Patient & Survivor Care

Although a new study of hyperbaric oxygen therapy in JAMA Oncology has been “ anxiously awaited” by breast radiation oncologists, the trial does not provide the smoking gun evidence that would justify its routine use, according to experts.

Here’s a snapshot of the current state of affairs regarding hyperbaric oxygen therapy in breast radiation oncology.

What Is Hyperbaric Oxygen Therapy?

Hyperbaric oxygen therapy is a medical procedure aimed at reducing the late toxic effects of breast irradiation, including pain, fibrosis, and edema. Patients breathe pure oxygen at greater than atmospheric pressure in a specialized chamber or room. The process leads to increased partial pressures of oxygen in blood and tissues, which can help form new blood vessels and repair damaged irradiated tissue.
 

What Is the Current State of Play?

In 2021, the US Food and Drug Administration (FDA) cleared the therapy for a variety of disorders, including radiation injuries. Some health insurers may cover the procedure as well.

Still, the FDA has cautioned clinicians “to be wary of unproven claims of effect,” University of Toronto radiation oncologist Ezra Hahn, MD, and colleagues Aron Popovtzer, MD, and Benjamin W. Corn, MD, said in a JAMA Oncology editorial.

Despite the FDA clearance, there is limited evidence to suggest hyperbaric oxygen therapy reduces the late toxic effects of breast irradiation, and the research to date has largely come from small and non-randomized studies.

While the procedure is “seldom used by many in practice,” there is growing industry for the procedure. More than 1000 facilities in the United States offer hyperbaric oxygen therapy, but only about 15% are accredited by the Undersea and Hyperbaric Medical Society, which may signal misuse of the procedure.
 

Does the Latest Study Clarify Whether This Therapy Works?

The most recent evidence on hyperbaric oxygen therapy comes from a single-institution, randomized trial from the Netherlands, dubbed HONEY. In the trial, 189 women who experienced late toxic effects following adjuvant breast radiation were randomized 2:1 to hyperbaric oxygen therapy or a control arm. Of the 125 women offered hyperbaric oxygen therapy, only 25% (31 patients) accepted and completed treatment; those who declined received usual follow-up care.

Among women who completed hyperbaric oxygen therapy, 32% (10 of 31) reported moderate or severe pain at follow-up vs 75% of controls — a 66% reduction. Similarly, 17% of women who completed hyperbaric oxygen therapy reported moderate or severe fibrosis at follow-up vs 86% among the hypothetical treatment-completing controls — an 86% reduction. However, the authors did not observe a significant effect of hyperbaric oxygen therapy on breast edema, movement restriction, or overall quality of life.

The authors also included an intention-to-treat analysis, which included patients who declined hyperbaric oxygen therapy as part of the intervention group. This analysis estimated clinical outcomes among patients who had the intervention available to them, with some taking advantage and others not.

Overall, hyperbaric oxygen therapy “seems effective for reducing pain and fibrosis in women with late local toxic effects after breast irradiation,” concluded investigators led by Dieuwke R. Mink van der Molen, PhD, a researcher at the University Medical Centre Utrecht, the Netherlands. However, most patients offered the therapy declined the invitation, largely because of the “high treatment intensity” burden.
 

What Are the Limitations of the Current Study?

The investigators and editorialists highlighted a handful of limitations.

For one, the trial had no sham hyperbaric oxygen therapy procedure in the control group. In fact, control patients were selected from a larger cohort of ongoing studies in the Netherlands who were not aware the trial was being conducted.

Because radiation toxicity fluctuates over time and can improve on its own, “a high-quality control arm” would be needed in such a trial, especially to account for subjective and patient-reported outcomes, the editorialists said.

Another key issue: Only a quarter of women offered hyperbaric oxygen therapy agreed to and completed treatment. The treatment burden was the most common reason for declining the procedure. Study participants underwent 30-40 2-hour sessions over 6-8 weeks.
 

Will the Latest Evidence Usher This Therapy Into More Standard Use?

Probably not, the editorialists concluded.

The HONEY trial “reminds us that convenience has become a factor weighted heavily by patients during the process of decision-making,” Dr. Hahn and colleagues wrote. “Despite experiencing relatively severe symptoms, many declined hyperbaric therapy after being counseled by HONEY investigators about the time commitment.”

Despite its limitations, the trial does offer “modest evidence to justify the use of [hyperbaric oxygen therapy] in treating the chronic morbidities associated with breast irradiation,” the editorialists said. But an “adequately powered randomized, sham-controlled, double-blind trials will be necessary to truly determine the benefit.”

HONEY was partially funded by The Da Vinci Clinic, the Netherlands. The investigators didn’t have any disclosures. One of Dr. Hahn’s coauthors reported personal fees from Lutris Pharma as Chief Medical Officer.
 

A version of this article appeared on Medscape.com.

Although a new study of hyperbaric oxygen therapy in JAMA Oncology has been “ anxiously awaited” by breast radiation oncologists, the trial does not provide the smoking gun evidence that would justify its routine use, according to experts.

Here’s a snapshot of the current state of affairs regarding hyperbaric oxygen therapy in breast radiation oncology.

What Is Hyperbaric Oxygen Therapy?

Hyperbaric oxygen therapy is a medical procedure aimed at reducing the late toxic effects of breast irradiation, including pain, fibrosis, and edema. Patients breathe pure oxygen at greater than atmospheric pressure in a specialized chamber or room. The process leads to increased partial pressures of oxygen in blood and tissues, which can help form new blood vessels and repair damaged irradiated tissue.
 

What Is the Current State of Play?

In 2021, the US Food and Drug Administration (FDA) cleared the therapy for a variety of disorders, including radiation injuries. Some health insurers may cover the procedure as well.

Still, the FDA has cautioned clinicians “to be wary of unproven claims of effect,” University of Toronto radiation oncologist Ezra Hahn, MD, and colleagues Aron Popovtzer, MD, and Benjamin W. Corn, MD, said in a JAMA Oncology editorial.

Despite the FDA clearance, there is limited evidence to suggest hyperbaric oxygen therapy reduces the late toxic effects of breast irradiation, and the research to date has largely come from small and non-randomized studies.

While the procedure is “seldom used by many in practice,” there is growing industry for the procedure. More than 1000 facilities in the United States offer hyperbaric oxygen therapy, but only about 15% are accredited by the Undersea and Hyperbaric Medical Society, which may signal misuse of the procedure.
 

Does the Latest Study Clarify Whether This Therapy Works?

The most recent evidence on hyperbaric oxygen therapy comes from a single-institution, randomized trial from the Netherlands, dubbed HONEY. In the trial, 189 women who experienced late toxic effects following adjuvant breast radiation were randomized 2:1 to hyperbaric oxygen therapy or a control arm. Of the 125 women offered hyperbaric oxygen therapy, only 25% (31 patients) accepted and completed treatment; those who declined received usual follow-up care.

Among women who completed hyperbaric oxygen therapy, 32% (10 of 31) reported moderate or severe pain at follow-up vs 75% of controls — a 66% reduction. Similarly, 17% of women who completed hyperbaric oxygen therapy reported moderate or severe fibrosis at follow-up vs 86% among the hypothetical treatment-completing controls — an 86% reduction. However, the authors did not observe a significant effect of hyperbaric oxygen therapy on breast edema, movement restriction, or overall quality of life.

The authors also included an intention-to-treat analysis, which included patients who declined hyperbaric oxygen therapy as part of the intervention group. This analysis estimated clinical outcomes among patients who had the intervention available to them, with some taking advantage and others not.

Overall, hyperbaric oxygen therapy “seems effective for reducing pain and fibrosis in women with late local toxic effects after breast irradiation,” concluded investigators led by Dieuwke R. Mink van der Molen, PhD, a researcher at the University Medical Centre Utrecht, the Netherlands. However, most patients offered the therapy declined the invitation, largely because of the “high treatment intensity” burden.
 

What Are the Limitations of the Current Study?

The investigators and editorialists highlighted a handful of limitations.

For one, the trial had no sham hyperbaric oxygen therapy procedure in the control group. In fact, control patients were selected from a larger cohort of ongoing studies in the Netherlands who were not aware the trial was being conducted.

Because radiation toxicity fluctuates over time and can improve on its own, “a high-quality control arm” would be needed in such a trial, especially to account for subjective and patient-reported outcomes, the editorialists said.

Another key issue: Only a quarter of women offered hyperbaric oxygen therapy agreed to and completed treatment. The treatment burden was the most common reason for declining the procedure. Study participants underwent 30-40 2-hour sessions over 6-8 weeks.
 

Will the Latest Evidence Usher This Therapy Into More Standard Use?

Probably not, the editorialists concluded.

The HONEY trial “reminds us that convenience has become a factor weighted heavily by patients during the process of decision-making,” Dr. Hahn and colleagues wrote. “Despite experiencing relatively severe symptoms, many declined hyperbaric therapy after being counseled by HONEY investigators about the time commitment.”

Despite its limitations, the trial does offer “modest evidence to justify the use of [hyperbaric oxygen therapy] in treating the chronic morbidities associated with breast irradiation,” the editorialists said. But an “adequately powered randomized, sham-controlled, double-blind trials will be necessary to truly determine the benefit.”

HONEY was partially funded by The Da Vinci Clinic, the Netherlands. The investigators didn’t have any disclosures. One of Dr. Hahn’s coauthors reported personal fees from Lutris Pharma as Chief Medical Officer.
 

A version of this article appeared on Medscape.com.

Although a new study of hyperbaric oxygen therapy in JAMA Oncology has been “ anxiously awaited” by breast radiation oncologists, the trial does not provide the smoking gun evidence that would justify its routine use, according to experts.

Here’s a snapshot of the current state of affairs regarding hyperbaric oxygen therapy in breast radiation oncology.

What Is Hyperbaric Oxygen Therapy?

Hyperbaric oxygen therapy is a medical procedure aimed at reducing the late toxic effects of breast irradiation, including pain, fibrosis, and edema. Patients breathe pure oxygen at greater than atmospheric pressure in a specialized chamber or room. The process leads to increased partial pressures of oxygen in blood and tissues, which can help form new blood vessels and repair damaged irradiated tissue.
 

What Is the Current State of Play?

In 2021, the US Food and Drug Administration (FDA) cleared the therapy for a variety of disorders, including radiation injuries. Some health insurers may cover the procedure as well.

Still, the FDA has cautioned clinicians “to be wary of unproven claims of effect,” University of Toronto radiation oncologist Ezra Hahn, MD, and colleagues Aron Popovtzer, MD, and Benjamin W. Corn, MD, said in a JAMA Oncology editorial.

Despite the FDA clearance, there is limited evidence to suggest hyperbaric oxygen therapy reduces the late toxic effects of breast irradiation, and the research to date has largely come from small and non-randomized studies.

While the procedure is “seldom used by many in practice,” there is growing industry for the procedure. More than 1000 facilities in the United States offer hyperbaric oxygen therapy, but only about 15% are accredited by the Undersea and Hyperbaric Medical Society, which may signal misuse of the procedure.
 

Does the Latest Study Clarify Whether This Therapy Works?

The most recent evidence on hyperbaric oxygen therapy comes from a single-institution, randomized trial from the Netherlands, dubbed HONEY. In the trial, 189 women who experienced late toxic effects following adjuvant breast radiation were randomized 2:1 to hyperbaric oxygen therapy or a control arm. Of the 125 women offered hyperbaric oxygen therapy, only 25% (31 patients) accepted and completed treatment; those who declined received usual follow-up care.

Among women who completed hyperbaric oxygen therapy, 32% (10 of 31) reported moderate or severe pain at follow-up vs 75% of controls — a 66% reduction. Similarly, 17% of women who completed hyperbaric oxygen therapy reported moderate or severe fibrosis at follow-up vs 86% among the hypothetical treatment-completing controls — an 86% reduction. However, the authors did not observe a significant effect of hyperbaric oxygen therapy on breast edema, movement restriction, or overall quality of life.

The authors also included an intention-to-treat analysis, which included patients who declined hyperbaric oxygen therapy as part of the intervention group. This analysis estimated clinical outcomes among patients who had the intervention available to them, with some taking advantage and others not.

Overall, hyperbaric oxygen therapy “seems effective for reducing pain and fibrosis in women with late local toxic effects after breast irradiation,” concluded investigators led by Dieuwke R. Mink van der Molen, PhD, a researcher at the University Medical Centre Utrecht, the Netherlands. However, most patients offered the therapy declined the invitation, largely because of the “high treatment intensity” burden.
 

What Are the Limitations of the Current Study?

The investigators and editorialists highlighted a handful of limitations.

For one, the trial had no sham hyperbaric oxygen therapy procedure in the control group. In fact, control patients were selected from a larger cohort of ongoing studies in the Netherlands who were not aware the trial was being conducted.

Because radiation toxicity fluctuates over time and can improve on its own, “a high-quality control arm” would be needed in such a trial, especially to account for subjective and patient-reported outcomes, the editorialists said.

Another key issue: Only a quarter of women offered hyperbaric oxygen therapy agreed to and completed treatment. The treatment burden was the most common reason for declining the procedure. Study participants underwent 30-40 2-hour sessions over 6-8 weeks.
 

Will the Latest Evidence Usher This Therapy Into More Standard Use?

Probably not, the editorialists concluded.

The HONEY trial “reminds us that convenience has become a factor weighted heavily by patients during the process of decision-making,” Dr. Hahn and colleagues wrote. “Despite experiencing relatively severe symptoms, many declined hyperbaric therapy after being counseled by HONEY investigators about the time commitment.”

Despite its limitations, the trial does offer “modest evidence to justify the use of [hyperbaric oxygen therapy] in treating the chronic morbidities associated with breast irradiation,” the editorialists said. But an “adequately powered randomized, sham-controlled, double-blind trials will be necessary to truly determine the benefit.”

HONEY was partially funded by The Da Vinci Clinic, the Netherlands. The investigators didn’t have any disclosures. One of Dr. Hahn’s coauthors reported personal fees from Lutris Pharma as Chief Medical Officer.
 

A version of this article appeared on Medscape.com.

The presence of any aberration in the SMAD4 gene and decreased messenger RNA sequencing expression of SMAD4 were both associated with worse overall survival in patients with resected pancreatic adenocarcinoma.

These were the main findings of a new study of more than 300 individuals.

Previous studies have shown an association between widespread disease and loss of SMAD4 immunolabeling, according to the paper. Biomarkers to predict which pancreatic adenocarcinoma patients may benefit from more aggressive therapy are lacking, wrote Emily J. Anstadt, MD, of the University of Pennsylvania, Philadelphia, and colleagues, in their paper published in Cancer.

The human transcription factor and tumor suppressor, mothers against decapentaplegic homolog 4 (SMAD4), “may be a promising biomarker for predicting the likelihood of experiencing distant failure in patients with pancreatic cancer,” the researchers wrote.

“For patients with pancreatic cancer, improving treatments and overall outcomes remains invaluable,” Dr. Anstadt said in an interview. However, the disparate clinical courses make studies of this patient population challenging.

“As with much of medicine and oncology at this time, we feel the key to better outcomes lies in personalizing treatment strategies and relying on tumor genetics to predict tumor behavior and guide us towards individualized optimal treatments,” she added.
 

Study Methods and Results

The researchers identified 322 patients with resected stage I–III pancreatic adenocarcinoma from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). The study population included 165 patients from the TCGA who served as the training set and 157 patients from the ICGC who served as the validation set.

The primary outcomes were overall survival (OS) and distant metastasis-free survival (DMFS).

A total of 50 patients in the TCGA group (30%) had at least one of the three identified SMAD4 genomic aberrations.

Using the TCGA group, the researchers conducted a regression analysis on the survival outcomes as a function of either the presence of an SMAD4 genomic aberration or the expression of messenger RNA sequencing (RNA-seq). They then used the ICGC to validate whether SMAD4 RNA-seq expression improved risk stratification for OS and DMFS in a separate group of patients.

In the TCGA group, 3-year OS for patients with any SMAD4 aberrations vs no SMAD4 aberrations was 18% vs 36% (hazard ratio, 1.55; P = .048). However, the 3-year DMFS for patients with and without SMAD4 aberrations was 14% vs 23%, a nonsignificant difference (HR, 1.33; P = .19).

In a multivariate analysis, SMAD4 aberrations also were associated with increased risk of stage III disease (HR, 1.89; P = .003). The researchers noted that adjuvant radiotherapy and adjuvant chemotherapy were significantly associated with a decreased risk of death in these patients (HR, 0.53 and HR, 0.28, respectively).

In addition, low SMAD4 RNA-seq expression was associated with worse OS and DMFS, (HR, 1.83 and HR, 1.70, respectively) in the TCGA group.

In the ICGC validation group, increased SMAD4 RNA‐seq expression correlated with improved OS (area under the curve .92) and DMFS (AUC, .84).

Dr. Anstadt said she and her colleagues were not surprised by any of their findings, given earlier research’s suggestions of SMAD4 loss having been associated with poor outcomes for pancreatic cancer.

“Prior studies determined SMAD4 status based on immunohistochemistry and different investigators used different scoring systems,” Dr. Anstadt noted, in an interview. “The results of those studies were conflicting, and consequently SMAD4 has not been adopted clinically as part of the work-up or to aid in treatment decisions.”

“It is essential to find robust, reliable, and cost-effective methods for implementing this in the clinic. As such, we were happy to find that expression of SMAD4 by mRNA sequencing may be that method,” she added.

Not Quite Clinic-Ready

“While we are hopeful that this tool will be a reliable method for use in the clinic, it has yet to be validated in a prospective manner,” Dr. Anstadt said in an interview. “In addition, this study showed that [genetic] expression levels are correlated with worse outcomes and can be of prognostic use; however, we have not directly studied whether expression levels can be predictive of treatment response,” she said.

“Practicing oncologists often have to make difficult decisions in situations where there are no clear answers,” Dr. Anstadt continued. “When considering gray-zone treatment recommendations, we often integrate multiple factors to form an opinion. The reality of cancer medicine is that not all those factors we consider have been validated in prospective studies, but together they produce a picture that is clinically useful. We would submit that SMAD4 status should be one of those factors taken into consideration in forming a comprehensive opinion about suitability for resection or radiotherapy.”

In practice, “if this test is prospectively validated in a future study and will impact clinical decision-making, then this cost will be similar to other genetic tests that have been adopted and have been practice-changing in other oncologic fields,” said Dr. Anstadt. “Being able to individualize treatment can also save overall cost; for instance, predicting which patients would not benefit from local radiation or surgery could decrease use and cost in that population,” she said.

Limitations of the current study included the inability to examine interactions between SMAD4 and radiotherapy because of the sample size and the potential for selection bias, the researchers wrote.
 

Potential Predictive Value

“A major challenge in the management of patients with pancreatic cancer is the difficulty in predicting which patients will develop metastasis early,” said Jatin Roper, MD, a gastroenterologist at Duke University, Durham, North Carolina, in an interview.

“SMAD4 has previously been evaluated as a prognostic marker in pancreatic cancer, but the association between SMAD4 gene expression, gene mutations, and cancer metastasis has not yet been systematically evaluated in patients, said Dr. Roper, who was not involved in the study.

The new study’s main findings that SMAD4 genomic alterations are associated with worse overall survival, but not distant metastasis-free survival, and that increased SMAD4 expression is associated with improved overall survival and distant metastasis-free survival, suggest that SMAD4 gene expression may be a useful marker in predicting clinical outcomes in pancreatic cancer, Dr. Roper said.

In the future the current study may prompt prospective research to determine a potential association between clinical assessment of SMAD4 gene expression at the time of surgical cancer resection and worse overall survival and distant metastasis-free survival, he said.

The study received no outside funding. Dr. Anstadt and Dr. Roper had no financial conflicts to disclose.

The presence of any aberration in the SMAD4 gene and decreased messenger RNA sequencing expression of SMAD4 were both associated with worse overall survival in patients with resected pancreatic adenocarcinoma.

These were the main findings of a new study of more than 300 individuals.

Previous studies have shown an association between widespread disease and loss of SMAD4 immunolabeling, according to the paper. Biomarkers to predict which pancreatic adenocarcinoma patients may benefit from more aggressive therapy are lacking, wrote Emily J. Anstadt, MD, of the University of Pennsylvania, Philadelphia, and colleagues, in their paper published in Cancer.

The human transcription factor and tumor suppressor, mothers against decapentaplegic homolog 4 (SMAD4), “may be a promising biomarker for predicting the likelihood of experiencing distant failure in patients with pancreatic cancer,” the researchers wrote.

“For patients with pancreatic cancer, improving treatments and overall outcomes remains invaluable,” Dr. Anstadt said in an interview. However, the disparate clinical courses make studies of this patient population challenging.

“As with much of medicine and oncology at this time, we feel the key to better outcomes lies in personalizing treatment strategies and relying on tumor genetics to predict tumor behavior and guide us towards individualized optimal treatments,” she added.
 

Study Methods and Results

The researchers identified 322 patients with resected stage I–III pancreatic adenocarcinoma from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). The study population included 165 patients from the TCGA who served as the training set and 157 patients from the ICGC who served as the validation set.

The primary outcomes were overall survival (OS) and distant metastasis-free survival (DMFS).

A total of 50 patients in the TCGA group (30%) had at least one of the three identified SMAD4 genomic aberrations.

Using the TCGA group, the researchers conducted a regression analysis on the survival outcomes as a function of either the presence of an SMAD4 genomic aberration or the expression of messenger RNA sequencing (RNA-seq). They then used the ICGC to validate whether SMAD4 RNA-seq expression improved risk stratification for OS and DMFS in a separate group of patients.

In the TCGA group, 3-year OS for patients with any SMAD4 aberrations vs no SMAD4 aberrations was 18% vs 36% (hazard ratio, 1.55; P = .048). However, the 3-year DMFS for patients with and without SMAD4 aberrations was 14% vs 23%, a nonsignificant difference (HR, 1.33; P = .19).

In a multivariate analysis, SMAD4 aberrations also were associated with increased risk of stage III disease (HR, 1.89; P = .003). The researchers noted that adjuvant radiotherapy and adjuvant chemotherapy were significantly associated with a decreased risk of death in these patients (HR, 0.53 and HR, 0.28, respectively).

In addition, low SMAD4 RNA-seq expression was associated with worse OS and DMFS, (HR, 1.83 and HR, 1.70, respectively) in the TCGA group.

In the ICGC validation group, increased SMAD4 RNA‐seq expression correlated with improved OS (area under the curve .92) and DMFS (AUC, .84).

Dr. Anstadt said she and her colleagues were not surprised by any of their findings, given earlier research’s suggestions of SMAD4 loss having been associated with poor outcomes for pancreatic cancer.

“Prior studies determined SMAD4 status based on immunohistochemistry and different investigators used different scoring systems,” Dr. Anstadt noted, in an interview. “The results of those studies were conflicting, and consequently SMAD4 has not been adopted clinically as part of the work-up or to aid in treatment decisions.”

“It is essential to find robust, reliable, and cost-effective methods for implementing this in the clinic. As such, we were happy to find that expression of SMAD4 by mRNA sequencing may be that method,” she added.

Not Quite Clinic-Ready

“While we are hopeful that this tool will be a reliable method for use in the clinic, it has yet to be validated in a prospective manner,” Dr. Anstadt said in an interview. “In addition, this study showed that [genetic] expression levels are correlated with worse outcomes and can be of prognostic use; however, we have not directly studied whether expression levels can be predictive of treatment response,” she said.

“Practicing oncologists often have to make difficult decisions in situations where there are no clear answers,” Dr. Anstadt continued. “When considering gray-zone treatment recommendations, we often integrate multiple factors to form an opinion. The reality of cancer medicine is that not all those factors we consider have been validated in prospective studies, but together they produce a picture that is clinically useful. We would submit that SMAD4 status should be one of those factors taken into consideration in forming a comprehensive opinion about suitability for resection or radiotherapy.”

In practice, “if this test is prospectively validated in a future study and will impact clinical decision-making, then this cost will be similar to other genetic tests that have been adopted and have been practice-changing in other oncologic fields,” said Dr. Anstadt. “Being able to individualize treatment can also save overall cost; for instance, predicting which patients would not benefit from local radiation or surgery could decrease use and cost in that population,” she said.

Limitations of the current study included the inability to examine interactions between SMAD4 and radiotherapy because of the sample size and the potential for selection bias, the researchers wrote.
 

Potential Predictive Value

“A major challenge in the management of patients with pancreatic cancer is the difficulty in predicting which patients will develop metastasis early,” said Jatin Roper, MD, a gastroenterologist at Duke University, Durham, North Carolina, in an interview.

“SMAD4 has previously been evaluated as a prognostic marker in pancreatic cancer, but the association between SMAD4 gene expression, gene mutations, and cancer metastasis has not yet been systematically evaluated in patients, said Dr. Roper, who was not involved in the study.

The new study’s main findings that SMAD4 genomic alterations are associated with worse overall survival, but not distant metastasis-free survival, and that increased SMAD4 expression is associated with improved overall survival and distant metastasis-free survival, suggest that SMAD4 gene expression may be a useful marker in predicting clinical outcomes in pancreatic cancer, Dr. Roper said.

In the future the current study may prompt prospective research to determine a potential association between clinical assessment of SMAD4 gene expression at the time of surgical cancer resection and worse overall survival and distant metastasis-free survival, he said.

The study received no outside funding. Dr. Anstadt and Dr. Roper had no financial conflicts to disclose.

The presence of any aberration in the SMAD4 gene and decreased messenger RNA sequencing expression of SMAD4 were both associated with worse overall survival in patients with resected pancreatic adenocarcinoma.

These were the main findings of a new study of more than 300 individuals.

Previous studies have shown an association between widespread disease and loss of SMAD4 immunolabeling, according to the paper. Biomarkers to predict which pancreatic adenocarcinoma patients may benefit from more aggressive therapy are lacking, wrote Emily J. Anstadt, MD, of the University of Pennsylvania, Philadelphia, and colleagues, in their paper published in Cancer.

The human transcription factor and tumor suppressor, mothers against decapentaplegic homolog 4 (SMAD4), “may be a promising biomarker for predicting the likelihood of experiencing distant failure in patients with pancreatic cancer,” the researchers wrote.

“For patients with pancreatic cancer, improving treatments and overall outcomes remains invaluable,” Dr. Anstadt said in an interview. However, the disparate clinical courses make studies of this patient population challenging.

“As with much of medicine and oncology at this time, we feel the key to better outcomes lies in personalizing treatment strategies and relying on tumor genetics to predict tumor behavior and guide us towards individualized optimal treatments,” she added.
 

Study Methods and Results

The researchers identified 322 patients with resected stage I–III pancreatic adenocarcinoma from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). The study population included 165 patients from the TCGA who served as the training set and 157 patients from the ICGC who served as the validation set.

The primary outcomes were overall survival (OS) and distant metastasis-free survival (DMFS).

A total of 50 patients in the TCGA group (30%) had at least one of the three identified SMAD4 genomic aberrations.

Using the TCGA group, the researchers conducted a regression analysis on the survival outcomes as a function of either the presence of an SMAD4 genomic aberration or the expression of messenger RNA sequencing (RNA-seq). They then used the ICGC to validate whether SMAD4 RNA-seq expression improved risk stratification for OS and DMFS in a separate group of patients.

In the TCGA group, 3-year OS for patients with any SMAD4 aberrations vs no SMAD4 aberrations was 18% vs 36% (hazard ratio, 1.55; P = .048). However, the 3-year DMFS for patients with and without SMAD4 aberrations was 14% vs 23%, a nonsignificant difference (HR, 1.33; P = .19).

In a multivariate analysis, SMAD4 aberrations also were associated with increased risk of stage III disease (HR, 1.89; P = .003). The researchers noted that adjuvant radiotherapy and adjuvant chemotherapy were significantly associated with a decreased risk of death in these patients (HR, 0.53 and HR, 0.28, respectively).

In addition, low SMAD4 RNA-seq expression was associated with worse OS and DMFS, (HR, 1.83 and HR, 1.70, respectively) in the TCGA group.

In the ICGC validation group, increased SMAD4 RNA‐seq expression correlated with improved OS (area under the curve .92) and DMFS (AUC, .84).

Dr. Anstadt said she and her colleagues were not surprised by any of their findings, given earlier research’s suggestions of SMAD4 loss having been associated with poor outcomes for pancreatic cancer.

“Prior studies determined SMAD4 status based on immunohistochemistry and different investigators used different scoring systems,” Dr. Anstadt noted, in an interview. “The results of those studies were conflicting, and consequently SMAD4 has not been adopted clinically as part of the work-up or to aid in treatment decisions.”

“It is essential to find robust, reliable, and cost-effective methods for implementing this in the clinic. As such, we were happy to find that expression of SMAD4 by mRNA sequencing may be that method,” she added.

Not Quite Clinic-Ready

“While we are hopeful that this tool will be a reliable method for use in the clinic, it has yet to be validated in a prospective manner,” Dr. Anstadt said in an interview. “In addition, this study showed that [genetic] expression levels are correlated with worse outcomes and can be of prognostic use; however, we have not directly studied whether expression levels can be predictive of treatment response,” she said.

“Practicing oncologists often have to make difficult decisions in situations where there are no clear answers,” Dr. Anstadt continued. “When considering gray-zone treatment recommendations, we often integrate multiple factors to form an opinion. The reality of cancer medicine is that not all those factors we consider have been validated in prospective studies, but together they produce a picture that is clinically useful. We would submit that SMAD4 status should be one of those factors taken into consideration in forming a comprehensive opinion about suitability for resection or radiotherapy.”

In practice, “if this test is prospectively validated in a future study and will impact clinical decision-making, then this cost will be similar to other genetic tests that have been adopted and have been practice-changing in other oncologic fields,” said Dr. Anstadt. “Being able to individualize treatment can also save overall cost; for instance, predicting which patients would not benefit from local radiation or surgery could decrease use and cost in that population,” she said.

Limitations of the current study included the inability to examine interactions between SMAD4 and radiotherapy because of the sample size and the potential for selection bias, the researchers wrote.
 

Potential Predictive Value

“A major challenge in the management of patients with pancreatic cancer is the difficulty in predicting which patients will develop metastasis early,” said Jatin Roper, MD, a gastroenterologist at Duke University, Durham, North Carolina, in an interview.

“SMAD4 has previously been evaluated as a prognostic marker in pancreatic cancer, but the association between SMAD4 gene expression, gene mutations, and cancer metastasis has not yet been systematically evaluated in patients, said Dr. Roper, who was not involved in the study.

The new study’s main findings that SMAD4 genomic alterations are associated with worse overall survival, but not distant metastasis-free survival, and that increased SMAD4 expression is associated with improved overall survival and distant metastasis-free survival, suggest that SMAD4 gene expression may be a useful marker in predicting clinical outcomes in pancreatic cancer, Dr. Roper said.

In the future the current study may prompt prospective research to determine a potential association between clinical assessment of SMAD4 gene expression at the time of surgical cancer resection and worse overall survival and distant metastasis-free survival, he said.

The study received no outside funding. Dr. Anstadt and Dr. Roper had no financial conflicts to disclose.

TOPLINE:

Multivitamin supplements at a moderate dose appear to lower the risk for both all-cause and cancer-related mortality in patients with colorectal cancer (CRC); however, high doses of multivitamin supplements may increase the risk for CRC-specific mortality.

METHODOLOGY:

• Some studies suggest that multivitamin supplements might increase a person’s risk for CRC, and other research indicates that certain components of multivitamins, such as vitamins C and D, may have anti-CRC properties.
• Because as many as half of CRC survivors take a multivitamin, researchers wanted to assess whether multivitamin use affects overall survival among people with CRC.
• In the current prospective cohort study, researchers evaluated the use and dose of multivitamin supplements in 2424 patients with stages I-III CRC, using detailed information from patients in the Nurses’ Health Study and Health Professionals Follow‐Up Study.
• The participants completed a mailed questionnaire every 2 years, which included questions about the current use of multivitamin supplements as well as doses per week (0, 1-2, 3-5, 6-9, and ≥ 10 tablets).
• The researchers assessed the potential association between multivitamin use and CRC-related as well as all‐cause mortality.

TAKEAWAY:

• Over a median follow-up period of 11 years, 1512 deaths and 343 cancer-specific deaths occurred.
• For patients diagnosed with CRC, a moderate dose of multivitamins (three to five tablets per week) vs no multivitamin use was associated with a 45% lower risk for cancer-related mortality (adjusted hazard ratio [aHR], 0.55; P = .005).
• Moderate multivitamin use was also associated with a lower risk for all-cause mortality (aHR, 0.81; P = .04) as was a higher dose of six to nine tablets per week (aHR, 0.79; P < .001).
• However, high doses of 10 or more tablets per week were associated with a 60% higher risk for cancer-related mortality (aHR, 1.60; P = .02).

IN PRACTICE:

The study findings suggested that moderate multivitamin supplement use may come with a survival benefit in patients with CRC, while high doses may not, but “further studies are needed before making clinical recommendations for multivitamin use in patients with CRC,” the authors said.

SOURCE:

This work, led by Ming‐ming He of Sun Yat‐sen University Cancer Center, Guangzhou, China, was published in Cancer.

LIMITATIONS:

Given the study’s observational design, residual confounding may be possible. Reverse causation and recall bias are also possible limitations.

DISCLOSURES:

This study was funded by the National Institutes of Health, American Institute for Cancer Research, Wellesley College, Dana‐Farber Cancer Institute, and the Entertainment Industry Foundation. Three study authors reported financial relationships outside this work.

A version of this article appeared on Medscape.com.

TOPLINE:

Multivitamin supplements at a moderate dose appear to lower the risk for both all-cause and cancer-related mortality in patients with colorectal cancer (CRC); however, high doses of multivitamin supplements may increase the risk for CRC-specific mortality.

METHODOLOGY:

• Some studies suggest that multivitamin supplements might increase a person’s risk for CRC, and other research indicates that certain components of multivitamins, such as vitamins C and D, may have anti-CRC properties.
• Because as many as half of CRC survivors take a multivitamin, researchers wanted to assess whether multivitamin use affects overall survival among people with CRC.
• In the current prospective cohort study, researchers evaluated the use and dose of multivitamin supplements in 2424 patients with stages I-III CRC, using detailed information from patients in the Nurses’ Health Study and Health Professionals Follow‐Up Study.
• The participants completed a mailed questionnaire every 2 years, which included questions about the current use of multivitamin supplements as well as doses per week (0, 1-2, 3-5, 6-9, and ≥ 10 tablets).
• The researchers assessed the potential association between multivitamin use and CRC-related as well as all‐cause mortality.

TAKEAWAY:

• Over a median follow-up period of 11 years, 1512 deaths and 343 cancer-specific deaths occurred.
• For patients diagnosed with CRC, a moderate dose of multivitamins (three to five tablets per week) vs no multivitamin use was associated with a 45% lower risk for cancer-related mortality (adjusted hazard ratio [aHR], 0.55; P = .005).
• Moderate multivitamin use was also associated with a lower risk for all-cause mortality (aHR, 0.81; P = .04) as was a higher dose of six to nine tablets per week (aHR, 0.79; P < .001).
• However, high doses of 10 or more tablets per week were associated with a 60% higher risk for cancer-related mortality (aHR, 1.60; P = .02).

IN PRACTICE:

The study findings suggested that moderate multivitamin supplement use may come with a survival benefit in patients with CRC, while high doses may not, but “further studies are needed before making clinical recommendations for multivitamin use in patients with CRC,” the authors said.

SOURCE:

This work, led by Ming‐ming He of Sun Yat‐sen University Cancer Center, Guangzhou, China, was published in Cancer.

LIMITATIONS:

Given the study’s observational design, residual confounding may be possible. Reverse causation and recall bias are also possible limitations.

DISCLOSURES:

This study was funded by the National Institutes of Health, American Institute for Cancer Research, Wellesley College, Dana‐Farber Cancer Institute, and the Entertainment Industry Foundation. Three study authors reported financial relationships outside this work.

A version of this article appeared on Medscape.com.

TOPLINE:

Multivitamin supplements at a moderate dose appear to lower the risk for both all-cause and cancer-related mortality in patients with colorectal cancer (CRC); however, high doses of multivitamin supplements may increase the risk for CRC-specific mortality.

METHODOLOGY:

• Some studies suggest that multivitamin supplements might increase a person’s risk for CRC, and other research indicates that certain components of multivitamins, such as vitamins C and D, may have anti-CRC properties.
• Because as many as half of CRC survivors take a multivitamin, researchers wanted to assess whether multivitamin use affects overall survival among people with CRC.
• In the current prospective cohort study, researchers evaluated the use and dose of multivitamin supplements in 2424 patients with stages I-III CRC, using detailed information from patients in the Nurses’ Health Study and Health Professionals Follow‐Up Study.
• The participants completed a mailed questionnaire every 2 years, which included questions about the current use of multivitamin supplements as well as doses per week (0, 1-2, 3-5, 6-9, and ≥ 10 tablets).
• The researchers assessed the potential association between multivitamin use and CRC-related as well as all‐cause mortality.

TAKEAWAY:

• Over a median follow-up period of 11 years, 1512 deaths and 343 cancer-specific deaths occurred.
• For patients diagnosed with CRC, a moderate dose of multivitamins (three to five tablets per week) vs no multivitamin use was associated with a 45% lower risk for cancer-related mortality (adjusted hazard ratio [aHR], 0.55; P = .005).
• Moderate multivitamin use was also associated with a lower risk for all-cause mortality (aHR, 0.81; P = .04) as was a higher dose of six to nine tablets per week (aHR, 0.79; P < .001).
• However, high doses of 10 or more tablets per week were associated with a 60% higher risk for cancer-related mortality (aHR, 1.60; P = .02).

IN PRACTICE:

The study findings suggested that moderate multivitamin supplement use may come with a survival benefit in patients with CRC, while high doses may not, but “further studies are needed before making clinical recommendations for multivitamin use in patients with CRC,” the authors said.

SOURCE:

This work, led by Ming‐ming He of Sun Yat‐sen University Cancer Center, Guangzhou, China, was published in Cancer.

LIMITATIONS:

Given the study’s observational design, residual confounding may be possible. Reverse causation and recall bias are also possible limitations.

DISCLOSURES:

This study was funded by the National Institutes of Health, American Institute for Cancer Research, Wellesley College, Dana‐Farber Cancer Institute, and the Entertainment Industry Foundation. Three study authors reported financial relationships outside this work.

A version of this article appeared on Medscape.com.

Circulating tumor cells (CTCs), the cells shed from a solid tumor into the bloodstream, may help doctors avoid having to do repeat needle biopsies on patients with unresectable non–small cell lung cancer.

Challenges to using CTCs clinically are that they are not abundant in the blood and have been difficult to isolate in patients with this type of cancer with commercially available assays.

New research published in Cell Reports may bring doctors closer to using CTCs as a biomarker for patients with non–small cell lung cancer (NSCLC) in clinic. In their paper, the authors show that an experimental nanotechnology can effectively isolate and measure CTCs in patients with stage 3 NSCLC. They also found that a precipitous drop in CTCs during chemoradiation treatment predicted significantly longer progression-free survival in those patients.
 

Study Results and Methods

For their research, study coauthors Shruti Jolly, MD, and Sunitha Nagrath, PhD, used a novel graphene oxide technology called the GO chip, developed more than a decade ago by Dr. Nagrath and her colleagues, to isolate CTCs from patients with stage 3 NSCLC. While a different technology, which is approved by the US Food and Drug Administration (FDA), uses a single antibody to pick up CTCs, the GO chip uses a cocktail of three antibodies to CTC proteins, making it more sensitive.

The 26 patients in the study (mean age 67, 27% female) all received radiation treatment for 6 weeks, plus weekly carboplatin and paclitaxel chemotherapy. Sixteen of the patients afterward went on to have immunotherapy with durvalumab. Blood was drawn at six fixed time points: before treatment, and at weeks 1, 4, 10, 18, and 30. CTCs were measured and analyzed with every draw.

Previous studies showed that absolute number of CTCs did not correlate with either tumor volume or progression-free survival in NSCLC.

Dr. Jolly and Dr. Nagrath sought to measure change in CTCs from baseline for each patient, having the patient serve as his or her own control. They found that patients whose individual CTC counts dropped by 75% or more between pretreatment and week 4 of chemoradiation saw a mean 21 months of progression-free survival compared with 7 months for patients whose CTCs dropped by less than 75% in the same period (P = .0076).

Dr. Jolly and Dr. Nagrath also aimed to determine, as an exploratory outcome of their study, whether other information collected from the CTCs could predict response to treatment with durvalumab immunotherapy. They found that having more than 50% of CTCs positive for the protein PD-L1 correlated to shorter progression-free survival among the 16 patients receiving durvalumab (P = .04).

“Every person’s tumor is unique in terms of its response to treatment,” said Dr. Jolly, a radiation oncologist and professor and associate chair of community practices in the Department of Radiation Oncology at the University of Michigan, Ann Arbor.

“Two people with a three-centimeter lung tumor will not necessarily shed the same amount of tumor cells into circulation. CTCs are reflective of disease burden; however, this is not related to the absolute numbers. That’s why we decided to use individualized baselines and look at the percentage of decrease,” she said.

Dr. Nagrath, professor of chemical and biomedical engineering at the University of Michigan, noted, in the same interview, that the findings argue for CTCs as a biomarker in stage 3 NSCLC.

“A lot of researchers who do lung cancer studies struggle with isolating lung cancer CTCs,” Dr. Nagrath said. “We showed, with repeated blood draws during treatment, what is changing at a molecular level and that you can see it with a simple blood draw. It also gives the proof of concept that if these cells are present, this is a good way to monitor and see if a treatment is working, even early in the treatment.” Moreover, she added, “many studies in lung cancer are in stage 4.”

Our study is unique as it followed patients with locally advanced tumors from their being treatment naive to all the way through immunotherapy,” she continued.

The University of Michigan has a patent on the GO chip technology, but thus far no company has made efforts to license it and submit it for approval. While “liquid biopsy” is an important emerging concept in lung cancer, there is little consensus yet as to which blood biomarkers — whether CTCs, circulating tumor DNA (ctDNA), or extracellular vesicles (EVs) — are most clinically relevant, Dr. Nagrath said.

The study’s small size is one of its weaknesses, according to the authors.
 

Findings are ‘Particularly Intriguing’

Majid Ebrahimi Warkiani, PhD, who was not involved in the study, described the new findings as “particularly intriguing [and] highlighting the efficacy of liquid biopsy using CTCs for predicting treatment outcomes.”

A challenge within the realm of CTCs lies in the community’s ongoing struggle to define and classify these cells accurately, Dr. Warkiani said in an interview.

“While surface protein markers offer valuable insights, emerging layers of analysis, such as metabolomics, are increasingly entering the scene to bolster the identification of putative cancer cells, alongside molecular tests like fluorescence in situ hybridization (FISH),” said Dr. Warkiani of the University of Technology Sydney in Australia. “The amalgamation of these approaches simultaneously presents a significant challenge, particularly in terms of standardization for patient care, unlike ctDNA, which faces fewer bottlenecks.

“The robustness of the research in this study is commendable. However, further clinical testing and randomized trials are imperative,” Dr. Warkiani continued. “Companies like Epic Sciences are actively engaged in advancing research and standardization in this field.”

The study by Dr. Jolly and Dr. Nagrath was funded by the National Institutes of Health. None of the study authors reported financial conflicts of interest. Dr. Warkiani reported no conflicts of interest related to his comment.

Circulating tumor cells (CTCs), the cells shed from a solid tumor into the bloodstream, may help doctors avoid having to do repeat needle biopsies on patients with unresectable non–small cell lung cancer.

Challenges to using CTCs clinically are that they are not abundant in the blood and have been difficult to isolate in patients with this type of cancer with commercially available assays.

New research published in Cell Reports may bring doctors closer to using CTCs as a biomarker for patients with non–small cell lung cancer (NSCLC) in clinic. In their paper, the authors show that an experimental nanotechnology can effectively isolate and measure CTCs in patients with stage 3 NSCLC. They also found that a precipitous drop in CTCs during chemoradiation treatment predicted significantly longer progression-free survival in those patients.
 

Study Results and Methods

For their research, study coauthors Shruti Jolly, MD, and Sunitha Nagrath, PhD, used a novel graphene oxide technology called the GO chip, developed more than a decade ago by Dr. Nagrath and her colleagues, to isolate CTCs from patients with stage 3 NSCLC. While a different technology, which is approved by the US Food and Drug Administration (FDA), uses a single antibody to pick up CTCs, the GO chip uses a cocktail of three antibodies to CTC proteins, making it more sensitive.

The 26 patients in the study (mean age 67, 27% female) all received radiation treatment for 6 weeks, plus weekly carboplatin and paclitaxel chemotherapy. Sixteen of the patients afterward went on to have immunotherapy with durvalumab. Blood was drawn at six fixed time points: before treatment, and at weeks 1, 4, 10, 18, and 30. CTCs were measured and analyzed with every draw.

Previous studies showed that absolute number of CTCs did not correlate with either tumor volume or progression-free survival in NSCLC.

Dr. Jolly and Dr. Nagrath sought to measure change in CTCs from baseline for each patient, having the patient serve as his or her own control. They found that patients whose individual CTC counts dropped by 75% or more between pretreatment and week 4 of chemoradiation saw a mean 21 months of progression-free survival compared with 7 months for patients whose CTCs dropped by less than 75% in the same period (P = .0076).

Dr. Jolly and Dr. Nagrath also aimed to determine, as an exploratory outcome of their study, whether other information collected from the CTCs could predict response to treatment with durvalumab immunotherapy. They found that having more than 50% of CTCs positive for the protein PD-L1 correlated to shorter progression-free survival among the 16 patients receiving durvalumab (P = .04).

“Every person’s tumor is unique in terms of its response to treatment,” said Dr. Jolly, a radiation oncologist and professor and associate chair of community practices in the Department of Radiation Oncology at the University of Michigan, Ann Arbor.

“Two people with a three-centimeter lung tumor will not necessarily shed the same amount of tumor cells into circulation. CTCs are reflective of disease burden; however, this is not related to the absolute numbers. That’s why we decided to use individualized baselines and look at the percentage of decrease,” she said.

Dr. Nagrath, professor of chemical and biomedical engineering at the University of Michigan, noted, in the same interview, that the findings argue for CTCs as a biomarker in stage 3 NSCLC.

“A lot of researchers who do lung cancer studies struggle with isolating lung cancer CTCs,” Dr. Nagrath said. “We showed, with repeated blood draws during treatment, what is changing at a molecular level and that you can see it with a simple blood draw. It also gives the proof of concept that if these cells are present, this is a good way to monitor and see if a treatment is working, even early in the treatment.” Moreover, she added, “many studies in lung cancer are in stage 4.”

Our study is unique as it followed patients with locally advanced tumors from their being treatment naive to all the way through immunotherapy,” she continued.

The University of Michigan has a patent on the GO chip technology, but thus far no company has made efforts to license it and submit it for approval. While “liquid biopsy” is an important emerging concept in lung cancer, there is little consensus yet as to which blood biomarkers — whether CTCs, circulating tumor DNA (ctDNA), or extracellular vesicles (EVs) — are most clinically relevant, Dr. Nagrath said.

The study’s small size is one of its weaknesses, according to the authors.
 

Findings are ‘Particularly Intriguing’

Majid Ebrahimi Warkiani, PhD, who was not involved in the study, described the new findings as “particularly intriguing [and] highlighting the efficacy of liquid biopsy using CTCs for predicting treatment outcomes.”

A challenge within the realm of CTCs lies in the community’s ongoing struggle to define and classify these cells accurately, Dr. Warkiani said in an interview.

“While surface protein markers offer valuable insights, emerging layers of analysis, such as metabolomics, are increasingly entering the scene to bolster the identification of putative cancer cells, alongside molecular tests like fluorescence in situ hybridization (FISH),” said Dr. Warkiani of the University of Technology Sydney in Australia. “The amalgamation of these approaches simultaneously presents a significant challenge, particularly in terms of standardization for patient care, unlike ctDNA, which faces fewer bottlenecks.

“The robustness of the research in this study is commendable. However, further clinical testing and randomized trials are imperative,” Dr. Warkiani continued. “Companies like Epic Sciences are actively engaged in advancing research and standardization in this field.”

The study by Dr. Jolly and Dr. Nagrath was funded by the National Institutes of Health. None of the study authors reported financial conflicts of interest. Dr. Warkiani reported no conflicts of interest related to his comment.

Circulating tumor cells (CTCs), the cells shed from a solid tumor into the bloodstream, may help doctors avoid having to do repeat needle biopsies on patients with unresectable non–small cell lung cancer.

Challenges to using CTCs clinically are that they are not abundant in the blood and have been difficult to isolate in patients with this type of cancer with commercially available assays.

New research published in Cell Reports may bring doctors closer to using CTCs as a biomarker for patients with non–small cell lung cancer (NSCLC) in clinic. In their paper, the authors show that an experimental nanotechnology can effectively isolate and measure CTCs in patients with stage 3 NSCLC. They also found that a precipitous drop in CTCs during chemoradiation treatment predicted significantly longer progression-free survival in those patients.
 

Study Results and Methods

For their research, study coauthors Shruti Jolly, MD, and Sunitha Nagrath, PhD, used a novel graphene oxide technology called the GO chip, developed more than a decade ago by Dr. Nagrath and her colleagues, to isolate CTCs from patients with stage 3 NSCLC. While a different technology, which is approved by the US Food and Drug Administration (FDA), uses a single antibody to pick up CTCs, the GO chip uses a cocktail of three antibodies to CTC proteins, making it more sensitive.

The 26 patients in the study (mean age 67, 27% female) all received radiation treatment for 6 weeks, plus weekly carboplatin and paclitaxel chemotherapy. Sixteen of the patients afterward went on to have immunotherapy with durvalumab. Blood was drawn at six fixed time points: before treatment, and at weeks 1, 4, 10, 18, and 30. CTCs were measured and analyzed with every draw.

Previous studies showed that absolute number of CTCs did not correlate with either tumor volume or progression-free survival in NSCLC.

Dr. Jolly and Dr. Nagrath sought to measure change in CTCs from baseline for each patient, having the patient serve as his or her own control. They found that patients whose individual CTC counts dropped by 75% or more between pretreatment and week 4 of chemoradiation saw a mean 21 months of progression-free survival compared with 7 months for patients whose CTCs dropped by less than 75% in the same period (P = .0076).

Dr. Jolly and Dr. Nagrath also aimed to determine, as an exploratory outcome of their study, whether other information collected from the CTCs could predict response to treatment with durvalumab immunotherapy. They found that having more than 50% of CTCs positive for the protein PD-L1 correlated to shorter progression-free survival among the 16 patients receiving durvalumab (P = .04).

“Every person’s tumor is unique in terms of its response to treatment,” said Dr. Jolly, a radiation oncologist and professor and associate chair of community practices in the Department of Radiation Oncology at the University of Michigan, Ann Arbor.

“Two people with a three-centimeter lung tumor will not necessarily shed the same amount of tumor cells into circulation. CTCs are reflective of disease burden; however, this is not related to the absolute numbers. That’s why we decided to use individualized baselines and look at the percentage of decrease,” she said.

Dr. Nagrath, professor of chemical and biomedical engineering at the University of Michigan, noted, in the same interview, that the findings argue for CTCs as a biomarker in stage 3 NSCLC.

“A lot of researchers who do lung cancer studies struggle with isolating lung cancer CTCs,” Dr. Nagrath said. “We showed, with repeated blood draws during treatment, what is changing at a molecular level and that you can see it with a simple blood draw. It also gives the proof of concept that if these cells are present, this is a good way to monitor and see if a treatment is working, even early in the treatment.” Moreover, she added, “many studies in lung cancer are in stage 4.”

Our study is unique as it followed patients with locally advanced tumors from their being treatment naive to all the way through immunotherapy,” she continued.

The University of Michigan has a patent on the GO chip technology, but thus far no company has made efforts to license it and submit it for approval. While “liquid biopsy” is an important emerging concept in lung cancer, there is little consensus yet as to which blood biomarkers — whether CTCs, circulating tumor DNA (ctDNA), or extracellular vesicles (EVs) — are most clinically relevant, Dr. Nagrath said.

The study’s small size is one of its weaknesses, according to the authors.
 

Findings are ‘Particularly Intriguing’

Majid Ebrahimi Warkiani, PhD, who was not involved in the study, described the new findings as “particularly intriguing [and] highlighting the efficacy of liquid biopsy using CTCs for predicting treatment outcomes.”

A challenge within the realm of CTCs lies in the community’s ongoing struggle to define and classify these cells accurately, Dr. Warkiani said in an interview.

“While surface protein markers offer valuable insights, emerging layers of analysis, such as metabolomics, are increasingly entering the scene to bolster the identification of putative cancer cells, alongside molecular tests like fluorescence in situ hybridization (FISH),” said Dr. Warkiani of the University of Technology Sydney in Australia. “The amalgamation of these approaches simultaneously presents a significant challenge, particularly in terms of standardization for patient care, unlike ctDNA, which faces fewer bottlenecks.

“The robustness of the research in this study is commendable. However, further clinical testing and randomized trials are imperative,” Dr. Warkiani continued. “Companies like Epic Sciences are actively engaged in advancing research and standardization in this field.”

The study by Dr. Jolly and Dr. Nagrath was funded by the National Institutes of Health. None of the study authors reported financial conflicts of interest. Dr. Warkiani reported no conflicts of interest related to his comment.

Using a new system for classifying established prognostic features of lymph nodes may lead to better staging of oral cavity squamous cell cancer (OSCC) than the TNM staging system, experts say.

The TNM staging system is used by most facilities for cancer reporting, as defined by the National Cancer Institute. This system combines the size and extent of the primary tumor (T), the number of neighboring lymph nodes with cancer and subcategories (N), and whether or not metastasis has occurred (M).

In a new study published in the journal Cancer, the researchers created a novel classification system to better account for extranodal extension (ENE). The study population included 1460 adults with OSCC (696 with no lymph node involvement and 764 with positive lymph nodes), who underwent surgical resections at four centers.

“Our findings build on the growing evidence base that historical factors do not improve staging performance and that their omission results in improved N‐classification [i.e., the nodal status or lymph node involvement in cancer staging] performance,” John R. de Almeida, MD, of the University of Toronto, and colleagues, wrote in their new paper.

For patients with OSCC, this system, known as the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N‐classification (TNM‐8‐N), has several limitations, the researchers explained. These limitations include redundancy in the rare N3a category (i.e., having single or multiple lymph nodes greater than 6 cm or 3-7 lymph nodes without ENE) and the impact of ENE as a new prognostic feature, they said.

“Recent studies have shown that major ENE is associated with a significantly worse outcome than minor ENE, suggesting that these two subgroups should be considered as separate entities,” the authors wrote.
 

Study Methods and Results

The researchers created N-classifications based on adjusted hazard ratios and statistical analysis (recursive partitioning) with a focus on lymph node (LN) size and number and the extent of ENE. They compared their classifications of OSCC cases to those of the TNM-8-N’s classifications of the same cases.

Using the new classification system, lymph node number and size and the extent of ENE were associated with overall survival. The adjusted hazard ratios for LN counts of 1 vs. zero and greater than 1 vs. 0 were 1.92 and 3.21, respectively. The adjusted hazard ratios (aHRs) for LN size of greater than 3 cm vs. 3 cm or less, and for major vs. minor ENE were 1.88 and 1.40, respectively.

The use of an aHR improved cancer staging compared to the TNM-8-N by eliminating the N2c and 6-cm threshold, stratifying the extent of ENE, and stratifying N2b by 3-cm threshold, the researchers wrote.

The researchers compared their new system to the TNM-8 and also two other classification systems and their own recursive partitioning analysis (another statistical model).

The aHR-based system ranked first out of five in terms of correctly staging cancer, while the TNM-8 was fifth in the discovery cohort and fifth in the validation cohorts.

Outcome predictions (percentage variance explained) were 19.81 with the aHR vs. 18.95 in theTNM-8 in the discovery cohort, and similarly were 11.72 vs. 10.13, respectively, in the validation cohort.

“Overall, 25 patients staged as IVa in TNM‐8 were upstaged to IVb in the aHR proposal, and one patient staged as IVb was downstaged to IVa. Otherwise, overall stage between TNM‐8 and aHR remained the same,” the authors wrote.

“Our proposed N-classification based on aHR challenges previous tenets such as the importance of the 6-cm threshold and the importance of contralateral nodes,” the researchers wrote in their discussion.

The results from the new classification system were limited by the relatively small sample sizes and may not generalize to nonsquamous oral cancers, the researchers noted.

Further validation is needed before this system may be routinely applied in practice, but the results support evidence in favor of eliminating historical factors from staging, they said.
 

Experts Tout Advantages of Proposed Classification System

Cancer staging must be as accurate as possible and reviewed frequently, Shawn Li, MD, an otolaryngologist at University Hospitals, Cleveland, said in an interview. “This study aims to optimize nodal staging in oral cavity cancer. The current staging system doesn’t reflect updated data, and may not be specific enough to oral cavity cancers.”

This study notes the importance of stratifying extranodal extension (ENE) by micro (less than 2 mm) and macro (greater than 2 mm),” he said. It also points out that metastatic disease greater than 6 cm without ENE is infrequent enough not to require its own subcategory, he said.

Finally, in the new classification, proposed in this paper, “N2c was removed, because, statistically, it doesn’t seem to be a worse prognosis in cancers of the oral cavity,” he said.

“The data [described in this new paper] suggests that certain traditional criteria used in nodal staging for oral cavity cancer, such as [involving] very large lymph nodes greater than 6 cm in size and contralateral nodal involvement, may be less important than criteria that have not as of yet been incorporated into head and neck staging,” Wesley Talcott, MD, said in an interview. “The current study provides evidence that in oral cavity cancer, the prognostic accuracy of staging may improve by dropping these older criteria and incorporating degree of extranodal extension.”

This evidence is apparent in the ranking of the new aHR classification as first of the five strategies compared in the study, said Dr. Talcott, who was not involved in the study.

Highlighting the importance of microscopic vs. macroscopic extension may lead to doctors improving their identification of patients at highest risk for recurrence and refining treatment strategies, suggested Dr. Talcott, MD, a radiation oncologist at Northwell Health, New York, NY. However, a larger dataset is needed to validate the diagnostic accuracy of the authors’ proposed staging system, he said.

The TNM‐8‐N was updated in 2017, Dr. Li noted. “Since this system is widely referenced, it will likely need to be updated again before the changes in this study are widely adopted,” he said.

The study was supported by the National Institutes of Health and the National Cancer Institute. The researchers, Dr. Li, and Dr. Talcott had no financial conflicts to disclose.

Using a new system for classifying established prognostic features of lymph nodes may lead to better staging of oral cavity squamous cell cancer (OSCC) than the TNM staging system, experts say.

The TNM staging system is used by most facilities for cancer reporting, as defined by the National Cancer Institute. This system combines the size and extent of the primary tumor (T), the number of neighboring lymph nodes with cancer and subcategories (N), and whether or not metastasis has occurred (M).

In a new study published in the journal Cancer, the researchers created a novel classification system to better account for extranodal extension (ENE). The study population included 1460 adults with OSCC (696 with no lymph node involvement and 764 with positive lymph nodes), who underwent surgical resections at four centers.

“Our findings build on the growing evidence base that historical factors do not improve staging performance and that their omission results in improved N‐classification [i.e., the nodal status or lymph node involvement in cancer staging] performance,” John R. de Almeida, MD, of the University of Toronto, and colleagues, wrote in their new paper.

For patients with OSCC, this system, known as the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N‐classification (TNM‐8‐N), has several limitations, the researchers explained. These limitations include redundancy in the rare N3a category (i.e., having single or multiple lymph nodes greater than 6 cm or 3-7 lymph nodes without ENE) and the impact of ENE as a new prognostic feature, they said.

“Recent studies have shown that major ENE is associated with a significantly worse outcome than minor ENE, suggesting that these two subgroups should be considered as separate entities,” the authors wrote.
 

Study Methods and Results

The researchers created N-classifications based on adjusted hazard ratios and statistical analysis (recursive partitioning) with a focus on lymph node (LN) size and number and the extent of ENE. They compared their classifications of OSCC cases to those of the TNM-8-N’s classifications of the same cases.

Using the new classification system, lymph node number and size and the extent of ENE were associated with overall survival. The adjusted hazard ratios for LN counts of 1 vs. zero and greater than 1 vs. 0 were 1.92 and 3.21, respectively. The adjusted hazard ratios (aHRs) for LN size of greater than 3 cm vs. 3 cm or less, and for major vs. minor ENE were 1.88 and 1.40, respectively.

The use of an aHR improved cancer staging compared to the TNM-8-N by eliminating the N2c and 6-cm threshold, stratifying the extent of ENE, and stratifying N2b by 3-cm threshold, the researchers wrote.

The researchers compared their new system to the TNM-8 and also two other classification systems and their own recursive partitioning analysis (another statistical model).

The aHR-based system ranked first out of five in terms of correctly staging cancer, while the TNM-8 was fifth in the discovery cohort and fifth in the validation cohorts.

Outcome predictions (percentage variance explained) were 19.81 with the aHR vs. 18.95 in theTNM-8 in the discovery cohort, and similarly were 11.72 vs. 10.13, respectively, in the validation cohort.

“Overall, 25 patients staged as IVa in TNM‐8 were upstaged to IVb in the aHR proposal, and one patient staged as IVb was downstaged to IVa. Otherwise, overall stage between TNM‐8 and aHR remained the same,” the authors wrote.

“Our proposed N-classification based on aHR challenges previous tenets such as the importance of the 6-cm threshold and the importance of contralateral nodes,” the researchers wrote in their discussion.

The results from the new classification system were limited by the relatively small sample sizes and may not generalize to nonsquamous oral cancers, the researchers noted.

Further validation is needed before this system may be routinely applied in practice, but the results support evidence in favor of eliminating historical factors from staging, they said.
 

Experts Tout Advantages of Proposed Classification System

Cancer staging must be as accurate as possible and reviewed frequently, Shawn Li, MD, an otolaryngologist at University Hospitals, Cleveland, said in an interview. “This study aims to optimize nodal staging in oral cavity cancer. The current staging system doesn’t reflect updated data, and may not be specific enough to oral cavity cancers.”

This study notes the importance of stratifying extranodal extension (ENE) by micro (less than 2 mm) and macro (greater than 2 mm),” he said. It also points out that metastatic disease greater than 6 cm without ENE is infrequent enough not to require its own subcategory, he said.

Finally, in the new classification, proposed in this paper, “N2c was removed, because, statistically, it doesn’t seem to be a worse prognosis in cancers of the oral cavity,” he said.

“The data [described in this new paper] suggests that certain traditional criteria used in nodal staging for oral cavity cancer, such as [involving] very large lymph nodes greater than 6 cm in size and contralateral nodal involvement, may be less important than criteria that have not as of yet been incorporated into head and neck staging,” Wesley Talcott, MD, said in an interview. “The current study provides evidence that in oral cavity cancer, the prognostic accuracy of staging may improve by dropping these older criteria and incorporating degree of extranodal extension.”

This evidence is apparent in the ranking of the new aHR classification as first of the five strategies compared in the study, said Dr. Talcott, who was not involved in the study.

Highlighting the importance of microscopic vs. macroscopic extension may lead to doctors improving their identification of patients at highest risk for recurrence and refining treatment strategies, suggested Dr. Talcott, MD, a radiation oncologist at Northwell Health, New York, NY. However, a larger dataset is needed to validate the diagnostic accuracy of the authors’ proposed staging system, he said.

The TNM‐8‐N was updated in 2017, Dr. Li noted. “Since this system is widely referenced, it will likely need to be updated again before the changes in this study are widely adopted,” he said.

The study was supported by the National Institutes of Health and the National Cancer Institute. The researchers, Dr. Li, and Dr. Talcott had no financial conflicts to disclose.

Using a new system for classifying established prognostic features of lymph nodes may lead to better staging of oral cavity squamous cell cancer (OSCC) than the TNM staging system, experts say.

The TNM staging system is used by most facilities for cancer reporting, as defined by the National Cancer Institute. This system combines the size and extent of the primary tumor (T), the number of neighboring lymph nodes with cancer and subcategories (N), and whether or not metastasis has occurred (M).

In a new study published in the journal Cancer, the researchers created a novel classification system to better account for extranodal extension (ENE). The study population included 1460 adults with OSCC (696 with no lymph node involvement and 764 with positive lymph nodes), who underwent surgical resections at four centers.

“Our findings build on the growing evidence base that historical factors do not improve staging performance and that their omission results in improved N‐classification [i.e., the nodal status or lymph node involvement in cancer staging] performance,” John R. de Almeida, MD, of the University of Toronto, and colleagues, wrote in their new paper.

For patients with OSCC, this system, known as the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N‐classification (TNM‐8‐N), has several limitations, the researchers explained. These limitations include redundancy in the rare N3a category (i.e., having single or multiple lymph nodes greater than 6 cm or 3-7 lymph nodes without ENE) and the impact of ENE as a new prognostic feature, they said.

“Recent studies have shown that major ENE is associated with a significantly worse outcome than minor ENE, suggesting that these two subgroups should be considered as separate entities,” the authors wrote.
 

Study Methods and Results

The researchers created N-classifications based on adjusted hazard ratios and statistical analysis (recursive partitioning) with a focus on lymph node (LN) size and number and the extent of ENE. They compared their classifications of OSCC cases to those of the TNM-8-N’s classifications of the same cases.

Using the new classification system, lymph node number and size and the extent of ENE were associated with overall survival. The adjusted hazard ratios for LN counts of 1 vs. zero and greater than 1 vs. 0 were 1.92 and 3.21, respectively. The adjusted hazard ratios (aHRs) for LN size of greater than 3 cm vs. 3 cm or less, and for major vs. minor ENE were 1.88 and 1.40, respectively.

The use of an aHR improved cancer staging compared to the TNM-8-N by eliminating the N2c and 6-cm threshold, stratifying the extent of ENE, and stratifying N2b by 3-cm threshold, the researchers wrote.

The researchers compared their new system to the TNM-8 and also two other classification systems and their own recursive partitioning analysis (another statistical model).

The aHR-based system ranked first out of five in terms of correctly staging cancer, while the TNM-8 was fifth in the discovery cohort and fifth in the validation cohorts.

Outcome predictions (percentage variance explained) were 19.81 with the aHR vs. 18.95 in theTNM-8 in the discovery cohort, and similarly were 11.72 vs. 10.13, respectively, in the validation cohort.

“Overall, 25 patients staged as IVa in TNM‐8 were upstaged to IVb in the aHR proposal, and one patient staged as IVb was downstaged to IVa. Otherwise, overall stage between TNM‐8 and aHR remained the same,” the authors wrote.

“Our proposed N-classification based on aHR challenges previous tenets such as the importance of the 6-cm threshold and the importance of contralateral nodes,” the researchers wrote in their discussion.

The results from the new classification system were limited by the relatively small sample sizes and may not generalize to nonsquamous oral cancers, the researchers noted.

Further validation is needed before this system may be routinely applied in practice, but the results support evidence in favor of eliminating historical factors from staging, they said.
 

Experts Tout Advantages of Proposed Classification System

Cancer staging must be as accurate as possible and reviewed frequently, Shawn Li, MD, an otolaryngologist at University Hospitals, Cleveland, said in an interview. “This study aims to optimize nodal staging in oral cavity cancer. The current staging system doesn’t reflect updated data, and may not be specific enough to oral cavity cancers.”

This study notes the importance of stratifying extranodal extension (ENE) by micro (less than 2 mm) and macro (greater than 2 mm),” he said. It also points out that metastatic disease greater than 6 cm without ENE is infrequent enough not to require its own subcategory, he said.

Finally, in the new classification, proposed in this paper, “N2c was removed, because, statistically, it doesn’t seem to be a worse prognosis in cancers of the oral cavity,” he said.

“The data [described in this new paper] suggests that certain traditional criteria used in nodal staging for oral cavity cancer, such as [involving] very large lymph nodes greater than 6 cm in size and contralateral nodal involvement, may be less important than criteria that have not as of yet been incorporated into head and neck staging,” Wesley Talcott, MD, said in an interview. “The current study provides evidence that in oral cavity cancer, the prognostic accuracy of staging may improve by dropping these older criteria and incorporating degree of extranodal extension.”

This evidence is apparent in the ranking of the new aHR classification as first of the five strategies compared in the study, said Dr. Talcott, who was not involved in the study.

Highlighting the importance of microscopic vs. macroscopic extension may lead to doctors improving their identification of patients at highest risk for recurrence and refining treatment strategies, suggested Dr. Talcott, MD, a radiation oncologist at Northwell Health, New York, NY. However, a larger dataset is needed to validate the diagnostic accuracy of the authors’ proposed staging system, he said.

The TNM‐8‐N was updated in 2017, Dr. Li noted. “Since this system is widely referenced, it will likely need to be updated again before the changes in this study are widely adopted,” he said.

The study was supported by the National Institutes of Health and the National Cancer Institute. The researchers, Dr. Li, and Dr. Talcott had no financial conflicts to disclose.

A study from the University of Texas demonstrates the feasibility of using robotic single-port laparoscopy in nipple-sparing mastectomy (NSM), a type of conservative mastectomy preserving the skin and nipple-areola complex. The new findings potentially expand the application of robotic surgery to a larger patient population but doubts about the safety of this approach linger.

Robotic Mastectomy

The first surgeries involving the Da Vinci robotic surgeon for breast removal date to 2015. Multiport robotic surgery faces significant obstacles in this field, however. Feasibility studies have primarily focused on women with small breasts, corresponding to cup size C or smaller.

In the study that was published in JAMA Surgery, surgeons used the more cost-effective single-port platform for bilateral NSM procedures. Among the 20 patients included in the analysis (age, 29-63 years), 11 underwent prophylactic mastectomy (for a high risk for cancer) and 9 had mastectomy for breast tumors. Breast sizes ranged from A cup to D cup.

The duration of the procedure, from skin incision to suture for both breasts, ranged from 205 to 351 minutes (median, 277 minutes). No immediate operative complications (eg, hematoma) occurred, and there was no need for conversion to open surgery in any case. Over the 36-month follow-up, there were no recurrences. About 95% of patients retained skin sensitivity and 55% retained nipple sensitivity.
 

Unanswered Questions

In an accompanying article, Monica Morrow, MD, director of surgical breast oncology at the Memorial Sloan-Kettering Cancer Center in New York, acknowledged that the new evidence confirms the surgical approach’s feasibility but deems it insufficient to adopt it lightly. “At this point, the issue is not whether robotic mastectomy can be done but whether there is sufficient information about its oncologic safety that it should be done,” she wrote.

In a 2019 statement that was updated in 2021, the US Food and Drug Administration stated, “The safety and effectiveness of using robotically assisted surgical devices in mastectomy procedures or in the prevention or treatment of breast cancer have not been established.” The significance of this caution is underscored by the experience with laparoscopic and robotic radical hysterectomies. These procedures were widely adopted until a randomized prospective study demonstrated lower disease-free and overall survival for the minimally invasive approach compared with open surgery.

The University of Texas surgeons stated that acceptable safety and oncological outcomes for robotic NSM compared with conventional NSM had been demonstrated. They cited two trials with 238 cases and a median follow-up of less than 3 years. Dr. Morrow wrote, “While these reports provide reassurance that gross residual tumor is not being left behind, they do not address the issue of failure to remove all of the breast tissue due to thick skin flaps, with the potential for development of late recurrence or new cancers.” It is worth noting that even with the traditional surgical approach, the 5-year local recurrence rate after NSM is approximately double when observed with shorter follow-ups.

According to Dr. Morrow, the high rate of sensory preservation observed with robotic surgery, a desirable outcome for patients, is also a cause for concern. “While this may be due to incision placement or minimal skin flap retraction, as suggested by the authors, it is equally plausible that this could be due to thick skin flaps with preservation of the terminal branches of the fourth intercostal nerve.”

Therefore, more information on long-term oncological outcomes in a large number of patients will be necessary to confirm the safety of the procedure. In addition, measuring patient-reported outcomes will be useful in demonstrating that the benefits of the procedure outweigh increased operating times and costs. 

This article was translated from Univadis Italy, which is part of the Medscape Professional Network. A version of this article appeared on Medscape.com.

A study from the University of Texas demonstrates the feasibility of using robotic single-port laparoscopy in nipple-sparing mastectomy (NSM), a type of conservative mastectomy preserving the skin and nipple-areola complex. The new findings potentially expand the application of robotic surgery to a larger patient population but doubts about the safety of this approach linger.

Robotic Mastectomy

The first surgeries involving the Da Vinci robotic surgeon for breast removal date to 2015. Multiport robotic surgery faces significant obstacles in this field, however. Feasibility studies have primarily focused on women with small breasts, corresponding to cup size C or smaller.

In the study that was published in JAMA Surgery, surgeons used the more cost-effective single-port platform for bilateral NSM procedures. Among the 20 patients included in the analysis (age, 29-63 years), 11 underwent prophylactic mastectomy (for a high risk for cancer) and 9 had mastectomy for breast tumors. Breast sizes ranged from A cup to D cup.

The duration of the procedure, from skin incision to suture for both breasts, ranged from 205 to 351 minutes (median, 277 minutes). No immediate operative complications (eg, hematoma) occurred, and there was no need for conversion to open surgery in any case. Over the 36-month follow-up, there were no recurrences. About 95% of patients retained skin sensitivity and 55% retained nipple sensitivity.
 

Unanswered Questions

In an accompanying article, Monica Morrow, MD, director of surgical breast oncology at the Memorial Sloan-Kettering Cancer Center in New York, acknowledged that the new evidence confirms the surgical approach’s feasibility but deems it insufficient to adopt it lightly. “At this point, the issue is not whether robotic mastectomy can be done but whether there is sufficient information about its oncologic safety that it should be done,” she wrote.

In a 2019 statement that was updated in 2021, the US Food and Drug Administration stated, “The safety and effectiveness of using robotically assisted surgical devices in mastectomy procedures or in the prevention or treatment of breast cancer have not been established.” The significance of this caution is underscored by the experience with laparoscopic and robotic radical hysterectomies. These procedures were widely adopted until a randomized prospective study demonstrated lower disease-free and overall survival for the minimally invasive approach compared with open surgery.

The University of Texas surgeons stated that acceptable safety and oncological outcomes for robotic NSM compared with conventional NSM had been demonstrated. They cited two trials with 238 cases and a median follow-up of less than 3 years. Dr. Morrow wrote, “While these reports provide reassurance that gross residual tumor is not being left behind, they do not address the issue of failure to remove all of the breast tissue due to thick skin flaps, with the potential for development of late recurrence or new cancers.” It is worth noting that even with the traditional surgical approach, the 5-year local recurrence rate after NSM is approximately double when observed with shorter follow-ups.

According to Dr. Morrow, the high rate of sensory preservation observed with robotic surgery, a desirable outcome for patients, is also a cause for concern. “While this may be due to incision placement or minimal skin flap retraction, as suggested by the authors, it is equally plausible that this could be due to thick skin flaps with preservation of the terminal branches of the fourth intercostal nerve.”

Therefore, more information on long-term oncological outcomes in a large number of patients will be necessary to confirm the safety of the procedure. In addition, measuring patient-reported outcomes will be useful in demonstrating that the benefits of the procedure outweigh increased operating times and costs. 

This article was translated from Univadis Italy, which is part of the Medscape Professional Network. A version of this article appeared on Medscape.com.

A study from the University of Texas demonstrates the feasibility of using robotic single-port laparoscopy in nipple-sparing mastectomy (NSM), a type of conservative mastectomy preserving the skin and nipple-areola complex. The new findings potentially expand the application of robotic surgery to a larger patient population but doubts about the safety of this approach linger.

Robotic Mastectomy

The first surgeries involving the Da Vinci robotic surgeon for breast removal date to 2015. Multiport robotic surgery faces significant obstacles in this field, however. Feasibility studies have primarily focused on women with small breasts, corresponding to cup size C or smaller.

In the study that was published in JAMA Surgery, surgeons used the more cost-effective single-port platform for bilateral NSM procedures. Among the 20 patients included in the analysis (age, 29-63 years), 11 underwent prophylactic mastectomy (for a high risk for cancer) and 9 had mastectomy for breast tumors. Breast sizes ranged from A cup to D cup.

The duration of the procedure, from skin incision to suture for both breasts, ranged from 205 to 351 minutes (median, 277 minutes). No immediate operative complications (eg, hematoma) occurred, and there was no need for conversion to open surgery in any case. Over the 36-month follow-up, there were no recurrences. About 95% of patients retained skin sensitivity and 55% retained nipple sensitivity.
 

Unanswered Questions

In an accompanying article, Monica Morrow, MD, director of surgical breast oncology at the Memorial Sloan-Kettering Cancer Center in New York, acknowledged that the new evidence confirms the surgical approach’s feasibility but deems it insufficient to adopt it lightly. “At this point, the issue is not whether robotic mastectomy can be done but whether there is sufficient information about its oncologic safety that it should be done,” she wrote.

In a 2019 statement that was updated in 2021, the US Food and Drug Administration stated, “The safety and effectiveness of using robotically assisted surgical devices in mastectomy procedures or in the prevention or treatment of breast cancer have not been established.” The significance of this caution is underscored by the experience with laparoscopic and robotic radical hysterectomies. These procedures were widely adopted until a randomized prospective study demonstrated lower disease-free and overall survival for the minimally invasive approach compared with open surgery.

The University of Texas surgeons stated that acceptable safety and oncological outcomes for robotic NSM compared with conventional NSM had been demonstrated. They cited two trials with 238 cases and a median follow-up of less than 3 years. Dr. Morrow wrote, “While these reports provide reassurance that gross residual tumor is not being left behind, they do not address the issue of failure to remove all of the breast tissue due to thick skin flaps, with the potential for development of late recurrence or new cancers.” It is worth noting that even with the traditional surgical approach, the 5-year local recurrence rate after NSM is approximately double when observed with shorter follow-ups.

According to Dr. Morrow, the high rate of sensory preservation observed with robotic surgery, a desirable outcome for patients, is also a cause for concern. “While this may be due to incision placement or minimal skin flap retraction, as suggested by the authors, it is equally plausible that this could be due to thick skin flaps with preservation of the terminal branches of the fourth intercostal nerve.”

Therefore, more information on long-term oncological outcomes in a large number of patients will be necessary to confirm the safety of the procedure. In addition, measuring patient-reported outcomes will be useful in demonstrating that the benefits of the procedure outweigh increased operating times and costs. 

This article was translated from Univadis Italy, which is part of the Medscape Professional Network. A version of this article appeared on Medscape.com.

TOPLINE:

Tumor regrowth predicts distant metastases in patients with rectal cancer undergoing surveillance after complete clinical responses to neoadjuvant therapy.

METHODOLOGY:

• “Watch and wait” is generally offered to patients with rectal cancer who have a complete clinical response to neoadjuvant therapy.
• Up to 30% of tumors regrow within 3 years, and about 5% of patients develop distant metastases.
• To get a better handle on the risk factors, investigators identified 508 watch-and-wait patients from the International Watch & Wait database who had a local regrowth and underwent resection.
• The team compared them with 893 patients from a Spanish registry who had total mesorectal excisions after neoadjuvant therapy and who were found to have had a nearly complete response to neoadjuvant therapy, meaning that 90% or more of their tumor was gone.

TAKEAWAY:

• Three-year distant metastasis–free survival was 75% in the watch-and-wait/regrowth group vs 87% in the upfront surgery arm (P = .001); the results held when the two groups were stratified by pathological T stage and nodal status.
• Patients with local regrowth also had a higher risk of developing distant metastasis (22.8% vs 10.2% at 3 years).
• Local regrowth was an independent risk factor for distant metastasis, along with higher pathological T stage and positive nodal status on the resected regrowth specimen.
• Baseline clinical T stage and nodal status were not significantly associated with risk.

IN PRACTICE:

“Leaving the primary undetectable tumor in situ until development of local regrowth may result in worse oncological outcomes ... Efforts should be made to minimize the risk of local regrowth among patients undergoing watch and wait by the use of very stringent criteria for the identification of a clinical complete response.” There may be a role for ctDNA to improve patient selection for watch and wait.

SOURCE:

The study was led by Laura Melina Fernandez of the Champalimaud Foundation in Lisbon, Portugal, and presented on January 20, 2024, at the ASCO Gastrointestinal Cancers Symposium.

LIMITATIONS:

The definition of “complete clinical response” and selection of patients for watch and wait varied across International Watch & Wait database institutions. Recruitment occurred before implementation of total neoadjuvant therapy regimens.

DISCLOSURES:

There was no external funding for the work. The lead investigator didn’t have any disclosures.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Tumor regrowth predicts distant metastases in patients with rectal cancer undergoing surveillance after complete clinical responses to neoadjuvant therapy.

METHODOLOGY:

• “Watch and wait” is generally offered to patients with rectal cancer who have a complete clinical response to neoadjuvant therapy.
• Up to 30% of tumors regrow within 3 years, and about 5% of patients develop distant metastases.
• To get a better handle on the risk factors, investigators identified 508 watch-and-wait patients from the International Watch & Wait database who had a local regrowth and underwent resection.
• The team compared them with 893 patients from a Spanish registry who had total mesorectal excisions after neoadjuvant therapy and who were found to have had a nearly complete response to neoadjuvant therapy, meaning that 90% or more of their tumor was gone.

TAKEAWAY:

• Three-year distant metastasis–free survival was 75% in the watch-and-wait/regrowth group vs 87% in the upfront surgery arm (P = .001); the results held when the two groups were stratified by pathological T stage and nodal status.
• Patients with local regrowth also had a higher risk of developing distant metastasis (22.8% vs 10.2% at 3 years).
• Local regrowth was an independent risk factor for distant metastasis, along with higher pathological T stage and positive nodal status on the resected regrowth specimen.
• Baseline clinical T stage and nodal status were not significantly associated with risk.

IN PRACTICE:

“Leaving the primary undetectable tumor in situ until development of local regrowth may result in worse oncological outcomes ... Efforts should be made to minimize the risk of local regrowth among patients undergoing watch and wait by the use of very stringent criteria for the identification of a clinical complete response.” There may be a role for ctDNA to improve patient selection for watch and wait.

SOURCE:

The study was led by Laura Melina Fernandez of the Champalimaud Foundation in Lisbon, Portugal, and presented on January 20, 2024, at the ASCO Gastrointestinal Cancers Symposium.

LIMITATIONS:

The definition of “complete clinical response” and selection of patients for watch and wait varied across International Watch & Wait database institutions. Recruitment occurred before implementation of total neoadjuvant therapy regimens.

DISCLOSURES:

There was no external funding for the work. The lead investigator didn’t have any disclosures.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Tumor regrowth predicts distant metastases in patients with rectal cancer undergoing surveillance after complete clinical responses to neoadjuvant therapy.

METHODOLOGY:

• “Watch and wait” is generally offered to patients with rectal cancer who have a complete clinical response to neoadjuvant therapy.
• Up to 30% of tumors regrow within 3 years, and about 5% of patients develop distant metastases.
• To get a better handle on the risk factors, investigators identified 508 watch-and-wait patients from the International Watch & Wait database who had a local regrowth and underwent resection.
• The team compared them with 893 patients from a Spanish registry who had total mesorectal excisions after neoadjuvant therapy and who were found to have had a nearly complete response to neoadjuvant therapy, meaning that 90% or more of their tumor was gone.

TAKEAWAY:

• Three-year distant metastasis–free survival was 75% in the watch-and-wait/regrowth group vs 87% in the upfront surgery arm (P = .001); the results held when the two groups were stratified by pathological T stage and nodal status.
• Patients with local regrowth also had a higher risk of developing distant metastasis (22.8% vs 10.2% at 3 years).
• Local regrowth was an independent risk factor for distant metastasis, along with higher pathological T stage and positive nodal status on the resected regrowth specimen.
• Baseline clinical T stage and nodal status were not significantly associated with risk.

IN PRACTICE:

“Leaving the primary undetectable tumor in situ until development of local regrowth may result in worse oncological outcomes ... Efforts should be made to minimize the risk of local regrowth among patients undergoing watch and wait by the use of very stringent criteria for the identification of a clinical complete response.” There may be a role for ctDNA to improve patient selection for watch and wait.

SOURCE:

The study was led by Laura Melina Fernandez of the Champalimaud Foundation in Lisbon, Portugal, and presented on January 20, 2024, at the ASCO Gastrointestinal Cancers Symposium.

LIMITATIONS:

The definition of “complete clinical response” and selection of patients for watch and wait varied across International Watch & Wait database institutions. Recruitment occurred before implementation of total neoadjuvant therapy regimens.

DISCLOSURES:

There was no external funding for the work. The lead investigator didn’t have any disclosures.
 

A version of this article appeared on Medscape.com.

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

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

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

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

Study Design Questioned

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

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

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

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

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

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

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

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

Real-World Practice

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

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

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

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

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

CONTACT-02 Details

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

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

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

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

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

Safety Data

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

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

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

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

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

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

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

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

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

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

Study Design Questioned

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

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

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

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

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

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

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

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

Real-World Practice

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

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

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

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

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

CONTACT-02 Details

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

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

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

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

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

Safety Data

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

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

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

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

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

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

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

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

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

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

Study Design Questioned

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

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

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

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

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

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

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

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

Real-World Practice

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

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

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

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

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

CONTACT-02 Details

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

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

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

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

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

Safety Data

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

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

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

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

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

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

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.

Men with advanced prostate cancer undergoing local therapies such as radiation therapy or radical prostatectomy experience significantly more gastrointestinal and sexual issues, along with problems with incontinence, in the following years, than systemically treated patients. These were the findings of a retrospective cohort study in JAMA Network Open.

The standard treatment of advanced prostate cancer is androgen deprivation therapy (ADT). “The role of local therapy has been debated for several years. Studies have shown that radiation therapy or radical prostatectomy can improve patient survival under certain conditions,” said Hubert Kübler, MD, director of the Clinic and Polyclinic for Urology and Pediatric Urology at the University Hospital Würzburg in Germany. “At academic centers, a local therapy is pursued for oligometastatic patients if they are fit enough.”

The hope is to spare patients the side effects of ADT over an extended period and thus improve their quality of life. “But what impact does local therapy itself have on the men’s quality of life, especially considering that the survival advantage gained may be relatively small?” wrote study author Saira Khan, PhD, MPH, assistant professor of surgery at Washington University School of Medicine in St. Louis, Missouri, and her colleagues.

Examining Side Effects

This question has not been thoroughly examined yet. “To our knowledge, this is one of the first studies investigating the side effects of local therapy in men with advanced prostate cancer for up to 5 years after treatment,” wrote the authors.

The cohort study included 5500 US veterans who were diagnosed with advanced prostate cancer between January 1999 and December 2013. The tumors were in stage T4 (tumor is fixed or has spread to adjacent structures), with regional lymph node metastases (N1), and partially detectable distant metastases (M1).

The average age was 68.7 years, and 31% received local therapy (eg, radiation therapy, radical prostatectomy, or both), and 69% received systemic therapy (eg, hormone therapy, chemotherapy, or both).

Types of Local Therapy

Combining radiation therapy and radical prostatectomy “diminishes the meaningfulness of the study results,” according to Dr. Kübler. “The issue should have been analyzed in much finer detail. Studies clearly show, for example, that radiation therapy consistently performs slightly worse than prostatectomy in terms of gastrointestinal complaints.”

In their paper, the researchers reported that the prevalence of side effects was high, regardless of the therapy. Overall, 916 men (75.2%) with initial local therapy and 897 men (67.1%) with initial systemic therapy reported experiencing at least one side effect lasting more than 2 years and up to 5 years.

In the first year after the initial therapy, men who underwent local therapy, compared with those who underwent systemic therapy, experienced more of the following symptoms:

• Gastrointestinal issues (odds ratio [OR], 4.08)
• Pain (OR, 1.57)
• Sexual dysfunction (OR, 2.96)
• Urinary problems, predominantly incontinence (OR, 2.25)

Lasting Side Effects

Even up to year 5 after the initial therapy, men with local therapy reported more gastrointestinal and sexual issues, as well as more frequent incontinence, than those with systemic therapy. Only the frequency of pain equalized between the two groups in the second year.

“Our results are consistent with the known side effect profile [of local therapy] in patients with clinically localized prostate cancer receiving surgery or radiation therapy instead of active surveillance,” wrote the authors.

The comparison in advanced prostate cancer, however, is not with active surveillance but with ADT. “As the study confirmed, ADT is associated with various side effects,” said Dr. Kübler. Nevertheless, it was associated with fewer side effects than local therapy in this study. The concept behind local therapy (improving prognosis while avoiding local problems) is challenging to reconcile with these results.

Contradictory Data

The results also contradict findings from other studies. Dr. Kübler pointed to the recently presented PEACE-1 study, where “local complications and issues were reduced through local therapy in high-volume and high-risk patients.”

The study did not consider subsequent interventions, such as how many patients needed transurethral manipulation in the later course of the disease to address local problems. “There are older data showing that a radical prostatectomy can reduce the need for further resections,” Dr. Kübler added.

“I find it difficult to reconcile these data with other data and with my personal experience,” said Dr. Kübler. However, he agreed with the study authors’ conclusion, emphasizing the importance of informing patients about expected side effects of local therapy in the context of potentially marginal improvements in survival.

Different Situation in Germany

“As practitioners, we sometimes underestimate the side effects we subject our patients to. We need to talk to our patients about the prognosis improvement that comes with side effects,” said Dr. Kübler. He added that a similar study in Germany might yield different results. “Dr. Khan and her colleagues examined a very specific patient population: Namely, veterans. This patient clientele often faces many social difficulties, and the treatment structure in US veterans’ care differs significantly from ours.”

This article was translated from the Medscape German edition. A version of this article appeared on Medscape.com.

Men with advanced prostate cancer undergoing local therapies such as radiation therapy or radical prostatectomy experience significantly more gastrointestinal and sexual issues, along with problems with incontinence, in the following years, than systemically treated patients. These were the findings of a retrospective cohort study in JAMA Network Open.

The standard treatment of advanced prostate cancer is androgen deprivation therapy (ADT). “The role of local therapy has been debated for several years. Studies have shown that radiation therapy or radical prostatectomy can improve patient survival under certain conditions,” said Hubert Kübler, MD, director of the Clinic and Polyclinic for Urology and Pediatric Urology at the University Hospital Würzburg in Germany. “At academic centers, a local therapy is pursued for oligometastatic patients if they are fit enough.”

The hope is to spare patients the side effects of ADT over an extended period and thus improve their quality of life. “But what impact does local therapy itself have on the men’s quality of life, especially considering that the survival advantage gained may be relatively small?” wrote study author Saira Khan, PhD, MPH, assistant professor of surgery at Washington University School of Medicine in St. Louis, Missouri, and her colleagues.

Examining Side Effects

This question has not been thoroughly examined yet. “To our knowledge, this is one of the first studies investigating the side effects of local therapy in men with advanced prostate cancer for up to 5 years after treatment,” wrote the authors.

The cohort study included 5500 US veterans who were diagnosed with advanced prostate cancer between January 1999 and December 2013. The tumors were in stage T4 (tumor is fixed or has spread to adjacent structures), with regional lymph node metastases (N1), and partially detectable distant metastases (M1).

The average age was 68.7 years, and 31% received local therapy (eg, radiation therapy, radical prostatectomy, or both), and 69% received systemic therapy (eg, hormone therapy, chemotherapy, or both).

Types of Local Therapy

Combining radiation therapy and radical prostatectomy “diminishes the meaningfulness of the study results,” according to Dr. Kübler. “The issue should have been analyzed in much finer detail. Studies clearly show, for example, that radiation therapy consistently performs slightly worse than prostatectomy in terms of gastrointestinal complaints.”

In their paper, the researchers reported that the prevalence of side effects was high, regardless of the therapy. Overall, 916 men (75.2%) with initial local therapy and 897 men (67.1%) with initial systemic therapy reported experiencing at least one side effect lasting more than 2 years and up to 5 years.

In the first year after the initial therapy, men who underwent local therapy, compared with those who underwent systemic therapy, experienced more of the following symptoms:

• Gastrointestinal issues (odds ratio [OR], 4.08)
• Pain (OR, 1.57)
• Sexual dysfunction (OR, 2.96)
• Urinary problems, predominantly incontinence (OR, 2.25)

Lasting Side Effects

Even up to year 5 after the initial therapy, men with local therapy reported more gastrointestinal and sexual issues, as well as more frequent incontinence, than those with systemic therapy. Only the frequency of pain equalized between the two groups in the second year.

“Our results are consistent with the known side effect profile [of local therapy] in patients with clinically localized prostate cancer receiving surgery or radiation therapy instead of active surveillance,” wrote the authors.

The comparison in advanced prostate cancer, however, is not with active surveillance but with ADT. “As the study confirmed, ADT is associated with various side effects,” said Dr. Kübler. Nevertheless, it was associated with fewer side effects than local therapy in this study. The concept behind local therapy (improving prognosis while avoiding local problems) is challenging to reconcile with these results.

Contradictory Data

The results also contradict findings from other studies. Dr. Kübler pointed to the recently presented PEACE-1 study, where “local complications and issues were reduced through local therapy in high-volume and high-risk patients.”

The study did not consider subsequent interventions, such as how many patients needed transurethral manipulation in the later course of the disease to address local problems. “There are older data showing that a radical prostatectomy can reduce the need for further resections,” Dr. Kübler added.

“I find it difficult to reconcile these data with other data and with my personal experience,” said Dr. Kübler. However, he agreed with the study authors’ conclusion, emphasizing the importance of informing patients about expected side effects of local therapy in the context of potentially marginal improvements in survival.

Different Situation in Germany

“As practitioners, we sometimes underestimate the side effects we subject our patients to. We need to talk to our patients about the prognosis improvement that comes with side effects,” said Dr. Kübler. He added that a similar study in Germany might yield different results. “Dr. Khan and her colleagues examined a very specific patient population: Namely, veterans. This patient clientele often faces many social difficulties, and the treatment structure in US veterans’ care differs significantly from ours.”

This article was translated from the Medscape German edition. A version of this article appeared on Medscape.com.

Men with advanced prostate cancer undergoing local therapies such as radiation therapy or radical prostatectomy experience significantly more gastrointestinal and sexual issues, along with problems with incontinence, in the following years, than systemically treated patients. These were the findings of a retrospective cohort study in JAMA Network Open.

The standard treatment of advanced prostate cancer is androgen deprivation therapy (ADT). “The role of local therapy has been debated for several years. Studies have shown that radiation therapy or radical prostatectomy can improve patient survival under certain conditions,” said Hubert Kübler, MD, director of the Clinic and Polyclinic for Urology and Pediatric Urology at the University Hospital Würzburg in Germany. “At academic centers, a local therapy is pursued for oligometastatic patients if they are fit enough.”

The hope is to spare patients the side effects of ADT over an extended period and thus improve their quality of life. “But what impact does local therapy itself have on the men’s quality of life, especially considering that the survival advantage gained may be relatively small?” wrote study author Saira Khan, PhD, MPH, assistant professor of surgery at Washington University School of Medicine in St. Louis, Missouri, and her colleagues.

Examining Side Effects

This question has not been thoroughly examined yet. “To our knowledge, this is one of the first studies investigating the side effects of local therapy in men with advanced prostate cancer for up to 5 years after treatment,” wrote the authors.

The cohort study included 5500 US veterans who were diagnosed with advanced prostate cancer between January 1999 and December 2013. The tumors were in stage T4 (tumor is fixed or has spread to adjacent structures), with regional lymph node metastases (N1), and partially detectable distant metastases (M1).

The average age was 68.7 years, and 31% received local therapy (eg, radiation therapy, radical prostatectomy, or both), and 69% received systemic therapy (eg, hormone therapy, chemotherapy, or both).

Types of Local Therapy

Combining radiation therapy and radical prostatectomy “diminishes the meaningfulness of the study results,” according to Dr. Kübler. “The issue should have been analyzed in much finer detail. Studies clearly show, for example, that radiation therapy consistently performs slightly worse than prostatectomy in terms of gastrointestinal complaints.”

In their paper, the researchers reported that the prevalence of side effects was high, regardless of the therapy. Overall, 916 men (75.2%) with initial local therapy and 897 men (67.1%) with initial systemic therapy reported experiencing at least one side effect lasting more than 2 years and up to 5 years.

In the first year after the initial therapy, men who underwent local therapy, compared with those who underwent systemic therapy, experienced more of the following symptoms:

• Gastrointestinal issues (odds ratio [OR], 4.08)
• Pain (OR, 1.57)
• Sexual dysfunction (OR, 2.96)
• Urinary problems, predominantly incontinence (OR, 2.25)

Lasting Side Effects

Even up to year 5 after the initial therapy, men with local therapy reported more gastrointestinal and sexual issues, as well as more frequent incontinence, than those with systemic therapy. Only the frequency of pain equalized between the two groups in the second year.

“Our results are consistent with the known side effect profile [of local therapy] in patients with clinically localized prostate cancer receiving surgery or radiation therapy instead of active surveillance,” wrote the authors.

The comparison in advanced prostate cancer, however, is not with active surveillance but with ADT. “As the study confirmed, ADT is associated with various side effects,” said Dr. Kübler. Nevertheless, it was associated with fewer side effects than local therapy in this study. The concept behind local therapy (improving prognosis while avoiding local problems) is challenging to reconcile with these results.

Contradictory Data

The results also contradict findings from other studies. Dr. Kübler pointed to the recently presented PEACE-1 study, where “local complications and issues were reduced through local therapy in high-volume and high-risk patients.”

The study did not consider subsequent interventions, such as how many patients needed transurethral manipulation in the later course of the disease to address local problems. “There are older data showing that a radical prostatectomy can reduce the need for further resections,” Dr. Kübler added.

“I find it difficult to reconcile these data with other data and with my personal experience,” said Dr. Kübler. However, he agreed with the study authors’ conclusion, emphasizing the importance of informing patients about expected side effects of local therapy in the context of potentially marginal improvements in survival.

Different Situation in Germany

“As practitioners, we sometimes underestimate the side effects we subject our patients to. We need to talk to our patients about the prognosis improvement that comes with side effects,” said Dr. Kübler. He added that a similar study in Germany might yield different results. “Dr. Khan and her colleagues examined a very specific patient population: Namely, veterans. This patient clientele often faces many social difficulties, and the treatment structure in US veterans’ care differs significantly from ours.”

This article was translated from the Medscape German edition. A version of this article appeared on Medscape.com.