Update on Malignant Mesothelioma

Malignant pleural mesothelioma (MPM) is an invasive locally aggressive tumor that is nearly always fatal. Historically, treatments resulting in durable control have seemed unobtainable and fostered a somewhat fatalistic management approach. Until recently, no novel therapies had emerged that offered real hope for improvement in the poor median overall and progression- free survival. In this issue of ONCOLOGY, Dr Antman and colleagues provide an overview of the epidemiology, natural history, and management strategies for malignant mesothelioma, with an emphasis on MPM.[1] Local and Regional Therapy
Failure to achieve local disease control within the thorax remains the primary problem in treating MPM. Patients most commonly succumb to pulmonary (restrictive, infectious) and/or cardiac deaths. At present, trimodality therapy (surgery, radiotherapy, and chemotherapy) might be considered the "gold standard." Three distinct surgical objectives are
(1) palliation of breathlessness,
(2) debulking (radical pleurectomy/decortication) and
(3) radical extirpation (extrapleural pneumonectomy). No randomized comparison has been performed, and though local control benefits for extrapleural pneumonectomy are reported, best available analyses have not demonstrated survival benefits.[2] Sugarbaker and colleagues have the largest reported experience with extrapleural pneumonectomy.[3] Median overall survival for 176 patients was 19 months; more favorable nodenegative patients with epithelial histology and R0 resections had a median survival of 51 months. Operative morbidity and mortality were 50% and 4%, respectively. Patients with one of three favorable prognostic features had medial survivals ranging from 21 to 26 months. In a review of 57 completely resected patients treated with extrapleural pneumonectomy (n = 54) or radical pleurectomy/decortication (n = 3) and adjuvant radiotherapy, Rusch and coworkers reported an overall median survival of 17 months (stage I/II, 34 months; stage III/IV, 10 months). Operative morbidity and mortality were 58% and 8%.[4] The approach at the University of California, San Francisco, differs: Unselected patients receive radical pleurectomy/decortication with focal intraoperative electron-beam radiotherapy followed by three-dimensional conformal (until 1997) or intensity- modulated radiation therapy (IMRT). The decision for radical pleurectomy/ decortication was not based on ability to tolerate pneumonectomy, but rather, on a belief that pleurectomy/decortication is better tolerated in patients with an essentially incurable disease. Lee et al reported a median overall survival of 18 months.[5] Operative morbidity and mortality rates were 15% and 7%. Systemic Therapy
Perhaps the most significant changes in MPM management have occurred with systemic therapies as a part of aggressive multimodality programs for potentially resectable patients and targeted therapies (antifolates, antiangiogenesis agents, and tyrosine kinase receptor inhibitors) for the majority of patients who present with unresectable MPM.[6-8] In the most promising study to date, Vogelzang et al reported extremely encouraging results from a phase III randomized trial of pemetrexed(Drug information on pemetrexed)/ cisplatin(Drug information on cisplatin) vs cisplatin alone.[9] Clinical response rates and median survivals were significantly better with multiagent treatment, and as demonstrated in previous trials, patients with better prognostic features (age, performance status, histology, and hematologic parameters) had a better overall response to treatment and outcome. These and other results highlight the importance of using relevant prognostic variables in addition to histology (50% to 70% have epithelioid histology) to better match patient and treatment. The authors briefly touch on this point but do not relate it to how such information might be used for better primary treatment planning or selection for clinical trials. It is undoubtedly naive to assume that a single management approach is appropriate for all patients; using prognotic features to develop risk groups and stratifying patients based on risk, may be a valuable therapeutic approach, predicting tumor response and the development of new therapies. Future Directions
Advances have been made in understanding the pathogenesis, diagnosis, and staging of MPM; however, this has not translated into markedly improved survival. It is what we have not mastered (earlier patient identification, assessment of disease extent) that thwarts our progress. The authors thoughtfully include future management directions, including novel systemic therapies and the potential use of mesothelin-related proteins for screening. Given long latent periods between carcinogen exposure and disease development, and the nonspecific insidious nature of symptoms preceding diagnosis, a sensitive and specific screening test would be invaluable; unfortunately effective screening approaches have eluded oncologists for the majority of cancers. We suggest that future approaches will need to incorporate improved imaging techniques for more accurate assessment of disease extent, evaluation of treatment response, and perhaps better matching of patient and treatment in the setting of clinical trials. Many thoracic oncologic surgeons have been unpleasantly surprised to encounter more extensive and/or unresectable disease at the time of thoracotomy. Lardinois et al described the superiority of integrated positron-emission tomography (PET)-computed tomography in tumor-node-metastasis (TNM) staging of non-small-cell lung cancer.[10] 18F-fluorodeoxyglucose (FDG)-PET has also been shown to be superior in distinguishing benign from malignant pleural disease, delineating disease extent, active tumor sites, and mediastinum, chest wall, and diaphragm invasion.[11] Benard et al showed that FDG-PET may have a prognostic role.[12] In a combined-modality approach, sophisticated image-based technologies (four-dimensional conformal radiotherapy, stereotactic and intraoperative radiotherapy, IMRT, protons) permitting more accurate, targeted treatment delivery will contribute to improved outcomes. Reports from M.D. Anderson Cancer Center and the German Research Cancer Center confirm the benefit of IMRT for safely delivering high-dose postpneumonectomy radiation.[ 13-14] Advanced imaging also has a role in adjuvant radiotherapy treatment planning.[15-19] Another essential task will be to develop approaches to efficaciously combine therapies, while minimizing normal tissue toxicity, thus achieving the best therapeutic ratio. Advances in each of these areas will benefit not only quantity but also quality of life. Conclusions
The final thought offered by Dr. Antman and colleagues is that "welldesigned clinical trials are essential," the sine qua non for therapeutic advancement. Given this truism, the relative paucity of cases of MPM has been both fortunate and unfortunate. Most clinical oncologists are gratified that MPM incidence is not higher; however, small patient numbers and lack of a uniform management approach have hampered the ability to conduct adequately powered prospective randomized trials. Unfortunately, the incidence of MPM secondary to asbestos exposure from the mid-19th century is predicted to increase, with peak incidence 10 to 20 years away,[20] and additional increases in the risk of mesothelioma following environmental exposures resulting from the World Trade Center disaster are feared.[21] The task ahead is clearly identified.