**6. Combination of capecitabine and mitomycin C (MMC)**

MMC is a cytotoxic antibiotic which shows moderate efficacy when used as monotherapy in colorectal cancer patients. Upregulation of intra-tumoral thymidine phosphorylase, an enzyme converting capecitabine to 5-FU, is the primary mechanism through which MMC acts synergistically to capecitabine [67]. According to literature, overall response rate in patients with metastatic colorectal cancer who received MMC (6 mg/m2 intravenously on day 1 every 3 weeks) plus capecitabine (1000 mg/m2 twice daily on days 1–14, followed by a 7-day treatmentfree interval) ranged between 15.2 and 55.5% [68–72]. The majority of patients received previously two, three, or even four lines of anticancer therapy. Median PFS varied between 1.7 and 5.4 months [68–71, 74] and median OS between 5.4 and 13 months [68–72, 74]. While those results might be considered disappointing, it should be emphasized that all patients were pretreated with many lines of systemic therapy and had metastases in multiple locations.

With no doubt, the combination therapy with capecitabine and MMC is dedicated primarily for patients with cumulative side effects after previous treatment and/or contraindications to targeted therapies [70]. Furthermore, capecitabine plus MMC constitutes a good option of the best supportive care in patients who still maintain good performance status and organ efficiency, especially in countries in which regorafenib and TAS-102 have been registered but are not reimbursed.

Toxicity of capecitabine plus MMC combination is mild, acceptable, and easily manageable, and no significant hematological AEs have been reported thus far [71, 73–74]. The main non-hematological AEs documented in patients treated with this regimen are palmar-plantar erythema, nausea, diarrhea, and fatigue [71, 73–74].
