- Email: [email protected]
Is there an indication for frozen section examination of the ureteral margins during cystectomy for transitional cell carcinoma of the bladder?
274
W.A. See / Urologic Oncology: Seminars and Original Investigations 25 (2007) 271–280
Should we screen for bladder cancer in a high-risk population? A cost per life-year saved analysis. Lotan Y, Svatek RS, Sagalowsky AI, Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. Cancer 2006;107:982–90 Background: The U.S. Food and Drug Administration recently approved screening high-risk patients for bladder cancer using urinebased markers. The cost and life-years saved associated with bladder cancer screening were evaluated. Methods: A Markov model was created to estimate cumulative cancer-related costs and efficacy of screening (vs. no screening) of a high-risk population for bladder cancer using a urine-based tumor marker over a 5-year period. Assumptions were based on literature review of survival and progression rates for patients with bladder cancer and costs associated with different bladder cancer disease states. Results: Screening for bladder cancer in a population with a 4% incidence of bladder cancer resulted in a gain of 3.0 life years per 1000 subjects at a cost savings of $101,000 for the population, assuming a 50% downstaging in the screened population from muscle-invasive to nonmuscle-invasive disease. One-way sensitivity analyses found that screening is the most cost-effective strategy if cancer incidence is ⬎1.6%, tumor marker costs ⬍$126, marker sensitivity is ⬎26%, marker specificity is ⬎54%, downstaging with screening is ⬎20%, and office cystoscopy costs ⬍$694. Varying costs of cystectomy, transurethral resection of bladder tumor (TURBT), chemotherapy, end-of-life care, costs of metastatic disease, and a computed tomography scan over a wide range did not affect the superiority of screening. Conclusions: The model found that urine-based markers are cost-effective in a high-risk population. Prospective randomized trials in a completely asymptomatic high-risk cohort are indicated before bladder cancer screening can be recommended.
Commentary Determining the value of screening for a specific disease process in a given population is a complex and challenging problem. The prevalence of the disease within a given population, the performance characteristics of the screening tool, the cost and morbidity of downstream diagnostic tests, the efficacy of available treatment options for the disease and, ultimately, in the case of cancer, the survival benefits associated with screening are among the variables to be considered. In settings where these variables are well established it is possible to reach concrete and valid conclusions regarding the value of screening for a given disease. Conversely, to the extent that these variables are less well established, and their values “assumed”, the conclusions reached become far less robust. In the manuscript by Lotan et al, the authors use a relatively sophisticated modeling technique to perform a “cost per life year saved” analysis for bladder cancer screening using a point of service assay. Regrettably, many of the assumptions upon which this analysis was based were “soft” at best. For example, the authors acknowledge the critical importance of disease incidence in risk reduction and screening costs. The use of a 4% incidence figure based upon a cited publication by Grossman et al (6% incidence in that study) may or may not be valid. The “high-risk” population cited in the Grossman article was derived from patients presenting to an urologist’s office with so-called bladder cancer risk factors. Although the percentage of patients who were asymptomatic in the Grossman study is not available, their mere presence in the urologist’s office suggests that many had signs or symptoms of urologic disease. In a truly asymptomatic population of patients the actual incidence of bladder cancer may be far less than the 4% figure for the Lotan manuscript. The concept of early bladder cancer detection and treatment through screening is intrinsically appealing. However, as the authors themselves have stated, in the case of bladder cancer screening, additional research is required prior to reaching any conclusion as to the cost and/or appropriateness of this strategy. doi:10.1016/j.urolonc.2007.03.009 William A. See, M.D. Is there an indication for frozen section examination of the ureteral margins during cystectomy for transitional cell carcinoma of the bladder? Schumacher MC, Scholz M, Weise ES, Fleischmann A, Thalmann GN, Studer UE, Department of Urology, Institute of Pathology, University Hospital Bern, Bern, Switzerland. J Urol 2006;D176:2409 –13 Purpose: We evaluated the incidence of pathological findings of the ureter at cystectomy for transitional cell carcinoma of the bladder and assessed the usefulness of intraoperative frozen section examination of the ureter. Materials and Methods: Histopathological findings of ureteral frozen section examination were compared with the corresponding permanent sections, and the diagnostic accuracy of frozen section examination was evaluated. These segments were then compared with the more proximal ureteral segments resected at the level where they cross over the common iliac arteries. The histopathological findings of the ureteral segments were then correlated for upper urinary tract recurrence and overall survival. Results: Transitional cell carcinoma or carcinoma in situ was found on frozen section examination of the distal ureter in 39 of 805 patients (4.8%) and on permanent sections in 29 (3.6%). In 755 patients, the false-negative rate of frozen section examination of the ureters was 0.8%. Of the patients with carcinoma in situ diagnosed on the first frozen section examination, 80% also had carcinoma in situ in the bladder. Transitional cell carcinoma or carcinoma in situ in the most proximally resected ureteral segments was found in 1.2% of patients. After radical cystectomy, there was tumor recurrence in the upper urinary tract in 3% of patients with negative ureteral frozen section examination, and in 17% with carcinoma in situ on frozen section examination. Conclusions: Routine frozen section examination of the ureters at radical cystectomy is only recommended for patients with carcinoma in situ of the bladder, provided the ureters are resected where they cross the common iliac arteries.
W.A. See / Urologic Oncology: Seminars and Original Investigations 25 (2007) 271–280
275
Commentary An axiom of medical testing is that one should only order a test if the results will influence one’s decision-making or actions. The corollary to this principal is that the value of the information obtained by the test must exceed the costs of the tests, both monetary- and risk-based. Frozen section analysis of the distal ureteral margins at the time of cystectomy has been advocated as an appropriate intraoperative test. The decision-making value purported to result from this test includes modification of the resection margins, a potential to decrease the incidence of anastomotic tumor recurrence, and tailoring of the upper tract follow-up strategy based upon a clear understanding of the presence or absence of residual disease. The “costs” associated with the performance of this test are the expense of the frozen section, the small risk of an incorrect frozen section interpretation, and the potential, albeit unlikely, delay to progress of the surgical procedure. In their manuscript, Schumacher et al question the benefit of frozen section examination (FSE) of the distal ureters in patients undergoing cystectomy. Their analysis of a large group of cystectomy patients demonstrated that, with the exception of patients with CIS in the bladder, FSE of the ureter was not necessary, provided that the ureters were transected at the level of the common iliac vessels. This approach decreases the cost associated with the test, eliminates the potential for an incorrect FSE of the ureters, and avoids any surgical delay. On the down side, a small percentage of patients with CIS at the ureteral margin will be missed at the time of surgery. Is the benefit of this strategy worth the risk? Given the minimal risks associated with frozen section evaluation on the distal ureters in the context of some potential benefit I will personally continue to obtain frozen section evaluation of the distal ureters at the time of cystectomy. doi:10.1016/j.urolonc.2007.03.010 William A. See, M.D. Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer. International Bladder Cancer Nomogram Consortium, Bochner BH, Kattan MW, Vora KC, Department of Urology, Memorial Sloan-Kettering Cancer Center, Kimmel Center for Prostate and Urologic Tumors, New York, NY. J Clin Oncol 2006;24:3967–72 Purpose: Radical cystectomy and pelvic lymphadenectomy (PLND) remain the standard treatment for localized and regionally advanced invasive bladder cancers. We have constructed an international bladder cancer database from centers of excellence in the management of bladder cancer consisting of patients treated with radical cystectomy and PLND. The goal of this study was the development of a prognostic outcomes nomogram to predict the 5-year disease recurrence risk after radical cystectomy. Patients and Methods: Institutional radical cystectomy databases containing detailed information on bladder cancer patients were obtained from 12 centers of excellence worldwide. Data were collected on more than 9000 postoperative patients and combined into a relational database formatted with patient characteristics, pathologic details of the pre- and postcystectomy specimens, and recurrence and survival status. Patients with available information for all selected study criteria were included in the formation of the final prognostic nomogram designed to predict 5-year progression-free probability. Results: The final nomogram included information on patient age, gender, time from diagnosis to surgery, pathologic tumor stage and grade, tumor histologic subtype, and regional lymph node status. The predictive accuracy of the constructed international nomogram (concordance index, 0.75) was significantly better than the standard American Joint Committee on Cancer TNM (concordance index, 0.68; P ⬍ 0.001) or standard pathologic subgroupings (concordance index, 0.62; P ⬍ 0.001). Conclusion: We have developed an international bladder cancer nomogram predicting recurrence risk after radical cystectomy for bladder cancer. The nomogram outperformed prognostic models that use standard pathologic subgroupings and should improve our ability to provide accurate risk assessments to patients after the surgical management of bladder cancer.
Commentary The ability to predict tumor recurrence in a specific patient has significant utility for both physicians and the patients. For the physician, risk predictive nomograms for disease recurrence allow treatment strategies to be presented to the patient in the context of the future risks posed by the disease. For the patient, risk nomograms enable them to better interpret the risks vs. benefits associated with adjuvant treatment strategies as well as to engage in appropriate future planning. The nomogram presented in the manuscript by the International Bladder Cancer Nomogram Consortium adds to a growing set of nomograms available to the urologist to aid in the management of their cancer patients. As a predictive tool, the nomogram presented in this manuscript does have some limitations. The database from which the nomogram was derived included patients across a long time interval, over which treatments and potentially outcome changed. In addition, as acknowledged by the authors, the outcomes data was gained from “centers of excellence” and may or may not be reproducible in other settings. Nonetheless, this study provides clinicians an additional valuable tool to aid them in their management of patients with bladder neoplasms. doi:10.1016/j.urolonc.2007.03.011 William A. See, M.D.
W.A. See / Urologic Oncology: Seminars and Original Investigations 25 (2007) 271–280
Should we screen for bladder cancer in a high-risk population? A cost per life-year saved analysis. Lotan Y, Svatek RS, Sagalowsky AI, Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. Cancer 2006;107:982–90 Background: The U.S. Food and Drug Administration recently approved screening high-risk patients for bladder cancer using urinebased markers. The cost and life-years saved associated with bladder cancer screening were evaluated. Methods: A Markov model was created to estimate cumulative cancer-related costs and efficacy of screening (vs. no screening) of a high-risk population for bladder cancer using a urine-based tumor marker over a 5-year period. Assumptions were based on literature review of survival and progression rates for patients with bladder cancer and costs associated with different bladder cancer disease states. Results: Screening for bladder cancer in a population with a 4% incidence of bladder cancer resulted in a gain of 3.0 life years per 1000 subjects at a cost savings of $101,000 for the population, assuming a 50% downstaging in the screened population from muscle-invasive to nonmuscle-invasive disease. One-way sensitivity analyses found that screening is the most cost-effective strategy if cancer incidence is ⬎1.6%, tumor marker costs ⬍$126, marker sensitivity is ⬎26%, marker specificity is ⬎54%, downstaging with screening is ⬎20%, and office cystoscopy costs ⬍$694. Varying costs of cystectomy, transurethral resection of bladder tumor (TURBT), chemotherapy, end-of-life care, costs of metastatic disease, and a computed tomography scan over a wide range did not affect the superiority of screening. Conclusions: The model found that urine-based markers are cost-effective in a high-risk population. Prospective randomized trials in a completely asymptomatic high-risk cohort are indicated before bladder cancer screening can be recommended.
Commentary Determining the value of screening for a specific disease process in a given population is a complex and challenging problem. The prevalence of the disease within a given population, the performance characteristics of the screening tool, the cost and morbidity of downstream diagnostic tests, the efficacy of available treatment options for the disease and, ultimately, in the case of cancer, the survival benefits associated with screening are among the variables to be considered. In settings where these variables are well established it is possible to reach concrete and valid conclusions regarding the value of screening for a given disease. Conversely, to the extent that these variables are less well established, and their values “assumed”, the conclusions reached become far less robust. In the manuscript by Lotan et al, the authors use a relatively sophisticated modeling technique to perform a “cost per life year saved” analysis for bladder cancer screening using a point of service assay. Regrettably, many of the assumptions upon which this analysis was based were “soft” at best. For example, the authors acknowledge the critical importance of disease incidence in risk reduction and screening costs. The use of a 4% incidence figure based upon a cited publication by Grossman et al (6% incidence in that study) may or may not be valid. The “high-risk” population cited in the Grossman article was derived from patients presenting to an urologist’s office with so-called bladder cancer risk factors. Although the percentage of patients who were asymptomatic in the Grossman study is not available, their mere presence in the urologist’s office suggests that many had signs or symptoms of urologic disease. In a truly asymptomatic population of patients the actual incidence of bladder cancer may be far less than the 4% figure for the Lotan manuscript. The concept of early bladder cancer detection and treatment through screening is intrinsically appealing. However, as the authors themselves have stated, in the case of bladder cancer screening, additional research is required prior to reaching any conclusion as to the cost and/or appropriateness of this strategy. doi:10.1016/j.urolonc.2007.03.009 William A. See, M.D. Is there an indication for frozen section examination of the ureteral margins during cystectomy for transitional cell carcinoma of the bladder? Schumacher MC, Scholz M, Weise ES, Fleischmann A, Thalmann GN, Studer UE, Department of Urology, Institute of Pathology, University Hospital Bern, Bern, Switzerland. J Urol 2006;D176:2409 –13 Purpose: We evaluated the incidence of pathological findings of the ureter at cystectomy for transitional cell carcinoma of the bladder and assessed the usefulness of intraoperative frozen section examination of the ureter. Materials and Methods: Histopathological findings of ureteral frozen section examination were compared with the corresponding permanent sections, and the diagnostic accuracy of frozen section examination was evaluated. These segments were then compared with the more proximal ureteral segments resected at the level where they cross over the common iliac arteries. The histopathological findings of the ureteral segments were then correlated for upper urinary tract recurrence and overall survival. Results: Transitional cell carcinoma or carcinoma in situ was found on frozen section examination of the distal ureter in 39 of 805 patients (4.8%) and on permanent sections in 29 (3.6%). In 755 patients, the false-negative rate of frozen section examination of the ureters was 0.8%. Of the patients with carcinoma in situ diagnosed on the first frozen section examination, 80% also had carcinoma in situ in the bladder. Transitional cell carcinoma or carcinoma in situ in the most proximally resected ureteral segments was found in 1.2% of patients. After radical cystectomy, there was tumor recurrence in the upper urinary tract in 3% of patients with negative ureteral frozen section examination, and in 17% with carcinoma in situ on frozen section examination. Conclusions: Routine frozen section examination of the ureters at radical cystectomy is only recommended for patients with carcinoma in situ of the bladder, provided the ureters are resected where they cross the common iliac arteries.
W.A. See / Urologic Oncology: Seminars and Original Investigations 25 (2007) 271–280
275
Commentary An axiom of medical testing is that one should only order a test if the results will influence one’s decision-making or actions. The corollary to this principal is that the value of the information obtained by the test must exceed the costs of the tests, both monetary- and risk-based. Frozen section analysis of the distal ureteral margins at the time of cystectomy has been advocated as an appropriate intraoperative test. The decision-making value purported to result from this test includes modification of the resection margins, a potential to decrease the incidence of anastomotic tumor recurrence, and tailoring of the upper tract follow-up strategy based upon a clear understanding of the presence or absence of residual disease. The “costs” associated with the performance of this test are the expense of the frozen section, the small risk of an incorrect frozen section interpretation, and the potential, albeit unlikely, delay to progress of the surgical procedure. In their manuscript, Schumacher et al question the benefit of frozen section examination (FSE) of the distal ureters in patients undergoing cystectomy. Their analysis of a large group of cystectomy patients demonstrated that, with the exception of patients with CIS in the bladder, FSE of the ureter was not necessary, provided that the ureters were transected at the level of the common iliac vessels. This approach decreases the cost associated with the test, eliminates the potential for an incorrect FSE of the ureters, and avoids any surgical delay. On the down side, a small percentage of patients with CIS at the ureteral margin will be missed at the time of surgery. Is the benefit of this strategy worth the risk? Given the minimal risks associated with frozen section evaluation on the distal ureters in the context of some potential benefit I will personally continue to obtain frozen section evaluation of the distal ureters at the time of cystectomy. doi:10.1016/j.urolonc.2007.03.010 William A. See, M.D. Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer. International Bladder Cancer Nomogram Consortium, Bochner BH, Kattan MW, Vora KC, Department of Urology, Memorial Sloan-Kettering Cancer Center, Kimmel Center for Prostate and Urologic Tumors, New York, NY. J Clin Oncol 2006;24:3967–72 Purpose: Radical cystectomy and pelvic lymphadenectomy (PLND) remain the standard treatment for localized and regionally advanced invasive bladder cancers. We have constructed an international bladder cancer database from centers of excellence in the management of bladder cancer consisting of patients treated with radical cystectomy and PLND. The goal of this study was the development of a prognostic outcomes nomogram to predict the 5-year disease recurrence risk after radical cystectomy. Patients and Methods: Institutional radical cystectomy databases containing detailed information on bladder cancer patients were obtained from 12 centers of excellence worldwide. Data were collected on more than 9000 postoperative patients and combined into a relational database formatted with patient characteristics, pathologic details of the pre- and postcystectomy specimens, and recurrence and survival status. Patients with available information for all selected study criteria were included in the formation of the final prognostic nomogram designed to predict 5-year progression-free probability. Results: The final nomogram included information on patient age, gender, time from diagnosis to surgery, pathologic tumor stage and grade, tumor histologic subtype, and regional lymph node status. The predictive accuracy of the constructed international nomogram (concordance index, 0.75) was significantly better than the standard American Joint Committee on Cancer TNM (concordance index, 0.68; P ⬍ 0.001) or standard pathologic subgroupings (concordance index, 0.62; P ⬍ 0.001). Conclusion: We have developed an international bladder cancer nomogram predicting recurrence risk after radical cystectomy for bladder cancer. The nomogram outperformed prognostic models that use standard pathologic subgroupings and should improve our ability to provide accurate risk assessments to patients after the surgical management of bladder cancer.
Commentary The ability to predict tumor recurrence in a specific patient has significant utility for both physicians and the patients. For the physician, risk predictive nomograms for disease recurrence allow treatment strategies to be presented to the patient in the context of the future risks posed by the disease. For the patient, risk nomograms enable them to better interpret the risks vs. benefits associated with adjuvant treatment strategies as well as to engage in appropriate future planning. The nomogram presented in the manuscript by the International Bladder Cancer Nomogram Consortium adds to a growing set of nomograms available to the urologist to aid in the management of their cancer patients. As a predictive tool, the nomogram presented in this manuscript does have some limitations. The database from which the nomogram was derived included patients across a long time interval, over which treatments and potentially outcome changed. In addition, as acknowledged by the authors, the outcomes data was gained from “centers of excellence” and may or may not be reproducible in other settings. Nonetheless, this study provides clinicians an additional valuable tool to aid them in their management of patients with bladder neoplasms. doi:10.1016/j.urolonc.2007.03.011 William A. See, M.D.