Abstract
Anti-vascular endothelial growth factor therapy enhances the activity of radiotherapy in experimental models, and bevacizumab has therapeutic activity in patients with metastatic colorectal cancer. Twenty-two patients with locally advanced inoperable colorectal carcinomas (LA/I-CRC) were treated with conformal hypofractionated (3.4 Gy/fraction x 15) split-course accelerated radiotherapy (biological equivalent dose, 67.2 Gy) supported with amifostine, capecitabine (600 mg/m2 daily, 5 days/week), and bevacizumab (5 mg/kg every 2 weeks, five cycles). Biopsies from nine patients, performed before and 1 week after bevacizumab administration, were analyzed for changes in mRNA expression with Illumina gene arrays. No serious grade 3 chemotherapy-related side effects were recorded. There was low acute toxicity, with moist perineal desquamation noted in 2 of 22 patients, diarrhea grade 2 to 3 in 5 of 22 patients, and severe proctalgia in 2 of 22 patients. One patient died from Fournier's gangrene before treatment completion. Within a median follow-up of 18 months, two patients with preradiotheraphy direct involvement of adjacent organs expressed recto-vaginal/perineal fistula. Out of 19 evaluable cases, 13 (68.5%) showed complete response and 4 showed (21.1%) partial response. Fourteen patients are alive with no evidence of loco-regional relapse. In the gene array analysis, 30 known genes associated with transcription factors, DNA repair, and proliferation were downregulated by bevacizumab. DUSP1 gene was the most consistently downregulated transcript. The combination of radiotherapy with bevacizumab is feasible and results in a high rate of durable complete responses in patients with LA/I-CRC. Radiosensitization may occur through a direct effect on tumor cells followed by a wide scale suppression of transcription factors and genes involved in DNA repair and proliferation.
Highlights
Anti–vascular endothelial growth factor therapy enhances the activity of radiotherapy in experimental models, and bevacizumab has therapeutic activity in patients with metastatic colorectal cancer
From October 2007 to January 2008, 22 patients with locally advanced inoperable colorectal cancer were recruited in a prospective phase I/II study aiming to investigate (a) the feasibility and efficacy of the combination of bevacizumab with a previously established accelerated chemoradiotherapy scheme used for radical intent [8] and (b) the effect of bevacizumab on tumor gene expression profile
Taking into account the clinically proven efficacy of the anti-VEGF monoclonal antibody bevacizumab [4, 15] and the evidence of tumor vascular “normalization” induced by the antibody [7, 16], we initiated this phase I/II trial to assess the toxicity and efficacy of radiotherapy combined with bevacizumab in locally advanced inoperable colorectal cancer
Summary
Anti–vascular endothelial growth factor therapy enhances the activity of radiotherapy in experimental models, and bevacizumab has therapeutic activity in patients with metastatic colorectal cancer. The anti–vascular endothelial growth factor (VEGF) monoclonal antibody (bevacizumab) has been approved for the treatment of metastatic colorectal cancer in combination with chemotherapy [4]. The combination of anti–vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab with radiotherapy showed an acceptable tolerance profile and high complete response rates that persisted through time. These data may help in the design of prospective trials on anti-VEGF therapy in combination with preoperative or adjuvant radiochemotherapy for rectal cancer. Using gene arrays, we provide evidence that bevacizumab, aside from its vascular effect, may have a direct effect on cancer cells themselves
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