Treatment Options Overview
Update in Medicine
Treatment of Mesothelioma
Daniel H. Sherman, MD
Leslie A. Litzky, MD
Larry R. Kaiser, MD
Steven M. Albelda, MD
September 24, 1996
Malignant mesothelioma is an insidious neoplasm with a dismal prognosis and a median survival of six to 18 months [1,2]. It arises from mesothelial surfaces of the pleural and peritoneal cavities, the tunica vaginalis, or the pericardium. This card will discuss the treatment of malignant mesothelioma. The epidemiology, pathology, clinical presentation, and staging of this disorder are discussed separately. (See card "Epidemiology and pathology of malignant mesothelioma" and see card "Clinical presentation and staging of malignant mesothelioma").
For many years, a nihilistic attitude has existed among many physicians and surgeons caring for patients with malignant mesothelioma because of the tumor's characteristically poor response to multiple forms of therapy. Much of this nihilism has been justified, but emerging therapies may offer hope for improved palliation, prolonged survival, and even possible cures in some patients.
CHEMOTHERAPY--Despite multiple single-agent and combination chemotherapy trials over the past two decades in patients with mesothelioma, there is currently little indication for primary use of this modality. Response rates to single-agent chemotherapy have been dismal, ranging from zero to 20 percent. Doxorubicin has the highest single-agent response rate, while methotrexate and cisplatin have demonstrated little efficacy.
Combination therapy with mitomycin and cisplatin showed significant activity in animal studies but only 25 percent total response rates in clinical trials [1,2].
RADIATION THERAPY--Palliative radiotherapy with an attempt to treat the entire involved pleural surface is technically difficult and associated with a high risk of radiation pneumonitis, myelitis, hepatitis, and myocarditis. Mesothelioma is more responsive to radiation therapy than non-small cell lung cancer, but it is not as sensitive as small cell carcinoma.
There have been anecdotal reports of long-term survivals following high-dose external-beam irradiation and even intrapleural administration of radioactive isotopes. Most studies have shown no significant effect upon overall survival in patients with mesothelioma [2]. However, radiation therapy may play a role by preventing chest wall recurrences after thoracoscopy /thoracotomy and in improving local control after pleurectomy or extrapleural pneumonectomy [1,2].
SURGICAL APPROACHES--Although potentially associated with substantial morbidity, surgical treatment of mesothelioma has made the greatest strides in palliating the major symptoms of the disease and has achieved some improvement in survival. The increased use of thoracoscopy has permitted the earlier diagnosis of more patients with mesothelioma, at which point they may be candidates for more aggressive attempts at surgical "cure."
PLEURODESIS--By far the most common and bothersome symptom in mesothelioma is persistent dyspnea from large, unilateral pleural effusions. A reasonable palliative approach is complete drainage of the pleural effusion (by tube thoracostomy or video thoracoscopy) and introduction of an irritative agent into the pleural space (by injection or insufflation) to produce pleurodesis.
At present, the most widely-used compound for pleurodesis is sterile, asbestos-free talc, administered either as a powder or a slurry. Unfortunately, chemical pleurodesis is often unsuccessful in patients with mesothelioma because of:
·Bulky tumor in the pleural space.
·"Trapping" of the lung by a thick visceral pleural peel of tumor.
PLEURECTOMY--Parietal pleurectomy, i.e. open surgical stripping of the pleura and pericardium from the apex of the lung to the diaphragm, is more successful than talc pleurodesis in reducing the recurrence of pleural effusion in mesothelioma. However, pleurectomy alone has not been shown to prolong survival.
Investigators at the Memorial-Sloan Kettering Cancer Center evaluated the combination of parietal pleurectomy with post-operative intrapleural therapy and/or external beam irradiation. They demonstrated a median survival of 22.5 months and a 2-year survival rate of 41 percent in a select group of 27 patients, predominantly with the epithelial subtype [2-4]. Although uncontrolled, these results are better than the usual six to 18 month median survival [1,2].
EXTRAPLEURAL PNEUMONECTOMY--Extrapleural pneumonectomy (EPP) is a radical surgical procedure involving complete removal of the ipsilateral lung along with the parietal and visceral pleura, pericardium with portions of the phrenic nerve, and the majority of the hemidiaphragm. This procedure alone is an excellent means of palliating the profound dyspnea and orthopnea associated with the severe ventilation/perfusion mismatch resulting from lung encasement by tumor. However, EPP has not been shown to significantly prolong survival without adjuvant therapy.
·One group has combined EPP with sequential postoperative chemotherapy (doxorubicin, cyclophosphamide, and cisplatin for four to six cycles) and up to 5500 cGy of adjuvant XRT to the postoperative hemithorax [3,5].
·Other groups have used intracavity chemotherapy or irradiation postoperatively.
·Researchers at the National Cancer Institute are currently investigating post-resectional, photodynamic therapy with/without adjuvant chemo/immunotherapy [6].
EPP in these contexts is designed as a cytoreductive, not a curative procedure. It is associated with significant morbidity and an operative mortality that ranges from five to 35 percent, depending upon the experience of the center and the preoperative condition of the patient. Therefore, patients must be carefully selected.
Candidates for this multimodal approach must initially undergo extensive preoperative evaluation, including chest MRI with sagittal views to assess mediastinal and diaphragmatic involvement, full pulmonary function testing with quantitative ventilation-perfusion scanning for patients with borderline FEV1, and echocardiography to evaluate mediastinal invasion and ventricular function (which is crucial before treatment with anthracycline chemotherapy). Patients greater than 55 years of age may not be candidates for EPP, even if they meet other criteria, because of the increased perioperative mortality rate with older patients.
One group has demonstrated improved short- and long-term survival in patients with mesothelioma using this combined-modality approach [3,5].
·Median overall survival was 16 months, but was improved to 24 months for those with the epithelial subtype.
·Patients who had epithelial mesothelioma and no mediastinal lymph node involvement at resection had a remarkable five-year survival rate of 45 percent.
RECOMMENDATIONS--Our currently recommended course of definitive treatment is to offer EPP with adjuvant chemotherapy +/- local radiotherapy for healthy patients under age of 55 with early-stage mesothelioma (IMIG stage Ia, Ib, II) (show figure), epithelioid histology, and no evidence of mediastinal lymph node involvement. Talc pleurodesis is utilized as a palliative procedure for patients with non-bulky mesothelioma who do not otherwise meet the above criteria. Decortication (visceral/parietal pleurectomy) is viable palliative option for those with more extensive stage mesothelioma. Because of the risk of seeding the peritoneal cavity, we do not recommend routine use of pleuroperitoneal shunts for this disease.
TREATMENT OF NON-PLEURAL FORMS OF MESOTHELIOMA--Patients with peritoneal mesothelioma may have an improved prognosis relative to the pleural form. This may reflect the technical ease of delivery of intraperitoneal chemotherapy as well as the capacity for multiple resections and debulking of peritoneal masses. One third of 25 selected patients with peritoneal mesothelioma in phase II series from the Dana-Farber Cancer Institute remain disease-free two to three years after treatment [7].
There is no effective therapy for mesothelioma of the pericardium or tunica vaginalis, and these neoplasms share the dismal prognosis of the pleural form of the disease [1].
NEW THERAPEUTIC APPROACHES--Despite the small, but significant improvement in survival achieved with intensive multimodality therapy for mesothelioma, it is obvious that less morbid and more effective interventions are needed. Several investigators over the past two decades have attempted to treat this disease primarily by direct instillation of chemotherapeutic and other compounds into the pleural space with minimal success [4,5,8]. Based upon reports that mesothelioma patients with greater amounts of intratumoral lymphocytic infiltration had improved median survival rates, several groups have studied immunotherapy as an alternative means of achieving better tumor response rates [9,10].
IMMUNOTHERAPY--The use of compounds to stimulate an antitumor immune response against pleural malignancy stemmed from the observation that patients who developed empyemas post-thoracotomy for primary lung carcinoma had improved survival rates. Subsequently, intrapleural BCG was studied as a surgical adjuvant, but no significant benefit was seen. Several systemic forms of immunotherapy have been administered to patients with mesothelioma, including interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), both of which demonstrated limited efficacy and substantial adverse effects. Subcutaneous IFN-alpha-2a was found to have some efficacy--one complete response and three partial responses out of 25 patients studied--and was well-tolerated [11].
One group has pioneered the intrapleural administration of immunostimulants to treat mesothelioma, demonstrating significant responses to both intrapleural IL-2 and IFN-gamma [12-14]. Most impressive were the results of intrapleural IFN-gamma in patients with early stage mesothelioma (Butchart Stage I and II) [13,14].
·Eighty-nine patients were treated over 46 months with an overall response rate of 20 percent.
·Eight patients (nine percent) had histologically confirmed complete responses, and nine (10 percent) had partial responses with greater than 50 percent reduction in tumor volume.
·Overall, patients with Stage I disease had a response rate of 45 percent.
New immunotherapy trials in Australia have demonstrated some significant regression with direct intratumoral injection of GM-CSF on a repeated basis. (A. Davidson, personal communication)
GENE THERAPY--Researchers at the University of Pennsylvania Medical Center are currently conducting a phase I clinical trial of gene therapy for malignant mesothelioma. This is the first gene therapy trial to be approved in the United States as primary therapy for any malignancy. Their approach involves intrapleural instillation of replication-deficient, recombinant adenovirus (rAd) which has been genetically engineered to contain the herpes simplex virus thymidine kinase gene (HSVtk).
It is hoped that this approach will induce the following effects:
·Administration of AdHSVtk into the pleural cavity of a patient with mesothelioma will transduce the tumor cells, enabling them to express viral tk, and conferring upon them exquisite sensitivity to the normally non-toxic antiviral drug ganciclovir (GCV).
·Viral tk, unlike mammalian kinases, can catalyze the rate-limiting step of the production of GCV-triphosphate (GCV-PPP), a strong cellular toxin which inhibits function of DNA polymerase.
·The so-called "bystander effect" may allow GCV-PPP and possibly other toxic metabolites to pass through gap junctions between transduced and non-transduced tumor cells.
Established mesothelioma tumors have been successfully eradicated with this approach in several animal models [15-19]. To date, 8 patients have been successfully treated in the Phase I study with minimal adverse effects and some definitive evidence of tk gene transfer [20].
Other gene therapy approaches to the treatment of mesothelioma under investigation in other laboratories include:
·A vaccinia virus-IL-2 construct for direct intratumoral injection [21].
·A recombinant Ad containing the wild-type p53 gene, which is purported to transduce mesothelioma cells, causing overexpression of wild-type p53 and inducing apotosis [22].
References
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