Adjuvant XELOX Improves Outcomes in Gastric Cancer

CHICAGO – Patients with gastric cancer have better outcomes if they are given adjuvant capecitabine plus oxaliplatin after undergoing curative resection that includes an extended lymph-node dissection, according to results of the CLASSIC trial from China, South Korea, and Taiwan

Investigators randomized 1,035 patients to either simple observation or XELOX (the combination of capecitabine plus oxaliplatin) after surgery. A full analysis was performed early because of interim efficacy findings in favor of the chemotherapy.

Trial results, which were reported at the annual meeting of the American Society of Clinical Oncology, showed that patients in the XELOX arm had a 44% reduction in the risk of recurrence. Their 3-year, disease-free survival rate (the primary end point) was 74%, compared with 60% in the observation-only group (hazard ratio, 0.56; P less than .0001). The benefit was similar across patients with stage II, IIIA, and IIIB disease.

Additionally, early data showed a 26% reduction in the 3-year risk of death, though the latter is not yet statistically significant.

"The CLASSIC [Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer] trial met its primary end point," said Dr. Yung-Jue Bang, presenting findings on behalf of his coinvestigators. "CLASSIC demonstrates superior efficacy of adjuvant XELOX vs. observation alone following D2 [extended] lymph-node dissection. The data presented support the use of adjuvant XELOX for gastric cancer."

The positive findings for chemotherapy in this trial contrast with negative findings of similar trials that have been conducted in Western countries, Dr. Bang acknowledged. He speculated that small sample sizes (which limit statistical power) and the lesser extent of surgery in the latter trials explain the difference.

"We need some kind of good surgery to prove the effect of adjuvant chemotherapy," he elaborated on the latter point. "For patients who receive [inadequate] surgery, we may need radiotherapy to compensate" for any remaining locoregional disease."

Another recent adjuvant trial, ACTS-GC (Adjuvant Chemotherapy for Gastric Cancer With S-1), which was conducted in Japan, found that monotherapy with S-1 (an oral fluoropyrimidine that has not been approved in the United States) provided similar benefit (NEJM 2007;357:1810-20), an attendee pointed out. Should oncologists select S-1 or XELOX, and is a randomized, head-to-head comparison warranted?

"It is impossible to compare the results of this study with that of ACTS-GC," asserted Dr. Bang, an oncologist at Seoul (South Korea) National University. But he did note that in the ACTS-GC trial, the benefit for patients with stage III disease was uncertain.

"So at this time, my suggestion is we can consider doublet [XELOX] especially for stage III patients," he said. "I don’t want to do another study comparing S-1 and XELOX because we have to move forward."

Discussant Dr. Florian Lordick, an oncologist with the Klinikum Braunschweig (Germany), said that a key question is whether the CLASSIC trial results can be transferred to Western countries. "I would answer [that] there are some caveats," he commented.

Those caveats include the comparatively older age of patients with gastric cancer in Western countries, which might reduce tolerance for adjuvant chemotherapy; the greater prevalence of proximal cancers, for which neoadjuvant chemotherapy has shown benefit; and the less-frequent use of D2 resection.

"D2 resection was mandatory in the CLASSIC trial, and a median of 42 lymph nodes – I repeat, 42 lymph nodes – [was] examined. ... This is not uniformly the standard in many Western centers," he pointed out. For example, in the U.S. Intergroup 0116 and U.K. MAGIC trials in gastric cancer, only 10% and 41% of resections, respectively, were D2 resections.

"So one could ask the question, does the surgical approach determine the optimal adjuvant treatment strategy?" Dr. Lordick said. "We have seen compelling results for adjuvant chemotherapy following radical resection, D2 resection, which is the standard of care in Asia. For those centers that perform more subradical resection ... the addition of adjuvant radiation makes sense."

Patients were eligible for the CLASSIC trial if they had stage II, IIIA, or IIIB gastric cancer, had undergone a D2 dissection in the preceding 6 weeks with neither macroscopic nor microscopic evidence of residual disease, and had not received any chemotherapy or radiation therapy.

Sufficiency of extent of surgery was rigorously ensured through quality assurance meetings, the use of a standard operating procedure for surgical technique, and a requirement of photographic documentation, Dr. Bang noted.

The patients were assigned in nearly equal numbers to observation or eight cycles (6 months) of the XELOX regimen, consisting of capecitabine (Xeloda) 1,000 mg/m² b.i.d on days 1-14 plus oxaliplatin (Eloxatin) 130 mg/m² on day 1 of 3-week cycles.

"We chose 3-year disease-free survival as our primary end point because most relapses in gastric cancer occur within 2 or 3 years, and the survival after relapse is around 1 year," he commented. "In addition, there is evidence that 3-year disease-free survival is a surrogate end point for 5-year overall survival."

The patients had a median age of about 56 years, and 71% were male. The median time between surgery and randomization was 1.12 months.

At the trial’s preplanned interim analysis, the median follow-up was 34.4 months. The median number of cycles of therapy received was eight for both capecitabine and oxaliplatin. The median dose intensity was 85% and 98%, respectively.

"The safety of adjuvant XELOX in gastric cancer was consistent with the known safety profile of XELOX, with no new or unexpected findings," Dr. Bang reported. The rate of grade 3/4 adverse events was 54% in the XELOX arm and 6% in the observation arm. Two patients in the former arm died of treatment-related causes.

In intention-to-treat analyses, the 3-year rate of disease-free survival benefit was apparent. "The two curves separated early and the difference was well maintained," he commented.

In subgroup analyses, hazard ratios consistently favored XELOX. Analyses according to histologic tumor type are still ongoing, but HER2 testing was not done in the study.

There was also a trend toward a better 3-year rate of overall survival with XELOX (HR, 0.74; P = .0775). "The overall survival curves started to separate at 24 months; however, at this time point, the data are not mature enough," he said. "Longer follow-up is needed to determine the effect of adjuvant XELOX on overall survival."

The trial was sponsored by Sanofi-Aventis and Roche. Dr. Bang reported that he is a consultant to and receives honoraria from Roche. Dr. Lordick reported that he is a consultant to Amgen and Ganymed; receives honoraria from Amgen, Fresenius, Merck Serono, Pfizer, and Roche; and receives research funding from Fresenius, GlaxoSmithKline, Merck Serono, and Sanofi-Aventis.

CHICAGO – Patients with gastric cancer have better outcomes if they are given adjuvant capecitabine plus oxaliplatin after undergoing curative resection that includes an extended lymph-node dissection, according to results of the CLASSIC trial from China, South Korea, and Taiwan

Investigators randomized 1,035 patients to either simple observation or XELOX (the combination of capecitabine plus oxaliplatin) after surgery. A full analysis was performed early because of interim efficacy findings in favor of the chemotherapy.

Trial results, which were reported at the annual meeting of the American Society of Clinical Oncology, showed that patients in the XELOX arm had a 44% reduction in the risk of recurrence. Their 3-year, disease-free survival rate (the primary end point) was 74%, compared with 60% in the observation-only group (hazard ratio, 0.56; P less than .0001). The benefit was similar across patients with stage II, IIIA, and IIIB disease.

Additionally, early data showed a 26% reduction in the 3-year risk of death, though the latter is not yet statistically significant.

"The CLASSIC [Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer] trial met its primary end point," said Dr. Yung-Jue Bang, presenting findings on behalf of his coinvestigators. "CLASSIC demonstrates superior efficacy of adjuvant XELOX vs. observation alone following D2 [extended] lymph-node dissection. The data presented support the use of adjuvant XELOX for gastric cancer."

The positive findings for chemotherapy in this trial contrast with negative findings of similar trials that have been conducted in Western countries, Dr. Bang acknowledged. He speculated that small sample sizes (which limit statistical power) and the lesser extent of surgery in the latter trials explain the difference.

"We need some kind of good surgery to prove the effect of adjuvant chemotherapy," he elaborated on the latter point. "For patients who receive [inadequate] surgery, we may need radiotherapy to compensate" for any remaining locoregional disease."

Another recent adjuvant trial, ACTS-GC (Adjuvant Chemotherapy for Gastric Cancer With S-1), which was conducted in Japan, found that monotherapy with S-1 (an oral fluoropyrimidine that has not been approved in the United States) provided similar benefit (NEJM 2007;357:1810-20), an attendee pointed out. Should oncologists select S-1 or XELOX, and is a randomized, head-to-head comparison warranted?

"It is impossible to compare the results of this study with that of ACTS-GC," asserted Dr. Bang, an oncologist at Seoul (South Korea) National University. But he did note that in the ACTS-GC trial, the benefit for patients with stage III disease was uncertain.

"So at this time, my suggestion is we can consider doublet [XELOX] especially for stage III patients," he said. "I don’t want to do another study comparing S-1 and XELOX because we have to move forward."

Discussant Dr. Florian Lordick, an oncologist with the Klinikum Braunschweig (Germany), said that a key question is whether the CLASSIC trial results can be transferred to Western countries. "I would answer [that] there are some caveats," he commented.

Those caveats include the comparatively older age of patients with gastric cancer in Western countries, which might reduce tolerance for adjuvant chemotherapy; the greater prevalence of proximal cancers, for which neoadjuvant chemotherapy has shown benefit; and the less-frequent use of D2 resection.

"D2 resection was mandatory in the CLASSIC trial, and a median of 42 lymph nodes – I repeat, 42 lymph nodes – [was] examined. ... This is not uniformly the standard in many Western centers," he pointed out. For example, in the U.S. Intergroup 0116 and U.K. MAGIC trials in gastric cancer, only 10% and 41% of resections, respectively, were D2 resections.

"So one could ask the question, does the surgical approach determine the optimal adjuvant treatment strategy?" Dr. Lordick said. "We have seen compelling results for adjuvant chemotherapy following radical resection, D2 resection, which is the standard of care in Asia. For those centers that perform more subradical resection ... the addition of adjuvant radiation makes sense."

Patients were eligible for the CLASSIC trial if they had stage II, IIIA, or IIIB gastric cancer, had undergone a D2 dissection in the preceding 6 weeks with neither macroscopic nor microscopic evidence of residual disease, and had not received any chemotherapy or radiation therapy.

Sufficiency of extent of surgery was rigorously ensured through quality assurance meetings, the use of a standard operating procedure for surgical technique, and a requirement of photographic documentation, Dr. Bang noted.

The patients were assigned in nearly equal numbers to observation or eight cycles (6 months) of the XELOX regimen, consisting of capecitabine (Xeloda) 1,000 mg/m² b.i.d on days 1-14 plus oxaliplatin (Eloxatin) 130 mg/m² on day 1 of 3-week cycles.

"We chose 3-year disease-free survival as our primary end point because most relapses in gastric cancer occur within 2 or 3 years, and the survival after relapse is around 1 year," he commented. "In addition, there is evidence that 3-year disease-free survival is a surrogate end point for 5-year overall survival."

The patients had a median age of about 56 years, and 71% were male. The median time between surgery and randomization was 1.12 months.

At the trial’s preplanned interim analysis, the median follow-up was 34.4 months. The median number of cycles of therapy received was eight for both capecitabine and oxaliplatin. The median dose intensity was 85% and 98%, respectively.

"The safety of adjuvant XELOX in gastric cancer was consistent with the known safety profile of XELOX, with no new or unexpected findings," Dr. Bang reported. The rate of grade 3/4 adverse events was 54% in the XELOX arm and 6% in the observation arm. Two patients in the former arm died of treatment-related causes.

In intention-to-treat analyses, the 3-year rate of disease-free survival benefit was apparent. "The two curves separated early and the difference was well maintained," he commented.

In subgroup analyses, hazard ratios consistently favored XELOX. Analyses according to histologic tumor type are still ongoing, but HER2 testing was not done in the study.

There was also a trend toward a better 3-year rate of overall survival with XELOX (HR, 0.74; P = .0775). "The overall survival curves started to separate at 24 months; however, at this time point, the data are not mature enough," he said. "Longer follow-up is needed to determine the effect of adjuvant XELOX on overall survival."

The trial was sponsored by Sanofi-Aventis and Roche. Dr. Bang reported that he is a consultant to and receives honoraria from Roche. Dr. Lordick reported that he is a consultant to Amgen and Ganymed; receives honoraria from Amgen, Fresenius, Merck Serono, Pfizer, and Roche; and receives research funding from Fresenius, GlaxoSmithKline, Merck Serono, and Sanofi-Aventis.

CHICAGO – Patients with gastric cancer have better outcomes if they are given adjuvant capecitabine plus oxaliplatin after undergoing curative resection that includes an extended lymph-node dissection, according to results of the CLASSIC trial from China, South Korea, and Taiwan

Investigators randomized 1,035 patients to either simple observation or XELOX (the combination of capecitabine plus oxaliplatin) after surgery. A full analysis was performed early because of interim efficacy findings in favor of the chemotherapy.

Trial results, which were reported at the annual meeting of the American Society of Clinical Oncology, showed that patients in the XELOX arm had a 44% reduction in the risk of recurrence. Their 3-year, disease-free survival rate (the primary end point) was 74%, compared with 60% in the observation-only group (hazard ratio, 0.56; P less than .0001). The benefit was similar across patients with stage II, IIIA, and IIIB disease.

Additionally, early data showed a 26% reduction in the 3-year risk of death, though the latter is not yet statistically significant.

"The CLASSIC [Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer] trial met its primary end point," said Dr. Yung-Jue Bang, presenting findings on behalf of his coinvestigators. "CLASSIC demonstrates superior efficacy of adjuvant XELOX vs. observation alone following D2 [extended] lymph-node dissection. The data presented support the use of adjuvant XELOX for gastric cancer."

The positive findings for chemotherapy in this trial contrast with negative findings of similar trials that have been conducted in Western countries, Dr. Bang acknowledged. He speculated that small sample sizes (which limit statistical power) and the lesser extent of surgery in the latter trials explain the difference.

"We need some kind of good surgery to prove the effect of adjuvant chemotherapy," he elaborated on the latter point. "For patients who receive [inadequate] surgery, we may need radiotherapy to compensate" for any remaining locoregional disease."

Another recent adjuvant trial, ACTS-GC (Adjuvant Chemotherapy for Gastric Cancer With S-1), which was conducted in Japan, found that monotherapy with S-1 (an oral fluoropyrimidine that has not been approved in the United States) provided similar benefit (NEJM 2007;357:1810-20), an attendee pointed out. Should oncologists select S-1 or XELOX, and is a randomized, head-to-head comparison warranted?

"It is impossible to compare the results of this study with that of ACTS-GC," asserted Dr. Bang, an oncologist at Seoul (South Korea) National University. But he did note that in the ACTS-GC trial, the benefit for patients with stage III disease was uncertain.

"So at this time, my suggestion is we can consider doublet [XELOX] especially for stage III patients," he said. "I don’t want to do another study comparing S-1 and XELOX because we have to move forward."

Discussant Dr. Florian Lordick, an oncologist with the Klinikum Braunschweig (Germany), said that a key question is whether the CLASSIC trial results can be transferred to Western countries. "I would answer [that] there are some caveats," he commented.

Those caveats include the comparatively older age of patients with gastric cancer in Western countries, which might reduce tolerance for adjuvant chemotherapy; the greater prevalence of proximal cancers, for which neoadjuvant chemotherapy has shown benefit; and the less-frequent use of D2 resection.

"D2 resection was mandatory in the CLASSIC trial, and a median of 42 lymph nodes – I repeat, 42 lymph nodes – [was] examined. ... This is not uniformly the standard in many Western centers," he pointed out. For example, in the U.S. Intergroup 0116 and U.K. MAGIC trials in gastric cancer, only 10% and 41% of resections, respectively, were D2 resections.

"So one could ask the question, does the surgical approach determine the optimal adjuvant treatment strategy?" Dr. Lordick said. "We have seen compelling results for adjuvant chemotherapy following radical resection, D2 resection, which is the standard of care in Asia. For those centers that perform more subradical resection ... the addition of adjuvant radiation makes sense."

Patients were eligible for the CLASSIC trial if they had stage II, IIIA, or IIIB gastric cancer, had undergone a D2 dissection in the preceding 6 weeks with neither macroscopic nor microscopic evidence of residual disease, and had not received any chemotherapy or radiation therapy.

Sufficiency of extent of surgery was rigorously ensured through quality assurance meetings, the use of a standard operating procedure for surgical technique, and a requirement of photographic documentation, Dr. Bang noted.

The patients were assigned in nearly equal numbers to observation or eight cycles (6 months) of the XELOX regimen, consisting of capecitabine (Xeloda) 1,000 mg/m² b.i.d on days 1-14 plus oxaliplatin (Eloxatin) 130 mg/m² on day 1 of 3-week cycles.

"We chose 3-year disease-free survival as our primary end point because most relapses in gastric cancer occur within 2 or 3 years, and the survival after relapse is around 1 year," he commented. "In addition, there is evidence that 3-year disease-free survival is a surrogate end point for 5-year overall survival."

The patients had a median age of about 56 years, and 71% were male. The median time between surgery and randomization was 1.12 months.

At the trial’s preplanned interim analysis, the median follow-up was 34.4 months. The median number of cycles of therapy received was eight for both capecitabine and oxaliplatin. The median dose intensity was 85% and 98%, respectively.

"The safety of adjuvant XELOX in gastric cancer was consistent with the known safety profile of XELOX, with no new or unexpected findings," Dr. Bang reported. The rate of grade 3/4 adverse events was 54% in the XELOX arm and 6% in the observation arm. Two patients in the former arm died of treatment-related causes.

In intention-to-treat analyses, the 3-year rate of disease-free survival benefit was apparent. "The two curves separated early and the difference was well maintained," he commented.

In subgroup analyses, hazard ratios consistently favored XELOX. Analyses according to histologic tumor type are still ongoing, but HER2 testing was not done in the study.

There was also a trend toward a better 3-year rate of overall survival with XELOX (HR, 0.74; P = .0775). "The overall survival curves started to separate at 24 months; however, at this time point, the data are not mature enough," he said. "Longer follow-up is needed to determine the effect of adjuvant XELOX on overall survival."

The trial was sponsored by Sanofi-Aventis and Roche. Dr. Bang reported that he is a consultant to and receives honoraria from Roche. Dr. Lordick reported that he is a consultant to Amgen and Ganymed; receives honoraria from Amgen, Fresenius, Merck Serono, Pfizer, and Roche; and receives research funding from Fresenius, GlaxoSmithKline, Merck Serono, and Sanofi-Aventis.