Raltitrexed ('Tomudex') and radiotherapy can be combined as postoperative treatment for rectal cancer

Background: The optimal adjuvant therapy for operable rectal cancer is like ly to be a combination of radiotherapy and chemotherapy. Raltitrexed ('Tomu dex') is a specific thymidylate synthase inhibitor with a convenient admini stration schedule, acceptable and manageable toxicity, radiosensitising pro perties, and proven efficacy in the treatment of advanced colorectal cancer . It may, therefore, offer advantages compared with standard 5-FU chemother apy regimens used in colorectal cancer. The aim of this phase I, dose-escal ation study was to determine the recommended dose of raltitrexed for use wi th postoperative pelvic radiotherapy in patients with rectal cancer. Patients and methods: Patients with resected Dukes' stage B or C rectal can cer were treated with a combination of raltitrexed and radiotherapy (50.4 G y at 1.8 Gy per fraction over five to six weeks). At least three patients w ere treated at each of three escalating raltitrexed dose levels (2.0, 2.6 a nd 3.0 mg/m(2)) once every three weeks. Toxicity was assessed by the record ing of WHO adverse events and biochemistry and haematology determinations. Results: A total of 22 patients entered the study, 17 of whom had Dukes' st age C disease. All three patients entered at a dose level of 3.0 mg/m(2) ex perienced dose-limiting toxicity (DLT) (2 patients had grade 3 leucopenia a nd 1 patient had grade 2 leucopenia and grade 3 diarrhoea); however, only 2 of 11 patients entered at a dose level of 2.6 mg/m(2) experienced DLT (1 p atient had grade 4 neutropenia and 1 patient died probably due to aspiratio n pneumonia unrelated to treatment). The most common haematological toxic e vents were leucopenia (8 patients) and anaemia (6 patients). Only four haem atological or biochemical toxic events were of grade 3 or 4. Other common t oxicities were diarrhoea and nausea, which occurred in 15 and 9 patients, r espectively. Conclusions: This study demonstrates that raltitrexed can be combined with postoperative radiotherapy for treatment of patients with Dukes' stage B or C rectal cancer. The recommended dose of raltitrexed in this setting is 2. 6 mg/m(2), which is close to the full monotherapy dose.