Biffi, Roberto

Chiappa, Antonio

Curigliano, Giuseppe

de Braud, Filippo

Fazio, Nicola

Goldhirsch, Aron

Lorizzo, Katia

Roth, Arnaud

Zampino, Maria Giulia

RERO DOC Digital Library

jnci.oxfordjournals.org   JNCI | Correspondence 1345 Re: Adjuvant Treatment of High-Risk, Radically Resected Gastric Cancer Patients with 5-Fluorouracil, Leucovorin, Cisplatin, and Epidoxorubicin in a Randomized Controlled Trial  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-fluo-rouracil/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. Never-theless, the take-home message of the authors is that intensive adjuvant chemo-therapy 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 Chemother-apy trial ( 2 ) showed that perioperative 1346 Correspondence | JNCI Vol. 99, Issue 17  |  September 5, 2007chemotherapy with ECF (epirubicin, cispla-tin, 5-ﬂ uorouracil) improves survival com-pared with surgery alone, although we cannot know if this advantage derives from preop-erative 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-ﬂ uoro-uracil/leucovorin regimen or if both are totally ineffective, given the lack of an obser-vation-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 conﬁ rm our experimental approach of some years ago, when we designed a randomized trial comparing preoperative versus post oper-ative therapy with a taxotere/cisplatin/ 5-fluorouracil combination in radically resected locally advanced gastric cancer patients. This study, born from a coopera-tion 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 efﬁ cacy because it was prematurely stopped due to slow accrual. Neoadjuvant studies are much more difﬁ cult 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 insti-tutions 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 chemo-therapy that was missing in the PELFw trial. In conclusion, given the increased investiga-tive 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 involv-ing all major reference groups.  NICOLA  FAZIO  ROBERTO  BIFFI  GIUSEPPE  CURIGLIANO  KATIA  LORIZZO  M ARIA GIULIA   ZAMPINO FILIPPO  DE BRAUD  ANTONIO  CHIAPPA  ARNAUD  ROTH  ARON  GOLDHIRSCH  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-ﬂ uorouracil, 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 sur-gery 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 che-motherapy 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 com-pared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction .  N Engl J Med  2001 ; 345 : 725 – 30 .  Notes  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@ieo.it ).  DOI: 10.1093/jnci/djm092  © The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org. shared. Our data, along with those deriv-ing from the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, seem to indicate that a bet-ter tolerability profile of a perioperative treatment approach is resp onsible, at least in part, for the improved outcome ( 2 ). However, when our trial was designed, about 10 years ago, this was not a wide-spread opinion. At about the same time, the Swiss Group designed a clinical trial comparing a preoperative versus a post-operative chemotherapeutic approach with a regimen that included docetaxel. Unfortunately, at that time definitive data about activity and tolerability of docetaxel as a treatment for gastric cancer were largely lacking, making the trial design somewhat problematic. In fact, it was only last year that a randomized trial clarified the role of docetaxel in gastric cancer ( 3 ). Furthermore, our trial was designed before the MAGIC trial, when data from pub-lished literature seemed to largely support a postoperative approach ( 4 ). However, we believe that even positive results obtained with a preoperative approach may require cautious interpretation. It is important to consider that the 5-year survival in the MAGIC trial was only 23% in the control arm and 36% in the treatment arm, whereas the 5-year survival approached 50% in the control arms, both in our study and in the Italian Trials of Medical Oncology trial ( 5 ). Once again, potentially positive results may depend on the quality of surgery, and adju-vant treatment may be useful only in patients not likely to receive an optimal surgical treatment. We note that a similar interpretation was applied to results obtained with adjuvant radiotherapy in the trial of MacDonald et al. ( 6 ).  Finally, Fazio et al. seem to question the choice by the Italian Intergroup to carry out a new postoperative therapy with a chemotherapy including 5-ﬂ uorouracil, cisplatin, irinotecan, and docetaxel in a sequential manner. Although we agree with most of the comments and concerns raised in the letter, we think that this new trial is exploring a novel treatment strategy in gastric cancer by allowing the administra-tion of several drugs but, at the same time, limiting their toxic effects. The sequential multidrug approach is biologically different from the intensive approach evaluated in our study and could not be explored with a  Response  We have read with interest the correspon-dence regarding the role of pre- and post-operative chemotherapy in gastric cancer in response to our recent report of an intensive adjuvant chemotherapy in gastric cancer ( 1 ). The idea that preoperative chemotherapy may be a more suitable treatment approach for locally advanced gastric cancer is, in fact, now widely neoadjuvant design. Preliminary safety data from this trial are encouraging. If this approach also fails to show any advantage, preoperative chemotherapy would be the only viable treatment strategy to pursue in the future.  STEFANO  CASCINU  MARIO  SCARTOZZI  CARLO  BARONE  ROBERTO  LABIANCA  ARMANDO  SANTORO  CARLO  CARNAGHI  GIORDANO D.  BERETTA  VINCENZO  CATALANO  SANDRO  BARNI  LUCIANO  FRONTINI  References   (1)  Cascinu  S ,  Labianca  R ,  Barone  C ,  Santoro  C ,  Carnaghi  C ,  Cassano  A , et al .  Adjuvant treat-ment of high-risk, radically resected gastric cancer patients with 5-ﬂ uorouracil, leucovo-rin, cisplatin, and epi-doxorubicin in a ran-domized 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 sur-gery alone for resectable gastro-esophageal cancer .  N Engl J Med  2006 ; 355 : 11 – 20 .   (3)  Van Cutsem  E ,  Moiseyenko  VM ,  Tjulandin  S ,  Majlis  A ,  Constenla  M ,  Boni  C , et al .  Phase III study of docetaxel and cisplatin plus ﬂ uoro-uracil compared with cisplatin and ﬂ uoroura-cil as ﬁ rst-line therapy for advanced gastric cancer: a report of the V325 Study Group .  J Clin Oncol  2006 ; 24 : 4991 – 7 .   (4)  Mari  E ,  Floriani  I ,  Tinazzi  A ,  Buda  A ,  Belﬁ glio  M ,  Valentini  M , et al .  Efﬁ cacy of adjuvant che-motherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente) .  Ann Oncol  2000 ; 11 : 837 – 43 .   (5)  Bajetta  E ,  Buzzoni  R ,  Mariani  L ,  Beretta  E ,  Bozzetti  F ,  Bordogna  G , et al .  Adjuvant che-motherapy in gastric cancer: 5-year results of a randomised study by the Italian trials in Medical Oncology (ITMO) Group .  Ann Oncol  2002 ; 13 : 299 – 307 .   (6)  Macdonald  JS ,  Smalley  SR ,  Benedetti  J ,  Hundahl  SA ,  Estes  NC ,  Stemmerman  GN , et al .  Chemoradiotherapy after surgery com-pared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction .  N Engl J Med  2001 ; 345 : 725 – 30 .  Notes  Affiliations of authors : Clinica di Oncologia Medica, Universita‘ Politecnica delle Marche, Ancona, Italy (SC, MS); Oncologia Medica, Universita’ Cattolica del Sacro Cuore, Policlinico A. Gemelli, Roma, Italy (CB); Oncologia Medica, Azienda Ospedaliera “Ospedali Riuniti di Bergamo,” Bergamo, Italy (RL, GDB); Oncologia Medica, Istituto Clinico Humanitas, Milano, Italy (AS, CC); Oncologia Medica, Azienda Ospedaliera S. Salvatore, Pesaro, Italy (VC); Oncologia Medica, Azienda Ospedaliera di Treviglio, Treviglio, Bergamo, Italy (SB); Clinical Trials Unit, GISCAD, Milano, Italy (LF) .  Correspondence to : Stefano Cascinu, MD, Clinica di Oncologia Medica, Universita ’ Politecnica delle Marche, Ospedali Riuniti di Ancona. Via Conca, 60020 Ancona, Italy (e-mail:  cascinu@yahoo.com ).  DOI: 10.1093/jnci/djm094  © The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org. jnci.oxfordjournals.org   JNCI | Erratum 1347

Re: Adjuvant Treatment of High-Risk, Radically Resected Gastric Cancer Patients with 5-Fluorouracil, Leucovorin, Cisplatin, and Epidoxorubicin in a Randomized Controlled Trial

Re: Adjuvant Treatment of High-Risk, Radically Resected Gastric Cancer Patients with 5-Fluorouracil, Leucovorin, Cisplatin, and Epidoxorubicin in a Randomized Controlled Trial

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