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.
Who Should Receive Adjuvant Therapy?
One of the first issues to consider is, who should receive adjuvant therapy? 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 carcinoma in situ is offered adjuvant intravesical therapy with bacillus Calmette-Guérin (BCG; Tice strain). The author's Table 1 testifies to the risk of recurrence as it relates to multifocality and rapidity of recurrence. For T1 tumors or larger tumors of higher grade, I may take the patient back to the operating room at 1 month to biopsy the tumor bed in order to ensure that the tumor 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 clinical practice. In the future, fluorescence in situ hybridization (FISH) with centromeric probes and quantitative imunofluorescence studies of urine cytologies may permit the determination of a more malignant phenotype to help stratify patients for adjuvant or earlier aggressive therapy. For now, I rely on clinical and pathologic parameters.
With regard to intravesical chemotherapy, Dr. Grossman cites disturbing data from Lamm et al indicating that intravesical chemotherapeutic agents fail to retard disease progression despite their effectiveness in delaying recurrence. These data have convinced me to use BCG as first-line therapy in all patients who are deemed at risk for progression.
The toxicity of the chemotherapeutic agents is clearly a function of absorption, which depends on molecular weight. Thiotepa(Drug information on thiotepa) has the lower molecular weight and poses more of a problem for myelosuppression, as compared with mitomycin(Drug information on mitomycin) (Mutamycin), which has a molecular weight close to 300. Because of its lower absorption, mitomycin also is less likely to produce urinary reflux, which may occur after transurethral resection of a tumor overlying the orifice. Thus, I tend to use mitomycin as my chemotherapeutic drug of choice for patients who refuse BCG or who may not be suitable candidates for BCG because of toxicity concerns.
Unfortunately, as is the case with BCG, there is no standard schedule for the use of intravesical chemotherapeutic agents. Weintjes et al and Badalament et al only recently applied rigorous pharmacokinetic techniques to the use of intravesical mitomycin, and showed that tissue concentrations and depth of bladder wall penetration were highly dependent on urine flow rate, bladder volume, and urine pH at the time of instillation--conditions that often are not well controlled for in the clinic. It is possible that differences in the optimization of these parameters may explain some of the differences in study outcomes alluded to by the author.
Finally, at our hospital, charges for 20 mg of mitomycin, 50 mg of thiotepa, and 50 mg of BCG are $343, $313, and $118, respectively.
There are ample data, much of which is cited in the article, to suggest that BCG lowers tumor recurrence and progression rates and is likely the most effective agent for treating carcinoma in situ. The mechanism of action of BCG is not clear but seems to be T-cell-mediated; the drug requires fibronectin binding in the bladder for efficacy. Patients receiving an antiplatelet or anticoagulant may not respond as well to BCG therapy.
I treat patients initially with 50 mg of BCG (Tice) once a week for 6 weeks and prescribe another 6 week cycle if the 3-month cystoscopy shows evidence of recurrence. Responders are offered maintenance therapy since the randomized Southwest Oncology Group (SWOG) trial of maintenance vs no maintenance therapy clearly gives the edge to maintenance treatment.
Although the toxicity of BCG is low, its one potential disadvantage compared to chemotherapeutic agents is the very small but real potential for treatment-related mortality due to overwhelming BCG infection. This complication can largely be avoided by not instilling the agent in patients who have blood in the urine at the time of catheter insertion. Patients suspected of having this complication should be treated with triple drug therapy that includes isoniazid(Drug information on isoniazid), rifampin (Rifadin, Rimactane), and cycloserine(Drug information on cycloserine) (Seromycin).
The article indirectly addresses the issue of BCG strain variability and treatment efficacy. The original Dutch study comparing mitomycin with BCG, which showed no difference in efficacy, was criticized on the basis that the RIVM strain was less efficacious. A subsequent trial comparing BCG (Tice), BCG (RIVM), and mitomycin again found no difference in disease-free rates among the groups. Because of the low percentage of patients with carcinoma in situ in this trial, however, a treatment difference might have been harder to detect.
If BCG Fails...
A major question is, what to do if BCG fails? For the patient with carcinoma in situ or a high-grade T1 tumor, there is the therapeutic risk of delaying more definitive therapy and possibly allowing progression of disease while efforts are made to control the tumor with intravesical therapy. The two agents that have shown some therapeutic benefit in this setting are bropiramine and high-dose interferon-alfa (Intron A, Roferon-A). The advantage to bropiramine is that it can be taken orally and treats the entire urothelium. Disadvantages of interferon therapy are the relatively smaller number of responders and higher cost.
As Dr. Grossman discusses, photodynamic therapy offers another alternative but has not come into widespread use probably due to its cost and increased technologic complexity.
New and Future Treatment Strategies
One of the interesting new treatment strategies discussed in the paper is the concept of perioperative chemotherapy to reduce the incidence of recurrence. This approach is based on the notion that tumor cells may implant on the denuded bladder surface and result in recurrence. This concept has been controversial. To my mind, the best evidence supporting its occurrence comes from studies in experimental animals showing that a suspension of tumor cells will implant on a scarified bladder wall as a reproducible model. The data cited in the manuscript support the notion that tumor implantation does occur and that perioperative treatment may prevent it.
The article alludes to the use of megadose vitamins as a chemoprevention strategy. I put all my patients on megadose vitamins for this purpose.
Finally, superficial bladder cancer provides a fertile ground for gene therapy strategies, which, in the future, may be able to target high-risk patients.