Drs. Baselli and Greenberg have
produced a comprehensive review of the literature concerning current maintenance regimens in the therapy of
superficial transitional cell carcinoma of the bladder, the most effective
intravesical agents, and the relative merits of bacillus Calmette-Guérin (BCG)
This is a very complex and confusing topic, and there are a
multitude of studies that suggest the benefits and potential complications of
each treatment. The majority of these studies include relatively few patients, a
variety of tumor stages and grades, and often insufficient follow-up. The
authors have done a commendable job in their article; however, it is debatable
whether adjuvant intravesical chemotherapy offers any long-term benefit or
alters the natural history of bladder cancer.
Large Studies of Intravesical Chemotherapy
In 1994, Traynelis and Lamm analyzed data from 23 controlled
clinical trials involving more than 4,000 patients and confirmed that the
average net benefit from intravesical chemotherapy, compared to transurethral
resection alone, was only 14% at 1 to 3 years. Furthermore, the therapeutic arms
(thiotepa [Thioplex], doxorubicin, and mitomycin [Mutamycin]) reported a
5-year recurrence rate that equaled or exceeded that of the control arms. These
findings were supported by the Medical Research Council and the European
Organization for Research and Treatment of Cancer (EORTC) when they performed an
analysis of randomized clinical trials for a variety of chemotherapeutic
agents. No clear advantage concerning progression, time to metastases,
progression-free survival, and survival was noted at a median of 7.8 years. Only
the disease-free survival duration was better in the treatment arms.
Finally, the Southwest Oncology Group (SWOG) study comparing
mitomycin to intravesical BCG was closed at the first interim analysis because
the BCG regimen was clearly superior in terms of recurrence rate and
prolongation of time to recurrence. The findings of these very large reviews
would not support Baselli and Greenberg’s views concerning chemotherapy.
Pros and Cons of BCG
This article makes a good case for the benefits of BCG
maintenance therapy. However, it should be emphasized that the role of
maintenance chemotherapy is controversial. Similar results have been reported
from either early single-dose chemotherapy or maintenance chemotherapy
protocols; but no enhancement has been evident when both are combined. Clearly,
the large cost issues underlying these findings need to be considered when
long-term treatment strategies are planned.
As Baselli and Greenberg expound, BCG has a clearly established
role as a maintenance therapy protocol. However, they offer little discussion of
options for patients in whom either induction or maintenance therapy fails.
Clearly, radical cystectomy remains a definite option, yet among those in whom
an initial induction course fails, a further 39% of patients will become disease
free after a second 6-week course. The value of a second induction course for
relapsing patients on maintenance BCG has not been reported.
The tolerability of BCG also deserves further consideration.
Rather than placing an intolerant patient on mitomycin, it would perhaps be
preferable to initiate a reduced-dose or slow-rate regimen of BCG, as has
recently been reported by Bassi et al.
for Bladder Cancer
I do not feel a review of this topic is complete without a
discussion of interferon alfa-2b (Intron A) and the impressive results being
reported for its combination with BCG in high-risk primary and relapsing
patients. This regimen has been developed due to reported evidence of
synergistic activity between these two agentsthe fact that they are
biocompatible and can be instilled simultaneously, and that by combining
interferon alfa-2b with a markedly reduced dose of BCG, toxicity can be reduced
while anticancer efficacy is maintained. This regimen is an effective
alternative for patients at high risk of disease recurrence and/or progression
in whom BCG therapy has previously failed. With this regimen, a 56% disease-free
survival has been reported at 24 months.
Currently, a multiphase 11-registry trial and at least two
randomized trials are ongoing. They will hopefully support these initial results
and establish this regimen as an option for both induction and maintenance
therapy of primary and recurrent superficial bladder cancer.
1. Traynelis CL, Lamm DL: Current status of intravesical therapy
for bladder cancer, in Rous SN (ed): Urology Annual, Volume 8, pp 113-143. New
York, W.W. Norton & Co, 1994.
2. Pawenski A, Sylvester R, Kurth KH, et al: A combined analysis
of European Organization for Research and Treatment of Cancer and the Medical
Research Council randomized clinical trials for the prophylactic treatment of
stage Ta/T1 bladder cancer. J Urol 156:1934-1941, 1996.
3. Lamm DL, Crawford ED, Blumenstein BA: SWOG 8795: A randomized
comparison of bacillus Calmette-Guérin and mitomycin with prophylaxis in stage
Ta/T1 transectional cell carcinoma (abstract). J Urol 149:275, 1993.
4. Catalona WJ, Hudson MA, Gillen DP, et al: Risks and benefits
of repeated courses of intravesical bacillus Calmette-Guérin therapy for
superficial bladder cancer. J Urol 137:220-224, 1987.
5. Bassi P, Spinadin R, Carando R, et al: Modified induction
course: A solution to side effects? Eur Urol 37(suppl 1):31-32, 2000.
6. O’Donnell MA, Downs TN, DeWolf WC, et al: Coadministration
of interferon alpha-2B with low dose BCG is effective in patients with
superficial bladder cancer previously failing BCG alone (abstract #676). J Urol
164(suppl 4): 2000.