Randomized phase II study of second-line chemotherapy with the best available 5-fluorouracil regimen versus weekly administration of paclitaxel in far advanced gastric cancer with severe peritoneal metastases refractory to 5-fluorouracil-containing regimens (JCOG0407)

Abstract

Background This randomized phase II study compared weekly administration of paclitaxel (wPTX) with the best available 5-fluorouracil (5-FU) regimen as second-line treatment for advanced gastric cancer patients with severe peritoneal metastasis refractory to fluoropyrimidine. Methods In the best available 5-FU arm, continuous infusion of 5-FU (800 mg/m 2 /day, days 1-5, every 4 weeks) was given to patients with prior chemotherapy including bolus 5-FU, and methotrexate and 5-FU sequential bolus injection (methotrexate at 100 mg/m 2 followed by bolus 5-FU at 600 mg/m 2 with leucovorin, weekly) was given to those who had previously received continuous infusion of 5-FU or oral administration of fluoropyrimidine. In the wPTX arm, paclitaxel (80 mg/m 2 ) was administered on days 1, 8, and 15, every 4 weeks. This study adopted a screening design (one-sided a = 30 %) with the primary end point of overall survival. Results One hundred patients were randomized to the 5-FU arm (n = 49) or the wPTX arm (n = 51). Although the median survival time was 7.7 months in both arms, the 2-year survival rates were 2.9 % in the 5-FU arm and 9.1 % in the wPTX arm [hazard ratio 0.89 (95 % confidence interval 0.57-1.38), one-sided p = 0.298}. The median progression-free survival was longer with wPTX than with 5-FU [3.7 months vs 2.4 months; hazard ratio 0.58 (95 % confidence interval 0.38-0.88), one-sided The incidences of grade 4 neutropenia, grade 3/4 febrile neutropenia, diarrhea, and treatment-related death were 6 %, 4 %, 10 %, and 2 %, respectively, in the 5-FU arm and 2 %, 0 %, 0 %, and 0 %, respectively, in the wPTX arm. ConclusionsAs second-line chemotherapy, wPTX appears feasible and promising. This regimen can be included in a test arm in future phase III trials for treatment of advanced gastric cancer with severe peritoneal metastasis.

Japanese gastric cancer treatment guidelines 2014 (ver. 4)

“…In a randomized phase II trial comparing second-line treatment by weekly administration of paclitaxel with the best available 5FU (either 5FUci or MTX + 5FU, which was not used in the first-line treatment) in patients with peritoneal metastases, a benefit in progression-free survival was proven, but no difference was detected in overall survival. However, paclitaxel was associated with a more favorable toxicity profile [54]. These results indicate that weekly paclitaxel can be considered for patients with severe peritoneal disease in both the first- and second-line setting.…”

Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated advanced gastric cancer: an exploratory analysis of the phase III ABSOLUTE trial

“…Moreover, the frequency of peritoneal metastasis increases with the clinical course; it is more common in pretreated patients with AGC than in chemotherapy-naïve patients. Several phase II trials showed the promising efficacy of w-sb-PTX for patients with AGC with peritoneal metastasis [2,3]. A subgroup analysis of the ABSOLUTE trial suggested that w-nab-PTX showed more favorable efficacy than w-sb-PTX in patients with peritoneal metastasis.…”

Second-line chemotherapy using taxane in patients with advanced gastric cancer who presented with severe peritoneal metastasis: A multicenter retrospective study

“…As shown in the RAINBOW trial, the combination therapy of paclitaxel and ramucirumab, which targets vascular endothelial growth factor receptor-2, has been established as a new standard second-line treatment for AGC [5]. In patients with mild to moderate PM, the administration of paclitaxel weekly is considered a promising treatment that results in longer progression-free survival (PFS) compared with the best available 5-FU regimen in the Japan Clinical Oncology Group (JCOG) 0407 trial [15]. However, to date, there are only few data about the use of second-line chemotherapy in patients with SPM.…”