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Cancer clinical trial participation was not associated with longer survival after accounting for biases and confounders, a systematic review and meta-analysis revealed.

At first, when all 39 studies that comprised 85 comparisons of trial participants and routine care patients were pooled, there was a statistically significant overall survival benefit for trial participants (HR 0.76, 95% CI 0.69-0.82), reported Jonathan Kimmelman, PhD, of McGill University in Montreal, and colleagues.

Survival benefits decreased in study subsets that matched trial participants and routine care patients for eligibility criteria (HR 0.85, 95% CI 0.75-0.97) and disappeared altogether when only high-quality studies were pooled (HR 0.91, 95% CI 0.80-1.05) and when estimates were adjusted for potential publication bias (HR 0.94, 95% CI 0.86-1.03), they wrote in .

"These findings may strike some trial advocates as discouraging, given how hard they work to improve patient outcomes within trials," noted Kimmelman and colleagues. "However, a more reassuring interpretation is that there is no evidence that excluding patients from trials due to geography, nonavailability of trials in their condition, or ineligibility deprives them of survival opportunities."

In an , Christopher M. Booth, MD, of Queen's University Cancer Research Institute in Kingston, Ontario, and colleagues wrote that "the fact that outcome differences disappear after adjusting for confounders suggests this observation is largely driven by what we already know -- patients enrolled in clinical trials are different from those in routine practice."

They pointed out that trial participants are usually younger, fitter, have fewer comorbidities, and tend to come from higher socioeconomic groups. "This enrollment bias largely explains the participation effect," they wrote. "The implications of this finding are important for understanding how trials are often viewed in clinical practice. The participation effect is often used to promote the view that 'a clinical trial is the best treatment option,' but this may be a false narrative."

While there are many reasons to participate in a clinical trial, this study "demonstrates that patient-oncologist decision-making should not be influenced by the notion that trial participation on its own affords benefit," Booth and colleagues argued.

In a accompanying the study, David I. Shalowitz, MD, MSHP, of the West Michigan Cancer Center in Kalamazoo, and Franklin G. Miller, PhD, of Weill Cornell Medical College in New York City, noted that the National Comprehensive Cancer Network (NCCN) guidelines feature a boxed statement at the beginning of each section 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."

Shalowitz and Miller suggested that this perspective on the benefits of clinical trial participation may be widespread in the oncology research community.

Kimmelman and colleagues said there are several factors that could account for this widespread perception that patients in clinical trials will achieve better outcomes -- including the fact that trial participants often experience better care processes, as well as the "efficacy-effectiveness gap," whereby trials often show survival outcomes exceeding those in clinical care.

"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," argued Shalowitz and Miller. "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."

"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," they concluded.

This systematic review and meta-analysis included 39 studies involving 85 comparisons of trial participants versus routine care patients from 2000 through 2022. These comparisons involved hematologic (21%), breast (16%), lung (14%), central nervous system (7%), prostate (7%), and pancreatic cancers (5%), as well as melanoma (6%), with bladder, cervical, colorectal, esophageal, gastric, head and neck, kidney, ovarian, and solid mix tumors making up the remaining 24%. One-third involved patients with advanced/metastatic disease.

The authors identified 16 factors associated with confounding or bias, including differences between trial participants and routine care patients in cancer treatment, eligibility criteria, time frame, demographics (age, sex, race, and ethnicity), and medical history (comorbidities, cancer stage, histology, performance status, and line of treatment).

From these factors, Kimmelman and colleagues created a 16-point scoring scale, ranging from the lowest (≤6 points) to the highest (≥8 points) quality levels.

The median sample sizes for the trial participant and routine care patient groups were 209 and 409 patients.

The authors acknowledged several limitations to the study. For example, they said many of the studies in the review were missing data or had unclear information leading to exclusions or difficulty in interpreting studies, and that incomplete descriptions on how participants and routine care patients were matched meant that it was also difficult to determine how well quality factors were implemented.