Interaction of radiation therapy with molecular targeted agents

Abstract

The development of molecular targeted therapeutics in oncology builds on many years of scientific investigation into the cellular mechanics of malignant transformation and progression. The past two decades have brought an accelerating pace to the clinical investigation of new molecular targeted agents, particularly in the setting of metastatic disease. The integration of molecular targeted agents into phase III clinical trial design has lagged in the curative treatment setting, particularly in combination with established therapeutic modalities such as radiation. In this review, we discuss the interaction of radiation and molecular targeted therapeutics. The dynamics of cellular and tumor response to radiation offer unique opportunities for beneficial interplay with molecular targeted agents that may go unrecognized with conventional screening and monotherapy clinical testing of novel agents. By using epidermal growth factor receptor (EGFR) as a primary example, we discuss recent clinical studies that illustrate the potential synergy of molecular targeted agents with radiation and highlight the clinical value of such interactions. For various molecular targeted agents, their greatest clinical impact may rest in combination with radiation, and efforts to facilitate systematic investigation of this approach appear highly warranted.

Fig 1.

Schematic illustration of a modernized Steel hypothesis. The interaction of radiation and molecular targeted therapeutics can take several forms and may be exploited to improve clinical outcomes in the treatment of malignancy. Originally described by Steel in the 1970s, the growing complexity of such interactions prompts revision of this original framework. The potentially exploitable interactions of radiation and molecularly targeted therapeutics include spatial cooperation, temporal modulation, biologic cooperation, cytotoxic enhancement, and normal tissue protection. RT, radiation therapy; SF, surviving fraction of cells. Adapted with permission.

Fig 2.

Distribution of current phase III clinical trials in oncology. A search of ClinicalTrials.gov for phase III clinical trials returned 5,035 trials for condition = “cancer.” When intervention = “radiation” was added to this search, 1,461 studies were identified. When the 5,035 phase III cancer trials were sorted by intervention, 896 studies involved a molecular targeted agent as defined in this review. Of these, only 46 studies examined a combination of a molecular targeted agent and radiation. Nine studies involving total-body irradiation were excluded from that category.