The Effects of Intravesical Chemoimmunotherapy with Gemcitabine and Bacillus Calmette Guérin in Superficial Bladder Cancer: a Preliminary Study

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1 The Journal of International Medical Research 2009; 37: The Effects of Intravesical Chemoimmunotherapy with Gemcitabine and Bacillus Calmette Guérin in Superficial Bladder Cancer: a Preliminary Study DY CHO, JH BAE, DG MOON, J CHEON, JG LEE, JJ KIM, DK YOON AND HS PARK Department of Urology, Korea University Medical College, Seoul, Republic of Korea This prospective study investigated the long-term effects of intravesical chemoimmunotherapy with gemcitabine (GEM) and bacillus Calmette Guérin (; n = 36) versus alone (n = 51) for the treatment of superficial bladder cancer. For the chemoimmunotherapy (GEM + ) group, GEM (1000 mg) was instilled immediately after transurethral resection of bladder tumour (TURBT) and again (2000 mg) 1 week later. From 2 to 7 weeks after TURBT, was instilled into the bladder of all patients once weekly. The recurrence-free period of the GEM + group (24.13 months) was significantly longer than that of the monotherapy group (19.81 months). The overall recurrence rate was similar between the groups, although at 6 and 9 months post-turbt, GEM + produced a significantly lower rate of recurrence compared with alone. This study suggests that intravesical chemoimmunotherapy with GEM + is effective in reducing early tumour recurrence and in prolonging the recurrence-free period of superficial bladder cancer. KEY WORDS: SUPERFICIAL BLADDER CANCER; INTRAVESICAL CHEMOIMMUNOTHERAPY; GEMCITABINE; ; RECURRENCE RATE This work was presented at a poster session of the 23rd Annual Congress of the European Association for Urology, Milan, Italy, March Introduction Superficial bladder cancer (SBC) represents nearly 70% of all bladder cancers at first presentation. 1 The 5-year recurrence rate after complete transurethral resection of bladder tumour (TURBT) is estimated to be as high as 80%, and progression to muscleinvasive disease occurs in 4 30% of patients. 1 Based on histology and other prognostic factors, the guidelines of the European Organization for Research and Treatment of Cancer (EORTC) and the 2002 European Association of Urology (EAU) rate patients risk of recurrence and progression of SBC into three categories: 2 low-risk patients are those with single Ta, G1 lesions < 3 cm in 1823

2 diameter, whereas high-risk patients are those with T1, G3 lesions or carcinoma in situ (CIS). All other tumours, i.e. Ta, T1, G1 G2, multifocal, recurrent lesions > 3 cm in diameter, are categorized into the intermediate-risk group. Several intravesical drugs have been proposed for intermediate- and high-risk disease in an attempt to reduce or delay both recurrence and progression. Intermediate-risk SBC is initially managed with prophylactic intravesical chemotherapy, whereas bacillus Calmette Guérin () immunotherapy has become the standard treatment for high-risk SBC, including T1, G3, CIS and some recurrent Ta diseases. 1 It is believed that tumour cell implantation immediately after TURBT is responsible for many early recurrences of disease, and this has been used to explain the observation that initial tumours are most commonly found on the floor and lower side walls of the bladder, whereas recurrences are often located near the dome. 3 Intravesical chemotherapy is used to try and kill such cells before they can implant. 4 The live vaccine,, cannot be safely administered immediately after resection as this produces a high risk of bacterial sepsis and death. 5 Thus, immunotherapy is generally started 2 4 weeks after tumour resection, allowing time for re-epithelialization to minimize the potential for intravasation of live bacteria. This prospective study was designed to investigate whether chemoimmunotherapy with gemcitabine (GEM) between TURBT and instillation was superior in reducing the rate of recurrence of SBC compared with TURBT and instillations alone, and to compare the side effect profiles of using GEM + versus alone. Patients and methods PATIENTS Patients with SBC, scheduled to undergo curative resection by TURBT, who attended the Department of Urology, Korea University Hospitals, Seoul, Republic of Korea, were enrolled into this prospective study between May 2005 and April 2006, and were followed up until February The EORTC and EAU guidelines were used to categorize patients according to their risk for SBC. Patients with intermediate-risk (i.e. Ta, T1, G1 G2 multifocal, recurrent lesions > 3 cm in diameter), or high-risk (i.e. T1, G3 lesions or CIS) SBC were included in the study. Patients were excluded from the study if they were considered to have low-risk SBC (i.e. single Ta, G1 lesions < 3 cm in diameter), or had any other severe illness. Patients were enrolled consecutively to the study and randomized to either group I or group II. The study protocol was designed to meet the criteria of the Declaration of Helsinki and was approved by the Korea University Ethics Committee. Written informed consent was obtained from each patient prior to participation. TREATMENT SCHEDULES Group I patients received six weekly intravesical instillations of (OncoTICE, Organon Laboratories, Cambridge, UK) 12.5 mg in 50 ml saline on weeks 2 7 after TURBT. Group II received intravesical instillations of GEM (Eli Lilly, Indianapolis, IN, USA) 1000 mg in 50 ml saline directly after TURBT, then 2000 mg in 50 ml saline 1 week later, followed by weekly intravesical instillations of on weeks 2 7 after TURBT (Fig. 1). was given no earlier than 2 weeks after the diagnostic transurethral procedure. Patients were evaluated every 3 months during the first 2 years and according to local practice 1824

3 Group I (n = 51) TURBT Post-operation week Group II (n = 36) GEM GEM FIGURE 1: Intravesical therapy schedule for superficial bladder cancer patients following transurethral resection of bladder tumour (TURBT): group I received intravesical infusions of bacillus Calmette Guérin () only (12.5 mg in 50 ml saline) on weeks 2 7; group II received similar intravesical infusions of on weeks 2 7 plus intravesical instillations of gemcitabine (GEM) 1000 mg in 50 ml saline directly after TURBT and 2000 mg in 50 ml saline 1 week later thereafter. The evaluation involved cytology, cystoscopy and biopsies of suspected lesions. STUDY ENDPOINTS The aim of this study was to investigate whether instillations of GEM + were superior to instillations of alone without causing severe side effects. The primary study endpoints were recurrence rate of SBC, recurrence-free interval, progression rate and progression-free interval. Secondary endpoints were survival and side effects. Recurrence (or persistent disease) was defined as biopsy-confirmed CIS, noninvasive papillary carcinoma, or malignant cytology. The severity of local and systemic side effects was recorded at 3 months. STATISTICAL ANALYSIS Data are reported as mean values ± SD. Results were analysed with the SPSS statistical package, version 12.0 (SPSS Inc., Chicago, IL, USA) for Windows. The χ 2 test was applied to cross-tabulations. Student s t- test was used to compare the means of normally distributed variables between the two treatment groups. All time-related endpoints with respect to treatment were analysed by the Kaplan Meier technique and the log rank test. 6,7 A P-value < 0.05 was considered to be statistically significant. Results In total, 87 patients were enrolled into the study, including 47 intermediate- and 40 high-risk patients; low-risk patients were excluded. Patients were randomized to receive treatment with alone (n = 51) or with GEM + (n = 36) after undergoing TURBT. Their baseline characteristics are reported in Table 1. The mean ± SD follow-up periods were ± and ± 6.57 months in groups I and II, respectively. The progression rate was similar in groups I and II (Table 2). The overall recurrence rate was slightly lower in group I (33.3%) compared with group II (38.9%; Table 2 and 3) but this difference was not statistically significant. Dual therapy (group II) was associated with a significantly lower recurrence rate than monotherapy at 6 and 9 months post-turbt (P = and P = 0.034, respectively; Table 3). Overall, 31 of the 87 patients (35.6%) in the study had recurrences of SBC after treatment. Both treatments produced similar progression-free periods (Table 2). The recurrence-free period was, however, significantly longer with monotherapy 1825

4 TABLE 1: Baseline characteristics of the patients with superficial bladder cancer who were randomized to receive six weekly intravesical instillations of bacillus Calmette Guérin () after transurethral resection of bladder tumour (TURBT) (group I), compared with patients who received similar treatment plus intravesical instillations of gemcitabine (GEM) (group II) Group I Group II only GEM + Baseline characteristic (n = 51) (n = 36) No. of patients, n Male/female, n 48/3 32/4 Age (years), mean ± SD ± ± Mean follow-up period (months), mean ± SD ± ± 6.57 Tumour stage, n Ta T CIS 7 5 Tumour grade, n G1 2 2 G G Risk n Intermediate High CIS, carcinoma in situ. compared with GEM + dual therapy (P = 0.013; Table 2). Kaplan Meier curves showed that the recurrence-free survival rate of patients given GEM + (group II) was higher than those on alone (group I) post-turbt, although this was not statistically significant between the two groups (log rank test) (Fig. 2). When patients were analysed according to risk group, Kaplan Meier curves showed that only those with a high risk of bladder cancer recurrence showed benefit from the additional intravesical GEM instillations, although this difference failed to reach significance (log rank test) (data not shown). Comparison of the side effects between the two treatment groups showed dysuria to be the most frequent local side effect, described by just over one-third of patients in each group (Table 2). Urinary frequency was the next most frequent side effect in both groups. In group II, gross haematuria was another frequent complaint, described by 19.4% of patients. In group II, there was a rare complaint (1/36) of temporary hair loss after GEM instillations. There were no statistically significant differences in side effects between the two study groups. Discussion Chemotherapy and immunotherapy with are the main forms of intravesical instillation therapy following TURBT. 8 Their aim is to treat residual disease after complete resection, particularly for intermediate- and high-risk tumours. Chemotherapy reduces recurrence frequency and, therefore, further resection requirements, and treatment is reported to delay the progression of highrisk tumours

5 TABLE 2: Progression, recurrence and side-effect profiles of patients with superficial bladder cancer who were randomized to receive six weekly intravesical instillations of bacillus Calmette Guérin () after transurethral resection of bladder tumour (TURBT) (group I), compared with patients who received similar treatment plus intravesical instillations of gemcitabine (GEM) (group II) Group I Group II only GEM + Statistical Progression, recurrence or side effect (n = 51) (n = 36) significance a Progression, n (%) 5/51 (9.8%) 3/36 (8.3%) NS Recurrence, n (%) 17/51 (33.3%) 14/36 (38.9%) NS Progression-free period (months), mean ± SD ± ± 7.03 NS Recurrence-free period (months), mean ± SD ± ± 5.48 P = Side effects, n (%) Dysuria 17 (33.3%) 13 (36.1%) NS Urinary frequency 15 (29.4%) 11 (30.6%) NS Gross haematuria 3 (5.9%) 7 (19.4%) NS Malaise 2 (3.9%) 2 (5.6%) NS Fever (> 38.3 C) 0 0 NS Hair loss (alopecia) 0 1 (2.8%) NS Neutropenia 0 0 NS a The χ 2 test was applied to analyse the differences between the two treatment groups. NS, not statistically significant (P > 0.05). There are limitations in the efficacy of intravesical treatments for intermediate- and high-risk SBC. In intermediate-risk tumours, conventional intravesical chemotherapy (i.e. doxorubicin, mitomycin C) or are used as a prophylaxis to prevent recurrence. Early recurrence can be decreased by half after mitomycin C therapy, while long-term recurrence rates seem to be reduced to a lesser extent (54% vs 41%). 9 Other authors TABLE 3: Follow-up recurrence rates for patients with superficial bladder cancer who were randomized to receive six weekly intravesical instillations of bacillus Calmette Guérin () after transurethral resection of bladder tumour (TURBT) (group I), compared with patients who received similar treatment plus intravesical instillations of gemcitabine (GEM) (group II) Group I Group II only GEM + Statistical Follow-up recurrence (n = 51) (n = 36) significance a Patients with recurrent disease, n (%) 17 (33.3%) 14 (38.9%) NS Month 3, n (%) 4 (7.8%) 0 (0%) NS Month 6, n (%) 9 (17.6%) 1 (2.8%) P = Month 9, n (%) 12 (23.5%) 4 (11.1%) P = Month 12, n (%) 12 (23.5%) 7 (19.4%) NS a Student s t-test was used to compare the means of normally distributed variables between the two treatment groups. NS, not statistically significant (P > 0.05). 1827

6 Recurrence-free rate Group I ( only) (n = 51) Group II (GEM + ) (n = 36) Time to first recurrence (months) FIGURE 2: Kaplan Meier curves showing a non-significant difference in recurrence free rates between patients with superficial bladder cancer treated with transurethral resection of bladder tumour (TURBT) who received intravesical infusions of bacillus Calmette Guérin () (group I) and patients who received similar intravesical infusions of plus intravesical instillations of gemcitabine (GEM) (group II) have reported even worse results: according to Lamm, 10 the short-term recurrence rate cannot be reduced by more than 15 20% and the long-term risk of recurrence cannot be reduced by more than 6%. Böhle et al. 11 reported that 46% of 1328 patients treated with mitomycin C developed recurrence in a median follow-up of 26 months. Metaanalyses have shown that is superior to intravesical chemotherapeutic agents in reducing recurrences, 12 although a 2-year recurrence rate of 40% has to be expected. 11 The role of intravesical treatment for highrisk tumours remains controversial and the involvement of mitomycin C in this risk category seems to be confined to a reduction of the recurrence rate with no effect on tumour progression. 13 Adding GEM instillations to conventional therapy did not decrease the overall recurrence and progression rates in the present study. The recurrence-free period was, however, significantly prolonged and early recurrence rates (6 and 9 months after TURBT) were significantly lower than with monotherapy. This suggests that chemoimmunotherapy in addition to helps delay the early recurrence of SBC. There is an emerging role for maintenance as a crucial requirement for optimum efficacy in SBC treatment following TURBT. Although an increase in toxicity with this treatment schedule has not been clearly shown, 14 usually 15% of patients complete the maintenance cycles (intravesical and percutaneous each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months from initiation of induction therapy). 15 For 1828

7 this reason, the present study used only induction therapy instead of adding maintenance therapy. Further clinical studies, that include maintenance therapy, need to be carried out. Local side effects can be experienced by up to 90% of patients treated with. 16 Cystitis is by far the most common complaint, which is described as moderate to severe by nearly half of patients. 1 Dysuria was the most common side effect observed in each group in the present study and there was no significant difference in occurrence between the groups. Chemotherapeutic agents, such as mitomycin C and doxorubicin, despite the low probability of systemic side effects, can give rise to severe forms of chemical cystitis. 17 The molecular weight of GEM, Da, is less than that of currently used intravesical drugs, yet is high enough to make significant systemic absorption unlikely (in an intact bladder) whilst being low enough for improved penetration of the bladder mucosa. 18 The safety of intravesical administration of up to 2000 mg GEM in 50 ml saline is substantiated by the evidence of how little GEM is actually absorbed into the systemic circulation. 18 There was no significant difference in incidence or severity of side effects in the two groups in the present study. One patient did, however, experience the unusual side effect of hair loss after GEM instillation. It was sustained for 5 months and spontaneously resolved. This may have been caused by an unidentified bladder perforation after the transurethral procedure, allowing greater systemic absorption of GEM. Overall, intravesical chemoimmunotherapy with GEM + was shown to be more effective in prolonging the recurrencefree period and in preventing early recurrence than monotherapy alone in SBC patients. Further studies are necessary to accumulate a larger amount of consistent data. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 30 June 2009 Accepted subject to revision 9 July 2009 Revised accepted 6 October 2009 Copyright 2009 Field House Publishing LLP References 1 Gontero P, Marini L, Frea B: Intravesical gemcitabine for superficial bladder cancer: rationale for a new treatment option. BJU Int 2005; 96: Oosterlinck W, Lobel B, Jakse G, et al: Guidelines on bladder cancer. Eur Urol 2002; 41: Heney NM, Nocks BN, Daly JJ, et al: Prognostic factors in carcinoma of the ureter. J Urol 1981; 125: Klan R, Loy V, Huland H: Residual tumor discovered in routine second transurethral resection in patients with stage T1 transitional cell carcinoma of the bladder. J Urol 1991; 146: Lamm DL: Complications of bacillus Calmette Guérin immunotherapy. Urol Clin North Am 1992; 19: Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: Chopin DK, Gattegno B: Superficial bladder tumors. Eur Urol 2002; 42: Solsona E, Iborra I, Ricós JV, et al: Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup. J Urol 1999; 161: Lamm DL: Intravesical therapy for superficial bladder cancer: slow but steady progress. J Clin Oncol 2003; 21: Böhle A, Jocham D, Bock PR: Intravesical bacillus Calmette Guerin versus mitomycin C for superficial bladder cancer: a formal metaanalysis of comparative studies on recurrence 1829

8 and toxicity. J Urol 2003; 169: Huncharek M, Kupelnick B: Impact of intravesical chemotherapy versus immunotherapy on recurrence of superficial transitional cell carcinoma of the bladder: metaanalytic reevaluation. Am J Clin Oncol 2003; 26: Krege S, Giani G, Meyer R, et al: A randomized multicenter trial of adjuvant therapy in superficial bladder cancer: transurethral resection only versus transurethral resection plus mitomycin C versus transurethral resection plus bacillus Calmette Guerin. Participating clinics. J Urol 1996; 156: van der Meijden AP, Sylvester RJ, Oosterlinck W, et al for the EORTC Genito-Urinary Tract Cancer Group: Maintenance bacillus Calmette Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer genito-urinary group phase III trial. Eur Urol 2003; 44: Lamm DL, Blumenstein BA, Crissman JD, et al: Maintenance bacillus Calmette Guerin 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: Gontero P, Frea B: Actual experience and future development of gemcitabine in superficial bladder cancer. Ann Oncol 2006; 17: Konety BR, Williams RD: Superficial transitional (Ta/T1/CIS) cell carcinoma of the bladder. BJU Int 2004; 94: Hendricksen K, Witjes JA: Intravesical gemcitabine: an update of clinical results. Curr Opin Urol 2006; 16: Author s address for correspondence Associate Professor Hong-Seok Park Department of Urology, Korea University Medical College, Anam-dong 5-ga, Seongbuk-gu, Seoul , Republic of Korea. hongseok@genetherapy.or.kr 1830