When to Use Intravesical Therapies

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Chemotherapy should be immediate after TUR in patients with non-muscle invasive disease.
  
Bladder cancer is projected to be the fourth most common cancer diagnosed in 2007 and the eighth most common cause of cancer-specific death in men, according to the American Cancer Society. Approximately 70% of bladder tumors present as non-muscle invasive (NMI) disease and 10%-20% will progress to muscle invasion.
 
Non-muscle-invasive disease is a diverse spectrum which includes Ta, Tis, and T1 lesions. It is well established that grade is an independent predictor of progression. Low- grade tumors tend to be NMI, with a recurrence rate of 50%-70%; however, progression to muscle invasion is low (less than 5% of cases).

High-grade tumors (including Tis) have a high recurrence rate of approximately 80%, and up to 50% may progress in stage, which places these patients at higher risk for metastasis and death. With high-grade NMI disease, the benefits of bladder preservation with intravesical therapy must not outweigh the potential cure by radical cystectomy if necessary. In this review, we will examine the latest data available regarding intravesical therapy for this disease.
 

Transurethral resection

When discussing institution of intravesical therapy, accurate patient selection is paramount. It has been well established in multiple studies that bladder cancer is often understaged, especially with regards to invasion of muscle (Cancer. 1999;86:1035-1043; J Urol. 1999; 162:74-76; J. Urol. 2002;60:822-824; J Urol. 2005;174:2134-2137).

For this reason, a repeat transurethral resection (TUR) is advocated, either if there is no muscle present in the original resection or if the primary resection reveals T1 disease, even if muscle was present. We wait for four to six weeks because this time interval allows an insight into the biology of the disease; for example, a tumor that recurs as T1 in four weeks is inherently more aggressive than one that does not recur or recurs as a Ta lesion only. The importance of re-TUR is emphasized by a recent report by Herr et al. They reported on early re-staging TUR of a cohort of 352 patients with T1 bladder cancer, finding that 58% had residual tumor (26% NMI), of which 66% had recurred and 35% progressed in stage during five years of follow-up (BJU Int. 2006;97:1194-1198; J Urol. 2007;177:75-79).

Of the 26% with residual T1 tumors at repeat-TUR, 82% progressed to muscle invasion in five years compared with 19% progression with P0 disease on re-staging TUR. These findings emphasize the need to appropriately stage patients with TUR and possibly re-stage TUR to identify patients who would be better managed by early cystectomy.
 

Bacillus Calmette-Guérin

Bacillus Calmette-Guérin (BCG), an attenuated form of Mycobacterium tuberculosus, is currently our most effective agent against NMI bladder cancer. The exact mechanism of action remains to be elucidated, but it is thought that BCG works with the assistance of helper T-cells and cytokines (including TRAIL), causing an immune reaction.

Many years ago, Morales and colleagues established its use as immunotherapy for bladder cancer (J Urol. 1976;116:180-183). Analysis of early trials revealed the unequivocal benefits of decreased recurrence and increased time to recurrence with maintenance prophylactic therapy (Urol.1991;38:507-513).
 
There are many commercial producers of BCG, and while efficacy data for different strains can vary slightly (with no clear “winner”), it has been established that 10 million organisms must be delivered per instillation. BCG is usually provided in a lyophilized format and, after reconstitution in 50 mL of saline for intravesical instillation, is introduced into the bladder via a catheter. Patients are then asked to ‘hold' BCG in their bladder for 60-120 minutes (although some data suggest that as little as 30 minutes might be sufficient).
 
Symptoms with therapy commonly include dysuria, urgency, frequency, and occasionally hematuria. Systemic symptoms are common but are self limiting (e.g., low grade fevers, flu-like symptoms). Serious adverse events, however, may be caused by an intravascular inoculation most commonly caused by traumatic catheterization resulting in severe BCGosis (systemic tuberculosis).

For this reason therapy should be delayed after TUR for a minimum of two to three weeks and traumatic catheterizations should preclude any further instillations at that setting. BCG is most efficacious against carcinoma in situ, with initial treatments responses of 70%-80% (Urol. 1991;38:507-513; J Urol. 2000;163:1124-1129; J Urol. 1995:153:564-572; J Urol. 1982;128:27-30).

Controversy surrounds BCG and its ability to prevent long-term progression of bladder cancer. Evidence is lacking that a single induction dose of BCG slows progression, but more data suggest that maintenance BCG prevents progression.

In a meta-analysis sponsored by the European Organization for Research and Treatment of Cancer (EORTC), Sylvester et al found a reduction of 27% in the odds of progression in patients who received maintenance BCG compared with controls (J Urol. 2002;168:1964-1970).
 
There are various maintenance schedules, but we have adopted the SWOG 6+3 schedule, which entails six weeks induction with additional three weekly instillations every three months for the first year, then every six months for the second year, and a final instillation at year 3.

This schedule (also known as the “Lamm protocol”) was reported by Lamm and demonstrated in complete responders that BCG using three weekly treatments at six-month intervals increases long-term response rates from 65% to nearly 90%.  

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