Bladder Cancer 7 (2021) 213–220 213 DOI 10.3233/BLC-201516 IOS Press Systematic Review Systematic Review of the Role of BCG in the Treatment of Urothelial Carcinoma of the Prostatic Urethra Oliver Patschana,∗ , Philippe E. Spiessb , George N. Thalmannc , Joan Palou Redortad and Georgios Gakise a Institution of Translational Medicine, Lund University, Malmö, Sweden b Department of GU Oncology and Department of Tumor Biology, Moffitt Cancer Center, Tampa, FL, USA c Department of Urology, University Hospital Inselspital, Bern, Switzerland d Department of Urology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Fundatió Puigvert, Barcelona, Spain e Department of Urology and Pediatric Urology, University Hospital of Würzburg, Würzburg, Germany Received 16 November 2020 Accepted 28 February 2021 Pre-press 16 March 2021 Published 25 May 2021 Abstract. BACKGROUND: In patients with non-invasive urothelial carcinoma of the prostatic urethra (PUC), treatment with Bacillus Calmette-Guérin (BCG) could be beneficial. OBJECTIVE: To assess the response rates to BCG in the different tumor stages, to describe the clinical impact of transurethral resection of the prostate (TURP) before BCG treatment, and to review the side effects of BCG treatment for PUC. METHODS: A systematic search was conducted using the PubMed database to identify original studies between 1977 and 2019 reporting on PUC and BCG. RESULTS: Of a total of 865 studies, ten were considered for evidence synthesis. An indication for BCG treatment was found in non-stromal invasive stages (Tis pu, Tis pd) and in stromal infiltrating cases (T1) of primary and secondary PUC when transitional cell carcinoma was the histology of origin. Studies including patients treated with TURP before BCG showed a better local response in the prostatic urethra with a higher disease free survival (DFS) (80–100% vs. 63–89%) and progression free survival (PFS) (90–100% vs. 75–94%) than patients in studies in which no TURP was performed. However, this difference in recurrence and progression in the prostate neither affected the total PFS (57–75% vs. 58–93%), nor the disease specific survival (70–100% vs. 66–100%). CONCLUSIONS: The use of resection loop biopsies of the prostatic urethra in appropriate cases during the primary work-up for suspected PUC, as well as the use of the current TNM classification for PUC, need to be improved. BCG therapy for non-stromal invasive stages of PUC show a good local response. Local response is further improved by a TURP before BCG therapy, although the overall prognosis does not seem to be affected. Further evidence for BCG treatment in the rare cases of stromal invasive PUC is needed. Specific side effects of BCG treatment for PUC are not reported. Keywords: BCG, transitional carcinoma, prostatic urethra INTRODUCTION ∗ Correspondence to: Oliver Patschan, MD, PhD, Institution of Translational Medicine, Lund University, Malmö, Sweden. E-mail: oliver.patschan@med.lu.se. ORCID: https://orcid.org/ Urethral carcinoma is a rare disease, accounting for 0000-0001-5788-794X less than 1% of all urogenital cancer cases [1]. In the ISSN 2352-3727 © 2021 – The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0). 214 O. Patschan et al. / Review: Role of BCG in Prostatic Urethral Carcinoma 28 European Union countries, it is estimated that 655 EVIDENCE ACQUISITION patients are being diagnosed with urethral carcinoma annually, striking patients from the fifth decade of A systematic review was carried out based on a lit- life and with a peak incidence in patients 75 years erature search by PubMed/Medline. Due to the low of age [2, 3]. Primary urethral carcinoma is detected incidence of the disease, no prospective clinical tri- in patients without a previous history of urothelial als on BCG treatment in PUC were available. This cancer. Secondary urethral carcinoma occurs during explains why a systematic review according to the the follow up of a known urothelial cancer of the PICO description was not possible. All authors par- bladder or the upper urinary tract (UUT). ticipated in the process of literature search and data The histological origin of urethral carcinoma dif- acquisition process. fers between the sexes: In women, adenocarcinoma This literature search was aimed at identifying all is the most frequent histology (38–47%) followed by articles that published the results of cohort studies SCC (25–28%), UC (25–28%) and other histological and retrospective clinical studies as full-length arti- entities (6%) [4, 5]. In women, both surgery and radi- cles published in English between 1977 (date of the ation therapy are practical treatment options [6]. In first publications relative to urethral carcinoma) and men, approximately 80% of the cases of urethral car- March 2019. Case reports and reviews were excluded. cinoma are urothelial cancers, followed by squamous The following keywords were used in the database cell carcinoma (15%) and adenocarcinoma (5%), just cited: Bacillus Calmette-Guérin OR BCG AND respectively [7]. The histologic features of these can- urethral carcinoma OR urothelial cancer or prostatic cers vary by anatomical location: Urethral cancers in urethra; carcinoma in situ OR CIS AND urethral car- the penile or bulbar urethra are of squamous cell dif- cinoma OR urothelial cancer prostatic urethra; radical ferentiation in about 90% of the cases. In contrast, cystectomy AND urethral carcinoma OR urothe- in the prostatic urethra, 90% of the cancers are of lial cancer prostatic urethra; Bacillus Calmette- urothelial origin [8]. Generally, the primary treatment Guérin OR BCG AND urethral carcinoma OR of male urethral carcinoma is surgical excision. In urothelial cancer prostatic urethra AND survival; the prostatic urethra, transurethral resection is often Bacillus Calmette-Guérin OR BCG AND urethral the first diagnostic and therapeutic step. In invasive carcinoma OR urothelial cancer prostatic ure- growth of prostatic urethral carcinoma (PUC), rad- thra AND transurethral resection prostate; Bacillus ical cystoprostaturethrectomy, either before or after Calmette-Guérin OR BCG AND urethral carcinoma chemotherapy, is indicated. OR urothelial cancer prostatic urethra AND radi- Bacillus Calmette-Guérin (BCG) is the currently cal cystectomy; Bacillus Calmette-Guérin OR BCG most potent drug for intravesical treatment of high- AND urethral carcinoma OR urothelial cancer pro- risk non-muscle invasive bladder cancer (NMIBC). static urethra AND side effects. It is known to improve intravesical recurrence-free The reference lists of all systematic reviews in the survival and might even improve progression-free field were screened for additional references. After survival in non-muscle invasive bladder cancer [9]. a first selection, based on the title and abstract of Since PUC originates almost exclusively from the the papers, duplicates were removed. Once selected, urothelium, BCG is a relevant drug even for the treat- the full text of the articles was studied to gather ment of urethral carcinoma of the prostatic urethra. information about study design, inclusion criteria, In patients without stromal invasion (Tis pu, Tis pd) baseline patient characteristics, TNM-stage, treat- and even with stromal invasion (T1) of urothelial ment regimen, follow up, disease free survival (DFS), carcinoma of the prostatic urethra, treatment with progression free survival (PFS), and disease specific BCG might be beneficial [6]. However, the evidence survival (DSS). for BCG treatment, with or without transurethral resection of the prostate (TURP) before treatment EVIDENCE SYNTHESIS induction, has been sparse. This systematic review aims to elucidate the clinical impact of BCG treat- BCG-response in the different tumor stages of ment in the different stages of urothelial carcinoma prostatic urethral carcinoma of the prostate. It also aims to assess the effect of TURP before BCG treatment on the risk for recur- BCG treatment was reported in two clinical sce- rence and progression, and to review the side effects narios of PUC: Primary and secondary urothelial of BCG treatment for PUC. carcinomas of the prostatic urethra [10–19]. No O. Patschan et al. / Review: Role of BCG in Prostatic Urethral Carcinoma 215 Fig. 1. Consolidated Standards of Reporting Trials diagram outlining the selection process of the included studies. Date of search: 30th september 2019. articles were found describing BCG treatment in Table 1 patients with primary urethral carcinoma of the ante- TNM classification (eighth edition) for urethral carcinoma. Non- muscle invasive stages of urothelial carcinoma of the prostatic rior urethra. There were also no articles specifically urethra only [20] addressing primary cases of PUC without concomi- Tis pu Carcinoma in situ, involvement of prostatic urethra tant carcinoma of the urinary bladder or the upper Tis pd Carcinoma in situ, involvement of prostatic ducts urinary tract. Figure 1 shows the selection process T1 Tumor invades subepithelial connective tissue for the included articles. A total of ten retrospective (fortumors involving prostatic urethra only) studies focused on patient outcomes in patients with Urothelial (transitional cell) carcinoma of the prostate. PUC treated with BCG. A total of 162 patients were included in the studies on this topic, of which only experience tumor progression to the prostate during 5 patients were shown to have tumor stage T1. The follow up (PFS 75–91%). In four out of ten studies, study by Taylor et al. [15] is an update of the study by only patients with primary urethral carcinoma were Schellhammer et al. [18], which in turn is an update included. Only three out of ten studies differentiated of the study by Hillyard et al. [19], and it cannot be between tumor stages, i.e. Tis pu versus Tis pd versus ruled out that some of the patients included in these T1. The results of these studies were recorded and studies were examined twice. BCG was used only in presented in different ways, which made it impossible superficial stages of PUC (Tis pu, Tis pd, T1). The to assess the different response rates of BCG therapy TNM classification of these tumor stages is shown in in the different tumor stages of PUC. In addition, Table 1 [20]. Data from all selected studies are shown the number of cases in the studies would have been in Table 2. too small to obtain reliable prognostic information. Almost two-thirds of patients who did not have A study by Ovesen et al. [11] examined the Danish TURP prior to BCG therapy had no recurrence (DFS BCG strain and not the commonly used Pasteur or 63–89%) in the prostatic urethra during follow up, Connaught BCG strains. In the study by Taylor et al. and at least three out of four of these patients did not [15] the strain used was not outlined. 216 Table 2 Follow-up studies on patients with different stages of non-invasive urothelial carcinoma of the prostatic urethra treated with or without TURP before BCG treatment. Tumor progression was defined by the development of muscle infiltration, metastatic disease or the occurrence of superficial disease refractory to transurethral resection and intravesical BCG necessitating a change in therapy. Survival data in relation to the median follow-up time of the cited study. Abbreviations: TURP = transurethral resection of the prostate; TURP = transurethral resection of the prostate; BCG = Bacillus Calmette-Guérin; DFS = disease free survival; DSS = disease specific survival (i.e. disease specific cause was including urothelial cancer in the bladder or the upper urinary tract); PFS = progression free survival; N.A. = not available/not applicable O. Patschan et al. / Review: Role of BCG in Prostatic Urethral Carcinoma Reference +/- Total Primary Mucosal Ductal Stromal BCG BCG strain Median Bladder Bladder Prostatic Prostatic Prostatic Prostatic DSS n/N (%) TURP number of prostatic prostatic prostatic prostatic regimen follow up in cancer DFS cancer PFS urethral urethral ure- ure- before prostatic urethral urethral urethral urethral months n/N (%) n/N (%) cancer DFS cancer PFS thral+bladder thral+bladder BCG urethral cancer cases cancer (Tis cancer (Tis cancer (T1) (range) n/N (%) n/N (%) cancer DFS cancer PFS cancer n/N (%) pu) n/N (%) pd) n/N (%) n/N (%) n/N (%) n/N (%) Patients treated with BCG Gofrit et al. + 20 16/20 (80%) N.A. N.A. N.A. 1/week for Connaught 52.5 (N.A.) 7/20 (35%) 17/20 (85%) 18/20 (90%) 20/20 (100%) 6/20 (30%) 15/20 (75%) 14/20 (70%) (2008) [10] 6 weeks Ovesen et al. + 10 10/10 (100%) N.A. N.A. N.A. 1/week for Danish 26 (3–68) N.A. N.A. 8/10 (80%) 9/10 (90%) N.A. N.A. 10/10 (100%) (1993) [11] 6 weeks in 8/10, for 12 weeks in 2/10 Bretton et al. + 23 23/23 (100%) 19/23 (83%) 4/23 (17%) 0/23 (0%) 1/week for Pasteur 51.6 (6–105) N.A. 13/23 (57%) 23/23 (100%) 23/23 (100%) 13/23 (57%) 13/23 (57%) 19/22 (91%) (1989) [12] 6 weeks Orihuela et al. –8/15 15 N.A. N.A. N.A. N.A. 1/week for Pasteur N.A. (18–51) 14/15 (93%) 15/15 (100%) 13/15 (86%) 14/15 (93%) 13/15 (86%) 14/15 (93%) 15/15 (100%) (1989) [13] + 7/15 6 weeks Palou et al. –17/18 18 15/18 (79%) N.A. N.A. N.A. 1/week for Connaught 31.1 (7–57) 17/18 (94%) 17/18 (94%) 13/18 (68%) 17/18 (94%) 15/18 (79%) 15/18 (79%) 17/18 (94%) (1996) [14] + 1/18 6 weeks Taylor et al. – 28 28/28 (100%) N.A. N.A. N.A. 1/week for N.A. 90 (N.A.) N.A. 20/28 (71%) 25/28 (89%) 25/28 (89%) N.A. 19/28 (68%) 25/28 (89%) (2007) [15] 6 weeks in most cases Palou et al. – 11 6/11 (54%) 11/11 (100%) 0/11 (0%) 0/11 (0%) 1/week for Connaught 40 (8–157) 7/11 (63%) 10/11 (90%) 9/11 (81%) 9/11 (81%) 6/11 (54%) 8/11 (72%) 11/11 (100%) (2006) [16] 6 weeks in 10/11, for 12 weeks in 1/11 Canda et al. – 12 12/12 (100%) 7/12 (58%) N.A. 5/12 (42%) 1/week for Connaught 62.5 (24–110) 6/12 (50%) 8/12 (66%) 10/12 (83%) 11/12 (91%) 5/12 (42%) 7/12 (58%) 8/12 (66%) (2004) [17] 6 weeks in 10/12, for 12 weeks in 2/12 Schellhammer et – 17 8/17 (47%) N.A. N.A. N.A. 1/week for Pasteur 64.0 (29–90) 9/17 (52%) 14/17 (82%) 11/17 (65%) 14/17 (82%) 8/17 (47%) 10/17 (59%) 16/17 (94%) al. (1995) [18] 6 weeks Hillyard et al. – 8 8/8 (100%) N.A. N.A. N.A. 1/week for Pasteur 22.3 (15–52) 6/8 (75%) 7/8 (86%) 5/8 (63%) 6/8 (75%) N.A. 5/8 (63%) 8/8 (100%) (1988) [19] 6 weeks O. Patschan et al. / Review: Role of BCG in Prostatic Urethral Carcinoma 217 Only in one study did 5 of 12 patients have stage T1 reviewing the published literature, it becomes clear urethral carcinoma of the prostate [17]. In this study, that the incidence of primary PUC is likely to be the DFS (83%) and the PFS (91%) in the prostate underestimated: Almost all cases of primary PUC were within the range of the remaining nine studies. were detected during the workup of primary blad- However, the overall DSS was only 66% compared der cancer or UC of the UUT. This impression is to an overall DSS of 70–100% in the other studies. It supported by the study by Giannarini et al, which could not be completely excluded that these stromal indicated that an undiagnosed PUC could often be the invasive cases reduced the survival of the patients cause of BCG failure. [21]. In this study, bladder CIS in this study compared to the other studies. Without was an independent risk factor for BCG failure due to access to the full data, we could not perform statistical recurrence in the prostatic urethra or UUT. Since not analyzes. every patient in this study had a TUR biopsy before starting BCG therapy, it was discussed that the actual The role of TURP before BCG in prostatic incidence of PUC is difficult to estimate and is likely urethral carcinoma to be underestimated. The most accurate method of detecting PUC during Prospective randomized clinical trials or even the primary workup of suspected urothelial cancer in directly applicable clinical studies of good quality the prostate is to perform a TUR biopsy, which has addressing the question if performing TURP prior been shown to be superior to prostate needle biopsy to BCG improves DSS or lowers morbidity with- and fine needle aspiration of the prostate [22]. Donat out compromising DSS in PUC were not available. and Herr suggested a resectoscope loop biopsy of This issue was exclusively addressed by retrospec- the prostatic urethra between the 5 and 7 o’clock tive cohort studies. Unfortunately, the authors of the positions from the bladder neck and distally around selected studies did not use the same format in pre- the verumontanum in patients with suspected PUC senting their data. Some authors only described the [23]. However, not only should suspicious lesions in results in the text, others used tables with limited the prostatic urethra be biopsied: Palou showed that information on e.g. follow-up, DFS, PFS or DSS. almost 12% of patients with T1G3 bladder cancer A total of ten articles found that examined the had carcinoma in situ of the prostatic urethra on a effectiveness of BCG in urethral carcinoma in the resection biopsy [24]. In several series for the eval- prostatic urethra with or without TURP prior to uation of cystectomy specimens, involvement of the BCG treatment (Table 2). The studies by Gofrit [10], prostatic urethra was found in 15–48% [25–27]. Both Ovesen [11] and Bretton [12] only included patients CIS in the bladder and multifocal tumor growth were who had been treated with TURP before BCG. Ori- associated with a higher risk of involvement of carci- huela [13] and Palou [14] included both patients with noma of the prostatic urethra. With the data available, and without TURP prior to BCG treatment. it seems reasonable to recommend resection biop- Although an appropriate comparative statistical sies in patients with positive urinary cytology of analysis is not suitable for these heterogeneously unknown origin, if CIS in the bladder or upper uri- designed studies, there appears to be a pattern that nary tract is suspected, if bladder cancer is multifocal suggests slightly better local response with higher or occurs around the bladder neck, and when radical DFS (80–100% vs. 63–89%) and PFS (90–100% cystectomy is pending especially if chemotherapy is vs. 75–94%) in the prostatic urethra in the studies planned before surgery [6]. The AUA/SUO guide- in which patients were treated with TURP prior to lines so far only recommend prostate loop biopsies BCG treatment compared to the studies in which no in cases with a suspicious lesion in the prostate and TURP was performed. However, this difference in in patients with a history of NMIBC with normal recurrence and progression in the prostate affected cystoscopy and positive cytology [5]. neither the total PFS (57–75% vs. 58–93%) nor the It was discussed that cases of PUC with stage T1 DSS (70–100% vs. 66–100%). and Tis pd might have a worse prognosis than tumors with stage Tis pu [28]. There are no prospective DISCUSSION studies on the conservative treatment of non-invasive PUC in its various tumor stages, which is why this Intravesical BCG treatment with or without TURP hypothesis has not yet been confirmed. In seven of prior BCG induction therapy was retrospectively the ten available studies in this review, no TNM stag- evaluated in non-invasive stages of PUC. Upon ing of PUC was carried out; and only one of the 218 O. Patschan et al. / Review: Role of BCG in Prostatic Urethral Carcinoma ten studies [17] included patients with stage T1 ure- data on the natural history of the various non-invasive thral carcinoma (n = 5). Accurate staging of tumors stages of PUC were available for comparison. Most is the basic requirement for evaluating the prog- studies only offered a BCG induction course. It nostic effects of the extent of TURP prior to BCG cannot be ruled out that maintenance therapy for non- treatment in malignant diseases of the urothelium of invasive PUC could have an improved prognosis. the prostatic urethra and ducts. This underscores the In addition, different BCG strains were used (Con- importance of improving the use of the current TNM naught and Pasteur). In one study [11] the rare Danish staging system for PUC in the future. BCG strain was used. It is uncertain how this affected According to the EAU-guidelines, a urethra- the results. Another problem is inconsistent follow- sparing approach with TURP and intravesical-BCG up of tumor status in the prostatic urethra: In some is indicated in patients with non-invasive UC or carci- studies, cold cup biopsies were used more or less noma in situ of the prostatic urethra and ducts (level routinely, and in other studies, TUR biopsies of the of evidence 3, grade of recommendation C) [6]. In prostate were taken only when there were visible or the available studies, of all BCG-treated patients who suspicious lesions. These differences in follow up were not treated with TURP, almost 2/3 of the patients schemes and methods might have affected differences had no tumor recurrence in the prostate and at least of the outcomes after BCG therapy significantly. 3/4 had no tumor progression in the prostate. In the available studies examining the use of TURP before CONCLUSIONS BCG therapy, about 4/5 of the patients had no recur- rence and 9/10 no tumor progression in the prostate. Taken together, the use of TUR biopsies of the pro- However, these improved local response rates after static urethra in appropriate cases during the primary TURP had no influence on the overall response (PFS, work-up for suspected urothelial cancer, as well as DSS) in these cohorts. This finding supports the ratio- the use of the current TNM classification for PUC, nale for performing TURP prior to BCG treatment for need to be improved. BCG therapy for non-stromal non-invasive PUC, namely improving effectiveness invasive stages of PUC show a good local response. of BCG treatment, at least with regard to the local Local response rates are further improved by a TURP, reaction in the prostate, without necessarily improv- although the overall prognosis does not seem to be ing the overall prognosis. Prospective studies need to affected. Further evidence for BCG treatment in the confirm these results. In particular, the treatment of rare cases of stromal invasive PUC is needed. Specific the rare cases of stage T1 PUC should be carefully side effects of BCG treatment for PUC, either with studied. or without TURP before treatment, are not reported. Systemic side effects are seen in approximately 30% of patients treated with BCG for bladder cancer. ACKNOWLEDGMENTS Local symptoms of BCG instillations are cystitis, epi- didymitis or granulomatous prostatitis with dysuria, The authors have no acknowledgments. urination problems and hematuria. These symptoms occur in about 60% of BCG treated bladder cancer patients [29]. Approximately 70% of bladder can- FUNDING cer patients treated with BCG have both systemic and local side effects. In 16–22% of treated patients The authors report no funding. BCG treatment is discontinued because of toxicity [30]. Since almost all patients with PUC also have AUTHORS CONTRIBUTIONS concomitant bladder cancer, specific side effects of BCG in the treatment of PUC could not be deter- All authors contributed to the conception, sampling mined and cannot be found in the literature. It was and interpretation of data, and writing of the article. therefore impossible to derive specific side effects of BCG therapy for PUC, which is a limitation of the ETHICAL CONSIDERATIONS study. Apart from that, several other limitations of the This study, as a literature review, is exempt from current study have to be mentioned: Different defini- any requirements for Institutional Review Board tions of progression were used in the cited studies. A approval. No human or animal research was involved comparative statistical analysis was not possible. No in the elaboration of this manuscript. O. Patschan et al. / Review: Role of BCG in Prostatic Urethral Carcinoma 219 CONFLICT OF INTEREST [11] Ovesen H, Poulsen AL, Steven K. Intravesical Bacillus Calmette-Guérin with the Danish strain for treatment of carcinoma in situ of the bladder. Br J Urol. 1993;72(5 Pt Georgios Gakis receives honoraria for advisory 2):744-8. doi:10.1111/j.1464-410x.1993.tb16260.x board activities: MSD, Astellas, Ferring, BMS, [12] Bretton PR, Herr HW, Whitmore WF Jr, et al. Intravesi- Bayer, Leo Pharma, medac, Merck, and he receives cal bacillus Calmette-Guérin therapy for in situ transitional speaker honoraria/travel grants: Roche, MSD, cell carcinoma involving the prostatic urethra. J Urol. 1989;141(4):853-6. doi:10.1016/s0022-5347(17)41031-7 IPSEN, Erbe, medac. Philippe E Spiess is the vice [13] Orihuela E, Herr HW, Whitmore WF Jr. Conservative treat- chair of the NCCN bladder and penile cancer panel; ment of superficial transitional cell carcinoma of prostatic he is as well the president of the Global Society urethra with intravesical BCG. Urology. 1989;34(5):231-7. of Rare GU Tumors. Joan Palou Redorta reports doi:10.1016/0090-4295(89)90314-2 [14] Palou J, Xavier B, Laguna P, Montlleó M, Vicente J. trial participation: Cepheid, Presurgery, Ipsen, Com- In situ transitional cell carcinoma involvement of pro- bat, Storz, Archer, IDL Biotech, Palex and receives static urethra: bacillus Calmette-Guérin therapy without honoraria or consultation fees from Combat BRS, previous transurethral resection of the prostate. Urology. 1996;47(4):482-4. doi:10.1016/S0090-4295(99)80481-6 Olympus, Sanofi, Cepheid, Ipsen, Fidia Farmaceu- [15] Taylor JH, Davis J, Schellhammer P. Long-term follow-up tici, and fees for Advisory/Scientific Board activities of intravesical bacillus Calmette-Guérin treatment for super- from: Pfizer, Astra Zeneca, Merck, Janssen, Ferring. ficial transitional-cell carcinoma of the bladder involving the Oliver Patschan and George N Thalmann have no prostatic urethra. Clin Genitourin Cancer. 2007;5(6):386-9. doi:10.3816/CGC.2007.n.021 conflict of interest to declare. [16] Palou Redorta J, Schatteman P, Huguet Párez J, et al. Intrav- esical instillations with bacillus calmette-guérin for the treatment of carcinoma in situ involving prostatic ducts. Eur REFERENCES Urol. 2006;49(5):834-8. doi:10.1016/j.eururo.2005.12.019 [17] Canda AE, Tuzel E, Mungan MU, Yorukoglu K, Kirkali [1] Gatta G, van der Zwan JM, Casali PG, et al. Rare cancers are Z. Conservative management of mucosal prostatic urethral not so rare: the rare cancer burden in Europe. Eur J Cancer. involvement in patients with superficial transitional cell 2011;47(17):2493-511. doi:10.1016/j.ejca.2011.08.008 carcinoma of the bladder. Eur Urol. 2004;45(4):465-70. [2] Visser O, Adolfsson J, Rossi S, et al. Incidence and sur- doi:10.1016/j.eururo.2003.12.014 vival of rare urogenital cancers in Europe. Eur J Cancer. [18] Schellhammer PF, Ladaga LE, Moriarty RP. Intravesical 2012;48(4):456-64. doi:10.1016/j.ejca.2011.10.031 bacillus Calmette-Guérin for the treatment of superficial [3] Swartz MA, Porter MP, Lin DW, Weiss NS. Incidence of transitional cell carcinoma of the prostatic urethra in associ- primary urethral carcinoma in the United States. Urology. ation with carcinoma of the bladder. J Urol. 1995;153(1):53- 2006;68(6):1164-8. doi:10.1016/j.urology.2006.08.1057 6. doi:10.1097/00005392-199501000-00020 [4] Aleksic I, Rais-Bahrami S, Daugherty M, Agarwal PK, [19] Hillyard RW Jr, Ladaga L, Schellhammer PF. Superfi- Vourganti S, Bratslavsky G. Primary urethral carcinoma: cial transitional cell carcinoma of the bladder associated A Surveillance, Epidemiology, and End Results data anal- with mucosal involvement of the prostatic urethra: results ysis identifying predictors of cancer-specific survival. Urol of treatment with intravesical bacillus Calmette-Guérin. Ann. 2018;10(2):170-4. doi:10.4103/UA.UA 136 17 J Urol. 1988;139(2):290-3. doi:10.1016/s0022-5347(17) [5] Sui W, RoyChoudhury A, Wenske S, Decastro GJ, McKier- 42389-5 nan JM, Anderson CB. Outcomes and Prognostic Factors [20] Brierley JD, et al. TNM classification of malignant of Primary Urethral Cancer. Urology. 2017;100:180-6. tumors. UICC International Union Against Cancer. Wiley/ doi:10.1016/j.urology.2016.09.042 Blackwell; 2017. pp. 208-9. [6] Gakis G, Bruins HM, Cathomas R, et al. European [21] Giannarini G, Birkhäuser FD, Recker F, Thalmann GN, Association of Urology Guidelines on Primary Urethral Studer UE. Bacillus Calmette-Guérin failure in patients with Carcinoma-2020 Update. Eur Urol Oncol. 2020;3(4):424- non-muscle-invasive urothelial carcinoma of the bladder 32. doi:10.1016/j.euo.2020.06.003 may be due to the urologist’s failure to detect urothelial [7] Rabbani F. Prognostic factors in male urethral cancer. Can- carcinoma of the upper urinary tract and urethra. Eur Urol. cer. 2011;117(11):2426-34. doi:10.1002/cncr.25787 2014;65(4):825-31. doi:10.1016/j.eururo.2013.09.049 [8] Dalbagni G, Zhang ZF, Lacombe L, Herr HW. Male ure- [22] Wood DP Jr, Montie JE, Pontes JE, Levin HS. Identification thral carcinoma: analysis of treatment outcome. Urology. of transitional cell carcinoma of the prostate in bladder can- 1999;53(6):1126-32. doi:10.1016/s0090-4295(98)00659-1 cer patients: a prospective study. J Urol. 1989;142(1):83-5. [9] Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical doi:10.1016/s0022-5347(17)38667-6 bacillus Calmette-Guérin reduces the risk of progression in [23] Donat SM, Wei DC, McGuire MS, Herr HW. The effi- patients with superficial bladder cancer: a meta-analysis of cacy of transurethral biopsy for predicting the long-term the published results of randomized clinical trials. J Urol. clinical impact of prostatic invasive bladder cancer. J Urol. 2002;168(5):1964-70. doi:10.1097/01.ju.0000034450. 2001;165(5):1580-4. 80198.1c [24] Palou J, Sylvester RJ, Faba OR, et al. Female gender and [10] Gofrit ON, Pode D, Pizov G, Zorn KC, Katz R, carcinoma in situ in the prostatic urethra are prognos- Shapiro A. Prostatic urothelial carcinoma: is transurethral tic factors for recurrence, progression, and disease-specific prostatectomy necessary before bacillus Calmette-Guérin mortality in T1G3 bladder cancer patients treated with bacil- immunotherapy? BJU Int. 2009;103(7):905-8. doi:10.1111/ lus Calmette-Guérin. Eur Urol. 2012;62(1):118-25. doi: j.1464-410X.2008.08210.x 10.1016/j.eururo.2011.10.029 220 O. Patschan et al. / Review: Role of BCG in Prostatic Urethral Carcinoma [25] Revelo MP, Cookson MS, Chang SS, Shook MF, Smith [29] Brausi M, Oddens J, Sylvester R, et al. Side effects JA Jr, Shappell SB. Incidence and location of prostate of Bacillus Calmette-Guérin (BCG) in the treatment of and urothelial carcinoma in prostates from cystoprostate- intermediate- and high-risk Ta, T1 papillary carcinoma of ctomies: implications for possible apical sparing surgery. the bladder: results of the EORTC genito-urinary cancers J Urol. 2004;171(2 Pt 1):646-51. doi:10.1097/01.ju.0000 group randomised phase 3 study comparing one-third dose 107380.40481.bc with full dose and 1 year with 3 years of maintenance BCG. [26] Esrig D, Freeman JA, Elmajian DA, et al. Transitional Eur Urol. 2014;65(1):69-76. doi:10.1016/j.eururo.2013. cell carcinoma involving the prostate with a proposed 07.021 staging classification for stromal invasion. J Urol. 1996; [30] Oddens JR, Sylvester RJ, Brausi MA, et al. Increasing age 156(3):1071-6. is not associated with toxicity leading to discontinuation of [27] Nixon RG, Chang SS, Lafleur BJ, Smith JA JA, Cook- treatment in patients with urothelial non-muscle-invasive son MS. Carcinoma in situ and tumor multifocality predict bladder cancer randomised to receive 3 years of main- the risk of prostatic urethral involvement at radical cystec- tenance bacille Calmette-Guérin results from European tomy in men with transitional cell carcinoma of the bladder. Organisation for Research and Treatment of Cancer Genito- J Urol. 2002;167(2 Pt 1):502-5. doi:10.1097/00005392- Urinary Group study 30911. BJU Int. 2016;118(3):423-8. 200202000-00012 doi:10.1111/bju.13474 [28] Njinou Ngninkeu B, Lorge F, Moulin P, Jamart J, Van Cangh PJ. Transitional cell carcinoma involving the prostate: a clinicopathological retrospective study of 76 cases. J Urol. 2003;169(1):149-52. doi:10.1097/01.ju.0000042810. 43380.36