Alternative Chemoradiotherapy in Anal Carcinoma Patients with Mutations in Thymidylate Synthase and Dihydropyrimidine Dehydrogenase Genes

Background: 5-fluorouracil (5-FU) and mitomycin-C (MMC) with radiotherapy (RT) remain an established treatment for patients with anal cancer (AC). Genetic mutations in two major metabolizing enzymes for 5-FU; dihydropyrimidine dehydrogenase ( and thymidylate synthetase (), have been associated with clinical response and toxicity. However, their place in the treatment of AC remains undetermined.

Methods: We retrospectively reviewed 21 patients with AC, including T2-4, N0-1, M0 or T1-4, N2-3, and M0 treated between 2012 and 2018. All patients were treated with 5-FU 1,000 mg/m/day via continuous intravenous (IV) infusion 1-4 and 29-32, MMC 10 mg/m IV bolus days 1 and 29 plus RT. Patients who developed ⩾3 grade toxicities were tested for the and genes. Treatment was either modified with reduced doses or changed to MMC 10 mg/m day 1 and 29 with cisplatin 25 mg/m/week plus RT. Toxicities and responses were collected.

Results: Six out of 21 patients who developed ⩾3 grade toxicities including pancytopenia, neutropenia, thrombocytopenia, mucositis, nausea, rash, and nephritis were found to have genetic mutations: 2RG/3RC ( = 2), 3RG/3RC ( = 1), 2R/2R ( = 2), T 3'UTR del/Ins ( = 2), and c.2864A > T heterozygous ( = 1). Two patients received 5-FU at a 50% reduced dose on days 29-32; one patient refused to receive 5-FU (continued with MMC and RT); one patient received only radiation therapy due to persistent pancytopenia despite the use of growth factors; two patients received an alternative regimen consisting of MMC 10 mg/m on day 29 with cisplatin (CDDP) 25 mg/m/week plus RT; and two patients received cisplatin/MMC with RT from the beginning as they were prospectively detected to have abnormalities prior to dosing the chemotherapy. These patients tolerated treatment very well with only grade 2 toxicities. All the patients (4/4) on cisplatin/MMC achieved clinical complete response (cCR), while four patients (4/15) on 5-FU/MMC reached cCR at the first assessment. Radiological response showed complete response at the end of 24 weeks assessment.

Conclusions: Molecular testing for and genes can allow us to identify patients who are most likely to respond or face severe toxicity to 5-FU in a potentially curable cancer. Combining radiation with CDDP with MMC in patients with AC is feasible. A prospective study based on pharmacogenetic testing comparing MMC/cisplatin with MMC/5-FU is indicated in patients with AC.