Genomic-Adjusted Radiation Dose Is Associated With First Recurrence and Survival in Solid Tumors

Jacob G. Scott, MD, DPhil

Genomic-adjusted radiation dose (GARD) demonstrated a significant association with time to first recurrence and overall survival (OS) in patients with certain solid tumors who had been treated with radiation therapy, indicating that genomics should be used to guide radiation dosing decisions, according to findings from a pooled retrospective analysis published in The Lancet Oncology.^1,2

The results showed that the hazard ratios (HRs) for GARD as a continuous variable were 0.98 for time to first recurrence (95% CI, 0.97-0.99; P = .0017) and 0.97 for OS (95% CI, 0.95-0.99; P = .0007).

“As opposed to physical radiotherapy dose, which is the measure of what comes out of the machine and is delivered to the patient, GARD quantifies the biological effect on an individual patient of that delivered dose,” said lead study author Jacob G. Scott, MD, DPhil, associate professor at Case Western Reserve University School of Medicine and radiation oncologist at Cleveland Clinic, in a press release. “What we’ve found by looking at 1600-plus patients is that the physical dose of radiation does not associate with outcome (time to first recurrence and overall survival), but GARD does.”

Currently, radiation therapy is given as a one-size-fits-all treatment. However, an algorithm using the GARD model had been put forth to personalize the dose of radiation therapy. The model calculated the biological effect a given dose of radiation would have based on a patient’s tumor genomics.³

“Historically, the field of radiotherapy has accepted that radiation therapy, a physical treatment, causes a biologic or clinical effect in patients with regard to tumor response, toxicity, and carcinogenesis,” said senior study author Javier Torres-Roca, MD, senior member in the Department of Radiation Oncology at Moffitt Cancer Center and professor of oncologic sciences at the University of South Florida Morsani College of Medicine. “However, up to now, radiation oncologists have always assumed that the biological effect was uniform across patients. GARD provides the first validated approach to quantify the biological effect of radiotherapy for each individual patient and tells you more about the clinical outcome and the benefit of radiotherapy than the physical dose.”

In the pooled analysis, investigators compiled data from 11 published clinical cohorts of 1615 patients spanning 7 types of solid tumors, including breast cancer, head and neck cancer, non–small cell lung cancer, pancreatic cancer, endometrial cancer, melanoma, and glioma.

A total of 1298 patients––982 who had received radiotherapy and 316 who had not received radiotherapy––were evaluated for time to first recurrence, and 677 patients––424 who had received radiotherapy and 253 who had not received radiotherapy––were evaluated for OS.

Cox regression, stratified by cohort, was used to assess the association between GARD and outcome. Separate models using dose of radiation and patients treated without radiotherapy, modelled as having a standard-of-care dose of radiotherapy (sham-GARD), were used for comparison. Interaction tests were performed between GARD and treatment with or without radiotherapy using the Wald statistic.

Findings from the interaction test showed that the effect of GARD on OS is dependent on the receipt of radiotherapy (Wald statistic, P = .011). The interaction test for GARD and radiotherapy was not significant for time to first recurrence (Wald statistic, P = .22).

Moreover, the HR for physical dose of radiation was 0.99 (95% CI, 0.97-1.01; P = .53) for time to first recurrence and 1.00 (95% CI, 0.96-1.04; P = .95) for OS. The HR for sham-GARD was 1.00 (95% CI, 0.97-1.03; P = 1.00) for time to first recurrence and 1.00 (95% CI, 0.98-1.02; P = .87) for OS.

“This does not require a departure from the current standard of care. Our view is that radiosensitivity index/GARD is a decision support tool that provides a view of the effect of radiotherapy dose for each individual patient providing critical information for the treating radiation oncologists, Scott concluded.”

References

1. 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. 2021;S1470-2045(21):00347-8. doi:10.1016/S1470-2045(21)00347-8
2. Study confirms effectiveness of new personalized approach for radiation therapy. News release. Cleveland Clinic. August 4, 2021. Accessed August 20, 2021. https://cle.clinic/3zhDdoE
3. Scott JG, Berglund A, Schell MJ, et al. A genome-based model for adjusting radiotherapy dose (GARD): a retrospective, cohort-based study. Lancet Oncol. 2017;18(2):202-211. doi:10.1016/S1470-2045(16)30648-9