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Update on Malignant Mesothelioma

Update on Malignant Mesothelioma

ABSTRACT: Mesotheliomas are uncommon in the United States, with an incidence of about 3,000 new cases per year (or a risk of about 11 per million Americans per year). Incidence and mortality, however, are probably underestimated. Most are associated with asbestos, although some have arisen in ports of prior radiation, and a reported association with simian virus (SV)40 remains controversial. About 85% of mesotheliomas arise in the pleura, about 9% in the peritoneum, and a small percentage in the pericardium or tunica vaginalis testis. The histology of about half of mesotheliomas is epithelial (tubular papillary), with the remainder sarcomatous or mixed. Multicystic mesotheliomas and well-differentiated papillary mesotheliomas are associated with long survival in the absence of treatment and should be excluded from clinical trials intended for the usual rapidly lethal histologic variants of the disease. The median survival is under a year, although longer median survivals for selected patients, particularly those with epithelial histology, have been reported in some combined-modality studies. Recent randomized trials have shown significant improvement in time to progression and survival for the addition of new antifolates to platinum-based chemotherapy.

Mesotheliomas are uncommon
in the United States, with an
incidence of about 3,000
new cases per year (or a risk of about
11 per million Americans per year,
Figure 1).[1] A fundamental issue for
research in mesothelioma is the lack
of accurate statistics. Available statistics
probably underestimate mortality.
The pathologic diagnosis is often
difficult and may be inaccurate as well.
Death certificates often cite lung cancer
or heart failure as the cause of
death. The disease is rare and thus
physicians are inexperienced, leading
to a delay in diagnosis and wide vari
ations
in care. Except at the few centers
with research and treatment programs,
few tissues are available for
research studies.

Epidemiology

About 50% to 70% of mesotheliomas
are associated with exposure to
asbestos. In Turkey, mesothelioma,
endemic in some areas, is associated
with an asbestiform mineral, erionite,
in white soil used as a whitewash.[2,3]
Familial susceptibility may also be a
factor.[4,5] In addition, mesothelio
delivered for a prior malignancy or
after extravasation of thorium dioxide
contrast (Thorotrast).[6-8] Smoking
and asbestos exposure substantially
increases the risk of lung cancer, but
smoking is not implicated in the etiology
of mesotheliomas.

Of uncertain significance, simian
virus (SV)40 DNA fragments have
been detected in mesotheliomas in
some but not other studies.[9,10]
SV40-contaminated polio vaccine was
distributed in the 1950s. SV40 sequences
have been found in microdis
sected tumor cells but not in stroma in
a substantial fraction of US mesothelioma
patients. SV40 can cause
mesothelioma in hamsters. The oncoproteins
of SV40 bind to Rb and p53.
A causal link in human mesothelioma,
however, remains controversial.[9,10]

Asbestos
Asbestos, a silicate mineral of magnesium,
calcium, and iron, occurs as
fibrous rock, which is mined and
milled. Asbestos fibers are either
needle-like (amphiboles including
amosite, tremolite and crocidolite) or
spiral (chrysotile). Risk of mesothelioma
varies by asbestos type broadly
in the ratio of 1:100:500 for chrysotile,
amosite, and crocidolite, respectively.[
11] Although chrysotile is
associated with the lowest risk, it nevertheless
appears to result in some
risk in animals and humans.[12]

The word "asbestos" is derived
from a Greek root for inextinguishable
or indestructible. Asbestos use is
documented for more than 6,000
years. Persians burned bodies in asbestos
cloth to preserve the ashes.
Pliny the Elder observed that the asbestos
quarry slaves died young and
thus recommended they not be purchased.
Modern recognition of the
health effects of asbestos exposure
were initially complicated by the high
incidence of tuberculosis in sweatshops
in Europe. In 1930, however,
Merewether convincingly demonstrated
pulmonary fibrosis in asbestos workers,
coining the term "asbestosis." In
1955, Doll recognized lung cancer arising
in asbestos workers,[13] and in
1960, Wagner et al described 47 cases
of mesothelioma in South Africa in a
crocidolite (blue amphibole asbestos)
mining community, and established the
diagnosis (which until then had been
debated) as well as both occupational
and bystander risk.[14]

Asbestos fibers in lung tissue are
found as either uncoated fibers or ferruginous
bodies, fibers coated by macrophages
with iron substance. Because
fibers persist once in situ, exposure
continues decades after fibers were
initially inhaled. Pleural calcified
plaques may develop decades after a
significant asbestos exposure. Asbestos
is not carcinogenic in the Ames
test; however, it induces reactive oxygen
species and damages DNA, producing
chronic inflammation and
eventual fibrosis.

Because of the pattern of asbestos
use, mesothelioma incidence will likely
peak in Europe[15,16] in about
2020. Surveillance, Epidemiology,
and End Results (SEER) data in the
United States show that the incidence
peaked in 1994-1995 at 1.2 cases per
100,000, with a small nonsignificant
decline to 1.0 cases per 100,000 in
2000-2002.[1] The incidence varies
considerably by location, being highest
along coastal towns associated with
shipyards and in states with industrial
asbestos textile mills (Figure 2). At-
risk occupations include asbestos
miners and millers, but also insulation,
shipyard, and maintenance workers,[
17] as well as auto mechanics.[18]
Workers manufacturing cigarette filters
were exposed due to asbestos in
the filter paper.[19] Incidence is lower
for African-Americans than for European-
Americans (Figure 1) because
of work place patterns favoring whites
for employment. Few women were
employed in these industry jobs at the
time.[1]

Presentation

About 85% of mesotheliomas arise
in the pleura, about 9% in the peritoneum,
and a small percentage in the pericardium
or tunica vaginalis testis.[1]
Peritoneal mesotheliomas may develop
more frequently in men with
heavier asbestos exposure. Women
comprise only about 18% of patients
with pleural mesothelioma, but 42%
of those with peritoneal mesothelioma.
Risk is highest at about age 80 to
84 (Figure 3).[1] The median age in
reported clinical trials is frequently a
decade or more younger than the
median age of patients in the SEER
database. Patients with pleural mesothelioma
initially complain of shortness
of breath or chest pain, whereas
those with peritoneal mesothelioma
present with increased abdominal girth
or abdominal pain.[20,21]

Fine-needle biopsy can be used to
document recurrence or metastases but
is not sufficiently reliable for primary
diagnosis.[22] The histology of about
half of mesotheliomas is epithelial
(tubular papillary), with the remainder
being sarcomatous, or mixed.[20,21]
Multicystic mesotheliomas and welldifferentiated
papillary mesotheliomas
are associated with a long survival in
the absence of treatment. Thus, these
patients should be excluded from
clinical trials intended for the usual
rapidly lethal histologic variants of
mesothelioma.[23-25]

Prognostic Variables
and Survival

The median survival in the Surveillance,
Epidemiology, and End
Results (SEER) database is approxi
mately
7 months and has not improved
over the past 2 decades, for either
pleural or peritoneal mesotheliomas
(Figure 4).[1]

Poor-prognostic variables include
sarcomatous histology, pleural as opposed
to peritoneal primaries, older
age, pain at diagnosis, male gender,
poor performance status, and perhaps
high lactate dehydrogenase (LDH),
white blood cell, and platelet levels.[
20,26] In a recent European Organization
for Research and Treatment
of Cancer (EORTC) analysis, poor
prognosis was associated with a poor
performance status, elevated white
blood cell (WBC) count, lack of a
definitive histologic diagnosis of mesothelioma,
male gender, and sarcomatous
histologic subtype.[27]

In a Cancer and Leukemia Group B
(CALGB) multivariate analysis, poor
performance, pleural involvement,
LDH > 500 IU/L, chest pain, platelets
> 400,000/μL, sarcomatous or mixed
histology, and age older than 75 years
predicted poor survival.[28] Grouping
prognostic variables, the group with
the best survival (14 months) had a
performance status of 0, and were ei-
ther younger than 49 years or aged 50
or more with a hemoglobin of 14.6 or
more. Those with a performance status
of 1 or 2 and WBC more than
15.6/μL had a median survival of only
1.4 months.[28]

Surgical and Radiologic
Treatment of Localized Disease
Pleural Mesothelioma
In the SEER 9 regions from 1987
to 2002, pleural mesothelioma constituted
74% of all mesotheliomas in
women and 88% in men.[1] Computed
tomography (CT), magnetic
resonance imaging (MRI), and 18Ffluorodeoxyglucose
(FDG) imaging
provide assessment of extent of
disease.[29,30]

Surgical alternatives include biopsy
only, pleurodesis, pleurectomy,
and pleuropneumonectomy. Optimal
management of localized disease with
surgery, radiation, or both is not established.
In studies of thoracoscopic
talc pleurodesis, the median survival
was 7 to 9 months-not significantly
different from survivals in the SEER
database. After pleurectomy, the median
survival ranges from 5 to 20
months. Extrapleural pneumonectomy
results in median survivals of 9 to
21 months in various series. Certainly,
selection of patients healthy enough to
undergo surgery accounts for some or
all of this difference.

Of 76 patients assessed with contrast-
enhanced MRI in Leicester,
United Kingdom, 51 underwent extrapleural
pneumonectomy or radical
pleurectomy/decortication. Pathologic
stage was correlated with radiologic
staging, with particular emphasis on
tumor resectability. On MRI, 17 patients
(22%) had unresectable disease
that was not visible on CT scan. Fiftyone
patients (67%) underwent surgery;
pathologic nodal data were incomplete
in three who were excluded from
further analyses. The median interval
from MRI to surgery was 17 days.
MRI correctly predicted resectability
in 97%. (Two patients had unexpected
extensive disease at thoracotomy.) MRI
tumor stage was accurate in 48%, and
understaged in 50%, largely due to
pericardial involvement, which significantly
affected neither resectability nor
prognosis. Nodal stage was correctly
identified in 60% of patients. Thus,
MRI is unlikely to contribute significantly
to nodal staging, but it remains
valuable for selection of patients for
surgery.[30]

In a Dana-Farber/Brigham and
Women's Hospital series (Table 1) of
52 selected patients who received
extrapleural pneumonectomy, cyclophosphamide,
doxorubicin, and cisplatin
(CAP) chemotherapy, and
radiotherapy, perioperative morbidity
and mortality rates were 17% and
5.8%, respectively. The median survival
was 16 months. One- and twoyear
survival rates were 77% and 50%
for patients with epithelial histology
and 45% and 7.5% for those with
sarcomatous and mixed variants
(P < .01); all of the latter patients died
by 25 months. Patients with negative
regional mediastinal lymph nodes survived
longer than those with positive
nodes (P < .01). Of the subset of patients
with epithelial histology and
negative mediastinal lymph nodes,
45% were alive at 5 years.[31]

Of 132 patients with malignant
pleural mesothelioma who underwent
surgery in a Leicester, UK, study, 53
underwent extrapleural pneumonectomy,
and 79, less radical resections.
Mortality at 30 days was similar for the
two groups (Table 1). Time to disease
progression and survival favored extrapleural
pneumonectomy, although
selection bias may account for the difference.
Nodal involvement of N2
nodes compared with N0/1 involvement
was associated with shorter survival
(197 vs 358 days, P = .02).[32]

Radiation series described symptom
control in some but not all patients.
Conformal radiotherapy is
currently under evaluation and would
at least theoretically deliver a higher
dose to the pleura while avoiding heart
and lung tissue. Recent studies of surgery,
radiation, or combined-modality
therapy are shown in Table 1. After
invasive procedures, the risk of tumor
masses growing out of needle or incision
scars was diminished by radiation
in one study[42] but not a second
randomized study (Table 2).[43]

Peritoneal Mesothelioma
The second most common site for
the development of mesothelioma is
the peritoneum. Though overall more
men than women develop peritoneal
mesothelioma, a higher proportion of
women than men develop the disease
in the peritoneal cavity. In the SEER 9
regions from 1987 to 2002, peritoneal
mesothelioma comprised 19% of
all mesotheliomas in women and 7%
in men. Typically, patients with peritoneal
mesothelioma present with increasing
abdominal girth, abdominal
pain, ascites, fever, and night sweats.
CT scan findings are varied and include
ascites, localized tumor masses,
or diffuse peritoneal involvement.
Some long-term survivors have been
described in a Dana-Farber Cancer
Institute study of surgical debulking,
intraperitoneal chemotherapy, and
radiotherapy.[51,52]

In a National Cancer Institute series,
49 patients underwent laparotomy,
tumor resection, hyperthermic
intraperitoneal (IP) cisplatin, and postoperative
IP fluorouracil and paclitaxel.
The median progression-free
survival was 17 months and the medi
an
survival was 92 months. Patients
with debulking surgery, superficial
tumor, minimal residual disease after
resection, and age less than 60 years
survived longer.[53] Given patient
selection, the contribution of any of
these modalities to prolonged survival
is unknown.

Pericardial Mesothelioma
Pericardial mesothelioma is a rare
but lethal malignancy for which treatment
options are limited.[54,55] Patients
present with symptoms of
constrictive pericarditis. MRI may
demonstrate the extent of infiltration
of the myocardium or cardiac vessels.
Misdiagnosis is common, with the
correct diagnosis frequently made at
surgery or autopsy. Occasionally, patients
survive disease-free after complete
resection, but myocardial invasion
usually precludes complete resection.
Surgery is often useful to relieve effusions,
pericardial tamponade, or constriction.
Chemotherapeutic regimens
established in pleural mesotheliomas,
as well as intracavitary chemotherapy
or irradiation and photodynamic therapy
treatments, have been reported with
modest benefit.[54,55]

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