Current Perspectives in Bladder Cancer Management
Current Perspectives in Bladder Cancer Management
An algorithm outlining the primary management of NMIBC (TCC) is presented in Figure 1.
(Enlarge Image)
Figure 1.
Management of non-muscle invasive bladder cancer (TCC). BCG, bacillus Calmette-Guérin; CT, computed tomography; EORTC, European Organization for Research and Treatment of Cancer; NMIBC, non-muscle invasive bladder cancer; TCC, transitional cell carcinoma; TUR, transurethral resection
Patients with NMIBC have a diverse prognosis. The European Organisation for Research and Treatment of Cancer (EORTC) has identified six key risk factors for the prediction of tumour recurrence and progression to muscle invasive disease. These are: number of tumours; prior recurrence rate; tumour size; stage (T-category); histological grade (1973 World Health Organization grade); presence of concomitant CIS. From these, risk scores are developed to enable patients to be classified into low-, intermediate-and high-risk groups for recurrence and progression. Risks of recurrence and progression at 5 years following diagnosis vary from 31% to 78% and 0.8% to 45% respectively.
The quality of the initial TUR has a substantial impact on outcomes – removal of adequate detrusor muscle is associated with reduced risk of recurrence. Local recurrence rates for a single tumour at first-check cystoscopy can vary from 3.5% to 20.6% depending on the institution.
To exclude muscle invasion at the primary TUR, larger tumours should be resected so that at least exophytic and deep biopsies are submitted in separate fractions. Repeat TUR is recommended where the initial resection is judged to be incomplete, either because of the absence of detrusor muscle in a high-grade tumour or caused by macroscopic residual disease; this is also currently recommended in all high-grade T1 tumours even if detrusor muscle was present in the first TUR specimen. Failure to adhere to these principles can adversely affect outcomes. Contemporary series have shown that in patients initially staged as T1, 20% were upstaged to muscle invasive disease after repeat TUR and residual tumour rates were 25–33%. Although EAU guidelines currently include high-grade Ta tumours in their recommendation for repeat resection, the evidence for repeat resection of high-grade Ta tumours is less robust than for high-grade T1 tumours.
The most commonly used intravesical chemotherapeutic agents are mitomycin C (MMC) and epirubicin. The intravesical immunotherapy of choice is bacillus Calmette-Guérin (BCG).
A single postoperative intravesical instillation of chemotherapy within 24 h of TUR (and ideally 6 h) is currently recommended for all newly diagnosed bladder tumours. In clinical studies, this reduced tumour recurrence rates by 39%; Another study involving patients with recurrent NMIBC showed that the recurrence rate was increased twofold if instillation was performed more than 24 h after TUR.
The effect of a single instillation of intravesical chemotherapy lasts for approximately 500 days. The choice between further intravesical chemotherapy or immunotherapy is guided by the patient's risk group. Further intravesical chemotherapy reduces the risk of recurrence, but has not been shown to reduce disease progression; BCG is more effective than chemotherapy in reducing recurrence, provided maintenance treatment is administered, but is associated with more side effects than chemotherapy. If maintenance therapy is given for at least 1 year, BCG is the only intravesical agent shown to reduce or at least delay the risk of disease progression, by around 37%. Compared with epirubicin, maintenance BCG was superior in preventing progression and also improving overall survival (OS). However, the relative benefit of maintenance BCG over MMC in terms of disease progression is more controversial.
For patients at low risk of recurrence and progression (EORTC recurrence and progression scores = 0), no further treatment after TUR is recommended prior to a further recurrence. The probability of recurrence at 1 year is 15% and for progression is 0.2%.
In intermediate-risk patients, the main priority is to reduce the risk of recurrence (46–62% at 5 years), although the risk of progression is not negligible (6–17% at 5 years). A maximum of 1 year of intravesical chemotherapy or 1–3 years of intravesical BCG is currently recommended, although the superior efficacy of BCG needs to be balanced against its increased toxicity. Three-year vs. one-year BCG maintenance at full-dose compared with one-third-dose BCG in patients with intermediate- and selected high-risk (solitary tumour without CIS) NMIBC has been tested in the EORTC 30962 RCT. Superiority could not be formally concluded for either comparison, although patients receiving full-dose BCG for 3 years had the highest disease-free survival (DFS) at 5 years, whereas those receiving one-third-dose for 1 year had the lowest. Clearly, extending maintenance treatment for more than 1 year is a balance of efficacy, side effects and inconvenience and is worthy of discussion with the patient. In routine clinical practice, many urologists in the UK delay the decision until the patient develops a further recurrence. Some administer a further single-dose chemotherapy instillation after TUR for recurrent disease, but this has not been validated for recurrent tumours. Others give six instillations (one instillation weekly for 6 weeks) of intravesical chemotherapy before the first-check cystoscopy at around 3 months after TUR.
In high-risk patients (EORTC progression score > 14), the 5-year probability of disease progression is 45%. Here, the primary goal of intravesical treatment is not only to prevent recurrence, but also to prevent progression. Maintenance BCG has been established as the bladder-sparing treatment of choice in these patients. The optimal duration of treatment has not yet been established, but at least 1 year of maintenance is recommended. The Southwest Oncology Group protocol is the most widely used and involves giving up to 27 instillations of BCG over a 3-year period.
There are no RCTs comparing BCG with immediate radical cystectomy. There is, however, consensus that immediate radical cystectomy should be considered for patients with high-risk NMIBC where the risk of tumour progression is especially high, or concomitant superficial urethral TCC is present, or where the patient requests it in preference to intravesical BCG. Added risk factors for progression in high-grade T1 disease include associated CIS, multifocality, tumour size > 3 cm and persistent T1 disease at repeat resection. If more than one of these risk factors is present, then radical cystectomy should be strongly considered. A growing body of urologists believe that radical cystectomy for high-grade T1 TCC is under-utilised at present. Their concerns are based on non-randomised evidence that suggests worse outcomes following cystectomy for failed intravesical treatment compared with immediate cystectomy, although such studies are likely to include selection bias. Immediate radical cystectomy for NMIBC may also be indicated when aggressive variants of TCC are present, e.g. diffuse areas of micropapillary variant are detected or in those where BCG is contraindicated, e.g. significant immunosuppression. Radical cystectomy is also indicated for squamous cell carcinoma and radical or partial cystectomy should be considered for adenocarcinoma.
The definition of BCG failure is controversial, but the persistence of T1 disease at the 3-month check cystoscopy after induction BCG (six instillations administered once-weekly for 6 weeks); high-grade Ta disease/CIS at 6 months; or detection of muscle invasive TCC should prompt consideration of radical cystectomy.
The incidence of concomitant UUT-TCC is low (1.8%), but in patients with trigonal tumours, the incidence is 7.5%. During follow-up, patients with high-grade and multifocal NMIBC are more likely to develop UUT-TCC. Ultrasound is routinely performed during diagnostic work-up of bladder cancer, but can miss small UUT-TCC. Computed tomography urography should therefore be considered where the bladder tumour is high-grade, multifocal or trigonal.
After a nephroureterectomy for UUT-TCC, up to 40% of patients will develop bladder cancer. In a phase III RCT (ODMIT-C), a single dose of postoperative intravesical MMC, administered at the time of urethral catheter removal, reduced the risk of a bladder tumour within the first year after nephroureterectomy; the absolute reduction in risk was 11%, the relative reduction was 40% and the number needed to treat to prevent one bladder tumour was 9. The trial was the largest randomised study ever conducted in the management of patients with UUT-TCC. However, it was not designed to determine the most effective method of nephroureterectomy, and so a number of techniques were allowed for management of the distal ureter. Patients with a previous history of bladder cancer were excluded.
Radical cystectomy remains the mainstay of treatment for patients who have failed BCG treatment. For patients who are unwilling or unfit to undergo this procedure, the treatment options are limited.
Intravesical chemotherapeutic agents, such as gemcitabine and docetaxel, novel immunotherapies, such as interferon-alpha, and device-assisted treatments have all shown promise. However, to date, much of the evidence to support their potential benefit is based on non-randomised or small Phase II studies. At best, currently available bladder-sparing treatments for those with BCG-refractory TCC are associated with 2-year DFS of approximately 50%.
Chemohyperthermia (c-HT) describes the combination of intravesical chemotherapy and hyperthermia, where the chemotherapy and the bladder wall are heated to temperatures of between 44 and 45 °C. The most common form of c-HT uses the Synergo HT system in which local HT is administered via a 915 MHz intravesical microwave applicator. c-HT increases cell membrane permeability, enhances urothelial exposure and in particular lamina propria exposure, alters intracellular drug trafficking and enhances the effects of cytostatic chemotherapy. Over the last 15 years, c-HT has been tested in a variety of clinical settings, including small several Phase II RCTs, in the BCG-naïve setting.
Data supporting the role of c-HT (using MMC) in BCG-refractory NMIBC has come from several proof-of-concept studies. In patients with BCG-refractory CIS, a complete response rate of 92% was shown, with 50% of patients remaining disease-free at 2-year follow-up. In patients with BCG-refractory NMIBC (77% high-risk) treated with a maintenance c-HT schedule, the recurrence-free rate was 56% at 2 years; 3% progressed to muscle invasive disease and 5% withdrew from treatment because of adverse events. The use of c-HT is being further evaluated in BCG-refractory patients with NMIBC who are unwilling or unfit for cystectomy in the UK-based HYMN Phase III trial (EUDRACT-2008-005428-99).
Electromotive drug administration (EMDA) is an alternative way of enhancing MMC absorption and urothelial exposure, by creating an electrical gradient across the bladder wall using electrodes placed within the catheter and on the lower abdominal wall. In patients with BCG-naïve high-risk NMIBC, EMDA-MMC has shown promise. To date, no studies have specifically evaluated EMDA-MMC in the BCG-refractory setting, although one RCT allowed crossover of patients to EMDA-MMC alone if they did not respond to primary BCG treatment.
Pivotal Considerations in the Management of NMIBC (TCC)
An algorithm outlining the primary management of NMIBC (TCC) is presented in Figure 1.
(Enlarge Image)
Figure 1.
Management of non-muscle invasive bladder cancer (TCC). BCG, bacillus Calmette-Guérin; CT, computed tomography; EORTC, European Organization for Research and Treatment of Cancer; NMIBC, non-muscle invasive bladder cancer; TCC, transitional cell carcinoma; TUR, transurethral resection
Allocation to a Risk Group
Patients with NMIBC have a diverse prognosis. The European Organisation for Research and Treatment of Cancer (EORTC) has identified six key risk factors for the prediction of tumour recurrence and progression to muscle invasive disease. These are: number of tumours; prior recurrence rate; tumour size; stage (T-category); histological grade (1973 World Health Organization grade); presence of concomitant CIS. From these, risk scores are developed to enable patients to be classified into low-, intermediate-and high-risk groups for recurrence and progression. Risks of recurrence and progression at 5 years following diagnosis vary from 31% to 78% and 0.8% to 45% respectively.
Detrusor Muscle Status
The quality of the initial TUR has a substantial impact on outcomes – removal of adequate detrusor muscle is associated with reduced risk of recurrence. Local recurrence rates for a single tumour at first-check cystoscopy can vary from 3.5% to 20.6% depending on the institution.
To exclude muscle invasion at the primary TUR, larger tumours should be resected so that at least exophytic and deep biopsies are submitted in separate fractions. Repeat TUR is recommended where the initial resection is judged to be incomplete, either because of the absence of detrusor muscle in a high-grade tumour or caused by macroscopic residual disease; this is also currently recommended in all high-grade T1 tumours even if detrusor muscle was present in the first TUR specimen. Failure to adhere to these principles can adversely affect outcomes. Contemporary series have shown that in patients initially staged as T1, 20% were upstaged to muscle invasive disease after repeat TUR and residual tumour rates were 25–33%. Although EAU guidelines currently include high-grade Ta tumours in their recommendation for repeat resection, the evidence for repeat resection of high-grade Ta tumours is less robust than for high-grade T1 tumours.
Requirement for Adjuvant Intravesical Treatment
The most commonly used intravesical chemotherapeutic agents are mitomycin C (MMC) and epirubicin. The intravesical immunotherapy of choice is bacillus Calmette-Guérin (BCG).
A single postoperative intravesical instillation of chemotherapy within 24 h of TUR (and ideally 6 h) is currently recommended for all newly diagnosed bladder tumours. In clinical studies, this reduced tumour recurrence rates by 39%; Another study involving patients with recurrent NMIBC showed that the recurrence rate was increased twofold if instillation was performed more than 24 h after TUR.
Need for Further Instillations of Chemotherapy or BCG
The effect of a single instillation of intravesical chemotherapy lasts for approximately 500 days. The choice between further intravesical chemotherapy or immunotherapy is guided by the patient's risk group. Further intravesical chemotherapy reduces the risk of recurrence, but has not been shown to reduce disease progression; BCG is more effective than chemotherapy in reducing recurrence, provided maintenance treatment is administered, but is associated with more side effects than chemotherapy. If maintenance therapy is given for at least 1 year, BCG is the only intravesical agent shown to reduce or at least delay the risk of disease progression, by around 37%. Compared with epirubicin, maintenance BCG was superior in preventing progression and also improving overall survival (OS). However, the relative benefit of maintenance BCG over MMC in terms of disease progression is more controversial.
For patients at low risk of recurrence and progression (EORTC recurrence and progression scores = 0), no further treatment after TUR is recommended prior to a further recurrence. The probability of recurrence at 1 year is 15% and for progression is 0.2%.
In intermediate-risk patients, the main priority is to reduce the risk of recurrence (46–62% at 5 years), although the risk of progression is not negligible (6–17% at 5 years). A maximum of 1 year of intravesical chemotherapy or 1–3 years of intravesical BCG is currently recommended, although the superior efficacy of BCG needs to be balanced against its increased toxicity. Three-year vs. one-year BCG maintenance at full-dose compared with one-third-dose BCG in patients with intermediate- and selected high-risk (solitary tumour without CIS) NMIBC has been tested in the EORTC 30962 RCT. Superiority could not be formally concluded for either comparison, although patients receiving full-dose BCG for 3 years had the highest disease-free survival (DFS) at 5 years, whereas those receiving one-third-dose for 1 year had the lowest. Clearly, extending maintenance treatment for more than 1 year is a balance of efficacy, side effects and inconvenience and is worthy of discussion with the patient. In routine clinical practice, many urologists in the UK delay the decision until the patient develops a further recurrence. Some administer a further single-dose chemotherapy instillation after TUR for recurrent disease, but this has not been validated for recurrent tumours. Others give six instillations (one instillation weekly for 6 weeks) of intravesical chemotherapy before the first-check cystoscopy at around 3 months after TUR.
In high-risk patients (EORTC progression score > 14), the 5-year probability of disease progression is 45%. Here, the primary goal of intravesical treatment is not only to prevent recurrence, but also to prevent progression. Maintenance BCG has been established as the bladder-sparing treatment of choice in these patients. The optimal duration of treatment has not yet been established, but at least 1 year of maintenance is recommended. The Southwest Oncology Group protocol is the most widely used and involves giving up to 27 instillations of BCG over a 3-year period.
Considerations for Radical Cystectomy
There are no RCTs comparing BCG with immediate radical cystectomy. There is, however, consensus that immediate radical cystectomy should be considered for patients with high-risk NMIBC where the risk of tumour progression is especially high, or concomitant superficial urethral TCC is present, or where the patient requests it in preference to intravesical BCG. Added risk factors for progression in high-grade T1 disease include associated CIS, multifocality, tumour size > 3 cm and persistent T1 disease at repeat resection. If more than one of these risk factors is present, then radical cystectomy should be strongly considered. A growing body of urologists believe that radical cystectomy for high-grade T1 TCC is under-utilised at present. Their concerns are based on non-randomised evidence that suggests worse outcomes following cystectomy for failed intravesical treatment compared with immediate cystectomy, although such studies are likely to include selection bias. Immediate radical cystectomy for NMIBC may also be indicated when aggressive variants of TCC are present, e.g. diffuse areas of micropapillary variant are detected or in those where BCG is contraindicated, e.g. significant immunosuppression. Radical cystectomy is also indicated for squamous cell carcinoma and radical or partial cystectomy should be considered for adenocarcinoma.
Failure of BCG
The definition of BCG failure is controversial, but the persistence of T1 disease at the 3-month check cystoscopy after induction BCG (six instillations administered once-weekly for 6 weeks); high-grade Ta disease/CIS at 6 months; or detection of muscle invasive TCC should prompt consideration of radical cystectomy.
Increased Risk of Concomitant or Metachronous Upper Urinary Tract (UUT)-TCC
The incidence of concomitant UUT-TCC is low (1.8%), but in patients with trigonal tumours, the incidence is 7.5%. During follow-up, patients with high-grade and multifocal NMIBC are more likely to develop UUT-TCC. Ultrasound is routinely performed during diagnostic work-up of bladder cancer, but can miss small UUT-TCC. Computed tomography urography should therefore be considered where the bladder tumour is high-grade, multifocal or trigonal.
Prevention of Bladder Tumours After Nephro-ureterectomy for Primary UUT-TCC
After a nephroureterectomy for UUT-TCC, up to 40% of patients will develop bladder cancer. In a phase III RCT (ODMIT-C), a single dose of postoperative intravesical MMC, administered at the time of urethral catheter removal, reduced the risk of a bladder tumour within the first year after nephroureterectomy; the absolute reduction in risk was 11%, the relative reduction was 40% and the number needed to treat to prevent one bladder tumour was 9. The trial was the largest randomised study ever conducted in the management of patients with UUT-TCC. However, it was not designed to determine the most effective method of nephroureterectomy, and so a number of techniques were allowed for management of the distal ureter. Patients with a previous history of bladder cancer were excluded.
Bladder-Sparing Treatments After BCG Failure
Radical cystectomy remains the mainstay of treatment for patients who have failed BCG treatment. For patients who are unwilling or unfit to undergo this procedure, the treatment options are limited.
Intravesical chemotherapeutic agents, such as gemcitabine and docetaxel, novel immunotherapies, such as interferon-alpha, and device-assisted treatments have all shown promise. However, to date, much of the evidence to support their potential benefit is based on non-randomised or small Phase II studies. At best, currently available bladder-sparing treatments for those with BCG-refractory TCC are associated with 2-year DFS of approximately 50%.
Chemohyperthermia (c-HT) describes the combination of intravesical chemotherapy and hyperthermia, where the chemotherapy and the bladder wall are heated to temperatures of between 44 and 45 °C. The most common form of c-HT uses the Synergo HT system in which local HT is administered via a 915 MHz intravesical microwave applicator. c-HT increases cell membrane permeability, enhances urothelial exposure and in particular lamina propria exposure, alters intracellular drug trafficking and enhances the effects of cytostatic chemotherapy. Over the last 15 years, c-HT has been tested in a variety of clinical settings, including small several Phase II RCTs, in the BCG-naïve setting.
Data supporting the role of c-HT (using MMC) in BCG-refractory NMIBC has come from several proof-of-concept studies. In patients with BCG-refractory CIS, a complete response rate of 92% was shown, with 50% of patients remaining disease-free at 2-year follow-up. In patients with BCG-refractory NMIBC (77% high-risk) treated with a maintenance c-HT schedule, the recurrence-free rate was 56% at 2 years; 3% progressed to muscle invasive disease and 5% withdrew from treatment because of adverse events. The use of c-HT is being further evaluated in BCG-refractory patients with NMIBC who are unwilling or unfit for cystectomy in the UK-based HYMN Phase III trial (EUDRACT-2008-005428-99).
Electromotive drug administration (EMDA) is an alternative way of enhancing MMC absorption and urothelial exposure, by creating an electrical gradient across the bladder wall using electrodes placed within the catheter and on the lower abdominal wall. In patients with BCG-naïve high-risk NMIBC, EMDA-MMC has shown promise. To date, no studies have specifically evaluated EMDA-MMC in the BCG-refractory setting, although one RCT allowed crossover of patients to EMDA-MMC alone if they did not respond to primary BCG treatment.
