Induction Chemotherapy and Dose Intensification of the Radiation Boost in Locally Advanced Anal Canal Carcinoma: Final Analysis of the Randomized UNICANCER ACCORD 03 Trial Didier Peiffert, Laetitia Tournier-Rangeard, Jean-Pierre Ge ´rard, Claire Lemanski, Eric Franc ¸ois, Marc Giovannini, Fre ´de ´rique Cvitkovic, Xavier Mirabel, Olivier Bouche ´, Elisabeth Luporsi, Thierry Conroy, Christine Montoto-Grillot, Franc ¸oise Mornex, Antoine Lusinchi, Jean-Michel Hannoun-Le ´vi, Jean-Franc ¸ois Seitz, Antoine Adenis, Christophe Hennequin, Bernard Denis, and Michel Ducreux Didier Peiffert, Laetitia Tournier-Rangeard, Elisabeth Luporsi, Thierry Conroy, EA 4360 Centre, Alexis Vautrin and Nancy Univer- sity, Vandoeuvre-le ` s-Nancy, France; Jean- Pierre Ge ´ rard, Eric Franc ¸ois, Jean-Michel Hannoun-Le ´ vi, Centre Antoine Lacassagne, Nice, France; Michel Ducreux, Institut Gustave Roussy, Villejuif, France; Claire Lemanski, Centre Val d’Aurelle, Montpel- lier, France; Marc Giovannini, Institut Paoli- Calmettes, Marseille, France; Fre ´ de ´ rique Cvitkovic, Ho ˆ pital Rene ´ Huguenin–Institut Curie–Saint-Cloud, Paris, France; Xavier Mirabel, Antoine Adenis, Centre Oscar Lambret, Lille, France; Olivier Bouche ´, Robert Debre ´ University Hospital, Reims, France; Christine Montoto-Grillot, Bureau d’Etudes Cliniques et The ´ rapeutiques, Fe ´ de ´ ration Nationale des Centres de Lutte Contre le Cancer, Paris, France; Franc ¸oise Mornex, University Hospital, Lyon-Sud, France; Jean-Franc ¸ois Seitz, Centre Hospitalier de la Timone, Marseille, France; Christophe Hennequin, Assistance Publique-Hopitaux de Paris, Ho ˆ pital Saint- Louis, Paris, France; Bernard Denis, Ho ˆ pital Pasteur, Colmar, France; Michel Ducreux, Groupe Tumeurs Digestives, Fe ´ de ´ ration Nationale des Centres de Lutte Contre le Cancer (UNICANCER). Submitted March 18, 2011; accepted February 22, 2012; published online ahead of print at www.jco.org on April 23, 2012. Supported by grants from Programme Hospitalier de Recherche Clinique 1997 from the French Ministry of Health, Comi- te ´ s de ´ partementaux de la Ligue Contre le Cancer (Meurthe et Moselle, Meuse, Moselle, Vosges), and Ligue Nationale Contre le Cancer. Presented in part at the 45th annual meet- ing of the American Society of Clinical Oncology, Orlando, Fl, May 29 to June 2, 2009. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Didier Peiffert, MD, PhD, Centre Alexis Vautrin, 6 avenue de Bourgogne, 54511 Vandoeuvre-le ` s-Nancy cedex, France; e-mail d.peiffert@ nancy.unicancer.fr. © 2012 by American Society of Clinical Oncology 0732-183X/12/3016-1941/$20.00 DOI: 10.1200/JCO.2011.35.4837 A B S T R A C T Purpose Concomitant radiochemotherapy (RCT) is the standard for locally advanced anal canal carcinoma (LAACC). Questions regarding the role of induction chemotherapy (ICT) and a higher radiation dose in LAACC are pending. Our trial was designed to determine whether dose escalation of the radiation boost or two cycles of ICT before concomitant RCT lead to an improvement in colostomy-free survival (CFS). Patients and Methods Patients with tumors  40 mm, or  40 mm and N1-3M0 were randomly assigned to one of four treatment arms: (A) two ICT cycles (fluorouracil 800 mg/m 2 /d intravenous [IV] infusion, days 1 through 4 and 29 to 32; and cisplatin 80 mg/m 2 IV, on days 1 and 29), RCT (45 Gy in 25 fractions over 5 weeks, fluorouracil and cisplatin during weeks 1 and 5), and standard-dose boost (SD; 15 Gy); (B) two ICT cycles, RCT, and high-dose boost (HD; 20-25 Gy); (C): RCT and SD boost (reference arm); and (D) RCT and HD boost. Results Two hundred eighty-three of 307 patients achieved full treatment. With a median follow-up period of 50 months, the 5-year CFS rates were 69.6%, 82.4%, 77.1%, and 72.7% in arms A, B, C, and D, respectively. Considering the 2  2 factorial analysis, the 5-year CFS was 76.5% versus 75.0% (P = .37) in groups A and B versus C and D, respectively (ICT effect), and 73.7% versus 77.8% in groups A and C versus B and D, respectively (RT-dose effect; P = .067). Conclusion Using CFS as our main end point, we did not find an advantage for either ICT or HD radiation boost in LAACC. Nevertheless, the results of the most treatment-intense arm B should prompt the design of further intensification studies. J Clin Oncol 30:1941-1948. © 2012 by American Society of Clinical Oncology INTRODUCTION The prognosis of locally advanced anal canal carci- nomas (LAACC) remains moderate. Two random- ized trials have demonstrated that the concomitant addition of fluorouracil (FU) and mitomycin C (MMC) chemotherapy (CT) to radiotherapy (RT) can benefit colostomy-free survival (CFS). 1,2 De- spite this, the 2-year local recurrence and colostomy rates remain relatively high at 25% and 30%, respec- tively, and metachronous metastases were frequent, although frequently not isolated. 2 Hence, the thera- peutic ratio of concomitant radiochemotherapy could potentially be increased by intensifying the RT dose, keeping in mind functional results and the risk of necrosis. Because of the toxicity related to MMC and to the proven efficacy of cisplatin-based regimens in other squamous cell carcinomas (SCC), a phase II trial was previously designed to test the combination of FU and cisplatin in SCC of the anal canal. This trial used induction CT (ICT) followed by concom- itant radiochemotherapy (RCT) and demonstrated good treatment tolerance and a high response rate after ICT, thereby partially providing the rationale for our current trial. 3 The split-course therapeutic scheme for irradi- ation and moderate doses of FU were chosen, as was JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 30  NUMBER 16  JUNE 1 2012 © 2012 by American Society of Clinical Oncology 1941 217.19.202.101 Information downloaded from jco.ascopubs.org and provided by at CENTRE OSCAR LAMBRET on April 5, 2013 from Copyright © 2012 American Society of Clinical Oncology. All rights reserved.