Title: PERSEPHONE - duration of trastuzumab study with chemotherapy in early breast cancer: six versus twelve months
Funder: Department of Health and Social Care

Abstract: DESIGN. PERSEPHONE - is a randomised controlled multi-centre clinical trial in HER-2 positive early breast cancer. The standard arm is 12 months(m)adjuvant trastuzumab, compared with the experimental arm of 6m trastuzumab. Duration of trastuzumab 12m and 6 m will be compared. The trial has an equivalence or non-inferiority hypothesis, that the 6m trastuzumab, will be equivalent to standard 12m. All patients will receive chemotherapy and trastuzumab will be given either concurrently with chemotherapy, or sequentially after chemotherapy has been completed. Patients may also receive chemotherapy in the adjuvant or neoadjuvant setting. Patients will be stratified by the following treatment variables (among others ):(i) Timing of trastuzumab - Concurrent/sequential with chemotherapy; (ii)Type of chemotherapy - anthracycline-based/taxane-based; (iii)Timing of chemotherapy - adjuvant /neoadjuvant. SETTING The health service setting is hospitals, predominantly outpatient and day patient facilities, with occasional use of inpatient facilities. The setting will 'map to clinical practice', and where trastuzumab and chemotherapy are being delivered at home under current arrangements, this can continue within the trial. TARGET POPULATION Patients with HER-2 positive early breast cancer (either 3+ or 2+/ FISH positive)(1), of sufficient risk to require adjuvant chemotherapy, and medically fit enough to receive chemotherapy and trastuzumab. HEALTH TECHNOLOGIES BEING ASSESSED. Adjuvant trastuzumab duration is the health technology being assessed. Trastuzumab now has a European licence for 12 months use with chemotherapy, either given concurrently or sequentially. In June 2006, NICE issued a Final Appraisal Determination (FAD) recommending 12 months use. This has very significant cost implications for the NHS in terms of drug treatment (including drug costs, and delivery), and side effects (line problems and cardiac complications). In a small Finnish [1] study, just 9 weeks of trastuzumab given concurrently with chemotherapy produced similar results for disease-free survival (HR=0.46, p=0.0078) to those seen in the larger randomised studies [2-4]. PERSEPHONE - Adjuvant is powered to look for equivalence between 6m trastuzumaband 12m treatment. The study arm would halve treatment time and potentially costs of this new health technology. MEASUREMENT OF COSTS AND OUTCOMES. Primary outcome measure of disease-free survival (DFS) will be used. An important health economic component is to be included in the study, to assess the 'real' costs of delivering the 2 durations of trastuzumab (drug costs, line and delivery costs, and costs of complications). Professor Chris McCabe (University of Warwick) will lead on the health economic component, and advise the trials team of data collection requirements prior to development of 'case record forms'. REFERENCES [1] Joensuu H et al. (FinHer Study). Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. NEJM 2006;354 809-820. [2] Piccart-Gebhart MJ, et al. for Trastuzumab Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-2 positive breast cancer. NEJM 2005; 353: 1659-1672. [3] Romond EH et al. (Joint analysis of NSABP B31, and NCCTG N9831) Trastuzumab plus adjuvant chemotherapy for operable HER2 positive breast cancer. NEJM 2005; 353 1673-1684. [4] Slamon D, et al (BCIRG Study) Phase III Trial comparing AC-T with AC-TH and with TCH in adjuvant treatment of HER2 positive early Breast Cancer Patients: First interim efficacy analysis. Proceedings 28th Annual San Antonio Breast Cancer Symposium. Dec 2005 Abstract No.1.

Lay abstract: Trastuzumab is a humanised monoclonal antibody treatment that works to prolong life and save the lives of women with breast cancers that carry the Her-2 receptor on the surface of their tumours. Trastuzumab reacts with this cell surface receptor, and blocks its normal action which is to make the cells divide and the cancer grow. Trials reported in 2005/6, show very considerable improvements in outcomes - preventing breast cancer coming back and spreading, in patients who were treated with trastuzumab as well as chemotherapy, when compared with those who simply received chemotherapy. A Finnish study showed that when trastuzumab was given at the same time as chemotherapy, only 9 weeks treatment could produce similar results. This latter study was small, and needs to be repeated. In the study presented here we plan to invite 4200 women with Her-2 positive breast cancer to take part, and to be allocated to either standard treatment - 12 months of trastuzumab, or to 6 months of trastuzumab. This 'study arm' of treatment allocation, would have a total treatment time of 6 months shorter than the equivalent 'standard' arm. We have set up an International Collaboration with the French Institut of Cancer (INCa) which has a study which is very similar. Entering 4000 patients into PERSEPHONE will allow us to definitively answer the question - 'Is 6 months trastuzumab treatment sufficient?' If it is enough this has very important implications for all Her 2 positive breast cancer patients, and for the costs of providing such treatment. Trastuzumab is defined as a targetted, anti-cancer therapy which is a 'biological' and not a chemotherapy. Many other similar such treatments are in development. Unless the question of duration of adjuvant treatment is answered, all these new treaments will be introduced for a 12 month duration. The study will carefully check all aspects of treatment, and also outcomes (survival and absence of cancer coming back) to make quite certain that patients who receive less treatment (6m), are not being disadvantaged. We are confident that this will not be the case, because of the exciting results of the Finnish study, but testing this properly within a clinical study is essential. The collaborative team for this project have track records individually in all aspects of the proposed research and its organisation; development, running, and analysis.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS