Aims and background: The availability of new drugs offers the opportunity to improve the outcome of locally advanced rectal cancer. Raltitrexed and oxaliplatin are effective in advanced colorectal cancer with acceptable toxicity and can act as radiation enhancers as shown in phase I-II studies. The aim of the study was thus to determine the recommended dose of oxaliplatin concomitantly administered with raltitrexed and concurrent preoperative radiotherapy in patients with stage II-III extraperitoneal rectal cancer.
Methods: From September 2001 to September 2002, 18 consecutive patients with T3/T4 rectal cancer were treated at our Institution with preoperative chemoradiation followed by surgery after 6-8 weeks. Pelvic radiotherapy was delivered at a dose of 45 Gy in 25 fractions in 5 weeks followed by a 5.4 Gy boost at 1.8 Gy daily. Concomitant chemotherapy consisted of 3 mg/m2/i.v. of raltitrexed on days 1, 19, 38 of radiotherapy treatment with incremental doses of oxaliplatin according to dose finding rules (4 dose levels: 65, 85, 110, 130 mg/m2). Dose-limiting toxicity for oxaliplatin was defined as either grade 3-4 hematological or grade 3-4 gastrointestinal or neurological toxicity. We studied a minimum of 3 patients at each dose level.
Results: Three patients were treated at 65, 85, and 110 mg/m2/i.v., respectively, while 9 patients were recruited at the last dose level. Neither grade 3-4 gastrointestinal nor neurological toxicity were documented. Dose-limiting toxicity was documented in 2/9 subjects at the 130 mg/m2 level consisting of grade 3 transient asymptomatic leukopenia. Thirteen patients developed transient increase of one or more liver enzymes (grade 3-4) and 2 patients developed grade 3 perineal dermatitis. All patients received the programmed dose of radiotherapy. The chemotherapy regimen was not completed in 4 cases due to grade 2 protracted leukopenia.
Conclusions: The maximum tolerated dose of oxaliplatin was not reached at the maximum dose level (i.v.); 130 mg/m2 can therefore be defined as the recommended dose. The combination of oxaliplatin with raltitrexed and radiotherapy can be considered feasible and well tolerated.