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. 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.
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.
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]
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.
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
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-cellmediated 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.
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.
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.
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 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).
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. Unfortunately, despite the promise of
TP-40 in patients with BCG-refractory Tis, phase II studies of this
agent have not been initiated.
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. 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.
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%. 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
Thus, it seems obvious that, in some patients, altering the expected
natural history of the transitional cell carcinoma represents a
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999.
Cancer J Clin 49:8-31, 1999.
2. Lynch CF, Cohen MB: Urinary system.Cancer 75:316, 1995.
3. Badalament RA, Farah RN: Treatment of superficial bladder cancer
with intravesical chemotherapy. Semin Surg Oncol 13:335-341, 1997.
4. Solloway MS: Managing superficial bladder cancer: An overview.
Urology 40:5-10, 1992.
5. Orozco RE, Martin AA, Murphy WM: Carcinoma in situ of the urinary
bladder: Clues to host involvement in human carcinogenesis.Cancer
6. Herr HW: Transurethral resection and intravesical therapy of
superficial bladder tumors. Urol Clin North Am 18:525-528, 1991.
7. Catalona WJ, Ratliffe TL: Bacillus Calmette Guerin and superficial
bladder cancer: Clinical experience and mechanism of action. Ann Surg
8. Belldegrun AS, Franklin JR, ODonnell MA, et al: Superficial
bladder cancer: The role of interferon-alpha. J Urol 159:1793-1801, 1998.
9. Glashan RW: A randomized controlled study of intravesical
alpha-2b- interferon in carcinoma in situ of the bladder. J Urol
10. Sarosdy MF: High-dose vs low-dose intravesical
Interferon-alpha-2b in the treatment of carcinoma in situ: A
randomized, controlled study. Anticancer Drugs 3(suppl 1):13-17, 1992.
11. Sarosdy MF, Lowe BA, Schellhammer PF, et al: Oral bropirimine
immunotherapy of carcinoma in situ of the bladder: Results of a phase
II trial. Urology 48:21-27, 1996.
12. Lotzova E, Savary CA, Khan A, et al: Stimulation of natural
killer cells in two random bred strains of athymic rats by
interferon-inducing pyrimidinone. J Immunol 132:2566-2570, 1984.
13. Goldberg MR, Heimbrook DC, Russo P, et al: Phase I clinical study
of the recombinant oncotoxin TP-40 in superficial bladder cancer.
Clin Cancer Res 1:57-59, 1995.
14. Nseyo UO: Photodynamic therapy. Urol Clin North Am 19:591-599, 1992.
15. Nseyo UO, DeHaven J, Dougherty TJ, et al: Photodynamic therapy in
the treatment of patients with resistant superficial bladder cancer:
A long-term experience. J Clin Laser Med Surg 16:61-68, 1998.
16. Nseyo UO, Shumaker B, Klein EA, et al: Photodynamic therapy using
porfimer sodium as an alternative to cystectomy in patients with
refractory transitional cell carcinoma in situ of the bladder:
Bladder Photofrin study group. J Urol 160:39-44, 1998.
17. Prout GR, Koontz WW Jr, Coombs LJ, et al: Long-term fate of 90
patients with superficial bladder cancer randomly assigned to receive
or not to receive thiotepa. J Urol 130:677-680, 1983.
18. Lamm DL, Blumenstein BA, Crawford ED, et al: A randomized trial
of intravesical therapy for superficial bladder cancer. Urology
19. Rajala P, Liukkonen T, Raitanen M, et al: Transurethral resection
with perioperative instillation of interferon-a or epirubicin for the
prophylaxis of recurrent primary superficial bladder cancer: A
prospective randomized multicenter studyFinnbladder III. J Urol
20. Oosterlinck W, Kurth K, Schroder F, et al: A prospective European
Organization for Research and Treatment of Cancer Genitourinary Group
randomized trial comparing transurethral resection followed by a
single intravesical instillation of epirubicin or water in single
stage Ta, T1 papillary carcinoma of the bladder. J Urol 149:749-752, 1993.
21. Zincke H, Utz D, Taylor W, et al: Influence of thiotepa and
doxorubicin instillation at time of transurethral surgical treatment
of bladder cancer on tumor recurrence: A prospective, randomized,
double-blind, controlled trial. J Urol 129:505-509, 1983.
22. Lundholm C, Norlen BJ, Ekman P, et al: A randomized prospective
study comparing long-term intravesical instillations of mitomycin-C
and bacillus Calmette-Guerin in patients with superficial bladder
carcinoma. J Urol 156:372-377,1996.
23. Krege S, Giani G, Meyer R, et al: A randomized multicenter trial
of adjuvant therapy in superficial bladder cancer: Transurethral
resection only vs transurethral resection plus mito-mycin-C vs
transurethral resection plus bacillus Calmette-Guerin. J Urol
24. Vegt PD, Witjes JA, Witjes WP, et al: A randomized study of
intravesical mitomycin-C, Calmette-Guerin Tice, and bacillus
Calmette-Guerin RIVM treatment in pTa-pT1 papillary carcinoma and
carcinoma in situ of the bladder.J Urol 153:929-934, 1995.
25. Melekos MD, Zarakovitis IE, Fokaefs ED, et al: Intravesical
bacillus Calmette-Guerin vs epirubicin in the prophylaxis of
recurrent and/or multiple superficial bladder tumors. Oncology
26. Lopez-Beltran A: Bladder treatment. Immunotherapy and
chemotherapy. Urol Clin North Am 26:535-554, 1999.
27. Hamdy FC, Hastie KJ, Kerry R, et al: Mitomycin-C in superficial
bladder cancer: Is long-term maintenance therapy worthwhile after
initial therapy? Br J Urol 71:183-186, 1993.
28. Tolley DA, Parmer MKB, Grigor KM, et al: The effect of
intravesical mitomycin-C on newly diagnosed superficial bladder
cancer: A further report with 7 years of follow-up. J Urol
29. Greenberg RE, Bahnson RR, Wood D, et al: Initial report on
intravesical administration of N-trifluoroacetyladriamycin-14-valerate
(AD-32) to patients with refractory superficial transitional cell
carcinoma of the urinary bladder. Urology 49:471-475, 1997.
30. Herr HW, Schwab DM, Zhang Z, et al: Intravesical bacillus
Calmette Guerin prevents tumor progression and death from superficial
bladder cancer: 10-Year follow-up of a prospective randomized trial.
J Clin Oncol 13:1404-1408, 1995.
31. Lamm DL: BCG in perspective: Advances in the treatment of
superficial bladder cancer. Eur Urol 27:2-8, 1995.
32. Reijke TM, DE Boer EC, Kurth KH, et al: Urinary interleukin-2
monitoring during prolonged bacillus Calmette-Guerin treatment: Can
it predict the optimal number of instillations? J Urol 161:67-71, 1999.