Phase I/II Study of Gefitinib and Concomitant Preoperative Radiotherapy in Patients with Locally Advanced Rectal Cancer*

Objective: To determine the recommended dose (RD) of gefitinib when combined with concomitant radiotherapy (RT) in a preoperative setting in patients with locally advanced rectal cancer. Secondary objectives were to evaluate acute toxicities, pathological response rate, progression-free and overall survival (OS). Materials and Methods: 20 patients with cT3-4 or cN+ cM0 tumors were enrolled. The planned RT consisted in 50 Gy given in 2 daily fractions of 1.25 Gy in 4 weeks. During RT, gefitinib was planned to be given orally once daily with 2 successive dose levels: 250 mg and 500 mg. Rectal surgery was scheduled 5- 6 weeks after completion of RT. The median follow-up for all patients was 57 months. Results: Among the first cohort of 6 patients, 1 patient presented a dose limiting toxicity (DLT) (Grade 3 diar-rhea/dehydration). In the second cohort, 2/6 patients presented with the same DLT so that 250 mg was considered as the RD. Main acute toxicities consisted in diarrhea (grade 2- 3, 63%), and skin reaction (in RT fields grade 2- 3 in 42%). The 5-year actuarial OS and loco-regional control rates were of 80 % and 84 % respectively. Conclusion: The concomi-tant daily administration of 250 mg of gefitinib with 50 Gy preoperative RT is feasible with manageable toxicity. Th