Current therapies for malignant pleural mesothelioma
Environ Health Prev Med
Current therapies for malignant pleural mesothelioma
Takashi Nakano 0 1
0 T. Nakano (&) Department of Thoracic Oncology, Hyogo College of Medicine , 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 , Japan
1 T. Nakano Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine , 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 , Japan
Mesothelioma is a highly lethal tumor derived from mesothelial cells, and its global incidence is increasing because of widespread exposure of numerous individuals to asbestos in the last 50 years. Mesothelioma is largely untreatable with any of the therapeutic modalities. Recently, a novel multitargeted antifolate pemetrexed has shown promising activity against malignant pleural mesothelioma, producing response rates of up to 40% when used in combination with cisplatin. In a large phase III study, use of a combination of pemetrexed and cisplatin was associated with significantly improved survival time and with greater antitumor activity compared with cisplatin alone. This combination also gave a significant response rate of approximately 50% in patients with epithelioid malignant pleural mesothelioma. These clinical benefits of pemetrexed-cisplatin doublet have changed the perception of mesothelioma chemotherapy. Other combinations, including gemcitabine in combination with cisplatin, have also shown encouraging response rates. Prognosis depends on gender, clinical stage of the tumor, histological subtype, platelet count, leukocyte counts, and performance status. Radiotherapy can palliate mesothelioma patients with chest pain, and has been indicated to be of benefit for the prevention of malignant seeding along the tract of a chest tube or needle biopsy. Trimodality treatment using extrapleural pneumonectomy, radiation and chemotherapy has shown promising therapeutic value. The development of chemotherapeutic regimens and the favorable outcomes of trimodality have led to new combined modality trials. In Japan, multicenter national trials against mesothelioma will begin in the near future.
Asbestos; Extrapleural pneumonectomy; Mesothelioma; Pemetrexed
Malignant mesothelioma used to be a relatively uncommon
disease, but its incidence has been rising in recent times
and is predicted to peak around the year 2030 in Japan.
There are currently 1,000 new mesothelioma cases per
year. In June 2005, several inhabitants suffered from
mesothelioma in Amagasaki, Hyogo, and their
environmental exposure to asbestos resulted in medico-legal
problems related to mesothelioma and social compensation
for asbestos-related diseases in Japan. Since then,
overwhelming media interest in the mesothelioma tragedy
caused by asbestos has produced a high level of awareness
of the risks of asbestos and mesothelioma.
Mesothelioma occurs at different anatomical sites that
contain mesothelial cells. The most common site is pleura,
followed by the peritoneum, the pericardium, and the male
genitalia. Malignant pleural mesothelioma (MPM) is a
highly lethal and particularly refractory tumor for which
conventional chemotherapeutic regimens have been far
from satisfactory in achieving a clinical response.
However, the role of chemotherapy in MPM has gradually
changed since the late 1990s, with the emergence of new
active agents and evidence that chemotherapy palliates
clinical symptoms. The majority of patients have clinical
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes
N2 Metastases in the subcarinal or the ipsilateral mediastinal lymph nodes, including the ipsilateral internal mammary nodes
N3 Metastases in the contralateral mediastinal, contralateral internal mammary, ipsilateral, or contralateral supraclavicular lymph nodes
Mx Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis present
Stage Ia Ib II
stage Ib or more locally advanced disease, as defined by
the International Mesothelioma Interest Group (IMIG;
Table 1; [
]). These patients do not benefit from radical
surgery; therefore, most patients are candidates for
chemotherapy at some point in their treatment. Patients
receiving best supportive care alone have short survivals
and suffer from progressive pain. Recent results from the
first large randomized, international phase III trial of a
multitargeted antifolate, pemetrexed combined with
cisplatin, demonstrated that the combination significantly
improved response rates, time to progression, and overall
survival in comparison with cisplatin alone [
]. Also, a
more recent trial demonstrated that cisplatin in
combination with raltitrexed significantly improved median
survival compared to single-agent cisplatin (11.4 vs.
8.8 months) [
]. MPM is a locally aggressive tumor within
and around the thoracic cavity and it uncommonly exhibits
clinical features of metastatic malignancy. The
singletreatment modality has not been effective; however,
multimodality approaches have demonstrated an improvement
in survival and quality of life [
Asbestos consumption and mesothelioma in Japan
Development of malignant mesothelioma is strongly
associated with asbestos exposure, with 80% of patients
previously exposed to asbestos fiber. In Japan, the incidence
of malignant mesothelioma is continuing to rise, with a
peak in the epidemic expected around the year 2030. A very
small amount of asbestos, mainly chrysotile, was produced
in Japan; therefore, the amount of asbestos imported is
nearly equal to the total used. In the history of the Japanese
asbestos industry, 30,000–40,000 tons was imported per
year before World War II. Thereafter, the import of
asbestos ceased between 1942 and 1948 because of the
economic blockade of Japan during World War II and the
complete destruction of its industry as a result of the war.
The recovery of Japanese industry has been accelerating
since the Korean War (1950–1953), and the import of
asbestos vastly increased in the late 1960s. In contrast to the
situation in Japan, the use of asbestos in the United States
increased rapidly during and soon after World War II, at
peaking from the 1950s through to 1970. The US imported
165,000 tons of chrysotile in 1935 and 650,000 tons in
1962. Starting in 1970, the consumption of asbestos
declined precipitously in the US as a result of its
carcinogenicity, thus accounting for the decreasing incidence rate
of mesothelioma in the twenty-first century there. The
number of asbestos lawsuits increased dramatically during
the early 1970s. In contrast, more than 300,000 tons of
asbestos were continuously imported between 1973 and
1977 in Japan. After asbestos spraying was prohibited in
1974, asbestos consumption began to decrease in Japan.
However, from the mid-1980s, one economic policy of the
Japanese government was to decrease Japan’s trade surplus,
markedly increasing demand for building construction. The
import of asbestos therefore rose again to 320,000 tons in
1988, but dropped again to 176,000 tons in 1997, because
of the serious recession in the Japanese economy.
Therefore, compared to the US, there is a time-lag of about
20 years in the decrease in use of asbestos. The last decades
of the twentieth century saw stabilization and/or declines in
mesothelioma rates in the US. However in Japan, the annual
numbers of deaths from mesothelioma increased markedly
from 500 cases in 1995 to 953 cases in 2004; this increase
occurred in parallel with the continued importation of
asbestos with a delay of 40 years, due to the long latency
period of mesothelioma (Fig. 1). Considering the long
latency period of about 40 years and the more than
300,000 tons of asbestos used between 1973 and 1977 in
Japan, the incidence of malignant mesothelioma can be
expected to increase dramatically in the near future,
possibly from 2010 onwards.
( Number of deaths/Year)
First-line chemotherapy for malignant pleural mesothelioma
MPM is a highly lethal tumor and is poorly responsive to
any conventional chemotherapy. Over the last few decades,
numerous clinical studies have been performed to identify
single agents or combinations of them that possess any
activity against MPM; however, no standard regimen has
emerged. Many of the phase II studies have been small,
single-institution trials because of the rarity of the
neoplasm, and the patients enrolled are usually heterogeneous
in prognostic factors, which may lead to statistical bias and
misleading interpretations. In the past, several small phase
II trials have reported relatively positive results. However,
these favorable outcomes have usually not been confirmed
by larger confirmatory trials.
Cytotoxic agents, including anthracyclines, platinum
derivatives, topoisomerase I inhibitors and
antimetabolites, have demonstrated some activity against MPM [
], although their single-agent response rates are
disappointingly low. Several combinations of these agents have
been tested in many phase II studies, but the role of drug
combinations in the treatment of MPM remains unclear.
A response rate of 13–14% can be achieved by using
cisplatin as a single agent against MPM. In a
meta-analysis of studies published between 1965 and 2001,
cisplatin was found to be the most active agent .
Treatment regimens in which one further active agent is
added to cisplatin have been used in attempts to enhance
anti-mesothelioma activity. Carboplatin was not superior
to cisplatin; single-agent response rates were similar to
those obtained with conventional doses of cisplatin (6–
]. A platinum analog, oxaliplatin, has only been
tested in combination with raltitrexed (response rate =
], or with gemcitabine (GEM) (response rate =
40%, median survival = 13 months) [
]; it has not been
tested as a single agent. However, when combined with
vinorelbin, oxaliplatin significantly increased in toxicity
and did not appear to offer any advantage over
vinorelbine alone [
]. The most widely tested combination is
the cisplatin–doxorubicin (DXR) doublet, which has given
response rates of 15–25% [
]. DXR was once believed
to be one of the most active agents against MPM;
however, the response rate to single-agent DXR was reported
to be 14%, with a median survival of 7.3 months. The
Cancer and Leukemia Group B (CALGB) tested
combinations of cisplatin plus DXR and cisplatin plus
mitomycin C (MMC) in a randomized trial [
]. A 14%
response rate was achieved using cisplatin plus DXR,
and a 26% response rate was achieved using cisplatin
plus MMC. The triplet of cisplatin–DXR–MMC had a
response rate of 20.9% against mesothelioma. The activity
of this triplet was similar to those of the respective
]. Berghmans et al. [
] reviewed 83 studies
with 88 treatment arms for MPM from 1965 to 2001, and
noted that cisplatin was the most active single agent and
that the cisplatin–DXR doublet had the highest response
rate, of 28.5%. This combination was recommended as
the control arm for subsequent trials.
Irinotecan (CPT-11) is a potent topoisomerase I
inhibitor with activity against various tumors, which has been
evaluated in MPM. There were no responses with
singleagent CPT-11 in a phase II trial of the CALGB [
CPT11 is converted to its more active metabolite, SN-38, which
has 1,000 times the potency of the parent compound.
Intravenous administration of CPT-11 at a dose of 60 mg/
m2 can produce distributions of CPT-11 and SN-38 into the
pleural fluid that allow the more active SN-38 to come into
contact with mesothelioma cells in the thoracic cavity for a
longer time and at a higher concentration than for CPT-11
]. It is also expected that CPT-11 is more active in
combination with other agents against MPM. The CPT-11–
cisplatin doublet produced response rates of 26.7% in
] and 24% in malignant peritoneal mesothelioma
], and the CPT-11–cisplatin–MMC triplet produced a
response rate of 35% and progression-free survival of
6.5 months [
Antimetabolites, such as the antifolates (methotrexate,
edatrexate and trimetrexate), are among the most active
agents for the treatment of MPM. Halme et al. have
demonstrated that high-dose methotrexate in combination with
interferon a or c had a response rate of 29% and a median
survival of 17 months [
]. Other antifolates, including
trimetrexate and edatrexate, did not show a clear benefit.
Although GEM, a pyrimidine antimetabolite, achieves
limited activity as a single agent (response rates of
0–7%), its combination with cisplatin shows an increased
response. Byrne et al. [
] reported a promising response
rate of 47.6% with the combination of cisplatin and
GEM in a four-week schedule. They performed a
multicenter trial of the same regimen, and confirmed its
anti-mesothelioma activity (response rate = 33%) [
however, a subsequent trial of similar design but using a
slightly higher planned dose intensity of GEM failed to
duplicate this result, demonstrating a response rate of
Pemetrexed has demonstrated a single-agent response
rate of 14% with acceptable toxicity. Two phase III
randomized trials have been reported with promising results.
The international trial of pemetrexed with cisplatin versus
cisplatin alone in chemotherapy-na¨ıve MPM patients
demonstrated a significant increase in overall survival (12.1
vs. 9.3 months), a longer median time to progression (5.7
vs. 3.9 months), and a greater response rate (41 vs. 17%)
for the combination of pemetrexed and cisplatin with
supplementation of vitamin B12 and folic acid [
effects of pemetrexed can be minimized with simultaneous
supplementation of folic acid and vitamin B12. This
supplementation does not diminish the efficacy and may
improve clinical outcome [
]. Pulmonary function tests
and quality of life were also better in the pemetrexed–
cisplatin arm. Also, the combination of raltitrexed and
cisplatin was reported to improve overall survival
compared with cisplatin in a first-line treatment of 250 patients
], confirming that cisplatin with an antifolate should be
the reference regimen in patients with MPM. In the
firstline setting, it has generally been accepted that the
combination of pemetrexed and cisplatin should be considered
standard for MPM.
Second-line chemotherapy for mesothelioma
Clinical trials of anticancer agents against MPM have
almost exclusively focused on chemotherapy-na¨ıve
patients. Those who have had clinical benefit from
firstline chemotherapy are often still in good performance
status when radiological progression is documented, and
commonly have expectations for second-line treatment.
However, there is no current standard second-line
chemotherapeutic regimen for MPM following the breakthrough
outcome of the treatment with the pemetrexed–cisplatin
]. Manegold et al. [
] examined the use of
poststudy chemotherapy of the patients treated in the
previously described phase III trial. Second-line chemotherapy
was administered to 37% of the patients treated with the
pemetrexed plus cisplatin arm and 47% of the patients
treated with the cisplatin arm. The most commonly used
second-line agents have been GEM, or the combination of
GEM and cisplatin. After adjusting for prognostic factors
and the first-line treatment group, a multiple regression
analysis indicated that post-study chemotherapy was
significantly associated with prolonged survival. The striking
key finding of this report was the survival advantage
observed in the pemetrexed plus cisplatin treatment group
in spite of the imbalance in post-study chemotherapy.
In second-line treatment of non-small cell lung cancer,
pemetrexed was approved partly because it had a favorable
toxicity pattern compared with docetaxel. Some
secondline studies have been performed for mesothelioma. Porta
et al. [
] reported that the antimetabolite raltitrexed in
combination with oxaliplatin was inactive as a second-line
treatment for MPM. There is currently insufficient
evidence to recommend second-line chemotherapy for
patients with a good performance status who progress
following first-line treatment. Patients with adequate
performance status should be enrolled into a clinical trial of
Combination chemotherapy represents the standard
treatment for the patients with local advanced
mesothelioma who are not amenable to any local approach, such as
extrapleural pneumonectomy (EPP). Novel and more
effective therapeutic strategies are needed for
mesothelioma. At present, the regimen of the combination of
pemetrexed and cisplatin is the first-line standard medical
treatment for MPM.
Radiological evaluation of tumor response
The impact of chemotherapy in mesothelioma has been
difficult to evaluate because of the rarity of the tumor, the
relatively small number of randomized studies, the
heterogeneity of the pathologic subtypes, and the difficulties in
assessing tumor response using CT scan. Radiological
measurement of the tumor is sometimes difficult in MPM
because of the diffuse spread of the tumor along the inner
thoracic wall and the variable volumes of pleural effusion
that obscure its actual extent (Fig. 2A,B). The guidelines of
measurement offered by WHO or RECIST (Response
Evaluation Criteria in Solid Tumors) are not appropriate
for mesothelioma, given its circumferential growth pattern
]. Accordingly, modified RECIST criteria have been
proposed specifically for MPM, in which between one and
three unidimensional measurements of tumor thickness
perpendicular to vital structures, such as the chest wall, the
vertebral column and mediastinum, are obtained on each of
three separate CT sections [
]. It may be simpler and
more reproducible than the RECIST criteria. The sum of
these unidimensional measurements is used to represent
tumor burden, and assessed according to the RECIST
response classification criteria. Nodal, subcutaneous, and
other bidimensionally measurable lesions are measured
unidimensionally as per the RECIST criteria. Recently
Armato et al. [
] have developed a computer-assisted
technique for mesothelioma tumor thickness
measurements, and have shown that their technique makes the
radiological assessment of mesothelioma more efficient
Recently, combined (18F) fluorodeoxyglucose positron
emission tomography (FDG-PET) and CT have been used
in the diagnosis of MPM (Fig. 3). In the past few years,
FDG-PET has been used to monitor response to treatment
in several neoplasms. Low standardized uptake value
(SUV) and epithelioid histology indicate the best survival,
whereas high SUV and nonepithelioid histology indicate
the worst survival. Ceresoli et al. [
] demonstrated that in
MPM treated with pemetrexed or the pemetrexed–cisplatin
doublet an early reduction of FDG uptake, as measured by
SUV max relative change, was significantly correlated to
patient outcome. However, this approach has not yet been
Radiotherapy for malignant pleural mesothelioma
Mesothelioma cells are unexpectedly sensitive to radiation
compared to non-small cell lung cancer cells in vitro [
however, radiotherapy for patients with MPM is limited
because of the large target volume and the radiosensitivity
of the adjacent lung, heart, mediastinum, liver, and spinal
cord. The role of radiotherapy in MPM is defined by
symptomatic relief and palliation, prevention of neoplastic
cell seeding, and adjuvant therapy following EPP.
Radiotherapy is most commonly used to palliate pain in
advanced MPM, but the effect of radiation monotherapy on
prolonging survival is minimal. Pain is fairly well
controlled with radiotherapy doses above 40 Gy. Chest wall
seeding following the previous invasive procedures, such
as pleural aspiration, biopsy, thoracoscopy, and
thoracostomy is a characteristic clinical feature of MPM.
Prophylactic radiotherapy at the dose of 21 Gy in three
fractions has been indicated to be of benefit for the
prevention of malignant seeding along the tracts [
However, a randomized study showed no benefit of a dose
of 10 Gy in a single fraction in preventing procedure tract
metastasis . Radiotherapy has often been added to
surgery in an attempt to improve local control. It is used as
adjuvant therapy after EPP as part of trimodality treatment,
which is effective at reducing local recurrence of the tumor
and improving overall survival [
Radiotherapy with an attempt to treat the entire involved
pleural surface at a potentially curative dose ([60 Gy) is
technically very difficult because of a high risk of radiation
pneumonitis, myelitis, hepatitis and myocarditis. EPP
removes radiation-sensitive lung, so it permits the delivery
of higher postoperative doses to the involved hemithorax.
A phase II trial conducted at the Memorial Sloan-Kettering
Cancer Center demonstrated that a high dose of
hemithoracic radiation (54 Gy) following EPP was well tolerated
with reduced local recurrence rates and prolonged survival
for early-stage MPM [
]. A new solution that produces
more conformal dose distributions by saving critical
structures is provided by intensity-modulated radiotherapy
]. Forster et al. [
] reported using IMRT after
EPP in seven MPM and saw no local recurrence during
13 months of follow-up. The combined use of
postoperative IMRT and EPP has been suggested to improve overall
survival and reduce recurrence. Recently, it has been
reported that standard-dose IMRT after EPP and adjuvant
chemotherapy resulted in a high rate (46%) of fatal
]. Thereafter, a new system for calculating
thoracic IMRT doses was established in the MD Anderson
Cancer Center [
The role of radiotherapy in the treatment of MPM has
yet to be fully defined. Many of the previous studies
on radiotherapy have been small and retrospective.
Prospective randomized trials are needed to evaluate
definitive radiotherapy in combination with novel
radiosensitizers and chemotherapy in MPM.
Surgical and multimodality approaches to the
management of malignant pleural mesothelioma
Two surgical interventions are used in the management of
MPM: EPP and pleurectomy–decortication (P/D). EPP is
aggressive surgical procedure which removes, en bloc, the
entire parietal pleura, visceral pleura, lung, pericardium,
and hemidiaphragm. P/D is a debulking procedure that
removes the involved parietal and visceral pleura and
possibly the diaphragm, providing an alternative
cytoreductive option for patients unfit for EPP. The lung is not
removed, so complete tumor resection cannot be achieved
if the interlobar fissure is involved. EPP offers a potential
complete tumor resection, and adjuvant radiotherapy can
be given at high dose. The number of operable MPM
patients is still rather small; 20–30% of patients diagnosed
with MPM are candidates for P/D or EPP at the time of
]. The role of surgery for MPM with the
intension of cure continues to be a matter of debate [
however, EPP is the most effective therapy for achieving
local control. Prolongation of survival has been reported in
MPM patients undergoing EPP followed by adjuvant
therapies. The Brigham and Women’s Hospital/Dana
Farber Cancer Institute Group in Boston has reported
promising results from a trimodality combining EPP with
sequential adjuvant chemotherapy using a regimen of DXR
+ cyclophosphamide + cisplatin initially, and paclitaxel +
carboplatin in later patients, as well as radiotherapy
(55 Gy), and they report that the median survival in the 176
patients was 19 months and the two- and five-year survival
rates were 38 and 14%, respectively [
]. The most recent
follow-up data from this group reported an operative
mortality rate for EPP of 4%, with a major morbidity rate
of 24% [
]. In contrast, McCormack et al. [
] reported an
operative mortality of 1.8% for P/D. The response rate of
the cisplatin–GEM doublet has been reported to range
between 16 and 47%, and was 32% in a neo-adjuvant trial
]. The response to the pemetrexed–cisplatin doublet has
been reported to be 41% in advanced MPM, so most groups
are now exploring this combination in a neo-adjuvant
Before a MPM patient is considered for EPP, judgment
is required to determine whether the patient can tolerate
radical surgical resection and induction chemotherapy.
Evaluation of clinical prognostic factors is also required; a
worse outcome has been associated with the male gender,
[75 years of age, poor PS, platelet count [ 400,000/mm3,
serum LDH [ 500 IU/L, low hemoglobin level and weight
loss. The criteria for selecting patients for EPP remains a
matter of debate. For patients being considered for EPP, a
predicted postoperative FEV1.0 of less than 1L is a
contraindication to EPP. MPM patients with unfavorable
characteristics such as N2 disease (Table 1) and
sarcomatoid histology would not be candidates for enrollment in a
trimodality clinical trial. Most trimodality trials for MPM
have included patients with IMIG T3 disease (Table 1), if
the extent of chest wall invasion was such that the thoracic
surgeon deemed resection to be possible. Both EPP and
P/D are technically complex and are not frequently
performed by most surgeons. EPP is associated with
significant rates of morbidity and mortality, so MPM patients
may benefit from referrals to institutions with significant
experience with the procedure.
Chemotherapy for MPM is now starting to have a clinical
benefit. The recent phase III trial demonstrated significant
improvements in survival and disease-related symptoms for
those patients treated with the pemetrexed–cisplatin
doublet. In January 2007, pemetrexed–cisplatin was approved
for the treatment of MPM by the Ministry of Health,
Labour and Welfare in Japan. Now we have a standard
chemotherapeutic regimen against MPM. Several
multicenter national trials against mesothelioma will also begin
in the near future in Japan.
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