Malignant Pleural Mesothelioma: A Focus on Current Therapies
Caroline D. Brownlee, M.D.
Internal Medicine Resident Grand
Rounds -
History
Mesothelioma, a tumor involving the
mesothelial lining of the pleura, pericardium, and peritoneum, is an uncommon
neoplasm accounting for fewer than one percent of cancer deaths worldwide. Pleural mesotheliomas are much more common
than peritoneal ones (10:1), and secondary pleural tumors are about 100 times
more frequent than primary pleural tumors.
Asbestos, meaning “inextinguishable or unquenchable”, has been used by
humans since 4000 BC for wicks and candles.
Due to its properties of being resistant to chemical damage and heat,
asbestos has numerous applications contributing to it industrial and economical
interest. It was a major component of
the insulating material in steam engines in the early 1800s and the primary
material in brake linings starting in the 1890s. Soldiers wore asbestos-woven fireproof suits
and used asbestos parachute flares in WWI and II. Post-war construction relied heavily on the
use of asbestos (Abratt et al., 2004).
Doll first pointed out the asbestos exposure/cancer connection in a
case-control study of lung cancer patients in 1955, and the mesothelioma and asbestos
exposure association has been recognized since Wagner’s 1960 descriptions of 33
patients with mesothelioma in persons who had previous environmental and
occupational exposure to crocidolite in a South African asbestos mining
community. Since then, multiple
case-control and epidemiologic studies from industrialized nations with heavy
commercial use of asbestos have shown rising rates of malignant
mesothelioma. Most of these cases have
been in shipyard workers and insulators, but other occupations including
miners, millers, railroad machinists, steam locomotive repair workers, and
asbestos factory workers have contributed to the caseload. Now, the solid fuel boosters of the space
shuttle are insulated with asbestos, one of its few remaining uses.
Crocidolite (blue asbestos),
chrysotile (white asbestos), and amosite (grey or brown asbestos) are the major
types of this mineral. After its
carcinogenic properties were shown, the concept of innocuous white asbestos and
harmful blue asbestos emerged, but this theory has been disproven. The two major species of asbestos are the
serpentines (white) – the curly, soft chrysotile fibers and the amphiboles
(blue) – hard, needle-shaped rods with subvarietites of crocidolite, amosite,
and tremolite.
Epidemiology
Malignant mesotheliomas (MM) are
highly aggressive and are especially rare with an estimated incidence in male
North Americans of 15-20 cases per million. The incidence in women is
significantly lower. Approximately 3,000
(2,000 men and 500 women) new cases of mesothelioma are diagnosed annually in
the United States. The rarity of
malignant mesothelioma combined with its strong link to asbestos exposure make
it an important epidemiologic marker.
Mesothelioma, usually diagnosed in
the fifth to eighth decades of life after a prolonged latent interval, the
period of time between initial exposure and manifestation of disease, is
typical of most asbestos-associated illnesses. The latent interval for
mesothelioma, almost never less than 15 years, is usually 30 to 40 years
post-exposure and may extend to 70 years after exposure. The incidence in US men aged 75 years or
older is rising with the maximum lifetime risk in the 1925-1929 birth cohort of
men calculated to be 2.1 x 10-3; however, the incidence in people
less than 75 years of age has been stable since 1983, coinciding with
regulations and restrictions regarding uses and allowed exposure limits for
asbestos in the workplace enacted in the 1970’s by the US Occupational Safety
and Health Administration (OSHA) and the Environmental Protection Agency.
Current incidences of mesothelioma range from 14 to 35 cases/million/year in
eleven industrialized countries that had used asbestos 2.0 to 5.5
kg/capita/year roughly 25 years earlier.
A significant (p 0.01) linear correlation exists between the number of
cases and the amount of asbestos used.
Indeed, about 170 tons of produced and consumed asbestos will cause at
least one death from mesothelioma.
(Tossavainen, 2004)The incidence of mesothelioma is projected to
increase dramatically over coming years peaking about the year 2020 and
returning to background levels by 2055.
The projected number of male mesothelioma cases from 2003-2054 is
71,000. (Fig 1-3, Price and Ware,
2004) An inverse relationship has been
observed between dose or level of exposure and latent interval as evidenced by
development of mesothelioma by insulators at a significantly younger age when
compared to age of other asbestos workers (Niklinski et al, 2004).
Figure 1. Age-adjusted incidence rates of
mesothelioma (pleural and peritoneal) in the United States based on
Surveillance, Epidemiology, and End Results (SEER) data released in April 2003.
(Price and Ware, Am J Epidemiology
2004; 159: 107-112).
Figure 2. Asbestos use (consumption) in the
United States and projected number of male and female mesothelioma cases based
on a birth-cohort and age model estimated from SEER Program data for two
periods, 1973-1992 and 1973-2000. (Price and Ware, Am J Epidemiology 2004; 159: 107-112).
Figure 3. Lifetime probability (risk) of
mesothelioma (pleural and peritoneal) and 95% confidence intervals (vertical
bars) based on a birth-cohort and age model estimated from 2003 SEER Program
data covering 1973-2000. (Price and Ware, Am
J Epidemiology 2004; 159: 107-112).
Interestingly, the annual estimate
of female mesothelioma cases is 560 and has been constant with annual risk
calculated to be 3.9 x 10-6, suggesting the existence of a
background rate as well as a threshold exposure for development of
mesothelioma. Female exposures to
asbestos have been primarily environmental as women generally did not work in
the industries in which men were exposed to high levels of asbestos in the
1930’3-60’s. Though all women have been
exposed to asbestos in the environment, and that exposure has increased since
the 1930’s – especially during the 1930-70 period of asbestos use in US
products (vehicle brake systems, construction materials)—the mesothelioma risk
for women has not increased (Price and Ware, 2004). A threshold higher than typical environmental
asbestos exposures suggests the presence of background mesotheliomas caused by
agents other than asbestos.
Occupational exposure to the narrow
and needle-like crocidolite and amosite forms of asbestos is the most important
known risk factor in North America and Western Europe. Other predisposing factors include sharing
homes with asbestos workers and living near asbestos factories and mines. Nevertheless, mesothelioma without asbestos
exposure does occur. Although about 80%
of patients with malignant mesothelioma have a history of asbestos exposure, only
10% of those people with asbestos exposure acquire mesothelioma (Pistolesi and
Rusthoven, 2004). Other possible factors
such as the presence of simian virus 40 and genetic susceptibility have been
suggested. Simian virus 40 was a contaminant in polio vaccines administered to
10-30 million people, mostly children,in the US between 1955-63(Carbone et al,
1999). Studies have demonstrated that
SV-40 is a poor prognostic factor in patients with MM (Procopio et al, 2000),
and other research has shown that asbestos and SV-40 can function as co-carcinogens. Metals, rubber, glass dust, pleural scarring,
sugar cane, dietary factors, man-made mineral fibers, lung infections, zeolite
mineral, and ionizing radiation have all been proposed as causes of
mesothelioma. Interestingly, no
association between asbestos and smoking has been found.
Biological markers including
overexpression of the alpha folate receptor, cyclooxygenase-2, and multidrug
resistant proteins 1 and 2 have been observed to be elevated in mesothelioma
compared with normal mesothelium. COX-2
has been correlated with other prognostic factors. (Edwards et al, 2002) Dhaene et al demonstrated that over 90% of
malignant mesotheliomas showed telomerase activity while hyperplastic
mesothelium did not, presenting immunochemistry for telomerase as a possible
diagnostic tool for MM.
Chromosomal abnormalities commonly
found in malignant pleural mesothelioma including deletions of 1p, 3p, 9p, 6q,
and chromosome 22 have also been proposed as the lost tumor suppressor genes
critical in the development of malignant pleural mesothelioma. (Papp et al,
2001)
Genetic susceptibility may also play
a role in the development of malignant mesothelioma. Roushdy-Hammady et al studied two small
villages in the Anatolia region of Turkey that share the rare environmental
pathogen for malignant mesothelioma, erionite exposure. Fifty percent of the men in one village died
of malignant mesothelioma, but only one woman in the other village suffered the
same fate; she was originally from the other village. Six families, and subsequently a large six generation
pedigree, have been identified with familial clustering of MM, making a case
for a founder effect and an autosomal dominant pattern of inheritance with
incomplete penetrance.
Despite advances in therapies
including radiation therapy and chemotherapy as well as surgery, malignant
mesothelioma is almost universally fatal.
A “gold standard” of treatment has yet to be identified due to a paucity
of randomized, controlled trials. Median
survival from onset of symptoms is about one year though initial stage and
other prognostic factors certainly shorten and lengthen the process (Yates,
1997). One key to mortality prevention
is early diagnosis, malignancy identification, and staging. Only patients with
early disease are considered for radical surgical resection, and accurate
preoperative tumor staging is critical.
Diagnosis and staging
Various techniques are used in
diagnosis including clinical investigation, X-ray (Fig. 4) thoracic ultrasound,
MRI, computed tomography (Fig. 5), ultrasound-guided puncture, and thorascopy
with biopsy. Pleural mesothelioma is the
most prevalent malignant tumor of the pleura.
The mesothelioma grows between the planes of the visceral pleura and the
parietal pleura and spreads by local invasion of the neighboring organs. Clinical symptoms are usually caused by the
displacement of the lung by the tumor as well as by accompanying pleural
effusions.
A study of 272 patients presenting
with malignant pleural mesothelioma in England revealed that dyspnea and
nonpleuritic chest wall pains are the most common presenting chief complaints.
(Yates et al,1997) Physical examination
findings may include dullness to percussion and decreased air entry at one base
indicating a unilateral pleural effusion; a slight right-sided predominance has
been shown in the literature. Patients
may also be asymptomatic with pleural effusion found only incidentally upon
physical exam or on routine chest x-ray.
A pleural mass, possibly covered by fluid, may also be seen on chest
x-ray. Metastaic disease is uncommon at
presentation. (Pistolesi and Rusthoven, 2004)
As the disease progresses, shortness of breath and chest pain become
worse, followed by B-type symptoms (weight loss, anorexia, and night sweats). Local tumor invasion of the chest wall and
surrounding anatomy causes pain and dysfunctionality such as dysphagia,
diaphragmatic paralysis, vocal cord paralysis, Horner syndrome, and superior
vena cava syndrome.
After pleural effusion is identified
on exam or by chest x-ray, chest ultrasound provides further cost-effective
information. The ultrasound’s diagnostic
utility is limited by the bony delineation of the chest including the ribs,
spinal column, sternum, and clavicle, as well as the gas in the lung; it is not
effective for evaluating the healthy lung.
However, ultrasound is an effective way of detecting pleural
pathological processes such as disease-associated changes to the chest wall,
the diaphragm, or the upper thoracic inlet.
Pleural effusions actually enhance ultrasound sensitivity with the
liquid acting as an acoustical window and thus allowing identification of of
both intrapleural and intrapulmonary processes.
Fibrinoid membranes in the effusions are helpful for determining
pulse-synchronous and breath-dependent mobility. Areas of pleural thickening present as
constant echo-poor regions, and their differentiation from effusions,
mesothelioma, and pleural lung tumors is challenging. Breath-dependent changes in configuration
suggests
Figure 4. AP chest x-ray demonstrating left-
sided pleural thickening with an
effusion.
Figure 5. Computed tomography scan of the
chest demonstrating marked
left-sided pleural
thickening.
an
effusion; an irregular delimination indicates a tumor, and a regular
delineation is a sign of pleural thickening.
Abscesses are fixed and are not breath-dependent. Pleural mesothelioma presents as an
irregular, echo-poor, knotty, or planar widening along the pleural surface; a
widening of more than 1 cm of the pleura is highly indicative of the presence
of a malignant tumor. Low-risk
ultrasound-guided needle puncture should precede more invasive diagnostic
procedures, and thoracentesis is often the initial diagnostic test; however,
cytologic diagnosis of malignant pleural mesothelioma is unreliable as other
malignant tumors including adenocarcinomas and sarcomas as well as reactive
mesothelial cells can look the same (Henderson et al, 1998). The cytological proof of malignant cells
after several punctures is successful only 50% of the time. Subsequently, histologic evaluation utilizing
CT guidance and thoracoscopy is more definitive. CT-guided biopsy has a 60% yield on first
pass, improved to 85% after additional biopsies (Metintas et al, 1995). Thoracoscopic biopsy by video-assistance has
a greater than 90% yield with a less than 10% complication (air leak,
infection, hemorrhage) (Boutin and Ret, 1993).
Open thoracotomy is the last choice for obtaining adequate tissue for
pathologic diagnosis.
CT or MRI studies are critical in
the staging of malignant pleural mesothelioma. Studies have shown accuracy of
staging of both CT and MRI independently to be in the 50-60% range. Computed tomography is more useful for
evaluating the costal and diaphragmatic portions of the pleura and can provide
information on all thoracic structures including central processes. MRI contrast agents can help predict
malignancy in patients with asbestos exposure; malignant pleural mesothelioma
usually is hyperintense on T2 weighted imaging and enhances after intravenous
gadolinium contrast on T1 weighted imaging.
A study of 30 patients with asbestos-related pleural disease by Boraschi
et al found the sensitivity, specificity, and diagnostic accuracy of the MRI in
classifying a lesion as malignant to be 100%, 95%, and 97% respectively. In a study comparing CT and MRI, Knuuttila et
al demonstrated that MRI was superior in showing focal thickening and
enhancement of interlobar fissures – useful evidence for detecting early
malignant pleural disease. MRI characteristics suggestive of malignant pleural
disease include mediastinal pleural involvement, circumferential pleural
thickening, nodularity, pleural contour irregularity, and infiltration of the
chest wall or diaphragm. Additionally, MRI
is used in assessing patients for radical surgery as it offers the ability to
view multiple planes (Entwisle, 2004). Both modalities are poor in
demonstrating nodal involvement as nodal size does not prove involvement.
Though CT and MRI help identify the
location and extent of involved pleural lesions, diffuse pleural thickening is
not specific and can be caused by asbestos exposure, hemorrhagic effusion,
empyema, tuberculosis, and multiple other infectious etiologies. Fluorodeoxyglucose (FDG)-positron emission
tomography (PET) imaging, based on changes in the metabolic pathways of
glucose, has been shown to differentiate benign from malignant processes in
asbestos-exposed patients; additionally, PET images have been found to
accurately identify active tumor sites.
In tumors, the glycolytic enzymes (glucokinase, phosphofructokinase,
pyruvate kinase) are upregulated, and the gluconeogenetic enzymes
(glucose-6-phosphatase, fructose-1,6, -diphosphatase, phosphoenolpyruvate
carboxykinase, pyruvate carboxylase) are downregulated Haberkorn, 2004). A study of 14 patients (ten with malignant
pleural mesothelioma, one with benign disease, three with other malignant (non
asbestos-related) tumors) with CT evidence of fluid or pleural thickening by
Carretta et al demonstrated that PET scanning showed significant FDG uptake in
12/13 patients with malignant disease; a false-negative result was obtained in
a patient with an epithelial mesothelioma, and benign pleural disease was
correctly diagnosed. Another small, similar
study of 16 patients showed that all twelve pleural or intrapulmonary malignant
tumors had high FDG uptake and were correctly classified (Buchmann et al,
2004); moreover, hypermetabolic lymph node involvement was noted in twelve
patients’ FDG-PET images, nine of which appeared normal on their CT scans.
Pathology
Typically, mesothelioma causes
complete obliteration of the pleural space and the interlobular septa
macroscopically. Usually both the
parietal and visceral pleura are involved.
The pathological confirmation of malignant mesothelioma is based on
examination of cytological material from pleural, peritoneal, or pericardial
exudates and biopsy from the pleura, peritoneum, pericardium, and tunica
vaginalis. Diagnosis relies on
identification of the mesothelial nature of the neoplastic cells, neoplastic
proliferation, and invasive properties of the proliferation. Cytological characteristics highly suggestive
of malignant mesothelioma include: a
highly cellular exudate, the presence of numerous cell clusters or cell balls,
intercellular windows (spaces), large mesothelial cells, and the absence of a
two-cell population (Fig. 6).
Mesothelial hyperplasia and metastatic adenocarcinoma cannot be
differentiated from malignant mesothelioma on the basis of cytology alone.
Figure 6. Cytologic preparation of pleural
fluid
demonstrating single and clusters of
malignant
mesothelial cells with nuclear
pleomorphism and
prominent nucleoli (Diff-quik stain,
photo courtesy
of Dr. J. Roux, Department of Pathology,
Wake
Forest University Baptist Medical
Center).
The three main histological types of
malignant mesothelioma are epithelial, mixed, and sarcomatous. The epithelial
variant of mesothelioma is the most common type, and may be confused with a
pulmonary adenocarcinoma or metastatic adenocarcinoma occurring in a subpleural
location. Immunohistochemical evaluation of biopsy material is an absolute
necessity in order to be able to discriminate pulmonary adenocarcinoma,
metastatic adenocarcinoma, and epithelial mesothelioma. This distinction has
both important clinical and medicolegal implications. Typically, mesotheliomas
are immunoreactive with monoclonal antibodies specific for calretinin,
mesothelin, and Wilms’ tumor -1 (WT-1) proteins, but non-reactive with
antibodies specific for certain cytokeratins and the thyroid transcription
factor -1 (TTF-1) protein (Ordonez et al., 2003). Both cytokeratin and TTF-1
staining are more specific for small cell and non-small cell lung carcinomas.
The mixed type of mesothelioma contains both an epithelial and a sarcomatous
component and carries an intermediate prognosis. Sarcomatous mesothelioma is
the rarest subtype, and is associated with the most dismal prognosis. Other
subtypes of mesothelioma (e.g. deciduoid and mesothelioma with heterologous
differentiation) occur but are much rarer.
A variety of other tumors and
non-neoplastic conditions simulating mesothelioma may involve the pleura. These
range from benign pleural plaques to aggressive neoplasms such as angiosarcoma.
Solitary fibrous tumors, epithelioid hemangioendothelioma, hemangiopericytoma,
and other soft tissue tumors such as synovial sarcoma may rarely involve the
pleura.
Prognosis
The International Mesothelioma
Interest Group staging system is a surgical system that considers tumor
involvement, metastatic disease, and nodal distribution in order to provide
prognostic information. The TMN-based system for staging malignant mesothelioma
is only one of the factors known to contribute to the equation of survival and
mortality. The Cancer and Leukemia Group
B studied patients with mesothelioma
treated during a ten-year period and amassed a group of factors predictive of
survival. Multivariate analysis of
their data identified pleural involvement, Poor Eastern Cooperative Oncology
Group (ECOG) performance status, chest pain, platelet count less than 400,000,
lactate dehydrogenase greater than 500, low hemoglobin, nonepithelial
histology, and age greater than 75 as independent predictors of reduced
survival time. Performance status,
discriminating between 0 and 1/2, revealed the most important prognostic
factor. Longest survival was observed in
patients younger than 49 with a performance status of zero and a hemoglobin
greater than 14.6 (Herndon et al, 1998).
A similar European study by Curran et al showed that poor prognosis was
associated with sarcomatoid histologic type, high white blood cell count, poor
performance status, and male sex. Additionally, Bernard et al examined the
efficacy of FDG-PET as an indicator of prognosis in seventeen patients, and the
group of patients with high FDG uptake showed significantly shorter survival as
compared with the low FDG uptake indicating that patients with highly active
mesotheliomas by PET have a poor prognosis.
Surgical, Medical, and
Radiation Therapy of Mesothelioma
There is no uniform approach to
therapy for malignant pleural mesothelioma. The best documented approach to
treatment of mesothelioma is tri-modality therapy involving extrapleural
pneumonectomy followed by chemotherapy and radiotherapy in selected patients
with earlier stages of disease (Weder et al., 2004). Extrapleural pneumonectomy
involves complete resection of the pleural envelope and all of its contents
including the ipsilateral lung, diaphragm, and a section of the pericardium.
There are three distinct objectives in the surgical management of mesothelioma:
(1) palliation of dyspnea, (2) debulking to increase the efficacy of other
treatments, and (3) radical surgery to eradicate disease. In an initial study,
perioperative mortality associated with extrapleural pneumonectomy was reported
at 30% (Butchart et al., 1976). Today, the perioperative mortality is
approximately 3.4% (Sugarbaker et al., 2004). In the latter report, 328
consecutive patients (median patient age 58) undergoing extrapleural
pneumonectomy between 1980 and 2003 were studied with regard to post-operative
complications. Reported complications included atrial fibrillation (44.2%),
prolonged intubation (7.9%), deep vein thrombosis (6.4%), cardiac tamponade due
to cardiac patch dysfunction (3.6%), cardiac arrest (3%), renal failure (2.7%),
myocardial infarction (1.5%), pulmonary embolus (1.5%), empyema (2.4%), and
bronchopleural fistula (0.6%).
Tri-modality therapy involving
extrapleural pneumonectomy and combination adjuvant chemotherapy and radiation
therapy was pioneered by surgeon, Dr. David Sugarbaker. In a recent study from
his group (Sugarbaker, et al., 1999), 183 patients underwent extrapleural
pneumonectomy followed by adjuvant chemoradiotherapy. Seven patients died
perioperatively. Median survival in 176 patients was 19 months, and the
estimated two- and five-year survival rates were 38% and 15%, respectively.
A recent study has examined the
potential role of neoadjuvant chemotherapy followed by extrapleural
pneumonectomy for the treatment of malignant mesothelioma (Weder et al., 2004).
In this study, nineteen patients with mesothelioma with clinical stages of
T1-3, N0-2, M0 (i.e. tumors felt to be completely resectable) were treated with
neoadjuvant chemotherapy including cisplatin and and gemcitabine (cisplatin 80
mg/m2 on day 1 and gemcitabine 1000 mg/m2 on days 1,8, and 15 given every 28
days) followed by extrapleural pneumonectomy. The response rate to neoadjuvant
chemotherapy was 32%. Extrapleural pneumonectomy was performed on 16 patients
with no perioperative mortality. Thirteen patients received postoperative
radiotherapy. The median survival of this patient group using this protocol was
23 months. These results are encouraging, and larger studies will be necessary
to understand the efficacy of neoadjuvant therapy followed by pneumonectomy.
Mesothelioma is relatively
unresponsive to chemotherapy. One study systematically reviewed evidence for
chemotherapy from 1965 through June 2001, and found 83 studies with 88
treatment arms (Berghmans, et al., 2002). Cisplatin was the most active single
drug, and cisplatin with doxorubicin had the highest response rate (28.5%
response rate, confidence intervals 21.3-35.7%). Since this report, results of
a phase III randomized trial (using 448 chemotherapy naive patients with
unresectable mesothelioma) involving use of combination cisplatin/ pemetrexed
(an antimetabolite) and cisplatin alone have demonstrated that median survival
is extended from 9.3 months, in those treated with cisplatin, to 12.1 months in
those treated with both agents (Vogelzang, et al., 2003). This trial also
reported a response rate of 41.3%, the highest ever reported for a
chemotherapeutic regimen. These results led the Food and Drug Administration to
approve combination of pemetrexed and cisplatin as the first chemotherapy
regimen approved for treatment of malignant pleural mesotheliomas.
Premetrexed,
also under investigation for treatment of non-small cell lung, gastric,
pancreatic, and breast cancers, is an antimetabolite that inhibits enzymes
involved in folate metabolism, including dihydrofolate reductase, thymidylate
synthase, and glycinamide ribonucleotide formyltransferase.
Radiotherapeutic treatment of
mesothelioma is somewhat difficult to perform in the preoperative setting due
to the fact that the exposure field is often difficult to define due to the
diffuse nature of the tumor (Sugarbaker, et al., 1999). Many times, adjacent
organs such as the heart receive significant toxicity because of this problem.
Radiation therapy is easier to administer following extrapleural pneumonectomy
when the field of exposure is easier to define.
Mesothelin, a differentiation
antigen present on normal mesothelial cells and overexpressed in mesothelioma,
ovarian adenocarcinoma, and pancreatic adenocarcinoma, is being evaluated as a
target for antibody and vaccine-based cancer therapies. SS1(dsFv)PE38 is a recombinant
anti-mesothelin immunotoxin tagged with Pseudomonas
exotoxin-A currently undergoing clinical evaluation in patients with
mesothelin-expressing tumors (Hassan et al.,2004). Additionally, a soluble mesothelin variant
has been identified and may prove to be a useful tumor marker for malignant
mesotheliomas (Ordonez, 2003). Other immunotoxins showing promise in mouse
xenografts of human mesothelioma include interleukin-4 receptor cytotoxins
tagged with Pseudomonas exotoxin-A (Beseth, et al., 2004).
Novel cytostatic agents are also on
the horizon for treatment of mesothelioma. These cytostatic agents target
vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and
platelet derived growth factor (PDGF) (Kindler, 2004). Patients with
mesothelioma have a marked increased level of expression of VEGF, a potent
mediator of angiogenesis. Three VEGF inhibitors (anti-angiogenic agents) are
currently being evaluated. These include SU5416, bevacizumab (Avastin ®,
Genentech), and thalidomide. Bevacizumab is a recombinant humanized monoclonal
antibody directed against the VEGF receptor on cells. VEGF is highly
synergistic with platinum compounds in animal models. PDGF also seems to be an
important autocrine mediator in mesothelioma cell growth. Imatinib mesylate
(Gleevec ® Novartis Pharmaceuticals), an oral selective inhibitor of tyrosine
kinases associated with receptors like PDGF-receptor, along with PTK787, also
being developed by Novartis, will soon enter clinical trials in mesothelioma
patients.
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