The Optimal Approach in Superficial Bladder Cancer

BCG: The Optimal Approach in Superficial Bladder Cancer Proceedings of a Symposium held at the 14th European Association of Urology Congress, Stockholm, Sweden, April 8, 1999

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A. Böhle, Lübeck, Germany

10 figures and 13 tables, 2000

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Vol. 37, Suppl. 1, 2000

Contents

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BCG's Mechanism of Action – Increasing our Understanding Böhle, A.; for the EBIN Group (Lübeck)

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Preventing Progression and Improving Survival with BCG Maintenance Lamm, D.L. (Morgantown, W.Va.)

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Improved Patient Outcomes with BCG Immunotherapy vs. Chemotherapy – Swedish and Worldwide Experience Malmström, P.-U. (Uppsala)

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Sensitivity of BCG to Modern Antibiotics Durek, C. (Lübeck); Rüsch-Gerdes, S. (Borstel); Jocham, D.; Böhle, A. (Lübeck)

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The Effect of Isoniazid on BCG-Induced Toxicity in Patients with Superficial Bladder Cancer Al Khalifa, M.; Elfving, P.; Månsson, W.; Colleen, S. (Lund); Hellsten, S. (Malmö); Duchek, M. (Umeå); Nyberg, G. (Boden); Callaghan, P. (Halmstad); Rademark, C. (Helsingborg); Eriksson, R. (Karlshamn); Olsson, R. (Trelleborg); Hagberg, G. (Växjö); Nelson, C.E. (Ystad)

31

Modified Induction Course: A Solution to Side-Effects? Bassi, P.; Spinadin, R.; Carando, R.; Balta, G.; Pagano, F. (Padova)

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BCG Intravesical Instillations: Recommendations for Side-Effects Management Rischmann, P.; Desgrandchamps, F.; Malavaud, B.; Chopin, D.K. (Toulouse)

Open Discussion 37

BCG: The Optimal Approach in Superficial Bladder Cancer Böhle, A. (Lübeck)

40

Author Index and Subject Index

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Eur Urol 2000;37(suppl 1):1–8

BCG’s Mechanism of Action – Increasing our Understanding A. Böhle

for the EBIN Group1

Department of Urology, Medical University of Lübeck, Germany

Key Words BCG W Immunotherapy W Chemotherapy W Intravesical therapy W Superficial bladder cancer

Abstract BCG immunotherapy against superficial bladder carcinoma recurrences is regarded as the most successful to date. However, the mode of action has not yet been fully explained. In this field, several European groups have recently significantly contributed by adding more details to the complex picture of the immunological processes of BCG effector mechanisms. BCG inflammation obviously differs from non-specific inflammation by its quality and subclinical duration. Infiltration of immunocompetent cells into the bladder wall with secretion of cytokines into the urine has been characterized. Specific humoral responses of patients towards mycobacterial antigens have been determined. These data clearly present a large body of evidence that the inflammatory reaction induced by BCG correlates with the anti-tumour response. In vitro models of cytotoxic effector cells have shown interesting and selective effector mechanisms induced by BCG. Animal models have proven valuable in supporting ex vivo and in vitro data and in clarifying new

1 EBIN Members (in alphabetical order): P. Bassi, Padova; A. Böhle, Lübeck; E. de Boer, Amsterdam; S. Brandau, Borstel; D. Chopin, Créteil; H.-D. Flad, Borstel; D. Jocham, Lübeck; J. Palou, Barcelona; D. Schamhart, Amsterdam; A.R. Zlotta, Brussels.

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aspects of the application of BCG in vivo. Future research efforts will certainly add understanding to the immediate and long-term humoral and cellular responses. All our investigations intend to define clearly surrogate parameters for efficacy and side-effects, to increase therapeutic efficacy further and to decrease side-effects associated with this therapy. Only the collaborative efforts of several groups will be able to achieve a highly effective immunotherapeutic regimen against bladder carcinoma. Copyright © 2000 S. Karger AG, Basel

Since the discovery of the immuno-activating properties of BCG, a number of analyses of its mode of action have been undertaken. These studies show that several immunological phenomena are involved. The following review provides background information and initial insights into this important and interesting topic.

Animal Studies

Background and Development Inhibition of growth in implanted sarcomas, carcinomas and ascites tumours in mice after pre-treatment with BCG was initially demonstrated by Old et al. [1]. Following this, the fundamental work of Zbar and colleagues at the National Cancer Institute, USA, developed the use of BCG in oncology [2, 3]. Using the guinea pig hepatocarcinoma model, they showed that injection of BCG into

PD Dr. med. A. Böhle Medizinische Universität zu Lübeck Klinik für Urologie, Ratzeburger Allee 160 D–23538 Lübeck (Germany) Tel./Fax +49 451 500 6112, E-Mail [email protected]

tumour cells led to a significant inhibition of tumour growth. Intralesional injections of BCG caused regression of both tumours and lymph node metastases. Furthermore, BCG-treated animals developed immunity against hepatocarcinoma, as a re-challenge with tumour cells in surviving animals did not lead to tumour growth. From their studies, Zbar and colleagues established several rules for the optimal immunotherapy of tumours with BCG [3– 6]. E Localized tumours respond better to BCG immunotherapy than generalized tumours. E Tumour load should be as small as possible before starting immunotherapy. E A direct and prolonged contact between tumour cells and BCG is necessary. E In animal models, the optimum dose of BCG for local or intratumoural application was 106–108 living bacilli (colony forming units, CFU). Using the rat sarcoma model, further favourable responses to treatment with BCG were reported by Baldwin and Pimm [7]. Bartlett et al. also obtained good results with BCG in their model of spontaneous and chemicallyinduced mice tumours [8, 9]. Numerous further studies examined the inhibitory effect of BCG on tumours in rats, mice, hamsters and guinea pigs. Even systemic pre-treatment (prophylaxis) led to significant inhibition of tumour growth in some models. From these studies, it was established that high doses of living BCG bacilli (106–108 CFU) are needed for anti-tumour activity. Differences between several BCG strains were obvious in these studies, but this could be due to differences in the animal models used or the strains analysed [10, 11]. Sparks et al. showed that intralesional BCG injection before the removal of spontaneously occurring metastasized adenocarcinomas of rats not only prolonged their median survival time, but also led to a significant amount of animals remaining tumour-free during long-term follow-up [12]. BCG therapy can therefore be considered effective against occult minimal residual disease. Intravesical Immunotherapy in the Rodent Bladder Schamhart et al. performed studies in guinea pigs which showed that adherence of BCG to the bladder is necessary for the inflammatory response [13]. In a series of papers, Ratliff and co-workers focused on the importance of fibronectin for adhesion of BCG to the bladder wall [14–17]. They showed that BCG almost exclusively binds to fibronectin-coated walls and that adhesion can be inhibited by fibronectin antibodies and by soluble fibronectin. No differences in adhesion were

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apparent in a comparison of commercially available strains [16–18]. Continuing these experiments in animals, the authors found that BCG was retained in the bladder only if the bladder wall was damaged by chemical or mechanical means [14]. Again, the binding could be inhibited by soluble fibronectin or by antifibronectin antibodies. Furthermore, after inhibiting the binding of BCG, the typical hypersensitivity reaction did not occur and tumour rejection was not obvious. From these studies, it can be concluded that, at least in the animal model, fibronectin is essential for the binding of BCG to the bladder wall. A difference in the quality of cellular infiltrates in the bladder wall after intravesical instillation of thiotepa and BCG was determined by Guinan et al. [19]. They proposed a T-cell-dependent mode of action, which was subsequently confirmed by Ratliff et al. [20]: athymic nude mice, which are unable to generate T-cells, did not show a BCG-induced tumour rejection. Following the transfer of homologous T-cells to these mice, tumour rejection was re-established. These results were supported by further experiments in immunocompetent mice, showing that depletion of CD4+ (T-helper) and of CD8+ (T-suppressor) cells completely abolished the BCG-induced antitumour effect on implanted bladder carcinoma cells [21]. Also, this model showed that CD4+ cells were essential for the development of a delayed-type hypersensitivity reaction.

Analyses in Patients

Background and Development Around 1880, the cure of a patient with recurring lymphosarcoma after two erysipelas infections led W.E. Coley, an American surgeon, to use filtered bacterial extracts for adjuvant carcinoma therapy (‘Coley’s toxin’) [22]. The pronounced immunogenic activity of mycobacterial preparations was subsequently applied therapeutically by Freund [23] and then Mathé et al. used M. bovis BCG as an adjuvant systemic therapy against acute lymphoblastic leukaemia [24]. Initially promising results could not be reproduced, however, so this approach was abandoned. In 1966, Coe and Feldman showed that, like the skin, the bladder is able to mount a delayed-type hypersensitivity response to an antigenic challenge and, therefore, might be an ideal organ for local immunotherapy [25]. These results form the theoretical basis for topical intravesical immunotherapy in human beings, first reported by Morales et al. in 1976 [26].

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Ex vivo Analyses

The exact mode of action of intravesical BCG is not yet completely clear, though initially, a number of authors considered non-specific effects, such as erosive cystitis, to underlie the therapeutic mechanism of BCG [27]. A substantial body of evidence now points towards the involvement of the immune system. Systematic analysis of the local immune response in the bladder has been performed by several groups. Techniques include immunochemical analysis of infiltrating cellular subpopulations [28] and of locally detectable cytokines [29], as well as the analysis of patient urine for cytokine secretion [30]. These studies have characterized the immediate and long-term local immune response of patients to intravesical immunotherapy with BCG. Immunohistology In some immunohistological studies, cold-cup biopsies of patients with bladder carcinoma were performed before and during follow-up. Immunohistological analysis revealed interesting differences: before therapy, biopsies of tumour-free areas of the bladder showed only a low concentration of mononuclear cells. These were found suburothelially, and the urothelium was free of inflammatory cells. In T-cell subpopulations, a lower number of CD4+ (T-helper) cells, in comparison to CD8+ (T-suppressor) cells was visible. Before BCG therapy, the local T-helper:T-suppressor cell ratio in the bladder wall was 1:2. Macrophages were sparsely visible in the suburothelial stroma [28, 31]. After the 6th instillation of BCG, a pronounced inflammatory reaction of the whole bladder wall was visible. Mononuclear cells and polymorphonuclear granulocytes infiltrated the submucosa and were visible even in the urothelium and the musculature. The urothelium flattened but showed a layer of intact basal membrane. In all biopsies, aggregations of immunocompetent cells, so-called BCG-induced granulomas [32, 33], were visible. These follicle-like structures were detectable almost exclusively in the vascular-rich submucosa. The mononuclear cell infiltrate of the bladder wall after completion of the 6th BCG course consisted mainly of T-cells with a predominance of CD4+ over CD8+ cells within the granuloma. The ratio of CD4+:CD8+ cells was then 2:1, so showing an inversion of the ratio in the untreated bladder. Three months after the BCG treatment course, the cellular infiltrate of T- and B-cells concentrated in the persisting granulomas. Proliferation-associated antigens

BCG’s Mechanism of Action

yielded a high turnover rate within these cellular aggregates. These immunohistological characteristics persisted to later follow-up analyses at 6, 9 and 12 months after beginning therapy. The quantitative analyses of several cellular populations showed a characteristic course. Activated HLA-D expressor cells were at a maximum within 6 weeks of the BCG induction course and subsequently declined, together with IL-2 receptor positive cells. Even 1 year after the initial treatment, the ratio of local T-helper: T-suppressor cells was increased in favour of the T-helper phenotype. Immunohistological examinations after BCG therapy point towards a stimulation of the local immune system of the bladder. This differs significantly from nonspecific cystitis in both its persistence and quality. While nonspecific cytostatic drug-induced cystitis is characterized by a predominantly polymorphonuclear cell infiltration, BCG induces a pronounced increase of mononuclear (immunocompetent) cells, such as lymphocytes and macrophages. Together with this quantitative difference, a qualitative difference of cellular infiltrates after BCG is obvious. Before therapy, T-suppressor cells predominate in the bladder wall, whereas the ratio of T-helper:T-suppressor cells reverses completely during the instillation course. Infiltrating cells are activated, as can be demonstrated by expression of the so-called activation markers, including IL-2-R and HLA-DR. This characteristically activated cellular infiltrate persists for more than 12 months, predominantly in suburothelially-localized granulomas. The accumulation of large amounts of immunocompetent cells can be recognized as centres of long-term local immunoactivity. These immunohistological characteristics correlate well with analyses of inflammatory cells in the urine. Urinary inflammatory cells give an excellent reflection of the quality and time-course of the cellular changes in the bladder wall [34, 35]. Urinary Humoral Immune Response Several groups have analysed urinary cytokine secretion after BCG immunotherapy [30, 36–40]. Within 24 h of BCG instillation, significant secretion of interleukin-1 (IL-1), interleukin-2 (IL-2), tumour necrosis factor (TNF), interferon-Á and other cytokines was seen, though cytokine titres differed significantly between individual patients. Within 2 h of BCG instillation, significantly elevated cytokine titres could be detected, with a maximum after 2–8 h. These increased titres decreased to normal values within 24 h in most patients.

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In a control group of patients with nonspecific cystitis, only very low titres of urinary cytokines were detectable in occasional cases. Comparison of a group with BCGinduced cystitis and a group with nonspecific cystitis showed a significant difference in the total 24-hour secretion [30]. The secretion of these cytokines clearly highlights the immunological character of the BCG-induced reaction, which should not be inhibited unspecifically [41]. IL-1 was detected in the urine of both healthy and febrile patients [30, 42] and may be regarded as undiscriminating. The pronounced decrease of IL-2 and TNF after BCG treatment, however, indicates a separate aspect of the inflammatory process, differentiating it from nonspecific cystitis. Neither IL-2 [30, 43] nor TNF were found in the urine of healthy subjects and only in very few cases was IL-2 detectable in patients with nonspecific cystitis. IL-2 is predominantly produced by activated T-helper cells and induces proliferation and differentiation of T-lymphocytes. An effect on tumour cells is exerted mainly through the generation of lymphokine-activated killer cells (LAK-cells) which have been used clinically as immunotherapy for human carcinomas [44]. TNF-· is secreted by activated macrophages [45, 46] and has, among other effects, a direct cytotoxic action on tumour cells and an inhibitory action on the vasculature of tumours, resulting in hemorrhagic necrosis [1]. In principle, BCG-induced urinary concentrations of TNF should be high enough to exert a cytotoxic effect on tumour cells. Few groups have looked at the antibody response to BCG after BCG intravesical therapy [47–51]. In an early study, van der Sloot and colleagues characterized the antibody response in the urine and peripheral blood after BCG [48, 52]. Zlotta et al. have studied in more detail the humoral response to defined mycobacterial antigens or heat-shock proteins. They showed not only a specific lymphoproliferative response in the majority of patients, but also an increase in antibodies against mycobacterial antigens [49–51]. Increases in urinary albumin during the 6 weeks of BCG treatment were also observed [53], indicating a urothelial leakage which could facilitate the entry of BCG into deeper layers of the bladder. Detection of Cytokines in the Bladder Wall Cytokines can be detected in the bladder wall by immunohistochemistry. The advantage of this method is that it shows the long-term persistence of these immunomodulators at the locus of their production, and their

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action on mononuclear cells. Within 24 h of the 6th BCG instillation, an intensive reaction against the cytokines IL-1, IL-2 and TNF was indicated in nearly all biopsies. During further follow-up, a regression of this initially very pronounced reaction was seen. Patients showed a positive reaction against IL-2, but only half of the biopsies still showed IL-1- or TNF-positive cells. The initially high number of IL-2-receptor-positive cells per high-power field also regresses with time. The reaction was detectable for about 12 months in the bladder [29]. Prognostic Value of ex vivo Studies in Patients The prognostic relevance of urinary cytokines after intravesical BCG immunotherapy is unclear. From the pattern of cytokine secretion, the importance of a socalled Th1 response seems important for a favourable outcome [54]. As the amount of cytokine secretion correlates with the inflammatory reaction, it may be possible to obtain prognostic information about the patient’s antitumour response. This hypothesis was tested by Schamhart and colleagues, who looked at a group of 23 patients with superficial bladder carcinoma [55]. Following BCG instillations, cytokine titres in the urine were examined and correlated with tumour recurrence during the first 6 months. A significant correlation between the amount of IL-2 and an early recurrence was found (p = 0.003). This study, however, also showed that 2/10 patients (20%) had a high urinary IL-2 titre and another 20% of patients with a recurrence after 6 months had low urinary IL-2 titre. Thus, this analysis appears to be insufficiently specific to provide a clear prognosis for individual patients. In further studies, the extent of the cellular immune reaction in the bladder wall was correlated with therapeutic success [56, 57]. Quantitative immunohistochemical analysis of immunocompetent cells in the bladder wall showed that cellular infiltration was more pronounced in patients with successful therapy than in those who had recurrent tumours (p ! 0.05). It can therefore be concluded that the extent of the cellular immune reaction after BCG is correlated with therapeutic response. However, in both the present author’s immunohistological studies and in the aforementioned studies, significant interindividual variability was evident. The prognostic relevance for any given patient therefore cannot be calculated [28]. The humoral response to mycobacterial antigens was determined by Zlotta et al. [49–51]. Again, this group showed the correlation within a small patient group, but there was insufficient statistical power to apply this finding to individual patients. It is plain that a large amount of

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data in a high number of patients is needed. Only a cooperative effort by several scientific groups will be able to achieve this important and clinically significant aim. Until then, the relevance of the above mentioned immunologic phenomena to the antitumour efficacy of BCG will remain unclear.

In vitro Analyses

The aforementioned studies were able to characterize the local immune response to intravesical BCG therapy, qualitatively and quantitatively, and showed clear differences from nonspecific cystitis. The reaction clearly indicates a complex immune response of the host towards the local intravesical instillation. Further analysis of these phenomena as possible effector mechanisms against bladder carcinoma required the clarification of several events in the complex immune response, each analysed independently in vitro [58]. Direct Cytotoxic Activity of BCG Several groups have analysed the direct cytotoxicity of BCG on bladder carcinoma cells [58, 59]. Co-incubation of increasing concentrations of BCG with several bladder carcinoma cell lines did not show significant cytotoxicity, though some degree of cytostatic activity was apparent at higher concentrations. Under known clinical conditions, therefore, any directly cytotoxic effect of BCG on bladder carcinoma cells is not of fundamental importance to its mechanism of action. Cytotoxicity of Unstimulated Mononuclear Cells Immunocompetent cells are also detectable in the bladder wall before BCG instillation. In order to clarify whether these unstimulated immunocompetent cells (a significant amount of which can be regarded as natural killer cells) would be effective in killing urothelial carcinoma cells, we analysed their cytotoxicity [60, 61]. All five urothelial carcinoma target cell lines were resistant towards unstimulated urothelial peripheral blood mononuclear cells. The erytholeukaemia cell line, K562, which has a known natural killer cell sensitivity, was shown to be sensitive to unstimulated peripheral blood mononuclear cells (PBMC) in control experiments. Not only these bladder carcinoma cell lines, but also short-term cultures of fresh surgical specimens of papillary urothelial carcinomas, demonstrated such resistance towards unstimulated PBMC [62]. This might be seen as an indication that the immune system is, indeed, incom-

BCG’s Mechanism of Action

petent in fighting the established carcinoma without adequate stimulation. These observations also lend support to the relevance of in vitro results to the in vivo situation in man. Cytotoxicity of Lymphokine-Activated Killer Cells (LAK-Cells) Mononuclear cells can be stimulated by means of coincubation with IL-2 towards a so-called LAK-cell cytotoxicity. We, and others, tested the cellular cytotoxicity of LAK-cells on bladder carcinoma cells [60, 63–66]. The results showed that a pronounced cytotoxic effect on bladder carcinoma cells and fresh specimens of bladder carcinoma resections could be induced by IL-2 and interferon-Á. This mechanism, therefore, can be seen as a possible mode of action of intravesical immunotherapy with BCG. Cytotoxicity of BCG-Activated Killer Cells (BAK-Cells) To demonstrate BCG-induced effects on immunocompetent cells in the bladder wall, we examined activation of the cells by BCG itself [59]. Following pre-incubation of mononuclear cells with BCG for several days, a significant increase in cellular cytotoxicity towards several bladder tumour cell lines was detectable. This BCG-induced cytotoxicity was similar to LAK-cell cytotoxicity, with comparable efficacy of both effector cell types [59, 67, 68]. A large body of evidence indicates that LAK- and BCGactivated killer (BAK)-cells are two different effector cell populations, with a different type of cell pattern. This obviously independent cellular cytotoxicity was termed ‘BAK-cell cytotoxicity’. Further results showed that only viable BCG was able to generate BAK-cells, whereas subcellular fractions or cell-free supernatants were not able to induce BAK-cells [69]. All these data are relevant to the in vivo situation. An optimum dose-response, in vitro, was found at 3.5 ! 105 CFU/105 effector cells. Characterization of BCG-Activated Cytotoxic Effector Cells Further characterization of phenotype BAK-effector cells was consequently the next step in our studies [69, 70]. It is well known that LAK-cells have a maximum cytotoxicity after 2–3 days of stimulation with IL-2 [71]. In contrast, BAK-cell cytotoxicity does not reach its peak until the 7th day. In contrast to BAK-cells, LAK-cells can be generated from CD4+ or CD8+ depleted cell populations. Because of these differences, it can be concluded that BAK-cells do, indeed, represent different effector cell

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populations to LAK-cells, as BAK-cells might be activated through a different pathway from LAK-cells. Further experiments were designed to characterize the BAKeffector cell more precisely. We showed that neither macrophages nor CD4+ T-cells were relevant effector cells, whereas CD8+ and CD56+ effector cells, putatively natural killer cells, were the relevant effector cells for BCGinduced cytotoxicity. The induction of BAK-cell cytotoxicity seems to be very complex, as all mononuclear cell sub-populations which are detectable in the bladder wall contribute to the generation of BAK-effector cells. Recently, the existence of BAK-cells has been shown clinically in a cooperative project [68]. BAK-cell activity in the peripheral blood of patients increased over the course of BCG therapy. In several patients, the maximum BAK activity was apparent after the 4th instillation.

Conclusions and Outlook

In conclusion, a complex local immune response involving humoral and cellular immune mechanisms is induced by BCG in the human bladder. Long-term follow-up examinations show a predominance of the T-help-

er/inducer cell population and the persistence of inflammatory (Th1-type) cytokines in the bladder wall. These subclinical local inflammatory mechanisms persist for a long time within the so-called BCG-induced granulomas, and so might have an important role in the recurrencefree status of the patient. In vitro, at least two cellular cytotoxic effector mechanisms have been determined. In addition to the well-known LAK-cell cytotoxicity towards bladder carcinoma, a further cytotoxic phenomenon can be characterized, which has been termed ‘the BCG-activated killer cell phenomenon’. Both effector cell phenomena are MHC-unrestricted and, thus, kill their targets more or less non-specifically. The next step is to decipher which parts of the complex immune response target the tumour, and which parts contribute to the side-effects clearly associated with BCG immunotherapy. Enhancing the former and suppressing the latter would lead to an even better therapy. The collaborative effort of a group of researchers is needed to generate a large database of the immunological parameters of BCG instillation. This could be used to identify the factors involved in successful treatment, and so move further towards the goal of individualized and optimized BCG therapy.

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8 Bartlett GL, Zbar B, Rapp HJ: Suppression of murine tumor growth by immune reaction to the bacillus Calmette-Guérin strain of Mycobacterium bovis. J Natl Cancer Inst 1972;48: 245–257. 9 Bartlett GL, Kreider JW, Purnell DM, Katsilas DC: Augmentation of immunity to line 10 hepatoma by BCG. Comparison of different BCG preparations. Cancer 1980;46:488–496. 10 Mathé G, Halle-Pannenko O, Bourut C: BCG in cancer immunotherapy. II. Results obtained with various BCG preparations in a screening study for systemic adjuvants applicable to cancer immunoprophylaxis and immunotherapy. Natl Cancer Inst Monogr 1973;39:107–112. 11 Sher NA, Pearson JW, Chaparas SD: Effect of three strains of BCG against a murine leukemia after drug therapy. J Natl Cancer Inst 1973;51: 2001–2003. 12 Sparks FC, O’Connell TX, Lee Y-Y: Adjuvant preoperative and postoperative immunochemotherapy for mammary adenocarcinoma in rats. Surg Forum 1973;24:118–121. 13 Schamhart DH, de Boer EC, Bevers RF, Kurth K-H, Steerenberg PA: Mycobacterial adherence and BCG treatment of superficial bladder cancer. Prog Clin Biol Res 1992;378:75–80.

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14 Kavoussi LR, Brown EJ, Ritchey JK, Ratliff TL: Fibronectin-mediated Calmette-Guérin Bacillus attachment to murine bladder mucosa. Requirement of the expression of an antitumor response. J Clin Invest 1990;85:62–67. 15 Ratliff TL, Kavoussi LR, Catalona WJ: Role of fibronectin in intravesical bacillus CalmetteGuérin therapy for superficial bladder cancer. J Urol 1988;139:410–414. 16 Ratliff TL, Palmer JO, McGarr JA, Brown EJ: Intravesical BCG therapy for murine bladder tumors: Initiation of the response by fibronectin-mediated attachment of BCG. Cancer Res 1987;47:1762–1766. 17 Hudson MA, Ritchey JK, Catalona WJ, Brown EJ, Ratliff TL: Comparison of the fibronectinbinding ability and antitumor efficacy of various mycobacteria. Cancer Res 1990;50:3843– 3847. 18 Hudson MA, Brown EJ, Ritchey JK, Ratliff TL: Modulation of fibronectin-mediated bacillus Calmette-Guérin attachment to murine bladder mucosa by drugs influencing the coagulation pathways. Cancer Res 1991;51:3726– 3732. 19 Guinan PD, Shaw M, Ray V: Histopathology of BCG and Thiotepa treated bladders. Urol Res 1986;14:211–215.

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20 Ratliff TL, Gillen DP, Catalona WJ: Requirement of a thymus-dependent immune response for BCG-mediated antitumor activity. J Urol 1987;137:155–158. 21 Ratliff TL, Ritchey JK, Yuan JJJ, Andriole GL, Catalona WJ: T-cell subsets required for intravesical BCG immunotherapy for bladder cancer. J Urol 1993;150:1018–1023. 22 Coley-Nauts H, Fowler GA, Bogatko FH: A review of the influence of bacterial infection and of bacterial products (Coleys toxins) on malignant tumors in man. Acta Med Scand 1953;276:5–14. 23 Freund J: The mode of action of immunologic adjuvants. Adv Tuberc Res 1956;7:130–148. 24 Mathé G, Amiel J, Schwarzenberg L, Schneider M, Catton A, Schlumberger J: Acute immunotherapy for acute lymphoblastic leukemia. Lancet 1969;1:679–699. 25 Coe JE, Feldman JD: Extracutaneous delayed hypersensitivity, particularly in the guinea pig bladder. Immunol 1966;10:127–136. 26 Morales A, Eidinger D, Bruce AW: Intracavitary bacillus Calmette-Guérin in the treatment of superficial bladder tumors. J Urol 1976;116: 180–183. 27 Connolly JG: Re: Immunotherapy of superficial bladder cancer. Letter to the Editor. J Urol 1983;130:368. 28 Böhle A, Gerdes J, Ulmer AJ, Hofstetter AG, Flad H-D: Effects of local bacillus CalmetteGuérin therapy in patients with bladder carcinoma on immunocompetent cells of the bladder wall. J Urol 1990;144:53–58. 29 Böhle A, Busemann E, Gerdes J, Ulmer AJ, Flad H-D, Jocham D: Long-term immunobiological effects of intravesical bacillus CalmetteGuérin against bladder carcinoma recurrences; in Brown F, Revillard RP (eds): Developments in Biological Standardization. Standardization of the Immunopharmacology of Natural and Synthetic Immunomodulators. Basel, Karger, 1992, pp 199–209. 30 Böhle A, Nowc C, Ulmer AJ, Musehold J, Gerdes J, Hofstetter AG: Elevations of cytokines interleukin-1, interleukin-2, and tumor necrosis factor in the urine of patients after intravesical bacillus Calmette-Guérin immunotherapy. J Urol 1990;144:59–64. 31 Jackson AM, Alexandroff AB, McIntyre M, Esuvaranathan K, James K, Chisholm GD: Induction of ICAM 1 expression on bladder tumours by BCG immunotherapy. J Clin Pathol 1994;47:309–312. 32 El-Demiry MIM, Smith G, Ritchie AWS, James K, Cumming JA, Hargreave TB: Local immune responses after intravesical BCG treatment for carcinoma in situ. Brit J Urol 1987;60:543–548. 33 Papadimitriou JM, Spector WG: The ultrastructure of high- and low-turnover inflammatory granulomata. J Pathol 1982;106:37. 34 de Boer EC, de Jong WH, van der Meijden APM, Steerenberg PA, Witjes F, Vegt PDJ: Presence of activated lymphocytes in the urine of patients after intravesical immunotherapy with bacillus Calmette-Guérin. Cancer Immunol Immunother 1991;33:411–416.

BCG’s Mechanism of Action

35 de Boer EC, de Jong WH, van der Meijden APM, Steerenberg PA, Witjes F, Vegt PDJ: Leukocytes in the urine after intravesical BCG treatment for superficial bladder cancer. Urol Res 1991;19:45–50. 36 Jackson AM, Alexandroff AB, Kelly RW, Skibinska A, Esuvaranathan K, Prescott S: Changes in urinary cytokines and soluble intercellular adhesion molecule-1 (ICAM-1) in bladder cancer patients after bacillus CalmetteGuerin (BCG) immunotherapy. Clin Exp Immunol 1995;99:369–375. 37 Jackson AM, Prescott S, Hawkyard SJ, James K, Chisholm GD: The immunomodulatory effects of urine from patients with superficial bladder cancer receiving intravesical Evans BCG therapy. Cancer Immunol Immunother 1993;36:25–30. 38 de Boer EC, de Jong WH, Steerenberg PA, van der Meijden APM, Aarden AL: Leukocytes and cytokines in the urine of superficial bladder cancer patients after immunotherapy with BCG. In Vivo 1991;5:671–677. 39 de Boer EC, de Jong WH, Steerenberg PA, Aarden LA, Tetteroo E, de Groot ER: Induction of urinary interleukin-1 (IL-1), IL-2, IL-6, and tumor necrosis factor during intravesical immunotherapy with bacillus Calmette-Guérin in superficial bladder cancer. Cancer Immunol Immunother 1992;34:306–312. 40 de Boer EC, Somogyi L, de Ruiter GJW, de Reijke TM, Kurth K-H, Schamhart DH: Role of interleukin-8 in onset of the immune response in intravesical BCG therapy for superficial bladder cancer. Urol Res 1997;25:31–34. 41 de Boer EC, Steerenberg PA, van der Meijden APM, van Klingeren B, de Jong WH, Elgersma A: Impaired immune response by isoniazid treatment during intravesical BCG administration in the guinea pig. J Urol 1992;148:1577– 1582. 42 Kimball ES, Pickeral SF, Oppenheim JJ, Rossio JL: Interleukin 1 activity in normal human urine. J Immunol 1984;133:256–260. 43 Donohue JH, Rosenberg SA: The fate of interleukin-2 after in vivo administration. J Immunol 1983;130:2203–2208. 44 Rosenberg SA: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987;316:889–897. 45 Adolf GR, Lamche HR: Highly sensitive enzyme immunoassay for human lymphotoxin (tumor necrosis factor ß) in serum. J Immunol Meth 1990; 130:177–185. 46 Ernst M, Lange A, Flad H-D, Havel A, Ennen J, Ulmer AJ: Dissociation of responses measured by natural cytotoxicity and chemiluminescence. Eur J Immunol 1984;14:634–639. 47 Lamm DL, Thor DE, Winters WD, Stogdill V, Radwin H: BCG immunotherapy of bladder cancer: Inhibition of tumor recurrence and associated immune responses. Cancer 1981;48: 82–88.

48 van der Sloot E, Kuster S, Böhle A, Braun J, Wood WG: Towards an understanding of the mode of action of bacillus Calmette-Guérintherapy in bladder cancer treatment, especially with regard to the role of fibronectin. Eur J Clin Chem Clin Biochem 1992;30:503–511. 49 Zlotta AR, Drowart A, Van Vooren JP, Simon J, Schulman CC, Huygen K: Evolution of cellular and humoral response against tuberculin and antigen 85 complex during intravesical treatment with BCG of superficial bladder cancer. Acta Urol Belg 1994;62:63–68. 50 Zlotta AR, Drowart A, Huygen K, De Bruyn J, Shekarsarai H, Decock M: Humoral response against heat shock proteins and other mycobacterial antigens after intravesical treatment with bacille Calmette-Guérin (BCG) in patients with superficial bladder cancer. Clin Exp Immunol 1997;109:157–165. 51 Zlotta AR, Drowart A, van Vooren J-P, de Cock M, Pirson M, Palfliet K: Evolution and clinical significance of the T cell proliferative and cytokine response directed against the fibronectin binding antigen 85 complex of Bacillus Calmette-Guerin during intravesical treatment of superficial bladder cancer. J Urol 1997;157:492–498. 52 Böhle A, van der Sloot E, Richter E, Gerdes J, Wood WG, Jocham D: Binding to Fibronectin (FN) – a prerequisite step? Investigations on the role of FN in intravesical BCG immunotherapy; in Thüroff JW, Miller K, Jocham D (eds): Investigative Urology 5. Weinheim, Chapman and Hall, 1994, pp 100–104. 53 de Boer EC, DeReijke TM, Schamhart DHJ, Vos PCN, Kurth K-H: Increased urinary albumin indicating urothelial leakage following intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. Urol Res 1993;21: 423–427. 54 Jackson AM, James K: Understanding the most successful immunotherapy for cancer. The Immunologist 1994;2:208–215. 55 de Reijke TM, de Boer EC, Kurth K-H, Schamhart DHJ: Urinary cytokines during intravesical Bacillus Calmette-Guerin therapy for superficial bladder cancer: Processing, stability and prognostic value. J Urol 1996;155:477–482. 56 Prescott S, James K, Hargreave TB, Chisholm GD, Smyth JF: Intravesical Evans strain BCG therapy: Quantitative immunohistochemical analysis of the immune response within the bladder wall. J Urol 1992;147:1636–1642. 57 Bassi P, Milani C, Meneghini A, Garbeglio A, Aragona F, Zattoni F: Clinical value of pathologic changes after intravesical BCG therapy of superficial bladder cancer. Urology 1992;40: 175–179. 58 Hawkyard SJ, Jackson AM, James K, Prescott S, Smyth JF, Chisholm GD: The inhibitory effects of interferon gamma on the growth of bladder cancer cells. J Urol 1992;147:1399–1403. 59 Thanhäuser A, Böhle A, Flad H-D, Ernst M, Mattern T, Ulmer AJ: Induction of bacillus Calmette-Guérin-activated killer cells from human peripheral blood mononuclear cells against human bladder carcinoma cell lines in vitro. Cancer Immunol Immunother 1993;37: 105–111.

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60 Wang M-H, Flad H-D, Böhle A, Chen Y-Q, Ulmer AJ: Cellular cytotoxicity of human natural killer cells and lymphokine-activated killer cells against bladder carcinoma cell lines. Immunol Lett 1991;27:191–198. 61 Böhle A, Wang M-H, Flad H-D, Ulmer AJ: In vitro cellular cytotoxicity against human bladder carcinoma cell lines; in Jocham D, Thüroff JW, Rübben H (eds): Investigative Urology 4. Berlin, Springer, 1991, pp 131–139. 62 Schäfer I, Braasch H, Wang S, Ulmer AJ, Flad H-D, Jocham D: The cytotoxicity of natural killer cells ex-vivo against isolated autologous human urothelial bladder tumor cells (abstract). Urol Res 1995;23:286. 63 Wang AM, Chen Y-Q, Gercken J, Ernst M, Böhle A, Flad H-D: Specific activation of human peripheral blood Ù/‰+T lymphocytes by sonicated antigens of mycobacterium tuberculosis: Role in vitro in killing human bladder carcinoma cell lines. Scand J Immunol 1993; 38:239–246.

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64 Jackson AM, Alexandrov AB, Prescott S, James K, Chisholm GD: Role of adhesion molecules in lymphokine-activated killer cell killing of bladder cancer cells: Further evidence for a third ligand for leucocyte function-associated antigen-1. Immunology 1992;76:286–291. 65 Jackson AM, Hawkyard SJ, Prescott S, Ritchie AWS, James K, Chisholm GD: An investigation of factors influencing the in vitro induction of LAK activity against a variety of human bladder cancer cell lines. J Urol 1992;147:207– 211. 66 Böhle A, Durek C, Schäfer I, Brandau S, Ulmer AJ, Flad H-D: Die BCG-aktivierte Killerzelle: Untersuchung spezifischer Erkennungs- und Tötungsmechanismen zur Charakterisierung des Wirkprinzips der intravesikalen Immuntherapie mit Bacillus Calmette-Guérin. Akt Urol 1998;29:175–187. 67 Böhle A, Thanhäuser A, Ulmer AJ, Ernst M, Flad H-D, Jocham D: Dissecting the immunobiological effects of bacillus Calmette-Guérin (BCG) in vitro: Evidence of a distinct BCGactivated killer (BAK) cell phenomenon. J Urol 1993;150:1932–1937.

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68 Tawab NA, Brandau S, Maille P, Zamattio S, Böhle A: Evolution and clinical significance of BAK cell-mediated cytotoxicity against bladder tumor cell lines during intravesical treatment of superficial bladder cancer (abstract). Eur Urol 1998;34:245–302. 69 Thanhäuser A, Böhle A, Schneider B, Reiling N, Mattern T, Ernst M: The induction of bacillus Calmette-Guérin-activated killer cells requires the presence of monocytes/macrophages and T-helper type 1 cells. Cancer Immunol Immunother 1995;40:103–108. 70 Böhle A, Thanhäuser A, Ulmer AJ, Mattern T, Ernst M, Flad H-D: On the mode of action of intravesical Bacillus Calmette-Guérin: In vitro characterization of BCG-activated killer cells. Urol Res 1994;22:185–190. 71 Coplen DE, Marcus MD, Myers JA, Ratliff TL, Catalona WJ: Long-term follow-up of patients treated with 1 or 2, 6-week courses of intravesical Bacillus Calmette-Guérin: Analysis of possible predictors of response free of tumor. J Urol 1990; 144:652–657.

Böhle

Eur Urol 2000;37(suppl 1):9–15

Preventing Progression and Improving Survival with BCG Maintenance D.L. Lamm West Virginia University, Morgantown, W. Va., USA

Key Words BCG W Immunotherapy W Chemotherapy W Intravesical therapy W Superficial bladder cancer

Abstract BCG immunotherapy provides a superior reduction in tumour recurrence compared with chemotherapy. Unlike chemotherapy, however, it also appears to reduce disease progression. The benefit of BCG is long-term, but protection from disease progression without maintenance therapy is lost when comparisons are made after 15 years. Data suggest that optimal maintenance therapy with BCG provides even better protection from tumour recurrence, reduces disease progression and improves survival. Maintenance BCG schedules using single instillations at 1–3 month intervals have not been proved to be better than induction alone. However, a Southwest Oncology Group (SWOG) study using three, weekly instillations of Connaught BCG, found this regimen to be markedly superior. Before the introduction of BCG, carcinoma in situ (CIS) would progress to muscle invasion in 52% of patients. In the SWOG study, the additional instillations increased the complete response rate in CIS from the expected 68% to 84%. With maintenance BCG, longterm (7 years) tumour recurrence in high-risk patients reduced from the expected 52% with a single 6-week

ABC

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course to only 25% (p ! 0.000001). Worsening-free survival, defined as the absence of evidence of disease progression, including pathologic stage T2 or greater disease, or the need for systemic chemotherapy, radiation therapy or cystectomy, significantly increased (p ! 0.049, log rank test). In 391 randomized patients, the already excellent 86% survival at 4 years observed with induction therapy improved to 92% in patients receiving maintenance BCG (p ! 0.04). There is thus increasingly good evidence that BCG maintenance therapy, at the optimal treatment schedule, provides superior protection from tumour progression and recurrence, and improves longterm survival. Copyright © 2000 S. Karger AG, Basel

Introduction

Mortality rates from bladder cancer in the USA, relative to the annual incidence, fell from 28% to 22% between 1980 and 1999. The improved survival rate is thought to be associated with the advent and increased use of bacillus Calmette-Guérin (BCG) immunotherapy and cisplatinum-based chemotherapy in addition to general advances in diagnosis, surgery and medical management of malignancies. However, the observed reductions in mortality from bladder cancer – to which improved

Prof. D.L. Lamm West Virginia University Morgantown, WV 26506 (USA) Tel. +1 304 293 2706, Fax +1 304 293 2807 E-Mail [email protected]

treatment with BCG has contributed significantly – have not been matched for other malignancies. While combination chemotherapy is clearly responsible for the improvement in survival in non-seminomatous testis tumour, cure of metastatic bladder cancer with combination chemotherapy is uncommon. In the US intergroup study [1], less than 5% of patients treated with MVAC (methotrexate-vinblastine-doxorubicin-cisplatin) combination chemotherapy survived during long-term follow up, therefore, the observed improvement in survival of patients with bladder cancer may largely be a result of BCG immunotherapy. Reductions in disease progression and improvement in survival have been difficult to demonstrate with intravesical therapy to date. The results of historical trials of the treatment of bladder cancer, particularly the reduction in disease progression and mortality of carcinoma in situ (CIS) and stage T1, grade 3 (G3) transitional cell carcinoma (TCC) following BCG immunotherapy, will be the primary focus of this review. Controlled trials using early BCG treatment schedules vs. surgery alone or surgery plus intravesical chemotherapy are evaluated, and data that have shown improved success rates of BCG immunotherapy using a 3-week maintenance schedule are presented.

Table 1. Incidence of progression and muscle invasive disease in patients with CIS

Reference

In situ

Invasion (%) Years

Melamed et al., 1964 [6] Kulatilake et al., 1970 [7] Sharma et al., 1970 [8] Utz et al., 1970 [9] Yates-Bell, 1971 [10] Barlebo et al., 1972 [11] Anderson, 1973 [12] Riddle, 1974 [13] Diffuse Focal Skinner et al., 1974 [14] Althausen et al., 1976 [15] Starklint et al., 1976 [16] Farrow et al., 1977 [17] Koss et al., 1979 [18] Herr, 1983 [19]

25 5 17 62 3 10 15

9 (36) 3 (60) 14 (82) 37 (60) 3 (100) 0 (0) 12 (80)

!5 2 NA !5 !3 NA NA

23 13 59 12 43 58 13 24

18 (78) 1 (8) 49 (83) 10 (83) 23 (53) 8 (14) 7 (54) 23 (96)

1–11 1–16 NA 1.5 11 !5 1–6 1–3

382

217 (57)

Total

–

Table 2. Comparison of BCG strains in the treatment of CIS of the

bladder [21]

Historical Studies

The natural and clinical histories of bladder cancer prior to the advent of BCG have been well documented. The results of transurethral surgery alone and surgery combined with intravesical chemotherapy are equivalent in terms of progression and survival rates. In a previous review of the long-term results of intravesical chemotherapy, the authors found no evidence of continued protection from tumour recurrence, and no reduction in progression or mortality [2]. The combined European Organization for Research and Treatment of Cancer (EORTC) and Medical Research Council (MRC) meta-analysis involving more than 2,500 patients in controlled trials demonstrated a significant 7% reduction in tumour recurrence on 5-year follow up but found no evidence of reduction in disease progression [3]. There are many explanations for the failure of intravesical chemotherapy to reduce disease progression significantly. The incidence of tumour progression is less than that of recurrence thus, even with effective treatment a very large sample size would be required to demonstrate statistically significant differences. Patients with a lower risk for recurrence and progression have generally been included in European

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Eur Urol 2000;37(suppl 1):9–15

Strain/series

Total patients

Complete responses

Complete response rate, %

Range of response rates, %

Connaught/8 Tokyo/4 Pasteur/7 Tice/6 Evans/6 A. Frappier/6 S. African/1 Danish/1 Romanian/1 RIVM/1

450 111 230 277 180 145 13 42 33 15

357 86 171 197 117 87 9 28 21 9

79 77 74 71 65 60 69 67 64 60

70–92 63–84 40–80 56–82 53–88 39–100 – – – –

1,496

1,082

72

39–100

Total

studies, whereas the Southwest Oncology Group (SWOG) investigators have selected higher risk patients. Differences in progression are more difficult to demonstrate in low-risk populations. Many patients who are initially randomized to the control group receive subsequent intravesical chemotherapy after tumour recurrence therefore these studies are really comparing early with delayed

Lamm

Table 3. BCG-treated history of T1,

G3 TCC

Study

Patients

Progression Follow-up % months

Number of instillations

Dal Bo et al., 1990 [23] Cookson and Sarosdy, 1992 [24] Eure et al., 1992 [25] Meng and Danda, 1995 [26] Hurle et al., 1996 [27] Zhang et al., 1996 [28] Baniel et al., 1998 [29] Pansadoro et al., 1999 [30]

24 16 30 49 51 23 78 60

25 19 7 16 14 35 8 15

6 3 2 8 7 8 6 9

Total

37

14

22 59 39 60 33 45 56 74

treatment. Patients with G3, stage T1, carcinoma in situ (CIS) or prostatic urethral transitional cell carcinoma (TCC) may also be treated with cystectomy for recurrent tumour before stage progression occurs, particularly following failure of conservative intravesical therapy. These considerations may explain the apparent low efficacy of chemotherapy, though a review by Lamm [2] and the EORTC/MRC meta-analysis [3] found insignificant increases in tumour progression rather than a trend towards reduced progression in patients treated with intravesical chemotherapy. It is thus possible that chemotherapy is ineffective in preventing muscle invasion. Chemotherapy kills cells by direct contact, and cell kill is proportional to the concentration and duration of exposure to the drug [4]. Tumour cell contact with intravesical chemotherapy occurs as a result of diffusion down a concentration gradient. Cells that are most likely to extend into muscle (i.e., those in the deepest portion of the tumour) receive the least effective treatment. Chemotherapy is mutagenic, and previous investigations have shown that repeated instillation of chemotherapy into normal rodent bladders can induce invasive TCC [5]. Evidence that BCG immunotherapy reduces progression and mortality in bladder cancer has been difficult to obtain, but can be supported by historical data. Prior to the advent of BCG, the incidence of progression in patients with CIS was greater than 50% (table 1) and only about 50% of patients with muscle invasive disease were cured by radical cystectomy [20]. Although patients with CIS may be effectively treated by cystectomy, a recently published report of 138 CIS patients followed up for 11 years found that survival was not significantly improved by immediate cystectomy. BCG immunotherapy has resulted in a complete response in more than 70% of CIS patients of studies in published series (table 2) and in the

SWOG study [21]. A total of 65% of patients with CIS who have complete response to BCG remained disease free for 5 years or more [21, 22]. Additional data suggest that BCG treatment reduces progression of stage T1, G3 TCC in comparison with historical data. Prior to the advent of BCG, historical reviews reported a 33% incidence of stage progression in patients with T1, G3 TCC. Review of the reported results of BCG-treated patients shows the incidence of subsequent muscle invasive disease is reduced to 14% (table 3). It is possible that early cystectomy leads to an improvement in survival as observed in stage T1, G3 patients, but computer modelling using the Markov model suggests that survival can be improved with an initial trial of BCG followed by salvage cystectomy, if required. The estimated 5-year survival rates are about 82% in those treated with immediate cystectomy and 91% with BCG [26].

BCG Maintenance Therapy

Eur Urol 2000;37(suppl 1):9–15

Controlled Studies

Although historical evidence is encouraging, controlled trials are required to prove that BCG immunotherapy significantly reduces progression and improves survival in bladder cancer. Controlled studies of BCG immunotherapy have been hampered by problems similar to those observed in chemotherapy trials: (1) low incidence of progression and consequent requirement for a large sample size; (2) alternative treatment, including BCG, at the time of tumour recurrence; and (3) preemptive cystectomy in patients who are at high risk for invasion. Several controlled studies have found a reduction in disease progression associated with BCG immunotherapy. In the SWOG randomized comparison of Connaught BCG vs. doxorubicin chemotherapy, progression (which

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Table 4. Long-term results of BCG immunotherapy in 86 random-

ized high-risk patients [32, 33] Follow-up

Progression TUR TUR+BCG Cancer death TUR TUR+BCG

p value

5 years, %

10 years, %

35 28

63 38

0. 0063

32 14

45 25

0.03

TUR = Transurethral resection.

included the requirement for cystectomy) was reduced from 37% with doxorubicin to 15% with BCG [22]. In a similar randomized comparison of BCG immunotherapy vs. surgical treatment, Pagano et al. [31] observed a reduction in progression from 17% in controls to 4% in those treated with BCG (p ! 0.01). In the series from Memorial Sloan Kettering, BCG immunotherapy gave a significant reduction compared with TUR alone in tumour recurrence, progression and cancer mortality at 5 and 10 years (table 4) [32, 33]. Despite the more frequent use of cystectomy in the control group (42% at a median of 11 months vs. 26% in the BCG group at a median of 36 months), mortality was significantly reduced in the BCG group from 45% to 25% at 10 years (p = 0.03) [34]. However, at 15 years there was no significant advantage with BCG immunotherapy [35]. At this stage most patients in the control arm had been treated with cystectomy and/or BCG, so the ability to demonstrate any benefit of BCG was reduced. More importantly, by 15 years the immune stimulation induced by BCG would have waned. The crucial question is whether or not maintenance BCG therapy could have provided continued protection from disease progression.

Maintenance BCG Immunotherapy

The 6-week induction course of BCG originally described by Morales et al. [36] is highly effective in providing long-term benefit, but is now considered sub-optimal. Initial controlled trials of BCG maintenance were inconclusive, possibly as a result of the small sample size and short follow-up [37, 38]. The subsequent SWOG study, involving 384 patients followed-up over 10 years, used a

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Eur Urol 2000;37(suppl 1):9–15

superior 3-week maintenance schedule and clearly demonstrated the superiority of maintenance BCG. Remarkably, in addition to reducing tumour recurrence in highrisk patients, the 3-week maintenance schedule provides even further protection from disease progression and appears to improve survival [39]. The SWOG study, which opened for registration in 1985 and closed in 1987, involved 550 patients with recurrent stage Ta, T1, or in situ TCC who were randomized after 6-week induction to observation or additional BCG instillations at 3, 6, 12, 18, 24, 30 and 36 months. Subsequent instillations were given weekly for 3 weeks, with the second or third weekly instillation withheld if increased side-effects were seen with the previous instillation. With each intravesical instillation of 81 mg of Connaught BCG, percutaneous administration was given using the Tine technique. Following randomization, 384 patients were determined to be disease-free at the initial 3-month cystoscopic examination. Recurrence was reduced from 52% in the no-maintenance to 25% in the maintenance arm (p ! 0.0001) over 7 years follow-up. Unlike other BCG studies which have universally found that patients with CIS have the greatest reduction in tumour recurrence when BCG is compared with surgery or surgery plus intravesical chemotherapy: the maximum benefit in this study was seen in patients with rapidly-recurring TCC (fig. 1). This may relate to the mechanism of action of BCG. Optimal response in animal studies has occurred with juxtaposition of BCG and tumour cells [38]. With CIS, which is rarely removed with biopsy and fulguration, juxtaposition occurs with the initial course of BCG instillations. Papillary tumours are often completely resected, and tumour may not be present at the time of BCG instillation. With the 3-week maintenance regimen, treatment can be applied as new tumours develop. The recurrence-free survival rate for this regimen increased from 30% to 48% (p ! 0.0001). In addition to stage progression, cystectomy, radiation therapy, or the use of systemic chemotherapy were included as evidence of disease worsening. Worsening-free survival increased from 52% to 60% (p ! 0.04). The advantage of maintenance BCG in reducing disease progression does not begin until 2 years after the induction is completed (fig. 2). The separation in the worsening-free survival curves continues for the duration of the study. Overall survival increased from 51.8% to 57.8% (p = 0.08). Although not significant, the improved survival rate (fig. 3) appears to persist for the duration of the study, and in fact may be increasing. All patients will eventually

Lamm

Fig. 1. The maximum benefit of BCG maintenance was seen in patients with rapidly recurring TCC.

Fig. 2. The advantage of the 3-week BCG maintenance regimen in reducing disease progression does not begin until 2 years after induction.

Fig. 3. 10-year survival after 3-week BCG maintenance regimen (all

Fig. 4. Comparative effect of different BCG maintenance regimens

patients).

on tumour recurrence in SWOG studies. SWOG 8507 is the 3-week maintenance regimen.

die of other causes if not bladder cancer therefore these curves must eventually meet. The relative advantage of the 3-week maintenance regimen compared with other BCG treatment schedules used in Southwest Oncology Group studies are illustrated in figure 4. The BCG arms from two previously reported studies illustrate the results of BCG therapy in patients who were entered predominantly by the same institutions

which had enforced similar entry criteria (not randomized against the induction and maintenance arms of the 8507 study). These criteria were: (1) patients receiving single quarterly instillations (SWOG 8216) entered into the study between 1982 and 1985; (2) patients receiving monthly maintenance between 1987 and 1989; and (3) patients receiving 3-week maintenance entered between 1985 and 1987. The curves show a marked superiority of

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3-week maintenance therapy, therefore in accordance with other investigators [35–37] the authors suggest that monthly maintenance for 1 year and single quarterly maintenance for 2 years provides no improvement over induction alone. It is also interesting that the initial gradient of the 3-week maintenance recurrence curve is shallow, while each of the other three curves is initially steep. This may reflect the intensive treatment schedule that was used during the initial 6 months of the 3-week maintenance schedule. This intensive initial course of treatments was designed with specific consideration of the high initial rate of tumour recurrence. Using a 3-week maintenance therapy there is an apparent increase in the rate of tumour recurrence 1 year after completion of the prescribed course. To avoid increased side effects only 16% of patients received the full complement of 8 courses of BCG, but high-risk patients may require continued BCG maintenance beyond 3 years.

Conclusions

The development of BCG immunotherapy has greatly improved the prognosis of superficial bladder cancer, particularly CIS and stage T1, G3 tumours. Controlled studies using sub-optimal treatment schedules have demonstrated that intravesical BCG significantly reduces disease progression and cancer mortality in contrast to current chemotherapy. The improvement in survival in BCG-treated patients is apparent even with decreased use of radical cystectomy [37]. Demonstration of reduction in progression and mortality in patients with superficial bladder cancer is difficult, however, the 3-week maintenance BCG schedule results in a further significant reduction in disease progression and an apparent reduction in overall mortality.

References 1 Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Ragharan D, Loehrer PJ Sr, Trump D: Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: A cooperative group study. J Clin Oncol 1997;15:2564–2569. 2 Lamm DL: Long-term results of intravesical therapy for superficial bladder cancer; in Lamm DL (ed): The Urologic Clinics of North America. Philadelphia, WB Saunders Co., 1992, pp 573–580. 3 Pawinski A, Bouffioux C, Sylvester R, Parmar M, Smith P, Van der Meijden A and members of the EORTC-GU Group and the British MRC: Meta-analysis of EORTC/MRC random mixed clinical trials for prophylactic treatment of Ta,T1 bladder cancer. J Urol 1996;155: 492A. 4 Walker MC, Master JRW, Parris CN, Hepburn PJ, English PJ: Intravesical chemotherapy: In vitro studies on the relationship between dose and toxicity. Urol Res 1986;14:137–140. 5 Friedman D, Mooppan UM, Rosen Y, Kim H: The effect of intravesical instillations of thiotepa, mitomycin C, and adriamycin on normal urothelium: An experimental study in rats. J Urol 1991;145:1060–1063. 6 Melamed MR, Voutsa NG, Grabstald H: Natural history and clinical behavior of in situ carcinoma of the human urinary bladder. Cancer 1964;17:1533. 7 Kulatilake AE, Chisholm GD, Olsen EG: In situ carcinoma of the urinary bladder. Proc R Soc Med 1970;63:95–97.

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8 Sharma TC, Melamed MR, Whitmore WF Jr: Carcinoma in situ of the ureter in patients with bladder carcinoma treated by cystectomy. Cancer 1970;26:583–587. 9 Utz DC, Hanash KA Farrow GM: The plight of the patient with carcinoma in situ of the bladder. J Urol 1970;10:160–164. 10 Yates-Bell AJ: Carcinoma in situ of the bladder. Br J Surg 1971;58:359–364. 11 Barlebo H, Sorensen BL, Ohlsen AS: Carcinoma in situ of the urinary bladder. Flat intra-epithelial neoplasia. Scand J Urol Nephrol 1972;6: 213–223. 12 Anderson CK: Current topics in the pathology of bladder cancer. Proc R Soc Med 1973;66: 283–286. 13 Riddle PR: Urinary tuberculosis. Nurs Times 1974;70:1976–1978. 14 Skinner DG, Richie JP, Cooper PH, Waisman J, Kaufman JJ: The clinical significance of carcinoma in situ of the bladder and its association with overt carcinoma. J Urol 1974;112: 68–71. 15 Althausen AF, Prout GR Jr, Daly JJ: Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 1976;116: 575–580. 16 Starklint H, Jensen NK, Thyro E: The extent of carcinoma in situ in urinary bladders with primary carcinomas. Acta Pathol Microbiol Scand. 1976;84:130–136. 17 Farrow GM, Utz DC, Rife CC, Greene LF: Clinical observations on sixty-nine cases of in situ carcinoma of the urinary bladder. Cancer Res 1977;37:2794–2798. 18 Koss LG: Mapping of the urinary bladder: Its impact on the concepts of bladder cancer. Hum Pathol 1979;10:533–548.

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19 Herr HW: Carcinoma in situ of the bladder. Semin Urol 1983;1:15–22. 20 Lamm DL: Carcinoma in situ. Urol Clin North Am 1992;19:499–508. 21 Lamm DL: BCG immunotherapy for transitional-cell carcinoma in situ of the bladder. Oncology 1995;9:947–966. 22 Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA Jr, Sarosdy MF: A randomized trial of intravesical doxorubicin and immunotherapy with Bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med 1991;325:1205–1209. 23 Dal Bo V, Belmonte P, Veronesi A, Lo Re G, Miotto E, Merlo A, Volpe R, Francini M: Intravesical BCG instillations in patients with carcinoma in situ and pT1 G3 transitional cell carcinoma of the bladder (abstract 82). Eur Urol 1990;18(suppl 1):43. 24 Cookson MS, Sarosdy MF: Management of stage T1 superficial bladder cancer with intravesical bacillus Calmette-Guerin therapy. J Urol 1992;148:797–801. 25 Eure GR, Cundiff MR, Schellhammer PF: Bacillus Calmette-Guerin therapy for high risk stage T1 superficial bladder cancer. J Urol 1992;147:376–379. 26 Meng MV, Danda MG: Comparison of intravesical BCG to radical cystectomy for high grade, T1 transitional cell carcinoma using Markov decision tree analysis. J Urol 1995; 153:466A. 27 Hurle R, Losa A, Ranieri A, Graziotti P, Lembo A: Low dose Pasteur bacillus CalmetteGuerin regimen in stage T1, grade 3 bladder cancer therapy. J Urol 1996;156:1602–1605.

Lamm

28 Zhang GK, Uke ET, Sharer WC, Borkon WD, Bernstein SM: Reassessment of conservative management for stage T1N0M0 transitional cell carcinoma of the bladder. J Urol 1996;155: 1907–1909. 29 Baniel J, Grauss D, Engenstein D, Sella A: Intravesical Bacillus Calmette-Guerin treatment for stage T1 grade 3 transitional cell carcinoma of the bladder. Urology 1998:52:758– 789. 30 Pansadoro V, dePaula F, Emilozzi P: Long term follow-up of G3T1 Bladder tumors treated with intravesical BCG. Eur Urol 1999; 35(suppl 2):38. 31 Pagano F, Bassi P, Milani C, Meneghini A, Manizzi D, Garbeglio A: A low-dose bacillus Calmette-Guérin regimen in superficial bladder cancer therapy: is it effective? J Urol 1991; 146:32.

BCG Maintenance Therapy

32 Herr HW, Laudone VP, Badalament RA, Oettgen HF, Sogani PC, Freedman BD, Melamed MR, Whitmore WF Jr.: Bacillus Calmette-Guérin therapy alters the progression of superficial bladder cancer. J Clin Oncol 1988; 6:1450–1455. 33 Herr HW, Wartinger DD, Fair WR, and Oettgen HF: Bacillus Calmette-Guérin therapy for superficial bladder cancer: A 10-year follow-up. J Urol 1992;147:1020–1023. 34 Herr HW, Schwalb DM, Zhang ZF, Sogani PC, Fair WR, Whitmore WF Jr., Oettgen HF: Intravesical bacillus Calmette-Guérin therapy prevents tumour progression and death from superficial bladder cancer: Ten-year follow-up of a prospective randomized trial. Clin Oncol 1995;13:1404–1408. 35 Herr HW, Cookson MS, Sogani PC, Soloway SM, Wartinger D, Fair WR: Treated natural history of high risk superficial bladder cancer: 15 year follow-up. J Urol 1996;155:494A. 36 Morales A, Eidinger D, Bruce AW: Intracavitary bacillus Calmette-Guérin in the treatment of superficial bladder tumours. J Urol 1976;116: 180.

37 Badalament RA, Herr HW, Wong GY, Gnecco C, Pinsky CM, Whitmore WF Jr. Fair WR, Oettgen HF: A prospective randomized trial of maintenance versus nonmaintenance intravesical Bacillus Calmette-Guérin therapy of superficial bladder cancer. J Clin Oncol 1987;5: 441–449. 38 Hudson MA, Ratliff TL, Gillen DP, Haaff EO, Dresner SM, Catalona WJ: Single course versus maintenance Bacillus Calmette-Guérin therapy for superficial bladder tumours: A prospective, randomized trial. J Urol 1987;138:295– 298. 39 Lamm DL, Blumenstein B, Sarosdy M, Grossman HB, Crawford ED: Significant long-term patient benefit with BCG maintenance therapy: A Southwest Oncology Group Study. J Urol 1997;157:831.

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Improved Patient Outcomes with BCG Immunotherapy vs. Chemotherapy – Swedish and Worldwide Experience P.-U. Malmström Department of Urology, University Hospital, Uppsala, Sweden

Key Words BCG W Immunotherapy W Chemotherapy W Intravesical therapy W Superficial bladder cancer

Abstract Intravesical therapy of superficial bladder cancer has been in routine use since the introduction of thiotepa in 1961. An empirical approach has been used to optimize this kind of treatment – clinical data are, unfortunately, often lacking. Marker lesion studies indicate that BCG is more effective than cytostatic drugs. For the prophylaxis of recurring disease, the recurrence rate is lower with chemotherapy than in controls, but no effect on the risk of progression has been verified. None of the chemotherapy drugs used has proved superior to the others. Randomized trials have recently been performed with mitomycin C vs. BCG. Comparison of the different trials is difficult due to the use of different methodologies. The majority of the studies found BCG to be more effective in lowering the number of recurrences, but progression rates were not significantly different. Trials with combinations of BCG-mitomycin C or epirubicin-interferon have yielded promising results. Copyright © 2000 S. Karger AG, Basel

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Introduction

Intravesical chemotherapy has been in use since the early 1900s, when Herring reported the use of silver nitrate for vesical papilloma [1]. However, it was not until the introduction of thiotepa by Jones and Swinney in 1961 [2] that this kind of treatment became routinely used. Over the last few decades, the focus has been on both intravesical chemotherapy and immunotherapy.

Methodology The bladder lining is a poorly permeable membrane, but changes caused by tumours, inflammation and surgical scars can affect permeability profoundly. In vivo studies have shown higher serum concentrations of instilled drugs with inflamed as opposed to intact bladder epithelium [3]. Clinically, increased plasma concentrations of instilled drugs have been found during the first 3 days following transurethral resection (TUR) compared with treatments carried out after a longer period [4]. The diffusion of drugs across the bladder epithelium decreases in a linear fashion with increasing depth [5]. Consequently, deeper parts are less exposed to drugs given by instillation compared with those administered systemically. Low absorption has been a major goal to avoid systemic toxicity. Conversely, deep tissue penetration to reach deep-growing tumours, is also an advantage. Theoretically, giving drugs simultaneously by both intravesical and systemic routes may prove to be an interesting approach.

Dr. P.-U. Malmström Department of Urology University Hospital S–751 85 Uppsala (Sweden) Tel. +46 18 664639, Fax +46 18 559159, E-Mail [email protected]

Other variables influencing absorption are the chemical properties of the drug, such as molecular weight and lipid solubility. Low molecular weight and high lipid solubility favour penetration of the bladder wall. Factors within the bladder cavity also have a large impact on absorption. These include the administered dose, volume of instillate, residual urine, urine production and the duration of the drug in the bladder. The approach to optimizing the methodology for this kind of therapy seems to have been mainly empirical. Usually, the instilled amount is equal to the daily parenteral dose, with an instillation time of 1–2 hours. Certain aspects have been studied in more detail, particularly in vitro. Using computer simulations, six factors have been identified that affect treatment efficacy [6]. The estimated rank order of importance is: dose, residual urine volume, urine production, urine pH, dosing volume, and dwell time. Consequently, it was recommended that physicians use the highest dose with the least amount of diluent, prior dehydration and complete emptying of the bladder, and an extended dwell time. Clinical correlates on the effects of several of these procedures are, unfortunately, lacking.

Drugs

Chemotherapeutic Agents Almost all the currently available chemotherapeutic agents kill cancer cells by affecting DNA synthesis or function – processes that occur throughout the cell cycle. Each drug varies in the way it acts during the cell cycle. The most common drugs are thiotepa, mitomycin C, doxorubicin and epirubicin. Thiotepa, which is an alkylating agent, kills cells by directly attacking their DNA. This drug has a relatively low molecular weight and consequently is highly absorbed, creating a risk of systemic toxicity at higher doses. It is highly lipophilic and its action is cell cycle-phase nonspecific. The standard dose is 30–60 mg. Mitomycin C (MMC) is a potent alkylating agent when activated. It has a high molecular weight and is cell cyclephase non-specific. The standard dose is 20–60 mg. Doxorubicin and epirubicin are antitumour antibiotics. They act by binding with DNA and preventing RNA synthesis. Their action occurs mainly during the S-phase of the cell cycle. These drugs have a high molecular weight. The standard dose is 30–100 mg for doxorubicin and 30–80 mg for epirubicin.

tested and there seems to be no major difference in their antitumour activity. The dose is usually between 108–109 colony-forming units. Another drug in this category is interferon-·, a cytokine with proven activity. The usual dose is 30–100 MIU.

Clinical Results

Intravesical therapy has mainly been used for therapy of carcinoma in situ and as prophylaxis for recurring superficial disease. The European Organization for Research and Treatment of Cancer (EORTC) Genito-Urinary Group has documented the feasibility and safety of the marker lesion model. In this model, a well-defined tumour (marker lesion) is left in the bladder after transurethral resection (TUR) in patients with multiple primary or recurrent Ta–T1 bladder cancer. This permits objective evaluation of the antitumour activity of intravesically administered drugs [7]. In studies using the model, complete response was found in 50% of cases MMC and in 56% after epirubicin. Marker studies with BCG have usually reported a complete response in two-thirds of patients, in close agreement with our own results of 65%. These data indicate that BCG is more effective than cytostatic treatment. However, in most of the studies, it is questionable whether chemotherapy was administered under optimal conditions. In a recent marker lesion study, comparing different doses of interferon-· to MMC, the complete response rate for MMC was 72% (21/29 patients) with a dose of 40 mg dissolved in 20 ml sterile water. This is a higher response rate than is generally found in the literature – probably due to the higher concentrations of the drug in the bladder [Malmström et al., unpublished data]. In the prophylaxis of recurring disease, a meta-analysis of EORTC data [8] showed that the short-term (over 2–3 years) recurrence rate is 14% lower with chemotherapy than in controls. Long-term protection from tumour recurrence was more difficult to evaluate, but was calculated to provide a 7% benefit. No effect on the risk of progression could be found with chemotherapy in this analysis. None of the chemotherapy drugs used was superior to the others.

Immunotherapy The predominant immunotherapy is bacillus Calmette-Guérin (BCG). It induces a delayed hypersensitivity reaction that is presumed to be the main reason for its antitumour effect. The exact mechanisms of action are unknown, however. Different strains of BCG have been

Efficacy of BCG vs. Chemotherapy Direct randomized comparisons have recently been performed with mitomycin C and BCG. One of these trials was carried out by the Swedish-Norwegian Bladder Cancer Study Group and has recently been updated [9].

Experience with BCG Immunotherapy

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Fig. 1. Proportion of all patients (n = 250) disease-free after a median follow-up of about 5 years – BCG vs. MMC.

Fig. 2. Proportion of patients with papillary disease (n = 167) disease-free after a median follow-up of about 5 years – BCG vs. MMC.

Fig. 3. Proportion of patients with non-papillary disease (n = 83)

disease-free after a median follow-up of about 5 years – BCG vs. MMC.

Fig. 4. Proportion of patients receiving crossover therapy (n = 60) who were free of disease recurrence – second-line BCG vs. secondline MMC.

This was a randomized comparison of either MMC, 40 mg, or BCG (Danish strain 1331), 120 mg, containing 109 colony forming units. Both MMC and BCG were dissolved in 50 ml saline. Therapy was started 1–3 weeks after TUR or biopsy. Treatments were given weekly for 6 weeks, then monthly for the remainder of 1 year, and subsequently every third month during the second year. Patients with stage Ta, grades 1 to 3, or stage T1, grades 1 and 2 tumours, were included, provided that the patient had demonstrated at least three tumour events during the 18 months before inclusion. Patients with T1, grade 3, and patients with primary or concomitant dysplasia or carcinoma in situ (CIS) were included, even if they had

not had previous tumour events. Patients presenting with both papillary and non-papillary lesions were classified as concomitant dysplasia or carcinoma in situ. Between 1987 and 1992, 261 patients were enrolled. After a median follow-up of about 5 years (64 months, range 5–106), 101 of the evaluable 250 patients (42%) were disease-free. When comparing the two treatment arms, a significant difference (log rank test) in favour of BCG was found, p = 0.04;42/125 (34%) disease-free in the MMC group and 59/125 (47%) disease-free in the BCG group (fig. 1). In patients with papillary disease, 28/83 (34%) remained disease-free after MMC and 36/84 (43%) after BCG therapy, p = n.s. (fig. 2). The corresponding

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Malmström

Table 1. Intravesical mitomycin-C vs. BCG – Results of randomized prospective studies

Reference

BCG strain (dose (CFU))

MMC dose

Treatment duration

Conclusion

Rintala et al. [13]

Pasteur F (6 ! 108) Tice and RIVM (5 ! 108) RIVM (5 ! 108)

20–40 mg

24 months

BCG superior

30 mg

MMC: 6 months BCG: 1–2 ! 6-weekly MMC: 6 months BCG: 1–2 ! 6-weekly

Tice (5 ! 108) Connaught (1 ! 109) Pasteur D (1 ! 109)

20 mg

12 months

RIVM and MMC superior to Tice No difference MMC superior reg. progression in Tis negative BCG superior

20 mg

MMC: 6 months BCG: 6, weekly + 4 months 24 months

Vegt et al. [10] Witjes et al. [14]

Lamm et al. [12] Krege et al. [11] Malmström et al. [9]

30 mg

40 mg

No difference BCG superior

results for non-papillary disease were 14/42 (33%) and 23/ 41 (56%), respectively, p = 0.07 (fig. 3). Tumour progression occurred in 47/250 (19%) of the patients (27/125 in the MMC arm and 20/125 in the BCG arm) with no significant difference between the arms. The calculated risk of progression for initial stage was 11% in Ta, 31% in T1, 9% in dysplasia, and 23% for those with CIS. The corresponding rate for grade was G1 7%, G2 19% and G3 23%. Seventy-four patients died. The crude 5-year survival was 80% and 75% for the MMC and BCG groups respectively, p = n.s. Thirty-three of these died of bladder cancer, of whom 14 were treated with MMC and 19 were treated with BCG. The corrected 5-year survival was 90% and 88% respectively, a difference that was not significant. According to the protocol, crossover treatment was possible for non-responders. It was administered in 60 patients; 39 patients had their treatment changed from MMC to second-line BCG and 21 patients from BCG to second-line MMC. Nineteen of the sixty patients (32%) remained free of recurrences;15/39 (39%) with secondline BCG and 4/21 (19%) with second-line MMC, p = n.s. (fig. 4). In this study therapy with BCG was superior to MMC for recurrence prophylaxis, but no difference was found in the effects of treatment on either progression or survival. Comparison with other BCG/MMC trials [10–13] is difficult due to the use of different BCG strains, MMC dose and concentration, and instillation schedules. The majority of studies found BCG to be more effective in

lowering the number of recurrences, but progression rates were not found to be significantly different (table 1).

Experience with BCG Immunotherapy

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Combination Treatment Combination therapy uses agents that differ in both the ways they act and their side-effects. This is done to achieve a maximum antitumour effect with the minimum of side-effects. Because tumour cells have different biological characteristics, combining drugs may effectively eliminate the resistance of cancer cells to a single agent. A Nordic trial of BCG combined with MMC vs. BCGonly in patients with carcinoma in situ has recently been reported [15]. With 308 patients enrolled, both treatment arms had 73% of no evidence of disease at the 1-year follow-up, but side-effects were more common in the BCGonly arm. In a study from Finland, the combination of epirubicin and interferon-Á yielded promising results [16]. Combining the two types of treatment appears to be beneficial.

The Future

In vitro tumour models of cytotoxic resistance could support the development of new cytotoxic drugs and the selection of suitable drugs for individual patients. We investigated whether the testing of tumour cells from patients with urinary bladder carcinoma by fluorometric microculture cytotoxicity assay (FMCA) could provide clinically relevant data for these tumour types [17]. Blad-

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der carcinomas were essentially as sensitive as those of the breast and ovary, but had a steeper dose-response relationship. Among the investigational drugs, gemcitabine, paclitaxel and suramin showed particularly promising activity in vitro, such that clinical trials with intravesical administration of paclitaxel and suramin have been started.

In conclusion, therapy with adjuvant intravesical chemotherapy reduces the risk of tumour recurrence but has no effect on the risk of progression. BCG is superior to chemotherapy for carcinoma in situ, but in Ta–T1 disease the efficacy is similar to chemotherapy. Preliminary data on the combination of immunotherapy and chemotherapy are promising.

References 1 Herring HT: The treatment of vesical papilloma by injections. Br Med J 1903;ii:1398. 2 Jones HC, Swinney J: Thiotepa in the treatment of tumours of the bladder. Lancet 1961;ii: 615–620. 3 Schmidbauer CP, Porpaczy P, Georgopoulos A, Rameis H: Absorption of doxorubicin hydrochloride and mitomycin C after instillation into non-infected and infected bladders of dogs. J Urol 1984;131:818–821. 4 Dalton JT, Wientjes MG, Badalament RA, Drago JR, Au JL: Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients. Cancer Res 1991;51:5144–5152. 5 Badalament RA, Farah RN: Treatment of superficial bladder cancer with intravesical chemotherapy. Semin Surg Oncol 1997;13:335– 341. 6 Wientjes MG, Badalament RA, Au JL: Use of pharmacologic data and computer simulations to design an efficacy trial of intravesical mitomycin C therapy for superficial bladder cancer. Cancer Chemother Pharmacol 1993;32:255– 262. 7 Bono AV, Hall RR, Denis L, Lovisolo JA, Sylvester R: Chemoresection in Ta-T1 bladder cancer. Members of the EORTC Genito-Urinary Group. Eur Urol 1996;29:385–390. 8 Pawinski A, Sylvester R, Kurth KH, Bouffioux C, van der Meijden A, Parmar MK, Bijnens L: A combined analysis of European Organization for Research and Treatment of Cancer, and Medical Research Council randomized clinical trials for the prophylactic treatment of stage Ta-T1 bladder cancer. European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council Working Party on Superficial Bladder Cancer. J Urol 1996;156:1934–1941.

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9 Malmström PU, Wijkstrom H, Lundholm C, Busch C, Wester K and Norlen BJ: Five-year follow-up of a randomized prospective study comparing intravesical instillations of mitomycin-C and Bacillus Calmette-Guérin in patients with superficial bladder carcinoma. J Urol. 1999 ;161:1124–1127. 10 Vegt PD, Witjes JA, Witjes WPJ, Doesburg WH, Debruyne FMJ, van de Mejden APM: A randomized study of intravesical Mitomycin C, Bacillus Calmette-Guérin Tice and Bacillus Calmette-Guérin RIVM treatment in pTa-pT1 papillary carcinoma and carcinoma in situ of the bladder. J Urol 1995;153:929–933. 11 Krege S, Giani G, Meyer R, Otto T, Rubben H: 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-Guérin. Participating Clinics [see comments]. J Urol 1996; 156:962–966. 12 Lamm DL, Blumenstein B, Crawford ED, Crissman JD, Lowe BA, Smith JA, Sarosdy MF, Schellhammer PF, Sagalowsky AI, Messing EM, Loehrer P, Grossman HB: Randomized intergroup comparison of Bacillus Calmette-Guérin immunotherapy and mitomycin C chemotherapy in superficial transitional cell carcinoma of the bladder. Urol Oncol 1995;1: 119–126.

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13 Rintala E, Jauhianien K, Alfthan O, Hansson E, Juusela H, Kanerva K, Korhonen H, Permi J, Sotarauta M, Vaalasti T: Intravesical chemotherapy (MMC) versus immunotherapy (BCG) in superficial bladder cancer. Eur Urol 1991; 20:19–25. 14 Witjes JA, van der Meijden AP, Sylvester LC, Debruyne FM, van Aubel A, Witjes WP: Longterm follow-up of an EORTC randomized prospective trial comparing intravesical bacillus Calmette-Guerin-RIVM and mitomycin C in superficial bladder cancer. EORTC GU Group and the Dutch South East Cooperative Urological Group. European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group. Urology 1998;52:403–410. 15 Wijkström H, Kaasinen E, Malmström PU, Hellsten S, Duchek M, Wahlkvist R, Rintala E: Intravesical instillations with alternating mitomycin C and BCG or BCG alone in carcinoma in situ of the urinary bladder. A Nordic study (abstract 155). Eur Urol 1999;39:155. 16 Raitanen MP, Lukkarinen O: A controlled study of intravesical epirubicin with or without alpha 2b-interferon as prophylaxis for recurrent superficial transitional cell carcinoma of the bladder. Finnish Multicentre Study Group. Br J Urol 1995;76:697–701. 17 Nygren P, Cso´ka K, Larsson R, Busch C, Wester K, Malmström PU: Activity of standard and investigational cytotoxic drugs in primary cultures of tumor cells from patients with kidney and urinary bladder carcinomas. (Manuscript submitted)

Malmström

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Sensitivity of BCG to Modern Antibiotics C. Durek a S. Rüsch-Gerdes b D. Jocham a A. Böhle a a Department of Urology, Medical University of Lübeck, and b Department of Mycobacteriology, National Reference Centre for Mycobacteria, Forschungszentrum Borstel, Germany

Key Words Bacillus Calmette-Guérin W BCG W Antibiotics W Cycloserine W Immunotherapy W Bladder cancer

Abstract The viability of bacillus Calmette-Guérin (BCG) in intravesical instillation therapy has been demonstrated to be crucial for the prevention of bladder tumour recurrence. The aim of the present study was to determine the effects of modern antibacterial chemotherapeutics on BCG viability, particularly cycloserine, which has been recommended in the treatment of BCG-induced sepsis. The minimal inhibitory concentrations (MICs) of 32 antibacterial drugs potentially effective against the Connaught BCG strain were measured in vitro by the radiometric BACTEC 460TB method. The MICs were compared with the drug concentrations achievable in blood and urine. Susceptibility testing of cycloserine was performed with three different strains (Connaught, Tice and RIVM), using the modified proportion method, as defined in the German guidelines for anti-tuberculosis drug testing. The Connaught BCG strain was highly susceptible to fluoroquinolones, but was resistant to ß-lactams, macrolides (except clarithromycin), and some aminoglycosides. It was also sensitive to doxycycline and gentamicin at dosages that typically occur in the urine of patients after a normal dose. Connaught BCG was susceptible to all the tuberculostatic drugs tested, except for pyrazinamide. All

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the BCG strains analysed were resistant to cycloserine. During intravesical BCG instillation therapy, simultaneous administration of fluoroquinolones, doxycycline or gentamicin should be avoided. In cases of severe systemic complications, or if one of the antituberculosis drugs is not tolerated, fluoroquinolones may be used. Cycloserine is no longer recommended for the early treatment of BCG sepsis. Copyright © 2000 S. Karger AG, Basel

Introduction

Intravesical BCG immunotherapy is widely used to prevent recurrences of superficial bladder carcinoma and for carcinoma in situ of the bladder. In controlled, prospective studies, BCG has been shown to be superior to intravesical chemotherapy for bladder cancer [1, 2]. The exact mode of the antitumor action of BCG still remains to be defined. However, viability of the BCG strain has proved to be a crucial factor in obtaining the high therapeutic efficacy that has been observed in clinical and animal studies [3–5]. Local and systemic side-effects, such as dysuria, lowgrade fever and malaise, frequently occur during BCG instillation therapy. Bacterial cystitis is a common complication of any instillation therapy. In rare cases, severe systemic side-effects (e.g. sepsis) have been observed [6].

PD Dr. A Böhle Department of Urology, Medical University of Lübeck Ratzeburger Allee 160 D–23538 Lübeck (Germany) Tel./Fax +49 451 500 6112, E-Mail [email protected]

Modern antibiotics (fluoroquinolones or third-generation cephalosporins) are commonly used for prophylactic purposes, and even for uncomplicated urinary tract infections. Given their ubiquity, it is important to determine the effects of these drugs on the viability of BCG. For example, though a decrease in immunotherapeutic activity after short-term isoniazid (INH) administration is not seen [7], long-term treatment, at least in animal studies, leads to a reduction of the antitumour effect of BCG [8]. In cases of severe systemic life-threatening side-effects, cycloserine has been proposed as the treatment of choice, because of its rapid in vitro killing within 24 hours, compared with days for other antituberculosis drugs [9]. In the literature, however, there is some disagreement as to the sensitivity of BCG to cycloserine [10, 11]. In order to evaluate this treatment recommendation for patients with BCG sepsis, we investigated different BCG strains for their susceptibility to cycloserine.

Methods Antimicrobial Susceptibility Testing The BACTEC 460TB system (Becton Dickinson Diagnostic Instruments, Sparks, Md., USA) is a radiometric detection method. As mycobacteria metabolize the broth substrate, 14CO2 is released. The amount of 14CO2 produced is directly proportional to the amount of growth occurring in the medium. This method of susceptibility testing has previously been described [12]. The minimal inhibitory concentration (MIC) was defined as the lowest drug concentration that inhibited more than 99% of the bacterial population. The culture medium was 7H12 Middlebrook TB medium, containing Middlebrook 7H9 caseine hydrolysate, albumin, catalase and 14C-labelled palmitic acid. This technique was developed by correlating the radiometric growth index (GI) readings in drug-containing vials with the increase rate in the drug-free control vials. MIC, as determined radiometrically in the BACTEC 460TB system, was defined as the lowest drug concentration (Ìg/ml) in the presence of which the daily GI increase was less than that in the controls, given that the GI in the controls was not greater than 30, observed on 3 consecutive days of cultivation. Antimicrobial Drugs Antimicrobial agents were diluted with distilled water or DMSO solution and adjusted to different concentrations until the exact MIC was obtained. In this study, the following antituberculosis drugs were tested: amikacin, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, rifabutin, rifampicin and streptomycin. Other antibiotics tested were: amoxycillin, amoxycillin-clavulanic acid, azithromycin, carbenicillin, cefaclor, cefoxitin, ciprofloxacin, clarithromycin, doxycycline, erythromycin, fosfomycin (trometamol salt), gentamicin, kanamycin, nitrofurantoin, norfloxacin, ofloxacin, pipemidic acid, sulfoxazole, tetracycline, tobramycin, trimethoprim and trimethoprim-sulfamethoxazole.

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Eur Urol 2000;37(suppl 1):21–25

BCG Preparation All drug susceptibility tests except those for cycloserine were performed with BCG strain Connaught (Lot 738-11), kindly provided by Pasteur Mérieux Connaught, Toronto, Canada. For cycloserine testing, we used the three major BCG strains that are commercially distributed: Connaught, Tice (Apogepha, Dresden, Germany), and RIVM (Medac, Hamburg, Germany). The Connaught strain was seeded on Löwenstein-Jensen agar (Merck, Darmstadt, Germany) and grown under standard conditions at 37 ° C. BCG suspension (0.5 ml in 0.9% NaCl) was inoculated in a BACTEC vial (the seed vial). The contents of the seed vial were homogenized and used to inoculate all the drug-containing vials (0.1 ml/vial). The working solution from the seed vial was further diluted to 1:100, and 0.1 ml of this was inoculated into a drug-free vial as the 1:100 control. Vials were incubated at 37 ° C and GI measurements were performed daily. Cycloserine Susceptibility Testing Cycloserine susceptibility testing was performed using a modified proportion method with a Löwenstein-Jensen medium, according to the German guidelines [13]. This method is a serial dilution assay that uses a modification of the proportion method described by Canetti and Grosset [14]. If mycobacterial growth at a certain critical concentration of cycloserine is 110% of the inocula, the isolate is considered resistant. The critical concentration for cycloserine on Löwenstein-Jensen agar in the German guidelines (DIN 58943-8) is 16 Ìg/ml.

Results

BCG was not susceptible to penicillin derivatives, including ß-lactams and cephalosporins. It was, however, susceptible to aminoglycosides such as amikacin, streptomycin and kanamycin. Furthermore, gentamicin and tobramycin, which are frequently used in hospitalized urology patients, were also effective against BCG. As these drugs reach high urinary concentrations at their usual dosages [12], they may interfere with BCG in the bladder. Clarithromycin was highly effective against BCG, but other macrolides, such as erythromycin and azithromycin, were less active. Among the tetracyclines, only doxycycline showed a MIC that corresponded well to drug levels occurring in urine, but rarely to levels occurring in the sera of patients [15]. Of the fluoroquinolones, ciprofloxacin and ofloxacin were highly effective against BCG at concentrations that are reached in the sera and urine of patients at the usual dosage. Norfloxacin showed an MIC of 4 Ìg/ml and was found to be less effective against BCG. Other antibiotics, such as nitrofurantoin, trimethoprimsulfamethoxazole and pipemidic acid did not show a pronounced activity against Connaught BCG. All antimycobacterial drugs were highly effective, except for pyrazinamide (MIC 1800 Ìg/ml).

Durek/Rüsch-Gerdes/Jocham/Böhle

Table 1. Results of BCG (strain Connaught

[Lot 738-11]) susceptibility testing

MIC, Ìg/ml

Sensitivitya

Group

Drug

Antituberculosis drugs

Capreomycin Ethambutol Ethionamide Isoniazid Pyrazinamide Rifampicin Rifabutin

0.5 2 4 0.125 1800 !0.031 0.063

Aminoglycosides

Amikacin Gentamicin Kanamycin Streptomycin Tobramycin

0.125 4 1 0.25 8

sensitive (sensitive)b sensitive sensitive resistant

ß-Lactams (penicillinderivatives)

Amoxicillin Amoxicillin-clavulanic acid (ß-lactamase inhibitor) Carbenicillin

128

resistant

32 1256

resistant resistant

ß-Lactams (cephalosporins)

Cefaclor Cefoxitine Ceftriaxone

256 1256 1256

resistant resistant resistant

Macrolides

Azithromycin Clarithromycin Erythromycin

16 0.25 16

resistant sensitive resistant

Tetracyclines

Tetracycline Doxycycline

16 4

resistant (sensitive)b

Fluoroquinolones

Ciprofloxacin Norfloxacin Ofloxacin

0.125 4 !0.031

sensitive resistant sensitive

Others

Nitrofurantoin Sulfoxazole Trimethoprim Trimethoprim-sulfamethoxazole Fosfomycin (trometamol salt) Pipemidic acid

64 32 1128 1128 132 128

resistant resistant resistant resistant resistant resistant

sensitive sensitive sensitive sensitive resistant sensitive sensitive

a

By comparison of MIC value with serum levels in patients [15]. Urinary levels of these antibiotics make them useful for the treatment of BCG cystitis but plasma levels render them ineffective for the treatment of systemic BCG reactions or infections.

b

The MIC values of all drugs tested are summarized in table 1.

Table 2. Cycloserine susceptibility

Strain

Cycloserine Testing BCG was resistant to cycloserine. The critical concentration for cycloserine, determined by the modified proportion-method, was 116 Ìg/ml for all strains tested (table 2).

Drug concentration Ìg/ml

Sensitivity (DIN)1

BCG-Connaught BCG-Tice BCG-RIVM

116 116 116

resistant resistant resistant

Sensitivity of BCG to Antibiotics

Eur Urol 2000;37(suppl 1):21–25

1

As defined by the German guidelines [13].

23

Discussion

Intravesical BCG instillation therapy in patients suffering from superficial bladder cancer has been demonstrated to be the most effective adjuvant regimen for the prevention of tumour recurrence [2, 16]. In clinical and animal studies, the viability of BCG has been shown to be crucial for its antitumor activity [3–5, 17–19]. The majority of patients complain about cystitis-like side-effects, such as dysuria, urinary frequency and urgency, or fever [20, 21]. Furthermore, nonspecific bacterial cystitis is a common complication of repeated bladder instillations, sometimes leading to postponement or even cessation of therapy [6]. For these reasons, many urologists prescribe prophylactic antimicrobial drugs before and during instillation therapy. Fluoroquinolones are of major interest, as these drugs are well-tolerated, provide a wide antibacterial spectrum and have rapid tissue penetration. They are poorly metabolized, with 50–90% of an oral dose recovered in the urine [22]. Therefore, quinolones are often used by urologists in the treatment of uncomplicated urinary tract infections. In a few cases, however, severe systemic side-effects require the use of appropriate antibacterial drugs to eliminate BCG. Cases of BCG sepsis mainly occur because of traumatic catheterization and are often accompanied by hyperergic reactions [11] resulting in a life-threatening condition. In such patients, the current treatment advice in the literature consists of triple-drug therapy with isoniazid, rifampicin and ethambutol [23], combined with prednisolone to control the hyperergic reaction. The additional administration of cycloserine was recommended in severe cases because of its rapid killing of BCG in other studies [9, 23]. The influence of various antibiotics on intravesical BCG treatment has previously been investigated by van der Meijden et al. [24]. The aim of the present study was to determine the effects of modern antibiotics, particularly the fluoroquinolones, on the viability of BCG, and to define the role of cycloserine as the proposed first-line drug in severe sepsis. Several antibiotic drugs appeared to interfere with BCG. Among the aminoglycosides, amikacin, kanamycin and, to a lesser extent, gentamicin exhibited antimicrobial effects against BCG, and may therefore interfere with its viability in the bladder. The use of antibiotics with intravesical BCG therapy has advantages and disadvantages. In the case of complications, such as prolonged fever or epididymitis during a treatment course with BCG, early administration of non-

24

Eur Urol 2000;37(suppl 1):21–25

specific but effective antibiotic drugs, such as quinolones or aminoglycosides, may be useful and therapeutically justified. If, in rare cases, the patient does not respond adequately to this nonspecific first line therapy, tripledrug tuberculostatic treatment (isoniazid, ethambutol and rifampicin) should be considered. However, such drugs should be avoided in cases of concomitant nonspecific urinary tract infections, because a potential loss of the antitumor activity of BCG may result [8]. Therefore, in cases where elimination of BCG is not of primary importance, drugs which do not interfere with BCG, such as trimethoprim-sulfamethoxazole, are recommended. All the BCG strains tested in the present study were resistant to cycloserine. However, in earlier in vitro studies, van der Meijden et al. [24] reported borderline BCG sensitivity to a high concentration (10 Ìg/ml) of cycloserine, while animal data published by Lamm et al. [9] and Koukol et al. [23] showed a partial susceptibility of BCG to cycloserine. Some authors therefore recommended cycloserine for the immediate (rescue) treatment of BCGrelated severe complications. Our findings agree with those of Rist et al., who also found BCG resistance to cycloserine [10]. In the case of severe systemic symptoms, the animal data and clinical experience of Lamm et al. [9] clearly show that the additional use of glucocorticoids can prevent life-threatening hyperergic reactions. Data from our MB49 animal bladder tumour model in mice support these findings. In an initial trial, 80 mice were infected with 35 mg of BCG intraperitoneally, and allocated to four treatment groups: (1) trimethoprim-sulfamethoxazole; (2) trimethoprim-sulfamethoxazole and prednisolone; (3) fluoroquinolone; and (4) fluoroquinolone and prednisolone. After an intraperitoneal rechallenge with BCG, the overall survival of mice treated with combination therapy was superior to the quinolone monotherapy group, and superior to a group of mice treated with other antibiotics (unpublished data). Further experiments with orthotopic MB49 tumours, intravesical BCG application and subsequent administration of antibiotics, including fluoroquinolones and cycloserine, are underway. In conclusion, our data may contribute towards enhancing the therapeutic safety of BCG immunotherapy by the appropriate use of drugs, without compromising its efficacy.

Durek/Rüsch-Gerdes/Jocham/Böhle

References 1 Lamm DL, Crawford ED, Blumenstein BA, Crissman J, White R, Wolf M, Lowe B, Sarosdy M, Schellhammer P, Sagalowsky A, Smith J, Grossman HB, Flanigan R, Moon T, Brendler C, Coltman CA: SWOG 8795: A randomized comparison of bacillus Calmette-Guérin and mitomycin C prophylaxis in stage Ta and T1 transitional cell carcinoma of the bladder. J Urol 1993;149:282A. 2 Martinez-Pineiro JA, Leon J, Martinez-Pineiro L., Fiter L, Mosteiro J, Navarro J, Matres M: Bacillus Calmette-Guérin versus doxorubicin versus thiotepa: A randomized prospective study in 202 patients with superficial bladder cancer. J Urol 1990;143:502–506. 3 Ratliff TL, Palmer JO, McGarr JA, Brown EJ: Intravesical BCG therapy for murine bladder tumours: Initiation of the response by fibronectin-mediated attachment of BCG. Cancer Res 1987;47:1762–1766. 4 Shapiro A, Ratliff TL, Oakley DM, Catalona WJ: Reduction of bladder tumour growth in mice treated with intravesical bacillus Calmette-Guérin and its correlation with bacillus Calmette-Guérin viability and natural killer cell activity. Cancer Res 1983;43:1611–1615. 5 Kelley DR, Ratliff TL, Catalona WJ, Shapiro A, Lage JM, Bauer WC, Haaff EO, Dresner SM: Intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer: Effect of bacillus Calmette-Guérin viability on treatment results. J Urol 1985;134:48–53. 6 Lamm DL, Steg A, Boccon-Gibod L, Morales A, Hanna MG, Pagano F, Alfthan O, Brosman S, Fisher HAF, Jakse G, Chisholm GD, van der Meijden APM, Debruyne FMJ: Complications of bacillus Calmette-Guérin immunotherapy: Review of 2,602 patients and comparison of chemotherapy complications; in Debruyne FMJ, Denis L, van der Meijden APM (eds): EORTC Genito-Urinary Group Monograph 6: BCG in Superficial Bladder Cancer. New York, Liss, 1989, pp 335–355.

Sensitivity of BCG to Antibiotics

7 Stassar MJJG, Vegt PDJ, Steerenberg PA, van der Meijden APM, Meiring HD, DessensKroon M, Geertzen HGM: Effects of isoniazid (INH) on the BCG-induced local immune response after intravesical BCG therapy for superficial bladder cancer. Urol Res 1994;22: 177–184. 8 de Boer EC, Steerenberg PA, van der Meijden APM, van Klingeren B, De Jong WH, Elgersma A, Debruyne FMJ, Ruitenberg EJ: Impaired immune response by isoniazid treatment during intravesical BCG administration in the guinea pig. J Urol 1992;148:1577–1582. 9 Lamm DL, Riggs DR, DeHaven JI, Ting E: Reduction of BCG fatal toxicity in mice. J Urol 1991;145(suppl):858–864. 10 Rist N, Canetti G, Boisvert H, LeLirzin M: L’Antibiogramme du BCG: Valeur diagnostique de la résistance à la cyclosérine. Rev Tuberc Pneumol Ther 1967;31:1060–1065. 11 DeHaven JI, Traynelis C, Riggs DR, Ting E, Lamm DL: Antibiotic and steroid therapy of massive systemic bacillus Calmette-Guérin toxicity. J Urol 1992;147:738–742. 12 Siddiqi SH, Libonati JP, Middlebrook G: Evaluation of a rapid radiometric method for drug susceptibility testing of Mycobacterium tuberculosis. J Clin Microbiol 198;13:908–912. 13 DIN-Norm 58943-8: Empfindlichkeitsprüfung von Tuberkulosebakterien gegen Chemotherapeutika. Berlin, Beuth Verlag, 1996. 14 Canetti G, Grosset J: Anonymous examens bactériologiques en tuberculose. Paris, de la Rivière, Paris, 1968. 15 Otten H, Plempel M, Siegenthaler W: Übersicht zur Pharmakokinetik der Antibiotika; in Walter AM, Heilmeyer L (eds): AntibiotikaFibel. Stuttgart, Thieme Verlag, 1980, pp 710– 721.

16 Herr HW, Pinsky CM, Whitmore WF Jr., Sogani PC, Oettgen HF, Melamed MR: Longterm effect of intravesical bacillus CalmetteGuérin on flat carcinoma in situ of the bladder. J Urol 1986;135:265–271. 17 Bartlett GL, Kreider JW, Purnell DM, Katsilas DC: Augmentation of immunity to line 10 hepatoma by BCG. Comparison of different BCG preparations. Cancer 1980;46:488–496. 18 Akaza H, Iwasaki A, Ohtani M, Ikeda N, Niijima K, Toida I, Koiso K: Expression of antitumor response. Role of attachment and viability of bacillus Calmette-Guérin to bladder cancer cells. Cancer 1993;72:558–563. 19 Brosman SA: Bacillus Calmette-Guérin immunotherapy. Techniques and results. Urol Clin N Am 1992;19:557–564. 20 Lamm DL, van der Meijden APM, Morales A, Brosman SA, Catalona WJ, Herr HW, Soloway MS, Steg A, Debruyne FM: Incidence and treatment of complications of bacillus Calmette-Guérin intravesical therapy in superficial bladder cancer. J Urol 1992;147:596–600. 21 Lamm DL: Complications of bacillus Calmette-Guérin immunotherapy. Urol Clin N Am 1992;19:565–572. 22 Beermann D, Scholl H, Wingender W, Förster D, Beubler E, Kukovetz WR: Metabolism of ciprofloxacin in man; in Neu HC, Weuta H (eds): Proceedings of the 1st International Ciprofloxacin Workshop. Excerpta Medica, 1986, pp 21–28. 23 Koukol SC, DeHaven JI, Riggs DR, Lamm DL: Drug therapy of bacillus Calmette-Guérin sepsis. Urol Res 1995;22:373–376. 24 van der Meijden APM, van Klingeren B, Steerenberg PA, de Boer EC, de Jong WH, Debruyne FMJ: The possible influence of antibiotics on results of bacillus Calmette-Guérin intravesical therapy for superficial bladder cancer. J Urol 1991;146:444–446.

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Eur Urol 2000;37(suppl 1):26–30

The Effect of Isoniazid on BCG-Induced Toxicity in Patients with Superficial Bladder Cancer M. Al Khalifa a P. Elfving a W. Månsson a S. Colleen a S. Hellsten b M. Duchek c G. Nyberg d P. Callaghan e C. Rademark f R. Eriksson g R. Olsson h G. Hagberg i C.E. Nelson j Departments and Sections of Urology, University Hospitals of a Lund, b Malmö and c Umeå; County Hospitals of d Boden, e Halmstad, f Helsingborg, g Karlshamn, h Trelleborg, i Växjö and j Ystad, Sweden

Key Words Bladder cancer W Isoniazid W BCG vaccine W INH prophylaxis W BCG toxicity W Bladder contraction

Abstract The use of bacillus Calmette-Guérin in the treatment of transitional cell cancer of the bladder has caused concern because of its associated adverse effects. We conducted a randomized prospective, double-blind, multicentre study to determine whether isoniazid prophylaxis could reduce BCG-induced toxicity without compromising its immunotherapeutic effects. Patients (n = 160) with histologically documented urothelial cancer (pTa-T1, pTis, G1–3) were treated with 6 weekly instillations of BCG Connaught strain, 81 mg, administered concomitantly with a 3-day course of isoniazid (300 mg o.d.) or placebo. Side-effects were recorded with each treatment and at follow-up. Of the patients treated with isoniazid, 19% remained free from side-effects, compared with 16% of the placebo group. Local side-effects confined to the bladder were significantly lower among those receiving isoniazid (35% vs. 48%, p ! 0.01). Local side-effects together with systemic adverse effects such as fever,

ABC

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Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/journals/eur

nausea or skin rash were experienced by 30% of patients in each arm. There were no differences in tumour recurrence between the two patient groups. Concomitant isoniazid reduces the local, but not the systemic sideeffects of topically applied BCG without compromising the antitumour effect on superficial, transitional cell cancer of the bladder during a follow-up period that now exceeds 2 years. Copyright © 2000 S. Karger AG, Basel

Intravesical immunotherapy with BCG, first popularized by Morales et al. [1], has proved to be one of the most effective treatments for superficial bladder cancer [2–9]. There is concern, however, about the potential complications of BCG therapy [10–12]. BCG treatment is generally well-tolerated by the majority of patients. Though frequent (90%), the adverse effects that do occur are usually mild, mainly confined to the bladder, of short duration and self-limiting or responsive to symptomatic medication (table 1). Major and lifethreatening complications are infrequent (!5%) [11, 21, 22]. Fatalities directly attributable to intravesical BCG

Stig Colleen, MD, PhD Department of Urology, Lund University Hospital S–221 85 Lund (Sweden) Tel. +46 46 17 10 00, Fax +46 46 211 25 98 E-Mail [email protected]

Table 1. Side-effects of BCG in the

Local

treatment of bladder cancer Mild and moderate (! 36 hours)

Dysuria Frequency Haematuria

Severe

Contracted bladder

have been reported [19, 20], but have usually been due to improper administration of BCG. Efforts to minimize side-effects have mainly been focused on ways of decreasing antigen exposure. For example, increasing the interval between treatments decreases side-effects. Reducing the dose has also been reported to reduce the side-effects [18, 19], though others have been unable to confirm this [20]. An alternative approach was recently reported by Chin et al., who administered only those antigens needed to elicit the immunological response, by the topical use of Mycobacteria cell wall extract [21]. Our attempt to minimize BCG-induced toxicity was by administering prophylactic isoniazid (INH), so reducing the duration of exposure to live bacilli. To determine whether this approach could reduce side-effects without compromising efficacy, we carried out a prospective, randomized, double-blind, placebo-controlled, multicentre study.

Materials and Methods A total of 172 patients with superficial bladder cancer (pTa-T1, pTis, G1–3) entered the study. Twelve were not evaluable due to protocol violation, leaving 160 evaluable patients (136 men and 24 women; overall mean age 73 years). All patients had a history of more than two histologically documented tumour recurrences during the preceding 12 months, or primary (first manifestation of TCC) or secondary (occurring after or associated with TCC) carcinoma in situ. The patients were randomized to receive either INH or placebo. Pre-treatment investigations included: plain chest X-ray (to exclude active tuberculosis or metastasis), excretory urography (IVU) and intracutaneous purified protein derivative (PPD/tuberculin)-test with 0.1 ml PPD tuberculin 2 TU given intracutaneously and read 72 h later. An area of induration 1 6 mm was regarded as positive. Patients with a negative PPD-test were retested with 5 TU and, if still negative, vaccinated with 0.1 ml BCG-vaccine (Statens Serum Institute, Copenhagen, Denmark). Complete blood count (CBC and WBC), serum chemistry (including: serum alkaline phosphatase, aspartate aminotransferase,

Isoniazid in BCG-Induced Toxicity

Regional

Systemic Flu-like symptoms Nausea Skin rash

Epididymitis Ureteral stricture

Fever 638.5 ° C Hepatitis Pneumonia Systemic BCG-itis

alanine aminotransferase, glutamyltransferase and creatinine), urine cytology and culture before and with each instillation were also obtained, as was a frequency/volume chart on day 5 of each treatment week, and at follow-up. All patients had either transurethral tumour resection (TUR-BT) or cold cup biopsies (pTis) before the start of the BCG instillations. Three vials of Connaught BCG (Immucyst®, Connaught Laboratories, Willowdale Ontario, Canada) together containing about 9.0 ! 108 colony forming units (CFUs) (81 mg) were dissolved in 50 ml sterile saline and instilled into an empty bladder via a Lofric® (Astra, Södertälje, Sweden) catheter Ch12 under strict aseptic conditions. The instillate was kept in place for at least 2 h. This procedure started 1–3 weeks after the TURB-T or the bladder biopsies and was repeated once a week for 6 consecutive weeks. Each patient also received either INH (Tibinide®, Recip AB, Årsta, Sweden) or placebo. The first tablet (300 mg) was taken when the BCG-instillate was emptied, the second and third (both 300 mg) in the mornings of the following 2 days respectively (on an empty stomach). This was repeated for all six treatments. Side-effects were recorded with each instillation, according to a specific formula. The formula incorporated graded information on micturition volume and frequency, voiding discomfort, haematuria, fever, shivering, skin reaction or arthralgia. Follow-up investigations, including cystoscopy, were performed every 3 months during the first year and thereafter every 6 months to register both tumour response and late complications. Plain chest Xrays were carried out after 1 and 2 years, and intravenous urography (IVU) was undertaken at the end of the second year. Reasons for withdrawal from treatment included patient request, intolerable side-effects or other causes that made it impossible to continue the treatment. Two-tailed t-tests and Wilcoxon tests (Mann-Whitney) were used for statistical analysis. Time-to-progression was calculated according to the Kaplan-Meier method and statistically tested with the log rank test and Cox’s proportional hazards regression model. The study was approved by the Ethics Committees of the health care regions involved.

Results

The results are summarized in tables 2 and 3. Of the 160 patients evaluable for BCG-related toxicity, 28 (18%) experienced neither local nor systemic adverse effects

Eur Urol 2000;37(suppl 1):26–30

27

Table 2. Severe side-effects causing

withdrawal of BCG treatment

BCG + INH (5 patients)

BCG + placebo (5 patients)

Fever 1 38.5 ° C + local reaction Fever 1 38.5 ° C + local reaction Fever 1 38.5 ° C Fever 1 38.5 ° C + liver function affected BCG-itis

Myocardial infarction + urosepsis Severe local reaction (urinary diversion) Renal insufficiency (no obstruction) Fever 1 38.5 ° C + epididymitis Distal ureteral stricture

Table 3. Side-effects of BCG with concomitant administration of INH or placebo

No side-effects Mild local reaction only Moderate local reaction only Severe local reaction only Mild local reaction + systemic Moderate local reaction + systemic Severe local reaction + systemic Fever only Severe somatic side-effects causing withdrawal of BCG treatment Total

Total

INH

Placebo

28

8

15 14 7 7 7 5 12 8

13 5 8 25 4 4 16 0

10

5

5

160

80

80

66

48

– 15 (19%) cases in the INH group and 13 (16%) in the placebo arm. Local Side-Effects Only Local side-effects confined to the bladder (dysuria, increased micturation frequency and/or haematuria) were significantly less common in the INH-treated group [28/80 (35%) patients in the INH group and 38/80 (48%) in the placebo group, p ! 0.01]. These symptoms were classified as ‘mild’ in 14 (18%) patients in the INH group and in 5 (6%) of the placebo group; as moderate in 7 (10.5%) compared with 8 (12%), and as severe in 7 (10.5%) and 25 (38%), respectively. Transient reduction in bladder capacity was observed in three patients (two in the INH group, both of whom responded to treatment and one in the placebo group who did not respond). Local and Systemic Side-Effects Discontinuation of BCG treatment due to adverse events occurred in 10/160 patients (6%), five from each arm (table 3). The causes of withdrawal in the INH group

28

Eur Urol 2000;37(suppl 1):26–30

Fig. 1. Probability of tumour recurrence in 160 patients treated with BCG with or without concomitant isoniazid.

were fever (4 patients) and insufficient retention of the instillate (1 patient). The fever subsided with medication in all four cases, though one with an associated urinary tract infection and slight liver impairment required a 3month course with INH and prednisolone. Of those withdrawing from the placebo group one had a myocardial infarction and urosepsis, one had severe cystitis, one had high levels of serum creatinine, one had a ureter outlet obstruction, causing several systemic symptoms, and one had fever due to epididymitis. There were no treatmentrelated deaths. BCG therapy was postponed for 2–3 weeks in 6/160 patients (4%) – two in the INH group and 4 in the placebo group. The reasons for delay were symptomatic bacteriuria (3 patients), fever (2 patients) and raised serum creatinine (1 patient). Local bladder symptoms in conjunction with systemic adverse effects were experienced by 48/160 patients (30%) – 24 in each arm. Fever (38.0–39.6 ° C) as the only systemic side-effect, in conjunction with local side-effects, was observed in 19 cases (6 in the INH group vs. 13 in the placebo group). These adverse events were reported along

Al Khalifa et al.

with nausea in 16 patients (10 vs. 6), and with both nausea and skin rash in 3 (1 vs. 2). Fever alone occurred in 8/160 (5%) patients, all of whom were in the INH group. A total of 21 patients had a positive urine culture, 17 of whom were asymptomatic (9 receiving INH, 8 receiving placebo) and required no delay or discontinuation of BCG instillations. Efficacy During the follow-up period so far (about 2 years), there have been no differences in curative (pTis) and prophylactic (pTa-T1) efficacy of BCG immunotherapy with or without INH prophylaxis (fig. 1).

Discussion

There is no consensus on how to define the toxicity of BCG therapy. Symptoms that may represent adverse events are difficult to distinguish from therapy-related symptoms that may indicate treatment efficacy. Local side-effects are an integral part of therapeutic efficacy, but not to the extent that the patient suffers or has a reduced quality of life. In this double-blind study, INH was found to induce a moderate but significant reduction of local side-effects together with a non-significant reduction of their intensity. Prophylactic use of INH did not, however, influence the frequency of systemic side-effects. During the limited follow-up period so far (just over 2 years), the use of INH prophylaxis has had no effect upon the therapeutic (pTis) or the curative (pTa–T1) efficacy of BCG immunotherapy on superficial bladder cancer. It should be noted that INH can itself cause side-effects – principally liver toxicity, but also gastrointestinal

complications, peripheral and central nervous system disturbances and fever [21]. However, such toxicity is generally seen during long-term INH treatment (6–12 months) and would therefore not be expected in this prophylactic setting [22]. Except for liver function disturbances (which were in fact attributable to systemic/allergic toxicity of BCG) there was no evidence in this study of any possible INH-induced adverse events. In another study on the influence of prophylactic INH in conjunction with BCG immunotherapy for bladder cancer, there were only minor and transient effects on liver function [23]. Persistent fever may indicate severe BCG toxicity, and most investigators would react by stopping BCG therapy and starting tuberculostatic medication. However, fever is also a recognized side-effect of INH, so it is useful to be aware that INH-induced fever could potentially deprive some patients of successful treatment with immunotherapy. In the healthcare sphere, cost-effectiveness is of increasing importance and reducing side-effects must be economically justifiable. Fortunately, the addition of prophylactic INH to BCG immunotherapy for superficial bladder cancer adds only about 0.7% to the overall cost of treatment. We therefore conclude that prophylactic use of INH in conjunction with BCG immunotherapy will decrease but not eliminate local side-effects, and will probably reduce their intensity. These benefits occur without affecting the prophylactic or curative effect of BCG on bladder cancer, and without any appreciable increase in cost. Acknowledgement We thank Connaught Laboratories, Willowdale Ontario, Canada for their support in making this study possible.

References 1 Morales A, Eidinger D, Bruse AW: Intracavitary bacillus Calmette-Guérin in the treatment of superficial bladder tumours. J Urol 1976;116: 180–183. 2 Herr H, Pinsky C, Whitmore W Jr, Sogani P, Oettgen H, Melamed M: Experience with intravesical bacillus Calmette-Guérin therapy of superficial bladder cancer. J Urol 1985;25: 119–123. 3 Lamm DL, Thir D, Stogdill V, Radwin H: Bladder cancer immunotherapy. J Urol 1982; 128:931–935.

Isoniazid in BCG-Induced Toxicity

4 Lamm DL: Bacillus Calmette-Guérin immunotherapy for bladder cancer. J Urol 1985;134: 40–47. 5 Sarosdy MF, Lamm DL: Long term results of intravesical BCG therapy for superficial bladder cancer. J Urol 1989;142:719–722. 6 Lamm DL: Optimal BCG treatment of superficial bladder cancer as defined by American trials. Eur Urol 1992;21(suppl 2):12–16. 7 Mori K, Lamm DL, Crawford E: A trial of bacillus Calmette-Guérin vs. adriamycin in superficial bladder cancer: A South-West Oncology Group study. Urol Int 1986;41:254–259.

8 Pagano F, Bassi P, Milani C, Piazza N, Meneghini A, Garbeglio A: BCG in superficial bladder cancer. A review of phase III European Trials. Eur Urol 1992;21(suppl 2):7–11. 9 Herr H, Laudone VP, Whitmore WF Jr: An overview of intravesical therapy for superficial bladder tumours. J Urol 1987;138:1363–1368. 10 Witjes JA, van der Meijden APM, Debruyne FMJ: Use of intravesical bacillus CalmetteGuérin in the treatment of superficial transitional cell carcinoma of the bladder: An overview. Urol Int 1990;45:129–132.

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11 Lamm DL: Complications of bacillus Calmette-Guérin immunotherapy; in Debruyne FMJ, Deis L, van der Meijden (eds): BCG in Superficial Bladder Cancer. APM. EORTC Genito-Urinary Group Monograph 6. New York, Alan R Liss Inc., 1989, pp 339–355. 12 Öbek C, Shelflo SW, Korman HJ, Soloway MS: Intravesical therapy for transitional cell carcinoma of the bladder: The community practice. Urology 1999;53:82–87. 13 Morales A: Long-term results and complications of intracavitary bacillus Calmette-Guérin therapy for bladder cancer. J Urol 1984;132: 457–459. 14 Deresiewicz RL, Stone RM, Aster JC: Fatal disseminated mycobacterial infection following intravesical bacillus Calmette-Guérin. J Urol 1990;144:1331–1334.

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15 Catalona WJ, Hudson MA, Gillen DP, Andriole GL, Ratliff TL: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guérin for superficial bladder cancer. J Urol 1987;137:220–224. 16 Steg A, Leleu C, Dbre B, Boccon-Gibod L, Sicard D: Systemic bacillus Calmette-Guérin infection, BCG-itis, in patients treated by intravesical bacillus Calmette-Guérin therapy for bladder cancer. Eur Urol 1989;16:161–164. 17 Rawls WH, Lamm DL, Lowe BA, Crawford ED, Sarosdy MF, Montie JE, Grossman HB, Scardino PTF: Sepsis following intravesical bacillus Calmette-Guérin administration for bladder cancer. J Urol 1990;144:1328–1330. 18 Pango F, Bassi P, Milani C, Meneghini A, Maruzzi D, Garbegglio A: A low dose bacillus Calmette-Guérin regimen in superficial bladder cancer: is it effective? J Urol 1991;146:32– 35.

Eur Urol 2000;37(suppl 1):26–30

19 Mack D, Frick J: Low-dose bacillus CalmetteGuérin (BCG) therapy in superficial high-risk bladder cancer: A phase II study with the BCG strain Connaught Canada. Brit J Urol 1995;75: 185–187. 20 Morales A, Nickel JC: Dose response of BCG in superficial bladder cancer. J Urol 1990;143: 340A(605). 21 Chin J, Kadhim SA, Batislam E, Karlik SJ, Garcia BM, Nickel JC, Morales A: Mycobacteria cell wall: An alternative to intravesical BCG therapy in orthotopic murine bladder cancer. J Urol 1996;156:1189–1193. 22 Lamm DL, Stogdill VD, Stogdill BJ, Crispen RG: Complications of bacillus Calmette-Guérin immunotherapy in 1,278 patients with bladder cancer. J Urol 1986;135:272–274. 23 Miller B: Preventive therapy for tuberculosis. Med Clin N Amer 1993;77:1263–1275.

Al Khalifa et al.

Eur Urol 2000;37(suppl 1):31–32

Modified Induction Course: A Solution to Side-Effects? P. Bassi R. Spinadin R. Carando G. Balta F. Pagano Department of Urology, University of Padova, Padova, Italy

Key Words BCG W Side-effects W Superficial bladder cancer W Phase III trials W Phase II trials W Review

Abstract Side-effects are commonly manifested during intravesical Bacillus Calmette-Guérin (BCG) immunotherapy of superficial bladder cancer. This often causes delays or interruptions of the instillations and consequently reduces the efficacy of treatment. Treatment strategies aimed at reducing the side-effects of BCG immunotherapy while maintaining efficacy are currently being considered in the search for an optimal treatment regimen. The following two approaches to BCG immunotherapy were investigated at the Department of Urology of Padova University by specific Phase II and III trials designed to evaluate the possibility of reducing BCG-related sideeffects without compromising therapeutic efficacy: (1) by reducing the dose of BCG per instillation ‘low-dose’ regimen, (2) by delaying the interval of the instillations ‘slowrate’ regimen. Copyright © 2000 S. Karger AG, Basel

The Low-Dose Regimen

A phase II study carried out during the 1980s suggested that a dose reduction was able to reduce the most common side-effects related to intravesical BCG therapy. To confirm those findings a Phase III trial was designed: the low-dose regimen was compared with the standard dose

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Fig. 1. Disease-free survival in all patients receiving 75 mg (low-

dose) or 150 mg (standard-dose) BCG immunotherapy.

in a randomized trial involving 210 patients with multifocal papillary tumour (Ta, T1) or carcinoma in situ (Tis). BCG was instilled in doses of 75 mg vs. 150 mg BCG (Pasteur strain) and patients were followed up over a median 58.5 months. Endpoints used in this study were diseasefree survival, tumour progression and toxicity (incidence of side-effects occurring after the induction course). No significant differences were found between low- and standard-dose groups in terms of disease-free survival for the overall patient population (fig. 1; p = 0.08) multifocal Ta (p = 0.98) and T1 (p = 0.53) tumours, however, the diseasefree survival rate was reduced for Tis patients receiving a standard dose of BCG (p = 0.01). Tumour progression was

Prof. P. Bassi Instituto di Urologia, Università degli Studi Monoblocco Ospedaliero, Via Gustiniani 2 I–35100 Padova (Italy) Tel. +39 49 8212719, Fax +39 49 8212721, E-Mail [email protected]

Table 1. Grading of toxicity following intravesical therapy [1]

Grade

Description

Grade 0 or absent Grade 1 or mild Grade 2 or moderate Grade 3 or severe Grade 4 or extreme

No side-effects Not requiring treatment Requiring treatment Requiring delay of instillation Requiring interruption of treatment

Table 2. Side-effects in slow-rate vs. standard-rate regimens in first diagnosis tumours

Slow-rate

Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

Standard-rate

cystitis

fever

cystitis

fever

6 (37.5) 6 (37.5) 4 (25) – –

12 (75) 4 (25) – –

– 6 (37.5) 6 (37.5) 4 (25) –

4 (25) 8 (50) 4 (25) – –

Delayed instillations Treatment interruption

– –

5 (31) 1 (6)

Figures in parentheses represent percentages.

experienced by 8% of patients receiving the low, 75 mg dose and by 9% of patients receiving the 150 mg dose. In terms of toxicity, the most common side-effects were significantly reduced (p ! 0.05) in the low-dose arm with incidences (low dose vs. standard dose, respectively) of: E 32% vs. 57% cystitis, E 9% vs. 18% severe cystitis, E 12% vs. 26% fever (!38.5 ° C), E 13% vs. 24% gross haematuria. In conclusion, this Phase III randomized trial clearly demonstrated similar or improved responses in terms of disease-free survival and progression for each stage in the low-dose group, and a significant decrease in side-effects was observed when compared with the standard dose.

not (personal communication). To verify this interesting finding, a Phase II trial was designed and carried out to determine whether the side-effects of BCG immunotherapy could be reduced, without compromising efficacy, when the instillation interval was doubled from 1 to 2 weeks. This trial focused on multifocal (stage Ta, G1–G3) tumours. A total of 17 patients with multifocal Ta G1/G3 (intermediate risk) tumours and no upper or lower urinary tract or transitional cell carcinoma involvement were included. Only 12.5% of the patients exhibited recurrence and no progression was observed. Side-effects were assessed using the WHO scale for toxic side-effects adapted to intravesical treatment (table 1) [1]. The percentage of grade 0, 1 and 2 side-effects for cystitis and fever in the slow-rate BCG group were reduced (table 2). In particular, grade 1 side-effects were the most commonly observed in patients following the slow-rate protocol – these side-effects were mild and did not require treatment. Only 25% of patients treated with slow-rate BCG instillation experienced grade 2 cystitis that required treatment. Surprisingly, no patients experienced delay or interruption of the scheduled treatment because of their side effects. Although the study was not randomized, there is a clear difference when data from a simultaneous cohort of patients receiving the same dose but at the standard weekly rate are compared with the slow-rate (two-weekly) regimen. The response rates to ‘slow-rate’ treatment were good and resulted in reduced side-effects. It is important to note that this treatment strategy has proven effective for reduction of side-effects in intermediate-risk patients, and that larger randomized studies with longer follow-up are now required. In conclusion, the author suggests that when using BCG immunotherapy for the treatment of bladder cancer, a modified induction course may provide a solution to reducing BCG-related side-effects. Decreasing the dose of BCG using a standard instillation program, using a standard dose of BCG and extending the interval between instillations from 1 to 2 weeks, or possibly incorporation of both methods will provide alternative mechanisms for reducing BCG-related side-effects without compromising efficacy.

The ‘Slow-Rate’ Regimen

In a previous investigation, the authors compared mitomycin C with a standard dose of BCG for treatment of bladder cancer and found no significant difference in disease-free survival between patients who experienced delays in instillation due to side-effects and those who had

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Reference

1 Bassi P: Methodology in superficial bladder cancer clinical trials: Objective evaluation of treatment: The need for standardization; in Pagano F, Fair WR (eds): Superficial Bladder Cancer. Oxford, Isis Medical Media, 1997, pp 82–89.

Bassi/Spinadin/Carando/Balta/Pagano

Eur Urol 2000;37(suppl 1):33–36

BCG Intravesical Instillations: Recommendations for Side-Effects Management P. Rischmann F. Desgrandchamps B. Malavaud D.K. Chopin Urologie, C.H.U. Purpan, Toulouse, France

Key Words BCG W Intravesical therapy W Side-effects W Isoniazid

Abstract Adverse events following intravesical BCG therapy are related to strain virulence, allergic reactions or to nosocomial urinary tract infections. Low grade fever and irritative symptoms are common side-effects of BCG. They subside within 48 hours and do not require any specific treatment, apart from standard painkillers and antispasmodics. Further instillations should be postponed until symptoms have resolved completely. If symptoms do not resolve, complementary investigations are recommended including urine culture, and isoniazid may be prescribed for 15 days. The BCG dose should be reduced if symptoms increase after subsequent instillations. Complications of BCG infection – either local or systemic – have been reported with an incidence of 10–15%. These complications include: granulomatous prostatitis or epididymitis (treated with isoniazid and rifampicin for 3 months), contracted bladder may occur, mainly during maintenance courses, systemic infection such as granulomatous nephritis and abscesses, pneumonitis, hepatitis, osteomyelitis (treated with isoniazid, rifampicin and ethambutol for 6 months), and life-threatening adverse events may be related to septicaemia or to immunoaller-

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gic reactions, the onset of which may be delayed several months after the end of BCG therapy. Such conditions require urgent treatment with standard antituberculous antibiotics and prednisolone. These complications are an absolute contraindication for further BCG instillations. Despite its toxicity, the risk-benefit ratio favours the use of BCG in patients who have moderate- and high-risk tumours. Copyright © 2000 S. Karger AG, Basel

Side-effects of intravesical bacillus Calmette-Guérin (BCG) therapy, which is used for treatment of superficial bladder cancer, may be BCG-specific or of a non-specific origin. The specific risks relate to the bacillus itself, and usually occur because: the virulence is attenuated, but the bacillus is still viable and the bacillus possesses allergic properties. Non-specific risks associated with bacterial therapy are those related to retrograde urethral catheterization and their prevention is primarily based on non-traumatic catheterization performed under rigorous aseptic conditions (sterile urine culture). The ambiguous definition of ‘usual’ and ‘undesirable’ side-effects makes it difficult to precisely evaluate the risk of complications associated with this treatment but it is estimated to be 5–10% [1].

Prof. P. Rischmann Urologie, C.H.U. Purpan F–31059 Toulouse (France) Tel. +33 5 61 77 74 83, Fax +33 5 61 77 76 28 E-Mail [email protected]

Common Side-Effects

Local Local effects generally consist of cystitis associated with dysuria in 80% of cases [2] and macroscopic haematuria in 40% of cases [3]. The severity of the symptoms can be classified into four stages, from minor to intolerable. These symptoms usually begin within 2 hours of instillation and last for about 48 hours. When necessary, these side-effects can be treated symptomatically by a combination of paracetamol and oxybutynin. However, they are not modified by preventive administration of isoniazid [4]. Further instillations must not be performed if burning persists, in which case it is advisable to postpone treatment and reduce the dose for subsequent courses. Systemic Low-grade fever (!38.5 ° C) has been shown to develop in about 30.5% of patients, without significant systemic effects, and usually subsides within 48 hours [5]. Common systemic side-effects are not modified by isoniazid prophylaxis and may be relieved by simple symptomatic treatment with paracetamol.

Local and Regional Severe Adverse Effects

Granulomatous Prostatitis This is common, but asymptomatic, in most male patients. Local and systemic reactions occur in 1–3% of patients [6, 7]. On digital rectal examination, the prostate is occasionally indurated. Prostate-specific antigen (PSA) may be elevated and ultrasound may show hypoechoic zones. Treatment consists of a combination of isoniazid (300 mg/day) and rifampicin (600 mg/day) for 3 months and subsequent intravesical BCG therapy is contraindicated. The local disease course is monitored clinically, and by laboratory parameters and ultrasound. The diagnosis of prostatic cancer should be considered if the appearance does not return to normal. Epididymitis This is an uncommon complication reported in just 0.2% of patients; treatment is similar to the one of granulomatous prostatitis, with which it may be associated. A nosocomial infection must be excluded or treated.

Ureteritis and Ureteric Obstruction This is a rare complication (0.3%). Carcinoma in situ must be excluded and permanent drainage may be indicated [6]. Renal Parenchymal Complications These complications may be facilitated by vesicoureteric reflux [6], which does not in itself constitute a contraindication to intravesical BCG. Haematogenous spread is another possible mechanism. Examination for specific histological signs by renal biopsy may be required to exclude a renal tumour. Triple-agent tuberculostatic therapy (isoniazid 300 mg/day, rifampicin 600 mg/day, ethambutol 1,200 mg/day) must be continued for 6 months and subsequent BCG is contraindicated.

Systemic Complications of BCG

Haematogenous spread of BCG and immunoallergic reactions are the two main mechanisms behind the development of systemic complications. The prognosis is more severe in cases where there is only a brief interval between catheterization, often traumatic in these cases, and the onset of adverse events. The patient and the attending physician must be clearly informed, because delayed diagnosis may result in severe complications. Generalized ‘BCGitis’ Severe multiple organ failure may occur, usually immediately after instillation. However, it has also been reported to occur several years after treatment has ceased, as a type of immunodepression [8]. Clinically, fever is high – greater than 38.5 ° C – with impaired general and haemodynamic status. Clinical examination is often non-specific, but may reveal hepatomegaly and crepitations in the lower lung. Blood tests often reveal leukopenia and abnormal liver function tests. Chest X-ray may show infiltrates in the lower lung bases. Based on the clinical history, four-agent antibiotic therapy is urgently required. After collecting bacteriological specimens for culture, tuberculostatic triple therapy (isoniazid, rifampicin and ethambutol) plus an empirical non-specific antibiotic to cover Gram-negative bacteria and/or Enterococcus, combined with early, high-dose corticosteroids should be given. Specific Lesions of Various Organs or Systems Pulmonary miliary tuberculosis and granulomatous hepatitis may occur alone or in combination. BCG may

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Eur Urol 2000;37(suppl 1):33–36

Rischmann/Desgrandchamps/Malavaud/ Chopin

Table 1. Management of BCG therapy adverse effects Common side-effects

Serious side-effects (complications)

Discontinuation of instillations Complete aetiological assessment Urine culture Blood culture Full blood count Creatinine Platelets Liver function tests Chest X-ray Grade 1: moderate and ! 48 hours

Grade 3: local, regional, systemic and immunoallergic

Burning , frequency, haematuria Fever = 38.5 ° C

Allergic reactions

Assessment None Symptomatic treatment: Anticholinergics without antispasmodics Analgesics with or without anti-inflammatory drugs

Skin rashes, joint pain, and rheumatoid arthritis with or without ocular involvement Treatment: Antihistamines with or without NSAID If symptoms persist after 10–15 days: INH and RFP (3 months) Resumption of instillations must be evaluated in the light of the benefit–risk ratio with dose reduction Epididymitis and granulomatous prostatitis (symptomatic)

Grade 2: severe and/or 1 48 hours

Immediately severe symptoms Symptoms lasting 1 48 hours Assessment Urine culture with or without chest X-ray and liver function tests Symptomatic treatment Anticholinergics without antispasmodics Analgesics with or without anti-inflammatory drugs

Treatment: INH and RFP (3 months) with or without fluoroquinolones Caseous abscess and granulomatous masses of the kidney Specific infection of other organs (hepatitis, pneumonitis, osteomyelitis)

Treatment: INH and RFP and ethambutol (6 months)

Grade 4: generalized ‘BCGitis’

Antibiotic therapy Do not wait for urine culture results INH 300 mg/day until resolution of symptoms Or treatment adapted to urine culture results BCG therapy Suspend instillations until complete resolution of symptoms Restart instillations with dose reduction in the case of severe adverse effects and/or postpone treatment (doses may be reduced to 1/3 or even 1/10)

Multiple organ failure (no bacteriological evidence of BCG is necessary to start treatment) Hospitalization – possible intensive care Emergency treatment INH 300 mg/day RFP 600 mg/day Ethambutol 1,200 mg/day Prednisolone 40 mg/day with or without fluoroquinolones

be detected by bronchoalveolar aspiration, transbronchial biopsy, or liver biopsy – following a positive detection the reverse transcriptase polymerase chain reaction (RTPCR) is useful to identify BCG strain [9]. Tuberculostatic therapy should be started immediately, without waiting for the results. Corticosteroids may be prescribed concomitantly but should never be prescribed alone. Other rare organ lesions are: vertebral osteomyelitis, psoas abscess and vascular infection or infection of implanted prosthetic material.

Allergic Complications Allergic reactions to intravesical BCG involve arthritis, migrating joint pain or skin rashes. These complications are uncommon (less than 1% of cases) and are related to cross-reactions between some BCG epitopes and some antigenic components of cartilage proteoglycans [10]. Treatment is symptomatic, and non-steroidal antiinflammatory drugs may be administered. Antihistaminic drugs may also be indicated, particularly in the case of rashes. BCG therapy must be stopped until these reactions resolve and subsequent courses should be consid-

BCG Side-Effects Management

Eur Urol 2000;37(suppl 1):33–36

35

ered only when the benefit appears to outweigh the risk with close surveillance during the first few hours after instillation.

The French Recommendations

In France, over the past 2 years, there have been sudden changes in BCG therapy. The replacement of BCG Pasteur strain by the lyophilized Connaught substrain, initially seemed to induce more side-effects than previously encountered. During this period, more than 5,000 patients were treated and the French National Drug Agency was spontaneously informed of 110 adverse events, of which 57 were serious (defined as hospital admissions, cases of sequelae and one death related to BCG therapy) according to the International Conference on Harmonisation definitions. The incidence of adverse events is probably under-reported but these figures appear to be consistent with current literature. Nevertheless, it has been questioned whether this strain, which probably has a greater stability in terms of

CFU, revealed, in fact, a certain degree of variation in our everyday practice. In order to standardize this practice, the Committee for Oncological Urology at the C.H.U. devised guidelines for the management of BCG sideeffects. These guidelines are based mainly on the available literature [6, 7]. The recommendations have been summarized in table 1 using the WHO recommendations for grading the toxic effects of drugs as a guide. Grades 3 and 4 result in a definitive contraindication for BCG. In conclusion, prevention is considered the best treatment for BCG complications and the following points should be considered: contraindications, particularly immunodeficiency, BCG within 2 weeks of TURB or if haematuria persists, sterile urine culture is needed before each instillation, BCG is contraindicated if catheterization is traumatic or bloody, and instill using the lowest pressure. Taking into account these remarks, and despite its potential toxicity, BCG provides the best risk–benefit ratio in the case of intermediate- and high-risk superficial transitional cell carcinoma of the bladder.

References 1 Lamm DL, Steg A, Boccon Gibod L, Morales A, Hanna MG, Pagano F, Alfthan O, Brosman S, Fisher Haf, Jakse G, Ghisolm GD, van der Meijden ADPM, Debruyne FMJ: Complications of bacillus Calmette-Guerin immunotherapy review of 2,602 patients and comparison of chemotherapy complications; in Debruyne FMJ, Denis L, van der Meijden ADPM (eds): EORTC Genitourinary Group Monograph 6: BCG in Superficial Bladder Cancer. New York, Alan R. Liss, 1989, pp 335–355. 2 Böhle A, Balck F, von Wietersheim J, Jocham D: The quality of life during intravesical bacillus Calmette-Guerin therapy. J Urol 1996;155: 1221–1226. 3 Böhle A, von Wietersheim J, Jocham D: The balance between side-effects and success in intravesical therapy. Aspect of quality of life in BCG-treated patients in Böhle A, Jocham D (eds): Optimal Therapy for Patients with HighRisk Superficial Bladder Cancer – Controversy and Consensus. Proceedings of the First Lübeck Symposium on Bladder Cancer. Oxford, The Medicine Publishing Foundation, 1997, no. 37, 109–117.

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4 Vegt PD, van der Meijden AP, Sylvester R, Brausi M, Höltl W, de Balincourt C and the members of the EORTC genitourinary group: Does isoniazid reduce side-effects of intravesical bacillus Calmette- Guerin therapy in superficial bladder cancer? Interim results of Cancer protocol 30911. J Urol 1997;157:1246–1249. 5 Thalmann GN, Studer UE: Fever as positive factor of BCG therapy; in Böhle A, Jocham D (eds): Optimal Therapy for Patients with HighRisk Superficial Bladder Cancer – Controversy and Consensus. Proceedings of the First Lübeck Symposium on Bladder Cancer. Oxford, The Medicine Publishing Foundation, 1997, no. 37, 119–124. 6 Lamm DL: Complications of bacillus Calmette-Guerin immunotherapy. Urol Clin North Am 1992;19:565–572.

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7 Steg A, Leleu C, Debre B, Boccon-Gibod L, Sicard D: Systemic Bacillus Calmette-Guerin infection. ‘BCGitis’ in patients treated by intravesical bacillus Calmette-Guerin therapy for bladder cancer. Eur Urol 1989;16:161–164. 8 Izes JK, Bihrle W, Thomas CB: Corticosteroidassociated fatal mycobacterial sepsis occuring 3 years after instillation of intra-vesical bacillus Calmette-Guerin. J Urol 1993;150:1498– 1500. 9 Kristansson M, Green P, Manning HL, Slutsky AM, Brecher SM, von Reyn CF, Arbeit RD, Maslow JN: Molecular confirmation of BCG as the cause of pulmonary infection following urinary tract instillation. Clin Infect Dis 1993;17: 228–30. 10 Smith MD, Chandran G, Parker A, Youssef PP, Ahern M, Coleman M, Macardle P, Roberts-Thomson P: Synovial membrane cytokine profiles in reactive arthritis secondary to intravesical BCG therapy. J Rheumatol 1997; 24:752–758.

Rischmann/Desgrandchamps/Malavaud/ Chopin

Open Discussion Eur Urol 2000;37(suppl 1):37–39

BCG: The Optimal Approach in Superficial Bladder Cancer A. Böhle Chairman

Floor: Dr Rischmann recommends urine culture if fever persists following BCG installation. Would not blood culture for mycobacteria also be appropriate if you are concerned about systemic BCG septicaemia? P. Rischmann: If fever and side-effects such as cystitis are moderate, then you should proceed with urine culture. While waiting for the results, fluoroquinolones and paracetamol can be given. In the case of severe systemic effects, one should not wait for bacteriological results before beginning treatment. Blood cultures are seldom positive; reverse-transcriptase-PCR may be more useful. A. Böhle: From our own experience, and from the experience in the literature, blood cultures are not very successful at revealing mycobacterial infection. Blood cultures are often negative even in the presence of systemic BCG infection. Floor: Is any of the various BCG strains superior? Furthermore, when referring to reductions in the dose of BCG, does it make more sense to talk about colony-forming units (CFUs) rather than milligrams? Equal doses (in milligrams) of different strains of BCG may have different numbers of CFUs. P.F. Bassi: Which parameters we use to measure BCG is an important topic, but one that is still largely unexplored. As a matter of fact, we do not know what the active component of the BCG is or how BCG works. As a consequence, we do not know what to measure: weight is only a manufacturer’s product information, which does not express the absolute therapeutic ability of the prepara-

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tion. It is, therefore, not possible to make a comparison by weight between, for example, 150 mg of Pasteur BCG, 81 mg of Connaught BCG or 50 mg of OncoTice. Consequently, it is impossible to say that 150 mg Pasteur BCG is threefold ‘better’ than 50 mg Tice strain. Also the number of viable colonies (CFUs) has been supposed, in the past, to make a difference in terms of efficacy, but in the long run, this highly imprecise parameter has failed to be a reliable indicator. D.L. Lamm: The variability not only between strain and strain, but also between one ampoule and another ampoule of the same preparation is very high. For this reason, Mike O’Donnell’s recommendation for dose reduction makes a lot of sense, and in our experience is very useful. When patients start to have increased side-effects we reduce the dose to one third; if side-effects persist or increase, the dose is reduced to one tenth, and even to one hundredth if necessary. Basically, the patient does not have to suffer at all to receive effective immune stimulation with BCG, and I think that dose reduction therefore really makes more sense than prophylactic isoniazid. With isoniazid we are adding another variable, and we don’t know what percentage kill isoniazid prophylaxis results in, unlike log reductions in BCG dose, which do give us a rough idea of the effective decrease in dose. Floor: Do you think there is any correlation between the pre-treatment tuberculin test and the subsequent development of side-effects?

D.L. Lamm: There is some correlation between PPD response and side-effects as well as immune response and anti-tumour effect, though this is not a one-to-one correlation. Generally speaking, you need to have some irritative symptoms to be certain that you are stimulating an immune response. Those patients who have been previously exposed to BCG will typically have a more rapid and more vigorous response to BCG. In patients with carcinoma in situ (CIS), for example, or patients with highrisk bladder cancer, those that were PPD-positive have a better response than those who were negative, and certainly there is a correlation between response and conversion of the skin test to positive after BCG. Experience from the Southwest Oncology Group (SWOG) shows that patients with CIS who converted to a positive PPD skin test had a 30% higher response than those who failed to convert – so the PPD is of some use. Floor: What percentage of patients in the SWOG study had muscle invasive disease on subsequent biopsies during maintenance BCG? Did the drop-outs in this study occur at a particular time after initial presentation? Also, what percentage of patients completed the three-year regimen? D.L. Lamm: The drop-out rate was 84%, and that was partly by intention. Investigators were specifically instructed not to give the second or the third instillation if there were increased side-effects from the first. Therefore, only 16% received BCG at the 36th month. We don’t have the specific percentages that had cystectomy vs. documented muscle invasion vs. requirement of systemic chemotherapy for clinical metastatic disease. The majority had muscle invasion, though a significant number did have implied progression based on those other factors. Floor: Of those who proceeded to cystectomy, what percentage did not have muscle invasive disease, but kept experiencing recurrences despite being on the maintenance therapy? D.L. Lamm: I don’t have those exact data, but there are patients who proceed to cystectomy because of recurrent CIS, grade 3 TCC or lamina propria invasion. Floor: Dr Rischmann has mentioned haematuria as a contraindication to BCG therapy. Is microscopic haematuria also a contraindication? P. Rischmann: No, only macroscopic haematuria is a contraindication. BCG instillation must not be performed after traumatic catheterization. Dipstick analyses always show microscopic haematuria. A. Böhle: However, you should of course treat and not wait in the case of CIS associated with microhaematuria. Basically, we are concerned that BCG does not enter the

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bloodstream, either after traumatic catheterization or through an open vessel caused by inflammation. Floor: Is the addition of prednisolone recommended to treat patients with immunoallergic arthritis secondary to BCG? In the last few years, three of our patients have had very good responses to this corticosteroid. P. Rischmann: We use prednisolone or corticosteroids in cases of sepsis or severe immunoallergic reaction. Moderate reactions such as arthralgia respond well, in our experience, to antihistamines and non-steroidal antiinflammatory drugs. Floor: What is the recommended protocol for a patient who experiences recurrences at 1, 2 and 3 years after an initial 6-week BCG course? D.L. Lamm: Part of the rationale for three weekly instillations is the heightened immune response to the secondary exposure to BCG. For this reason, for patients who responded well to a single 6-week course but have subsequently failed or have not been on maintenance, I recommend, not a second 6-week course, but two 3-week courses separated by an interval of 3 months, followed by 3-week maintenance at 6 months. However, the protocol does depend on how long it has been since the patient’s initial exposure to BCG. If you look at the cytokine response, those that have had BCG more recently will respond earlier in the series of subsequent treatments. Therefore, if it has been many years since a patient had intravesical BCG, you may need to continue with 4 or 5 treatments until you start to have symptoms. Floor: We heard that BCG is sensitive to fluoroquinolones, and I took that to imply that we should not use fluoroquinolones to treat a proven UTI, as this would reduce the BCG effectiveness; yet in France the recommendation is that a fluoroquinolone should be used to treat a proven UTI. A. Böhle: The important point that we wished to convey is that fluoroquinolones interact with BCG. Whether you want to kill BCG depends on the severity of the concomitant inflammation or infection. Certainly there are situations where you do not want to kill BCG, and in such cases fluoroquinolones should not be administered. In contrast, epididymitis is very easily resolved with fluoroquinolone treatment. Testicular loss did occur in the earlier series of our patients; however, severe epididymitis or testicular loss did not occur after we started to use fluoroquinolones to treat initial testicular symptoms. So it makes sense to use fluoroquinolones if you want to kill BCG very early. P. Rischmann: Severe side-effects occur most often after the third day. At that time, in my opinion, eradicat-

Böhle

ing BCG will not significantly reduce the efficacy of the immunological reaction which has already begun. Floor: The French recommendations for side-effects management advise that granulomatous prostatitis should be treated with isoniazid and rifampicin for 3 months – but what do you mean by granulomatous prostatitis? If you do a rectal examination after BCG, you feel nodules in the majority of patients, and biopsies show changes characteristic of granulomatous prostatitis. P. Rischmann: We agree that nearly every patient has histological granulomatous prostatitis. However, the French recommendations focus on patients with grade III adverse events, that present with fever or other systemic symptoms and a clinically apparent prostatitis. Such a severe, symptomatic adverse event occurs in about 1–3% of cases and requires treatment. A. Böhle: At least 40% of patients receiving BCG will have asymptomatic granulomatous prostatitis, but no patient has ever been reported in the literature as having symptomatic granulomatous prostatitis as a sole event. No treatment is necessary for patients with asymptomatic granulomatous prostatitis alone. However, patients who present with severe symptoms should of course be treated. Floor: In the future will it be possible to individualize BCG treatment for each patient? A. Böhle: The EBIN group is working on this. Of course we need some prognostic indicators of when the BCG treatment course has been optimally completed, and we are not at that point yet. Examples are interleukin-2, cytokine titres and immune response in the bladder.

Floor: At what stage would you go over to cystectomy? Bill Catalona’s group has previously reported that if a cystoscopic evaluation shows recurrence after an initial 6week induction course, then patients should receive another 6-week induction course; if they then again recur, you should go over to cystectomy. Is this still the feeling? D.L. Lamm: It is true that a patient who has T1 or CIS at 6 months or beyond has a markedly increased risk for progression. I think it is also important to state that ‘failure’ at 3 months may not be failure. In our experience, and in the SWOG experience of patients with CIS at 3 months, the complete response rate will increase by 14% at 6 months even without additional BCG, and if we give three more BCG instillations the response rate will increase by an additional 30%. So clearly 3 months is still too early. As a rule of thumb, 6 months would be correct, but in fact we have seen patients who have taken 9 months to effect a complete response. If a patient shows continual improvement – for example from symptomatic CIS where every biopsy is positive to biopsies where half are positive to one focal remaining positive biopsy at 6 months – I would not insist that the patient have a cystectomy. Floor: Please could you provide some more information on the use of aspirin to prevent side-effects. A. Böhle: We do not use aspirin prophylactically. We use it only as a mild analgesic, for example if a patient experiences pain owing to inflammation. Here, however, we have had very good experience with it, and so we recommend oral acetyl salicylic acid.

BCG: The Optimal Approach in Superficial Bladder Cancer

Eur Urol 2000;37(suppl 1):37–39

39

Author Index

Al Khalifa, M. 26 Balta, G. 31 Bassi, P. 31 Böhle, A. 1, 21, 37 Callaghan, P. 26 Carando, R. 31 Chopin, D.K. 33 Colleen, S. 26 Desgrandchamps, F. 33 Duchek, M. 26 Durek, C. 21 EBIN Group 1 Elfving, P. 26 Eriksson, R. 26 Hagberg, G. 26

Hellsten, S. 26 Jocham, D. 21 Lamm, D.L. 9 Malavaud, B. 33 Malmström, P.-U. 16 Månsson, W. 26 Nelson, C.E. 26 Nyberg, G. 26 Olsson, R. 26 Pagano, F. 31 Rademark, C. 26 Rischmann, P. 33 Rüsch-Gerdes, S. 21 Spinadin, R. 31

Subject Index

Antibiotics 21 Bacillus Calmette-Guérin 21 BCG 1, 9, 16, 21, 31, 33 – toxicity 26 – vaccine 26 Bladder cancer 21, 26 – contraction 26 Chemotherapy 1, 9, 16 Cycloserine 21

ABC Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

© 2000 S. Karger AG, Basel

Accessible online at: www.karger.com/journals/eur

Immunotherapy 1, 9, 16, 21 INH prophylaxis 26 Intravesical therapy 1, 9, 16, 33 Isoniazid 26, 33 Phase II trials 31 – III trials 31 Review 31 Side-effects 31, 33 Superficial bladder cancer 1, 9, 16, 31