Trastuzumab (Herceptin) for HER2 positive early, locally advanced and inflammatory breast cancer neoadjuvant treatment

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1 Trastuzumab (Herceptin) for HER2 positive early, locally advanced and inflammatory breast cancer neoadjuvant treatment August 2010 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

2 Trastuzumab (Herceptin) for HER2 positive early, locally advanced and inflammatory breast cancer neoadjuvant treatment Target group Breast cancer: HER2 positive early, locally advanced and inflammatory neoadjuvant treatment. Technology description Trastuzumab (Herceptin) is a humanised monoclonal antibody, which specifically targets the human epidermal growth factor 2 (HER2) protein, which is over expressed on breast cancer cells. Over expression (or amplification) of the HER2 protein is associated with accelerated cell division. By binding to the protein receptors on these cells, trastuzumab interrupts the growth signal, thereby slowing the growth and spread of tumours. Immunohistochemistry (IHC) and/or in situ hybridisation (ISH) is typically used to assess HER2 levels in patients who are potentially eligible for trastuzumab treatment. Neoadjuvant trastuzumab is intended to be used with adjuvant trastuzumab already received by suitable patients post surgery. In clinical trials trastuzumab is administered by intravenous (IV) infusion at a loading dose of 8mg/kg, followed by 6mg/kg for 10 cycles each of 3 weeks in combination with neoadjuvant chemotherapy. The company state that the license may not be prescriptive about the number of cycles that are given neoadjuvantly. Trastuzumab is licensed in the EU for the treatment of: HER2 positive early breast cancer following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable). HER2 positive metastatic breast cancer: i. as monotherapy for patients who have received at least two chemotherapy regimens including, where appropriate, an anthracycline and a taxane. Hormone receptor positive patients must also have failed hormonal therapy, where appropriate. ii. in combination with paclitaxel for patients who have not received chemotherapy for their metastatic disease and for whom anthracycline is not suitable. iii. in combination with docetaxel for patients who have not received chemotherapy for their metastatic disease. iv. in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive HER2 positive tumours, not previously treated with trastuzumab. HER2 positive metastatic gastric cancer in combination with capecitabine or 5- fluorouracil and cisplatin. Recognised adverse effects of trastuzumab include chills, fever and other flu-like symptoms during infusion, and diarrhoea, weakness, skin rashes, chest pain, abdominal pain, joint pain, and muscle pain 1. Cardiac functional assessments should be repeated every 3 months during trastuzumab treatment 2. Trastuzumab is also in phase II trials for non-small cell lung cancer, bladder cancer, renal cancer, colorectal cancer and pancreatic cancer. 2

3 Innovation and/or advantages If successful in clinical trials and licensing trastuzumab has the potential to target HER2 over expression earlier in the disease process and may increase tumour response and survival. Developer Roche Products Ltd. Availability, launch or marketing dates, and licensing plans In phase III trials NHS or Government priority area This topic is relevant to the NHS Cancer Plan (2000) and Cancer Reform Strategy (2007). Relevant guidance NICE Technology Appraisals In development. Lapatinib for the treatment of previously treated women with advanced, metastatic or recurrent breast cancer. Expected date of issue to be 3 confirmed. In development. Bevacizumab in combination with non-taxane chemotherapy for the first line treatment of metastatic breast cancer. Expected date of issue to be 4 confirmed. In development. Bevacizumab in combination with a taxane for the first-line treatment of HER2 negative metastatic breast cancer. Expected date of issue to be 5 confirmed. Gemcitabine for the treatment of metastatic breast cancer Docetaxel for the adjuvant treatment of early node-positive breast cancer Paclitaxel for the adjuvant treatment of early node-positive breast cancer Hormonal therapies for the adjuvant treatment of early oestrogen-receptor-positive 9 breast cancer Trastuzumab for the adjuvant treatment of early-stage HER2-positive breast cancer The clinical effectiveness and cost effectiveness of trastuzumab for breast cancer NICE Clinical Guidelines 11 Advanced breast cancer: diagnosis and treatment Early & locally advanced breast cancer: diagnosis and treatment Familial breast cancer. The classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care Other Guidelines 14 SIGN. Management of breast cancer in women National Cancer Research Institute. UK clinical guidelines for the use of adjuvant trastuzumab (Herceptin) with or following chemotherapy in HER2-positive early breast cancer Clinical need and burden of disease Breast cancer is the most common cancer affecting women in the UK, accounting for about 31% of all cancers in women 16. In 2007, there were 40,757 new cases of breast 6 3

4 cancer diagnosed in England and Wales; 40,504 in women and 253 in men 18. Breast cancer risk is strongly related to age, with 81% of cases occurring in women aged over 50 years, and is greater in those in higher socioeconomic groups 18. In 2008, there were 10,754 deaths registered for breast cancer in England and Wales 17. Breast cancer is described as early if it is only in the breast or in the breast and the lymph nodes nearby (most often under the arm), and has not spread to other parts of the body 12. The term 'locally advanced' is used when the cancer is in a large part of the breast and may be present in the lymph nodes, but has not spread to other parts of the body 12. Local control can be achieved in 80 90% of women, and about 30% of women with stage IIIb tumours (locally advanced) remain cancer free after 10 years 18. Amplification of the HER2 gene and over expression of the receptor occurs in around 15 25% of women with early breast cancer 19, and is associated with aggressive disease, a higher likelihood of recurrence after initial treatment, and a poor prognosis 20 Existing comparators and treatments The choice of treatment for each patient depends upon many factors including stage and grade of cancer, site of tumour, receptor status of tumour cells, menopausal status, health and patient choice. Current management options for early, locally advanced HER2 positive breast cancer include 21 : Surgery lumpectomy or mastectomy. Radiotherapy to the remainder of the breast tissue or the chest wall. Standard chemotherapy regimens adjuvant or neoadjuvant. o 5-fluorouracil (5FU), epirubicin and cyclophosphamide (FEC). o Doxorubicin and cyclophosphamide (AC). o Cyclophosphamide, methotrexate and 5FU (CMF). o Epirubicin and CMF (E-CMF). o FEC plus docetaxel (FEC-T). Hormonal therapy e.g. tamoxifen and aromatase inhibitors. Biological therapy e.g. trastuzumab (Herceptin) after surgery and adjuvant chemotherapy (and radiotherapy, if appropriate). Efficacy and safety Roche Products Ltd, intend to use the NOAH study for the Marketing Authorisation Application to the EMA. In addition to the phase III trials reported below there have been two phase II randomised trials published in abstracts combining neoadjuvant chemotherapy with or without trastuzumab for the treatment of locally advanced, HER2 positive breast cancer 22,23. There are several other published phase II trials combining trastuzumab with different neoadjuvant chemotherapy regimens for the treatment of locally advanced, HER2-positive breast cancer but most are uncontrolled 24,25,26,27,28,29,30,31,32,33. There are several ongoing phase II randomised trials of neoadjuvant chemotherapy with or without trastuzumab. Trial NOAH, ISRCTN ; neoadjuvant chemotherapy +/- trastuzumab; phase III. GeparQuattro, NCT ; neoadjuvant chemotherapy +/- capecitabine with trastuzumab for HER2 positive breast cancer; phase III. MDACC; neoadjuvant chemotherapy +/-trastuzumab for HER2 positive breast cancer; phase III 4

5 Sponsor Hoffman La Roche. German Breast Group. M.D. Anderson Cancer Centre. Status Published. Published. Published. Source of Publication ,36 Publication. Publication. information Location EU, Russia. Germany. USA. Design Randomised, stratified by HER2 status.. Trastuzumab nonrandomised, noncontrolled. Randomised, controlled. Participants and schedule n=334; females; breast cancer; locally advanced T3N1 or T4, or N2 or N3, or involvement of ipsilateral supraclavicular nodes; left ventricular ejection fraction (LVEF) 55%. All HER2 positive randomised to: Arm 1 Trastuzumab 8mg/kg IV, then 6mg/kg for 10, 3 week cycles with neoadjuvant chemotherapy (doxorubicin 60mg/m 2 plus paclitaxel for 3 cycles each of 3 weeks, followed by paclitaxel 175mg/m 2 for four cycles each of 3 weeks). Additional CMF on days 1 and 8 every 4 weeks for three cycles. Completed 1 year of trastuzumab postsurgery. Arm 2 Neoadjuvant chemotherapy as arm 1. All had surgery followed by radiotherapy after completing neoadjuvant chemotherapy. Those with hormone receptorpositive disease received adjuvant tamoxifen for 5 years. n=1,509; females; breast cancer; locally advanced; T3 or T4; hormone receptor-negative or hormone receptor-positive but lymph node-positive. All received four cycles (3 weeks each) of epirubicin 90mg/m 2 with cyclophosphamide 600mg/m 2 (EC), then randomised to: Arm 1 four cycles docetaxel 100mg/m 2 (EC-T). Arm 2 four cycles docetaxel 75mg/m 2 plus capecitabine 1,800mg/m 2 (EC-TX). Arm 3 four cycles docetaxel 75mg/m 2 followed by 4 cycles of capecitabine 1,800mg/m 2 (EC-T-X). HER2 positive received trastuzumab 8mg/kg, then 6mg/kg every 3 weeks on day 1 of EC cycle and completed 1 year of trastuzumab post-surgery. Surgery within days of completing chemotherapy. Active treatment period 1 n=42; breast cancer stage II- IIIA; invasive but non inflammatory; HER2 positive. Randomised to 4 cycles of neoadjuvant paclitaxel followed by four cycles of FEC with or without simultaneous trastuzumab 4mg/kg IV on day 1 of first cycle then 2mg/kg subsequently. 24 doses of trastuzumab administered, after which, patients receive local therapy. Those with oestrogen receptor positive disease received tamoxifen 20mg daily or anatrozole 1mg daily if postmenopausal. Follow-up Active treatment period 1 year, 24 week treatment period. then 5 year follow-up. year. Primary Event-free survival (EFS), Pathologic complete pcr rates. outcomes defined as time to disease response (no invasive or in recurrence or progression, or situ residual tumours). death. Secondary Pathological complete Rate of breast conservation; - outcomes response (pcr) in breast tissue clinical and pathological (bpcr); total pcr in breast response rate at surgery. and axilla (tpcr); overall clinical response; cardiac safety; survival; EFS in HER2 negative disease. Key results For neoadjuvant chemotherapy For HER2 positive (n=451) For neoadjuvant chemotherapy 5

6 Adverse effects (AEs) ± trastuzumab respectively: 3-year EFS 71% and 56%; unadjusted hazard ratio 0.59 (95% CI ; p=0.013); 3-year overall survival 87% (95% CI 79 92) and 79% (95% CI 70 86); bpcr: 43% vs 22% (p=0.0007); tpcr: 38% vs 19% (p=0.001); overall response 87% vs 74% (p=0.009). AEs were similar in all arms. Cardiac events in 11%, 11% and 2% of HER2 positive with trastuzumab, without trastuzumab and HER2 negative disease respectively. Left ventricular dysfunction in 2% (mostly grade 1), 0% and 0% respectively. and HER2 negative (n=1,058) respectively: pcr 31.7% vs 15.7%; no nodal involvement in 70.3% and 52.3%; breastconserving surgery in 63.1% vs 64.7%; patients without response to EC had pcr 16.7% vs 3.3%. For HER2 positive and HER2 negative respectively: Grade 3 or 4 febrile neutropenia (9.9% vs 6.1%) and conjunctivitis (2.5% vs 0.9%). Congestive heart failure and cardiac ischemia in 1 vs 2 patients. One patient in the HER2 positive group died of unknown cause during the fifth cycle, 4 died from sepsis and 1 from progression. ± trastuzumab respectively: pcr 65.2% (95% CI 43-84) vs 26.3% (95% CI ); p= No residual disease in 15 vs 5 patients (p=0.01). No significant difference in extent of residual disease in lymph nodes, measured by number of positive nodes. For neoadjuvant chemotherapy with or without trastuzumab respectively: Grade 4 neutropenia: 21 vs 11 patients (p=0.03). Chemotherapy dose reduction as a result of neutropenia in 10 vs 5 patients. Neutropenic fever in 8 vs 8 patients. >10% decrease in LVEF in 7 vs 5 patients. Trial NCT ; neoadjuvant lapatinib and/or trastuzumab; HER2 positive; phase III. Neo ALTTO; NCT ; neoadjuvant lapatinib and/or trastuzumab; HER2 positive; phase III. GlaxoSmithKline. NSABP B-41; NCT ; neoadjuvant chemotherapy and/or trastuzumab; HER2 positive; phase III. GlaxoSmithKline. Sponsor Cancer and Leukaemia Group B. Status Ongoing. Ongoing. Ongoing. Source of Trial registry Trial registry. Trial registry. information Location USA. EU (inc UK), Canada and USA, Canada and Puerto Rico. other countries. Design Randomised, controlled, Randomised, controlled. Randomised, controlled. stratified by stage and hormone receptor status. Participants and schedule n=400; breast cancer; stage II or III; resectable; HER2 positive; no inflammatory or metastatic disease; hormone receptor status known; no prior therapy. Randomised to: Arm 1 Trastuzumab and paclitaxel IV once weekly with oral lapatinib ditosylate once daily for 16 weeks. Arm 2 n=450; females; breast cancer; no metastasis; HER2 positive; known hormone receptor status. Randomised to: Arm 1 Lapatinib 1,500mg for 6 weeks followed by lapatinib with weekly paclitaxel for 12 weeks. Arm 2 Trastuzumab 4mg/kg, then 2mg/kg weekly for 6 weeks, n=522; female; breast cancer; HER2 positive. All received doxuribicin 60mg/m 2 IV every 3 weeks and cyclophosphamide 600mg/m 2 IV every 3 weeks for cycles 1-4 and paclitaxel 80mg/m 2 IV days 1,8,15 every 4 weeks for cycles 5-8 and randomised to additional: Arm 1 Trastuzumab 4mg/kg then 2mg/kg on day 1 of first 6

7 Follow-up Primary outcome Secondary outcomes Expected reporting date Trastuzumab and paclitaxel as in arm 1. Arm 3 Lapatinib ditosylate and paclitaxel as in arm 1. All patients received surgery with 42 days of completing neoadjuvant chemotherapy. followed by 2mg/kg trastuzumab with weekly paclitaxel for 12 weeks. Arm 3 Lapatinib 1,000mg with trastuzumab 4mg/kg, then trastuzumab 2mg/kg weekly for 6 weeks, followed by lapatinib 750mg plus, trastuzumab 2mg/kg weekly with weekly paclitaxel for 12 weeks. 16 week treatment period with 52 week total treatment period. Unknown. a total follow-up period of 10 years. pcr. pcr at surgery. pcr. pcr in the breast and axilla; residual cancer burden; correlation between clinical, radiographic, and pathologic response; overall survival, invasive disease-free survival, and time to first failure; breast conservation and sentinel lymphadenectomy. Study started Dec 2008; estimated completion June Objective response; % with node-negative disease at surgery; rate of conversion to breast conserving surgery; disease-free survival; overall survival; PET/CT imaging; circulating tumour cells. Study started Jan 2008; estimated primary completion Feb paclitaxel cycle until 1-7 days before surgery. Arm 2 Lapatinib 1,250mg or 750mg oral daily on day 1 of first paclitaxel cycle until 1 day before surgery. Arm 3 Trastuzumab plus lapatinib as arms 1 and 2. pcr in surgical breast and lymph; clinical tumour measurements; overall survival; recurrence-free interval. Study started July 2007; estimated primary completion July Estimated cost and cost impact The cost of trastuzumab 8mg/kg followed by 6mg/kg every 3 weeks for 12 months, split between neoadjuvant and adjuvant treatment would be approximately 21,000 a,41. Other costs include HER2 testing, intravenous administration and monitoring costs. Claimed or potential impact speculative Patients Reduced mortality or increased length of survival Other: Reduction in associated morbidity or Improved quality of life for patients and/or carers Quicker, earlier or more accurate diagnosis or identification of disease None identified Services Increased use: administration and monitoring of cardiotoxicity Decreased use: long-term if disease free survival increased Service organisation Other: Staff requirements None identified Costs Increased unit cost compared to alternative New costs Increased costs: more patients coming for treatment Savings: long-term if disease free survival increased Increased costs: capital investment needed Other: a Costings based on average weight 67.5kg (men and women) and average surface area 1.7m 2 7

8 References 1 The Electronic Medicines Compendium. Package leaflet: information for the user. Herceptin 150mg powder for concentrate for solution for infusion. DataPharm Communications. 2 National Institute for Health and Clinical Excellence. Trastuzumab for the adjuvant treatment of early-stage HER2-positive breast cancer. Technology appraisal TA107. London: NICE; August National Institute for Health and Clinical Excellence. Technology appraisal in development. Lapatinib for breast cancer (for use in women with previously treated advanced or metastatic breast cancer). Expected date of issue to be confirmed. 4 National Institute for Health and Clinical Excellence. Technology appraisal in development. Bevacizumab in combination with non-taxane chemotherapy for the first line treatment of metastatic breast cancer. Expected date of issue to be confirmed. 5 National Institute for Health and Clinical Excellence. Technology appraisal in development. Bevacizumab in combination with a taxane for the first-line treatment of HER2 negative metastatic breast cancer (to include a reinitiation of terminated TA147). Expected date of issue to be confirmed. 6 National Institute for Health and Clinical Excellence. Breast cancer - gemcitabine for the treatment of metastatic breast cancer. Technology appraisal TA116. London: NICE; January National Institute for Health and Clinical Excellence. Docetaxel for the adjuvant treatment of early nodepositive breast cancer. Technology appraisal TA109. London: NICE; September National Institute for Health and Clinical Excellence. Paclitaxel for the adjuvant treatment of early nodepositive breast cancer. Technology appraisal TA108. London: NICE; September National Institute for Health and Clinical Excellence. Hormonal therapies for the adjuvant treatment of early oestrogen-receptor-positive breast cancer. Technology appraisal TA112. London: NICE; November National Institute for Health and Clinical Excellence. The clinical effectiveness and cost effectiveness of trastuzumab for breast cancer. Technology appraisal TA34. London: NICE; March National Institute for Health and Clinical Excellence. Advanced breast cancer diagnosis and treatment. Clinical guideline CG81. London: NICE; February National Institute for Health and Clinical Excellence. Breast cancer (early & locally advanced): diagnosis and treatment. Clinical guideline CG80. Cardiff: National Collaborating Centre for Cancer; February National Institute for Health and Clinical Excellence. Familial breast cancer. Clinical guideline CG41. London: NICE; October Scottish Intercollegiate Guidelines Network. Management of breast cancer in women. Clinical guideline No. 84. Edinburgh: SIGN; December National Cancer Research Institute. UK clinical guidelines for the use of adjuvant trastuzumab (Herceptin) with or following chemotherapy in HER2-positive early breast cancer. Care guideline. NCRI, December Cancer Research UK. Breast cancer: UK incidence statistics Cancer Research UK. Breast cancer: UK mortality statistics Jones L, Hawkins N, Westwood M et al. Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda) for locally advanced and/or metastatic breast cancer. Health Technology Assessment 2004; 8 (5). 19 Smith I, Procter M, Gelber RD et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2- positive breast cancer: a randomised controlled trial. The Lancet 2007; 369: Baselga J, Perez EA, Pienkowski T et al. Adjuvant trastuzumab: a milestone in the treatment of HER-2- positive early breast cancer. The Oncologist 2006; 11 (suppl 1): Macmillan cancer support. Treating breast cancer. stcancer.aspx. Accessed 09 June Guarneri V, Frassoldati A, Bottini A et al. Safety and activity report for a randomized phase II trial of preoperative anthracycline-based chemotherapy plus lapatinib, trastuzumab or both in HER2 positive breast cancer: CHERLOB trial. San Antonio Breast Cancer Symposium Abstract No Chang HR, Slamon D, Gornbein JA et al. Preferential pathologic complete response (pcr) by triple-negative (_) breast cancer to neoadjuvant docetaxel (t) and carboplatin (c). Journal of Clinical Oncology 2008; 26 (May 20 suppl). Abstract Untch M, Stoeckl D, Konecny G et al. A multicenter phase II study of preoperative epirubicin, cyclophosphamide (EC) followed by paclitaxel (p) plus trastuzumab (t) in HER2 positive primary breast cancer. San Antonio Breast Cancer Symposium Poster Sawaki M, Iwata H, Sato Y et al. Phase II study of preoperative systemic treatment with the combination of docetaxel and trastuzumab in patients with locally advanced HER-2-overexpressing breast cancer. The Breast doi: /j.breast

9 26 Steven A, Limentani, Adam M et al. Phase II study of neoadjuvant docetaxel, vinorelbine and trastuzumab followed by surgery and adjuvant doxorubicin plus cyclophosphamide in women with human epidermal growth factor receptor 2 overexpressing locally advanced breast cancer. Journal of Clinical Oncology 2007; 25: Coudert BP, Arnould L, Moreau L et al. Pre-operative systemic (neo-adjuvant) therapy with trastuzumab and docetaxel for HER2-overexpressing stage II or III breast cancer: results of a multicenter phase II trial. Annals of Oncology 2006; 17: Carillio G, Aiello R, Alì M. Neoadjuvant trastuzumab in a sequential nonanthracyline-based regimen for patients with stage II-III breast cancer. Journal of Clinical Oncology 2009; 27 (May 20 suppl). Abstract e Iorfida M, Bagnardi V, Balduzzi A et al. Preoperative therapy with trastuzumab and oral vinorelbine (± endocrine therapy) in patients with HER2-positive breast cancer. The Breast 2010;19: Coudert BP, Largillier R, Arnould L. Multicenter phase II trial of neoadjuvant therapy with trastuzumab, docetaxel, and carboplatin for human epidermal growth factor receptor-2 overexpressing stage II or III breast cancer: results of the GETN (A)-1 Trial. Journal of Clinical Oncology 2007; 25 (19): Wildiers H, Neven P,Christiaens MR et al. Multicenter phase II study of neoadjuvant capecitabine, docetaxel ± trastuzumab for patients with locally advanced breast cancer: final analysis. San Antonio Breast Cancer Symposium Poster Chia S, Bryce C, Pansegrau G et al. Phase II trial of neoadjuvant chemotherapy of sequential FEC100 followed by docetaxel, carboplatin and trastuzumab (TCH) for HER-2 over-expressing locally advanced breast cancer (LABC): a multi-centre study from British Columbia. San Antonio Breast Cancer Symposium Abstract Chang HR, Glaspy J, Gornbein J et al. Clinical advantages of neoadjuvant docetaxel (t) nd carboplatin (c) ± trastuzumab (h) in locally advanced brast cancer (LABC). San Antonio Breast Cancer Symposium Abstract Gianni L, Eiermann W, Semiglazov V et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trials with parallel HER2- negative cohort. The Lancet 2010:375: Untch M, Rezai M, Loibl S et al. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. Journal of Clinical Oncology 2010;28: von Minckwitz G, Rezai M, Loibl S et al. Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. Journal of Clinical Oncology 2010;28: Buzdar AU, Ibrahim NK, Francis D et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomised trial in human epidermal growth factor receptor 2-positive operable breast cancer. 38 ClinicalTrials.gov. Paclitaxel and trastuzumab and/or lapatinib in treating patients with stage II or stage III breast cancer that can be removed by surgery. Accessed 25 June ClinicalTrials.gov. Neo ALTTO (neoadjuvant lapatinib and/or trastuzumab treatment optimisation) study. Accessed 21 June ClinicalTrials.gov. A study of AC followed by a combination of paclitaxel plus trastuzumab or lapatinib or both given before surgery with operable HER2 positive invasive breast cancer. Accessed 21 June British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London; March

10 The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0) Fax +44 (0)