Genomic-Adjusted Radiation Dose Model May Inform Radiotherapy Effects in Pan-Cancer Setting

The use of a genomic-adjusted radiation dose (GARD) appeared to be associated with survival and radiotherapy benefit pan-cancer, according to a study published in The Lancet Oncology.

The use of GARD was significantly with time to first recurrence was (HR 0.98; 95% CI, 0.97-0.99; P = .0017) and OS (HR 0.97; 95% CI, 0.95-0.99; P = .0007). Moreover, an interaction test indicated that GARD’s impact on survival was dependent on whether a patient received treatment with radiotherapy (Wald statistic P = .011). However, the interaction test indicated that GARD and radiotherapy were not significant for time to first recurrence (Wald statistic P = .011). Investigators also did a 3-year analysis for probability of recurrence and OS. The analysis indicated that GARD was a significant, continuous, and predictive biomarker of OS and recurrence for patients treated with radiotherapy.

“GARD is commonly mistaken to be a model of clinical outcome; however, GARD was never developed, trained, or [optimized] to predict clinical outcome. GARD is a model of the biological effect of radiotherapy and is capable of predicting outcome because it captures the differential clinical benefit of radiotherapy across patients. But an important caveat is that the effect size of its impact on outcome is limited to the therapeutic effect of radiotherapy,” the study’s investigators wrote.

The study utilized 11 previously published datasets across 7 tumor types, including breast cancer, glioma, pancreatic cancer, endometrial cancer, melanoma, head and neck cancer, and non–small cell lung cancer. The dataset included 1615 unique patients with 1298 either being treated with radiotherapy (n= 982) or without radiotherapy (n= 316) for first recurrence. Additionally, 424 patients who were treated with radiotherapy and 253 who were treated without radiotherapy were assessed for OS.

“The fundamental goal of radiotherapy planning is to deliver the prescribed physical dose of radiotherapy to the target volume while [minimizing] the dose to normal tissue. The integration of three-dimensional anatomy into radiation treatment planning systems, brought about

by the invention of the CT scanner, enabled the geometric [optimization] of radiation fields. This new method of planning led to a shift from one-size-fits-all radiotherapy field shapes to ones that are anatomically [personalized], improving the ability of radiation oncologists to further spare normal tissue for each individual patient,” the investigators noted.

Additional findings from the study indicated that in the control cohort of patients who were not treated with radiotherapy, no association was identified between GARD and either time to first recurrence (HR 1.00; 95% CI, 0.97-1.03; P = 1.00) or OS (HR 1.00; 95% CI, 0.98-1.02; P = 0.87). There was a significant interaction between GARD and radiotherapy treatment status for OS (Wald statistic P = .011), although the same was not identified for time to first recurrence (Wald statistic P = .22). There was no association with the physical dose of radiotherapy and time to first recurrence (HR 0.99; 95% CI, 0.97-1.01; P = .53) or OS (HR 1.00; 95% CI, 0.96-1.04; P = .95).

“Our findings make sense in the setting of clinical trials of dose escalation of radiotherapy in unselected patients, which has not been found to improve [OS] but does not mean that physical dose of radiation is not an important parameter,” investigators concluded.

Reference

Scott JG, Sedor G, Ellsworth P, et al. Pan-cancer prediction of radiotherapy benefit using genomic-adjusted radiation dose (GARD): a cohort-based pooled analysis. Lancet Oncol. Published online August 4, 2021. doi:10.1016/S1470-2045(21)00347-8