M. Alexander Otto

Reducing the dose of radiation to the esophagus during palliative radiotherapy for advanced lung cancer significantly reduced the incidence of esophagitis among a small group of patients, according to a new randomized study.

Even though fewer patients experienced esophagitis, the procedure did little to significantly improve quality of life for these patients.

The study, called Palliative Radiation for Advanced Central Lung Tumors with Intentional Avoidance of the Esophagus (PROACTIVE), explored the use of a technique called intensity-modulated radiotherapy (IMRT) to sculpt the radiation dose around the esophagus, reducing its exposure. IMRT is a standard technique to avoid healthy tissue with higher radiation doses in the curative setting, but it hasn’t been explored much in the palliative setting, said investigators led by Alexander V. Louie, MD, PhD, a radiation oncologist at the University of Toronto’s Odette Cancer Centre.

The study included 90 patients (mean age 70 years, 56% female) with stage 3 and 4 non–small cell lung cancer. They were randomized evenly to standard radiotherapy with the esophagus getting the same dose as the tumor, or to esophagus-sparing IMRT (ES-IMRT) with the esophagus exposed to no more than 80% of the prescribed dose.

The overall survival was similar between both groups: 8.6 months for standard therapy and 8.7 months for IMRT. Forty percent of patients received 20 Gy in 5 fractions and the rest 30 Gy in 10 fractions. The reduction in esophagitis with IMRT was most evident in the 30 Gy group.

Only one patient in the esophagus-sparing group developed grade 2 esophagitis versus 11 patients (24%) in the standard radiotherapy group. There were no grade 3 or higher cases. There was also an almost 4-point improvement (54.3 points with ES-IMRT versus 50.5 points) on an esophagus-related quality of life (QOL) measure, which is a subscale of the Functional Assessment of Cancer Therapy: Esophagus questionnaire, but it wasn’t statistically significant (P = 0.06).

“The ES-IMRT technique we describe herein represents a paradigm shift in palliative radiotherapy planning,” the investigators wrote. “This technique holds merit for translation into clinical practice.”

However, in their editorial, Ashley A. Weiner, MD, PhD, and Joel E. Tepper, MD, of the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill, wrote that it is too preliminary to recommend esophagus-sparing IMRT to patients. “In the absence of meeting the primary quality of life end point and without demonstration of adequate symptom palliation, one cannot recommend ES-IMRT as a standard therapy for palliation of thoracic symptoms due to NSCLC,” they wrote.

They said the study raises an important issue: The balance between tumor coverage and sparing healthy tissue when symptom palliation instead of cure is the goal.

Striking the right balance “is challenging and part of the art of radiotherapy” particularly in the palliative setting, where there are many unanswered questions, they said.

Unlike in curative intent scenarios, “the ideal dose to the tumor to provide a maximal palliative benefit is unknown, and perhaps there is no ideal dose,” Dr. Weiner and Dr. Tepper said.

It’s also unclear whether the entire tumor needs to be irradiated to the full dose when the goal is simply to shrink the tumor and relieve symptoms. “Perhaps a lower dose to a portion of the tumor makes sense,” especially when radiation doses for palliation are “somewhat arbitrary,” they said.

Indeed, the portion of the tumor next to the esophagus in the IMRT subjects was necessarily undercovered to achieve the esophagus-sparing effect. “It seems very likely to us that underdosing a small portion of the tumor will have little adverse effect” on palliation, Dr. Weiner and Dr. Tepper wrote.

Also, “if undercovering” the tumor with lower doses “results in adequate tumor reduction for palliation,” they wondered if IMRT – a more expensive and complex technique than standard radiotherapy – is even needed.

The work was funded by the Canadian Cancer Society. Dr. Louie reported payments from AstraZeneca as an advisor and personal fees from Varian Medical Systems and Reflexion, the makers of IMRT technology. The authors of the editorial reported no conflicts of interest.

Reducing the dose of radiation to the esophagus during palliative radiotherapy for advanced lung cancer significantly reduced the incidence of esophagitis among a small group of patients, according to a new randomized study.

Even though fewer patients experienced esophagitis, the procedure did little to significantly improve quality of life for these patients.

The study, called Palliative Radiation for Advanced Central Lung Tumors with Intentional Avoidance of the Esophagus (PROACTIVE), explored the use of a technique called intensity-modulated radiotherapy (IMRT) to sculpt the radiation dose around the esophagus, reducing its exposure. IMRT is a standard technique to avoid healthy tissue with higher radiation doses in the curative setting, but it hasn’t been explored much in the palliative setting, said investigators led by Alexander V. Louie, MD, PhD, a radiation oncologist at the University of Toronto’s Odette Cancer Centre.

The study included 90 patients (mean age 70 years, 56% female) with stage 3 and 4 non–small cell lung cancer. They were randomized evenly to standard radiotherapy with the esophagus getting the same dose as the tumor, or to esophagus-sparing IMRT (ES-IMRT) with the esophagus exposed to no more than 80% of the prescribed dose.

The overall survival was similar between both groups: 8.6 months for standard therapy and 8.7 months for IMRT. Forty percent of patients received 20 Gy in 5 fractions and the rest 30 Gy in 10 fractions. The reduction in esophagitis with IMRT was most evident in the 30 Gy group.

Only one patient in the esophagus-sparing group developed grade 2 esophagitis versus 11 patients (24%) in the standard radiotherapy group. There were no grade 3 or higher cases. There was also an almost 4-point improvement (54.3 points with ES-IMRT versus 50.5 points) on an esophagus-related quality of life (QOL) measure, which is a subscale of the Functional Assessment of Cancer Therapy: Esophagus questionnaire, but it wasn’t statistically significant (P = 0.06).

“The ES-IMRT technique we describe herein represents a paradigm shift in palliative radiotherapy planning,” the investigators wrote. “This technique holds merit for translation into clinical practice.”

However, in their editorial, Ashley A. Weiner, MD, PhD, and Joel E. Tepper, MD, of the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill, wrote that it is too preliminary to recommend esophagus-sparing IMRT to patients. “In the absence of meeting the primary quality of life end point and without demonstration of adequate symptom palliation, one cannot recommend ES-IMRT as a standard therapy for palliation of thoracic symptoms due to NSCLC,” they wrote.

They said the study raises an important issue: The balance between tumor coverage and sparing healthy tissue when symptom palliation instead of cure is the goal.

Striking the right balance “is challenging and part of the art of radiotherapy” particularly in the palliative setting, where there are many unanswered questions, they said.

Unlike in curative intent scenarios, “the ideal dose to the tumor to provide a maximal palliative benefit is unknown, and perhaps there is no ideal dose,” Dr. Weiner and Dr. Tepper said.

It’s also unclear whether the entire tumor needs to be irradiated to the full dose when the goal is simply to shrink the tumor and relieve symptoms. “Perhaps a lower dose to a portion of the tumor makes sense,” especially when radiation doses for palliation are “somewhat arbitrary,” they said.

Indeed, the portion of the tumor next to the esophagus in the IMRT subjects was necessarily undercovered to achieve the esophagus-sparing effect. “It seems very likely to us that underdosing a small portion of the tumor will have little adverse effect” on palliation, Dr. Weiner and Dr. Tepper wrote.

Also, “if undercovering” the tumor with lower doses “results in adequate tumor reduction for palliation,” they wondered if IMRT – a more expensive and complex technique than standard radiotherapy – is even needed.

The work was funded by the Canadian Cancer Society. Dr. Louie reported payments from AstraZeneca as an advisor and personal fees from Varian Medical Systems and Reflexion, the makers of IMRT technology. The authors of the editorial reported no conflicts of interest.

Reducing the dose of radiation to the esophagus during palliative radiotherapy for advanced lung cancer significantly reduced the incidence of esophagitis among a small group of patients, according to a new randomized study.

Even though fewer patients experienced esophagitis, the procedure did little to significantly improve quality of life for these patients.

The study, called Palliative Radiation for Advanced Central Lung Tumors with Intentional Avoidance of the Esophagus (PROACTIVE), explored the use of a technique called intensity-modulated radiotherapy (IMRT) to sculpt the radiation dose around the esophagus, reducing its exposure. IMRT is a standard technique to avoid healthy tissue with higher radiation doses in the curative setting, but it hasn’t been explored much in the palliative setting, said investigators led by Alexander V. Louie, MD, PhD, a radiation oncologist at the University of Toronto’s Odette Cancer Centre.

The study included 90 patients (mean age 70 years, 56% female) with stage 3 and 4 non–small cell lung cancer. They were randomized evenly to standard radiotherapy with the esophagus getting the same dose as the tumor, or to esophagus-sparing IMRT (ES-IMRT) with the esophagus exposed to no more than 80% of the prescribed dose.

The overall survival was similar between both groups: 8.6 months for standard therapy and 8.7 months for IMRT. Forty percent of patients received 20 Gy in 5 fractions and the rest 30 Gy in 10 fractions. The reduction in esophagitis with IMRT was most evident in the 30 Gy group.

Only one patient in the esophagus-sparing group developed grade 2 esophagitis versus 11 patients (24%) in the standard radiotherapy group. There were no grade 3 or higher cases. There was also an almost 4-point improvement (54.3 points with ES-IMRT versus 50.5 points) on an esophagus-related quality of life (QOL) measure, which is a subscale of the Functional Assessment of Cancer Therapy: Esophagus questionnaire, but it wasn’t statistically significant (P = 0.06).

“The ES-IMRT technique we describe herein represents a paradigm shift in palliative radiotherapy planning,” the investigators wrote. “This technique holds merit for translation into clinical practice.”

However, in their editorial, Ashley A. Weiner, MD, PhD, and Joel E. Tepper, MD, of the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill, wrote that it is too preliminary to recommend esophagus-sparing IMRT to patients. “In the absence of meeting the primary quality of life end point and without demonstration of adequate symptom palliation, one cannot recommend ES-IMRT as a standard therapy for palliation of thoracic symptoms due to NSCLC,” they wrote.

They said the study raises an important issue: The balance between tumor coverage and sparing healthy tissue when symptom palliation instead of cure is the goal.

Striking the right balance “is challenging and part of the art of radiotherapy” particularly in the palliative setting, where there are many unanswered questions, they said.

Unlike in curative intent scenarios, “the ideal dose to the tumor to provide a maximal palliative benefit is unknown, and perhaps there is no ideal dose,” Dr. Weiner and Dr. Tepper said.

It’s also unclear whether the entire tumor needs to be irradiated to the full dose when the goal is simply to shrink the tumor and relieve symptoms. “Perhaps a lower dose to a portion of the tumor makes sense,” especially when radiation doses for palliation are “somewhat arbitrary,” they said.

Indeed, the portion of the tumor next to the esophagus in the IMRT subjects was necessarily undercovered to achieve the esophagus-sparing effect. “It seems very likely to us that underdosing a small portion of the tumor will have little adverse effect” on palliation, Dr. Weiner and Dr. Tepper wrote.

Also, “if undercovering” the tumor with lower doses “results in adequate tumor reduction for palliation,” they wondered if IMRT – a more expensive and complex technique than standard radiotherapy – is even needed.

The work was funded by the Canadian Cancer Society. Dr. Louie reported payments from AstraZeneca as an advisor and personal fees from Varian Medical Systems and Reflexion, the makers of IMRT technology. The authors of the editorial reported no conflicts of interest.

The U.S. Food and Drug Administration has approved nivolumab for neoadjuvant treatment of non–small cell lung cancer (NSCLC) in combination with platinum-doublet chemotherapy, regardless of PDL-1 status.

Nivolumab is the first immune checkpoint inhibitor to be approved for resectable NSCLC; its three prior NSCLC indications are for metastatic disease, the agency said in its announcement. 

Approval was based on the CheckMate 816 trial, which randomized 358 patients evenly to either nivolumab plus platinum doublets or to platinum doublets alone every 3 weeks for up to 3 cycles.

Trial participants had histologically confirmed stage IB, II, or IIIA disease, which was measurable by RECIST criteria. They were enrolled regardless of tumor PD-L1 status.

At surgery, the pathologic complete response rate was 24% in the nivolumab arm versus 2.2% in the chemotherapy-alone group.

Median event-free survival was 31.6 months with nivolumab but 20.8 months without it, which translated to a 37% reduction in the risk for progression, recurrence, or death following surgery. A trend toward better overall survival was not statistically significant, Bristol Myers Squibb said in its own announcement.

Nivolumab’s new neoadjuvant indication is for adult patients with resectable NSCLC (tumors greater than or equal to 4 cm or node positive). The recommended dosage is 360 mg in combination with platinum-doublet chemotherapy on the same day every 3 weeks for three cycles.

In a press release from Bristol Myers Squibb, CheckMate 816 investigator and Dana-Farber Cancer Institute thoracic oncologist Mark Awad, MD, PhD, called the approval “a turning point in how we treat resectable NSCLC.”

Patients with known EGFR mutations or ALK translocations, grade 2 or higher peripheral neuropathy, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded.

There were no fatal adverse events in the nivolumab arm, but 30% of participants had serious adverse events, most commonly pneumonia and vomiting.

The most common side effects across all grades were nausea (38%), constipation (34%), fatigue (26%), decreased appetite (20%), and rash (20%). Surgical complications and hospital lengths were similar between the two study groups.

Rival checkpoint inhibitor pembrolizumab is also being investigated for neoadjuvant NSCLC.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved nivolumab for neoadjuvant treatment of non–small cell lung cancer (NSCLC) in combination with platinum-doublet chemotherapy, regardless of PDL-1 status.

Nivolumab is the first immune checkpoint inhibitor to be approved for resectable NSCLC; its three prior NSCLC indications are for metastatic disease, the agency said in its announcement. 

Approval was based on the CheckMate 816 trial, which randomized 358 patients evenly to either nivolumab plus platinum doublets or to platinum doublets alone every 3 weeks for up to 3 cycles.

Trial participants had histologically confirmed stage IB, II, or IIIA disease, which was measurable by RECIST criteria. They were enrolled regardless of tumor PD-L1 status.

At surgery, the pathologic complete response rate was 24% in the nivolumab arm versus 2.2% in the chemotherapy-alone group.

Median event-free survival was 31.6 months with nivolumab but 20.8 months without it, which translated to a 37% reduction in the risk for progression, recurrence, or death following surgery. A trend toward better overall survival was not statistically significant, Bristol Myers Squibb said in its own announcement.

Nivolumab’s new neoadjuvant indication is for adult patients with resectable NSCLC (tumors greater than or equal to 4 cm or node positive). The recommended dosage is 360 mg in combination with platinum-doublet chemotherapy on the same day every 3 weeks for three cycles.

In a press release from Bristol Myers Squibb, CheckMate 816 investigator and Dana-Farber Cancer Institute thoracic oncologist Mark Awad, MD, PhD, called the approval “a turning point in how we treat resectable NSCLC.”

Patients with known EGFR mutations or ALK translocations, grade 2 or higher peripheral neuropathy, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded.

There were no fatal adverse events in the nivolumab arm, but 30% of participants had serious adverse events, most commonly pneumonia and vomiting.

The most common side effects across all grades were nausea (38%), constipation (34%), fatigue (26%), decreased appetite (20%), and rash (20%). Surgical complications and hospital lengths were similar between the two study groups.

Rival checkpoint inhibitor pembrolizumab is also being investigated for neoadjuvant NSCLC.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved nivolumab for neoadjuvant treatment of non–small cell lung cancer (NSCLC) in combination with platinum-doublet chemotherapy, regardless of PDL-1 status.

Nivolumab is the first immune checkpoint inhibitor to be approved for resectable NSCLC; its three prior NSCLC indications are for metastatic disease, the agency said in its announcement. 

Approval was based on the CheckMate 816 trial, which randomized 358 patients evenly to either nivolumab plus platinum doublets or to platinum doublets alone every 3 weeks for up to 3 cycles.

Trial participants had histologically confirmed stage IB, II, or IIIA disease, which was measurable by RECIST criteria. They were enrolled regardless of tumor PD-L1 status.

At surgery, the pathologic complete response rate was 24% in the nivolumab arm versus 2.2% in the chemotherapy-alone group.

Median event-free survival was 31.6 months with nivolumab but 20.8 months without it, which translated to a 37% reduction in the risk for progression, recurrence, or death following surgery. A trend toward better overall survival was not statistically significant, Bristol Myers Squibb said in its own announcement.

Nivolumab’s new neoadjuvant indication is for adult patients with resectable NSCLC (tumors greater than or equal to 4 cm or node positive). The recommended dosage is 360 mg in combination with platinum-doublet chemotherapy on the same day every 3 weeks for three cycles.

In a press release from Bristol Myers Squibb, CheckMate 816 investigator and Dana-Farber Cancer Institute thoracic oncologist Mark Awad, MD, PhD, called the approval “a turning point in how we treat resectable NSCLC.”

Patients with known EGFR mutations or ALK translocations, grade 2 or higher peripheral neuropathy, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded.

There were no fatal adverse events in the nivolumab arm, but 30% of participants had serious adverse events, most commonly pneumonia and vomiting.

The most common side effects across all grades were nausea (38%), constipation (34%), fatigue (26%), decreased appetite (20%), and rash (20%). Surgical complications and hospital lengths were similar between the two study groups.

Rival checkpoint inhibitor pembrolizumab is also being investigated for neoadjuvant NSCLC.

A version of this article first appeared on Medscape.com.

The results of a large, matched cohort study from three major institutions have led investigators to call for broader use of trimodal therapy for muscle-invasive bladder cancer.

Radical cystectomy (RC), or the surgical removal of the whole bladder, prostate glands and seminal vesicles in men, or the bladder, uterus and fallopian tubes in women, is the traditional gold standard. But with trimodal therapy (TMT), patients can keep their bladders and avoid a long surgery. The procedure, which is called transurethral tumor resection, requires removing cancerous tumors from the bladder followed by chemoradiation.

After matching hundreds of patients requiring RC or TMT, “the oncologic outcomes seem to be equivalent. ...We do believe that TMT should be offered as an effective alternative for these patients,” said lead investigator Alexandre Zlotta, MD, PhD, director of uro-oncology at Mount Sinai Hospital, Toronto, after he presented the findings at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium

“The findings that patients with clinical T2 disease have similar outcomes with either approach is encouraging,” said Matthew Zibelman, MD,, an assistant hematology/oncology professor at Fox Chase Cancer Center, Philadelphia, when asked for comment.

Trimodal therapy is already an alternative to cystectomy in guidelines for patients with clinical T2-T3 disease who have no, or minor, unilateral hydronephrosis, and unifocal tumors of 7 cm or less, among other criteria.

However, oncologists shy away from it preferring to reserve trimodal therapy mostly for patients who are not candidates for surgery, Dr. Zlotta explained.

The problem is a lack of head-to-head randomized data comparing the two approaches. Attempts at trials in the past closed early because of lack of accrual, and it seems unlikely there’ll be another attempt in the future.
 

A ‘very valuable’ option

Dr. Zlotta and associates wanted to address the evidence gap with the next best thing, a large, matched cohort study. In lieu of a level 1 data, he said their work provides “the best possible evidence” comparing the two approaches and supports TMT as a “very valuable” option so long as centers can provide the necessary follow-up, including salvage cystectomy if needed.

Dr. Zibelman said the retrospective study “cannot completely account for unmeasured variables that may have predisposed patients to get trimodal therapy over surgery, which may have influenced the final data.”

Sill, “trimodal therapy likely provides oncologic outcomes similar to surgery in carefully selected patients ... and should be discussed ... as a bladder-preserving option,” he said.

The study matched 1 to 3, 282 patients undergoing trimodal therapy with 421 patients undergoing radical cystectomy. The patients were treated during 2005-2017 at Massachusetts General Hospital, Boston; the University of California, Los Angeles; or the Princess Margaret Cancer Centre, Toronto.

Patients had cT2-T3/4a disease without positive nodes or metastases. The entire cohort would have been eligible for either TMT or RC under current guidelines.

Propensity score matching produced well-balanced study arms, with a median age of about 71 years; cT2 disease in about 90%; hydronephrosis in about 11%, and adjuvant or neoadjuvant chemotherapy in about 60% of both arms.

At 5 years, both cancer-specific survival (78% with RC and 85% with TMT; P = .02) and overall survival favored TMT (66% RC vs. 78% TMT; P < .001), although Dr. Zlotta said the stark OS difference could have resulted from chance.

Trends also favored TMT in the primary outcome – 5-year metastasis free survival (73% RC vs. 78% TMT; P = .07) – as well as in distant failure-free survival (78% RC vs. 82% TMT; P = .14). The 5-year pelvic node failure-free survival was 96% in the RC group versus 94% with TMT (P = .33).

There were slight differences in surgical protocols between the study centers, and while adjuvant therapy was used at Massachusetts General, neoadjuvant chemotherapy was used in Toronto.

The differences might have introduced confounders, but “I have to say we were pretty reassured to see that we observed exactly the same results” regardless of where subjects were treated. It was “incredibly surprising, but comforting,” Dr. Zlotta said.

Another potential confounder – poor surgical technique – also wasn’t an issue. A median of 40 lymph nodes were removed during cystectomy, which “speaks to the quality of the surgical series,” he said.

The tumor recurrence rate was 20.5% in the TMT arm; 13% of patients had subsequent salvage cystectomies. Perioperative mortality was 2.1% in the RC arm.

There was no outside funding for the work. Dr. Zlotta had ties to numerous companies and honoraria/research funding from or being a consultant to AstraZeneca, Merck, Verity Pharmaceuticals, and others. Dr. Zibelman didn’t have any disclosures.

This article was updated on 3/10/22.

The results of a large, matched cohort study from three major institutions have led investigators to call for broader use of trimodal therapy for muscle-invasive bladder cancer.

Radical cystectomy (RC), or the surgical removal of the whole bladder, prostate glands and seminal vesicles in men, or the bladder, uterus and fallopian tubes in women, is the traditional gold standard. But with trimodal therapy (TMT), patients can keep their bladders and avoid a long surgery. The procedure, which is called transurethral tumor resection, requires removing cancerous tumors from the bladder followed by chemoradiation.

After matching hundreds of patients requiring RC or TMT, “the oncologic outcomes seem to be equivalent. ...We do believe that TMT should be offered as an effective alternative for these patients,” said lead investigator Alexandre Zlotta, MD, PhD, director of uro-oncology at Mount Sinai Hospital, Toronto, after he presented the findings at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium

“The findings that patients with clinical T2 disease have similar outcomes with either approach is encouraging,” said Matthew Zibelman, MD,, an assistant hematology/oncology professor at Fox Chase Cancer Center, Philadelphia, when asked for comment.

Trimodal therapy is already an alternative to cystectomy in guidelines for patients with clinical T2-T3 disease who have no, or minor, unilateral hydronephrosis, and unifocal tumors of 7 cm or less, among other criteria.

However, oncologists shy away from it preferring to reserve trimodal therapy mostly for patients who are not candidates for surgery, Dr. Zlotta explained.

The problem is a lack of head-to-head randomized data comparing the two approaches. Attempts at trials in the past closed early because of lack of accrual, and it seems unlikely there’ll be another attempt in the future.
 

A ‘very valuable’ option

Dr. Zlotta and associates wanted to address the evidence gap with the next best thing, a large, matched cohort study. In lieu of a level 1 data, he said their work provides “the best possible evidence” comparing the two approaches and supports TMT as a “very valuable” option so long as centers can provide the necessary follow-up, including salvage cystectomy if needed.

Dr. Zibelman said the retrospective study “cannot completely account for unmeasured variables that may have predisposed patients to get trimodal therapy over surgery, which may have influenced the final data.”

Sill, “trimodal therapy likely provides oncologic outcomes similar to surgery in carefully selected patients ... and should be discussed ... as a bladder-preserving option,” he said.

The study matched 1 to 3, 282 patients undergoing trimodal therapy with 421 patients undergoing radical cystectomy. The patients were treated during 2005-2017 at Massachusetts General Hospital, Boston; the University of California, Los Angeles; or the Princess Margaret Cancer Centre, Toronto.

Patients had cT2-T3/4a disease without positive nodes or metastases. The entire cohort would have been eligible for either TMT or RC under current guidelines.

Propensity score matching produced well-balanced study arms, with a median age of about 71 years; cT2 disease in about 90%; hydronephrosis in about 11%, and adjuvant or neoadjuvant chemotherapy in about 60% of both arms.

At 5 years, both cancer-specific survival (78% with RC and 85% with TMT; P = .02) and overall survival favored TMT (66% RC vs. 78% TMT; P < .001), although Dr. Zlotta said the stark OS difference could have resulted from chance.

Trends also favored TMT in the primary outcome – 5-year metastasis free survival (73% RC vs. 78% TMT; P = .07) – as well as in distant failure-free survival (78% RC vs. 82% TMT; P = .14). The 5-year pelvic node failure-free survival was 96% in the RC group versus 94% with TMT (P = .33).

There were slight differences in surgical protocols between the study centers, and while adjuvant therapy was used at Massachusetts General, neoadjuvant chemotherapy was used in Toronto.

The differences might have introduced confounders, but “I have to say we were pretty reassured to see that we observed exactly the same results” regardless of where subjects were treated. It was “incredibly surprising, but comforting,” Dr. Zlotta said.

Another potential confounder – poor surgical technique – also wasn’t an issue. A median of 40 lymph nodes were removed during cystectomy, which “speaks to the quality of the surgical series,” he said.

The tumor recurrence rate was 20.5% in the TMT arm; 13% of patients had subsequent salvage cystectomies. Perioperative mortality was 2.1% in the RC arm.

There was no outside funding for the work. Dr. Zlotta had ties to numerous companies and honoraria/research funding from or being a consultant to AstraZeneca, Merck, Verity Pharmaceuticals, and others. Dr. Zibelman didn’t have any disclosures.

This article was updated on 3/10/22.

The results of a large, matched cohort study from three major institutions have led investigators to call for broader use of trimodal therapy for muscle-invasive bladder cancer.

Radical cystectomy (RC), or the surgical removal of the whole bladder, prostate glands and seminal vesicles in men, or the bladder, uterus and fallopian tubes in women, is the traditional gold standard. But with trimodal therapy (TMT), patients can keep their bladders and avoid a long surgery. The procedure, which is called transurethral tumor resection, requires removing cancerous tumors from the bladder followed by chemoradiation.

After matching hundreds of patients requiring RC or TMT, “the oncologic outcomes seem to be equivalent. ...We do believe that TMT should be offered as an effective alternative for these patients,” said lead investigator Alexandre Zlotta, MD, PhD, director of uro-oncology at Mount Sinai Hospital, Toronto, after he presented the findings at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium

“The findings that patients with clinical T2 disease have similar outcomes with either approach is encouraging,” said Matthew Zibelman, MD,, an assistant hematology/oncology professor at Fox Chase Cancer Center, Philadelphia, when asked for comment.

Trimodal therapy is already an alternative to cystectomy in guidelines for patients with clinical T2-T3 disease who have no, or minor, unilateral hydronephrosis, and unifocal tumors of 7 cm or less, among other criteria.

However, oncologists shy away from it preferring to reserve trimodal therapy mostly for patients who are not candidates for surgery, Dr. Zlotta explained.

The problem is a lack of head-to-head randomized data comparing the two approaches. Attempts at trials in the past closed early because of lack of accrual, and it seems unlikely there’ll be another attempt in the future.
 

A ‘very valuable’ option

Dr. Zlotta and associates wanted to address the evidence gap with the next best thing, a large, matched cohort study. In lieu of a level 1 data, he said their work provides “the best possible evidence” comparing the two approaches and supports TMT as a “very valuable” option so long as centers can provide the necessary follow-up, including salvage cystectomy if needed.

Dr. Zibelman said the retrospective study “cannot completely account for unmeasured variables that may have predisposed patients to get trimodal therapy over surgery, which may have influenced the final data.”

Sill, “trimodal therapy likely provides oncologic outcomes similar to surgery in carefully selected patients ... and should be discussed ... as a bladder-preserving option,” he said.

The study matched 1 to 3, 282 patients undergoing trimodal therapy with 421 patients undergoing radical cystectomy. The patients were treated during 2005-2017 at Massachusetts General Hospital, Boston; the University of California, Los Angeles; or the Princess Margaret Cancer Centre, Toronto.

Patients had cT2-T3/4a disease without positive nodes or metastases. The entire cohort would have been eligible for either TMT or RC under current guidelines.

Propensity score matching produced well-balanced study arms, with a median age of about 71 years; cT2 disease in about 90%; hydronephrosis in about 11%, and adjuvant or neoadjuvant chemotherapy in about 60% of both arms.

At 5 years, both cancer-specific survival (78% with RC and 85% with TMT; P = .02) and overall survival favored TMT (66% RC vs. 78% TMT; P < .001), although Dr. Zlotta said the stark OS difference could have resulted from chance.

Trends also favored TMT in the primary outcome – 5-year metastasis free survival (73% RC vs. 78% TMT; P = .07) – as well as in distant failure-free survival (78% RC vs. 82% TMT; P = .14). The 5-year pelvic node failure-free survival was 96% in the RC group versus 94% with TMT (P = .33).

There were slight differences in surgical protocols between the study centers, and while adjuvant therapy was used at Massachusetts General, neoadjuvant chemotherapy was used in Toronto.

The differences might have introduced confounders, but “I have to say we were pretty reassured to see that we observed exactly the same results” regardless of where subjects were treated. It was “incredibly surprising, but comforting,” Dr. Zlotta said.

Another potential confounder – poor surgical technique – also wasn’t an issue. A median of 40 lymph nodes were removed during cystectomy, which “speaks to the quality of the surgical series,” he said.

The tumor recurrence rate was 20.5% in the TMT arm; 13% of patients had subsequent salvage cystectomies. Perioperative mortality was 2.1% in the RC arm.

There was no outside funding for the work. Dr. Zlotta had ties to numerous companies and honoraria/research funding from or being a consultant to AstraZeneca, Merck, Verity Pharmaceuticals, and others. Dr. Zibelman didn’t have any disclosures.

This article was updated on 3/10/22.

Investigators presenting at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium called for neoadjuvant chemotherapy to be a new standard of care for high-grade upper tract urothelial carcinoma.

They made the call after finding that 63% of patients (36/57) had a pathologic response to gemcitabine/cisplatin before extirpative surgery, with pathologic response defined as less than pT2NO disease on postoperative pathology. Nineteen percent (11/57) had complete responses, with no evidence of the main tumor (ypT0N0).

The approach has a “favorable pathologic response, is well tolerated ... and thus should be considered a new standard of care option,” said investigators led by Wesley Yip, MD, a urologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York.

There was no comparator arm, but the results are in line with previous reports, including a 2014 investigation that found a 5-year disease specific survival (DSS) of 90.1% and 5-year overall survival (OS) of 80.2% among 31 upper tract urothelial carcinoma patients who received neoadjuvant chemotherapy, versus a 5-year DSS and OS of 57.6% among 81 historical controls.

Presentation moderator Stephen Boorjian, MD, chair of urology at the Mayo Clinic in Rochester, Minn., called the findings “valuable” but noted there’s level 1 evidence for an alternative approach, chemotherapy or nivolumab after surgery for patients with particularly worrisome postop pathology. It makes it tough to know if patients should be treated beforehand or afterwards.

“What do we do?” he asked.

Dr. Yip said it’s an open question at this point but that trials are underway to address the issue. In the meantime, “it’s definitely a multidisciplinary discussion to know what’s best for each patient,” he said. One of the factors that argues for the neoadjuvant approach is that substantially fewer patients are eligible for chemotherapy after nephroureterectomy because of diminished renal function. “Patients who might not be eligible ... are the ones we’d be targeting for” neoadjuvant chemotherapy (NAC), he said.

In the study, gemcitabine 1000 mg/m² and cisplatin 35 mg/m² were administered on days 1 and 8 of four 21-day cycles, followed by radical nephroureterectomy or ureterectomy.

Fifty-three of the subjects had high-grade disease by endoscopic biopsy, and the remaining four were enrolled based on imaging and selective cytology. There was no nodal disease on CT within 30 days of neoadjuvant chemotherapy initiation.

Two-year progression-free survival (PFS) was 91% among pathologic responders but only 52% among nonresponders. Every responder was alive at 2 years versus 80% of nonresponders.

Across the entire cohort, 5-year PFS was 61% and 5-year OS 79%; 89.5% of patients were alive at a median follow-up of 3.5 years.

Almost all of the patients completed at least three NAC cycles, and all of them went to surgery, which had a 90-day grade 3 or higher complication rate of 7%.

Sixty-three percent were men, and 95% were White. The median age was 66 years.

The work was funded by the National Institutes of Health and Memorial Sloan Kettering. Dr. Yip had no disclosures. Dr. Boorjian advises ArTara Therapeutics, FerGene, and Ferring.

Investigators presenting at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium called for neoadjuvant chemotherapy to be a new standard of care for high-grade upper tract urothelial carcinoma.

They made the call after finding that 63% of patients (36/57) had a pathologic response to gemcitabine/cisplatin before extirpative surgery, with pathologic response defined as less than pT2NO disease on postoperative pathology. Nineteen percent (11/57) had complete responses, with no evidence of the main tumor (ypT0N0).

The approach has a “favorable pathologic response, is well tolerated ... and thus should be considered a new standard of care option,” said investigators led by Wesley Yip, MD, a urologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York.

There was no comparator arm, but the results are in line with previous reports, including a 2014 investigation that found a 5-year disease specific survival (DSS) of 90.1% and 5-year overall survival (OS) of 80.2% among 31 upper tract urothelial carcinoma patients who received neoadjuvant chemotherapy, versus a 5-year DSS and OS of 57.6% among 81 historical controls.

Presentation moderator Stephen Boorjian, MD, chair of urology at the Mayo Clinic in Rochester, Minn., called the findings “valuable” but noted there’s level 1 evidence for an alternative approach, chemotherapy or nivolumab after surgery for patients with particularly worrisome postop pathology. It makes it tough to know if patients should be treated beforehand or afterwards.

“What do we do?” he asked.

Dr. Yip said it’s an open question at this point but that trials are underway to address the issue. In the meantime, “it’s definitely a multidisciplinary discussion to know what’s best for each patient,” he said. One of the factors that argues for the neoadjuvant approach is that substantially fewer patients are eligible for chemotherapy after nephroureterectomy because of diminished renal function. “Patients who might not be eligible ... are the ones we’d be targeting for” neoadjuvant chemotherapy (NAC), he said.

In the study, gemcitabine 1000 mg/m² and cisplatin 35 mg/m² were administered on days 1 and 8 of four 21-day cycles, followed by radical nephroureterectomy or ureterectomy.

Fifty-three of the subjects had high-grade disease by endoscopic biopsy, and the remaining four were enrolled based on imaging and selective cytology. There was no nodal disease on CT within 30 days of neoadjuvant chemotherapy initiation.

Two-year progression-free survival (PFS) was 91% among pathologic responders but only 52% among nonresponders. Every responder was alive at 2 years versus 80% of nonresponders.

Across the entire cohort, 5-year PFS was 61% and 5-year OS 79%; 89.5% of patients were alive at a median follow-up of 3.5 years.

Almost all of the patients completed at least three NAC cycles, and all of them went to surgery, which had a 90-day grade 3 or higher complication rate of 7%.

Sixty-three percent were men, and 95% were White. The median age was 66 years.

The work was funded by the National Institutes of Health and Memorial Sloan Kettering. Dr. Yip had no disclosures. Dr. Boorjian advises ArTara Therapeutics, FerGene, and Ferring.

Investigators presenting at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium called for neoadjuvant chemotherapy to be a new standard of care for high-grade upper tract urothelial carcinoma.

They made the call after finding that 63% of patients (36/57) had a pathologic response to gemcitabine/cisplatin before extirpative surgery, with pathologic response defined as less than pT2NO disease on postoperative pathology. Nineteen percent (11/57) had complete responses, with no evidence of the main tumor (ypT0N0).

The approach has a “favorable pathologic response, is well tolerated ... and thus should be considered a new standard of care option,” said investigators led by Wesley Yip, MD, a urologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York.

There was no comparator arm, but the results are in line with previous reports, including a 2014 investigation that found a 5-year disease specific survival (DSS) of 90.1% and 5-year overall survival (OS) of 80.2% among 31 upper tract urothelial carcinoma patients who received neoadjuvant chemotherapy, versus a 5-year DSS and OS of 57.6% among 81 historical controls.

Presentation moderator Stephen Boorjian, MD, chair of urology at the Mayo Clinic in Rochester, Minn., called the findings “valuable” but noted there’s level 1 evidence for an alternative approach, chemotherapy or nivolumab after surgery for patients with particularly worrisome postop pathology. It makes it tough to know if patients should be treated beforehand or afterwards.

“What do we do?” he asked.

Dr. Yip said it’s an open question at this point but that trials are underway to address the issue. In the meantime, “it’s definitely a multidisciplinary discussion to know what’s best for each patient,” he said. One of the factors that argues for the neoadjuvant approach is that substantially fewer patients are eligible for chemotherapy after nephroureterectomy because of diminished renal function. “Patients who might not be eligible ... are the ones we’d be targeting for” neoadjuvant chemotherapy (NAC), he said.

In the study, gemcitabine 1000 mg/m² and cisplatin 35 mg/m² were administered on days 1 and 8 of four 21-day cycles, followed by radical nephroureterectomy or ureterectomy.

Fifty-three of the subjects had high-grade disease by endoscopic biopsy, and the remaining four were enrolled based on imaging and selective cytology. There was no nodal disease on CT within 30 days of neoadjuvant chemotherapy initiation.

Two-year progression-free survival (PFS) was 91% among pathologic responders but only 52% among nonresponders. Every responder was alive at 2 years versus 80% of nonresponders.

Across the entire cohort, 5-year PFS was 61% and 5-year OS 79%; 89.5% of patients were alive at a median follow-up of 3.5 years.

Almost all of the patients completed at least three NAC cycles, and all of them went to surgery, which had a 90-day grade 3 or higher complication rate of 7%.

Sixty-three percent were men, and 95% were White. The median age was 66 years.

The work was funded by the National Institutes of Health and Memorial Sloan Kettering. Dr. Yip had no disclosures. Dr. Boorjian advises ArTara Therapeutics, FerGene, and Ferring.

There was a remarkable reduction in bowel and urinary side effects when MRI was used instead of CT to guide stereotactic body radiotherapy (SBRT) for localized prostate cancer, shows a study from the University of California, Los Angeles.

Among the first 100 men in the phase 3 MIRAGE trial (Magnetic Resonance Imaging–Guided Versus Computed Tomography–Guided Stereotactic Body Radiotherapy for Prostate Cancer), MRI guidance more than halved the incidence of grade 2 or higher physician-reported genitourinary toxicity within 90 days of the procedure, which fell from 47.1% with CT to 22.4% with MRI.

While 13.7% of men had gastrointestinal complications with CT guidance, there wasn’t a single case in the MRI arm. The findings were presented Feb. 17 at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

The investigators thought they’d need 300 men to detect a safety difference, but the results are so strong that they’ve scaled back enrollment to 154. In the meantime, MRI-guided SBRT is now offered routinely to men with localized prostate cancer at UCLA.

“Our final results are expected later this year, but we are extremely optimistic by what we’re seeing, and hope this technology will soon begin to offer men undergoing radiotherapy for prostate cancer better outcomes,” said lead investigator Amar Upadhyaya Kishan, MD, a genitourinary oncology radiologist, in a UCLA press release.

The better outcomes are caused by the enhanced imaging capabilities of MRI, including real time tracking and automatic beam shutoff when the prostate moves too far outside of the treatment boundary, Dr. Kishan explained on Twitter.

Because of the extra precision, “we felt we could safely reduce the planning margins to only 2 mm” with MRI, down from 4 mm with CT. It translated to smaller treatment volumes and less collateral tissue damage, he said.

Across the first 100 subjects, 49 men were randomized to MRI-guided SBRT and 51 to SBRT with CT guidance. Their prostates and proximal seminal vesicles were dosed with 40 Gy of radiation in five fractions. Rectal spacing and nodal irradiation were at physician discretion.

Patients in the MRI arm also reported significantly fewer urinary symptoms, including urgency, incontinence, burning sensations, and bowel dysfunction, such as pain, diarrhea, and obstruction, among others, at 1 month with MRI guidance. The differences diminished at 3 months with adverse event management in the CT arm.

Lymph nodes were irradiated in 29% of men in the CT group versus 20% in the MRI arm, and 37% of the CT group versus 27% with MRI had rectal spacing.

Baseline gland size was a median of 39 mL in both groups. Baseline International Prostate Symptom Scores were a median of 8 points in the MRI group but 5 points in the CT arm.

The work was funded by UCLA, among others. Dr. Kishan has ownership interests in ViewRay, the company that makes the MRI-guiding technology used in the trial, and reported honoraria and research funding from the company.

There was a remarkable reduction in bowel and urinary side effects when MRI was used instead of CT to guide stereotactic body radiotherapy (SBRT) for localized prostate cancer, shows a study from the University of California, Los Angeles.

Among the first 100 men in the phase 3 MIRAGE trial (Magnetic Resonance Imaging–Guided Versus Computed Tomography–Guided Stereotactic Body Radiotherapy for Prostate Cancer), MRI guidance more than halved the incidence of grade 2 or higher physician-reported genitourinary toxicity within 90 days of the procedure, which fell from 47.1% with CT to 22.4% with MRI.

While 13.7% of men had gastrointestinal complications with CT guidance, there wasn’t a single case in the MRI arm. The findings were presented Feb. 17 at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

The investigators thought they’d need 300 men to detect a safety difference, but the results are so strong that they’ve scaled back enrollment to 154. In the meantime, MRI-guided SBRT is now offered routinely to men with localized prostate cancer at UCLA.

“Our final results are expected later this year, but we are extremely optimistic by what we’re seeing, and hope this technology will soon begin to offer men undergoing radiotherapy for prostate cancer better outcomes,” said lead investigator Amar Upadhyaya Kishan, MD, a genitourinary oncology radiologist, in a UCLA press release.

The better outcomes are caused by the enhanced imaging capabilities of MRI, including real time tracking and automatic beam shutoff when the prostate moves too far outside of the treatment boundary, Dr. Kishan explained on Twitter.

Because of the extra precision, “we felt we could safely reduce the planning margins to only 2 mm” with MRI, down from 4 mm with CT. It translated to smaller treatment volumes and less collateral tissue damage, he said.

Across the first 100 subjects, 49 men were randomized to MRI-guided SBRT and 51 to SBRT with CT guidance. Their prostates and proximal seminal vesicles were dosed with 40 Gy of radiation in five fractions. Rectal spacing and nodal irradiation were at physician discretion.

Patients in the MRI arm also reported significantly fewer urinary symptoms, including urgency, incontinence, burning sensations, and bowel dysfunction, such as pain, diarrhea, and obstruction, among others, at 1 month with MRI guidance. The differences diminished at 3 months with adverse event management in the CT arm.

Lymph nodes were irradiated in 29% of men in the CT group versus 20% in the MRI arm, and 37% of the CT group versus 27% with MRI had rectal spacing.

Baseline gland size was a median of 39 mL in both groups. Baseline International Prostate Symptom Scores were a median of 8 points in the MRI group but 5 points in the CT arm.

The work was funded by UCLA, among others. Dr. Kishan has ownership interests in ViewRay, the company that makes the MRI-guiding technology used in the trial, and reported honoraria and research funding from the company.

There was a remarkable reduction in bowel and urinary side effects when MRI was used instead of CT to guide stereotactic body radiotherapy (SBRT) for localized prostate cancer, shows a study from the University of California, Los Angeles.

Among the first 100 men in the phase 3 MIRAGE trial (Magnetic Resonance Imaging–Guided Versus Computed Tomography–Guided Stereotactic Body Radiotherapy for Prostate Cancer), MRI guidance more than halved the incidence of grade 2 or higher physician-reported genitourinary toxicity within 90 days of the procedure, which fell from 47.1% with CT to 22.4% with MRI.

While 13.7% of men had gastrointestinal complications with CT guidance, there wasn’t a single case in the MRI arm. The findings were presented Feb. 17 at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

The investigators thought they’d need 300 men to detect a safety difference, but the results are so strong that they’ve scaled back enrollment to 154. In the meantime, MRI-guided SBRT is now offered routinely to men with localized prostate cancer at UCLA.

“Our final results are expected later this year, but we are extremely optimistic by what we’re seeing, and hope this technology will soon begin to offer men undergoing radiotherapy for prostate cancer better outcomes,” said lead investigator Amar Upadhyaya Kishan, MD, a genitourinary oncology radiologist, in a UCLA press release.

The better outcomes are caused by the enhanced imaging capabilities of MRI, including real time tracking and automatic beam shutoff when the prostate moves too far outside of the treatment boundary, Dr. Kishan explained on Twitter.

Because of the extra precision, “we felt we could safely reduce the planning margins to only 2 mm” with MRI, down from 4 mm with CT. It translated to smaller treatment volumes and less collateral tissue damage, he said.

Across the first 100 subjects, 49 men were randomized to MRI-guided SBRT and 51 to SBRT with CT guidance. Their prostates and proximal seminal vesicles were dosed with 40 Gy of radiation in five fractions. Rectal spacing and nodal irradiation were at physician discretion.

Patients in the MRI arm also reported significantly fewer urinary symptoms, including urgency, incontinence, burning sensations, and bowel dysfunction, such as pain, diarrhea, and obstruction, among others, at 1 month with MRI guidance. The differences diminished at 3 months with adverse event management in the CT arm.

Lymph nodes were irradiated in 29% of men in the CT group versus 20% in the MRI arm, and 37% of the CT group versus 27% with MRI had rectal spacing.

Baseline gland size was a median of 39 mL in both groups. Baseline International Prostate Symptom Scores were a median of 8 points in the MRI group but 5 points in the CT arm.

The work was funded by UCLA, among others. Dr. Kishan has ownership interests in ViewRay, the company that makes the MRI-guiding technology used in the trial, and reported honoraria and research funding from the company.

Three physicians with the Food and Drug Administration suggest in a recent JAMA Oncology viewpoint article that it might be time to give drug companies a deadline to meet accelerated approval requirements, as is done in other countries.

The FDA launched its accelerated approval program in 1992 in response to the AIDS crisis, but the bulk of approvals since then have been for cancer drugs, wrote the authors who included Gautam U. Mehta, MD, a clinical reviewer with the FDA’s Center for Drug Evaluation and Research; R. Angelo de Claro, MD, associate director of the FDA’s Global Clinical Sciences division within the Oncology Center of Excellence; and Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.

Accelerated approvals are typically granted in oncology based on overall response rate with a requirement that companies confirm that there’s actually a clinical benefit in postmarketing studies.

The system has inspired European nations and Australia to launch their own programs, but with a key difference: Conditional approvals expire within 1 year or 2.

To be reinstated and remain on the market, companies have to submit a timeline for when they’ll meet their outstanding obligations and demonstrate that the benefit of leaving their product on the market outweighs the risk.

The approach puts “the onus of timely completion of confirmatory trials and verification of benefit” on the drug maker. In the meantime, the system limits “public exposure to stale claims of effectiveness that cannot be expeditiously substantiated,” Dr. Mehta and colleagues wrote.

There aren’t any deadlines in the United States, however, so the FDA has “to initiate a resource-intensive withdrawal process” when proof of clinical benefit is not forthcoming, they said.

In the United States, only 14 of 167 oncology indications granted accelerated approval since 1992 were withdrawn voluntarily and one was withdrawn by FDA request, and one was forced by the agency. The median time from accelerated approval to withdrawal was 8.8 years.

The actual withdrawal process itself took 11 months when bevacizumab’s breast cancer indication was canceled in 2011.

The authors didn’t call for change outright, but they did say that “future discussions of the accelerated approval program in the U.S.” will seek “to coordinate regulatory processes” with other countries, with an eye towards building “harmony between” agencies.

Among other targets for possible harmonization, they noted that only new molecular entities are eligible for accelerated approval in Europe, whereas supplemental indications are also eligible in the United States

Europe also requires a risk-benefit assessment for conditional approvals, which “has led to relatively few approvals based on single-arm clinical trial data,” the authors said.

Dr. Mehta, Dr. de Claro, and Dr. Pazdur had no conflicts of interest.

Three physicians with the Food and Drug Administration suggest in a recent JAMA Oncology viewpoint article that it might be time to give drug companies a deadline to meet accelerated approval requirements, as is done in other countries.

The FDA launched its accelerated approval program in 1992 in response to the AIDS crisis, but the bulk of approvals since then have been for cancer drugs, wrote the authors who included Gautam U. Mehta, MD, a clinical reviewer with the FDA’s Center for Drug Evaluation and Research; R. Angelo de Claro, MD, associate director of the FDA’s Global Clinical Sciences division within the Oncology Center of Excellence; and Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.

Accelerated approvals are typically granted in oncology based on overall response rate with a requirement that companies confirm that there’s actually a clinical benefit in postmarketing studies.

The system has inspired European nations and Australia to launch their own programs, but with a key difference: Conditional approvals expire within 1 year or 2.

To be reinstated and remain on the market, companies have to submit a timeline for when they’ll meet their outstanding obligations and demonstrate that the benefit of leaving their product on the market outweighs the risk.

The approach puts “the onus of timely completion of confirmatory trials and verification of benefit” on the drug maker. In the meantime, the system limits “public exposure to stale claims of effectiveness that cannot be expeditiously substantiated,” Dr. Mehta and colleagues wrote.

There aren’t any deadlines in the United States, however, so the FDA has “to initiate a resource-intensive withdrawal process” when proof of clinical benefit is not forthcoming, they said.

In the United States, only 14 of 167 oncology indications granted accelerated approval since 1992 were withdrawn voluntarily and one was withdrawn by FDA request, and one was forced by the agency. The median time from accelerated approval to withdrawal was 8.8 years.

The actual withdrawal process itself took 11 months when bevacizumab’s breast cancer indication was canceled in 2011.

The authors didn’t call for change outright, but they did say that “future discussions of the accelerated approval program in the U.S.” will seek “to coordinate regulatory processes” with other countries, with an eye towards building “harmony between” agencies.

Among other targets for possible harmonization, they noted that only new molecular entities are eligible for accelerated approval in Europe, whereas supplemental indications are also eligible in the United States

Europe also requires a risk-benefit assessment for conditional approvals, which “has led to relatively few approvals based on single-arm clinical trial data,” the authors said.

Dr. Mehta, Dr. de Claro, and Dr. Pazdur had no conflicts of interest.

Three physicians with the Food and Drug Administration suggest in a recent JAMA Oncology viewpoint article that it might be time to give drug companies a deadline to meet accelerated approval requirements, as is done in other countries.

The FDA launched its accelerated approval program in 1992 in response to the AIDS crisis, but the bulk of approvals since then have been for cancer drugs, wrote the authors who included Gautam U. Mehta, MD, a clinical reviewer with the FDA’s Center for Drug Evaluation and Research; R. Angelo de Claro, MD, associate director of the FDA’s Global Clinical Sciences division within the Oncology Center of Excellence; and Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.

Accelerated approvals are typically granted in oncology based on overall response rate with a requirement that companies confirm that there’s actually a clinical benefit in postmarketing studies.

The system has inspired European nations and Australia to launch their own programs, but with a key difference: Conditional approvals expire within 1 year or 2.

To be reinstated and remain on the market, companies have to submit a timeline for when they’ll meet their outstanding obligations and demonstrate that the benefit of leaving their product on the market outweighs the risk.

The approach puts “the onus of timely completion of confirmatory trials and verification of benefit” on the drug maker. In the meantime, the system limits “public exposure to stale claims of effectiveness that cannot be expeditiously substantiated,” Dr. Mehta and colleagues wrote.

There aren’t any deadlines in the United States, however, so the FDA has “to initiate a resource-intensive withdrawal process” when proof of clinical benefit is not forthcoming, they said.

In the United States, only 14 of 167 oncology indications granted accelerated approval since 1992 were withdrawn voluntarily and one was withdrawn by FDA request, and one was forced by the agency. The median time from accelerated approval to withdrawal was 8.8 years.

The actual withdrawal process itself took 11 months when bevacizumab’s breast cancer indication was canceled in 2011.

The authors didn’t call for change outright, but they did say that “future discussions of the accelerated approval program in the U.S.” will seek “to coordinate regulatory processes” with other countries, with an eye towards building “harmony between” agencies.

Among other targets for possible harmonization, they noted that only new molecular entities are eligible for accelerated approval in Europe, whereas supplemental indications are also eligible in the United States

Europe also requires a risk-benefit assessment for conditional approvals, which “has led to relatively few approvals based on single-arm clinical trial data,” the authors said.

Dr. Mehta, Dr. de Claro, and Dr. Pazdur had no conflicts of interest.

In the wake of the pivotal IDEA TRIAL, oncologists have shifted towards shorter adjuvant chemotherapy regimens for stage III colon cancer and a greater reliance on CAPOX (capecitabine plus oxaliplatin) instead of FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin), according to a review of 366 patients.

The international IDEA trial showed that, across almost 13,000 subjects, 3 months of treatment with either regimen was not inferior to 6 months, which was standard at the time for low-risk disease and often led to significantly less grade 2, but more neuropathy.

In high-risk patients (T4, N2), 3-year disease-free survival was almost identical between 3 months of CAPOX (64.1%) and 6 months (64.0%), but 3 months of FOLFOX was inferior to 6 months of FOLFOX (61.5% vs. 64.7%).

Oncologists paid attention, according to the new review, which was presented at the 2022 Gastrointestinal Cancers Symposium.

Overall, 16.3% of patients were prescribed CAPOX in June 2016, but before the study was published in the New England Journal of Medicine, the number rose to 66.8% by June 2020.

“We are using a lot more CAPOX in this country now, and it’s interesting we are doing that because the data aren’t quite there” yet for patients in the United States, said lead investigator Daniel Walden, MD, a hematology/oncology fellow at Mayo Clinic Arizona, Phoenix.

IDEA pulled data from six trials, but only one included U.S. patients and it did not permit CAPOX, only FOLFOX. As a result, the growing use of CAPOX in the United States is based on outcomes elsewhere, primarily Europe and Japan.

The problem, Dr. Walden said, is that U.S. patients don’t tolerate capecitabine as well as people in other countries because of the high intake of dietary folic acid, which is added to grains in the United States and interferes with capecitabine clearance.

He and his team are now looking into outcomes, particularly with CAPOX, in their U.S. cohort, which was pulled from Mayo Clinic campuses in Arizona, Minnesota, and Florida, with additional subjects from Emory and Vanderbilt Universities. “Hopefully,” data to support the shift to adjuvant CAPOX in the United States “will be here soon. I feel more confident prescribing 3 months of CAPOX for high-risk patients, seeing that more people do it than I would have thought,” Dr. Walden said. His study found a 25.9% adoption in June 2020, which was up from 1.3% in June 2016.

Among other findings, 78.3% of patients received 6 months of FOLFOX in June 2016, which fell to 17.3% 4 years later. There was a corresponding shift in 3-month courses of CAPOX, up from 7.4% to 67.5% over the same period.

By June 2020, low-risk patients were far more likely to receive 3 months of CAPOX (67.9%) than any other regimen.

Among high-risk patients, the number who received 6 months of FOLFOX fell from 86.6% to 47.8%, while the number who received 3 months of FOLFOX increased from 0.9% to 3.9%. Use of CAPOX for 6 months in high-risk patients climbed from 11.2% of patients to 22.4%.

There was no funding for the work, and Dr. Walden didn’t have any disclosures.

In the wake of the pivotal IDEA TRIAL, oncologists have shifted towards shorter adjuvant chemotherapy regimens for stage III colon cancer and a greater reliance on CAPOX (capecitabine plus oxaliplatin) instead of FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin), according to a review of 366 patients.

The international IDEA trial showed that, across almost 13,000 subjects, 3 months of treatment with either regimen was not inferior to 6 months, which was standard at the time for low-risk disease and often led to significantly less grade 2, but more neuropathy.

In high-risk patients (T4, N2), 3-year disease-free survival was almost identical between 3 months of CAPOX (64.1%) and 6 months (64.0%), but 3 months of FOLFOX was inferior to 6 months of FOLFOX (61.5% vs. 64.7%).

Oncologists paid attention, according to the new review, which was presented at the 2022 Gastrointestinal Cancers Symposium.

Overall, 16.3% of patients were prescribed CAPOX in June 2016, but before the study was published in the New England Journal of Medicine, the number rose to 66.8% by June 2020.

“We are using a lot more CAPOX in this country now, and it’s interesting we are doing that because the data aren’t quite there” yet for patients in the United States, said lead investigator Daniel Walden, MD, a hematology/oncology fellow at Mayo Clinic Arizona, Phoenix.

IDEA pulled data from six trials, but only one included U.S. patients and it did not permit CAPOX, only FOLFOX. As a result, the growing use of CAPOX in the United States is based on outcomes elsewhere, primarily Europe and Japan.

The problem, Dr. Walden said, is that U.S. patients don’t tolerate capecitabine as well as people in other countries because of the high intake of dietary folic acid, which is added to grains in the United States and interferes with capecitabine clearance.

He and his team are now looking into outcomes, particularly with CAPOX, in their U.S. cohort, which was pulled from Mayo Clinic campuses in Arizona, Minnesota, and Florida, with additional subjects from Emory and Vanderbilt Universities. “Hopefully,” data to support the shift to adjuvant CAPOX in the United States “will be here soon. I feel more confident prescribing 3 months of CAPOX for high-risk patients, seeing that more people do it than I would have thought,” Dr. Walden said. His study found a 25.9% adoption in June 2020, which was up from 1.3% in June 2016.

Among other findings, 78.3% of patients received 6 months of FOLFOX in June 2016, which fell to 17.3% 4 years later. There was a corresponding shift in 3-month courses of CAPOX, up from 7.4% to 67.5% over the same period.

By June 2020, low-risk patients were far more likely to receive 3 months of CAPOX (67.9%) than any other regimen.

Among high-risk patients, the number who received 6 months of FOLFOX fell from 86.6% to 47.8%, while the number who received 3 months of FOLFOX increased from 0.9% to 3.9%. Use of CAPOX for 6 months in high-risk patients climbed from 11.2% of patients to 22.4%.

There was no funding for the work, and Dr. Walden didn’t have any disclosures.

In the wake of the pivotal IDEA TRIAL, oncologists have shifted towards shorter adjuvant chemotherapy regimens for stage III colon cancer and a greater reliance on CAPOX (capecitabine plus oxaliplatin) instead of FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin), according to a review of 366 patients.

The international IDEA trial showed that, across almost 13,000 subjects, 3 months of treatment with either regimen was not inferior to 6 months, which was standard at the time for low-risk disease and often led to significantly less grade 2, but more neuropathy.

In high-risk patients (T4, N2), 3-year disease-free survival was almost identical between 3 months of CAPOX (64.1%) and 6 months (64.0%), but 3 months of FOLFOX was inferior to 6 months of FOLFOX (61.5% vs. 64.7%).

Oncologists paid attention, according to the new review, which was presented at the 2022 Gastrointestinal Cancers Symposium.

Overall, 16.3% of patients were prescribed CAPOX in June 2016, but before the study was published in the New England Journal of Medicine, the number rose to 66.8% by June 2020.

“We are using a lot more CAPOX in this country now, and it’s interesting we are doing that because the data aren’t quite there” yet for patients in the United States, said lead investigator Daniel Walden, MD, a hematology/oncology fellow at Mayo Clinic Arizona, Phoenix.

IDEA pulled data from six trials, but only one included U.S. patients and it did not permit CAPOX, only FOLFOX. As a result, the growing use of CAPOX in the United States is based on outcomes elsewhere, primarily Europe and Japan.

The problem, Dr. Walden said, is that U.S. patients don’t tolerate capecitabine as well as people in other countries because of the high intake of dietary folic acid, which is added to grains in the United States and interferes with capecitabine clearance.

He and his team are now looking into outcomes, particularly with CAPOX, in their U.S. cohort, which was pulled from Mayo Clinic campuses in Arizona, Minnesota, and Florida, with additional subjects from Emory and Vanderbilt Universities. “Hopefully,” data to support the shift to adjuvant CAPOX in the United States “will be here soon. I feel more confident prescribing 3 months of CAPOX for high-risk patients, seeing that more people do it than I would have thought,” Dr. Walden said. His study found a 25.9% adoption in June 2020, which was up from 1.3% in June 2016.

Among other findings, 78.3% of patients received 6 months of FOLFOX in June 2016, which fell to 17.3% 4 years later. There was a corresponding shift in 3-month courses of CAPOX, up from 7.4% to 67.5% over the same period.

By June 2020, low-risk patients were far more likely to receive 3 months of CAPOX (67.9%) than any other regimen.

Among high-risk patients, the number who received 6 months of FOLFOX fell from 86.6% to 47.8%, while the number who received 3 months of FOLFOX increased from 0.9% to 3.9%. Use of CAPOX for 6 months in high-risk patients climbed from 11.2% of patients to 22.4%.

There was no funding for the work, and Dr. Walden didn’t have any disclosures.

A 2021 update to the U.S. Preventive Services Task Force lung cancer screening guidelines eliminated racial disparities that were prevalent in the group’s 2013 guidance, according to a report in JAMA Oncology.

Fewer Black people qualified for screening in the earlier guideline of which the majority of its participants were White. In response, the group changed the screening eligibility age from 55 to 50 years and lowered the smoking pack by year requirement from 30 to 20 years.

The changes showed that Black smokers tend to develop lung cancer earlier and with fewer pack-years than White smokers.
 

The study details

To gauge the impact, investigators from Wayne State University, Detroit, reviewed 912 patients with lung cancer and 1,457 controls without lung cancer to see who would have qualified for screening under the 2013 and 2021 criteria.

They were participants in the Detroit-area INHALE (Inflammation, Health, Ancestry, and Lung Epidemiology) study from 2012 to 2018. Over 30% were Black.

“Lowering the age and smoking criteria successfully bridged the gap in racial disparity,” said investigators led by Chan Yeu Pu, MD, a lung cancer specialist at Wayne State University.

With the 2021 criteria, 65% of White patients and 63% of Black patients with lung cancer would have been eligible for screening. Under the 2013 guidance, 52% of White patients were eligible for screening, but only 42% of Black patients.

The update also eliminated racial disparities among controls. The new guidance excluded 48% of White controls without lung cancer from screening and 50% of Black controls. The 2013 criteria excluded fewer White controls (61%) than Black control subjects (70%).

“As expected, broader inclusion criteria increased sensitivity, but at the cost of decreased specificity,” the investigators wrote.
 

Why is screening important?

The hope of screening is to catch lung cancer early, when curative surgical resection is still possible, the team wrote, but although screening has increased over the years, uptake remains dismal, just 5% in 2018, for instance.

In an editorial, Philadelphia-area thoracic surgeons Jonathan Nitz, MD, and Cherie Erkmen, MD, wrote that “multiple and changing criteria” and “nebulous payment plans” have made “for a confusing message. ... We need standardized” guidelines to deliver “a clear message about lung cancer screening.”

The fact that nearly two-thirds of lung cancer patients wouldn’t have qualified for screening under current guidelines also needs to be addressed. “We need standardized practice guidelines based on evidence from diverse populations and policies to ensure equitable access for high-risk individuals. Although this study demonstrates improved, calculated sensitivity of the 2021 USPSTF guidelines to detect lung cancer, these refinements of criteria do not address the nearly two-thirds of patients with diagnosed lung cancer who are not eligible for screening. There is a pressing need to redefine screening criteria,” Dr. Nitz and Dr. Erkmen wrote.

Both the 2013 and 2021 guidelines were outperformed in the study by the 2012 modification of the model from the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCOm2012 criteria), but only marginally so in the case of USPSTF’s 2021 guidance.

PLCOm2012 screening eligibility, however, are based on a complicated risk factor assessments that include race but also education level and other factors which might not be readily available in electronic records. USPSTF’s criteria “are much more straightforward to use in a clinical setting,” the investigators noted.

Study subjects were 21-89 years old and were in their early 60s, on average. Just over half were women. The analysis excluded lung cancer patients and controls who had never smoked.

The authors noted some limitations, including the retrospective nature of the study, plus, few lung cancers were diagnosed among the control group, which were not only small, but they did not include follow-ups with CT scans.

The work was funded by the National Institutes of Health and the Herrick Foundation. Dr. Pu didn’t have any commercial disclosures. One investigator disclosed personal fees from Takeda, AstraZeneca, Genentech/Roche, Pfizer, and other companies. Dr. Erkmen reported an American Cancer Society-Pfizer Award to address disparities.

A 2021 update to the U.S. Preventive Services Task Force lung cancer screening guidelines eliminated racial disparities that were prevalent in the group’s 2013 guidance, according to a report in JAMA Oncology.

Fewer Black people qualified for screening in the earlier guideline of which the majority of its participants were White. In response, the group changed the screening eligibility age from 55 to 50 years and lowered the smoking pack by year requirement from 30 to 20 years.

The changes showed that Black smokers tend to develop lung cancer earlier and with fewer pack-years than White smokers.
 

The study details

To gauge the impact, investigators from Wayne State University, Detroit, reviewed 912 patients with lung cancer and 1,457 controls without lung cancer to see who would have qualified for screening under the 2013 and 2021 criteria.

They were participants in the Detroit-area INHALE (Inflammation, Health, Ancestry, and Lung Epidemiology) study from 2012 to 2018. Over 30% were Black.

“Lowering the age and smoking criteria successfully bridged the gap in racial disparity,” said investigators led by Chan Yeu Pu, MD, a lung cancer specialist at Wayne State University.

With the 2021 criteria, 65% of White patients and 63% of Black patients with lung cancer would have been eligible for screening. Under the 2013 guidance, 52% of White patients were eligible for screening, but only 42% of Black patients.

The update also eliminated racial disparities among controls. The new guidance excluded 48% of White controls without lung cancer from screening and 50% of Black controls. The 2013 criteria excluded fewer White controls (61%) than Black control subjects (70%).

“As expected, broader inclusion criteria increased sensitivity, but at the cost of decreased specificity,” the investigators wrote.
 

Why is screening important?

The hope of screening is to catch lung cancer early, when curative surgical resection is still possible, the team wrote, but although screening has increased over the years, uptake remains dismal, just 5% in 2018, for instance.

In an editorial, Philadelphia-area thoracic surgeons Jonathan Nitz, MD, and Cherie Erkmen, MD, wrote that “multiple and changing criteria” and “nebulous payment plans” have made “for a confusing message. ... We need standardized” guidelines to deliver “a clear message about lung cancer screening.”

The fact that nearly two-thirds of lung cancer patients wouldn’t have qualified for screening under current guidelines also needs to be addressed. “We need standardized practice guidelines based on evidence from diverse populations and policies to ensure equitable access for high-risk individuals. Although this study demonstrates improved, calculated sensitivity of the 2021 USPSTF guidelines to detect lung cancer, these refinements of criteria do not address the nearly two-thirds of patients with diagnosed lung cancer who are not eligible for screening. There is a pressing need to redefine screening criteria,” Dr. Nitz and Dr. Erkmen wrote.

Both the 2013 and 2021 guidelines were outperformed in the study by the 2012 modification of the model from the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCOm2012 criteria), but only marginally so in the case of USPSTF’s 2021 guidance.

PLCOm2012 screening eligibility, however, are based on a complicated risk factor assessments that include race but also education level and other factors which might not be readily available in electronic records. USPSTF’s criteria “are much more straightforward to use in a clinical setting,” the investigators noted.

Study subjects were 21-89 years old and were in their early 60s, on average. Just over half were women. The analysis excluded lung cancer patients and controls who had never smoked.

The authors noted some limitations, including the retrospective nature of the study, plus, few lung cancers were diagnosed among the control group, which were not only small, but they did not include follow-ups with CT scans.

The work was funded by the National Institutes of Health and the Herrick Foundation. Dr. Pu didn’t have any commercial disclosures. One investigator disclosed personal fees from Takeda, AstraZeneca, Genentech/Roche, Pfizer, and other companies. Dr. Erkmen reported an American Cancer Society-Pfizer Award to address disparities.

A 2021 update to the U.S. Preventive Services Task Force lung cancer screening guidelines eliminated racial disparities that were prevalent in the group’s 2013 guidance, according to a report in JAMA Oncology.

Fewer Black people qualified for screening in the earlier guideline of which the majority of its participants were White. In response, the group changed the screening eligibility age from 55 to 50 years and lowered the smoking pack by year requirement from 30 to 20 years.

The changes showed that Black smokers tend to develop lung cancer earlier and with fewer pack-years than White smokers.
 

The study details

To gauge the impact, investigators from Wayne State University, Detroit, reviewed 912 patients with lung cancer and 1,457 controls without lung cancer to see who would have qualified for screening under the 2013 and 2021 criteria.

They were participants in the Detroit-area INHALE (Inflammation, Health, Ancestry, and Lung Epidemiology) study from 2012 to 2018. Over 30% were Black.

“Lowering the age and smoking criteria successfully bridged the gap in racial disparity,” said investigators led by Chan Yeu Pu, MD, a lung cancer specialist at Wayne State University.

With the 2021 criteria, 65% of White patients and 63% of Black patients with lung cancer would have been eligible for screening. Under the 2013 guidance, 52% of White patients were eligible for screening, but only 42% of Black patients.

The update also eliminated racial disparities among controls. The new guidance excluded 48% of White controls without lung cancer from screening and 50% of Black controls. The 2013 criteria excluded fewer White controls (61%) than Black control subjects (70%).

“As expected, broader inclusion criteria increased sensitivity, but at the cost of decreased specificity,” the investigators wrote.
 

Why is screening important?

The hope of screening is to catch lung cancer early, when curative surgical resection is still possible, the team wrote, but although screening has increased over the years, uptake remains dismal, just 5% in 2018, for instance.

In an editorial, Philadelphia-area thoracic surgeons Jonathan Nitz, MD, and Cherie Erkmen, MD, wrote that “multiple and changing criteria” and “nebulous payment plans” have made “for a confusing message. ... We need standardized” guidelines to deliver “a clear message about lung cancer screening.”

The fact that nearly two-thirds of lung cancer patients wouldn’t have qualified for screening under current guidelines also needs to be addressed. “We need standardized practice guidelines based on evidence from diverse populations and policies to ensure equitable access for high-risk individuals. Although this study demonstrates improved, calculated sensitivity of the 2021 USPSTF guidelines to detect lung cancer, these refinements of criteria do not address the nearly two-thirds of patients with diagnosed lung cancer who are not eligible for screening. There is a pressing need to redefine screening criteria,” Dr. Nitz and Dr. Erkmen wrote.

Both the 2013 and 2021 guidelines were outperformed in the study by the 2012 modification of the model from the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCOm2012 criteria), but only marginally so in the case of USPSTF’s 2021 guidance.

PLCOm2012 screening eligibility, however, are based on a complicated risk factor assessments that include race but also education level and other factors which might not be readily available in electronic records. USPSTF’s criteria “are much more straightforward to use in a clinical setting,” the investigators noted.

Study subjects were 21-89 years old and were in their early 60s, on average. Just over half were women. The analysis excluded lung cancer patients and controls who had never smoked.

The authors noted some limitations, including the retrospective nature of the study, plus, few lung cancers were diagnosed among the control group, which were not only small, but they did not include follow-ups with CT scans.

The work was funded by the National Institutes of Health and the Herrick Foundation. Dr. Pu didn’t have any commercial disclosures. One investigator disclosed personal fees from Takeda, AstraZeneca, Genentech/Roche, Pfizer, and other companies. Dr. Erkmen reported an American Cancer Society-Pfizer Award to address disparities.

The label for axicabtagene ciloleucel (Yescarta, Kite) has been updated to include prophylactic corticosteroids to manage cytokine release syndrome (CRS).

This is a chimeric antigen receptor T-cell product indicated for use in adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy.

The product label carries a black box warning that CRS is a potentially fatal complication. With the update, the new labeling advises clinicians to “consider the use of prophylactic corticosteroid in patients after weighing the potential benefits and risks ... to delay the onset and decrease the duration of CRS.”

However, labeling also notes that “prophylactic corticosteroids ... may result in [a] higher grade of neurologic toxicities or prolongation of neurologic toxicities,” another potentially fatal complication noted in the black box warning.

The addition of prophylactic corticosteroids to labeling was based on data from 39 patients with relapsed or refractory LBCL who received dexamethasone 10 mg orally once daily for 3 days starting prior to Yescarta infusion. In this cohort, 31 of the 39 patients (79%) developed CRS, at which point they were managed with tocilizumab and/or corticosteroids. No one developed grade 3 or higher CRS. The median time to CRS onset was 5 days and the median duration was 4 days, according to labeling.

In contrast, in another cohort of 41 patients who were started on tocilizumab and/or corticosteroids only after becoming symptomatic, the overall incidence of CRS was 93% (38/41), with a median onset at 2 days, median duration of 7 days, and two patients who developed grade 3 CRS.

Prophylactic steroids do not compromise the activity of the cell therapy, Kite said in a press release.

“These new data will enable doctors to more easily and confidently manage treatment for patients,” said Frank Neumann, MD, PhD, the company’s global head of clinical development.

Yescarta is currently under review in the United States and Europe for second-line use in relapsed or refractory LBCL, Kite noted.

A version of this article first appeared on Medscape.com.

The label for axicabtagene ciloleucel (Yescarta, Kite) has been updated to include prophylactic corticosteroids to manage cytokine release syndrome (CRS).

This is a chimeric antigen receptor T-cell product indicated for use in adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy.

The product label carries a black box warning that CRS is a potentially fatal complication. With the update, the new labeling advises clinicians to “consider the use of prophylactic corticosteroid in patients after weighing the potential benefits and risks ... to delay the onset and decrease the duration of CRS.”

However, labeling also notes that “prophylactic corticosteroids ... may result in [a] higher grade of neurologic toxicities or prolongation of neurologic toxicities,” another potentially fatal complication noted in the black box warning.

The addition of prophylactic corticosteroids to labeling was based on data from 39 patients with relapsed or refractory LBCL who received dexamethasone 10 mg orally once daily for 3 days starting prior to Yescarta infusion. In this cohort, 31 of the 39 patients (79%) developed CRS, at which point they were managed with tocilizumab and/or corticosteroids. No one developed grade 3 or higher CRS. The median time to CRS onset was 5 days and the median duration was 4 days, according to labeling.

In contrast, in another cohort of 41 patients who were started on tocilizumab and/or corticosteroids only after becoming symptomatic, the overall incidence of CRS was 93% (38/41), with a median onset at 2 days, median duration of 7 days, and two patients who developed grade 3 CRS.

Prophylactic steroids do not compromise the activity of the cell therapy, Kite said in a press release.

“These new data will enable doctors to more easily and confidently manage treatment for patients,” said Frank Neumann, MD, PhD, the company’s global head of clinical development.

Yescarta is currently under review in the United States and Europe for second-line use in relapsed or refractory LBCL, Kite noted.

A version of this article first appeared on Medscape.com.

The label for axicabtagene ciloleucel (Yescarta, Kite) has been updated to include prophylactic corticosteroids to manage cytokine release syndrome (CRS).

This is a chimeric antigen receptor T-cell product indicated for use in adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy.

The product label carries a black box warning that CRS is a potentially fatal complication. With the update, the new labeling advises clinicians to “consider the use of prophylactic corticosteroid in patients after weighing the potential benefits and risks ... to delay the onset and decrease the duration of CRS.”

However, labeling also notes that “prophylactic corticosteroids ... may result in [a] higher grade of neurologic toxicities or prolongation of neurologic toxicities,” another potentially fatal complication noted in the black box warning.

The addition of prophylactic corticosteroids to labeling was based on data from 39 patients with relapsed or refractory LBCL who received dexamethasone 10 mg orally once daily for 3 days starting prior to Yescarta infusion. In this cohort, 31 of the 39 patients (79%) developed CRS, at which point they were managed with tocilizumab and/or corticosteroids. No one developed grade 3 or higher CRS. The median time to CRS onset was 5 days and the median duration was 4 days, according to labeling.

In contrast, in another cohort of 41 patients who were started on tocilizumab and/or corticosteroids only after becoming symptomatic, the overall incidence of CRS was 93% (38/41), with a median onset at 2 days, median duration of 7 days, and two patients who developed grade 3 CRS.

Prophylactic steroids do not compromise the activity of the cell therapy, Kite said in a press release.

“These new data will enable doctors to more easily and confidently manage treatment for patients,” said Frank Neumann, MD, PhD, the company’s global head of clinical development.

Yescarta is currently under review in the United States and Europe for second-line use in relapsed or refractory LBCL, Kite noted.

A version of this article first appeared on Medscape.com.

A new French study raises the possibility that immunotherapy can help some people with stomach cancer avoid surgery.

GERCOR NEONIPIGA was a phase 2 study with no comparator group and only 32 patients, but even so, after a 6-cycle course of nivolumab and ipilimumab, there was no sign of tumor in 17 of the 29 patients (59%) who had surgery specimens evaluable by pathology.

Indeed, two patients refused surgery after their preop endoscopic biopsies came back clear with no tumor cells. Surgery was called off in a third patient who developed metastases beforehand.

After a median of 12 months follow-up, there’s was no recurrence or progression in 30 patients (94%). The remaining two included the metastatic patient and one who died 3 days after surgery from cardiovascular complications.

If the findings pan out with additional research, the approach could be a boon for people who respond. “Avoiding surgery is a dream for these patients,” said lead investigator Thierry Andre, MD, a medical oncology professor at Sorbonne University, Paris, when he presented the findings at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

The trial “raises the question whether surgery can be delayed or avoided in some patients with localized” disease. Given the findings, “it seems possible not for all but probably for half, maybe more.” As in the two subjects who opted out of surgery, preop endoscopic biopsies could be used to identify complete responders with active surveillance afterwards, he said.

The study included 16 patients with gastric cancer and 16 with esophagogastric adenocarcinoma. They were mismatch repair deficient, which Dr. Andre said predicts response to immunotherapy.

At baseline, 22 had stage T3 disease and four had stage T2 disease, and stage was not evaluable by echo-endoscopy in 6. Nodal status was unknown, but the patients had no metastases at baseline.

They underwent six nivolumab 240-mg infusions and two ipilimumab 1–mg/kg infusions over 12 weeks, followed by R0 resections a median of 5 weeks after the last nivolumab injection.

Surgical specimens from 17 patients (59%) showed a complete pathological response to neoadjuvant immunotherapy (Becker tumor regression grade (TRG) 1a, ypT0N0). TRG was 1b – less than 10% residual tumor in tumor bed in four patients. TRG was 2 in two patients with 10%-50% of residual tumor remaining, and six had a TRG of 3 with more than half of the tumor remaining after immunotherapy.

Based on tumor response, 25 patients had nine additional nivolumab infusions after surgery with 480 mg infused monthly.

Dr. Andre explained that people want to avoid surgery because of the substantial morbidity that was shown in the study, plus 54% of patients had complications, including anastomotic leaks, pancreatitis, pneumonia, and other problems.

There were no new safety signals with neoadjuvant therapy; 25% of patients had grade 3 or 4 events.

The study was conducted in 10 centers in France. About three-quarters of the subjects were men and the median age was 65 years.

Bristol Meyers Squibb supplied the nivolumab and ipilimumab and partially funded the work. Many of the investigators had ties to the company, including Dr. Andre, who is a consultant for BMS and reported payments from the company.

A new French study raises the possibility that immunotherapy can help some people with stomach cancer avoid surgery.

GERCOR NEONIPIGA was a phase 2 study with no comparator group and only 32 patients, but even so, after a 6-cycle course of nivolumab and ipilimumab, there was no sign of tumor in 17 of the 29 patients (59%) who had surgery specimens evaluable by pathology.

Indeed, two patients refused surgery after their preop endoscopic biopsies came back clear with no tumor cells. Surgery was called off in a third patient who developed metastases beforehand.

After a median of 12 months follow-up, there’s was no recurrence or progression in 30 patients (94%). The remaining two included the metastatic patient and one who died 3 days after surgery from cardiovascular complications.

If the findings pan out with additional research, the approach could be a boon for people who respond. “Avoiding surgery is a dream for these patients,” said lead investigator Thierry Andre, MD, a medical oncology professor at Sorbonne University, Paris, when he presented the findings at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

The trial “raises the question whether surgery can be delayed or avoided in some patients with localized” disease. Given the findings, “it seems possible not for all but probably for half, maybe more.” As in the two subjects who opted out of surgery, preop endoscopic biopsies could be used to identify complete responders with active surveillance afterwards, he said.

The study included 16 patients with gastric cancer and 16 with esophagogastric adenocarcinoma. They were mismatch repair deficient, which Dr. Andre said predicts response to immunotherapy.

At baseline, 22 had stage T3 disease and four had stage T2 disease, and stage was not evaluable by echo-endoscopy in 6. Nodal status was unknown, but the patients had no metastases at baseline.

They underwent six nivolumab 240-mg infusions and two ipilimumab 1–mg/kg infusions over 12 weeks, followed by R0 resections a median of 5 weeks after the last nivolumab injection.

Surgical specimens from 17 patients (59%) showed a complete pathological response to neoadjuvant immunotherapy (Becker tumor regression grade (TRG) 1a, ypT0N0). TRG was 1b – less than 10% residual tumor in tumor bed in four patients. TRG was 2 in two patients with 10%-50% of residual tumor remaining, and six had a TRG of 3 with more than half of the tumor remaining after immunotherapy.

Based on tumor response, 25 patients had nine additional nivolumab infusions after surgery with 480 mg infused monthly.

Dr. Andre explained that people want to avoid surgery because of the substantial morbidity that was shown in the study, plus 54% of patients had complications, including anastomotic leaks, pancreatitis, pneumonia, and other problems.

There were no new safety signals with neoadjuvant therapy; 25% of patients had grade 3 or 4 events.

The study was conducted in 10 centers in France. About three-quarters of the subjects were men and the median age was 65 years.

Bristol Meyers Squibb supplied the nivolumab and ipilimumab and partially funded the work. Many of the investigators had ties to the company, including Dr. Andre, who is a consultant for BMS and reported payments from the company.

A new French study raises the possibility that immunotherapy can help some people with stomach cancer avoid surgery.

GERCOR NEONIPIGA was a phase 2 study with no comparator group and only 32 patients, but even so, after a 6-cycle course of nivolumab and ipilimumab, there was no sign of tumor in 17 of the 29 patients (59%) who had surgery specimens evaluable by pathology.

Indeed, two patients refused surgery after their preop endoscopic biopsies came back clear with no tumor cells. Surgery was called off in a third patient who developed metastases beforehand.

After a median of 12 months follow-up, there’s was no recurrence or progression in 30 patients (94%). The remaining two included the metastatic patient and one who died 3 days after surgery from cardiovascular complications.

If the findings pan out with additional research, the approach could be a boon for people who respond. “Avoiding surgery is a dream for these patients,” said lead investigator Thierry Andre, MD, a medical oncology professor at Sorbonne University, Paris, when he presented the findings at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

The trial “raises the question whether surgery can be delayed or avoided in some patients with localized” disease. Given the findings, “it seems possible not for all but probably for half, maybe more.” As in the two subjects who opted out of surgery, preop endoscopic biopsies could be used to identify complete responders with active surveillance afterwards, he said.

The study included 16 patients with gastric cancer and 16 with esophagogastric adenocarcinoma. They were mismatch repair deficient, which Dr. Andre said predicts response to immunotherapy.

At baseline, 22 had stage T3 disease and four had stage T2 disease, and stage was not evaluable by echo-endoscopy in 6. Nodal status was unknown, but the patients had no metastases at baseline.

They underwent six nivolumab 240-mg infusions and two ipilimumab 1–mg/kg infusions over 12 weeks, followed by R0 resections a median of 5 weeks after the last nivolumab injection.

Surgical specimens from 17 patients (59%) showed a complete pathological response to neoadjuvant immunotherapy (Becker tumor regression grade (TRG) 1a, ypT0N0). TRG was 1b – less than 10% residual tumor in tumor bed in four patients. TRG was 2 in two patients with 10%-50% of residual tumor remaining, and six had a TRG of 3 with more than half of the tumor remaining after immunotherapy.

Based on tumor response, 25 patients had nine additional nivolumab infusions after surgery with 480 mg infused monthly.

Dr. Andre explained that people want to avoid surgery because of the substantial morbidity that was shown in the study, plus 54% of patients had complications, including anastomotic leaks, pancreatitis, pneumonia, and other problems.

There were no new safety signals with neoadjuvant therapy; 25% of patients had grade 3 or 4 events.

The study was conducted in 10 centers in France. About three-quarters of the subjects were men and the median age was 65 years.

Bristol Meyers Squibb supplied the nivolumab and ipilimumab and partially funded the work. Many of the investigators had ties to the company, including Dr. Andre, who is a consultant for BMS and reported payments from the company.