AP Chahinian

CG Moertel

H. Richard Alexander

HR Alexander

K Antman

M Borow

MK Samson

R Govindan

R Hassan

English

PubMed

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Surgical Treatment of Malignant Peritoneal Mesothelioma: Past, Present, and Future

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EDITORIAL
Surgical Treatment of Malignant Peritoneal Mesothelioma:
Past, Present, and Future
H. Richard Alexander Jr., MD
Department of Surgery, University of Maryland, School of Medicine, Baltimore, MD
Malignant peritoneal mesothelioma (MPM) is a rare
malignancy that arises from the serosal membranes of the
abdominal cavity. In 1972, Moertel published a paper
characterizing the clinical course of patients afflicted with
MPM and the now recognized clinical features associated
with tumor progression within the abdominal cavity.1 Bo-
row first reported the association between asbestos
exposure and mesothelioma that same year.2 Despite the
current recognition that MPM is a distinct entity from its
pleural variant, progress in the treatment of patients
afflicted with MPM has been hampered by several factors.
First, it is an extraordinarily rare condition: only 10–15%
of all patients with mesothelioma present with the perito-
neal form of the disease, and this translates into
approximately 300–400 cases in the USA annually. As a
consequence, throughout the last two decades many clini-
cal trials testing systemic agents for patients with
malignant mesothelioma did not distinguish between those
with the pleural versus the peritoneal form of disease.3–5
Many of these trials included a small number of patients
with MPM and for whom no confident conclusions
regarding efficacy of the experimental regimen could be
made. It is now becoming increasingly recognized that
patients with MPM have a distinct disease for which spe-
cific therapies should be developed.
Another significant feature of MPM that has challenged
our ability to understand the contribution of various thera-
peutic interventions to patient outcome is the remarkable
variability in the biology of this condition. In 1973,
Rogoff and colleagues reported outcomes in four patients
treated at Memorial Sloan–Kettering Cancer Center in New
York using surgical cytoreduction and whole-abdominal
radiotherapy.6 Two of the four patients survived longer than
5 years. Antman and colleagues reported outcomes of 37
patients with MPM treated at the Dana Farber Cancer
Institute and the Brigham and Women’s Hospital between
1965 and 1984 and also noted that, while some patients
progressed and succumbed rapidly, others survived for
many years after treatment.7 In their series, patients treated
after 1982 underwent cytoreduction, placement of an intra-
peritoneal (IP) catheter, and received between 8–10 cycles
of IP doxorubicin and cisplatin. Subsequent to that 30 Gy of
whole-abdominal radiation was administered. In their
analysis, patients with smaller tumor burden and female
gender had prolonged survival; those with epithelioid
tumors did poorly compared with those with other histopa-
thological types. Since that initial description, the use of
multimodal therapy using cytoreduction with some form of
high-dose regional chemotherapy has become increasingly
utilized.
Because MPM progresses almost exclusively in the
abdominal cavity, locoregional therapies designed to con-
trol disease progression in the abdomen appear justified.
Cytoreduction and hyperthermic intraoperative intraperito-
neal perfusion with chemotherapy (HIPEC) takes advantage
of two complementary treatments. Cytoreduction has the
goal of achieving a complete resection of all grossly iden-
tifiable tumor, and high-dose chemotherapy is intended to
treat the micrometastatic residual sites of disease. The use
of HIPEC has the theoretical advantage of being the most
effective way of uniformly distributing high-dose IP che-
motherapy to all of the peritoneal surfaces at risk of
harboring disease and allows one to apply chemotherapy
with clinically relevant amounts of hyperthermia, which is
known to enhance the cytotoxic effects of multiple different
types of chemotherapeutic agents. Outcomes using this
strategy in selected patients with a disease burden amenable
to resection and with a good performance status have been
the topic of numerous reports. They show that patient
 Society of Surgical Oncology 2009
Published Online: 4 November 2009
H. R. Alexander Jr., MD
e-mail: HRAlexander@smail.umaryland.edu
Ann Surg Oncol (2010) 17:21–22
DOI 10.1245/s10434-009-0763-3
outcome after this therapy is variable and that treatment is
associated with some morbidity and occasional mortality.8
Therefore, identification of prognostic factors that could aid
in patient selection and treatment planning are of increasing
importance.
In this issue, Dr. Baratti and colleagues analyze the
significance of lymph node metastases as a possible inde-
pendent prognostic factor associated with outcome in
patients undergoing cytoreduction and HIPEC for MPM.9
Their data suggest that the overall frequency of lymph node
metastases is low; in a group of 15 patients whose nodes
were routinely sampled the overall frequency of nodal
metastases was 20%, compared with 40% in a cohort
whose lymph nodes appeared to be pathological enlarged
and suspicious. In the overall series of 83 patients, they
identified epithelioid histology, low mitotic count, com-
plete gross cytoreduction, and pathologically negative
nodes as independent factors associated with increased
survival. It is not clear from the paper whether or not the
lymph node metastases were a consequence of advanced
tumor burden versus tumor biology. There was a notable
association between a higher peritoneal cancer index, a
reflection of tumor burden within the peritoneal cavity, and
node positivity, suggesting that nodal metastases may
simply have been the consequence of extensive tumor
burden within the peritoneal tissues. It is noteworthy that
no patient with lymph node metastases developed recur-
rences in nodal basins on follow-up.
The challenge for us now is to understand how to use
this information to assist us in the management of patients
with MPM. There are a number of factors that have been
consistently recognized as important in predicting better
outcome in patients undergoing cytoreduction and HIPEC
such as age, histology, and the ability to achieve a com-
plete gross cytoreduction. Whether or not nodal status can
now be used routinely to predict better outcome in cases of
pathological negative nodes or indicate a high risk of early
recurrence and disease progression in cases of pathological
positive nodes needs to be validated in additional studies.
Ultimately, the understanding of this disease’s clinical
behavior may best be determined by a better understanding
of its molecular biology.
The authors are from the National Cancer Institute of
Italy and are acknowledged leaders in the treatment of
MPM. It is remarkable that, at a world-recognized center of
expertise in this area, the number of patients reported with
diffuse MPM over a 13-year interval was only 83. Their
volume of patients with this condition compares similarly
to other centers around the world with acknowledged
expertise in treating this condition. For us to make mean-
ingful advances in the treatment of this condition we must
now move from reporting institutional experiences to more
collective and cooperative efforts in the study of this rare
disease.
REFERENCES
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346–50.
2. Borow M, Conston A, Livornese LL, et al. Mesothelioma and its
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3. Samson MK, Wasser LP, Borden EC, et al. Randomized compar-
ison of cyclophosphamide, imidazole carboxamide, and adriamycin
versus cyclophosphamide and adriamycin in patients with
advanced stage malignant mesothelioma: a Sarcoma Intergroup
Study. J Clin Oncol. 1987;5:86–91.
4. Chahinian AP, Antman K, Goutsou M, et al. Randomized phase II
trial of cisplatin with mitomycin or doxorubicin for malignant
mesothelioma by the Cancer and Leukemia Group B. J Clin Oncol.
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5. Govindan R, Kratzke RA, Herndon JE, et al. Gefitinib in patients
with malignant mesothelioma: a phase II study by the Cancer and
Leukemia Group B. Clin Cancer Res. 2005;11:2300–4.
6. Hassan R, Remaley AT, Sampson ML, et al. Detection and
quantitation of serum mesothelin, a tumor marker for patients with
mesothelioma and ovarian cancer. Clin Cancer Res. 2006;12:447–53.
7. Antman K, Osteen R, Klegar K, et al. Early peritoneal mesothe-
lioma: a treatable malignancy. Lancet. 1985;2:977–81.
8. Alexander HR, Hanna N, Pingpank JF. Clinical results of
cytoreduction and HIPEC for malignant peritoneal mesothelioma.
Cancer Treat Res. 2007;134:343–55.
9. Baratti D, Kusamura S, Cabras AD, Laterza B, Balestra MR,
Deraco M. Lymph-node metastases in diffuse malignant peritoneal
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22 H. R. Alexander


Clinical results of cytoreduction and HIPEC for malignant peritoneal mesothelioma. Cancer Treat Res.

Detection and quantitation of serum mesothelin, a tumor marker for patients with mesotheliomaandovariancancer.ClinCancerRes.2006;12:447–53.

Early peritoneal mesothelioma: a treatable malignancy.

Geﬁtinib in patients with malignant mesothelioma: a phase II study by the Cancer and Leukemia Group B. Clin Cancer Res.

Lymph-node metastases in diffuse malignant peritoneal mesothelioma. Ann Surg Oncol.

Mesothelioma and its association with asbestosis.

Peritoneal mesothelioma.

Randomized comparison of cyclophosphamide, imidazole carboxamide, and adriamycin versus cyclophosphamide and adriamycin in patients with advanced stage malignant mesothelioma: a Sarcoma Intergroup Study. J Clin Oncol.

Randomized phase II trial of cisplatin with mitomycin or doxorubicin for malignant mesothelioma by the Cancer and Leukemia Group B. J Clin Oncol.

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Surgical Treatment of Malignant Peritoneal Mesothelioma: Past, Present, and Future

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