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Bladder Cancer BJUI Mini Reviews - Systemic Therapy for Metastatic Urothelial Carcinoma
Bladder Cancer BJUI Mini Reviews - Systemic Therapy for Metastatic Urothelial Carcinoma | BJUI Mini Reviews - Systemic Therapy for Metastatic Urothelial Carcinoma |
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(BJUI Mini Reviews) - Metastatic UC remains a challenging disease and continued clinical research efforts as well as studies to evaluate drug-resistance are warranted.
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![2007 BJU INTERNATIONAL | 101, 795–803 | doi:10.1111/j.1464-410X.2007.07356.x
795
Systemic therapy for metastatic urothelial carcinoma
Chia-Chi Lin*†‡, Chih-Hung Hsu*, Yeong-Shiau Pu† and Nicholas J. Vogelzang¶
Departments of *Oncology and †Urology, National Taiwan University Hospital, Taipei, Taiwan; ‡Translational Genomics
Research Institute’s Clinical Research Services at Scottsdale Healthcare, Scottsdale, Arizona, USA and ¶Nevada Cancer
Institute, Las Vegas, Nevada, USA
Accepted for publication 14 September 2007
showed that intensified MVAC (HD-MVAC)
with growth-factor support was less toxic
than classic MVAC. Overall RR, complete
response (CR) rate, and progression-free
survival (PFS) were superior for HD-MVAC but
the difference in overall survival (OS) was not
significant in the initial publication [5]. With a
longer follow-up the initial results have been
confirmed, with PFS and OS hazard ratios of
0.73 and 0.76, respectively. The 2-year OS of
HD-MVAC and MVAC was 36% and 26%,
respectively; the 5-year OS was 21% and 13%,
respectively [6].
FIRST-LINE PLATINUM-CONTAINING
TWO-DRUG CHEMOTHERAPY
In an important randomized study, the
combination of gemcitabine and cisplatin
(GC) was equally effective, as assessed by RR,
PFS and OS, but less toxic than classic MVAC.
The study was designed to detect a 4-month
survival benefit of GC and that the two
combinations were not equivalent [7]. The
long-term results of this study confirmed
similar 5-year OS and PFS of GC (13.0% and
9.8%) and of MVAC (15.3% and 11.3%) [8].
Although the study did not reach either
endpoint, GC has effectively become the
standard of care in UC. Thus two-drug
platinum-containing regimens such as GC
have been widely studied in phase II and III
trials. In a randomized phase III trial from the
Hellenic Oncology Cooperative Group, the
combination of docetaxel and cisplatin was
compared with growth factor-supported
MVAC. Docetaxel plus cisplatin was not as
good as MVAC, although the difference in
survival was not statistically significant due to
an imbalance in performance status (PS)
between the arms [9]. Another phase III study,
which was designed to compare MVAC with
paclitaxel plus carboplatin, never completed
accrual and thus no conclusions can be drawn
[10]. The M.D. Anderson group compared
MVAC with cisplatin, 5-fluorouracil and
interferon-
good as MVAC, although the difference in
survival was not statistically significant due to
an imbalance in performance status (PS)
between the arms [9]. Another phase III study,
which was designed to compare MVAC with
paclitaxel plus carboplatin, never completed
accrual and thus no conclusions can be drawn
[10]. The M.D. Anderson group compared
MVAC with cisplatin, 5-fluorouracil and
interferon-
α
, and reported equivalent survival
[4]. Cisplatin and 5-fluorouracil-based
regimens are clearly active. We reported a
phase II trial of cisplatin and high-dose 24-h
infusion of 5-fluorouracil plus leucovorin in
35 chemotherapy-naive patients with
metastatic UC, with a RR of 57%, a median
survival of 12.3 months and a very favourable
toxicity profile [12]. Further studies of
platinum and fluoropyramidine combinations
are needed. The oral fluoropyramidine,
capecitabine, has not been studied. Despite
some statistical limitations, the results of
randomized phase III trials indicate that HD-
MVAC with growth-factor sup, and reported equivalent survival
[4]. Cisplatin and 5-fluorouracil-based
regimens are clearly active. We reported a
phase II trial of cisplatin and high-dose 24-h
infusion of 5-fluorouracil plus leucovorin in
35 chemotherapy-naive patients with
metastatic UC, with a RR of 57%, a median
survival of 12.3 months and a very favourable
toxicity profile [12]. Further studies of
platinum and fluoropyramidine combinations
are needed. The oral fluoropyramidine,
capecitabine, has not been studied. Despite
some statistical limitations, the results of
randomized phase III trials indicate that HD-
MVAC with growth-factor support, and GC,
have favourable toxicity profiles and survival
comparable to MVAC (Table 1).
The more favourable toxicity profile of
carboplatin, especially for emesis,
nephrotoxicity and neurotoxicity, as well as
ease of administration, makes this agent
an attractive alternative to cisplatin.
Unfortunately, three randomized phase
II studies showed an inferior RR with
carboplatin as opposed to cisplatin-based
chemotherapy, indicating the inferiority of
carboplatin-based chemotherapy [13–15].
Presently, cisplatin-based chemotherapy
KEYWORDS
bladder cancer, cisplatin, gemcitabine,
paclitaxel, transitional cell carcinoma
INTRODUCTION
Urothelial carcinoma (UC) is a relatively
chemosensitive malignancy. The current
standard treatment for metastatic disease is
combined chemotherapy, e.g. methotrexate,
vinblastine, doxorubicin and cisplatin (MVAC).
Response rates (RRs) of metastatic UC to
combined chemotherapy are 40–70% [1].
Randomized trials show that the MVAC
regimen is superior to cisplatin alone [2], to a
combination of cisplatin, cyclophosphamide
and doxorubicin [3], or to a combination of
cisplatin, 5-fluorouracil and interferon-
α
[4]
(Table 1) [2–11]. Although MVAC generates
high tumour RRs, the impact of
chemotherapy on patient survival requires
improvement. An update of a large
[4]
(Table 1) [2–11]. Although MVAC generates
high tumour RRs, the impact of
chemotherapy on patient survival requires
improvement. An update of a large
multicentre trial revealed that only 3.7% of
the patients treated with MVAC were alive
and disease-free at 6 years [2]. Furthermore,
the toxicity of these regimens is considerable,
with 20–30% of patients having febrile
neutropenia, 10–20% having grade 3 or 4
mucositis, and 3–4% having treatment-
related mortality. Consequently, investigators
continue to search for new drugs and better
combinations with greater activity and fewer
side-effects.
A study by the European Organisation for the
Research and Treatment of Cancer (EORTC)
LIN
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2007 THE AUTHORS
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2007 BJU INTERNATIONAL
represents the standard of care for patients
who can tolerate such regimens.
The combination of gemcitabine and
carboplatin has been studied in six phase II
trials [16–21]. In three phase II trials, which
did not specifically include patients unfit for
cisplatin treatment, RRs of 38–59% and a
median OS of 10–16 months were reported
[18–20]. Gemcitabine combined with
oxaliplatin has been reported by several
groups [22–25]. One encouraging phase II
trial, which included eight of 30 patients with
a creatinine clearance of
<
60 mL/min,
reported a RR of 47% and a median OS of 15
months [24]. In another phase II trial, which
included 46 patients of whom 75% had a
creatinine clearance of
<
60 mL/min, 53% had
visceral metastases and 50% had an Eastern
Cooperative Oncology Group (ECOG) PS of 2,
reported a RR of 48% and a median OS of 6.5
months [25].
FIRST-LINE TWO-DRUG CHEMOTHERAPY
WITH NO CISPLATIN
Most studies using non-cisplatin two-drug
chemotherapy included patients who could
not receive cisplatin due to impaired renal
function (creatinine clearance of
<
60 mL/
min), a poor PS (ECOG PS
>
1), elderly (age
>
70
years), or cardiac/pulmonary comorbidities
precluding the hydration required for
cisplatin administration. By contrast, data on
the efficacy of non-cisplatin two-drug
chemotherapy in patients who are fit for
cisplatin-based treatment are few. Most of
the regimens are gemcitabine-based.
Gemcitabine and taxane represent the best
studied non-platinum two-drug combination.
In four phase II trials using different
schedules of gemcitabine and paclitaxel, RRs
were 30–69% in previously treated or
untreated patients [26–29]. Specifically in
patents who had previously received MVAC as
adjuvant or first-line treatment for metastatic
disease, Sternberg
et al.
[26] showed a 60%
RR and a median OS of 14.4 months. However,
a later study, using the same schedule, did not
confirm such a high RR, even after adjusting
for prognostic factors [27]. Finally, an
impressive RR of 69%, with a CR rate of 42%,
in 36 patients was reported with a weekly
schedule. However, because of the high
incidence of pulmonary toxicity associated
with this schedule, the authors recommended
against the use of this regimen in metastatic
UC [28]. In two phase II trials using
gemcitabine plus docetaxel, RRs of 33% and
51% were reported. The combination was well
tolerated [30,31].
The combination of gemcitabine and
pemetrexed as first-line treatment for
metastatic disease was studied in two phase II
trials, with RRs being 20% and 28%. Toxicities
were significant, including one toxic death.
Further development of this combination
might be limited by toxicity and the lack of
apparent benefit in antitumour response over
single-agent gemcitabine [32,33]. The
addition of vinorelbine [34] or anthracycline
[35,36] to gemcitabine has also been studied
with varying results.
FIRST-LINE THREE-DRUG CHEMOTHERAPY
The promising single-agent activity of
gemcitabine, platinum and taxane led to
the development of a variety of new triplets
(Table 2) [37–46]. The Spanish Oncology
Genitourinary Group conducted a phase
TABLE 1
Selected randomized phase III trials for metastatic UC
Agent/Ref Response, % Survival, months P Toxic death, %
MVAC 36 12.5
<
0.001 4
Cisplatin [2] 11 8.2
MVAC 65 12.6
<
0.05 5
CISCA [3] 46 10.0
MVAC 59 12.5 NS 9
FIP [4] 42 12.5
MVAC 58 14.1 NS 4
HD-MVAC, G-CSF [5,6] 72 14.5 3
MVAC 46 14.8 NS 3
GC [7,8] 50 13.8 1
MVAC, G-CSF 54 14.2 0.026 2
Cisplatin, docetaxel [9] 37 9.3 1
MVAC 36 15.4 NS 2
Carboplatin, paclitaxel [10] 28 13.8 2
GCP 57 15.7 NS 1
GC [11] 46 12.8 1
CISCA, cisplatin, cyclophosphamide and doxorubicin; FIP, 5-fluorouracil, interferon-
α
and cisplatin; NS,
not significant.
TABLE 2
Selected phase II trials of three-drug combination for metastatic UC
Agents/Ref
No. of
patients
Visceral
metastasis, % RR, % CR, % OS, months
GCP [37] 61 36 76 26 15.6
Paclitaxel, carboplatin, gemcitabine [38] 49 49 68 32 14.7
Paclitaxel, carboplatin, gemcitabine [39] 60 58 43 12 11.0
Docetaxel, cisplatin, gemcitabine [40] 35 NR 65 29 15.5
Paclitaxel, cisplatin, ifosfamide [41] 44 48 68 23 20.0
Gemcitabine, cisplatin, ifosfamide [42] 51 48 41 4 9.5
Paclitaxel, cisplatin, 5-fluorouracil [43] 44 50 68 25 17.0
Gemcitabine, cisplatin, etoposide [44] 31 39 68 19 13.1
Paclitaxel, methotrexate, gemcitabine [45] 25 36 57 29 18.0
Paclitaxel, carboplatin, gemcitabine,
trastuzumab [46]
44 52 57 9 14.1
NR, not reported.
SYSTEMIC THERAPY FOR METASTATIC UROTHELIAL CARCINOMA
©
2007 THE AUTHORS
JOURNAL COMPILATION
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2007 BJU INTERNATIONAL
797
I/II trial of the combination of gemcitabine,
cisplatin and paclitaxel (GCP). The overall RR
and CR rate at the phase II part of the study
were 76% and 26%, respectively, and the
median OS was 15.6 months [37]. Hussain
et al.
[38] conducted a phase II trial evaluating
the efficacy of the combination of paclitaxel,
carboplatin and gemcitabine in patients with
advanced UC. Most of the 49 patients who
were enrolled would have been eligible for
cisplatin-based chemotherapy. The overall RR
was 68%, with a CR rate of 32% and a median
OS of 14.7 months. In a similarly designed
study, the Minnie Pearl Cancer Research
Network failed to duplicate these results, with
a lower RR (43%), CR rate (12%) and median
OS (11 months) in 60 patients with similar
prognostic features [39]. Pectasides
et al.
[40]
assessed a weekly regimen of docetaxel,
carboplatin and gemcitabine in 35 patients;
the RR was 65% and the median OS 15.5
months in a population with a predominantly
good prognosis (77% ECOG PS 0 or 1).
There have been two ifosfamide-based three-
drug combinations (Table 2). The Memorial
Sloan Kettering Cancer Center (MSKCC)
evaluated the combination of paclitaxel,
cisplatin and ifosfamide. The overall RR was
68%, with a CR rate of 23% and a median
OS of 20.0 months [41]. The M.D. Anderson
Cancer Center evaluated the combination of
gemcitabine, cisplatin and ifosfamide; the
overall RR was 41%, with a CR rate of 4% and
a median OS of 9.5 months [42]. Our group
evaluated the combination of paclitaxel,
cisplatin and 5-fluorouracil; the overall RR
was 68%, with a CR rate of 25% and a median
survival of 17.0 months [43]. A Japanese
group evaluated the combination of
gemcitabine, cisplatin and etoposide,
reporting an overall RR of 68%, with a CR rate
of 19% and a median OS of 13.1 months [44].
The results of a phase I/II study by Lara
et al.
[45] reported the use of a triplet comprising
paclitaxel, methotrexate and gemcitabine. In
20 evaluable patients, the overall RR was 45%
and the median OS was 18 months, with the
most common toxicity being neutropenia.
The first phase III study of a doublet vs a
triplet regimen was recently reported by the
EORTC. From June 2001 to May 2004, 627
patients were randomized to GC or GCP. The
study was designed to detect a 4-month
survival benefit (from 14 months of GC to 18
months of GCP). The RR of GCP (57%) was
significantly higher than that of GC (46%),
with CR rate of GCP and GC being 15% and
10%, respectively. The OS of GCP and GC was
15.7 months and 12.8 months, respectively.
This was not a statistically significant
difference (hazard ratio 0.86;
P
=
0.10).
However, in an unplanned subgroup analysis
involving 512 patients with bladder primary
tumour, the OS of GCP was significantly
longer than that of GC (hazard ratio 0.81;
P
=
0.03). The GCP regimen resulted in a
significantly higher rate of grade 3 or 4
neutropenia and the GC regimen had more
grade 3 or 4 thrombocytopenia. The toxic
death rate was the same and low (two
patients each arm) [11].
PROGNOSTIC FACTORS
The reported survival of patients with
metastatic UC treated in chemotherapy
trials varies widely, possibly explained by
pretreatment disease- and patient-related
factors. In a retrospective multivariate
analysis evaluating 18 variables in 203
patients treated in five different MVAC trials, a
Karnofsky PS of
<
80% and the presence of
visceral metastasis were independently
prognostic of poor survival. The presence of
the none, one and two adverse factors was
associated with a median survival of 33.0,
13.4 and 9.3 months, respectively, with
respective 5-year survival rates of 33%, 11%
and 0% [47]. More recent analyses also
identified the same or similar factors to be
associated with prognosis (Table 3) [8,47–50].
Among 121 patients treated in three different
GC phase II trials, the presence of visceral
metastasis was the only independent
prognostic factor. Patients with no visceral
metastases had a 24% chance of 4-year
survival [48]. Long-term survival results of a
randomized phase III trial of 405 patients
treated with MVAC or GC showed that a
Karnofsky PS of 70%, the presence of visceral
metastasis, more than three metastatic
sites, the M1 stage and elevated alkaline
phosphatase were the most important poor
prognostic factors [8]. Another phase II trial of
56 patients treated with GCP showed almost
identical median survival times for patients
within the same risk categories treated with
MVAC [49]. Our multivariate analysis
evaluating 12 variables in 79 patients treated
with two cisplatin and 5-fluorouracil-based
regimens, a Karnofsky PS of
<
80%, the
presence of visceral metastasis and elevated
alkaline phosphatase were independently
prognostic of poor survival. The presence of
the none, one or two, and three adverse
factors was associated with a median survival
of
>
81.8, 13.2 and 4.6 months, respectively,
with respective 2-year OS rates of 79%, 20%
and 0% [50]. As phase II outcomes are
susceptible to selection bias, understanding
the impact of these prognostic features,
especially PS and presence or absence of
visceral metastasis, allows for a better
interpretation of phase II trial results.
Besides the clinical prognostic factors
mentioned above, attention has recently been
drawn to the role of genetic and molecular
factors in predicting the response to
chemotherapy [51]. Cisplatin resistance
appears to be mediated by the nucleotide
excision repair (NER) system which removes
bulky platinum DNA adducts. The excision
repair cross-complementing 1 (ERCC1) gene
plays a pivotal role in NER and an increase in
protein expression of ERCC1 is likely to cause
TABLE 3
Independent prognostic factors of overall survival for metastatic UC treated with systemic
chemotherapy
Study
[47] [48] [8] [49] [50]
Regimen MVAC GC MVAC vs. GC GCP (P)CF
Trials – 3 phase II 1 phase III 1 phase I/II 2 phase II
Patients 203 121 405 56 79
PS Yes Yes Yes Yes
Visceral metastasis Yes Yes Yes Yes Yes
No. of metastatic sites Yes
TNM stage Yes
Alkaline phosphatase Yes Yes
(P)CF, paclitaxel, cisplatin and 5-fluorouracil.
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ET AL.
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the cisplatin-resistance phenotype. Patients
with completely resected non-small-cell lung
cancer (NSCLC) and ERCC1-negative tumours
appeared to benefit from adjuvant cisplatin-
based chemotherapy, whereas patients with
ERCC1-positive tumours did not [52].
Similarly, ribonucleotide reductase subunit
M1 (RRM1) has been shown to be involved in
gemcitabine metabolism and DNA repair after
chemotherapy damage. A high level of mRNA
expression of RRM1 is predictive of the
resistance of NSCLC to gemcitabine and
platinum [52]. In the only published data for
UC, Bellmunt
et al.
[53] used a multivariate
analysis to evaluate nine variables, including
ERCC mRNA expression, in 57 patients treated
in two different GCP trials. An ECOG PS of 1
and high ERCC mRNA expression (defined as
>
7, with the median ERCC1 mRNA expression
relative to the housekeeping
β
-actin being
6.6, range 2.2–19.9) were independently
prognostic of poor survival. The presence of
the none, one and two adverse factors was
associated with median survivals of 26.4, 23.4
and 13.2 months, respectively.
SECOND-LINE CHEMOTHERAPY
There is no standard salvage regimen for
patients who are refractory to cisplatin-based
chemotherapy. Many single agents and
regimens have been tested in the second-line
setting, with varying degrees of activity.
Taxane-based therapies are currently the
most commonly used regimens in the second-
line setting. Docetaxel resulted in a modest
13% RR in a phase II study of 30 patients
previously treated with cisplatin-based
chemotherapy [54]. Paclitaxel has been tested
as a single agent in cisplatin-pretreated
advanced UC; the RR was 7% using an every
3-week schedule [55]. Weekly paclitaxel as
second-line therapy was associated with a
low (10%) RR only, and a short time to
progression [56]. Gemcitabine resulted in a
23% RR in a phase II study of 35 patients
previously treated with cisplatin-based
chemotherapy. Ifosfamide has significant
single-agent activity in patients with
previously treated UC [57]; in a phase II study
of single-agent ifosfamide as second-line
therapy, the overall RR was 20%, albeit with
significant toxicity [58].
The combination of docetaxel and ifosfamide
was tested in a phase II study of 22 patients
who had previously received platinum-based
chemotherapy. Four patients had a CR (RR
25%) and three of these responses lasted
>
1
year [59]. The combination of paclitaxel and
ifosfamide was tested in a phase II study of 13
patients who had previously received
platinum-based chemotherapy. The RR was
15%, with a CR in two patients [60]. The
gemcitabine-ifosfamide combination also
showed activity in the second-line setting,
resulting in a 21% RR in 34 platinum and/or
taxane-pretreated patients with advanced UC.
Probably the most important finding was the
significant symptomatic improvement in
significantly many patients [61]. We reported
the results of the combination of gemcitabine
and ifosfamide in 23 patients who did not
respond to cisplatin-based chemotherapy, or
who progressed from previously cisplatin-
sensitive status in
<
6 months; the RR was
22%, and the median PFS and OS were 3.5 and
4.8 months, respectively. The gemcitabine and
ifosfamide regimen has an acceptable toxicity
profile, but shows insufficient clinical activity
in patients with cisplatin-refractory UC to
warrant further testing [62]. Di Lorenzo
et al.
[63] used the combination of oxaliplatin and
5-fluorouracil plus folinic acid in pre-treated
patients with advanced UC of the bladder.
Oxaliplatin has minimal single-agent activity
in previously treated patients with UC [64],
but it has a pronounced synergistic effect
with 5-fluorouracil, which has been
confirmed in colorectal cancer. The RR
was 19% (three of 16 patients) and low
compared with the similar regimen in
colorectal cancer.
Given the similarities of UC and NSCLC, it is
not surprising that pemetrexed has shown
second-line activity in UC, as it does in NSCLC
[65]. Forty-seven patients were enrolled in a
phase II trial of pemetrexed as the second-line
treatment; the overall RR was 28%, with three
CRs, and the median OS was 9.6 months [66].
Another phase II trial of pemetrexed as the
second-line treatment was reported from the
MSKCC. Of the 12 evaluable patients, one
patient had a PR, for an overall RR of one of
12. This level of activity did not meet the
criteria for expansion, based on the
predefined optimum two-stage Simon design,
and the trial was concluded. The treatment
was generally well tolerated, but two of 13
patients developed febrile neutropenia [67].
Vinflunine, a fluorinated
Vinca
alkaloid, also
has activity in both NSCLC and UC as second-
line therapy [68]. Culine
et al.
[69] enrolled 51
patients in a phase II trial of vinflunine as the
second-line treatment. The overall RR was
18% and the median OS was 6.6 months.
Notably, there were responses in patients with
an interval of
<
12 months from previous
platinum therapy (19%), with previous
treatment with
Vinca
alkaloids (14%) and
with previous treatment for visceral
involvement (20%). Vinflunine is currently
being compared with the best supportive care
as second-line treatment after progression
following platinum-based chemotherapy. This
is the first phase III trial in a setting with no
standard treatment, underlining the necessity
for expanding clinical research in this area. A
tubulin-interactive agent, ixabepilone, was
studied by the ECOG in the second-line
setting in 45 patients. The overall RR was 12%
and the median OS was 8.0 months.
Neuropathy was a common and significant
toxicity, as was neutropenia. Interestingly
there were responses in patients previously
treated with paclitaxel [70].
TARGETED THERAPY
Targeted therapies might be useful after the
failure of first-line chemotherapy, especially
due to their favourable toxicity profile for
patients pre-treated with chemotherapy.
However, few studies have been published on
the use of targeted therapies to treat UC
(Table 4) [46,71–77]. One molecular target
which holds promise in UC is the epidermal
growth factor receptor (EGFR). EGFR is a
receptor tyrosine kinase (TK) that is strongly
expressed in about half of bladder UC and has
is associated with prognosis. EGFR can be
targeted at the level of the extracellular
domain using a monoclonal antibody against
the receptor or at the level of the intracellular
TK using a small molecule TK inhibitor (TKI).
The anti-EGFR antibodies, such as cetuximab
and panitumumab, have shown promising
efficacy in colorectal cancer, but data on the
activity in metastatic UC are not available so
far. The Fox Chase Cancer Center is currently
conducting a randomized phase II trial of
cetuximab vs cetuximab plus weekly paclitaxel
as the second-line therapy of metastatic UC.
Several TKIs of the EGFR have been developed
and already tested in other neoplasms. An
EGFR and HER2/neu TKI, lapatinib (1250 mg/
day), has been tested as second-line
treatment in UC showing only a 2% RR [71].
The combination of gefitinib (500 mg/day), an
EFGR TKI, with gemcitabine and cisplatin, has
been tested in a Cancer and Leukaemia Group
B (CALGB) phase II trial of 55 chemotherapy-
naive patients. The RR was 51% and the
SYSTEMIC THERAPY FOR METASTATIC UROTHELIAL CARCINOMA
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2007 THE AUTHORS
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2007 BJU INTERNATIONAL
799
median OS was 14.4 months [72]. As these
values were not noticeably better than with
GC alone, the CALGB has not chosen to
pursue EGFR modulation. However, the group
is exploring therapy using antibodies to
vascular endothelial growth factor (VEGF),
with a planned phase III trial of GC with or
without bevacizumab (see below). Much
effort has been spent in trying to understand
the determinants of tumour response to
gefitinib in UC. A recent study failed to detect
any mutations in exons 18–21 of EGFR in 11
cell lines and 75 tumour specimens of UC.
In these experiments, four cell lines were
sensitive to gefitinib
in vitro
, whereas the
other seven cell lines were drug-resistant.
Resistance to gefitinib was associated with
uncoupling between the EGFR and mitogen-
activated protein kinase, and could be
predicted by analysing the activation of
GSK-3
β
and cyclin D1. These data lead us
to understand that other variables and
cell properties apart from the status of
EGFR mutations can affect the response to
gefitinib [78].
The receptor coded by the HER2/neu gene also
represents a promising target for UC, and
trastuzumab, a monoclonal antibody
targeting this receptor, is already approved for
treating breast cancer over-expressing the
receptor. A series of muscle-invasive bladder
UC had a 28% rate of expression (2
+
and 3
+
),
and an 18% rate of high expression (3
+
) in
primary tumours. The level and intensity of
expression appeared to be higher in lymph
nodes and distant metastases than in primary
tumours, although its association with
prognosis has not been confirmed [79]. Based
on the efficacy of the combination of GCP and
the synergy of trastuzumab with paclitaxel
and platinum, the National Cancer Institute
sponsored a multicentre phase II trial of
this combination in metastatic UC. The
combination was administered to 44 patients
with HER2-positive tumours, with a RR of
57% and a median OS of 14.1 months; thus
the combination was feasible. Cardiac toxicity
rates were higher than projected, but most
were grade
≤
2 [46]. Determining the true
contribution of trastuzumab requires a
randomized trial. However, the median
survival of 14.1 months is not sufficiently
better than expected to warrant such an
endeavour.
Disturbances in Ras-signalling pathways have
been implicated in the pathogenesis of UC.
Protein farnesylation by farnesyl transferase
(FT) is required for membrane localization and
effective signal transduction by Ras. FT
inhibitors (FTIs), e.g. tipifarnib (R115777) [73]
and lonafarnib (SCH66336) [74,75], have been
tested in the clinical setting. A phase II trial
was conducted of tipifarnib (300 mg oral
twice daily for 21 days, repeated every
28 days) as the second-line therapy in 34
patients with metastatic UC. Neutropenia was
the main toxicity and two patients (6%) with
no previous chemotherapy had PRs. Thirteen
patients (38%) had disease stabilization that
lasted a median of 4 months. However, this
response rate was not considered sufficient to
warrant further investigations of tipifarnib as
single agent in metastatic UC [73]. A phase II
trial of lonafarnib (200 mg oral twice daily,
continuously) in 19 previously treated
patients with UC was done by the National
Cancer Institute of Canada. Five patients
discontinued the study protocol due to
toxicity. There were no responses in 10
patients who were assessable, fulfilling the
criteria to stop the study [74]. The
pharmacokinetics and activity of lonafarnib
(150 mg oral in the morning and 100 mg oral
in the evening, continuously) combined with
gemcitabine (1000 mg/m
2
on days 1, 8 and 15,
repeated every 28 days) were evaluated in 33
patients with advanced UC in an EORTC study.
The toxicity was acceptable; the RR was 32%,
with nine PRs and one CR. There was no
influence of exposure to lonafarnib on the
plasma level of gemcitabine or its metabolites
[75]. The results of the FTIs in UC are
disappointing, given that most low-grade,
noninvasive papillary urothelial tumours have
either HRAS or FGFR3 mutant proteins
[80,81]. One explanation could be that FTIs
inhibit proteins other than the FTs. In addition,
inhibition of HRAS by FTIs could cause
compensatory activation of other RAS
proteins (NRAS and KRAS) through
geranylgeranyl transferases, resulting in
treatment failure. Moreover, UCs might lose
the dependency on the Ras-signalling
pathway when they progress from superficial
to muscle-invasive stage [82].
Deacetylases are enzymes that catalyse the
removal of the acetyl moiety from the lysine
residues of proteins, including the core
nucleosomal histones. Together with
acetyltransferases, deacetylases regulate the
level of protein acetylation. Alterations in
both acetyltransferase and deacetylase
activity have been reported to occur in UC.
Deacetylases inhibitors induce growth arrest,
differentiation or apoptosis in a variety of
transformed cells. The antiproliferative effects
of deacetylases inhibitors are thought to be
due to drug-induced accumulation of
acetylated proteins, including the core
nucleosomal histones and other proteins
(e.g. BCL6, p53 and Hsp90). Vorinostat
(suberoylanilide hydroxamic acid) is a small-
molecule deacetylase inhibitor. A multicentre
phase II trial of vorinostat (200 mg oral twice
daily continuously) for patients with
advanced UC is being conducted by the
California Cancer Consortium. Concepts
are being developed to add suberoylanilide
hydroxamic acid or other deacetylase
inhibitors to GC.
The proteasome is responsible for the
degradation of intracellular proteins,
including several involved in the control of
the cell cycle and the regulation of apoptosis.
Proteasome inhibition with bortezomib has
TABLE 4
Selected phase II trials of targeted therapy for metastatic UC
Agents/ref Line
No. of
patients
Visceral
metastasis RR, % CR, % OS, months
Gefitinib, GC [72] 1st 55 67 51 NR 14.4
Trastuzumab, paclitaxel,
carboplatin, gemcitabine [46]
1st 44 52 57 9 14.1
Lapatinib [71] 2nd 59 NR 2 0 3.5
Tipifarnib [73] 1st or 2nd 34 62 6 0 6.8
Lonafarnib [74] 2nd 19 58 0 0 3.1
Lonafarnib, Gemcitabine [75] 2nd 33 NR 30 3 11.5
Bortezomib [76] 2nd 25 65 0 0 5.5
Sunitinib [77] 2nd 21 67 5 0 NR
NR, not reported.
LIN
ET AL.
©
2007 THE AUTHORS
800
JOURNAL COMPILATION
©
2007 BJU INTERNATIONAL
specifically promoted apoptosis of tumour
cells through the stabilization of p53, p27
and I
κ
B
α
, resulting in nuclear factor-
κ
B
inhibition. Bortezomib (1.3 mg/m
2
on days 1,
4, 8 and 11, repeated every 21 days) has been
tested in a phase II trial by the CALGB in
advanced or metastatic UC. Of 18 patients, 11
were evaluable for response and all had
progressive disease. Further studies of this
drug as a single agent were not recommended
by the investigators [76].
A functional vascular supply is critical for
continued proliferation and metastasis of
solid tumours. VEGF is central to angiogenesis
because it stimulates endothelial cell
proliferation and migration. Bevacizumab is a
neutralising anti-VEGF antibody approved for
use in combination with chemotherapy for
the treatment of metastatic colorectal cancer
and NSCLC. Several ongoing trials will
evaluate this agent in UC. The Hoosier
Oncology Group is conducting a phase II trial
to evaluate the combination of GC and
bevacizumab in patients with good renal
function, with the primary endpoint being
time to progression. The MSKCC is conducting
a phase II trial to evaluate the combination of
gemcitabine, carboplatin and bevacizumab in
patients with poor renal function. Sorafenib
and sunitinib are orally bioavailable multi-
targeted TKIs that inhibit TK activity of the
VEGF receptor. The ECOG is currently
recruiting patients for a phase II trial of
sorafenib in patients with progressive
advanced UC. Yale University is recruiting
patients for a phase II trial of sorafenib plus
gemcitabine and carboplatin for chemo-naive
patients with metastatic UC. A phase II trial of
sunitinib for the second-line treatment of
metastatic UC has been conducted at the
MSKCC; of 21 patients, 67% of whom had
visceral metastases, the RR was 5% [77].
CONCLUSIONS
Standard chemotherapy regimens of GC and
MVAC achieve median survivals of 14–16
months and are the standard of care. The
addition of a third chemotherapy agent,
paclitaxel, has had no major impact on
survival. Adding non-chemotherapy
targeted agents has also not yet improved
survival or RRs. Metastatic UC remains a
challenging disease and continued clinical
research efforts are warranted. Studies to
evaluate drug-resistance mechanisms in UC
are needed.
CONFLICT OF INTEREST
None declared.
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Correspondence: Nicholas J. Vogelzang,
Nevada Cancer Institute, 1 Breakthrough Way,
Suite 3–181, Las Vegas, NV 89144, USA.
e-mail:
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</script>
Abbreviations: UC, urothelial carcinoma;
(HD)-MVAC, (high-dose) methotrexate,
vinblastine, doxorubicin and cisplatin; RR,
response rate; EORTC, European Organisation
for the Research and Treatment of Cancer;
C(P)R, complete (partial) response; OS, overall
survival; PFS, progression-free survival; PS,
performance status; GC(P), gemcitabine,
cisplatin (paclitaxel); ECOG, Eastern
Cooperative Oncology Group; MSKCC,
Memorial Sloan Kettering Cancer Center;
NER, nucleotide excision repair; ERCC1,
excision repair cross-complementing 1;
NSCLC, non-small-cell lung cancer; RRM1,
ribonucleotide reductase subunit M1; EGFR,
epidermal growth factor receptor; CALGB,
Cancer and Leukaemia Group B; VEGF,
vascular endothelial growth factor; FT(I),
farnesyl transferase (inhibitor).](http://urotoday.com/images/stories/bjui_april2008cover.jpg)
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