Standard Chemotherapy for Gastric Carcinoma: Is It a Myth?
Authors: Jaffer A. Ajani, Hansjochen Wilke, Udo Vanhoefer, Phillipe Rougier, Bernard Nordlinger, Eric Van Cutsem, Jacques A. Wils, Benoit Baron
Journal: Journal of Clinical Oncology (2000)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2000.18.23.4001 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11099333 Standard Chemotherapy for Gastric Carcinoma: Is It a Myth? Jaffer A. AjanixJaffer A. AjaniSearch for articles by this author Hansjochen WilkexHansjochen WilkeSearch for articles by this author , Udo VanhoeferxUdo VanhoeferSearch for articles by this author , Phillipe RougierxPhillipe RougierSearch for articles by this author , Bernard NordlingerxBernard NordlingerSearch for articles by this author , Eric Van CutsemxEric Van CutsemSearch for articles by this author , Jacques A. WilsxJacques A. WilsSearch for articles by this author , Benoit BaronxBenoit BaronSearch for articles by this author Show More The University of Texas, M.D. Anderson Cancer Center Houston, TXFor the European Organization for Research and Treatment of Cancer—Gastrointestinal Tract Cancer Cooperative Group: , West German Cancer Center University of Essen Medical School Essen, GermanyHôpital Ambroise Paré Boulogne, FranceUniversity Hospital Gasthuisberg Leuven, BelgiumSt Laurentius Ziekenhuis Roermond, the NetherlandsFor the European Organization for Research and Treatment of Cancer Data Center Brussels, Belgium https://doi.org/10.1200/JCO.2000.18.23.4001 First Page Full Text PDF Figures and Tables © 2000 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01122000In Reply:Dr Ajani commented that our conclusions were overstated and not supported by the methodology used or data presented.Our trial was designed in 1990 as a comparative phase III trial with tumor response as the primary end point and progression-free survival (PFS) and overall survival (OS) as secondary end points.1 It was conducted according to GCP and ICH guidelines (once they were published). Today, objective response rate would not be used as the primary end point in a phase III trial. The main reason for this change in philosophy was that many trials showed an increase in the response rate while in fact no long-term benefit had been found for PFS or OS. Therefore, PFS and OS would now be recommended (“Note for guidance on evaluation of anticancer medicinal products in man”, ICH CPMP section 4, December 1996). Independent of these developments, a phase III trial is defined as a comparison of different treatments based on given end points and statistical calculations. Not the end point but changing the primary end point after the trial is already open to patient entry could be seen as a real methodologic mistake.The conclusion that we drew from this study was that none of the three investigated regimens can be regarded as a standard therapy, ie, none of the regimens should be recommended to treat patients on a routine basis outside clinical trials. Why does Ajani believe that this conclusion is not valid? Probably the criticism arises because of different interpretations of standard chemotherapy.Our trial was performed by a large number of participating investigators, reflecting the “actual” outcome of a chemotherapy regimen when administered in academic institutions, in community hospitals, or by private practitioners.At the time the trial was planned and initiated, the fluorouracil (5-FU), doxorubicin, and methotrexate (FAMTX) regimen was regarded as the reference treatment against which other chemotherapy regimens should be compared. Etoposide, leucovorin, and 5-FU (ELF) and infusional 5-FU and cisplatin (FUP) were chosen because results of phase II trials suggested that they were at least as effective as FAMTX but less toxic and easier to handle.To be precise, the protocol stipulated that “the percentage of response… considered to be of interest in all three regimens was assumed to be ≥ 35%. To detect a difference of 20% (with a power of 80% using a two-sided significance level of 5%) in response rate between any two treatment groups, 400 patients were needed.” The percentage of responses that was considered of interest in all three regimens was assumed to be at least 35%. This was independent of the assumption that one of the regimens could induce a 20% higher response rate than the other ones.Although there was a small difference in response rate between the FUP regimen (20%) and ELF (9%) or FAMTX (12%), this difference was not significant. Assuming that the trial would have ended with a higher number of patients assessable for objective response (ie, 130 or 140 per treatment arm), the statistical probability that the threshold 35% remission rate would have been reached for any of the three regimens was calculated to be less than 1%. Would a shift to 10% higher objective responses have made a difference in recommending one of these regimens for routine treatment?It is difficult to understand why it should not be legitimate to discuss the results of OS and PFS for this trial. A trial may have a number of end points, with one being the main end point to answer the first question of interest and on which the sample size has to be calculated. OS and PFS were defined as secondary end points and therefore had to be included in our analysis. The number of events was more than 100 in each treatment arm, which makes both analyses very relevant. The fact that the survival times of all three regimens were uniformly poor further supports our conclusions that no difference in the antitumor activity of the three regimens could be detected in this trial and that none of these combinations can be regarded as the standard of care. This does not mean that it would be illegitimate to use a cisplatin/5-FU–based regimen as a reference arm in randomized trials.In conclusion, our trial could not define a standard of care for advanced gastric cancer, and given the published data of other trials, it is indeed difficult to define one, as has also been discussed by Ajani.As long as a widely accepted and reproducible active regimen for the treatment of advanced gastric cancer is not available, it is probably unwise to embark again upon randomized phase III trials rather than perform randomized phase II studies with response as primary end point, in order to define new active regimens.REFERENCE1. Vanhoefer U, Rougier P, Wilke H, et al: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18:: 2648,2000-2657, Link, Google Scholar