Authors' objectives:

This report is intended to assess the usefulness of trastuzumab in breast cancer treatment and determine its valid indications.

Authors' results and conclusions: Trastuzumab efficacy on metastatic disease: As second line or subsequent treatment: A Phase II study assessed the efficacy of trastuzumab in 222 women with metastatic disease and HER-2/neu overexpression after one or more chemotherapy treatments. The complete response rate was 15% with a median survival of 13 months, median to progression of 3.1 months and median response duration of 9.1 months. As first line monotherapy: A Phase II study which included 114 patients with metastatic breast cancer with HER2 overexpression who received first line trastuzumab treatment found that the objective response rate (complete or partial response) was 26% (CI 95% 18.2 to 34.4%), lower than the response achieved with standard first line schemes. As first line in combination with other chemotherapy agents: A study randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. The addition of trastuzumab to the chemotherapy treatment was associated with an increase in median time to disease progression (7.4 vs 4.6 months; p<0.001), a greater rate of objective response (50% vs. 32%; p< 0.001), a greater response duration (9.1 vs. 6.1 months), a lower mortality rate at one year (22% vs. 33%, p=0.008), a greater median survival (25.1 vs 20.3 months, p=0.046) and a 20% death risk reduction. Trastuzumab efficacy in surgical invasive breast cancer: As neoadjuvant therapy (prior to surgery): A randomized study included patients with surgical, invasive, stage II or IIIA, HER2 positive breast cancer to receive paclitaxel followed by 5-fluorouracil + epirubicin + cyclophosphamide or the same scheme associated to weekly trastuzumab for 24 weeks, prior to surgery. The study was discontinued with 42 patients due to superiority of the second treatment modality: the rate of pathologic complete remission (disappearance of all residual invasive cancer from the breast or axilla) was 26.3% for chemotherapy alone and 65.2% for chemotherapy in combination with trastuzumab. As adjuvant therapy (post-surgery): In a joint interim analysis of both studies which included patients with positive HER2 who had positive lymph nodes or high risk negative lymph nodes, 3,676 patients were randomized after surgery to receive doxorubicin, cyclophosphamide and paclitaxel or the same regimen plus 52 weeks of trastuzumab. The occurrence of the combined endpoint of recurrence, second primary cancer or death after recurrence took place most frequently in the control groups than in the trastuzumab groups: 261 vs. 133 event with a HR of 0.48 with p<0.001. The mean follow-up was 2 years. The percentage of disease-free patients at 3 years was 75.4% in the control group and 87.1% the trastuzumab group, with an absolute difference of 11.8% (CI 95% 8.1 to 15.4). At 4 years, the percentages were 67.1% and 85.3% respectively, and the absolute difference was 18.2% (CI 95% 12.7 to 23.7). There were 62 deaths in the trastuzumab group and 92 the control group (HR 0.67 with a CI95% 0.48 to 0.93, p=0.015). Similar results were reported in the interim analysis of the HERA study with 5090 patients. Safety profile The most serious adverse event is heart dysfunction, which worsens when trastuzumab is associated with anthracyclines. Trastuzumab is associated with rates of heart dysfunction of 2 to 13%, increasing to 27% when anthracyclines are added, especially doxorubicin. Suppliers and health technology assessment agencies: There is consensus among technology evaluations and coverage policies of the NHS Centre for Reviews and Dissemination of York University and the National Horizon Scanning Centre of Birmingham University, United Kingdom, and BlueCross BlueShield from Tennessee and Aetna from United States, about the efficacy of trastuzumab in the treatment of metastatic breast tumors that have HER2 overexpression as second line monotherapy and subsequent treatment or as first line combined with taxanes. Most of them were carried out before the publication of the interim analysis of studies which evaluate trastuzumab for the treatment of surgical invasive breast cancer.

Authors' recommendations: As regards trastuzumab usefulness for the treatment of metastatic breast cancer with HER2 overexpression when used as first line monotherapy, it does not show superiority when compared to standard treatments, however as second line or subsequent therapy it shows a discrete objective response rate which would allow its consideration as an alternative when the tumor has not responded to other chemotherapy agents. When trastuzumab is combined with other standard chemotherapy agents as first line treatment, a marked benefit is observed, even showing a lower mortality rate at one year in these patients with short-term bad prognosis. Regarding trastuzumab usefulness for surgical, invasive, stage II or IIIA, HER2 positive breast cancer, there is only evidence from interim analysis of different studies with an important number of patients which show median-term benefits when adding trastuzumab to standard treatment (surgery plus standard chemotherapy with or without radiotherapy and with or without hormone therapy), referring to tumoral response and mortality as well. The studies that have the greatest number of patients were performed administering trastuzumab as post-surgical adjuvant treatment and only one study, which was interrupted early in course, was done using it as neoadjuvant therapy In oncology practice, the results of these works can, in general, be extrapolated because the determining factor is the tumor's sensitivity to chemotherapy. One important consideration is the cardiotoxicity incidence with trastuzumab administration, especially when it is associated with anthracyclines. In this group of patients, whose survival at 5 years is approximately 80%, the development of heart disease is a point to be seriously considered. The studies currently being carried out could give more detailed information about the long term evolution of this complication. Economic assessments performed up to date have not found a good cost-effectiveness profile and trastuzumab coverage is heterogeneous, for example in England it is not covered, whereas some U.S. health sponsors cover it. Although the economic evidence can not be easily extrapolated, probably in our country the cost effectiveness of this treatment would be lower.

Authors' methods: Overview

Project Status: Completed

URL for project: http://www.iecs.org.ar/

Year Published: 2005

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Argentina

Organisation Name: Institute for Clinical Effectiveness and Health Policy

Contact Address: Dr. Emilio Ravignani 2024, Buenos Aires - Argentina, C1414 CABA

Contact Name: info@iecs.org.ar

Contact Email: info@iecs.org.ar

Copyright: Institute for Clinical Effectiveness and Health Policy (IECS)