Clinical Investigation
Phase II Trial of Neoadjuvant Bevacizumab, Capecitabine, and Radiotherapy for Locally Advanced Rectal Cancer

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Purpose

We designed this Phase II trial to assess the efficacy and safety of the addition of bevacizumab to concurrent neoadjuvant capecitabine-based chemoradiation in locally advanced rectal cancer.

Methods

Between April 2004 and December 2007, 25 patients with clinically staged T3N1 (n = 20) or T3N0 (n = 5) rectal cancer received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m2 orally twice daily only on days of radiation), followed by surgical resection a median of 7.3 weeks later.

Results

Procedures included abdominoperineal resection (APR; 6 patients), proctectomy with coloanal anastamosis (8 patients), low anterior resection (10 patients), and local excision (1 patient). Eight (32%) of 25 patients had a pathologic complete response, and 6 (24%) of 25 had <10% viable tumor cells in the specimen. No patient had Grade 3 hand-foot syndrome, gastrointestinal toxicity, or significant hematologic toxicity. Three wound complications required surgical intervention (one coloanal anastamostic dehiscence requiring completion APR and two perineal wound dehiscences after initial APR). Five minor complications occurred that resolved without operative intervention. With a median follow-up of 22.7 months (range, 4.5–32.4 months), all patients were alive; one patient has had a recurrence in the pelvis (2-year actuarial rate, 6.2%) and 3 had distant recurrences.

Conclusions

The addition of bevacizumab to neoadjuvant chemoradiation resulted in encouraging pathologic complete response without an increase in acute toxicity. The impact of bevacizumab on perineal wound and anastamotic healing due to concurrent bevacizumab requires further study.

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,

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  • 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.

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