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Predicting Prognosis in Patients With Superficial Bladder Cancer

Predicting Prognosis in Patients With Superficial Bladder Cancer

ABSTRACT: Bladder cancer is the most common urologic malignancy and is expected to affect approximately 54,000 people in 1998. Superficial bladder tumors (Tis, Ta, and T1 lesions) account for approximately 70% to 80% of these malignancies. Although many advances have been made in the management of patients with superficial bladder cancer, such disease often recurs and can progress, leading to death. It is therefore imperative to find an accurate method of identifying patients at risk for disease progression. Many recent investigations have been conducted to determine whether new biological markers will help predict disease progression and, to a lesser extent, tumor response to treatment. These new markers include DNA ploidy, S-phase, certain monoclonal antibodies, the p53 (alias TP53) tumor-suppressor gene, the retinoblastoma (Rb) gene, cell adhesion molecules, and angiogenesis. It is hoped that such prognostic indicators, coupled with cytoscopic and pathologic characteristics of the tumor, will lead to selective aggressive treatment of patients at high risk for progression while sparing low-risk patients from unnecessary procedures. [ONCOLOGY 12(12):1717-1723, 1998]

Introduction

Bladder cancer is the most common malignancy
encountered by urologists. It is estimated that, in 1998, 54,400
cases of bladder cancer will be diagnosed in the United States,
leading to approximately 12,500 deaths.[1]

More than 90% of bladder tumors are transitional cell carcinomas.
Risk factors for the development transitional cell carcinoma include
cigarette smoking and exposure to arylamines (such as aniline dyes),
certain drugs, and pelvic radiation.[2-5] Cigarette smoking is the
cause of 25% to 60% of all bladder cancers, and smokers have two
times the risk of developing this cancer than do nonsmokers.[5]

Fortunately, most patients (80%) with newly diagnosed bladder cancer
present with “superficial” disease, which can be managed
with transurethral resection or intravesical therapy. The term
“superficial bladder cancer” refers to tumors confined to
the mucosa (Ta), those with lamina propria invasion (T1), and
carcinoma in situ (Tis).[6]

The recurrence rate for superficial bladder tumors is high
(two-thirds), and, despite advances in management, some patients
still develop stage progression. It is well known that such stage
progression occurs more often in patients with high-grade lesions and
T1 tumors. For this reason, it seems imprecise to group all
“superficial” tumors together.

Tumors that pose a high risk for progression and death are multifocal
Ta lesions, tumors with associated Tis disease, and T1 lesions.
Eventually, one-half of these high-risk patients will require a
cystectomy, and one-third are at risk of dying from bladder cancer
over 15 to 20 years.[6]

A prognostic marker that could identify individuals at risk for
recurrence and progression might dramatically change the clinical
management of patients with bladder cancer. The availability of such
a marker would permit the selective use of aggressive treatment in
patients who are at high risk of recurrence and progression while
sparing low-risk patients from un-necessary procedures.[7]

Researchers are investigating several prognostic factors that may
provide such a model. Traditional prognostic factors in bladder
cancer have included tumor characteristics based on cystoscopic and
pathologic findings. Certain biological markers may also play
important roles in predicting high-risk tumors. These include DNA
ploidy, S-phase, certain monoclonal antibodies, the p53 (alias TP53)
tumor-suppressor gene, the retinoblastoma (Rb) gene, cell adhesion
molecules, and angiogenesis.

Tumor Characteristics

Cystoscopic Findings

Characteristics of bladder tumors that are visible with cystoscopy
can have important prognostic implications. For example, tumor size
may play a role in progression to muscle invasive disease. In one
series, tumors > 5 cm had a 35% progression rate, as compared with
a 9% rate for smaller tumors.[8]

The number of tumors is also important for predicting recurrence but
not progression.[8] Recurrence rates in patients with single tumors
range from 18% to 60%, as opposed to rates of 40% to 90% in those
with multiple tumors.[6]

The timing of first recurrence is another significant cystoscopic
finding. Fitzpatrick et al reported that, among patients with Ta
lesions who had no recurrences at their first post-resection
cystoscopy, 79% had no subsequent recurrences.[9] In contrast, 90% of
patients with recurrences at 3 months also had additional recurrences.

Lastly, tumor appearance or morphology can also be prognostic, with
sessile (solid) masses having a higher recurrence rate than papillary masses.[9]

Pathologic Findings

Pathologic characteristics of superficial bladder tumors that have
the greatest prognostic significance are tumor stage and grade. The
most commonly used staging system for transitional cell carcinoma is
the tumor, node, metastasis (TNM) classification, which has recently
been updated (Table 1).[10] It has
been documented that recurrence and progression rates for Tis, Ta,
and T1 lesions vary greatly. However, most of the studies reporting
on the prognostic value of tumor stage and grade in superficial
transitional cell carcinoma have follow-up periods of only 5 years or
less.[9-12] Table 2 lists a few of
the studies that have followed patients for more than 5 years.[8,13,14]

Clinical Studies With Long-Term Follow-up—Heney and
colleagues in the National Bladder Cancer Group studied 207 patients
with superficial tumors who were followed for a mean of 39 months.[8]
Their findings, which are similar to those of other researchers,
confirm that higher-grade and higher-stage lesions recur and progress
more often. Patients with grade 1, 2, or 3 disease had progression
rates to muscle invasive disease of 2%, 11%, and 45%, respectively.

In terms of stage, patients with Ta lesions progressed only 4% of the
time, as compared with 30% of individuals with T1 tumors. Rates of
progression were also higher in patients who had dysplasia elsewhere
in the bladder at the time of initial resection. Lamina propria
invasion was a significant prognostic factor when combined with
grade. Progression was observed in only 6% of patients with grade 2,
Ta tumors, as compared with 21% of those with grade 2, T1 lesions.

Holmang et al followed 176 patients with primary Ta or T1 tumors for
20 years.[13] All 176 patients were treated initially with
transurethral resection (TUR), while 65 patients required either
cystectomy or radiation therapy immediately or within a year after
TUR. Therefore, the results of the study need to be interpreted with
some caution.

Overall, the study showed that there were frequent (52%) tumor
recurrences, which were confined to the bladder, with a 14%
progression rate for Ta lesions and 39% for T1 lesions. The overall
risk of dying from superficial bladder cancer was 22% (11% for Ta
lesions and 30% for T1 tumors). Similar progression rates were
reported by Kurth et al in the European Organization for Research and
Treatment of Cancer genitourinary (EORTC-GU) study.[14]

Long-term studies have also been performed in “high-risk”
populations, including patients with T1 lesions, multiple Ta lesions,
or associated Tis. Herr et al reported the 10-year outcome of 221
such patients who had undergone multiple TURs and one or more cycles
of intravesical bacillus Calmette-Guérin (BCG) therapy.[15]
Tumor progression developed in 42% of patients by 10 years, and
superficial tumor recurrences occurred in 49%. Most (82%) of these
stage progressions or recurrences had occurred by 5 years. Of note,
18% of patients had a disease-free interval of 5 years or more prior
to recurrence or invasion.[1]

Proposed Substaging of T1 Lesions—Some researchers have
proposed that the current TNM clas-sification system should be
modified to include substaging of T1 lesions into T1a and T1b.[16,17]
It is felt that this substaging might improve prognostic information.
As proposed, T1a lesions would not involve the muscularis mucosa of
the lamina propria, whereas T1b lesions may invade into or through
this layer.

Holmang et al studied 121 patients with T1 transitional cell
carcinomas in whom they subclassified 90% of the lesions as either
T1a or T1b.[16] The T1b tumors were more often grade 3 than the T1a
tumors (79% vs 40%;

P < .001). The T1b tumors had a significantly higher overall rate
of progression than the T1a lesions (53% vs 31%). The death rate from
bladder cancer was nearly twice as high for patients with T1b disease
than for those with T1a disease (44% vs 23%; P < .05).

Similar results have been reported by Hasui and coworkers.[17]
Although this substaging system appears to provide prognostic
information using TUR chips, it may be an impractical to use due to
technical difficulties, such as the cautery effect, orientation, and
lack of observer agreement.[2]

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