The optimal induction systemic regimen for patients with initially unresectable colorectal cancer liver metastases is yet to be established. Published data in this patient population are difficult to interpret due to absent or varying criteria for resectability or unresectability, scarcity of long-term follow-up of patients who received local treatment, and heterogeneity in study populations, trial design, and use of RAS/BRAF V600E mutation status. The open-label CAIRO5 included 530 patients enrolled at 46 Dutch centers and one Belgian center. All patients had histologically confirmed colorectal cancer, known RAS/BRAF V600E mutation status, a WHO performance status of 0-1, and initially unresectable colorectal cancer liver metastases.
Study Results
According to a phase III randomized trial, for patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI plus bevacizumab (Avastin) was the “preferred” systemic induction regimen for those with a right-sided or RAS- or BRAF V600E-mutated primary tumor. FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus bevacizumab also significantly increased objective response rates and disease control rates compared with FOLFOX or FOLFIRI plus bevacizumab. Complete local treatment was done in 51% and 37% of patients, respectively. Although the benefit in median progression-free survival was small, the increase in the proportion of patients who had complete local treatment could be considered of greater clinical significance.
Punt and colleagues also evaluated patients with left-sided and RAS or BRAF V600E wild-type tumors who were treated with FOLFOX or FOLFIRI in combination with either bevacizumab or the anti-EGFR antibody panitumumab (Vectibix). Median PFS was similar among the patients treated with bevacizumab and those treated with panitumumab. The addition of panitumumab did significantly increase the objective response rate, but complete local treatment rate was done in 58% of both groups.
Regarding safety, serious adverse events occurred in 31% of patients who received FOLFOX or FOLFIRI plus bevacizumab and 52% of those who received FOLFOXIRI plus bevacizumab. Panitumumab was also associated with increased toxicity, which Punt and colleagues said was in line with previous studies. Serious adverse events occurred in 36% patients in those who received bevacizumab, and 42% of those who received panitumumab.
In explaining the rationale behind CAIRO5, the researchers pointed out that patients with initially unresectable colorectal cancer liver metastases can subsequently qualify for curative local treatment (such as surgery or local ablative treatment) if they achieve a sufficient response to systemic induction treatment. Local treatment remains the only form of treatment that offers the possibility of prolonged survival.
In general, objective response rate is substantially associated with resection rate. Punt and colleagues said that this association between objective response rate and resection rate will be analyzed in the future, and that overall survival data “should be awaited before drawing final conclusions.”
The CAIRO5 trial compared the most active systemic induction regimens for patients with initially unresectable colorectal cancer liver metastases. FOLFOXIRI plus bevacizumab was the preferred induction regimen for those with a right-sided or RAS- or BRAF V600E-mutated primary tumor. Median PFS was similar among patients treated with bevacizumab and those treated with panitumumab. The addition of panitumumab did significantly increase the objective response rate, but complete local treatment rate was done in 58% of both groups. The researchers pointed out that patients with initially unresectable colorectal cancer liver metastases can subsequently qualify for curative local treatment if they achieve a sufficient response to systemic induction treatment. The association between objective response rate and resection rate will be analyzed in the future, and overall survival data should be awaited before drawing final conclusions.
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