Emerging Intravesical Therapies for Non Muscle Invasive Urothelial Carcinoma

Emerging Intravesical Therapies for Non Muscle Invasive Urothelial Carcinoma

Marc C. Smaldone
Fellow in Urologic Oncology, FoxChaseCancerCenter

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% and32% 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 group29. 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 BCG30. 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.

References

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Marc C. Smaldone, MD
Fellow in Urologic Oncology, FoxChaseCancerCenter