by Dr. C.H. Weaver M.D. updated 1/2020
Patients with Stage 0 (Ta or Tis) bladder cancer have the earliest stage of bladder cancer that involves only the surface layer of the bladder. Depending upon the appearance of cancer cells under the microscope, Stage 0 bladder cancer is pathologically classified as a non-invasive papillary carcinoma or carcinoma in situ (CIS).
Both non-invasive papillary carcinoma and carcinoma in situ are classified as superficial bladder cancers. Standard treatment of superficial bladder cancer is surgical removal and adjuvant therapy to decrease the risk of recurrent cancer or progression to more invasive disease. (1) Despite standard treatment, the majority of patients with superficial bladder cancer experience recurrence of their cancer. Research is ongoing to evaluate several new approaches for the treatment of superficial or recurrent superficial bladder cancer.
Non-Invasive Papillary Carcinoma
Papillary carcinoma of the bladder is a superficial cancer that grows on the surface of the bladder and can be easily removed with surgery. Standard treatment of papillary carcinoma is a transurethral resection (TUR). A TUR is an operation that is performed for both the diagnosis and management of bladder cancer. During a TUR, a urologist inserts a thin, lighted tube called a cystoscope into the bladder through the urethra to examine the lining of the bladder. The urologist can remove samples of tissue through this tube or can remove some or all of the cancer in the bladder.
Following a TUR, the standard approach for the management of patients with non-invasive papillary carcinoma is surveillance, which means frequent follow-up examinations. During surveillance, patients undergo frequent evaluations performed at regular intervals to detect recurrent or new cancers before they become invasive. Routine surveillance tests include urinary cytology (looking for new cancer cells in the urine) and direct visualization of the lining of the bladder (cystoscopy) typically performed every 3 months. Recurrences can be expected to occur in 50-75% of patients but are usually of the same grade and stage as the original cancer and can be successfully treated by repeat TUR. To learn more about TUR, go to Surgery for Bladder Cancer.
Carcinoma in Situ (CIS)
Carcinoma in situ is a superficial bladder cancer that is confined to the surface layer of the bladder. The cellular growth pattern of CIS differs from that of papillary carcinoma. Furthermore, CIS is more likely than papillary carcinoma to lead to invasive bladder cancer.
All patients with CIS are initially treated with transurethral resection (TUR), biopsy with electrical (cautery) or laser thermal destruction of all visualized cancer. Radical cystectomy (complete removal of the bladder) is used for treatment of extensive multiple superficial cancers or CIS unresponsive to intravesical therapies. To learn more, go to Surgery for Bladder Cancer.
TUR alone is effective in preventing recurrences in approximately 50% of patients with superficial bladder cancer. Failure of treatment is usually due to the appearance of new superficial cancers, which can be retreated with TUR and cautery or laser therapies. Within 15 or 20 years, more than half of surviving patients will have experienced progressive cancer or have developed new cancers, including cancers of the upper urinary tract (ureters and pelvis of the kidney). Approximately 20-30% of these cancers will require treatment with cystectomy.
Since this is a cancer of older individuals, many patients will die of other causes before progression of bladder cancer. However, approximately 25% of patients treated for superficial bladder cancer will ultimately die of bladder cancer. Since the risk of developing invasive bladder cancer never goes away, it is important to have frequent follow-up examinations (cystoscopy) no matter what form of therapy is selected. It is extremely important to detect early progression because there are effective treatments for small invasive bladder cancers.
Stage I Bladder Cancer
Patients with Stage I bladder cancer have a cancer that invades the subepithelial connective tissue, but does not invade the muscle of the bladder and has not spread to lymph nodes. Stage I disease is classified as a “superficial” bladder cancer.
Standard initial treatment for all patients with Stage I bladder cancer is also a transurethral resection (TUR) with electrical (cautery) or laser thermal destruction of all visualized cancer.
Rarely, for more extensive or multiple superficial cancers, a segmental cystectomy (removal of part of the bladder) is necessary. Even more rarely, radical cystectomy (complete removal of the bladder) is used for extensive multiple superficial cancers. To learn more about TUR, go to Surgery for Bladder Cancer.
Surgery (TUR) alone is effective in preventing recurrences in approximately 50% of patients with superficial bladder cancer. Failure of treatment is usually due to the appearance of new superficial cancers, which can be retreated with TUR and cautery or laser therapies. Within 15 or 20 years, more than half of surviving patients will have experienced progressive cancer or, more commonly, will develop new cancers, including cancers of the upper urinary tract (ureters and renal pelvis). Approximately 20-30% of these cancers will require treatment with a cystectomy.
Because this is a cancer of older individuals, many patients will die of other causes before progression of bladder cancer. However, approximately 25% of patients treated for superficial bladder cancer will ultimately die of bladder cancer. Because the risk of developing invasive bladder cancer never goes away, it is important to have frequent follow-up examinations (cystoscopy) no matter what form of therapy is selected. It is extremely important to detect early progression because there are effective treatments for small advanced bladder cancers.
Since recurrences of bladder cancer can occur frequently, it is important to develop strategies to prevent these recurrences. Adjuvant therapy is additional treatment that increases the effectiveness of a primary therapy. The goal of adjuvant therapy is to improve the chance of cure, prevent cancer from recurring or progressing to a worse stage, and/or improve the duration of overall survival. Adjuvant therapy for papillary carcinoma and carcinoma in situ typically consists of chemotherapy and/or immunotherapy delivered directly into the bladder through the urethra (intravesical therapy). Patients with carcinoma in situ are at particular risk not only for superficial cancer recurrences, but also for progression to more aggressive invasive bladder cancers. All patients with this stage of disease should consider adjuvant treatment.
Bladder Instillation of Bacille Calmette-Guérin (BCG)
Bacille Calmette-Guérin (BCG) is one of the most common adjuvant therapies for treatment of superficial bladder cancer, and is commonly used for patients with high-grade papillary cancers or carcinoma in situ. (2) BCG is an immunotherapy that is a weakened form of the bacterium related to bacteria causing tuberculosis. BCG is instilled directly into the bladder through the urethra and exerts its anti-cancer effect by stimulating the body’s immune system to kill cancer cells. The primary side effects of BCG are pain in the bladder, blood in the urine and rarely, autoimmune disorders. Because BCG is a live bacteria, it may occasionally grow and cause an infection that requires antibiotic treatment.
Compared to treatment of superficial bladder cancer with TUR alone, treatment with TUR and intravesical BCG reduces the risk of recurrence and may also reduce the risk of cancer progression. (3) However, even with optimal BCG therapy, many patients with superficial bladder cancer will ultimately have progression to invasive bladder cancer. This indicates the importance of frequent follow-up examinations (cystoscopy) to detect early progression to invasive cancer or new superficial cancers. Early invasive bladder cancer can be treated effectively.
The Food and Drug Administration (FDA) approved Keytruda (pembrolizumab) for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
The approval was based on data from the Keynote-057 clinical trial that enrolled 148 patients of which 96 had BCG-unresponsive high-risk non-muscle invasive bladder cancer. Patients received Keytruda 200mg every 3 weeks. After a median follow-up of 28.0 months, results showed a complete response rate of 41% and an average response duration of 16.2 months, 46% of responding patients experienced a complete response lasting greater than one year. (4)
Bladder Instillation of Chemotherapy
Instillation of chemotherapy drugs (mitomycin, thiotepa, or doxorubicin) into the bladder can reduce the incidence of superficial cancer recurrences, but no single drug has been confirmed to reduce progression of superficial cancer to invasive bladder cancer. This means that multiple small new cancers can be prevented, but progression to a more invasive bladder cancer may occur despite treatment.
The optimal time to administer chemotherapy is immediately after TUR, as the drugs might prevent reseeding of cancer cells that were disrupted with surgery. Mitomycin is probably the preferred drug because it produces few side effects and is not well absorbed into the system, which allows more of the drug to remain in the bladder to treat the cancer. Thiotepa is rapidly absorbed and produces low blood counts. Doxorubicin produces the most local side effects.
Strategies to Improve Treatment
Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new treatment strategies. The development of more effective cancer treatment for bladder cancer requires that new and innovative therapies be evaluated in patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of bladder cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits with their physician.
Photodynamic Therapy: Photodynamic therapy combines a photosensitizer, such as Photofrin®, with red laser light to destroy cancer cells. The photosensitizer is injected into a vein, travels through the bloodstream and is picked up and incorporated into cancer cells. When the laser is directed at the cancer, the photosensitizer in the cancer cell captures the light from the laser, which kills the cell.
Photodynamic therapy was evaluated in 58 patients with resistant superficial bladder cancer (papillary and carcinoma in situ) who could not receive local treatment with chemotherapy or BCG immunotherapy. (5) With a single photodynamic treatment, 84% of patients with residual resistant papillary transitional cell carcinoma and 75% of patients with refractory carcinoma in situ experienced a complete response or disappearance of all cancer. At 4 years from treatment, 59% of the patients responding to treatment were alive and 31 of 34 survived without cancer recurrence. Photodynamic therapy appears to be a safe and effective treatment for refractory carcinoma in situ or recurrent papillary transitional cell carcinoma. Clinical trials are ongoing to determine how best to utilize this form of treatment.
Combining Other Agents with BCG: BCG is the most active treatment modality for superficial bladder cancer. In general, adding chemotherapy to BCG has not been successful. The results of a clinical trial conducted among patients with Stage I bladder cancer, however, suggest that the combination of BCG and electromotive mitomycin C (mitomycin delivered with the assistance of electric current) may be more effective than BCG alone. (6) The addition of other biologic agents to BCG, such as interferon alpha, interleukin-2 and interleukin 12, is also being evaluated.
Enhanced Delivery of Mitomycin: Researchers have theorized that slowing down the production of urine and making urine more alkaline might enhance the results of adjuvant treatment with mitomycin. This is accomplished by restricting fluid intake, administering sodium bicarbonate and emptying the bladder more frequently with catheterization.
In a clinical trial, 230 patients with superficial bladder cancer were either treated with techniques that enhanced the concentration of mitomycin in the urine or with standard mitomycin and the results were then directly compared. Patients who received the enhanced concentrations of mitomycin developed recurrences in an average of 29 months, compared to 14 months for patients who received standard mitomycin treatment. (7)
The researchers concluded that techniques that increase drug exposure in the bladder appear to improved standard treatment with intravesical mitomycin for superficial bladder cancer.
- National Cancer Institute. Bladder Cancer (PDQ®): Treatment. Health Professional Version. Available here
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology.™ Bladder Cance.. © National Comprehensive Cancer Network, Inc. NCCN and NATIONAL COMPREHENSIVE CANCER NETWORK are registered trademarks of National Comprehensive Cancer Network, Inc.
- Dalbagni G. The management of superficial bladder cancer. Nature Clinical Practice Urology. 2007. 4:254-260.
- FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer
- Nseyo UO, DeHaven J, Dougherty TJ et al. Photodynamic therapy (PDT) in the treatment of patients with resistant superficial bladder cancer: a long-term experience. Journal of Clinical Laser Medicine and Surgery. 1998;16:61-8.
- Stasi S, Giannantoni A, Giurioli A, et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomized controlled trial. Lancet Oncology. 2006; 7: 43-51.
- AU JLS, Badalament RA, Wientjes MG et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. Journal of the National Cancer Institute. 2001;93:597-604.