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Current Status of Therapy for Advanced Gastric Carcinoma

Current Status of Therapy for Advanced Gastric Carcinoma

ABSTRACT: Advanced gastric carcinoma remains an incurable disease with a median survival of 6 to 9 months, and available therapeutic approaches are predominantly palliative. In small controlled trials, systemic chemotherapy has improved survival and quality of life of patients with advanced gastric carcinoma when compared with best supportive care. Patients with good performance status (Zubrod £ 2), low tumor bulk, and good organ function are most likely to benefit from chemotherapy or combined-modality therapy. There is no generally accepted standard chemotherapy for advanced gastric carcinoma. Fluorouracil- and/or cisplatin-based combinations are often employed. Recently, several new classes of drugs have demonstrated activity against advanced disease. These include the taxanes (paclitaxel [Taxol] and docetaxel [Taxotere]), camptothecins (irinotecan [Camptosar]), and fluorouracil prodrugs (second- and third-generation agents, such as UFT [uracil and tegafur] and S-1). Early results with either single-agent therapy or combinations of new agents (irinotecan, paclitaxel, and docetaxel) and more conventional agents (cisplatin [Platinol] and fluorouracil) are encouraging. Several of these results need to be confirmed and eventually studied in well-designed, phase III trials. Similarly, a number of new combinations may be used in the future as preoperative therapies for gastric carcinoma. Nearly all of the new agents have radiosensitizing properties. This affords another opportunity to investigate new chemotherapeutic agents in conjunction with radiation therapy in patients with locoregional gastric carcinoma. [ONCOLOGY 12(Suppl 6):99-102, 1998]

Introduction

Gastric carcinoma continues to be a serious health problem throughout
the world. The decline in its incidence is a global, consistent
phenomenon, although this decrease has been more noticeable in the
western world than in Asia and eastern Europe. Despite the fact that
the United States has one of the lowest incidences of gastric cancer
in the world, more than 22,600 new cases of this cancer are
anticipated in this country in 1998, and a total of 13,700 patients
are expected to die as a result of it.[1] Gastric carcinoma also
remains the eighth leading cause of cancer death in the United States.[1]

Since the stomach is a rather large organ, a space-occupying lesion
often does not cause symptoms until it has reached a substantial
size. Early detection is neither carried out nor financially feasible
in most countries around the globe. Thus, it is not uncommon for a
significant number of patients with gastric carcinoma to have widely
disseminated cancer at diagnosis. It is estimated that nearly
one-half of US patients have gastric carcinoma beyond the local
confines at diagnosis.

Advanced gastric carcinoma is incurable, and chemotherapy remains
palliative. The median survival of patients with advanced disease is
6 to 9 months.

Conventional Agents

In patients with metastatic gastric carcinoma, chemotherapy appears
to provide a significant survival advantage over best supportive
care.[2] However, all four published prospective randomized trials of
chemotherapy vs supportive care involved only a small number of patients.[3-6]

Single Agents

Although a number of conventional agents are used to treat gastric
carcinoma, there is no standard chemotherapy. The use of
fluorouracil- or cisplatin-based combinations in patients with good
performance status (Zubrod £ 2) may
be considered acceptable. The response rate to fluorouracil alone is
less than 20%.[7] Other agents, such as mitomycin (Mutamycin),[7]
etoposide (VePesid),[8] and cisplatin (Platinol),[9] are also
considered active and result in response rates of approximately 20%
when used as single agents. However, responses are short-lived.

Combination Regimens

Combination chemotherapy for advanced gastric cancer has been
attractive to investigators for many decades. In a pivotal study
performed by the North Central Cancer Therapy Group (NCCTG) comparing
the FAM (fluorouracil, Adriamycin, and mitomycin) regimen to
fluorouracil alone and fluorouracil plus doxorubicin, no significant
survival difference was detected among the three regimens.[10]
Combination chemotherapy produced a higher response rate, however. In
the United States, there have been no further comparisons of any
combination vs fluorouracil alone.

On the other hand, many comparative studies have been carried out in
Europe. In a phase III trial conducted by the European Organization
for Research and Treatment of Cancer (EORTC), in which FAMTX
(fluorouracil, Adriamycin, and methotrexate) was compared to FAM,
FAMTX resulted in a superior response rate (41% vs 9%) and a superior
median survival (40 vs 29 weeks).[11]

More recently, researchers at the Royal Marsden Hospital compared
FAMTX to ECF (epirubicin, cisplatin, and fluorouracil) in a total of
274 patients.[12] In this study, ECF produced a higher response rate
than FAMTX (45% vs 22%), as well as a better median survival (8.9 vs
< 6 months).

Thus, in the EORTC study, FAM performed less than optimally (9%
response rate) compared to FAMTX (33% response rate), whereas in the
Royal Marsden study, FAMTX performed less optimally (22% response
rate) than expected compared to ECF (45% response rate). To date,
however, the median survival barrier of approximately 9 months has
not been overcome in any randomized trial.

A trial reported by Wilke et al prospectively compared FAMTX, ELF
(etoposide, leucovorin, and fluorouracil), and cisplatin plus
fluorouracil in patients with advanced gastric carcinoma and found no
advantage in any of the regimens.[13] The response rate was less than
28% and the median survival, again, was less than 9 months.

Standard Chemotherapy

Patients with poor performance status should be offered only best
supportive care and those with good perform- ance status (Zubrod £
2) may be offered best supportive care or combination chemotherapy.
There is not an accepted standard chemotherapy regimen for patients
with advanced gastric carcinoma. Previously proposed standards are
not widely practiced. Every effort should be made to enter all
eligible and willing patients into approved protocols. For patients
who are not entered on any protocols, either 5-FU-based therapy (eg,
5-FU plus leucovorin) or cisplatin-based therapy (eg, 5-FU plus
cisplatin) may be considered standard.

An argument can be made for the use of single-agent 5-FU as standard
therapy, however, the use of 5-FU alone poses some limitations: (a)
higher response rate (thus higher rate of palliation) has been
reported with combination chemotherapy in the NCCTG randomized
trial[10]; (b) all studies comparing best supportive care with
chemotherapy have demonstrated advantage to the use of combination
chemotherapy. Such trials have not been done with single-agent
therapy, and (c) reluctance of physicians and patients to accept
single-agent 5-FU as standard for patients with advanced gastric
carcinoma. Such a proposal is very likely to cripple a randomized trial.

The combination of cisplatin and 5-FU is widely used around the world
as "standard" therapy. Regimens like ELF, FAMTX, and EAP
should be considered outdated for the treatment of patients with
advanced gastric carcinoma. ECF does deserve a mention here. ECF has
been proposed as a possible "standard" recently, however,
it is neither used widely in Europe nor considered standard by many
investigators. Since, epirubicin is an investigational agent, ECF is
not used in North America. In addition, it is a cumbersome regimen
and the value of anthracyclines in this disease at present is
considered quite limited. Most likely, the benefit of ECF is due to
cisplatin and 5-FU. Therefore, at present, use of cisplatin plus 5-FU
is justifiable. For patients in whom cisplatin is contraindicated,
use of 5-FU-based therapy is recommended to achieve palliation.
Clearly, new active agents are needed in the treatment of gastric carcinoma.

New Agents

Taxanes

The taxanes represent a new class of antimitotic agents that
preferentially bind to microtubules.[14] These drugs promote
microtubular assembly and stabilize microtubules.[15] Both paclitaxel
(Taxol) and docetaxel (Taxotere) are broad-spectrum anticancer agents
that have demonstrated significant clinical activity against a
variety of solid tumors.

Paclitaxel--Based on paclitaxel’s activity against
adenocarcinoma of the esophagus and gastroesophageal junction,[16] a
phase II study of this taxane in chemotherapy-naive patients with
advanced, unresectable gastric carcinoma was initiated at the
University of Texas M. D. Anderson Cancer Center. In 30 evaluable
patients treated with single-agent paclitaxel, the overall response
rate was 17% (95% confidence interval [CI], 6% to 35%).[17] The drug
was well tolerated, and toxicities in patients with gastric carcinoma
were similar to those described in other patient groups.[18]

Both 3- and 24-hour schedules of paclitaxel (starting dose, 200
mg/m²) were studied in this protocol. The study was not intended
to compare the efficacy of different schedules of administration.

Other groups also have studied paclitaxel in advanced gastric
carcinoma. An Eastern Cooperative Oncology Group (ECOG) phase II
study of paclitaxel resulted in one partial response among 22
eligible patients (response rate 5%; 95% confidence interval, 0% to
25%).[19] In a preliminary study by Tamura et al, 3 of 14 evaluable
patients (21%) achieved a partial response when treated with a 3-hour
infusion of single-agent paclitaxel.[20] All three responders had
received prior chemotherapy.

These preliminary reports suggest that paclitaxel has modest activity
against gastric carcinoma. In addition, treatment with paclitaxel in
combination with fluorouracil and cisplatin produced a response rate
of 50% in 34 patients.[21]

Docetaxel has also been studied in patients with advanced
gastric carcinoma and has demonstrated a level of activity similar to
that of paclitaxel.[22-24] Taguchi reported 9 partial responses (22%)
among 45 evaluable patients with advanced gastric carcinoma treated
with 60 mg/m² of docetaxel administered every 3 weeks.[22]
Sulkes et al treated 37 patients with advanced gastric carcinoma with
100 mg/m² of docetaxel every 3 weeks and achieved a partial
response rate of 24% (8 of 33 assessable patients).[23] In addition,
an ECOG study of 41 eligible chemotherapy-naive patients with
advanced gastric carcinoma demonstrated a 17% response rate.[24]
These data suggest that taxanes may be useful in the treatment of
patients with advanced gastric carcinoma.

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