**1. Introduction**

92 Malignant Mesothelioma

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Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour with a poor prognosis, directly related to chronic inhalation of asbestos fibres. Despite the extraction, import and marketing of the mineral were banned in most of the industrialized nations, the epidemiologic data foresee a sharp rise of MPM incidence and mortality in the next fifteen years because of the long lag time (even 40 years) from exposure to clinical evidence (Marinaccio et al., 2007).

Malignant mesothelioma is usually diagnosed in the advanced stages and single-modality treatment generally did not achieve higher results than supportive care. MPM shows high refractoriety to systemic treatment, and the response rate in previous series was about 10%- 20% with anthracyclines, antimetabolites, or single agents platinum analogs.

Doublet chemotherapy showed similar results, even though some combinations yielded higher response rates than single agents. Responses are of short duration and complete responses are rarely observed. Currently available chemotherapy regimens achieved a response rate of 30-40% with rare complete responses, a median progression free and overall survival of approximately 6 and 12 months respectively (van Meerbeeck et al., 2005; Vogelzang et al., 2003).

With regard to local treatments, radiotherapy to the entire hemithorax may cause lifethreatening pulmonary toxicity when the lung is not removed.

Extrapleural pneumonectomy (EPP), a surgical procedure introduced in the seventies which implies en bloc resection of the parietal pleurae, lung, ipsilateral pericardium and hemidiaphragm, did not improve the incidence of local and distant recurrences and that was the reason for some centres to perform combined treatments.

Multimodality therapies adopting a combination of surgical resection and adjuvant treatments (chemotherapy, radiotherapy or both) seem to be a better therapeutic option in selected patients (Sugarbaker et al., 1999); the successful results with neoadjuvant chemotherapy in the management of stage III Non-Small Cell Lung Cancer (Rosell et al., 1994) paved the way to several groups for applying this strategy in malignant mesothelioma.

Neoadjuvant Chemotherapy in Malignant Pleural Mesothelioma 95

In 1994, two randomized clinical trials compared the combination of preoperative chemotherapy and surgery to surgery alone (Rosell et al., 1994; Roth et al., 1994). Median survival time, in two trials respectively, were 26 and 64 months in patients treated with platinum-based chemotherapy followed by surgery compared to 8 and 11 months, respectively, in the group who underwent to surgery alone. The effectiveness of such approach was confirmed in a systematic review and meta-analysis where data from 7 randomized clinical trials were available; the authors reported a 18% relative reduction in the risk of death, a significant increase of overall survival and an absolute benefit of 6 % at five years with the use of induction chemotherapy (Burdett et al., 2006, 2007). Subsequently, Song W. and colleagues, published an updated metanalysis with data from 13 studies, included 6 new randomized clinical trials; they reported a significant benefit in terms of overall survival in non-small lung cancer patients treated with chemotherapy followed by surgery compared to surgery alone, and the results were confirmed in the subgroup analysis

where only stage III NSCLC patients were evaluated (Song et al., 2010).

disease, even though the optimal sequence of the three is still unclear.

and 46%, respectively; median 51 months) (Sugarbaker et al., 1999)

adjuvant chemotherapy and radiotherapy in 183 patients.

by carboplatin plus paclitaxel to later patients.

to 11% (Cao et al.,2010).

trimodality treatment.

**2.2. Path to neoadjuvant chemotherapy in malignant pleural mesothelioma** 

The addition of systemic treatment to surgery and radiotherapy aims at reducing metastatic

A major experience in surgical management of malignant mesothelioma was conducted by Sugarbaker et al. who tested the efficacy of extrapleural pneumonectomy followed by

Chemotherapy regimen changed during study time window; doxorubicin and cyclophosphamide with or without cisplatin was administered in the first period, followed

In their experience, patients with microscopic negative resection margins, epithelial histotype and negative lymphnodes, had a better long-term survival (2 and 5 year survival: 68

Patients with non-epithelial histology and extrapleural nodal involvement had worse survival and that underlines the need for a careful selection of patients undergoing a multimodality approach. A number of other studies were published with different regimens of adjuvant chemotherapy with a median overall survival of 13 to 23.9 months. Perioperative mortality in patients treated with adjuvant chemoradiotherapy ranged from 0

The difficult deliver of both postoperative chemotherapy and radiotherapy in most patients induced many groups to explore a trimodality approach based on preoperative chemotherapy,

Furthermore, as well as in non-small cell lung cancer, neoadjuvant chemotherapy could maximize cytoreduction and increase the proportion of patients able to complete the entire

surgery and postoperative radiotherapy in the attempt of improving compliance.

Despite the improvement in diagnosis and treatment, the optimal therapy for mesothelioma patients is highly controversial and the role of surgery and trimodality treatment is under debate. There is no consensus about the benefits of neoadjuvant chemotherapy and about the more effective chemotherapy regimen, despite several clinical trials in this setting were performed.
