FOLFIRI Alternate With FOLFOX in Untreated Metastatic Gastric and Esophageal Adenocarcinoma. The LOGIC Study

1. Current Knowledge and Rationale Gastro-esophageal (GE) cancers are a highly aggressive disease and are one of the major causes of cancer-related death in the world. Despite improvements in surgical and radiation techniques and the availability of newer agents, the prognosis of recurrent GE cancers remains very poor (1-4). GE cancers comprise one of the solid organ cancers with a high fatality rate. Although 5,600 (2.8%) of the estimated 196,900 newly diagnosed cancers in Canada in 2015 were GE cancer, 4,100 (5.2%) of the 78,000 cancer related deaths were from GE cancers (3). The need for novel strategies to improve current therapy is therefore vital in the management of GE cancer.

In many clinical trials, the treatment of metastatic gastric and esophageal cancers has merged, and the majority of patients with gastric, esophageal, or GE cancers are treated with a parallel chemotherapeutic regimens. The goal of treatment in patients with metastatic GE cancer is to control the disease, to maintain or improve quality of life, and to prolong survival. In a meta-analysis of three trials comparing chemotherapy versus best supportive care, there was a significant benefit in overall survival in favor of chemotherapy (hazard ratio [HR] 0.37; 95% CI 0.24 -0.55) (5). Hence, chemotherapy should be considered for patients with appropriate performance status.

In general combination chemotherapy has been associated with higher response rates, and better progression free survival (PFS), and overall survival (OS) compared with single agent chemotherapy. For most patients with GE cancers combination chemotherapy represents the standard of care.

The ECF (epirubicin, cisplatin, 5-fluorouracil) remains one of the reference regimens for the first-line treatment of metastatic GE cancers. However, when both oxaliplatin (O) and capecitabine (X) are substituted for cisplatin (C) and 5FU (F), respectively in the ECF regimen (EOX, EOF, ECX), outcomes are at least as good as with ECF (6). FOLFOX has also been compared to ECF with comparable results. An intergroup phase 2 trial evaluated ECF, irinotecan and cisplatin (IC), or FOLFOX in combination with cetuximab, and concluded that response rates, PFS, and median OS were comparable in the ECF and FOLFOX groups. FOLFOX-based regimen required fewer treatment modifications compared with other regimens (7).

Irinotecan-based regimens also appeared to be superior to cisplatin/5FU in response rates and survival being in the 10-12 month range (8,9). A randomized phase 3 trial evaluated 416 patients with advanced gastric or esophagogastric junction (EGJ) adenocarcinoma who were assigned to either FOLFIRI or ECX (10). There were no significant differences in median PFS, OS, or response rates between the two regimens. Time to treatment failure favored FOLFIRI (5.1 versus 4.2 months). Furthermore, FOLFIRI was better tolerated overall (rate of grade 3 or 4 toxicity 69 versus 84% with ECX). Although docetaxel based regimens such as DCF have shown significant improvement in response, PFS, and OS compared to cisplatin/5-FU, it is a more toxic regimen with a higher rates of grade 3 or 4 toxicities and is not commonly used in Canada (11-13).