Dr. Grossman's article provides a well-organized review of the
literature on the treatment of superficial bladder cancer. At
the time of diagnosis, approximately 80% of patients with bladder
cancer have superficial tumors (limited to the urothelial lining
of the bladder or the underlying lamina propria). In such patients,
the risk of distant disease is low, and the natural history of
bladder cancer is based on two separate, but related processes:
tumor recurrence and progression to a higher stage of disease.
The risk factors for tumor recurrence in patients with newly diagnosed
superficial bladder cancer are summarized in Table 1 of the article.
These factors must be taken into consideration when deciding which
patients to treat with adjunctive therapy after transurethral
Causes of Tumor Recurrence
Bladder tumor recurrence may be due to regrowth of previously
resected cancers, growth of new cancers at remote sites in the
bladder, or implantation and subsequent proliferation of cells
released into the bladder at the time of endoscopic treatment
of the original tumor. Evidence exists to support all three mechanisms,
and it is likely that all play a role in cancer recurrence to
Various agents and treatment regimens have been evaluated for
their ability to decrease tumor recurrence after transurethral
resection, and Dr. Grossman concisely summarizes the literature
on this subject. Single-dose, perioperative intravesical chemotherapy
is an attempt to decrease tumor recurrence caused by tumor cell
implantation at the time of transurethral resection. It has previously
been demonstrated that bladder mucosa injured by electrocautery
is very likely to produce tumor implants, and that the site of
urothelial injury represents a preferential site for tumor cell
implantation.[1,2] We agree with Dr. Grossman that perioperative
intravesical chemotherapy may be a very efficacious, cost-effective
way of delivering adjunctive treatment to patients at high risk
for bladder tumor recurrence.
Decreasing the Risk of Tumor Progression
A second factor to consider when deciding how to manage a patient
with superficial bladder cancer following transurethral resection
is the risk of tumor progression. Most Ta tumors (noninvasive
papillary) will not progress to muscle-invasive disease. However,
as stated in the article, the risk of progression for patients
with stage T1 tumors (lamina propria invasion) is 30% at 3 years.
This risk may be higher for high-grade lesions and those associated
with carcinoma in situ.
Although intravesical chemotherapeutic agents may lower the rate
of disease recurrence in patients with superficial bladder cancer,
at present there is no evidence to suggest that intravesical chemotherapy
has any beneficial influence on the risk of tumor progression.
Intravesical bacillus Calmette-Guérin (BCG), however, is
effective in treating carcinoma in situ of the bladder and has
been shown to lower the rate of disease progression in patients
with superficial bladder cancer. A trial of intravesical BCG therapy,
therefore, is appropriate for patients with carcinoma in situ
or stage T1 disease. While the optimal treatment protocol for
BCG is yet to be defined, weekly instillation of BCG for 6 weeks,
followed by 3 weekly instillations at 12 weeks (the 6 + 3 regimen)
has been recommended by some as the preferred induction regimen.
Recently, a cooperative study demonstrated that bropiramine, an
orally administered immunostimulant, is also effective in patients
with carcinoma in situ (61% complete response rate). Furthermore,
bropirimine produced complete responses in 6 of 12 patients with
carcinoma in situ in whom prior BCG therapy failed. Due to
its effectiveness and ease of administration, bropiramine may
have the potential to eventually replace BCG as front-line therapy
for carcinoma in situ of the bladder.
When to Proceed to Aggressive Therapy?
There is currently no consensus regarding when to abandon conservative
therapy and proceed with more aggressive treatment for superficial
bladder cancer in the face of BCG failure. Although the risk of
disease progression in patients with stage T1 bladder cancer is
30% at 3 years, there is no way to reliably predict which of these
patients will progress. Lymphatic and vascular invasion, high-grade
tumor, multifocality, and tumor adjacent atypia or carcinoma in
situ have all been associated with more aggressive behavior by
superficial lesions. In the future, markers that predict aggressive
behavior in invasive bladder cancer, such as p53 alterations or
microvessel count (angiogenesis), may also prove useful in predicting
aggressive behavior of high-risk superficial disease.
There is evidence to suggest that patients who do not respond
to two courses of intravesical BCG should be considered for more
aggressive treatment, such as radical cystectomy. This form
of treatment has proven safe and effective in patients with recurrent
high-grade T1 lesions and Tis lesions refractory to conservative
measures, with 37% of these patients being upstaged to at least
muscle-invasive disease (P2) on the cystectomy specimen. Therefore,
in the current era of continent and orthotopic urinary diversion,
with modern surgical advances that have diminished the morbidity
associated with surgery, radical cystectomy should be offered
to high-risk patients with superficial bladder cancer in whom
previous conservative treatment has proved ineffective.
1. Soloway MS, Masters S: Urothelial susceptibility to tumor cell
implantation: Influence of cauterization. Cancer 46:1158, 1980.
2. See WA, Miller JS, Williams RD: Pathophysiology of transitional
tumor cell adherence to sites of urothelial injury in rats: Mechanisms
mediating intravesical recurrence due to implantation. Cancer
Res 50:2499, 1989.
3. Lamm DL, Riggs DR, Traynelis CL, et al: Apparent failure of
current intravesical chemotherapy prophylaxis to influence the
long-term course of superficial transitional cell carcinoma of
the bladder. J Urol 153:1444-1450, 1995.
4. Sarosdy MF, Lowe BA, Schelhammer PF, et al: Oral bropiramine
immunotherapy of carcinoma in situ of the bladder: Results of
a phase II trial. Urology 48:21-27, 1996.
5. Malkowicz SB, Nichols P, Lieskovsky G, et al: The role of radical
cystectomy in the management of high grade superficial bladder
cancer (PA, P1, PIS and P2). J Urol 144:641-645, 1990.
6. Catalona WJ, Hudson MA, Gillen DP, et al: Risks and benefits
of repeated courses of intravesical bacillus Calmette-Guerin therapy
for superficial bladder cancer. J Urol 137:220-224, 1987.
7. Freeman JA, Esrig D, Simoneau A, et al: Radical cystectomy
for patients with superficial bladder cancer (abstract). J Urol