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Clinical Trial
. 2025 Jan 1;11(1):36-45.
doi: 10.1001/jamaoncol.2024.5174.

First-Line Systemic Treatment for Initially Unresectable Colorectal Liver Metastases: Post Hoc Analysis of the CAIRO5 Randomized Clinical Trial

Marinde J G Bond  1 , Karen Bolhuis  2 , Olaf J L Loosveld  3 , Jan Willem B de Groot  4 , Helga Droogendijk  5 , Helgi H Helgason  6 , Mathijs P Hendriks  7 , Joost M Klaase  8 , Geert Kazemier  9   10 , Mike S L Liem  11 , Arjen M Rijken  12 , Cornelis Verhoef  13 , Johannes H W de Wilt  14 , Koert P de Jong  8 , Michael F Gerhards  15 , Martinus J van Amerongen  16 , Marc R W Engelbrecht  17 , Krijn P van Lienden  18 , John J Hermans  19 , I Quintus Molenaar  20 , Dirk J Grünhagen  13 , Bart de Valk  21 , Brigitte C M Haberkorn  22 , Emile D Kerver  23 , Frans Erdkamp  24 , Robbert J van Alphen  25 , Daniëlle Mathijssen-van Stein  26 , Aysun Komurcu  27 , Anne M May  1 , Rutger-Jan Swijnenburg  10   28 , Cornelis J A Punt  1   29 ; Dutch Colorectal Cancer Group
Collaborators, Affiliations
Clinical Trial

First-Line Systemic Treatment for Initially Unresectable Colorectal Liver Metastases: Post Hoc Analysis of the CAIRO5 Randomized Clinical Trial

Marinde J G Bond et al. JAMA Oncol. .

Erratum in

  • Errors in Figures 2 and 3.
    [No authors listed] [No authors listed] JAMA Oncol. 2025 Jan 1;11(1):80. doi: 10.1001/jamaoncol.2024.6650. JAMA Oncol. 2025. PMID: 39821218 Free PMC article. No abstract available.

Abstract

Importance: 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.

Objective: 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.

Design, setting, and participants: 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.

Intervention: 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.

Main outcomes and measures: Overall survival (OS) was analyzed as a secondary outcome. Other outcomes were post hoc analyses.

Results: 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).

Conclusions and relevance: 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.

Trial registration: ClinicalTrials.gov NCT02162563.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bolhuis reported personal fees from Amgen and Nordic Pharma outside the submitted work. Dr de Groot reported personal fees from BMS outside the submitted work. Dr de Jong reported a salary from the University Medical Center Groningen. Dr Punt reported grants from Nordic Pharma outside the submitted work. No other disclosures were reported.

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References

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