Surrogate Endpoints in Cancer Clinical Trials

  • Stephen L. George
Part of the The IMA Volumes in Mathematics and its Applications book series (IMA, volume 116)


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 [1]. 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.


Prostate Cancer Beta Carotene Surrogate Endpoint Cancer Clinical Trial Chemoprevention Trial 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    Parker, S.L., Tong, T., Bolden, S. and Wingo, P.A., Cancer statistics, CA, 46:5–27, 1996.Google Scholar
  2. [2]
    Ellenberg, S.S., Surrogate endpoints in clinical trials (editorial), British Medical Journal 302:63–64, 1991.CrossRefGoogle Scholar
  3. [3]
    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
  4. [4]
    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
  5. [5]
    De Gruttola, V., Fleming, T., Lin, D.Y. and Coombs, R., Perspective: validating surrogate markers — are we being naive?, J. Infect. Dis., 175:237–246, 1997.CrossRefGoogle Scholar
  6. [6]
    Mildvan, D., Landay, A., De Gruttola, V., Machado, S.G. and Kagan, J., An approach to the validation of markers for use in AIDS clinical trials, Clin. Infect. Dis., 24:764–774, 1997.CrossRefGoogle Scholar
  7. [7]
    Fleming, T.R., Surrogate markers in AIDS and cancer trials, Stat. Med., 13:1423–1435, 1994.CrossRefGoogle Scholar
  8. [8]
    Ellenberg, S.S., Surrogate endpoints [editorial], Br. J. Cancer, 68:457–459, 1993.CrossRefGoogle Scholar
  9. [9]
    Ellenberg, S.S. and Hamilton, J.M., Surrogate endpoints in clinical trials: Cancer., Stat. Med., 8:405–413, 1989.CrossRefGoogle Scholar
  10. [10]
    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
  11. [11]
    Prentice, R.L., Surrogate endpoints in clinical trials: definition and operational criteria, Stat. Med., 8:431–440, 1989.CrossRefGoogle Scholar
  12. [12]
    Anonymous, Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction, The Cardiac Arrhythmia Suppression Trial Ii Investigators, N. Engl J. Med., 327:227–233, 1992.CrossRefGoogle Scholar
  13. [13]
    Anonymous, Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction, The Cardia Arrhythmia Suppression Trial (CAST) Investigators, N. Engl J. Med., 321:406–412, 1989.CrossRefGoogle Scholar
  14. [14]
    Byar, D.P., Proceedings: The Veterans Administration Cooperative Urological Research Group’s studies of cancer of the prostate, Cancer, 32:1126–1130, 1973.CrossRefGoogle Scholar
  15. [15]
    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
  16. [16]
    Freedman, L.S., Graubard, B.I. and Schatzkin, A., Statistical validation of intermediate endpoints for chronic diseases, Stat. Med., 11:167–178, 1992.CrossRefGoogle Scholar
  17. [17]
    Schatzkin, A., Freedman, L.S. and Schiffman, M.H., Validation of intermediate end points in cancer research, J. Natl. Can. Inst., 82:1746–1752, 1990.CrossRefGoogle Scholar
  18. [18]
    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
  19. [19]
    Fleming, T.R., Prentice, R.L., Pepe, M.S. and Glidden, D., Surrogate and auxiliary endpoints in clinical trials, with potential applications in cancer and AIDS research, Stat. Med., 13:955–968, 1994.CrossRefGoogle Scholar
  20. [20]
    Meyskens, F.L., Jr., Biomarker intermediate endpoints and cancer prevention, [Review], Monogr. Natl. Cancer Inst., 177–181, 1992.Google Scholar
  21. [21]
    Szarka, C.E., Grana, G. and Engstrom, P.F., Chemoprevention of cancer, Curr. Probl. Cancer, 18:6–79, 1994.CrossRefGoogle Scholar
  22. [22]
    Bostwick, D.G. and Aquilina, J.W., Prostatic intraepithelial neoplasia (PIN) and other prostatic lesions as risk factors and surrogate endpoints for cancer chemoprevention trials, J. Cell Biochem. Suppl., 25:156–164, 1996.CrossRefGoogle Scholar
  23. [23]
    Grizzle, W.E., Myers, R.B. and Manne, U., The use of biomarker expression to characterize neoplastic process, Biotech. Histochem, 72:96–104, 1997.CrossRefGoogle Scholar
  24. [24]
    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
  25. [25]
    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
  26. [26]
    La, D.K. and Swenberg, J.A., DNA adducts: biological markers of exposure and potential applications to risk assessment, Mutat. Res., 365:129–146, 1996.CrossRefGoogle Scholar
  27. [27]
    Gohagan, J.K., Kramer, B.S. and Greenwald, P., Screening for prostate cancer [editorial], Am. J. Prev. Med., 10:245–246, 1994.Google Scholar
  28. [28]
    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
  29. [29]
    Feigl, P., Blumenstein, B., Thompson, I., et al., Design of the Prostate Cancer Prevention Trial (PCPT), Control. Clin. Trials, 16:150–163, 1995.CrossRefGoogle Scholar
  30. [30]
    Pitot, H.C., The tamoxifen controversy-clinical chemopreventive agent and experimental carcinogen, Proc. Soc. Exp. Biol. Med., 208:139–140, 1995.Google Scholar
  31. [31]
    Anonymous, The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers, The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group, N. Engl. J. Med., 330:1029–1035, 1994.CrossRefGoogle Scholar
  32. [32]
    Thornquist, M.D., Omenn, G.S., Goodman, G.E., et al., Statistical design and monitoring of the Carotene and Retinol Efficacy Trial (CARET), Control. Clin. Trials, 14:308–324, 1993.CrossRefGoogle Scholar
  33. [33]
    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
  34. [34]
    Fletcher, S.W., Black, W., Harris, R., Rimer, B.K. and Shapiro, S., Report of the International Workshop on Screening for Breast Cancer, J. Natl. Cancer Inst., 85:1644–1656, 1993.CrossRefGoogle Scholar
  35. [35]
    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
  36. [36]
    Fontana, R.S., Sanderson, D.R., Woolner, L.B., et al., Screening for lung cancer. A critique of the Mayo Lung Project, Cancer, 67:Suppl.:1155–1164, 1991.CrossRefGoogle Scholar
  37. [37]
    Strauss, G.M., Gleason, R.E. and Sugarbaker, D.J., Chest X-ray screening improves outcome in lung cancer. A reappraisal of randomized trials on lung cancer screening, Chest, 107:Suppl.:270S–279S, 1995.CrossRefGoogle Scholar
  38. [38]
    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
  39. [39]
    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
  40. [40]
    Schellhammer, P., Cockett, A., Boccon-Gibod, L., et al., Assessment of endpoints for clinical trials for localized prostate cancer, Urology, 49:27–38, 1997.CrossRefGoogle Scholar
  41. [41]
    Scher, H.I., Mazumdar, M. and Kelly, W.K., Clinical trials in relapsed prostate cancer: defining the target, J. Natl. Can. Inst., 88:1623–1634, 1996.CrossRefGoogle Scholar
  42. [42]
    Steineck, G., Kelly, W.K., Mazumdar, M., Vlamis, V., Schwartz, M. and Scher, H.I., Acid phosphatase: defining a role in androgen-independent prostate cancer, Urology, 47:719–726, 1996.CrossRefGoogle Scholar
  43. [43]
    Zietman, A.L., Dallow, K.C., Mcmanus, P.A., Heney, N.M. and Shipley, W.U., Time to second prostate-specific antigen failure is a surrogate endpoint for prostate cancer death in a prospective trial of therapy for localized disease, UROLOGY, 47:236–239, 1996.CrossRefGoogle Scholar
  44. [44]
    Dunn, J., Doxorubicin-induced cardiomyopathy, J. Pediatr Oncol Nurs, 11:152–160, 1994.CrossRefGoogle Scholar
  45. [45]
    De Forni, M. and Armand, J.P., Cardiotoxicity of chemotherapy, Curr Opin Oncol, 6:340–344, 1994.CrossRefGoogle Scholar
  46. [46]
    Lawley, P.D., Alkylation of DNA and its aftermath, Bioessays, 17:561–568, 1995.CrossRefGoogle Scholar
  47. [47]
    Wood, W.C., Budman, D.R., Korzun, A.H., et al., Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma, N.Engl.J. Med., 330:1253–1259, 1994.CrossRefGoogle Scholar
  48. [48]
    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
  49. [49]
    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
  50. [50]
    Buyse, M. and Piedbois, P., On the relationship between response to treatment and survival time, Stat. Med., 15:2797–2812, 1996.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Stephen L. George
    • 1
  1. 1.Division of BiometryDuke University Medical CenterDurhamUSA

Personalised recommendations