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Advances in the Treatment of Malignant Pleural Mesothelioma

Chest, August, 1999 by Daniel H. Sterman, Larry R. Kaiser, and Steven M. Albelda

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. (CHEST 1999; 116:504-520)

Key words: chemotherapy; extrapleural pneumonectomy; gene therapy; immunotherapy; mesothelioma; photodynamic therapy; pleurectomy; pleurodesis; pneumonectomy; radiation

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 = hematoporpyhrin 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-[Beta] = transforming growth factor-[Beta]; VV = vaccinia virus

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.[4-14] 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

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%.[15-21] 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.[15-18] 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.[15,22-27] 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 toxicity[29]; 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).[16,33,37-46] 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.[16,46-48] A recent report of a phase II trial from Australia involving a combination of cisplatin and gemcitabine demonstrated a partial response rate of [is greater than] 50%, and a 90% rate of symptom improvement among responders.[49]