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



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 (1) . 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 [pic](2) 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[pic](3) (4) .

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 [pic](5) .

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 (6). 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(7).

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 [pic](8). However, false-positivity can be induced by inflammation or recent TUR, and during the first 3 months after BCG intravesical instillation [pic](9, 10).

The benefit of ALA fluorescence-guided TUR for recurrence-free survival has been demonstrated in several small, randomised clinical trials (11). 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 [pic](8). 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 [pic](12) 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[pic](13). 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[pic](14). 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 [pic](15, 16).

Second resection

The significant risk of residual tumour and under staging after initial TUR of TaT1 lesions has been demonstrated [pic](17, 18) . 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 [pic](19-22). 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 [pic](23). 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(24). 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 . The validation of the EORTC scoring system in an independent patient population with long-term follow-up has confirmed its prognostic value [pic](25).

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 [pic](26, 27). 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 [pic](28, 29). 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(30).

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 [pic](3). It is therefore necessary to consider adjuvant therapy in most patients.

One, immediate, postoperative intravesical instillation of chemotherapy

In a meta-analysis [pic](31) 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 [pic](32-35). In 2 of these [pic](32, 34), 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 [pic](36) . 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(37).

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 [pic](38).

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 [pic](36) . Moreover, a study in which the instillation was not given strictly on the same day did not find any advantage [pic](39). This is in contradiction with a recent prospective, randomised trial in prevention of bladder recurrence after upper tract urothelial tumours [pic](40). 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 [pic](41). In one study, gemcitabine plus 24 h bladder irrigation with physiological saline was not superior to irrigation with physiological saline during 24 hours [pic](42). 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 [pic](43).

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 [pic](44) .

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 [pic](45). The efficacy of intravesical chemotherapy in reducing the risk of tumour recurrence has been confirmed by two meta-analyses in primary (46) and recurrent tumours [pic](47).

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 [pic](48). 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 (49).

Optimising intravesical chemotherapy

One randomised trial has demonstrated that adapting urinary pH, decreasing urinary excretion and buffering the intravesical solution reduce the recurrence rate [pic](50) .

Another randomised trial has documented that concentration is more important than duration of the treatment [pic](51). 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 (52). In 83 patients 53% were tumour free at 10years with 86% of bladder preservation [pic](53).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 [pic](54).This resulted in very long disease free period :69 months in the BCG+electromotive MMC arm versus21 months in the BGG alone arm[pic](55) 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)[pic](56) .

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 [pic](57-61) . 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 [pic](62), mitomycin C [pic](63) or epirubicin [pic](64, 65) 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 [pic](64).

One meta-analysis [pic](66) 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 [pic](67, 68). 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 [pic](64, 68). 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 [pic](64). 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 [pic](66). 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 [pic](59, 69) In the most recent meta-analysis, however, BCG maintenance was more effective than MMC also in patients who were previously treated with chemotherapy [pic](66).

Optimal BCG schedule

According to the meta-analysis BCG must be given more than an induction cycle to obtain maximal response [pic](68). 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 [pic](60, 67). 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 [pic](70).

Recently a large series of T1 high grade tumours with a long follow-up (71)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 [pic](72, 73) . 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 [pic](73).

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 [pic](74). 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 [pic](23, 26).

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 [pic](2).

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 [pic](75-79). 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 (80).

A meta-analysis of clinical trials that has compared intravesical BCG to intravesical chemotherapy (MMC, epirubicin or adriamycin) [pic](69) 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 [pic](68) .Sequential intravesical chemotherapy and BCG did not obtain better results [pic](81).

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 (82).

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 [pic](29).

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 [pic](83) 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 [pic](84, 85). 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 (86).

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(87) ). A control cystoscopy after 3 months is advocated of its prognostic value [pic](2). 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 [pic](88, 89). 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 [pic](90-92) .

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 (93). 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 [pic](56) can solve this problem .Or is rinsing the bladder also effective [pic](43)?

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(94). 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.

References

1. Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World journal of urology. 2009;27(3):289-93. Epub 2009/02/17.

2. Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Bohle A, Palou-Redorta J, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. European urology. 2011;59(6):997-1008. Epub 2011/04/05.

3. Brausi M, Collette L, Kurth K, van der Meijden AP, Oosterlinck W, Witjes JA, et al. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. European urology. 2002;41(5):523-31. Epub 2002/06/21.

4. Mariappan P, Finney SM, Head E, Somani BK, Zachou A, Smith G, et al. Good quality white-light transurethral resection of bladder tumours (GQ-WLTURBT) with experienced surgeons performing complete resections and obtaining detrusor muscle reduces early recurrence in new non-muscle-invasive bladder cancer: validation across time and place and recommendation for benchmarking. BJU international. 2011. Epub 2011/11/03.

5. Mariappan P, Zachou A, Grigor KM, Edinburgh Uro-Oncology G. Detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. European urology. 2010;57(5):843-9. Epub 2009/06/16.

6. van der Meijden A, Oosterlinck W, Brausi M, Kurth KH, Sylvester R, de Balincourt C. Significance of bladder biopsies in Ta,T1 bladder tumors: a report from the EORTC Genito-Urinary Tract Cancer Cooperative Group. EORTC-GU Group Superficial Bladder Committee. European urology. 1999;35(4):267-71. Epub 1999/07/27.

7. Palou J, Sylvester RJ, Rodriguez Faba O, Parada R, Pena JA, Algaba F, et al. Female Gender and Carcinoma In Situ in the Prostatic Urethra Are Prognostic Factors for Recurrence, Progression, and Disease-Specific Mortality in T1G3 Bladder Cancer Patients Treated With Bacillus Calmette-Guerin. European urology. 2011. Epub 2011/11/22.

8. Kausch I, Sommerauer M, Montorsi F, Stenzl A, Jacqmin D, Jichlinski P, et al. Photodynamic diagnosis in non-muscle-invasive bladder cancer: a systematic review and cumulative analysis of prospective studies. European urology. 2010;57(4):595-606. Epub 2009/12/17.

9. Ray ER, Chatterton K, Khan MS, Chandra A, Thomas K, Dasgupta P, et al. Hexylaminolaevulinate fluorescence cystoscopy in patients previously treated with intravesical bacille Calmette-Guerin. BJU international. 2010;105(6):789-94. Epub 2009/10/17.

10. Draga RO, Grimbergen MC, Kok ET, Jonges TN, van Swol CF, Bosch JL. Photodynamic diagnosis (5-aminolevulinic acid) of transitional cell carcinoma after bacillus Calmette-Guerin immunotherapy and mitomycin C intravesical therapy. European urology. 2010;57(4):655-60. Epub 2009/10/13.

11. Geavlete B, Multescu R, Georgescu D, Jecu M, Stanescu F, Geavlete P. Treatment changes and long-term recurrence rates after hexaminolevulinate (HAL) fluorescence cystoscopy: does it really make a difference in patients with non-muscle-invasive bladder cancer (NMIBC)? BJU international. 2011. Epub 2011/06/30.

12. Schumacher MC, Holmang S, Davidsson T, Friedrich B, Pedersen J, Wiklund NP. Transurethral resection of non-muscle-invasive bladder transitional cell cancers with or without 5-aminolevulinic Acid under visible and fluorescent light: results of a prospective, randomised, multicentre study. European urology. 2010;57(2):293-9. Epub 2009/11/17.

13. Stenzl A, Burger M, Fradet Y, Mynderse LA, Soloway MS, Witjes JA, et al. Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. The Journal of urology. 2010;184(5):1907-13. Epub 2010/09/21.

14. Witjes JA, Redorta JP, Jacqmin D, Sofras F, Malmstrom PU, Riedl C, et al. Hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: review of the evidence and recommendations. European urology. 2010;57(4):607-14. Epub 2010/02/02.

15. Cauberg EC, Mamoulakis C, de la Rosette JJ, de Reijke TM. Narrow band imaging-assisted transurethral resection for non-muscle invasive bladder cancer significantly reduces residual tumour rate. World journal of urology. 2011;29(4):503-9. Epub 2011/02/26.

16. Shen YJ, Zhu YP, Ye DW, Yao XD, Zhang SL, Dai B, et al. Narrow-band imaging flexible cystoscopy in the detection of primary non-muscle invasive bladder cancer: a "second look" matters? International urology and nephrology. 2011. Epub 2011/07/28.

17. Kulkarni GS, Hakenberg OW, Gschwend JE, Thalmann G, Kassouf W, Kamat A, et al. An updated critical analysis of the treatment strategy for newly diagnosed high-grade T1 (previously T1G3) bladder cancer. European urology. 2010;57(1):60-70. Epub 2009/09/11.

18. Fritsche HM, Burger M, Svatek RS, Jeldres C, Karakiewicz PI, Novara G, et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: results from an international cohort. European urology. 2010;57(2):300-9. Epub 2009/09/22.

19. Grimm MO, Steinhoff C, Simon X, Spiegelhalder P, Ackermann R, Vogeli TA. Effect of routine repeat transurethral resection for superficial bladder cancer: a long-term observational study. The Journal of urology. 2003;170(2 Pt 1):433-7. Epub 2003/07/11.

20. Divrik RT, Yildirim U, Zorlu F, Ozen H. The effect of repeat transurethral resection on recurrence and progression rates in patients with T1 tumors of the bladder who received intravesical mitomycin: a prospective, randomized clinical trial. The Journal of urology. 2006;175(5):1641-4. Epub 2006/04/08.

21. Divrik RT, Sahin AF, Yildirim U, Altok M, Zorlu F. Impact of routine second transurethral resection on the long-term outcome of patients with newly diagnosed pT1 urothelial carcinoma with respect to recurrence, progression rate, and disease-specific survival: a prospective randomised clinical trial. European urology. 2010;58(2):185-90. Epub 2010/03/23.

22. Dalbagni G, Vora K, Kaag M, Cronin A, Bochner B, Donat SM, et al. Clinical outcome in a contemporary series of restaged patients with clinical T1 bladder cancer. European urology. 2009;56(6):903-10. Epub 2009/07/28.

23. Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. European urology. 2006;49(3):466-5; discussion 75-7. Epub 2006/01/31.

24. Jancke G, Rosell J, Jahnson S. Impact of tumour size on recurrence and progression in Ta/T1 carcinoma of the urinary bladder. Scandinavian journal of urology and nephrology. 2011;45(6):388-92. Epub 2011/06/18.

25. van Rhijn BW, Zuiverloon TC, Vis AN, Radvanyi F, van Leenders GJ, Ooms BC, et al. Molecular grade (FGFR3/MIB-1) and EORTC risk scores are predictive in primary non-muscle-invasive bladder cancer. European urology. 2010;58(3):433-41. Epub 2010/07/22.

26. Fernandez-Gomez J, Madero R, Solsona E, Unda M, Martinez-Pineiro L, Gonzalez M, et al. Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model. The Journal of urology. 2009;182(5):2195-203. Epub 2009/09/18.

27. Fernandez-Gomez J, Madero R, Solsona E, Unda M, Martinez-Pineiro L, Ojea A, et al. The EORTC tables overestimate the risk of recurrence and progression in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin: external validation of the EORTC risk tables. European urology. 2011;60(3):423-30. Epub 2011/05/31.

28. Chade DC, Shariat SF, Godoy G, Savage CJ, Cronin AM, Bochner BH, et al. Clinical outcomes of primary bladder carcinoma in situ in a contemporary series. The Journal of urology. 2010;184(1):74-80. Epub 2010/06/16.

29. Lerner SP, Tangen CM, Sucharew H, Wood D, Crawford ED. Failure to achieve a complete response to induction BCG therapy is associated with increased risk of disease worsening and death in patients with high risk non-muscle invasive bladder cancer. Urologic oncology. 2009;27(2):155-9. Epub 2008/03/28.

30. Zuiverloon TC, Nieuweboer AJ, Vekony H, Kirkels WJ, Bangma CH, Zwarthoff EC. Markers predicting response to bacillus Calmette-Guerin immunotherapy in high-risk bladder cancer patients: a systematic review. European urology. 2012;61(1):128-45. Epub 2011/10/18.

31. Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials. The Journal of urology. 2004;171(6 Pt 1):2186-90, quiz 435. Epub 2004/05/06.

32. De Nunzio C, Carbone A, Albisinni S, Alpi G, Cantiani A, Liberti M, et al. Long-term experience with early single mitomycin C instillations in patients with low-risk non-muscle-invasive bladder cancer: prospective, single-centre randomised trial. World journal of urology. 2011;29(4):517-21. Epub 2011/05/20.

33. Berrum-Svennung I, Granfors T, Jahnson S, Boman H, Holmang S. A single instillation of epirubicin after transurethral resection of bladder tumors prevents only small recurrences. The Journal of urology. 2008;179(1):101-5; discussion 5-6. Epub 2007/11/13.

34. Gudjonsson S, Adell L, Merdasa F, Olsson R, Larsson B, Davidsson T, et al. Should all patients with non-muscle-invasive bladder cancer receive early intravesical chemotherapy after transurethral resection? The results of a prospective randomised multicentre study. European urology. 2009;55(4):773-80. Epub 2009/01/21.

35. Jung SJ, Chang HS, Park CH, Kim CI, Kim BH. Effectiveness of an immediate mitomycin C instillation in patients with superficial bladder cancer receiving periodic mitomycin C instillation. Korean journal of urology. 2011;52(5):323-6. Epub 2011/06/21.

36. Kaasinen E, Rintala E, Hellstrom P, Viitanen J, Juusela H, Rajala P, et al. Factors explaining recurrence in patients undergoing chemoimmunotherapy regimens for frequently recurring superficial bladder carcinoma. European urology. 2002;42(2):167-74. Epub 2002/08/06.

37. Badalato GM, Hruby G, Razmjoo M, McKiernan JM. Maximizing intravesical therapy options: is there an advantage to the administration of perioperative mitomycin C prior to an induction course of BCG? The Canadian journal of urology. 2011;18(5):5890-5. Epub 2011/10/25.

38. Chamie K, Saigal CS, Lai J, Hanley JM, Setodji CM, Konety BR, et al. Compliance with guidelines for patients with bladder cancer: variation in the delivery of care. Cancer. 2011;117(23):5392-401. Epub 2011/07/23.

39. Hendricksen K, Witjes WP, Idema JG, Kums JJ, van Vierssen Trip OB, de Bruin MJ, et al. Comparison of three schedules of intravesical epirubicin in patients with non-muscle-invasive bladder cancer. European urology. 2008;53(5):984-91. Epub 2008/02/06.

40. O'Brien T, Ray E, Singh R, Coker B, Beard R, British Association of Urological Surgeons Section of O. Prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma: a prospective, multicentre, randomised clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT-C Trial). European urology. 2011;60(4):703-10. Epub 2011/06/21.

41. Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials. J Urol. 2004;171(6 Pt 1):2186-90, quiz 435. Epub 2004/05/06.

42. Bohle A, Leyh H, Frei C, Kuhn M, Tschada R, Pottek T, et al. Single postoperative instillation of gemcitabine in patients with non-muscle-invasive transitional cell carcinoma of the bladder: a randomised, double-blind, placebo-controlled phase III multicentre study. Eur Urol. 2009;56(3):495-503. Epub 2009/06/30.

43. Onishi T, Sasaki T, Hoshina A, Yabana T. Continuous saline bladder irrigation after transurethral resection is a prophylactic treatment choice for non-muscle invasive bladder tumor. Anticancer research. 2011;31(4):1471-4. Epub 2011/04/22.

44. Engeler DS, Wyler S, Neyer M, Hobi C, Muller J, Schmid HP. Feasibility of early intravesical instillation chemotherapy after transurethral resection of the bladder: a prospective evaluation in a consecutive series of 210 cases. Scandinavian journal of urology and nephrology. 2008;42(6):522-7. Epub 2008/07/09.

45. 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. The Journal of urology. 1996;156(6):1934-40, discussion 40-1. Epub 1996/12/01.

46. 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. Journal of clinical epidemiology. 2000;53(7):676-80. Epub 2000/08/15.

47. Huncharek M, McGarry R, Kupelnick B. Impact of intravesical chemotherapy on recurrence rate of recurrent superficial transitional cell carcinoma of the bladder: results of a meta-analysis. Anticancer research. 2001;21(1B):765-9. Epub 2001/04/13.

48. Sylvester RJ, Oosterlinck W, Witjes JA. The schedule and duration of intravesical chemotherapy in patients with non-muscle-invasive bladder cancer: a systematic review of the published results of randomized clinical trials. European urology. 2008;53(4):709-19. Epub 2008/01/22.

49. Jones G, Cleves A, Wilt TJ, Mason M, Kynaston HG, Shelley M. Intravesical gemcitabine for non-muscle invasive bladder cancer. Cochrane database of systematic reviews. 2012;1:CD009294. Epub 2012/01/20.

50. 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. Journal of the National Cancer Institute. 2001;93(8):597-604. Epub 2001/04/20.

51. Kuroda M, Niijima T, Kotake T, Akaza H, Hinotsu S, th Trial of the Japanese Urological Cancer Research G. Effect of prophylactic treatment with intravesical epirubicin on recurrence of superficial bladder cancer--The 6th Trial of the Japanese Urological Cancer Research Group (JUCRG): a randomized trial of intravesical epirubicin at dose of 20mg/40ml, 30mg/40ml, 40mg/40ml. European urology. 2004;45(5):600-5. Epub 2004/04/15.

52. Lammers RJ, Witjes JA, Inman BA, Leibovitch I, Laufer M, Nativ O, et al. The role of a combined regimen with intravesical chemotherapy and hyperthermia in the management of non-muscle-invasive bladder cancer: a systematic review. European urology. 2011;60(1):81-93. Epub 2011/05/03.

53. Colombo R, Salonia A, Leib Z, Pavone-Macaluso M, Engelstein D. Long-term outcomes of a randomized controlled trial comparing thermochemotherapy with mitomycin-C alone as adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC). BJU international. 2011;107(6):912-8. Epub 2010/10/30.

54. Kalsi J, Harland SJ, Feneley MR. Electromotive drug administration with mitomycin C for intravesical treatment of non-muscle invasive transitional cell carcinoma. Expert opinion on drug delivery. 2008;5(1):137-45. Epub 2007/12/22.

55. Di Stasi SM, Giannantoni A, Giurioli A, Valenti M, Zampa G, Storti L, et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. The lancet oncology. 2006;7(1):43-51. Epub 2006/01/04.

56. Di Stasi SM, Valenti M, Verri C, Liberati E, Giurioli A, Leprini G, et al. Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial non-muscle invasive bladder cancer: a randomised controlled trial. The lancet oncology. 2011;12(9):871-9. Epub 2011/08/13.

57. Shelley MD, Wilt TJ, Court J, Coles B, Kynaston H, Mason MD. Intravesical bacillus Calmette-Guerin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU international. 2004;93(4):485-90. Epub 2004/03/11.

58. Shelley MD, Kynaston H, Court J, Wilt TJ, Coles B, Burgon K, et al. A systematic review of intravesical bacillus Calmette-Guerin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU international. 2001;88(3):209-16. Epub 2001/08/08.

59. Han RF, Pan JG. Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology. 2006;67(6):1216-23. Epub 2006/06/13.

60. Bohle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. The Journal of urology. 2003;169(1):90-5. Epub 2002/12/13.

61. Shang PF, Kwong J, Wang ZP, Tian J, Jiang L, Yang K, et al. Intravesical Bacillus Calmette-Guerin versus epirubicin for Ta and T1 bladder cancer. Cochrane database of systematic reviews. 2011(5):CD006885. Epub 2011/05/13.

62. Duchek M, Johansson R, Jahnson S, Mestad O, Hellstrom P, Hellsten S, et al. Bacillus Calmette-Guerin is superior to a combination of epirubicin and interferon-alpha2b in the intravesical treatment of patients with stage T1 urinary bladder cancer. A prospective, randomized, Nordic study. European urology. 2010;57(1):25-31. Epub 2009/10/13.

63. Jarvinen R, Kaasinen E, Sankila A, Rintala E, FinnBladder G. Long-term efficacy of maintenance bacillus Calmette-Guerin versus maintenance mitomycin C instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up. European urology. 2009;56(2):260-5. Epub 2009/04/28.

64. Sylvester RJ, Brausi MA, Kirkels WJ, Hoeltl W, Calais Da Silva F, Powell PH, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. European urology. 2010;57(5):766-73. Epub 2009/12/26.

65. Hinotsu S, Akaza H, Naito S, Ozono S, Sumiyoshi Y, Noguchi S, et al. Maintenance therapy with bacillus Calmette-Guerin Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumour for non-muscle-invasive bladder cancer. BJU international. 2011;108(2):187-95. Epub 2010/12/24.

66. Malmstrom PU, Sylvester RJ, Crawford DE, Friedrich M, Krege S, Rintala E, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. European urology. 2009;56(2):247-56. Epub 2009/05/05.

67. Bohle A, Bock PR. Intravesical bacille Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. Urology. 2004;63(4):682-6; discussion 6-7. Epub 2004/04/10.

68. Sylvester RJ, van der MA, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. The Journal of urology. 2002;168(5):1964-70. Epub 2002/10/24.

69. Sylvester RJ, van der Meijden AP, Witjes JA, Kurth K. Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. The Journal of urology. 2005;174(1):86-91; discussion -2. Epub 2005/06/11.

70. Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. The Journal of urology. 2000;163(4):1124-9. Epub 2000/03/29.

71. Herr HW, Dalbagni G, Donat SM. Bacillus Calmette-Guerin without maintenance therapy for high-risk non-muscle-invasive bladder cancer. European urology. 2011;60(1):32-6. Epub 2011/04/19.

72. Martinez-Pineiro JA, Martinez-Pineiro L, Solsona E, Rodriguez RH, Gomez JM, Martin MG, et al. Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial. The Journal of urology. 2005;174(4 Pt 1):1242-7. Epub 2005/09/08.

73. Ojea A, Nogueira JL, Solsona E, Flores N, Gomez JM, Molina JR, et al. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. European urology. 2007;52(5):1398-406. Epub 2007/05/09.

74. van der Meijden AP, Sylvester RJ, Oosterlinck W, Hoeltl W, Bono AV, Group EG-UTC. Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial. European urology. 2003;44(4):429-34. Epub 2003/09/23.

75. Losa A, Hurle R, Lembo A. Low dose bacillus Calmette-Guerin for carcinoma in situ of the bladder: long-term results. The Journal of urology. 2000;163(1):68-71; discussion -2. Epub 1999/12/22.

76. Griffiths TR, Charlton M, Neal DE, Powell PH. Treatment of carcinoma in situ with intravesical bacillus Calmette-Guerin without maintenance. The Journal of urology. 2002;167(6):2408-12. Epub 2002/05/07.

77. Jakse G, Hall R, Bono A, Holtl W, Carpentier P, Spaander JP, et al. Intravesical BCG in patients with carcinoma in situ of the urinary bladder: long-term results of EORTC GU Group phase II protocol 30861. European urology. 2001;40(2):144-50. Epub 2001/08/31.

78. Takenaka A, Yamada Y, Miyake H, Hara I, Fujisawa M. Clinical outcomes of bacillus Calmette-Guerin instillation therapy for carcinoma in situ of urinary bladder. International journal of urology : official journal of the Japanese Urological Association. 2008;15(4):309-13. Epub 2008/04/03.

79. Gofrit ON, Pode D, Pizov G, Zorn KC, Katz R, Duvdevani M, et al. The natural history of bladder carcinoma in situ after initial response to bacillus Calmette-Guerin immunotherapy. Urologic oncology. 2009;27(3):258-62. Epub 2008/04/29.

80. van der Meijden AP, Sylvester R, Oosterlinck W, Solsona E, Boehle A, Lobel B, et al. EAU guidelines on the diagnosis and treatment of urothelial carcinoma in situ. European urology. 2005;48(3):363-71. Epub 2005/07/05.

81. Oosterlinck W, Kirkali Z, Sylvester R, da Silva FC, Busch C, Algaba F, et al. Sequential intravesical chemoimmunotherapy with mitomycin C and bacillus Calmette-Guerin and with bacillus Calmette-Guerin alone in patients with carcinoma in situ of the urinary bladder: results of an EORTC genito-urinary group randomized phase 2 trial (30993). European urology. 2011;59(3):438-46. Epub 2010/12/16.

82. Palou J, Baniel J, Klotz L, Wood D, Cookson M, Lerner S, et al. Urothelial carcinoma of the prostate. Urology. 2007;69(1 Suppl):50-61. Epub 2007/02/07.

83. Steinberg GD, Smith ND, Ryder K, Strangman NM, Slater SJ. Factors affecting valrubicin response in patients with bacillus Calmette-Guerin-refractory bladder carcinoma in situ. Postgraduate medicine. 2011;123(3):28-34. Epub 2011/05/14.

84. Lightfoot AJ, Rosevear HM, O'Donnell MA. Recognition and treatment of BCG failure in bladder cancer. TheScientificWorldJournal. 2011;11:602-13. Epub 2011/03/15.

85. Yates DR, Roupret M. Contemporary management of patients with high-risk non-muscle-invasive bladder cancer who fail intravesical BCG therapy. World journal of urology. 2011;29(4):415-22. Epub 2011/05/06.

86. Gallagher BL, Joudi FN, Maymi JL, O'Donnell MA. Impact of previous bacille Calmette-Guerin failure pattern on subsequent response to bacille Calmette-Guerin plus interferon intravesical therapy. Urology. 2008;71(2):297-301. Epub 2008/03/01.

87. Oosterlinck W, Solsona E, Akaza H, Busch C, Goebell PJ, Malmstrom PU, et al. Low-grade Ta (noninvasive) urothelial carcinoma of the bladder. Urology. 2005;66(6 Suppl 1):75-89. Epub 2006/01/10.

88. Soloway MS. Expectant treatment of small, recurrent, low-grade, noninvasive tumors of the urinary bladder. Urol Oncol. 2006;24(1):58-61. Epub 2006/01/18.

89. Gofrit ON, Pode D, Lazar A, Katz R, Shapiro A. Watchful waiting policy in recurrent Ta G1 bladder tumors. European urology. 2006;49(2):303-6; discussion 6-7. Epub 2006/01/18.

90. Gofrit ON, Pode D, Lazar A, Katz R, Shapiro A. Watchful waiting policy in recurrent Ta G1 bladder tumors. Eur Urol. 2006;49(2):303-6; discussion 6-7. Epub 2006/01/18.

91. Pruthi RS, Baldwin N, Bhalani V, Wallen EM. Conservative management of low risk superficial bladder tumors. J Urol. 2008;179(1):87-90; discussion Epub 2007/11/13.

92. Hernandez V, Alvarez M, de la Pena E, Amaruch N, Martin MD, de la Morena JM, et al. Safety of active surveillance program for recurrent nonmuscle-invasive bladder carcinoma. Urology. 2009;73(6):1306-10. Epub 2009/04/21.

93. Donat SM, North A, Dalbagni G, Herr HW. Efficacy of office fulguration for recurrent low grade papillary bladder tumors less than 0.5 cm. The Journal of urology. 2004;171(2 Pt 1):636-9. Epub 2004/01/10.

94. Yutkin V, Chin J. Apaziquone as an intravesical therapeutic agent for urothelial non-muscle-invasive bladder cancer. Expert opinion on investigational drugs. 2012;21(2):251-60. Epub 2011/12/23.

Reference annotations

Ref 2:°° Last version of EUA guidelines.

8: ° review on Photodynamic TUR

2:° Swedish study contradicting the enthusiasm on PPD

21 °°: 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 based

41°° frequently citated meta-analysis on the early instillation studies

48°° Review on all chemotherapy instillations with different schedules and duration

52°° 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 BCG

73°°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

................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download