BACKGROUND Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative. PATIENTS AND METHODS In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m(2)) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m(2)) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m(2)). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS). RESULTS A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7-FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7-FOLFIRI. CONCLUSIONS FOLFOX7-FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing. CLINICAL TRIALS NUMBER NCT00268398.

4533 Background: There are several standard chemotherapies in locally advanced or metastatic gastric or cardia adenocarcinoma, including ECF. Methods: Patients (pts) with a gastric or cardiac adenocarcinoma, locally advanced or metastatic, not surgically curable, with a WHO PS ≤2 and evaluable or measurable lesions, were randomized (1:1) according to the following sequences: ECC (epirubicin 50 mg/m2 D1+ cisplatin 60 mg/m2 D1 + capecitabine 2000 mg/m2 D2 to D15, every 3 weeks) in 1st line, then FOLFIRI (IRI 180 mg/m2 D1, leucovorin 400 mg/m2 D1, bolus 5FU 400 mg/m2 D1 and continuous 5FU 2400 mg/m2 in 46h, every 2 weeks) in 2nd line (Arm A) vs the reverse sequence (Arm B) with a stratification for center, PS, adjuvant treatment, site, linitis and measurable disease. To show an improvement in median time to treatment failure for the 1st line (TTF: time between randomization and progression, or treatment discontinuation or recurrence or death) of 15 to 20 weeks for arm B (α bilateral 5%; β 20 %), 381 failures and 416 pts are required in 4-year period. An interim analysis is planned when at least 190 failures are observed (ITT). TTF is estimated according to the Kaplan Meier method and compared with a Log-rank test. Results: In arm A and B, 174 and 175 pts were included respectively, between 17/06/05 and 21/12/07. Pts characteristics are: PS 1: 51%, med. age 60 years, gastric 67%, M+ 88%, resected primary tumor 27% and linitis 23%. In arms A and B respectively, 141 and 147 pts received at least one dose in 1st line and 61 and 44 pts in 2nd line. Toxicities during the first line is more frequent in the ECC than in the FOLFIRI arm: grade 3/4 (88 vs 68% - p ≤0.0001) and grade 3/4 hemato toxicities (69 vs 36% - p ≤0.001). In 2nd line, toxicities frequency is not different in both arms. The median TTF in 1st line (n = 310 pts) is 4.7 months [3.8 - 5.7] for ECC and 5.2 months [4.4–6.0] for FOLFIRI (Log Rank p = 0. 78). Regarding the 252 failures observed (67% of the required events), the significance level to reject H0 is p = 0.012 (EAST V5). Conclusions: It is not possible yet to conclude to the superiority of FOLFIRI in 1st line; the final analysis after observation of 381 failures is required. Regarding toxicity, hemato-toxicity is more frequent with ECC in 1st line. [Table: see text]

Plusieurs schémas, dont l’ECF, sont des standards pour les adénocarcinomes gastrique ou du cardia localement avancés ou métastatiques. Les schémas à base d’irinotécan et la place d’un traitement de deuxième ligne sont peu évalués en phase III. L’objectif de cet essai est de comparer 2 séquences de polychimiothérapie : ECC puis FOLFIRI vs FOLFIRI puis ECC. Les pts porteurs d’un adénocarcinome de l’estomac ou du cardia histologiquement prouvé, localement avancé ou métastatique, non traitable chirurgicalement, avec un IP OMS ≤ 2 et des lésions mesurables ou évaluables (mais non mesurables), ont été randomisés 1 : 1 selon une séquence ECC (Epirubicine 50 mg/m2 J1 + Cisplatine 60 mg/m2 J1 + Capécitabine 2 000 mg/m2 J2 à J15, toutes les 3 s) en 1ère ligne puis FOLFIRI (IRI 180 mg/m2 J1, AF 400 mg/m2 J1, 5FU bolus 400 mg/m2 J1 et 5FU continu 2 400 mg/m2 sur 46 h, toutes les 2 s) en 2ème ligne (Bras A) vs la séquence inverse (Bras B) avec une stratification selon le centre, l’IP OMS, l’existence d’une chimiothérapie ou d’une radio-chimiothérapie adjuvante, la localisation, le type linite et le caractère mesurable. Pour mettre en évidence une amélioration de la médiane du Temps jusqu’à l’Echec du Traitement pour les 2 lignes (TET : délai entre la date de randomisation et la date de progression, ou de l’arrêt thérapeutique, ou de rechute ou de décès) de 15 à 20 semaines pour le bras B (α bilatéral 5 % et β 20 %) il est requis 381 échecs et d’inclure 416 pts en 4 ans. Une analyse intermédiaire était planifiée quand au moins 190 échecs seraient observés (ITT). Le TET est estimé selon la méthode de Kaplan Meier et comparé à l’aide de test du Log-rank. Dans le Bras A et B ont été inclus respectivement 174 et 175 pts entre le 17/06/2005 et le 21/12/2007 (recul médian 1 an). Les caractéristiques des pts sont : IP OMS 1 51 %, âge médian 60 ans, localisation gastrique 67 %, métastases 88 % (dont 83 % synchrones), tumeur primitive réséquée 27 % (dont 71 % R0) et linites 23 %. Dans le bras A et B respectivement, 141 et 147 pts ont reçu au moins une dose en 1ère ligne (soit 100 % des pts non pdv temporaires) et 61 et 44 pts en 2ème ligne. Les toxicités au cours de la 1ère ligne sont plus fréquentes dans le bras ECC que dans le bras FOLFIRI des toxicités grade 3/4 : 88 % vs 68 % (p ≤ 0,0001) et des toxicités hématologiques grade 3/4 : 69 % vs 36 % (p ≤ 0,001). En deuxième ligne, la fréquence des toxicités ne diffèrent pas selon les bras. Le TET médian préliminaire (n = 310 pts) est de 6,3 mois [4,8 - 6,8] pour ECC 1ère ligne et de 6,0 mois [4,8 - 7,1] pour FOLFIRI en 1ère Ligne (Log Rank p = 0,6848). Pour les 252 échecs observés (67 % des événements requis), le seuil de significativité pour rejeter H0 est p = 0,012 (EAST V5). Cette analyse intermédiaire ne permet pas de conclure à la supériorité du bras B (FOLFIRI en 1ère Ligne). Il est requis de réaliser l’analyse après l’observation de 381 échecs. Concernant la tolérance, Les toxicités hématologiques sont plus fréquentes pour l’ECC en 1ère ligne.

1108 Objectives: To evaluate efficacy and safety of SEGEMOX regimen for previously A and T pre-treated MBC patients. Methods: Forty-five women with MBC not eligible for A and/or T chemotherapy were enrolled on SEGEMOX study. SEGEMOX was delivered as follows: Gemcitabine was given at 1000 mg/m 2 /100min on day 1, followed by oxaliplatin at 100 mg/m 2 /120min iv on day 2 every 2 weeks. Efficacy results were analyzed and are presented in an intention to treat analysis and toxicity according to the total number of cycles regimen. Results: Forty-four of the 45 patients received at least 1 cycle of SEGEMOX. Fifty-eight perccent of the patients have received previous adjuvant chemo, 36% 1st line and 42% 2nd line for MBC before the protocol inclusion. Visceral metastases were dominant site of disease (44% liver; 36% lung; 44% bone). Median age of the population was 55.8 years (36–73). After a median of 7.7 cycles (3.5 months of treatment); the overall response rate (ORR) is 38% [95%CI; 23%-51%] [1 CR (2.2%) and 16 PR (35.6%)]; 33% of stable disease [95%CI; 17%-43%], 24.4% progressive disease with a clinical benefit (CB) of 71% [95%CI; 57%-85%]. The median progression free survival (PFS) is 7.1 months for responders and 4.8 months for patients with stable disease. The all population median overall survival (OS) is 21.4 months with 22.7 months MOS for responders. Concerning toxicity analysis: 339 cycles of gemcitabine and 312 of oxaliplatinum were delivered. Respectively, grade 3–4 neutropenia occurred in 43% of patients (febrile neutropenia in 7%), grade 3–4 thrombocytopenia in 41%, and anemia in 2.3%. The most frequent non hematologic toxicities were represented by grade 3 peripheral neuropathy (Levi Scale) in 11.4% of the patients and grade 2 alopecia in 11.4%. For the subgroup of hormone receptor negative MBC (n = 12) the ORR is 33% [95%CI; 2%-64%], CB 50% [95%CI; 16%-73%], PFS of 2.8 months and MOS of 12 months. Conclusions: The SEGEMOX combination has relevant activity in A and T not eligible MBC patients, with a manageable toxicity profile. In the limited number of patients with HRN MBC even if the response rate is close to the overall population the prognosis seems still worse. No significant financial relationships to disclose.