AVAHO

Gene therapies, especially chimeric antigen receptor (CAR) T-cell therapies, experienced significant growth in 2017. The CAR T-cell therapies are among the most clinically important of the adoptive cell transfer therapies. In August, the FDA approved tisagenlecleucel for patients aged < 26 years with acute or relapsed lymphoblastic leukemia (ALL). In October, the FDA approved axicabtagene ciloleucel for treatment of adult patients nonresponsive to, or relapsed from treatment of, certain types of large B-cell lymphoma. And in November, the FDA granted breakthrough therapy designation to Celgene and Bluebird Bio for the bb2121 anti-B-cell maturation antigen (BCMA) CAR T-cell therapy for relapsed and refractory multiple myeloma (MM).

Chimeric antigen receptor T-cells circumvent the human major histocompatibility complex that T-cell receptors must navigate, shifting cell-based therapy away from identification of existing cells and toward creating T-cell products through genetic engineering. This broadens the potential for CAR T-cell applications and allows for rapid manufacture of tumor and patient-specific agents.¹ Both Novartis’ Kymriah and Kite Pharma’s Yescarta are derived from investigations into anti-CD19 CAR therapy, which has been the most heavily researched of the CARs due to its links with B-cell malignancies, expression in most tumor cells, and absence from vital tissues.² Studied in relation to a number of cancers, CD19 has not shown much success in either MM or solid tumor cancers.

Targeting the right antigen for myeloma is complicated: first because common MM antigens—CD38, CD56, CD138—also are expressed on essential normal cells, and second, because myeloma cells are synonymous with heterogeneity. The FDA based its designation of bb2121, or BCMA CAR T-cell therapy, on preliminary data from an ongoing phase 1 CRB-401 trial that, as of December 2017, concluded that 94% of 21 patients with MM treated with the highest doses showed complete or partial remissions and high rates of progression-free survival.³ The trial also showed that cytokine-release toxicity (CRS), although severe in some patients, was generally reversible and short lived.

Multiple myeloma BCMA is only one of several CAR targets under consideration for MM treatment; others include CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain. However, B-cell maturation antigen is attractive to researchers because BCMA–specific CAR-expressing T lymphocytes recognize and kill B-cell maturation antigen–expressing tumor cells. Also, BCMA acts as a receptor for both a proliferation-inducing ligand and as a B-cell–activating factor and is a member of the tumor necrosis factor receptor superfamily, playing a key role in plasma cell survival. B-cell maturation antigen is expressed in most, if not all, myeloma cells but not in epithelial tissues. Finally, integration of CAR-Ts with other myeloma therapies is an important area of future research.⁴

Most of the 23 trials looking at CAR T-cell therapy for MM are in the U.S. or China, and several deal jointly with MM, leukemia, and lymphoma. The THINK (THerapeutic Immunotherapy with NKR-2) multinational open-label phase 1 study stands alone in assessing the safety and clinical activity of multiple administrations of autologous NKR-2 cells in 7 refractory cancers, including 5 solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and 2 hematologic tumors (acute myeloid leukemia and MM). Unlike traditional CAR T-cell therapy, which targets only 1 tumor antigen, NK cell receptors enable a single receptor to recognize multiple tumor antigens.

Despite challenges of toxicity, costs, and restricted availability for immunotherapies, CAR T-cell therapies seem to offer great possibilities of groundbreaking treatments and possible cures for formerly hard to treat cancers, including MM.⁵

Click here to read the digital edition.

Gene therapies, especially chimeric antigen receptor (CAR) T-cell therapies, experienced significant growth in 2017. The CAR T-cell therapies are among the most clinically important of the adoptive cell transfer therapies. In August, the FDA approved tisagenlecleucel for patients aged < 26 years with acute or relapsed lymphoblastic leukemia (ALL). In October, the FDA approved axicabtagene ciloleucel for treatment of adult patients nonresponsive to, or relapsed from treatment of, certain types of large B-cell lymphoma. And in November, the FDA granted breakthrough therapy designation to Celgene and Bluebird Bio for the bb2121 anti-B-cell maturation antigen (BCMA) CAR T-cell therapy for relapsed and refractory multiple myeloma (MM).

Chimeric antigen receptor T-cells circumvent the human major histocompatibility complex that T-cell receptors must navigate, shifting cell-based therapy away from identification of existing cells and toward creating T-cell products through genetic engineering. This broadens the potential for CAR T-cell applications and allows for rapid manufacture of tumor and patient-specific agents.¹ Both Novartis’ Kymriah and Kite Pharma’s Yescarta are derived from investigations into anti-CD19 CAR therapy, which has been the most heavily researched of the CARs due to its links with B-cell malignancies, expression in most tumor cells, and absence from vital tissues.² Studied in relation to a number of cancers, CD19 has not shown much success in either MM or solid tumor cancers.

Targeting the right antigen for myeloma is complicated: first because common MM antigens—CD38, CD56, CD138—also are expressed on essential normal cells, and second, because myeloma cells are synonymous with heterogeneity. The FDA based its designation of bb2121, or BCMA CAR T-cell therapy, on preliminary data from an ongoing phase 1 CRB-401 trial that, as of December 2017, concluded that 94% of 21 patients with MM treated with the highest doses showed complete or partial remissions and high rates of progression-free survival.³ The trial also showed that cytokine-release toxicity (CRS), although severe in some patients, was generally reversible and short lived.

Multiple myeloma BCMA is only one of several CAR targets under consideration for MM treatment; others include CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain. However, B-cell maturation antigen is attractive to researchers because BCMA–specific CAR-expressing T lymphocytes recognize and kill B-cell maturation antigen–expressing tumor cells. Also, BCMA acts as a receptor for both a proliferation-inducing ligand and as a B-cell–activating factor and is a member of the tumor necrosis factor receptor superfamily, playing a key role in plasma cell survival. B-cell maturation antigen is expressed in most, if not all, myeloma cells but not in epithelial tissues. Finally, integration of CAR-Ts with other myeloma therapies is an important area of future research.⁴

Most of the 23 trials looking at CAR T-cell therapy for MM are in the U.S. or China, and several deal jointly with MM, leukemia, and lymphoma. The THINK (THerapeutic Immunotherapy with NKR-2) multinational open-label phase 1 study stands alone in assessing the safety and clinical activity of multiple administrations of autologous NKR-2 cells in 7 refractory cancers, including 5 solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and 2 hematologic tumors (acute myeloid leukemia and MM). Unlike traditional CAR T-cell therapy, which targets only 1 tumor antigen, NK cell receptors enable a single receptor to recognize multiple tumor antigens.

Despite challenges of toxicity, costs, and restricted availability for immunotherapies, CAR T-cell therapies seem to offer great possibilities of groundbreaking treatments and possible cures for formerly hard to treat cancers, including MM.⁵

Click here to read the digital edition.

Gene therapies, especially chimeric antigen receptor (CAR) T-cell therapies, experienced significant growth in 2017. The CAR T-cell therapies are among the most clinically important of the adoptive cell transfer therapies. In August, the FDA approved tisagenlecleucel for patients aged < 26 years with acute or relapsed lymphoblastic leukemia (ALL). In October, the FDA approved axicabtagene ciloleucel for treatment of adult patients nonresponsive to, or relapsed from treatment of, certain types of large B-cell lymphoma. And in November, the FDA granted breakthrough therapy designation to Celgene and Bluebird Bio for the bb2121 anti-B-cell maturation antigen (BCMA) CAR T-cell therapy for relapsed and refractory multiple myeloma (MM).

Chimeric antigen receptor T-cells circumvent the human major histocompatibility complex that T-cell receptors must navigate, shifting cell-based therapy away from identification of existing cells and toward creating T-cell products through genetic engineering. This broadens the potential for CAR T-cell applications and allows for rapid manufacture of tumor and patient-specific agents.¹ Both Novartis’ Kymriah and Kite Pharma’s Yescarta are derived from investigations into anti-CD19 CAR therapy, which has been the most heavily researched of the CARs due to its links with B-cell malignancies, expression in most tumor cells, and absence from vital tissues.² Studied in relation to a number of cancers, CD19 has not shown much success in either MM or solid tumor cancers.

Targeting the right antigen for myeloma is complicated: first because common MM antigens—CD38, CD56, CD138—also are expressed on essential normal cells, and second, because myeloma cells are synonymous with heterogeneity. The FDA based its designation of bb2121, or BCMA CAR T-cell therapy, on preliminary data from an ongoing phase 1 CRB-401 trial that, as of December 2017, concluded that 94% of 21 patients with MM treated with the highest doses showed complete or partial remissions and high rates of progression-free survival.³ The trial also showed that cytokine-release toxicity (CRS), although severe in some patients, was generally reversible and short lived.

Multiple myeloma BCMA is only one of several CAR targets under consideration for MM treatment; others include CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain. However, B-cell maturation antigen is attractive to researchers because BCMA–specific CAR-expressing T lymphocytes recognize and kill B-cell maturation antigen–expressing tumor cells. Also, BCMA acts as a receptor for both a proliferation-inducing ligand and as a B-cell–activating factor and is a member of the tumor necrosis factor receptor superfamily, playing a key role in plasma cell survival. B-cell maturation antigen is expressed in most, if not all, myeloma cells but not in epithelial tissues. Finally, integration of CAR-Ts with other myeloma therapies is an important area of future research.⁴

Most of the 23 trials looking at CAR T-cell therapy for MM are in the U.S. or China, and several deal jointly with MM, leukemia, and lymphoma. The THINK (THerapeutic Immunotherapy with NKR-2) multinational open-label phase 1 study stands alone in assessing the safety and clinical activity of multiple administrations of autologous NKR-2 cells in 7 refractory cancers, including 5 solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and 2 hematologic tumors (acute myeloid leukemia and MM). Unlike traditional CAR T-cell therapy, which targets only 1 tumor antigen, NK cell receptors enable a single receptor to recognize multiple tumor antigens.

Despite challenges of toxicity, costs, and restricted availability for immunotherapies, CAR T-cell therapies seem to offer great possibilities of groundbreaking treatments and possible cures for formerly hard to treat cancers, including MM.⁵

Click here to read the digital edition.

Patient Perspective

Breast cancer has been one of my life’s greatest blessings. Its highs and lows, prospects, and disappointments have only strengthened my faith and turned me more to God.

In March 2012, I had a bad cold, and while I was coughing and grabbing my chest, I discovered a small knot in my left breast, and for whatever reason, I suspected it was cancer. I immediately woke my wife. She, groggy and in usual humor exclaimed, “Oh great! You have breast cancer! Well guess what? I have prostate cancer…now go back to sleep!” I laughed at the prospect of her having prostate cancer. It certainly would’ve changed a few dynamics in our relationship.

Two weeks later my fears were confirmed. I was told that I needed to have a mastectomy of my left breast. I wanted nothing but to have this poison removed. Yesterday would not have been too soon.

My surgery was scheduled a month later; it was a long wait. And it soon became clear that as I recovered from the impending mastectomy, I also would be in line for open-heart surgery.

The mastectomy was a textbook procedure with no complications. My surgeon apprehensively warned me that follow-up visits would be at the Women’s Health Center. I must admit, it was awkward every time I went. Realistically though, I cared more about my health than about others’ perceptions.

While I prepared for my cardiac surgery, the blood test revealed triglyceride levels that were through the roof. In fact, the cardiac surgeon described them as “industrial strength.” After an exhaustive review, it was determined that my adjuvant therapy with tamoxifen was the culprit! I immediately stopped taking it, and within days my levels returned to normal. I was now left to fight any future bouts of cancer with just my body’s own defenses.

It probably seems strange, but if I had not found the breast lump, the problems with my heart would have gone undetected. I most likely would’ve died. Had the cancer not been a part of my life, I wouldn’t have been able to keep on living.

In the middle of March 2016, during preliminary testing for surgery to remove a skin tag, my chest X-ray displayed abnormalities. The workup showed that my breast cancer had returned. Worse yet, it had metastasized to my lungs. It had gone into my lymph nodes and lower spine.

The fight was on. A treatment plan was outlined; 12 weeks of chemotherapy infusions was a reasonable plan of attack. A second opinion was not necessarily an opportunity to find a differing plan, but as in my case, it was comforting affirmation of a good plan. I remember wondering if the rest of my life was going to be a mix of hospital visits, blood transfusions, chemotherapies, and injections.

While fear of the unknown works on one’s psyche, I made a decision to focus on my faith and God. My cancer experiences are probably no worse or different from the experiences of most other patients. I do believe that my perception of how cancer affected me psychologically is a different story. I know and trust that I am in the capable and knowledgeable hands of my doctor.

While the experience of good health care is remarkable, living with cancer does not end with medical care. I am blessed to have a partner who loves me infinitely. I cannot imagine my life without her.

I am grateful my cancer has allowed me to remain alive. The prospect of death does not shake me. I plan on living my life to the fullest.

Oncologist Perspective

Yes, men do get breast cancer! Unlike female breast cancer (FBC), male breast cancer (MBC) makes up about 1% of all cases in the U.S. The lifetime risk of a man developing breast cancer is about 1 in 1,000 vs 1 in 8 women.¹ Little is known about MBC because its rarity renders prospective randomized trials problematic. As a result, the management of breast cancer in males from diagnosis to treatment is based on research on FBC. Patients with MBC have higher mortality, and the incidence is rising 1.1% per year; by comparison both trends are decreasing for females with breast cancer.^2,3

Males are usually older and present with an advanced stage of the disease at the time of the diagnosis. Most MBC is ER+/PR+ and HER2−.⁴ Comparison data of 1,123 male veterans with 5,320 females revealed that the mean age at diagnosis was 70 years for MBC and 57 years for FBC, respectively (P < .01); 95% of patients with MBC and 72% of patients with FBC were aged > 50 years (P < .01). Patients with MBC were more likely to present with stage III or IV disease (40% vs 24%, respectively). Eighty percent of patients with MBC had ER+/PR+ tumors. Mortality was 31.6% in males vs 14.9% in females.

Given the high prevalence of ER/PR positivity, MBC usually is considered to have a better prognosis, but that does not explain the high mortality. Unlike FBC, delay in diagnosis due to lack of MBC awareness and no screening guidelines for MBC, older age at diagnosis, and comorbidities have been considered the etiology of higher mortality in MBC, but there has to be more than that. I believe that the differences in MBC biology and pathology also have to be contributing factors to MBC mortality.

As a VA oncologist, I have treated a number of patients with MBC. Surprisingly, my experience treating these patients has been different from treating FBC. In 2011, when I first met Mr. Lewis, he laughed and questioned his diagnosis—how could he have breast cancer if males don’t have breasts, and none of his family member had any type of cancer. Prior to his cancer diagnoses, he had gone through multiple cardiac stents and had a history of hypertriglyceridemia. His cancer workup and treatment plan were the same as that of females with breast cancer, and he questioned me again, “Why am I being treated like a female breast cancer patient?”

Unlike females with breast cancer, he had to have a complete mastectomy given the small breast tissue. His final diagnosis was stage IIA invasive ductal carcinoma of the left breast.

Because of Mr. Lewis’ cardiac history and recent stent placement, I was hesitant to give him first-line adjuvant anthracycline. The Oncotype DX test is highly recommended and easily done for FBC, but I had to go through great difficulty to order this test for him. The Oncotype Dx RS score for him was 17 (a so-called low score) with distant recurrence risk of 11%. I interpreted the test the same way as I would for a patient with FBC. We were happy that he did not have to be exposed to toxic chemotherapies.

Because of the lack of data for aromatase inhibitors (AIs) use in males, adjuvant tamoxifen was given but had to be stopped after a month because of hypertriglyceridemia > 8,000 mg/dL and cholesterol > 700 mg/dL. Tamoxifen as well as an AI was deemed not to be the right adjuvant treatment for him. There were no data on adjuvant fulvestrant; not even for females in 2012. Mr. Lewis was among the unlucky 11% and presented with stage IV disease in his lungs and bones 4 years after the initial diagnosis. He has not had a great response to taxanes and now is being treated with fulvestrant. He remains positive and hopeful, he told me only God—not medical science—has the power to take back the gift of life.

My experience with Mr. Lewis and others has underscored that MBC is not the same disease as FBC. I am hopeful we will see more clinical trials to further identify MBC biology and genomics.

Click here to read the digital edition.

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

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

Patient Perspective

Breast cancer has been one of my life’s greatest blessings. Its highs and lows, prospects, and disappointments have only strengthened my faith and turned me more to God.

In March 2012, I had a bad cold, and while I was coughing and grabbing my chest, I discovered a small knot in my left breast, and for whatever reason, I suspected it was cancer. I immediately woke my wife. She, groggy and in usual humor exclaimed, “Oh great! You have breast cancer! Well guess what? I have prostate cancer…now go back to sleep!” I laughed at the prospect of her having prostate cancer. It certainly would’ve changed a few dynamics in our relationship.

Two weeks later my fears were confirmed. I was told that I needed to have a mastectomy of my left breast. I wanted nothing but to have this poison removed. Yesterday would not have been too soon.

My surgery was scheduled a month later; it was a long wait. And it soon became clear that as I recovered from the impending mastectomy, I also would be in line for open-heart surgery.

The mastectomy was a textbook procedure with no complications. My surgeon apprehensively warned me that follow-up visits would be at the Women’s Health Center. I must admit, it was awkward every time I went. Realistically though, I cared more about my health than about others’ perceptions.

While I prepared for my cardiac surgery, the blood test revealed triglyceride levels that were through the roof. In fact, the cardiac surgeon described them as “industrial strength.” After an exhaustive review, it was determined that my adjuvant therapy with tamoxifen was the culprit! I immediately stopped taking it, and within days my levels returned to normal. I was now left to fight any future bouts of cancer with just my body’s own defenses.

It probably seems strange, but if I had not found the breast lump, the problems with my heart would have gone undetected. I most likely would’ve died. Had the cancer not been a part of my life, I wouldn’t have been able to keep on living.

In the middle of March 2016, during preliminary testing for surgery to remove a skin tag, my chest X-ray displayed abnormalities. The workup showed that my breast cancer had returned. Worse yet, it had metastasized to my lungs. It had gone into my lymph nodes and lower spine.

The fight was on. A treatment plan was outlined; 12 weeks of chemotherapy infusions was a reasonable plan of attack. A second opinion was not necessarily an opportunity to find a differing plan, but as in my case, it was comforting affirmation of a good plan. I remember wondering if the rest of my life was going to be a mix of hospital visits, blood transfusions, chemotherapies, and injections.

While fear of the unknown works on one’s psyche, I made a decision to focus on my faith and God. My cancer experiences are probably no worse or different from the experiences of most other patients. I do believe that my perception of how cancer affected me psychologically is a different story. I know and trust that I am in the capable and knowledgeable hands of my doctor.

While the experience of good health care is remarkable, living with cancer does not end with medical care. I am blessed to have a partner who loves me infinitely. I cannot imagine my life without her.

I am grateful my cancer has allowed me to remain alive. The prospect of death does not shake me. I plan on living my life to the fullest.

Oncologist Perspective

Yes, men do get breast cancer! Unlike female breast cancer (FBC), male breast cancer (MBC) makes up about 1% of all cases in the U.S. The lifetime risk of a man developing breast cancer is about 1 in 1,000 vs 1 in 8 women.¹ Little is known about MBC because its rarity renders prospective randomized trials problematic. As a result, the management of breast cancer in males from diagnosis to treatment is based on research on FBC. Patients with MBC have higher mortality, and the incidence is rising 1.1% per year; by comparison both trends are decreasing for females with breast cancer.^2,3

Males are usually older and present with an advanced stage of the disease at the time of the diagnosis. Most MBC is ER+/PR+ and HER2−.⁴ Comparison data of 1,123 male veterans with 5,320 females revealed that the mean age at diagnosis was 70 years for MBC and 57 years for FBC, respectively (P < .01); 95% of patients with MBC and 72% of patients with FBC were aged > 50 years (P < .01). Patients with MBC were more likely to present with stage III or IV disease (40% vs 24%, respectively). Eighty percent of patients with MBC had ER+/PR+ tumors. Mortality was 31.6% in males vs 14.9% in females.

Given the high prevalence of ER/PR positivity, MBC usually is considered to have a better prognosis, but that does not explain the high mortality. Unlike FBC, delay in diagnosis due to lack of MBC awareness and no screening guidelines for MBC, older age at diagnosis, and comorbidities have been considered the etiology of higher mortality in MBC, but there has to be more than that. I believe that the differences in MBC biology and pathology also have to be contributing factors to MBC mortality.

As a VA oncologist, I have treated a number of patients with MBC. Surprisingly, my experience treating these patients has been different from treating FBC. In 2011, when I first met Mr. Lewis, he laughed and questioned his diagnosis—how could he have breast cancer if males don’t have breasts, and none of his family member had any type of cancer. Prior to his cancer diagnoses, he had gone through multiple cardiac stents and had a history of hypertriglyceridemia. His cancer workup and treatment plan were the same as that of females with breast cancer, and he questioned me again, “Why am I being treated like a female breast cancer patient?”

Unlike females with breast cancer, he had to have a complete mastectomy given the small breast tissue. His final diagnosis was stage IIA invasive ductal carcinoma of the left breast.

Because of Mr. Lewis’ cardiac history and recent stent placement, I was hesitant to give him first-line adjuvant anthracycline. The Oncotype DX test is highly recommended and easily done for FBC, but I had to go through great difficulty to order this test for him. The Oncotype Dx RS score for him was 17 (a so-called low score) with distant recurrence risk of 11%. I interpreted the test the same way as I would for a patient with FBC. We were happy that he did not have to be exposed to toxic chemotherapies.

Because of the lack of data for aromatase inhibitors (AIs) use in males, adjuvant tamoxifen was given but had to be stopped after a month because of hypertriglyceridemia > 8,000 mg/dL and cholesterol > 700 mg/dL. Tamoxifen as well as an AI was deemed not to be the right adjuvant treatment for him. There were no data on adjuvant fulvestrant; not even for females in 2012. Mr. Lewis was among the unlucky 11% and presented with stage IV disease in his lungs and bones 4 years after the initial diagnosis. He has not had a great response to taxanes and now is being treated with fulvestrant. He remains positive and hopeful, he told me only God—not medical science—has the power to take back the gift of life.

My experience with Mr. Lewis and others has underscored that MBC is not the same disease as FBC. I am hopeful we will see more clinical trials to further identify MBC biology and genomics.

Click here to read the digital edition.

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

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

Patient Perspective

Breast cancer has been one of my life’s greatest blessings. Its highs and lows, prospects, and disappointments have only strengthened my faith and turned me more to God.

In March 2012, I had a bad cold, and while I was coughing and grabbing my chest, I discovered a small knot in my left breast, and for whatever reason, I suspected it was cancer. I immediately woke my wife. She, groggy and in usual humor exclaimed, “Oh great! You have breast cancer! Well guess what? I have prostate cancer…now go back to sleep!” I laughed at the prospect of her having prostate cancer. It certainly would’ve changed a few dynamics in our relationship.

Two weeks later my fears were confirmed. I was told that I needed to have a mastectomy of my left breast. I wanted nothing but to have this poison removed. Yesterday would not have been too soon.

My surgery was scheduled a month later; it was a long wait. And it soon became clear that as I recovered from the impending mastectomy, I also would be in line for open-heart surgery.

The mastectomy was a textbook procedure with no complications. My surgeon apprehensively warned me that follow-up visits would be at the Women’s Health Center. I must admit, it was awkward every time I went. Realistically though, I cared more about my health than about others’ perceptions.

While I prepared for my cardiac surgery, the blood test revealed triglyceride levels that were through the roof. In fact, the cardiac surgeon described them as “industrial strength.” After an exhaustive review, it was determined that my adjuvant therapy with tamoxifen was the culprit! I immediately stopped taking it, and within days my levels returned to normal. I was now left to fight any future bouts of cancer with just my body’s own defenses.

It probably seems strange, but if I had not found the breast lump, the problems with my heart would have gone undetected. I most likely would’ve died. Had the cancer not been a part of my life, I wouldn’t have been able to keep on living.

In the middle of March 2016, during preliminary testing for surgery to remove a skin tag, my chest X-ray displayed abnormalities. The workup showed that my breast cancer had returned. Worse yet, it had metastasized to my lungs. It had gone into my lymph nodes and lower spine.

The fight was on. A treatment plan was outlined; 12 weeks of chemotherapy infusions was a reasonable plan of attack. A second opinion was not necessarily an opportunity to find a differing plan, but as in my case, it was comforting affirmation of a good plan. I remember wondering if the rest of my life was going to be a mix of hospital visits, blood transfusions, chemotherapies, and injections.

While fear of the unknown works on one’s psyche, I made a decision to focus on my faith and God. My cancer experiences are probably no worse or different from the experiences of most other patients. I do believe that my perception of how cancer affected me psychologically is a different story. I know and trust that I am in the capable and knowledgeable hands of my doctor.

While the experience of good health care is remarkable, living with cancer does not end with medical care. I am blessed to have a partner who loves me infinitely. I cannot imagine my life without her.

I am grateful my cancer has allowed me to remain alive. The prospect of death does not shake me. I plan on living my life to the fullest.

Oncologist Perspective

Yes, men do get breast cancer! Unlike female breast cancer (FBC), male breast cancer (MBC) makes up about 1% of all cases in the U.S. The lifetime risk of a man developing breast cancer is about 1 in 1,000 vs 1 in 8 women.¹ Little is known about MBC because its rarity renders prospective randomized trials problematic. As a result, the management of breast cancer in males from diagnosis to treatment is based on research on FBC. Patients with MBC have higher mortality, and the incidence is rising 1.1% per year; by comparison both trends are decreasing for females with breast cancer.^2,3

Males are usually older and present with an advanced stage of the disease at the time of the diagnosis. Most MBC is ER+/PR+ and HER2−.⁴ Comparison data of 1,123 male veterans with 5,320 females revealed that the mean age at diagnosis was 70 years for MBC and 57 years for FBC, respectively (P < .01); 95% of patients with MBC and 72% of patients with FBC were aged > 50 years (P < .01). Patients with MBC were more likely to present with stage III or IV disease (40% vs 24%, respectively). Eighty percent of patients with MBC had ER+/PR+ tumors. Mortality was 31.6% in males vs 14.9% in females.

Given the high prevalence of ER/PR positivity, MBC usually is considered to have a better prognosis, but that does not explain the high mortality. Unlike FBC, delay in diagnosis due to lack of MBC awareness and no screening guidelines for MBC, older age at diagnosis, and comorbidities have been considered the etiology of higher mortality in MBC, but there has to be more than that. I believe that the differences in MBC biology and pathology also have to be contributing factors to MBC mortality.

As a VA oncologist, I have treated a number of patients with MBC. Surprisingly, my experience treating these patients has been different from treating FBC. In 2011, when I first met Mr. Lewis, he laughed and questioned his diagnosis—how could he have breast cancer if males don’t have breasts, and none of his family member had any type of cancer. Prior to his cancer diagnoses, he had gone through multiple cardiac stents and had a history of hypertriglyceridemia. His cancer workup and treatment plan were the same as that of females with breast cancer, and he questioned me again, “Why am I being treated like a female breast cancer patient?”

Unlike females with breast cancer, he had to have a complete mastectomy given the small breast tissue. His final diagnosis was stage IIA invasive ductal carcinoma of the left breast.

Because of Mr. Lewis’ cardiac history and recent stent placement, I was hesitant to give him first-line adjuvant anthracycline. The Oncotype DX test is highly recommended and easily done for FBC, but I had to go through great difficulty to order this test for him. The Oncotype Dx RS score for him was 17 (a so-called low score) with distant recurrence risk of 11%. I interpreted the test the same way as I would for a patient with FBC. We were happy that he did not have to be exposed to toxic chemotherapies.

Because of the lack of data for aromatase inhibitors (AIs) use in males, adjuvant tamoxifen was given but had to be stopped after a month because of hypertriglyceridemia > 8,000 mg/dL and cholesterol > 700 mg/dL. Tamoxifen as well as an AI was deemed not to be the right adjuvant treatment for him. There were no data on adjuvant fulvestrant; not even for females in 2012. Mr. Lewis was among the unlucky 11% and presented with stage IV disease in his lungs and bones 4 years after the initial diagnosis. He has not had a great response to taxanes and now is being treated with fulvestrant. He remains positive and hopeful, he told me only God—not medical science—has the power to take back the gift of life.

My experience with Mr. Lewis and others has underscored that MBC is not the same disease as FBC. I am hopeful we will see more clinical trials to further identify MBC biology and genomics.

Click here to read the digital edition.

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

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

The following is a lightly edited transcript of a teleconference discussion recorded in April 2018.

Suman Kambhampati, MD. Immuno-oncology is a paradigm-shifting treatment approach. It is an easy-to-understand term for both providers and for patients. The underlying principle is that the body’s own immune system is used or stimulated to fight cancer, and there are drugs that clearly have shown huge promise for this, not only in oncology, but also for other diseases. Time will tell whether that really pans out or not, but to begin with, the emphasis has been inoncology, and therefore, the term immunooncology is fitting.

Dr. Kaster. It was encouraging at first, especially when ipilimumab came out, to see the effects on patients with melanoma. Then the KEYNOTE-024 trial came out, and we were able to jump in anduse monoclonal antibodies directed against programmed death 1 (PD-1) in the first line, which is when things got exciting.¹ We have a smaller populationin Boise, so PD-1s in lung cancer have had the biggest impact on our patients so far.

Ellen Nason, RN, MSN. Patients are open to immunotherapies.They’re excited about it. And as the other panelists have said, you can start broadly, as the body fights the cancer on its own, to providing more specific details as a patient wants more information. Immuno-oncology is definitely accepted by patients, and they’re very excited about it, especially with all the news about new therapies.

Dr. Kambhampati. For the Department of Veteran Affairs (VA) population, lung cancer has seen significant impact, and now it’s translating into other diseases through more research, trials, and better understanding about how these drugs are used and work. 

The paradigm is shifting toward offering these drugs not only in metastatic cancers, but also in the surgically resectable tumors. The 2018 American Association for Cancer Research (AACR) meeting, just concluded. At the meeting several abstracts reported instances where immunooncology drugs are being introduced in the early phases of lung cancer and showing outstanding results. It’s very much possible that we’re going to see less use of traditional chemotherapy in the near future.

Ms. Nason. I primarily work with solid tumors,and the majority of the population I work with have lung cancer. So we’re excited about some of the results that we’ve seen and the lower toxicity involved. Recently, we’ve begun using durvalumab with patients with stage III disease. We have about 5 people now that are using it as a maintenance or consolidative treatment vs just using it for patients with stage IV disease. Hopefully, we’ll see some of the same results describedin the paper published on it.²

Dr. Kaster. Yes, we are incorporating these new changes into care as they're coming out. As Ms. Nason mentioned, we're already using immunotherapies in earlier settings, and we are seeing as much research that could be translated into care soon, like combining immunotherapies
in first-line settings, as we see in the Checkmate-227 study with nivolumab and ipilimumab.^3,4 The landscape is going to change dramatically in the next couple of years.

Accessing Testing For First-Line Treatments

Dr. Lynch. There has been an ongoing discussionin the literature on accessing appropriate testing—delays in testing can result in patients who are not able to access the best targeted drugs on a first-line basis. The drug companiesand the VA have become highly sensitized to ensuring that veterans are accessing the appropriate testing. We are expanding the capability of VA labs to do that testing.

Ms. Nason. I want to put in a plug for the VA Precision Oncology Program (POP). It’s about 2 years into its existence, and Neil Spector, MD, is the director. The POP pays for sequencing the tumor samples.

A new sequencing contract will go into effect October 2018 and will include sequencing for hematologic malignancies in addition to the current testing of solid tumors. Patients from New York who have been unable to receive testing through the current vendors used by POP, will be included in the new contract. It is important to note that POP is working closely with the National Pharmacy Benefit Management Service (PBM) to develop a policy for approving off-label use of US Food and Drug Administration-approved targeted therapies based on sequenced data collected on patients tested through POP.

In addition, the leadership of POP is working to leverage the molecular testing results conducted through POP to improve veterans' access to clinical trials, both inside and outside the VA. Within the VA people can access information at tinyurl.com/precisiononcology. There is no reason why any eligible patient with cancer in the VA health care system should not have their tumor tissue sequenced through POP, particularly once the new contract goes into effect.

Dr. Lynch. Fortunately, the cost of next-generation sequencing has come down so much that most VA contracted reference laboratories offer next-generation sequencing, including LabCorp (Burlington,NC), Quest Diagnostics (Secaucus, NJ), Fulgent (Temple City, CA), and academic partners such as Oregon Health Sciences University and University of Washington.

Ms. Nason. At the Durham VAMC, sometimes a lack of tissue has been a barrier, but we now have the ability to send blood (liquid biopsy) for next-generation sequencing. Hopefully that will open up options for veterans with inadequate tissue. Importantly, all VA facilities can request liquid biopsiesthrough POP.

Dr. Lynch. That’s an important point. There have been huge advances in liquid biopsy testing.The VA Salt Lake City Health Care System (VASLCHCS) was in talks with Genomic Health (Redwood City, CA) to do a study as part of clinical operations to look at the concordance between the liquid biopsy testing and the precision oncology data. But Genomic Health eventually abandoned its liquid biopsy testing. Currently, the VA is only reimbursing or encouraging liquid biopsy if the tissue is not available or if the veteran has too high a level of comorbidities to undergo tissue biopsy. The main point for the discussion today is that access to testing is a key component of access to all of these advanced drugs.

Dr. Kambhampati. The precision medicine piece will be a game changer—no question about that. Liquid biopsy is very timely. Many patients have difficulty getting rebiopsied, so liquid biopsy is definitely a big, big step forward.

Still, there has not been consistency across the VA as there should be. Perhaps there are a few select centers, including our site in Kansas City, where access to precision medicine is readily available and liquid biopsies are available. We use the PlasmaSELECT test from Personal Genome Diagnostics (Baltimore, MD). We have just added Foundation Medicine (Cambridge, MA) also in hematology. Access to mutational profilingis absolutely a must for precision medicine.

All that being said, the unique issue with immuno-oncology is that it pretty much transcends the mutational profile and perhaps has leveled the playing field, irrespective of the tumor mutation profile or burden. In some solid tumors these immuno-oncology drugs have been shown to work across tumor types and across different mutation types. And there is a hint now in the recent data presented at AACR and in the New England Journalof Medicine showing that the tumor mutational burden is a predictor of pathologic response to at least PD-1 blockade in the resectable stages of lung cancer.^1,3 To me, that’s a very important piece of data because that’s something that can be tested and can have a prognostic impact in immuno-oncology, particularly in the early stages of lung cancer and is further proof of the broad value of immunotherapics in targeting tumors irrespective of the precise tumor targets.

Dr. Kaster. Yes, it’s nice to see other options like tumor mutational burden and Lung Immune Prognostic Index being studied.5 It would be nice if we could rely a little more on these, and not PD-L1, which as we all know is a variable and an unreliable target.

Dr. Kambhampati. I agree.

Rural Challenges In A Veterans Population

Dr. Lynch. Providing high-quality cancer care to rural veterans care can be a challenge but it is a VA priority. The VA National Genomic Medicine Services offers better access for rural veterans to germline genetic testing than any other healthcare system in the country. In terms of access to somatic testing and next-generation sequencing, we are working toward providing the same level of cancer care as patients would receive at National Cancer Institute (NCI) cancer centers. The VA oncology leadership has done teleconsults and virtual tumor boards, but for some rural VAMCs, fellowsare leading the clinical care. As we expand use of oral agents for oncology treatment, it will be easier to ensure that rural veterans receive the same standard of care for POP that veterans being cared for at VASLCHCS, Kansas City VAMC, or Durham VAMC get.

Dr. Kambhampati. The Kansas City VAMC in its catchment area includes underserved areas, such as Topeka and Leavenworth, Kansas. What we’ve been able to do here is something that’s unique—Kansas City VAMC is the only standalone VA in the country to be recognized as a primary SWOG (Southwestern Oncology Group) institution, which provides access to many trials, such as the Lung-MAP trial and others. And that has allowed us to use the full expanse of precision medicine without financial barriers. The research has helped us improve the standard of
care for patients across VISN 15.

Dr. Lynch. In precision oncology, the chief of pathology is an important figure in access to advanced care. I’ve worked with Sharad Mathur,MD, of the Kansas City VAMC on many clinical trials. He’s on the Kansas City VAMC Institutional Review Board and the cancer committee and is tuned in to veterans’ access to precision oncology. Kansas City was ordering Foundation One for select patients that met the criteria probably sooner than any other VA and participated in NCI Cooperative Group clinical trials. It is a great example of how veterans are getting access to
the same level of care as are patients who gettreated at NCI partners.

Comorbidities

Dr. Kambhampati. I don’t treat a lot of patients with lung cancer, but I find it easier to use these immuno-oncology drugs than platinums and etoposide. I consider them absolutely nasty chemotherapy drugs now in this era of immuno-oncology and targeted therapy.

Dr. Lynch. The VA is very important in translational lung cancer research and clinical care. It used to be thought that African American patients don’t get epidermal growth factor receptor mutations. And that’s because not enough African American patients with lung cancer were included in the NCI-based clinical trial.There are7,000 veterans who get lung cancer each year, and 20% to 25% of those are African Americans. Prevalence of various mutations and the pharmacogenetics of some of these drugs differ by patient ancestry. Including veterans with lung
cancer in precision oncology clinical trials and clinical care is not just a priority for the VA but a priority for NCI and internationally. I can’t emphasize this enough—veterans with lung cancer should be included in these studies and should be getting the same level of care that our partners are getting at NCI cancer centers. In the VA we’re positioned to do this because of our nationalelectronic health record (EHR) and becauseof our ability to identify patients with specific variants and enroll them in clinical trials.

Ms. Nason. One of the barriers that I find withsome of the patients that I have treated is getting them to a trial. If the trial isn’t available locally, specifically there are socioeconomic and distance issues that are hard to overcome.

Dr. Kaster. For smaller medical centers, getting patients to clinical trials can be difficult. The Boise VAMC is putting together a proposal now to justify hiring a research pharmacist in order to get trials atour site. The goal is to offer trial participation to our patients who otherwise might not be able to participate while offsetting some of the costs of immunotherapy. We are trying to make what could be a negative into a positive.

Measuring Success

Dr. Kambhampati. Unfortunately, we do not have any calculators to incorporate the quality of lives saved to the society. I know there are clearmetrics in transplant and in hematology, but unfortunately, there are no established metrics in solid tumor treatment that allow us to predict the cost savings to the health care system or to society or the benefit to the society. I don’t use any such predictive models or metrics in my decision making. These decisions are made based on existing evidence, and the existing evidence overwhelmingly supports use of immuno-oncology in certain types of solid tumors and in a select group of hematologic malignancies.

Dr. Kaster. This is where you can get more bang for your buck with an oncology pharmacist these days. A pharmacist can make a minor dosing change that will allow the same benefit for the patient, but could equal tens of thousands of dollars in cost-benefit for the VA. They can also be the second set of eyes when adjudicating a nonformulary request to ensure that a patient will benefit.

Dr. Lynch. Inappropriate prescribing is far more expensive than appropriate treatment. And the care for veterans whose long-term health outcomes could be improved by the new immunotherapies. It’s cheaper for veterans to be healthy and live longer than it is to take care of them in
their last 6 weeks of life. Unfortunately, there are not a lot of studies that have demonstrated that empirically, but I think it’s important to do those studies.

Role of Pharmacists

Dr. Lynch. I was at a meeting recently talking about how to improve veteran access to clinical trials. Francesca Cunningham, PharmD, director of the VA Center for Medication Safety of the VA Pharmacy Benefit Management Service (PBM) described the commitment that pharmacy has in taking a leadership role in the integration of precision medicine. Linking veterans’ tumor mutation status and pharmacogenetic variants to pharmacy databases is the best way to ensure treatment is informed by genetics. We have to be realistic about what we’re asking community oncologists to do. With the onset of precision oncology, 10 cancers have become really 100 cancers. In the prior model of care, it was the oncologist, maybe in collaboration with a pathologist, but it was mostly oncologists who determined care.

And in the evolution of precision oncology, Ithink that it’s become an interdisciplinary adventure. Pharmacy is going to play an increasinglyimportant role in precision medicine around all of the molecular alterations, even immuno-oncology regardless of molecular status in which the VA has an advantage. We’re not talking about some community pharmacist. We’re talking about a national health care system where there’s a national EHR, where there’s national PBM systems. So my thoughts on this aspect is that it’s an intricate multidisciplinary team who can ensure that veteran sget the best care possible: the best most cost-effective care possible.

Dr. Kaster. As an oncology pharmacist, I have to second that.

Ms. Nason. As Dr. Kaster said earlier, having a dedicated oncology pharmacist is tremendouslybeneficial. The oncology/hematology pharmacists are following the patients closely and notice when dose adjustments need to be made, optimizing the drug benefit and providing additional safety. Not to mention the cost benefit that can be realized with appropriate adjustment and the expertise they bring to managing possible interactionsand pharmacodynamics.

Dr. Kambhampati. To brag about the Kansas City VAMC program, we have published in Federal Practitioner our best practices showing the collaboration between a pharmacist and providers^.6 And we have used several examples of cost savings, which have basically helped us build the research program, and several examples of dual monitoring oral chemotherapy monitoring. And we have created these templates within the EHR that allow everyone to get a quick snapshot of where things are, what needs to be done, and what needs to be monitored.

Now, we are taking it a step further to determine when to stop chemotherapy or when to stop treatments. For example, for chronic myeloid leukemia (CML), there are good data onstopping tyrosine kinase inhibitors.⁷ And that alone, if implemented across the VA, could bring
in huge cost savings, which perhaps could be put into investments in immuno-oncology or other efforts. We have several examples here that we have published, and we continue to increaseand strengthen our collaboration withour oncology pharmacist. We are very lucky and privileged to have a dedicated oncology pharmacistfor clinics and for research.

Dr. Lynch. The example of CML is perfect, because precision oncology has increased the complexity of care substantially. The VA is wellpositioned to be a leader in this area when care becomes this complex because of its ability to measure access to testing, to translate the results
of testing to pharmacy, to have pharmacists take the lead on prescribing, to have pathologists take the lead on molecular alterations, and to have oncologists take the lead on delivering the cancer care to the patients.

With hematologic malignancies, adherence in the early stages can result in patients getting offcare sooner, which is cost savings. But that requires access to testing, monitoring that testing, and working in partnership with pharmacy. This is a great story about how the VA is positioned to lead in this area of care.

Dr. Kaster. I would like to put a plug in for advanced practice providers and the use of nurse practitioners (NPs) and physician assistants (PAs).The VA is well positioned because it often has established interdisciplinary teams with these providers, pharmacy, nursing, and often social work, to coordinate the care and manage symptoms outside of oncologist visits.

Dr. Lynch. In the NCI cancer center model, once the patient has become stable, the ongoing careis designated to the NP or PA. Then as soon as there’s a change and it requires reevaluation, the oncologist becomes involved again. That pointabout the oncology treatment team is totally in line
with some of the previous comments.

Areas For Further Investigation

Dr. Kaster. There are so many nuances that we’re finding out all of the time about immunotherapies. A recent study brought up the role of antibiotics in the 30 or possibly 60 days prior to immunotherapy.³ How does that change treatment? Which patients are more likely to benefit from immunotherapies, and which are susceptible to “hyperprogression”? How do we integrate palliative care discussions into the carenow that patients are feeling better on treatment and may be less likely to want to discuss palliative care?

Ms. Nason. I absolutely agree with that, especially keeping palliative care integrated within our services. Our focus is now a little different, in thatwe have more optimistic outcomes in mind, butthere still are symptoms and issues where our colleaguesin palliative care are invaluable.

Dr. Lynch. I third that motion. What I would really like to see come out of this discussion is how veterans are getting access to leading oncology care. We just published an analysis of Medicare data and access to EGFR testing. The result of that analysis showed that testing in the VA was consistent with testing in Medicare.

For palliative care, I think the VA does a better job. And it’s just so discouraging as VA employees and as clinicians treating veterans to see publicationsthat suggest that veterans are getting a lower quality of care and that they would be better if care was privatized or outsourced. It’s just fundamentally not the case.

In CML, we see it. We’ve analyzed the data, in that there’s a far lower number of patients with CML who are included in the registry because patients who are diagnosed outside the VA are incorporated in other cancer registries^.8 But as soon as their copays increase for access to targeted drugs, they immediately activate their VA benefits so that theycan get their drugs at the VA. For hematologic malignancies that are diagnosed outside the VA and are captured in other cancer registries, as soon as the drugs become expensive, they start getting their care in the VA. I don’t think there’s beena lot of empirical research that’s shown this, but we have the data to illustrate this trend. I hope thatthere are more publications that show that veterans with cancer are getting really good care inside the VA in the existing VA health care system.

Ms. Nason. It is disheartening to see negativepublicity, knowing that I work with colleagues who are strongly committed to providing up-to-date and relevant oncology care.

Dr. Lynch. As we record this conversation, I am in Rotterdam, Netherlands, in a meeting about genomewide testing. In hematologic malignancies, prostate cancer, and breast cancer, it’s a huge issue. And that is the other area that MVP (Million Veteran Program) is leading the way with the MVP biorepository data. Frankly, there’s no other biorepository that has this many patients, that has so many African Americans, and that has such rich EHR data. So inthat other area, the VA is doing really well.

The following is a lightly edited transcript of a teleconference discussion recorded in April 2018.

Suman Kambhampati, MD. Immuno-oncology is a paradigm-shifting treatment approach. It is an easy-to-understand term for both providers and for patients. The underlying principle is that the body’s own immune system is used or stimulated to fight cancer, and there are drugs that clearly have shown huge promise for this, not only in oncology, but also for other diseases. Time will tell whether that really pans out or not, but to begin with, the emphasis has been inoncology, and therefore, the term immunooncology is fitting.

Dr. Kaster. It was encouraging at first, especially when ipilimumab came out, to see the effects on patients with melanoma. Then the KEYNOTE-024 trial came out, and we were able to jump in anduse monoclonal antibodies directed against programmed death 1 (PD-1) in the first line, which is when things got exciting.¹ We have a smaller populationin Boise, so PD-1s in lung cancer have had the biggest impact on our patients so far.

Ellen Nason, RN, MSN. Patients are open to immunotherapies.They’re excited about it. And as the other panelists have said, you can start broadly, as the body fights the cancer on its own, to providing more specific details as a patient wants more information. Immuno-oncology is definitely accepted by patients, and they’re very excited about it, especially with all the news about new therapies.

Dr. Kambhampati. For the Department of Veteran Affairs (VA) population, lung cancer has seen significant impact, and now it’s translating into other diseases through more research, trials, and better understanding about how these drugs are used and work. 

The paradigm is shifting toward offering these drugs not only in metastatic cancers, but also in the surgically resectable tumors. The 2018 American Association for Cancer Research (AACR) meeting, just concluded. At the meeting several abstracts reported instances where immunooncology drugs are being introduced in the early phases of lung cancer and showing outstanding results. It’s very much possible that we’re going to see less use of traditional chemotherapy in the near future.

Ms. Nason. I primarily work with solid tumors,and the majority of the population I work with have lung cancer. So we’re excited about some of the results that we’ve seen and the lower toxicity involved. Recently, we’ve begun using durvalumab with patients with stage III disease. We have about 5 people now that are using it as a maintenance or consolidative treatment vs just using it for patients with stage IV disease. Hopefully, we’ll see some of the same results describedin the paper published on it.²

Dr. Kaster. Yes, we are incorporating these new changes into care as they're coming out. As Ms. Nason mentioned, we're already using immunotherapies in earlier settings, and we are seeing as much research that could be translated into care soon, like combining immunotherapies
in first-line settings, as we see in the Checkmate-227 study with nivolumab and ipilimumab.^3,4 The landscape is going to change dramatically in the next couple of years.

Accessing Testing For First-Line Treatments

Dr. Lynch. There has been an ongoing discussionin the literature on accessing appropriate testing—delays in testing can result in patients who are not able to access the best targeted drugs on a first-line basis. The drug companiesand the VA have become highly sensitized to ensuring that veterans are accessing the appropriate testing. We are expanding the capability of VA labs to do that testing.

Ms. Nason. I want to put in a plug for the VA Precision Oncology Program (POP). It’s about 2 years into its existence, and Neil Spector, MD, is the director. The POP pays for sequencing the tumor samples.

A new sequencing contract will go into effect October 2018 and will include sequencing for hematologic malignancies in addition to the current testing of solid tumors. Patients from New York who have been unable to receive testing through the current vendors used by POP, will be included in the new contract. It is important to note that POP is working closely with the National Pharmacy Benefit Management Service (PBM) to develop a policy for approving off-label use of US Food and Drug Administration-approved targeted therapies based on sequenced data collected on patients tested through POP.

In addition, the leadership of POP is working to leverage the molecular testing results conducted through POP to improve veterans' access to clinical trials, both inside and outside the VA. Within the VA people can access information at tinyurl.com/precisiononcology. There is no reason why any eligible patient with cancer in the VA health care system should not have their tumor tissue sequenced through POP, particularly once the new contract goes into effect.

Dr. Lynch. Fortunately, the cost of next-generation sequencing has come down so much that most VA contracted reference laboratories offer next-generation sequencing, including LabCorp (Burlington,NC), Quest Diagnostics (Secaucus, NJ), Fulgent (Temple City, CA), and academic partners such as Oregon Health Sciences University and University of Washington.

Ms. Nason. At the Durham VAMC, sometimes a lack of tissue has been a barrier, but we now have the ability to send blood (liquid biopsy) for next-generation sequencing. Hopefully that will open up options for veterans with inadequate tissue. Importantly, all VA facilities can request liquid biopsiesthrough POP.

Dr. Lynch. That’s an important point. There have been huge advances in liquid biopsy testing.The VA Salt Lake City Health Care System (VASLCHCS) was in talks with Genomic Health (Redwood City, CA) to do a study as part of clinical operations to look at the concordance between the liquid biopsy testing and the precision oncology data. But Genomic Health eventually abandoned its liquid biopsy testing. Currently, the VA is only reimbursing or encouraging liquid biopsy if the tissue is not available or if the veteran has too high a level of comorbidities to undergo tissue biopsy. The main point for the discussion today is that access to testing is a key component of access to all of these advanced drugs.

Dr. Kambhampati. The precision medicine piece will be a game changer—no question about that. Liquid biopsy is very timely. Many patients have difficulty getting rebiopsied, so liquid biopsy is definitely a big, big step forward.

Still, there has not been consistency across the VA as there should be. Perhaps there are a few select centers, including our site in Kansas City, where access to precision medicine is readily available and liquid biopsies are available. We use the PlasmaSELECT test from Personal Genome Diagnostics (Baltimore, MD). We have just added Foundation Medicine (Cambridge, MA) also in hematology. Access to mutational profilingis absolutely a must for precision medicine.

All that being said, the unique issue with immuno-oncology is that it pretty much transcends the mutational profile and perhaps has leveled the playing field, irrespective of the tumor mutation profile or burden. In some solid tumors these immuno-oncology drugs have been shown to work across tumor types and across different mutation types. And there is a hint now in the recent data presented at AACR and in the New England Journalof Medicine showing that the tumor mutational burden is a predictor of pathologic response to at least PD-1 blockade in the resectable stages of lung cancer.^1,3 To me, that’s a very important piece of data because that’s something that can be tested and can have a prognostic impact in immuno-oncology, particularly in the early stages of lung cancer and is further proof of the broad value of immunotherapics in targeting tumors irrespective of the precise tumor targets.

Dr. Kaster. Yes, it’s nice to see other options like tumor mutational burden and Lung Immune Prognostic Index being studied.5 It would be nice if we could rely a little more on these, and not PD-L1, which as we all know is a variable and an unreliable target.

Dr. Kambhampati. I agree.

Rural Challenges In A Veterans Population

Dr. Lynch. Providing high-quality cancer care to rural veterans care can be a challenge but it is a VA priority. The VA National Genomic Medicine Services offers better access for rural veterans to germline genetic testing than any other healthcare system in the country. In terms of access to somatic testing and next-generation sequencing, we are working toward providing the same level of cancer care as patients would receive at National Cancer Institute (NCI) cancer centers. The VA oncology leadership has done teleconsults and virtual tumor boards, but for some rural VAMCs, fellowsare leading the clinical care. As we expand use of oral agents for oncology treatment, it will be easier to ensure that rural veterans receive the same standard of care for POP that veterans being cared for at VASLCHCS, Kansas City VAMC, or Durham VAMC get.

Dr. Kambhampati. The Kansas City VAMC in its catchment area includes underserved areas, such as Topeka and Leavenworth, Kansas. What we’ve been able to do here is something that’s unique—Kansas City VAMC is the only standalone VA in the country to be recognized as a primary SWOG (Southwestern Oncology Group) institution, which provides access to many trials, such as the Lung-MAP trial and others. And that has allowed us to use the full expanse of precision medicine without financial barriers. The research has helped us improve the standard of
care for patients across VISN 15.

Dr. Lynch. In precision oncology, the chief of pathology is an important figure in access to advanced care. I’ve worked with Sharad Mathur,MD, of the Kansas City VAMC on many clinical trials. He’s on the Kansas City VAMC Institutional Review Board and the cancer committee and is tuned in to veterans’ access to precision oncology. Kansas City was ordering Foundation One for select patients that met the criteria probably sooner than any other VA and participated in NCI Cooperative Group clinical trials. It is a great example of how veterans are getting access to
the same level of care as are patients who gettreated at NCI partners.

Comorbidities

Dr. Kambhampati. I don’t treat a lot of patients with lung cancer, but I find it easier to use these immuno-oncology drugs than platinums and etoposide. I consider them absolutely nasty chemotherapy drugs now in this era of immuno-oncology and targeted therapy.

Dr. Lynch. The VA is very important in translational lung cancer research and clinical care. It used to be thought that African American patients don’t get epidermal growth factor receptor mutations. And that’s because not enough African American patients with lung cancer were included in the NCI-based clinical trial.There are7,000 veterans who get lung cancer each year, and 20% to 25% of those are African Americans. Prevalence of various mutations and the pharmacogenetics of some of these drugs differ by patient ancestry. Including veterans with lung
cancer in precision oncology clinical trials and clinical care is not just a priority for the VA but a priority for NCI and internationally. I can’t emphasize this enough—veterans with lung cancer should be included in these studies and should be getting the same level of care that our partners are getting at NCI cancer centers. In the VA we’re positioned to do this because of our nationalelectronic health record (EHR) and becauseof our ability to identify patients with specific variants and enroll them in clinical trials.

Ms. Nason. One of the barriers that I find withsome of the patients that I have treated is getting them to a trial. If the trial isn’t available locally, specifically there are socioeconomic and distance issues that are hard to overcome.

Dr. Kaster. For smaller medical centers, getting patients to clinical trials can be difficult. The Boise VAMC is putting together a proposal now to justify hiring a research pharmacist in order to get trials atour site. The goal is to offer trial participation to our patients who otherwise might not be able to participate while offsetting some of the costs of immunotherapy. We are trying to make what could be a negative into a positive.

Measuring Success

Dr. Kambhampati. Unfortunately, we do not have any calculators to incorporate the quality of lives saved to the society. I know there are clearmetrics in transplant and in hematology, but unfortunately, there are no established metrics in solid tumor treatment that allow us to predict the cost savings to the health care system or to society or the benefit to the society. I don’t use any such predictive models or metrics in my decision making. These decisions are made based on existing evidence, and the existing evidence overwhelmingly supports use of immuno-oncology in certain types of solid tumors and in a select group of hematologic malignancies.

Dr. Kaster. This is where you can get more bang for your buck with an oncology pharmacist these days. A pharmacist can make a minor dosing change that will allow the same benefit for the patient, but could equal tens of thousands of dollars in cost-benefit for the VA. They can also be the second set of eyes when adjudicating a nonformulary request to ensure that a patient will benefit.

Dr. Lynch. Inappropriate prescribing is far more expensive than appropriate treatment. And the care for veterans whose long-term health outcomes could be improved by the new immunotherapies. It’s cheaper for veterans to be healthy and live longer than it is to take care of them in
their last 6 weeks of life. Unfortunately, there are not a lot of studies that have demonstrated that empirically, but I think it’s important to do those studies.

Role of Pharmacists

Dr. Lynch. I was at a meeting recently talking about how to improve veteran access to clinical trials. Francesca Cunningham, PharmD, director of the VA Center for Medication Safety of the VA Pharmacy Benefit Management Service (PBM) described the commitment that pharmacy has in taking a leadership role in the integration of precision medicine. Linking veterans’ tumor mutation status and pharmacogenetic variants to pharmacy databases is the best way to ensure treatment is informed by genetics. We have to be realistic about what we’re asking community oncologists to do. With the onset of precision oncology, 10 cancers have become really 100 cancers. In the prior model of care, it was the oncologist, maybe in collaboration with a pathologist, but it was mostly oncologists who determined care.

And in the evolution of precision oncology, Ithink that it’s become an interdisciplinary adventure. Pharmacy is going to play an increasinglyimportant role in precision medicine around all of the molecular alterations, even immuno-oncology regardless of molecular status in which the VA has an advantage. We’re not talking about some community pharmacist. We’re talking about a national health care system where there’s a national EHR, where there’s national PBM systems. So my thoughts on this aspect is that it’s an intricate multidisciplinary team who can ensure that veteran sget the best care possible: the best most cost-effective care possible.

Dr. Kaster. As an oncology pharmacist, I have to second that.

Ms. Nason. As Dr. Kaster said earlier, having a dedicated oncology pharmacist is tremendouslybeneficial. The oncology/hematology pharmacists are following the patients closely and notice when dose adjustments need to be made, optimizing the drug benefit and providing additional safety. Not to mention the cost benefit that can be realized with appropriate adjustment and the expertise they bring to managing possible interactionsand pharmacodynamics.

Dr. Kambhampati. To brag about the Kansas City VAMC program, we have published in Federal Practitioner our best practices showing the collaboration between a pharmacist and providers^.6 And we have used several examples of cost savings, which have basically helped us build the research program, and several examples of dual monitoring oral chemotherapy monitoring. And we have created these templates within the EHR that allow everyone to get a quick snapshot of where things are, what needs to be done, and what needs to be monitored.

Now, we are taking it a step further to determine when to stop chemotherapy or when to stop treatments. For example, for chronic myeloid leukemia (CML), there are good data onstopping tyrosine kinase inhibitors.⁷ And that alone, if implemented across the VA, could bring
in huge cost savings, which perhaps could be put into investments in immuno-oncology or other efforts. We have several examples here that we have published, and we continue to increaseand strengthen our collaboration withour oncology pharmacist. We are very lucky and privileged to have a dedicated oncology pharmacistfor clinics and for research.

Dr. Lynch. The example of CML is perfect, because precision oncology has increased the complexity of care substantially. The VA is wellpositioned to be a leader in this area when care becomes this complex because of its ability to measure access to testing, to translate the results
of testing to pharmacy, to have pharmacists take the lead on prescribing, to have pathologists take the lead on molecular alterations, and to have oncologists take the lead on delivering the cancer care to the patients.

With hematologic malignancies, adherence in the early stages can result in patients getting offcare sooner, which is cost savings. But that requires access to testing, monitoring that testing, and working in partnership with pharmacy. This is a great story about how the VA is positioned to lead in this area of care.

Dr. Kaster. I would like to put a plug in for advanced practice providers and the use of nurse practitioners (NPs) and physician assistants (PAs).The VA is well positioned because it often has established interdisciplinary teams with these providers, pharmacy, nursing, and often social work, to coordinate the care and manage symptoms outside of oncologist visits.

Dr. Lynch. In the NCI cancer center model, once the patient has become stable, the ongoing careis designated to the NP or PA. Then as soon as there’s a change and it requires reevaluation, the oncologist becomes involved again. That pointabout the oncology treatment team is totally in line
with some of the previous comments.

Areas For Further Investigation

Dr. Kaster. There are so many nuances that we’re finding out all of the time about immunotherapies. A recent study brought up the role of antibiotics in the 30 or possibly 60 days prior to immunotherapy.³ How does that change treatment? Which patients are more likely to benefit from immunotherapies, and which are susceptible to “hyperprogression”? How do we integrate palliative care discussions into the carenow that patients are feeling better on treatment and may be less likely to want to discuss palliative care?

Ms. Nason. I absolutely agree with that, especially keeping palliative care integrated within our services. Our focus is now a little different, in thatwe have more optimistic outcomes in mind, butthere still are symptoms and issues where our colleaguesin palliative care are invaluable.

Dr. Lynch. I third that motion. What I would really like to see come out of this discussion is how veterans are getting access to leading oncology care. We just published an analysis of Medicare data and access to EGFR testing. The result of that analysis showed that testing in the VA was consistent with testing in Medicare.

For palliative care, I think the VA does a better job. And it’s just so discouraging as VA employees and as clinicians treating veterans to see publicationsthat suggest that veterans are getting a lower quality of care and that they would be better if care was privatized or outsourced. It’s just fundamentally not the case.

In CML, we see it. We’ve analyzed the data, in that there’s a far lower number of patients with CML who are included in the registry because patients who are diagnosed outside the VA are incorporated in other cancer registries^.8 But as soon as their copays increase for access to targeted drugs, they immediately activate their VA benefits so that theycan get their drugs at the VA. For hematologic malignancies that are diagnosed outside the VA and are captured in other cancer registries, as soon as the drugs become expensive, they start getting their care in the VA. I don’t think there’s beena lot of empirical research that’s shown this, but we have the data to illustrate this trend. I hope thatthere are more publications that show that veterans with cancer are getting really good care inside the VA in the existing VA health care system.

Ms. Nason. It is disheartening to see negativepublicity, knowing that I work with colleagues who are strongly committed to providing up-to-date and relevant oncology care.

Dr. Lynch. As we record this conversation, I am in Rotterdam, Netherlands, in a meeting about genomewide testing. In hematologic malignancies, prostate cancer, and breast cancer, it’s a huge issue. And that is the other area that MVP (Million Veteran Program) is leading the way with the MVP biorepository data. Frankly, there’s no other biorepository that has this many patients, that has so many African Americans, and that has such rich EHR data. So inthat other area, the VA is doing really well.

The following is a lightly edited transcript of a teleconference discussion recorded in April 2018.

Suman Kambhampati, MD. Immuno-oncology is a paradigm-shifting treatment approach. It is an easy-to-understand term for both providers and for patients. The underlying principle is that the body’s own immune system is used or stimulated to fight cancer, and there are drugs that clearly have shown huge promise for this, not only in oncology, but also for other diseases. Time will tell whether that really pans out or not, but to begin with, the emphasis has been inoncology, and therefore, the term immunooncology is fitting.

Dr. Kaster. It was encouraging at first, especially when ipilimumab came out, to see the effects on patients with melanoma. Then the KEYNOTE-024 trial came out, and we were able to jump in anduse monoclonal antibodies directed against programmed death 1 (PD-1) in the first line, which is when things got exciting.¹ We have a smaller populationin Boise, so PD-1s in lung cancer have had the biggest impact on our patients so far.

Ellen Nason, RN, MSN. Patients are open to immunotherapies.They’re excited about it. And as the other panelists have said, you can start broadly, as the body fights the cancer on its own, to providing more specific details as a patient wants more information. Immuno-oncology is definitely accepted by patients, and they’re very excited about it, especially with all the news about new therapies.

Dr. Kambhampati. For the Department of Veteran Affairs (VA) population, lung cancer has seen significant impact, and now it’s translating into other diseases through more research, trials, and better understanding about how these drugs are used and work. 

The paradigm is shifting toward offering these drugs not only in metastatic cancers, but also in the surgically resectable tumors. The 2018 American Association for Cancer Research (AACR) meeting, just concluded. At the meeting several abstracts reported instances where immunooncology drugs are being introduced in the early phases of lung cancer and showing outstanding results. It’s very much possible that we’re going to see less use of traditional chemotherapy in the near future.

Ms. Nason. I primarily work with solid tumors,and the majority of the population I work with have lung cancer. So we’re excited about some of the results that we’ve seen and the lower toxicity involved. Recently, we’ve begun using durvalumab with patients with stage III disease. We have about 5 people now that are using it as a maintenance or consolidative treatment vs just using it for patients with stage IV disease. Hopefully, we’ll see some of the same results describedin the paper published on it.²

Dr. Kaster. Yes, we are incorporating these new changes into care as they're coming out. As Ms. Nason mentioned, we're already using immunotherapies in earlier settings, and we are seeing as much research that could be translated into care soon, like combining immunotherapies
in first-line settings, as we see in the Checkmate-227 study with nivolumab and ipilimumab.^3,4 The landscape is going to change dramatically in the next couple of years.

Accessing Testing For First-Line Treatments

Dr. Lynch. There has been an ongoing discussionin the literature on accessing appropriate testing—delays in testing can result in patients who are not able to access the best targeted drugs on a first-line basis. The drug companiesand the VA have become highly sensitized to ensuring that veterans are accessing the appropriate testing. We are expanding the capability of VA labs to do that testing.

Ms. Nason. I want to put in a plug for the VA Precision Oncology Program (POP). It’s about 2 years into its existence, and Neil Spector, MD, is the director. The POP pays for sequencing the tumor samples.

A new sequencing contract will go into effect October 2018 and will include sequencing for hematologic malignancies in addition to the current testing of solid tumors. Patients from New York who have been unable to receive testing through the current vendors used by POP, will be included in the new contract. It is important to note that POP is working closely with the National Pharmacy Benefit Management Service (PBM) to develop a policy for approving off-label use of US Food and Drug Administration-approved targeted therapies based on sequenced data collected on patients tested through POP.

In addition, the leadership of POP is working to leverage the molecular testing results conducted through POP to improve veterans' access to clinical trials, both inside and outside the VA. Within the VA people can access information at tinyurl.com/precisiononcology. There is no reason why any eligible patient with cancer in the VA health care system should not have their tumor tissue sequenced through POP, particularly once the new contract goes into effect.

Dr. Lynch. Fortunately, the cost of next-generation sequencing has come down so much that most VA contracted reference laboratories offer next-generation sequencing, including LabCorp (Burlington,NC), Quest Diagnostics (Secaucus, NJ), Fulgent (Temple City, CA), and academic partners such as Oregon Health Sciences University and University of Washington.

Ms. Nason. At the Durham VAMC, sometimes a lack of tissue has been a barrier, but we now have the ability to send blood (liquid biopsy) for next-generation sequencing. Hopefully that will open up options for veterans with inadequate tissue. Importantly, all VA facilities can request liquid biopsiesthrough POP.

Dr. Lynch. That’s an important point. There have been huge advances in liquid biopsy testing.The VA Salt Lake City Health Care System (VASLCHCS) was in talks with Genomic Health (Redwood City, CA) to do a study as part of clinical operations to look at the concordance between the liquid biopsy testing and the precision oncology data. But Genomic Health eventually abandoned its liquid biopsy testing. Currently, the VA is only reimbursing or encouraging liquid biopsy if the tissue is not available or if the veteran has too high a level of comorbidities to undergo tissue biopsy. The main point for the discussion today is that access to testing is a key component of access to all of these advanced drugs.

Dr. Kambhampati. The precision medicine piece will be a game changer—no question about that. Liquid biopsy is very timely. Many patients have difficulty getting rebiopsied, so liquid biopsy is definitely a big, big step forward.

Still, there has not been consistency across the VA as there should be. Perhaps there are a few select centers, including our site in Kansas City, where access to precision medicine is readily available and liquid biopsies are available. We use the PlasmaSELECT test from Personal Genome Diagnostics (Baltimore, MD). We have just added Foundation Medicine (Cambridge, MA) also in hematology. Access to mutational profilingis absolutely a must for precision medicine.

All that being said, the unique issue with immuno-oncology is that it pretty much transcends the mutational profile and perhaps has leveled the playing field, irrespective of the tumor mutation profile or burden. In some solid tumors these immuno-oncology drugs have been shown to work across tumor types and across different mutation types. And there is a hint now in the recent data presented at AACR and in the New England Journalof Medicine showing that the tumor mutational burden is a predictor of pathologic response to at least PD-1 blockade in the resectable stages of lung cancer.^1,3 To me, that’s a very important piece of data because that’s something that can be tested and can have a prognostic impact in immuno-oncology, particularly in the early stages of lung cancer and is further proof of the broad value of immunotherapics in targeting tumors irrespective of the precise tumor targets.

Dr. Kaster. Yes, it’s nice to see other options like tumor mutational burden and Lung Immune Prognostic Index being studied.5 It would be nice if we could rely a little more on these, and not PD-L1, which as we all know is a variable and an unreliable target.

Dr. Kambhampati. I agree.

Rural Challenges In A Veterans Population

Dr. Lynch. Providing high-quality cancer care to rural veterans care can be a challenge but it is a VA priority. The VA National Genomic Medicine Services offers better access for rural veterans to germline genetic testing than any other healthcare system in the country. In terms of access to somatic testing and next-generation sequencing, we are working toward providing the same level of cancer care as patients would receive at National Cancer Institute (NCI) cancer centers. The VA oncology leadership has done teleconsults and virtual tumor boards, but for some rural VAMCs, fellowsare leading the clinical care. As we expand use of oral agents for oncology treatment, it will be easier to ensure that rural veterans receive the same standard of care for POP that veterans being cared for at VASLCHCS, Kansas City VAMC, or Durham VAMC get.

Dr. Kambhampati. The Kansas City VAMC in its catchment area includes underserved areas, such as Topeka and Leavenworth, Kansas. What we’ve been able to do here is something that’s unique—Kansas City VAMC is the only standalone VA in the country to be recognized as a primary SWOG (Southwestern Oncology Group) institution, which provides access to many trials, such as the Lung-MAP trial and others. And that has allowed us to use the full expanse of precision medicine without financial barriers. The research has helped us improve the standard of
care for patients across VISN 15.

Dr. Lynch. In precision oncology, the chief of pathology is an important figure in access to advanced care. I’ve worked with Sharad Mathur,MD, of the Kansas City VAMC on many clinical trials. He’s on the Kansas City VAMC Institutional Review Board and the cancer committee and is tuned in to veterans’ access to precision oncology. Kansas City was ordering Foundation One for select patients that met the criteria probably sooner than any other VA and participated in NCI Cooperative Group clinical trials. It is a great example of how veterans are getting access to
the same level of care as are patients who gettreated at NCI partners.

Comorbidities

Dr. Kambhampati. I don’t treat a lot of patients with lung cancer, but I find it easier to use these immuno-oncology drugs than platinums and etoposide. I consider them absolutely nasty chemotherapy drugs now in this era of immuno-oncology and targeted therapy.

Dr. Lynch. The VA is very important in translational lung cancer research and clinical care. It used to be thought that African American patients don’t get epidermal growth factor receptor mutations. And that’s because not enough African American patients with lung cancer were included in the NCI-based clinical trial.There are7,000 veterans who get lung cancer each year, and 20% to 25% of those are African Americans. Prevalence of various mutations and the pharmacogenetics of some of these drugs differ by patient ancestry. Including veterans with lung
cancer in precision oncology clinical trials and clinical care is not just a priority for the VA but a priority for NCI and internationally. I can’t emphasize this enough—veterans with lung cancer should be included in these studies and should be getting the same level of care that our partners are getting at NCI cancer centers. In the VA we’re positioned to do this because of our nationalelectronic health record (EHR) and becauseof our ability to identify patients with specific variants and enroll them in clinical trials.

Ms. Nason. One of the barriers that I find withsome of the patients that I have treated is getting them to a trial. If the trial isn’t available locally, specifically there are socioeconomic and distance issues that are hard to overcome.

Dr. Kaster. For smaller medical centers, getting patients to clinical trials can be difficult. The Boise VAMC is putting together a proposal now to justify hiring a research pharmacist in order to get trials atour site. The goal is to offer trial participation to our patients who otherwise might not be able to participate while offsetting some of the costs of immunotherapy. We are trying to make what could be a negative into a positive.

Measuring Success

Dr. Kambhampati. Unfortunately, we do not have any calculators to incorporate the quality of lives saved to the society. I know there are clearmetrics in transplant and in hematology, but unfortunately, there are no established metrics in solid tumor treatment that allow us to predict the cost savings to the health care system or to society or the benefit to the society. I don’t use any such predictive models or metrics in my decision making. These decisions are made based on existing evidence, and the existing evidence overwhelmingly supports use of immuno-oncology in certain types of solid tumors and in a select group of hematologic malignancies.

Dr. Kaster. This is where you can get more bang for your buck with an oncology pharmacist these days. A pharmacist can make a minor dosing change that will allow the same benefit for the patient, but could equal tens of thousands of dollars in cost-benefit for the VA. They can also be the second set of eyes when adjudicating a nonformulary request to ensure that a patient will benefit.

Dr. Lynch. Inappropriate prescribing is far more expensive than appropriate treatment. And the care for veterans whose long-term health outcomes could be improved by the new immunotherapies. It’s cheaper for veterans to be healthy and live longer than it is to take care of them in
their last 6 weeks of life. Unfortunately, there are not a lot of studies that have demonstrated that empirically, but I think it’s important to do those studies.

Role of Pharmacists

Dr. Lynch. I was at a meeting recently talking about how to improve veteran access to clinical trials. Francesca Cunningham, PharmD, director of the VA Center for Medication Safety of the VA Pharmacy Benefit Management Service (PBM) described the commitment that pharmacy has in taking a leadership role in the integration of precision medicine. Linking veterans’ tumor mutation status and pharmacogenetic variants to pharmacy databases is the best way to ensure treatment is informed by genetics. We have to be realistic about what we’re asking community oncologists to do. With the onset of precision oncology, 10 cancers have become really 100 cancers. In the prior model of care, it was the oncologist, maybe in collaboration with a pathologist, but it was mostly oncologists who determined care.

And in the evolution of precision oncology, Ithink that it’s become an interdisciplinary adventure. Pharmacy is going to play an increasinglyimportant role in precision medicine around all of the molecular alterations, even immuno-oncology regardless of molecular status in which the VA has an advantage. We’re not talking about some community pharmacist. We’re talking about a national health care system where there’s a national EHR, where there’s national PBM systems. So my thoughts on this aspect is that it’s an intricate multidisciplinary team who can ensure that veteran sget the best care possible: the best most cost-effective care possible.

Dr. Kaster. As an oncology pharmacist, I have to second that.

Ms. Nason. As Dr. Kaster said earlier, having a dedicated oncology pharmacist is tremendouslybeneficial. The oncology/hematology pharmacists are following the patients closely and notice when dose adjustments need to be made, optimizing the drug benefit and providing additional safety. Not to mention the cost benefit that can be realized with appropriate adjustment and the expertise they bring to managing possible interactionsand pharmacodynamics.

Dr. Kambhampati. To brag about the Kansas City VAMC program, we have published in Federal Practitioner our best practices showing the collaboration between a pharmacist and providers^.6 And we have used several examples of cost savings, which have basically helped us build the research program, and several examples of dual monitoring oral chemotherapy monitoring. And we have created these templates within the EHR that allow everyone to get a quick snapshot of where things are, what needs to be done, and what needs to be monitored.

Now, we are taking it a step further to determine when to stop chemotherapy or when to stop treatments. For example, for chronic myeloid leukemia (CML), there are good data onstopping tyrosine kinase inhibitors.⁷ And that alone, if implemented across the VA, could bring
in huge cost savings, which perhaps could be put into investments in immuno-oncology or other efforts. We have several examples here that we have published, and we continue to increaseand strengthen our collaboration withour oncology pharmacist. We are very lucky and privileged to have a dedicated oncology pharmacistfor clinics and for research.

Dr. Lynch. The example of CML is perfect, because precision oncology has increased the complexity of care substantially. The VA is wellpositioned to be a leader in this area when care becomes this complex because of its ability to measure access to testing, to translate the results
of testing to pharmacy, to have pharmacists take the lead on prescribing, to have pathologists take the lead on molecular alterations, and to have oncologists take the lead on delivering the cancer care to the patients.

With hematologic malignancies, adherence in the early stages can result in patients getting offcare sooner, which is cost savings. But that requires access to testing, monitoring that testing, and working in partnership with pharmacy. This is a great story about how the VA is positioned to lead in this area of care.

Dr. Kaster. I would like to put a plug in for advanced practice providers and the use of nurse practitioners (NPs) and physician assistants (PAs).The VA is well positioned because it often has established interdisciplinary teams with these providers, pharmacy, nursing, and often social work, to coordinate the care and manage symptoms outside of oncologist visits.

Dr. Lynch. In the NCI cancer center model, once the patient has become stable, the ongoing careis designated to the NP or PA. Then as soon as there’s a change and it requires reevaluation, the oncologist becomes involved again. That pointabout the oncology treatment team is totally in line
with some of the previous comments.

Areas For Further Investigation

Dr. Kaster. There are so many nuances that we’re finding out all of the time about immunotherapies. A recent study brought up the role of antibiotics in the 30 or possibly 60 days prior to immunotherapy.³ How does that change treatment? Which patients are more likely to benefit from immunotherapies, and which are susceptible to “hyperprogression”? How do we integrate palliative care discussions into the carenow that patients are feeling better on treatment and may be less likely to want to discuss palliative care?

Ms. Nason. I absolutely agree with that, especially keeping palliative care integrated within our services. Our focus is now a little different, in thatwe have more optimistic outcomes in mind, butthere still are symptoms and issues where our colleaguesin palliative care are invaluable.

Dr. Lynch. I third that motion. What I would really like to see come out of this discussion is how veterans are getting access to leading oncology care. We just published an analysis of Medicare data and access to EGFR testing. The result of that analysis showed that testing in the VA was consistent with testing in Medicare.

For palliative care, I think the VA does a better job. And it’s just so discouraging as VA employees and as clinicians treating veterans to see publicationsthat suggest that veterans are getting a lower quality of care and that they would be better if care was privatized or outsourced. It’s just fundamentally not the case.

In CML, we see it. We’ve analyzed the data, in that there’s a far lower number of patients with CML who are included in the registry because patients who are diagnosed outside the VA are incorporated in other cancer registries^.8 But as soon as their copays increase for access to targeted drugs, they immediately activate their VA benefits so that theycan get their drugs at the VA. For hematologic malignancies that are diagnosed outside the VA and are captured in other cancer registries, as soon as the drugs become expensive, they start getting their care in the VA. I don’t think there’s beena lot of empirical research that’s shown this, but we have the data to illustrate this trend. I hope thatthere are more publications that show that veterans with cancer are getting really good care inside the VA in the existing VA health care system.

Ms. Nason. It is disheartening to see negativepublicity, knowing that I work with colleagues who are strongly committed to providing up-to-date and relevant oncology care.

Dr. Lynch. As we record this conversation, I am in Rotterdam, Netherlands, in a meeting about genomewide testing. In hematologic malignancies, prostate cancer, and breast cancer, it’s a huge issue. And that is the other area that MVP (Million Veteran Program) is leading the way with the MVP biorepository data. Frankly, there’s no other biorepository that has this many patients, that has so many African Americans, and that has such rich EHR data. So inthat other area, the VA is doing really well.

Patients with cancer are at an increased risk of both venous thromboembolism (VTE) and bleeding complications. Risk factors for development of cancer-associated thrombosis (CAT) include indwelling lines, antineoplastic therapies, lack of mobility, and physical/chemical damage from the tumor.¹ Venous thromboembolism may manifest as either deep vein thrombosis (DVT) or pulmonary embolism (PE). Cancer-associated thrombosis can lead to significant mortality in patients with cancer and may increase health care costs for additional medications and hospitalizations.

Zullig and colleagues estimated that 46,666 veterans received cancer care from the US Department of Veteran Affairs (VA) health care system in 2010. This number equates to about 3% of all patients with cancer in the US who receive at least some of their health care from the VA health care system.² In addition to cancer care, these veterans receive treatment for various comorbid conditions. One such condition that is of concern in a prothrombotic state is atrial fibrillation (AF). For this condition, patients often require anticoagulation therapy with aspirin, warfarin, or one of the recently approved direct oral anticoagulant agents (DOACs), depending on risk factors.

Background

Due to their ease of administration, limited monitoring requirements, and proven safety and efficacy in patients with AF requiring anticoagulation, the American Heart Association (AHA) and American College of Cardiology recently switched their recommendations for rivaroxaban and dabigatran for oral stroke prevention to a class 1/level B recommendation.³

The American College of Chest Physicians (ACCP) recommends treatment with DOACs over warfarin therapy for acute VTE in patients without cancer; however, the ACCP prefers low molecular-weight heparin (LMWH) over the DOACs for treatment of CAT.⁴ Recently, the National Comprehensive Cancer Network (NCCN) updated its guidelines for the treatment of cancer-associated thromboembolic disease to recommend 2 of the DOACs (apixaban, rivaroxaban) for treatment of acute VTE over warfarin. These guidelines also recommend LMWH over DOACs for treatment of acute VTE in patients with cancer.⁵ These NCCN recommendations are largely based on prespecified subgroup meta-analyses of the DOACs compared with those of LMWH or warfarin in the cancer population.

In addition to stroke prevention in patients with AF, DOACs have additional FDA-approved indications, including treatment of acute VTE, prevention of recurrent VTE, and postoperative VTE treatment and prophylaxis. Due to a lack of head-to-head, randomized controlled trials comparing LMWH with DOACs in patients with cancer, these agents have not found their formal place in the treatment or prevention of CAT. Several meta-analyses have suggested similar efficacy and safety outcomes in patients with cancer compared with those of LMWH.^6-8 These meta-analysis studies largely looked at subpopulations and compared the outcomes with those of the landmark CLOT (Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer Investigators) and CATCH (Comparison of Acute Treatments in Cancer Hemostasis) trials.^9,10

As it is still unclear whether the DOACs are effective and safe for treatment/prevention of CAT, some confusion remains regarding the best management of these at-risk patients. In patients with cancer on DOAC therapy for an approved indication, it is assumed that the therapeutic benefit seen in approved indications would translate to treatment and prevention of CAT. This study aims to determine the incidence of VTE and rates of major and clinically relevant nonmajor bleeding (CRNMB) in veterans with cancer who received a DOAC.

Methods

This retrospective, single-center chart review was approved by the local institutional review board and research safety committee. A search within the VA Corporate Data Warehouse identified patients who had an active prescription for one of the DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) along with an ICD 9 or ICD 10 code corresponding to a malignancy.

Patients were included in the final analysis if they were aged 18 to 89 years at time of DOAC receipt, undergoing active treatment for malignancy, had evidence of a history of malignancy (either diagnostic or charted evidence of previous treatment), or received cancer-related surgery within 30 days of DOAC prescription with curative intent. Patients were excluded from the final analysis if they did not receive a DOAC prescription or have any clear evidence of malignancy documented in the medical chart.

Patients’ charts were evaluated for the following clinical endpoints: patient age, height (cm), weight (kg), type of malignancy, type of treatment for malignancy, serum creatinine (SCr), creatinine clearance (CrCl) calculated with the Cockcroft-Gault equation using actual body weight, serum hemoglobin, aspartate aminotransferase, alanine aminotransferase, total bilirubin, indication for DOAC, type of VTE, presence of a prior VTE, and diagnostic test performed for VTE. Major bleeding and CRNMB criteria were based on the definitions provided by the International Society on Thrombosis and Haemostasis (ISTH).¹¹ All laboratory values and demographic information were gathered at the time of initial DOAC prescription.

The primary endpoint for this study was incidence of VTE. The secondary endpoints included major bleeding and CRNMB. All data collection and statistical analysis were done using Microsoft Excel 2016 (Redmond, WA). Comparisons of data between trials were done using the chi-squared calculation.

Results

From initial FDA approval of dabigatran (first DOAC on the market) on October 15, 2012, to January 1, 2017, there were 343 patients who met initial inclusion criteria. Of those, 115 did not have any clear evidence of malignancy, 22 did not have any records of DOAC receipt, 15 did not receive a DOAC within the date range, and 23 patients’ charts were unavailable. 

The majority of the patients were males (96.6%), with an average age of 74.5 years. The average weight of all patients was 92.5 kg, with an average SCr of 1.1 mg/dL. This equated to an average CrCl of 85.5 mL/min based on the Cockcroft-Gault equation using actual bodyweight. Of the 177 patients evaluated, 30 (16.9%) were receiving active cancer treatment at time of DOAC initiation. 

Two (1.1%) patients developed a VTE while receiving a DOAC. 

Among the 177 evaluable patients in this study, there were 7 patients (4%) who developed a major bleed and 13 patients (7.3%) who developed a clinically relevant nonmajor bleed according to the definitions provided by ISTH.¹¹ 

Discussion

The CLOT and CATCH trials were chosen as historic comparators. Although the active treatment interventions and comparator arms were not similar between the patients included in this study and the CLOT and CATCH trials, the authors felt the comparison was appropriate as these trials were designed specifically for patients with malignancy. Additionally, these trials sought to assess rates of VTE formation and bleeding in the patient with malignancies—outcomes that aligned with this study. Alternative trials for comparison are the subgroup analyses of patients with malignancies in the AMPLIFY, RE-COVER, and EINSTEIN trials.^12-14 Although these trials were designed to stratify patients based on presence of malignancy, they were not powered to account for increased risk of VTE in patients with malignancies.

There are multiple risk factors that increase the risk of CAT. Khoranna and colleagues identified primary stomach, pancreas, brain, lung, lymphoma, gynecologic, bladder, testicular, and renal carcinomas as a high risk of VTE formation.¹⁵ Additionally, Khoranna and colleagues noted that elderly patients and patients actively receiving treatment are at an increased risk of VTE formation.¹⁵ The low rate of VTE formation (1.1%) in the patients in this study may be due to the low risk for VTE formation. As previously mentioned, only 30 of the patients (16.9%) in this study were receiving active treatment.

Additionally, there were only 42 patients (23.7%) who had a high-risk malignancy. The increased age of the patient population (74.5 years old) in this study is one risk factor that could largely skew the risks of VTE formation in the patient population. In addition to age, the average body mass index (BMI) of this study’s patient population (30 kg/m²) may further increase risk of VTE. Although Khoranna and colleagues identified a BMI of 35 kg/m² as the cutoff for increased risk of CAT, the increased risk based on a BMI of 30 kg/m² cannot be ignored in the patients in this study.¹⁵

Another risk inherent in the treatment of patients with cancer is pancytopenia, which may lead to increased risks of bleeding and infection. When patients are exposed to an anticoagulant agent in the setting of decreased platelets and hemoglobin (from treatment or disease process), the risk for major bleeds and CRNMB are increased drastically. In this patient population, the combined rate of bleeding (11.3%) was relatively decreased compared with that of the CLOT (16.5% for all bleeding events) and CATCH (15.7% for all bleeding events) trials.^9,10

Compared with the oncology subgroup analysis of the AMPLIFY, RE-COVER, and EINSTEIN trials, the differences are more noticeable. The AMPLIFY trial reported a 1.1% incidence of bleeding in patients with cancer on apixaban, whereas the RE-COVER trial did not report bleeding rates, and the EINSTEIN trial reported a 14% incidence of bleeding in all patients with cancer on rivaroxaban for VTE treatment.^12-14 This study found a bleeding incidence of 12.2% with apixaban, 5.7% with dabigatran, and 14.7% with rivaroxaban. In this trial the incidence of bleeding with rivaroxaban were similar; however, the incidence of bleeding with apixaban was markedly higher. There is no obvious explanation for this, as the dosing of apixaban was appropriate in all patients in this trial except for one. There was no documented bleed in this patient’s medical chart.

A meta-analysis conducted by Vedovati and colleagues identified 6 studies in which patients with cancer received either a DOAC (with or without a heparin product) or vitamin K antagonist.¹⁶ That analysis found a nonsignificant reduction in VTE recurrence (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.31-1.1), major bleeding (OR, 0.77; 95% CI, 0.41-1.44), and CRNMB (OR, 0.85; 95% CI, 0.62-1.18).¹⁶ The meta-analysis adds to the growing body of evidence in support of both safety and efficacy of DOACs in patients with cancer. Although the Vedovati and colleagues study does not directly compare rates between 2 treatment groups, the findings of similar rates of VTE recurrence, major bleed, and CRNMB are consistent with the current study. Despite differing patient characteristics, the meta-analysis by Vedovati and colleagues supports the ongoing use of DOACs in patients with malignancy, as does the current study.¹⁶

Limitations

Although it seems that apixaban, dabigatran, and rivaroxaban are effective in reducing the risk of VTE in veterans with malignancy, there are some inherent weaknesses in the current study. Most notably is the choice of comparator trials. The authors’ believe that the CLOT and CATCH trials were the most appropriate based on similarities in population and outcomes. Considering the CLOT and CATCH trials compared LMWH to coumarin products for treatment of VTE, future studies should compare use of these agents with DOACs in the cancer population. In addition, the study did not include outcomes that would adequately assess risks of VTE and bleeding formation. This information would have been beneficial to more effectively categorize this study’s patient population based on risks of each of its predetermined outcomes. Understanding safety and efficacy of DOACs in patients at various risks would help practitioners to choose more appropriate agents in practice. Last, this study did not assess the incidence of stroke in study patients. This is important because the DOACs were used mostly for stroke prevention in AF and atrial flutter. The increased risk of VTE in patients with cancer cannot directly correlate to risk of stroke with a comorbid cardiac condition, but the hypercoagulable state cannot be ignored in these patients.

Conclusion

This study provided some preliminary evidence for the safety and efficacy of DOACs in patients with cancer. The low incidence of VTE formation and similar rates of bleeding among other clinical trials indicate that DOACs are safe alternatives to currently recommended anticoagulation medication in patients with cancer.

Patients with cancer are at an increased risk of both venous thromboembolism (VTE) and bleeding complications. Risk factors for development of cancer-associated thrombosis (CAT) include indwelling lines, antineoplastic therapies, lack of mobility, and physical/chemical damage from the tumor.¹ Venous thromboembolism may manifest as either deep vein thrombosis (DVT) or pulmonary embolism (PE). Cancer-associated thrombosis can lead to significant mortality in patients with cancer and may increase health care costs for additional medications and hospitalizations.

Zullig and colleagues estimated that 46,666 veterans received cancer care from the US Department of Veteran Affairs (VA) health care system in 2010. This number equates to about 3% of all patients with cancer in the US who receive at least some of their health care from the VA health care system.² In addition to cancer care, these veterans receive treatment for various comorbid conditions. One such condition that is of concern in a prothrombotic state is atrial fibrillation (AF). For this condition, patients often require anticoagulation therapy with aspirin, warfarin, or one of the recently approved direct oral anticoagulant agents (DOACs), depending on risk factors.

Background

Due to their ease of administration, limited monitoring requirements, and proven safety and efficacy in patients with AF requiring anticoagulation, the American Heart Association (AHA) and American College of Cardiology recently switched their recommendations for rivaroxaban and dabigatran for oral stroke prevention to a class 1/level B recommendation.³

The American College of Chest Physicians (ACCP) recommends treatment with DOACs over warfarin therapy for acute VTE in patients without cancer; however, the ACCP prefers low molecular-weight heparin (LMWH) over the DOACs for treatment of CAT.⁴ Recently, the National Comprehensive Cancer Network (NCCN) updated its guidelines for the treatment of cancer-associated thromboembolic disease to recommend 2 of the DOACs (apixaban, rivaroxaban) for treatment of acute VTE over warfarin. These guidelines also recommend LMWH over DOACs for treatment of acute VTE in patients with cancer.⁵ These NCCN recommendations are largely based on prespecified subgroup meta-analyses of the DOACs compared with those of LMWH or warfarin in the cancer population.

In addition to stroke prevention in patients with AF, DOACs have additional FDA-approved indications, including treatment of acute VTE, prevention of recurrent VTE, and postoperative VTE treatment and prophylaxis. Due to a lack of head-to-head, randomized controlled trials comparing LMWH with DOACs in patients with cancer, these agents have not found their formal place in the treatment or prevention of CAT. Several meta-analyses have suggested similar efficacy and safety outcomes in patients with cancer compared with those of LMWH.^6-8 These meta-analysis studies largely looked at subpopulations and compared the outcomes with those of the landmark CLOT (Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer Investigators) and CATCH (Comparison of Acute Treatments in Cancer Hemostasis) trials.^9,10

As it is still unclear whether the DOACs are effective and safe for treatment/prevention of CAT, some confusion remains regarding the best management of these at-risk patients. In patients with cancer on DOAC therapy for an approved indication, it is assumed that the therapeutic benefit seen in approved indications would translate to treatment and prevention of CAT. This study aims to determine the incidence of VTE and rates of major and clinically relevant nonmajor bleeding (CRNMB) in veterans with cancer who received a DOAC.

Methods

This retrospective, single-center chart review was approved by the local institutional review board and research safety committee. A search within the VA Corporate Data Warehouse identified patients who had an active prescription for one of the DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) along with an ICD 9 or ICD 10 code corresponding to a malignancy.

Patients were included in the final analysis if they were aged 18 to 89 years at time of DOAC receipt, undergoing active treatment for malignancy, had evidence of a history of malignancy (either diagnostic or charted evidence of previous treatment), or received cancer-related surgery within 30 days of DOAC prescription with curative intent. Patients were excluded from the final analysis if they did not receive a DOAC prescription or have any clear evidence of malignancy documented in the medical chart.

Patients’ charts were evaluated for the following clinical endpoints: patient age, height (cm), weight (kg), type of malignancy, type of treatment for malignancy, serum creatinine (SCr), creatinine clearance (CrCl) calculated with the Cockcroft-Gault equation using actual body weight, serum hemoglobin, aspartate aminotransferase, alanine aminotransferase, total bilirubin, indication for DOAC, type of VTE, presence of a prior VTE, and diagnostic test performed for VTE. Major bleeding and CRNMB criteria were based on the definitions provided by the International Society on Thrombosis and Haemostasis (ISTH).¹¹ All laboratory values and demographic information were gathered at the time of initial DOAC prescription.

The primary endpoint for this study was incidence of VTE. The secondary endpoints included major bleeding and CRNMB. All data collection and statistical analysis were done using Microsoft Excel 2016 (Redmond, WA). Comparisons of data between trials were done using the chi-squared calculation.

Results

From initial FDA approval of dabigatran (first DOAC on the market) on October 15, 2012, to January 1, 2017, there were 343 patients who met initial inclusion criteria. Of those, 115 did not have any clear evidence of malignancy, 22 did not have any records of DOAC receipt, 15 did not receive a DOAC within the date range, and 23 patients’ charts were unavailable. 

The majority of the patients were males (96.6%), with an average age of 74.5 years. The average weight of all patients was 92.5 kg, with an average SCr of 1.1 mg/dL. This equated to an average CrCl of 85.5 mL/min based on the Cockcroft-Gault equation using actual bodyweight. Of the 177 patients evaluated, 30 (16.9%) were receiving active cancer treatment at time of DOAC initiation. 

Two (1.1%) patients developed a VTE while receiving a DOAC. 

Among the 177 evaluable patients in this study, there were 7 patients (4%) who developed a major bleed and 13 patients (7.3%) who developed a clinically relevant nonmajor bleed according to the definitions provided by ISTH.¹¹ 

Discussion

The CLOT and CATCH trials were chosen as historic comparators. Although the active treatment interventions and comparator arms were not similar between the patients included in this study and the CLOT and CATCH trials, the authors felt the comparison was appropriate as these trials were designed specifically for patients with malignancy. Additionally, these trials sought to assess rates of VTE formation and bleeding in the patient with malignancies—outcomes that aligned with this study. Alternative trials for comparison are the subgroup analyses of patients with malignancies in the AMPLIFY, RE-COVER, and EINSTEIN trials.^12-14 Although these trials were designed to stratify patients based on presence of malignancy, they were not powered to account for increased risk of VTE in patients with malignancies.

There are multiple risk factors that increase the risk of CAT. Khoranna and colleagues identified primary stomach, pancreas, brain, lung, lymphoma, gynecologic, bladder, testicular, and renal carcinomas as a high risk of VTE formation.¹⁵ Additionally, Khoranna and colleagues noted that elderly patients and patients actively receiving treatment are at an increased risk of VTE formation.¹⁵ The low rate of VTE formation (1.1%) in the patients in this study may be due to the low risk for VTE formation. As previously mentioned, only 30 of the patients (16.9%) in this study were receiving active treatment.

Additionally, there were only 42 patients (23.7%) who had a high-risk malignancy. The increased age of the patient population (74.5 years old) in this study is one risk factor that could largely skew the risks of VTE formation in the patient population. In addition to age, the average body mass index (BMI) of this study’s patient population (30 kg/m²) may further increase risk of VTE. Although Khoranna and colleagues identified a BMI of 35 kg/m² as the cutoff for increased risk of CAT, the increased risk based on a BMI of 30 kg/m² cannot be ignored in the patients in this study.¹⁵

Another risk inherent in the treatment of patients with cancer is pancytopenia, which may lead to increased risks of bleeding and infection. When patients are exposed to an anticoagulant agent in the setting of decreased platelets and hemoglobin (from treatment or disease process), the risk for major bleeds and CRNMB are increased drastically. In this patient population, the combined rate of bleeding (11.3%) was relatively decreased compared with that of the CLOT (16.5% for all bleeding events) and CATCH (15.7% for all bleeding events) trials.^9,10

Compared with the oncology subgroup analysis of the AMPLIFY, RE-COVER, and EINSTEIN trials, the differences are more noticeable. The AMPLIFY trial reported a 1.1% incidence of bleeding in patients with cancer on apixaban, whereas the RE-COVER trial did not report bleeding rates, and the EINSTEIN trial reported a 14% incidence of bleeding in all patients with cancer on rivaroxaban for VTE treatment.^12-14 This study found a bleeding incidence of 12.2% with apixaban, 5.7% with dabigatran, and 14.7% with rivaroxaban. In this trial the incidence of bleeding with rivaroxaban were similar; however, the incidence of bleeding with apixaban was markedly higher. There is no obvious explanation for this, as the dosing of apixaban was appropriate in all patients in this trial except for one. There was no documented bleed in this patient’s medical chart.

A meta-analysis conducted by Vedovati and colleagues identified 6 studies in which patients with cancer received either a DOAC (with or without a heparin product) or vitamin K antagonist.¹⁶ That analysis found a nonsignificant reduction in VTE recurrence (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.31-1.1), major bleeding (OR, 0.77; 95% CI, 0.41-1.44), and CRNMB (OR, 0.85; 95% CI, 0.62-1.18).¹⁶ The meta-analysis adds to the growing body of evidence in support of both safety and efficacy of DOACs in patients with cancer. Although the Vedovati and colleagues study does not directly compare rates between 2 treatment groups, the findings of similar rates of VTE recurrence, major bleed, and CRNMB are consistent with the current study. Despite differing patient characteristics, the meta-analysis by Vedovati and colleagues supports the ongoing use of DOACs in patients with malignancy, as does the current study.¹⁶

Limitations

Although it seems that apixaban, dabigatran, and rivaroxaban are effective in reducing the risk of VTE in veterans with malignancy, there are some inherent weaknesses in the current study. Most notably is the choice of comparator trials. The authors’ believe that the CLOT and CATCH trials were the most appropriate based on similarities in population and outcomes. Considering the CLOT and CATCH trials compared LMWH to coumarin products for treatment of VTE, future studies should compare use of these agents with DOACs in the cancer population. In addition, the study did not include outcomes that would adequately assess risks of VTE and bleeding formation. This information would have been beneficial to more effectively categorize this study’s patient population based on risks of each of its predetermined outcomes. Understanding safety and efficacy of DOACs in patients at various risks would help practitioners to choose more appropriate agents in practice. Last, this study did not assess the incidence of stroke in study patients. This is important because the DOACs were used mostly for stroke prevention in AF and atrial flutter. The increased risk of VTE in patients with cancer cannot directly correlate to risk of stroke with a comorbid cardiac condition, but the hypercoagulable state cannot be ignored in these patients.

Conclusion

This study provided some preliminary evidence for the safety and efficacy of DOACs in patients with cancer. The low incidence of VTE formation and similar rates of bleeding among other clinical trials indicate that DOACs are safe alternatives to currently recommended anticoagulation medication in patients with cancer.

Patients with cancer are at an increased risk of both venous thromboembolism (VTE) and bleeding complications. Risk factors for development of cancer-associated thrombosis (CAT) include indwelling lines, antineoplastic therapies, lack of mobility, and physical/chemical damage from the tumor.¹ Venous thromboembolism may manifest as either deep vein thrombosis (DVT) or pulmonary embolism (PE). Cancer-associated thrombosis can lead to significant mortality in patients with cancer and may increase health care costs for additional medications and hospitalizations.

Zullig and colleagues estimated that 46,666 veterans received cancer care from the US Department of Veteran Affairs (VA) health care system in 2010. This number equates to about 3% of all patients with cancer in the US who receive at least some of their health care from the VA health care system.² In addition to cancer care, these veterans receive treatment for various comorbid conditions. One such condition that is of concern in a prothrombotic state is atrial fibrillation (AF). For this condition, patients often require anticoagulation therapy with aspirin, warfarin, or one of the recently approved direct oral anticoagulant agents (DOACs), depending on risk factors.

Background

Due to their ease of administration, limited monitoring requirements, and proven safety and efficacy in patients with AF requiring anticoagulation, the American Heart Association (AHA) and American College of Cardiology recently switched their recommendations for rivaroxaban and dabigatran for oral stroke prevention to a class 1/level B recommendation.³

The American College of Chest Physicians (ACCP) recommends treatment with DOACs over warfarin therapy for acute VTE in patients without cancer; however, the ACCP prefers low molecular-weight heparin (LMWH) over the DOACs for treatment of CAT.⁴ Recently, the National Comprehensive Cancer Network (NCCN) updated its guidelines for the treatment of cancer-associated thromboembolic disease to recommend 2 of the DOACs (apixaban, rivaroxaban) for treatment of acute VTE over warfarin. These guidelines also recommend LMWH over DOACs for treatment of acute VTE in patients with cancer.⁵ These NCCN recommendations are largely based on prespecified subgroup meta-analyses of the DOACs compared with those of LMWH or warfarin in the cancer population.

In addition to stroke prevention in patients with AF, DOACs have additional FDA-approved indications, including treatment of acute VTE, prevention of recurrent VTE, and postoperative VTE treatment and prophylaxis. Due to a lack of head-to-head, randomized controlled trials comparing LMWH with DOACs in patients with cancer, these agents have not found their formal place in the treatment or prevention of CAT. Several meta-analyses have suggested similar efficacy and safety outcomes in patients with cancer compared with those of LMWH.^6-8 These meta-analysis studies largely looked at subpopulations and compared the outcomes with those of the landmark CLOT (Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer Investigators) and CATCH (Comparison of Acute Treatments in Cancer Hemostasis) trials.^9,10

As it is still unclear whether the DOACs are effective and safe for treatment/prevention of CAT, some confusion remains regarding the best management of these at-risk patients. In patients with cancer on DOAC therapy for an approved indication, it is assumed that the therapeutic benefit seen in approved indications would translate to treatment and prevention of CAT. This study aims to determine the incidence of VTE and rates of major and clinically relevant nonmajor bleeding (CRNMB) in veterans with cancer who received a DOAC.

Methods

This retrospective, single-center chart review was approved by the local institutional review board and research safety committee. A search within the VA Corporate Data Warehouse identified patients who had an active prescription for one of the DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) along with an ICD 9 or ICD 10 code corresponding to a malignancy.

Patients were included in the final analysis if they were aged 18 to 89 years at time of DOAC receipt, undergoing active treatment for malignancy, had evidence of a history of malignancy (either diagnostic or charted evidence of previous treatment), or received cancer-related surgery within 30 days of DOAC prescription with curative intent. Patients were excluded from the final analysis if they did not receive a DOAC prescription or have any clear evidence of malignancy documented in the medical chart.

Patients’ charts were evaluated for the following clinical endpoints: patient age, height (cm), weight (kg), type of malignancy, type of treatment for malignancy, serum creatinine (SCr), creatinine clearance (CrCl) calculated with the Cockcroft-Gault equation using actual body weight, serum hemoglobin, aspartate aminotransferase, alanine aminotransferase, total bilirubin, indication for DOAC, type of VTE, presence of a prior VTE, and diagnostic test performed for VTE. Major bleeding and CRNMB criteria were based on the definitions provided by the International Society on Thrombosis and Haemostasis (ISTH).¹¹ All laboratory values and demographic information were gathered at the time of initial DOAC prescription.

The primary endpoint for this study was incidence of VTE. The secondary endpoints included major bleeding and CRNMB. All data collection and statistical analysis were done using Microsoft Excel 2016 (Redmond, WA). Comparisons of data between trials were done using the chi-squared calculation.

Results

From initial FDA approval of dabigatran (first DOAC on the market) on October 15, 2012, to January 1, 2017, there were 343 patients who met initial inclusion criteria. Of those, 115 did not have any clear evidence of malignancy, 22 did not have any records of DOAC receipt, 15 did not receive a DOAC within the date range, and 23 patients’ charts were unavailable. 

The majority of the patients were males (96.6%), with an average age of 74.5 years. The average weight of all patients was 92.5 kg, with an average SCr of 1.1 mg/dL. This equated to an average CrCl of 85.5 mL/min based on the Cockcroft-Gault equation using actual bodyweight. Of the 177 patients evaluated, 30 (16.9%) were receiving active cancer treatment at time of DOAC initiation. 

Two (1.1%) patients developed a VTE while receiving a DOAC. 

Among the 177 evaluable patients in this study, there were 7 patients (4%) who developed a major bleed and 13 patients (7.3%) who developed a clinically relevant nonmajor bleed according to the definitions provided by ISTH.¹¹ 

Discussion

The CLOT and CATCH trials were chosen as historic comparators. Although the active treatment interventions and comparator arms were not similar between the patients included in this study and the CLOT and CATCH trials, the authors felt the comparison was appropriate as these trials were designed specifically for patients with malignancy. Additionally, these trials sought to assess rates of VTE formation and bleeding in the patient with malignancies—outcomes that aligned with this study. Alternative trials for comparison are the subgroup analyses of patients with malignancies in the AMPLIFY, RE-COVER, and EINSTEIN trials.^12-14 Although these trials were designed to stratify patients based on presence of malignancy, they were not powered to account for increased risk of VTE in patients with malignancies.

There are multiple risk factors that increase the risk of CAT. Khoranna and colleagues identified primary stomach, pancreas, brain, lung, lymphoma, gynecologic, bladder, testicular, and renal carcinomas as a high risk of VTE formation.¹⁵ Additionally, Khoranna and colleagues noted that elderly patients and patients actively receiving treatment are at an increased risk of VTE formation.¹⁵ The low rate of VTE formation (1.1%) in the patients in this study may be due to the low risk for VTE formation. As previously mentioned, only 30 of the patients (16.9%) in this study were receiving active treatment.

Additionally, there were only 42 patients (23.7%) who had a high-risk malignancy. The increased age of the patient population (74.5 years old) in this study is one risk factor that could largely skew the risks of VTE formation in the patient population. In addition to age, the average body mass index (BMI) of this study’s patient population (30 kg/m²) may further increase risk of VTE. Although Khoranna and colleagues identified a BMI of 35 kg/m² as the cutoff for increased risk of CAT, the increased risk based on a BMI of 30 kg/m² cannot be ignored in the patients in this study.¹⁵

Another risk inherent in the treatment of patients with cancer is pancytopenia, which may lead to increased risks of bleeding and infection. When patients are exposed to an anticoagulant agent in the setting of decreased platelets and hemoglobin (from treatment or disease process), the risk for major bleeds and CRNMB are increased drastically. In this patient population, the combined rate of bleeding (11.3%) was relatively decreased compared with that of the CLOT (16.5% for all bleeding events) and CATCH (15.7% for all bleeding events) trials.^9,10

Compared with the oncology subgroup analysis of the AMPLIFY, RE-COVER, and EINSTEIN trials, the differences are more noticeable. The AMPLIFY trial reported a 1.1% incidence of bleeding in patients with cancer on apixaban, whereas the RE-COVER trial did not report bleeding rates, and the EINSTEIN trial reported a 14% incidence of bleeding in all patients with cancer on rivaroxaban for VTE treatment.^12-14 This study found a bleeding incidence of 12.2% with apixaban, 5.7% with dabigatran, and 14.7% with rivaroxaban. In this trial the incidence of bleeding with rivaroxaban were similar; however, the incidence of bleeding with apixaban was markedly higher. There is no obvious explanation for this, as the dosing of apixaban was appropriate in all patients in this trial except for one. There was no documented bleed in this patient’s medical chart.

A meta-analysis conducted by Vedovati and colleagues identified 6 studies in which patients with cancer received either a DOAC (with or without a heparin product) or vitamin K antagonist.¹⁶ That analysis found a nonsignificant reduction in VTE recurrence (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.31-1.1), major bleeding (OR, 0.77; 95% CI, 0.41-1.44), and CRNMB (OR, 0.85; 95% CI, 0.62-1.18).¹⁶ The meta-analysis adds to the growing body of evidence in support of both safety and efficacy of DOACs in patients with cancer. Although the Vedovati and colleagues study does not directly compare rates between 2 treatment groups, the findings of similar rates of VTE recurrence, major bleed, and CRNMB are consistent with the current study. Despite differing patient characteristics, the meta-analysis by Vedovati and colleagues supports the ongoing use of DOACs in patients with malignancy, as does the current study.¹⁶

Limitations

Although it seems that apixaban, dabigatran, and rivaroxaban are effective in reducing the risk of VTE in veterans with malignancy, there are some inherent weaknesses in the current study. Most notably is the choice of comparator trials. The authors’ believe that the CLOT and CATCH trials were the most appropriate based on similarities in population and outcomes. Considering the CLOT and CATCH trials compared LMWH to coumarin products for treatment of VTE, future studies should compare use of these agents with DOACs in the cancer population. In addition, the study did not include outcomes that would adequately assess risks of VTE and bleeding formation. This information would have been beneficial to more effectively categorize this study’s patient population based on risks of each of its predetermined outcomes. Understanding safety and efficacy of DOACs in patients at various risks would help practitioners to choose more appropriate agents in practice. Last, this study did not assess the incidence of stroke in study patients. This is important because the DOACs were used mostly for stroke prevention in AF and atrial flutter. The increased risk of VTE in patients with cancer cannot directly correlate to risk of stroke with a comorbid cardiac condition, but the hypercoagulable state cannot be ignored in these patients.

Conclusion

This study provided some preliminary evidence for the safety and efficacy of DOACs in patients with cancer. The low incidence of VTE formation and similar rates of bleeding among other clinical trials indicate that DOACs are safe alternatives to currently recommended anticoagulation medication in patients with cancer.

A rise in medical malpractice insurance premiums and malpractice claims has brought the issue of medical malpractice to the forefront of medicine over the past few decades.¹ The VA has more than tripled the number of legal settlements it has made over the past 5 years, and it has paid more than $871 million in medical malpractice settlements over the past decade.^2,3 Legislation by the federal and state governments in the U.S., collectively referred to as tort reform, has been passed to curb the rate at which malpractice claims are filed; to set caps on noneconomic damages, such as pain and suffering; to control the effect of these claims on insurance premiums; and to prevent the delivery of negligent and harmful medical care.¹

An observed high prevalence of medical malpractice claims has significant consequences within the clinical setting and has given rise to the practice of defensive medicine.^4-8 Even the perceived threat of possible tort action may lead to aberrant practice behaviors. These defensive medical practices may include excessive testing, unnecessary referrals to other physicians or health facilities, or even refusal to treat particular patients.^4,9-11 Furthermore, physicians devote valuable time and energy engaging in lawsuits rather than in delivering quality care to their patients.¹²

The increasingly litigious environment has discouraged physicians from practicing medicine, leading to earlier retirement, geographic relocation, and restriction of scope of services, all limiting patients’ access to health care.¹³ One such figure reported in 2008 found that in the U.S., defensive medicine costs can total nearly $56 billion.¹⁴ Radiation oncology is generally considered a medium-to-low risk specialty for litigation.^15,16 Its average annual indemnity payment in 2006 was $276,792 and has increased at a rate of $1,500 per year, ranking it fifth among 22 specialty groups.¹⁶ Studies revealed that the practice of defensive medicine is not strictly limited to the U.S. and has been reported in other countries.^6,17-20,21

A recent study by Jena and colleagues found that nearly 10% of oncologists face a malpractice claim annually, the 10th highest among the specialties surveyed.²² Malpractice within the field of radiation oncology has been previously discussed in the literature.^16,23,24 There are limited data that examine the basis for these claims, the resulting jury verdicts, and the subsequent indemnity payments associated with claims.^24,25

In this study, the authors sought to describe radiation oncology malpractice claims over the past 30 years. It is hoped that this study will not only help traditional oncologists in particular, but also all other practitioners who might be included as co-defendants to be more aware of the common causes of action that plaintiffs have been using to sue.

Methods

This public and online study did not involve human subjects research and accordingly did not require institutional review board approval. The WestlawNext (Thomson Reuters, New York) online legal database was used to search retrospectively for state and federal jury verdicts and settlements related to radiation oncology and medical malpractice. The database is a collection of several thousand search engines that can locate court dockets, jury verdicts, and settlements compiled by attorney-editors. Local cases and claims that were dismissed prior to proceeding to trial or that were settled out of court were not available. All cases in the database were considered and provided this study’s sample size, spanning from January 1, 1985, to December 31, 2015.

Given the boolean search functionality integrated into the Westlaw database, search parameters included “radiation oncology” and “medical malpractice” to yield the greatest number of cases (n = 223). All derived cases were manually reviewed, and files that were duplicates or associated with litigation unrelated to radiation oncology were excluded from analysis (n = 191).

Analysis

Factors that were collected and considered included the state and county in which the claim was filed, the age and sex of the litigant at the time of malpractice, the year the case was settled, co-defendant specialties, jury verdicts, award payouts, death status of the litigant and the alleged basis for the medical malpractice claim. A lack of informed consent, a failure to treat in a timely manner, a failure to order appropriate tests or to make a timely referral, misinterpretation of a test, excessive radiation, unnecessary radiation, unnecessary surgery, and procedural error all were included as alleged bases for the malpractice claim. Descriptive statistics were then compiled.

Results

A total of 32 cases were included for analysis (Tables 1, 2, and 3). Anonymized summaries of all 32 cases are provided in the Appendix. The average age of the patient was 54.6 years (range 34-83) and included 17 (54.8%) female and 14 (45.2%) male patients. 

Excessive radiation (n = 11, 34.4%), unnecessary radiation (n = 8, 25%), and a failure to refer and/or order appropriate tests (n = 9, 28.1%) were the 3 most commonly alleged causes of malpractice. A lack of informed consent was implicated in less than one-seventh of cases (4; 12.5%). In 7 (21.9%) cases, the patient passed away.

Between 1985 and 2015, decisions were made in radiation oncologists’ favor in more than half of the cases. The jury ruled for the plaintiff in 11 (34.4%) cases and for the defendant in 17 (53.1%) cases. Settlements were reached in 4 (12.5%) cases, with a mean payout of $1,476,775. 

Discussion

A physician’s duty is to provide medical care within the standard of care. In the courtroom, a radiation oncologist is judged on what a “reasonably prudent” radiation oncologist would do in similar circumstances.²⁶ The plaintiff must establish the standard of care for the patient’s specific diagnosis with evidence, which is often accomplished through expert testimony. A physician is deemed negligent when deviating from this standard of care. The plaintiff must establish 4 factors to be awarded compensation for medical negligence: (1) the physician owed a professional duty to the patient such as the doctor-patient relationship; (2) the physician breeched this duty or failed to meet the standard of care; (3) proximate cause—the breach of duty by the physician directly caused the patient’s injury; and (4) the patient experienced emotional and/or physical damage while in the care of the physician.²⁷

Reasons for Malpractice Claims

The WestlawNext search revealed 3 top theories of breach of standard of care: excessive radiation, unnecessary radiation, and a failure to refer and/or order appropriate tests. As a result, these theories can be interpreted as medical malpractice law in evolution. In other words, the courts still may be laying groundwork to clarify these theories.

However, a more cynical interpretation of why these 3 top theories of breech of standard of care were seen would note the practice of using expert witness testimony as “hired guns” in the U.S. legal system. Plaintiff attorneys know that use of expert witnesses can increase the attorney’s billable hours during the discovery phase and can decrease the likelihood that the case would be thrown out as lacking merit. Nevertheless, when the claim eventually does go to trial, it may lack merit, but not before plaintiff and defense attorneys complete many hours of work. This use of the legal system for financial gains can potentially confound the true reasons why the search resulted in these 3 top theories of breach of standard of care.

A lack of informed consent was not a major issue and was cited only in 4 (12.5%) cases as the cause of alleged malpractice. This finding was reassuring, as informed consent is an important issue that reinforces the physician-patient relationship and enhances patient trust. Previous studies found a perceived lack of informed consent as a basis for a malpractice claim in more than 34% of otolaryngology cases,25% of cranial nerve surgery cases,and 39% of facial plastic surgery cases.^28-30 Perhaps the physician patient discussion in radiation oncology may be different compared with that of surgery, as treatments in radiation oncology are guided by large clinical trials, and patients are often referred after discussions with other specialty providers, such as surgeons and medical oncologists. Improving patients’ understanding of their radiation treatment plans is important in reducing malpractice claims relating to informed consent, and recent studies have identified areas where patient education can be improved.^31,32

Settlements

Although settlements were reached in a minority of cases, the monetary value of jury verdicts favoring the plaintiff were 3-fold higher than those of out-of-court settlements. Specifically, cases that were settled had a mean payout of $1,476,775, which sharply contrasts with cases that proceeded to trial and a mean payout of $4,744,219. The highest jury award to the plaintiff was $16,000,000, involving a case where it was determined that a double dose of radiation was delivered to a patient’s shoulder. In a simple risk-reward analysis, this suggests that radiation oncologists should consider settling out of court if a malpractice guilty verdict seems possible. However, given the retrospective nature of the analysis, only limited conclusions can be drawn regarding the effectiveness of such a strategy.

Regardless, cases that were settled or judged on the plaintiff’s behalf were for a much higher value in radiation oncology compared with indemnity payment claims data in other high-risk specialties (emergency medicine, general surgery, obstetrics and gynecologic surgery, and radiology).³³ It is important to highlight the magnitude of real and perceived harm that can be associated with radiation oncology. Regarding perceived harm, the public may lack an understanding of how radiation works. Interestingly, even though the perceived harm may be misplaced, the real harm is still there. Unlike other specialties where some errors can be reversed (ie, if heparin is mistakenly administered, its effects can be reversed by protamine sulfate), once radiation is delivered, it is not reversible. The harm is permanent and can cause disability.

Settlements are often lower in legal cases due to insurance policy limitations, the time line of award payout (settlement funds are paid more rapidly, as verdict awards are dependent on the conclusion of the case), and the inherent risk that an appeals court may overturn a verdict or reduce the amount of the award.³⁴ For all the radiation oncology cases that proceeded to trial, more than half (53.1%) of the cases were in favor of the physician (Table 3). While this is positive news for radiation oncologists, it is still lower than the national average of 75% of malpractice verdicts in favor of the physician.^34,35 In contrast, 65% of colorectal surgery cases resulted in a verdict in favor of the physician.³⁶

Geographic Locations

The concentration of cases in a few states in this analysis is likely due to a combination of factors, including the distinct legal climates in individual states and the geographic unequal distribution of radiation oncologists across the country. For instance, California’s Medical Injury Compensation Reform Act of 1975 caps limited pain, suffering, inconvenience, physical impairment, disfigurement, and other noneconomic and nonmedical damages in malpractice to $250,000.^37-39 Because of this cap, plaintiffs and their attorneys may be more hesitant to file a suit.

Radiation oncologists also remain concentrated in highly populated metropolitan health service areas, likely due to the attractiveness of academic centers, the large patient base required to sustain a practice, and the large capital investment needed to obtain the radiation equipment and staff resources to establish practices.^40-42

Evolving Malpractice Theories

Zaorsky and colleagues used a similar methodology to this study.²⁴ However, the distinction between this study and the Zaorsky study is that the latter attempted to use medical malpractice cases to draw conclusions on the validity and utility of quality assurance programs, specifically the Accreditation Program for Excellence (APEx) and the Radiation Oncology Incident Learning System (RO-ILS).^43-45 The APEx/RO-ILS systems report only errors and faults, and medical malpractice is based on different sets of variables, such as legal theories, litigation procedures, plaintiff/defense zealousness, and the judicial system of inclusion and exclusion of cases in the docket. It is not possible to control for these confounding variables. This study, in contrast to the Zaorsky study, distills the essence of medical malpractice in radiation oncology and draws conclusions to advance the theories of recovery of monetary damage.

Limitations

The WestlawNext database is a comprehensive source for outcomes and details in malpractice litigation and draws from multiple legal sources, but there are limitations to acknowledge. This study is a retrospective analysis and is limited by the inherent bias associated with its design. As noted in previous studies,^28,46 some jurisdictions may include only cases reported by attorneys on a voluntary basis with the purpose of predicting future outcomes and awards.⁴⁷ Settlements may be underrepresented in this study. Out-of-court settlements often are not filed with state or federal courts and thus do not become part of the public record. The level of detail in jury verdicts in this database also is heterogeneous, and each case has different details and varying depths emphasized.

A better source of settlements and plaintiff verdict awards may be the National Practitioner Data Bank (NPDB), an electronic repository created by the U.S. Congress. It contains information on medical malpractice payments and certain adverse actions related to health care practitioners, entities, providers, and suppliers. However, the reports are confidential and not available to the public.

This study had a low number of cases (n = 32), but the information provided is impactful given there is a lack of access to a better source. For instance, insurance companies provide claims data, but the data have been criticized because insurers may be biased in determining which data to release. As discussed previously, the NPDB is not available for public review. Therefore, it is uncertain how many of the medical malpractice cases the WestlawNext database captures.

Based on the discussion with multiple medical malpractice lawyers practicing in various jurisdictions across the country and law school reference librarians, there is a concurrence that about 70% to 90% of claims are not taken on by plaintiff attorneys because of lack of merit or for procedural legal reasons, such as when there is no standing or when the statute of limitations has expired. Of the 10% to 30% claims that proceed to trial, about 90% result in a confidential settlement. Moreover, the court can render an order or an opinion. If it is an order, the case is never recorded. If it is an opinion, the case still may not be included in the WestlawNext database. Only cases that are on appeal, with controversy, proceed through the state and federal appellate system; judges still can decide whether to publish the results from these cases. Depending on jurisdiction, these factors result in 20% to 92% of opinions not being published for any given year. However, opinions that are marked for publishing should be included in the WestlawNext database with negligible omissions and errors. The percentage of published cases in WestlawNext database of all claims could very well be only 1% to 5%.

Nevertheless, the WestlawNext database covers a large geographic area and is a comprehensive source of litigation information. The authors selected WestlawNext over other online legal databases (ie, Bloomberg Law, LexisNexis, VerdictSearch) due to its reputation, quality of case entries, and ease of navigation. WestlawNext is well known among lawyers and legal professions, and it has been validated through previous studies in other medical fields such as general surgery and its subspecialties,^36,48 otolaryngology,^28,46,47,49 ophthalmology,⁵⁰ urology,⁵¹ dermatology,⁵² and plastic surgery.⁵³

Conclusion

Litigation involving radiation oncologists were infrequent, and most verdicts were in favor of defendant radiation oncologists. Excessive radiation, unnecessary radiation, and a failure to refer and/or order appropriate tests were noted in most cases. Settlements were reached in the minority of cases, although mean payouts were more than 3 times less in these cases compared with jury verdicts. An increased awareness of radiation oncology malpractice litigation has the potential to improve physician-patient relationships and provide insight into the situations and conditions that commonly lead to litigation within the radiation oncology field.

Click here to read the digital edition.

A rise in medical malpractice insurance premiums and malpractice claims has brought the issue of medical malpractice to the forefront of medicine over the past few decades.¹ The VA has more than tripled the number of legal settlements it has made over the past 5 years, and it has paid more than $871 million in medical malpractice settlements over the past decade.^2,3 Legislation by the federal and state governments in the U.S., collectively referred to as tort reform, has been passed to curb the rate at which malpractice claims are filed; to set caps on noneconomic damages, such as pain and suffering; to control the effect of these claims on insurance premiums; and to prevent the delivery of negligent and harmful medical care.¹

An observed high prevalence of medical malpractice claims has significant consequences within the clinical setting and has given rise to the practice of defensive medicine.^4-8 Even the perceived threat of possible tort action may lead to aberrant practice behaviors. These defensive medical practices may include excessive testing, unnecessary referrals to other physicians or health facilities, or even refusal to treat particular patients.^4,9-11 Furthermore, physicians devote valuable time and energy engaging in lawsuits rather than in delivering quality care to their patients.¹²

The increasingly litigious environment has discouraged physicians from practicing medicine, leading to earlier retirement, geographic relocation, and restriction of scope of services, all limiting patients’ access to health care.¹³ One such figure reported in 2008 found that in the U.S., defensive medicine costs can total nearly $56 billion.¹⁴ Radiation oncology is generally considered a medium-to-low risk specialty for litigation.^15,16 Its average annual indemnity payment in 2006 was $276,792 and has increased at a rate of $1,500 per year, ranking it fifth among 22 specialty groups.¹⁶ Studies revealed that the practice of defensive medicine is not strictly limited to the U.S. and has been reported in other countries.^6,17-20,21

A recent study by Jena and colleagues found that nearly 10% of oncologists face a malpractice claim annually, the 10th highest among the specialties surveyed.²² Malpractice within the field of radiation oncology has been previously discussed in the literature.^16,23,24 There are limited data that examine the basis for these claims, the resulting jury verdicts, and the subsequent indemnity payments associated with claims.^24,25

In this study, the authors sought to describe radiation oncology malpractice claims over the past 30 years. It is hoped that this study will not only help traditional oncologists in particular, but also all other practitioners who might be included as co-defendants to be more aware of the common causes of action that plaintiffs have been using to sue.

Methods

This public and online study did not involve human subjects research and accordingly did not require institutional review board approval. The WestlawNext (Thomson Reuters, New York) online legal database was used to search retrospectively for state and federal jury verdicts and settlements related to radiation oncology and medical malpractice. The database is a collection of several thousand search engines that can locate court dockets, jury verdicts, and settlements compiled by attorney-editors. Local cases and claims that were dismissed prior to proceeding to trial or that were settled out of court were not available. All cases in the database were considered and provided this study’s sample size, spanning from January 1, 1985, to December 31, 2015.

Given the boolean search functionality integrated into the Westlaw database, search parameters included “radiation oncology” and “medical malpractice” to yield the greatest number of cases (n = 223). All derived cases were manually reviewed, and files that were duplicates or associated with litigation unrelated to radiation oncology were excluded from analysis (n = 191).

Analysis

Factors that were collected and considered included the state and county in which the claim was filed, the age and sex of the litigant at the time of malpractice, the year the case was settled, co-defendant specialties, jury verdicts, award payouts, death status of the litigant and the alleged basis for the medical malpractice claim. A lack of informed consent, a failure to treat in a timely manner, a failure to order appropriate tests or to make a timely referral, misinterpretation of a test, excessive radiation, unnecessary radiation, unnecessary surgery, and procedural error all were included as alleged bases for the malpractice claim. Descriptive statistics were then compiled.

Results

A total of 32 cases were included for analysis (Tables 1, 2, and 3). Anonymized summaries of all 32 cases are provided in the Appendix. The average age of the patient was 54.6 years (range 34-83) and included 17 (54.8%) female and 14 (45.2%) male patients. 

Excessive radiation (n = 11, 34.4%), unnecessary radiation (n = 8, 25%), and a failure to refer and/or order appropriate tests (n = 9, 28.1%) were the 3 most commonly alleged causes of malpractice. A lack of informed consent was implicated in less than one-seventh of cases (4; 12.5%). In 7 (21.9%) cases, the patient passed away.

Between 1985 and 2015, decisions were made in radiation oncologists’ favor in more than half of the cases. The jury ruled for the plaintiff in 11 (34.4%) cases and for the defendant in 17 (53.1%) cases. Settlements were reached in 4 (12.5%) cases, with a mean payout of $1,476,775. 

Discussion

A physician’s duty is to provide medical care within the standard of care. In the courtroom, a radiation oncologist is judged on what a “reasonably prudent” radiation oncologist would do in similar circumstances.²⁶ The plaintiff must establish the standard of care for the patient’s specific diagnosis with evidence, which is often accomplished through expert testimony. A physician is deemed negligent when deviating from this standard of care. The plaintiff must establish 4 factors to be awarded compensation for medical negligence: (1) the physician owed a professional duty to the patient such as the doctor-patient relationship; (2) the physician breeched this duty or failed to meet the standard of care; (3) proximate cause—the breach of duty by the physician directly caused the patient’s injury; and (4) the patient experienced emotional and/or physical damage while in the care of the physician.²⁷

Reasons for Malpractice Claims

The WestlawNext search revealed 3 top theories of breach of standard of care: excessive radiation, unnecessary radiation, and a failure to refer and/or order appropriate tests. As a result, these theories can be interpreted as medical malpractice law in evolution. In other words, the courts still may be laying groundwork to clarify these theories.

However, a more cynical interpretation of why these 3 top theories of breech of standard of care were seen would note the practice of using expert witness testimony as “hired guns” in the U.S. legal system. Plaintiff attorneys know that use of expert witnesses can increase the attorney’s billable hours during the discovery phase and can decrease the likelihood that the case would be thrown out as lacking merit. Nevertheless, when the claim eventually does go to trial, it may lack merit, but not before plaintiff and defense attorneys complete many hours of work. This use of the legal system for financial gains can potentially confound the true reasons why the search resulted in these 3 top theories of breach of standard of care.

A lack of informed consent was not a major issue and was cited only in 4 (12.5%) cases as the cause of alleged malpractice. This finding was reassuring, as informed consent is an important issue that reinforces the physician-patient relationship and enhances patient trust. Previous studies found a perceived lack of informed consent as a basis for a malpractice claim in more than 34% of otolaryngology cases,25% of cranial nerve surgery cases,and 39% of facial plastic surgery cases.^28-30 Perhaps the physician patient discussion in radiation oncology may be different compared with that of surgery, as treatments in radiation oncology are guided by large clinical trials, and patients are often referred after discussions with other specialty providers, such as surgeons and medical oncologists. Improving patients’ understanding of their radiation treatment plans is important in reducing malpractice claims relating to informed consent, and recent studies have identified areas where patient education can be improved.^31,32

Settlements

Although settlements were reached in a minority of cases, the monetary value of jury verdicts favoring the plaintiff were 3-fold higher than those of out-of-court settlements. Specifically, cases that were settled had a mean payout of $1,476,775, which sharply contrasts with cases that proceeded to trial and a mean payout of $4,744,219. The highest jury award to the plaintiff was $16,000,000, involving a case where it was determined that a double dose of radiation was delivered to a patient’s shoulder. In a simple risk-reward analysis, this suggests that radiation oncologists should consider settling out of court if a malpractice guilty verdict seems possible. However, given the retrospective nature of the analysis, only limited conclusions can be drawn regarding the effectiveness of such a strategy.

Regardless, cases that were settled or judged on the plaintiff’s behalf were for a much higher value in radiation oncology compared with indemnity payment claims data in other high-risk specialties (emergency medicine, general surgery, obstetrics and gynecologic surgery, and radiology).³³ It is important to highlight the magnitude of real and perceived harm that can be associated with radiation oncology. Regarding perceived harm, the public may lack an understanding of how radiation works. Interestingly, even though the perceived harm may be misplaced, the real harm is still there. Unlike other specialties where some errors can be reversed (ie, if heparin is mistakenly administered, its effects can be reversed by protamine sulfate), once radiation is delivered, it is not reversible. The harm is permanent and can cause disability.

Settlements are often lower in legal cases due to insurance policy limitations, the time line of award payout (settlement funds are paid more rapidly, as verdict awards are dependent on the conclusion of the case), and the inherent risk that an appeals court may overturn a verdict or reduce the amount of the award.³⁴ For all the radiation oncology cases that proceeded to trial, more than half (53.1%) of the cases were in favor of the physician (Table 3). While this is positive news for radiation oncologists, it is still lower than the national average of 75% of malpractice verdicts in favor of the physician.^34,35 In contrast, 65% of colorectal surgery cases resulted in a verdict in favor of the physician.³⁶

Geographic Locations

The concentration of cases in a few states in this analysis is likely due to a combination of factors, including the distinct legal climates in individual states and the geographic unequal distribution of radiation oncologists across the country. For instance, California’s Medical Injury Compensation Reform Act of 1975 caps limited pain, suffering, inconvenience, physical impairment, disfigurement, and other noneconomic and nonmedical damages in malpractice to $250,000.^37-39 Because of this cap, plaintiffs and their attorneys may be more hesitant to file a suit.

Radiation oncologists also remain concentrated in highly populated metropolitan health service areas, likely due to the attractiveness of academic centers, the large patient base required to sustain a practice, and the large capital investment needed to obtain the radiation equipment and staff resources to establish practices.^40-42

Evolving Malpractice Theories

Zaorsky and colleagues used a similar methodology to this study.²⁴ However, the distinction between this study and the Zaorsky study is that the latter attempted to use medical malpractice cases to draw conclusions on the validity and utility of quality assurance programs, specifically the Accreditation Program for Excellence (APEx) and the Radiation Oncology Incident Learning System (RO-ILS).^43-45 The APEx/RO-ILS systems report only errors and faults, and medical malpractice is based on different sets of variables, such as legal theories, litigation procedures, plaintiff/defense zealousness, and the judicial system of inclusion and exclusion of cases in the docket. It is not possible to control for these confounding variables. This study, in contrast to the Zaorsky study, distills the essence of medical malpractice in radiation oncology and draws conclusions to advance the theories of recovery of monetary damage.

Limitations

The WestlawNext database is a comprehensive source for outcomes and details in malpractice litigation and draws from multiple legal sources, but there are limitations to acknowledge. This study is a retrospective analysis and is limited by the inherent bias associated with its design. As noted in previous studies,^28,46 some jurisdictions may include only cases reported by attorneys on a voluntary basis with the purpose of predicting future outcomes and awards.⁴⁷ Settlements may be underrepresented in this study. Out-of-court settlements often are not filed with state or federal courts and thus do not become part of the public record. The level of detail in jury verdicts in this database also is heterogeneous, and each case has different details and varying depths emphasized.

A better source of settlements and plaintiff verdict awards may be the National Practitioner Data Bank (NPDB), an electronic repository created by the U.S. Congress. It contains information on medical malpractice payments and certain adverse actions related to health care practitioners, entities, providers, and suppliers. However, the reports are confidential and not available to the public.

This study had a low number of cases (n = 32), but the information provided is impactful given there is a lack of access to a better source. For instance, insurance companies provide claims data, but the data have been criticized because insurers may be biased in determining which data to release. As discussed previously, the NPDB is not available for public review. Therefore, it is uncertain how many of the medical malpractice cases the WestlawNext database captures.

Based on the discussion with multiple medical malpractice lawyers practicing in various jurisdictions across the country and law school reference librarians, there is a concurrence that about 70% to 90% of claims are not taken on by plaintiff attorneys because of lack of merit or for procedural legal reasons, such as when there is no standing or when the statute of limitations has expired. Of the 10% to 30% claims that proceed to trial, about 90% result in a confidential settlement. Moreover, the court can render an order or an opinion. If it is an order, the case is never recorded. If it is an opinion, the case still may not be included in the WestlawNext database. Only cases that are on appeal, with controversy, proceed through the state and federal appellate system; judges still can decide whether to publish the results from these cases. Depending on jurisdiction, these factors result in 20% to 92% of opinions not being published for any given year. However, opinions that are marked for publishing should be included in the WestlawNext database with negligible omissions and errors. The percentage of published cases in WestlawNext database of all claims could very well be only 1% to 5%.

Nevertheless, the WestlawNext database covers a large geographic area and is a comprehensive source of litigation information. The authors selected WestlawNext over other online legal databases (ie, Bloomberg Law, LexisNexis, VerdictSearch) due to its reputation, quality of case entries, and ease of navigation. WestlawNext is well known among lawyers and legal professions, and it has been validated through previous studies in other medical fields such as general surgery and its subspecialties,^36,48 otolaryngology,^28,46,47,49 ophthalmology,⁵⁰ urology,⁵¹ dermatology,⁵² and plastic surgery.⁵³

Conclusion

Litigation involving radiation oncologists were infrequent, and most verdicts were in favor of defendant radiation oncologists. Excessive radiation, unnecessary radiation, and a failure to refer and/or order appropriate tests were noted in most cases. Settlements were reached in the minority of cases, although mean payouts were more than 3 times less in these cases compared with jury verdicts. An increased awareness of radiation oncology malpractice litigation has the potential to improve physician-patient relationships and provide insight into the situations and conditions that commonly lead to litigation within the radiation oncology field.

Click here to read the digital edition.

A rise in medical malpractice insurance premiums and malpractice claims has brought the issue of medical malpractice to the forefront of medicine over the past few decades.¹ The VA has more than tripled the number of legal settlements it has made over the past 5 years, and it has paid more than $871 million in medical malpractice settlements over the past decade.^2,3 Legislation by the federal and state governments in the U.S., collectively referred to as tort reform, has been passed to curb the rate at which malpractice claims are filed; to set caps on noneconomic damages, such as pain and suffering; to control the effect of these claims on insurance premiums; and to prevent the delivery of negligent and harmful medical care.¹

An observed high prevalence of medical malpractice claims has significant consequences within the clinical setting and has given rise to the practice of defensive medicine.^4-8 Even the perceived threat of possible tort action may lead to aberrant practice behaviors. These defensive medical practices may include excessive testing, unnecessary referrals to other physicians or health facilities, or even refusal to treat particular patients.^4,9-11 Furthermore, physicians devote valuable time and energy engaging in lawsuits rather than in delivering quality care to their patients.¹²

The increasingly litigious environment has discouraged physicians from practicing medicine, leading to earlier retirement, geographic relocation, and restriction of scope of services, all limiting patients’ access to health care.¹³ One such figure reported in 2008 found that in the U.S., defensive medicine costs can total nearly $56 billion.¹⁴ Radiation oncology is generally considered a medium-to-low risk specialty for litigation.^15,16 Its average annual indemnity payment in 2006 was $276,792 and has increased at a rate of $1,500 per year, ranking it fifth among 22 specialty groups.¹⁶ Studies revealed that the practice of defensive medicine is not strictly limited to the U.S. and has been reported in other countries.^6,17-20,21

A recent study by Jena and colleagues found that nearly 10% of oncologists face a malpractice claim annually, the 10th highest among the specialties surveyed.²² Malpractice within the field of radiation oncology has been previously discussed in the literature.^16,23,24 There are limited data that examine the basis for these claims, the resulting jury verdicts, and the subsequent indemnity payments associated with claims.^24,25

In this study, the authors sought to describe radiation oncology malpractice claims over the past 30 years. It is hoped that this study will not only help traditional oncologists in particular, but also all other practitioners who might be included as co-defendants to be more aware of the common causes of action that plaintiffs have been using to sue.

Methods

This public and online study did not involve human subjects research and accordingly did not require institutional review board approval. The WestlawNext (Thomson Reuters, New York) online legal database was used to search retrospectively for state and federal jury verdicts and settlements related to radiation oncology and medical malpractice. The database is a collection of several thousand search engines that can locate court dockets, jury verdicts, and settlements compiled by attorney-editors. Local cases and claims that were dismissed prior to proceeding to trial or that were settled out of court were not available. All cases in the database were considered and provided this study’s sample size, spanning from January 1, 1985, to December 31, 2015.

Given the boolean search functionality integrated into the Westlaw database, search parameters included “radiation oncology” and “medical malpractice” to yield the greatest number of cases (n = 223). All derived cases were manually reviewed, and files that were duplicates or associated with litigation unrelated to radiation oncology were excluded from analysis (n = 191).

Analysis

Factors that were collected and considered included the state and county in which the claim was filed, the age and sex of the litigant at the time of malpractice, the year the case was settled, co-defendant specialties, jury verdicts, award payouts, death status of the litigant and the alleged basis for the medical malpractice claim. A lack of informed consent, a failure to treat in a timely manner, a failure to order appropriate tests or to make a timely referral, misinterpretation of a test, excessive radiation, unnecessary radiation, unnecessary surgery, and procedural error all were included as alleged bases for the malpractice claim. Descriptive statistics were then compiled.

Results

A total of 32 cases were included for analysis (Tables 1, 2, and 3). Anonymized summaries of all 32 cases are provided in the Appendix. The average age of the patient was 54.6 years (range 34-83) and included 17 (54.8%) female and 14 (45.2%) male patients. 

Excessive radiation (n = 11, 34.4%), unnecessary radiation (n = 8, 25%), and a failure to refer and/or order appropriate tests (n = 9, 28.1%) were the 3 most commonly alleged causes of malpractice. A lack of informed consent was implicated in less than one-seventh of cases (4; 12.5%). In 7 (21.9%) cases, the patient passed away.

Between 1985 and 2015, decisions were made in radiation oncologists’ favor in more than half of the cases. The jury ruled for the plaintiff in 11 (34.4%) cases and for the defendant in 17 (53.1%) cases. Settlements were reached in 4 (12.5%) cases, with a mean payout of $1,476,775. 

Discussion

A physician’s duty is to provide medical care within the standard of care. In the courtroom, a radiation oncologist is judged on what a “reasonably prudent” radiation oncologist would do in similar circumstances.²⁶ The plaintiff must establish the standard of care for the patient’s specific diagnosis with evidence, which is often accomplished through expert testimony. A physician is deemed negligent when deviating from this standard of care. The plaintiff must establish 4 factors to be awarded compensation for medical negligence: (1) the physician owed a professional duty to the patient such as the doctor-patient relationship; (2) the physician breeched this duty or failed to meet the standard of care; (3) proximate cause—the breach of duty by the physician directly caused the patient’s injury; and (4) the patient experienced emotional and/or physical damage while in the care of the physician.²⁷

Reasons for Malpractice Claims

The WestlawNext search revealed 3 top theories of breach of standard of care: excessive radiation, unnecessary radiation, and a failure to refer and/or order appropriate tests. As a result, these theories can be interpreted as medical malpractice law in evolution. In other words, the courts still may be laying groundwork to clarify these theories.

However, a more cynical interpretation of why these 3 top theories of breech of standard of care were seen would note the practice of using expert witness testimony as “hired guns” in the U.S. legal system. Plaintiff attorneys know that use of expert witnesses can increase the attorney’s billable hours during the discovery phase and can decrease the likelihood that the case would be thrown out as lacking merit. Nevertheless, when the claim eventually does go to trial, it may lack merit, but not before plaintiff and defense attorneys complete many hours of work. This use of the legal system for financial gains can potentially confound the true reasons why the search resulted in these 3 top theories of breach of standard of care.

A lack of informed consent was not a major issue and was cited only in 4 (12.5%) cases as the cause of alleged malpractice. This finding was reassuring, as informed consent is an important issue that reinforces the physician-patient relationship and enhances patient trust. Previous studies found a perceived lack of informed consent as a basis for a malpractice claim in more than 34% of otolaryngology cases,25% of cranial nerve surgery cases,and 39% of facial plastic surgery cases.^28-30 Perhaps the physician patient discussion in radiation oncology may be different compared with that of surgery, as treatments in radiation oncology are guided by large clinical trials, and patients are often referred after discussions with other specialty providers, such as surgeons and medical oncologists. Improving patients’ understanding of their radiation treatment plans is important in reducing malpractice claims relating to informed consent, and recent studies have identified areas where patient education can be improved.^31,32

Settlements

Although settlements were reached in a minority of cases, the monetary value of jury verdicts favoring the plaintiff were 3-fold higher than those of out-of-court settlements. Specifically, cases that were settled had a mean payout of $1,476,775, which sharply contrasts with cases that proceeded to trial and a mean payout of $4,744,219. The highest jury award to the plaintiff was $16,000,000, involving a case where it was determined that a double dose of radiation was delivered to a patient’s shoulder. In a simple risk-reward analysis, this suggests that radiation oncologists should consider settling out of court if a malpractice guilty verdict seems possible. However, given the retrospective nature of the analysis, only limited conclusions can be drawn regarding the effectiveness of such a strategy.

Regardless, cases that were settled or judged on the plaintiff’s behalf were for a much higher value in radiation oncology compared with indemnity payment claims data in other high-risk specialties (emergency medicine, general surgery, obstetrics and gynecologic surgery, and radiology).³³ It is important to highlight the magnitude of real and perceived harm that can be associated with radiation oncology. Regarding perceived harm, the public may lack an understanding of how radiation works. Interestingly, even though the perceived harm may be misplaced, the real harm is still there. Unlike other specialties where some errors can be reversed (ie, if heparin is mistakenly administered, its effects can be reversed by protamine sulfate), once radiation is delivered, it is not reversible. The harm is permanent and can cause disability.

Settlements are often lower in legal cases due to insurance policy limitations, the time line of award payout (settlement funds are paid more rapidly, as verdict awards are dependent on the conclusion of the case), and the inherent risk that an appeals court may overturn a verdict or reduce the amount of the award.³⁴ For all the radiation oncology cases that proceeded to trial, more than half (53.1%) of the cases were in favor of the physician (Table 3). While this is positive news for radiation oncologists, it is still lower than the national average of 75% of malpractice verdicts in favor of the physician.^34,35 In contrast, 65% of colorectal surgery cases resulted in a verdict in favor of the physician.³⁶

Geographic Locations

The concentration of cases in a few states in this analysis is likely due to a combination of factors, including the distinct legal climates in individual states and the geographic unequal distribution of radiation oncologists across the country. For instance, California’s Medical Injury Compensation Reform Act of 1975 caps limited pain, suffering, inconvenience, physical impairment, disfigurement, and other noneconomic and nonmedical damages in malpractice to $250,000.^37-39 Because of this cap, plaintiffs and their attorneys may be more hesitant to file a suit.

Radiation oncologists also remain concentrated in highly populated metropolitan health service areas, likely due to the attractiveness of academic centers, the large patient base required to sustain a practice, and the large capital investment needed to obtain the radiation equipment and staff resources to establish practices.^40-42

Evolving Malpractice Theories

Zaorsky and colleagues used a similar methodology to this study.²⁴ However, the distinction between this study and the Zaorsky study is that the latter attempted to use medical malpractice cases to draw conclusions on the validity and utility of quality assurance programs, specifically the Accreditation Program for Excellence (APEx) and the Radiation Oncology Incident Learning System (RO-ILS).^43-45 The APEx/RO-ILS systems report only errors and faults, and medical malpractice is based on different sets of variables, such as legal theories, litigation procedures, plaintiff/defense zealousness, and the judicial system of inclusion and exclusion of cases in the docket. It is not possible to control for these confounding variables. This study, in contrast to the Zaorsky study, distills the essence of medical malpractice in radiation oncology and draws conclusions to advance the theories of recovery of monetary damage.

Limitations

The WestlawNext database is a comprehensive source for outcomes and details in malpractice litigation and draws from multiple legal sources, but there are limitations to acknowledge. This study is a retrospective analysis and is limited by the inherent bias associated with its design. As noted in previous studies,^28,46 some jurisdictions may include only cases reported by attorneys on a voluntary basis with the purpose of predicting future outcomes and awards.⁴⁷ Settlements may be underrepresented in this study. Out-of-court settlements often are not filed with state or federal courts and thus do not become part of the public record. The level of detail in jury verdicts in this database also is heterogeneous, and each case has different details and varying depths emphasized.

A better source of settlements and plaintiff verdict awards may be the National Practitioner Data Bank (NPDB), an electronic repository created by the U.S. Congress. It contains information on medical malpractice payments and certain adverse actions related to health care practitioners, entities, providers, and suppliers. However, the reports are confidential and not available to the public.

This study had a low number of cases (n = 32), but the information provided is impactful given there is a lack of access to a better source. For instance, insurance companies provide claims data, but the data have been criticized because insurers may be biased in determining which data to release. As discussed previously, the NPDB is not available for public review. Therefore, it is uncertain how many of the medical malpractice cases the WestlawNext database captures.

Based on the discussion with multiple medical malpractice lawyers practicing in various jurisdictions across the country and law school reference librarians, there is a concurrence that about 70% to 90% of claims are not taken on by plaintiff attorneys because of lack of merit or for procedural legal reasons, such as when there is no standing or when the statute of limitations has expired. Of the 10% to 30% claims that proceed to trial, about 90% result in a confidential settlement. Moreover, the court can render an order or an opinion. If it is an order, the case is never recorded. If it is an opinion, the case still may not be included in the WestlawNext database. Only cases that are on appeal, with controversy, proceed through the state and federal appellate system; judges still can decide whether to publish the results from these cases. Depending on jurisdiction, these factors result in 20% to 92% of opinions not being published for any given year. However, opinions that are marked for publishing should be included in the WestlawNext database with negligible omissions and errors. The percentage of published cases in WestlawNext database of all claims could very well be only 1% to 5%.

Nevertheless, the WestlawNext database covers a large geographic area and is a comprehensive source of litigation information. The authors selected WestlawNext over other online legal databases (ie, Bloomberg Law, LexisNexis, VerdictSearch) due to its reputation, quality of case entries, and ease of navigation. WestlawNext is well known among lawyers and legal professions, and it has been validated through previous studies in other medical fields such as general surgery and its subspecialties,^36,48 otolaryngology,^28,46,47,49 ophthalmology,⁵⁰ urology,⁵¹ dermatology,⁵² and plastic surgery.⁵³

Conclusion

Litigation involving radiation oncologists were infrequent, and most verdicts were in favor of defendant radiation oncologists. Excessive radiation, unnecessary radiation, and a failure to refer and/or order appropriate tests were noted in most cases. Settlements were reached in the minority of cases, although mean payouts were more than 3 times less in these cases compared with jury verdicts. An increased awareness of radiation oncology malpractice litigation has the potential to improve physician-patient relationships and provide insight into the situations and conditions that commonly lead to litigation within the radiation oncology field.

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