- Email: [email protected]
Conservative Management of Low Risk Superficial Bladder Tumors
Conservative Management of Low Risk Superficial Bladder Tumors Raj S. Pruthi,* Nathan Baldwin, Vishal Bhalani and Eric M. Wallen From the Division of Urologic Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Purpose: The most common approach for nonmuscle invasive urothelial cancers of the bladder is transurethral resection of the bladder tumor, often under regional or general anesthesia. Due to the high rate of recurrence, many such patients experience the potential risks and morbidity of frequent surgical intervention, despite the often slow growth rate and low risk of progression of such tumors. Recent experiences have suggested that some patients with low grade superficial tumors may be treated expectantly. We report on our experience with expectant management of low risk superficial bladder tumors. Materials and Methods: We retrospectively evaluated 173 patients with superficial bladder cancer who are currently actively treated at our institution and who have complete clinical information. From this population we identified 22 cases (12.7%) under expectant management for bladder tumors in the last 12 months. Demographic and clinical information on this cohort are described as well as clinical and pathological outcomes, and disease interventions on followup. Results: All patients had a prior history of recurrent low risk (Ta, low grade) bladder tumors. The mean followup was 25 months. Of the 22 patients 8 had no growth, 9 had minimal growth and 5 had moderate growth of their tumors. Fifteen patients have required no intervention, 3 have undergone office fulguration and 4 have undergone repeat transurethral bladder tumor resection. Two men (9%) had evidence of grade progression on followup transurethral bladder tumor resection, and 1 of these men (4.5%) had stage progression (T1 disease). Both men had evidence of moderate tumor growth and suspicious/malignant cytology which resulted in the repeat transurethral bladder tumor resection. Interestingly, these 2 men had a 6 and 11 year history of recurrent Ta, low grade disease before progression and had been under expectant management for 18 and 12 months before progression. Interestingly all smokers had a recurrence during the surveillance period and this represented a 3.3-fold increased rate of recurrence over nonsmokers. Conclusions: Expectant management of recurrent bladder tumors may be an appropriate option for some patients with a history of Ta, low grade tumors, especially those who are older and with significant medical comorbidities. Such a strategy may avoid potential risks and morbidities associated with frequent, repeat transurethral bladder tumor resection. However, under such an expectant management strategy, patients should remain under careful cystoscopic and cytologic surveillance as there remains some risk for grade and stage progression in this patient population. Key Words: carcinoma, transitional cell; urinary bladder neoplasms; disease progression
he majority of patients who present with newly diagnosed bladder cancer will have superficial disease.1–3 The best treatment for these patients with low risk disease is being debated in the literature today. Current American Urological Association guidelines suggest that the standard of practice is complete resection of all visible bladder tumor in patients with any Ta or T1 disease.4 However, following resection patients have a high likelihood of recurrence, which is dependent on stage, grade and multiplicity, as well as other clinical factors.4 – 6 For example, low grade lesions recur at a rate of 50% to 70% while high grade lesions recur in greater than 80% of patients.2,5
Though tumor resection is usually well tolerated, it is not without risks, especially in the elderly or those with significant medical comorbidities. These patients face greater risks with general anesthesia and often require postoperative hospital stays, both of which increase cost and use valuable physician time. In deciding treatment options other important aspects are not only tumor recurrence rates but more importantly halting tumor invasion, especially into the muscle layer as this denotes a decidedly poorer prognosis in bladder cancer. It has been demonstrated that low risk tumors are unlikely to metastasize, and that elderly patients with such tumors may die with disease and not because of it.7 Recent experiences have shown that conservative management (ie active surveillance or watchful waiting), or inoffice fulguration may be appropriate choices in certain patient populations with superficial disease.8 –10 This requires that urologists be able to appropriately determine, cystoscopically, when a recurrent tumor has progressed, without
T
Submitted for publication May 18, 2007. Study received institutional review board approval. Nothing to disclose. * Correspondence and requests for reprints: Division of Urologic Surgery, The University of North Carolina at Chapel Hill, 2140 Bioinformatics Bldg., CB7235, Chapel Hill, North Carolina 27599 (telephone: 919-966-2574; FAX: 919-966-0098; e-mail: rpruthi@ med.unc.edu).
Editor’s Note: This article is the first of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 388 and 389.
See Editorial on page 13. For another article on a related topic see pages 346 and 353.
0022-5347/08/1791-0087/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
87
Vol. 179, 87-90, January 2008 Printed in U.S.A. DOI:10.1016/j.juro.2007.08.171
88
CONSERVATIVE MANAGEMENT OF BLADDER TUMORS TABLE 1. Patient characteristics
Pt age Mos followup Recurrences TURBT Fulgurations
Mean
Median
SD
Range
70.6 25 1.5 0.4 0.1
72.2 23 1.0 0.0 0.0
10.8 11.2 1.4 1.1 0.4
49.4–86.0 11.0–62.0 0–5 0–4.0 0–1.0
the need for TURBT or biopsy. There is evidence that physicians have this capability.11 We report on our experience with conservative management of low risk superficial bladder tumors. Recurrence rates, stage and grade progression are evaluated to determine the feasibility and safety of this approach. METHODS In accordance with the principles and practices of our institutional review board and in recognition of and compliance with HIPAA guidelines (United States Health Insurance Portability and Accountability Act of 1996), we retrospectively evaluated 173 patients diagnosed with nonmuscle invasive bladder cancer who are currently being actively treated at our institution. Only patients with noninvasive low or high grade papillary urothelial carcinoma or urothelial carcinoma in situ (excluding patients with urothelial papilloma, papillary urothelial neoplasm of low malignant potential, or other lesions of atypia), according to the 2004 WHO/International Society of Urological Pathology criteria, were included. A total of 22 patients (12.7%) who had been under conservative management, ie did not undergo transurethral resection of bladder tumor for bladder tumors in the last 12 months, were identified and analyzed. We used electronic records to analyze patient age, sex, race, recurrence rate, smoking history, initial diagnosis date, followup time, treatment, original tumor stage and grade, and tumor stage and grade progression. In addition, qualitative assessment of the change in tumor size was evaluated and recorded by a single surgeon in all cases, and was categorized as regression, no growth, minimal growth, moderate growth or severe growth. The primary end points observed were recurrence rate and tumor stage at 1 year. Recurrence rates at 3 and 5-year periods were also observed when available. All statistical analyses were done using SAS® statistical software (version 9.1). Each tumor was considered a separate record in all analyses except for descriptive analyses of patients. In this case, each patient was considered a separate record. Routine clinical followup adhered to the recommendations set forth by the American Urological Association guidelines for the management of noninvasive bladder cancer. Following resection or fulguration, cystoscopy was performed at 3-month intervals for the first 2 years, and then surveillance was decreased to every 6 months for years 2 to 5 and yearly afterward. Treatment modalities consisted of TURBT and office fulguration via Bugbee electrocautery or holmium laser ablation. The decision regarding necessity of treatment was made on a case by case basis, as was the decision of which procedure was to be performed. RESULTS Patient characteristics are shown in table 1. Mean patient age was 70.6 years (range 49.4 to 86.0). The male-to-female
ratio was 16:6, and there were 2 black females and 1 black male in the cohort while the remaining patients were white. Twelve (55%) patients had a history of solitary tumors only and 10 (45%) had a history of multifocal tumors. The majority of patients (77%) had a history of multiple recurrences before conservative management with only 23% having a history of only a single tumor recurrence. Three (13.6%) patients were actively smoking and 5 (22.7%) had a past history, while 14 (63.6%) patients denied any significant history of tobacco use. A history of intravesical therapy (mitomycin C and/or bacillus Calmette-Guerin) was present in 15 (68.8%) patients. All patients had a prior history of recurrent and low risk (Ta, low grade) bladder tumors. Mean followup was 25 months (range 11 to 62). There were 32 recurrences during a cumulative followup of 550 months for an overall recurrence rate of 0.70 recurrences per 12 months. The mean number of tumor recurrences was 1.5 (range 0 to 5). During the followup period 3 patients had 0 recurrences, 13 had 1 recurrence, 1 had 2 recurrences, 2 had 3 recurrences, 1 had 4 recurrences and 1 had 5 recurrences. Table 2 shows the pathological changes seen during the observation period. Of the 22 patients, 18 (82%) initially had a history of stage Ta disease, 3 (14%) had a history of Tis, and 1 (4%) had a history of T1 disease. At the end of the observation period 8 patients had either complete absence of tumor either by regression or fulguration. Additionally 11 patients had Ta disease, 0 had Tis disease and 2 had T1 disease. In total 9 patients had disease regression and 2 had disease progression, while 11 had persistent disease and stage. Of the 22 patients 8 had no growth, 9 had minimal growth and 5 had moderate growth of tumors. Fifteen patients (68%) have required no intervention, 3 (14%) have undergone office fulguration and 4 (18%) have undergone repeat TURBT (see figure). Two men (9%) had evidence of grade or stage progression on followup TURBT. Both men (9% of cohort) had grade progression and 1 (4.5% of cohort) had stage progression (Ta to T1 disease). Both men had evidence of moderate tumor growth and suspicious/malignant cytology that resulted in repeat TURBT. Interestingly these 2 men had a 6-year history and 11-year history of recurrent Ta, low grade disease before progression, and had been under expectant management for 18 and 12 months before progression, respectively. Of patients with a smoking history 100% had tumor recurrence whereas 72% without a history had recurrence. Interestingly of patients with a smoking history recurrence per patient was 2.6 mean compared to 0.8 mean recurrence per patient for those who did not smoke. This represents a 3.3-fold increase in recurrences for those with a smoking history.
TABLE 2. Pathological outcomes After Observation
Before Observation
Ta
Tis
T1
No Tumor*
Ta (18) Tis (3) T1 (1)
11 1 0
0 0 0
1 0 1
6 2 0
* Patient had no observable tumor due to tumor fulguration or regression.
CONSERVATIVE MANAGEMENT OF BLADDER TUMORS
Interventions received by 22 patients during mean followup of 25 months.
DISCUSSION Complete transurethral resection is still considered to be the gold standard in managing superficial bladder tumors. However, there is increasing evidence that is beginning to conclude that these tumors can be divided into low and high risk groups. These groups can then be treated differently without any apparent loss of efficacy. Soloway et al were the first to expectantly observe patients with low risk disease.8 They observed that in 32 patients with stage Ta or T1 tumors only 3 (9%) progressed in either stage or grade, and none had progression to stage T2 disease. Similarly, Gofrit et al also demonstrated that expectant management may be an acceptable course in patients with low risk disease.10 They followed 28 patients for 38 observation periods. Although 30 of these periods were terminated because of recurrence or additional growth, all resected tumors were found to be Ta and grade 1 or 2 (ie no grade or stage progression). They also observed that initial tumor diameter was predictive of tumor growth during the observation period. In the present study the majority of patients had no evidence of stage or grade progression. Two men (9%) were observed to have grade progression of their disease, with 1 (4.5%) having stage progression as well. Both men had evidence of moderate tumor growth and suspicious or malignant cytology heralding such progression and resulting in repeat TURBT. However, similar to the results of Soloway et al, neither of these tumors progressed to muscle invasive disease.8 Interestingly these 2 men had prolonged histories of recurrent Ta, low grade disease before progression, thus, demonstrating the ability of low risk tumors to progress even at distant followup. Accordingly the recommendations for lifelong surveillance of all bladder tumor patients seem justified. As urologists we must weigh the risks and benefits of aggressive vs conservative treatment in dealing with superficial bladder tumors. The goal of TURBT is to eliminate any visible tumor, and this is the most assured way to prevent disease progression. However, it does so with an increased risk of bladder scarring, and requires an operative experience. Thus, a patient’s American Society of Anesthesiologists risk score could also have an important role in determining the appropriate course of treatment. Patients with known high risk scores (ie 3 or 4) may be better treated with
89
conservative in-office treatment. This would save them not only the risk associated with a general or regional anesthetic. A balance must be found between the risk of progression and the patient’s current state of health and medical comorbidities. Although expectant management appears to be a safe treatment option, it is likely not the best choice for everyone. Patients who are young and healthy would be apt to benefit from TURBT. This population would likely have less difficulty with anesthesia and decreased morbidity from the procedure itself, while benefiting more with definitive treatment. We must acknowledge several possible shortcomings of this study. It is a retrospective observational study that does not have the strength of a randomized control trial, the gold standard of evaluating treatment efficacy and superiority. Accordingly there were no clear and uniform selection criteria for conservative management. In addition, certain assessments were of a subjective nature including tumor growth assessments, decisions to intervene and subsequent management. Nevertheless, qualitative assessments of tumor change/growth combined with more quantitative evaluations of urine cytopathology seem to best reflect the tools used in everyday clinical practice. Such tools combined with the ability for urologists to appropriately determine, cystoscopically, when a recurrent tumor has progressed (without the need for TURBT or biopsy) as demonstrated by Herr et al, appear to be adequate in identifying early disease progression before muscle invasive disease occurs.11 Since there are no data to demonstrate that such an ability can be transferred to low volume bladder cancer providers, clinicians need to remain cautious and conservative with regard to the indiscriminate use of such a conservative approach. CONCLUSIONS Conservative management of recurrent bladder tumors is an appropriate option for some patients with a history of Ta, low grade tumors, especially those who are older and with significant medical comorbidities. Such a strategy may avoid potential risks and morbidities associated with frequent, repeat TURBT as well as reduce total health care expenses. However, under such a conservative management strategy, patients should remain under careful cystoscopic and cytologic surveillance as there remains some risk for grade and stage progression in this patient population.
Abbreviations and Acronyms TURBT ⫽ transurethral bladder tumor resection
REFERENCES 1.
2.
3.
Heney NM, Ahmed S, Flanagan MJ, Frable W, Corder MP, Hafermann MD et al: Superficial bladder cancer: progression and recurrence. J Urol 1983; 130: 1083. Messing EM and Catalona W: Urothelial tumors of the urinary tract. In: Campbell’s Urology, 7th ed. Edited by PC Walsh, AB Retik, ED Vaughan Jr and AJ Wein. Philadelphia: WB Saunders 1998; chapt 77, pp 2327–2408. Fleshner NE, Herr HW, Stewart AK, Murphy GP, Mettlin C and Menck HR: The National Cancer Data Base report on bladder carcinoma. Cancer 1996; 78: 1505.
90 4.
5.
6.
7.
8.
9.
10.
11.
CONSERVATIVE MANAGEMENT OF BLADDER TUMORS Smith JA Jr, Labasky RF, Cockett ATK, Fracchia JA, Montie JE and Rowland RG: Bladder Cancer Clinical Guidelines Panel summary report on the management of nonmuscle invasive bladder cancer (stages Ta, T1 and TIS). J Urol 1999; 162: 1697. Holmang S, Andius P, Hedelin H, Wester K, Busch C and Johansson SL: Stage progression in Ta papillary urothelial tumors: relationship to grade, immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy. J Urol 2001; 165: 1124. Holmang S, Hedelin H, Anderstrom C and Johansson SL: The relationship among multiple recurrences, progression and prognosis of patients with stages Ta and T1 transitional cell cancer of the bladder followed for at least 20 years. J Urol 1995; 153: 1823. Holmang S, Hedelin H, Anderstrom C, Holmberg E, Busch C and Johansson SL: Recurrence and progression in low grade papillary urothelial tumors. J Urol 1999; 162: 702. Soloway M, Bruck D and Kim S: Expectant management of small, recurrent, noninvasive, papillary bladder tumors. J Urol 2003; 170: 438. Donat S, North A, Dalbagni G and Herr H: Efficacy of office fulguration for recurrent low grade papillary bladder tumors less than 0.5 cm. J Urol 2004; 171: 636. Gofrit O, Pode D, Lazar A, Katz R and Shapiro A: Watchful waiting policy in recurrent Ta G1 bladder tumors. Eur Urol 2006; 49: 303. Herr H, Donat S and Dalbagni G: Correlation of cystoscopy with histology of recurrent papillary tumors of the bladder. J Urol 2002; 168: 978.
EDITORIAL COMMENT Transurethral resection has been established as the standard treatment for superficial bladder tumors. Recent studies have shown experienced urologists can reliably identify a select group of patients with recurrent low risk Ta tumors (papillary, less than 0.5 cm, less than 5 tumors, low grade appearance, negative voided cytology) in which office fulguration via a flexible scope can be a safe and efficacious alternative to transurethral resection (references 9 and 11 in text).1 Due to the slow growth and minimal risk of progression of low grade noninvasive tumors, Soloway et al initially proposed expectant management as another alternative to transurethral resection with the patient under anesthesia with the goal of decreasing morbidity and health care costs (reference 8 in article).
The authors present their experience with expectant management of low risk superficial bladder cancer in 22 patients representing 13% of their total active patient population. Definitive treatment (transurethral resection or fulguration) was ultimately required in 32% (7 of 22) of patients during a median followup of 23 months, with 13% (3 of 22) having progression in tumor stage or grade but none to muscle invasive disease. They conclude expectant management is an appropriate option for some patients with noninvasive low grade Ta tumors, especially in older patients with significant comorbidities, but appropriately warn that this approach may not be reproducible in less experienced hands. The conflicting data regarding the ability of endoscopic appearance alone to accurately predict papillary tumor stage and grade support the author’s cautionary note on expectant management.1 Furthermore, since office fulguration provides an efficacious definitive treatment without morbidity for this same subset of patients proposed for expectant management, one could question the usefulness of observation. Although the authors assume expectant management will decrease health care cost and morbidity, there are no prospective data comparing differences in costs and complications between treatment and observation to support that assumption. In addition, no guidelines have been established for the ideal frequency of surveillance in patients with tumor under expectant management. Until higher level evidentiary data are available on the safety and efficacy of expectant tumor management, and guidelines are established for appropriate patient selection and surveillance methods, expectant management should not be considered for standard practice. A prospective randomized trial comparing office fulguration to expectant management is the logical next step to answer the question. S. Machele Donat Department of Urology Memorial Sloan-Kettering Cancer Center/Weill Cornell Medical College New York, New York 1.
Soloway MS: International Consultation on Bladder Tumors. Urology 2005; 66: 1.
Purpose: The most common approach for nonmuscle invasive urothelial cancers of the bladder is transurethral resection of the bladder tumor, often under regional or general anesthesia. Due to the high rate of recurrence, many such patients experience the potential risks and morbidity of frequent surgical intervention, despite the often slow growth rate and low risk of progression of such tumors. Recent experiences have suggested that some patients with low grade superficial tumors may be treated expectantly. We report on our experience with expectant management of low risk superficial bladder tumors. Materials and Methods: We retrospectively evaluated 173 patients with superficial bladder cancer who are currently actively treated at our institution and who have complete clinical information. From this population we identified 22 cases (12.7%) under expectant management for bladder tumors in the last 12 months. Demographic and clinical information on this cohort are described as well as clinical and pathological outcomes, and disease interventions on followup. Results: All patients had a prior history of recurrent low risk (Ta, low grade) bladder tumors. The mean followup was 25 months. Of the 22 patients 8 had no growth, 9 had minimal growth and 5 had moderate growth of their tumors. Fifteen patients have required no intervention, 3 have undergone office fulguration and 4 have undergone repeat transurethral bladder tumor resection. Two men (9%) had evidence of grade progression on followup transurethral bladder tumor resection, and 1 of these men (4.5%) had stage progression (T1 disease). Both men had evidence of moderate tumor growth and suspicious/malignant cytology which resulted in the repeat transurethral bladder tumor resection. Interestingly, these 2 men had a 6 and 11 year history of recurrent Ta, low grade disease before progression and had been under expectant management for 18 and 12 months before progression. Interestingly all smokers had a recurrence during the surveillance period and this represented a 3.3-fold increased rate of recurrence over nonsmokers. Conclusions: Expectant management of recurrent bladder tumors may be an appropriate option for some patients with a history of Ta, low grade tumors, especially those who are older and with significant medical comorbidities. Such a strategy may avoid potential risks and morbidities associated with frequent, repeat transurethral bladder tumor resection. However, under such an expectant management strategy, patients should remain under careful cystoscopic and cytologic surveillance as there remains some risk for grade and stage progression in this patient population. Key Words: carcinoma, transitional cell; urinary bladder neoplasms; disease progression
he majority of patients who present with newly diagnosed bladder cancer will have superficial disease.1–3 The best treatment for these patients with low risk disease is being debated in the literature today. Current American Urological Association guidelines suggest that the standard of practice is complete resection of all visible bladder tumor in patients with any Ta or T1 disease.4 However, following resection patients have a high likelihood of recurrence, which is dependent on stage, grade and multiplicity, as well as other clinical factors.4 – 6 For example, low grade lesions recur at a rate of 50% to 70% while high grade lesions recur in greater than 80% of patients.2,5
Though tumor resection is usually well tolerated, it is not without risks, especially in the elderly or those with significant medical comorbidities. These patients face greater risks with general anesthesia and often require postoperative hospital stays, both of which increase cost and use valuable physician time. In deciding treatment options other important aspects are not only tumor recurrence rates but more importantly halting tumor invasion, especially into the muscle layer as this denotes a decidedly poorer prognosis in bladder cancer. It has been demonstrated that low risk tumors are unlikely to metastasize, and that elderly patients with such tumors may die with disease and not because of it.7 Recent experiences have shown that conservative management (ie active surveillance or watchful waiting), or inoffice fulguration may be appropriate choices in certain patient populations with superficial disease.8 –10 This requires that urologists be able to appropriately determine, cystoscopically, when a recurrent tumor has progressed, without
T
Submitted for publication May 18, 2007. Study received institutional review board approval. Nothing to disclose. * Correspondence and requests for reprints: Division of Urologic Surgery, The University of North Carolina at Chapel Hill, 2140 Bioinformatics Bldg., CB7235, Chapel Hill, North Carolina 27599 (telephone: 919-966-2574; FAX: 919-966-0098; e-mail: rpruthi@ med.unc.edu).
Editor’s Note: This article is the first of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 388 and 389.
See Editorial on page 13. For another article on a related topic see pages 346 and 353.
0022-5347/08/1791-0087/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
87
Vol. 179, 87-90, January 2008 Printed in U.S.A. DOI:10.1016/j.juro.2007.08.171
88
CONSERVATIVE MANAGEMENT OF BLADDER TUMORS TABLE 1. Patient characteristics
Pt age Mos followup Recurrences TURBT Fulgurations
Mean
Median
SD
Range
70.6 25 1.5 0.4 0.1
72.2 23 1.0 0.0 0.0
10.8 11.2 1.4 1.1 0.4
49.4–86.0 11.0–62.0 0–5 0–4.0 0–1.0
the need for TURBT or biopsy. There is evidence that physicians have this capability.11 We report on our experience with conservative management of low risk superficial bladder tumors. Recurrence rates, stage and grade progression are evaluated to determine the feasibility and safety of this approach. METHODS In accordance with the principles and practices of our institutional review board and in recognition of and compliance with HIPAA guidelines (United States Health Insurance Portability and Accountability Act of 1996), we retrospectively evaluated 173 patients diagnosed with nonmuscle invasive bladder cancer who are currently being actively treated at our institution. Only patients with noninvasive low or high grade papillary urothelial carcinoma or urothelial carcinoma in situ (excluding patients with urothelial papilloma, papillary urothelial neoplasm of low malignant potential, or other lesions of atypia), according to the 2004 WHO/International Society of Urological Pathology criteria, were included. A total of 22 patients (12.7%) who had been under conservative management, ie did not undergo transurethral resection of bladder tumor for bladder tumors in the last 12 months, were identified and analyzed. We used electronic records to analyze patient age, sex, race, recurrence rate, smoking history, initial diagnosis date, followup time, treatment, original tumor stage and grade, and tumor stage and grade progression. In addition, qualitative assessment of the change in tumor size was evaluated and recorded by a single surgeon in all cases, and was categorized as regression, no growth, minimal growth, moderate growth or severe growth. The primary end points observed were recurrence rate and tumor stage at 1 year. Recurrence rates at 3 and 5-year periods were also observed when available. All statistical analyses were done using SAS® statistical software (version 9.1). Each tumor was considered a separate record in all analyses except for descriptive analyses of patients. In this case, each patient was considered a separate record. Routine clinical followup adhered to the recommendations set forth by the American Urological Association guidelines for the management of noninvasive bladder cancer. Following resection or fulguration, cystoscopy was performed at 3-month intervals for the first 2 years, and then surveillance was decreased to every 6 months for years 2 to 5 and yearly afterward. Treatment modalities consisted of TURBT and office fulguration via Bugbee electrocautery or holmium laser ablation. The decision regarding necessity of treatment was made on a case by case basis, as was the decision of which procedure was to be performed. RESULTS Patient characteristics are shown in table 1. Mean patient age was 70.6 years (range 49.4 to 86.0). The male-to-female
ratio was 16:6, and there were 2 black females and 1 black male in the cohort while the remaining patients were white. Twelve (55%) patients had a history of solitary tumors only and 10 (45%) had a history of multifocal tumors. The majority of patients (77%) had a history of multiple recurrences before conservative management with only 23% having a history of only a single tumor recurrence. Three (13.6%) patients were actively smoking and 5 (22.7%) had a past history, while 14 (63.6%) patients denied any significant history of tobacco use. A history of intravesical therapy (mitomycin C and/or bacillus Calmette-Guerin) was present in 15 (68.8%) patients. All patients had a prior history of recurrent and low risk (Ta, low grade) bladder tumors. Mean followup was 25 months (range 11 to 62). There were 32 recurrences during a cumulative followup of 550 months for an overall recurrence rate of 0.70 recurrences per 12 months. The mean number of tumor recurrences was 1.5 (range 0 to 5). During the followup period 3 patients had 0 recurrences, 13 had 1 recurrence, 1 had 2 recurrences, 2 had 3 recurrences, 1 had 4 recurrences and 1 had 5 recurrences. Table 2 shows the pathological changes seen during the observation period. Of the 22 patients, 18 (82%) initially had a history of stage Ta disease, 3 (14%) had a history of Tis, and 1 (4%) had a history of T1 disease. At the end of the observation period 8 patients had either complete absence of tumor either by regression or fulguration. Additionally 11 patients had Ta disease, 0 had Tis disease and 2 had T1 disease. In total 9 patients had disease regression and 2 had disease progression, while 11 had persistent disease and stage. Of the 22 patients 8 had no growth, 9 had minimal growth and 5 had moderate growth of tumors. Fifteen patients (68%) have required no intervention, 3 (14%) have undergone office fulguration and 4 (18%) have undergone repeat TURBT (see figure). Two men (9%) had evidence of grade or stage progression on followup TURBT. Both men (9% of cohort) had grade progression and 1 (4.5% of cohort) had stage progression (Ta to T1 disease). Both men had evidence of moderate tumor growth and suspicious/malignant cytology that resulted in repeat TURBT. Interestingly these 2 men had a 6-year history and 11-year history of recurrent Ta, low grade disease before progression, and had been under expectant management for 18 and 12 months before progression, respectively. Of patients with a smoking history 100% had tumor recurrence whereas 72% without a history had recurrence. Interestingly of patients with a smoking history recurrence per patient was 2.6 mean compared to 0.8 mean recurrence per patient for those who did not smoke. This represents a 3.3-fold increase in recurrences for those with a smoking history.
TABLE 2. Pathological outcomes After Observation
Before Observation
Ta
Tis
T1
No Tumor*
Ta (18) Tis (3) T1 (1)
11 1 0
0 0 0
1 0 1
6 2 0
* Patient had no observable tumor due to tumor fulguration or regression.
CONSERVATIVE MANAGEMENT OF BLADDER TUMORS
Interventions received by 22 patients during mean followup of 25 months.
DISCUSSION Complete transurethral resection is still considered to be the gold standard in managing superficial bladder tumors. However, there is increasing evidence that is beginning to conclude that these tumors can be divided into low and high risk groups. These groups can then be treated differently without any apparent loss of efficacy. Soloway et al were the first to expectantly observe patients with low risk disease.8 They observed that in 32 patients with stage Ta or T1 tumors only 3 (9%) progressed in either stage or grade, and none had progression to stage T2 disease. Similarly, Gofrit et al also demonstrated that expectant management may be an acceptable course in patients with low risk disease.10 They followed 28 patients for 38 observation periods. Although 30 of these periods were terminated because of recurrence or additional growth, all resected tumors were found to be Ta and grade 1 or 2 (ie no grade or stage progression). They also observed that initial tumor diameter was predictive of tumor growth during the observation period. In the present study the majority of patients had no evidence of stage or grade progression. Two men (9%) were observed to have grade progression of their disease, with 1 (4.5%) having stage progression as well. Both men had evidence of moderate tumor growth and suspicious or malignant cytology heralding such progression and resulting in repeat TURBT. However, similar to the results of Soloway et al, neither of these tumors progressed to muscle invasive disease.8 Interestingly these 2 men had prolonged histories of recurrent Ta, low grade disease before progression, thus, demonstrating the ability of low risk tumors to progress even at distant followup. Accordingly the recommendations for lifelong surveillance of all bladder tumor patients seem justified. As urologists we must weigh the risks and benefits of aggressive vs conservative treatment in dealing with superficial bladder tumors. The goal of TURBT is to eliminate any visible tumor, and this is the most assured way to prevent disease progression. However, it does so with an increased risk of bladder scarring, and requires an operative experience. Thus, a patient’s American Society of Anesthesiologists risk score could also have an important role in determining the appropriate course of treatment. Patients with known high risk scores (ie 3 or 4) may be better treated with
89
conservative in-office treatment. This would save them not only the risk associated with a general or regional anesthetic. A balance must be found between the risk of progression and the patient’s current state of health and medical comorbidities. Although expectant management appears to be a safe treatment option, it is likely not the best choice for everyone. Patients who are young and healthy would be apt to benefit from TURBT. This population would likely have less difficulty with anesthesia and decreased morbidity from the procedure itself, while benefiting more with definitive treatment. We must acknowledge several possible shortcomings of this study. It is a retrospective observational study that does not have the strength of a randomized control trial, the gold standard of evaluating treatment efficacy and superiority. Accordingly there were no clear and uniform selection criteria for conservative management. In addition, certain assessments were of a subjective nature including tumor growth assessments, decisions to intervene and subsequent management. Nevertheless, qualitative assessments of tumor change/growth combined with more quantitative evaluations of urine cytopathology seem to best reflect the tools used in everyday clinical practice. Such tools combined with the ability for urologists to appropriately determine, cystoscopically, when a recurrent tumor has progressed (without the need for TURBT or biopsy) as demonstrated by Herr et al, appear to be adequate in identifying early disease progression before muscle invasive disease occurs.11 Since there are no data to demonstrate that such an ability can be transferred to low volume bladder cancer providers, clinicians need to remain cautious and conservative with regard to the indiscriminate use of such a conservative approach. CONCLUSIONS Conservative management of recurrent bladder tumors is an appropriate option for some patients with a history of Ta, low grade tumors, especially those who are older and with significant medical comorbidities. Such a strategy may avoid potential risks and morbidities associated with frequent, repeat TURBT as well as reduce total health care expenses. However, under such a conservative management strategy, patients should remain under careful cystoscopic and cytologic surveillance as there remains some risk for grade and stage progression in this patient population.
Abbreviations and Acronyms TURBT ⫽ transurethral bladder tumor resection
REFERENCES 1.
2.
3.
Heney NM, Ahmed S, Flanagan MJ, Frable W, Corder MP, Hafermann MD et al: Superficial bladder cancer: progression and recurrence. J Urol 1983; 130: 1083. Messing EM and Catalona W: Urothelial tumors of the urinary tract. In: Campbell’s Urology, 7th ed. Edited by PC Walsh, AB Retik, ED Vaughan Jr and AJ Wein. Philadelphia: WB Saunders 1998; chapt 77, pp 2327–2408. Fleshner NE, Herr HW, Stewart AK, Murphy GP, Mettlin C and Menck HR: The National Cancer Data Base report on bladder carcinoma. Cancer 1996; 78: 1505.
90 4.
5.
6.
7.
8.
9.
10.
11.
CONSERVATIVE MANAGEMENT OF BLADDER TUMORS Smith JA Jr, Labasky RF, Cockett ATK, Fracchia JA, Montie JE and Rowland RG: Bladder Cancer Clinical Guidelines Panel summary report on the management of nonmuscle invasive bladder cancer (stages Ta, T1 and TIS). J Urol 1999; 162: 1697. Holmang S, Andius P, Hedelin H, Wester K, Busch C and Johansson SL: Stage progression in Ta papillary urothelial tumors: relationship to grade, immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy. J Urol 2001; 165: 1124. Holmang S, Hedelin H, Anderstrom C and Johansson SL: The relationship among multiple recurrences, progression and prognosis of patients with stages Ta and T1 transitional cell cancer of the bladder followed for at least 20 years. J Urol 1995; 153: 1823. Holmang S, Hedelin H, Anderstrom C, Holmberg E, Busch C and Johansson SL: Recurrence and progression in low grade papillary urothelial tumors. J Urol 1999; 162: 702. Soloway M, Bruck D and Kim S: Expectant management of small, recurrent, noninvasive, papillary bladder tumors. J Urol 2003; 170: 438. Donat S, North A, Dalbagni G and Herr H: Efficacy of office fulguration for recurrent low grade papillary bladder tumors less than 0.5 cm. J Urol 2004; 171: 636. Gofrit O, Pode D, Lazar A, Katz R and Shapiro A: Watchful waiting policy in recurrent Ta G1 bladder tumors. Eur Urol 2006; 49: 303. Herr H, Donat S and Dalbagni G: Correlation of cystoscopy with histology of recurrent papillary tumors of the bladder. J Urol 2002; 168: 978.
EDITORIAL COMMENT Transurethral resection has been established as the standard treatment for superficial bladder tumors. Recent studies have shown experienced urologists can reliably identify a select group of patients with recurrent low risk Ta tumors (papillary, less than 0.5 cm, less than 5 tumors, low grade appearance, negative voided cytology) in which office fulguration via a flexible scope can be a safe and efficacious alternative to transurethral resection (references 9 and 11 in text).1 Due to the slow growth and minimal risk of progression of low grade noninvasive tumors, Soloway et al initially proposed expectant management as another alternative to transurethral resection with the patient under anesthesia with the goal of decreasing morbidity and health care costs (reference 8 in article).
The authors present their experience with expectant management of low risk superficial bladder cancer in 22 patients representing 13% of their total active patient population. Definitive treatment (transurethral resection or fulguration) was ultimately required in 32% (7 of 22) of patients during a median followup of 23 months, with 13% (3 of 22) having progression in tumor stage or grade but none to muscle invasive disease. They conclude expectant management is an appropriate option for some patients with noninvasive low grade Ta tumors, especially in older patients with significant comorbidities, but appropriately warn that this approach may not be reproducible in less experienced hands. The conflicting data regarding the ability of endoscopic appearance alone to accurately predict papillary tumor stage and grade support the author’s cautionary note on expectant management.1 Furthermore, since office fulguration provides an efficacious definitive treatment without morbidity for this same subset of patients proposed for expectant management, one could question the usefulness of observation. Although the authors assume expectant management will decrease health care cost and morbidity, there are no prospective data comparing differences in costs and complications between treatment and observation to support that assumption. In addition, no guidelines have been established for the ideal frequency of surveillance in patients with tumor under expectant management. Until higher level evidentiary data are available on the safety and efficacy of expectant tumor management, and guidelines are established for appropriate patient selection and surveillance methods, expectant management should not be considered for standard practice. A prospective randomized trial comparing office fulguration to expectant management is the logical next step to answer the question. S. Machele Donat Department of Urology Memorial Sloan-Kettering Cancer Center/Weill Cornell Medical College New York, New York 1.
Soloway MS: International Consultation on Bladder Tumors. Urology 2005; 66: 1.