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IF 7.191 (2017); International audience; BACKGROUND:Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI.PATIENTS AND METHODS:A pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5-24) and thin patients (BMI

IF 6.029; International audience; BackgroundDiagnosis and management of poorly differentiated gastro-entero-pancreatic (GEP) neuroendocrine carcinomas (NECs) remain challenging. Recent studies suggest prognostic heterogeneity. We designed within the French Group of Endocrine Tumours a prospective cohort to gain insight in the prognostic stratification and treatment of GEP-NEC.Patients and methodsAll patients with a diagnosis of GEP-NEC between 1st January 2010 and 31st December 2013 could be included in this national cohort. Adenoneuroendocrine tumours were excluded.Results253 patients from 49 centres were included. Median age was 66 years. Main primary locations were pancreas (21%), colorectal (27%), oesophagus-stomach (18%); primary location was unknown in 20%. Tumours were metastatic at diagnosis in 78% of cases. Performance status (PS) at diagnosis was 0–1 in 79% of patients. Among the 147 (58%) cases reviewed by an expert pathological network, 39% were classified as small cell NEC and 61% as large cell NEC. Median Ki67 index was 75% (range, 20–100). Median overall survival was 15.6 (13.6–17.0) months. Significant adverse prognostic factors in univariate analysis were PS > 1 (hazard ratio [HR] = 2.5), metastatic disease (HR = 1.6), NSE > 2 upper limit of normal [ULN]; HR = 3.2), CgA > 2 ULN (HR = 1.7) and lactate dehydrogenase >2 ULN (HR = 2.1). After first-line palliative chemotherapy (CT1) with platinum-etoposide (n = 152), objective response, progression-free survival and overall survival were 50%, 6.2 and 11.6 months; they were 24%, 2.9 and 5.9, respectively, after post-CT1 FOLFIRI regimen (n = 72).ConclusionsWe report a large prospective series of GEP-NEC which show the predominance of large cell type and advanced stage at diagnosis. Prognosis was found more homogeneous than previously reported, mainly impacted by PS and tumour burden.

Introduction Trastuzumab in combination with platinum-based chemotherapy is the standard first-line regimen in HER2-positive advanced gastric cancer. However, there are very few data concerning efficacy of continuing trastuzumab beyond first-line progression. Methods This retrospective multicenter study included all consecutive patients with HER2-positive advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma who received a second-line of chemotherapy with or without trastuzumab after progression on platinum-based chemotherapy plus trastuzumab. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the Kaplan-Meier method and compared using log-rank test. The prognostic variables with P values ≤ 0.05 in univariate analysis were eligible for the Cox multivariable regression model. Results From May 2010 to December 2015, 104 patients were included (median age, 60.8 years; male, 78.8%; ECOG performance status [PS] 0-1, 71.2%). The continuation (n=39) versus discontinuation (n=65) of trastuzumab beyond progression was significantly associated with an improvement of median PFS (4.4 versus 2.3 months; P=0.002) and OS (12.6 versus 6.1 months; P=0.001. In the multivariate analysis including the ECOG PS, number of metastatic sites and measurable disease, the continuation of trastuzumab beyond progression remained significantly associated with longer PFS (HR, 0.56; 95% CI, 0.35-0.89; P=0.01) and OS (HR, 0.47; 95% CI, 0.28-0.79; P=0.004). Conclusion This study suggests that continuation of trastuzumab beyond progression has clinical benefit in patients with HER2-positive advanced gastric cancer. These results deserve a prospective randomized validation.

Resume Objectif Un guide d’entretien base sur les donnees de la litterature a ete redige afin de recueillir les attentes des patients cancereux en termes d’information concernant leur prise en charge therapeutique. Patients et methodes Trente-quatre patients recevant une chimiotherapie intraveineuse en hopital de jour d’oncologie-hematologie, selectionnes selon la technique dite des choix raisonnes, ont accepte de realiser un entretien avec un pharmacien selon un mode semi-directif. Resultats Les patients sont globalement satisfaits de l’information recue. Trois-quarts des patients expriment des attentes concernant l’organisation de leur prise en charge, et notamment sur l’acces a une information personnalisee. Les attentes specifiques aux traitements medicamenteux sont essentiellement liees a la gestion des effets indesirables : 72 % des patients declarent que leur qualite de vie est affectee par les effets indesirables (principalement fatigue, douleurs et troubles digestifs). L’utilisation de medecines alternatives et complementaires est rapportee par quatre patients. Conclusion Les attentes mises en evidence concernant les traitements medicamenteux justifient la construction d’un dispositif de suivi personnalise assure par un pharmacien au sein de l’hopital de jour.

Neoplastic meningitis is often the final outcome of disseminated cancer and is rapidly lethal. Its limited treatment relies on systemic or intrathecal chemotherapy with methotrexate (MTX) or thiotepa. When 5-iodo-2'-deoxyuridine labeled with (125)I ((125)IUdR) is incorporated into the DNA of mitotic tumor cells, the Auger electrons emitted during iodine decay are highly cytotoxic. The radiotherapeutic efficacy of (125)IUdR administered intrathecally has also been established in animals bearing spinal cord tumors, and MTX is known to potentiate the response. This approach has not been tested in the clinic.A 44-year-old woman, with locally advanced pancreatic cancer, was treated for three years with complete systemic remission, but then relapsed with cytologically proven neoplastic meningitis. The patient was given four successive intrathecal injections of MTX (10 mg) every 12 h and, with the fourth dose, 1850 MBq (125)IUdR, followed by four additional MTX doses. The response was monitored by cytology and CA19.9 (carbohydrate antigen 19.9) levels in the cerebrospinal fluid (CSF) as well as by clinical status of the patient.The follow-up of cytology and CA19.9 levels in the CSF showed dramatic improvement within 26 days followed by a biological relapse on Day +36. There was no evidence of local central nervous system toxicity. Three months later, neoplastic meningitis recurred and meningeal tumor infiltration was observed on magnetic resonance imaging. Six months after MTX-(125)IUdR treatment, the patient died.(125)IUdR treatment proved to be feasible without acute neurological toxicity and seemed to have produced a biological response. This attempt provides the basis for designing prospective clinical trials.

The antitumor efficacy of irinotecan may be dose dependent. This study aimed to determine the safety and efficacy of high-dose (HD) irinotecan combined with LV5FU2 or simplified LV5FU (LV5FUs) in first-line treatment of metastatic colorectal cancer. Patients and Methods: Patients with unresectable and measurable metastatic colorectal cancer, not pretreated for metastatic disease, were given irinotecan 260 mg/m2 combined with LV5FU2 in the first 25 patients, then with LV5FUs (HD-FOLFIRI) in 35 patients. G-CSF was given in case of febrile neutropenia, grade 4 neutropenia >7 days or neutropenia grade >1 at day 15. Results: The response rate was 57% (95% confidence interval 43–69%). Second surgery with curative intent was performed in 28% of patients, leading to 20% radiological complete response. Median response duration, time to progression and overall survival were 11, 9 and 22 months, respectively. The median dose intensity of irinotecan was 117 mg/m2/week. G-CSF was given to 45% of patients over 33% of cycles. Usual toxicity of irinotecan and 5-FU were observed without major increased frequency, except hematological toxicity. Tolerance was similar with LV5FU2 and LV5FUs, though more asymptomatic grade 3–4 neutropenia was observed with LV5FU2. Conclusion: HD-irinotecan plus LV5FU2 or HD-FOLFIRI is feasible and achieved a high response rate and postsurgery complete response rate.

International audience; BACKGROUND:Metastatic colorectal cancer (mCRC) frequently occurs in elderly patients. However, data from a geriatric tailored randomized trial about tolerance to and the efficacy of doublet chemotherapy (CT) with irinotecan in the elderly are lacking. The benefit of first-line CT intensification remains an issue in elderly patients.PATIENTS AND METHODS:Elderly patients (75+) with previously untreated mCRC were randomly assigned in a 2 × 2 factorial design (four arms) to receive 5-FU (5-fluorouracil)-based CT, either alone (FU: LV5FU2 or simplified LV5FU2) or in combination with irinotecan [IRI: LV5FU2-irinotecan or simplified LV5FU2-irinotecan (FOLFIRI)]. The CLASSIC arm was defined as LV5FU2 or LV5FU2-irinotecan and the SIMPLIFIED arm as simplified LV5FU2 or FOLFIRI. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), safety and objective response rate (ORR).RESULTS:From June 2003 to May 2010, 71 patients were randomly assigned to LV5FU2, 71 to simplified LV5FU2, 70 to LV5FU2-irinotecan and 70 to FOLFIRI. The median age was 80 years (range 75-92 years). No significant difference was observed for the median PFS: FU 5.2 months versus IRI 7.3 months, hazard ratio (HR) = 0.84 (0.66-1.07), P = 0.15 and CLASSIC 6.5 months versus SIMPLIFIED 6.0 months, HR = 0.85 (0.67-1.09), P = 0.19. The ORR was superior in IRI (P = 0.0003): FU 21.1% versus IRI 41.7% and in CLASSIC (P = 0.04): CLASSIC 37.1% versus SIMPLIFIED 25.6%. Median OS was 14.2 months in FU versus 13.3 months in IRI, HR = 0.96 (0.75-1.24) and 15.2 months in CLASSIC versus 11.4 months in SIMPLIFIED, HR = 0.71 (0.55-0.92). More patients presented grade 3-4 toxicities in IRI (52.2% versus 76.3%).CONCLUSION:In this elderly population, adding irinotecan to an infusional 5-FU-based CT did not significantly increase either PFS or OS. Classic LV5FU2 was associated with an improved OS compared with simplified LV5FU2.CLINICALTRIALSGOV:NCT00303771.

Neoadjuvant chemotherapy or chemoradiotherapy is an important concept in the treatment of colorectal liver metastasis, gastric cancer, and esophageal or rectal tumors. This treatment strategy improves disease-free survival and sometimes overall survival. It allows surgical resection of lesions that where not resectable at diagnosis. The new standards of neoadjuvant treatments in gastrointestinal oncology are described in this article.

Purpose: To characterize conditions of radiation induced liver diseases (RILD) after radiation therapy administered for upper gastrointestinal tract tumours, not involving the liver. Method & Materials: this is a retrospective study of 169 patients treated by three dimensional conformal radiations for upper gastrointestinal tract tumours between 2002 and 2008 at the Michallon hospital. Cumulative and differential DVHs (Dose Volume Histogram) were extracted from TPS generated files and liver function tests (ALAT, ASAT, GGT and AP) and tumour markers (CA 19.9 and CEA) from patient records at four different time points (before treatment, and one, three, and six months after the end of treatment). Liver function alteration was defined as an increase in one parameter over 1.5 times the upper normal limit. All these data have been stored and statistically worked out using Lyman model parameters. Results: 34 patient records were studied. Twelve patients had RILD but none at six months. Results are consistent with the Burman description. Dosimetric profiles are different and a correlation appears between RILD and the level of doses given to liver. V40Gy is the most predictive dosimetric parameter for subclinical liver function changes. Conclusion: While dosimetric parameters are predictive of liver biological disorder, the Lyman model is not predictive of these mild disorders.

94 Background: Trastuzumab in combination with platinum-based chemotherapy is the standard first line regimen in HER2 positive advanced gastric cancer. However, there is no data concerning continuation of trastuzumab beyond first line progression. Methods: This retrospective multicenter study include all consecutive patients with HER2 + advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma who received after progression of trastuzumab plus platinum-based chemotherapy, a second line chemotherapy with irinotecan, taxane or platinum salt, with or without trastuzumab. The prognostic variables with P values ≤0.10 in univariate analysis were eligible for the Cox multivariable regression model. Results: From August 2007 to March 2015, 104 patients were included (median age, 60.8 years; male, 78.8%; PS 0-1, 71.2%) with advanced (metastatic : 99%) gastric (45.2%) or GEJ (54.8%) cancer. All patients had received first line treatment based on trastuzumab plus fluoropyrimidine and cisplatin (n=54; 51.9%) or oxaliplatin (n=50; 48.1%). As second line chemotherapy, 67 patients (64.4%) received FOLFIRI regimen, including 19 who have continued trastuzumab; 23 patients (22.1%) received a taxane regimen (paclitaxel or docetaxel), including 12 with trastuzumab; and 14 patients (13.5%) received a platinum-based chemotherapy (different from that used in first-line), including 8 with trastuzumab. When considering all regimens of second-line chemotherapy, continuation (n=39) versus discontinuation (n=65) of trastuzumab was significantly associated with an increase on PFS (4.4 vs 2.3 months; p=0.002) and OS (12.6 vs 6.1 months; p=0.001). In multivariate Cox model (including ECOG PS, tumor grade, number of metastatic site, and second-line treatment), continuation of trastuzumab was significantly associated with longer PFS (HR=0.56; 95%CI [0.35-0.89]; p=0.01) and OS (HR=0.47; 95%CI [0.28-0.79]; p=0.004). Conclusions: This study suggests that maintenance of trastuzumab plus second line chemotherapy beyond disease progression has clinical benefit in patients with HER2 positive advanced gastric cancer. These results deserve a prospective randomized validation.

Neoadjuvant chemotherapy or chemoradiotherapy is an important concept in the treatment of colorectal liver metastasis, gastric cancer, and esophageal or rectal tumors. This treatment strategy improves disease-free survival and sometimes overall survival. It allows surgical resection of lesions that where not resectable at diagnosis. The new standards of neoadjuvant treatments in gastrointestinal oncology are described in this article.

We have investigated a PCR-based approach for one-step gene targeting in the filamentous fungus Ashbya gossypii. Short guide sequences with 40-46 bp of homology to two sequences of a targeted gene, provided by PCR, were sufficient to mediate homologous recombination. The PCR products used for transformation were generated from the newly constructed chimeric selection marker GEN3. This consists of the open reading frame of the Escherichia coli kanR gene under the control of promoter and terminator sequences of the Saccharomyces cerevisiae TEF2 gene and allows selection of G418/geneticin-resistant transformants. Verification of gene targeting was performed either by PCR or by DNA hybridization analyses, and in all 18 cases tested, correct targeting was confirmed. This approach was used for the complete deletion of the open reading frame of the A. gossypii RHO4 gene for which a double-strand sequence was available as information source for the design of PCR primers. We also demonstrated successful partial deletion of four other ORFs using single-read sequences (SRS) as sole information for the design of targeting primers. A gossypii is the first filamentous fungus in which a PCR-based gene disruption technique has been established. Since short target guide sequences are sufficient to direct homologous integration into the A. gossypii genome it is not necessary to obtain and sequence large DNA fragments from a target locus to provide the long flanking homology regions usually required for efficient targeting of cloned disruption cassettes in filamentous fungi. Thus functional analysis of A. gossypii genes is already possible, based on single-pass sequence information.

We studied the mechanisms of colon and rectal carcinogenesis by analysing in a series of 83 rectal tumors the prevalence of the two tumor types characteristic of colon cancer, i.e., the LOH+ type, defined by p53 and APC mutations (studied by DGGE and protein truncation assay), and the RER+ type, which is characterized by the instability of some mononucleotide repeat microsatellites (Bat 25 and Bat 26). Additionally, we analyzed the occurrence of Ki-Ras mutations (direct sequencing).Only one tumor turned out to be RER+. Moreover, in 59% of the tumor cases mutations were found in p53, essentially affecting codon 175. The APC and Ki-Ras genes were found to be mutated in 40 and 26% of the rectal tumors, respectively. In 18 tumors (21%) none of the genes studied were mutated.The RER+ phenotype is rare among rectal tumors, which are essentially LOH+. In these LOH+ tumors the p53 gene is more frequently mutated than in colorectal tumors with the same phenotype. Mutations in the APC and Ki-Ras genes, on the other hand, are less frequent in rectal tumors. Tumors with the RER- and LOH- phenotype may develop as a result of a third carcinogenesis model which must be defined.

We have fused the open reading frames of his3-complementing genes from Saccharomyces kluyveri and Schizosac-charomyces pombe to the strong TEF gene promotor of the filamentous fungus Ashbya gossypii. Both chimeric modules and the cognate S. kluyveri HIS3 gene were tested in transformations of his3 S. cerevisiae strains using PCR fragments flanked by 40 bp target guide sequences. The 1.4 kb chimeric Sz. pombe module (HIS3MX6) performed best. With less than 5% incorrectly targeted transformants, it functions as reliably as the widely used geniticin resistance marker kanMX. The rare false-positive His+ transformants seem to be due to non-homologous recombination rather than to gene conversion of the mutated endogenous his3 allele. We also cloned the green fluorescent protein gene from Aequorea victoria into our pFA-plasmids with HIS3MX6 and kanMX markers. The 0.9 kb GFP reporters consist of wild-type GFP or GFP-S65T coding sequences, lacking the ATG, fused to the S. cerevisiae ADH1 terminator. PCR-synthesized 2.4 kb-long double modules flanked by 40-45 bp-long guide sequences were successfully targeted to the carboxy-terminus of a number of S. cerevisiae genes. We could estimate that only about 10% of the transformants carried inactivating mutations in the GFP reporter.

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]

Introduction L’efficacite du cetuximab seul ou associe avec la chimiotherapie dans le traitement du cancer colorectal metastatique (CCRM) est liee au statut mutationnel KRas. Les donnees CRYSTAL ont montre que l’association du cetuximab au FOLFIRI (FIRI) en 1 ere ligne de tt du CCRm ameliorait significativement le taux de reponse objective (RO) et la survie sans progression (SSP) (critere principal de jugement). Nous rapportons les donnees de survie globale (SG) et l’influence du statut KRas. Patients et Methodes L’ADN a ete extrait a partir d’echantillons tumoraux archives sur 578 des 1 198 patients randomises et le statut mutationnel KRas a ete determine sur les codons 12/13 par PCR quantitative specifique. Les bras de traitement ont ete compares par des tests de log rank bilateraux (5 % de significativite) pour la SSP et la SG, et par test de Cochran-Mantel-Haenszel (CMH) pour le taux de RO. Resultats Le groupe evaluable pour KRas (n = 540 ; 35,6 % de KRas mute) etait representatif du groupe en intention de traiter. Les patients ayant des tumeurs de type KRas non mute, avec l’ajout du cetuximab ont eu une augmentation significative de leur taux de RO (p = 0,0025), et de leur SSP (p = 0,0167). Leur mediane de SG a ete augmentee de 3,9 mois (cf tableau). Respectivement, 73,1 % et 68,6 % des pts (bras FIRI et bras FIRI + cetuximab) ont recu au moins une ligne de tt supplementaire et pour 25,4 % et 6,2 % d’entre eux un traitement par un anticorps anti-EGFR. Discussion Seule une partie des tumeurs ont pu etre retrospectivement analysee, mais nous rapportons l’importance du statut KRas non mute comme facteur de reponse et de SSP (p = 0,0167). Les SG sont importantes mais non significatifs probablement en raison d’un manque de puissance et des traitements de 2 eme ligne. Conclusion Les benefices de l’association du cetuximab a la chimiotherapie sont significatifs chez les patients de statut KRas non mute pour le controle tumoral. Le gene KRas est le premier biomarqueur utile de selection pour un traitement cible associe a une chimiotherapie standard dans le traitement de 1 ere ligne du CCR metastatique.

Rationnel La chimiotherapie d’induction des metastases hepatiques (MH) doit etre envisagee devant des MH non resecables d’emblee ou de resecabilite limite (classe II des RPC). Les chimiotherapies donnant les meilleurs taux de reponse objective, sans morbidite excessive, sont theoriquement les plus adaptees. Les RPC sur la prise en charge des MH parues en 2003 ont etabli les schemas FOLFOX et FOLFIRI comme les standards. Cependant, dans cette situation, ces schemas ne permettent pas d’obtenir des taux importants de resecabilite. Depuis, des schemas intensifies de type tritherapie (FOLFIRINOX ou FOLFOXIRI) ont ete proposes avec des taux de reponse objective et de resection encourageants. L’objectif de cet essai randomise est de selectionner la chimiotherapie intensifiee la plus efficace dans cette situation (FOLFIRI Haute DOSE / Irinotecan 260 mg/m 2 ; FOLFOX-7 / Oxaliplatine 130 mg/m 2 ; FOLFIRINOX / Irinotecan 180 mg/m 2 + Oxaliplatine 85 mg/m 2 ). Materiels et Methodes Principaux criteres d’inclusion : Metastase hepatiques d’un adenocarcinome colorectal non pretraitees et potentiellement resecables (classe II) ou non resecables. Absence de metastases extra hepatiques (excepte 1 a 3 metastases pulmonaires resecables). Randomisation selon 5 bras de traitement : chimiotherapie standard (A/B) ou intensifiee (C/D/E) : FOLFIRI (A), FOLFOX-4 (B), FOLFIRI-HD (C), FOLFOX-7 (D), or FOLFIRINOX(E). Dans les bras C/D/E, un traitement prophylactique par facteurs de croissance (G-CSF) etait realise. L’objectif principal etait le taux de reponse objective (RECIST) apres 4 cycles. Les objectifs secondaires etaient l’etude des toxicites, le taux de resection R0, le meilleur taux de reponse, la SSP et la SG. Un total de 120 patients randomises selon un ratio 1 : 1 : 2 : 2 : 2 etait statistiquement necessaire (2-stage Fleming design, p0 = 0,40, p1 = 0,60, alpha = 10 %, beta = 20 %). Resultats Entre octobre 2004 et aout 2007, 125 patients (17 centres) ont ete randomises. 122 etaient eligibles et ont recu les traitements suivant : 30 (A+B), 32 (C), 30 (D) and 30(E). Les causes de non resecabilite des metastases hepatiques etaient respectivement : parenchyme hepatique sain residuel Conclusion Les trois schemas experimentaux ont permis d’obtenir les taux de RR attendus a 4 cycles, avec un profil de tolerance acceptable. Dans cet essai multicentrique les taux de resection complete etaient encourageants (particulierement dans les bras FOLFIRI-HD et FOLFIRINOX). Cependant un recul plus important avec notamment le recueil des taux de rechute apres chirurgie est necessaire. Enfin, la place des therapies ciblees sera a envisager a l’avenir.

Introduction Plusieurs schemas, dont l’ECF, sont des standards pour les adenocarcinomes gastrique ou du cardia localement avances ou metastatiques. Les schemas a base d’irinotecan et la place d’un traitement de deuxieme ligne sont peu evalues en phase III. L’objectif de cet essai est de comparer 2 sequences de polychimiotherapie : ECC puis FOLFIRI vs FOLFIRI puis ECC. Materiels et Methodes Les pts porteurs d’un adenocarcinome de l’estomac ou du cardia histologiquement prouve, localement avance ou metastatique, non traitable chirurgicalement, avec un IP OMS ≤ 2 et des lesions mesurables ou evaluables (mais non mesurables), ont ete randomises 1 : 1 selon une sequence ECC (Epirubicine 50 mg/m 2 J1 + Cisplatine 60 mg/m 2 J1 + Capecitabine 2 000 mg/m 2 J2 a J15, toutes les 3 s) en 1 ere ligne puis FOLFIRI (IRI 180 mg/m 2 J1, AF 400 mg/m 2 J1, 5FU bolus 400 mg/m2 J1 et 5FU continu 2 400 mg/m 2 sur 46 h, toutes les 2 s) en 2 eme ligne (Bras A) vs la sequence inverse (Bras B) avec une stratification selon le centre, l’IP OMS, l’existence d’une chimiotherapie ou d’une radio-chimiotherapie adjuvante, la localisation, le type linite et le caractere mesurable. Pour mettre en evidence une amelioration de la mediane du Temps jusqu’a l’Echec du Traitement pour les 2 lignes (TET : delai entre la date de randomisation et la date de progression, ou de l’arret therapeutique, ou de rechute ou de deces) de 15 a 20 semaines pour le bras B (α bilateral 5 % et β 20 %) il est requis 381 echecs et d’inclure 416 pts en 4 ans. Une analyse intermediaire etait planifiee quand au moins 190 echecs seraient observes (ITT). Le TET est estime selon la methode de Kaplan Meier et compare a l’aide de test du Log-rank. Resultats Dans le Bras A et B ont ete inclus respectivement 174 et 175 pts entre le 17/06/2005 et le 21/12/2007 (recul median 1 an). Les caracteristiques des pts sont : IP OMS 1 51 %, âge median 60 ans, localisation gastrique 67 %, metastases 88 % (dont 83 % synchrones), tumeur primitive resequee 27 % (dont 71 % R0) et linites 23 %. Dans le bras A et B respectivement, 141 et 147 pts ont recu au moins une dose en 1 ere ligne (soit 100 % des pts non pdv temporaires) et 61 et 44 pts en 2 eme ligne. Les toxicites au cours de la 1 ere ligne sont plus frequentes dans le bras ECC que dans le bras FOLFIRI des toxicites grade 3/4 : 88 % vs 68 % (p ≤ 0,0001) et des toxicites hematologiques grade 3/4 : 69 % vs 36 % (p ≤ 0,001). En deuxieme ligne, la frequence des toxicites ne different pas selon les bras. Le TET median preliminaire (n = 310 pts) est de 6,3 mois [4,8 - 6,8] pour ECC 1 ere ligne et de 6,0 mois [4,8 - 7,1] pour FOLFIRI en 1 ere Ligne (Log Rank p = 0,6848). Pour les 252 echecs observes (67 % des evenements requis), le seuil de significativite pour rejeter H0 est p = 0,012 (EAST V5). Conclusion Cette analyse intermediaire ne permet pas de conclure a la superiorite du bras B (FOLFIRI en 1 ere Ligne). Il est requis de realiser l’analyse apres l’observation de 381 echecs. Concernant la tolerance, Les toxicites hematologiques sont plus frequentes pour l’ECC en 1 ere ligne.

Introduction Dans le traitement du cancer colorectal metastatique par FOLFIRI, le rapport efficacite – toxicite de la chimiotherapie peut etre optimise par la connaissance a priori du statut genotypique TS (Thymidylate Synthase) pour l’efficacite du 5-FU et UGT1A1 (Uridine diphosphate glucuronosyltransferase) pour la toxicite de l’irinotecan. Le polymorphisme de repetition 3R/3 R est associe a une hyperactivite TS et a une resistance au 5FU. L’homozygotie 7/7 est associee a une diminution de l’activite d’UGT1A1 et par consequent a une surexposition plasmatique du SN 38, metabolite actif de l’irinotecan. Patients et Methodes Une etude genotypique lymphocytaire a ete realisee, dans le cadre d’un essai prospectif multicentrique national de phase 2, chez 72 patients atteints de cancer colorectal metastatique. Les patients ayant un profil TS « favorable » (2R/3 R ou 2R/2R) beneficiaient ensuite d’un genotypage pour UGT1A1. En presence d’un polymorphisme « favorable » (6/6 ou 6/7), les patients etaient traites par FOLFIRI HD (Haute Dose : Irinotecan 260 mg/m). En cas de polymorphisme 7/7, un FOLFIRI standard etait administre. L’adjonction de bevacizumab etait optionnelle. Le GCSF en prophylaxie primaire etait autorise apres FOLFIRI HD. Resultats Soixante-douze patients ont ete inclus, dont 55 s’averent « TS favorable » et se repartissent en profil UGT1A1 « favorable » : 47 et « defavorable » : 8. Le delai median de rendu du genotypage est de 5 jours. Le nombre median de cycles de FOLFIRI HD est de 7 avec une dose-intensite de 87 %. Quarante pour cent des patients ont recu du GCSF. Aucune toxicite severe n’a ete observee. Un seul patient (2 %) a presente une diarrhee grade 3. Aucune neutropenie febrile n’est rapportee. Le taux de neutropenie grade 4 est de 9 %. Quatorze patients de plus de 70 ans, dont 6 âges de plus de 80 ans ont recu du FOLFIRI HD sans complication. Les donnees d’efficacite sont en cours d’analyse. Chez 41 patients evaluables a ce jour, le taux de benefice clinique est de 85 %. Conclusion Dans un sous groupe de patients selectionnes par le genotypage predictif, faisable dans un cadre multicentrique avec un delai raisonnable, la chimiotherapie par FOLFIRI peut etre intensifiee sans risque, meme chez les patients âges, avec ou sans GCSF. Le genotypage permet d’eviter des toxicites severes chez 15 % de patients deficitaires en UGT1A1.

4075 Background: LVFU combinations with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) have shown to improve outcome of advanced colorectal cancer. However, the standard doses of these regimens applied to patients with initially unresectable LMCRC have shown poor rates of resectability. The aim of this randomized trial was to select the most efficacious experimental intensified chemotherapy arm among high dose (HD) FOLFIRI (Iri 260mg/m²), FOLFOX-7 (Ox 130mg/m²) and FOLFIRINOX (Iri 180mg/m² + Ox 85mg/m²) in patients (pts) with initially unresectable or potentially resectable LMCRC. Methods: Main inclusion criteria: non pretreated potentially resectable LM (class II) or unresectable LM without extra-hepatic metastases except 1 to 3 resectable lung metastases. Pts were randomized to either standard (A/B) or intensified chemotherapy (C/D/E): FOLFIRI (A), FOLFOX-4 (B), FOLFIRI-HD (C), FOLFOX-7 (D), or FOLFIRINOX (E). In arms C/D/E, prophylactic G-CSF was given. Primary endpoint was objective response rate (RR) (...

4029 Background: X has comparable efficacy, safety and convenience benefits over 5-FU/LV (Mayo clinic) in adjuvant colon cancer and first-line MCRC. A recent phase III trial in first line MCRC showed that XELOX is well tolerated and non inferior to FOLFOX-4 for progression-free survival (PFS) [Cassidy ESMO 2006]. Methods: We initiated a phase III trial to demonstrate non inferiority in terms of best response rates (RR, RECIST) of XELOX versus FOLFOX-6 as first-line therapy in patients (pts) with MCRC. Between 16 May 03 and 31 Aug 04, 306 patients (intention to treat), were randomized to receive either XELOX (n=156: × 1,000mg/m2 bid d1–14, O 130mg/m2 d1, q3w) or FOLFOX-6 (n=150: O 100mg/m2 d1 LV 400mg/m2 2h infusion then 5-FU 400mg/m2 i.v. bolus then 2,400–3,000mg/m2 46h infusion, q2w) for 6 months. Efficacy results are presented in the per protocol population (PP) (n=284:144 pts XELOX; 140 pts FOLFOX-6). Results: Baseline characteristics were well balanced. Pts received a median of 8 and 11 cycles of XELOX (range 0–8) and FOLFOX-6 (range 0–12), respectively. Dose intensity (median) for oxaliplatin was 99.6% and 95.4% with XELOX and FOLFOX-6, respectively. Best RR (independent review, PP) was 42% and 46% with XELOX and FOLFOX-6, respectively. Difference between groups for RR was 4.7%; upper limit of 95% unilateral CI (14.4%) was below non-inferiority margin of 15%. RR by investigators (PP) was 46% for each arm. With a median follow up of 16.5 months (range 0.4–38.3), median PFS and overall survival (PP) were 9.3/19.9 vs. 9.7/18.4 months with XELOX and FOLFOX-6, respectively. In the safety population (n=304), XELOX pts had more grade 3/4 hand-foot syndrome (3 vs. 0%, p=0.21), thrombocytopenia (12 vs. 5% p=0.052), and diarrhea (12% vs. 7% p=0.1), but less grade 3/4 febrile neutropenia (0 vs. 6% p=0.001), neuropathy (8 vs. 19% p=0.003), than those on FOLFOX-6. Treatment discontinuation for toxicity was 19% and 23% in XELOX and FOLFOX-6 arms, respectively. Conclusions: The primary endpoint has been met: XELOX is non inferior to FOLFOX-6, with a good safety profile in first-line MCRC. No significant financial relationships to disclose.

2510 Background: Thymidilate synthase (TS) and UGT1A1 genetic polymorphisms assessment helps to predict 5-FU efficacy and irinotecan toxicity - SN38 inactivation - respectively. We used this information to individualize MCRC first-line chemotherapy in the multi-centre COLOGEN trial. Methods: Were included first-line histologically proven MCRC patients (pts) aged 18–85, PS=2. Genotyping was performed on pts’ lymphocytes sampled at most 10 days before chemotherapy. Pts with 2R/2R or 2R/3R TS profile had subsequent UGT1A1 polymorphism determination. Those with 6/6 or 6/7 UGT1A1 profile received high dose bimonthly FOLFIRI (Irinotecan 260 mg/m2), whereas those with “defavorable” 7/7 polymorphism received standard FOLFIRI (Irinotecan 180 mg/m2). In pts with overexpressed TS (3R/3R), chemotherapy was left to investigator’s decision. Results: To date, 32 pts/65 planned have been included, aged 44 to 83 (mean: 65,2, median: 64). Six pts (19 %) had 3R/3R TS profile. Among those with 2R/2R or 2R/3R profile, 15 % (4/26) had defavorable 7/7 UGT1A1 profile. Median time for genotypic determination was 5 days for UGTA1 and 5 for TS. Treatment was: high-dose FOLFIRI, 23 pts (72 %); standard FOLFIRI ± bevacizumab, 3 pts (9 %); other regimens including capecitabine and/or oxaliplatin, 6 pts (16 %). Toxicities: we observed no toxic death. Serious adverse events were: febrile neutropenia (1, high dose FOLFIRI regimen) and grade 4 hypokaliemia (1, non FOLFIRI regimen). Eight patients over 70 years old and 3 over 80 received high-dose FOLFIRI without significant toxicity. Conclusions: Those preliminary results are the first ever reported on individual genotyping as a tool for treatment optimization in a multi-centre setting. This strategy appears clearly feasible and allows to safely intensify chemotherapy, even in elderly patients. No significant financial relationships to disclose.

4099 Background: A recent phase III trial in first-line MCRC showed that XELOX is non-inferior to infusional 5-FU + oxaliplatin (FOLFOX-4) for progression-free survival (PFS) [Cassidy ESMO 2006]. Here we present safety and QoL findings from a study of XELOX vs. FOLFOX-6 in first-line MCRC. Methods: Between 16 May 03 and 31 Aug 04, 306 patients (pts) were randomized to receive either XELOX (156 pts: × 1,000mg/m2 bid d1–14, O 130mg/m2 d1, q3w) or FOLFOX-6 (150 pts: O 100mg/m2 d1 LV 400mg/m2 2h infusion then 5-FU 400mg/m2 i.v. bolus then 2,400–3,000mg/m2 46h infusion, q2w) for 6 months. Primary objective: demonstrate non inferiority of XELOX in terms of best response rate (RECIST). Secondary objectives: evaluate QoL and pt satisfaction with care by EORTC QLQ-C30 and FACIT (chemotherapy convenience and satisfaction) questionnaires. Pts completed questionnaires at baseline, before cycles 3/4, 6/8 and at final visit in XELOX/FOLFOX-6 arms, respectively. Results: 245 pts (QLQ-C30) and 225 pts (satisfaction) were evaluable for QoL. The compliance rate was >70%. At baseline, QoL scores were not significantly different. QLQ-C30 functional and symptomatic scores were stable in both arms. According to FACIT, there was no difference between arms, although XELOX-treated pts wasted less hours of their free time than those on FOLFOX-6: 10±23 vs. 37±68 hours, respectively (p=0.007). XELOX was a more ‘comfortable’ treatment (p No significant financial relationships to disclose.