Guidelines for preclinical and early phase clinical assessment of novel radiosensitisers

Inhibition of Fatty Acid Synthase Sensitizes Prostate Cancer Cells to Radiotherapy

“…In contrast, in the current study, clonogenic survival was assayed, enabling the determination of the toxicity of experimental therapy to cells with unlimited capacity for proliferation. Clonogenic assay is considered the gold standard for in vitro preclinical studies of radiosensitizers (49,50). Clonogenic assay data were used to calculate combination indices and dose enhancement ratios as recommended by Alcorn et al (48).…”

Clinical development of new drug–radiotherapy combinations

“…Several types of trial design exist and are used according to the specific setting and research question under evaluation 47,58 . Acute toxicity from radiotherapy is not generally a good predictor of late toxic effects, with the exception of particularly severe or durable acute reactions that can have consequential late effects.…”

“…The addition of concomitant cytotoxic chemotherapy to radical radiotherapy has resulted in increases in overall survival and/or disease-free survival in a broad range of tumour types (such as cancers of the head and neck, lung, cervix, rectum, glioblastoma) and addition of molecular targeted agents to radiotherapy has improved overall survival and disease-free survival in head and neck cancer 47,48 . Regarding the interests of individuals with cancer, regulatory agencies increasingly recognize the value of patient-reported outcomes as end points of clinical trials 49 .…”

“…Alternatively, in cases in which multiple drugs might be combined with radiotherapy for the first time, and recruitment is likely to be steady, cohort allocation could take the form of a FLIP-FLOP design. In this design, dose escalation of each drug occurs in alternate cohorts of patients, enabling continued recruitment during the toxicity observation period of the previous cohort and maximising patient recruitment rates 47 . Scenarios in which a run-in period of single agent can precede a drug-radiotherapy combination would support efficient evaluation of any changes in the pharmaco kinetic and/or pharmacodynamic (PK/PD) effects of the drug in the presence of radiotherapy.…”

The Challenges Faced in Developing Novel Drug Radiation Combinations in Non-small Cell Lung Cancer

“…Innovative trial design will also be key to the success of future drug/radiotherapy combination studies in NSCLC [33]. One of the key dose limiting toxicities in these patients is pneumonitis, and the timings and severity of this side effect are variable and poorly understood.…”