Céline Lepère

E15036 Background: Early tumor shrinkage has been associated with improved long-term outcome in patients (pts) with chemotherapy (chemo)-refractory LM-CRC. We examined the prognostic relevance of early tumor response after hepatic artery infusion of triplet chemotherapy combined with intravenous (IV) Cetuximab (Cet) in pts with unresectable LM-CRC. Methods: Pts received IV-Cet (500 mg/m2) and HAI of Irinotecan (180mg/m2), 5–Fluorouracil (2800 mg/m2), and Oxaliplatin (85mg/m2) every two weeks. Tumor response (RECIST) was based on CT scans ± MRI q3 courses. Pts were categorized as early-responders (CR or PR after 3 courses – at » 6 weeks), late responders (CR or PR > 3 courses) and non-responders (SD or PD). The rate of conversion to liver surgery (R0-R1), progression free survival (PFS) and overall survival (OS) were compared. Results: 57/64 registered pts (89%) received ³ 3 courses. They were assessed for response, which occurred early for 16/57 pts (28%), late for 10 pts (17.5%) or not at all for 31 pts (54.4%). The early-responders had similarly extensive disease as the other pts (median of 12 LM, median largest diameter = 37 mm, bilateral LM for 81% pts). Grade 3-4 diarrhea and asthenia were least in the early responders (6.3% vs 22.0%, and 0% vs 26.8%, p = 0.024, respectively).R0-R1 resection rate was twice as high in the early response group as compared to the other group (7/16; 48,8% vs 10/41; 24,4%, p = 0.10). PFS curves did not differ. In contrast. median OS was significantly longer in the 16 early-responders - 34.5 months [32.1 -36.9] - as compared to both the 41 non-early responders - 20.2 [13.6 – 26.8]; p = 0.010); and the 10 late responders - 12.0 [6.9 -17.2]; p = 0.001. Conclusions: Best clinical tolerability, LM conversion-to-resection, and survival outcomes were obtained in pts achieving an early tumor response on combined triplet hepatic artery infusion and IV Cet. The rapid disease-modifying effect of HAI is an important asset for curative intent medico-surgical strategies, and awaits prospective confirmation. Clinical trial information: NCT00852228.

466 Background: Multiple, large and bilateral LM-CRC can be downsized with chemotherapy (chemo) and resected with curative intent in ~15% pts (Adam et al. 2004). The complete resection rate (R0+R1) may be increased with Cet addition, triplet chemotherapy, chronomodulated delivery (Chrono) and hepatic artery infusion (HAI) (Bouchahda et al. 2009; Kemeny et al. 2009; Garufi et al. 2010; Goere et al. 2010). Purpose: To increase the R0+R1 rate from 15% to 30% in pts with unresectable KRAS wt LM-CRC despite failure of 1-3 prior chemo protocols. Methods: 64 pts received iv Cet (500 mg/m²) and Chrono (18 pts) or conventional (Conv, 46 pts) HAI of Irinotecan (180 mg/m²), 5-Fluorouracil (2800 mg/m²), and Oxaliplatin (85 mg/m²) q2 weeks. Liver surgery was performed according to q6wks multidisciplinary meetings. Results: There were 22F and 42 M, aged 33-76 years, with good PS (0/1/2: 40/22/2). Liver lesions were bilateral in 50 pts (78.1%), with a median of 10 metastases (1-50) and largest diameter of 52 mm (15-172). Five courses (1-13) were given to 61 pts (3 never treated), as 3-4^th line for 35 pts (54.6%). Grade 3-4 toxicities per pt were neutropenia (40%), abdominal pain (26%), fatigue (18%) and diarrhea (16%). Tumor response (RECIST) was achieved in 28 pts (2 CR, 26 PR), with an objective response rate of 46% [95%CL, 33-58]. Disease control rate was 95% [90-100]. The main endpoint was met, with R0-R1 resections in 19/61 pts, for an overall complete macroscopic resection rate of 28% [17-39]. R0+R1 resections were performed in 33.3% Chrono pts and 25.6% Conv pts, with worse initial prognosis for the Chrono pts (>6 segments involved, 50% vs 9%; > 9 metastases, 75% vs 27%). Median progression-free and overall survival were 8.7 months [6.9-10.5], and 25.7 months [14.2-37.2] respectively. Conclusions: The combination of intravenous Cet and triplet hepatic artery infusion safely doubled the expected rate of complete resections of LM-CRC, despite prior failure of systemic chemo. This most effective treatment option now deserves upfront testing. Clinical trial information: NCT00852228.