Original Paper
Chemotherapy for operable gastric cancer: results of the Dutch randomised FAMTX trial

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Abstract

The aim of this trial was to investigate whether pre-operative chemotherapy leads to a 15% higher curative resectability rate in patients with operable gastric cancer. In this randomised trial, patients were allocated to receive either four courses of chemotherapy using 5-fluorouracil, doxorubicin and methotrexate (FAMTX) prior to surgery or to undergo surgery only. Patients younger than 75 years of age with a good physical and mental condition and a histologically proven adenocarcinoma of the stomach without clinical or radiographic (computed tomography scan) evidence of distant metastases were eligible for this trial. Early gastric cancer or cardia carcinoma were excluded. The response to chemotherapy was evaluated after two and four courses. In case of progressive disease (PD) after two courses, patients were operated upon as soon as possible. Otherwise complete response (CR) partial response (PR) or stable disease (SD), two more courses were scheduled. The standard surgical procedure was a limited lymphadenectomy (D1) with staging biopsy of the para-aortic lymph nodes. Between September 1993 and February 1996, 56 eligible and evaluable patients were entered: 27 were randomised to receive FAMTX before surgery and 29 to undergo surgery only. In the FAMTX+surgery treatment group, 15/27 (56%) had curative resections versus 18/29 (62%) in the surgery only arm. There was no difference in the frequency of TNM stages I+II in both treatment arms: 15/27 versus 15/29. Due to PD and/or toxicity, 12 patients (44%) could not complete the planned four courses of FAMTX. Response evaluation after chemotherapy was possible in 25 patients: 2 CR, 6 PR, 8 SD and 9 PD. The difference in curative resectability rate was 6.5% (95% confidence interval −32 to +19%) in favour of surgery only. Downstaging for stages I+II did not occur. PD was more often the reason for not completing the planned four courses than toxicity. More active regimens than FAMTX are required for future randomised trials.

Introduction

Gastric cancer has a poor prognosis, despite a slowly declining incidence and an associated decline in mortality rate. Surgery is the only treatment modality offering hope for a cure. In Western countries, most patients are diagnosed at an advanced stage, when curative surgery is no longer possible. However, even after curative surgery, the 5 year survival is still approximately 30%1, 2, 3and most patients die of locoregional recurrence or distant metastasis, illustrating the shortcomings of pre-operative staging and surgical technique. ‘More radical’ operations with extended lymphadenectomy (D2–D4) are associated with higher morbidity and mortality rates compared with limited lymphadenectomy, and a possible survival benefit is not proven in Western countries. The 5-year survival results of two large prospectively randomised, controlled trials (the Dutch Gastric Cancer Trial and the British MRC Trial) comparing extended lymphadenectomy (D2) with limited lymphadenectomy (D1) are still awaited, but preliminary results show no difference in survival rates between both treatment arms (data not shown). In both trials a significant increase in morbidity and hospital mortality rates was found with extended lymphadenectomy4, 5. These facts suggest that the limits of surgical possibilities for improving the treatment results in patients with gastric cancer seem to have been reached.

In order to improve survival following surgery, many phase II trials with limited numbers of patients have been performed to investigate the value of adjuvant therapy. In a meta-analysis of 14 randomised trials of adjuvant (postoperative) chemotherapy with regimens that are now considered suboptimal, only a small, but statistically significant, additional survival advantage was found in favour of the adjuvant chemotherapy compared with surgery only6, 7. In some pilot studies, gastric cancer before resection showed a promising responsiveness to chemotherapy8, 9, 10, 11, 12.

More active combination chemotherapy regimens, e.g. EAP (etoposide, 5-fluorouracil (5-FU) and methotrexate), FAMTX (5-FU, doxorubicin and methotrexate), FEMTX-P (5-FU, epidoxorubicin, methotrexate and cisplatin) and ECF (epidoxorubicin, cisplatin and continuous infusion of 5-FU), have been developed and their results in locally advanced and metastatic gastric cancer have shown response rates of 41–71%. In some cases, even a complete response could be achieved9, 13, 14, 15, 16. With FEMTX-P, it was reported that the primary tumour had a higher response rate compared with its metastases[17], suggesting that earlier stages are more chemosensitive than advanced stages. The development of these more active chemotherapy regimens and insights into the timing of the administration of chemotherapy against the background of poor surgical results have opened new possibilities for the treatment of gastric cancer.

In order to evaluate the effect of pre-operative chemotherapy in potentially operable gastric cancer, a randomised trial was conducted in The Netherlands. Out of the four potentially suitable options, the DGCG (Dutch Gastric Cancer Group) decided on FAMTX in 1993, because of its repeatedly demonstrated steady response rates, lower toxicity compared with EAP2, 3, 9, 18, 19, 20, 21lower costs and lower toxicity compared with FEMTX-P (FAMTX is less toxic due to the omission of cisplatin8, 22). Moreover, at that time FAMTX was considered the golden standard for future randomised trials10, 14, 18.

The major aim of the trial was to study the hypothesis that pre-operative chemotherapy would give rise to a 15% higher curative resectability rate compared with surgery only. The results of this randomised multicentre trial are presented here.

Section snippets

Patients and methods

Patients younger than 75 years of age with a good physical and mental condition and histologically proven adenocarcinoma of the stomach were eligible for this trial with informed consent.

Exclusion criteria were clinical and radiological (computed tomography scan, CT) evidence of distant metastases, prior treatment, early gastric cancer (T1), cardia carcinoma, malignancy in history (other than carcinoma in situ of the uterine cervix and basal cell carcinoma of the skin), leucocyte count below

Results

Between September 1993 and January 1996, 59 patients were randomised: 29 were allocated to receive FAMTX before surgery and 30 to undergo surgery only. Because of this slow accrual of patients the National Health Council (‘Ziekenfondsraad’) stopped further financial support of the trial. The trial committee then decided to study the evidence of the available data in order to judge whether continuation of the trial would be justified. Several patients, mainly in the FAMTX arm, were not yet

Discussion

In this prospective, randomised trial, we compared four courses of pre-operative FAMTX chemotherapy followed by surgery with surgery alone for operable gastric adenocarcinoma. Of the 25 patients receiving pre-operative chemotherapy, in which clinical response was assessed, 32% had a clinical response (2 CRs and 6 PRs), while 36% (9/25) had PD during the courses, mainly locoregional. The overall clinical response rate in our trial is comparable with the lower results of the reported data in the

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    See Appendix Afor the participating hospitals.

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