Update on Mesothelioma

Malignant pleural mesothelioma (MPM) is an orphan disease that has been challenging researchers and clinicians since it was first recognized as a distinct disease entity in the 1960s. There are approximately 3,500 new cases of mesothelioma diagnosed yearly in the United States. Pleural mesothelioma accounts for approximately 80% of cases, peritoneal mesothelioma accounts for 10% to 15% of cases, and there are rare reports of cases originating in the pericardium, testes, and tunica vaginalis.

Asbestos exposure has been directly linked to the development of malignant mesothelioma. The male to female incidence of mesothelioma is reported as 4:1, due largely to workplace exposure to asbestos. Secondhand exposure, due to fibers brought home on clothing and non-workplace exposure during home remodeling/ repair, often leads to a diagnosis at a younger age rather than the average age of diagnosis, which is reported as 70 years. Mesothelioma can also develop following radiation exposure, and a genetic predisposition has been implicated. Erionite, a mineral in the zeolite family with properties similar to asbestos, was found to be the causative agent in the development of mesothelioma with alarming mortality rates in villagers on the Anatolian plateau in Turkey. Geological surveys have also discovered erionite in at least 12 US states, and it has recently been reported that 300 miles of roads in North Dakota, over the past few decades, were surfaced with erionite-containing gravel, thus exposing potentially countless citizens (Carbone et al. Proc Natl Acad Sci U S A. 2011;108[33]:13618). The latency period from exposure, primarily to asbestos, to the development of disease has been reported to be between 20 and 60 years.

The development of accurate studies of early detection seems to be an important aspect of management because the vast majority of patients are still today diagnosed at late stages of the disease, which contributes to the ongoing high mortality. Serum proteins such as mesothelin and osteopontin, though promising, have not achieved the specificity and sensitivity required for routine screening. Tissue biopsy remains the standard for confirming the diagnosis of mesothelioma and distinguishing it from adenocarcinoma of the lung and other malignant conditions. Fluorodeoxyglucose F18 PET-CT imaging is superior to both CT scan and MRI in overall staging and monitoring the response to therapy.

Chemotherapy
In 2004, pemetrexed and cisplatin were granted a US FDA indication for the treatment of malignant mesothelioma. No other agents have been approved thus far in either the first-line or second-line setting. In a randomized controlled trial, Vogelzang and colleagues (J Clin Oncol. 2003;21[14]:2636) reported the results of 456 patients randomized to receive either cisplatin plus placebo vs cisplatin coupled with pemetrexed. In the pemetrexed arm, median survival was reported at 12.1 months vs 9.3 months in the control arm (P =.020, two-sided log-rank test). Median time to progression was also significantly improved: 5.7 months in the doublet vs 3.9 months (P =.001). Response rates were 41.3% in the pemetrexed/cisplatin arm vs 16.7% in the control arm (P < .0001). Smaller trials have evaluated the combination of pemetrexed and carboplatin, with response rates ranging from 19% to 22% and median survival ranging from 13 to 15 months. Substitution of carboplatin for cisplatin in patients for whom cisplatin is not thought to be tolerable remains a viable option. The role of maintenance therapy with pemetrexed is currently under investigation in the Cancer and Leukemia Group B (CALGB) 30901 trial. The overall goal of this trial will be progression-free survival. In this study, patients receive four cycles of pemetrexed and cisplatin, and those who have demonstrated any response or stability of disease will be randomized to receive pemetrexed every 3 weeks vs no further treatment. The patients who receive maintenance therapy will then be compared with those who do not, with regard to disease progression or the development of unacceptable toxicity requiring discontinuation of the chemotherapy. It is expected that up to 96 patients will be enrolled in this multicenter trial. A recent multicenter, multinational trial (Abstract 1LBA. Abstract presented at: 2011 European Multidisciplinary Cancer Congress; September 24, 2011; Stockholm, Sweden), in which 660 patients who were previously treated but had a relapse were randomized to receive vorinostat (a suberoylanilide hydroxamic acid) vs placebo, reported that it did not meet its criteria for response at the study endpoint, which was increased overall survival. Referral to chemotherapy clinical trials should be considered for either first-line therapy or following failure of the now standard pemetrexed/cisplatin regimen.

Surgery
Some would argue that there is no role for surgery based upon the recently reported results of the Mesothelioma and Radical Surgery (MARS) trial. Others debate the optimal nature of surgery for mesothelioma, that is, Update on Mesothelioma extrapleural pneumonectomy (EPP) vs a radical pleurectomy and decortication (PD). Questions addressing the timing of chemotherapy, neoadjuvant vs adjuvant therapy, performance of radiation therapy, and the role of intensity-modulated radiation therapy all complicate the development of a standard treatment protocol for patients with mesothelioma. Is it the failure of chemotherapy or the surgery that prevents patients from enjoying a long remission or even a cure in this disease? These are questions that need to be addressed. However, unfortunately, in a rare disease, randomized trials to answer these many disparate questions are not feasible, and we must look at clinical data from large referral centers where the vast majority of surgical patients are treated.

The MARS trial was designed to be a feasibility study to determine if patients could indeed be randomized to either a surgical or chemotherapy arm. The trial was designed to accrue 50 patients in 1 year to determine if randomization to such radically different arms was feasible, thus paving the way for a much larger trial. The goal was not met in that it took 3 years to accrue 50 patients. Patients were to receive three cycles of a platinum-based chemotherapy (neoadjuvant chemotherapy), and if they met surgical criteria, subsequently randomized to receive an EPP followed by radiation therapy vs the physician’s choice of treatment. Between October 2005 and November 2008, 112 patients were registered, of whom 50 were randomly assigned to EPP (n=24) vs no surgery (n=26). Of those who did not go on to randomization, 33 patients had disease progression, 5 patients had an inoperable status, and 19 patients withdrew from the study. Sixteen of the 24 randomized patients underwent a complete EPP. Of those eight patients who did not complete the EPP, surgery was not even attempted in five patients, and it was abandoned in three patients. Eight of the 16 patients who underwent EPP completed radiation therapy. Median survival was reported at 14.4 months for the EPP group vs 19.5 months for the non EPP group (Treasure et al; MARS trialists. Lancet Oncol. 2011;12[8]:763). Many criticisms have been leveled at this much-advertised study. The number of patients was, in fact, smaller than most published series; the overall survival was lower than presently reported in tertiary care centers; and the morbidity and mortality rates fall outside those that have come to be acceptable (2%-5%) among surgeons who operate on large numbers of patients with mesothelioma.

A recent paper (Flores et al. J Thorac Cardiovasc Surg. 2008;135[3]:620) describing the surgical experience in 663 consecutive patients from three large referral centers was analyzed in an attempt to define the overall survival difference among patients who underwent either PD or an EPP between the years 1990 and 2006. The study concluded that patients who underwent an EPP had a poorer survival than those undergoing a PD, although the author concluded that the reasons for this difference in survival were multifactoral and subject to selection bias. Operative mortality for PD was reported at 4% vs 7% for EPP. The median survival of patients with stage I mesothelioma undergoing either EPP or PD was 38 months vs 7 months for those assessed as stage IV. Others have reported that, for those patients with epithelial disease who have early-stage disease, 45% will be alive at 5 years. This is a significant improvement over the dismal figures that were reported in earlier series of patients. Operative morbidity is limited, and mortality is reported at 3% to 5% by surgeons with a vast experience in operating on patients with this disease. Unfortunately, advanced-stage disease is the first diagnosis for the majority of patients, and, for this group, new strategies need to be developed.

Research and Clinical Trials
In mesothelioma, it is important that patients, if at all possible, be referred to clinical trials, from which data regarding the development of methods of early detection and the optimization of treatment can be derived. This treatment may involve surgery, chemotherapy, and radiation therapy vs a varied combination of these different modalities. These modalities are potentially administered in a varying order with the aim of ultimately defining the best approach to management.

New and often molecularly targeted therapies are being developed on a much more regular basis. There is hope that we will ultimately develop an approach to treatment that will be helpful in prolonging the lives of those with mesothelioma and even potentially curing the disease. Refer to www.cancer.gov/clinicaltrials for a list of trials currently accruing patients diagnosed with mesothelioma.

Mary Hesdorffer, MS, APRN
Mesothelioma Applied Research
Foundation
Alexandria, VA

Dr Harvey I. Pass
Stephen E. Banner Professor of Thoracic
Oncology
Vice Chairman, Research
Department of Cardiothoracic Surgery
NYU Langone Medical Center
New York, NY