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Advances in the Treatment of Malignant Pleural Mesothelioma^*

^* From the Division of Pulmonary, Allergy, and Critical Care Medicine (Drs. Sterman and Albelda), the Section of General Thoracic Surgery (Dr. Kaiser), and the Thoracic Oncology Research Laboratory/Mesothelioma Program (Drs. Sterman, Kaiser, and Albelda), University of Pennsylvania Medical Center, Philadelphia, PA.

Correspondence to: Daniel H. Sterman, MD, Assistant Professor of Medicine, Pulmonary, Allergy, and Critical Care Medicine Division, 833 W Gates Bldg, University of Pennsylvania Medical Center, 3400 Spruce St, Philadelphia, PA 19104; e-mail: sterman{at}mail.med.upenn.edu

	Abstract

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Malignant pleural mesothelioma is a neoplasm that is commonly fatal and for which there are no widely accepted curative approaches. Mesothelioma is unresponsive to most chemotherapy and radiotherapy regimens, and it typically recurs even after the most aggressive attempts at surgical resection. Multimodality approaches have been of some benefit in prolonging survival of very highly selected subgroups of patients, but they have had a relatively small impact on the majority of the patients diagnosed with this disease. As the incidence of pleural mesothelioma peaks in the United States and Europe over the next 10 to 20 years, new therapeutic measures will be necessary. This review will discuss the roles of chemotherapy, radiotherapy, surgery, and combined modality approaches in the treatment of pleural mesothelioma, as well as scientific advances made in the past decade that have led to the development of experimental techniques, such as photodynamic therapy, immunotherapy, and gene therapy, that are currently undergoing human clinical trials. These promising new avenues may modify the therapeutic nihilism that is rampant among clinicians dealing with mesothelioma.

Key Words: chemotherapy • extrapleural pneumonectomy • gene therapy • immunotherapy • mesothelioma • photodynamic therapy • pleurectomy • pleurodesis • pneumonectomy • radiation

	Introduction

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Mesotheliomas are neoplasms of the serosal membranes of the body cavities, arising from the pleura, peritoneum, pericardium, tunica vaginalis testis, and ovarian epithelium. Eighty percent of mesotheliomas originate in the pleural space, and they represent the most common primary tumor of the pleural cavity. Despite its relative rarity in the United States, mesothelioma remains an area of special interest in pulmonary medicine because of its increasing frequency, dismal prognosis, and attendant medicolegal issues related to asbestos exposure. Mesotheliomas are classified into three general categories: diffuse malignant, localized benign, and localized malignant. The so-called "benign mesotheliomas" are usually localized, and they have been reclassified as benign fibrous tumors of the pleura, probably arising from a cell of origin other than the mesothelium. Ten percent of localized mesotheliomas are malignant, but they are often low-grade and potentially resectable.^{1 2} Diffuse pleural mesothelioma, the focus of this review, accounts for the preponderance of primary pleural tumors.

For many years, the medical community has harbored a nihilistic attitude toward malignant mesothelioma because of the tumor's characteristically poor response to treatment. No particular therapy has reliably emerged superior to supportive therapy alone in terms of survival. Investigators from the Brompton and Royal Marsden Hospitals in London reported a study of 116 patients divided between treatment and palliative care, and they found no survival advantage in the treatment group.³ The median survival for patients without treatment was 6 to 8 months, quite similar to the survival for those who received therapy.^{4 5 6 7 8 9 10 11 12 13 14} The most favorable outcomes reported have been in uncontrolled, nonrandomized studies of multimodality treatment involving surgery, chemotherapy, and radiation therapy in highly selected groups of patients. Much of this medical pessimism is, therefore, justified, but emerging therapies may offer hope for improved palliation, prolonged survival, and even potential cure for certain mesothelioma patients. At the present time, however, there is no widely accepted standard of care for patients with pleural mesothelioma.

	Chemotherapy

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Despite numerous single-agent and combination chemotherapy trials in patients with mesothelioma in the past two decades, there is currently little indication for routine, off-protocol use of this treatment modality. Anthracyclines and antimetabolites have shown the greatest promise, but nonetheless, response rates to single-agent chemotherapy have been dismal, with doxorubicin, the most extensively studied agent, having an average partial response rate of 20%.^{15 16 17 18 19 20 21} There have been unconfirmed reports of response rates of 26%, 37%, and 25% in single trials with detorubicin, high-dose methotrexate, and edatrexate, respectively. In several studies, methotrexate with leukovorin rescue was found to have an overall response rate ranging from 35 to 45%, but treatment with other antimetabolites such as 5-fluorouracil has shown, at best, to have a 15% response rate.^{15 16 17 18} Carboplatin, an analog of cisplatin, has demonstrated some activity against mesothelioma when used as a single agent, and it is less nephrotoxic and better tolerated than cisplatin.^{15 22 23 24 25 26 27} Plant derivatives, such as the vinca alkaloids vincristine and vinblastine, are generally inactive against mesothelioma.²⁸ Among the alkylating agents, only mitomycin has demonstrated any significant tumor reduction in mesothelioma, with a 21% overall response rate in a single phase II trial, albeit with significant pulmonary toxicity²⁹ ; ifosfamide and cyclophosphamide had only meager activity.^{30 31}

Among the newer agents, paclitaxel has not been demonstrated to have any significant single-agent activity against mesothelioma but may ultimately be useful as a radiosensitizer.³² In isolated cases of partial tumor response to paclitaxel, there are reports of associated cardiac arrythmias and peripheral neuropathy.^{33 34} Docetaxel may have increased single-agent activity compared with paclitaxel in limited studies (J. Ruckdeschel, MD; personal communication; September 1998). Newer single agents currently under investigation include gemcitabine, which has demonstrated antitumor activity and symptom palliation in a small pilot study,³⁵ and P-30 protein, a novel ribonuclease isolated from leopard frog eggs. The antitumor activity of P-30 protein is thought to occur via degradation of RNA and inhibition of protein synthesis, inducing apoptosis in malignant cells. Phase I studies in mesothelioma demonstrated minimal toxicity (primarily arthralgia, paresthesia, and renal dysfunction) and showed response rates approximating those seen with the best single agents.^{15 36} P-30 therapy for mesothelioma is currently being tested in a multicenter phase III randomized clinical trial in comparison with doxorubicin.

Although there have been more than 20 different multidrug trials since 1978, combinations of chemotherapeutic agents have provided no significant survival advantage for patients. The majority of studies combined anthracyclines (doxorubicin) with alkylating agents (cyclophosphamide, mitomycin, ifosfamide) or platinum agents (cisplatin, carboplatin).^{16 33 37 38 39 40 41 42 43 44 45 46} The Cancer and Leukemia Group B has tried four phase II and phase III studies in mesothelioma since 1985, with no notable improvement over single-agent therapy.^{25 43} The combination of doxorubicin, cisplatin, bleomycin, and mitomycin produced response rates of 44% in one study; however, other investigators have been unable to repeat this.¹⁶ Combination therapy with mitomycin and cisplatin showed significant activity in animal models, but only 25% total response rates in clinical trials.^{16 46 47 48} A recent report of a phase II trial from Australia involving a combination of cisplatin and gemcitabine demonstrated a partial response rate of > 50%, and a 90% rate of symptom improvement among responders.⁴⁹

Because systemic chemotherapy has had so little success in mesothelioma, several investigators have studied direct intrapleural delivery of chemotherapy with the rationale of achieving high local drug concentrations while minimizing systemic toxicity. Intrapleural delivery requires the presence of a patent pleural space, which limits the candidate pool to those with earlier stages of disease, because the pleural space is often obliterated in advanced mesothelioma. Agents that have been evaluated for intracavitary treatment to date include cisplatin, cytosine arabinoside, doxorubicin, and mitomycin C.^{50 51 52 53} One of the first attempts at intrapleural chemotherapy without surgery for malignant mesothelioma involved 21 patients who received 20 to 30 mg doxorubicin weekly for 4 weeks and then monthly. Average survival was 21 months.⁵⁴ Cisplatin has been the most extensively studied agent for intracavitary use, but it has proven much more successful for peritoneal than pleural mesotheliomas.⁴⁷

One of the major problems encountered in chemotherapy trials has been how to reliably and objectively assess treatment efficacy. Numerous criteria have been used to define response. For studies of mesothelioma patients, several investigators have utilized resolution of pleural effusion as a marker of efficacy, but this may merely indicate pleural sclerosis and not regression of malignancy. There has been no standardization of patient populations with a uniform staging system to allow valid intergroup and interstudy comparisons. Only a handful of studies had sufficiently large cohorts of patients. Many studies based results on groups of fewer than 15 patients, making it difficult to draw conclusions about response rates and especially survival.

	Radiation Therapy

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External beam radiation therapy, like chemotherapy, has been ineffective in prolonging survival in mesothelioma patients, although several studies have demonstrated some degree of regression of gross disease.⁵⁵

There are a number of reasons why mesotheliomas are not responsive or conducive to radiation therapy; among them is the large tissue volume required for treatment encompassing the following several vital structures: the heart, lungs, liver, spinal cord, and esophagus. More than 5,000 cGy is needed over the course of treatment to achieve adequate palliation in most cases. The target beam must include the entire pleural surface, including the diaphragm and mediastinum. The target borders include the first rib superiorly, below the diaphragmatic reflection of pleura inferiorly (12th thoracic vertebral body), the full ipsilateral depth of the mediastinum, and the ipsilateral margin of the bony rib cage. CT scans can help delineate sites of gross disease.⁵⁶ Complications of radiotherapy for mesothelioma can include nausea and vomiting, radiation hepatitis, esophagitis, myelitis, myocarditis, and pneumonitis with deterioration of pulmonary function (decreased FVC, decreased diffusing capacity, hypoxemia).⁵⁷ Radiation injury to the contralateral lung may be devastating in a patient with mesothelioma.

Many new techniques have been designed to protect the pulmonary parenchyma from radiation injury. Combined photon and electron beams use large, opposed anterior and posterior external beam portals with central lung blocking.⁵⁸ The pleural areas underneath the blocks are treated with electron beams of appropriate energy (10 to 15 MeV). This technique is limited by an inability to reliably "match" electrons and photons in different planes, and it also retains significant lung exposure. Tissue compensators can help improve dose distribution. Off-axis beam rotation techniques radiate a maximal area of the pleural space to high dose while shielding the underlying lung. However, even with these complex techniques, up to one third of the lung can still be damaged.^{22 59}

Radiation therapy may be effective as an adjunct to surgical resection, either by external beam or brachytherapy (direct intrapleural installation of radioactive isotopes) with the goal of improving local control of disease. Demarcation of the sites of residual gross tumor with surgical clips after pleurectomy helps in accurate planning of adjuvant radiation therapy. Radioactive colloids, such as gold (no longer available) and chromic phosphate (P³²), have low tissue penetrability, but they are effective in delivering high doses to large volumes of pleural space. These colloids are best used for control of recurrent pleural effusions and patients with diffuse miliary seeding of the pleura. One problem with the use of radioactive colloids is the difficulty in determining the exact dose delivered over six half-lives of isotope, secondary to the movement over time of the solution within the pleural cavity. Perhaps the most promising use of radiation in mesothelioma is in the prophylactic treatment of incision sites after invasive diagnostic studies to prevent chest wall implantation.^{46 47 60}

	Surgery

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Surgical treatment of pleural mesothelioma increasingly plays a central role in the therapeutic armamentarium, particularly in the use of videothoracoscopy to diagnose patients at earlier stages of disease. In the past, only 20% of all patients with malignant mesothelioma were deemed candidates for surgical resection, but often, less aggressive surgical approaches may be successful in providing palliation.⁶¹ More recently, aggressive attempts at surgical "cure" have been made for selected mesothelioma patients, usually with some form of adjuvant therapy. There are three primary indications for surgical intervention: (1) thoracoscopy or thoracotomy for diagnosis (if other diagnostic techniques have failed); (2) pleurectomy or pleuropneumonectomy for early-stage, potentially resectable disease; and (3) palliation via pleurodesis or decortication for later-stage, unresectable disease.

Preoperative Evaluation
Before a patient goes to the operating room, preoperative evaluation should assess whether the patient will be able to withstand a pleurectomy or pneumonectomy. The patient's overall health and nutritional status should be evaluated, with a particular focus placed on preexisting cardiac history. Patients with a myocardial infarction in the past 3 months or with a history of life-threatening arrhythmia should not be considered for extrapleural pneumonectomy (EPP).⁶² Echocardiography should be performed to evaluate ventricular function (especially if considering adjuvant anthracycline chemotherapy), mediastinal and pericardial invasion, and the presence of pulmonary hypertension.

To a large degree, the success of the surgical procedure will rely on the status of the contralateral, noninvolved lung. Pulmonary function tests that include arterial blood gases should be performed to ensure adequate pulmonary reserve. Mesothelioma patients often have underlying abnormalities of pulmonary function unrelated to their malignancy secondary to coexisting asbestosis, pleural fibrosis, and COPD.⁶² The degree of pulmonary dysfunction correlates with the degree of costophrenic angle involvement, width and length of pleural fibrosis, and presence of either circumscribed plaque or diffuse pleural thickening.⁶² If an EPP is being considered, a quantitative ventilation-perfusion scan should be performed to allow prediction of postoperative FEV₁. Relative pulmonary contraindications for EPP include postoperative predicted FEV₁ < 1 L/s, PaO₂ < 55 mm Hg, PCO₂ > 45 mm Hg, and evidence of pulmonary hypertension.

Noninvasive radiographic techniques, such as CT and MRI, are useful in determining the patient's candidacy for surgical resection, although often, the ultimate determination is made at the time of surgery. A tumor of any size may be resectable if it is confined to one hemithorax and demonstrates minimal invasion of the diaphragm, visceral pericardium, and chest wall; and there is no evidence of mediastinal lymph node involvement.⁶³ The CT and MRI criteria for resectability are as follows: (1) preserved extrapleural fat planes; (2) normal CT attenuation values and magnetic resonance signal intensity characterisitics of structures adjacent to the tumor; (3) absence of extrapleural soft tissue masses; and (4) smooth diaphragmatic surface on sagittal and coronal images.⁶³

Any tumor that extends through the diaphragm or that diffusely invades the chest wall or essential mediastinal structures, such as the great vessels, esophagus, trachea, aorta, or heart, is considered surgically unresectable. In addition, patients with distant metastases are not surgical candidates.⁶³ Criteria for unresectability on CT or MRI include tumor encasement of the diaphragm; invasion of the extrapleural soft tissues or fat; infiltration, displacement, or separation of ribs by a tumor; and obvious bone destruction.⁶³

Positron emission tomography (PET) scanning with 18-fluoro-2-deoxyglucose (18-FDG) is an emerging modality for the evaluation of pleural mesothelioma that may be useful in the preoperative setting to document and quantify the extent of pleural disease, establish mediastinal lymph node involvement, evaluate chest wall and transdiaphragmatic invasion, and estimate tumor aggressiveness (Fig 1 ). The utility of 18-FDG PET scanning for evaluation of the tumor extent in pleural mesothelioma awaits direct comparison with more common imaging modalities such as CT and MRI.⁶⁴

View larger version (155K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Top left, A: posterior-anterior chest radiograph in a patient with malignant pleural mesothelioma demonstrating significant right-sided pleural effusion and diffuse pleural thickening associated with marked volume loss of the right hemithorax. No definite pleural plaques are seen. Top right, B: CT image from a patient with a right-sided pleural mesothelioma, illustrating complete encasement of the ipsilateral lung with a thick rind of tumor, neoplastic invasion of the interlobar fissures, small residual pleural effusion, and marked unilateral volume loss. Center, C: MRI with transaxial, sagittal, and coronal views from a patient with a right-sided pleural mesothelioma. MRI may be most beneficial in the determination of chest wall, mediastinal, and diaphragmatic invasion. Bottom, D: PET scan with 18-FDG in the same patient as in center panel (C) with transaxial, sagittal, and coronal views. 18-FDG PET scanning in mesothelioma can aid in tumor staging, localization of biopsy sites, and distinguishing between pleural fibrosis and active malignant tissue.

Pleurectomy
Parietal pleurectomy involves a posterolateral thoracotomy with extrapleural stripping of the pleura and pericardium from the apex of the lung to the diaphragm. Most of the parietal pleura can be removed, but the diaphragmatic pleura and much of the mediastinal pleura usually cannot be completely resected. Operative mortality is 1 to 2%. Median survival times using this approach range from 9.0 to 18.3 months. As a pure palliative measure, parietal pleurectomy is the most effective means of reducing the recurrence of pleural effusion in mesothelioma. Complications of pleurectomy include bronchopleural fistulae with prolonged air leak, hemorrhage, pneumonia subcutaneous emphysema, incomplete tumor removal, and rarely, empyema and vocal cord paralysis.^{47 62 68}

EPP
An EPP is a radical procedure that includes en bloc removal of the parietal pleura, ipsilateral lung, pericardium, and the ipsilateral hemidiaphragm (Fig 2 ). The intent is to remove all gross disease, particularly from the diaphragmatic and visceral pleural surfaces. It is necessary to remove parietal pericardium in order to facilitate complete resection as well as to allow for intrapericardial control of the hilar vessels if necessary.⁶² The earliest reported attempt at complete resection of mesothelioma was in 1922 in Germany by Eiselsberg, when an "endothelioma of the pleura" was removed from a 46-year-old man. He recommended radical surgery but removed only the fourth through eighth ribs and a portion of the lung.⁶⁵ EPP was first performed in 1949 by Mason. At the present time, EPP is indicated for stage I, technically resectable tumors that are contained within the pleural envelope, with no involvement of the mediastinal lymph nodes.⁶² Because EPP can be associated with significant morbidity and an operative mortality rate ranging from 5 to 35%, it should be carried out in institutions with significant experience with this procedure.^{69 70}

View larger version (93K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Photograph of a postmortem mesothelioma specimen after overnight formalin inflation and fixation. The right lung is covered by a thick, whitish rind of tumor involving the entire pleural surface, which has also infiltrated and demarcated the interlobar fissures. EPP involves removal of all gross tumor (lung and visceral pleura) as well as the parietal and mediastinal pleura, parietal pericardium, and ipsilateral hemidiaphragm.

A frequent complication of EPP is supraventricular arrhythmia, occurring in as many as 25 to 40% of patients.⁷⁸ Pneumonia in the remaining contralateral lung is perhaps the most feared complication, as respiratory failure and death can rapidly ensue. The incidence of postoperative respiratory infections has decreased significantly with the introduction of thoracic epidural anesthesia, which facilitates rapid extubation and allows for better secretion management because of the improved ability to cough. A small percentage of patients undergoing EPP will develop bronchopleural fistulae, especially with right-sided EPPs, although this complication may be more associated with adjuvant therapy, ie, radiation.⁶² Other complications of EPP include empyema, vocal cord paralysis, chylothorax, myocardial infarction, and congestive heart failure.⁷⁸

Combination Therapies
Single-modality treatment for pleural mesothelioma, whether chemotherapy, radiation therapy, or surgery, is unable to prolong life by more than several months at best. More recently, combined modality approaches to improve efficacy have been reported.^{5 79 80} EPP, in these contexts, is designed as a cytoreductive, not a curative, procedure.⁶⁹ Bimodal and trimodal treatment plans have been tried: chemotherapy with radiation, surgery with chemotherapy, surgery with radiation, and all three modalities combined. Combinations of chemotherapy with radiation have met with very limited success.^{6 9 81 82} At present, a randomized intergroup study is testing the role of radiotherapy with and without the subsequent administration of doxorubicin.

Several investigators, including those at the Dana Farber Cancer Institute, have combined EPP with sequential postoperative chemotherapy and up to 5,500 cGy of adjuvant radiotherapy to the postoperative hemithorax. The initial adjuvant chemotherapy regimen of four to six cycles of doxorubicin, cyclophosphamide, and cisplatin, was thought to be effective, but because of significant myocardial depression, it has been changed to a regimen of paclitaxel and carboplatin.⁸³ Overall median survival of 44 Butchart stage I patients in the Dana Farber study was 16 months, but improved to 24 months for those with the epithelial subtype. Patients in this study who had epithelial mesothelioma and no mediastinal lymph node involvement at resection had a remarkable 5-year survival rate of 39%.^{69 70 83} Patients with sarcomatous tumors or tumors with mixed histologic findings had 2- and 5-year survival rates of 20% and 0%, respectively. Full-thickness involvement of the hemidiaphragm at the time of surgical resection was also associated with a poor prognosis.⁸³ The most common site of tumor recurrence was the ipsilateral hemithorax (35%), followed by the peritoneal cavity (26%) and the contralateral hemithorax (17%). Only 4% of patients who received trimodality therapy developed recurrence at distant sites.^{69 70 83 84 85}

A similar approach has been tried in Germany on 93 patients. Aggressive surgical management in low-risk patients is followed by doxorubicin, vindesine, and cyclophosphamide. Those patients who demonstrated partial remission received 4,500 to 6,000 cGy of radiation therapy. Overall median survival was 13 months.⁸⁶ In a series of 26 patients, Alberts et al⁷ reported a median survival of only 10.9 months after maximal pleural cytoreduction, 4,500 cGy of postoperative radiation therapy and doxorubicin, cyclophosphamide, and procarbazine.

Although pleurectomy alone has not been shown to significantly prolong survival in mesothelioma, there have been several studies documenting increased survival with the combination of parietal pleurectomy and postoperative intrapleural brachytherapy and/or external beam irradiation. Median survival for the entire group was 12.6 months, with a 2-year survival rate of 35%. Those with pure epithelial histologic findings and who did not require an implant had a median survival of 22.5 months and a 2-year survival of 41%. The majority of the complications were secondary to the radiotherapy—pneumonitis, pulmonary fibrosis, esophagitis, and pericardial effusion.^{47 58 69 77 87}

Rusch and colleagues^{76 77 88} combined pleurectomy and decortication with intrapleural chemotherapy by using cisplatin and cytosine arabinoside followed by systemic cisplatin chemotherapy. In a subsequent phase II trial, pleurectomy and decortication were followed by immediate postoperative intrapleural cisplatin and mitomycin. Of the 36 patients entered into the study, 28 had pleurectomy/decortication and intrapleural chemotherapy. The median survival was 17 months, and locoregional disease was the most common location of relapse. Investigators at the University of California, Los Angeles used a similar protocol of intrapleural cisplatin and cytosine arabinoside after subtotal pleurectomy and found that, although the treatment was associated with low morbidity, there was no significant prolongation of overall survival.⁸⁹ A similar study performed at the Fox Chase Cancer Center, involving subtotal pleurectomy, intrapleural chemotherapy, and postoperative systemic chemotherapy, demonstrated significant toxicity and, again, no effect on survival.⁵¹

	Palliative Therapy

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Palliative management of mesotheliomas involves treatment of the two major symptoms: dyspnea and chest pain. Dyspnea in pleural mesothelioma can be multifactorial in etiology, but it most often results from a combination of pleural fluid accumulation and encasement of the lung from a tumor growing through the visceral pleura into lung parenchyma. Chest pain results from tumor invasion of chest wall structures, including the parietal pleura, ribs, muscle, and especially intercostal nerves.

Pain Management
A number of modalities exist to manage pain in patients with malignant mesothelioma. Radiation therapy has been successful in palliating the pain from tumor involvement of the chest wall. Radiation in moderate doses of 4,000 to 5,000 cGy has been demonstrated to relieve symptoms of pain, superior vena cava obstruction, dyspnea, and dysphagia in up to two thirds of cases.^{55 56} Narcotics are usually needed in late-stage disease to control the pain associated with malignant mesothelioma invasion of the chest wall. Transcutaneous fentanyl patches are easy for patients to use and provide continuous, controlled delivery of a narcotic for 72 h. Chronic indwelling epidural catheters can be inserted by pain management consultants for constant infusion of narcotic and/or local anesthetic.⁶² Palliative chemotherapy has, in some circumstances, resulted in decreased chest wall pain and dyspnea, even without significant objective radiographic tumor responses. In a study at the Royal Marsden Hospital in England, 39 patients with advanced mesothelioma and profound symptoms of dyspnea and chest wall pain were treated with a combination of mitomicin, vinblastine, and cisplatin. An objective partial response rate of only 20% was seen (median duration of response was 9 months), but 62% of patients noted partial or complete relief of all symptoms, and 79% described significant mitigation in chest wall pain.⁹⁰

Pleurodesis
By far the most common and bothersome symptom for patients with mesothelioma is persistent dyspnea from large, rapidly reaccumulating, pleural effusions. A reasonable approach to palliation of this disabling dyspnea is complete drainage of the pleural effusion via tube thoracostomy or video thoracoscopy, and then introduction of a sclerosing agent into the pleural space by injection or insufflation. The goal is to produce an inflammatory reaction of the parietal and visceral pleural surface, and subsequent obliteration of the pleural space (ie, pleurodesis), thereby preventing significant reaccumulation of pleural fluid. Complete drainage and full re-expansion of the lung are necessary before attempting pleurodesis. Multiple compounds have been used in the past to achieve pleural symphysis, including tetracycline, minocycline, quinacrine, and bleomycin. At present, the most widely used and most effective compound for pleurodesis is sterile talc, as either a powder or a slurry.⁹¹ Unfortunately, talc pleurodesis is often unsuccessful in patients with mesothelioma because of a bulky tumor covering the pleural cavity and causing the lung to be "trapped." In these cases, pleurectomy/decortication may be required if the patient can withstand the procedure.²² Pleurectomy is more successful than talc pleurodesis in reducing the recurrence of pleural effusion in mesothelioma, but it also has greater morbidity. Albeit an aggressive approach, EPP is an excellent means of palliating the profound dyspnea and orthopnea associated with the significant ventilation-perfusion mismatch resulting from lung encasement by tumor.⁷⁹

Pleuroperitoneal Shunt
An alternative approach to relieving the unrelenting dyspnea resulting from the rapid reaccumulation of pleural fluid in patients with a hemithorax diffusely involved with mesothelioma is pleuroperitoneal shunting. This involves insertion of a catheter into the pleural space, which is tunneled subcutaneously into the peritoneal cavity. A manual pump and one-way valve are interposed, allowing the patient to control the drainage of pleural fluid from the affected hemithorax. The insertion of the pleuroperitoneal shunt is well-tolerated and provides significant palliation from recurrent malignant effusion. Complications are primarily related to occlusion of the catheter.⁹² One theoretical problem, which has been borne out by anecdotal reports, is the rapid spread of mesothelioma to the abdomen, with subsequent development of bowel obstruction.⁹³ Outpatient external fluid drainage via a semipermanent intrapleural catheter (Pleuryx Catheter; Denver Biomaterials, Inc; Evergreen, CO) may be an attractive alternative for mesothelioma patients with recurrent, symptomatic pleural effusions in the setting of a trapped lung.

	Emerging Modalities

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Photodynamic Therapy
Pass and Donington,⁹⁴ at the National Cancer Institute, investigated the use of intracavitary photodynamic therapy (PDT) as adjuvant therapy after EPP. PDT is based on the systemic administration of light-sensitive molecules (photosensitizers) that localize in neoplastic cells and produce toxic singlet oxygen when activated by light of a particular wavelength. Hematoporphyrin derivative (HpD; Porfimer sodium, Photofrin), the most common photosensitizer in clinical use, selectively lyses neoplastic cells when exposed to 630-nm laser light, consistent with the absorption spectrum of HpD.⁹⁵ A primary side effect of HpD is temporary skin photosensitivity secondary to photosensitizer deposition in cutaneous tissues.

Moderate success has been achieved using HpD PDT as a surgical adjuvant therapy in low-risk patients with low tumor burden.^{94 96 97} Pass and Donington⁹⁴ conducted a phase I trial in 42 mesothelioma patients who underwent maximal surgical debulking followed by escalating doses of PDT with HpD. Patients with isolated hemithorax pleural malignancy (mesothelioma or lung adenocarcinoma) were prospectively entered into the trial in groups of three to receive light doses between 15 to 35 J/cm² 2 days after systemic HpD delivery. No significant toxicities were seen related to adjuvant PDT. A follow-up phase III randomized trial of surgical debulking, followed by chemoimmunotherapy with or without HpD PDT, demonstrated no survival or local control benefit for PDT with this first-generation photosensitizer.⁹⁸ Other attempts to use HpD PDT as an adjuvant to maximal surgical cytoreduction in mesothelioma have demonstrated limited therapeutic benefit and a high morbidity rate, with several reports of mortality related to bronchopleural fistulas, esophageal perforations, and empyemas.^{99 100 101}

In the Netherlands and the United States, there are ongoing phase I clinical trials of surgical debulking followed by intracavitary PDT utilizing a new photosensitizer, meta-tetrahydroxyl phenylchlorin (m-THPC, Foscan), which is thought to have better tissue penetration, a higher singlet oxygen yield, and a shorter duration of skin photosensitivity than Photofrin. In a preliminary report by Baas and colleagues,¹⁰² adjuvant PDT with m-THPC proved relatively safe in four mesothelioma patients, three of whom were alive with no evidence of recurrent tumor with a follow-up of 9 to 11 months. Complications of treatment with m-THPC included skin burn in two of four patients, diaphragmatic rupture, and hemopericardium. One mesothelioma patient developed local recurrence at the thoracoscopy site and died 7 months after treatment secondary to intra-abdominal metastasis.

Immunotherapy
Like many human malignancies, pleural mesothelioma appears to be resistant to mechanisms of immune-mediated destruction. In "immunogenic" tumors such as malignant melanoma, immunotherapy via exogenous cytokines, monoclonal antibody, and tumor vaccines have demonstrated some significant responses. Immunotherapy has also been applied to mesothelioma, despite the observations that mesothelioma cells induce intratumoral downregulation of cellular, cytokine, and humoral immune responses, which might significantly inhibit any approaches to augment the antitumor immune response.¹⁰³ In particular, high levels of transforming growth factor-ß (TGF-ß) elaborated by mesothelioma cells and tumor-infiltrating macrophages cause downregulation of CD3 molecules on the cell membrane of tumor-infiltrating T lymphocytes, leading to a state of "tolerance" toward the tumor.^{104 105} Mesothelioma cells express abundant class I major histocompatibility complex molecules but only small amounts of class II, and there is no demonstrable expression of the important costimulatory molecule B7–1. This results in minimal natural killer cell antitumor activity, poor presentation of tumor antigens to CD4 helper T lymphocytes, and inadequate stimulation of CD8 cytotoxic T lymphocytes. In addition to the tumor's innate mechanisms of immune evasion, it has been demonstrated that patients with mesothelioma have impaired immune systems: abnormal humoral and cell-mediated immunity, abnormal cell-mediated antibody-dependent cellular toxicity, and defective macrophage and natural killer cell function.^{104 106 107 108}

High local levels of certain proinflammatory cytokines may, however, be able to overcome mesothelioma's innate immune resistance. This rationale has supported several human clinical trials demonstrating varying degrees of tumor regression with intrapleural or systemic infusion of various cytokines, including interleukin (IL)-2, interferon (IFN)-), and IFN-.^{109 110 111 112} IFN- has immunoregulatory effects on antibody production, macrophage function, delayed-type hypersensitivity, and major histocompatability complex antigen expression. It has also been demonstrated to directly inhibit the cellular proliferation of some mesothelioma cells in vitro. In human clinical trials, however, subcutaneous administration of IFN-2a to patients with mesothelioma has yielded only a 12% response rate, although the drug was well tolerated clinically, and there was one complete response.^{113 114} IFN-ß is unlikely to be useful because it is associated with significant toxic side effects. The Southwest Oncology Study Group reported no clinical responses after 6 weeks of systemic IFN-ß treatment in 14 patients with pleural mesothelioma.^{115 116}

Administration of IL-2 in patients with malignant mesothelioma, either alone or in combination with autologous lymphokine-activated killer (LAK) cells, has been evaluated by several groups. Based on in vitro data demonstrating LAK cell–mediated lysis of cultured mesothelioma cells in the presence of IL-2, a small pilot phase I trial was conducted in Australia in which patients received intrapleural LAK cells and recombinant IL-2. Tumor responses were not reported, and there was significant attendant toxicity, including several pleural space infections, noncardiogenic pulmonary edema, liver enzyme elevations, flu-like illness, and skin rash. One of five patients treated died as a result of encephalopathy and noncardiogenic pulmonary edema.¹¹⁷ Recent European phase I–II clinical trials of IL-2 administered by continuous intrapleural infusion revealed a 19% partial response rate with significant dose-related toxicity, primarily the development of ipsilateral empyemas.¹¹⁸ Of note were the high intrapleural:systemic ratios of IL-2, approaching 1,000:1 at the highest dose levels.^{110 118} At the University of Turin in Italy, there is an ongoing clinical trial involving combined systemic and intrapleural IL-2. As of May 1997, 31 patients were enrolled with a response rate of 22.5%, although 90% of patients demonstrated significant reductions in pleural effusion, presumably from an inflammatory pleurodesis. Toxicities were minimal, primarily fever, eosinophilia, and mild cardiac and neurologic side effects.¹¹⁹ The results of a recent French phase II trial of intrapleural IL-2 in patients with mesothelioma revealed a 54% overall response rate with a 41% 3-year survival rate among the responders.¹²⁰

The most impressive clinical results of cytokine therapy in mesothelioma have been with intrapleural delivery of IFN-, a lymphokine produced by T lymphocytes in response to specific antigenic or mitogenic stimuli. IFN- shares the antiproliferative effects of other IFNs and is a potent activator of macrophage antitumor cytotoxicity. In a study of 89 patients treated with intrapleural delivery of IFN-, the overall response rate was 20%, with good tolerance of the cytokine. Eight stage I patients had thoracoscopically and histologically confirmed complete remissions, and nine had partial responses with a > 50% reduction in tumor volume. Most of the significant responses were seen in patients with disease confined to the parietal and diaphragmatic pleura. Overall, patients with stage I disease had a response rate of 45%.^{111 112}

Based on the relative success of intrapleural IFN- in early-stage mesothelioma patients, there is an ongoing French clinical trial of intrapleural delivery of IFN- in combination with IFN-–activated autologous macrophages, harvested from peripheral blood via leukopheresis. The rationale for this trial is that IFN- mediates its antitumor effects by activating tumor-associated macrophages. As of February 1997, 10 patients in International Mesothelioma Interest Group stage IA/B or II had been enrolled, and no significant local or systemic toxicity was seen. Antitumor response remains under evaluation.¹²¹

Other investigators have focused their attention on the use of colony-stimulating factors to initiate an antitumor immune response. Robinson's group¹²² at the University of Western Australia has conducted a phase I clinical trial involving direct intratumoral injection of granulocyte-macrophage colony-stimulating factor (GM-CSF). They reported some local reduction in tumor mass associated with an intense intratumoral lymphocytic infiltrate in two patients. This same group has demonstrated significant therapeutic effects with intraperitoneal delivery of cytokine genes for IFN-, IL-2, and antisense TGF-ß in a murine model of mesothelioma.¹²⁰

Combinations of immunotherapy (cytokines) and chemotherapy have been evaluated in a series of phase I and phase II clinical trials in mesothelioma. These trials have as their rationale in vitro synergistic antiproliferative effects on mesothelioma cell lines of cytokines, such as IFN- in combination with standard chemotherapeutic agents. In human trials, most investigators have focused on the use of the most active single chemotherapeutic drugs (such as doxorubin, mitomycin, and cisplatin) in combination with cytokines with proven antitumor activity (ie, IFN-). No significant difference in survival or relapse rates has been noticed in comparison with single modalities; however, further trials need to be evaluated.^{38 121 122 123}

Gene Therapy
In the absence of other reliably effective therapies for malignant mesothelioma, several groups are investigating the evolving technology of gene therapy. There are several characteristics that make mesothelioma an attractive target for gene therapy. First is the absence of any effective standard therapy. Second is its unique accessibility in the pleural space for vector delivery, biopsy, and subsequent analysis of treatment effects; a surgical debulking procedure to remove gross disease, followed by gene therapy to remove residual disease, would thus be technically feasible. Third, local extension of disease, rather than distant metastases, is responsible for much of the morbidity and mortality associated with this neoplasm. Thus, unlike other more widespread neoplasms, small increments of improvement in local control could engender significant improvements in palliation or survival. Accordingly, a number of gene therapy trials aimed at treating mesothelioma by using a wide variety of approaches have begun or are in the planning stages (Table 1 ).

Experiments have been conducted showing that replication-deficient adenovirus encoding HSVtk (Ad.HSVtk) efficiently transduced mesothelioma cells both in tissue culture and in animal models,^{128 129 130} and that infection with this vector rendered human mesothelioma cells sensitive to doses of GCV that were 2 to 4 logs lower than the doses required to kill cells infected with control virus.¹²⁸ Subsequently, the Ad.HSVtk vector was used to treat established human mesothelioma tumors and human lung cancers growing within the peritoneal cavities of severe combined immunodeficient mice.^{131 132}

Based on this efficacy data in animals and on successful preclinical toxicity testing, a phase I clinical trial for patients with mesothelioma began in November 1995 at the University of Pennsylvania Medical Center in conjunction with Penn's Institute for Human Gene Therapy. In this protocol, one dose of increasing concentrations of Ad.HSVtk vector was administered intrapleurally in patients with mesothelioma who had patent pleural cavities, followed by 2 weeks of IV GCV.¹³³ The protocol was designed as a dose escalation study, starting with a vector dose of 1 x 10⁹ plaque-forming units (pfu) and increasing in half-log intervals to the current dose level of 1 x 10¹² pfu. At the completion of the 14-day GCV course, patients were discharged for outpatient follow-up that included biochemical and hematologic testing and a chest CT scan performed on study day 30. Throughout the study, the patients were carefully evaluated for evidence of toxicity, viral shedding, immune responses to the virus, and radiographic evidence of tumor response.

Between November 1995 and November 1997, 26 patients (21 male, 5 female) were enrolled in the study.¹³⁴ Clinical toxicities of the Ad.HSVtk/GCV gene therapy were minimal, and a maximally tolerated dose was not achieved. Detectable gene transfer was documented in 17 of 25 evaluable patients in a dose-dependent fashion by either DNA polymerase chain reaction (PCR), reverse transcription PCR, in situ hybridization, and/or immunohistochemistry utilizing a murine monoclonal antibody directed against thymidine kinase. All patients treated at dose levels of 3.2 x 10¹¹ pfu demonstrated evidence of tk protein on posttreatment biopsy specimens via immunoblot or immunohistochemistry, with positive staining on the latter of tumor 40 to 50 cell layers below the mesothelial surface (Table 2 ).¹³⁴

As in most phase I trials, the actual clinical effects of Ad.HSVtk/GCV gene therapy on the patients' tumors were difficult to gauge. This is made more difficult because of the heterogeneity of the patient population in terms of age, stage, histologic findings, and vector dose. Given these caveats, 18 of 26 patients have died, with a median posttreatment survival of approximately 11 months and no fatal complications attributable to the gene therapy protocol. One early-stage patient remains without evidence of disease 31 months after completing the protocol. Another patient showed evidence of partial tumor response on follow-up chest CT scan, although his disease subsequently progressed clinically and radiographically. In addition, 3 of the initial 18 patients remained clinically stable for up to 2 years, with no evidence of tumor growth on serial chest radiographs and chest CT scans, before demonstrating evidence of progression.¹³⁴

This initial phase I trial indicated that intrapleural Ad.HSVtk gene therapy was safe, could effectively deliver transgene to superficial areas of mesothelioma tumor nodules, and might be leading to some degree of tumor reduction.¹³⁴ Nevertheless, improved intratumoral gene transfer will likely be necessary for significant clinical responses. This can be achieved by (1) using higher intrapleural doses of Ad.HSVtk; (2) intrapleural injection of Ad.HSVtk after surgical debulking; (3) repeated intrapleural dosing of vector; and (4) direct intratumoral vector injections. Additional phase I trials involving all of these approaches are planned, including an ongoing clinical trial continuing the dose-escalation protocol with a less immunogenic and hepatotoxic adenoviral vector deleted in the E1 and E4 early gene regions.

Immunomodulatory Approaches: Using gene therapy to augment the immune response to tumors is another active area for cancer gene therapy research, as systemic and/or intrapleural administration of cytokines may partially overcome mesothelioma's resistance to immune destruction, but clinical applications are limited by significant associated toxicity (Table 1) . Investigators at Queen Elizabeth II Hospital in Perth, Australia, evaluated intratumoral delivery of cytokine genes in their murine model of mesothelioma as means of stimulating antitumor immune responses without systemic toxicity. Based on successful tumor reduction in animals, they conducted a phase I clinical trial in pleural mesothelioma using a recombinant vaccinia virus (VV) expressing the human IL-2 gene.^{136 137 138} VV was chosen as the vector because of its large genome, proven safety in human vaccines, and the availability of anti-VV antibodies for diagnostic use.

The VV–IL-2 vector was injected intratumorally into palpable chest wall masses in six patients with advanced-stage malignant mesothelioma on a repeated basis. VV–IL-2 messenger RNA was detected in serial tumor biopsy specimens for 3 to 6 days after injection, but uniformly declined to low levels by day 8. Significant serum anti-VV IgG antibody titers were induced in all patients by intratumoral injection of recombinant VV but, interestingly, did not have any bearing on the pattern or duration of VV–IL-2 messenger RNA expression. The presence of anti-VV neutralizing antibodies did, however, correlate with an inability to culture live VV from tumor biopsy samples. Toxicity was minimal aside from fever, and there was no clinical or serologic evidence of spread of VV to patient contacts. No significant tumor regressions were seen in any of the patients, and only minimal intratumoral cellular immune responses were detected.^{136 137 138} In future gene therapy approaches to mesothelioma, VV–IL-2 may prove more efficacious in a more replication-competent form, or as part of a cocktail of cytokine genes delivered via VV (ie, IL-2, IL-12, and GM-CSF).¹³⁶

Another immunomodulatory approach to gene therapy of mesothelioma under intense investigation is intratumoral delivery of a gene encoding for the bacterial heat shock protein HSP-65, one of the most immunogenic molecules known. This "molecular chaperone" is involved in protein folding and transport and mediates increased presentation of tumor antigens. Animal experiments in murine mesothelioma models at the National Heart and Lung Institute in London, England, involving intraperitoneal delivery of HSP-65 by using polycationic liposomes demonstrated a dose-dependent decrease in tumor size and significant prolongation of survival compared with controls, with some mice living as long as 1 year after treatment.¹³⁹

"Combination" Gene Therapy: Tumor Vaccines: A phase I clinical trial combining elements of both the toxic prodrug and genetic immunopotentiation gene therapy approaches is currently underway at the Louisiana State University Medical Center in New Orleans (Table 1) .¹⁴⁰ This approach involves the intrapleural instillation of an allogeneic, irradiated ovarian carcinoma cell line retrovirally transfected with HSVtk (PA1-STK cells), followed by systemic administration of GCV.¹⁴⁰ The rationale behind this trial is that the PA1-STK cells will migrate to areas of intrapleural tumor after instillation, and then facilitate bystander killing of mesothelioma cells after GCV infusion. This bystander killing is theorized to result from passage of toxic GCV metabolites from PA1-STK cells to mesothelioma cells via gap junctions or apoptotic vesicles, as well as the local generation of proinflammatory cytokines, such as tumor necrosis factor- and IL-1, that elicit an influx of cytotoxic lymphocytes producing hemorrhagic tumor necrosis. In experimental models, the combination of intrapleural instillation of HSVtk gene–modified cells and systemic GCV infusion alters the tumor microenvironment in mesothelioma from inhibitory to stimulatory, thereby engendering an antitumor immune response.^{140 141 142}

The Louisiana State University gene therapy trial is a modified phase I dose-escalation study designed to determine the maximally tolerated dose of intrapleurally delivered PA1-STK cells. Patients are admitted to the hospital after insertion of a small intrapleural catheter and receive an initial dose of lethally irradiated PA1-STK cells combined with intrapleural bacille Calmette-Guérin as an adjuvant. Twenty-four hours after instillation of the HSVtk positive cells, a 7-day course of IV GCV is started at a dose of 5 mg/kg twice daily. The indwelling pleural catheter remains in place thoughout the duration of the protocol, providing an opportunity to monitor the intrapleural immune response to HSVtk gene–modified cell therapy. Patients are followed clinically for signs of toxicity and radiographically for evidence of response or progression. Serial intradermal challenges with autologous irradiated tumor are performed before, during, and after vaccine therapy to assay for antitumor delayed-type hypersensitivity reactions.^{140 141}

As of October 1998, six patients have been treated at two dose levels with a maximal dose of 1 x 10⁸ PA1-STK cells. An additional three patients have started a protocol of repeated intrapleural administration of PA1-STK cells followed by courses of systemic GCV. Minimal side effects of treatment have been seen, with no documented toxicities greater than National Cancer Institute grade 3. The most serious complication to date was an episode of transitory atrial fibrillation precipitated by intrapleural catheter insertion. At the present time, two of the initial six patients are still alive. One patient died secondary to extensive pericardial involvement with a tumor, with no obvious direct complication of therapy. Pericardial tissue obtained at the autopsy proved to be negative for thymidine kinase DNA via PCR. Immunologic evaluation of the initial patients' samples is still ongoing, but preliminary findings have shown significant increases in the percentage of CD8 T lymphocytes in pleural fluid after instillation of PA1-STK cells.¹⁴¹ Although all patients underwent skin testing for recall antigens and alloreactivity to PA1-STK cells, only recall reactions to intradermal paramyxovirus (mumps) and Candida were observed, with no demonstrable response to the gene-modified tumor cells.¹⁴⁰ Pleural fluid was analyzed sequentially in patients before and after administration of PA1-STK cells. These results suggest that within 2 h after administration, GCV is present within the pleural space at concentrations observed to elicit tumor killing in vitro and in in vivo models (P. Schwarzenberger, MD; personal communication; September 1998).

Problems and Future Approaches: Optimization of gene delivery remains the major challenge in gene therapy for mesothelioma. Current nonreplicating vectors are limited in their ability to transduce all (or most) tumor cells in a localized malignancy, and they are even less capable of efficiently delivering genes to tumor cells interspersed in a dense, fibrous stroma, as seen in biphasic and sarcomatoid mesotheliomas. One strategy that might be particularly efficient in increasing gene delivery to mesothelioma cells could be the use of replicating viral vectors that have the capability of killing tumors by primary viral lysis and/or via delivery of therapeutic genes to cancer cells.¹⁴³ Promising viruses in this regard are replication-competent adenoviruses and mutants of the herpes simplex virus type 1.¹⁴⁴

	Summary

TOP Abstract Introduction Chemotherapy Radiation Therapy Surgery Palliative Therapy Emerging Modalities Summary References

 
For many years, mesothelioma has been viewed with dread because of its insidious presentation, inexorable progression, and refractoriness to all standard forms of therapy. In the past decade, advances have been made on several fronts that may improve the quality and quantity of life for patients with mesothelioma. New chemotherapy drugs may provide symptomatic relief, and perhaps clinical/radiographic responses, to patients with advanced mesothelioma. Radiation therapy is useful for palliation of localized symptoms as well as for prophylaxis against chest wall implantantion. Multimodality treatment programs that combine surgical cytoreduction with radiation therapy and more effective, less toxic chemotherapeutic agents may offer significant increases in survival for certain subgroups of mesothelioma patients. Other palliative surgical approaches have proved successful in palliation of the significant dyspnea experienced by many mesothelioma patients. Experimental treatments such as PDT, immunotherapy, and gene therapy present a window of hope for all patients with mesothelioma, even if application of these modalities in a routine fashion is years away. The days of therapeutic nihilism by clinicians managing mesothelioma patients may soon be over.

	Acknowledgements

 
The authors would like to acknowledge the contribution of Dr. Sunil Singhal toward the production of this manuscript, as well as the many collaborators and colleagues whose work was described here. This includes past and present members of the Thoracic Oncology Laboratory (Drs. Kunjlata Amin, Leslie Litzky, Katherine Molnar-Kimber, Roy Smythe, Harry Hwang, Claude El-Kouri, Ashraf Elshami, John Roberts, John Kucharczuk, Nabil Rizk, Michael Chang, Seth Force, Michael Lanuti, and Laura Coonrod), members of the Penn Institute for Human Gene Therapy (Drs. Stephen Eck, Joseph Hughes, Nelson Wivel, and James Wilson), Penn Cancer Center (Drs. Steven Hahn, Joseph Friedberg, Joseph Treat, and John Glick, and Adri Ricio, RN) and Drs. Nigel Fraser and Bruce Randazzo at the Wistar Institute. We would also like to thank Drs. Eli Glatstein and Kenneth Algazy for their assistance in reviewing certain aspects of the manuscript.

	Footnotes

 
Abbreviations: Ad.HSVtk = replication-deficient adenovirus encoding herpes simplex thymidine kinase; EPP = extrapleural pneumonectomy; 18-FDG = 18-fluoro-2-deoxyglucose; GCV = ganciclovir; GM-CSF = granulocyte-macrophage colony-stimulating factor; HpD = hematoporphyrin derivative; HSVtk = herpes simplex thymidine kinase; IFN = interferon; IL = interleukin; LAK = lymphokine-activated killer; m-THPC = meta-tetrahydroxyl phenylchlorin; PA1-STK = ovarian carcinoma cell line retrovirally transfected with HSVtk; PCR = polymerase chain reaction; PDT = photodynamic therapy; PET = positron emission tomography; pfu = plaque-forming unit; TGF-ß = transforming growth factor-ß; VV = vaccinia virus

Received for publication November 19, 1998. Accepted for publication January 14, 1999.

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