Pleural Mesothelioma Multimodality Management of Malignant

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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
        mesotheliomas has yet
                                                                      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

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               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
     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-
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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¬
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

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        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
                                                                               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-
                                                                               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
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64S                                                                                                International   Symposium on Thoracic Malignancies

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                                          1998 by the American College of Chest Physicians
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                                                                               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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