User login
Lasting benefit with nivo plus ipi in advanced HCC
Long-term follow-up data show a continued benefit for patients with advanced hepatocellular carcinoma (HCC) treated with nivolumab and ipilimumab after disease progression on sorafenib, according to investigators from the Checkmate 040 trial.
At a minimum follow-up of 44 months, the 3-year overall survival rate ranged from 30% to 42% in patients who received three different nivolumab-ipilimumab regimens, reported Anthony B. El-Khoueiry, MD, of the University of Southern California in Los Angeles.
“Durable responses were achieved across treatment arms, with the duration of response approaching 4 years in some cases,” Dr. El-Khoueiry said at the 2021 Gastrointestinal Cancers Symposium (Abstract 269).
The Checkmate 040 trial was designed to compare second- or later-line therapy with the two checkpoint inhibitors at two different dose schedules, followed by maintenance therapy, plus a third continuous therapy arm.
The trial included 148 patients with advanced HCC who experienced disease progression on sorafenib or could not tolerate the drug. They were randomly assigned on a 1:1:1 basis to receive:
- Nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance at 240 mg every 2 weeks (nivo 1 + ipi 3).
- Nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance (nivo 3 + ipi 1).
- Nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity (nivo 3 + ipi 1 Q6).
Based on earlier results of this trial, the nivo 1 + ipi 3 dose with nivolumab maintenance was approved in the United States for patients with advanced HCC previously treated with sorafenib.
Four years on
“Response outcomes at 44 months of follow-up were consistent with the primary analysis,” Dr. El-Khoueiry said.
The overall response rate at the most recent follow-up was 32% for nivo 1 + ipi 3, and 31% in each of the other arms.
The disease control rate – a combination of complete and partial responses and stable disease – was 54% in the nivo 1 + ipi 3 arm, 43% in the nivo 3 + ipi 1 arm, and 49% in the nivo 3 + ipi 1 Q6 arm.
The 36-month overall survival rates were 42%, 26%, and 30%, respectively. Kaplan-Meier curves for overall survival for both the primary analysis and the long-term follow-up displayed a survival advantage for nivo 1 + ipi 3 compared with the other two arms.
Safety
Treatment-related adverse events occurred more frequently in the nivo 1 + ipi 3 arm, which investigators attribute to the higher dose of ipilimumab. The most common grade 3 or 4 events in this arm were elevated liver enzymes and hyponatremia.
Immune-related adverse events also occurred more frequently in the nivo 1 + ipi 3 arm.
“Most immune-mediated adverse events were reversible and resolved when treated using an established algorithm, with steroids being the most common immune-modulating medication used. There were no additional discontinuations due to immune-mediated adverse events during the longer follow-up,” Dr. El-Khoueiry said.
Best combination?
“It’s certainly good data, and we’re happy about the response rate of about 30%, and that was confirmed at [the Gastrointestinal Cancers Symposium] with further follow-up of these patients,” said Lipika Goyal, MD, of Mass General Cancer Center in Boston.
Whether the nivo/ipi combination will turn out to be the optimum choice for patients with advanced HCC is still unknown; however, many different combinations of checkpoint inhibitors with or without tyrosine kinase inhibitors are currently being explored, and have not been compared in head-to-head trials, Dr. Goyal said in an interview. Dr. Goyal was not involved in the Checkmate 040 study.
Checkmate 040 was supported by Bristol Myers Squibb. Dr. El-Khoueiry disclosed honoraria from and consulting/advising for the company and others. Dr. Goyal reported no relevant disclosures.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Long-term follow-up data show a continued benefit for patients with advanced hepatocellular carcinoma (HCC) treated with nivolumab and ipilimumab after disease progression on sorafenib, according to investigators from the Checkmate 040 trial.
At a minimum follow-up of 44 months, the 3-year overall survival rate ranged from 30% to 42% in patients who received three different nivolumab-ipilimumab regimens, reported Anthony B. El-Khoueiry, MD, of the University of Southern California in Los Angeles.
“Durable responses were achieved across treatment arms, with the duration of response approaching 4 years in some cases,” Dr. El-Khoueiry said at the 2021 Gastrointestinal Cancers Symposium (Abstract 269).
The Checkmate 040 trial was designed to compare second- or later-line therapy with the two checkpoint inhibitors at two different dose schedules, followed by maintenance therapy, plus a third continuous therapy arm.
The trial included 148 patients with advanced HCC who experienced disease progression on sorafenib or could not tolerate the drug. They were randomly assigned on a 1:1:1 basis to receive:
- Nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance at 240 mg every 2 weeks (nivo 1 + ipi 3).
- Nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance (nivo 3 + ipi 1).
- Nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity (nivo 3 + ipi 1 Q6).
Based on earlier results of this trial, the nivo 1 + ipi 3 dose with nivolumab maintenance was approved in the United States for patients with advanced HCC previously treated with sorafenib.
Four years on
“Response outcomes at 44 months of follow-up were consistent with the primary analysis,” Dr. El-Khoueiry said.
The overall response rate at the most recent follow-up was 32% for nivo 1 + ipi 3, and 31% in each of the other arms.
The disease control rate – a combination of complete and partial responses and stable disease – was 54% in the nivo 1 + ipi 3 arm, 43% in the nivo 3 + ipi 1 arm, and 49% in the nivo 3 + ipi 1 Q6 arm.
The 36-month overall survival rates were 42%, 26%, and 30%, respectively. Kaplan-Meier curves for overall survival for both the primary analysis and the long-term follow-up displayed a survival advantage for nivo 1 + ipi 3 compared with the other two arms.
Safety
Treatment-related adverse events occurred more frequently in the nivo 1 + ipi 3 arm, which investigators attribute to the higher dose of ipilimumab. The most common grade 3 or 4 events in this arm were elevated liver enzymes and hyponatremia.
Immune-related adverse events also occurred more frequently in the nivo 1 + ipi 3 arm.
“Most immune-mediated adverse events were reversible and resolved when treated using an established algorithm, with steroids being the most common immune-modulating medication used. There were no additional discontinuations due to immune-mediated adverse events during the longer follow-up,” Dr. El-Khoueiry said.
Best combination?
“It’s certainly good data, and we’re happy about the response rate of about 30%, and that was confirmed at [the Gastrointestinal Cancers Symposium] with further follow-up of these patients,” said Lipika Goyal, MD, of Mass General Cancer Center in Boston.
Whether the nivo/ipi combination will turn out to be the optimum choice for patients with advanced HCC is still unknown; however, many different combinations of checkpoint inhibitors with or without tyrosine kinase inhibitors are currently being explored, and have not been compared in head-to-head trials, Dr. Goyal said in an interview. Dr. Goyal was not involved in the Checkmate 040 study.
Checkmate 040 was supported by Bristol Myers Squibb. Dr. El-Khoueiry disclosed honoraria from and consulting/advising for the company and others. Dr. Goyal reported no relevant disclosures.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Long-term follow-up data show a continued benefit for patients with advanced hepatocellular carcinoma (HCC) treated with nivolumab and ipilimumab after disease progression on sorafenib, according to investigators from the Checkmate 040 trial.
At a minimum follow-up of 44 months, the 3-year overall survival rate ranged from 30% to 42% in patients who received three different nivolumab-ipilimumab regimens, reported Anthony B. El-Khoueiry, MD, of the University of Southern California in Los Angeles.
“Durable responses were achieved across treatment arms, with the duration of response approaching 4 years in some cases,” Dr. El-Khoueiry said at the 2021 Gastrointestinal Cancers Symposium (Abstract 269).
The Checkmate 040 trial was designed to compare second- or later-line therapy with the two checkpoint inhibitors at two different dose schedules, followed by maintenance therapy, plus a third continuous therapy arm.
The trial included 148 patients with advanced HCC who experienced disease progression on sorafenib or could not tolerate the drug. They were randomly assigned on a 1:1:1 basis to receive:
- Nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance at 240 mg every 2 weeks (nivo 1 + ipi 3).
- Nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 cycles, followed by nivolumab maintenance (nivo 3 + ipi 1).
- Nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity (nivo 3 + ipi 1 Q6).
Based on earlier results of this trial, the nivo 1 + ipi 3 dose with nivolumab maintenance was approved in the United States for patients with advanced HCC previously treated with sorafenib.
Four years on
“Response outcomes at 44 months of follow-up were consistent with the primary analysis,” Dr. El-Khoueiry said.
The overall response rate at the most recent follow-up was 32% for nivo 1 + ipi 3, and 31% in each of the other arms.
The disease control rate – a combination of complete and partial responses and stable disease – was 54% in the nivo 1 + ipi 3 arm, 43% in the nivo 3 + ipi 1 arm, and 49% in the nivo 3 + ipi 1 Q6 arm.
The 36-month overall survival rates were 42%, 26%, and 30%, respectively. Kaplan-Meier curves for overall survival for both the primary analysis and the long-term follow-up displayed a survival advantage for nivo 1 + ipi 3 compared with the other two arms.
Safety
Treatment-related adverse events occurred more frequently in the nivo 1 + ipi 3 arm, which investigators attribute to the higher dose of ipilimumab. The most common grade 3 or 4 events in this arm were elevated liver enzymes and hyponatremia.
Immune-related adverse events also occurred more frequently in the nivo 1 + ipi 3 arm.
“Most immune-mediated adverse events were reversible and resolved when treated using an established algorithm, with steroids being the most common immune-modulating medication used. There were no additional discontinuations due to immune-mediated adverse events during the longer follow-up,” Dr. El-Khoueiry said.
Best combination?
“It’s certainly good data, and we’re happy about the response rate of about 30%, and that was confirmed at [the Gastrointestinal Cancers Symposium] with further follow-up of these patients,” said Lipika Goyal, MD, of Mass General Cancer Center in Boston.
Whether the nivo/ipi combination will turn out to be the optimum choice for patients with advanced HCC is still unknown; however, many different combinations of checkpoint inhibitors with or without tyrosine kinase inhibitors are currently being explored, and have not been compared in head-to-head trials, Dr. Goyal said in an interview. Dr. Goyal was not involved in the Checkmate 040 study.
Checkmate 040 was supported by Bristol Myers Squibb. Dr. El-Khoueiry disclosed honoraria from and consulting/advising for the company and others. Dr. Goyal reported no relevant disclosures.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
FROM GI CANCERS SYMPOSIUM 2021
TACTICS: TACE plus sorafenib improves PFS in unresectable HCC
The lack of a statistically significant difference in OS may have been due to the fact that patients randomized to receive TACE alone had more frequent post-trial therapies compared with patients assigned to TACE plus sorafenib, said study investigator Masatoshi Kudo, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan.
“These subsequent anticancer procedures and active systemic therapies have potentially diluted OS benefit in TACE plus sorafenib by extending post-progression survival and confounding survival analysis, implying the OS endpoint is not feasible anymore for TACE combination trials in the era of multitargeted agents and immune checkpoint inhibitors,” Dr. Kudo said at the 2021 Gastrointestinal Cancers Symposium (abstract 270).
Unresectable HCC
The TACTICS trial was launched in October 2010. Investigators enrolled 156 patients with unresectable HCC, Child-Pugh scores of 7 or less, treatable tumors (10 or fewer nodules of 10 cm or less) and adequate organ function.
Patients were randomized to receive TACE alone or with sorafenib. Sorafenib was delivered at a dose of 400 mg daily starting 2-3 weeks before the first TACE procedure to assess tolerability, followed by 800-mg daily doses. Sorafenib was interrupted for 2 days before and 3 days after each TACE session.
The trial had a gate-keeping design, which specified that OS would be formally analyzed only if PFS results were positive.
As reported in GUT in 2020, the trial met its PFS coprimary endpoint, with a median PFS of 25.2 months for the combination, compared with 13.5 months for TACE alone, at a median follow-up of 122.3 weeks. The hazard ratio (HR) for progression with the combination was 0.59 (P = .006).
Updated results
At the symposium, Dr. Kudo presented updated PFS results. At a median follow-up for all randomized patients of 33.4 months, the median PFS with the combination was 22.8 months, compared with 13.5 months for TACE alone (HR, 0.661; P = .02).
However, OS did not differ significantly between the groups, with a median of 36.2 months for the combination and 30.8 months for TACE alone (HR, 0.861; P = .40)
In a subgroup analysis of OS, there were small trends in favor of the combination compared with TACE alone in most categories, but the benefit of the combination was statistically significant only for the 12 patients with HCC of hepatitis B virus etiology (HR, 0.72; 95% CI, 0.006-0.808).
There were also trends favoring TACE plus sorafenib for PFS in a subgroup analysis, but none of the differences were statistically significant, except for patients who had received one or two TACE treatments prior to study entry (HR, 0.474; 95% CI, 0.276-0.812).
Treatment-emergent adverse events were consistent with those seen in the primary analysis, with no new safety signals seen at the last follow-up, Dr. Kudo said.
A majority of patients in both arms had subsequent anticancer therapy – 76.3% of the TACE-alone arm and 58.8% of the combination arm.
Patients in the TACE-alone arm were more likely than were those in the combination arm to have ablation (22.4% vs. 14.9%) or additional sorafenib (50% vs. 10.6%). Patients in the TACE-alone arm were also more likely to receive hepatic artery infusion chemotherapy a single time (27.6% vs. 19.1%) but less likely to receive it continuously (10.3% vs. 19.1%).
Dr. Kudo noted that in six trials in which TACE was combined with another agent, the correlation coefficient between PFS and OS was low, and the slope of weighted linear regression was more gentle than that seen in trials of other therapies for advanced HCC, “suggesting that long post-progression survivals strongly affected the OS in TACE combination trials.”
The TACTICS study was funded by the Japan Liver Oncology Group. Dr. Kudo disclosed relationships with Bayer, codeveloper of sorafenib, and multiple other companies.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The lack of a statistically significant difference in OS may have been due to the fact that patients randomized to receive TACE alone had more frequent post-trial therapies compared with patients assigned to TACE plus sorafenib, said study investigator Masatoshi Kudo, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan.
“These subsequent anticancer procedures and active systemic therapies have potentially diluted OS benefit in TACE plus sorafenib by extending post-progression survival and confounding survival analysis, implying the OS endpoint is not feasible anymore for TACE combination trials in the era of multitargeted agents and immune checkpoint inhibitors,” Dr. Kudo said at the 2021 Gastrointestinal Cancers Symposium (abstract 270).
Unresectable HCC
The TACTICS trial was launched in October 2010. Investigators enrolled 156 patients with unresectable HCC, Child-Pugh scores of 7 or less, treatable tumors (10 or fewer nodules of 10 cm or less) and adequate organ function.
Patients were randomized to receive TACE alone or with sorafenib. Sorafenib was delivered at a dose of 400 mg daily starting 2-3 weeks before the first TACE procedure to assess tolerability, followed by 800-mg daily doses. Sorafenib was interrupted for 2 days before and 3 days after each TACE session.
The trial had a gate-keeping design, which specified that OS would be formally analyzed only if PFS results were positive.
As reported in GUT in 2020, the trial met its PFS coprimary endpoint, with a median PFS of 25.2 months for the combination, compared with 13.5 months for TACE alone, at a median follow-up of 122.3 weeks. The hazard ratio (HR) for progression with the combination was 0.59 (P = .006).
Updated results
At the symposium, Dr. Kudo presented updated PFS results. At a median follow-up for all randomized patients of 33.4 months, the median PFS with the combination was 22.8 months, compared with 13.5 months for TACE alone (HR, 0.661; P = .02).
However, OS did not differ significantly between the groups, with a median of 36.2 months for the combination and 30.8 months for TACE alone (HR, 0.861; P = .40)
In a subgroup analysis of OS, there were small trends in favor of the combination compared with TACE alone in most categories, but the benefit of the combination was statistically significant only for the 12 patients with HCC of hepatitis B virus etiology (HR, 0.72; 95% CI, 0.006-0.808).
There were also trends favoring TACE plus sorafenib for PFS in a subgroup analysis, but none of the differences were statistically significant, except for patients who had received one or two TACE treatments prior to study entry (HR, 0.474; 95% CI, 0.276-0.812).
Treatment-emergent adverse events were consistent with those seen in the primary analysis, with no new safety signals seen at the last follow-up, Dr. Kudo said.
A majority of patients in both arms had subsequent anticancer therapy – 76.3% of the TACE-alone arm and 58.8% of the combination arm.
Patients in the TACE-alone arm were more likely than were those in the combination arm to have ablation (22.4% vs. 14.9%) or additional sorafenib (50% vs. 10.6%). Patients in the TACE-alone arm were also more likely to receive hepatic artery infusion chemotherapy a single time (27.6% vs. 19.1%) but less likely to receive it continuously (10.3% vs. 19.1%).
Dr. Kudo noted that in six trials in which TACE was combined with another agent, the correlation coefficient between PFS and OS was low, and the slope of weighted linear regression was more gentle than that seen in trials of other therapies for advanced HCC, “suggesting that long post-progression survivals strongly affected the OS in TACE combination trials.”
The TACTICS study was funded by the Japan Liver Oncology Group. Dr. Kudo disclosed relationships with Bayer, codeveloper of sorafenib, and multiple other companies.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The lack of a statistically significant difference in OS may have been due to the fact that patients randomized to receive TACE alone had more frequent post-trial therapies compared with patients assigned to TACE plus sorafenib, said study investigator Masatoshi Kudo, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan.
“These subsequent anticancer procedures and active systemic therapies have potentially diluted OS benefit in TACE plus sorafenib by extending post-progression survival and confounding survival analysis, implying the OS endpoint is not feasible anymore for TACE combination trials in the era of multitargeted agents and immune checkpoint inhibitors,” Dr. Kudo said at the 2021 Gastrointestinal Cancers Symposium (abstract 270).
Unresectable HCC
The TACTICS trial was launched in October 2010. Investigators enrolled 156 patients with unresectable HCC, Child-Pugh scores of 7 or less, treatable tumors (10 or fewer nodules of 10 cm or less) and adequate organ function.
Patients were randomized to receive TACE alone or with sorafenib. Sorafenib was delivered at a dose of 400 mg daily starting 2-3 weeks before the first TACE procedure to assess tolerability, followed by 800-mg daily doses. Sorafenib was interrupted for 2 days before and 3 days after each TACE session.
The trial had a gate-keeping design, which specified that OS would be formally analyzed only if PFS results were positive.
As reported in GUT in 2020, the trial met its PFS coprimary endpoint, with a median PFS of 25.2 months for the combination, compared with 13.5 months for TACE alone, at a median follow-up of 122.3 weeks. The hazard ratio (HR) for progression with the combination was 0.59 (P = .006).
Updated results
At the symposium, Dr. Kudo presented updated PFS results. At a median follow-up for all randomized patients of 33.4 months, the median PFS with the combination was 22.8 months, compared with 13.5 months for TACE alone (HR, 0.661; P = .02).
However, OS did not differ significantly between the groups, with a median of 36.2 months for the combination and 30.8 months for TACE alone (HR, 0.861; P = .40)
In a subgroup analysis of OS, there were small trends in favor of the combination compared with TACE alone in most categories, but the benefit of the combination was statistically significant only for the 12 patients with HCC of hepatitis B virus etiology (HR, 0.72; 95% CI, 0.006-0.808).
There were also trends favoring TACE plus sorafenib for PFS in a subgroup analysis, but none of the differences were statistically significant, except for patients who had received one or two TACE treatments prior to study entry (HR, 0.474; 95% CI, 0.276-0.812).
Treatment-emergent adverse events were consistent with those seen in the primary analysis, with no new safety signals seen at the last follow-up, Dr. Kudo said.
A majority of patients in both arms had subsequent anticancer therapy – 76.3% of the TACE-alone arm and 58.8% of the combination arm.
Patients in the TACE-alone arm were more likely than were those in the combination arm to have ablation (22.4% vs. 14.9%) or additional sorafenib (50% vs. 10.6%). Patients in the TACE-alone arm were also more likely to receive hepatic artery infusion chemotherapy a single time (27.6% vs. 19.1%) but less likely to receive it continuously (10.3% vs. 19.1%).
Dr. Kudo noted that in six trials in which TACE was combined with another agent, the correlation coefficient between PFS and OS was low, and the slope of weighted linear regression was more gentle than that seen in trials of other therapies for advanced HCC, “suggesting that long post-progression survivals strongly affected the OS in TACE combination trials.”
The TACTICS study was funded by the Japan Liver Oncology Group. Dr. Kudo disclosed relationships with Bayer, codeveloper of sorafenib, and multiple other companies.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
FROM GI CANCERS SYMPOSIUM 2021
The jury’s still out on trifluridine/tipiracil plus bevacizumab in mCRC
The median progression-free survival (PFS) in the phase 2 trial showed a difference of 1.41 months favoring TT-B over C-B, but this difference was not statistically significant.
The median overall survival was 4.64 months longer with TT-B than with C-B. However, the final analysis of TASCO1 was not designed to be comparative for overall survival, “so no formal statistical analysis is presented, and survival is a secondary endpoint,” noted investigator Eric Van Cutsem, MD, PhD, of University Hospital Gasthuisberg in Leuven, Belgium.
Dr. Van Cutsem presented the final results of TASCO1 at the 2021 Gastrointestinal Cancers Symposium (abstract 14).
Prior results from the trial were reported last year (Ann Oncol. 2020 Sep;31[9]:1160-68).
About trifluridine/tipiracil
Trifluridine/tipiracil is an oral drug combining the thymidine analogue trifluridine with tipiracil, an inhibitor of trifluridine degradation. The drug was approved by the Food and Drug Administration in 2015 under the trade name Lonsurf for the treatment of refractory metastatic colorectal cancer, and in 2019 for patients with metastatic gastric cancer or gastroesophageal junction cancer that had been treated with at least two lines of chemotherapy.
Trifluridine/tipiracil was associated with a brief but statistically significant survival benefit when compared with placebo in patients with heavily pretreated metastatic gastric cancer in the TAS-102 Gastric Study (Lancet Oncol. 2018 Nov;19[11]:1437-48).
In a separate analysis of the study, trifluridine/tipiracil was associated with significantly better overall survival and PFS than placebo in patients who had undergone gastrectomy (JAMA Oncol. 2019 Oct 10;6[1]:e193531).
TASCO1 details
In TASCO1, investigators enrolled patients with colorectal cancer who had never received systemic therapy for unresectable metastatic disease, and who were judged to be ineligible for intensive therapy due to advanced age, low tumor burden, poor performance status, comorbidities, or other clinical reasons.
After stratification by RAS status, performance status, and region, patients were randomly assigned to receive TT-B (n = 77) or C-B (n = 76).
TT-B consisted of oral trifluridine/tipiracil at 35 mg/m2 twice daily on days 1-5 and 8-12 every 4 weeks plus bevacizumab at 5 mg/kg intravenously on days 1 and 15 every 4 weeks.
C-B consisted of oral capecitabine at 1,250 or 1,000 mg/m2 twice a day on days 1-14 every 3 weeks plus bevacizumab at 7.5 mg/kg IV on day 1 every 3 weeks.
Final results
The median PFS, the primary endpoint, was 9.23 months with TT-B and 7.82 months with C-B. The difference was not statistically significant, with the upper limit of the 95% confidence interval crossing 1.
The median overall survival was 22.31 months with TT-B and 17.67 months with C-B (hazard ratio, 0.78; 95% CI, 0.55-1.10).
Dr. Van Cutsem pointed out that more patients in the TT-B arm had subsequent therapies compared with patients in the C-B arm – 59.7% vs. 40.8%.
He also noted that the safety profile of TT-B “remains unchanged from the initial analysis.”
Grade 3 or greater neutropenia, decreased neutrophil count, anemia, and decreased white blood cell count were all higher among patients on TT-B, but grade 3 or greater febrile neutropenia was similar between the groups.
Patients in the TT-B arm had more frequent grade 3 or greater nausea, vomiting, and hypertension. Grade 3 or higher hand-foot syndrome and diarrhea were both more common with C-B.
At the study cutoff date in September 2020, 66 patients in each arm had died.
Dr. Van Cutsem said more data on the efficacy of TT-B vs. C-B will come from the ongoing phase 3 SOLSTICE trial. Results from this trial are expected in late 2022.
‘The jury is still out’
The final results from TASCO1 suggest there may be some benefit from TT-B in patients with treatment-naive metastatic colorectal cancer, “but we don’t use it in the first line,” said Jeffery Clark, MD, an oncologist who was not involved in the study.
The trial supports the benefit of combining trifluridine/tipiracil with bevacizumab, and the results were “somewhat better” than he had expected, said Dr. Clark, director of clinical trials support at Mass General Cancer Center in Boston.
“Even though the results are encouraging, there were a couple of things about the trial that one has to at least think about,” Dr. Clark said in an interview.
He noted, for example, that a higher proportion of patients assigned to TT-B had prior adjuvant therapy (27.3% vs. 19.7%), and patients in the TT-B arm were also more likely to have second lines of systemic therapy, which could have skewed the results in favor of the experimental arm.
“I think, basically, the jury is still out until we see the results of the SOLSTICE trial,” he said.
The TASCO1 study was funded by Servier and Taiho. Dr. Van Cutsem has received research funding and served on an advisory board for Servier and other companies. Dr. Clark reported no relevant disclosures.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The median progression-free survival (PFS) in the phase 2 trial showed a difference of 1.41 months favoring TT-B over C-B, but this difference was not statistically significant.
The median overall survival was 4.64 months longer with TT-B than with C-B. However, the final analysis of TASCO1 was not designed to be comparative for overall survival, “so no formal statistical analysis is presented, and survival is a secondary endpoint,” noted investigator Eric Van Cutsem, MD, PhD, of University Hospital Gasthuisberg in Leuven, Belgium.
Dr. Van Cutsem presented the final results of TASCO1 at the 2021 Gastrointestinal Cancers Symposium (abstract 14).
Prior results from the trial were reported last year (Ann Oncol. 2020 Sep;31[9]:1160-68).
About trifluridine/tipiracil
Trifluridine/tipiracil is an oral drug combining the thymidine analogue trifluridine with tipiracil, an inhibitor of trifluridine degradation. The drug was approved by the Food and Drug Administration in 2015 under the trade name Lonsurf for the treatment of refractory metastatic colorectal cancer, and in 2019 for patients with metastatic gastric cancer or gastroesophageal junction cancer that had been treated with at least two lines of chemotherapy.
Trifluridine/tipiracil was associated with a brief but statistically significant survival benefit when compared with placebo in patients with heavily pretreated metastatic gastric cancer in the TAS-102 Gastric Study (Lancet Oncol. 2018 Nov;19[11]:1437-48).
In a separate analysis of the study, trifluridine/tipiracil was associated with significantly better overall survival and PFS than placebo in patients who had undergone gastrectomy (JAMA Oncol. 2019 Oct 10;6[1]:e193531).
TASCO1 details
In TASCO1, investigators enrolled patients with colorectal cancer who had never received systemic therapy for unresectable metastatic disease, and who were judged to be ineligible for intensive therapy due to advanced age, low tumor burden, poor performance status, comorbidities, or other clinical reasons.
After stratification by RAS status, performance status, and region, patients were randomly assigned to receive TT-B (n = 77) or C-B (n = 76).
TT-B consisted of oral trifluridine/tipiracil at 35 mg/m2 twice daily on days 1-5 and 8-12 every 4 weeks plus bevacizumab at 5 mg/kg intravenously on days 1 and 15 every 4 weeks.
C-B consisted of oral capecitabine at 1,250 or 1,000 mg/m2 twice a day on days 1-14 every 3 weeks plus bevacizumab at 7.5 mg/kg IV on day 1 every 3 weeks.
Final results
The median PFS, the primary endpoint, was 9.23 months with TT-B and 7.82 months with C-B. The difference was not statistically significant, with the upper limit of the 95% confidence interval crossing 1.
The median overall survival was 22.31 months with TT-B and 17.67 months with C-B (hazard ratio, 0.78; 95% CI, 0.55-1.10).
Dr. Van Cutsem pointed out that more patients in the TT-B arm had subsequent therapies compared with patients in the C-B arm – 59.7% vs. 40.8%.
He also noted that the safety profile of TT-B “remains unchanged from the initial analysis.”
Grade 3 or greater neutropenia, decreased neutrophil count, anemia, and decreased white blood cell count were all higher among patients on TT-B, but grade 3 or greater febrile neutropenia was similar between the groups.
Patients in the TT-B arm had more frequent grade 3 or greater nausea, vomiting, and hypertension. Grade 3 or higher hand-foot syndrome and diarrhea were both more common with C-B.
At the study cutoff date in September 2020, 66 patients in each arm had died.
Dr. Van Cutsem said more data on the efficacy of TT-B vs. C-B will come from the ongoing phase 3 SOLSTICE trial. Results from this trial are expected in late 2022.
‘The jury is still out’
The final results from TASCO1 suggest there may be some benefit from TT-B in patients with treatment-naive metastatic colorectal cancer, “but we don’t use it in the first line,” said Jeffery Clark, MD, an oncologist who was not involved in the study.
The trial supports the benefit of combining trifluridine/tipiracil with bevacizumab, and the results were “somewhat better” than he had expected, said Dr. Clark, director of clinical trials support at Mass General Cancer Center in Boston.
“Even though the results are encouraging, there were a couple of things about the trial that one has to at least think about,” Dr. Clark said in an interview.
He noted, for example, that a higher proportion of patients assigned to TT-B had prior adjuvant therapy (27.3% vs. 19.7%), and patients in the TT-B arm were also more likely to have second lines of systemic therapy, which could have skewed the results in favor of the experimental arm.
“I think, basically, the jury is still out until we see the results of the SOLSTICE trial,” he said.
The TASCO1 study was funded by Servier and Taiho. Dr. Van Cutsem has received research funding and served on an advisory board for Servier and other companies. Dr. Clark reported no relevant disclosures.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The median progression-free survival (PFS) in the phase 2 trial showed a difference of 1.41 months favoring TT-B over C-B, but this difference was not statistically significant.
The median overall survival was 4.64 months longer with TT-B than with C-B. However, the final analysis of TASCO1 was not designed to be comparative for overall survival, “so no formal statistical analysis is presented, and survival is a secondary endpoint,” noted investigator Eric Van Cutsem, MD, PhD, of University Hospital Gasthuisberg in Leuven, Belgium.
Dr. Van Cutsem presented the final results of TASCO1 at the 2021 Gastrointestinal Cancers Symposium (abstract 14).
Prior results from the trial were reported last year (Ann Oncol. 2020 Sep;31[9]:1160-68).
About trifluridine/tipiracil
Trifluridine/tipiracil is an oral drug combining the thymidine analogue trifluridine with tipiracil, an inhibitor of trifluridine degradation. The drug was approved by the Food and Drug Administration in 2015 under the trade name Lonsurf for the treatment of refractory metastatic colorectal cancer, and in 2019 for patients with metastatic gastric cancer or gastroesophageal junction cancer that had been treated with at least two lines of chemotherapy.
Trifluridine/tipiracil was associated with a brief but statistically significant survival benefit when compared with placebo in patients with heavily pretreated metastatic gastric cancer in the TAS-102 Gastric Study (Lancet Oncol. 2018 Nov;19[11]:1437-48).
In a separate analysis of the study, trifluridine/tipiracil was associated with significantly better overall survival and PFS than placebo in patients who had undergone gastrectomy (JAMA Oncol. 2019 Oct 10;6[1]:e193531).
TASCO1 details
In TASCO1, investigators enrolled patients with colorectal cancer who had never received systemic therapy for unresectable metastatic disease, and who were judged to be ineligible for intensive therapy due to advanced age, low tumor burden, poor performance status, comorbidities, or other clinical reasons.
After stratification by RAS status, performance status, and region, patients were randomly assigned to receive TT-B (n = 77) or C-B (n = 76).
TT-B consisted of oral trifluridine/tipiracil at 35 mg/m2 twice daily on days 1-5 and 8-12 every 4 weeks plus bevacizumab at 5 mg/kg intravenously on days 1 and 15 every 4 weeks.
C-B consisted of oral capecitabine at 1,250 or 1,000 mg/m2 twice a day on days 1-14 every 3 weeks plus bevacizumab at 7.5 mg/kg IV on day 1 every 3 weeks.
Final results
The median PFS, the primary endpoint, was 9.23 months with TT-B and 7.82 months with C-B. The difference was not statistically significant, with the upper limit of the 95% confidence interval crossing 1.
The median overall survival was 22.31 months with TT-B and 17.67 months with C-B (hazard ratio, 0.78; 95% CI, 0.55-1.10).
Dr. Van Cutsem pointed out that more patients in the TT-B arm had subsequent therapies compared with patients in the C-B arm – 59.7% vs. 40.8%.
He also noted that the safety profile of TT-B “remains unchanged from the initial analysis.”
Grade 3 or greater neutropenia, decreased neutrophil count, anemia, and decreased white blood cell count were all higher among patients on TT-B, but grade 3 or greater febrile neutropenia was similar between the groups.
Patients in the TT-B arm had more frequent grade 3 or greater nausea, vomiting, and hypertension. Grade 3 or higher hand-foot syndrome and diarrhea were both more common with C-B.
At the study cutoff date in September 2020, 66 patients in each arm had died.
Dr. Van Cutsem said more data on the efficacy of TT-B vs. C-B will come from the ongoing phase 3 SOLSTICE trial. Results from this trial are expected in late 2022.
‘The jury is still out’
The final results from TASCO1 suggest there may be some benefit from TT-B in patients with treatment-naive metastatic colorectal cancer, “but we don’t use it in the first line,” said Jeffery Clark, MD, an oncologist who was not involved in the study.
The trial supports the benefit of combining trifluridine/tipiracil with bevacizumab, and the results were “somewhat better” than he had expected, said Dr. Clark, director of clinical trials support at Mass General Cancer Center in Boston.
“Even though the results are encouraging, there were a couple of things about the trial that one has to at least think about,” Dr. Clark said in an interview.
He noted, for example, that a higher proportion of patients assigned to TT-B had prior adjuvant therapy (27.3% vs. 19.7%), and patients in the TT-B arm were also more likely to have second lines of systemic therapy, which could have skewed the results in favor of the experimental arm.
“I think, basically, the jury is still out until we see the results of the SOLSTICE trial,” he said.
The TASCO1 study was funded by Servier and Taiho. Dr. Van Cutsem has received research funding and served on an advisory board for Servier and other companies. Dr. Clark reported no relevant disclosures.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
FROM GI CANCERS SYMPOSIUM 2021
Triplet shows ‘promising’ activity in unresectable/metastatic CRC
The trial was designed to test the combination of panitumumab, ipilimumab, and nivolumab in patients with previously treated, unresectable and/or metastatic, microsatellite stable or mismatch repair–proficient CRC without mutations in KRAS, NRAS, or BRAF.
Among 49 evaluable patients treated with the triplet, 35% had a partial response at 12 weeks of follow-up, which met the trial’s primary response endpoint, according to investigator Michael S. Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Though toxicities were, of course, observed, they were consistent overall with the expected adverse event profiles of anti-EGFR therapy and combination ipilimumab and nivolumab. Correlative studies are ongoing to identify potential biomarkers of response,” Dr. Lee said when presenting the trial results at the 2021 Gastrointestinal Cancers Symposium (Abstract 7).
Immune activation?
The rationale for adding panitumumab to immune checkpoint inhibitors comes, in part, from a trial published in 2014 in The Lancet Oncology. The trial showed that panitumumab was noninferior to cetuximab. Panitumumab was associated with a 22% response rate in patients with KRAS wild-type, metastatic CRC that was refractory to chemotherapy. Progression-free survival (PFS) and overall survival (OS) were similar between the treatment arms.
In addition, in mouse models of RAS wild-type CRC, treatment with an anti-EGFR antibody induced immunogenic cell death.
“Moreover, translational studies of tumor biopsies from patients who were treated with the anti-EGFR antibody cetuximab showed that responders had significant increases in T-cell infiltration and cytolytic activity within tumors after starting treatment,” Dr. Lee said.
In the latter studies, tumor samples taken at the time of disease progression also showed increased expression of immune checkpoint inhibitor pathways, including PD-L1, the primary target of nivolumab, and CTLA-4, the primary target of ipilimumab.
“Given this, we hypothesized that combining anti–PD-1 and anti–CTLA-4 antibodies with anti-EGFR therapy would be synergistic,” Dr. Lee said.
Single-arm study
Investigators enrolled patients with unresectable and/or metastatic CRC in the trial. All patients had disease that was KRAS, NRAS, and BRAF wild-type, and they had either microsatellite stability or proficient mismatch repair. Patients also had to have received one or two prior lines of therapy, not including an anti-EGFR agent.
The patients received panitumumab at 6 mg/kg IV every 2 weeks, nivolumab at 240 mg IV every 2 weeks, and ipilimumab at 1 mg/kg IV every 6 weeks.
Of all 56 patients enrolled, 28 (50%) had tumors in the left colon, 3 (5%) had tumors in the right colon, 2 (4%) had tumors in the transverse colon, 16 (29%) had rectal tumors, and 7 (13%) were not specified.
As noted before, 49 patients were evaluable, and the trial met its primary endpoint of responses in at least 17 patients (35%) at 12 weeks. All were partial responses.
Of the remaining patients, 21 (43%) had stable disease, and 11 (22%) had disease progression. Of the latter group, five patients did not have documented radiographic progression at 12 weeks, but they discontinued therapy before restaging because of unequivocal clinical progression.
The best response rate (confirmed and unconfirmed) at any time was 41%.
At a median follow-up of 12.1 months, the median PFS was 5.7 months. The OS data were not mature at the time of data cutoff. However, the median OS was 27 months.
There were two deaths on study, one from myocarditis possibly related to the study treatment, and one from colonic perforation, which was deemed unlikely to be treatment related.
Grade 3 or 4 adverse events included hypomagnesemia (n = 6), acneiform rash (n = 6), increased lipase (n = 5), increased amylase (n = 4), alanine aminotransferase elevation (n = 3), aspartate aminotransferase elevation (n = 3), diarrhea (n = 3), hyophosphatemia (n = 3), and maculopapular rash (n = 3).
‘Disappointing PFS’
In the question and answer session following the presentation, moderator Michael J. Hall, MD, of Fox Chase Cancer Center in Philadelphia, asked whether the response rate seen with the addition of panitumumab was what the investigators expected, independent of the dual–checkpoint inhibitor therapy, and “with the relatively disappointing PFS you saw, what are the plans moving forward with this regimen?”
“These are great questions and thoughts I’ve had as well,” Dr. Lee replied.
He noted that studies of other anti-EGFR and checkpoint inhibitor combinations have had relatively low response rates, and his group’s study was conducted with “an effort to try and get over this immune-cold environment that we know exists in the tumor microenvironment,” he said.
Dr. Lee also acknowledged that the response rate may have been slightly higher than that seen in other studies because of the preponderance of left colon tumors, which are generally more amenable to systemic therapy.
Regarding PFS, Dr. Lee said the analyses of durability of response are still ongoing, and the median PFS was better than that seen in a trial of single-agent panitumumab in a similar population.
The current study was funded by Amgen and Bristol Myers Squibb. Dr. Lee disclosed institutional research funding from the companies, consulting/advising for Pfizer, and travel expenses from Genentech/Roche. Dr. Hall disclosed relationships with Ambry Genetics, AstraZeneca, Caris Life Sciences, Foundation Medicine, InVitae, and Myriad Genetics. He also shares a patent with several Fox Chase investigators for a novel method to investigate hereditary CRC genes.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The trial was designed to test the combination of panitumumab, ipilimumab, and nivolumab in patients with previously treated, unresectable and/or metastatic, microsatellite stable or mismatch repair–proficient CRC without mutations in KRAS, NRAS, or BRAF.
Among 49 evaluable patients treated with the triplet, 35% had a partial response at 12 weeks of follow-up, which met the trial’s primary response endpoint, according to investigator Michael S. Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Though toxicities were, of course, observed, they were consistent overall with the expected adverse event profiles of anti-EGFR therapy and combination ipilimumab and nivolumab. Correlative studies are ongoing to identify potential biomarkers of response,” Dr. Lee said when presenting the trial results at the 2021 Gastrointestinal Cancers Symposium (Abstract 7).
Immune activation?
The rationale for adding panitumumab to immune checkpoint inhibitors comes, in part, from a trial published in 2014 in The Lancet Oncology. The trial showed that panitumumab was noninferior to cetuximab. Panitumumab was associated with a 22% response rate in patients with KRAS wild-type, metastatic CRC that was refractory to chemotherapy. Progression-free survival (PFS) and overall survival (OS) were similar between the treatment arms.
In addition, in mouse models of RAS wild-type CRC, treatment with an anti-EGFR antibody induced immunogenic cell death.
“Moreover, translational studies of tumor biopsies from patients who were treated with the anti-EGFR antibody cetuximab showed that responders had significant increases in T-cell infiltration and cytolytic activity within tumors after starting treatment,” Dr. Lee said.
In the latter studies, tumor samples taken at the time of disease progression also showed increased expression of immune checkpoint inhibitor pathways, including PD-L1, the primary target of nivolumab, and CTLA-4, the primary target of ipilimumab.
“Given this, we hypothesized that combining anti–PD-1 and anti–CTLA-4 antibodies with anti-EGFR therapy would be synergistic,” Dr. Lee said.
Single-arm study
Investigators enrolled patients with unresectable and/or metastatic CRC in the trial. All patients had disease that was KRAS, NRAS, and BRAF wild-type, and they had either microsatellite stability or proficient mismatch repair. Patients also had to have received one or two prior lines of therapy, not including an anti-EGFR agent.
The patients received panitumumab at 6 mg/kg IV every 2 weeks, nivolumab at 240 mg IV every 2 weeks, and ipilimumab at 1 mg/kg IV every 6 weeks.
Of all 56 patients enrolled, 28 (50%) had tumors in the left colon, 3 (5%) had tumors in the right colon, 2 (4%) had tumors in the transverse colon, 16 (29%) had rectal tumors, and 7 (13%) were not specified.
As noted before, 49 patients were evaluable, and the trial met its primary endpoint of responses in at least 17 patients (35%) at 12 weeks. All were partial responses.
Of the remaining patients, 21 (43%) had stable disease, and 11 (22%) had disease progression. Of the latter group, five patients did not have documented radiographic progression at 12 weeks, but they discontinued therapy before restaging because of unequivocal clinical progression.
The best response rate (confirmed and unconfirmed) at any time was 41%.
At a median follow-up of 12.1 months, the median PFS was 5.7 months. The OS data were not mature at the time of data cutoff. However, the median OS was 27 months.
There were two deaths on study, one from myocarditis possibly related to the study treatment, and one from colonic perforation, which was deemed unlikely to be treatment related.
Grade 3 or 4 adverse events included hypomagnesemia (n = 6), acneiform rash (n = 6), increased lipase (n = 5), increased amylase (n = 4), alanine aminotransferase elevation (n = 3), aspartate aminotransferase elevation (n = 3), diarrhea (n = 3), hyophosphatemia (n = 3), and maculopapular rash (n = 3).
‘Disappointing PFS’
In the question and answer session following the presentation, moderator Michael J. Hall, MD, of Fox Chase Cancer Center in Philadelphia, asked whether the response rate seen with the addition of panitumumab was what the investigators expected, independent of the dual–checkpoint inhibitor therapy, and “with the relatively disappointing PFS you saw, what are the plans moving forward with this regimen?”
“These are great questions and thoughts I’ve had as well,” Dr. Lee replied.
He noted that studies of other anti-EGFR and checkpoint inhibitor combinations have had relatively low response rates, and his group’s study was conducted with “an effort to try and get over this immune-cold environment that we know exists in the tumor microenvironment,” he said.
Dr. Lee also acknowledged that the response rate may have been slightly higher than that seen in other studies because of the preponderance of left colon tumors, which are generally more amenable to systemic therapy.
Regarding PFS, Dr. Lee said the analyses of durability of response are still ongoing, and the median PFS was better than that seen in a trial of single-agent panitumumab in a similar population.
The current study was funded by Amgen and Bristol Myers Squibb. Dr. Lee disclosed institutional research funding from the companies, consulting/advising for Pfizer, and travel expenses from Genentech/Roche. Dr. Hall disclosed relationships with Ambry Genetics, AstraZeneca, Caris Life Sciences, Foundation Medicine, InVitae, and Myriad Genetics. He also shares a patent with several Fox Chase investigators for a novel method to investigate hereditary CRC genes.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The trial was designed to test the combination of panitumumab, ipilimumab, and nivolumab in patients with previously treated, unresectable and/or metastatic, microsatellite stable or mismatch repair–proficient CRC without mutations in KRAS, NRAS, or BRAF.
Among 49 evaluable patients treated with the triplet, 35% had a partial response at 12 weeks of follow-up, which met the trial’s primary response endpoint, according to investigator Michael S. Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Though toxicities were, of course, observed, they were consistent overall with the expected adverse event profiles of anti-EGFR therapy and combination ipilimumab and nivolumab. Correlative studies are ongoing to identify potential biomarkers of response,” Dr. Lee said when presenting the trial results at the 2021 Gastrointestinal Cancers Symposium (Abstract 7).
Immune activation?
The rationale for adding panitumumab to immune checkpoint inhibitors comes, in part, from a trial published in 2014 in The Lancet Oncology. The trial showed that panitumumab was noninferior to cetuximab. Panitumumab was associated with a 22% response rate in patients with KRAS wild-type, metastatic CRC that was refractory to chemotherapy. Progression-free survival (PFS) and overall survival (OS) were similar between the treatment arms.
In addition, in mouse models of RAS wild-type CRC, treatment with an anti-EGFR antibody induced immunogenic cell death.
“Moreover, translational studies of tumor biopsies from patients who were treated with the anti-EGFR antibody cetuximab showed that responders had significant increases in T-cell infiltration and cytolytic activity within tumors after starting treatment,” Dr. Lee said.
In the latter studies, tumor samples taken at the time of disease progression also showed increased expression of immune checkpoint inhibitor pathways, including PD-L1, the primary target of nivolumab, and CTLA-4, the primary target of ipilimumab.
“Given this, we hypothesized that combining anti–PD-1 and anti–CTLA-4 antibodies with anti-EGFR therapy would be synergistic,” Dr. Lee said.
Single-arm study
Investigators enrolled patients with unresectable and/or metastatic CRC in the trial. All patients had disease that was KRAS, NRAS, and BRAF wild-type, and they had either microsatellite stability or proficient mismatch repair. Patients also had to have received one or two prior lines of therapy, not including an anti-EGFR agent.
The patients received panitumumab at 6 mg/kg IV every 2 weeks, nivolumab at 240 mg IV every 2 weeks, and ipilimumab at 1 mg/kg IV every 6 weeks.
Of all 56 patients enrolled, 28 (50%) had tumors in the left colon, 3 (5%) had tumors in the right colon, 2 (4%) had tumors in the transverse colon, 16 (29%) had rectal tumors, and 7 (13%) were not specified.
As noted before, 49 patients were evaluable, and the trial met its primary endpoint of responses in at least 17 patients (35%) at 12 weeks. All were partial responses.
Of the remaining patients, 21 (43%) had stable disease, and 11 (22%) had disease progression. Of the latter group, five patients did not have documented radiographic progression at 12 weeks, but they discontinued therapy before restaging because of unequivocal clinical progression.
The best response rate (confirmed and unconfirmed) at any time was 41%.
At a median follow-up of 12.1 months, the median PFS was 5.7 months. The OS data were not mature at the time of data cutoff. However, the median OS was 27 months.
There were two deaths on study, one from myocarditis possibly related to the study treatment, and one from colonic perforation, which was deemed unlikely to be treatment related.
Grade 3 or 4 adverse events included hypomagnesemia (n = 6), acneiform rash (n = 6), increased lipase (n = 5), increased amylase (n = 4), alanine aminotransferase elevation (n = 3), aspartate aminotransferase elevation (n = 3), diarrhea (n = 3), hyophosphatemia (n = 3), and maculopapular rash (n = 3).
‘Disappointing PFS’
In the question and answer session following the presentation, moderator Michael J. Hall, MD, of Fox Chase Cancer Center in Philadelphia, asked whether the response rate seen with the addition of panitumumab was what the investigators expected, independent of the dual–checkpoint inhibitor therapy, and “with the relatively disappointing PFS you saw, what are the plans moving forward with this regimen?”
“These are great questions and thoughts I’ve had as well,” Dr. Lee replied.
He noted that studies of other anti-EGFR and checkpoint inhibitor combinations have had relatively low response rates, and his group’s study was conducted with “an effort to try and get over this immune-cold environment that we know exists in the tumor microenvironment,” he said.
Dr. Lee also acknowledged that the response rate may have been slightly higher than that seen in other studies because of the preponderance of left colon tumors, which are generally more amenable to systemic therapy.
Regarding PFS, Dr. Lee said the analyses of durability of response are still ongoing, and the median PFS was better than that seen in a trial of single-agent panitumumab in a similar population.
The current study was funded by Amgen and Bristol Myers Squibb. Dr. Lee disclosed institutional research funding from the companies, consulting/advising for Pfizer, and travel expenses from Genentech/Roche. Dr. Hall disclosed relationships with Ambry Genetics, AstraZeneca, Caris Life Sciences, Foundation Medicine, InVitae, and Myriad Genetics. He also shares a patent with several Fox Chase investigators for a novel method to investigate hereditary CRC genes.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
FROM GI CANCERS SYMPOSIUM 2021
Coronasomnia: Pervasive sleeplessness, self-medicating raise concerns of sleep experts
Among the many losses suffered by millions worldwide during the COVID-19 pandemic, the loss of sleep may be the most widespread, with potentially long-lasting, negative consequences on physical, mental, and emotional health, sleep researchers have found.
Results from multiple studies and surveys conducted during the pandemic show that a majority of subjects report clinically meaningful changes in sleep quality, sleep patterns, and sleep disturbances.
For example, a cross-sectional international survey conducted from late March through late April 2020 found that among more than 3,000 responders from 49 countries, 58% reported dissatisfaction with their sleep, and 40% reported a decrease in sleep quality during the pandemic, compared with pre-COVID-19 sleep, according to Uri Mandelkorn of the Natural Sleep Clinic in Jerusalem, and colleagues.
“In particular, this research raises the need to screen for worsening sleep patterns and use of sleeping aids in the more susceptible populations identified in this study, namely, women and people with insecure livelihoods or those subjected to strict quarantine. Health care providers should pay special attention to physical and psychological problems that this surge in sleep disturbances may cause,” they wrote. The report is in the Journal of Clinical Sleep Medicine.
Sleeping, more or less
A coauthor of that study, David Gozal, MD, FCCP, a pediatric pulmonologist and sleep medicine specialist at the University of Missouri in Columbia, said that the pandemic has had paradoxical effects on sleeps patterns for many.
“At the beginning, with the initial phases of lockdown for COVID, for most of the people whose jobs were not affected and who did not lose their jobs, [for whom] there was not the anxiety of being jobless and financially strapped, but who now were staying at home, there was actually a benefit. People started reporting getting more sleep and, more importantly, more vivid dreams and things of that nature,” he said in an interview.
“But as the lockdown progressed, we saw progressively and increasingly more people having difficulty falling asleep and staying asleep, using more medicines such as hypnotics to induce sleep, and we saw a 20% increase in the overall consumption of sleeping pills,” he said.
Similar results were seen in a cross-sectional survey of 843 adults in the United Kingdom, which showed that nearly 70% of participants reported a change in sleep patterns, only 45% reported having refreshing sleep, and 46% reported being sleepier during lockdown than before. Two-thirds of the respondents reported that the pandemic affected their mental health, and one-fourth reported increased alcohol consumption during lockdown. Those with suspected COVID-19 infections reported having more nightmares and abnormal sleep rhythms.
It is possible that the effects of COVID-19 infection on sleep may linger long after the infection itself has resolved, results of a cohort study from China suggest. As reported in The Lancet, among 1,655 patients discharged from the Jin Yin-tan hospital in Wuhan, 26% reported sleep disturbances 6 months after acute COVID-19 infection.
Self-medicating
Among 5,525 Canadians surveyed from April 3 through June 24, 2020, a large proportion reported the use of pharmacologic sleeps aids, said Tetyana Kendzerska, MD, PhD, assistant professor of medicine in the division of respirology at the University of Ottawa.
“At the time of the survey completion, 27% of participants reported taking sleeping aids (prescribed or [over] the counter); across the entire sample, 8% of respondents reported an increase in the frequency of sleeping medication use during the outbreak compared to before the outbreak,” she said in an interview.
Many people resort to self-medicating with over-the-counter preparations such as melatonin and pain-relief nighttime formulations containing diphenhydramine (Benadryl), a first-generation antihistamine with sedative properties, noted Kannan Ramar, MBBS, MD, a critical care, pulmonary, and sleep medicine specialist at the Mayo Clinic in Rochester, Minn., and current president of the American Academy of Sleep Medicine.
“When people are self-medicating for what they think is difficulty sleeping, the concern is that even if a diagnosis of insomnia has been established, there could be another, ongoing sleep disorder that may be undiagnosed, which might be causing the problem with insomnia,” he said in an interview.
“For example, obstructive sleep apnea might be causing people to wake up in the night or even contribute to difficulty falling asleep in the first place. So medicating for something without a known diagnosis may leave an underlying sleep disorder untreated, which won’t help the patient in either the short or the long term,” Dr. Ramar said.
Causes for concern
“For those people who have COVID, we have seen quite a few sleep issues develop. Those were not reported in the actual study, but in the clinic and subsequent studies published from other places,” Dr. Gozal said.
“People who suffered from COVID, and even people who supposedly did very well and were virtually asymptomatic or maybe had only a headache or fever but did not need to go to the hospital, many of those people reported either excessive sleepiness for a long period of time, and would sleep 2 or 3 hours more per night. Or the opposite was reported: There were those that after recovering reported that they couldn’t sleep – they were sleeping 4 or 5 hours when they normally sleep 7 or 8,” he said.
It’s also unclear from current evidence whether the reported uptick in sleep problems is related to stress or, in patients who have had COVID-19 infections, to physiologic causes.
Dr. Gozal said that insomnia in the time of COVID-19 could be attributed to a number of factors such as less daily exposure to natural light from people sheltering indoors, stress related to financial or health worries, depression, or other psychological factors.
It’s also, possible, however, that COVID-19-related physiological changes could contribute to sleep disorders, he said, pointing to a recent study in the Journal of Experimental Medicine showing that SARS-CoV-2, the virus that causes COVID-19, can bind to neurons and cause metabolic changes in both infected and neighboring cells.
“My guess is that some of it is related more to behavioral impacts – people develop depression, changes in mood, anxiety, and so on, and all of these can translate into difficulties with sleep,” he said.
“It could be that in some instances – not very commonly – the virus will affect areas that control sleep in our brain, and that therefore we may see too much or too little sleep, and how to differentiate between all of these is the area that clearly needs to be explored, particularly in light of the finding that the virus can bind to brain cells and can induce substantial issues in the brain cells.”
Compromised immunity
It has been well documented that in addition to being, as Shakespeare called it, “the balm of hurt minds,” sleep has an important role in supporting the immune system.
“Sleep and immunity go together,” Dr. Ramar said. “When people have adequate sleep, their immune system is boosted. We know that there are good data from hepatitis A and hepatitis B vaccinations, and recently on flu vaccination, that if people get sufficient duration of sleep before and after they receive the shot, their likelihood of building an immune response to that particular vaccination tends to go up.”
It’s reasonable to assume that the same would hold true for COVID-19 vaccinations, but this has yet to be shown, he added.
“We do know from the previous studies that persistent sleep problems can make people more susceptible to infection or impair recovery; not yet, I believe, from the COVID-19 infection perspective,” Dr. Kendzerska said. “In our study, we did find that, among other factors, having a chronic illness was associated with new sleep difficulties during the pandemic. We did not look separately if sleep difficulties were associated with the COVID-19 infection or symptoms, but this is a great question to address with longitudinal data we have.”
What to do?
All three sleep experts contacted for this article agreed that for patients with insomnia, mitigating stress through relaxation techniques or cognitive behavioral therapy is more beneficial than medication.
“Medications, even over-the-counter medications, all have side effects, and if one is taking a medication that has stimulants in place, such as pseudoephedrine in antihistamine combinations, that can potentially contribute to or exacerbate any underlying sleep disorders,” Dr. Ramar said.
Dr. Kendzerska recommended reserving medications such as melatonin, a chronobiotic therapy, for patients with sleep disorders related to circadian rhythm problems, including a sleep phase delay. Supplemental, short-term treatment with hypnotic agents such as zolpidem (Ambien), eszopiclone (Lunesta), or zaleplon (Sonata) should be used only as a last resort, she said.
Sleep medicine specialists recommend good sleep hygiene as the best means of obtaining restful sleep, including regular bed and wake times, limited exposure to stressful news (including COVID-19 stories), reduced consumption of alcohol and stimulants such as coffee or caffeine drinks, avoiding use of electronic devices in bed or near bedtime, and healthy lifestyle, including diet and exercise.
They also frown on self-medication with over-the-counter aids, because these products may not be addressing the underlying issue, as noted before.
“It is also foreseeable that there may be an increase in individuals who may require professional guidance to taper off from sleeping medications started or increased during the pandemic. While some of these sleep problems may be transient, it should be a high priority to ensure they do not evolve into chronic sleep disorders,” Dr. Kendzerska and colleagues wrote.
Research avenues
If there’s anything that causes specialists to lose sleep, it’s the lack of data or evidence to guide clinical care and research. Dr. Gozal emphasized that little is still known about the potential central nervous system effects of COVID-19, and said that should be an important focus for research into the still novel coronavirus.
“What happens post COVID and how might that affect subsequent recovery is a great question, and I don’t think we have good data there,” Dr. Ramar said. “What we do know is that patients develop the symptoms of fatigue, disrupted sleep, even ongoing fever, and unfortunately, this may persist for a long period of time even among patients who have otherwise recovered from COVID-19. We know that leaving that untreated from a sleep disorder perspective can exacerbate their daytime symptoms, and that’s where I would strongly recommend that they seek help with a sleep provider or if there are symptoms other than insomnia at least with a primary care provider.”
Among the many losses suffered by millions worldwide during the COVID-19 pandemic, the loss of sleep may be the most widespread, with potentially long-lasting, negative consequences on physical, mental, and emotional health, sleep researchers have found.
Results from multiple studies and surveys conducted during the pandemic show that a majority of subjects report clinically meaningful changes in sleep quality, sleep patterns, and sleep disturbances.
For example, a cross-sectional international survey conducted from late March through late April 2020 found that among more than 3,000 responders from 49 countries, 58% reported dissatisfaction with their sleep, and 40% reported a decrease in sleep quality during the pandemic, compared with pre-COVID-19 sleep, according to Uri Mandelkorn of the Natural Sleep Clinic in Jerusalem, and colleagues.
“In particular, this research raises the need to screen for worsening sleep patterns and use of sleeping aids in the more susceptible populations identified in this study, namely, women and people with insecure livelihoods or those subjected to strict quarantine. Health care providers should pay special attention to physical and psychological problems that this surge in sleep disturbances may cause,” they wrote. The report is in the Journal of Clinical Sleep Medicine.
Sleeping, more or less
A coauthor of that study, David Gozal, MD, FCCP, a pediatric pulmonologist and sleep medicine specialist at the University of Missouri in Columbia, said that the pandemic has had paradoxical effects on sleeps patterns for many.
“At the beginning, with the initial phases of lockdown for COVID, for most of the people whose jobs were not affected and who did not lose their jobs, [for whom] there was not the anxiety of being jobless and financially strapped, but who now were staying at home, there was actually a benefit. People started reporting getting more sleep and, more importantly, more vivid dreams and things of that nature,” he said in an interview.
“But as the lockdown progressed, we saw progressively and increasingly more people having difficulty falling asleep and staying asleep, using more medicines such as hypnotics to induce sleep, and we saw a 20% increase in the overall consumption of sleeping pills,” he said.
Similar results were seen in a cross-sectional survey of 843 adults in the United Kingdom, which showed that nearly 70% of participants reported a change in sleep patterns, only 45% reported having refreshing sleep, and 46% reported being sleepier during lockdown than before. Two-thirds of the respondents reported that the pandemic affected their mental health, and one-fourth reported increased alcohol consumption during lockdown. Those with suspected COVID-19 infections reported having more nightmares and abnormal sleep rhythms.
It is possible that the effects of COVID-19 infection on sleep may linger long after the infection itself has resolved, results of a cohort study from China suggest. As reported in The Lancet, among 1,655 patients discharged from the Jin Yin-tan hospital in Wuhan, 26% reported sleep disturbances 6 months after acute COVID-19 infection.
Self-medicating
Among 5,525 Canadians surveyed from April 3 through June 24, 2020, a large proportion reported the use of pharmacologic sleeps aids, said Tetyana Kendzerska, MD, PhD, assistant professor of medicine in the division of respirology at the University of Ottawa.
“At the time of the survey completion, 27% of participants reported taking sleeping aids (prescribed or [over] the counter); across the entire sample, 8% of respondents reported an increase in the frequency of sleeping medication use during the outbreak compared to before the outbreak,” she said in an interview.
Many people resort to self-medicating with over-the-counter preparations such as melatonin and pain-relief nighttime formulations containing diphenhydramine (Benadryl), a first-generation antihistamine with sedative properties, noted Kannan Ramar, MBBS, MD, a critical care, pulmonary, and sleep medicine specialist at the Mayo Clinic in Rochester, Minn., and current president of the American Academy of Sleep Medicine.
“When people are self-medicating for what they think is difficulty sleeping, the concern is that even if a diagnosis of insomnia has been established, there could be another, ongoing sleep disorder that may be undiagnosed, which might be causing the problem with insomnia,” he said in an interview.
“For example, obstructive sleep apnea might be causing people to wake up in the night or even contribute to difficulty falling asleep in the first place. So medicating for something without a known diagnosis may leave an underlying sleep disorder untreated, which won’t help the patient in either the short or the long term,” Dr. Ramar said.
Causes for concern
“For those people who have COVID, we have seen quite a few sleep issues develop. Those were not reported in the actual study, but in the clinic and subsequent studies published from other places,” Dr. Gozal said.
“People who suffered from COVID, and even people who supposedly did very well and were virtually asymptomatic or maybe had only a headache or fever but did not need to go to the hospital, many of those people reported either excessive sleepiness for a long period of time, and would sleep 2 or 3 hours more per night. Or the opposite was reported: There were those that after recovering reported that they couldn’t sleep – they were sleeping 4 or 5 hours when they normally sleep 7 or 8,” he said.
It’s also unclear from current evidence whether the reported uptick in sleep problems is related to stress or, in patients who have had COVID-19 infections, to physiologic causes.
Dr. Gozal said that insomnia in the time of COVID-19 could be attributed to a number of factors such as less daily exposure to natural light from people sheltering indoors, stress related to financial or health worries, depression, or other psychological factors.
It’s also, possible, however, that COVID-19-related physiological changes could contribute to sleep disorders, he said, pointing to a recent study in the Journal of Experimental Medicine showing that SARS-CoV-2, the virus that causes COVID-19, can bind to neurons and cause metabolic changes in both infected and neighboring cells.
“My guess is that some of it is related more to behavioral impacts – people develop depression, changes in mood, anxiety, and so on, and all of these can translate into difficulties with sleep,” he said.
“It could be that in some instances – not very commonly – the virus will affect areas that control sleep in our brain, and that therefore we may see too much or too little sleep, and how to differentiate between all of these is the area that clearly needs to be explored, particularly in light of the finding that the virus can bind to brain cells and can induce substantial issues in the brain cells.”
Compromised immunity
It has been well documented that in addition to being, as Shakespeare called it, “the balm of hurt minds,” sleep has an important role in supporting the immune system.
“Sleep and immunity go together,” Dr. Ramar said. “When people have adequate sleep, their immune system is boosted. We know that there are good data from hepatitis A and hepatitis B vaccinations, and recently on flu vaccination, that if people get sufficient duration of sleep before and after they receive the shot, their likelihood of building an immune response to that particular vaccination tends to go up.”
It’s reasonable to assume that the same would hold true for COVID-19 vaccinations, but this has yet to be shown, he added.
“We do know from the previous studies that persistent sleep problems can make people more susceptible to infection or impair recovery; not yet, I believe, from the COVID-19 infection perspective,” Dr. Kendzerska said. “In our study, we did find that, among other factors, having a chronic illness was associated with new sleep difficulties during the pandemic. We did not look separately if sleep difficulties were associated with the COVID-19 infection or symptoms, but this is a great question to address with longitudinal data we have.”
What to do?
All three sleep experts contacted for this article agreed that for patients with insomnia, mitigating stress through relaxation techniques or cognitive behavioral therapy is more beneficial than medication.
“Medications, even over-the-counter medications, all have side effects, and if one is taking a medication that has stimulants in place, such as pseudoephedrine in antihistamine combinations, that can potentially contribute to or exacerbate any underlying sleep disorders,” Dr. Ramar said.
Dr. Kendzerska recommended reserving medications such as melatonin, a chronobiotic therapy, for patients with sleep disorders related to circadian rhythm problems, including a sleep phase delay. Supplemental, short-term treatment with hypnotic agents such as zolpidem (Ambien), eszopiclone (Lunesta), or zaleplon (Sonata) should be used only as a last resort, she said.
Sleep medicine specialists recommend good sleep hygiene as the best means of obtaining restful sleep, including regular bed and wake times, limited exposure to stressful news (including COVID-19 stories), reduced consumption of alcohol and stimulants such as coffee or caffeine drinks, avoiding use of electronic devices in bed or near bedtime, and healthy lifestyle, including diet and exercise.
They also frown on self-medication with over-the-counter aids, because these products may not be addressing the underlying issue, as noted before.
“It is also foreseeable that there may be an increase in individuals who may require professional guidance to taper off from sleeping medications started or increased during the pandemic. While some of these sleep problems may be transient, it should be a high priority to ensure they do not evolve into chronic sleep disorders,” Dr. Kendzerska and colleagues wrote.
Research avenues
If there’s anything that causes specialists to lose sleep, it’s the lack of data or evidence to guide clinical care and research. Dr. Gozal emphasized that little is still known about the potential central nervous system effects of COVID-19, and said that should be an important focus for research into the still novel coronavirus.
“What happens post COVID and how might that affect subsequent recovery is a great question, and I don’t think we have good data there,” Dr. Ramar said. “What we do know is that patients develop the symptoms of fatigue, disrupted sleep, even ongoing fever, and unfortunately, this may persist for a long period of time even among patients who have otherwise recovered from COVID-19. We know that leaving that untreated from a sleep disorder perspective can exacerbate their daytime symptoms, and that’s where I would strongly recommend that they seek help with a sleep provider or if there are symptoms other than insomnia at least with a primary care provider.”
Among the many losses suffered by millions worldwide during the COVID-19 pandemic, the loss of sleep may be the most widespread, with potentially long-lasting, negative consequences on physical, mental, and emotional health, sleep researchers have found.
Results from multiple studies and surveys conducted during the pandemic show that a majority of subjects report clinically meaningful changes in sleep quality, sleep patterns, and sleep disturbances.
For example, a cross-sectional international survey conducted from late March through late April 2020 found that among more than 3,000 responders from 49 countries, 58% reported dissatisfaction with their sleep, and 40% reported a decrease in sleep quality during the pandemic, compared with pre-COVID-19 sleep, according to Uri Mandelkorn of the Natural Sleep Clinic in Jerusalem, and colleagues.
“In particular, this research raises the need to screen for worsening sleep patterns and use of sleeping aids in the more susceptible populations identified in this study, namely, women and people with insecure livelihoods or those subjected to strict quarantine. Health care providers should pay special attention to physical and psychological problems that this surge in sleep disturbances may cause,” they wrote. The report is in the Journal of Clinical Sleep Medicine.
Sleeping, more or less
A coauthor of that study, David Gozal, MD, FCCP, a pediatric pulmonologist and sleep medicine specialist at the University of Missouri in Columbia, said that the pandemic has had paradoxical effects on sleeps patterns for many.
“At the beginning, with the initial phases of lockdown for COVID, for most of the people whose jobs were not affected and who did not lose their jobs, [for whom] there was not the anxiety of being jobless and financially strapped, but who now were staying at home, there was actually a benefit. People started reporting getting more sleep and, more importantly, more vivid dreams and things of that nature,” he said in an interview.
“But as the lockdown progressed, we saw progressively and increasingly more people having difficulty falling asleep and staying asleep, using more medicines such as hypnotics to induce sleep, and we saw a 20% increase in the overall consumption of sleeping pills,” he said.
Similar results were seen in a cross-sectional survey of 843 adults in the United Kingdom, which showed that nearly 70% of participants reported a change in sleep patterns, only 45% reported having refreshing sleep, and 46% reported being sleepier during lockdown than before. Two-thirds of the respondents reported that the pandemic affected their mental health, and one-fourth reported increased alcohol consumption during lockdown. Those with suspected COVID-19 infections reported having more nightmares and abnormal sleep rhythms.
It is possible that the effects of COVID-19 infection on sleep may linger long after the infection itself has resolved, results of a cohort study from China suggest. As reported in The Lancet, among 1,655 patients discharged from the Jin Yin-tan hospital in Wuhan, 26% reported sleep disturbances 6 months after acute COVID-19 infection.
Self-medicating
Among 5,525 Canadians surveyed from April 3 through June 24, 2020, a large proportion reported the use of pharmacologic sleeps aids, said Tetyana Kendzerska, MD, PhD, assistant professor of medicine in the division of respirology at the University of Ottawa.
“At the time of the survey completion, 27% of participants reported taking sleeping aids (prescribed or [over] the counter); across the entire sample, 8% of respondents reported an increase in the frequency of sleeping medication use during the outbreak compared to before the outbreak,” she said in an interview.
Many people resort to self-medicating with over-the-counter preparations such as melatonin and pain-relief nighttime formulations containing diphenhydramine (Benadryl), a first-generation antihistamine with sedative properties, noted Kannan Ramar, MBBS, MD, a critical care, pulmonary, and sleep medicine specialist at the Mayo Clinic in Rochester, Minn., and current president of the American Academy of Sleep Medicine.
“When people are self-medicating for what they think is difficulty sleeping, the concern is that even if a diagnosis of insomnia has been established, there could be another, ongoing sleep disorder that may be undiagnosed, which might be causing the problem with insomnia,” he said in an interview.
“For example, obstructive sleep apnea might be causing people to wake up in the night or even contribute to difficulty falling asleep in the first place. So medicating for something without a known diagnosis may leave an underlying sleep disorder untreated, which won’t help the patient in either the short or the long term,” Dr. Ramar said.
Causes for concern
“For those people who have COVID, we have seen quite a few sleep issues develop. Those were not reported in the actual study, but in the clinic and subsequent studies published from other places,” Dr. Gozal said.
“People who suffered from COVID, and even people who supposedly did very well and were virtually asymptomatic or maybe had only a headache or fever but did not need to go to the hospital, many of those people reported either excessive sleepiness for a long period of time, and would sleep 2 or 3 hours more per night. Or the opposite was reported: There were those that after recovering reported that they couldn’t sleep – they were sleeping 4 or 5 hours when they normally sleep 7 or 8,” he said.
It’s also unclear from current evidence whether the reported uptick in sleep problems is related to stress or, in patients who have had COVID-19 infections, to physiologic causes.
Dr. Gozal said that insomnia in the time of COVID-19 could be attributed to a number of factors such as less daily exposure to natural light from people sheltering indoors, stress related to financial or health worries, depression, or other psychological factors.
It’s also, possible, however, that COVID-19-related physiological changes could contribute to sleep disorders, he said, pointing to a recent study in the Journal of Experimental Medicine showing that SARS-CoV-2, the virus that causes COVID-19, can bind to neurons and cause metabolic changes in both infected and neighboring cells.
“My guess is that some of it is related more to behavioral impacts – people develop depression, changes in mood, anxiety, and so on, and all of these can translate into difficulties with sleep,” he said.
“It could be that in some instances – not very commonly – the virus will affect areas that control sleep in our brain, and that therefore we may see too much or too little sleep, and how to differentiate between all of these is the area that clearly needs to be explored, particularly in light of the finding that the virus can bind to brain cells and can induce substantial issues in the brain cells.”
Compromised immunity
It has been well documented that in addition to being, as Shakespeare called it, “the balm of hurt minds,” sleep has an important role in supporting the immune system.
“Sleep and immunity go together,” Dr. Ramar said. “When people have adequate sleep, their immune system is boosted. We know that there are good data from hepatitis A and hepatitis B vaccinations, and recently on flu vaccination, that if people get sufficient duration of sleep before and after they receive the shot, their likelihood of building an immune response to that particular vaccination tends to go up.”
It’s reasonable to assume that the same would hold true for COVID-19 vaccinations, but this has yet to be shown, he added.
“We do know from the previous studies that persistent sleep problems can make people more susceptible to infection or impair recovery; not yet, I believe, from the COVID-19 infection perspective,” Dr. Kendzerska said. “In our study, we did find that, among other factors, having a chronic illness was associated with new sleep difficulties during the pandemic. We did not look separately if sleep difficulties were associated with the COVID-19 infection or symptoms, but this is a great question to address with longitudinal data we have.”
What to do?
All three sleep experts contacted for this article agreed that for patients with insomnia, mitigating stress through relaxation techniques or cognitive behavioral therapy is more beneficial than medication.
“Medications, even over-the-counter medications, all have side effects, and if one is taking a medication that has stimulants in place, such as pseudoephedrine in antihistamine combinations, that can potentially contribute to or exacerbate any underlying sleep disorders,” Dr. Ramar said.
Dr. Kendzerska recommended reserving medications such as melatonin, a chronobiotic therapy, for patients with sleep disorders related to circadian rhythm problems, including a sleep phase delay. Supplemental, short-term treatment with hypnotic agents such as zolpidem (Ambien), eszopiclone (Lunesta), or zaleplon (Sonata) should be used only as a last resort, she said.
Sleep medicine specialists recommend good sleep hygiene as the best means of obtaining restful sleep, including regular bed and wake times, limited exposure to stressful news (including COVID-19 stories), reduced consumption of alcohol and stimulants such as coffee or caffeine drinks, avoiding use of electronic devices in bed or near bedtime, and healthy lifestyle, including diet and exercise.
They also frown on self-medication with over-the-counter aids, because these products may not be addressing the underlying issue, as noted before.
“It is also foreseeable that there may be an increase in individuals who may require professional guidance to taper off from sleeping medications started or increased during the pandemic. While some of these sleep problems may be transient, it should be a high priority to ensure they do not evolve into chronic sleep disorders,” Dr. Kendzerska and colleagues wrote.
Research avenues
If there’s anything that causes specialists to lose sleep, it’s the lack of data or evidence to guide clinical care and research. Dr. Gozal emphasized that little is still known about the potential central nervous system effects of COVID-19, and said that should be an important focus for research into the still novel coronavirus.
“What happens post COVID and how might that affect subsequent recovery is a great question, and I don’t think we have good data there,” Dr. Ramar said. “What we do know is that patients develop the symptoms of fatigue, disrupted sleep, even ongoing fever, and unfortunately, this may persist for a long period of time even among patients who have otherwise recovered from COVID-19. We know that leaving that untreated from a sleep disorder perspective can exacerbate their daytime symptoms, and that’s where I would strongly recommend that they seek help with a sleep provider or if there are symptoms other than insomnia at least with a primary care provider.”
Higher intensity therapy doesn’t increase surgical risk in esophageal cancer
The trial included patients with clinical stage IB, II, or III (non-T4) thoracic esophageal cancer randomly assigned to cisplatin plus 5-fluorouracil (CF), CF plus radiotherapy (CF-RT), or docetaxel plus CF (DCF) prior to surgery.
Results showed the type of therapy did not significantly affect risk for either perioperative complications or deaths. There was also evidence to suggest that a lower risk of postoperative complications with DCF compared with CF might translate into improved prognosis with the addition of docetaxel, said Kazuo Koyanagi, MD, PhD, of National Cancer Center Hospital in Tokyo.
Dr. Koyanagi presented these results at the 2021 Gastrointestinal Cancers Symposium.
“Based on these results, we could say that preoperative chemotherapy with DCF and CF-RT didn’t increase the risk of postoperative complications when compared with standard CF, and whether the decrease in the risk in the DCF would be reflected in the improvement of prognosis should be examined in the future,” Dr. Koyanagi said.
Trial details
The JCOG1109 trial is a three-arm, phase 3 trial designed to see whether adding docetaxel or radiation to CF could improve outcomes. In the analysis presented here, the investigators examined whether the choice of regimen could affect the safety of esophagectomy, and they looked for risk factors for postoperative complications.
Patients with histologically proven squamous cell, adenosquamous, or basaloid carcinoma with locally advanced lesions in the thoracic esophagus were eligible.
The patients had to have good performance status (Eastern Cooperative Oncology Group 0 or 1) and could not have had chemotherapy, radiotherapy, or hormonal therapy for any cancer, or prior therapy for esophageal cancer except for complete endoscopic mucosal or submucosal dissection.
A total of 601 patients were enrolled and randomized to receive one of the following treatments:
- CF, with cisplatin at a dose of 80 mg/m2 on day 1 and 5-fluorouracil at 800 mg/m2 on days 1-5 every 3 weeks for two cycles (199 assigned; 185 had surgery)
- DCF, with cisplatin at 70 mg/m2 on day 1, 5-fluorouracil at 750 mg/m2 on days 1-5, and docetaxel at 70 mg/m2 on day 1 every 3 weeks for three cycles (202 assigned; 183 had surgery)
- CF-RT, with cisplatin at 75 mg/m2 on day 1, 5-fluorouracil at 1,000 mg/m2 on days 1-4 every 4 weeks for two cycles, plus 1.8 Gy radiation divided into 23 fractions for a total of 41.4 Gy (200 assigned; 178 had surgery).
Patient age, body mass index, tumor location, clinical stage and node status were comparable among the treatment groups.
Operative characteristics (duration, blood loss, approach, extent of lymph node dissection) were generally similar between the arms as well, except that significantly fewer lymph nodes were harvested with CF-RT compared with either CF or DCF (median of 49, 58, and 59, respectively).
Results
Incidence rates of major postoperative complications – pneumonia, leakage, and recurrent laryngeal nerve paralysis – were generally similar among the groups.
The cumulative rate of grade 2 or greater postoperative complications was significantly lower for DCF than for CF (P = .02), but not for DCF compared with CF-RT (P = .11). The rates were 43.7% with DCF, 47.8% with CF-RT, and 56.2% with CF.
The rate of grade 2 or greater chylothorax (leakage of lymphatics into the pleural space) was significantly higher with CF-RT than CF (5.1% vs. 1.1%, P = .03) but not with DCF vs. CF (3.8% vs. 1.1%, P = .10)
In multivariable analysis controlling for demographic, clinical, and operative characteristics, factors associated with lower risk for complications included:
- Middle esophageal tumor location vs. upper esophageal tumors (relative risk [RR], 0.79; P = .03)
- DCF (RR, 0.79; P = .02)
- A thoracoscopic vs. open approach (RR, 0.77; P = .002).
The only factor associated with higher risk was operative time longer than 492 minutes (RR, 1.26; P = .008).
Dr. Koyanagi said the reasons for the lower lymph node yield and more frequent chylothorax with CF-RT are unclear but may be related to tissue fibrosis from radiation exposure.
CROSS talk
“As a North American surgeon, I generally look to CROSS induction chemotherapy for the majority of my patients for both adenocarcinoma and squamous cell carcinoma of the esophagus,” said invited discussant Jonathan Yeung, MD, PhD, of the Princess Margaret Cancer Centre in Toronto.
The CROSS regimen consists of carboplatin titrated to an area under the curve of 2 mg/mL per minute and paclitaxel at 50 mg/m2 for 5 weeks with concurrent radiotherapy to a total dose of 41.4 Gy delivered in 23 fractions, 5 days per week.
Dr. Yeung noted that, of the eligible patients in JCOG1109, 92% of those assigned to DCF actually underwent surgery, and 90% of those assigned to CF-RT went on to surgery, compared with 98% of patients who had surgery in the CROSS trial, suggesting that the DCF and CF-RT regimens may be more toxic.
He also noted that the lower lymph node harvest seen with CF-RT was seen in other studies.
“I must say I’m always impressed by the lymph node yields that our Japanese colleagues can obtain at surgery, but this lower lymph node yield is also borne out in the CROSS data, where there are less lymph nodes harvested following chemoradiotherapy,” he said.
A higher rate of chylothorax with CF-RT was also seen in patients in the CROSS trial who were randomized to receive radiation compared with those who received chemotherapy alone.
“I await the final results to see if there is ultimately better survival,” Dr. Yeung said.
JCOG1109 was supported by grants from the National Cancer Center Research and Development Funds and Agency for Medical Research and Development of Japan. Dr. Koyanagi and Dr. Yeung reported no conflicts of interest.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The trial included patients with clinical stage IB, II, or III (non-T4) thoracic esophageal cancer randomly assigned to cisplatin plus 5-fluorouracil (CF), CF plus radiotherapy (CF-RT), or docetaxel plus CF (DCF) prior to surgery.
Results showed the type of therapy did not significantly affect risk for either perioperative complications or deaths. There was also evidence to suggest that a lower risk of postoperative complications with DCF compared with CF might translate into improved prognosis with the addition of docetaxel, said Kazuo Koyanagi, MD, PhD, of National Cancer Center Hospital in Tokyo.
Dr. Koyanagi presented these results at the 2021 Gastrointestinal Cancers Symposium.
“Based on these results, we could say that preoperative chemotherapy with DCF and CF-RT didn’t increase the risk of postoperative complications when compared with standard CF, and whether the decrease in the risk in the DCF would be reflected in the improvement of prognosis should be examined in the future,” Dr. Koyanagi said.
Trial details
The JCOG1109 trial is a three-arm, phase 3 trial designed to see whether adding docetaxel or radiation to CF could improve outcomes. In the analysis presented here, the investigators examined whether the choice of regimen could affect the safety of esophagectomy, and they looked for risk factors for postoperative complications.
Patients with histologically proven squamous cell, adenosquamous, or basaloid carcinoma with locally advanced lesions in the thoracic esophagus were eligible.
The patients had to have good performance status (Eastern Cooperative Oncology Group 0 or 1) and could not have had chemotherapy, radiotherapy, or hormonal therapy for any cancer, or prior therapy for esophageal cancer except for complete endoscopic mucosal or submucosal dissection.
A total of 601 patients were enrolled and randomized to receive one of the following treatments:
- CF, with cisplatin at a dose of 80 mg/m2 on day 1 and 5-fluorouracil at 800 mg/m2 on days 1-5 every 3 weeks for two cycles (199 assigned; 185 had surgery)
- DCF, with cisplatin at 70 mg/m2 on day 1, 5-fluorouracil at 750 mg/m2 on days 1-5, and docetaxel at 70 mg/m2 on day 1 every 3 weeks for three cycles (202 assigned; 183 had surgery)
- CF-RT, with cisplatin at 75 mg/m2 on day 1, 5-fluorouracil at 1,000 mg/m2 on days 1-4 every 4 weeks for two cycles, plus 1.8 Gy radiation divided into 23 fractions for a total of 41.4 Gy (200 assigned; 178 had surgery).
Patient age, body mass index, tumor location, clinical stage and node status were comparable among the treatment groups.
Operative characteristics (duration, blood loss, approach, extent of lymph node dissection) were generally similar between the arms as well, except that significantly fewer lymph nodes were harvested with CF-RT compared with either CF or DCF (median of 49, 58, and 59, respectively).
Results
Incidence rates of major postoperative complications – pneumonia, leakage, and recurrent laryngeal nerve paralysis – were generally similar among the groups.
The cumulative rate of grade 2 or greater postoperative complications was significantly lower for DCF than for CF (P = .02), but not for DCF compared with CF-RT (P = .11). The rates were 43.7% with DCF, 47.8% with CF-RT, and 56.2% with CF.
The rate of grade 2 or greater chylothorax (leakage of lymphatics into the pleural space) was significantly higher with CF-RT than CF (5.1% vs. 1.1%, P = .03) but not with DCF vs. CF (3.8% vs. 1.1%, P = .10)
In multivariable analysis controlling for demographic, clinical, and operative characteristics, factors associated with lower risk for complications included:
- Middle esophageal tumor location vs. upper esophageal tumors (relative risk [RR], 0.79; P = .03)
- DCF (RR, 0.79; P = .02)
- A thoracoscopic vs. open approach (RR, 0.77; P = .002).
The only factor associated with higher risk was operative time longer than 492 minutes (RR, 1.26; P = .008).
Dr. Koyanagi said the reasons for the lower lymph node yield and more frequent chylothorax with CF-RT are unclear but may be related to tissue fibrosis from radiation exposure.
CROSS talk
“As a North American surgeon, I generally look to CROSS induction chemotherapy for the majority of my patients for both adenocarcinoma and squamous cell carcinoma of the esophagus,” said invited discussant Jonathan Yeung, MD, PhD, of the Princess Margaret Cancer Centre in Toronto.
The CROSS regimen consists of carboplatin titrated to an area under the curve of 2 mg/mL per minute and paclitaxel at 50 mg/m2 for 5 weeks with concurrent radiotherapy to a total dose of 41.4 Gy delivered in 23 fractions, 5 days per week.
Dr. Yeung noted that, of the eligible patients in JCOG1109, 92% of those assigned to DCF actually underwent surgery, and 90% of those assigned to CF-RT went on to surgery, compared with 98% of patients who had surgery in the CROSS trial, suggesting that the DCF and CF-RT regimens may be more toxic.
He also noted that the lower lymph node harvest seen with CF-RT was seen in other studies.
“I must say I’m always impressed by the lymph node yields that our Japanese colleagues can obtain at surgery, but this lower lymph node yield is also borne out in the CROSS data, where there are less lymph nodes harvested following chemoradiotherapy,” he said.
A higher rate of chylothorax with CF-RT was also seen in patients in the CROSS trial who were randomized to receive radiation compared with those who received chemotherapy alone.
“I await the final results to see if there is ultimately better survival,” Dr. Yeung said.
JCOG1109 was supported by grants from the National Cancer Center Research and Development Funds and Agency for Medical Research and Development of Japan. Dr. Koyanagi and Dr. Yeung reported no conflicts of interest.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The trial included patients with clinical stage IB, II, or III (non-T4) thoracic esophageal cancer randomly assigned to cisplatin plus 5-fluorouracil (CF), CF plus radiotherapy (CF-RT), or docetaxel plus CF (DCF) prior to surgery.
Results showed the type of therapy did not significantly affect risk for either perioperative complications or deaths. There was also evidence to suggest that a lower risk of postoperative complications with DCF compared with CF might translate into improved prognosis with the addition of docetaxel, said Kazuo Koyanagi, MD, PhD, of National Cancer Center Hospital in Tokyo.
Dr. Koyanagi presented these results at the 2021 Gastrointestinal Cancers Symposium.
“Based on these results, we could say that preoperative chemotherapy with DCF and CF-RT didn’t increase the risk of postoperative complications when compared with standard CF, and whether the decrease in the risk in the DCF would be reflected in the improvement of prognosis should be examined in the future,” Dr. Koyanagi said.
Trial details
The JCOG1109 trial is a three-arm, phase 3 trial designed to see whether adding docetaxel or radiation to CF could improve outcomes. In the analysis presented here, the investigators examined whether the choice of regimen could affect the safety of esophagectomy, and they looked for risk factors for postoperative complications.
Patients with histologically proven squamous cell, adenosquamous, or basaloid carcinoma with locally advanced lesions in the thoracic esophagus were eligible.
The patients had to have good performance status (Eastern Cooperative Oncology Group 0 or 1) and could not have had chemotherapy, radiotherapy, or hormonal therapy for any cancer, or prior therapy for esophageal cancer except for complete endoscopic mucosal or submucosal dissection.
A total of 601 patients were enrolled and randomized to receive one of the following treatments:
- CF, with cisplatin at a dose of 80 mg/m2 on day 1 and 5-fluorouracil at 800 mg/m2 on days 1-5 every 3 weeks for two cycles (199 assigned; 185 had surgery)
- DCF, with cisplatin at 70 mg/m2 on day 1, 5-fluorouracil at 750 mg/m2 on days 1-5, and docetaxel at 70 mg/m2 on day 1 every 3 weeks for three cycles (202 assigned; 183 had surgery)
- CF-RT, with cisplatin at 75 mg/m2 on day 1, 5-fluorouracil at 1,000 mg/m2 on days 1-4 every 4 weeks for two cycles, plus 1.8 Gy radiation divided into 23 fractions for a total of 41.4 Gy (200 assigned; 178 had surgery).
Patient age, body mass index, tumor location, clinical stage and node status were comparable among the treatment groups.
Operative characteristics (duration, blood loss, approach, extent of lymph node dissection) were generally similar between the arms as well, except that significantly fewer lymph nodes were harvested with CF-RT compared with either CF or DCF (median of 49, 58, and 59, respectively).
Results
Incidence rates of major postoperative complications – pneumonia, leakage, and recurrent laryngeal nerve paralysis – were generally similar among the groups.
The cumulative rate of grade 2 or greater postoperative complications was significantly lower for DCF than for CF (P = .02), but not for DCF compared with CF-RT (P = .11). The rates were 43.7% with DCF, 47.8% with CF-RT, and 56.2% with CF.
The rate of grade 2 or greater chylothorax (leakage of lymphatics into the pleural space) was significantly higher with CF-RT than CF (5.1% vs. 1.1%, P = .03) but not with DCF vs. CF (3.8% vs. 1.1%, P = .10)
In multivariable analysis controlling for demographic, clinical, and operative characteristics, factors associated with lower risk for complications included:
- Middle esophageal tumor location vs. upper esophageal tumors (relative risk [RR], 0.79; P = .03)
- DCF (RR, 0.79; P = .02)
- A thoracoscopic vs. open approach (RR, 0.77; P = .002).
The only factor associated with higher risk was operative time longer than 492 minutes (RR, 1.26; P = .008).
Dr. Koyanagi said the reasons for the lower lymph node yield and more frequent chylothorax with CF-RT are unclear but may be related to tissue fibrosis from radiation exposure.
CROSS talk
“As a North American surgeon, I generally look to CROSS induction chemotherapy for the majority of my patients for both adenocarcinoma and squamous cell carcinoma of the esophagus,” said invited discussant Jonathan Yeung, MD, PhD, of the Princess Margaret Cancer Centre in Toronto.
The CROSS regimen consists of carboplatin titrated to an area under the curve of 2 mg/mL per minute and paclitaxel at 50 mg/m2 for 5 weeks with concurrent radiotherapy to a total dose of 41.4 Gy delivered in 23 fractions, 5 days per week.
Dr. Yeung noted that, of the eligible patients in JCOG1109, 92% of those assigned to DCF actually underwent surgery, and 90% of those assigned to CF-RT went on to surgery, compared with 98% of patients who had surgery in the CROSS trial, suggesting that the DCF and CF-RT regimens may be more toxic.
He also noted that the lower lymph node harvest seen with CF-RT was seen in other studies.
“I must say I’m always impressed by the lymph node yields that our Japanese colleagues can obtain at surgery, but this lower lymph node yield is also borne out in the CROSS data, where there are less lymph nodes harvested following chemoradiotherapy,” he said.
A higher rate of chylothorax with CF-RT was also seen in patients in the CROSS trial who were randomized to receive radiation compared with those who received chemotherapy alone.
“I await the final results to see if there is ultimately better survival,” Dr. Yeung said.
JCOG1109 was supported by grants from the National Cancer Center Research and Development Funds and Agency for Medical Research and Development of Japan. Dr. Koyanagi and Dr. Yeung reported no conflicts of interest.
The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
FROM GI Cancers Symposium 2021
Boost dose reduces recurrence in high-risk DCIS
Giving a tumor bed boost (TBB) reduced the risk of local recurrence and overall disease recurrence, but there were no significant differences in recurrence rates between conventional WBI and hypofractionated WBI.
Boon Hui Chua, MD, of the University of New South Wales, Sydney, presented these results at the 2020 San Antonio Breast Cancer Symposium.
Dr. Chua and colleagues studied 1,608 women with DCIS resected by conservative surgery. Patients were either younger than 50 years or age 50 and older with at least one of the following risk factors: symptomatic presentation, palpable tumor, multifocal disease, tumor size 1.5 cm or larger, intermediate or high nuclear grade, central necrosis, comedo histology, and/or surgical margins less than 10 mm.
The patients were randomized to treatment in three categories. In randomization A (n = 503), patients were randomized to one of the following treatments:
- WBI at 50 Gy in 25 fractions
- WBI at 42.5 Gy in 16 fractions
- WBI at 50 Gy in 25 fractions plus TBB at 16 Gy in 8 fractions
- WBI at 42.5 Gy in 16 fractions plus TBB at 16 Gy in 8 fractions.
In randomization B (n = 581), patients received WBI at 50 Gy in 25 fractions, with or without TBB at 16 Gy in 8 fractions. In randomization C (n = 524), patients received WBI at 42.5 Gy in 16 fractions, with or without TBB at 16 Gy in 8 fractions.
All patients underwent CT-based radiation planning. WBI was delivered with tangential MV photon beams, and TBB was performed with CT contouring of protocol-defined tumor bed target volumes, with electron or photon energy. The median follow-up was 6.6 years.
Giving a boost to better outcomes
The 5-year rate of freedom from local recurrence was 97% for patients who received TBB and 93% for patients who did not (hazard ratio, 0.47; P < .001). The benefit of TBB was consistent across subgroups.
There were no significant differences in 5-year rates of freedom from local recurrence by WBI fractionation, either in randomization A (P = .837) or among all randomized patients (P = .887).
The tests for interactions between TBB and WBI fractionation on local recurrence were not significant in randomization A (P = .89) or in all randomized patients (P = .89).
The risk of overall disease recurrence was lower among patients who had received TBB, with an HR of 0.63 (P = .004). The 5-year rate of freedom from disease recurrence was 97% with TBB and 91% with no boost (P = .002).
There were no significant differences in freedom from disease recurrence rates by WBI fractionation either in randomization A (P = .443) or among all randomized patients (P = .605).
Acute radiation dermatitis occurred in significantly more patients who received TBB (P = .006), as did late breast pain (P = .003), induration or fibrosis (P < .0001), and telangiectasia (P = .02). There were no significant differences by boost status for acute or late fatigue, pneumonitis, cardiac complications, or second malignancies.
Reduce the boost dose?
A radiation oncologist who was not involved in this study said that, while the results confirm a benefit of boost dose for patients with non–low-risk DCIS, the doses used in the BIG-3-07 study may be higher than needed to achieve a protective effect.
“Here in America, we usually give 10 Gy in five fractions, and, in many countries, actually, it’s 10 Gy in five fractions, although a few European centers give 16 Gy in eight fractions,” said Alphose Taghian, MD, of Massachusetts General Hospital in Boston.
“I personally only give 10 Gy in five fractions. I am not under the impression that 16 Gy in eight fractions will give better results. The local failure rate is so low, it’s likely that 10 Gy will do the job,” Dr. Taghian said in an interview.
Dr. Taghian noted that raising the dose to 16 Gy increases the risk of fibrosis, as seen in the BIG-3-07 trial.
Nonetheless, the trial demonstrates the benefit of radiation boost dose in patients with high-risk DCIS, he said, adding that the local recurrence-free benefit curves may separate further with longer follow-up.
The study was sponsored by the Trans Tasman Radiation Oncology Group. Dr. Chua and Dr. Taghian reported no conflicts of interest.
Giving a tumor bed boost (TBB) reduced the risk of local recurrence and overall disease recurrence, but there were no significant differences in recurrence rates between conventional WBI and hypofractionated WBI.
Boon Hui Chua, MD, of the University of New South Wales, Sydney, presented these results at the 2020 San Antonio Breast Cancer Symposium.
Dr. Chua and colleagues studied 1,608 women with DCIS resected by conservative surgery. Patients were either younger than 50 years or age 50 and older with at least one of the following risk factors: symptomatic presentation, palpable tumor, multifocal disease, tumor size 1.5 cm or larger, intermediate or high nuclear grade, central necrosis, comedo histology, and/or surgical margins less than 10 mm.
The patients were randomized to treatment in three categories. In randomization A (n = 503), patients were randomized to one of the following treatments:
- WBI at 50 Gy in 25 fractions
- WBI at 42.5 Gy in 16 fractions
- WBI at 50 Gy in 25 fractions plus TBB at 16 Gy in 8 fractions
- WBI at 42.5 Gy in 16 fractions plus TBB at 16 Gy in 8 fractions.
In randomization B (n = 581), patients received WBI at 50 Gy in 25 fractions, with or without TBB at 16 Gy in 8 fractions. In randomization C (n = 524), patients received WBI at 42.5 Gy in 16 fractions, with or without TBB at 16 Gy in 8 fractions.
All patients underwent CT-based radiation planning. WBI was delivered with tangential MV photon beams, and TBB was performed with CT contouring of protocol-defined tumor bed target volumes, with electron or photon energy. The median follow-up was 6.6 years.
Giving a boost to better outcomes
The 5-year rate of freedom from local recurrence was 97% for patients who received TBB and 93% for patients who did not (hazard ratio, 0.47; P < .001). The benefit of TBB was consistent across subgroups.
There were no significant differences in 5-year rates of freedom from local recurrence by WBI fractionation, either in randomization A (P = .837) or among all randomized patients (P = .887).
The tests for interactions between TBB and WBI fractionation on local recurrence were not significant in randomization A (P = .89) or in all randomized patients (P = .89).
The risk of overall disease recurrence was lower among patients who had received TBB, with an HR of 0.63 (P = .004). The 5-year rate of freedom from disease recurrence was 97% with TBB and 91% with no boost (P = .002).
There were no significant differences in freedom from disease recurrence rates by WBI fractionation either in randomization A (P = .443) or among all randomized patients (P = .605).
Acute radiation dermatitis occurred in significantly more patients who received TBB (P = .006), as did late breast pain (P = .003), induration or fibrosis (P < .0001), and telangiectasia (P = .02). There were no significant differences by boost status for acute or late fatigue, pneumonitis, cardiac complications, or second malignancies.
Reduce the boost dose?
A radiation oncologist who was not involved in this study said that, while the results confirm a benefit of boost dose for patients with non–low-risk DCIS, the doses used in the BIG-3-07 study may be higher than needed to achieve a protective effect.
“Here in America, we usually give 10 Gy in five fractions, and, in many countries, actually, it’s 10 Gy in five fractions, although a few European centers give 16 Gy in eight fractions,” said Alphose Taghian, MD, of Massachusetts General Hospital in Boston.
“I personally only give 10 Gy in five fractions. I am not under the impression that 16 Gy in eight fractions will give better results. The local failure rate is so low, it’s likely that 10 Gy will do the job,” Dr. Taghian said in an interview.
Dr. Taghian noted that raising the dose to 16 Gy increases the risk of fibrosis, as seen in the BIG-3-07 trial.
Nonetheless, the trial demonstrates the benefit of radiation boost dose in patients with high-risk DCIS, he said, adding that the local recurrence-free benefit curves may separate further with longer follow-up.
The study was sponsored by the Trans Tasman Radiation Oncology Group. Dr. Chua and Dr. Taghian reported no conflicts of interest.
Giving a tumor bed boost (TBB) reduced the risk of local recurrence and overall disease recurrence, but there were no significant differences in recurrence rates between conventional WBI and hypofractionated WBI.
Boon Hui Chua, MD, of the University of New South Wales, Sydney, presented these results at the 2020 San Antonio Breast Cancer Symposium.
Dr. Chua and colleagues studied 1,608 women with DCIS resected by conservative surgery. Patients were either younger than 50 years or age 50 and older with at least one of the following risk factors: symptomatic presentation, palpable tumor, multifocal disease, tumor size 1.5 cm or larger, intermediate or high nuclear grade, central necrosis, comedo histology, and/or surgical margins less than 10 mm.
The patients were randomized to treatment in three categories. In randomization A (n = 503), patients were randomized to one of the following treatments:
- WBI at 50 Gy in 25 fractions
- WBI at 42.5 Gy in 16 fractions
- WBI at 50 Gy in 25 fractions plus TBB at 16 Gy in 8 fractions
- WBI at 42.5 Gy in 16 fractions plus TBB at 16 Gy in 8 fractions.
In randomization B (n = 581), patients received WBI at 50 Gy in 25 fractions, with or without TBB at 16 Gy in 8 fractions. In randomization C (n = 524), patients received WBI at 42.5 Gy in 16 fractions, with or without TBB at 16 Gy in 8 fractions.
All patients underwent CT-based radiation planning. WBI was delivered with tangential MV photon beams, and TBB was performed with CT contouring of protocol-defined tumor bed target volumes, with electron or photon energy. The median follow-up was 6.6 years.
Giving a boost to better outcomes
The 5-year rate of freedom from local recurrence was 97% for patients who received TBB and 93% for patients who did not (hazard ratio, 0.47; P < .001). The benefit of TBB was consistent across subgroups.
There were no significant differences in 5-year rates of freedom from local recurrence by WBI fractionation, either in randomization A (P = .837) or among all randomized patients (P = .887).
The tests for interactions between TBB and WBI fractionation on local recurrence were not significant in randomization A (P = .89) or in all randomized patients (P = .89).
The risk of overall disease recurrence was lower among patients who had received TBB, with an HR of 0.63 (P = .004). The 5-year rate of freedom from disease recurrence was 97% with TBB and 91% with no boost (P = .002).
There were no significant differences in freedom from disease recurrence rates by WBI fractionation either in randomization A (P = .443) or among all randomized patients (P = .605).
Acute radiation dermatitis occurred in significantly more patients who received TBB (P = .006), as did late breast pain (P = .003), induration or fibrosis (P < .0001), and telangiectasia (P = .02). There were no significant differences by boost status for acute or late fatigue, pneumonitis, cardiac complications, or second malignancies.
Reduce the boost dose?
A radiation oncologist who was not involved in this study said that, while the results confirm a benefit of boost dose for patients with non–low-risk DCIS, the doses used in the BIG-3-07 study may be higher than needed to achieve a protective effect.
“Here in America, we usually give 10 Gy in five fractions, and, in many countries, actually, it’s 10 Gy in five fractions, although a few European centers give 16 Gy in eight fractions,” said Alphose Taghian, MD, of Massachusetts General Hospital in Boston.
“I personally only give 10 Gy in five fractions. I am not under the impression that 16 Gy in eight fractions will give better results. The local failure rate is so low, it’s likely that 10 Gy will do the job,” Dr. Taghian said in an interview.
Dr. Taghian noted that raising the dose to 16 Gy increases the risk of fibrosis, as seen in the BIG-3-07 trial.
Nonetheless, the trial demonstrates the benefit of radiation boost dose in patients with high-risk DCIS, he said, adding that the local recurrence-free benefit curves may separate further with longer follow-up.
The study was sponsored by the Trans Tasman Radiation Oncology Group. Dr. Chua and Dr. Taghian reported no conflicts of interest.
FROM SABCS 2020
Von Willebrand disease guidelines address women’s bleeding concerns
New guidelines issued jointly by four major international hematology groups focus on the management of patients with von Willebrand disease (VWD), the most common bleeding disorder in the world.
The evidence-based guidelines, published in Blood Advances, were developed in collaboration by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia. They outline key recommendations spanning the care of patients with a broad range of therapeutic needs.
“We addressed some of the questions that were most important to the community, but certainly there are a lot of areas that we couldn’t cover” said coauthor Veronica H. Flood, MD, of the Medical College of Wisconsin in Milwaukee.
The guidelines process began with a survey sent to the von Willebrand disease community, including patients, caregivers, nurses, physicians, and scientists. The respondents were asked to prioritize issues that they felt should be addressed in the guidelines.
“Interestingly, some of the issues were the same between patients and caregivers and physicians, and some were different, but there were obviously some areas that we just couldn’t cover,” she said in an interview.
One of the areas of greatest concern for respondents was bleeding in women, and many of the recommendations include specific considerations for management of gynecologic and obstetric patients, Dr. Flood said.
“We also tried to make the questions applicable to as many patients with von Willebrand disease as possible,” she added.
Some of the questions, such as recommendation 1, regarding prophylaxis, are geared toward management of patients with severe disease, while others, such as recommendations for treatment of menstrual bleeding, are more suited for patients with milder VWD.
All of the recommendations in the guidelines are “conditional” (suggested), due to very low certainty in the evidence of effects, the authors noted.
Prophylaxis
The guidelines suggest long-term prophylaxis for patients with a history of severe and frequent bleeds, with periodic assessment of the need for prophylaxis.
Desmopressin
For those patients who may benefit from the use of desmopressin, primarily those with type 1 VWD, and who have a baseline von Willebrand factor (VWF) level below 0.30 IU/mL, the panel issued a conditional recommendation for a desmopressin trial with treatment based on the patient’s results compared with not performing a trial and treating with tranexamic acid or factor concentrate. The guidelines also advise against treating with desmopressin in the absence of a trial. In a section of “good practice statements,” the guidelines indicate that using desmopressin in patients with type 2B VWD is generally contraindicated, because of the risk of thrombocytopenia as a result of increased platelet binding. In addition, desmopressin is generally contraindicated in patients with active cardiovascular disease, patients with seizure disorders, patients less than 2 years old, and patients with type 1C VWD in the setting of surgery.
Antithrombotic therapy
The guideline panelists conditionally recommend antithrombotic therapy with either antiplatelet agents or anticoagulants, with an emphasis on reassessing bleeding risk throughout the course of treatment.
An accompanying good practice statement calls for individualized assessments of risks and benefits of specific antithrombotic therapies by a multidisciplinary team including hematologists, cardiovascular specialists, and the patient.
Major surgery
This section includes a recommendation for targeting both factor VIII and VWF activity levels to a minimum of 50 IU/mL for at least 3 days after surgery, and a suggestion against using factor VIII target levels alone.
Minor surgery/invasive procedures
The panelists suggest increasing VWF activity levels to a minimum of 0.50 IU/mL with desmopressin or factor concentrate with the addition of tranexamic acid over raising VWF levels to at least 0.50 IU/mL with desmopressin or factor concentrate alone.
In addition, the panelists suggest “giving tranexamic acid alone over increasing VWF activity levels to a minimum threshold of 0.50 IU/mL with any intervention in patients with type 1 VWD with baseline VWF activity levels of 0.30 IU/mL and a mild bleeding phenotype undergoing minor mucosal procedures.”
Heavy menstrual bleeding
In women with heavy menstrual bleeding who do not plan to conceive, the panel suggests either combined hormonal therapy or levonorgestrel-releasing intrauterine system, or tranexamic acid over desmopressin.
In women who wish to conceive, the panel suggests using tranexamic acid over desmopressin.
Neuraxial anesthesia during labor
For women in labor for whom neuraxial anesthesia is considered, the guidelines suggest targeting a VWF activity level from 0.50 to 1.50 IU/mL over targeting a level above 1.50 IU/mL.
Postpartum management
“The guideline panel suggests the use of tranexamic acid over not using it in women with type 1 VWD or low VWF levels (and this may also apply to types 2 and 3 VWD) during the postpartum period,” the guidelines say.
An accompanying good practice statement says that tranexamic acid can be provided orally or intravenously. The oral dose is 25 mg/kg three times daily for 10-14 days, or longer if blood loss remains heavy.
Dr. Flood said that the guidelines were developed under the assumption that they would apply to care of patients in regions with a high or moderately high degree of clinical resources.
“We recognize that this eliminates a great deal of the globe, and our hope is that ASH and the other sponsoring organizations are going to let us revise this and do a version for lower-resourced settings,” she said.
New guidelines issued jointly by four major international hematology groups focus on the management of patients with von Willebrand disease (VWD), the most common bleeding disorder in the world.
The evidence-based guidelines, published in Blood Advances, were developed in collaboration by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia. They outline key recommendations spanning the care of patients with a broad range of therapeutic needs.
“We addressed some of the questions that were most important to the community, but certainly there are a lot of areas that we couldn’t cover” said coauthor Veronica H. Flood, MD, of the Medical College of Wisconsin in Milwaukee.
The guidelines process began with a survey sent to the von Willebrand disease community, including patients, caregivers, nurses, physicians, and scientists. The respondents were asked to prioritize issues that they felt should be addressed in the guidelines.
“Interestingly, some of the issues were the same between patients and caregivers and physicians, and some were different, but there were obviously some areas that we just couldn’t cover,” she said in an interview.
One of the areas of greatest concern for respondents was bleeding in women, and many of the recommendations include specific considerations for management of gynecologic and obstetric patients, Dr. Flood said.
“We also tried to make the questions applicable to as many patients with von Willebrand disease as possible,” she added.
Some of the questions, such as recommendation 1, regarding prophylaxis, are geared toward management of patients with severe disease, while others, such as recommendations for treatment of menstrual bleeding, are more suited for patients with milder VWD.
All of the recommendations in the guidelines are “conditional” (suggested), due to very low certainty in the evidence of effects, the authors noted.
Prophylaxis
The guidelines suggest long-term prophylaxis for patients with a history of severe and frequent bleeds, with periodic assessment of the need for prophylaxis.
Desmopressin
For those patients who may benefit from the use of desmopressin, primarily those with type 1 VWD, and who have a baseline von Willebrand factor (VWF) level below 0.30 IU/mL, the panel issued a conditional recommendation for a desmopressin trial with treatment based on the patient’s results compared with not performing a trial and treating with tranexamic acid or factor concentrate. The guidelines also advise against treating with desmopressin in the absence of a trial. In a section of “good practice statements,” the guidelines indicate that using desmopressin in patients with type 2B VWD is generally contraindicated, because of the risk of thrombocytopenia as a result of increased platelet binding. In addition, desmopressin is generally contraindicated in patients with active cardiovascular disease, patients with seizure disorders, patients less than 2 years old, and patients with type 1C VWD in the setting of surgery.
Antithrombotic therapy
The guideline panelists conditionally recommend antithrombotic therapy with either antiplatelet agents or anticoagulants, with an emphasis on reassessing bleeding risk throughout the course of treatment.
An accompanying good practice statement calls for individualized assessments of risks and benefits of specific antithrombotic therapies by a multidisciplinary team including hematologists, cardiovascular specialists, and the patient.
Major surgery
This section includes a recommendation for targeting both factor VIII and VWF activity levels to a minimum of 50 IU/mL for at least 3 days after surgery, and a suggestion against using factor VIII target levels alone.
Minor surgery/invasive procedures
The panelists suggest increasing VWF activity levels to a minimum of 0.50 IU/mL with desmopressin or factor concentrate with the addition of tranexamic acid over raising VWF levels to at least 0.50 IU/mL with desmopressin or factor concentrate alone.
In addition, the panelists suggest “giving tranexamic acid alone over increasing VWF activity levels to a minimum threshold of 0.50 IU/mL with any intervention in patients with type 1 VWD with baseline VWF activity levels of 0.30 IU/mL and a mild bleeding phenotype undergoing minor mucosal procedures.”
Heavy menstrual bleeding
In women with heavy menstrual bleeding who do not plan to conceive, the panel suggests either combined hormonal therapy or levonorgestrel-releasing intrauterine system, or tranexamic acid over desmopressin.
In women who wish to conceive, the panel suggests using tranexamic acid over desmopressin.
Neuraxial anesthesia during labor
For women in labor for whom neuraxial anesthesia is considered, the guidelines suggest targeting a VWF activity level from 0.50 to 1.50 IU/mL over targeting a level above 1.50 IU/mL.
Postpartum management
“The guideline panel suggests the use of tranexamic acid over not using it in women with type 1 VWD or low VWF levels (and this may also apply to types 2 and 3 VWD) during the postpartum period,” the guidelines say.
An accompanying good practice statement says that tranexamic acid can be provided orally or intravenously. The oral dose is 25 mg/kg three times daily for 10-14 days, or longer if blood loss remains heavy.
Dr. Flood said that the guidelines were developed under the assumption that they would apply to care of patients in regions with a high or moderately high degree of clinical resources.
“We recognize that this eliminates a great deal of the globe, and our hope is that ASH and the other sponsoring organizations are going to let us revise this and do a version for lower-resourced settings,” she said.
New guidelines issued jointly by four major international hematology groups focus on the management of patients with von Willebrand disease (VWD), the most common bleeding disorder in the world.
The evidence-based guidelines, published in Blood Advances, were developed in collaboration by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia. They outline key recommendations spanning the care of patients with a broad range of therapeutic needs.
“We addressed some of the questions that were most important to the community, but certainly there are a lot of areas that we couldn’t cover” said coauthor Veronica H. Flood, MD, of the Medical College of Wisconsin in Milwaukee.
The guidelines process began with a survey sent to the von Willebrand disease community, including patients, caregivers, nurses, physicians, and scientists. The respondents were asked to prioritize issues that they felt should be addressed in the guidelines.
“Interestingly, some of the issues were the same between patients and caregivers and physicians, and some were different, but there were obviously some areas that we just couldn’t cover,” she said in an interview.
One of the areas of greatest concern for respondents was bleeding in women, and many of the recommendations include specific considerations for management of gynecologic and obstetric patients, Dr. Flood said.
“We also tried to make the questions applicable to as many patients with von Willebrand disease as possible,” she added.
Some of the questions, such as recommendation 1, regarding prophylaxis, are geared toward management of patients with severe disease, while others, such as recommendations for treatment of menstrual bleeding, are more suited for patients with milder VWD.
All of the recommendations in the guidelines are “conditional” (suggested), due to very low certainty in the evidence of effects, the authors noted.
Prophylaxis
The guidelines suggest long-term prophylaxis for patients with a history of severe and frequent bleeds, with periodic assessment of the need for prophylaxis.
Desmopressin
For those patients who may benefit from the use of desmopressin, primarily those with type 1 VWD, and who have a baseline von Willebrand factor (VWF) level below 0.30 IU/mL, the panel issued a conditional recommendation for a desmopressin trial with treatment based on the patient’s results compared with not performing a trial and treating with tranexamic acid or factor concentrate. The guidelines also advise against treating with desmopressin in the absence of a trial. In a section of “good practice statements,” the guidelines indicate that using desmopressin in patients with type 2B VWD is generally contraindicated, because of the risk of thrombocytopenia as a result of increased platelet binding. In addition, desmopressin is generally contraindicated in patients with active cardiovascular disease, patients with seizure disorders, patients less than 2 years old, and patients with type 1C VWD in the setting of surgery.
Antithrombotic therapy
The guideline panelists conditionally recommend antithrombotic therapy with either antiplatelet agents or anticoagulants, with an emphasis on reassessing bleeding risk throughout the course of treatment.
An accompanying good practice statement calls for individualized assessments of risks and benefits of specific antithrombotic therapies by a multidisciplinary team including hematologists, cardiovascular specialists, and the patient.
Major surgery
This section includes a recommendation for targeting both factor VIII and VWF activity levels to a minimum of 50 IU/mL for at least 3 days after surgery, and a suggestion against using factor VIII target levels alone.
Minor surgery/invasive procedures
The panelists suggest increasing VWF activity levels to a minimum of 0.50 IU/mL with desmopressin or factor concentrate with the addition of tranexamic acid over raising VWF levels to at least 0.50 IU/mL with desmopressin or factor concentrate alone.
In addition, the panelists suggest “giving tranexamic acid alone over increasing VWF activity levels to a minimum threshold of 0.50 IU/mL with any intervention in patients with type 1 VWD with baseline VWF activity levels of 0.30 IU/mL and a mild bleeding phenotype undergoing minor mucosal procedures.”
Heavy menstrual bleeding
In women with heavy menstrual bleeding who do not plan to conceive, the panel suggests either combined hormonal therapy or levonorgestrel-releasing intrauterine system, or tranexamic acid over desmopressin.
In women who wish to conceive, the panel suggests using tranexamic acid over desmopressin.
Neuraxial anesthesia during labor
For women in labor for whom neuraxial anesthesia is considered, the guidelines suggest targeting a VWF activity level from 0.50 to 1.50 IU/mL over targeting a level above 1.50 IU/mL.
Postpartum management
“The guideline panel suggests the use of tranexamic acid over not using it in women with type 1 VWD or low VWF levels (and this may also apply to types 2 and 3 VWD) during the postpartum period,” the guidelines say.
An accompanying good practice statement says that tranexamic acid can be provided orally or intravenously. The oral dose is 25 mg/kg three times daily for 10-14 days, or longer if blood loss remains heavy.
Dr. Flood said that the guidelines were developed under the assumption that they would apply to care of patients in regions with a high or moderately high degree of clinical resources.
“We recognize that this eliminates a great deal of the globe, and our hope is that ASH and the other sponsoring organizations are going to let us revise this and do a version for lower-resourced settings,” she said.
FROM BLOOD ADVANCES
Bemarituzumab FIGHTs gastric/GEJ cancers, improving survival
Among 155 patients followed for a median of 10.9 months, the combination of bemarituzumab and modified FOLFOX chemotherapy (leucovorin, fluorouracil, and oxaliplatin) resulted in a median progression-free survival (PFS) of 9.5 months, compared with 7.4 months with chemotherapy alone.
The median overall survival (OS) was not reached in the combination arm but was 12.9 months for patients treated with modified FOLFOX plus placebo
Zev A. Wainberg, MD, of the University of California, Los Angeles, presented these results at the 2021 Gastrointestinal Cancers Symposium.
Dr. Wainberg explained that bemarituzumab is an IgG1 antibody targeted specifically to the FGFR2b receptor to block growth factor signaling. The findings from FIGHT suggest FGFR2b is a new biomarker and therapeutic target for advanced gastric and GEJ cancers.
“The FIGHT trial results support a prospective, randomized, phase 3 study in gastric and gastroesophageal adenocarcinoma and the evaluation of bemarituzumab in other FGFR2b tumor types,” Dr. Wainberg said.
FGFR2b is a splice isoform of FGFR2 that is thought to be overexpressed in anywhere from 3% to 61% of gastric cancers, depending on the tumor stage and assay used, he explained at the meeting sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Study downgrading and design
The FIGHT trial was originally designed as a phase 3, randomized trial with the primary endpoint of OS, but it was converted to a phase 2 trial with a PFS primary endpoint and OS secondary endpoint.
In the question-and-answer phase following his presentation, Dr. Wainberg explained that the trial was downgraded because “we wanted to get a little more comfortable with the biomarker,” and because the prevalence of FGFR2b, which was unknown during the planning phase, played a large role in the statistical assumptions.
Patients were eligible for FIGHT if they had received no prior therapy for unresectable, locally advanced or metastatic gastric or GEJ cancers. They also had to have FGFR2b overexpression on immunohistochemistry and/or FGFR2 gene amplification by circulating tumor DNA. They had to have good Eastern Cooperative Oncology Group performance status (0 or 1) and could not have tumors positive for HER2.
Patients were allowed to have one cycle of FOLFOX while their FGFR2b status was being determined, prior to randomization.
After stratification for geographic region, FOLFOX use during screenings, and prior adjuvant or neoadjuvant chemotherapy, the patients were randomized to receive FOLFOX with either placebo or 15 mg/kg of bemarituzumab every 2 weeks, plus an additional 7.5-mg/kg dose on day 8 of cycle 1.
A total of 77 patients were randomized to the bemarituzumab arm, and 78 were randomized to the placebo arm.
Patient status at cutoff
As of the September 2020 cutoff, 14 patients continued on bemarituzumab, and 63 were off the assigned drug: 26 because of radiographic progression, 3 for consent withdrawal, 5 because of death, 20 because of adverse events, and 9 for other unspecified causes.
There were 42 patients in the bemarituzumab arm who were still being followed at the cutoff, and 35 were off study. Of this latter group, 28 died, 6 withdrew consent, and 1 was off study for an unspecified cause.
In the placebo arm, 8 patients were still receiving the assigned therapy, and 70 were off that treatment. Of the patients who discontinued study treatment, 4 died, 39 had radiographic progression, 7 withdrew consent, 3 had adverse events, and 17 discontinued for other unspecified reasons.
A total of 27 patients assigned to placebo were still on follow-up at the data cutoff. Of the remaining 51 patients, 40 died, 10 withdrew consent, and 1 had other, unspecified causes for going off study.
Primary endpoint met
The PFS rate at 9 months was 52.5% in the experimental arm and 33.8% in the control arm. The median PFS was 9.5 months with bemarituzumab and 7.4 months with placebo, which translated to a hazard ratio of 0.68 (P = .0727). This met the prespecified level of statistical significance for the phase 2 version of the trial, which required a two-sided alpha of 0.2
OS at 12 months was also superior in the experimental arm, at 65.3% with bemarituzumab and 56.9% with placebo (HR, 0.58; P = .0268).
The benefit of bemarituzumab for both PFS and OS was greatest among patients whose tumors had the highest levels of FGFR2b expression.
Overall response rates were 47% in the experimental arm and 33% in the placebo arm. Among patients with measurable disease at baseline, the respective response rates were 53% and 40%. The median duration of response was 12.2 months in the bemarituzumab arm and 7.1 months in the placebo arm.
Corneal toxicities, stomatitis
The incidence of grade 3 or greater adverse events was 82.9% in the experimental arm and 74% in the placebo arm. Five patients in the bemarituzumab arm and four in the placebo arm died from treatment-related causes.
Grade 3 or greater stomatitis occurred in seven patients in the experimental arm, compared with just one patient in the placebo arm. Grade 3 or greater dry eye occurred in two patients in the experimental arm but none in the placebo arm.
Corneal adverse events occurred in 67.1% of patients treated with bemarituzumab and 10.4% of patients on placebo. Respective rates of grade 3 or greater corneal events were 23.7% and 0%.
Twenty patients assigned to bemarituzumab had to discontinue the drug because of corneal problems, compared with no patients on placebo.
At last follow-up, corneal adverse events had resolved in 60% of patients, while 40% had continuing problems. The median time to resolution of corneal adverse events was 27 weeks.
New biomarker
“FIGHT study is the first study to demonstrate that biomarker selection exists beyond HER2,” commented invited discussant Rutika Mehta, MD, of the Moffitt Cancer Center and University of South Florida, both in Tampa.
“These are promising results, with toxicities that need to be watched out for. It calls for a larger phase 3 study with special attention to the toxicity profile for bema[rituzumab],” she added.
The trial was supported by Five Prime Therapeutics. Dr. Wainberg disclosed relationships with Five Prime and other companies. Dr. Mehta disclosed relationships with several companies, not including Five Prime.
Among 155 patients followed for a median of 10.9 months, the combination of bemarituzumab and modified FOLFOX chemotherapy (leucovorin, fluorouracil, and oxaliplatin) resulted in a median progression-free survival (PFS) of 9.5 months, compared with 7.4 months with chemotherapy alone.
The median overall survival (OS) was not reached in the combination arm but was 12.9 months for patients treated with modified FOLFOX plus placebo
Zev A. Wainberg, MD, of the University of California, Los Angeles, presented these results at the 2021 Gastrointestinal Cancers Symposium.
Dr. Wainberg explained that bemarituzumab is an IgG1 antibody targeted specifically to the FGFR2b receptor to block growth factor signaling. The findings from FIGHT suggest FGFR2b is a new biomarker and therapeutic target for advanced gastric and GEJ cancers.
“The FIGHT trial results support a prospective, randomized, phase 3 study in gastric and gastroesophageal adenocarcinoma and the evaluation of bemarituzumab in other FGFR2b tumor types,” Dr. Wainberg said.
FGFR2b is a splice isoform of FGFR2 that is thought to be overexpressed in anywhere from 3% to 61% of gastric cancers, depending on the tumor stage and assay used, he explained at the meeting sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Study downgrading and design
The FIGHT trial was originally designed as a phase 3, randomized trial with the primary endpoint of OS, but it was converted to a phase 2 trial with a PFS primary endpoint and OS secondary endpoint.
In the question-and-answer phase following his presentation, Dr. Wainberg explained that the trial was downgraded because “we wanted to get a little more comfortable with the biomarker,” and because the prevalence of FGFR2b, which was unknown during the planning phase, played a large role in the statistical assumptions.
Patients were eligible for FIGHT if they had received no prior therapy for unresectable, locally advanced or metastatic gastric or GEJ cancers. They also had to have FGFR2b overexpression on immunohistochemistry and/or FGFR2 gene amplification by circulating tumor DNA. They had to have good Eastern Cooperative Oncology Group performance status (0 or 1) and could not have tumors positive for HER2.
Patients were allowed to have one cycle of FOLFOX while their FGFR2b status was being determined, prior to randomization.
After stratification for geographic region, FOLFOX use during screenings, and prior adjuvant or neoadjuvant chemotherapy, the patients were randomized to receive FOLFOX with either placebo or 15 mg/kg of bemarituzumab every 2 weeks, plus an additional 7.5-mg/kg dose on day 8 of cycle 1.
A total of 77 patients were randomized to the bemarituzumab arm, and 78 were randomized to the placebo arm.
Patient status at cutoff
As of the September 2020 cutoff, 14 patients continued on bemarituzumab, and 63 were off the assigned drug: 26 because of radiographic progression, 3 for consent withdrawal, 5 because of death, 20 because of adverse events, and 9 for other unspecified causes.
There were 42 patients in the bemarituzumab arm who were still being followed at the cutoff, and 35 were off study. Of this latter group, 28 died, 6 withdrew consent, and 1 was off study for an unspecified cause.
In the placebo arm, 8 patients were still receiving the assigned therapy, and 70 were off that treatment. Of the patients who discontinued study treatment, 4 died, 39 had radiographic progression, 7 withdrew consent, 3 had adverse events, and 17 discontinued for other unspecified reasons.
A total of 27 patients assigned to placebo were still on follow-up at the data cutoff. Of the remaining 51 patients, 40 died, 10 withdrew consent, and 1 had other, unspecified causes for going off study.
Primary endpoint met
The PFS rate at 9 months was 52.5% in the experimental arm and 33.8% in the control arm. The median PFS was 9.5 months with bemarituzumab and 7.4 months with placebo, which translated to a hazard ratio of 0.68 (P = .0727). This met the prespecified level of statistical significance for the phase 2 version of the trial, which required a two-sided alpha of 0.2
OS at 12 months was also superior in the experimental arm, at 65.3% with bemarituzumab and 56.9% with placebo (HR, 0.58; P = .0268).
The benefit of bemarituzumab for both PFS and OS was greatest among patients whose tumors had the highest levels of FGFR2b expression.
Overall response rates were 47% in the experimental arm and 33% in the placebo arm. Among patients with measurable disease at baseline, the respective response rates were 53% and 40%. The median duration of response was 12.2 months in the bemarituzumab arm and 7.1 months in the placebo arm.
Corneal toxicities, stomatitis
The incidence of grade 3 or greater adverse events was 82.9% in the experimental arm and 74% in the placebo arm. Five patients in the bemarituzumab arm and four in the placebo arm died from treatment-related causes.
Grade 3 or greater stomatitis occurred in seven patients in the experimental arm, compared with just one patient in the placebo arm. Grade 3 or greater dry eye occurred in two patients in the experimental arm but none in the placebo arm.
Corneal adverse events occurred in 67.1% of patients treated with bemarituzumab and 10.4% of patients on placebo. Respective rates of grade 3 or greater corneal events were 23.7% and 0%.
Twenty patients assigned to bemarituzumab had to discontinue the drug because of corneal problems, compared with no patients on placebo.
At last follow-up, corneal adverse events had resolved in 60% of patients, while 40% had continuing problems. The median time to resolution of corneal adverse events was 27 weeks.
New biomarker
“FIGHT study is the first study to demonstrate that biomarker selection exists beyond HER2,” commented invited discussant Rutika Mehta, MD, of the Moffitt Cancer Center and University of South Florida, both in Tampa.
“These are promising results, with toxicities that need to be watched out for. It calls for a larger phase 3 study with special attention to the toxicity profile for bema[rituzumab],” she added.
The trial was supported by Five Prime Therapeutics. Dr. Wainberg disclosed relationships with Five Prime and other companies. Dr. Mehta disclosed relationships with several companies, not including Five Prime.
Among 155 patients followed for a median of 10.9 months, the combination of bemarituzumab and modified FOLFOX chemotherapy (leucovorin, fluorouracil, and oxaliplatin) resulted in a median progression-free survival (PFS) of 9.5 months, compared with 7.4 months with chemotherapy alone.
The median overall survival (OS) was not reached in the combination arm but was 12.9 months for patients treated with modified FOLFOX plus placebo
Zev A. Wainberg, MD, of the University of California, Los Angeles, presented these results at the 2021 Gastrointestinal Cancers Symposium.
Dr. Wainberg explained that bemarituzumab is an IgG1 antibody targeted specifically to the FGFR2b receptor to block growth factor signaling. The findings from FIGHT suggest FGFR2b is a new biomarker and therapeutic target for advanced gastric and GEJ cancers.
“The FIGHT trial results support a prospective, randomized, phase 3 study in gastric and gastroesophageal adenocarcinoma and the evaluation of bemarituzumab in other FGFR2b tumor types,” Dr. Wainberg said.
FGFR2b is a splice isoform of FGFR2 that is thought to be overexpressed in anywhere from 3% to 61% of gastric cancers, depending on the tumor stage and assay used, he explained at the meeting sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Study downgrading and design
The FIGHT trial was originally designed as a phase 3, randomized trial with the primary endpoint of OS, but it was converted to a phase 2 trial with a PFS primary endpoint and OS secondary endpoint.
In the question-and-answer phase following his presentation, Dr. Wainberg explained that the trial was downgraded because “we wanted to get a little more comfortable with the biomarker,” and because the prevalence of FGFR2b, which was unknown during the planning phase, played a large role in the statistical assumptions.
Patients were eligible for FIGHT if they had received no prior therapy for unresectable, locally advanced or metastatic gastric or GEJ cancers. They also had to have FGFR2b overexpression on immunohistochemistry and/or FGFR2 gene amplification by circulating tumor DNA. They had to have good Eastern Cooperative Oncology Group performance status (0 or 1) and could not have tumors positive for HER2.
Patients were allowed to have one cycle of FOLFOX while their FGFR2b status was being determined, prior to randomization.
After stratification for geographic region, FOLFOX use during screenings, and prior adjuvant or neoadjuvant chemotherapy, the patients were randomized to receive FOLFOX with either placebo or 15 mg/kg of bemarituzumab every 2 weeks, plus an additional 7.5-mg/kg dose on day 8 of cycle 1.
A total of 77 patients were randomized to the bemarituzumab arm, and 78 were randomized to the placebo arm.
Patient status at cutoff
As of the September 2020 cutoff, 14 patients continued on bemarituzumab, and 63 were off the assigned drug: 26 because of radiographic progression, 3 for consent withdrawal, 5 because of death, 20 because of adverse events, and 9 for other unspecified causes.
There were 42 patients in the bemarituzumab arm who were still being followed at the cutoff, and 35 were off study. Of this latter group, 28 died, 6 withdrew consent, and 1 was off study for an unspecified cause.
In the placebo arm, 8 patients were still receiving the assigned therapy, and 70 were off that treatment. Of the patients who discontinued study treatment, 4 died, 39 had radiographic progression, 7 withdrew consent, 3 had adverse events, and 17 discontinued for other unspecified reasons.
A total of 27 patients assigned to placebo were still on follow-up at the data cutoff. Of the remaining 51 patients, 40 died, 10 withdrew consent, and 1 had other, unspecified causes for going off study.
Primary endpoint met
The PFS rate at 9 months was 52.5% in the experimental arm and 33.8% in the control arm. The median PFS was 9.5 months with bemarituzumab and 7.4 months with placebo, which translated to a hazard ratio of 0.68 (P = .0727). This met the prespecified level of statistical significance for the phase 2 version of the trial, which required a two-sided alpha of 0.2
OS at 12 months was also superior in the experimental arm, at 65.3% with bemarituzumab and 56.9% with placebo (HR, 0.58; P = .0268).
The benefit of bemarituzumab for both PFS and OS was greatest among patients whose tumors had the highest levels of FGFR2b expression.
Overall response rates were 47% in the experimental arm and 33% in the placebo arm. Among patients with measurable disease at baseline, the respective response rates were 53% and 40%. The median duration of response was 12.2 months in the bemarituzumab arm and 7.1 months in the placebo arm.
Corneal toxicities, stomatitis
The incidence of grade 3 or greater adverse events was 82.9% in the experimental arm and 74% in the placebo arm. Five patients in the bemarituzumab arm and four in the placebo arm died from treatment-related causes.
Grade 3 or greater stomatitis occurred in seven patients in the experimental arm, compared with just one patient in the placebo arm. Grade 3 or greater dry eye occurred in two patients in the experimental arm but none in the placebo arm.
Corneal adverse events occurred in 67.1% of patients treated with bemarituzumab and 10.4% of patients on placebo. Respective rates of grade 3 or greater corneal events were 23.7% and 0%.
Twenty patients assigned to bemarituzumab had to discontinue the drug because of corneal problems, compared with no patients on placebo.
At last follow-up, corneal adverse events had resolved in 60% of patients, while 40% had continuing problems. The median time to resolution of corneal adverse events was 27 weeks.
New biomarker
“FIGHT study is the first study to demonstrate that biomarker selection exists beyond HER2,” commented invited discussant Rutika Mehta, MD, of the Moffitt Cancer Center and University of South Florida, both in Tampa.
“These are promising results, with toxicities that need to be watched out for. It calls for a larger phase 3 study with special attention to the toxicity profile for bema[rituzumab],” she added.
The trial was supported by Five Prime Therapeutics. Dr. Wainberg disclosed relationships with Five Prime and other companies. Dr. Mehta disclosed relationships with several companies, not including Five Prime.
FROM GI CANCERS SYMPOSIUM 2021
Four-item prognostic index predicts survival in adult Burkitt lymphoma
A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.
In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.
“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
Inconsistent criteria
There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.
“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.
A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.
To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.
They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.
For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.
The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).
Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.
In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.
Rituximab was administered to 91% of U.S. and 95% of international patients.
Higher survival rates outside US
Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.
In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.
Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.
In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).
“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.
Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.
“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).
Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).
Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).
There were no significant differences in either PFS or OS when either LDH or stage was added into the model.
The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.
As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
Why the CNS discrepancy?
In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.
“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.
Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”
Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”
He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”
No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.
SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.
A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.
In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.
“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
Inconsistent criteria
There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.
“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.
A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.
To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.
They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.
For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.
The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).
Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.
In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.
Rituximab was administered to 91% of U.S. and 95% of international patients.
Higher survival rates outside US
Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.
In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.
Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.
In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).
“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.
Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.
“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).
Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).
Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).
There were no significant differences in either PFS or OS when either LDH or stage was added into the model.
The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.
As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
Why the CNS discrepancy?
In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.
“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.
Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”
Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”
He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”
No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.
SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.
A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.
In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.
“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
Inconsistent criteria
There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.
“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.
A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.
To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.
They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.
For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.
The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).
Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.
In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.
Rituximab was administered to 91% of U.S. and 95% of international patients.
Higher survival rates outside US
Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.
In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.
Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.
In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).
“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.
Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.
“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).
Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).
Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).
There were no significant differences in either PFS or OS when either LDH or stage was added into the model.
The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.
As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
Why the CNS discrepancy?
In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.
“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.
Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”
Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”
He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”
No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.
SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.
FROM ASH 2020