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Background Colon adenocarcinoma occurs mainly in older patients (pts). Oxaliplatin based adjuvant chemotherapy has demonstrated an improvement on disease-free survival (DFS) after a stage III colon cancer resection in young pts. Nevertheless, the benefit of adjuvant chemotherapy is matter of debate in old pts. Methods The purpose of ADAGE trial is to compare the DFS obtain with oxaliplatin combined with fluoropyrimidine (F) to F alone in fit pts over 70 years (group 1) and F to observation in frail pts (group 2) after resection of a stage III colon cancer. We here report a preliminary tolerance analysis on 50% of the first pts enrolled in the study. Results The analysis was performed on 491 pts (378 in group 1 and 113 in group 2). Main pts characteristics were respectively for the group 1 and 2: male in 57% and 50%, median age of 76 and 83 years, ECOG=0 in 59% and 29%, abnormal IADL in 23% and 62%, no caregiver in 26% and 28%, fall ≤6 months in 9% and 14%, depression possible 28% and 40%, fail of one-leg balance in 20% and 59%, impaired cognition in 21% and 38%, G8 score

IF 6.029; International audience; BackgroundA recent prospective randomised trial did not reveal significant differences in median progression-free survival between two chemoradiotherapy (CRT) regimens for inoperable non-metastatic oesophageal cancer patients. This secondary analysis aimed to describe the impact of CRT on health-related quality of life (HRQOL), physical functioning, dysphagia, fatigue and pain and to evaluate whether baseline HRQOL domains can predict overall survival.Patients and methodsA total of 267 patients were randomly assigned to receive with 50 Gy of radiotherapy in 25 fractions six cycles of FOLFOX or four cycles of fluorouracil and cisplatin on day 1. HRQOL was prospectively assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire version 3.0 with the oesophageal cancer module (QLQ-OES18).ResultsBoth groups showed high baseline compliance. Subsequently, compliance reduced to 41% at the 6-month follow-up. Baseline HRQOL scores showed no statistical differences between treatment arms. During treatment, both groups exhibited lower physical and social functioning and increased fatigue and dyspnoea, although dysphagia moderately improved in the fluorouracil–cisplatin arm only (p = 0.047).During follow-up, HRQOL scores revealed no significant differences between chemotherapy regimens. Linear mixed model exhibited a treatment-by-time interaction effect for dysphagia (p = 0.017) with a greater decrease in dysphagia in the fluorouracil–cisplatin group. Time until definitive deterioration analysis showed no significant differences in global HRQOL, functional or main symptom domains. However, time until definitive deterioration was significantly longer for the fluorouracil and cisplatin arm compared with FOLFOX for appetite loss (p = 0.002), QLQ-OES-18 pain (p = 0.008), trouble swallowing saliva (p = 0.011) and trouble talking (p = 0.020).ConclusionAnalyses of HRQOL scores revealed no statistically significant differences between patients with inoperable non-metastatic oesophageal cancer treated by FOLFOX versus those treated with a fluorouracil–cisplatin regimen as part of definitive CRT.

Aim of the study The optimal therapeutic strategy in patients with rectal cancer and synchronous unresectable metastases remains unknown. We evaluated the efficacy of FOLFIRINOX induction therapy in this setting. Patients and methods Chemotherapy-naive patients received at least 8 cycles of FOLFIRINOX. The primary end-point was the 4-month disease control (4 m DC) rate. Tumour responses were centrally reviewed and assessed by computed tomography scan for metastases (Response Evaluation Criteria in Solid Tumours criteria) and magnetic resonance imaging for rectal tumorus. With a Simon 2-stage design and a targeted (H1) 4 m DC > 75%, 65 patients were enrolled from July 2012 to February 2015: male, 78%; median age, 61 years; performance status, 0–1, 98%; liver metastases, 92%; ≥2 metastatic sites, 63%. Results Fifty-six (85%) of the 65 patients received the 8 planned FOLFIRINOX cycles. The primary objective was achieved (4 m DC rate: 94%; 95% confidence interval [CI], 86.3–97.8). Primary tumour symptoms decreased from 72% at baseline to 10% at 4 months. Response rate was 86%, and a >70% primary tumour volume decrease was seen in 63% of patients. Forty-four patients (68%) had at least one grade 3 side-effect; no toxic deaths occurred. Median follow-up was 35.0 months (95% CI, 31.3–43.7). Median progression-free survival and overall survival were 10.9 m (95% CI, 8.8–12.9) and 33.4 m (95% CI, 22.6–38.2), respectively. Conclusion Upfront FOLFIRINOX is feasible and allows good local and distant control. It therefore offers the opportunity to choose the best therapeutic strategy for each patient and to personalise treatment according to the local and distant efficacy results of this induction step. Trial registration Clinicaltrials.gov, NCT01674309 .

IF 11.855; International audience; Background :Metastatic colorectal cancer frequently occurs in elderly patients. Bevacizumab in combination with front line chemotherapy (CT) is a standard treatment but some concern raised about tolerance of bevacizumab for these patients. The purpose of PRODIGE 20 was to evaluate tolerance and efficacy of bevacizumab according to specific end points in this population.Patients and methods :Patients aged 75 years and over were randomly assigned to bevacizumab + CT (BEV) versus CT. LV5FU2, FOLFOX and FOLFIRI regimen were prescribed according to investigator’s choice. The composite co-primary end point, assessed 4 months after randomization, was based on efficacy (tumor control and absence of decrease of the Spitzer QoL index) and safety (absence of severe cardiovascular toxicities and unexpected hospitalization). For each arm, the treatment will be consider as inefficient if 20% or less of the patients met the efficacy criteria and not safe if 40% or less met the safety criteria.Results :About 102 patients were randomized (51 BEV and 51 CT), median age was 80 years (range 75–91). Primary end point was met for efficacy in 50% and 58% and for safety in 61% and 71% of patients in BEV and CT, respectively. Median progression-free survival was 9.7 months in BEV and 7.8 months in CT. Median overall survival was 21.7 months in BEV and 19.8 months in CT. The 36-month overall survival rate was 27% in BEV and 10.1% in CT. Severe toxicities grade 3/4 were mainly non-hematologic toxicities (80.4% in BEV, 63.3% in CT).Conclusion :Bevacizumab combined with CT was safe and efficient. Both arms met the primary safety and efficacy criteria.

IF 11.855; International audience

The FFCD 2000–05 randomised trial included 410 patients with advanced colorectal cancer and compared a sequential arm S treated with 5-fluorouracil and leucovorin (LV5FU2) followed by FOLFOX (LV5FU2 + oxaliplatin) and then FOLFIRI (LV5FU2 + irinotecan) and a combination arm C that begins directly with FOLFOX followed by FOLFIRI. The first aim of this study was to analyse the prognostic effects on overall survival of disease progression, and of toxicities under first-line therapy. We also studied the benefit of introducing irinotecan in each arm. Finally, we compared the effect of treatment on repeated progression and toxicities. For this purpose, we used Cox regression models with time-dependent variables and shared gamma frailty regression models. We found that early on during follow-up, the prognostic effect on survival of progression under first-line therapy was greater in C (hazard ratio [HR] = 18.0 [7.9–41.2]) than in S (HR = 7.7 [3.9–17.4]). This difference was significant, but it decreased over time. The prognostic effect of severe toxicities was greater in S (HR = 2.0 [1.4–2.9]) than in C (HR = 1.3 [0.9–1.9]). Introducing irinotecan was significantly more beneficial in S (HR = 0.2 [0.1–0.4]) than in C (HR = 0.3 [0.2–1.5]). The risk of repeated progression was not significantly different between the two groups (HR = 0.9 [0.8–1.1]) whereas the risk of toxicities was greater in C (HR = 1.7 [1.4–2.1]). Overall, this study suggests that starting with less toxic first-line treatment is a valid option since it does not exert a deleterious effect on the risk of overall progression or death.

International audience

Background: A randomized phase II, open-label multicenter study evaluating oxaliplatin alone (OXA), infusional 5-fluorouracil alone (5-FU) and an oxaliplatin/infusional 5-FU combination (OXFU) in untreated, advanced pancreatic carcinoma (APC). Patients and methods: Chemotherapy-naive patients with advanced or metastatic, histologically/cytologically proven pancreatic carcinoma with measurable disease, received OXA [130 mg/m 2 , 2-h intravenous (i.v.) infusion] alone, OXA combined with 5-FU (1000 mg/m 2 /day, continuous i.v., days 1–4), or 5-FU alone, every 3 weeks. Results: Sixty-three patients (42 males/21 females) were treated: 17 patients/52 cycles OXA, 31 patients/ 175 cycles OXFU, 15 patients/41 cycles 5-FU, with a median of three, six and two cycles/patient, respectively. Patient characteristics were similar in all arms. Median age was 57 years (range 21–75), and 83% of patients had PS 0–1. Most patients (62%) had moderate to well-differentiated tumors, 90% had metastatic disease, 81% with liver metastases. All responses (three partial responses; WHO) occurred in the OXFU arm (10% response rate). Five of 32 patients evaluable for clinical benefit were responders (OXA, 14%; OXFU, 21%). Median time to progression and overall survival were higher in the combination arm (4.2 and 9.0 months, respectively) than either single-agent arm (OXA, 2.0 and 3.4 months; 5-FU, 1.5 and 2.4 months, respectively). Moderate hematotoxicity without morbidity was seen in all arms. Two OXFU patients had grade 3 oxaliplatin neurosensory toxicity. Conclusions: With a 10% response rate, median overall survival of 9 months and an encouraging safety profile, the OXFU combination is effective, appears superior to infusional 5-FU and warrants further studies in APC patients.

Objectif de l’etude L’objectif de cette etude etait d’evaluer la toxicite aigue et la qualite de vie avec et sans escalade de dose chez des patients pris en charge par chimioradiotherapie exclusive avec irradiation prophylactique ganglionnaire pour un cancer de l’œsophage. Materiel et methode Les patients atteints d’un cancer de l’œsophage localement evolue ou non resecable et prouve histologiquement ont ete randomises entre une irradiation prophylactique ganglionnaire de 40 Gy et un complement de 10 Gy dans la maladie macroscopique (bras A) et la meme irradiation prophylactique ganglionnaire et un complement de 26 Gy (bras B). Une chimiotherapie concomitante par folfox-4 (5-fluoro-uracile, oxalipaltine, acide folinique) a ete delivree dans les deux bras. L’objectif principal etait d’evaluer la toxicite aigue a 3 mois avec l’echelle du National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), v4.0. La qualite de vie a ete evaluee par les questionnaires de l’European Organization for Research and Treatment of Cancer (EORTC) QLQ C30 et OES18. Les analyses ont ete realisees en intention de traitement. Resultats Cent-soixante patients ont ete randomises : 81 patients dans le bras A et 79 patients dans le bras B. Soixante-dix patients dans chaque bras etaient atteints d’un carcinome epidermoide et 59 patients contre 58 d’ une maladie de stade III. Les taux de toxicite non hematologique de grade 3 ou plus etaient de 76,5 % dans le bras A et 86 % dans le bras B. Les taux de toxicite hematologique de grade 3 ou plus etaient de 82,7 % et 88,6 %. Les scores moyens de sante globale au moment du diagnostic et a 3 mois etaient de 63,9 (standard deviation [sd] : 21,4) contre 69,6 (sd = 23,1) dans le bras A et 65,3 (sd = 19,5) contre 58,8 (sd = 19,9) dans le bras B. La presence d’une dysphagie n’etait significativement pas differente au moment du diagnostic entre le bras A (89,2 %) et le bras B (86,2 %) et a 3 mois (77,8 % contre 86,8 %). Conclusion Une escalade de dose sur la maladie macroscopique associee a une irradiation prophylactique ganglionnaire est faisable sans augmentation de la toxicite aigue et sans modifications de la qualite de vie immediate.

This comparative phase III trial of mitoxantrone+vinorelbine (MV) versus 5-fluorouracil+cyclophosphamide+either doxorubicin or epirubicin (FAC/FEC) in the treatment of metastatic breast cancer was conducted to determine whether MV would produce equivalent efficacy, while resulting in an improved tolerance in relation to alopecia and nausea/vomiting. This multicentre study recruited and randomised 281 patients with metastatic breast cancer; 280 were evaluable for response survival and toxicity (138 received FAC/FEC, 142 received MV). Patient characteristics were matched in each arm and stratification for prior exposure to adjuvant therapy was made prospectively. The overall response rate (ORR) was equivalent in the two arms (33.3% for FAC/FEC versus 34.5% for MV), but MV was more effective in patients who had received prior adjuvant therapy (13% (95% confidence interval (CI) 3-23) for FAC/FEC versus 33% (95% CI 20-47) for MV P=0.025) with a better progression-free survival (PFS) (5 months (range 1-18 months) versus 8 months (range 1-27 months); P=0.0007 for FAC/FEC versus MV, respectively) while FAC/FEC was more effective in previously untreated patients (ORR 43% (95% CI 33-53) versus 35% (95% CI 25-45), P=0.26; PFS 9 months (range 0-29 months) versus 6 months (range 0-26 months) P=0.014). Toxicity was monitored through the initial six cycles of therapy; febrile neutropenia and delayed haematological recovery was more frequent for MV (P=0.001), while nausea/vomiting of grades 3-4 was greater for FAC/FEC (P=0.031), as was alopecia (P=0.0001), cardiotoxicity was the same for the two regimens. MV represents a chemotherapy combination with equivalent efficacy to standard FAC/FEC and improved results for patients who have previously received adjuvant chemotherapy. Toxicity must be balanced to allow for increased haematological suppression and risk of febrile neutropenia with MV compared with a higher risk of subjectively unpleasant side-effects such as nausea/vomiting and alopecia with FAC/FEC.

PURPOSE This multicenter study compared the therapeutic ratio of a monthly schedule of low-dose leucovorin (LV) and fluorouracil (5-FU) bolus with a bimonthly schedule of high-dose LV and 5-FU bolus plus continuous infusion in patients with advanced colorectal cancer. PATIENTS AND METHODS Of the 448 patients randomly assigned to treatment, 433 were assessable. Treatment A was a monthly regimen of intravenous (IV) LV 20 mg/m2 plus bolus 5-FU 425 mg/m2 for 5 days every 4 weeks. Treatment B was a bimonthly regimen of IV LV 200 mg/m2 as a 2-hour infusion followed by bolus 5-FU 400 mg/m2 and 22-hour infusion 5-FU 600 mg/m2 for 2 consecutive days every 2 weeks. Therapy was continued until disease progression. Second-line chemotherapy, which included 5-FU continuous infusion, was allowed in both arms. RESULTS The response rates in 348 patients with measurable lesions were 14.4% (monthly regimen) and 32.6% (bimonthly regimen) (P = .0004). The median progression-free survival times were 22 weeks (monthly regimen) and 27.6 weeks (bimonthly regimen) (P = .0012). The median survival times were 56.8 weeks (monthly regimen) and 62 weeks (bimonthly regimen) (P = .067). Grade 3-4 toxicities occurred in 23.9% of patients in the monthly arm compared with 11.1% of those in the bimonthly arm (P = .0004). Patients in arm A more frequently experienced severe granulocytopenia (7.3% v 1.9%), diarrhea (7.3% v 2.9%), and mucositis (7.3% v 1.9%) than patients in arm B. CONCLUSION The bimonthly regimen was more effective and less toxic than the monthly regimen and definitely increased the therapeutic ratio. However, there was no evidence of increased survival.

Background: Vinorelbine and cisplatin are active against squamous cell oesophageal carcinoma. The purpose of this phase II study was to evaluate the efficacy and safety of vinorelbine plus cisplatin in previously untreated patients with metastatic squamous cell oesophageal carcinoma and to estimate the progression-free survival, overall survival and quality of life (QoL) of the patient population. Patients and methods: Seventy-one eligible patients were entered into a study of vinorelbine 25 mg/m 2 on days 1 and 8 plus cisplatin 80 mg/m 2 on day 1, every 3 weeks. Degree of dysphagia relief was monitored and QoL was measured using the EORTC QLQ-C30. Results: All eligible patients were assessed for response and 24 achieved a confirmed partial response (33.8%; 95% confidence interval 23–46); the median duration of response was 6.8 months, progressionfree survival was 3.6 months and median survival of the whole group was 6.8 months. Toxicity was mainly related to neutropenia (grade 3/4 in 41% of patients). At cycle 2, 43% of the patients reported at least a moderate improvement in global health status/QoL and 25% experienced a large improvement. Conclusions: Vinorelbine plus cisplatin represents a well-tolerated active palliative regimen for patients with advanced squamous cell carcinoma of the oesophagus. This combination may offer a better therapeutic index than cisplatin–5-fluorouracil.

Aim: REG is a multi-kinase inhibitor with survival benefits in pts with pretreated mCRC, as demonstrated in the phase III CORRECT study. As a result, REG has been made available for medical practice use in the US, and in the EU. However, prescribing conditions in the real-life setting are known to be less stringent than selection criteria in clinical trials. The REgorafeniB in mEtastatic Colorectal cancer: a French Compassionate progrAm (REBECCA) is an ambispective cohort study designed to elucidate safety and effectiveness outcomes associated with REG as used in clinical practice for mCRC refractory to all available therapies. Methods: Pts were identified from the database of the French ATU (Temporary Authorization for Use), approved by the French Health Authorities to provide early access to innovative, not yet approved medicinal products such as REG. Baseline patient and tumor characteristics, REG dosing and dose-intensity, REG-related adverse events, pre- and post REG treatments, predictors of events, and effectiveness data (PFS, OS) were collected from pts who agreed, and whom physicians accepted to collaborate to the REBECCA study which had OS estimate as a primary objective. Results: 1178 pts met the ATU criteria, of whom 1119 started on REG. 681/1178 (58%) were male. Median age was 64 years (range 25-92). ECOG PS was 0 (31%), 1 (59%), and ≥ 2 (10%). Median time since diagnosis of the metastatic disease was 2.7 years. KRAS mutation was documented in 604/1178 (51%) of pts. Metastases were predominantly located in the liver (76%) and lungs (62%). The starting dose of REG was 160 mg/day in 89.7% of pts. Of the 1178 pts who met the ATU criteria, 787 pts treated by 283 physicians were included in the REBECCA study. Analyses in these patients are in progress. Conclusions: Apart from a baseline PS > 1 in 10% of the pts, the patterns of pts included in the ATU seem to be comparable to those of pts included in the phase III CORRECT study. REBECCA, which is the largest cohort study of REG in mCRC pts ever reported, will provide valuable insights in the therapeutic benefit of this new compound in the real-life setting. Full results of this study will be presented at the meeting. Disclosure: A. Adenis: Bayer (advisory board, research funding). All other authors have declared no conflicts of interest.

Aim: There is little evidence that CT has any impact on outcome of pts with MSCC. This analysis was aimed to identify predictors for DC at first disease assessment, in MSCC pts receiving first-line CT. Methods: In the development cohort (68 pts from the multicentric and ongoing E-Dis trial [NCT01248299]), we have developed predictors for DC using a logistic regression model. Then, we applied the predictive model to an independent retrospective cohort of 60 consecutive pts from one center (Lille), and assessed Sensitivity (Se), Specificity (Sp), Positive Predictive Value (PPV), Negative Predictive Value (NPV), Accuracy (A), Discriminative slope (DS) and the calibration with the Brier score (BS). Results: In the development cohort, gender (women), ECOG 0-1, BMI ≥ 18.5, no bone metastasis, albumin ≥ 35g/l and hemoglobin ≥ LLN were associated with DC. Using logistic regression we identified the following 3 prognosticators: BMI ≥ 18.5 (OR 4.5; 95% CI: 0.91-22.5), no bone metastasis (OR 4.6; 95% CI: 0.91-23.2), albumin ≥ 35 g/l (OR 3.5; 95% CI: 1-12.1). Based on the presence or absence of these 3 independent prognosticators, we have built a predictive model using a score from 0 to 3. 64/68 pts were assessable. The DC rate was 64% (41/64), 14.3% (2/14), and 78% (39/50), in the overall population, when score = 0-1, and when score = 2-3, respectively. In the validation cohort, 51/60 patients were assessable. The DC rate was 39.2% (20/51), 12.5% (1/8), and 44.2% (19/43) in the overall population, when score = 0-1, and when score = 2-3, respectively. Se, Sp, PPV, NPV, A, and DS were 95%, 22%, 44%, 88%, 51% and 31.5%, respectively. Model calibration was good since the BS was very low (0.203). Our score was also predictive for death within 90 days (data not shown). Conclusions: We have developed and validated a predictive score for DC at first disease assessment, which includes BMI assessment, bone metastasis status, and albumin level for pts with MSCC receiving first-line CT. Disclosure: E. Francois: Participation to boards : Roche, Merck, Sanofi, Novartis, Celgene; A. Adenis: Bayer (advisory board, research funding). All other authors have declared no conflicts of interest.

PURPOSE To evaluate the response rate and toxic effects of vinorelbine (VNB) administered as a single agent in metastatic squamous cell esophageal carcinoma. PATIENTS AND METHODS Forty-six eligible patients with measurable lesions were included and were stratified according to previous chemotherapy. Thirty patients without prior chemotherapy and 16 pretreated with cisplatin-based chemotherapy were assessable for toxicity and response. VNB was administered weekly as a 25-mg/m2 short intravenous (i.v.) infusion. RESULTS Six of 30 patients (20%) without prior chemotherapy achieved a partial response (PR) (95% confidence interval [CI], 8% to 39%). The median duration of response was 21 weeks (range, 17 to 28). One of 16 patients (6%) with prior chemotherapy had a complete response (CR) of 31 weeks' duration (95% CI, 0% to 30%). The overall response rate (World Health Organization [WHO] criteria) was 15% (CR, 2%; PR 13%; 95% CI, 6% to 29%). The median dose-intensity (DI) was 20 mg/m2/wk. VNB was well tolerated and zero instances of WHO grade 4 nonhematologic toxicity occurred. At least one episode of grade 3 or 4 granulocytopenia was seen in 59% of patients. A grade 2 or 3 infection occurred in 16% of patients, but no toxic deaths occurred. Other side effects were rare, and peripheral neurotoxicity has been minor (26% grade 1). CONCLUSION These data indicate that VNB is an active agent in metastatic esophageal squamous cell carcinoma. Given its excellent tolerance profile and low toxicity, further evaluation of VNB in combination therapy is warranted.

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.

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...

4532 Background: The RTOG regimen of concurrent CRT with 5FU/CDDP represents the standard treatment of pts with IEC (Al- Sarraf JCO, 1997). As new combinations are required to improve survival, we launched a multicenter randomized phase II study to assess the feasibility and endoscopic complete response rate (ECRR) of combination CRT with Folfox 4 (arm A) or 5FU/CDDP (arm B) in pts with IEC. Methods: Radiotherapy (RT) was in both arms 50 Gy (2Gy/fraction) 5 days/ week for 5 weeks. In Arm A, pts received 6 biweekly cycles (cy): Oxaliplatin 85mg/m2 d1 and Leucovorin 200mg/m2 followed by 5-FU 400mg/m2 bolus and 600mg/m2 22h continuous infusion (C.I.) d1–2 ; the first 3 cy were delivered during RT, the 3 other after. Arm B: 4 cy were delivered: CDDP 75mg/m2 d1 followed by 5FU 1,000 mg/m2/d C.I. d1–4, the first two cy during RT and 2 other after RT. To be evaluable pts must have completed the concurrent CRT. Response evaluation (esophagoscopy + CT-scan) was done on week 15; ECRR was reviewed by an independent expert committee. Results: 97 pts (A/B= 53/44) were included and 95 treated: 19% adenocarcinoma, 81% squamous cell carcinoma; median age 59 [39–81] and PS 0–1: 98%. In arms A/B, 89/91% of pts completed the concurrent CRT and 75/70% the full treatment. Main NCI-CTC grade (G) 3–4 toxicities (% per pt) were in arms A/B: neutropenia 19/19, febrile neutropenia 12/5, neutropenic infection 2/7, esophagitis 8/14. Neurotoxicity: in arms A/B, 13%/ 2% of pts had G 2 and 46%/13% G 1 neuropathy, no G 3 neuropathy occurred. 47/40 pts (90%) were evaluable for response. In the ITT population, the ECRR was 44.7% and 30.0%, median TTP was 15.0 [9.9–18.9] / 9.5 [7.6- not reached (NR)] months (mos), median Event Free Survival was 11.6 [8.6–17.2]/ 7.8 [5.1–9.9] mos and the median overall survival was 22.7 [16.7-NR]/ 14.7 [9.2–17.2] mos, in arms A and B respectively. Conclusions: The new concurrent CRT with Folfox4 is a well tolerated and convenient combination with promising efficacy associated with very good survival results. Final data will be presented at the meeting. The study continues as a phase III trial. 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.

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...

3525 Background: FOLFOX4 has shown superiority over LV5FU2 and IFL in first line therapy. Limiting toxicities are neutropenia mainly due to 5FU bolus and cumulative sensory neurotoxicity which imposes to stop oxaliplatin (ox). OPTIMOX is a phase III study in pts with conventional inclusion criteria (526 pts), and two exploratory studies in pts not included in previous studies (37 pts > 75 yrs, 63 pts Alk Ph > 3xUNV) of a new strategy with ox stop and go: FOLFOX7 (high-dose ox and 5FU infusion, 6 cy) followed by 12 cy simplified (s) LV5FU2 and later FOLFOX7 reintroduction. Methods : 526 pts ≤ 75 yrs and/or Alk Ph ≤ 3xUNL were randomized Arm A FOLFOX4 (Ox 85mg/m2 d1, LV 200mg/m2, 5FU bolus 400mg/m2 and 22h 600mg/m2 d1–2, q2w) or Arm B FOLFOX7 x 6 cy (ox 130mg/m2 d1, LV 400mg/m2, 5FU 46h 2.4g/m2, q2w) followed by sLV5FU2 x 12 cy (LV 400mg/m2, 5FU bolus 400mg/m2 d1 and 46-h infusion 2.4g/m2, q2w) then FOLFOX7 reintroduction. Results : Arm A, 262 pts: M/F 58/42%, PS 0/1–2 55/45%, median age 63 yrs; Arm B, 264 ...

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.