Repeat Bacillus Calmette-Guerin

Select patients may undergo repeat BCG induction. In the setting of CIS or positive cytology at 3 months after induction, repeat induction can achieve complete response (CR) in more than 50% of cases based on meta-analysis of 9 randomized trials including 700 patients over a median follow-up of 3.6 years. Patients with a high-grade Ta tumor or CIS at 3 months after induction may also undergo repeat induction with reevaluation at 6 months. In the setting of a BCG relapse, a second induction course of BCG may be given if no maintenance was given; in an older cohort, this has been associated with a 40% response rate. However, more than 2 courses of induction BCG are not recommended because of the greatly reduced chance of success (<20%), coupled with increased likelihood of tumor progression (30%) and metastasis (50%). Finally, patients with late BCG relapse, recurrence more than 1 year after BCG treatments, have been shown to have similar cancer-free rates as BCG-naïve patients and reinduction BCG should be considered. ^, As discussed previously, although reinduction BCG is appropriate for these select BCG-resistant and BCG-relapsing disease states, data to support its use in BCG-refractory or recurrent T1 disease is insufficient.

Overall, as one of the earliest effective immunotherapies, intravesical BCG has been embraced as the standard of care for NMIBC for more than 3 decades and is appropriate to use in select salvage settings; however, it is not without its inherent challenges. BCG is dependent on the growth of the mycobacterium under controlled circumstances, which can be achieved by a limited number of manufacturers, and as such, BCG is susceptible to shortages. Furthermore, for those unwilling or unable to undergo induction or maintenance BCG secondary to BCG side effects or for those with an unwillingness or inability to undergo cystectomy, alternative treatment strategies are required.

Intravesical Chemotherapy: Mitomycin C

Mitomycin C (MMC) is an antineoplastic antibiotic that cross-links DNA preventing synthesis. In addition, MMC is a desiccant of urothelial tissue allowing for increased permeability to intravesical agents. It has been most commonly used as a single instillation administered at the time of transurethral resection of a bladder tumor, particularly for low-grade disease. The role of MMC alone as a salvage therapy in high-risk NMIBC has not been fully elucidated in a randomized trial, although some inferential conclusions may be made. Malmström and colleagues enrolled 261 patients including patients with primary high-risk and recurrent Ta and T1 bladder cancer. According to the protocol, crossover treatment was administered to 21 patients who changed from BCG to second-line MMC. Of this group, only 4 (19%) had recurrence-free survival (RFS) at 3 years.

Intravesical Chemotherapy: Valrubicin

Valrubicin is a semisynthetic anthracycline. Currently, valrubicin is the only FDA-approved therapy for BCG-refractory CIS based on a single-arm trial of 90 patients who had CIS or high-grade Ta and T1 disease; 99% of whom who had failed at least 2 cycles of prior intravesical therapy, most commonly BCG. In this cohort, 18% to 21% had a CR at 6 months and 8% at 24 months, with a median follow-up of 30 months. RC was completed in 56% of the patients, and 15% had pT3 or greater staging at time of cystectomy. All cancer-specific deaths were in patients who did not undergo cystectomy or experienced a CR. Updated reports of the original study were reported along with a reports from a second single-arm study of valrubicin for BCG-refractory CIS, which included 80 BCG-refractory and BCG-intolerant patients (39% of whom had received ≥2 courses of BCG and 11% of whom had received ≥3 courses of BCG). In this study, the CR was 18% for both groups.

Since the reintroduction of valrubicin in 2009, a contemporary cohort of 100 patients who completed salvage valrubicin treatment (51.3% with CIS alone) were retrospectively reviewed. RFS was 51.6% at 3 months, 30.4% at 6 months, and 16.4% at 12 months, consistent with previous clinical trial findings. Overall, despite its FDA approval, valrubicin has very low response rates, and is a suboptimal salvage therapy in the setting of BCG failure. This has been one of the major impetuses for trials in this disease space.

Intravesical Chemotherapy: Gemcitabine

Gemcitabine is a pyrimidine analog that blocks DNA replication leading to apoptosis of cancer cells that has been extensively studied for salvage therapy. As a nonvesicant chemotherapy, it does not cause direct tissue injury when applied intravesically.

A phase II trial of 30 patients who were BCG refractory or BCG intolerant (20 with ≥2 prior BCG courses) who refused cystectomy were given 2 courses of intravesical gemcitabine twice weekly for 3 weeks. Dalbagni and colleagues reported a disease-free rate of 21% at 12 months. A multicenter phase II Southwest Oncology Group study evaluated single-agent intravesical gemcitabine given as a 6-week induction course followed by monthly maintenance for a year in high-risk patients (86% of the cohort) who had received ≥2 prior BCG courses. They found RFS rates of 28% at 1 year and 21% at 2 years after therapy. Two patients had disease progression, and 32% underwent cystectomy, although only 6% of those were found to have pT2 disease or higher in the pathologic specimen.

The true efficacy of gemcitabine in the pure BCG-refractory cohort is not known based on these studies, as these study populations were heterogeneous. However, direct comparisons have been made with known existing therapies. Di Lorenzo and colleagues directly compared gemcitabine (GC) with BCG and demonstrated that, after failure of single BCG course, patients with high risk NMIBC have significantly better (52.3% vs 87.5%) disease recurrence if they were given intravesical gemcitabine induction with maintenance versus repeat BCG. Progression was greater than 35% in both groups, likely owing to the greater than 70% of patients with T1 disease in this very high-risk cohort. Overall, these data suggest GC may be an improved option relative to BCG alone. Similarly, when compared with MMC, gemcitabine has superior disease-free survival and lower toxicity.

Intravesical Chemotherapy: Taxanes

Docetaxel is a microtubule depolymerization inhibitor with antimitotic tumor activity. In a phase II trial of 54 patients with BCG-refractory disease (28 who received BCG alone, 26 who received BCG and interferon [IFN]α, and 12 who additionally received MMC), a 6-week induction course of weekly intravesical docetaxel with monthly maintenance was administered. A CR rate was achieved in 59%. At 1 year and 3 years, the RFS rates were 40% and 25%, respectively. An RC was performed in 24% at a median 24-month follow-up, and 4 of the 17 specimens showed progression to muscle-invasive disease.

Abraxane, a nanoparticle albumin-bound version of paclitaxel that is thought to have increased bioavailability when compared with docetaxel, has also been studied in a phase II trial. At 1 year, RFS was 36% in a similar cohort of 28 patients.

Combination Therapies

Combination chemotherapy regimens have been explored similar to multi-agent intravenous therapy, and these have been described in detail. Although the combination of drugs may result in increased toxicity, it may be advantageous to combine non-desiccant cytotoxic therapeutic drugs, such as gemcitabine and docetaxel, with desiccant drugs, such as mitomycin, to enable both drugs to be administered sequentially and take advantage of multiple mechanisms of action.

Steinberg and colleagues first described sequential intravesical GC and docetaxel. They demonstrated 66% success at first surveillance, 54% at 1 year, and 34% at 2 years. Of those who proceeded to cystectomy, the findings were of favorable pathology without lymph node involvement or positive surgical margins.

Combination intravesical therapies with MMC also have been examined. Cockerill and colleagues retrospectively reviewed a small cohort given sequential GC and MMC weekly. Durable responses were seen in 37% at 22.1 months of follow-up. In another multi-institutional series of 47 patients, an initial CR of 68% was seen, with RFS rates of 48% at 1 year and 38% at 2 years posttreatment. ^,

These small trials suggest that couplet and combination therapies may demonstrate improved efficacy and warrant further investigation. Novel drug combinations are currently being explored and multiple combinations are in phase 1 trial testing. For example, NCT02202772 is testing intravesical gemcitabine, cabazitaxel, and cisplatin in BCG-unresponsive patients.

Granulocyte-Macrophage Colony-Stimulating Factor

Incomplete immunostimulation has been proposed as a possible etiology for BCG failure. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been identified as a stimulatory cytokine in the proinflammatory BCG pathway. Therefore, its addition to intravesical treatment is thought to augment the proinflammatory response. Steinberg and colleagues performed a retrospective review of BCG-failure patients who were given quadruple immunotherapy (reduced dose BCG, IFNα, interleukin [IL]-2, and GM-CSF). Treatment success was 53% at 2 years. Of those who underwent cystectomy, no patients had positive surgical margins or positive lymph nodes. This is promising, as it implies there is a window between BCG failure during which time salvage therapies may be explored without compromising curative surgery.

Chemoradiation

Although historically reserved for the muscle-invasive bladder cancer setting, chemoradiation has been explored in the NMIBC setting. Weiss and colleagues published their experience at a single institution of 141 patients with high-risk T1 bladder cancer. They performed a debulking transurethral resection followed by pelvic (50.4 Gy) and bladder (55.8 Gy) radiation and cisplatin or carboplatin. CR was found to be 88%, with 5-year and 10-year progression rates of 19% and 30%, respectively. Although this was a primary treatment for NMIBC (not in a BCG-refractory cohort) and may not directly apply to the salvage setting, the results are promising.

A small cohort of 18 patients who had T1 tumors and progressed to T2 disease despite BCG therapy were treated with chemoradiotherapy, and at the median follow-up of 7 years, 54% were alive without cystectomy, without metastatic disease, and without muscle-invasive recurrence. The investigators suggest this may be a viable option in the setting of T1 tumors that recur after BCG. However, in the setting of CIS, radiotherapy is not appropriate, as there is a high risk of bladder tumor recurrence.

Currently ongoing is a nonrandomized phase II trial in patients with high-grade NMIBC after BCG failure giving either 61.2 Gy of radiation therapy with cisplatin after maximal transurethral resection or radiation therapy with 5-fluorouracil or MMC ( NCT00981656 ). The primary endpoint is cystectomy-free survival. Based on the results, trimodal therapy may become an option for selected patients with BCG failure who are unfit for RC.

The National Cancer Institute’s Clinical Trials planning meeting on novel therapeutics for NMIBC highlights that although the data are limited for the role of radiation therapy in NMIBC, radiation therapy is known to have direct impacts on immune-mediated effects, including chemotherapy or immune checkpoint inhibitors and should be explored.

Novel Drug Administration: Chemohyperthermia

Chemohyperthermia (C-HT) is the combination of intravesical chemotherapy with hyperthermia of the intravesical agent. Hyperthermia raises temperatures within the bladder to 40 to 44°C. The heat alters intracellular metabolism resulting in DNA damage and induced apoptosis. There is also an increase in blood perfusion and cell permeability allowing for increased uptake of intravesical agents. ^, Currently, the European Association of Urology guidelines on C-HT holds a grade B recommendation for patients with BCG failure who are ineligible for RC.

Hyperthermia can be achieved by intravesical microwave-induced heating via a radiofrequency-emitting antenna in a catheter, conductive heating via externally heated chemotherapy fluid, or loco-regionally via external radiofrequency antennas. Synergo is an FDA-approved computerized C-HT administration system and is the most widely used and studied. COMBAT BRS is a recirculating system that externally heats MMC via conductive aluminum heating, which is then delivered via a 3-way urethral catheter. BSD-200 is an FDA-approved system that uses electromagnetic waves to induce heat. Computerized tomography is used to plan treatment and localized temperature probes within the rectum and bladder, while externally located antenna pairs deliver radiofrequency waves to the pelvis.

Optimized delivery strategies for MMC have been well studied and reviewed. Routine clinical practice includes increased drug concentration to 40 mg MMC in 20 mL saline solution, alkalization of urine with oral sodium bicarbonate preoperatively, decreased drug dilution with fluid restriction, confirmation of an empty bladder with ultrasonography after catheterization, and a 2-hour dwell time. Although multiple studies have been published with addition of C-HT for optimization, most include patients with no prior intravesical therapies alongside chemotherapy and BCG treatments. It also must be mentioned that MMC displays greater toxicity under increased temperature.

Colombo and colleagues completed a small, multicenter prospective randomized control trial using Synergo comparing C-HT with MMC versus conventional MMC administration in 83 patients with high-risk primary NMIBC (35%–39% of the cohort) or recurrent NMIBC (approximately 60%–65% of the cohort). After a 24-month median follow-up, recurrence rate in the C-HT with the MMC group was 17.1% versus 57.5% with the MMC group alone. Although promising, this cohort did include primary treatment, and these data have not been replicated.

Other retrospective analyses exist of C-HT with MMC in a BCG-refractory cohort. These have variable results. One-year and 2-year RFS of 85% and 56% respectively have been reported, and these are lower in BCG-refractory patients with CIS with 1-year and 2-year recurrence rates at 23% and 41%, respectively. In another CIS cohort, an initial response rate to hyperthermia was reported with MMC of 92% at 1 year and 50% at 2 years. There was no difference in response rates seen in the subgroup of 34 BCG-failure patients.

Overall, recurrence rates are variable for patients with prior BCG failure after C-HT. Data on progression are scarce, and longer follow-up is needed. But these study designs portend slow accrual. For example, a direct comparison of MMC versus BCG in intermediate-risk and high-risk NMIBC ( NCT00384891 ) was terminated early for slow accrual.

Novel Drug Administration: Electromotive Administration

Electromotive administration (EMDA) accelerates drug delivery through bladder mucosa by application of an electric field. The lower abdomen is grounded with electrodes and a transurethral catheter serves as the active electrode. Electrokinetic mechanisms of iontophoresis, electroosmosis, electrophoresis, and electroporation are suggested. Current data have focused on its use as primary treatment. Racioppi and colleagues carried out a single-arm phase II study of 26 BCG-refractory patients with 3-year follow-up. EMDA-MMC was given as induction with maintenance and surveilled with systemic mapping biopsies. At the end of follow-up, 61.5% of patients were able to preserve their bladders. The 23.1% who had recurrent high-grade disease and 15.4% who progressed to muscle-invasive disease underwent cystectomy. Disease-free states were lowest (25%) for patients with both high-grade disease and CIS and highest for Ta-only recurrence (75%).

Novel Drug Administration: Viral Gene Therapy and Vaccines

A nonreplicating adenovirus that is able to infect bladder urothelium and contains transgenes is thought to enhance cytotoxic immune response to tumor serves as the basis of viral gene therapy. CG00700 was found in a phase I and II trial of BCG-refractory and BCG-relapsing disease to have 49% response rate at 10.4 months. ^,

Instiladrin (rAd-IFNα/Syn3) is an adenovirus encoding the human IFNα 2b transgene along with Syn3, a surfactant that enhances adenoviral transduction into the urothelium. In phase I and phase II trials of BCG-unresponsive patients, a CR of 36% was noted at 12 months. ^, A single-arm phase III trial ( NCT02773849 ) is pending.

PANVAC is a poxviral vaccine that encodes genes for tumor-associated mucin-1 and carcinoembryonic antigens as well as T-cell costimulatory molecules. NCT02015104 is a phase II trial of BCG with PANVAC in patients having failed 1 course of BCG induction.

Data from a single-arm phase Ib/II trial of BCG-refractory and BCG-relapsing patients showed CR >12 months in 2 of 6 patients on ALT-801, a recombinant fusion protein of IL-2 plus a T-cell receptor domain that recognizes human p53 antigen on cancer cells. A review of the agents discussed, and their efficacy, is shown in Tables 1 and 2 .

Table 1

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