european urology supplements 5 (2006) 654 659 available at www.sciencedirect.com journal homepage: www.europeanurology.com Review Improving Patient Outcomes: Optimal BCG Treatment Regimen to Prevent Progression in Superficial Bladder Cancer Dr. Donald Lamm is President of BCG Oncology in Phoenix, Arizona and Clinical Professor at the University of Arizona. He has had a lifelong interest in urologic oncology and clinical trials and has a particular interest in immunotherapy and chemoprevention. He is former professor of urology at the Mayo Clinic, Scottsdale, Arizona, and professor and chief of urology at West Virginia University and the University of Texas, San Antonio. Donald Lamm * BCG Oncology, 16620 North 40th Street, Suite E, Phoenix, AZ, United States Article info Published online ahead of print on June 5, 2006 Keywords: BCG immunotherapy Maintenance schedule Progression Recurrence Please visit www.eu-acme.org to read and answer the EU-ACME questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Bacillus Calmette-Guérin (BCG) immunotherapy has been demonstrated in randomised clinical trials and meta-analyses to provide superior protection from tumour recurrence and, unlike chemotherapy, even reduce disease progression. Although the optimal maintenance schedule has not been defined by controlled comparison, review of controlled studies suggests that Dr. Lamm s 3-wk schedule with maintenance at 3, 6, 12, 18, 24, 30, and 36 mo may be best, but dose reduction and delay or suspension of treatments is frequently needed to reduce side-effects. Randomised comparison of this regimen using full-strength Connaught BCG versus one-third strength suggests the former is superior, but in some populations dose reduction may be superior. Moreover, long-term (15-yr) follow-up of BCG-treated patients demonstrates the need for continued protection from recurrence and progression. These considerations, plus the marginal improvement demonstrated with systemic BCG immunisation and the reduction in side-effects with dose reduction have led Dr. Lamm to use the following protocol. Induction consists of full-strength BCG given weekly for 6 wk with concomitant percutaneous administration. The dose is reduced to one third at the first sign of significant side-effects. Maintenance BCG in high-risk (G3, T1, or CIS) patients is given using one-third dose BCG at 3, 6, 12, 18, 24, 36, 48, 60, and 72 mo, and then every other year to the 12th year, with dose reductions to 1/10th, 1/30th, 1/100th as needed to prevent increasing side-effects. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Tel. +1 602 493 6626; Fax: +1 480 609 0410. E-mail address: dlamm@bcgoncology.com. 1569-9056/$ see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2006.04.008
european urology supplements 5 (2006) 654 659 655 1. Introduction Bacillus Calmette-Guérin (BCG) immunotherapy has been demonstrated in randomised clinical trials and meta-analyses to provide superior protection from tumour recurrence and, unlike chemotherapy, even reduce disease progression. Optimal BCG therapy, however, is an individual affair. Optimal treatment varies according to multiple host and tumour factors. Host factors for BCG include age, general immune status, previous exposure to BCG, and BCG response gene. Tumour factors include location, stage, grade, antigenicity, and doubling time, among others. Risk groups also improve treatment selection. Low-risk groups include G1, Ta solitary tumours with no recurrence at 3 mo. Intermediate-risk groups include multiple or recurrent G1Ta and G2Ta. High-risk groups are any G3, carcinoma in situ (CIS), lamina propria invasion (T1) tumours, or 3-mo recurrence. Low-grade tumors are relatively resistant to BCG immunotherapy. In a study of intravesical BCG and epirubicin comparing the prophylaxis of recurrent or multiple superficial bladder tumours, a significant advantage for BCG was only observed in T1 and G3 transitional cell carcinoma (TCC) [1]. 2. Diet and lifestyle as an adjunct to BCG therapy Diet, lifestyle, and environmental factors also play a significant role in reducing risk. Diets low in vitamin A and serum carotene and high in fat increase the risk of bladder cancer. Soy, garlic, selenium, nonsteroidal anti-inflammatory drugs, and green tea may reduce the risk. Furthermore, vitamins such as A, B 6, C, E, and possibly folic acid and D, may be protective. Megavitamin supplements (Oncovite), with higher than recommended dietary allowance of vitamins A, B 6, C, and E, have been shown to reduce overall recurrence of bladder cancer from 80% to 40% ( p = 0.0011) in patients receiving BCG therapy for bladder carcinoma (Fig. 1). In Ta and T1 TCC, recurrence was reduced by 42%, and recurrence in low-grade (G1, G2) TCC was reduced by 53%. Oncovite was also associated with a statistically significant increase in long-term natural killer (NK) cell activity in patients treated with BCG [2]. The benefit of high-dose vitamins is currently being evaluated again in patients receiving optimal BCG maintenance therapy with or without interferon alfa. 3. Chemotherapy Intravesical therapy (with chemotherapeutic agents or BCG) is most often used in patients with multiple tumours or recurrent tumours or as a prophylactic measure in high-risk patients after transurethral resection (TUR). A meta-analysis of seven randomised trials that included close to 1500 patients evaluated tumour recurrence in Ta, T1 TCC after a single postoperative chemotherapy and showed that instillation within 6 h is clearly effective [3]. Comparison studies show that single immediate chemotherapy treatment after TUR is better than delayed, extended treatment. One instillation, however, may be insufficient with multiple tumours [3]. 4. BCG versus chemotherapy Many studies in superficial TCC of the bladder found that BCG was associated with significantly fewer recurrences than mitomycin C. In our Southwest Oncology Group (SWOG) study, although there was no significant difference seen in disease progression, recurrence with grade 3 superficial disease was significantly lower in patients being treated with BCG. Overall reduction in tumour recurrence is illustrated in Fig. 2. A meta-analysis of randomised trials showed that intravesical BCG is superior to mitomycin C in reducing tumour recurrence in high-risk TCC [5]. Fig. 1 Kaplan Meier estimate of 5-yr tumour-free rate in patients receiving vitamin supplement and BCG therapy for bladder carcinoma [2]. 5. CIS In a meta-analysis of nine randomised trials including 700 patients with CIS [6], BCG therapy
656 european urology supplements 5 (2006) 654 659 Evidence indicates that doses of BCG as low as 1 mg (1/50th the standard dose) are effective in supporting an immune response 5 yr after starting treatment [9]. Comparison studies using dose reduction, however, have not been done. Initial immune stimulation peaks at 6 wk, but with subsequent courses it usually peaks at 3 wk, and the stimulation wanes with time. Furthermore, Th1 immune component host and antigenic tumour are needed for effectiveness. Fig. 2 BCG versus mitomycin C (Southwest Oncology Group 8795) [4]. showed 68% complete response compared to 52% complete response in chemotherapy-treated patients ( p = 0.0002). With a 3.6-yr mean followup, 47% of BCG-treated patients showed no evidence of disease compared to 26% of chemotherapy patients. Patients treated with BCG also showed 26% reduction in disease progression. This shows that BCG reduces the risk of short- and long-term treatment failure compared with chemotherapy, and BCG should be the agent of choice in the treatment of CIS. 6. BCG versus TUR alone Meta-analysis of six trials with 585 patients of BCG versus TUR alone showed that BCG provides significantly better prophylaxis of tumour recurrence in Ta, T1 TCC. In terms of first recurrence, a 56% reduction in the hazard was attributable to BCG, whereas the odds ratio for recurring at 12 mo significantly favoured BCG therapy [7]. 7. Principles of BCG immunotherapy Optimal BCG therapy is based on several goals and principles. The goal of BCG therapy is to minimise the tumour burden by juxtaposing BCG and tumour cells. Intravesical administration of BCG generally provides good juxtaposition for TCC within the bladder. The urologist should use sufficient but not excess BCG. Excess BCG, such as repeated 6-wk courses, suppresses the immune response. Individual responses vary, but using too little or too much BCG reduces its effect. The dose-response curve is bell-shaped (as illustrated by murine models) [8]. 8. Low-dose versus high-dose BCG Intravesical BCG is effective in the prophylaxis of papillary tumour recurrences, in the therapy of CIS, and in delaying progression to muscle invasion. A low-dose regimen (BCG, 75 mg) achieved clinically significant response rates with a decrease in sideeffects compared with standard-dose BCG (150 mg). Patients having a low-dose BCG regimen showed significantly better response rates ( p = 0.0009) and a significant decrease in most of the common sideeffects (cystitis, fever, and haematuria; p < 0.05). Although no differences in progression rates were observed, a higher proportion of T1 patients receiving the low-dose BGC regimen were free of tumours [10]. Low-dose BCG after one-cycle BCG failure provides 60% durable complete response. Chemotherapy for BCG failures, however, provides poor response rates (19% for mitomycin C) [11]. 9. Maintenance 9.1. Effect on recurrence A comparison of BCG and doxorubicin in patients with bladder TCC also showed that BCG provided long-term protection against recurrence (Fig. 3) [12]. Fig. 3 BCG versus doxorubicin: treatment failure free [12].
european urology supplements 5 (2006) 654 659 657 Fig. 4 BCG maintenance [15]. Moreover, an evaluation of 3-wk BCG maintenance found no significant increase in toxicity during further maintenance [13]. 9.2. Effect on progression A 15-yr follow-up of Ta and T1 patients showed that without BCG maintenance 5% of TaG1 patients progressed, 39% of TaG3 patients progressed and 26% died, and 56% T1G3 patients progressed and 38% died. These results show that patients with highgrade Ta tumours have a lifelong risk of disease stage progression similar to those with T1 tumors [14]. Although BCG immunotherapy has been widely accepted as the optimal treatment for CIS and highgrade superficial TCC, controversy remains regarding the role of maintenance therapy, and its longterm effect on recurrence and progression. Compared to standard induction therapy, maintenance BCG immunotherapy has been beneficial in patients with CIS and select patients with Ta, T1 bladder cancer (Fig. 4). Median recurrence-free survival in patients with maintenance was twice as long compared to no maintenance ( p < 0.0001) [15]. A meta-analysis of 24 randomised trials showed that BCG significantly reduced the risk of progression after TUR in patients with intermediate- and high-risk papillary tumours and those with CIS who receive maintenance treatment. BCG, however, was only effective in trials with maintenance, where it reduced the risk of progression by 37% ( p = 0.00004). In terms of survival, the reduction in the odds of death of 11% overall and 19% in bladder cancer were not statistically significant, as might be expected with 2.5-yr mean follow up [16]. 10. Percutaneous BCG Although studies have failed to demonstrate benefit for percutaneous BCG, complete response in CIS patients increased from 49% to 77% with purified protein derivative (PPD) conversion ( p < 0.001) [15]. PPD is clearly not a requisite for response to BCG, but statistically significant correlations have been reported. Although percutaneous BCG and PPD skin testing add virtually nothing to the morbidity or cost of treatment, immune status is clearly related to the course of cancer and PPD is a measure of cellular immunity. Although data are controversial, percutaneous BCG for PPD-negative patients may be beneficial and is worthy of study. 11. Predicting BCG response 11.1. Molecular markers Overexpression of p53, tumor suppression gene, does not predict response to BCG [17,18]. Proliferation rate, however, assessed by Ki-67 protein using MBI-1 antibody, could be a useful predictive marker of outcome in T1G3 bladder carcinoma. Patients
658 european urology supplements 5 (2006) 654 659 with <20% expression were associated with a positive response to BCG instillations [19]. 11.2. Urinary leukocytes A study of urinary leukocyte count on the third day after BCG treatment in patients treated with 3-wk maintenance BCG showed that a white blood cell count of 165,000/ml was associated with significant reduction in tumour recurrence ( p = 0.0009) and increase in side-effects ( p = 0.0001) [20]. 12. Proposed optimal BCG maintenance schedule Although the optimal maintenance schedule has not been defined by controlled comparison, review of controlled studies suggests that a 3-wk schedule with maintenance at 3, 6, 12, 18, 24, 30, and 36 mo may be best, but dose reduction and delay or suspension of treatments is frequently needed to reduce side-effects. Randomised comparison of this regimen using full-strength Connaught BCG versus one-third strength suggests the former is superior, but in some populations dose reduction may be superior. Moreover, long-term (15-yr) follow up of BCGtreated patients demonstrates the need for continued protection from recurrence and progression. These considerations plus the marginal improvement demonstrated with systemic BCG immunisation and the reduction in side-effects with dose reduction have led me to use the following protocol. Induction consists of full-strength BCG given weekly for 6 wk with concomitant percutaneous administration. Percutaneous administration is given by the Tine technique. The inner upper thigh is cleansed with alcohol, wet with 2 drops of the BCG suspension to be instilled in the bladder, and then punctured 4 times with a 28-gauge needle. Percutaneous BCG is discontinued when significant or bothersome inflammation occurs. The dose of intravesical BCG is reduced to one third at the first sign of significant side-effects. Maintenance BCG in high risk (G3, T1, or CIS) patients is given using onethird dose BCG at 3, 6, 12, 18, 24, 36, 48, 60, and 72 mo, and then every other year to the 12th year, with dose reductions to 1/10th, 1/30th, 1/100th as needed to prevent increasing side-effects. 13. Conclusions Maintenance with BCG immunotherapy is the current standard treatment for intermediate- and high-risk TCC. Low-risk patients benefit from immediate perioperative chemotherapy. Diet, carcinogen reduction, and Oncovite supplements can also have a significant effect on treatment. In terms of managing BCG side-effects, dose reduction of BCG is a less toxic and less expensive alternative to isoniazid, but isoniazid and fluoroquinolone antibiotics are important in the treatment of infectious complications of BCG. The proposed BCG maintenance schedule is what the author now uses, but it has yet to be proven by randomised clinical trials. The schedule is based on the goals of reducing side-effects and improving ability to tolerate the maintenance treatment. References [1] Melekos MD, Zarakovitis IE, Fokaefs ED, et al. Intravesical bacillus Calmette-Guérin versus epirubicin in the prophylaxis of recurrent and/or multiple superficial bladder tumours. Oncology 1996;53:281 8. [2] Lamm DL, Riggs DR, Shriver JS, vangilder PF, Rach JF, DeHaven JI. Megadose vitamins in bladder cancer: a double-blind clinical trial. J Urol 1994;151:21 6. [3] 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 meta-analysis of published results of randomized clinical trials. J Urol 2004;171:2186 90 quiz 2435. [4] Lamm DL, Blumenstein BA, Crawford ED, et al. Randomized intergroup comparison of bacillus Calmette-Guérin immunotherapy and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder a Southwest Oncology Group study. Urol Oncol 1995;1:119 26. [5] Shelley MD, Wilt TJ, Court J, Coles B, Kynaston H, Mason MD. Intravesical bacillus Calmette-Guérin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int 2004;93:485 90. [6] Sylvester RJ, van der Meijden AP, Witjes JA, Kurth K. Bacillus Calmette-Guérin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J Urol 2005;174: 86 91. [7] Shelley MD, Kynaston H, Court J, et al. A systematic review of intravesical bacillus Calmette-Guérin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU Int 2001;88:209 16. [8] Lamm DL, Reichert DF, Harris SC, Lucio RM. Immunotherapy of murine transitional cell carcinoma. J Urol 1982;128: 1104 8. [9] Rivera P, Orio M, Hinostroza J, et al. Our experience with 1 mg BCG vaccine instillation in T1 stage cancer of the bladder. Actas Urol Esp 1999;23:757 62.
european urology supplements 5 (2006) 654 659 659 [10] Pagano F, Bassi P, Piazza N, Abatangelo G, Drago Ferrante GL, Milani C. Improving the efficacy of BCG immunotherapy by dose reduction. Eur Urol 1995;27:19 22. [11] Malmstrom PU, Wijkstrom H, Lundholm C, Wester K, Busch C, Norlen BJ. 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guérin in patients with superficial bladder carcinoma. Swedish-Norwegian Bladder Cancer Study Group. J Urol 1999;161:1124 7. [12] Lamm DL, Blumenstein BA, Crawford ED, et al. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitionalcell carcinoma of the bladder. N Engl J Med 1991;325: 1205 9. [13] van der Meijden AP, Sylvester RJ, Oosterlinck W, Hoeltl W, Bono AV, EORTC Genito-Urinary Tract Cancer Group. Maintenance Bacillus Calmette-Guérin 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;44:429 34. [14] Herr HW. Tumor progression and survival of patients with high grade, noninvasive papillary (TaG3) bladder tumors: 15-year outcome. J Urol 2000;163:60 1. [15] 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;163:1124 9. [16] Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guérin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 2002;168:1964 70. [17] Lacombe L, Dalbagni G, Zhang ZF, et al. Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after bacillus Calmette-Guérin therapy: correlation to clinical outcome. J Clin Oncol 1996;14:2646 52. [18] Lebret T, Becette V, Barbagelatta M, et al. Correlation between p53 over expression and response to bacillus Calmette-Guérin therapy in a high risk select population of patients with T1G3 bladder cancer. J Urol 1998;159:788 91. [19] Lebret T, Becette V, Herve JM, et al. Prognostic value of MIB-1 antibody labeling index to predict response to Bacillus Calmette-Guérin therapy in a high-risk selected population of patients with stage T1 grade G3 bladder cancer. Eur Urol 2000;37:654 9. [20] Saint F, Irani J, Salomon L, Legrand P, Abbou CC, Chopin D. Urinary leukocytes as a new prognostic marker of therapeutic response and of adverse effects associated with the maintenance treatment with endovesical BCG, for the prophylaxis of superficial bladder tumors. Prog Urol 2001;11:1242 50.