Advances in the systemic therapy of malignant pleural mesothelioma

Article (PDF Available)inNature Clinical Practice Oncology 5(3):136-47 · April 2008with57 Reads
DOI: 10.1038/ncponc1039 · Source: PubMed
Abstract
Malignant pleural mesothelioma is an aggressive thoracic malignancy associated with exposure to asbestos, and its incidence is anticipated to increase during the first half of this century. Chemotherapy is the mainstay of treatment, yet sufficiently robust evidence to substantiate the current standard of care has emerged only in the past 5 years. This Review summarizes the evidence supporting the clinical activity of chemotherapy, discusses the use of end points for its assessment and examines the influence of clinical and biochemical prognostic factors on the natural history of malignant pleural mesothelioma. Early-phase clinical trials of second-line and novel agents are emerging from an increased understanding of mesothelioma cell biology. Coupled with high-quality translational research, such developments have real potential to improve the outlook of patients at a time of increasing incidence.
136 nature clinical practice ONCOLOGY marCh 2008 vOL 5 NO 3
www.nature .com/clinicalpractice/onc
S u M M a rY
Advances in the systemic therapy of malignant
pleural mesothelioma
Dean A Fennell*, Giovanni Gaudino, Kenneth J O’Byrne, Luciano Mutti and Jan van Meerbeeck
Continuing Medical Education online
Medscape, LLC is pleased to provide online continuing
medical education (CME) for this journal article,
allowing clinicians the opportunity to earn CME credit.
Medscape, LLC is accredited by the Accreditation
Council for Continuing Medical Education (ACCME) to
provide CME for physicians. Medscape, LLC designates
this educational activity for a maximum of 1.0 AMA PRA
Category 1 Credits
TM
. Physicians should only claim credit
commensurate with the extent of their participation in the
activity. All other clinicians completing this activity will
be issued a certificate of participation. To receive credit,
please go to http://www.medscape.com/cme/ncp
and complete the post-test.
Learning objectives
Upon completion of this activity, participants should be
able to:
1 Describe the clinical presentation of malignant
pleural mesothelioma (MPM).
2 Identify best practices with regard to systemic
therapy of MPM.
3 List clinical prognostic factors for MPM.
4 Describe future directions of care for patients with
MPM.
Competing interests
The authors declared no competing interests. Charles P
Vega, the CME questions author, declared that he has
served as an advisor or consultant to Novartis, Inc.
INTRODUCTION
The incidence of malignant pleural mesothelioma
(MPM) is anticipated to increase over the next
10 years in both Europe and the developing
nations.
1
Although the outcome for patients
remains poor, recent advances in the systemic
treatment of this disease have emerged. The prin-
cipal goals of this Review are to summarize the
role of chemotherapy in treating MPM, discuss
the determinants of prognosis and outline the
novel therapeutic approaches in development.
CHEMOTHERAPEUTIC EFFICACY
The majority of patients with MPM present with
stage III or IV disease, which is usually detected by
PET imaging. For example, in a recent CT–PET-
staged series 3% of patients had stage I disease, 9%
of patients had stage II disease, 48% of patients had
stage III disease and 40% of patients had stage IV
Malignant pleural mesothelioma is an aggressive thoracic malignancy
associated with exposure to asbestos, and its incidence is anticipated
to increase during the first half of this century. Chemotherapy is the
mainstay of treatment, yet sufficiently robust evidence to substantiate the
current standard of care has emerged only in the past 5 years. This Review
summarizes the evidence supporting the clinical activity of chemotherapy,
discusses the use of end points for its assessment and examines the
influence of clinical and biochemical prognostic factors on the natural
history of malignant pleural mesothelioma. Early-phase clinical
trials of second-line and novel agents are emerging from an increased
understanding of mesothelioma cell biology. Coupled with high-quality
translational research, such developments have real potential to improve
the outlook of patients at a time of increasing incidence.
KEYWORDS biomarkers, chemotherapy, mesothelioma, novel therapy, pleural
DA Fennell is a Cancer Research UK Clinician Scientist, Consultant and
Senior Lecturer in Medical Oncology at Queens University Belfast and at the
Northern Ireland Cancer Centre, Belfast, Northern Ireland, UK, G Gaudino
is Full Professor of Molecular Biology in the DISCAFF Department at the
University of Piemonte Orientale A. Avogadro, Novara, Italy, KJ O’Byrne is
Clinical Director of the Hematology, Oncology and Palliative Care Services
at St James’s Hospital, Dublin, Republic of Ireland, L Mutti is Chief of the
Department of General Medicine and Director of the Laboratory of Clinical
Oncology at the Vercelli Hospital, Vercelli, Italy, and J van Meerbeeck is Head
of the Unit of Thoracic Oncology at the University Hospital Ghent, and
Professor in Thoracic Oncology at Ghent University, Ghent, Belgium.
Correspondence
*3rd Floor 008, Centre for Cancer Research and Cell Biology, Queen’s University Belfast,
97 Lisburn Road, Belfast BT9 7BL, UK
d.fennell@qub.qc.uk
Received 24 May 2007 Accepted 2 October 2007 Published online 29 January 2008
www.nature.com/clinicalpractice
doi:10.1038/ncponc1039
REVIEW CRITERIA
The information for this Review was compiled by searching the PubMed and
MEDLINE databases for articles published until 1 September 2007. Only
articles published in English were considered. The search terms used included
“mesothelioma in association with the following search terms: clinical trial”,
“phase, biomarker”, gene expression profiling, “prognosis”, “tumor markers”
and “PET. Primary sources have been quoted. Full articles were obtained and
references were checked for additional material when appropriate. References
were chosen on the basis of the best clinical or laboratory evidence, especially if
the work had been corroborated by published work from other centers.
S u M M a rY
c M e
r e v i e w r e v i e w
Nature.indt 1Nature.indt 1 28/11/07 9:46:50 am28/11/07 9:46:50 am
marCh 2008 vOL 5 NO 3 FENNELL ET AL. nature clinical practice ONCOLOGY 137
www.nature .com/clinicalpractice/onc
disease.
2
Approximately 85–90% of patients with
MPM present with unresectable disease at diag-
nosis and such patients rely on palliative treat-
ment. The efficacy of chemotherapy for MPM
has been evaluated predominantly in single-arm,
uncontrolled trials in which the objective response
rate can be classified as low (<10%), moderate
(10–15%) or high (>20%), as shown in Table 1.
The results of older studies require cautious
interpretation, however, because they differ
widely in trial design, patient selection, response
criteria, sample size and power. These are factors
that might affect the outcome significantly.
Nevertheless, a number of conclusions can
be drawn from these series, which have been
subjected to meta-analyses.
3,4
Most single agents
exhibit low intrinsic activity, with the exception
of cisplatin.
3,4
Patient response rates have essen-
tially remained below 50%, which is consistent
with intrinsic drug resistance. The response rate
and survival are generally greater for combination
than single-agent regimens, as illustrated in
Figure 1A, which summarizes the response rate of
59 first-line clinical trials. Moreover, two phase III
trials showed that responses were generally
higher for combination versus single-agent
trials (26% versus 8%, respectively; P <0.001).
5,6
Interestingly, the improvement in median sur-
vival with combination therapy versus single-
agent therapy was less impressive across this
series of trials (i.e. 10 vs 8.1 months, respectively;
Figure 1B). Platinum-containing regimens have
a greater activity than nonplatinum-containing
combinations, with cisplatin and doxorubicin
showing the highest reported response rates.
3
Figure 1C shows the distribution and greater
response rates for platinum-containing versus
nonplatinum-containing regimens in the same
series of 59 published trials (24% vs 8%, respec-
tively). The effect of platinum-containing regi-
mens on survival seems to be modest, as indicated
by meta-analyses that compared the median
survival times of patients receiving platinum-
based regimens with those of patients receiving
nonplatinum regimens (8.6 vs 9.6 months,
respectively; Figure 2A). Three-drug chemo-
therapy combinations were found to be no more
active than two-drug combinations. Finally, the
meta-analyses revealed that the activity of agents
was consistently higher when CT scanning was
used to measure the response. This outcome is
due to the high sensitivity of CT scanning for
Table 1 Response rate outcomes of phase III trials.
Study type or regimen Number
of studies
Number
of patients
Intention to treat response
rate % (95% CI)
Single agent
Long-term alkylating agents 7 194 4.6 (1.8–7.5)
Anthracyclines, liposomal anthracyclines
or mitoxantrone
10 319 6.1 (3.6–8.7)
Taxanes 4 111 5.1 (1.2–9.1)
Vinca alkaloids 5 115 3.6 (0.4–6.8)
Gemcitabine 3 72 6.7 (1.2–12.2)
Antimetabolites 8 319 9.0 (6.0–11.9)
Topoisomerase inhibitors 4 117 4.9 (1.0–8.8)
Cisplatin 5 108 20.0 (12.8–27.2)
Carboplatin 3 89 10.1 (3.9–16.3)
Other experimental agents 12 376 4.0 (2.0–5.9)
Combination regimens
Platinum-based 19 790 24.9 (22.0–27.9)
Cisplatin- but not anthracycline-containing 20 547 23.2 (19.7–26.8)
Anthracycline- and nonplatinum-based 8 213 11.3 (7.0–15.5)
Cisplatin- and anthracycline-containing 6 151 28.5 (21.3–35.7)
Nonplatinum- and nonanthracycline-based 54 409 11.6 (10.0–13.3)
The data were originally published in references 1 and 3.
r e v i e w r e v i e w
Nature.indt 1Nature.indt 1 28/11/07 9:46:50 am28/11/07 9:46:50 am
138 nature clinical practice ONCOLOGY FENNELL ET AL. marCh 2008 vOL 5 NO 3
www.nature .com/clinicalpractice/onc
detecting a response in the type of disease that
has a rind-like pleural thickening and pleural
fluid masking the measurable target lesions.
End points for efficacy evaluation
Adequate response evaluation is a corner-
stone for the identification of active drugs. The
average response rate across 59 published trials
conducted over 30 years was 15.7%. Over this
time interval, however, the response rate reached a
plateau, reflecting the underlying chemoresistant
phenotype of MPM.
7
Nevertheless, the sugges-
tion of a positive correlation (r) between activity
and survival (r = 0.50), as shown in Figure 2B,
provides a rationale for development of novel
chemosensitization strategies.
Response assessment typically employs a
modified set of RECIST (Response, Evaluation,
Criteria In Solid Tumors) criteria that are based
on measurement of tumor thickness rather than its
maximum diameter.
8
The change in tumor volume
required to achieve a partial response is smaller
for models of MPM geometry than for spherical
tumor models. Volume changes associated with a
partial response according to the RECIST criteria
were much smaller than volume changes associ-
ated with a partial response according to different
criteria.
9
It is still unclear whether an objective
response rate determined by radiology is suffici-
ently predictive for MPM, and this could be particu-
larly relevant in emerging trials of novel targeted
compounds, which function primarily to stabilize
growth rather than induce tumor shrinkage.
Progression-free survival (PFS) reported for
29 trials over the past 30 years demonstrates only
a minor upward trend in this outcome measure
(r = 0.2); however, there is a relatively strong
correlation between PFS and survival (r = 0.73),
suggesting predictive value of this end point
(Figure 2C). Furthermore, patients who received
platinum-based combinations had longer PFS
than patients who received nonplatinum single-
agent therapy (6.8 vs 4 months; Figure 2C).
The European Organisation for Research and
Treatment of Cancer (EORTC) has analyzed the
relationship between PFS and activity through
meta-analysis of 10 trials (523 patients).
10
Three
groups with insufficient, moderate, or good
activity were defined by the distribution of PFS
rates at 3, 4, 5 and 6 months, supporting the use
of PFS as an end point for evaluation of clinical
activity, particularly if stabilization rather than
tumor shrinkage is anticipated.
Timing of chemotherapy
The optimum timing of chemotherapy treatment
according to the natural history of the disease
has only been addressed recently. A pilot study
randomized 43 patients with a good performance
status and stable symptoms to either immediate
or delayed chemotherapy with mitomycin–
vindesine and cisplatin.
11
The median time to
delayed treatment was 17 weeks. Trends towards
ncponc_2006_187f1.eps
50
45
40
35
30
25
20
15
10
5
0
1982 1987 1992 1997
Year
Response rate (%)
2002 2007
Combination regimen Single-agent regimen
Combination regimen Single-agent regimen
Platinum-based regimen Non-platinum-based regimen
50
45
40
35
30
25
20
15
10
5
0
1982 1987 1992 1997
Year
Response rate (%)
2002 2007
18
16
14
12
10
8
6
4
2
0
1980 1985 1990 1995 2000
Year
Survival (months)
2005 2010
A
B
C
Figure 1 Objective responses from a series of 59 clinical trials. (A) Reported
objective response rates over the past three decades from a series of 59
published clinical trials. The distribution of response rates achieved by trials
examining combination versus single-agent regimens. (B) Reported survival
from the same series of 59 clinical trials over the same period. The relative
distribution of reported survival for combination and single-agent clinical
trials is shown. (C) Distribution of response rates reported by trials comparing
platinum-based and nonplatinum-based regimens.
r e v i e w
r e v i e w
Nature.indt 1Nature.indt 1 28/11/07 9:46:50 am28/11/07 9:46:50 am
marCh 2008 vOL 5 NO 3 FENNELL ET AL. nature clinical practice ONCOLOGY 139
www.nature .com/clinicalpractice/onc
worse survival (14 vs 10 months; P = 0.1), PFS
(25 vs 11 weeks;
P = 0.1) and quality of life
were determined in the group receiving delayed
chemotherapy. Although this is a very small
randomized study, one interpretation might be
that early therapy for MPM does not adversely
affect the natural history of the disease.
Third-generation antifolates
Although there is little doubt among investigators
about the potential benefit of chemotherapy over
best supportive care—also called active symptom
control’ (ASC)—no randomized data support this
approach. Following a feasibility trial to establish
whether patients could be randomized to ASC,
12
a three-armed randomized phase III study was
conducted in the UK to evaluate the efficacy of
chemotherapy—mitomycin, vinblastine and cis-
platin
13
or vinorelbine
14
—compared with ASC.
Since the initiation of this study, however, data
from two pivotal randomized trials have provided
evidence to suggest that a platinum-based doublet
containing a third-generation antifolate is superior
to platinum alone.
5,6
Pemetrexed and raltitrexed are thought to be
concentrated within MPM cells and to specifically
inhibit one or several of the key enzymes involved
in the synthesis of purines and pyrimidines.
On the basis of the moderate-to-high activity
observed with these agents either alone or in combi-
nation with platinum, investigators compared
them in randomized trials using cisplatin as a
comparator drug. Vogelzang et al. were the first
to report the improved efficacy of the combi-
nation of cisplatin and pemetrexed (Table 2).
6
This chemotherapy combination was unexpect-
edly toxic and resulted in several treatment-
related deaths; this outcome was also observed in
several previous phase II studies. Toxicity was due
to interference with homocysteine metabolism,
and could be prevented by the prophylactic use of
vitamin B
12
and folate, although the outcome in
the subgroup of vitamin-substituted patients was
not significantly better than those who did not
receive prophylactic vitamin B
12
and folate. This
outcome is possibly because of the small sample
size of the subgroup, although doubt about a
possible detrimental effect of vitamin substitu-
tion on efficacy cannot be completely excluded.
On the basis of the results of this trial, pemetrexed
has been licensed for the treatment of MPM in
several countries.
15
The EORTC Lung Cancer Group reported
the results of a randomized trial that compared
cisplatin and raltitrexed with cisplatin only;
5
significant improvements in efficacy and
disease-related symptoms (pain and dyspnea)
were observed with raltitrexed and cisplatin.
16
Although the increased increments in overall
survival were numerically smaller than in the
phase III trial that compared pemetrexed and
cisplatin with cisplatin alone, the outcome is
considered equivalent in the absence of a head-
to-head comparison. Of note, no significant
serious additional toxicity was observed with
the raltitrexed–cisplatin combination.
ncponc_2006_187f2.eps
25
20
15
10
5
0
1982 1987 1992 1997
Year
Survival (months)
2002 2007
Platinum-based regimen Non-platinum-based regimen
1982 1987 1992 1997
Progression-free survival (months)
Survival (months)
2002 2007 2002 2007
18
16
14
12
10
8
6
4
2
0
20
18
16
14
12
10
8
6
4
2
0
0 10 20 30
Response rate (%)
Survival (months)
40 50
A
B
C
Figure 2 Comparison of response rates for platinum-based regimens.
(A) The trend in reported survival over the past 30 years for 59 clinical trials
that compared platinum-based and nonplatinum-based treatment regimens
(correlation, r = 0.2). (B) Association between objective response and survival
across 57 clinical trials (r = 0.50). (C) Association between progression-free
and overall survival across 28 clinical trials examining platinum-based and
nonplatinum-based regimens (r = 0.73).
r e v i e w
r e v i e w
Nature.indt 1Nature.indt 1 28/11/07 9:46:50 am28/11/07 9:46:50 am
140 nature clinical practice ONCOLOGY FENNELL ET AL. marCh 2008 vOL 5 NO 3
www.nature .com/clinicalpractice/onc
From these two pivotal randomized trials, it
can be concluded that modern chemotherapy
improves symptoms and has no deleterious effect
on quality of life, despite the associated toxicity.
16
Response and PFS were borderline improved with
the raltitrexed–cisplatin regimen compared
with cisplatin alone (5.3 months PFS for the
combination vs 4 months for cisplatin;
P = 0.058).
By contrast the pemetrexed–cisplatin regimen
produced significantly better PFS than cisplatin
alone (3.7 vs 5.7 months;
P = 0.001). Survival in
the cisplatin-only arm of both of these phase III
trials was similar, enabling some comparison
between them. A combination of cisplatin with
pemetrexed improves the outcome, as measured
by symptomatic and objective response rates,
overall survival and PFS. The pooled observed
reduction in the risk of death at 1 year is 10%,
corresponding to an estimated increase in median
survival of 6–8 weeks (J van Meerbeeck, unpub
-
lished data). Currently, the cisplatin and antifolate
combination is to be regarded as the standard
chemotherapy regimen in patients with good
performance and unresectable disease and should
be administered for a median of four to six cycles,
unless progression or severe toxicity occurs. The
results cannot be extrapolated to subgroups that
have been insufficiently studied, such as patients
with a moderate or poor performance status, the
elderly (those >75 years of age) and patients with
the sarcomatous histologic subtype. The relative
activity of platinum–antimetabolite combinations
compared with other platinum doublets has not
been addressed in phase III studies.
Recent observations in phase II trials regarding
the equivalent efficacy of three-drug regimens,
novel agent–platinum regimens, nonplatinum
combinations, maintenance treatment with a single
agent and carboplatin-based instead of cisplatin-
based regimens are speculative, and such claims
cannot be adequately addressed in the absence of
large comparative series or meta-analyses. Patients
unable to receive third-generation antifolates,
therefore, are treated according to drug avail-
ability, toxicity, ease of administration and their
physicians personal experience.
Multimodality therapy
The development of active drug combinations
has led to their use as part of combined-modality
treatments, with sequential surgery and/or radio-
therapy. Weder et al. were the first to report on
Table 2 Characteristics of phase III trials.
Reference Vogelzang et al. (2003)
6
van Meerbeeck et al. (2005)
5
Study arms Cisplatin Pemetrexed–cisplatin Cisplatin Raltitrexed–cisplatin
Number of patients 222 226 124 126
Drug dosage C: 75 mg/m²
once every
3 weeks
P: 500 mg/m²
C: 75 mg/m²
Both: once every 3 weeks
C: 80 mg/m²
Once every 3 weeks
R: 3 mg/m²
C: 80 mg/m²
Both: once every 3 weeks
Median number of cycles given 4 6 4 5
% Response rate with 95% CI 17 (12–22) 41 (35–48) 14 (7–20) 24 (16–32)
P value <0.001 0.056
Overall survival
Median (months) 9.3 12.1 8.8 11.4
1 year (%)
38 50 40 46
2 year (%)
17 22 10 19
Hazard ratio (95% CI) 1 0.77 (0.60–0.90) 1 0.76 (0.58–1.00)
P value (log rank) 0.002 0.048
PFS/TTP
Median 3.9 5.7 4.0 5.3
Hazard ratio 1 0.68 1 0.78
P value (log rank) 0.001 0.058
The data were originally published from references 5 and 6. Abbreviations: C, cisplatin; P, pemetrexed; PFS, progression-free survival; R, raltitrexed; TTP, time
to progression.
r e v i e w
r e v i e w
Nature.indt 1Nature.indt 1 28/11/07 9:46:50 am28/11/07 9:46:50 am
marCh 2008 vOL 5 NO 3 FENNELL ET AL. nature clinical practice ONCOLOGY 141
www.nature .com/clinicalpractice/onc
the use of gemcitabine and cisplatin as induc-
tion therapy preceding an extrapleural pneumo-
nectomy (EPP).
17
Although currently not regarded
as the induction regimen of choice, the promising
results of this trial paved the way for the use of
cisplatin–pemetrexed in several similar ongoing
phase II studies. Trimodality therapy, involving
adjuvant chemotherapy and radiotherapy, was
investigated in a single-arm study of 183 patients
with early-stage disease who underwent EPP
followed by radiotherapy.
18
The mortality rate was
3.8%, the morbidity rate was 50%; and median
overall survival was 19 months. In a subgroup
of 31 patients with epithelial histology, nega-
tive resection margins and no evidence of extra-
pleural nodal involvement, median survival was
51 months.
18
To date, no randomized trials evalu-
ating the net benefit of EPP have been reported;
one UK study is currently enrolling patients into a
clinical trial designed to address this issue.
19
Second-line therapy
Second-line therapy of MPM might have an
important role in increasing overall survival;
however, no standard has been defined in this
setting, partly because of a paucity of reported
studies.
20
Despite this limitation, there is
increasing evidence from single-arm studies that
chemotherapy in the second-line setting is not
only feasible, but also active.
21–24
Recently, the
efficacies of single-agent pemetrexed therapy and
pemetrexed and carboplatin following platinum-
based therapy without pemetrexed have been
reported.
25
Patients received an average of six
cycles of therapy, and the response rates for the
monotherapy and doublet arms, were 21% and
18%, respectively. PFS and overall survival were 21
and 32 weeks, and 42 and 39 weeks, respectively.
A recent phase III trial that randomized patients
in the second-line setting to either pemetrexed,
vitamin supplementation and best supportive
care or to best supportive care alone showed no
survival advantage for the combination arm.
26
Despite an increase in the response rate and PFS,
overall survival was not increased significantly.
The authors suggested that this might have been
owing to poststudy therapy in the control arm.
DETERMINANTS OF CLINICAL OUTCOME
Reliable prognostic and predictive factors can
facilitate treatment planning. The Surveillance,
Epidemiology and End Results Program review
(published in 1988) is a landmark study of prog-
nostic factors in MPM. This study included 1,475
patients with histologically confirmed MPM
and demonstrated that age, gender, tumor stage,
treatment and geographic area of residence are
important predictors of patient survival.
27
This
result led to the evaluation of prognostic factors
as predictors of outcome following treatment of
patients in clinical trials (Figure 3A). The Cancer
and Leukemia Group B
28
and EORTC
29
devel-
oped prognostic scoring systems that discrimi-
nated between patients with good and poor
outlooks receiving systemic treatment. The Cancer
and Leukemia Group B prognostic tree uses data
on performance status, age, hemoglobin, white-
blood-cell count, the presence of chest pain and
weight loss to define six patient groups with
significantly different survival experiences. The
different patient groups defined by this scoring
system have different median survival times,
ranging from 1.4 months in the worst group to
13.9 months in the best group.
28
The EORTC system divided patients into two
groups according to gender, performance status,
white-blood-cell count, histologic subtype and
probability of histologic diagnosis. The median
survival of the low-risk group (i.e. patients
with two or fewer poor prognostic factors) was
10.8 months, compared with 5.5 months in the
high-risk group.
29
A subsequent retrospective
analysis of 145 patients included in three
phase II studies validated the EORTC scoring
system.
30
Both systems have been shown to
be applicable to a general hospital population
(Figures 3B,C).
31
The impact of clinical prognostic
factors on outcome underscores the potential for
considerable bias in single-arm phase II trials.
Functional imaging as a predictive tool
Although the role of PET–CT imaging in the diag-
nostic evaluation of MPM remains to be defined,
there is emerging evidence that high accumulation
of [
18
F]fluorodeoxyglucose (FDG) in the tumor,
as measured by the standardized uptake value
(SUV), before treatment is associated with resis-
tance to chemotherapy and a poor outcome.
32,33
PET imaging was used to assess 137 patients before
surgery.
32
A PET SUV of 10 was used as the cut-
off point between high and low values. Following
a median follow-up period of 24 months for
all surviving patients, median survival in the
high-SUV group was 9 months compared with
21 months in the low-SUV group. Multivariable
analysis revealed that tumors with a high SUV
were associated with a considerably greater risk
of death than tumors with a low SUV.
32
r e v i e w
r e v i e w
Nature.indt 1Nature.indt 1 28/11/07 9:46:50 am28/11/07 9:46:50 am
142 nature clinical practice ONCOLOGY FENNELL ET AL. marCh 2008 vOL 5 NO 3
www.nature .com/clinicalpractice/onc
There is controversy as to whether the tumor
response evaluated by CT imaging criteria
predicts patient survival following systemic
chemotherapy for MPM. Nonetheless, there is
growing evidence that therapy-induced changes
in tumor FDG uptake might predict response and
patient outcome early in the course of treatment.
In a study of 22 patients evaluated by FDG–PET
and CT imaging at baseline and after 2 cycles of
therapy, 8 out of 20 evaluable patients showed a
decrease of 25% or more in tumor FDG uptake (as
measured by SUV) and were defined as having a
metabolic response. Metabolic response correlated
to PFS, which was 14 months in responders and
7 months in nonresponders. By contrast, no corre
-
lation was found between PFS and the radiologic
response evaluated by CT imaging. Patients with
a metabolic response had a trend towards a longer
overall survival.
33
Taken together these findings
indicate that FDG–PET imaging could be useful
in the early assessment of treatment efficacy.
Biological prognostic factors
Several retrospective studies have reported novel
biomarkers of MPM, but no biomarker has been
successfully translated into the clinic as a useful
predictive or prognostic tool. An underlying
problem is how to define a patient subpopulation in
which single or multiple biological variables accu-
rately predict sensitivity to therapy and prognosis
by significantly adding to, or supplanting, clinical
variables.
34
Many biomarkers have indicated associ-
ations between certain biochemical pathways and
clinical outcome, and provide a useful hypothesis
generator for novel, early clinical trials.
Proteins involved in regulating the angio-
genic process have been implicated in the prog-
nosis of MPM and can be indirectly assessed
using immunohistochemistry and microvessel
counting. Studies have indicated that increased
microvessel density is associated with a poor
outcome.
35,36
VEGF, the VEGF receptors
(VEGFRs) flt1 (VEGFR1), KDR (VEGFR2), and
VEGFC and its cognate receptor VEGFR3 have
been shown to be co-expressed in MPM.
37,38
Both VEGF and VEGFC function as autocrine
growth factors for the development of MPM.
Other angiogenic growth factors expressed in
this disease include transforming growth factor β,
fibroblast growth factor (FGF) 1, FGF2, thrombo-
spondin 1, methionine aminopeptidases, inter-
leukin (IL)-6 and IL-8. High levels of VEGF and
FGF2 or co-expression of TGFβ, VEGF, FGF1
and FGF2 have been found to be associated with
a poor outcome.
39
MPM exhibits high levels of
expression of the surrogate marker of hypoxia,
hypoxia-inducible factor 1α.
40
Tumor hypoxia
ncponc_2006_187f3.eps
30
25
20
15
10
5
0
Histology
Stag
e
PS
Ag
e
Chest pain
Gender
We
ight loss
Platelet coun
t
Tr
eatment yes/no
Duration of symptoms
Side
Node
Smoking
Leucocyte count
LDH
Hb
PET
Ty
pe of tr
eatment
Geography
V
isceral
pleura
Reported frequency
Survival (days)
Survival (months)
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
0 500 1,000 1,500
Survival (days)
Cumulative survival
2,000 2,500
0 500 1,000 1,500 2,000 2,500
*
*
+
+
+
+
+
+
+
*
*
CACGB
EORTC
SEER
EORTC group
High risk
Low risk
Censored
*
CALGB group
Groups 5 and 6
Groups 3 and 4
Groups 1 and 2
Censored
A
B
C
Figure 3 Prognostic factors as predictors of outcome. (A) Prognostic factors
shown according to their reported frequency in 70 studies. The top 20 clinical
prognostic factors are shown with those factors corresponding to the SEER,
CALGB and EORTC prognostic factor analyses indicated in the legend. This
figure shows the survival curves of patients stratified into EORTC prognostic
groups (low risk, n = 103; high risk, n = 147; P = 0.0018). (B) Expanded and updated
survival data for 240 consecutive patients from the series originally published
by Edwards et al.
31
(C) Stratification of the above dataset by CALGB prognostic
groups (groups 1 and 2, n = 65; groups 3 and 4, n = 118; groups 5 and 6, n = 57;
P <0.0001). Abbreviations: CALGB, the Cancer and Leukemia Group B; EORTC,
European Organisation for Research and Treatment of Cancer; Hb, hemoglobin;
LDH, lactate dehydrogenase; PS, performance status; SEER, Surveillance
Epidemiology and End Results.
r e v i e w
r e v i e w
Nature.indt 1Nature.indt 1 28/11/07 9:46:50 am28/11/07 9:46:50 am
marCh 2008 vOL 5 NO 3 FENNELL ET AL. nature clinical practice ONCOLOGY 143
www.nature .com/clinicalpractice/onc
contributes directly to chemoresistance; for
example, through downregulation of BAX.
41
The
reduced level of this tumor suppressor has been
associated with a poor outcome.
42
Despite the
expression of multiple antiapoptotic BCL2 family
members,
43,44
expression of these proteins does
not predict an outcome consistent with findings
in vitro.
45,46
Global gene-expression analysis has identi-
fied a four-gene signature comprising KIAA097,
GDP-dissociation inhibitor 1 (GDIA1), cytosolic
thyroid hormone-binding protein (CTHBP) and
an expressed sequence tag similar to the L6 tumor
antigen, which correctly classified a training
sample into good and poor prognostic groups.
47
This gene signature was subsequently tested on
29 samples and predicted the correct outcome in
a significant number of cases. This signature was
also validated in a subsequent study, supporting
the identification of novel disease-specific and
treatment-specific prognostic molecular marker
candidates.
48
A further study by Pass and co-
authors used two different methods of micro-
array analysis to identify a common subset of 27
genes that could be used to predict both survival
and progression of MPM.
49
Despite the poten-
tially useful data that have resulted from gene-
array studies, the clinical applicability of this
technology remains unclear.
An analysis of primary tumors and metastases
from transgenic mouse models of prostate cancer
and cancer patients has identified an 11-gene,
oncogene-driven-pathway signature that consis-
tently has a stem-cell-like expression profile. The
presence of this 11-gene profile is associated with
a poor prognosis in patients with MPM.
50
A large
gene-expression analysis has identified and vali-
dated aurora kinases as predictive of outcome.
This study also identified increased expression
of regulators of mitosis and cell-cycle control in
more-aggressive cancers,
34
supporting several
previous studies that have reported mitosis or
proliferation, diploidy and S-phase fraction as
indices of significance.
NOVEL THERAPEUTIC STRATEGIES
Angiogenesis and survival pathways
Deregulated expression of growth factors or
proteins involved in downstream signaling path-
ways has an important role in malignant trans-
formation of mesothelial cells. Autocrine circuits
of activation have been identified in MPM for
VEGF,
37,51
insulin-like growth factors I and II,
52
platelet-derived growth factor receptor β
(PDGFRβ),
53
hepatocyte growth factor (HGF)
receptor–Met
54
and epidermal growth factor
(erbB) receptor family receptors.
55
Expression
of c-Kit in MPM cells has been associated with
chemoresistance in mesothelial cells.
56
These
receptors activate the PI3K–Akt pathway, which
has a crucial role in MPM cell survival
57–60
and
contributes to the antiapoptotic phenotype.
7
Indirect inhibition of Akt by abrogation of
PDGFRβ activity has been shown to increase the
chemosensitivity of MPM cells.
61
This has led to
a pilot, stratified phase II trial, with the PDGFRβ
inhibitor imatinib mesylate combined with
gemcitabine in both the chemorefractory and
second-line settings.
Angiogenesis is a validated target for anti-
cancer therapy, as shown by the activity of
anti-VEGF-targeted therapy in other solid
tumors.
62
Bevacizumab is a recombinant human-
ized IgG monoclonal antibody against VEGF and
its use is being explored in phase II trials with
pemetrexed and carboplatin or cisplatin. Data
from a recent randomized phase II trial failed to
demonstrate an increase in survival when beva-
cizumab was given in addition to gemcitabine
carboplatin therapy.
63
AZD2171, a pan-VEGFR
inhibitor,
64
has demonstrated activity in patients
with glioblastoma and is being evaluated in
a phase II trial of patients with MPM in the
second-line setting.
Inhibition of tyrosine kinase activity can disrupt
survival pathways. The multikinase inhibitor
sorafenib (Nexavar®, Bayer Aktiengesellschaft,
Leverkusen-Bayerwerk, Germany) inhibits the
Ras/Raf/MEK/ERK and p38 signaling pathways,
VEGFR2 and VEGFR3, and members of the
PDGF receptor family, PDGFRβ and c-Kit.
65
First-line and second-line phase II clinical trials
are currently enrolling patients with MPM.
Sunitinib malate (Sutent® Pharmacia & Upjohn
Company, North Peapack, NJ) that acts on
several targets, such as VEGFRs, PDGFRβ and
c-Kit, has shown promising activity in phase III
trials enrolling patients with renal cell carcinoma
and gastrointestinal stromal tumors.
66–68
A first-
line phase II trial with sunitinib in patients with
inoperable MPM has been recently approved.
Proteome-modifying strategies
Methylation of tumor-suppressor promoters in
MPM results in inhibition of gene expression
and might contribute to chemoresistance and
tumor aggressiveness through specific alterations
of the proteome.
69
Histone deacetylase (HDAC)
r e v i e w
r e v i e w
Nature.indt 1Nature.indt 1 28/11/07 9:46:50 am28/11/07 9:46:50 am
144 nature clinical practice ONCOLOGY FENNELL ET AL. marCh 2008 vOL 5 NO 3
www.nature .com/clinicalpractice/onc
inhibitors derepress methylated genes, leading
to apoptotic cell death, and are associated with
Bcl-xL downregulation and antiproliferating
activity, which warrants their evaluation in MPM
and other cancers.
70
PXD101 is a novel HDAC
inhibitor being explored in a phase II study of
patients with unresectable MPM. A placebo-
controlled phase III trial of the HDAC inhibitor
suberoylanilide hydroxamic acid is also currently
enrolling patients. Decitabine is a novel agent that
induces promoter hypomethylation and is being
explored in combination with the HDAC inhib-
itor depsipeptide in a phase I trial. Depsipeptide
causes dose-dependent inhibition of growth
and apoptosis of MPM cells and synergizes
with the cyclin-dependent kinase inhibitor flavo-
piridol.
70
In light of these findings, a phase I trial
of depsipeptide and flavopiridol in patients with
refractory MPM has been initiated.
Argininosuccinate synthetase has a key role
in the metabolism of arginine and is frequently
methylated in malignant MPM cells, leading to
loss of expression in vivo. As a consequence, MPM
cells are frequently auxotrophic for exogenous
arginine and argininosuccinyl synthetase-negative
cells that lack this amino acid exhibit BAX activa-
tion and loss of viability.
71
On the basis of preclin-
ical results, an arginine-lowering drug (ADI-PEG
20), which has been approved by the FDA,
will be evaluated in a stratified phase II trial in
chemonaïve patients with inoperable disease who
are unfit for platinum-based, antifolate-containing
doublet therapy.
Regulation of protein degradation by the ubiq-
uitin proteosome is altered in cancers, including
peritoneal MPM.
72
Bortezomib inhibits nuclear
factor-kappa B and upregulates proapoptotic BH3
proteins.
73
Proteosome inhibition induces apop-
tosis of mesothelioma cells in vivo and in vitro.
74,75
On the basis of promising preclinical data, two
phase II trials of bortezomib have been initiated in
Europe. One trial is exploring single-agent activity
in the second-line setting and in patients with a
performance status of 2 in the first-line setting.
The second trial, conducted by the EORTC, is
exploring the use of this agent in a combination
regimen with cisplatin in the first-line setting.
76
Immune-activation strategies
Mesothelin, a membrane-bound glycosyl phos-
phatidylinositol-anchored glycoprotein, is over-
expressed on the surface of MPM, ovarian and
pancreatic cells and can elicit a humoral immune
response in patients with MPM.
77,78
Two phase I
clinical trials examining the use of antimesothelin
monoclonal antibodies in patients with recurrent
or refractory MPM have been initiated on the
basis of the restricted expression and immuno-
genicity of this antigen. Gene-delivery strategies
offer an alternative strategy for immune activa-
tion. For example, intratumoral delivery of a
recombinant adenovirus encoding the CD40
ligand can stimulate and recruit MPM-specific
CD8
+
T cells in immunocompetent mice, leading
to antitumor effects.
79
Delivery of an adenovirus
expressing interferon β achieves similar effects
in nu/nu immunodeficient mice,
80
and these
approaches are, therefore, currently being tested
in phase I clinical trials. A pilot phase II second-
line clinical trial is currently evaluating the effi-
cacy of cyclophosphamide and a vaccine against
MPM cells treated with interferon α followed by
granulocytemacrophage colony-stimulating
factor,
81
in promoting an immune response.
In summary, a considerable number of trials of
novel agents are now ongoing, some of which are
moving beyond early-phase evaluations.
CONCLUSIONS
The past 5 years have seen major advances in the
first-line therapy of inoperable MPM. The most
important of these have undoubtedly been the
positive results of two randomized trials. These
benchmark studies have now established the
use of antifolate–platinum doublets as a widely
adopted standard, supporting the evidence
from meta-analyses for the superior activity of
platinum-based combinations. The once nihil-
istic perception of second-line therapy for
mesothelioma has now been supplanted by early
evidence showing clinical activity in this setting.
This body of evidence is likely to grow in the
near future. Clinical prognostic scores provide
tools for a priori identification of patients likely
to do better or worse following a diagnosis of
MPM; however, good predictive biomarkers that
can reliably identify chemoresistant subgroups
are yet to be translated into routine clinical
practice. Having now entered the era in which
translational research is considered a standard
component of the design process of clinical
trials, it is possible that tailored therapy for
MPM could become a reality in routine practice.
Finally, new preclinical research is shedding light
on the underlying cell biology of MPM. It is the
translation of this knowledge that will ultimately
help to develop therapies for MPM that progress
beyond the existing therapeutic plateau.
r e v i e w
r e v i e w
Nature.indt 1Nature.indt 1 28/11/07 9:46:50 am28/11/07 9:46:50 am
marCh 2008 vOL 5 NO 3 FENNELL ET AL. nature clinical practice ONCOLOGY 145
www.nature .com/clinicalpractice/onc
KEY POINTS
Malignant pleural mesothelioma remains a
highly lethal cancer, which is increasing in
incidence in several countries
Chemotherapy is the mainstay of treatment
for the majority of patients presenting as
inoperable
Despite the therapeutic plateau of the past
20 years, randomized trials have now confirmed
that combining antifolates with platinum-based
therapy confers a survival benefit
No standard therapy has yet been defined in
the second-line setting
New approaches for treating this disease are
arising from a better understanding of the
underlying biology and are beginning to be
translated into the clinical setting
References
1 Hodgson JT et al. (2005) The expected burden of
mesothelioma mortality in Great Britain from 2002 to
2050. Br J Cancer 92: 587–593
2 Flores RM (2005) The role of PET in the surgical
management of malignant pleural mesothelioma. Lung
Cancer 49 (Suppl 1): S27–S32
3 Berghmans T et al. (2002) Activity of chemotherapy
and immunotherapy on malignant mesothelioma:
a systematic review of the literature with meta-
analysis. Lung Cancer 38: 111–121
4 Ellis P et al. (2006) The use of chemotherapy in patients
with advanced malignant pleural mesothelioma: a
systematic review and practice guideline. J Thorac
Oncol 1: 591–601
5 van Meerbeeck JP et al. (2005) Randomized phase III
study of cisplatin with or without raltitrexed in patients
with malignant pleural mesothelioma: an intergroup
study of the European Organisation for Research and
Treatment of Cancer Lung Cancer Group and the
National Cancer Institute of Canada. J Clin Oncol 23:
6881–6889
6 Vogelzang NJ et al. (2003) Phase III study of
pemetrexed in combination with cisplatin versus
cisplatin alone in patients with malignant pleural
mesothelioma. J Clin Oncol 21: 2636–2644
7 Fennell DA and Rudd RM (2004) Defective core-
apoptosis signalling in diffuse malignant pleural
mesothelioma: opportunities for effective drug
development. Lancet Oncol 5: 354–362
8 Byrne MJ and Nowak AK (2004) Modified RECIST
criteria for assessment of response in malignant
pleural mesothelioma. Ann Oncol 15: 257–260
9 Oxnard GR et al. (2006) Modeling of mesothelioma
growth demonstrates weaknesses of current response
criteria. Lung Cancer 52: 141–148
10 Francart J et al. (2006) Progression-free survival rate
as primary end point for phase II cancer clinical trials:
application to mesothelioma. The EORTC Lung Cancer
Group. J Clin Oncol 24: 3007–3012
11 O’Brien ME et al. (2006) A randomised trial in malignant
mesothelioma (M) of early (E) versus delayed (D)
chemotherapy in symptomatically stable patients:
the MED trial. Ann Oncol 17: 270–275
12 Muers MF et al. (2004) BTS randomised feasibility
study of active symptom control with or without
chemotherapy in malignant pleural mesothelioma:
ISRCTN 54469112. Thorax 59: 144–148
13 Andreopoulou E
et al. (2004) The palliative
benefits of MVP (mitomycin C, vinblastine and
cisplatin) chemotherapy in patients with malignant
mesothelioma. Ann Oncol 15: 1406–1412
14 Steele JP et al. (2000) Phase II study of vinorelbine in
patients with malignant pleural mesothelioma. J Clin
Oncol 18: 3912–3917
15 Green J et al. Pemetrexed disodium in combination
with cisplatin versus other cytotoxic agents or
supportive care for the treatment of malignant pleural
mesothelioma. Cochrane Database Systematic
Reviews 2007, Issue 1. Art No.:CD005574.
doi:10.1002/14651858.CD005574.pub2.
16 Bottomley A et al. (2006) Short-term treatment-
related symptoms and quality of life: results from an
international randomized phase III study of cisplatin
with or without raltitrexed in patients with malignant
pleural mesothelioma: an EORTC Lung-Cancer Group
and National Cancer Institute, Canada, Intergroup
Study. J Clin Oncol 24: 1435–1442
17 Weder W et al. (2004) Neoadjuvant chemotherapy
followed by extrapleural pneumonectomy in malignant
pleural mesothelioma. J Clin Oncol 22: 3451–3457
18 Sugarbaker DJ et al. (1999) Resection margins,
extrapleural nodal status, and cell type determine
postoperative long-term survival in trimodality therapy
of malignant pleural mesothelioma: results in 183
patients. J Thorac Cardiovasc Surg 117: 54–63
19 MARS (mesothelioma and radical surgery) trial.
http://pfsearch.ukcrn.org.uk/
StudyDetail.aspx?TopicID=1&StudyID=1189
20 Zucali PA and Giaccone G (2006) Biology and
management of malignant pleural mesothelioma. Eur J
Cancer 42: 2706–2714
21 Fennell DA et al. (2007) Efficacy and safety of first- or
second-line irinotecan, cisplatin, and mitomycin in
mesothelioma. Cancer 109: 93–99
22 Nagel S et al. (2005) Second-line treatment of
malignant pleural mesothelioma with Pemetrexed
(Alimta)—a case report. Pneumologie 59: 108–111
23 Giaccone G et al. (2002) Phase II trial of ZD0473 as
second-line therapy in mesothelioma. Eur J Cancer 38
(Suppl 8): S19–S24
24 Manegold C et al. (2005) Second-line (post-study)
chemotherapy received by patients treated in the
phase III trial of pemetrexed plus cisplatin versus
cisplatin alone in malignant pleural mesothelioma.
Ann Oncol 16: 923–927
25 Sorensen JB et al. (2007) Pemetrexed as second-line
treatment in malignant pleural mesothelioma after
platinum-based first-line treatment. J Thorac Oncol 2:
147–152
26 Jassem J et al. (2006) A randomized phase III trial
comparing pemetrexed plus best supportive care (BSC)
versus BSC in previously treated patients with advanced
malignant pleural mesothelioma. Ann Oncol 17: ix214
27 Spirtas R et al. (1988) Survival patterns for malignant
mesothelioma: the SEER experience. Int J Cancer 41:
525–530
28 Herndon JE et al. (1998) Factors predictive of survival
among 337 patients with mesothelioma treated
between 1984 and 1994 by the Cancer and Leukemia
Group B. Chest 113: 723–731
29 Curran D et al. (1998) Prognostic factors in patients
with pleural mesothelioma: the European Organization
for Research and Treatment of Cancer experience.
J Clin Oncol 16: 145–152
30 Fennell DA et al. (2005) Statistical validation of the
EORTC prognostic model for malignant pleural
mesothelioma based on three consecutive phase II
trials. J Clin Oncol 23: 184–189
31 Edwards JG et al. (2000) Prognostic factors for
malignant mesothelioma in 142 patients: validation
r e v i e w
r e v i e w
Nature.indt 1Nature.indt 1 28/11/07 9:46:50 am28/11/07 9:46:50 am
146 nature clinical practice ONCOLOGY FENNELL ET AL. marCh 2008 vOL 5 NO 3
www.nature .com/clinicalpractice/onc
of CALGB and EORTC prognostic scoring systems.
Thorax 55: 731–735
32 Flores RM et al. (2006) Positron emission tomography
predicts survival in malignant pleural mesothelioma.
J Thorac Cardiovasc Surg 132: 763–768
33 Ceresoli GL et al. (2006) Early response evaluation in
malignant pleural mesothelioma by positron emission
tomography with [18F]fluorodeoxyglucose. J Clin
Oncol 24: 4587–4593
34 Lopez-Rios F et al. (2006) Global gene expression
profiling of pleural mesotheliomas: overexpression of
aurora kinases and P16/CDKN2A deletion as prognostic
factors and critical evaluation of microarray-based
prognostic prediction. Cancer Res 66: 2970–2979
35 Ohta Y et al. (1999) Tumor angiogenesis and
recurrence in stage I non-small cell lung cancer. Ann
Thorac Surg 68: 1034–1038
36 Edwards JG et al. (2001) Angiogenesis is an
independent prognostic factor in malignant
mesothelioma. Br J Cancer 85: 863–868
37 Strizzi L et al. (2001) Vascular endothelial growth factor
is an autocrine growth factor in human malignant
mesothelioma. J Pathol 193: 468–475
38 Ohta Y et al. (1999) VEGF and VEGF type C play an
important role in angiogenesis and lymphangiogenesis
in human malignant mesothelioma tumours. Br J
Cancer 81: 54–61
39 Kumar-Singh S et al. (1999) Angiogenic cytokines in
mesothelioma: a study of VEGF, FGF-1 and -2, and
TGF beta expression. J Pathol 189: 72–78
40 Klabatsa A et al. (2006) Expression and prognostic
significance of hypoxia-inducible factor 1alpha
(HIF-1alpha) in malignant pleural mesothelioma (MPM).
Lung Cancer 51: 53–59
41 Erler JT et al. (2004) Hypoxia-mediated down-
regulation of Bid and Bax in tumors occurs via hypoxia-
inducible factor 1-dependent and -independent
mechanisms and contributes to drug resistance. Mol
Cell Biol 24: 2875–2889
42 Kokturk N et al. (2005) Prognostic significance of
Bax and Fas ligand in erionite and asbestos induced
Turkish malignant pleural mesothelioma. Lung Cancer
50: 189–198
43 Soini Y et al. (1999) Apoptosis and expression of
apoptosis regulating proteins bcl-2, mcl-1, bcl-X, and
bax in malignant mesothelioma. Clin Cancer Res 5:
3508–3515
44 O’Kane SL et al. (2006) Expression of bcl-2 family
members in malignant pleural mesothelioma. Acta
Oncol 45: 449–453
45 Segers K et al. (1994) Immunoreactivity for bcl-2
protein in malignant mesothelioma and non-neoplastic
mesothelium. Virchows Arch 424: 631–634
46 Narasimhan SR et al. (1998) Resistance of pleural
mesothelioma cell lines to apoptosis: relation to
expression of Bcl-2 and Bax. Am J Physiol 275:
L165–L171
47 Gordon GJ et al. (2003) Using gene expression
ratios to predict outcome among patients with
mesothelioma. J Natl Cancer Inst 95: 598–605
48 Gordon GJ et al. (2005) Validation of genomics-based
prognostic tests in malignant pleural mesothelioma.
Clin Cancer Res 11: 4406–4414
49 Pass HI et al. (2004) Gene expression profiles predict
survival and progression of pleural mesothelioma. Clin
Cancer Res 10: 849–859
50 Glinsky GV et al. (2005) Microarray analysis identifies a
death-from-cancer signature predicting therapy failure
in patients with multiple types of cancer. J Clin Invest
115: 1503–1521
51 Romano M et al. (2001) 5-lipoxygenase regulates
malignant mesothelial cell survival: involvement of
vascular endothelial growth factor. Faseb J 15: 2326–2336
52 Hoang CD et al. (2004) Selective activation of insulin
receptor substrate-1 and -2 in pleural mesothelioma
cells: association with distinct malignant phenotypes.
Cancer Res 64: 7479–7485
53 Vogelzang NJ et al. (2005) New agents in the
management of advanced mesothelioma. Semin
Oncol 32: 336–350
54 Jagadeeswaran R et al. (2006) Functional analysis of
c-Met/hepatocyte growth factor pathway in malignant
pleural mesothelioma. Cancer Res 66: 352–361
55 Mukohara T et al. (2005) Inhibition of the met receptor
in mesothelioma. Clin Cancer Res 11: 8122–8130
56 Catalano A et al. (2004) Induction of stem cell factor/
c-Kit/slug signal transduction in multidrug-resistant
malignant mesothelioma cells. J Biol Chem 279:
46706–46714
57 Cacciotti P et al. (2005) SV40-dependent AKT activity
drives mesothelial cell transformation after asbestos
exposure. Cancer Res 65: 5256–5262
58 Ramos-Nino ME et al. (2005) Human mesothelioma
cells exhibit tumor cell-specific differences in
phosphatidylinositol 3-kinase/AKT activity that predict
the efficacy of Onconase. Mol Cancer Ther 4: 835–842
59 Pespeni MH et al. (2007) Sensitization of mesothelioma
cells to tumor necrosis factor-related apoptosis-
inducing ligand-induced apoptosis by heat stress via
the inhibition of the 3-phosphoinositide-dependent
kinase 1/Akt pathway. Cancer Res 67: 2865–2871
60 Altomare DA et al. (2005) Human and mouse
mesotheliomas exhibit elevated AKT/PKB activity,
which can be targeted pharmacologically to inhibit
tumor cell growth. Oncogene 24: 6080–6089
61 Bertino P et al. (2007) Preliminary data suggestive of a
novel translational approach to mesothelioma therapy:
imatinib mesylate with gemcitabine or pemetrexed.
Thorax 62: 690–695
62 Shih T and Lindley C (2006) Bevacizumab: an
angiogenesis inhibitor for the treatment of solid
malignancies. Clin Ther 28: 1779–1802
63 Karrison T et al. (2007) Final analysis of a multi-centre,
double blind, placebo controlled, randomized phase II
trial of gemcitabine/cisplatin plus bevacizumab or
placebo in patients with malignant mesothelioma
[abstract #7526]. Proc Am Soc Clin Oncol Part 1: 25
64 Wedge SR et al. (2005) AZD2171: a highly potent,
orally bioavailable, vascular endothelial growth factor
receptor-2 tyrosine kinase inhibitor for the treatment of
cancer. Cancer Res 65: 4389–4400
65 Adnane L et al. (2005) Sorafenib (BAY 43-9006,
Nexavar((R))), a dual-action inhibitor that targets
RAF/MEK/ERK pathway in tumor cells and tyrosine
kinases VEGFR/PDGFR in tumor vasculature. Methods
Enzymol 407: 597–612
66 Prenen H et al. (2006) Efficacy of the kinase inhibitor
SU11248 against gastrointestinal stromal tumor
mutants refractory to imatinib mesylate. Clin Cancer
Res 12: 2622–2627
67 Motzer RJ et al. (2006) Activity of SU11248, a
multitargeted inhibitor of vascular endothelial
growth factor receptor and platelet-derived growth
factor receptor, in patients with metastatic renal cell
carcinoma. J Clin Oncol 24: 16–24
68 Motzer RJ et al. (2006) Sunitinib in patients
with metastatic renal cell carcinoma. JAMA 295:
2516–2524
69 Fischer JR et al. (2006) Promoter methylation of
RASSF1A, RARbeta and DAPK predict poor prognosis
of patients with malignant mesothelioma. Lung Cancer
54: 109–116
70 Nguyen DM et al. (2004) Abrogation of p21 expression
by flavopiridol enhances depsipeptide-mediated
apoptosis in malignant pleural mesothelioma cells.
Clin Cancer Res 10: 1813–1825
r e v i e w
r e v i e w
Nature.indt 1Nature.indt 1 28/11/07 9:46:50 am28/11/07 9:46:50 am
marCh 2008 vOL 5 NO 3 FENNELL ET AL. nature clinical practice ONCOLOGY 147
www.nature .com/clinicalpractice/onc
71 Szlosarek PW et al. (2006) In vivo loss of expression
of argininosuccinate synthetase in malignant pleural
mesothelioma is a biomarker for susceptibility to
arginine depletion. Clin Cancer Res 12: 7126–7131
72 Borczuk AC et al. (2007) Molecular profiling of
malignant peritoneal mesothelioma identifies the
ubiquitin-proteasome pathway as a therapeutic
target in poor prognosis tumors. Oncogene 26:
610–617
73 Fennell DA et al. (2007) BCL-2 family regulation by
the 20S proteosome inhibitor bortezomib. Oncogene
[doi:10.1038/sj.onc.1210744]
74 Sartore-Bianchi A et al. (2007) Bortezomib inhibits
nuclear factor-kappa B-dependent survival and has
potent in vivo activity in mesothelioma. Clin Cancer
Res 13: 5942–5951
75 Gordon GJ et al. (2007) Preclinical studies of the
proteasome inhibitor bortezomib in malignant pleural
mesothelioma. Cancer Chemother Pharmacol
[doi: 10.1007/s00280-007-0500-1]
76 US National Institutes of Health. http://www.cancer.gov/
search/psrv.aspx?cid=9817&protocolsearchid=3540567
77 Hassan R et al. (2004) Mesothelin: a new target for
immunotherapy. Clin Cancer Res 10: 3937–3942
78 Ho M et al. (2005) Humoral immune response to
mesothelin in mesothelioma and ovarian cancer
patients. Clin Cancer Res 11: 3814–3820
79 Friedlander PL et al. (2003) Efficacy of CD40 ligand
gene therapy in malignant mesothelioma. Am J Respir
Cell Mol Biol 29: 321–330
80 Gattacceca F et al. (2002) Ad-IFN gamma induces
antiproliferative and antitumoral responses in malignant
mesothelioma. Clin Cancer Res 8: 3298–3304
81 Powell A et al. (2006) Recombinant GM-CSF plus
autologous tumor cells as a vaccine for patients with
mesothelioma. Lung Cancer 52: 189–197
Acknowledgments
The authors would like
to thank Dr Van Shoote
for her help in editing the
manuscript. Charles P Vega,
University of California,
Irvine, CA, is the author of
and is solely responsible for
the content of the learning
objectives, questions and
answers of the Medscape-
accredited continuing
medical education activity
associated with this article.
Competing interests
The authors declared no
competing interests.
r e v i e w
r e v i e w
Nature.indt 1Nature.indt 1 28/11/07 9:46:50 am28/11/07 9:46:50 am
    • "The combination of carboplatin and pemetrexed could be an alternative treatment option for patients who are not candidates to cisplatin-based therapy. On the other hand, in patients unfit for platinum-based chemotherapy, the use of single agent vinorelbine as first-line therapy could be considered, although the consensus panel was not unanimous, due to the limited evidence supporting this treatment (Fennell et al., 2008). A better knowledge of major molecular pathways involved in MPM biology has lead to the identification of potential new therapeutic targets (Stahel et al., 2015). "
    [Show abstract] [Hide abstract] ABSTRACT: Malignant pleural mesothelioma (MPM) remains a relevant public health issue, and asbestos exposure is the most relevant risk factor. The incidence has considerably and constantly increased over the past two decades in the industrialized countries and is expected to peak in 2020-2025. In Italy, a standardized-rate incidence in 2011 among men was 3.5 and 1.25 per 100,000 in men and women, respectively, and wide differences are noted among different geographic areas. The disease remains challenging in terms of diagnosis, staging and treatment and an optimal strategy has not yet been clearly defined. The Third Italian Multidisciplinary Consensus Conference on Malignant Pleural Mesothelioma was held in Bari (Italy) in January 30-31, 2015. This Consensus has provided updated recommendations on the MPM management for health institutions, clinicians and patients.
    Full-text · Article · May 2016
    • "Patient selection is important as the prolonged survival must be weighted against the potential morbidity and mortality associated with aggressive cytoreductive surgery [13]. Systemic chemotherapy in recent years using a combination of cisplatin and permetrexed (antimetabolite) have demonstrated an improved median survival of 12-14 month [14,15], compared to the older combination of cisplatin and gemcitabine with a median survival of 6-9 months [16]. However, the median survival of about 1 year is dismal and its role has been limited to palliation and should be considered as the standard of care for patients with unresectable malignant mesothelioma or for patients who are not fit for surgery. "
    [Show abstract] [Hide abstract] ABSTRACT: Malignant mesothelioma is a rare but highly aggressive and fatal tumour arising from the mesothelial cells, which is associated with an involvement of the peritoneum in 30% of cases. We report a 48-year-old man with malignant peritoneal mesothelioma who presented with ascites of unknown origin, and discussed the clinical presentation, investigation and management, as well as the diagnostic difficulties in managing this unusual and unfortunate case.
    Full-text · Article · Jan 2015
    • "The first line treatment for MPM lies in the combination of cisplatin with an antimetabolite: the Pemetrexed (Alimta). There are several clinical trials relating this combination to treat MPM34, that lead to better response compared to cisplatin alone [5]. However, this improvement remains modest and only half of the patients respond to the combination [6]. "
    [Show abstract] [Hide abstract] ABSTRACT: Malignant pleural mesothelioma (MPM) is a very aggressive form of cancer with a poor diagnosis and prognosis. The first line treatment for MPM is a combination of cisplatin and Pemetrexed, which displayed limited efficacy and severe side effects. The naturally occurring compound phenethyl isothiocyanate (PEITC) previously showed interesting anti-tumor properties on several cancer cell lines. We thus aim at evaluating PEITC used alone or in combination with cisplatin in order to improve MPM treatment. Nine MPM cell lines and primary mesothelial cells (PMC), co-cultured or not with M2 macrophages present in MPM microenvironment, were used to assess PEITC and cisplatin anti-tumor properties. Compounds were used alone or in combination. Both PEITC and cisplatin were cytotoxic on MPM cells in a dose dependent manner. We herein showed that PEITC-induced cytotoxicity was due to the generation of reactive oxygen species. Moreover, we showed that cisplatin-PEITC combination allowed the potentialization of both compounds' cytotoxic effects and prevented the emergence of resistant MPM cells. Interestingly, PMC were not sensitive to the combination. Finally, we showed that M2 macrophages did not alter the anti-tumor properties of the combination. Cisplatin-PEITC combination thus represents a promising strategy to induce a selective toxicity towards malignant cells.
    Full-text · Article · Oct 2014
Show more

  • undefined · undefined
  • undefined · undefined
  • undefined · undefined