Download Gemcitabine in the treatment of advanced transitional cell carcinoma

Annals of Oncology 17 (Supplement 5): v113–v117, 2006
doi:10.1093/annonc/mdj964
symposium article
Gemcitabine in the treatment of advanced transitional
cell carcinoma of the urothelium
J. Bellmunt*, S. Albiol, A. Ramı́rez de Olano, J. Pujadas & P. Maroto
On behalf the Spanish Oncology Genitourinary Group (SOGUG)
Medical Oncology Service, Hospital General Universitari Vall d’Hebron, Barcelona, Spain
Systemic chemotherapy is the only modality that has been
shown to improve survival in responding patients with
advanced bladder cancer [1, 2]. In randomized trials, M-VAC
(cisplatin, methotrexate, adriamycin, vinblastine) has
produced a modest, though significant survival benefit when
compared to cisplatin as a single agent, CISCA or
carboplatin-based regimens [1–3].Other extensively studied
combination regimens in metastatic urothelial carcinoma are
cisplatin and methotrexate (CM) and CMV (with vinblastine)
[4–6]. CMV has been shown to be superior to MV
(methotrexate and vinblastine) in a randomized study of 214
patients undertaken by the Medical Research Council [7]. This
study demonstrated the significant survival impact of cisplatin
and has helped to justify the routine use of cisplatin in all
designed combination chemotherapies. Although CM, CMV,
and M-VAC have never been compared in randomised
studies, the majority of the clinicians consider M-VAC as the
standard regimen. However, the limited results with the classical
M-VAC combination led in the nineties to the search for new
treatment approaches aiming to improve outcome and
treatment tolerance.
gemcitabine as single agent in bladder
cancer
Anti-tumor activity has been demonstrated with several single
agents including gemcitabine, the taxanes (paclitaxel and
docetaxel), ifosfamide and recently, pemetrexed, the
epothilones, and vinflunine [8–15], although these have rarely
*Correspondence to: Dr J. Bellmunt, Medical Oncology Service, Hospital General
Universitari Vall d’Hebron. P. Vall d’Hebron 119–129. 08035 Barcelona, Spain.
Tel: +34-93-2746085; Fax: +34-93-2746059; E-mail: [email protected],
[email protected]
ª 2006 European Society for Medical Oncology
produced an improvement in survival when used alone [16–18].
Among these new active chemotherapy agents, gemcitabine was
shown and is still, the most highly promising single-agent
activity in this disease.
Gemcitabine was initially evaluated in an Italian phase I study
conducted in 15 patients with metastatic bladder cancer [19].
The doses ranged from 875 to 1.370 mg/m2. One complete
response and 2 partial responses were seen in 14 previously
treated patients and 1 partial response was observed in
a chemotherapy-naive patient. The overall response rate was
27% (4.3–49.1%, 95% CI). In two phase II trials in previously
treated patients, a response rate of 28% and 50% was reported
[20, 21]. Two trials evaluating gemcitabine in previously
untreated patients confirmed the high activity of this agent.
Stadler et al. [22] treated 40 patients with gemcitabine
1200 mg/m2 weekly times three, repeated every 28 days, and
reported an overall response rate of 28% (15–45%, 95% CI).
Three complete responses were obtained in patients with liver
metastasis. Additionally, Moore et al. [23] confirmed in
37 non treated patients an overall response rate of 24.3%
(12–41%, 95% CI).
gemcitabine containing combination
regimens
Because of the high antitumor activity reported with various of
the previously mentioned new agents, particularly the
gemcitabine but also with the taxanes, a great deal of effort was
aimed at integrating these agents into combination regimens,
mainly with cisplatin and, in some instances, with carboplatin.
These newly designed double and triple combination therapies
have been evaluated in patients with advanced disease in several
phase II and III trials.
symposium
article
M-VAC (cisplatin, methotrexate, adriamycin, vinblastine) combination chemotherapy has been for long time the
standard of care in fit patient with advanced urothelial tumors. Gemcitabine/cisplatin with similar results and an
improved toxicity profile has proved to be a new standard alternative. Whether or not we can improve survival
with newer triplet regimens will depend upon the results of ongoing phase III trials. In addition to the new active
drug combinations and targeted therapies, new approaches are emerging for treatment. Chemotherapy
optimization using molecular markers predicting chemosensitivity are being applied. There is an obvious need to
incorporate in clinical trials a systematic translational approach to explain both our successes and our failures.
Key words: bladder cancer, chemotherapy, gemcitabine, urothelial cell cancer
symposium article
cisplatin-Gemcitabine vs. M-VAC
Following several phase II studies [24–27] gemcitabine and
cisplatin (GC) were combined in a randomized international
trial and compared to M-VAC. The trial revealed a similar
efficacy with respect to response, time to progressive disease and
survival between the two treatment arms, whereas GC was
significantly less toxic than M-VAC [28]. The median survival
was 13.8 months for GC treated patients and 14.8 months for
M-VAC treated patients with a hazard ratio of 1.04. The study
was designed to demonstrate a 4 months improvement in
survival benefit with GC and although this trial was not
designed to show the equivalence of the two regimens, many
researchers have interpreted the results as showing therapeutic
non-inferiority and determined that any difference in survival
was unlikely to be sufficiently large to offset the improvement in
toxicity with GC. Based on the favorable balance in the riskbenefit ratio in favor of GC, this regimen is considered
a standard alternative to M-VAC.
carboplatin-based regimens vs. M-VAC
Gemcitabine has been studied in combination with carboplatin
in different studies.
The gemcitabine/carboplatin [29] trial was a dose finding
study and it was evaluated in a clearly predefined ‘unfit’ bladder
cancer patients: PS > 2 and or creatinine clearance less than 60
ml/min. Using this combination investigators reported an
overall response rate of 43.5% with a median survival time of
14.4 months in 16 patients that were ineligible for a cisplatinbased regimen. The preliminary results found on this phase II
trial using the carboplatin/gemcitabine doublet prompted an
EORTC randomized phase II/III trial (EORTC protocol 30986)
comparing carboplatin/gemcitabine with methotrexate/
carboplatin/vinblastine (M-CAVI) in patients ineligible for
cisplatin-based chemotherapy. This trial is presently ready to
start the phase III.
triple combination chemotherapy
Several triple combinations with and without gemcitabine have
been studied in urothelial cancer patients. Bajorin et al. have
reported the activity of the combination of ifosfamide,
paclitaxel, and cisplatin (ITP). They demonstrated a response
rate of 68% and a median survival in the range of 20 months,
which was reported initially as a 50% increment in survival
compared historically to the original M-VAC series [30].
Based on these results, and on concepts derived from kinetic
models studied in breast cancer, investigators at Memorial
Sloan-Kettering have developed the concept of
dose-dense-sequential chemotherapy in bladder cancer using
the two-drug regimen of doxorubicin and gemcitabine (AG)
followed by the three-drug regimen of ifosfamide, paclitaxel
and cisplatin (ITP). In a phase I study with 15 patients, AG was
well tolerated at all dose levels and no grade 3 or 4
myelosuppression was observed [31]. In a phase II trial in 21
patients, the overall response rate reported was 86%. ITP
increased the response seen after AG in 6 patients. This
suggests non-cross resistance for the two regimens. The same
v114 | Bellmunt et al.
Annals of Oncology
approach has been evaluated in patients with impaired renal
function using AG, but followed by paclitaxel and carboplatin
with a median survival time as high of 15 months in these
unfit patients reported at recent ASCO meeting this year [32].
Taking in consideration the significant activity of paclitaxel
and gemcitabine, either alone or in combination with cisplatin,
their different mechanism of action, and their non-overlapping
toxicities, the Spanish Group (SOGUG) studied the feasibility of
adding paclitaxel to the doublet of gemcitabine/cisplatin in
a phase I/II trial. In 58 patients, an overall response rate of
78% was observed with a median survival time of 24 months
for the phase I segment of the trial and 15.6 months for the
phase II part of the study [33]. Similarly, another triplet was
evaluated but using carboplatin. Investigators at Wayne State
University, Detroit incorporated gemcitabine in the
carboplatin/paclitaxel combination in a phase II trial with 49
previously untreated patients with advanced urothelial
malignancy and normal renal function. Of the 47 patients
assessable for response, 15 obtained a CR and 15 obtained
a PR, for an overall response rate of 68%. The median
survival was 14.7 months [34].
To elucidate the role of paclitaxel when added to CG, a large
Global International study (EORTC 30987/Intergroup Study)
has now been closed to patient accrual (with 610 patients),
comparing cisplatin/gemcitabine/paclitaxel with the
conventional GC doublet. This trial will shed light on the role of
the triplets in the management of advanced urothelial tumors.
Whether or not we can improve survival with the newer triple
regimen will depend upon the results of this phase III trial.
As shown, throughout the years, many phase III trials have
evaluated new combinations such as, gemcitabine/cisplatin,
carboplatin/paclitaxel, docetaxel/cisplatin and interferon-a/
5-fluorouracil/cisplatin with M-VAC. Unfortunately, in all of
these randomized trials, the new regimens have failed to
demonstrate superiority in terms of overall survival when
compared with the classical M-VAC [34–37].
reducing toxicity: unfit, elderly and
renal-impaired patients
One major problem in urothelial tumors is that ‘unfit’ or ‘poor
performance status’ patients are often mixed or confused with
‘elderly’ and ‘renal-impaired patients.’ Clinical trials should be
designed to clearly distinguish among these three groups of
patients. Efficacy data about the use of chemotherapeutic
combinations in clearly defined ‘unfit’ patients as effective and
safe palliative therapy are still scant and the results of
EORTC30986 trial are awaited.
In a mixture of fit/unfit patients several carboplatin-based
regimens have been evaluated. The EGOC reported on
a 20.6% response rate with the combination of paclitaxel/
carboplatin [38]. With gemcitabine-based regimens the
response rates are the following: gemcitabine/epirubicin 46%, gemcitabine/vinorelbine - 47.6% and gemcitabine/
carboplatin - 44% [38, 39].
With the aim of diminishing cisplatin toxicity, the platinumfree combination of gemcitabine and paclitaxel combination
chemotherapy has been evaluated in also a mixture of fit/unfit
Volume 17 | Supplement 5 | May 2006
Annals of Oncology
patients with favorable results, even in pretreated patients [
40–45]. Of concern was the pulmonary toxicity observed in
the Hoosier group study in which a weekly regimen of this
combination (gemcitabine 1000 mg/m2 and paclitaxel 110 mg/
m2 on days 1, 8, and 15 every four weeks) was utilized in
unpretreated patients. Overall the combination of gemcitabine
and a taxane is active and well-tolerated as first- or second-line
treatment of patients with advanced urothelial carcinoma, as
well as in patients with compromised renal function.
Outside of a clinical trial, M-CAVI, carboplatin-gemcitabine,
CBDCA-paclitaxel, gemcitabine-taxane, or monotherapy with
gemcitabine, CBDCA, or a taxane can be considered for ‘unfit’
patients on an individual basis.
future directions
The next logical question to address is how to further optimize
therapy. In addition to incorporating the new active agents in
two, three or multiple drug combinations, dose intensification
of conventional agents, dose-dense sequential administration of
new agents or cisplatin-free combinations, several other new
approaches are being defined as: chemotherapy optimization
using molecular markers predicting chemosensitivity,
improvement of delivery/activity of chemotherapy agents like
gemcitabine, and the use of the new biologicals.
chemotherapy response predictive
factors
molecular predictive factors
Little has been done to date to address the genetic/molecular
and growth factor alterations in patients with advanced disease.
This represents a major obstacle to therapeutic progress for both
metastatic disease and the adjuvant setting [46].
Studies on P-glycoprotein [47], glutathione [48] and
metalloproteinase [49] expression in tumor specimens of
metastatic urothelial disease have indicated that these
parameters could predict resistance and toxicity to
chemotherapy.
Alterations in p53 and pRb occur in approximately 50% and
35% respectively of bladder cancers and have been reported to
correlate with high grade and stage [50–52]. There are
conflicting reports regarding the relationship between
chemosensitivity and p53 and several authors suggest that
altered expression of p53 may be associated with resistance to
M-VAC although others suggest the contrary [53]. Paclitaxel
seems to act independently to the presence of p53 mutations
[54]. The identification of prognostic and predictive
markers has guided the way for a series of ‘first-generation’,
biologically-driven trials. One of the lead trials involves the
study of M-VAC in patients with organ-confined bladder cancer
based on p53 status. The results of the currently ongoing
studies are eagerly awaited. In addition, some studies have
shown that the metastatic potential of bladder cancer correlates
with the expression of several genes that regulate proliferation
(EGF-R) and angiogenesis (bFGF, VEGF, MMP-9 and
interleukin-8, some of them being predictors of response.
Adding paclitaxel to EGFr directed therapy has produced
Volume 17 | Supplement 5 | May 2006
symposium article
a synergistic biologic effect on xenographs [55, 56]. It is
suggested that advances in molecular research may help to
develop reliable tumor markers that enable the clinician
a more accurately selection of appropriate therapy for each
individual patient based on predicted response. At the
moment, none of these molecular markers has been yet widely
accepted in routine clinical practice.
molecular pharmacology predicting response to
chemotherapy
In addition to what is known about the variability of expression
of intratumoral determinants of cytotoxic response, there is also
an emerging understanding of the role of molecular
pharmacology in the prediction of response to chemotherapy.
Paradigms developed from the treatment of colorectal
malignancy and lung cancer, in which the metabolism of
cytotoxic agents is affected by genetic factors, specially the
nucleotide repair system, are now being applied to the
management of bladder cancer. Some data is emerging in the
adjuvant setting [57]. It is clear that the future design of clinical
trials that assess novel anticancer treatments will have to take
into account the significant differences in drug metabolism
systems among individuals and also among population
groups [57].
The SOGUG is presently conducting a retrospective
analysis on patients treated with either CG or TCG. The
study objective is to test the hypotheses of whether the relative
mRNA expression of the excision cross-complementing
(ERCC1), Ribonucleotide reductase subunit M1 (RRM1),
BRCA1, and Caveolin 1 genes (all potentially related to Cisplatin
sensitivity) are associated with response and survival in
advanced bladder cancer patients treated with cisplatin-based
chemotherapy.
improving chemo delivery/activity
Phosphorylation of gemcitabine by deoxycytidine kinase is
saturable and the optimal infusion dose rate that maximizes
amount of gemcitabine triphosphate is 10 mg/m2/min. In
a study phase I [58], biweekly constant rate infusion (CRI) of
gemcitabine has been feasible and can be given safely up to
a dose of 5400 mg/m2 in 9 h infusion every 15 days without
growth factor support. Activity has been seen in patients
pretreated with gemcitabine including one patient with
metastatic bladder cancer who received prior standard 30-min
gemcitabine treatment and in one prostate cancer patient.
Minor response with prolonged disease stabilization has been
observed in a renal cancer patient.
targeted treatments
Advances in the molecular biology of urothelial malignancies
may allow identification of specific genetic lesions and
biochemical pathways upon which future therapeutic
approaches can be focused.
Her-2/neu is over-expressed in several advanced bladder
tumors [59]. Recently, Hussain et al. [60] have reported the
activity of the combination of carboplatin, paclitaxel,
gemcitabine and trastuzumab, a monoclonal antibody against
Her-2/neu, in metastatic Her-2 over-expressing bladder cancer
doi:10.1093/annonc/mdj964 | v115
symposium article
patients. There were 32 responses (5 complete and 27 partial)
with an overall response rate of 72.7%. Time to progression and
median survival were 8.5 and 15.2 months, respectively.
Epidermal growth factor receptors (EGFRs), are
overexpressed in high-grade invasive tumors. Gefitinib
(Iressa) is a selective orally-active EGFR tyrosine kinase
inhibitor, which in preclinical and clinical studies has
demonstrated activity in tumors expressing EGFR. Philips
et al. [61] have reported the activity of the combination of
cisplatin, gemcitabine administered at a fixed dose rate of
10 mg/m2/min and gefitinib in 27 patients with chemo-naive
advanced bladder cancer. Of 24 evaluable patients there were
12 responses for an overall response rate of 50% (95% CI =
29–71%). Median time to progression was 6.9 months (95%
CI: 3.8–8.9). Unfortunately this regimen was associated with
excessive toxicity, precluding further development.
conclusions
With reduced toxicity, improved quality of life and similar
survival to MVAC, gemcitabine/cisplatin is a new standard of
care for patients with advanced bladder cancer. Whether or not
the activity of the new triplet TCG is superior to the existing
two-drug regimens needs to be settled in the closed
EORTC30987 phase III study. The role of HD-CRI of
Gemcitabine is evolving and need further testing in GU
malignancies.
The improved understanding of the molecular biology of
urothelial malignancies is helping to define the role of new
targeted agents for the future in the treatment of advanced
disease. There is an obvious need to incorporate in clinical trials
a systematic translational approach to explain both our
successes and our failures.
disclosures
Dr Bellmunt has indicated that he has been an invited speaker
of Eli Lilly.
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