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

In 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. To present long-term outcomes of treatment with FOLFOXIRI plus bevacizumab vs FOLFOX/FOLFIRI plus bevacizumab and FOLFOX/FOLFIRI plus panitumumab vs FOLFOX/FOLFIRI + bevacizumab. The 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. Patients 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. Overall survival (OS) was analyzed as a secondary outcome. Other outcomes were post hoc analyses. A 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). These 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. ClinicalTrials.gov NCT02162563.