Salvage Therapy Using Bacillus Calmette-Guérin Derivatives or Single Agent Chemotherapy

Despite therapy with intravesical Bacillus Calmette-Guérin, roughly 50% of patients with high-risk non-muscle-invasive bladder cancer will recur. Although cystectomy is the oncologic gold standard in BCG unresponsive disease, salvage intravesical therapies are valuable treatment options that aim to preserve quality of life while decreasing the risk of cancer recurrence and progression. Single-agent intravesical chemotherapy has been a mainstay salvage treatment and foundational to future trials of combination therapy. Treatment with Bacillus Calmette-Guérin derivative therapies has shown promise with response rates comparable with those of single agent chemotherapy and may warrant further investigation in the continued climate of Bacillus Calmette-Guérin shortages.

Key points

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Patients with Bacillus Calmette-Guérin–unresponsive disease who refuse or are ineligible for cystectomy remain a challenging patient population to treat without a gold standard treatment.
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Studies of single-agent chemotherapy with valrubicin, gemcitabine, and docetaxel in the salvage setting after Bacillus Calmette-Guérin failure have demonstrated moderate efficacy at a cost of slightly increased oncologic risk.
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Bacillus Calmette-Guérin derivates such as mycobacterial cell wall nucleic acid complex achieved response rates comparable with single-agent intravesical chemotherapy in the salvage setting; however, disease progression was fairly high.

Introduction to salvage intravesical therapies

Patients who have high-grade recurrences after intravesical Bacillus Calmette-Guérin (BCG) represent a particularly challenging disease state to manage. Radical cystectomy (RC) remains the oncologic gold standard in patients at high risk of recurrence after BCG failure in non–muscle-invasive bladder cancer (NMIBC); however, the significant morbidity of this operation makes some patients ineligible and others highly desirous of a bladder sparing approach. The term salvage therapy implies an attempt to salvage the patient’s bladder in lieu of undergoing a radical cystectomy. Historically, the majority of trials testing salvage intravesical therapies have been single-arm trials that have enrolled patients with varying degrees of prior exposure to BCG and varying degrees of pathologic risk, making direct comparisons of efficacy between agents very difficult. Therefore, when assessing the efficacy of the various salvage agents presented in the following articles, the reported recurrence and progression-free survival rates must be tempered with knowledge of the initial disease severity and prior BCG exposure of patients included in the trials. With this in mind, overall 1- to 2-year recurrence-free survival (RFS) rates of various agents are modest ranging from 18% to 43%.

In an effort to clarify and simplify BCG failure for ease of comparison across trials and to identify appropriate eligibility criteria for novel salvage intravesical therapies, Kamat and colleagues suggested that new trials investigating salvage intravesical therapy primarily include BCG-unresponsive patients, with a further breakdown of the proportion of patients who fit into BCG-refractory, -relapsing, and -intolerant categories. BCG-unresponsive disease combines BCG-refractory and BCG-relapsing disease to provide the urologist a clear definition for when further intravesical BCG is unlikely to provide benefit. For the purposes of being considered as BCG unresponsive, BCG-relapsing patients must have a high-grade recurrence within 6 months of achieving a disease-free state after 2 induction courses of BCG or high-grade recurrence after induction plus maintenance. Numerous studies have found that earlier high-risk recurrences after BCG carry a higher risk of progression, with salvage intravesical therapies having poor success rates in this setting. ^, As detailed more extensively in the Russell E.N. Becker and colleagues’ article in this issue, “ Identification of Candidates for Salvage Therapy: The Past, Present, and Future of Defining BCG Failure ,” BCG-refractory disease is composed of persistent high-grade NMIBC at 6 months despite adequate BCG treatment. Although intermediate-or high-risk patients with persistent or recurrent Ta disease or carcinoma in situ (CIS) after a single course of induction BCG may benefit from an additional induction course of BCG, patients with high-grade T1 disease after a single BCG induction course are also deemed BCG refractory and should be offered radical cystectomy as a gold standard.

Should patients either be unfit for radical cystectomy or refuse cystectomy after demonstrating BCG-unresponsive disease, we recommend that the patient enroll in clinical trials if able because no single or combined agent has demonstrated clear superiority in the salvage setting. In this article, we detail prior studies of salvage therapy using a single agent intravesical chemotherapy or BCG derivatives with the aim of giving the reader a sense of their comparable efficacy by looking at outcomes in the context of their often heterogenous treatment populations ( Table 1 ).

Table 1

Summary of studies examining single agent salvage intravesical chemotherapy and BCG derivatives

First Author	Design	Patients	Treatment	Median Follow-Up	Recurrence-Free Survival	Prog, %	RC, %	Comments
Steinberg et al, 2000	Single arm, phase I/II	n = 90, all ≥1 BCG induction, 70% with ≥2	Valrubicin 800 mg, 6 wk induction	30 mo	6 mo: 25% 1 y: 17% End of study: 8%	n/a	56%	Rate of progression not specified as suspected many owing to understaged TURs. 90% with local AEs, 3 unable to complete course.
Dinney et al, 2013	Single modified arm, phase III	n = 80, all had ≥1 BCG induction, 39% with ≥2	Valrubicin 800 mg, 6 wk vs 9 wk	n/a	6 mo: 18% 1 y: 10% 2 y: 4%	n/a	25%	Most did not have progression; however, 4 patients died of bladder cancer.
Dalbagni et al, 2006	Single arm, phase II	n = 30, BCG “refractory” or intolerant	Gemcitabine 2 g, ×12 biweekly doses over 7 wk	19 mo (0–35)	3 mo: 50% 1 y: 21%	7%	37%	Well-tolerated with only 36% patient developing local symptoms. No maintenance used.
Di Lorenzo et al, 2010	RCT, gemcitabine vs second induction course of BCG	n = 80, all received 1 prior BCG, 30% LG	Gemcitabine 2 g biweekly ×6 weeks + maintenance vs BCG + maintenance ×3	15.5 mo (6–22)	Gem: 1 y, 55%; 2 y, 19% BCG: 1 y, 27%; 2 y ( P <.008)	Gem: 33% BCG: 37.5%	Gem: 43% BCG: 40%	First and only RCT of gemcitabine vs BCG in this unique setting. High rates of disease progression and metastasis in both groups.
Skinner et al, 2013	Single arm, phase II	n = 58, all received 2 prior BCG courses, 89% considered high risk	Gemcitabine 2 g/wk ×6 + monthly maintenance ×10	15 mo	3 mo: 47% 1 y: 28% 2 y: 21%	3.4%	26%	Only 3 patients had progression to MIBC at RC.
Laudano et al, 2010	Single arm, phase I	n = 18, all had ≥1 BCG induction; mean of 3 prior IVT courses	Docetaxel escalating dose to 75 mg/100 mL NS ×6, no maintenance	4 y	1 y: 61% 2 y: 44% Median: 13.3 mo	11%	33%	4 (22%) patients remained disease free without further treatment.
McKiernan et al, 2014	Single arm, phase II	n = 28, only 1 patient with low grade pathology, all received ≥1 prior BCG	Nab-paclitaxel, 500 mg/100 mL NS weekly ×6 + monthly maintenance ×6	21 mo (range, 5–47 mo)	3 mo: 36% 1 y: 36%	3%	32%	Median number of prior IVT was 2 with high enrichment of CIS (71%). Long-term follow-up of cohort showed RFS of 18% at median follow-up of 41 mo.
Morales et al, 2001	Single arm	n = 61, 46% prior BCG induction; all CIS	MCWE 6 wk induction + maintenance	Range, 3–12 mo; poor long-term follow-up	3 mo: 62.5%, 1 y: 41%	n/a	n/a	Similar rates of response in BCG-naïve patients and prior induction.
Morales et al, 2009	Dual arm: 4 vs 8 mg MCNA	n = 55 85% prior BCG induction All with CIS, 35% also with Ta/T1 disease	MCNA 6 wk induction + maintenance	Range, 3–18 mo, median not given	4 mg: 3 mo, 40%, 1 y,40% 8 mg: 3 mo, 62%; 1 y, 33%	n/a	n/a	Similar adverse effects in both dosage groups (33%). 8 mg thought to be more effective.
Morales et al, 2015	Single arm, phase III	n = 129, all received BCG, 82% BCG refractory	MCNA 8 mg, followed by 3 weekly maintenance ×5	34.7 mo	1 y: 25%, 2 y: 19% Papillary only tumors, 1-y RFS: 35%	22%	43%	21% of RC specimens had pT2 or greater, metastasis occurred in 10 (8%) patients.