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Keywords:

  • bacillus Calmette–Guérin;
  • intravesical treatment;
  • non-muscle invasive bladder cancer;
  • prognostic factors;
  • side-effects

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Route of administration
  5. Local and systemic side-effects
  6. Schedule and duration of treatment
  7. BCG strain
  8. Prognostic factors for recurrence and progression
  9. Intravesical BCG versus intravesical chemotherapy
  10. Prognostic and predictive factors
  11. BCG failure
  12. Conclusions
  13. Acknowledgments
  14. References

Bacillus Calmette–Guérin (BCG) has been used in the intravesical treatment of non-muscle invasive bladder cancer (NMIBC) for nearly 35 years; however, its use is still subject to controversy. The objective of this paper is to review the role of BCG in the treatment of patients with NMIBC. Clinical trials, meta-analyses and guidelines related to the administration, safety and efficacy of intravesical BCG were reviewed. Intravesical BCG is more effective than intravesical chemotherapy in decreasing the risk of recurrence and progression to muscle invasive disease; however, it is associated with more local and systemic side-effects. It is the gold standard in patients at high risk of progression. Maintenance BCG is required in order to achieve the best therapeutic results; however, the optimal dose, induction and maintenance schedules, and duration of treatment are unknown and might be different for each patient. Patients failing BCG treatment have a poor prognosis, and cystectomy is then the recommended treatment. Patients at low risk of recurrence and progression should not receive BCG, because of its side effects. Intermediate-risk patients might be treated with either intravesical chemotherapy or BCG; however, for patients at high risk of progression, BCG is recognized as the treatment of choice. Further research is urgently needed to identify markers associated with BCG failure and to develop effective alternatives to cystectomy in patients failing BCG.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Route of administration
  5. Local and systemic side-effects
  6. Schedule and duration of treatment
  7. BCG strain
  8. Prognostic factors for recurrence and progression
  9. Intravesical BCG versus intravesical chemotherapy
  10. Prognostic and predictive factors
  11. BCG failure
  12. Conclusions
  13. Acknowledgments
  14. References

Bacillus Calmette–Guérin (BCG) is an attenuated strain of Mycobacterium bovis, where the virulence has been brought under control. In 1974, Zbar and Rapp published the conditions necessary to obtain an anti-tumor effect with BCG1:

  • 1
    Ability to develop an immune response to mycobacteria antigens.
  • 2
    Adequate number of living bacilli.
  • 3
    Close contact between BCG and tumor cells.
  • 4
    The tumor burden must be small.

In 1976, Morales made the link to the intravesical treatment of non-muscle invasive bladder cancer (NMIBC) with BCG2. Intravesical BCG, a non-specific immunotherapy, is known to generate a cellular immune response, which wanes over time; however, its exact mechanism of action is not yet fully understood.3

The purpose of this paper is to review the literature related to the administration, safety and efficacy of intravesical BCG in the treatment of NMIBC patients.

Route of administration

  1. Top of page
  2. Abstract
  3. Introduction
  4. Route of administration
  5. Local and systemic side-effects
  6. Schedule and duration of treatment
  7. BCG strain
  8. Prognostic factors for recurrence and progression
  9. Intravesical BCG versus intravesical chemotherapy
  10. Prognostic and predictive factors
  11. BCG failure
  12. Conclusions
  13. Acknowledgments
  14. References

Various studies have looked at different routes of administration of BCG, including:

  • • 
    Percutaneous administration alone4
  • • 
    Intralesional injections4,5
  • • 
    Oral administration6
  • • 
    Intravesical instillations7
  • • 
    Intravesical and percutaneous administration.2,6,8–10

Percutaneous scarification alone was tested in seven patients, in three patients with curative intent, all of whom failed, and in another four patients for prophylaxis of recurrence. It has since been abandoned, despite insufficient testing in the prophylactic setting.4 Intralesional injections have been associated with morbidity and severe adverse events and have likewise been abandoned.4,5 Despite being safe, oral administration was found to be completely ineffective in an adjuvant setting.6

Intravesical BCG instillations alone converted 13 of 16 purified protein derivative (PPD) skin test negative patients to PPD positive after 6 weeks of therapy, with the remaining three negative patients becoming positive after 12 weeks, thus providing evidence that BCG instillations alone can induce an immune response.7

The combination of percutaneous administration and intravesical instillations of BCG has been studied in a number of trials.2,6,8–10 Although it has been shown to be safe and not to be more toxic than intravesical BCG, randomized studies have not been able to prove its superiority compared with intravsical BCG alone.8,10

Local and systemic side-effects

  1. Top of page
  2. Abstract
  3. Introduction
  4. Route of administration
  5. Local and systemic side-effects
  6. Schedule and duration of treatment
  7. BCG strain
  8. Prognostic factors for recurrence and progression
  9. Intravesical BCG versus intravesical chemotherapy
  10. Prognostic and predictive factors
  11. BCG failure
  12. Conclusions
  13. Acknowledgments
  14. References

Compared with intravesical chemotherapy, intravesical BCG is associated with more local and systemic side-effects. In 1992, Lamm et al. reviewed the incidence, type and severity of toxicity in 2602 patients treated with BCG according to the mode of administration.11 More recently, Gontero et al.,3 Witjes et al.12 and Rischmann et al.13 have provided overviews of both the local and systemic side-effects that might be encountered with BCG instillations, their incidence, severity and recommendations for their management.

The most frequent local side-effects of BCG intravesical instillations include BCG induced cystitis, irritative voiding symptoms and hematuria, which occur in approximately 75% of all patients. More rarely, serious local adverse events as a result of BCG infection, such as symptomatic granulomatous prostatitis and epididymo-orchitis, might occur and require permanent discontinuation of BCG treatment.

Systemic side-effects include flu-like symptoms, such as general malaise and fever, and occur in approximately 40% of patients. A high persistent fever might be related to BCG infection or sepsis. In this case, BCG treatment should be stopped and treatment with antimicrobial agents, such as fluoroquinolones, isoniazid and rifampicin, should be considered.

Local and systemic side-effects might lead to stopping intravesical BCG treatment in approximately 20% of patients. In a recent study of 487 patients receiving BCG, the majority of local and systemic side-effects were already reported during induction and the first half year of maintenance. Two-thirds of patients who stopped treatment as a result of BCG side-effects did so during the first 6 months of treatment. During further maintenance, the incidence of BCG local and systemic side-effects did not increase and the instillations were generally well tolerated. One-third of the patients completed the full 36 months of BCG.14 In another study, single maintenance instillations of BCG at 3, 6, 9 and 12 months after induction were associated with fewer adverse drug reactions than during the eight weekly induction instillations.15

In order to reduce the incidence of BCG side-effects, it has been recommended to withhold the administration of BCG in the situations described in Table 1:3,12

Table 1.  Contraindications to bacillus Calmette–Guérin administration
Transurethral resection within previous 2 weeks
Traumatic catheterization
Macroscopic hematuria
Urethral stenosis
Active tuberculosis
Prior bacillus Calmette–Guérin sepsis
Immuno-suppression
Urinary tract infection

As a result of the increased risk of systemic absorption of BCG and infection, BCG should not be instilled within 2 weeks of transurethral resection (TUR). For the same reason, it should not be instilled if there are still signs or symptoms of macroscopic hematuria or of a traumatic catherization. BCG infection, especially in immuno-compromised patients who might be less likely to develop an immune response, can be progressive and fatal. Additional BCG treatment is contraindicated in patients with a previously documented BCG sepsis.

It is recommended to withhold BCG instillations during the treatment of bacterial urinary tract infections, because the combination of bacterial cystitis and BCG induced cystitis can cause severe inflammatory reactions that might lead to more side-effects. In addition, BCG bacilli are sensitive to antibiotic therapy and thus a decrease in BCG antitumor efficacy might occur.

Other measures that have been proposed to decrease the incidence of BCG related side-effects include the prophylactic administration of isoniazid or ofloxacin, modifications to the BCG treatment schedule and dose reductions. The concomitant administration of the tuberculostatic agent, isoniazid, has not been found to decrease the incidence of BCG related side-effects.16 In contrast, ofloxacin, a fluoroquinolone with tuberculostatic properties, reduced the incidence of moderate to severe BCG related adverse events, especially those related to treatment discontinuation, when given prophylactically in a randomized double blind trial in 115 patients.17,18 However, further studies are required to confirm these initial findings and to ensure that there is no impairment of treatment efficacy.

Other methods to reduce BCG related side-effects usually involve dose reductions. Martinez-Pineiro et al. compared 12 instillations of standard full dose Connaught BCG (81 mg) to 12 instillations of one-third dose BCG (27 mg) in patients with non-muscle invasive bladder cancer. The first study was carried out in 500 patients across all stages and grades. They found significantly less toxicity on the reduced dose. The authors recommended that although the reduced dose was safe and effective in intermediate risk patients and for maintenance schedules, the full dose should be used in the treatment of high-risk patients.19 The second study in 155 high-risk patients with T1G3 tumors and/or carcinoma in situ (CIS) concluded that one-third dose was indeed as effective as full dose, but was associated with significantly less toxicity.20

Finally, a third study in 430 intermediate risk patients compared 12 instillations of one-third (low) dose Connaught BCG (27 mg) to 12 instillations of very low dose BCG (13.5 mg) to 12 instillations of mitomycin C (MMC; 30 mg). This study concluded that one-third dose is the minimum effective dose of BCG, but that it has more local and systemic toxicity than MMC.21

No significant differences in side-effects between the various BCG strains have been detected.22–24

A correlation between BCG side-effects and treatment efficacy has been reported by various authors; that is, patients with local side-effects have a significantly longer time to first recurrence. However, patients with a better outcome remain on treatment for a longer period of time and receive more BCG, thus increasing their risk of developing side-effects. Neither local nor systemic BCG toxicity before 6 months was found to be a prognostic factor for subsequent recurrence. Thus, it is not possible to confirm that BCG toxicity is actually responsible for an improved outcome and a causal effect cannot be inferred from the data.25

Schedule and duration of treatment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Route of administration
  5. Local and systemic side-effects
  6. Schedule and duration of treatment
  7. BCG strain
  8. Prognostic factors for recurrence and progression
  9. Intravesical BCG versus intravesical chemotherapy
  10. Prognostic and predictive factors
  11. BCG failure
  12. Conclusions
  13. Acknowledgments
  14. References

The standard induction course of BCG developed by Morales is six weekly instillations. This was chosen empirically; the Frappier strain that was used was packed in six separate vials and the adverse events lasted less than 1 week. Instillations are started 2–3 weeks after TUR to allow healing of the urothelium and reduce the risk of side-effects. The dwell time is generally 1–2 h.

The optimum number of BCG instillations during the induction period is unknown. Four rather than six weekly instillations of BCG might be sufficient to maximize the peripheral response in patients previously immune to mycobacterial antigens. However, patients not previously immunized against mycobacterial antigens might require the full six weekly instillations to achieve a maximum level of stimulation.26 Likewise, the optimal schedule of induction instillations is also unknown. A reduction in the number of induction instillations and a change in their schedule might decrease treatment morbidity while maintaining efficacy, but this has never been addressed in clinical trials. Experimental and clinical evidence through the monitoring of cytokine levels suggests that this is feasible.27–29

As the cellular immune response, which is generated through BCG instillations, decreases over time, maintenance instillations have been used. Both the Southwest Oncology Group (SWOG) and the European Organisation for Research and Treatment of Cancer (EORTC) have used a 3-year maintenance schedule. After the six weekly induction instillations, three weekly maintenance instillations at 3, 6, 12, 18, 24, 30 and 36 months are given for a total of 27 instillations over 3 years.30,31 Other schedules, such as single maintenance instillations of BCG at 3, 6, 9 and 12 months after induction therapy, have produced promising results.15 Here again, the optimum number of maintenance instillations, their schedule and their duration are unknown and is likely to be patient specific, depending on their immune status. However, as discussed later, 12 months of treatment seems to be the minimum required duration in order for BCG to have a beneficial treatment effect.

BCG strain

  1. Top of page
  2. Abstract
  3. Introduction
  4. Route of administration
  5. Local and systemic side-effects
  6. Schedule and duration of treatment
  7. BCG strain
  8. Prognostic factors for recurrence and progression
  9. Intravesical BCG versus intravesical chemotherapy
  10. Prognostic and predictive factors
  11. BCG failure
  12. Conclusions
  13. Acknowledgments
  14. References

Herr and Morales provide an overview of the history of BCG in the treatment of NMIBC and discuss the emergence of various strains from the original Pasteur strain developed by Calmette and Guérin. Although they express different phenotypes, the various BCG substrains have retained the same antigenic potency.32 Although the data are limited, there is no evidence of a difference in efficacy between the different strains.23,24,33 In particular, a meta-analysis of progression in 4863 NMIBC patients included in 24 randomized trials was unable to detect a difference in efficacy between the Pasteur, Frappier, Connaught and Tice strains. The seemingly worse results with the RIVM strain were attributed to the lack of maintenance treatment.33

Prognostic factors for recurrence and progression

  1. Top of page
  2. Abstract
  3. Introduction
  4. Route of administration
  5. Local and systemic side-effects
  6. Schedule and duration of treatment
  7. BCG strain
  8. Prognostic factors for recurrence and progression
  9. Intravesical BCG versus intravesical chemotherapy
  10. Prognostic and predictive factors
  11. BCG failure
  12. Conclusions
  13. Acknowledgments
  14. References

Patients with NMIBC have a very heterogeneous prognosis.34,35 The EORTC has identified six of the most important factors related to a patient's prognosis: (i) number of tumors; (ii) prior recurrence rate; (iii) tumor size; (iv) T category (stage); (v) grade (1973 WHO grade); and (vi) the presence of concomitant carcinoma in situ.35 Based on these six factors, risk scores that predict a patient's risk of recurrence and progression to muscle invasive disease can be calculated.35 Using these scores, patients are then classified into risk groups of low-, intermediate-, and high-risk of recurrence and progression, where the risks of recurrence and progression at 5 years vary from 31% to 78% and 0.8% to 45%, respectively,.35,36

Intravesical BCG versus intravesical chemotherapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Route of administration
  5. Local and systemic side-effects
  6. Schedule and duration of treatment
  7. BCG strain
  8. Prognostic factors for recurrence and progression
  9. Intravesical BCG versus intravesical chemotherapy
  10. Prognostic and predictive factors
  11. BCG failure
  12. Conclusions
  13. Acknowledgments
  14. References

The European Association of Urology (EAU) Guidelines recommend that all patients receive an immediate instillation of chemotherapy within 24 h after TUR.36 The choice between further intravesical chemotherapy or intravesical BCG is guided by the patient's risk of recurrence and progression to muscle invasive disease.35–37

In patients at low risk of recurrence and progression (EORTC recurrence and progression scores = 0), the probability of recurrence and progression at 1 year is 15% and 0.2%, respectively. In these patients, no further treatment after TUR is recommended before a further recurrence.

In the intermediate-risk patients (intermediate or high risk of recurrence and intermediate risk of progression), the probability of recurrence and progression at 1 year is approximately 31% and 1%, respectively, whereas at 5 years it increases to approximately 54% and 6%, respectively. Thus, the main priority in these patients is to reduce the risk or recurrence; however, the risk of progression is not negligible.

In the patients at the highest risk of progression (progression score 14–23), the probability of progression within 1 year is 17% and increases to 45% at 5 years. In the high-risk patients, which includes patients with Ta/T1 high grade tumors and/or carcinoma in situ, the priority is clearly to prevent or at least reduce the incidence of progression to muscle invasive disease.

Compared with TUR alone, meta-analyses have concluded that intravesical chemotherapy reduces the risk of recurrence;38–41 however, there is no evidence that it also reduces the risk of progression to muscle invasive disease.38,42 Likewise, meta-analyses have also shown that intravesical BCG reduces the risk of recurrence compared with either TUR alone43,44 or to chemotherapy.45–48 An individual patient data (IPD) meta-analysis comparing BCG with MMC clearly showed the necessity of giving maintenance when BCG is used. In the studies where patients received BCG maintenance, there was a 32% reduction in the risk of recurrence on BCG as compared with MMC (P < 0.0001), whereas there was a 28% increase in the risk of recurrence on BCG (P = 0.006) in the studies where BCG maintenance was not given. BCG with maintenance reduced the risk of recurrence in both the patients previously treated and not previously treated with chemotherapy.48

Although somewhat controversial,49 there is now clear evidence that BCG reduces or at least delays the risk of progression to muscle invasive disease, but only when BCG maintenance is given.31,33,50 In a large meta-analysis of 4863 patients treated in 24 randomized studies where various treatment strategies were applied in the control group, BCG reduced the odds of progression by 27%, from 13.8% to 9.8% (OR = 0.73, P = 0.001), and by 37% when maintenance BCG of any duration was given (OR = 0.63, P = 0.00004). However, there was no reduction when maintenance BCG was not used (OR = 1.28, P = 0.27).33 Similar size treatment effects were seen in the patients with only papillary tumors, in whom 6% progressed, and in patients with CIS where 14% progressed.

In studies and meta-analyses comparing BCG with intravesical chemotherapy, contradictory results have been obtained with respect to the relative benefit of BCG on progression. In a literature-based meta-analysis, Bohle et al. found that BCG was more effective than MMC, but only when maintenance BCG was given.50 He concluded that a minimum of 12 months of maintenance was necessary for BCG to have an effect on progression. It is to be noted, however, that several non-randomized studies were included in this meta-analysis.

In the Malmstrom IPD meta-analysis comparing BCG with MMC, there were no significant differences in the long-term end-points of progression, survival or disease specific survival, neither overall nor in the subgroup of trials where patients received maintenance BCG.48 In contrast, BCG with maintenance significantly reduced the risk of progression/distant metastases (HR = 0.63), overall survival (HR = 0.76) and disease specific survival (HR = 0.47) compared with intravesical epirubicin in a large randomized study of 837 patients.31 The benefit of BCG was not limited to just the high risk patients in this study. The observed treatment benefit was at least as large, if not larger in the intermediate-risk patients as compared with the high-risk patients. Of note, the high-risk patients did not have a second look TUR. These discordant results have raised the question of whether MMC might be more effective than epirubicin; however, no randomized trials have compared these two treatments.

In a literature-based meta-analysis of nine trials that included 700 patients with carcinoma in situ, BCG significantly reduced the risk of both short-term and long-term treatment failure compared with intravesical chemotherapy.47 The complete response rate on BCG was 68% as compared with 51% on chemotherapy, P = 0.0002; however, the recurrence rate in complete responders was high: 50% on chemotherapy and 34% on BCG. With a median follow up of 3.6 years, 47% of patients receiving BCG remained disease free as compared with 26% of patients receiving chemotherapy. BCG was superior to MMC in trials where maintenance BCG was given. In CIS patients who do not respond to an initial induction course of six weekly BCG instillations, approximately 40–60% of patients respond to a second induction course of six instillations.51

As summarized in Table 2, treatment is determined according to the patient's risk of progression.

Table 2.  Treatment according to progression risk group
Progression risk groupProgression scoreTreatment after an immediate instillation
Low0None
Intermediate1–6Chemotherapy or bacillus Calmette–Guérin
High≥7Bacillus Calmette–Guérin

In the intermediate risk patients, EAU Guidelines recommend that either a maximum of 1 year of intravesical chemotherapy or 1–3 years of BCG might be given.36 The superior efficacy of BCG needs to be balanced against its increased toxicity. The choice in any given patient needs to take into account their previous and current disease status, age and comorbidities. One could, for example, start with chemotherapy and switch to BCG if the patient continues to recur.

BCG has been established as the intravesical treatment of choice in high-risk patients where the primary goal is to prevent progression to muscle invasive disease. Before starting BCG, it is recommended that high-risk patients have a second look TUR 4–6 weeks after the initial TUR.36 The optimal duration of treatment is unknown, but a minimum of 1 year of BCG maintenance is recommended.36 Alternatively, upfront radical cystectomy with urinary diversion might be considered. Although radical cystectomy produces excellent results, upfront radical cystectomy might be overtreatment in patients with high-grade disease, many of whom can be successfully treated with intravesical BCG, especially if there is no concomitant carcinoma in situ.52

Prognostic and predictive factors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Route of administration
  5. Local and systemic side-effects
  6. Schedule and duration of treatment
  7. BCG strain
  8. Prognostic factors for recurrence and progression
  9. Intravesical BCG versus intravesical chemotherapy
  10. Prognostic and predictive factors
  11. BCG failure
  12. Conclusions
  13. Acknowledgments
  14. References

Because patients failing BCG have a very poor prognosis, it is important to be able to identify which patients will or will not respond to BCG.53 There are only a limited number of studies assessing prognostic and predictive factors in patients treated with BCG. Saint et al. concluded that no independent prognostic factors for response to BCG could be identified, except that patients with a tumor 3 months after starting BCG had a significantly higher risk of progression.54 Zlotta et al. likewise concluded that no single prognostic factor is capable of predicting an outcome on BCG.55

The CUETO group has carried out the largest multivariate prognostic factor analysis in patients treated with BCG.56,57 They combined data from four trials in 1062 intermediate- and high-risk patients who received 12 instillations of BCG over 5–6 months. Similar to the previously identified prognostic factors in NMIBC, they found that age, history of recurrence, high grade, T1 stage and recurrence at the first follow-up cystoscopy were independent predictors of progression on BCG. Because the immune system weakens with age, it is not surprising that age has been found to be a prognostic factor for treatment outcome on BCG. In a recent study, 27% of patients aged more than 70 years were tumor free at 5 years compared with 37% of patients aged less than 70 years.58 A number of authors have cautioned against giving BCG to patients older than 80 years-of-age.59,60 Further data are required, however, to better define the efficacy and safety of BCG in elderly patients.

BCG failure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Route of administration
  5. Local and systemic side-effects
  6. Schedule and duration of treatment
  7. BCG strain
  8. Prognostic factors for recurrence and progression
  9. Intravesical BCG versus intravesical chemotherapy
  10. Prognostic and predictive factors
  11. BCG failure
  12. Conclusions
  13. Acknowledgments
  14. References

In high-risk patients (T1, high-grade and/or carcinoma in situ), an upfront cystectomy is overtreatment in the majority of the cases. However, up to 40% of patients might eventually fail intravesical BCG. Patients failing BCG have a very poor prognosis with a high risk of progression to muscle invasive disease and death as a result of bladder cancer. The 3-year bladder cancer specific survival is 67% in patients initially presenting with muscle invasive disease, but only 37% in patients who progress after intravesical treatment.53 In high-risk patients, the questions of: (i) whether to initially start BCG instillations or proceed to an immediate cystectomy; and (ii) when intravesical BCG should be abandoned in favor of cystectomy if there isn't a complete response are crucial ones. Unfortunately, there is no universally accepted definition of BCG failure and there are no randomized trials comparing BCG with cystectomy. Zlotta et al. provide an overview of reasons for BCG failure, definitions of BCG failure, prediction of BCG failure and conservative treatment options in patients who fail BCG.55

Treatment with BCG is generally considered to have failed in the following cases:36,55,61

  • 1
    Detection of muscle invasive disease
  • 2
    Presence of high-grade papillary tumors and or carcinoma in situ at both 3 months and 6 months
  • 3
    Disease worsening (stage, grade, CIS) under BCG treatment.

Herr et al. concluded that a minimum treatment and follow up of 6 months is required to classify high-risk, superficial bladder tumors as being truly BCG refractory.61 Patients who recur after completion of BCG treatment can be retreated with intravesical therapy according to their disease characteristics at recurrence.

For patients who are unable or unwilling to have a cystectomy after BCG failure, the treatment options are limited. Intravesical chemotherapy, device assisted chemotherapy, photodynamic therapy and BCG plus interferon alpha are the most frequently used treatment options.55 However, the results with conservative treatment after BCG failure are disappointing and research to discover new treatment options in these patients is an important priority.

Current models do not accurately predict which patients will fail BCG treatment. Molecular markers are the hope of the future;62–64 however, there is still insufficient evidence to support their use in daily clinical practice to help identify which patients will fail BCG.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Route of administration
  5. Local and systemic side-effects
  6. Schedule and duration of treatment
  7. BCG strain
  8. Prognostic factors for recurrence and progression
  9. Intravesical BCG versus intravesical chemotherapy
  10. Prognostic and predictive factors
  11. BCG failure
  12. Conclusions
  13. Acknowledgments
  14. References

Intravesical BCG is more effective than intravesical chemotherapy; however, it is also more toxic. Maintenance BCG is required in order to achieve the best therapeutic results; however, the optimal dose, induction and maintenance schedules, and duration of treatment are unknown and might be different for each patient. Patients at low risk of recurrence and progression should not receive BCG, because of its side-effects. Intermediate-risk patients might be treated with either intravesical chemotherapy or BCG; however, for patients at high risk of progression, BCG is recognized as the treatment of choice. Further research is urgently needed to identify markers associated with BCG failure and to develop effective alternatives to cystectomy in patients failing BCG.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Route of administration
  5. Local and systemic side-effects
  6. Schedule and duration of treatment
  7. BCG strain
  8. Prognostic factors for recurrence and progression
  9. Intravesical BCG versus intravesical chemotherapy
  10. Prognostic and predictive factors
  11. BCG failure
  12. Conclusions
  13. Acknowledgments
  14. References

This review was supported by grant number “5U10 CA011488-40” from the National Cancer Institute (Bethesda, Maryland, USA) and by Fonds Cancer (FOCA) from Belgium. Its content is solely the responsibility of the author and does not necessarily reflect the official views of the National Cancer Institute.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Route of administration
  5. Local and systemic side-effects
  6. Schedule and duration of treatment
  7. BCG strain
  8. Prognostic factors for recurrence and progression
  9. Intravesical BCG versus intravesical chemotherapy
  10. Prognostic and predictive factors
  11. BCG failure
  12. Conclusions
  13. Acknowledgments
  14. References
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  • 14
    Van der Meijden APM, Sylvester RJ, Oosterlinck W, Hoeltl W, Bono AV. Maintenance bacillus Calmette-Guérin for TaT1 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. Eur. Urol. 2003; 44: 42934.
  • 15
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