treatment-related concerns.³¹ Magnetic resonance imaging-based techniques coupled with machine learning approaches represent emerging tools that may have a role in identifying early radiation-induced bone changes that can facilitate early detection of ORN.^32,33 Although conventional and newer tools can be used to generate objective metrics of treatment-related toxicity, consistent and appropriate deployment across the entire cohort of OPC survivors in the United States remains a distant goal.

Calibrating Treatment Intensity to Disease Intensity 

Given the risk of severe and potentially life-threatening consequences of radiation-based treatment, there is a large unmet need to better calibrate treatment intensity to the intensity of HPV-associated OPC.^14,34 In light of the good prognosis of the disease in most patients, recent efforts have focused on identifying ways to de-escalate treatment intensity while preserving the good outcomes known to be possible for patients with HPV-associated OPC. Improving tolerability and limiting the risk of late effects of radiation-based treatment is especially important with the aging population of HPV-associated OPC survivors, who would also be expected to have unrelated comorbidities.¹

Various modes of de-escalation have been studied, including adding surgery to CRT, reducing radiation dose, and modifying systemic therapy regimens. Most of these efforts have largely failed to identify a safe regimen for treatment de-escalation that applies to a majority or even a significant plurality of patients with OPC.^14,35,36 Although CheckMate 141 and KEYNOTE-048 garnered excitement when immune checkpoint inhibitors (ICIs) significantly prolonged overall survival and had a more favorable safety profile than standard systemic therapy in recurrent and metastatic OPC,^11,37,38 adding definitive frontline avelumab to CRT failed to prolong progression-free survival versus CRT alone in the phase 3 JAVELIN Head and Neck 100 trial.¹³ Combined with additional recent trial data, these findings make it unlikely that an ICI-based regimen will provide previously unavailable de-escalation options for patients with OPC in the near future.

Considering continued de-escalation efforts, it is important to remember that survival is not uniform among all patients with HPV-associated OPC. For example, patients with HPV-associated OPC and a history of current or prior heavy tobacco use have not experienced the same dramatic prolongation in overall survival as their nonsmoking counterparts.³⁶ Patients with recurrent disease also face a dismal prognosis, with failure rates of about 70% with salvage treatment with surgery, re-irradiation, or systemic therapy.^38-41 Therefore, de-escalation may not be appropriate in all patients, but identifying which patients are at risk of overtreatment is not straightforward. Better risk stratification of patients may provide part of the solution but will require rigorous testing and long-term follow-up to establish.

Discussion

There is an urgent need to carefully consider how to manage long-term survivors of HPV-associated OPC. With ever-increasing numbers of patients who are living years beyond their OPC treatment, continual reevaluation of treatment strategies in certain subsets of patients and making concerted efforts to identify and manage late toxicities early is paramount. Yet there remains a critical gap in knowledge due to insufficient metrics for both toxicity intensity and the frequency of debilitating, life-threatening toxicity. Unfortunately, the lack of tools available combined with the mismatch in disease intensity with treatment intensity likely results in excessive treatment-induced toxicity for many patients.

In the absence of clear evidence about which treatment strategy to use for individual patients, clinicians are tasked with making therapeutic choices without being fully able to predict outcomes. Patient preference is important to consider, but these conversations can be complicated. How does one talk to a patient about their willingness to risk a cancer recurrence and potentially risk late toxicities when the clinician does not know whether that individual patient will develop late toxicities, or know how severe they will be? It is a tradeoff between QOL (ie, possible feeding tube dependence) and survival—yet the magnitude of the effect on QOL remains impossible to predict at present for the individual patient.

Moreover, the needs of individual OPC survivors vary. A cross-sectional study performed at Princess Margaret Cancer Centre found that 61% of the 158 participants had unmet needs related to their cancer survivorship.⁴² Meeting the needs of survivors may require the development of better screening instruments that can manage various complications early and effectively. Continuing to follow OPC survivors with a multidisciplinary team would most certainly be beneficial and has been reported to improve QOL.⁴³ Continual Speech Pathology management and therapy from the time of diagnosis into the survivorship phase of care has been suggested as one way to improve functional outcomes.⁴⁴ Given that coordinating long-term care teams is logistically challenging, well-planned research is warranted to equip these teams to provide OPC survivors with the care they need. These efforts will be particularly important considering the large number of survivors who will need this type of care in the coming decades. The time to start is now well past.

Click to read more from 2023 Rare Diseases Report: Cancers

A 65-year-old African American man presented to an Otolaryngology Head and Neck Surgery clinic at a tertiary Veterans Health Administration (VHA) facility for evaluation. The patient recalled a past diagnosis of oropharyngeal cancer (OPC), possibly associated with the human papillomavirus (HPV). After receiving the diagnosis at another VHA facility, the patient opted to seek care at a local, non-VHA facility and received approximately 7 weeks of daily radiation and weekly infusions of chemotherapy.

Six years after his initial diagnosis and treatment, the patient said he had a persistent cough with any meaningful attempts to eat or drink. He also noted he lost at least 10 lbs in the last 3 months and had been hospitalized twice during the past winter. During his second hospitalization he spent 4 days on a ventilator in the intensive care unit.

On examination, the patient appeared frail and cachectic, with significant fibrosis of the neck skin and moderate trismus. His dentition was in poor health, and an in-clinic flexible endoscopy demonstrated clear silent aspiration of oral secretions. Given his failure to thrive, the patient was urgently admitted to the hospital. A modified barium swallow study performed by the head and neck Speech Pathology team demonstrated gross aspiration with all consistencies. After extensive counseling, the patient agreed to the placement of a gastrostomy tube. He was discharged in stable condition with adequate supplies and self-care training. He was advised to continue follow-up in the Head and Neck Cancer Survivorship clinic.

Two years later, in the early phase of the COVID-19 pandemic, the patient was admitted to the hospital with COVID pneumonia. Given the damage to his lungs over the previous decade from recurrent episodes of aspiration pneumonia, the patient succumbed.

An Unexpected, Unrelenting Epidemic

Shifting population dynamics and behaviors have led to an explosion in the incidence of cancers associated with infection by oncogenic subtypes of HPV, among which cancer of the oropharynx represents the most common malignancy.^1,2 OPC now afflicts more than 30,000 new patients in the United States each year.³ Given current vaccination rates against oncogenic HPV, the overall trend of increasing incidence is not expected to stabilize until the 2040s.³ Traditional cancers of the head and neck region were previously fatal after 5 years in more than 60% of cases; however, today patients with HPV-associated OPC can expect a more than 80% chance of being alive 5 years after treatment.^4-7 Combining the increasing incidence of OPC with a high chance of oncologic cure has led to an ever-expanding cohort of OPC survivors.

Enthusiasm about a high rate of survival after an HPV-associated OPC diagnosis is now partially dampened by an increasing realization that neither oncologists nor healthcare systems are remotely prepared for this rapidly expanding cohort of OPC survivors. Their unique needs and problems have yet to be objectively defined and quantified.

Relationship Between Survival and Long-Term Toxicity in HPV-Associated OPC

Survivorship care after OPC treatment is a growing challenge in terms of the number of patients affected, the negative impact on quality of life (QOL), and the potential burden on the healthcare system. The rapidly growing number of OPC survivors who are living long enough to develop delayed adverse effects related to their past OPC treatment^1,2,8 includes many patients in whom toxicities can be truly debilitating,^9,10 generating significant unmet needs.

Tumor and Treatment Toxicity

Although HPV-associated OPC demonstrates an excellent response to conventional chemoradiotherapy (CRT), this finding cannot be interpreted to mean that reducing treatment intensity is safe for patients with this disease. Prospective trials have now demonstrated that neither replacing or eliminating conventional chemotherapy, nor significantly reducing radiation doses, can be considered safe at this time.^11-15 As a result, a patient with newly diagnosed HPV-associated OPC in 2025, and potentially even 2030, is likely to receive the same treatment as patients who were treated in the late 2010s.¹⁴

Three decades ago, the chronic effects of tumor and treatment were largely limited to a small cohort of survivors; however, today they affect more patients.^1,2,7 Chronic xerostomia, dysphagia, trismus, radiation fibrosis, and osteoradionecrosis (ORN) now confront tens of thousands of OPC survivors; over the coming decades, these treatment effects have the potential to affect millions of patients.^16-22

While most acute toxicities resolve within several months of completing CRT, late CRT sequelae tend to be dynamic and can progress silently over many years.^16,23 Adverse effects vary widely, with many toxicities (eg, dysphagia, ORN) being particularly debilitating. Many of these effects occur in a radiation dose–dependent fashion, but radiation dose does not fully predict late toxicities, pointing to a role for other, yet unidentified contributing factors.^24,25

Dysphagia in Survivors of OPC

About two-thirds of survivors of head and neck cancer (HNC) who seek follow-up care 5 years after treatment report dysphagia and at least partial dependence on a feeding tube.²⁶ The incidence of dysphagia increases proportionately with higher radiation doses delivered to the pharyngeal constrictors and supraglottic larynx.¹⁸ Dysphagia can severely reduce QOL years after treatment, necessitating substantial changes in diet and social behavior among OPC survivors. Often, patients are forced to choose between chronic malnutrition or starvation and feeding tube dependence.²⁷ Loss of a normal oral diet is frequently one of the most affected QOL measures for OPC survivors.²⁸

In addition to effects on QOL, dysphagia can have life-threatening consequences. In a recent systematic review and meta-analysis, life-threatening aspiration occurred after > 24 months at a reported incidence ranging from 3% to nearly 35%. Although a reduction in radiation dose to the pharyngeal constrictors can reduce chronic dysphagia,²⁷ whether this can be done safely in most OPC patients, particularly those with bulky primary tumors, remains unclear.

Osteoradionecrosis (ORN) in Survivors of OPC

ORN is one of the most potentially serious complications of CRT and may not manifest for years after treatment. Its median time of onset after radiotherapy is 8 years in patients with OPC.²⁴ Bone injury and impaired healing of the alveolar mucosa are signs of ORN, which occurs in ~7% of patients receiving intensity-modulated radiation therapy for OPC.¹⁷ ORN is accompanied by pain, difficulties with chewing, exacerbation of concomitant dysphagia and, in the advanced stage—gross cosmetic deformity secondary to mandibular or maxillary fracture and/or decay.²⁹ Despite the severity of this complication, we are just beginning to understand why ORN develops in a subset of patients. Although ORN is generally more common in patients with advanced-stage OPC who receive higher doses of radiation to a larger overall bone volume,^17,19,24,30 comprehensive translational research efforts focused on ORN (as well as other late toxicities of OPC treatment) are still in their infancy.

Unmet Needs in Predicting and Evaluating Late Toxicities

Predicting which patients will experience long-term treatment toxicities or which types of late toxicities they may develop is not yet possible. Whereas increased data collection and prognostic models can help inform healthcare systems as to the expected frequencies of toxicity, they are unlikely to be prognostic at the individual patient level. As such, there is a critical need for individualized biomarker strategies that can predict one’s risk of toxicity and identify normal tissue shifts in biology and function early in the process to initiate interventions before significant deterioration. Adding to the complexity of predicting late toxicities is the lack of standardization in instruments used to categorize them. Examples of tools that may be used to categorize dysphagia include the Common Terminology Criteria for Adverse Events v4.0 grading scale, the Radiation Therapy Oncology Group grading system, and the European Organization for Research and Treatment of Cancer Performance Status Scale for Head and Neck Cancer.²⁰ The MD Anderson Symptom Inventory for head and neck cancer may also be used to catalog dysphagia and other common symptoms of HNC, as well as treatment-related concerns.³¹ Magnetic resonance imaging-based techniques coupled with machine learning approaches represent emerging tools that may have a role in identifying early radiation-induced bone changes that can facilitate early detection of ORN.^32,33 Although conventional and newer tools can be used to generate objective metrics of treatment-related toxicity, consistent and appropriate deployment across the entire cohort of OPC survivors in the United States remains a distant goal.

Calibrating Treatment Intensity to Disease Intensity 

Given the risk of severe and potentially life-threatening consequences of radiation-based treatment, there is a large unmet need to better calibrate treatment intensity to the intensity of HPV-associated OPC.^14,34 In light of the good prognosis of the disease in most patients, recent efforts have focused on identifying ways to de-escalate treatment intensity while preserving the good outcomes known to be possible for patients with HPV-associated OPC. Improving tolerability and limiting the risk of late effects of radiation-based treatment is especially important with the aging population of HPV-associated OPC survivors, who would also be expected to have unrelated comorbidities.¹

Various modes of de-escalation have been studied, including adding surgery to CRT, reducing radiation dose, and modifying systemic therapy regimens. Most of these efforts have largely failed to identify a safe regimen for treatment de-escalation that applies to a majority or even a significant plurality of patients with OPC.^14,35,36 Although CheckMate 141 and KEYNOTE-048 garnered excitement when immune checkpoint inhibitors (ICIs) significantly prolonged overall survival and had a more favorable safety profile than standard systemic therapy in recurrent and metastatic OPC,^11,37,38 adding definitive frontline avelumab to CRT failed to prolong progression-free survival versus CRT alone in the phase 3 JAVELIN Head and Neck 100 trial.¹³ Combined with additional recent trial data, these findings make it unlikely that an ICI-based regimen will provide previously unavailable de-escalation options for patients with OPC in the near future.

Considering continued de-escalation efforts, it is important to remember that survival is not uniform among all patients with HPV-associated OPC. For example, patients with HPV-associated OPC and a history of current or prior heavy tobacco use have not experienced the same dramatic prolongation in overall survival as their nonsmoking counterparts.³⁶ Patients with recurrent disease also face a dismal prognosis, with failure rates of about 70% with salvage treatment with surgery, re-irradiation, or systemic therapy.^38-41 Therefore, de-escalation may not be appropriate in all patients, but identifying which patients are at risk of overtreatment is not straightforward. Better risk stratification of patients may provide part of the solution but will require rigorous testing and long-term follow-up to establish.

Discussion

There is an urgent need to carefully consider how to manage long-term survivors of HPV-associated OPC. With ever-increasing numbers of patients who are living years beyond their OPC treatment, continual reevaluation of treatment strategies in certain subsets of patients and making concerted efforts to identify and manage late toxicities early is paramount. Yet there remains a critical gap in knowledge due to insufficient metrics for both toxicity intensity and the frequency of debilitating, life-threatening toxicity. Unfortunately, the lack of tools available combined with the mismatch in disease intensity with treatment intensity likely results in excessive treatment-induced toxicity for many patients.

In the absence of clear evidence about which treatment strategy to use for individual patients, clinicians are tasked with making therapeutic choices without being fully able to predict outcomes. Patient preference is important to consider, but these conversations can be complicated. How does one talk to a patient about their willingness to risk a cancer recurrence and potentially risk late toxicities when the clinician does not know whether that individual patient will develop late toxicities, or know how severe they will be? It is a tradeoff between QOL (ie, possible feeding tube dependence) and survival—yet the magnitude of the effect on QOL remains impossible to predict at present for the individual patient.

Moreover, the needs of individual OPC survivors vary. A cross-sectional study performed at Princess Margaret Cancer Centre found that 61% of the 158 participants had unmet needs related to their cancer survivorship.⁴² Meeting the needs of survivors may require the development of better screening instruments that can manage various complications early and effectively. Continuing to follow OPC survivors with a multidisciplinary team would most certainly be beneficial and has been reported to improve QOL.⁴³ Continual Speech Pathology management and therapy from the time of diagnosis into the survivorship phase of care has been suggested as one way to improve functional outcomes.⁴⁴ Given that coordinating long-term care teams is logistically challenging, well-planned research is warranted to equip these teams to provide OPC survivors with the care they need. These efforts will be particularly important considering the large number of survivors who will need this type of care in the coming decades. The time to start is now well past.

Click to read more from 2023 Rare Diseases Report: Cancers