A significant proportion of patients with locally advanced rectal cancer encountered ≧ grade 3 toxicity and postoperative complications in trials adding bevacizumab (BV) to preoperative chemotherapy and conventional radiotherapy. The aims of this phase I trial were to determine the maximum tolerated dose (MTD) and pathological complete response (pCR) rate of neoadjuvant dose-escalated intensity modulated radiation therapy (IMRT), combined with BV and 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) followed by total mesorectal excision (TME).
Patients with clinical T3-4 or N+ and M0 rectal adenocarcinoma were treated in 3 escalating dose levels (45 Gy/50 Gy/55 Gy in 25 fractions) of prone-positioned IMRT on belly board to spare small bowels. Patients received BV (5 mg/kg) and FOLFOX concurrently with IMRT in week 1, 3, and 5 for 3 cycles. TME was carried out 6-10 weeks following completion of IMRT.
Fifteen patients (5 at each IMRT dose level) were enrolled and completed IMRT, BV/FOLFOX, and TME. Twelve patients had rectal tumor within 5 cm from anal verge. No patient had grade 4 toxicity, and 5 patients had grade 3 acute toxicity, including 2 (13%) with afebrile neutropenia, 2 (13%) with anal skin reaction, and 1 (7%) with diarrhea. The MTD was not reached. Fourteen of 15 patients had anus preservation surgery, and 13 (87%) maintained functional anus. The median hospital stay of TME was 9 days (8-24 days). One (7%) patient had grade 3 postoperative bowel obstruction requiring reoperation. Of 15 patients, 5 (33%) had pCR, and 13 (87%) had downstaging effect. Rectal tumor volume <100 ml at diagnosis was significantly associated with pCR (5/12 vs. 0/3, p = 0.016). Post-/pre-IMRT serum VEGFa ratio <1 was significantly associated with nodal downstage (8/8 vs. 4/6, p = 0.046). With a median follow-up of 25.1 months, 1 patient developed liver metastasis, and no patient had local recurrence or died. The 3-year disease-free survival was 83%.
High pCR and anus preservation rates, as well as low toxicity rates, were achieved by neoadjuvant bowel-sparing IMRT, BV, FOLFOX, and TME. Rectal tumor volume <100 ml was associated with pCR.
Clinical trial identification
J.C.-H. Cheng: Bevacizumab in this trial was sponsored by Roche, and oxaliplatin was sponsored by TTY Biopharm. All other authors have declared no conflicts of interest.