Stage I Bladder Cancer Treatment
Standard Treatment Options for Stage I Bladder Cancer
Patients with stage I bladder tumors are unlikely to die from bladder cancer, but the tendency for new tumor formation is high. In a series of patients with Ta or T1 tumors who were followed for a minimum of 20 years or until death, the risk of bladder recurrence after initial resection was 80%. Of greater concern than recurrence is the risk of progression to muscle-invasive, locally-advanced, or metastatic bladder cancer. While progression is rare for low-grade tumors, it is common among high-grade cancers.
One series of 125 patients with TaG3 cancers followed for 15 to 20 years reported that 39% progressed to more advanced stage disease, while 26% died of urothelial cancer. In comparison, among 23 patients with TaG1 tumors, none died and only 5% progressed. Risk factors for recurrence and progression include the following:[2-6]
- High-grade disease.
- Presence of carcinoma in situ.
- Tumor larger than 3 cm.
- Multiple tumors.
- History of prior bladder cancer.
Standard treatment options for stage I bladder cancer include the following:
- Transurethral resection (TUR) with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy.
- TUR with fulguration.
- TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by periodic intravesical instillations of bacillus Calmette-Guérin (BCG).
- TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by intravesical chemotherapy.
- Segmental cystectomy (rarely indicated).
- Radical cystectomy (in selected patients with extensive or refractory superficial tumors).
TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy
TUR and fulguration are the most common and conservative forms of management. Careful surveillance of subsequent bladder tumor progression is important. Because most bladder cancers recur after TUR, one immediate intravesical instillation of chemotherapy after TUR is widely used. Numerous randomized, controlled trials have evaluated this practice, and a meta-analysis of seven trials reported that a single intravesical treatment with chemotherapy reduced the odds of recurrence by 39% (odds ratio [OR], 0.61; P< .0001).[7,8]
TUR with fulguration
Staging a bladder cancer via TUR is based on the extent of invasion. To assess whether cancer has invaded the muscle, muscularis propria must be present in the resected tissue. While a repeat TUR is generally considered mandatory for T1 and high-grade noninvasive bladder cancers if no muscularis propria is present in the resected tissue from the first TUR, many experts recommend that a second TUR be routinely performed within 2 to 6 weeks of the first TUR to confirm staging and achieve a more complete resection. The rationale for this derives from numerous findings, including the following:
- The risk of local recurrence after TUR is high.
- Residual cancer is often found when a repeat TUR is performed.
- More-advanced–stage cancer is sometimes found with repeat TUR.
- Patients undergoing radical cystectomy for nonmuscle-invasive bladder cancer are often found to have T2 or greater disease when the cystectomy specimen is examined.
- A substantial number of patients with high-grade nonmuscle-invasive bladder cancer subsequently die from their disease.
Evidence (routine repeat TUR):
- A review of more than 2,400 patients from over 60 different institutions reported a 3-month recurrence rate of roughly 14% to 20% after TUR, while a literature review reported that up to 10% of patients who underwent a second TUR for Ta to T1 cancer were upstaged to T2. The likelihood of being upstaged to T2 is much higher when no muscularis propria is present in the initial TUR tissue.
- One retrospective series of 38 patients with Tis or Ta disease who underwent a second TUR found that nine patients (24%) had lamina propria invasion (T1) and three patients (8%) had muscle invasion (T2).
- A subsequent study from a different institution reported that among 214 patients with Ta to T1 cancers who underwent a second TUR, 27% of Ta and 37% of T1 patients had residual cancer detected.
- A review of other published papers reported that residual tumor was present in 27% to 62% of cases, and muscle-invasive disease was discovered in 1% to 10% of case series with at least 50 subjects.
Repeat TUR has not been shown to reduce relapse rates or prolong survival, but there is a clear rationale for seeking accurate staging information on which to base treatment decisions. Such information may change the definitive management options for patients and identify patients who are more likely to benefit from more aggressive treatment.
TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by periodic intravesical instillations of bacillus Calmette-Guérin (BCG)
Intravesical BCG is the treatment of choice for reducing the risk of cancer progression and is mainly used for cancers with an intermediate or high risk of progressing.[6,13-15] An individual patient meta-analysis of randomized trials that compared intravesical BCG with intravesical mitomycin C (MMC) reported that there was a 32% reduction in risk of recurrence with BCG but only when the BCG treatment included a maintenance phase whereby BCG was given periodically for at least 1 year (typically an induction phase of six weekly treatments followed by three weekly treatments every 3 months). Intravesical chemotherapy is tolerated better than intravesical BCG.[16-20] Although BCG may not prolong overall survival for Tis disease, it appears to afford complete response rates of about 70%, thereby decreasing the need for salvage cystectomy. Studies show that intravesical BCG delays tumor recurrence and tumor progression.[20,21]
Evidence (immediate intravesical chemotherapy after transurethral resection):
- A 2004 meta-analysis of seven randomized controlled trials (1,476 patients with Ta or T1 bladder cancer) compared TUR alone with TUR followed by a single immediate intravesical instillation of chemotherapy.
- The relapse rates were 48% with TUR alone and 37% for TUR plus intravesical chemotherapy (OR, 0.61; P < .0001). The risk of recurrence declined for patients with single (OR, 0.61) or multiple (OR, 0.44) tumors, but 65% of those with multiple tumors relapsed despite intravesical chemotherapy.
- Agents studied included epirubicin, MMC, thiotepa, and pirarubicin.
- A subsequent multicenter, randomized, controlled trial confirmed the reduction in risk of recurrence. A 404-patient study reported a relapse rate of 51% for epirubicin immediately after TUR and a relapse rate of 63% for placebo immediately after TUR (P = .04). However, only small recurrences were prevented in this study, drawing into question the magnitude of benefit.
- Similarly, another multicenter, randomized, controlled trial confirmed the reduction in risk of recurrence. A 305-patient study randomly assigned subjects to an instillation of epirubicin or no further treatment after TUR and reported relapse rates of 62% with epirubicin versus 77% in the control arm (P = .016).
- The hazard ratio for recurrence was 0.56 (P = .002) with epirubicin. However, the main benefit was seen in patients at lower risk of relapse. Among patients at intermediate or high risk of relapse, the relapse rates were 81% with epirubicin versus 85% with no further treatment (P = .35).
Evidence (intravesical BCG with maintenance BCG treatments):
- An individual patient meta-analysis of nine randomized trials (2,820 subjects with Ta or T1 bladder cancer) that compared intravesical BCG with intravesical MMC was published.
- Among trials in which the BCG treatment included a maintenance component, there was a 32% reduction in risk of recurrence (P < .0001) compared with MMC; BCG was associated with a 28% increase in the risk of recurrence when no maintenance BCG was given compared with MMC.
- There were no differences in progression or death.
- A meta-analysis of nine randomized, controlled trials (2,410 subjects) that compared intravesical BCG to MMC was published.
- Progression was seen in 7.67% of the BCG subjects and 9.44% of MMC subjects at a median follow-up of 26 months (P = .08).
- When the analysis was limited to trials in which the BCG arm included a maintenance component, the progression rate was significantly lower in the BCG subjects (OR, 0.66; 95% confidence interval, 0.47–0.94; P = .02).
- A meta-analysis of the published results of nine randomized, controlled trials that compared intravesical BCG with intravesical chemotherapy in 700 patients with carcinoma in situ of the bladder was published.
- With a median follow-up of 3.6 years, 47% of the BCG group had no evidence of disease and 26% of the chemotherapy group had no evidence of disease.
- In this meta-analysis, BCG was superior to MMC at preventing recurrence only when maintenance BCG was part of the treatment.
- A controlled trial evaluated 384 patients randomly assigned to induction intravesical BCG or induction intravesical BCG followed by maintenance intravesical BCG.
- Median recurrence-free survival was 36 months without maintenance BCG and 77 months in the maintenance arm (P < .0001). The risk of disease worsening (progression to T2 or greater disease, use of cystectomy, systemic chemotherapy, or radiation therapy) was greater in the induction arm than in the maintenance arm (P = .04).
- Overall 5-year survival was 78% in the induction-only arm versus 83% in the maintenance arm, but this difference was not statistically significant.
BCG is associated with a risk of significant toxicity, including rare deaths from BCG sepsis. Compared with MMC, BCG produces more local toxicity (44% with BCG vs. 30% with MMC) and systemic side effects (19% with BCG vs. 12% with MMC). Because of concerns about side effects and toxicity, BCG is not generally used for patients with a low risk of progression to more-advanced–stage disease.[6,23]
Evidence (two treatment courses of intravesical BCG):
- Two nonconsecutive 6-week courses with BCG may be necessary to obtain optimal response. Patients with a T1 tumor at the 3-month evaluation after a 6-week course of BCG and patients with Tis that persists after a second 6-week BCG course have a high likelihood of developing muscle-invasive disease and should be considered for cystectomy.[18,25,26]
TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by intravesical chemotherapy
Intravesical therapy with thiotepa, mitomycin, doxorubicin, or BCG is most often used in patients with multiple tumors or recurrent tumors or as a prophylactic measure in high-risk patients after TUR.[27,28]
Evidence (intravesical chemotherapy):
- Three meta-analyses of randomized controlled trials that compared TUR alone with TUR followed by intravesical chemotherapy reported that adjuvant therapy was associated with a statistically significant increase in time to recurrence. No advantage has been shown with respect to survival or prevention of progression to invasive disease or metastases.[29-31]
- One analysis of eight studies with a combined total of 1,609 patients reported that intravesical chemotherapy reduced the risk of relapse at 1 year by 38% and by as much as 70% at 3 years, depending on which drugs were used.
- Another analysis of 11 studies that enrolled a total of 3,703 patients reported a 44% reduction in 1-year recurrence rates.
- An earlier study of 2,535 patients enrolled in six different randomized controlled trials reported a decreased risk of recurrence but not significant benefit with regard to risk of progression to more-advanced–stage disease or survival.
Segmental cystectomy (rarely indicated)
Segmental cystectomy is rarely indicated. It is applicable to only a small minority of patients because of the tendency of bladder carcinoma to involve multiple regions of the bladder mucosa and to occur in areas that cannot be segmentally resected. Moreover, cystectomy (whether segmental or radical) is generally not indicated for patients with T0 bladder cancer.[33,34]
Radical cystectomy in selected patients with extensive or refractory superficial tumors
Radical cystectomy is used in selected patients with extensive or refractory superficial tumor.[35-43] Patients at high risk of progression, typically those with recurrent high-grade tumors with carcinoma in situ after intravesical therapy with BCG, should be considered for radical cystectomy. Other risk factors include multiple tumors and tumors larger than 3 cm.
Certain patients with nonmuscle-invasive bladder cancer face a substantial risk of progression and death from their cancers.
Evidence (radical cystectomy):
- One analysis of 307 patients enrolled in studies of intravesical BCG in the 1980s reported that among 85 patients with T1 recurrence, 60 progressed to at least stage II disease. Five years after T1 recurrence, 71% had progressed and 48% had died of their cancer.
- By comparison, in another cohort of 589 patients treated with BCG between 1992 and 2004, 65 of the 120 patients with T1 recurrence underwent immediate cystectomy. Among all patients with T1 recurrence, 28% progressed to more-advanced–stage disease and 31% died of their cancer. While these data confirm that patients with recurring cancer after intravesical BCG face a substantial risk of dying of their disease, they do not provide strong evidence that immediate cystectomy results in a lower risk of death or progression.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I bladder cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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