Survival is presented as the mean value.
Should all patients receive single chemotherapeutic agent instillation after bladder tumour resection?
Version of Record online: 2 JUN 2009
© 2009 BJU INTERNATIONAL. NO CLAIM TO US GOVERNMENT WORKS
Volume 104, Issue 2, pages 170–174, July 2009
How to Cite
Dobruch, J. and Herr, H. (2009), Should all patients receive single chemotherapeutic agent instillation after bladder tumour resection?. BJU International, 104: 170–174. doi: 10.1111/j.1464-410X.2009.08654.x
- Issue online: 25 JUN 2009
- Version of Record online: 2 JUN 2009
- Accepted for publication 31 March 2009
- bladder tumour;
- transurethral resection;
- single intraoperative chemotherapeutic instillation
non-muscle-invasive bladder cancer
muscle-invasive bladder cancer
transurethral resection of bladder tumour
European Organization for Research and Treatment of Cancer
European Association of Urology.
Bladder cancer is the most common cancer of the urinary tract. It is estimated that in 2008, 68 810 new cases of bladder cancer will be diagnosed in the USA . In Europe almost 120 000 cases of the disease are diagnosed each year . Most present with non-muscle-invasive bladder cancer (NMIBC) and require conservative management in contrast to those who present with muscle-invasive disease (MIBC), which mandates early radical bladder removal. The definite establishment of bladder cancer character is usually done after pathological evaluation of the specimen obtained during transurethral resection of the bladder tumour (TURBT). Despite a thorough TURBT, 50–70% of bladder cancers recur and 15–30% progress to muscle invasion. Therefore, to predict future recurrence and/or progression of NMIBC, the European Organization for Research and Treatment of Cancer (EORTC) developed a scoring system. High-, intermediate- and low-risk groups of patients in terms of recurrence and/or progression of bladder cancer can be recognized based on the number, size and the grade of the tumours, T category, previous recurrence rate and concomitant carcinoma in situ (Tis). The individual risk category influences follow-up of repeated cystoscopies. The first follow-up cystoscopy is recommended to be done 3 months after TURBT in each patient, but frequency of further endoscopies varies from one done every 3 months to once a year.
For patients diagnosed with NMIBC there are various treatment methods. According to a recently published meta-analysis, patients who underwent TURBT followed by at least six intravesical instillations of BCG showed significantly lower rates of recurrence and progression compared with those in whom BCG was not used. BCG is reserved for high-risk tumours (T1 G3, Tis). In cases of high- or intermediate-risk of recurrence (i.e. patients with multiple tumours), BCG is usually replaced by a series of instillations using various chemotherapeutic agents. Such therapy reduces the frequency of tumour recurrences but does not influence tumour progression. Traditionally, both BCG and chemotherapeutic agent instillations are performed every week for 6–8 consecutive weeks and many cases receive additional (maintenance) instillations at regular intervals.
High rates of tumour recurrence in patients diagnosed with NMIBC raised the possibility that inevitable spillage of tumour cells during TURBT may provoke their implantation into bladder mucosa and facilitates future tumour growth. Several randomized trials have addressed the role of a single intravesical instillation of various chemotherapeutic agents just after TURBT, showing significant reductions in subsequent tumour recurrences. According to recently published European Association of Urology (EAU) Guidelines, immediate instillation of a cytotoxic drug after TURBT is strongly recommended, independent of whether tumour was confined to mucosa (Ta, Tis) or submucosa (T1) . The AUA Guidelines also recommend a single dose of intravesical intraoperative chemotherapy . However, despite Level I evidence supporting its use, perhaps owing to differences in opinion, and culture adaptation, perioperative chemotherapy is not widely used. In one of the surveys dedicated to evaluate practice patterns in the USA, only 4% of eligible patients received a single perioperative instillation of a chemotherapeutic agent . Integration of perioperative chemotherapy into an overall management strategy of NMIBC also has not been adequately discussed, perhaps limiting its wider application.
We aimed to critically evaluate the role of a single intravesical instillation of chemotherapy in patients undergoing TURBT and to answer the question of whether all patients should receive single chemotherapeutic agent instillation after TURBT.
PATIENTS AND METHODS
We searched PubMed databases for randomized trials that compared TURBT alone and TURBT followed by single instillation of a chemotherapeutic agent to answer the following question: should all patients receive single chemotherapeutic agent instillation after TURBT? The words used in that setting were: single instillation and bladder tumour/cancer. Nonrandomized trials were excluded from analysis. Trials using thiotepa as an intravesical cytotoxic agent were excluded as it is not widely accepted due to its toxicity and is not commonly used in clinical practice.
We identified eight randomized trials testing perioperative chemotherapy after TURBT [6–13]. Most of them (six) were included in a recently published meta-analysis . Collectively, all studies included data of 1776 eligible patients who underwent TURBT alone or TURBT and a single instillation of cytotoxic agent (Table 1) [6–14]. The most prominent group consisted of those who received instillation of epirubicin. The median follow-up time was short, usually <3 years.
|Report||Agent used||TURBT, n (%)||Median follow-up, years|
|Gudjonsson et al. ||Epirubicin||117 (53)||102 (47)||219||3.9|
|Rajala et al. ||Epirubicin||66 (49)||68 (51)||134||2|
|Berrum-Svennung et al. ||Epirubicin||152 (50)||155 (51)||307||2|
|Ali-el-Dein et al. ||Epirubicin||54 (50)||55 (51)||109||2.7*|
|Oosterlinck et al. ||Epirubicin||215 (51)||205 (49)||420||2*|
|Solsona et al. ||Mitomycin C||64 (53)||57 (47)||121||7.8|
|Tolley et al. ||Mitomycin C||157 (51)||149 (49)||306||7|
|Okamura et al. ||Doxorubicin||79 (49)||81 (51)||160||3.4|
|Total||904 (51)||872 (49)||1776||–|
|Sylvester et al.†||Cytotoxic agent||748 (51)||728 (49)||1476||–|
Table 2[6–14] shows the oncological characteristics of the tumours at study entry. In all, >70% of patients presented with single and primary tumours. Moreover, the tumours were almost all low stage and low grade. The rate of Ta tumours was 71–74% and the rate of G1–2 tumours was >90%.
|Report||Agent used||Tumour type: primary/recurrent (% primary)||Number of tumours: single/multiple (% single)||Tumour stage, n (%)||Tumour grade, n (%)|
|Gudjonsson et al. ||Epirubicin||55/47 (54)||45/55 (45)||83 (89)||10||55 (58)||40||–|
|Control||60/57 (51)||54/62 (47)||101 (93)||8||57 (52)||52||–|
|Rajala et al. ||Epirubicin||68/–||52/16 (77)||54 (79)||14||34 (50)||25 (37)||9|
|Control||66/–||47/19 (71)||55 (83)||11||38 (58)||21 (31)||7|
|Berrum-Svennung et al. ||Epirubicin||78/77 (50)||87/68 (56)||132 (94)||8||140||–|
|Control||75/77 (49)||93/59 (61)||125 (91)||12||137||–|
|Ali-el-Dein et al. ||Epirubicin||29/26 (53)||34/21 (62)||9 (16)||46||6 (10)||30 (55)||19 (35)|
|Control||31/24 (57)||35/19 (65)||10 (19)||44||14 (26)||29 (54)||11 (20)|
|Oosterlinck et al. ||Epirubicin||162/43 (79)||205/–||145 (71)||60||78 (39)||98 (49)||24|
|Control||166/49 (77)||215/–||165 (77)||49||109 (51)||88 (42)||15|
|Solsona et al. ||Mitomycin C||6/51 (11)||57/–||28 (49)||29||30 (53)||27 (47)||–|
|Control||8/56 (13)||64/–||31 (48)||33||33 (58)||31 (42)||–|
|Tolley et al. ||Mitomycin C||149/–||119/30 (80)||75 (51)||72||55 (37)||77 (52)||15|
|Control||157/–||111/46||88 (57)||67||71 (45)||73 (47)||13|
|Okamura et al. ||Doxorubicin||75/6 (93)||75/6 (93)||77 (96)||4||41 (51)||38 (47)||2|
|Control||77/2 (98)||77/2 (98)||74 (94)||5||36 (46)||39 (49)||4|
|Total||Cytotoxic agent||622/231 (73)||674/196 (78)||603 (71)||243||299 (43)||335 (48)||69|
|Control||640/265 (71)||696/207 (77)||649 (74)||229||358 (48)||333 (45)||50|
|Sylvester et al.†||Cytotoxic agent||660/81 (89)||630/111 (85)||479 (66)||248||326 (45)||324 (44)||83|
|Control||683/82 (89)||639/126 (84)||525 (70)||227||381 (50)||320 (42)||59|
The recurrence rate in the group of patients who underwent TURBT followed by chemotherapeutic agent instillation was in all studies significantly lower than in the group of patients who only had TURBT, with rates of 24–62% and 48–77%, respectively (Table 3) [6–14]. However, there were no significant differences in recurrence rates in patients who presented with multiple tumours. As the rate of high-grade tumours was negligibly small, the influence of a single instillation on the recurrence rate (or progression) could not be accurately assessed. Only a few trials published data concerning tumour progression, which was reported to be extremely low.
|Report||Agent used||Progression rate, n (%)||Recurrence rate, n (%)||Recurrence rate N (%)|
|Single||Multiple||Low grade (G1–2)||High grade (G3)|
|Gudjonsson et al. ||Epirubicin||–||63 (62)*||16 (36)*||46 (84)||–||–|
|Control||–||90 (77)||36 (67)||53 (85)||–||–|
|Rajala et al. ||Epirubicin||–||23 (34)*||14 (27)*||9 (56)||18 (31)*‡||5 (56)|
|Control||–||40 (60)||26 (55)||14 (74)||55 (69)||6 (86)|
|Berrum-Svennung et al. ||Epirubicin||4 (3)||79 (51)*||–||–||–||–|
|Control||2 (1)||95 (63)||–||–||–||–|
|Ali-el-Dein et al. ||Epirubicin||3 (6)||13 (24)*||–||–||–||–|
|Control||5 (9)||28 (52)||–||–||–||–|
|Oosterlinck et al. ||Epirubicin||–||(29)||–||–||–||–|
|Solsona et al. ||Mitomycin C||1 (2)||23 (40)||–||–||–||–|
|Control||1 (2)||35 (54)||–||–||–||–|
|Tolley et al. ||Mitomycin C||Not||P < 0.05*||–||–||–||–|
|Okamura et al. ||Doxorubicin||0||P < 0.05*||–||–||–||–|
|Sylvester et al.†||Cytoxic agent||NA||267 (37)*||151 (36)*||30 (65)||–||–|
|Control||NA||362 (48)||201 (47)||53 (82)||–||–|
The safety profile of the single cytotoxic agent instillations usually was not presented. In the two recent studies, there is no information concerning safety of epirubicin administration (Table 4) [6–14]. However, according to other studies where safety profiles were presented, there were adverse events in up to 22% of treated patients (Table 4).
|Report||Agent used||Adverse events, n (%)|
|Gudjonsson et al. ||Epirubicin||Not stated|
|Rajala et al. ||Epirubicin||4 (6)|
|Berrum-Svennung et al. ||Epirubicin||Not stated|
|Ali-el-Dein et al. ||Epirubicin||12 (22)|
|Oosterlinck et al. ||Epirubicin||33 (16)|
|Solsona et al. ||Mitomycin C||2 (4)|
|Tolley et al. ||Mitomycin C||Few cases|
|Okamura et al. ||Doxorubicin||Not stated|
|Sylvester et al.†||Cytotoxic agent||≈10% of patients|
The results of randomized studies and a meta-analysis strongly suggest that single instillation of a cytotoxic agent after TURBT is associated with significantly lower future recurrence rates of bladder tumour. The EAU has incorporated perioperative chemotherapy into its Guidelines for each patient undergoing a TURBT. However, according to Sylvester et al.  the number needed to treat is 8.5, which means that at least eight patients would have to have a perioperative instillation to prevent one recurrence. Moreover, most patients included into the studies were strictly selected, excluding those with Tis or high-grade (G3) disease. One of the five randomized trials not included in the meta-analysis did enroll patients with Tis . Patients treated for Tis did not gain any benefit after single instillation of chemotherapy compared with those treated with TURBT only. It was shown that patients with high-risk bladder cancer would benefit most from BCG therapy. A single instillation that would precede this form of management in cases were histological examination shows high-grade disease, would not influence the progression or recurrence rate compared with patients treated with BCG therapy only . Patients with multiple tumours also did not benefit from a single instillation. To our knowledge, there is no reliable, prospective data showing that a single chemotherapeutic instillation adds any benefit to a series of instillations in such cases. As the final diagnosis is available after histological examination of the TURBT specimen, many more than 8.5 patients would have to be treated to spare one recurrence, unless it is possible to predict pathological outcome based on endoscopic evaluation of the tumour.
To summarize, patients with multiple and/or high-risk tumours would be subjected to therapy of uncertain efficiency, which might influence their quality of life. Most authors failed to present safety profiles of the tested cytotoxic agent. According to those who did, single intravesical chemotherapy was not associated with significant morbidity, at least in no more then 22% of cases. However, serious toxicity was described, especially after vigorous or aggressive TURBT.
Although numerous trials proved a favourable role of a single instillation on bladder cancer recurrences, there is little knowledge on oncological characteristics of such recurrences. Among the studies that were included into the meta-analysis, only one stated that early recurrences comprised only a few small papillary tumours . Authors of recently published data investigated the problem in more detail . Only patients who had tumours of <5 mm had fewer tumour recurrences. There was no significant difference in the rate of recurrence of tumours of >5 mm between patients treated with TURBT and a single instillation of epirubicin and patients treated with TURBT alone. So, the small tumours are prevented, which can easily be fulgurated in the office. Moreover, according to Solsona et al.  a single instillation of mitomycin C was able to decrease the rate of early recurrences (≤2 year after TURBT) but not late recurrences (>2 year after TURBT). Most of the trials had the follow-up restricted to ≤3 years. As a result, only small, single and low-grade tumours seem to benefit from a single cytotoxic agent instillation. It may be explained by the favourable influence of intravesical chemotherapy on tumour cells spread during the TURBT. High-risk tumours recur because of their biological nature or genetic instability of the urothelium, and a single instillation is unlikely to change that.
According to EORTC tables, low-risk tumours have no more then 21–26% probability of recurrence within 1 year. Results of the meta-analysis showed the reduction in the recurrence rate was 24%, so the likelihood of recurrence of small, single and low-grade tumour additionally treated with single instillation would be as low as 16–20%. Is watchful waiting acceptable in case of such tumours? Gofrit et al.  have shown that bladder tumours of <5 mm often grow slowly. The EAU Guidelines do not incorporate the potential benefit of single instillation chemotherapy into follow-up recommendations. Instead, guidelines recommend that patients should be followed in the same frequent manner, irrespectively of being subjected or not to perioperative intravesical therapy. If so, is single instillation necessary? Donat et al.  reported that treatment of small recurrences is possible under local anaesthesia in the office. We have shown that follow-up of 215 patients with low-grade papillary tumours with biannual flexible cystoscopy and immediate fulguration reduces the number of TURBTs needed to one every 3 years . If cystoscopy cannot be avoided by a single instillation as suggested by EAU Guidelines, what would be the reason for its implementation? The risk of progression of low-risk bladder tumours is, as shown by EORTC studies, extremely low.
Healthcare policy differs among various countries. In Europe, single instillation of a chemotherapeutic agent in patients treated with TURBT was easily adopted in contrast to usual practice in the USA. If patients treated with TURBT are admitted to hospitals as is done in Europe, single instillation of a cytotoxic agent is usually possible, and makes sense to avoid morbidity of anaesthesia and TURBT or biopsy, not to mention time and costs. It was estimated that intravesical chemotherapeutic instillations would allow a saving of nearly $700 per patient per year. However, the inevitable necessity of patients’ hospitalizations instead of office fulguration in terms of cost-analysis was not studied. In the USA, the healthcare policy would not accept a longer hospital stay, where the standard is same-day surgery, and rapid turnover. Is it possible then to predict with high accuracy the character of the tumour recognized during cystoscopy, done for example in a patient presenting with an episode of haematuria to plan future instillation during TURBT done in few days? The correlation between endoscopic findings and histological evaluation of bladder tumour done by experienced urologists appears to be high. Cystoscopy correctly identified the stage and the grade in 93% of recurrent, papillary bladder tumours . If so, it is possible to prepare the instillation, so the patient selected for TURBT due to a small, solitary and low-grade tumour has the resection with planned intravesical, intraoperative therapy to avoid a prolonged hospital stay.
Single instillation of a chemotherapeutic agent in patients treated with TURBT for NMIBC significantly reduces the recurrence rate of small, solitary and low-risk bladder tumours. The reduction is seen during the first 2 years of follow-up. The importance of the findings and its implementation is however, strongly influenced by local healthcare system policy and organization.
CONFLICT OF INTEREST
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