Purpose: Established that the only approved agents in previously treated metastatic colorectal cancer (CRC) are trifluoridine/tipiracil and regorafenib, we conducted a systematic review of all the published phase 2-3 trials, with the scope to evaluate the benefit of any later-line regimens in refractory metastatic CRC.
Methods: Phase 2-3 studies that enrolled patients with stage IV disease receiving salvage therapies for refractory CRC were identified using electronic databases (Pubmed, EMBASE, and Cochrane Library). Clinical outcomes were pooled using a point estimates for the weighted values of median overall survival (OS), progression-free survival (PFS), response rate (ORR), stable disease rate (SD), and 6-month and 1-year OS.
Results: Overall, 7556 patients were included from 67 studies (n = 70 arms). Overall, the pooled ORR and SD were 15.4% (95% CI 13-18%) and 36.9% (95% CI 33.5-40.6%). Median PFS, 6-month and 1-year OS, and median OS were 3.2 (95% CI 2.9-3.3) months, 65.4% (95% CI 61.9-68.8%), 36% (95% CI 32.3-39.9%) and 8.8 (95% CI 8.3-9.2) months. Overall survival was different in the monochemotherapy, polychemotherapy, chemotherapy + targeted therapy, and targeted therapy alone arms (7.6, 9.5, 10.3, and 7.9 months, respectively, P for difference = 0.01). Median PFS were respectively 2.3, 3.9, 3.8, and 2.6, respectively (P for difference < 0.01).
Conclusions: Overall, combination therapy (polychemotherapy with or without targeted agents) is associated with a higher control of disease and better outcome than approved agents. Treatment, if possible, should be personalized according to the patients' conditions, physician preference and molecular profile of disease.
Keywords: Chemotherapy; Colorectal cancer; Refractory; Review; Third line.