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SAN DIEGO -- While using an endpoint of late-stage cancer incidence may be a suitable alternative to cancer-specific mortality for some cancers in screening trials, it doesn't work for others, researchers said here.

A systematic review and meta-analysis of randomized cancer screening trials showed that the correlation between the reduction in stage III and IV cancers and the reduction in cancer-specific mortality varied by cancer type, with that correlation strongest for ovarian and lung cancers, reported Hilary A. Robbins, PhD, MHS, of the International Agency for Research on Cancer in Lyon, France, during a session at the American Association for Cancer Research annual meeting.

The results of the study, which were published simultaneously in , have implications for trials of multi-cancer early detection tests -- may use the incidence of late-stage cancer as a primary endpoint, she noted.

One question Robbins and her colleagues asked is whether the ability of multi-cancer tests to reduce late-stage cancer incidence could be used to draw conclusions about their ability to reduce cancer deaths.

"Unfortunately, the answer is probably not," she said. "Because here we were able to study five different cancer types for which we've screened for in the past, and we learned something about how these two endpoints relate to each other. Multi-cancer tests, depending on the test, are detecting many other kinds of cancers for which we cannot examine this relationship, and we don't know what it is."

Robbins and her team pointed out that among the five cancer types evaluated, the correlation and degree of correspondence between reductions in incidence of stage III-IV cancers and cancer mortality were heterogeneous. "Thus, extrapolating from screening effects on late-stage cancer to screening effects on cancer mortality for the various cancer types targeted by multi-cancer early detection tests is likely to be invalid," they wrote.

In an , Peter B. Bach, MD, of DELFI Diagnostics in Baltimore, noted that while late-stage cancer incidence has not been validated as an acceptable alternative outcome to cancer-related mortality, using it as an endpoint would have the potential advantage of shortening the duration of a clinical trial evaluating cancer screening tests because late-stage cancer occurs before death from cancer.

However, this study "showed that cancer-related mortality remains the most appropriate endpoint for clinical evaluation of the new blood-based tests that aim to detect many cancers for which there is no evidence that screening is beneficial," Bach wrote. "Studies might take a little longer, but will yield a more reliable answer."

For their analysis, Robbins and colleagues included 41 randomized clinical trials of cancer screening conducted in Europe, North America, and Asia published through Feb. 19, 2024. Their inclusion criteria required that these studies reported the numbers of cancer-specific deaths and numbers of cancer cases by stage that could be categorized as stage III-IV as opposed to stage I-II.

For each clinical trial, they calculated the effect of screening as the percentage reduction between the intervention and comparison groups in the incidence of cancer-specific mortality and stage III-IV cancers.

They found that the correlation between reductions in cancer-specific mortality and stage III-IV cancers varied by cancer type, and that correlation was:

• Highest for trials that screened for ovarian (Pearson P=0.99) and lung (Pearson P=0.92) cancers
• Moderate for breast cancer (Pearson P=0.70)
• Weak for colorectal (Pearson P=0.39) and prostate (Pearson P = -0.69) cancers

Slopes from linear regression were estimated as 1.15 for ovarian cancer, 0.75 for lung cancer, 0.40 for colorectal cancer, 0.28 for breast cancer, and -3.58 for prostate cancer.

"So there is heterogeneity among cancer types and how these two different endpoints relate to each other," Robbins explained. "There is heterogeneity in the correlation (P=0.02) and the tightness of the relationship, and, in particular, there is heterogeneity in the linear slopes (P=0.004). So for a given size of reduction in late-stage cancer, we expect different sizes of reductions in cancer-specific mortality, depending on which cancer type we are talking about."

Furthermore, Robbins and her team reported that of 13 trials that showed a reduction in stage III-IV cancers, 62% showed no effect on cancer mortality, while nine trials that showed a reduction in cancer mortality, showed no effect on incidence of stage III-IV cancers.

As for the study's limitations, Robbins and colleagues acknowledged that the sample size for each cancer type was small because their analysis was limited to clinical trials that met their inclusion criteria, and their results might have been different if more trials had been available for analysis.