American cancer patients have collectively gained up to 14 million years of life since 1980 as a result of NCI-funded cancer trials conducted by the National Clinical Trials Network, a study led by SWOG Cancer Research Network found.
The study, presented Sept. 20 at the annual meeting of the European Society for Medical Oncology, was designed and conducted by SWOG biostatistician and health services researcher Joseph Unger.
This is the first paper to model the cumulative survival benefits of phase III NCTN trials across all adult cooperative groups and through wider adoption by oncologists. The study also quantifies the clinical and scientific impact of the trials.
“I think a critical point that I want people to understand as a takeaway is there’s a lot of discussion in our country right now about infrastructure, and the need to rebuild infrastructure,” Unger, an associate professor in the cancer prevention program at Fred Hutchinson Cancer Research Center, said to The Cancer Letter. “My opinion is that scientific infrastructure is a really critical issue.
“The network groups have been supported by the NCI for 50 years or more, and they really do represent an example of durable infrastructure support from a federal agency, which has had a profound impact on the lives of patients over a long period of time.”
Unger et al. analyzed the results and impact of 163 randomized, phase III studies published over the past 40 years (from 1980 through 2019), and found that more than 80% of the NCTN studies influenced treatment guideline recommendations, demonstrating the scientific impact of these trials on cancer research and care.
Unger’s study, co-authored by the NCTN group chairs, builds on Unger’s earlier paper that quantified the survival benefits of SWOG clinical trials over 60 years (The Cancer Letter, Aug. 8, 2017).
Consistent federal funding is key to maintaining—and growing—NCI’s clinical research enterprise, said Margaret Mooney, associate director of NCI’s Cancer Therapy Evaluation Program.
“The cooperative group clinical trials system represented today by [NCTN] has benefited from sustained, continuous investment by the American people in clinical research for more than 50 years,” Mooney said to The Cancer Letter. “This sustained commitment has allowed the clinical research community to build a collaborative network of investigators, health providers, and patient advocates and the NCI to develop an infrastructure to support that effort by sharing resources.
“Any increases in funding would allow this clinical research community to address additional opportunities to evaluate new therapies and treatment strategies in an era of precision medicine in which we are just beginning to understand more about the underlying complexity of various cancers and their impact on the lifespan and quality of life for the U.S. public.”
The NCTN includes five groups: Alliance for Clinical Trials in Oncology, ECOG-ACRIN Cancer Research Group, NRG Oncology, SWOG Cancer Research Network, and Children’s Oncology Group.
“Although this study focuses only on the impact of the adult network group trials in the NCTN, the Children’s Oncology Group is also part of the NCTN and its clinical trials over the past 50 years have also had a dramatic impact on improving treatments for childhood cancers and extending survival,” Mooney said.
“Additional federal support over the last several years through the Childhood Cancer Survivorship, Treatment, Access & Research (STAR) Act, the Research to Accelerate Cures and Equity (RACE) for Children Act, and the NCI Childhood Cancer Data Initiative (CCDI) have brought new resources to bear to help support the continued effort to improve treatments and address the burden of cancer in children, adolescents, and young adults.”
NCTN runs clinical trials at more than 2,000 academic and community treatment sites across the U.S. and internationally, and conducts publicly funded research into effective new cancer treatments.
“We have always known NCTN research profoundly benefited the lives of people affected by cancer,” Charles Blanke, SWOG group chair and senior author on the abstract, said in a statement. “Dr. Unger’s work quantifies that benefit and demonstrates cooperative research is an incredibly low-cost, high-impact investment.”
The authors identified 163 trials that had, over 40 years starting in 1980, reported statistically significant findings in favor of the experimental treatment for at least one clinical, time-dependent outcome.
Results from most of the studies were published in either The New England Journal of Medicine (49 trials) or the Journal of Clinical Oncology (72 trials). Those published results have been cited 166,711 times in later publications, an average of 64 citations per year for each trial, influencing subsequent cancer research and guidelines for treating patients with cancer. More than 80% of the trials were cited in cancer treatment guidelines in favor of recommended treatments.
The researchers then estimated life-year gains for the 128 trials that found either statistically significant improvement in overall survival time (91 trials) or a trend to improved overall survival (37 trials) for patients, and mapped these gains onto the U.S. population of people with cancer. The analysis finds that, through 2020, these trial results yielded an additional 14 million years of life to people with cancer in the U.S.
“Dr. Unger’s findings are all the more important in this time of increasing costs of clinical research,” Peter J. O’Dwyer, group co-chair of the ECOG-ACRIN Cancer Research Group and a co-author of the study, said in a statement. “The return to the American people of government-funded investment in better cancer care has been remarkably solid—a huge impact.”
The federal government should continue to grow its investment in NCI-funded trials, because NCTN plays a unique role in improving treatment regimens and increasing survival benefits for cancer patients, Unger said.
“The argument, I think, is essentially the pharma trials are designed to obtain an indication for a new treatment. They’re very specific in that regard, but the NCTN trials have a larger mandate,” Unger said. “They’re about combining different regimens, different modalities, different individual agents that have been or received approval from different drug companies.
“They’re not the kind of trials that pharma would necessarily do, and that’s why I think they’re so critical because they’re driven by that sort of patient-friendly perspective of how do we put together the best of treatments that are already out there—to continue to try to advance survival for cancer patients?
“It’s not about getting the next registration for an agent that would be motivated by a pharmaceutical company, which has their own critical role.”
Efficacy vs. effectiveness
Benefits from these NCTN trials are expected to continue to accrue.
“We did a projection out to 2030, that the same set of trials that are estimated to save 14 million life years by 2020 will save 23.4 million life years by 2030,” Unger said. “So, those estimates get big fast, and those immunotherapy trials, those target therapy trials that are included will become more meaningful in terms of their benefits, 10 years in the future.”
Unger said his estimates are conservative. For instance, the study looked only at trials that conclusively contributed to measurable gains in overall survival.
“There are certainly instances where there are treatments that were clearly beneficial and likely would have provided overall survival gains to patients, but simply didn’t meet our criteria,” Unger said. “We had some trials that show whopping differences in progression-free survival, but they either didn’t report the overall survival, because there wasn’t enough follow-up at that time or it didn’t map to overall survival.
“I think we tried to err on the side of making conservative assumptions.”
Who are the patients on the receiving end of these 14 million life-years in survival gains? Is this calculation built on the “healthy volunteer” effect that is characteristic of clinical trial participants?
While it’s important to acknowledge the significance of the study results, it’s equally important to consider the number of life-years lost in vulnerable populations, said Robert Winn, director and Lipman Chair in Oncology at Virginia Commonwealth University Massey Cancer Center, senior associate dean for cancer innovation, and professor of pulmonary disease and critical care medicine at VCU School of Medicine.
“The study from SWOG is really an example of what can happen when folks with cancer are participating in these clinical trials—when they’re looking at how we’ve gained 14 million years of additional life, it’s a direct result of those trials,” Winn said to The Cancer Letter. “But we have to recognize that there are many at-risk populations, many rural populations, and other communities that have not participated in these clinical trials.”
From a health equity perspective, is the 14 million estimate—strictly in terms of measurable gains in overall survival—a realistic representation of real-world patient outcomes? Or is it an idealized estimate, based on the assumption that each cancer patient, regardless of race and socioeconomic status, had equal access to the standard of care over 40 years?
“While I celebrate the 14 million years of additional life, I also would not be honest if I didn’t say that there’s a little piece of me that wishes we could be talking about the 14 billion years of additional life gained,” Winn said. “While we’re talking about the millions of years of additional life, I’d probably tell you about the years lost.
“We know in Engelwood, eight miles from downtown Chicago, there’s a 30-year life expectancy gap. Some of that life expectancy gap isn’t actually due to gun violence, it’s due to some chronic diseases, especially cancer. So, when we look at survival rates of patients who aren’t in a SWOG or an NCTN trial, or who aren’t getting their care from an NCI-designated cancer center—which is 85% of most patients—it’s not going out on a limb to say, if you really go below the surface, the survival rates of African Americans still are lower.”
NCI has a long history of funding research aimed at reducing cancer health disparities and increasing diversity in clinical trials, NCI’s Mooney said.
“Over the last two decades, the proportion of racial and ethnic minority patients enrolled in NCTN and NCI Community Oncology Research Program clinical trials has nearly doubled from 14% in 1999 to 25% in 2019,” Mooney said. “Newer efforts to increase diversity in clinical trials include a focus on broadening eligibility in NCI-funded clinical trials based on the ASCO and Friends of Cancer Research eligibility criteria guidelines and the recently released request for research proposals under the CUSP2CT program (Connecting Underrepresented Populations to Clinical Trials).
“CUSP2CT is a program that will implement and evaluate multi-level and culturally tailored outreach and education interventions with the primary goal of increasing referral and ultimately, accrual of underrepresented racial/ethnic minority populations, to NCI-supported clinical trials.”
In a 2020 SWOG study, published in JAMA Network Open, on whether positive treatment effects in phase III cancer clinical trials apply to specific demographic or insurance subgroups, Unger found that patients with Medicaid or no insurance may have smaller added benefits from experimental therapies compared with standard treatments in clinical trials. The study included 10,804 patients from 19 trials.
“What we found was that the treatment benefits [within trials] were not meaningfully discrepant by sex, by race, ethnicity, coded as minority in aggregate versus not minority,” Unger said. “They were somewhat less for patient individuals who are 65 or older than for younger individuals, but still quite large. Where there was a discrepancy was by type of insurance, as it turned out—it was basically individuals with Medicaid or no insurance were not benefiting in the same way as individuals with private insurance.
“I’ve written about this before, that really gets at the issue of whether individuals with reduced access to financial medical resources, because of issues of income or wealth, regardless of race or ethnicity, suffer disproportionately worse outcomes compared to those who have better access to those resources.”
Another Unger study from March 2021, published in the Journal of Clinical Oncology, found that socioeconomic deprivation was associated with worse survival in patients with cancer with access to protocol-directed care in phase III and large phase II SWOG clinical trials—encompassing 41,105 patients from 55 trials. Compared with trial participants in the most affluent areas, trial participants from areas with the highest socioeconomic deprivation had worse overall, progression-free, and cancer-specific survival. The results were similar after adjusting for insurance status, prognostic risk, and rural or urban residency.
When applying trial-based calculations to real-world data, an analysis of disparities in cancer mortality must also take into consideration the lack of insurance coverage as well as the financial toxicity of cancer therapy, Winn said.
The return to the American people of government-funded investment in better cancer care has been remarkably solid—a huge impact.Peter J. O’Dwyer
“Of those who have access to cutting-edge care, there is a larger number of people who don’t actually have access to either these trials or that kind of care—and they’re not gaining years, they’re losing here,” Winn said. “That’s not to say or take anything away from the SWOG trial, with what we do with the NCTN—which I absolutely believe in with my heart and soul—but just to put this out there for a reality check.
“The reality is, when you have to make a decision of whether you want your treatment or whether you have to take care of your family, these are decisions that clearly impact all cancer patients, but they certainly have a much more negative impact on communities of color and very rural communities.”
The study on NCTN trials underscores the need for universal access to oncology clinical trials, said John Stewart, director of LSU New Orleans – Louisiana Children’s Medical Center Cancer Center and professor of surgery at the LSU New Orleans School of Medicine.
“Fourteen million lives is significant. The population of patients considered in the [study] receive their cancer treatment at high-performing cancer treatment centers,” Stewart said to The Cancer Letter. “Unfortunately, the unequal playing field for centers that treat underserved patients with cancer results in poorer outcomes. Real-world factors include consideration of co-morbidities in the pool of potential patients. Many minority patients are excluded from clinical trials due to co-morbidities.”
Unger said he plans to address cancer disparities in the paper.
“To what extent might [the 14 million estimate] be attenuated if you make different assumptions about how often people actually get the recommended treatment?” Unger said. “It’s a translation from efficacy to effectiveness.
“There’s room for everyone to see benefits, those populations who have worse survival on average, because of issues of social determinants of health. I could conceivably see even more benefits simply because they’re starting off at a lower baseline.
“I have the privilege of analyzing these data and presenting this. It stands on the shoulders of thousands of investigators and hundreds of thousands of patients, and I am fully appreciative of that,” Unger said. “So, I try to consider what I’m putting out there from a fairly humble perspective, that it is the accumulated benefit of all of those contributions that go into this study.”