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Emerging Intravesical Therapies for Non Muscle Invasive Urothelial Carcinoma
Marc C. Smaldone
Fellow in Urologic Oncology, Fox Chase Cancer Center
for
Introduction
Although BCG is the reference standard for high risk non-muscle invasive bladder cancer
(NMIBC), up to one third of patients recur, and a substantial number of patients progress to
muscle invasive disease1. In addition, use of BCG is limited due to local or systemic toxicity in
approximately 20% of patients. As a result, use of alternative intravesical agents has sparked
significant interest in patients that are intolerant to BCG or not candidates for cystectomy due
to competing risks.
Immunomodulatory Agents
Interferon α2B (IFN), a host immune response modulator, has been utilized as both
monotherapy and adjunct therapy in BCG refractory patients. The results of early investigations
of IFN as monotherapy to prevent disease recurrence have been disappointing, demonstrating
no benefit or inferior recurrence rates when compared to placebo controls2 or other
intravesical agents (BCG, MMC, MMC/IFN)3. In contrast, results from initial trials investigating
the combination of IFN and BCG have been more promising4. In a multicenter phase II trial, BCG
plus IFN was administered in 536 BCG naïve patients and 467 BCG refractory patients with
NMIBC. With a median follow up of 24 months, recurrence free rates were 59% and 45% in the
BCG naïve and BCG refractory groups respectively; factors associated with tumor recurrence
were tumor size >5cm, prior BCG failure, and tumor multifocality5. Based on contemporary
data, BCG+IFN appears to be a well tolerated alternative for salvage therapy in select patients,
but should not be considered equivalent to radical therapy in appropriate surgical candidates.
Additional immunomodulatory agents that are currently in phase I and II trials include
Bropirimine6, Keyhole-limpet Hemocyanin7, Mistletoe Lection8, and Mycobacterial Cell Wall
Complexes9. Although the majority of these agents have exhibited encouraging response rates
in small trials, further investigation is necessary before they can be recommended in BCG
refractory or intolerant patients.
Chemotherapeutic Agents
In addition to Mitomycin C, which is described in a separate chapter, multiple
chemotherapeutic agents are currently being investigated as primary and secondary therapy
for non-muscle invasive bladder cancer. Early data suggested that the addition of intravesical
chemotherapy to TUR yields a 14% reduction of tumor recurrence but has limited benefit with
respect to disease progression10. However, two recent meta-analyses reported that recurrence
rates following intravesical administration of chemotherapy may be reduced by as much as 70%
when compared to TUR alone11, 12. Current efforts are focused on defining ideal treatment
schedules, optimizing the efficacy of traditionally utilized therapies, and investigating novel
chemotherapeutic agents.
Thiotepa, an alkylating agent that inhibits nucleic acid synthesis by inducing DNA and
RNA cross-linkage, is currently the only chemotherapeutic agent FDA approved for papillary
TCC13. Although initial trials were encouraging, a meta-analysis of nine controlled trials reported
only a modest 12% benefit with thiotepa therapy, and risk of systemic myelosuppression
clinically limits its use10. Gemcitabine, a pyrimidine analog that inhibits cell growth and induces
apoptosis, is currently utilized in systemic chemotherapeutic regimens for both localized and
metastatic urothelial carcinoma14. Due to its high molecular weight (299.66 kDa) systemic
toxicity is low, and a phase II trial reported recurrence rates for intermediate and high risk
disease of 26% and 77% respectively following TUR15. A phase III trial randomizing gemcitabine
or MMC for patients with recurrent disease reported 3 year disease free recurrence rates of
72% and 61% respectively16. While promising as both a primary and adjuvant therapy, further
prospective comparison with contemporary agents are warranted, and clinical trials for BCG
refractory disease are currently accruing.
Doxorubicin, Epirubicin, and Valrubicin are anthracycline antibiotics that function as
topoisomerase inhibitors and prevent protein synthesis. While high prevalence of local effects
has hampered the use of doxorubicin, randomized trials have demonstrated that recurrence
rates following treatment with epirubicin is inferior to BCG17, 18, which has limited its use to
immediate post-operative instillation, BCG refractory disease, and carcinoma in situ. A recent
multi-institutional study investigating the role of valrubicin in 90 patients with refractory
carcinoma in-situ reported a 21% complete response rate and 10% remained disease free over
a ten year follow up period19. Based on this data, valrubicin is currently the only intravesical
agent FDA approved for the treatment of BCG refractory urothelial carcinoma.
Apaziquone, an alkylating agent that results in cell death, is currently in the early phases
of investigation with promising results. In the largest clinical experience to date, Van der
Heigden et al. reported a complete histologic response rate in 67% of 46 patients with NMIBC
at one month, and recurrence free rates at one and two years in complete responders was 57%
and 50%20, 21. Docetaxel and Paclitaxel belong to a class of cytotoxic agents (taxoids) that
induce cell death by inhibiting the polymerization of microtubules. Also used as second line
systemic therapy in metastatic urothelial carcinoma, a recent phase I trial reported a 22%
durable complete response rate in patients with recurrent refractory disease with 61% failed
treatment at a median of 48 months22. A recent update of this series reported one and two
year recurrence free survival rates of 45% and 32% respectively23. Suramin, a polysulphonated
naphthylurea and a potent antagonist of vascular endothelial growth factor, has demonstrated
potent anti-tumor activity in bench studies24 and phase I studies have demonstrated minimal
local or systemic toxicity25. With acceptable side effect profiles and promising efficacy, each of
the above mentioned agents is currently the focus of studies investigating their role as both a
primary agent for non muscle invasive bladder cancer as well as BCG refractory disease.
Increasing Bladder Wall Penetration, Prolonging Residence Time, and Site Directed Targeting
A number of novel chemical and physical approaches have been utilized in an effort to
increase bladder wall penetration and enhance chemotherapeutic efficacy. Chemical methods
of increasing bladder wall permeability include use of dimethyl sulfoxide (DMSO), Chitosan,
Polycarbophil, and Hyaluronidase26. Initially utilized in the treatment of patients with
interstitial cystitis, DMSO has been shown to induce and alter inflammatory tissue responses
and neurotransmission, but concerns still exist regarding systemic absorption when
administered with chemotherapeutic agents27. Permeability enhancers that enhance drug
transport by rearrangement of cellular tight junctions (Chitosan; Polycarbophil) or hydrolization
of the bladder mucosal hyaluronan network (Hyaluronidase) have also been investigated28.
Physical methods to enhance permeability by urothelial disruption include hyperthermia,
electromotive drug administration (EMDA), and photodynamic therapy (PDT). Hyperthermia
has been shown to enhance the efficacy of chemotherapeutic agents to inhibit DNA synthesis
and repair, increase cell membrane permeability, and alter intracellular drug transport, and
initial trials investigating hyperthermia + MMC versus MMC alone following TUR have reported
reduced recurrence rates in the combination therapy group 29. EMDA, which utilizes
iontophoresis to create a potential difference across the bladder wall, has been shown to
increase drug transport through biologic membranes and to enhance the effectiveness of
intravesical agents when compared to passive administration alone. Initial trials investigating
EMDA in combination with MMC have reported encouraging recurrence free intervals when
compared to MMC alone, BCG alone, and when used sequentially in combination with BCG 30.
PDT, which utilizes the photosensitizing agent 5-aminolaevulinic acid (ALA) to selectively
destroy malignant cells following exposure to light, is currently in the early phases of
investigation in patients with NMIBC refractory to traditional intravesical agents31.
Prolonging bladder mucosal exposure to intravesically administered chemotherapy is
challenging due to agent insolubility in the aqueous form and immediate evacuation with
voiding, which has led to interest in the development of sustained-retention delivery
platforms26. Delivery platforms currently being investigated in experimental models that show
exciting potential include bioadhesive microspheres32, hydrogel systems, and liposomes33.
Magnetically targeted carrier (MTC) therapy is another intriguing experimental treatment
modality that utilizes a magnet placed externally on the skin covering a predetermined bladder
site to localize drug containing magnetic particles in tumors and provide prolonged exposure to
higher drug concentrations34. While still in the initial investigatory period, these novel methods
of enhancing the delivery and maximizing the efficacy of existing intravesical agents
demonstrate significant promise and clinical trial results are eagerly anticipated.
The management of patients with NMIBC refractory or intolerable to BCG with or
without maintenance therapy due to local or systemic toxicity constitutes a growing
management challenge, particularly in patients that are not suitable for or refuse cystectomy.
In addition, conflicting definitions of BCG refractory disease and inclusion of Ta in addition to T1
tumors in contemporary trials has resulted in a growing body of data that is difficult to interpret
and apply clinically26. In spite of these limitations, exciting progress is being made in the
optimization, identification, and development of these promising new intravesical therapies.
While promising, it will likely be several more years at minimum to determine if these emerging
treatment strategies will supplant BCG or surgical resection in NMIBC that is refractory to
intravesical therapy.
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Marc C. Smaldone, MD
Fellow in Urologic Oncology, Fox Chase Cancer Center