High‐frequency microsatellite instability predicts better chemosensitivity to high‐dose 5‐fluorouracil plus leucovorin chemotherapy for stage IV sporadic colorectal cancer after palliative bowel resection

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Abstract
The influence of MSI on treatment outcome of colorectal cancers remains unclear and deserves further investigation. We recruited 244 patients with stage IV sporadic colorectal cancers for our study, based on appropriate eligibility criteria. Patients were nonrandomly allocated to 2 treatment groups of either with or without high‐dose 5‐FU plus leucovorin chemotherapy (HDFL, 5‐FU 2,600 mg/m2 leucovorin 300 mg/m2 maximum 500 mg). Each treatment group was further divided into 2 subgroups according to high‐frequency MSI (MSI‐H) status. MSI‐H was defined as the appearance of MSI in at least 2 of the 5 examined chromosomal loci (BAT‐25, BAT‐26, D5S346, D2S123, D17S250). We compared clinicopathologic parameters, p53 overexpression and overall survival between the groups. In addition, 4 subgroups were identified as follows: MSI‐H+HDFL+, n = 35; MSI‐H−HDFL+, n = 134; MSI‐H+HDFL−, n = 17; MSI‐H−HDFL−, n = 58. There was no significant difference of background clinicopathologic data between the HDFL+ and HDFL− treatment groups (p > 0.05). Survival analyses indicated that the patients of subgroup MSI‐H+HDFL+ survived significantly longer than those of subgroup MSI‐H−HDFL+, with median survival times of 24 (95% CI 20.2–27.9) and 13 (95% CI 11.6–14.4) months, respectively (p = 0.0001, log‐rank test). In contrast, in patients without chemotherapy, the prognosis was poor irrespective of MSI status, with median survival times of 7.0 (95% CI 4.6–9.4) and 7.0 (95% CI 6.1–7.9) months in the MSI‐H+HDFL− and MSI‐H−HDFL− subgroups, respectively (p = 0.8205, log‐rank test). MSI‐H cancers responded significantly better to HDFL (p = 0.001), with a mean response rate of 65.71% (95% CI 49.98–81.44%) in subgroup MSI‐H+HDFL+ compared to 35.07% (95% CI 26.99–43.15%) in subgroup MSI‐H−HDFL+. There appeared to be no preferential metastatic site where response to HDFL can be predicted based on the MSI status of the primary tumor. Toxicity to HDFL was similarly minimal between MSI‐H+ and MSI‐H− patients (p > 0.05). Multivariate analysis of all patients further indicated that MSI‐H and chemotherapy were independent favorable prognostic parameters (p < 0.05). Thus, the better prognosis of stage IV sporadic colorectal cancers with MSI‐H may be associated with better chemosensitivity, rather than lower aggressiveness in biologic behavior.