- Email: [email protected]
Clinical Outcome of Primary Versus Secondary Bladder Carcinoma In Situ
Clinical Outcome of Primary Versus Secondary Bladder Carcinoma In Situ Daher C. Chade, Shahrokh F. Shariat, Ari Adamy, Bernard H. Bochner, S. Machele Donat, Harry W. Herr and Guido Dalbagni* From the Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
Abbreviations and Acronyms BCG ⫽ bacillus Calmette-Guerin CIS ⫽ carcinoma in situ RC ⫽ radical cystectomy TUR ⫽ transurethral resection UBC ⫽ urothelial bladder carcinoma Submitted for publication December 1, 2009. Study received institutional review board approval. Supported by the Sidney Kimmel Center for Prostate and Urologic Cancers, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil (DCC), and National Institutes of Health T32-CA82088 (SFS). * Correspondence: Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial SloanKettering Cancer Center, 353 East 68th St., New York, New York 10065 (telephone: 646-422-4394; FAX: 212-988-0760; e-mail: [email protected]).
Purpose: Differences in clinical outcome are still unclear between primary and secondary bladder carcinoma in situ. We compared the clinical outcomes of primary and secondary carcinoma in situ, and identified predictive factors. Materials and Methods: We retrospectively analyzed the records of 476 patients with high grade cTis, including 221 with primary and 255 with secondary carcinoma in situ, from 1990 to 2008 at a high volume cancer center after transurethral resection and intravesical bacillus Calmette-Guerin therapy. End points were time to progression to invasive disease (cT1 or higher) or radical cystectomy before progression, and progression to muscle invasive disease (cT2 or higher) or radical cystectomy before progression. We used Cox proportional hazards regression models. Results: Patients with primary carcinoma in situ responded significantly more within 6 months of bacillus Calmette-Guerin than those with secondary carcinoma in situ (65% vs 39%, p ⬍0.001). In the primary vs secondary groups the 5-year cumulative incidence of progression to cT1 or higher was 43% (95% CI 36 –51) vs 32% (95% CI 27–39) and for progression to cT2 or higher it was 17% (95% CI 12–23) vs 8% (95% CI 5–13). On multivariate analysis primary carcinoma in situ was significantly more likely to progress to cT1 or higher (HR 1.38, 95% CI 1.05–1.81, p ⫽ 0.020) and to cT2 or higher, or radical cystectomy (HR 1.72, 95% CI 1.27–2.33, p ⫽ 0.001). We found no significance for age, gender or response to bacillus Calmette-Guerin as outcome predictors. Median followup was 5.1 years. Conclusions: Patients presenting with primary carcinoma in situ have a worse outcome than those with secondary carcinoma in situ, suggesting a need to differentiate these 2 entities in the treatment decision process. Key Words: urinary bladder, carcinoma, Mycobacterium bovis, carcinoma in situ, urinary bladder neoplasms
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SINCE 1952, when Melicow first described the importance of bladder CIS for UBS recurrence and progression rates,1 the understanding of this disease has evolved greatly, allowing improved patient care.2 The pathological finding of CIS implies a worse prognosis in patients with nonmuscle invasive UBC despite widely variable
outcomes in the long term.3 The clinical and biological impact of CIS continues to be controversial but it was suggested that CIS represents a distinct entity.4 More recently groups began to distinguish primary CIS (isolated CIS with no prior or concomitant papillary tumors, that is de novo CIS) from secondary CIS (that diag-
0022-5347/10/1842-0464/0 THE JOURNAL OF UROLOGY® © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 184, 464-469, August 2010 Printed in U.S.A. DOI:10.1016/j.juro.2010.03.134
AND
RESEARCH, INC.
CLINICAL OUTCOME OF PRIMARY VERSUS SECONDARY BLADDER CARCINOMA IN SITU
nosed concomitantly with or after a papillary tumor).3,5,6 However, it remains unclear whether primary or secondary CIS carries a worse prognosis.7 Also, to our knowledge the distinction between primary and secondary CIS has not yet been shown to be clinically relevant or associated with particular oncological outcomes after intravesical BCG therapy. Although many groups have addressed the issue of the clinical significance of primary or secondary CIS, studies show that conclusions have been drawn in a small number of patients in each category or in studies with inadequate patient selection at mixed stages, thus not allowing a thorough understanding of the natural history of this disease.3,8 –11 In this context we compared clinical outcomes in a large cohort of patients presenting with primary or secondary CIS to a tertiary referral cancer center.
PATIENTS AND METHODS We retrospectively analyzed our institutional database with the approval of the institutional review board. The CIS diagnosis was based on urine cytology, cystoscopy with biopsy or TUR, bimanual examination and pathological evaluation by a dedicated genitourinary pathologist at our institution. We excluded patients with pathological slides unavailable for review. Patients were followed every 3 months with urine cytology and cystoscopy. Random biopsy and repeat TUR were done in all suspicious cases. Positive cytology was considered a recommendation for random biopsy and upper tract imaging even when cystoscopy was not suspicious. Negative cytology was acceptable since all cases required random biopsy and pathological confirmation of CIS. BCG therapy consisted of an induction course of 6 weekly intravesical instillations. The study comprised a consecutive cohort of 476 patients diagnosed with primary (221) or secondary (255) CIS from 1990 to 2008. Primary CIS was defined as isolated, high grade cTis at initial TUR without any prior or concomitant papillary tumor. Secondary CIS was defined as high grade cTis diagnosed concomitantly with or after a
465
prior papillary cTa tumor. Patients with CIS concomitant to cT1 or higher were not included in analysis. To analyze the response to BCG we excluded from study 48 patients who progressed before BCG therapy and 36 missing the date of BCG therapy, leaving 182 with primary and 210 with secondary CIS available for analysis. Diagnosis was based on the UICC TNM system and graded according to the 1998 WHO/International Society of Urological Pathology grading system of bladder urothelial neoplasms.12 We reviewed the medical records for clinical information on patient characteristics. To compare the clinical outcome of primary vs secondary CIS we analyzed time to separate end points, including progression to invasive disease, defined as cT1 or higher, and progression to muscle invasive disease, defined as cT2 or higher. Because RC is an adverse outcome that may be related to disease severity, we considered the earlier of RC or progression as a single end point. Since many patients underwent RC before progression to invasive disease, we plotted the risk of progression using the cumulative incidence function in the presence of a competing risk. We created separate multivariate Cox regression models for each end point, including 1) progression to cT1 or higher, or RC before progression and 2) progression to cT2 or higher, or RC before progression. As predictors, we used primary vs secondary CIS presentation, patient age, gender and response to intravesical BCG. We defined responders as patients in whom disease did not recur within 6 months of BCG therapy and nonresponders as those in whom disease recurred within 6 months of BCG therapy. All analysis was done using SPSS® 16.0 and R with the cmprsk package.
RESULTS A total of 476 patients received BCG therapy after presenting with CIS. At initial bladder cancer diagnosis median patient age was 66.7 years (IQR 13.1) overall, including 68.6 (IQR 11.8) in those with primary CIS and 65.2 (IQR 14.6) in those with secondary CIS (Mann-Whitney U test p ⫽ 0.002). Of the patients 389 (82%) were male, 446 (94%) were white and 341 (72%) were current or former smokers (table 1).
Table 1. Clinical characteristics in patients with primary or secondary CIS
Male White Smoking history: None Former Current Unknown Initial symptoms: Asymptomatic* Gross hematuria Irritative or obstructive voiding symptoms Unknown * Incidental finding and microhematuria.
No. Pts (%)
No. Primary (%)
No. Secondary (%)
389 (81.7) 446 (93.7)
185 (83.7) 210 (95.5)
204 (80.0) 236 (92.9)
111 (23.3) 282 (59.2) 59 (12.4) 24 (5.0)
63 (28.5) 125 (56.6) 22 (10.0) 11 (5.0)
48 (18.8) 157 (61.6) 37 (14.5) 13 (5.1)
101 (21.2) 198 (41.6) 88 (18.5) 89 (18.7)
48 (21.7) 69 (31.2) 63 (28.5) 41 (18.6)
53 (20.8) 129 (50.6) 25 (9.8) 48 (18.8)
p Value (chi-square test) 0.342 0.329 0.027
⬍0.001
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CLINICAL OUTCOME OF PRIMARY VERSUS SECONDARY BLADDER CARCINOMA IN SITU
Gross hematuria was more often diagnosed in the secondary CIS group (51% vs 31%) while irritative or obstructive voiding symptoms were more commonly reported by patients diagnosed with primary CIS (29% vs 10%, p ⬍0.001). Overall median followup was 5.1 years (IQR 2.5, 8.2). Of patients in the primary vs secondary CIS group 65% vs 39% responded to BCG within 6 months (p ⬍0.001, table 2). A total of 179 patients progressed to invasive disease and 57 progressed to muscle invasive UBC. In the primary vs secondary CIS group median time to progression to cT1 or higher/RC was 3.4 (IQR 2.4, 4.5) vs 5.8 years (IQR 3.7, 7.8) and to cT2 or higher/RC it was 5.2 (IQR 3.2, 7.4) vs 9.9 years (IQR 5, 12.7). Median followup in the primary vs secondary CIS groups was 3.4 (IQR 2.4, 4.5) vs 5.7 years (IQR 3.7, 7.8). Median followup in patients without disease progression was 3.9 years (IQR 1.2, 6.7). Direct progression from CIS to cT2 occurred in 27 patients with primary and in 17 with secondary CIS. Overall 173 patients underwent RC, including 92 with primary and 81 with secondary CIS. RC was done before progression in 67 patients with primary and in 66 with secondary CIS. Pathological stage at RC did not differ between the 2 groups (p ⫽ 0.26). In the primary vs secondary CIS groups 31 (34.5%) vs 23 patients (29.2%) had pT2 or greater at RC, respectively. Disease specific survival at 10
Table 2. Clinical outcomes in patients with primary or secondary CIS
Intravesical BCG:* Responders Nonresponders Intravesical chemotherapy Recurrence Progression to: T1 or greater T2 or greater Direct T2 RC: All stages Before progression Before progression for CIS Before progression for T1 Distant metastasis Second primary urothelial Ca: Upper tract Urethra Death: Bladder Ca Upper tract urothelial Ca Other cause Unknown * p ⬍ 0.001.
No. Pts (%)
No. Primary (%)
No. Secondary (%)
243 (51) 233 (49) 79 (17) 367
144 (65) 77 (35) 33 (15) 182
99 (39) 156 (61) 46 (18) 185
179 57 44
93 37 27
86 20 17
173 132 57 75 51
92 67 27 40 28
81 66 30 36 23
32 25 95 33 6 28 28
10 8 50 18 0 11 21
22 17 45 15 6 17 7
Table 3. Multivariate analysis of progression to cT1 or higher invasive disease and cT2 or higher muscle invasive disease adjusted for RC before progression cT1 or Higher, or RC
cT2 or Higher, or RC
Variables*
HR (95% CI)
p Value
HR (95% CI)
p Value
Primary vs secondary CIS Age Gender BCG response
1.37 (1.05–1.81)
0.020
1.72 (1.27–2.33)
0.001
1.01 (0.99–1.02) 1.18 (0.86–1.63) 1.12 (0.85–1.46)
0.178 0.300 0.421
1.01 (0.99–1.02) 1.15 (0.80–1.65) 1.03 (0.76–1.39)
0.568 0.455 0.865
* Excluding 84 patients due to progression before BCG or missing data.
years was 82% vs 96% in the primary vs secondary CIS groups. On multivariate analysis primary CIS carried a significantly higher risk of progression to cT1 or higher/RC (HR 1.38, 95% CI 1.05–1.81, p ⫽ 0.020) and to cT2 or higher/RC (HR 1.72, 95% CI 1.27–2.33, p ⫽ 0.001) than secondary CIS (table 3). Age, gender and response to BCG were not significantly associated with disease progression or RC. Figure 1 shows a higher cumulative incidence of progression to cT1 or higher in patients with primary CIS. RC before progression to cT1 or higher was similar in the 2 groups. Progression to cT2 or higher was consistently higher in the primary CIS group despite the higher incidence of RC before progression to cT2 or higher in this group (fig. 2). The competing risk of RC before progression was greater than the cumulative incidence of progression to cT2 or higher in each group. This inversion was related to the higher recommendation of RC before progression for cT1 than for CIS.
Figure 1. Cumulative incidence of progression to cT1 or higher invasive disease, or RC before progression in patients with primary or secondary CIS.
CLINICAL OUTCOME OF PRIMARY VERSUS SECONDARY BLADDER CARCINOMA IN SITU
Figure 2. Cumulative incidence of progression to cT2 or higher muscle invasive disease, or RC before progression in patients with primary or secondary CIS.
The 5-year cumulative incidence of progression to cT1 or higher was 43% (95% CI 36 –51) in the primary CIS group vs 32% (95% CI 27–39) in the secondary CIS group. In patients with primary CIS the RC rate at 5 years for less than cT1 was 15% (95% CI 10 –21) and for less than cT2 it was 32% (95% CI 26 –39). In patients with secondary CIS at 5 years the RC rate for less than cT1 was 12% (95% CI 7–19) and for less than cT2 it was 25% (95% CI 20 –32). The 5-year cumulative incidence of progression to cT2 or higher was 17% (95% CI 12–23) vs 8% (95% CI 5–13) in the primary vs secondary CIS groups.
DISCUSSION In this large cohort of patients with primary or secondary CIS we compared oncological outcomes after intravesical BCG failure and identified evidence that primary CIS carries a higher risk of progression than secondary CIS. Primary CIS was significantly associated with higher progression to invasive disease or RC and to muscle invasive disease or RC. The mechanism of progression from CIS to life threatening disease may be related to the invasion pattern. Historical studies introduced the concept of divergent routes for flat and papillary tumors, and presumably these patterns behave differently.2,13,14 Thus, if we consider secondary CIS an initiation of the papillary tumor type, that is if 2 patterns of invasion actually coexist, distinct clinical outcomes may be expected from the different invasion patterns. Recent evidence showed genomic alterations
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related to CIS carcinogenesis that further distinguish flat and papillary lesions by supporting the notion of 2 separate biological pathways in bladder tumors. Zieger et al found a series of chromosomal instability characterized by chromosome gain (5p, 6p22.3 and 10p15.1) and loss of heterozygosity (5q and 13q13-q14) associated with CIS while fibroblast growth factor receptor-3 mutations were associated with papillary tumors.6 Despite not clearly defining the impact of CIS on oncological outcomes, several previous studies identified CIS as a poor prognostic factor since it is associated with increasing the risk of progression to muscle invasive disease and the risk of death from bladder cancer.3,15–17 However, few groups have compared outcomes in patients with primary vs secondary CIS and, thus, they could not determine whether this classification is important for disease management.8,18 To our knowledge no previous study has clearly shown significant differences in outcome between primary and secondary CIS in a homogenous cohort of nonmuscle invasive UBC cases. Most groups have suggested similar disease progression rates or noted confounding results by favoring primary CIS as better biological behavior, mostly due to small sample size or mixed stage groups. In a landmark study Orozco et al compared patients with primary CIS vs patients with CIS associated with UBC at any invasion level, of whom more than 50% had muscle invasive disease at initial diagnosis.19 Not surprisingly the mixed secondary CIS group had a worse outcome, leading to the misleading conclusion that primary CIS may be a less aggressive disease. However, more recently in a small cohort Cheng et al found that patients with primary CIS had lower progression-free survival at 15 years than those with secondary CIS, although this was not statistically significant (54% vs 65%, p ⫽ 0.34).20 Gofrit et al studied 104 patients with primary and secondary CIS combined, and observed no significant difference between pure and concomitant CIS.8 Takenaka et al reported findings based on a small number of patients that also showed no difference between CIS types.21 Although they reported a sample of 185 patients with CIS, analysis included primary, secondary and concomitant disease in the same risk group. In our study the higher cumulative incidence of progression to invasive and to muscle invasive disease at 5 years after adjusting for the competing risk of RC before progression underscores the aggressiveness of primary CIS. When considering at risk patients with primary CIS who underwent RC before progression to cT2, the 5-year cumulative incidence of progression to muscle invasive UBC was as high as 49% in the absence of RC before progression.
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CLINICAL OUTCOME OF PRIMARY VERSUS SECONDARY BLADDER CARCINOMA IN SITU
Moreover, since RC is recommended more often in the primary CIS group with the goal of avoiding progression, one could expect a decreased incidence of progression in this group, in contrast to our findings in this cohort. Thus, our results support recommending surgery in patients at presumably higher risk and even suggest that more common recommendations for surgical treatment could benefit patients with primary CIS. RC before progression is an acceptable recommendation in patients with nonmuscle invasive UBC after failed BCG.22–24 In our study the relatively high incidence of RC before progression to muscle invasive UBC showed a trend toward considering these patients to be at high risk. Moreover, similar RC rates before progression to cT1 or higher in each CIS group and the higher RC rate before progression to cT2 or higher in the primary CIS group suggest that the poorer outcome in the primary CIS group is reliable since it was not biased by surgery, which could have precluded this group from progressing at an even higher rate. However, several other factors that may influence RC timing may have also affected our results. Herr reported that aging is significantly associated with recurrence in a large cohort of 805 patients with nonmuscle invasive disease (Ta or T1 with concomitant CIS in 78%).25 In our series age was not associated with progression to muscle invasive disease or RC before progression. This may possibly be related to a higher cumulative incidence of RC before progression in the younger population in the primary CIS group. Although the response to BCG was significantly higher in the primary than in the secondary CIS group (65% vs 39%, p ⬍0.001), this did not impact
the progression rate when controlled for age, gender and CIS group. This may have been due to the higher rate of RC before progression in the primary CIS group. Recent studies also showed no significant association of response to BCG with outcome.8 However, Andius et al found that initial cystoscopy had predictive value for progression, BCG failure and death in a cohort of 173 patients but showed no difference between CIS types.9 Our study has several limitations. It is retrospective in nature. Patients treated at our tertiary referral hospital may differ from patients with bladder cancer treated at community centers. Also, the cohort covered 19 years, during which a trend occurred toward earlier RC. Although the indication for earlier RC has only recently gained more support, this treatment option was part of our recommendation during this interval, which may have prevented a greater impact on our series.22
CONCLUSIONS Results suggest that primary CIS is more aggressive than secondary CIS and these 2 tumor types are distinct. Although patients with primary CIS respond better to BCG therapy, we found no association with progression. RC before progression was recommended more often in the primary CIS group but this was not enough to decrease the progression rate close to that in the secondary CIS group. While additional data are required to validate these findings, the distinction between these 2 entities may influence clinical management of this disease, decision making for RC before progression and prognostic models.
REFERENCES 1. Melicow MM: Histological study of vesical urothelium intervening between gross neoplasms in total cystectomy. J Urol 1952; 68: 261. 2. Utz DC and Farrow GM: Carcinoma in situ of the urinary tract. Urol Clin North Am 1984; 11: 735. 3. Sylvester RJ, van der Meijden A, Witjes JA et al: High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder. Urology 2005; 66: 90. 4. Weinstein RS, Miller AW 3rd and Pauli BU: Carcinoma in situ: comments on the pathobiology of a paradox. Urol Clin North Am 1980; 7: 523. 5. Nese N, Gupta R, Bui MH et al: Carcinoma in situ of the urinary bladder: review of clinicopathologic characteristics with an emphasis on aspects related to molecular diagnostic techniques and prognosis. J Natl Compr Cancer Netw 2009; 7: 48.
6. Zieger K, Marcussen N, Borre M et al: Consistent genomic alterations in carcinoma in situ of the urinary bladder confirm the presence of two major pathways in bladder cancer development. Int J Cancer 2009; 125: 2095. 7. Hudson MA and Herr HW: Carcinoma in situ of the bladder. J Urol 1995; 153: 564. 8. Gofrit ON, Pode D, Pizov G et al: The natural history of bladder carcinoma in situ after initial response to bacillus Calmette-Guerin immunotherapy. Urol Oncol 2009; 27: 258.
11. Sylvester RJ: Natural history, recurrence, and progression in superficial bladder cancer. Sci World J 2006; 6: 2617. 12. Reuter VE, Epstein JI, Amin MB et al: The “WHO/ ISUP Consensus Classification of Urothelial (Transitional Cell) Neoplasms”: continued discussion. Hum Pathol 1999; 30: 879. 13. Utz DC, Farrow GM, Rife CC et al: Carcinoma in situ of the bladder. Cancer 1980; 45: 1842. 14. Farrow GM, Utz DC, Rife CC et al: Clinical observations on sixty-nine cases of in situ carcinoma of the urinary bladder. Cancer Res 1977; 37: 2794.
9. Andius P, Damm O and Holmang S: Prognostic factors in patients with carcinoma in situ treated with intravesical bacille Calmette-Guerin. Scand J Urol Nephrol 2004; 38: 285.
15. Lamm DL: Carcinoma in situ. Urol Clin North Am 1992; 19: 499.
10. Witjes JA: Bladder carcinoma in situ in 2003: state of the art. Eur Urol 2004; 45: 142.
16. Althausen AF, Prout GR Jr and Daly JJ: Noninvasive papillary carcinoma of the bladder asso-
CLINICAL OUTCOME OF PRIMARY VERSUS SECONDARY BLADDER CARCINOMA IN SITU
ciated with carcinoma in situ. J Urol 1976; 116: 575.
involvement in human carcinogenesis. Cancer 1994; 74: 115.
17. Sylvester RJ, van der Meijden AP, Oosterlinck W et al: Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006; 49: 466.
20. Cheng L, Cheville JC, Neumann RM et al: Survival of patients with carcinoma in situ of the urinary bladder. Cancer 1999; 85: 2469.
18. Prout GR Jr, Griffin PP, Daly JJ et al: Carcinoma in situ of the urinary bladder with and without associated vesical neoplasms. Cancer 1983; 52: 524. 19. Orozco RE, Martin AA and Murphy WM: Carcinoma in situ of the urinary bladder. Clues to host
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23. Denzinger S, Fritsche HM, Otto W et al: Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? Eur Urol 2008; 53: 146.
21. Takenaka A, Yamada Y, Miyake H et al: Clinical outcomes of bacillus Calmette-Guerin instillation therapy for carcinoma in situ of urinary bladder. Int J Urol 2008; 15: 309.
24. Hall MC, Chang SS, Dalbagni G et al: Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol 2007; 178: 2314.
22. Herr HW and Sogani PC: Does early cystectomy improve the survival of patients with high risk superficial bladder tumors? J Urol 2001; 166: 1296.
25. Herr HW: Age and outcome of superficial bladder cancer treated with bacille Calmette-Guerin therapy. Urology 2007; 70: 65.
EDITORIAL COMMENT These authors further clarify the impact of primary CIS (isolated CIS without prior or concomitant papillary tumors) vs secondary CIS (diagnosed concomitantly with or after a papillary tumor) on disease progression in a large cohort of patients presenting at a tertiary referral cancer center. Patients with primary CIS were significantly more likely to progress than patients with secondary CIS. Other groups have addressed the prognostic impact of primary vs secondary CIS but results have not been consistent. Interestingly in this study no patient received maintenance BCG, an approach that potentially impacts disease progression. Furthermore, since patients with clinical T1 disease were excluded from study, it is not clear whether the distinction between primary and secondary CIS has a biological impact when the papillary tumor is T1. From a practical standpoint it remains difficult to properly
allocate patients to each group since it is well acknowledged that cystoscopy can miss papillary tumors and some patients with primary CIS may actually have secondary CIS. Similarly in patients with primary CIS who had a papillary tumor at 3-month cystoscopy that tumor may have been missed on initial cystoscopy. Currently to our knowledge there is insufficient evidence showing whether a distinction between these 2 entities may influence clinical management of this disease. In essence all patients with primary or secondary CIS are recommended to undergo BCG therapy with RC upon BCG failure. Wassim Kassouf Division of Urology McGill University Health Center Montreal, Quebec Canada
Abbreviations and Acronyms BCG ⫽ bacillus Calmette-Guerin CIS ⫽ carcinoma in situ RC ⫽ radical cystectomy TUR ⫽ transurethral resection UBC ⫽ urothelial bladder carcinoma Submitted for publication December 1, 2009. Study received institutional review board approval. Supported by the Sidney Kimmel Center for Prostate and Urologic Cancers, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil (DCC), and National Institutes of Health T32-CA82088 (SFS). * Correspondence: Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial SloanKettering Cancer Center, 353 East 68th St., New York, New York 10065 (telephone: 646-422-4394; FAX: 212-988-0760; e-mail: [email protected]).
Purpose: Differences in clinical outcome are still unclear between primary and secondary bladder carcinoma in situ. We compared the clinical outcomes of primary and secondary carcinoma in situ, and identified predictive factors. Materials and Methods: We retrospectively analyzed the records of 476 patients with high grade cTis, including 221 with primary and 255 with secondary carcinoma in situ, from 1990 to 2008 at a high volume cancer center after transurethral resection and intravesical bacillus Calmette-Guerin therapy. End points were time to progression to invasive disease (cT1 or higher) or radical cystectomy before progression, and progression to muscle invasive disease (cT2 or higher) or radical cystectomy before progression. We used Cox proportional hazards regression models. Results: Patients with primary carcinoma in situ responded significantly more within 6 months of bacillus Calmette-Guerin than those with secondary carcinoma in situ (65% vs 39%, p ⬍0.001). In the primary vs secondary groups the 5-year cumulative incidence of progression to cT1 or higher was 43% (95% CI 36 –51) vs 32% (95% CI 27–39) and for progression to cT2 or higher it was 17% (95% CI 12–23) vs 8% (95% CI 5–13). On multivariate analysis primary carcinoma in situ was significantly more likely to progress to cT1 or higher (HR 1.38, 95% CI 1.05–1.81, p ⫽ 0.020) and to cT2 or higher, or radical cystectomy (HR 1.72, 95% CI 1.27–2.33, p ⫽ 0.001). We found no significance for age, gender or response to bacillus Calmette-Guerin as outcome predictors. Median followup was 5.1 years. Conclusions: Patients presenting with primary carcinoma in situ have a worse outcome than those with secondary carcinoma in situ, suggesting a need to differentiate these 2 entities in the treatment decision process. Key Words: urinary bladder, carcinoma, Mycobacterium bovis, carcinoma in situ, urinary bladder neoplasms
464
www.jurology.com
SINCE 1952, when Melicow first described the importance of bladder CIS for UBS recurrence and progression rates,1 the understanding of this disease has evolved greatly, allowing improved patient care.2 The pathological finding of CIS implies a worse prognosis in patients with nonmuscle invasive UBC despite widely variable
outcomes in the long term.3 The clinical and biological impact of CIS continues to be controversial but it was suggested that CIS represents a distinct entity.4 More recently groups began to distinguish primary CIS (isolated CIS with no prior or concomitant papillary tumors, that is de novo CIS) from secondary CIS (that diag-
0022-5347/10/1842-0464/0 THE JOURNAL OF UROLOGY® © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 184, 464-469, August 2010 Printed in U.S.A. DOI:10.1016/j.juro.2010.03.134
AND
RESEARCH, INC.
CLINICAL OUTCOME OF PRIMARY VERSUS SECONDARY BLADDER CARCINOMA IN SITU
nosed concomitantly with or after a papillary tumor).3,5,6 However, it remains unclear whether primary or secondary CIS carries a worse prognosis.7 Also, to our knowledge the distinction between primary and secondary CIS has not yet been shown to be clinically relevant or associated with particular oncological outcomes after intravesical BCG therapy. Although many groups have addressed the issue of the clinical significance of primary or secondary CIS, studies show that conclusions have been drawn in a small number of patients in each category or in studies with inadequate patient selection at mixed stages, thus not allowing a thorough understanding of the natural history of this disease.3,8 –11 In this context we compared clinical outcomes in a large cohort of patients presenting with primary or secondary CIS to a tertiary referral cancer center.
PATIENTS AND METHODS We retrospectively analyzed our institutional database with the approval of the institutional review board. The CIS diagnosis was based on urine cytology, cystoscopy with biopsy or TUR, bimanual examination and pathological evaluation by a dedicated genitourinary pathologist at our institution. We excluded patients with pathological slides unavailable for review. Patients were followed every 3 months with urine cytology and cystoscopy. Random biopsy and repeat TUR were done in all suspicious cases. Positive cytology was considered a recommendation for random biopsy and upper tract imaging even when cystoscopy was not suspicious. Negative cytology was acceptable since all cases required random biopsy and pathological confirmation of CIS. BCG therapy consisted of an induction course of 6 weekly intravesical instillations. The study comprised a consecutive cohort of 476 patients diagnosed with primary (221) or secondary (255) CIS from 1990 to 2008. Primary CIS was defined as isolated, high grade cTis at initial TUR without any prior or concomitant papillary tumor. Secondary CIS was defined as high grade cTis diagnosed concomitantly with or after a
465
prior papillary cTa tumor. Patients with CIS concomitant to cT1 or higher were not included in analysis. To analyze the response to BCG we excluded from study 48 patients who progressed before BCG therapy and 36 missing the date of BCG therapy, leaving 182 with primary and 210 with secondary CIS available for analysis. Diagnosis was based on the UICC TNM system and graded according to the 1998 WHO/International Society of Urological Pathology grading system of bladder urothelial neoplasms.12 We reviewed the medical records for clinical information on patient characteristics. To compare the clinical outcome of primary vs secondary CIS we analyzed time to separate end points, including progression to invasive disease, defined as cT1 or higher, and progression to muscle invasive disease, defined as cT2 or higher. Because RC is an adverse outcome that may be related to disease severity, we considered the earlier of RC or progression as a single end point. Since many patients underwent RC before progression to invasive disease, we plotted the risk of progression using the cumulative incidence function in the presence of a competing risk. We created separate multivariate Cox regression models for each end point, including 1) progression to cT1 or higher, or RC before progression and 2) progression to cT2 or higher, or RC before progression. As predictors, we used primary vs secondary CIS presentation, patient age, gender and response to intravesical BCG. We defined responders as patients in whom disease did not recur within 6 months of BCG therapy and nonresponders as those in whom disease recurred within 6 months of BCG therapy. All analysis was done using SPSS® 16.0 and R with the cmprsk package.
RESULTS A total of 476 patients received BCG therapy after presenting with CIS. At initial bladder cancer diagnosis median patient age was 66.7 years (IQR 13.1) overall, including 68.6 (IQR 11.8) in those with primary CIS and 65.2 (IQR 14.6) in those with secondary CIS (Mann-Whitney U test p ⫽ 0.002). Of the patients 389 (82%) were male, 446 (94%) were white and 341 (72%) were current or former smokers (table 1).
Table 1. Clinical characteristics in patients with primary or secondary CIS
Male White Smoking history: None Former Current Unknown Initial symptoms: Asymptomatic* Gross hematuria Irritative or obstructive voiding symptoms Unknown * Incidental finding and microhematuria.
No. Pts (%)
No. Primary (%)
No. Secondary (%)
389 (81.7) 446 (93.7)
185 (83.7) 210 (95.5)
204 (80.0) 236 (92.9)
111 (23.3) 282 (59.2) 59 (12.4) 24 (5.0)
63 (28.5) 125 (56.6) 22 (10.0) 11 (5.0)
48 (18.8) 157 (61.6) 37 (14.5) 13 (5.1)
101 (21.2) 198 (41.6) 88 (18.5) 89 (18.7)
48 (21.7) 69 (31.2) 63 (28.5) 41 (18.6)
53 (20.8) 129 (50.6) 25 (9.8) 48 (18.8)
p Value (chi-square test) 0.342 0.329 0.027
⬍0.001
466
CLINICAL OUTCOME OF PRIMARY VERSUS SECONDARY BLADDER CARCINOMA IN SITU
Gross hematuria was more often diagnosed in the secondary CIS group (51% vs 31%) while irritative or obstructive voiding symptoms were more commonly reported by patients diagnosed with primary CIS (29% vs 10%, p ⬍0.001). Overall median followup was 5.1 years (IQR 2.5, 8.2). Of patients in the primary vs secondary CIS group 65% vs 39% responded to BCG within 6 months (p ⬍0.001, table 2). A total of 179 patients progressed to invasive disease and 57 progressed to muscle invasive UBC. In the primary vs secondary CIS group median time to progression to cT1 or higher/RC was 3.4 (IQR 2.4, 4.5) vs 5.8 years (IQR 3.7, 7.8) and to cT2 or higher/RC it was 5.2 (IQR 3.2, 7.4) vs 9.9 years (IQR 5, 12.7). Median followup in the primary vs secondary CIS groups was 3.4 (IQR 2.4, 4.5) vs 5.7 years (IQR 3.7, 7.8). Median followup in patients without disease progression was 3.9 years (IQR 1.2, 6.7). Direct progression from CIS to cT2 occurred in 27 patients with primary and in 17 with secondary CIS. Overall 173 patients underwent RC, including 92 with primary and 81 with secondary CIS. RC was done before progression in 67 patients with primary and in 66 with secondary CIS. Pathological stage at RC did not differ between the 2 groups (p ⫽ 0.26). In the primary vs secondary CIS groups 31 (34.5%) vs 23 patients (29.2%) had pT2 or greater at RC, respectively. Disease specific survival at 10
Table 2. Clinical outcomes in patients with primary or secondary CIS
Intravesical BCG:* Responders Nonresponders Intravesical chemotherapy Recurrence Progression to: T1 or greater T2 or greater Direct T2 RC: All stages Before progression Before progression for CIS Before progression for T1 Distant metastasis Second primary urothelial Ca: Upper tract Urethra Death: Bladder Ca Upper tract urothelial Ca Other cause Unknown * p ⬍ 0.001.
No. Pts (%)
No. Primary (%)
No. Secondary (%)
243 (51) 233 (49) 79 (17) 367
144 (65) 77 (35) 33 (15) 182
99 (39) 156 (61) 46 (18) 185
179 57 44
93 37 27
86 20 17
173 132 57 75 51
92 67 27 40 28
81 66 30 36 23
32 25 95 33 6 28 28
10 8 50 18 0 11 21
22 17 45 15 6 17 7
Table 3. Multivariate analysis of progression to cT1 or higher invasive disease and cT2 or higher muscle invasive disease adjusted for RC before progression cT1 or Higher, or RC
cT2 or Higher, or RC
Variables*
HR (95% CI)
p Value
HR (95% CI)
p Value
Primary vs secondary CIS Age Gender BCG response
1.37 (1.05–1.81)
0.020
1.72 (1.27–2.33)
0.001
1.01 (0.99–1.02) 1.18 (0.86–1.63) 1.12 (0.85–1.46)
0.178 0.300 0.421
1.01 (0.99–1.02) 1.15 (0.80–1.65) 1.03 (0.76–1.39)
0.568 0.455 0.865
* Excluding 84 patients due to progression before BCG or missing data.
years was 82% vs 96% in the primary vs secondary CIS groups. On multivariate analysis primary CIS carried a significantly higher risk of progression to cT1 or higher/RC (HR 1.38, 95% CI 1.05–1.81, p ⫽ 0.020) and to cT2 or higher/RC (HR 1.72, 95% CI 1.27–2.33, p ⫽ 0.001) than secondary CIS (table 3). Age, gender and response to BCG were not significantly associated with disease progression or RC. Figure 1 shows a higher cumulative incidence of progression to cT1 or higher in patients with primary CIS. RC before progression to cT1 or higher was similar in the 2 groups. Progression to cT2 or higher was consistently higher in the primary CIS group despite the higher incidence of RC before progression to cT2 or higher in this group (fig. 2). The competing risk of RC before progression was greater than the cumulative incidence of progression to cT2 or higher in each group. This inversion was related to the higher recommendation of RC before progression for cT1 than for CIS.
Figure 1. Cumulative incidence of progression to cT1 or higher invasive disease, or RC before progression in patients with primary or secondary CIS.
CLINICAL OUTCOME OF PRIMARY VERSUS SECONDARY BLADDER CARCINOMA IN SITU
Figure 2. Cumulative incidence of progression to cT2 or higher muscle invasive disease, or RC before progression in patients with primary or secondary CIS.
The 5-year cumulative incidence of progression to cT1 or higher was 43% (95% CI 36 –51) in the primary CIS group vs 32% (95% CI 27–39) in the secondary CIS group. In patients with primary CIS the RC rate at 5 years for less than cT1 was 15% (95% CI 10 –21) and for less than cT2 it was 32% (95% CI 26 –39). In patients with secondary CIS at 5 years the RC rate for less than cT1 was 12% (95% CI 7–19) and for less than cT2 it was 25% (95% CI 20 –32). The 5-year cumulative incidence of progression to cT2 or higher was 17% (95% CI 12–23) vs 8% (95% CI 5–13) in the primary vs secondary CIS groups.
DISCUSSION In this large cohort of patients with primary or secondary CIS we compared oncological outcomes after intravesical BCG failure and identified evidence that primary CIS carries a higher risk of progression than secondary CIS. Primary CIS was significantly associated with higher progression to invasive disease or RC and to muscle invasive disease or RC. The mechanism of progression from CIS to life threatening disease may be related to the invasion pattern. Historical studies introduced the concept of divergent routes for flat and papillary tumors, and presumably these patterns behave differently.2,13,14 Thus, if we consider secondary CIS an initiation of the papillary tumor type, that is if 2 patterns of invasion actually coexist, distinct clinical outcomes may be expected from the different invasion patterns. Recent evidence showed genomic alterations
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related to CIS carcinogenesis that further distinguish flat and papillary lesions by supporting the notion of 2 separate biological pathways in bladder tumors. Zieger et al found a series of chromosomal instability characterized by chromosome gain (5p, 6p22.3 and 10p15.1) and loss of heterozygosity (5q and 13q13-q14) associated with CIS while fibroblast growth factor receptor-3 mutations were associated with papillary tumors.6 Despite not clearly defining the impact of CIS on oncological outcomes, several previous studies identified CIS as a poor prognostic factor since it is associated with increasing the risk of progression to muscle invasive disease and the risk of death from bladder cancer.3,15–17 However, few groups have compared outcomes in patients with primary vs secondary CIS and, thus, they could not determine whether this classification is important for disease management.8,18 To our knowledge no previous study has clearly shown significant differences in outcome between primary and secondary CIS in a homogenous cohort of nonmuscle invasive UBC cases. Most groups have suggested similar disease progression rates or noted confounding results by favoring primary CIS as better biological behavior, mostly due to small sample size or mixed stage groups. In a landmark study Orozco et al compared patients with primary CIS vs patients with CIS associated with UBC at any invasion level, of whom more than 50% had muscle invasive disease at initial diagnosis.19 Not surprisingly the mixed secondary CIS group had a worse outcome, leading to the misleading conclusion that primary CIS may be a less aggressive disease. However, more recently in a small cohort Cheng et al found that patients with primary CIS had lower progression-free survival at 15 years than those with secondary CIS, although this was not statistically significant (54% vs 65%, p ⫽ 0.34).20 Gofrit et al studied 104 patients with primary and secondary CIS combined, and observed no significant difference between pure and concomitant CIS.8 Takenaka et al reported findings based on a small number of patients that also showed no difference between CIS types.21 Although they reported a sample of 185 patients with CIS, analysis included primary, secondary and concomitant disease in the same risk group. In our study the higher cumulative incidence of progression to invasive and to muscle invasive disease at 5 years after adjusting for the competing risk of RC before progression underscores the aggressiveness of primary CIS. When considering at risk patients with primary CIS who underwent RC before progression to cT2, the 5-year cumulative incidence of progression to muscle invasive UBC was as high as 49% in the absence of RC before progression.
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CLINICAL OUTCOME OF PRIMARY VERSUS SECONDARY BLADDER CARCINOMA IN SITU
Moreover, since RC is recommended more often in the primary CIS group with the goal of avoiding progression, one could expect a decreased incidence of progression in this group, in contrast to our findings in this cohort. Thus, our results support recommending surgery in patients at presumably higher risk and even suggest that more common recommendations for surgical treatment could benefit patients with primary CIS. RC before progression is an acceptable recommendation in patients with nonmuscle invasive UBC after failed BCG.22–24 In our study the relatively high incidence of RC before progression to muscle invasive UBC showed a trend toward considering these patients to be at high risk. Moreover, similar RC rates before progression to cT1 or higher in each CIS group and the higher RC rate before progression to cT2 or higher in the primary CIS group suggest that the poorer outcome in the primary CIS group is reliable since it was not biased by surgery, which could have precluded this group from progressing at an even higher rate. However, several other factors that may influence RC timing may have also affected our results. Herr reported that aging is significantly associated with recurrence in a large cohort of 805 patients with nonmuscle invasive disease (Ta or T1 with concomitant CIS in 78%).25 In our series age was not associated with progression to muscle invasive disease or RC before progression. This may possibly be related to a higher cumulative incidence of RC before progression in the younger population in the primary CIS group. Although the response to BCG was significantly higher in the primary than in the secondary CIS group (65% vs 39%, p ⬍0.001), this did not impact
the progression rate when controlled for age, gender and CIS group. This may have been due to the higher rate of RC before progression in the primary CIS group. Recent studies also showed no significant association of response to BCG with outcome.8 However, Andius et al found that initial cystoscopy had predictive value for progression, BCG failure and death in a cohort of 173 patients but showed no difference between CIS types.9 Our study has several limitations. It is retrospective in nature. Patients treated at our tertiary referral hospital may differ from patients with bladder cancer treated at community centers. Also, the cohort covered 19 years, during which a trend occurred toward earlier RC. Although the indication for earlier RC has only recently gained more support, this treatment option was part of our recommendation during this interval, which may have prevented a greater impact on our series.22
CONCLUSIONS Results suggest that primary CIS is more aggressive than secondary CIS and these 2 tumor types are distinct. Although patients with primary CIS respond better to BCG therapy, we found no association with progression. RC before progression was recommended more often in the primary CIS group but this was not enough to decrease the progression rate close to that in the secondary CIS group. While additional data are required to validate these findings, the distinction between these 2 entities may influence clinical management of this disease, decision making for RC before progression and prognostic models.
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EDITORIAL COMMENT These authors further clarify the impact of primary CIS (isolated CIS without prior or concomitant papillary tumors) vs secondary CIS (diagnosed concomitantly with or after a papillary tumor) on disease progression in a large cohort of patients presenting at a tertiary referral cancer center. Patients with primary CIS were significantly more likely to progress than patients with secondary CIS. Other groups have addressed the prognostic impact of primary vs secondary CIS but results have not been consistent. Interestingly in this study no patient received maintenance BCG, an approach that potentially impacts disease progression. Furthermore, since patients with clinical T1 disease were excluded from study, it is not clear whether the distinction between primary and secondary CIS has a biological impact when the papillary tumor is T1. From a practical standpoint it remains difficult to properly
allocate patients to each group since it is well acknowledged that cystoscopy can miss papillary tumors and some patients with primary CIS may actually have secondary CIS. Similarly in patients with primary CIS who had a papillary tumor at 3-month cystoscopy that tumor may have been missed on initial cystoscopy. Currently to our knowledge there is insufficient evidence showing whether a distinction between these 2 entities may influence clinical management of this disease. In essence all patients with primary or secondary CIS are recommended to undergo BCG therapy with RC upon BCG failure. Wassim Kassouf Division of Urology McGill University Health Center Montreal, Quebec Canada