World J Urol (2008) 26:5–11 DOI 10.1007/s00345-008-0240-9
TOPIC PAPER
Guidelines for development of diagnostic markers in bladder cancer Peter J. Goebell · Susan L. Groshen · Bernd J. Schmitz-Dräger
Received: 3 October 2007 / Accepted: 19 January 2008 / Published online: 6 February 2008 © Springer-Verlag 2008
Abstract Objectives Advances in understanding cancer at the molecular level have identiWed numerous alterations associated with cancer development and progression. The eVorts in evaluating these putative biomarkers in clinical studies of patients with cancer are increasing in order to improve the clinical management of the disease. However, despite numerous attempts, the results of such biomarker studies are frequently inconsistent and sometimes even contradictory. Aim of this work is to discuss some of the recognized problems which have impeded our understanding of the role of new markers and prevented the introduction of these markers into patient management. Results These Problems include standardization issues, selection of patient cohorts and endpoints and statistical considerations. In order to improve and standardize marker development a stepwise procedure in four phases, analogous to clinical trials is proposed. Furthermore, a common terminology, considerations on the population to study as well as general recommendations for planning and conducting the evaluation of markers will be presented.
P. J. Goebell (&) Department of Urology, Friedrich-Alexander University of Erlangen, Maximiliansplatz 1, 91054 Erlangen, Germany e-mail:
[email protected] S. L. Groshen Department of Preventive Medicine Norris Comprehensive Cancer Center, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA B. J. Schmitz-Dräger Department of Urology, EuromedClinic, Fürth, Germany
Conclusion The implementation of this discussion may foster the integration of new tools and strategies screening, diagnosis and surveillance of patients with bladder cancer. Keywords
Marker · Bladder · Cancer · Phases
Introduction Advances in understanding cancer at the molecular level have identiWed numerous alterations associated with cancer development and progression. In case of bladder cancer, there is a strong need for new markers supporting screening, initial diagnosis, surveillance for recurrent lesions, detection of early progression, and prediction of the biological potential of a particular tumor with the ultimate aim to alter clinical patient management [1–8]. With voided urine there is a unique source available for bladder cancer diagnosis. This medium can be collected absolutely non-invasive and at more or less unlimited quantity. In consequence, it appears relatively easy to develop a bladder cancer test, since many molecular determinants of bladder tumor growth and invasion are released into urine [9, 10]. Thus, many bladder cancer tests, such as BTA-Stat/ TRAK, UBC-Rapid, UBC-IRMA, BLCA-4, HA-HAase, NMP-22, and survivin detect soluble markers released in urine (product inserts of BTA-Stat/TRAK, NMP-22, UBC) and are used to evaluate their clinical use [11–24]. Moreover, due to a reduced cell-cell adherence preferably tumor cells are released into urine. This fact has not only been the rationale for the development of urine cytology but also other cell-based tests such as UroVysion (multicolor FISH), uCyt+™, microsatellite DNA analysis, telomerase, DD23, etc., detect either genetic alterations or cell-surface antigens that may indicate biologic characteris-
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tics of a particular cancer and may be used for treatment decisions [25–40]. In addition, a wide range of alterations has been detected through high-throughput analyses of tissue samples comparing malignant lesions with adjacent “normal” tissue [41–47]. However, there is a substantial lack of comprehensive studies investigating the presence of the identiWed molecular alterations from high throughput analyses in serum or urine samples from the same individual. Serum levels of a given alteration may diVer and be less informative or proteins apparently important for the ability of a tumor cell to spread may not be found in urine. In summary, numerous attempts have been made to provide clinicians and consequentially patients with such a “marker”-test. Many of these markers have been extensively studied in case-control trials. However, the results of these studies are often inconsistent and sometimes contradictory. Recognized problems include diVerent methods of performing assays, the use of diVerent subsets of patients (diVerence in stage or treatment) and endpoints (e.g. local versus distant recurrence versus survival), and inadequate study design, leading to incompatible data sets. This has impeded understanding the role of new markers. Since replication and independent conWrmation are hallmarks of the scientiWc method, the implementation of standards and conventions is essential prior to any conclusive recommendation for the introduction of new markers to the clinic [48, 49]. New markers are typically evaluated in single institutional settings and comparison due to diVerences in study design, experimental methods, and data analysis remains diYcult [50, 51]. Another often underestimated obstacle is the fact, that there is no common terminology in place for authors to describe the actual position of a given biomarker in its development. Thus, the circumstances and purpose under which a tumor-biologic determinant is evaluated and eventually used in a clinical setting should be well deWned and clearly indicated, since its level of evidence may hamper its clinical use [52, 53]. Currently, it is diYcult to conclude from reports whether a determinant could be useful for risk assessment (who may get cancer?), diagnosis (who has cancer?), the prediction of outcome (prognosis), the prediction of response to a given therapy (prediction) or as a possible target for intervention. Although there has been discussion for establishing general methodological principles and guidelines for design, conduct, analysis, and reporting of marker studies (analogous to those for clinical trials) [48, 54–62], they are not generally accepted. Therefore, funding agencies and research groups will need standardized guidelines for the conduction of maker studies in the future. One of the tasks of the International Bladder Cancer Network (IBCN), a multi-institutional interdisciplinary consortium formed to
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develop and assess biomarkers for diagnostic and prognostic use, was and is to take a closer look at general methodological issues associated with Marker development and evaluation [63]. The IBCN reached consensus, that in establishing the utility of a marker for clinical use, investigators must demonstrate that (a) the marker can be reliably and consistently measured, (b) the marker has good sensitivity and speciWcity—so it can, with reasonably high probability, identify patients with a better or worse prognosis or with a greater or lesser likelihood of having a speciWed condition—and (c) the use of the marker will improve outcome by targeting therapeutic or diagnostic interventions. Accordingly, this group has deWned four phases through which markers are developed [64].
Phases of marker studies Phase I: assay development and evaluation of clinical prevalence (feasibility studies) This phase comprises the identiWcation of a target potentially suited for diagnostic use. IdentiWcation of the target may occur on many ways, classically by identifying the target in tumor cells, however, with the advent of molecular technology other ways or deWnitions of a variety of target are conceivable. Key issue remains that a diVerence between tumor cells and normal urothelial cells is prerequisite and must be demonstrated. It has to be of note that Weld eVects are an established integral part of the development of bladder cancer, which warrants not only including “normal” adjacent tissue but also tissue and samples from healthy individuals as important controls. Furthermore, an adequate medium to be studied must be identiWed. For bladder cancer this will be urine is most cases, however, other sources are conceivable. A reproducible and optimized assay is the essential prerequisite prior to the application to clinical samples. This should be complemented with feasibility studies documenting the prevalence and expression of the markers of interest and examining the association with demographic and clinical characteristics in a representative study cohort (target population). A case-control setting will be suYcient in this state of development. Phase II: evaluation studies for clinical utility This phase comprises further optimization of the assay technique (e.g., standardization, automatisation) and/or interpretation of the assay results develop. The ultimate goal of this phase of investigation is to develop hypotheses and to deWne standards that can be used to perform the Phase III studies.
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One of the reasons that no marker has been included in clinical guidelines until today is a lack of adequate assessment in a distinct clinical setting. Therefore, in this phase it is necessary to deWne indications of future marker use and to prospectively assess a given marker in this scenario. For bladder cancer markers evaluation in the following indications is required: • Screening • Assessment of patients with hematuria (gross/microhematuria) • Follow-up of patients with bladder cancer The reason behind is that a “diagnosis of bladder cancer” per se does not exist as a clinical question. Patients require examination due to, mostly unspeciWc symptoms or are investigated for tumor recurrence after a previous episode of bladder cancer. Screening of high risk populations may be another potential indication [65], however, it should be noted that screening studies for bladder cancer are mostly carried out prospectively in a large, well deWned cohort based upon an elaborate protocol and thus may rather be considered phase III. Ethical approval should be obtained although at this stage no consequences are drawn from the results. Phase II trials are mostly mono-institutional studies. However, adequately sized and representative samples of patients may be easier to achieve in a large collaborative network with suYcient numbers of specimens to deWne and select the most appropriate set of samples. In addition, identifying sources of variability during these phases of biomarker development is required for designing a Phase III study. Based upon the results adequate cut-oV values will be deWned for quantitative assays. It is essential that the outcome from Phase II studies translates into hypotheses that may form the basis for Phase III analysis.
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of cystoscopies in low risk patients or additional cystoscopies or even biopsies in high risk patients with a positive test. If applicable, the new test must be compared with the current standard (currently cytology in most situations). SpeciWc attention must be paid to the fact that side-by-side comparision must consider the nature of the assay. Therefore, it must be guaranteed that a suYcient expertise for all tests included in the study is available. This is of speciWc relevance for cell-based assays (e.g. urine cytology, FISH, immunocytology). Otherwise, the results for these tests might be negatively biased. If available, quality control measures must be taken. An elaborate study protocol also deWning the cut-oV values prospectively and approval by an ethics committee as well as sample size calculation are mandatory; a randomized, multi-center study design is routineously applied. Phase IV: validation and technology transfer as application studies The aims of Phase IV studies are (a) to transfer the techniques and established methods of the assays and other aspects of the technology and (b) to evaluate the ability of other investigators and clinicians at other institutions to apply these methods and interpret the results. In consequence, standardization issues and quality control measures need to be addressed. If the assay is to be performed in centralized labs, sample procurement, storage and shipping need to be deWned. In addition, cost/beneWt analyses may be done based upon information obtained through phase III and/or phase IV trials. The Phase IV study is the Wnal step in the translational research process, in which a given biomarker is incorporated into clinical practice. Phase IV trials are prospective multi-center studies. The establishment of a collaborative network would clearly facilitate these essential interactions.
Phase III: conWrmation studies In Phase III hypotheses generated previously are tested with suYcient power in a larger deWned clinical setting in an independent, prospective cohort of patients. The clinical utility of a given marker assay, its performance, and interpretation is established in that phase. The aim of Phase III trials is the generation of information (evidence-based) that may eventually be included into clinical guidelines. In order to comply with this goal it is necessary to include the marker into decision making in this phase and to upfront deWne consequences drawn from a given result (positive or negative). E.g. for screening studies this would result in urological assessment of individuals that tested positive for a marker. For follow-up analyses after bladder cancer a negative test could lead to a decreased frequency
Which population would beneWt ? Cystoscopy, the gold standard for the detection of bladder cancer, is invasive and relatively expensive. In fact, due to the lifelong need for recurrence monitoring by cystoscopy and the treatment of recurrent tumors, the cost per bladder cancer patient from diagnosis to death is the highest among all cancers [65]. Thus, a noninvasive, highly sensitive and speciWc marker for detecting bladder cancer could decrease the morbidity associated with cystoscopy, improve patient quality of life, and—depending on the assay cost—decrease costs by substituting a less expensive, noninvasive test for the more expensive endoscopic procedure.
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In consequence, it has to be discussed whether the introduction of a biologic determinant/marker is useful in speciWc a setting (Table 1). The majority of patients with high grade bladder cancer, at the time of initial presentation, have tumors that invade the lamina propria (stage T1) and beyond [8, 15, 66–68]. These patients have a high risk of developing distant metastasis and cancer speciWc death despite aggressive treatment. Early detection of bladder tumors, before they become muscle–invasive, might improve survival [69, 70]. Insofar, screening of a high risk population could be of strong interest [65, 70]. Bladder tumors recur frequently; typically 40–80% of patients with bladder cancer will have a recurrence within 3 years following initial treatment [68]. Furthermore, tumors that recur may be of higher grade or stage. Thus, patients with bladder cancer usually undergo 3- to 6-month surveillance. To avoid unneccessary cystoscopies and/or to have a non-invasive tool for the decision on whom to perform a cystoscopy would clearly be beneWcial. Thus, for the surveillance of Bladder Cancer the investigation of biologic determinants are urgently needed and would deWnite alter the management of the disease [70–73].
The potential of non-invasive markers in the assessment of patients with hematuria was recently demonstrated by several authors [74–77]. SpeciWcally in the assessment of patients with gross hematuria sensitive assays might improve diagnosis of bladder cancer in this population.
Material and data—mandatory steps to harmonize the procurement of samples As indicated above, the proper collection of samples will be a crucial step in the entire process and needs a precise, reliable and transparent description of the used standard operating procedures. In addition, the annotaion of the clinical data linked to the sample should also follow common rules to allow comparison of the results in the future. The harmonization of biorepositories used for marker research and the implementation of a common infrastructure as in clinical study-networks and interdisciplinary multi-institutional groups will facilitate the exchance for meaningful research in the Weld as it has for other tumor enteties [78–80].
Statistical considerations Table 1 The use of biologic determinants in diVerent clinical settings Indication
Potential role of markers
Screening
(q)
Microhematuria
(q)
Gross hematuria
q
Voiding symptoms
-
Follow up
q
Statistical assessment of marker trials may vary considering the phase of development of a given marker or the targeted study population. Phase 1 studies will make for example use of geneexpression analyses and yield in hundreds of altered species of mRNA. The reliability and reproducability may be crucial not to obscure important determinants. The ability of the analyses to discriminate between a cancerous or non-
Table 2 Possible work-Xow for a Phase I study To do 1. DeWne Primary aims • IdentiWcation of leads for potentially useful determinants for follow-up
Review previous work on follow-up schedules and crucial steps during the monitoring of a patient
• Prioritize identiWed leads
Identify and prioritize beneWcial role in the schedule for a marker
2. Select specimen • Consider/determine variability of subjects in demographics, histology, prognosis, mode of detection
Review of variability in the follow-up population
• Consider/determine inXuence of disease prevalence
Review prevalence of primary aims
3. Primary outcome measures • Value of biologic determinant
Identify measures that control for assay variability
4. Evaluating results • Binary scale
Provide true-positive and false-positive rates to determine sensitivity and speciWcity
• Multiple values
Provide Receiver operating curve (ROC) Development of a statistical algorithm for the use of the determinant
5. Plan conWrmatory study
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cancerous lesion as measured on a binary scale as well as true positive and true negative values will be indicative for the robustness of the results. In addition, sensitivity and speciWcity will be applicable as reciever operating curves (ROC) as descriptive parameters of the test used in case the alteration may take many values being more or less indicative for malignant chances [81–83]. To exemplify these methodological considerations a possible work-Xow for a Phase I study to identify determinants during follow-up is provided in Table 2 (modiWed acc. to [84]).
Conclusions There is a clear need to further harmonize terminology, approaches and circumstances under which markers are evaluated in the future. The successful transition of marker/ determinants into useful clinical tools to either detect inividuals at risk or to avoid unnecessary invasive procedures will depend on the implementation of general methodological principles and guidelines for design, conduct, analysis and reporting of marker studies. ConXict of interest statement
There is no conXict of interest.
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