The article by Drs. Grondin and Sugarbaker discussing the
clinical management of malignant pleural mesothelioma provides an
excellent overview but also highlights many of the controversies
surrounding the diagnosis and treatment of this difficult disease.
The natural history of mesothelioma, role of surgery and of
multimodality therapy, best algorithm for preoperative staging, and,
indeed, the system used for staging are all still subject to debate.
Several points in this article warrant discussion.
The natural history of malignant mesothelioma is important because it
provides insights into the development of treatment strategies for
this disease. Grondin and Sugarbaker correctly describe the initial
clinical presentation as variable in symptoms and duration, and
disease progression as initially being local. However, the importance
of systemic disease has been underemphasized. At least half of all
patients have distant metastatic disease at autopsy, and systemic
disease is the most common form of relapse in patients who have
achieved local control of their disease via extrapleural pneumonectomy.
It is not clear whether aggressive local therapy promotes the
development of systemic metastases through some undefined mechanism,
or whether good local control merely highlights the problem of
systemic disease. Nonetheless, distant metastases are a major problem
in the treatment of mesothelioma and must be considered in the
development of future therapies.
Optimal Preoperative Staging Algorithm
The optimal algorithm for preoperative staging is also debated.
Grondin and Sugarbaker suggest that magnetic resonance imaging (MRI)
should be a standard part of the staging evaluation. However, at
least one prospective trial has failed to confirm the benefit of
doing MRI routinely in addition to computed tomography (CT).
On the other hand, laparoscopy is probably the best way to determine
whether or not disease extends through the diaphragm in cases in
which CT is equivocal. Although mesotheliomas show increased uptake
on positron emission tomography (PET), the role of PET scanning in
staging this disease remains undefined.
As the authors point out, the decreasing mortality associated with
extrapleural pneumonectomy is related to surgical expertise and to
careful preoperative assessment of the patient. Patients with
mesothelioma tend to be older (median age of 55 years in most series)
and often have underlying pulmonary and cardiovascular disease. The
hemodynamic stress and risk of supraventricular arrhythmias after
extrapleural pneumonectomy are greater than after any other type of
In addition to the evaluation described by Grondin and Sugarbaker,
routine measurement of the diffusion capacity is mandatory when
pulmonary function tests are performed because mesothelioma patients
often have significant underlying interstitial lung disease in the
face of relatively well-preserved lung volumes or spirometry. A
quantitative ventilation perfusion scan is also mandatory for
determining whether the patient has adequate pulmonary reserve. It is
usually wise to subject the patient to a pharmacologic stress test to
make certain that there is no evidence of clinically silent
myocardial ischemia before performing an extrapleural pneumonectomy.
The staging system for malignant pleural mesothelioma remains
controversial. The system proposed by the Brigham group differs
somewhat from that developed by the International Mesothelioma
Interest Group (IMIG). However, the latter system supercedes all
previously proposed staging systems (of which there were at least
six) because it was developed as a result of an international
consensus conference on the staging of this disease.
Without doubt, both the IMIG and Brigham staging systems will need to
be reexamined as further data on the natural history of this disease
accumulate. Such data usually derive from meticulous staging and
follow-up in surgical series, not from prospective, multicenter,
randomized trials, as Grondin and Sugarbaker suggest.
Role of Chemotherapy
Chemotherapy has thus far had disappointing results in the treatment
of malignant pleural mesothelioma. Grondin and Sugarbaker discuss the
use of adjuvant paclitaxel (Taxol) and carboplatin (Paraplatin), and
the Brigham group has previously used CAP (cyclophosphamide,
Adriamycin, and Platinol) chemotherapy. However, multiple phase II
trials suggest that all currently available chemotherapeutic agents,
whether given alone or in combination, produce only a 20% to 25%
response rate in patients with locally advanced disease.
Paclitaxel, in particular, has not been considered to be an active
drug. However, this does not mean that chemotherapy does not deserve
Because of the importance of systemic disease, particularly in
patients who have achieved local control after extrapleural
pneumonectomy and radiation, there is clearly a need for effective
chemotherapy. In the United States, most patients present to surgeons
when they have stage III disease. The use of surgical resection and
radiation probably is of limited benefit in such patients.
Chemotherapy, given either preoperatively or adjuvantly, does need to
be tested further but must still be considered investigational. Its
benefit cannot be assumed at present.
Finally, Grondin and Sugarbaker describe some of the preliminary
efforts in gene therapy for malignant mesothelioma. The association
between SV-40 virus and malignant mesothelioma is now well
documented, but the precise etiologic mechanism has not been
elucidated. Whether the link to SV-40 could ever be the basis of
vaccine therapy is entirely speculative.
Grondin and Sugarbaker are to be congratulated for their efforts in
treating this disease, which is often viewed with complete nihilism
by the thoracic oncology community at large. The differences in
opinion and experience discussed above emphasize the importance of
centers with expertise in this disease continuing to conduct careful
prospective trials to evaluate the staging and treatment of malignant
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