Radiation/Drug Interactions and the Combinational Effects of Tyrosine Kinase Inhibitors and Radiation Therapy in the Treatment of Cancer

Abstract

Introduction: Progress in both the development of Tyrosine Kinase Inhibitors (TKIs) and modern radiation therapy (RT) have opened new horizons for the safe and effective treatments of cancer. Combination therapies of TKIs and radiation therapy have been evaluated with variable sequencing and dosing of both agents. Radiation therapy induces cellular damage to cancer and normal tissue DNA by the production of direct and indirect ionization leading to a cascade of biological events. These ultimately lead to potential loss of cellular reproductive capacity, cell death or impotency. Repair mechanisms of RT-induced cell damage require repair pathways dependent on TK. TKIs are key regulators of cellular function and signaling proteins that catalyze phosphorylation reactions of tyrosine molecules. The purpose of this study was to briefly review the basic biology of RT and TKIs and to review the modern literature pertaining to the toxic and therapeutic effects of their combination in the treatment of cancer based on preclinical and clinical data. Methods: A retrospective review of the basic biology of RT and TKIs with the aim of identifying their combined toxicity and benefit in the treatment of cancer was performed. A systematic search of the standard published radiotherapeutic, radiobiology, chemotherapy and radiotherapy texts, PubMed, Google Scholar, and Clinical Key using the search terms; TKI, RT and combination TKI and RT from 1985-2020 was employed. Data were abstracted from 222 entries from the literature published in English. Issues of toxicity and therapeutic efficacy were defined to evaluate the safe and effective use of combined modality therapy (CMT). Results: Few randomized studies were available for high-level recommendations. The combined treatment of cancer with TKIs and RT may have benefit for palliation, progression free survival, and potential survival under well-defined circumstances. Any benefit of combined therapy is accompanied by significant potential for enhanced radiation toxicity in addition to the baseline potential toxicities of both agents. Conclusion: The data reviewed suggest potential benefit from the CMT of TKIs and RT but at a significant risk of toxicity, which may include severe, hematological, cardiac, gastrointestinal, pulmonary and central nervous system toxicity. Further randomized prospective studies are necessary to define their safe and effective combined therapies. New TKI’s and radiotherapeutic modalities are constantly under development necessitating ongoing and often long term clinical evaluation to define benefits and risks.