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 diarrhea/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 concomitant daily administration of 250 mg of gefitinib with 50 Gy preoperative RT is feasible with manageable toxicity. The major pathologic response rate is encouraging, though it needs further confirmation. Distant metastasis still represents a concern and new strategies to overcome this issue are warranted.
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