Surrogate Endpoints in Cancer Clinical Trials
Cancer is a major public health problem in the United States and worldwide. In the U.S. in 1996, an estimated 1,360,000 new cases of cancer were diagnosed, and an estimated 555,000 cancer patients died of their disease . The current estimated lifetime risk of developing an invasive cancer is one in three for woman and an amazing one in two for men. The disease “cancer” is a diverse set of diseases, with the common characteristics of invasion of normal tissues by cancer cells and the propensity of these cells to spread, or metastasize, beyond the site of origin. All cancers also share the potential to cause significant morbidity and death. However, the natural history, epidemiology, biology, prevention, detection, and treatment of cancer varies widely by the specific type of cancer. Among other things, these differences necessitate different approaches for each type of cancer in the design and analysis of cancer clinical trials.
Although the field with the largest literature and interest in surrogate endpoints is perhaps AIDS research [2–6], this topic has received increasing attention in recent years in cancer research as well [7–9]. The purpose of this paper is to discuss the role of surrogate endpoints in cancer clinical trials, including prevention, screening, and therapeutic trials. Examples of trials in prostate cancer, breast cancer, and lung cancer will be used to illustrate the key points.
KeywordsProstate Cancer Beta Carotene Surrogate Endpoint Cancer Clinical Trial Chemoprevention Trial
Unable to display preview. Download preview PDF.
- Parker, S.L., Tong, T., Bolden, S. and Wingo, P.A., Cancer statistics, CA, 46:5–27, 1996.Google Scholar
- Machado, S.G., Gail, M.H. and Ellenberg, S.S., On the use of laboratory markers as surrogates for clinical endpoints in the evaluation of treatment for HIV infection, Journal of AIDS, 3:1065–1073, 1990.Google Scholar
- Tsiatis, A.A., Dafni, U., Degruttola, V., Propert, K.J., Strawderman, R.L. and Wulfsohn, M., The relationship of CD4 counts over time to survival in patients with AIDS: Is CD4 a good surrogate marker? In: AIDS Epidemiology: Methodological Issues, edited by Jewell, N.P., Dietz, K. and Farewell, V.T. Boston: Birkhauser, 1992, 245–274.Google Scholar
- Temple, R.J., A regulatory authority’s opinion about surrogate endpoints, In: Clinical Measurement in Drug Evaluation, edited by Nimmo, W.S. and Tucker, G.T., New York: John Wiley & Sons, 1995, 3–22.Google Scholar
- Fleming, T.R. and Demets, D.L., Surrogate end points in clinical trials: are we being misled? Ann. Intern. Med., 125:605–613, 1996.Google Scholar
- Jewell, N.P. and Kalbfleisch, J.D., Marker models in survival analysis and applications to issues associated with AIDS. In: AIDS epidemiology: Methodological Issues, edited by Jewell, N.P., Dietz, K. and Farewell, V. Boston: Birkhauser, 1992, 211–230.Google Scholar
- Meyskens, F.L., Jr., Biomarker intermediate endpoints and cancer prevention, [Review], Monogr. Natl. Cancer Inst., 177–181, 1992.Google Scholar
- Kelloff, G.J., Hawk, E.T., Crowell, J.A., et al., Strategies for identification and clinical evaluation of promising chemopreventive agents, Oncology, 10:1471–1484, 1996.Google Scholar
- Kelloff, G.J., Boone, C.W., Crowell, J.A., et al., Risk biomarkers and current strategies for cancer chemoprevention, J. Cell Biochem. Suppl., 25:1–14, 1996.Google Scholar
- Gohagan, J.K., Kramer, B.S. and Greenwald, P., Screening for prostate cancer [editorial], Am. J. Prev. Med., 10:245–246, 1994.Google Scholar
- Bostwick, D.G., Burke, H.B., Wheeler, T.M., et al., The most promising surrogate endpoint biomarkers for screening candidate chemopreventive compounds for prostatic adenocarcinoma in short-term phase II clinical trials, J. Cell Biochem. Suppl., 19:283–289, 1994.Google Scholar
- Pitot, H.C., The tamoxifen controversy-clinical chemopreventive agent and experimental carcinogen, Proc. Soc. Exp. Biol. Med., 208:139–140, 1995.Google Scholar
- Gohagan, J.K., Prorok, P.C., Kramer, B.S. and Cornett, J.E., Prostate cancer screening in the prostate, lung, colorectal and ovarian cancer screening trial of the National Cancer Institute, J. Urol, 152:1905–1909, 1994.Google Scholar
- Harris, R. and Leininger, L., Clinical strategies for breast cancer screening: weighing and using the evidence, Ann. Intern. Med., 122:539–547, 1995.Google Scholar
- Carter, S.K., Clinical research and drug development of antivirals in HIV: an industry perspective, J. Acquir. Immune. Defic. Syndr. Hum. Retrovirol., 10:Suppl 2:S107–S113, 1995.Google Scholar
- Johnson, J.R. and Temple, R., Food and Drug Administration requirements for approval of new anticancer drugs, Cancer Treat. Rep., 69:1155–1159, 1985.Google Scholar
- Jacobs, C., Lyman, G., Velez-Garcia, E., et al., A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck, J Clin. Oncol, 10:257–263, 1992.Google Scholar
- Forastiere, A.A., Metch, B., Schuller, D.E., et al., Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study, J Clin.Oncol, 10:1245–1251, 1992.Google Scholar