Phase I study of 5‑fluorouracil, leucovorin and bevacizumab in combination with radiation therapy in patients with locally advanced rectal cancer

Inoue,Yasuhiro; Okigami,Masato; Kawamoto,Aya; Okugawa,Yoshinaga; Hiro,Junichiro; Saigusa,Susumu; Toiyama,Yuji; Tanaka,Koji; Mohri,Yasuhiko; Kusunoki,Masato

doi:10.3892/mco.2013.78

Phase I study of 5‑fluorouracil, leucovorin and bevacizumab in combination with radiation therapy in patients with locally advanced rectal cancer

Authors:
- Yasuhiro Inoue
- Masato Okigami
- Aya Kawamoto
- Yoshinaga Okugawa
- Junichiro Hiro
- Susumu Saigusa
- Yuji Toiyama
- Koji Tanaka
- Yasuhiko Mohri
- Masato Kusunoki
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Affiliations: Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514‑8507, Japan
Published online on: February 20, 2013 https://doi.org/10.3892/mco.2013.78
Pages: 511-516

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Abstract

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 mg̸m2 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.

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1.	Douglass HO Jr, Moertel CG, Mayer RJ, et al: Survival after postoperative combination treatment of rectal cancer. N Engl J Med. 315:1294–1295. 1986. View Article : Google Scholar : PubMed/NCBI
2.	Cammà C, Giunta M, Fiorica F, et al: Preoperative radiotherapy for resectable rectal cancer: a meta-analysis. JAMA. 284:1008–1015. 2000.PubMed/NCBI
3.	Bosset JF, Collette L, Calais G, et al: Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 355:1114–1123. 2006. View Article : Google Scholar : PubMed/NCBI
4.	Gérard JP, Conroy T, Bonnetain F, et al: Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–4 rectal cancers: results of FFCD 9203. J Clin Oncol. 24:4620–4625. 2006.
5.	Sato T, Ozawa H, Hatate K, et al: A phase II trial of neoadjuvant preoperative chemoradiotherapy with S-1 plus irinotecan and radiation in patients with locally advanced rectal cancer: clinical feasibility and response rate. Int J Radiat Oncol Biol Phys. 79:677–683. 2011. View Article : Google Scholar
6.	Rödel C, Liersch T, Hermann RM, et al: Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol. 25:110–117. 2007.PubMed/NCBI
7.	Mohiuddin M, Winter K, Mitchell E, et al: Randomized phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer: Radiation Therapy Oncology Group Trial 0012. J Clin Oncol. 24:650–655. 2006. View Article : Google Scholar
8.	Cancer and Leukemia Group B 89901; Ryan DP, Niedzwiecki D, Hollis D, et al: Phase I/II study of preoperative oxaliplatin, fluorouracil, and external-beam radiation therapy in patients with locally advanced rectal cancer: Cancer and Leukemia Group B 89901. J Clin Oncol. 24:2557–2562. 2006. View Article : Google Scholar : PubMed/NCBI
9.	Wadlow RC and Ryan DP: The role of targeted agents in preoperative chemoradiation for rectal cancer. Cancer. 116:3537–3548. 2010. View Article : Google Scholar : PubMed/NCBI
10.	Inoue Y, Ojima E, Watanabe H, et al: Does preoperative chemoradiotherapy enhance the expression of vascular endothelial growth factor in patients with rectal cancer? Oncol Rep. 18:369–375. 2007.PubMed/NCBI
11.	Toiyama Y, Inoue Y, Saigusa S, et al: Gene expression profiles of epidermal growth factor receptor, vascular endothelial growth factor and hypoxia-inducible factor-1 with special reference to local responsiveness to neoadjuvant chemoradiotherapy and disease recurrence after rectal cancer surgery. Clin Oncol (R Coll Radiol). 22:272–280. 2010.
12.	Dipetrillo T, Pricolo V, Lagares-Garcia J, et al: Neoadjuvant bevacizumab, oxaliplatin, 5-fluorouracil, and radiation for rectal cancer. Int J Radiat Oncol Biol Phys. 82:124–129. 2012. View Article : Google Scholar : PubMed/NCBI
13.	Kennecke H, Berry S, Wong R, et al: Pre-operative bevacizumab, capecitabine, oxaliplatin and radiation among patients with locally advanced or low rectal cancer: a phase II trial. Eur J Cancer. 48:37–45. 2012. View Article : Google Scholar : PubMed/NCBI
14.	Kozin SV, Boucher Y, Hicklin DJ, et al: Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. Cancer Res. 61:39–44. 2001.
15.	Willett CG, Boucher Y, di Tomaso E, et al: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 10:145–147. 2004. View Article : Google Scholar : PubMed/NCBI
16.	Giralt J, Navalpotro B, Hermosilla E, et al: Prognostic significance of vascular endothelial growth factor and cyclooxygenase-2 in patients with rectal cancer treated with preoperative radiotherapy. Oncology. 71:312–319. 2006. View Article : Google Scholar
17.	Nozue M, Isaka N and Fukao K: Over-expression of vascular endothelial growth factor after preoperative radiation therapy for rectal cancer. Oncol Rep. 8:1247–1249. 2001.PubMed/NCBI
18.	Willett CG, Boucher Y, Duda DG, et al: Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J Clin Oncol. 23:8136–8139. 2005. View Article : Google Scholar
19.	Willett CG, Duda DG, di Tomaso E, et al: Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol. 27:3020–3026. 2009. View Article : Google Scholar : PubMed/NCBI
20.	Crane CH, Eng C, Feig BW, et al: Phase II trial of neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 76:824–830. 2010. View Article : Google Scholar : PubMed/NCBI
21.	Kabbinavar F, Hambleton J, Mass RD, et al: Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol. 23:3706–3712. 2005. View Article : Google Scholar : PubMed/NCBI