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© 2000 American Society for Clinical Oncology
Adjuvant Chemotherapy in Gastric CancerUniversity Hospital of Ioannina Ioannina, Greece To the Editor:The findings of the randomized trial comparing surgery and chemotherapy (treatment group) with surgery alone (control group) for patients with gastric cancer, reported by Cirera et al,1 should be interpreted with caution. A surgical resection with curative intent (R0 resection) is the treatment of choice. However, even after a Japanese-type radical R0 resection that includes extended lymph node dissection, the proportion of treatment failure in advanced gastric cancer is substantially high.2 Thus the need for an adjuvant treatment is considerable. However, despite the great efforts in the last 30 years to develop an effective adjuvant chemotherapy, there is still no established adjuvant regimen. The results of numerous clinical trials with adjuvant chemotherapy indicate no survival advantage, whereas there are few reports of survival benefit.3 Therefore, the trial by Cirera et al1 that showed a significant improvement in survival for patients treated with postoperative chemotherapy of mitomycin plus tegafur should be evaluated with particular consideration. Cirera et al1 felt the need to explain the high survival rate in the control group (36%) with the argument of inclusion in the study of patients with early-stage disease, but in the design of the study, they assumed an expected 5-year survival rate of 35% to 40% for patients in the control group with resected stage III disease. As Table 1 in the article shows, early-stage cancers constituted a very small subgroup of patients (T1, 2%; T2, 7%), whereas the majority of enrolled patients had at treatment a very advanced tumor stage: T3 category, 26%; T4a category, 64%; distant node metastasis (N2), 48%. Survival for patients with these advanced stages of IIIb and IV disease is extremely poor. Five-year survival rates reported from a large German study are at best 13%.4 Similarly low are the survival rates reported from Japan, a country that provides the best treatment results worldwide. In a recent state-of-the-art report from 18 cancer institutions and university hospitals in Japan, 5-year survival rates for patients with stages IIIb and IVa gastric cancer after extended (D2-D4) node dissection and adjuvant chemotherapy were 30% and 15%, respectively.5 In a recent well designed and well conducted randomized controlled trial, there was no survival benefit between the treatment group (mitomycin, fluorouracil, and oral uracil plus tegafur after surgery) and the control group (surgery alone) in 579 patients with serosa-negative cancer (T1, T2 tumors).6 On the basis of these findings and a previous review, Nakajima et al6 concluded that adjuvant chemotherapy for patients with advanced stage IIIb or IV disease does not improve survival (because of large amounts of residual disease) and thus should not be given. The negative results of late postoperative therapy have led many investigators to conduct randomized ongoing trials for locally advanced gastric cancer to test the efficacy of neoadjuvant (preoperative) and/or intraperitoneal administration of chemotherapy, because the timing of drug administration may increase its effectiveness.2 The positive results reported by Cirera et al1 are in contrast to those of many other studies, although a similar chemotherapy regimen was used. Furthermore, survival was marginally significantly better in the treatment group according to the log-rank test (P = .04). However, it would be of interest to show whether this adjuvant chemotherapy was significantly and independently associated with better survival in a Cox multiple regression analysis, in which the established prognostic factors (pN, pT stage) should also be included. In our opinion, the data reported by Cirera et al1 cannot establish the efficacy of the adjuvant chemotherapy used. The multimodal treatment of advanced gastric cancer will be the most important theme in the coming years and is expected to focus on neoadjuvant and intraperitoneal chemotherapy for localized advanced disease, as well as in the incorporation of new drugs that are more effective and less toxic.2 REFERENCES
1.
Cirera L, Balil A, Batiste-Alentorn E, et al: Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer. J Clin Oncol 17:3810–3815, 1999 2. Roukos DH: Current status in gastric cancer management and future perspectives. Cancer Treat Rev (in press)
3.
Hermans J, Bonenkamp JJ, Boon MC, et al: Adjuvant therapy after curative resection for gastric cancer: Meta-analysis of randomized trials. J Clin Oncol 11:1441–1447, 1993 4. Siewert JR, Boetcher K, Stein HJ, et al: Relevant prognostic factors in gastric cancer. Ann Surg 228:449–461, 1998[Medline] 5. Fujii M, Sasaki J, Nakajima T: State of the art in the treatment of gastric cancer: From the 71st Japanese gastric cancer congress. Gastric Cancer 2:151–157, 1999[Medline] 6. Nakajima T, Nashimoto A, Kitamura M, et al: Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: A randomized trial. Lancet 354:273–277, 1999[Medline]
ResponseHospital Mútua de Terrassa Terrassa (Barcelona), Spain In Reply:Drs Roukos and Paraschou emphasize, in reference to our work recently published in the Journal of Clinical Oncology,1 the high survival rates of the control group to 5 years (36%). This survival coincides with the expected survival for a group of patients with stage III disease (American Joint Committee on Cancer, 1983) the results for whom were published in 1985.2 It is not advisable to compare survival when the groups in question do not use the same TNM classification system. Roukos and Paraschou say that it would be of interest to show whether adjuvant chemotherapy was significantly and independently associated with better survival in a Cox regression analysis that included the pN-pT stage. As can be seen in Table 1 of our article,1 primary tumor size was equally distributed in the two comparison groups (P = .35). Therefore, its inclusion in a Cox regression model would not have changed the measure of the treatment effect. On the other hand, as we commented in the article, although nodal status was a significant variable for mortality and for relapse, the imbalance that was observed in nodal status between the two groups in our study (P = .07) did not confound the estimated effect of the treatment. After including the variable nodal status in a multivariate Cox regression model, the estimated effect of the treatment for mortality was 0.59 (range, 0.38 to 0.93) and for relapse was 0.55 (range, 0.36 to 0.84). We are entirely in agreement that the use of adjuvant chemotherapy cannot be definitively recommended for gastric cancer, and this was explicitly stated in our comments. Nevertheless, our results may be of use in defining strategies for future clinical trials. REFERENCES 1. Cirera L, Balil A, Batiste-Alentorn E, et al: Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer. J Clin Oncol 17:3810–3815, 1999 2. Curtis RE, Kennedy BJ, Myers MH, et al: Evaluation of AJC stomach cancer staging using the SEER Population, Semin Oncol 12:21–31, 1985
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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