Year : 2006 | Volume
: 22 | Issue : 4 | Page : 317--321
A randomized trial comparing low dose (40 or 80 mg) with standard dose (120 mg) of bacillus Calmette-Guerin for superficial bladder cancer
Vivek Vijjan, Anil Mandhani, Rakesh Kapoor, Deepak Dubey, Aneesh Srivastava, MS Ansari, Pratipal Singh, Anant Kumar
Department of Urology and Renal Transplantation, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
Department of Urology, SGPGIMS, Lucknow - 226 014
Objective: Intravesical bacillus Calmette-Guerin (BCG) therapy is considered to be the most effective therapy for high-risk superficial cancer of bladder. Reduction in dose has been tried to decrease the toxicity following instillations of BCG while maintaining efficacy. This study compares the efficacy and toxicity of three different doses of modified Danish 1331 strain of BCG in patients with high risk superficial bladder cancers. Materials and Methods: A prospective randomized study was undertaken between January 2000 to March 2005 to include all patients with superficial bladder cancer who received BCG after fulfilling one or more of the appropriate criteria (grade above 1, stage above Ta, size >1 cm, multiple or recurrent). One hundred and six patients received 40 mg, 80 mg or 120 mg Danish 1331 strain BCG weekly for six weeks. The recurrence rates, tumor progression, toxicity and long-term outcome of three different doses of BCG were studied. No maintenance therapy was given. Results: Of the 106 patients, 28 received 40 mg, 37 received 80 mg and 41 received 120 mg of intravesical BCG for six weeks. The mean follow-up was three years (range one to six years). Overall, 77.4% patients responded to a single cycle of BCG, with a recurrence rate of 32.1% in 40 mg, 13.5% in 80 mg and 24.3% in the 120 mg groups. Median time to recurrence was seven months, eight months and nine months in the three groups respectively. Overall, six patients (5.6%) developed disease progression, two (7.1%) in the 40 mg, one (2.7%) in the 80 mg and three (7.3%) in the 120 mg arm. Kaplan - Meier analysis for time to recurrence ( P =0.1839) and time to progression ( P =0.595) was not significantly different in the three treatment arms. Adverse effects were seen in 55.6% patients with most being of class 1 severity. Significantly less patients developed severe adverse effects in the 40 mg group as compared to the higher dose groups. Conclusions: We conclude that 40 mg dose of intravesical BCG is as effective as the standard dose in reducing the risk of recurrence and progression. Moreover this dose is associated with significantly less toxicity.
|How to cite this article:|
Vijjan V, Mandhani A, Kapoor R, Dubey D, Srivastava A, Ansari M S, Singh P, Kumar A. A randomized trial comparing low dose (40 or 80 mg) with standard dose (120 mg) of bacillus Calmette-Guerin for superficial bladder cancer.Indian J Urol 2006;22:317-321
|How to cite this URL:|
Vijjan V, Mandhani A, Kapoor R, Dubey D, Srivastava A, Ansari M S, Singh P, Kumar A. A randomized trial comparing low dose (40 or 80 mg) with standard dose (120 mg) of bacillus Calmette-Guerin for superficial bladder cancer. Indian J Urol [serial online] 2006 [cited 2022 Dec 1 ];22:317-321
Available from: https://www.indianjurol.com/text.asp?2006/22/4/317/29117
Intravesical Bacillus Calmette-Guerin (BCG) is considered to be the most effective therapy for carcinoma in situ (CIS) and superficial cancer of bladder. The BCG contacts tumor cells through a novel fibronectin attachment protein which is followed by internalization of the BCG in the tumor cells. Interleukin-12 release resulting in Th1 response mediates the therapeutic effect of BCG. In addition to eradication of subclinical tumors, BCG has been shown to reduce the risk of recurrence and progression of superficial bladder cancer., In a recent meta-analysis of randomized trials the 6.4% of patients with papillary tumors and 13.9% of patients with carcinoma in situ on BCG therapy progressed at a median follow-up of 2.5 years.
Despite its efficacy, BCG therapy is associated with frequent local and systemic adverse effects. These are most prominent during the induction and early maintenance instillations., Reduction in dose has been tried to decrease the toxicity following instillations of BCG. The first large trial using a low-dose regimen was published by Pagano et al . Reduction in BCG dose by half to one-third has been associated with a corresponding reduction in BCG-related toxicity while maintaining, or improving outcome. Various strains of BCG have been used in low doses by various authors with favorable results. The modified Danish 1331 strain (BCG laboratory, Guindy, Chennai, India) has never been used in a low-dose regimen.
We report our experience with the standard (120 mg) and the low doses (40 and 80 mg) of modified Danish 1331 strain of BCG in patients with high-risk superficial bladder cancers, with a aim to evaluate the efficacy and toxicity of the lower doses as compared to the standard dose.
Materials and methods
Data were analyzed to include patients with superficial bladder cancer who received BCG between January 2000 and March 2005. The present study is an extension of a previously published study comparing 40 mg dose of BCG with 120 mg dose of BCG. Herein, a third arm of 80 mg of intravesical BCG was added. Dose stratification in 40 mg, 80 mg and 120 mg was based on availability of BCG and ease of preparation as one ampoule contains 40 mg of BCG.
One hundred and six consecutive patients with superficial bladder cancer (Ta or T1) with one or more of the appropriate criteria (grade above 1, stage above Ta, size >1 cm, multiple or recurrent), were included for the study. After a complete transurethral resection, the bladder tumors were staged using 1997 TNM classification and WHO grading system. These patients were randomly assigned to three different groups based on the different BCG doses. A table of random numbers was used for randomization. Group 1 patients received 40 mg, Group 2 patients 80 mg and Group 3 patients received 120 mg of Danish 1331 strain of BCG, intravesically, weekly for six weeks. The patients, the personnel administering the drug and those assessing the outcome were not blinded to group assignment. The predetermined dose of BCG was diluted in 50 ml saline and instilled intravesically by a 14 Fr Foley catheter. The retention time was two hours, during which the patient turned to either side, prone and supine position for half hour duration each. No maintenance therapy was given.
End points and follow-up
The primary outcome measures were recurrence rates and tumor progression. Adverse effects constituted the secondary outcome measures. The adverse effects were recorded based on a four-class rating scale developed by Saint et al using the WHO's adverse reaction terminology, the National Cancer Institute's terminology and a review of published reports on adverse effects to BCG.
The patients were followed at three-monthly intervals with urine cytology and cystoscopy. Patients with superficial recurrence underwent a re-resection followed by a second course of BCG. Those having progression to muscle invasive disease underwent radical cystectomy or radiotherapy.
Quantitative data are shown as mean ± SD and qualitative data are shown as percent. The difference between the groups was tested by Chi square test. Time to recurrence and time to progression was calculated using Kaplan-Meier analysis and evaluated by log rank test.
Of the 106 patients, 28 received 40 mg, 37 received 80 mg and 41 received the standard 120 mg intravesical BCG. As this trial was a continuation of a previously published study there was a difference in the number of patients in the three groups. Patients in the 120 mg and 40 mg groups, who were a part of the previous study and met the eligibility criteria of the present study, were included.
The mean age was 54 years, 54 years and 59 years in Groups 1, 2 and 3 respectively. The demographic profile of the patients has been shown in [Table 1]. The mean follow-up was two years (range 4-60 months) in Group 1, 2.8 years (range 8-48 months) in Groups 2 and 3 years (range 4-60 months) in Group 3. The mean tumor size was 2.8 cm in Group 1, 2.7 cm in Group 2 and 2.4 cm in Group 3. In Group 1, 21.4% patients,, 16.2% in Group 2 and 29.2% patients in Group 3 had multiple tumors at presentation. In approximately 32% patients in both Groups 1 and 2 and 44% in Group 3 recurrent tumors was an indication for BCG instillation. The tumor characteristics are shown in [Table 2]. Most of the tumors were of T1G1 histopathology in all the three groups. All these tumors were either recurrent or multifocal or had size greater than 1 cm.
Ninety-eight patients completed the entire course of BCG. The BCG instillations were stopped in four patients who required ATT and four patients who developed Class 3 toxicity. None of these patients belonged to the 40 mg group.
Recurrence: Overall, 22.6% of the patients suffered from tumor recurrence. The recurrence rate was 32.1% in Group 1 (nine patients), 13.5% in Group 2 (five patients) and 24.3% in Group 3 (10 patients). The median time to first recurrence was seven months, eight months and nine months in Groups 1, 2 and 3 respectively. Kaplan-Meier analysis [Figure 1] of the time to recurrence demonstrated no difference in the three treatment arms ( P = 0.1839).
Progression: Overall, six patients (5.6%) developed disease progression, two (7.1%) in 40 mg, one (2.7%) in 80 mg and three (7.3%) in the 120 mg arm. Four patients had superficial (lamina propria) and two patients had deep progression (invasion of detrusor muscle) [Table 3]. The two patients having deep progression belonged to the 40 mg and 120 mg groups. They were managed with radical radiotherapy and radical cystectomy respectively. Kaplan-Meier analysis [Figure 2] for time to progression did not reveal any significant difference in the three treatment arms ( P =0.595).
Overall survival: Overall, three deaths occurred, two in the 80 mg group and one in the 120 mg group, all due to unrelated causes. No cancer-specific death occurred in either of the groups at last follow-up.
Side-effects: Adverse effects were seen in 55.6% patients with most being of class 1 severity. In the 40 mg group 28.6% patients developed adverse effects as compared to 54% and 75.5% in the 80 mg and 120 mg groups respectively. The details of the side-effects are summarized in [Table 4]. The side-effects were significantly greater in Group 3 patients. The most common local reaction was cystitis and the commonest systemic adverse effect was fever and myalgia. No class 4 toxicity was observed in any group. Four patients, two each in the 80 mg and 120 mg groups required ATT. Two patients had arthralgia (class 3 toxicity) and two patients had high-grade fever (class 3 toxicity).
BCG is the most effective immunotherapeutic agent against superficial transitional cell carcinoma. Data support that BCG has a positive impact on tumor recurrence, disease progression and survival. In an EORTC meta-analysis of randomized clinical trials comparing transurethral resection plus intravesical BCG to either resection alone or resection plus another treatment other than BCG, 9.8% patients on BCG had progression compared to 13.8% patients in the control groups, a reduction of 27% in the odds of progression on BCG (odd ratio 0.73, P = 0.001), at a median follow-up of 2.5 years. SWOG studies have demonstrated that BCG immunotherapy was superior to intravesival chemotherapy.,
The use of BCG is, however, hindered by bothersome adverse reactions. Vegt et al reported 30-80% patients with minor side-effects and 5% with severe adverse effects during a course of six, weekly BCG instillations. In order to decrease the toxicity of BCG, reduced dose of BCG has been used by a number of groups.,, A reduction in the standard dose is aimed at decreasing the side-effects while maintaining the overall clinical response. This study was with a aim to evaluate the efficacy and toxicity of the lower doses of BCG as compared to the standard dose.
Martinez-Pinerio et al have used standard 81 mg and reduced 27 mg dose of Connought strain of BCG in superficial bladder tumors. The rates of recurrence (28% vs. 31%) and progression (11.5% vs. 13.3%) were similar in the two groups at a median follow-up of 69 months. However, significantly fewer patients had toxicity in the reduced dose arm resulting in delayed instillations or withdrawal. The recurrence rates (32.1% for 40 mg and 13.5% for 80 mg) and progression rates (7.1% for 40 mg and 2.7% for 80 mg) for lower doses of BCG in our study were statistically similar to the standard dose group (24.3% recurrence rate and 7.3% progression rate)
In a literature review by Cheng et al , four of the five studies comparing low and standard doses on BCG showed a statistically significant lower toxicity. In the 12 studies employing a low-dose regimen, the overall response rate ranged from 28-84%. In our study also, patients receiving lower doses of BCG had a response rate of 67.9 and 86.5% for doses 40 mg and 80 mg respectively. These were not statistically different from the results for the standard dose of 120 mg (75.7%).
In an EORTC Phase 2 trial, low and intermediate-risk patients (Ta, T1, G1-2) were studied for the efficacy of reduced dose BCG. A similar efficacy with a 61% complete response was noted with a quarter of the standard dose. There have been numerous trials testing low dose of BCG in superficial bladder cancer. All these trials underscore the importance of reduced doses of BCG to decrease the degree of toxic side-effects.
Various strains of BCG have been used but we have no data on patients using modified Danish 1331 strain of BCG in a lower dose for superficial bladder cancer. We had earlier studied the IL-8 response to standard and low doses of this strain of BCG and had found no difference. This trial is a continuum of the previous study with an addition of an extra arm with a different dose.
In our series, the BCG doses were well tolerated and the patient compliance was good with 92% of the patients completing the therapy. Stoppage of BCG instillations was required in four patients who were put on ATT and four patients who developed class 3 toxicity. The 40mg group had significantly reduced side-effects as compared to the other two groups, but with similar recurrence and progression rates. No patient in this group suffered toxicity of greater than class 1. The two patients who required antitubercular treatment belonged to the higher dose groups. None of the patients developed bladder contracture requiring cystectomy.
Though the follow-up is short and the number of patients is not enough to strongly recommend the reduced doses as a routine, early results and a randomization would at least form a basis for further multi-center trials to consolidate the findings.
We conclude that a 40 mg dose of intravesical BCG is as effective as the standard dose in reducing the risk of recurrence and progression. Moreover, this dose is associated with significantly less toxicity.
|1||Bohle A, Joeham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: A formal met-analysis of comparative studies on recurrence and toxicity. J Urol 2003;169:90-5.|
|2||Sylvester RJ, Van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: A met-analysis of published results of randomized clinical trials. J Urol 2002;168:1964-70.|
|3||Saint F, Irani J, Patard JJ, Salomon L, Hoznek A, Zammattio S, et al . Tolerability of bacillus Calmette-Guerin maintenance therapy for superficial bladder cancer. Urology 2001;57:883-8.|
|4||van der Meijden AP, Sylvester RJ, Oosterlinck W, Hoeltl W, Bono AV, et al . Maintenance bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: Results of a European Organization for Research and Treatment of Cancer Genito-Urinary group Phase III trial. Eur Urol 2003;44:429-34.|
|5||Pagano F, Bassi P, Milani C, Meneghini A, Maruzzi D, Garbegilo A. A low dose bacillus Calmette-Guerin regimen in superficial bladder cancer therapy: Is it effective? J Urol 1991;146:32-5.|
|6||Martinez-Pineiro JA, Flores N, Isorna S, Solsona E, Sebastian JL, Pertusa C, et al . Long-term follow-up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacille Calmette-Guerin with a reduced dose of 27 mg in superficial bladder cancer. BJU Int 2002;89:671-80.|
|7||Morales A, Nickel JC, Wilson JW. Dose response of bacillus Calmette-Guerin in the treatment of superficial bladder cancer. J Urol 1992;147:1256-8.|
|8||Papagallo GL. Low dose vs. standard dose BCG therapy of superficial bladder cancer: Final results of a phase 3 randomized trial. Eur Urol 1999;35.|
|9||Kumar A, Dubey D, Bansal P, Mandhani A, Naik S. Urinary interleukin-8 predicts the response of standard and low dose intravesical bacillus Calmette-Guerin (modified Danish 1331 strain) for superficial bladder cancer. J Urol 2002;168:2232-5.|
|10||Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, et al . A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional cell carcinoma of the bladder. N Engl J Med 1991;325:1205-9.|
|11||Lamm DL, Blumenstein BA, Crawford ED. Randomized inter group comparison of bacillus Calmette-Guerin immunotherapy and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of bladder: A Southwest Oncology Group study. Urol Oncol 1995;1:119. |
|12||Vegt PD, van der Meijden AP, Sylvester R, Brausi M, Holtl W, de Balincourt C. Does isoniazid reduce side effects of intravesical bacillus Calmette-Guerin therapy in superficial bladder cancer? Interim results of European Organization for Research and Treatment of Cancer Protocol 30911. J Urol 1997;157:1246-9.|
|13||Bassi P, Spinadin R, Carando R, Balta G, Pagano F. Modified induction course: A solution to side effects? Eur Urol 2000;37:31-2.|
|14||Lebret D, Bohin D, Kassardjian Z, Herve JM, Molinie V, Barre P, et al . Recurrence, progression and success in stage Ta grade 3 bladder tumors treated with low dose bacillus Calmette-Guerin instillations. J Urol 2000;163:63-7.|
|15||Yalcinkaya F, Kamis L, Ozteke O, Gunlusoy B, Yigitbasi O, Unal S. Prospective randomized comparison of intravesical BCG therapy with standard dose versus low dose in superficial bladder carcinoma. Int Urol Nephrol 1998;30:41-4.|
|16||Cheng CW, Ng MT, Chan SY, Sun WH. Low dose BCG as adjuvant therapy for superficial bladder cancer and literature review. ANZ J Surg 2004;74:569-72.|
|17||Mack D, Holtl W, Bassi P, Brausi M, Ferrari P, de Balincourt C, et al . the ablative effect of quarter dose bacillus Calmette-Guerin on a papillary marker lesion of the bladder. J Urol 2001;165:401-3.|