Trial Suggests Optimal Approach to Unresectable CRC Liver Mets

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, according to a phase III randomized trial.

Among these patients, the median progression-free survival (PFS) was 9.0 months in those receiving FOLFOX or FOLFIRI plus bevacizumab versus 10.6 months in those receiving FOLFOXIRI plus bevacizumab (stratified HR 0.76, 95% CI 0.60-0.98, P=0.032), reported Cornelis Punt, MD, PhD, of the University Medical Centre Utrecht at Utrecht University in the Netherlands, and colleagues in the Dutch Colorectal Cancer Study Group.

FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus bevacizumab also significantly increased objective response rates (54% vs 33%, P=0.0004) and disease control rates (93% vs 81%, P=0.0028) compared with FOLFOX or FOLFIRI plus bevacizumab, they noted in Lancet Oncology.

Complete local treatment was done in 51% and 37% of patients, respectively (P=0.013).

"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 wrote.

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 (10.8 months and 10.4 months, respectively; stratified HR 1.11, 95% CI 0.84-1.48, P=0.46).

The addition of panitumumab did significantly increase the objective response rate (80% vs 53%, P<0.0001), but complete local treatment rate was done in 58% of both groups.

"Given that local treatment remains the only form of treatment that offers the possibility of prolonged survival, the fact that a better objective response did not translate into a better conversion rate must be noted," wrote Katsunori Imai, MD, PhD, and Hideo Baba, MD, PhD, both of Kumamoto University in Japan, in a commentary accompanying the study. "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."

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.

'The significantly higher incidence of grade 3 or worse adverse events with the use of FOLFOXIRI versus FOLFOX or FOLFIRI plus bevacizumab is consistent with previous studies, and was mainly caused by a higher incidence of diarrhea and non-febrile neutropenia," the authors noted.

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, with the difference mainly due to higher rates of skin toxicity and diarrhea with panitumumab, while bevacizumab was associated with a higher incidence of hypertension.

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.

However, "there is no consensus on the optimal induction systemic regimen for patients with initially unresectable colorectal cancer liver metastases," they wrote. "Moreover, 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."

Thus, they wanted to compare the currently most active systemic induction regimens in this setting. They also noted that this was the first study to prospectively compare bevacizumab with an anti-EGFR antibody -- both with a chemotherapy backbone -- and which considered both RAS and BRAF V600E mutation status and sidedness of the primary tumor.

The open-label CAIRO5 included 530 patients (median age 62 years, 62% men) 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.

Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists at baseline and every 2 months thereafter by predefined criteria.

Most patients had synchronous disease and colorectal cancer liver metastases that were considered to be potentially resectable by the expert panel.

From November 2014 through January 2022, patients with right-sided primary tumor site or RAS- or BRAF V600E-mutated tumors were randomly assigned 1:1 to receive FOLFOX or FOLFIRI plus bevacizumab (n=148) or FOLFOXIRI plus bevacizumab (n=146). Patients with left-sided and RAS- and BRAF V600E wild-type tumors were randomly assigned 1:1 to receive FOLFOX or FOLFIRI plus bevacizumab (n=118) or FOLFOX or FOLFIRI plus panitumumab (n=118).

Median follow-up at the time of this analysis was 51.1 months in the first two groups and 49.9 months in the second two groups.

A limitation of this study was that the use of FOLFOXIRI was not investigated in patients with left-sided and RAS- and BRAF V600E wild-type tumors.

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