AVAHO

For years, people living and working at Camp Lejeune in Jacksonville, N.C., drank and showered in water contaminated with trichloroethylene (TCE) and other industrial solvents. Now, a Centers for Disease Control and Prevention (CDC) study has determined that the exposure markedly increased their risk for certain cancers.

In one of the largest cohort cancer incidence studies ever completed in the US, researchers compared cancer risk between 161,315 military personnel and civilian workers at Camp Lejeune and 169,281 military personnel and civilian workers at Camp Pendleton in Oceanside, Calif., where the water was not contaminated.

Data from diagnoses between 1996 and 2017 documented 12,083 cancers among Camp Lejeune Marine and Navy personnel and 1,563 among civilian workers. By comparison, 12,144 cancers were documented among Camp Pendleton personnel and 1,372 among civilian workers. However, personnel stationed at Camp Lejeune between 1975 and 1985 had at least a 20% higher risk for all myeloid cancers including polycythemia vera, acute myeloid leukemia, myelodysplastic and myeloproliferative syndromes, and cancers of the esophagus, larynx, soft tissue, and thyroid. Civilian workers had a higher risk for all myeloid cancers, squamous cell lung cancer, and female ductal breast cancer.

The water exposures included contributions to total internal body dose from 3 routes: ingestion, inhalation, and dermal. The researchers note that a Marine in training may consume as much as 6 liters a day of drinking water, but the combined dose from inhalation and dermal routes could be as high or higher than that from ingestion. For example, they note that an internal dose via inhalation to TCE during a 10-minute shower could equal the internal dose via ingestion of 2 liters of contaminated drinking water.

Health risks at Camp Lejeune have been studied before, but this study “more fully establishes the scope,” Richard Clapp, a Boston University emeritus public health professor, told the Associated Press.

For years, people living and working at Camp Lejeune in Jacksonville, N.C., drank and showered in water contaminated with trichloroethylene (TCE) and other industrial solvents. Now, a Centers for Disease Control and Prevention (CDC) study has determined that the exposure markedly increased their risk for certain cancers.

In one of the largest cohort cancer incidence studies ever completed in the US, researchers compared cancer risk between 161,315 military personnel and civilian workers at Camp Lejeune and 169,281 military personnel and civilian workers at Camp Pendleton in Oceanside, Calif., where the water was not contaminated.

Data from diagnoses between 1996 and 2017 documented 12,083 cancers among Camp Lejeune Marine and Navy personnel and 1,563 among civilian workers. By comparison, 12,144 cancers were documented among Camp Pendleton personnel and 1,372 among civilian workers. However, personnel stationed at Camp Lejeune between 1975 and 1985 had at least a 20% higher risk for all myeloid cancers including polycythemia vera, acute myeloid leukemia, myelodysplastic and myeloproliferative syndromes, and cancers of the esophagus, larynx, soft tissue, and thyroid. Civilian workers had a higher risk for all myeloid cancers, squamous cell lung cancer, and female ductal breast cancer.

The water exposures included contributions to total internal body dose from 3 routes: ingestion, inhalation, and dermal. The researchers note that a Marine in training may consume as much as 6 liters a day of drinking water, but the combined dose from inhalation and dermal routes could be as high or higher than that from ingestion. For example, they note that an internal dose via inhalation to TCE during a 10-minute shower could equal the internal dose via ingestion of 2 liters of contaminated drinking water.

Health risks at Camp Lejeune have been studied before, but this study “more fully establishes the scope,” Richard Clapp, a Boston University emeritus public health professor, told the Associated Press.

For years, people living and working at Camp Lejeune in Jacksonville, N.C., drank and showered in water contaminated with trichloroethylene (TCE) and other industrial solvents. Now, a Centers for Disease Control and Prevention (CDC) study has determined that the exposure markedly increased their risk for certain cancers.

In one of the largest cohort cancer incidence studies ever completed in the US, researchers compared cancer risk between 161,315 military personnel and civilian workers at Camp Lejeune and 169,281 military personnel and civilian workers at Camp Pendleton in Oceanside, Calif., where the water was not contaminated.

Data from diagnoses between 1996 and 2017 documented 12,083 cancers among Camp Lejeune Marine and Navy personnel and 1,563 among civilian workers. By comparison, 12,144 cancers were documented among Camp Pendleton personnel and 1,372 among civilian workers. However, personnel stationed at Camp Lejeune between 1975 and 1985 had at least a 20% higher risk for all myeloid cancers including polycythemia vera, acute myeloid leukemia, myelodysplastic and myeloproliferative syndromes, and cancers of the esophagus, larynx, soft tissue, and thyroid. Civilian workers had a higher risk for all myeloid cancers, squamous cell lung cancer, and female ductal breast cancer.

The water exposures included contributions to total internal body dose from 3 routes: ingestion, inhalation, and dermal. The researchers note that a Marine in training may consume as much as 6 liters a day of drinking water, but the combined dose from inhalation and dermal routes could be as high or higher than that from ingestion. For example, they note that an internal dose via inhalation to TCE during a 10-minute shower could equal the internal dose via ingestion of 2 liters of contaminated drinking water.

Health risks at Camp Lejeune have been studied before, but this study “more fully establishes the scope,” Richard Clapp, a Boston University emeritus public health professor, told the Associated Press.

Dry January has come to an end — at least for those who jumped on the trendy post-holiday no-booze wagon.

The benefits of drinking less alcohol are well documented. A systematic review of 63 studies, for example, found that reducing or giving up alcohol reduced people’s risk for hospitalization, injuries, and death. The lifestyle change also improved people’s physical and mental health as well as their quality of life.

When it comes to cancer risk, however, the benefits of quitting or cutting back on alcohol remain much less clear, according to a new report from the cancer agency of the World Health Organization (WHO).

After reviewing dozens of studies, the International Agency for Research on Cancer (IARC) concluded that, for most alcohol-related cancers, there is limited evidence to support a link between eliminating or reducing alcohol consumption and lowering of cancer risk.

More specifically, the IARC Working Group, which included 15 scientists from eight countries, reported “limited” evidence on this association for laryngeal, colorectal (CRC), and breast cancer as well as «inadequate» evidence for pharyngeal and liver cancer.

The report did highlight two exceptions: Reducing or quitting alcohol was associated with a lower risk for both oral and esophageal cancer. The IARC working group based this conclusion on large studies of long-term alcohol cessation in these cancer types.

Still, the authors noted, “significant scientific gaps” exist for most alcohol-related cancers.

Take the data on CRC. Two studies found that reducing alcohol consumption did appear to lower CRC risk, while two others — which focused on the duration of quitting — did not suggest a reduced risk for CRC.

“Given the inconsistencies among studies and the few studies on duration of cessation, the Working Group concluded that there was limited evidence that alcohol reduction or cessation reduces colorectal cancer risk,” the authors wrote.

For liver cancer, the experts did note an association between quitting alcohol and lower cancer risk, but that cohort study only included individuals with alcohol-related liver disease. Outside of this study, the IARC group found no clear association between quitting drinking and liver cancer among people without alcohol-related liver disease in the other 11 studies evaluated.

For pharyngeal cancer, the evidence was limited overall, but one analysis looking at long-term cessation and oropharyngeal or hypopharyngeal cancer found a 26% lower risk (95% CI, 0.50-1.09). That association went away, however, after adjusting for detailed smoking history (odds ratio, 0.95; 95% CI, 0.56-1.61), and the working group concluded, overall, that «there was inadequate evidence that alcohol reduction or cessation reduces pharyngeal cancer risk.”

The IARC working group did find sufficient evidence linking drinking cessation and reduced risk for oral and esophageal cancers.

For instance, an international pooled analysis, which included 12 studies assessing a link between quitting smoking and alcohol and oral cancer risk, found that longer duration since quitting was associated with lower risk. Not drinking for up to 4 years was associated with a 19% lower risk for oral cancer, quitting for 5-9 years was associated with a 23% lower risk, while quitting for 20 years was associated with 55% lower risk. 

“Given the consistent evidence of a reduced risk of oral cancer associated with long-term alcohol cessation,” the IARC working group concluded that there was “sufficient evidence that alcohol reduction or cessation reduces oral cancer risk.”

The working group also found “sufficient evidence from mechanistic studies that alcohol cessation reduces alcohol-related carcinogenesis.” In other words, quitting drinking appeared to reverse certain cancer-promoting biological mechanisms. 

Outside the recent IARC report, some individual studies have suggested that quitting or cutting back on alcohol can reduce the risk for certain cancers. 

For example, a large population-based study of about 4.5 million individuals in Korea found a lower risk for alcohol-related cancers among mild drinkers who quit (adjusted hazard ratio [aHR], 0.96) and heavy drinkers who reduced their drinking levels to mild (aHR, 0.92) or moderate (aHR, 0.91). These findings, however, may not be generalizable beyond East Asian populations.

Addressing the existing evidence gaps could help “support alcohol-control measures to reduce consumption,” the IARC working group concluded.

The Case for Limiting Alcohol

While the evidence linking reducing or stopping drinking and lower cancer risk remains limited, the opposite association is well-established — greater alcohol consumption does increase cancer risk. 

A previous IARC analysis estimated that alcohol consumption accounts for about 4% of newly diagnosed cancers worldwide, most commonly esophagus, liver, and breast cancer. The IARC has even classified alcohol as a group 1 carcinogen, highlighting the strong evidence demonstrating that alcohol can cause cancer in humans.

Experts also recommend following existing guidelines for alcohol intake. Guidelines from the American Cancer Society and from the US Department of Agriculture and Department of Health and Human Services specify limiting alcohol intake to one drink or less for women and two drinks or less for men on any given day. 

In a January 9, 2023, blog post, National Institute on Alcohol Abuse and Alcoholism director George F. Koob, PhD, touted the known benefits of limiting drinking.

“Research shows that even small amounts of alcohol can carry health risks, including for certain cancers and cardiovascular issues,” Dr. Koob said. 

A version of this article appeared on Medscape.com.

Dry January has come to an end — at least for those who jumped on the trendy post-holiday no-booze wagon.

The benefits of drinking less alcohol are well documented. A systematic review of 63 studies, for example, found that reducing or giving up alcohol reduced people’s risk for hospitalization, injuries, and death. The lifestyle change also improved people’s physical and mental health as well as their quality of life.

When it comes to cancer risk, however, the benefits of quitting or cutting back on alcohol remain much less clear, according to a new report from the cancer agency of the World Health Organization (WHO).

After reviewing dozens of studies, the International Agency for Research on Cancer (IARC) concluded that, for most alcohol-related cancers, there is limited evidence to support a link between eliminating or reducing alcohol consumption and lowering of cancer risk.

More specifically, the IARC Working Group, which included 15 scientists from eight countries, reported “limited” evidence on this association for laryngeal, colorectal (CRC), and breast cancer as well as «inadequate» evidence for pharyngeal and liver cancer.

The report did highlight two exceptions: Reducing or quitting alcohol was associated with a lower risk for both oral and esophageal cancer. The IARC working group based this conclusion on large studies of long-term alcohol cessation in these cancer types.

Still, the authors noted, “significant scientific gaps” exist for most alcohol-related cancers.

Take the data on CRC. Two studies found that reducing alcohol consumption did appear to lower CRC risk, while two others — which focused on the duration of quitting — did not suggest a reduced risk for CRC.

“Given the inconsistencies among studies and the few studies on duration of cessation, the Working Group concluded that there was limited evidence that alcohol reduction or cessation reduces colorectal cancer risk,” the authors wrote.

For liver cancer, the experts did note an association between quitting alcohol and lower cancer risk, but that cohort study only included individuals with alcohol-related liver disease. Outside of this study, the IARC group found no clear association between quitting drinking and liver cancer among people without alcohol-related liver disease in the other 11 studies evaluated.

For pharyngeal cancer, the evidence was limited overall, but one analysis looking at long-term cessation and oropharyngeal or hypopharyngeal cancer found a 26% lower risk (95% CI, 0.50-1.09). That association went away, however, after adjusting for detailed smoking history (odds ratio, 0.95; 95% CI, 0.56-1.61), and the working group concluded, overall, that «there was inadequate evidence that alcohol reduction or cessation reduces pharyngeal cancer risk.”

The IARC working group did find sufficient evidence linking drinking cessation and reduced risk for oral and esophageal cancers.

For instance, an international pooled analysis, which included 12 studies assessing a link between quitting smoking and alcohol and oral cancer risk, found that longer duration since quitting was associated with lower risk. Not drinking for up to 4 years was associated with a 19% lower risk for oral cancer, quitting for 5-9 years was associated with a 23% lower risk, while quitting for 20 years was associated with 55% lower risk. 

“Given the consistent evidence of a reduced risk of oral cancer associated with long-term alcohol cessation,” the IARC working group concluded that there was “sufficient evidence that alcohol reduction or cessation reduces oral cancer risk.”

The working group also found “sufficient evidence from mechanistic studies that alcohol cessation reduces alcohol-related carcinogenesis.” In other words, quitting drinking appeared to reverse certain cancer-promoting biological mechanisms. 

Outside the recent IARC report, some individual studies have suggested that quitting or cutting back on alcohol can reduce the risk for certain cancers. 

For example, a large population-based study of about 4.5 million individuals in Korea found a lower risk for alcohol-related cancers among mild drinkers who quit (adjusted hazard ratio [aHR], 0.96) and heavy drinkers who reduced their drinking levels to mild (aHR, 0.92) or moderate (aHR, 0.91). These findings, however, may not be generalizable beyond East Asian populations.

Addressing the existing evidence gaps could help “support alcohol-control measures to reduce consumption,” the IARC working group concluded.

The Case for Limiting Alcohol

While the evidence linking reducing or stopping drinking and lower cancer risk remains limited, the opposite association is well-established — greater alcohol consumption does increase cancer risk. 

A previous IARC analysis estimated that alcohol consumption accounts for about 4% of newly diagnosed cancers worldwide, most commonly esophagus, liver, and breast cancer. The IARC has even classified alcohol as a group 1 carcinogen, highlighting the strong evidence demonstrating that alcohol can cause cancer in humans.

Experts also recommend following existing guidelines for alcohol intake. Guidelines from the American Cancer Society and from the US Department of Agriculture and Department of Health and Human Services specify limiting alcohol intake to one drink or less for women and two drinks or less for men on any given day. 

In a January 9, 2023, blog post, National Institute on Alcohol Abuse and Alcoholism director George F. Koob, PhD, touted the known benefits of limiting drinking.

“Research shows that even small amounts of alcohol can carry health risks, including for certain cancers and cardiovascular issues,” Dr. Koob said. 

A version of this article appeared on Medscape.com.

Dry January has come to an end — at least for those who jumped on the trendy post-holiday no-booze wagon.

The benefits of drinking less alcohol are well documented. A systematic review of 63 studies, for example, found that reducing or giving up alcohol reduced people’s risk for hospitalization, injuries, and death. The lifestyle change also improved people’s physical and mental health as well as their quality of life.

When it comes to cancer risk, however, the benefits of quitting or cutting back on alcohol remain much less clear, according to a new report from the cancer agency of the World Health Organization (WHO).

After reviewing dozens of studies, the International Agency for Research on Cancer (IARC) concluded that, for most alcohol-related cancers, there is limited evidence to support a link between eliminating or reducing alcohol consumption and lowering of cancer risk.

More specifically, the IARC Working Group, which included 15 scientists from eight countries, reported “limited” evidence on this association for laryngeal, colorectal (CRC), and breast cancer as well as «inadequate» evidence for pharyngeal and liver cancer.

The report did highlight two exceptions: Reducing or quitting alcohol was associated with a lower risk for both oral and esophageal cancer. The IARC working group based this conclusion on large studies of long-term alcohol cessation in these cancer types.

Still, the authors noted, “significant scientific gaps” exist for most alcohol-related cancers.

Take the data on CRC. Two studies found that reducing alcohol consumption did appear to lower CRC risk, while two others — which focused on the duration of quitting — did not suggest a reduced risk for CRC.

“Given the inconsistencies among studies and the few studies on duration of cessation, the Working Group concluded that there was limited evidence that alcohol reduction or cessation reduces colorectal cancer risk,” the authors wrote.

For liver cancer, the experts did note an association between quitting alcohol and lower cancer risk, but that cohort study only included individuals with alcohol-related liver disease. Outside of this study, the IARC group found no clear association between quitting drinking and liver cancer among people without alcohol-related liver disease in the other 11 studies evaluated.

For pharyngeal cancer, the evidence was limited overall, but one analysis looking at long-term cessation and oropharyngeal or hypopharyngeal cancer found a 26% lower risk (95% CI, 0.50-1.09). That association went away, however, after adjusting for detailed smoking history (odds ratio, 0.95; 95% CI, 0.56-1.61), and the working group concluded, overall, that «there was inadequate evidence that alcohol reduction or cessation reduces pharyngeal cancer risk.”

The IARC working group did find sufficient evidence linking drinking cessation and reduced risk for oral and esophageal cancers.

For instance, an international pooled analysis, which included 12 studies assessing a link between quitting smoking and alcohol and oral cancer risk, found that longer duration since quitting was associated with lower risk. Not drinking for up to 4 years was associated with a 19% lower risk for oral cancer, quitting for 5-9 years was associated with a 23% lower risk, while quitting for 20 years was associated with 55% lower risk. 

“Given the consistent evidence of a reduced risk of oral cancer associated with long-term alcohol cessation,” the IARC working group concluded that there was “sufficient evidence that alcohol reduction or cessation reduces oral cancer risk.”

The working group also found “sufficient evidence from mechanistic studies that alcohol cessation reduces alcohol-related carcinogenesis.” In other words, quitting drinking appeared to reverse certain cancer-promoting biological mechanisms. 

Outside the recent IARC report, some individual studies have suggested that quitting or cutting back on alcohol can reduce the risk for certain cancers. 

For example, a large population-based study of about 4.5 million individuals in Korea found a lower risk for alcohol-related cancers among mild drinkers who quit (adjusted hazard ratio [aHR], 0.96) and heavy drinkers who reduced their drinking levels to mild (aHR, 0.92) or moderate (aHR, 0.91). These findings, however, may not be generalizable beyond East Asian populations.

Addressing the existing evidence gaps could help “support alcohol-control measures to reduce consumption,” the IARC working group concluded.

The Case for Limiting Alcohol

While the evidence linking reducing or stopping drinking and lower cancer risk remains limited, the opposite association is well-established — greater alcohol consumption does increase cancer risk. 

A previous IARC analysis estimated that alcohol consumption accounts for about 4% of newly diagnosed cancers worldwide, most commonly esophagus, liver, and breast cancer. The IARC has even classified alcohol as a group 1 carcinogen, highlighting the strong evidence demonstrating that alcohol can cause cancer in humans.

Experts also recommend following existing guidelines for alcohol intake. Guidelines from the American Cancer Society and from the US Department of Agriculture and Department of Health and Human Services specify limiting alcohol intake to one drink or less for women and two drinks or less for men on any given day. 

In a January 9, 2023, blog post, National Institute on Alcohol Abuse and Alcoholism director George F. Koob, PhD, touted the known benefits of limiting drinking.

“Research shows that even small amounts of alcohol can carry health risks, including for certain cancers and cardiovascular issues,” Dr. Koob said. 

A version of this article appeared on Medscape.com.

Dr. Richard: The first thing we as physicians are worried about is patients with PV developing thrombosis. We start prophylaxis with aspirin, as aspirin remains the best treatment for reducing this risk. It is essential to make sure patients with PV understand the importance of taking an aspirin, even at a low dosage.

The second step is trying to control patients’ red blood cell counts. Phlebotomy has been used for this purpose for many decades and continues to be effective. You will find some experts in the field who consider phlebotomy to be the mainstay of treatment for patients with PV, and that it has benefits in and of itself.

However, despite the benefits, phlebotomy can be a little tough on patients. For instance, patients with PV cannot donate blood at a traditional blood center such as Red Cross, and therefore need to go to an actual infusion center. They also must stop their day and travel to a site to receive therapeutic phlebotomy treatment, which is most effective for patients with a blood disorder. I work in Seattle taking care of patients throughout the Northwest, and it is not always easy to find a close location to send patients for phlebotomy. Nevertheless, phlebotomy should be part of the treatment options for patients with PV, especially patients in the high-risk range who have high hemoglobin and hematocrit values.

The third step is controlling hemoglobin and hematocrit levels. Hydroxyurea is our standard of care with strong beneficial data for this purpose.

These are the 3 approaches to treatment we initially discuss with our patients during their first visit. These 3 strategies can improve a patient's life and reduce their risk for thrombosis.

Which treatment do you recommend depending on the patient’s symptoms?

Dr. Richard: The treatment that we offer can vary. The first thing I want to know is how their symptoms respond to aspirin. For instance, symptoms such as erythromelalgia oftentimes respond beautifully to aspirin. Most patients do not have massive splenomegaly—that would give me a high suspicion for myelofibrosis—but they can develop and present with some level of splenomegaly.

If the symptoms are bothersome to the patient, I will probably want to get them on some kind of cytoreduction to see if that is effective. Hydroxyurea, although not as effective as aspirin and associated with adverse effects in some patients, is a good medication to start cytoreductive therapy. The National Comprehensive Cancer Network® (NCCN®) Guidelines suggest that if a patient taking hydroxyurea experiences severe gastrointestinal (GI) toxicity, go ahead and move to a Janus kinase 2 (JAK2) inhibitor or try interferon. JAK2 inhibition with ruxolitinib, in this case, is effective, at least initially for treating splenomegaly. Unfortunately, symptoms sometimes get confused with effects from the medications. You have to use an individualized treatment approach and see what works for each patient.
 

What are some of the common adverse effects of treatment?

Dr. Richard: As you probably can tell, I never skip aspirin since it is such an important part of treatment for patients with PV. However, I do talk to patients about GI upset and the bleeding risks, such as the potential for GI bleed. Obviously, clotting is what causes an increase in morbidity and mortality, but bleeding can be an important adverse effect with platelets that do not function, or for other issues.

Hydroxyurea is generally well tolerated, but some patients can develop skin issues or ulcers due to GI toxicity. I have a lot of confidence in the use of hydroxyurea, and I use it without hesitation. However, you may have a patient who already has a relatively low neutrophil count or has some level of thrombocytopenia from either liver disease or some other issue, and they just cannot tolerate hydroxyurea. Some other bothersome symptoms include change of taste, skin changes, and brittle nails. It can be tricky. I will attempt hydroxyurea, if needed, but sometimes they just cannot tolerate it.

What happens when a patient cannot tolerate one or all the medications you mentioned?

Dr. Richard: Now that we have JAK2 inhibitors, ruxolitinib is generally my choice for patients who cannot tolerate hydroxyurea, which is more common than maybe we would like. Other problems with hydroxyurea include that it might not work, or phlebotomy combined with hydroxyurea results in cytopenias, or patients have a particularly aggressive form of PV.

There are numerous other JAK2 drug inhibitors on the market for myelofibrosis. The assumption is they probably work as well as ruxolitinib for PV, but right now ruxolitinib is what is approved by the US Food and Drug Administration for these patients.

The other drug that we do not use much is interferon, or now, pegylated interferon. It is a drug that has been around for a long time and worked well in chronic myelogenous leukemia before we had the tyrosine kinase inhibitors. Pegylated interferon is a well-tolerated drug that can be used for patients with PV who are pregnant or could get pregnant. It is not the interferon of our parents or grandparents. We now have options for controlling the disease and its complications, but the hardest thing is to tell patients that none of these treatments are going to cure them or reverse the overproduction of red blood cells in their bone marrow. There has always been discussion about whether there could be some effect of interferon on the actual tumor burden, but that remains to be proven.

Can you go a little bit more into your recommended approach to managing newly diagnosed patients with PV in your day-to-day practice?

Dr. Richard: Oftentimes these patients are identified through our consultation service. It can be hard on the primary care physician to identify whether a patient has secondary or primary PV.

We are lucky now that JAK2 has been identified. The JAK2-V617F and the other exon 12 mutations were identified back in 2006 by several groups and is a great test. With JAK2 along with an erythropoietin test, you can feel confident whether you have identified PV.

PV encompasses a wide variety of syndromes. Patients can come into the office with terrible symptoms, including aquagenic pruritus or erythromelalgia. I have seen young people in their 30s who happen to have a slightly elevated hematocrit and a positive JAK2 test. When this occurs, you try to understand how much the disease is affecting their life, whether they are going to be in a high-risk category or a low-risk category, whether they have had thrombosis, and how their age figures into all of it. To try to figure out this high-risk versus low-risk factor, we use a simple staging system to help determine whether they are going to need cytoreductive therapy or whether you can just start with phlebotomy and see how they do.

Oftentimes in the first visit, I recommend a bone marrow study. Is that going to be true 5 years from now? I am not sure. You know, next-generation sequencing (NGS) is turning into such an important part of determining prognosis in these patients. It helps if you have a great colleague down in hematopathology who can look at the bone marrow as it relates to megakaryocyte morphology, or whether there is early fibrosis.

Although these techniques may not be as prominent in practice today for determining diagnosis, they help us understand the prognosis. A bone marrow study or NGS is particularly useful when you have patients who you are convinced have PV, but it turns out they already have extensive fibrosis and are actually moving more toward the post-polycythemia phase a little faster than you think. While we do not use an allogeneic transplant often, in this scenario we may recommend it. Our primary goal at this point is to try to determine which patients would benefit from a transplant early on and to prepare the patient for this option.

What socioeconomic disparities have you observed in newly diagnosed patients?

Dr. Richard: There are definitely social disparities for people who have low income. I work in a veteran’s hospital where we take care of a lot of people who do not have health insurance, but who come to the VA because they do have benefits. If they are in our system, they get identified and their care is great. However, if they have been out in the regular system without health insurance, oftentimes they get diagnosed late. Identifying and treating patients from low socioeconomic backgrounds is an issue. I think everyone can agree with that.

We have a delicate situation with women veterans. Something that is incredibly painful that I think people should be aware of is the amount of military sexual trauma (MST) that has occurred over the years. These patients are in a unique place of trust with their care providers. They have spent a lot of time not being listened to in a variety of arenas. I see this in young military women who no one expects to have a stem cell disorder. We as health care providers do them a disservice if their complaints lead to referral to a psychotherapist or being prescribed a nonsteroidal anti-inflammatory drug or something like that. As health care providers, we are in a unique position to listen to and accurately evaluate these patients. We have a large population of veterans and, increasingly more women veterans, but I think we can all agree that they need better care, especially if they have suffered from MST. That is what I see in my patient population.

When I was a resident in Baltimore, it was Black people with lower income who did not trust doctors. We still have a lot of work to do.

Dr. Richard: The first thing we as physicians are worried about is patients with PV developing thrombosis. We start prophylaxis with aspirin, as aspirin remains the best treatment for reducing this risk. It is essential to make sure patients with PV understand the importance of taking an aspirin, even at a low dosage.

The second step is trying to control patients’ red blood cell counts. Phlebotomy has been used for this purpose for many decades and continues to be effective. You will find some experts in the field who consider phlebotomy to be the mainstay of treatment for patients with PV, and that it has benefits in and of itself.

However, despite the benefits, phlebotomy can be a little tough on patients. For instance, patients with PV cannot donate blood at a traditional blood center such as Red Cross, and therefore need to go to an actual infusion center. They also must stop their day and travel to a site to receive therapeutic phlebotomy treatment, which is most effective for patients with a blood disorder. I work in Seattle taking care of patients throughout the Northwest, and it is not always easy to find a close location to send patients for phlebotomy. Nevertheless, phlebotomy should be part of the treatment options for patients with PV, especially patients in the high-risk range who have high hemoglobin and hematocrit values.

The third step is controlling hemoglobin and hematocrit levels. Hydroxyurea is our standard of care with strong beneficial data for this purpose.

These are the 3 approaches to treatment we initially discuss with our patients during their first visit. These 3 strategies can improve a patient's life and reduce their risk for thrombosis.

Which treatment do you recommend depending on the patient’s symptoms?

Dr. Richard: The treatment that we offer can vary. The first thing I want to know is how their symptoms respond to aspirin. For instance, symptoms such as erythromelalgia oftentimes respond beautifully to aspirin. Most patients do not have massive splenomegaly—that would give me a high suspicion for myelofibrosis—but they can develop and present with some level of splenomegaly.

If the symptoms are bothersome to the patient, I will probably want to get them on some kind of cytoreduction to see if that is effective. Hydroxyurea, although not as effective as aspirin and associated with adverse effects in some patients, is a good medication to start cytoreductive therapy. The National Comprehensive Cancer Network® (NCCN®) Guidelines suggest that if a patient taking hydroxyurea experiences severe gastrointestinal (GI) toxicity, go ahead and move to a Janus kinase 2 (JAK2) inhibitor or try interferon. JAK2 inhibition with ruxolitinib, in this case, is effective, at least initially for treating splenomegaly. Unfortunately, symptoms sometimes get confused with effects from the medications. You have to use an individualized treatment approach and see what works for each patient.
 

What are some of the common adverse effects of treatment?

Dr. Richard: As you probably can tell, I never skip aspirin since it is such an important part of treatment for patients with PV. However, I do talk to patients about GI upset and the bleeding risks, such as the potential for GI bleed. Obviously, clotting is what causes an increase in morbidity and mortality, but bleeding can be an important adverse effect with platelets that do not function, or for other issues.

Hydroxyurea is generally well tolerated, but some patients can develop skin issues or ulcers due to GI toxicity. I have a lot of confidence in the use of hydroxyurea, and I use it without hesitation. However, you may have a patient who already has a relatively low neutrophil count or has some level of thrombocytopenia from either liver disease or some other issue, and they just cannot tolerate hydroxyurea. Some other bothersome symptoms include change of taste, skin changes, and brittle nails. It can be tricky. I will attempt hydroxyurea, if needed, but sometimes they just cannot tolerate it.

What happens when a patient cannot tolerate one or all the medications you mentioned?

Dr. Richard: Now that we have JAK2 inhibitors, ruxolitinib is generally my choice for patients who cannot tolerate hydroxyurea, which is more common than maybe we would like. Other problems with hydroxyurea include that it might not work, or phlebotomy combined with hydroxyurea results in cytopenias, or patients have a particularly aggressive form of PV.

There are numerous other JAK2 drug inhibitors on the market for myelofibrosis. The assumption is they probably work as well as ruxolitinib for PV, but right now ruxolitinib is what is approved by the US Food and Drug Administration for these patients.

The other drug that we do not use much is interferon, or now, pegylated interferon. It is a drug that has been around for a long time and worked well in chronic myelogenous leukemia before we had the tyrosine kinase inhibitors. Pegylated interferon is a well-tolerated drug that can be used for patients with PV who are pregnant or could get pregnant. It is not the interferon of our parents or grandparents. We now have options for controlling the disease and its complications, but the hardest thing is to tell patients that none of these treatments are going to cure them or reverse the overproduction of red blood cells in their bone marrow. There has always been discussion about whether there could be some effect of interferon on the actual tumor burden, but that remains to be proven.

Can you go a little bit more into your recommended approach to managing newly diagnosed patients with PV in your day-to-day practice?

Dr. Richard: Oftentimes these patients are identified through our consultation service. It can be hard on the primary care physician to identify whether a patient has secondary or primary PV.

We are lucky now that JAK2 has been identified. The JAK2-V617F and the other exon 12 mutations were identified back in 2006 by several groups and is a great test. With JAK2 along with an erythropoietin test, you can feel confident whether you have identified PV.

PV encompasses a wide variety of syndromes. Patients can come into the office with terrible symptoms, including aquagenic pruritus or erythromelalgia. I have seen young people in their 30s who happen to have a slightly elevated hematocrit and a positive JAK2 test. When this occurs, you try to understand how much the disease is affecting their life, whether they are going to be in a high-risk category or a low-risk category, whether they have had thrombosis, and how their age figures into all of it. To try to figure out this high-risk versus low-risk factor, we use a simple staging system to help determine whether they are going to need cytoreductive therapy or whether you can just start with phlebotomy and see how they do.

Oftentimes in the first visit, I recommend a bone marrow study. Is that going to be true 5 years from now? I am not sure. You know, next-generation sequencing (NGS) is turning into such an important part of determining prognosis in these patients. It helps if you have a great colleague down in hematopathology who can look at the bone marrow as it relates to megakaryocyte morphology, or whether there is early fibrosis.

Although these techniques may not be as prominent in practice today for determining diagnosis, they help us understand the prognosis. A bone marrow study or NGS is particularly useful when you have patients who you are convinced have PV, but it turns out they already have extensive fibrosis and are actually moving more toward the post-polycythemia phase a little faster than you think. While we do not use an allogeneic transplant often, in this scenario we may recommend it. Our primary goal at this point is to try to determine which patients would benefit from a transplant early on and to prepare the patient for this option.

What socioeconomic disparities have you observed in newly diagnosed patients?

Dr. Richard: There are definitely social disparities for people who have low income. I work in a veteran’s hospital where we take care of a lot of people who do not have health insurance, but who come to the VA because they do have benefits. If they are in our system, they get identified and their care is great. However, if they have been out in the regular system without health insurance, oftentimes they get diagnosed late. Identifying and treating patients from low socioeconomic backgrounds is an issue. I think everyone can agree with that.

We have a delicate situation with women veterans. Something that is incredibly painful that I think people should be aware of is the amount of military sexual trauma (MST) that has occurred over the years. These patients are in a unique place of trust with their care providers. They have spent a lot of time not being listened to in a variety of arenas. I see this in young military women who no one expects to have a stem cell disorder. We as health care providers do them a disservice if their complaints lead to referral to a psychotherapist or being prescribed a nonsteroidal anti-inflammatory drug or something like that. As health care providers, we are in a unique position to listen to and accurately evaluate these patients. We have a large population of veterans and, increasingly more women veterans, but I think we can all agree that they need better care, especially if they have suffered from MST. That is what I see in my patient population.

When I was a resident in Baltimore, it was Black people with lower income who did not trust doctors. We still have a lot of work to do.

Dr. Richard: The first thing we as physicians are worried about is patients with PV developing thrombosis. We start prophylaxis with aspirin, as aspirin remains the best treatment for reducing this risk. It is essential to make sure patients with PV understand the importance of taking an aspirin, even at a low dosage.

The second step is trying to control patients’ red blood cell counts. Phlebotomy has been used for this purpose for many decades and continues to be effective. You will find some experts in the field who consider phlebotomy to be the mainstay of treatment for patients with PV, and that it has benefits in and of itself.

However, despite the benefits, phlebotomy can be a little tough on patients. For instance, patients with PV cannot donate blood at a traditional blood center such as Red Cross, and therefore need to go to an actual infusion center. They also must stop their day and travel to a site to receive therapeutic phlebotomy treatment, which is most effective for patients with a blood disorder. I work in Seattle taking care of patients throughout the Northwest, and it is not always easy to find a close location to send patients for phlebotomy. Nevertheless, phlebotomy should be part of the treatment options for patients with PV, especially patients in the high-risk range who have high hemoglobin and hematocrit values.

The third step is controlling hemoglobin and hematocrit levels. Hydroxyurea is our standard of care with strong beneficial data for this purpose.

These are the 3 approaches to treatment we initially discuss with our patients during their first visit. These 3 strategies can improve a patient's life and reduce their risk for thrombosis.

Which treatment do you recommend depending on the patient’s symptoms?

Dr. Richard: The treatment that we offer can vary. The first thing I want to know is how their symptoms respond to aspirin. For instance, symptoms such as erythromelalgia oftentimes respond beautifully to aspirin. Most patients do not have massive splenomegaly—that would give me a high suspicion for myelofibrosis—but they can develop and present with some level of splenomegaly.

If the symptoms are bothersome to the patient, I will probably want to get them on some kind of cytoreduction to see if that is effective. Hydroxyurea, although not as effective as aspirin and associated with adverse effects in some patients, is a good medication to start cytoreductive therapy. The National Comprehensive Cancer Network® (NCCN®) Guidelines suggest that if a patient taking hydroxyurea experiences severe gastrointestinal (GI) toxicity, go ahead and move to a Janus kinase 2 (JAK2) inhibitor or try interferon. JAK2 inhibition with ruxolitinib, in this case, is effective, at least initially for treating splenomegaly. Unfortunately, symptoms sometimes get confused with effects from the medications. You have to use an individualized treatment approach and see what works for each patient.
 

What are some of the common adverse effects of treatment?

Dr. Richard: As you probably can tell, I never skip aspirin since it is such an important part of treatment for patients with PV. However, I do talk to patients about GI upset and the bleeding risks, such as the potential for GI bleed. Obviously, clotting is what causes an increase in morbidity and mortality, but bleeding can be an important adverse effect with platelets that do not function, or for other issues.

Hydroxyurea is generally well tolerated, but some patients can develop skin issues or ulcers due to GI toxicity. I have a lot of confidence in the use of hydroxyurea, and I use it without hesitation. However, you may have a patient who already has a relatively low neutrophil count or has some level of thrombocytopenia from either liver disease or some other issue, and they just cannot tolerate hydroxyurea. Some other bothersome symptoms include change of taste, skin changes, and brittle nails. It can be tricky. I will attempt hydroxyurea, if needed, but sometimes they just cannot tolerate it.

What happens when a patient cannot tolerate one or all the medications you mentioned?

Dr. Richard: Now that we have JAK2 inhibitors, ruxolitinib is generally my choice for patients who cannot tolerate hydroxyurea, which is more common than maybe we would like. Other problems with hydroxyurea include that it might not work, or phlebotomy combined with hydroxyurea results in cytopenias, or patients have a particularly aggressive form of PV.

There are numerous other JAK2 drug inhibitors on the market for myelofibrosis. The assumption is they probably work as well as ruxolitinib for PV, but right now ruxolitinib is what is approved by the US Food and Drug Administration for these patients.

The other drug that we do not use much is interferon, or now, pegylated interferon. It is a drug that has been around for a long time and worked well in chronic myelogenous leukemia before we had the tyrosine kinase inhibitors. Pegylated interferon is a well-tolerated drug that can be used for patients with PV who are pregnant or could get pregnant. It is not the interferon of our parents or grandparents. We now have options for controlling the disease and its complications, but the hardest thing is to tell patients that none of these treatments are going to cure them or reverse the overproduction of red blood cells in their bone marrow. There has always been discussion about whether there could be some effect of interferon on the actual tumor burden, but that remains to be proven.

Can you go a little bit more into your recommended approach to managing newly diagnosed patients with PV in your day-to-day practice?

Dr. Richard: Oftentimes these patients are identified through our consultation service. It can be hard on the primary care physician to identify whether a patient has secondary or primary PV.

We are lucky now that JAK2 has been identified. The JAK2-V617F and the other exon 12 mutations were identified back in 2006 by several groups and is a great test. With JAK2 along with an erythropoietin test, you can feel confident whether you have identified PV.

PV encompasses a wide variety of syndromes. Patients can come into the office with terrible symptoms, including aquagenic pruritus or erythromelalgia. I have seen young people in their 30s who happen to have a slightly elevated hematocrit and a positive JAK2 test. When this occurs, you try to understand how much the disease is affecting their life, whether they are going to be in a high-risk category or a low-risk category, whether they have had thrombosis, and how their age figures into all of it. To try to figure out this high-risk versus low-risk factor, we use a simple staging system to help determine whether they are going to need cytoreductive therapy or whether you can just start with phlebotomy and see how they do.

Oftentimes in the first visit, I recommend a bone marrow study. Is that going to be true 5 years from now? I am not sure. You know, next-generation sequencing (NGS) is turning into such an important part of determining prognosis in these patients. It helps if you have a great colleague down in hematopathology who can look at the bone marrow as it relates to megakaryocyte morphology, or whether there is early fibrosis.

Although these techniques may not be as prominent in practice today for determining diagnosis, they help us understand the prognosis. A bone marrow study or NGS is particularly useful when you have patients who you are convinced have PV, but it turns out they already have extensive fibrosis and are actually moving more toward the post-polycythemia phase a little faster than you think. While we do not use an allogeneic transplant often, in this scenario we may recommend it. Our primary goal at this point is to try to determine which patients would benefit from a transplant early on and to prepare the patient for this option.

What socioeconomic disparities have you observed in newly diagnosed patients?

Dr. Richard: There are definitely social disparities for people who have low income. I work in a veteran’s hospital where we take care of a lot of people who do not have health insurance, but who come to the VA because they do have benefits. If they are in our system, they get identified and their care is great. However, if they have been out in the regular system without health insurance, oftentimes they get diagnosed late. Identifying and treating patients from low socioeconomic backgrounds is an issue. I think everyone can agree with that.

We have a delicate situation with women veterans. Something that is incredibly painful that I think people should be aware of is the amount of military sexual trauma (MST) that has occurred over the years. These patients are in a unique place of trust with their care providers. They have spent a lot of time not being listened to in a variety of arenas. I see this in young military women who no one expects to have a stem cell disorder. We as health care providers do them a disservice if their complaints lead to referral to a psychotherapist or being prescribed a nonsteroidal anti-inflammatory drug or something like that. As health care providers, we are in a unique position to listen to and accurately evaluate these patients. We have a large population of veterans and, increasingly more women veterans, but I think we can all agree that they need better care, especially if they have suffered from MST. That is what I see in my patient population.

When I was a resident in Baltimore, it was Black people with lower income who did not trust doctors. We still have a lot of work to do.

In a joint discussion with European counterparts, the top US regulator for cancer medicines called for the streamlining of processes for testing oncology medicines and for a greater focus on designing research that answers the most important questions raised by physicians and their patients.

Richard Pazdur, MD, who leads the cancer division at the US Food and Drug Administration (FDA), said there’s a need to simplify the paperwork involved in clinical trials. Before joining the FDA in 1999, Dr. Pazdur participated in and published cancer research. He says the informed consent forms used for studies have grown too elaborate over the years, such that they can intimidate even experts.

“When I read informed consents now in clinical trials, folks, it gives me a headache. Okay, I can’t follow them,” Dr. Pazdur said.

Dr. Pazdur said informed consent forms can be “mind-boggling” these days.

“They’re so damn complicated with so many damn questions being answered,” he said. “So our point is what’s the essential question that you need answered and what’s the quickest way of answering that question with the least amount of data that can be collected?”

Dr. Pazdur made these comments during a joint meeting of the FDA and the European Medicines Agency (EMA).

The meeting was a broad discussion about how to build on the successes seen in treatment of blood cancers in the past two decades. No formal recommendations were introduced or considered at the meeting. Instead, the meeting served as a chance for oncologists and patients to discuss ways to more quickly and efficiently address the key questions in drug research: Do medicines deliver a significant benefit to patients?

Dr. Pazdur also said at the meeting that there needs to be a way to attract more people to enroll in clinical trials.

“When I started in oncology, it was about 5%. When I’m sitting here now, 40 years later, it’s 5%. Basically it hasn’t moved,” he said at the discussion, held on February 1.

Ellin Berman, MD, of Memorial Sloan Kettering Cancer Center in New York, spoke at the meeting about the changes she has witnessed in her career in oncology. Until 2001, there were limited drug options, and physicians tried to get patients to transplant teams as possible. Then the FDA in 2001 approved imatinib to treat patients with chronic myelogenous leukemia (CML) that has the Philadelphia chromosome. That set the stage, Dr. Berman said, for a sea change in treatment of CML.

“The fellows now have no idea what it is like to talk to a CML patient about transplant and the question is which among the treasures we have of drugs do we start people on? And that’s always a conversation,” Dr. Berman said.

She noted that advances in treatment have also let some female patients get pregnant and have children.

“We have at least half a dozen women who bring their kids to clinic. And boy, if that doesn’t bring tears to our eyes, our collective eyes, I don’t know what does,” she said.

Dr. Pazdur also recalled his experience treating patients in the 1970s and 1980s for cancers for which “you had nothing so to speak” in terms of effective treatment.

“So then ask yourself the question, what would their stories be now?” with the many options available, Dr. Pazdur said.

 

Seeking clinician feedback

To try to improve the development and testing of cancer drugs, the FDA is seeking to get more feedback from clinicians about which questions trials should address, Dr. Pazdur said.

The agency is considering a way to poll clinicians on what their most crucial questions are about the medicines, he said. Better design of trial questions might serve to improve enrollment in studies.

“What we’re thinking of doing is taking the common disease areas and asking clinicians what are the five basic questions that you want answered in the next 5 years,” he said.

He cited PD-1 drugs as a possible example of a class where regulators could consider new approaches. There could be a discussion about the safety data collection for this class of drugs, which has been used by millions of patients.

Dr. Pazdur said he has been discussing these kinds of themes with his European and Japanese counterparts, who also are interested in simplifying clinical trials.

The goal is to have trials better represent real-world experiences rather than “artificial” ones created when patients must meet extensive eligibility requirements. Improved use of emerging technologies could aid in the needed streamlining, Dr. Pazdur said.

“As an oncology community, we have made our lives somewhat too complicated and need to draw back and ask the basic questions,” Dr. Pazdur said.

In a joint discussion with European counterparts, the top US regulator for cancer medicines called for the streamlining of processes for testing oncology medicines and for a greater focus on designing research that answers the most important questions raised by physicians and their patients.

Richard Pazdur, MD, who leads the cancer division at the US Food and Drug Administration (FDA), said there’s a need to simplify the paperwork involved in clinical trials. Before joining the FDA in 1999, Dr. Pazdur participated in and published cancer research. He says the informed consent forms used for studies have grown too elaborate over the years, such that they can intimidate even experts.

“When I read informed consents now in clinical trials, folks, it gives me a headache. Okay, I can’t follow them,” Dr. Pazdur said.

Dr. Pazdur said informed consent forms can be “mind-boggling” these days.

“They’re so damn complicated with so many damn questions being answered,” he said. “So our point is what’s the essential question that you need answered and what’s the quickest way of answering that question with the least amount of data that can be collected?”

Dr. Pazdur made these comments during a joint meeting of the FDA and the European Medicines Agency (EMA).

The meeting was a broad discussion about how to build on the successes seen in treatment of blood cancers in the past two decades. No formal recommendations were introduced or considered at the meeting. Instead, the meeting served as a chance for oncologists and patients to discuss ways to more quickly and efficiently address the key questions in drug research: Do medicines deliver a significant benefit to patients?

Dr. Pazdur also said at the meeting that there needs to be a way to attract more people to enroll in clinical trials.

“When I started in oncology, it was about 5%. When I’m sitting here now, 40 years later, it’s 5%. Basically it hasn’t moved,” he said at the discussion, held on February 1.

Ellin Berman, MD, of Memorial Sloan Kettering Cancer Center in New York, spoke at the meeting about the changes she has witnessed in her career in oncology. Until 2001, there were limited drug options, and physicians tried to get patients to transplant teams as possible. Then the FDA in 2001 approved imatinib to treat patients with chronic myelogenous leukemia (CML) that has the Philadelphia chromosome. That set the stage, Dr. Berman said, for a sea change in treatment of CML.

“The fellows now have no idea what it is like to talk to a CML patient about transplant and the question is which among the treasures we have of drugs do we start people on? And that’s always a conversation,” Dr. Berman said.

She noted that advances in treatment have also let some female patients get pregnant and have children.

“We have at least half a dozen women who bring their kids to clinic. And boy, if that doesn’t bring tears to our eyes, our collective eyes, I don’t know what does,” she said.

Dr. Pazdur also recalled his experience treating patients in the 1970s and 1980s for cancers for which “you had nothing so to speak” in terms of effective treatment.

“So then ask yourself the question, what would their stories be now?” with the many options available, Dr. Pazdur said.

 

Seeking clinician feedback

To try to improve the development and testing of cancer drugs, the FDA is seeking to get more feedback from clinicians about which questions trials should address, Dr. Pazdur said.

The agency is considering a way to poll clinicians on what their most crucial questions are about the medicines, he said. Better design of trial questions might serve to improve enrollment in studies.

“What we’re thinking of doing is taking the common disease areas and asking clinicians what are the five basic questions that you want answered in the next 5 years,” he said.

He cited PD-1 drugs as a possible example of a class where regulators could consider new approaches. There could be a discussion about the safety data collection for this class of drugs, which has been used by millions of patients.

Dr. Pazdur said he has been discussing these kinds of themes with his European and Japanese counterparts, who also are interested in simplifying clinical trials.

The goal is to have trials better represent real-world experiences rather than “artificial” ones created when patients must meet extensive eligibility requirements. Improved use of emerging technologies could aid in the needed streamlining, Dr. Pazdur said.

“As an oncology community, we have made our lives somewhat too complicated and need to draw back and ask the basic questions,” Dr. Pazdur said.

In a joint discussion with European counterparts, the top US regulator for cancer medicines called for the streamlining of processes for testing oncology medicines and for a greater focus on designing research that answers the most important questions raised by physicians and their patients.

Richard Pazdur, MD, who leads the cancer division at the US Food and Drug Administration (FDA), said there’s a need to simplify the paperwork involved in clinical trials. Before joining the FDA in 1999, Dr. Pazdur participated in and published cancer research. He says the informed consent forms used for studies have grown too elaborate over the years, such that they can intimidate even experts.

“When I read informed consents now in clinical trials, folks, it gives me a headache. Okay, I can’t follow them,” Dr. Pazdur said.

Dr. Pazdur said informed consent forms can be “mind-boggling” these days.

“They’re so damn complicated with so many damn questions being answered,” he said. “So our point is what’s the essential question that you need answered and what’s the quickest way of answering that question with the least amount of data that can be collected?”

Dr. Pazdur made these comments during a joint meeting of the FDA and the European Medicines Agency (EMA).

The meeting was a broad discussion about how to build on the successes seen in treatment of blood cancers in the past two decades. No formal recommendations were introduced or considered at the meeting. Instead, the meeting served as a chance for oncologists and patients to discuss ways to more quickly and efficiently address the key questions in drug research: Do medicines deliver a significant benefit to patients?

Dr. Pazdur also said at the meeting that there needs to be a way to attract more people to enroll in clinical trials.

“When I started in oncology, it was about 5%. When I’m sitting here now, 40 years later, it’s 5%. Basically it hasn’t moved,” he said at the discussion, held on February 1.

Ellin Berman, MD, of Memorial Sloan Kettering Cancer Center in New York, spoke at the meeting about the changes she has witnessed in her career in oncology. Until 2001, there were limited drug options, and physicians tried to get patients to transplant teams as possible. Then the FDA in 2001 approved imatinib to treat patients with chronic myelogenous leukemia (CML) that has the Philadelphia chromosome. That set the stage, Dr. Berman said, for a sea change in treatment of CML.

“The fellows now have no idea what it is like to talk to a CML patient about transplant and the question is which among the treasures we have of drugs do we start people on? And that’s always a conversation,” Dr. Berman said.

She noted that advances in treatment have also let some female patients get pregnant and have children.

“We have at least half a dozen women who bring their kids to clinic. And boy, if that doesn’t bring tears to our eyes, our collective eyes, I don’t know what does,” she said.

Dr. Pazdur also recalled his experience treating patients in the 1970s and 1980s for cancers for which “you had nothing so to speak” in terms of effective treatment.

“So then ask yourself the question, what would their stories be now?” with the many options available, Dr. Pazdur said.

 

Seeking clinician feedback

To try to improve the development and testing of cancer drugs, the FDA is seeking to get more feedback from clinicians about which questions trials should address, Dr. Pazdur said.

The agency is considering a way to poll clinicians on what their most crucial questions are about the medicines, he said. Better design of trial questions might serve to improve enrollment in studies.

“What we’re thinking of doing is taking the common disease areas and asking clinicians what are the five basic questions that you want answered in the next 5 years,” he said.

He cited PD-1 drugs as a possible example of a class where regulators could consider new approaches. There could be a discussion about the safety data collection for this class of drugs, which has been used by millions of patients.

Dr. Pazdur said he has been discussing these kinds of themes with his European and Japanese counterparts, who also are interested in simplifying clinical trials.

The goal is to have trials better represent real-world experiences rather than “artificial” ones created when patients must meet extensive eligibility requirements. Improved use of emerging technologies could aid in the needed streamlining, Dr. Pazdur said.

“As an oncology community, we have made our lives somewhat too complicated and need to draw back and ask the basic questions,” Dr. Pazdur said.

In December, in what’s known as the “Take Care of Maya” case, a Florida jury returned a record $261 million verdict against Johns Hopkins All Children’s Hospital, St. Petersburg, Florida, for its treatment of a young patient and her family after an emergency room visit.

A month earlier, in New York, a jury ordered Westchester Medical Center Health Network to pay $120 million to a patient and his family following delayed stroke care that resulted in brain damage.

Mega malpractice awards like these are rising against physicians and hospitals around the country, according to new data from TransRe, an international reinsurance company that tracks large verdicts.

“2023 blew away every record previously set among high medical malpractice verdicts,” said Richard Henderson, senior vice president for TransRe. “If we look at the 50 largest verdicts in 2023 and average them out, we have a higher monetary amount than any other year.”

In 2023, there were 57 medical malpractice verdicts of $10 million or more in the United States, the data showed. Slightly more than half of those reached $25 million or more.

From 2012 to 2022, verdicts of $10 million or more ranged from 34 in 2013 to 52 in 2022, TransRe research found.

While New York, Illinois, and Florida typically saw the highest dollar verdicts in previous years, so-called “nuclear” verdicts now occur in states like Utah and Georgia where they once were uncommon, said Robert E. White Jr., president of TDC Group and The Doctors Company, a national medical liability insurer for physicians.

A rollback of tort reforms across the country is one contributor, he said. For example, Georgia’s cap on noneconomic damages is among those that have been ruled unconstitutional by courts. Utah’s cap on noneconomic damages still stands, but the limit was deemed unconstitutional in wrongful death cases. In 2019, a portion of Utah›s pre-litigation panel process was also struck down by the state’s Supreme Court.

“We used to be able to predict where these high verdicts would occur,” Mr. White said. “We can’t predict it anymore.”

Research shows a majority of malpractice cases are dropped or settled before trial, and claims that go before juries usually end in doctors’ favor. Plaintiffs’ attorneys cite large jury verdicts in similar cases to induce settlements and higher payouts, Mr. White said.

And while mega verdicts rarely stick, they can have lasting effects on future claims. The awards lead to larger settlement demands from plaintiffs and drive up the cost to resolve claims, according to Mr. Henderson and Mr. White.

“Verdicts are the yardstick by which all settlements are measured,” Mr. White said. “That’s where the damage is done.” The prospect of a mega verdict can make insurers leery of fighting some malpractice cases and motivate them to offer bigger settlements to stay out of the courtroom, he added.

Why Are Juries Awarding Higher Verdicts?

There’s no single reason for the rise in nuclear verdicts, Mr. Henderson said.

One theory is that plaintiffs’ attorneys held back on resolving high-dollar cases during the COVID pandemic and let loose with high-demand claims when courts returned to normal, he said.

Another theory is that people emerged from the pandemic angrier.

“Whether it was political dynamics, masking [mandates], or differences in opinions, people came out of it angry, and generally speaking, you don’t want an angry jury,” Mr. Henderson said. “For a while, there was the halo effect, where health professionals were seen as heroes. That went away, and all of a sudden [they] became ‘the bad guys.’ ”

“People are angry at the healthcare system, and this anger manifests itself in [liability] suits,” added Bill Burns, vice president of research for the Medical Professional Liability Association, an industry group for medical liability insurers.

Hospital and medical group consolidation also reduces the personal connection juries may have with healthcare providers, Mr. Burns said.

“Healthcare has become a big business, and the corporatization of medicine now puts companies on the stand and not your local community hospital or your family doctor that you have known since birth,” he said.

Plaintiffs’ attorneys also deploy tactics that can prompt higher verdicts, Mr. White said. They may tell a jury that the provider or hospital is a threat to the community and that awarding a large verdict will deter others in the healthcare community from repeating the same actions.

Juries may then want to punish the defendant in addition to assessing damages for economic harm or pain and suffering, Mr. White said.

“I am concerned that jurors are trying to right social wrongs rather than judging cases on the facts presented to them,” added Mike Stinson, vice president for policy and legal affairs for the Medical Professional Liability Association.

Third-party litigation financing also can lead to mega verdicts. That’s an emerging practice in which companies unrelated to a lawsuit provide capital to plaintiffs in return for a portion of any financial award. The firms essentially “invest” in the litigation.

“What this does is provide an additional financial backdrop for plaintiffs,” Mr. Henderson said. “It allows them to dig in harder on cases. They can hold out for higher numbers, and if nothing else, it can prolong litigation.”

Do High Awards Actually Stick?

Multimillion-dollar verdicts may grab headlines, but do plaintiffs actually receive them?

Rarely, said TransRe, which tracks the final outcomes of verdicts. In many cases, large verdicts are reduced on appeal.

In the Maya case, which involved child protection authorities, a judge later lowered the damages against Johns Hopkins All Children’s Hospital by $47.5 million.

A federal judge in October, for example, rejected a record $110 million medical malpractice award in Minnesota, reducing it to $10 million. The district judge ruled the award was “shockingly excessive” and that the plaintiff should either accept the $10 million award or retry the case.

After a verdict is awarded, the defendant typically challenges the award, and the case goes through the appellate pipeline, Mr. Henderson explained. A judge may reduce some elements of the verdict, he said, but more often, the plaintiff and defendant agree on a compromised figure.

Seattle medical liability defense attorney Jennifer Crisera has experienced this firsthand. She recalled a recent case where a plaintiff’s attorney demanded what she describes as an unreasonable amount to settle a claim. Ms. Crisera did not want to give exact numbers but said the plaintiff made an 8-figure demand and the defense offered a low 7-figure range.

“My impression was that plaintiff’s counsel believed that they could get a nuclear verdict from the jury, so they kept their settlement demand artificially high,” she said. “The division between the numbers was way too high. Ultimately, we had to let a jury decide the value.”

The plaintiff won the case, and the verdict was much less than the settlement demand, she said. Even so, the defense incurred trial costs, and the health provider was forced to endure the emotional stress of a trial that could have been avoided, Ms. Crisera said.

Higher medical malpractice premiums are another consequence of massive awards.

Premium rates are associated with how much insurers pay on average for cases and how frequently they are making payouts, Mr. White said.

Medical liability insurance premiums for physicians have steadily increased since 2019, according to data from the Medical Liability Monitor, a national publication that analyzes liability insurance premiums. The Monitor studies insurance premium data from insurers that cover internists, general surgeons, and obstetrician-gynecologists.

From 2019 to 2023, average premium rates for physicians increased between 1.1% and 3% each year in states without patient compensation funds, according to Monitor data.

“Nuclear verdicts are a real driver of the industry’s underwriting losses and remain top of mind for every malpractice insurance company,” said Michael Matray, editor for the Medical Liability Monitor. “Responses to this year’s rate survey questionnaire indicate that most responding companies have experienced an increase in claims greater than $1 million and claims greater than $5 million during the past 2 years.”

However, increases vary widely by region and among counties. In Montgomery County, Alabama, for instance, premiums for internists rose by 24% from 2022 to 2023, from $8,231 to $10,240. Premiums for Montgomery County general surgeons rose by 11.9% from 2022 to 2023, from $30,761 to $34,426, according to survey data.

In several counties in Illinois (Adams, Knox, Peoria, and Rock Island), premiums for some internists rose by 15% from $24,041 to $27,783, and premiums for some surgeons increased by 27% from $60,202 to $76,461, according to survey data. Some internists in Catoosa County, Georgia, meanwhile, paid $17,831 in 2023, up from $16,313 in 2022. Some surgeons in Catoosa County paid $65,616 in 2023, up from $60,032 in 2022. Inflation could be one factor behind higher liability premium rates. Claim severity is a key driver of higher premium rates, Mr. White added.

“We have not seen stability in claims severity,” he said. “It is continuing to go up and, in all likelihood, it will drive [premium] rates up further from this point.”
 

A version of this article appeared on Medscape.com.

In December, in what’s known as the “Take Care of Maya” case, a Florida jury returned a record $261 million verdict against Johns Hopkins All Children’s Hospital, St. Petersburg, Florida, for its treatment of a young patient and her family after an emergency room visit.

A month earlier, in New York, a jury ordered Westchester Medical Center Health Network to pay $120 million to a patient and his family following delayed stroke care that resulted in brain damage.

Mega malpractice awards like these are rising against physicians and hospitals around the country, according to new data from TransRe, an international reinsurance company that tracks large verdicts.

“2023 blew away every record previously set among high medical malpractice verdicts,” said Richard Henderson, senior vice president for TransRe. “If we look at the 50 largest verdicts in 2023 and average them out, we have a higher monetary amount than any other year.”

In 2023, there were 57 medical malpractice verdicts of $10 million or more in the United States, the data showed. Slightly more than half of those reached $25 million or more.

From 2012 to 2022, verdicts of $10 million or more ranged from 34 in 2013 to 52 in 2022, TransRe research found.

While New York, Illinois, and Florida typically saw the highest dollar verdicts in previous years, so-called “nuclear” verdicts now occur in states like Utah and Georgia where they once were uncommon, said Robert E. White Jr., president of TDC Group and The Doctors Company, a national medical liability insurer for physicians.

A rollback of tort reforms across the country is one contributor, he said. For example, Georgia’s cap on noneconomic damages is among those that have been ruled unconstitutional by courts. Utah’s cap on noneconomic damages still stands, but the limit was deemed unconstitutional in wrongful death cases. In 2019, a portion of Utah›s pre-litigation panel process was also struck down by the state’s Supreme Court.

“We used to be able to predict where these high verdicts would occur,” Mr. White said. “We can’t predict it anymore.”

Research shows a majority of malpractice cases are dropped or settled before trial, and claims that go before juries usually end in doctors’ favor. Plaintiffs’ attorneys cite large jury verdicts in similar cases to induce settlements and higher payouts, Mr. White said.

And while mega verdicts rarely stick, they can have lasting effects on future claims. The awards lead to larger settlement demands from plaintiffs and drive up the cost to resolve claims, according to Mr. Henderson and Mr. White.

“Verdicts are the yardstick by which all settlements are measured,” Mr. White said. “That’s where the damage is done.” The prospect of a mega verdict can make insurers leery of fighting some malpractice cases and motivate them to offer bigger settlements to stay out of the courtroom, he added.

Why Are Juries Awarding Higher Verdicts?

There’s no single reason for the rise in nuclear verdicts, Mr. Henderson said.

One theory is that plaintiffs’ attorneys held back on resolving high-dollar cases during the COVID pandemic and let loose with high-demand claims when courts returned to normal, he said.

Another theory is that people emerged from the pandemic angrier.

“Whether it was political dynamics, masking [mandates], or differences in opinions, people came out of it angry, and generally speaking, you don’t want an angry jury,” Mr. Henderson said. “For a while, there was the halo effect, where health professionals were seen as heroes. That went away, and all of a sudden [they] became ‘the bad guys.’ ”

“People are angry at the healthcare system, and this anger manifests itself in [liability] suits,” added Bill Burns, vice president of research for the Medical Professional Liability Association, an industry group for medical liability insurers.

Hospital and medical group consolidation also reduces the personal connection juries may have with healthcare providers, Mr. Burns said.

“Healthcare has become a big business, and the corporatization of medicine now puts companies on the stand and not your local community hospital or your family doctor that you have known since birth,” he said.

Plaintiffs’ attorneys also deploy tactics that can prompt higher verdicts, Mr. White said. They may tell a jury that the provider or hospital is a threat to the community and that awarding a large verdict will deter others in the healthcare community from repeating the same actions.

Juries may then want to punish the defendant in addition to assessing damages for economic harm or pain and suffering, Mr. White said.

“I am concerned that jurors are trying to right social wrongs rather than judging cases on the facts presented to them,” added Mike Stinson, vice president for policy and legal affairs for the Medical Professional Liability Association.

Third-party litigation financing also can lead to mega verdicts. That’s an emerging practice in which companies unrelated to a lawsuit provide capital to plaintiffs in return for a portion of any financial award. The firms essentially “invest” in the litigation.

“What this does is provide an additional financial backdrop for plaintiffs,” Mr. Henderson said. “It allows them to dig in harder on cases. They can hold out for higher numbers, and if nothing else, it can prolong litigation.”

Do High Awards Actually Stick?

Multimillion-dollar verdicts may grab headlines, but do plaintiffs actually receive them?

Rarely, said TransRe, which tracks the final outcomes of verdicts. In many cases, large verdicts are reduced on appeal.

In the Maya case, which involved child protection authorities, a judge later lowered the damages against Johns Hopkins All Children’s Hospital by $47.5 million.

A federal judge in October, for example, rejected a record $110 million medical malpractice award in Minnesota, reducing it to $10 million. The district judge ruled the award was “shockingly excessive” and that the plaintiff should either accept the $10 million award or retry the case.

After a verdict is awarded, the defendant typically challenges the award, and the case goes through the appellate pipeline, Mr. Henderson explained. A judge may reduce some elements of the verdict, he said, but more often, the plaintiff and defendant agree on a compromised figure.

Seattle medical liability defense attorney Jennifer Crisera has experienced this firsthand. She recalled a recent case where a plaintiff’s attorney demanded what she describes as an unreasonable amount to settle a claim. Ms. Crisera did not want to give exact numbers but said the plaintiff made an 8-figure demand and the defense offered a low 7-figure range.

“My impression was that plaintiff’s counsel believed that they could get a nuclear verdict from the jury, so they kept their settlement demand artificially high,” she said. “The division between the numbers was way too high. Ultimately, we had to let a jury decide the value.”

The plaintiff won the case, and the verdict was much less than the settlement demand, she said. Even so, the defense incurred trial costs, and the health provider was forced to endure the emotional stress of a trial that could have been avoided, Ms. Crisera said.

Higher medical malpractice premiums are another consequence of massive awards.

Premium rates are associated with how much insurers pay on average for cases and how frequently they are making payouts, Mr. White said.

Medical liability insurance premiums for physicians have steadily increased since 2019, according to data from the Medical Liability Monitor, a national publication that analyzes liability insurance premiums. The Monitor studies insurance premium data from insurers that cover internists, general surgeons, and obstetrician-gynecologists.

From 2019 to 2023, average premium rates for physicians increased between 1.1% and 3% each year in states without patient compensation funds, according to Monitor data.

“Nuclear verdicts are a real driver of the industry’s underwriting losses and remain top of mind for every malpractice insurance company,” said Michael Matray, editor for the Medical Liability Monitor. “Responses to this year’s rate survey questionnaire indicate that most responding companies have experienced an increase in claims greater than $1 million and claims greater than $5 million during the past 2 years.”

However, increases vary widely by region and among counties. In Montgomery County, Alabama, for instance, premiums for internists rose by 24% from 2022 to 2023, from $8,231 to $10,240. Premiums for Montgomery County general surgeons rose by 11.9% from 2022 to 2023, from $30,761 to $34,426, according to survey data.

In several counties in Illinois (Adams, Knox, Peoria, and Rock Island), premiums for some internists rose by 15% from $24,041 to $27,783, and premiums for some surgeons increased by 27% from $60,202 to $76,461, according to survey data. Some internists in Catoosa County, Georgia, meanwhile, paid $17,831 in 2023, up from $16,313 in 2022. Some surgeons in Catoosa County paid $65,616 in 2023, up from $60,032 in 2022. Inflation could be one factor behind higher liability premium rates. Claim severity is a key driver of higher premium rates, Mr. White added.

“We have not seen stability in claims severity,” he said. “It is continuing to go up and, in all likelihood, it will drive [premium] rates up further from this point.”
 

A version of this article appeared on Medscape.com.

In December, in what’s known as the “Take Care of Maya” case, a Florida jury returned a record $261 million verdict against Johns Hopkins All Children’s Hospital, St. Petersburg, Florida, for its treatment of a young patient and her family after an emergency room visit.

A month earlier, in New York, a jury ordered Westchester Medical Center Health Network to pay $120 million to a patient and his family following delayed stroke care that resulted in brain damage.

Mega malpractice awards like these are rising against physicians and hospitals around the country, according to new data from TransRe, an international reinsurance company that tracks large verdicts.

“2023 blew away every record previously set among high medical malpractice verdicts,” said Richard Henderson, senior vice president for TransRe. “If we look at the 50 largest verdicts in 2023 and average them out, we have a higher monetary amount than any other year.”

In 2023, there were 57 medical malpractice verdicts of $10 million or more in the United States, the data showed. Slightly more than half of those reached $25 million or more.

From 2012 to 2022, verdicts of $10 million or more ranged from 34 in 2013 to 52 in 2022, TransRe research found.

While New York, Illinois, and Florida typically saw the highest dollar verdicts in previous years, so-called “nuclear” verdicts now occur in states like Utah and Georgia where they once were uncommon, said Robert E. White Jr., president of TDC Group and The Doctors Company, a national medical liability insurer for physicians.

A rollback of tort reforms across the country is one contributor, he said. For example, Georgia’s cap on noneconomic damages is among those that have been ruled unconstitutional by courts. Utah’s cap on noneconomic damages still stands, but the limit was deemed unconstitutional in wrongful death cases. In 2019, a portion of Utah›s pre-litigation panel process was also struck down by the state’s Supreme Court.

“We used to be able to predict where these high verdicts would occur,” Mr. White said. “We can’t predict it anymore.”

Research shows a majority of malpractice cases are dropped or settled before trial, and claims that go before juries usually end in doctors’ favor. Plaintiffs’ attorneys cite large jury verdicts in similar cases to induce settlements and higher payouts, Mr. White said.

And while mega verdicts rarely stick, they can have lasting effects on future claims. The awards lead to larger settlement demands from plaintiffs and drive up the cost to resolve claims, according to Mr. Henderson and Mr. White.

“Verdicts are the yardstick by which all settlements are measured,” Mr. White said. “That’s where the damage is done.” The prospect of a mega verdict can make insurers leery of fighting some malpractice cases and motivate them to offer bigger settlements to stay out of the courtroom, he added.

Why Are Juries Awarding Higher Verdicts?

There’s no single reason for the rise in nuclear verdicts, Mr. Henderson said.

One theory is that plaintiffs’ attorneys held back on resolving high-dollar cases during the COVID pandemic and let loose with high-demand claims when courts returned to normal, he said.

Another theory is that people emerged from the pandemic angrier.

“Whether it was political dynamics, masking [mandates], or differences in opinions, people came out of it angry, and generally speaking, you don’t want an angry jury,” Mr. Henderson said. “For a while, there was the halo effect, where health professionals were seen as heroes. That went away, and all of a sudden [they] became ‘the bad guys.’ ”

“People are angry at the healthcare system, and this anger manifests itself in [liability] suits,” added Bill Burns, vice president of research for the Medical Professional Liability Association, an industry group for medical liability insurers.

Hospital and medical group consolidation also reduces the personal connection juries may have with healthcare providers, Mr. Burns said.

“Healthcare has become a big business, and the corporatization of medicine now puts companies on the stand and not your local community hospital or your family doctor that you have known since birth,” he said.

Plaintiffs’ attorneys also deploy tactics that can prompt higher verdicts, Mr. White said. They may tell a jury that the provider or hospital is a threat to the community and that awarding a large verdict will deter others in the healthcare community from repeating the same actions.

Juries may then want to punish the defendant in addition to assessing damages for economic harm or pain and suffering, Mr. White said.

“I am concerned that jurors are trying to right social wrongs rather than judging cases on the facts presented to them,” added Mike Stinson, vice president for policy and legal affairs for the Medical Professional Liability Association.

Third-party litigation financing also can lead to mega verdicts. That’s an emerging practice in which companies unrelated to a lawsuit provide capital to plaintiffs in return for a portion of any financial award. The firms essentially “invest” in the litigation.

“What this does is provide an additional financial backdrop for plaintiffs,” Mr. Henderson said. “It allows them to dig in harder on cases. They can hold out for higher numbers, and if nothing else, it can prolong litigation.”

Do High Awards Actually Stick?

Multimillion-dollar verdicts may grab headlines, but do plaintiffs actually receive them?

Rarely, said TransRe, which tracks the final outcomes of verdicts. In many cases, large verdicts are reduced on appeal.

In the Maya case, which involved child protection authorities, a judge later lowered the damages against Johns Hopkins All Children’s Hospital by $47.5 million.

A federal judge in October, for example, rejected a record $110 million medical malpractice award in Minnesota, reducing it to $10 million. The district judge ruled the award was “shockingly excessive” and that the plaintiff should either accept the $10 million award or retry the case.

After a verdict is awarded, the defendant typically challenges the award, and the case goes through the appellate pipeline, Mr. Henderson explained. A judge may reduce some elements of the verdict, he said, but more often, the plaintiff and defendant agree on a compromised figure.

Seattle medical liability defense attorney Jennifer Crisera has experienced this firsthand. She recalled a recent case where a plaintiff’s attorney demanded what she describes as an unreasonable amount to settle a claim. Ms. Crisera did not want to give exact numbers but said the plaintiff made an 8-figure demand and the defense offered a low 7-figure range.

“My impression was that plaintiff’s counsel believed that they could get a nuclear verdict from the jury, so they kept their settlement demand artificially high,” she said. “The division between the numbers was way too high. Ultimately, we had to let a jury decide the value.”

The plaintiff won the case, and the verdict was much less than the settlement demand, she said. Even so, the defense incurred trial costs, and the health provider was forced to endure the emotional stress of a trial that could have been avoided, Ms. Crisera said.

Higher medical malpractice premiums are another consequence of massive awards.

Premium rates are associated with how much insurers pay on average for cases and how frequently they are making payouts, Mr. White said.

Medical liability insurance premiums for physicians have steadily increased since 2019, according to data from the Medical Liability Monitor, a national publication that analyzes liability insurance premiums. The Monitor studies insurance premium data from insurers that cover internists, general surgeons, and obstetrician-gynecologists.

From 2019 to 2023, average premium rates for physicians increased between 1.1% and 3% each year in states without patient compensation funds, according to Monitor data.

“Nuclear verdicts are a real driver of the industry’s underwriting losses and remain top of mind for every malpractice insurance company,” said Michael Matray, editor for the Medical Liability Monitor. “Responses to this year’s rate survey questionnaire indicate that most responding companies have experienced an increase in claims greater than $1 million and claims greater than $5 million during the past 2 years.”

However, increases vary widely by region and among counties. In Montgomery County, Alabama, for instance, premiums for internists rose by 24% from 2022 to 2023, from $8,231 to $10,240. Premiums for Montgomery County general surgeons rose by 11.9% from 2022 to 2023, from $30,761 to $34,426, according to survey data.

In several counties in Illinois (Adams, Knox, Peoria, and Rock Island), premiums for some internists rose by 15% from $24,041 to $27,783, and premiums for some surgeons increased by 27% from $60,202 to $76,461, according to survey data. Some internists in Catoosa County, Georgia, meanwhile, paid $17,831 in 2023, up from $16,313 in 2022. Some surgeons in Catoosa County paid $65,616 in 2023, up from $60,032 in 2022. Inflation could be one factor behind higher liability premium rates. Claim severity is a key driver of higher premium rates, Mr. White added.

“We have not seen stability in claims severity,” he said. “It is continuing to go up and, in all likelihood, it will drive [premium] rates up further from this point.”
 

A version of this article appeared on Medscape.com.

Men with cardiorespiratory fitness (CRF) who increased their CRF by more than 3% had a significantly lower risk of prostate cancer incidence, a large Swedish study found.

The prospective analysis, published in the British Journal of Sports Medicine, done in a cohort of nearly 58,000, was conducted by Kate A. Bolam, PhD, a clinical exercise physiologist at the Swedish School of Sport and Health Sciences in Stockholm.

“The findings suggest that physicians could work toward supporting patients to understand what types of activities could improve their fitness and ways they can incorporate these activities into their lives in an enjoyable way, or at the very least refer patients on to an exercise specialist,” Dr. Bolam said in an interview.

Grouped by baseline CRF, the association between change in absolute CRF and prostate cancer incidence was significant only for participants with a moderate baseline CRF. Moreover, changes in both absolute and relative CRF were not associated with prostate cancer mortality.

The lack of mortality significance may be due to the relatively few deaths from prostate cancer in the cohort, Dr. Bolam said. “It may be we weren’t powered to detect anything with such low numbers. And it’s not likely men will die from prostate cancer but more likely from more common chronic diseases such as heart disease.” The authors noted that unlike the case with other common cancers, there are relatively few preventable risk factors with strong evidence for reducing overall prostate cancer risk. “Aside from developmental factors, being diagnosed with overweight or obesity are the main risk factors for developing advanced prostate cancer, but insufficient evidence exists to extend this conclusion to non-advanced prostate cancer,” they wrote.

There is evidence, however, that exercise reduces all-cause mortality risk across many cancer types, including prostate.
 

Study details

The cohort was drawn from Swedish national health-profile database figures from 1982 to 2019. Participants completed an occupational health profile assessment including at least two valid CRF tests on a cycle ergometer. During a mean follow-up of 6.7 years, 592 (1%) of 57,652 men (mean age 41.3 years, standard deviation 10.55) were diagnosed with prostate cancer, and in 46 (.08%) prostate cancer was the primary cause of death.

An increase in absolute CRF (as a percentage of liters per minute of cardiac output) was associated with a reduced incidence risk, with a hazard ratio of 0.98 (95% CI, 0.96-0.99). Grouping participants as having increased (+3%), stable (±3%), or decreased (−3%) CRF, the investigators found increased fitness was associated with an HR for prostate cancer incidence of 0.65 (95% CI, 0.49-0.86), vs decreased fitness.

According to the authors, this and similar investigations of mechanisms behind physical activity benefits will lead to more targeted prevention recommendations. The results highlight the importance of encouraging the general public to increase CRF or reach moderate fitness levels, Dr. Bolam’s group wrote. The group is planning a similar study in breast cancer.

This study was funded by the Swedish Cancer Society. The authors declared no competing interests.

Men with cardiorespiratory fitness (CRF) who increased their CRF by more than 3% had a significantly lower risk of prostate cancer incidence, a large Swedish study found.

The prospective analysis, published in the British Journal of Sports Medicine, done in a cohort of nearly 58,000, was conducted by Kate A. Bolam, PhD, a clinical exercise physiologist at the Swedish School of Sport and Health Sciences in Stockholm.

“The findings suggest that physicians could work toward supporting patients to understand what types of activities could improve their fitness and ways they can incorporate these activities into their lives in an enjoyable way, or at the very least refer patients on to an exercise specialist,” Dr. Bolam said in an interview.

Grouped by baseline CRF, the association between change in absolute CRF and prostate cancer incidence was significant only for participants with a moderate baseline CRF. Moreover, changes in both absolute and relative CRF were not associated with prostate cancer mortality.

The lack of mortality significance may be due to the relatively few deaths from prostate cancer in the cohort, Dr. Bolam said. “It may be we weren’t powered to detect anything with such low numbers. And it’s not likely men will die from prostate cancer but more likely from more common chronic diseases such as heart disease.” The authors noted that unlike the case with other common cancers, there are relatively few preventable risk factors with strong evidence for reducing overall prostate cancer risk. “Aside from developmental factors, being diagnosed with overweight or obesity are the main risk factors for developing advanced prostate cancer, but insufficient evidence exists to extend this conclusion to non-advanced prostate cancer,” they wrote.

There is evidence, however, that exercise reduces all-cause mortality risk across many cancer types, including prostate.
 

Study details

The cohort was drawn from Swedish national health-profile database figures from 1982 to 2019. Participants completed an occupational health profile assessment including at least two valid CRF tests on a cycle ergometer. During a mean follow-up of 6.7 years, 592 (1%) of 57,652 men (mean age 41.3 years, standard deviation 10.55) were diagnosed with prostate cancer, and in 46 (.08%) prostate cancer was the primary cause of death.

An increase in absolute CRF (as a percentage of liters per minute of cardiac output) was associated with a reduced incidence risk, with a hazard ratio of 0.98 (95% CI, 0.96-0.99). Grouping participants as having increased (+3%), stable (±3%), or decreased (−3%) CRF, the investigators found increased fitness was associated with an HR for prostate cancer incidence of 0.65 (95% CI, 0.49-0.86), vs decreased fitness.

According to the authors, this and similar investigations of mechanisms behind physical activity benefits will lead to more targeted prevention recommendations. The results highlight the importance of encouraging the general public to increase CRF or reach moderate fitness levels, Dr. Bolam’s group wrote. The group is planning a similar study in breast cancer.

This study was funded by the Swedish Cancer Society. The authors declared no competing interests.

Men with cardiorespiratory fitness (CRF) who increased their CRF by more than 3% had a significantly lower risk of prostate cancer incidence, a large Swedish study found.

The prospective analysis, published in the British Journal of Sports Medicine, done in a cohort of nearly 58,000, was conducted by Kate A. Bolam, PhD, a clinical exercise physiologist at the Swedish School of Sport and Health Sciences in Stockholm.

“The findings suggest that physicians could work toward supporting patients to understand what types of activities could improve their fitness and ways they can incorporate these activities into their lives in an enjoyable way, or at the very least refer patients on to an exercise specialist,” Dr. Bolam said in an interview.

Grouped by baseline CRF, the association between change in absolute CRF and prostate cancer incidence was significant only for participants with a moderate baseline CRF. Moreover, changes in both absolute and relative CRF were not associated with prostate cancer mortality.

The lack of mortality significance may be due to the relatively few deaths from prostate cancer in the cohort, Dr. Bolam said. “It may be we weren’t powered to detect anything with such low numbers. And it’s not likely men will die from prostate cancer but more likely from more common chronic diseases such as heart disease.” The authors noted that unlike the case with other common cancers, there are relatively few preventable risk factors with strong evidence for reducing overall prostate cancer risk. “Aside from developmental factors, being diagnosed with overweight or obesity are the main risk factors for developing advanced prostate cancer, but insufficient evidence exists to extend this conclusion to non-advanced prostate cancer,” they wrote.

There is evidence, however, that exercise reduces all-cause mortality risk across many cancer types, including prostate.
 

Study details

The cohort was drawn from Swedish national health-profile database figures from 1982 to 2019. Participants completed an occupational health profile assessment including at least two valid CRF tests on a cycle ergometer. During a mean follow-up of 6.7 years, 592 (1%) of 57,652 men (mean age 41.3 years, standard deviation 10.55) were diagnosed with prostate cancer, and in 46 (.08%) prostate cancer was the primary cause of death.

An increase in absolute CRF (as a percentage of liters per minute of cardiac output) was associated with a reduced incidence risk, with a hazard ratio of 0.98 (95% CI, 0.96-0.99). Grouping participants as having increased (+3%), stable (±3%), or decreased (−3%) CRF, the investigators found increased fitness was associated with an HR for prostate cancer incidence of 0.65 (95% CI, 0.49-0.86), vs decreased fitness.

According to the authors, this and similar investigations of mechanisms behind physical activity benefits will lead to more targeted prevention recommendations. The results highlight the importance of encouraging the general public to increase CRF or reach moderate fitness levels, Dr. Bolam’s group wrote. The group is planning a similar study in breast cancer.

This study was funded by the Swedish Cancer Society. The authors declared no competing interests.

This transcript has been edited for clarity.

I’ve been spending time recently reflecting on the biggest developments from last year. I have to say that the breakthrough of the year, based on the amount of data presented and the importance of the data, is chemotherapy. I never thought I would say that. Many folks have tried to relegate chemotherapy to the museum, but last year it came to the forefront.

Let’s start with neoadjuvant therapy. We now have multiple drug approvals for giving a checkpoint inhibitor and neoadjuvant therapy in what I would say is a new standard of care for patients with locally advanced lung cancers who are candidates for surgery. In all those trials, there was a clear improvement in progression-free survival by adding a checkpoint inhibitor to chemotherapy. The cornerstone of this regimen is chemotherapy.

What about adjuvant therapy? I think one of the most astounding pieces of data last year was in the adjuvant realm. In the trial comparing adjuvant osimertinib with placebo in patients with EGFR-mutant disease, patients who received chemotherapy in addition to osimertinib had a 7% improvement in 5-year survival. Patients who had placebo, who got chemotherapy vs didn’t, had a 9% improvement in 5-year survival. Those are huge numbers for that kind of metric, and it happened with chemotherapy.

What about targeted therapies? Again, I think people were astounded that, by adding chemotherapy to osimertinib compared with osimertinib alone, there was a 9-month improvement overall in progression-free survival. I think in the presentation of the data that has been made, the most remarkable piece of data is that, in patients with brain metastases, chemotherapy on top of osimertinib improved progression-free survival. Not only did it improve progression-free survival, but it did it with brain metastases, where people think it just doesn’t help at all.

What about other, newer agents with chemotherapy? Amivantamab, I would say, has hitched itself to chemotherapy. A trial in EGFR exon 20 compared chemo to amivantamab plus chemotherapy. There again, chemo is the common denominator. Amivantamab added approximately 5 months of improved progression-free survival. Again, chemo was used. In adjuvant, neoadjuvant, and targeted therapies, chemotherapy adds.

What about the second line? I think everybody was very disappointed when second-line sotorasib gave a very tiny amount of progression-free survival improvement over docetaxel. I think we all want more for our patients than we can deliver with docetaxel. The roughly 5-week improvement seen with sotorasib was one that raised a question about the place of sotorasib in this setting.

Clearly, we’ve all seen patients have an excellent result with sotorasib as an additional option for treating patients with long progression-free survival, high rates of response, and good tolerability even at the 960 mg dose. But in the randomized trial, it wasn’t better than docetaxel. Again, I think we were disappointed with tusamitamab ravtansine in that it could not beat docetaxel either. I think the idea here is that chemo still has a huge place and still remains the treatment that we have to beat.

We’re all very excited about the antibody-drug conjugates and I think everybody sees them as another advance. Many folks have said that they are just a more precise way of delivering chemotherapy, and when you look at the side effects, it supports that — they’re largely side effects of chemotherapy with these drugs across the board. Also, when you look at the patterns of resistance, the resistance really isn’t a resistance to the targeted therapy; it’s a resistance to chemotherapy more than anything else.

So we’re happy that the antibody-drug conjugates are available and we were disappointed with tusamitamab ravtansine because we thought that it could beat docetaxel. But in truth, it didn’t, and unfortunately, that pivotal trial led to the end of the entire development program for that agent, as stated in a press release.

The molecule or treatment of the year is chemotherapy — added to targeted therapies, used with immunotherapy, and now attached to antibodies as part of antibody-drug conjugates. I think it remains, more than any one treatment, a very effective treatment for patients and deserves to be used.

There are a lot of choices here. I think you have to be very careful to choose wisely, and you also have to be careful because chemotherapy has side effects. The nice thing is that many of those side effects can be ameliorated. We have to make sure that we use all the supportive medications we can.

Who would have thought that chemotherapy would be the treatment of the year in 2023 for lung cancers?
 

Dr. Kris is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York City. He disclosed ties with AstraZeneca, Roche/Genentech, Ariad Pharmaceuticals, Pfizer Inc, and PUMA.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

I’ve been spending time recently reflecting on the biggest developments from last year. I have to say that the breakthrough of the year, based on the amount of data presented and the importance of the data, is chemotherapy. I never thought I would say that. Many folks have tried to relegate chemotherapy to the museum, but last year it came to the forefront.

Let’s start with neoadjuvant therapy. We now have multiple drug approvals for giving a checkpoint inhibitor and neoadjuvant therapy in what I would say is a new standard of care for patients with locally advanced lung cancers who are candidates for surgery. In all those trials, there was a clear improvement in progression-free survival by adding a checkpoint inhibitor to chemotherapy. The cornerstone of this regimen is chemotherapy.

What about adjuvant therapy? I think one of the most astounding pieces of data last year was in the adjuvant realm. In the trial comparing adjuvant osimertinib with placebo in patients with EGFR-mutant disease, patients who received chemotherapy in addition to osimertinib had a 7% improvement in 5-year survival. Patients who had placebo, who got chemotherapy vs didn’t, had a 9% improvement in 5-year survival. Those are huge numbers for that kind of metric, and it happened with chemotherapy.

What about targeted therapies? Again, I think people were astounded that, by adding chemotherapy to osimertinib compared with osimertinib alone, there was a 9-month improvement overall in progression-free survival. I think in the presentation of the data that has been made, the most remarkable piece of data is that, in patients with brain metastases, chemotherapy on top of osimertinib improved progression-free survival. Not only did it improve progression-free survival, but it did it with brain metastases, where people think it just doesn’t help at all.

What about other, newer agents with chemotherapy? Amivantamab, I would say, has hitched itself to chemotherapy. A trial in EGFR exon 20 compared chemo to amivantamab plus chemotherapy. There again, chemo is the common denominator. Amivantamab added approximately 5 months of improved progression-free survival. Again, chemo was used. In adjuvant, neoadjuvant, and targeted therapies, chemotherapy adds.

What about the second line? I think everybody was very disappointed when second-line sotorasib gave a very tiny amount of progression-free survival improvement over docetaxel. I think we all want more for our patients than we can deliver with docetaxel. The roughly 5-week improvement seen with sotorasib was one that raised a question about the place of sotorasib in this setting.

Clearly, we’ve all seen patients have an excellent result with sotorasib as an additional option for treating patients with long progression-free survival, high rates of response, and good tolerability even at the 960 mg dose. But in the randomized trial, it wasn’t better than docetaxel. Again, I think we were disappointed with tusamitamab ravtansine in that it could not beat docetaxel either. I think the idea here is that chemo still has a huge place and still remains the treatment that we have to beat.

We’re all very excited about the antibody-drug conjugates and I think everybody sees them as another advance. Many folks have said that they are just a more precise way of delivering chemotherapy, and when you look at the side effects, it supports that — they’re largely side effects of chemotherapy with these drugs across the board. Also, when you look at the patterns of resistance, the resistance really isn’t a resistance to the targeted therapy; it’s a resistance to chemotherapy more than anything else.

So we’re happy that the antibody-drug conjugates are available and we were disappointed with tusamitamab ravtansine because we thought that it could beat docetaxel. But in truth, it didn’t, and unfortunately, that pivotal trial led to the end of the entire development program for that agent, as stated in a press release.

The molecule or treatment of the year is chemotherapy — added to targeted therapies, used with immunotherapy, and now attached to antibodies as part of antibody-drug conjugates. I think it remains, more than any one treatment, a very effective treatment for patients and deserves to be used.

There are a lot of choices here. I think you have to be very careful to choose wisely, and you also have to be careful because chemotherapy has side effects. The nice thing is that many of those side effects can be ameliorated. We have to make sure that we use all the supportive medications we can.

Who would have thought that chemotherapy would be the treatment of the year in 2023 for lung cancers?
 

Dr. Kris is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York City. He disclosed ties with AstraZeneca, Roche/Genentech, Ariad Pharmaceuticals, Pfizer Inc, and PUMA.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

I’ve been spending time recently reflecting on the biggest developments from last year. I have to say that the breakthrough of the year, based on the amount of data presented and the importance of the data, is chemotherapy. I never thought I would say that. Many folks have tried to relegate chemotherapy to the museum, but last year it came to the forefront.

Let’s start with neoadjuvant therapy. We now have multiple drug approvals for giving a checkpoint inhibitor and neoadjuvant therapy in what I would say is a new standard of care for patients with locally advanced lung cancers who are candidates for surgery. In all those trials, there was a clear improvement in progression-free survival by adding a checkpoint inhibitor to chemotherapy. The cornerstone of this regimen is chemotherapy.

What about adjuvant therapy? I think one of the most astounding pieces of data last year was in the adjuvant realm. In the trial comparing adjuvant osimertinib with placebo in patients with EGFR-mutant disease, patients who received chemotherapy in addition to osimertinib had a 7% improvement in 5-year survival. Patients who had placebo, who got chemotherapy vs didn’t, had a 9% improvement in 5-year survival. Those are huge numbers for that kind of metric, and it happened with chemotherapy.

What about targeted therapies? Again, I think people were astounded that, by adding chemotherapy to osimertinib compared with osimertinib alone, there was a 9-month improvement overall in progression-free survival. I think in the presentation of the data that has been made, the most remarkable piece of data is that, in patients with brain metastases, chemotherapy on top of osimertinib improved progression-free survival. Not only did it improve progression-free survival, but it did it with brain metastases, where people think it just doesn’t help at all.

What about other, newer agents with chemotherapy? Amivantamab, I would say, has hitched itself to chemotherapy. A trial in EGFR exon 20 compared chemo to amivantamab plus chemotherapy. There again, chemo is the common denominator. Amivantamab added approximately 5 months of improved progression-free survival. Again, chemo was used. In adjuvant, neoadjuvant, and targeted therapies, chemotherapy adds.

What about the second line? I think everybody was very disappointed when second-line sotorasib gave a very tiny amount of progression-free survival improvement over docetaxel. I think we all want more for our patients than we can deliver with docetaxel. The roughly 5-week improvement seen with sotorasib was one that raised a question about the place of sotorasib in this setting.

Clearly, we’ve all seen patients have an excellent result with sotorasib as an additional option for treating patients with long progression-free survival, high rates of response, and good tolerability even at the 960 mg dose. But in the randomized trial, it wasn’t better than docetaxel. Again, I think we were disappointed with tusamitamab ravtansine in that it could not beat docetaxel either. I think the idea here is that chemo still has a huge place and still remains the treatment that we have to beat.

We’re all very excited about the antibody-drug conjugates and I think everybody sees them as another advance. Many folks have said that they are just a more precise way of delivering chemotherapy, and when you look at the side effects, it supports that — they’re largely side effects of chemotherapy with these drugs across the board. Also, when you look at the patterns of resistance, the resistance really isn’t a resistance to the targeted therapy; it’s a resistance to chemotherapy more than anything else.

So we’re happy that the antibody-drug conjugates are available and we were disappointed with tusamitamab ravtansine because we thought that it could beat docetaxel. But in truth, it didn’t, and unfortunately, that pivotal trial led to the end of the entire development program for that agent, as stated in a press release.

The molecule or treatment of the year is chemotherapy — added to targeted therapies, used with immunotherapy, and now attached to antibodies as part of antibody-drug conjugates. I think it remains, more than any one treatment, a very effective treatment for patients and deserves to be used.

There are a lot of choices here. I think you have to be very careful to choose wisely, and you also have to be careful because chemotherapy has side effects. The nice thing is that many of those side effects can be ameliorated. We have to make sure that we use all the supportive medications we can.

Who would have thought that chemotherapy would be the treatment of the year in 2023 for lung cancers?
 

Dr. Kris is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York City. He disclosed ties with AstraZeneca, Roche/Genentech, Ariad Pharmaceuticals, Pfizer Inc, and PUMA.

A version of this article appeared on Medscape.com.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

The benefit of immunotherapy in combination with chemotherapy for programmed death–ligand 1–positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC) has been shown in both the IMpassion130 and KEYNOTE-355 trials.^[2,3] However, the IMpassion131 trial, which evaluated atezolizumab plus paclitaxel, did not show a progression-free survival (PFS) or overall survival (OS) benefit vs paclitaxel alone in PD-L1+ mTNBC.^[4] Various explanations for these divergent results have been proposed, including the inherent properties of the chemotherapy backbone, patient populations, and the heterogenous nature of TNBC, which can affect response to immunotherapy. Of present, the various KEYNOTE-355 regimens (pembrolizumab plus investigator's choice chemotherapy [nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin]) are US Food and Drug Administration approved for PD-L1+ mTNBC in the first-line setting. The phase 2 randomized TBCRC 043 trial investigated the effect of atezolizumab with carboplatin in patients with mTNBC and further looked at clinical and molecular correlates of response (Lehmann et al). A total of 106 patients were randomly assigned to carboplatin or carboplatin plus atezolizumab; the combination improved PFS (median PFS, 4.1 vs 2.2 mo; hazard ratio [HR] 0.66; P = .05) and OS (12.6 vs 8.6 mo; HR 0.60; P = .03). Grade 3/4 serious adverse events were more common with carboplatin-atezolizumab vs carboplatin alone (41% vs 8%). In addition, an association of better responses with PD-L1 immunotherapy was seen in patients with obesity, uncontrolled blood glucose levels, high tumor mutation burden, and increased tumor infiltrating lymphocytes. These data support the role of immunotherapy in mTNBC, highlight tumor heterogeneity within this subtype and encourage correlative studies to better define which patients benefit from immunotherapy.

Various studies have demonstrated the favorable impact of physical activity on breast cancer risk in postmenopausal women.^[5] However, data in premenopausal women is less clear. Various mechanisms connecting physical activity to premenopausal breast cancer risk have been proposed including the effect of exercise on sex steroid hormones, fasting insulin levels, and inflammation.^[6] A pooled analysis from 19 cohort studies including 547,601 premenopausal women, with 10,231 incident cases of breast cancer, aimed to examine the relationship between leisure-time physical activity (sports, exercise, recreational walking) and breast cancer risk in young women (Timmins et al). Higher (90th percentile) vs lower (10th percentile) levels of leisure-time physical activity were associated with a 10% reduction in breast cancer risk after adjustment for body mass index (BMI; adjusted HR 0.90; 95% CI 0.85-0.95; P < .001). They also found a significant reduction in risk: 32% (HR 0.68; P = .01) and 9% (HR 0.91; P = .005) for women with underweight (BMI < 18.5) and with average weight (BMI 18.5-24.9), respectively. Further, the effect of physical activity was most pronounced in the human epidermal growth factor receptor 2 (HER2)–enriched breast cancer subtype, wherein higher vs lower levels of activity were associated with an estimated 45% reduction in breast cancer risk (adjusted HR 0.55; 95% CI 0.37-0.82). These findings support the beneficial role of aerobic exercise and healthy body weight on breast cancer risk among premenopausal women and highlight the value of incorporating this information into counseling for our patients.

Additional References

1. Figueroa JD, Gierach GL, Duggan MA, et al. Risk factors for breast cancer development by tumor characteristics among women with benign breast disease. Breast Cancer Res. 2021;23:34. doi: 10.1186/s13058-021-01410-1 Source
2. Schmid P, Adams S, Rugo HS, et al, for the IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121. doi: 10.1056/nejmoa1809615 Source
3. Cortes J, Rugo HS, Cescon DW, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387:217-226. doi: 10.1056/NEJMoa2202809 Source
4. Miles D, Gligorov J, André F, et al, on behalf of the IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32:994-1004. doi: 10.1016/j.annonc.2021.05.801 Source
5. Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med. 2010;170:1758-1764. doi: 10.1001/archinternmed.2010.363 Source
6. Swain CTV, Drummond AE, Boing L, et al. Linking physical activity to breast cancer via sex hormones, part 1: The effect of physical activity on sex steroid hormones. Cancer Epidemiol Biomarkers Prev. 2022;31:16-27. doi: 10.1158/1055-9965.EPI-21-0437 Source

The benefit of immunotherapy in combination with chemotherapy for programmed death–ligand 1–positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC) has been shown in both the IMpassion130 and KEYNOTE-355 trials.^[2,3] However, the IMpassion131 trial, which evaluated atezolizumab plus paclitaxel, did not show a progression-free survival (PFS) or overall survival (OS) benefit vs paclitaxel alone in PD-L1+ mTNBC.^[4] Various explanations for these divergent results have been proposed, including the inherent properties of the chemotherapy backbone, patient populations, and the heterogenous nature of TNBC, which can affect response to immunotherapy. Of present, the various KEYNOTE-355 regimens (pembrolizumab plus investigator's choice chemotherapy [nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin]) are US Food and Drug Administration approved for PD-L1+ mTNBC in the first-line setting. The phase 2 randomized TBCRC 043 trial investigated the effect of atezolizumab with carboplatin in patients with mTNBC and further looked at clinical and molecular correlates of response (Lehmann et al). A total of 106 patients were randomly assigned to carboplatin or carboplatin plus atezolizumab; the combination improved PFS (median PFS, 4.1 vs 2.2 mo; hazard ratio [HR] 0.66; P = .05) and OS (12.6 vs 8.6 mo; HR 0.60; P = .03). Grade 3/4 serious adverse events were more common with carboplatin-atezolizumab vs carboplatin alone (41% vs 8%). In addition, an association of better responses with PD-L1 immunotherapy was seen in patients with obesity, uncontrolled blood glucose levels, high tumor mutation burden, and increased tumor infiltrating lymphocytes. These data support the role of immunotherapy in mTNBC, highlight tumor heterogeneity within this subtype and encourage correlative studies to better define which patients benefit from immunotherapy.

Various studies have demonstrated the favorable impact of physical activity on breast cancer risk in postmenopausal women.^[5] However, data in premenopausal women is less clear. Various mechanisms connecting physical activity to premenopausal breast cancer risk have been proposed including the effect of exercise on sex steroid hormones, fasting insulin levels, and inflammation.^[6] A pooled analysis from 19 cohort studies including 547,601 premenopausal women, with 10,231 incident cases of breast cancer, aimed to examine the relationship between leisure-time physical activity (sports, exercise, recreational walking) and breast cancer risk in young women (Timmins et al). Higher (90th percentile) vs lower (10th percentile) levels of leisure-time physical activity were associated with a 10% reduction in breast cancer risk after adjustment for body mass index (BMI; adjusted HR 0.90; 95% CI 0.85-0.95; P < .001). They also found a significant reduction in risk: 32% (HR 0.68; P = .01) and 9% (HR 0.91; P = .005) for women with underweight (BMI < 18.5) and with average weight (BMI 18.5-24.9), respectively. Further, the effect of physical activity was most pronounced in the human epidermal growth factor receptor 2 (HER2)–enriched breast cancer subtype, wherein higher vs lower levels of activity were associated with an estimated 45% reduction in breast cancer risk (adjusted HR 0.55; 95% CI 0.37-0.82). These findings support the beneficial role of aerobic exercise and healthy body weight on breast cancer risk among premenopausal women and highlight the value of incorporating this information into counseling for our patients.

Additional References

1. Figueroa JD, Gierach GL, Duggan MA, et al. Risk factors for breast cancer development by tumor characteristics among women with benign breast disease. Breast Cancer Res. 2021;23:34. doi: 10.1186/s13058-021-01410-1 Source
2. Schmid P, Adams S, Rugo HS, et al, for the IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121. doi: 10.1056/nejmoa1809615 Source
3. Cortes J, Rugo HS, Cescon DW, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387:217-226. doi: 10.1056/NEJMoa2202809 Source
4. Miles D, Gligorov J, André F, et al, on behalf of the IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32:994-1004. doi: 10.1016/j.annonc.2021.05.801 Source
5. Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med. 2010;170:1758-1764. doi: 10.1001/archinternmed.2010.363 Source
6. Swain CTV, Drummond AE, Boing L, et al. Linking physical activity to breast cancer via sex hormones, part 1: The effect of physical activity on sex steroid hormones. Cancer Epidemiol Biomarkers Prev. 2022;31:16-27. doi: 10.1158/1055-9965.EPI-21-0437 Source

The benefit of immunotherapy in combination with chemotherapy for programmed death–ligand 1–positive (PD-L1+) metastatic triple-negative breast cancer (mTNBC) has been shown in both the IMpassion130 and KEYNOTE-355 trials.^[2,3] However, the IMpassion131 trial, which evaluated atezolizumab plus paclitaxel, did not show a progression-free survival (PFS) or overall survival (OS) benefit vs paclitaxel alone in PD-L1+ mTNBC.^[4] Various explanations for these divergent results have been proposed, including the inherent properties of the chemotherapy backbone, patient populations, and the heterogenous nature of TNBC, which can affect response to immunotherapy. Of present, the various KEYNOTE-355 regimens (pembrolizumab plus investigator's choice chemotherapy [nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin]) are US Food and Drug Administration approved for PD-L1+ mTNBC in the first-line setting. The phase 2 randomized TBCRC 043 trial investigated the effect of atezolizumab with carboplatin in patients with mTNBC and further looked at clinical and molecular correlates of response (Lehmann et al). A total of 106 patients were randomly assigned to carboplatin or carboplatin plus atezolizumab; the combination improved PFS (median PFS, 4.1 vs 2.2 mo; hazard ratio [HR] 0.66; P = .05) and OS (12.6 vs 8.6 mo; HR 0.60; P = .03). Grade 3/4 serious adverse events were more common with carboplatin-atezolizumab vs carboplatin alone (41% vs 8%). In addition, an association of better responses with PD-L1 immunotherapy was seen in patients with obesity, uncontrolled blood glucose levels, high tumor mutation burden, and increased tumor infiltrating lymphocytes. These data support the role of immunotherapy in mTNBC, highlight tumor heterogeneity within this subtype and encourage correlative studies to better define which patients benefit from immunotherapy.

Various studies have demonstrated the favorable impact of physical activity on breast cancer risk in postmenopausal women.^[5] However, data in premenopausal women is less clear. Various mechanisms connecting physical activity to premenopausal breast cancer risk have been proposed including the effect of exercise on sex steroid hormones, fasting insulin levels, and inflammation.^[6] A pooled analysis from 19 cohort studies including 547,601 premenopausal women, with 10,231 incident cases of breast cancer, aimed to examine the relationship between leisure-time physical activity (sports, exercise, recreational walking) and breast cancer risk in young women (Timmins et al). Higher (90th percentile) vs lower (10th percentile) levels of leisure-time physical activity were associated with a 10% reduction in breast cancer risk after adjustment for body mass index (BMI; adjusted HR 0.90; 95% CI 0.85-0.95; P < .001). They also found a significant reduction in risk: 32% (HR 0.68; P = .01) and 9% (HR 0.91; P = .005) for women with underweight (BMI < 18.5) and with average weight (BMI 18.5-24.9), respectively. Further, the effect of physical activity was most pronounced in the human epidermal growth factor receptor 2 (HER2)–enriched breast cancer subtype, wherein higher vs lower levels of activity were associated with an estimated 45% reduction in breast cancer risk (adjusted HR 0.55; 95% CI 0.37-0.82). These findings support the beneficial role of aerobic exercise and healthy body weight on breast cancer risk among premenopausal women and highlight the value of incorporating this information into counseling for our patients.

Additional References

1. Figueroa JD, Gierach GL, Duggan MA, et al. Risk factors for breast cancer development by tumor characteristics among women with benign breast disease. Breast Cancer Res. 2021;23:34. doi: 10.1186/s13058-021-01410-1 Source
2. Schmid P, Adams S, Rugo HS, et al, for the IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121. doi: 10.1056/nejmoa1809615 Source
3. Cortes J, Rugo HS, Cescon DW, et al, for the KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387:217-226. doi: 10.1056/NEJMoa2202809 Source
4. Miles D, Gligorov J, André F, et al, on behalf of the IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32:994-1004. doi: 10.1016/j.annonc.2021.05.801 Source
5. Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med. 2010;170:1758-1764. doi: 10.1001/archinternmed.2010.363 Source
6. Swain CTV, Drummond AE, Boing L, et al. Linking physical activity to breast cancer via sex hormones, part 1: The effect of physical activity on sex steroid hormones. Cancer Epidemiol Biomarkers Prev. 2022;31:16-27. doi: 10.1158/1055-9965.EPI-21-0437 Source

Two drugs delivered in combination are better than one after the other for the first-line treatment of men with metastatic castration-resistant prostate cancer bearing homologous recombination-repair mutations.

That’s the conclusion of investigators in the phase 2 BRCAAway trial, which compared a combination of abiraterone (Zytiga) and prednisone plus olaparib (Lynparza) against sequential therapy with the same agents.

At the time of data cutoff, median progression-free survival (PFS), the primary endpoint, was 39 months for patients randomized to the combination, compared with 8.4 months for those assigned to abiraterone/prednisone, and 14 months for those assigned to olaparib monotherapy, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center in Chicago.

“In patients with metastatic castration-resistant prostate cancer [mCRPC] and BRCA1/2 or ATM alterations, abiraterone and prednisone plus olaparib was well tolerated and resulted in better progression-free survival and response rates vs. single-agent olaparib or abiraterone/prednisone,” she said in an oral abstract presentation at the ASCO Genitourinary Cancers Symposium.

Although the study allowed crossover between the single-agent arms at the time of progression, only a few patients made the switch. Nonetheless, in these patients the PFS with the frontline combination was superior to that of sequential therapy, she noted.
 

Study Rationale and Design

Germline or somatic mutations in genes encoding for homologous recombination-repair occur in about 20% of men with mCRPC. Olaparib, a PARP1 (poly-adp ribose polymerase-1) inhibitor, interacts with androgen signaling, and preclinical studies have shown that castration-resistant prostate tumor cells have increased PARP1 activity. In addition, PARP1 has been shown preclinically to synergize with androgen receptor pathway inhibitors (ARPIs) such as abiraterone, Dr. Hussain explained.

The BRCAAway trial was designed to test whether co-targeting the androgen receptor and PARP1 could result in higher and more durable responses than current frontline therapies in patients with mCRPC with DNA-damage response mutations.

Patients with mCRPC with no prior exposure to either a PARP1 inhibitor, androgen receptor inhibitor, or mCRPC-directed chemotherapy underwent next-generation sequencing and germline testing of tumor tissues, and those patients found to have inactivating BRCA1/2 and/or ATM alterations were randomized on a 1:1:1 basis to either abiraterone 1000 mg daily plus prednisone 5 mg twice daily (19 patients); olaparib 300 mg twice daily (21 patients); or to the combination (21 patients).

The primary endpoint was radiographic PFS according to RECIST 1.1 criteria, Prostate Cancer Working Group 3 criteria, clinical assessment, or death.

As noted, the median PFS was 8.4 months with abiraterone/prednisone, 14 months with olaparib, and 39 months with the combination.

Secondary endpoints also favored the combination therapy arm, with objective response rates of 22%, 14%, and 33%, respectively; PSA response rates of 61%, 67% and 95%; and undetectable PSA response rates of 17%, 14%, and 33%.

A total of 8 of 19 patients on abiraterone were crossed over to olaparib, and 8 of 21 initially assigned to olaparib were crossed over to abiraterone. In these patients the median PFS from crossover was 8.3 and 7.2 months, respectively. In each crossover group the median PFS from the time of randomization was 16 months.

There were no grade 4 adverse events or treatment-related deaths reported in any of the study arms, and “essentially when you look at the adverse events, they pretty much are consistent with what you would expect to see with these particular agents,” Dr. Hussain said.

“Overall the patients were tolerating the treatment well,” she added.
 

Practice Changing with Caveats

Kim N. Chi, MD, FRCPC, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant, said that the strengths of the study included an olaparib monotherapy arm — something that was missing from phase 3 trials — that provides insights into how PARP inhibitors perform in this population. He also applauded the inclusion of clinical assessment as a primary endpoint, noting that “this is what we do in routine practice, and therefore, the generalizability of the trial becomes more evident.”

The crossover design provides important information about whether an upfront combination or a sequential therapy approach is more effective, as well, he added.

He pointed out, however, that the trial was limited by small sample size and by its “horse race” design rather than as a comparison trial.

“So how does the BRCAAway trial change our practice? Despite the limitations, I think it does support an upfront PARP inhibitor-ARPI combination as firstline therapy for HRR gene-mutated metastatic CRPC. These data suggest synergy, and most importantly, there is no loss of opportunity [for more effective therapies]. However, the limitations of the trial will not end this debate today,” he said.

The trial was funded by AstraZeneca. Both Dr. Hussain and Dr. Chi disclosed honoraria, consulting/advising, and institutional research funding from AstraZeneca and others.

Two drugs delivered in combination are better than one after the other for the first-line treatment of men with metastatic castration-resistant prostate cancer bearing homologous recombination-repair mutations.

That’s the conclusion of investigators in the phase 2 BRCAAway trial, which compared a combination of abiraterone (Zytiga) and prednisone plus olaparib (Lynparza) against sequential therapy with the same agents.

At the time of data cutoff, median progression-free survival (PFS), the primary endpoint, was 39 months for patients randomized to the combination, compared with 8.4 months for those assigned to abiraterone/prednisone, and 14 months for those assigned to olaparib monotherapy, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center in Chicago.

“In patients with metastatic castration-resistant prostate cancer [mCRPC] and BRCA1/2 or ATM alterations, abiraterone and prednisone plus olaparib was well tolerated and resulted in better progression-free survival and response rates vs. single-agent olaparib or abiraterone/prednisone,” she said in an oral abstract presentation at the ASCO Genitourinary Cancers Symposium.

Although the study allowed crossover between the single-agent arms at the time of progression, only a few patients made the switch. Nonetheless, in these patients the PFS with the frontline combination was superior to that of sequential therapy, she noted.
 

Study Rationale and Design

Germline or somatic mutations in genes encoding for homologous recombination-repair occur in about 20% of men with mCRPC. Olaparib, a PARP1 (poly-adp ribose polymerase-1) inhibitor, interacts with androgen signaling, and preclinical studies have shown that castration-resistant prostate tumor cells have increased PARP1 activity. In addition, PARP1 has been shown preclinically to synergize with androgen receptor pathway inhibitors (ARPIs) such as abiraterone, Dr. Hussain explained.

The BRCAAway trial was designed to test whether co-targeting the androgen receptor and PARP1 could result in higher and more durable responses than current frontline therapies in patients with mCRPC with DNA-damage response mutations.

Patients with mCRPC with no prior exposure to either a PARP1 inhibitor, androgen receptor inhibitor, or mCRPC-directed chemotherapy underwent next-generation sequencing and germline testing of tumor tissues, and those patients found to have inactivating BRCA1/2 and/or ATM alterations were randomized on a 1:1:1 basis to either abiraterone 1000 mg daily plus prednisone 5 mg twice daily (19 patients); olaparib 300 mg twice daily (21 patients); or to the combination (21 patients).

The primary endpoint was radiographic PFS according to RECIST 1.1 criteria, Prostate Cancer Working Group 3 criteria, clinical assessment, or death.

As noted, the median PFS was 8.4 months with abiraterone/prednisone, 14 months with olaparib, and 39 months with the combination.

Secondary endpoints also favored the combination therapy arm, with objective response rates of 22%, 14%, and 33%, respectively; PSA response rates of 61%, 67% and 95%; and undetectable PSA response rates of 17%, 14%, and 33%.

A total of 8 of 19 patients on abiraterone were crossed over to olaparib, and 8 of 21 initially assigned to olaparib were crossed over to abiraterone. In these patients the median PFS from crossover was 8.3 and 7.2 months, respectively. In each crossover group the median PFS from the time of randomization was 16 months.

There were no grade 4 adverse events or treatment-related deaths reported in any of the study arms, and “essentially when you look at the adverse events, they pretty much are consistent with what you would expect to see with these particular agents,” Dr. Hussain said.

“Overall the patients were tolerating the treatment well,” she added.
 

Practice Changing with Caveats

Kim N. Chi, MD, FRCPC, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant, said that the strengths of the study included an olaparib monotherapy arm — something that was missing from phase 3 trials — that provides insights into how PARP inhibitors perform in this population. He also applauded the inclusion of clinical assessment as a primary endpoint, noting that “this is what we do in routine practice, and therefore, the generalizability of the trial becomes more evident.”

The crossover design provides important information about whether an upfront combination or a sequential therapy approach is more effective, as well, he added.

He pointed out, however, that the trial was limited by small sample size and by its “horse race” design rather than as a comparison trial.

“So how does the BRCAAway trial change our practice? Despite the limitations, I think it does support an upfront PARP inhibitor-ARPI combination as firstline therapy for HRR gene-mutated metastatic CRPC. These data suggest synergy, and most importantly, there is no loss of opportunity [for more effective therapies]. However, the limitations of the trial will not end this debate today,” he said.

The trial was funded by AstraZeneca. Both Dr. Hussain and Dr. Chi disclosed honoraria, consulting/advising, and institutional research funding from AstraZeneca and others.

Two drugs delivered in combination are better than one after the other for the first-line treatment of men with metastatic castration-resistant prostate cancer bearing homologous recombination-repair mutations.

That’s the conclusion of investigators in the phase 2 BRCAAway trial, which compared a combination of abiraterone (Zytiga) and prednisone plus olaparib (Lynparza) against sequential therapy with the same agents.

At the time of data cutoff, median progression-free survival (PFS), the primary endpoint, was 39 months for patients randomized to the combination, compared with 8.4 months for those assigned to abiraterone/prednisone, and 14 months for those assigned to olaparib monotherapy, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center in Chicago.

“In patients with metastatic castration-resistant prostate cancer [mCRPC] and BRCA1/2 or ATM alterations, abiraterone and prednisone plus olaparib was well tolerated and resulted in better progression-free survival and response rates vs. single-agent olaparib or abiraterone/prednisone,” she said in an oral abstract presentation at the ASCO Genitourinary Cancers Symposium.

Although the study allowed crossover between the single-agent arms at the time of progression, only a few patients made the switch. Nonetheless, in these patients the PFS with the frontline combination was superior to that of sequential therapy, she noted.
 

Study Rationale and Design

Germline or somatic mutations in genes encoding for homologous recombination-repair occur in about 20% of men with mCRPC. Olaparib, a PARP1 (poly-adp ribose polymerase-1) inhibitor, interacts with androgen signaling, and preclinical studies have shown that castration-resistant prostate tumor cells have increased PARP1 activity. In addition, PARP1 has been shown preclinically to synergize with androgen receptor pathway inhibitors (ARPIs) such as abiraterone, Dr. Hussain explained.

The BRCAAway trial was designed to test whether co-targeting the androgen receptor and PARP1 could result in higher and more durable responses than current frontline therapies in patients with mCRPC with DNA-damage response mutations.

Patients with mCRPC with no prior exposure to either a PARP1 inhibitor, androgen receptor inhibitor, or mCRPC-directed chemotherapy underwent next-generation sequencing and germline testing of tumor tissues, and those patients found to have inactivating BRCA1/2 and/or ATM alterations were randomized on a 1:1:1 basis to either abiraterone 1000 mg daily plus prednisone 5 mg twice daily (19 patients); olaparib 300 mg twice daily (21 patients); or to the combination (21 patients).

The primary endpoint was radiographic PFS according to RECIST 1.1 criteria, Prostate Cancer Working Group 3 criteria, clinical assessment, or death.

As noted, the median PFS was 8.4 months with abiraterone/prednisone, 14 months with olaparib, and 39 months with the combination.

Secondary endpoints also favored the combination therapy arm, with objective response rates of 22%, 14%, and 33%, respectively; PSA response rates of 61%, 67% and 95%; and undetectable PSA response rates of 17%, 14%, and 33%.

A total of 8 of 19 patients on abiraterone were crossed over to olaparib, and 8 of 21 initially assigned to olaparib were crossed over to abiraterone. In these patients the median PFS from crossover was 8.3 and 7.2 months, respectively. In each crossover group the median PFS from the time of randomization was 16 months.

There were no grade 4 adverse events or treatment-related deaths reported in any of the study arms, and “essentially when you look at the adverse events, they pretty much are consistent with what you would expect to see with these particular agents,” Dr. Hussain said.

“Overall the patients were tolerating the treatment well,” she added.
 

Practice Changing with Caveats

Kim N. Chi, MD, FRCPC, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant, said that the strengths of the study included an olaparib monotherapy arm — something that was missing from phase 3 trials — that provides insights into how PARP inhibitors perform in this population. He also applauded the inclusion of clinical assessment as a primary endpoint, noting that “this is what we do in routine practice, and therefore, the generalizability of the trial becomes more evident.”

The crossover design provides important information about whether an upfront combination or a sequential therapy approach is more effective, as well, he added.

He pointed out, however, that the trial was limited by small sample size and by its “horse race” design rather than as a comparison trial.

“So how does the BRCAAway trial change our practice? Despite the limitations, I think it does support an upfront PARP inhibitor-ARPI combination as firstline therapy for HRR gene-mutated metastatic CRPC. These data suggest synergy, and most importantly, there is no loss of opportunity [for more effective therapies]. However, the limitations of the trial will not end this debate today,” he said.

The trial was funded by AstraZeneca. Both Dr. Hussain and Dr. Chi disclosed honoraria, consulting/advising, and institutional research funding from AstraZeneca and others.