User login
M. Alexander Otto began his reporting career early in 1999 covering the pharmaceutical industry for a national pharmacists' magazine and freelancing for the Washington Post and other newspapers. He then joined BNA, now part of Bloomberg News, covering health law and the protection of people and animals in medical research. Alex next worked for the McClatchy Company. Based on his work, Alex won a year-long Knight Science Journalism Fellowship to MIT in 2008-2009. He joined the company shortly thereafter. Alex has a newspaper journalism degree from Syracuse (N.Y.) University and a master's degree in medical science -- a physician assistant degree -- from George Washington University. Alex is based in Seattle.
Nivolumab gets additional adjuvant indication for bladder cancer
The new indication builds on the PD-1 inhibitor’s prior approvals for advanced or metastatic UC that’s progressed during or following platinum-containing chemotherapy or that’s progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
The new indication is based results from the CheckMate-274 trial, which found an almost doubling of median disease-free survival (DFS) with nivolumab compared with placebo.
BMS noted that the new approval makes nivolumab “the first and only PD-1 inhibitor approved for urothelial carcinoma in the adjuvant setting,” regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status.
It “has the potential to become a new standard-of-care option in this setting,” said CheckMate-274’s primary investigator, Matthew Galsky, MD, a genitourinary medical oncologist at the Icahn School of Medicine at Mount Sinai, New York, in the company press release.
Rival PD-1 blocker pembrolizumab (Keytruda), from Merck, carries several UC indications of its own for locally advanced or metastatic disease in patients who are ineligible for platinum-containing chemotherapy or that has progressed despite it, as well as for high-risk, non–muscle invasive bladder cancer that has not responded to bacillus Calmette-Guérin (BCG) treatment in cases in which patients are ineligible for or opt out of cystectomy, according to labeling.
In the CheckMate-274 trial, 353 patients with UC were randomly assigned to receive nivolumab after radical resection, and 356 others were assigned to receive placebo. Nivolumab was adminstered at 240 mg by intravenous infusion every 2 weeks until recurrence or unacceptable toxicity for a maximum duration of 1 year. Neoadjuvant cisplatin chemotherapy was allowed.
Median DFS was 20.8 months with nivolumab versus 10.8 months in the placebo arm. Among patients with PD-L1 expression of 1% or more, median DFS was 8.4 months in the placebo group; it was not reached with nivolumab.
Serious adverse reactions occurred in 30% of patients who received nivolumab. The most frequent was urinary tract infection. Fatal reactions, including pneumonitis, occurred in 1%. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, the labeling notes.
The trial was funded by BMS and Ono Pharmaceutical. Dr. Galsky has been a paid consultant for BMS.
A version of this article first appeared on Medscape.com.
The new indication builds on the PD-1 inhibitor’s prior approvals for advanced or metastatic UC that’s progressed during or following platinum-containing chemotherapy or that’s progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
The new indication is based results from the CheckMate-274 trial, which found an almost doubling of median disease-free survival (DFS) with nivolumab compared with placebo.
BMS noted that the new approval makes nivolumab “the first and only PD-1 inhibitor approved for urothelial carcinoma in the adjuvant setting,” regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status.
It “has the potential to become a new standard-of-care option in this setting,” said CheckMate-274’s primary investigator, Matthew Galsky, MD, a genitourinary medical oncologist at the Icahn School of Medicine at Mount Sinai, New York, in the company press release.
Rival PD-1 blocker pembrolizumab (Keytruda), from Merck, carries several UC indications of its own for locally advanced or metastatic disease in patients who are ineligible for platinum-containing chemotherapy or that has progressed despite it, as well as for high-risk, non–muscle invasive bladder cancer that has not responded to bacillus Calmette-Guérin (BCG) treatment in cases in which patients are ineligible for or opt out of cystectomy, according to labeling.
In the CheckMate-274 trial, 353 patients with UC were randomly assigned to receive nivolumab after radical resection, and 356 others were assigned to receive placebo. Nivolumab was adminstered at 240 mg by intravenous infusion every 2 weeks until recurrence or unacceptable toxicity for a maximum duration of 1 year. Neoadjuvant cisplatin chemotherapy was allowed.
Median DFS was 20.8 months with nivolumab versus 10.8 months in the placebo arm. Among patients with PD-L1 expression of 1% or more, median DFS was 8.4 months in the placebo group; it was not reached with nivolumab.
Serious adverse reactions occurred in 30% of patients who received nivolumab. The most frequent was urinary tract infection. Fatal reactions, including pneumonitis, occurred in 1%. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, the labeling notes.
The trial was funded by BMS and Ono Pharmaceutical. Dr. Galsky has been a paid consultant for BMS.
A version of this article first appeared on Medscape.com.
The new indication builds on the PD-1 inhibitor’s prior approvals for advanced or metastatic UC that’s progressed during or following platinum-containing chemotherapy or that’s progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
The new indication is based results from the CheckMate-274 trial, which found an almost doubling of median disease-free survival (DFS) with nivolumab compared with placebo.
BMS noted that the new approval makes nivolumab “the first and only PD-1 inhibitor approved for urothelial carcinoma in the adjuvant setting,” regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status.
It “has the potential to become a new standard-of-care option in this setting,” said CheckMate-274’s primary investigator, Matthew Galsky, MD, a genitourinary medical oncologist at the Icahn School of Medicine at Mount Sinai, New York, in the company press release.
Rival PD-1 blocker pembrolizumab (Keytruda), from Merck, carries several UC indications of its own for locally advanced or metastatic disease in patients who are ineligible for platinum-containing chemotherapy or that has progressed despite it, as well as for high-risk, non–muscle invasive bladder cancer that has not responded to bacillus Calmette-Guérin (BCG) treatment in cases in which patients are ineligible for or opt out of cystectomy, according to labeling.
In the CheckMate-274 trial, 353 patients with UC were randomly assigned to receive nivolumab after radical resection, and 356 others were assigned to receive placebo. Nivolumab was adminstered at 240 mg by intravenous infusion every 2 weeks until recurrence or unacceptable toxicity for a maximum duration of 1 year. Neoadjuvant cisplatin chemotherapy was allowed.
Median DFS was 20.8 months with nivolumab versus 10.8 months in the placebo arm. Among patients with PD-L1 expression of 1% or more, median DFS was 8.4 months in the placebo group; it was not reached with nivolumab.
Serious adverse reactions occurred in 30% of patients who received nivolumab. The most frequent was urinary tract infection. Fatal reactions, including pneumonitis, occurred in 1%. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, the labeling notes.
The trial was funded by BMS and Ono Pharmaceutical. Dr. Galsky has been a paid consultant for BMS.
A version of this article first appeared on Medscape.com.
‘Remarkable’ results for targeted therapy of rare CNS tumors
The results from three small studies of targeted therapy for rare brain tumors were “remarkable,” according to Jaishri Blakeley, MD, a neurology professor at Johns Hopkins Medicine, Baltimore, who discussed the studies after they were presented at the American Society of Clinical Oncology meeting.
Although most patients don’t have targetable mutations, molecular testing “is well worth the effort,” for those that do. “I think it’s fair to say that precision medicine” – well established in other tumor types – “is finally here in full force for neuro-oncology,” Dr. Blakeley said.
A promising start
Fifteen of 16 patients (94%) in one study had newly diagnosed and untreated papillary craniopharyngiomas (PCPs) that harbored BRAF V600E mutations, a common finding in PCPs, which have no effective medical treatment.
Tumors shrunk 68%-99% in 14 patients (93%) after treatment with the BRAF inhibitor vemurafenib plus the MEK inhibitor cobimetinib, which was included to stave off resistance to vemurafenib. The 24-month progression free survival was 93%.
The combination resulted in significant response in all patients who received at least one cycle of therapy, with a median 91% volume reduction. “Our study indicates that BRAF/MEK inhibitors could be a powerful tool in the treatment of previously untreated PCP, with the potential to avoid the morbidity associated with radiation and surgery,” concluded lead investigator and presenter Priscilla K. Brastianos, MD, associate professor of medicine at Mass General Cancer Center, Boston.
Thirty-three people in the second study had a mix of high and low grade gliomas or other CNS tumors positive for TRK gene fusions, a known oncogenic driver; the majority were children. They were treated with the TRK inhibitor larotrectinib after progressing on other systemic therapies.
The objective response rate was 30%, and the disease control rate was 73% at 24 weeks, with a median time to best response of 1.9 months. Tumors shrank in 82% of evaluable patients. Median progression-free survival was 18.3 months, and overall survival was not reached.
“These results support testing for TRK gene fusions for all patients with CNS tumors, especially if there is no known driver and especially in infants,” concluded lead investigator and presenter Sebastien Perreault, MD, a clinical assistant neurosciences professor at the University of Montreal.
The third study tested ALK inhibitors such as crizotinib in seven patients with adult-onset neuroblastoma, a rare and almost invariably fatal tumor known to be enriched for ALK mutations; the subjects were positive for them.
Their disease remained stable anywhere from 3.4 to 37.4 months. Median time to progression was 15.5 months, and median overall survival was 46.5 months.
ALK inhibitors “can be a well-tolerated options for treatment, improving time to progression. Development of resistance to one agent does not preclude use of other agents in the same drug class. ALK inhibitors should be considered when treating patients with this diagnosis,” said lead investigator and presenter Jessica Stiefel, MD, a pediatric hematology oncology fellow at Memorial Sloan Kettering Cancer Center, New York.
A ‘strong’ recommendation
The data “are great news” across the board. Targeted therapy applied to the right CNS tumor can have “dramatic” benefit for tumor control, Dr. Blakeley said.
But organizing molecular testing is not straightforward and requires strategies to balance “the use of precious resources, such as time money, and tissue,” with the potential benefit. Interpretation of testing results isn’t straightforward either, and is best handled by a molecular tumor board. Clinical pharmacists are also key to accessing expensive medications off label for CNS tumors.
Adverse events are also a consideration. Most of the subjects in the PCP study had grade 3/4 toxicity. Three patients in the ALK inhibitor study had to stop because of adverse events. Almost 40% on larotrectinib had grade 3 or 4 toxicity; nobody came off treatment, but a third had to skip doses.
Once an actionable mutation is identified, Dr. Blakeley’s “strong recommendation” is to enroll patients in a clinical trial that targets it, to take advantage the structure already in place to secure treatment, managed patients, and assess outcomes.
The National Cancer Institute’s MATCH trial is one of several options.
The BRAF/MEK inhibitor study was funded by Genentech and the National Institutes of Health. Dr. Brastianos had ties to numerous companies, including Pfizer, Lilly, and Merck. The TRK inhibitor study was funded by Bayer/Lilly. Dr. Perreault is a speaker and researcher for the company and has other ties. Dr. Blakeley is an adviser and/or researcher for a number of companies, including AbbVie, Astellas, BMS, and Exelixis. Dr. Stiefel didn’t have any disclosures, and didn’t report outside funding.
The results from three small studies of targeted therapy for rare brain tumors were “remarkable,” according to Jaishri Blakeley, MD, a neurology professor at Johns Hopkins Medicine, Baltimore, who discussed the studies after they were presented at the American Society of Clinical Oncology meeting.
Although most patients don’t have targetable mutations, molecular testing “is well worth the effort,” for those that do. “I think it’s fair to say that precision medicine” – well established in other tumor types – “is finally here in full force for neuro-oncology,” Dr. Blakeley said.
A promising start
Fifteen of 16 patients (94%) in one study had newly diagnosed and untreated papillary craniopharyngiomas (PCPs) that harbored BRAF V600E mutations, a common finding in PCPs, which have no effective medical treatment.
Tumors shrunk 68%-99% in 14 patients (93%) after treatment with the BRAF inhibitor vemurafenib plus the MEK inhibitor cobimetinib, which was included to stave off resistance to vemurafenib. The 24-month progression free survival was 93%.
The combination resulted in significant response in all patients who received at least one cycle of therapy, with a median 91% volume reduction. “Our study indicates that BRAF/MEK inhibitors could be a powerful tool in the treatment of previously untreated PCP, with the potential to avoid the morbidity associated with radiation and surgery,” concluded lead investigator and presenter Priscilla K. Brastianos, MD, associate professor of medicine at Mass General Cancer Center, Boston.
Thirty-three people in the second study had a mix of high and low grade gliomas or other CNS tumors positive for TRK gene fusions, a known oncogenic driver; the majority were children. They were treated with the TRK inhibitor larotrectinib after progressing on other systemic therapies.
The objective response rate was 30%, and the disease control rate was 73% at 24 weeks, with a median time to best response of 1.9 months. Tumors shrank in 82% of evaluable patients. Median progression-free survival was 18.3 months, and overall survival was not reached.
“These results support testing for TRK gene fusions for all patients with CNS tumors, especially if there is no known driver and especially in infants,” concluded lead investigator and presenter Sebastien Perreault, MD, a clinical assistant neurosciences professor at the University of Montreal.
The third study tested ALK inhibitors such as crizotinib in seven patients with adult-onset neuroblastoma, a rare and almost invariably fatal tumor known to be enriched for ALK mutations; the subjects were positive for them.
Their disease remained stable anywhere from 3.4 to 37.4 months. Median time to progression was 15.5 months, and median overall survival was 46.5 months.
ALK inhibitors “can be a well-tolerated options for treatment, improving time to progression. Development of resistance to one agent does not preclude use of other agents in the same drug class. ALK inhibitors should be considered when treating patients with this diagnosis,” said lead investigator and presenter Jessica Stiefel, MD, a pediatric hematology oncology fellow at Memorial Sloan Kettering Cancer Center, New York.
A ‘strong’ recommendation
The data “are great news” across the board. Targeted therapy applied to the right CNS tumor can have “dramatic” benefit for tumor control, Dr. Blakeley said.
But organizing molecular testing is not straightforward and requires strategies to balance “the use of precious resources, such as time money, and tissue,” with the potential benefit. Interpretation of testing results isn’t straightforward either, and is best handled by a molecular tumor board. Clinical pharmacists are also key to accessing expensive medications off label for CNS tumors.
Adverse events are also a consideration. Most of the subjects in the PCP study had grade 3/4 toxicity. Three patients in the ALK inhibitor study had to stop because of adverse events. Almost 40% on larotrectinib had grade 3 or 4 toxicity; nobody came off treatment, but a third had to skip doses.
Once an actionable mutation is identified, Dr. Blakeley’s “strong recommendation” is to enroll patients in a clinical trial that targets it, to take advantage the structure already in place to secure treatment, managed patients, and assess outcomes.
The National Cancer Institute’s MATCH trial is one of several options.
The BRAF/MEK inhibitor study was funded by Genentech and the National Institutes of Health. Dr. Brastianos had ties to numerous companies, including Pfizer, Lilly, and Merck. The TRK inhibitor study was funded by Bayer/Lilly. Dr. Perreault is a speaker and researcher for the company and has other ties. Dr. Blakeley is an adviser and/or researcher for a number of companies, including AbbVie, Astellas, BMS, and Exelixis. Dr. Stiefel didn’t have any disclosures, and didn’t report outside funding.
The results from three small studies of targeted therapy for rare brain tumors were “remarkable,” according to Jaishri Blakeley, MD, a neurology professor at Johns Hopkins Medicine, Baltimore, who discussed the studies after they were presented at the American Society of Clinical Oncology meeting.
Although most patients don’t have targetable mutations, molecular testing “is well worth the effort,” for those that do. “I think it’s fair to say that precision medicine” – well established in other tumor types – “is finally here in full force for neuro-oncology,” Dr. Blakeley said.
A promising start
Fifteen of 16 patients (94%) in one study had newly diagnosed and untreated papillary craniopharyngiomas (PCPs) that harbored BRAF V600E mutations, a common finding in PCPs, which have no effective medical treatment.
Tumors shrunk 68%-99% in 14 patients (93%) after treatment with the BRAF inhibitor vemurafenib plus the MEK inhibitor cobimetinib, which was included to stave off resistance to vemurafenib. The 24-month progression free survival was 93%.
The combination resulted in significant response in all patients who received at least one cycle of therapy, with a median 91% volume reduction. “Our study indicates that BRAF/MEK inhibitors could be a powerful tool in the treatment of previously untreated PCP, with the potential to avoid the morbidity associated with radiation and surgery,” concluded lead investigator and presenter Priscilla K. Brastianos, MD, associate professor of medicine at Mass General Cancer Center, Boston.
Thirty-three people in the second study had a mix of high and low grade gliomas or other CNS tumors positive for TRK gene fusions, a known oncogenic driver; the majority were children. They were treated with the TRK inhibitor larotrectinib after progressing on other systemic therapies.
The objective response rate was 30%, and the disease control rate was 73% at 24 weeks, with a median time to best response of 1.9 months. Tumors shrank in 82% of evaluable patients. Median progression-free survival was 18.3 months, and overall survival was not reached.
“These results support testing for TRK gene fusions for all patients with CNS tumors, especially if there is no known driver and especially in infants,” concluded lead investigator and presenter Sebastien Perreault, MD, a clinical assistant neurosciences professor at the University of Montreal.
The third study tested ALK inhibitors such as crizotinib in seven patients with adult-onset neuroblastoma, a rare and almost invariably fatal tumor known to be enriched for ALK mutations; the subjects were positive for them.
Their disease remained stable anywhere from 3.4 to 37.4 months. Median time to progression was 15.5 months, and median overall survival was 46.5 months.
ALK inhibitors “can be a well-tolerated options for treatment, improving time to progression. Development of resistance to one agent does not preclude use of other agents in the same drug class. ALK inhibitors should be considered when treating patients with this diagnosis,” said lead investigator and presenter Jessica Stiefel, MD, a pediatric hematology oncology fellow at Memorial Sloan Kettering Cancer Center, New York.
A ‘strong’ recommendation
The data “are great news” across the board. Targeted therapy applied to the right CNS tumor can have “dramatic” benefit for tumor control, Dr. Blakeley said.
But organizing molecular testing is not straightforward and requires strategies to balance “the use of precious resources, such as time money, and tissue,” with the potential benefit. Interpretation of testing results isn’t straightforward either, and is best handled by a molecular tumor board. Clinical pharmacists are also key to accessing expensive medications off label for CNS tumors.
Adverse events are also a consideration. Most of the subjects in the PCP study had grade 3/4 toxicity. Three patients in the ALK inhibitor study had to stop because of adverse events. Almost 40% on larotrectinib had grade 3 or 4 toxicity; nobody came off treatment, but a third had to skip doses.
Once an actionable mutation is identified, Dr. Blakeley’s “strong recommendation” is to enroll patients in a clinical trial that targets it, to take advantage the structure already in place to secure treatment, managed patients, and assess outcomes.
The National Cancer Institute’s MATCH trial is one of several options.
The BRAF/MEK inhibitor study was funded by Genentech and the National Institutes of Health. Dr. Brastianos had ties to numerous companies, including Pfizer, Lilly, and Merck. The TRK inhibitor study was funded by Bayer/Lilly. Dr. Perreault is a speaker and researcher for the company and has other ties. Dr. Blakeley is an adviser and/or researcher for a number of companies, including AbbVie, Astellas, BMS, and Exelixis. Dr. Stiefel didn’t have any disclosures, and didn’t report outside funding.
FROM ASCO 2021
Adjuvant capecitabine shown a less punishing option after NPC chemoradiation
Adjuvant capecitabine is an effective and better tolerated alternative to chemotherapy following chemoradiation for locoregionally advanced nasopharyngeal carcinoma, according to two phase 3 trials from China.
Despite using different dosing strategies, 3-year failure-free survival approached 90% in both trials, comparable to the standard approach with adjuvant platinum doublets, but with better compliance.
The study teams were looking for “a way to make adjuvant therapy more tolerable,” said oncologist Herbert Loong, MBBS, clinical associate professor at the Chinese University of Hong Kong, who discussed both trials after they were presented at the American Society for Clinical Oncology annual meeting.
Compliance is low with platinum doublets because of the toxicity. About 60%-70% of patients can tolerate 2-3 cycles after chemoradiation, and about a third can’t even start because of the toll chemoradiation took on their bodies, he said.
Induction chemotherapy is an alternative, but patients seem to derive more benefit form adjuvant therapy after chemoradiation. Indeed, “given the fact that we may now have a well established, well tolerated adjuvant therapy for our patients” – capecitabine – “the role of induction therapy” is in question, Dr. Loong said.
Metronomic dosing
One trial randomized 204 patients to metronomic dosing of capecitabine, 650 mg/m2 twice daily for 1 year within 12 to 16 weeks after the last radiation, and 202 others to observation.
The idea of metronomic dosing was to give a lower dose of the agent over a longer period to reduce side effects and perhaps improve efficacy.
Subjects had high-risk stage III to IVA disease with no locoregional disease or distant metastasis after chemoradiotherapy. Almost 80% in both arms also had induction chemotherapy, most commonly docetaxel and cisplatin.
Almost three-quarters of people in the treatment arm complied with capecitabine for an entire year.
At a median follow-up of 38 months, 3-year failure-free survival was 85.3% with metronomic capecitabine vs. 75.7% with observation (hazard ratio, .50, P = .002). Three-year overall survival was 93.3% with capecitabine and 88.6% with observation (HR .44, P = .018).
The incidence of grade 3/4 adverse events was 17.4% with metronomic capecitabine vs. 5.5% with observation. Hand-foot syndrome was the most common complication, occurring in 9% of capecitabine subjects. There were no treatment-related deaths, and there was no clinically meaningful deterioration in quality of life associated with treatment.
The approach “significantly improved” outcomes, “with a manageable safety profile and no compromise to quality of life ... Metronomic adjuvant capecitabine can be an option for first-line treatment in this high-risk” group, concluded investigators led by Jun Ma, MD, professor of radiation oncology and deputy president of Sun Yat-sen University Cancer Center in Guangzhou, China.
Standard dosing
The second trial used standard dosing. The researchers randomized 90 subjects to capecitabine 1,000 mg/m2 twice daily for 14 days in eight 21-day cycles after chemoradiation; 90 subjects were randomized to observation. None of the subjects received induction chemotherapy.
Patients had stage III-IVb disease plus at least one high-risk feature, such as high Epstein Barr virus DNA titers. The majority of patients in both arms had three or more high risk features.
Over 80% of capecitabine subjects completed all eight cycles of treatment.
At a median follow-up of 44.8 months, 3-year failure-free survival was 87.7% with capecitabine vs. 73.3% in the control arm (HR .52, P = .037). Three-year overall survival was 92.6% with capecitabine vs. 88.9% with observation, which wasn’t statistically significant.
The incidence of acute grade 3/4 adverse events was 57.8% with standard dose capecitabine. Rates of hand foot syndrome, mucositis, anemia, and other problems were substantially higher than with observation.
For high-risk patients unable to tolerate chemotherapy, adjuvant capecitabine is a “suitable alternative treatment option,” said lead investigator Jingjing Miao, MD, of the department of nasopharyngeal carcinoma at Sun Yat-sen University Cancer Center, Guangzhou, China.
The trials were funded by Sun Yat-sen University and others. The investigators had no disclosures. Dr. Loong is an adviser, speaker, and/or researcher for a number of companies, including Novartis, Pfizer, and Lilly.
Adjuvant capecitabine is an effective and better tolerated alternative to chemotherapy following chemoradiation for locoregionally advanced nasopharyngeal carcinoma, according to two phase 3 trials from China.
Despite using different dosing strategies, 3-year failure-free survival approached 90% in both trials, comparable to the standard approach with adjuvant platinum doublets, but with better compliance.
The study teams were looking for “a way to make adjuvant therapy more tolerable,” said oncologist Herbert Loong, MBBS, clinical associate professor at the Chinese University of Hong Kong, who discussed both trials after they were presented at the American Society for Clinical Oncology annual meeting.
Compliance is low with platinum doublets because of the toxicity. About 60%-70% of patients can tolerate 2-3 cycles after chemoradiation, and about a third can’t even start because of the toll chemoradiation took on their bodies, he said.
Induction chemotherapy is an alternative, but patients seem to derive more benefit form adjuvant therapy after chemoradiation. Indeed, “given the fact that we may now have a well established, well tolerated adjuvant therapy for our patients” – capecitabine – “the role of induction therapy” is in question, Dr. Loong said.
Metronomic dosing
One trial randomized 204 patients to metronomic dosing of capecitabine, 650 mg/m2 twice daily for 1 year within 12 to 16 weeks after the last radiation, and 202 others to observation.
The idea of metronomic dosing was to give a lower dose of the agent over a longer period to reduce side effects and perhaps improve efficacy.
Subjects had high-risk stage III to IVA disease with no locoregional disease or distant metastasis after chemoradiotherapy. Almost 80% in both arms also had induction chemotherapy, most commonly docetaxel and cisplatin.
Almost three-quarters of people in the treatment arm complied with capecitabine for an entire year.
At a median follow-up of 38 months, 3-year failure-free survival was 85.3% with metronomic capecitabine vs. 75.7% with observation (hazard ratio, .50, P = .002). Three-year overall survival was 93.3% with capecitabine and 88.6% with observation (HR .44, P = .018).
The incidence of grade 3/4 adverse events was 17.4% with metronomic capecitabine vs. 5.5% with observation. Hand-foot syndrome was the most common complication, occurring in 9% of capecitabine subjects. There were no treatment-related deaths, and there was no clinically meaningful deterioration in quality of life associated with treatment.
The approach “significantly improved” outcomes, “with a manageable safety profile and no compromise to quality of life ... Metronomic adjuvant capecitabine can be an option for first-line treatment in this high-risk” group, concluded investigators led by Jun Ma, MD, professor of radiation oncology and deputy president of Sun Yat-sen University Cancer Center in Guangzhou, China.
Standard dosing
The second trial used standard dosing. The researchers randomized 90 subjects to capecitabine 1,000 mg/m2 twice daily for 14 days in eight 21-day cycles after chemoradiation; 90 subjects were randomized to observation. None of the subjects received induction chemotherapy.
Patients had stage III-IVb disease plus at least one high-risk feature, such as high Epstein Barr virus DNA titers. The majority of patients in both arms had three or more high risk features.
Over 80% of capecitabine subjects completed all eight cycles of treatment.
At a median follow-up of 44.8 months, 3-year failure-free survival was 87.7% with capecitabine vs. 73.3% in the control arm (HR .52, P = .037). Three-year overall survival was 92.6% with capecitabine vs. 88.9% with observation, which wasn’t statistically significant.
The incidence of acute grade 3/4 adverse events was 57.8% with standard dose capecitabine. Rates of hand foot syndrome, mucositis, anemia, and other problems were substantially higher than with observation.
For high-risk patients unable to tolerate chemotherapy, adjuvant capecitabine is a “suitable alternative treatment option,” said lead investigator Jingjing Miao, MD, of the department of nasopharyngeal carcinoma at Sun Yat-sen University Cancer Center, Guangzhou, China.
The trials were funded by Sun Yat-sen University and others. The investigators had no disclosures. Dr. Loong is an adviser, speaker, and/or researcher for a number of companies, including Novartis, Pfizer, and Lilly.
Adjuvant capecitabine is an effective and better tolerated alternative to chemotherapy following chemoradiation for locoregionally advanced nasopharyngeal carcinoma, according to two phase 3 trials from China.
Despite using different dosing strategies, 3-year failure-free survival approached 90% in both trials, comparable to the standard approach with adjuvant platinum doublets, but with better compliance.
The study teams were looking for “a way to make adjuvant therapy more tolerable,” said oncologist Herbert Loong, MBBS, clinical associate professor at the Chinese University of Hong Kong, who discussed both trials after they were presented at the American Society for Clinical Oncology annual meeting.
Compliance is low with platinum doublets because of the toxicity. About 60%-70% of patients can tolerate 2-3 cycles after chemoradiation, and about a third can’t even start because of the toll chemoradiation took on their bodies, he said.
Induction chemotherapy is an alternative, but patients seem to derive more benefit form adjuvant therapy after chemoradiation. Indeed, “given the fact that we may now have a well established, well tolerated adjuvant therapy for our patients” – capecitabine – “the role of induction therapy” is in question, Dr. Loong said.
Metronomic dosing
One trial randomized 204 patients to metronomic dosing of capecitabine, 650 mg/m2 twice daily for 1 year within 12 to 16 weeks after the last radiation, and 202 others to observation.
The idea of metronomic dosing was to give a lower dose of the agent over a longer period to reduce side effects and perhaps improve efficacy.
Subjects had high-risk stage III to IVA disease with no locoregional disease or distant metastasis after chemoradiotherapy. Almost 80% in both arms also had induction chemotherapy, most commonly docetaxel and cisplatin.
Almost three-quarters of people in the treatment arm complied with capecitabine for an entire year.
At a median follow-up of 38 months, 3-year failure-free survival was 85.3% with metronomic capecitabine vs. 75.7% with observation (hazard ratio, .50, P = .002). Three-year overall survival was 93.3% with capecitabine and 88.6% with observation (HR .44, P = .018).
The incidence of grade 3/4 adverse events was 17.4% with metronomic capecitabine vs. 5.5% with observation. Hand-foot syndrome was the most common complication, occurring in 9% of capecitabine subjects. There were no treatment-related deaths, and there was no clinically meaningful deterioration in quality of life associated with treatment.
The approach “significantly improved” outcomes, “with a manageable safety profile and no compromise to quality of life ... Metronomic adjuvant capecitabine can be an option for first-line treatment in this high-risk” group, concluded investigators led by Jun Ma, MD, professor of radiation oncology and deputy president of Sun Yat-sen University Cancer Center in Guangzhou, China.
Standard dosing
The second trial used standard dosing. The researchers randomized 90 subjects to capecitabine 1,000 mg/m2 twice daily for 14 days in eight 21-day cycles after chemoradiation; 90 subjects were randomized to observation. None of the subjects received induction chemotherapy.
Patients had stage III-IVb disease plus at least one high-risk feature, such as high Epstein Barr virus DNA titers. The majority of patients in both arms had three or more high risk features.
Over 80% of capecitabine subjects completed all eight cycles of treatment.
At a median follow-up of 44.8 months, 3-year failure-free survival was 87.7% with capecitabine vs. 73.3% in the control arm (HR .52, P = .037). Three-year overall survival was 92.6% with capecitabine vs. 88.9% with observation, which wasn’t statistically significant.
The incidence of acute grade 3/4 adverse events was 57.8% with standard dose capecitabine. Rates of hand foot syndrome, mucositis, anemia, and other problems were substantially higher than with observation.
For high-risk patients unable to tolerate chemotherapy, adjuvant capecitabine is a “suitable alternative treatment option,” said lead investigator Jingjing Miao, MD, of the department of nasopharyngeal carcinoma at Sun Yat-sen University Cancer Center, Guangzhou, China.
The trials were funded by Sun Yat-sen University and others. The investigators had no disclosures. Dr. Loong is an adviser, speaker, and/or researcher for a number of companies, including Novartis, Pfizer, and Lilly.
FROM ASCO 2021
Cabozantinib gains ground for salvage in differentiated thyroid cancer
The vascular endothelial growth factor receptor 2 blocker cabozantinib prolonged progression-free survival in radioiodine-refractory differentiated thyroid cancer following progression on first-line VEGFR inhibitors in a phase 3 trial from cabozantinib maker, Exelixis.
After a median follow up of 6.2 months, the 125 subjects on cabozantinib 60 mg every day had not reached median progression-free survival, but among the 62 randomized to placebo, mPFS was only 1.9 months.
The results led the Food and Drug Administration to grant cabozantinib breakthrough therapy status for salvage after progression on lenvatinib or sorafenib, the two VEGFR inhibitors approved for first-line treatment in radioiodine refractory differentiated thyroid cancer. Cabozantinib already carries a first-line indication for progressive, metastatic medullary thyroid cancer.
“We were all so excited to have sorafenib and lenvatinib,” but patients need another option after they develop resistance. “Cabozantinib is positioned to be the next in line,” said lead investigator Marcia Brose, MD, PhD, a thyroid specialist and professor at the University of Pennsylvania, Philadelphia, who presented the findings at the American Society of Clinical Oncology Annual Meeting.
The trial discussant, medical oncologist Nicole Chau, MD, clinical associate professor at the University of British Columbia, Vancouver, said the results “support cabozantinib as a potential second- or third-line” option, but its impact on quality of life and financial toxicity “should be evaluated.”
Subjects in the trial – dubbed COSMIC-311 – had locally advanced or metastatic disease that had progressed during or after first-line VEGFR treatment, including about 40% with lenvatinib, almost 40% with sorafenib, and over 20% with both.
The median age in the study was 66 years, and 55% of the subjects were women. Bone and liver metastases were more common in the cabozantinib arm.
Promising results
The robust of mPFS benefit (hazard ratio, 0.22; P < .0001) held across subgroups. The mPFS in the placebo arm of 1.9 months demonstrates that “these patients [progress rapidly], so you have to be ready with the next thing in line” to start it quickly, Dr. Brose said.
Overall survival favored cabozantinib (HR, 0.54) but didn’t reach statistical significance perhaps because placebo patients were allowed to cross over to cabozantinib after progression.
The overall response rate was 15% with cabozantinib versus no responders with placebo, which also didn’t meet the study’s criteria for clinical significance. Even so, the disease control rate of 60% with cabozantinib versus 27% with placebo, “is clinically meaningful in this heavily pretreated population,” Dr. Chau said.
Adverse events
Safety was consistent with previous reports and included diarrhea in 51% of cabozantinib subjects, hand-foot skin reaction in 46%, hypertension in 28%, fatigue in 27%, and nausea in 24%, all substantially higher than with placebo. Over half of cabozantinib subjects had grade 3-4 adverse events versus 26% on placebo. There were no treatment related deaths.
Adverse events led to dose reductions or holds in the majority of cabozantinib subjects, but only 5% discontinued the drug; the number might have been higher with longer follow-up, Dr. Chau said.
Genotype-targeted therapy is an option for patients with fusion alterations, but whether it should come before or after VEGFR inhibition is unclear, Dr. Brose noted.
Biomarkers to help with such treatment decisions will become “increasingly important as we move beyond the era of single-agent” VEGFR inhibitors, Dr. Chau said.
The study was funded by cabozantinib maker Exelixis, and three investigators were employees. Dr. Brose disclosed research funding and honoraria from the company, and is an adviser. Dr. Chau has no involvement with Exelixis.
The vascular endothelial growth factor receptor 2 blocker cabozantinib prolonged progression-free survival in radioiodine-refractory differentiated thyroid cancer following progression on first-line VEGFR inhibitors in a phase 3 trial from cabozantinib maker, Exelixis.
After a median follow up of 6.2 months, the 125 subjects on cabozantinib 60 mg every day had not reached median progression-free survival, but among the 62 randomized to placebo, mPFS was only 1.9 months.
The results led the Food and Drug Administration to grant cabozantinib breakthrough therapy status for salvage after progression on lenvatinib or sorafenib, the two VEGFR inhibitors approved for first-line treatment in radioiodine refractory differentiated thyroid cancer. Cabozantinib already carries a first-line indication for progressive, metastatic medullary thyroid cancer.
“We were all so excited to have sorafenib and lenvatinib,” but patients need another option after they develop resistance. “Cabozantinib is positioned to be the next in line,” said lead investigator Marcia Brose, MD, PhD, a thyroid specialist and professor at the University of Pennsylvania, Philadelphia, who presented the findings at the American Society of Clinical Oncology Annual Meeting.
The trial discussant, medical oncologist Nicole Chau, MD, clinical associate professor at the University of British Columbia, Vancouver, said the results “support cabozantinib as a potential second- or third-line” option, but its impact on quality of life and financial toxicity “should be evaluated.”
Subjects in the trial – dubbed COSMIC-311 – had locally advanced or metastatic disease that had progressed during or after first-line VEGFR treatment, including about 40% with lenvatinib, almost 40% with sorafenib, and over 20% with both.
The median age in the study was 66 years, and 55% of the subjects were women. Bone and liver metastases were more common in the cabozantinib arm.
Promising results
The robust of mPFS benefit (hazard ratio, 0.22; P < .0001) held across subgroups. The mPFS in the placebo arm of 1.9 months demonstrates that “these patients [progress rapidly], so you have to be ready with the next thing in line” to start it quickly, Dr. Brose said.
Overall survival favored cabozantinib (HR, 0.54) but didn’t reach statistical significance perhaps because placebo patients were allowed to cross over to cabozantinib after progression.
The overall response rate was 15% with cabozantinib versus no responders with placebo, which also didn’t meet the study’s criteria for clinical significance. Even so, the disease control rate of 60% with cabozantinib versus 27% with placebo, “is clinically meaningful in this heavily pretreated population,” Dr. Chau said.
Adverse events
Safety was consistent with previous reports and included diarrhea in 51% of cabozantinib subjects, hand-foot skin reaction in 46%, hypertension in 28%, fatigue in 27%, and nausea in 24%, all substantially higher than with placebo. Over half of cabozantinib subjects had grade 3-4 adverse events versus 26% on placebo. There were no treatment related deaths.
Adverse events led to dose reductions or holds in the majority of cabozantinib subjects, but only 5% discontinued the drug; the number might have been higher with longer follow-up, Dr. Chau said.
Genotype-targeted therapy is an option for patients with fusion alterations, but whether it should come before or after VEGFR inhibition is unclear, Dr. Brose noted.
Biomarkers to help with such treatment decisions will become “increasingly important as we move beyond the era of single-agent” VEGFR inhibitors, Dr. Chau said.
The study was funded by cabozantinib maker Exelixis, and three investigators were employees. Dr. Brose disclosed research funding and honoraria from the company, and is an adviser. Dr. Chau has no involvement with Exelixis.
The vascular endothelial growth factor receptor 2 blocker cabozantinib prolonged progression-free survival in radioiodine-refractory differentiated thyroid cancer following progression on first-line VEGFR inhibitors in a phase 3 trial from cabozantinib maker, Exelixis.
After a median follow up of 6.2 months, the 125 subjects on cabozantinib 60 mg every day had not reached median progression-free survival, but among the 62 randomized to placebo, mPFS was only 1.9 months.
The results led the Food and Drug Administration to grant cabozantinib breakthrough therapy status for salvage after progression on lenvatinib or sorafenib, the two VEGFR inhibitors approved for first-line treatment in radioiodine refractory differentiated thyroid cancer. Cabozantinib already carries a first-line indication for progressive, metastatic medullary thyroid cancer.
“We were all so excited to have sorafenib and lenvatinib,” but patients need another option after they develop resistance. “Cabozantinib is positioned to be the next in line,” said lead investigator Marcia Brose, MD, PhD, a thyroid specialist and professor at the University of Pennsylvania, Philadelphia, who presented the findings at the American Society of Clinical Oncology Annual Meeting.
The trial discussant, medical oncologist Nicole Chau, MD, clinical associate professor at the University of British Columbia, Vancouver, said the results “support cabozantinib as a potential second- or third-line” option, but its impact on quality of life and financial toxicity “should be evaluated.”
Subjects in the trial – dubbed COSMIC-311 – had locally advanced or metastatic disease that had progressed during or after first-line VEGFR treatment, including about 40% with lenvatinib, almost 40% with sorafenib, and over 20% with both.
The median age in the study was 66 years, and 55% of the subjects were women. Bone and liver metastases were more common in the cabozantinib arm.
Promising results
The robust of mPFS benefit (hazard ratio, 0.22; P < .0001) held across subgroups. The mPFS in the placebo arm of 1.9 months demonstrates that “these patients [progress rapidly], so you have to be ready with the next thing in line” to start it quickly, Dr. Brose said.
Overall survival favored cabozantinib (HR, 0.54) but didn’t reach statistical significance perhaps because placebo patients were allowed to cross over to cabozantinib after progression.
The overall response rate was 15% with cabozantinib versus no responders with placebo, which also didn’t meet the study’s criteria for clinical significance. Even so, the disease control rate of 60% with cabozantinib versus 27% with placebo, “is clinically meaningful in this heavily pretreated population,” Dr. Chau said.
Adverse events
Safety was consistent with previous reports and included diarrhea in 51% of cabozantinib subjects, hand-foot skin reaction in 46%, hypertension in 28%, fatigue in 27%, and nausea in 24%, all substantially higher than with placebo. Over half of cabozantinib subjects had grade 3-4 adverse events versus 26% on placebo. There were no treatment related deaths.
Adverse events led to dose reductions or holds in the majority of cabozantinib subjects, but only 5% discontinued the drug; the number might have been higher with longer follow-up, Dr. Chau said.
Genotype-targeted therapy is an option for patients with fusion alterations, but whether it should come before or after VEGFR inhibition is unclear, Dr. Brose noted.
Biomarkers to help with such treatment decisions will become “increasingly important as we move beyond the era of single-agent” VEGFR inhibitors, Dr. Chau said.
The study was funded by cabozantinib maker Exelixis, and three investigators were employees. Dr. Brose disclosed research funding and honoraria from the company, and is an adviser. Dr. Chau has no involvement with Exelixis.
FROM ASCO 2021
Chemotherapy/local excision avoids proctectomy in rectal cancer
Chemotherapy and local excision led to organ preservation in over half of early-stage rectal cancer patients in a small study, but follow-up was only a median of 15.4 months.
Even so, “we believe that subsequent trials ... are warranted,” said lead investigator Hagen F. Kennecke, MD, medical director of GI oncology at Providence Cancer Institute, Portland, Ore., who presented the findings at the American Society of Clinical Oncology annual meeting.
“The results are quite promising,” said study discussant Karyn Stitzenberg, MD, a surgical oncologist at the University of North Carolina, Chapel Hill.
“The reported organ preservation rates of 57% to 79% compare favorably with the rates previously demonstrated in studies of neoadjuvant chemoradiation followed by local excision,” but longer-term follow up is needed “to know the true organ preservation rate,” she said.
Organ preservation – sparing the rectum during treatment – is a hot topic in rectal cancer. Total mesorectal excision (TME) is still the go-to option, but it’s fraught with bad GI, urinary, sexual, and other complications for patients. “Consequently, the concept of organ preservation ... is very appealing,” Dr. Stitzenberg explained.
The chemoradiation/local excision approach she referenced is gaining traction as an alternative, but the radiation component is itself associated with substantial short- and long-term problems, including sphincter dysfunction and wound healing complications.
The goal of Dr. Kennecke’s study, dubbed NEO [Neoadjuvant, Excision, Observation], was to see if the radiation could be left out altogether.
Recruited at eight centers in Canada and one in the United States, the 58 subjects had clinical stage T1-T3 A/B node-negative tumors with no pathologic high-risk features.
They received neoadjuvant FOLFOX (six cycles in 32 patients, 91% completion rate) or CAPOX (four cycles in 26 patients, 89% completion); 56 of the 58 subjects then went on to transanal endoscopic tumor excision; one of the other two patients wasn’t eligible because of tumor progression and the other one declined.
The 33 patients who were stage T0/T1N0 after treatment were spared organ removal and underwent observation every 3-6 months. TME was recommended for the 23 others who were stage 2 or higher or had nodal metastases following chemotherapy and excision.
The numbers translated to a per-protocol organ preservation rate of 57% over a median follow-up of 15.4 months; when the 13 patients who declined TME were added, the rate climbed to 79%.
Although “organ preservation in rectal cancer is becoming an increasingly promising and realistic option for a subset of patients,” Dr. Stitzenberg said, there are more reasons to be cautious beyond the short follow-up.
“The standard of care treatment for these patients would have been proctectomy ... Most would not have [had] systemic chemotherapy. As a result, the added morbidity of FOLFOX or CAPOX needs to be considered.” The study reported that there were no unexpected toxicities, but “what were the expected toxicities? How many patients experienced grade 3 to 5 complications?” she wondered.
Also, how realistic is it to expect patients to report for surveillance every few months outside of a trial? And how can they best be watched to make sure recurrence is caught “while salvage TME is still feasible? There are many longer-term follow-up questions that remain to be answered,” Dr. Stitzenberg said.
Even with short follow-up, there were two locoregional recurrences across the cohort (3.5%), both treated by TME to R0/1 resection. There were no distant relapses.
Subjects were a median of 67 years old, and over two-thirds were men. The majority had stage 2 disease at baseline. Tumors were well to moderately differentiated nonmucinous rectal adenocarcinomas with a median height of 6 cm.
The work was funded by the Canadian Cancer Trials Group. Dr. Kennecke disclosed relationships with Advanced Accelerator Applications, Ipsen, and Taiho Pharmaceutical. Dr. Stitzenberg had no relevant disclosures.
Chemotherapy and local excision led to organ preservation in over half of early-stage rectal cancer patients in a small study, but follow-up was only a median of 15.4 months.
Even so, “we believe that subsequent trials ... are warranted,” said lead investigator Hagen F. Kennecke, MD, medical director of GI oncology at Providence Cancer Institute, Portland, Ore., who presented the findings at the American Society of Clinical Oncology annual meeting.
“The results are quite promising,” said study discussant Karyn Stitzenberg, MD, a surgical oncologist at the University of North Carolina, Chapel Hill.
“The reported organ preservation rates of 57% to 79% compare favorably with the rates previously demonstrated in studies of neoadjuvant chemoradiation followed by local excision,” but longer-term follow up is needed “to know the true organ preservation rate,” she said.
Organ preservation – sparing the rectum during treatment – is a hot topic in rectal cancer. Total mesorectal excision (TME) is still the go-to option, but it’s fraught with bad GI, urinary, sexual, and other complications for patients. “Consequently, the concept of organ preservation ... is very appealing,” Dr. Stitzenberg explained.
The chemoradiation/local excision approach she referenced is gaining traction as an alternative, but the radiation component is itself associated with substantial short- and long-term problems, including sphincter dysfunction and wound healing complications.
The goal of Dr. Kennecke’s study, dubbed NEO [Neoadjuvant, Excision, Observation], was to see if the radiation could be left out altogether.
Recruited at eight centers in Canada and one in the United States, the 58 subjects had clinical stage T1-T3 A/B node-negative tumors with no pathologic high-risk features.
They received neoadjuvant FOLFOX (six cycles in 32 patients, 91% completion rate) or CAPOX (four cycles in 26 patients, 89% completion); 56 of the 58 subjects then went on to transanal endoscopic tumor excision; one of the other two patients wasn’t eligible because of tumor progression and the other one declined.
The 33 patients who were stage T0/T1N0 after treatment were spared organ removal and underwent observation every 3-6 months. TME was recommended for the 23 others who were stage 2 or higher or had nodal metastases following chemotherapy and excision.
The numbers translated to a per-protocol organ preservation rate of 57% over a median follow-up of 15.4 months; when the 13 patients who declined TME were added, the rate climbed to 79%.
Although “organ preservation in rectal cancer is becoming an increasingly promising and realistic option for a subset of patients,” Dr. Stitzenberg said, there are more reasons to be cautious beyond the short follow-up.
“The standard of care treatment for these patients would have been proctectomy ... Most would not have [had] systemic chemotherapy. As a result, the added morbidity of FOLFOX or CAPOX needs to be considered.” The study reported that there were no unexpected toxicities, but “what were the expected toxicities? How many patients experienced grade 3 to 5 complications?” she wondered.
Also, how realistic is it to expect patients to report for surveillance every few months outside of a trial? And how can they best be watched to make sure recurrence is caught “while salvage TME is still feasible? There are many longer-term follow-up questions that remain to be answered,” Dr. Stitzenberg said.
Even with short follow-up, there were two locoregional recurrences across the cohort (3.5%), both treated by TME to R0/1 resection. There were no distant relapses.
Subjects were a median of 67 years old, and over two-thirds were men. The majority had stage 2 disease at baseline. Tumors were well to moderately differentiated nonmucinous rectal adenocarcinomas with a median height of 6 cm.
The work was funded by the Canadian Cancer Trials Group. Dr. Kennecke disclosed relationships with Advanced Accelerator Applications, Ipsen, and Taiho Pharmaceutical. Dr. Stitzenberg had no relevant disclosures.
Chemotherapy and local excision led to organ preservation in over half of early-stage rectal cancer patients in a small study, but follow-up was only a median of 15.4 months.
Even so, “we believe that subsequent trials ... are warranted,” said lead investigator Hagen F. Kennecke, MD, medical director of GI oncology at Providence Cancer Institute, Portland, Ore., who presented the findings at the American Society of Clinical Oncology annual meeting.
“The results are quite promising,” said study discussant Karyn Stitzenberg, MD, a surgical oncologist at the University of North Carolina, Chapel Hill.
“The reported organ preservation rates of 57% to 79% compare favorably with the rates previously demonstrated in studies of neoadjuvant chemoradiation followed by local excision,” but longer-term follow up is needed “to know the true organ preservation rate,” she said.
Organ preservation – sparing the rectum during treatment – is a hot topic in rectal cancer. Total mesorectal excision (TME) is still the go-to option, but it’s fraught with bad GI, urinary, sexual, and other complications for patients. “Consequently, the concept of organ preservation ... is very appealing,” Dr. Stitzenberg explained.
The chemoradiation/local excision approach she referenced is gaining traction as an alternative, but the radiation component is itself associated with substantial short- and long-term problems, including sphincter dysfunction and wound healing complications.
The goal of Dr. Kennecke’s study, dubbed NEO [Neoadjuvant, Excision, Observation], was to see if the radiation could be left out altogether.
Recruited at eight centers in Canada and one in the United States, the 58 subjects had clinical stage T1-T3 A/B node-negative tumors with no pathologic high-risk features.
They received neoadjuvant FOLFOX (six cycles in 32 patients, 91% completion rate) or CAPOX (four cycles in 26 patients, 89% completion); 56 of the 58 subjects then went on to transanal endoscopic tumor excision; one of the other two patients wasn’t eligible because of tumor progression and the other one declined.
The 33 patients who were stage T0/T1N0 after treatment were spared organ removal and underwent observation every 3-6 months. TME was recommended for the 23 others who were stage 2 or higher or had nodal metastases following chemotherapy and excision.
The numbers translated to a per-protocol organ preservation rate of 57% over a median follow-up of 15.4 months; when the 13 patients who declined TME were added, the rate climbed to 79%.
Although “organ preservation in rectal cancer is becoming an increasingly promising and realistic option for a subset of patients,” Dr. Stitzenberg said, there are more reasons to be cautious beyond the short follow-up.
“The standard of care treatment for these patients would have been proctectomy ... Most would not have [had] systemic chemotherapy. As a result, the added morbidity of FOLFOX or CAPOX needs to be considered.” The study reported that there were no unexpected toxicities, but “what were the expected toxicities? How many patients experienced grade 3 to 5 complications?” she wondered.
Also, how realistic is it to expect patients to report for surveillance every few months outside of a trial? And how can they best be watched to make sure recurrence is caught “while salvage TME is still feasible? There are many longer-term follow-up questions that remain to be answered,” Dr. Stitzenberg said.
Even with short follow-up, there were two locoregional recurrences across the cohort (3.5%), both treated by TME to R0/1 resection. There were no distant relapses.
Subjects were a median of 67 years old, and over two-thirds were men. The majority had stage 2 disease at baseline. Tumors were well to moderately differentiated nonmucinous rectal adenocarcinomas with a median height of 6 cm.
The work was funded by the Canadian Cancer Trials Group. Dr. Kennecke disclosed relationships with Advanced Accelerator Applications, Ipsen, and Taiho Pharmaceutical. Dr. Stitzenberg had no relevant disclosures.
FROM ASCO 2021
Drug conjugate extends life in HER2+ end-stage metastatic colorectal cancer
, according to a phase 2 report.
Among the 53 patients with the highest expression in the study – defined as 3+ expression on immune histochemical staining or 2+ with positive in situ hybridization – median progression median progression-free survival (mPFS) was 6.9 months after failure of a median of four prior regimens.
With standard drugs, mPFS would be expected to be about 2 months or less, said investigator Kanwal Pratap Singh Raghav, MD, an associate professor of GI medical oncology at MD Anderson Cancer Center, Houston.
Many of the 86 study participants were enrolled at MD Anderson, and “they all derived some benefit from the conjugate. “It’s fairly well tolerated,” and “our experience has been pretty good; I think it’s actually a pretty good drug,” Dr. Raghav said shortly before presenting the findings at the American Society of Clinical Oncology Annual Meeting.
HER2 is over-expressed in about 5% of colorectal cancer patients. The conjugate is a kind of “smart bomb” for them that combines the anti-HER2 antibody trastuzumab (Herceptin) with a potent topoisomerase I inhibitor. The trastuzumab portion of the combination zeros in on cancer cells expressing HER2, delivering the cytotoxic agent directly to them.
“The amount of [cytotoxic] drug delivered by the antibody inside the cell is far in excess” to the standard approach of delivering chemotherapy agents individually, Dr. Raghav said.
“Single-agent treatments targeting HER2 only have modest activity. Seeing a response rate of [almost] 50% in colorectal cancer tumors that have high expression of HER2 is very exciting,” Muhammad Beg, MD, a GI oncologist and associate professor at UT Southwestern Medical Center, Dallas, said when asked for comment.
Trastuzumab deruxtecan already is approved for metastatic HER2-positive breast cancer after at least two anti-HER2-based regimens and locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab-based regime.
The phase 2 study, dubbed DESTINY-CRC01, divided patients by HER2 expression. In addition to the 53 “high-expressors,” there were 15 medium-expressors – defined as 2+ on immunohistochemical staining and no in situ hybridization – and 18 low-expressors with 1+ HER2 expression.
The patients had run out of other options, having experienced progression on 2 to 11 previous regimens. All participants had been on the topoisomerase I inhibitor irinotecan before, and almost a third of the high-expressors had been on anti-HER2 regimen.
They were treated with 6.4 mg/kg trastuzumab deruxtecan every 3 weeks for a median of 3 months. There was no control group.
The overall response rate was 45.3% among high-expressors. In addition to the mPFS of 6.9 months, median overall survival was 15.5 months. Among those on prior anti-HER2 therapy, the overall response rate was 43.8%.
Benefit was minimal in the lower-expression groups, with a mPFS of 2.1 months and overall survival of 7.3 months in medium-expressors and a mPFS of 1.4 months and overall survival of 7.7 months in low-expressors.
Sixty-five percent of patients (56) had treatment-emergent grade 3 or worse adverse events, most commonly hematologic and gastrointestinal; 13 subjects (15.1%) discontinued due to adverse events.
Eight patients (9.3%) developed interstitial lung disease, a particular concern with trastuzumab deruxtecan; it was fatal for three. “We need to study the lung toxicity. It will become a bigger factor as we think about using this drug for earlier lines of treatment,” Dr. Beg noted.
The median age in the study was 58.5 years, just over half the subjects were men, and more than 90% had left-sided colon or rectum cancer.
The next step in development is a randomized trial in unresectable/metastatic HER2-positive colorectal cancer dubbed DESTINY-CRC02, comparing the 6.4 mg dose with 5.4 mg. It’s already started recruiting.
The work was funded by trastuzumab deruxtecan maker Daiichi Sankyo. Dr. Raghav is an advisor and researcher for the company; Dr. Beg had no relationships with it.
, according to a phase 2 report.
Among the 53 patients with the highest expression in the study – defined as 3+ expression on immune histochemical staining or 2+ with positive in situ hybridization – median progression median progression-free survival (mPFS) was 6.9 months after failure of a median of four prior regimens.
With standard drugs, mPFS would be expected to be about 2 months or less, said investigator Kanwal Pratap Singh Raghav, MD, an associate professor of GI medical oncology at MD Anderson Cancer Center, Houston.
Many of the 86 study participants were enrolled at MD Anderson, and “they all derived some benefit from the conjugate. “It’s fairly well tolerated,” and “our experience has been pretty good; I think it’s actually a pretty good drug,” Dr. Raghav said shortly before presenting the findings at the American Society of Clinical Oncology Annual Meeting.
HER2 is over-expressed in about 5% of colorectal cancer patients. The conjugate is a kind of “smart bomb” for them that combines the anti-HER2 antibody trastuzumab (Herceptin) with a potent topoisomerase I inhibitor. The trastuzumab portion of the combination zeros in on cancer cells expressing HER2, delivering the cytotoxic agent directly to them.
“The amount of [cytotoxic] drug delivered by the antibody inside the cell is far in excess” to the standard approach of delivering chemotherapy agents individually, Dr. Raghav said.
“Single-agent treatments targeting HER2 only have modest activity. Seeing a response rate of [almost] 50% in colorectal cancer tumors that have high expression of HER2 is very exciting,” Muhammad Beg, MD, a GI oncologist and associate professor at UT Southwestern Medical Center, Dallas, said when asked for comment.
Trastuzumab deruxtecan already is approved for metastatic HER2-positive breast cancer after at least two anti-HER2-based regimens and locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab-based regime.
The phase 2 study, dubbed DESTINY-CRC01, divided patients by HER2 expression. In addition to the 53 “high-expressors,” there were 15 medium-expressors – defined as 2+ on immunohistochemical staining and no in situ hybridization – and 18 low-expressors with 1+ HER2 expression.
The patients had run out of other options, having experienced progression on 2 to 11 previous regimens. All participants had been on the topoisomerase I inhibitor irinotecan before, and almost a third of the high-expressors had been on anti-HER2 regimen.
They were treated with 6.4 mg/kg trastuzumab deruxtecan every 3 weeks for a median of 3 months. There was no control group.
The overall response rate was 45.3% among high-expressors. In addition to the mPFS of 6.9 months, median overall survival was 15.5 months. Among those on prior anti-HER2 therapy, the overall response rate was 43.8%.
Benefit was minimal in the lower-expression groups, with a mPFS of 2.1 months and overall survival of 7.3 months in medium-expressors and a mPFS of 1.4 months and overall survival of 7.7 months in low-expressors.
Sixty-five percent of patients (56) had treatment-emergent grade 3 or worse adverse events, most commonly hematologic and gastrointestinal; 13 subjects (15.1%) discontinued due to adverse events.
Eight patients (9.3%) developed interstitial lung disease, a particular concern with trastuzumab deruxtecan; it was fatal for three. “We need to study the lung toxicity. It will become a bigger factor as we think about using this drug for earlier lines of treatment,” Dr. Beg noted.
The median age in the study was 58.5 years, just over half the subjects were men, and more than 90% had left-sided colon or rectum cancer.
The next step in development is a randomized trial in unresectable/metastatic HER2-positive colorectal cancer dubbed DESTINY-CRC02, comparing the 6.4 mg dose with 5.4 mg. It’s already started recruiting.
The work was funded by trastuzumab deruxtecan maker Daiichi Sankyo. Dr. Raghav is an advisor and researcher for the company; Dr. Beg had no relationships with it.
, according to a phase 2 report.
Among the 53 patients with the highest expression in the study – defined as 3+ expression on immune histochemical staining or 2+ with positive in situ hybridization – median progression median progression-free survival (mPFS) was 6.9 months after failure of a median of four prior regimens.
With standard drugs, mPFS would be expected to be about 2 months or less, said investigator Kanwal Pratap Singh Raghav, MD, an associate professor of GI medical oncology at MD Anderson Cancer Center, Houston.
Many of the 86 study participants were enrolled at MD Anderson, and “they all derived some benefit from the conjugate. “It’s fairly well tolerated,” and “our experience has been pretty good; I think it’s actually a pretty good drug,” Dr. Raghav said shortly before presenting the findings at the American Society of Clinical Oncology Annual Meeting.
HER2 is over-expressed in about 5% of colorectal cancer patients. The conjugate is a kind of “smart bomb” for them that combines the anti-HER2 antibody trastuzumab (Herceptin) with a potent topoisomerase I inhibitor. The trastuzumab portion of the combination zeros in on cancer cells expressing HER2, delivering the cytotoxic agent directly to them.
“The amount of [cytotoxic] drug delivered by the antibody inside the cell is far in excess” to the standard approach of delivering chemotherapy agents individually, Dr. Raghav said.
“Single-agent treatments targeting HER2 only have modest activity. Seeing a response rate of [almost] 50% in colorectal cancer tumors that have high expression of HER2 is very exciting,” Muhammad Beg, MD, a GI oncologist and associate professor at UT Southwestern Medical Center, Dallas, said when asked for comment.
Trastuzumab deruxtecan already is approved for metastatic HER2-positive breast cancer after at least two anti-HER2-based regimens and locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab-based regime.
The phase 2 study, dubbed DESTINY-CRC01, divided patients by HER2 expression. In addition to the 53 “high-expressors,” there were 15 medium-expressors – defined as 2+ on immunohistochemical staining and no in situ hybridization – and 18 low-expressors with 1+ HER2 expression.
The patients had run out of other options, having experienced progression on 2 to 11 previous regimens. All participants had been on the topoisomerase I inhibitor irinotecan before, and almost a third of the high-expressors had been on anti-HER2 regimen.
They were treated with 6.4 mg/kg trastuzumab deruxtecan every 3 weeks for a median of 3 months. There was no control group.
The overall response rate was 45.3% among high-expressors. In addition to the mPFS of 6.9 months, median overall survival was 15.5 months. Among those on prior anti-HER2 therapy, the overall response rate was 43.8%.
Benefit was minimal in the lower-expression groups, with a mPFS of 2.1 months and overall survival of 7.3 months in medium-expressors and a mPFS of 1.4 months and overall survival of 7.7 months in low-expressors.
Sixty-five percent of patients (56) had treatment-emergent grade 3 or worse adverse events, most commonly hematologic and gastrointestinal; 13 subjects (15.1%) discontinued due to adverse events.
Eight patients (9.3%) developed interstitial lung disease, a particular concern with trastuzumab deruxtecan; it was fatal for three. “We need to study the lung toxicity. It will become a bigger factor as we think about using this drug for earlier lines of treatment,” Dr. Beg noted.
The median age in the study was 58.5 years, just over half the subjects were men, and more than 90% had left-sided colon or rectum cancer.
The next step in development is a randomized trial in unresectable/metastatic HER2-positive colorectal cancer dubbed DESTINY-CRC02, comparing the 6.4 mg dose with 5.4 mg. It’s already started recruiting.
The work was funded by trastuzumab deruxtecan maker Daiichi Sankyo. Dr. Raghav is an advisor and researcher for the company; Dr. Beg had no relationships with it.
FROM ASCO 2021
Study findings support consideration of second biopsy for transected melanomas
in a review of cases at the university.
Had their true Breslow depths been known before definitive surgery, sentinel lymph node (SLN) biopsies and wider surgical margins would likely have been recommended.
The findings led the investigators to conclude that a second biopsy should be considered when the first one is transected to ensure surgical and other management decisions are based on an accurate Breslow depth.
A second biopsy is especially warranted for broadly transected biopsies and transected T1a tumors with gross residual tumor or pigment on preoperative exam; both scenarios significantly increased the risk of up-staging in the study, according to lead investigator James Duncan, MD, a Mohs surgery and dermatologic oncology fellow at the University of Alabama at Birmingham, who presented the findings at the annual meeting of the American College of Mohs Surgery.
“Accurate staging of malignancies, especially melanoma, is critical to determine prognosis and the best treatment approach,” said Vishal Patel, MD, director of cutaneous oncology at George Washington University, Washington, when asked for comment.
“This study identifies how transected biopsies can underestimate a melanoma’s true depth and thus impact treatment and outcomes. The authors highlight that when a biopsy is transected, or there is notable pigment at the base, attempts should be taken to sample the remaining tumor prior to surgery so the accurate tumor depth can be determined and treatment options be fully discussed with the patient,” Dr. Patel said.
The Birmingham team reviewed invasive melanoma cases at their university from 2017 to 2019.
Almost half (49.6%) of the 726 melanomas they identified were transected on biopsy, which is in line with prior reports. About 60% of the patients were men and 98% were White; the average age was 63 years.
Of the 360 transected tumors, 49 (13.6%) had up-staging at final excision that “would have prompted discussion of alternate surgical treatment such as SLN biopsy or wider surgical margins,” the team said.
Of the 89 transected pT1a melanomas identified, 47.1% with gross residual tumor or pigment on preoperative physical examination were up-staged following excision versus 6.9% with no remaining pigment or tumor prior to surgery (P < .01).
Broadly transected tumors were up-staged in 21.7% of cases versus 4.9% of focally transected tumors (P = .038). The average increase in Breslow depth for broadly transected tumors was 1.03 mm versus 0.03 mm for focally transected lesions (P = .04).
Shave biopsies, ulceration, and lack of concern for melanoma at the initial biopsy were among the factors associated with a higher risk of transection.
Superficial spreading melanoma was the most common subtype. Tumors were evenly distributed between the head, neck, and extremities. The average Breslow depth was 1.51 mm, and the majority of tumors were pT1a or pT2a.
The review excluded melanoma in situ, recurrences, metastases, noncutaneous melanomas, and biopsies where deep margin status was unknown.
There was no funding for the study, and Dr. Duncan and Dr. Patel had no relevant disclosures.
in a review of cases at the university.
Had their true Breslow depths been known before definitive surgery, sentinel lymph node (SLN) biopsies and wider surgical margins would likely have been recommended.
The findings led the investigators to conclude that a second biopsy should be considered when the first one is transected to ensure surgical and other management decisions are based on an accurate Breslow depth.
A second biopsy is especially warranted for broadly transected biopsies and transected T1a tumors with gross residual tumor or pigment on preoperative exam; both scenarios significantly increased the risk of up-staging in the study, according to lead investigator James Duncan, MD, a Mohs surgery and dermatologic oncology fellow at the University of Alabama at Birmingham, who presented the findings at the annual meeting of the American College of Mohs Surgery.
“Accurate staging of malignancies, especially melanoma, is critical to determine prognosis and the best treatment approach,” said Vishal Patel, MD, director of cutaneous oncology at George Washington University, Washington, when asked for comment.
“This study identifies how transected biopsies can underestimate a melanoma’s true depth and thus impact treatment and outcomes. The authors highlight that when a biopsy is transected, or there is notable pigment at the base, attempts should be taken to sample the remaining tumor prior to surgery so the accurate tumor depth can be determined and treatment options be fully discussed with the patient,” Dr. Patel said.
The Birmingham team reviewed invasive melanoma cases at their university from 2017 to 2019.
Almost half (49.6%) of the 726 melanomas they identified were transected on biopsy, which is in line with prior reports. About 60% of the patients were men and 98% were White; the average age was 63 years.
Of the 360 transected tumors, 49 (13.6%) had up-staging at final excision that “would have prompted discussion of alternate surgical treatment such as SLN biopsy or wider surgical margins,” the team said.
Of the 89 transected pT1a melanomas identified, 47.1% with gross residual tumor or pigment on preoperative physical examination were up-staged following excision versus 6.9% with no remaining pigment or tumor prior to surgery (P < .01).
Broadly transected tumors were up-staged in 21.7% of cases versus 4.9% of focally transected tumors (P = .038). The average increase in Breslow depth for broadly transected tumors was 1.03 mm versus 0.03 mm for focally transected lesions (P = .04).
Shave biopsies, ulceration, and lack of concern for melanoma at the initial biopsy were among the factors associated with a higher risk of transection.
Superficial spreading melanoma was the most common subtype. Tumors were evenly distributed between the head, neck, and extremities. The average Breslow depth was 1.51 mm, and the majority of tumors were pT1a or pT2a.
The review excluded melanoma in situ, recurrences, metastases, noncutaneous melanomas, and biopsies where deep margin status was unknown.
There was no funding for the study, and Dr. Duncan and Dr. Patel had no relevant disclosures.
in a review of cases at the university.
Had their true Breslow depths been known before definitive surgery, sentinel lymph node (SLN) biopsies and wider surgical margins would likely have been recommended.
The findings led the investigators to conclude that a second biopsy should be considered when the first one is transected to ensure surgical and other management decisions are based on an accurate Breslow depth.
A second biopsy is especially warranted for broadly transected biopsies and transected T1a tumors with gross residual tumor or pigment on preoperative exam; both scenarios significantly increased the risk of up-staging in the study, according to lead investigator James Duncan, MD, a Mohs surgery and dermatologic oncology fellow at the University of Alabama at Birmingham, who presented the findings at the annual meeting of the American College of Mohs Surgery.
“Accurate staging of malignancies, especially melanoma, is critical to determine prognosis and the best treatment approach,” said Vishal Patel, MD, director of cutaneous oncology at George Washington University, Washington, when asked for comment.
“This study identifies how transected biopsies can underestimate a melanoma’s true depth and thus impact treatment and outcomes. The authors highlight that when a biopsy is transected, or there is notable pigment at the base, attempts should be taken to sample the remaining tumor prior to surgery so the accurate tumor depth can be determined and treatment options be fully discussed with the patient,” Dr. Patel said.
The Birmingham team reviewed invasive melanoma cases at their university from 2017 to 2019.
Almost half (49.6%) of the 726 melanomas they identified were transected on biopsy, which is in line with prior reports. About 60% of the patients were men and 98% were White; the average age was 63 years.
Of the 360 transected tumors, 49 (13.6%) had up-staging at final excision that “would have prompted discussion of alternate surgical treatment such as SLN biopsy or wider surgical margins,” the team said.
Of the 89 transected pT1a melanomas identified, 47.1% with gross residual tumor or pigment on preoperative physical examination were up-staged following excision versus 6.9% with no remaining pigment or tumor prior to surgery (P < .01).
Broadly transected tumors were up-staged in 21.7% of cases versus 4.9% of focally transected tumors (P = .038). The average increase in Breslow depth for broadly transected tumors was 1.03 mm versus 0.03 mm for focally transected lesions (P = .04).
Shave biopsies, ulceration, and lack of concern for melanoma at the initial biopsy were among the factors associated with a higher risk of transection.
Superficial spreading melanoma was the most common subtype. Tumors were evenly distributed between the head, neck, and extremities. The average Breslow depth was 1.51 mm, and the majority of tumors were pT1a or pT2a.
The review excluded melanoma in situ, recurrences, metastases, noncutaneous melanomas, and biopsies where deep margin status was unknown.
There was no funding for the study, and Dr. Duncan and Dr. Patel had no relevant disclosures.
FROM ACMS 2021
Mohs surgery favorable as monotherapy for early Merkel cell carcinomas
Pittsburgh.
The results compare favorably with the standard treatment approach, wide local excision with or without radiation, which has a local recurrence rate of 4.2%-31.7% because of incomplete excision or false negative margins, said Vitaly Terushkin, MD, a Mohs surgeon who presented the findings of the study, a retrospective chart review, at the annual meeting of the American College of Mohs Surgery.
Mohs surgery as monotherapy offered “survival at least as good as historical controls treated with wide local excision plus radiation therapy, and because of the superior local control, Mohs surgery may obviate the need for adjuvant radiation and decrease the chance for additional surgery for the treatment of local recurrence,” said Dr. Terushkin, now in practice in the New York City area.
“We hope this data fuel additional studies with larger cohorts to continue to explore the value of Mohs for Merkel cell carcinoma,” he said.
The findings add to a growing body of literature supporting Mohs for many types of rare tumors. “Micrographic surgery or complete circumferential peripheral and deep margin analysis has been shown to be superior to wide local excision in a variety of tumors and clinical scenarios,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington.
“When the entire margin is able to be evaluated over random bread-loafed sections, there is growing evidence that this leads to superior outcomes and disease specific mortality,” he said when asked for comment on the study results.
In all, 56 primary Merkel cell carcinomas were treated in the 53 patients from 2001 to 2019; about two-thirds of the patients had stage 1 tumors and the rest stage 2a.
They were treated with Mohs alone, without radiation. Average follow up was 4.6 years, with about a third of patients followed for 5 or more years.
The average age of the patients was 78 years, and just over half were men. In more than half the cases, tumors were located on the head and neck (62.5%), and the mean tumor size was 1.7 cm. Patients were negative for lymphadenopathy and declined lymph node biopsy.
Although there was no local recurrence, defined as tumor reemerging within or adjacent to the surgery site, 7 patients (12.7%) developed in-transit metastases, 13 (23.6%) developed nodal metastases, and 3 developed distant metastases.
The 5-year disease-specific survival rate was 91.2% for stage 1 and 68.6% for stage 2a patients, which compared favorably with historical controls treated with wide local excision with or without radiation, with reported 5-year disease-specific survival rates of 81%-87% for stage 1 disease and 63%-67% for stage 2. Although radiation wasn’t used in the study, Dr. Patel noted that more investigation is needed about the role of adjuvant radiation therapy after Mohs surgery “given recent publications showing improved outcomes in patients with narrow margin excision and postoperative radiation therapy.”
No external funding of the study was reported. Dr. Terushkin had no disclosures. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.
Pittsburgh.
The results compare favorably with the standard treatment approach, wide local excision with or without radiation, which has a local recurrence rate of 4.2%-31.7% because of incomplete excision or false negative margins, said Vitaly Terushkin, MD, a Mohs surgeon who presented the findings of the study, a retrospective chart review, at the annual meeting of the American College of Mohs Surgery.
Mohs surgery as monotherapy offered “survival at least as good as historical controls treated with wide local excision plus radiation therapy, and because of the superior local control, Mohs surgery may obviate the need for adjuvant radiation and decrease the chance for additional surgery for the treatment of local recurrence,” said Dr. Terushkin, now in practice in the New York City area.
“We hope this data fuel additional studies with larger cohorts to continue to explore the value of Mohs for Merkel cell carcinoma,” he said.
The findings add to a growing body of literature supporting Mohs for many types of rare tumors. “Micrographic surgery or complete circumferential peripheral and deep margin analysis has been shown to be superior to wide local excision in a variety of tumors and clinical scenarios,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington.
“When the entire margin is able to be evaluated over random bread-loafed sections, there is growing evidence that this leads to superior outcomes and disease specific mortality,” he said when asked for comment on the study results.
In all, 56 primary Merkel cell carcinomas were treated in the 53 patients from 2001 to 2019; about two-thirds of the patients had stage 1 tumors and the rest stage 2a.
They were treated with Mohs alone, without radiation. Average follow up was 4.6 years, with about a third of patients followed for 5 or more years.
The average age of the patients was 78 years, and just over half were men. In more than half the cases, tumors were located on the head and neck (62.5%), and the mean tumor size was 1.7 cm. Patients were negative for lymphadenopathy and declined lymph node biopsy.
Although there was no local recurrence, defined as tumor reemerging within or adjacent to the surgery site, 7 patients (12.7%) developed in-transit metastases, 13 (23.6%) developed nodal metastases, and 3 developed distant metastases.
The 5-year disease-specific survival rate was 91.2% for stage 1 and 68.6% for stage 2a patients, which compared favorably with historical controls treated with wide local excision with or without radiation, with reported 5-year disease-specific survival rates of 81%-87% for stage 1 disease and 63%-67% for stage 2. Although radiation wasn’t used in the study, Dr. Patel noted that more investigation is needed about the role of adjuvant radiation therapy after Mohs surgery “given recent publications showing improved outcomes in patients with narrow margin excision and postoperative radiation therapy.”
No external funding of the study was reported. Dr. Terushkin had no disclosures. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.
Pittsburgh.
The results compare favorably with the standard treatment approach, wide local excision with or without radiation, which has a local recurrence rate of 4.2%-31.7% because of incomplete excision or false negative margins, said Vitaly Terushkin, MD, a Mohs surgeon who presented the findings of the study, a retrospective chart review, at the annual meeting of the American College of Mohs Surgery.
Mohs surgery as monotherapy offered “survival at least as good as historical controls treated with wide local excision plus radiation therapy, and because of the superior local control, Mohs surgery may obviate the need for adjuvant radiation and decrease the chance for additional surgery for the treatment of local recurrence,” said Dr. Terushkin, now in practice in the New York City area.
“We hope this data fuel additional studies with larger cohorts to continue to explore the value of Mohs for Merkel cell carcinoma,” he said.
The findings add to a growing body of literature supporting Mohs for many types of rare tumors. “Micrographic surgery or complete circumferential peripheral and deep margin analysis has been shown to be superior to wide local excision in a variety of tumors and clinical scenarios,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington.
“When the entire margin is able to be evaluated over random bread-loafed sections, there is growing evidence that this leads to superior outcomes and disease specific mortality,” he said when asked for comment on the study results.
In all, 56 primary Merkel cell carcinomas were treated in the 53 patients from 2001 to 2019; about two-thirds of the patients had stage 1 tumors and the rest stage 2a.
They were treated with Mohs alone, without radiation. Average follow up was 4.6 years, with about a third of patients followed for 5 or more years.
The average age of the patients was 78 years, and just over half were men. In more than half the cases, tumors were located on the head and neck (62.5%), and the mean tumor size was 1.7 cm. Patients were negative for lymphadenopathy and declined lymph node biopsy.
Although there was no local recurrence, defined as tumor reemerging within or adjacent to the surgery site, 7 patients (12.7%) developed in-transit metastases, 13 (23.6%) developed nodal metastases, and 3 developed distant metastases.
The 5-year disease-specific survival rate was 91.2% for stage 1 and 68.6% for stage 2a patients, which compared favorably with historical controls treated with wide local excision with or without radiation, with reported 5-year disease-specific survival rates of 81%-87% for stage 1 disease and 63%-67% for stage 2. Although radiation wasn’t used in the study, Dr. Patel noted that more investigation is needed about the role of adjuvant radiation therapy after Mohs surgery “given recent publications showing improved outcomes in patients with narrow margin excision and postoperative radiation therapy.”
No external funding of the study was reported. Dr. Terushkin had no disclosures. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.
FROM ACMS 2021
Checkpoint inhibitors earn spot in new ESMO SCLC guidelines
In new small cell lung cancer guidelines, the European Society of Medical Oncology calls for upfront atezolizumab or durvalumab in combination with four to six cycles of etoposide and a platinum for stage 4 disease.
The strong recommendation is based on two phase 3 trials that showed improved overall survival when the checkpoint inhibitors were added to standard chemotherapy. “With very similar results, and in the context of a severe unmet need, both trials justify the need for immunotherapy in the frontline setting” and established “new standards of care” for stage 4 disease, the group said. “Atezolizumab or durvalumab in combination with a platinum plus etoposide should be offered to all eligible chemotherapy-naive patients” with a performance status of 0-1, said the group led by Anne-Marie Dingemans, MD, PhD, a pulmonology professor at Maastricht (the Netherlands) University Medical Center.
Alessio Cortellini, MD, a consulting oncologist and visiting researcher at Imperial College London, said he strongly endorses the recommendation when asked for comment.
“The addition of a PD-L1 inhibitor to a platinum/etoposide backbone is the first strategy that has led to a significant benefit in terms of overall survival. After decades of disappointing results, the bar has” been raised, said Dr. Cortellini.
New inhibitor
EMSO also incorporated the new RNA polymerase II inhibitor lurbinectedin into their guidelines as an option for patients progressing on or after first-line platinum-based chemotherapy.
The agent was approved by the U.S. Food and Drug Administration in June 2020 for metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.
The recommendations – more than 50 in all – are based on a literature review and expert opinion, and cover SCLC diagnosis, staging, treatment, and follow-up, with flowcharts outlining treatment pathways.
Atezolizumab earned the endorsement following the IMpower133 trial, which showed a median overall survival of 12.3 months for atezolizumab in combination with carboplatin and etoposide, versus 10.3 months on chemotherapy alone; 34% of the atezolizumab group was alive at 18 months versus 21% in the placebo arm.
The durvalumab recommendation is based on the CASPIAN trial, in which the addition of durvalumab to platinum plus etoposide improved median overall survival from 10.5 to 12.9 months; 32% of durvalumab patients were alive at 18 months versus 24.8% in the chemotherapy-alone arm.
ESMO said “it is important to stress that, in both trials,” patients were in good clinical condition with a median age in the early 60s, so relatively young for SCLC. Also, the modest benefits “clearly emphasize the need for” biomarkers that predict response in order to better select patients.
Immunotherapy has improved cancer treatment across many malignancies and continues to be actively investigated in SCLC, but so far only atezolizumab and durvalumab have phase 3 evidence of benefit.
Makers of the blockbuster checkpoint inhibitors nivolumab and pembrolizumab recently withdrew their FDA approval for stage 4 SCLC that’s progressed after platinum-based chemotherapy and at least one other line of therapy; phase 3 trials failed to confirm the modest survival benefit found in early studies.
Lurbinectedin earned its place in the guidelines based on a single-arm study with 105 relapsed patients that showed an overall response rate of 22.2% in platinum-resistant and 45% in platinum-sensitive patients, with a median overall survival of 9.3 months.
The jury is still out, however. A phase 3 trial of lurbinectedin plus doxorubicin versus topotecan or CAV [cyclophosphamide, adriamycin, and vincristine] for advanced recurrent disease failed to meet its endpoint of superior overall survival, according to a recent press release from the its maker.
“It might be a bit early to discuss” routine use of lurbinectedin, although having it available is good “since literally nothing works in the second line setting,” Dr. Cortellini said.
There was no external funding for the work. The authors had numerous ties to pharmaceutical companies, including Dr. Dingemans who reported adviser and speakers fees and/or research funding from Roche, Lilly, Bristol-Myers Squib, and others. Dr. Costellini reported speakers fees from Novartis, Astrazeneca, and Astellas and consultant payments from Bristol-Myers Squibb, Roche, MSD, and AstraZeneca.
In new small cell lung cancer guidelines, the European Society of Medical Oncology calls for upfront atezolizumab or durvalumab in combination with four to six cycles of etoposide and a platinum for stage 4 disease.
The strong recommendation is based on two phase 3 trials that showed improved overall survival when the checkpoint inhibitors were added to standard chemotherapy. “With very similar results, and in the context of a severe unmet need, both trials justify the need for immunotherapy in the frontline setting” and established “new standards of care” for stage 4 disease, the group said. “Atezolizumab or durvalumab in combination with a platinum plus etoposide should be offered to all eligible chemotherapy-naive patients” with a performance status of 0-1, said the group led by Anne-Marie Dingemans, MD, PhD, a pulmonology professor at Maastricht (the Netherlands) University Medical Center.
Alessio Cortellini, MD, a consulting oncologist and visiting researcher at Imperial College London, said he strongly endorses the recommendation when asked for comment.
“The addition of a PD-L1 inhibitor to a platinum/etoposide backbone is the first strategy that has led to a significant benefit in terms of overall survival. After decades of disappointing results, the bar has” been raised, said Dr. Cortellini.
New inhibitor
EMSO also incorporated the new RNA polymerase II inhibitor lurbinectedin into their guidelines as an option for patients progressing on or after first-line platinum-based chemotherapy.
The agent was approved by the U.S. Food and Drug Administration in June 2020 for metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.
The recommendations – more than 50 in all – are based on a literature review and expert opinion, and cover SCLC diagnosis, staging, treatment, and follow-up, with flowcharts outlining treatment pathways.
Atezolizumab earned the endorsement following the IMpower133 trial, which showed a median overall survival of 12.3 months for atezolizumab in combination with carboplatin and etoposide, versus 10.3 months on chemotherapy alone; 34% of the atezolizumab group was alive at 18 months versus 21% in the placebo arm.
The durvalumab recommendation is based on the CASPIAN trial, in which the addition of durvalumab to platinum plus etoposide improved median overall survival from 10.5 to 12.9 months; 32% of durvalumab patients were alive at 18 months versus 24.8% in the chemotherapy-alone arm.
ESMO said “it is important to stress that, in both trials,” patients were in good clinical condition with a median age in the early 60s, so relatively young for SCLC. Also, the modest benefits “clearly emphasize the need for” biomarkers that predict response in order to better select patients.
Immunotherapy has improved cancer treatment across many malignancies and continues to be actively investigated in SCLC, but so far only atezolizumab and durvalumab have phase 3 evidence of benefit.
Makers of the blockbuster checkpoint inhibitors nivolumab and pembrolizumab recently withdrew their FDA approval for stage 4 SCLC that’s progressed after platinum-based chemotherapy and at least one other line of therapy; phase 3 trials failed to confirm the modest survival benefit found in early studies.
Lurbinectedin earned its place in the guidelines based on a single-arm study with 105 relapsed patients that showed an overall response rate of 22.2% in platinum-resistant and 45% in platinum-sensitive patients, with a median overall survival of 9.3 months.
The jury is still out, however. A phase 3 trial of lurbinectedin plus doxorubicin versus topotecan or CAV [cyclophosphamide, adriamycin, and vincristine] for advanced recurrent disease failed to meet its endpoint of superior overall survival, according to a recent press release from the its maker.
“It might be a bit early to discuss” routine use of lurbinectedin, although having it available is good “since literally nothing works in the second line setting,” Dr. Cortellini said.
There was no external funding for the work. The authors had numerous ties to pharmaceutical companies, including Dr. Dingemans who reported adviser and speakers fees and/or research funding from Roche, Lilly, Bristol-Myers Squib, and others. Dr. Costellini reported speakers fees from Novartis, Astrazeneca, and Astellas and consultant payments from Bristol-Myers Squibb, Roche, MSD, and AstraZeneca.
In new small cell lung cancer guidelines, the European Society of Medical Oncology calls for upfront atezolizumab or durvalumab in combination with four to six cycles of etoposide and a platinum for stage 4 disease.
The strong recommendation is based on two phase 3 trials that showed improved overall survival when the checkpoint inhibitors were added to standard chemotherapy. “With very similar results, and in the context of a severe unmet need, both trials justify the need for immunotherapy in the frontline setting” and established “new standards of care” for stage 4 disease, the group said. “Atezolizumab or durvalumab in combination with a platinum plus etoposide should be offered to all eligible chemotherapy-naive patients” with a performance status of 0-1, said the group led by Anne-Marie Dingemans, MD, PhD, a pulmonology professor at Maastricht (the Netherlands) University Medical Center.
Alessio Cortellini, MD, a consulting oncologist and visiting researcher at Imperial College London, said he strongly endorses the recommendation when asked for comment.
“The addition of a PD-L1 inhibitor to a platinum/etoposide backbone is the first strategy that has led to a significant benefit in terms of overall survival. After decades of disappointing results, the bar has” been raised, said Dr. Cortellini.
New inhibitor
EMSO also incorporated the new RNA polymerase II inhibitor lurbinectedin into their guidelines as an option for patients progressing on or after first-line platinum-based chemotherapy.
The agent was approved by the U.S. Food and Drug Administration in June 2020 for metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.
The recommendations – more than 50 in all – are based on a literature review and expert opinion, and cover SCLC diagnosis, staging, treatment, and follow-up, with flowcharts outlining treatment pathways.
Atezolizumab earned the endorsement following the IMpower133 trial, which showed a median overall survival of 12.3 months for atezolizumab in combination with carboplatin and etoposide, versus 10.3 months on chemotherapy alone; 34% of the atezolizumab group was alive at 18 months versus 21% in the placebo arm.
The durvalumab recommendation is based on the CASPIAN trial, in which the addition of durvalumab to platinum plus etoposide improved median overall survival from 10.5 to 12.9 months; 32% of durvalumab patients were alive at 18 months versus 24.8% in the chemotherapy-alone arm.
ESMO said “it is important to stress that, in both trials,” patients were in good clinical condition with a median age in the early 60s, so relatively young for SCLC. Also, the modest benefits “clearly emphasize the need for” biomarkers that predict response in order to better select patients.
Immunotherapy has improved cancer treatment across many malignancies and continues to be actively investigated in SCLC, but so far only atezolizumab and durvalumab have phase 3 evidence of benefit.
Makers of the blockbuster checkpoint inhibitors nivolumab and pembrolizumab recently withdrew their FDA approval for stage 4 SCLC that’s progressed after platinum-based chemotherapy and at least one other line of therapy; phase 3 trials failed to confirm the modest survival benefit found in early studies.
Lurbinectedin earned its place in the guidelines based on a single-arm study with 105 relapsed patients that showed an overall response rate of 22.2% in platinum-resistant and 45% in platinum-sensitive patients, with a median overall survival of 9.3 months.
The jury is still out, however. A phase 3 trial of lurbinectedin plus doxorubicin versus topotecan or CAV [cyclophosphamide, adriamycin, and vincristine] for advanced recurrent disease failed to meet its endpoint of superior overall survival, according to a recent press release from the its maker.
“It might be a bit early to discuss” routine use of lurbinectedin, although having it available is good “since literally nothing works in the second line setting,” Dr. Cortellini said.
There was no external funding for the work. The authors had numerous ties to pharmaceutical companies, including Dr. Dingemans who reported adviser and speakers fees and/or research funding from Roche, Lilly, Bristol-Myers Squib, and others. Dr. Costellini reported speakers fees from Novartis, Astrazeneca, and Astellas and consultant payments from Bristol-Myers Squibb, Roche, MSD, and AstraZeneca.
FROM ANNALS OF ONCOLOGY
Study supports intensifying chemoradiotherapy for head and neck cancer
Of the 16 treatment options compared and ranked, HFCRT topped the list for overall survival, event-free survival, locoregional control, and cancer-specific death.
The results also suggested that taxane-based induction chemotherapy followed by locoregional therapy, especially with concomitant chemotherapy, “is another good option in selected patients with a good performance status and minor comorbidities,” according to investigator Claire Petit, MD, PhD, of Centre hospitalier de l’Université de Montréal in Canada, and colleagues.
The investigators concluded that further intensifying chemoradiotherapy with these approaches “could improve outcomes over chemoradiotherapy.”
The findings, published in The Lancet Oncology, “could help to guide clinical decision-making in locally advanced head and neck cancer with a high risk of locoregional failure, especially human papillomavirus–negative tumours,” the authors wrote.
However, Jared Weiss, MD, of the University of North Carolina, Chapel Hill, cautioned that this “study is an individual patient data network meta-analysis, not a randomized controlled trial. As the authors note, it can help frame existing data but cannot define standard of care.”
Still, “it does support the efficacy of two commonly considered intensification strategies for high-risk patients – hyperfractionation of the radiation and the addition of preceding induction chemotherapy. Both of these intensifications substantially increase the time commitment from the patient, and many patients find this unacceptable. But, for select patients, hyperfractionation and induction chemotherapy have a role and may be considered for patients at high risk of treatment failure,” Dr. Weiss said.
Study details
The goal of this study was to find the best option among many chemoradiation approaches for head and neck cancer. The investigators pulled together and reanalyzed individual patient data from recently updated meta-analyses.
The current analysis included 115 randomized trials that enrolled patients between Jan. 1, 1980, and April 30, 2012. This encompassed 28,978 patients with 20,579 progression events and 19,253 deaths over a median follow-up of 6.6 years.
Treatments were ranked by P score, with higher scores indicating more effective therapies.
For overall survival, HFCRT had a P score of 97%. The hazard ratio (HR) was 0.63 for the comparison with locoregional therapy alone (surgery, radiotherapy, or both). The absolute benefit at 5 years, compared with locoregional therapy alone, was 16.7% with HFCRT.
The P score for the second most effective treatment option – induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT) – was 89%, with a hazard ratio of 0.69 and an absolute benefit at 5 years of 13.4%, versus locoregional therapy.
The HR of HFCRT versus the accepted standard of care worldwide – locoregional therapy with concomitant platinum-based chemotherapy and radiotherapy (CLRTP) – was 0.82 in favor of HFCRT for overall survival and 0.80 for event-free survival.
For overall survival, the P score for CLRTP was 78%. Three other treatment options had a better P score than CLRTP but not a better HR (0.77). These included ICTaxPF-LRT (P score, 89%; HR, 0.69), accelerated radiotherapy with concomitant chemotherapy (P score, 82%; HR, 0.75), and ICTaxPF-LRT followed by CLRTP (P score, 80%; HR, 0.75).
In the end, the investigators found “superiority of HFCRT over other treatments,” but noted it can be difficult to implement HFCRT in the era of intensity-modulated radiotherapy for head and neck cancer. Even so, HFCRT “could be considered as an option for tertiary centres with a high throughput of patients,” the investigators wrote.
The team noted that one of the limitations of this study is that cancer care has improved substantially since the very earliest trials that were included in the analysis. This introduces potential confounders, including that patients in older trials might have been understaged so that even an experimental local therapy would have been less effective.
Toxicity wasn’t part of this analysis but must be taken into account when making therapeutic decisions, “especially because HFCRT and induction chemotherapy based on taxane, cisplatin, and fluorouracil are known to be toxic,” the investigators wrote.
This research was funded by the French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC. The authors disclosed relationships with numerous companies, including AbbVie, Lilly, and Merck. Dr. Weiss did not report any relevant conflicts.
Of the 16 treatment options compared and ranked, HFCRT topped the list for overall survival, event-free survival, locoregional control, and cancer-specific death.
The results also suggested that taxane-based induction chemotherapy followed by locoregional therapy, especially with concomitant chemotherapy, “is another good option in selected patients with a good performance status and minor comorbidities,” according to investigator Claire Petit, MD, PhD, of Centre hospitalier de l’Université de Montréal in Canada, and colleagues.
The investigators concluded that further intensifying chemoradiotherapy with these approaches “could improve outcomes over chemoradiotherapy.”
The findings, published in The Lancet Oncology, “could help to guide clinical decision-making in locally advanced head and neck cancer with a high risk of locoregional failure, especially human papillomavirus–negative tumours,” the authors wrote.
However, Jared Weiss, MD, of the University of North Carolina, Chapel Hill, cautioned that this “study is an individual patient data network meta-analysis, not a randomized controlled trial. As the authors note, it can help frame existing data but cannot define standard of care.”
Still, “it does support the efficacy of two commonly considered intensification strategies for high-risk patients – hyperfractionation of the radiation and the addition of preceding induction chemotherapy. Both of these intensifications substantially increase the time commitment from the patient, and many patients find this unacceptable. But, for select patients, hyperfractionation and induction chemotherapy have a role and may be considered for patients at high risk of treatment failure,” Dr. Weiss said.
Study details
The goal of this study was to find the best option among many chemoradiation approaches for head and neck cancer. The investigators pulled together and reanalyzed individual patient data from recently updated meta-analyses.
The current analysis included 115 randomized trials that enrolled patients between Jan. 1, 1980, and April 30, 2012. This encompassed 28,978 patients with 20,579 progression events and 19,253 deaths over a median follow-up of 6.6 years.
Treatments were ranked by P score, with higher scores indicating more effective therapies.
For overall survival, HFCRT had a P score of 97%. The hazard ratio (HR) was 0.63 for the comparison with locoregional therapy alone (surgery, radiotherapy, or both). The absolute benefit at 5 years, compared with locoregional therapy alone, was 16.7% with HFCRT.
The P score for the second most effective treatment option – induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT) – was 89%, with a hazard ratio of 0.69 and an absolute benefit at 5 years of 13.4%, versus locoregional therapy.
The HR of HFCRT versus the accepted standard of care worldwide – locoregional therapy with concomitant platinum-based chemotherapy and radiotherapy (CLRTP) – was 0.82 in favor of HFCRT for overall survival and 0.80 for event-free survival.
For overall survival, the P score for CLRTP was 78%. Three other treatment options had a better P score than CLRTP but not a better HR (0.77). These included ICTaxPF-LRT (P score, 89%; HR, 0.69), accelerated radiotherapy with concomitant chemotherapy (P score, 82%; HR, 0.75), and ICTaxPF-LRT followed by CLRTP (P score, 80%; HR, 0.75).
In the end, the investigators found “superiority of HFCRT over other treatments,” but noted it can be difficult to implement HFCRT in the era of intensity-modulated radiotherapy for head and neck cancer. Even so, HFCRT “could be considered as an option for tertiary centres with a high throughput of patients,” the investigators wrote.
The team noted that one of the limitations of this study is that cancer care has improved substantially since the very earliest trials that were included in the analysis. This introduces potential confounders, including that patients in older trials might have been understaged so that even an experimental local therapy would have been less effective.
Toxicity wasn’t part of this analysis but must be taken into account when making therapeutic decisions, “especially because HFCRT and induction chemotherapy based on taxane, cisplatin, and fluorouracil are known to be toxic,” the investigators wrote.
This research was funded by the French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC. The authors disclosed relationships with numerous companies, including AbbVie, Lilly, and Merck. Dr. Weiss did not report any relevant conflicts.
Of the 16 treatment options compared and ranked, HFCRT topped the list for overall survival, event-free survival, locoregional control, and cancer-specific death.
The results also suggested that taxane-based induction chemotherapy followed by locoregional therapy, especially with concomitant chemotherapy, “is another good option in selected patients with a good performance status and minor comorbidities,” according to investigator Claire Petit, MD, PhD, of Centre hospitalier de l’Université de Montréal in Canada, and colleagues.
The investigators concluded that further intensifying chemoradiotherapy with these approaches “could improve outcomes over chemoradiotherapy.”
The findings, published in The Lancet Oncology, “could help to guide clinical decision-making in locally advanced head and neck cancer with a high risk of locoregional failure, especially human papillomavirus–negative tumours,” the authors wrote.
However, Jared Weiss, MD, of the University of North Carolina, Chapel Hill, cautioned that this “study is an individual patient data network meta-analysis, not a randomized controlled trial. As the authors note, it can help frame existing data but cannot define standard of care.”
Still, “it does support the efficacy of two commonly considered intensification strategies for high-risk patients – hyperfractionation of the radiation and the addition of preceding induction chemotherapy. Both of these intensifications substantially increase the time commitment from the patient, and many patients find this unacceptable. But, for select patients, hyperfractionation and induction chemotherapy have a role and may be considered for patients at high risk of treatment failure,” Dr. Weiss said.
Study details
The goal of this study was to find the best option among many chemoradiation approaches for head and neck cancer. The investigators pulled together and reanalyzed individual patient data from recently updated meta-analyses.
The current analysis included 115 randomized trials that enrolled patients between Jan. 1, 1980, and April 30, 2012. This encompassed 28,978 patients with 20,579 progression events and 19,253 deaths over a median follow-up of 6.6 years.
Treatments were ranked by P score, with higher scores indicating more effective therapies.
For overall survival, HFCRT had a P score of 97%. The hazard ratio (HR) was 0.63 for the comparison with locoregional therapy alone (surgery, radiotherapy, or both). The absolute benefit at 5 years, compared with locoregional therapy alone, was 16.7% with HFCRT.
The P score for the second most effective treatment option – induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT) – was 89%, with a hazard ratio of 0.69 and an absolute benefit at 5 years of 13.4%, versus locoregional therapy.
The HR of HFCRT versus the accepted standard of care worldwide – locoregional therapy with concomitant platinum-based chemotherapy and radiotherapy (CLRTP) – was 0.82 in favor of HFCRT for overall survival and 0.80 for event-free survival.
For overall survival, the P score for CLRTP was 78%. Three other treatment options had a better P score than CLRTP but not a better HR (0.77). These included ICTaxPF-LRT (P score, 89%; HR, 0.69), accelerated radiotherapy with concomitant chemotherapy (P score, 82%; HR, 0.75), and ICTaxPF-LRT followed by CLRTP (P score, 80%; HR, 0.75).
In the end, the investigators found “superiority of HFCRT over other treatments,” but noted it can be difficult to implement HFCRT in the era of intensity-modulated radiotherapy for head and neck cancer. Even so, HFCRT “could be considered as an option for tertiary centres with a high throughput of patients,” the investigators wrote.
The team noted that one of the limitations of this study is that cancer care has improved substantially since the very earliest trials that were included in the analysis. This introduces potential confounders, including that patients in older trials might have been understaged so that even an experimental local therapy would have been less effective.
Toxicity wasn’t part of this analysis but must be taken into account when making therapeutic decisions, “especially because HFCRT and induction chemotherapy based on taxane, cisplatin, and fluorouracil are known to be toxic,” the investigators wrote.
This research was funded by the French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC. The authors disclosed relationships with numerous companies, including AbbVie, Lilly, and Merck. Dr. Weiss did not report any relevant conflicts.
FROM THE LANCET ONCOLOGY