Induction Therapy for Patients with Metastatic Colorectal Cancer and Liver Metastases

1. In patients with right-sided or RAS/BRAF^V600E mutated tumors, the PFS was favorable with FOLFOXIRI plus bevacizumab compared to FOLFOX or FOLFIRI plus bevacizumab.

2. In patients with left-sided and RAS/BRAF^V600E wild-type tumors, there were similar PFS with FOLFOX or FOLFIRI plus bevacizumab compared to FOLFOX or FOLFIRI plus panitumumab.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Induction systemic treatment can potentially render patients with initially unresectable colorectal cancer liver metastases eligible for curative local treatment by reducing the tumor size. However, there is a lack of consensus on unresectability criteria and heterogeneity in past study designs and patient selection has made it challenging to interpret results and determine the best treatment approach. This phase 3 study investigated the optimal induction regimen for these patients. The primary outcome was progression-free survival (PFS), with secondary outcomes being R0-1 resection rate, overall survival (OS), objective response rate (ORR), and toxicity. The median PFS was 9.0 months in group A versus 10.6 months in group B, with a HR of 0.76, and 10.8 months in group C versus 10.4 months in group D, with a HR of 1.11. Median PFS was significantly longer in patients receiving local treatment (surgery or ablation) compared to not receiving local treatment, whereas PFS was not significantly different in patients with R0 versus R1 resections nor RAS/BRAF^V600E status. After a median of 6-7 induction cycles, 37% of group A vs 51% of group B, and 58% of group C vs 58% of group D received complete local treatment. Grade 3 or worse adverse events occurred in 59% of group A vs 76% of group B, and 54% of group C vs 69% of group D. Within groups A and B, the most frequent grade 3–4 events were neutropenia (13% vs 40%), hypertension (14% vs 14%), and diarrhea (3% vs 19%). Within groups C and D, the most frequent grade 3–4 events were neutropenia (25% vs 21%), skin toxicity (1% vs 25%), hypertension (18% vs 7%), and diarrhea (4% vs 16%). The strengths of this study include the evaluation of different treatment arms whereas the limitations of this study include the pending maturity of some findings (OS). Overall, in patients with initially unresectable colorectal cancer with liver metastases, there were some favorable outcomes with certain induction regimens depending on tumor characteristics.

Click to read the study in LANCET

Relevant Reading: Conversion strategies with chemotherapy plus targeted agents for colorectal cancer liver-only metastases: A systematic review

In-Depth [randomized controlled trial]: This open-label, multicenter, phase 3 study enrolled otherwise healthy adults with histologically proven colorectal cancer with deemed unresectable liver-only metastases and randomized them into 4 groups based on tumor type (with a protocol amendment); patients with right-sided or RAS/BRAF^V600E mutated tumors were randomized to receive FOLFOX or FOLFIRI plus bevacizumab (group A, 147 patients) or FOLFOXIRI plus bevacizumab (group B, 144), patients with left-sided and RAS/BRAF^V600E wild-type tumors were randomized to receive FOLFOX or FOLFIRI plus bevacizumab (group C, 114) or FOLFOX or FOLFIRI plus panitumumab (group D, 116), with the choice between FOLFOX or FOLFIRI at the discretion of the local investigator. Median number of liver metastases was 12. Median follow-up time was 51.1 months in groups A and B, and 49.9 months in groups C and D. The median PFS was 9.0 months (95%CI, 7.7-10,5) in group A versus 10.6 months (9.9-12.1) in group B, with HR 0.76 (95%CI, 0.60-0.98, p=0·032), and 10.8 months (95%CI, 9.9-12.6) in group C versus 10.4 months (9.8-13.0) in group D, with HR 1·11 (95%CI, 0.84-1.48, p=0·46). Median PFS was significantly longer in patients receiving local treatment (surgery or ablation) compared to not receiving local treatment, whereas PFS was not significantly different in patients with R0 versus R1 resections nor RAS/BRAF^V600E status. Data on OS was not mature at this time. After a median of 6-7 induction cycles (based on group), 37% of group A vs 51% of group B (p=0.013), and 58% of group C vs 58% of group D (p=1.00) received complete local treatment. Grade 3 or worse adverse events occurred in 59% of group A vs 76% of group B (p-0.0027), and 54% of group C vs 69% of group D (p=0.021). Within groups A and B, the most frequent grade 3–4 events were neutropenia (13% vs 40%, p<0.0001), hypertension (14% vs 14%, p=1.00), and diarrhea (3% vs 19%, p<0.0001). Within groups C and D, the most frequent grade 3–4 events were neutropenia (25% vs 21%, p=0.44), skin toxicity (1% vs 25%, p<0.0001), hypertension (18% vs 7%, p=0.016), and diarrhea (4% vs 16%, p=0.0072). Overall, in patients with initially unresectable colorectal cancer with liver metastases, there were some favorable outcomes with certain induction regimens depending on tumor characteristics.

Image: PD

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