Clinical investigation
Rectum
Bevacizumab, Oxaliplatin, and Capecitabine With Radiation Therapy in Rectal Cancer: Phase I Trial Results

A portion of this data was presented at the meeting of the American Society of Clinical Oncology, June 3, 2006, in Atlanta, GA. All work contained within the manuscript is original.
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Purpose: The overexpression of vascular endothelial growth factor (VEGF) is associated with poor outcomes in colorectal cancer patients. Bevacizumab, a VEGF inhibitor, enhances the effects of chemotherapy and radiation therapy on tumor cytotoxicity in preclinical models, including colorectal cancer. A Phase I trial was undertaken to evaluate the combination of bevacizumab, capecitabine, oxaliplatin, and radiation therapy in patients with rectal cancer.

Methods and Materials: Patients with pathologically confirmed adenocarcinoma of the rectum were eligible. Pretreatment staging included computerized tomography, endoscopic ultrasound, and surgical evaluation. Patients received 50.4 Gy of external beam radiation therapy (EBRT) to the tumor in 28 fractions. Capecitabine, oxaliplatin, and bevacizumab were administered concurrently with radiation therapy. After EBRT completion, patients were restaged and evaluated for surgery. Primary endpoints included the determination of dose-limiting toxicity and a recommended Phase II dose, non dose-limiting toxicity, and preliminary radiographic and pathologic response rates.

Results: Eleven patients were enrolled. All were evaluable for toxicity and efficacy. Dose level 2 was associated with unacceptable toxicity (primarily diarrhea). Dose level 1 had an acceptable toxicity profile. The recommended Phase II dose in our study was bevacizumab 15 mg/kg Day 1 + 10 mg/kg Days 8 and 22, oxaliplatin 50 mg/m2 weekly, and capecitabine 625 mg/m2 bid during radiation days. Six patients had clinical responses. Two patients had a pathologic complete response, and 3 had microscopic disease only. One patient experienced a postoperative abscess, one a syncopal episode during adjuvant chemotherapy, and one a subclinical myocardial infarction during adjuvant chemotherapy.

Conclusions: The combination of bevacizumab, capecitabine, oxaliplatin, and radiation therapy in rectal cancer was tolerable, with encouraging response rates. Further investigation with this regimen is being pursued in a Phase II setting.

Introduction

Angiogenesis is a critical element in tumor growth and dissemination. Vascular endothelial growth factor (VEGF) plays an important role in this process, effecting vascular permeability as well as endothelial-cell activation, migration, invasion, and proliferation. The overexpression of VEGF was associated with poor outcomes in colorectal cancer patients (1, 2). VEGF overexpression was also linked to radiation resistance in preclinical and clinical models (3). Bevacizumab (Avastin; Genentech Pharmaceuticals, South San Francisco, CA) is a humanized monoclonal antibody directed against VEGF. When combined with 5-fluorouracil (5-FU)-based chemotherapy, bevacizumab improves survival in patients with metastatic colorectal cancer, in both the first- and second-line settings (4, 5). Bevacizumab enhances tumor blood flow, reduces tumor interstitial pressure, and decreases mean vessel density when infused neoadjuvantly in rectal-cancer patients. These physiologic changes may enhance the activity of radiation and chemotherapy (6, 7). Oxaliplatin (Eloxatin; Sanofi-Aventis Pharmaceuticals, Paris, France) causes intrastrand and interstrand DNA crosslink formation, inhibiting tumor replication. When combined with 5-FU-based chemotherapy, oxaliplatin improves outcomes in Stage II–IV colon cancer (8, 9). In addition, oxaliplatin is a potent radiosensitizer. Neoadjuvant delivery of oxaliplatin with 5-FU-based chemotherapy and radiation therapy in rectal cancer patients is feasible, with encouraging response rates in pilot studies (10, 11, 12).

In rectal cancer, the combination of radiation therapy with fluoropyrimidines improves local control and survival compared with radiation therapy alone (13). Many patients are not cured with this therapy, and novel approaches to improve efficacy, toxicity, and convenience are needed. Capecitabine (Xeloda; Roche Pharmaceuticals, Basel, Switzerland), an oral fluorouracil analog, has theoretical and established advantages as a radiosensitizer in rectal cancer (14, 15, 16). Phase III studies demonstrated that capecitabine has equivalent efficacy to IV 5-FU in the therapy of both metastatic and resected colorectal cancer (17, 18, 19). To test the hypothesis that the combination of bevacizumab, capecitabine, and oxaliplatin with radiation therapy would be well-tolerated and clinically active, a Phase I–II study was initiated, evaluating this combination in patients with Stage II–IV rectal cancer.

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Methods and Materials

This protocol was reviewed and approved by the Duke University Institutional Review Board and the study performed in accordance with the Declaration of Helsinki, as amended in Somerset West in 1996. All patients were required to provide written, informed consent before entry into the trial.

Results

Eleven patients were enrolled in this Phase I study between September 2004–September 2005. Patient characteristics are summarized in Table 2. All patients had de novo disease; 4 had distant metastases at presentation.

Discussion

Radiation therapy with 5-FU-based chemotherapy improves local control, disease-free and overall survival in patients with rectal cancer (13, 20). In addition to its clinical activity as monotherapy and in combination regimens in advanced colorectal cancer, capecitabine is also active and well-tolerated as a radiosensitizer for localized rectal cancers (15, 16, 21). This study builds upon its platform, combining an oral fluoropyrimidine with a platinum agent and VEGF inhibitor. Oxaliplatin is a

Acknowledgments

The authors thank the patients who participated in these studies, their families and caregivers, study coordinator Amy Franklin, and Wanda Lawrence for assistance in manuscript preparation.

References (28)

  • D. Citrin et al.

    Combining radiotherapy and angiogenesis inhibitors: Clinical trial design

    Int J Radiat Oncol Biol Phys

    (2006)
  • J. Kim et al.

    Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer: Tumor response, sphincter preservation and survival

    Int J Radiat Oncol Biol Phys

    (2002)
  • S. Krishnan et al.

    Phase II study of capecitabine (Xeloda) and concomitant boost radiotherapy in patients with locally advanced rectal cancer

    Int J Radiat Oncol Biol Phys

    (2006)
  • R. Frank et al.

    Tumor angiogenesis as a predictor of recurrence and survival in patients with node-negative colon cancer

    Ann Surg

    (1995)
  • H. Choi et al.

    Tumor angiogenesis as a prognostic predictor in colorectal carcinoma with special reference to mode of metastasis and recurrence

    Oncology

    (1998)
  • H. Hurwitz et al.

    Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

    N Engl J Med

    (2004)
  • B. Giantonio et al.

    High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200

    J Clin Oncol

    (2005)
  • C. Willett et al.

    Direct evidence that the VEGF specific antibody bevacizumab has antivascular effects in human rectal cancer

    Nat Med

    (2004)
  • C. Willett 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

    (2005)
  • R. Goldberg et al.

    A randomized controlled trial of fluorouracil plus leucovorin, irinotecan and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer

    J Clin Oncol

    (2004)
  • T. André et al.

    Oxaliplatin, fluorouricil and leucovorin as adjuvant treatment for colon cancer

    N Engl J Med

    (2004)
  • J. Gerard et al.

    Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: Lyon R0–04 Phase II trial

    J Clin Oncol

    (2003)
  • D. Sebag-Montefiore et al.

    A phase I/II study of oxaliplatin when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: A Colorectal Clinical Oncology Group (CCOG) study

    Br J Cancer

    (2005)
  • C. Rodel et al.

    Phase I/II trial of capecitabine, oxaliplatin and radiation for rectal cancer

    J Clin Oncol

    (2003)
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    Research support for this study was provided by Genentech Pharmaceuticals (South San Francisco, CA), Sanofi-Aventis Pharmaceuticals (Paris, France), and Roche Pharmaceuticals (Basel, Switzerland).

    Conflict of interest: none.

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