Intravesical Chemotherapy for Non-Muscle Invasive Urothelial Carcinoma
Marc C. Smaldone
Fellow in Urologic Oncology, Fox Chase Cancer Center
for
Introduction
Following prostate, lung, and colon cancer, bladder cancer is the fourth most
common malignancy in men in the Western world1. Predominantly urothelial
carcinomas, more than 70% present as superficial, or non-muscle invasive bladder
cancers (NMIBC)2. Bladder cancer is traditionally diagnosed and initially managed with
transurethral resection (TUR), which facilitates accurate tumor staging and grading and
can provide local disease control. However, NMIBC recurs at rate of 50-80% and has a
14% chance of disease progression following TUR alone3. Since the 1970s, perioperative
instillation of chemotherapy immediately following TUR has been advocated to destroy
residual microscopic tumor cells and to prevent re-implantation. Intravesical therapy
has also been employed in an induction and/or maintenance fashion to provide longterm immuno-stimulation of chemotoxicity in an effort to prevent disease recurrence4.
Bacillus Calmette-Guerin (BCG)
BCG, an attenuated mycobacterium developed as a vaccine for tuberculosis, has
been shown to have significant anti-tumor activity against many different malignancies.
First described by Morales for the treatment of superficial bladder cancer nearly 20
years ago, its use in the treatment of NMIBC has gained widespread acceptance in the
urologic community5. BCG’s action is based on inducing cytokine release in the urine and
bladder wall resulting in the chemo-attraction of granulocyte and mononuclear cells.
Although the exact mechanism of action is debatable, the initial step appears to be the
binding of fibronectin, facilitating attachment to the urothelium and subsequent
incorporation of glycoproteins into the bladder wall. The resulting non-specific immune
stimulation leads to release of macrophages, T lymphocytes, B lymphocytes, natural
killer cells, and various cytokines. Cytokine release (interferon-γ, IL-2, and tumor
necrosis factor) which induces a TH1 mediated response and anti-tumor activity6.
In large meta-analyses, intravesical administration of BCG as induction therapy
for NMIBC has been shown to delay the time to first recurrence7 and may reduce the
risk of disease progression when compared to transurethral resection alone 8. Of
importance, these benefits were only seen in patients receiving maintenance therapy
and there was no effect in overall or disease specific survival. Induction treatment
regimens of BCG typically begin 2 to 4 weeks following resection and are most
commonly administered weekly for a six week interval. However, although response has
been demonstrated with maintenance therapy, there is debate as to optimal dosing
schedule and controversy remains regarding its long-term effects on disease recurrence
and progression9.
The use of BCG can be limited by its side effect profile and subsequent
intolerance that occurs in approximately 20% of patients during maintenance therapy.
BCG toxicity includes local and systemic reactions, ranging from cystitis, hematuria,
bladder contracture, and mild flu like symptoms, to life threatening sepsis. However,
findings of recent large meta-analyses suggest that while the toxicity with BCG is higher
than with intravesical chemotherapy, systemic effects do not predict efficacy10, and
there is no difference in toxicity between induction and maintenance regimens 10, 11.
Some recent trials have demonstrated that a reduced regimen (one-third dose) may be
as effective as standard dosing with fewer side effects12.
Concern regarding BCG related toxicity and disease progression has led to the
study of other intravesical chemotherapeutic agents in the treatment of NMIBC, most
notably Mitomycin C (MMC). However, large meta-analyses examining patients with Ta
and T1 TCC have concluded that BCG is superior to intravesical chemotherapy in
preventing tumor recurrence in patients with high risk (T1, multi-focal, high grade, or
presence of CIS)13, 14 and when maintenance therapy is utilized15. Further review of
these analyses has led to the current AUA consensus that an induction course of BCG
followed by maintenance therapy is recommended for the treatment of high grade Ta or
T1 TCC and CIS4.
Although currently first line therapy for high risk NMIBC, 5 year recurrence rates
are estimated to be 34% in patients receiving BCG maintenance therapy4. BCG’s efficacy
is also hampered by side effects and treatment intolerance, as well as the risks of under
staging or progression to muscle invasive disease. Radical cystoprostatectomy and
urinary diversion is currently the standard of care for muscle invasive TCC, and there is
growing consensus that relative indications for early cystectomy include recurrent
NMIBC refractory to intravesical therapy and naïve T1 disease with high risk features for
tumor progression16. However, the risk of peri-operative complications and morbidity
associated with cystectomy has spawned further interest in the utility of novel
intravesical agents for BCG refractory disease.
Mitomycin C (MMC)
Mitomycin C is a cross-linking chemotherapeutic agent that inhibits DNA
synthesis. Due to its high molecular weight (329 kd), there is reduced risk of
transurothelial absorption resulting in minimal local toxicity even in the immediate post
operative period17. While dosage varies (20-60mg/instillation) the most commonly used
regimen is 40mg in 40mL of saline or sterile water as a one time perioperative dose or
administered weekly for eight weeks followed by monthly instillations for one year4.
Initial efforts investigating the use of MMC as monotherapy for NMIBC following TUR
have demonstrated reduced recurrence rates and an increased recurrence free interval
compared to TUR alone18. Significant attention is currently being directed towards
defining the optimal MMC treatment schedule, and identifying which patients will
benefit from a single perioperative treatment (within 24 hours of TUR) compared to
chronic maintenance therapy.
Chemotherapeutic agents are preferred to BCG in the immediate perioperative
period due to reduced risks of systemic absorption following TUR. In a meta-analysis of
7 randomized trials comparing TUR alone to TUR plus one immediate instillation of
chemotherapy, Sylvester et al. reported a 39% reduction in risk of recurrence (OR 0.61,
p<0.0001), particularly in patients with solitary lesions19. Based on these data, the
current AUA superficial bladder cancer guidelines recommend that a single dose of
intravesical chemotherapy be administered immediately postoperatively (<6hrs) in
patients with small volume solitary tumors when there is no evidence of bladder
perforation4. Currently consensus is lacking regarding effectiveness of perioperative
MMC on decreasing recurrence rates compared to other chemotherapeutic agents.
While immediate post operative instillation has become integrated into
contemporary practice, the role of induction and maintenance MMC therapy is less
clear. A recent meta-analysis reported a reduced incidence of local and systemic
toxicities with MMC induction compared to BCG13, with no significant differences in
recurrence, progression or survival. While the overall analysis, which included low risk
patients, failed to show a difference in risk of recurrence, a subgroup analysis of three
trials including only patients with high risk NMIBC revealed a 31% reduced risk of tumor
recurrence with BCG compared to MMC20. Recent evidence suggests that maintenance
BCG is required to achieve these results15. Early meta-analyses reported that MMC was
effective in reducing short term risk for recurrence with only marginal long term
effects21. However, emerging data suggests that a recurrence free benefit with long
term instillation of MMC may be achievable22. Current efforts to improve the efficacy of
MMC have focused on simple maneuvers designed to maximize tumor exposure to
MMC while limiting systemic absorption and host toxicity. In a recent phase III trial, the
International Mitomycin C Consortium recently reported that treatment with an
optimized MMC protocol (ultrasound guided bladder emptying, voluntary dehydration,
and urine alkalinization with sodium bicarbonate) resulted in increased time to
recurrence and increase 5 year disease free survival compared to a conventional
regimen23.
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Marc C. Smaldone, MD
Fellow in Urologic Oncology, Fox Chase Cancer Center