THE USE OF HALF DOSE BCG FOR INTRAVESICAL IMMUNOTHERAPY IN NON MUSCLE INVASIVE BLADDER CANCER

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1 THE USE OF HALF DOSE BCG FOR INTRAVESICAL IMMUNOTHERAPY IN NON MUSCLE INVASIVE BLADDER CANCER Mihály Zoltán Attila 1, Rusu Cristian Bogdan 2, Mihály Orsolya Maria 3, Bolboacă Sorana Daniela 4, Bungărdean Cătălina 5, Giurgiu Radu Călin 1, Logigan Horia 1, Coman Ioan 1 1 Department of Urology, Cluj-Napoca Municipal Clinic Hospital, 2 Department of Urology, Satu Mare County Hospital, 3 Department of Anaesthesia and Intesive Care, Cluj County Clinic Hospital, 4 Department of Imunology, Cluj County Emergency Hospital, 5 Department of Pathology, Cluj Municipal Clinic Hospital Address for correspondence: Dr. Mihály Zoltán Attila 171 Maramuresului St. Cluj-Napoca mzattika@yahoo.com Received: Accepted: Med Con December 2012, Vol 7, No 4, Abstract Introduction: Intravesical Bacillus Calmette- Guérin (BCG) immunotherapy is now considered as the treatment of choice for intermediate and high-risk non muscle-invasive bladder cancer (NMIBC), but there are variations with regard to the optimal use of BCG in NMIBC adjuvant treatment. Material and methods: In a prospective observational study 23 patients with intermediate and high-risk NMIBC underwent adjuvant intravesical Bacillus Calmette-Guerin instillation therapy after a complete TUR-BT. Patients received six weekly instillations of half dose BCG, 3 mo rest, and three further weekly instillations of half dose BCG. Maintenance therapy with three weekly instillations at 6, 12, 18, 24, 30 and 36 months. Results and limitations: Twenty-three patients were included, complete response rate at the first control (recurrence free cystoscopy at 3 months after start of treatment) was 100%. Based on a median follow up of 29 month, no BCG-refractory (progression in stage or grade by 3 mo after first cycle of BCG) and no BCGresistant (recurrence or persistence after 3 mo after the induction cycle) patients were observed. At one year no tumor recurrence or progression was observed. None of the patients receiving intravesical therapy stopped treatment do to toxicity. Conclusions: Bacillus Calmette-Guerin maintenance with half dose BCG proved effective. Complete response rate with half dose intravesical BCG immunotherapy were similar to those with complete dose from literature. The half dose had acceptable toxicity, mainly local side effects: cystitis 76% respectively and grade 1 gross haematuria 10%. Keywords: Bacillus Calmette-Guerin, Intravesical immunotherapy, Non-muscle-invasive bladder cancer Introduction The primary approach to the management of intermediate and high risk non muscle invasive bladder cancer (NMIBC) is transurethral resection of the bladder tumor (TURBT) followed by intravesical immunotherapy with Bacillus Calmette-Guerin [1,2]. The intravesical administration of BCG produce an immune response cascade, which is responsible for the tumoral apoptosis [3,4]. Intravesical BCG immunotherapy is now considered as the treatment of choice for intermediate and high- The Use Of Half Dose Bcg For Intravesical Immunotherapy In Non Muscle Invasive Bladder Cancer 31

2 risk NMIBC [5], but there are variations with regard to the optimal use of BCG in NMIBC immunotherapy [6]. The optimal dose is unknown, most studies used the standard dose which is a global standard of care based on the Southwest Oncology Group (SWOG) maintenance schedule [7]. To decrease the toxicity of BCG and improve patients long time adherence, some authors have proposed reducing the dose of instilled BCG [8,], showing no overall difference in efficacy [9]. Objectives Evaluate the efficacy of half dose intravesical BCG in our patients and to provide more information regarding the half dose in the prevention or delay of disease progression and tumor recurrence. Material and methods 23 male patients with intermediate and high-risk NMIBC (Table I) underwent adjuvant intravesical Bacillus Calmette-Guerin instillation therapy after a complete TUR-BT and single, immediate instillation of 50mg Epirubicin [2]. The tumoral stage and grade, significant prognostic factors for recurrence, progression and survival were established at our hospital s Pathological Department, according to tumor-nodemetastases (TMN) system for tumoral stage (depth of invasion), and according to the World Health Organization (WHO) 1973 classification and WHO 2004 classification for tumoral grade. Based on number of tumors, tumor diameter, stage and grade patients were categorizes into intermediateand high-risk groups according to EORTC scoring system [1]. Six patients were with high risk (TaT1 high grade (G2/G3) papillary urothelial neoplasms with or without CIS) and the other eighteen were considered as intermediate risk group (TaT1 low grade G1/G2 large or/and multiple and recurrent tumor) patients. BCG was administered at minimum 4wk after TUR-BT, but in the most cases the 6 wk interval was preferred. Patients included were without urinary tract Table I. Prior recurrence rate and patient s tumoral stage and grade next to transurethral resection of the bladder tumors, before BCG induction. 1 ID First TUR-BT Second TUR-BT Third TUR-BT Fourth TUR-BT 2 MB ptag1 3 mo; pt1g1>3cm 3 JV ptag1 7mo; ptag2m+ 4 PV ptag1m+ 5 PN pt1g1 36mo; pt1ag1 6 RI pt1g2m+ 2mo; pt0 6mo; pt1g2/g3 <5% 3mo; pt0 7 KI ptag2m+ 6mo; ptag2m+ 6mo; ptag2m+ 3mo; ptag2 8 MA ptag2m+ 6wk; pt0 9 BA pt1ag2 6wk; pt0 10 HL pt1g2 3mo; pt0 11 LT pt1ag2 6wk; pt0 12 DV ptag2m+ 2mo; pt0 13 CM pt1g2m+ 6wk; pt0 14 II pt1g3 6wk; pt0 15 AG pt1g2 6wk; pt0 16 PI ptag1m+ 4wk; pt0 17 HC pt2 nested 6wk; pt0 18 BT pt1g2 3mo;pT1G2 7mo; pt1g1 19 SV pt1ag2 6wk; pt0 20 AP ptag2 2mo; ptag3 7mo; pt0 15mo; ptag2/3m+ 21 SI pt1g1 6wk; pt0 22 BK pt1g1 6wk; pt0 23 TO pt1g1 6wk; pt0 24 CS pt2ag1 4wk; pt0 32 Mihály et al

3 infections (UTI) and without haematuria before instillations. Two different BCG stains were used (BCGmedac and ImmuCyst). The standard dose of 81 mg was reduced to half, regarding toxicity and financial considerations. The BCG maintenance schedule was based on the Southwest Oncology Group (SWOG) regimen of six weekly instillations followed by three weekly instillations at 3 and 6 months and every 6 months for three years [7]. Patients were informed about possible side effects for an early recognition, and educated for post instillations behavior: the solution containing BCG to be held in bladder for two hours, to change position in every 15 minutes for an optimal contact with the bladder wall and voiding in sitting position. The BCG containing serum was administered with a proper catheterization technique into an empty bladder passively by gravity. Ofloxacin 200 mg and Indometacin suppository were administered twice at each instillation after the first urination to reduce the local discomfort and side effects [10]. Results On the basis of a median follow-up of 29 months, with a mean of 29.17±18.88 months, no BCGrefractory (progression in stage or grade by 3 months after first cycle of BCG) and no BCG-resistant (recurrence or persistence after 3 months after the induction cycle) patients were observed. At one year no tumor recurrence or progression was observed. One BCG relapsing patient at 13 months with a nested subtype developed in submucosal layer. The complication rate associated with BCG instillations was 37% (95%CI [32%-42%]) from overall instillations and includes mainly local side effects. 76% of the complications were cystitis 76% (95%CI [67%- 93%]), grade 1 gross haematuria 10% (95%CI [5%- 16%]), orhiepididimitis 2% (95%CI [0%-6%]), and fever with or without general malaise 11% (95%CI [6%-19%]) resolved in 48 hours with or without antipyretics. 64% (95%CI [58%-69%]) from absolute number of instillations had no adverse events. BCG-associated systemic side effects were less frequent. One patient presented after the second cycle of maintenance systemic BCG reactions treated with ethambutol, pirazinamin, and sinerdol for 3 months. Instillations were suspended but restarted at patient s strong demand. Discussions Initially the instillations were started between 3-6 weeks after a complete TUR-BT according to the SWOG regimen [7,10], but at the 6 week starters the intensity of local side effects was less higher than in the others, so we decide to make the first instillation at 6 weeks after TUR-BT in all patients who undergo intravesical immunotherapy. Several studies suggest that a 6-wk induction course alone is not sufficient to an optimal response and the Figure 1. (A) Median follow up and (B) Complication rates of BCG Figure 2. (A) Instillation induced side effects and (B) their percentage The Use Of Half Dose Bcg For Intravesical Immunotherapy In Non Muscle Invasive Bladder Cancer 33

4 maintenance therapy is mandatory [11,12,13,14]. The Southwest Oncology Group (SWOG) reported the most significant impact of maintenance therapy with full dose BCG on disease free survival [7], the 3-wk maintenance schedule leads to the best outcomes in terms of reducing progression, recurrence and mortality in NMIBC, are further supported by the European Organization for Research and Treatment for Cancer (EORTC) trial [13], and the Japanese Cooperative Study [14]. For this reason we adopt for our patients the SWOG regimen. A consensus about the optimal dose and schedule for BCG has not been established. Morales replying to an editorial comment this regimen is arbitrary, and may be modified in the future as additional data become avaible [19]. Most studies and meta-analyses have utilized the full 81 mg dose, and this remains the global standard of care. Evidence suggests that one-half and one-third dose produce similar benefits in preventing recurrence and progression as the standard dose [15,16,17,18]. Because our median follow up is only 29 mo comparing to the 77 mo of the SWOG study, the recurrence free survival is not comparable, but in the SWOG study two thirds of the patients stopped BCG due to side effects in the first six months and many patients failed to complete the full course of treatment. In our small group none of the patients receiving intravesical therapy stopped treatment do to toxicity. Our initial tumor-free response rate was complete (100%) comparing to the literature 84% [20, 21]. Some authors consider the use of quinolones as a potential effectiveness lowering factor because may affect the viability of BCG [22], but the International Bladder Cancer Group recommendations contains the use of ofloxacin twice after each BCG for prevention of Bacillus Calmette-Guerin associated adverse events. In our patients the frequency and intensity of adverse events decreased markedly after the usual administration at each patient. 34 Conclusions Bacillus Calmette-Guerin maintenance with half dose BCG proved effective. There was no need to stop BCG administration for toxicity reasons. Dose reduction, use of ofloxacin and patient education are strategies that help prevent BCG-associated adverse events. The first step in improving compliance with maintenance BCG is to ensure that physicians are both believe and trust in value of BCG instillational therapy. References 1. Babjuk M, Oosterlinck W, Sylvester R, et al. EAU Guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2008;54(2): Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a metaanalysis of published results of randomized clinical trials. J Urol 2004;171(6 Pt 1): Taniguchi K, Koga S, Nishikido M, et al. Systemic immune response after intravesical instillation of bacille Calmette-Guérin (BCG) for superficial bladder cancer. Clin Exp Immunol 1999;115: Chen F, Zhang G, Iwamoto Y, See WA. BCG directly induces cell cycle arrest in human transitional carcinoma cell lines as a consequence of integrin cross-linking. BMC Urol 2005;5:8 5. Lamm D, Persad R, Colombel M, Brausi M. Maintenance Bacillus Calmette-Guérin: The Standard of Care for the Prophylaxis and Management of Intermediate-and High-Risk Non-Muscle-Invasive Bladder Cancer. Eur Urol Suppl 2010;9(9): Han RF, Pan JC. Can intravesical bacillus Calmette- Guérin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 2006;67: Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guérin 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: Martinez-Pineiro JA, Flores N, Isorna S, et al., for CUETO (Club Urologico Espanol de Tratamiento Oncologico). Long-term follow-up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacille Calmette-Guérin with a reduced dose of 27 mg in superficial bladder cancer. BJU Int 2002;89: Martinez-Pineiro JA, Martinez-Pineiro L, Solsona E, et al., for CUETO (Club Urologico Espanol de Tratamiento Oncologico). Has a 3-fold decreased dose of bacillus Calmette-Guérin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial. J Urol 2005;174: Witjes JA, Palou J, Soloway M, et al. Clinical practice recommendations for the prevention and management of intravesical therapy-associated adverse events. Eur Urol Suppl 2008;7: Catalona WJ, Hudson MA, Gillen DP, et al. Risks and benefits of repeated courses of intravesical BCG for superficial bladder cancer. J Urol1987;137:220-4 Mihály et al

5 12..Lamm DL. Long term results of intravesical therapy for superficial bladder cancer. Urol Clin North Am 1992;19: Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC Genito-Urinary Group randomized phase 3 study comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol 2010;57: Hinotsu S, Akaza H, Naito S, et al. Maintenance therapy with bacillus Calmette-Guérin (BCG) Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumor (TURBT) for non-muscle-invasive transitional cell carcinoma of the bladder. BJU Int. In press. 15. Martinez-Pineiro JA, Flores N, Isorna S, et al., for CUETO (Club Urologico Espanol de Tratamiento Oncologico). Long-term follow-up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacille Calmette-Guérin with a reduced dose of 27 mg in superficial bladder cancer. BJU Int 2002;89: Martinez-Pineiro JA, Martinez-Pineiro L, Solsona E, et al., for CUETO (Club Urologico Espanol de Tratamiento Oncologico). Has a 3-fold decreased dose of bacillus Calmette-Guérin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial. J Urol 2005;174: Sylvester RJ, van der Meijden APM, 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: Soloway MS, editor. International consultation on bladder tumours. Urology 2005;66(Suppl 1): Morales A, Eidinger D, Bruce AW. Intracavity BCG in the treatment of superficial bladder tumours. J Urol 1976;116: Brosman SA. Experience with bacillus Calmette-Guerin in patients with superficial bladder carcinoma. J Urol 1982;128(1): Hudson MA, Herr HW. Carcinoma in situ of the bladder. J Urol. 1995;153(3 Pt 1): Review 22. Durek C, Rüsch-Gerdes S, Jocham D, Böhle A. Interference of modern antibacterials with bacillus Calmette-Guerin viability. J Urol. 1999;162(6): The Use Of Half Dose Bcg For Intravesical Immunotherapy In Non Muscle Invasive Bladder Cancer 35

Maintenance Therapy with Intravesical Bacillus Calmette Guérin in Patients with Intermediate- or High-risk Non-muscle-invasive

Jpn J Clin Oncol 2013;43(3)305 313 doi:10.1093/jjco/hys225 Advance Access Publication 9 January 2013 Maintenance Therapy with Intravesical Bacillus Calmette Guérin in Patients with Intermediate- or High-risk