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The natural history of bladder carcinoma in situ after initial response to bacillus Calmette-Gúerin immunotherapy
Urologic Oncology: Seminars and Original Investigations 27 (2009) 258 –262
Original article
The natural history of bladder carcinoma in situ after initial response to bacillus Calmette-Gúerin immunotherapy Ofer N. Gofrit, M.D., Ph.D.a,c,*, Dov Pode, M.D.a, Galina Pizov, M.D.b, Kevin C. Zorn, M.D.c, Ran Katz, M.D.a, Mordechi Duvdevani, M.D.a, Amos Shapiro, M.D.a a
Department of Urology, Hadassah Hebrew University Hospital, Jerusalem, Israel Department of Pathology, Hadassah Hebrew University Hospital, Jerusalem, Israel c Department of Surgery, Section of Urology, Chicago University Hospital, Chicago, IL 60637, USA b
Received 6 November 2007; received in revised form 13 December 2007; accepted 13 December 2007
Abstract Objectives: To explore patterns of recurrence, muscle invasion, and disease specific mortality in patients with bladder carcinoma in situ (CIS) who responded to an induction course with intravesical bacillus Calmette-Gúerin (BCG) immunotherapy. Methods: Between June 1985 and December 2003, 104 patients (mean age 67 years) were diagnosed with either pure (38 patients) or concomitant (66 patients) CIS. Patients who responded to one (92 patients) or two (12 patients) induction courses of intravesical BCG instillation were included in the study. Response was determined and monitored by routine periodic bladder biopsies. Outcome of patients and the effect of various prognostic parameters were assessed after a median follow-up of 75 months. Results: The 5- and 10-year recurrence-free survival rates were 63% and 54%, respectively. The 5- and 10-year muscle-invasive-free survival rates were 79% and 77%, and the 5- and 10-year disease-specific survival rates were 90.5 and 85.8%, respectively. Median time to recurrence, muscle invasion, and disease-specific mortality was 18, 19, and 40 months, respectively. Pure and concomitant CIS were associated with a similar outcome. The recurrence of nonmuscle-invasive tumor did not increase the risk for muscle invasion or mortality. Conclusions: Pure and concomitant bladder CIS share similar biologic behavior. Muscle-invasive disease is expected in about 25% of the BCG responders followed for long time periods and disease-specific mortality in 15%. Tumor recurrence, whether nonmuscle-invasive or muscle-invasive, follows a similar time table suggesting that these are not sequential but parallel and independent processes. © 2009 Elsevier Inc. All rights reserved. Keywords: Bladder carcinoma in situ; Bacillus Calmette-Gúerin immunotherapy; Prognosis
1. Introduction Carcinoma in situ (CIS) of the urinary bladder is a flat, noninvasive neoplastic mucosal change of the urothelium similar morphometrically and immunohistochemically to muscle-invasive cancer, and is probably its precursor [1–5]. CIS either adjacent or remote from the overt tumor is a common finding in radical cystectomy specimens [6,7], and muscle-invasive bladder cancer has developed in 10/12 patients with CIS in the epithelium surrounding a low grade tumor [8]. The risk of muscle invasion in untreated patients with CIS is extremely high (80%) and the disease specific mortality may reach 60% [8]. * Corresponding author. Tel.: ⫹972-2-6776874; fax: ⫹972-2-6430929. E-mail address: [email protected] (O.N. Gofrit). 1078-1439/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2007.12.011
Immunotherapy with bacillus Calmette-Gúerin (BCG) for patients with CIS has been shown to provide a favorable short-term outcome. Approximately 65% to 70% of the patients with CIS achieve complete response to intravesical immunotherapy with BCG [9 –12]. The durability of this response is not universal and when patients are followed for long periods, up to 36% develop muscle-invasive disease [13]. The natural history of patients with CIS who achieved CR with BCG immunotherapy is still puzzling. Clearly, some patients enjoy long periods of freedom from disease while others rapidly progress to muscle invasion and metastases. Some authors have suggested a distinction between pure CIS and concomitant CIS [14], and attributed a more favorable prognosis to pure CIS [15], but this was not universally verified [16,17]. Herr et al. suggested that a patient’s 6-month status can be used as a useful prognostic
O.N. Gofrit et al. / Urologic Oncology: Seminars and Original Investigations 27 (2009) 258 –262
parameter, and that treatment strategy should be reconsidered in patients with tumor recurrence [18]. We undertook this study in an attempt to provide contemporary data on the patterns of tumor recurrence, muscle invasion, and disease specific mortality in BCG responders, and to test various prognostic factors.
2. Materials and methods 2.1. Patients Patients diagnosed with concomitant or pure bladder CIS on random cold cup biopsies from June 1985 to December 2003 were recruited to a prospective protocol. The 1973 World Health Organization (WHO) classification was used for pathologic diagnosis [19]. None of the patients had previous or coexisting muscle-invasive urothelial carcinoma at the time of diagnosis. All patients were given an induction course of 6 weekly intravesical instillations of 81 mg Connaught BCG in 50 cc of normal saline. Treatment was initiated 10 to 20 days following the diagnostic biopsy and complete transurethral removal of all visible lesions. Six weeks after the last instillation, random bladder biopsies were obtained in all cases. If CIS persisted, a second induction course was given [20], and random bladder biopsies obtained again 6 weeks after the last instillation. Cases of CIS persistence despite two induction courses were not included in the study. The follow-up protocol included urinary cytology and bladder biopsies every 3 months for 2 years, then every 6 months for an additional 3 years, and then annually with urinary cytology and cystoscopy without biopsies. Upper tract evaluation (intravenous pyelogram) was done annually. Since March 1995, maintenance therapy (2 instillations every 3 months for 1 year and 2 instillations every 6 months for another 2 years) was given to newly diagnosed patients. Patients were followed for at least 3 years from the diagnosis of CIS unless censored due to death (either disease-specific or not disease-specific). The study was approved by the International Review Board (IRB) (approval no. 210-03.08.07).
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3. Results A total of 104 patients (95 men) with bladder CIS were recruited during the study period. Their mean age was 67.4 years (SD 11 years). Pure CIS was diagnosed in 38 patients (36.5%) and concomitant CIS in 66 patients (63.5%), including 47 cases of CIS with concomitant high grade tumor (20 Stage Ta and 27 Stage T1), and 19 cases with concomitant low grade tumor (all Stage Ta). A single induction course was given to 92 patients (88.5%), and 12 patients (11.5%) required a second course. Maintenance BCG therapy was given to 48 patients (46%). Median follow-up was 75 months; 120 months after BCG instillation 26 patients were still “at risk”. During follow-up, 42 patients (40.4%) developed recurrence of a nonmuscle-invasive tumor after a median period of 18 months (range 5–264 months) from diagnosis of bladder CIS to first recurrence. These included 33 cases (78.6%) of grade 3 and 9 cases (21.4%) of grades 1–2 disease. Muscle-invasive cancer developed in 22 patients (21.1%) after a median period of 19 months (range 3–248 months). Bladder cancer metastases occurred in 13 patients (12.5%) after a median period of 28 months (range 7–264 months). A total of 45 patients died (43.3%); in 12 patients (11.5%) death was disease-specific and occurred after a median period of 39.5 months (range 16 –264 months). The 5- and 10-year recurrence-free survival rates were 63% and 54%, respectively. The 5- and 10-year muscle-invasive-free survival rates were 79% and 77%, and the 5- and 10-year disease-specific survival rates were 90.5% and 85.8%. Fig. 1 presents the timing of recurrence of nonmuscle-invasive and muscle-invasive bladder cancer. The two curves are parallel. Cox proportional hazard analysis of the effect of
2.2. Statistical analysis Kaplan-Meier curves and the Cox proportional hazard analysis were used to assess recurrence-free survival (of nonmuscle-invasive disease), muscle-invasive free survival, metastases-free survival, and disease-specific survival. Cox proportional hazard analysis was used to asses the effect of the following parameters on patients’ outcome: patient age, sex, CIS type (pure or concomitant), the need for a second induction course, the effect of maintenance therapy, recurrence of nonmuscle-invasive tumor (as a predictor of muscle-invasive disease), and 6-month bladder status. A Pvalue ⬍0.05 was considered statistically significant.
Fig. 1. Timing of nonmuscle-invasive and muscle-invasive bladder tumor diagnosis in patients with bladder carcinoma in situ (CIS) who responded to an induction course with intravesical BCG immunotherapy. (Color version of figure is available online.)
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Table 1 Cox proportional hazard analysis for muscle invasive tumor progression
Age Sex (M/F) Pure/concomitant Response to first BCG course (Y/N) Maintenance BCG (Y/N) Nonmuscle invasive recurrence (Y/N) 6-months status (recurrence vs. no recurrence)
Hazard ratio
95% CI
SE
P-Value
1.01 0.97 1.1 1.6
0.98–1.06 0.39–1.8 0.71–1.78 0.94–2.6
0.02 0.37 0.23 0.25
0.34 0.67 0.67 0.08
1.1 1.6
0.73–1.73 0.67–4.1
0.2 0.46
0.6 0.3
0.37
0.1–2.35
0.7
0.24
various parameters on the risk for muscle invasion and disease-specific mortality are shown in Tables 1 and 2. None of the parameters tested showed a statistically significant effect. Recurrence of a nonmuscle-invasive tumor at 6 months or at any time did not increase the risk of muscleinvasion or disease-specific mortality. The grade of nonmuscle-invasive recurring tumor had no effect either. Patients with pure CIS and concomitant low- and high-grade tumor had a similar outcome. Radical cystectomy was performed in 22 patients (21.5%) for the treatment of either muscle-invasive cancer (12 patients) or refractory CIS (10 patients). Partial cystectomy was done in 2 patients (for muscle-invasive disease in 1 case and for grade 3 nonmuscle-invasive tumor in another case). Upper tract urothelial cancer was diagnosed in 5 patients (4.8%), after a median time of 39 months from diagnosis of bladder CIS, and was fatal in three patients.
4. Discussion CIS is believed to be the precursor of muscle-invasive and metastatic bladder cancer. Preventing these life-threatening events is a foremost therapeutic goal. The natural history of CIS is often unpredictable with rapid progression to muscle invasion and metastases in some patients and an indolent, nonprogressive course in others. While BCG has a proven short-term curative effect, its efficacy in prevention of tumor progression is less well defined. In this study, we have shown that 77% of the biopsy proven BCG responders remained progression-free 10 years later, and that only 14% of them die from metastatic disease. These results are encouraging and are comparable to the best long-term studies reported (Table 3). One of the reasons for this could be the use of mandatory bladder biopsies for defining BCG responsiveness and for follow-up. When routine biopsies are not obtained, and follow-up utilizes only cystoscopy and cytology, “early failure” may occur [24]. The favorable outcome reported here is comparable to the results obtained when immediate radical cystectomy is the treatment for CIS [16]. Even with this radical therapy,
only 76% of the patients achieve long term disease-specific survival. The inevitable conclusion is that as many as 10% of the patients with CIS have concealed lymph node or systemic metastases at initial CIS diagnosis. Many attempts have been made to define clinical or molecular prognostic markers for patients with bladder CIS [25,26], but none entered routine clinical use. Orozco et al. suggested that the clinical behavior of primary and concomitant CIS is different. In their study, the risk of death from bladder cancer was 45% among patients with concomitant CIS but only 7% among patients with primary CIS, after a median follow-up of 49 months [15]. Other investigators, employing longer periods of follow-up, were not able to verify this finding [16,17], and also in the current study, patients with pure or concomitant CIS had a similar prognosis (Tables 1 and 2). It seems, therefore, that CIS itself is the major determinant of patients’ prognosis and not other past or concomitant bladder tumors. Herr et al. suggested that the bladder status at 6 months following BCG induction therapy identifies the probability for progression, and that in patients with tumor recurrence at 6 months, an alternative treatment strategy should be required [18]. On a broader level, the question to answer is whether a recurrence of a nonmuscle-invasive tumor is a precursor or a risk factor for disease progression. In the current study, recurrence of nonmuscle-invasive tumor at 6 months or later was not associated with a higher risk of progression or mortality (Tables 1 and 2). Moreover, tumor recurrence, whether nonmuscle-invasive or muscle-invasive, followed a similar timetable (Fig. 1), suggesting that these are not sequential but parallel and independent processes. Therefore, from our perspective, recurrence of a nonmuscle-invasive bladder cancer is neither a precursor nor a predictor of pending, more serious events. With regard to initial BCG failure, no difference in outcome was found between patients who responded to a single course of BCG and patients who required two induction courses (Tables 1 and 2). It seems that the immune system of some patients requires more stimulation, but once activated, it provides the same benefit to the patient. Lamm et al. have demonstrated that maintenance treatment reduced the risk for recurrence in patients with CIS and may also be associated with longer time to progression [27]. These results were supported by a meta-analysis perTable 2 Cox proportional hazard analysis for disease-specific survival
Age Sex (M/F) Pure/concomitant Response to first BCG course (Y/N) Maintenance BCG (Y/N) Nonmuscle invasive recurrence (Y/N)
Hazard ratio
95% CI
SE
P-Value
1.01 1.38 1.37 1.52
0.96–1.07 0.54–2.7 0.75–2.92 0.59–2.96
0.03 0.4 0.32 0.4
0.67 0.4 0.3 0.32
0.86 0.97
0.48–1.56 0.95–0.99
0.29 0.01
0.62 0.0007
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Table 3 Progression-free survival and cancer-specific survival among patients with bladder CIS given various therapies Author
No. of patients with clinical CIS
Treatment
Median follow-up (months)
Muscle-invasion free survival
% Cancer-specific survival
Althausen (1976) [8] Cheng (1999) [16] Malkowicz (1990) [21] Jenkins (1988) [22] Herr (1992) [13] Reijke (2005) [11] Reijke (2005) [11] Kaasinen (2003) [23] Current study
12 41 49 71 44 84 84 145 104
No treatment Immediate cystectomy Delayed cystectomy Systemic cylophosphamid BCG BCG Epirubicin BCG BCG responders
36 180 60 36 142 67 67 56 75
17% — — 91.5% 64% 86% 83% n.a. 79%
42% 76% 81% 94% 84% 89% 84.5% 93% 89.5%
formed by Sylvester et al. [28]. Maintenance treatment, however, did not improve the prognosis of patients in the current study. Two major protocol differences can explain the different results; first, the study of Lamm et al. recruited patients who did not achieve CR with the induction course, while only patients who achieved biopsy proven CR were included in the current study. Second, Lamm et al. employed a more intense maintenance schedule of eight 3-weekly instillations while in the current study, only seven 2-weekly instillations were given [26].
5. Conclusions Bladder CIS is a relatively uniform disease that is the major determinant of patients’ prognosis and not any other concomitant bladder disease. Muscle-invasive disease is expected in about 25% of the BCG responders, followed for long time periods and disease-specific mortality in 15%. Tumor recurrence, whether nonmuscle-invasive or muscle-invasive, follows a similar timetable, suggesting that these are not sequential but parallel and independent processes. Thus, the recurrence of nonmuscle-invasive tumor is neither the precursor nor a predictor of muscle-invasive or metastatic cancer.
References [1] Bostwick DG, Ramnani D, Cheng L. Diagnosis and grading of bladder cancer and associated lesions. Urol Clin North Am 1999;26:493–507. [2] Sanchez-Fernandez de Sevilla MC, Morell-Quadreny L, Gil-Salom M, et al. Morphometric and immunohistochemical characterization of bladder carcinoma in situ and its preneoplastic lesions. Eur Urol 1992;21(Suppl)1:5–9. [3] Brawn PN. The origin of invasive carcinoma of the bladder. Cancer 1982;50:515–9. [4] Lee R, Droller MJ. The natural history of bladder cancer. Implications for therapy. Urol Clin North Am 2000;27:1–13. [5] Esrig D, Elmajian D, Groshen S, et al. Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 1994;331: 1259 – 64. [6] Skinner DG, Richie JP, Cooper PH, et al. The clinical significance of carcinoma in situ of the bladder and its association with overt carcinoma. J Urol 1974;112:68 –71.
[7] Koss LG, Tiamson EM, Robbins MA. Mapping cancerous and precancerous bladder changes. A study of the urothelium in ten surgically removed bladders. JAMA 1974;227:281– 6. [8] Althausen AF, Prout GR Jr, Daly JJ. Noninvasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 1976;116:575– 80. [9] Hudson MA, Herr HW. Carcinoma in situ of the bladder. J Urol 1995;153:564 –72. [10] Lamm DL, Blumenstein BA, Crawford ED, et al. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Gúerin for transitional-cell carcinoma of the bladder. N Engl J Med 1991;325:1205–9. [11] de Reijke TM, Kurth KH, Sylvester RJ, et al. Bacillus Calmette-Gúerin vs. epirubicin for primary, secondary, or concurrent carcinoma in situ of the bladder: Results of a European Organization for the Research and Treatment of Cancer, Genito-Urinary Group, Phase III trial (30906). J Urol 2005;173:405–9. [12] Sylvester RJ, van der Meijden AP, Witjes JA, et al. Bacillus Calmette-Guérin vs. chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladderA meta-analysis of the published results of randomized clinical trials. J Urol 2005; 174:86 –91. [13] Herr HW, Wartinger DD, Fair WR, et al. Bacillus Calmette-Gúerin therapy for superficial bladder cancerA 10-year followup. J Urol 1992;147:1020 –3. [14] 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 –32. [15] Orozco RE, Martin AA, Murphy WM. Carcinoma in situ of the urinary bladder. Clues to host involvement in human carcinogenesis. Cancer 1994;74:115–22. [16] Cheng L, Cheville JC, Neumann RM, et al. Survival of patients with carcinoma in situ of the urinary bladder. Cancer 1999;85: 2469 –74. [17] Jakse G, Hall R, Bono A, et al. Intravesical BCG in patients with carcinoma in situ of the urinary bladder: Long-term results of EORTC GU Group Phase II protocol 30861. Eur Urol 2001;40:144 –50. [18] Herr HW, Badalament RA, Amato DA, et al. Superficial bladder cancer treated with bacillus Calmette-Gúerin: A multivariate analysis of factors affecting tumor progression. J Urol 1989;141:22–9. [19] Mostofi FK, Sobin LH, Torloni H. International histological classification of tumors, No 10. Histological typing of urinary bladder tumors Geneva: World Health Organization, 1973. [20] Haaff EO, Dresner SM, Ratliff TL, et al. Two courses of intravesical bacillus Calmette-Gúerin for transitional cell carcinoma of the bladder. J Urol 1986;136:820 – 4. [21] Malkowicz SB, Nichols P, Lieskovsky G, et al. The role of radical cystectomy in the management of high grade superficial bladder cancer (PA, P1, PIS, and P2) J Urol 1990;144:641–5.
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[22] Jenkins BJ, England HR, Fowler CG, et al. Chemotherapy for carcinoma in situ of the bladder. Br J Urol 1988;61:326 –9. [23] Kaasinen E, Wijkström H, Malmström PU, et al. Alternating mitomycin C and BCG instillations vs. BCG alone in treatment of carcinoma in situ of the urinary bladder: A Nordic study. Eur Urol 2003;43:637– 45. [24] Merz VW, Marth D, Kraft R, et al. Analysis of early failures after intravesical instillation therapy with bacille Calmette-Gúerin for carcinoma in situ of the bladder. Br J Urol 1995;75:180 – 4. [25] Pfister C, Moore L, Allard P, et al. Predictive value of cell cycle markers p53, MDM2, p21, and Ki-67 in superficial bladder tumor recurrence. Clin Cancer Res 1999;5:4079 – 84.
[26] Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: Associations with localized stage progression. Cancer 2007;109:1499–505. [27] Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Gúerin immunotherapy for recurrent TA, T1, and carcinoma in situ transitional cell carcinoma of the bladder: A randomized Southwest Oncology Group Study. J Urol 2000;163:1124 –9. [28] Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Gúerin reduces the risk of progression in patients with superficial bladder cancer: A meta-analysis of the published results of randomized clinical trials. J Urol 2002;168:1964 –70.
Original article
The natural history of bladder carcinoma in situ after initial response to bacillus Calmette-Gúerin immunotherapy Ofer N. Gofrit, M.D., Ph.D.a,c,*, Dov Pode, M.D.a, Galina Pizov, M.D.b, Kevin C. Zorn, M.D.c, Ran Katz, M.D.a, Mordechi Duvdevani, M.D.a, Amos Shapiro, M.D.a a
Department of Urology, Hadassah Hebrew University Hospital, Jerusalem, Israel Department of Pathology, Hadassah Hebrew University Hospital, Jerusalem, Israel c Department of Surgery, Section of Urology, Chicago University Hospital, Chicago, IL 60637, USA b
Received 6 November 2007; received in revised form 13 December 2007; accepted 13 December 2007
Abstract Objectives: To explore patterns of recurrence, muscle invasion, and disease specific mortality in patients with bladder carcinoma in situ (CIS) who responded to an induction course with intravesical bacillus Calmette-Gúerin (BCG) immunotherapy. Methods: Between June 1985 and December 2003, 104 patients (mean age 67 years) were diagnosed with either pure (38 patients) or concomitant (66 patients) CIS. Patients who responded to one (92 patients) or two (12 patients) induction courses of intravesical BCG instillation were included in the study. Response was determined and monitored by routine periodic bladder biopsies. Outcome of patients and the effect of various prognostic parameters were assessed after a median follow-up of 75 months. Results: The 5- and 10-year recurrence-free survival rates were 63% and 54%, respectively. The 5- and 10-year muscle-invasive-free survival rates were 79% and 77%, and the 5- and 10-year disease-specific survival rates were 90.5 and 85.8%, respectively. Median time to recurrence, muscle invasion, and disease-specific mortality was 18, 19, and 40 months, respectively. Pure and concomitant CIS were associated with a similar outcome. The recurrence of nonmuscle-invasive tumor did not increase the risk for muscle invasion or mortality. Conclusions: Pure and concomitant bladder CIS share similar biologic behavior. Muscle-invasive disease is expected in about 25% of the BCG responders followed for long time periods and disease-specific mortality in 15%. Tumor recurrence, whether nonmuscle-invasive or muscle-invasive, follows a similar time table suggesting that these are not sequential but parallel and independent processes. © 2009 Elsevier Inc. All rights reserved. Keywords: Bladder carcinoma in situ; Bacillus Calmette-Gúerin immunotherapy; Prognosis
1. Introduction Carcinoma in situ (CIS) of the urinary bladder is a flat, noninvasive neoplastic mucosal change of the urothelium similar morphometrically and immunohistochemically to muscle-invasive cancer, and is probably its precursor [1–5]. CIS either adjacent or remote from the overt tumor is a common finding in radical cystectomy specimens [6,7], and muscle-invasive bladder cancer has developed in 10/12 patients with CIS in the epithelium surrounding a low grade tumor [8]. The risk of muscle invasion in untreated patients with CIS is extremely high (80%) and the disease specific mortality may reach 60% [8]. * Corresponding author. Tel.: ⫹972-2-6776874; fax: ⫹972-2-6430929. E-mail address: [email protected] (O.N. Gofrit). 1078-1439/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2007.12.011
Immunotherapy with bacillus Calmette-Gúerin (BCG) for patients with CIS has been shown to provide a favorable short-term outcome. Approximately 65% to 70% of the patients with CIS achieve complete response to intravesical immunotherapy with BCG [9 –12]. The durability of this response is not universal and when patients are followed for long periods, up to 36% develop muscle-invasive disease [13]. The natural history of patients with CIS who achieved CR with BCG immunotherapy is still puzzling. Clearly, some patients enjoy long periods of freedom from disease while others rapidly progress to muscle invasion and metastases. Some authors have suggested a distinction between pure CIS and concomitant CIS [14], and attributed a more favorable prognosis to pure CIS [15], but this was not universally verified [16,17]. Herr et al. suggested that a patient’s 6-month status can be used as a useful prognostic
O.N. Gofrit et al. / Urologic Oncology: Seminars and Original Investigations 27 (2009) 258 –262
parameter, and that treatment strategy should be reconsidered in patients with tumor recurrence [18]. We undertook this study in an attempt to provide contemporary data on the patterns of tumor recurrence, muscle invasion, and disease specific mortality in BCG responders, and to test various prognostic factors.
2. Materials and methods 2.1. Patients Patients diagnosed with concomitant or pure bladder CIS on random cold cup biopsies from June 1985 to December 2003 were recruited to a prospective protocol. The 1973 World Health Organization (WHO) classification was used for pathologic diagnosis [19]. None of the patients had previous or coexisting muscle-invasive urothelial carcinoma at the time of diagnosis. All patients were given an induction course of 6 weekly intravesical instillations of 81 mg Connaught BCG in 50 cc of normal saline. Treatment was initiated 10 to 20 days following the diagnostic biopsy and complete transurethral removal of all visible lesions. Six weeks after the last instillation, random bladder biopsies were obtained in all cases. If CIS persisted, a second induction course was given [20], and random bladder biopsies obtained again 6 weeks after the last instillation. Cases of CIS persistence despite two induction courses were not included in the study. The follow-up protocol included urinary cytology and bladder biopsies every 3 months for 2 years, then every 6 months for an additional 3 years, and then annually with urinary cytology and cystoscopy without biopsies. Upper tract evaluation (intravenous pyelogram) was done annually. Since March 1995, maintenance therapy (2 instillations every 3 months for 1 year and 2 instillations every 6 months for another 2 years) was given to newly diagnosed patients. Patients were followed for at least 3 years from the diagnosis of CIS unless censored due to death (either disease-specific or not disease-specific). The study was approved by the International Review Board (IRB) (approval no. 210-03.08.07).
259
3. Results A total of 104 patients (95 men) with bladder CIS were recruited during the study period. Their mean age was 67.4 years (SD 11 years). Pure CIS was diagnosed in 38 patients (36.5%) and concomitant CIS in 66 patients (63.5%), including 47 cases of CIS with concomitant high grade tumor (20 Stage Ta and 27 Stage T1), and 19 cases with concomitant low grade tumor (all Stage Ta). A single induction course was given to 92 patients (88.5%), and 12 patients (11.5%) required a second course. Maintenance BCG therapy was given to 48 patients (46%). Median follow-up was 75 months; 120 months after BCG instillation 26 patients were still “at risk”. During follow-up, 42 patients (40.4%) developed recurrence of a nonmuscle-invasive tumor after a median period of 18 months (range 5–264 months) from diagnosis of bladder CIS to first recurrence. These included 33 cases (78.6%) of grade 3 and 9 cases (21.4%) of grades 1–2 disease. Muscle-invasive cancer developed in 22 patients (21.1%) after a median period of 19 months (range 3–248 months). Bladder cancer metastases occurred in 13 patients (12.5%) after a median period of 28 months (range 7–264 months). A total of 45 patients died (43.3%); in 12 patients (11.5%) death was disease-specific and occurred after a median period of 39.5 months (range 16 –264 months). The 5- and 10-year recurrence-free survival rates were 63% and 54%, respectively. The 5- and 10-year muscle-invasive-free survival rates were 79% and 77%, and the 5- and 10-year disease-specific survival rates were 90.5% and 85.8%. Fig. 1 presents the timing of recurrence of nonmuscle-invasive and muscle-invasive bladder cancer. The two curves are parallel. Cox proportional hazard analysis of the effect of
2.2. Statistical analysis Kaplan-Meier curves and the Cox proportional hazard analysis were used to assess recurrence-free survival (of nonmuscle-invasive disease), muscle-invasive free survival, metastases-free survival, and disease-specific survival. Cox proportional hazard analysis was used to asses the effect of the following parameters on patients’ outcome: patient age, sex, CIS type (pure or concomitant), the need for a second induction course, the effect of maintenance therapy, recurrence of nonmuscle-invasive tumor (as a predictor of muscle-invasive disease), and 6-month bladder status. A Pvalue ⬍0.05 was considered statistically significant.
Fig. 1. Timing of nonmuscle-invasive and muscle-invasive bladder tumor diagnosis in patients with bladder carcinoma in situ (CIS) who responded to an induction course with intravesical BCG immunotherapy. (Color version of figure is available online.)
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O.N. Gofrit et al. / Urologic Oncology: Seminars and Original Investigations 27 (2009) 258 –262
Table 1 Cox proportional hazard analysis for muscle invasive tumor progression
Age Sex (M/F) Pure/concomitant Response to first BCG course (Y/N) Maintenance BCG (Y/N) Nonmuscle invasive recurrence (Y/N) 6-months status (recurrence vs. no recurrence)
Hazard ratio
95% CI
SE
P-Value
1.01 0.97 1.1 1.6
0.98–1.06 0.39–1.8 0.71–1.78 0.94–2.6
0.02 0.37 0.23 0.25
0.34 0.67 0.67 0.08
1.1 1.6
0.73–1.73 0.67–4.1
0.2 0.46
0.6 0.3
0.37
0.1–2.35
0.7
0.24
various parameters on the risk for muscle invasion and disease-specific mortality are shown in Tables 1 and 2. None of the parameters tested showed a statistically significant effect. Recurrence of a nonmuscle-invasive tumor at 6 months or at any time did not increase the risk of muscleinvasion or disease-specific mortality. The grade of nonmuscle-invasive recurring tumor had no effect either. Patients with pure CIS and concomitant low- and high-grade tumor had a similar outcome. Radical cystectomy was performed in 22 patients (21.5%) for the treatment of either muscle-invasive cancer (12 patients) or refractory CIS (10 patients). Partial cystectomy was done in 2 patients (for muscle-invasive disease in 1 case and for grade 3 nonmuscle-invasive tumor in another case). Upper tract urothelial cancer was diagnosed in 5 patients (4.8%), after a median time of 39 months from diagnosis of bladder CIS, and was fatal in three patients.
4. Discussion CIS is believed to be the precursor of muscle-invasive and metastatic bladder cancer. Preventing these life-threatening events is a foremost therapeutic goal. The natural history of CIS is often unpredictable with rapid progression to muscle invasion and metastases in some patients and an indolent, nonprogressive course in others. While BCG has a proven short-term curative effect, its efficacy in prevention of tumor progression is less well defined. In this study, we have shown that 77% of the biopsy proven BCG responders remained progression-free 10 years later, and that only 14% of them die from metastatic disease. These results are encouraging and are comparable to the best long-term studies reported (Table 3). One of the reasons for this could be the use of mandatory bladder biopsies for defining BCG responsiveness and for follow-up. When routine biopsies are not obtained, and follow-up utilizes only cystoscopy and cytology, “early failure” may occur [24]. The favorable outcome reported here is comparable to the results obtained when immediate radical cystectomy is the treatment for CIS [16]. Even with this radical therapy,
only 76% of the patients achieve long term disease-specific survival. The inevitable conclusion is that as many as 10% of the patients with CIS have concealed lymph node or systemic metastases at initial CIS diagnosis. Many attempts have been made to define clinical or molecular prognostic markers for patients with bladder CIS [25,26], but none entered routine clinical use. Orozco et al. suggested that the clinical behavior of primary and concomitant CIS is different. In their study, the risk of death from bladder cancer was 45% among patients with concomitant CIS but only 7% among patients with primary CIS, after a median follow-up of 49 months [15]. Other investigators, employing longer periods of follow-up, were not able to verify this finding [16,17], and also in the current study, patients with pure or concomitant CIS had a similar prognosis (Tables 1 and 2). It seems, therefore, that CIS itself is the major determinant of patients’ prognosis and not other past or concomitant bladder tumors. Herr et al. suggested that the bladder status at 6 months following BCG induction therapy identifies the probability for progression, and that in patients with tumor recurrence at 6 months, an alternative treatment strategy should be required [18]. On a broader level, the question to answer is whether a recurrence of a nonmuscle-invasive tumor is a precursor or a risk factor for disease progression. In the current study, recurrence of nonmuscle-invasive tumor at 6 months or later was not associated with a higher risk of progression or mortality (Tables 1 and 2). Moreover, tumor recurrence, whether nonmuscle-invasive or muscle-invasive, followed a similar timetable (Fig. 1), suggesting that these are not sequential but parallel and independent processes. Therefore, from our perspective, recurrence of a nonmuscle-invasive bladder cancer is neither a precursor nor a predictor of pending, more serious events. With regard to initial BCG failure, no difference in outcome was found between patients who responded to a single course of BCG and patients who required two induction courses (Tables 1 and 2). It seems that the immune system of some patients requires more stimulation, but once activated, it provides the same benefit to the patient. Lamm et al. have demonstrated that maintenance treatment reduced the risk for recurrence in patients with CIS and may also be associated with longer time to progression [27]. These results were supported by a meta-analysis perTable 2 Cox proportional hazard analysis for disease-specific survival
Age Sex (M/F) Pure/concomitant Response to first BCG course (Y/N) Maintenance BCG (Y/N) Nonmuscle invasive recurrence (Y/N)
Hazard ratio
95% CI
SE
P-Value
1.01 1.38 1.37 1.52
0.96–1.07 0.54–2.7 0.75–2.92 0.59–2.96
0.03 0.4 0.32 0.4
0.67 0.4 0.3 0.32
0.86 0.97
0.48–1.56 0.95–0.99
0.29 0.01
0.62 0.0007
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Table 3 Progression-free survival and cancer-specific survival among patients with bladder CIS given various therapies Author
No. of patients with clinical CIS
Treatment
Median follow-up (months)
Muscle-invasion free survival
% Cancer-specific survival
Althausen (1976) [8] Cheng (1999) [16] Malkowicz (1990) [21] Jenkins (1988) [22] Herr (1992) [13] Reijke (2005) [11] Reijke (2005) [11] Kaasinen (2003) [23] Current study
12 41 49 71 44 84 84 145 104
No treatment Immediate cystectomy Delayed cystectomy Systemic cylophosphamid BCG BCG Epirubicin BCG BCG responders
36 180 60 36 142 67 67 56 75
17% — — 91.5% 64% 86% 83% n.a. 79%
42% 76% 81% 94% 84% 89% 84.5% 93% 89.5%
formed by Sylvester et al. [28]. Maintenance treatment, however, did not improve the prognosis of patients in the current study. Two major protocol differences can explain the different results; first, the study of Lamm et al. recruited patients who did not achieve CR with the induction course, while only patients who achieved biopsy proven CR were included in the current study. Second, Lamm et al. employed a more intense maintenance schedule of eight 3-weekly instillations while in the current study, only seven 2-weekly instillations were given [26].
5. Conclusions Bladder CIS is a relatively uniform disease that is the major determinant of patients’ prognosis and not any other concomitant bladder disease. Muscle-invasive disease is expected in about 25% of the BCG responders, followed for long time periods and disease-specific mortality in 15%. Tumor recurrence, whether nonmuscle-invasive or muscle-invasive, follows a similar timetable, suggesting that these are not sequential but parallel and independent processes. Thus, the recurrence of nonmuscle-invasive tumor is neither the precursor nor a predictor of muscle-invasive or metastatic cancer.
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