Intravesical Immunotherapy and Recurrence Progression Rates

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Intravesical immunotherapy using BCG was first proposed by Morales et al. [49] in 1976. Conventional prophylactic regimes of 6 weekly instillations, similar to those used for chemotherapy, resulted in complete response rates of 60% to 100% at 1 year, 55% to 75% after 2 years, and mean recurrence-free intervals of 10 to

22.5 months [50]. Although the long-term response rates with BCG are less enduring, the reduction in recurrence appears to be better than the rates achieved using most chemotherapy agents. This superiority is supported by comparative studies of BCG and anthracycline agents, which suggest that BCG has a roughly twofold advantage over Adriamycin and epirubicin (with an overall BCG tumor recurrence rate reduction of approximately 30%) [51]. In contrast, trials comparing MMC directly with BCG have been less consistent in outcome, and passionately debated. Of the published comparative MMC-BCG studies, three have suggested that MMC may have therapeutic equivalence to BCG for patients with low risk stage pTa and lower grade 1 and 2 tumors [52-54]. The inter- and cross-trial inconsistencies (inclusion criteria) and the interpretation of clinical and pathological factors have compounded the problems of analyses. However, in each of these three studies, the BCG schedules used were suboptimal. The balance of evidence still suggests an (small) advantage for BCG immunotherapy. Series reported by the Finnbladder Group [55] and Lundholm et al. [56] showed short-term response rates between 49% and 65% for BCG, compared with 34% and 38% for MMC. The Southwest Oncology Group (SWOG) trial 8795 was terminated early when a significant advantage for high-risk patients was demonstrated for those in the BCG arm [57]. In a recent meta-analysis of published and unpublished MMC-BCG comparative studies, seven of the 11 trials demonstrated superiority for BCG with mean 2-year recurrence rates of 46.4% and 38.6%, respectively [58]. It must be recognized that it has not yet been established whether this advantage is durable. The current American Urological Association (AUA) guidelines (published in 1999) still recommend the use of either MMC or BCG for the prophylaxis of pT1 and high-grade pTa disease [59].

Despite many studies, definitive evidence that BCG immunotherapy improves the overall survival for those with superficial bladder cancer has not been established. However, BCG may affect the rate of disease progression. Some of the largest studies that have attempted to assess the risk of progression are shown in Table 5.3. These studies can be criticized for their inclusion criteria, power (most having an insufficient number of patients to detect small differences in outcome) and ill-defined end points. Accepting these limitations, there now exists a body of evidence that suggests that BCG therapy may delay stage progression or delay the necessity for radical

Table 5.3. Selected studies of disease progression following bacille Calmette-Guérin (BCG) immunotherapy

No. of

Follow-up

Study (year)

Study design

patients

(months)

Progression""

Herr (86)

TUR alone vs. BCG induction

86

72

37% TUR vs. 28% BCG (p = .01)

(1988)

Martinez-

BCG induction vs. thiotepa

176

36

1.5% BCG vs. 3.6% thiotepa vs.

Pineiro

induction and maintenance

7.5% Adriamycin

(87) (1990)

monthly (year) vs. Adriamycin induction and maintenance monthly (year)

Lamm (88)

BCG induction and

131

65

6% BCG vs. 16% Adriamycin

(1991)

maintenance 6 monthly (2 years) vs. Adriamycin induction and monthly maintenance (year)

(not significant)

Pagano (89)

TUR alone vs. BCG induction

126

21

17% TUR vs. 4% BCG (p < .05)

(1991)

and maintenance monthly (year) and quarterly (second year)

Lamm (69)

BCG induction vs. BCG

384

60

30% induction vs. 24%

(2000)

induction and six monthly maintenance (3 years)

maintenance (p = .04)

Millan-

Retrospective analysis of

1529

50

Relative risk of progression

Rodriguez

TUR alone vs. BCG vs.

decreased 0.3 for BCG

(90) (2000)

chemotherapy

Sylvester (60)

Meta-analysis of 24 trials

4863

30

9.8% BCG vs. 13.8% controls

(2002)

(p = .001)

TUR, transurethral resection.

* The wide variation in progression rates reflects the widely different inclusion criteria and definitions of disease progression used in different studies.

TUR, transurethral resection.

* The wide variation in progression rates reflects the widely different inclusion criteria and definitions of disease progression used in different studies.

(cystectomy or radiotherapy) intervention for those with high-risk disease. This view is supported by Sylvester et al.'s [60] metaanalysis of 4863 patients enrolled in 24 trials (see Treatment Options in G3pTl Disease, below) [60].

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