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The promise and peril of surrogate end points in cancer research

Nature Reviews Cancer volume 2, pages 19–27 (2002)Cite this article

Key Points

  • Intervention studies or prospective observational epidemiological investigations that use incident cancer as an end point are large, lengthy and costly. Similarly, therapeutic trials based on time to recurrence or mortality can require large numbers of patients and a long follow-up.

  • Therefore, studies with surrogate end points — biomarkers of preclinical carcinogenesis — are attractive because they are potentially smaller, shorter and considerably less costly than their counterparts with cancer end points.

  • Studies based on surrogate end points, however, are inherently less reliable than studies with the 'true' end point (for example, incident cancer, cancer recurrence or mortality). It is important to know when the use of surrogate end points is appropriate and when it is not.

  • A key issue is whether the test of an association between an exposure (or treatment) and a surrogate end point will reliably indicate whether there is an association between the exposure (treatment) and cancer. Three statistical conditions are needed to establish this: first, the surrogate end point is associated with cancer; second, the exposure (treatment) is associated with the surrogate end point; and third, the surrogate end point 'mediates' the association between exposure (treatment) and cancer. Causal pathway diagrams are useful in understanding these conditions.

  • A second important issue is whether the magnitude of the association between exposure (treatment) and the surrogate end point predicts the magnitude of the association between exposure (treatment) and cancer. A promising approach to this problem relies on the meta-analysis of a series of studies in which exposure (treatment), surrogate end points and cancer are measured concurrently.

  • Even a strong surrogate end point, such as colorectal adenomatous polyps, might not yield definitive results for colorectal cancer.

  • Nevertheless, there are settings, such as preliminary evaluations of potential therapeutic agents or exploratory investigations of aetiological factors, in which data based on surrogate end points could pave the way for subsequent definitive studies.

Abstract

Both experimental and observational studies of cancer need to have an end point. Traditionally, in aetiological and prevention studies, that end point has been the incidence of cancer itself, whereas in therapeutic trials, the end point is usually time to cancer recurrence or death. But cancer takes a long time to develop in an individual and is rare in the population. Therefore, aetiological studies and prevention trials must be large and lengthy to be meaningful. Similarly, many therapeutic trials require a long follow-up of large numbers of patients. Surrogate end points — markers of preclinical cancer or of imminent recurrence — are therefore an attractive alternative. But how can we be sure that a study with a surrogate outcome gives us the right answer about the true end point?

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Figure 1: Relationships between surrogates and true end points.
Figure 2: Alternative pathways from normal colorectal mucosa to neoplasia (adenoma or cancer).
Figure 3: A limitation of colorectal adenoma recurrence as a surrogate for colorectal cancer.

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Author information

Authors and Affiliations

  1. Division of Cancer Epidemiology and Genetics, Nutritional Epidemiology Branch, National Cancer Institute, Bethesda, 20892-7232, Maryland, USA

    Arthur Schatzkin

  2. Division of Cancer Epidemiology and Genetics, Biostatistics Branch, National Cancer Institute, Bethesda, 20892-7244, Maryland, USA

    Mitchell Gail

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DATABASES

CancerNet:

breast cancer

cervical cancer

colorectal cancer

endometrial cancer

oesophageal cancer

ovarian cancer

prostatic cancer

 GenBank:

E6

E7

 LocusLink:

PCNA

PSA

RAS

RB

TP53

FURTHER INFORMATION

FDA Center for Drug Evaluation and Research — approval of drugs based on surrogate end points

NCI Biometric Research Branch

NCI Division of Cancer Epidemiology and Genetics

NCI Early Detection Research Network

Tutorials on randomized clinical studies from Beth Israel Deaconess Biometrics Center

Glossary

INTERVENTION STUDIES

Also known as clinical trials, these are clinical experiments in which the types of treatment and their allocation to study participants are under the control of the investigator. Usually the treatments are randomly allocated to study participants.

PROSPECTIVE OBSERVATIONAL STUDIES

Studies of well-defined groups (cohorts) of individuals for whom exposure data are available initially and for whom follow-up procedures are in place to determine if and when subsequent disease end points arise. The exposures and their allocations to cohort members are not controlled by the investigator.

PROLIFERATION INDICES

Measures of the rate of cell turnover or DNA synthesis derived from one of several proliferation bioassays that are currently available.

RELATIVE RISK

An epidemiological measure of treatment effect in an intervention study (clinical trial) or exposure association in a non-experimental observational study. The relative risk is the ratio of risk in an exposed (treated) group to the risk in an unexposed (control) group.

ATTRIBUTABLE PROPORTION

(AP). An epidemiological measure of the proportion of all disease cases that is attributable to exposure. The attributable proportion is 1.0 minus the ratio of risk in an unexposed population to the risk in the mixed population of exposed and unexposed individuals. In the context of surrogate markers of cancer, the AP can indicate the proportion of incident cancer that is attributable to marker positivity.

MULTIPLE REGRESSION

A statistical regression model with more than one independent variable.

STATISTICAL REGRESSION MODEL

A statistical approach to quantifying the relationship between an end point ('dependent variable') and other factors ('independent variables') such as treatments or exposures. Regression models are available for continuous, dichotomous, and survival end points.

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Schatzkin, A., Gail, M. The promise and peril of surrogate end points in cancer research. Nat Rev Cancer 2, 19–27 (2002). https://doi.org/10.1038/nrc702

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