Hostname: page-component-78c5997874-v9fdk Total loading time: 0 Render date: 2024-11-14T01:29:04.943Z Has data issue: false hasContentIssue false
  • English
  • Français

Progression-free survival as a surrogate endpoint in advanced breast cancer

Published online by Cambridge University Press:  01 October 2008

Rebecca A. Miksad ,
Vera Zietemann ,
Raffaella Gothe ,
Ruth Schwarzer ,
Annette Conrads-Frank ,
Petra Schnell-Inderst ,
Björn Stollenwerk  and
Uwe Siebert
Rebecca A. Miksad
Affiliation:
Harvard Medical School
Vera Zietemann
Affiliation:
UMIT—University for Health Sciences, Medical Informatics and Technology
Raffaella Gothe
Affiliation:
UMIT—University for Health Sciences, Medical Informatics and Technology
Ruth Schwarzer
Affiliation:
UMIT—University for Health Sciences, Medical Informatics and Technology
Annette Conrads-Frank
Affiliation:
UMIT—University for Health Sciences, Medical Informatics and Technology
Petra Schnell-Inderst
Affiliation:
UMIT—University for Health Sciences, Medical Informatics and Technology
Björn Stollenwerk
Affiliation:
UMIT—University for Health Sciences, Medical Informatics and Technology
Uwe Siebert
Affiliation:
UMIT—University for Health Sciences, Medical Informatics and Technology and Harvard Medical School
Get access Rights & Permissions [Opens in a new window]

Abstract

Objectives: Progression-free survival (PFS) has not been validated as a surrogate endpoint for overall survival (OS) for anthracycline (A) and taxane-based (T) chemotherapy in advanced breast cancer (ABC). Using trial-level, meta-analytic approaches, we evaluated PFS as a surrogate endpoint.

Methods: A literature review identified randomized, controlled A and T trials for ABC. Progression-based endpoints were classified by prospective definitions. Treatment effects were derived as hazard ratios for PFS (HRPFS) and OS (HROS). Kappa statistic assessed overall agreement. A fixed-effects regression model was used to predict HROS from observed HRPFS. Cross-validation was performed. Sensitivity and subgroup analyses were performed for PFS definition, year of last patient recruitment, line of treatment, and constant rate assumption.

Results: Sixteen A and fifteen T trials met inclusion criteria, producing seventeen A (n = 4,323) and seventeen T (n = 5,893) trial-arm pairs. Agreement (kappa statistic) between the direction of HROS and HRPFS was 0.71 for A (p = .0029) and 0.75 for T (p = .0028). While HRPFS was a statistically significant predictor of HROS for both A (p = .0019) and T (p = .012), the explained variances were 0.49 (A) and 0.35 (T). In cross-validation, 97 percent of the 95 percent prediction intervals crossed the equivalence line, and the direction of predicted HROS agreed with observed HROS in 82 percent (A) and 76 percent (T). Results were robust in sensitivity and subgroup analyses.

Conclusions: This meta-analysis suggests that the trial-level treatment effect on PFS is significantly associated with the trial-level treatment effect on OS. However, prediction of OS based on PFS is surrounded with uncertainty.

Keywords

Progression-free survivalSurrogate endpointMeta-analytic validationAdvanced breast cancerOverall survival
Type
GENERAL ESSAYS
Information
International Journal of Technology Assessment in Health Care , Volume 24 , Issue 4 , October 2008 , pp. 371 - 383
Copyright
Copyright © Cambridge University Press 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

1. A'Hern, RP, Ebbs, SR, Baum, MB. Does chemotherapy improve survival in advanced breast cancer? A statistical overview. Br J Cancer. 1988;57:615–618.CrossRefGoogle ScholarPubMed
2. Ackland, SP, Anton, A, Breitbach, GP, et al. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: A randomized multinational study. J Clin Oncol. 2001;19:943–953.CrossRefGoogle Scholar
3. Aisner, J, Cirrincione, C, Perloff, M, et al. Combination chemotherapy for metastatic or recurrent carcinoma of the breast—A randomized phase III trial comparing CAF versus VATH versus VATH alternating with CMFVP: Cancer and Leukemia Group B Study 8281. J Clin Oncol.1995;13:1443–52.CrossRefGoogle ScholarPubMed
4. Altman, DG. Practical statistics for medical research. 1st ed. New York: Chapman and Hall; 1991.Google Scholar
5. Armitage, P, Berry, G, Matthews, JNS. Statistical methods in medical research. 4th ed. Malden, MA: Blackwell Science; 2001.Google Scholar
6. Baker, SG, Kramer, BS. A perfect correlate does not a surrogate make. BMC Med Res Methodol. 2003;3:16.CrossRefGoogle ScholarPubMed
7. Baker, SG. Surrogate endpoints: Wishful thinking or reality? J Natl Cancer Inst. 2006;98:502–503.CrossRefGoogle ScholarPubMed
8. Bennett, JM, Muss, HB, Doroshow, JH, et al. A randomized multicenter trial comparing mitoxantrone, cyclophosphamide, and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast carcinoma. J Clin Oncol. 1988;6:1611–1620.CrossRefGoogle ScholarPubMed
9. Biganzoli, L, Cufer, T, Bruning, P, et al. Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial. J Clin Oncol. 2002;20:3114–3121.CrossRefGoogle ScholarPubMed
10. Bishop, JF, Dewar, J, Toner, GC, et al. Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncol. 1999;17:2355–2364.CrossRefGoogle ScholarPubMed
11. Boccardo, F, Rubagotti, A, Rosso, R, Santi, L. Chemotherapy with or without tamoxifen in postmenopausal patients with late breast cancer. A randomized study. J Steroid Biochem. 1985;23:1123–1127.CrossRefGoogle ScholarPubMed
12. Burzykowski, T, Molenberghs, G, Buyse, M. The validation of surrogate end points by using data from randomized clinical trials: A case-study in advanced colorectal cancer. J R Stat Soc Ser A Stat Soc. 2004;167:103–124.CrossRefGoogle Scholar
13. Burzykowski, T, Piccart, MJ, Sledge, G, et al. A quantitative study of tumor response and progression-free survival as surrogate endpoints for overall survival in first-line treatment of metastatic breast cancer. 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas, United States, 2005. Abstract 6084.Google Scholar
14. Burzykowski, T, Buyse, M, Piccart-Gebhart, MJ, et al. Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol. 2008;26:1987–1992.CrossRefGoogle ScholarPubMed
15. Buyse, M, Molenberghs, G. Criteria for the validation of surrogate endpoints in randomized experiments. Biometrics. 1998;54:1014–1029.CrossRefGoogle ScholarPubMed
16. Chan, S, Friedrichs, K, Noel, D, et al. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999;17:2341–2354.CrossRefGoogle ScholarPubMed
17. Conte, PF, Pronzato, P, Rubagotti, A, et al. Conventional versus cytokinetic polychemotherapy with estrogenic recruitment in metastatic breast cancer: Results of a randomized cooperative trial. J Clin Oncol. 1987;5:339–347.CrossRefGoogle ScholarPubMed
18. Conte, PF, Baldini, E, Gardin, G, et al. Chemotherapy with or without estrogenic recruitment in metastatic breast cancer. A randomized trial of the Gruppo Oncologico Nord Ovest (GONO). Ann Oncol. 1996;7:487–490.CrossRefGoogle ScholarPubMed
19. De Gruttola, V, Fleming, T, Lin, DY, Coombs, R. Perspective: Validating surrogate markers–are we being naive? J Infect Dis. 1997;175:237–246.CrossRefGoogle ScholarPubMed
20. De Gruttola, VG, Clax, P, DeMets, DL, et al. Considerations in the evaluation of surrogate endpoints in clinical trials. Summary of a National Institutes of Health workshop. Control Clin Trials. 2001;22:485–502.CrossRefGoogle ScholarPubMed
21. Del Mastro, L, Venturini, M, Lionetto, R, et al. Accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with standard CEF in metastatic breast cancer patients: Results of a multicenter, randomized phase III study of the Italian Gruppo Oncologico Nord-Ouest-Mammella Inter Gruppo Group. J Clin Oncol. 2001;19:2213–2221.CrossRefGoogle ScholarPubMed
22. Di Leo, A, Bleiberg, H, Buyse, M. Overall survival is not a realistic end point for clinical trials of new drugs in advanced solid tumors: A critical assessment based on recently reported phase III trials in colorectal and breast cancer. J Clin Oncol. 2003;21:2045–2047.CrossRefGoogle Scholar
23. Efron, B. Estimating the error rate of a prediction rule: Improvement on cross-validation. J Am Stat Assoc. 1983;78:316–331.CrossRefGoogle Scholar
24. Ejlertsen, B, Pfeiffer, P, Pedersen, D, et al. Decreased efficacy of cyclophosphamide, epirubicin and 5-fluorouracil in metastatic breast cancer when reducing treatment duration from 18 to 6 months. Eur J Cancer. 1993;29A:527–531.CrossRefGoogle ScholarPubMed
25. European Medicines Agency. Appendix 1 to the guidelines on the evaluation of anticancer medicinal products in man: Methodological considerations for using Progression Free Survival (PFS) as primary endpoint in confirmatory trials for registration [Draft]. www.emea.europa.eu/pdfs/human/ewp/26757506en.pdf. December 2006.Google Scholar
26. Fleming, TR, DeMets, DL. Surrogate end points in clinical trials: Are we being misled? Ann Intern Med. 1996;125:605–613.CrossRefGoogle ScholarPubMed
27. Fleming, TR. Surrogate endpoints and FDA's accelerated approval process. Health Aff (Millwood). 2005;24:67–78.CrossRefGoogle ScholarPubMed
28. Gelber, RD, Goldhirsch, A. A new endpoint for the assessment of adjuvant therapy in postmenopausal women with operable breast cancer. J Clin Oncol. 1986;4:1772–1779.CrossRefGoogle ScholarPubMed
29. Gelber, RD, Gelber, S. Quality-of-life assessment in clinical trials. Cancer Treat Res. 1995;75:225–246.CrossRefGoogle ScholarPubMed
30. Gennari, A, Conte, P, Rosso, R, et al. Survival of metastatic breast carcinoma patients over a 20-year period: A retrospective analysis based on individual patient data from six consecutive studies. Cancer. 2005;104:1742–1750.CrossRefGoogle Scholar
31. Gennari, A, Amadori, D, De Lena, M, et al. Lack of benefit of maintenance paclitaxel in first-line chemotherapy in metastatic breast cancer. J Clin Oncol. 2006;24:3912–3918.CrossRefGoogle ScholarPubMed
32. Ghersi, D, Wilcken, N, Simes, RJ. A systematic review of taxane-containing regimens for metastatic breast cancer. Br J Cancer. 2005;93:293–301.CrossRefGoogle ScholarPubMed
33. Hackshaw, A, Knight, A, Barrett-Lee, P, Leonard, R. Surrogate markers and survival in women receiving first-line combination anthracycline chemotherapy for advanced breast cancer. Br J Cancer. 2005;93:1215–1221.CrossRefGoogle ScholarPubMed
34. Jassem, J, Pienkowski, T, Pluzanska, A, et al. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: Final results of a randomized phase III multicenter trial. J Clin Oncol. 2001;19:1707–1715.CrossRefGoogle ScholarPubMed
35. Jassem, J, Pluzanska, A, Pienkowski, T, et al. Randomized phase III multicenter trial of doxorubicin and paclitaxel (AT) versus fluorouracil-doxorubicin-cyclophosphamide (FAC) as first-line therapy metastatic breast cancer (MBC): Long-term efficacy and external review of results. San Antonio Breast Cancer Symposium. San Antonio, Texas, USA, 2004. Abstract 5043.Google Scholar
36. Jones, SE, Erban, J, Overmoyer, B, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer [see comment]. J Clin Oncol. 2005;23:5542–5551.CrossRefGoogle ScholarPubMed
37. Landis, JR, Koch, GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–174.CrossRefGoogle ScholarPubMed
38. Langley, RE, Carmichael, J, Jones, AL, et al. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005;23:8322–8330.CrossRefGoogle ScholarPubMed
39. Miller, K, Wang, M, Gralow, J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–2676.CrossRefGoogle ScholarPubMed
40. Moher, D, Schulz, KF, Altman, D. The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA. 2001;285:1987–1991.CrossRefGoogle Scholar
41. Molenberghs, G, Burzykowski, T, Alonso, A, Buyse, M. A perspective on surrogate endpoints in controlled clinical trials. Stat Methods Med Res. 2004;13:177–206.CrossRefGoogle ScholarPubMed
42. Molenberghs, G, Buyse, ME, Burzykowski, T. The history of surrogate endpoint validation. In: Molenberghs, G, Buyse, ME, Burzykowski, T, eds. Statistics for biology and health: The evaluation of surrogate endpoints. New York: Springer; 2005:67–82.CrossRefGoogle Scholar
43. Nabholtz, JM, Gelmon, K, Bontenbal, M, et al. Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer [see comment]. J Clin Oncol. 1996;14:1858–1867.CrossRefGoogle ScholarPubMed
44. Nabholtz, JM, Senn, HJ, Bezwoda, WR, et al. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group. J Clin Oncol. 1999;17:1413–1424.CrossRefGoogle ScholarPubMed
45. Namer, M, Soler-Michel, P, Turpin, F, et al. Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer. Eur J Cancer. 2001;37:1132–1140.CrossRefGoogle ScholarPubMed
46. Niimi, M, Yamamoto, S, Fukuda, H, et al. The Influence of handling censored data on estimating progression-free survival in cancer clinical trials (JCOG9913-A). Jpn J Clin Oncol. 2002;32:19–26.CrossRefGoogle ScholarPubMed
47. Panageas, KS, Ben-Porat, L, Dickler, MN, et al. When you look matters: The effect of assessment schedule on progression-free survival. J Natl Cancer Inst. 2007;99:428–432.CrossRefGoogle ScholarPubMed
48. Paridaens, R, Biganzoli, L, Bruning, P, et al. Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: A European Organization for Research and Treatment of Cancer Randomized Study with cross-over. J Clin Oncol. 2000;18:724–733.CrossRefGoogle ScholarPubMed
49. Parmar, MK, Torri, V, Stewart, L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17:2815–2834.3.0.CO;2-8>CrossRefGoogle ScholarPubMed
50. Parnes, HL, Cirrincione, C, Aisner, J, et al. Phase III study of cyclophosphamide, doxorubicin, and fluorouracil (CAF) plus leucovorin versus CAF for metastatic breast cancer: Cancer and Leukemia Group B 9140. J Clin Oncol. 2003;21:1819–1824.CrossRefGoogle ScholarPubMed
51. Perry, MC, Kardinal, CG, Korzun, AH, et al. Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. J Clin Oncol. 1987;5:1534–1545.CrossRefGoogle Scholar
52. Pierga, JY, Jouve, M, Asselain, B, et al. Randomized trial comparing two different modalities of administration of the same cytotoxic drugs in metastatic breast cancer. J Infus Chemother. 1995;5:197–200.Google ScholarPubMed
53. Pierga, JY, Jouve, M, Asselain, B, et al. Randomized trial comparing protracted infusion of 5-fluorouracil with weekly doxorubicin and cyclophosphamide with a monthly bolus FAC regimen in metastatic breast carcinoma (SPM90). Br J Cancer. 1998;77:1474–1479.CrossRefGoogle ScholarPubMed
54. Sargent, DJ, Wieand, HS, Haller, DG, et al. Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: Individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2005;23:8664–8670.CrossRefGoogle Scholar
55. Sargent, DJ, Patiyil, S, Yothers, G, et al. End points for colon cancer adjuvant trials: Observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol. 2007;25:4569–4574.CrossRefGoogle Scholar
56. Sargent, DJ, Hayes, DF. Assessing the measure of a new drug: Is survival the only thing that matters? J Clin Oncol. 2008;26:1922–1923.CrossRefGoogle ScholarPubMed
57. Sjostrom, J, Blomqvist, C, Mouridsen, H, et al. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: A randomised phase III study with crossover on progression by the Scandinavian Breast Group. Eur J Cancer. 1999;35:1194–1201.CrossRefGoogle ScholarPubMed
58. Sledge, GW, Neuberg, D, Bernardo, P, et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: An intergroup trial (E1193). J Clin Oncol. 2003;21:588–592.CrossRefGoogle ScholarPubMed
59. Sledge, GW Jr, Hu, P, Falkson, G, et al. Comparison of chemotherapy with chemohormonal therapy as first-line therapy for metastatic, hormone-sensitive breast cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol. 2000;18:262–266.CrossRefGoogle ScholarPubMed
60. Smith, RE, Brown, AM, Mamounas, EP, et al. Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26. J Clin Oncol. 1999;17:3403–3411.CrossRefGoogle ScholarPubMed
61. Speyer, JL, Green, MD, Zeleniuch-Jacquotte, A, et al. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol. 1992;10:117–127.CrossRefGoogle ScholarPubMed
62. Tang, PA, Bentzen, SM, Chen, EX, Siu, LL. Surrogate end points for median overall survival in metastatic colorectal cancer: literature-based analysis from 39 randomized controlled trials of first-line chemotherapy. J Clin Oncol. 2007;25:4562–4568.CrossRefGoogle ScholarPubMed
63. Trotti, A, Colevas, AD, Setser, A, et al. CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol. 2003;13:176–181.CrossRefGoogle ScholarPubMed
64. V. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) & Center for Biologics Evaluation and Research (CBER). Oncologic Drugs Advisory Committee Meeting December 16, 2003.Google Scholar
65. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) & Center for Biologics Evaluation and Research (CBER). Guidance for Industry. Clinical trial endpoints for the approval of cancer drugs and biologics. [Draft Guidance]. 2005:1–26.Google Scholar
66. Winer, EP, Berry, DA, Woolf, S, et al. Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and leukemia group B trial 9342. J Clin Oncol. 2004;22:2061–2068.CrossRefGoogle Scholar
67. Yu, RX, Holmgren, E. Endpoints for agents that slow tumor growth. Contemp Clin Trials. 2007;28:18–24.CrossRefGoogle ScholarPubMed
68. Zielinski, C, Beslija, S, Mrsic-Krmpotic, Z, et al. Gemcitabine, epirubicin, and paclitaxel versus fluorouracil, epirubicin, and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: A Central European Cooperative Oncology Group International, multicenter, prospective, randomized phase III trial. J Clin Oncol. 2005;23:1401–1408.CrossRefGoogle Scholar