Malignant pleural mesothelioma (MPM) is a rare cancer commonly associated with asbestos exposure.¹ Recently, it was determined that germline mutations in BRCA1-associated protein-1 (BAP1) may predispose to mesothelioma development in nonasbestos-exposed patients.² Although basic biologic knowledge about MPM has increased during the past decade, and many new potentially active agents have reached various stages of development, the number of novel treatments that have been approved for MPM patients is limited.

The increasing experience of phase II trials assessing the efficacy of surgery-based multimodal treatment of MPM has reached the point where consistent overall survival data ranging between a median survival of 14 and 25.5 months is demonstrated for extrapleural pneumonectomy (EPP).³ To date, combined multimodality treatment is the most commonly used treatment for MPM in many centers. One particular approach involves sequencing the surgery to follow induction chemotherapy—a concept that has been adapted from stage III NSCLC with the idea of downstaging the tumor or eradicating the outer tumor layer for better resectability.⁴ Further justification for sequencing chemotherapy before surgery is the expectation that the chemotherapy regimen will be better tolerated prior to surgery, and the full required dose will be applied.

Recent reviews^5,6 confirm that combined treatment with the antifolate, pemetrexed, and cisplatin achieve best overall survival and quality of life for patients. Therefore, cisplatin plus an antifolate is currently the most frequently used regimen for first line chemotherapy in a neo- or adjuvant setting. The use of induction chemotherapy is supported not only in a response rate of 30% to 40%, but also in convincing resectability rates (up to 74%) for EPP after induction chemotherapy reported in prospective trials.^4,7 Unfortunately, clinical assessment of the chemotherapy treatment response is difficult, and the only available tool for measuring this response is the modified RECIST criteria⁸ which are lacking in reliable reproducibility.⁹ Therefore, although the exact value of induction chemotherapy may be difficult to assess, the reported outcome after induction chemotherapy followed by EPP described in the following paragraph (MST ranging from 14 to 25.5 months) supports this approach and is definitely not inferior to other multimodal concepts, such as adjuvant chemotherapy after surgery (MST ranging from 13 to 24 months.³ The fact that MPM does not respond very well to chemotherapy in comparison with other malignancies has been confirmed in all neoadjuvant treatment studies. Nevertheless, there are reports of chemotherapy-induced complete pathological responses in the literature.¹⁰ However, in our experience of 128 EPP after neoadjuvant chemotherapy with cisplatin/gemcitabine or cisplatin/pemetrexed, we have observed only one complete response to date. The strongest argument for induction versus adjuvant chemotherapy is that chemotherapy is often difficult to administer in the postsurgery period after EPP or P/D, and the necessity of dose reduction is not unusual. Not surprisingly, the physical ability to tolerate chemotherapy as well as compliance and motivation of the patient is much better before major surgery.

Regarding the surgical technique for MPM resection, for the time being, there remains no evidence-based answer as to which procedure – P/D or EPP – is the more appropriate technique for achieving long-term survivors. Most studies have studied one or the other technique, and when studied together, P/D was chosen for earlier stages and EPP for more advanced stages, a decision which is often made only in the operating theatre as a consequence of unreliable clinical staging. A large retrospective multicenter study of 663 patients combining the experience of three large centers in the United States, analyzed the outcome after EPP or P/D in MPM patients treated between 1990 and 2006.¹¹ The authors concluded that the study emphasized the similarities in outcome after EPP or P/D for MPM in a multicenter setting, and they were unable to recommend one surgical approach over the other. In general, patients selected for EPP had locally more advanced disease and P/D was applied in earlier stages. The local recurrence rate was higher for P/D.

The one situation where P/D is clearly advised is for patients with compromised cardiac or pulmonary function, or with certain comorbidities, who are unable to tolerate EPP without excessive risk. If all gross tumor cannot be removed macroscopically especially in stage IV patients, a parenchyma-sparing procedure in the sense of debulking P/D might be recommended.¹² Besides these quite unambiguous situations, the decision to perform P/D or EPP in stage I, II, and III should be individually tailored by combining patients’ performance status, personal wish, and the resectability of the tumor load. Furthermore, adjuvant radiotherapy cannot be applied safely after P/D, because radiation of the intact lungs, results most likely in high rates of pneumonitis, even if modern techniques are applied.

EPP has been a matter of recent controversy despite an increasing amount of phase II studies reporting favorable results (Table 125-1). Recently, the MARS trial¹³ concluded prematurely that “EPP within trimodal therapy offers no benefit and possibly harms patients” although the trial included 16 patients in the EPP arm only. The study was not designed to answer the question of benefit or not of EPP but rather of the feasibility of such a trial. A definitive answer to this question would need an accrual of 670 patients to identify a survival benefit.¹⁴ Also their criticism of too high morbidity and mortality rate is not supported by recently reported trials for trimodality therapy including EPP (Table 125-1) showing that mortality can be reduced to 0% to 5% in experienced centers, while taking into account all studies published between 1985 and 2010 it is reduced to 0 to a maximum of 11.8%.³ Morbidity stays high (22%–82%) but seems to be manageable in terms of improvement in the quality of life for all parameters at 3 months postoperatively.³

Patients with histologically proved mesothelioma and resectable tumor load who would tolerate the different treatment modalities including surgery are considered for a multimodal approach. The patient selection should be discussed by a multidisciplinary panel, including a medical oncologist and a radio-oncologist in addition to the thoracic surgeon, pathologist, and pulmonologist. The clinical staging and functional assessment is mandatory as a basis for this discussion (see Preprocedure Assessment). In many centers, patients only with the epithelial type of MPM and without N2 lymph node metastases are considered as candidates. However, we propose that N2 nodes in MPM are “local” nodes and therefore should not be an exclusion factor. Furthermore, all types of histologies, as long as they are considered to be resectable tumors, should be included within clinical trials. The final analysis of this extended selection concept is pending.