A phase I clinical study was conducted to determine the maximum tolerated dose (MTD) and recommended dose (RD) of the standard treatment of
5-fluorouracil/l-
leucovorin (5-FU/LV) with
bevacizumab, in combination with
radiation therapy in patients with locally advanced
rectal cancer. Eligible patients had previously untreated stage T3 or T4 locally advanced
rectal cancer. Patients received
radiotherapy to the pelvis, at a total dose of 45 Gy in 25 fractions. During
radiotherapy, patients received three courses of a simplified LV and
5-FU regimen (sLV5FU2), in combination with
bevacizumab.
Bevacizumab was infused at a fixed dose of 5 mg/kg on Days 1, 15 and 29. The sLV5FU2 regimen consisted of 200 mg/m2 of LV administered by continuous intravenous (i.v.) infusion over 2 h, followed by 400 mg/m2 of
5-FU administered by i.v. bolus injection, delivered at an initial loading dose of 2,000 mg/m2 over 46 h. The dose was gradually increased to determine the MTD and RD of this regimen. Of the patients enrolled in the study, two developed Grade 3
diarrhea and one developed Grade 3
neutropenia. Since dose-limiting toxicity (DLT) occurred in two out of the six patients,
5-FU at a dose of 2,000 mg/m2 over 46 h was determined as the MTD and designated as the RD, taking into consideration the toxicities in matched patients who received standard preoperative
chemoradiotherapy with sLV5FU2 during the same period. The combination of
5-FU, LV,
bevacizumab and
radiotherapy in patients with locally advanced
rectal cancer was found to be tolerable, with encouraging response rates. Further investigation is required in a phase II setting.