Does Cancer Screening Actually Extend Lives?

A series of articles published in JAMA Internal Medicine have taken on the question of whether cancer screening actually saves lives.

A systematic review and meta-analysis involving more than 2 million patients showed that with the possible exception of colorectal cancer screening with sigmoidoscopy, the "current evidence does not substantiate the claim that common cancer screening tests save lives by extending lifetime," reported Michael Bretthauer, MD, PhD, of the University of Oslo in Norway, and colleagues.

Their study, which included 18 long-term randomized clinical trials, indicated that sigmoidoscopy was the only screening test with a significant lifetime gain (110 days, 95% CI 0-274).

There was no significant difference following:

• Mammography (0 days, 95% CI -190 to 237)
• Prostate-specific antigen (PSA) testing for prostate cancer (37 days, 95% CI -37 to 73)
• Colonoscopy (37 days, 95% CI -146 to 146)
• Fecal occult blood testing (FOBT) every year or every other year (0 days, 95% CI -70.7 to 70.7)
• CT lung cancer screening (107 days, 95% CI -286 days to 430)

The reported relative risks of all-cause mortality for screening versus no screening were 0.98 (95% CI 0.95-1.00) for sigmoidoscopy, 0.99 (95% CI 0.96-1.04) for colonoscopy, 1.00 (95% CI 0.98-1.03) for FOBT every year, 1.00 (95% CI 0.95-1.04) for mammography, 0.99 (95% CI 0.98-1.01) for PSA testing, and 0.97 (95% CI 0.88-1.08) for CT lung cancer screening.

"Organizations, institutions, and policymakers who promote cancer screening tests by their effect to save lives may find other ways of encouraging screening," Bretthauer and team wrote. "It might be wise to reconsider priorities and dispassionately inform interested people about the absolute benefits, harms, and burden of screening tests that they consider undertaking. Our estimates may serve that purpose."

The systematic review and meta-analysis included four randomized clinical trials on sigmoidoscopy screening, four on fecal testing for colorectal cancer, four on PSA screening for prostate cancer, three on CT lung cancer screening for current and former smokers, two on mammography for breast cancer, and one on colonoscopy for colorectal cancer.

Bretthauer and colleagues noted that while they may not have observed longer lives with five of the six screening tests, that does not mean that some individuals don't prolong their lives with screening.

"Without screening, these patients may have died of cancer because it would have been detected at a later, incurable stage," they wrote. "Thus, these patients experience a gain in lifetime."

However, they added that other individuals experience a lifetime loss due to the harms associated with screening or treatments from screening-detected cancers, such as colon perforation during colonoscopy or myocardial infarction following radical prostatectomy.

In a simultaneously published Viewpoint article, Bretthauer and two colleagues suggested that despite concerns about overdiagnosis and harms of screening, it is "difficult, or indeed impossible" to phase screening programs out, "even when research has failed to document significant benefits," and discussions about the balance of harms and benefits associated with screening "have become a threat to powerful stakeholders."

"Cancer screening guidelines are often developed by screening professionals, screening organizations, and patient representatives, with their vested interests," they pointed out. "We propose that screening guidelines should not allow individuals or organizations with clinical, financial, or intellectual interests in leading roles of guideline development. This would improve quality and trustworthiness of recommendations."

"Healthcare representatives and experts must be honest, transparent, and dispassionate about the benefits and harms of screening, expressed in a way that allows real shared decision-making," they stressed.

Multicancer Early Detection and Saving Lives

Researchers also looked at multicancer early detection (MCED) blood testing and its role in cancer screening.

In a special communication accompanying the study by Bretthauer and colleagues, H. Gilbert Welch, MD, MPH, and Tanujit Dey, PhD, both of Brigham and Women's Hospital in Boston, said the question of whether cancer screening saves lives has become increasingly relevant with "increasing enthusiasm" for MCED blood tests.

This raises several challenges, they noted, one of which is what "saves lives" means.

"It is possible in randomized clinical trials for screening to reduce deaths due to the targeted cancer without reducing deaths due to all causes," they wrote, arguing that the important metric is all-cause mortality, rather than cancer-specific mortality.

They suggested that while it is not feasible to determine all-cause mortality when screening for an individual cancer because of the large sample size requirements, it can be done with multicancer screening "because cancer deaths are such a large component of deaths in general."

Welch, along with David J. Carr, MD, of Wayne State University School of Medicine in Detroit, also addressed the issue of the clinical utility of liquid biopsies for five indications, noting that it must be proven considering this testing will "add cost, complexity, and unintended adverse effects for patients."

While the idea of using it is appealing, since it would be a single test that could detect many types of cancer, and could simplify and standardize cancer screening, the low sensitivity of multicancer screening tests for early-stage tumors "raises questions as to whether screening can help patients live longer or live better," they wrote.

Furthermore, considering the current cost of Galleri -- an MCED test that is being evaluated in a randomized trial in the U.K. -- is $949 per person, it would cost about $100 billion a year, or about 10 times the 2023 budget for the CDC, if it was given annually to every U.S. resident over the age of 50.

"Clearly, this cost warrants a rigorous demonstration of benefit -- that patients are living longer or living better -- in a randomized clinical trial," Welch and Carr wrote.

Moreover, they pointed out that one of the quandaries of screening is that while only a few benefit, "all can be potentially harmed."

"The critical question is whether the benefits for the few are sufficiently large to warrant the associated harms for the many," they asserted. "To address this question, randomized clinical trials of MCED testing must not only measure the effect of screening on death, but also provide a full accounting of its harms."

Finally, in an editorial accompanying the review, Rita F. Redberg, MD, MSc, of the University of California San Francisco, and colleagues agreed that potential harms and costs to individuals, and society as a whole, warrant a long and large randomized trial evaluating the effect of MCED screening on all-cause mortality in order to "avoid rushing a dangerous blood test to market."

"Such a study unfortunately never occurs after marketing approval," they wrote. "Although the potential for early cancer detection may have broad appeal, we need actual evidence from [randomized clinical trials] that screening reduces all-cause mortality with acceptable levels of harm before MCED tests are approved, covered, or adopted into clinical practice."