Early Single-Instillation Chemotherapy Has No Real Benefit and Should Be Abandoned in Non Muscle-Invasive Bladder Cancer

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1 european urology supplements 8 (2009) available at journal homepage: Early Single-Instillation Chemotherapy Has No Real Benefit and Should Be Abandoned in Non Muscle-Invasive Bladder Cancer Sten Holmäng Department of Urology, Sahlgrenska University Hospital, Gothenburg, Sweden Article info Keywords: Single instillation Chemotherapy Bladder cancer Abstract Context: Most bladder tumours recur after a transurethral resection (TUR). The European Association of Urology (EAU) guidelines recommend a single immediate instillation of chemotherapy after every TUR of a suspected Ta/T1 bladder tumour. Objective: To provide a review of the results of a single immediate instillation of chemotherapy and to draw attention to alternative treatment strategies. Evidence acquisition: The author reviewed data from published clinical bladder cancer studies from 1976 to 2008 on single instillation. Evidence synthesis: A single immediate postoperative instillation results in less recurrence compared with TUR alone. It seems, however, that between 20 and 50 patients have to be treated to prevent one harmless, small-sized recurrence if the EAU guidelines are followed. There is no evidence that the instillation has any impact on progression, quality of life, and economy. Conclusions: It is recommended that single instillations should not be used outside of clinical trials. The EAU guidelines should be revised. # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. addresses: sten.holmang@telia.com, sten.holmang@vgregion.se. 1. Introduction Transurethral resection (TUR) is performed for diagnosis and treatment of non muscle-invasive bladder cancer. Approximately 75% of all patients will experience at least one recurrence, and some patients may have >10 recurrences. Intravesical instillation of a 6-wk series of bacillus Calmette- Guérin (BCG), mitomycin, or epirubicin results in less recurrence. BCG instillations will also lead to a lower progression rate. A number of randomised studies show that a single early postoperative instillation of chemotherapy will reduce the number of patients with recurrences [1 17]. The European Association of Urology (EAU) guidelines strongly recommend a single instillation after every TUR in which Ta/T1 bladder cancer is suspected [18]. This recommendation can be questioned because the scientific basis is very weak. The aim of this paper is to present the results of published data on single instillation, making it possible for a common urologist to understand the pros and cons, and to present an alternative to single instillation, which is biopsy and diathermia under local anaesthesia /$ see front matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 european urology supplements 8 (2009) Evidence acquisition A PubMed search was performed using the search words single instillation and bladder cancer. Reference lists in published papers and review articles were also used to identify published single-instillation studies. 3. Evidence synthesis 3.1. Effect of a single instillation on marker tumours Popart and associates performed TURs of bladder tumours but left behind a 5-mm tumour in every patient [19]. A single instillation of epirubicin was instilled d later. This so-called marker lesion had disappeared in 46% of patients at cystoscopy 3 mo after TUR. This study, as well as other similar reports, clearly shows that a single instillation exerts a considerable effect on small bladder tumours Comparison of single instillation and placebo More than a dozen studies comparing immediate single instillation and placebo have been published since the first report by Burnand and associates in 1976 [1 16]. Four of these reports [8 10,14] are updates of earlier publications, and 11 remain for analysis. First author, year of publication, number of patients, net benefit, and percentage of excluded patients is seen in Table 1. The net benefit is the percent of patients in the placebo group who had a recurrence during follow-up minus the percent of patients in the single instillation group who had a recurrence. In one study [8], for example, 41% of the Fig. 1 Relationship between number of patients and results. patients in the placebo group had at least one recurrence during follow-up and only 29% had a recurrence in the treatment group, so the net benefit was 12% (ie, 12% of all patients benefited from the treatment). Another way to put it is to say that 8.5 patients have to be treated to prevent one patient from getting recurrences. This is the same as number needed to treat (NNT), which probably is more comprehensible for most urologists. The net benefit of published reports is seen in Table 1 and in Fig. 1. Interestingly, the trend line in Fig. 1 clearly shows that the benefit of a single instillation is smaller in the large-sized studies. The three largest studies, all with >300 patients, show a remarkably similar net benefit between 12% and 15% [8,10,16]. Only one report showed a disadvantage with a single instillation [9]. One possible explanation is that the thiotepa dose was too low, at only 30 mg. As seen in Table 1, up to 29% of all study patients were excluded after they had been given Table 1 Comparison of single immediate instillation and placebo First author Year No. patients a Net benefit b Excluded patients Burnand et al [1] % 0% Abrams et al [3] % 5% Zincke et al [4] % 25% Oosterlinck et al [8] % 22% MRC [9] % 12% Tolley et al [10] % 10% Ali-El-Dein et al [11] % 7% Solsona et al [12] % 5% Rajala et al [14] % 29% Okamura et al [15] % 6% Berrum-Svennung et al [16] % 24% MRC = Medical Research Council. a Number of evaluated patients. b The net benefit is the percent of patients in the placebo group who had a recurrence during follow-up minus the percent of patients in the single instillation group who had a recurrence.

3 460 european urology supplements 8 (2009) the postoperative instillation, mainly because the histopathologic examination showed that they had a muscle-invasive tumour or no malignant tumour at all. This is consistent with earlier reports that show nonmalignant lesions between 17% and 25% following TUR of suspected bladder tumours [20]. The urologist cannot expect to get results that are as good as those in the published studies because a urologist cannot exclude a patient who has been given an instillation. Thus, in the clinic, the NNT is reasonably rather than 8.5. A prerequisite for this is, of course, that the clinician selects patients with solitary primary low-grade bladder tumours. If every patient with a suspected stage Ta/T1 bladder tumour is given a single instillation, as recommended in the EAU guidelines, the NNT will increase considerably. Furthermore, the reader should be aware of the fact that clinical studies in general are designed to show differences that are as large as possible to increase the possibility of publication in highly ranked magazines. The results of a scientific study cannot be directly transferred to everyday practice. As a rule, treatment results are inferior compared with clinical study results. Another way to present the results is to show the recurrence rate after treatment. The recurrence rate is the number of positive cystoscopies during follow-up divided by the number of follow-up months. Results presented in this manner show a considerable effect of a single instillation. The recurrence rate has been criticised because it allows several recurrences per patient but the effect of a single instillation is reasonably gone after the first recurrence [14]. When a urologist diagnoses a recurrence, he may or may not change the therapy and start a more intense chemotherapy schedule or change to BCG treatment. This is in contrast to single-instillation studies, in which participating urologists probably tend to adhere to the study schedule for as long as possible Size of recurrences There is very little knowledge about what kinds of recurrence are actually prevented as a result of a single instillation. Clearly, the benefit of a single instillation would be high if mainly large-sized, high-grade, or invasive recurrences were reduced in numbers. Berrum-Svennung et al looked at the size of the first recurrence and found that a single instillation of epirubicin seemed to reduce only the number of small-sized recurrences [16]. In another paper, Solsona et al stated that early recurrences comprised a few small-sized tumours [12] Time with a catheter and hospital stay Solsona et al further found that a single instillation, compared with placebo, did not significantly reduce hospital time and time with a catheter [12] Effect on low- and high-grade tumours Some studies have shown an effect on patients with initial high-grade tumours, but it is unknown whether these patients had fewer high-grade recurrences compared with patients in the placebo group [11,14]. Patients with initial high-grade tumours can get high-grade or low-grade recurrences, and it could be the case that only such small-sized lowgrade recurrences were reduced in numbers by a single instillation Duration of effect Most authors believe that the effect of a single instillation wanes and is gone after 1 yr or possibly later. When studying the Kaplan-Meier curves of the time to first recurrence, it is evident that the maximal effect is close to 12 mo after the instillation, since the curves are parallel after that time point [14,15]. Solsona found no difference between the study groups in the number of recurrences after 12 mo [12] Side effects The general impression is that side effects are few and mild but are difficult to identify because the patient has also undergone TUR. Approximately 10% of patients treated with a single instillation of epirubicin experience a mild bladder reaction [8]. Extensive fat necrosis perivesically has been reported, and it is recommended not to give single instillations when a deep bladder wall resection was done [21]. One patient developed serious neutropenia after a single instillation that was given after a bladder perforation [22] Comparison between single instillation and placebo in patients treated with a series of chemotherapy To date, only two publications report the potential additional benefit of a single immediate instillation in patients treated with a series of intravesical chemotherapy. In 1995, Bouffioux reported the results of two similar randomised studies for which data were combined [23]. One of the studies had 457 eligible patients treated with a single instillation of 30 mg mitomycin or no instillation, followed by four weekly and five monthly instillations of the same drug. The second study had 377 eligible patients who were treated in the same way, but with 50 mg doxorubicin. There was no significant difference

4 european urology supplements 8 (2009) between the number of patients with recurrences after 2.75 yr of follow-up (43% vs 49%), but a trend existed in favour of early treatment. The authors came to the conclusion that early treatment after transurethral resection seems to be slightly superior to delayed treatment. In a recent report by Hendricksen and associates from the Netherlands, the potential benefit of a single instillation of 50 mg epirubicin was studied in patients treated with the standard nine instillations [24]. After 5 yr of followup, 44.4% of 266 patients treated with nine standard instillations were tumour free compared with 42.7% of 287 patients treated with nine instillations plus an additional immediate instillation. One weakness of this study is that only 68% of patients in the singleinstillation group were treated within 24 h. Nevertheless, these data in combination with those of Bouffioux strongly suggest that the benefit of a single immediate instillation is very small, if there is any at all, in patients who commence a series of chemotherapy instillations within a few weeks Comparison between single instillation and placebo in patients treated with bacillus Calmette-Guérin There is only one paper in which the potential additive benefit of a single instillation in patients treated with intravesical BCG was studied. Cai and associates randomised patients after TUR of a bladder tumour to either an immediate single instillation of 80 mg epirubicin or no single instillation [25]. All patients started a 6-wk course of BCG 3 wk after TUR. At the end of follow-up, 46 of 80 patients (57.5%) in the single instillation group had no recurrence compared with 41 of 81 patients (50.6%) in the BCG-only group. There was no statistical difference between the groups. It seems that one should not draw any firm conclusion from this single underpowered study but rather hope that similar, much larger studies are in preparation Timing of the instillation Retrospective data suggest that the relative risk for future recurrences is reduced by half when a mitomycin instillation was given within 12 h of the TUR [26]. There are no prospective data that could elucidate the optimal time for a single instillation Financial considerations No formal economic study has been performed. Some authors have discussed the financial side of the single instillation concept [16]. The conclusion seems to be that single instillations result in economic savings in urology units in which patients with small-sized recurrences (up to 5 mm in diameter) stay overnight in hospital and are treated in the operating theatre under general anaesthesia. Alternatively, single instillations will result in increased costs in units in which such recurrences are biopsied and fulgurated immediately at the time of the follow-up cystoscopy Effect on quality of life No formal quality-of-life study has been performed to date. It seems unlikely that the small reduction in harmless recurrences would influence the quality of life more than marginally at best The European Association of Urology Guidelines The most recent update of the EAU guidelines suggests that all patients with a suspected stage Ta /T1 bladder tumour should be given an immediate instillation of a cytostatic drug after TUR [18]. Patients with single primary low-grade tumours do not need more treatment. Patients with high-risk tumours, such as high-grade or stage T1 tumours, should be treated with BCG. Intermediate-risk tumours, such as multiple low-grade tumours, should be treated with a series of either BCG or chemotherapy. Single primary low-grade tumours compose approximately 40% of all primary non muscleinvasive bladder tumours [27]. The number of TURs for recurrence depends on how many patients are treated with BCG and repeated chemotherapy instillations, but in one population-based report, it exceeded the number of TUR for primary tumours with a factor of 1.5 [20]. Consequently, 10 20% of all TURs for non muscle-invasive bladder cancer in a urology department are for single primary lowgrade tumours. In other words, 80 90% of resections are performed for tumours for which the guidelines suggest that a single instillation is not enough and a series of chemotherapy or BCG is recommended. As previously discussed, no additional benefit of a single instillation was found in the published studies when a subsequent series of instillations was given. The recommendation to give every patient a single instillation results in a large dilution of the effect so that many more than 8.5 or 10 patients have to be treated to prevent one (small) recurrence. The NNT can actually be anywhere up to 50 patients. More and clinically relevant singleinstillation studies are urgently needed to resolve this issue.

5 462 european urology supplements 8 (2009) Alternative strategies There are other ways to reduce recurrence. The percentage of patients with recurrence at 3 mo varies from 3% to 20% between different departments [28]. The most reasonable explanation is that the quality of the TUR differed considerably. Seeing the possibility to improve results, Brausi and associates took the initiative to start an education programme in Brausi s department. A dedicated teaching programme, including intense supervision by a senior urologist, resulted in a considerable reduction of the recurrence rate [29]. One way to reduce recurrence is to increase the percentage of patients treated with a series of chemotherapy or BCG. Patients with initial largesized or multifocal low-grade tumours should be treated with a series of chemotherapy or BCG, and patients with initial high-grade tumours should be treated with a series of BCG. Patients with solitary low-grade tumours have such a low recurrence rate and have so small-sized recurrences that they do not need any initial instillations. Most recurrences, in particular those from initial low-grade tumours, are no more than 5 mm in diameter and can easily be biopsied and fulgurated under local anaesthesia in the office [30,31]. This has been known for many decades, and it can be done with either rigid or flexible cystoscope. Most smallsized tumours can be fulgurated using urethral jelly only. There is also experience with intravesical instillation of lidocaine, which can diminish the pain, although there is no randomised study comparing it to placebo [32]. A third alternative is to inject 2 5 ml of lidocaine into the submucosa using a thin long needle inserted through the cystoscope [33]. The cost for a bladder tumour operation under local anaesthesia is approximately 20% of the cost for an operation under full anaesthesia with the patient staying overnight [20,30,32]. Considerable economic savings are possible, since the cost of TUR composes half the total cost for bladder tumour treatment [27]. 4. Conclusions One immediate postoperative instillation of epirubicin or mitomycin results in less recurrence but does not influence the progression rate. Patients treated with a series of chemotherapy or BCG seem to have no or minimal benefit from a single instillation. Some data suggest that only small-sized recurrences are prevented, and it cannot be ruled out that between 20 and 50 patients have to be treated to prevent one recurrence. Quality-of-life studies and economic calculations have not been done. Complications may occur but are rare. The benefit of a single instillation seems small, and there is not enough evidence at present to recommend it outside of clinical trials. Convincing evidence suggests that substantial economic savings can be made by treating patients with small-sized recurrences under local anaesthesia instead of trying to prevent them using single instillations. Conflicts of interest The author has nothing to disclose. Funding support None. References [1] Burnand KG, Boyd PJR, Mayo ME, Shuttleworth KED, Lloyd-Davies RW. Single dose intravesical thiotepa as an adjuvant to cystodiathermy in the treatment of transitional cell bladder carcinoma. Br J Urol 1976;48:55 9. [2] Gavrell GJ, Lewis RW, Meehan WL, Leblanc GA. Intravesical thiotepa in the immediate postoperative period in patients with recurrent transitional cell carcinoma of the bladder. J Urol 1978;120: [3] Abrams PH, Choa RG, Gaches CGC, Ashken MH, Green NA. A controlled trial of single dose intravesical adriamycin in superficial bladder tumours. Br J Urol 1981;53: [4] Zincke H, Utz DC, Taylor WF, Myers RP, Leary FJ. Influence of thiotepa and doxorubicin instillation at time of transurethral surgical treatment of bladder cancer on tumor recurrence: a prospective, randomized, double-blind, controlled trial. J Urol 1983;129: [5] MRC Working Party on Urological Cancer. The effect of intravesical thiotepa on the recurrence rate of newly diagnosed superficial bladder cancer. Br J Urol 1985;57: [6] Tolley DA, Hargreave TB, Smith PH, et al. Effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: interim report from the Medical Research Council Subgroup on superficial bladder cancer (Urological Cancer Working Party). Br J Urol 1988;296: [7] Van der Meijden APM, Kurth K-H, Oosterlinck W, Debruyne FMJ, Members of the EORTC Genito-Urinary Group. Intravesical therapy with adriamycin and 4-epirubicin for superficial bladder cancer: the experience of the EORTC GU Group. Cancer Chemother Phamacol 1992;30(Suppl): [8] Oosterlinck W, Kurth K-H, Schröder F, et al. A prospective European Organization for research and treatment of

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