Originally published as JCO Early Release 10.1200/JCO.2003.08.099 on October 27 2003

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Intravesical Therapy for Superficial Bladder Cancer: Slow but Steady Progress

Deparment of Urology, Mayo Clinic in Scottsdale, Scottsdale, AZ

INTRAVESICAL INSTILLATION of cytotoxic chemotherapy or immunotherapy is used to treat existing tumors, reduce or postpone tumor recurrence, and delay or prevent tumor progression and subsequent patient mortality. Randomized trials have demonstrated that intravesical chemotherapy reduces short-term recurrence of superficial bladder cancer by 15% to 20% and long-term recurrence by approximately 6% but fails to reduce disease progression to invasive tumor or mortality. Intravesical bacillus Calmette-Guerin (BCG) immunotherapy is recognized as the treatment of choice for patients with intermediate- and high-risk superficial bladder cancer, and randomized controlled trials, as well as meta-analysis, confirm that BCG is not only superior to chemotherapy in the prevention of tumor recurrence, but—unlike chemotherapy—does reduce the risk of disease progression when maintenance schedules are used.¹ Previous comparison studies, however, have typically not used optimal chemotherapy (or for that matter, BCG) protocols.

The multicenter randomized trial of mitomycin C (MMC) plus hyperthermia compared with mitomycin without hyperthermia in intermediate and high-risk patients with superficial bladder cancer by Colombo et al² in this issue of the Journal of Clinical Oncology clearly demonstrates that hyperthermia significantly reduces tumor recurrence. The observed reduction in tumor recurrence from 57.5% to 17% cannot be explained by differences in risk factors between groups or other differences in treatment. The design of the study is scientifically sound and ideally controlled to determine whether or not hyperthermia increases the efficacy of mitomycin. The observed difference in recurrence is highly significant and may represent a major improvement in the management of superficial bladder cancer. However, the study was not designed to compare hyperthermia with current optimal intravesical therapy, and therefore we cannot yet evaluate the ultimate impact of hyperthermia on the management of superficial bladder cancer.

To put this apparent advance in perspective, we should look at the other advances in the chemotherapy of superficial bladder cancer, including immediate postoperative instillation and concentration optimization, which seem to provide similar advantages with less cost and possibly less toxicity. Three studies of mitomycin, using multiple instillations given 1 or more weeks after transurethral tumor resection, failed to show that chemotherapy significantly reduced tumor recurrence compared with surgery alone.³ However, when chemotherapy is given immediately following tumor resection, significant reduction in tumor recurrence is seen when compared with surgery alone, but continued instillation of mitomycin does not significantly further reduce recurrence.⁴ A controlled trial of MMC plus BCG compared with MMC given with alternating BCG and interferon alfa-2b found BCG to be superior to BCG plus interferon (P < .001). In this study, the timing of MMC was found to significantly (P < .0002) affect tumor recurrence. Recurrence was in the range of 40% when MMC was given on the day of surgery, compared with 60% to 80% when given 1 or more days later. Although this aspect of the study was not in the initial design, it suggests that instillation within 24 hours provides superior protection from tumor recurrence. Therefore, it appears that tumor recurrence can be reduced by approximately 30% simply by giving chemotherapy close to the time of surgery, possibly by preventing implantation of tumor cells at the time of resection.

The second significant advance is the recognition that it is not drug dose, but drug concentration, that is most important in delivering effective intravesical chemotherapy. With topical chemotherapy, cell kill is proportional to the duration of exposure and concentration, rather than to the dose of the drug.⁵ An ineffective concentration of chemotherapy may be unsuccessful even if given immediately postoperatively. For example, the Medical Research Council randomized comparison of surgery alone to surgery plus immediate Thiotepa at a dose of 30 mg in 60 mL of water, half the usual concentration, resulted in no reduction of recurrence.⁶ In a multicenter randomized trial of 230 intermediate- to high-risk patients in which the concentration of MMC was increased from 20 mg/20 mL to 40 mg/20 mL, patients were dehydrated overnight, ultrasound confirmed complete bladder drainage, and the urine was alkalinized with 1.3g bicarbonate at bedtime, on rising, and at time of instillation, the proportion of patients who were recurrence free increased from 24.6% to 41.0%.⁷

The proportionate reduction in tumor recurrence achieved by the addition of hyperthermia, optimal drug concentration, and early postoperative instillation of chemotherapy, each approach that observed with BCG immunotherapy. Though chemotherapy has not achieved the ultimate goal of reducing disease progression, which has been recently confirmed with maintenance BCG schedules,¹ we remain optimistic that further research, perhaps by combining these advances, will achieve this goal.

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author indicated no potential conflicts of interest.

REFERENCES

1. Sylvester RJ, van der Meijden AP, Lamm DL: Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: A meta-analysis of the published results of randomized clinical trials. J Urol 168:1964–1970, 2002[CrossRef][Medline]

2. Colombo R, Da Pozzo LF, Salonia A, et al: Multicentric study comparing intravesical chemotherapy alone and with local microwave hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma. J Clin Oncol 21:4270–4276, 2003[Abstract/Free Full Text]

3. Lamm DL, Riggs DR, Traynelis CT, et al: Apparent failure of current intravesical chemotherapy prophylaxis to influence the long term course of superficial transitional cell carcinoma of the bladder. J Urol 153:1444–1450, 1995[CrossRef][Medline]

4. Tolley DA, Parmar MK, Grigor KM, et al: The effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: A further report with 7 years of follow up. J Urol 155:1233–1238, 1996[CrossRef][Medline]

5. Walker MC, Master JRW, Parris CN, et al: Intravesical chemtherapy: In vitro studies on the relationship between dose and toxicity. Urol Res 14:137, 1986[Medline]

6. The effect of intravesical thiotepa on the recurrence rate of newly diagnosed superficial bladder cancer: An MRC study—MRC Working Party on Urological Cancer. Br J Urol 57:680–685, 1985[Medline]

7. Au JL, Badalament RA, Wientjes MG, et al: International Mitomycin C Consortium: Methods to improve efficacy of intravesical mitomycin C—Results of a randomized phase III trial. J Natl Cancer Inst 93:597–604, 2001[Abstract/Free Full Text]

8. Kaasinen E, Rintala E, Pere AK, et al: Weekly mitomycin C followed by monthly bacillus Calmette-Guerin or alternating monthly interferon-alpha2B and bacillus Calmette-Guerin for prophylaxis of recurrent papillary superficial bladder carcinoma. J Urol 164:47–52, 2000[Medline]

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