Superficial Bladder Cancer: Decreasing the Risk of Recurrence

November 1, 1996

Superficial bladder cancer can be a frustrating disease for both the patient and physician. It has been referred to as a "nuisance disease" because of its propensity for recurrence, necessitating frequent cystoscopies and trips to the operating room for resection of recurrent disease. In addition, however, there looms for the patient and physician the 10% to 15% probability of disease progression, often requiring cystectomy to achieve local control and placing the patient at much greater risk for disease mortality. The challenge is to predict which patients will benefit from adjuvant therapy in order to avoid disease progression and, secondarily, disease recurrence.

Superficial bladder cancer can be a frustrating disease for boththe patient and physician. It has been referred to as a "nuisancedisease" because of its propensity for recurrence, necessitatingfrequent cystoscopies and trips to the operating room for resectionof recurrent disease. In addition, however, there looms for thepatient and physician the 10% to 15% probability of disease progression,often requiring cystectomy to achieve local control and placingthe patient at much greater risk for disease mortality. The challengeis to predict which patients will benefit from adjuvant therapyin order to avoid disease progression and, secondarily, diseaserecurrence.

Who Should Receive Adjuvant Therapy?

One of the first issues to consider is, who should receive adjuvanttherapy? In my practice, a patient whose tumor demonstrates multifocality,rapid recurrence(< 3 to 6 months), lamina propria invasion(T1 disease), large size, high histologic grade, or carcinomain situ is offered adjuvant intravesical therapy with bacillusCalmette-Guérin (BCG; Tice strain). The author's Table1 testifies to the risk of recurrence as it relates to multifocalityand rapidity of recurrence. For T1 tumors or larger tumors ofhigher grade, I may take the patient back to the operating roomat 1 month to biopsy the tumor bed in order to ensure that thetumor is not actually more deeply invasive.

As Dr. Grossman notes, alterations in tumor-suppressor genes (p53,Rb gene) may have prognostic implications for disease progression,but these tests have not been widely incorporated into clinicalpractice. In the future, fluorescence in situ hybridization (FISH)with centromeric probes and quantitative imunofluorescence studiesof urine cytologies may permit the determination of a more malignantphenotype to help stratify patients for adjuvant or earlier aggressivetherapy. For now, I rely on clinical and pathologic parameters.

Intravesical Chemotherapy

With regard to intravesical chemotherapy, Dr. Grossman cites disturbingdata from Lamm et al indicating that intravesical chemotherapeuticagents fail to retard disease progression despite their effectivenessin delaying recurrence. These data have convinced me to use BCGas first-line therapy in all patients who are deemed at risk forprogression.[1]

The toxicity of the chemotherapeutic agents is clearly a functionof absorption, which depends on molecular weight. Thiotepa hasthe lower molecular weight and poses more of a problem for myelosuppression,as compared with mitomycin (Mutamycin), which has a molecularweight close to 300. Because of its lower absorption, mitomycinalso is less likely to produce urinary reflux, which may occurafter transurethral resection of a tumor overlying the orifice.Thus, I tend to use mitomycin as my chemotherapeutic drug of choicefor patients who refuse BCG or who may not be suitable candidatesfor BCG because of toxicity concerns.

Unfortunately, as is the case with BCG, there is no standard schedulefor the use of intravesical chemotherapeutic agents. Weintjeset al and Badalament et al only recently applied rigorous pharmacokinetictechniques to the use of intravesical mitomycin, and showed thattissue concentrations and depth of bladder wall penetration werehighly dependent on urine flow rate, bladder volume, and urinepH at the time of instillation--conditions that often are notwell controlled for in the clinic.[2] It is possible that differencesin the optimization of these parameters may explain some of thedifferences in study outcomes alluded to by the author.

Finally, at our hospital, charges for 20 mg of mitomycin, 50 mgof thiotepa, and 50 mg of BCG are $343, $313, and $118, respectively.

Intravesical BCG

There are ample data, much of which is cited in the article, tosuggest that BCG lowers tumor recurrence and progression ratesand is likely the most effective agent for treating carcinomain situ. The mechanism of action of BCG is not clear but seemsto be T-cell-mediated; the drug requires fibronectin binding inthe bladder for efficacy. Patients receiving an antiplatelet oranticoagulant may not respond as well to BCG therapy.

I treat patients initially with 50 mg of BCG (Tice) once a weekfor 6 weeks and prescribe another 6 week cycle if the 3-monthcystoscopy shows evidence of recurrence. Responders are offeredmaintenance therapy since the randomized Southwest Oncology Group(SWOG) trial of maintenance vs no maintenance therapy clearlygives the edge to maintenance treatment.[3]

Although the toxicity of BCG is low, its one potential disadvantagecompared to chemotherapeutic agents is the very small but realpotential for treatment-related mortality due to overwhelmingBCG infection. This complication can largely be avoided by notinstilling the agent in patients who have blood in the urine atthe time of catheter insertion. Patients suspected of having thiscomplication should be treated with triple drug therapy that includesisoniazid, rifampin (Rifadin, Rimactane), and cycloserine (Seromycin).

The article indirectly addresses the issue of BCG strain variabilityand treatment efficacy. The original Dutch study comparing mitomycinwith BCG, which showed no difference in efficacy, was criticizedon the basis that the RIVM strain was less efficacious. A subsequenttrial comparing BCG (Tice), BCG (RIVM), and mitomycin again foundno difference in disease-free rates among the groups. Becauseof the low percentage of patients with carcinoma in situ in thistrial, however, a treatment difference might have been harderto detect.

If BCG Fails...

A major question is, what to do if BCG fails? For the patientwith carcinoma in situ or a high-grade T1 tumor, there is thetherapeutic risk of delaying more definitive therapy and possiblyallowing progression of disease while efforts are made to controlthe tumor with intravesical therapy. The two agents that haveshown some therapeutic benefit in this setting are bropiramineand high-dose interferon-alfa (Intron A, Roferon-A). The advantageto bropiramine is that it can be taken orally and treats the entireurothelium. Disadvantages of interferon therapy are the relativelysmaller number of responders and higher cost.

As Dr. Grossman discusses, photodynamic therapy offers anotheralternative but has not come into widespread use probably dueto its cost and increased technologic complexity.

New and Future Treatment Strategies

One of the interesting new treatment strategies discussed in thepaper is the concept of perioperative chemotherapy to reduce theincidence of recurrence. This approach is based on the notionthat tumor cells may implant on the denuded bladder surface andresult in recurrence. This concept has been controversial. Tomy mind, the best evidence supporting its occurrence comes fromstudies in experimental animals showing that a suspension of tumorcells will implant on a scarified bladder wall as a reproduciblemodel.[4] The data cited in the manuscript support the notionthat tumor implantation does occur and that perioperative treatmentmay prevent it.

The article alludes to the use of megadose vitamins as a chemopreventionstrategy. I put all my patients on megadose vitamins for thispurpose.

Finally, superficial bladder cancer provides a fertile groundfor gene therapy strategies, which, in the future, may be ableto target high-risk patients.

References:

1. Lamm DL, Riggs DR, Trynelis CL, et al: Apparent failure ofcurrent intravesical chemotherapy prophylaxis to influence thelong term course of superficial transitional cell carcinoma ofthe bladder. J Urol 153:144-1450, 1995.

2. Weintjes MG, Badalament RA, Wang RC, et al: Penetration ofmitomycin C in human bladder. Cancer Res 53(14):3314-3320, 1993.

3. Lamm DL, Crawford ED, Blumenstein B, et al: Maintenance BCGimmunotherapy of superficial bladder cancer: A randomized prospectiveSouthwest Oncology Group study. Proc Am Soc Clin Oncol 11:203,1992.

4. Soloway MS, Masters S: Urothelial susceptability to tumor cellimplantation: Influence of caterization. Cancer 46:1158, 1980.