First-Line Systemic Treatment for Initially Unresectable Colorectal Liver Metastases
Authors: Bond Marinde J. G. , Bolhuis Karen , Loosveld Olaf J. L. , de Groot Jan Willem B. , Droogendijk Helga , Helgason Helgi H. , Hendriks Mathijs P. , Klaase Joost M. , Kazemier Geert , Liem Mike S. L. , Rijken Arjen M. , Verhoef Cornelis , de Wilt Johannes H.W. , de Jong Koert P. , Gerhards Michael F. , van Amerongen Martinus J. , Engelbrecht Marc R.W. , van Lienden Krijn P. , Hermans John J. , Molenaar I. Quintus , Grünhagen Dirk J. , de Valk Bart , Haberkorn Brigitte C. M. , Kerver Emile D. , Erdkamp Frans , van Alphen Robbert J. , Mathijssen-van Stein Daniëlle , Komurcu Aysun , May Anne M. , Swijnenburg Rutger-Jan , Punt Cornelis J. A. ,   Dutch Colorectal Cancer Group, van Dam Ronald M. , Patijn Gijs A. , Ruers Theo J.M. , Chapelle Thiery , Leclercq Wouter K.G. , Valkenburg-van Iersel Liselot B.J. , Grootscholten Cecile , Van Dodewaard-de Jong Joyce M. , Vincent Jeroen , Houtsma Danny , Los Maartje , Den Boer Marien , Trajkovic-Vidakovic Marija , Van Voorthuizen Theo , Koopman Miriam , Vestjens Johanna H.M.J. , Torrenga Hans , Mekenkamp Leonie J.M. , Veldhuis Gerrit Jan , Polee Marco B. , Dohmen Serge E. , Schut Heidi , Vulink Annelie J.E. , Van Halteren Henk K. , Oulad Hadj Jamal , Schiphorst Pieter-Paul J.B.M. , Hoekstra Ronald 
Published: November 2024

ImportanceIn patients with colorectal cancer and unresectable liver-only metastases (CRLM), treatment with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) plus irinotecan (FOLFOXIRI) and bevacizumab vs FOLFOX/folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus bevacizumab increased progression-free survival, response, and R0/R1 resection/ablation rates, as well as toxic effects in RAS/BRAFV600E-variant and/or right-sided tumors. FOLFOX/FOLFIRI–panitumumab vs FOLFOX/FOLFIRI–bevacizumab increased response at the cost of more toxic effects in RAS/BRAFV600E wild-type, left-sided tumors.ObjectiveTo present long-term outcomes of treatment with FOLFOXIRI plus bevacizumab vs FOLFOX/FOLFIRI plus bevacizumab and FOLFOX/FOLFIRI plus panitumumab vs FOLFOX/FOLFIRI + bevacizumab.Design, Setting, and ParticipantsThe randomized phase 3 CAIRO5 trial included patients with initially unresectable CRLM in 46 Dutch centers and 1 Belgian center between November 2014 and January 2022. A liver expert panel repeatedly evaluated resectability.InterventionPatients with RAS/BRAFV600E-variant and/or right-sided tumors randomly received FOLFOX/FOLFIRI–bevacizumab (group 1) or FOLFOXIRI-bevacizumab (group 2), and those with RAS/BRAFV600E wild-type, left-sided tumors received FOLFOX/FOLFIRI–bevacizumab (group 3) or FOLFOX/FOLFIRI–panitumumab (group 4). Adjuvant chemotherapy (ACT) after complete local treatment was recommended but not standard.Main Outcomes and MeasuresOverall survival (OS) was analyzed as a secondary outcome. Other outcomes were post hoc analyses.ResultsA total of 530 patients (327 male [62%] and 203 female individuals [38%]; median age, 62 [IQR, 54–69] years) were randomized: 148 in group 1, 146 in group 2, 118 in group 3, and 118 in group 4. The median OS in group 1 was 23.6 (95% CI, 20.1-27.5) vs 24.1 (95% CI, 21.0-30.9) months in group 2 (hazard ratio [HR], 0.90; 95% CI, 0.70-1.17; P = .44), and 39.9 (95% CI, 30.7-44.6) in group 3 vs 38.3 (95% CI, 35.3-51.3) months in group 4 (HR, 0.95; 95% CI, 0.68-1.32; P = .75). OS was longest after complete local treatment without early (≤6 months) recurrence (64.3 months; 95% CI, 57.6 to not reached) and salvage local treatment options after early recurrence (58.9; 95% CI, 47.3 to not reached), followed by patients without salvage local treatment after early recurrence (30.5; 95% CI, 24.4-33.4) and with incomplete local treatment (28.7; 95% CI, 25.9-38.3), and worst in patients with continued unresectability (18.3; 95% CI, 15.7-20.0). After confounder adjustment, ACT was associated with longer OS (HR, 0.66; 95% CI, 0.44-0.98) and relapse-free survival (HR, 0.65; 95% CI, 0.48-0.88) and less early recurrence without salvage local treatment (odds ratio, 0.46; 95% CI, 0.25-0.85).Conclusions and RelevanceThese results support using FOLFOX/FOLFIRI–bevacizumab for patients with initially unresectable CRLM irrespective of RAS/BRAFV600E status and tumor sidedness. Patients with complete local liver treatment with salvage local treatment in case of early recurrence had the longest OS. ACT might be considered for these patients.Trial RegistrationClinicalTrials.gov NCT02162563