After Bacillus Calmette-Guerin (BCG) failure, there is likely a 6- to 24-month window whereby salvage intravesical therapy might allow for preservation of the bladder without disease worsening. Combination intravesical, salvage therapy for nonmuscle invasive bladder cancer represents a promising avenue for treatment in patients unfit or unwilling to undergo cystectomy. BCG with concomitant immune stimulating agents or immune checkpoint inhibitors, combination chemotherapy regimens, such as gemcitabine and docetaxol, and novel agents currently in clinical trials provide hope for a bladder-sparing alternative for patients after BCG failure.
Key points
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Salvage intravesical therapy for nonmuscle invasive bladder cancer remains experimental, and cystectomy should be considered when clinically appropriate.
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Salvage therapy with gemcitabine and docetaxol has the greatest amount of evidence supporting use, is generally well tolerated, and appears efficacious after Bacillus Calmette-Guerin failure.
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This is an exciting time for salvage therapy because there are multiple, ongoing, prospective clinical trials with results expected in the next 2 to 3 years.
Introduction
Bladder cancer accounts for around 80,000 new cancer diagnoses per year in the United States with 75% of patients presenting with nonmuscle invasive disease. In developed areas, urothelial histology at diagnosis is present in 90% of patients. , For the subset of patients presenting with high-risk, nonmuscle invasive bladder cancer (NMIBC), intravesical administration of Bacillus Calmette-Guerin (BCG) with maintenance therapy remains the standard of care. BCG administration has largely remained unaltered since its initial description more than 40 years ago and around 40% to 50% of patients will experience recurrence of disease within 5 years of diagnosis with up to 78% of patients experiencing recurrence in the highest-risk groups. Recurrence of NMIBC, classified by BCG failure discussed in a previous section, represents a challenging issue to the treating urologist. Clinical guidelines suggest a risk-stratified approach, including a second BCG course, radical cystectomy, or clinical trial enrollment.
Despite these recommendations, utilization of cystectomy remains low, especially among older, more frail patients, those with a lower socioeconomic status, and those in rural communities. , Practical, salvage alternatives to cystectomy and clinical trial enrollment are therefore of the utmost importance for the patient and the treating urologist, who fail initial BCG administration. Single-agent and device-delivered intravesical therapy have already been discussed. However, as increasing the efficacy of systemic chemotherapy and immunotherapy becomes predicated on multiagent regimens, so might a nuanced approach to intravesical therapy. In this section, multiagent intravesical salvage chemotherapy, immunotherapy, and combined systemic therapy with intravesical therapy are discussed, including a discussion of the mechanisms of action of each ( Table 1 ), potential side effects with mitigation strategies, and oncologic outcomes ( Table 2 ). Finally, current clinical trials and emerging therapies are discussed ( Table 3 ).
| Agent | Mechanism of Action | Common Adverse Reactions: Treatment | Dose Administered |
|---|---|---|---|
| IFN |
|
| 50 MU Or 100 MU if used with 1/10th dose BCG |
| IL-2 |
|
| 22 MU |
| GMCSF |
|
| 250 μg (subq) |
| Doxorubicin epirubicin |
|
| 40–50 mg in 50 mL NS |
| MMC |
|
| 20–40 mg in 20–40 mL NS |
| Gem |
|
| 1–2 g in 50 mL NS |
| Doce |
|
| 40 mg (4 mL) in 50 mL NS (final volume 54 mL) |
| Drug Regimen | Complete Response Rate, % | Disease-Free Survival, % | Progression-Free Survival, % | Cystectomy-Free Survival, % | Cancer-Specific Survival, % | Percent Intolerant |
|---|---|---|---|---|---|---|
| 1/3 dose BCG + IFN a , , | 79.8 | 2 y: 45 | 92.2 | 96.1 | 99 at interim analysis | 4.8 serious adverse event rate |
| 7.8 intolerance rate | ||||||
| Quadruple immunotherapy c , | 65 | 2 y: 53 | 92.3 at a median of 11.5 mo | 75 at a median of 17.3 mo | 2 y: 95 5 y: 82 | 17.5 delay in treatment schedule, 6 unable to complete induction |
| Gem + MMC | 68 | 2 y: 37–38 | Not reported | 81 | 96.3 | 7.7–15 |
| Gem + Doce b , , | 66 | 2 y: 24–60 | 82–94 | 78–79 | 2 y: 89–94 | 11 |
a Six weekly induction course followed by 3 cycles of weekly maintenance there for 3 wk at 3, 9, and 15 mo.
b High-grade RFS, 60% ALL grade RFS, 53%.
c Includes data from multi-institutional review of 278 patients pending publication.
| Trial Name | Phase | Agents | Completion Date | Design |
|---|---|---|---|---|
| Adapt Bladder: NCRN GU16-243 NCT03317158 | 1/2 |
| 9/2021 | Randomized, multiarm, crossover |
| NCT03258593 | 1 | Durvalumab with intravesical oportuzumab monatox | 7/2021 | Nonrandomized, open-label, single-arm |
| QUILT-3.032 NCT03022825 | 2 | Intravesical BCG and ALT-803 | 9/2020 | Nonrandomized, open-label, single-arm |
| NCT01625260 | 1b/2 | Intravenous Gem and intravenous ALT-801 | 3/2018 | Nonrandomized, open-label, single-arm |
| NCT02015104 | 1 |
| 2/2020 | Randomized, parallel assignment, open label |
| NCT02202772 | 1 |
| 12/2020 | Randomized, open label, multiarm |
| NCT02792192 | 1b/2 |
| 3/2020 | Randomized, parallel assignment, open label |
Immunotherapy Combinations
Immunotherapy combinations have generally been used to augment the immunogenicity of BCG itself. Therapies have included intravesical and parenteral administration of cytokines, chemokines, and immune checkpoint inhibition.
Bacillus Calmette-Guerin with interferon
Interferon-α (IFN) has been shown to inhibit cell proliferation, enhance immune stimulation, and lead to cell apoptosis. , Single-agent IFN demonstrates antitumor prevention activity, although with decreased efficacy compared with BCG. However, synergy between BCG and IFN has been demonstrated with IFN enhancing the BCG immune-mediated response. With this understanding, multiple evaluations of BCG coadministered with IFN have been undertaken, the largest of which enrolled more than 1000 patients in a phase 2, prospective trial of BCG + IFN in patients after prior BCG failure or patients who were BCG naïve. ,
The 467 patients who had failed 1 prior course of BCG received one-third dose BCG with 50 million units (MU) of IFN for a 6-week induction course and then three, 3-week maintenance courses 3, 9, and 15 months after induction completion. Two-year disease-free survival (DFS) in the BCG failure arm was 45% for all patients. Multiple subanalyses from this study have been generated, including the following:
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The efficacy of BCG with IFN significantly declines for each decade older than 50 years old. This is especially evident for patients older than 80, whereby BCG is approximately one-third less effective than in 60- to 70-year-old patients (40% vs 60% 2-year DFS).
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Patients with carcinoma in situ (CIS) and BCG failure within 12 months, refractory disease, or more than 1 course of BCG have a worse response to repeat BCG with IFN.
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BCG failure within 12 months after initial BCG therapy portends a worse prognosis for BCG with IFN.
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BCG with IFN leads to local adverse toxicity during treatment but without effecting long-term quality of life.
A second, prospective, randomized, multicenter study compared BCG ± megadose vitamins with BCG + IFN ± megadose vitamins. All patients in this trial were BCG naïve, and no difference in DFS was determined between treatment arms. However, patients who received BCG with IFN experience more toxicity, including systemic side effects, such as fever and malaise. No prospective trial had directly compared BCG and BCG with IFN for patients after BCG failure. Given the lack of clear differences in efficacy of BCG and BCG with IFN in BCG-naïve disease and the increased side effects, BCG with IFN likely has limited utility. However, 100 MU IFN with one-tenth dose BCG might show some promise in treating BCG intolerant patients.
Quadruple immunotherapy (Bacillus Calmette-Guerin, interferon, interleukin-2, and granulocyte colony stimulating factor)
The success of immunotherapy in NMIBC remains one of the historic triumphs in cancer therapy. Clinically, patients older than 80 experience the largest discrepancy in BCG efficacy. Age-related immune dysfunction has been implicated in this process but remains incompletely understood. Evaluation of the BCG vaccine itself, however, has unveiled that T-cell cytotoxic potential declines with aging. Both granulocyte macrophage colony stimulating factors (granulocyte colony stimulating factor [GMCSF] also sold for injection as sargramostim) and interleukin-2 (IL-2) have been shown to induce and augment a cytotoxic T-cell response.
To circumvent age-related immune response decline, a regimen of 6 weekly intravesical installations of one-third dose BCG, 50 MU IFN, and 22 MU IL-2 in combination with a 250-μg sargramostim injection (weekly) followed by 3 weekly maintenance treatments at 3, 9, and 15 months has been evaluated retrospectively in 52 patients after BCG failure. The initial response rate to therapy was 65% and DFS was 53% at 2 years. Bladder cancer–specific survival was 82% at 5 years, and 28% of eligible patients underwent cystectomy. Although not statistically significant, DFS was 60% at 2 years in patients older than 80 years old. Notably, 90% of patients experienced a side effect of therapy; 20% of patients required treatment delay, and 6% of patients could not tolerate a full 6-treatment induction course. Quadruple immunotherapy might represent an option for salvage therapy after BCG failure, especially in older adults, although with some tradeoff because patients will likely experience some adverse effects during therapy. Further evaluation needs to be performed.
Bacillus Calmette-Guerin in combination with systemic immunotherapy
The advent of systemic immune checkpoint inhibitor therapy (ICI) and specifically programmed cell death receptor 1 (PD-1) or programmed cell death receptor ligand 1 (PDL-1) blockade for advanced bladder cancer has been met with optimism and early success. Preclinical studies in NMIBC have identified overexpression of PDL-1 on T cells during BCG therapy, shown that blockade of PDL-1 increases the antitumor response to BCG, and that there is a role for the PD-1/PDL-1 axis in BCG unresponsive disease. Mouse models suggest that PDL-1 blockade allows for enhanced local immune-mediated tumor control. Preclinical models and ICI success in advanced disease have provided exciting evidence for the potential efficacy in the NMIBC space. The use of single-agent ICI (pembrolizumab) without concomitant BCG in patients with BCG unresponsive disease has demonstrated a complete response rate of 38.8% and an 80% DFS at 6 months for those with a complete response. Currently, no published results for BCG in combination with systemic immunotherapy for patients after BCG failure are available. However, results of a phase 1 trial (KEYNOTE-676) of BCG with pembrolizumab after BCG failure were recently presented and demonstrated good tolerability and 78% DFS at 5 months. Clinical trials in this area with both ICI monotherapy and combination therapy for BCG and other agents with both atezolizumab (anti-PDL-1) and durvalumab (anti-PDL-1) are ongoing and discussed in the emerging therapy article and Table 3 .
Chemotherapy Combinations
Historic combination chemotherapy studies
Historic reports on combination intravesical chemotherapy reveal where the urologist has been, so that we may know where we need to go. Most reports are fraught with significant bias, including retrospective studies on small patient populations where classification by BCG failure status and tumor risk are difficult to parse out or simply not provided. The following agents have been studied, and with these limitations in mind, are mentioned for the sake of completeness, but have not gained favor in mainstream practices.
Doxorubicin, mitomycin C, and the addition of cisplatin
Doxorubicin is an anthracycline derivative commonly used to treat multiple solid malignancies. The mechanism of action is 2-fold and includes inhibition of topoisomerase-II–mediated DNA repair as well as direct cellular toxicity via free radical generation. Mitomycin C (MMC) is an antitumor antibiotic that acts to cross-link DNA. These 2 agents (20 mg MMC and 40 mg doxorubicin) were compared in the first report of combination intravesical chemotherapy at which time tolerability and efficacy were notably low. As a follow-up to this initial study, a slightly larger cohort of 43 patients (the minority having failed BCG) with carcinoma in situ was evaluated with a progression rate approaching 20%. Likely owing to poor tolerability, efficacy, and significant disease progression rates, MMC and doxorubicin combination therapy has not been reported in the literature since 1994. A regimen of MMC, doxorubicin, and intravesical cisplatin was reported for BCG-naïve patients in comparison to BCG alone with promising results, although the addition of intravesical cisplatin resulted in severe, debilitating lower urinary tract symptoms for several patients. This regimen has not been evaluated further.
Epirubicin and interferon-alpha
A prospective, randomized trial that evaluated instillation of epirubicin with IFN-α compared with BCG in patients naïve to intravesical therapy demonstrated superiority of BCG for preventing recurrence without a difference in adverse events or progression. , Further evaluation of this regimen in the salvage setting has not been performed.
Gemcitabine, cabazitaxel, and cisplatin
First reported in a phase 1 trial in 2017 in 9 BCG-refractory patients, gemcitabine, cabazitaxel, and cisplatin (GCP) intravesical therapy was noted to be well tolerated and associated with a 78% complete response rate. This trial was expanded to 18 BCG-unresponsive in 2019. Results of a phase 1 study redemonstrated tolerability as well as a complete response rate of 94% and a DFS of 78% at 9.5 months. Results with GCP are promising; however, results have only been presented thus far in abstract form.
Modern combination chemotherapy studies
The following studies represent the more well-studied combination intravesical chemotherapy regimens. Studies are generally hampered by the retrospective nature of their results but are bolstered, if only slightly, through larger, more well-defined patient cohorts. Recommended administration regimen, side effects, and outcomes are reported in Tables 1 and 2 .
Gemcitabine and mitomycin C
Gemcitabine (Gem) is a deoxynucleotide analogue, which prevents DNA chain elongation during DNA synthesis. First reported in 2006, the combination of sequentially administered salvage Gem and MMC showed promising results (20-month median DFS) in 27 patients after BCG failure. Further evaluation of this regimen as salvage therapy after BCG therapy has been performed at multiple institutions. Two-year DFS was reported at 37% and 38%; progression occurred in 3.7% of patients, and 19% of patients underwent radical cystectomy. The regimen was generally well tolerated with most adverse events related to the MMC component or Gem-induced nausea. , Nausea may be treated with prophylactic ondansetron.
Administration
Administration order for these agents is thought to be important. Patients should be pretreated with an oral urinary alkalization agent (such as 1300 mg sodium bicarbonate the night before and the morning of installation). Gem does not generally directly irritate the bladder; however, its solution is very acidic (pH ∼2.6), whereby MMC is inactivated under acidic conditions and does irritate the bladder. Patients receive 6 weekly intravesical installations for induction, which includes administration of the following:
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1 g Gem in 50 mL normal saline (dwell time: 90 minutes)
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The bladder is drained without rinsing
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Instill 40 mg MMC diluted in 20 mL sterile saline (dwell time 90 minutes)
Monthly maintenance administrations are generally given for 1 to 2 years or until recurrence.
Gemcitabine and docetaxol
Docetaxol (Doce) inhibits microtube disassembly inhibiting mitosis and cell division. Recent preclinical work has demonstrated that Gem acts as an exfoliant for urothelial cells increasing the cellular penetration efficacy of Doce. Gem/Doce thus represents one of the most promising new intravesical salvage therapy regimens. The efficacy of salvage Gem/Doce has been evaluated in 2 retrospective series. One- and 2-year DFS ranged from 42% to 54% and 27% to 37%, respectively. Up to 10% of patients experienced disease progression to muscle invasive disease. , Preliminary results from a multi-institutional analysis of 278 patients receiving salvage Gem/Doce demonstrated that the regimen was very well tolerated with less than 5% of patients discontinuing therapy, a 60% high-grade recurrence free survival at 2 years, 6% progression rate to muscle invasive disease, 94% 2-year cancer-specific survival, and 15% cystectomy rate (Michael A. O’Donnell, 2019, unpublished data). These promising results will likely lead to a multi-institutional, prospective evaluation of Gem/Doce in the salvage setting.
Administration
Patients should be pretreated with an oral urinary alkalization agent (such as 1300 mg sodium bicarbonate the night before and the morning of installation). Gem can induce nausea, and pretreatment with ondansetron can be beneficial. Neither Gem nor Doce irritates the bladder. Patients receive 6 weekly intravesical installations for induction, which includes administration of the following:
- •
1 g Gem in 50 mL normal saline (dwell time: 90 minutes)
- •
The bladder is drained without rinsing
- •
40 mg of Doce instilled, diluted in 50 mL sterile saline (dwell time: 90–120 minutes)
Monthly maintenance administrations are generally given for 1 to 2 years or until recurrence.
Current clinical trials and emerging therapies
Given the tangible need for better, bladder-sparing treatment options after BCG failure, multiple, combination therapy regimens continue to emerge. Guidance from the Food and Drug Administration (FDA) (updated in 2018) regarding trial design includes documenting an initial complete response rate whereby the lower bound of the 95% confidence interval rules out a nonmeaningful response at 3 months for CIS and a clinically meaningful, durable DFS. Trials are generally single-arm, phase 2 clinical trials. Current clinical trials evaluating combination therapy are reviewed in Table 3 .
Novel agents in these clinical trials include the following:
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Oportuzumab monatox, an antibody to the Epithelial Cell Adhesion Molecule, fused to a bacterial toxin, which has shown initial promise when administered alone for NMIBC after BCG failure.
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ALT-803, an IL-15 superagonist, which has been shown to be an effective and well-tolerated intravesical additive to BCG treatment in BCG-naïve patients.
- •
ALT-801, an IL-2 agonist, which has shown promise in combination with systemic ICI for metastatic bladder cancer.
- •
PANVAC pox virus vaccine therapy targeting 2 common overexpressed cancer genes: carcinoembryonic antigen and epithelial mucin 1.
Multiple additional clinic trials for single-agent or device-delivered therapy are also ongoing. , Most trial results are expected by 2021, making this an exciting time for growth in this field for both the urologist and patient.
Summary
The management of the 30% to 40% of patients with recurrent high-risk, NMIBC after initial definitive intravesical therapy remains a quagmire: burdened by the weight of poor-quality, muddied evidence admixed with time-consuming, often morbid, and sometimes effective therapy. Although clinical guidelines suggest radical extirpative therapy, many patients are unfit, and urologists remain unwilling to perform this, for good reason. Data supporting the use of cystectomy are retrospective in nature with disease progressing in 1% to 70% of patients, although generally only after a surgery delay of 1 to 2 years. , Thus, there is very likely a window whereby salvage therapy might play a role in disease treatment and bladder preservation. Pragmatically, enrollment of patients in a trial whereby they receive radical cystectomy versus intravesical therapy in this setting is unlikely to accrue given the major difference in therapies. Having recognized the aforementioned limitations, the FDA has now approved guidance for clinical trial design in this setting, and, going forward, many single- and combination-agent clinical trials promise results reporting by 2021.
Until such time, the urologist must make every effort to guide patients through the milieu of treatment options. Combination agent intravesical therapy presents an excitingly efficacious avenue. Combinations of BCG with IFN have so far not demonstrated a benefit for BCG unresponsive patients, but may be useful, allowing for dose reduction to one-tenth dose BCG for patients previously BCG intolerant. Likewise, quadruple immunotherapy with one-third dose BCG may provide some benefit, possibly for patients with age-related immune dysfunction, however, with an increased incidence of side effects and therapy discontinuation than BCG alone. Historic combination chemotherapy regimens as discussed above were never explored in large patient populations. However, combination therapy with Gem/MMC and Gem/Doce has been reviewed in the largest series of patients at multiple institutions. Results from a large, multi-institutional analysis of Gem/Doce suggest that 2-year, high-risk DFS occurs in 60% of patients with only a 6% progression rate, and less than a 5% discontinuation rate owing to side effects, thus making Gem/Doce the most well studied, well tolerated, and efficacious combination chemotherapy regimen in this patient population. One barrier to Gem/Doce and Gem/MMC instillations is the requirement of a fume hood at the practice site for therapy mixing. However, a fume hood will soon be required for mixing of BCG, which will necessitate this expense if intravesical therapy is a part of the practice.
To date, combination intravesical therapy, especially with Gem/Doce, represents an available promising treatment of salvage therapy in patients with high-risk NMIBC who are unfit or unwilling to undergo cystectomy. These therapy alternatives remain outside the standard of care and do not replace definitive surgical cure. Prior to initiating therapy, this should be discussed with the patient. Growth in this field of study is currently taking off with several exciting clinical trial results expected over the next several years. It is the authors’ hope that evidence-based alternatives to cystectomy and a better understanding of targeting therapy to specific patients and tumors will begin to change the treatment paradigm in this challenging and complex patient population.
Disclosure Statement
This work was partially supported by the John and Carol Walter Family Foundation.
References
Related posts:
Identification of Candidates for Salvage Therapy
Predictors of Response to Intravesical Therapy
Genomic and Therapeutic Landscape of Non-muscle-invasive Bladder Cancer
Intravesical Gene Therapy
Immuno-Oncology Approaches to Salvage Treatment for Non-muscle invasive Bladder Cancer
Role of Indoleamine-2,3-Dioxygenase Inhibitors in Salvage Therapy for Non-Muscle Invasive Bladder Cancer
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