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4531 Background: The FFCD 9102 trial demonstrated that CRT is an alternative to CRT+S for responding patients. We investigated the type of PP in the follow-up (FU) period, according to the RT scheme: protracted (P-RT) vs. split course (SC-RT). Methods: Resectable T3 N0–1 M0 thoracic esophageal carcinoma were included. First sequence : 2 cycles of cisplatin and 5-FU (day (d)1 - d22) combined with RT. Two schemes of RT were allowed: P-RT (46 Gy / 4.5 weeks (w), 2 Gy / f) or SC-RT (2 one-week courses of 15 Gy, 3 Gy / f). For CRT, the same chemotherapy was given on d43, d64 and d92 combined with 20 Gy / 2w (P-RT) or 15 Gy / 1w (SC-RT). Responding patients after the first sequence were randomized between CRT and CRT+S. The impact of SC-RT vs. P-RT on PP in the FU period was explored using a Mann-Whitney test. Results: From February 1993 to December 2000, 451 pts were registered and 446 were eligible. P-RT: 161 pts, SC-RT: 285 pts. After a median FU of 47.4 months, 2-year overall survival and local relapse-free survival were for P-RT vs. SC-RT: 37.1% vs. 30.5% (p = 0.25) and 76.7% vs. 56.8% (p = 0.002), respectively. P-RT vs. SC-RT: mean length of hospital stay: 48 d vs. 60.5 d (p= 0.0003). Mean number of dilatation sessions: 0.56 vs. 0.66 (p= 0.43). Mean number of stents: 0.21 vs. 0.34 (p= 0.03). Mean number of any PP: 1.01 vs. 1.50 (p= 0.001). Mean dysphagia grade: 2.99 vs. 3.12 (p= 0.21). In the CRT+S-group, P-RT vs. SC-RT: mean length of hospital stay 55.0d vs. 68.7d (p =0.051). Mean number of dilatation sessions: 0.74 vs. 0.74 (p= 0.77). Mean number of stents: 0.09 vs. 0.18 (p= 0.44). Mean number of PP: 1.00 vs. 1.37 (p= 0.054). In the CRT-group, P-RT vs. SC-RT, mean length of hospital stay: 42.6d vs 54.0d (p= 0.053). Mean number of dilatation sessions : 0.38 vs. 0.67 (p= 0.12). Mean number of stents: 0.31 vs. 0.50 (p= 0.03). Mean number of PP: 0.83 vs. 1.86 (p= 0.0005). Conclusions: Stents, rate of PP and length of hospital stay were significantly increased with SC-RT. Dysphagia score was similar between SC-RT and P-RT at last FU. No significant financial relationships to disclose.

4069 Background: The survival benefit of using a combination therapy instead of keeping it for a second line (L2) has not been demonstrated in metastatic colorectal cancer. The purpose of this trial was to compare the efficacy of simplified LV5FU2 (s) followed by FOLFOX6 (arm A) to FOLFOX6 followed by FOLFIRI (arm B) on progression-free survival after two lines of chemotherapy. We present here preliminary results relating to toxicity, observance and overall survival. Methods: Inclusion criteria: a) non resectable metastases of histologically proven colorectal adenocarcinoma , b) evaluable disease (WHO criteria), c) absence of previous chemotherapy other than adjuvant. Treatment was as follows: LV5FU2s = at day 1, folinic acid 400 mg/m2, 5-FU bolus 400 mg/m2 and continuous infusion over 46 hours 2,400 mg/m2/2 weeks; FOLFOX6 = LV5FU2s + oxaliplatin 100 mg/m2 at day 1; FOLFIRI = LV5FU2s + irinotecan 180 mg/m2 at day 1. Results: 410 pts out of 570 initially planned (early stopping due to slow accrual and new treatments) were included from 02/2002 to 02/2006 (205 in each arm). Median follow-up was 25 months. The median number (range) of cycles (28 days) in first line (L1) was respectively 5 (1–24) and 6 (1–24) in the arms A and B (p=0.01), and for L2 (152 and 144 pts in the arms A/B): 5 (1–17) and 3 (1–33) (NS). In the arms A and B, 74% and 70% of pts had L2. L1 was stopped for toxicity for 1% and 16% of the pts in arms A and B (p No significant financial relationships to disclose.

4620 Introduction: Few chemotherapies have been tested in the first-line treatment of endocrine carcinomas. The aim of the study was to evaluate the efficacy of FOLFIRI in the first-line therapy of evolutive, metastatic or locally invasive, well-differentiated endocrine carcinomas of the duodeno-pancreatic area. Methods: To show a 6-month tumoral non-progression (RECIST) rate ≥ 60% (a = 5%), 20 pts had to be included in a phase II, prospective, multicentric trial. Inclusion criteria were : well-differentiated endocrine carcinoma of the duodeno-pancreatic area, functioning or non functioning, with hepatic or extra-hepatic metastases or locally invasive tumor > 50 mm, not resectable; tumoral growth within 6 months; no previous antitumoral therapy except interferon ( = 3 months) or somatostatin analogs; PS 0–2. Treatment administration every 14 days : D1 : irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5 FU 400 mg/m2 bolus; D1-D2 : 5 FU 2,400 mg/m2 in 46 hrs. Evaluation (clinical, radiological, biological) every 3 months. In case of progression during a chemotherapy free-interval following an objective tumoral response, treatment was reintroduced. All analyses were performed in intent to treat. Data cut off was done at July 1st 2006. Results: Between May 2004 and July 2005, 20 pts (13 M, 7 F) were included with median age 57 yrs (37–82). 19 pts had liver metastases and 1 pt had metastatic lymph nodes. 5 tumors were functioning; 2 pts had MEN 1. Median proliferation index was 7% (0–58). All pts were treated and evaluation at 6 months for the primary endpoint was available in 19 pts. The 6-month non-progression rate was 75% (CI 95% = 51–91%,), including 14 stabilization (70%) and 1 partial response (5%). 4 pts had 1 chemotherapy free-interval and 2 pts had 2 with reintroduction of the same chemotherapy regimen. Median number of cycles was 11.5 (1–28). 80% had at least 1 grade 3–4 toxicity and 25% had grade 3–4 hematological toxicity. 10% had grade 3 diarrhoea.. Conclusion: FOLFIRI has an antitumoral effect in the first-line therapy of evolutive well-differentiated pancreatic endocrine carcinomas. Frequency of grade 3–4 toxicities can be explained by length of therapy. No significant financial relationships to disclose.

4589 Background: The aims of our study were to compare performances of 4 staging systems and to explore how to improve prognostic classification among French patients with HCC whose main aetiology is alcoholic cirrhosis. Methods: We have pooled 2 RCTs in palliative condition from Federation Francophone de Cancerologie Digestive (FFCD): - FFCD 9403 comparing tamoxifen vs symptomatic treatment and - FFCD 9402 comparing chemoembolization + tamoxifen vs tamoxifen alone. They had respectively included 416 and 122 patients. Performance of Okuda, Cancer of the Liver Italian Program (CLIP), Barcelona Clinic Liver Cancer group (BCLC) and GRoupe d’Etude et de Traitement du Carcinome Hépatocellulaire scores have been compared using: Akaike information criteria (AIC), discriminatory ability (Harrell’s c and the Royston’s D statistics), monocity of gradients and predictive accuracy (Schemper statistics Vs). To explore how to improve classifications univariate and multivariate Cox model were performed. Variables with univariate p< 0.10 have been retained for multivariate analyses. A forward selection procedure has then been implemented. Bootstraps validation was performed to test the robustness of our results. Analyses were done for each trial and for the pooled database with trial stratification. Results: Median OS was 5,3 months (IC 95%: [4,6; 6,2]), 402 patients had (75%) an alcoholic cirrhosis aetiology . As shown in Table 1 , CLIP staging had the best properties, followed by Okuda and BCLC. Performances of all staging systems were rather disappointing. WHO staging for CLIP or alphafetoprotein for BCLC allowed a significant improvement of prognostic information. Conclusions: Our results suggest that CLIP staging seems to be most adapted to french patients, it could be better by associating WHO PS. An external validation of our result will be performed on another trial in palliative condition. [Table: see text] No significant financial relationships to disclose.

4510 Background: The combination of 5FU in continuous infusion and cisplatin (FP) is one of the most active regimen in advanced ASLE. The trial was designed to evaluate the impact on survival of 2–3 cycles of preoperative FP in resectable ASLE. Methods: Patients (pts) with resectable adenocarcinoma of the stomach (S) without cardia involvement, cardia (C) or lower esophagus (LE), age ≤ 75 yrs, WHO performance status (PS) < 2 were eligible. Pts were centrally randomized between surgery alone (arm 1) and preoperative FP (arm 2). Chemotherapy (CT) included 2–3 cycles of P (100 mg/m2) and F (800 mg/m2 d1-d5 continuous infusion) every 28 days. Post- operative FP was recommended in arm 2 in case of response to FP preoperative or stable disease with pN+. The main endpoint was overall survival. Comparison of disease-free survival (DFS) used 6-month landmark method and two-sided logrank test. Results: Between 1995 and 2003, 224 pts (arm 1 = 111 pts, arm 2 = 113 pts) were randomized from 28 centers. Initial pts characteristics were equally balanced for age (mean, 61 yrs), gender (83 % male), PS (75 % WHO 0), tumor site (S = 25 %,C = 64 %, LE = 11 %). Median follow-up was 5.7 years. In arm 2, FP was given before surgery in 109 pts (98 pts > 2 cycles) and after surgery in 54 pts. R0 resection rate was 73 % in arm 1 versus 84 % in arm 2 (p=0.04). Preoperative CT improved DFS (p=0.003): hazard ratio (HR) 0.65 (95%CI 0.48–0.89), with 3 and 5-year DFS of 25% (18–34%) and 21% (14–30%) in arm 1 vs. 40% (31–49%) and 34% (26–44%) in arm 2, respectively. HR of death was 0.69 (0.50–0.95, p=0.02) with 3 and 5- year overall survival (OS) of 35% (27–44%) and 24% (17–33%) vs. 48% (39–57%) and 38% (29–47%), respectively. Similar results on OS were observed using Cox model stratified on center and adjusted on gender, age, performance status, and tumor localization. No significant variation of chemotherapy effect with tumor localization was observed. Conclusions: Preoperative chemotherapy using 5- fluorouracil/cisplatin improves disease-free and overall survival in patients with resectable adenocarcinoma of stomach and lower esophagus. No significant financial relationships to disclose.

4026 Background: The combination of 5FU in continuous infusion and cisplatin (FP) is one of the more active regimen in advanced ASLE. The trial was designed to evaluate the impact on survival of 2–3 cycles of preoperative FP in resectable ASLE. Methods: Patients (pts) with resectable adenocarcima of the stomach (S) without cardia involvement, cardia (C) or lower esophagus (LE), age ≤ 75 yrs, WHO performance status (PS) < 2 were eligible. Pts were centrally randomized between surgery alone (arm 1) and preoperative FP (arm 2). Chemotherapy (CT) included 2–3, cycles of P (100 mg/m2) and F (800 mg/m2 d1-d5 continuous infusion) every 28 days. Post-operative FP was recommended in arm 2 in case of response to FP preoperative or stable disease with pN+. The main endpoint was overall survival. Sample size was 250 (20 % vs 35 % 5-year rates, two-sided logrank test, α = 5 %, β = 20 %). Results: Between 1995 and 2003, 224 pts (arm 1 = 111 pts, arm 2 = 113 pts) were randomized from 28 centers with early stopping because of low accrual. Initial pts characteristics were equally balanced for age (61 yrs), gender (83 % male), PS (75 % WHO 0), tumor site (S = 25 %,C = 64 %, LE = 11 %). In arm 2, FP was given before surgery in 109 pts (98 pts > 2 cycles) and after surgery in 54 pts. Preoperative FP toxicity : 41 pts with at least one grade 3–4 toxicity (polynuclear, 22 pts, vomiting 10 pts), 9 treatment interruption, 1 toxic death. The number of patients with no surgery / no tumor resection / macroscopic incomplete resection (R2)/ microscopic incomplete resection (R1) by arm were 1/10/12/6 in arm 1 and 4/7/2/4 in arm 2. The number of postoperative deaths were 5 in each arm. Complete resection (R0) rate were 73 % in arm 1 versus 84 % in arm 2 (p=0.04). Among eligible RO, R1 patients (85 & 98 pts in arm 1 & 2): the numbers of pts with T0–2/N0/M+ were 27/17/6 and 41/32/1 en arm 1 & 2, the corresponding p-value were 0.16, 0.05 and 0.05 respectively; 3 pts with complete response in arm 2. For DFS, 160 events are observed so far with a median follow-up of 5 years. Conclusions: Preoperative chemotherapy was well tolerated and led to an increase in R0 resection rate, and a decrease in N+/M+ tumors. Disease-free survival will be presented at the meeting. No significant financial relationships to disclose.

3563 Background: Patients with stage III colon cancer have a high risk for recurrence. Infusional 5-FU may be more active than bolus application. Methods: From 01/1997 to 03/2004 a total of 1601 patients with UICC stage III colon cancer were randomized to receive the Mayo-Clinic regimen or infusional 5-FU either the weekly high dose AIO regimen, the bi-weekly LV5FU2 regimen or the Spanish weekly high dose TTD-regime. The major aim of this study was to demonstrate a difference of 7 % in the 5 year survival rate in favour of the infusional arm for which a total of 424 events were required. Results: After a median follow-up of 31 months 478 events have occurred. 804 patients received the standard arm and 797 the experimental arm (AIO N=331, EORTC N=92, FFCD N=211, TTD N=163). The median age was 64 years; patients were well distributed according to TNM-category (T3 73 vs. 75%, T4 17 vs. 16%, N2 31 vs. 34%), vascular and lymphatic invasion and grading. The bolus regimen induced a higher rate of grade 3 or 4 leukopenia (7.1% versus 2.0%), stomatitis grade 3 or 4 (9.8% versus 3.3%) or diarrhea grade 3 or 4 (16% vs. 15%). Hand-Foot-Syndrome was more frequent in the experimental arm (4.4% versus 0.4%). There was no difference in the recurrence free survival at 5 years (57% versus 56%; hazard ratio 1.00, 95% CI, 0.84 to 1.21; P=0.9) or overall survival at 5 years 71% versus 72%; hazard ratio 0.91, 95% CI, 0.71 to 1.16; P=0.44). Conclusions: Infusional 5-FU does not improve RFS or overall survival of stage III colon cancer compared to the Mayo regimen but is less toxic. Supported by Deutsche Krebshilfe No significant financial relationships to disclose.

4008 Background: The GITSG studies have shown a greater survival after 5 FU-based chemoradiotherapy (CHRT) than radiotherapy or polychemotherapy alone in patients (pts) with locally advanced non metastatic pancreatic cancer. This randomized trial evaluated whether initial CHRT adds to modern gemcitabine in term of Overall Survival (OS). Methods: Pts with WHO status 0–2, proven adenocarcinoma of the pancreas, without metastasis at CT-scan, and deemed non resectable, were randomized 1:1 between CHRT ( 60 Gy in 6 weeks, 2 Gy/fraction, concomitant with 5-FU, 300 mg/m2/24 h as a continuous infusion, day 1–5 every week and cisplatin, 20 mg/m2/d, day 1–5 at week 1 and 5) or gemcitabine (G) (1000 mg/m2 weekly 7q8w) as induction treatment. Maintenance treatment was G (1000 mg/ m2 weekly 3q4w) in both arms until progression or limiting toxicity. Stratification criteria were: center, WHO status and initial surgery. It was required to include 176 pts to detect an expected change in median OS from 6 to 12 months (bilateral α = 1% and β = 10%). Intent to treat survival analysis used the Logrank test. Results: Between 03/00 and 07/05, 59 pts were randomized to CHRT and 60 to G. Median follow-up at the 05/05 was 16 months. Pt characteristics were well balanced (CHRT/G) with mean age (60.1/62.7 year), sex ratio (1/ 1.4) and WHO status ( 0–1: 88%/73%, 2: 9%/23%). During the induction phase, more than 75% of the planned dose was completed in 81.4% of pts for radiotherapy, 52.5% for 5-FU and 50.8% for cisplatin and 76.7% of pts in the G arm. In CHRT and G arms, OS at 6 and 12 months were respectively 78/82% and 24/51%, with a median survival of 8.4/14.3 months (stratified log-rank p = 0.014). CHRT or G related toxicities during induction phase were grade 3/4 leukopenia (17%/10%), thrombopenia (8.5%/0%), non-haematological toxicity (37%/ 17%) with diarrhea (7%/0% ), cutaneous toxicity (0%/3%). One treatment-related death was observed in the CHRT arm (aplasia). Conclusion: Study was stopped before the planned inclusion due to lower survival with initial CHRT when compared to G alone. Reasons explaining this difference are under investigation. No significant financial relationships to disclose.

4128 Background: Chemotherapy has low efficacy in HCC, a poor prognostic disease. Evaluation of new drug combination is needed. The trial was designed to evaluate the efficacy of XELOX in HCC. Methods: Inclusion criteria: measurable HCC, unresectable or unsuitable for local treatment; Child-Pugh A or B, CLIP < 4. The patients (pts) received every three weeks: capecitabine 2000 mg/m2 d1-d14, oxaliplatine 130 mg/m2 as a 2-hour infusion d1. The main endpoint was tumor response. Results: From December 2003 to September 2004, 50 pts were included in this phase II trial: 44 men, 6 women; median age (range) 68 years [24–82]; Pugh score A, 42 pts and B, 8 pts; CLIP 0–1, 17 pts, CLIP 2–3, 28, CLIP unknown, 5 pts. The median number of cycles was 5.5 [1 - 12]. Treatment is ongoing in 6 pts. The main reasons for stopping treatment were progression (19 pts) and death (8 pts). Grade 3–4 toxicity: neutropenia 2 pts; febrile neutropenia 1 pt; thrombopenia 5 pts; diarrhea 8 pts; vomiting 2 pts; mucositis 1 pt; sensitive n...

4006 Background: Chemoembolization in the palliative treatment of HCC remains controversial. The FFCD 9402 multicenter phase III trial was designed to compare the effects of the association chemoem...

4162 Background: The aim of this study was to explore whether pre-treatment quality of life (QoL) predicts survival in patients with non-operable HCC. Methods: Between 1995 and 2002, 123 eligible c...

4150 Background: The results of a randomized phase II trial in pts with MGA showed that LV5FU2-irinotecan (CPT arm) combination as first-line therapy had a better efficacy and toxicity profile than LV5FU2 (5FU arm) alone or LV5FU2-cisplatin (CIS arm) (Bouche et al. Proc ASCO 2003; 22: 258). QoL was assessed using the EORTC QLQ-C30 to investigate the risk-benefit ratio and to test the infrastructure for future data collection before a phase III study. Methods: QLQ-C30 was self-administered at baseline and every 8 weeks in the 134 eligible pts: 5FU arm (45 pts), CIS (44 pts) and CPT (45 pts). Scores were compared to baseline with an analysis of variance (ANOVA). During a 6-month follow-up: - QLQ C30 scores and compliance were analyzed with mean (SD) and percent of missing scores; - a mixed ANOVA model for repeated measurements was applied to summarize the better longitudinal QoL profile. The same analyses were performed with the extreme poorest QLQ-C30 allocation for non-ignorable missing scores. Results: C...

Monthly 5 day course of 5FU bolus infusion with low dose Leucovorin (FUFOL 1d) has the best therapeutic index for 5FU modulation in metastatic colorectal cancer. Delivering 5FU protracted continuous infusion has also a better index than 5FU bolus. The bi-monthly combination of 5FU bolus followed by 5FU continuous infusion and high dose (LV 5FU2) has show a good efficacy with low toxicity in several phase II studies. The current study compares FUFOLId and LV 5FU2. From March 1991 until April 1994, 437 patients (pts), stratified according to performance status, presence of measurable disease, and synchroneous or metachroneous disease, were randomized to (A) FUFOLld: IV bolus 5FU 425 mg/m2 d1-5 with folinic acid 20 mg/m2 IV d1-5 q 4 wk or (B) LV 5FU2: folinic acid 200 mg/m2 2-hour infusion followed by IV bolus 5FU 400 mg/m2 and 22-hour infusion FU 600 mg/m2 d1-2 q 2 wk. Therapy was continued until disease progression and second-line chemotherapy including 5FU continuous infusion was allowed in both arms. Response rate (306 evaluable pts), progressionfree survival (PFS) and overall survival (OS) are as follows: Treatment Pts Response Pts PFS (wk) OS (wk) FUFOL1d 147 17% 218 22.8 57.2 LVSFU2 159 34% 219 29.5 61.4 P = 0.002 P = 0.008 P = 0.006 41 pts (21.5%) experienced grade 3–4 toxicities in arm A versus 18 pts (9.2%) in arm B, P = 0.0004. grade 3–4 toxicities (%) were in arm A: neutrophils 7.9 platelets 1, nausea 2.6, diarrhea 4.7, mucositis 9.9, alopecia I, skin 0.5 and in arm B: neutrophils 2, platelets 0.5, nausea 3.1, mucositis 1.5, alopecia 0.5, skin 0.5. Treatment was stopped in one patient in arm A and 3 in arm B who experienced angina pectoris. We conclude that the bi-monthly combination of 5FU bolus and continuous infusion with high-dose folinic acid is more active and less toxic than monthly 5 day course of bolus 5FU with low dose Leucovorin.

The registry of digestive tract tumours established for the department of Cote d'Or (France) was used to study the incidence and some of the characteristics of primary liver cancer (PLC) in this area. The annual age-standardized incidence rate was 7.6/100,000 for males, and 1.8/100,000 for females. As compared to other areas the Cote d'Or is in the intermediate incidence areas. The risk of PLC was higher in urban than in rural areas in men (p less than 0.01). There was no significant variation in PLC incidence over the eight years of the study. Alfafoetoprotein levels over 200 ng/ml were observed in only 48.9% of the cases. Alfafoetoprotein measurement has to be complemented by other investigations in screening of high-risk patients. Liver cirrhosis was present in 70.9% of the cases in which the information was available. The male:female ratio in the non-cirrhotic group was 1.5:1, very different to the 8.8:1 in the cirrhotic group. Cirrhosis was associated with excessive alcohol consumption in 92% of cases. The prevalence of serological markers of hepatitis B virus infection was investigated in 91 patients. Hepatitis Bs-antigen was found in 8.8% and evidence of past or present infection in 28.2%. In view of the prevalence of chronic alcoholism in patients with cirrhosis it is suggested that alcohol leads to an increased risk of cirrhosis followed by an increased incidence of PLC. Further studies are needed to elucidate the eventual role of HBV infection and other suspected environmental factors in the aetiology of PLC.

The registry of digestive tract tumours established for the department of Cote d'Or (France) was used to study the epidemiological characteristics of large bowel cancer subsites for the period 1976-1983. Age standardised incidence rates for colon cancers were 18.9/100,000 for men and 14.2/100,000 for women. The corresponding rates for rectal cancers were 18.4/100,000 and 10.2/100,000. The sex ratio for right colon cancer (caecum, ascending colon, hepatic flexure, transverse, splenic flexure) was close to 1 and did not change with advancing age, while that for the left colon (sigmoid, descending colon) showed a male excess after 65. For rectal cancer (rectosigmoid junction, rectal ampulla) the male predominance was more marked and occurred earlier, after 55 years of age. There was no significant variation in incidence between rural and urban areas for the different sublocalisations. In males the risk was high in the highest social classes for left colon cancer (p less than 0.01), and among farmers for rectal cancer (p less than 0.01). The risk of left colon cancer in males increased with the comfort of housing (p less than 0.01), but this marker of social class had little influence on incidence for the other localisations in males, or for any localisation in females. No significant variation was found with education. The incidence of colon cancer tended to increase over the 8 years of study. The variations were significant for left colon cancer. For rectal subsites cancer incidence decreased in women (p less than 0.05). The observed differences suggest differences in the aetiological factors within large bowel cancers. Therefore right colon cancer, left colon cancer and rectal cancer should be considered separately in epidemiological analytical investigations.

Available population based survival statistics for colorectal cancers were compared. The results based on relative survival rates showed similar data in Finland, Norway, Geneva and Cote d'Or. The survival rates were lower in Great Britain and Iceland. Several factors complicate survival comparisons: age, exact localization of the tumour, definitions and distribution of tumour stages. Adjustment of these factors is necessary. If their definitions differ, no conclusion can be based upon the data. Population based survival figures provide public health authorities with a basis for monitoring cancer patient care. They are also useful for assessing the resources required for cancer treatment, follow-up and rehabilitation. They provide clinicians with survival data for reference.

The registry of digestive tract tumours established for the department of Cote-d'Or (France) was used to study the epidemiological characteristics and the natural history of biliary tract cancers. Age standardised incidence rates for gallbladder cancers were 2.7/100,000 for women and 0.9/100,000 for men. The corresponding rates for extrahepatic bile duct cancers were 0.5/100,000 and 1.7/100,000, and for ampulla of Vater cancer 0.3/100,000 and 0.3/100,000. The three cancers differ in their descriptive epidemiology and should be considered separately in epidemiological analytical investigations. The incidence of each of the three diseases increased with age, and cancers of known histological type were mainly adenocarcinomas. Some gallbladder cancers were undifferentiated or squamous cell carcinomas. There was no significant variation in incidence for gallbladder cancer and extrahepatic bile duct cancer over the eight years of the study. The association with gallstones was frequent in gallbladder cancer: 70.5% compared to 13.0% in other biliary tract cancers (less than 0.001). Although the association of gallbladder cancer with gallstones is frequent, few patients with cholelithiasis experience development of a gallbladder cancer. It is necessary to identify among patients with gallstones a subgroup at high risk of gallbladder cancer in whom prophylactic surgery might be justified. Biliary tract cancers are seldom diagnosed early: lymph nodes or visceral metastases were present in 77% of gallbladder cancers, in 83% of extrahepatic bile duct cancers, and in 55% of ampulla of Vater cancers at the time of diagnosis. The corresponding resectability rates were 46.1%, 11.9%, and 38.9%. The five-year overall survival rates were 2.9% for gallbladder cancer, 0% for extrahepatic bile duct cancer, and 18.3% for ampulla of Vater cancer. The corresponding five-year survival rates after surgery for cure were 10.3%, 0%, and 35.7%. Biliary tract cancer still represent a great therapeutic challenge.

3525^ Background: Potential benefit of adding CTX to the current standard treatment for stage III CC, was assessed. Subgroup analyses of demographic, clinical and molecular data may improve our understanding of this patient population. Methods: Patients (pts) were randomized 28-56 days following resection. They received 12 biweekly cycles of oxaliplatin 85 mg/m2 day (d) 1, with leucovorin 200 mg/m2, 5-FU 400 mg/m2 bolus IV, followed by 5-FU 600 mg/m2 22-hr IV on d1-2 (FOLFOX4), without (arm A) or with weekly CTX (arm B) 250 mg/m2 (initial dose 400 mg/m2). Primary endpoint was disease free survival time (DFS). Secondary endpoints included overall survival (OS), treatment compliance and safety. Enrolment was restricted to KRAS wt pts in 06/2008. Planned accrual of 1,407 KRAS wild-type (wt) pts provided 90% power to detect a hazard ratio (HR) of 0.75 with 2-sided α=0.05, with interim analyses after 65% of planned events. Preplanned subgroup analyses were performed. Results: 1,602 KRAS wt pts (811 arm A, 791 arm B) and 742 mutated (m) KRAS (prior to the amendment), were randomized. BRAF status was determined in 1134 (71%) KRAS wt pts. Median follow-up was 40 months. This interim analysis showed no difference between arms for DFS (HR 1.05, 95% CI 0.85-1.29; p=0.66) or OS (HR 1.09, 95% CI 0.81-1.47; p=0.55) in KRAS wt pts or for DFS (HR 0.99, 95% CI 0.75-1.28; p=0.91) or OS (HR 0.98, 95% CI 0.67-1.44; p=0.92) in KRAS/BRAF wt pts (n=984). Similar results were seen in KRAS mutant (mt) pts without any detrimental effect. In KRAS wt pts worse outcomes were seen with CTX in pts >70 years (n=149, DFS: HR 1.97, 95% CI 0.99-3.93; p=0.05), in females (n=666, HR 1.45, 95% CI 1.03-2.03; p=0.03) and in pts with right-sided CC (n=570, HR 1.40, 95% CI 1.01-1.94; p=0.04). Conversely, a better outcome was seen in pts with pT4pN2 CC (n=146, HR 0.55, 95% CI 0.35-0.89; p=0.01). Conclusions: Adding CTX to FOLFOX4 offered no benefit to pts with resected stage III KRAS wt, KRAS/BRAF wt and KRAS mt CC. Subgroup analyses suggest that KRAS wt pts with pT4pN2 tumors may derive benefit from CTX. MSI status determination is ongoing to explore its potential interaction with poor outcome in female and/or with right-sided tumors pts. Clinical trial information: NCT00265811.

3614 Background: Gilbert’s disease patients (pts) (homozygotous for the UGT1A1*28 allele) have a major risk (>30%) of severe, life-threatening, neutropenia when treated with Irinotecan (IRI). The aim of this study was to demonstrate that, in these pts, treated with IRI 1st line for mCRC, primary prevention with GCSF (lenograstim) reduces under 10% the risk of grade 4 or febrile neutropenia. Methods: This is a prospective, multicenter, phase II study of FOLFIRI + bevacizumab 1st line (IRI 180 mg/m² every 2 weeks) and primary prophylactic GCSF (D5 to D11 each course) in mCRC pts with Gilbert’s disease. Pre-chemotherapy UGT1A1 genotyping was centralized and standardized using a biological molecular technique applied on DNA blood-extracted lymphocytes. Using a 2-step Fleming design, (α=5% and β=90%), 30 pts had to be included with an interim analysis (IA) planned after 20 pts and 4 months of follow-up. Results: Twenty pts from 7 centers were included between 10/2007 and 02/2012 and 19 analysed for the IA. Median pts age was 63 years (range: 45-73), 60% were females, 90% were PS 0 or 1, 80% had a colic primary site and 73% hepatic metastases. The primary site was non- resected in 1/3 of pts. The total number of administered courses of chemotherapy was 229 with a median of 12 per pt (range: 1-40). Among all these courses, 213 were administered with GCSF. IRI was administered as defined by the protocol with a nearly 100% rate of received /theoretical dose. Grade 3 neutropenia rate was 10.5%. No grade 3-4 diarrhea, no grade 4 or febrile neutropenia and no toxic death were observed. No declared SAEs were related to GCSF. In term of best response at 6 months, 7 pts were in complete or partial response and 9 had stable disease. Median progression free survival and overall survival were respectively 8.7 months (4.9; 13.4) and 24.4 months (12.6; ND). Conclusions: This study is the first to demonstrate that a pharmacogenetic approach based on a simple genetic test easy to perform can achieve a high rate of safe and performant administration of IRI in high risk mCRC pts. Clinical trial information: NCT00541125.

SummaryBackground Whether aminosalicylates or thiopurines reduce the risk of colorectal cancer (CRC) in inflammatory bowel (IBD) disease is controversial. Aim To assess simultaneously the chemopreventive effect of aminosalicylates or thiopurines in a case–control study nested in the CESAME observational cohort that enrolled consecutive patients with IBD between May 2004 and June 2005. Patients were followed up to December 2007. Methods Study population comprised 144 case patients who developed CRC from the diagnosis of IBD (65 and 79 cases diagnosed, respectively, before and from 2004, starting year of the prospective observational period of CESAME) and 286 controls matched for gender, age, IBD subtype and year of diagnosis, and cumulative extent of colitis. Exposure to aminosalicylates or thiopurines was defined by an exposure to the treatment during the year of the diagnosis of cancer. The propensity of receiving 5-ASA and thiopurines was quantified by a composite score taking into account patient and IBD characteristics. The role of aminosalicylates or thiopurines was assessed by multivariate analysis. Propensity scores and the history of primary sclerosing cholangitis were entered into the multivariate model for adjustment. Results By multivariate analysis adjusted for propensity, a significant protective effect of exposure to drugs during the year of cancer was found for aminosalicylates (OR = 0.587, 95% CI: 0.367–0.937, P = 0.0257), but not for thiopurines (OR = 0.762, 95% CI: 0.432–1.343, P = 0.3468). Conclusion In a case–control study nested in the CESAME cohort, a significant decrease in the risk of colorectal cancer in IBD was associated with exposure to aminosalicylates, not to thiopurines.

With 700,000 deaths in 2008, hepatocellular carcinoma is the 3rd most common cause of cancer-related death worldwide. Transarterial chemoembolization is the standard treatment for intermediate-stage hepatocellular carcinoma. This intraarterial treatment is performed by injecting an anticancer drug carried by ethiodized oil or by drug-eluting beads and followed by the occlusion of the artery when ethiodized oil is used. Median survival of patients remains < 2 years, and there is no consensus about the optimal treatment regimen. The aim of our work was to improve the efficacy of transarterial chemoembolization in optimizing the anticancer drug and its carrier.We have demonstrated that idarubicin was the most cytotoxic anticancer drug in an in vitro screening study of 11 anticancer drugs on 3 human hepatocellular carcinoma cell lines. Idarubicin was more cytotoxic in our experiment than the anticancer drugs which are currently used for transarterial chemoembolization of hepatocellular carcinoma.The randomized LIPIOAMIO phase II trial has shown that the addition of amiodarone to stabilize an emulsion composed of an anthracycline and of ethiodized oil injected for transarterial chemoembolization does not improve significantly survival of patients with a non resectable, non metastatic hepatocellular carcinoma. We have also demonstrated that idarubicin could be loaded in drug-eluting DC Bead™ and that the resulting solution was stable during several months.We designed the dose-escalation IDASPHERE phase I trial to determine the limiting dose of idarubicin administred in a solution of drug-eluting DC Bead™ during a transarterial chemoembolization session in patients with non resectable, non metastatic hepatocellular carcinoma. First results of the trial are presented in the manuscript., Avec environ 700 000 décès en 2008, le carcinome hépatocellulaire se situe au 3ème rang de la mortalité par cancers dans le monde. La chimioembolisation est le traitement recommandé chez les patients atteints d’un carcinome hépatocellulaire de stade intermédiaire B de la classification Barcelona Clinic Liver Cancer. Cette technique de radiologie interventionnelle consiste en l’injection intraartérielle d’un agent anticancéreux à l’aide d’un vecteur (lipiodol ou microsphères d’embolisation) complétée par une occlusion artérielle lorsque le lipiodol est utilisé. La médiane de survie des patients traités par chimioembolisation pour un carcinome hépatocellulaire n’excède pas 2 ans et il n’existe aucun consensus sur la procédure optimale.L’objectif de notre travail est d’essayer d’améliorer la procédure de chimioembolisation en optimisant d’une part l’agent anticancéreux et d’autre part, son vecteur.Il a été démontré au cours d’un travail de sélection in vitro, que l’idarubicine est l’agent anticancéreux le plus cytotoxique sur 3 lignées humaines de carcinome hépatocellulaire. Cette anthracycline présente une cytotoxicité supérieure à 10 autres agents anticancéreux dont ceux utilisés en pratique clinique pour la chimioembolisation des carcinomes hépatocellulaires.L’essai de chimioembolisation de phase II randomisé LIPIOAMIO a montré que l’addition d’amiodarone utilisé pour stabiliser une émulsion à base de lipiodol et d’anthracycline n’augmente pas signicativement la survie des patients atteints d’un carcinome hépatocellulaire non résécable non métastatique. Nous avons par ailleurs montré que l’idarubicine était chargeable et donnait une solution stable plusieurs mois avec les microsphères d’embolisation DC Bead™. Un essai de phase I est en cours pour déterminer la dose limitante de l’idarubicine administrée dans une solution de microsphères DC Bead™ au cours d’une séance de chimioembolisation chez des patients atteints d’un carcinome hépatocellulaire non résécable, non métastatique. Quelques résultats préliminaires de cet essai sont présentés dans le manuscrit.