**2. Rationale for neoadjuvant treatment in malignant pleural mesothelioma**

Treatment failure after surgery of malignant mesothelioma occurs frequently; in the attempt of reducing the incidence of local recurrences after extrapleural pneumonectomy, a multimodality approach with surgery followed by adjuvant radiotherapy was explored.

Extrapleural pneumonectomy allows higher doses of radiotherapy to the whole hemithorax by avoiding pulmonary toxicity and the results of this approach is a significant reduction of loco-regional relapses (Rusch et al., 2001).

The issue of extrathoracic metastasis represent a major challenge in the management of the disease because of the impact on overall survival (Rice et al., 2007)

Once a chemotherapy regimen showes activity in malignant pleural mesothelioma, the subsequent step is the addition of such treatment to surgery and radiotherapy to improve the systemic control of the disease.

The success with surgical resection after neoadjuvant chemotherapy in stage IIIA non-small cell lung cancer (Rosell et al., 1994) has been the impetus for several groups to apply this strategy in malignant mesothelioma aiming at reducing the incidence of distant relapse after surgery.

#### **2.1. Neoadjuvant chemotherapy in non-small cell lung cancer**

Until the nineties, local treatments such as surgery or radiotherapy were used alone to treat stage IIIA non-small cell lung cancer (locally invasive primary tumors or tumors associated with involvement of ipsilateral mediastinal or subcarineal lymphnodes). Five-years survival of non-small cell lung cancer patients is highly affected by stage of disease and lymphnodes involvement, and new approaches to improve overall survival has been investigated. The administration of systemic therapy before local treatment is generally referred to as induction or neoadjuvant therapy, and aims to prevent systemic spread of disease, to fight back micrometastasis and to reduce tumor size.

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).

94 Malignant Mesothelioma

mesothelioma.

performed.

**mesothelioma** 

loco-regional relapses (Rusch et al., 2001).

the systemic control of the disease.

back micrometastasis and to reduce tumor size.

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

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

Treatment failure after surgery of malignant mesothelioma occurs frequently; in the attempt of reducing the incidence of local recurrences after extrapleural pneumonectomy, a multimodality approach with surgery followed by adjuvant radiotherapy was explored.

Extrapleural pneumonectomy allows higher doses of radiotherapy to the whole hemithorax by avoiding pulmonary toxicity and the results of this approach is a significant reduction of

The issue of extrathoracic metastasis represent a major challenge in the management of the

Once a chemotherapy regimen showes activity in malignant pleural mesothelioma, the subsequent step is the addition of such treatment to surgery and radiotherapy to improve

The success with surgical resection after neoadjuvant chemotherapy in stage IIIA non-small cell lung cancer (Rosell et al., 1994) has been the impetus for several groups to apply this strategy in malignant mesothelioma aiming at reducing the incidence of distant relapse after surgery.

Until the nineties, local treatments such as surgery or radiotherapy were used alone to treat stage IIIA non-small cell lung cancer (locally invasive primary tumors or tumors associated with involvement of ipsilateral mediastinal or subcarineal lymphnodes). Five-years survival of non-small cell lung cancer patients is highly affected by stage of disease and lymphnodes involvement, and new approaches to improve overall survival has been investigated. The administration of systemic therapy before local treatment is generally referred to as induction or neoadjuvant therapy, and aims to prevent systemic spread of disease, to fight

**2. Rationale for neoadjuvant treatment in malignant pleural** 

disease because of the impact on overall survival (Rice et al., 2007)

**2.1. Neoadjuvant chemotherapy in non-small cell lung cancer** 

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

The addition of systemic treatment to surgery and radiotherapy aims at reducing metastatic disease, even though the optimal sequence of the three is still unclear.

A major experience in surgical management of malignant mesothelioma was conducted by Sugarbaker et al. who tested the efficacy of extrapleural pneumonectomy followed by adjuvant chemotherapy and radiotherapy in 183 patients.

Chemotherapy regimen changed during study time window; doxorubicin and cyclophosphamide with or without cisplatin was administered in the first period, followed by carboplatin plus paclitaxel to later patients.

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

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

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

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 trimodality treatment.
