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The Treatment of Advanced Gastric Cancer: In Search of the Right Combination

Dana-Farber Cancer Institute, Boston, MA

ASSESSING THE EFFICACY of combination chemotherapy in advanced gastric cancer has been a frustrating exercise. Enthusiasm for many chemotherapy regimens, initially stimulated by promising results in phase II studies, has subsequently waned after these regimens were more objectively evaluated in randomized trials. The report from Vanhoefer et al¹ in this issue is no exception to this pattern. These investigators compared three commonly used regimens for the treatment of gastric cancer: fluorouracil, doxorubicin, and methotrexate (FAMTX); etoposide, leucovorin, and bolus fluorouracil (ELF); and infusional fluorouracil plus cisplatin (FUP). The results of this trial are on the one hand disappointing. Only modest activity was observed for all three regimens, and no single-drug combination was associated with a survival advantage when compared with the others. By objectively demonstrating the limitations of these regimens, however, this trial provides useful information and will be helpful in planning future studies in the treatment of this malignancy.

Interest in combination therapy for gastric cancer began with the realization that single agents have only modest activity against this disease. Fluorouracil, doxorubicin, mitomycin, and cisplatin have all been extensively evaluated in gastric cancer and have been associated with response rates of only approximately 20%.^2-10 In the late 1970s, a three-drug combination consisting of fluorouracil, doxorubicin, and mitomycin (FAM) was initially associated with a response rate in excess of 40%.¹¹ However, the efficacy of this regimen was called into question when, in 1985, the North Central Cancer Treatment Group demonstrated equivalent response rates and overall survival times for patients treated with either FAM or fluorouracil alone.¹² A second trial, performed by the Sydney Cooperative Oncology Group, found no survival differences between patients randomized to receive a three-drug combination of fluorouracil, doxorubicin, and carmustine (FAB) or doxorubicin alone and led many to question the value of combination chemotherapy in gastric cancer.³

The failure of FAM and FAB to provide any advantage over single-agent therapy led to interest in the development of new, potentially more effective regimens. This goal proved elusive, as high initial response rates in phase II trials dropped dramatically when these regimens were subjected to the scrutiny of larger studies and randomized trials. The FAMTX regimen uses high-dose methotrexate followed by fluorouracil given in combination with doxorubicin. FAMTX therapy was initially reported to lead to significant tumor regression in 58% of patients; however, subsequent studies demonstrated more modest response rates of only 30% to 40%.^13-18 The combination of etoposide, doxorubicin, and cisplatin (EAP) was associated with a response rate of 64% in an early phase II trial.¹⁹ In randomized studies, however, EAP resulted in significantly lower response rates and was associated with a high rate of toxic deaths.^18,20 The ELF regimen was developed in response to the significant toxicity observed with EAP and was first used in patients who were either older than 65 years of age or had cardiac disease. Although initially associated with a response rate of 53%, subsequent studies again found this regimen to be less active and called into question its value.^21-23

These unimpressive results led some investigators to question whether chemotherapy was of any worthwhile benefit at all in patients with metastatic gastric cancer. Three small, randomized studies compared therapy with either FAMTX; fluorouracil, epirubicin, and methotrexate (FEMTX); or ELF to best supportive care.^24-26 Although these trials comprised only a limited number of patients, all three demonstrated a significant survival benefit associated with the use of systemic chemotherapy. These studies dispelled the impending threat of nihilism and provided strong evidence for the use of systemic chemotherapy in the treatment of patients with this disease.

It has been more difficult to assess which of the many available combination regimens is most efficacious, although several have been compared in a randomized manner. In one such trial, the European Organization for Research and Treatment of Cancer (EORTC) compared FAM with FAMTX. Objective response rates were significantly better in the FAMTX group (41%) compared with the FAM group (9%); moreover, the median survival for patients receiving FAMTX (42 weeks) was also superior to that for patients receiving FAM (29 weeks).¹⁷ The relatively high response rate associated with FAMTX and the low response rate associated with FAM in this trial were surprising; nevertheless, FAMTX became the standard comparison arm for future trials.

The present EORTC trial¹ compares FAMTX with two other commonly used regimens, ELF and FUP. In contrast to earlier trials, the response rate associated with FAMTX in the current study is only 12%. This low response rate can be partially explained by the fact that only 57% of the patients assigned to this form of treatment received the intended dose of doxorubicin. Dose reductions or delays were also necessary in 41% of patients receiving ELF and in 42% of patients receiving FUP, which perhaps explains the lack of efficacy observed with these regimens. Interestingly, the median survival times associated with FAMTX (6.7 months), ELF (7.2 months), and FUP (7.2 months) are similar not only to each other but also to those reported in other trials with these regimens. The results of the EORTC trial may therefore accurately reflect the efficacy of these regimens in a general population.

Recently, the combination of epirubicin, cisplatin, and fluorouracil given as a prolonged infusion (ECF) was associated with a response rate of 71% in a phase II trial of 128 patients.²⁷ This encouraging response rate led to a randomized trial of 274 patients in which ECF was compared with FAMTX.²⁸ The response rate for ECF (45%) in this study was found to be superior to that of FAMTX (21%). The median survival duration of patients receiving ECF (8.9 months) was also superior to that of those receiving FAMTX (5.7 months). The results of this trial raise an interesting paradox: why has one platinum/fluorouracil-containing regimen (ECF) been found to be superior to FAMTX, whereas another (FUP) has now been found to offer little benefit? One explanation, pointed out by Vanhoefer et al,¹ may be differences in the patient populations in the two trials. It is also possible, however, that the superiority of ECF is due to the addition of epirubicin to platinum and fluorouracil or to the use of fluorouracil as a prolonged intravenous infusion in this regimen.

The current EORTC trial¹ lays important groundwork for future clinical trials in advanced gastric cancer. The low activity and equivalent survival times associated with all three arms support the authors’ conclusion that none of these regimens should be considered standard therapy for advanced gastric cancer. These findings allow us to close the chapter on ELF, FUP, and FAMTX as reference arms in future trials. The ECF regimen, although currently considered by many to be the standard of care, has only been evaluated in one randomized trial and bears further investigation. Several newer agents, including the taxanes and irinotecan, have activity in advanced gastric cancer and have yet to be evaluated as part of combination regimens in the randomized setting. With the continued development of new, promising agents, we can now look forward to more rapid progress in the treatment of metastatic gastric cancer.

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