Avant GARD.

Top Line: Does genomically-adjusted radiation dose (GARD) explain differences in treatment outcomes across different cancer types treated with conventionally fractionated radiation?

The Study: In radiation oncology, we often deliver a standard range of prescription doses to various tumor types and get a range of responses. We clump tumor types to determine an “average” radiosensitivity and then perform dose-escalation (or de-escalation) studies to find doses that balance acceptable tumor control and acceptable toxicity. The GARD folks have been honing a method to characterize radiosensitivity for a particular tumor and to individualize radiation dose. As a refresher, biologically effective dose (BED) is a measure of the biological effect of a specific dose per fraction and total dose in a particular tissue with a specific ɑ/β. BED = n*d*[1 + d ÷ (ɑ/β)]. Alpha represents intrinsic radiosensitivity, and it is usually assigned a value for an entire class of tumors. The GARD equation is similar, but uses a patient/tumor specific ɑ (derived from the RSI and cell survival equation): GARD = n*d*[ɑ + β*d]. A higher GARD means that the same dose of radiation has a greater biological effect than in a tumor with a lower GARD. Here, they analyzed >1000 different tumors from 11 cancer datasets including breast cancer, glioma, pancreatic cancer, endometrial cancer, melanoma, head and neck cancer, and non-small cell lung cancer. Among these, 1218 were treated with conventionally fractionated radiation and they were compared to 397 from the same datasets who were not. Breast cancer represented the largest proportion followed by glioma and then endometrial cancer--meaning quite a number of patients were receiving adjuvant (not definitive) radiation therapy. For each irradiated patient, GARD and physical dose were quantified while for unirradiated patients, a sham-GARD was calculated using standard doses for the disease site. The latter was performed to determine whether GARD is simply a predictive biomarker of disease outcome regardless of radiation. Across tumor types, GARD was associated with time to recurrence and overall survival in patients treated with radiation whereas physical dose was not. In addition, GARD was not associated with recurrence or survival in patients who did not receive radiation--ie, it’s not just a predictor of good outcomes.

TBL: Across multiple disease sites and tumor types, variation in GARD (akin to a tumor-specific biologically effective dose) is associated with recurrence and survival following treatment with standard radiation regimens. | Scott, Lancet Oncol 2021