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of this tumor has been rising in our country since 1980,
Multimodality Management of which may be reflective of the 20- to 40-year latency
Malignant Pleural asbestos exposure and disease presenta¬
period betweenenvironmental
Mesothelioma* tion. Previous legislation curbing asbestos
use will not influence the disease incidence until the next
David J. Sugarbaker, MD, FCCP; and Jose J. Norberto, MD century. The aggressive behavior of the tumor is reflected
in the median survival of 4 to 12 months in untreated
In this article, explain the current trimodality
we patients.56
Three major histologic types of MPM have been de¬
approach used to treat malignant pleural mesotheli¬ scribed: epithelial, sarcomatous, and mixed. The epithelial
oma. Our current approach employs extrapleural
type has been equated with better patient prognosis.7
pneumonectomy as the cytoreductive procedure fol¬ The clinical presentation of MPM is varied and depends
lowed by combination chemoradiotherapy. Trimo¬ on the stage of disease. Men between 50 and 60 years of
dality therapy was performed at the Dana-Farber age are most often stricken. Most patients (80%) present
Cancer Institute/Brigham and Women's Hospital with dyspnea secondary to a pleural effusion; cough (60%
Thoracic Oncology Program. From 1980 to 1995, we of patients), chest pain (40%), and weight loss are also
prospectively followed up a series of 120 patients common symptoms. In late stages, the disease may cause
with confirmed malignant pleural mesothelioma who chest wall deformity, abdominal mass with or without
underwent trimodality therapy. Two- and 5-year bowel obstruction (30%), ascites, and cachexia. In most
survival rates for the entire cohort were 45% and cases, the patient ultimately dies from the mechanical
22%, respectively. Survival rates were 65% and 27%, effect of the invasive tumor on vital organs (heart and
respectively, at 2 and 5 years for patients with lungs).
epithelial histology. Patients with sarcomatous or The radiologic workup of the patient suspected of
mixed histology had the poorest prognosis, with 2- having MPMCT includes chest radiograph (posterior-anterior
and 5-year survival rates of 20% and 0%, respec¬ and lateral), scanning, and, more recently, MRI of the
tively. For patients with2epithelial tumors and nega¬ chest and upper abdomen. The usual finding is pleural
tive nodes, survival at and 5 years was 74% and effusion with or without pleural calcifications. The com¬
39%, respectively. Extrapleural pneumonectomy in bination of chest CT scan and chest MRI has increased
the context of trimodality therapy is a potential our ability to detect mediastinal and transdiaphragmatic
surgical option for a selected group of patients with tumor invasion, which are signs of unresectable disease.8
malignant pleural mesothelioma. The histopathologic diagnosis can be difficult, especially in
(CHEST 1998; 113:61S-65S) differentiating MPM from adenocarcinoma. During thefluid ini¬
tial evaluation, thoracentesis may reveal yellow pleural
that is different from the sanguineous effusion frequently
\M alignant pleural mesothelioma (MPM) is an uncom- seen with adenocarcinoma. Although the cytologic diagnosis
1T A mon tumor of the chest. of mesothelioma is possible, most often a pleural biopsy
Typically, there is pernicious
local invasion of the pleural space and surrounding organs. specimen is necessary7 to confirm the diagnosis. Although
Previous studies have shown the strong association be¬ pleural biopsy specimens have been obtained using a closed
tween exposure to asbestos, in particular the amphibole technique, the thoracoscopic technique is preferred as it
type, and the development of this malignancy.1 The provides more reliable tumor specimens. and mucicar-
geometry of amphibole asbestos enables it to traverse the Histologic staining (periodic acid-Schiff
respiratory tree and lodge in the subpleural space, where mine) is a useful tool to differentiate MPM from adeno¬
carcinogenesis occurs. carcinoma, yielding negative results in patients with MPM.
The potential link between simian vacuolating virus 40 MPM is usually diagnosed with certain immunostaining
(SV40) and certain types of cancers, including mesotheli¬ techniques (vimentin and cytokeratin), which alsomicro¬ help
oma and brain tumors, has recently been reported. In differentiate it from adenocarcinoma. The electron
1994, Carbone et al2 reported fragments of SV40 in 60% scope can definitely differentiate the two diseases.9
of mesotheliomas. It is epidemiologically disconcerting Our ability to evaluate the results of therapy for MPM
that SV40 may have been given to millions of children who has been hindered by several factors: the lack of a standard
received polio vaccines in the 1950s and 1960s. The staging system, the relative rarity of MPM, the unknown
impact of SV40-infected patients on the incidence of biological behavior oftreatment modalities.lack of random¬
ized trials of current
this tumor, and the
pleural to three thousand new to be of mesothelioma are
Two
mesotheliomas has yet
cases
seen.
An accurate staging system should be able to stratify
reported each year in the United States.35 The incidence survival, predict prognosis according to pathology, guide
treatment, and evaluate the success of that treatment. The
*From the Division of Thoracic Surgery (Drs. Sugarbaker and current staging systems for MPM have not shown a
Norberto), Brigham and Women's Hospital, Division of Surgical correlation between stage and survival. The staging system
Services (Dr. Sugarbaker), Dana-Farber Cancer Institute, and of Butchart et al,10 currently the most widely used, de¬
Harvard Medical School (Dr. Sugarbaker), Boston. fines tumor location but does not specify tumor burden
Reprint requests: David J. and Women'sMD, FCCP, Division of
Sugarbaker, (Table 1).
Thoracic Surgery, Brigham Hospital, 75 Francis St,
Boston, MA 02115 The International Union Against Cancer proposed a
CHEST/113/1 /JANUARY, 1998 SUPPLEMENT 61S
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1998 by the American College of Chest Physicians
Table 1.The Butchart Staging System* 1.00-
Stage Definition
I Tumor contained within capsule of the parietal pleura:
ipsilateral pleura, lung, pericardium, diaphragm
II Tumor invades chest wall or mediastinum: esophagus,
heart, opposite pleura
Positive chest lymph nodes
III Tumor invasion through diaphragm to peritoneum;
opposite pleura
Positive lymph nodes outside chest
IV Distant blood-borne metastases
*
Adapted from Butchart et al.
Figure 1. Kaplan-Meier survival curve in a series of 120 patients
with mesothelioma demonstrates a significant stratification of
survival when all patients are classified as having stage I, II, or III
TNM (tumor, node, metastasis) staging system based on proposed
according to the et at.13 Brigham staging system. Reprinted
the more traditionally used TNM categories.11 However, from Sugarbaker
the clinical T category frequently underestimates the
pathologic extent of MPM tumors, and the N category is
the same as that for the lung cancer staging system,
despite the fact that the pattern of lymphatic nodal
combination chemotherapy using cyclophosphamide,
involvement of MPM is unknown. Furthermore, this doxorubicin, and cisplatin (CAP) produced a 20 to 30%
response rate, yet had no effect on long-term survival.5
system has not been validated in terms of survival based on Radiotherapy by itself has also been ineffective in improv¬
stage. ing survival but has produced mild to moderate palliation
Previously, we proposed a staging system for MPM12 in in some series.16
which subgroups of Butchart stages II and III are com¬
bined into stage III. This system is also based on resect¬ Multimodality Management
ability, histology of the tumor, and node status (Table 2).12 The current multimodality approach to the treatment of
Our staging system, based initially on the survival of 52
patients, subsequently stratified the survival of 120 pa¬ MPM employs cytoreductive surgety followed by chemo¬
tients. We believe this may be the only system prospec¬ therapy and radiotherapy. The theoretical basis for this
tively validated based on survival (Fig l).13 approach is that debulking the tumor mass maximizes the
The therapeutic approach to MPM has gone from effectiveness of chemotherapy and radiotherapy.13 Pleu-
single-modality to bi-modality and, more recently, to rectomy/decortication and extrapleural pneumonectomy
are the two cytoreductive operations used for MPM.
multimodality management. Single-modality and bi-mo¬ Patients with MPM undergoing pleurectomy/decortica-
dality therapy have not been effective in improving sur¬ tion in a multimodality setting have achieved median
vival. Early series investigating surgery as a single-modality
therapy10,14-15 reported significant palliation but no impact survivals ranging between 9 and 17 months with an
on long-term survival. operative mortality rate in the range of 1.5 to 5.4%.1718
Single-modality chemotherapy has had no impact on The disadvantage of this procedure relates to its limited
survival and provided poor palliation. More recently, cytoreduction, especially when the tumor invades the
fissures; it is further limited by the amount of postopera¬
tive radiotherapy that can be delivered without the pa¬
tients developing radiation pneumonitis. An increased
Table 2.The Brigham Staging System* recurrence rate has also been observed.19
Stage Definition Initially employed as a surgical treatment for tubercu¬
lous empyema,20'22 extrapleural pneumonectomy (EPP) is
I Disease confined to within capsule of parietal currently used as a debulking procedure in multimodality
pleura: ipsilateral pleura, lung, pericardium, therapy for MPM, making possible the delivery of higher
diaphragm, or chest wall disease limited to doses of postoperative radiation. Our 1996 report demon¬
previous biopsy sites strated a rise in median survival (21 months) and a lowered
II All of stage I with positive intrathoracic (Nl or N2)
lymph nodes operative mortality rate (5%) compared with previous
III Local extension of disease into chest wall or series.13 The disadvantage of EPP is the requirement that
mediastinum, heart, or through diaphragm and the patient be able to tolerate a pneumonectomy.
peritoneum; with or without extrathoracic or The surgical steps in an EPP include posterolateral
contralateral (N3) lymph node involvement
IVDistant metastatic disease
thoracotomy incision, exposure of parietal pleura, dissec¬
tion of parietal pleura from the endothoracic fascia,
*Note: Subgroups of Butchart stages II and III are combined into control of pulmonary vessels and main bronchus, removal
stage Stage I represents patients who have resectable disease
III. of the specimen, and reconstruction of the diaphragm and
and
negative nodes. Stage II patients have resectable disease but pericardium. The specimen consists of parietal and vis¬
positive nodes. Reprinted from Sugarbaker et al.12 ceral pleura, lung parenchyma, pericardium, and dia-
62S International Symposium on Thoracic Malignancies
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1998 by the American College of Chest Physicians
phragm. Postoperative patient care involves pain control, 1.00 -
aggressive pulmonary toilet, early ambulation, and careful
fluid management. 15 0.75
>
At the Dana-Farber Cancer Institute/Brigham and
Women's Hospital Oncology Program, patients offered a CO 0.50
trimodality protocol undergo EPP as the cytoreductive
procedure followed by chemotherapy (four to six cycles) 0.25 -
and radiotherapy. Prior to initiating the protocol, patients
are evaluated by a multidisciplinary thoracic oncology
team to assess their resectability, premorbid conditions, 36 48 60
and their physiologic status. Our preoperative/preprotocol Months
evaluation includes complete history and physical exami¬
nation, arterial blood gases, pulmonary function test, Figure 2. Kaplan-Meier survival curve for all patients surviving
ventilation perfusion scan, echocardiogram to assess peri- surgery7 (n=114). Median survival was 21 months. Reprinted
cardial involvement and cardiac function, and CT scan and from Sugarbaker et al.13
MRI of the chest and upper abdomen. Eligibility require¬
ments for aggressive therapy include a positive tissue
diagnosis for mesothelioma, no mediastinal or transdia- respectively (Fig 2),13 with a median survival of 21 months
phragmatic involvement seen on CT <1.5 scan/MRI, Karnofsky (range, 1 to 96 months). Analysis by a multivariate Cox
performance status >70, creatinine mg/dL, ejection proportional hazards model showed lack positive prognos¬
two
fraction >45%, and a predicted postoperative FEVj. >1 L. tic factors: epithelial cell type and of nodal involve¬
Patients begin adjuvant chemotherapy 4 to 6 weeks ment. Patients with sarcomatous or mixed histology tu¬
after surgeiy. Our initial series received four to six cycles mors (n=47) had 2- and 5-year survival rates of 20% and
of CAP chemotherapy (doxorubicin, 50 to 60 mg/m2; 0%, respectively. Patients with pure epithelial cell type
cyclophosphamide, 600 mg/m2; and cisplatin, 70 mg/m2).13 tumors (n=67; 59%) had significantly longer 2- and 5-year
We have recently changed our adjuvant chemotherapy to survival rates (65% and 27%, respectively; Fig 3).13 Pa¬
reduce the myocardial depression associated with CAP tients with negative lymph nodes in the EPP specimen
chemotherapy. Current therapy begins with paclitaxel (n=66) had better survival at 2 and 5 years (50% and 25%,
(200 mg/m2 by continuous IV 3-h infusion) and carbopla¬ respectively) than did the group with positive lymph nodes
tin (at an area under [plasma concentration time] the (n=48), who had survival rates of 35% and 0%, respec¬
curve of 6) for two cycles administered 3 weeks apart.
Radiation therapy is then given with concurrent weekly tively (p=0.02) (Fig 4).13
Nodal status additionally stratified patient survival
paclitaxel, 60 mg/m2. Following radiation therapy, two based on histologic group (Fig 5).13 Thirty-nine of the 67
cycles of paclitaxel and carboplatin are repeated. the patients (58%) with epithelial histologic findings had
External-beam radiotherapy is administered after negative lymph nodes. This particular subgroup had 2- and
chemotherapy. Utilizing linear accelerators (4 to 10 mega- 5-year survival rates of 74% and 39%, respectively. Of the
volts), a dose of approximately 30 Gy is delivered to the remaining 28 patients with epithelial histologic findings
ipsilateral hemithorax and mediastinum, with subsequent and positive lymph nodes, 52% and 10%, respectively,
boosts given to positive margins and areas of previous survived 2 and 5 years (p=0.002) (Fig 5).
bulky disease. The total maximum dose is 50 to 55 Gy. The variables that influenced survival were microscop¬
From 1980 to 1995, 120 consecutive patients (median ically compromised margins, partial-thickness involvement
age, 56 years; range, 31 to 74 years) were enrolled in the of diaphragm and/or pericardium, size of tumor, length of
above treatment protocol.13 Median follow-up was 15
months (range, 2 to 91 months). Symptoms appeared at a
median of 2 months (range, 0.5 to 27 months) before
diagnosis. Chest pain and dyspnea were the initial com¬ 1.00-
plaints in 51% (n=61) and 73% (n=88) ofinpatients,
respectively. Asbestos exposure was reported 78% of
cases (94 patients); 67% of patients (n=80) were current
or former smokers.
Hospital stays averaged 9 days (median) with a range of
5 to 101 days. There were six perioperative deaths: two
due to myocardial infarction, two to pulmonary embolism,
and one each to cardiac herniation and respiratory failure.
At least one major complication was experienced by 12.5%
of patients (n 15), including bleeding (4 patients), respi¬
=
36 48
ratory failure (4 patients), pneumonia (5 patients), dis¬ Months
rupted diaphragmatic patch (1 patient), perforated ulcer Figure 3. Kaplan-Meier survival curve for all patients with
(2 patients), empyema (1 patient), upper GI bleed (1 epithelial tumorsPatients with nonepithelial (sarcomatous or
vs those with
patient), and deep venous thrombosis (3 patients). mixed) tumors. epithelial tumors had a longer
In thisseries, and years
survival at 2 5 was 45 and 22%, survival (p=0.0001). Reprinted from Sugarbaker et al.13
CHEST/113/1 /JANUARY, 1998 SUPPLEMENT 63S
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1998 by the American College of Chest Physicians
1.00 -
transdiaphragmatic invasion. EPP with adjuvant chemo¬
therapy and radiotherapy has been demonstrated to be
safe and effective in this setting.13
In patients with surgically resectable disease, this tri¬
modality approach stratifies survival by cell type and
prognostic factors contained in our revised staging system.
These factors include nodal involvement, histologic type,
and transdiaphragmatic invasion. In our series, the sub¬
group of patients with epithelial histology and negative
36 48 60 lymph nodes had the best prognosis. Irrespective of cell
Months
type or nodal status, full-thickness involvement of the
diaphragm was related to poor prognosis. Evaluation of
this treatment strategy, as well as the revised staging
Figure 4. Kaplan-Meier survival curve for all patientsNode-
with
system, in multi-institutional prospective trials would fa¬
node-positive pathologic specimens. from
node-negative vshad a cilitate surgeons'
negative patients longer survival (p=0.02). Reprinted disease.
abilityto treat patients with resectable
Sugarbaker et al.13
ACKNOWLEDGMENT: The authors thank Mary S. Visciano
and Dr. Michael T. Jaklitsch for editorial assistance.
operation, asbestos exposure, cigarette smoking, gender, References
and age. Full-thickness microscopic diaphragmatic in¬
volvement was related to poorer survival (median, 11 1 Antman KH, Pass HI, DeLaney T, et al. Benign and malig¬
months; n=14) irrespective of histologic type or nodal nant mesothelioma. In: DeVita VT Jr, Hellman S, Rosenberg
status. SA, eds. Cancer: principles and practice of oncology. 4th ed.
In this series of 120 patients, the Brigham staging Philadelphia: JB Lippincott, 1993; 1489-1508
2 Carbone M, Pass HI, Rizzo P, et al. Simian virus 40-like DNA
system predicted survival. Patients categorized as having sequences in human pleural mesothelioma. Oncogene 1994;
stage I disease (n=57) survived a median of 22 months. 9:1781-90
Patients with stages II and III disease survived a median of
17 and 11 months, respectively (p=0.04) (Fig 1).
3 Walker AM, Loughlin JE, Freidlander ER, et al. Projections
of asbestos-related disease 1980-2009. J Occup Med 1983;
25:409-25
Conclusion 4 Enterline PE, Henderson VL. Geographic patterns of pleural
It has not been determined what percentage of patients mesothelioma deaths in the United States, 1968-81. J Natl
Cancer Inst 1987; 79:31-37
present with each stage, ie, resectable vs unresectable.
5 Antman K, Pass HI, Recht A. Benign and malignant mesothe¬
Because we surgical
are a service, all patients referred to
us for evaluation have been preselected by primary care
lioma. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.
Cancer: principles and practice of oncology. 3rd ed. Philadel¬
physicians as surgical candidates. This inherent bias pre¬ phia: JB Lippincott, 1989; 1399-1414
cludes our ability to estimate what percentage of the entire 6 Ruffie P, Feld R, Minkin S, et al. Diffuse malignant mesothe¬
disease population is suitable for surgical therapy. lioma of the pleura in Ontario and Quebec: a retrospective
Aggressive trimodality therapy for MPM is indicated in study of 332 patients. J Clin Oncol 1989; 7:1157-68
a select group of patients who have Brigham stage I or II 7 Sugarbaker DJ, Heher EC, Lee TH, et al. Extrapleural
or Butchart stage I disease, ie, confined to a single pleural pneumonectomy,
treatment
chemotherapy, and radiotherapy in the
of diffuse malignant pleural mesothelioma. J Tho¬
space without mediastinal organ invasion or full-thickness rac Cardiovasc Surg 1991; 102:10-14
8 Patz EF Jr, Shaffer K, Piwnica-Worms DR, et al. Malignant
pleural mesothelioma: value of CT and MR imaging in predict¬
1.00- ing resectability. AJR Am J Roentgenol 1992; 159:961-66
9 Corson JM. Pathology of mesothelioma. In: Antman K, Aisner
J, eds. Asbestos-related malignancy. Orlando, Fla: Grune &
Stratton, 1986; 179-99
10 Butchart EG, Ashcroft T, Barnsley WC, et al. Pleuropneu-
monectomy in the management of diffuse malignant me¬
Epithelial, Node Negative (N 39)
=
sothelioma of the pleura: experience with 29 patients. Thorax
-1_ 1976; 31:15-24
Epithelial, Node Positive (N 28)
= 11 Rusch VW, Ginsberg RJ. New concepts in the staging of
mesothelioma: invited comment to chapter 26. In: Deslauri-
J, Lacquet LK, eds. Thoracic surgery: surgical manage¬
ers
12 24 ment of pleural diseases; international trends in general
36 48 60 72 84
Months thoracic surgery (vol 6). St. Louis: CV Mosby, 1990; 336-43
12 Sugarbaker DJ, Strauss GM, Lynch TJ, et al. Node status has
Figure 5. Kaplan-Meier survival curve for patients with epithe¬ prognostic significance in the multimodality therapy of dif¬
lial with node-negative vs node-positive pathologic spec¬
tumors fuse, malignant mesothelioma. J Clin Oncol 1993; 11:1172-78
imens. Patients with negative nodes had a longer survival 13 Sugarbaker DJ, Garcia JP, Richards WG, et al. Extrapleural
(p.0.002). Reprinted from Sugarbaker et al.13 pneumonectomy in the multimodality therapy of malignant
64S International Symposium on Thoracic Malignancies
Downloaded from chestjournal.chestpubs.org by guest on March 2, 2010
1998 by the American College of Chest Physicians
pleural mesothelioma: results in 120 consecutive patients. 18 Rusch V, Saltz L, Venkatraman E, et al. A phase II trial of
Ann Surg 1996; 224:288-96 pleurectomy/decortication followed by intrapleural and sys¬
14 Worn H. Moglichkeiten und ergebnisse der chirurgischen temic chemotherapy for malignant pleural mesothelioma.
behandlung des 22:391-93 pleuramesotheliomas. Thoraxchir
malignen J Clin Oncol 1994; 12:1156-63
Vask Chir 1974; 19 Rusch VW, Venkatraman E. The importance of surgical
15 Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural staging in the treatment of malignant pleural mesothelioma.
pneumonectomy in malignant pleural mesothelioma: a Lung J Thorac Cardiovasc Surg 1996; 111:815-26
Cancer Study Group [see comments]. J
trial Thorac Cardio¬ 20 Sarot IA. Extrapleural pneumonectomy and pleurectomy in
vasc Surg 1991; 102:1-9 pulmonary tuberculosis. Thorax 1949; 4:173-223
21 Hood RM, Antman K, Boyd A, et al. Surgical diseases of
16 Gordon W Jr, Antman KH, Greenberger JS, et al. Radiation
therapy in the management of patients with mesothelioma. the pleura and chest wall. Philadelphia: WB Saunders,
Int J Radiat Oncol Biol Phys 1982; 8:19-25 1986
17 McCormack PM, Nagasaki F, Hilaris BS, et al. Surgical 22 Moran JF. Surgical treatment of pulmonary tuberculosis. In:
treatment of pleural mesothelioma. J Thorac Cardiovasc Surg Sabiston DC Jr, Spencer FC, eds. Surgery of the chest. 5th
1982; 84:834-42 ed. Philadelphia: WB Saunders, 1990; 690-707
CHEST / 113 / 1 / JANUARY, 1998 SUPPLEMENT 65S
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Multimodality Management of Malignant Pleural Mesothelioma
David J. Sugarbaker and Jose J. Norberto
Chest 1998;113; 61S-65S
DOI 10.1378/chest.113.1_Supplement.61S
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