Clinical trials may not offer ‘best management’ for cancer care
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Key takeaways:
- Cancer trial participants and those receiving routine care did not have OS differences after accounting for trial quality or biases.
- Claims that trial participation produces “best management” may be harmful.
Patients participating in clinical trials for anticancer drugs do not gain a survival benefit compared with individuals who received routine care, according to study results published in JAMA.
Although trial participants had significantly improved OS when researchers performed a pooled analysis of all the studies evaluated, those benefits diminished when they focused solely on high-quality trials, or they adjusted for confounders or publication bias.
“Clinical trial participation in and of itself does not result in longer survival for cancer patients,” Renata Iskander, MSc, lead author and PhD student at McGill University in Montreal, told Healio. “Doctors should be realistic and draw on evidence when discussing the benefits of trial participation. They should emphasize the benefits to future patients, rather than the participants themselves. Our results are also reassuring for patients who are disappointed that they cannot participate in trials due to ineligibility or geography.”
Background and methodology
Randomized clinical trials inform the public about efficacy and safety of new therapies and can alter treatment landscapes. However, a belief exists that participation in trials can improve survival, Brooke E. Wilson, MBBS, MSc, FRACP, assistant professor at Queens University, and colleagues wrote in an accompanying editorial.
“The trial effect is composed of potential gains offered by the new treatment [ie, the treatment effect] and potential gains offered by virtue of participating in the trial itself [ie, the participation effect],” Wilson and colleagues said. “Gains due to treatment effect can only be realized by patients in an experimental group that proves to be superior to standard care, while participation effect can be experienced by participants in both groups.”
“Many medical societies and organizations [such as the National Comprehensive Caner Network] claim that a patient’s best option is to participate in a clinical trial,” Iskander added. “Many others, including physicians and patients, make decisions based on the idea that trial participation leads to better outcomes. We wanted to know how strong the evidence is to support these claims and beliefs.”
Iskander and colleagues used the PubMed and Embase databases to examine the issue.
They evaluated studies published between Jan. 1, 2000, and Aug. 31, 2022, that compared OS in trial participants and patients receiving routine care.
Researchers included 39 studies, which had 85 total comparisons, in their investigation.
Results
The analysis showed trial participants did have a superior OS when they included all the examined studies (HR = 0.76; 95% CI, 0.69-0.82).
However, when they separated trials based on their quality, which they based on “susceptibility to bias or confounding,” researchers wrote, they found no significant OS differences between participants and routine-care patients in high-quality trials and significant difference in low ones.
Researchers also found publication bias in two of their three examination methods.
“No statistically significant trial effect was observed for studies that accounted for comorbidities, histology, or race and ethnicity,” they wrote.
“Studies varied in how well they addressed biases and confounders,” Iskander explained. “Survival gains diminished to a null effect the more studies controlled for confounders or the more we controlled for bias. We approached this with an open mind, but our results were — broad strokes — consistent with what others observed in reviews in the early 2000s.”
Iskander noted future studies could investigate whether clinical trials could improve measures other than survival.
“We did not find evidence of participation effects for overall survival. However, this does not mean that trial participants will not experience other benefits by being in trials,” she said. “Future research should explore whether trial participation leads to improvements for patient-reported outcomes like quality of life.”
‘Pragmatic trial designs’
The results indicate the need for more “pragmatic trial designs,” Wilson and colleagues wrote.
They explained that trial participants tend to be younger, in better physical condition, have fewer comorbidities and have better socioeconomic status. These differences constitute an “efficacy-effectiveness gap.”
They noted how patients with colorectal cancer have a median OS of 3 years when in a clinical trial but 18 months in routine care.
“Pragmatic trial designs that address questions that matter most to patients and enroll patients that are more representative of the general population will provide greater access to [randomized clinical trials] for those who wish to participate, allow investigators to answer questions more quickly, and reduce the efficacy-effectiveness gap,” they wrote. “Trials should carefully consider the end points selected to ensure that, when possible, overall survival and quality of life are prioritized over putative surrogate measures.”
Change the narrative
The NCCN has a boxed statement on each page of its Clinical Practice Guidelines in Oncology that reads, “NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged,” David I. Shalowitz, MD, MSHP, director for health equity and community outreach at West Michigan Cancer Center, and Franklin G. Miller, PhD, professor of medical ethics in medicine at Weill Cornell Medical College, wrote in an accompanying viewpoint in JAMA.
They feel this needs to change.
Clinical trials undoubtedly have significant value, but they discussed a multitude of issues with the NCCN’s statement.
Trials can help future patients, but participants may not derive similar benefits. They may have worse quality of life or prognosis following the trial, or it could impact them in other ways, such as financially.
They also explained how “best management” could be seen as an insult to oncologists who may recommend a different treatment based on a multitude of factors, or to patients who can make informed decisions.
The phrase could also cause funding to shift from community care to the trial complex since it offers the “best management.”
“The best management for some patients with cancer may be participation in a clinical trial; however, it is problematic to claim that trials offer the best management for any patient with cancer,” Shalowitz and Franklin concluded. “Consideration of participation in research should be offered whenever appropriate with attention to potential therapeutic benefit, altruistic contribution to biomedical knowledge, and burdens and risks associated with enrollment. Management plans should always be selected through shared decision-making considering patients’ and caregivers’ circumstances, values and preferences.
“We therefore call on NCCN and other cancer-focused organizations to revise the narrative that clinical trials offer the best management for any patient with cancer.”
References:
- Iskander R, et al. JAMA. 2024;doi:10.1001/jama.2024.6281.
- Shalowitz DI, et al. JAMA. 2024;doi:10.1001/jama.2024.1235.
- Wilson BE, et al. JAMA. 2024;doi:10.1001/jama.2024.1281.
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