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Chemotherapy for Gastric Carcinoma: New and Old Options

Chemotherapy for Gastric Carcinoma: New and Old Options

ABSTRACT: Although gastric carcinoma is an uncommon disease in North America, its incidence is alarmingly high in Asia, South America, Eastern Europe, and countries of the former Soviet Union. Screening for gastric carcinoma is performed only on a limited basis in Japan; in the rest of the world, therefore, patients often present with advanced disease at the time of diagnosis. Chemotherapy, radiotherapy, or both rarely cure patients with unresectable or metastatic carcinoma; therapy thus remains palliative for such patients. Chemotherapy seems to be beneficial, however, and continues to evolve in the treatment of patients with advanced gastric carcinoma. Four small randomized trials demonstrated survival and quality-of-life benefits for patients who received chemotherapy compared with those who received best supportive care. In the past 20 years, several “old” drugs have been studied either alone or in combination to treat this disease; and new active drugs have been identified. Recently, quality of life, convenience, and cost-containment have been emphasized in the treatment of cancer. This has increased interest in oral agents. At present, several promising oral 5-fluorouracil prodrugs are being studied in clinical trials. This article summarizes current developments in the treatment of advanced gastric carcinoma.[ONCOLOGY 12(Suppl 7):44-47, 1998]

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,[7] etoposide,[8] and 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, 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),[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) 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 and docetaxel, 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]

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