BERKELEY, CA (UroToday.com) - Multiple intravesical chemotherapy agents are available for use in conjunction with transurethral resection of a bladder tumor (TURBT) for non-muscle invasive bladder cancer (NMIBC). These agents theoretically act to destroy residual tumor cells left after incomplete resection, as well as free-floating cells that may reimplant into the bladder mucosa after TURBT.
Superior efficacy of a particular chemotherapeutic agent has not been directly proven, however mitomycin C (MMC) is the most commonly studied and frequently used. The presumed superiority of MMC is inferred from indirect comparisons of other cytotoxic agents with bacillus Calmette-Guerin (BCG). A 2007 meta-analysis of 3 trials with greater than 1 000 patients demonstrated a greater reduction in recurrence after induction and maintenance MMC compared to induction BCG without maintenance;[1] whereas, no other chemotherapeutic agents have shown superiority to BCG.
The primary application for intravesical chemotherapy is a single perioperative instillation with the goal of reducing recurrence for lower-risk NMIBC. A single instillation of perioperative intravesical chemotherapy reduces the risk of recurrence by up to 40%,[2] an effect that is typically seen within 2 years of resection.[3] This risk reduction is significant in both solitary and multiple tumors, but appears more efficacious in solitary tumors. In summary, a single perioperative dose of MMC is well tolerated, cost-effective, and recommended to reduce the risk of recurrence in lower-risk NMIBC, though has not been shown to reduce progression or increase survival.[1, 4, 5, 6]
Less well defined is the role of induction and maintenance intravesical chemotherapy in intermediate risk NMIBC. Guidelines uniformly recommend some form of adjuvant intravesical therapy, however considerable variation in the recommendations exists regarding the agent of choice (chemotherapy vs immunotherapy), the interval and duration of induction therapy, and the use, timing, and duration of maintenance therapy.[1, 4, 5, 6] This is largely due to lack of high- quality, head-to-head comparisons of different agents and dosing regimens.
In low-grade Ta and T1 disease, recommended induction chemotherapy courses range from a single perioperative dose to weekly instillations for 6 weeks.[1, 4, 5, 6] No studies have shown additional benefit from this prolonged induction course, nor have they demonstrated increased morbidity.
Concrete recommendations on maintenance MMC are elusive due to the lack of direct comparisons of induction MMC only vs induction plus maintenance MMC. Guidelines generally classify the use of maintenance chemotherapy as optional,[1, 4, 5]however the European Association of Urology (EAU) does recommend a minimum of 1 year of maintenance intravesical chemotherapy in intermediate-risk disease, though the optimal dosing interval and schedule remains undefined.[6] A contemporary meta-analysis[1] and randomized trial[7] suggest that maintenance MMC of at least 2-3 years duration may lower the risk of recurrence compared to induction MMC only. Unfortunately, these studies were not designed as head-to-head comparisons, and none have reported a benefit on progression or survival. The additional cost, inconvenience, and potential morbidity of prolonged maintenance therapy must be weighed against these largely unproven benefits.
BCG is the preferred intravesical agent in high-grade bladder tumors and CIS due to the 27% reduction in progression compared to MMC. Intravesical chemotherapy is not considered first-line treatment in these patients.
For patients with intermediate-high risk NMIBC, particularly those patients who failed BCG or had recurrence after BCG, early radical cystectomy is the treatment of choice. For those patients either refusing cystectomy or who are not surgical candidates, MMC has limited benefit as a secondary intravesical therapy after BCG failure, with disease-free rates less than 20% after 3 years.[8] Valrubicin, the only FDA-approved intravesical chemotherapy for BCG-refractory bladder cancer, also has limited benefit, with a complete response rate of only 18%.[9, 10] Intravesical gemcitabine has recently shown promise in BCG-refractory NMIBC, including high-risk disease, for those patients unable to tolerate or who refuse cystectomy. However, more data is required before adopting this as a routine second-line therapy.
Ongoing clinical trials aim to clarify a number of the aforementioned controversies, as well as to identify novel agents, applications, and modes of delivery to improve outcomes. A direct comparison of optimal dosing regimens of induction plus maintenance MMC vs induction plus maintenance BCG on tumor recurrence is currently recruiting. Methods for optimizing delivery of MMC, including electromotive instillation, and combined bladder wall hyperthermia, are currently being evaluated. Additional applications of gemcitabine are being studied, including as primary treatment for low-risk disease, in addition to providing more robust evidence on the efficacy of induction and maintenance therapy for BCG-refractory NMIBC. A combined phase I and II trial is accruing to evaluate the efficacy of a nanoparticle albumin-bound formulation of paclitaxel for BCG-refractory disease. Finally, results of two identical multi-center phase III trials of apaziquone, a promising new chemical analogue of MMC, are pending.
In summary, a single dose of perioperative intravesical chemotherapy is a well-established, effective, well-tolerated strategy for reducing the risk of recurrence, but not progression, in lower-risk NMIBC. In high-grade, higher-risk disease, intravesical BCG is superior to chemotherapy based on its ability to reduce progression. The area of uncertainty lies in the intermediate-risk patient, as the lack of direct comparisons of various induction and maintenance courses impedes definitive recommendations on optimal treatment intervals and duration. Additionally, further investigation of alternative roles for existing drugs and novel agents for BCG-refractory disease is desperately needed given the dearth of effective options in this patient population.
References:
- Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages ta, T1, and tis): 2007 update. J Urol. 2007;178(6):2314-2330.
- Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage ta T1 bladder cancer: A meta-analysis of published results of randomized clinical trials. J Urol. 2004;171(6 Pt 1):2186-90.
- Solsona E, Iborra I, Ricos JV, Monros JL, Casanova J, Dumont R. Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: Short and long-term followup. J Urol. 1999;161(4):1120-1123.
- Soloway MS. International consultation on bladder tumours. Urology. 2005;66(1).
- National comprehensive cancer network: Clinical practice guidelines in oncology: Bladder cancer including upper tract tumors and urothelial carcinoma of the prostate. Available at www.nccn.org. Updated 2010.
- Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol. 2011;59(6):997-1008.
- Friedrich MG, Pichlmeier U, Schwaibold H, Conrad S, Huland H. Long-term intravesical adjuvant chemotherapy further reduces recurrence rate compared with short-term intravesical chemotherapy and short-term therapy with bacillus calmette-guerin (BCG) in patients with non-muscle-invasive bladder carcinoma. Eur Urol. 2007;52(4):1123-1129.
- Malmstrom PU, Wijkstrom H, Lundholm C, Wester K, Busch C, Norlen BJ. 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma.swedish-norwegian bladder cancer study group. J Urol. 1999;161(4):1124-1127.
- Steinberg GD, Smith ND, Ryder K, Strangman NM, Slater SJ. Factors affecting valrubicin response in patients with bacillus calmette-guerin-refractory bladder carcinoma in situ. Postgrad Med. 2011;123(3):28-34.
- Dinney CP, Greenberg RE, Steinberg GD. Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus calmette-guerin. Urol Oncol. 2012.
Written by:
David C. Johnson, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Urology, University of North Carolina, 2113 Physicians Office Building, CB 7235, 170 Manning Drive, Chapel Hill, NC 27599-7235 USA
Perioperative chemotherapy: When to use it, what to use, and why - Abstract
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