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
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.
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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
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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
Competing interests
The authors declared no competing interests. Charles P
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served as an advisor or consultant to Novartis, Inc.
The incidence of malignant pleural mesothelioma
(MPM) is anticipated to increase over the next
10 years in both Europe and the developing
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.
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.
*3rd Floor 008, Centre for Cancer Research and Cell Biology, Queen’s University Belfast,
97 Lisburn Road, Belfast BT9 7BL, UK
Received 24 May 2007 Accepted 2 October 2007 Published online 29 January 2008
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
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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.
Most single agents
exhibit low intrinsic activity, with the exception
of cisplatin.
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).
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.
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
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.
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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.
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.
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
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).
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.
The median time to
delayed treatment was 17 weeks. Trends towards
1982 1987 1992 1997
Response rate (%)
2002 2007
Combination regimen Single-agent regimen
Combination regimen Single-agent regimen
Platinum-based regimen Non-platinum-based regimen
1982 1987 1992 1997
Response rate (%)
2002 2007
1980 1985 1990 1995 2000
Survival (months)
2005 2010
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.
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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,
a three-armed randomized phase III study was
conducted in the UK to evaluate the efficacy of
chemotherapy—mitomycin, vinblastine and cis-
or vinorelbine
—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.
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).
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
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
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.
The EORTC Lung Cancer Group reported
the results of a randomized trial that compared
cisplatin and raltitrexed with cisplatin only;
significant improvements in efficacy and
disease-related symptoms (pain and dyspnea)
were observed with raltitrexed and cisplatin.
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.
1982 1987 1992 1997
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
0 10 20 30
Response rate (%)
Survival (months)
40 50
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).
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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.
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)
van Meerbeeck et al. (2005)
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
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.
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the use of gemcitabine and cisplatin as induc-
tion therapy preceding an extrapleural pneumo-
nectomy (EPP).
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.
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.
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.
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
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.
Recently, the
efficacies of single-agent pemetrexed therapy and
pemetrexed and carboplatin following platinum-
based therapy without pemetrexed have been
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.
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.
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.
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
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.
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.
A subsequent retrospective
analysis of 145 patients included in three
phase II studies validated the EORTC scoring
Both systems have been shown to
be applicable to a general hospital population
(Figures 3B,C).
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 [
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.
PET imaging was used to assess 137 patients before
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.
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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.
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
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
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.
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.
MPM exhibits high levels of
expression of the surrogate marker of hypoxia,
hypoxia-inducible factor 1α.
Tumor hypoxia
Chest pain
ight loss
Platelet coun
eatment yes/no
Duration of symptoms
Leucocyte count
pe of tr
Reported frequency
Survival (days)
Survival (months)
0 500 1,000 1,500
Survival (days)
Cumulative survival
2,000 2,500
0 500 1,000 1,500 2,000 2,500
EORTC group
High risk
Low risk
CALGB group
Groups 5 and 6
Groups 3 and 4
Groups 1 and 2
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.
(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.
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contributes directly to chemoresistance; for
example, through downregulation of BAX.
reduced level of this tumor suppressor has been
associated with a poor outcome.
Despite the
expression of multiple antiapoptotic BCL2 family
expression of these proteins does
not predict an outcome consistent with findings
in vitro.
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.
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
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.
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.
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,
supporting several
previous studies that have reported mitosis or
proliferation, diploidy and S-phase fraction as
indices of significance.
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
insulin-like growth factors I and II,
platelet-derived growth factor receptor β
hepatocyte growth factor (HGF)
and epidermal growth factor
(erbB) receptor family receptors.
of c-Kit in MPM cells has been associated with
chemoresistance in mesothelial cells.
receptors activate the PI3K–Akt pathway, which
has a crucial role in MPM cell survival
contributes to the antiapoptotic phenotype.
Indirect inhibition of Akt by abrogation of
PDGFRβ activity has been shown to increase the
chemosensitivity of MPM cells.
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
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.
AZD2171, a pan-VEGFR
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.
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.
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.
Histone deacetylase (HDAC)
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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.
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-
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.
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.
Bortezomib inhibits nuclear
factor-kappa B and upregulates proapoptotic BH3
Proteosome inhibition induces apop-
tosis of mesothelioma cells in vivo and in vitro.
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.
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.
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
T cells in immunocompetent mice, leading
to antitumor effects.
Delivery of an adenovirus
expressing interferon β achieves similar effects
in nu/nu immunodeficient mice,
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
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.
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.
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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
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
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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.
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    • "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
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