CLEVELAND, Ohio and TAMPA, Fla — Researchers from Cleveland Clinic, Case Western Reserve University School of Medicine, and Moffitt Cancer Center have found that the genomic adjusted radiation dose (GARD) may be used to personalize radiotherapy (RT) to maximize the therapeutic effect of a given physical RT dose.
The research, published in The Lancet Oncology, validates the association between GARD and radiation therapy outcome in a large cohort of patients, across seven different cancer types.
“As opposed to physical RT 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 Cleveland Clinic radiation oncologist and Case Western Reserve University School of Medicine associate professor Jacob G. Scott, M.D., DPhil, the first author of the study. “What we’ve found by looking at 1,600-plus patients is that the physical dose of radiation does not associate with outcome (time to first recurrence and overall survival), but GARD does.”
The study represents the validation of a quantifiable parameter of the clinical effect of radiation; a parameter that serves as a predictor of the therapeutic benefit of RT for each individual patient.
According to Moffitt Cancer Center radiation oncologist Javier Torres-Roca, M.D., this new study changes the field of radiation therapy.
“Historically, the field of RT has accepted that radiation therapy, a physical treatment, causes a biologic or clinical effect in patients with regard to tumor response, toxicity, carcinogenesis, etc.,” Dr. Torres-Roca said. “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 RT for each individual patient and tells you more about the clinical outcome and the benefit of RT than the physical dose”.
Both authors propose that the new paradigm for radiation therapy should incorporate GARD for all patients because it provides critical information about its therapeutic benefit.
The field of radiation oncology has been trailing behind in the translation of the new biology learned through genomics into treatment benefits and has not entered the precision medicine era, where patient-specific genomic data drives therapeutic decision-making. In an attempt to move the field forward, and away from a one-size-fits-all approach, the team of collaborators successfully devised and introduced the concept of GARD in a previous study.
GARD is derived from the gene-expression-based radiation-sensitivity index (RSI) and the physical dose given to a patient using the canonical linear quadratic model used to describe the biological response to radiation. Put simply, GARD is a reflection of the effect of a given physical dose on an individual patient.
Currently, measuring the dose of RT is done at the machine and up until now the field has assumed the clinical or biological effect of a given dose is uniform. This paper demonstrates that GARD is associated with clinical outcome while radiation dose is not.
“Changing radiation doses near the range of the current standard of care does not associate with the outcome, but the effect of the dose is,” Dr. Torres-Roca said. “GARD predicts for the benefit of radiation therapy and quantifies the relative potential benefit of radiation therapy.”
In explaining the utility of GARD, Dr. Scott noted that it quantifies the biologic effect of radiation into a numerical parameter that involves physical RT dose, giving oncologists an objective way to understand the relative therapeutic benefit of their prescribed RT, and allowing them to modify the physical dose of RT in order to optimize radiation therapy benefit for each individual patient. GARD provides the first validated decision support tool where radiation oncologists can utilize genomic information to modulate the potential benefit of radiation therapy for each patient.
The current study used previously published data on cancers of the breast, head and neck, endometrium, melanoma, glioma, pancreas and lung (NSCLC) to test the association between GARD, RT dose and patient outcomes using two endpoints: time to first recurrence and overall survival. The study included 1,615 patients from 11 separate cohorts -- from seven disease sites -- in the analysis. To test whether the GARD-based RT dosing paradigm is associated with the outcomes, a pooled pan-cancer analysis was performed.
“The important part is that GARD is not a standalone biomarker; rather, it is a dynamic parameter that changes based on the prescribed RT dose, which allows the clinician to directly modulate it,” said Dr. Scott. The higher the GARD value, the higher the predicted therapeutic benefit of radiotherapy at that specific dose, but, he adds, these increases may not, for some radiation plans, be worth the risk of dose escalation. “The point is that some patients have large increases in GARD with more dose, and some patients do not respond as well near the range of standard of care. The discussion with the clinician, as well as the treating oncologist’s understanding of the risk-benefit balance of dose-escalation’s benefits vs. increased toxicity, remain paramount.”
Dr. Torres-Roca believes this analysis provides enough evidence to justify initial clinical adoption of the GARD-based paradigm of RT dose.
“This does not require a departure from the current standard of care,” he emphasized. “Our view is that RSI/GARD is a decision support tool that provides a view of the effect of RT dose for each individual patient providing critical information for the treating radiation oncologists.”
The test is now available from a CLIA laboratory at Moffitt Cancer Center and researchers hope to make it available more widely by engaging with a large-scale genomics company.
About Moffitt Cancer Center
Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 51 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s scientific excellence, multidisciplinary research, and robust training and education. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 7,500 team members, Moffitt has an economic impact in the state of $2.4 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter, Instagram and YouTube.
About Cleveland Clinic
Cleveland Clinic – now in its centennial year – is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S. News & World Report consistently names Cleveland Clinic as one of the nation’s best hospitals in its annual “America’s Best Hospitals” survey. Among Cleveland Clinic’s 70,800 employees worldwide are more than 4,660 salaried physicians and researchers, and 18,500 registered nurses and advanced practice providers, representing 140 medical specialties and subspecialties. Cleveland Clinic is a 6,500-bed health system that includes a 173-acre main campus near downtown Cleveland, 19 hospitals, more than 220 outpatient facilities, and locations in southeast Florida; Las Vegas, Nevada; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2020, there were 8.7 million total outpatient visits, 273,000 hospital admissions and observations, and 217,000 surgical cases throughout Cleveland Clinic’s health system. Patients came for treatment from every state and 185 countries. Visit us at clevelandclinic.org. Follow us at twitter.com/ClevelandClinic. News and resources available at newsroom.clevelandclinic.org.
About Case Western Reserve University
Case Western Reserve University is one of the country's leading private research institutions. Located in Cleveland, we offer a unique combination of forward-thinking educational opportunities in an inspiring cultural setting. Our leading-edge faculty engage in teaching and research in a collaborative, hands-on environment. Our nationally recognized programs include arts and sciences, dental medicine, engineering, law, management, medicine, nursing and social work. About 5,100 undergraduate and 6,700 graduate students comprise our student body. Visit case.edu to see how Case Western Reserve thinks beyond the possible.