Intravesical Chemotherapy: An Update önew Trends and Perspectives

EAU Update Series 1 (2003) 71 79 Intravesical Chemotherapy: An Update önew Trends and Perspectives A.G. van der Heijden, J.A. Witjes * Department of Urology, University Medical Center Nymegen, Geert Grooteplein 10, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands Abstract More than 90% of all malignant bladder tumours are transitional cell carcinomas (TCC). Superficial TCC of the bladder is characterized by a high risk of recurrence (30 85%) after transurethral resection (TUR) of the initial tumour. Despite this high risk of recurrence, the 5-year survival rate is 85% to 90%. Unfortunately 10% to 30% of the superficial tumours will progress to a muscle invasive tumour, which has a poorer prognosis. The greatest concern in patients with superficial TCC is therefore twofold: to lower the number of recurrences and to prevent progression. In an attempt to prevent or delay tumour recurrence or progression, adjuvant therapy after TUR has become common practice. The different chemotherapeutical modalities currently used and investigated for the treatment of TCC of the bladder are reviewed, starting with the first drug shown to be effective for treatment of superficial bladder cancer and chronologically leading to the latest treatment options. # 2003 Elsevier Science B.V. All rights reserved. Keywords: Superficial bladder cancer; Chemotherapeutic instillation; Review; Doxorubicin; Epirubicin; Mitomycin C; Valrubicin; Pirarubicin; Gemcitabin; Intravesical hyperthermia 1. Introduction Superficial transitional cell carcinoma (TCC) of the bladder is characterized by a high risk of recurrence (30 85%) after transurethral resection (TUR) of the initial tumour [1,2]. Clinical prognostic factors for recurrence and progression are size, multiplicity, reaction to intravesical therapy, grade, stage and the presence of CIS. Nevertheless, recurrence anywhere in the bladder at first follow-up cystoscopy after TUR is one of the most important prognostic factors for time to progression [3,4]. It is possible to identify three groups of patients. A minority of patients has a relatively benign type of TCC, with a low recurrence rate. In such patients no adjuvant treatment is an option, but one immediate instillation with a chemotherapeutic agent lowers the recurrence * Corresponding author. Tel. þ31-24-361-67-12; Fax: þ31-24-354-10-31. E-mail address: f.witjes@uro.umcn.nl (J.A. Witjes). rate in the first years significantly [5 7], and therefore is the treatment of choice. The largest group consists of patients who develop a superficial recurrence, but seldom progression. In an attempt to reduce the number of recurrences, adjuvant therapy after TUR has become common practice. Finally, a small group of patients has a relatively malignant superficial tumour at presentation and despite maximum intravesical treatment, 50% of all patients will develop invasive cancer. These high-risk patients must be selected as soon as possible. 2. Principles of intravesical prophylaxis and therapy The aim of intravesical treatment in superficial bladder cancer is to prevent or delay tumour recurrence or progression. The mechanism of action for prophylactic intravesical chemotherapy remains unclear. Even though topical immuno- and chemotherapy may be useful to delay recurrence and progression, chromosomal patterns remain basically unstable [8]. 1570-9124/03/$ see front matter # 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/s1570-9124(03)00020-5

72 A.G. van der Heijden, J.A. Witjes / EAU Update Series 1 (2003) 71 79 Because most chemotherapeutic drugs are cell cycle specific, repeated instillations seem to be more effective than a single one. The drug is dissolved in sterile water, that provides better results as a diluent than saline [9]. The effect of the ph of the solution is not clear. Theoretically the ph can influence the stability and efficacy of the drug. An in vitro study, for example, showed that the cytotoxic activity of ThioTEPA was markedly enhanced when cells were treated with a diluent ph of 5.5. Significant differences were also observed after treatment with adriamycin (ADM) and mitomycin C (MMC) with a diluent ph of 7.0 [10]. Wientjes and Badalament [11] used pharmacokinetic data to develop a computer model which can predict the antitumour effect of MMC. The therapeutic outcome of MMC was influenced in the following rank order: dose> residual volume> urine production> dosing volume> urine ph> dwell time. They hypothesized that under optimal conditions the average recurrence free rate could increase from 56% to 76%. Before instillation the patient is advised to limit fluid intake in order to minimize dilution of the drug with urine. Systemic absorption is possible when the urothelium is damaged. In case of trauma or infection, instillation should be postponed for one week. The instillation is left for 1 to 2 hours in the bladder. Although cytotoxicity is proportional to drug concentration and exposure time, longer instillation time might increase toxicity and is unpractical [12]. An advantage of the intravesical administration route is no or little systemic uptake of the drug and direct contact between tumour or urothelium at risk, and the drug. Disadvantages are local side effects and the need for transurethral manipulation. 3. ThioTEPA ThioTEPA was the first drug shown to be effective for treatment of superficial bladder cancer when given intravesically [13]. It is an alkylating agent that inhibits the synthesis of nucleic acid, thereby interfering with protein synthesis. Unlike other drugs used to treat superficial bladder cancer, such as ADM and MMC, ThioTEPA has the disadvantage that it easily passes through the bladder wall [14]. Generally 30 to 60 mg of ThioTEPA is given in volumes ranging from 20 to 100 ml. Exposure time varies between 30 and 120 minutes. The use of 60 mg in 30 ml seems to increase the dose rate to the tumour without increasing systemic toxicity [15]. Note that these benefits will be greater for drugs as ADM and MMC because they are not absorbed into the circulation. Generally 6 weekly ThioTEPA instillations are continued for 1 year with monthly instillations. Although the molecular weight of ThioTEPA is low, 189, ThioTEPA induced myelosuppression is considered to be rare, usually mild and transient [16]. This was confirmed in later studies. In 1992 Trasher and Crawford reviewed the toxicity of ThioTEPA [17]. Intravesical instillations of ThioTEPA have resulted in incidences of leukopenia of 8% to 54%, of thrombocytopenia of 3% to 31%, and of irritative voiding symptoms of 12% to 69%. These wide ranges in the reported side effects are due to differences in dose, instillation time and schedules. It was concluded that the risk of myelosuppression and irritative complaints increased with the dose and with the number and frequency of instillations. Combining the results of ThioTEPA as definite therapy from two reviews, the success rate is approximately 38% (109/285) in 10 small series [18,19]. However, single adjuvant instillations with ThioTEPA conducted in a large Medical Research Council (MRC) trial showed no advantage over TUR [20]. In conclusion, ThioTEPA is better than no additional therapy, although not always statistically significant. ThioTEPA is no longer frequently used due to its (systemic) toxicity and limited efficacy. Since 1994 no data are published about new ThioTEPA bladder cancer treatment trials. 4. Ethoglucid (Epodyl) Epodyl has a molecular weight of 262 and is thus poorly absorbed. Drug induced cystitis, dysuria and frequency are the most common side effects [17]. The mechanism of action is still unknown. Kurth et al. compared the efficacy of TUR with TUR followed by 1 year ADM or ethoglucid [21]. In total, 432 patients were evaluated. The median follow-up time to first recurrence was 3.4 years. Time to first recurrence was prolonged by both drugs compared to TUR alone ( p < 0:001). The recurrence rate per year was 0.30 for both adjuvant treatment arms and 0.68 for the group only receiving TUR. Progression rates were 15% in all groups. So recurrence is influenced by use of ADM or ethoglucid. However, progression in stage is not influenced by this treatment. Long-term follow-up was studied in 111 patients retrospectively with 6.4 years follow-up [22]. In total 65% of all patients responded completely after 12 weekly instillations and 46% of these remained free of disease for 5 years. Currently, Epodyl is not frequently used anymore.

A.G. van der Heijden, J.A. Witjes / EAU Update Series 1 (2003) 71 79 73 5. Adriamycin (Doxorubicin, ADM) The dose of ADM ranges from 30 to 100 mg in several instillation schedules. The molecular weight of ADM is 580, thus absorption and systemic toxicity are extremely rare. The most frequent side effect of ADM is chemical cystitis in 25 30% of the patients [17]. Rare side effects are allergic reactions (0.3%), gastrointestinal side effects (1.7%) and fever (0.8%). These side effects disappear after cessation of therapy. The response rates of ADM used as definite treatment for papillary tumours, varies between 28 and 56%, with an average of 38% (273/712), depending on the dose used [19]. However, for CIS the complete response is only 34% in a multicentre trial with 67 CIS patients. The median time to treatment failure in this trial is reported as only 5 months [23]. Lamm reviewed 4 large controlled studies where ADM was used as prophylactic, the percentage of patients with a recurrence in the ADM groups was 38% versus 56% in the control groups, indicating an advantage for ADM of 18% [24]. Nevertheless, the three largest series showed no significant advantage for ADM. For example, in a study in which 268 patients after TUR were randomized for no further treatment, 12 bi-weekly instillations and 1 year of ADM treatment, there was no significant difference for the recurrence rate, progression and survival between the three groups [25]. In an EORTC randomized study, which was also an adjuvant study, ADM and ethoglucid were compared with transurethral resection alone [21]. The analysis of treatment results for recurrence included 432 patients at a median follow-up of 3.4 years for time to first recurrence, 5 years for analysis of time to invasion and 10.7 years for duration of survival. Both drugs compared to transurethral resection alone showed a significantly prolonged time to first recurrence. Recurrence rate per year was 0.30 for both adjuvant treatments and 0.68 for the resection only group. Progression to muscle invasion was rare (15.1% of all cases) and not different in the three different treatment arms. There was a strong relation between death from malignant disease and T category and tumour grade but this was not influenced by the treatment regimen. In an attempt to improve the ADM treatment Naito et al. performed a randomized controlled trial in which ADM treatment was compared with ADM combined with verapamil [26]. The ADM plus verapamil instillation group did show a significantly higher no recurrence rate than the ADM instillation group. The Japanese urological cancer research group studied the possible advantages of maintenance therapy. In the first study only short-term schedules were used with two doses ADM, MMC and controls [27]. In all, 575 patients were evaluated ( p < 0:05). The disease free rates were significantly better in all treatment groups compared to controls. In the second study, same drugs and dosages were used, but with a two-year maintenance schedule. The results of both studies were comparable, suggesting no advantage to the maintenance therapy. In conclusion, ADM is a safe drug with almost no systemic side effects. ADM is more effective than no adjuvant treatment, but again these figures often are not significant. ADM is more effective when combined with verapamil. ADM maintenance is clearly of no additional value. 6. Epirubicin (EPI) The dose of EPI varies from 20 to 100 in several instillation schedules. The antitumour effect of EPI is similar to ADM [28]. Absorption of EPI, even when EPI is given immediately after TUR [29], is very limited due to a molecular weight of 544. The most frequent side effect is chemical cystitis. Burk et al. reported that 14% of patients in a large series had chemical cystitis [30]. However, in the EORTC study (30863) with a single 80 mg EPI instillation, the frequency of drug induced cystitis was also only 6.8% [5]. In the same study the recurrence rate was significantly less in the EPI group ( p < 0:0001) as compared to an instillation with sterile water. The EPI dose is still controversial. In a randomized UK study with 122 patients, the difference in response to standard and high doses of intravesical EPI (50 mg/50 ml respectively 100 mg/50 ml) of a marker tumour were determined [31]. Epirubicin at double the standard dose for intravesical chemotherapy of superficial bladder cancer is not superior with regard to marker tumour response, time to first recurrence or recurrence rate. Also the number of instillations is controversial. A Chinese group compared a single 80 mg EPI instillation with consecutive 40 mg EPI or consecutive 40 mg MMC [32]. Disease free intervals of these 3 groups did not differ significantly. However, side effects in the single instillation group were significantly lower then in the consecutive treatment groups. Also Rajala studied the effect of a single instillation with EPI. In this trial the long-term efficacy of a single dose of 100 mg EPI administered immediately after TUR was compared with TUR alone for primary TCC in 200 patients [33]. At a median follow-up of 72 months the recurrence rate was 46% for patients treated with EPI and 73% for the control group ( p ¼ 0:002), so a single

74 A.G. van der Heijden, J.A. Witjes / EAU Update Series 1 (2003) 71 79 perioperative instillation of 100 mg epirubicin causes a significant decrease in recurrence rate. Similar results were found using a much lower dose of 40 mg/40 ml EPI in 119 patients [34]. Again, the yearly recurrence rate was significantly less in the treated group (0.13 versus 0.29) with mild toxicity (13.8% bladder irritation). With regard to maintenance therapy many studies have been performed. Eto et al. compared EPI to ADM [35]. During one year 114 evaluable Ta/T1 patients were treated with each 19 instillations of 30 mg/30 ml EPI or ADM. The tumour free rates at 1 and 2 years were 92.8% and 88.6% for EPI, 86.4% and 81.7% for ADM respectively (not significant). In another study, 45 patients with primary superficial bladder cancer were treated with EPI 20 mg every second week for 4 months and then once a month or every 2 weeks for the next 8 months after TUR. The overall recurrence rate was 23.9% at 2 years and 47.7% at 5 years followup. These results were better than patients treated with TUR alone [36]. Also Torelli showed that maintenance treatment with EPI can be effective [37]. In total, 169 patients with a T1G2 tumour were treated within 3 weeks after TUR with 4 weekly and 11 monthly instillations of 80 mg EPI. Treatment was well tolerated. At a median follow-up of 38 months the recurrence rate was 43,3%. Nevertheless, another study with a similar treatment schedule suggested that maintenance therapy did not improve the efficacy [38]. A possible explanation is the use of a lower dose of EPI (40 mg). In conclusion, the efficacy of EPI seems similar to other chemotherapeutic drugs, however, with less drug induced cystitis. The additional advantage of EPI maintenance therapy is controversial. 7. Mitomycin C (MMC) MMC has an intracellular effect resulting in the production of an alkylating agent. The mode of action is poorly understood. With a molecular weight of 334 MMC is hardly absorbed so myelosuppression is rare (0.7%). The dose varies between 20 and 80 mg per instillation. In a meta-analysis of 181 articles, published from 1966 to 1998, incidence of frequency ranges between 26 and 59% with a mean of 42%, bacterial cystitis ranged between 17 and 23% with a mean of 20% and allergic reactions, mainly skin symptoms, ranged between 8 and 19% with a mean of 13% [39]. Most skin reactions are due to a delayed type hypersensitivity reaction, usually occurring after several instillations [40]. In an EORTC marker lesion study (30864), the complete response rate for the marker lesion after 8 instillations with 80 mg of MMC was 50% (48/96) [19]. The effectiveness of a single immediate MMC instillation in patients with low risk superficial bladder cancer was studied in a prospective controlled trial by Solsona et al. [6]. In this study 64 patients received no treatment and 57 received one immediate instillation of 30 mg MMC after complete TUR. Recurrences developed during the first 12 months in 59% of the control group but only 22.2% of the MMC group ( p ¼ 0:005). However, at long-term follow-up these differences were not statistically significant. For prophylactic use, after complete TUR, data from 23 clinical trials were analyzed and confirmed that the average net benefit from intravesical chemotherapy compared to TUR alone was 14% at 1 to 3 years [41]. This EORTC meta-analysis even confirmed that intravesical chemotherapy decreases recurrence by 7% after 7 years. Although the recurrence rate decreased, disease progression was not influenced by MMC. Lamm also reviewed five controlled prophylactic trials with 859 patients [24]. The advantage of MMC was 15% (52% recurrences in the control groups versus 37% in the MMC group). Nevertheless, Lamm could not demonstrate a long-term effect on recurrence and disease progression. The long-term follow-up was also studied in a prospective EORTC study with 344 (173/171) eligible patients. The efficacy with regard to tumour recurrence was similar for patients treated with 6 weekly MMC and 6 weekly BCG-RIVM [42]. In another study 9 weekly MMC instillations were compared with 6 weekly BCG-Tice or BCG-RIVM instillations [43]. The disease-free percentage showed no difference for the three arms for papillary tumours ( p ¼ 0:08), nor for CIS ( p ¼ 0:20). However, studies directly comparing BCG and MMC give conflicting results. Two possible causes might be patient selection and the use of different MMC and especially BCG schedules. In an attempt to improve the MMC treatment Au et al. performed a randomized 2-arm study (119/111), in which instillation of 40 mg MMC with pharmacokinetic intervention to increase drug concentration by decreasing urine volume, was compared with 20 mg MMC instillation without intervention. After 5 years follow-up the optimized arm showed a time to recurrence of 29.1 months and a recurrence-free fraction of 41.0% versus 11.8 months and 24.6% ( p < 0:005) for the normal treatment [44]. The advantage of MMC maintenance therapy is controversial. The results of a Japanese study showed no advantage for maintenance therapy over short-term

A.G. van der Heijden, J.A. Witjes / EAU Update Series 1 (2003) 71 79 75 therapy. Instillations of MMC were combined with ADM [45]. In this study complete responders on an induction course of 5 weekly instillations were randomized between no adjuvant therapy and 12 monthly instillations of MMC and ADM. In this group of complete responders no beneficial effect of maintenance therapy was seen in patients with papillary tumours. For CIS patients the 2-year recurrence rate after maintenance therapy was significantly better ( p < 0:05), but the curves suggest that with a longer follow-up this difference will disappear. Nevertheless, some studies showed an advantage of maintenance therapy. Huland compared 3-year MMC instillation therapy (42 instillations of 20 mg) to no intravesical therapy in a randomized trial after complete TUR [46]. The percentage of recurrences was 10.4% in the MMC group compared to 51% in the control group. A later multicentre trial confirmed these results of long-term prophylaxis [47]. With a mean follow-up of 62.5 months the recurrence rate was higher (20.7%), the overall progression rate was 9.3%. However, the majority of these patients were at low risk for recurrence. Schwaibold et al. also implemented two 3-year prophylactic protocols with either MMC or ADM [48]. In total 419 patients were evaluated after a median follow-up of 57 months. An overall recurrence rate of 22.7% and an overall progression rate of 9.8% were found. A possible explanation for this controverse in advantage of maintenance therapy is found in a pairwise comparison which showed that a combination of a short-term intensive (weekly) instillation schedule combined with long-term maintenance instillation was significantly more effective as compared to long-term maintenance instillation alone [48]. In other words the effect of the short-term intensive MMC therapy may be of more importance than the long-term maintenance therapy. Finally, several studies compared maintenance MMC with maintenance BCG [49,50]. In one study, the relative risk of recurrence, despite MMC (0.508) or BCG (0.618), was similar [49]. Nevertheless, in a prophylactic study of Malmström, maintenance BCG was superior in preventing recurrence compared to maintenance MMC, but no difference was found for progression and survival [50]. In conclusion, although the frequency of druginduced cystitis is comparable to other chemotherapeutic drugs and systemic side effects are rare, up to 13% of the patients can experience allergic reactions. The response rates of MMC seem higher than other chemotherapeutic drugs, however again not all studies show a significant advantage of MMC over no additional treatment. The advantage of MMC maintenance therapy is again controversial. 8. Valrubicin (AD32) Valrubicin (AD32) is an N-trifluoroacetyl, 14-valerate derivative of the anthracycline ADM [51]. In patients with BCG-refractory CIS or recurrent papillary tumours of the bladder that have failed other intravesical therapies and refuse cystectomy, AD32 has been used. In an open label noncomparative study 90 patients received 6 weekly instillations of 800 mg valrubicin [52]. Of all patients 21% had a complete response. Additionally, 16% had Ta recurrence only. In a prospective phase II study, 40 patients with TCC underwent TUR at which a tumour <1 cm in diameter was deliberately left in the bladder [53]. All patients received 6 instillations of 800 mg valrubicin. In all, 54% were found clinically free of disease, whereas 46% were found histologically free of disease after 3 months. The current estimate of mean time to recurrence is 248 days. Adverse events were assessed in a pilot study including 22 patients who received a single dose of valrubicin [54]. The most commonly reported events were dysuria (77%), hematuria (59%) and urgency/frequency (23%). These preliminary results indicate that valrubicin is effective and well tolerated in patients with CIS of the bladder refractory to BCG therapy. Furthermore a sixweek course of valrubicin has proved effective in ablating a marker tumour. However, additional follow-up and more studies are needed to define the role of valrubicin in the treatment of superficial bladder cancer. 9. Pirarubicin (THP) Another anthracycline under investigation is pirarubicin. An initial study comparing 20 mg of ADM, EPI, pirarubicin and a control group, showed no significant difference in efficacy for the three drugs used, although pirarubicin failed to show a significant advantage over the control group [55]. However, a few years later the optimal dose in terms of anti-tumour effect and minimal side effects was found to be 30 mg/30 ml during 30 minutes [56]. In a randomized study of single early THP instillation for a single superficial bladder carcinoma 84 patients were treated with either THP within 6 hours after TUR versus the controls who underwent TUR alone [57]. The recurrence free rate at 1 year was 92% versus 67%, and 79% versus 53% after 3 years. This indicates that a single THP instillation immediately after TUR reduces the recurrence of TCC.

76 A.G. van der Heijden, J.A. Witjes / EAU Update Series 1 (2003) 71 79 10. Gemcitabin Gemcitabine is a novel deoxycytidine analogue with a broad spectrum of antitumour activity. It has a molecular weight of 300 and after intracellular activation, the active metabolite is incorporated into DNA, resulting in inhibition of further DNA synthesis. Only one study, Cozzi et al., with safety data on the intravesical use in dogs is published [58]. In this study at all intravesical doses, significant systemic absorption was seen. However, preclinical results of our own department show no systemic absorption in pigs. Possible explanations are the difference in animal size and the instillation schedule (three times per week versus weekly). Preliminary results in twelve small studies (142 patients) show almost no systemic toxicity (personal communication). Drug concentrations varied from 5 mg/ml to 40 mg/ml. Volumes varied from 50 to 100 ml. Efficacy results with short follow-up (1 year maximally) show that higher doses seem to be more effective, although not in all trials. In those studies that mentioned recurrences (mostly in BCG refractory groups), 26/53 complete responders were reported, and 27/53 had no or a partial response. In the two ablative trials 5/18 patients were reported to have a complete response. These results are confirmed in the first of these studies published, a phase 1 trial in BCG refractory CIS, using twice weekly intravesical gemcitabine in 18 patients with four dose levels [59]. 11. Sequential chemo/immunotherapy The theoretical advantage of sequential use of chemotherapy and immunotherapy might be the combination of different working mechanisms with possible potentiation of antitumour effect. A second advantage might be the increase in the fibronectin activity [60] due to chemical cystitis which can have a positive effect on the adherence of BCG particles to the bladder wall [61]. A disadvantage could be that intravesical combination of a chemotherapeutic drug and BCG might also enhance toxicity. An EORTC marker lesion study (30897) with sequential MMC and BCG (4 times versus 6 times), for low stage, low grade recurrent bladder tumours, gave a complete response of 69% [62]. The Finnbladder group conducted 2 studies comparing MMC with an alternating MMC/BCG schedule in patients with CIS [63] or rapidly recurring papillary tumours [64].In both studies the side effects in the MMC/BCG group were similar to those in the MMC group. In CIS patients the alternating schedule was significantly more effective than MMC alone with regard to the CR rate (74% versus 47% at 24 months, p ¼ 0:041), disease free interval ( p ¼ 0:043) and recurrence rate ( p ¼ 0:013). Efficacy results in papillary tumours, were equal in both arms [64]. Results from a study of our own department showed that the sequential use of intravesical BCG and MMC had no advantage over intravesical MMC alone in intermediate and high risk superficial bladder cancer patients with regard to tumour recurrence and progression [65]. This difference can be explained by the fact that only 4% of all patients in our group had CIS, where the Finnlander group considered the alternating schedule to be more effective. 12. Intravesical hyperthermia and mitomycin C Intravesical hyperthermia has been used to improve the efficacy of MMC. A study to assess the effect of local hyperthermia on systemic absorption of MMC during intravesical chemotherapy showed that the MMC plasma concentration was always 6 times lower than those to show myelosuppression [66]. Colombo et al. studied microwave induced hyperthermia and intravesical chemotherapy. In a neoadjuvant study 52 patients were randomly assigned to receive hyperthermia combined with MMC or MMC alone [67]. A pathologically complete response was seen in 19 cases (66%) in the MMC/hyperthermia group versus 22% in the group receiving MMC ( p < 0:01). Afterwards they studied microwave induced hyperthermia as a debulking approach in 19 patients with multifocal recurrent bladder tumours where radical cystectomy was considered the treatment of choice [68]. After 8 weekly one-hour sessions with 40 mg/40 ml MMC, 47% had a complete response, 37% had a partial response, and 16% were considered nonresponder. After a median 33 month follow-up 42% had a recurrence. Recently, data of 81 intermediate-risk and high-risk patients, treated with microwave induced hyperthermia and intravesical chemotherapy (1994 2002), were analyzed. This neoadjuvant treatment induced complete tumour eradication for 88% (71/81) of all patients. After an average follow-up of 13 months, 66% were still free of disease (abstract will be published April 2003 Journal of Urology Supplements). Microwave induced hyperthermia combined with MMC is a safe approach and has potentially additional value, particularly where other treatments have failed.

A.G. van der Heijden, J.A. Witjes / EAU Update Series 1 (2003) 71 79 77 13. Conclusions Intravesical chemotherapy is an effective treatment for patients with superficial bladder cancer. A frequent side effect of all drugs is chemical cystitis in 20 30%, although reversible and seldom severe. However, there are differences in other side effects. Adjuvant intravesical chemotherapy has no impact on progression and survival benefit [41,69], but it does influence the recurrence rate. For example, one immediate single chemotherapeutic instillation in patients with a relatively benign type of TCC lowers therecurrencerateinthefirst year with 40 50%. Furthermore, in optimal conditions all chemotherapeutics administered in an adjuvant setting to TUR are able to improve recurrence rates with 15 to 25% for one to three years [69]. Greater reductions in the 1 to 3 year recurrence rates have been suggested by others, which in part might be explained by the study design of the studies included in this meta-analysis [70]. After a median follow-up of eight years, 8% fewer recurrences were seen after intravesical chemotherapy. Of most drugs, different doses and schedules are used, without significant impact on results. Finally, for all drugs the advantage of maintenance treatment is controversial. References [1] Kiemeney LA, Witjes JA, Heijbroek RP, Verbeek AL, Debruyne FM. Predictability of recurrent and progressive disease in individual patients with primary superficial bladder cancer. J Urol 1993;150(1): 60 4. [2] Amling CL. Diagnosis and management of superficial bladder cancer. Curr Probl Cancer 2001;25(4):219 78. [3] Kurth KH, Denis L, Bouffioux C, Sylvester R, Debruyne FM, Pavone-Macaluso M, et al. Factors affecting recurrence and progression in superficial bladder tumours. Eur J Cancer 1995;31A(11): 1840 6. [4] Holmang S, Johansson SL. Stage Ta-T1 bladder cancer: the relationship between findings at first followup cystoscopy and subsequent recurrence and progression. J Urol 2002;167(4):1634 7. [5] Oosterlinck W, Kurth KH, Schroder F, Bultinck J, Hammond B, Sylvester R. A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. J Urol 1993;149(4):749 52. [6] Solsona E, Iborra I, Ricos JV, Monros JL, Casanova J, Dumont R. Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup. J Urol 1999;161(4):1120 3. [7] Oosterlinck W, Lobel B, Jakse G, Malmström PU, Stockle M, Sternberg C. Guidelines on bladder cancer. Eur Urol 2002;41(2): 105 12. [8] Pycha A, Mian C, Hofbauer J, Haitel A, Wiener H, Marberger M. Does topical instillation therapy influence chromosomal aberrations in superficial bladder cancer? J Urol 1998;159(1):265 9. [9] Groos E, Masters JR. Intravesical chemotherapy: studies on the relationship between osmolality and cytotoxicity. J Urol 1986;136(2): 399 402. [10] Tarkington M, Sommers CL, Gelmann EP, Tefft MC, Lynch JH. The effect of PH on the in vitro colony forming ability of transitional cell carcinoma cells treated with various chemotherapeutic agents: implications for in vivo therapy. J Urol 1992;147(2):511 3. [11] 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(4):255 62. [12] Walker MC, Masters JR, Parris CN, Hepburn PJ, English PJ. Intravesical chemotherapy: in vitro studies on the relationship between dose and cytotoxicity. Urol Res 1986;14(3):137 40. [13] Jones HC, Swinney J. ThioTEPA in the treatment of tumours of the bladder. Lancet 1961;II:615 8. [14] Cohen BE, Egorin MJ, Kohlhepp EA, Aisner J, Gutierrez PL. Human plasma pharmacokinetics and urinary excretion of thiotepa and its metabolites. Cancer Treat Rep 1986;70(7):859 64. [15] Masters JR, McDermott BJ, Harland S, Bibby MC, Loadman PM. ThioTEPA pharmacokinetics during intravesical chemotherapy: the influence of dose and volume of instillate on systemic uptake and dose rate to the tumour. Cancer Chemother Pharmacol 1996;38(1): 59 64. [16] Soloway MS, Ford KS. Thiotepa-induced myelosuppression: review of 670 bladder instillations. J Urol 1983;130(5):889 91. [17] Thrasher JB, Crawford ED. Complications of intravesical chemotherapy. Urol Clin North Am 1992;19(3):529 39. [18] Richie JP. Intravesical Chemotherapy. Treatment selection, techniques, and results. Urol Clin North Am 1992;19(3):521 7. [19] Bouffioux C, Meijden A, Kurth KH, Jakse G, Bono A, Hall R, et al. Objective response of superficial bladder tumors to intravesical treatment (including review of response of marker lesions). Prog Clin Biol Res 1992;378:29 42. [20] The effect of intravesical thiotepa on tumour recurrence after endoscopic treatment of newly diagnosed superficial bladder cancer. A further report with long-term follow-up of a Medical Research Council randomized trial. Medical Research Council Working Party on Urological Cancer, Subgroup on Superficial bladder cancer. Br J Urol 1994;73(6):632 8. [21] Kurth K, Tunn U, Ay R, Schroder FH, Pavone-Macaluso M, Debruyne F, et al. Adjuvant chemotherapy for superficial transitional cell bladder carcinoma: long-term results of a European Organization for Research and Treatment of Cancer randomized trial comparing doxorubicin, ethoglucid and transurethral resection alone. J Urol 1997;158(2):378 84. [22] Mufti GR, Virdi JS, Hall MH. Long-term follow-up of intravesical epodyl therapy for superficial bladder cancer. Br J Urol 1990; 65(1):32 5. [23] Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, et al. A Randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitionalcell carcinoma of the bladder. N Engl J Med 1991;325(17):1205 9. [24] Lamm DL. Long-term results of intravesical therapy for superficial bladder cancer. Urol Clin North Am 1992;19(3):573 80. [25] Rubben H, Lutzeyer W, Fischer N, Deutz F, Lagrange W, Giani G. Natural history and treatment of low and high risk superficial bladder tumors. J Urol 1988;139(2):283 5. [26] Naito S, Kotoh S, Omoto T, Osada Y, Sagiyama K, Iguchi A, et al. Prophylactic intravesical instillation chemotherapy against recurrence after a transurethral resection of superficial bladder cancer: a

78 A.G. van der Heijden, J.A. Witjes / EAU Update Series 1 (2003) 71 79 randomized controlled trial of doxorubicin plus verapamil versus doxorubicin alone. The Kyushu University Urological Oncology Group. Cancer Chemother Pharmacol 1998;42(5):367 72. [27] Akaza H, Isaka S, Koiso K, Kotake T, Machida T, Maru A, et al. Comparative analysis of short-term and long-term prophylactic intravesical chemotherapy of superficial bladder cancer. prospective, randomized, controlled studies of the Japanese Urological Cancer Research Group. Cancer Chemother Pharmacol 1987;20(Suppl): S91 6. [28] Onrust SV, Wiseman LR, Goa KL. Epirubicin: a review of its intravesical use in superficial bladder cancer. Drugs Aging 1999; 15(4):307 33. [29] Tsushima T, Miyaji Y, Noda M, Nasu Y, Kumon H, Ohmori H. Absorption of epirubicin instilled intravesically immediately after transurethral resection of superficial bladder cancer. Urol Int 1998; 60(3):161 4. [30] Burk K, Kurth KH, Newling D. Epirubicin in treatment and recurrence prophylaxis of patients with superficial bladder cancer. Prog Clin Biol Res 1989;303:423 34. [31] Masters JR, Popert RJ, Thompson PM, Gibson D, Coptcoat MJ, Parmar MK. Intravesical chemotherapy with epirubicin: a dose response study. J Urol 1999;161(5):1490 3. [32] Liu B, Zhang Y, Wang Z, Ding Q, Chen B, Wang J, et al. Single instillation of epirubicin for the prophylaxis of recurrent primary superficial bladder carcinoma. Zhonghua Wai Ke Za Zhi 2002;40(2): 112 5. [33] Rajala P, Kaasinen E, Raitanen M, Liukkonen T, Rintala E. Perioperative single dose instillation of epirubicin or interferonalpha after transurethral resection for the prophylaxis of primary superficial bladder cancer recurrence: a prospective randomized multicenter Study FinnBladder III Long-Term Results. J Urol 2002;168(3):981 5. [34] Okamura K, Murase T, Obata K, Ohshima S, Ono Y, Sakata T, et al. A randomized trial of early intravesical instillation of epirubicin in superficial bladder cancer. The Nagoya University Urological Oncology Group. Cancer Chemother Pharmacol 1994;35(Suppl): S31 35. [35] Eto H, Oka Y, Ueno K, Nakamura I, Yoshimura K, Arakawa S, et al. Comparison of the prophylactic usefulness of epirubicin and doxorubicin in the treatment of superficial bladder cancer by intravesical instillation: a multicenter randomized trial. Kobe University Urological Oncology Group. Cancer Chemother Pharmacol 1994;35(Suppl):S46 51. [36] Kondo T, Onitsuka S, Ryoji O, Kihara T, Goto Y, Satoh T, et al. Analysis of prognostic factors related to primary superficial bladder cancer tumor recurrence in prophylactic intravesical epirubicin therapy. Int J Urol 1999;6(4):178 83. [37] Torelli F, Catanzaro F, Conti G, Comeri CG, Risi O, Pino R, et al. High-dose epirubicin in the prophylactic treatment of T1G2 superficial bladder tumors. Eur Urol 2001;39(Suppl 2):11 4. [38] Okamura K, Kinukawa T,Tsumura Y,OtaniT,ItohH,Kobayashi H, et al. A randomized study of short versus long-term intravesical epirubicin instillation for superficial bladder cancer. Nagoya University Urological Oncology Group. Eur Urol 1998;33(3): 285 8. [39] Smith Jr JA, Labasky RF, Cockett AT, Fracchia JA, Montie JE, Rowland RG. Bladder cancer clinical guidelines panel summary report on the management of nonmuscle invasive bladder cancer (stages Ta, T1 and TIS). The American Urological Association. J Urol 1999;162(5):1697 701. [40] de Groot AC, Conemans JM. Systemic allergic contact dermatitis from intravesical instillation of the antitumor antibiotic mitomycin C. Contact Dermatitis 1991;24(3):201 9. [41] Pawinski A, Sylvester R, Kurth KH, Bouffioux C, van der Meijden A, Parmar MK, et al. 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 TaT1 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(6):1934 40 [Discussion]. [42] Witjes JA, van der Meijden AP, Sylvester LC, Debruyne FM, van Aubel A, Witjes WP. Long-term follow-up of an EORTC randomized prospective trial comparing intravesical Bacille Calmette-Guérin- 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(3):403 10. [43] Witjes JA, van der Meijden AP, Witjes WP, Doesburg W, Schaafsma HE, Debruyne FM. A randomised prospective study comparing intravesical instillations of mitomycin C, BCG-Tice, and BCG- RIVM in PTa-PT1 tumours and primary carcinoma in situ of the urinary bladder. Dutch South-East Cooperative Urological Group. Eur J Cancer 1993;29A(12):1672 6. [44] Au JL, Badalament RA, Wientjes MG, Young DC, Warner JA, Venema PL, et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst 2001;93(8):597 604. [45] Fukui I, Kihara K, Sekine H, Tachibana Y, Kawai T, Ishiwata D, et al. Intravesical combination chemotherapy with mitomycin C and doxorubicin for superficial bladder cancer: a randomized trial of maintenance versus no maintenance following a complete response. Cancer Chemother Pharmacol 1992;30(Suppl):S37 40. [46] Huland H, Otto U, Droese M, Kloppel G. Long-term mitomycin C instillation after transurethral resection of superficial bladder carcinoma: influence on recurrence, progression and survival. J Urol 1984;132(1):27 9. [47] Schwaibold H, Klingenberger HJ, Huland H. Long-term results of intravesical prevention of recurrence with mitomycin C and adriamycin in patients with superficial bladder cancer. Urologe A 1994;33(6):479 83. [48] Schwaibold H, Pichlmeier U, Klingenberger HJ, Huland H. Longterm follow-up of cytostatic intravesical instillation in patients with superficial bladder carcinoma. Is short-term, intensive instillation better than maintenance therapy? Eur Urol 1997;31(2):153 9. [49] Krege S, Giani G, Meyer R, Otto T, Rübben 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. J Urol 1996;156(3):962 6. [50] Malmström PU, Wijkstrom H, Lundholm C, Wester K, Busch C, Norlen BJ. 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guérin in patients with superficial bladder carcinoma. Swedish-Norwegian Bladder Cancer Study Group. J Urol 1999;161(4):1124 7. [51] Onrust SV, Lamb HM. Valrubicin. Drugs Aging 1999;15(1):69 75. [52] Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M. Efficacy and safety of valrubicin for the treatment of bacillus Calmette-Guérin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. J Urol 2000;163(3):761 7. [53] Newling DW, Hetherington J, Sundaram SK, Robinson MR, Kisbenedek L. The use of valrubicin for the chemoresection of superficial bladder cancer a marker lesion study. Eur Urol 2001; 39(6):643 7. [54] Patterson AL, Greenberg RE, Weems L, Bahnson R, Wajsman Z, Israel M, et al. Pilot study of the tolerability and toxicity of intravesical valrubicin immediately after transurethral resection of superficial bladder cancer. Urology 2000;56(2):232 5. [55] Lundbeck F, Mogensen P, Jeppesen N. Intravesical therapy of noninvasive bladder tumors (stage Ta) with doxorubicin and urokinase. J Urol 1983;130(6):1087 9.

A.G. van der Heijden, J.A. Witjes / EAU Update Series 1 (2003) 71 79 79 [56] Kobayashi M, Sugaya Y, Yuzawa M, Ochi M, Morita T, Kobayashi Y, et al. Appropriate intravesical retention time of pirarubicin concentration based on its level in tumor tissue, anti-tumor effect and side effect in intravesical instillation therapy for bladder tumor. Gan To Kagaku Ryoho 1998;25(11):1771 4. [57] Okamura K, Ono Y, Kinukawa T, Matsuura O, Yamada S, Ando T, et al. Randomized study of single early instillation of (2 00 R)-4 0 -otetrahydropyranyl-doxorubicin for a single superficial bladder carcinoma. Cancer 2002;94(9):2363 8. [58] Cozzi PJ, Bajorin DF, Tong W, Nguyen H, Scott J, Heston WD, et al. Toxicology and pharmacokinetics of intravesical gemcitabine: a preclinical study in dogs. Clin Cancer Res 1999;5(9):2629 37. [59] Dalbagni G, Russo P, Sheinfeld J, Mazumdar M, Tong W, Rabbani F, et al. Phase I trial of intravesical gemcitabine in bacillus Calmette- Guérin-refractory transitional-cell carcinoma of the bladder. J Clin Oncol 2002;20(15):3193 8. [60] Mosher DF. Physiology of fibronectin. Annu Rev Med 1984;35: 561 75. [61] Kavoussi LR, Brown EJ, Ritchey JK, Ratliff TL. Fibronectinmediated Calmette-Guérin bacillus attachment to murine bladder Mucosa. Requirement for the expression of an antitumor response. J Clin Invest 1990;85(1):62 7. [62] Maffezzini M, Simonato A, Zanon M, Raber M, Carmignani G. Upfront intravesical chemotherapy for low stage, low grade recurrent bladder cancer. J Urol 1996;155(1):91 3. [63] Rintala E, Jauhiainen K, Rajala P, Ruutu M, Kaasinen E, Alfthan O. Alternating mitomycin C and bacillus Calmette-Guérin instillation therapy for carcinoma in situ of the bladder. The FinnBladder Group. J Urol 1995;154(6):2050 3. [64] Rintala E, Jauhiainen K, Kaasinen E, Nurmi M, Alfthan O. Alternating mitomycin C and bacillus Calmette-Guérin instillation prophylaxis for recurrent papillary (stages Ta to T1) superficial bladder cancer. FinnBladder Group. J Urol 1996;156(1):56 9. [65] Witjes JA, Caris CT, Mungan NA, Debruyne FM, Witjes WP. Results of a randomized phase III trial of sequential intravesical therapy with mitomycin C and bacillus Calmette-Guérin versus mitomycin C alone in patients with superficial bladder cancer. J Urol 1998; 160(5):1668 71. [66] Paroni R, Salonia A, Lev A, Da Pozzo LF, Cighetti G, Montorsi F, et al. Effect of local hyperthermia of the bladder on mitomycin C pharmacokinetics during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma. Br J Clin Pharmacol 2001;52(3):273 8. [67] Colombo R, Da Pozzo LF, Lev A, Freschi M, Gallus G, Rigatti P. Neoadjuvant combined microwave induced local hyperthermia and topical chemotherapy versus chemotherapy alone for superficial bladder cancer. J Urol 1996;155(4):1227 32. [68] Colombo R, Da Pozzo LF, Lev A, Salonia A, Rigatti P, Leib Z, et al. Local microwave hyperthermia and intravesical chemotherapy as bladder sparing treatment for select multifocal and unresectable superficial bladder tumors. J Urol 1998;159(3):783 7. [69] Nilsson S, Ragnhammar P, Glimelius B, Nygren P. A systematic overview of chemotherapy effects in urothelial bladder cancer. Acta Oncol 2001;40(2 3):371 90. [70] Huncharek M, Geschwind JF, Witherspoon B, McGarry R, Adcock D. Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of 3703 patients from 11 randomized trials. J Clin Epidemiol 2000;53(7):676 80. CME questions Please visit http://www.uroweb.org/updateseries to answer these CME questions on-line. The CME credits will then be attributed automatically. 1. One of the most important factors for progression of superficial bladder cancer is: A. initial number of tumours. B. tumour size. C. recurrence at first follow up cystoscopy. D. the intravesical drug used. 2. What is (one of the) advantages of intravesical epirubicin? A. the optimal dose is well defined. B. the low molecular weight, responsible for good penetration of the urothelium. C. the superior efficacy as compared to other intravesical chemotherapeutic drugs. D. epirubicin seems to have less local side effects. 3. What is the benefit of gemcitabine in treatment of transitional cell carcinoma? A. no drug induced cystitis. B. the molecular weight of gemcitabine is more than ADM, so systemic side effects are rare. C. it is very effective on urothelial cells. D. one single gemcitabine treatment is equally effective as BCG maintenance therapy. 4. Why intravesical hyperthermia combined with mitomycin C instead of heated mitomycin C? A. very shallow heating. B. mitomycin C disintegrates faster in more active components. C. homogeneous temperature distribution. D. fast decrease of intravesical temperature impossible. 5. What is the theoretical advantage of sequential chemotherapy and immunotherapy? A. less side effects. B. potentiation of antitumour effect due to the combination of different mechanisms. C. no chemical cystitis. D. in papillary tumours the sequential treatment is significantly more effective.