Radiation-Drug Combinations to Improve Clinical Outcomes and Reduce Normal Tissue Toxicities: Current Challenges and New Approaches: Report of the Symposium Held at the 63rd Annual Meeting of the Radiation Research Society, 15–18 October 2017; Cancun, Mexico

Abstract

The National Cancer Institute’s (NCI) Radiation Research Program (RRP) is endeavoring to increase the relevance of preclinical research to improve outcomes of radiation therapy for cancer patients. These efforts include conducting symposia, workshops and educational sessions at annual meetings of professional societies, including the American Association of Physicists in Medicine, American Society of Radiation Oncology, Radiation Research Society (RRS), Radiosurgery Society, Society of Nuclear Medicine and Molecular Imaging, Society for Immunotherapy of Cancer and the American Association of Immunology. A symposium entitled “Radiation-Drug Combinations to Improve Clinical Outcomes and Reduce Normal Tissue Toxicities” was conducted by the NCI’s RRP during the 63rd Annual Meeting of the RRS on October 16, 2017 in Cancun, Mexico. In this symposium, discussions were held to address the challenges in developing radiation-drug combinations, optimal approaches with scientific evidence to replace standard-of-care, approaches to reduce normal tissue toxicities and enhance post-treatment quality-of-life and recent advances in antibody-drug conjugates. The symposium included two broad overview talks followed by two talks illustrating examples of radiation-drug combinations under development. The overview talks identified the essential preclinical infrastructure necessary to accelerate progress in the development of evidence and important challenges in the translation of drug combinations to the clinic from the laboratory. Also addressed, in the example talks (in light of the suggested guidelines and identified challenges), were the development and translation of novel antibody drug conjugates as well as repurposing of drugs to improve efficacy and reduce normal tissue toxicities. Participation among a cross section of clinicians, scientists and scholars-in-training alike who work in this focused area highlighted the importance of continued discussions to identify and address complex challenges in this emerging area in radiation oncology.

Precision Chemoradiotherapy for HER2 Tumors Using Antibody Conjugates of an Auristatin Derivative with Reduced Cell Permeability

“…Tumor volume was measured with digital calipers using the formula In vivo tumor xenograft response experiments Mice were randomized into treatment groups once mean tumor volumes reached >100 mm 3 . Drug was intravenously injected through the tail vein in 50 mL.…”

“…5D). To quantitate tumor growth statistics, we determined the number of days it took for tumors to reach 500 mm 3 . For control, IR, T-MMAF alone, or T-MMAF þ IR, it took 25, 39, 47, and 62 days respectively to reach 500 mm 3 .…”

“…Their infiltrative nature into surrounding critical normal structures precludes surgical resection. For such patients, combining chemotherapy and radiotherapy forms the basis of organ-sparing curative treatment (1)(2)(3). The paradigm of concurrent cytotoxic chemotherapy [i.e., cisplatinum, paclitaxel, 5-fluorouracil (5-FU), and mitomycin C] and radiotherapy was established over four decades ago (4).…”

“…Although cytotoxic chemotherapies improve tumor control with radiotherapy, these nontargeted drugs increase normal tissue damage in the irradiated field in addition to their systemic toxicities (1)(2)(3). Treatment-induced side effects during therapy interfere with delivering full-dose chemotherapy and radiotherapy resulting in treatment delays and/or dose reduction negatively affecting patient outcomes.…”

“…Unfortunately, clinical success with inhibitors of DNA damage repair is lacking (15)(16)(17). One explanation for the lack of progress beyond current chemoradiotherapy regimens is that conventional cytotoxic chemotherapies set a high bar that more targeted radiosensitizing drugs have difficulty surpassing because in addition to any radiosensitization potential, cisplatin, taxanes, and 5-FU have an established role in cancer therapy for their intrinsic tumoricidal activity (3).…”