2009 THE AUTHORS; JOURNAL COMPILATION Urological Oncology
2009 BJU INTERNATIONAL
WEST MIDLANDS BLADDER CANCER PROGNOSIS PROGRAMME ZEEGERS et al.
BJUI
The West Midlands Bladder Cancer Prognosis Programme: rationale and design
BJU INTERNATIONAL
Maurice P. Zeegers, Richard T. Bryan, Carolyn Langford, Lucinda Billingham*, Paul Murray†, Neeta S. Deshmukh†, Syed Hussain†, Nick James†, D. Michael A. Wallace‡ and K.K. Cheng Department of Public Health, Epidemiology and Biostatistics, *CRUK Clinical Trials Unit, and †CRUK Institute of Cancer Studies, University of Birmingham, and ‡University Hospital Birmingham NHS Trust, Birmingham, UK Accepted for publication 8 June 2009
Study Type – Prognosis (inception cohort) Level of Evidence 1b
OBJECTIVE To describe the rationale and design of the Bladder Cancer Prognosis Programme (BCPP), and to demonstrate the capability of this design. METHODS There is a need to understand the determinants of bladder cancer to help reduce recurrence, progression, morbidity, mortality and related costs. We previously showed that lifestyle factors are important for determining the risk of bladder cancer, but little is known about their importance in determining the risk of recurrence or progression after diagnosis. Also,
INTRODUCTION Bladder cancer is the fifth most common cancer in the UK, affecting >10 000 individuals each year [1]. It is the most frequently occurring tumour of the urinary system and accounts for one in every 28 new cases of cancer each year. Bladder cancer causes >5000 deaths each year in the UK [1], and the incidence and mortality rates increase sharply with age, with about two-thirds of patients aged ≥65 years, with a median age of 69 years. The strong relationship between risk and age means that bladder cancer will remain an important health problem, given the increasingly ageing population. In the
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histopathological factors alone provide only crude prognostication; the analysis of molecular markers represents a method for refinement but research in this area has not been useful in informing therapeutic decisions or prognostication. The BCPP is a prospective longitudinal cohort study of all patients with newly diagnosed bladder cancer within the West Midlands (UK), investigating the influence of lifestyle factors on recurrence and progression, health-related quality of life, the predictive effect of a panel of molecular markers on recurrence or progression, and the establishment of Europe’s largest comprehensive bladder cancer biorepository. It also incorporates the first randomized clinical trial on the efficacy of selenium and vitamin E on bladder cancer. The numbers and proportions of eligible patients recruited, questionnaires completed and specimens obtained were all recorded.
RESULTS
USA, bladder cancer is the fifth most expensive cancer in terms of healthcare expenditure [2]. It also has the highest cost per patient from diagnosis to death among all cancers in the Medicare system [3]. In the UK, individual patient management is more costly for bladder cancer than for, e.g. prostate cancer [4], but this remains underinvestigated. There is therefore a need to understand the determinants of bladder cancer development to help reduce recurrence, progression, morbidity, mortality and related costs. We have shown in metaanalyses [5–7] that lifestyle factors are important for determining the risk of bladder cancer. These lifestyle risk factors might
represent exposures to be avoided after the diagnosis is made. However, there is almost no information on the importance of lifestyle factors in determining the risk of recurrence or progression of bladder cancer after diagnosis.
Since December 2005, 771 patients have been recruited (68% of eligible patients) and of these, 331 are currently being followed up by questionnaires. We have obtained blood, urine and tumour tissues from 92%, 80% and 80% of patients, respectively. CONCLUSIONS The design of the BCPP has allowed this study to be incorporated into routine clinical work throughout the West Midlands, achieving high levels of recruitment, and data and specimen collection. This might represent a model for the future investigation of urological and other malignancies. KEYWORDS bladder cancer, epidemiology, cohort study, biobank
Bladder cancer is novel amongst epithelial cancers in its divergent pathways of tumorigenesis. Most (70–80%) bladder cancers are confined to the urothelium or the lamina propria, i.e. non-muscle-invasive bladder cancer (NMIBC), and these patients are subject to frequent follow-up by cystoscopy. Although the negative effect of one cystoscopy might not be significant, the
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overall impact on quality of life might be considerable, as many patients will have to undergo these tests regularly for the rest of their lives. Shover et al. [8] provided some anecdotal evidence that repeated cystoscopy and intravesical treatment can have adverse psychological effects that lead to sexual dysfunction. However, previous investigations of the quality of life of patients with bladder cancer have yielded limited evidence [9], and particularly of the psychological effects of cystoscopic surveillance and tumour recurrences. Many patients (about half) will have no recurrence after the initial diagnosis and treatment. For these patients, accurate prediction, using a good prognostic tool, could spare them unnecessary physical discomfort and psychological stress. Alternatively, lack of cystoscopic surveillance could result in an undetected recurrence and this might cause anxiety. A previous study [10] examined patient preference for urinary tests as a prognostic tool, with reduced surveillance, compared to regular cystoscopic surveillance in bladder cancer follow-up. The study found that 89% of patients preferred cystoscopic surveillance if the sensitivity of the urinary test was 99% before they would opt out of cystoscopic surveillance. However, this study was cross-sectional and the sample size was small (102 patients, with only 15 women). Currently, histopathological factors alone provide only very crude prognostication. In this regard, the analysis of molecular markers could represent a potential method for refinement. Unfortunately, research in this area has not been useful in informing therapeutic decisions or prognostication [11]. We recently conducted a systematic review of molecular markers in bladder cancer and identified seven markers, including FGFR3, EGFR, pRB, p53, Ki-67, VEGF and CK20 for which there has been relatively strong or most consistent evidence [12,13].
METHODS The West Midlands Bladder Cancer Prognosis Programme (BCPP) was initiated by the Cancer Research UK Bladder Cancer Group, based at the University of Birmingham, to study the determinants of recurrence and progression of NMIBC and to design a
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prognostic tool that could predict adverse outcomes. Apart from the direct benefit to patients, the reduction in frequency of cystoscopic surveillance could bring considerable healthcare savings. The BCPP cohort encompasses three linked projects each with separate objectives. The core of BCPP is a large epidemiological prospective cohort study of patients with NMIBC. In this cohort, common and modifiable lifestyle exposures (project 1), health-related quality of life (project 2) and molecular markers (project 3) are related to the recurrence and progression of bladder cancer. In addition, BCPP aims to establish a bladder cancer tissue bank that comprises blood, urine, and tumour tissues. BCPP aims to recruit patients with newly diagnosed bladder cancer over a 3-year period from urological centres within the West Midlands, a region at the heart of the UK including >5 million people (≈8% of the British population). Potentially eligible patients are being identified at haematuria clinics on the basis of abnormal cystoscopic findings suggestive of bladder cancer. Adult patients (aged ≥18 years), with newly diagnosed pathologically confirmed urothelial carcinoma of any stage, comprise the BCPP cohort. To obtain standardized pathological data, 10% of all diagnostic haematoxylin and eosin-stained slides are reviewed centrally. Patients with a previous diagnosis of cancer of the urethra, bladder, ureter or renal pelvis within the last decade, patients with HIV infection, and patients with any other condition that might interfere with the safety of the patient or evaluation of the study objectives, are excluded from recruitment. Based on the previous incidence of bladder cancer (derived from regional cancer registry data), it has been estimated that ≈4220 new cases of bladder cancer will be registered in the West Midlands during the 3-year study period, of which ≈80% (3400) will meet the inclusion criteria for the study. Of these, it is expected that 1600 cases of NIMBC will be included in the primary analysis. Detailed data are being collected at the time of diagnosis by trained research nurses who conduct semi-structured face-to-face interviews before transurethral resection of bladder tumour (TURBT). In these interviews information about socio-demographics (age, sex, ethnicity, marital status, education) health-related lifestyle (lifetime smoking
history, passive smoking, use of hair dye), medical and drug history, dietary intake (food-type frequency, alcohol, caffeine and total fluid intake, use of vitamins and artificial sweeteners), social support and quality of life are collected (Table 1). The quality-of-life questions were developed by the European Organization for Research and Treatment for Cancer (EORTC). Assessments using the general cancer questionnaire QLQ-C30 will be made at baseline in the entire cohort. Biological samples are also collected at the time of diagnosis. These include blood, fresh and paraffin-embedded tumour samples, and urine. Blood from all patients are collected in two 5-mL EDTA tubes and one plain 10-mL tube by a research nurse during routine preclerking. At the same time, urine samples are collected in a 50-mL centrifuge tube, the presence of UTI is assessed and urinary pH is measured (Fig. 1). Blood and urine samples are then centrifuged and supernatant is transferred into several smaller aliquots. All specimen collection and processing is performed by trained BCPP research nurses according to detailed standard operating procedures. Fresh tumour samples are selected by the operating surgeon, taking into consideration the absolute priority for clinical samples for histopathological diagnosis. The BCPP tissue samples are immediately placed directly into cryovial storage tubes and snapfrozen in liquid nitrogen. All blood, urine and tissue samples are temporarily stored onsite at − 80 °C and are periodically transferred to the central laboratory subject to local pathologist authorisation (Fig. 1). If the local pathologist is not satisfied with the tissue sample that they have received then they can ask for the BCPP specimen to be returned. In addition, paraffin-embedded tumour tissue blocks are identified from pathology records. 5 mm ‘Tru-Cut’ needle cores are taken from a representative region of each tumour block and mounted in normal liver to construct tissue arrays, each comprising 50 different tumours. The array blocks are subsequently sectioned, stained and assessed by two independent pathologists. In all, four cores from each block are taken to create different sets of tissue arrays. The selection of the amount and location of tumour tissue for BCPP collection and storage is purely at the discretion of the operating surgeon. When the smallest tumours are removed, generally with cold-cup biopsy forceps to avoid diathermy damage, then the
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whole tumour sample is used for histopathological diagnosis without tissue being collected for BCPP. In this scenario, the molecular markers are analysed on normal paraffin tissue sections provided by the local pathology department, without the need for them to relinquish the solitary tissue block. In addition, patients receive a postal selfcompletion questionnaire after TURBT and before their first follow-up (≈3 months after diagnosis) comprising questions on occupational and residential history, and family history of cancer (Table 1). In this period patients are also asked to keep a 7-day food [14], fluid and micturition diary and samples of toenail clippings are taken to measure dietary selenium levels. At 3 months and then annually (up to 5 years after diagnosis), changes in health-related lifestyle, quality of life and utility-based patient preferences for surveillance are assessed (Table 1). At each of these times assessments using the general cancer questionnaire QLQC30 will be repeated, with the addition of disease-specific assessments using the QLQC30, the QLQ-BLS24, with 24 questions specific to NMIBC, the EORTC QLQ-BLM30, with 30 questions specific to muscle-invasive bladder cancer [15]. The questions on utilitybased preferences have been adopted from the ‘Standard Gamble’ technique [16]. The hypothetical options are to continue repeated invasive cystoscopy or to take a gamble and choose a less-invasive prognostic tool with two possible outcomes: a true-negative prediction with probability P or a falsenegative prediction with the probability 1 − P. The probability of outcomes is varied until the patient is indifferent about the two alternatives. A measure of the utility of the new prognostic test is the lowest P acceptable to patients. A full version of the baseline, postal and follow-up questionnaires and the 7-day food, fluid and micturition diary are available for free download at http://www.bcpp.bham.ac. uk/patients.shtml. Patients’ medical records are continuously examined by the research nurses for information on clinical treatment, histopathology, and outcome measures which are reported on case report forms (Table 1). The case report forms are available upon request. The primary endpoints are recurrence and progression. Recurrence is defined as the new occurrence of a bladder cancer at the same or
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TABLE 1 Measurements in the West Midlands BCPP Phase Baseline (at diagnosis)
Postal (1–2 months after diagnosis) Follow-up (3 months after diagnosis and then yearly)
Ongoing
Measurements Residence GP contact information Marital status Ethnic origin Education and qualifications Life smoking history (filter, nonfilter, hand-rolled, cigar and pipe) Passive smoking Food frequency (staple, meat, fish, vegetables, fruit, dairy and other) Fluid intake (alcoholic drinks, hot drinks, soft drinks) Artificial sweeteners Vitamins and supplements Hair colouring Industrial chemicals Medications Medical history Reproductive history Social support Quality of life Occupational history Residential history Family history of cancer Life smoking history (filter, nonfilter, hand-rolled, cigar and pipe) Food frequency (staple, meat, fish, vegetables, fruit, dairy and other) Fluid intake (alcoholic drinks, hot drinks, soft drinks) Vitamins and supplements Medications Medical history Standard gamble Social support Quality of Life Cystoscopy TURBT Urinary pH Cystectomy and staging investigations Local and review pathology Pre and postoperative treatments End of primary treatment Recurrence or progression Recurrence local and review pathology Death
different site as the initial index primary cancer, and excluding recurrences identified at the first 3-month check cystoscopy. These earlier lesion have been excluded because they might be indistinguishable from residual primary tumours. Progression is defined as a recurrence with an increase in tumour grade from 1/2 to grade 3, or an increase in TNM stage, or the new occurrence of carcinoma in situ (CIS) in a bladder previously free from such lesions, or the new occurrence of multiple tumours following resection of a
solitary tumour, or the need for a cystectomy because of refractory disease.
RESULTS In all, 771 patients with new bladder tumours have been recruited into the cohort since the launch of the study in December 2005, comprising 68% of eligible patients. We have obtained blood, urine and tumour tissues from 92%, 80% and 80% of the patients,
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FIG. 1. Specimen collection (blood, urine, tissue) and handling in the West Midlands BCPP. Cystoscopy Clinic Researcher takes patient through Informed Consent process Pre-Clerking Written Informed Consent obtained. Consent Form checked to confirm consent for tissue, blood and urine collection is given Consent for specimen collection
NO
No further action
YES Blood and Urine Collection TURBT Samples collected at Surgeon divides tumour same visit or subsequent specimen for histopathology Histopathology attendance for and BCPP Tissue Bank surgery Tissue sent to pathology laboratory for Specimens processed histopathological diagnosis and transferred to Sufficient material cryovials labelled with for diagnosis? unique identifier No (Specimen Number) Request retrieval from Yes local storage Stored locally at –80°C Local pathologist writes pathology report Periodically transferred to BCPP Tissue Bank Pathologist and for long-term storage Researcher complete pathology Case Report Form Pathology Case Report Form sent to BCPP Study Office
respectively. Patient recruitment rate and sample acquisition is set to increase as the number of centres actively recruiting is increasing. Of the 771 patients recruited to the study, 331 are currently being followed up by questionnaires. Recruitment and attrition rates can be monitored at http:// www.bcpp.bham.ac.uk. An overview of key findings and publications derived from the BCPP programme can be found at http://www.bcpp.bham.ac.uk.
DISCUSSION The first project in BCPP examines whether common and potentially modifiable lifestyle factors that have been reported to influence
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BCPP Tissue Bank Specimens transferred to cryovials labelled with unique identifier (Specimen Number) Specimens snap-frozen in theatre Stored locally at –80°C for a min. of 2 weeks Responsible pathologist signs release of tumour specimens Periodically transferred to BCPP Tissue Bank for long-term storage
bladder cancer risk also affect the risk of recurrence and progression. The primary research questions in project 1 are selected on the basis of the strength of available evidence [5]. They are also potentially amenable to modification by behavioural and lifestyle changes: (i) Among patients who are cigarette smokers at diagnosis, is stopping smoking associated with a lower risk of recurrence or progression compared to those who continue?; (ii) Is total fluid intake associated with the risk of recurrence or progression?; (iii) Is total fruit consumption associated with the risk of recurrence or progression?; (iv) Is toenail-based selenium level associated with the risk of recurrence or progression? Due to the distinct disease characteristics and natural histories of NMIBC and muscleinvasive bladder cancer, these subgroups will
be investigated separately. BCPP will also investigate other putative risk factors associated with bladder cancer recurrence or progression. These factors include smoking (active and passive), diet (including vitamins and minerals), types of beverages, medications, hair dye, urinary pH, artificial sweeteners, medical history, menstrual and reproductive factors, family history of cancer, residential and occupational histories as proxies for environmental exposures. BCPP will investigate longitudinally the health-related quality of life in a large sample of bladder cancer patients. The assessments made at various times during patient followup will provide a general description of the quality of life of patients at diagnosis and during the course of the disease. The questionnaires will provide information on physical, emotional, social, cognitive and role functioning as well as a measure of overall health status. Measures of general symptoms will also be available, together with measures of the impact of the disease on urinary, sexual and bowel symptoms. The research objectives in this second project are to study the effects of recurrence and progression on quality of life; to study the effects of repeat cystoscopy, urostomy and self-catheterization on quality of life; and to study the patients’ assessments of a hypothetical prognostic model and how this affects their preference for the mode of surveillance. A third project within the BCPP cohort will investigate whether molecular markers are useful in predicting recurrence and progression. Immunohistochemistry on tissue arrays will be used to detect the expression of the selected molecular markers that have potential predictive value. Current time pressures and workload mean that it is very difficult to superimpose new research projects onto routine clinical work whilst using the existing staff. From its inception the BCPP has been designed with this in mind. The need for additional human resources to be provided to each participating urology unit was identified early in the development process. A fully funded studydedicated research nurse has therefore been provided to each participating unit. The BCPP Research Nurses are highly trained in all aspects of the programme and undertake all of the extra duties required, without adversely affecting clinicians’ workload and the normal pathways of clinical care.
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When completed, BCPP will comprise the largest study on bladder cancer prognosis in Europe. BCPP also offers a platform for other projects. For example, the SELENIB trial is currently recruiting patients from within the BCPP cohort with histologically confirmed NMI TCC of the bladder. SELENIB is a randomized double-blinded placebocontrolled trial which will examine the effect of selenium and vitamin E (d-α-tocopherol) supplementation on recurrence and progression amongst patients with bladder TCC in a 2 × 2 factorial design. It is anticipated that 800 patients from the cohort will be randomized over 3 years.
Jackie Sears, Claire Slater, Helen Shackleford and Claire Taylor. The BCPP programme is funded by Cancer Research UK and supported by the Department of Public Health and Epidemiology and Institute for Cancer Studies, University of Birmingham. The West Midlands Bladder Cancer Prognosis Programme is funded by Cancer Research UK.
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CONFLICT OF INTEREST
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None declared. 12 REFERENCES
BCPP collects different biological materials, together with detailed linked information on behavioural and environmental exposures and clinical outcomes. This tissue bank will form a unique resource in the UK. It offers opportunities for new projects in genomics and translational medicine. The resource will also be useful for future research into the identification and testing of markers that might be used in screening, diagnosis and surveillance of bladder cancer. BCPP data and access to specimens stored within the BCPP tissue bank will be made available to research groups, subject to ethical approval and permission from the BCPP Working Group. Requests should be made to the BCPP Study Office. More information about BCPP and contact details can be found at http://www.bcpp.bham.ac.uk.
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ACKNOWLEDGEMENTS 6 With thanks to all participating clinicians and their staff from within the West Midlands region for their continued support: Mr P. Cooke, Mr K. Desai, Mr L.A. Emtage, Mr M. Foster, Mr K.W. Kadow, Mr C. Luscombe, Mr A. Makar, and Mr B.D. Sarmah. We would also like to recognize the invaluable contribution made by the BCPP nursing, research and administrative staff to the programme: Rukhsana Abid, Jeanette Allison, Debra Bird, Krys Castro, Tina Coles, Stuart Collins, Alison McGuire, Janis Goodall, Carolyn Letchford, Terry Martin, Laura Moore, Joy Robinson,
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Correspondence: Professor Maurice Zeegers, Unit of Genetic Epidemiology, Department of Public Health, Epidemiology and Biostatistics, University of Birmingham, Public Health Building, Edgbaston, Birmingham, B15 2TT, UK. e-mail:
[email protected] Abbreviations: BCCP, Bladder Cancer Prognosis Programme; TURBT, transurethral resection of bladder tumour; NMIBC, nonmuscle-invasive bladder cancer; EORTC, European Organization for Research and Treatment for Cancer; TCC, Traditional Cell Carcinoma.
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