Superficial bladder cancer refers to cancer that remains localized within the outermost (most superficial) layers of the bladder and has not spread to deeper layers. Individuals with superficial bladder cancer are routinely treated with surgical removal of the cancer and adjuvant therapy to decrease the risk of cancer recurrence and prevent progression to more invasive disease. Despite standard treatment, many patients with superficial bladder cancer experience recurrence of their cancer. 

Following the initial removal of the cancer superficial bladder cancer is usually treated with adjuvant intravesical therapy (placement of the drug directly into the bladder). BCG is the standard treatment of superficial bladder cancer utilizing the instillation of BCG into the bladder over a prolonged period of time following transurethral resection. BCG, an immunotherapy agent, is derived from a weakened form of a bacterium related to bacteria that cause tuberculosis. While this therapy is beneficial, recurrences are common and researchers are evaluating ways to reduce the risk of recurrences in patients with superficial bladder cancer.

Vicinium™

Vicinium™, also known as VB4-845, is an antibody-drug conjugate (ADC), developed for the treatment of high-grade non-muscle invasive bladder cancer (NMIBC). Vicinium is comprised of a recombinant fusion protein that targets epithelial cell adhesion molecule (EpCAM) antigens on the surface of tumor cells to deliver a potent protein payload, Pseudomonas Exotoxin A (ETA). EpCAM has been shown to be overexpressed in NMIBC cells with minimal to no EpCAM expression observed on normal bladder cells.

Keytruda for BCG-Unresponsive, Non–Muscle-Invasive Bladder Cancer

Keytruda (pembrolizumab) immunotherapy produces enduring responses in patients with Bacillus Calmette-Guérin (BCG)-unresponsive, non–muscle-invasive bladder cancer, according to study results published in The Lancet Oncology.

About Keytruda

Keytruda (pembrolizumab) is a monoclonal antibody that helps to restore the body’s immune system in fighting cancer. It creates its anti-cancer effects by blocking a specific protein used by cancer cells called PD-L1, to escape an attack by the immune system. Once PD-L1 is blocked, cells of the immune system are able to identify cancer cells as a threat, and initiate an attack to destroy the cancer. Keytruda is approved for the treatment of advanced bladder cancer.

Transurethral resection of bladder tumor followed by intravesical BCG immunotherapy is the current standard of care for patients with high-risk, non–muscle-invasive bladder cancer. Despite high initial response rates, approximately 50% of these patients relapse or become resistant to BCG immunotherapy. BCG resistance is attributed to the potential activation of the programmed death-1 (PD-1).

The phase 2 KEYNOTE-057 clinical trial evaluated the PD-1 inhibitor Keytruda in 96 BCG-unresponsive, non–muscle-invasive bladder cancer. All participants received Keytruda 200 mg intravenously every 3 weeks for up to 24 months or until disease persistence, recurrence, progression, or unacceptable toxicity. The median follow-up of the study was 36.4 months.

By 3 months 41% of the 96 patients had achieved a complete remission. The median duration of remission was 16.2 months and 46% maintained their remission for 12 months or longer. Based on these study results, the authors stated that “Keytruda fulfills an unmet need for efficacious, nonsurgical therapies in BCG-unresponsive carcinoma in situ and provides a clinically meaningful option for patients who are ineligible for or decline radical cystectomy.”

Taxotere

Administration of the chemotherapy agent Taxotere® (docetaxel) directly into the bladder can be an effective treatment option for patients with early bladder cancer that has recurred following standard therapies.

Researchers from Columbia University Medical Center in New York recently conducted a clinical study to evaluate intravesical administration of Taxotere in patients with recurrent superficial bladder cancer. This trial included 18 patients who had received at least one prior intravesical treatment for their disease.

  • 56% of patients had no evidence of cancer following treatment with intravesical Taxotere.
  • Those who experienced a cancer recurrence following intravesical Taxotere did not experience progression of their cancer.
  • No severe side effects were reported.

The researchers concluded that intravesical administration with Taxotere appears to provide an effective treatment alternative for patients with superficial bladder cancer whose cancer has recurred following prior therapies.8

Photodynamic Therapy

Photodynamic therapy, combines a photo-sensitizer 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.

Physicians at West Virginia University evaluated photodynamic therapy in 58 patients with resistant superficial bladder cancer and reported the results in the Journal of Clinical Laser Medicine and Surgery.8

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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 their cancer. Now, over 4 years from treatment, 59% of the patients responding to treatment are alive and 31 of 34 survive without cancer recurrence. Photodynamic therapy was safe and effective treatment for refractory carcinoma in situ or recurrent papillary transitional cell carcinoma.

BCG + Mitomycin

The combination of BCG plus electromotive mitomycin C improves outcomes compared to BCG alone in the treatment of superficial bladder cancer.3

Researchers from Italy conducted a clinical trial to evaluate different intravesical treatments for patients with superficial bladder cancer who had undergone the surgical removal of their cancer. This trial included 211 patients treated with BCG once per week for 6 weeks, or BCG once per week for 2 weeks followed by intravesical electromotive mitomycin C (chemotherapy assisted with electric current to stimulate the passage of the agent through the tissues) once per week for 3 weeks.

At a median follow-up of 88 months, patients treated with BCG plus electromotive mitomycin C had significantly improved outcomes compared to those treated with BCG alone:Cancer-free interval following therapy was 69 months for those treated with BCG/mitomycin C, compared with 21 months for those treated with BCG only-a difference of 4 years.Cancer recurrences occurred in 41.9% of patients who underwent BCG/mitomycin C and in 57.9% of patients who underwent BCG treatment only.Cancer progression occurred in 9.3% of patients treated with BCG/mitomycin C and 21.9% of patients treated with BCG only.Overall mortality was 21.5% in patients treated with BCG/mitomycin C, compared with 32.4% for those treated with BCG only.Mortality caused by bladder cancer occurred in only 5.6% of patients treated with BCG/mitomycin C, compared with 16.2% of patients treated with BCG only.Side effects primarily remained localized to the bladder.The researchers concluded that the combination of BCG and electromotive mitomycin C provides superior results to BCG alone in the treatment of superficial bladder cancer, including mortality caused by bladder cancer. The researchers state that the initial infusion of BCG may allow greater permeation of mitomycin C into the tissues of the bladder.

Mitomycin

In this clinical study, physicians in Sweden randomly assigned 261 patients with superficial bladder cancer to receive treatment with either BCG immunotherapy or mitomycin chemotherapy for 2 years. The 2 treatments were directly compared and the results reported in the April issue of the Journal of Urology.

Whether patients received BCG or mitomycin there were no differences in the risk of progression to more invasive cancer or in overall survival. With a median follow-up of 64 months, the disease-free survival for all patients was 42%. BCG immunotherapy prevented cancer recurrences more than mitomycin especially in patients with carcinoma in situ. Thirty-nine percent of patients who progressed on mitomycin responded to subsequent treatment with BCG and 19% of patients who progressed on BCG responded to treatment with mitomycin.

Although BCG was shown to be superior in preventing superficial cancer recurrences, a large number of patients progressed to more invasive cancers following treatment with either drug. This study points out the major problem with treatment of superficial bladder cancer. Despite current treatment, these patients are at high risk of progressing to more advanced bladder cancer and require frequent follow-up evaluation. Early detection of progression allows for effective treatment with cystectomy or combined radiation chemotherapy and remains the best method to ensure a good outcome until better treatments are developed. 

Interferon

Alfa interferon is a type of biological response modifier (a substance that can improve the body's natural response to disease). It slows the rate of growth and the division of cancer cells, causing them to become sluggish and die. Physicians in Greece performed a clinical trial comparing 3 different doses of alfa interferon to no treatment following transurethral resection (TUR) of cancer for patients with superficial bladder cancer.

Patients who received no treatment other than TUR experienced a recurrence rate of 65%. Patients treated with alfa interferon were less likely to develop recurrent cancer as evidence by recurrence rates of 22-36%. The lowest recurrence rate was observed with the highest dose of alfa interferon. There were no significant side effects of alfa interferon administration at any dose level tested.

These results suggest that alfa interferon is an active anti-cancer therapy that may be useful for the prevention of superficial bladder cancer. Because BCG reduces the risk of recurrent superficial bladder cancer and progression to more invasive cancer, it is currently the standard of care. Alfa interferon will need to be directly compared to BCG in order to evaluate whether it is more or less effective in preventing superficial bladder cancer or progression to more invasive bladder cancer. Alfa interferon could also be evaluated in combination with BCG or other agents as initial therapy or utilized when BCG fails.6

Could One Strain of BCG be Better Than Another?

For non-muscle-invasive bladder cancer, use of the Connaught strain of bacillus Calmette-Guérin (BCG) may be more effective at preventing recurrences than the Tice strain of BCG. BCG is an immunotherapy that is a weakened form of a bacterium that 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. Different strains of BCG are available for use in the treatment of bladder cancer, and it’s possible that these different strains could differ in effectiveness.

To compare two strains of BCG that are commonly used in the United Statesand Europe—the Connaught strain and the Tice strain—researchers in Europe conducted a Phase III clinical trial among 149 patients with early bladder cancer. Half the patients were treated with the Connaught strain and half were treated with the Tice strain.5

Five-year survival without a recurrence was 75 percent among patients treated with the Connaught strain of BCG and 46 percent among patients treated with the Tice strain. Side effects did not vary significantly by type of BCG.

These results suggest that the Connaught strain of BCG may be more effective than the Tice strain for the treatment of non-muscle-invasive bladder cancer.

References

  1. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-930. doi:10.1016/S1470-2045(21)00147-9
  2. Merck’s KEYNOTE-045 studying keytruda in advanced bladder cancer (urothelial cancer) meets Primary Endpoint and stops early. [Press release.] Can be retrieved here
  3. 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.
  4. Journal of Urology, Vol 161, No 4, pp 1124-1127, 1999.
  5. RentschCA, Birkhauser F, Studer UE et al. A randomized phase III study comparing the efficacy of bacillus Calmette-Guérin strain Tice versus Connaught for immunotherapy of non-muscle invasive bladder cancer. Paper presented at: 2012 annual meeting of the American Association for Cancer Research; March 31-April 4, 2012; Chicago,IL. Abstract 2691.
  6. British Journal of Urology, Vol 82, No 6, pp 829-834, 1998.
  7. Journal of Clinical Laser Medicine and Surgery, Vol16, No 1, pp 61-68, 1998.
  8. McKiernan J, Masson P, Murphy A, et al. Phase I Trial of Intravesical Docetaxel in the Management of Superficial Bladder Cancer Refractory to Standard Intravesical Therapy. Journal of Clinical Oncology. 2006; 24: 3075-3080.