GARD Brings Personalized Medicine to Radiotherapy

Pam Harrison

January 04, 2017

Personalized medicine is now a step closer in the application of radiotherapy across many tumor types with the development of a genomics model that allows experts to determine how sensitive a tumor might be to radiotherapy and adjust the dose to maximize efficacy and minimize toxicity, new research suggests.

"Despite its common use in cancer treatment, radiotherapy has not yet entered the era of precision medicine, and there have been no approaches to adjust dose based on biological differences between or within tumours," write lead author Jacob Scott, MD, Moffitt Cancer Center and Research Institute, Tampa, Florida, and colleagues.

"[W]e provide a method by which to customise radiation dose to match the radiosensitivity of an individual patient's tumour with existing technology," they add.

The study was published online December 16 in the Lancet Oncology.

GARD Scores and Response to Radiotherapy

In previously reported research, the Moffitt team, led by senior author Javier Torres-Roca, MD, developed a gene-expression based radiosensitivity index (RSI) that can predict the sensitivity of a tumor to radiation therapy based on the expression of 10 specific genes.

This RSI accurately predicted clinical outcomes in many different cancer types, including breast and metastatic colorectal cancer.

In the current study, the same researchers used the RSI to develop a genomics model, genomic-adjusted radiation dose (GARD), that is able to predict the therapeutic effect that radiotherapy will have on specific tumors.

This in turn will help guide the dose of radiation used to match an individual tumor's sensitivity to radiation.

To calculate GARD scores, investigators used 8271 primary tumor samples from patients enrolled in the Total Cancer Care (TCC) cohort and assessed the range of GARD values within and between tumor types.

"There was a wide range of GARD values (range 1.66 - 172.4) across the TCC cohort despite assignment of uniform radiotherapy doses within disease types," the researchers report.

Furthermore, they write, "GARD scores show that a higher radiotherapy dose does not always result in a higher radiotherapeutic effect across a population."

For example, radiation oncologists might expect that patients treated with 45 Gy would have a low GARD score and that as the dose of radiation increased, GARD scores would be higher.

Although this was somewhat true, they found that patients with highly radiosensitive tumors assigned to 45 Gy had GARD values that were similar to those of some patients who were assigned to much higher doses of radiotherapy but whose tumors were less sensitive to radiation and vice versa.

They also found that cancers that are usually treated with high doses of radiotherapy, including cervical and head and neck cancer, had the highest median GARD values.

This is "consistent with the superior clinical outcomes after radiotherapy in patients with oropharyngeal cancer," Dr Scott and colleagues observe.

In contrast, median GARD values were lowest for gliomas and sarcomas, which are less responsive to radiation therapy.

Five Clinical Cohorts

Dr Scott and colleagues also analyzed data from five different patient cohorts to evaluate whether GARD scores correlated with clinical outcomes.

In an analysis of one of these cohorts, the Erasmus Breast Cancer Cohort, researchers again found that GARD values were widely variable.

However, they also observed that distant metastasis–free survival rates were longer for patients with a GARD value at or above the 75th percentile than for those with a GARD value beneath the 75th percentile.

As for the other clinical cohorts, GARD independently predicted outcomes in these cohorts as well, which included patients with breast cancer, glioblastoma, lung cancer, and pancreatic cancer.

"GARD has been developed to enable adjustment of radiotherapy dose to match an individual tumour's radiosensitivity, with higher GARD values predicting a higher therapeutic effect from radiotherapy," Dr Scott and colleagues write.

"The GARD model provides the first opportunity to genomically inform radiation dose and is a safe and feasible approach to precision radiation oncology," Louis B. Harrison, MD, chair of Moffitt’s Radiation Oncology Department, commented in a statement. "With multi-disciplinary care becoming standard for the majority of cancer patients, it is critical that precision medicine is expanded beyond drug therapy," he added.

Pave the Road

Commenting on the new approach in an accompanying editorial, Philip Poortmans, MD, and Paul Span, MD, both from the Radboud University Medical Center in Nijmegen, the Netherlands, and Orit Kaidar-Person, MD, from the University of North Carolina, Chapel Hill, say "these findings should be considered as an excellent way to pave the road for biologically directing the dose of radiation therapy for individual tumours."

The editorialists caution that the proposed GARD approach to determine radiation dosing should not be generalized to unconventional forms of radiotherapy, including hypofractionation and ablative radiotherapy.

They also caution that oncologists will need to take clinicopathologic factors into account, and not just GARD values, when this model is eventually incorporated into clinical practice.

However, the editorialists also encourage oncologists to embrace the new findings. Efforts to enhance one of the mostly widely used and effective treatments for many different cancer types "should be recognised, supported, and funded by our community," they write.

Up to two thirds of all patients with cancer in the United States receive radiotherapy, and it's responsible for approximately 40% of all cancers that are cured, they point out.

Dr Scott and several of his coauthors are named inventors in a patent pending for systems for providing personalized radiation therapy. None of the editorialists have disclosed any relevant financial relationships.

Lancet Oncol. Published online December 16, 2016. Abstract, Editorial

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