Originally published as JCO Early Release 10.1200/JCO.2005.02.106 on June 13 2005

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Objective Response to Chemotherapy As a Potential Surrogate End Point of Survival in Metastatic Breast Cancer Patients

From the Units of Clinical Epidemiology and Medical Oncology, National Institute for Cancer Research, Genoa; Department of Medical Oncology, University and Istituto di Ricovero e Cura a Carattere Scientifico San Matteo, Pavia, Italy; Department of Oncology, Odense University Hospital, Odense, Denmark; Department of Oncology, CHC Clinique Saint Joseph, Liege, Belgium; Department of Medical Oncology, Papageorgiou Hospital, Thessaloniki, Greece; and CRUK Trials Unit, Beatson Oncology Centre, Glasgow, Scotland, United Kingdom

Address reprint requests to Paolo Bruzzi MD, MPH, PhD, Unit of Clinical Epidemiology, National Institute for Cancer Research, Largo Rosanna Benzi 10, 16132 Genoa, Italy; e-mail: paolo.bruzzi{at}istge.it

PURPOSE: To assess the validity of objective response to chemotherapy as a surrogate end point for survival in metastatic breast cancer.

PATIENTS AND METHODS: We carried out a meta-analysis on individual data from 2,126 metastatic breast cancer patients who were enrolled onto 10 randomized trials comparing standard versus intensified epirubicin-containing chemotherapy.

RESULTS: The intensified chemotherapy was associated with a significantly higher tumor response rate compared with standard chemotherapy (pooled odds ratio for nonresponse, 0.60; 95% CI, 0.51 to 0.72). The intensified regimens also led to better (although not significant) survival (pooled odds ratio, 0.94; 95% CI, 0.86 to 1.04; P = .22). Tumor response was a highly significant predictor of survival (P < .0001). When tumor response was introduced in the Cox model, the hazard ratio in favor of experimental treatment changed from 0.94 to 1.005 (95% CI, 0.91 to 1.11; P = .92), indicating that no residual effect of the experimental treatment on survival was present once tumor response was adjusted for. This suggests that the overall survival benefit of intensified epirubicin was a result of the increase in response rate. The median survival time of patients with complete response and partial response was 28.8 months (95% CI, 25.4 to 45.3 months) and 21.3 months (95% CI, 19.2 to 22.4 months), respectively; whereas, the median survival time of patients with no response was 14.6 months (95% CI, 13.9 to 15.4 months).

CONCLUSION: These results support the hypothesis that the achievement of an objective response to chemotherapy in metastatic breast cancer is associated with a true survival benefit. The potential role of objective response as a surrogate end point for survival in chemotherapy trials of metastatic breast cancer warrants further investigation.

Supported by grants from the Associazione Italiana per la Ricerca sul Cancro (grant No. 0301) and from the Ministero della Salute (Ricerca Corrente 2002-2004).

Presented at the IV Congresso Nazionale di Oncologia Medica, Torino, Italy, September 28-October 1, 2002 and at The 26th Annual San Antonio Breast Cancer Symposium, Antonio, TX, December 3-6, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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