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Malignant Pleural Mesothelioma: A Comprehensive Review


Abstract and Figures

The incidence of malignant mesothelioma continues to increase, but the disease remains difficult to detect early and treat effectively. The authors review the pathogenesis, incidence, clinical presentation, diagnosis, pathology, and both standard and experimental treatments for mesothelioma. When possible, surgery (video-assisted thoracoscopy, pleurectomy/decortication, or extrapleural pneumonectomy) is utilized. Effects on underlying structures limit application of radiation therapy, but some systemic agents are beginning to enhance survival. The disease is expected to increase in incidence till 2020, so awareness of this entity as a possible diagnosis should be heightened. In patients with advanced disease, several newer antitumor agents are already showing a capability of extending survival so it is not unreasonable to expect further progress in this area.
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Malignant Pleural Mesothelioma: A Comprehensive Review
Roohi Ismail-Khan, MD; Lary A. Robinson, MD; Charles C Williams, Jr, MD; Christopher R. Garrett, MD;
Gerold Bepler, MD, PhD; George R. Simon, MD
Cancer Control. 2006;13(4):255-263. ©2006 H. Lee Moffitt Cancer Center and Research Institute, Inc.
Posted 01/08/2007
Abstract and Introduction
Background: The incidence of malignant mesothelioma continues to increase, but the disease remains difficult to
detect early and treat effectively.
Methods: The authors review the pathogenesis, incidence, clinical presentation, diagnosis, pathology, and both
standard and experimental treatments for mesothelioma.
Results: When possible, surgery (video-assisted thoracoscopy, pleurectomy/decortication, or extrapleural
pneumonectomy) is utilized. Effects on underlying structures limit application of radiation therapy, but some
systemic agents are beginning to enhance survival.
Conclusions: The disease is expected to increase in incidence till 2020, so awareness of this entity as a possible
diagnosis should be heightened. In patients with advanced disease, several newer antitumor agents are already
showing a capability of extending survival so it is not unreasonable to expect further progress in this area.
Mesothelioma is an uncommon neoplasm arising from the mesothelial cells lining the pleura. Rarely, pleural
mesothelioma is localized, benign, and readily resectable for cure. A variant of localized pleural mesothelioma is a
fibrous tumor of the pleura that probably arises from a different layer of cells in the pleura, and it also is usually
completely resectable. For the purposes of this review, only the more common and aggressive diffuse malignant
pleural mesothelioma (MPM) will be discussed. MPM is usually associated with history of chronic asbestos
exposure. Despite its relatively rare incidence, there is a great interest in this disease as it has spawned many legal
battles and consequently has led to the elimination of asbestos in all the industrial sectors, particularly in shipping
and construction.
In the United States, MPM occurs in approximately 2,500 persons per year, with nearly 200 individuals diagnosed
in Florida annually, and 19% are women.
Almost 72,000 cases are expected to occur in the United States in the
next 20 years. In Western Europe, 5,000 patients die of the disease each year. Worldwide, the incidence is
increasing and it is expected to peak in the year 2020.
Nevertheless, most physicians will encounter MPM only a
few times in their careers. Historically, the untreated median survival has only been 6 months, which explains the
palliative approach taken by the oncologists treating patients with MPM.
Malignant mesothelioma was first recognized in 1870,
but the link between asbestos and MPM was not discovered
until 1960 in South Africa when the first convincing evidence of a link between malignant mesothelioma and both
occupational and incidental asbestos exposure was reported.
It was not until the second half of the 20th century
that mesotheliomas and lung cancer were considered separate entities.
Due to the extraordinary fire-resistant
properties of asbestos, this substance was widely used in the United States and Europe in an uncontrolled fashion,
mostly in the shipbuilding and construction industries, between the 1940s and 1979 when the US government
curtailed its use. During that time, an estimated 40% of the entire workforce, or about 27 million individuals, were
exposed to asbestos. Although its industrial use was largely eliminated, asbestos is still present in countless
buildings where it was commonly used as insulation and a fire retardant. Manmade and natural disasters that
destroy these building could therefore still expose millions to asbestos. An estimated 10 million New Yorkers were
possibly exposed to this carcinogen during the World Trade Center disaster on September 11, 2001, where dust
laden with asbestos filled the air.
Of the two basic types of asbestos, the larger amphibole fibers are the most carcinogenic. Their greater
biopersistence and higher iron content catalyze the production of reactive oxygen radicals. When inhaled, the fibers
are too large to be phagocytized by pulmonary macrophages, and over the years they burrow back into the serosal
surfaces of the pleura, pericardium, and peritoneum. Asbestos may lead to a variety of other conditions such as
benign pleural plaques, diffuse pleural thickening, benign pleuritis with effusion, and asbestosis. However, it is
unknown why MPM occurs in the relatively few individuals within the large total population exposed to asbestos.
Only 2% to 10% of individuals with heavy, prolonged asbestos exposure develop MPM. Conversely, up to 80% of
MPM patients have a history of asbestos exposure.
Due to the lack of asbestos exposure in some patients with MPM as well as its failure to produce the neoplasm in
all exposed individuals, investigators have been looking for other etiologies or cofactors for MPM. Genetic
predisposition for MPM may play a strong role, such that even minimal or apparently inconsequential asbestos
exposure may lead to tumor development. An intriguing and controversial putative cofactor linked to MPM
development is exposure to the tumorigenic simian vacuolating virus 40 (SV40), one of over 40 viruses that
infected Macacus monkey kidney cells that were used to prepare early batches of live polio vaccine. SV40 viral
gene sequences have been demonstrated in a variety of malignancies including certain brain cancers, sarcomas of
bone, non-Hodgkin's lymphoma, and in over 50% of epithelial MPM.
Of the estimated 62% of the 92 million US
residents who received the potentially SV40-contaminated Salk polio vaccine for the 8 years it was used (1955-
1963), at least one fifth may have received live, infectious SV40-containing vaccine. Despite numerous and quite
compelling studies of the possible role and malignant transformation capacity of SV40 virus in vitro and in animal
studies of MPM,
epidemiologic studies of age-specific trends in the US incidence of MPM are not consistent with
an etiologic effect of exposure to SV40-contaminated polio virus.
Although testing for SV40 was done rigorously,
not all cohorts born after 1963 were SV40-free. A major eastern European manufacturer used a procedure to
deactivate SV40 that did not fully inactivate SV40 in oral poliovirus vaccine; these SV40-contaminated vaccines
were produced from the early 1960s to about 1978 and were used throughout the world.
This remains a highly
controversial aspect of MPM etiology and pathogenesis.
Clinical Presentation
The initial clinical presentation for most patients with MPM is progressive dyspnea and/or steady chest wall pain.
Dyspnea is usually the result of a large pleural effusion, and the nonpleuritic chest pain is generally caused by
significant chest wall invasion. There also may be a dry cough, weight loss, fever, fatigue, or night sweats. The
disease is more commonly found unilaterally (95%) located in the right chest (60%), and it occurs predominantly in
men, usually presenting in the 6th through 8th decades. Eighty percent of patients will have a definite asbestos
exposure history, often with a 20- to 50-year latency between asbestos exposure and development of the
malignancy. The symptoms of MPM may be insidious and nonspecific such that the time from initial presentation
until diagnosis is often 3 to 6 months. Common prior occupational exposures include pipefitters, plumbers,
steamfitters, heavy construction or shipbuilding industry workers, and those working aboard ships, especially in the
boiler room.
The physical examination and chest radiographs will demonstrate a large pleural effusion in 80% to 95% of patients
with MPM.
Conversely, 10% to 29% have little or no fluid. As the disease advances, there tends to be less pleural
fluid present. Initially, the fluid is free flowing and layers out on decubitus chest radiographs, which may be similar
in appearance to the effusion seen in heart failure, early empyema, and other benign causes. Later, as MPM
progresses, the effusion becomes loculated. Localized chest pain and a palpable chest wall mass indicate chest
wall invasion and nonresectability.
Computed chest tomography (CT) with contrast is a much more sensitive examination. CT scans will show the
pleural effusion, the size of the lymph nodes in the hilum and mediastinum, and the presence of pleural masses,
especially as the tumor tends to form a rind of tissue that encases the lung and often extending into the fissures
and along the mediastinal pleura and diaphragm. Although chest wall invasion and transdiaphragmatic spread of
tumor may be visible or suspected on chest CT scans, magnetic resonance imaging (MRI) of the chest with
contrast, which includes coronal and sagittal views, is more sensitive in illustrating this and is especially important
when a potentially curative surgery is being considered for the patient. Fig 1 illustrates some of the findings typically
seen on imaging studies in MPM. Positron emission tomography (PET) may offer some additional information in the
staging of MPM since it reliably detects contralateral chest involvement and extrathoracic metastases such as
supraclavicular nodal disease. In some cases, it may be difficult to differentiate the primary tumor from N2
mediastinal lymph node involvement because of their close anatomic proximity.
Figure 1.
Typical radiographic appearance of pleural mesothelioma. (A) Chest CT showing (small arrow) borderline enlarged right paratracheal lymph node in right-
sided mesothelioma (large arrow). (B) Axial T2-weighted MR image at the same level showing (arrow) enhancement (white) of this lymph node, which
was found to contain metastatic mesothelioma on mediastinoscopy. (C) Coronal T2-weighted MR image of same patient showing enhancing right-sided
pleural tumor with arrow showing the sharp line of the diaphragm indicating no definite tumor invasion. (D) Axial T2-weighted MR image at the level of the
heart showing (arrow) typical thick pleural tumor and some fluid pockets in right-sided MPM. Images provided courtesy of OncoView: Current Opinions in
Thoracic Oncology, a publication of the Moffitt Cancer Center's Thoracic Oncology Program. February 2005;2(1).
Pleural fluid cytology may yield a definitive diagnosis of MPM in 20% to 33% of patients. A blind core needle biopsy
of the pleura modestly improves the yield. A CT-guided core needle biopsy of one of the pleural masses is more
sensitive (87%) in making a diagnosis. Diagnostic accuracy of greater than 95% is possible using video-assisted
thoracoscopy (VATS), which allows directed pleural biopsy and drainage of the effusion after breaking up
loculations. Intrapleural talc, which yields the highest pleurodesis rate in MPM, can then be instilled to prevent
reaccumulation of the effusion. One disadvantage of VATS in mesothelioma is the possible seeding of tumor along
the surgical incisions and chest tube tracts, which ultimately results in tumor growth in the chest wall in up to 20%
of patients.
In addition to standard histology, special immunohistochemical stains of the biopsy tissue may be necessary to
make a definitive diagnosis of MPM because of its histomorphologic similarities to adenocarcinoma. Mesothelioma
is characterized by staining for calretinin in 88% and vimentin in 50% of patients. However, adenocarcinoma
usually lacks these markers and instead stains positive for carcinoembryonic antigen (84%), CD15 (77%) and Ber-
EP-4 (82%). A complete array of immunostains must be performed to make a reliable diagnosis. Electron
microscopy, although more costly, may be needed in equivocal cases to make the distinction between the two
Adequate tumor tissue not only allows a definitive diagnosis but also helps to determine which of the histologic
subtypes is present. Epithelial mesothelioma is the most common, is found in approximately 50% of cases, and has
the best prognosis. The more aggressive sarcomatoid type is seen in 16%, and the mixed type is seen in 34%.
Recently, investigators in Australia have discovered a new serum marker called soluble mesothelin-related protein
(SMRP) in 84% of patients with mesothelioma.
This protein, which is detected with a simple blood test, may offer
not only a useful diagnostic test for MPM, but also a means of monitoring treatment responses. It could also be a
method for screening at-risk individuals. SMRP is elevated in only 2% of patients with other pleural diseases. A
commercial SMRP tumor marker assay test kit should be available soon.
In a recently published study, serum osteopontin levels were found to be significantly higher in patients with pleural
mesothelioma than in patients with exposure to asbestos or those patients who have fibrosis alone.
Immunohistochemical analysis revealed osteopontin staining of the tumor cells in 36 of 38 samples of pleural
mesothelioma. This indicates that osteopontin levels may help us in the near future in early diagnoses of patients
who have a known history of asbestos exposure.
Despite the ready availability of multiple diagnostic techniques with this neoplasm, a definitive diagnosis of MPM is
often delayed due to a low clinical suspicion for this disease. Hence the clinician must have a high index of
suspicion, especially in a patient with a history of asbestos exposure who has a pleural effusion or atypical
noncardiac chest pain to ensure that a timely diagnosis is made.
As with all malignancies, proper staging is crucial in MPM for rational treatment planning. Over the years, many
staging systems have been proposed. The most widely accepted is the TNM-type system of the International
Mesothelioma Interest Group (IMIG).
The IMIG system is the most comprehensive classification, albeit somewhat
more detailed. A brief explanation of the classification follows:
Stage I includes lymph node-negative patients with minimal tumor confined to the parietal pleura (stage Ia) or with
minimal visceral pleural involvement (stage Ib).
Stage II includes lymph node-negative patients with confluent superficial tumor on all pleural surfaces or
involvement of the diaphragmatic muscle or lung parenchyma. Stage I and II patients have potentially resectable
Stage III is the most common presenting stage and includes patients with metastasis to hilar (N1) or ipsilateral
mediastinal (N2) lymph nodes, or those with extension of tumor into the soft tissues of the chest wall, the
endothoracic fascia, mediastinal fat or pericardium (T3 tumor).
Stage IV includes patients who have locally advanced tumor invading the spine or ribs, the chest wall extensively,
transdiaphragmatic spread, or contralateral pleural spread. Patients with stage IV disease also may have
contralateral or supraclavicular lymph node involvement (N3) or distant metastases.
MPM does not have one widely accepted treatment modality since none reliably results in cure. Moreover, there is
a striking lack of randomized, clinical trials comparing treatment regimens in this disease, due in part to the
relatively low incidence of this neoplasm. Clinical series generally are either at best phase II trials of one treatment
regimen or retrospective reviews of a small number of patients treated over a long period of time. Despite these
shortcomings, significant improvements in therapy for MPM offer a ray of hope in this aggressive malignancy.
Complete surgical resection is theoretically the most effective treatment. However, with the usual diffuse spread of
MPM throughout the hemithorax, complete resection of this neoplasm with histologically negative margins is rarely
achieved. Hence, the term cytoreduction was coined to describe the type of resection usually employed in MPM,
which results in removal of the vast bulk of the tumor, but generally at least micro-scopic tumor is left behind.
Three surgical procedures may be used with MPM for palliation and/or treatment: (1) VATS talc pleurodesis, (2)
pleurectomy/decortication (P/D), or (3) extrapleural pneumonectomy (EPP). There are no randomized studies
comparing these techniques, and results are generally found in retrospective series that often used different staging
systems, further confounding comparisons.
Video-Assisted Thoracoscopy
VATS plays an important role in MPM by permitting directed biopsy to obtain diagnostic tissue. Then at the same
procedure, the effusion is drained, loculations are lysed, and pleurodesis is accomplished usually with aerosolized
talc. Although no cytoreduction of tumor is performed, this technique is effective in creating a pleurodesis that
relieves the dyspnea caused by the commonly seen effusion in this disease. However, this procedure does not
prevent the occasional patient from undergoing subsequent EPP. VATS pleurodesis by itself does not prolong
survival, but it is preferred in patients with comorbidities or advanced-stage disease, who then may undergo
systemic chemotherapy.
One therapeutic surgical option that is intended to cytoreduce actual tumor burden is P/D. This procedure is
performed through an open thoracotomy and consists of removing the parietal pleura including the portion over the
mediastinum, pericardium, and diaphragm (often requiring removal of part of the diaphragm) and stripping off of the
visceral pleura to decorticate the lung. Compared with EPP, this procedure poses somewhat less physiologic stress
on the patient since it leaves the lung in place, and it has a slightly lower operative mortality rate of 1.5% to 5%.
Common disadvantages of P/D are the large postoperative air leak, empyema, hemorrhage, the frequent inability to
remove all of the tumor from lung fissures, impairment or lack of diaphragmatic (or phrenic nerve) function, and the
obvious limitation on any postoperative radiotherapy because the lung is still present. Macroscopic tumor is left in
the chest at the end of the procedure almost 80% of the time.
By itself, P/D provides good palliation and prevents
return of a symptomatic effusion, but there is usually a high locoregional recurrence (80% to 90%),
and generally
it is not considered a potentially curative procedure.
Extrapleural Pneumonectomy
The most aggressive surgical procedure is EPP, which involves en bloc resection of the parietal and visceral pleura
along with the involved lung, mediastinal lymph nodes, diaphragm, and pericardium. The diaphragm and
pericardium are then reconstructed with Gortex or Marlex mesh. Although this procedure has a profound
physiologic impact on the patient since the lung is removed, it may be performed in experienced centers with less
than a 5% mortality.
This is the most complete cytoreductive procedure and essentially the only procedure with
which long-term survivorship is seen.
Selection of the appropriate subset of patients for EPP is crucial. Table 1 lists the patient selection criteria used at
our institution for EPP. Aside from the obvious selection criteria listed, prior coronary bypass grafting usually
precludes performing an EPP since at least one bypass graft on either side is usually located out in the pleural
cavity encased by tumor, and the tumor cannot be separated from the graft. Patients with nonepithelial-type
mesothelioma have an aggressive tumor that EPP does not control. Chest wall pain usually is found where there is
unresectable tumor deeply invading the chest wall. Prior pleurectomy generally precludes the technical
performance of EPP since any potential resection planes are obliterated and only an incomplete resection is
possible. In the patient population seen at our institution, only approximately 10% to 15% of all MPM patients seen
may qualify for EPP. In view of the documented lack of survival benefit of cytoreductive surgery in patients with
metastases to often normal-sized mediastinal nodes in MPM,
we favor routine mediastinoscopy in all patients
considered for EPP.
Unlike most tumors, MPM grows as a diffuse sheet of tumor throughout the pleural cavity, enveloping the lung. As a
result, it is difficult to deliver to the entire neoplasm the radiotherapy needed to be tumoricidal (>60Gy) because of
the limitations on dose to the underlying structures (lung 20 Gy, liver 30 Gy, spinal cord 45 Gy, heart 45 Gy, and
esophagus 45-50 Gy). Radiation pneumonitis, myelitis, and hepatitis have been well described in early series
attempting primary treatment with whole chest radiotherapy. Some recent reports have shown promise for the use
of the more complex technique of intensity-modulated radiotherapy (IMRT) to treat the unresected tumor.
conformal technique requires three-dimensional treatment planning that delivers a homogeneous dose to the tumor
with good protection of organs at risk.
Currently, radiotherapy in MPM is used effectively to treat localized chest wall recurrences such as those seen
occasionally in a chest tube tract or surgical wound tumor implantation. Some groups employ hemithoracic adjuvant
radiotherapy, after EPP, for treatment of the entire resected hemithorax or for treatment of known residual localized
unresected tumor. Although adjuvant radiotherapy along with chemotherapy is used by some groups after radical
EPP, there are no randomized studies that show that radiotherapy adds any value to just adjuvant chemotherapy
alone in the setting of a fully resected tumor.
The role of chemotherapy in MPM is now established beyond any ambiguity. The recently reported phase III trial of
cisplatin plus pemetrexed
demonstrated a statistically significant survival advantage (12.1 months) for the
combination vs cisplatin alone (9.3 months) in all eligible patients. The study was initially started without vitamin
supplementation. Vitamin supplementation was initiated after chemotherapy-related deaths occurred in the
pemetrexed arm. Fig 2 shows the over-all survival curves of all patients and for those patients in whom full vitamin
supplementation was instituted. Fig 3 shows the Kaplan-Meier estimates of time to progressive disease for all
patients and for fully supplemented patients.
Figure 2.
Kaplan-Meier estimates of overall survival time for all patients (A) and for fully supplemented patients (B). From Vogelzang NJ, Rusthoven JJ,
Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J
Clin Oncol. 2003;21:2636-2644. Reprinted with permission from the American Society of Clinical Oncology.
Figure 3.
Kaplan-Meier estimates of time to progressive disease for all patients (A) and for fully supplemented patients (B). From Vogelzang NJ, Rusthoven JJ,
Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J
Clin Oncol. 2003;21:2636-2644. Reprinted with permission from the American Society of Clinical Oncology.
Additionally, there was statistically significant improvement in response rate for the doublet (41% vs 17%; P<.0001),
improvement in lung function by the sixth cycle (P = .006), improvement in dyspnea by the sixth cycle (P = .004),
and improvement in pain by the fourth cycle (P = .017). Based on these data, cisplatin in combination with
pemetrexed is the currently accepted first-line treatment for MPM.
Fig 4 depicts a chest CT of a patient treated
with cisplatin and pemetrexed at our institution who continues to be progression-free 3 years after the initial
Figure 4.
Effect of chemotherapy (3 cycles of cisplatin/pemetrexed) on T2N2 epithelial pleural mesothelioma. Chest CT at level of cardiac ventricles. Images
provided courtesy of OncoView: Current Opinions in Thoracic Oncology, a publication of the Moffitt Cancer Center's Thoracic Oncology Program.
February 2005;2(1).
Other drugs have also shown activity in MPM. Table 2 outlines the single-agent efficacy of agents active in MPM,
and Table 3 outlines studies using the most popular cisplatin combinations. Data from studies using some of the
newer agents are presented in Table 4 , showing that response rates with some of these targeted agents have
been singularly disappointing.
Patients with MPM have some of the highest vascular endothelial growth factor (VEGF) levels compared to most
solid tumors. Bevacizumab is a recombinant humanized monoclonal antibody to VEGF. Compounds targeting
VEGF have demonstrated promise in MPM and therefore are being evaluated in several clinical trials.
Currently, a multicenter, double-blind, placebo-controlled, randomized trial
is looking at bevacizumab in
combination with gemcitabine and cisplatin. The safety analysis done so far does not show any significant increase
in toxicities in the bevacizumab arm. Response and survival data are anxiously awaited. As pemetrexed and
cisplatin demonstrated a survival advantage over cisplatin alone, we are currently conducting a phase II trial where
bevacizumab is being added to cisplatin and pemetrexed.
There are no standard second-line treatment options for the treatment of advanced MPM. Typically, one of the
agents listed in Table 1 is used as a second-line treatment. The most commonly used second-line treatments are
gemcitabine, vinorelbine, doxorubicin, and irinotecan (CPT-11). Ranpirnase (Onconase), an antitumor
ribonuclease, is a novel agent under active investigation in the second-line treatment of MPM. Used as a single
agent at 480 µg/m
intravenously weekly, ranpirnase demonstrated prolonged periods of stable disease in phase II
trials and a potential survival benefit, compared with doxorubicin, in a small unpublished phase III trial.
In all
clinical studies, it has generally demonstrated a favorable safety profile except for easily controlled allergic
reactions and dose modifications for renal impairment. At present, a phase III trial of doxorubicin with or without
ranpirnase is nearing completion in patients with MPM without prior chemotherapy or one prior chemotherapy
regimen. Results of this trial are anxiously awaited.
Multimodality Therapy
Due to the failure of any single modality of treatment to significantly affect long-term survival, a variety of
combinations of therapy, usually involving cytoreductive surgery (P/D or EPP), have been used to treat MPM.
Unfortunately, most reports are retrospective case series so results are difficult to compare objectively.
The most well-known and largest series comes from the Brigham and Women's Hospital, involving EPP followed by
In 137 patients treated in a 17-year period beginning in 1980, the mortality rate of EPP was 3.8%
(morbidity 50%), with adjuvant chemotherapy using varying regimens given beginning 4 to 6 weeks after surgery,
then followed by hemithoracic radiation (30 to 40 Gy). The median survival was 19 months, and 2-year and 5-year
survival rates were 38% and 15%, respectively. In the subset with epithelial histology and negative nodes with
complete resection, the 5-year survival rate was 46%. Locoregional recurrence was the predominant mode of
failure in most patients despite intensive local treatment with surgery and radiotherapy.
Nevertheless, other series with EPP and systemic chemotherapy or EPP and adjuvant radiotherapy have shown
median survivals similar to the Brigham series, also with better results occurring in the subset of node-negative
epithelial tumors. With complete macroscopic tumor resection, there are no convincing data to suggest that
employing two adjuvant modalities (with the increased toxicity) improves results more than using one.
Phase I reports of other multimodality approaches include radical P/D with intraoperative radiotherapy and
conformal radiotherapy and, in some patients, adjuvant chemotherapy. In a small, highly selected series of 32
patients, there was a 6.3% mortality rate and an 18-month median survival; most treatment failures were
Cytoreductive surgery with intraoperative photo-dynamic therapy (PDT) has been studied in several centers. The
use of intraoperative intrapleural chemotherapy has been reported in several small series including hyperthermic
(40-41 °C) perfusion, most with cisplatin. This modality appears feasible, albeit with significantly increased
morbidity, but currently there is no documented survival benefit of this technique.
Malignant mesothelioma continues to be a difficult disease to treat. Maintaining a high index of suspicion may result
in an earlier diagnosis and a more successful treatment outcome. The overall outlook for the treatment of this
disease has improved with the emergence of newer therapies. Several new agents are currently under active
investigation and hold promise to further improve treatment outcomes. Results of currently ongoing clinical trials are
anxiously awaited. In fact, survival for patients with MPM is now generally greater than for patients with advanced
non-small cell lung cancer.
As with any rare disease, referral of the patient to a center with extensive experience and expertise in this disease
is recommended to enhance the probability of accruing such patients to clinical trials.
CE Information
The print version of this article was originally certified for CME credit. For accreditation details, contact the
publisher . H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612.
Telephone: (813) 632-1349. Fax: (813) 903-4950. Email: .
Table 1. Patient Selection Criteria for EPP
Table 2. Response Rate of Mesothelioma to Available
Chemotherapeutic Agents
Table 3. Malignant Pleural Mesothelioma Treated With
Combination Chemotherapy
Table 4. Recent Phase II Trials of New Agents in Mesothelioma
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Abbreviation Notes
MPM = malignant pleural mesothelioma; CT = computed tomography; VATS = video-assisted thoracoscopy; P/D =
pleurectomy/decortication; EPP = extrapleural pneumonectomy.
Reprint Address
George R. Simon, MD, Thoracic Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, 12902
Magnolia Drive, MRC-4W, Tampa, FL 33612. E-mail: simongr@ moffitt.
Roohi Ismail-Khan, MD, Lary A. Robinson, MD, Charles C Williams, Jr, MD, Christopher R. Garrett, MD,
Gerold Bepler, MD, PhD, and George R. Simon, MD, Division of Thoracic Oncology & Experimental Therapeutics
at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Disclosure: Dr Simon receives honoraria from Eli Lilly and Co and Genentech, Inc.
Disclosure: No significant relationship exists between the other authors and the companies/organizations whose
products or services may be referenced in this article.
... In the last decade, a shift towards P/D was appreciated considering the high morbidity and mortality associated with the EPP technique [65]. Nevertheless, it is important to mention that the P/D procedure has been associated with a high rate of recurrence as reported by Ismail-Khan et al [66]. ...
Asbestos refers to naturally occurring hydrated magnesium silicates which when inhaled as dust is associated with considerable toxicity for humans. The spectrum of diseases caused secondary to inhalation of asbestos dust include several pleuropulmonary conditions, of which malignant pleural mesothelioma and lung cancer are the most feared complications with significant morbidity and mortality. While the relationship between malignant pleural mesothelioma and asbestos exposure is well recognized, controversy exists with regards to the risk of lung cancer secondary to asbestos exposure. Nonetheless, current evidence is consistent with an increased risk of lung cancer secondary to asbestos exposure, and cigarette smoking has been proven to have a supra-additive effect within this context. The aim of the book chapter is to review asbestos, its associated toxicity, discuss about pleuropulmonary malignancies and their pathogenesis in relation to asbestos exposure.KeywordsAsbestosMiningAsbestosisMalignant pleural mesotheliomaLung cancerPathogenesis
... The prognosis is often miserable, as most patients diagnosed with mesothelioma have inoperable tumors at the time of diagnosis. The surgical options are pleurodesis, pleurectomy/decortication, and extrapleural pneumonectomy (EPP) in the treatment of mesothelioma if the tumors are suitable for surgery (14). Patients who have surgery have been reported to have improved OS, which is consistent with our findings (15). ...
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Aim: Malignant pleural mesothelioma (MPM) is an extremely mortal condition. Only a few prognostic biomarkers have been described for MPM. Our study looked into the association between patient survival and the Systemic Immune Inflammation Index (SII). Material and Method: A total of 158 patients who were admitted to our hospital between January 2013 and December 2022, and had a histopathologically confirmed diagnosis of MPM were included in the study. Before treatment, hematological parameters and SII were determined. A Spearman's correlation analysis was performed to analyze the correlation of mean survival with hematological parameters. Results: The study involved 158 patients in all. 70 patients had a history of smoking, the median age was 63 years, the mean survival time was 15.3 months, and 57.6% of the participants were men. The epithelioid type (84.2%) was the most prevalent histological subtype, and 29 patients had stage 4 illnesses. Of the participants, 84% had received chemotherapy, and 22% had received radiotherapy before. Among the 39 patients who had surgery, 5 had an extrapleural pneumonectomy. SII mean±sd was (1427.2±1207.3). The patients with stage 4 disease had significantly shorter survival (p=0.001). The patients who had surgery survived significantly longer (p=0.01). Hemoglobin (Hb) (r:0.21, p:0.01) and Hematocrit (Hct) (r:0.18, p:0.03) values showed weak positive correlations with mean survival. It was evident that mean survival got shorter as SII (r:-0.17, p:0.04) and neutrophil-lymphocyte ratio (NLR) (r:-0.19, p:0.02) values got higher. On the other hand, there was a strong positive association between mean survival and the lymphocyte-monocyte ratio (LMR) (r:0.21, p:0.01). When the parameters that had statistically significant differences among the groups were taken as control variables and the statistical analysis was re-performed, it was found that Hgb and Hct values as well as NLR and LMR ratios lost their significant correlations with survival. However, the SII ratio was still negatively correlated with survival (r:-0.16, p:0.04). Conclusion: Pretreatment SII is a noninvasive and easy-to-calculate biomarker that predicts the prognosis of MPM. It is negatively correlated with mean survival regardless of the tumor stage and surgical management.
... Malignant pleural mesothelioma (MPM) represents a rare and violent neoplasm that primarily affects the pleural cavity [1,2]. It is a male-dominating disease, with almost 80% of cases occurring due to occupational or environmental exposure to asbestos [3][4][5][6][7]. ...
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Malignant pleural mesothelioma (MPM) is a fatal disease of respiratory system. Despite the availability of invasive biomarkers with promising results, there are still significant diagnostic and therapeutic challenges in the treatment of MPM. One of three main mesothelioma cell types, epithelioid mesothelioma makes up approximately 70% of all mesothelioma cases. Different observational findings are under process, but the molecular heterogeneity and pathogenesis of epithelioid malignant pleural mesothelioma (eMPM) are still not well understood. Through molecular analysis, expression profiling data were used to determine the possibility and optimal number of eMPM molecular subtypes. Next, clinicopathological characteristics and different molecular pathways of each subtype were analyzed to prospect the clinical applications and advanced mechanisms of eMPM. In this study, we identified two distinct epithelioid malignant pleural mesothelioma subtypes with distinct gene expression patterns. Subtype I eMPMs were involved in steroid hormone biosynthesis, porphyrin and chlorophyll metabolism, and drug metabolism, while subtype II eMPMs were involved in rational metabolism, tyrosine metabolism, and chemical carcinogenesis pathways. Additionally, we identified potential subtype-specific therapeutic targets, including CCNE1, EPHA3, RNF43, ROS1, and RSPO2 for subtype I and CDKN2A and RET for subtype II. Considering the need for potent diagnostic and therapeutic biomarkers for eMPM, we are anticipating that our findings will help both in exploring underlying mechanisms in the development of eMPM and in designing targeted therapy for eMPM.
... It is worth noting that if the tumor is removed as early as possible, the survival of patients with early diseases will be prolonged to some extent [9][10][11]. Although mesothelioma treatment does not significantly prolong life, early diagnosis of MPM can strive for a certain time for subsequent treatment [12]. Therefore, it is urgent to find accurate means to identify MPM in the early stage. ...
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In previous studies, non-invasive diagnostic biomarkers showed great benefit in the early-stage diagnosis of malignant pleural mesothelioma (MPM). However, the accuracy of different biomarkers was controversial. In this study, meta-analysis and bioinformatics analysis were conducted to compare the accuracy of the following three biomarkers and explore the relationship between the gene expression levels and MPM. A systematic search of meta-analysis was conducted using PubMed, EMBASE and Cochrane Library to identify relevant studies from the inception to March 2021. QUADAS-2 for Quality Assessment of Diagnostic Accuracy Studies was used to evaluate the quality of eligible studies. The meta-analysis was performed utilizing Stata 15.0 and Review Manager 5.4 software. The meta-analysis results showed that 31 studies that involved 8750 participants were included. The pooled sensitivity and specificity (SPE) were 0.90 (95% CI: 0.74, 0.97) and 0.91 (95% CI: 0.84, 0.95) for Fibulin-3, 0.66 (95% CI, 0.51–0.78) and 0.91 (95% CI, 0.82–0.96) for mesothelin (MSLN), 0.68 (95% CI: 0.63,0.73) and 0.86 (95% CI: 0.82,0.90) for soluble mesothelin-related peptides (SMRP), and 0.74 (95% CI, 0.66-0.80) and 0.89 (95% CI, 0.85–0.91) for MSLN + SMRP + Fibulin-3. Compared with the other two biomarkers, Fibulin-3 may be more appropriate to be one of the indicators for combined diagnosis. Bioinformatics analysis showed that the low expression level of the MSLN gene was significantly related to longer survival time and better prognosis of MPM patients. However, considering the limitation in the quality and sample size of the included research, further studies are required.
Introduction: Mesothelioma is a rare but highly aggressive malignancy with poor prognosis that frequently present with recurrent effusions. Establishing the diagnosis by cytology can lead to early diagnosis and treatment and consequently improve prognosis. Materials and methods: This review examines the cytological diagnosis of mesothelioma in the context of its historical and morphologic evolution and provides an update of the current reporting systems. Clues to identify the mesothelial and malignant nature of the sample are detailed as well as the supporting ancillary tests. Results: Cytologically, the samples are overwhelmingly cellular and malignancy is recognized by both architectural and cytological atypia. Numerous variably sized clusters and enlarged cells are easily identified, some with papillary architecture and collagen cores. Recognizing the mesothelial nature of the cells and supportive immunostains are essential to rule out the differential diagnosis of metastatic carcinomas and reactive mesothelium. Current ancillary tests such as homozygous deletion of CDKN2A, loss of BRCA1-associated protein, and methylthioadenosine phosphorylase expression can provide further support of malignancy. Conclusions: At this time with the aid of current ancillary tests and in the hands of cytopathologists with adequate experience with the interpretation of effusions, the diagnosis of mesothelioma can be established with accuracy in most cases.
Photodynamic therapy (PDT) has been used to treat malignant pleural mesothelioma. Current practice involves delivering light to a prescribed light fluence with a point source, monitored by eight isotropic detectors inside the pleural cavity. An infrared (IR) navigation system was used to track the location of the point source throughout the treatment. The recorded data was used to reconstruct the pleural cavity and calculate the light fluence to the whole cavity. An automatic algorithm was developed recently to calculate the detector positions based on recorded data within an hour. This algorithm was applied to patient case studies and the calculated results were compared to the measured positions, with an average difference of 2.5 cm. Calculated light fluence at calculated positions were compared to measured values. The differences between the calculated and measured light fluences were within 14% for all cases, with a fixed scattering constant and a dual correction method. Fluence surface histogram (FSH) was calculated for photofrin‐mediated PDT to be able to cover 80% of pleural surface area to 50 J/cm2(83.3% of 60 J/cm2). The study demonstrates that it will be possible to eliminate the manual measurement of the detector positions, reducing the patient’s time under anesthesia.
Malignant pleural mesothelioma is a rare type of cancer, whose incidence, however, is increasing and will presumably continue to rise in the coming years. Key features of this disease comprise its mantle-shaped, pleura-associated, often multifocal growth, which cause diagnostic challenges. A growing number of mesotheliomas are being treated with novel immunotherapies for which no image derived general response criteria have been established. However, recent studies indicate that FDG-PET/CT could be superior for response assessment compared to CT-based criteria. This article aims at providing an overview of response assessment criteria dedicated to malignant pleural mesothelioma, such as mRECIST, iRECIST, and PERCIST. In addition, the potential future role of PET/CT in the management of malignant pleural mesothelioma will also be discussed.
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Poliovirus vaccines that were used during the late 1950s and early 1960s were contaminated with simian virus 40 (SV40), a monkey virus that is tumorigenic in rodents. SV40 DNA sequences have been detected in some human cancers, especially pleural mesotheliomas, although results are conflicting. We examined the relationship between SV40-contaminated poliovirus vaccine exposure and subsequent rates of pleural mesothelioma in the United States. We used data from the Surveillance, Epidemiology, and End Results Program to estimate age- and sex-specific pleural mesothelioma incidence rates per 10(5) person-years (py) from 1975 through 1997 and the Poisson distribution to determine 95% confidence intervals (CIs) for each rate. The prevalence, by birth cohort, of poliovirus vaccine exposure during the period of widespread SV40 contamination was determined from published survey data. Trends in mesothelioma incidence rates were assessed by examining age- and sex-specific rates over calendar periods and with the use of the age-period-cohort model. Trends in mesothelioma incidence were then compared with trends in prevalence of exposure. All statistical tests were two-sided. The age-standardized pleural mesothelioma incidence rate for 1975 through 1997 was 1.29/10(5) py (95% CI = 1.24/10(5) to 1.34/10(5) py) in males and 0.21/10(5) py (95% CI = 0.20/10(5) to 0.23/10(5) py) in females. The rate in males increased from 0.79/10(5) py (95% CI = 0.62/10(5) to 1.0/10(5) py) in 1975 to a peak of 1.69/10(5) py (95% CI = 1.46/10(5) to 1.95/10(5) py) in 1992. Incidence rates increased the most among males who were 75 years of age or older, the age group least likely to have been immunized against poliovirus. Incidence rates among males in the age groups most heavily exposed to SV40-contaminated poliovirus vaccine remained stable or decreased from 1975 through 1997. Similar age-specific trends were observed among females. The age-period-cohort models for men and women also indicated that the trends in pleural mesothelioma incidence were not related to trends in exposure to SV40-contaminated poliovirus vaccine. Age-specific trends in U.S. pleural mesothelioma incidence rates are not consistent with an effect of exposure to SV40-contaminated poliovirus vaccine. Nonetheless, given reports of the detection of SV40 genomic DNA sequences in human mesotheliomas, monitoring of vaccine-exposed cohorts should continue.
PURPOSE: A multicenter phase II trial of ranpirnase (Onconase; Alfacell Corp, Bloomfield, NJ) as a single agent was conducted to further assess the safety and clinical efficacy of this novel antitumor ribonuclease. Patients with unresectable and histologically confirmed malignant mesothelioma (MM) were eligible. PATIENTS AND METHODS: One hundred five patients with Eastern Cooperative Oncology Group performance status 0 to 2 were enrolled onto the study. Thirty-seven percent of patients had not responded to prior chemotherapy. The primary end point of the study was survival. Tumor responses and time to progression were also assessed. The Cancer and Leukemia Group B (CALGB) prognostic group criteria were used to define a treatment target group (TTG). Both the intent-to-treat (ITT) and the TTG populations were analyzed for survival. RESULTS: Median survival times of 6 months for the ITT and 8.3 months for the TTG populations were observed. The 1- and 2-year survival rates were 34.3% and 21.6% for ITT, respectively, and 42% and 26.8% for TTG, respectively. Among the 81 patients assessable for tumor response, four had partial responses, two had minor regressions, and thirty-five experienced stabilization of previously progressive disease. Patients with responses and stable disease demonstrated markedly prolonged survival. Ranpirnase was well tolerated in the majority of patients, and there were no drug-related deaths. CONCLUSION: Ranpirnase demonstrated activity and a tolerable toxicity profile in patients with unresectable MM. The prognostic value of the CALGB groups was confirmed.
In 1985 the Lung Cancer Study Group (LCSG) initiated clinical trials in malignant pleural mesothelioma because LCSG member institutions had access to large numbers of patients and had significant experience treating this uncommon cancer. The first trial, LCSG 851, defined the patient population seen by the LCSG, and the feasibility of performing surgical resection by extrapleural pneumonectomy in a multi-institutional setting. Of 83 patients entered on this study from September 1985 to June 1988, only 20 could undergo an extrapleural pneumonectomy, and 3 of 20 patients died postoperatively. This experience prompted the LCSG to explore combining a potentially less morbid operation, pleurectomy/decortication, with adjuvant therapy. The results of another LCSG trial (LCSG 861) and of a small single institutional pilot study demonstrated the feasibility of intrapleural cisplatin-based chemotherapy, and led to the development of LCSG 882, which combined pleurectomy/decortication with postoperative intrapleural, and subsequent systemic, cisplatin-based chemotherapy. This study was not completed because of discontinuation of funding for the LCSG. However, a single-institution phase 2 trial of very similar design has subsequently shown the feasibility of this combined modality approach.
Pleurectomy/decortication is a frequently performed operation for patients with diffuse malignant pleural mesothelioma (DMPM). It has a low surgical mortality rate (less than 5%), but is associated with a significant risk of local recurrence. To date, intensive adjuvant radiation or chemotherapy has not diminished that risk. Despite these disappointing results, pleurectomy/decortication may still be the best treatment option for some patients, particularly those with early stage disease whose medical condition precludes pneumonectomy. The role of pleurectomy/decortication in conjunction with newer treatment strategies such as neoadjuvant therapy or gene therapy warrants investigation.
Our aim was to identify prognostic variables for long-term postoperative survival in trimodality management of malignant pleural mesothelioma. From 1980 to 1997, 183 patients underwent extrapleural pneumonectomy followed by adjuvant chemotherapy and radiotherapy. Forty-three women and 140 men (age range 31-76 years) had a median follow-up of 13 months. The perioperative mortality rate was 3.8% (7 deaths) and the morbidity, 50%. Survival in the 176 remaining patients was 38% at 2 years and 15% at 5 years (median 19 months). Univariate analysis identified 3 prognostic variables associated with improved survival: epithelial cell type (52% 2-year survival, 21% 5-year survival, 26-month median survival; P =.0001), negative resection margins (44% at 2 years, 25% at 5 years, median 23 months; P =.02), and extrapleural nodes without metastases (42% at 2 years, 17% at 5 years, median 21 months; P =.004). Using the Cox proportional hazards, the relative risk of death was calculated for nonepithelial cell type (OR 3.0, CI 2.0-4.5; P <.0001), positive resection margins (OR 1.7, CI 1.2-2.6; P =.0082), and metastatic extrapleural nodes (OR 2.0, CI 1.3-3.2; P =.0026). Thirty-one patients with 3 positive variables had the best survival (68% 2-year survival, 46% 5-year survival, median 51 months; P =.013). A previously published staging system using these variables stratified survival (P <.05). (1) Multimodality therapy including extrapleural pneumonectomy is feasible in selected patients with malignant pleural mesotheliomas, (2) pre-resectional evaluation of extrapleural nodes may select patients for radical therapy, (3) microscopic resection margins affect long-term survival, highlighting the need for further investigation of locoregional control, and (4) patients with epithelial, margin-negative, extrapleural node-negative resection had extended survival.
Diffuse malignant pleural mesothelioma (DMPM) is a challenging disease in all of its aspects, from presentation and diagnosis to staging and treatment. Single-modality therapy was the initial approach to this disease. It generally has not been effective in changing the natural history of DMPM. As a result, multimodality regimens involving surgery with radiation, chemotherapy, or immunotherapy delivered regionally or systemically have been evaluated. Randomized controlled studies comparing various strategies are lacking and, thus, the debate continues regarding the effectiveness of different treatment approaches.
We performed a retrospective review of the efficacy and morbidity of radical pleurectomy/decortication and intraoperative radiotherapy followed by external beam radiation therapy with or without chemotherapy for diffuse malignant pleural mesothelioma. A total of 32 patients with diffuse malignant pleural mesothelioma were initially evaluated between January 1995 and September 2000. Three patients were excluded from analysis because of unresectable disease. Two patients died postoperatively, and one patient had recurrent disease previously treated at an outside institution. Of the remaining 26 patients included in the analysis, 24 received intraoperative radiotherapy. External beam radiation therapy was generally started 1 to 2 months after resection and delivered by means of 3-dimensional conformal radiation therapy or with inverse treatment planning intensity-modulated radiation therapy. When given, chemotherapy consisted of 2 to 3 cycles of cyclophosphamide, doxorubicin (Adriamycin), and cisplatin initiated 1 to 2 months after completion of radiation. At the time of data analysis, 5 of 26 patients were alive. The median follow-up was 9.7 months (range, 2-67.6 months). The median overall survival and progression-free interval from the time of the operation were 18.1 and 12.2 months, respectively. The Kaplan-Meier estimates of overall survival and freedom from progression at 1 year were 64% and 50%, respectively. The site of failure was mostly locoregional. However, there were 4 abdominal failures and 1 contralateral lung failure. Radical pleurectomy/decortication with aggressive radiotherapy with or without chemotherapy might offer an alternative treatment option to those who cannot tolerate extrapleural pneumonectomy.