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BCG Immunotherapy for Transitional-Cell Carcinoma in Situ of the Bladder

BCG Immunotherapy for Transitional-Cell Carcinoma in Situ of the Bladder

Prior to the advent of BCG immunotherapy, bladder carcinoma in situ often progressed to muscle invasion. Intravesical chemotherapy completely eradicates the disease in 50% of patients, but fewer than 20% remain disease free after 5 years. Complete responses have been reported in 70% or more of BCG treated patients, nearly two-thirds of which are durable. Controversy over the optimal induction and maintenance regimens for BCG immunotherapy remain, but SWOG investigators have demonstrated that complete response rates can be increased from the expected 73% to 87% with just three additional BCG instillations given at 3 months. In complete responders, maintenance BCG using three weekly treatments at 6-month intervals improves long-term complete response rates from 65% to nearly 90%. Caution must be exercised to avoid serious side effects.

Introduction

Unlike in situ carcinomas of other organs, transitional-cell carcinoma in situ (CIS) of the bladder is a highly aggressive, potentially life-threatening malignancy. The recognized lethality of CIS, and the general ineffectiveness of such treatment options as transurethral fulguration, radiation therapy, and intravesical chemotherapy, led to the use of radical cystectomy as the treatment of choice.

In 1990, based on a Southwest Oncology Group (SWOG) comparison of TheraCys (Connaught) bacillus Calmette-Guérin (BCG) vs doxorubicin chemotherapy and six studies of Tice (Organon) BCG, the FDA approved BCG for the treatment of CIS. Continued experience confirms that intravesical BCG immunotherapy is now the initial treatment of choice for patients with CIS and that cystectomy can be safely reserved for the minority of patients who fail to respond completely to intravesical therapy.

This review will summarize BCG immunotherapy for CIS, specifically discussing treatment techniques, results, adverse reactions, and alternative immunotherapeutic strategies. As background to this discussion, a brief overview of transitional-cell CIS will be provided.

Carcinoma in Situ of the Bladder

Carcinoma in situ of the bladder was first described in 1952 by Melicow [1]. The diffuse nature of CIS was demonstrated in a subsequent report of 30 cases in which CIS extended from the renal pelvis to the penile urethra [2]. Carcinoma in situ may occur as a primary disease, in association with papillary or solid tumors, or following tumor resection.

Irritative symptoms are common in patients with primary or concurrent CIS [3]. Hematuria also is a frequent presenting feature. Urinary cytology is positive in more than 90% of patients with CIS and is an important diagnostic procedure because cystoscopic findings and even bladder biopsy may be falsely negative.

Clinical Course

The clinical course of CIS is highly variable, but overall, prior to the advent of BCG immunotherapy, 54% of patients progressed to muscle-invasive disease [4]. Extensive, diffuse disease is considered to pose an increased risk for progression, whereas focal disease may exist for years and has a reported incidence of progression as low as 8% [5].

Focal CIS is the earliest stage in the evolution of invasive bladder cancer, and although its course is often protracted, regression virtually never occurs. Patients with focal disease are optimal candidates for intravesical therapy.

Diffuse, widespread disease is typically associated with irritative symptoms, and up to 34% of patients treated with cystectomy will be found to have unsuspected microinvasive carcinoma [6]. In situ disease extends to the distal ureter in as many as 57% of patients and to the prostatic urethra in as many as 62% [6]. Despite cystectomy, death from metastatic disease occurs in up to 6% of high-risk CIS patients.

Radiation and Systemic Chemotherapy

The results of radiation therapy for CIS are disappointing. In a series of 11 patients treated with external-beam radiation therapy, 10 (91%) died at a mean follow-up of 3.5 years [5]. Similarly, although systemic chemotherapy may temporarily eradicate CIS, local recurrence is a virtual certainty.

Intravesical Chemotherapy

The results of topical intravesical chemotherapy have been much more encouraging, and this treatment modality continues to have a role in the management of CIS. In a review of 448 patients treated with intravesical chemotherapy, the overall complete response rate averaged 48%. Complete responses were reported in 38% of 89 patients treated with thiotepa (Thiotepa), 48% of 212 patients treated with doxorubicin, and 53% of 147 patients treated with mitomycin (Mutamycin) [4].

In most series, fewer than 20% of patients treated with intravesical chemotherapy remain disease free for 5 years or more, but preliminary encouraging results have been reported with the combination of mitomycin and doxorubicin followed by maintenance chemotherapy [7]. In the absence of a clear indication for intravesical chemotherapy (ie, suspected or confirmed residual disease), unnecessary instillations should be avoided, as repeated instillation of thiotepa, doxorubicin, or mitomycin in normal rodent bladders reportedly induces atypia, CIS, and even invasive transitional-cell carcinoma [8].

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