Abstract
As our understanding of the molecular pathways driving tumorigenesis improves and more druggable targets are identified, we have witnessed a concomitant increase in the development and production of novel molecularly targeted agents. Radiotherapy is commonly used in the treatment of various malignancies with a prominent role in the care of prostate cancer patients, and efforts to improve the therapeutic ratio of radiation by technologic and pharmacologic means have led to important advances in cancer care. One promising approach is to combine molecularly targeted systemic agents with radiotherapy to improve tumor response rates and likelihood of durable control. This review first explores the limitations of preclinical studies as well as barriers to successful implementation of clinical trials with radiosensitizers. Special considerations related to and recommendations for the design of preclinical studies and clinical trials involving molecularly targeted agents combined with radiotherapy are provided. We then apply these concepts by reviewing a representative set of targeted therapies that show promise as radiosensitizers in the treatment of prostate cancer.
Highlights
Introduction to Targeted RadiosensitizersRadiotherapy (RT) is a mainstay of cancer treatment, offering both definitive and palliative strategies for disease management
Targeted agents can be broadly grouped into tumor-specific and tumor non-specific groups. For those agents that are hypothesized to interact with targets that are aberrantly expressed in a wide range of cancers, the selection of cell lines should be based on knowledge of expression of the target with consideration of what types of tumors will be studied in clinical trials [6,11,14]
As we have nearly exhausted our ability to improve radiation conformality and dose escalation, it is critical that we pursue biologic methods of exploiting inherent weaknesses within the tumor using molecularly targeted agents in an effort to increase the therapeutic ratio of radiation
Summary
Radiotherapy (RT) is a mainstay of cancer treatment, offering both definitive and palliative strategies for disease management. In combination with definitive RT for patients with cancer of the supraglottic larynx and pharynx in a phase III trial, the addition of nimorazole significantly improved locoregional control by 16% without excess toxicity as compared to RT alone [8] This agent failed to become adopted as the standard of care given multiple factors as reviewed by Overgaard et al [9], and is only routinely used in Denmark [6]. In a phase III trial, the addition of cetuximab to definitive RT in patients with squamous head and neck cancers improved 5-year overall survival by 10%, while the side effect profile between placebo and cetuximab treatment arms was comparable [10] Such molecularly targeted agents—Shown to improve tumor control without resulting in untoward normal tissue toxicity—Demonstrate the considerable potential for the development of molecularly targeted radiosensitizers to be used in combination with RT. We provide a brief summary of these recommendations [6,11,13,14,15]
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