Irinotecan is inactive as a first-line treatment, but plays an important part in gastric cancer treatment

Abstract

Based on the results of the GC0301/TOP002 (S-1 versus irinotecan plus S-1) randomized control study, which were reported in this journal–Gastric Cancer [1]–can we conclude that irinotecan is not important in gastric cancer treatment? Currently, the answer to this question may be ‘‘yes’’, because irinotecan-based regimens did not meet any primary endpoint as a first-line treatment in three randomized control studies, including the GC0301/TOP002 study [1–3]. When these clinical studies were planned, standard treatment in the field of gastric cancer was absent; there was no appropriate, universal control. At that time, the National Comprehensive Cancer Network proposed 5-fluorouracil (FU)-based or cisplatin-based combinations as acceptable standard therapy. 5-FU alone or S-1 (an oral fluoropyrimidine) was standard therapy in Japan, but 5-FU plus cisplatin (CF) was also used frequently. CF was frequently employed in Korea, Japan, many South American countries, and many European countries. Epirubicin plus CF (ECF) was considered the standard in a few European countries and possibly in Canada. Thus, a 5-FU-based or cisplatin-based combination was an appropriate control in the West and, for that matter, in most of the world. Based on this background, the control arms varied among studies. Three randomized control studies (1 in Europe/the United States, 2 in Japan) were conducted to verify the efficacy of irinotecan-based regimens as a first-line treatment. A study in Europe and the United States was first reported. In these countries, irinotecan was emphasized as a new active agent for gastric cancer. This study was planned as a phase II/III trial [1]. In the phase II part, irinotecan combined with an infusional 5-FU Arbeitsgemeinschaft Internistische Onkologie (AIO) regimen [irinotecan/5-FU (IF)] was selected over irinotecan combined with cisplatin on the basis of the risk/benefit ratio. At the time, the IF regimen was considered to be the most active irinotecan-based regimen available in the West. In the phase III part, the usefulness of IF in comparison with CF was examined with respect to the time to progression (TTP) as a primary endpoint. When reviewing the antitumor effects of IF and CF in this study, the response rates (RRs) were 31.8 and 25.8%, respectively. The TTP was 5.0 and 4.2 months, respectively. The median survival time (MST) was 9.0 and 8.7 months, respectively. The toxicity profile of IF was also markedly more favorable than that of CF. However, with respect to the primary endpoint, TTP, the usefulness of IF in comparison with CF could not be demonstrated. In the protocol, it was also impossible to verify the non-inferiority of IF. Based on the results of this study, IF may not become a standard regimen for first-line treatment; the first study was unsuccessful in the West. Combination therapy with irinotecan and cisplatin (IC) was initially investigated as a first-line treatment in the JCOG9912 study, which was conducted by the Japan Clinical Oncology Group (JCOG); in this study, the usefulness of combination therapy with IC in comparison with the continuous intravenous infusion of 5-FU (5-FUci) was examined [2]. The RR and time to treatment failure (TTF) were significantly more favorable with IC. However, with respect to the primary endpoint, overall survival (OS), the usefulness of combination therapy with IC in comparison with 5-FUci was not demonstrated to be statistically significant (p = 0.055). Clinical studies not only in Europe and the United States but also in Japan failed to propose combination therapy with IC as a standard treatment. When reviewing the survival curve for this combination therapy