Thiotepa is an alkylating agent that works through cross-linkage of DNA, RNA, and proteins. Thiotepa is cytotoxic but unfortunately has a low molecular weight (189 kDa) which allows for systemic absorption and myelosuppressive side effects in up to 50% of patients (JAMA. 1980;244: 2065-2067).
Gemcitabine is a nucleoside analogue that inhibits DNA synthesis and results in apoptosis. Even though the molecular weight is relatively low, five independent phase I/II studies using intravesical gemcitabine demonstrated low systemic levels. Studies giving intravesical doses of 500-2,000 mg have shown a complete response rate between 23%-56% (J Clin Oncol. 2006;24:2729-2734; J Clin Oncol. 2003;21:697-703; Eur Urol. 2004;45:182-186; BJU Int. 2004;93:491-494; J Urol. 2004;172:485-488). While initial reports showed promise, with longer term follow up, Dalbagni et al were unable to demonstrate long-term efficacy with this agent because the one-year recurrence free rates were only 21% in complete responders.
Keyhole-limpet hemocyanin (KLH), a respiratory pigment of the sea mollusk Megathura crenulata, is a non-specific immunomodulator that stimulates both humoral and T-cell mediated immune responses (Int Arch Allergy Appl Immunol. 1974;47:155-160; Br J Urol. 1995;76:702-707). Lamm et al reported a multicenter phase I/II trial using intravesical KLH and demonstrated complete responses in 58% of patients with CIS without papillary disease, followed by responses in 50% with CIS with papillary disease, and 33% in those with residual papillary disease (Eur Urol. 2000;37 [Suppl 3]:41-44). Data suggested that KLH is more effective than MMC at preventing recurrence. The risk of recurrence with KLH (mean follow-up 20 months) was 14% vs. 39% for MMC (mean follow-up 18 months). With its minimal adverse effects, KLH has great potential for combination therapy with BCG (J Urol. 1988;139:723-726).
Another potentially useful agent is mycobacterial cell-wall-DNA complexes (MCC), which, in theory, maintain the antigenicity of the cell wall. This results in the immunomodulatory impact that yields the “BCG effect” without the pathogenic potential on the intact organism. In an early trial in which MCC was administered to patients with CIS, the combined complete and partial response rates were 56% at 12 months with 31% classified as responders even at four years (J Urol. 2001;166:1633-1637). Large multicenter trials are currently underway evaluating a novel suspension form of MCC in both BCG failures as well as in a phase III fashion, compared with BCG as upfront therapy in BCG naïve patients.
A critical analysis of the literature to date suggests that patients with bladder cancer should undergo a complete TUR. In patients suspected of having NMI disease, TUR should be followed by immediate postoperative instillation of intravesical chemotherapy, preferably within six hours, unless there are contraindications (e.g., bladder perforation). For patients with high-grade T1 disease, a re-look and re-TUR at four to six weeks should be performed before bladder salvage with intravesical therapy or early cystectomy is considered.
For patients who decide on bladder-sparing treatment, a six-week induction course of BCG should be followed by maintenance (we use the 6+3 SWOG protocol) because evidence suggests that only those who receive maintenance derive any protection from progression of disease. Patients who fail BCG early (i.e., within 12-24 months) or who never achieve a disease-free state (non-responders) should be counseled on radical cystectomy. No alternate therapy exists that can be considered safe and effective, although several are being studied.
Drs. Gaston and Kamat are affiliated with the University of Texas M.D. Anderson Cancer Center in Houston. Dr.Gaston is a fellow in urologic oncology. Dr. Kamat is assistant professor and director of the fellowship program in urology.