Transurethral resection of all visible tumors remains the ultimate method for the diagnosis and initial management of transitional cell carcinoma of the bladder. In patients with low-grade, low-stage, small-volume disease, careful surveillance with endoscopy and intermittent resection or fulguration alone may be sufficient.
In a previous article, we provided a comprehensive review of the intravesical agents that are useful in the management of superficial transitional cell carcinoma of the bladder. Adjuvant intravesical chemotherapy or immunotherapy is indicated in patients at high risk for tumor recurrence based on multiple or large tumors at initial resection (tumor burden), tumor recurrence(s), high-grade tumors, or papillary tumors associated with carcinoma in situ, as well as carcinoma in situ without papillary transitional cell carcinoma.
It is widely accepted among urologists worldwide that adjuvant intravesical chemotherapy and bacillus Calmette-Guérin (BCG) immunotherapy significantly alter the natural history, as it is currently understood, of superficial transitional cell carcinoma of the bladder. Most urologists agree upon the short-term effectiveness of induction intravesical, adjuvant treatment with chemotherapy or BCG. However, the long-term efficacy of prolonged intravesical treatment, otherwise known as maintenance therapy, is a topic of continued debate.
Previous studies evaluating the prophylactic efficacy of thiotepa(Drug information on thiotepa) (Thioplex), mitomycin(Drug information on mitomycin) (Mutamycin), doxorubicin(Drug information on doxorubicin), epirubicin(Drug information on epirubicin) (Ellence), and BCG have established the superiority of BCG and mitomycin. Consequently, many of the contemporary studies that utilize maintenance schedules focus on the use of BCG and mitomycin.
The literature is replete with clinical studies both in support of and opposition to maintenance therapy. Substantial contributions to the subject of maintenance intravesical therapy have originated from the efforts of the Southwest Oncology Group (SWOG), the Swedish-Norwegian Bladder Cancer Study Group, and the European Organization for Research and Treatment of Cancer.[3-10]
Many urologists agree that potential clinical advantages accompany the use of maintenance strategies. Such regimens are most prudently applied in patients with carcinoma in situ and high-grade papillary transitional cell carcinoma. These patients represent the subgroup at higher risk of either additional recurrence or progression to muscle-invasive disease with traditional induction therapy alone.
Advantages of BCG Therapy
Studies directly comparing the efficacy of BCG to doxorubicin or thiotepa demonstrate a clear advantage for BCG. This advantage is not always so clear, however, when BCG is directly compared to mitomycin, largely due to differences in study design.
Overall, the results of mitomycin and other adjuvant intravesical chemotherapy regimens remain inferior to BCG, especially in patients at high risk of tumor recurrence.[11-14] Various studies have demonstrated the reduction of tumor recurrence from 65% to 30% with the use of BCG.[15-17] Additionally, investigators have been able to show an increase in time to recurrence and time to progression with a consequent reduction in the number of radical cystectomies, as well as cancer-related mortalities. Data from long-term follow-up studies by these investigators show statistically significant reductions in cancer-specific deaths, from 37% in the control group to 12% in the BCG group (P < .01).
Improved Complete Response Rates: BCG is undeniably the best currently available intravesical agent for the management of carcinoma in situ. An analysis by De Jager et al of six phase II clinical trials highlighted a complete remission in 76% of BCG-treated patients. Moreover, cystectomy rates in responders were one-fifth that of nonresponders, and time to cystectomy was better than double in the BCG group.
Studies by Lamm et al,[19,20] Kavoussi et al, Sarosdy and Lamm, Okamura et al, and SWOG have further advanced the notion that improved complete response rates can be achieved by additional intravesical instillations of BCG spread over time and administered at select intervals. These studies, which compared induction-only therapy to various maintenance regimens, reported improvements in complete response rates from approximately 55% to 90%.
Most urologists believe in the efficacy of administering a second 6-week induction course of BCG for recurrence. Yet, outside of study protocols, the actual definition for recurrence remains murky. This definition is critical, as small differences in interpretation may be responsible for the variable results that have beeen noted among investigators in this field.
6 + 3 Protocol: Differences in practice patterns begin to emerge, however, when urologists are asked to consider additional instillations of BCG, either in conjunction with transurethral resection for recurrence or, especially, as maintenance therapy. In 1997, SWOG published data supporting the practice of maintenance therapy. They proposed that patients be treated with a 6-week induction course of BCG followed by three weekly instillations at months 3, 6, 12, 18, 24, 30, and 36the so-called 6 + 3 protocol. This regimen produced complete response rates of 87% in patients with carcinoma in situ and 83% in patients with rapidly recurring Ta/T1 disease.
In 2000, SWOG published data from longer follow-up periods, comparing patients receiving maintenance therapy vs control patients. These results further supported the long-term durability of maintenance (6 + 3) BCG therapy, demonstrating a significant therapeutic advantage in the maintenance arm of the study. Median recurrence-free survival was 35.7 months in the no-maintenance arm and 76.8 months in the maintenance arm (P < .0001). Estimated median time to progression was 111.5 months in the no-maintenance arm and could not be estimated in the maintenance arm.
Studies evaluating urinary cytokine levels[5,24] in patients undergoing initial intravesical BCG therapy have shed light on a possible mechanism behind the success of the 6 + 3 protocol. De Boer et al reported a peak in urinary cytokines during week 6 of induction therapy with BCG. However, immune stimulation was shown to decrease with subsequent instillations, demonstrating a peak in urinary cytokines during week 3, and a continued decline in levels during weeks 4, 5, and 6 with continued intravesical BCG instillation.
Investigators have published results demonstrating no clear clinical advantage with maintenance intravesical doxorubicin or mitomycin chemotherapy.[6,26] However, several published studies have described a clinical advantage with short-term maintenance therapy using mitomycin.[7,8] According to these data, no significant differences were found in time to recurrence, progression, and cancer survival between the BCG 6-week induction group and the mitomycin group undergoing a 6-week induction period plus instillations every month for 5 months.
More recently, however, the Swedish-Norwegian Bladder Cancer Study Group published their results comparing maintenance mitomycin with maintenance BCG. Patients were randomized and treated weekly for 6 weeks every month for year 1, and then every 3 months for year 2. Median follow-up was 5 years (5 to 105 months). They found no difference in progression rates (47 of 250 patients, 19%), with calculated risks of progression of 31% for T1 disease, 23% for carcinoma in situ, 23% for grade 3 disease, and 19% for grade 2 disease. There was, however, a reduction in tumor recurrence and an improved disease-free survival (after crossover) in the BCG-treated group.
One study evaluated the efficacy of monthly mitomycin for 12 months following an 8-week induction course. Tumor recurrence rates were 45% at month 12 and 58% at month 48 in the control group, compared with 29% at month 12 and 44% at month 48 in the maintenance group (Table 1).
We must also take into account those patients who have become refractory to primary therapy with intravesical BCG. These patients may show a secondary response to mitomycin therapy.
Transurethral resection remains the foundation of diagnosis and initial treatment for superficial transitional cell carcinoma. If recurrence develops or pathologic assessment places the patient at a higher risk for recurrence and/or progression to muscle-invasive disease, then adjuvant intravesical maintenance therapy is warranted. The higher the grade, the larger the tumor volume, and the higher the pathologic stage at initial diagnosis, the more likely it is that superficial transitional cell carcinoma will recur.
When choosing an agent for intravesical maintenance therapy after transurethral resection, one must take into consideration the pathologic assessment of the lesion, the number of lesions, patient comorbidities, potential toxicities of the therapy, and the patient’s ability to tolerate a course of maintenance therapy to completion, including sufficient bladder capacity to maximize retention time of the selected intravesical agent. This last point cannot be overstated. The authors of the SWOG study reported only a 16% completion rate among the 243 patients in the maintenance arm who had been scheduled to receive eight maintenance courses during 3 years of treatment.
Currently, evidence is overwhelmingly in favor of BCG as the agent of choice for maintenance intravesical therapy. Moreover, it appears that the 6 + 3 protocol has superior efficacy against recurrence, but more importantly, against tumor progression.
However, for patients unable to tolerate BCG, as well as for those who fail initial therapy, it is encouraging to know that mitomycin is a potentially viable option when given monthly (5 to 48 months) following an induction course (6 to 8 weeks). Larger randomized studies comparing maintenance schemes for BCG and mitomycin are necessary to more accurately assess differences between the two modalities in progression and cancer survival rates.
With the availability of new agents, either alone or in combination, we may be able to offer our patients the possibility of bladder salvage therapy with fewer therapy-limiting side effects. Investigators are continuing to extract potential clinical value from urinary cytokine levels and genetic molecular marker research. This work may lead to more refined maintenance therapy schedules.
One day, we may individualize maintenance intravesical therapy in a supraselective manner by utilizing each patient’s unique "profile." This profile would consist of data on tumor volume, grade, stage, ploidy, p53, p21, Ki-67, and Bax genes, urinary cytokines, and information not yet appreciated. We may achieve improved results with precisely timed intravesical combination cocktails with any number of different induction and maintenance therapy schemes. Until such a time, we will continue to investigate.