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Update on Malignant Mesothelioma
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Update on Malignant Mesothelioma
Review Article [1] | September 01, 2005
By Karen Antman, MD [2], Raffit Hassan, MD [3], Milton Eisner, PhD [4], Lynn A. G. Ries, MS [5], and
Brenda K. Edwards, PhD [6]
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]
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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
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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]
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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
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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 contrastenhanced 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
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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.
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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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Mesothelioma
of the Tunica Vaginalis Testis
Men typically present with scrotal masses that include a hydrocele. Age at diagnosis varies widely.
Staging should include CT of the chest and abdomen, as disease is frequently found
intra-abdominally. The optimal primary surgical approach appears to be inguinal orchiectomy.
Intra-abdominal disease found at diagnostic laparotomy may be effectively treated by surgery or
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abdominal radiotherapy. Testicular mesotheliomas are frequently indolent with a long interval from
initial treatment to clinical recurrence. Testicular mesotheliomas have responded to chemotherapy
reported to be effective for pleural and peritoneal primaries.[56] Systemic Treatment
Randomized Trials
Two recent randomized trials (Table 2) have both demonstrated significantly higher response rates
for the addition of newer antifols to cisplatin therapy. Eligibility was confined to pleural
mesotheliomas. Survival was significantly improved in one study,[45] with a trend in the other.[46]
In another randomized trial of ranpirnase (Onconase) vs doxorubicin, ranpirinase produced similar
survival to that associated with doxorubicin; however, whether doxorubicin improves survival over
best supportive care is unknown.[47] Thus, based on a survival advantage in one randomized trial
and a trend in a smaller European trial (Table 2), and a significantly increased response rate in both
trials, the combination of cisplatin and pemetrexed (Alimta), or possibly cisplatin and raltitrexed
(Tomudex), would be an appropriate initial palliative regimen for patients with pleural mesothelioma.
Phase I/II Trials
Reported response rates for single chemotherapy agents prior to the advent of CT scanning were up
to 30% for methotrexate, cyclophosphamide, and doxorubicin; however, using CT scan
measurements, response rates were considerably lower (10%-15%). Certainly platinum and antifol
combinations again appear to be effective based on response data. Platinum and gemcitabine
(Gemzar) regimens are also associated with reasonable response rates. Raltitrexed or weekly
vinorelbine, with reported response rates of 21% and 24%, respectively, provide attractive singleagent regimens.[57,58] Some biologics, particularly those delivered intrapleurally, also provide
reasonable reported response rates.[59-62] Interferon alfa and gamma (Actimmune) have resulted in
respectable response rates, particularly when delivered intrapleurally. Gemcitabine, temozolomide
(Temodar), liposomal doxorubicin (Doxil), and topotecan (Hycamtin) produce response rates in the
single digits. Future Directions in Systemic Treatment
Potential targets in mesothelioma include platelet-derived growth factor (PDGF)-A and -B, vascular
endothelial growth factor (VEGF), p53 mutations, mesothelin, and epidermal growth factor receptor
(EGFR); therefore, evaluating targeted therapies in mesothelioma is totally appropriate.[ 63-65]
Mesothelin, a cell surface glycoprotein present on normal mesothelial cells, is overexpressed in the
majority of epithelial mesotheliomas.[ 66] SS1(dsFv)PE38 (SS1P) is a recombinant antimesothelin
immunotoxin that is currently undergoing phase I clinical evaluation at the National Institutes of
Health.[67] Tumor Markers No reliable serum tumor markers are available for screening or
diagnosis of mesothelioma or to monitor response to treatment. However, soluble mesothelinrelated proteins could be a useful marker. Of 44 patients with mesothelioma in Perth, Australia, 37
(84%) had elevated serum-soluble mesothelin- related protein levels, compared with 3 (2%) of 160
patients with other cancers or other inflammatory lung or pleural diseases, and with none of 28
controls. Soluble mesothelinrelated protein levels correlated with tumor size and disease
progression. Seven of 40 asbestos-exposed participants had increased concentrations of soluble
mesothelin-related proteins. Of these, three developed mesothelioma and one developed lung
cancer within 5 years.[68] Thus, soluble mesothelinrelated proteins could potentially be developed to
screen asbestos-exposed individuals for mesothelioma. Quality of Life In a University of Sydney
study, 53 patients treated with cisplatin and gemcitabine completed quality-of-life studies. At
baseline, role and social function were impaired and symptoms included cough, fatigue, dyspnea,
pain, insomnia, and anorexia. Dyspnea, pain, insomnia, and cough improved with chemotherapy,
although chemotherapy- related symptoms increased.[69] Dyspnea scores correlated strongly with
measured forced vital capacity.[69] Conclusions In summary, the median survival after a diagnosis
of mesothelioma is short and has not changed over the past 2 decades for which statistics are
available. Available treatments offer modestly improved survival, with few long-term disease-free
survivors. Welldesigned clinical trials are essential.
Disclosures:
The authors have no significant financial interest or other relationship with the manufacturers of any
products or providers of any service mentioned in this article.
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Source URL: http://www.diagnosticimaging.com/update-malignant-mesothelioma
Links:
[1] http://www.diagnosticimaging.com/review-article
[2] http://www.diagnosticimaging.com/authors/karen-antman-md
[3] http://www.diagnosticimaging.com/authors/raffit-hassan-md
[4] http://www.diagnosticimaging.com/authors/milton-eisner-phd
[5] http://www.diagnosticimaging.com/authors/lynn-g-ries-ms
[6] http://www.diagnosticimaging.com/authors/brenda-k-edwards-phd
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