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Factors influencing conversion to resectability and survival after resection of metastases in RAS WT metastatic colorectal cancer (mCRC): a FIRE-3 analysis

Background

Paired tumor evaluations before randomization and at best response (nadir) of 270 patients with RAS WT tumors treated with first-line therapy with cetuximab (cet) vs. bevacizumab (bev)- in combination with FOLFIRI were reviewed for resectability of metastates. We assessed parameters influencing resectability, conversion to resectability and survival after nadir.

Methods

Baseline information and resectability were correlated with Fisher’s exact tests. Conversion to resectability was defined as unresectable disease before randomization and resectable disease at nadir. Univariate and multivariate logistic models were fitted with resectability at nadir as response variable. A Cox model comparing the survival from nadir was used to measure the influence of treatment, resectability at nadir and resection (time dependent variable). Interaction of resection and treatment arm on survival was tested by likelihood ratio test.

Results

Initial Lung metastases (OR = 0.35 95% CI = (0.19 - 0.63), p = 0.001), BRAF mutation (OR = 0.33 95% CI = (0.12-0.82), p = 0.03) and high alkaline phosphatase (OR = 0.51, 95% CI = (0.31-0.81), p = 0.006) were associated with less chance of conversion to resectability and in case of lung metastases also of being resected if resectability at nadir was observed (OR = 0.33, 95% CI = (0.08-1.04) p = 0.046). Early tumor shrinkage (=ETS: -20% tumor diameter after 6 weeks therapy) and depth of response (DpR) were associated with conversion to resectability (ETS: OR = 1.86, 95% CI = (1.06-3.3), p = 0.034, DpR: OR = 1.02, 95% CI = (1.01-1.03), p < 0.001). Metastatic resection improved post-nadir survival (HR = 0.53, 95% CI = (0.29- 0.97), p = 0.04). This was pronounced in cet-treated patients as compared to bev-treated patients (HR (cet)=0.17, 95% CI = (0.04-0.69), p = 0.01; HR (bev)=0.89, 95% CI = (0.47-1.69), p = 0.73; interaction test p = 0.02).

Conclusions

Conversion to resectability is associated with baseline characteristics like lung metastases and BRAF mutation as well as with early efficacy parameters (ETS, DpR). In FIRE-3, resection of metastases was associated with improved post-nadir survival, this effect originated predominantly from the cetuximab-based study arm.

Clinical trial identification

NCT00433927