Stage 0 Bladder Cancer Treatment
Standard Treatment Options for Stage 0 Bladder Cancer
Patients with stage 0 bladder tumors can be cured by a variety of treatments, even though 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 cancer 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 patients with low-grade tumors, it is common among patients with 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 are 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 0 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 rare, highly selected patients with extensive or refractory superficial high-grade tumors).
Transurethral resection (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 often administered. 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] However, although a single instillation of chemotherapy lowers the relapse rate in patients with multiple tumors, the majority still relapse. Such treatment is thus not sufficient by itself for these patients.
One retrospective series addressed the value of performing a second TUR within 2 to 6 weeks of the first TUR.[Level of evidence: 3iiDiv] A second TUR performed on 38 patients with Tis or Ta disease revealed that nine patients (24%) had lamina propria invasion (T1) and three patients (8%) had muscle invasion (T2).
Such information may change the definitive management options in these individuals. Patients with extensive multifocal recurrent disease and/or other unfavorable prognostic features require more aggressive forms of treatment.
Evidence (TUR with fulguration followed by immediate postoperative instillation of intravesical chemotherapy):
- A 2004 meta-analysis of seven randomized controlled trials (1,476 subjects with stage Ta or stage T1 bladder cancer) compared TUR alone with TUR followed by a single immediate intravesical instillation of chemotherapy.
- The relapse rate for TUR alone was 48% 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, mitomycin C (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 versus no further treatment after TUR and reported relapse rates of 62% with epirubicin and 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).
TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by periodic intravesical instillations of 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.[6,11-13] An individual patient meta-analysis of randomized trials comparing intravesical BCG with intravesical 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 treatment every 3 months). Intravesical chemotherapy is tolerated better than intravesical BCG.[14-18] 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.[18,19]
Intravesical therapy with thiotepa, MMC, 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.[20-22]
Evidence (TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by periodic intravesical instillations of BCG):
- 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.[23-25] No advantage has been shown with respect to survival or prevention of progression to invasive disease or metastases.
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 there was no maintenance BCG administered 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 with MMC was published.
- Progression was observed 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.
- 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 advanced-stage disease.[6,26]
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 T0 bladder cancer (see radical cystectomy below).[28,29]
Radical cystectomy (in rare, highly selected patients with extensive or refractory superficial high-grade tumors)
Radical cystectomy is used in selected patients with extensive or refractory superficial tumor,[2,30,31] based on reports that up to 20% of patients with Tis will die of bladder cancer. However, cystectomy (whether segmental or radical) is generally not indicated for patients with Ta or Tis bladder cancer. 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.[32-35]
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 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.
- Holmäng S, Hedelin H, Anderström C, et al.: The relationship among multiple recurrences, progression and prognosis of patients with stages Ta and T1 transitional cell cancer of the bladder followed for at least 20 years. J Urol 153 (6): 1823-6; discussion 1826-7, 1995. [PUBMED Abstract]
- Herr HW: Tumor progression and survival of patients with high grade, noninvasive papillary (TaG3) bladder tumors: 15-year outcome. J Urol 163 (1): 60-1; discussion 61-2, 2000. [PUBMED Abstract]
- Millán-Rodríguez F, Chéchile-Toniolo G, Salvador-Bayarri J, et al.: Upper urinary tract tumors after primary superficial bladder tumors: prognostic factors and risk groups. J Urol 164 (4): 1183-7, 2000. [PUBMED Abstract]
- Millán-Rodríguez F, Chéchile-Toniolo G, Salvador-Bayarri J, et al.: Multivariate analysis of the prognostic factors of primary superficial bladder cancer. J Urol 163 (1): 73-8, 2000. [PUBMED Abstract]
- Babjuk M, Oosterlinck W, Sylvester R, et al.: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 54 (2): 303-14, 2008. [PUBMED Abstract]
- Babjuk M, Oosterlinck W, Sylvester R, et al.: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol 59 (6): 997-1008, 2011. [PUBMED Abstract]
- Sylvester RJ, Oosterlinck W, van der Meijden AP: A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials. J Urol 171 (6 Pt 1): 2186-90, quiz 2435, 2004. [PUBMED Abstract]
- Gudjónsson S, Adell L, Merdasa F, et al.: Should all patients with non-muscle-invasive bladder cancer receive early intravesical chemotherapy after transurethral resection? The results of a prospective randomised multicentre study. Eur Urol 55 (4): 773-80, 2009. [PUBMED Abstract]
- Herr HW: The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol 162 (1): 74-6, 1999. [PUBMED Abstract]
- Berrum-Svennung I, Granfors T, Jahnson S, et al.: A single instillation of epirubicin after transurethral resection of bladder tumors prevents only small recurrences. J Urol 179 (1): 101-5; discussion 105-6, 2008. [PUBMED Abstract]
- Sylvester RJ, van der Meijden AP, Witjes JA, et al.: Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J Urol 174 (1): 86-91; discussion 91-2, 2005. [PUBMED Abstract]
- Malmström PU, Sylvester RJ, Crawford DE, et al.: An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non-muscle-invasive bladder cancer. Eur Urol 56 (2): 247-56, 2009. [PUBMED Abstract]
- Stenzl A, Cowan NC, De Santis M, et al.: Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines. Eur Urol 59 (6): 1009-18, 2011. [PUBMED Abstract]
- Herr HW, Schwalb DM, Zhang ZF, et al.: Intravesical bacillus Calmette-Guérin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. J Clin Oncol 13 (6): 1404-8, 1995. [PUBMED Abstract]
- Sarosdy MF, Lamm DL: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol 142 (3): 719-22, 1989. [PUBMED Abstract]
- Catalona WJ, Hudson MA, Gillen DP, et al.: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol 137 (2): 220-4, 1987. [PUBMED Abstract]
- De Jager R, Guinan P, Lamm D, et al.: Long-term complete remission in bladder carcinoma in situ with intravesical TICE bacillus Calmette Guerin. Overview analysis of six phase II clinical trials. Urology 38 (6): 507-13, 1991. [PUBMED Abstract]
- Herr HW, Wartinger DD, Fair WR, et al.: Bacillus Calmette-Guerin therapy for superficial bladder cancer: a 10-year followup. J Urol 147 (4): 1020-3, 1992. [PUBMED Abstract]
- Lamm DL, Griffith JG: Intravesical therapy: does it affect the natural history of superficial bladder cancer? Semin Urol 10 (1): 39-44, 1992. [PUBMED Abstract]
- Igawa M, Urakami S, Shirakawa H, et al.: Intravesical instillation of epirubicin: effect on tumour recurrence in patients with dysplastic epithelium after transurethral resection of superficial bladder tumour. Br J Urol 77 (3): 358-62, 1996. [PUBMED Abstract]
- Lamm DL, Blumenstein BA, Crawford ED, et al.: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med 325 (17): 1205-9, 1991. [PUBMED Abstract]
- Soloway MS: The management of superficial bladder cancer. In: Javadpour N, ed.: Principles and Management of Urologic Cancer. 2nd ed. Baltimore, Md: Williams and Wilkins, 1983, pp 446-467.
- Pawinski A, Sylvester R, Kurth KH, et al.: A combined analysis of European Organization for Research and Treatment of Cancer, and Medical Research Council randomized clinical trials for the prophylactic treatment of stage TaT1 bladder cancer. European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council Working Party on Superficial Bladder Cancer. J Urol 156 (6): 1934-40, discussion 1940-1, 1996. [PUBMED Abstract]
- Huncharek M, Geschwind JF, Witherspoon B, et al.: Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of 3703 patients from 11 randomized trials. J Clin Epidemiol 53 (7): 676-80, 2000. [PUBMED Abstract]
- Huncharek M, McGarry R, Kupelnick B: Impact of intravesical chemotherapy on recurrence rate of recurrent superficial transitional cell carcinoma of the bladder: results of a meta-analysis. Anticancer Res 21 (1B): 765-9, 2001 Jan-Feb. [PUBMED Abstract]
- Böhle A, Bock PR: Intravesical bacille Calmette-Guérin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. Urology 63 (4): 682-6; discussion 686-7, 2004. [PUBMED Abstract]
- Lamm DL, Blumenstein BA, Crissman JD, et al.: Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 163 (4): 1124-9, 2000. [PUBMED Abstract]
- Holzbeierlein JM, Lopez-Corona E, Bochner BH, et al.: Partial cystectomy: a contemporary review of the Memorial Sloan-Kettering Cancer Center experience and recommendations for patient selection. J Urol 172 (3): 878-81, 2004. [PUBMED Abstract]
- Fahmy N, Aprikian A, Tanguay S, et al.: Practice patterns and recurrence after partial cystectomy for bladder cancer. World J Urol 28 (4): 419-23, 2010. [PUBMED Abstract]
- Amling CL, Thrasher JB, Frazier HA, et al.: Radical cystectomy for stages Ta, Tis and T1 transitional cell carcinoma of the bladder. J Urol 151 (1): 31-5; discussion 35-6, 1994. [PUBMED Abstract]
- Sylvester RJ, van der Meijden A, Witjes JA, et al.: High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder. Urology 66 (6 Suppl 1): 90-107, 2005. [PUBMED Abstract]
- Madersbacher S, Hochreiter W, Burkhard F, et al.: Radical cystectomy for bladder cancer today--a homogeneous series without neoadjuvant therapy. J Clin Oncol 21 (4): 690-6, 2003. [PUBMED Abstract]
- Stein JP, Dunn MD, Quek ML, et al.: The orthotopic T pouch ileal neobladder: experience with 209 patients. J Urol 172 (2): 584-7, 2004. [PUBMED Abstract]
- Lerner SP, Tangen CM, Sucharew H, et al.: Failure to achieve a complete response to induction BCG therapy is associated with increased risk of disease worsening and death in patients with high risk non-muscle invasive bladder cancer. Urol Oncol 27 (2): 155-9, 2009 Mar-Apr. [PUBMED Abstract]
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