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Treatment intensification by induction chemotherapy (ICT) and radiation dose escalation in locally advanced squamous cell anal canal carcinoma (LAAC): definitive analysis of the Intergroup ACCORD 03 trial. Abstract #4033 T. Conroy(1), M. Ducreux (2), C.Lemanski (3), E. François (4), M. Giovannini (5), F. Cvitkovic (6), X. Mirabel (7), O. Bouché (8), C. Montoto-Grillot (9), D. Peiffert (1) Institut Gustave Roussy – Villejuif ; (3) Centre Val d’Aurelle-Paul Lamarque – Montpellier; (4) Centre Antoine Lacassagne – Nice; (5) Institut Paoli-Calmettes – Marseille; (6) Centre René Huguenin – Saint-Cloud; (7) Centre Oscar Lambret – Lille; (8) Hôpital Robert Debré – Reims; (9) Fédération Nationale des Centres de Luttre Contre le Cancer – Paris France Intergroup trial : FNCLCC: Fédération Nationale des Centres de Lutte Contre le Cancer, SFRO : Société Française de Radiothérapie Oncologique, FFCD : Fédération Francophone de Cancérologie Digestive (1) Centre Alexis Vautrin – Nancy; Backgroun d (2) Trial design : 4 arms study Patients with larger tumors or clinical N+ locally advanced anal canal carcinoma cancer have poor local control and higher colostomy rates. Local relapse remains the first cause of failure. Pelvic irradiation with concomitant 5-FU and Mitomycin C chemotherapy and radiation boost is the standard treatment. Bartelink H et al: J Clin Oncol 1997;5:2040-9 UKCCCR : Lancet 1996;348:1049-54 A 5-FU/Cisplatin regimen delivered as induction and concomitant treatment was tested in a Phase II trial and achieved promising results : Perspectives RT: 45 Gy over 5 weeks after completion RT-CT : 98% FUP: 5-FU-Cisplatin 3-year survival Colostomy-free : 73% Relapse-free Tumour-specific : 88% Actuarial 3-year results (%) Arm C is the reference arm after induction CT : 61% Acute toxicity (number gr. 3-4 toxicities) during induction (ind) and concomitant treatment (cc) Status of cases Local response Concomitant chemoradiotherapy: delivered vs planned dose of 5-FU 307 patients were enrolled between January 1999 and March 2005 Previous phase II Study Results Eligibility : 70% Patients’ characteristics No grade 3-4 bleeding or neurological toxicities occurred Analysis of quality of life data Exploratory analysis of colostomy-free survival per arm One toxic death occurred in each arm • Anal canal primary : Peiffert D et al: Ann Oncol 2001; 12: 397-404 Rationale for the experimental arms : downstaging Induction chemotherapy Concurrent chemo and RT Size after chemotherapy Original size Local boost Higher dose Size before boost • • Follow-up – > 50% of T. volume inside the canal – Squamous cell carcinoma histologically proven – Adequate organ function B Primary end point Locally advanced clinical stage M0 : – T. diameter > 4 cm (T2-4), any N, or – T. diameter < 4 cm (T1-2) and N1-3 or usN1 Hb > 11g/dL – Neutrophils > 2,000 /µL – Platelets > 100,000 /µL – Creatinine < 130 µmol/L Pelvic radiotherapy • Age 18 – 80 years and performance status of 0-1 • Written informed consent D % Log rank: ns Conclusions • This trial analyzed according to the 2 X 2 factorial design, did not detect any significant benefit of induction chemotherapy with 5-FU and cisplatin at these doses nor of a radiation dose over 60 Gy on colostomy-free survival Treatment delivery - higher local control - better functional results A Colostomy-free survival : role of induction chemotherapy Biology : – C • Oncologic and functional results are good in all the 4 groups Treatment Objective s • • • Results were better than expected in the reference arm C: 77% colostomy-free survival at 3 years • Full dose of 5-FU during concomitant chemoradiation was not delivered in 19.3% of the cycles in the induction chemotherapy group vs 9% of the cycles in the upfront chemoradiation group To define the role of induction chemotherapy before definitive chemoradiation To define the role of higher dose of radiation delivered as a boost after pelvic CRT Treatment arms (chemotherapy details) • Radiotherapy doses were delivered respecting the prescribed doses in the 4 arms Arms A and B: induction chemotherapy then chemoradiation Induction and concomitant chemotherapy at W1, W5, W9 and W12 Primary end point • Colostomy–free survival at 3 years Secondary end point • Disease-free survival • Overall survival • Cumulative colostomy rate • Local-regional failure rate • Specific survival • Quality of life (EORTC QLQ– C30) • All treatments were well tolerated – 5-FU 800 mg/m2/d continuous infusion on D1 to D4 • Further analysis will be performed to identify a subgroup of patients who may benefit from the intensification – Cisplatin 80 mg/m2 at D1 Pelvic irradiation was initiated with chemo starting on W9. Arms C and D: upfront chemoradiation: Boost irradiation : techniques and doses Concomitant chemotherapy at W1 and W5 Colostomy-free survival : role of higher dose of the boost # 281 patients – 5-FU 800 mg/m2/d continuous infusion D1 to D4 – Cisplatin 80 mg/m2 at D1 Pelvic irradiation was initiated on W1 at D1 Acknowledgments : Treatment arms (radiotherapy details) 1. Large pelvic field with superior border at L5/S1 junction • Box technique or 3-field technique • Inguinal fields when indicated • 45 Gy in 25 fractions of 1.80 Gy / 5 W The patients and their families % Mireille Hirsch, Elisabeth Luporsi, Monique Maire Log rank: p:0.067 Induction chemotherapy: delivered vs planned dose of 5-FU 2. Short gap 8 – 21 days 3. Reduction for boost irradiation Hypothesis, sample size and statistics Arms A and C: 15 Gy Arms B and D: 20-25 Gy All investigators Pr Peiffert, Pr Conroy, Dr Kaminsky, Dr Tournier-Rangeard -Centre Alexis Vautrin Nancy; Pr Gérard, Pr Mornex, Dr Romestaing, Dr Chapet, Dr Ardiet - Centre Hospitalier de Lyon-Sud Lyon; Pr Ducreux, Dr Lusinchi, Dr Villing, Dr Deutsch, Dr Malka, Dr Boige Institut Gustave Roussy Villejuif; Dr François, Dr Hannoun-Lévy, Dr Thomas - Centre Antoine Lacassagne Nice; Dr Lemanski, Dr Senesse, Dr Jacquot, Dr Azria - Centre Val d'Aurelle Montpellier; Dr Giovannini, Pr Seitz, Dr Magnin, Dr Viret - Institut PaoliCalmettes Marseille; Pr Adenis, Dr Mirabel - Centre Oscar Lambret Lille; Dr Martel, Dr Carrie, Dr Desseigne, Dr Montbarbon - Centre Léon Bérard Lyon; Pr Hennequin, Dr Bleichner-Hennequin - Hôpital Saint-Louis Paris; Dr Etienne, Dr Lamezec - Clinique Armoricaine Saint-Brieuc; Dr Ollivier, Dr Jacob, Dr Vie - Centre François Baclesse Caen ;Pr Guimbaud, Pr Bugat, Dr Delors, Dr Rives - Institut Claudius Regaud Toulouse; Dr Goineau, Dr Atlani, Dr Denis - Hôpital Pasteur Colmar; Pr Mahé - Centre René Gauducheau Nantes; Pr Bouché - CHU Robert Debré Reims; Dr Sobhani, Dr Aparicio - Hôpital Bichat Paris; Dr Cvitkovic - Centre René Huguenin Saint-Cloud; Dr Paillot, Pr Michel - CHU Charles Nicolle Rouen; Dr Seng, Dr Hamidou - Centre Henri Becquerel Rouen; Pr Piedbois, Dr Sobhani - CHU Henri Mondor Créteil; Dr Zawadi - Centre Hospitalier Départemental La Roche-sur-Yon; Dr Leloup - Hôpital La Source Orléans; Pr Seitz, Dr Paoli - CHU La Timone Marseille; Pr Rixe, Dr Pourel-Hôpital Claude Bernard Metz; Dr Huchet, Dr Laporte - Hôpital Georges Pompidou Paris; Dr Nasca - Institut Jean Godinot Reims; Dr Noirclerc - Centre Hospitalier du Hasenrein Mulhouse; Pr Raoul - Centre Eugène Marquis Rennes; Dr Borel - Centre Paul Strauss Strasbourg; Dr Platini - Hôpital Bon-Secours Metz; Dr Saidi - Hôpital Clarac Fort-de-France; Dr Albin - Clinique Pasteur Evreux; Dr Soulié - Centre Paul Papin Angers; Dr Cailleux - Clinique Fleming Tours. • Brachytherapy LDR delivered on reference isodose • Hypothesis: induction chemotherapy or a higher dose of RT would increase colostomy-free survival from 70% to 85% • External beam irradiation: 1.8 to 2.0 Gy per fraction • Number of pts= 288: assumed a constant accrual rate of 60 patients per year, a 5year duration of inclusion inclusion was expected • 2 x 2 factorial design • Data were analyzed according to intention to treat 0 6 This study was supported by grants from the Ligue Nationale Contre le Cancer and Clinical Research Program (PHRC 1997) from the French Ministry of Health © Centre Alexis Vautrin – mai 2009 • alpha= 5%, beta= 10%, unilateral test