Chemotherapy for Gastric Carcinoma: New and Old Options

Introduction

Gastric carcinoma is a major health problem around the world. Its incidence, however, has steadily dropped globally since World War II. This decreased incidence has been termed an “unplanned success.” Although the incidence of gastric cancer is lowest in North America, it still ranks as the eighth leading cause of cancer death in the United States. In 1998, more than 22,600 new cases of gastric cancer are expected to occur in the United States, and 13,700 deaths are anticipated as a result.[1] Patients with gastric carcinoma often present with advanced disease, because early detection is neither practiced nor possible in many countries. Screening for early detection of gastric cancer is carried out on a limited basis in Japan. Approximately 50% of patients are diagnosed with unresectable, locally advanced, or metastatic cancer. Median survival for patients with advanced disease ranges from 6 to 10 months.[2]

Although advanced gastric cancer is not curable, chemotherapy can have a palliative effect in symptomatic patients. In four randomized studies comparing combination chemotherapy with best supportive care in patients with advanced gastric carcinoma, quality of life and overall survival improved in patients receiving chemotherapy.[3-6] All four of these studies, however, were limited by small numbers of patients.

Single-Agent Therapy

Few drugs are active when used as single agents to treat gastric cancer. Response rates are usually £ 20%, with rare complete remissions and brief response durations. The pyrimidine analogue 5-fluorouracil (5-FU) has been studied most extensively, producing a response rate of less than 20%.[7] Other agents such as mitomycin(Drug information on mitomycin),[7] etoposide(Drug information on etoposide),[8] and cisplatin(Drug information on cisplatin)[9] are also considered active, producing response rates of approximately < 20% when used as single agents.

Randomized Studies

In the early 1980s, the FAM (5-FU, doxorubicin(Drug information on doxorubicin), mitomycin) regimen was considered the gold standard for treatment of patients with advanced gastric carcinoma. In a revealing study performed by the North Central Cancer Therapy Group (NCCTG),[10] the FAM regimen was compared with single-agent 5-FU and 5-FU plus doxorubicin. No significant survival difference was detected among the three regimens; however, response rates were higher in patients receiving more than one agent (highest response rate seen with FAM, and higher response rate with 5-FU/doxorubicin than with 5-FU alone). These results suggest that combination chemotherapy is more appropriate than single-agent therapy for palliative treatment.

Several randomized studies, comparing FAM with FAMTX (5-FU, doxorubicin, methotrexate(Drug information on methotrexate)),[11] FAMTX with ECF (epirubicin, cisplatin, 5-FU),[12] and FAMTX vs ELF (etoposide, leucovorin, 5-FU) vs 5-FU/cisplatin have been reported.[13] No one standard therapy has emerged from these trials. The ECF regimen, which produced the best response rates in the most recent comparison, has not been widely accepted as standard therapy because it includes an experimental agent (epirubicin) and uses a prolonged infusion schedule of 5-FU. In addition, doxorubicin (a predecessor to epirubicin(Drug information on epirubicin)) is no longer a primary agent used to treat advanced gastric carcinoma. Epirubicin as a single agent is practically inactive against gastric carcinoma (with less than 10% response rate). In addition, survival data from ECF is similar to the survival data from FAMTX in a previous randomized trial.[11] This degree of overlap should cast some doubts in embracing ECF as a standard. Thus it would appear that infusional 5-FU in combination with cisplatin is likely to produce satisfactory palliation that is comparable to any combination studied thus far. Recommended treatment (outside of clinical trials) is usually with cisplatin-based or 5-FU-based combination chemotherapy. Clearly, more active agents are needed for the treatment of this disease.

New Single-Agent IV Drugs and Their Use In Combination

Chemotherapeutic approaches for gastric carcinoma, as for many solid tumors, are continually evolving. Several new agents have been studied recently in patients with gastric carcinoma, including paclitaxel(Drug information on paclitaxel) and docetaxel(Drug information on docetaxel), irinotecan(Drug information on irinotecan), oral etoposide, and oral 5-FU biomodulators such as UFT and S-1.

Paclitaxel

Based on the activity of paclitaxel against adenocarcinoma of the esophagus and gastroesophageal junction,[14] a phase II study of single-agent paclitaxel in chemotherapy-naive patients with advanced, unresectable gastric carcinoma was undertaken at M. D. Anderson Cancer Center. A response rate of 17% was established.[15] Other studies of paclitaxel in advanced gastric carcinoma include a phase II trial performed by the Eastern Cooperative Oncology Group (ECOG), in which one partial response was achieved among 22 eligible patients (response rate 5%; 95% confidence interval [CI], 0% to 25%).[16] In a preliminary study by Tamura et al, three (21%) of 14 evaluable patients achieved a partial response when treated with 3-hour infusional single-agent paclitaxel.[17] All three responders had previously received chemotherapy. These preliminary reports suggest that paclitaxel is modestly active against gastric carcinoma. In addition, in a study of 34 patients treated with paclitaxel combined with 5-FU and cisplatin, 50% responded.[18]

Docetaxel

Docetaxel has also been studied in patients with advanced gastric carcinoma. The observed level of activity is similar to that reported with paclitaxel. Taguchi et al reported 9 (20%) partial responses among 45 evaluable patients with advanced gastric carcinoma who received only 60 mg/m2 of docetaxel administered every 3 weeks.[19] Sulkes et al treated 37 advanced gastric carcinoma patients with 100 mg/m2 of docetaxel every 3 weeks and reported a 24% (8 of 33 assessable patients) partial response rate.[20] In addition, a 17% response rate was observed in an ECOG study of 41 chemotherapy-naive patients with advanced gastric carcinoma.[21] More recently, assessment of combination chemotherapy including docetaxel (ie, docetaxel-cisplatin) has demonstrated substantial activity against advanced gastric carcinoma.[22]

Irinotecan

The topoisomerase-I inhibitor, irinotecan (CPT-11), has also demonstrated activity against gastric carcinoma when used as a single agent.[23] Interestingly, irinotecan was shown in this study to be active in patients previously treated with chemotherapy. In a study using a combination of irinotecan plus cisplatin, 42% of patients with gastric carcinoma responded[24]; this high response rate was confirmed in another study performed in Japan.[25] Similarly, the irinotecan/cisplatin combination appears to be active against carcinoma of the esophagus.[26]