Randomized Phase III Study of 5-Fluorouracil Continuous Infusion vs. Sequential Methotrexate and 5-Fluorouracil Therapy in Far Advanced Gastric Cancer with Peritoneal Metastasis (JCOG0106)

Abstract

Objective: Owing to the risks of serious and sustained toxicity, anticancer drugs such as cisplatin and irinotecan cannot be readily administered to patients with gastric cancer and severe peritoneal metastasis. Therefore, a standard chemotherapy regimen has yet to be established for these types of patients. This randomized study investigated the utility of sequential methotrexate and 5-fluorouracil therapy vs. 5-fluorouracil continuous infusion for gastric cancer with peritoneal metastasis. Methods: Eligible patients had radiologically confirmed peritoneal metastasis with intestinal stenosis, peritoneal tumor or ascites. Treatment with 5-fluorouracil continuous infusion (800 mg/m 2 /day, ci, d1-5, q4w) or methotrexate and 5-fluorouracil therapy (methotrexate, 100 mg/m 2 , bolus infusion, followed 3 h later by 5-fluorouracil, 600 mg/m 2 , bolus infusion, with leucovorin rescue, q1w) was continued until disease progression or unacceptable toxicity. The projected sample size was 236, providing 80% power to detect a 40% increase in median overall survival in methotrexate and 5-fluorouracil therapy with a one-sided a of 0.05. Results: All 237 randomized patients were included in the primary analysis. The methotrexate and 5-fluorouracil therapy arm was not superior to the 5-fluorouracil continuous infusion arm (median survival time, 9.4 months in the 5-fluorouracil continuous infusion arm, 10.6 months in the methotrexate and 5-fluorouracil therapy arm; hazard ratio, 0.94; 95% confidence interval, 0.72 -1.22; one-sided P ¼ 0.31). Frequencies of Grade 3 or higher neutropenia, Grade 3 or higher anorexia and treatment-related deaths were 0.9, 27.4 and 1.7%, respectively, in the 5-fluorouracil continuous infusion arm, and 31.9, 33.6 and 0.9%, respectively, in the methotrexate and 5-fluorouracil therapy arm. Conclusions: Methotrexate and 5-fluorouracil therapy is not suitable for use as standard therapy for advanced gastric cancer with peritoneal metastasis.

Conversion therapy for inoperable advanced gastric cancer patients by docetaxel, cisplatin, and S-1 (DCS) chemotherapy: a multi-institutional retrospective study

“…In group 2 patients, peritoneal metastasis is the most common non-curative factor for gastric cancer and is known to be relatively resistant to systemic chemotherapy. In fact, the MST in patients with peritoneal metastasis was reportedly only about 10 months in the JCOG 0106 study, using 5-FU plus methotrexate or 5-FU alone [31]. The DCS regimen, in which three effective drugs are administered as frontline treatment, is considered to be effective and feasible for the treatment of patients with peritoneal metastasis, because S-1 contains a dihydropyrimidine dehydrogenase inhibitor, which may be preferable for the treatment of peritoneal metastases, as these are commonly associated with high dihydropyrimidine dehydrogenase activity [32].…”

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)

“…The Japan Clinical Oncology Group (JCOG) conducted a randomized phase III study (JCOG0106) of 5-fluorouracil (5-FU) continuous infusion (5-FUci) versus sequential methotrexate (MTX) and 5-FU therapy in patients having AGC with PM and concluded that 5-FUci, which is one of the most feasible regimens, is the standard first-line chemotherapy for such patients [9]. Many of these patients have some complications that adversely affect their general condition and, thereby, make it difficult to perform chemotherapy, especially after failure of first-line chemotherapy.…”

Survival outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis from gastric cancer: a systematic review

“…Hence, the response rates of patients with peritoneal only disease is about 14 % to 25% [13,50,51]. The median survival of patients with PC undergoing palliative chemotherapy is 9.5 to 12 months [52,53]. The SRC histology portends a worse prognosis.…”