Genitourinary Cancer

Cancer patients with behavioral health disorders are significantly less likely to undergo surgical resections, and more likely to experience poor outcomes when they do have surgery, based on data from a new study of nearly 700,000 individuals.

The reason for this association remains unclear, and highlights the need to address existing behavioral health disorders (BHDs), which can be exacerbated after a patient is diagnosed with cancer, wrote Timothy M. Pawlik, MD, of The Ohio State University, Columbus, and colleagues. A cancer diagnosis can cause not only physical stress, but mental, emotional, social, and economic stress that can prompt a new BHD, cause relapse of a previous BHD, or exacerbate a current BHD, the researchers noted.
 

What is Known About BHDs and Cancer?

Although previous studies have shown a possible association between BHDs and increased cancer risk, as well as reduced compliance with care, the effect of BHDs on outcomes in cancer patients undergoing surgical resection has not been examined, wrote Dr. Pawlik and colleagues.

Previous research has focused on the impact of having a preexisting serious mental illness (SMI) such as schizophrenia and bipolar disorder on cancer care.

A 2023 literature review of 27 studies published in the Journal of Medical Imaging and Radiation Sciences showed that patients with preexisting severe mental illness (such as schizophrenia or bipolar disorder) had greater cancer-related mortality. In that study, the researchers also found that patients with severe mental illness were more likely to have metastatic disease at diagnosis, but less likely to receive optimal treatments, than individuals without SMIs.

Many studies also have focused on patients developing mental health problems (including BHDs) after a cancer diagnosis, but the current study is the first known to examine outcomes in those with BHDs before cancer. 
 

Why Was It Important to Conduct This Study?

“BHDs are a diverse set of mental illnesses that affect an individual’s psychosocial wellbeing, potentially resulting in maladaptive behaviors,” Dr. Pawlik said in an interview. BHDs, which include substance abuse, eating disorders, and sleep disorders, are less common than anxiety/depression, but have an estimated prevalence of 1.3%-3.1% among adults in the United States, he said.

What Does the New Study Add?

In the new review by Dr. Pawlik and colleagues, published in the Journal of the American College of Surgeons (Katayama ES. J Am Coll Surg. 2024 Feb 29. doi: 2024. 10.1097/XCS.0000000000000954), BHDs were defined as substance abuse, eating disorders, or sleep disorders, which had not been the focus of previous studies. The researchers reviewed data from 694,836 adult patients with lung, esophageal, gastric, liver, pancreatic, or colorectal cancer between 2018-2021 using the Medicare Standard Analytic files. A total of 46,719 patients (6.7%) had at least one BHD.

Overall, patients with a BHD were significantly less likely than those without a BHD to undergo surgical resection (20.3% vs. 23.4%). Patients with a BHD also had significantly worse long-term postoperative survival than those without BHDs (median 37.1 months vs. 46.6 months) and significantly higher in-hospital costs ($17,432 vs. 16,159, P less than .001 for all).

Among patients who underwent cancer surgery, the odds of any complication were significantly higher for those with a BHD compared to those with no BHD (odds ratio 1.32), as were the odds of a prolonged length of stay (OR 1.67) and 90-day readmission (OR 1.57).

Dr. Pawlik said he was surprised by several of the findings, including that 1 in 15 Medicare beneficiaries had a BHD diagnosis, “with male sex and minority racial status, as well as higher social vulnerability, being associated with a higher prevalence of BHD.”

Also, the independent association of having a BHD with 30%-50% higher odds of a complication, prolonged length of stay, and 90-day readmission was higher than Dr. Pawlik had anticipated.
 

Why Do Patients With BHDs Have Fewer Surgeries and Worse Outcomes?

The reasons for this association were likely multifactorial and may reflect the greater burden of medical comorbidity and chronic illness in many patients with BHDs because of maladaptive lifestyles or poor nutrition status, Dr. Pawlik said.

“Patients with BHDs also likely face barriers to accessing care, which was noted particularly among patients with BHDs who lived in socially vulnerable areas,” he said. BHD patients also were more likely to be treated at low-volume rather than high-volume hospitals, “which undoubtedly contributed in part to worse outcomes in this cohort of patients,” he added.
 

What Can Oncologists Do to Help?

The take-home message for clinicians is that BHDs are linked to worse surgical outcomes and higher health care costs in cancer patients, Dr. Pawlik said in an interview.

“Enhanced accessibility to behavioral healthcare, as well as comprehensive policy reform related to mental health services are needed to improve care of patients with BHDs,” he said. “For example, implementing psychiatry compensation programs may encourage practice in vulnerable areas,” he said.

Other strategies include a following a collaborative care model involving mental health professionals working in tandem with primary care and mid-level practitioners and increasing use and establishment of telehealth systems to improve patient access to BHD services, he said.
 

What Are the Limitations?

The study by Dr. Pawlik and colleagues was limited by several factors, including the lack of data on younger patients and the full range of BHDs, as well as underreporting of BHDs and the high copays for mental health care, the researchers noted. However, the results suggest that concomitant BHDs are associated with worse cancer outcomes and higher in-hospital costs, and illustrate the need to screen for and target these conditions in cancer patients, the researchers concluded.

What Are the Next Steps for Research?

The current study involved Medicare beneficiaries aged 65 years or older, and more research is needed to investigate the impact of BHDs among younger cancer patients in whom the prevalence may be higher and the impact of BHDs may be different, Dr. Pawlik said in an interview. In addition, the analysis of BHDs as a composite of substance abuse, eating disorders, and sleep disorders (because the numbers were too small to break out data for each disorder, separately) prevented investigation of potential differences and unique challenges faced by distinct subpopulations of BHD patients, he said.

“Future studies should examine the individual impact of substance abuse, eating disorders, and sleep disorders on access to surgery, as well as the potential different impact that each one of these different BHDs may have on postoperative outcomes,” Dr. Pawlik suggested.

The study was supported by The Ohio State University College of Medicine Roessler Summer Research Scholarship. The researchers had no financial conflicts to disclose.

Cancer patients with behavioral health disorders are significantly less likely to undergo surgical resections, and more likely to experience poor outcomes when they do have surgery, based on data from a new study of nearly 700,000 individuals.

The reason for this association remains unclear, and highlights the need to address existing behavioral health disorders (BHDs), which can be exacerbated after a patient is diagnosed with cancer, wrote Timothy M. Pawlik, MD, of The Ohio State University, Columbus, and colleagues. A cancer diagnosis can cause not only physical stress, but mental, emotional, social, and economic stress that can prompt a new BHD, cause relapse of a previous BHD, or exacerbate a current BHD, the researchers noted.
 

What is Known About BHDs and Cancer?

Although previous studies have shown a possible association between BHDs and increased cancer risk, as well as reduced compliance with care, the effect of BHDs on outcomes in cancer patients undergoing surgical resection has not been examined, wrote Dr. Pawlik and colleagues.

Previous research has focused on the impact of having a preexisting serious mental illness (SMI) such as schizophrenia and bipolar disorder on cancer care.

A 2023 literature review of 27 studies published in the Journal of Medical Imaging and Radiation Sciences showed that patients with preexisting severe mental illness (such as schizophrenia or bipolar disorder) had greater cancer-related mortality. In that study, the researchers also found that patients with severe mental illness were more likely to have metastatic disease at diagnosis, but less likely to receive optimal treatments, than individuals without SMIs.

Many studies also have focused on patients developing mental health problems (including BHDs) after a cancer diagnosis, but the current study is the first known to examine outcomes in those with BHDs before cancer. 
 

Why Was It Important to Conduct This Study?

“BHDs are a diverse set of mental illnesses that affect an individual’s psychosocial wellbeing, potentially resulting in maladaptive behaviors,” Dr. Pawlik said in an interview. BHDs, which include substance abuse, eating disorders, and sleep disorders, are less common than anxiety/depression, but have an estimated prevalence of 1.3%-3.1% among adults in the United States, he said.

What Does the New Study Add?

In the new review by Dr. Pawlik and colleagues, published in the Journal of the American College of Surgeons (Katayama ES. J Am Coll Surg. 2024 Feb 29. doi: 2024. 10.1097/XCS.0000000000000954), BHDs were defined as substance abuse, eating disorders, or sleep disorders, which had not been the focus of previous studies. The researchers reviewed data from 694,836 adult patients with lung, esophageal, gastric, liver, pancreatic, or colorectal cancer between 2018-2021 using the Medicare Standard Analytic files. A total of 46,719 patients (6.7%) had at least one BHD.

Overall, patients with a BHD were significantly less likely than those without a BHD to undergo surgical resection (20.3% vs. 23.4%). Patients with a BHD also had significantly worse long-term postoperative survival than those without BHDs (median 37.1 months vs. 46.6 months) and significantly higher in-hospital costs ($17,432 vs. 16,159, P less than .001 for all).

Among patients who underwent cancer surgery, the odds of any complication were significantly higher for those with a BHD compared to those with no BHD (odds ratio 1.32), as were the odds of a prolonged length of stay (OR 1.67) and 90-day readmission (OR 1.57).

Dr. Pawlik said he was surprised by several of the findings, including that 1 in 15 Medicare beneficiaries had a BHD diagnosis, “with male sex and minority racial status, as well as higher social vulnerability, being associated with a higher prevalence of BHD.”

Also, the independent association of having a BHD with 30%-50% higher odds of a complication, prolonged length of stay, and 90-day readmission was higher than Dr. Pawlik had anticipated.
 

Why Do Patients With BHDs Have Fewer Surgeries and Worse Outcomes?

The reasons for this association were likely multifactorial and may reflect the greater burden of medical comorbidity and chronic illness in many patients with BHDs because of maladaptive lifestyles or poor nutrition status, Dr. Pawlik said.

“Patients with BHDs also likely face barriers to accessing care, which was noted particularly among patients with BHDs who lived in socially vulnerable areas,” he said. BHD patients also were more likely to be treated at low-volume rather than high-volume hospitals, “which undoubtedly contributed in part to worse outcomes in this cohort of patients,” he added.
 

What Can Oncologists Do to Help?

The take-home message for clinicians is that BHDs are linked to worse surgical outcomes and higher health care costs in cancer patients, Dr. Pawlik said in an interview.

“Enhanced accessibility to behavioral healthcare, as well as comprehensive policy reform related to mental health services are needed to improve care of patients with BHDs,” he said. “For example, implementing psychiatry compensation programs may encourage practice in vulnerable areas,” he said.

Other strategies include a following a collaborative care model involving mental health professionals working in tandem with primary care and mid-level practitioners and increasing use and establishment of telehealth systems to improve patient access to BHD services, he said.
 

What Are the Limitations?

The study by Dr. Pawlik and colleagues was limited by several factors, including the lack of data on younger patients and the full range of BHDs, as well as underreporting of BHDs and the high copays for mental health care, the researchers noted. However, the results suggest that concomitant BHDs are associated with worse cancer outcomes and higher in-hospital costs, and illustrate the need to screen for and target these conditions in cancer patients, the researchers concluded.

What Are the Next Steps for Research?

The current study involved Medicare beneficiaries aged 65 years or older, and more research is needed to investigate the impact of BHDs among younger cancer patients in whom the prevalence may be higher and the impact of BHDs may be different, Dr. Pawlik said in an interview. In addition, the analysis of BHDs as a composite of substance abuse, eating disorders, and sleep disorders (because the numbers were too small to break out data for each disorder, separately) prevented investigation of potential differences and unique challenges faced by distinct subpopulations of BHD patients, he said.

“Future studies should examine the individual impact of substance abuse, eating disorders, and sleep disorders on access to surgery, as well as the potential different impact that each one of these different BHDs may have on postoperative outcomes,” Dr. Pawlik suggested.

The study was supported by The Ohio State University College of Medicine Roessler Summer Research Scholarship. The researchers had no financial conflicts to disclose.

Cancer patients with behavioral health disorders are significantly less likely to undergo surgical resections, and more likely to experience poor outcomes when they do have surgery, based on data from a new study of nearly 700,000 individuals.

The reason for this association remains unclear, and highlights the need to address existing behavioral health disorders (BHDs), which can be exacerbated after a patient is diagnosed with cancer, wrote Timothy M. Pawlik, MD, of The Ohio State University, Columbus, and colleagues. A cancer diagnosis can cause not only physical stress, but mental, emotional, social, and economic stress that can prompt a new BHD, cause relapse of a previous BHD, or exacerbate a current BHD, the researchers noted.
 

What is Known About BHDs and Cancer?

Although previous studies have shown a possible association between BHDs and increased cancer risk, as well as reduced compliance with care, the effect of BHDs on outcomes in cancer patients undergoing surgical resection has not been examined, wrote Dr. Pawlik and colleagues.

Previous research has focused on the impact of having a preexisting serious mental illness (SMI) such as schizophrenia and bipolar disorder on cancer care.

A 2023 literature review of 27 studies published in the Journal of Medical Imaging and Radiation Sciences showed that patients with preexisting severe mental illness (such as schizophrenia or bipolar disorder) had greater cancer-related mortality. In that study, the researchers also found that patients with severe mental illness were more likely to have metastatic disease at diagnosis, but less likely to receive optimal treatments, than individuals without SMIs.

Many studies also have focused on patients developing mental health problems (including BHDs) after a cancer diagnosis, but the current study is the first known to examine outcomes in those with BHDs before cancer. 
 

Why Was It Important to Conduct This Study?

“BHDs are a diverse set of mental illnesses that affect an individual’s psychosocial wellbeing, potentially resulting in maladaptive behaviors,” Dr. Pawlik said in an interview. BHDs, which include substance abuse, eating disorders, and sleep disorders, are less common than anxiety/depression, but have an estimated prevalence of 1.3%-3.1% among adults in the United States, he said.

What Does the New Study Add?

In the new review by Dr. Pawlik and colleagues, published in the Journal of the American College of Surgeons (Katayama ES. J Am Coll Surg. 2024 Feb 29. doi: 2024. 10.1097/XCS.0000000000000954), BHDs were defined as substance abuse, eating disorders, or sleep disorders, which had not been the focus of previous studies. The researchers reviewed data from 694,836 adult patients with lung, esophageal, gastric, liver, pancreatic, or colorectal cancer between 2018-2021 using the Medicare Standard Analytic files. A total of 46,719 patients (6.7%) had at least one BHD.

Overall, patients with a BHD were significantly less likely than those without a BHD to undergo surgical resection (20.3% vs. 23.4%). Patients with a BHD also had significantly worse long-term postoperative survival than those without BHDs (median 37.1 months vs. 46.6 months) and significantly higher in-hospital costs ($17,432 vs. 16,159, P less than .001 for all).

Among patients who underwent cancer surgery, the odds of any complication were significantly higher for those with a BHD compared to those with no BHD (odds ratio 1.32), as were the odds of a prolonged length of stay (OR 1.67) and 90-day readmission (OR 1.57).

Dr. Pawlik said he was surprised by several of the findings, including that 1 in 15 Medicare beneficiaries had a BHD diagnosis, “with male sex and minority racial status, as well as higher social vulnerability, being associated with a higher prevalence of BHD.”

Also, the independent association of having a BHD with 30%-50% higher odds of a complication, prolonged length of stay, and 90-day readmission was higher than Dr. Pawlik had anticipated.
 

Why Do Patients With BHDs Have Fewer Surgeries and Worse Outcomes?

The reasons for this association were likely multifactorial and may reflect the greater burden of medical comorbidity and chronic illness in many patients with BHDs because of maladaptive lifestyles or poor nutrition status, Dr. Pawlik said.

“Patients with BHDs also likely face barriers to accessing care, which was noted particularly among patients with BHDs who lived in socially vulnerable areas,” he said. BHD patients also were more likely to be treated at low-volume rather than high-volume hospitals, “which undoubtedly contributed in part to worse outcomes in this cohort of patients,” he added.
 

What Can Oncologists Do to Help?

The take-home message for clinicians is that BHDs are linked to worse surgical outcomes and higher health care costs in cancer patients, Dr. Pawlik said in an interview.

“Enhanced accessibility to behavioral healthcare, as well as comprehensive policy reform related to mental health services are needed to improve care of patients with BHDs,” he said. “For example, implementing psychiatry compensation programs may encourage practice in vulnerable areas,” he said.

Other strategies include a following a collaborative care model involving mental health professionals working in tandem with primary care and mid-level practitioners and increasing use and establishment of telehealth systems to improve patient access to BHD services, he said.
 

What Are the Limitations?

The study by Dr. Pawlik and colleagues was limited by several factors, including the lack of data on younger patients and the full range of BHDs, as well as underreporting of BHDs and the high copays for mental health care, the researchers noted. However, the results suggest that concomitant BHDs are associated with worse cancer outcomes and higher in-hospital costs, and illustrate the need to screen for and target these conditions in cancer patients, the researchers concluded.

What Are the Next Steps for Research?

The current study involved Medicare beneficiaries aged 65 years or older, and more research is needed to investigate the impact of BHDs among younger cancer patients in whom the prevalence may be higher and the impact of BHDs may be different, Dr. Pawlik said in an interview. In addition, the analysis of BHDs as a composite of substance abuse, eating disorders, and sleep disorders (because the numbers were too small to break out data for each disorder, separately) prevented investigation of potential differences and unique challenges faced by distinct subpopulations of BHD patients, he said.

“Future studies should examine the individual impact of substance abuse, eating disorders, and sleep disorders on access to surgery, as well as the potential different impact that each one of these different BHDs may have on postoperative outcomes,” Dr. Pawlik suggested.

The study was supported by The Ohio State University College of Medicine Roessler Summer Research Scholarship. The researchers had no financial conflicts to disclose.

Food emulsifiers are among the most widespread food additives. A large cohort study highlighted an association between the consumption of certain emulsifiers and an increased risk for certain cancers, particularly breast and prostate cancer.

Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.

Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.

Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.

The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.

In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).

Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.

In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.

The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.

It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.

This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Food emulsifiers are among the most widespread food additives. A large cohort study highlighted an association between the consumption of certain emulsifiers and an increased risk for certain cancers, particularly breast and prostate cancer.

Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.

Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.

Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.

The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.

In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).

Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.

In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.

The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.

It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.

This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Food emulsifiers are among the most widespread food additives. A large cohort study highlighted an association between the consumption of certain emulsifiers and an increased risk for certain cancers, particularly breast and prostate cancer.

Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.

Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.

Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.

The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.

In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).

Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.

In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.

The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.

It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.

This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

A group of 16 Democratic legislators on the House Committee on Oversight and Reform has demanded in a letter that the drugmaker Pfizer present details on how the company is responding to shortages of the generic chemotherapy drugs carboplatin, cisplatin, and methotrexate.

In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.

A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”

What is the basis for concern?

All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.

What has the government done in response to the recent shortages?

The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.

What can the lawmakers expect to achieve with their letter?

By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”

Why did the committee target Pfizer specifically?

Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”

The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.

What is being demanded of Pfizer?

Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.

A group of 16 Democratic legislators on the House Committee on Oversight and Reform has demanded in a letter that the drugmaker Pfizer present details on how the company is responding to shortages of the generic chemotherapy drugs carboplatin, cisplatin, and methotrexate.

In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.

A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”

What is the basis for concern?

All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.

What has the government done in response to the recent shortages?

The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.

What can the lawmakers expect to achieve with their letter?

By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”

Why did the committee target Pfizer specifically?

Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”

The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.

What is being demanded of Pfizer?

Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.

A group of 16 Democratic legislators on the House Committee on Oversight and Reform has demanded in a letter that the drugmaker Pfizer present details on how the company is responding to shortages of the generic chemotherapy drugs carboplatin, cisplatin, and methotrexate.

In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.

A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”

What is the basis for concern?

All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.

What has the government done in response to the recent shortages?

The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.

What can the lawmakers expect to achieve with their letter?

By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”

Why did the committee target Pfizer specifically?

Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”

The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.

What is being demanded of Pfizer?

Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

TOPLINE:

Upon reviewing repeated prostate cancer screenings, researchers observed the absence of suspicious MRI findings in over 86% of men who had prostate-specific antigen (PSA) levels of 3 ng/mL or higher during their second screening.

METHODOLOGY:

• New initiatives are focusing on organizing prostate cancer screening using MRI to reduce overdiagnosis, as current evidence does not support the effectiveness of a single PSA test, with guidelines now recommending repeated testing every 1-4 years.
• In the STHLM3-MRI trial, men, aged 50-74 years, living in Stockholm County, Sweden, were invited to participate in prostate cancer screening and randomly assigned to traditional screening with systematic  or an MRI-based strategy.
• Blood samples were analyzed for PSA levels and Stockholm3 risk score; men with elevated risk underwent targeted MRI and biopsy procedures.
• In this follow-up analysis, 2,078 men with PSA levels of 1.5 ng/mL or higher and a Stockholm3 risk score less than 0.11 were re-invited for screening 2-3 years after their initial screening.
• The primary outcome was clinically significant prostate cancer (Gleason score of 3 + 4 or greater). A Gleason score of 6 was detected in 0.7% of patients, and a score of 4 + 3 or greater was detected in 19 (1.3%) men.

TAKEAWAY:

• Of 1,500 men (median age of 67 years) who underwent a blood test, the median PSA level was 2.8 ng/mL and 26.0% changed risk classification groups (PSA levels < 3 vs 3 ng/mL).
• Out of 667 men with PSA levels of 3 ng/mL or higher, 617 (92.5%) had an MRI. Of the 617, 51 (7.6%) had equivocal lesions (a Prostate Imaging-Reporting and Data System score of 3) and 33 (4.9%) had suspicious lesions.
• Of the 1,500 rescreened men, clinically significant prostate cancer was detected in 48 men (3.2%); this corresponds to 59.2% of the biopsied men.
• Out of 383 men who had previously received a negative MRI result, only 10 (2.6%) exhibited a lesion with a Prostate Imaging-Reporting and Data System score of 4 or higher.

IN PRACTICE:

In an accompanying editorial, Ola Bratt, MD, PhD, noted that the “most important finding was the very high proportion of nonsuspicious repeat MRI scans,” but also emphasizes the necessity of observing a decrease in overall prostate cancer incidence before asserting that the current cancer diagnostics effectively reduce overdiagnosis.

SOURCE:

This study, led by Tobias Nordström, MD, PhD, from Karolinska Institute, Stockholm, Sweden, was published on February 7, 2024, in JAMA Network Open.

LIMITATIONS:

Long-term outcomes like prostate cancer mortality were not evaluated. Information on cancer detection in men with a negative MRI result at rescreening was not available. Authors noted that a subset of individuals may still be at risk despite lower PSA levels.

DISCLOSURES:

This study was funded by the Swedish Research Council for Health, Working Life and Welfare, Karolinska Institute, Prostatacancerförbundet, Region Stockholm, and Åke Wibergs Stiftelse. The authors reported financial relationships outside this work.

A version of this article appeared on Medscape.com.

TOPLINE:

Upon reviewing repeated prostate cancer screenings, researchers observed the absence of suspicious MRI findings in over 86% of men who had prostate-specific antigen (PSA) levels of 3 ng/mL or higher during their second screening.

METHODOLOGY:

• New initiatives are focusing on organizing prostate cancer screening using MRI to reduce overdiagnosis, as current evidence does not support the effectiveness of a single PSA test, with guidelines now recommending repeated testing every 1-4 years.
• In the STHLM3-MRI trial, men, aged 50-74 years, living in Stockholm County, Sweden, were invited to participate in prostate cancer screening and randomly assigned to traditional screening with systematic  or an MRI-based strategy.
• Blood samples were analyzed for PSA levels and Stockholm3 risk score; men with elevated risk underwent targeted MRI and biopsy procedures.
• In this follow-up analysis, 2,078 men with PSA levels of 1.5 ng/mL or higher and a Stockholm3 risk score less than 0.11 were re-invited for screening 2-3 years after their initial screening.
• The primary outcome was clinically significant prostate cancer (Gleason score of 3 + 4 or greater). A Gleason score of 6 was detected in 0.7% of patients, and a score of 4 + 3 or greater was detected in 19 (1.3%) men.

TAKEAWAY:

• Of 1,500 men (median age of 67 years) who underwent a blood test, the median PSA level was 2.8 ng/mL and 26.0% changed risk classification groups (PSA levels < 3 vs 3 ng/mL).
• Out of 667 men with PSA levels of 3 ng/mL or higher, 617 (92.5%) had an MRI. Of the 617, 51 (7.6%) had equivocal lesions (a Prostate Imaging-Reporting and Data System score of 3) and 33 (4.9%) had suspicious lesions.
• Of the 1,500 rescreened men, clinically significant prostate cancer was detected in 48 men (3.2%); this corresponds to 59.2% of the biopsied men.
• Out of 383 men who had previously received a negative MRI result, only 10 (2.6%) exhibited a lesion with a Prostate Imaging-Reporting and Data System score of 4 or higher.

IN PRACTICE:

In an accompanying editorial, Ola Bratt, MD, PhD, noted that the “most important finding was the very high proportion of nonsuspicious repeat MRI scans,” but also emphasizes the necessity of observing a decrease in overall prostate cancer incidence before asserting that the current cancer diagnostics effectively reduce overdiagnosis.

SOURCE:

This study, led by Tobias Nordström, MD, PhD, from Karolinska Institute, Stockholm, Sweden, was published on February 7, 2024, in JAMA Network Open.

LIMITATIONS:

Long-term outcomes like prostate cancer mortality were not evaluated. Information on cancer detection in men with a negative MRI result at rescreening was not available. Authors noted that a subset of individuals may still be at risk despite lower PSA levels.

DISCLOSURES:

This study was funded by the Swedish Research Council for Health, Working Life and Welfare, Karolinska Institute, Prostatacancerförbundet, Region Stockholm, and Åke Wibergs Stiftelse. The authors reported financial relationships outside this work.

A version of this article appeared on Medscape.com.

TOPLINE:

Upon reviewing repeated prostate cancer screenings, researchers observed the absence of suspicious MRI findings in over 86% of men who had prostate-specific antigen (PSA) levels of 3 ng/mL or higher during their second screening.

METHODOLOGY:

• New initiatives are focusing on organizing prostate cancer screening using MRI to reduce overdiagnosis, as current evidence does not support the effectiveness of a single PSA test, with guidelines now recommending repeated testing every 1-4 years.
• In the STHLM3-MRI trial, men, aged 50-74 years, living in Stockholm County, Sweden, were invited to participate in prostate cancer screening and randomly assigned to traditional screening with systematic  or an MRI-based strategy.
• Blood samples were analyzed for PSA levels and Stockholm3 risk score; men with elevated risk underwent targeted MRI and biopsy procedures.
• In this follow-up analysis, 2,078 men with PSA levels of 1.5 ng/mL or higher and a Stockholm3 risk score less than 0.11 were re-invited for screening 2-3 years after their initial screening.
• The primary outcome was clinically significant prostate cancer (Gleason score of 3 + 4 or greater). A Gleason score of 6 was detected in 0.7% of patients, and a score of 4 + 3 or greater was detected in 19 (1.3%) men.

TAKEAWAY:

• Of 1,500 men (median age of 67 years) who underwent a blood test, the median PSA level was 2.8 ng/mL and 26.0% changed risk classification groups (PSA levels < 3 vs 3 ng/mL).
• Out of 667 men with PSA levels of 3 ng/mL or higher, 617 (92.5%) had an MRI. Of the 617, 51 (7.6%) had equivocal lesions (a Prostate Imaging-Reporting and Data System score of 3) and 33 (4.9%) had suspicious lesions.
• Of the 1,500 rescreened men, clinically significant prostate cancer was detected in 48 men (3.2%); this corresponds to 59.2% of the biopsied men.
• Out of 383 men who had previously received a negative MRI result, only 10 (2.6%) exhibited a lesion with a Prostate Imaging-Reporting and Data System score of 4 or higher.

IN PRACTICE:

In an accompanying editorial, Ola Bratt, MD, PhD, noted that the “most important finding was the very high proportion of nonsuspicious repeat MRI scans,” but also emphasizes the necessity of observing a decrease in overall prostate cancer incidence before asserting that the current cancer diagnostics effectively reduce overdiagnosis.

SOURCE:

This study, led by Tobias Nordström, MD, PhD, from Karolinska Institute, Stockholm, Sweden, was published on February 7, 2024, in JAMA Network Open.

LIMITATIONS:

Long-term outcomes like prostate cancer mortality were not evaluated. Information on cancer detection in men with a negative MRI result at rescreening was not available. Authors noted that a subset of individuals may still be at risk despite lower PSA levels.

DISCLOSURES:

This study was funded by the Swedish Research Council for Health, Working Life and Welfare, Karolinska Institute, Prostatacancerförbundet, Region Stockholm, and Åke Wibergs Stiftelse. The authors reported financial relationships outside this work.

A version of this article appeared on Medscape.com.

In 2013, a prostate-specific antigen (PSA) blood test revealed that Richard LaFrate’s levels had jumped. 

Previously in a normal range, his PSA was now above 6 ng/mL, indicating an elevated likelihood for prostate cancer. The jazz guitarist from Leesburg, Florida, then 70 years old, underwent a biopsy, which found two Gleason 6 lesions. 

Mr. LaFrate had low-risk prostate cancer.

Guidelines now recommend active surveillance for patients like Mr. LaFrate, who have low-risk disease. This strategy would mean monitoring the cancer until LaFrate required treatment, with the upside being he might never need therapy.

Mr. LaFrate’s urologist, however, was pushing whole gland surgery — an invasive and unnecessary procedure given his diagnosis and age. 

Mr. LaFrate decided to look for another doctor. He filled out a form online that pointed him to a new urologist who offered him one option: An investigational procedure known as high-intensity focused ultrasound.

At the time, high-intensity focused ultrasound — a form of focal therapy — was being studied in the United States to treat men with low or intermediate-risk prostate cancer, but it was still relatively early days.

Mr. LaFrate’s urologist asked him to pay $25,000 out of pocket to undergo the focal procedure at a clinic in the Bahamas. He refused and, ultimately, landed on active surveillance as the best strategy to manage for his low-risk disease.

That urologist was “a shyster in my opinion,” Mr. LaFrate said. 

Over the past 10 years, the popularity of focal therapy has grown among men with intermediate-risk prostate cancer — Gleason 3+4 (grade group 2) tumors — as an alternative to invasive surgery and active surveillance. Prestigious medical centers, such as Cleveland Clinic, Mayo Clinic, Memorial Sloan Kettering, UCLA, and the University of Chicago, routinely offer focal therapy. 

But use of the techniques remains controversial and costly.

As the Cleveland Clinic’s website acknowledges, although “the use of focal therapy for localized prostate cancer appears to be a promising development in a number of ways, it is still considered investigational and not yet part of standard therapy.” Major caveats to focal therapy include unknown long-term effectiveness, the possibility of leaving behind untreated cancer, and higher overall costs. 

No major national guidelines endorse the use of focal therapy, unless offered in a research or clinical trial setting. Insurance companies, such as Aetna, Blue Cross Blue Shield, and United, also consider focal therapy for prostate cancer investigational and don’t cover it.

Without a stamp of approval from guideline bodies and insurance companies, patients, like Mr. LaFrate, remain vulnerable to the high out-of-pocket costs for these focal techniques. 

“Almost every place charges $15,000-$30,000 in cash,” said Daniel Spratt, MD, radiation oncology chair at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland. 

Dr. Spratt has seen hundreds of patients after focal therapy, some from prominent centers, who have emptied their bank accounts to undergo treatment with the promise of great results and ultimately felt misled when the cancer has recurred.

“It pains me that there are doctors willing to ignore the Hippocratic oath of ‘Do No Harm’ simply to jump on this fad to bring in revenue,” Dr. Spratt said. 
 

Evidence-Based or Oversold?

Focal therapy gained a foothold in the United Kingdom well before the United States.

Hashim Ahmed, FRCS, urology chair at Imperial College London, has used focal therapy for 15 years, treated over 1000 patients, and taught dozens of surgeons how to use the leading focal therapies — focal cryoablation, in which surgeons use a needle-thin probe to target, freeze, and kill prostate tumors, as well as high-intensity focused ultrasound, which uses sound wave energy to superheat and kill tumors.

“Certainly, in the United Kingdom, focal therapy has been prime time in a number of centers for a number of years,” Dr. Ahmed said. 

In the United States, focal therapy has become an attractive option for men with prostate cancer who want to avoid radiation or radical prostatectomy but don’t feel comfortable simply monitoring their disease with active surveillance. Experts from specialized focal therapy centers touting the promise of this “innovative technique” predict its routine use in the next few years.

But the excitement surrounding the use of focal therapy in prostate cancer has outpaced broader acceptance.

In 2015, the FDA approved high-intensity focused ultrasound to treat prostatic disease, but not prostate cancer specifically. Although the approval language “means that companies cannot advertise that their devices can be used for prostate cancer,” physicians can still determine how to use the technology, which includes treating prostate cancer, Dr. Ahmed said. 

The evidence is starting to catch up to the demand. The latest research suggests that the partial-gland techniques may stand up well to radical prostatectomy.

A 2022 prospective database study comparing radical prostatectomies to focal therapy — mostly high-intensity focused ultrasound — in more than 800 men found similar rates of failure-free survival in the two groups at the 8-year follow-up. A 2019 registry study found that failure-free survival at 3 years was just over 90% in high and intermediate-risk patients receiving focal cryotherapy, with the rate rising to about 93% for the intermediate-risk group. And a 2018 prospective study of 625 patients with intermediate or high-risk prostate cancer who underwent high-intensity focused ultrasound had 5-year metastasis-free survival of 98% and overall survival rates of 100%.

One of the biggest draws of focal therapy vs more aggressive treatments is the “massive differences in side-effect profiles,” said Dr. Ahmed.

In a 2021 meta-analysis, researchers found that 6 months after high-intensity focused ultrasound, 98% of patients remained continent and 80% retained erectile function, while erectile dysfunction can occur in 30% to as many as 85% of patients following prostatectomy or radiotherapy and urinary incontinence can occur in as many as 40% of patients.

Despite these potential advantages of focal therapy, the long-term efficacy of the techniques remains uncertain.

A recent study from a team at MSK, for instance, reported that 40% of men with intermediate (grade 2) or high-risk (grade 3) disease had residual cancer following MRI-guided focused ultrasound. A 2020 prospective registry study found that almost 20% of patients undergoing high-intensity focal ultrasound required a second round following a recurrence. 

Dr. Spratt worries that patients who recur after focal therapy may go on to receive a second round — often offered at half price — and will still ultimately need surgery or radiation therapy later. By that point, however, patients may have spent as much as $45,000 — ie, $30,000 on the initial and another $15,000 on the follow-up procedure.

When patients see Dr. Spratt after a recurrence, he informs them that their side effects will be worse if he gives them radiation or surgery now vs if he had given them curative therapy upfront. “But this is what we’re left with,” he tells them.

Another big concern in the field is “the quality of data for focal therapy is overwhelmingly poor,” said Jonathan Shoag, MD, a urologic oncologist at University Hospitals and an associate professor of urology at Case Western Reserve University School of Medicine in Cleveland. “Essentially, the bulk of the data is from single-institution retrospective series without defined follow-up protocols or endpoints.”

The American Urological Association (AUA) has even cautioned experts and patients about the lack of high-quality data comparing focal therapy techniques to radiation therapy, surgery, and active surveillance. According to the AUA, focal options should only be considered in intermediate-risk prostate cancer in a clinical trial setting.

“The lack of randomized clinical trials poses a major stumbling block for the field,” said Dr. Ahmed.

Although randomized trials would be ideal, the results would take many years to mature, and growing patient demand for these less invasive focal procedures has made randomized trials difficult to complete, explained Arvin George, MD, associate professor at Johns Hopkins School of Medicine in Baltimore. Several randomized trials attempted in Norway and the United Kingdom, for instance, fell apart when patients refused to be randomized between focal and radical therapy, Dr. George said.

Focal therapy is now in the same position that active surveillance was a few years ago, according to Dr. George.

“We are hearing the same concerns about focal therapy now as we did about active surveillance,” he said. The initial evidence supporting active surveillance largely came from real-world experience and retrospective studies. The randomized data came later, and skeptics of active surveillance “were proven wrong,” he added.

But Dr. Shoag has a different take on the trajectory of focal therapy research and care in the United States. 

“I think there’s this emerging kind of tragedy happening in our field now, where you have even academic institutions offering focal therapy to patients off-trial with essentially no data to suggest it is oncologically effective,” Dr. Shoag said.

William Catalona, MD, Northwestern University Feinberg School of Medicine, Chicago, agreed, noting that too many low-risk patients are undergoing focal treatment who should be on active surveillance. “Many men are attracted to focal because they just are uncomfortable having a cancer in their body that’s not treated,” Dr. Catalona said. But “giving these patients focal therapy is really overtreatment.”

Patients with higher-risk disease who want to avoid aggressive treatment are also being lured into focal without guidelines or clear evidence to back up that option, Dr. Catalona explained.

Although it’s not clear how many men in the United States are receiving focal therapy who shouldn’t, even proponents of focal therapy, like George, have expressed concern.

Dr. George agreed that focal therapy marketing geared towards patients is drawing in some men who are not good candidates for these techniques, and feels there’s not enough objective material from medical societies or academic centers giving patients a realistic picture of focal therapy. 

“There is concern that patients may be receiving biased information,” Dr. George said, adding that it’s ultimately up to the physician to reconcile the best available evidence, understand the outcomes, and discuss these options with the patient to guide them to what’s best.

At the end of the day, Dr. Spratt said, physicians giving focal therapy off a clinical trial need to pause and ask themselves “why are they giving a treatment that remains investigational by payers, not recommended by any major guideline, and that lacks any randomized evidence?” 

Mr. LaFrate does not regret his decision to forgo focal therapy in 2013. He has been on active surveillance for about a decade now.

Following an MRI in 2022, Mr. LaFrate’s radiology report found that “clinically significant cancer is very unlikely to be present.”

Still, his PSA has risen two points in the past year to 14. His current urologist feels that the PSA is going up because there’s cancer present and is suggesting focal therapy for Mr. LaFrate.

Mr. LaFrate, who has prostate enlargement issues, remains skeptical of focal therapy and is still resisting the sales pitch.

“My doctor is not aggressively pushing it. He’s just giving me that as one of my options,” he said. “I just have a hunch I don’t need it at this point.”

A version of this article appeared on Medscape.com.

In 2013, a prostate-specific antigen (PSA) blood test revealed that Richard LaFrate’s levels had jumped. 

Previously in a normal range, his PSA was now above 6 ng/mL, indicating an elevated likelihood for prostate cancer. The jazz guitarist from Leesburg, Florida, then 70 years old, underwent a biopsy, which found two Gleason 6 lesions. 

Mr. LaFrate had low-risk prostate cancer.

Guidelines now recommend active surveillance for patients like Mr. LaFrate, who have low-risk disease. This strategy would mean monitoring the cancer until LaFrate required treatment, with the upside being he might never need therapy.

Mr. LaFrate’s urologist, however, was pushing whole gland surgery — an invasive and unnecessary procedure given his diagnosis and age. 

Mr. LaFrate decided to look for another doctor. He filled out a form online that pointed him to a new urologist who offered him one option: An investigational procedure known as high-intensity focused ultrasound.

At the time, high-intensity focused ultrasound — a form of focal therapy — was being studied in the United States to treat men with low or intermediate-risk prostate cancer, but it was still relatively early days.

Mr. LaFrate’s urologist asked him to pay $25,000 out of pocket to undergo the focal procedure at a clinic in the Bahamas. He refused and, ultimately, landed on active surveillance as the best strategy to manage for his low-risk disease.

That urologist was “a shyster in my opinion,” Mr. LaFrate said. 

Over the past 10 years, the popularity of focal therapy has grown among men with intermediate-risk prostate cancer — Gleason 3+4 (grade group 2) tumors — as an alternative to invasive surgery and active surveillance. Prestigious medical centers, such as Cleveland Clinic, Mayo Clinic, Memorial Sloan Kettering, UCLA, and the University of Chicago, routinely offer focal therapy. 

But use of the techniques remains controversial and costly.

As the Cleveland Clinic’s website acknowledges, although “the use of focal therapy for localized prostate cancer appears to be a promising development in a number of ways, it is still considered investigational and not yet part of standard therapy.” Major caveats to focal therapy include unknown long-term effectiveness, the possibility of leaving behind untreated cancer, and higher overall costs. 

No major national guidelines endorse the use of focal therapy, unless offered in a research or clinical trial setting. Insurance companies, such as Aetna, Blue Cross Blue Shield, and United, also consider focal therapy for prostate cancer investigational and don’t cover it.

Without a stamp of approval from guideline bodies and insurance companies, patients, like Mr. LaFrate, remain vulnerable to the high out-of-pocket costs for these focal techniques. 

“Almost every place charges $15,000-$30,000 in cash,” said Daniel Spratt, MD, radiation oncology chair at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland. 

Dr. Spratt has seen hundreds of patients after focal therapy, some from prominent centers, who have emptied their bank accounts to undergo treatment with the promise of great results and ultimately felt misled when the cancer has recurred.

“It pains me that there are doctors willing to ignore the Hippocratic oath of ‘Do No Harm’ simply to jump on this fad to bring in revenue,” Dr. Spratt said. 
 

Evidence-Based or Oversold?

Focal therapy gained a foothold in the United Kingdom well before the United States.

Hashim Ahmed, FRCS, urology chair at Imperial College London, has used focal therapy for 15 years, treated over 1000 patients, and taught dozens of surgeons how to use the leading focal therapies — focal cryoablation, in which surgeons use a needle-thin probe to target, freeze, and kill prostate tumors, as well as high-intensity focused ultrasound, which uses sound wave energy to superheat and kill tumors.

“Certainly, in the United Kingdom, focal therapy has been prime time in a number of centers for a number of years,” Dr. Ahmed said. 

In the United States, focal therapy has become an attractive option for men with prostate cancer who want to avoid radiation or radical prostatectomy but don’t feel comfortable simply monitoring their disease with active surveillance. Experts from specialized focal therapy centers touting the promise of this “innovative technique” predict its routine use in the next few years.

But the excitement surrounding the use of focal therapy in prostate cancer has outpaced broader acceptance.

In 2015, the FDA approved high-intensity focused ultrasound to treat prostatic disease, but not prostate cancer specifically. Although the approval language “means that companies cannot advertise that their devices can be used for prostate cancer,” physicians can still determine how to use the technology, which includes treating prostate cancer, Dr. Ahmed said. 

The evidence is starting to catch up to the demand. The latest research suggests that the partial-gland techniques may stand up well to radical prostatectomy.

A 2022 prospective database study comparing radical prostatectomies to focal therapy — mostly high-intensity focused ultrasound — in more than 800 men found similar rates of failure-free survival in the two groups at the 8-year follow-up. A 2019 registry study found that failure-free survival at 3 years was just over 90% in high and intermediate-risk patients receiving focal cryotherapy, with the rate rising to about 93% for the intermediate-risk group. And a 2018 prospective study of 625 patients with intermediate or high-risk prostate cancer who underwent high-intensity focused ultrasound had 5-year metastasis-free survival of 98% and overall survival rates of 100%.

One of the biggest draws of focal therapy vs more aggressive treatments is the “massive differences in side-effect profiles,” said Dr. Ahmed.

In a 2021 meta-analysis, researchers found that 6 months after high-intensity focused ultrasound, 98% of patients remained continent and 80% retained erectile function, while erectile dysfunction can occur in 30% to as many as 85% of patients following prostatectomy or radiotherapy and urinary incontinence can occur in as many as 40% of patients.

Despite these potential advantages of focal therapy, the long-term efficacy of the techniques remains uncertain.

A recent study from a team at MSK, for instance, reported that 40% of men with intermediate (grade 2) or high-risk (grade 3) disease had residual cancer following MRI-guided focused ultrasound. A 2020 prospective registry study found that almost 20% of patients undergoing high-intensity focal ultrasound required a second round following a recurrence. 

Dr. Spratt worries that patients who recur after focal therapy may go on to receive a second round — often offered at half price — and will still ultimately need surgery or radiation therapy later. By that point, however, patients may have spent as much as $45,000 — ie, $30,000 on the initial and another $15,000 on the follow-up procedure.

When patients see Dr. Spratt after a recurrence, he informs them that their side effects will be worse if he gives them radiation or surgery now vs if he had given them curative therapy upfront. “But this is what we’re left with,” he tells them.

Another big concern in the field is “the quality of data for focal therapy is overwhelmingly poor,” said Jonathan Shoag, MD, a urologic oncologist at University Hospitals and an associate professor of urology at Case Western Reserve University School of Medicine in Cleveland. “Essentially, the bulk of the data is from single-institution retrospective series without defined follow-up protocols or endpoints.”

The American Urological Association (AUA) has even cautioned experts and patients about the lack of high-quality data comparing focal therapy techniques to radiation therapy, surgery, and active surveillance. According to the AUA, focal options should only be considered in intermediate-risk prostate cancer in a clinical trial setting.

“The lack of randomized clinical trials poses a major stumbling block for the field,” said Dr. Ahmed.

Although randomized trials would be ideal, the results would take many years to mature, and growing patient demand for these less invasive focal procedures has made randomized trials difficult to complete, explained Arvin George, MD, associate professor at Johns Hopkins School of Medicine in Baltimore. Several randomized trials attempted in Norway and the United Kingdom, for instance, fell apart when patients refused to be randomized between focal and radical therapy, Dr. George said.

Focal therapy is now in the same position that active surveillance was a few years ago, according to Dr. George.

“We are hearing the same concerns about focal therapy now as we did about active surveillance,” he said. The initial evidence supporting active surveillance largely came from real-world experience and retrospective studies. The randomized data came later, and skeptics of active surveillance “were proven wrong,” he added.

But Dr. Shoag has a different take on the trajectory of focal therapy research and care in the United States. 

“I think there’s this emerging kind of tragedy happening in our field now, where you have even academic institutions offering focal therapy to patients off-trial with essentially no data to suggest it is oncologically effective,” Dr. Shoag said.

William Catalona, MD, Northwestern University Feinberg School of Medicine, Chicago, agreed, noting that too many low-risk patients are undergoing focal treatment who should be on active surveillance. “Many men are attracted to focal because they just are uncomfortable having a cancer in their body that’s not treated,” Dr. Catalona said. But “giving these patients focal therapy is really overtreatment.”

Patients with higher-risk disease who want to avoid aggressive treatment are also being lured into focal without guidelines or clear evidence to back up that option, Dr. Catalona explained.

Although it’s not clear how many men in the United States are receiving focal therapy who shouldn’t, even proponents of focal therapy, like George, have expressed concern.

Dr. George agreed that focal therapy marketing geared towards patients is drawing in some men who are not good candidates for these techniques, and feels there’s not enough objective material from medical societies or academic centers giving patients a realistic picture of focal therapy. 

“There is concern that patients may be receiving biased information,” Dr. George said, adding that it’s ultimately up to the physician to reconcile the best available evidence, understand the outcomes, and discuss these options with the patient to guide them to what’s best.

At the end of the day, Dr. Spratt said, physicians giving focal therapy off a clinical trial need to pause and ask themselves “why are they giving a treatment that remains investigational by payers, not recommended by any major guideline, and that lacks any randomized evidence?” 

Mr. LaFrate does not regret his decision to forgo focal therapy in 2013. He has been on active surveillance for about a decade now.

Following an MRI in 2022, Mr. LaFrate’s radiology report found that “clinically significant cancer is very unlikely to be present.”

Still, his PSA has risen two points in the past year to 14. His current urologist feels that the PSA is going up because there’s cancer present and is suggesting focal therapy for Mr. LaFrate.

Mr. LaFrate, who has prostate enlargement issues, remains skeptical of focal therapy and is still resisting the sales pitch.

“My doctor is not aggressively pushing it. He’s just giving me that as one of my options,” he said. “I just have a hunch I don’t need it at this point.”

A version of this article appeared on Medscape.com.

In 2013, a prostate-specific antigen (PSA) blood test revealed that Richard LaFrate’s levels had jumped. 

Previously in a normal range, his PSA was now above 6 ng/mL, indicating an elevated likelihood for prostate cancer. The jazz guitarist from Leesburg, Florida, then 70 years old, underwent a biopsy, which found two Gleason 6 lesions. 

Mr. LaFrate had low-risk prostate cancer.

Guidelines now recommend active surveillance for patients like Mr. LaFrate, who have low-risk disease. This strategy would mean monitoring the cancer until LaFrate required treatment, with the upside being he might never need therapy.

Mr. LaFrate’s urologist, however, was pushing whole gland surgery — an invasive and unnecessary procedure given his diagnosis and age. 

Mr. LaFrate decided to look for another doctor. He filled out a form online that pointed him to a new urologist who offered him one option: An investigational procedure known as high-intensity focused ultrasound.

At the time, high-intensity focused ultrasound — a form of focal therapy — was being studied in the United States to treat men with low or intermediate-risk prostate cancer, but it was still relatively early days.

Mr. LaFrate’s urologist asked him to pay $25,000 out of pocket to undergo the focal procedure at a clinic in the Bahamas. He refused and, ultimately, landed on active surveillance as the best strategy to manage for his low-risk disease.

That urologist was “a shyster in my opinion,” Mr. LaFrate said. 

Over the past 10 years, the popularity of focal therapy has grown among men with intermediate-risk prostate cancer — Gleason 3+4 (grade group 2) tumors — as an alternative to invasive surgery and active surveillance. Prestigious medical centers, such as Cleveland Clinic, Mayo Clinic, Memorial Sloan Kettering, UCLA, and the University of Chicago, routinely offer focal therapy. 

But use of the techniques remains controversial and costly.

As the Cleveland Clinic’s website acknowledges, although “the use of focal therapy for localized prostate cancer appears to be a promising development in a number of ways, it is still considered investigational and not yet part of standard therapy.” Major caveats to focal therapy include unknown long-term effectiveness, the possibility of leaving behind untreated cancer, and higher overall costs. 

No major national guidelines endorse the use of focal therapy, unless offered in a research or clinical trial setting. Insurance companies, such as Aetna, Blue Cross Blue Shield, and United, also consider focal therapy for prostate cancer investigational and don’t cover it.

Without a stamp of approval from guideline bodies and insurance companies, patients, like Mr. LaFrate, remain vulnerable to the high out-of-pocket costs for these focal techniques. 

“Almost every place charges $15,000-$30,000 in cash,” said Daniel Spratt, MD, radiation oncology chair at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland. 

Dr. Spratt has seen hundreds of patients after focal therapy, some from prominent centers, who have emptied their bank accounts to undergo treatment with the promise of great results and ultimately felt misled when the cancer has recurred.

“It pains me that there are doctors willing to ignore the Hippocratic oath of ‘Do No Harm’ simply to jump on this fad to bring in revenue,” Dr. Spratt said. 
 

Evidence-Based or Oversold?

Focal therapy gained a foothold in the United Kingdom well before the United States.

Hashim Ahmed, FRCS, urology chair at Imperial College London, has used focal therapy for 15 years, treated over 1000 patients, and taught dozens of surgeons how to use the leading focal therapies — focal cryoablation, in which surgeons use a needle-thin probe to target, freeze, and kill prostate tumors, as well as high-intensity focused ultrasound, which uses sound wave energy to superheat and kill tumors.

“Certainly, in the United Kingdom, focal therapy has been prime time in a number of centers for a number of years,” Dr. Ahmed said. 

In the United States, focal therapy has become an attractive option for men with prostate cancer who want to avoid radiation or radical prostatectomy but don’t feel comfortable simply monitoring their disease with active surveillance. Experts from specialized focal therapy centers touting the promise of this “innovative technique” predict its routine use in the next few years.

But the excitement surrounding the use of focal therapy in prostate cancer has outpaced broader acceptance.

In 2015, the FDA approved high-intensity focused ultrasound to treat prostatic disease, but not prostate cancer specifically. Although the approval language “means that companies cannot advertise that their devices can be used for prostate cancer,” physicians can still determine how to use the technology, which includes treating prostate cancer, Dr. Ahmed said. 

The evidence is starting to catch up to the demand. The latest research suggests that the partial-gland techniques may stand up well to radical prostatectomy.

A 2022 prospective database study comparing radical prostatectomies to focal therapy — mostly high-intensity focused ultrasound — in more than 800 men found similar rates of failure-free survival in the two groups at the 8-year follow-up. A 2019 registry study found that failure-free survival at 3 years was just over 90% in high and intermediate-risk patients receiving focal cryotherapy, with the rate rising to about 93% for the intermediate-risk group. And a 2018 prospective study of 625 patients with intermediate or high-risk prostate cancer who underwent high-intensity focused ultrasound had 5-year metastasis-free survival of 98% and overall survival rates of 100%.

One of the biggest draws of focal therapy vs more aggressive treatments is the “massive differences in side-effect profiles,” said Dr. Ahmed.

In a 2021 meta-analysis, researchers found that 6 months after high-intensity focused ultrasound, 98% of patients remained continent and 80% retained erectile function, while erectile dysfunction can occur in 30% to as many as 85% of patients following prostatectomy or radiotherapy and urinary incontinence can occur in as many as 40% of patients.

Despite these potential advantages of focal therapy, the long-term efficacy of the techniques remains uncertain.

A recent study from a team at MSK, for instance, reported that 40% of men with intermediate (grade 2) or high-risk (grade 3) disease had residual cancer following MRI-guided focused ultrasound. A 2020 prospective registry study found that almost 20% of patients undergoing high-intensity focal ultrasound required a second round following a recurrence. 

Dr. Spratt worries that patients who recur after focal therapy may go on to receive a second round — often offered at half price — and will still ultimately need surgery or radiation therapy later. By that point, however, patients may have spent as much as $45,000 — ie, $30,000 on the initial and another $15,000 on the follow-up procedure.

When patients see Dr. Spratt after a recurrence, he informs them that their side effects will be worse if he gives them radiation or surgery now vs if he had given them curative therapy upfront. “But this is what we’re left with,” he tells them.

Another big concern in the field is “the quality of data for focal therapy is overwhelmingly poor,” said Jonathan Shoag, MD, a urologic oncologist at University Hospitals and an associate professor of urology at Case Western Reserve University School of Medicine in Cleveland. “Essentially, the bulk of the data is from single-institution retrospective series without defined follow-up protocols or endpoints.”

The American Urological Association (AUA) has even cautioned experts and patients about the lack of high-quality data comparing focal therapy techniques to radiation therapy, surgery, and active surveillance. According to the AUA, focal options should only be considered in intermediate-risk prostate cancer in a clinical trial setting.

“The lack of randomized clinical trials poses a major stumbling block for the field,” said Dr. Ahmed.

Although randomized trials would be ideal, the results would take many years to mature, and growing patient demand for these less invasive focal procedures has made randomized trials difficult to complete, explained Arvin George, MD, associate professor at Johns Hopkins School of Medicine in Baltimore. Several randomized trials attempted in Norway and the United Kingdom, for instance, fell apart when patients refused to be randomized between focal and radical therapy, Dr. George said.

Focal therapy is now in the same position that active surveillance was a few years ago, according to Dr. George.

“We are hearing the same concerns about focal therapy now as we did about active surveillance,” he said. The initial evidence supporting active surveillance largely came from real-world experience and retrospective studies. The randomized data came later, and skeptics of active surveillance “were proven wrong,” he added.

But Dr. Shoag has a different take on the trajectory of focal therapy research and care in the United States. 

“I think there’s this emerging kind of tragedy happening in our field now, where you have even academic institutions offering focal therapy to patients off-trial with essentially no data to suggest it is oncologically effective,” Dr. Shoag said.

William Catalona, MD, Northwestern University Feinberg School of Medicine, Chicago, agreed, noting that too many low-risk patients are undergoing focal treatment who should be on active surveillance. “Many men are attracted to focal because they just are uncomfortable having a cancer in their body that’s not treated,” Dr. Catalona said. But “giving these patients focal therapy is really overtreatment.”

Patients with higher-risk disease who want to avoid aggressive treatment are also being lured into focal without guidelines or clear evidence to back up that option, Dr. Catalona explained.

Although it’s not clear how many men in the United States are receiving focal therapy who shouldn’t, even proponents of focal therapy, like George, have expressed concern.

Dr. George agreed that focal therapy marketing geared towards patients is drawing in some men who are not good candidates for these techniques, and feels there’s not enough objective material from medical societies or academic centers giving patients a realistic picture of focal therapy. 

“There is concern that patients may be receiving biased information,” Dr. George said, adding that it’s ultimately up to the physician to reconcile the best available evidence, understand the outcomes, and discuss these options with the patient to guide them to what’s best.

At the end of the day, Dr. Spratt said, physicians giving focal therapy off a clinical trial need to pause and ask themselves “why are they giving a treatment that remains investigational by payers, not recommended by any major guideline, and that lacks any randomized evidence?” 

Mr. LaFrate does not regret his decision to forgo focal therapy in 2013. He has been on active surveillance for about a decade now.

Following an MRI in 2022, Mr. LaFrate’s radiology report found that “clinically significant cancer is very unlikely to be present.”

Still, his PSA has risen two points in the past year to 14. His current urologist feels that the PSA is going up because there’s cancer present and is suggesting focal therapy for Mr. LaFrate.

Mr. LaFrate, who has prostate enlargement issues, remains skeptical of focal therapy and is still resisting the sales pitch.

“My doctor is not aggressively pushing it. He’s just giving me that as one of my options,” he said. “I just have a hunch I don’t need it at this point.”

A version of this article appeared on Medscape.com.

A plant-based diet, low in dairy and meat but rich in fruits, vegetables, grains, and nuts, can improve sexual and urinary health in patients treated for local prostate cancer, new research showed.

The findings, published on February 13, 2024, in the journal Cancer, bolster previous research showing plant-based diets can reduce the risk for recurrence and improve survivorship in men with prostate cancer.

“The current study shows for the first time an association between eating more plant-based food with better scores for quality of life among patients diagnosed with prostate cancer,” Stacy Loeb, MD, a urologist in the departments of Urology and Population Health at NYU Langone Health, in New York City, who led the research.

For the new study, Dr. Loeb and her colleagues looked at data from more than 3500 men with prostate cancer in the Health Professionals Follow-Up Study, an ongoing investigation begun in 1986 and sponsored by Harvard T.H. Chan School of Public Health. The dataset included more than 50,000 male dentists, pharmacists, optometrists, osteopaths, podiatrists, and veterinarians.

The median age of prostate cancer diagnosis was 68 years; 48% of patients underwent radical prostatectomy and 35% had radiation as primary therapy. None of the patients were known to have had metastatic disease.

Men in the study answered a questionnaire every 4 years about the kinds of foods they ate and in what proportions. Another survey, administered every 2 years, assessed the frequency of incontinence, difficulties maintaining an erection, and problems with bowels, energy, and mood, among many other health concerns.

Dr. Loeb and her colleagues sorted patients into quintiles based on the proportion of plant vs animal foods the men said they eat. The authors found those who consumed the most plant-based foods scored 8%-11% better in measures of sexual function than the group that consumed the least of these products.

These men also reported up to 14% better scores for urinary health, with fewer instances of incontinence, obstruction, and irritation, and up to 13% better scores in hormonal health, marked by symptoms like low energy, depression, and hot flashes.

Justin Gregg, MD, a urology researcher at the University of Texas MD Anderson Cancer Center, in Houston, Texas, whose research has found the Mediterranean diet can slow tumor progression among men with localized prostate cancer on active surveillance, called the results “not entirely surprising, as prior studies have shown associations between plant-based diet and outcomes like erectile function among men who do not have prostate cancer.”

But Kenneth Jacobsohn, MD, professor of urology and director of lifestyle medicine at the Medical College of Wisconsin, in Milwaukee, said the new findings help establish “the positive role of diet quality and plant-based diets, specifically on quality of life after prostate cancer diagnosis and treatment for men with nonmetastatic prostate cancer.”

Dr. Jacobsohn said the study was limited by its retrospective nature and the manner of the dietary assessment.

“As the authors point out, a plant-based diet may be helpful, though it’s important to keep in mind the strong data for its protective effect in terms of cardiovascular disease risk, which is very important for men who have a history of prostate cancer as many will die of cardiovascular disease,” Dr. Gregg added.

Dr. Loeb, Dr. Gregg, and Dr. Jacobsohn reported no conflicts of interest. Some of the study authors reported a variety of potential conflicts.
 

A version of this article appeared on Medscape.com .

A plant-based diet, low in dairy and meat but rich in fruits, vegetables, grains, and nuts, can improve sexual and urinary health in patients treated for local prostate cancer, new research showed.

The findings, published on February 13, 2024, in the journal Cancer, bolster previous research showing plant-based diets can reduce the risk for recurrence and improve survivorship in men with prostate cancer.

“The current study shows for the first time an association between eating more plant-based food with better scores for quality of life among patients diagnosed with prostate cancer,” Stacy Loeb, MD, a urologist in the departments of Urology and Population Health at NYU Langone Health, in New York City, who led the research.

For the new study, Dr. Loeb and her colleagues looked at data from more than 3500 men with prostate cancer in the Health Professionals Follow-Up Study, an ongoing investigation begun in 1986 and sponsored by Harvard T.H. Chan School of Public Health. The dataset included more than 50,000 male dentists, pharmacists, optometrists, osteopaths, podiatrists, and veterinarians.

The median age of prostate cancer diagnosis was 68 years; 48% of patients underwent radical prostatectomy and 35% had radiation as primary therapy. None of the patients were known to have had metastatic disease.

Men in the study answered a questionnaire every 4 years about the kinds of foods they ate and in what proportions. Another survey, administered every 2 years, assessed the frequency of incontinence, difficulties maintaining an erection, and problems with bowels, energy, and mood, among many other health concerns.

Dr. Loeb and her colleagues sorted patients into quintiles based on the proportion of plant vs animal foods the men said they eat. The authors found those who consumed the most plant-based foods scored 8%-11% better in measures of sexual function than the group that consumed the least of these products.

These men also reported up to 14% better scores for urinary health, with fewer instances of incontinence, obstruction, and irritation, and up to 13% better scores in hormonal health, marked by symptoms like low energy, depression, and hot flashes.

Justin Gregg, MD, a urology researcher at the University of Texas MD Anderson Cancer Center, in Houston, Texas, whose research has found the Mediterranean diet can slow tumor progression among men with localized prostate cancer on active surveillance, called the results “not entirely surprising, as prior studies have shown associations between plant-based diet and outcomes like erectile function among men who do not have prostate cancer.”

But Kenneth Jacobsohn, MD, professor of urology and director of lifestyle medicine at the Medical College of Wisconsin, in Milwaukee, said the new findings help establish “the positive role of diet quality and plant-based diets, specifically on quality of life after prostate cancer diagnosis and treatment for men with nonmetastatic prostate cancer.”

Dr. Jacobsohn said the study was limited by its retrospective nature and the manner of the dietary assessment.

“As the authors point out, a plant-based diet may be helpful, though it’s important to keep in mind the strong data for its protective effect in terms of cardiovascular disease risk, which is very important for men who have a history of prostate cancer as many will die of cardiovascular disease,” Dr. Gregg added.

Dr. Loeb, Dr. Gregg, and Dr. Jacobsohn reported no conflicts of interest. Some of the study authors reported a variety of potential conflicts.
 

A version of this article appeared on Medscape.com .

A plant-based diet, low in dairy and meat but rich in fruits, vegetables, grains, and nuts, can improve sexual and urinary health in patients treated for local prostate cancer, new research showed.

The findings, published on February 13, 2024, in the journal Cancer, bolster previous research showing plant-based diets can reduce the risk for recurrence and improve survivorship in men with prostate cancer.

“The current study shows for the first time an association between eating more plant-based food with better scores for quality of life among patients diagnosed with prostate cancer,” Stacy Loeb, MD, a urologist in the departments of Urology and Population Health at NYU Langone Health, in New York City, who led the research.

For the new study, Dr. Loeb and her colleagues looked at data from more than 3500 men with prostate cancer in the Health Professionals Follow-Up Study, an ongoing investigation begun in 1986 and sponsored by Harvard T.H. Chan School of Public Health. The dataset included more than 50,000 male dentists, pharmacists, optometrists, osteopaths, podiatrists, and veterinarians.

The median age of prostate cancer diagnosis was 68 years; 48% of patients underwent radical prostatectomy and 35% had radiation as primary therapy. None of the patients were known to have had metastatic disease.

Men in the study answered a questionnaire every 4 years about the kinds of foods they ate and in what proportions. Another survey, administered every 2 years, assessed the frequency of incontinence, difficulties maintaining an erection, and problems with bowels, energy, and mood, among many other health concerns.

Dr. Loeb and her colleagues sorted patients into quintiles based on the proportion of plant vs animal foods the men said they eat. The authors found those who consumed the most plant-based foods scored 8%-11% better in measures of sexual function than the group that consumed the least of these products.

These men also reported up to 14% better scores for urinary health, with fewer instances of incontinence, obstruction, and irritation, and up to 13% better scores in hormonal health, marked by symptoms like low energy, depression, and hot flashes.

Justin Gregg, MD, a urology researcher at the University of Texas MD Anderson Cancer Center, in Houston, Texas, whose research has found the Mediterranean diet can slow tumor progression among men with localized prostate cancer on active surveillance, called the results “not entirely surprising, as prior studies have shown associations between plant-based diet and outcomes like erectile function among men who do not have prostate cancer.”

But Kenneth Jacobsohn, MD, professor of urology and director of lifestyle medicine at the Medical College of Wisconsin, in Milwaukee, said the new findings help establish “the positive role of diet quality and plant-based diets, specifically on quality of life after prostate cancer diagnosis and treatment for men with nonmetastatic prostate cancer.”

Dr. Jacobsohn said the study was limited by its retrospective nature and the manner of the dietary assessment.

“As the authors point out, a plant-based diet may be helpful, though it’s important to keep in mind the strong data for its protective effect in terms of cardiovascular disease risk, which is very important for men who have a history of prostate cancer as many will die of cardiovascular disease,” Dr. Gregg added.

Dr. Loeb, Dr. Gregg, and Dr. Jacobsohn reported no conflicts of interest. Some of the study authors reported a variety of potential conflicts.
 

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.

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.

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.