Advancing Treatment of
Bladder Cancer
A Continuing Medical Education Activity sponsored by InforMEDical Communications, Inc.
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Managing Non‐Muscle‐Invasive Disease
Non‐muscle‐invasive bladder cancer, or superficial bladder cancer, encompasses a broad spectrum of disease, ranging from the hyperplastic, biologically benign low-grade papillary tumors that rarely progress (Ta) to a potentially life-threatening high-grade T1 lesion, of which 50% will progress and one-third will be lethal. Also typically life-threatening is diffuse CIS. Historically, the presence or absence of muscularis invasion was recognized to signal a substantial risk of surgical failure. Hence, Tis, Ta, and T1 tumors are commonly lumped together as "superficial disease," and T2 through T4 are often combined as "invasive disease." The fact that this grouping ignores that T1 cancers have become "invasive," as well as emerging fundamental insights into tumor biology, has not been sufficient to break the long historical tradition of using this designation. Since at least 70% of all bladder cancers initially present with non‐muscle-invasive disease, the urologist is faced with the dilemma of balancing the risk of recurrent, invasive disease (which occurs despite therapy in at least 15% of patients) with the risk of overtreating patients not destined to have an invasive, threatening cancer45, 46.
Patient Assessment
In contrast to most epithelial cancers, urothelial cancers typically present long before dissemination to nodal or distant sites is clinically apparent. Gross hematuria is the most important clinical sign. The diagnosis of urothelial cancer follows from endoscopic examination coupled with histologic evaluation of material obtained by transurethral biopsy. Unfortunately, cystoscopy can fail to detect the most important indicator of dangerously unstable urothelium: CIS. Areas of CIS can be visually indistinguishable from the surrounding normal bladder. Furthermore, fluorescence cystoscopy (still an investigational technique) demonstrates that conventional cystoscopy can miss not only CIS but small papillary lesions as well. A variety of biomarkers have been used to enhance the detection of bladder cancer. The "gold standard" and oldest such biomarker is urine cytologic testing. Urine cytologic testing can accurately detect occult CIS, and a positive cytologic test result in the absence of a positive cystoscopy result is used as an indication for random bladder biopsies. A variety of newer markers have been developed that generally have higher sensitivity but lower specificity than urine cytologic testing. As with many epithelial cancers, it is likely that DNA-based tests will soon be widely used to find pathognomonic genetic alterations in urine and thus revolutionize the detection and clinical follow-up of bladder cancer. Advances in molecular biology have provided the opportunity to take advantage of genomic and proteomic changes in cancer cells to enhance their detection. Microsatellite analysis is promising and is currently undergoing validation through the NCI Early Detection Research Network47.
In evaluating patients presenting with hematuria, evaluation of the upper urinary tracts is recommended. Even if a bladder tumor is confirmed on initial cystoscopy, excretory or computed tomographic (CT) urography is still appropriate. Synchronous or metachronous tumors of the upper tracts are commonly silent; however, they can also present with flank or groin pain, mimicking urolithiasis. Irritative voiding symptoms, including frequency, dysuria, and dribbling, are important historical features that raise the possibility of extensive CIS or large, infiltrative tumors that may be far more extensive than revealed by the initial cystoscopy. Tumors of the bladder neck or prostatic urethra may present with obstructive symptoms. This is another important historical point, since tumors that involve the ureteral orifices, prostatic urethra, and bladder neck are far less likely to be anatomically confined than are similarly muscle-invasive bladder cancers that are well away from these thinly walled areas in the bladder.
Although some low-grade, papillary tumors will evolve into higher-grade, life-threatening cancers, identifying those individuals is difficult. Likewise, whereas patients with CIS and invasion of the lamina propria have a potentially lethal disease, many of them can be managed with various intravesical therapies. Thus, the clinical problem presented by bladder cancer is largely the problem of accurately identifying patients for cystectomy who will lose an opportunity for cure by means of a less aggressive management strategy. Put another way, we need not only sensitive means of detecting bladder cancer but also tests that identify biologic potential before the full-blown metastatic phenotype is apparent.
Treatment
Transurethral Resection
Transurethral resection with surveillance cystoscopy is sufficient therapy for most low-grade noninvasive (Ta) tumors. Most of these tumors will recur within a 5-year period, but will rarely invade or result in a death from bladder cancer. A single dose of perioperative intravesical chemotherapy will reduce the risk of recurrence of these low-grade papillary tumors and is more effective for index and solitary tumors. No one agent appears to be superior, although thiotepa yields inferior results48. The overall impact of perioperative chemotherapy is modest, with a 10% to 15% reduction in recurrence rates. Findings on subsequent cystoscopies, usually performed at 3-month intervals, assist in determining the clinical course of these tumors49, 50. For patients with a solitary low-grade noninvasive tumor, the interval between cystoscopy can be extended after an interval examination that reveals no signs of disease51. Adjuvant therapy is generally reserved for those patients who have multiple or multifocal recurrence or who demonstrate progression in stage or grade. In this circumstance, intravesical chemotherapy will decrease the probability of recurrence and the number of tumors at a recurrence. Recent data suggest that maintenance mitomycin is more effective at preventing recurrence than a single 6-week course52.
Certain subgroups of patients with non‐muscle-invasive bladder cancer have a higher risk of recurrence and progression and should be considered for intravesical therapy after TUR and perioperative chemotherapy. These high-risk groups include patients with tumors classified as high grade, which are associated with a 45% risk of progression at 3 years and the greatest risk for cancer-related death50, and patients with CIS, which is associated with a greater than 50% rate of progression to muscle-invasive disease46. In addition, irrespective of grade, patients with large lesions (>3 cm), multifocal tumors, evidence of lamina propria invasion, or early recurrence (within 2 years) have been shown to be at increased risk50. Although T1 tumors are considered to be superficial lesions, they invade the lamina propria and are generally of higher grade than Ta lesions. Although aggressive intervention with intravesical therapy in this high-risk group leads to response rates up to 85%53, recurrence rates are at least 50% within the first year and 90% by 5 years. In addition, up to 50% of high-risk lesions will progress to muscle-invasive disease despite intravesical therapy46.
Patients with high-grade or T1 tumors should undergo repeat transurethral resection at 4 weeks to ensure accurate staging and complete eradication of all gross disease. The importance of re-resection cannot be overemphasized, since up to one-third of patients have residual disease, and intravesical therapy does not compensate for inadequate resection. When patients with T1 tumors were randomized to undergo a single resection plus mitomycin therapy versus repeat resection at 2 to 6 weeks plus mitomycin therapy, overall recurrence rates were about 63% in the group who underwent re-resection and 267% in the group that did not (P < .001)54. This finding may be attributable to the understaging that occurs in 10% to 30% of cases with T1 disease even when muscle is present in the specimen and up to 50% when muscle is not present. Patients with residual T1 disease after an adequate initial resection should be cautioned against intravesical therapy and directed toward cystectomy because of the almost certain risk of progression following attempts with intravesical bacille Calmette-Guerin (BCG) therapy55.
Intravesical BCG Therapy
Intravesical BCG is widely accepted as the most effective therapy for patients with high-risk superficial transitional cell carcinoma (TCC; high grade Ta, T1, or CIS) compared with chemotherapy or TUR alone and will delay recurrence and progression, decreasing the need for immediate cystectomy56. Usually, intravesical BCG is administered as a 6-week induction course. There is some controversy regarding whether regular maintenance therapy should be delivered routinely to delay recurrence and progression or whether patients in whom initial induction therapy fails should receive an additional 6-week induction course of BCG rather than maintenance therapy, since the response rate is approximately 40%53. There is now strong evidence that a course of induction therapy followed by a course of maintenance therapy leads to better outcomes than induction therapy alone. In a recent meta-analysis that included 24 trials, 260 (approximately 10%) of 2658 receiving BCG experienced disease progression, compared with 304 (14%) of 2205 in the control groups. This finding represented a 27% reduction in the odds of progression (odds ratio, 0.73; P = .001). On subset analysis, only those receiving maintenance BCG therapy benefited, indicating that without a maintenance regimen, intravesical BCG therapy loses its recurrence advantage over intravesical chemotherapy and does not act as a deterrent to progression57.
Not all maintenance BCG therapy schedules provide the same benefit. Use of monthly or quarterly schedules of BCG after induction therapy are associated with no improvements during a single 6-week induction course. In contrast, the 3-week maintenance course used in the SWOG 8507 study results in a 20% absolute reduction in the recurrence rate that persists for at least 5 years. Furthermore, the "6 + 3" SWOG regimen decreases the number of cancer-related adverse events.
Surveillance After Intravesical Therapy
After intravesical therapy for a high-risk urothelial carcinoma, patients should undergo surveillance with regular cystoscopy, urinary cytology, and upper tract imaging. Although tumor may recur in the renal pelvis, ureters, and urethra, the bladder is the most common site of recurrence after TUR or intravesical therapy. The use of porphyrin-based fluorescence cystoscopy may improve the detection of both CIS and early papillary lesions within the bladder. In a recent study, more than 20% of CIS lesions in the bladder were diagnosed only after hexaminolevulinate fluorescence cystoscopy58. The development of TCC in extravesical sites supports the field change theory of urothelial carcinogenesis.
Voided cytology specimens are commonly evaluated because they are easy to collect without the need for an invasive procedure. Cytologic specimens obtained by bladder barbotage are more sensitive than those obtained from a voided specimen, but their specificity is limited by the presence of clumps of normal transitional cells shed into the urine, which are often mistaken for low-grade papillary tumor cells. Patients with positive urine cytologic test results and no obvious tumor within the bladder (i.e., negative random or directed biopsies) require evaluation of the urethra and upper tracts. The timing of the positive cytologic test results provides a clue as to its origin. The bladder is the most common site of recurrence if the cytologic specimen was obtained within a year of treatment of a bladder tumor. However, the prostatic urethra should be considered as a site for an occult malignancy in men with multifocal tumors, tumor at the bladder neck, or CIS. A positive cytologic test result later in the bladder cancer is more likely to have arisen from the upper tracts.
The risk of upper tract recurrence in patients with superficial bladder cancer is related to the pathologic features of the bladder tumor. Patients with low-grade papillary urothelial carcinoma are at a low risk of developing upper tract recurrence after successful treatment of their bladder tumor, and routine upper tract surveillance in the absence of symptoms is not recommended. However, patients with high-risk superficial disease are at risk for an upper tract recurrence. The risk increases over time and is approximately 15% at 5 years, 25% at 10 years, and 33% after 15 years of follow-up46. These patients should be monitored with cytologic testing and yearly upper tract imaging. Selected tumors can be managed with ureteroscopy or by instilling BCG into the renal pelvis; however, most are treated by nephroureterectomy.
The incidence of recurrence within the prostatic urethra after treatment of a high-risk bladder cancer also increases over time. The late recurrence in this extravesical site may reflect the limited contact time between the urothelium and BCG therapy. Men with a positive cytologic test result and no obvious tumor within the bladder should undergo transurethral biopsy of the prostate at 5 and 7 o'clock at the verumontanum in addition to random bladder biopsies. Prostate recurrence is detected in approximately 10% to 15% of patients within 5 years of treatment of their bladder tumor and in 20% to 40% by 10 years46. Patient outcome depends on the extent of tumor involvement in both the bladder and prostate. Patients with a superficial recurrence within the prostate can be treated with intravesical BCG therapy with an anticipated long-term survival of 80%, whereas patients with invasion of the prostatic stroma have a much worse prognosis and should be treated with systemic chemotherapy and radical cystectomy59.
Treating Patients in Whom BCG Therapy Fails
Despite the approach taken, BCG therapy, which can be defined as 2 courses of BCG vaccine administered either as two 6-week induction courses or as a "6 + 3" treatment course administered as part of the SWOG maintenance regimen53, will eventually fail in more than 40% of patients with high-risk superficial TCC. Cystectomy should be considered since these patients are at high risk of developing muscle-invasive or metastatic disease. Patients who have received a single course of BCG but have persistent T1 bladder cancer should be cautioned against additional BCG or second-line therapy and guided toward a salvage radical cystectomy because they have a real chance of progressing if cystectomy is delayed46. Unfortunately, up to 50% of patients who undergo salvage cystectomy in this scenario experience disease recurrence after surgery, a sobering testimony to the double-edged sword of attempting bladder preservation in the absence of a truly effective intravesical therapy. Thus, effective second-line therapy for superficial bladder cancer is critically needed to avoid early radical cystectomy.
Several investigational approaches are under study as second-line intravesical therapy for refractory superficial bladder cancer (Table 4).
Table 4. Agents in Development
Complete response rates to such treatment range from 20% to 50%, depending on the definition of refractory disease used to select patients for the study. However, prolonged disease-free intervals have not been maintained. One common approach has been to evaluate newer chemotherapeutic agents in this scenario. Intravesical valrubicin and gemcitabine have been tested in phase I and II studies60, 61. Interferon alfa 2b (IFN2b) is well tolerated as monotherapy for superficial bladder cancer and has shown some dose-related clinical efficacy after BCG therapy failure, although the durability of the response is limited. Recently, IFN2b was combined with BCG therapy in an attempt to enhance the cellular immune response to BCG therapy and improve response62. The combination was effective in some cases of BCG-refractory disease, but many with initial responses later experienced relapse and ultimately required cystectomy. Furthermore, patients who received 2 or more courses of BCG were unlikely to achieve a prolonged disease-free state after BCG therapy plus interferon. Another approach has been to combine therapy with mitomycin and BCG therapy. Initial reports indicated no added benefit of combination therapy over either agent alone63-66. However, a recent report in a cohort of high-risk patients with T1 tumors found that the combination of BCG therapy and electromotive mitomycin reduced the recurrence rate by 16%, the progression rate by 12.6%, the risk for death from bladder cancer by 10.6%, and the risk for death from any cause by 10.9% compared with BCG therapy alone. Furthermore, this combination therapy was not associated with increased morbidity67.
Intravesical gene therapy remains a promising new approach for the treatment of non‐muscle-invasive bladder cancer. Hypothetically, therapeutic genes can be introduced into target cells after direct contact with the urothelium after intravesical instillation. The development of intravesical gene therapy in this clinical scenario has been hindered by limitations in gene delivery to the urothelium imposed presumably by the presence of the glycosaminoglycan layer and the loss of the coxackie-adenovirus receptor by high-grade urothelial carcinoma cells, despite the ease at which bladder tumors can be exposed to intravesically instilled vectors. Various approaches to enhance gene transfer are under study, including the administration of the polyamide Syn3, which enhanced adenoviral-mediated gene transfer of the IFN gene in preclinical studies to both urothelial cancer and the normal urothelium, resulting in the regression of established human xenografts68. Furthermore, intravesical instillation of IFN-producing adenovirus produced sustained tissue and urine IFN levels for days and induced marked tumor regression, with limited effect on the normal urothelium. This activity was evident even in cell lines that were resistant to treatment with high levels of IFN alone and seemed to be mediated by caspase-dependent cell death. A multicenter phase I trial of intravesical instillation of an IFN-producing adenovirus is under way at The University of Texas M. D. Anderson Cancer Center and The University of Iowa. These studies follow up on a prior trial that investigated the intravesical instillation of a live vaccinia virus before cystectomy69. It is our hope that one or more of these strategies will fullfill the critical need for the establishment of effective therapy for this disease.