Genomic-Adjusted Radiation Dose Model May Improve Patient Outcomes

Author: By Lynda Williams, Senior medwireNews Reporter

medwireNews: A genomics-based approach to radiation treatment planning may improve patient outcomes by taking into account the clinical heterogeneity of radiation response found within tumour types, researchers suggest in The Lancet Oncology.

The US team combined the radiosensitivity index – which uses gene expression data to classify tumours as radiosensitive or radioresistant – with information on physical radiation dose to create the genomic-adjusted radiation dose (GARD), a measure of the biological effect of a specific radiation dose in an individual patient.

To test the hypothesis that GARD could improve patient outcomes compared with standard radiotherapy dosing, Javier Torres-Roca, from Moffitt Cancer Center in Tampa, Florida, and co-workers pooled data from 11 studies including 1615 patients with cancers of the breast, head and neck, pancreas or endometrium, non-small-cell lung cancer, melanoma or glioma.

The researchers calculated GARD for the 75.4% of patients who received radiotherapy and a sham GARD, based on a standard-of-care treatment schedule, for those who did not.

“Although the range of physical radiation doses in these modern cohorts was limited to values near those of standard of care and were delivered in standard fraction sizes, GARD reveals a wide range of predicted biological effects, enabling understanding of outcomes at a higher resolution”, the investigators say.

In pooled analysis, GARD was significantly associated with improved time to first recurrence and overall survival, with hazard ratios of 0.98 and 0.97, respectively, in radiation-treated patients, whereas there was no correlation between the sham GARD and these outcomes in patients who did not receive radiotherapy.

There was a significant interaction between GARD and actual receipt of radiotherapy for the prediction of overall survival but not for time to first recurrence, the researchers say.

And further analysis indicated that GARD was a “significant linear variable” for both time to first recurrence and overall survival, with an increase in GARD units translating to a decrease in the GARD-specific relative hazard ratios for both endpoints, including in 3-year probability analyses.

By contrast, there was no significant association between the actual or sham physical dose of radiation received and time to first recurrence or overall survival, the researchers say.

Javier Torres-Roca and co-authors suggest that differences in the biological effect of radiation may explain why radiation dose escalation does not always translate to improved survival in clinical trials.

“A GARD-based approach allows for the understanding of this non-uniform response to dose escalation: some patients benefit while others are potentially harmed when they receive unnecessary extra doses and associated toxicity”, they write, postulating that “GARD allows us see which patients would benefit most from dose optimisation, permitting next-generation trials of personalised radiotherapy dose.”

The researchers emphasize that they do not suggest “abandoning physical dose of radiation, but instead, like the CT scanner did for x-ray, we suggest enhancing dose with another dimension—genomic data—allowing us to see each individual patient’s potential for radiotherapy benefit at a higher resolution.”

The authors of a linked comment say there are important questions to be answered before GARD can be used to individualise radiotherapy in the clinic, such as the impact on GARD of systemic therapy and changes in the tumour microenvironment or the use of hypofractionated radiotherapy regimens.

Nevertheless, Orit Kaidar-Person, from Sheba Medical Center in Ramat Gan, Israel, and co-commentators agree that “a GARD-based framework for radiotherapy should be adopted as the new paradigm for trial design and suggest that the assay should be developed and integrated into clinical trials following a set of criteria set forth by the US National Cancer Institute.”

“By supporting such projects, including those aiming to identify genetic variants associated with susceptibility to radiotoxicity, we can move towards a more personalised radiotherapy approach for our patients”, they conclude.

References

• 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; Advance online publication 4 August 2021. doi:10.1016/S1470-2045(21)00347-8 
• Kaidar-Person O, Poortmans P, Salgado R. Genomic-adjusted radiation dose to personalise radiotherapy. Lancet Oncol; Advance online publication 4 August 2021. https://doi.org/10.1016/S1470-2045(21)00411-3