European Journal of Cancer (2015) 51, 907– 914
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Original Research
Do participants in adjuvant breast cancer trials reflect the breast cancer patient population? Shaun Treweek a,⇑, Ruth Dryden b, Colin McCowan c, Alison Harrow d, Alastair M. Thompson e a
Health Services Research Unit, University of Aberdeen, AB25 2ZD, UK Institute for Research and Innovation in Social Services, Glasgow G1 1UZ, UK c Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, G12 8QQ, UK d Dundee Cancer Centre, University of Dundee, Dundee DD1 9SY, UK e Department of Surgical Oncology, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston Texas 77030, USA b
Received 13 January 2015; accepted 13 January 2015 Available online 7 April 2015
KEYWORDS Breast cancer Adjuvant treatment Phase III trials Applicability Generalisabilty Record linkage
Abstract Aim: To describe the proportion of women in Tayside, Scotland diagnosed with early breast cancer who would have been eligible for influential adjuvant breast cancer trials. Methods: Phase III trials of adjuvant treatment for breast cancer referenced in five national guidelines were shortlisted by breast cancer specialists to identify the twelve considered most influential. Eligibility criteria were extracted from protocols and applied to a 16-year cohort of women who had received a diagnosis of breast cancer and the proportion meeting trial criteria calculated. The criteria used clinically in Tayside to make decisions about use of the trial treatments were also applied to the cohort. Finally, the proportion of women receiving adjuvant endocrine therapy as part of their care and who would have been eligible for the trial evaluating that therapy was calculated. Results: Of the cohort’s 4811 women, 3535 (73%) were eligible for at least one trial but eligibility for an individual trial rarely exceeded 45%. There were substantial differences between the proportion of women meeting trial eligibility criteria and the proportion considered clinically eligible for the same treatment. The proportion of women receiving an endocrine therapy as part of their care who would also have been eligible for the trial evaluating that treatment ranged from 17% to 56%.
⇑ Corresponding author at: Health Services Research Unit, University of Aberdeen, 3rd Floor, Health Sciences Building, Foresterhill, Aberdeen AB25 2ZD, UK. Mobile: +44 777 901 6955; fax: +44 1224 438165. E-mail addresses: [email protected] (S. Treweek), [email protected] (R. Dryden), [email protected] (C. McCowan), [email protected] (A. Harrow), [email protected] (A.M. Thompson).
http://dx.doi.org/10.1016/j.ejca.2015.01.064 0959-8049/Ó 2015 Elsevier Ltd. All rights reserved.
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Conclusion: Clinical eligibility criteria may be at variance with trial criteria. For adjuvant endocrine therapy, a substantial proportion of women who would have been ineligible for a trial nevertheless received the trial treatment as part of their care. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Poor applicability of trial results to routine clinical practice is the most frequent criticism by clinicians of randomised trials, systematic reviews and guidelines [1]. Relevance needs to be designed into trials [2,3]. This does not always happen. Consider community-based asthma and chronic obstructive pulmonary disease patients, whose clinical management is based on the results of 17 major trials cited in the Global Initiative for Asthma (GINA) guidelines and 18 major trials cited in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines [4,5]. A median 4% of patients in the community with current asthma (range 0% to 36%) met the eligibility criteria for the GINA trials [4]; the equivalent figure for GOLD was 5% (range 0% to 20%) [5]. Saunders and colleagues found that the proportion of people with Type 2 diabetes who met the eligibility criteria for seven diabetes trials ranged from 3.5% to 50.7% [6]. In breast cancer, a recent study reported greater toxicities in patients outside a trial than within the trial [7]. Trials underpin guideline recommendations so differences between trial and community populations affect many clinical decisions. Indeed, generalisability is acknowledged as a common challenge faced by guideline development groups [8]. Calls for trials with wider applicability have come from those interested in clinical decision-making [3,9,10] and those interested in health policy [11]. A comparison of trial and community-based populations is challenged by the availability of high quality community data. Previous work in Tayside, Scotland has characterised a cohort of all incident breast cancers over a 16 year period between 1992
and 2008 and includes data from 4811 women [12,13]. This cohort includes cancer characteristics at presentation, linked via each woman’s unique Community Health Index number to other datasets such as prescribing, hospital discharge, cancer registry and General Registrar’s Office death certificate records. The current study had four aims: To identify recent adjuvant endocrine therapy, chemotherapy and radiotherapy breast cancer trials which have been influential in the treatment of women with breast cancer. To examine how many of the women in the Tayside cohort would have been eligible to participate in each of these trials. To compare the proportion of women who would have received the treatment evaluated in the trials based on clinical decisions in Tayside versus trial eligibility criteria. To assess the proportion of women in the cohort who received a trial treatment but would not have been eligible for the trial evaluating that treatment.
2. Methods 2.1. Identification and prioritisation of randomised controlled trials Four national guidelines (two UK, two USA) [14–17] and one best practice document [18] were used to identify phase III trials of adjuvant treatment for breast cancer. The inclusion and exclusion criteria used to select trials are given in Table 1.
Table 1 Inclusion and exclusion criteria. Inclusion criteria
Exclusion criteria
Incident/Primary breast cancer
Prevention, diagnostic, surgical and neoadjuvant trials; metastatic breast cancer Studies where Human Epidermal Growth Factor
Phase III trial Receptor 2 (HER2) was investigated/treatment effects on HER2 patients2 Adjuvant radiotherapy and adjuvant systemic therapy Women P400 participants1 Published in English between 2003 and 2012 1
Trials focusing on women with advanced or metastatic disease Male breast cancer
Based on the assumption that larger trials are more influential; the same cut-off was used by Travers and colleagues [4,5]. Human Epidermal Growth Factor Receptor 2 (HER2) trials were excluded as the Tayside cohort had no data on HER2 status prior to 2000, in keeping with national testing guidelines; it was therefore not possible to assess patient eligibility for these trials within the cohort. 2
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Trials were identified and screened by four of the authors (RD, AH, AMT, ST). Where trials could not be excluded based on the abstract, the full text was obtained. To select trials considered by breast cancer clinical specialists and researchers as most influential on practice, the initial list of trials was reviewed by delegates attending the 2012 Scottish Cancer Trials Breast Group annual meeting. Delegates were asked to identify up to ten trials they felt had most influenced current practice and to suggest additional trials. The 12 trials receiving the most votes were included in this study. 2.2. Extraction of trial inclusion and exclusion criteria Full text copies of the most recent study protocols were obtained for all 12 selected trials. The lists of inclusion/exclusion criteria for each trial were extracted (by RD) and agreed by the co-authors. These were then matched to the data available in the cohort. Eligibility for adjuvant therapy was assessed using three different approaches: 1. Apply the trial inclusion/exclusion criteria to calculate the proportion of women in the cohort who would have been eligible for each selected trial. 2. Apply the criteria used to make clinical decisions [14– 18] about the use of the treatments evaluated in each trial to the women in the cohort to calculate the proportion of women who would receive the treatment in Tayside. 3. Identify women in the cohort who received a treatment evaluated in a trial as part of their clinical care and calculate the proportion of women who would have been eligible for the trial evaluating that treatment.
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cancer audit records. Treatment received was derived from prescribing, Cancer Registry and audit records. Menopausal status was taken from local coding, ie. pre-, peri- and post-menopausal. Hospital discharge records were used to identify the presence of a medical condition or procedure prior to a patient’s breast cancer diagnosis. Charlson’s Comorbidity Index P6 was used as a proxy for a life expectancy under 10 years or where the trial protocol excluded any serious concomitant disease [12,20]. The inclusion and exclusion criteria for each trial were applied to the extracted data for each woman. Search syntax was developed for each criterion, which were then run sequentially. Where there were no data to test a criterion, the individual concerned was treated as if she was eligible for the trial on that criterion. An example of trial eligibility criteria, the sources that provided data against which to apply these criteria, how these criteria were interpreted and translated into syntax and the effect of each eligibility criterion on the pool of included women is given in Supplementary file 1. 2. Apply clinical eligibility criteria to the cohort Three senior members of a multidisciplinary group of breast cancer specialists based at Ninewells Hospital, Dundee, Tayside and also experienced in clinical trials (breast clinical oncologist, breast medical oncologist, breast surgeon) defined the local clinical criteria used to decide whether a woman was eligible for the treatments evaluated in the selected trials. These criteria were then applied to the cohort in the same way as for the trial eligibility criteria. 3. Identify women in the cohort who received a trial intervention
The methods for each aim are described in turn. 1. Apply trial inclusion/exclusion criteria to the cohort Previous work had identified all women (n = 4811) who were residents of Tayside, (population 420,000) with an incident breast cancer from January 1993 to December 2008 [12,19]. The cohort was characterised in terms of demographics (eg. age, menopausal status), cancer presentation (including tumour size, node and metastases (TNM) status, oestrogen receptor (ER) status, pathological grading, pathological description of axillary node metastases, screening mammography or symptomatic presentation), co-morbidity and type of surgery. Electronic linkage was used to provide additional data for the cohort. Past medical history was obtained using International Classification of Diseases versions 9 and 10 codes from hospital discharge records and linked to prescribing records; details of cancer at presentation were recorded from Cancer Registry and
Women in the cohort who had received a trial intervention as part of their clinical care were identified and the proportion who would have met the relevant trial’s eligibility criteria calculated. The type or dose of chemotherapy or radiotherapy each patient received was not available and so this analysis was restricted to adjuvant endocrine therapies. Additionally, we have previously documented that while endocrine therapy utilisation is comparable to that expected in the population served [21], chemotherapy utilisation may be as low as 40% of the potential in the Tayside region. This also supported a focus on endocrine therapy. 3. Approvals NHS Tayside Research & Development approved the study (reference number 2012ON51). Data were remotely accessed through a Safe Haven facility in accordance with data protection principles.
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4. Results A total of 421 trials were identified from the guidelines [14–17] and best practice document [18]. After exclusions 39 trials were presented to the Scottish Cancer Trials Breast Group (Fig. 1). Delegates placed 306 votes and the 12 trials that received most votes became the trials selected for this study (see Table 2; the full list of 39 trials is in Supplementary file 2). Delegates did not suggest any trials that met our inclusion criteria in addition to the 39 listed. Two radiotherapy trials, START A [29] and START B [30], had identical eligibility criteria and were counted as a single trial, giving 11 sets of inclusion/exclusion criteria. Almost three quarters (3535/4811) of women in the cohort met eligibility criteria for at least one trial and 58% (2787) were eligible for four or more trials. Chemotherapy trials (NSABP B-28 [28], TACT [31]) imposed the strictest exclusion criteria; just over one third (1653; 34%) of the cohort would have been eligible for at least one chemotherapy trial. Radiotherapy trials (CANADIAN [24], EORTC [25], START A [29], START B [30], TARGIT-A [32]) were more inclusive with 71% (3419) of the cohort meeting the inclusion criteria for at least one radiotherapy trial; 24% (1143) would have been eligible for all four radiotherapy trials. Almost half the cohort, 47% (2247), would have been eligible for at least one of the endocrine therapy trials (ATAC [22], BIG 1-98 [23], IES [26], MA17 [27], TEAM [33]). The proportion of women in the cohort meeting the eligibility criteria for each trial varied between 19% for MA17 [27] and 71% for START A [29] and B [30] (Table 2). Clinical eligibility criteria for trial treatments in Tayside, as judged by a multidisciplinary specialist
team produced a narrower eligibility range: 19% for NSABP B-28 [28] to 59% for TEAM [33] (Table 2). The proportion of women in the cohort who received an endocrine therapy evaluated in ATAC [22], BIG 1-98 [23], IES [26] and MA17 [27] as part of their care and who would also have been eligible for a trial evaluating that treatment ranged from 17% to 56% (Table 3). 5. Discussion This study suggests that around three quarters of women in a population-based cohort who had early breast cancer over a 16-year period would have been eligible for at least one of the major adjuvant endocrine therapy, chemotherapy or radiotherapy trials informing guidelines for breast cancer management. More women in the community with breast cancer would have met the eligibility criteria of major breast cancer trials than seen in similar studies for other medical conditions [4–6]. While encouraging, eligibility was rarely more than 45% (Table 2) and, for endocrine therapies at least, many women were ineligible for trials evaluating treatments that they nevertheless received as part of their care (Table 3). The potential impact on the effectiveness and safety of the treatment for patients ineligible for the trial is unclear. There may be no difference between the efficacy and safety of the treatment for this excluded group compared with those who were included in the trial; however, if a person is a potential candidate for a treatment in routine care, he or she ought to be eligible for the trial of that treatment [3]. Mass exclusions are common: children, the elderly and pregnant women are often excluded from trials and yet receive the evaluated treatments in routine care [35] and differences in prognosis and outcomes are often clear between those included in trials and those
Fig. 1. Selection of trials for study inclusion.
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Table 2 Eligibility of cohort by trial and clinical criteria. Trial
Number of women in cohort (n = 4811) meeting trial criteria (%)
Number of women in cohort (n = 4811) meeting Tayside clinical criteria for intervention (%)
ATAC (Arimadex, tamoxifen alone or in combination) [22]* Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer BIG 1-98 (Breast International Group) [23]* Letrozole with tamoxifen given in sequence as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer CANADIAN [24] Hypofractionated radiation therapy EORTC (European Organization for Research and Treatment of Cancer) [25] The addition of a boost dose on the primary tumour bed after lumpectomy in breast conserving treatment for breast cancer IES (Intergroup Exemestane Study) [26] Exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment MA17 [27] Letrozole following tamoxifen as extended adjuvant therapy in receptorpositive breast cancer NSABP B-28 (National Surgical Adjuvant Breast and Bowel Project) [28] Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer START (Standardisation of Breast Radiotherapy Trial) A [29] and START B [30]* Radiotherapy hypofractionation for treatment of early breast cancer TACT (Taxotere as Adjuvant Chemotherapy Trial) [31] Sequential docetaxel as adjuvant chemotherapy for early breast cancer TARGIT-A (Targeted intra-operative radiotherapy versus whole breast radiotherapy) [32]* Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer TEAM (Tamoxifen Exemestane Adjuvant Multinational) [33]* Five years of exemestane as initial therapy compared to 5 years of tamoxifen followed by exemestane: The TEAM Trial, a prospective, randomised, phase III trial in postmenopausal women with hormonesensitive early breast cancer.
2053 (43%)
1150 (24%)
2141 (45%)
2328 (48%)
2163 (45%)
2462 (51%)
2086 (43%)
1292 (27%)
2087 (43%)
1958 (41%)
905 (19%)
2424 (50%)
943 (20%)
923 (19%)
3419 (71%)
2554 (53%)
1098 (23%)
2240 (47%)
2088 (43%)
1550 (32%)
2186 (45%)
2848 (59%)
*
Patients in the cohort actually contributed to these trials.
Table 3 Receipt of adjuvant endocrine therapy against eligibility for specific endocrine trials. Trial
Treatment
Number of women in database receiving treatment
% who would have met trial eligibility criteria
ATAC [22]
Tamoxifen Anastrozole1 Tamoxifen Letrozole Sequential Letrozole and Tamoxifen Tamoxifen Exemestane Sequential Exemestane and Tamoxifen Tamoxifen Letrozole Letrozole and Tamoxifen
3170 859 3170 452 311 3170 168 160 3170 452 311
48 56 50 33 38 49 43 44 29 17 24
BIG 1-98 [23]
IES [26]
MA17 [27]
1 ATAC also had a combined therapy arm but this was withdrawn relatively early in the trial and not recommended for clinical use. See Howell et al. [34].
excluded [36]. The current study demonstrates that while more inclusive than for pulmonary or diabetic conditions, four major breast cancer trials (ATAC [22], BIG 1-98 [23], IES [26] and MA17 [27]) have eligibility criteria
that excluded women who nevertheless received the treatment under evaluation in clinical practice. As we were conservative in favour of inclusion, actual eligibility rates are likely to be lower.
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The difference between trial eligibility criteria and the criteria used clinically in Tayside for the same treatment was often striking (Table 2). Age was often used clinically as a criterion while most trials did not. Conversely, trials often excluded women with prior surgery, previous cancers, or were very specific about how much treatment women could have had prior to the trial, which were not generally used as clinical criteria in everyday practice. MA17, for example, required women to have completed between 4.5 and six years of adjuvant tamoxifen after surgery. This trial criterion excluded over 3000 women from the cohort but was not a clinical eligibility criterion used in Tayside. The small number of clinicians involved in selecting criteria used for Table 2 (three senior members of the multidisciplinary team at Ninewells Hospital, Tayside, with a total of 75 years clinical experience) means that we remain uncertain as to why the difference is as large as it is, or whether the differences would remain if physicians based at other centres had been involved instead of, or as well as, the three Tayside physicians. Despite the subjectivity of these judgements, and the small number of physicians involved, we do believe that this issue merits further exploration. What is clear is that trial eligibility criteria do not translate directly into clinical practice in Tayside (most breast cancer care in Tayside is delivered through Ninewells Hospital) and this may be true elsewhere. Indeed, this is likely to be an issue of importance well beyond Scotland. This study has a number of strengths. It focused on 12 trials influential in breast cancer management, identified through major guidelines and best practice documents with the final selection being made by representatives of breast cancer multidisciplinary teams with cancer trials expertise. Secondly, the populationbased cohort presents a comprehensive dataset describing the management of breast cancer over a long period. It is based on record linkage of routine data and is therefore large, unselected and highly representative of women in Tayside with breast cancer. The Tayside population is stable, with few people moving in or out and we believe our cohort is also likely to be representative of similar populations elsewhere. It may be less representative of dynamic populations, and/or where people move into an area specifically for cancer treatment. Some data needed to make decisions about trial eligibility were missing from the cohort and we were either forced to ignore the criterion and include the woman, or occasionally use a proxy (eg. Charlson Index score of P6 as a proxy for frailty). The quality of data from the various sources used to create the cohort is not uniformly high, with, for example, prescription data being more detailed than chemotherapy or radiotherapy data, which may mean representativeness is overestimated in chemotherapy and radiotherapy trials. Dates were a particular problem, meaning we
were often unable to apply criteria based on timing. Human Epidermal Growth Factor Receptor 2 (HER2) targeted therapies have made a significant impact since 2000 [37]; however, the lack of HER2 receptor data prior to 2000 did not allow us to assess the relevance of the anti HER2 trials to the population under consideration. Generally, these limitations mean that we have been favourable to trials with regard to inclusion and only exclude women when we had good data to make an exclusion decision. 6. Conclusions The eligibility criteria used in 12 major adjuvant drug or radiotherapy trials for early breast cancer are more inclusive than seen in similar studies for chronic medical conditions. However, it was rare for more than 45% of women in the community to be eligible for a given trial and many women prescribed endocrine treatments would have been excluded from the trials evaluating those treatments. Trial and clinical eligibility criteria are clearly different and trialists should think carefully about the criteria that might be used clinically when defining the eligibility criteria for their trial. 7. Contributors ST, CM and AH conceived the study design. All authors contributed to the development of the search strategy and RD, AH, AMT and ST selected and screened trials identified by that search. RD and AMT ran the consultation with the Scottish Cancer Trials Breast Group. RD extracted data for the 12 trials selected by this group and all authors discussed and agreed the data extracted. RD and CM did the record linkage. RD led the analysis, in discussion with all authors. All authors discussed the results. RD wrote the first draft of the paper, with ST leading further revisions. All authors contributed to revisions of the paper. Funding CR-UK Dundee Cancer Centre Development Fund. Conflict of interest statement AMT was a contributor to TEAM, BIG 1-98, ATAC and TARGIT-A, and a named author on the BIG 1-98 and TARGIT-A publications. He and the other authors have no other conflict of interest. Acknowledgements We acknowledge the support of the Health Informatics Centre, University of Dundee for managing and supplying the anonymised data, Dr. Caroline
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Michie and Professor John Dewar for their clinical input and NHS Tayside for providing the original data source. The work was funded by the CR-UK Dundee Cancer Centre Development Fund. The funder played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.ejca.2015.01.064. References [1] Rothwell PM. External validity of randomised controlled trials: “to whom do the results of this trial apply?”. Lancet 2005;365(9453):82–93. [2] Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis 1967;20:637–48. [3] Treweek S, Zwarenstein M. Making trials matter: pragmatic and explanatory trials and the problem of applicability. Trials 2009;10:37. [4] Travers J, Marsh S, Williams M, Weatherall M, Caldwell B, Shirtcliffe P, et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax 2007;62:219–23. [5] Travers J, Marsh S, Caldwell B, Williams M, Aldington S, Weatherall M, et al. External validity of randomized controlled trials in COPD. Respir Med 2007;101:1313–20. [6] Saunders C, Byrne CD, Guthrie B, Lindsay RS, McKnight JA, Philip S, et al. External validity of randomized controlled trials of glycaemic control and vascular disease: how representative are participants? Diabet Med 2013;30(3):300–8. [7] Fraser J, Steele N, Al Zaman A, Yule A. Are patients in clinical trials representative of the general population? Dose intensity and toxicities associated with FE100C-D chemotherapy in a non-trial population of node positive breast cancer patients compared with PACS-01 trial group. Eur J Cancer 2011;47:215–20. [8] National Institute for Health and Clinical Excellence. The guidelines manual. London: National Institute for Health and Clinical Excellence; 2009. [9] Zwarenstein M, Treweek S. What kind of randomized trials do we need? J Clin Epidemiol 2009;62:461–3. [10] Rothwell PM. Factors that can affect the external validity of randomised controlled trials. PLoS Clin Trials 2006;1:e9. [11] Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA 2003;290:1624–32. [12] McCowan C, Shearer J, Donnan PT, Dewar JA, Crilly M, Thompson AM, et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer 2008;99:1763–8. [13] McCowan C, Thompson AM. The importance of nonpharmacogenetic factors in endocrine therapy. Pharmacogenomics 2012;13:721–8. [14] Yarnold J. Early and locally advanced breast cancer: diagnosis and treatment National Institute for Health and Clinical Excellence guideline 2009. Clin Oncol (R Coll Radiol) 2009;21:159–60.
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[15] Burstein HJ, Prestrud AA, Seidenfeld J, Anderson H, Buchholz TA, Davidson NE, et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 2010;28(23):3784–96. [16] Smith BD, Bentzen SM, Correa CR, Hahn CA, Hardenbergh PH, Ibbott GS, et al. Fractionation for whole breast irradiation: an American Society for Radiation Oncology (ASTRO) evidencebased guideline. Int J Radiat Oncol Biol Phys 2011;81(1):59–68. [17] Scottish Intercollegiate Guidelines Network. SIGN 84 Management of breast cancer in women. A national clinical guideline. Scottish Intercollegiate Guidelines Network. Edinburgh 2005. [18] British Medical Journal. Best Practice: Primary invasive breast cancer. 2012 cited; Available from: . [19] Makubate B, Donnan PT, Dewar JA, Thompson AM, McCowan C. Cohort study of adherence to adjuvant endocrine therapy, breast cancer recurrence and mortality. Br J Cancer 2013;108:1515–24. [20] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83. [21] Fong A, Shafiq J, Saunders C, Thompson A, Tyldesley S, Barton MB, et al. A comparison of systemic therapy utilization in British Columbia, Scotland, and Western Australia with models of “optimal” therapy. Breast 2012;21:562–9. [22] The ATAC. (Arimidex, tamoxifen alone or in combination) trialists’ group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomized trial. Lancet 2002;359:2131–9. [23] The Breast International Group(BIG) 1–98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353:2747–57. [24] Whelan T, MacKenzie R, Julian J, Levine M, Shelley W, Grimond L, et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 2002;94:1143–50. [25] Bartelink H, Horiot J-C, Poortmans P, Struikmans H, Van den Bogaert W, Barillot I, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001;345:1378–87. [26] Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081–92. [27] Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, et al. Randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793–802. [28] Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 2005;23:3686–96. [29] The START Trialists’ Group. The UK Standardisation of Breast Radiotherapy (START) trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol 2008;9:331–41. [30] The START Trialists’ Group. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet 2008;371:1098–107. [31] Ellis P, Barrett LP, Johnson L, Cameron D, Wardley A, O’Reilly S, et al. TACT Trial Management Group; tact trialists. sequential docetaxel as adjuvant chemotherapy for early breast cancer
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Original Research
Do participants in adjuvant breast cancer trials reflect the breast cancer patient population? Shaun Treweek a,⇑, Ruth Dryden b, Colin McCowan c, Alison Harrow d, Alastair M. Thompson e a
Health Services Research Unit, University of Aberdeen, AB25 2ZD, UK Institute for Research and Innovation in Social Services, Glasgow G1 1UZ, UK c Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, G12 8QQ, UK d Dundee Cancer Centre, University of Dundee, Dundee DD1 9SY, UK e Department of Surgical Oncology, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston Texas 77030, USA b
Received 13 January 2015; accepted 13 January 2015 Available online 7 April 2015
KEYWORDS Breast cancer Adjuvant treatment Phase III trials Applicability Generalisabilty Record linkage
Abstract Aim: To describe the proportion of women in Tayside, Scotland diagnosed with early breast cancer who would have been eligible for influential adjuvant breast cancer trials. Methods: Phase III trials of adjuvant treatment for breast cancer referenced in five national guidelines were shortlisted by breast cancer specialists to identify the twelve considered most influential. Eligibility criteria were extracted from protocols and applied to a 16-year cohort of women who had received a diagnosis of breast cancer and the proportion meeting trial criteria calculated. The criteria used clinically in Tayside to make decisions about use of the trial treatments were also applied to the cohort. Finally, the proportion of women receiving adjuvant endocrine therapy as part of their care and who would have been eligible for the trial evaluating that therapy was calculated. Results: Of the cohort’s 4811 women, 3535 (73%) were eligible for at least one trial but eligibility for an individual trial rarely exceeded 45%. There were substantial differences between the proportion of women meeting trial eligibility criteria and the proportion considered clinically eligible for the same treatment. The proportion of women receiving an endocrine therapy as part of their care who would also have been eligible for the trial evaluating that treatment ranged from 17% to 56%.
⇑ Corresponding author at: Health Services Research Unit, University of Aberdeen, 3rd Floor, Health Sciences Building, Foresterhill, Aberdeen AB25 2ZD, UK. Mobile: +44 777 901 6955; fax: +44 1224 438165. E-mail addresses: [email protected] (S. Treweek), [email protected] (R. Dryden), [email protected] (C. McCowan), [email protected] (A. Harrow), [email protected] (A.M. Thompson).
http://dx.doi.org/10.1016/j.ejca.2015.01.064 0959-8049/Ó 2015 Elsevier Ltd. All rights reserved.
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Conclusion: Clinical eligibility criteria may be at variance with trial criteria. For adjuvant endocrine therapy, a substantial proportion of women who would have been ineligible for a trial nevertheless received the trial treatment as part of their care. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Poor applicability of trial results to routine clinical practice is the most frequent criticism by clinicians of randomised trials, systematic reviews and guidelines [1]. Relevance needs to be designed into trials [2,3]. This does not always happen. Consider community-based asthma and chronic obstructive pulmonary disease patients, whose clinical management is based on the results of 17 major trials cited in the Global Initiative for Asthma (GINA) guidelines and 18 major trials cited in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines [4,5]. A median 4% of patients in the community with current asthma (range 0% to 36%) met the eligibility criteria for the GINA trials [4]; the equivalent figure for GOLD was 5% (range 0% to 20%) [5]. Saunders and colleagues found that the proportion of people with Type 2 diabetes who met the eligibility criteria for seven diabetes trials ranged from 3.5% to 50.7% [6]. In breast cancer, a recent study reported greater toxicities in patients outside a trial than within the trial [7]. Trials underpin guideline recommendations so differences between trial and community populations affect many clinical decisions. Indeed, generalisability is acknowledged as a common challenge faced by guideline development groups [8]. Calls for trials with wider applicability have come from those interested in clinical decision-making [3,9,10] and those interested in health policy [11]. A comparison of trial and community-based populations is challenged by the availability of high quality community data. Previous work in Tayside, Scotland has characterised a cohort of all incident breast cancers over a 16 year period between 1992
and 2008 and includes data from 4811 women [12,13]. This cohort includes cancer characteristics at presentation, linked via each woman’s unique Community Health Index number to other datasets such as prescribing, hospital discharge, cancer registry and General Registrar’s Office death certificate records. The current study had four aims: To identify recent adjuvant endocrine therapy, chemotherapy and radiotherapy breast cancer trials which have been influential in the treatment of women with breast cancer. To examine how many of the women in the Tayside cohort would have been eligible to participate in each of these trials. To compare the proportion of women who would have received the treatment evaluated in the trials based on clinical decisions in Tayside versus trial eligibility criteria. To assess the proportion of women in the cohort who received a trial treatment but would not have been eligible for the trial evaluating that treatment.
2. Methods 2.1. Identification and prioritisation of randomised controlled trials Four national guidelines (two UK, two USA) [14–17] and one best practice document [18] were used to identify phase III trials of adjuvant treatment for breast cancer. The inclusion and exclusion criteria used to select trials are given in Table 1.
Table 1 Inclusion and exclusion criteria. Inclusion criteria
Exclusion criteria
Incident/Primary breast cancer
Prevention, diagnostic, surgical and neoadjuvant trials; metastatic breast cancer Studies where Human Epidermal Growth Factor
Phase III trial Receptor 2 (HER2) was investigated/treatment effects on HER2 patients2 Adjuvant radiotherapy and adjuvant systemic therapy Women P400 participants1 Published in English between 2003 and 2012 1
Trials focusing on women with advanced or metastatic disease Male breast cancer
Based on the assumption that larger trials are more influential; the same cut-off was used by Travers and colleagues [4,5]. Human Epidermal Growth Factor Receptor 2 (HER2) trials were excluded as the Tayside cohort had no data on HER2 status prior to 2000, in keeping with national testing guidelines; it was therefore not possible to assess patient eligibility for these trials within the cohort. 2
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Trials were identified and screened by four of the authors (RD, AH, AMT, ST). Where trials could not be excluded based on the abstract, the full text was obtained. To select trials considered by breast cancer clinical specialists and researchers as most influential on practice, the initial list of trials was reviewed by delegates attending the 2012 Scottish Cancer Trials Breast Group annual meeting. Delegates were asked to identify up to ten trials they felt had most influenced current practice and to suggest additional trials. The 12 trials receiving the most votes were included in this study. 2.2. Extraction of trial inclusion and exclusion criteria Full text copies of the most recent study protocols were obtained for all 12 selected trials. The lists of inclusion/exclusion criteria for each trial were extracted (by RD) and agreed by the co-authors. These were then matched to the data available in the cohort. Eligibility for adjuvant therapy was assessed using three different approaches: 1. Apply the trial inclusion/exclusion criteria to calculate the proportion of women in the cohort who would have been eligible for each selected trial. 2. Apply the criteria used to make clinical decisions [14– 18] about the use of the treatments evaluated in each trial to the women in the cohort to calculate the proportion of women who would receive the treatment in Tayside. 3. Identify women in the cohort who received a treatment evaluated in a trial as part of their clinical care and calculate the proportion of women who would have been eligible for the trial evaluating that treatment.
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cancer audit records. Treatment received was derived from prescribing, Cancer Registry and audit records. Menopausal status was taken from local coding, ie. pre-, peri- and post-menopausal. Hospital discharge records were used to identify the presence of a medical condition or procedure prior to a patient’s breast cancer diagnosis. Charlson’s Comorbidity Index P6 was used as a proxy for a life expectancy under 10 years or where the trial protocol excluded any serious concomitant disease [12,20]. The inclusion and exclusion criteria for each trial were applied to the extracted data for each woman. Search syntax was developed for each criterion, which were then run sequentially. Where there were no data to test a criterion, the individual concerned was treated as if she was eligible for the trial on that criterion. An example of trial eligibility criteria, the sources that provided data against which to apply these criteria, how these criteria were interpreted and translated into syntax and the effect of each eligibility criterion on the pool of included women is given in Supplementary file 1. 2. Apply clinical eligibility criteria to the cohort Three senior members of a multidisciplinary group of breast cancer specialists based at Ninewells Hospital, Dundee, Tayside and also experienced in clinical trials (breast clinical oncologist, breast medical oncologist, breast surgeon) defined the local clinical criteria used to decide whether a woman was eligible for the treatments evaluated in the selected trials. These criteria were then applied to the cohort in the same way as for the trial eligibility criteria. 3. Identify women in the cohort who received a trial intervention
The methods for each aim are described in turn. 1. Apply trial inclusion/exclusion criteria to the cohort Previous work had identified all women (n = 4811) who were residents of Tayside, (population 420,000) with an incident breast cancer from January 1993 to December 2008 [12,19]. The cohort was characterised in terms of demographics (eg. age, menopausal status), cancer presentation (including tumour size, node and metastases (TNM) status, oestrogen receptor (ER) status, pathological grading, pathological description of axillary node metastases, screening mammography or symptomatic presentation), co-morbidity and type of surgery. Electronic linkage was used to provide additional data for the cohort. Past medical history was obtained using International Classification of Diseases versions 9 and 10 codes from hospital discharge records and linked to prescribing records; details of cancer at presentation were recorded from Cancer Registry and
Women in the cohort who had received a trial intervention as part of their clinical care were identified and the proportion who would have met the relevant trial’s eligibility criteria calculated. The type or dose of chemotherapy or radiotherapy each patient received was not available and so this analysis was restricted to adjuvant endocrine therapies. Additionally, we have previously documented that while endocrine therapy utilisation is comparable to that expected in the population served [21], chemotherapy utilisation may be as low as 40% of the potential in the Tayside region. This also supported a focus on endocrine therapy. 3. Approvals NHS Tayside Research & Development approved the study (reference number 2012ON51). Data were remotely accessed through a Safe Haven facility in accordance with data protection principles.
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4. Results A total of 421 trials were identified from the guidelines [14–17] and best practice document [18]. After exclusions 39 trials were presented to the Scottish Cancer Trials Breast Group (Fig. 1). Delegates placed 306 votes and the 12 trials that received most votes became the trials selected for this study (see Table 2; the full list of 39 trials is in Supplementary file 2). Delegates did not suggest any trials that met our inclusion criteria in addition to the 39 listed. Two radiotherapy trials, START A [29] and START B [30], had identical eligibility criteria and were counted as a single trial, giving 11 sets of inclusion/exclusion criteria. Almost three quarters (3535/4811) of women in the cohort met eligibility criteria for at least one trial and 58% (2787) were eligible for four or more trials. Chemotherapy trials (NSABP B-28 [28], TACT [31]) imposed the strictest exclusion criteria; just over one third (1653; 34%) of the cohort would have been eligible for at least one chemotherapy trial. Radiotherapy trials (CANADIAN [24], EORTC [25], START A [29], START B [30], TARGIT-A [32]) were more inclusive with 71% (3419) of the cohort meeting the inclusion criteria for at least one radiotherapy trial; 24% (1143) would have been eligible for all four radiotherapy trials. Almost half the cohort, 47% (2247), would have been eligible for at least one of the endocrine therapy trials (ATAC [22], BIG 1-98 [23], IES [26], MA17 [27], TEAM [33]). The proportion of women in the cohort meeting the eligibility criteria for each trial varied between 19% for MA17 [27] and 71% for START A [29] and B [30] (Table 2). Clinical eligibility criteria for trial treatments in Tayside, as judged by a multidisciplinary specialist
team produced a narrower eligibility range: 19% for NSABP B-28 [28] to 59% for TEAM [33] (Table 2). The proportion of women in the cohort who received an endocrine therapy evaluated in ATAC [22], BIG 1-98 [23], IES [26] and MA17 [27] as part of their care and who would also have been eligible for a trial evaluating that treatment ranged from 17% to 56% (Table 3). 5. Discussion This study suggests that around three quarters of women in a population-based cohort who had early breast cancer over a 16-year period would have been eligible for at least one of the major adjuvant endocrine therapy, chemotherapy or radiotherapy trials informing guidelines for breast cancer management. More women in the community with breast cancer would have met the eligibility criteria of major breast cancer trials than seen in similar studies for other medical conditions [4–6]. While encouraging, eligibility was rarely more than 45% (Table 2) and, for endocrine therapies at least, many women were ineligible for trials evaluating treatments that they nevertheless received as part of their care (Table 3). The potential impact on the effectiveness and safety of the treatment for patients ineligible for the trial is unclear. There may be no difference between the efficacy and safety of the treatment for this excluded group compared with those who were included in the trial; however, if a person is a potential candidate for a treatment in routine care, he or she ought to be eligible for the trial of that treatment [3]. Mass exclusions are common: children, the elderly and pregnant women are often excluded from trials and yet receive the evaluated treatments in routine care [35] and differences in prognosis and outcomes are often clear between those included in trials and those
Fig. 1. Selection of trials for study inclusion.
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Table 2 Eligibility of cohort by trial and clinical criteria. Trial
Number of women in cohort (n = 4811) meeting trial criteria (%)
Number of women in cohort (n = 4811) meeting Tayside clinical criteria for intervention (%)
ATAC (Arimadex, tamoxifen alone or in combination) [22]* Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer BIG 1-98 (Breast International Group) [23]* Letrozole with tamoxifen given in sequence as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer CANADIAN [24] Hypofractionated radiation therapy EORTC (European Organization for Research and Treatment of Cancer) [25] The addition of a boost dose on the primary tumour bed after lumpectomy in breast conserving treatment for breast cancer IES (Intergroup Exemestane Study) [26] Exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment MA17 [27] Letrozole following tamoxifen as extended adjuvant therapy in receptorpositive breast cancer NSABP B-28 (National Surgical Adjuvant Breast and Bowel Project) [28] Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer START (Standardisation of Breast Radiotherapy Trial) A [29] and START B [30]* Radiotherapy hypofractionation for treatment of early breast cancer TACT (Taxotere as Adjuvant Chemotherapy Trial) [31] Sequential docetaxel as adjuvant chemotherapy for early breast cancer TARGIT-A (Targeted intra-operative radiotherapy versus whole breast radiotherapy) [32]* Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer TEAM (Tamoxifen Exemestane Adjuvant Multinational) [33]* Five years of exemestane as initial therapy compared to 5 years of tamoxifen followed by exemestane: The TEAM Trial, a prospective, randomised, phase III trial in postmenopausal women with hormonesensitive early breast cancer.
2053 (43%)
1150 (24%)
2141 (45%)
2328 (48%)
2163 (45%)
2462 (51%)
2086 (43%)
1292 (27%)
2087 (43%)
1958 (41%)
905 (19%)
2424 (50%)
943 (20%)
923 (19%)
3419 (71%)
2554 (53%)
1098 (23%)
2240 (47%)
2088 (43%)
1550 (32%)
2186 (45%)
2848 (59%)
*
Patients in the cohort actually contributed to these trials.
Table 3 Receipt of adjuvant endocrine therapy against eligibility for specific endocrine trials. Trial
Treatment
Number of women in database receiving treatment
% who would have met trial eligibility criteria
ATAC [22]
Tamoxifen Anastrozole1 Tamoxifen Letrozole Sequential Letrozole and Tamoxifen Tamoxifen Exemestane Sequential Exemestane and Tamoxifen Tamoxifen Letrozole Letrozole and Tamoxifen
3170 859 3170 452 311 3170 168 160 3170 452 311
48 56 50 33 38 49 43 44 29 17 24
BIG 1-98 [23]
IES [26]
MA17 [27]
1 ATAC also had a combined therapy arm but this was withdrawn relatively early in the trial and not recommended for clinical use. See Howell et al. [34].
excluded [36]. The current study demonstrates that while more inclusive than for pulmonary or diabetic conditions, four major breast cancer trials (ATAC [22], BIG 1-98 [23], IES [26] and MA17 [27]) have eligibility criteria
that excluded women who nevertheless received the treatment under evaluation in clinical practice. As we were conservative in favour of inclusion, actual eligibility rates are likely to be lower.
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The difference between trial eligibility criteria and the criteria used clinically in Tayside for the same treatment was often striking (Table 2). Age was often used clinically as a criterion while most trials did not. Conversely, trials often excluded women with prior surgery, previous cancers, or were very specific about how much treatment women could have had prior to the trial, which were not generally used as clinical criteria in everyday practice. MA17, for example, required women to have completed between 4.5 and six years of adjuvant tamoxifen after surgery. This trial criterion excluded over 3000 women from the cohort but was not a clinical eligibility criterion used in Tayside. The small number of clinicians involved in selecting criteria used for Table 2 (three senior members of the multidisciplinary team at Ninewells Hospital, Tayside, with a total of 75 years clinical experience) means that we remain uncertain as to why the difference is as large as it is, or whether the differences would remain if physicians based at other centres had been involved instead of, or as well as, the three Tayside physicians. Despite the subjectivity of these judgements, and the small number of physicians involved, we do believe that this issue merits further exploration. What is clear is that trial eligibility criteria do not translate directly into clinical practice in Tayside (most breast cancer care in Tayside is delivered through Ninewells Hospital) and this may be true elsewhere. Indeed, this is likely to be an issue of importance well beyond Scotland. This study has a number of strengths. It focused on 12 trials influential in breast cancer management, identified through major guidelines and best practice documents with the final selection being made by representatives of breast cancer multidisciplinary teams with cancer trials expertise. Secondly, the populationbased cohort presents a comprehensive dataset describing the management of breast cancer over a long period. It is based on record linkage of routine data and is therefore large, unselected and highly representative of women in Tayside with breast cancer. The Tayside population is stable, with few people moving in or out and we believe our cohort is also likely to be representative of similar populations elsewhere. It may be less representative of dynamic populations, and/or where people move into an area specifically for cancer treatment. Some data needed to make decisions about trial eligibility were missing from the cohort and we were either forced to ignore the criterion and include the woman, or occasionally use a proxy (eg. Charlson Index score of P6 as a proxy for frailty). The quality of data from the various sources used to create the cohort is not uniformly high, with, for example, prescription data being more detailed than chemotherapy or radiotherapy data, which may mean representativeness is overestimated in chemotherapy and radiotherapy trials. Dates were a particular problem, meaning we
were often unable to apply criteria based on timing. Human Epidermal Growth Factor Receptor 2 (HER2) targeted therapies have made a significant impact since 2000 [37]; however, the lack of HER2 receptor data prior to 2000 did not allow us to assess the relevance of the anti HER2 trials to the population under consideration. Generally, these limitations mean that we have been favourable to trials with regard to inclusion and only exclude women when we had good data to make an exclusion decision. 6. Conclusions The eligibility criteria used in 12 major adjuvant drug or radiotherapy trials for early breast cancer are more inclusive than seen in similar studies for chronic medical conditions. However, it was rare for more than 45% of women in the community to be eligible for a given trial and many women prescribed endocrine treatments would have been excluded from the trials evaluating those treatments. Trial and clinical eligibility criteria are clearly different and trialists should think carefully about the criteria that might be used clinically when defining the eligibility criteria for their trial. 7. Contributors ST, CM and AH conceived the study design. All authors contributed to the development of the search strategy and RD, AH, AMT and ST selected and screened trials identified by that search. RD and AMT ran the consultation with the Scottish Cancer Trials Breast Group. RD extracted data for the 12 trials selected by this group and all authors discussed and agreed the data extracted. RD and CM did the record linkage. RD led the analysis, in discussion with all authors. All authors discussed the results. RD wrote the first draft of the paper, with ST leading further revisions. All authors contributed to revisions of the paper. Funding CR-UK Dundee Cancer Centre Development Fund. Conflict of interest statement AMT was a contributor to TEAM, BIG 1-98, ATAC and TARGIT-A, and a named author on the BIG 1-98 and TARGIT-A publications. He and the other authors have no other conflict of interest. Acknowledgements We acknowledge the support of the Health Informatics Centre, University of Dundee for managing and supplying the anonymised data, Dr. Caroline
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Michie and Professor John Dewar for their clinical input and NHS Tayside for providing the original data source. The work was funded by the CR-UK Dundee Cancer Centre Development Fund. The funder played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.ejca.2015.01.064. References [1] Rothwell PM. External validity of randomised controlled trials: “to whom do the results of this trial apply?”. Lancet 2005;365(9453):82–93. [2] Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis 1967;20:637–48. [3] Treweek S, Zwarenstein M. Making trials matter: pragmatic and explanatory trials and the problem of applicability. Trials 2009;10:37. [4] Travers J, Marsh S, Williams M, Weatherall M, Caldwell B, Shirtcliffe P, et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax 2007;62:219–23. [5] Travers J, Marsh S, Caldwell B, Williams M, Aldington S, Weatherall M, et al. External validity of randomized controlled trials in COPD. Respir Med 2007;101:1313–20. [6] Saunders C, Byrne CD, Guthrie B, Lindsay RS, McKnight JA, Philip S, et al. External validity of randomized controlled trials of glycaemic control and vascular disease: how representative are participants? Diabet Med 2013;30(3):300–8. [7] Fraser J, Steele N, Al Zaman A, Yule A. Are patients in clinical trials representative of the general population? Dose intensity and toxicities associated with FE100C-D chemotherapy in a non-trial population of node positive breast cancer patients compared with PACS-01 trial group. Eur J Cancer 2011;47:215–20. [8] National Institute for Health and Clinical Excellence. The guidelines manual. London: National Institute for Health and Clinical Excellence; 2009. [9] Zwarenstein M, Treweek S. What kind of randomized trials do we need? J Clin Epidemiol 2009;62:461–3. [10] Rothwell PM. Factors that can affect the external validity of randomised controlled trials. PLoS Clin Trials 2006;1:e9. [11] Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA 2003;290:1624–32. [12] McCowan C, Shearer J, Donnan PT, Dewar JA, Crilly M, Thompson AM, et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer 2008;99:1763–8. [13] McCowan C, Thompson AM. The importance of nonpharmacogenetic factors in endocrine therapy. Pharmacogenomics 2012;13:721–8. [14] Yarnold J. Early and locally advanced breast cancer: diagnosis and treatment National Institute for Health and Clinical Excellence guideline 2009. Clin Oncol (R Coll Radiol) 2009;21:159–60.
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