Antiangiogenics: the potential role of integrating this novel treatment modality with chemoradiation for solid cancers

Abstract

Although still in very early stages of clinical development, the combination of antiangiogenics with contemporary chemoradiotherapy regimens has emerged as a feasible and promising approach to many cancers. We review the rationale and the current understanding of antiangiogenics and their therapeutic potential in combination with chemoradiotherapy. Finally, we offer a perspective on future research directions aimed at making this complex therapeutic approach successful in the clinic.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Figures

Fig 1

Antitumor effects of antiangiogenics. In normal tissue, there is balance between (A) proangiogenic (pro) and antiangiogenic (anti) factors; in (B) tumors, proangiogenic signals preponderate and induce an abnormal vasculature. Antiangiogenics are intended to kill angiogenic vessels and starve tumors, but most tumors relapse, presumably (D) using pathways not blocked by the antiangiogenic agent used; alternatively, antiangiogenesis agents transiently normalize the vasculature, (C) making it more efficient for drug and oxygen delivery. Adapted with permission.,

Fig 2

Rectal tumor response to bevacizumab (BV) and chemoradiotherapy. Sigmoidoscopy at day 12 showed no response in any patient after bevacizumab alone (A, B); a marked tumor response was seen presurgery in all patients, with an ulcer and no evidence of macroscopic disease. Histopathological evaluation of surgical specimens usually showed marked tumor regression. H&E, hematoxylin and eosin stain. Adapted with permission.,

Fig 3

Effect of bevacizumab (BV) on cancer cells. The percentage of tumor cell undergoing (A) apoptosis and (B) proliferation was determined in serial biopsies by terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick-end labeling and immunostaining for proliferation cell–nuclear antigen, respectively. Cell apoptosis increased in seven of eight patients and cell proliferation increased in four of eight patients. Adapted with permission.

Fig 4

Effect of bevacizumab on interstitial fluid pressure (IFP). (A) Tumor IFP measurement at sigmoidoscopy using the wick-in-needle technique. At day 12 after the first bevacizumab dose, tumor IFP decreased in seven of nine patients analyzed, who had higher IFP values before treatment. Tx, treatment. Adapted with permission.,

Fig 5

Rectal tumor response to bevacizumab and chemoradiotherapy evaluated by positron emission tomography. [18F]fluorodeoxyglucose ([18F]FDG) uptake was evaluated before treatment (Tx), on day 12, and presurgery (tumor highlighted in box). No change in FDG uptake was observed on day 12 after bevacizumab infusion. Nevertheless, the FDG uptake was significantly lower at presurgery compared with pretreatment (*P < .01). Adapted with permission.,,