Gemcitabine and Vinorelbine in Pemetrexed-Pretreated
Patients With Malignant Pleural Mesothelioma
Paolo A. Zucali, MD1
Giovanni L. Ceresoli, MD1
Isabella Garassino, MD1
Fabio De Vincenzo, MD1
Raffaele Cavina, MD1
Elisabetta Campagnoli, MD1
Federico Cappuzzo, MD1
Silvia Salamina, MD1
Hector J. Soto Parra, MD2
Armando Santoro, MD1
1Department of Medical Oncology and Hematol-
ogy, Humanitas Clinical Institute of Rozzano,
2Department of Medical Oncology, Garibaldi-
Nesima Hospital, Catania, Italy.
BACKGROUND. Pemetrexed-cisplatin chemotherapy is the standard of care in the
first-line treatment of unresectable malignant pleural mesothelioma (MPM). Sec-
ond-line cytotoxic therapy is considered for a growing group of patients, but the
optimal treatment has not been defined to date. Gemcitabine and vinorelbine
have shown activity in the first-line setting. The objective of this study was to
evaluate the activity and toxicity of the gemcitabine-vinorelbine combination in
pemetrexed-pretreated patients with MPM.
METHODS. From January 2004 to September 2006, 30 consecutive patients who
were pretreated with pemetrexed with or without a platinum-derivative were
enrolled. Gemcitabine 1000 mg/m2and vinorelbine 25 mg/m2were administered
intravenously on Days 1 and 8 every 3 weeks. Treatment was repeated for a maxi-
mum of 6 cycles or until progression or unacceptable toxicity.
RESULTS. A partial response was observed in 3 patients (10%; 95% confidence
interval [CI], 2.1–26.5%), and 10 patients (33.3%; 95% CI, 17.3–52.8%) had stable
disease after treatment. Overall, 13 patients (43.3%; 95% CI, 25.5–62.6%) achieved
disease control. The median time to progression was 2.8 months (range, 0.6–12.1
months), and the median survival was 10.9 months (range, 0.8–25.3 months).
Hematologic toxicity was acceptable, with grade 3 or 4 neutropenia occurring in
11% of patients and thrombocytopenia occurring in 4% of patients; no case of
febrile neutropenia was observed. Nonhematologic toxicity generally was mild.
CONCLUSIONS. The gemcitabine and vinorelbine combination was moderately
active and had an acceptable toxicity profile in pemetrexed-pretreated patients
with MPM. The role of second-line treatment in MPM needs to be evaluated in
prospective trials in large series of patients who are stratified according to previ-
ous treatment and prognostic factors. Cancer 2008;112:1555–61. ? 2008 Ameri-
can Cancer Society.
KEYWORDS: malignant pleural mesothelioma, second-line chemotherapy, peme-
trexed-pretreated patients, gemcitabine-vinorelbine combination.
that usually has a poor prognosis. Its incidence is increasing
throughout most of the world, and it is predicted that it will rise in
the next 10 to 20 years.1Most patients with MPM are not amenable
to radical surgery, and systemic therapy is the only potential treat-
ment option for the majority of patients. The combination of cispla-
tin (Platinol; Bristol-Myers Squibb, New York, NY) and pemetrexed
(Alimta; Eli-Lilly and Company, Indianapolis, Ind) has recently
become the standard of care in the first-line treatment of MPM. In
fact, this combination significantly improved the response rate (RR),
time to progression (TTP), overall survival (OS), and quality of
life compared with cisplatin alone.2For patients who are unfit
to receive a cisplatin-based chemotherapy, pemetrexed alone3or
alignant pleural mesothelioma (MPM) is an aggressive tumor
Address for reprints: Polo A. Zucali, MD, Depart-
ment of Medical Oncology and Hematology, Isti-
tuto Clinico Humanitas, Via Manzoni 56, 20089
Rozzano (Milan), Italy; Fax: (011) 390282244591;
ª2008 American Cancer Society
Published online 19 February 2008 in Wiley InterScience (www.interscience.wiley.com).
combined with carboplatin (Paraplatin; Bristol-Myers
Squibb4) has been proposed as an alternative treat-
The role of second-line chemotherapy in MPM is
not yet established. Two small trials dedicated to
second-line chemotherapy with the cisplatin analog
ZD0473 (cis-amminedichloro [2 methylpyridine] plat-
inum [II]; AstraZeneca Pharmaceuticals, Cheshire,
United Kingdom) and with the combination of ralti-
trexed (Tomudex; AstraZeneca Pharmaceuticals) and
oxaliplatin (Eloxatin; Sanofi-Aventis, Paris, France)
did not report efficacy but demonstrated the possi-
bility of recruiting patients with good performance
status to second-line studies.5,6In addition, case
study reports and Phase II studies that included
some pretreated patients have provided evidence
that additional response is possible after second-line
chemotherapy.7–9Recently, a noteworthy activity of
pemetrexed, both alone and combined with carbo-
platin, as second-line treatment after prior platinum-
based chemotherapy was reported.10In a rando-
mized, multicenter Phase III study examining peme-
trexed as second-line chemotherapy versus best
supportive care (BSC), treatment with pemetrexed
provided clinical benefit with a statistically signifi-
cant improvement in TTP, whereas improvement in
OS was not reported, possibly because of the influ-
ence of poststudy chemotherapy (PSC) on the BSC
arm.11However, because pemetrexed-based regimens
are being used increasingly in the first-line set-
ting,2,12second-line chemotherapy should focus on
other compounds in the future.
Gemcitabine (Gemzar; Eli-Lilly and Company, In-
dianapolis, Ind) and vinorelbine (Navelbine; Pierre
Fabre, Castres, France) have shown some activity as
single agents13–15or in combination16–19in first-line
treatment of MPM. Gemcitabine showed an activity
as a single agent ranging from 0% to 31%,13,20and it
is not known to be cross-resistant with pemetrexed.
Moreover, as a single agent or in combination, gem-
citabine was the most commonly used agent in PSC
patients who were treated in the Phase III peme-
trexed trial21and is considered 1 of most interesting
drugs to explore in the second-line setting after
pemetrexed-based chemotherapy. However, the cu-
mulative cisplatin neurotoxicity and ototoxicity limit
the enthusiasm for a cisplatin/gemcitabine combina-
tion approach in a second-line setting.16,17Alterna-
tively, carboplatin22–24and oxaliplatin7,25,26could be
combined with gemcitabine. Vinorelbine is the only
vinca alkaloid with proven single-agent activity in
MPM. Treatment of 29 assessable MPM patients with
weekly vinorelbine 30 mg/m2produced a partial
response (PR) rate of 24% and an improvement in
general physical symptoms in 41% of patients.15In a
dose-finding study, Delord and colleagues observed
that the coadministration of gemcitabine and vinor-
elbine did not enhance the toxicity profile of either
drug in patients with advanced, previously treated
malignancies. Moreover, this regimen demonstrated
activity in a pretreated patient with MPM.27On the
basis of this background, the objective of the current
study was to assess the antitumor activity and toxic-
ity of the combination of gemcitabine and vinorel-
patients with MPM.
MATERIALS AND METHODS
Patients were eligible for this trial if they had histolo-
gically confirmed MPM that was not amenable to
curative surgery and that was relapsing or progres-
sing after 1 prior pemetrexed-based chemotherapy
regimen. Eligibility criteria included age >18 years,
an Eastern Cooperative Oncology Group (ECOG)
performance status (PS) ?2, and an estimated life
expectancy ?12 weeks. Adequate organ function was
required along with an absolute neutrophil count
?1.5 3 109/L, platelets ?100 3 1109/L, hemoglobin
?9 g/dL, bilirubin ?1.5 times the upper limit of nor-
mal, aspartate and alanine transferase levels ?3
times the upper limit of normal, and creatinine <2.0
mg/dL. Patients who were receiving palliative radia-
tion therapy for painful lesions were allowed to enter
the trial provided the patient had measurable disease
outside the irradiated site.
Previous treatment without pemetrexed-based
chemotherapy, documented brain metastases, serious
comorbidities, or other malignancies were not allowed.
Written, informed consent was obtained from each
patient before beginning treatment.
Patients received gemcitabine at the dose of 1000
mg/m2intravenously as a 30-minute infusion fol-
lowed by vinorelbine administered as a bolus infu-
sion at the dose of 25 mg/m2. Both drugs were given
on Days 1 and 8 every 3 weeks. Standard antiemetic
prophylaxis with intravenous metoclopramide was
used before chemotherapy. Treatment was adminis-
tered on an outpatient basis. Patients who demon-
strated no disease progression continued treatment
for a maximum of 6 cycles or until the withdrawal
criteria were met.
Dose adjustments at the start of a subsequent
cycle of therapy were based on hematologic and
nonhematologic toxicity observed during the preced-
1556CANCERApril 1, 2008 / Volume 112 / Number 7
ing course. Any patient who required a dose reduc-
tion continued to receive a reduced dose for the
remainder of the study. The administration of the
next cycle was delayed in the case of: 1) an absolute
neutrophil count of <1.5 3 1109/L and/or a platelet
count of <100 3 109/L; 2) any grade 3 or 4 nonhema-
tologic toxicity (except for nausea/vomiting) that did
not resolve to grade 1 or less; or 3) an ECOG PS >2.
If these toxicities had not resolved by Day 28, then
the dose was reduced for the next cycle at 75% of
the previous dose level.
No other systemic anticancer therapies were per-
mitted. Patients were allowed supportive care mea-
sures and symptomatic treatment for any drug-related
Baseline assessment included a complete medical
history, physical examination, and complete blood
count and chemistries. A chest and abdomen com-
puted tomography (CT) scan was obtained at baseline.
Patients were staged according to the International
Mesothelioma Interest Group Tumor, Lymph Node,
Metastasis (TNM) staging system.28
Best tumor response was evaluated according to
validated hybrid unidimensional and bidimensional
criteria.2No confirmatory scans were conducted on
patients who exhibited a PR or stable disease (SD).
Treatment toxicity was evaluated according to the
National Cancer Institute Common Toxicity Criteria
version 3.0 grading system.29Dose intensity (DI) was
assessed separately for gemcitabine and vinorelbine
in patients who received at least 2 cycles of chemo-
therapy as the median dose in milligrams per square
meter per week. The percentage of planned DI deliv-
ered for both drugs also was calculated and reported
as the relative DI (RDI).
After completion of the study treatment, patients
were evaluated every 2 months with chest and abdo-
men CT scans until disease progression. Patients also
were followed for survival until death or last contact
if they remained alive.
Study Design and Statistical Analysis
This study was planned as a single-institution Phase
II trial. Patients were enrolled prospectively. The
sample size of the trial was calculated according to
the Simon 2-stage design,30with a type I and II error
of <10% each, to differentiate between an RR of 10%
and a response of 30%. According to this model, ini-
tial analysis was planned after 14 patients had been
treated, and there was further accrual to a total of 25
patients if at least 1 objective response was observed
in the first 14 patients. The planned accrual period
was 24 months.
The primary endpoints of the study were tumor
RR and tolerability; secondary endpoints included
TTP and OS. TTP was defined as time from study
entry (first day of study treatment) until the time of
patient progression (as demonstrated on radiologic
or clinical examination) or death from any cause.
Patients without any evidence of progressive disease
were censored at the date of the last follow-up. OS
was calculated as the time from study entry until
death from any cause; patients who were alive at the
date of last follow-up were censored at that date. The
Kaplan-Meier method was used to calculate actuarial
survival and follow-up.31,32Survival rates were ana-
lyzed according to the following variables: age (<70
years vs ?70 years), ECOG PS (0 vs 1 vs 2), histology
(epithelial vs nonepithelial), European Organization
for Research and Treatment of Cancer (EORTC) prog-
nostic score (good score vs poor score),33response to
previous pemetrexed-based chemotherapy (PR or SD
vs progressive disease), and TTP on previous peme-
months). The impact of these variables on TTP and
OS was evaluated by using the Gehan Wilcoxon
test.34Statistical analyses were performed by using
the software package Stata 10 (STATA Corp, College
(<6 months vs
Between January 2004 and September 2006, 30 con-
secutive patients who progressed after pemetrexed-
based chemotherapy were enrolled. Their character-
istics are listed in Table 1. There were 22 men and 8
women. The median age was 66 years (range, 46–85
years). Most patients had a PS ?1 (83%), an epithe-
lial histologic subtype (70%), and a poor EORTC
prognostic score (73%). Twenty-five patients (84%)
had chest involvement only, whereas the remaining
patients also had extrathoracic tumor sites. All
patients had previously received a pemetrexed-based
chemotherapy, and a PR and SD were reported in 6
patients (20%) and 15 patients (50%), respectively.
Four patients (13%) had previously received peme-
trexed as single agent, and 26 patients (87%) had
received it in combination with a platinum agent,
including cisplatin in 1 patient and carboplatin in 25
Twenty-nine of the 30 patients were evaluated for
response, and 1 refused further treatment after 1
Gemcitabine-Vinorelbine in MPM Patients/Zucali et al. 1557
cycle and was not reassessed. According to an inten-
tion-to-treat analysis, 3 patients had a PR (10%; 95%
confidence interval [CI], 2.1–26.5%), 10 patients had
SD (33.3%; 95% CI, 17.3–52.8%) and 17 patients had
progressive disease (56.7%; 95% CI, 37.4–74.5%). No
complete responses were observed. The disease con-
trol rate (PR and SD for at least 6 weeks) was 43.3%
(95% CI, 25.5–62.6%). Table 2 summarizes the out-
come of the study population according to clinical
characteristics. With a median follow-up of 10.8
months (95% CI, 6.8–15.9 months) for all patients
and 14.2 months (95% CI, 4.6–25.3 months) for the
patients who remained alive, 21 patients died and 9
were still alive. The median TTP was 2.8 months
(range, 0.6–12.1 months), and the median OS was
10.9 months (range 0.8–25.3 months) (Fig. 1). Pro-
gression-free survival (PFS) rates at 3 months, 4
months, and 6 months were 44.8% (95% CI, 26.4–
64.3%), 44.8% (95% CI, 26.4–64.3%), and 31% (95%
CI, 15.3–50.8%), respectively.
Treatment Delivery and Toxicity
In total, 111 cycles of chemotherapy were delivered,
and dose reductions occurred in 19 cycles (17% of all
cycles). Patients received a median of 3 cycles of
treatment (range, 1–6 cycles). Twenty-five patients
(83%) received 2 or more cycles; in these patients,
the median delivered DI was 13.73 mg/m2per week
for vinorelbine (RDI, 82.4%) and 583.33 mg/m2per
week for gemcitabine (RDI, 87.5%).
Treatment generally was tolerated well. Hemato-
logic toxicity was the most frequently reported side
effect (Table 3), with grade 3 or 4 neutropenia
observed in 3 patients (10%). No episodes of febrile
neutropenia were reported. Nonhematologic toxicity
generally was mild (Table 3). One death occurred
duringthe treatment because
(without neutropenia) in a patient with SD who pre-
viously underwent extrapleural pneumonectomy. At
the end of chemotherapy, among 13 patients achiev-
ing disease control, ECOG PS was stable in 9
patients, improved in 2 and worsened in 2.
No. of patients
(N 5 30)%
ECOG performance status
EORTC prognostic score
Response to prior P-ChT
Median time of previous P-ChT response (range), mo
ECOG indicates Eastern Cooperative Oncology Group; EORTC, European Organization for Research
and Treatment of Cancer; P-ChT, pemetrexed-based chemotherapy; CR, complete response; PR,
partial response; SD, stable disease; PD, progressive disease.
Outcome of the Study Population According to Clinical
TTP, moOS, mo
ECOG performance status
TTP of previous treatment, mo
Response to previous treatment
PR and SD
TTP indicates time to progression; OS, overall survival; ECOG, Eastern Cooperative Oncology Group;
EORTC, European Organization for Research and Treatment of Cancer; CR, complete response; PR,
partial response; SD, stable disease; PD, progressive disease.
1558CANCERApril 1, 2008 / Volume 112 / Number 7
Second-line chemotherapy is being used increasingly
in MPM, because patients who achieve a clinical
benefit from first-line chemotherapy frequently still
are healthy at the time of disease progression. How-
ever, to date, the role of second-line chemotherapy
in MPM has not been proven, and few data are avail-
able to select effective drugs. In particular, prospective
trials of second-line chemotherapy in pemetrexed-
pretreated patients with MPM are lacking (Table 4).
In a retrospective analysis of patients who were trea-
ted in the Phase III pemetrexed trial, approximately
42% of all patients received some form of PSC. This
group of patients had a significantly prolonged sur-
vival. However, because PSC was not randomized, it
is impossible to know whether the reduced risk of
death was associated with PSC or whether patients
who had prolonged survival were able to receive
more PSC.21In fact, the crucial point is to distinguish
between the clinical/radiologic stability caused by
treatment effect and the natural history of disease.
To our knowledge, only 2 randomized studies have
demonstrated that chemotherapy may be better than
BSC in patients with MPM.11,35In particular, vinorel-
bine plus BSC in the first-line setting produced an
improvement in terms of OS compared with BSC
alone, although the difference was not statistically
significant,35whereas pemetrexed in the second-line
setting provided clinical benefit with a statistically
significant improvement in terms of TTP, but not in
terms of OS.11
In the current study, we tested vinorelbine com-
bined with gemcitabine in a population of patients
who progressed after receiving pemetrexed-based
toxicities were mild. Grade 3 and 4 neutropenia was
observed as the main toxicity in 3 patients (12.5%).
One death occurred during the treatment because of
pneumonitis (without neutropenia) in a patient with
SD who previously underwent extrapleural pneumo-
The low rate of reduced cycles and the high
median delivered DI of both study drugs provided
evidence of good tolerability of this regimen in this
group of patients. Although quality of life was not
evaluated in our study, we observed that ECOG PS
achieved disease control. Overall, the RR (10%), dis-
ease control rate (43.3%), TTP (2.8 months), and OS
(10.9 months) were in line with data reported in the
literature (Table 5). It is noteworthy that the propor-
tion of patients who had SD was considerable. Emer-
faithfully reflect the drugs’ activity and should repre-
sent the best treatment endpoints in patients with
MPM in view of the marked difficulty in assessing
radiologic response.36,37Fennell et al. demonstrated
that the radiologic response did not appear to be
in most patientswho
FIGURE 1. Survival curves. TTP indicates time to progression; OS, overall
Hematologic and Nonhematologic Toxicity by Patient (N 5 30)*
No. of patients
Grade 3–4, % Grade 1Grade 2Grade 3 Grade 4
* Other toxicities that were reported as rare events included grade 2 hepatotoxicity (1 patient) and
grade 2 peripheral neurotoxicity (1 patient).
Gemcitabine-Vinorelbine in MPM Patients/Zucali et al. 1559
correlated with survival improvement.38A recent
overview of the EORTC Lung Cancer Group pointed
out that replacement of the RR by TTP as the pri-
mary endpoint would allow a better selection of
clinically active drugs.39In our study, PFS was not
designed as the primary endpoint. However, consid-
ering the 3 EORTC categories (although they were
not derived from second-line studies), our regimen
demonstrated an activity between insufficient and
moderate. Accordingly, the PFS rate at 6 months was
31%, which is in the range of regimens with poor ac-
tivity in the first-line setting, but it could be revalued
in view of the second-line setting of our combination
and the characteristics of our population.
The majority of our population (73%) had a poor
EORTC prognostic score, which is expected to be
associated with a shorter survival.33Indeed, stratify-
ing our data for EORTC score, patients who had
good scores had a significantly improved OS com-
pared with patients who had poor scores (Table 2).
Similarly, OS was significantly longer in patients who
had a good ECOG PS. In addition, as reported in ran-
domized trials of second-line therapy in patients
with small cell and nonsmall cell lung cancer, in our
MPM population, disease progression during first-
line therapy and a shorter interval from completion
of first-line therapy were correlated with shorter TTP
and OS after second-line treatment (Table 2).
In conclusion, the results from this study suggest
the feasibility of giving second-line chemotherapy to
patients with MPM. Unfortunately, the results remain
modest, although chemotherapy could be offered to
these patients for palliation. However, MPM should
be considered an ideal field in which to test new
chemotherapy agents as well as new therapeutic stra-
tegies, including antiangiogenic compounds, small
molecules or monoclonal antibodies that target dif-
ferent molecular pathways,
Although it has been demonstrated that targeted
therapy with epidermal growth factor receptor and
platelet-derived growth factor receptor inhibitors and
antiangiogenic drugs is ineffective in unselected
patients, an improvement in our knowledge of the
major molecular pathways involved in MPM should
define proper targets for the systemic treatment of
this disease. Reinduction of apoptosis by manipulat-
ing its critical control points (tumor necrosis factor
10 receptor, histone deacetylases, and the protea-
some), the inhibition of hepatocyte growth factor
and its receptor c-Met, the inhibition of angiogen-
esis, and evaluating the synergism between chemo-
therapy and targeted therapy all are interesting fields
in which to develop new, effective treatments. The
role of second-line treatment in MPM needs to be
evaluated in prospective trials on large series of
patients stratified according to previous treatment,
prognostic factors, and biologic features.
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