Current strategies in the treatment of non-muscle invasive bladder cancer.

Willem Oosterlinck* and Karel Decaestecker°

*Professor in Urology,°MD, Department of Urology , Ghent University Hospital, Ghent ,

Belgium.

Correspondence address: Department of Urology, Ghent University Hospital

De Pintelaan,185, 9000 Ghent, Belgium

Tel.+3293322284; fax +3293323889

willem.oosterlinck@ugent.be

Keywords: urothelial neoplasm, non-muscle invasive bladder cancer, review, bacillus Calmette-

Guérin, mitomycine C, epirubicine.

Conflict of interest: W.Oosterlinck was speaker at several occasions for Kyowa (Mitomycin)

and General Electric (Hexvix). No other disclosers to mention.

Abstract

This is a review based on a data search until the end of Jan 2012 on strategies in the treatment of

non-muscle invasive bladder cancer. As one of the authors was chairman of the guidelines

writing committee of the European Association of Urology, these guidelines served as a

backbone. They are updated and adapted according to the most recent data. It is astonishing how

many important data were published in the last 2 years. Many data have a high level of evidence

and allow well supported recommendations. However, recommendations are not given as this is

not the scope of this paper, but the information for reflexion on the guidelines is in this article.

Introduction

Bladder carcinoma is the most common malignancy of the urinary tract. The worldwide

age standardized incidence rate (ASR) is 10.1 per 100,000 for males and 2.5 per 100,000 for

females . Because of its tendency to recurrence this tumour has a high financial impact on health

care. Approximately 75–85% of patients with bladder cancer present with disease that is confined

to the mucosa (stage Ta, CIS) or submucosa (stage T1). These categories are grouped as non-

muscle invasive tumours (NMIBC) and are the subject of the present expert review and

comments. This review is using the EUA guidelines 2011 as a backbone as one of us (WO) was

co-author and chairman of this guidelines writing committee. It is updated with data which

appeared after September 2010.

Transurethral resection of the tumour (TUR)

The goal of the TUR in TaT1 bladder tumours is to make the correct diagnosis and remove all

visible lesions. Complete and correct TUR is considered by all experts as an outmost important

step in the diagnosis and treatment of NMIBC .

Larger tumours should be resected separately in fractions, which include the exophytic part of the

tumour, the underlying bladder wall with the detrusor muscle, and the edges of the resection area

and the specimens from different fractions must be referred to the pathologist in separate

containers. The absence of detrusor muscle in the specimen is associated with a significantly

higher risk of residual disease and early recurrence .

Bladder and prostatic urethral biopsies

When abnormal areas of urothelium are seen, it is advised to take biopsies .So-called random

biopsies should be performed in patients with positive urinary cytology and absence of visible

tumour in the bladder. In patients with TaT1 tumours random biopsies are not routinely

recommended because the likelihood of detecting CIS, especially in low-risk tumours, is

extremely low (< 2%), and the choice of adjuvant intravesical therapy is not influenced by the

biopsy result . Cold cup biopsies from normal-looking mucosa should be performed when

cytology is positive suggesting a high grade tumour.

In T1, high grade tumours involvement of the prostatic urethra with CIS was found the only

prognostic factor for recurrence and progression. Therefore it is important to perform a biopsy of

the prostatic urethra in patients with high grade NMIBC.

Photodynamic diagnosis (fluorescence cystoscopy).

As a standard procedure, cystoscopy and TUR are performed using white light. Photodynamic

diagnosis (PDD) is performed using violet light after intravesical instillation of 5-aminolaevulinic

acid or hexaminolaevulinic acid. It has been confirmed that fluorescence-guided biopsy and

resection are more sensitive than conventional procedures for detection of malignant tumours,

particularly CIS The additional detection rate of PDD was 20% for all tumours and 23% for CIS .

However, false-positivity can be induced by inflammation or recent TUR, and during the first 3

months after BCG intravesical instillation .

The benefit of ALA fluorescence-guided TUR for recurrence-free survival has been demonstrated

in several small, randomised clinical trials . Cumulative analysis of three trials has shown that

recurrence-free survival was 15.8–27% higher at 12 months and 12–15% higher at 24 months in

the fluorescence-guided TUR groups compared to the white light alone groups . However, a large

Swedish study could not detect any advantage in using ALA fluorescence-guided TUR routinely

in all patients with non-muscle-invasive bladder cancer A large, multicentre, prospective

randomised trial that compared HAL fluorescence-guided TUR with standard TUR reported an

absolute reduction of no more than 9% in the recurrence rate within 9 months in the HAL arm.

The value of fluorescence cystoscopy for improvement of the outcome in relation to progression

rate remains to be demonstrated.

PDD is most useful for detection of CIS, and therefore, it should be restricted to those patients

who are suspected of harbouring a high-grade tumour, ea. for biopsy guidance in patients with

positive cytology or with the history of high-grade tumour. The additional cost of the PDD

equipment is considerable.

If other narrow band imaging is able to obtain similar improvements in TUR needs to be

demonstrated but the preliminary results are promising .

Second resection

The significant risk of residual tumour and under staging after initial TUR of TaT1 lesions has

been demonstrated . A second TUR should be considered when the initial resection is

incomplete, for example, when multiple and/or large tumours are present, or when the pathologist

has reported that the specimen contains no muscle tissue. Furthermore, a second TUR is

advocated when a high-grade or T1 tumour has been detected at initial TUR. It has been

demonstrated that a second TUR can increase recurrence-free survival . Most authors

recommend resection at 2–6 weeks after initial TUR.

Predicting recurrence and progression

At the beginning of the seventies of the last century every bladder tumour was considered as a

potentially deadly disease. As a consequence every bladder tumour was attacked maximal

diagnostic and therapeutic means .Progressively one learned that papillary tumours of the bladder

had a wide range of aggressiveness, from almost nothing to life endangering. The tailoring of

treatment and follow-up is one of the mayor achievements of the last decades of clinical NMIBC

research.

Ta and T1 tumours.

Classically one divides patients into low-risk, intermediate-risk and high-risk groups. However,

no distinction is drawn between the risk of recurrence and progression. Although prognostic

factors may indicate a high risk for recurrence, the risk of progression might still be low, and

other tumours might have a high risk of recurrence and progression. The score system developed

by he European Organization for Research and Treatment of Cancer (EORTC) still is the most

suitable way to predict separately the risks of recurrence and progression in individual patients .

The scoring system is based on the six most significant clinical and pathological factors. Number

of tumours is the most important prognostic factor for recurrence but not to predict progression.

Prior recurrence rate or early recurrence is the second most important factor for recurrence. The

third factor was tumour size which was refined in a recent study. Presence of CIS was found to

be the strongest predictor for progression to invasive cancer. Tumour grade is the second most

important bad prognostic factor. Electronic calculator is available at

http://www.eortc.be/tools/bladdercalculator/. The validation of the EORTC scoring system in an

independent patient population with long-term follow-up has confirmed its prognostic value .

A scoring model for BCG-treated patients that predicts the short- and long-term risks of

recurrence and progression has also been presented. The calculated risk of recurrence is lower

than that obtained by the EORTC . For progression probabilities, it is lower only in high-risk

patients. The lower risks may be attributed to using a more effective instillation therapy.

CIS

Without any intravesical treatment, more than half of patients with CIS progress to muscle-

invasive disease. Unfortunately, there are no reliable prognostic factors that can be used to

predict the course of the disease. Various publications have shown that the response to

intravesical treatment with BCG or chemotherapy is an important prognostic factor for

subsequent progression caused by bladder cancer . Approximately 10–20% of complete

responders eventually progress to muscle-invasive disease, compared with 66% of non-

responders .Several markers have been tested to predict response to BCG. Urinary interleukin 2

came out as the most promising.

Intravesical treatment after TUR.

Although TUR by itself can eradicate a TaT1 tumour completely, these tumours recur in a high

percentage of cases and progress to muscle-invasive bladder cancer in a limited number of cases.

The high variability in the 3-month recurrence rate indicates that TUR is incomplete or provokes

recurrences in a high percentage of patients . It is therefore necessary to consider adjuvant

therapy in most patients.

One, immediate, postoperative intravesical instillation of chemotherapy

In a meta-analysis of seven randomised trials (1,476 patients with a median follow-up of 3.4

years), one immediate instillation of chemotherapy after TUR significantly reduced recurrence

rate compared to TUR alone. In absolute values, the reduction was 11.7% (from 48.4% to

36.7%), which implies a 24.2% decrease in the relative risk. The majority of patients (> 80%) in

the meta-analysis had a single tumour, but an almost significant (p=0.06) and even greater

reduction in recurrence was noted among the limited number of patients with multiple tumours.

The efficacy of the single instillation has been confirmed also by 4 recently published studies . In

2 of these , the benefit was mainly seen in primary and single tumours and was in these tumour

categories even greater than the 11.7% demonstrated in the meta-analysis. By stratification

according to EORTC recurrence scores, the benefit was observed in patients with scores 0–2, but

not with scores ≥ 3. However, the study was not sufficiently powered for subgroup analyses.

Insufficient data are available showing that the single instillations significantly reduce recurrence

rates in patients with recurrent tumours. Nevertheless, there is significant evidence from one

subgroup analysis that immediate instillation might have an impact on the repeat instillation

regimens for treatment of patients who are at intermediate and high risk of recurrence . There are

no statistically relevant data that address the role of immediate chemotherapy instillation in

tumours at high risk of progression before BCG intravesical treatment .However, one

retrospective study showed significant benefit of early instillation in patients who received BCG

afterwards.

So further studies are required to determine the definitive role of immediate chemotherapy in

intermediate- and high-risk groups. At the end of TUR grade and T stage remains uncertain and

thus also the risk group. Therefore it seems reasonable to advocate the early instillation in most

cases. Not any later given instillation obtains the same amplitude in prevention of recurrence. In

spite of the overwhelming evidence this practice is uncommon among urologists .

The effect of early instillation can be explained by the destruction of circulating tumour cells

immediately after TUR, or as an ablative effect on residual tumour. Prevention of tumour cell

implantation should be initiated within the first hours after cell seeding. Within a few hours, the

cells are implanted firmly and are covered by extracellular matrix. In all single instillation

studies, the instillation was administered within 24 h. Subgroup analysis of one study has shown

that, if the first instillation was not given on the same day as TUR, there was a two fold increase

in the relative risk of recurrence . Moreover, a study in which the instillation was not given

strictly on the same day did not find any advantage . This is in contradiction with a recent

prospective, randomised trial in prevention of bladder recurrence after upper tract urothelial

tumours . In which the mitomycin (MMC) instillation was given only at the removal of the

bladder catheter.

There is no single drug that is superior with regard to efficacy. Mitomycin C, epirubicin and

doxorubicin have all shown a beneficial effect . In one study, gemcitabine plus 24 h bladder

irrigation with physiological saline was not superior to irrigation with physiological saline during

24 hours . The recurrence was very low in both arms, suggesting that rinsing itself could prevent

implantation of tumour cells which seems an acceptable explanation. This is confirmed in a

recent study .

The immediate post-operative chemotherapy instillation should be omitted in any case of overt or

suspected intra- or extraperitoneal perforation, which is most likely to appear in extensive TUR

procedures. Severe complications have been reported in patients in whom extravasation of the

drug occurs. Clear instructions should be given to the nursing staff to control the free flow of the

bladder catheter at the end of the instillation. It has been demonstrated that administration of

instillation is possible in the majority of cases .

Additional intravesical chemotherapy instillations

In patients with a low risk of tumour recurrence, a single immediate instillation reduces the risk

of recurrence and is considered as the standard treatment. No further treatment should be given in

these patients before subsequent recurrence. For other patients the likelihood of recurrence and/

sometimes progression is considerable.

The choice between further chemotherapy and immunotherapy largely depends on the risk that

needs to be reduced: recurrence or progression. Chemotherapy prevents recurrence but not

progression . The efficacy of intravesical chemotherapy in reducing the risk of tumour recurrence

has been confirmed by two meta-analyses in primary and recurrent tumours .

It is still controversial how long and how frequently instillations of intravesical chemotherapy

have to be given. From a systematic review of the literature of randomised clinical trials, which

has compared different schedules of intravesical chemotherapy instillations, one can only

conclude that the ideal duration and intensity of the schedule remains undefined because of

conflicting data . Nevertheless, the available evidence does not support any treatment longer than

1 year.

The place of gemcitabine and possible advantages over other intravesical drugs remains uncertain

.

Optimising intravesical chemotherapy

One randomised trial has demonstrated that adapting urinary pH, decreasing urinary excretion

and buffering the intravesical solution reduce the recurrence rate .

Another randomised trial has documented that concentration is more important than duration of

the treatment . In view of these data, which need confirmation, it seems advisable to ask the

patient not to drink on the morning before instillation, and to dissolve the drug in a buffered

solution at optimal pH.

Device assisted intravesical chemotherapy

Due to suboptimal results of current therapies the search for better outcomes continues.

Application of microwave induced hyperthermia during MMC instillation has been tested now

for 15 years. A review including 22 studies suggest a 59% reduction in recurrence when

compared to MMC alone with slightly more local side effects . In 83 patients 53% were tumour

free at 10years with 86% of bladder preservation .These results make this technique to an

alternative for highly recurrent high grade tumours in patients unsuitable for cystectomy and for

those who do not support BCG.

Another technique is the electromotive assisted instillation of MMC .The penetration in the

bladder wall of the small molecules is enhanced by electro-osmosis .This resulted in very long

disease free period :69 months in the BCG+electromotive MMC arm versus21 months in the

BGG alone arm Even more astonishing results were obtained with electromotive instillation of

MMC immediately before TUR. After MMC immediately after alone 59% of the tumours

recurred while after pre-TUR electromotive MMC it was only 38%;the disease free period also

was amazingly long (52 vs16 months) .

The excellent results obtained by these devices assisted can no longer be neglected. They should

be confirmed by other investigators than the pioneers and then become standard of care for the

most difficult cases of NMIBC.

Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy

Five meta-analyses have confirmed that BCG after TUR is superior to TUR alone or TUR and

chemotherapy for prevention of recurrence of non-muscle invasive tumours . Since the

publication of these meta-analyses, 4 randomised studies of intermediate- and high-risk tumours

have been presented. In these studies, BCG was compared with the combination of epirubicin and

interferon , mitomycin C or epirubicin alone. All of these studies have confirmed the superiority

of BCG for prevention of tumour recurrence. It has been shown that the effect was long lasting

and was also observed in separate analysis of patients with tumours at intermediate risk .

One meta-analysis has evaluated the individual data from 2,820 patients enrolled in nine

randomised studies that have compared MMC versus BCG. In the trials with BCG maintenance,

a 32% reduction in the risk of recurrence for BCG compared to MMC was found (p < 0.0001),

whereas there was a 28% increase in the risk of recurrence (p = 0.006) for BCG in the trials

without BCG any maintenance. However, maintenance schedules varied from 10 to 27

instillations in total.

Two meta-analyses have demonstrated that BCG therapy prevents, or at least delays, the risk of

tumour progression . A meta-analysis has evaluated data from 4,863 patients enrolled in 24

randomised trials. A total of 3,967 (81.6%) patients had only papillary tumours and 896 (18.4%)

had primary or concurrent CIS. Five different BCG strains were used, and in 20 out of the 24

trials, some form of BCG maintenance was used. In four trials only, a 6-week induction course

was used. Based on a median follow-up of 2.5 years and a maximum of 15 years, 9.8% of 2,658

patients on BCG progressed compared to 13.8% out of 2,205 in the control groups (TUR alone,

TUR plus intravesical chemotherapy, or TUR plus other immunotherapy). This shows a relative

reduction of 27% of progression with BCG treatment (p = 0.0001). The size of the reduction is

similar in patients with TaT1 papillary tumours and in those with CIS . A recent randomised

study with long-term observation has demonstrated significantly fewer distant metastases and

better overall and disease-specific survival in patients treated with BCG compared to epirubicin .

On the contrary, a meta-analysis of individual patient data was not able to confirm any

statistically significant difference between MMC and BCG for progression, survival and cause of

death . In spite of these conflicting results, the majority of data was able to show the reduction

in the risk of progression in tumours at high and intermediate risk if the BCG included more than

a 6weeks induction schedule.

Two other meta-analyses have suggested a possible bias in favour of BCG by the inclusion of

patients who were previously treated with intravesical chemotherapy In the most recent meta-

analysis, however, BCG maintenance was more effective than MMC also in patients who were

previously treated with chemotherapy .

Optimal BCG schedule

According to the meta-analysis BCG must be given more than an induction cycle to obtain

maximal response . In the four trials in which no maintenance was given, no reduction in

progression was observed. In the 20 trials in which some form of BCG maintenance was given, a

relative reduction of 37% of progression was observed (p = 0.00004). The meta-analysis was

unable to determine which BCG maintenance schedule was the most effective. In 2 other meta-

analyses it was concluded that at least 1 year of maintenance BCG is required to show the

superiority of BCG over MMC for prevention of recurrence or progression . However, many

different maintenance schedules have been used, ranging from a total of 10 instillations given in

18 weeks, to 27 instillations over 3 years .

Recently a large series of T1 high grade tumours with a long follow-up demonstrated that those

patients ,who are disease free 6 months after induction BCG, don’t need further instillations

unless they recur. Percentage of progression and disease free period were comparable with the

results mentioned in the meta-analysis, but sparing a lot of instillations and toxicity. At a first

glance this is in contradiction with this meta-analysis but it is not because in the recent study all

non-BCG responders at 6 months were eliminated from further analysis while they were not in

the meta-analysis. The final message is that in responders there is no further need for BCG, while

non early responders may benefit from additional instillations.

To reduce BCG toxicity, one has proposed one-third and one-quarter dose instillations of BCG.

Comparing one-third dose to full-dose BCG in 500 patients, one has found no overall difference

in efficacy. However, it has been suggested that a full dose of BCG is more effective in

multifocal tumours . Although fewer patients have reported toxicity with the reduced dose, the

incidence of severe systemic toxicity has been similar in the standard- and reduced-dose groups.

The same Spanish group has shown in a prospective randomised trial that one-third of the

standard dose of BCG might be the minimum effective dose in intermediate-risk tumours. A

further reduction to one-sixth dose resulted in a decrease in efficacy for prevention of recurrence

with no decrease in toxicity .

BCG toxicity

As a result of the more pronounced side effects of BCG compared to intravesical chemotherapy,

there is still reluctance about the use of BCG. Deaths due to BCG sepsis and the high frequency

of BCG-induced cystitis have compromised its use . Serious side effects are encountered in < 5%

of patients and can be effectively treated in most cases. BCG should not be administered during

the first 2 weeks after TUR, in macroscopic haematuria or urinary tract infection, or after

traumatic catheterisation because of the fear that BCG enters the blood stream.

Indications for BCG

Ultimately, the choice of treatment depends upon the patients’ risk of recurrence and progression.

The use of BCG in tumours at low risk of recurrence is an over-treatment. In patients with

tumours at high risk of progression, for whom cystectomy is not carried out, BCG is indicated. In

patients at intermediate or high risk of recurrence and intermediate risk of progression, BCG is

more effective for prevention of recurrence but it has more side effects than chemotherapy. For

this reason both BCG and intravesical chemotherapy remain an option. The final choice should

reflect individual patients’ risk of recurrence and progression and efficacy and side effects of

each treatment.

Specific aspects of treatment of CIS

The detection of CIS with TaT1 tumours increases the risk of recurrence and progression of TaT1

tumours .

CIS cannot be cured by an endoscopic procedure only, although it is now possible to resect areas

of CIS which are visualized by fluorescence. The value of such a procedure in the cure of patients

with TIS is unknown for the moment. The diagnosis of CIS must be followed by either

intravesical instillations or radical cystectomy. No consensus exists about whether intravesical

instillations or cystectomy should be done, especially when there are concurrent high-grade

papillary tumours. There are no randomised trials of instillation therapy and early cystectomy.

Tumour-specific survival rates after early cystectomy for CIS are excellent, but as many as 40–

50% of patients might be over-treated .

In retrospective evaluations of patients with CIS, a complete response rate of 48% was achieved

with intravesical chemotherapy and 72–93% with BCG. Up to 50% of complete responders might

eventually show recurrence with a risk of invasion and/or extravesical recurrence . There have

been few randomised trials in patients with CIS alone. Most trials have included patients with

either papillary tumours or CIS, which has resulted in only a small number of CIS patients being

entered. Thus, the power to detect treatment differences has been low and the reliability of the

conclusions is limited .

A meta-analysis of clinical trials that has compared intravesical BCG to intravesical

chemotherapy (MMC, epirubicin or adriamycin) in patients with CIS has shown a significantly

increased response rate after BCG and a reduction of 59% of treatment failure with BCG (p =

0.0001). In trials that have compared BCG with MMC, the long-term benefit of BCG was

smaller, but BCG was superior to MMC if maintenance BCG was given.

In another meta-analysis on tumour progression, in a subgroup of 403 patients with CIS, BCG

reduced the relative risk of progression by 35% as compared to intravesical chemotherapy or

different immunotherapy .Sequential intravesical chemotherapy and BCG did not obtain better

results .

Patients with CIS are at high risk of involvement of the upper urinary tract and the prostatic

urethra. In the prostate, CIS might be present only in the epithelial lining of the prostatic urethra

or in the prostatic ducts. Patients with CIS in the epithelial lining of the prostatic urethra can be

treated by intravesical instillations of BCG. TUR of the prostate can improve the contact of BCG

with the prostatic urethra. In patients with prostatic duct involvement, the data are insufficient to

provide clear treatment recommendations. As no conclusive results have been attained with

regard to the use of conservative therapy, radical surgery should be considered in these patients .

Treatment of BCG failure

Treatment with BCG is considered to have failed when a high-grade, non-muscle-invasive

tumour is present at both 3 and 6 months. In patients with tumour present at 3 months, an

additional BCG course provokes complete response in >50% of cases, both in patients with

papillary tumours and CIS (154,155), but with increasing risk of progression .

Any worsening of the disease under BCG treatment, such as a higher number of recurrences,

higher T stage or higher grade, or appearance of CIS, in spite of an initial response is considered

BCG relapsing.

Changing from BCG to intravesical chemotherapy, including valrubicin and gemcitabine,

device-assisted chemotherapy instillations, or additional interferon α-2b immunotherapy can

yield responses in selected cases with non-muscle-invasive BCG treatment failure . However,

experience is limited and these strategies are considered experimental. As a result of the high risk

of development of muscle-invasive tumour in these patients, immediate cystectomy is strongly

advocated upon BCG failure in fit patients.

Patients with recurrence at > 1 year after completion of BCG therapy can be treated according to

the risk classification .

Recurrences of low grade tumours.

Low grade Ta tumours represent about half of the non-muscle invasive bladder cancers. They

became a particular entity among NMBC because of the fact that they rarely become invasive,

but are still frequently relapsing. Their diagnostic work -up, treatment, prognosis, prevention and

follow-up is different from other NMIBC. This resulted even in particular guidelines on this

disease ). A control cystoscopy after 3 months is advocated of its prognostic value . It will also

pick up the overlooked tumours. When this cystoscopy doesn’t show any tumour, the following

control can be postponed until 1 year after TURB and yearly thereafter. the and the grow of low

grade tumours is slow . Overlooking a tumour during some months is without adverse

consequences .Tumour growth is slow and it is unlikely that large tumours will develop. These

few controls are allowed because evolution to an aggressive tumour is rare and leaving some

small low grade papillary tumours untreated during a certain period is not dangerous .

If a recurrence is detected, the follow-up schedule restarts. There is no evidence on any schedule

of follow-up and it is only based on common sense and expert opinion. It seems logic to adapt the

follow-up cystoscopies according to the prognostic factors.

Most recurrences appear in the 2 first years after diagnosis, already less in the third year and

rarely there after when no recurrence appeared in the first 3 years. Yearly follow-up can be

stopped when no recurrence at 5years.

Urinary cytology will not detect most low grade tumours but when it shows clearly malignant

cells this is suggestive for the evolution to a high grade tumour.

Office fulguration of recurrence in low grade tumours

Office fulguration of a few small papillary recurrences is feasible and safe . It can spare

anaesthesia and hospitalisation. However, on any suspicion of higher grade tumour because of its

macroscopic appearance or positive cytology a TURB must be performed like at primary

diagnosis. For the treatment of a recurrence, it is advocated to give again an early instillation.

Expert commentary:

A good TURB still is the keystone of diagnosis, treatment and prognosis of NMIBC. Although all

experts agree on that, this is only weakly documented. PPD is a step forwards in detection of TIS

but it is of questionable value in papillary tumours.

Many recommendations on the post TURB management of NMIBC are based on a high level of

evidence as NMBC has been extensively studied in large, well conducted phase 3 trials and

several meta-analyses. In spite of this, the applications of it is often lacking among urologists, not

for scientific, but for economical and organizational reasons. Potential severe side effects also

hamper the application of some recommendations.

Insufficient data exist on the best schedule and treatment duration of intravesical treatments and

it is very unlikely that trials in the future will done to deliver the evidence. In the absence of data

it seems wise to advocate rather less than more. The amazing good results reported on device

assisted intravesical chemotherapy application merit further exploration

An important achievement of 40 years of clinical research was the differentiation of different risk

categories in NMIBC .The difference in the management and follow-up between low and high

grade tumours is one of the mayor advances in this regard.

Five year view:

Which are the problems of which we hope that they can be solved the coming years?

TURB remains a procedure with unwanted side effects such as provoking implantation sites and

missing small tumours . Chemoresection may offer an alternative in many cases but is

insufficiently studied to advocate it. More active intravesical drugs and /or application EMDA

can improve the efficacy of this treatment.

A problem on the use of the immediate instillation after TURB is the danger of extravasation of

the intravesical drug which certainly is among the important reasons for its non application. New

drugs without this toxicity profile or application of the drug with EMDA just before TURB can

solve this problem .Or is rinsing the bladder also effective ?

The toxicity profile of BCG is high and any drug that can improve this situation, keeping the

same efficacy, will become a winner. There are such drugs in the pipeline. Combination of

intravesical chemo- and immunotherapy is another way to diminish the application of BCG alone

but the ideal schedule is insufficiently studied.

The population of NMBC is very heterogeneous. Predicting recurrence and, even more important,

progression is a mayor task for the future. Currently only clinical parameters insufficiently

predict this. The prediction of the need to early cystectomy also is an unmet need.

Key issues

-A complete and well performed TUR is an outmost important step in diagnosis and treatment.

The expensive fluorescence TUR helps in detecting TIS but its role in papillary tumours is

questionable. Other methods for improving this key step should be explored.

-Second resection is recommended in all T1 high grade tumours.

- Low grade papillary tumours, which are the majority of the NMIBC, are a different entity with

different diagnostic work-up, therapy and follow-up.

-The prognostic factors for recurrence and progression are different and intravesical treatment

must be adapted accordingly.

-An immediate post-TUR chemo-instillation is the most efficient adjuvant treatment to prevent

recurrence and is a sufficient treatment in low risk patients.

-The optimal schedule and duration of intravesical chemotherapy is unknown.

-Device assisted application of chemo gives excellent results which needs further attention.

-BCG is superior to chemotherapy for prevention of recurrence and progression of NMIBC.

-Early BCG failures have a bad prognosis and conservative treatment has little to offer.

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Reference annotationsRef 2:°° Last version of EUA guidelines.

8: ° review on Photodynamic TUR2:° Swedish study contradicting the enthusiasm on PPD21 °°: study on effect of second resection with however some methodological problems; read also the editorial comment of Babjuc M.23°°: EORTC prognostic factors studies, a standard!26°: prognostic factors from BCG treated patients in the Spanish study.30°: review on possible markers for failure of BCG.36°° study on which the necessity of immediate instillation is based41°° frequently citated meta-analysis on the early instillation studies 48°° Review on all chemotherapy instillations with different schedules and duration52°° review on the value of hyperthermia instillations.54 °° review on electromotive application of drugs.56° remarkable results of EMDA pre-TUR.66°° excellent recent meta-analysis comparing BCG vs. chemo.68°° meta-analysis on BCG vs. chemo.69°° meta-analysis on BCG in CIS specifically.71°° paper contradicting the need for maintenance therapy of BCG73°°the largest studies on 1/3 dose of BCG.80°° EUA guidelines specifically for CIS with extensive review of the data.84° review on possibilities when BCG fails