Journal of the National Cancer Institute Advance Access originally published online on August 28, 2007
JNCI Journal of the National Cancer Institute 2007 99(17):1345-1346; doi:10.1093/jnci/djm092
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© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Re: Adjuvant Treatment of High-Risk, Radically Resected Gastric Cancer Patients with 5-Fluorouracil, Leucovorin, Cisplatin, and Epidoxorubicin in a Randomized Controlled Trial
Affiliations of authors: European Institute of Oncology, Milan, Italy (NF, RB, GC, KL, MGZ, FDB, AC, AG); Geneva University Hospital, Geneva, Switzerland (AR)
Correspondence to: Nicola Fazio, MD, Department of Medicine, Division of Medical Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy (e-mail: nicola.fazio{at}ieo.it).
We read with great interest the recent article by Cascinu et al. (1). The authors compared an 8-week intensive platinum, epirubicin, leucovorin, fluorouracil regimen (PELFw) with a much less intensive "control" 5-fluorouracil/leucovorin regimen in patients with radically resected locally advanced gastric cancer (1) and reported no difference in terms of overall survival and disease-free survival. The negative results of this trial could be due to several reasons, including the lack of new drugs in the experimental arm and inadequate sample size. Nevertheless, the take-home message of the authors is that intensive adjuvant chemotherapy is ineffective and uselessly toxic, and, therefore, they suggest a move toward a preoperative setting of investigation.
Other trials have revealed the problems of postoperative intensive chemotherapy; among them, the Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial (2) showed that perioperative chemotherapy with ECF (epirubicin, cisplatin, 5-fluorouracil) improves survival compared with surgery alone, although we cannot know if this advantage derives from preoperative or postoperative treatment or both. Based on the report of Cascinu et al. (1), we cannot know if the PELFw chemotherapy regimen is equally effective as the 5-fluorouracil/leucovorin regimen or if both are totally ineffective, given the lack of an observation-only arm. We agree with the authors that the unexpectedly high survival rate observed could be due to adequate nodal dissection, as previously shown in the Italian Trials of Medical Oncology trial (3), where the surgery-alone arm produced a 48% 5-year survival rate after D2-dissection.
Another important message from the study of Cascinu et al. (1) is the uselessness of radiotherapy after high-quality surgery, as suggested by the low local recurrence rate. This is a further demonstration that the American standard option of adjuvant chemoradiotherapy, derived from the study of Macdonald et al. (4), is not applicable to the Italian reality.
The authors' conclusions confirm our experimental approach of some years ago, when we designed a randomized trial comparing preoperative versus postoperative therapy with a taxotere/cisplatin/5-fluorouracil combination in radically resected locally advanced gastric cancer patients. This study, born from a cooperation between the Swiss Group for Cancer Research and the European Institute of Oncology in Milan, found that preoperative therapy was better tolerated and more feasible compared with postoperative therapy (unpublished data) but did not furnish useful information on relative efficacy because it was prematurely stopped due to slow accrual. Neoadjuvant studies are much more difficult than adjuvant ones, requiring a high level of multidisciplinary management. This is demonstrated by the fact that the conclusions from the trial of Cascinu et al. (1) were not applied even by the same investigative institutions involved in the trial. Indeed, many of them preferred to participate in an ongoing two-arm adjuvant Italian intergroup trial with a large accrual goal of 1100 patients to obtain statistical evidence in favor of an intensive new drug postoperative chemotherapy that was missing in the PELFw trial. In conclusion, given the increased investigative focus toward a preoperative setting in resectable gastric cancer, the time is ripe to conduct a large, international multicentric randomized phase III trial of a new-drug neoadjuvant chemotherapy regimen involving all major reference groups.
REFERENCES
(1) Cascinu S, Labianca R, Barone C, Santoro A, Carnaghi C, Cassano A, et al. Adjuvant treatment of high-risk, radically resected gastric cancer patients with 5-fluorouracil, leucovorin, cisplatin, and epidoxorubicin in a randomized controlled trial. J Natl Cancer Inst (2007) 99:601–7.
(2) Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for respectable gastroesophageal cancer. N Engl J Med (2006) 355:11–20.
(3) Bajetta E, Buzzoni R, Mariani L, Beretta E, Bozzetti F, Bordogna G, et al. Adjuvant chemotherapy in gastric cancer: 5-year results of a randomised study by the Italian Trias in Medical Oncology (ITMO) Group. Ann Oncol (2002) 13:299–307.
(4) Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Sternmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med (2001) 345:725–30.
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J Natl Cancer Inst 2007 99: 601-607.
J Natl Cancer Inst 2007 99: 601-607.
J Natl Cancer Inst 2007 99: 1346-1347.
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