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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/m2/d intravenous [IV] infusion, days 1 through 4 and 29 to 32; and cisplatin 80 mg/m2 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.

International audience; BACKGROUND:The combination of bevacizumab and bolus 5-fluorouracil, leucovorin and irinotecan is highly effective in patients with metastatic colorectal cancer (mCRC). This randomised, multicenter, non-comparative phase II trial assessed the efficacy and safety of bevacizumab plus oral capecitabine plus irinotecan (XELIRI) or infusional 5-fluorouracil, leucovorin plus irinotecan (FOLFIRI) as first-line therapy for patients with mCRC.PATIENTS AND METHODS:Patients received bevacizumab 7.5mg/kg on day 1 plus XELIRI (irinotecan 200mg/m(2) on day 1 and oral capecitabine 1,000 mg/m(2) bid on days 1-14) every 3 weeks or bevacizumab 5mg/kg on day 1 plus FOLFIRI (5-fluorouracil 400mg/m(2) on day 1 plus 2,400 mg/m(2) as a 46-h infusion, leucovorin 400mg/m(2) on day 1, and irinotecan 180 mg/m(2) on day 1) every 2 weeks. Patients aged ≥ 65 years received a lower dose of capecitabine (800 mg/m(2) twice daily). The primary endpoint was 6-month progression-free survival (PFS) rate.RESULTS:A total of 145 patients were enrolled (bevacizumab-XELIRI, n=72; bevacizumab-FOLFIRI, n=73). The 6-month PFS rate was 82% (95% confidence intervals (CI) 71-90%) in the bevacizumab-XELIRI arm and 85% (95% CI 75-92%) in the bevacizumab-FOLFIRI arm. In both the bevacizumab-XELIRI and bevacizumab-FOLFIRI arms, median PFS and overall survival (OS) were 9 and 23 months, respectively. The most frequent toxicities were grade 3/4 neutropenia (bevacizumab-XELIRI 18%; bevacizumab-FOLFIRI 26%) and grade 3 diarrhoea (12% and 5%, respectively).CONCLUSIONS:This randomised non-comparative study demonstrates that bevacizumab-XELIRI and bevacizumab-FOLFIRI are effective regimens for the first-line treatment of patients with mCRC with manageable toxicity profiles.

Les Centres de Lutte Contre le Cancer (CLCC) sont des etablissements de Sante prives a but non lucratif, participant au service public hospitalier, exclusivement dedies a la prise en charge des cancers. Ils assurent des missions de soins, de recherche et d’enseignement, avec la volonte permanente d’accroitre la qualite de la prise en charge et l’accessibilite aux soins. Constituant un reseau a la fois regional et national, les Centres sont porteurs d’un modele de prise en charge globale et pluridisciplinaire des personnes atteintes d’un cancer,modele qui a largement servi de socle aux propositions de prise en charge des malades du Plan Cancer 1.

Background To assess activity and safety of an experimental combination of irinotecan and oxaliplatin (IRINOX) as first-line treatment in advanced colorectal cancer. Patients and methods In this randomized phase II trial, 80 patients were treated: arm A (IRINOX) in 40 patients received at day 1 oxaliplatin 85 mg/m2 and irinotecan 180 mg/m2 biweekly, standard arm B received a biweekly simplified folinic acid (FA) and fluorouracil (FU), FA 200 mg/m2 in a 2-h infusion and bolus injection of 5FU 400 mg/m2 on day 1, then a two 400 mg/m2 continuous infusion of FU on days 1 and 2 with either oxaliplatin 85 mg/m2 (20 patients) or irinotecan 180 mg/m2 (20 patients). Results Twenty-one partial responses (52.5%, median duration 7.2 months) were observed with the IRINOX arm and two complete and 20 partial responses (55%, median duration 6.4 months) with arm B. Median progression-free and overall survival times were 8.4 and 19 months, respectively, in the IRINOX arm and 8.1 and 20.4 months in arm B. Main grade 3/4 toxic effects were, respectively, neutropenia 42.5% and 32.5%; febrile neutropenia 10% and 5%; diarrhea 32.5% and 7.5%; vomiting 10.0% and 5%; neurosensory toxicity 17.5% and 7.5%. Conclusion The IRINOX arm has a manageable toxicity and is active.

e14041 Background: The measurement of ETS at 8 weeks was reported to predict long-term outcome in first line mCRC treated with irinotecan based chemotherapy (CT) + cetuximab. This study has for aim...

4010 Background: In a randomized phase II trial of F vs G in 88 MPA patients (pts), we reported that F induces a response rate > 30% (Ychou, ASCO 2007). Because the trial met its planned objectives, it has been pursued as a phase III to compare overall survival (OS). Methods: Chemotherapy-naive pts aged 18-75 years with histologically/cytologically-confirmed measurable MPA were randomized to receive F (O 85 mg/m2 d1 + I 180 mg/m2 d1 + LV 400 mg/m2 d1 followed by 5FU 400 mg/m2 bolus d1 and 2,400 mg/m2 46h continuous infusion biweekly) or G (1g/m2 IV weekly x7, 1 w rest, then weekly × 3q4w). Eligibility included adequate organ function, performance status (PS) 0-1, no prior chemotherapy or radiotherapy. Pts were stratified by centre, PS, and primary tumor location (head vs. other). The primary endpoint was OS. With a planned sample size of 360 pts, the trial was designed to detect an improvement from 7 to 10 months (m) median survival (HR = 0.70) with 80% power and α = 0.05. Results: 342 pts were enrolled b...

LBA4007 Background: Following the results of randomized trials FFCD 9203 and EORTC 2291, neoadjuvant CT-RT is considered standard treatment for LARC. The ACCORD 12/0405 PRODIGE 2 trial was initiated to optimize this regimen. Methods: Pts with T3 or resectable T4 N0–1-2 M0, rectal adenocarcinoma were randomized to arm A: concurrent RT 45Gy/25f/5 weeks (w) + capecitabine (800mg/m2/bid) or arm B: concurrent RT 50Gy/25f/5w + capecitabine (800mg/m2/bid/5/7days) + oxaliplatine 50mg/m2/w. Resection with Total Mesorectum Excision was scheduled 6 weeks after the end of CT-RT. Adjuvant chemotherapy was optional. 590 patients were needed to show an increase in the pathological complete response (Dworak) rate from 11% (arm A) to 20% (arm B). Circumferential positive rectal margin (CRM R1) was defined as the presence of residual cancer cells within 0 to 1 mm from the perirectal surface. Results: This trial closed in 07/2008 after randomization of 598 pts since 11/2005. Patients characteristics of 586 eligible pts were well balanced: male 66%, median age 61 years, 66% low rectum, 87% T3 stage. Data base was locked in March 2009. Results are reported in Table . Conclusions: The RT 50 capox regimen is compatible with surgery in 98% of cases with no increase in postoperative complication. In the RT 50 arm, there is a trend in favour of a higher rate of pathological complete sterilization and lower rate of positive CRM. These data could contribute to design a new standard preoperative regimen for LARC. 50 Gy/25 F/5 weeks combined with concurrent chemotherapy could be proposed as an efficient schedule. [Table: see text] No significant financial relationships to disclose.

4071 Background: There is no validated biomarker to predict the efficacy of BEV, an anti-VEGF monoclonal antibody. Rare cell subpopulations such as CEC are good candidates. Methods: Pts with mCRC, aged 18–75 yrs, ECOG performance status (PS) 0–2, and no prior palliative chemotherapy were randomized to either BEV (5 mg/kg) + FOLFIRI every 2 weeks (arm A, 12 cycles) or BEV (7,5 mg/kg) + XELIRI every 3 weeks (arm B, 8 cycles). BEV was continued until disease progression [PD]. The primary endpoint was crude 6-month progression-free survival (PFS) rate. In consenting pts, CEC (CD45-CD31+CD146+7- amino-actinomycin- cells) were measured at baseline (Day [D]1, before treatment), D8, and at the end of cycle 1 (D15 or 22) in 1-mL whole blood by four-color flow cytometry according to a method we established previously (J Immunol Methods 2008). Results were correlated to pts’ characteristics and primary endpoint (Wilcoxon's, Fisher's, and trend tests). Results: From 03/06 to 01/08, we enrolled 145 pts (male, 56%; median age, 61 yrs; PS 0–1, 91%; number of metastatic sites [1/2/>2], 45/48/8%). Pts with at least one CEC measurement (n=99; arm A, 51; arm B, 48) did not differ from the 46 other pts regarding sex, age, PS, and number of metastatic sites. Baseline CEC levels (n=97; median, 16/mL) were higher in PS 1–2 pts (n=42) than in PS 0 pts (n=55) (17 vs. 12/mL, p=0.02) (age, sex, number of metastatic sites: NS) and in pts with PD (n=17) than in pts with non- PD (n=80) at 6 months (30 vs. 15/mL, p=0.004). CEC levels were higher at the end of cycle 1 in the PD group (n=17) than in the non-PD group (n=74) (34 vs. 14/mL, p=0.01). The 6-month PFS rate varied from 0% to 32% in the 4 groups defined by baseline and end-of-cycle- 1 CEC values (cutoff: baseline median) (trend test, p=0.006) ( table ). Conclusions: Baseline and end-of-cycle-1 CEC levels may predict tumor control in patients with mCRC starting first-line BEV + chemotherapy. [Table: see text] [Table: see text]

4033 Background: Concomitant radiochemotherapy (CRT) is the standard treatment of LAAC. The addition of an ICT (2 cycles of 5 FU-Cisplatin) and of a higher dose of irradiation boost (HDRT) to CRT were evaluated in a factorial 2X2 arms trial (A= ICT; B=ICT+HDRT; C= Reference arm = Pelvic RT 45 Gy/25 fractions with 2 cycles of 5FU-Cisplatin and a boost of 15 Gy; D= HDRT). The aim of the study was to detect a increase from 70 to 85% of colostomy-free survival (CFS) at 3 years. Methods: 307 pts with T2 > 4 cm or T3-T4 Nx or any T, N1–3 M0 LAAC were included. Mean age was 59 y and sex-ratio was 1/6. The 4 arms were well balanced concerning the sex-ratio, age, stage, T size and differentiation. Results: 306/307 pts were eligible. Toxicities were similar in the 4 arms (toxic deaths: A=4, B=2, C=2, D=1). The compliance was: 99% for ICT, 100% for pelvic RT-CT, and 96% for the boost. The tumour complete response (+ partial response) at 2 months were: A=78% (+18%), B=86% (+13%), C=74% (+21%), D=74 % (+22%) (NS). The median follow-up was 43 months. Overall failure rates were 28% (A=28%, B=21%, C=30%, D= 30%). The actuarial results at 3 years were: CFS was 83%: A= 83%, B= 85%, C= 86%, D= 80% with no significant difference of ICT nor HDRT (A+B=84% vs C+D=83% for ICT; A+C= 84% vs B+D=83% for HDRT). Local control was 88%: A= 80%, B= 96%, C= 90 %, D= 87%: (NS). Event-free survival was 71% : A= 70%, B= 78%, C= 67%, D= 68%: (NS). Overall survival was 78% at 3 y (73% at 5 y) with no difference between arms. Specific survival was 84 % : A= 79%, B= 88,5%, C= 89%, D= 79%: (NS) Conclusions: Neither ICT nor HDRT improved the CFS at 3 years, nor the secondary end points. No significant financial relationships to disclose.

4086 Background: The combination of BEV and chemotherapy is highly effective in patients with mCRC and improves response rate, progression-free survival and overall survival compared with chemotherapy alone. This randomized non-comparative phase II trial evaluated the efficacy and safety of BEV in combination with either XELIRI or FOLFIRI as first-line therapy for mCRC. Methods: Patients were eligible for inclusion in this study if they had histologically proven measurable mCRC, were aged 18–75 years, and had an ECOG performance status (PS) of 0–2. Patients were treated with 8 cycles of XELIRI (irinotecan 200 mg/m2 on Day 1 and capecitabine 1000 mg/m2 bid on Days 1–14) + BEV 7.5 mg/kg on Day 1, every 3 weeks or 12 cycles of FOLFIRI (irinotecan 200 mg/m2 on Day 1 + 5-fluorouracil (5-FU) 400 mg/m2 + folinic acid 400 mg/m2 on day 1 followed by 5-FU 2400 mg/m2 via 46-h infusion) + BEV 5 mg/kg on day 1, every 2 weeks. BEV was continued to disease progression. Patients aged ≥65 years received a lower daily dose of capecitabine (800 mg/m2 bid). The primary endpoint was crude progression-free survival (PFS) at 6 months. Results: In total, 145 patients were entered in the study between March 2006 and January 2008; 72 patients received BEV + XELIRI and 73 patients received BEV + FOLFIRI (male 64%/48%; median age 61/61 years; 35/36% aged >65 years). Preliminary results from the first 6 months of follow-up are reported here. A total of 491/783 cycles was administered, 63%/67% receiving at least the initially planned number of cycles (8 cycles for BEV + XELIRI and 12 for BEV + FOLFIRI). Main results are given in the table . Conclusions: This randomized non-comparative study has shown that BEV + XELIRI and BEV + FOLFIRI are similarly effective treatments for patients with mCRC, with manageable toxicity profiles. Results with updated follow-up will be presented at the Meeting. [Table: see text] [Table: see text]

Introduction Le cancer du pancreas localement avance reste un probleme therapeutique difficile ou l’interet de la radiochimiotherapie n’est pas demontre peut-etre en raison du caractere obsolete des protocoles utilises. L’essai ACCORD 09/0201 avait pour but d’evaluer l’efficacite et la toxicite de deux schemas nouveaux de radiochimiotherapie des cancers du pancreas localement avances. Materiels et Methodes Dans le bras A les patients (pts) recevaient le docetaxel 20 mg/m 2 par semaine et une administration en continu de 5FU a 200 mg/m 2 par jour pendant 6 semaines, ce bras a fait l’objet d’une analyse intermediaire apres inclusion de 20 patients et a ete arrete faute d’efficacite conformement aux regles du protocole. Dans le bras B les pts recevaient le docetaxel 20 mg/m 2 et le cisplatine 20 mg/m 2 le meme jour une fois par semaine pendant 6 semaines. La radiotherapie externe comportait 54 Gy par fractions de 1,8 Gy en six semaines. Apres l’analyse intermediaire le bras B a ete continue seul en principe jusqu’a un nombre total de 60 patients, l’inclusion a ete arrete en fevrier 2008 en raison du ralentissement des inclusions et de l’arrivee de nouveaux projets. Resultats 51 patients, 31 hommes et 20 femmes, de 62 ans d’âge median et ayant une tumeur non resecable limitee au pancreas et au plexus caeliaque ont ete inclus du 06/10/2003 au 15/ 02/2008. 36 patients (71 %) avaient un indice de Karnofsky 2 . La dose mediane totale de radiotherapie recue par les patients etait de 54 Gy. La radiotherapie a ete interrompue chez 6 patients. 29 patients ont eu au moins un episode de toxicite de grade 3 ou 4 pendant le traitement, principalement digestif (nausees retrouvees chez 9 patients, vomissements chez 9 patients, douleurs abdominales chez 5 patients). La toxicite a ete la cause du deces d’un patient a 6 mois, 30 patients ont progresse. Les donnees sur la progression ne sont actuellement validees que chez 47 patients. Chez ces patients, le taux de survie sans progression a 6 mois, critere de jugement principal, etait de 47 % [33-61]. Trois patients ont pu etre operes secondairement de leur tumeur dont une patiente en vie maintenant depuis 4 ans avec une remission complete histologique lors de l’intervention. Conclusion L’association de docetaxel, de cisplatine et de radiotherapie a une activite limitee en cas de cancer du pancreas localement avance, neanmoins certaines reponses morphologiques d’excellente qualite ont permis de realiser une resection seconde et des reponses completes pathologiques ont ete observees. Remerciements, financements, autres Avec le soutien de la Ligue Nationale Contre le Cancer et des laboratoires Amgen et Sanofi-Aventis.

Introduction Le bevacizumab, anti-angiogenique, represente une avancee majeure dans le traitement du cancer colorectal metastatique. A ce jour, aucun biomarqueur ne permet d’en predire l’efficacite. Des sous-populations cellulaires tres rares comme les cellules endotheliales circulantes sont de bons candidats. Patients et Methodes L’essai ACCORD 13 a randomise dans 15 centres entre 03/2006 et 01/2008 en premiere ligne 149 patients avec cancer colorectal metastatique entre : 1/FOLFIRI (irinotecan 180 mg/m 2 jour [J] 1, acide folinique 400 mg/m 2 J1, 5-fluoro-uracile 400 mg/m 2 J1 puis 2 400 mg/m 2 sur 48 h) plus bevacizumab (5 mg/kg) tous les 14 J ; 2/ XELIRI (irinotecan 200 mg/m 2 J1, capecitabine 2 000 mg/m 2 /j J1 a J14) plus bevacizumab (7,5 mg/kg) tous les 21 J. Dans les centres participants et chez les patients consentants, un prelevement sanguin etait effectue a J1 (avant traitement), J8 (facultatif) et avant debut de la 2 e cure (J14 [FOLFIRI] ou J21 [XELIRI]). Les cellules endotheliales circulantes, identifiees par le phenotype CD45 - , CD31 + , CD146 + , 7-amino-actinomycine - , ont ete quantifiees en cytometrie de flux 4 couleurs. Les marquages ont ete realises dans 1 ml de sang total afin d’accumuler un grand nombre d’evenements (jusqu’a 5 10 6 par test). Resultats Les 102 patients ayant eu au moins un dosage de cellules endotheliales circulantes n’etaient pas significativement differents des 47 autres patients en termes de sexe, d’etat general et de nombre de sites metastatiques, mais etaient significativement plus jeunes ( vs 47 %, p = 0,03). Les valeurs initiales de cellules endotheliales circulantes n’etaient pas correlees a l’etat general ou au nombre de sites metastatiques. Une diminution ou une augmentation du taux de cellules endotheliales circulantes superieure a un facteur 2 etait observee chez 3 et 13 patients, respectivement, entre J1 et J8, et 47 et 2 patients, respectivement, entre J8 et J14/21. Les correlations entre les taux de cellules endotheliales circulantes et les facteurs pronostiques et la reponse therapeutique, ainsi qu’une analyse multivariee, seront presentees lors des JFHOD 2009. Conclusion Le monitorage des cellules endotheliales circulantes pourrait aider a predire precocement la reponse a une association chimiotherapie-bevacizumab en premiere ligne de traitement du cancer colorectal metastatique. Remerciements, financements, autres Roche, Pfizer.

4089 Background: Both the FFCD 9203 [J Clin Oncol 2006;24:4620–5] and the EORTC 22921 [NEJM 2006;355:1114–23] trials showed superiority of neoadjuvant chemoradiation (CT-RT) to radiotherapy (RT) al...

4516 Background: In a phase II trial of Folfirinox (F) in 35 MPA patients (pts), we reported a 26% response rate and median survival of 9.5 months (mo) with quality of life improvement (Conroy, JCO 2005). The aim of this phase II trial was to compare the response rate and safety of F vs G in pts with MPA. Methods: Chemotherapy-naïve pts aged 18–75 years with histologically or cytologically confirmed measurable MPA were randomized to receive G (1,000 mg/m2 IV weekly x 7 for 8 weeks [wks] then weekly x 3 out of 4 wks) or F (O 85mg/m2 d1 + I 180mg/m2 d1 + LV 400mg/m2 d1 followed by 5FU 400mg/m2 bolus d1 and 2,400 mg/m2 46h continuous infusion biweekly). Patients were stratified by centre, performance status (ECOG 0 versus 1), and primary tumor location (head vs other). Primary endpoint was response rate. Results: From 01/05 to 11/06, all planned 88 pts (44 per arm) were enrolled. Median age was 56 yrs [35–76]. Currently, safety data for 81 pts (41F/40G) and efficacy data for 65 pts (31F/34G) are available (17 too early). One pt was ineligible in arm F. Two pts, one in each arm, did not receive protocol therapy. Median number of wks on treatment was 18 (F) and 7 (G). No toxic death occurred. Main grade 3–4 toxicities (arm F vs G) were G3 neutropenia (32%/17.5), G4 neutropenia (19.5%/0), G3–4 thrombocytopenia (12%/0), G3 vomiting (17%/2.5), G3 transaminases (0%/15) and G3–4 fatigue (27%/15).Confirmed partial responses (PR) rates (F/G) were 38.7% (12/31) and 11.7 % (4/34) according to the investigators and median duration of response was 6,3 and 4,6 mo. PR and stable disease (SD) were documented for 21/31 evaluable pts in arm F and expert review confirmed 13 PR (41.9 %) and 6 SD (19.3%). Conclusions: Folfirinox induces a response rate > 30% with manageable toxicity in ECOG 0–1 pts with MPA. According to these interim results, this trial will continue as a phase III study. Updated results will be presented at the meeting. Supported by a PHRC 2004 grant from the French Ministry of Health. [Table: see text]

3586 Background: LV5-FU2 + CPT-11 or oxaliplatin (OHP) are standard therapies in first line MCRC. This phase II trial evaluates an experimental regimen of CPT-11 + oxaliplatin, without 5FU. Methods: First line MCRC evaluable patients (pts) were randomized to receive, every two weeks, either: Arm A = OHP 85 mg/m2 d1 followed by CPT-11 180 mg/m2 (IRINOX), or Arm B = simplified LV5-FU2 (leucovorin 200 mg/m2 as a 2 h-infusion d1, 5FU bolus 400 mg/m2 d1, and 5FU continuous infusion 2400 mg/m2 d1–2) and CPT-11 180 mg/m2 d1 (FOLFIRI), or simplified LV5-FU2 and OHP 85 mg/m2 d1 (FOLFOX). Results were combined for the two standard arms (FOLFIRI + FOLFOX). Results: 80 pts were included between 09/2002 and 04/2005, 40 in IRINOX (arm A), 20 each in FOLFIRI and FOLFOX (arm B). Pts characteristics (A:B): M/F = 27/13:29/11; median age (range): 63 (41–76):61 (47–75); PS (0/1/2): 16/21/3:16/22/2; median number of cycles (range): 8.0 (1–16):12 (1–26). Safety data: no toxic death. IRINOX (318 cycles): NCI G3–4 neutropenia, 43.6% (pts), 14.7% (cycles); G3–4 neurotoxicity, 17.9% (pts), 5.0% (cycles); G3–4 diarrhea, 33.3% (pts), 5.3% (cycles). FOLFIRI (238 cycles) and FOLFOX (186 cycles): G3–4 neutropenia, 40% (pts) and 23.8% (pts) respectively (8.8% and 7.6% of cycles); G3–4 neurotoxicity, 0% and 14.3% (pts), 0% and 2.7% (cycles); G3–4 diarrhea 15% and 0% (pts), 2.1% and 0% (cycles). Median relative dose-intensity was 0.86 (0.57–1.0) for CPT-11, 0.86 (0.57 -1.0) for OHP in the IRINOX arm. We observed 21 PR in the IRINOX arm, 19 PR and 2 CR in the 2 control arms, for an ORR = 52.5%, 90% CI (38–66). Median follow-up: 17 months, median PFS for IRINOX: 8.4 months. Conclusions: The combination of CPT-11 and OHP (IRINOX) at these doses, every 2 weeks, appears safe and active in first line MCRC. [Table: see text]