Combined vascular endothelial growth factor-targeted therapy and radiotherapy for rectal cancer: theory and clinical practice.
Despite the routine use of adjuvant and neoadjuvant chemoradiotherapy, patients with advanced rectal tumors experience significant rates of treatment failure and disease recurrence. Resistance to radiation is a particular problem. Adding a vascular endothelial growth factor (VEGF)-targeted therapy may improve outcomes in these patients. Epidemiologic studies have shown that tumor expression of VEGF predicts disease recurrence and lower overall survival in patients treated with radiation. In tumor xenograft models in mice, VEGF-targeted agents increase the response to radiation, with a greater probability of tumor control and a greater delay in tumor growth. In addition to killing cancer cells indirectly by damaging tumor blood vessels (antivascular effect), VEGF-targeted therapy may sensitize tumors to radiation through two mechanisms: by normalizing the tumor vasculature, leading to greater tumor oxygenation, and thereby increasing the cytotoxicity of radiation to cancer cells, and by increasing the radiosensitivity of tumor-associated endothelial cells. In addition, anti-VEGF agents may inhibit the regrowth of tumors after radiation by decreasing the number of circulating endothelial cells and endothelial progenitor cells. A phase I dose-escalation study has shown the safety of bevacizumab at a dose of 5 mg/kg in combination with 5-fluorouracil and radiation in patients with rectal carcinoma, and has provided evidence of both vascular normalization and antivascular mechanisms. Phase II evaluation of bevacizumab in this setting is under way.
Willett
Christopher G
CG
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Kozin
Sergey V
SV
Duda
Dan G
DG
di Tomaso
Emmanuelle
E
Kozak
Kevin R
KR
Boucher
Yves
Y
Jain
Rakesh K
RK
D000818:Animals; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D006801:Humans; D011879:Radiotherapy Dosage; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012004:Rectal Neoplasms / Q000628:therapy*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor