In the phase III CAIRO5 study, conducted by the Dutch Colorectal Cancer Group, triplet vs doublet chemotherapy plus bevacizumab significantly increased progression-free survival, response rate, and the rate of R0/R1 resections, with and without ablation, in patients with initially unresectable liver metastases related to colorectal cancer and right-sided primary tumors with RAS or BRAF V600E mutations.¹ The results were reported at the 2022 ASCO Annual Meeting by Cornelis J.A. Punt, MD, PhD, of University Medical Center Utrecht and Amsterdam University Medical Center in the Netherlands.

“CAIRO is the first randomized study to prospectively evaluate systemic induction regimens in patients with initially unresectable colorectal liver metastases according to predefined criteria by a central liver expert panel,” Dr. Punt noted. “The use of a liver expert panel is feasible and allows the selection of an increased number of patients for local treatment with curative intent.”

Study Addresses Unresolved Issues

As Dr. Punt pointed out, there are many unresolved issues pertaining to the treatment of colorectal cancer liver metastases. There is no consensus on the criteria for resectability and none on the optimal systemic induction regimen for potentially resectable metastases. Retrospective studies in unselected metastatic patients and most prospective studies in patients with liver metastases are hampered by absent or varying criteria for unresectability, lack of long-term outcomes after liver resection, and heterogeneity in study populations, trial design, and the use of RAS/BRAF mutational status, he said.

To address these issues, the randomized CAIRO5 trial prospectively compared the most active systemic regimens in defined subgroups of patients with initially unresectable colorectal liver metastases. Dr. Punt presented the results for patients with right-sided disease and/or with RAS or BRAF V600E mutations. Accrual in patients with left-sided and RAS or BRAF wild-type tumors is ongoing.

Study Design

CAIRO5 enrolled 294 patients from 44 centers with no previous systemic therapy or local therapy for metastases. They were randomly assigned to either (1) FOLFOX (fluorouracil, leucovorin, oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, irinotecan) plus bevacizumab (by patient preference; 90% chose FOLFOX) vs (2) FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab. Both arms received up to 12 cycles followed by maintenance with fluorouracil, leucovorin, and bevacizumab. Established local treatments were allowed (ie, ablation, two-stage surgery, portal vein embolization).

Approximately 86% of patients had primary tumor RAS mutations, whereas about 7% had BRAF mutations. The median number of colorectal liver metastases was 12 in each study arm.

Unresectability of liver metastases at baseline was assessed by an online liver expert panel of surgeons and radiologists based on predefined criteria, and resectability was determined every 2 months thereafter based on a panel majority vote. The primary endpoint was progression-free survival.

Progression-Free Survival Improved With FOLFOXIRI Plus Bevacizumab

Patients received a median of 10 induction regimens in the FOLFOX/FOLFIRI arm and 9 in the FOLFOXIRI arm. Median follow-up was 41 months.

With 259 events, median progression-free survival was 9.0 months with FOLFOX/FOLFIRI plus bevacizumab vs 10.6 months with FOLFOXIRI plus bevacizumab (HR = 0.77; P = .038), showing the superiority of a triplet vs a doublet in this population, Dr. Punt reported.

Subgroup analysis found a benefit for FOLFOXIRI plus bevacizumab in all subsets. “There was no significant interaction between baseline unresectability status or mutation status and progression-free survival,” Dr. Punt added.

Outcomes After Successful Local Treatment

Objective response rates were 53.5% in the FOLFOXIRI arm vs 33.3% in the FOLFOX/FOLFIRI arm (P < .001).

“Most importantly, the rate of successful local treatment, meaning that all liver metastases were treated with R0 or R1 resection with or without ablation, is significantly higher in the triplet chemotherapy arm, 51% vs 37% (P = .02),” he reported. The triplet arm was also significantly more likely to undergo two-stage surgery with or without portal vein embolization, 32% vs 16%, respectively (P = .04).

When local treatment was successful, as determined by R0/R1 resections with or without ablation, progression-free survival was further improved in both arms, with highly significant reductions in risk of more than 50%. Median progression-free survivals for patients without successful local treatment vs successful treatment were as follows: 

• FOLFOX or FOLFIRI plus bevacizumab: 7.0 vs 11.9 months (HR = 0.49; P < .0001)
• FOLFOXIRI plus bevacizumab: 9.0 vs 12.7 months (HR = 0.43; P < .0001).

The improvements in outcome with FOLFOXIRI plus bevacizumab, however, came at the cost of more grade ≥ 3 adverse events, which occurred in 75.7% of the triplet arm vs 59.2% of the doublet arm (P = .003). This included more neutropenia (38.2% vs 12.9%; P < .001) and diarrhea (19.4% vs 3.4%; P < .001). There were two deaths, as well, in the triplet arm, he reported.

The use of a liver expert panel translated into more patients deriving meaningful benefit from systemic and local treatment of their liver metastases, Dr. Punt said. The panel evaluated 676 computed tomography (CT) scans with a median turnaround time of 6 days. They reached consensus on (un)resectability at the baseline evaluation in 66% of cases and at follow-up evaluation in 41% of cases. Consensus was defined by three liver surgeons making the same recommendation. When consensus was not reached, an additional two liver surgeons were included, followed by a majority vote.

“From these data, we conclude that as compared to the opinion of a single liver surgeon, the use of a liver panel with three to five surgeons increases the number of patients in whom local treatment with curative intent is possible,” Dr. Punt commented. 

DISCLOSURE: Dr. Punt has served in an advisory role for Nordic Pharma.

REFERENCE

1. Punt CJA, Bond MJG, Bolhuis K, et al: FOLFOXIRI + bevacizumab vs FOLFOX/FOLFIRI + bevacizumab in patients with initially unresectable colorectal liver metastases and right-sided and/or RAS/BRAFV600E mutated primary tumor: Phase III CAIRO5 study of the Dutch Colorectal Cancer Group. 2022 ASCO Annual Meeting. Abstract LBA3506. Presented June 5, 2022.