Case-Based Review

Noninvasive Bladder Cancer: Diagnosis and Management

Journal of Clinical Outcomes Management. 2014 September;21(9)

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When determining treatment and surveillance options for NMIBC patients, not only are the stage and grade determining factors, but future risk of recurrence and progression dictates

treatment options. Bladder cancer patients may be stratified into low-, intermediate-, and high-risk groups ( Table 3 ).

Intravesical Chemotherapy/Immunotherapy

Intravesical therapy is the use of chemotherapeutic or immunotherapeutic substances instilled within the bladder. It is indicated for the treatment of NMIBC but is not the recommended treatment for T2 or greater lesions. The goals of intravesical therapy are to reduce recurrence and progression of resected disease and eradicate carcinoma in situ as well as incompletely resected papillary tumor [42].

Intravesical chemotherapeutic agents include mitomycin C, thiotepa, doxorubicin, valrubicin, epirubicin, and gemcitabine [42]. Mitomycin C is an alkylating agent that acts by inhibiting DNA synthesis. Because of mitomycin C’s relatively high molecular weight, systemic absorption is minimal, although there is a small risk of myelosuppression. Thiotepa is an alkylating agent that cross-links nucleic acids. Doxorubicin, epirubicin, and valrubicin are intercalating agents that inhibit DNA synthesis. Gemcitabine is a deoxycytidine analog that also inhibits DNA synthesis.

Immunotherapy utilizes bacillus Calmette-Guérin (BCG), a live, attenuated strain of Mycobacterium bovis. Though the mechanism of action of BCG is not fully understood, it is known that instillation of BCG stimulates a large immune response [57]. BCG is taken up by antigen-presenting cells as well as urothelial cells and bladder cancer cells, initiating the immune response. Cytokine release in response to BCG is thought to be mediated by macrophages and activated lymphocytes as well as urothelial cells directly [58]. Recent studies have found that interleukin-17 plays an important role in neutrophil recruitment and the generation of the Th1- cell response, which mediates the antitumor effect [59,60]. The innate immune response is also felt to be important in the antitumor effect of BCG, with studies suggesting that BCG is ineffective in the absence of natural killer cell activity and that neutrophils and macrophages are important in the immune response [58,61,62].

Administration of BCG is typically held for at least 2 weeks following TURBT to minimize the risk of sepsis and adverse events. BCG also should not be used in patients who have had traumatic catheterization, recent gross hematuria, or urinary tract infection, in immunocompromised hosts, or in patients with active autoimmune disease, known allergy, or history of BCG sepsis. Adverse events associated with BCG use include sepsis, prostatitis, epididymitis, cystitis, and flu-like symptoms [63].

Interferon alpha-2b is a cytokine that helps modulate the immune response. In cases of refractory bladder cancer that have failed BCG treatment, modulation with interferon alfa-2b therapy has been investigated. In vitro studies show that administration of interferon alfa-2b enhanced the ability of BCG to induce interferon-gamma production, upregulated tumor necrosis factor-α and interleukin-12, and down-regulated interleukin-10, thus favoring the upregulation of the Th1 immune-mediated response [64]. Used in conjunction with BCG in patients who have failed BCG therapy, interferon alfa-2b has been shown to have a 2-year recurrence-free survival rate of up to 45% [65].