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Intravesical Therapy for Superficial Bladder Cancer

Intravesical Therapy for Superficial Bladder Cancer

ABSTRACT: Approximately 54,400 new cases of transitional cell carcinoma of the bladder were reported in the United States in 1999, with an estimated 12,500 deaths attributable to this cancer. Close to 75% of all bladder tumors are confined to the urothelium (stage Ta, or carcinoma in situ), and nearly 30% of papillary tumors invade the lamina propria (stage T1). The majority of superficial tumors are low grade with low rates of progression. Transurethral resection is the standard initial treatment for transitional cell carcinoma. Intravesical therapy is an important adjunct to transurethral resection in patients with superficial bladder cancer, many of whom are at risk for disease recurrence and progression. Cytotoxic and immunomodulating agents and, more recently, photosensitizers have demonstrated utility against superficial transitional cell carcinoma. Many studies have assessed and continue to examine the efficacy of various agents at different doses and in different combinations and schedules. Recently, valrubicin (Valstar) won Food and Drug Administration (FDA) approval only for the treatment of refractory carcinoma in situ. However, bacillus Calmette-Guérin (BCG) and mitomycin (Mutamycin) remain the most commonly used, most effective agents available for prophylaxis against recurrence and subsequent progression of superficial bladder cancer. This article reviews traditional and alternative intravesical agents useful in the therapy and prophylaxis of superficial transitional cell carcinoma of the bladder. [ONCOLOGY 14 (5):719-729, 2000]


Transitional cell carcinoma of the bladder
remains a significant health problem in the United States.
Approximately 54,400 new cases of transitional cell carcinoma were
reported in the United States in 1999, and an estimated 12,500 deaths
were attributed to this cancer.[1] These statistics have remained
relatively unchanged over the last several decades despite
improvements in both diagnostic instrumentation and therapeutic
intervention, as well as greater awareness of cigarette smoking and
occupational chemical exposure as important risk factors.

The prevalence of transitional cell carcinoma is at least 400,000
cases. The disease represents the fourth most common neoplasm in
males and the eighth most common malignancy in females. The incidence
of bladder cancer is four times higher in men than it is in women.
The median age at diagnosis is 65 years.[2]

The majority of transitional cell carcinomas are papillary in
morphology and are derived from the urothelium. At initial
presentation, 70% of these tumors are superficial, defined as
involving the mucosa (epithelium) or submucosa (lamina propria) only
(stage Ta, T1, or Tis).

The natural history of superficial transitional cell carcinoma is
still largely unpredictable because of tumor heterogeneity, as well
as the multifocal nature of the disease. Tumors recur in 40% to 80%
of patients and progress in 5% to 30%, despite complete resection. In
general, superficial transitional cell carcinoma, when it does recur,
remains stable with regard to stage and grade. Yet, in selected
cases, the risk of progression to a muscle-invasive tumor is as high
as 50% to 80%. The two basic categories of risk factors are tumor
burden and dedifferentiation.[3]

Transitional cell carcinoma in situ (Tis) histologically consists of
poorly differentiated transitional cell carcinoma confined to the
urothelium. Frequently associated with high-grade yet superficial
papillary tumors, Tis portends a poor prognosis. Patients with
carcinoma in situ have the highest recurrence rate. When treated with
endoscopic resection alone, between 40% and 80% of these patients
will progress to high-stage, muscle-invasive transitional cell carcinoma.

The time to progression to muscle-invasive disease remains
unpredictable; however, patients with marked voiding symptoms, which
implies increased tumor burden, clearly have a shorter interval
preceding the development of invasive tumor. As many as 20% of
patients with diffuse Tis are found to have evidence of muscle
invasion on final pathologic examination when ultimately treated with
radical cystectomy. Furthermore, as many as 10% of those patients
with only focal Tis are found to have occult regional metastases at
the time of radical surgery.[4,5]

Treatment Approach

Transurethral resection of all visible transitional cell carcinoma
(when possible) remains the ultimate method of pathologic staging and
primary treatment. Pathologic review and appropriate additional
clinical staging are required to identify patients at risk for
recurrence and those for whom intravesical treatment is appropriate.

In patients with low-grade, low-stage, small-volume disease, careful
surveillance endoscopy and intermittent resection or fulguration
alone may be sufficient. In patients with higher-grade tumors,
large-volume, and/or multifocal disease, adjuvant therapies should be considered.[6]

Adjuvant intravesical therapy, whether in the form of
chemotherapeutic or immunologic agents, is indicated in patients at
high risk for tumor recurrence. High-risk patients include those with
multiple or large tumors at initial resection, tumor recurrence(s),
high-grade tumors, or papillary tumors associated with carcinoma in
situ, as well as those with carcinoma in situ without papillary
transitional cell carcinoma.

When intravesical agents are used to destroy residual transitional
cell carcinoma following incomplete resection, the treatment is
considered to be therapeutic in nature. However, when the
agents are selected after complete resection of all visible tumor,
treatment is defined as prophylactic.

Chemotherapeutic agents that have historically been used for treating
superficial transitional cell carcinoma of the bladder include
thiotepa (triethyl-enethiophosphoramide [Thioplex]), mitomycin
(Mutamycin), doxorubicin, epirubicin (4¢-epidoxorubicin
[Ellence]), and, most recently, valrubicin
(N-tri-fluoroacetyladriamycin-14-valerate [Valstar]). Biological
therapies employing immunologically active agents include bacillus
Calmette-Guérin (BCG), bropiramine (2-amino-5-bromo-6-phenyl-4-[3H]-pyrimidinone),
recombinant interferon-alfa-2b (Intron A), and photosensitizers
combined with laser therapy.

It remains a peculiarity of urologic practice that many agents
commonly used to treat bladder cancer have never actually been
approved by the Food and Drug Administration (FDA) for that specific
use. This is especially relevant when discussing the management of
intravesical treatment of superficial transitional cell carcinoma of
the bladder. The only agents approved by the FDA for use in patients
with transitional cell carcinoma are thiotepa, BCG, and valrubicin.
Thiotepa was approved only for the treatment of low-grade, low-stage
papillary transitional cell carcinoma, whereas bacillus Calmette-Guérin
was approved only for patients with Tis. Valrubicin recently
received FDA approval only for the treatment of refractory Tis.

Yet, in most urologic practices, the “off-label” use of
these agents frequently benefits the patient. For example, BCG is
used as a first-line therapy for both papillary transitional cell
carcinoma and Tis despite the fact that it has been approved only for
the management of Tis. In addition, a number of other options are
available for patients who do not respond to or cannot tolerate
intravesical BCG.

Immunologic Agents


Although not yet completely understood, the mechanism of BCG, and,
indeed, of all biologically active agents, is immunomodulation. It
appears that the mycobacteria of BCG attach to the surface epithelium
of the bladder tumor and normal bladder; this attachment is
facilitated by fibronectin. The mycobacteria are subsequently
internalized and form complexes with various glycoproteins; the
mycobacteria-glycoprotein complexes presumably stimulate a
T-cell–mediated immune response. In addition, BCG directly
activates macrophages, T and B lymphocytes, and natural killer cells,
as well as antibody-dependent killer cells. These factors then
activate lymphokine and interferon production.

Bacillus Calmette-Guérin should not be administered to
immunocompromised hosts, patients receiving therapeutic (rather than
replacement) exogenous steroids, those who have had a traumatic
catheterization, or those with persistent gross hematuria following
bladder tumor resection. Patients with gross hematuria at the time of
catheterization are at greatest risk for the development of systemic
BCG-induced infection and possibly death.[7]


Since interferon is clearly one of the end products of successful BCG
treatment of superficial transitional cell carcinoma, it would seem
logical that direct instillation of interferon into the bladder
should also control this cancer. Various subtypes of interferon have,
in fact, been used, unfortunately with only limited effect.

Recombinant interferon-alfa-2b has demonstrated some efficacy in the
treatment of Tis in clinical trials. The appropriate intravesical
dosage seems to be in the range of 50 to 100 million units
administered weekly for 6 weeks. Durable responses to interferon,
however, are clearly less impressive than with BCG, possibly
indicating that some other factor or combination of factors, such as
the cell-mediated cascade, is necessary for a maximal beneficial
effect. Also, intravesical interferon-alfa-2b seems to be more
effective when used as initial treatment, rather than as a salvage
regimen in patients who have not responded to BCG.[8]

In an earlier study looking at doses of interferon-alfa-2b, patients
treated with a high dose (100 million units) had clearly superior
responses than those given a low dose (10 million units).
Interestingly, however, six of the nine patients in this study had
proved unresponsive to prior intravesical BCG therapy, and maximum
follow-up was only 12 months.[9]

Greenberg is currently conducting a phase II trial to determine
whether the combination of BCG plus interferon-alfa-2b is more
effective than either agent alone. Other investigators are attempting
to define the best possible dose of BCG and interferon-alfa-2b when
used in combination. There is ample clinical as well as laboratory
evidence that, with biologically active agents, more is not always
better, and lower- dose combinations may not only keep the cost of
these treatments down but also yield superior results.[9,10]

Other Immunomodulators

Other immunomodulators that have been evaluated in the management of
transitional cell carcinoma include bropiramine and TP-40.

Bropiramine is an oral inducer of interferon and other
cytokines that can activate several related immunologic defense
mechanisms.[11,12] Initial reports indicated exceptional response
rates, especially in patients with stage Tis disease. Among this
latter group, biopsies and bladder wash cytologies became negative in
61% of patients, including complete responses in 50% to 60% patients
who had received prior BCG treatment. Complete responses occurred in
60% to 70% of patients who had not received prior BCG treatment and
80% of patients with primary Tis cancers (de novo tumors not
associated with papillary disease).[11]

Subsequent, careful monitoring failed to demonstrate sufficient
efficacy of bropiramine to win FDA approval, however. In addition,
significant cardiac-related toxicity was associated with this
treatment, and it is currently no longer in clinical trials or
available for general use.

TP-40, a Pseudomonas exotoxin, was used in phase I research
studies and found to have excellent response in patients with stage
Tis bladder tumors, although little or no activity against
superficial papillary transitional cell carcinoma. Since no apparent
toxicity was uncovered in this phase I study, the maximum tolerated
dose was not determined.[13] Unfortunately, despite the promise of
TP-40 in patients with BCG-refractory Tis, phase II studies of this
agent have not been initiated.

Photodynamic Therapy

A number of recent reports have demonstrated a possible role for
photodynamic therapy (PDT) in the treatment of recurrent Ta, T1, and
Tis transitional cell carcinoma. Photodynamic therapy is a form of
cancer treatment based on the destruction of cells by the interaction
of light (400 to 760 nm) with a photosensitizing dye and oxygen. When
administered systemically, these substances accumulate in both tumor
and normal tissues. Upon exposure to light of an appropriate
wavelength, based on the nature of the specific photosensitizing
agent, an in situ chemical reaction ensues. The ultimate effect is
the local production of reactive oxygen radicals that are cytotoxic.

First-generation photosensitizers caused prolonged phototoxicity and
had inferior tumor specificity, resulting in accumulation within the
detrusor muscle with subsequent permanent loss of bladder capacity
and acute post-PDT syndrome, characterized by frequency, urgency,
nocturia, and bladder spasms.[14] Since the tumor cells
preferentially take up the newer photosensitizing agents, these drugs
appear to have a more specific cytotoxic effect against the malignant
cells and, thus, less toxicity. A newer agent, 5-aminolaevulinic acid
(ALA), generates a photosensitizer called protoporphyrin IX (PpIX),
which has fewer side effects and a much shorter period of systemic
phototoxicity than previous photosensitizing agents.

Patients with resistant superficial bladder cancer who were treated
with prophylactic whole-bladder PDT demonstrated complete response
rates at 3 months of 84% and 75% for residual-resistant papillary
transitional cell carcinoma and refractory Tis, respectively. At a
median of 50 months, 59% of responding patients were alive, and 31 of
34 responders remained disease free.[15]

In a similar study, 36 patients with BCG-refractory Tis demonstrated
a complete response rate of 58% at 3 months with a durable response
rate (no tumor recurrence at 12 months) of 31%.[16] At 12 months, 14
patients subsequently underwent cystectomy, 12 for persistent disease
and 2 for a recurrence. Most patients initially diagnosed with Tis
who subsequently developed a recurrence following whole-bladder PDT
were easily managed with trans-urethral resection for superficial
recurrence only.

Thus, it seems obvious that, in some patients, altering the expected
natural history of the transitional cell carcinoma represents a
beneficial outcome.


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