In 2019, medical staff at David Grant USAF Medical Center perform thoracoscopic surgery to remove the upper left lobe in a lung cancer patient at the heart, lung and vascular center, Travis Air Force Base, California. Because of its partnership with the VA Northern California Health Care System, the HLVC provides one-stop care for patients with diseases of the heart, lungs and circulation. U.S. Air Force photo by Heide Couch
PORTLAND, OR — The open secret about most clinical trials is that they are not particularly useful, at least not for patients and practicing physicians. Trials typically establish criteria that restrict participation to unusually healthy patients. That makes their results look better for the drugs being tested but limits their utility for the practicing clinician. Nowhere is the disconnect more acute than at the VA, which serves an older and sicker than average population, the kind of patients excluded from most trials.
“The whole system is ripe for an overhaul,” said Joseph Unger, MD, of the Fred Hutchinson Cancer Research Center and the SWOG Cancer Research Network in Seattle. “We need to make trials more accessible to patients. It’s not the patients who are the issue; it’s the system.”
Unger and Hong Xiao, PhD, also of the Fred Hutchison Cancer Research Center and SWOG, co-led a team of researchers who recently analyzed the impact of the pandemic on clinical trial participation. They documented a “precipitous decrease in enrollments during the initial COVID-19 wave, but only a modest reduction during the winter 2020 to 2021 wave. Over the entire year, steep enrollment reductions were found for cancer control and prevention trials, whereas for treatment trials, enrollments were similar to expected rates.”1
The ability of treatment trials to quickly pivot to online formats in dispersed centers speaks to the system’s capacity for adaptation. Unger and many others say they think it’s time to show that same flexibility in clinical trial criteria. “Overly restrictive eligibility criteria without scientific justification has led to an underrepresentation of older adults, racial/ethnic and sexual/gender minorities, and patients with well-managed comorbidities,” said American Society of Clinical Oncology President Lori J. Pierce, MD.
The central problem is that overly restrictive criteria often exclude exactly the kind of patients most likely to be treated based on the trial’s results and most in need of treatment through a clinical trial. As a result, safety issues may be significantly underestimated and response rates inflated. Very limiting criteria also extend the time required for enrollment and are a significant factor in the failure of many trials to meet their enrollment targets.
Expanding the Eligible Patient Base
ASCO and Friends of Cancer Research recommended elimination of exclusions for brain metastases, HIV status, organ dysfunction, prior or concurrent malignancies, and minimum age unless demonstrably relevant five years ago. The CancerLinQ Discovery database showed that loosening three common criteria regarding renal function, brain metastases, and prior malignancies doubled the eligible population for advanced non-small cell lung cancer (NSCLC) trials.
Recommendations by the same groups this year urged investigators to strike washout periods for prior treatments and discontinuation of concomitant medications unrelated to the treatment being evaluated, performance status requirements, laboratory results except for those that identify a safety concern, and restrictions on the number or type of prior therapies unless directly relevant to the trial.2
The National Cancer Institute’s Cancer Therapy Evaluation Program (CTEP) pledged to incorporate the new recommendations into its protocol template and to require investigators who add limitations to the broadened template to explain the scientific rationale. “The era of precision oncology increases the potential for limitations in clinical trial participation due to molecular profiling of participants’ tumors,” CTEP said. “Therefore, eligibility criteria must be as broad as safely possible to achieve diverse and representative populations in future clinical trials.”
Including More Veterans
While many of the current trials are evaluating agents for use in metastatic cancer, better understanding of the characteristics of patients that respond to earlier therapies has also been an area of active research at the VA.
The recommended first-line treatment of patients with Stage 1 non-small cell lung cancer (NSCLC) calls for lobectomy to remove the cancerous tissue, but not everyone can withstand surgery. With an average age of 70 at diagnosis, in fact, many patients with NSCLC may not be candidates for resection. Among veterans, the high rate of comorbidities, particularly chronic obstructive pulmonary disease (COPD) and coronary artery disease (CAD) further complicate the treatment picture.
Researchers including Susan Bates, MD, of the James J. Peters VAMC in the Bronx, and Kristina Crothers, MD of the Puget Sound VAMC in Seattle, recently released results from a mathematical model of lung cancer to explore the best options for treatment of veterans with Stage 1 NSCLC with comorbid COPD with or without CAD.2
The team used data from 14,029 veterans diagnosed with NSCLC between 2000 and 2015. They simulated multiple randomized trials comparing lobectomy, limited resection or stereotactic body radiation therapy (SBRT), a non-invasive treatment that delivers high-dose X-rays to cancer cells. SBRT has been shown to effectively cure Stage 1 NSCLC, but large studies in NSCLC patients who could tolerate surgery have not been conducted.
The researcher found that, for veterans younger than age 70, lobectomy provided the best quality adjusted life expectancy regardless of COPD or CAD status. In general, for veterans 80 years of age and older, “less invasive treatment were often superior to lobectomy” but there was no dominant treatment modality. The treatment choice varied based on CAD status for one-third of veterans 70 or older.
While informative, simulations do not carry the same weight as clinical trials; nor do they fully reflect that variability among patients seen in clinical practice. To provide a more definitive answer to the question of the best treatment choice for veterans based on age, frailty and comorbidities, the VA launched the VALOR (VA Lung Cancer and Stereotactic Radiotherapy) trial. In a Phase 3 randomized clinical trial, VALOR is investigating the role of high-dose radiation therapy as an alternative to surgery for early-stage lung cancer.
“If we had data that showed that surgery or radiation therapy was better for a given patient, then we would be able to use safety and other criteria to decide which treatment to give,” said Drew Moghanaki, radiation oncologist at the Los Angeles VAMC and co-chair of the VALOR study. “We would have more options to better match each patient to the optimal treatment.”
- Unger JM, Xiao H, LeBlanc M, Hershman DL, Blanke CD. Cancer Clinical Trial Participation at the 1-Year Anniversary of the Outbreak of the COVID-19 Pandemic. JAMA Netw Open. 2021;4(7):e2118433. doi:10.1001/jamanetworkopen.2021.18433
- Kim ES, Uldrick TS, Schenkel C, Bruinooge SS, Harvey RD, Magnuson A, Spira A, Wade JL, Stewart MD, Vega DM, Beaver JA, Denicoff AM, Ison G, Ivy SP, George S, Perez RP, Spears PA, Tap WD, Schilsky RL. Continuing to Broaden Eligibility Criteria to Make Clinical Trials More Representative and Inclusive: ASCO-Friends of Cancer Research Joint Research Statement. Clin Cancer Res. 2021 May 1;27(9):2394-2399. doi: 10.1158/1078-0432.CCR-20-3852. Epub 2021 Feb 9. PMID: 33563632.