M. Alexander Otto

Intensive surveillance with carcinoembryonic antigen (CEA) testing and CT scans after colorectal cancer resection did not improve recurrence-free or overall survival when compared with standard abdominal ultrasound and chest x-ray monitoring in a phase 3 trial of almost 2,000 patients.

However, among patients with colon cancer recurrence, those randomized to intensive surveillance more often had a second surgery with curative intent. Even so, there was no overall survival benefit versus standard surveillance in this group.

In short, “none of the follow-up modalities resulted in a difference,” said investigator Come Lepage, MD, PhD, of Centre Hospitalier Universitaire de Dijon (France).

Dr. Lepage presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

Dr. Lepage said the study’s results suggest guidelines that include CT and CEA monitoring should be amended, and the standard surveillance methods should be ultrasound and chest x-ray. Dr. LePage called CEA surveillance “useless” and said CT scans should be performed only in cases of suspected recurrence.

However, study discussant Tim Price, MBBS, DHSc, of the University of Adelaide, noted that both the intensive and standard arms in this study had abdominal imaging every 3 months, be it ultrasound or CT, so even in the standard arms, surveillance “was still fairly aggressive.”

Because of that, the study does not “suggest we should decrease our intensity,” Dr. Price said.

He added that the study’s major finding was that more intensive surveillance led to higher rates of secondary surgery with curative intent, probably because recurrences were caught earlier than they would have been with standard surveillance, when curative surgery was still possible.

Patients in the study were treated during 2009-2015, and that might have also made a difference. “We need to remember that, in 2020, care is very different,” Dr. Price said. This includes increased surgical interventions and options for oligometastatic disease, plus systemic therapies such as pembrolizumab. With modern treatments, detecting recurrences earlier “may well have an impact on survival.”

Perhaps patients would live longer with “earlier diagnosis in today’s setting with more active agents and more aggressive surgery and radiotherapy [e.g., stereotactic ablative radiation therapy],” Dr. Price said in an interview.
 

Study details

The trial, dubbed PRODIGE 13, was done to bring clarity to the surveillance issue. Intensive follow-up after curative surgery for colorectal cancer, including CT and CEA monitoring, is recommended by various scientific societies, but it’s based mainly on expert opinion. Results of the few clinical trials on the issue have been controversial, Dr. Lepage explained.

PRODIGE 13 included 1,995 subjects with colorectal cancer. About half of patients had stage II disease, and the other half had stage III. Most patients were 75 years or younger at baseline, and there were more men in the study than women. All patients underwent resection with curative intent and had no evidence of residual disease 3 months after surgery. Some patients received adjuvant chemotherapy.

Patients were first randomized to no CEA monitoring or CEA monitoring every 3 months for the first 2 years, then every 6 months for an additional 3 years. Members in both groups were then randomized a second time to either intensive or standard radiologic surveillance.

Surveillance in the standard arm consisted of an abdominal ultrasound every 3 months for the first 3 years, then biannually for an additional 2 years, plus chest x-rays every 6 months for 5 years. Intensive surveillance consisted of CT imaging, including thoracic imaging, alternating with abdominal ultrasound, every 3 months, then biannually for another 2 years.

At baseline, the surveillance groups were well balanced with regard to demographics, primary tumor location, and other factors, but stage III disease was more prevalent among patients randomized to standard radiologic monitoring without CEA.
 

Results

The median follow up was 6.5 years. There were no significant differences between the surveillance groups with regard to 5-year overall survival (P = .340) or recurrence-free survival (P = .473).

There were no significant differences in recurrence-free or overall survival when patients were stratified by age, sex, stage, CEA at a cut point of 5 mcg/L, and primary tumor characteristics including location, perineural invasion, and occlusion/perforation.

There were 356 recurrences in patients initially treated for colon cancer. CEA surveillance with or without CT scan was associated with an increased incidence of secondary resection with curative intent. The rate of secondary resection was 66.3% in the standard imaging with CEA arm, 59.5% in the CT plus CEA arm, 50.7% with CT imaging but no CEA, and 40.9% with standard imaging and no CEA (P = .0035).

The rates were similar among the 83 patients with recurrence after initial treatment for rectal cancer, but the between-arm differences were not significant. The rate of secondary resection with curative intent was 57.9% in the standard imaging with CEA arm, 47.8% in the CT plus CEA arm, 55% with CT imaging but no CEA, and 42.9% with standard imaging and no CEA.

The research is ongoing, and the team expects to report on secondary outcomes and ancillary studies of circulating tumor DNA, among other things, in 2021.

The study is being funded by the Federation Francophone de Cancerologie Digestive. Dr. Lepage disclosed ties with Novartis, Amgen, Bayer, Servier, and AAA. Dr. Price disclosed institutional research funding from Amgen and being an uncompensated adviser to Pierre-Fabre and Merck.

[email protected]

SOURCE: Lepage C et al. ESMO 2020, Abstract 398O.

Intensive surveillance with carcinoembryonic antigen (CEA) testing and CT scans after colorectal cancer resection did not improve recurrence-free or overall survival when compared with standard abdominal ultrasound and chest x-ray monitoring in a phase 3 trial of almost 2,000 patients.

However, among patients with colon cancer recurrence, those randomized to intensive surveillance more often had a second surgery with curative intent. Even so, there was no overall survival benefit versus standard surveillance in this group.

In short, “none of the follow-up modalities resulted in a difference,” said investigator Come Lepage, MD, PhD, of Centre Hospitalier Universitaire de Dijon (France).

Dr. Lepage presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

Dr. Lepage said the study’s results suggest guidelines that include CT and CEA monitoring should be amended, and the standard surveillance methods should be ultrasound and chest x-ray. Dr. LePage called CEA surveillance “useless” and said CT scans should be performed only in cases of suspected recurrence.

However, study discussant Tim Price, MBBS, DHSc, of the University of Adelaide, noted that both the intensive and standard arms in this study had abdominal imaging every 3 months, be it ultrasound or CT, so even in the standard arms, surveillance “was still fairly aggressive.”

Because of that, the study does not “suggest we should decrease our intensity,” Dr. Price said.

He added that the study’s major finding was that more intensive surveillance led to higher rates of secondary surgery with curative intent, probably because recurrences were caught earlier than they would have been with standard surveillance, when curative surgery was still possible.

Patients in the study were treated during 2009-2015, and that might have also made a difference. “We need to remember that, in 2020, care is very different,” Dr. Price said. This includes increased surgical interventions and options for oligometastatic disease, plus systemic therapies such as pembrolizumab. With modern treatments, detecting recurrences earlier “may well have an impact on survival.”

Perhaps patients would live longer with “earlier diagnosis in today’s setting with more active agents and more aggressive surgery and radiotherapy [e.g., stereotactic ablative radiation therapy],” Dr. Price said in an interview.
 

Study details

The trial, dubbed PRODIGE 13, was done to bring clarity to the surveillance issue. Intensive follow-up after curative surgery for colorectal cancer, including CT and CEA monitoring, is recommended by various scientific societies, but it’s based mainly on expert opinion. Results of the few clinical trials on the issue have been controversial, Dr. Lepage explained.

PRODIGE 13 included 1,995 subjects with colorectal cancer. About half of patients had stage II disease, and the other half had stage III. Most patients were 75 years or younger at baseline, and there were more men in the study than women. All patients underwent resection with curative intent and had no evidence of residual disease 3 months after surgery. Some patients received adjuvant chemotherapy.

Patients were first randomized to no CEA monitoring or CEA monitoring every 3 months for the first 2 years, then every 6 months for an additional 3 years. Members in both groups were then randomized a second time to either intensive or standard radiologic surveillance.

Surveillance in the standard arm consisted of an abdominal ultrasound every 3 months for the first 3 years, then biannually for an additional 2 years, plus chest x-rays every 6 months for 5 years. Intensive surveillance consisted of CT imaging, including thoracic imaging, alternating with abdominal ultrasound, every 3 months, then biannually for another 2 years.

At baseline, the surveillance groups were well balanced with regard to demographics, primary tumor location, and other factors, but stage III disease was more prevalent among patients randomized to standard radiologic monitoring without CEA.
 

Results

The median follow up was 6.5 years. There were no significant differences between the surveillance groups with regard to 5-year overall survival (P = .340) or recurrence-free survival (P = .473).

There were no significant differences in recurrence-free or overall survival when patients were stratified by age, sex, stage, CEA at a cut point of 5 mcg/L, and primary tumor characteristics including location, perineural invasion, and occlusion/perforation.

There were 356 recurrences in patients initially treated for colon cancer. CEA surveillance with or without CT scan was associated with an increased incidence of secondary resection with curative intent. The rate of secondary resection was 66.3% in the standard imaging with CEA arm, 59.5% in the CT plus CEA arm, 50.7% with CT imaging but no CEA, and 40.9% with standard imaging and no CEA (P = .0035).

The rates were similar among the 83 patients with recurrence after initial treatment for rectal cancer, but the between-arm differences were not significant. The rate of secondary resection with curative intent was 57.9% in the standard imaging with CEA arm, 47.8% in the CT plus CEA arm, 55% with CT imaging but no CEA, and 42.9% with standard imaging and no CEA.

The research is ongoing, and the team expects to report on secondary outcomes and ancillary studies of circulating tumor DNA, among other things, in 2021.

The study is being funded by the Federation Francophone de Cancerologie Digestive. Dr. Lepage disclosed ties with Novartis, Amgen, Bayer, Servier, and AAA. Dr. Price disclosed institutional research funding from Amgen and being an uncompensated adviser to Pierre-Fabre and Merck.

[email protected]

SOURCE: Lepage C et al. ESMO 2020, Abstract 398O.

Intensive surveillance with carcinoembryonic antigen (CEA) testing and CT scans after colorectal cancer resection did not improve recurrence-free or overall survival when compared with standard abdominal ultrasound and chest x-ray monitoring in a phase 3 trial of almost 2,000 patients.

However, among patients with colon cancer recurrence, those randomized to intensive surveillance more often had a second surgery with curative intent. Even so, there was no overall survival benefit versus standard surveillance in this group.

In short, “none of the follow-up modalities resulted in a difference,” said investigator Come Lepage, MD, PhD, of Centre Hospitalier Universitaire de Dijon (France).

Dr. Lepage presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

Dr. Lepage said the study’s results suggest guidelines that include CT and CEA monitoring should be amended, and the standard surveillance methods should be ultrasound and chest x-ray. Dr. LePage called CEA surveillance “useless” and said CT scans should be performed only in cases of suspected recurrence.

However, study discussant Tim Price, MBBS, DHSc, of the University of Adelaide, noted that both the intensive and standard arms in this study had abdominal imaging every 3 months, be it ultrasound or CT, so even in the standard arms, surveillance “was still fairly aggressive.”

Because of that, the study does not “suggest we should decrease our intensity,” Dr. Price said.

He added that the study’s major finding was that more intensive surveillance led to higher rates of secondary surgery with curative intent, probably because recurrences were caught earlier than they would have been with standard surveillance, when curative surgery was still possible.

Patients in the study were treated during 2009-2015, and that might have also made a difference. “We need to remember that, in 2020, care is very different,” Dr. Price said. This includes increased surgical interventions and options for oligometastatic disease, plus systemic therapies such as pembrolizumab. With modern treatments, detecting recurrences earlier “may well have an impact on survival.”

Perhaps patients would live longer with “earlier diagnosis in today’s setting with more active agents and more aggressive surgery and radiotherapy [e.g., stereotactic ablative radiation therapy],” Dr. Price said in an interview.
 

Study details

The trial, dubbed PRODIGE 13, was done to bring clarity to the surveillance issue. Intensive follow-up after curative surgery for colorectal cancer, including CT and CEA monitoring, is recommended by various scientific societies, but it’s based mainly on expert opinion. Results of the few clinical trials on the issue have been controversial, Dr. Lepage explained.

PRODIGE 13 included 1,995 subjects with colorectal cancer. About half of patients had stage II disease, and the other half had stage III. Most patients were 75 years or younger at baseline, and there were more men in the study than women. All patients underwent resection with curative intent and had no evidence of residual disease 3 months after surgery. Some patients received adjuvant chemotherapy.

Patients were first randomized to no CEA monitoring or CEA monitoring every 3 months for the first 2 years, then every 6 months for an additional 3 years. Members in both groups were then randomized a second time to either intensive or standard radiologic surveillance.

Surveillance in the standard arm consisted of an abdominal ultrasound every 3 months for the first 3 years, then biannually for an additional 2 years, plus chest x-rays every 6 months for 5 years. Intensive surveillance consisted of CT imaging, including thoracic imaging, alternating with abdominal ultrasound, every 3 months, then biannually for another 2 years.

At baseline, the surveillance groups were well balanced with regard to demographics, primary tumor location, and other factors, but stage III disease was more prevalent among patients randomized to standard radiologic monitoring without CEA.
 

Results

The median follow up was 6.5 years. There were no significant differences between the surveillance groups with regard to 5-year overall survival (P = .340) or recurrence-free survival (P = .473).

There were no significant differences in recurrence-free or overall survival when patients were stratified by age, sex, stage, CEA at a cut point of 5 mcg/L, and primary tumor characteristics including location, perineural invasion, and occlusion/perforation.

There were 356 recurrences in patients initially treated for colon cancer. CEA surveillance with or without CT scan was associated with an increased incidence of secondary resection with curative intent. The rate of secondary resection was 66.3% in the standard imaging with CEA arm, 59.5% in the CT plus CEA arm, 50.7% with CT imaging but no CEA, and 40.9% with standard imaging and no CEA (P = .0035).

The rates were similar among the 83 patients with recurrence after initial treatment for rectal cancer, but the between-arm differences were not significant. The rate of secondary resection with curative intent was 57.9% in the standard imaging with CEA arm, 47.8% in the CT plus CEA arm, 55% with CT imaging but no CEA, and 42.9% with standard imaging and no CEA.

The research is ongoing, and the team expects to report on secondary outcomes and ancillary studies of circulating tumor DNA, among other things, in 2021.

The study is being funded by the Federation Francophone de Cancerologie Digestive. Dr. Lepage disclosed ties with Novartis, Amgen, Bayer, Servier, and AAA. Dr. Price disclosed institutional research funding from Amgen and being an uncompensated adviser to Pierre-Fabre and Merck.

[email protected]

SOURCE: Lepage C et al. ESMO 2020, Abstract 398O.

Atezolizumab failed to improve progression-free survival (PFS) when added to first-line bevacizumab plus chemotherapy in a phase 3 trial of patients with stage III/IV epithelial ovarian, primary peritoneal, or fallopian tube cancer.

“Despite notable success with the incorporation of bevacizumab and atezolizumab in the treatment of other solid tumors ... the first such study in ovarian cancer did not meet its first primary endpoint” of extending PFS in the intention-to-treat population or in patients positive for programmed death-ligand 1 (PD-L1), said investigator Kathleen Moore, MD, of the University of Oklahoma in Oklahoma City.

Dr. Moore presented this study, IMagyn050/GOG 3015/ENGOT-OV39, at the European Society for Medical Oncology Virtual Congress 2020.
 

Explaining the negative results

The rationale for this study was good, said discussant Isabelle Ray-Coquard, MD, PhD, of the University Claude Bernard Lyon I in Villeurbanne, France, who was an investigator on the study but not an author on the meeting report.

Unfortunately, the study’s results were ultimately negative. A prior phase 3 trial of an immune checkpoint inhibitor in ovarian cancer also had negative results. In the JAVELIN OVARIAN 100 trial, adding avelumab to chemotherapy did not improve PFS, and the trial was stopped early for futility.

Dr. Ray-Coquard posed the question of whether checkpoint inhibitors are “dead” for epithelial ovarian cancer but said the answer isn’t clear.

There might be something unique about the tumor microenvironment that shields ovarian cancer from the immune system, or perhaps the PD-L1 pathway is the wrong target for immunotherapy.

It might also be that the first-line setting is the wrong place for checkpoint inhibitors, and they might work better in the second line, Dr. Ray-Coquard said.

Another possibility is that the delayed effect of immunotherapy means that overall survival – which isn’t yet mature for IMagyn050 – might be a better primary outcome than PFS.
 

Patient and treatment details

IMagyn050 enrolled 1,301 patients with newly diagnosed, stage III/IV epithelial ovarian, primary peritoneal, or fallopian tube cancer.

Patients were randomized to atezolizumab (n = 651) or placebo (n = 650) in combination with bevacizumab, paclitaxel, and carboplatin every 3 weeks for six cycles. For cycles 7-22, patients received bevacizumab with placebo or atezolizumab.

Most patients had ovarian cancer (73% in the placebo arm and 75% in the atezolizumab arm), followed by fallopian tube cancer (17% and 15%, respectively) and primary peritoneal cancer (10% and 9%, respectively).

In both arms, 31% of patients had stage IV disease, and 60% were PD-L1 positive (at least 1% of tumor cells staining positive).

Treatment was given in the neoadjuvant setting for 25% of patients in both arms and after primary cytoreductive surgery for the remaining patients.
 

Efficacy and safety

In the intention-to-treat population, the median PFS was 19.5 months with atezolizumab and 18.4 months in the placebo arm. In PD-L1–positive patients, the median PFS was 20.8 months and 18.5 months, respectively.

The differences in PFS were not statistically significant or clinically meaningful, Dr. Ray-Coquard said.

She noted that results were not stratified by BRCA status, which has been linked to PFS in ovarian cancer, and a potential imbalance between the groups might have contributed to the negative results.

Overall survival data won’t be mature until 2023, but, in the first interim analysis, “there was no apparent difference in the curves,” Dr. Moore said.

In the intention-to-treat population, the median overall survival was not reached in either treatment arm. In the PD-L1–positive population, the median overall survival was 31.2 months in the placebo arm and was not reached in the atezolizumab arm.

Adverse events were consistent with the known safety profiles of atezolizumab and the other drugs, Dr. Moore said. There were more serious events and more events leading to discontinuation with atezolizumab.

Adverse events more common with atezolizumab included febrile neutropenia, pyrexia, thyroid abnormalities, and rash, including severe cutaneous reactions. Colitis, pancreatitis, and infusion-related reactions were relatively infrequent but more common with atezolizumab, Dr. Moore said.
 

What the future holds

Dr. Ray-Coquard said there are signals in IMagyn050 that warrant follow-up, including a trend toward improved PFS among women who had high-grade nonserous clear cell histology. In this group, the median PFS was 12.3 months in the placebo arm and 13.6 months in the atezolizumab arm (hazard ratio, 0.64).

Additionally, there was a significant PFS improvement in women with at least 5% of their tumor cells staining positive for PD-L1. The median PFS was 20.2 months in the placebo arm but was not reached in the atezolizumab arm (HR, 0.64; P = .0278).

Dr. Ray-Coquard said we need to know who these PD-L1–high patients are in terms of BRCA status, histology, and residual disease.

She went on to say that companies haven’t given up on checkpoint inhibitors for ovarian cancer. Phase 3 trials are testing the atezolizumab/bevacizumab/chemotherapy combination for late relapsed disease, atezolizumab with niraparib and chemotherapy for recurrent ovarian cancer, and nivolumab with rucaparib following response to chemotherapy.

The IMagyn050 study was funded by F. Hoffmann-La Roche, the company developing atezolizumab. Dr. Moore and Dr. Ray-Coquard disclosed relationships with Roche and many other companies.

[email protected]

SOURCE: Moore K et al. ESMO 2020, Abstract LBA31.

Atezolizumab failed to improve progression-free survival (PFS) when added to first-line bevacizumab plus chemotherapy in a phase 3 trial of patients with stage III/IV epithelial ovarian, primary peritoneal, or fallopian tube cancer.

“Despite notable success with the incorporation of bevacizumab and atezolizumab in the treatment of other solid tumors ... the first such study in ovarian cancer did not meet its first primary endpoint” of extending PFS in the intention-to-treat population or in patients positive for programmed death-ligand 1 (PD-L1), said investigator Kathleen Moore, MD, of the University of Oklahoma in Oklahoma City.

Dr. Moore presented this study, IMagyn050/GOG 3015/ENGOT-OV39, at the European Society for Medical Oncology Virtual Congress 2020.
 

Explaining the negative results

The rationale for this study was good, said discussant Isabelle Ray-Coquard, MD, PhD, of the University Claude Bernard Lyon I in Villeurbanne, France, who was an investigator on the study but not an author on the meeting report.

Unfortunately, the study’s results were ultimately negative. A prior phase 3 trial of an immune checkpoint inhibitor in ovarian cancer also had negative results. In the JAVELIN OVARIAN 100 trial, adding avelumab to chemotherapy did not improve PFS, and the trial was stopped early for futility.

Dr. Ray-Coquard posed the question of whether checkpoint inhibitors are “dead” for epithelial ovarian cancer but said the answer isn’t clear.

There might be something unique about the tumor microenvironment that shields ovarian cancer from the immune system, or perhaps the PD-L1 pathway is the wrong target for immunotherapy.

It might also be that the first-line setting is the wrong place for checkpoint inhibitors, and they might work better in the second line, Dr. Ray-Coquard said.

Another possibility is that the delayed effect of immunotherapy means that overall survival – which isn’t yet mature for IMagyn050 – might be a better primary outcome than PFS.
 

Patient and treatment details

IMagyn050 enrolled 1,301 patients with newly diagnosed, stage III/IV epithelial ovarian, primary peritoneal, or fallopian tube cancer.

Patients were randomized to atezolizumab (n = 651) or placebo (n = 650) in combination with bevacizumab, paclitaxel, and carboplatin every 3 weeks for six cycles. For cycles 7-22, patients received bevacizumab with placebo or atezolizumab.

Most patients had ovarian cancer (73% in the placebo arm and 75% in the atezolizumab arm), followed by fallopian tube cancer (17% and 15%, respectively) and primary peritoneal cancer (10% and 9%, respectively).

In both arms, 31% of patients had stage IV disease, and 60% were PD-L1 positive (at least 1% of tumor cells staining positive).

Treatment was given in the neoadjuvant setting for 25% of patients in both arms and after primary cytoreductive surgery for the remaining patients.
 

Efficacy and safety

In the intention-to-treat population, the median PFS was 19.5 months with atezolizumab and 18.4 months in the placebo arm. In PD-L1–positive patients, the median PFS was 20.8 months and 18.5 months, respectively.

The differences in PFS were not statistically significant or clinically meaningful, Dr. Ray-Coquard said.

She noted that results were not stratified by BRCA status, which has been linked to PFS in ovarian cancer, and a potential imbalance between the groups might have contributed to the negative results.

Overall survival data won’t be mature until 2023, but, in the first interim analysis, “there was no apparent difference in the curves,” Dr. Moore said.

In the intention-to-treat population, the median overall survival was not reached in either treatment arm. In the PD-L1–positive population, the median overall survival was 31.2 months in the placebo arm and was not reached in the atezolizumab arm.

Adverse events were consistent with the known safety profiles of atezolizumab and the other drugs, Dr. Moore said. There were more serious events and more events leading to discontinuation with atezolizumab.

Adverse events more common with atezolizumab included febrile neutropenia, pyrexia, thyroid abnormalities, and rash, including severe cutaneous reactions. Colitis, pancreatitis, and infusion-related reactions were relatively infrequent but more common with atezolizumab, Dr. Moore said.
 

What the future holds

Dr. Ray-Coquard said there are signals in IMagyn050 that warrant follow-up, including a trend toward improved PFS among women who had high-grade nonserous clear cell histology. In this group, the median PFS was 12.3 months in the placebo arm and 13.6 months in the atezolizumab arm (hazard ratio, 0.64).

Additionally, there was a significant PFS improvement in women with at least 5% of their tumor cells staining positive for PD-L1. The median PFS was 20.2 months in the placebo arm but was not reached in the atezolizumab arm (HR, 0.64; P = .0278).

Dr. Ray-Coquard said we need to know who these PD-L1–high patients are in terms of BRCA status, histology, and residual disease.

She went on to say that companies haven’t given up on checkpoint inhibitors for ovarian cancer. Phase 3 trials are testing the atezolizumab/bevacizumab/chemotherapy combination for late relapsed disease, atezolizumab with niraparib and chemotherapy for recurrent ovarian cancer, and nivolumab with rucaparib following response to chemotherapy.

The IMagyn050 study was funded by F. Hoffmann-La Roche, the company developing atezolizumab. Dr. Moore and Dr. Ray-Coquard disclosed relationships with Roche and many other companies.

[email protected]

SOURCE: Moore K et al. ESMO 2020, Abstract LBA31.

Atezolizumab failed to improve progression-free survival (PFS) when added to first-line bevacizumab plus chemotherapy in a phase 3 trial of patients with stage III/IV epithelial ovarian, primary peritoneal, or fallopian tube cancer.

“Despite notable success with the incorporation of bevacizumab and atezolizumab in the treatment of other solid tumors ... the first such study in ovarian cancer did not meet its first primary endpoint” of extending PFS in the intention-to-treat population or in patients positive for programmed death-ligand 1 (PD-L1), said investigator Kathleen Moore, MD, of the University of Oklahoma in Oklahoma City.

Dr. Moore presented this study, IMagyn050/GOG 3015/ENGOT-OV39, at the European Society for Medical Oncology Virtual Congress 2020.
 

Explaining the negative results

The rationale for this study was good, said discussant Isabelle Ray-Coquard, MD, PhD, of the University Claude Bernard Lyon I in Villeurbanne, France, who was an investigator on the study but not an author on the meeting report.

Unfortunately, the study’s results were ultimately negative. A prior phase 3 trial of an immune checkpoint inhibitor in ovarian cancer also had negative results. In the JAVELIN OVARIAN 100 trial, adding avelumab to chemotherapy did not improve PFS, and the trial was stopped early for futility.

Dr. Ray-Coquard posed the question of whether checkpoint inhibitors are “dead” for epithelial ovarian cancer but said the answer isn’t clear.

There might be something unique about the tumor microenvironment that shields ovarian cancer from the immune system, or perhaps the PD-L1 pathway is the wrong target for immunotherapy.

It might also be that the first-line setting is the wrong place for checkpoint inhibitors, and they might work better in the second line, Dr. Ray-Coquard said.

Another possibility is that the delayed effect of immunotherapy means that overall survival – which isn’t yet mature for IMagyn050 – might be a better primary outcome than PFS.
 

Patient and treatment details

IMagyn050 enrolled 1,301 patients with newly diagnosed, stage III/IV epithelial ovarian, primary peritoneal, or fallopian tube cancer.

Patients were randomized to atezolizumab (n = 651) or placebo (n = 650) in combination with bevacizumab, paclitaxel, and carboplatin every 3 weeks for six cycles. For cycles 7-22, patients received bevacizumab with placebo or atezolizumab.

Most patients had ovarian cancer (73% in the placebo arm and 75% in the atezolizumab arm), followed by fallopian tube cancer (17% and 15%, respectively) and primary peritoneal cancer (10% and 9%, respectively).

In both arms, 31% of patients had stage IV disease, and 60% were PD-L1 positive (at least 1% of tumor cells staining positive).

Treatment was given in the neoadjuvant setting for 25% of patients in both arms and after primary cytoreductive surgery for the remaining patients.
 

Efficacy and safety

In the intention-to-treat population, the median PFS was 19.5 months with atezolizumab and 18.4 months in the placebo arm. In PD-L1–positive patients, the median PFS was 20.8 months and 18.5 months, respectively.

The differences in PFS were not statistically significant or clinically meaningful, Dr. Ray-Coquard said.

She noted that results were not stratified by BRCA status, which has been linked to PFS in ovarian cancer, and a potential imbalance between the groups might have contributed to the negative results.

Overall survival data won’t be mature until 2023, but, in the first interim analysis, “there was no apparent difference in the curves,” Dr. Moore said.

In the intention-to-treat population, the median overall survival was not reached in either treatment arm. In the PD-L1–positive population, the median overall survival was 31.2 months in the placebo arm and was not reached in the atezolizumab arm.

Adverse events were consistent with the known safety profiles of atezolizumab and the other drugs, Dr. Moore said. There were more serious events and more events leading to discontinuation with atezolizumab.

Adverse events more common with atezolizumab included febrile neutropenia, pyrexia, thyroid abnormalities, and rash, including severe cutaneous reactions. Colitis, pancreatitis, and infusion-related reactions were relatively infrequent but more common with atezolizumab, Dr. Moore said.
 

What the future holds

Dr. Ray-Coquard said there are signals in IMagyn050 that warrant follow-up, including a trend toward improved PFS among women who had high-grade nonserous clear cell histology. In this group, the median PFS was 12.3 months in the placebo arm and 13.6 months in the atezolizumab arm (hazard ratio, 0.64).

Additionally, there was a significant PFS improvement in women with at least 5% of their tumor cells staining positive for PD-L1. The median PFS was 20.2 months in the placebo arm but was not reached in the atezolizumab arm (HR, 0.64; P = .0278).

Dr. Ray-Coquard said we need to know who these PD-L1–high patients are in terms of BRCA status, histology, and residual disease.

She went on to say that companies haven’t given up on checkpoint inhibitors for ovarian cancer. Phase 3 trials are testing the atezolizumab/bevacizumab/chemotherapy combination for late relapsed disease, atezolizumab with niraparib and chemotherapy for recurrent ovarian cancer, and nivolumab with rucaparib following response to chemotherapy.

The IMagyn050 study was funded by F. Hoffmann-La Roche, the company developing atezolizumab. Dr. Moore and Dr. Ray-Coquard disclosed relationships with Roche and many other companies.

[email protected]

SOURCE: Moore K et al. ESMO 2020, Abstract LBA31.

A higher dose of thoracic radiotherapy (TRT) may improve overall survival in limited-stage small-cell lung cancer (LS-SCLC), but it’s not clear if this dose should become the new standard of care.

In a phase 2 trial, the 2-year overall survival rate was 51.3% when twice-daily TRT was given at a dose of 45 Gy in 30 fractions and 75% when it was given at a dose of 60 Gy in 40 fractions in patients with LS-SCLC. The two treatment arms had similar safety and quality of life outcomes.

The higher dose “did not add toxicity,” a significant concern with higher radiation doses, said Bjorn Gronberg, MD, PhD, of the Norwegian University of Science and Technology in Trondheim, when presenting this study at the European Society for Medical Oncology Virtual Congress 2020.

However, the discussant for this study pointed out several limitations of the trial and concluded that the 45 Gy dose should remain the standard of care.

Dr. Gonberg explained that concurrent platinum/etoposide (PE) chemotherapy and TRT is the standard treatment for LS-SCLC, and the most recommended schedule for TRT is twice daily at 45 Gy in 30 fractions. He noted, however, that “there’s clearly a need for better treatment” because less than 30% of patients are cured.

“We hypothesized that increasing the dose of radiotherapy might improve survival,” he said.
 

Study details

Dr. Gonberg and colleagues conducted a phase 2 trial of patients with stage I-III SCLC confined to one hemithorax plus regional lymph nodes. The trial enrolled 176 patients and randomized 170 of them.

The patients received four courses of PE 3 weeks apart. For TRT, 81 patients were randomized to 45 Gy in 30 fractions, and 89 patients were randomized to 60 Gy in 40 fractions, with 10 fractions per week starting with the second PE course.

All patients who responded to chemoradiotherapy were offered prophylactic cranial irradiation at 25 Gy in 10 fractions or 30 Gy in 15 fractions.

Baseline characteristics were well balanced between the treatment arms. The median age was 65 years in both arms, and most patients were women (60.5% in the 45 Gy arm and 56% in the 60 Gy arm).

The mean number of chemotherapy courses was 3.8 in each arm, about 85% of patients received prophylactic cranial radiation, and roughly half received second-line chemotherapy. Overall, 73 patients completed TRT in the 45 Gy arm, and 81 completed TRT in the 60 Gy arm.
 

Efficacy

There was no significant difference in overall response rate between the treatment arms. It was 81.6% in the 45 Gy arm and 82.1% in the 60 Gy arm (P = .81).

Similarly, there was no significant difference in progression-free survival. The median progression-free survival was 11.1 months in the lower-dose arm and 18.7 months in the higher-dose arm (P = .22).

Still, there was a significant difference in overall survival between the arms. The 2-year overall survival rate was 51.3% in the lower-dose arm and 75% in the higher-dose arm (P = .002). The median overall survival was 24 months and 37.2 months, respectively (P = .034).

Discussant Corinne Faivre-Finn, MD, PhD, of the University of Manchester (England), cautioned that the lower-dose arm appeared to underperform, compared with prior research.

Additionally, “the survival curves separate at about 9 months, [with a] significant difference at 2 years, but the survival curves are coming back together at around 5 years, and that shows that there is a small difference in terms of long-term cure,” she said.
 

Safety

There were no significant differences in toxicity between the treatment arms.

Dr. Gronberg noted that esophagitis is considered the main dose-limiting toxicity with TRT, but there was no difference in incidence between the two arms (P = .916). Grade 3 esophagitis occurred in 18.4% of patients in the lower-dose arm and 19% of those in the higher-dose arm. There was no grade 4 esophagitis.

Rates of grade 3 and 4 neutropenic infections were higher in the lower-dose arm than in the higher-dose arm, but the difference was not statistically significant (P = .08).

There were also no significant differences in quality of life surveys that patients filled out periodically from baseline until week 52.

“Not so surprisingly,” Dr. Gronberg said, dysphagia was more common at the end of TRT. However, patients had recovered to baseline levels at week 22.

“There’s no difference in the maximum dysphagia reported between the treatment arms, but ... patients in the high-dose arm needed longer time to recover from dysphagia,” Dr. Gronberg said.

Scores for dyspnea, physical function, and global quality of life were similar between the treatment arms.

The similar toxicity between the arms “is quite puzzling,” Dr. Faivre-Finn said, given the 33% increase in radiation dose in the experimental arm. She said this “probably points out an imbalance in some of the factors” between the groups, including tumor volume and doses to organs at risk, which were not reported.

“There are some important missing data, in terms of interpretation of results,” she said.

Given the limitations, and the fact that the study population was relatively small, Dr. Faivre-Finn said “the results cannot be considered definitive and practice changing,” pending additional study.

“So my final conclusion is that twice-a-day radiotherapy at a dose of 45 Gy remains the standard of care, as recommended in the recently published ASTRO [American Society for Radiation Oncology] guidelines,” Dr. Faivre-Finn said.

The study was funded by the Norwegian Cancer Society, the Nordic Cancer Union, and the Norwegian University of Science and Technology. Dr. Gronberg disclosed relationships with Pfizer, Roche, Eli Lilly, and other companies. Dr. Faivre-Finn disclosed relationships with AstraZeneca, Merck, Pfizer, Elekta, and Boehringer Ingelheim.

[email protected]

SOURCE: Gronberg B et al. ESMO 2020, Abstract 1783O.

A higher dose of thoracic radiotherapy (TRT) may improve overall survival in limited-stage small-cell lung cancer (LS-SCLC), but it’s not clear if this dose should become the new standard of care.

In a phase 2 trial, the 2-year overall survival rate was 51.3% when twice-daily TRT was given at a dose of 45 Gy in 30 fractions and 75% when it was given at a dose of 60 Gy in 40 fractions in patients with LS-SCLC. The two treatment arms had similar safety and quality of life outcomes.

The higher dose “did not add toxicity,” a significant concern with higher radiation doses, said Bjorn Gronberg, MD, PhD, of the Norwegian University of Science and Technology in Trondheim, when presenting this study at the European Society for Medical Oncology Virtual Congress 2020.

However, the discussant for this study pointed out several limitations of the trial and concluded that the 45 Gy dose should remain the standard of care.

Dr. Gonberg explained that concurrent platinum/etoposide (PE) chemotherapy and TRT is the standard treatment for LS-SCLC, and the most recommended schedule for TRT is twice daily at 45 Gy in 30 fractions. He noted, however, that “there’s clearly a need for better treatment” because less than 30% of patients are cured.

“We hypothesized that increasing the dose of radiotherapy might improve survival,” he said.
 

Study details

Dr. Gonberg and colleagues conducted a phase 2 trial of patients with stage I-III SCLC confined to one hemithorax plus regional lymph nodes. The trial enrolled 176 patients and randomized 170 of them.

The patients received four courses of PE 3 weeks apart. For TRT, 81 patients were randomized to 45 Gy in 30 fractions, and 89 patients were randomized to 60 Gy in 40 fractions, with 10 fractions per week starting with the second PE course.

All patients who responded to chemoradiotherapy were offered prophylactic cranial irradiation at 25 Gy in 10 fractions or 30 Gy in 15 fractions.

Baseline characteristics were well balanced between the treatment arms. The median age was 65 years in both arms, and most patients were women (60.5% in the 45 Gy arm and 56% in the 60 Gy arm).

The mean number of chemotherapy courses was 3.8 in each arm, about 85% of patients received prophylactic cranial radiation, and roughly half received second-line chemotherapy. Overall, 73 patients completed TRT in the 45 Gy arm, and 81 completed TRT in the 60 Gy arm.
 

Efficacy

There was no significant difference in overall response rate between the treatment arms. It was 81.6% in the 45 Gy arm and 82.1% in the 60 Gy arm (P = .81).

Similarly, there was no significant difference in progression-free survival. The median progression-free survival was 11.1 months in the lower-dose arm and 18.7 months in the higher-dose arm (P = .22).

Still, there was a significant difference in overall survival between the arms. The 2-year overall survival rate was 51.3% in the lower-dose arm and 75% in the higher-dose arm (P = .002). The median overall survival was 24 months and 37.2 months, respectively (P = .034).

Discussant Corinne Faivre-Finn, MD, PhD, of the University of Manchester (England), cautioned that the lower-dose arm appeared to underperform, compared with prior research.

Additionally, “the survival curves separate at about 9 months, [with a] significant difference at 2 years, but the survival curves are coming back together at around 5 years, and that shows that there is a small difference in terms of long-term cure,” she said.
 

Safety

There were no significant differences in toxicity between the treatment arms.

Dr. Gronberg noted that esophagitis is considered the main dose-limiting toxicity with TRT, but there was no difference in incidence between the two arms (P = .916). Grade 3 esophagitis occurred in 18.4% of patients in the lower-dose arm and 19% of those in the higher-dose arm. There was no grade 4 esophagitis.

Rates of grade 3 and 4 neutropenic infections were higher in the lower-dose arm than in the higher-dose arm, but the difference was not statistically significant (P = .08).

There were also no significant differences in quality of life surveys that patients filled out periodically from baseline until week 52.

“Not so surprisingly,” Dr. Gronberg said, dysphagia was more common at the end of TRT. However, patients had recovered to baseline levels at week 22.

“There’s no difference in the maximum dysphagia reported between the treatment arms, but ... patients in the high-dose arm needed longer time to recover from dysphagia,” Dr. Gronberg said.

Scores for dyspnea, physical function, and global quality of life were similar between the treatment arms.

The similar toxicity between the arms “is quite puzzling,” Dr. Faivre-Finn said, given the 33% increase in radiation dose in the experimental arm. She said this “probably points out an imbalance in some of the factors” between the groups, including tumor volume and doses to organs at risk, which were not reported.

“There are some important missing data, in terms of interpretation of results,” she said.

Given the limitations, and the fact that the study population was relatively small, Dr. Faivre-Finn said “the results cannot be considered definitive and practice changing,” pending additional study.

“So my final conclusion is that twice-a-day radiotherapy at a dose of 45 Gy remains the standard of care, as recommended in the recently published ASTRO [American Society for Radiation Oncology] guidelines,” Dr. Faivre-Finn said.

The study was funded by the Norwegian Cancer Society, the Nordic Cancer Union, and the Norwegian University of Science and Technology. Dr. Gronberg disclosed relationships with Pfizer, Roche, Eli Lilly, and other companies. Dr. Faivre-Finn disclosed relationships with AstraZeneca, Merck, Pfizer, Elekta, and Boehringer Ingelheim.

[email protected]

SOURCE: Gronberg B et al. ESMO 2020, Abstract 1783O.

A higher dose of thoracic radiotherapy (TRT) may improve overall survival in limited-stage small-cell lung cancer (LS-SCLC), but it’s not clear if this dose should become the new standard of care.

In a phase 2 trial, the 2-year overall survival rate was 51.3% when twice-daily TRT was given at a dose of 45 Gy in 30 fractions and 75% when it was given at a dose of 60 Gy in 40 fractions in patients with LS-SCLC. The two treatment arms had similar safety and quality of life outcomes.

The higher dose “did not add toxicity,” a significant concern with higher radiation doses, said Bjorn Gronberg, MD, PhD, of the Norwegian University of Science and Technology in Trondheim, when presenting this study at the European Society for Medical Oncology Virtual Congress 2020.

However, the discussant for this study pointed out several limitations of the trial and concluded that the 45 Gy dose should remain the standard of care.

Dr. Gonberg explained that concurrent platinum/etoposide (PE) chemotherapy and TRT is the standard treatment for LS-SCLC, and the most recommended schedule for TRT is twice daily at 45 Gy in 30 fractions. He noted, however, that “there’s clearly a need for better treatment” because less than 30% of patients are cured.

“We hypothesized that increasing the dose of radiotherapy might improve survival,” he said.
 

Study details

Dr. Gonberg and colleagues conducted a phase 2 trial of patients with stage I-III SCLC confined to one hemithorax plus regional lymph nodes. The trial enrolled 176 patients and randomized 170 of them.

The patients received four courses of PE 3 weeks apart. For TRT, 81 patients were randomized to 45 Gy in 30 fractions, and 89 patients were randomized to 60 Gy in 40 fractions, with 10 fractions per week starting with the second PE course.

All patients who responded to chemoradiotherapy were offered prophylactic cranial irradiation at 25 Gy in 10 fractions or 30 Gy in 15 fractions.

Baseline characteristics were well balanced between the treatment arms. The median age was 65 years in both arms, and most patients were women (60.5% in the 45 Gy arm and 56% in the 60 Gy arm).

The mean number of chemotherapy courses was 3.8 in each arm, about 85% of patients received prophylactic cranial radiation, and roughly half received second-line chemotherapy. Overall, 73 patients completed TRT in the 45 Gy arm, and 81 completed TRT in the 60 Gy arm.
 

Efficacy

There was no significant difference in overall response rate between the treatment arms. It was 81.6% in the 45 Gy arm and 82.1% in the 60 Gy arm (P = .81).

Similarly, there was no significant difference in progression-free survival. The median progression-free survival was 11.1 months in the lower-dose arm and 18.7 months in the higher-dose arm (P = .22).

Still, there was a significant difference in overall survival between the arms. The 2-year overall survival rate was 51.3% in the lower-dose arm and 75% in the higher-dose arm (P = .002). The median overall survival was 24 months and 37.2 months, respectively (P = .034).

Discussant Corinne Faivre-Finn, MD, PhD, of the University of Manchester (England), cautioned that the lower-dose arm appeared to underperform, compared with prior research.

Additionally, “the survival curves separate at about 9 months, [with a] significant difference at 2 years, but the survival curves are coming back together at around 5 years, and that shows that there is a small difference in terms of long-term cure,” she said.
 

Safety

There were no significant differences in toxicity between the treatment arms.

Dr. Gronberg noted that esophagitis is considered the main dose-limiting toxicity with TRT, but there was no difference in incidence between the two arms (P = .916). Grade 3 esophagitis occurred in 18.4% of patients in the lower-dose arm and 19% of those in the higher-dose arm. There was no grade 4 esophagitis.

Rates of grade 3 and 4 neutropenic infections were higher in the lower-dose arm than in the higher-dose arm, but the difference was not statistically significant (P = .08).

There were also no significant differences in quality of life surveys that patients filled out periodically from baseline until week 52.

“Not so surprisingly,” Dr. Gronberg said, dysphagia was more common at the end of TRT. However, patients had recovered to baseline levels at week 22.

“There’s no difference in the maximum dysphagia reported between the treatment arms, but ... patients in the high-dose arm needed longer time to recover from dysphagia,” Dr. Gronberg said.

Scores for dyspnea, physical function, and global quality of life were similar between the treatment arms.

The similar toxicity between the arms “is quite puzzling,” Dr. Faivre-Finn said, given the 33% increase in radiation dose in the experimental arm. She said this “probably points out an imbalance in some of the factors” between the groups, including tumor volume and doses to organs at risk, which were not reported.

“There are some important missing data, in terms of interpretation of results,” she said.

Given the limitations, and the fact that the study population was relatively small, Dr. Faivre-Finn said “the results cannot be considered definitive and practice changing,” pending additional study.

“So my final conclusion is that twice-a-day radiotherapy at a dose of 45 Gy remains the standard of care, as recommended in the recently published ASTRO [American Society for Radiation Oncology] guidelines,” Dr. Faivre-Finn said.

The study was funded by the Norwegian Cancer Society, the Nordic Cancer Union, and the Norwegian University of Science and Technology. Dr. Gronberg disclosed relationships with Pfizer, Roche, Eli Lilly, and other companies. Dr. Faivre-Finn disclosed relationships with AstraZeneca, Merck, Pfizer, Elekta, and Boehringer Ingelheim.

[email protected]

SOURCE: Gronberg B et al. ESMO 2020, Abstract 1783O.

Quadrivalent human papillomavirus (HPV) vaccination was associated with a substantial reduction in the incidence of cervical cancer in a Swedish review of more than 1 million girls and women vaccinated from 2006 to 2017.

It’s been shown that the vaccine (Gardasil) helps prevent genital warts and high-grade cervical lesions, but until now, data on the ability of the vaccine to prevent cervical cancer, although widely assumed, had been lacking.

“Our results extend [the] knowledge base by showing that quadrivalent HPV vaccination is also associated with a substantially reduced risk of invasive cervical cancer, which is the ultimate intent of HPV vaccination programs,” said investigators led by Jiayao Lei, PhD, a researcher in the department of medical epidemiology and biostatistics at the Karolinska Institute, Stockholm.

The study was published online Oct. 1 in the New England Journal of Medicine.

“This work provides evidence of actual cancer prevention,” commented Diane Harper, MD, an HPV expert and professor in the departments of family medicine and obstetrics & gynecology at the University of Michigan, Ann Arbor. She was the principal investigator on the original Gardasil trial.

This study “shows that the quadrivalent HPV vaccine provides prevention from the sexually transmitted HPV infection that actually reduces the incidence of cervical cancer in young women up to 30 years of age,” she said when approached for comment.

However, she also added a note of caution. These new results show “that vaccinated women still develop cervical cancer, but at a slower rate. This makes the connection between early-age vaccination and continued adult life screening incredibly important,” Dr. Harper said in an interview

Cervical cancer was diagnosed in 19 of the 527,871 women (0.004%) who had received at least one dose of the vaccine versus 538 among the 1,145,112 women (0.05%) who had not.

The cumulative incidence was 47 cases per 100,000 vaccinated women and 94 cases per 100,000 unvaccinated women. The cervical cancer incidence rate ratio for the comparison of vaccinated versus unvaccinated women was 0.37 (95% confidence interval, 0.21-0.57).

The risk reduction was even greater among women who had been vaccinated before the age of 17, with a cumulative incidence of 4 versus 54 cases per 100,000 for women vaccinated after age 17. The incidence rate ratio was 0.12 (95% CI, 0.00-0.34) for women who had been vaccinated before age 17 versus 0.47 (95% CI, 0.27-0.75) among those vaccinated from age 17 to 30 years.

Overall, “the risk of cervical cancer among participants who had initiated vaccination before the age of 17 years was 88% lower than among those who had never been vaccinated,” the investigators noted.

These results “support the recommendation to administer quadrivalent HPV vaccine before exposure to HPV infection to achieve the most substantial benefit,” the investigators wrote.
 

Details of the Swedish review

For their review, Dr. Lei and colleagues used several Swedish demographic and health registries to connect vaccination status to incident cervical cancers, using the personal identification numbers Sweden issues to residents.

Participants were followed starting either on their 10th birthday or on Jan. 1, 2006, whichever came later. They were followed until, among other things, diagnosis of invasive cervical cancer; their 31st birthday; or until Dec. 31, 2017, whichever came first.

The quadrivalent HPV vaccine, approved in Sweden in 2006, was used almost exclusively during the study period. Participants were considered vaccinated if they had received only one shot, but the investigators set out to analyze a relationship between the incidence of invasive cervical cancer and the number of shots given.

Among other things, the team controlled for age at follow-up, calendar year, county of residence, maternal disease history, and parental characteristics, including education and household income.

The investigators commented that it’s possible that HPV-vaccinated women could have been generally healthier than unvaccinated women and so would have been at lower risk for cervical cancer.

“Confounding by lifestyle and health factors in the women (such as smoking status, sexual activity, oral contraceptive use, and obesity) cannot be excluded; these factors are known to be associated with a risk of cervical cancer,” the investigators wrote.

HPV is also associated with other types of cancer, including anal and oropharyngeal cancers. But these cancers develop over a longer period than cervical cancer.

Dr. Harper noted that the “probability of HPV 16 cancer by time since infection peaks at 40 years after infection for anal cancers and nearly 50 years after infection for oropharyngeal cancers. This means that registries, such as in Sweden, for the next 40 years will record the evidence to say whether HPV vaccination lasts long enough to prevent [these] other HPV 16–associated cancers occurring at a much later time in life.”

The work was funded by the Swedish Foundation for Strategic Research, the Swedish Cancer Society, and the Swedish Research Council and by the China Scholarship Council. Dr. Lei and two other investigators reported HPV vaccine research funding from Merck, the maker of Gardasil. Harper disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Quadrivalent human papillomavirus (HPV) vaccination was associated with a substantial reduction in the incidence of cervical cancer in a Swedish review of more than 1 million girls and women vaccinated from 2006 to 2017.

It’s been shown that the vaccine (Gardasil) helps prevent genital warts and high-grade cervical lesions, but until now, data on the ability of the vaccine to prevent cervical cancer, although widely assumed, had been lacking.

“Our results extend [the] knowledge base by showing that quadrivalent HPV vaccination is also associated with a substantially reduced risk of invasive cervical cancer, which is the ultimate intent of HPV vaccination programs,” said investigators led by Jiayao Lei, PhD, a researcher in the department of medical epidemiology and biostatistics at the Karolinska Institute, Stockholm.

The study was published online Oct. 1 in the New England Journal of Medicine.

“This work provides evidence of actual cancer prevention,” commented Diane Harper, MD, an HPV expert and professor in the departments of family medicine and obstetrics & gynecology at the University of Michigan, Ann Arbor. She was the principal investigator on the original Gardasil trial.

This study “shows that the quadrivalent HPV vaccine provides prevention from the sexually transmitted HPV infection that actually reduces the incidence of cervical cancer in young women up to 30 years of age,” she said when approached for comment.

However, she also added a note of caution. These new results show “that vaccinated women still develop cervical cancer, but at a slower rate. This makes the connection between early-age vaccination and continued adult life screening incredibly important,” Dr. Harper said in an interview

Cervical cancer was diagnosed in 19 of the 527,871 women (0.004%) who had received at least one dose of the vaccine versus 538 among the 1,145,112 women (0.05%) who had not.

The cumulative incidence was 47 cases per 100,000 vaccinated women and 94 cases per 100,000 unvaccinated women. The cervical cancer incidence rate ratio for the comparison of vaccinated versus unvaccinated women was 0.37 (95% confidence interval, 0.21-0.57).

The risk reduction was even greater among women who had been vaccinated before the age of 17, with a cumulative incidence of 4 versus 54 cases per 100,000 for women vaccinated after age 17. The incidence rate ratio was 0.12 (95% CI, 0.00-0.34) for women who had been vaccinated before age 17 versus 0.47 (95% CI, 0.27-0.75) among those vaccinated from age 17 to 30 years.

Overall, “the risk of cervical cancer among participants who had initiated vaccination before the age of 17 years was 88% lower than among those who had never been vaccinated,” the investigators noted.

These results “support the recommendation to administer quadrivalent HPV vaccine before exposure to HPV infection to achieve the most substantial benefit,” the investigators wrote.
 

Details of the Swedish review

For their review, Dr. Lei and colleagues used several Swedish demographic and health registries to connect vaccination status to incident cervical cancers, using the personal identification numbers Sweden issues to residents.

Participants were followed starting either on their 10th birthday or on Jan. 1, 2006, whichever came later. They were followed until, among other things, diagnosis of invasive cervical cancer; their 31st birthday; or until Dec. 31, 2017, whichever came first.

The quadrivalent HPV vaccine, approved in Sweden in 2006, was used almost exclusively during the study period. Participants were considered vaccinated if they had received only one shot, but the investigators set out to analyze a relationship between the incidence of invasive cervical cancer and the number of shots given.

Among other things, the team controlled for age at follow-up, calendar year, county of residence, maternal disease history, and parental characteristics, including education and household income.

The investigators commented that it’s possible that HPV-vaccinated women could have been generally healthier than unvaccinated women and so would have been at lower risk for cervical cancer.

“Confounding by lifestyle and health factors in the women (such as smoking status, sexual activity, oral contraceptive use, and obesity) cannot be excluded; these factors are known to be associated with a risk of cervical cancer,” the investigators wrote.

HPV is also associated with other types of cancer, including anal and oropharyngeal cancers. But these cancers develop over a longer period than cervical cancer.

Dr. Harper noted that the “probability of HPV 16 cancer by time since infection peaks at 40 years after infection for anal cancers and nearly 50 years after infection for oropharyngeal cancers. This means that registries, such as in Sweden, for the next 40 years will record the evidence to say whether HPV vaccination lasts long enough to prevent [these] other HPV 16–associated cancers occurring at a much later time in life.”

The work was funded by the Swedish Foundation for Strategic Research, the Swedish Cancer Society, and the Swedish Research Council and by the China Scholarship Council. Dr. Lei and two other investigators reported HPV vaccine research funding from Merck, the maker of Gardasil. Harper disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Quadrivalent human papillomavirus (HPV) vaccination was associated with a substantial reduction in the incidence of cervical cancer in a Swedish review of more than 1 million girls and women vaccinated from 2006 to 2017.

It’s been shown that the vaccine (Gardasil) helps prevent genital warts and high-grade cervical lesions, but until now, data on the ability of the vaccine to prevent cervical cancer, although widely assumed, had been lacking.

“Our results extend [the] knowledge base by showing that quadrivalent HPV vaccination is also associated with a substantially reduced risk of invasive cervical cancer, which is the ultimate intent of HPV vaccination programs,” said investigators led by Jiayao Lei, PhD, a researcher in the department of medical epidemiology and biostatistics at the Karolinska Institute, Stockholm.

The study was published online Oct. 1 in the New England Journal of Medicine.

“This work provides evidence of actual cancer prevention,” commented Diane Harper, MD, an HPV expert and professor in the departments of family medicine and obstetrics & gynecology at the University of Michigan, Ann Arbor. She was the principal investigator on the original Gardasil trial.

This study “shows that the quadrivalent HPV vaccine provides prevention from the sexually transmitted HPV infection that actually reduces the incidence of cervical cancer in young women up to 30 years of age,” she said when approached for comment.

However, she also added a note of caution. These new results show “that vaccinated women still develop cervical cancer, but at a slower rate. This makes the connection between early-age vaccination and continued adult life screening incredibly important,” Dr. Harper said in an interview

Cervical cancer was diagnosed in 19 of the 527,871 women (0.004%) who had received at least one dose of the vaccine versus 538 among the 1,145,112 women (0.05%) who had not.

The cumulative incidence was 47 cases per 100,000 vaccinated women and 94 cases per 100,000 unvaccinated women. The cervical cancer incidence rate ratio for the comparison of vaccinated versus unvaccinated women was 0.37 (95% confidence interval, 0.21-0.57).

The risk reduction was even greater among women who had been vaccinated before the age of 17, with a cumulative incidence of 4 versus 54 cases per 100,000 for women vaccinated after age 17. The incidence rate ratio was 0.12 (95% CI, 0.00-0.34) for women who had been vaccinated before age 17 versus 0.47 (95% CI, 0.27-0.75) among those vaccinated from age 17 to 30 years.

Overall, “the risk of cervical cancer among participants who had initiated vaccination before the age of 17 years was 88% lower than among those who had never been vaccinated,” the investigators noted.

These results “support the recommendation to administer quadrivalent HPV vaccine before exposure to HPV infection to achieve the most substantial benefit,” the investigators wrote.
 

Details of the Swedish review

For their review, Dr. Lei and colleagues used several Swedish demographic and health registries to connect vaccination status to incident cervical cancers, using the personal identification numbers Sweden issues to residents.

Participants were followed starting either on their 10th birthday or on Jan. 1, 2006, whichever came later. They were followed until, among other things, diagnosis of invasive cervical cancer; their 31st birthday; or until Dec. 31, 2017, whichever came first.

The quadrivalent HPV vaccine, approved in Sweden in 2006, was used almost exclusively during the study period. Participants were considered vaccinated if they had received only one shot, but the investigators set out to analyze a relationship between the incidence of invasive cervical cancer and the number of shots given.

Among other things, the team controlled for age at follow-up, calendar year, county of residence, maternal disease history, and parental characteristics, including education and household income.

The investigators commented that it’s possible that HPV-vaccinated women could have been generally healthier than unvaccinated women and so would have been at lower risk for cervical cancer.

“Confounding by lifestyle and health factors in the women (such as smoking status, sexual activity, oral contraceptive use, and obesity) cannot be excluded; these factors are known to be associated with a risk of cervical cancer,” the investigators wrote.

HPV is also associated with other types of cancer, including anal and oropharyngeal cancers. But these cancers develop over a longer period than cervical cancer.

Dr. Harper noted that the “probability of HPV 16 cancer by time since infection peaks at 40 years after infection for anal cancers and nearly 50 years after infection for oropharyngeal cancers. This means that registries, such as in Sweden, for the next 40 years will record the evidence to say whether HPV vaccination lasts long enough to prevent [these] other HPV 16–associated cancers occurring at a much later time in life.”

The work was funded by the Swedish Foundation for Strategic Research, the Swedish Cancer Society, and the Swedish Research Council and by the China Scholarship Council. Dr. Lei and two other investigators reported HPV vaccine research funding from Merck, the maker of Gardasil. Harper disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Adding neoadjuvant chemotherapy to standard treatment of locally advanced rectal cancer more than doubled the pathologic complete response rate and significantly improved 3-year disease-free survival (DFS) in a multicenter, phase 3 trial.

The pathologic complete response rate was 12.1% in the standard therapy arm and 27.8% with the addition of neoadjuvant chemotherapy – modified FOLFIRINOX (oxaliplatin, irinotecan, folinic acid, and 5-fluorouracil). The 3-year DFS rates were 68.5% and 75.7%, respectively.

It’s not clear if the response and DFS benefits of modified FOLFIRINOX will translate to improved overall survival (OS). Nevertheless, neoadjuvant therapy with modified FOLFIRINOX “should now be considered as a new option” for T3-T4 rectal cancer, said investigator Christophe Borg, MD, PhD, of the University of Besancon (France).

Dr. Borg presented this research at the European Society for Medical Oncology Virtual Congress 2020.

Study discussant David Sebag-Montefiore, MBBS, of the University of Leeds (England), was more cautious about these findings. Although the results were “clear” in this trial, “we have not seen any overall survival data,” Dr. Sebag-Montefiore stressed.
 

Study details

In explaining the trial, dubbed PRODIGE 23, Dr. Borg noted that local recurrence is minimal with modern standard treatment – chemoradiation followed by total mesorectal excision (TME) – but distant metastases occur in up to 30% of patients and remain a significant problem despite years of research. Adjuvant chemotherapy after surgery might help, but it “is still not proven” to reduce the risk, so compliance is poor, Dr. Borg said.

He and his colleagues conducted the PRODIGE 23 trial to see if neoadjuvant chemotherapy could reduce the risk of metastases.

The study enrolled 461 patients, 18-75 years old, with cT3-4 rectal cancer. Patients were randomized to receive:

• Standard therapy, consisting of chemoradiation (50.4 gy/5 weeks plus capecitabine), followed 7 weeks later by TME, then 6 months of adjuvant chemotherapy with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) or XELOX (capecitabine and oxaliplatin, also known as CAPOX).
• Six cycles of modified FOLFIRINOX, followed by chemoradiation (50.4 gy/5 weeks plus capecitabine), TME, and FOLFOX/XELOX adjuvant therapy for 3 months instead of 6 months.

Overall, 119 patients in the standard therapy arm and 130 in the neoadjuvant arm completed their assigned protocol.
 

Results

The median follow-up was 46.5 months. The 3-year DFS, the primary endpoint, was significantly higher in the neoadjuvant arm than in the standard therapy arm (75.7% vs. 68.5%; hazard ratio = 0.69; P = .034). This correlated with a significant improvement in 3-year metastasis-free survival (78.8% vs. 71.7%; HR = 0.64; P < .02).

The rate of palliative surgery was significantly higher in the standard therapy arm (3.7% vs. 0%; P = .007), but there were no significant differences in other surgical outcomes.

A difference in 60-day postoperative mortality favored neoadjuvant therapy (0% vs. 2.8%, P = .03).

Grade 3 or 4 adverse events during adjuvant therapy were less common when subjects had neoadjuvant chemotherapy (44.4% vs. 74.1%, P < .001).

Quality of life outcomes were similar between the treatment arms, except that men in the neoadjuvant arm were significantly less likely to suffer from impotence (P = .03).

Dr. Sebag-Montefiore said these findings are “very important,” but PRODIGE 23 is not “a practice-defining or practice-changing study,” especially without OS data.

He noted that the RAPIDO trial had similar outcomes with a different neoadjuvant regimen.

RAPIDO had a standard treatment arm with capecitabine-based chemoradiotherapy followed by TME and optional CAPOX/FOLFOX, and the experimental arm consisted of short-course radiotherapy followed by CAPOX/FOLFOX then TME. The experimental arm had superior 3-year disease-related treatment failure (30.4% vs. 23.7%, P = .019) but no better OS (89.1% vs. 88.8%, P = .59).

PRODIGE 23 was funded by the French National Cancer Institute and the French National League Against Cancer. Dr. Borg disclosed relationships with Roche, Servier, Pierre Fabre, and Merck Sharp & Dohme. Dr. Sebag-Montefiore didn’t have any disclosures.

[email protected]

SOURCE: Borg C et al. ESMO 2020. Abstract LBA21.

Adding neoadjuvant chemotherapy to standard treatment of locally advanced rectal cancer more than doubled the pathologic complete response rate and significantly improved 3-year disease-free survival (DFS) in a multicenter, phase 3 trial.

The pathologic complete response rate was 12.1% in the standard therapy arm and 27.8% with the addition of neoadjuvant chemotherapy – modified FOLFIRINOX (oxaliplatin, irinotecan, folinic acid, and 5-fluorouracil). The 3-year DFS rates were 68.5% and 75.7%, respectively.

It’s not clear if the response and DFS benefits of modified FOLFIRINOX will translate to improved overall survival (OS). Nevertheless, neoadjuvant therapy with modified FOLFIRINOX “should now be considered as a new option” for T3-T4 rectal cancer, said investigator Christophe Borg, MD, PhD, of the University of Besancon (France).

Dr. Borg presented this research at the European Society for Medical Oncology Virtual Congress 2020.

Study discussant David Sebag-Montefiore, MBBS, of the University of Leeds (England), was more cautious about these findings. Although the results were “clear” in this trial, “we have not seen any overall survival data,” Dr. Sebag-Montefiore stressed.
 

Study details

In explaining the trial, dubbed PRODIGE 23, Dr. Borg noted that local recurrence is minimal with modern standard treatment – chemoradiation followed by total mesorectal excision (TME) – but distant metastases occur in up to 30% of patients and remain a significant problem despite years of research. Adjuvant chemotherapy after surgery might help, but it “is still not proven” to reduce the risk, so compliance is poor, Dr. Borg said.

He and his colleagues conducted the PRODIGE 23 trial to see if neoadjuvant chemotherapy could reduce the risk of metastases.

The study enrolled 461 patients, 18-75 years old, with cT3-4 rectal cancer. Patients were randomized to receive:

• Standard therapy, consisting of chemoradiation (50.4 gy/5 weeks plus capecitabine), followed 7 weeks later by TME, then 6 months of adjuvant chemotherapy with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) or XELOX (capecitabine and oxaliplatin, also known as CAPOX).
• Six cycles of modified FOLFIRINOX, followed by chemoradiation (50.4 gy/5 weeks plus capecitabine), TME, and FOLFOX/XELOX adjuvant therapy for 3 months instead of 6 months.

Overall, 119 patients in the standard therapy arm and 130 in the neoadjuvant arm completed their assigned protocol.
 

Results

The median follow-up was 46.5 months. The 3-year DFS, the primary endpoint, was significantly higher in the neoadjuvant arm than in the standard therapy arm (75.7% vs. 68.5%; hazard ratio = 0.69; P = .034). This correlated with a significant improvement in 3-year metastasis-free survival (78.8% vs. 71.7%; HR = 0.64; P < .02).

The rate of palliative surgery was significantly higher in the standard therapy arm (3.7% vs. 0%; P = .007), but there were no significant differences in other surgical outcomes.

A difference in 60-day postoperative mortality favored neoadjuvant therapy (0% vs. 2.8%, P = .03).

Grade 3 or 4 adverse events during adjuvant therapy were less common when subjects had neoadjuvant chemotherapy (44.4% vs. 74.1%, P < .001).

Quality of life outcomes were similar between the treatment arms, except that men in the neoadjuvant arm were significantly less likely to suffer from impotence (P = .03).

Dr. Sebag-Montefiore said these findings are “very important,” but PRODIGE 23 is not “a practice-defining or practice-changing study,” especially without OS data.

He noted that the RAPIDO trial had similar outcomes with a different neoadjuvant regimen.

RAPIDO had a standard treatment arm with capecitabine-based chemoradiotherapy followed by TME and optional CAPOX/FOLFOX, and the experimental arm consisted of short-course radiotherapy followed by CAPOX/FOLFOX then TME. The experimental arm had superior 3-year disease-related treatment failure (30.4% vs. 23.7%, P = .019) but no better OS (89.1% vs. 88.8%, P = .59).

PRODIGE 23 was funded by the French National Cancer Institute and the French National League Against Cancer. Dr. Borg disclosed relationships with Roche, Servier, Pierre Fabre, and Merck Sharp & Dohme. Dr. Sebag-Montefiore didn’t have any disclosures.

[email protected]

SOURCE: Borg C et al. ESMO 2020. Abstract LBA21.

Adding neoadjuvant chemotherapy to standard treatment of locally advanced rectal cancer more than doubled the pathologic complete response rate and significantly improved 3-year disease-free survival (DFS) in a multicenter, phase 3 trial.

The pathologic complete response rate was 12.1% in the standard therapy arm and 27.8% with the addition of neoadjuvant chemotherapy – modified FOLFIRINOX (oxaliplatin, irinotecan, folinic acid, and 5-fluorouracil). The 3-year DFS rates were 68.5% and 75.7%, respectively.

It’s not clear if the response and DFS benefits of modified FOLFIRINOX will translate to improved overall survival (OS). Nevertheless, neoadjuvant therapy with modified FOLFIRINOX “should now be considered as a new option” for T3-T4 rectal cancer, said investigator Christophe Borg, MD, PhD, of the University of Besancon (France).

Dr. Borg presented this research at the European Society for Medical Oncology Virtual Congress 2020.

Study discussant David Sebag-Montefiore, MBBS, of the University of Leeds (England), was more cautious about these findings. Although the results were “clear” in this trial, “we have not seen any overall survival data,” Dr. Sebag-Montefiore stressed.
 

Study details

In explaining the trial, dubbed PRODIGE 23, Dr. Borg noted that local recurrence is minimal with modern standard treatment – chemoradiation followed by total mesorectal excision (TME) – but distant metastases occur in up to 30% of patients and remain a significant problem despite years of research. Adjuvant chemotherapy after surgery might help, but it “is still not proven” to reduce the risk, so compliance is poor, Dr. Borg said.

He and his colleagues conducted the PRODIGE 23 trial to see if neoadjuvant chemotherapy could reduce the risk of metastases.

The study enrolled 461 patients, 18-75 years old, with cT3-4 rectal cancer. Patients were randomized to receive:

• Standard therapy, consisting of chemoradiation (50.4 gy/5 weeks plus capecitabine), followed 7 weeks later by TME, then 6 months of adjuvant chemotherapy with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) or XELOX (capecitabine and oxaliplatin, also known as CAPOX).
• Six cycles of modified FOLFIRINOX, followed by chemoradiation (50.4 gy/5 weeks plus capecitabine), TME, and FOLFOX/XELOX adjuvant therapy for 3 months instead of 6 months.

Overall, 119 patients in the standard therapy arm and 130 in the neoadjuvant arm completed their assigned protocol.
 

Results

The median follow-up was 46.5 months. The 3-year DFS, the primary endpoint, was significantly higher in the neoadjuvant arm than in the standard therapy arm (75.7% vs. 68.5%; hazard ratio = 0.69; P = .034). This correlated with a significant improvement in 3-year metastasis-free survival (78.8% vs. 71.7%; HR = 0.64; P < .02).

The rate of palliative surgery was significantly higher in the standard therapy arm (3.7% vs. 0%; P = .007), but there were no significant differences in other surgical outcomes.

A difference in 60-day postoperative mortality favored neoadjuvant therapy (0% vs. 2.8%, P = .03).

Grade 3 or 4 adverse events during adjuvant therapy were less common when subjects had neoadjuvant chemotherapy (44.4% vs. 74.1%, P < .001).

Quality of life outcomes were similar between the treatment arms, except that men in the neoadjuvant arm were significantly less likely to suffer from impotence (P = .03).

Dr. Sebag-Montefiore said these findings are “very important,” but PRODIGE 23 is not “a practice-defining or practice-changing study,” especially without OS data.

He noted that the RAPIDO trial had similar outcomes with a different neoadjuvant regimen.

RAPIDO had a standard treatment arm with capecitabine-based chemoradiotherapy followed by TME and optional CAPOX/FOLFOX, and the experimental arm consisted of short-course radiotherapy followed by CAPOX/FOLFOX then TME. The experimental arm had superior 3-year disease-related treatment failure (30.4% vs. 23.7%, P = .019) but no better OS (89.1% vs. 88.8%, P = .59).

PRODIGE 23 was funded by the French National Cancer Institute and the French National League Against Cancer. Dr. Borg disclosed relationships with Roche, Servier, Pierre Fabre, and Merck Sharp & Dohme. Dr. Sebag-Montefiore didn’t have any disclosures.

[email protected]

SOURCE: Borg C et al. ESMO 2020. Abstract LBA21.

Patients with higher intraoperative blood loss and those treated at lower-volume surgical centers had a greater risk of high-grade complications after undergoing cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (RCC), according to an analysis of registry data.

Higher intraoperative blood loss was also associated with low-grade postoperative complications. Intraoperative complications were more likely in patients who had concurrent thrombectomy and surgery on adjacent organs.

Eduard Roussel, MD, of University Hospitals Leuven (Belgium) and colleagues reported these findings in European Urology Oncology.

The authors noted that the role of CN in metastatic RCC is controversial. The CARMENA trial, published in the New England Journal of Medicine, “shifted treatment paradigms” away from surgery by suggesting that sunitinib alone is noninferior to sunitinib after CN.

“Nonetheless, there is a general consensus that certain selected subgroups of patients with low-volume, single-site metastases and few adverse IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] criteria would still benefit from the continued use of upfront CN,” the authors wrote.

They advised clinicians to weigh the risks and benefits of CN, particularly because “postoperative morbidity might preclude or delay the use of subsequent systemic therapies.” However, the risk/benefit calculation for CN has been difficult because past investigations have tended to focus only on survival outcomes, so there isn’t much data on morbidity, the authors wrote.

Patient characteristics and complications

To investigate morbidity associated with CN, Dr. Roussel and colleagues reviewed data from the Registry of Metastatic RCC (REMARCC). The team analyzed the clinical records of 736 patients who underwent nephrectomy for metastatic RCC during 1980-2019.

The patients’ median age was 63 years (range, 55-70 years), and about three-quarters were men. The majority had clear cell carcinoma, and the lungs were the most common site of metastases.

More than 97% of procedures were complete nephrectomies, and the rest were partial. The median estimated blood loss was 400 mL, and the median follow-up was 16.5 months.

There were 69 patients who had intraoperative complications, most commonly bleeding (n = 25), spleen laceration (n = 13), and vascular injury (n = 11).

There were 217 patients who had postoperative complications, including 45 patients with high-grade complications (grade 3-5) and 10 who died.

The most common postoperative complications were vascular/lymphatic in nature. These occurred in 67 patients and included 10 lymphoceles.

“[G]iven the relatively high rate of postoperative lymphoceles, which is probably attributable to the performance of lymph node dissections and the lack of proven oncological survival benefit thereof, surgeons might reconsider the performance of lymphadenectomy during CN,” the investigators wrote.

Other common postoperative complications included infectious and cardiopulmonary issues, which occurred in 42 and 39 patients, respectively.
 

Predictors of complications

Thrombectomy and adjacent organ removal were significant predictors of intraoperative complications on multivariable analysis. The odds ratios were 1.38 (P = .009) for thrombectomy and 2.71 (P = .004) for adjacent organ removal.

Estimated blood loss was a significant predictor of low- and high-grade postoperative complications. The OR for high-grade complications per 200 mL of blood lost was 1.06 (P = .007), and the OR for low-grade complications per 200 mL blood lost was 1.09 (P = .001).

There was a strong inverse correlation with CN case load at each center and high-grade postoperative complications, which highlights “the impact of centralization of care on postoperative outcomes in complex surgical scenarios,” the investigators wrote. The OR per 25 cases was 0.88 (P = .04).

Results were largely the same when the analysis was limited to the 560 subjects treated since 2006, in the targeted therapy era, except that adjacent organ removal as a predictor of intraoperative complications did not quite reach statistical significance (P = .06).

The presurgery risk factors identified in this study should assist with presurgical counseling, said Zachery Reichert, MD, PhD, a genitourinary medical oncologist and assistant professor at the University of Michigan, Ann Arbor, who was not involved in this study.

“This is especially important for patients who require thrombectomy or adjacent organ removal or do not have access to a surgeon with high cytoreductive nephrectomy caseloads,” he said.

Dr. Reichert reported having no disclosures. There was no external funding for this study, and the investigators didn’t have any disclosures.

[email protected]

SOURCE: Roussel E et al. Eur Urol Oncol. 2020 Aug;3(4):523-9.

Patients with higher intraoperative blood loss and those treated at lower-volume surgical centers had a greater risk of high-grade complications after undergoing cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (RCC), according to an analysis of registry data.

Higher intraoperative blood loss was also associated with low-grade postoperative complications. Intraoperative complications were more likely in patients who had concurrent thrombectomy and surgery on adjacent organs.

Eduard Roussel, MD, of University Hospitals Leuven (Belgium) and colleagues reported these findings in European Urology Oncology.

The authors noted that the role of CN in metastatic RCC is controversial. The CARMENA trial, published in the New England Journal of Medicine, “shifted treatment paradigms” away from surgery by suggesting that sunitinib alone is noninferior to sunitinib after CN.

“Nonetheless, there is a general consensus that certain selected subgroups of patients with low-volume, single-site metastases and few adverse IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] criteria would still benefit from the continued use of upfront CN,” the authors wrote.

They advised clinicians to weigh the risks and benefits of CN, particularly because “postoperative morbidity might preclude or delay the use of subsequent systemic therapies.” However, the risk/benefit calculation for CN has been difficult because past investigations have tended to focus only on survival outcomes, so there isn’t much data on morbidity, the authors wrote.

Patient characteristics and complications

To investigate morbidity associated with CN, Dr. Roussel and colleagues reviewed data from the Registry of Metastatic RCC (REMARCC). The team analyzed the clinical records of 736 patients who underwent nephrectomy for metastatic RCC during 1980-2019.

The patients’ median age was 63 years (range, 55-70 years), and about three-quarters were men. The majority had clear cell carcinoma, and the lungs were the most common site of metastases.

More than 97% of procedures were complete nephrectomies, and the rest were partial. The median estimated blood loss was 400 mL, and the median follow-up was 16.5 months.

There were 69 patients who had intraoperative complications, most commonly bleeding (n = 25), spleen laceration (n = 13), and vascular injury (n = 11).

There were 217 patients who had postoperative complications, including 45 patients with high-grade complications (grade 3-5) and 10 who died.

The most common postoperative complications were vascular/lymphatic in nature. These occurred in 67 patients and included 10 lymphoceles.

“[G]iven the relatively high rate of postoperative lymphoceles, which is probably attributable to the performance of lymph node dissections and the lack of proven oncological survival benefit thereof, surgeons might reconsider the performance of lymphadenectomy during CN,” the investigators wrote.

Other common postoperative complications included infectious and cardiopulmonary issues, which occurred in 42 and 39 patients, respectively.
 

Predictors of complications

Thrombectomy and adjacent organ removal were significant predictors of intraoperative complications on multivariable analysis. The odds ratios were 1.38 (P = .009) for thrombectomy and 2.71 (P = .004) for adjacent organ removal.

Estimated blood loss was a significant predictor of low- and high-grade postoperative complications. The OR for high-grade complications per 200 mL of blood lost was 1.06 (P = .007), and the OR for low-grade complications per 200 mL blood lost was 1.09 (P = .001).

There was a strong inverse correlation with CN case load at each center and high-grade postoperative complications, which highlights “the impact of centralization of care on postoperative outcomes in complex surgical scenarios,” the investigators wrote. The OR per 25 cases was 0.88 (P = .04).

Results were largely the same when the analysis was limited to the 560 subjects treated since 2006, in the targeted therapy era, except that adjacent organ removal as a predictor of intraoperative complications did not quite reach statistical significance (P = .06).

The presurgery risk factors identified in this study should assist with presurgical counseling, said Zachery Reichert, MD, PhD, a genitourinary medical oncologist and assistant professor at the University of Michigan, Ann Arbor, who was not involved in this study.

“This is especially important for patients who require thrombectomy or adjacent organ removal or do not have access to a surgeon with high cytoreductive nephrectomy caseloads,” he said.

Dr. Reichert reported having no disclosures. There was no external funding for this study, and the investigators didn’t have any disclosures.

[email protected]

SOURCE: Roussel E et al. Eur Urol Oncol. 2020 Aug;3(4):523-9.

Patients with higher intraoperative blood loss and those treated at lower-volume surgical centers had a greater risk of high-grade complications after undergoing cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (RCC), according to an analysis of registry data.

Higher intraoperative blood loss was also associated with low-grade postoperative complications. Intraoperative complications were more likely in patients who had concurrent thrombectomy and surgery on adjacent organs.

Eduard Roussel, MD, of University Hospitals Leuven (Belgium) and colleagues reported these findings in European Urology Oncology.

The authors noted that the role of CN in metastatic RCC is controversial. The CARMENA trial, published in the New England Journal of Medicine, “shifted treatment paradigms” away from surgery by suggesting that sunitinib alone is noninferior to sunitinib after CN.

“Nonetheless, there is a general consensus that certain selected subgroups of patients with low-volume, single-site metastases and few adverse IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] criteria would still benefit from the continued use of upfront CN,” the authors wrote.

They advised clinicians to weigh the risks and benefits of CN, particularly because “postoperative morbidity might preclude or delay the use of subsequent systemic therapies.” However, the risk/benefit calculation for CN has been difficult because past investigations have tended to focus only on survival outcomes, so there isn’t much data on morbidity, the authors wrote.

Patient characteristics and complications

To investigate morbidity associated with CN, Dr. Roussel and colleagues reviewed data from the Registry of Metastatic RCC (REMARCC). The team analyzed the clinical records of 736 patients who underwent nephrectomy for metastatic RCC during 1980-2019.

The patients’ median age was 63 years (range, 55-70 years), and about three-quarters were men. The majority had clear cell carcinoma, and the lungs were the most common site of metastases.

More than 97% of procedures were complete nephrectomies, and the rest were partial. The median estimated blood loss was 400 mL, and the median follow-up was 16.5 months.

There were 69 patients who had intraoperative complications, most commonly bleeding (n = 25), spleen laceration (n = 13), and vascular injury (n = 11).

There were 217 patients who had postoperative complications, including 45 patients with high-grade complications (grade 3-5) and 10 who died.

The most common postoperative complications were vascular/lymphatic in nature. These occurred in 67 patients and included 10 lymphoceles.

“[G]iven the relatively high rate of postoperative lymphoceles, which is probably attributable to the performance of lymph node dissections and the lack of proven oncological survival benefit thereof, surgeons might reconsider the performance of lymphadenectomy during CN,” the investigators wrote.

Other common postoperative complications included infectious and cardiopulmonary issues, which occurred in 42 and 39 patients, respectively.
 

Predictors of complications

Thrombectomy and adjacent organ removal were significant predictors of intraoperative complications on multivariable analysis. The odds ratios were 1.38 (P = .009) for thrombectomy and 2.71 (P = .004) for adjacent organ removal.

Estimated blood loss was a significant predictor of low- and high-grade postoperative complications. The OR for high-grade complications per 200 mL of blood lost was 1.06 (P = .007), and the OR for low-grade complications per 200 mL blood lost was 1.09 (P = .001).

There was a strong inverse correlation with CN case load at each center and high-grade postoperative complications, which highlights “the impact of centralization of care on postoperative outcomes in complex surgical scenarios,” the investigators wrote. The OR per 25 cases was 0.88 (P = .04).

Results were largely the same when the analysis was limited to the 560 subjects treated since 2006, in the targeted therapy era, except that adjacent organ removal as a predictor of intraoperative complications did not quite reach statistical significance (P = .06).

The presurgery risk factors identified in this study should assist with presurgical counseling, said Zachery Reichert, MD, PhD, a genitourinary medical oncologist and assistant professor at the University of Michigan, Ann Arbor, who was not involved in this study.

“This is especially important for patients who require thrombectomy or adjacent organ removal or do not have access to a surgeon with high cytoreductive nephrectomy caseloads,” he said.

Dr. Reichert reported having no disclosures. There was no external funding for this study, and the investigators didn’t have any disclosures.

[email protected]

SOURCE: Roussel E et al. Eur Urol Oncol. 2020 Aug;3(4):523-9.

First-line lorlatinib significantly prolonged progression-free survival (PFS) when compared with crizotinib in advanced ALK-positive non–small cell lung cancer (NSCLC), according to an interim analysis of the phase 3 CROWN trial.

Lorlatinib also produced a higher overall and intracranial response rate, prolonging progression to CNS disease.

These findings “support the use of lorlatinib as a highly effective first-line therapy for patients with advanced ALK-positive NSCLC,” said Benjamin Solomon, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne.

“The CROWN study clearly establishes lorlatinib as another option” among other first-line ALK inhibitors, Dr. Solomon said when presenting the findings at the European Society for Medical Oncology Virtual Congress 2020.

“We now have multiple options for first-line treatment of patients with ALK-positive lung cancer,” noted study discussant Christine Lovly, MD, PhD, a medical oncologist and associate professor at Vanderbilt University Medical Center in Nashville, Tenn.

The question now, she said, is how to choose among these options. The drugs have all bested crizotinib in trials but haven’t gone head to head against one another.
 

Lorlatinib and CROWN

Lorlatinib is currently approved in the United States to treat ALK-positive metastatic NSCLC that has progressed on crizotinib and at least one other ALK inhibitor. Lorlatinib was granted accelerated approval for this indication based on response rate and duration.

The CROWN study was intended to support the conversion to full approval, according to Pfizer, which is developing both lorlatinib and crizotinib. Pfizer also plans to use the results of CROWN to seek a first-line indication for lorlatinib in NSCLC.

CROWN enrolled 296 patients with stage IIIB/IV ALK-positive NSCLC who had received no prior systemic treatment. Patients with asymptomatic treated or untreated CNS metastases were eligible.

There were 149 patients randomized to lorlatinib at 100 mg daily and 147 randomized to crizotinib at 250 mg twice daily. Five patients in the crizotinib arm were included in the analysis but were not treated, Dr. Solomon said.

The median age was 61 years in the lorlatinib arm and 56 years in the crizotinib arm. Nearly all patients were White (48% in the lorlatinib arm and 49% in the crizotinib arm) or Asian (44% in both arms). A majority of patients were women (56% in the lorlatinib arm and 62% in the crizotinib arm), and more than half said they never smoked (54% in the lorlatinib arm and 64% in the crizotinib arm).
 

Response and PFS

According to blinded independent central review, the objective response rate was 76% with lorlatinib (113/149) and 58% with crizotinib (85/147). There were four complete responses with lorlatinib and none with crizotinib.

Among patients who had measurable or nonmeasurable brain metastases at baseline, the intracranial ORR was 66% with lorlatinib (25/38) and 20% (8/40) with crizotinib. In patients with only measurable brain metastases at baseline, the intracranial ORR was 82% with lorlatinib (14/17) and 23% with crizotinib (3/13).

The 12-month PFS rate was 78% in the lorlatinib arm and 39% in the crizotinib arm. The median PFS was 9.3 months in the crizotinib arm but was not reached in the lorlatinib arm, which “corresponded to a 72% reduction in the risk of death or progression [hazard ratio, 0.21; P < .001],” Dr. Solomon said.

“[T]he PFS for alectinib in the first line is approximately 3 years,” Dr. Lovly noted. “We anxiously await additional data for lorlatinib to see how long the PFS will be.”

The median time to intracranial progression was 16.6 months in the crizotinib arm but was not reached in the lorlatinib arm (HR, 0.07; P < .001).

“These data indicate the ability of lorlatinib not only to delay the progression of existing brain metastases, but also to prevent the development of new brain metastases,” Dr. Solomon said.

Dr. Lovly noted that the efficacy of lorlatinib in the brain is “quite compelling,” but other ALK inhibitors have demonstrated similar results.

As for overall survival, the data are still immature. The median overall survival was not reached with lorlatinib or crizotinib (HR, 0.72).
 

Toxicity

Dr. Solomon noted that lorlatinib “does have a different toxicity profile, compared to other ALK inhibitors.” Specifically, lorlatinib is associated with hypercholesterolemia and hypertriglyceridemia, which have not been seen with other ALK inhibitors.

Lorlatinib is also associated with neurocognitive problems, including inattention, memory impairment, and mild confusion. Mood effects include emotional lability – “someone watching a movie might burst into tears when they wouldn’t have otherwise,” Dr. Solomon said – as well as anxiety and depression.

“So it’s important to tell not just the patient but their family about these things so that they identify when [the events] happen,” Dr. Solomon said. “That’s key because [the events are] completely reversible when you stop the drug. With dose interruption, those effects will resolve.”

Other adverse events that were more common with lorlatinib (a 10% or greater difference in frequency from crizotinib) included edema, weight gain, and peripheral neuropathy. Diarrhea, nausea, fatigue, vision disorders, constipation, and increased liver enzymes were more common with crizotinib. Grade 3-4 adverse events led to discontinuation in fewer than 10% of patients in each arm.

The study was funded by Pfizer, and the investigators included employees. Dr. Solomon is an adviser for Pfizer and other companies, and Dr. Lovly’s industry ties included being both an advisor and speaker for Pfizer.

[email protected]

SOURCE: Solomon B et al. ESMO 2020, Abstract LBA2.

First-line lorlatinib significantly prolonged progression-free survival (PFS) when compared with crizotinib in advanced ALK-positive non–small cell lung cancer (NSCLC), according to an interim analysis of the phase 3 CROWN trial.

Lorlatinib also produced a higher overall and intracranial response rate, prolonging progression to CNS disease.

These findings “support the use of lorlatinib as a highly effective first-line therapy for patients with advanced ALK-positive NSCLC,” said Benjamin Solomon, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne.

“The CROWN study clearly establishes lorlatinib as another option” among other first-line ALK inhibitors, Dr. Solomon said when presenting the findings at the European Society for Medical Oncology Virtual Congress 2020.

“We now have multiple options for first-line treatment of patients with ALK-positive lung cancer,” noted study discussant Christine Lovly, MD, PhD, a medical oncologist and associate professor at Vanderbilt University Medical Center in Nashville, Tenn.

The question now, she said, is how to choose among these options. The drugs have all bested crizotinib in trials but haven’t gone head to head against one another.
 

Lorlatinib and CROWN

Lorlatinib is currently approved in the United States to treat ALK-positive metastatic NSCLC that has progressed on crizotinib and at least one other ALK inhibitor. Lorlatinib was granted accelerated approval for this indication based on response rate and duration.

The CROWN study was intended to support the conversion to full approval, according to Pfizer, which is developing both lorlatinib and crizotinib. Pfizer also plans to use the results of CROWN to seek a first-line indication for lorlatinib in NSCLC.

CROWN enrolled 296 patients with stage IIIB/IV ALK-positive NSCLC who had received no prior systemic treatment. Patients with asymptomatic treated or untreated CNS metastases were eligible.

There were 149 patients randomized to lorlatinib at 100 mg daily and 147 randomized to crizotinib at 250 mg twice daily. Five patients in the crizotinib arm were included in the analysis but were not treated, Dr. Solomon said.

The median age was 61 years in the lorlatinib arm and 56 years in the crizotinib arm. Nearly all patients were White (48% in the lorlatinib arm and 49% in the crizotinib arm) or Asian (44% in both arms). A majority of patients were women (56% in the lorlatinib arm and 62% in the crizotinib arm), and more than half said they never smoked (54% in the lorlatinib arm and 64% in the crizotinib arm).
 

Response and PFS

According to blinded independent central review, the objective response rate was 76% with lorlatinib (113/149) and 58% with crizotinib (85/147). There were four complete responses with lorlatinib and none with crizotinib.

Among patients who had measurable or nonmeasurable brain metastases at baseline, the intracranial ORR was 66% with lorlatinib (25/38) and 20% (8/40) with crizotinib. In patients with only measurable brain metastases at baseline, the intracranial ORR was 82% with lorlatinib (14/17) and 23% with crizotinib (3/13).

The 12-month PFS rate was 78% in the lorlatinib arm and 39% in the crizotinib arm. The median PFS was 9.3 months in the crizotinib arm but was not reached in the lorlatinib arm, which “corresponded to a 72% reduction in the risk of death or progression [hazard ratio, 0.21; P < .001],” Dr. Solomon said.

“[T]he PFS for alectinib in the first line is approximately 3 years,” Dr. Lovly noted. “We anxiously await additional data for lorlatinib to see how long the PFS will be.”

The median time to intracranial progression was 16.6 months in the crizotinib arm but was not reached in the lorlatinib arm (HR, 0.07; P < .001).

“These data indicate the ability of lorlatinib not only to delay the progression of existing brain metastases, but also to prevent the development of new brain metastases,” Dr. Solomon said.

Dr. Lovly noted that the efficacy of lorlatinib in the brain is “quite compelling,” but other ALK inhibitors have demonstrated similar results.

As for overall survival, the data are still immature. The median overall survival was not reached with lorlatinib or crizotinib (HR, 0.72).
 

Toxicity

Dr. Solomon noted that lorlatinib “does have a different toxicity profile, compared to other ALK inhibitors.” Specifically, lorlatinib is associated with hypercholesterolemia and hypertriglyceridemia, which have not been seen with other ALK inhibitors.

Lorlatinib is also associated with neurocognitive problems, including inattention, memory impairment, and mild confusion. Mood effects include emotional lability – “someone watching a movie might burst into tears when they wouldn’t have otherwise,” Dr. Solomon said – as well as anxiety and depression.

“So it’s important to tell not just the patient but their family about these things so that they identify when [the events] happen,” Dr. Solomon said. “That’s key because [the events are] completely reversible when you stop the drug. With dose interruption, those effects will resolve.”

Other adverse events that were more common with lorlatinib (a 10% or greater difference in frequency from crizotinib) included edema, weight gain, and peripheral neuropathy. Diarrhea, nausea, fatigue, vision disorders, constipation, and increased liver enzymes were more common with crizotinib. Grade 3-4 adverse events led to discontinuation in fewer than 10% of patients in each arm.

The study was funded by Pfizer, and the investigators included employees. Dr. Solomon is an adviser for Pfizer and other companies, and Dr. Lovly’s industry ties included being both an advisor and speaker for Pfizer.

[email protected]

SOURCE: Solomon B et al. ESMO 2020, Abstract LBA2.

First-line lorlatinib significantly prolonged progression-free survival (PFS) when compared with crizotinib in advanced ALK-positive non–small cell lung cancer (NSCLC), according to an interim analysis of the phase 3 CROWN trial.

Lorlatinib also produced a higher overall and intracranial response rate, prolonging progression to CNS disease.

These findings “support the use of lorlatinib as a highly effective first-line therapy for patients with advanced ALK-positive NSCLC,” said Benjamin Solomon, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne.

“The CROWN study clearly establishes lorlatinib as another option” among other first-line ALK inhibitors, Dr. Solomon said when presenting the findings at the European Society for Medical Oncology Virtual Congress 2020.

“We now have multiple options for first-line treatment of patients with ALK-positive lung cancer,” noted study discussant Christine Lovly, MD, PhD, a medical oncologist and associate professor at Vanderbilt University Medical Center in Nashville, Tenn.

The question now, she said, is how to choose among these options. The drugs have all bested crizotinib in trials but haven’t gone head to head against one another.
 

Lorlatinib and CROWN

Lorlatinib is currently approved in the United States to treat ALK-positive metastatic NSCLC that has progressed on crizotinib and at least one other ALK inhibitor. Lorlatinib was granted accelerated approval for this indication based on response rate and duration.

The CROWN study was intended to support the conversion to full approval, according to Pfizer, which is developing both lorlatinib and crizotinib. Pfizer also plans to use the results of CROWN to seek a first-line indication for lorlatinib in NSCLC.

CROWN enrolled 296 patients with stage IIIB/IV ALK-positive NSCLC who had received no prior systemic treatment. Patients with asymptomatic treated or untreated CNS metastases were eligible.

There were 149 patients randomized to lorlatinib at 100 mg daily and 147 randomized to crizotinib at 250 mg twice daily. Five patients in the crizotinib arm were included in the analysis but were not treated, Dr. Solomon said.

The median age was 61 years in the lorlatinib arm and 56 years in the crizotinib arm. Nearly all patients were White (48% in the lorlatinib arm and 49% in the crizotinib arm) or Asian (44% in both arms). A majority of patients were women (56% in the lorlatinib arm and 62% in the crizotinib arm), and more than half said they never smoked (54% in the lorlatinib arm and 64% in the crizotinib arm).
 

Response and PFS

According to blinded independent central review, the objective response rate was 76% with lorlatinib (113/149) and 58% with crizotinib (85/147). There were four complete responses with lorlatinib and none with crizotinib.

Among patients who had measurable or nonmeasurable brain metastases at baseline, the intracranial ORR was 66% with lorlatinib (25/38) and 20% (8/40) with crizotinib. In patients with only measurable brain metastases at baseline, the intracranial ORR was 82% with lorlatinib (14/17) and 23% with crizotinib (3/13).

The 12-month PFS rate was 78% in the lorlatinib arm and 39% in the crizotinib arm. The median PFS was 9.3 months in the crizotinib arm but was not reached in the lorlatinib arm, which “corresponded to a 72% reduction in the risk of death or progression [hazard ratio, 0.21; P < .001],” Dr. Solomon said.

“[T]he PFS for alectinib in the first line is approximately 3 years,” Dr. Lovly noted. “We anxiously await additional data for lorlatinib to see how long the PFS will be.”

The median time to intracranial progression was 16.6 months in the crizotinib arm but was not reached in the lorlatinib arm (HR, 0.07; P < .001).

“These data indicate the ability of lorlatinib not only to delay the progression of existing brain metastases, but also to prevent the development of new brain metastases,” Dr. Solomon said.

Dr. Lovly noted that the efficacy of lorlatinib in the brain is “quite compelling,” but other ALK inhibitors have demonstrated similar results.

As for overall survival, the data are still immature. The median overall survival was not reached with lorlatinib or crizotinib (HR, 0.72).
 

Toxicity

Dr. Solomon noted that lorlatinib “does have a different toxicity profile, compared to other ALK inhibitors.” Specifically, lorlatinib is associated with hypercholesterolemia and hypertriglyceridemia, which have not been seen with other ALK inhibitors.

Lorlatinib is also associated with neurocognitive problems, including inattention, memory impairment, and mild confusion. Mood effects include emotional lability – “someone watching a movie might burst into tears when they wouldn’t have otherwise,” Dr. Solomon said – as well as anxiety and depression.

“So it’s important to tell not just the patient but their family about these things so that they identify when [the events] happen,” Dr. Solomon said. “That’s key because [the events are] completely reversible when you stop the drug. With dose interruption, those effects will resolve.”

Other adverse events that were more common with lorlatinib (a 10% or greater difference in frequency from crizotinib) included edema, weight gain, and peripheral neuropathy. Diarrhea, nausea, fatigue, vision disorders, constipation, and increased liver enzymes were more common with crizotinib. Grade 3-4 adverse events led to discontinuation in fewer than 10% of patients in each arm.

The study was funded by Pfizer, and the investigators included employees. Dr. Solomon is an adviser for Pfizer and other companies, and Dr. Lovly’s industry ties included being both an advisor and speaker for Pfizer.

[email protected]

SOURCE: Solomon B et al. ESMO 2020, Abstract LBA2.

Adding metformin to standard care for advanced prostate cancer appeared to lengthen time to castration-resistant disease in a small, randomized trial.

“According to our data, metformin potentially prolongs the time to progression … when combined with androgen deprivation therapy,” said investigator Reham ALGhandour, MD, PhD, an assistant lecturer of medical oncology at Mansoura (Egypt) University.

Dr. ALGhandour presented the data at the European Society for Medical Oncology Virtual Congress 2020.

Prior observational studies have indicated that metformin may benefit patients with prostate cancer. A meta-analysis of cohort studies suggested metformin can significantly improve overall, cancer-specific, and recurrence-free survival in prostate cancer patients.

To explore this further, Dr. ALGhandour and colleagues conducted a randomized trial. They enrolled 124 men with high-risk locally advanced or metastatic hormone-sensitive prostate cancer.

The investigators randomized 62 patients to testosterone suppression with or without antiandrogen, and 62 others to a standard regimen plus metformin at 850 mg twice daily.

All patients had an Easter Cooperative Oncology Group performance score of 0-2, were set to receive androgen deprivation therapy long term, and had no prior metformin use. Docetaxel was permitted for metastatic patients, and external beam radiation therapy was used for localized and regional disease.
 

Results: ‘Dramatic’ but not ‘definitive’

At a median follow-up of 18 months, there was a significant difference in time to castration-resistant prostate cancer. The median time to progression was 29 months with metformin and 20 months with standard therapy alone (P = .01).

Subgroup analyses showed a benefit with metformin in men with N1 disease (P = .001) and men with localized disease/low tumor burden (P = .008).

There was no significant difference in overall survival between the treatment arms (P = .1). The median overall survival was not reached in either arm.

About 4% of metformin patients had grade 2 diarrhea, but adverse events were otherwise comparable between the arms and mostly related to androgen deprivation.

“The authors have got some pretty dramatic findings,” said Noel Clarke, MBBS, a consultant urologist at Salford Royal Hospital and The Christie, Manchester, England, who was a discussant for the study.

Dr. Clarke said the data are “hypothesis generating,” but, because of small numbers, the study “really falls well short of anything that is definitive.”

“We’ll have to wait for bigger studies,” Dr. Clarke said, adding that one arm of the STAMPEDE trial has recruited 2,200 prostate cancer patients to standard of care plus metformin.

“We will report on this trial presently,” he said. “Hopefully, this will add to the body of literature which will determine whether or not metformin is useful with standard of care in this disease.”

Dr. Clarke said the possible benefits of metformin are probably related to energetics in prostate cancer.

“AMPK [AMP-activated protein kinase] is the energy superhighway regulator,” he explained. “[I]t slows down the effects of cell proliferation and energy usage, and it promotes the use of energy storage mechanisms.

“Metformin, because it acts on AMPK to up-regulate it … enhances the effect of AMPK, shutting down the catabolic elements and impeding other elements of prostate cancer migration. So AMPK inhibits epithelial to mesenchymal transition, which is well known as a metastatic mechanism.”

There was no outside funding for this study, and the investigators didn’t report any disclosures. Dr. Clarke disclosed relationships with Janssen, Astellas, Sanofi, and AstraZeneca.

[email protected]

SOURCE: ALGhandour R et al. ESMO 2020, Abstract 617MO.

Adding metformin to standard care for advanced prostate cancer appeared to lengthen time to castration-resistant disease in a small, randomized trial.

“According to our data, metformin potentially prolongs the time to progression … when combined with androgen deprivation therapy,” said investigator Reham ALGhandour, MD, PhD, an assistant lecturer of medical oncology at Mansoura (Egypt) University.

Dr. ALGhandour presented the data at the European Society for Medical Oncology Virtual Congress 2020.

Prior observational studies have indicated that metformin may benefit patients with prostate cancer. A meta-analysis of cohort studies suggested metformin can significantly improve overall, cancer-specific, and recurrence-free survival in prostate cancer patients.

To explore this further, Dr. ALGhandour and colleagues conducted a randomized trial. They enrolled 124 men with high-risk locally advanced or metastatic hormone-sensitive prostate cancer.

The investigators randomized 62 patients to testosterone suppression with or without antiandrogen, and 62 others to a standard regimen plus metformin at 850 mg twice daily.

All patients had an Easter Cooperative Oncology Group performance score of 0-2, were set to receive androgen deprivation therapy long term, and had no prior metformin use. Docetaxel was permitted for metastatic patients, and external beam radiation therapy was used for localized and regional disease.
 

Results: ‘Dramatic’ but not ‘definitive’

At a median follow-up of 18 months, there was a significant difference in time to castration-resistant prostate cancer. The median time to progression was 29 months with metformin and 20 months with standard therapy alone (P = .01).

Subgroup analyses showed a benefit with metformin in men with N1 disease (P = .001) and men with localized disease/low tumor burden (P = .008).

There was no significant difference in overall survival between the treatment arms (P = .1). The median overall survival was not reached in either arm.

About 4% of metformin patients had grade 2 diarrhea, but adverse events were otherwise comparable between the arms and mostly related to androgen deprivation.

“The authors have got some pretty dramatic findings,” said Noel Clarke, MBBS, a consultant urologist at Salford Royal Hospital and The Christie, Manchester, England, who was a discussant for the study.

Dr. Clarke said the data are “hypothesis generating,” but, because of small numbers, the study “really falls well short of anything that is definitive.”

“We’ll have to wait for bigger studies,” Dr. Clarke said, adding that one arm of the STAMPEDE trial has recruited 2,200 prostate cancer patients to standard of care plus metformin.

“We will report on this trial presently,” he said. “Hopefully, this will add to the body of literature which will determine whether or not metformin is useful with standard of care in this disease.”

Dr. Clarke said the possible benefits of metformin are probably related to energetics in prostate cancer.

“AMPK [AMP-activated protein kinase] is the energy superhighway regulator,” he explained. “[I]t slows down the effects of cell proliferation and energy usage, and it promotes the use of energy storage mechanisms.

“Metformin, because it acts on AMPK to up-regulate it … enhances the effect of AMPK, shutting down the catabolic elements and impeding other elements of prostate cancer migration. So AMPK inhibits epithelial to mesenchymal transition, which is well known as a metastatic mechanism.”

There was no outside funding for this study, and the investigators didn’t report any disclosures. Dr. Clarke disclosed relationships with Janssen, Astellas, Sanofi, and AstraZeneca.

[email protected]

SOURCE: ALGhandour R et al. ESMO 2020, Abstract 617MO.

Adding metformin to standard care for advanced prostate cancer appeared to lengthen time to castration-resistant disease in a small, randomized trial.

“According to our data, metformin potentially prolongs the time to progression … when combined with androgen deprivation therapy,” said investigator Reham ALGhandour, MD, PhD, an assistant lecturer of medical oncology at Mansoura (Egypt) University.

Dr. ALGhandour presented the data at the European Society for Medical Oncology Virtual Congress 2020.

Prior observational studies have indicated that metformin may benefit patients with prostate cancer. A meta-analysis of cohort studies suggested metformin can significantly improve overall, cancer-specific, and recurrence-free survival in prostate cancer patients.

To explore this further, Dr. ALGhandour and colleagues conducted a randomized trial. They enrolled 124 men with high-risk locally advanced or metastatic hormone-sensitive prostate cancer.

The investigators randomized 62 patients to testosterone suppression with or without antiandrogen, and 62 others to a standard regimen plus metformin at 850 mg twice daily.

All patients had an Easter Cooperative Oncology Group performance score of 0-2, were set to receive androgen deprivation therapy long term, and had no prior metformin use. Docetaxel was permitted for metastatic patients, and external beam radiation therapy was used for localized and regional disease.
 

Results: ‘Dramatic’ but not ‘definitive’

At a median follow-up of 18 months, there was a significant difference in time to castration-resistant prostate cancer. The median time to progression was 29 months with metformin and 20 months with standard therapy alone (P = .01).

Subgroup analyses showed a benefit with metformin in men with N1 disease (P = .001) and men with localized disease/low tumor burden (P = .008).

There was no significant difference in overall survival between the treatment arms (P = .1). The median overall survival was not reached in either arm.

About 4% of metformin patients had grade 2 diarrhea, but adverse events were otherwise comparable between the arms and mostly related to androgen deprivation.

“The authors have got some pretty dramatic findings,” said Noel Clarke, MBBS, a consultant urologist at Salford Royal Hospital and The Christie, Manchester, England, who was a discussant for the study.

Dr. Clarke said the data are “hypothesis generating,” but, because of small numbers, the study “really falls well short of anything that is definitive.”

“We’ll have to wait for bigger studies,” Dr. Clarke said, adding that one arm of the STAMPEDE trial has recruited 2,200 prostate cancer patients to standard of care plus metformin.

“We will report on this trial presently,” he said. “Hopefully, this will add to the body of literature which will determine whether or not metformin is useful with standard of care in this disease.”

Dr. Clarke said the possible benefits of metformin are probably related to energetics in prostate cancer.

“AMPK [AMP-activated protein kinase] is the energy superhighway regulator,” he explained. “[I]t slows down the effects of cell proliferation and energy usage, and it promotes the use of energy storage mechanisms.

“Metformin, because it acts on AMPK to up-regulate it … enhances the effect of AMPK, shutting down the catabolic elements and impeding other elements of prostate cancer migration. So AMPK inhibits epithelial to mesenchymal transition, which is well known as a metastatic mechanism.”

There was no outside funding for this study, and the investigators didn’t report any disclosures. Dr. Clarke disclosed relationships with Janssen, Astellas, Sanofi, and AstraZeneca.

[email protected]

SOURCE: ALGhandour R et al. ESMO 2020, Abstract 617MO.

An artificial intelligence (AI) computer algorithm performed on par with, and in some cases exceeded, radiologists in reading mammograms in a case-control study of 8,805 women undergoing routine screening.

The algorithm – from the company Lunit, which was not involved in the study – had an area under the curve of 0.956 for detection of pathologically confirmed breast cancer.

When operating at a specificity of 96.6%, the sensitivity was 81.9% for the algorithm, 77.4% for first-reader radiologists, and 80.1% for second-reader radiologists. Combining the algorithm with first-reader radiologists identified more cases than combining first- and second-reader radiologists.

These findings were published in JAMA Oncology.

The study’s authors wrote that the algorithm results are a “considerable” achievement because, unlike the radiologists, the algorithm had no access to prior mammograms or information about hormonal medications or breast symptoms.

“We believe that the time has come to evaluate AI CAD [computer-aided detection] algorithms as independent readers in prospective clinical studies,” Mattie Salim, MD, of Karolinska Institute/Karolinska University Hospital in Stockholm, and colleagues wrote.

“The authors are to be commended for providing data that support this next critical phase of discovery,” Constance Dobbins Lehman, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, wrote in a related editorial. She added that “it is time to move beyond simulation and reader studies and enter the critical phase of rigorous, prospective clinical evaluation.”
 

Study rationale and details

Routine mammograms save lives, but the workload for radiologists is high, and the quality of assessments varies widely, Dr. Salim and colleagues wrote. There are also problems with access in areas with few radiologists.

To address these issues, academic and commercial researchers have worked hard to apply AI – specifically, deep neural networks – to computer programs that read mammograms.

For this study, the investigators conducted the first third-party external validation of three competing algorithms. The three algorithms were not named in the report, but Lunit announced that its algorithm was the best-performing algorithm after the study was published. The other two algorithms did not perform as well and remain anonymous.

The investigators compared the algorithms’ assessments with the original radiology reports for 739 women who were diagnosed with breast cancer within 12 months of their mammogram and 8,066 women with negative mammograms who remained cancer free at a 2-year follow-up.

The women, aged 40-74 years, had conventional two-dimensional imaging read by two radiologists at the Karolinska University Hospital during 2008-2015. The subjects’ median age at screening was 54.5 years.

The algorithms gave a prediction score between 0 and 1 for each breast, with 1 denoting the highest level of cancer suspicion. To enable a comparison with the binary decisions of the radiologists, the output of each algorithm was dichotomized (normal or abnormal) at a cut point defined by the mean specificity of the first-reader radiologists, 96.6%.

At a specificity of 96.6%, the sensitivity was 81.9% for the Lunit algorithm, 67.0% for one anonymous algorithm (AI-2), 67.4% for the other anonymous algorithm (AI-3), 77.4% for first-reader radiologists, and 80.1% for second-reader radiologists

The investigators also ran their analysis at a cut point of 88.9% specificity. The sensitivity was 88.6% for the Lunit algorithm, 80.0% for AI-2, and 80.2% for AI-3.

“This can be compared with the Breast Cancer Surveillance Consortium benchmarks of 86.9% sensitivity at 88.9% specificity,” the authors wrote.

The most potent screening strategy was combining the Lunit algorithm with the first reader, which increased cancer detection by 8% but came at the cost of a 77% increase in abnormal assessments.

“More true-positive cases would likely be found, but a much larger proportion of false-positive examinations would have to be handled in the ensuing consensus discussion,” the authors wrote. “[A] cost-benefit analysis is required ... to determine the economic implications of adding a human reader at all.”

The team noted that the Lunit algorithm was trained on images of South Korean women from GE equipment.

“Although we do not have ethnic descriptors of our study population, the vast majority of women in Stockholm are White, and all images in our study were acquired on Hologic equipment,” the authors wrote. “In training AI algorithms for mammographic cancer detection, matching ethnic and equipment distributions between the training population and the clinical test population may not be of highest importance.”

As for why the Lunit algorithm outperformed the other two algorithms, one explanation may be that the Lunit algorithm was trained on more mammograms – 72,000 cancer and 680,000 normal images (vs. 10,000 cancer and 229,000 normal images for AI-2; 6,000 cancer and 106,000 normal images for AI-3).

As for next steps, the investigators are planning a prospective clinical study to see how AI works as an independent reviewer of mammograms in a day-to-day clinical environment, both as a third reviewer and to help select women for follow-up MRI.

The current study was funded by the Stockholm County Council. The investigators disclosed financial relationships with the Swedish Research Council, the Swedish Cancer Society, Stockholm City Council, Collective Minds Radiology, and Pfizer. Dr Lehman’s institution receives grants from GE Healthcare.

[email protected]

SOURCE: Salim M et al. JAMA Oncol. 2020 Aug 27. doi: 10.1001/jamaoncol.2020.3321.

An artificial intelligence (AI) computer algorithm performed on par with, and in some cases exceeded, radiologists in reading mammograms in a case-control study of 8,805 women undergoing routine screening.

The algorithm – from the company Lunit, which was not involved in the study – had an area under the curve of 0.956 for detection of pathologically confirmed breast cancer.

When operating at a specificity of 96.6%, the sensitivity was 81.9% for the algorithm, 77.4% for first-reader radiologists, and 80.1% for second-reader radiologists. Combining the algorithm with first-reader radiologists identified more cases than combining first- and second-reader radiologists.

These findings were published in JAMA Oncology.

The study’s authors wrote that the algorithm results are a “considerable” achievement because, unlike the radiologists, the algorithm had no access to prior mammograms or information about hormonal medications or breast symptoms.

“We believe that the time has come to evaluate AI CAD [computer-aided detection] algorithms as independent readers in prospective clinical studies,” Mattie Salim, MD, of Karolinska Institute/Karolinska University Hospital in Stockholm, and colleagues wrote.

“The authors are to be commended for providing data that support this next critical phase of discovery,” Constance Dobbins Lehman, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, wrote in a related editorial. She added that “it is time to move beyond simulation and reader studies and enter the critical phase of rigorous, prospective clinical evaluation.”
 

Study rationale and details

Routine mammograms save lives, but the workload for radiologists is high, and the quality of assessments varies widely, Dr. Salim and colleagues wrote. There are also problems with access in areas with few radiologists.

To address these issues, academic and commercial researchers have worked hard to apply AI – specifically, deep neural networks – to computer programs that read mammograms.

For this study, the investigators conducted the first third-party external validation of three competing algorithms. The three algorithms were not named in the report, but Lunit announced that its algorithm was the best-performing algorithm after the study was published. The other two algorithms did not perform as well and remain anonymous.

The investigators compared the algorithms’ assessments with the original radiology reports for 739 women who were diagnosed with breast cancer within 12 months of their mammogram and 8,066 women with negative mammograms who remained cancer free at a 2-year follow-up.

The women, aged 40-74 years, had conventional two-dimensional imaging read by two radiologists at the Karolinska University Hospital during 2008-2015. The subjects’ median age at screening was 54.5 years.

The algorithms gave a prediction score between 0 and 1 for each breast, with 1 denoting the highest level of cancer suspicion. To enable a comparison with the binary decisions of the radiologists, the output of each algorithm was dichotomized (normal or abnormal) at a cut point defined by the mean specificity of the first-reader radiologists, 96.6%.

At a specificity of 96.6%, the sensitivity was 81.9% for the Lunit algorithm, 67.0% for one anonymous algorithm (AI-2), 67.4% for the other anonymous algorithm (AI-3), 77.4% for first-reader radiologists, and 80.1% for second-reader radiologists

The investigators also ran their analysis at a cut point of 88.9% specificity. The sensitivity was 88.6% for the Lunit algorithm, 80.0% for AI-2, and 80.2% for AI-3.

“This can be compared with the Breast Cancer Surveillance Consortium benchmarks of 86.9% sensitivity at 88.9% specificity,” the authors wrote.

The most potent screening strategy was combining the Lunit algorithm with the first reader, which increased cancer detection by 8% but came at the cost of a 77% increase in abnormal assessments.

“More true-positive cases would likely be found, but a much larger proportion of false-positive examinations would have to be handled in the ensuing consensus discussion,” the authors wrote. “[A] cost-benefit analysis is required ... to determine the economic implications of adding a human reader at all.”

The team noted that the Lunit algorithm was trained on images of South Korean women from GE equipment.

“Although we do not have ethnic descriptors of our study population, the vast majority of women in Stockholm are White, and all images in our study were acquired on Hologic equipment,” the authors wrote. “In training AI algorithms for mammographic cancer detection, matching ethnic and equipment distributions between the training population and the clinical test population may not be of highest importance.”

As for why the Lunit algorithm outperformed the other two algorithms, one explanation may be that the Lunit algorithm was trained on more mammograms – 72,000 cancer and 680,000 normal images (vs. 10,000 cancer and 229,000 normal images for AI-2; 6,000 cancer and 106,000 normal images for AI-3).

As for next steps, the investigators are planning a prospective clinical study to see how AI works as an independent reviewer of mammograms in a day-to-day clinical environment, both as a third reviewer and to help select women for follow-up MRI.

The current study was funded by the Stockholm County Council. The investigators disclosed financial relationships with the Swedish Research Council, the Swedish Cancer Society, Stockholm City Council, Collective Minds Radiology, and Pfizer. Dr Lehman’s institution receives grants from GE Healthcare.

[email protected]

SOURCE: Salim M et al. JAMA Oncol. 2020 Aug 27. doi: 10.1001/jamaoncol.2020.3321.

An artificial intelligence (AI) computer algorithm performed on par with, and in some cases exceeded, radiologists in reading mammograms in a case-control study of 8,805 women undergoing routine screening.

The algorithm – from the company Lunit, which was not involved in the study – had an area under the curve of 0.956 for detection of pathologically confirmed breast cancer.

When operating at a specificity of 96.6%, the sensitivity was 81.9% for the algorithm, 77.4% for first-reader radiologists, and 80.1% for second-reader radiologists. Combining the algorithm with first-reader radiologists identified more cases than combining first- and second-reader radiologists.

These findings were published in JAMA Oncology.

The study’s authors wrote that the algorithm results are a “considerable” achievement because, unlike the radiologists, the algorithm had no access to prior mammograms or information about hormonal medications or breast symptoms.

“We believe that the time has come to evaluate AI CAD [computer-aided detection] algorithms as independent readers in prospective clinical studies,” Mattie Salim, MD, of Karolinska Institute/Karolinska University Hospital in Stockholm, and colleagues wrote.

“The authors are to be commended for providing data that support this next critical phase of discovery,” Constance Dobbins Lehman, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, wrote in a related editorial. She added that “it is time to move beyond simulation and reader studies and enter the critical phase of rigorous, prospective clinical evaluation.”
 

Study rationale and details

Routine mammograms save lives, but the workload for radiologists is high, and the quality of assessments varies widely, Dr. Salim and colleagues wrote. There are also problems with access in areas with few radiologists.

To address these issues, academic and commercial researchers have worked hard to apply AI – specifically, deep neural networks – to computer programs that read mammograms.

For this study, the investigators conducted the first third-party external validation of three competing algorithms. The three algorithms were not named in the report, but Lunit announced that its algorithm was the best-performing algorithm after the study was published. The other two algorithms did not perform as well and remain anonymous.

The investigators compared the algorithms’ assessments with the original radiology reports for 739 women who were diagnosed with breast cancer within 12 months of their mammogram and 8,066 women with negative mammograms who remained cancer free at a 2-year follow-up.

The women, aged 40-74 years, had conventional two-dimensional imaging read by two radiologists at the Karolinska University Hospital during 2008-2015. The subjects’ median age at screening was 54.5 years.

The algorithms gave a prediction score between 0 and 1 for each breast, with 1 denoting the highest level of cancer suspicion. To enable a comparison with the binary decisions of the radiologists, the output of each algorithm was dichotomized (normal or abnormal) at a cut point defined by the mean specificity of the first-reader radiologists, 96.6%.

At a specificity of 96.6%, the sensitivity was 81.9% for the Lunit algorithm, 67.0% for one anonymous algorithm (AI-2), 67.4% for the other anonymous algorithm (AI-3), 77.4% for first-reader radiologists, and 80.1% for second-reader radiologists

The investigators also ran their analysis at a cut point of 88.9% specificity. The sensitivity was 88.6% for the Lunit algorithm, 80.0% for AI-2, and 80.2% for AI-3.

“This can be compared with the Breast Cancer Surveillance Consortium benchmarks of 86.9% sensitivity at 88.9% specificity,” the authors wrote.

The most potent screening strategy was combining the Lunit algorithm with the first reader, which increased cancer detection by 8% but came at the cost of a 77% increase in abnormal assessments.

“More true-positive cases would likely be found, but a much larger proportion of false-positive examinations would have to be handled in the ensuing consensus discussion,” the authors wrote. “[A] cost-benefit analysis is required ... to determine the economic implications of adding a human reader at all.”

The team noted that the Lunit algorithm was trained on images of South Korean women from GE equipment.

“Although we do not have ethnic descriptors of our study population, the vast majority of women in Stockholm are White, and all images in our study were acquired on Hologic equipment,” the authors wrote. “In training AI algorithms for mammographic cancer detection, matching ethnic and equipment distributions between the training population and the clinical test population may not be of highest importance.”

As for why the Lunit algorithm outperformed the other two algorithms, one explanation may be that the Lunit algorithm was trained on more mammograms – 72,000 cancer and 680,000 normal images (vs. 10,000 cancer and 229,000 normal images for AI-2; 6,000 cancer and 106,000 normal images for AI-3).

As for next steps, the investigators are planning a prospective clinical study to see how AI works as an independent reviewer of mammograms in a day-to-day clinical environment, both as a third reviewer and to help select women for follow-up MRI.

The current study was funded by the Stockholm County Council. The investigators disclosed financial relationships with the Swedish Research Council, the Swedish Cancer Society, Stockholm City Council, Collective Minds Radiology, and Pfizer. Dr Lehman’s institution receives grants from GE Healthcare.

[email protected]

SOURCE: Salim M et al. JAMA Oncol. 2020 Aug 27. doi: 10.1001/jamaoncol.2020.3321.

Proton pump inhibitors may short-circuit the benefits of atezolizumab (Tecentriq) in patients with advanced/metastatic urothelial cancer, according to a post hoc analysis of 1,360 subjects from two atezolizumab trials.

Proton pump inhibitor (PPI) use was associated with worse overall and progression-free survival among patients on atezolizumab, but there was no such association in a matched cohort receiving chemotherapy alone. In short, concomitant “PPI users had no atezolizumab benefit,” wrote the investigators led by Ashley Hopkins, PhD, a research fellow at Flinders University in Adelaide, Australia.

This is the first time that PPI use has been shown to be an independent prognostic factor for worse survival in this setting with atezolizumab use – but not with chemotherapy, wrote the authors of the study, published online in Clinical Cancer Research.

“PPIs are overused, or inappropriately used, in patients with cancer by up to 50%, seemingly from a perspective that they will cause no harm. The findings from this study suggest that noncritical PPI use needs to be approached very cautiously, particularly when an immune checkpoint inhibitor is being used to treat urothelial cancer,” Hopkins said in a press release.

Although about one third of cancer patients use PPIs, there has been growing evidence that the changes they induce in the gut microbiome impact immune checkpoint inhibitor (ICI) effectiveness. A similar study of pooled trial data recently found that PPIs, as well as antibiotics, were associated with worse survival in advanced non–small cell lung cancer treated with atezolizumab, while no such tie was found with chemotherapy (Ann Oncol. 2020;31:525-31. doi: 10.1016/j.annonc.2020.01.006).

The mechanism is uncertain. PPIs have been associated with T-cell tolerance, pharmacokinetic changes, and decreased gut microbiota diversity. High diversity, the investigators noted, has been associated with stronger ICI responses in melanoma. Antibiotics have been associated with similar gut dysbiosis.

“It is increasingly evident that altered gut microbiota impacts homeostasis, immune response, cancer prognosis, and ICI efficacy. The hypothetical basis of [our] research is that PPIs are associated with marked changes to the gut microbiota, driven by both altered stomach acidity and direct compound effects, and these changes may impact immunotherapy,” Hopkins said in an email to Medscape.

The associations with urothelial cancer hadn’t been investigated before, so Hopkins and his team pooled patient-level data from the single-arm IMvigor210 trial of atezolizumab for urothelial cancer and the randomized IMvigor211 trial, which pitted atezolizumab against chemotherapy for the indication.

The investigators compared the outcomes of the 471 subjects who were on a PPI from 30 days before to 30 days after starting atezolizumab with the outcomes of 889 subjects who were not on a PPI. Findings were adjusted for tumor histology and the number of prior treatments and metastases sites, as well as age, body mass index, performance status, and other potential confounders.

PPI use was associated with markedly worse overall survival (hazard ratio, 1.52; 95% confidence interval, 1.27-1.83; P < .001) and progression-free survival (HR, 1.38; 95% CI, 1.18-1.62; P < .001) in patients on atezolizumab but not chemotherapy. PPI use was also associated with worse objective response to the ICI (HR, 0.51; 95% CI, 0.32-0.82; P = .006).

In the randomized trial, atezolizumab seemed to offer no overall survival benefit versus chemotherapy when PPIs were onboard (HR, 1.04; 95% CI, 0.81-1.34), but atezolizumab offered a substantial benefit when PPIs were not in use (HR, 0.69; 95% CI, 0.56-0.84). Findings were consistent when limited to the PD-L1 IC2/3 population.

It seems that PPIs negate “the magnitude of atezolizumab efficacy,” the investigators wrote.

Concomitant antibiotics made the effect of PPIs on overall survival with atezolizumab even worse (antibiotics plus PPI: HR 2.51; 95% CI, 1.12-5.59; versus no antibiotics with PPI: HR, 1.44; 95% CI, 1.19-1.74).

The investigators cautioned that, although “the conducted analyses have been adjusted, there is the potential that PPI use constitutes a surrogate marker for an unfit or immunodeficient patient.” They called for further investigation with other ICIs, cancer types, and chemotherapy regimens.

The dose and compliance with PPI therapy were unknown, but the team noted that over 90% of the PPI subjects were on PPIs for long-term reasons, most commonly gastric protection and gastroesophageal reflux disease (GERD). Omeprazole, pantoprazole, and esomeprazole were the most frequently used. 

There were no significant associations between PPI use and the first occurrence of atezolizumab-induced adverse events.

The study was funded by the National Breast Cancer Foundation (Australia) and the Cancer Council South Australia. Hopkins has disclosed no relevant financial relationships. Multiple study authors have financial ties to industry, including makers of ICIs. The full list can be found with the original article.

This article first appeared on Medscape.com.

Proton pump inhibitors may short-circuit the benefits of atezolizumab (Tecentriq) in patients with advanced/metastatic urothelial cancer, according to a post hoc analysis of 1,360 subjects from two atezolizumab trials.

Proton pump inhibitor (PPI) use was associated with worse overall and progression-free survival among patients on atezolizumab, but there was no such association in a matched cohort receiving chemotherapy alone. In short, concomitant “PPI users had no atezolizumab benefit,” wrote the investigators led by Ashley Hopkins, PhD, a research fellow at Flinders University in Adelaide, Australia.

This is the first time that PPI use has been shown to be an independent prognostic factor for worse survival in this setting with atezolizumab use – but not with chemotherapy, wrote the authors of the study, published online in Clinical Cancer Research.

“PPIs are overused, or inappropriately used, in patients with cancer by up to 50%, seemingly from a perspective that they will cause no harm. The findings from this study suggest that noncritical PPI use needs to be approached very cautiously, particularly when an immune checkpoint inhibitor is being used to treat urothelial cancer,” Hopkins said in a press release.

Although about one third of cancer patients use PPIs, there has been growing evidence that the changes they induce in the gut microbiome impact immune checkpoint inhibitor (ICI) effectiveness. A similar study of pooled trial data recently found that PPIs, as well as antibiotics, were associated with worse survival in advanced non–small cell lung cancer treated with atezolizumab, while no such tie was found with chemotherapy (Ann Oncol. 2020;31:525-31. doi: 10.1016/j.annonc.2020.01.006).

The mechanism is uncertain. PPIs have been associated with T-cell tolerance, pharmacokinetic changes, and decreased gut microbiota diversity. High diversity, the investigators noted, has been associated with stronger ICI responses in melanoma. Antibiotics have been associated with similar gut dysbiosis.

“It is increasingly evident that altered gut microbiota impacts homeostasis, immune response, cancer prognosis, and ICI efficacy. The hypothetical basis of [our] research is that PPIs are associated with marked changes to the gut microbiota, driven by both altered stomach acidity and direct compound effects, and these changes may impact immunotherapy,” Hopkins said in an email to Medscape.

The associations with urothelial cancer hadn’t been investigated before, so Hopkins and his team pooled patient-level data from the single-arm IMvigor210 trial of atezolizumab for urothelial cancer and the randomized IMvigor211 trial, which pitted atezolizumab against chemotherapy for the indication.

The investigators compared the outcomes of the 471 subjects who were on a PPI from 30 days before to 30 days after starting atezolizumab with the outcomes of 889 subjects who were not on a PPI. Findings were adjusted for tumor histology and the number of prior treatments and metastases sites, as well as age, body mass index, performance status, and other potential confounders.

PPI use was associated with markedly worse overall survival (hazard ratio, 1.52; 95% confidence interval, 1.27-1.83; P < .001) and progression-free survival (HR, 1.38; 95% CI, 1.18-1.62; P < .001) in patients on atezolizumab but not chemotherapy. PPI use was also associated with worse objective response to the ICI (HR, 0.51; 95% CI, 0.32-0.82; P = .006).

In the randomized trial, atezolizumab seemed to offer no overall survival benefit versus chemotherapy when PPIs were onboard (HR, 1.04; 95% CI, 0.81-1.34), but atezolizumab offered a substantial benefit when PPIs were not in use (HR, 0.69; 95% CI, 0.56-0.84). Findings were consistent when limited to the PD-L1 IC2/3 population.

It seems that PPIs negate “the magnitude of atezolizumab efficacy,” the investigators wrote.

Concomitant antibiotics made the effect of PPIs on overall survival with atezolizumab even worse (antibiotics plus PPI: HR 2.51; 95% CI, 1.12-5.59; versus no antibiotics with PPI: HR, 1.44; 95% CI, 1.19-1.74).

The investigators cautioned that, although “the conducted analyses have been adjusted, there is the potential that PPI use constitutes a surrogate marker for an unfit or immunodeficient patient.” They called for further investigation with other ICIs, cancer types, and chemotherapy regimens.

The dose and compliance with PPI therapy were unknown, but the team noted that over 90% of the PPI subjects were on PPIs for long-term reasons, most commonly gastric protection and gastroesophageal reflux disease (GERD). Omeprazole, pantoprazole, and esomeprazole were the most frequently used. 

There were no significant associations between PPI use and the first occurrence of atezolizumab-induced adverse events.

The study was funded by the National Breast Cancer Foundation (Australia) and the Cancer Council South Australia. Hopkins has disclosed no relevant financial relationships. Multiple study authors have financial ties to industry, including makers of ICIs. The full list can be found with the original article.

This article first appeared on Medscape.com.

Proton pump inhibitors may short-circuit the benefits of atezolizumab (Tecentriq) in patients with advanced/metastatic urothelial cancer, according to a post hoc analysis of 1,360 subjects from two atezolizumab trials.

Proton pump inhibitor (PPI) use was associated with worse overall and progression-free survival among patients on atezolizumab, but there was no such association in a matched cohort receiving chemotherapy alone. In short, concomitant “PPI users had no atezolizumab benefit,” wrote the investigators led by Ashley Hopkins, PhD, a research fellow at Flinders University in Adelaide, Australia.

This is the first time that PPI use has been shown to be an independent prognostic factor for worse survival in this setting with atezolizumab use – but not with chemotherapy, wrote the authors of the study, published online in Clinical Cancer Research.

“PPIs are overused, or inappropriately used, in patients with cancer by up to 50%, seemingly from a perspective that they will cause no harm. The findings from this study suggest that noncritical PPI use needs to be approached very cautiously, particularly when an immune checkpoint inhibitor is being used to treat urothelial cancer,” Hopkins said in a press release.

Although about one third of cancer patients use PPIs, there has been growing evidence that the changes they induce in the gut microbiome impact immune checkpoint inhibitor (ICI) effectiveness. A similar study of pooled trial data recently found that PPIs, as well as antibiotics, were associated with worse survival in advanced non–small cell lung cancer treated with atezolizumab, while no such tie was found with chemotherapy (Ann Oncol. 2020;31:525-31. doi: 10.1016/j.annonc.2020.01.006).

The mechanism is uncertain. PPIs have been associated with T-cell tolerance, pharmacokinetic changes, and decreased gut microbiota diversity. High diversity, the investigators noted, has been associated with stronger ICI responses in melanoma. Antibiotics have been associated with similar gut dysbiosis.

“It is increasingly evident that altered gut microbiota impacts homeostasis, immune response, cancer prognosis, and ICI efficacy. The hypothetical basis of [our] research is that PPIs are associated with marked changes to the gut microbiota, driven by both altered stomach acidity and direct compound effects, and these changes may impact immunotherapy,” Hopkins said in an email to Medscape.

The associations with urothelial cancer hadn’t been investigated before, so Hopkins and his team pooled patient-level data from the single-arm IMvigor210 trial of atezolizumab for urothelial cancer and the randomized IMvigor211 trial, which pitted atezolizumab against chemotherapy for the indication.

The investigators compared the outcomes of the 471 subjects who were on a PPI from 30 days before to 30 days after starting atezolizumab with the outcomes of 889 subjects who were not on a PPI. Findings were adjusted for tumor histology and the number of prior treatments and metastases sites, as well as age, body mass index, performance status, and other potential confounders.

PPI use was associated with markedly worse overall survival (hazard ratio, 1.52; 95% confidence interval, 1.27-1.83; P < .001) and progression-free survival (HR, 1.38; 95% CI, 1.18-1.62; P < .001) in patients on atezolizumab but not chemotherapy. PPI use was also associated with worse objective response to the ICI (HR, 0.51; 95% CI, 0.32-0.82; P = .006).

In the randomized trial, atezolizumab seemed to offer no overall survival benefit versus chemotherapy when PPIs were onboard (HR, 1.04; 95% CI, 0.81-1.34), but atezolizumab offered a substantial benefit when PPIs were not in use (HR, 0.69; 95% CI, 0.56-0.84). Findings were consistent when limited to the PD-L1 IC2/3 population.

It seems that PPIs negate “the magnitude of atezolizumab efficacy,” the investigators wrote.

Concomitant antibiotics made the effect of PPIs on overall survival with atezolizumab even worse (antibiotics plus PPI: HR 2.51; 95% CI, 1.12-5.59; versus no antibiotics with PPI: HR, 1.44; 95% CI, 1.19-1.74).

The investigators cautioned that, although “the conducted analyses have been adjusted, there is the potential that PPI use constitutes a surrogate marker for an unfit or immunodeficient patient.” They called for further investigation with other ICIs, cancer types, and chemotherapy regimens.

The dose and compliance with PPI therapy were unknown, but the team noted that over 90% of the PPI subjects were on PPIs for long-term reasons, most commonly gastric protection and gastroesophageal reflux disease (GERD). Omeprazole, pantoprazole, and esomeprazole were the most frequently used. 

There were no significant associations between PPI use and the first occurrence of atezolizumab-induced adverse events.

The study was funded by the National Breast Cancer Foundation (Australia) and the Cancer Council South Australia. Hopkins has disclosed no relevant financial relationships. Multiple study authors have financial ties to industry, including makers of ICIs. The full list can be found with the original article.

This article first appeared on Medscape.com.