Management of Mesothelioma

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					From Medscape Today
Management of Mesothelioma
Ramaswamy Govindan, MD


Malignant mesothelioma is a locally invasive disease with a dismal outcome and limited treatment
options. Indeed, the median survival of patients treated in 10 consecutive prospective Cancer and
Leukemia Study Group B (CALGB) studies was only 7 months,[1] although more recent data show
that treatment regimens with newer agents, such as the combination of cisplatin and pemetrexed, is
associated with better survival outcomes.[2] Nevertheless, because the incidence of malignant
mesothelioma is expected to peak around 2010 before declining, continued improvements are still

No significant breakthroughs in the systemic therapy of mesothelioma were reported at the 10th
World Conference on Lung Cancer, but a number of interesting preclinical studies were presented
that could lead to improved treatment options.

Systemic Therapy

Single-agent chemotherapy regimens have not shown great promise in the past,[2] so there has been
an attempt to identify active and tolerable combinations. In a multi-institutional phase 2 study of
gemcitabine (1000 mg/m2 on days 1,8, and 15) and carboplatin (AUC 5), 26% of patients had a
partial response, with a median response duration of 55 weeks.[3] Median survival was 66 weeks,
with a 2-year survival rate of 30%. The most common side effects were hematologic, with 11% of
patients experiencing grade 3/4 leukopenia.

Slightly lower response rates were noted with the combination of mitomycin, vinblastine, and
cisplatin (MVP), which was associated with an overall response rate of 15% in 150 patients.[4]
However, 69% of patients reported symptom improvement, and no treatment-related deaths were
seen with the use of MVP chemotherapy. Median survival in this study was 7 months, with a 1-year
survival rate of 31%. In a multivariate analysis, low hemoglobin, weight loss, and nonepithelioid
histology were associated with poor prognosis.

The use of newer agents either singly or in combination with older agents is also being explored.
For example, raltitrexed produced a partial response rate of 21% in patients with malignant
mesothelioma in a prospective EORTC study.[5] However, as noted in the studies conducted by
Pavlakis and colleagues,[6] combination therapy might be slightly more effective than monotherapy.
Preliminary results were reported in 2 parallel nonrandomized phase 2 studies in which patients
received either thalidomide alone or thalidomide in combination with cisplatin and gemcitabine. Of
16 evaluable patients, thalidomide monotherapy resulted in partial response in 1 patient (6%), stable
disease in 8 patients (50%), and progressive disease in 7 patients (44%). By contrast, the
combination of cisplatin, gemcitabine, and thalidomide resulted in 3 partial responses (14%), 12
stable disease (55%), and 7 progressive disease (32%). Thalidomide was well tolerated except for
mild constipation, dry mouth, and paresthesias.

An alternative novel combination studied by investigators from the United Kingdom consisted of
irinotecan (100 mg/m2 days 1 and 15), cisplatin (40 mg/m2 days 1 and 15), and mitomycin C (6
mg/m2 day 1) on a 28-day cycle in patients with previously untreated malignant mesothelioma.[7] Of
43 evaluable patients, partial responses were seen in 15 patients (43%) and stable disease was noted
in an additional 23 patients (53%), with progression-free survival and overall survival of 6.5 months
and 10.1 months, respectively. The most common toxicities were hematologic, with 25 patients
experiencing grade 3 or 4 neutropenia. Of note, when the same regimen was tested in a group of
previously treated patients with malignant mesothelioma, partial responses were seen in 3 of 10
evaluable patients. Vinorelbine was the most commonly used therapy in the first-line setting in
these patients.[8]

Symptom Improvement

Results of a phase 3 trial published earlier this year[2] showed that the addition of pemetrexed to
cisplatin improves survival in patients with malignant mesothelioma compared with cisplatin alone
(median survival 12.1 months vs 9.3 months). As a follow-up to the survival data, Boyer and
colleagues[9] reported the results of health-related quality of life (QOL) assessments performed in
this study. QOL was evaluated at baseline and on a weekly basis using a modified Lung Cancer
Symptom Scale (LCSS-meso). Nearly 90% of patients completed the LCSS scores.

Results showed that pain scores were significantly improved in the combination chemotherapy arm
beginning with cycle 3 (P < .05 for cycles 3-6). At the same time, dyspnea scores stabilized in the
combination arm while they worsened in the monotherapy arm. Anorexia and fatigue worsened in
both arms at the beginning, but there was an improvement in fatigue scores in the combination
chemotherapy arm by cycle 6 (P = .039). While there was progressive decline in global QOL up to
cycle 3 in both arms, there was an improvement in the global scores by cycle 6 in the combination
chemotherapy arm.

Thus, the combination of cisplatin and pemetrexed appears to improve QOL in patients with
malignant mesothelioma. In addition, the combination chemotherapy used in this study improved
pulmonary function tests compared with single-agent cisplatin therapy.[10]

Combined-Modality Therapy

The preliminary results of a neoadjuvant therapy from the Swiss Group for Clinical Cancer
Research (SAKK) were reported at this meeting.[11] Patients with potentially resectable malignant
mesothelioma were enrolled in order to assess resectability rates and to evaluate the toxicity of
combined-modality therapy. Patients underwent preoperative mediastinoscopy to rule out N2
disease, but any histologic subtype of malignant mesothelioma was allowed. Patients received 3
cycles of cisplatin (80 mg/m2 on day 1) and gemcitabine (1000 mg/m2 on days 1, 8, and 15)
administered every 28 days. Preoperative therapy was well tolerated, with no grade 4 toxicities
noted. Of 30 evaluable patients, 24 underwent surgery and 22 underwent pleuropneumonectomy,
for a resectability rate of 73%. No pathologic complete responses were seen in any patients. The
most common postoperative complication was atrial arrhythmia, with 1 death in the immediate
postoperative period attributed to respiratory failure. The investigators concluded that induction
chemotherapy was well tolerated in patients with potentially resectable mesothelioma.

Molecular Biology Considerations

Manganese-containing superoxide dismutase (MnSOD), a primary antioxidant enzyme, plays a key
role in detoxification of superoxide radicals and protects tissue from free-radical damage. The
formation of superoxide radicals is considered to be important in asbestos-induced carcinogenesis.
A major genetic polymorphism of the MnSOD gene (MnSOD Ala9Val) could interfere with the
mitochondrial transport of this enzyme and its anti oxidant properties. Of note, in a preliminary
report from Australian investigators, there were significant differences in allelic frequencies
between those with pleural plaque only and those with malignant mesothelioma.[12]
TNF-related apoptosis-inducing ligand (TRAIL) selectively induces programmed cell death in
various cancer cell lines. TRAIL binds to 2 proapoptotic (DR4 and DR5) and antiapoptotic (DcR1
and DcR2) receptors. Aberrant methylation of DcR1 was demonstrated in 44 of 66 samples of
malignant mesothelioma (66%) and aberrant methylation of DcR2 was noted in 39% of primary
mesotheliomas.[13] No significant methylation was found in normal tissues. Of note, treatment with
5-aza-2-L-deoxycytidine restored DcR1 and DcR2 expression.

The methylthioadenosine phosphorylase (MTAP) gene is homozygously co-deleted with CDKN2A
in pleural mesothelioma.[14] MTAP encodes an enzyme that is essential in the salvage of cellular
adenine and methionine and is co-deleted with CDKN2A (encoding the p16 protein). In 2 separate
fluorescent in situ hybridization (FISH) assays performed in frozen tissue from 58 cases of pleural
mesothelioma, investigators from Memorial Sloan-Kettering Cancer Center in New York, NY,
reported homozygous co-deletion of CDKN2A in 39 cases (67%). MTAP co-deletion was
demonstrated in 87% of those who had deletion of CDKN2A, and no case of MTAP deletion was
found in those without CDKN2A deletion. A novel immunohistochemistry method revealed very
strong correlation with FISH analysis. This development is significant, as MTAP represents a
potential target for therapy.

It has been shown that loss of heterozygosity of tumor suppressor genes, such as NF2, p16INK4A,
and TP53, is common in malignant mesothelioma, and the development of mesothelioma in NF2
knockout mice further enforces this concept.[15] Kratzke and colleagues[16] previously reported that
loss of p16 INK4a is the most common molecular lesion in malignant mesothelioma. Re-expression
of p16INK4a using a first-generation adenovirus gene therapy resulted in cell-cycle arrest,
apoptosis, and tumor regression in xenograft models. This group of investigators also observed cell
death in treated mesothelioma cell lines using synthetic TATp16INK4a, while the control peptide
had no effect. Further studies examining this approach in mesothelioma xenograft models in mice
are ongoing.

Prognostic and Predictive Markers

In order to better identify patients who will respond to therapy and to improve outcomes overall,
researchers have attempted to identify prognostic and predictive markers in patients with malignant
mesothelioma. Hypoxia-inducible factor 1 alpha (HIF-1a) is a subunit of a heterodimeric
transcription complex that regulates a number of genes associated with tumor proliferation and
inhibition of apoptosis. Expression of HIF-1a was seen 79% of mesothelioma specimens and a third
of these patients had intense expression of HIF-1a, but none of the specimens from the normal
mesothelium expressed HIF-1a. Unfortunately, no correlation was seen between HIF-1a expression
and response to chemotherapy or survival.[17]

Because mesothelioma is classically seen as a tumor that does not respond well to systemic
chemotherapies, Italian investigators sought to identify key genetic factors that might help predict
which patients would respond more favorably.[18] They theorized that overexpression of thymidylate
synthase (TS) mRNA, the primary target for the antifolate pemetrexed, might correlate with
resistance to pemetrexed, and that overexpression of nucleotide excision repair genes, such as
ERCC1, might be associated with resistance to the cytotoxic agent cisplatin. After studying the TS
and ERCC1 expression profiles in 38 paraffin-embedded specimens, they found that more than 50%
of samples had low levels of TS expression and low to medium levels of ERCC1 expression, and
that median mRNA expression levels did not differ significantly between the epithelial and
nonepithelial types. An arbitrary cut-off value of 8 for ERCC1 was associated with trend toward
better survival (437 days vs 318 days, P = .2), suggesting that ERCC1 expression might show a
small predictive value.
Focusing more on clinical factors, a number of research groups have been able to identify a few
markers that help predict better outcomes.

A 20-year cohort of 553 patients with malignant mesothelioma was analyzed for factors that could
predict survival.[19] The mean survival of the cohort was only 8 months (range, 1 month-11 years),
with only 3 patients surviving longer than 5 years. The 2 most important prognostic factors favoring
better survival were young age and epithelioid subtype.

The EORTC had previously reported a prognostic model based on age, sex, histology, and white
blood cell count. This prognostic model was tested in 3 consecutive prospective phase 2 studies
conducted by EORTC, and validated the model by finding trends toward worse survival associated
with a prognostic score of > 1.27.[20] Of note, in a retrospective analysis, Rusch and colleagues[21]
reported that postoperative adjuvant therapy (radiotherapy or chemotherapy) had a favorable impact
on survival apart from other known prognostic markers, such as stage and histology. Other clinical
factors that might play a role in survival outcomes include QOL parameters. Gralla and
colleagues[22] presented data from the randomized study of cisplatin with or without pemetrexed,[2]
showing that baseline QOL parameters can predict time to disease progression and survival.


   1. Herndon JE, Green MR, Chahinian AP, Corson JM, Suzuki Y, Vogelzang NJ. Factors
       predictive of survival among 337 patients with mesothelioma treated between 1984 and
       1994 by the Cancer and Leukemia Group B. Chest. 1998;113:723-731. Abstract
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14. Illei PB, Leoni L, Huang W, et al. The methylthioadenosine phosphorylase (MTAP) gene is
    homozygously co-deleted with CDKN2A in most pleural mesotheliomas: detection by
    fluorescent in situ hybridization (FISH) and by immunohistochemistry (IHC) using a novel
    MTAP monoclonal antibody. Lung Cancer. 2003;41(suppl 2):S12. Abstract O-29.
15. Jongsma J, van Montfort E, Zevenhoven J, et al. Compound Nf2 (p53, Ink4a, Rb)
    conditional knockout mice develop malignant mesotheliomas. Lung Cancer. 2003;41(suppl
    2):S60. Abstract O-204.
16. Frizelle SP, Tricker EM, Kratzke MG, Niehans GA, Kratzke RA. Gene therapy of
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17. Fennell DA, Klabatsa A, Sheaff M, et al. Expression and prognostic significance of
    hypoxia-inducible factor 1 alpha in malignant pleural mesothelioma. Lung Cancer.
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21. Rusch VW, Venkatraman E, Rosenzweig KE, Krug LM. Adjuvant therapy, stage and tumor
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22. Gralla RJ, Symanowski JT, Liepa AM, et al. Can baseline quality of life parameters predict
    survival and other efficacy outcomes in malignant pleural mesothelioma? Results from a
    448-patient phase III trial. Lung Cancer. 2003;41(suppl 2):S220. Abstract P-514.