Philippe Rougier

Introduction: Since more than 30 years the combinations of adriamycine (A) and streptozotocine (STZ) is considered as one of the standard chemotherapy regimens (Moertel et al, N Engl J Med 1992, 326 : 519-23) and proposed to patients with aggressive grade 2 metastatic pancreatic NET (PNET). This combination has many drawbacks: as an heterogeneous response rate (from 25% to 67%), an overall survival which depends on many factors and range from 11 to 19 months, and a poor tolerance when using the classical 5 days ‘schedule of administration every 6 weeks with frequent nausea and vomiting. To overcome these limits since 2011 we have developed a simplified 2 days ‘regimen repeated every 3 weeks.

Variability in the definition of survival endpoints in oncology trials was identified. Lack of a formal consensus could cause this, which limits inter-trial comparisons. The DATECAN project aimed at obtaining a formal consensus recommendation for defining survival endpoints for randomized clinical trials (RCTs) in the following cancer sites: pancreas, sarcoma/GISTs, breast, colorectal, gastric/œsophagus, head and neck, kidney-bladder. We report results for pancreatic cancer.

E14102 Background: HAI of chronomodulated irinotecan (I), 5-Fluorouracil (F) and oxaliplatin (O) (chronoIFO) as well as HAI of O combined with iv F and leucovorin allowed complete macroscopic resections of CRC liver metastases in patients with prior failure on systemic chemotherapy (Bouchahda, Cancer 2009; Goere, Ann Surg 2010). Purpose: To evaluate the resection rate of CRC liver metastases through combining HAI of IFO with cetuximab (Cet) in the first prospective European trial (Lévi, ASCO 2010, TPS#198). Methods: Patients with wt KRAS CRC and unresectable liver metastases receive iv Cet (500 mg/m², D 1 10:00-12:30) and chrono or conventional HAI of I (180 mg/m² D1), F (2800 mg/m²/d D2-D3/4), and O (85 mg/m² D2-3/4) q2 weeks. Grade 3-4 toxicities were managed with dose adaptation and/or supportive measures. Results: 23 patients (9F, 14 M; 33-76 y; PS 0-1) completed full assessment. They had bilateral liver lesions (82%), a median of 7 metastases [2-30; largest diameter, 38 mm (11-150)] and received ≥2 prior iv chemotherapy lines (61%). A median of 4 protocol courses (1-12) was given. Main grade 3-4 toxicities per patient were neutropenia (39%), abdominal pain (30%), fatigue (22%), and leukopenia (17%). An objective tumor response was achieved in 10/23 patients (43.4%). Seven patients underwent liver surgery (30.4%). 17 pts are alive with a median follow up of 16 months. One responding patient with 25 metastases measuring up to 6 cm and involving all liver segments had pathologic complete response in 24 of 25 lesions removed through three-stage hepatectomy. Conclusions: OPTILIV offers a safe and unusually effective treatment option. The trial aims at accruing 48 eligible patients to provide a statistical estimate of the complete macroscopic resection rate and survival in patients with liver metastases from refractory colorectal cancer receiving intravenous cetuximab and hepatic artery infusion of triplet chemotherapy.

493 Background: The addition of oxaliplatin to 5-fluorouracil (5-FU; FOLFOX regimen) was demonstrated to improve the adjuvant treatment of stage III colon cancer. For patients with microsatellite instability (MSI) tumors, several studies suggested a lack of benefit from 5-FU adjuvant chemotherapy but very little data are available regarding FOLFOX adjuvant therapy. The aim of this study was to further assess the value of MSI status as a marker of clinical outcome from FOLFOX adjuvant chemotherapy in stage III colon cancer. Methods: This multicentric retrospective study included 223 unselected patients with stage III colon cancer treated by FOLFOX adjuvant chemotherapy between 2003 and 2007. MSI status was determined by immunohistochemistry as the absence of MLH1, MSH2 or MSH6 expression. Disease-free survival (DFS) and relapse-free survival (RFS) were analyzed according to the MSI status using Kaplan Meier method and compared by log-rank test. Results: Twenty three tumors (10.3%) were MSI. The rate of 3-year DFS was 88.6% and 76.6% for MSI and MSS groups, respectively (HR=0.64; 95% CI, 0.25 to 1.60; P=0.34). The rate of 3-year RFS was 88.6% and 76.7% for MSI and MSS groups, respectively (HR=0.52; 95% CI, 0.20 to 1.30; P=0.18). Conclusions: A trend toward longer survival was observed for patients with MSI tumors compared with those with MSS tumors but the differences in survival were not significant. Interestingly, DFS at 3-years of patients with stage III MSI tumors treated by FOLFOX was higher in our series (88.6%) than in the largest study published for patients treated by 5-FU-based adjuvant chemotherapy (around 67.5%) or surgery alone (around 62.5%) (Sargent et al, JCO 2010). These observations suggest that adding oxaliplatin to 5-FU re-establishes a benefit of adjuvant treatment in the stage III MSI population. These results should be confirmed by analyzing materials of previously completed trials comparing FOLFOX to 5-FU such as the MOSAIC study. [Table: see text]

TPS198 Background: Circadian clocks control drug metabolism and cell cycle over the 24 h in healthy liver and are disrupted in cancer cells (Lévi et al. Annu Rev Pharm. Toxicol 2010). Hepatic artery infusion (HAI) of chronomodulated (chrono) irinotecan, 5-FU and oxaliplatin offered a first proof of principle of improved therapeutic index in patients (pts) with liver metastases from colorectal cancer (mCRC) failing 3 prior chemotherapy (chemo) lines (Bouchahda et al. Cancer 2009). Intravenous cetuximab (iv cetux) addition could further enhance efficacy of HAI in pts with predominantly hepatic mCRC with wt K-Ras, through allowing complete macroscopic resections of metastases. Methods: This is among the first international trials specifically targeting liver mCRC for enhancing the rate of complete macroscopic resections. It is an open label nonrandomized strategic phase II study of iv cetux and HAI of irinotecan (180 mg/m²), 5-FU (2,800 mg/m²), and oxaliplatin (85 mg/m²) q 2-wks. The primary objective_is to increase from 15% to 30% the complete macroscopic resection rate of liver mCRC. Chemo is given as chrono or conventional infusion, according to institution. Secondary endpoints include the rates of pathologic complete responses, and relapses, and usual efficacy (RECIST) and toxicity (NCIC v3.0) criteria. Eligible patients received 1-3 prior chemo lines for mCRC, deemed as non resectable with curative intent in multidisciplinary staff meeting (<30% estimated residual liver after resection; prior progressive disease). Pts undergo partial hepatectomy after 3-9 courses whenever possible. Translational studies include a pharmacokinetic analysis of all drugs during 1st course (16 pts), a monitoring of cytokines and rest-activity rhythm at baseline, and during 1st and 4th course, and a genetic study in host and tumor cells for assessing clock and pharmacology gene determinants. Current status:21 of 60 expected pts are registered at 6 centers. Adequate safety in the initial 6 pts on each schedule led the French Agency (AFSSAPS) to let the trial proceed. Efficacy data are expected in March 2011.

4088 Background: Irinotecan combined with 5FU/LV improves the outcome of patients (pts) with advanced colorectal cancer. R98 trial tests the hypothesis that this combination is superior to 5FU/LV alone to prevent recurrence or death in resected stages II-III rectal cancers. Methods: Between 03/1999 and 12/2005, 357 pts were postoperatively randomized to 5FU/LV (control arm) or 5FU/LV + irinotecan. Primary endpoint was DFS. The control arm consisted of either a Mayo-Clinic regimen (A: LV 20 mg/m², 5FU 425 mg/m² bolus days 1–5, repeated at d29, d57, d92, d127 and d162) or a LV5FU2 regimen (A’: LV 200 mg/m² over 2-hour, 5FU 400 mg/m² bolus and 600 mg/m² 22-hour infusion, d1–2, Q2W for 12 cycles), depending on centre choice. Experimental arm (B) consisted of LV5FU2 + irinotecan 180 mg/m² d1 of every cycle. Results: We present here the final safety analysis based on 341 evaluable pts. 172 pts were treated in the control arm (A, 56 pts or A’,116 pts), and 169 pts in the experimental arm (B). Pretreatment characteristics were well balanced between the groups; median age 62 years, stage II in 32% of pts. 68% of pts received preoperative RT, and 80% had sphincter conservation. 95% arm A and A’, and 72% arm B pts received more than 75% of planned chemotherapy dose. No toxic death was reported. G3–4 toxicity per pt was as follows for arms A, A’, and B: neutropenia 36%, 6%, 33%; diarrhea 9%, 9%, 13%; nausea-vomiting 2%, 1%, 7%; mucositis: 5%, 0%, 1%; infection: 7%, 2%, 1%; any toxicity (except alopecia): 50%, 20%, 47%; other G3–4 toxicities <5%. G3- 4 neutropenia and vomiting were significantly higher in the experimental arm than in the control arm (33% vs 16%; P<0.0001 and 5% vs 0%; p=0.002, respectively). RT was not associated with a statistically significant increase risk of diarrhea. Conclusions: The addition of irinotecan to a LV5FU2 regimen led to a decrease of dose intensity, and to an increase of neutropenia and of vomiting in the adjuvant treatment of rectal cancer. The safety profile of 5FU/LV + irinotecan remained however acceptable compared to 5FU/LV alone. First efficacy analysis is expected at the end of 2008. Study supported by Pfizer, France