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Management of Patients With Muscle-Invasive and Metastatic Bladder Cancer

Management of Patients With Muscle-Invasive and Metastatic Bladder Cancer

ABSTRACT: Bladder cancer is the fifth most common cancer diagnosed in the United States. Prognosis for this disease is dependent on both tumor stage and grade. Radical cystectomy has been the standard treatment for muscle-invasive local disease; however, combined-modality approaches with the use of chemotherapy are gaining momentum with data suggesting survival improvement. Patients with metastatic disease have poor long-term survival rates despite systemic multiagent chemotherapy. A variety of agents, including newer cytotoxic drugs and biologically targeted agents, are under investigation to determine the most effective regimen. The special needs of specific patient populations, such as the elderly, those with a suboptimal performance status, and patients with medical comorbidities have gained more attention. Progress in the treatment of this disease is dependent on supporting ongoing and future clinical trials.

Bladder cancer is the fifth most
common malignancy, with an
estimated 63,210 newly diagnosed
cases and 13,180 deaths in the
United States in 2005.[1] Approximately
75% of patients present with
superficial disease[1] and are managed
primarily by urologists with cystoscopy
and transurethral resection
(TUR) with or without intravesicular
therapy, depending on grade, presence
of carcinoma in situ, and depth
of invasion. The remaining patients-
approximately 25%-have muscleinvasive
disease on a biopsy specimen
and have a worse prognosis. Outcomes
in these patients are dependent upon
tumor stage and grade, and high
recurrence rates are seen even with
disease confined to the bladder wall
managed with cystectomy or primary
radiotherapy. Patients who subsequently
develop metastatic disease or
present with it can expect a median
survival of about 14 months with combination
systemic chemotherapy.

Current areas of clinical research
for urothelial carcinomas are focused
on improving the outcomes of patients
with muscle-invasive disease with the
use of local and systemic therapy, as
mounting evidence suggests a role for
chemotherapy in the perioperative setting.
Work continues toward the de
velopment
of multimodality, bladdersparing
approaches that incorporate
surgery, radiotherapy, and chemotherapy
with the intent of avoiding radical
cystectomy. For patients with metastatic
disease, the focus has been on new
cytotoxic agents and combinations that
have better therapeutic and toxicity profiles
in addition to investigating the
role of targeted therapies.

Management of Locally
Invasive Disease
Surgery
The current standard approach for
treatment of muscle-invasive bladder
cancer involves radical cystectomy
and bilateral pelvic lymphadenectomy.
Long-term survival in this setting
has been evaluated in multiple surgical
series (Table 1).[2-4] The 5-year
survival rate is 68% for patients with
pathologically organ-confined bladder
cancer (pT2), compared with about
25% to 30% for those with extravesicular
extension.[3] Analysis of subsets
of patients with muscle-invasive
disease has determined that both extravesicular
disease and node-positive
disease are predictive of decreased
survival.[4] The poor outcomes seen
with surgical resection alone have provided
the rationale for investigating a
multimodality approach to the management
of invasive bladder cancer
patients. Learning from the positive
outcomes with the utilization of adjuvant
or neoadjuvant chemotherapy for
a variety of other solid tumors, such
trials evaluating perioperative chemotherapy
for invasive bladder cancer
have been conducted.

Neoadjuvant Chemotherapy
The goal of neoadjuvant chemotherapy
is to improve survival via the
"eradication" of micrometastatic disease.
There are several potential advantages
to the neoadjuvant approach,
including the facilitation of bladdersparing
strategies. In addition, because
patients have the bladder in place,
oncologists are able to monitor for
response during treatment, which has
prognostic value.[5] Patients may also
be better able to tolerate chemotherapy
before surgery when their performance
status is higher, whereas they
may not be good candidates for chemotherapy
following a major surgical
procedure. One of the disadvantages
of this approach is that patients with
chemoresistant disease may progress
while receiving neoadjuvant treatment
and, therefore, risk progressing to a
nonoperable stage due to the delay in
providing definitive local therapy.

Several randomized clinical trials
have been performed to evaluate the
use of neoadjuvant platinum-based regimens
(Table 2).[6-15] Most of these
trials failed to demonstrate a survival
advantage, but many of the studies have
shortcomings. They included small
numbers of patients and are underpowered
to detect a difference in survival.
Some trials evaluated single-agent chemotherapy,
which is known to be less
efficacious than combination regimens.
Other trials allowed patients to receive
either radiation or cystectomy for local
therapy, and these two modalities have
not been directly compared. Poor local
control may impact overall outcomes
and affect the results of these
studies. Three of these trials, however,
strongly suggest an advantage for
neoadjuvant chemotherapy.

  • International Collaboration-A
    multi-institutional trial randomized 976
    patients to either local therapy alone or
    three cycles of CMV (cisplatin, methotrexate,
    vinblastine) followed by local
    therapy.[6] Local therapy consisted of
    either cystectomy or radiation therapy
    at the treating physician's discretion,
    and a portion of patients received both
    radiation and surgical resection. Eligible
    patients had T2-4a, N0 or NX, M0
    disease, and T3 patients comprised 58%
    of the study population. Eighty percent
    of patients in the chemotherapy
    arm were able to receive all three cycles
    of neoadjuvant chemotherapy.

    Study results showed a 3-year
    absolute survival difference of 5.5%
    (P = .075).[6] The survival rate was
    55.5% in the chemotherapy arm vs
    50% in the local therapy-only arm. A
    trend toward improved overall survival
    with neoadjuvant chemotherapy
    was demonstrated, although these
    differences did not reach statistical
    significance. In a follow-up published
    in abstract form only, after 7.4 years,
    a 6% statistically significant improvement
    in overall survival was observed
    in patients treated with neoadjuvant
    chemotherapy (P = .048).[16]

  • INT-0080-In 2003, Grossman et
    al reported the results of a Southwest
    Oncology Group (SWOG)-intergroup
    randomized neoadjuvant trial, which
    also suggested a trend toward a survival
    advantage with combination
    therapy.[9] In this study, 307 patients
    with invasive bladder cancer were randomized
    to either radical cystectomy
    alone or to three cycles of MVAC
    (methotrexate, vinblastine, doxorubicin,
    cisplatin) followed by radical cystectomy.
    The study included patients
    who had T2-4a disease without evidence
    of lymph node involvement or
    distant metastasis, and 60% of patients
    had more advanced disease (either
    T3 or T4a).

    By intent-to-treat analysis, the median
    survival in the surgery arm was
    46 months and in the combinationtherapy
    arm was 77 months, but this
    trend failed to reach statistical significance
    when evaluated by a two-sided
    stratified log-rank test (P = .06). Similar
    results were found for 5-year overall
    survival rates. Of note, the study
    was initially designed to be analyzed
    using a one-sided stratified log-rank
    test. At the time of cystectomy, a significant
    difference in residual disease
    was noted between the two groups.
    While only 15% of the cystectomy
    group were without residual disease,
    38% of the combination-therapy
    group were disease free at cystectomy
    (P < .001), and 85% of patients
    with pT0 disease at the time of surgery
    were alive at 5 years.

    In patients who received neoadjuvant
    MVAC, the toxicity profile was
    acceptable with no associated toxic
    deaths reported, and compared to the
    surgery-alone arm they did not experience
    an increase in postoperative
    complications. This study demonstrated
    the feasibility of neoadjuvant
    MVAC in patients with muscle-invasive
    muscle bladder cancer. A strong
    trend toward a survival advantage was
    identified, as well as a reduction in
    risk of death and an increased disease-
    free rate at cystectomy.

  • Nordic Trials-Trials-A more recent
    publication by Sherif et al presented
    the combined results of two Nordic
    trials that evaluated neoadjuvant platinum-
    containing regimens prior to cystectomy.[
    12] A total of 620 patients
    with grade 3 T1 disease or T2-4a, NX
    disease were included, and 51% of
    enrolled patients had T3 or T4a disease.
    The first trial included 311 patients
    and evaluated cisplatin plus
    doxorubicin vs no chemotherapy, followed
    by radiation therapy and then
    surgery.[10] In this right, the second
    trial included 309 patients and compared
    cisplatin plus methotrexate followed
    by surgery to surgery alone.[13]
    Overall survival at 5 years in the neoadjuvant
    chemotherapy group was
    56% and in the surgery-alone group
    was 48% (P = .049). Although this
    report is a combination of two trials
    that differ both in the chemotherapeutic
    agents used and in the use of
    radiation therapy, the results support
    the use of neoadjuvant chemotherapy
    in patients with muscle-invasive bladder
    cancer.
  • Meta-analysis-A meta-analysis
    of data for 2,688 individual patients
    with T2-4a transitional cell carcinoma
    from 10 trials demonstrated a non-
    statistically significant 9% reduction
    in the relative risk of death for patients
    treated with neoadjuvant chemotherapy,
    equivalent to an absolute
    survival increase of 3% at 5 years.[7]
    While no benefit for neoadjuvant chemotherapy
    was observed in patients
    treated with cisplatin alone, patients
    treated with platinum-based combination
    chemotherapy regimens had a
    statistically significant 13% reduction
    in relative risk of death, equivalent to
    an absolute survival benefit of 5% at
    5 years. Five-year overall survival increased
    from 45% to 50%, an effect
    that was seen regardless of the local
    treatment modality.

    In summary, although no single
    trial has conclusively demonstrated
    the benefit of neoadjuvant chemotherapy,
    the preponderance of the evidence
    from multiple randomized trials
    indicate that neoadjuvant combination
    chemotherapy should be offered to
    all patients with muscle-invasive bladder
    cancer.

Adjuvant Chemotherapy
Adjuvant chemotherapy has also
been evaluated in an attempt to improve
outcome in patients with muscle-
invasive bladder cancer. By treating
patients postoperatively, definitive local
treatment is provided up front without
delay. Because the surgery is
performed first, complete pathologic
staging information can be obtained
for making treatment decisions, allowing
better patient selection. Some of
the limitations of the adjuvant approach
include delay in initiating systemic therapy
directed toward micrometastatic
disease, an inability to assess response
to chemotherapy postcystectomy, and
difficulties in the delivery of chemotherapy
in the adjuvant setting due to
surgical complications and decreased
patient tolerance.

  • Randomized Trials-Two randomized
    trials suggested a benefit for
    adjuvant therapy for bladder cancer.
    Skinner et al randomized 91 high-risk
    patients to cystectomy alone or to cystectomy
    and adjuvant CISCA (cisplatin,
    cyclophosphamide, doxorubicin
    [Adriamycin]).[17] No significant
    difference in 5-year overall survival
    was identified, but patients in the chemotherapy
    arm had a prolonged disease-
    free survival of 51% vs 34% for
    cystectomy alone at 5 years (P = .011).
    Although this difference in disease-
    free survival reached statistical significance,
    the disease-free survival
    curves crossed after 7 years. Investigators
    have suggested that this pattern
    reflects the fact that the chemotherapy
    regimen was ineffective for
    curing disease and merely delayed
    progression. The subgroup of patients
    with only one positive lymph node
    had an improved disease-free survival
    and overall survival with adjuvant
    chemotherapy, but no survival benefit
    was found if two or more lymph
    nodes were involved.[17] Numerous
    aspects of this study have been
    criticized, including its retrospective
    use of subgroup analyses, small sample
    size, and questionable statistical
    methodology.

    Another small trial was reported
    by Stockle et al, who randomized patients
    with pT3-pT4a disease postcystectomy
    to either observation,
    three cycles of MVAC, or three cycles
    of MVEC (methotrexate, vinblastine,
    epirubicin [Ellence], cisplatin).[18]
    After 3.5 years, the study was halted
    because an interim analysis of 49 patients
    demonstrated a large difference
    in disease-free survival at 3 years. In
    an intention-to-treat analysis, the 3.5-
    year disease-free survival rate was
    63% with adjuvant therapy and only
    13% with cystectomy alone. A significant
    benefit was noted for patients
    with lymph node-positive disease
    who received adjuvant chemotherapy.
    Only 27% of patients who received
    chemotherapy had evidence
    of disease progression, as compared
    to 92% of those treated with surgery
    alone.

    In 2000, Sylvester et al published
    a review of four previously conducted
    adjuvant chemotherapy trials, including
    the two described above. The
    authors determined that these trials
    contained significant flaws in methodology
    and are therefore insufficient
    to justify the routine use of adjuvant
    chemotherapy.[19] Although the
    studies performed have included
    small numbers of patients and are
    underpowered to demonstrate a survival
    benefit, current data demonstrate
    that adjuvant chemotherapy delays
    recurrence of disease. Current guidelines
    from the National Comprehensive
    Cancer Network (NCCN)
    therefore recommend the use of adjuvant
    chemotherapy to radiation in
    patients at high risk for relapse.[20]

Combined-Modality Therapy
Not all patients are candidates for
radical cystectomy, either because of
significant comorbidities or due to
unresectable disease. Other patients
refuse surgery for fear of compromising
quality of life. As an alternative,
these patients may be treated with definitive
radiotherapy, but radiation
alone has poor curative potential, as
data indicate that up to 70% of these
patients may experience a local recurrence
and 5-year survival rates are
generally suboptimal.[21] The addition
of chemotherapy to radiation has
been shown to improve local control
but not overall survival.[8]

Typically, a trimodality approach
is used in which a maximum transurethral
resection (TUR) is performed
followed by bladder irradiation
concurrent with radiosensitizing chemotherapy.
In addition, either neoad-
juvant or adjuvant chemotherapy is
sometimes given. Periodic cystoscopies
are performed to monitor for
disease, and if recurrence is noted,
patients undergo salvage radical cystectomy.
To date, there has not been a
randomized trial to address the issue
of bladder preservation adequately.

  • Clinical Trials-Rodel et al evaluated
    415 patients with high-risk T1
    and T2-4 disease treated with transurethral
    resection of bladder tumor
    (TURBT) followed by radiation or
    radiochemotherapy.[22] The patients
    underwent restaging TUR 6 weeks
    after completion of adjuvant therapy,
    and 72% achieved a complete response.
    Combination radiation and
    chemotherapy resulted in higher rates
    of complete response and survival
    than radiotherapy alone. Overall survival
    for all patients was 51% and
    31% at 5 and 10 years, respectively.
    Patients with muscle-invasive tumors
    had 5- and 10-year overall survival
    rates of 45% and 29%, respectively.
    Of surviving patients, 80% maintained
    their bladders. Patients who
    did not achieve a complete response
    following initial therapy underwent
    radical cystectomy. The major limitation
    of this series is that patients
    were not prospectively randomized,
    hence limiting the conclusions regarding
    outcome.

    Shipley et al performed a similar
    study of 190 patients with muscleinvasive
    T2-4a disease.[23] Following
    TURBT and radiochemotherapy, only
    35% of patients required radical cystectomy,
    either because of inability to
    achieve complete response or because
    of disease recurrence. The 5- and 10-
    year overall survival rates were 54%
    and 36%, respectively, similar to results
    reported for radical cystectomy.

    Sternberg et al investigated an alternative
    approach. A total of 104 patients
    with T2-4, N0, M0 bladder
    cancer were treated with three cycles
    of neoadjuvant MVAC.[24] Patients
    then underwent treatment with
    TURBT, partial cystectomy, or radical
    cystectomy based on response to
    chemotherapy. Of the 52 patients who
    underwent TURBT, 44% maintained
    an intact bladder and 60% were alive
    at a median follow-up of 56 months.
    The subset of patients who underwent
    radical cystectomy after chemotherapy
    had a survival rate of 38% at a
    median follow-up of 45 months. In
    both cohorts, patients had higher survival
    rates if they were staged as T0
    following chemotherapy.

  • Limitations of Bladder Preservation-Despite encouraging outcomes,
    there are concerns regarding bladderpreservation
    approaches. Critics of
    bladder preservation fear that with an
    intact bladder, metachronous bladder
    cancers remain and are a source for
    recurrent and possibly fatal disease. In
    the series by Shipley et al, 13% of
    patients experienced recurrent invasive
    disease necessitating cystectomy,[23]
    but similar outcomes were observed
    whether cystectomy was performed for
    incomplete initial response or for recurrence,
    suggesting that even with recurrent
    disease, bladder preservation
    protocols can achieve similar outcomes
    to primary cystectomy. The use of neoadjuvant
    chemotherapy is associated
    with a lack of up-front pathologic staging
    and a significant rate of understaging
    of patients by clinical measures.
    As many as 30% of clinically T0 tumors
    following chemotherapy have
    been found to have residual disease at
    cystectomy.[25]
  • Conclusions-Until definitive data
    are available, it is reasonable to conclude
    that bladder preservation may
    be a suitable alternative to radical cystectomy
    for a select group of patients
    who achieve complete response to initial
    therapy. No randomized trials
    comparing radical cystectomy to a
    bladder-sparing approach have been
    conducted. While prospective studies
    are needed to address the important
    question regarding the efficacy of organ
    preservation relative to cystectomy-
    based therapy, it is important to
    establish several key metrics to judge
    the success and suitability of the preservation
    approaches. Possible measures
    include not only survival and rates
    of adequate local control, but also primary
    disease relapse rates, rates of
    functioning bladder, development of
    new bladder primaries, systemic disease
    control, and feasibility in the general
    bladder cancer population.

    Patients must be carefully selected
    for bladder-preservation protocols.
    Ideal candidates have minimal or no
    carcinoma in situ, have small-volume
    unifocal disease, have no poor risk
    features such as hydronephrosis, have
    undergone maximum TUR,[22,23]
    and are motivated to participate in
    regular follow-up.

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