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CURRENT
INDICATIONS AND NEW POSSIBILITIES FOR ORGAN PRESERVATION IN CARCINOMA
OF THE BLADDER
RICARDO BEDUSCHI,
JAMES E. MONTIE
Section of
Urology, University of Michigan, Ann Arbor, Michigan, USA
ABSTRACT
Objective:
To assess the efficacy of bladder-sparing strategies in the treatment
of muscle-invasive bladder cancer.
Patient and Methods: This overview discusses
the evolving role of transurethral resection of bladder tumors, radiation
therapy, systemic chemotherapy, and combination therapy in the treatment
of invasive bladder cancer. The pertinent literature was reviewed and
the specific aspects of each modality were analyzed. The results of bladder-sparing
strategies were compared with radical cystectomy.
Results: The bladder preservation strategies
that are currently available are capable of eradicating invasive bladder
tumors in some patients, but most patients are unlikely to be durably
cured by any of these regimens. Tumor recurrence
occurs in approximately 40% to 60% of patients participating in bladder-sparing
regimens. Approximately half of these recurrences
are muscle invasive, placing the patients at risk for metastasis. Pelvic
recurrence rates after radical cystectomy range between 10% and 30%. The
disease specific five-year survival rates in pathological stages T1/T2
are close to 70% to 80%; less than 50% for pathological stages T3b/T4.
Decreasing morbidity post radical cystectomy
and the advent of the orthotopic neobladder technique using either the
small or the large bowel is capable of restoring urinary function, which
lessens the qualitative benefits of any organ-sparing modality currently
available.
Conclusion: While radical cystectomy with
neobladders remains the preferred therapy for invasive bladder cancer,
research into improved bladder preservation strategies, possibly using
biomarkers to predict responsiveness to treatment, should continue.
Key words:
bladder, carcinoma, invasive, organ preservation, radiotherapy, chemotherapy
Braz J Urol, 26: 234-241, 2000
INTRODUCTION
Management
of high-grade urothelial carcinoma of the bladder is one of the most challenging
problems facing urologists today. Radical cystectomy is currently accepted
as the most effective treatment for muscle invasive disease based on the
fact that it provides excellent local control in the pelvis with a low
perioperative mortality rate. Nevertheless, the morbidity related to this
procedure is significant and issues of impotence and urinary incontinence
remain. The negative impact on the quality of life of patients undergoing
radical cystectomy fosters a search for alternative ways to treat invasive
bladder cancer that would allow a patient to retain the natural organ.
Alternative therapies would have to provide fewer complications without
compromising control of the primary tumor or survival. Several options
tested in clinical practice attempt to preserve the urinary bladder in
patients with invasive bladder cancer using a combination of chemotherapy
and radiation or bladder-sparing surgery.
The aim of this article is to review the
existing bladder preservation strategies. It is our view that current
bladder-sparing techniques are less effective than radical cystectomy
for cancer control, and thus reserved for highly selected patients.
RATIONAL
FOR BLADDER PRESERVATION
Eradication
of a tumor without removal of the affected organ is the ideal treatment
for any cancer. Therefore, for bladder cancer, the best treatment is the
one capable of providing control of the primary tumor without compromising
survival, thus avoiding the morbidity and adverse effect in quality of
life associated with radical cystectomy. Several options have been tested
in clinical practice, from transurethral resection alone to a combination
of multiple therapies.
TRANSURETHRAL RESECTION
OF BLADDER TUMOR (TURBT)
Transurethral
resection is the mainstay of treatment for noninvasive (Ta) or minimally
invasive (T1) bladder cancer. It is apparent that TURBT may also effectively
cure some patients with higher stage disease (T2a). This is supported
by 2 pieces of evidence: 1)- TURBT yields a prolonged disease-free survival
in selected patients with T2 disease; and 2)- no residual tumor is found
in the radical cystectomy specimens in approximately 10% of patients (pathological
stage T0), indicating that the TURBT effectively removed the tumor (1-4).
Early studies have shown that TURBT alone can provide a five-year survival
rate close to 50% in selected patients, which is not substantially different
from that of some large cystectomy series (1-4).
Treatment selection is clearly important.
In a series of patients adversely selected by advanced age and poor surgical
risk that underwent TURBT alone for muscle-invasive bladder cancer, the
five-year survival was 14% (5). Although capable of controlling the cancer
in some cases, TURBT alone will fail to cure most patients with high stage
bladder cancer. TURBT as a primary treatment is more likely to be successful
in patients with small volume tumors, who likely may have an even greater
chance of cure by cystectomy. Circumstantial evidence to support this
observation has also been reported. The five-year survival rate for patients
with smaller T2 tumors, who underwent radical cystectomy, ranges from
60% to 80% as compared to the 50% rate observed after TUR alone (6-9).
However, TURBT is an invaluable tool for evaluating bladder cancer therapy
and staging after other modalities of bladder preservation (10). Patients
who achieve a clinical T0 status on a transurethral resection of the primary
tumor site are likely to respond better to further therapy (chemical or
radiation) than those who do not achieve this condition (4).
PARTIAL CYSTECTOMY
Resection
of only the cancerous portion of the bladder has some theoretical advantages
over either TURBT or cystectomy in the management of invasive bladder
cancer. It allows full-thickness resection of the bladder wall and more
certain removal of the tumor confined to that segment compared to TURBT.
It also preserves the patient’s bladder and sexual function. The
trade off is the risk of remaining or new cancer in the bladder, since
the urothelium remains exposed to the same predisposing factors to bladder
carcinoma. Approximately 50% to 70% of the patients who undergo partial
cystectomy develop later tumors in the bladder; some of which will be
muscle invasive and potentially lethal. The commonly reported five-year
survival rates for partial cystectomy is approximately 50%, which is similar
to TURBT alone (11). It ranges from 70% for early stages (T2 tumors) to
17% for more advances tumors (T3b and T4 tumors). Patient selection remains
critical. Ideal patients for partial cystectomy have: 1)- a single tumor
in space and time (no previous history of bladder cancer); 2)- the tumor
located in a site favorable to resection (dome or high posterior wall
of the bladder); and 3)- no carcinoma in situ (CIS). Patients with a urachal
tumor or occasionally a tumor in a bladder diverticulum may be reasonable
candidates for partial cystectomy. The number of patients meeting these
criteria is extremely low, much less than 5% of the patients with stage
T2a or higher disease. Good functional results with radical cystectomy
and ileal neobladder formation have diminished considerably the role of
partial cystectomy in patients with invasive bladder cancer. When indicated,
it should be performed removing the overlying peritoneum along with the
involved bladder and a 2 cm margin of normal bladder around the entire
circumference of the bladder tumor. Biopsies around the resected area
and elsewhere in the bladder are necessary to exclude concomitant CIS.
The ill-advised partial cystectomy commonly turns into a nightmare and
diminishes later success even with total cystectomy.
EXTERNAL RADIATION
THERAPY
Ionizing
radiation therapy has been extensively used in the treatment of invasive
bladder cancer, particularly in Europe. In the United States, its role
remains limited. Results with external radiation therapy (RT) in the U.S.A.
have been consistently less optimistic than those from Europe.
In a large randomized European trial comparing
pre-operative pelvic RT and radical cystectomy versus RT only for patients
with T2b and T3 bladder cancer, the survival rate was not statistically
different between the two groups. A five-year survival rate of 38% was
reported for those who underwent radical cystectomy, compared to 29% for
those treated with RT only (12). Similar results were reported in a more
recent study (13). For those patients that underwent immediate surgery,
a five-year survival rate of 29% was reported, versus 23% for the RT only
group. In one of the largest series of patients treated with primary radiation
therapy alone (cystectomy was reserved as salvage treatment), the complete
clinical response rate was 45% for clinical stages T1 to T4. Fifty percent
of the patients had locally recurrent tumors, with an overall five-year
local control rate of 25% for stages T1 through T3 tumors. Those with
clinical stage T4 achieved a five-year local control rate of only 16%.
Patients with persistent tumors underwent radical cystectomy, with an
overall five-year survival rate following surgery of approximately 45%.
In this series, the overall survival rate for patients with deeply invasive
tumors was approximately 25%; 69% for those with more superficial tumors
(14).
As a single modality for the treatment of
muscle invasive cancers, RT may provide local control in 30% to 50% of
the cases at best, with a five-year overall survival rate ranging from
23% to 40% (15-18). Analyzing data from several trials of primary radiation
therapy for T2 disease, an overall five-year survival rate of approximately
40% was reported, with a local control rate ranging between 40% and 50%.
Primary recurrence was a serious concern in all studies (19-24). Patients
with T3 disease had a five-year survival rate of only 20%, with 50% to
70% having local recurrence (19-24).
More recently, several drugs (radiosensitizers)
have been investigated as a possible means of improving the efficacy of
RT. Most interesting have been the studies investigating the concurrent
use of RT and Cisplatin. One small randomized study that compared radiotherapy
with and without the concurrent use of Cisplatin demonstrated a significant
improvement in local control with the concurrent regimen, but it failed
to show any benefit in terms of overall survival (25). A pilot trial is
currently under way at the University of Michigan to evaluate the combination
of gemcitabine and radiation therapy as a bladder preservation strategy.
Gemcitabine is an antimetabolite that was initially synthesized as an
antiviral drug. Further investigations demonstrate that the drug is a
potent radiosensitizer and has significant activity against urothelial
carcinoma as a single agent.
In summary, the results with RT for invasive
bladder cancer in the U.S.A. have been systematically inferior to those
of radical cystectomy, therefore RT is only exceptionally recommended
as a primary option for invasive bladder cancer.
SYSTEMIC CHEMOTHERAPY
The
search for an effective chemotherapy regimen for metastatic bladder cancer
led to the evaluation of various cytotoxic agents in patients with disseminated
disease. Cisplatin was found to be the most active single agent against
urothelial cancer, but other agents such as 5-FU, methotrexate, vinblastine
and doxorubicin have also been tested with partial success. Nevertheless,
none of these agents was found to be solely effective. Combination regiments
are more effective and capable of inducing a complete response in patients
with metastatic bladder cancer (26). Several combination regiments were
tested in clinical practice until the introduction of the MVAC regiment
(methotrexate, vinblastine, doxorubicin and cisplatin) at the Memorial
Sloan Kettering Center. The first results of a phase-II trial were reported
in 1985, and since then, MVAC has evolved into the preferred chemotherapy
treatment for bladder cancer. An updated report from 1989 revealed that
121 patients had been enrolled in the clinical trial. An overall response
rate of up to 70% was reported, but a durable disease-free survival was
observed in only a small percentage of patients (27). The median survival
duration for the entire group was 13.3 months; only 20% of the patients
were long-term disease-free survivors. MVAC was subsequently compared
to other systemic regiments and found to be the most effective. This relative
success in treating metastatic disease led to the utilization of MVAC
in bladder-sparing protocols at the same institution. In a series of patients
treated with both TURBT and MVAC, 54% achieved an early T0 status (28).
Unfortunately, additional studies revealed that only in a few patients
was the response durable and complete (29). In addition, the toxicity
of the regiment is substantial and another limitation. Even at a standard
dosage, the side effects of MVAC were poorly tolerated by most patients.
The toxicity and limited efficacy of this
regimen led to new investigational agents. Two of the most promising agents
are paclitaxel and gemcitabine (30). Both have shown significant activity
as single agents against urothelial carcinoma. In a one phase-II trial,
27% of the patients with metastatic bladder cancer that were treated with
paclitaxel achieved a complete response (31). When combined with carboplatin,
an overall response rate of 50% was achieved. This combination was well
tolerated, with only moderate side effects (granulocytopenia and thrombocytopenia)
(32,33).
The combination of gemcitabine and cisplatin
also appears particularly promising. Longer follow-up and randomized trials
are required to reveal if any of them will supplant MVAC as the standard
therapy for metastatic urothelial carcinoma of the bladder. The diminished
toxicity of these new regiments as compared to MVAC makes them attractive.
Data on the efficacy on localized disease must be obtained to judge a
role for this treatment for bladder preservation.
Currently, systemic chemotherapy fails to
produces results comparable to radical cystectomy, and the results may
be no better than TURBT or partial cystectomy alone. Until more effective
and less toxic regiments are fully investigated, it should not be recommended
as a primary treatment for invasive bladder cancer. Data using adjuvant
or neoadjuvant chemotherapy combined with radical cystectomy is sparse,
and thus far, no conclusive improvement in survival has been shown.
COMBINATION THERAPY
Combined
approaches using all 3 modalities of therapy (TURBT, RT and chemotherapy)
have also been investigated in organ preservation approaches with more
encouraging results. A combination of maximal TURBT with initial chemotherapy
(cisplatin, methotrexate and vinblastine), followed by RT with concurrent
cisplatin was tested in a series of patients at Massachusetts General
Hospital (34,35). Patients were evaluated after 4,000cGy and those with
complete response received an additional 2,480cGy. For those who did not
reach complete response, total cystectomy was recommended. After a median
follow-up of four years, 53% of the patients had achieved complete response;
bladder function was adequately preserved in 89% (34,35). In a recent
update from the same institution with the same regimen, a complete response
was observed in 76 of 106 patients enrolled in the study (66%). Twenty-one
of the 76 patients developed Ta or T1 recurrence. Recurrence was controlled
with TURBR and intravesical therapy in 15 of these patients; 13 patients
presented with an invasive recurrence. After a median follow-up of five
years, 54% of the enrolled patients had no cancer found in the bladder
at their most recent evaluation (36). In other trials similar results
were reported, with five-year survival with an intact bladder ranging
from 39% to 45% (37-41). However, in another study, a disappointingly
low rate of disease-free bladder preservation with no definitive improvement
in survival was reported; only 18% of the enrolled population was alive
with an intact bladder at the end of the study. The five-year survival
rate of patients who had a cystectomy at some point in the study was 65%,
compared to 40% for those who had their bladder spared (41). The data
from these studies suggests that the combined regimen is capable of preserving
the bladder in some patients with muscle invasive disease; however, a
significant number will have an incomplete response or will develop recurrent
disease within the bladder, including some of these invading muscle tissue.
Therefore, until new agents or more effective approaches become apparent,
combinations of all 3 modalities remain as a secondary alternative for
the management of invasive bladder cancer.
IMPROVING PATIENT
SELECTION FOR BLADDER PRESERVATION
Not
all patients with muscle invasive disease require radical cystectomy to
eliminate the cancer in their pelvis. The dilemma is how to select which
patients are appropriate candidates for bladder-sparing strategy. Most
of the studies addressing bladder-sparing strategies are retrospective,
and although capable of providing helpful information and some estimate
of the efficacy of the different regiments, they are not appropriate to
compare results achieved with cystectomy or for patient selection.
Tumor markers capable of predicting responsiveness
to bladder-sparing strategies would be beneficial. Recent studies have
identified several molecular markers important in the progression of urothelial
carcinoma. Most of the attention has been focused on the p53 (42). p53
is a tumor suppressor gene that plays a significant role in determining
cellular responses to DNA damage, leading to both cell cycle arrest and
programmed cell death (42). Mutations of this gene and accumulation of
the p53 protein are associated with the transition to an invasive phenotype
of transitional cell malignancies (43). The gene may also influence the
response to chemotherapy treatment, since most antineoplastic drugs act
by promoting DNA damage. Several studies have now examined the proportion
of invasive bladder cancer that express an abnormal p53 protein and how
this finding would impact prognosis (44-48). According to these studies,
from 43% to 66% of the invasive tumors expressed an abnormal p53 protein;
an over expression of p53 was associated with a high recurrence rate and
reduced survival. Conversely, patients with
a tumor lacking p53 expression were more likely to have long-term survival,
especially those with organ-confined T2 tumors. However, the influence
of p53 on the response to treatment remains controversial. There is some
evidence that patients with abnormal p53 may benefit from adjuvant chemotherapy
(49). A recent report from the Memorial Sloan-Kettering Center suggests
that long-term bladder preservation (up to ten years) is feasible in patients
with T2 tumors who lack p53 if they respond completely to neoadjuvant
chemotherapy with MVAC. Patients with T3 disease or T2 p53 expressing
tumors are best treated with radical cystectomy (50). To better address
the clinical usefulness of p53, a multi-center clinical trial is underway.
Patients with organ-confined but invasive urothelial carcinoma of the
bladder (T1 and T2) after cystectomy are randomized on the basis of their
p53 status to receive adjuvant chemotherapy (MVAC) or observation with
later chemotherapy.
Since not all muscle invasive cancer express
p53, progression of the disease in the bladder must be regulated by pathways
other than p53. Recent investigations have suggested that the retinoblastoma
gene protein (pRb) may also play a role in this process (51-53). Studies
have shown that deletion of the Rb gene is a negative prognostic factor
for disease progression and overall survival. Whether or not Rb abnormalities
affect response to chemotherapy in bladder cancer is yet to be determined.
Several others tumor markers (histological and molecular markers) are
currently under investigation (54). The development of molecular biomarkers
will hopefully allow us to determine more appropriately which patients
are suitable for bladder-sparing therapy.
CONCLUSION
It
is clear that the strategies for bladder preservation currently available
are capable of eradicating invasive bladder tumors in some patients, but
most patients with muscle invasive bladder cancer are unlikely to be durably
cured by any of these regimens.
Tumor recurrence occurs in approximately
60% of patients participating in bladder-sparing regimens, and approximately
half of these recurrences are muscle invasive, placing the patients at
a high risk for metastasis. Not all of these patients will be saved by
salvage cystectomy. Patients with superficial recurrence require further
treatment with intravesical treatment and long-term surveillance, since
they are also at a high risk for progression of the disease. Bladder function
is another concern, and may not be ideal in those receiving multiple TURBTs,
intravesical therapy with BCG, and a high dose of RT. It is also evident
that patients with high stage disease (T3 and T4), who are at highest
risk for developing metastatic cancer, are the ones with the lowest chance
for complete elimination of the local cancer. Twenty percent of these
will have a complete response with bladder preservation therapy, a figure
inferior to radical cystectomy that is capable of providing local control
of the disease in 60% to 90% of the cases. Expanding the indications for
organ preservation likely exposes a greater proportion of the patients
to a higher risk of metastasis or local progression of the disease. Do
the qualitative benefits warrant this risk?
In our opinion, radical cystectomy remains
a preferred local therapy. The peri-operative mortality rate currently
ranges between 1% and 3% (55). Under close monitoring and a good pre-operative
evaluation, it can be performed safely on patients of all ages who are
reasonably healthy (56). The therapeutic results of radical cystectomy
are dependent on the clinical and pathological stage; most failures are
due to distant metastasis. The pelvic recurrence rate after radical cystectomy
ranges from 10% to 30%, with the higher rate for larger T3b tumors (palpable
mass) (57,58). Disease-specific five-year survival rates in pathological
stages T1/T2 are close to 70% to 80%, compared to less than 50% for pathological
stages T3b/T4. High-grade cancers (as most invasive tumors are) tend to
perform worse; lymph node involvement is also a strong predictor of relapse,
but cure is possible with surgery alone even in the presence of positive
lymph nodes (58,59).
Improved quality of life and decreasing
morbidity post radical cystectomy are clearly evident in the last 5 to
10 years. Nerve-sparing cystoprostatectomy allows preservation of the
autonomic innervation of the corpora cavernosa with preservation of erectile
function in some patients. In a highly selected series, recovery of sexual
function was seen in up to 62% of patients between 40 and 49 years of
age, without compromising cancer control (60). Orthotopic neobladder,
using either the small or large bowel, is capable of restoring urinary
function, bringing it closer to that of a preserved bladder, and should
be recommended as the first option for diversion in most of the patients
undergoing radical cystectomy. External urinary diversion (ileal conduit)
is recommended only for patients with poor general health, sedentary lifestyles,
or decreased renal function.
Until better molecular tumor markers are
available to predict patients that are likely to respond to either RT
or chemotherapy, radical cystectomy with neobladders should remain as
the preferred therapy for invasive bladder cancer.
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_______________________
Received: January 18, 2000
Accepted: February 25, 2000
_______________________
Correspondence
address:
James E. Montie, M.D.
Head, Section of Urology
University of Michigan
A. Alfred Taubman Health Care Center
Room 2325, Box 0330
1500 East Medical Center Drive
Ann Arbor, Michigan, 48109-0330, USA
Fax: + + (1) (734) 936-9127
E-mail: jmontie@umich.edu
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