Female Urology The efficacy and Safety of Intravesical Bacillus-Calmette- Guerin in the Treatment of Female Patients with Interstitial Cystitis: A double-blinded Prospective Placebo Controlled Study IRANI D, HEIDARI M, KHEZRI AA Faghihi Hospital, Shiraz University Of Medical Sciences, Shiraz, Iran ABSTRACT Purpose: To evaluate the efficacy and safety of intravesical Bacillus Calmette-Gurein injection in the treatment of female patients with interstitial cystitis. Materials and Methods: Thirty women meeting the National Institute of Arthritis, Diabetes, digestive and kidney diseases criteria for interstitial cystitis, were random- ized in a double-blinded fashion in two groups each consisted of 15 patients to receive six, weekly instillation of 120 mg BCG vaccine of Iranian Institute of pastor or place- bo. Periodic questionnaires on symptoms of interstitial cystitis, voiding diaries, blad- der capacity at first desire to void, and maximum bladder capacity were obtained. Adverse events were closely monitored during the treatment and follow-up phases of the study. Subjective and objective baseline values were compared with the follow-up data. Results: With a mean follow-up of 24 (range 6 to 33) months 11 out of 15 (73%) in BCG group, and 3 out of 15 (20%) in placebo group responded to the treatment (p<0.002). Responders were defined the patients with more than 40% improvement in the symptoms of interstitial cystitis. The global improvement in symptoms and signs of interstitial cystitis was 62%. Adverse events were similar in both groups, mostly irri- tative in nature and no significant systemic event was noted. BCG did not worsen interstitial cystitis symptoms. Conclusion: We concluded that intravesical BCG is safe, effective, available, and inexpensive with relatively durable results in the treatment of interstitial cystitis. KEY WORDS: interstitial cystitis, BCG vaccine, immunotherapy 27 Urology Journal UNRC/IUA Vol. 2, 27-30 Spring 2004 Printed in IRAN Introduction Interstitiad cystitis is a chronic disabling disease presenting with irritative symptoms, pain, and sterile urine. It was described for the first time by Hunner in 1915.(1) Although near a hundred years have been passed form then, the etiology and def- inite treatment is unknown. A series of various causes have been suggested including mast cell related inflammation, infection, and immunologic system alteration.(1) Zeidman et al reported the experience of effective Bacillus Calmette-Guerin (BCG) intravesical installation in 1994. They selected five patients with resistant inter- stitial cystitis as candidates for a 6-week therapy with intravesical installation of BCG and observed significant improvement in bladder capacity (p=0.027), daytime frequency (p=0.013), nocturnal frequency (p=0.019), and pain and bladder discom- fort (p=0.031).(2) Zeidman's interest was attracted Accepted for publication in August 2003 THE EFFICACY AND SAFETY OF INTRAVESICAL BACILLUS-CALMETTE-GUERIN IN THE TREATMENT OF FEMALE PATIENTS WITH INTERSTITIAL CYSTITIS: A DOUBLE- BLINDED PROSPECTIVE PLACEBO to BCG when he found that its installation into bladders with suspected tumors led to improve- ment of symptoms which were later defined to be due to interstitial cystitis.(2,3) BCG vaccine is FDA approved and produced by Pastor Institute in Iran with a low cost and acceptable availability; thus we decided to try the efficacy and safety of BCG vac- cine on interstitial cystitis in the patients referred to educational medical centers of Shiraz University of Medical Sciences. Materials and Methods This study was designed as a double-blinded ran- domized controlled trial at Shiraz University of Medical Sciences' hospitals to be done from January 1999 to September 2002. Thirty patients who met NIDDK diagnostic criteria were selected from among 150 females with irritative symptoms and bladder pain, after performing cystoscopy under anesthesia, bladder hydrodistention, and other preliminary evaluations. They were random- ly assigned into the study and control groups, each containing 15 patients, based on the predic- tion of 15% response to the treatment vs. 20% response in the control group, the study power of 80%, and error of 5%.(2-5) The excluding criteria were immunocompromis- ing conditions, steroids, Warfarin, or immunosup- pressant administration, pregnancy, vesicoureteral reflux, a history of interavesical installation in the last 3 months, positive HIV serology, positive cuta- neous PPD, and males due to the risk of catheter- ization.(3,4) Primary evaluations consisted of history and physical examination, complete blood count, bio- chemical HIV selorogic test, cutaneous PPD test, chest x-ray, cystography, cystoscopy, bladder hydrodistension, and bladder capacity measure- ment. Bladder biopsy would be done if tumor was suspected or in some particular conditions. A general questionnaire was filled before and after (during the study) the intervention in which vaginal or urethral pain, pelvic pain, painful inter- course, urgency, dysuria, feeling of healthy, sleep status, life quality,(6) and validated questions of Viscontin University about interstitial cystitis symptoms,(7) day time urination profile, the aver- age volume of the bladder that induces fullness, and the average tolerable urine volume were included. Also, patients with involuntary contraction of the bladder or the ones responded to anticoliner- gic medications were excluded in this study. Routine cystometrography was not performed in all the patients in order to minimize the research costs and physicians' intervention. Thirty patients who had positive hydrodistension and glomerulization in more than 75% of bladder mocusa under general anesthesia and met the NIDDK criteria for interstitial cystitis, were ran- domly assigned into two groups each contained 15 patients. They received intravesical installation of 120 mg of BCG vaccine or 50 cc of normal saline (as placebo) through foley catheter for six weeks. Vials of placebo with similar appearance were pro- duced. Consecutive cases were selected to received either the placebo or BCG, Vials nominated blind- ly as drugs A and B. The staff who were involved with the therapy were blind to the drugs type and nominating the drugs and listing the patients were done by a third person not enrolled in the study. In case of severe fever or a serious complication the patient would be excluded from the blind pro- cedure to be treated for BCG complications. The patients were informed about the details of place- bo controlled design of the study and their written consent was taken before the study. Also charges were omitted. They were asked to maintain the solution in the bladder for two hours and change the position every 15 minutes. In case of inconvenience the bladder would be emptied temporarily and the contents would be installed again. An emergency telephone number was available to contact if any probable complica- tions occurred over the first three days of treat- ment. Follow-up after 1,2,3, and 6 months was done when the 6-week therapy period finished. The last follow-up was performed at least six months later. The study remained double-blinded until the end of the follow-up. The comparison of the symptoms and signs before and after the treat- ment was done preceding the revealing of the groups. According to Parson, over 40% improvement of valid scores of Wisconsin University for intersti- tial cystitis were considered as response to the treatment. This was selected as a criterion to eval- uate other symptoms.(8) Patients were asked to show the severity of the symptoms before and after the treatment on a graded 10 cm rulers. Statistic analysis was done by Mann-Whitney U signed rank test using SPSS software. 28 THE EFFICACY AND SAFETY OF INTRAVESICAL BACILLUS-CALMETTE-GUERIN IN THE TREATMENT OF FEMALE PATIENTS WITH INTERSTITIAL CYSTITIS: A DOUBLE- BLINDED PROSPECTIVE PLACEBO Results Demographic characteristics of the two group were similar with no significant statistic differ- ence. These parameters are demonstrated in table 1. Changes in primary symptoms and signs were evaluated during 1,2,3, and 6 months follow-ups. Eleven out of 15 patients who received BCG vac- cine (73%, p<0.002) responded to the treatment, compared to 3 out of 15 in the control group (20%, p<0.05). The mean two year follow-up showed that of 11 patients improved with BCG installation 7 (63.6%) did not required any excessive therapy in order to control the symptoms. The overall improvement was 62% (p<0.05). Frequency and nocturia reduced by 33.5% and 40%, respectively, in the BCG group, while no con- siderable change was observed in the control group. Some of the other symptoms and signs in BCG group vs. control group improved as follows: dysuria 75% vs. 42%, urgency 42% vs. 24.3%, painful coitus 61% vs. 13.4%, pelvic pain 65% vs. 22%, appropriate sleep 63% vs. 17%, and feeling healthy 51% vs. 18%. Improvement of valid scores of Wisconsin University for interstitial cystitis was achieved 56% vs. 16.5%. Life quality (FS 36) increased by 63% vs. 16%. Mean bladder capacity at the first feeling of fullness increased approximately by 27 cc (47%) vs. 7 cc (9.6%). Maximum tolerable vol- ume increased by a mean of 53 cc (70%) in BCG group compared to 13 cc (21%) in control group. Differences between the two group and P values are presented in tables 2 and 3. Analysis of the results in the control group did not reveal any statistically meaningful changes in symptoms and signs of interstitial cystitis neither before the study, nor during or after then (p>0.1). No complication interrupted the double-blinded design of the study and all patients were coopera- tive and with high compliance. Discussion BCG vaccine has been used widespread in blad- der cancer for 20 years. The first investigation was reported in 1970 showing its efficacy in the treat- ment of bladder tumors.(9,10) Although BCG therapeutic mechanism is still unknown, mediating and adjusting the immune system has been suggested. As a whole its effica- cy has been proved by Peter and it is easy to administer.(3,4,11) 29 TABLE 1. The comparison of symptoms and signs of the patients receive BCG and placebo Variable BCG group Placebo group P value Patients 15 15 1 Age (year) 40.8±13.96 36±12.84 0.529 Disease (year) 9.4±5.98 6.8±5.5 0.315 Urination per day (times) 14.6±4.35 12.7±5.25 0.218 Urination per night (centimeter) 4.9±1.19 4.2±1.31 0.218 Urgency (centimeter) 5.45±1.11 5.6±1.14 0.315 Dysuria (centimeter) 5.56±1.1 5.51±1.16 0.971 Painful intercourse (centimeter) 5.32±0.93 4.89±0.9 0.393 Pelvic pain (centimeter) 4.88±1.2 4.76±0.95 0.853 Valid scores of Wisconsin University for interstitial cystitis (No.) 31.2±8.5 25.4±6.7 0.105 Feeling well (centimeter) 4.66±8.5 4.98±0.95 0.393 Sleep (centimeter) 4.7±1.3 4.5±1 0.393 Bladder volume in the first feeling of urination (cc) 57±243.52 62.2±27.61 0.796 Maximum tolerable bladder capacity (cc) 187±81.79 183±61.1 0.796 Score of 36 graded questions of life quality (No.) 53±4.3 54±3.75 0.165 TABLE 2. The comparison of symptoms and signs of the patients enrolled in BCG and placebo groups 24 months after the treatment Variable BCG group Placebo group P value Interstitial cystitis validated score of the University of Viscontine (No.) 16.6±11.45 21.2±7.69 0.143 Urination per day (times) 9.7±4.39 12.2±3.55 0.123 Urination per night (centimeter) 2.9±1.91 3.9±1.52 0.19 Dysuria (centimeter) 2.59±2.31 5.16±1.22 0.015 Urgency (centimeter) 3.39±2.23 4.74±1.3 0.165 Painful intercourse (centimeter) 2.59±1.86 4.23±1.46 0.009 Pelvic pain (centimeter) 2.32±2.15 4.61±0.99 0.015 Sleep (centimeter) 2.3±1.4 4.2±0.7 0.016 Feeling well (centimeter) 2.27±2 4.49±0.83 0.019 Bladder volume in the first feeling of urination (cc) 85±35.35 68.5±27.6 0.529 Maximum tolerable bladder capacity (cc) 240.5±93.7 196.5±61.8 0.165 Score of 36 graded questions of life quality (No.) 31.2±8.05 57.6±8.15 0.001 TABLE 3. Mean differences in the symptoms between the two groups after 24 months Variable Mean±SD P value Interstitial cystitis validated score of the University of Viscontine (No.) 9.4±8.59 0.003 Urination per day (times) 2.7±3.18 0.001 Urination per night (centimeter) 1.15±1.59 0.023 Dysuria (centimeter) 1.66±1.79 0.002 Urgency (centimeter) 1.23±1.49 0.002 Painful intercourse (centimeter) 1.94±1.76 0.001 Pelvic pain (centimeter) 1.35±1.40 0.002 Feeling well (centimeter) 1.39±1.40 0.015 Bladder volume in the first feeling of urination (cc) 16.7±15.06 0.002 Maximum tolerable bladder capacity (cc) -35.25±28.75 0.001 Score of 36 graded questions of life quality (No.) -14.9±14.73 0.0001 THE EFFICACY AND SAFETY OF INTRAVESICAL BACILLUS-CALMETTE-GUERIN IN THE TREATMENT OF FEMALE PATIENTS WITH INTERSTITIAL CYSTITIS: A DOUBLE- BLINDED PROSPECTIVE PLACEBO Why BCG vaccine is effective in interstitial Cystitis? BCG is a strong stimulator of the immune system and some evidence indicate that interstitial cystitis is an autoimmune disease.(11-19) Presence of abnormal HLA in bladder mucosa pro- vides this fact. It seems that a type of immune reaction occurring in the bladder wall causes increased activity of type II T helper cells com- pared to type Is, leading to tissue injury. BCG vac- cine induces the activity of type I T helper cells, so that it regulates the adjustment of type II ones and protection of the tissues.(12,18) These patients have Interleukin-6 in their urine, six times as much as normal individuals and the severity of the disease is directly related to the amount of IL-6. BCG vaccine can reduce IL-6.(17-19) Interstitial cystitis is associated with low amounts of nitric oxide (NO) in the urine and BCG is a strong stimulator of NO secretion in the urine, so that it may have a role in the treat- ment.(20) Eventually, BCG may lower the sensitivity of sensory neuron fibers and consequently reduce pain and increase urinary reservoir.(3,4) Sixty two percent of our respective patients responded to BCG installation that is comparable with Zeidman findings (75%) and Peter's studies (60% and 70%).(2-4) In this study patients who had a bladder capaci- ty of lower than 250 cc under general anesthesia and severe symptoms, did not respond to the treat- ment properly. However, BCG installation did not yield any case of aggravating symptoms. Conclusion This study showed that intravesical injection of BCG vaccine is an effective, safe, and cost-effective treatment of interstitial cystitis which is easily available and durable. References 1. Hunner GL. 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