Evaluation of Short-Course Radiotherapy Followed by Neoadjuvant Bevacizumab, Capecitabine, and Oxaliplatin and Subsequent Radical Surgical Treatment in Primary Stage IV Rectal Cancer

T. H. van Dijk K. Tamas; J. C. Beukema; G. L. Beets; A. J. Gelderblom; K. P. de Jong; I. D. Nagtegaal; H. J. Rutten; C. J. van de Velde; T. Wiggers; G. A. Hospers; K. Havenga


Ann Oncol. 2013;24(7):1762-1769. 

In This Article

Abstract and Introduction


Background To evaluate the efficacy and tolerability of preoperative short-course radiotherapy followed by capecitabine and oxaliplatin treatment in combination with bevacizumab and subsequent radical surgical treatment of all tumor sites in patients with stage IV rectal cancer.

Patients and methods Adults with primary metastasized rectal cancer were enrolled. They received radiotherapy (5 × 5 Gy) followed by bevacizumab (7.5 mg/kg, day 1) and oxaliplatin (130 mg/m2, day 1) intravenously and capecitabine (1000 mg/m2 twice daily orally, days 1–14) for up to six cycles. Surgery was carried out 6–8 weeks after the last bevacizumab dose. The percentage of radical surgical treatment, 2-year survival and recurrence rates, and treatment-related toxicity was evaluated.

Results Of 50 included patients, 42 (84%) had liver metastases, 5 (10%) lung metastases, and 3 (6%) both liver and lung metastases. Radical surgical treatment was possible in 36 (72%) patients. The 2-year overall survival rate was 80% [95% confidence interval (CI) 66.3%–90.0%]. The 2-year recurrence rate was 64% (95% CI 49.8%–84.5%). Toxic effects were tolerable. No treatment-related deaths occurred.

Conclusions Radical surgical treatment of all tumor sites carried out after short-course radiotherapy, and bevacizumab–capecitabine–oxaliplatin combination therapy is a feasible and potentially curative approach in primary metastasized rectal cancer.


Optimal treatment of patients with primary metastasized rectal cancer is controversial. Curative treatment would include resection of the primary tumor and all metastases, and many treatment options are available.

Most of the primary tumors are T3 (extending into the outer lining of the bowel or into adjacent tissue) or T4 (extending to the visceral peritoneum or other organs) rectal lesions with regional lymph nodes involved, and these tumors require downstaging before resection. Preoperative long-course radiotherapy is used with radiosensitizers, such as 5-fluorouracil, to downsize the primary tumor and to reduce the risk of locoregional failure after resection.[1,2] Nevertheless, 5-fluorouracil as a radiosensitizer has limited effects on systemic metastases. Systemic chemotherapy can be sequenced with chemoradiotherapy either before or after, but disadvantages include the extended period without systemic doses of chemotherapy and the additional acute toxicity of chemoradiotherapy when compared with radiotherapy alone. Furthermore, molecularly targeted agents that improved the survival of patients with advanced colorectal cancer are being tested as neoadjuvant therapy for rectal cancer.[3–9]

Although there is limited evidence, the 'liver first' approach has been proposed. It includes systemic chemotherapy followed by resection of liver metastases, and subsequent surgery for the primary rectal tumor.[10] This treatment sequence seems safe and effective, but it includes two surgical interventions and delayed treatment of the primary tumor.

To overcome the logistical problem of combining radiotherapy for primary rectal cancer with an adequate dose of systemic chemotherapy for metastatic disease, we propose a treatment sequence including preoperative short-course pelvic radiotherapy of five fractions of 5 Gy each (5 × 5 Gy), followed by capecitabine and oxaliplatin (CapeOx) given in combination with bevacizumab. Radical surgical treatment at all tumor sites is carried out 6–8 weeks after the last dose of bevacizumab. This short-course radiotherapy (5 × 5 Gy) has comparable biological effective dose as a long-course regimen of 28 fractions of 1.8 Gy each (28 × 1.8 Gy).[11] Furthermore, similar clinical outcomes have been shown when preoperative 5 × 5 Gy radiotherapy has been compared with 5-fluorouracil-based 28 × 1.8 Gy chemoradiotherapy for T3 and T4 rectal carcinoma.[12]

The purpose of the present study was to evaluate the efficacy and tolerability of this proposed regimen in a prospective, interventional, multicenter trial in patients with resectable primary metastasized rectal cancer in The Netherlands.