Malignant Pleural Mesothelioma: Surgical Roles and Novel Therapies

c omprehensive review Malignant Pleural Mesothelioma: Surgical Roles and Novel Therapies Harvey I. Pass Abstract Malignant pleural mesothelioma (MPM) is a uniformly fatal disease that has been recalcitrant to curative therapies. Median survivals of 8-18 months have, for the most part, led to a sense of frustration and nihilism in the medical and surgical community with regard to management of the disease, and the relatively small numbers of patients with mesothelioma have made it an orphan among other cancers with regard to research efforts and funding. This review will comment on the clinical presentation of the disease and therapeutic options that are available at this time. The role, timing, degree, and availability of cytoreductive surgery in the context of a multimodality approach for MPM will be highlighted, and various strategies that incorporate adjunctive therapies before, during, or after the operation will be discussed. Newer cytotoxic chemotherapies, either alone or in combination, are reviewed, with an emphasis on the increasing number of options with increased response rates that are becoming available for MPM patients. The results of protocols at selected centers that offer gene therapy, photodynamic therapy, hyperthermic chemotherapeutic perfusion, and intrapleural chemokines will be discussed, as well as newer preclinical approaches that base targeted therapies on novel molecular findings. In considering the newest approaches to the disease, one is encouraged to seek specialty consultation at centers that concentrate programmatic efforts on mesothelioma in order to design translational-based approaches on preclinical findings. By using such an approach, the patient and physician will find that there are considerably more options in the new century for mesothelioma. Clinical Lung Cancer, Vol. 3, No. 2, 102-117, 2001

Key words: Extrapleural pneumonectomy, Multimodality treatment, Brachytherapy, Intrapleural chemotherapy, Photodynamic therapy

Introduction

Clinical Presentation

Malignant pleural mesothelioma (MPM) is an incredibly challenging malignancy to deal with. The small number of cases in the United States, the lack of uniform standards of care for its treatment both in academic and community institutions, the prevailing sense of nihilism, and the litigious association with the disease are all barriers to a unified approach for disease eradication. Moreover, epidemiologic surveys regarding the development of asbestos-related malignancy might project peak incidences in the final quarter of the 21st century; however, deaths from mesothelioma from 1995 to 2029 could reach as many as 250,000 individuals in Western Europe alone, according to Peto et al.1

Symptoms

Karmanos Cancer Institute, Wayne State University, Detroit, MI Submitted: Aug. 8, 2001; Revised: Sept. 19, 2001; Accepted: Sept. 25, 2001 Address for correspondence: Harvey I. Pass, MD, Professor of Surgery and Oncology, Karmanos Cancer Institute, Wayne State University, 3990 John R, Suite 2102, Detroit, Michigan 48201 Fax: 313-993-0572 e-mail: [email protected]

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Diffuse malignant mesothelioma can be insidious in its onset, and as many as 25% of patients with the disease can have symptoms for 6 months or more before seeking medical attention.2 The length of time it takes patients to report symptoms varies, but the duration can range from 2 weeks to 2 years, with most series having a median time to diagnosis from symptoms of 2-3 months. Classically, the disease affects males in their 50s, 60s, and 70s due to the long latency period between occupational asbestos exposure and the development of the tumor. Women and children can have the disease, but the male to female ratio is approximately 5 to 1.3 The right side is affected more often than the left side (60% vs. 40%), most likely due to the greater volume of the right lung.4 Approximately 60% of patients will present with nonpleuritic chest pain. Classically the pain is posterolateral and low in the thorax, and the pain can be severe enough to require narcotics. Dyspnea will be present in 50%-70% of cases and, indeed, 80%

Figure 1 Computed Tomography of a Patient with Right-Sided Pleural Mesothelioma A

R

B

L

C

R

R

L

D

L

R

L

Computed tomography scans of a patient with right-sided pleural mesothelioma that extended from the apex of the lung to the diaphragm and shows thickened pleura (red arrows) with loculated pleural effusion (bold green arrows) and thickened pericardium (gold arrows) (B, C, and D).

of the patients will present with dyspnea and effusion. In some series, shortness of breath and chest pain are seen either singly or in combination in 90% of cases.5 The presence of a pleural effusion will be documented at some time in the course of the disease in 95% of patients with MPM. Cough, fever, fatigue, and weight loss will occur in approximately 30% of patients.6 A minority of cases will present with hoarseness, hemoptysis, Horner’s syndrome, superior vena caval syndrome, or paralysis from invasion of the spinal canal.

Laboratory Examination The laboratory workup of the mesothelioma patient is usually nonrevealing. Nonspecific laboratory findings include hypergammaglobulinemia, eosinophilia, and/or anemia of chronic disease.4 The most striking laboratory abnormality is thrombocytosis (platelets > 400/μL), which is seen in 60%-90% of the patients, and approximately 15% of patients will have platelet counts greater than 1000/μL.2,8 Leukocytosis can also occur and is, in some series, a negative prognostic indicator.9 There are, however, no specific serum markers for mesothelioma.

Physical Examination Physical examination usually reveals signs associated with a pleural effusion by decreased breath sounds or dullness to percussion. In the late stages of the disease there can be marked contraction of the chest with narrowed interspaces and/or a possible chest wall mass. Such masses, which are associated with aspiration sites postthoracotomy or thoracoscopy, can occur in up to 25% of patients.7 Lymph node examination (cervical, supraclavicular, and axillary) is usually negative for pathologic disease, although externally palpable, asymmetrically enlarged nodes should be biopsied. The abdomen must be inspected for the signs of ascites.

Diagnostic Imaging Roentgenographic Examination Malignant mesothelioma can present with varied radiographic pictures. Many of the early changes are associated with a previous exposure to asbestos, consisting of both pleural and parenchymal changes, including pleural plaques or parenchymal pulmonary fibrosis. The most common features associated with progression and symptoms include the presence of a pleural effusion, diffuse pleural thickening, and nodularity. The involved hemithorax can eventually have a multilobulated thickening with contraction

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Malignant Pleural Mesothelioma Figure 2 Magnetic Resonance Images of a Mesothelioma Patient

A

Coronal View

B

Coronal View

C

Sagittal View

Magnetic resonance images (MRI) of a patient with mesothelioma. (A) Coronal MRI showing right-sided pleural mesothelioma with diaphragm involvement (arrow); (B) a more posterior coronal MRI view showing thickened pleura trapping of the lung (arrows); (C) Sagittal MRI showing thickened pleura (white arrows), the involvement of the fissure (green arrow), and diaphragm (blue arrows).

and fixation of the chest. The lung becomes encased and the mediastinum will shift due to volume loss. The apex might appear to have minimal pleural thickening on the chest radiograph, only to reveal a grossly thickened and nodular appearance on computed tomography (CT). Usually the chest radiograph adds nothing to the staging of mesothelioma. It is useful, however, to guide the workup toward a thoracoscopic approach if fluid is present. The effusion can be loculated, chiefly in the lower portion of the chest, completely obscuring view of the diaphragm, lower lobes, and pericardium. In many of these instances the lower lobe is viewed on CT to be completely collapsed. One must assess the contralateral chest for effusion, which could raise the possibility of 2-cavity involvement. Moreover, careful perusal of the opposite lung might reveal nodularity or evidence of asbestos involvement, which might impact the functional ability of the patient to undergo diagnostic or therapeutic interventions.

Computed Tomography Computed tomography allows for density resolution that is not available with chest radiography (Figure 1). These characteristics are useful not only in the evaluation of the patient with mesothelioma, but also with other asbestos-related diseases.10-15 Such asbestos changes on the CT will frequently be present concomitantly in the mesothelioma patient. Pleural changes on chest CT will include pleural plaques, diffuse pleural thickening, and pleural effusion. Up to 10% of pleural plaques are calcified, and they will appear characteristically on the posterolateral aspect of the lower parietal pleura or diaphragm. They might also occur less frequently at the costophrenic angles, on the visceral pleura, or at the apices. Pleural thickening can vary in degree from only a thin white line to a thickened peel, classi-

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cally effecting the lower third of the thorax, particularly in the diaphragmatic gutters and over the lower lobe. The mesothelioma patient can have all the aforementioned findings in addition to a circumferentially lobulated, soft-tissue mass. Additional CT features of mesothelioma include localized nodular or plaque-like pleural thickening possibly associated with pleural effusion. The lobulated pleural encasement frequently causes lower lobe collapse. Intrapulmonary nodules can occur in 60% of patients,13 and infiltration into fissures and enlarged hilar and mediastinal lymph nodes may be seen. The CT allows a better view of the involved pericardium that is irregularly thickened and associated with infiltration to the pericardial fat pad. Chest wall involvement is still problematic with CT assessment of mesothelioma; unfortunately, this finding is an important aspect in the staging of the disease. CT signs of chest wall invasion include distortion of the intercostal spaces, infiltration of extrapleural soft tissue and ribs, and undefined densities infiltrating the chest wall musculature.16 The diaphragm, although more clearly delineated on CT than by conventional radiography, is also problematic. A clear fat plane between the inferior diaphragmatic surface and the adjacent abdominal organs as well as a smooth inferior diaphragmatic contour might connote resectability according to Patz et al.16 CT might reveal a hemidiaphragm encased by a mass, or poor definition between the liver, stomach, and inferior diaphragmatic surface. CT findings are found to correlate well with the pathologic description of mesothelioma; however, the sensitivity of CT is lowest in the region of the diaphragmatic pleura.15 Many investigators recognize that the criteria for enlarged lymph nodes on CT for lung cancer (> 1 cm being suspicious) might not apply to mesothelioma; nevertheless, the realization of the importance of mediastinal nodal involvement in the disease is increasing.

Harvey I. Pass Figure 3 FDG-PET of a Patient with an Unresectable Stage IV Mesothelioma A

B

C

Whole body fluorodeoxyglucose-positron emission tomography images outlining bulky disease in the superior part of the lung (red arrows) and an occult metastasis in the abdomen (green arrow) (A); Posterior infracrural mediastinal lymph node disease (green arrow) (B); Diaphragm involvement (green arrow) as well as medial disease (blue arrows) (C).

Magnetic Resonance Imaging

Clinical Diagnosis

Magnetic resonance imaging (MRI) can frequently classify poorly defined margins between abdominal structures and the inferior diaphragmatic surface when it is analyzed in the coronal and sagittal planes (Figure 2).16 MRI might also be useful in defining the extent of chest wall disease compared to CT, because the MRI reveals signal alterations due to contiguous extension of tumor from the pleura. A diffuse or irregular interface between the chest wall and the tumor might indicate chest wall invasion. MRI and CT are probably equally effective in the evaluation of mediastinal involvement in that both reveal soft tissue infiltration, with the loss of normal fat planes as an indication of unresectability.

Thoracentesis and Pleural Biopsy

FDG-PET Recently, the role of fluorodeoxyglucose positron emission tomography (FDG-PET) imaging has been examined in a cohort of 28 patients with suspected mesothelioma (confirmed in 22 patients) (Figure 3).17 Standardized uptake values (SUVs) were determined from the most active tumor site in each patient. A high SUV was inversely correlated with survival, and FDG-PET was also useful in detecting lymph node involvement in patients who had normal appearing lymph nodes on CT. These important data require verification in larger numbers of patients, but could be useful in deciding which patient might be a candidate for an aggressive approach, since a high FDG uptake in these tumors could indicate a shorter patient survival.

Patients who present with a large pleural effusion and minimal or moderate evidence of pleural thickening should have initial thoracentesis and pleural biopsy. However, the diagnosis of mesothelioma will be made from pleural fluid in only 33% of cases due to difficulty in distinguishing between reactive mesothelial cells and tumor cells.6 In a large series from London of 140 patients, a definitive diagnosis of malignancy could be obtained in 60% of the pleural effusions18; however, in no cases could the malignancy definitively be called mesothelioma. This is contrasted, however, with an Australian series19 in which it was possible to make a diagnosis of malignant mesothelioma in 84% of pleural fluids. Most recent studies combine both histochemical and immunohistochemical staining techniques with electron microscopic analysis of pleural fluid cell blocks, significantly increasing the diagnostic efficacy of the thoracentesis.

Pleural Biopsy In cases of a large pleural effusion, closed pleural biopsy with the Abrams needle or Cope needle can aid in the diagnoses in 30%-50% of cases.20 Multiple biopsies should be performed to try to avoid sampling error.

Video-Assisted Thoracoscopy For patients with a large effusion and no dominant mass in the lung, video-assisted thoracoscopy has become the preferred

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Malignant Pleural Mesothelioma Figure 4 Histologic Features of Mesothelioma A

incision is employed for the definitive cytoreduction. Large biopsies can then be analyzed with the proper pathologic markers (Figure 4). Extent of disease with regard to the diaphragm, pericardium, chest wall, and nodes can give further staging information. In any evaluation of the patient with mesothelioma, careful attention must be paid to the diaphragmatic extent of the tumor, with suspicious scans confirmed by laparoscopic evaluation for transdiaphragmatic extension.24

Open Biopsy

B

If there is no free pleural space due to previous treatment of pleural effusion, and the bulk of the disease in the hemithorax is solid, open biopsy is usually required. Such a biopsy should be carefully planned such that the scar could be incorporated into the definitive incision if a major resection is entertained after definitive diagnosis. The importance of a generous-sized biopsy is emphasized in a study by van Gelder et al25 where small specimens, ie, those obtained using an Abrams needle, significantly underestimated the percentage of cases ultimately found to have mixed-type tumors almost by a factor of 2 compared to large specimens.

Natural History

C

(A) Epithelial or tubulopapillary features are seen in 50%-70% of the cases. (B) Mixed or biphasic features are intermediate in frequency (20%-25% of cases). (C) Mesenchymal or fibrosarcomatous features are seen in 7%-20% of the cases.

method of diagnosis21-23 and must occasionally be complemented by laparoscopy. Thoracoscopic examination allows the surgeon to evaluate specific areas for guided biopsy and to assess the ability of the lung to expand. In planning such a diagnostic thoracoscopy, the surgeon should be sensitive to possible future extended resections, including pleurectomy and extrapleural pneumonectomy (EPP). In order to decrease the chance of a port recurrence, it is generally recommended that the port sites from previous thoracoscopies be excised. Hence, if possible, one should employ a single thoracoscopy site that can be easily excised when the standard, low, seventh interspace thoracotomy

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The majority of patients with pleural mesothelioma, treated or untreated, will die of complications of local disease. The increasing tumor bulk replaces the effusive component, causing progressive respiratory compromise. The unrelenting chest pain requiring narcotics leads to an inability to eat and occasionally dysphagia from tumor compression of the esophagus. Direct involvement of the epicardium will lead to pericardial effusion or myocardial dysfunction with arrhythmias. Nevertheless, extrathoracic metastases are frequently seen late in the course of disease but are not the direct cause of the patient’s death. In the large series of patients with malignant pleural mesothelioma who had autopsy, 54%-82% had distant metastases, with the most frequently involved organs being the liver, adrenal gland, kidney, and contralateral lung.18,26,27 Intracranial metastases will be seen in approximately 3% and are predominantly of the sarcomatous type.26,28 Indeed, the degree of extrathoracic spread might be influenced by the histology, because the propensity for extrathoracic metastases in the sarcomatoid variant is like that of the epithelioid tumor,18 although other studies dispute this finding.29 Clinically, epithelial mesotheliomas are associated with large pleural effusions, contralateral effusions, and ascites, while sarcomatous tumors have little or no effusion but a large bulky component with extrathoracic metastases. Lymph node metastases, at least in autopsy series, are also surprisingly frequent, with Kim et al30 reporting that 44% of 183 autopsy cases had hilar or mediastinal lymph node involvement. This has been confirmed by Huncharek and Smith in the Canadian Tumor Reference Center Review with N1 (41%) or N2 (77%) node involvement with MPM.31

Treatment Multimodality Approaches The treatment of mesothelioma is influenced not only by the

Harvey I. Pass functional evaluation of these often elderly individuals, but also by the philosophy of the treating physician. Physicians who rarely see patients with the disease (1 per year) might not be aware of national protocols for novel chemotherapeutic regimens, or they might feel that the standard of care should be symptom palliation only. Moreover, the arguments regarding appropriate management of mesothelioma can have geographic differences. This is illustrated in a United Kingdom poll of chest physicians regarding MPM, which revealed that only 46% of the physicians surveyed would consider referral to a thoracic surgeon for radical resection (E. G. Butchart, personal communication, 1995). The French approach to the disease has been a concentration on the detection of early stage I disease that could be treated with intrapleural therapy, including interferon-γ with or without cisplatin.32 Surgery is performed after this therapy only to improve local control, either by pleurectomy or EPP. In patients with stage II or III mesothelioma, Boutin et al recommend surgery and postoperative radiation therapy. In the United States a cohort of specialized cancer centers have evolved that maintain an interest in the surgical management of the disease, yet the centers have individualized approaches that are usually performed in phase I/II trials. At the present time, however, the evolution of the use of surgery in MPM, with or without intraoperative and/or postoperative innovative adjuvant therapies, is being defined by these centers, and innovative multimodality protocols that incorporate surgery as part of the package are being explored in larger numbers of patients.

Effusion Control Unfortunately the most common symptom, shortness of breath, caused by recurring pleural effusions, could signal a knee-jerk reaction to perform chemical or talc pleurodesis. Not only does such treatment potentially interfere with ongoing novel strategies that incorporate intrapleural therapy, but sclerosis alone will influence the difficulty and possibly the type of cytoreductive procedure performed. Pleural symphysis, which is caused by a pleurodesis, can ameliorate effusions; however, the natural history after such a pleurodesis inevitably includes the development of solid bulky disease, which diminishes the opportunity for a lung-sparing pleurectomy decortication option. Nevertheless, effusion control is important for individuals who either are not candidates for an aggressive approach or who refuse more invasive surgical procedures.

Table 1

Videothoracoscopic Talc Pleurodesis for Malignant Pleural Mesothelioma Number of Patients

Success*

Median Survival

Viallat33

88

84%

9.0 months

Canto34

46

80%

9.4 months

13

100%

6.8 months

Author

35

Charvat

* Success is defined as no further need for tapping after 1 month in patients with a resulting normal x-ray or less than 500 mL of residual fluid remaining.

whether the extent of visceral and parietal pleural disease would be amenable to cytoreductive surgery as part of a trial. Table 1 reviews the results of videothoracoscopic talc pleurodesis specifically for mesothelioma.33-35 Patients who were able to have a successful pleurodesis had a significantly longer survival than those who did not, and success depended on presence of trapped lung or the degree of invasion of the pleura.

Pleurectomy Effusion control via palliative surgery is occasionally attempted after lesser procedures (including sclerotherapy) have failed due to the inability of the lung to expand. Generally, the procedure of choice for such palliation is a pleurectomy with or without decortication of the underlying lung. The use of EPP for palliative intent is only rarely described in the literature, and due to its morbidity and mortality, some surgeons state that EPP should never be used for palliative purposes. Other techniques for palliation of pleural effusion with nonexpansile lung include the use of newer, long-term indwelling subcutaneously tunneled catheters that can be intermittently used for drainage,36 or internal drainage from the pleura to the abdomen using the Denver pleuroperitoneal shunt.

The Problem of Stage Once the diagnosis of mesothelioma is obtained through cytologic sampling of effusive material via thoracentesis/thoracoscopy or by histologic examination of pleural biopsy via Cope needle or thoracoscopic techniques, the patient should seek consultation from centers that routinely deal with this disease. Options should be presented to the patient based on relevant series, not anecdotes. Unfortunately, however, the criteria that determine the appropriate patient management for malignancies like lung cancer, ie, staging, are not as concrete for mesothelioma.

Pleurodesis The most efficacious and least invasive of the surgical procedures to accomplish effusion control is thoracoscopy with talc pleurodesis. Two to 5 grams of asbestos-free, sterile talc can be insufflated over the lung and the parietal surfaces. Success rates in effusion control with talc, used either via thoracoscopy or via slurry, approach 90%. Failure of these techniques is usually associated with mesothelioma that prevents lung expansion, a large solid tumor mass, a long history of effusion with multiple thoracenteses leading to loculations, or age older than 70 years. Primary care physicians and thoracic surgeons, however, should carefully deliberate prior to the use of sclerosants, and consider

Staging Systems Prior to the International Mesothelioma Interest Group Staging As described by Rusch, the 5 staging systems prior to the International Mesothelioma Interest Group (IMIG) staging system have been “to some extent imprecise and incompletely validated.”37 All are similar in one regard: their ability to predict the actual pathologic stage in the patient with mesothelioma is poor, since all of these staging systems are surgically/pathologically based. Moreover, since the minority of patients with mesothelioma are placed in surgical-based protocols, most patients will never have a truly accurate stage at the time of diagnosis.

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Malignant Pleural Mesothelioma International Mesothelioma Interest Group Staging The International Union Against Cancer (UICC) proposed a tumor-node-metastasis (TNM) staging system that evolved into the presently described IMIG staging system. The IMIG staging system has only recently been available, but it has been validated in 2 large surgical series of mesothelioma.38,39 Sugarbaker et al have proposed the alternative but complementary Brigham staging system based on tumor, resectability, and nodal status.40

Other Classification Systems The Butchart classification suffers from an absence of TNM descriptors and vague statements regarding lymph node involvement and the degrees of chest wall invasion. Mattson’s classification recognizes contralateral involvement as stage II rather than stage III and has largely been abandoned. Chahinian was the first to devise a TNM-based mesothelioma staging system, with an attempt to qualify the influence of such parameters as locoregional lymph node involvement, site specificity, and the extent of invasion.

The Surgical Issue An aggressive approach to the treatment of mesothelioma involves the use of surgery as part of the treatment package (Figure 5). The operations involved in this management include thoracoscopy, pleurectomy/decortication, or EPP. The indications for each of these operations will depend on the extent of disease, performance and functional status of the patient, and the philosophy of the treating institution. Basically, operative intervention in mesothelioma will fall into 1 of 3 categories: (1) primary effusion control; (2) cytoreduction prior to multimodal therapy; or (3) delivery and monitoring of innovative intrapleural therapies. The majority of patients seeking treatment for mesothelioma are middle- to older-aged individuals with a long latency period between asbestos exposure and tumor development. If surgical intervention is to be considered, a detailed physiologic-functional workup directed chiefly at the cardiopulmonary axis must be performed.

Pulmonary Evaluation Poor underlying pulmonary function in patients with malignant mesothelioma usually reflects the burden of asbestos exposure, concomitant smoking history (up to 70% of the patients have had a heavy tobacco intake), degree of lung trapped by tumor or fluid, and patient age. The extent of fibrosis will correlate with the amount of dyspnea on exertion, and the diffusion capacity of carbon dioxide is reduced in these patients. There will be restriction of chest wall motion resulting in reduced lung volumes. Asbestos-influenced decreases in pulmonary function might be bilateral, and, thus, the extent of surgical therapy will be influenced by the patient’s respiratory functional reserve. In general, a forced expiratory volume per second (FEV1) of less than 1 liter, a PO2 < 55, or a pCO2 > 45 are relative contraindications to performance of EPP.40 If the patient presents with an FEV1 of less than 2 liters, or if the predicted FEV1 is less than 1.2 liters per minute after pneumonectomy, quantitative perfusion scanning should be performed and corre-

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lated to the pulmonary function tests to estimate the individual’s pulmonary reserve after operation.

Cardiac Evaluation Operations for MPM are associated with profound blood loss and potentially significant cardiac demands. The patient should be carefully screened for a history of hypertension, angina, and previous myocardial infarction, and routine electrocardiograms should reveal no signs of previous injury. Any patient sustaining a myocardial infarction within the past 3 months or having an arrhythmia requiring medication should not be considered for EPP. Patients without objective evidence of cardiac injury who have a history of chest pain compatible with angina or remote myocardial infarction should have nuclear medicine studies to investigate reversible perfusion defects indicative of myocardium at risk. In general, patients with an ejection fraction of less than 45% are not considered to be candidates for EPP.40 Cardiac status might also impact enrollment in innovative multimodality programs utilizing potentially cardiotoxic drugs, including doxorubicin. Patients with coronary disease might be considered for angioplasty prior to operative intervention for their disease, and indeed, might be better candidates after such interventions if a multimodality approach is being contemplated.

Other Preoperative Evaluations Careful scrutiny of preoperative medications must be performed, specifically any nonsteroidal anti-inflammatory drugs that could impact on platelet function. Patients should have complete extrathoracic staging evaluation including bone scan, abdominal CT, and head CT to rule out systemic involvement. If patients are to participate in multimodality programs that utilize drugs with potential renal toxicity (ie, cisplatin), a preoperative creatinine clearance should be performed. Obviously, the question then becomes “who is a surgical candidate in this disease?” In the United States, patients with stage I disease who have a good performance status are considered candidates for surgical-based multimodal schemes. However, how does one know they are stage I given the aforementioned problems with staging? Nodal status is highlighted as an independent predictor of survival in mesothelioma; therefore, a realistic question is whether thoracic surgeons should be performing mediastinoscopy or mediastinotomy for patients with mesothelioma. Since only 30%-40% of nodes involved from resected patients are in the upper mediastinum, routine mediastinal staging prior to thoracotomy for mesothelioma will give a significant number of false negatives due to level variation.41 It is also unclear whether the prognostic importance of mediastinal nodal involvement in mesothelioma is equal to or greater than the prognostic importance of those nodes within the visceral envelope of the lung; these nodes within the lung might reflect disease at a later timepoint in the natural history of the disease. Therefore, in the absence of routine thoracoscopic sampling of multiple nodal stations in mesothelioma prior to definitive resection, mediastinoscopy may be justified in those patients with obvious (ie, > 1.5 cm) nodal involvement in levels 7, 4R, 4L, 5L, 6L, or in patients suspicious for contralateral nodal

Harvey I. Pass Figure 5 Intraoperative View and Specimens From a Mesothelioma Patient A

B Resected Diaphragm Atrium

SVC Pericardium Esophagus

C

Gortex Patches

D Resected Diaphragm

Pericardium

A case whose computerized tomograms were shown previously (Figure 1). (A) Right hemithorax after resection of lung, pleura, diaphragm, pericardium, and lymph nodes. (B) Replacement of the diaphragm and pericardium with Gortex material. (C) View of lateral aspect of specimen, which reveals the entire lung, coated with thickened, mesothelioma-involved pleura. (D) Medial view of specimen reveals the resected pericardium and diaphragm, hilar structures, and lung. Abbreviation: SVC = superior vena cava

involvement on presentation. It is possible that FDG-PET scanning will help to at least define those patients with higher-stage mesothelioma in the future.

Which Operation? Some investigators feel that EPP offers the best chance for complete surgical extirpation of mesothelioma. Mesothelioma, however, is unlike other surgical-based malignancies, and it is difficult to imagine that any diffuse pleural mesothelioma is amenable to en bloc removal. A small proportion of mesothelioma tumors might present as an encapsulated mass, not associated with pleural effusion, and these might be amenable to surgical extirpation with negative margins of resection. The majority of diffuse malignant mesotheliomas, however, cannot be surgically removed en bloc with truly negative histologic margins because many of the patients have had a previous biopsy and there is invasion of the endothoracic fascia and intercostal muscles at that site. These patients might also have pleural effusion, which, although cytologically negative, might be breached, leading to local permeation of tumor cells into the residual cavity or into the abdomen. Nevertheless, it is encouraging that in

the largest series of EPP performed for mesothelioma, 66 of 183 patients were defined as having negative resection margins after EPP. Patients with negative margins at resection who had epithelial mesothelioma were found to have 2- and 5-year survival rates of 68% and 46%, respectively, if the node dissection did not reveal tumor.40 Hence, the minority of patients, approximately one third, could have a margin-free resection, and these patients usually have less bulky disease than other patients. The question, then, is that if negative margins are the exception to the rule, is it justifiable to spare the functioning lung by performing a parietal pleurectomy instead of EPP, if the visceral pleura is minimally involved? Minimal visceral pleural disease is an undefined entity. There are no criteria for the number of sites that should be involved, the size of the involved sites, or whether involvement of the fissure is worse than nonfissural involvement. Suffice it to say that individual surgeons with expertise in the management of mesothelioma have different philosophies about the use of pleurectomy in this situation, and some will make the decision regarding the type of operation in an individual patient at the time of the exploration. There is no doubt that EPP is a more extensive dissection and

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Malignant Pleural Mesothelioma may serve to remove more bulk disease than a pleurectomy, chiefly in the diaphragmatic and visceral pleural surfaces. Some surgeons, however, will include diaphragmatic resection and pericardial resection with their pleurectomies to accomplish removal of all gross disease. For EPP, it is almost a necessity to include pericardiotomy during the resection, because the procedure aids in the exposure of the vessels and allows intrapericardial control to prevent a surgical catastrophe. There are no existent preoperative guidelines that can be followed to guarantee which operation will be necessary to accomplish tumor removal. The presence of irregular, bulky disease on the CT that infiltrates into the fissures probably dictates the necessity for EPP; a large effusion with minimal bulk disease might call for pleurectomy/decortication. Moreover, the philosophy of the surgeon regarding the operation can impact his choice; some surgeons reserve EPP for those patients with bulk disease that present simple pleurectomy, while others feel that the greatest chance for complete gross excision will be via EPP performed in the patient with minimal disease. This important factor, preoperative quantitative bulk of disease, might not only influence the choice of resection, but might be an important preoperative prognostic factor in any patient with MPM. Moreover, the discussion regarding the type of resection might be influenced by analysis of the regional lung function by quantitative lung perfusion.42 The final decision as to whether pleurectomy and decortication or EPP is to be performed, given the above caveats, becomes an intraoperative decision unless a protocol calls specifically for one operation over another.

Pleurectomy Morbidity and Mortality When performed routinely, pleurectomy for mesothelioma has few major complications. In the series that specify postoperative morbidity, the most common complication is prolonged air leak (ie, > 7 days) occurring in 10% of patients. On average, chest tubes can be removed in approximately 5.5 days, with greater than 50% of the patients having the chest tube removed within 4 days. Pneumonia and respiratory insufficiency might occur and are usually related to the burden of disease and preoperative functional status. Empyema is a rare occurrence (2%) and is managed by prolonged chest tube drainage and antibiotics. Hemorrhage requiring re-exploration is very rare (ie, < 1%). Earlier studies in patients requiring pleurectomy (but not having mesothelioma) had an in-hospital or operative mortality of 10%-18% in the 1960s.43,44 The modern day mortality from pleurectomy has decreased and is generally considered to be 1.5%-2%, with death either from respiratory insufficiency or hemorrhage. Most recently total pleurectomy in 50 patients performed for mesothelioma had a 30-day mortality of 2%.6 In a recent series of 39 pleurectomies, the hospital mortality was 0%.42,45

Short- and Long-Term Results Pleurectomy and decortication are very effective in controlling malignant pleural effusion. Law et al report effusion control in 88% of patients having decortication for mesothelioma.46 In

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63 patients having partial decortication and pleurectomy, Ruffie et al reported 86% control of effusion,47 and Brancatisano et al reported a 98% control of effusion after pleurectomy in 50 cases of pleural mesothelioma.48 Many of the published series using pleurectomy for palliative management have added postoperative therapies in an uncontrolled, institution-related fashion. The majority have had no sampling of the mediastinal nodes, and fewer have had a mediastinal dissection. Nevertheless, the overall median survival for patients having pleurectomy alone is approximately 13 months (Table 2). The patients who receive pleurectomy and decortication usually have early effusive disease with minimal bulk tumor. If these patients have epithelial mesothelioma and are not found to have nodal involvement, survival rates can be significantly longer than those quoted above.

Extrapleural Pneumonectomy Radical EPP classically has been described for a pure epithelial stage I tumor that is technically resectable and encapsulated by the parietal pleura. Due to sampling error, it is impossible to clarify with 100% certainty whether the tumor is a pure epithelial type or mixed tumor based on the preoperative or intraoperative biopsy. In reality, there are few patients who actually qualify for exploration for EPP. In the review by Butchart et al, 29 of 46 patients (63%) were eligible for EPP,49 and in a series of EPPs performed at Rush Presbyterian-St. Luke’s Hospital in Chicago, 33 of 56 patients (59%) over a 27-year period had EPP.50 Sugarbaker et al have recently reported that 25%-33% of patients seen at their institution are not eligible for EPP and adjuvant therapy.40 Unfortunately, these series do not define why one patient might have pleurectomy while another would have EPP, and it is obvious that some institutions have simply never adopted the operation as feasible for treatment of the disease. One of the more enlightening studies on eligibility for EPP was the Lung Cancer Study Group malignant mesothelioma pilot study from 1985-1988.41 To be eligible for entry into the study, the patient was required to have disease limited to the hemithorax by roentgenographic evaluation, a residual FEV1 after resection of at least 1 liter, and no significant cardiovascular illness. These criteria are clearly more lenient than those that limited eligibility due to age, histologic type, or presumed stage. Even with these relaxed criteria, only 20 of the 83 evaluated patients were resected with EPP. The reasons that EPP could not be performed were chiefly: extent of disease not allowing complete gross resection (54%), inadequate respiratory reserve (33%), stage IV disease (11%), and concurrent medical illness (10%).

Morbidity and Mortality Due to its magnitude, EPP has significantly greater morbidity than pleurectomy. The major complication rate ranges from 20%-40%, and arrhythmia requiring medical management is the most common complication. In the most recent report by Sugarbaker et al, major morbidity occurred in 24% of the patients having EPP and minor morbidity occurred in 41%.40 The

Harvey I. Pass rate for bronchopleural fistula is greater with right-sided EPPs, with an overall fistula rate of 3%-20%. Bronchopleural fistula can be handled, for the most part, with open thoracostomy drainage with or without muscle flap interposition. The mortality rates following EPP were unacceptably high in the 1970s with 31% reported by Butchart et al.49 Since then, however, there has been a steady decline in the operative mortality to consistent rates less than 10% in series of 20 or more patients. Mortality occurs chiefly in older patients from respiratory failure, myocardial infarction, or pulmonary embolus. Rusch and Venkatraman38 reported a perioperative mortality of 6% (3 of 50 patients) after EPP, and Sugarbaker et al reported a benchmark perioperative mortality of 3.8%.40 Mortalities were due to myocardial infarction and presumed pulmonary emboli.

a uniform postoperative adjuvant therapy regimen to the cytoreduction will influence postoperative survival. This is illustrated in a comparison of patients treated for mesothelioma under phase I trials at the NCI treated from 1990-1993 who did not receive adjuvant therapy, to patients from 1993-1996 who received cytoreduction followed by adjuvant immunochemotherapy with cisplatin/interferon/tamoxifen (Figure 7).45 These data have recently been corroborated by Rusch and Venkatraman from their series of patients having resection with or without adjuvant therapy for mesothelioma (Figure 8).52 Therefore, the performance of a cytoreductive procedure in MPM should mandate close postoperative surveillance and a finite number of cycles of novel or standard agents efficacious in the treatment of mesothelioma.

Recurrence After EPP

Multimodality Treatment

EPP with distant sites of recurrence was compared to sites of recurrence in patients having biopsy only or pleurectomy/decortication, and the local control for EPP was superior to that of the other modalities. Pass et al also found a higher proportion of first sites of local recurrence seen in the pleurectomy population compared to the patients having EPP.45 Baldini et al reported that the sites of first recurrence were local in 35% of patients, abdominal in 26%, in the contralateral thorax in 17%, and in other distant sites in 8%.51

Pleurectomy/Intraoperative Brachytherapy/Postoperative Radiation

Survival Long-term survival rates after EPP remain disappointing, with median survival ranging from 9.3-17 months for the majority of series. Rusch et al report a median survival of 10 months in their series,41 and the median survival of MPM patients having EPP (all histologies) in the National Cancer Institute (NCI) series is 9.4 months.45 The majority of patients were pathologic stage II or III in these 2 series. Most recently, Sugarbaker et al40 reported a 17-month median survival for all patients in a series heavily weighted with stage I, epithelial patients (52 of 183), whose 2- and 5-year survivals were 68% and 46%, respectively. In the series by Rusch and Venkatraman, the 2- and 5-year survivals of stage I patients (16 of 131) were 65% and 30%, respectively.52

Adjuvant Therapy Carefully selected series of MPM patients who have received treatment by surgery and postoperative adjuvant therapy report improved survival compared to palliative therapy alone. This would seem odd when the disease is characterized by: (1) the inability to surgically cure patients and (2) chemotherapeutic options with response rates less than 20%. Analogies to ovarian cancer, however, are not unreasonable. The 2 series in the literature with the best results (Sugarbaker and Rusch) are characterized by a reproducible cytoreduction that leaves minimal disease behind.40,52 The importance of the cytoreduction has been quantitatively elucidated by Pass et al.39 For patients who have a more complete cytoreduction, the survival time is longer, as is the time to progression as documented by CT (Figure 6). For patients who have had comparable cytoreduction, the addition of

The Memorial Sloan-Kettering Cancer Center has been the leading proponent of this technique that includes a complete parietal pleurectomy to remove the bulk of the tumor, followed by permanent (Iodine 125) or temporary (Iridium 192) implantation to deliver 3000 rads in 3 days to a 1-cm distance from the implant plane. Radioactive phosphorus is selectively instilled intrapleurally 5-7 days after thoracotomy, and external beam radiation therapy commences 4-6 weeks postoperatively, using electrons and photons to deliver 4500 rads in 4.5 weeks. In this series there was minimum morbidity in the 41 patients discussed, and median survival was 21 months at the time of report. The majority of patients recurred at distant sites (54%) with or without local recurrence. Unfortunately, there has been little follow-up information with regard to the ongoing status of these patients, as the median follow-up in 40% of the patients was 12 months or less at the time of the first report in 1984. Most recently, Rusch et al have investigated the role of highTable 2

Treatment Results for Pleural Mesothelioma Treatment

Median Survival

Supportive Care

6-8 months

Thoracoscopic Pleurodesis

7-9 months

Pleurectomy

≈ 13 months

Pleurectomy/Brachytherapy

≈ 11 months

Pleurectomy/Intracavitary Chemotherapy

≈ 13-19 months

Extrapleural Pneumonectomy (Multimodal Setting)

≈ 13-17 months

Surgery/Photodynamic Therapy

≈ 14 months

Radiotherapy Alone

≈ 8-15 months

Single-Agent Chemotherapy

≈ 6-9 months

Combination Chemotherapy (Studies with > 20 Patients)

≈ 6-16 months

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Malignant Pleural Mesothelioma Figure 6

Measurement of Solid Tumor Volume Remaining After Surgery for MPM

100

80

Phase II and III surgical trials of mesothelioma at NCI with adjuvant therapy

90 80

Percent Survival

70 60 50 40 30 20

70 60 50 40 30 20

10

10 0

6

12

18

24

30

36

42

Survival Time (Months) Patients who have more aggressive cytoreduction leaving less residual solid tumor have longer survival. Abbreviation: MPM = malignant pleural mesothelioma

Reproduced with permission from: Pass HI et al. Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1998; 115:310-318.

dose hemithoracic radiation after complete resection of MPM to determine feasibility, rates of local recurrence, and survival.53 Sixty-two patients (70%) had EPP, 5 patients (6%) had pleurectomy/decortication, and 21 patients (24%) had exploratory surgery only. Adjuvant radiation, administered to 57 patients at a median dose of 54 Gy, was well tolerated except for 1 late esophageal fistula. Recurrences were locoregional in 1 patient, distant in 30 patients (53%), and locoregional and distant in 6 patients. Median survival was 33.8 months for stages I/II versus 10 months for stage III/IV tumors, implying that postoperative hemithorax radiation might impact on local control and survival in early-stage mesothelioma. These are encouraging data; however, careful analysis of the T status of these patients must be performed to determine whether the increased survival of the stage I patients was on the basis of radiation therapy or due to less tumor bulk at the time of resection.

Pleurectomy/Intrapleural Chemotherapy ± Postoperative Chemotherapy There has been interest in combining debulking surgery with intracavitary treatment of pleural mesothelioma since the first reports of intrapleural chemotherapy alone for malignant mesothelioma. Rusch et al combined the elements of intrapleural chemotherapy with cisplatin and Ara-C after surgical debulking followed by systemic chemotherapy in 10 patients.54 This regimen was followed up with an even more aggressive regimen of pleurectomy, immediate intracavitary cisplatin, and mitomycin C, with 2 cycles of cisplatin and mitomycin C systemically. In the initial trial, there was 1 postoperative death, and the chemotherapy complications were reversible, making such an approach feasible. The most recent trial revealed an overall survival rate of

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Influence of Adjuvant Postoperative Therapy After Resection of Mesothelioma

100

Residual volume ≤ 9cc 9/24 failed Residual volume > 9cc 19/23 failed

90

Percent Survival

Figure 7

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0

Phase I surgical trials of mesothelioma at NCI without adjuvant therapy 6

12

18

24

30

36

Survival Time (Months) All patients were operated on at 1 institution by 1 surgeon. Patients in earlier trials of photodynamic therapy without postoperative adjuvant therapy had decreased survival compared to similarly staged patients in phase II and III trials that involved surgery and postoperative adjuvant therapy with or without photodynamic therapy. Abbreviation: NCI = National Cancer Institute

68% at 1 year and 44% at 2 years in the 27 patients who received the therapy, with a median survival of 17 months. Recurrences, however, were chiefly locoregional, and there was acceptable toxicity in the trial. A very similar regimen combining cisplatin and mitomycin C has been attempted at the Cleveland Clinic Foundation in 14 patients.55 A projected 18-month survival of 31% has been reported, but patient tolerance permitted delivery of only 50% of the chemotherapy treatments adjuvantly. In an Italian study of 20 patients, pleurectomy and diaphragmatic or pericardial resection, combined with intrapleural chemotherapy with cisplatin and cytarabine for 4 hours immediately after pleurectomy, and systemic chemotherapy consisting of epirubicin and mitomycin C, revealed a median time to disease progression of 7.4 months and a median survival of 11.5 months.56 The intrapleural route with standard agents or radiation therapy remains intriguing but unanswered with regard to its efficacy. Certainly for any consistent answer to be drawn: (1) a tolerable regimen with proven efficacy will be necessary in the design; (2) standard debulking to define the extent of residual disease will need to be implemented; and (3) compulsive follow-up to document recurrence patterns will need to be performed.

EPP/Intravenous Chemotherapy/Postoperative Radiotherapy An ongoing interest in a multimodal approach to malignant mesothelioma was developed at the Dana Farber Cancer Institute beginning in 1980. The program has evolved with regard to chemotherapy, and presently consists of EPP followed by 2 cy-

Harvey I. Pass Figure 8

Influence of Adjuvant Therapy in Resected Mesothelioma

chemotherapy, EPP, and adjuvant radiation therapy for selected individuals with MPM.

Survival Probability

1.0 0.8

Adujuvant Therapy (n = 142)

Intrapleural Photodynamic Therapy

No Adjuvant Therapy (n = 24) P < 0.01

Photodynamic therapy (PDT) involves the light-activated sensitization of malignant cells.58 Photofrin II, the sensitizer, is retained by malignant tissue in vivo in comparison to normal tissue. The sensitizer is activated by 630 nm light and then interacts with molecular oxygen to produce an excited reactive oxygen species. Singlet oxygen forms the basis of PDT cytotoxicity. The potential for minimal normal tissue toxicity due to the selective retention of the sensitizer within tumors has prompted an interest in studying PDT for the treatment of a variety of tumors including skin, bladder, lung, head and neck, brain, and esophagus. From July 1993 to June 1996, 63 patients at the NCI National Institutes of Health with localized MPM were randomized to surgery, with or without intraoperative PDT.59 All patients received postoperative immunochemotherapy with cisplatin/tamoxifen/interferon. There were no differences in median survival (14.4 vs. 14.1 months) or median progressionfree survival (8.5 vs. 7.7 months), and sites of first recurrence were similar. These data revealed that aggressive multimodal therapy incorporating PDT can be delivered for patients with later-stage MPM, but first-generation PDT does not prolong survival or increase local control for MPM. At least 5 other centers have had an interest in the management of pleural mesothelioma with PDT.60-63 Most recently, preliminary results using intrapleural PDT with meta-tetrahydroxy-phenylchlorin after EPP have revealed significant toxicities without survival benefit.64

0.6 0.4 0.2 0.0 0

12

24

36

48

60

72

84

96

Survival Time (Months) Patients having adjuvant therapy had increased survival compared to others without adjuvant therapy after cytoreductive surgery.

Reproduced with permission from: Rusch VW and Venkatraman ES. Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically. Ann Thorac Surg 1999; 68:1799-1804.

cles of paclitaxel/carboplatin.40 Concurrent radiation to a dose of 40.5 Gy is given with weekly paclitaxel. Over a 19-year period, 183 patients were treated, with a perioperative mortality of 3.8%. The median survival in this group of patients is approximately 17 months, which is a significant improvement over other trials. Favorable subgroups include those with no mediastinal nodal involvement or epithelial histology. A large, nonrandomized series from Hamburg has also shown prolonged life expectancy with multimodal treatment compared to best supportive care.57 The treated patients, however, were younger, had a better performance status at presentation, and had no medical contraindications to surgery. These 93 patients chose either best supportive care or multimodal treatment. Surgery consisted of pleurectomy/decortication or EPP followed by systemic chemotherapy with doxorubicin/cyclophosphamide/vindesine. Patients in remission at the end of the chemotherapy (16 of the 57 accrued) received 45-60 Gy of radiation therapy to the hemithorax. Median survival was 13 months compared to 7 months for those receiving best supportive care.

Induction Therapy In general, induction therapy for MPM followed by surgery has been more challenging than such therapy with non–smallcell lung cancer. Previous attempts at the M.D. Anderson Cancer Center were disappointing due to the inability of the patients to tolerate both aspects of cytotoxic chemotherapy and thoracic surgery (G. Walsh, personal communication, 1994). Other investigators who have used this approach have commented on a greater difficulty in dissection after induction chemotherapy with doxorubicin (L. Robinson, personal communication, 1997). With newer and more efficacious agents presently available, as discussed below, a cohort of institutions including the University of Washington, Mayo Clinic, Memorial Sloan-Kettering Hospital, and Johns Hopkins University, are performing a feasibility study investigating induction

Newer Cytotoxic Drugs and Drug Combinations There are a number of new drugs and drug combinations that have shown promise in small phase I/II trials in patients with mesothelioma, and these are comprehensively covered in a recent review. The anthracyclines, the platinums, and the antimetabolites have the most activity in the disease, but the response rates are consistently between 12%-20%. Doxorubicin has a singleagent activity of 14%,65 and high-dose methotrexate with leucovorin rescue has had a 37% response rate in 60 patients.66 Gemcitabine in combination with cisplatin, first reported as having a 48% response rate from Australian investigators,67 is presently under investigation in a Southwest Oncology Group trial. When gemcitabine is combined with carboplatin, the response rate is reported to be 20%.68 Newer agents that have been used in non–small-cell lung cancer have demonstrated the usual low response rates in MPM: paclitaxel, 9%69; docetaxel, 5%-20%70; and vinorelbine, 21%.71 Despite the low response rates, there is documentation that patients treated for mesothelioma have improved quality of life compared to untreated patients .67,71-73 Newer agents for mesothelioma include the multitargeted antifolate, pemetrexed (Alimta®), that has demonstrated a 38% response rate in 13 patients in a phase I trial with cisplatin74 and a 50% response rate with carboplatin.75 Pemetrexed is presently under investigation in MPM in a phase III trial comparing

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Malignant Pleural Mesothelioma the multitargeted antifolate plus cisplatin vs. cisplatin alone. The ribonuclease, ranpirnase (Onconase®), has demonstrated a survival rate equal to that of doxorubicin in MPM,76,77 and is presently in phase II trials in combination with doxorubicin. Raltitrexed (Tomudex®), a folate-based thymidylate synthase inhibitor, has also shown impressive single-agent activity (23%) in phase II trials of MPM,78 which have led to phase III trials comparing the agent with cisplatin vs. cisplatin alone. New platinum analogues are also under investigation, including L-NDDP (AroplatinTM), a lipophilic cisplatin derivative formulated in liposomes. A response rate of 73% has been documented with L-NDDP when administered thoracoscopically in patients with early diseases.79

Novel Multimodal Approaches Involving Surgery Pleural Perfusion There has been a resurgence of interest in the delivery of intrapleural cytotoxic chemotherapy at the time of operation for pleural mesothelioma. Ratto et al delivered cisplatin to the pleural space after pleurectomy or EPP in 10 patients using hyperthermic pleural space perfusion.80 This study has recorded the pharmacokinetics but has no data as of yet on survival or recurrence. This approach is under investigation in Boston as a phase I trial administering hyperthermic cisplatin (43°C) by intracavitary lavage following EPP. This approach is a thoracic corollary to other studies that have demonstrated ascite control and occasional long-term survival for patients with abdominal mesothelioma who have been treated with cytoreductive surgery and hyperthermic perfusion with cisplatin and/or mitomycin.81,82

Gene Therapy Intrapleural Ad.HSVtk By transferring the herpes simplex thymidine kinase (HSKtk) gene to a tumor by infecting it with an adenovirus construct containing the thymidine kinase gene (Ad.HSVtk), one essentially kills the tumor with the addition of ganciclovir (GCV). This therapy was the subject of a recently completed phase I trial at the University of Pennsylvania.83 The goals were to assess the safety, toxicity, and maximum tolerated dose of intrapleural Ad.HSVtk, to examine patient inflammatory response to the viral vector, and to evaluate the efficiency of intratumoral gene transfer. Twenty-one previously untreated patients were enrolled in this viral titer dose-escalation study. A replication-incompetent recombinant adenoviral vector containing the HSVtk gene under control of the Rous sarcoma virus (RSV)-promoter enhancer was introduced into the pleural cavity of patients with malignant mesothelioma followed by 2 weeks of systemic therapy with GCV at a dose of 5 mg/kg twice a day. The initial 15 patients underwent thoracoscopic pleural biopsy prior to, and 3 days after, vector delivery. The last 6 patients underwent only the postvector instillation biopsy. Dose-limiting toxicity was not reached. Side effects were minimal and included fever, anemia, transient liver enzyme elevations, and bullous skin eruptions, as well as a temporary systemic inflammatory response in those receiving the highest dose. Strong intrapleural and intratumoral immune responses were generated. Using RNA polymerase

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chain reaction, in situ hybridization, immunohistochemistry, and immunoblotting, HSVtk gene transfer was documented in 11 of 20 evaluable patients in a dose-related fashion. The University of Pennsylvania group is continuing their preclinical studies of gene therapy for mesothelioma by investigating novel delivery systems, vectors, and methods to decrease confounding immune responses.84,85

HSVtk-Transduced Ovarian Cells A similar approach is under investigation by a group at Louisiana State University.86-88 In in vitro mixing experiments, gene-modified ovarian tumor cells killed both mouse and human mesothelioma cells in a dose-dependent manner. Use of the HSVtk ovarian cells also prolonged survival of mice with MPM in a dose-dependent fashion. These data have served as the basis for an ongoing phase I clinical gene-therapy trial for MPM to determine the maximum tolerated dose of HSVtktransduced ovarian cancer cells infused into the pleural cavities of mesothelioma patients followed by systemic administration of GCV.

ONYX-015 Another adenovirus, ONYX-015, has been shown to lyse cell lines with abnormalities in p53 genes, as well as tumor cell lines with normal sequences in exons 5 to 9 of the p53 gene. Homozygous deletions of the INK4a/ARF locus were reported to be a predominant event at a frequency of over 70% in mesothelioma. Loss of p14ARF results in functional inactivation of p53. Such an inactivation of p53 might, thus, make mesothelioma a potential target for ONYX-015 adenovirus therapy. In one study, ONYX-015 lysed 2 of 3 mesothelioma cell lines and was selective for those cell lines with loss of p14ARF expression. Further in vivo studies might define whether this mutant virus will be useful in treating human mesothelioma.89

Intrapleural Cytokine Therapy Interferon-γ Interferon-γ has had intriguing results in the intrapleural route as documented by Boutin et al.90 Interferon-γ was administered to 89 patients at a dose of 40 million units twice a week for 8 weeks intrapleurally via a catheter or an implantable port over 46 months. Thoracoscopic or surgical biopsy was performed if CT scan 2 weeks after the end of treatment demonstrated a reduction in tumor size. Eight histologically confirmed complete responses and 9 partial responses with at least a 50% reduction in tumor size were obtained. The overall response rate was 20%. The response rate for patients with stage I disease was 45%, with the main side effects being hyperthermia, liver toxicity, neutropenia, and catheter-related infection.

Interleukin-2 Interleukin-2 (IL-2)–based regimens have also been exploited in mesothelioma. The largest experience to date with intrapleural IL-2–based therapy has been reported by Astoul et al.91 Intrapleural IL-2 (21 x 106 IU/m2/day for 5 days) was given to 22 patients with MPM. Three patients had stage IA dis-

Harvey I. Pass ease, 1 had stage IB, 16 had stage II, 1 had stage III, and 1 had stage IV (Butchart classification). There were 19 epithelial, 2 mixed, and 1 fibrosarcomatous mesotheliomas. Patients were evaluated for response 36 days after treatment by CT scan and thoracoscopy with biopsies. There were 11 partial responses and 1 complete response. Stable disease occurred in 3 patients and disease progression occurred in 7 patients. The overall median survival time was 18 months, and the 24- and 36-month survival rates for responders were 58% and 41%, respectively.

DNA Viruses and Mesothelioma

Figure 9

Treatment Algorithm for Pleural Mesothelioma Based on Standard and Novel Therapies Histologic Evidence of Pleural Mesothelioma

Cytoreduction workup PFTs Quantitative V/Q scan ± Cardiology consult

Refuses surgery Not a cytoreduction candidate

Talc pleurodesis

Pleurex catheter

Candidate for cytoreductive surgery

Consider referral to mesothelioma center for protocol-driven therapy

Standard chemotherapy

Simian virus 40 (SV40) is a DNA (ie, gemcitabine/cisplatin) Not Cytoreducible tumor virus that preferentially causes cytoreducible mesothelioma when injected intracardially and/or intrapleurally into hamProgression sters.92 SV40 also transforms human Intrapleural therapies Pleurectomy vs. EPP Chemotherapy Preoperative chemotherapy cells in tissue culture, and these cells IL-2 Intraoperative therapy contain extensive DNA damage. A Consider referral to IFN Hyperthermic perfusion mesothelioma center for number of laboratories have now conL-NDDP PDT protocol-driven therapy firmed that at least 60% of human Standard chemotherapy Chemotherapy mesotheliomas contain and express Postoperative therapy Chemotherapy SV40.93-100 In these tumor cells, the Radiation Novel Agents SV40 tumor antigen binds and inhibits Antiangiogenesis MTA the cellular tumor suppressors p53 and Antiangiogenesis Rb.101,102 These findings suggest that Phase I SV40 might contribute to the developProgression Gene therapy ment of those human mesotheliomas that are not associated with asbestos exposure. SV40 might also facilitate as- Early referral to a center that has nationwide or investigator-initiated protocols for the disease should be bestos-mediated carcinogenicity. The considered. Abbreviations: EPP = extrapleural pneumonectomy; IFN = interferon; IL-2 = interleukin-2; MTA = epidemiological data available are in- multitargeted antifolate; PDT = photodynamic therapy; PFT = pulmonary function test; V/Q = sufficient to address the role that SV40 ventilation-perfusion might have played in contributing to was an independent prognostic factor. the increased incidence of mesothelioma in the second half of this century.103-106 The use of vaccination therapy against the SU5416 SV40 tumor antigen is presently under investigation in preclinSU5416, a novel antiangiogenic compound that inhibits the ical studies.107,108 thymidine kinase activity of the VEGF receptor, Flk-1, is presently being evaluated at the University of Chicago.73 Newer Angiogenesis and Mesothelioma Angiogenic mechanisms are active in mesothelioma. Ohta et therapies incorporating antiangiogenic strategies, potentially al have demonstrated increased vessel density as well as vascular after cytoreduction, could prove intriguing based on these progendothelial growth factor (VEGF) and its receptors (Flt and nostic findings. The first of these trials is underway at the KarKDR) in mesothelioma specimens using reverse transcriptase manos Cancer Institute of Wayne State University in a phase II polymerase chain reaction.109 Patients with elevated microvessel setting in which patients having cytoreduction of pleural density (MVD) had poorer prognosis and resection of disease mesothelioma are subjected to moderate copper deficiency than patients who did not have elevated MVD. These data were using the drug tetrathiomolybdate.111 The oral agent that deconfirmed by Edwards et al110 with MVD analysis from 76 surcreases serum and cellular copper levels has been used in pagically resected mesotheliomas. Epithelial mesotheliomas had tients with Wilson’s disease, and stabilization of disease in canlower MVDs than sarcomatoid and biphasic MPMs, and MVD cer patients has been reported in a phase I trial. The hypothesis

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Malignant Pleural Mesothelioma for its use is derived from the findings that copper is a necessary element for angiogenesis, and copper levels have profound effects on the formation of new capillary tube assembly units as well as on levels of VEGF, osteonectin, and basic fibroblast growth factor.

Conclusion The management of pleural mesothelioma is rapidly changing in that there are a number of therapeutic options that are now available to interested patients that were not previously available (Figure 9). Surgery for the disease is safer when it is performed at specialized centers, and standard chemotherapy with newer combinations has shown greater efficacy. Treatment for the disease seems to be heading toward a multimodal approach that will take advantage of maximal tumor cytoreduction with the addition of preoperative, intraoperative, or postoperative novel adjuvants. In the future, detailed molecular phenotyping of the tumor might lead to further specific therapies for individual patients.

References 001. Peto J, Decarli A, La Vecchia C, et al. The European mesothelioma epidemic. Br J Cancer 1999; 79:666-672. 002. Chahinian AP, Pajak TF, Holland JF, et al. Diffuse malignant mesothelioma. Prospective evaluation of 69 patients. Ann Intern Med 1982; 96:746-755. 003. Antman K, Pass HI, Schiff P. Benign and malignant mesothelioma. In: VT DeVita Jr., Hellman S, Rosenberg S, eds. Cancer: Principles and Practices of Oncology. Philadelphia: Lippincott-Raven, 1997. 004. Hillerdal G. Malignant mesothelioma 1982: review of 4710 published cases. Br J Dis Chest 1983; 77:321-343. 005. Kannerstein M, Churg J, McCaughey WT. Asbestos and mesothelioma: a review. Pathol Annu 1978; 13:81-129. 006. Rusch VW. Diagnosis and treatment of pleural mesothelioma. Semin Surg Oncol 1990; 6:279-285. 007. Dorward AJ, Stack BH. Diffuse malignant pleural mesothelioma in Glasgow. Br J Dis Chest 1981; 75:397-402. 008. De Pangher Manzini V, Brollo A, Bianchi C. Thrombocytosis in malignant pleural mesothelioma. Tumori 1990; 76:576-578. 009. Herndon JE, Green MR, Chahinian AP, et al. 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. 010. Dedrick CG, McLoud TC, Shepard JA, et al. Computed tomography of localized pleural mesothelioma. AJR Am J Roentgenol 1985; 144:275-280. 011. Aberle DR, Balmes JR. Computed tomography of asbestos-related pulmonary parenchymal and pleural diseases. Clin Chest Med 1991; 12:115-131. 012. Gamsu G, Aberle DR, Lynch D. Computed tomography in the diagnosis of asbestosrelated thoracic disease. J Thorac Imaging 1989; 4:61-67. 013. Kreel L. Computed tomography in mesothelioma. Semin Oncol 1981; 8:302-312. 014. Rusch VW, Godwin JD, Shuman WP. The role of computed tomography scanning in the initial assessment and the follow-up of malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1988; 96:171-177. 015. Maasilta P, Vehmas T, Kivisaari L, et al. Correlations between findings at computed tomography (CT) and at thoracoscopy/thoracotomy/autopsy in pleural mesothelioma. Eur Respir J 1991; 4:952-954. 016. Patz EF, Jr., Shaffer K, Piwnica-Worms DR, et al. Malignant pleural mesothelioma: value of CT and MR imaging in predicting resectability. AJR Am J Roentgenol 1992; 159:961-966. 017. Benard F, Sterman D, Smith RJ, et al. Prognostic value of FDG PET imaging in malignant pleural mesothelioma. J Nucl Med 1999; 40:1241-1245. 018. Law MR, Hodson ME, Heard BE. Malignant mesothelioma of the pleura: relation between histological type and clinical behaviour. Thorax 1982; 37:810-815. 019. Whitaker D, Sterrett G, Shilkin K. Early diagnosis of malignant mesothelioma: The contribution of effusion and fine needle aspiration cytology and ancillary techniques. In: Peters G, Peters B, eds. Asbestos Disease Update. New York: Garland Law Publishing, 1989:73-112. 020. Herbert A, Gallagher PJ. Pleural biopsy in the diagnosis of malignant mesothelioma. Thorax 1982; 37:816-821. 021. Rodriguez-Panadero F. Malignant pleural diseases. Monaldi Arch Chest Dis 2000; 55: 17-19. 022. de Groot M, Walther G. Thoracoscopy in undiagnosed pleural effusions. S Afr Med J 1998; 88:706-711. 023. Hansen M, Faurschou P, Clementsen P. Medical thoracoscopy, results and complications in 146 patients: a retrospective study. Respir Med 1998; 92:228-232.

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Clinical Lung Cancer November 2001

024. Conlon KC, Rusch VW, Gillern S. Laparoscopy: an important tool in the staging of malignant pleural mesothelioma. Ann Surg Oncol 1996; 3:489-494. 025. van Gelder T, Hoogsteden HC, Vandenbroucke JP, et al. The influence of the diagnostic technique on the histopathological diagnosis in malignant mesothelioma. Virchows Arch A Pathol Anat Histopathol 1991; 418:315-317. 026. Falconieri G, Grandi G, DiBonito L, et al. Intracranial metastases from malignant pleural mesothelioma. Report of three autopsy cases and review of the literature. Arch Pathol Lab Med 1991; 115:591-595. 027. Huncharek M, Muscat J. Metastases in diffuse pleural mesothelioma: influence of histological type. Thorax 1987; 42:897-898. 028. Harrison RN. Sarcomatous pleural mesothelioma and cerebral metastases: case report and a review of eight cases. Eur J Respir Dis 1984; 65:185-188. 029. Craighead JE. Current pathogenetic concepts of diffuse malignant mesothelioma. Hum Pathol 1987; 18:544-557. 030. Kim SB, Varkey B, Choi H. Diagnosis of malignant pleural mesothelioma by axillary lymph node biopsy. Chest 1987; 91:279-281. 031. Huncharek M, Smith K. Extrathoracic lymph node metastases in malignant pleural mesothelioma. Chest 1988; 93:443-444. 032. Boutin C, Schlesser M, Frenay C, et al. Malignant pleural mesothelioma. Eur Respir J 1998; 12:972-981. 033. Viallat JR, Rey F, Astoul P, et al. Thoracoscopic talc poudrage pleurodesis for malignant effusions. A review of 360 cases. Chest 1996; 110:1387-1393. 034. Canto A, Guijarro R, Arnau A, et al. Videothoracoscopy in the diagnosis and treatment of malignant pleural mesothelioma with associated pleural effusions. Thorac Cardiovasc Surg 1997; 45:16-19. 035. Charvat JC, Brutsche M, Frey JG, et al. [Value of thoracoscopy and talc pleurodesis in diagnosis and palliative treatment of malignant pleural mesothelioma]. Schweiz Rundsch Med Prax 1998; 87:336-340. 036. Pien GW, Gant MJ, Washam CL, et al. Use of an implantable pleural catheter for trapped lung syndrome in patients with malignant pleural effusion. Chest 2001; 119:1641-1646. 037. Rusch VW. A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group. Chest 1995; 108:1122-1128. 038. Rusch VW, Venkatraman E. The importance of surgical staging in the treatment of malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1996; 111:815-825. 039. Pass HI, Temeck BK, Kranda K, et al. Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1998; 115:310318. 040. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al. Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg 1999; 117:54-63. 041. Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A Lung Cancer Study Group trial. J Thorac Cardiovasc Surg 1991; 102:1-9. 042. Rusch VW. Pleurectomy/decortication in the setting of multimodality treatment for diffuse malignant pleural mesothelioma. Semin Thorac Cardiovasc Surg 1997; 9:367372. 043. Beattie E. The treatment of malignant pleural effusions by partial pleurectomy. Surg Clin North Am 1963; 43:99-107. 044. Jensik R, Cagle J, Milloy F, et al. Pleurectomy in the treatment of pleural effusion due to metastatic malignancy. J Thorac Cardiovasc Surg 1963; 46:322-330. 045. Pass HI, Kranda K, Temeck BK, et al. Surgically debulked malignant pleural mesothelioma: results and prognostic factors. Ann Surg Oncol 1997; 4:215-222. 046. Law MR, Gregor A, Hodson ME, et al. Malignant mesothelioma of the pleura: a study of 52 treated and 64 untreated patients. Thorax 1984; 39:255-259. 047. Ruffie P, Feld R, Minkin S, et al. Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J Clin Oncol 1989; 7:11571168. 048. Brancatisano RP, Joseph MG, McCaughan BC. Pleurectomy for mesothelioma. Med J Aust 1991; 154:455-457, 460. 049. Butchart EG, Ashcroft T, Barnsley WC, et al. Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients. Thorax 1976; 31:15-24. 050. Faber LP. 1986: Extrapleural pneumonectomy for diffuse, malignant mesothelioma. Updated in 1994. Ann Thorac Surg 1994; 58:1782-1783. 051. Baldini EH, Recht A, Strauss GM, et al. Patterns of failure after trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 1997; 63:334-338. 052. Rusch VW, Venkatraman ES. Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically. Ann Thorac Surg 1999; 68:1799-1804. 053. Rusch V, Rosenzweig K, Venkatraman E, et al. A phase II trial of surgical resection and high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001; 122:788-795. 054. Rusch VW, Saltz L, Venkatraman E, et al. A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol 1994; 12:1156-1163. 055. Netaji B, Adelstein D, Rice T, et al. Aggressive combined modality treatment for malignant mesothelioma. Proc Am Soc Clin Oncol 1992; 11:354. 056. Colleoni M, Sartori F, Calabro F, et al. Surgery followed by intracavitary plus systemic chemotherapy in malignant pleural mesothelioma. Tumori 1996; 82:53-56. 057. Calavrezos A, Koschel G, Husselmann H, et al. Malignant mesothelioma of the pleura. A prospective therapeutic study of 132 patients from 1981-1985. Klin Wochenschr

Harvey I. Pass 1988; 66:607-613. 058. Pass HI, Donington JS. Use of photodynamic therapy for the management of pleural malignancies. Semin Surg Oncol 1995; 11:360-367. 059. Pass HI, Temeck BK, Kranda K, et al. Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma. Ann Surg Oncol 1997; 4:628-633. 060. Warloe T, Heyerdahl H, Peng Q, et al. Photodynamic therapy of pleural mesothelioma. Proceedings of the 5th International PDT Association 1994:(Abstract #65). 061. Baas P, Murrer L, Zoetmulder FA, et al. Photodynamic therapy as adjuvant therapy in surgically treated pleural malignancies. Br J Cancer 1997; 76:819-826. 062. Koderhold G, Jindra R, Koren H, et al. Experiences of photodynamic therapy in dermatology. J Photochem Photobiol B 1996; 36:221-223. 063. Moskal TL, Dougherty TJ, Urschel JD, et al. Operation and photodynamic therapy for pleural mesothelioma: 6-year follow-up. Ann Thorac Surg 1998; 66:1128-1133. 064. Schouwink H, Baas P, Rutgers E, et al. Malignant pleural mesothelioma (MPM) treatment with extrapleural pneumonectomy (EPP) and intra-operative photodynamic therapy (iPDT) using mTHPC as photosensitiser: Long term outcome and toxicity. Lung Cancer 2000; 29 (suppl 1):103 (Abstract #337). 065. Lerner HJ, Schoenfeld DA, Martin A, et al. Malignant mesothelioma. The Eastern Cooperative Oncology Group (ECOG) experience. Cancer 1983; 52:1981-1985. 066. Solheim OP, Saeter G, Finnanger AM, et al. High-dose methotrexate in the treatment of malignant mesothelioma of the pleura. A phase II study. Br J Cancer 1992; 65:956960. 067. Byrne MJ, Davidson JA, Musk AW, et al. Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study. J Clin Oncol 1999; 17:25-30. 068. Aversa S, Favaretto A. Carboplatin and gemcitabine chemotherapy for malignant pleural mesothelioma: a phase II study of the GSTPV. Clin Lung Cancer 1999; 1:73-75. 069. Vogelzang NJ, Herndon JE, 2nd, Miller A, et al. High-dose paclitaxel plus G-CSF for malignant mesothelioma: CALGB phase II study 9234. Ann Oncol 1999; 10:597-600. 070. Belani C, Adak S, Aisner S. Docetaxel for malignant mesothelioma: phase II study of the Eastern Cooperative Oncology Group (ECOG 2595). Proc Am Soc Clin Oncol 1999; 18:(Abstract #1829). 071. Steele JP, Shamash J, Evans MT, et al. Phase II study of vinorelbine in patients with malignant pleural mesothelioma. J Clin Oncol 2000; 18:3912-3917. 072. Middleton GW, Smith IE, O'Brien ME, et al. Good symptom relief with palliative MVP (mitomycin-C, vinblastine and cisplatin) chemotherapy in malignant mesothelioma. Ann Oncol 1998; 9:269-273. 073. Kindler H. Malignant Pleural Mesothelioma. Current Treatment Options in Oncology 2000; 1:313-326. 074. Thodtmann R, Depenbrock H, Dumez H, et al. Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin. J Clin Oncol 1999; 17:3009-3016. 075. Calvert A, Hughes A, Calvert P, et al. Alimta in combination with carboplatin demonstrates clinical activity against malignant mesothelioma in a phase I trial. Proc Am Soc Clin Oncol 2000; 19:(Abstract #1936). 076. Taub R, Keohan M, Vogelzang NJ, et al. Phase II trial of Onconase® (ONC) in patients (pts) with advanced malignant mesothelioma (MM): analysis of survival. Proc Am Soc Clin Oncol 1999; 18:(Abstract #2021). 077. Vogelzang NJ, Taub R, Shin D, et al. Phase III randomized trial of onconase (ONC) vs. doxorubicin (DOX) in patients (pts) with unresectable malignant mesothelioma (UMM): analysis of survival. Proc Am Soc Clin Oncol 2000; 19:(Abstract #2274). 078. Fizazi K, Caliandro R, Soulie P, et al. Combination raltitrexed (Tomudex(R))-oxaliplatin: a step forward in the struggle against mesothelioma? The Institut Gustave Roussy experience with chemotherapy and chemo-immunotherapy in mesothelioma. Eur J Cancer 2000; 36:1514-1521. 079. Perez-Soler R, Walsh G, Swisher S, et al. Phase II study of a liposome-entrapped cisplatin analog (L-NDDP) administered intrapleurally in patients (pts) with malignant pleural mesothelioma (MPM). Proc Am Soc Clin Oncol 1999; 18:(Abstract #1626). 080. Ratto GB, Civalleri D, Esposito M, et al. Pleural space perfusion with cisplatin in the multimodality treatment of malignant mesothelioma: a feasibility and pharmacokinetic study. J Thorac Cardiovasc Surg 1999; 117:759-765. 081. Sugarbaker PH. Management of peritoneal-surface malignancy: the surgeon's role. Langenbecks Arch Surg 1999; 384:576-587. 082. Ma GY, Bartlett DL, Reed E, et al. Continuous hyperthermic peritoneal perfusion with cisplatin for the treatment of peritoneal mesothelioma. Cancer J Sci Am 1997; 3:174-179. 083. Sterman DH, Treat J, Litzky LA, et al. Adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir gene therapy in patients with localized malignancy: results of a phase I clinical trial in malignant mesothelioma. Hum Gene Ther 1998; 9:1083-1092. 084. Lanuti M, Rudginsky S, Force SD, et al. Cationic lipid:bacterial DNA complexes elicit adaptive cellular immunity in murine intraperitoneal tumor models. Cancer Res 2000; 60:2955-2963.

085. Lanuti M, Gao GP, Force SD, et al. Evaluation of an E1E4-deleted adenovirus expressing the herpes simplex thymidine kinase suicide gene in cancer gene therapy. Hum Gene Ther 1999; 10:463-475. 086. Schwarzenberger P, Harrison L, Weinacker A, et al. The treatment of malignant mesothelioma with a gene modified cancer cell line: a phase I study. Hum Gene Ther 1998; 9:2641-2649. 087. Schwarzenberger P, Harrison L, Weinacker A, et al. Gene therapy for malignant mesothelioma: a novel approach for an incurable cancer with increased incidence in Louisiana. J La State Med Soc 1998; 150:168-174. 088. Schwarzenberger P, Lei D, Freeman SM, et al. Antitumor activity with the HSV-tkgene-modified cell line PA-1-STK in malignant mesothelioma. Am J Respir Cell Mol Biol 1998; 19:333-337. 089. Yang CT, You L, Yeh CC, et al. Adenovirus-mediated p14(ARF) gene transfer in human mesothelioma cells. J Natl Cancer Inst 2000; 92:636-641. 090. Boutin C, Nussbaum E, Monnet I, et al. Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma. Cancer 1994; 74:2460-2467. 091. Astoul P, Picat-Joossen D, Viallat JR, et al. Intrapleural administration of interleukin2 for the treatment of patients with malignant pleural mesothelioma: a phase II study. Cancer 1998; 83:2099-2104. 092. Cicala C, Pompetti F, Carbone M. SV40 induces mesotheliomas in hamsters. Am J Pathol 1993; 142:1524-1533. 093. Dhaene K, Verhulst A, Van Marck E. SV40 large T-antigen and human pleural mesothelioma. Screening by polymerase chain reaction and tyramine-amplified immunohistochemistry. Virchows Arch 1999; 435:1-7. 094. Procopio A, Marinacci R, Marinetti MR, et al. SV40 expression in human neoplastic and non-neoplastic tissues: perspectives on diagnosis, prognosis and therapy of human malignant mesothelioma. Dev Biol Stand 1998; 94:361-367. 095. Galateau-Salle F, Bidet P, Iwatsubo Y, et al. SV40-like DNA sequences in pleural mesothelioma, bronchopulmonary carcinoma, and non-malignant pulmonary diseases. J Pathol 1998; 184:252-257. 096. Griffiths DJ, Nicholson AG, Weiss RA. Detection of SV40 sequences in human mesothelioma. Dev Biol Stand 1998; 94:127-136. 097. Gibbs AR, Jasani B, Pepper C, et al. SV40 DNA sequences in mesotheliomas. Dev Biol Stand 1998; 94:41-45. 098. Pepper C, Jasani B, Navabi H, et al. Simian virus 40 large T antigen (SV40LTAg) primer specific DNA amplification in human pleural mesothelioma tissue. Thorax 1996; 51:1074-1076. 099. Cristaudo A, Vivaldi A, Sensales G, et al. Molecular biology studies on mesothelioma tumor samples: preliminary data on H-ras, p21, and SV40. J Environ Pathol Toxicol Oncol 1995; 14:29-34. 100. Testa JR, Carbone M, Hirvonen A, et al. A multi-institutional study confirms the presence and expression of simian virus 40 in human malignant mesotheliomas. Cancer Res 1998; 58:4505-4509. 101. De Luca A, Baldi A, Esposito V, et al. The retinoblastoma gene family pRb/p105, p107, pRb2/p130 and simian virus-40 large T-antigen in human mesotheliomas. Nat Med 1997; 3:913-916. 102. Carbone M, Rizzo P, Grimley PM, et al. Simian virus-40 large-T antigen binds p53 in human mesotheliomas. Nat Med 1997; 3:908-912. 103. Fisher S, Weber L, Carbone M, et al. Cancer risk associated with simian virus 40 contaminated polio vaccine. Anticancer Res 1999; 19:2173-2180. 104. Olin P, Giesecke J. Potential exposure to SV40 in polio vaccines used in Sweden during 1957: no impact on cancer incidence rates 1960 to 1993. Dev Biol Stand 1998; 94:227-233. 105. Strickler HD, Rosenberg PS, Devesa SS, et al. Contamination of poliovirus vaccines with simian virus 40 (1955-1963) and subsequent cancer rates. JAMA 1998; 279:292295. 106. Brochard P. [Epidemiological approach to mesothelioma]. Rev Prat 1997; 47:13261332. 107. Bright RK, Shearer MH, Pass HI, et al. Immunotherapy of SV40 induced tumours in mice: a model for vaccine development. Dev Biol Stand 1998; 94:341-353. 108. Xie YC, Hwang C, Overwijk W, et al. Induction of tumor antigen-specific immunity in vivo by a novel vaccinia vector encoding safety-modified simian virus 40 T antigen. J Natl Cancer Inst 1999; 91:169-175. 109. Ohta Y, Shridhar V, Bright RK, et al. VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer 1999; 81:54-61. 110. Edwards JG, Abrams KR, Leverment JN, et al. Prognostic factors for malignant mesothelioma in 142 patients: validation of CALGB and EORTC prognostic scoring systems. Thorax 2000; 55:731-735. 111. Brewer GJ, Dick RD, Grover DK, et al. Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: Phase I study. Clin Cancer Res 2000; 6:1-10.

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