This article provides an overview of intravesical chemotherapy agents used for non–muscle invasive bladder cancer; summarizes the evidence on single-dose perioperative administration, induction therapy, and maintenance therapy; and briefly discusses ongoing research.
Key points
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Numerous intravesical chemotherapy agents are available for use in non-muscle invasive bladder cancer with different mechanisms of action and side-effect profiles.
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In the absence of suspected bladder perforation, immediate perioperative dose of intravesical chemotherapy reduces the risk of recurrence for low-grade disease.
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Induction and maintenance therapy is recommended in intermediate-risk disease.
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Intravesical chemotherapy is being investigated as a possible second-line treatment of high-risk non-muscle invasive bladder cancer in patients who are not operative candidates or who refuse cystectomy.
Introduction
Although transurethral resection of bladder tumor (TURBT) is the gold standard for initial diagnosis and primary treatment of non-muscle invasive bladder cancer (NMIBC), up to 45% of patients will have a tumor recurrence within the first year after TURBT alone and 3% to 15% of patients will have tumor progression. Tumor cells left in the bladder mucosa after incomplete TURBT as well as free tumor cells that reimplant immediately following TURBT are thought to contribute to the high rate of recurrence. Cytotoxic intravesical chemotherapy is a recommended adjunct to endoscopic resection to reduce the risk of post-TURBT tumor cell implantation and subsequent tumor recurrence, particularly in lower-risk tumors. Instillation of antitumor agents into the bladder allows direct contact with the mucosa and tumor cells and minimizes systemic effects.
A variety of agents are available with distinct characteristics, mechanism of action, cost, and side-effect profile. These agents include mitomycin C (MMC); thiotepa; gemcitabine; and intercalating agents, such as doxorubicin, epirubicin, and valrubicin ( Table 1 ). The cytotoxic ability of the chemotherapy agents is proportional to the concentration of the agent in the bladder and duration of exposure rather than the size of the dose administered. Absorption, efficacy, and systemic toxicity depend on molecular characteristics, pH during instillation, and time to administration following resection.
| Agent | MW (kD) | Cystitis (%) | Other Toxicity | Dropout Rate (%) | Dose/Concentration | Cost ($) |
|---|---|---|---|---|---|---|
| Doxorubicin | 580 | 20–40 | Fever, allergy, bladder contraction (5%) | 2–16 | 50 mg/50 mL | 36 |
| Epirubicin | 580 | 10–30 | Contracted bladder (rare) | 3–6 | 50 mg/50 mL | 595 |
| Valrubicin | 724 | 23–77 | Rash (rare) | — | 800 mg/55 mL | 4400 |
| MMC | 328 | 30–40 | Rash (8%–19%), contracted bladder (5%) | 2–14 | 40 mg/20 mL | 130 |
| Thiotepa | 189 | 10–30 | Myelosuppression (8%–19%) | 2–11 | 30 mg/30 mL | 80 |
| Gemcitabine | 300 | Minimal | Nausea (rare) | <10 | 1–2 g/50–100 mL | 540–1080 |
Most chemotherapy agents are well tolerated, particularly a single perioperative dose. Local lower urinary tract symptoms, including frequency, urgency, and dysuria, are the most frequently reported side effects. Hematuria, bladder pain, and prostatitis are encountered with similar frequency in all agents. Bladder contracture is a rare event with chemotherapy treatment; and systemic side effects (immunologic reactions, malaise/fatigue, nausea/vomiting, and neurologic, cardiovascular, or pulmonary complications) are less frequently seen than with immunotherapy regimens, such as bacilli Calmette-Guerin (BCG) and/or interferon. Side effects significantly increase with multiple doses of chemotherapy, which can make completing these regimens difficult.
In clinical practice, significant variations exist in treatment intensity and adherence to best-practice guidelines that tend toward underuse of intravesical therapy. Physician self-reporting suggests that practice setting (private vs academic), years in practice, and tumor grade were associated with deviations from published guidelines. These variations likely have significant economic as well as oncologic implications that warrant further study and efforts for quality improvement. Clinicians should be informed on the most up-to-date evidence-based guidelines for intravesical chemotherapy for NMIBC.
Introduction
Although transurethral resection of bladder tumor (TURBT) is the gold standard for initial diagnosis and primary treatment of non-muscle invasive bladder cancer (NMIBC), up to 45% of patients will have a tumor recurrence within the first year after TURBT alone and 3% to 15% of patients will have tumor progression. Tumor cells left in the bladder mucosa after incomplete TURBT as well as free tumor cells that reimplant immediately following TURBT are thought to contribute to the high rate of recurrence. Cytotoxic intravesical chemotherapy is a recommended adjunct to endoscopic resection to reduce the risk of post-TURBT tumor cell implantation and subsequent tumor recurrence, particularly in lower-risk tumors. Instillation of antitumor agents into the bladder allows direct contact with the mucosa and tumor cells and minimizes systemic effects.
A variety of agents are available with distinct characteristics, mechanism of action, cost, and side-effect profile. These agents include mitomycin C (MMC); thiotepa; gemcitabine; and intercalating agents, such as doxorubicin, epirubicin, and valrubicin ( Table 1 ). The cytotoxic ability of the chemotherapy agents is proportional to the concentration of the agent in the bladder and duration of exposure rather than the size of the dose administered. Absorption, efficacy, and systemic toxicity depend on molecular characteristics, pH during instillation, and time to administration following resection.
| Agent | MW (kD) | Cystitis (%) | Other Toxicity | Dropout Rate (%) | Dose/Concentration | Cost ($) |
|---|---|---|---|---|---|---|
| Doxorubicin | 580 | 20–40 | Fever, allergy, bladder contraction (5%) | 2–16 | 50 mg/50 mL | 36 |
| Epirubicin | 580 | 10–30 | Contracted bladder (rare) | 3–6 | 50 mg/50 mL | 595 |
| Valrubicin | 724 | 23–77 | Rash (rare) | — | 800 mg/55 mL | 4400 |
| MMC | 328 | 30–40 | Rash (8%–19%), contracted bladder (5%) | 2–14 | 40 mg/20 mL | 130 |
| Thiotepa | 189 | 10–30 | Myelosuppression (8%–19%) | 2–11 | 30 mg/30 mL | 80 |
| Gemcitabine | 300 | Minimal | Nausea (rare) | <10 | 1–2 g/50–100 mL | 540–1080 |
Most chemotherapy agents are well tolerated, particularly a single perioperative dose. Local lower urinary tract symptoms, including frequency, urgency, and dysuria, are the most frequently reported side effects. Hematuria, bladder pain, and prostatitis are encountered with similar frequency in all agents. Bladder contracture is a rare event with chemotherapy treatment; and systemic side effects (immunologic reactions, malaise/fatigue, nausea/vomiting, and neurologic, cardiovascular, or pulmonary complications) are less frequently seen than with immunotherapy regimens, such as bacilli Calmette-Guerin (BCG) and/or interferon. Side effects significantly increase with multiple doses of chemotherapy, which can make completing these regimens difficult.
In clinical practice, significant variations exist in treatment intensity and adherence to best-practice guidelines that tend toward underuse of intravesical therapy. Physician self-reporting suggests that practice setting (private vs academic), years in practice, and tumor grade were associated with deviations from published guidelines. These variations likely have significant economic as well as oncologic implications that warrant further study and efforts for quality improvement. Clinicians should be informed on the most up-to-date evidence-based guidelines for intravesical chemotherapy for NMIBC.
Chemotherapy agents: characteristics, dosing, and adverse events
MMC
MMC is the most frequently used and thoroughly studied intravesical chemotherapy agent for NMIBC (see Table 1 ). It is a 328-kD DNA alkylating agent derived from Streptomyces caespitosus . It binds to DNA and causes a reductive activation reaction followed by 2 N-alkylations. This reaction results in DNA crosslinking, synthesis inhibition, and strand breakage. Although MMC is cell-cycle nonspecific, it seems to be more active during the G1 and S phases.
Optimal dosing and administration schedule continue to be debated. Dosage varies between 20 to 80 mg per instillation. Previously, the most commonly used dosing for multidose regimens was 40 mg in 40 mL of saline or sterile water administered weekly for 8 weeks followed by monthly for 1 year. In 2001, Au and colleagues studied measures to optimize the efficacy of MMC in a phase III randomized trial, which have largely been adopted as the standard of care. Higher drug dose (40 mg vs 20 mg), higher concentration (20 mL vs 40 mL) urinary alkalization (1.3 g NaHCO 3 by mouth the night prior, morning of, and 30 minutes before treatment), a period of dehydration before treatment (no fluids for 8 hours prior), and confirmed bladder emptying before instillation (<10 mL by ultrasound bladder scan) in the treatment arm resulted in increased recurrence-free survival. MMC is more stable in alkaline environments, yet its cytotoxic effect is greater in acidic urine. Whether its increased cytotoxic effect in lower pH outweighs its greater stability at a higher pH is unknown and a potential area for future study. Other methods of optimizing drug delivery, including microwave hyperthermia and electromotive instillation to accelerate drug delivery into and across biologic membranes, have shown promise; but further confirmatory studies are required before becoming routinely used.
Because of its moderately high molecular weight of 328 kD, transurothelial absorption of MMC is minimal. Therefore, systemic symptoms and life-threatening complications, such as myelosuppression, are rare. Bladder contraction and bladder wall calcification are also uncommon to MMC. Primary complications include chemical cystitis, contact dermatitis, and allergic reactions, which resolve with discontinuation of therapy and topical steroid application if necessary. A meta-analysis reveals that local complication rate after TURBT with single-dose MMC is approximately 2%, which is comparable with the rate after TURBT alone. However, the rate of local cystitis increases to 20% to 40% of patients receiving multiple administrations and/or maintenance courses of MMC.
Intercalating Agents
Doxorubicin (580 kD), epirubicin (580 kD), and valrubicin (724 kD) are 3 chemotherapy agents in the anthracycline antibiotic class and are derived from the bacterium Streptomyces peucetius . These drugs are DNA intercalating agents, acting primarily by binding to DNA and inhibiting the progression of the enzyme topoisomerase II during DNA replication. The topoisomerase II complex is unable to reseal the replicating DNA double helix, thus resulting in strand breaks and inhibition of essential cellular protein synthesis. The intercalating agents have a broad range of chemotherapy activity, disrupting the cell by several mechanisms, including cell membrane disruption through the production of free radicals. These agents are not cell-cycle specific but have maximal activity during the S phase.
Dosing of doxorubicin ranges from 10 to 100 mg, with a wide variety of administration schedules, from 3 times a week to monthly.
Increased side effects with doxorubicin, including local symptoms of chemical cystitis in up to 50% of patients, hematuria, and reports of decreased bladder capacity, make this agent a less desirable choice. Systemic side effects are rare because of the high molecular weight of this compound, but occasional reports of life-threatening myelosuppression have been reported.
Epirubicin is a derivative of doxorubicin (4′ carbon epimere), differing only in to the presence of a daunosamine side chain. Similar in terms of mechanism of action and efficacy, the different spatial orientation of the hydroxyl group at the 4′ carbon of the sugar moiety may account for faster elimination and potentially reduced toxicity. Although epirubicin is approved by the Food and Drug Administration (FDA) for use in various malignancies in the United States, it is only available for use in urothelial cancer in Europe.
Epirubicin has been evaluated as a single perioperative dose and a full 8-week course. Dosing ranges from 50 mg per instillation for weekly dosing to 100 mg per dose with single instillations.
Multiple investigators have demonstrated efficacy of doxorubicin and epirubicin in reducing recurrence but not progression on NMIBC ; however, current guidelines make no clear recommendation on the use of these agents for prophylactic chemotherapy because of the side-effect profile, lack of long-term efficacy results, and controversial results.
Valrubicin is a semisynthetic analogue of doxorubicin reserved for use in select BCG-refractory tumors. Similar to the other intercalating agents, valrubicin inhibits nucleoside incorporation into nucleic acids resulting in cell-cycle arrest in G2. In addition, the principal metabolites of valrubicin inhibit DNA synthesis through inhibition of topoisomerase II.
It has several molecular-level differences from doxorubicin, which allows for more rapid uptake and accumulation into cells. These differences account for valrubicin’s decreased contact and cardiac toxicity. The fact that valrubicin is a macromolecule explains the lack of systemic absorption and toxicity.
It was previously removed from the market in 2002 because of impurities in the original formulation but reintroduced in 2009 and approved for the treatment of BCG-refractory carcinoma in situ (CIS) in patients who are not candidates for radical cystectomy. Valrubicin is typically administered weekly for 6 weeks at a dose of 800 mg per instillation.
Thiotepa
N,N′,N′-triethylenethiophosphoramide (Thiotepa, thiotepa, 189 kD) is an organophosphorous compound that disrupts DNA synthesis and promotes strand breakage through its DNA alkylation activity. This agent is not cell-cycle specific.
Thiotepa is the first and only chemotherapeutic agent specifically approved for intravesical treatment of papillary bladder cancer. Although efficacy has been proven through numerous clinical trials dating back to the 1970s, its low molecular weight results in systemic absorption of up to half of the administered dose and a subsequent higher rate of systemic side effects, including myelosuppression and skin rash. Consequently, the risk-benefit analysis of thiotepa is less favorable than other currently available agents and infrequently used in clinical practice.
Gemcitabine
Gemcitabine (300 kD) is a relatively novel chemotherapy agent. First approved in the United States for the treatment of pancreatic cancer, it is classified as an antimetabolite and has a broad range of anticancer activity. Its structure mimics that of cytosine, one of the pyrimidine molecules of DNA.
Phosphorylation of gemcitabine by nucleoside kinases within the cancer cell forms active metabolites (gemcitabine diphosphate and gemcitabine triphosphate), which block DNA synthesis and lead to apoptosis.
Several pharmacologic properties of gemcitabine are conducive to effective intravesical treatment and support utility in NMIBC. In vitro, researchers have demonstrated a robust cytotoxic effect against cultured bladder cancer cells. In vivo, low molecular weight and high lipid solubility allows adequate uptake into malignant cells, whereas high plasma clearance reduces the risk of systemic side effects caused by absorption of the drug.
Doses of 500 mg, 1000 mg, and 2000 mg in 50 mL saline, instilled for 1 to 2 hours, and administered weekly for 6 weeks have been studied. Recent phase I trials demonstrate a favorable safety profile, and several small phase II trials have subsequently reported good tolerability and potential efficacy in tumor response and disease-free survival in certain patient populations. Systemic and local toxicities were generally minimal; these studies suggest that dose escalation may be possible, potentially increasing efficacy with a tolerable side-effect profile.
Despite promising initial efficacy and tolerability data, recommendations on the use of intravesical gemcitabine cannot yet be made given the current available evidence. Variable clinical settings, patient population, trial objectives, and study design limit the current evidence base. Further evaluation by additional phase II and randomized phase III trials in an expanded patient population is warranted and ongoing.
Indications
Risk Category Definitions
The major guidelines do not uniformly agree on the definition of low-, intermediate-, and high-risk disease. For the remainder of this review, risk categories coincide with the following practical definitions outlined by the International Bladder Cancer Group: low risk is defined as solitary, primary low-grade Ta; intermediate risk as multiple or recurrent low-grade tumors; and high risk as any T1 and/or G3 and/or CIS.
Single Perioperative Dose
A single perioperative dose of intravesical chemotherapy is recommended immediately after initial TURBT in suspected low-risk disease in the absence of concern for bladder perforation. The National Cancer Control Network (NCCN) maintains that TURBT alone is the gold standard for low-risk patients but that an immediate postoperative chemotherapy dose should be considered based on the risk of recurrence and progression. A single instillation at the time of TURBT reduces the rate of recurrence primarily in the first 2 years but does not reduce the risk of progression or survival. This benefit disappears in recurrent, large (>5 cm), high-grade or high-risk patients receiving BCG. Studies have shown that the combination of negative urine cytology and cystoscopic expertise accurately identifies histologically confirmed low-grade tumors in greater than 90% of cases, which supports the ability of the urologist to predict which patients will benefit from a single instillation of perioperative chemotherapy preprocedurally.
MMC is the most frequently administered single-dose agent and is the most widely investigated. Although optimal timing for post-TURBT MMC administration has not yet been determined, improved recurrence outcomes are found only in studies that administer MMC within 24 hours of TURBT. Therefore, single-dose therapy should be administered immediately after TURBT, and ideally within 6 hours, when there is no suspicion of perforation.
It is the authors’ practice to administer MMC in the following manner. After resection and confirmation of absence of clinical perforation, place a 3-way catheter into the bladder and attach the inflow port to a saline infusion bag while still in the operating room. Administer MMC through the outflow port either in the operating room or in recovery and clamp the outflow tubing with a hemostat. After 1 hour, release the outflow tubing and allow irrigation and drainage to gravity for 30 to 60 minutes. The catheter may then be removed and discarded in a biohazard container. Gloves should be worn at all times when handling this agent.
A 2004 meta-analysis of 7 randomized trials compared a single perioperative instillation of intravesical chemotherapy following TURBT versus TURBT alone in patients with Ta or T1 bladder cancer. Three trials included epirubicin (728 patients, 49.3%), 2 studied MMC (427 patients, 28.9%), and thiotepa (247 patients, 16.7%) and pirarubicin (160 patients, 10.8%) were evaluated in 1 trial each. Chemotherapy was instilled within 24 hours in all trials and generally immediately after or within 6 hours after TURBT. The trials were published between 1985 and 2002 and reported on patients who were accrued between 1981 and 1994. The mean follow-up was 3.4 years (range 2.0–10.7 years).
Recurrence occurred in 36.7% of patients receiving chemotherapy compared with 48.4% in the TURBT-only groups. This finding represented a 12% absolute reduction in risk of recurrence and a 39% decrease in the odds of recurrence within the study timeframe.
There was no difference in the size of treatment effect in the epirubicin, MMC, and pirarubicin trials, although no benefit was observed in the trial using thiotepa, potentially because of the lower concentration used in the included study. It must be noted that this meta-analysis was not designed to determine superiority of a single agent.
Time to realization of treatment benefit varied between the studies, with 3 studies showing a benefit within 1 to 3 months, 1 study showing a benefit within 6 months, and 1 showing a benefit after 1 year. All studied that eventually showed reduced recurrence rate did so within the first 2 years, as previously suggested by Solsona and colleagues in their trial of single-dose MMC.
The treatment effect was observed in patients with both solitary and multiple tumors; however, the recurrence rate was significantly higher in patients with multiple tumors after a single instillation (65.2% vs 35.8%). This finding suggests that a single instillation alone immediately after TURBT may be suboptimal in this patient population.
The number needed to treat based on this meta-analysis was 8.5 (11.7 TURBTs were avoided for every 100 patients treated with single-dose chemotherapy). The authors suggest that treatment is cost-effective because the cost of a TURBT, anesthesia, and possible hospitalization is greater than 8.5 times that of a single instillation of intravesical chemotherapy.
Notably, in the absence of suspected perforation, a single dose of perioperative intravesical chemotherapy confers no additional morbidity to a TURBT alone.
The American Urologic Association (AUA) Bladder Cancer Guideline Panel performed a meta-analysis focusing on the single-dose instillation of perioperative MMC after TURBT. This analysis is comprised of the 2 studies on MMC included in the aforementioned meta-analysis but differs in that all risk groups are taken into account. Tolley and colleagues reported a 60% recurrence rate in patients treated with TURBT alone and a 45% recurrence rate in those treated with a single perioperative dose of MMC. Solsana and colleagues found a statistically significant decrease in the recurrence rate in the MMC group up to 2 years; however, the benefit disappeared at the long-term follow-up of 8 years. A total of 427 patients were included in this meta-analysis. Single-dose MMC immediately after TURBT was found to decrease the recurrence rate by a statistically significant 17% (95% confidence interval [CI]: −28%, −8%).
Neither meta-analysis revealed a significant difference in disease progression or survival. Therefore, the benefit of a single instillation of perioperative intravesical MMC is limited to a reduction in the risk of tumor recurrence, predominantly in low-risk patients and primarily in the first 2 years.
Despite gemcitabine’s encouraging efficacy and side-effect profile in certain applications, single perioperative instillations have not been found to reduce recurrence rates and currently should not be used for this purpose.
Induction Therapy, With or Without Maintenance
Summary of guidelines
Although all guidelines recommend some form of adjuvant therapy for intermediate and high-risk bladder cancer, considerable controversy still exists as to the agent of choice for induction therapy (chemotherapy vs immunotherapy), the interval and duration of induction therapy, and the use and timing of maintenance therapy. The varying definitions of risk stratification between the guideline organizations contribute to the controversy.
The International Consultation on Bladder Tumors recommends a single immediate postoperative instillation of chemotherapy followed by further adjuvant intravesical chemotherapy for less than 6 months for intermediate-risk disease; however, the optimal schedule is not well defined.
The AUA recommends an induction course of either MMC or BCG for intermediate-risk disease. Induction courses evaluated by the AUA ranged from a single perioperative dose to weekly instillations for 6 weeks, and no specific induction course was recommended. Despite acknowledging that maintenance therapy with MMC likely reduces the recurrence rate compared with induction MMC only, the AUA identified maintenance therapy as optional and does not define an optimal interval or duration.
For low-grade Ta disease, the NCCN recommends observation, single-dose, or induction intravesical chemotherapy. For high-grade Ta disease, observation or intravesical therapy is recommended. BCG is the preferred intravesical agent; however, chemotherapy is also an acceptable alternative for high-grade Ta. The decision to administer intravesical therapy in patients with Ta pathology is based on factors such as tumor size and number of tumors, which may increase the risk of recurrence and progression. For T1 disease, adjuvant intravesical chemotherapy is only considered as a second-line treatment after BCG failure. Optimal dosing interval and duration for induction and maintenance therapies are not explicitly stated for either risk group.
For low-risk disease, the European Association of Urology (EAU) recommends a single immediate postoperative instillation of chemotherapy. For patients with intermediate risk disease, the EAU recommends the addition of a minimum of 1 year of intravesical chemotherapy or BCG. Intravesical chemotherapy has no role as a first-line therapy in high-risk disease, including CIS.
Evidence
Uniform superiority in terms of recurrence, progression, and/or survival of one particular intravesical agent has yet to be determined for the treatment of bladder cancer. MMC is widely considered to be the most active and effective of the available intravesical chemotherapy agents, but this perception has yet to be directly proven in a clinical trial. Rather, its superiority is inferred from a lack of any trials demonstrating superiority of any other chemotherapy agent when compared with BCG; a meta-analysis of 3 trials (1066 patients) that suggests MMC with maintenance was superior to BCG induction without maintenance for reducing the risk of recurrence.
Historically, adjuvant BCG was found to be more effective in preventing recurrence when compared with thiotepa or doxorubicin. However, subsequent meta-analyses comparing BCG with several different chemotherapeutic agents do not uniformly agree, partly because of inconsistencies in patient populations, treatment schedules, tumor characteristics, and/or institutional variation in outcomes. Recently, randomized controlled trials have proven equal efficacy between BCG and MMC in both short-term and long-term regimens. Notably, both of these studies include high-risk patients. In addition, no evidence exists to suggest superiority of BCG over MMC in reducing tumor progression in direct comparison analysis. But a large meta-analysis of more than 4800 patients demonstrated a 27% reduction in progression with BCG plus maintenance versus MMC.
Two randomized trials compared a 6-week course of intravesical gemcitabine with similar BCG schedules with or without maintenance. In patients with primary Ta or T1 disease, gemcitabine was found to have equivalent efficacy in recurrence-free survival but was inferior to BCG in high-risk groups. Gemcitabine toxicity was consistently less than BCG and could potentially serve as an alternative to patients with high-risk disease who are unable to tolerate BCG. In conclusion, there is no direct evidence to suggest superiority of a single chemotherapeutic agent.
Similarly, controversy exists about the utility of additional intravesical chemotherapy as compared with a single perioperative instillation for patients with intermediate-risk bladder cancer. A meta-analysis of 22 trials published in 1995 reported that maintenance chemotherapy was actually less effective than a single postoperative instillation. Despite no randomized controlled trials directly comparing induction MMC with induction MMC plus maintenance, subsequent meta-analyses contradict this conclusion and suggest that maintenance therapy with MMC significantly enhances recurrence-free survival as compared with induction (either single-dose or short induction course) without maintenance therapy. Notably, the decrease in recurrence rate was not observed until at least 2 years of maintenance therapy. Furthermore, the analysis includes studies that had yet to incorporate modifications of the administration protocol of single-dose MMC that were shown to significantly improve efficacy and have largely been adopted as the standard of care. A more recent randomized trial showed that a group of patients with intermediate- to high-risk bladder cancer undergoing a 6-week induction course with MMC plus monthly maintenance instillations for up to 3 years had significantly higher recurrence-free rates (86.1% [95% CI: 77.9%, 91.4%]) than the group undergoing the same induction course with no maintenance (65.5% [95% CI: 55.9%, 73.5%]). Again, no studies comparing the effect on progression of maintenance MMC versus induction MMC alone are currently available for analysis; therefore, the effect on progression remains unclear.
The optimal dosing interval and duration for induction and maintenance chemotherapy is not well defined. Only 2 of the 6 studies included in the 2007 AUA meta-analysis used identical induction and maintenance schedules. The remaining 4 studies used widely variable schedules. Results from studies, such as Friedrich and colleagues, seem to support longer courses (greater than 12 months) of maintenance therapy and call into question the recommendations that limit maintenance chemotherapy to a maximum of 1 year.
In conclusion, there is no consensus on the optimal maintenance dose, schedule, and duration due to lack of sufficient data, but more recent studies suggest an increased benefit to a more prolonged maintenance course.
Secondary/Salvage Therapies: Recurrent and/or BCG-Refractory
Because of the high risk of progressing to muscle-invasive disease, early radical cystectomy is the recommended treatment of BCG-refractory bladder cancer. However, intravesical chemotherapy may have a role in salvage therapy in certain patient populations who are either unable to tolerate or refuse cystectomy.
BCG failure is defined by the EAU as (1) detection of muscle-invasive tumor during follow-up; (2) high-grade NMIBC present at both 3- and 6-month follow-up; or (3) any worsening of disease under BCG treatment, such as a higher number of recurrences, higher T stage or grade, or appearance of CIS despite an initial response. The International Bladder Cancer Group distinguishes recurrence (reappearance of disease after the completion of therapy) from treatment failure (any recurrence or progression of disease during therapy).
In patients with recurrent disease, the management must take into account previous and current levels of risk as well as previous treatments received. For select low- to intermediate-risk recurrences, treatment with repeat TURBT, single instillation of chemotherapy, and maintenance chemotherapy or BCG with a minimum of 1 year of maintenance may be considered. Guidelines uniformly recommend cystectomy as the first-line treatment of patients with an intermediate to high risk of disease progression and a high risk of recurrence or treatment failure. The following discussion outlines the existing data on the use of different intravesical agents in the BCG refractory setting.
MMC
Initial reports of secondary treatment with MMC for BCG-refractory bladder cancer demonstrate a minimal benefit. Only 19% (4 of 21 patients) who crossed over to receive MMC after BCG failure were disease free after 3 years. A subsequent randomized trial evaluating only recurrent Ta and T1 disease reported more encouraging results with a 61% (33 of 55 patients) disease-free rate at a median follow-up of 3 years. This trial also studied gemcitabine, however, and concluded that MMC was inferior in terms of both efficacy and tolerability; but it should be noted that only a 4-week induction course was used.
Valrubicin
Valrubicin is the only intravesical chemotherapy agent approved by the FDA for BCG-refractory bladder cancer in patients who are not candidates for radical cystectomy. An initial evaluation of 32 patients, 22 of whom had received prior BCG, reported a 42% complete response rate (negative biopsies and cytology) and a 22% partial response rate (negative biopsies but positive cytology), with a mean disease-free interval of 23 months. Five of the 8 patients (64%) who remained disease free at the time of last contact (12.1–38.5 months after treatment) had previously failed treatment that included BCG.
A recent phase II/III trial designed to complement the pivotal phase III trial published in 2000 on valrubicin in BCG-refractory disease was conducted to further investigate the efficacy and tolerability of valrubicin as an alternative to cystectomy in patients with BCG-refractory CIS. Although this earlier trial included only patients who had previously failed at least 2 intravesical therapies (including at least one BCG course), the supportive trial additionally included patients who were BCG intolerant or BCG naïve. Both trials, despite the dissimilarity in the patient population, reported an identical 18% complete response rate. This finding suggests that valrubicin may be equally effective in patients with less intensive prior intravesical courses and is consistent with the post hoc analysis of the 2000 trial, which concluded that the number of prior courses or instillations of intravesical therapy did not affect the response rate.
Gemcitabine
Gemcitabine seems to be an increasingly viable option for salvage intravesical chemotherapy for both recurrent and BCG-refractory disease. Reported treatment regimens studied consisted of a 2000-mg dose in 50 mL saline once a week for 6 weeks, whereas one trial treated patients with two 3-week courses of 2000 mg in 100 mL administered twice weekly. Of note, no maintenance therapy was administered in any of these studies.
Addeo and colleagues reported that a 6-week course of gemcitabine for recurrent Ta and T1 bladder tumors resulted in a 72% disease-free rate after 3 years of follow-up. The reduction in the recurrence rate was significantly higher, whereas toxicity, particularly chemical cystitis, was lower than in the group treated with a 4-week course of MMC. Mohanty and colleagues reported a 60% (21 of 35 patients) tumor-free rate after 18 months in a similar cohort of patients with Ta or T1 BCG-refractory bladder cancer.
Several more observational studies have evaluated the efficacy and tolerability of gemcitabine as an alternative intravesical treatment in patients who are BCG refractory or BCG intolerant. Oosterlink and colleagues reported a 12-month recurrence-free survival rate of 75% (18 of 24 patients) in the intermediate-risk subset (Ta-T1, G1-2, multifocal, >3 cm) and 46% (7 of 16 patients) in the high-risk (T1, G3, multifocal, highly recurrent, CIS) subset as defined by the EAU Working Group on Oncological Urology. The regimen was well tolerated, with less than 20% of patients experiencing local side effects. Dalbagni and colleagues studied 30 patients (14 with CIS, 14 with T1 ± CIS, and 2 with high-grade Ta) who were refractory or intolerant of BCG and refused cystectomy. Fifty percent (15 of 30 patients) had a complete response and 23% (7 of 30 patients) had a partial response. Recurrence-free survival was 21% after 1 year.
One recently published study reported on 20 patients with high-risk NMIBC with BCG-refractory disease who received a standard 6-week induction course and additional maintenance therapy of 2000 mg/50 mL weekly for 3 weeks at 3, 6, and 12 months. After 15 months, 45% (9 of 20 patients) were recurrence free with a mean time to the first recurrence of 3.5 months. In addition, 45% (5 of 11) of the patients who recurred had disease progression.
In summary, recent data suggest that gemcitabine is well tolerated and has activity against BCG-refractory bladder cancer. It may also be considered in cases of higher-risk BCG-refractory bladder cancer in patients who are unable to tolerate BCG or who are not candidates for or refuse radical cystectomy. However, until further data are available, intravesical gemcitabine as a second-line agent for BCG-refractory NMIBC should continue to be considered experimental.
Related posts:
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New Agents for Bacillus Calmette-Guérin–Refractory Bladder Cancer
Side Effects of Perioperative Intravesical Treatment and Treatment Strategies for These Side Effects
The Costs of Non-Muscle Invasive Bladder Cancer
New Imaging Techniques for Non-Muscle Invasive Bladder Cancer
Diagnostically Challenging Cases
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