International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationPhase II Trial of Neoadjuvant Bevacizumab, Capecitabine, and Radiotherapy for Locally Advanced Rectal Cancer
Introduction
Trials conducted in the 1980s established the role of postoperative 5-fluorouracil (5-FU)–based chemoradiation for locally advanced rectal cancer (LARC) 1, 2. More recent trials have shown that the addition of 5-FU to preoperative radiation-only regimens leads to improved local tumor control in patients with LARC 3, 4 and, in another study, that preoperative chemoradiation results in local tumor control and sphincter preservation with lower toxicity rates than those seen with postoperative chemoradiation (5). The desire to improve local tumor control in the highest-risk patients (those with T3, N+, and T4 tumors), to increase the sphincter-preservation rate in patients with low rectal tumors, and to enhance the feasibility of organ-preservation strategies in selected patients (responding patients with T3, N0 tumors) (6) have led to the continued exploration of strategies for selectively enhancing the effect of chemoradiation through the incorporation of novel molecular-targeted agents.
Bevacizumab is an anti–vascular endothelial growth factor (VEGF) targeted agent that has been shown to prolong median survival when added to chemotherapy in many solid tumor types. Its use has not been established in the adjuvant setting or as a radiation sensitizer. In a previous Phase I/II trial of concurrent bevacizumab, infusional 5-FU–based chemotherapy, and radiation in LARC, therapy was reported to be well tolerated, with minimal wound-healing concerns 7, 8. A larger Phase I dose-escalation study was conducted at our institution to evaluate the safety of the addition of concurrent bevacizumab to capecitabine-based chemoradiation in patients with locally advanced pancreatic cancer (LAPC) (9). On the basis of findings in both the LARC and the LAPC trials, but for different reasons, investigators recommended a bevacizumab dose of 5 mg/kg every 2 weeks. In the Phase I component of the neoadjuvant rectal cancer study, a 10-mg/kg dose resulted in dose-limiting gastrointestinal toxicity in 2 of 5 patients (8); in the LAPC study, bevacizumab dose levels up to 10 mg/kg were well tolerated (2 [4.3%] of 47 patients had Grade 3 gastrointestinal toxicity), but the objective response rate appeared highest at 5 mg/kg (6 of 12 patients [50%] had partial responses), although this study was too small to draw firm conclusions. Although no perioperative complications were seen among the 11 patients in the Phase I rectal cancer trial (8) or among the 4 patients who underwent pancreaticoduodenectomy in the LAPC trial (9), appropriate questions have been raised about the possibility that bevacizumab may increase wound complications in the neoadjuvant setting; moreover, the clinical benefit of the addition of bevacizumab to chemoradiation in localized tumors remains unclear.
The purpose of this trial was to evaluate the safety and efficacy of neoadjuvant chemoradiation with concurrent bevacizumab, capecitabine, and radiation in patients with LARC. The primary endpoint for our evaluation was pathologic complete response. We also evaluated the secondary endpoints of acute toxicity, perioperative morbidity, disease-free survival duration, overall survival duration, and patient-reported symptoms.
Section snippets
Patient evaluation
This Phase II single-arm, single-institution study was reviewed, approved, and monitored by the University of Texas M. D. Anderson Cancer Center Institutional Review Board. All patients were required to sign a study-specific consent form. Pretreatment evaluation included a complete patient history and physical examination, tumor biopsy, colonoscopy, pelvic and abdominal computed tomography (CT), and chest X-ray. Unless there was clear evidence of transmural penetration of the rectal wall or
Patient characteristics
A total of 25 patients were accrued onto the study at M. D. Anderson Cancer Center from April 2004 through December 2007. All patients had newly diagnosed rectal cancer and excellent performance status (ECOG 0 or 1). Patient characteristics are listed in Table 4. Eighty percent of the patients were clinically staged to be T3N+ disease, and 20% were staged to beT3N0. The median tumor length was 5.0 cm (range, 2–10 cm), and 60% of tumors were within 5 cm of the anal verge. All 25 patients were
Discussion
Neoadjuvant chemoradiation followed by mesorectal excision is an effective standard of care for patients with LARC. For patients with T3, N0 tumors of the mid and upper rectum, pelvic tumor control rates are satisfactory with combined-modality therapy. For these patients with more favorable prognoses, treatment intensification will not likely result in improved survival outcomes (although improved organ or sphincter-preservation rates may be possible for patients with distal tumors). However,
References (24)
- et al.
Long-term results using local excision after preoperative chemoradiation among selected T3 rectal cancer patients
Int J Radiat Oncol Biol Phys
(2004) - et al.
Combining radiation with oxaliplatin: A review of experimental results
Cancer/Radiother
(2008) - et al.
Radiation enhancement by 9-aminocamptothecin: The effect of fractionation and timing of administration
Int JRadiat Oncol Biol Phys
(1999) - et al.
Neoadjuvant chemoradiation with capecitabine versus infusional 5-fluorouracil (5-FU) for locally advanced rectal cancer: A matched pair analysis
Int J Radiat Oncol Biol Phys
(2005) - et al.
Phase I study of preoperative radiation therapy with concurrent infusional 5-fluorouracil and oxaliplatin followed by surgery and postoperative 5-fluorouracil plus leucovorin for t3/t4 rectal adenocarcinoma: ECOG E1297
Int J Radiat Oncol Biol Phys
(2008) - et al.
Combined-modality therapy for rectal cancer: Future prospects
Clin Colorectal Cancer
(2007) - et al.
Phase II trial of preoperative 3D conformal radiotherapy, protracted venous infusion 5-fluorouracil, and weekly CPT-11, followed by surgery for ultrasound-staged T3 rectal cancer
Int J Radiat Oncol Biol Phys
(2003) - et al.
Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: Phase I trial results
Int J Radiat Oncol Biol Phys
(2007) Gastrointestinal Tumor Study Group
N Engl J Med
(1985)- et al.
Effective surgical adjuvant therapy for high-risk rectal carcinoma
N Engl J Med
(1991)
Chemotherapy with preoperative radiotherapy in rectal cancer
N Engl J Med
Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in t3-4 rectal cancers: Results of FFCD 9203
J Clin Oncol
Cited by (0)
This was an investigator initiated trial supported with a grant from Genentech, Inc. and was also supported by Core Grant CA 16672
Dr. Crane has received honoraria from Roche and research support from Genentech. The other authors report no conflicts of interest.