Key Points
General
- Non-muscle invasive bladder cancer (NMIBC – sometimes referred to as “superficial” bladder cancer) is the most common presentation of urothelial cancer.
Bacillus Calmette-Guérin (BCG)
- Treatment of NMIBC depends on clinical and pathological risk stratification. The mainstay of treatment is transurethral resection followed by intravesical chemotherapy or immunotherapy with BCG, a live attenuated strain of Mycobacterium bovis.
- BCG activates the immune system to recognize and destroy malignant cells.
- Intravesical BCG reduces the risk of progression and recurrence of NMIBC after transurethral resection (TUR) compared to chemotherapy and is hence preferred primary choice for all high risk and intermediate risk tumors.
Immuno-Oncology
- The approval of immune checkpoint blockade for patients with platinum-resistant or -ineligible metastatic bladder cancer supports expanded use for both advanced and, potentially, localized disease.
- Novel treatment strategies — such as those involving immune checkpoint blockade, cytokines, monoclonocal antibodies, T-cell therapies, oncolytic viruses and vaccines — rely on agents with immunomodulatory mechanisms. These treatments have allowed a subset of patients to benefit from durable response rates, often with a more tolerable adverse event profile than traditional therapies.
- Atezolizumab, durvalumab, avelumab, pembrolizumab and nivolumab are FDA-approved and recommended in locally advanced or metastatic urothelial carcinoma that has previously been treated with platinum-based chemotherapy, or has relapsed within 12 months of perioperative platinum-based chemotherapy.
- Pembrolizumab demonstrated significant improvement in overall survival over chemotherapy. It is the first and only therapy to show level A evidence at this time.
- There is no reason to select one agent over the others, aside from practical considerations of dosing and convenience.
BCG Treatment for Bladder Cancer
- Clinical parameters (grade, stage, presence of carcinoma in situ (CIS), age, and pattern of prior BCG failure) are the strongest predictors of response to BCG.
- Wait at least 2 weeks after TUR to start induction BCG (6 weekly treatments).
- For maintenance, use the 6+3 schedule (also known as the 'Lamm' or 'SWOG' schedule). (A)
- Use full doses of BCG for induction, and dose reduction during maintenance, if necessary, based on side effects. (A)
- Patients with increasing disease (number, size, grade, or stage of disease) at the 3 month cystoscopic examination should be considered unresponsive to BCG, and alternate treatment should be instituted. (B)
- Patients who have recurrent disease after adequate BCG treatment should undergo evaluation of upper tracts and prostatic urethra, followed by intravesical immunotherapy with M. bovis or intravesical chemotherapy.
- Continued BCG is not useful in patients with BCG unresponsive disease (see full Consensus Statement*). These patients should be offered radical cystectomy.
- BCG should not be administered in the presence of active infection.
- Oral quinolones should not be administered prior to, or within 6 hours of, BCG instillation but, when given appropriately, can reduce BCG toxicity. (A)
- There is no evidence that combination BCG plus interferon is more effective than BCG alone. (B)
Consensus Recommendations
- The use of lidocaine or excessive lubricants is not recommended with the administration of intravesical BCG.
- It is not necessary to rotate patients every 15 min post BCG instillation. However, patients should hold the BCG in their bladder for 2 hrs.
- Patients should be provided with a template to record BCG treatment/cystoscopy dates and bring it to subsequent appointments (see full Consensus Statement for template*).
* https://jitc.biomedcentral.com/articles/10.1186/s40425-017-0271-0
See Figure 1 note for definitions of Low, Intermediate and High Risk stratification levels.
High Risk Patients
- BCG therapy for high risk patients should be considered standard of care (Figure 1). (A)
- Maintenance BCG is critical for successful management of high risk patients.
- The SWOG schedule offers the best efficacy.
- High risk (high grade) patients should receive maintenance BCG therapy for 3 years, while intermediate risk patients should receive maintenance therapy for ≥1 year. (A)
- Patients with residual or recurrent CIS at the 3 month cystoscopy may benefit from 3 additional weekly BCG treatments, but those with disease at 6 months should be considered unresponsive to BCG. (B)
- Intravesical chemotherapy is a reasonable option for those patients who do not tolerate intravesical BCG.
Intermediate Risk Patients
- BCG induction and at least 1 year of maintenance therapy should be used for patients with intermediate risk tumors. (A)
- Risk stratification should be the basis for deciding therapy, with careful assessment and definition of of the tumor risk category in transition from low risk to intermediate risk.
Low Risk Patients
- Low risk patients should not receive BCG (Figure 1).
Figure 1. Treatment Algorithm for Non-Muscle Invasive Bladder Cancer
Figure 2. Treatment Algorithm for Locally Advanced or Metastatic Bladder Cancer
Table 1. Selected Immunotherapy Trials in Bladder Cancer
Completed
| Drug/Agent | Clinical trial identifier | Study | Stage of Diseasea |
|---|---|---|---|
| Atezolizumab (MPDL3280A) Anti-PD-L1 | Cohort 1: NCT02951767, Cohort 2: NCT02108652 | Phase II | Locally advanced or metastatic – progressed after platinum-based treatment |
| Pembrolizumab | NCT02256436 | Phase III vs. standard of care chemotherapy | Locally advanced or metastatic – progressed after platinum-based treatment |
| Pembrolizumab | NCT02335424 | Phase II | Non-cisplatin eligible patients |
Ongoing
| Drug/Agent | Clinical trial identifier | Study | Stage of Disease a |
|---|---|---|---|
| Pembrolizumab | NCT02625961 | Phase II | High risk NMIBC unresponsive to BCG therapy |
| Atezolizumab | NCT02844816 | Phase II | NMIBC unresponsive to BCG Therapy |
| Atezolizumab | NCT02662309 | Phase II preoperative MPDL3280A | Transitional cell carcinoma of the bladder |
| Atezolizumab combination with cisplatin and gemcitabine | NCT02989584 | Pilot safety, neoadjuvant phase II study | Metastatic bladder cancer |
| Atezolizumab | NCT02450331 | Randomized phase III atezolizumab as adjuvant therapy vs. observation | High risk muscle-invasive bladder cancer |
| Nivolumab | NCT02632409 | Randomized phase III nivolumab as adjuvant therapy vs. placebo | High risk muscle-invasive bladder cancer |
| Maintenance avelumab | NCT02603432 | Phase III vs. best supportive care alone | Locally advanced or metastatic bladder cancer that did not progress after completion of first-line platinum-containing chemotherapy |
| MEDI-4736 (anti-PD-L1) ± tremelimumab (anti-CTLA-4) | NCT02516241 | Phase III, three arms: MEDI-4736 ± tremelimumab vs. standard of care chemotherapy | Unresectable stage IV bladder cancer |
