Mitomycin-C + fluoropyrimidines in heavily pretreated metastatic colorectal cancer: a systematic review and evidence synthesis Fausto Petrelli a , Antonio Ghidini b , Alessandro Inno c and Sandro Barni a Mitomycin-C (MMC) combined with fluoropyrimidines has historically been used for pretreated patients with some activity in this setting, in particular, as third-line chemotherapy (CT) or beyond. We have evaluated the efficacy and safety of MMC-based therapy as a further line of CT in advanced colorectal cancer. Prospective or retrospective studies of MMC-based CT were included in the pooled analysis. PubMed, EMBASE, SCOPUS, Web of Science, the Cochrane Library database and CINAHL were searched systematically. The outcomes were progression- free survival, overall survival, overall response rate and grades 3–4 drug-related adverse events. Seventeen trials involving 681 patients were included in the analysis. Overall, the pooled average weighted progression-free survival and overall survival were 2.84 [95% confidence interval (CI) 2.5–3.1] and 7.47 (95% CI 6–8.9) months, respectively. The corresponding pooled overall response rate was 7.2% (95% CI 5.2–9.9%) and the pooled disease control rate was 38.7% (95% CI 31.7–46.3%). The G3–4 neutropenia and anaemia were the most frequent haematological toxicities (range 0–20%). Nonhaematological G3–4 toxicities were compatible with the associated agent. MMC with fluoropyrimidines represents a viable and active combination for pretreated metastatic colorectal cancer patients. It is thus an option when other agents have failed, or are unavailable or not indicated. Anti-Cancer Drugs 00:000–000 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Anti-Cancer Drugs 2016, 00:000–000 Keywords: colorectal cancer, fluoropyrimidines, metastatic, mitomycin-C, pretreated a ASST Bergamo Ovest, Treviglio, b Igea Hospital, Milan and c Sacro Cuore Don Calabria Hospital, Verona, Italy Correspondence to Fausto Petrelli, MD, ASST Bergamo Ovest, Piazzale Ospedale 1, 24047 Treviglio, Italy Tel: + 39 0363424420; fax: + 39 0363424380; e-mail: faupe@libero.it Received 5 January 2016 Revised form accepted 29 February 2016 Introduction Metastatic colorectal cancer (mCRC) is the third most common cause of cancer-related deaths in men and the fourth in women, accounting for almost 700 000 fatalities per year worldwide [1]. In the past few decades, the median overall survival (OS) has improved from 6 to 12 months to more than 30 months with modern targeted therapies [2]. A relevant proportion of patients progres- sing through all the available active regimens (fluoro- pyrimidines, irinotecan, oxaliplatin, antivascular agents and, if the disease is RAS wild type, anti-EGFR mono- clonal antibodies) maintain a good performance status and may potentially benefit from further treatment. In the setting of refractory disease, the efficacy of the multikinase inhibitor regorafenib in terms of significantly improving the median OS has been reported in two randomized phase III placebo-controlled trials [3,4]. More recently, the oral agent TAS-102, which combines trifluridine and tipiracil hydrochloride, has been found to significantly extend OS from 5.3 to 7.1 months compared with a placebo in a randomized phase III trial with refractory patients [5] Historically, before the advent of regorafenib and TAS-102, mitomycin-C (MMC) was used widely in patients with mCRC whose cancer had progressed after treatment with all the available active drugs. MMC is an aziridine-containing antibiotic isolated from Streptomyces and its anticancer activity acts as an alky- lating agent [6]. Because of in-vitro data showing syner- gistic activity with fluoropyrimidines [7], this combination has been investigated in several clinical trials. However, in the front-line setting, MMC did not confer a survival benefit compared with fluoropyr- imidines alone [8]. This finding is corroborated by the recent results of a randomized, three-arm phase III trial comparing capecitabine alone, capecitabine plus bev- acizumab or capecitabine, MMC and bevacizumab as the first-line treatment for mCRC [9]. In this trial, the OS of the MMC-containing arm (16.4 months) did not differ significantly from the OS obtained with the capecitabine plus bevacizumab arm (18.9 months), suggesting that the addition of MMC to capecitabine and bevacizumab in the first-line treatment is not beneficial. Notwithstanding the disappointing results in the front-line setting, the combination of MMC and fluoropyrimidines has been investigated widely in a number of relatively small-size studies in refractory patients, with OS times ranging from about 5 to 13 months [10–26]. This can be compared favourably with the OS rates obtained with new drugs in the refractory setting. Clinical report 1 0959-4973 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/CAD.0000000000000363 Copyright r 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.