**4.1. Effects of neoadjuvant chemotherapy on the risk of perioperative morbidity and mortality**

Many chemotherapeutic agents can cause lung and heart damage even if the type of the injury and its pathogenesis is unclear; however, the alveolo-capillary membrane seems to be the main target of chemotherapy.

Several evidences reported an increased mortality rate and risk of respiratory complications after induction chemotherapy in lung cancer, especially in those patients who received pneumonectomy.

In 2005, data from 74 mesothelioma patients who underwent EPP were analyzed to assess the incidence of perioperative complications (Stewart et al., 2005).

The authors identified three preoperative variables associated to perioperative complications.

Neoadjuvant chemotherapy with cisplatin doublet in combination with gemcitabine (9), pemetrexed (5) or vinorelbine (1) was administered in 20% of the study population, and it was associated to a higher risk of acute lung injury and symptomatic mediastinal shift. Long-standing operations were associated to increased risk of technical and gastrointestinal complications; finally, procedures on the right lung seemed to increase the risk of postoperative pneumonia and overall risk of perioperative mortality.

On the basis of previous results, our group conducted a prospective study to evaluate the effect of neoadjuvant chemotherapy on lung function and exercise capacity in 36 mesothelioma patients suitable for extrapleural pneumonectomy (Marulli et al., 2010).

Pulmonary function tests were performed twice: after the diagnostic video-assisted thoracoscopic surgery and before the first cycle of chemotherapy, and then four weeks after the last chemotherapy cycle. The tests comprised a spirometry with the measurement of slow and forced vital capacity (Vc and FVC), forced expiratory volume in the first second (FEV1), total lung capacity and diffusing capacity of the lung for carbon monoxide (DLCO); and an incremental exercise test using a cycle ergometer to assess the oxygen uptake (VO2), CO2 production (VCO2) and minute ventilation (VE). Blood gas analysis was also performed.

Among the 36 patients included in the study, 52.8% received three cycles of induction chemotherapy with carboplatin (AUC 5) and pemetrexed (500 mg/m2) on day 1 every three weeks; 47.2% received pemetrexed with cisplatin (75 mg/m2) on day 1 every 21 days.

Radiologic assessment after chemotehrapy showed a 44.5% partial response, stable disease in 47.2% and progressive disease in 8.3%. Performance status after induction chemotherapy improved in 27.8%, was stable in 50% and worsened in 22.2% of the patients.

Neoadjuvant Chemotherapy in Malignant Pleural Mesothelioma 113

received extrapleural pneumonectomy with a perioperative mortality of 7%. Perioperative

The decision to perform EPP rather than P/D was based on patients' clinical condition,

In the EPP group there was a higher proportion of patients who received a multimodality

Median overall survival and 5 –year survival in all the patients were 14 months and 12% respectively. Significant prognostic variables were stage, gender, asbestos exposure,

When overall survival was analyzed in the two subgroups, extrapleural pneumonectomy was associated to a worse prognosis, irrespective of stage and perioperative mortality (12 versus 16 months, p<0.001). The difference seemed less evident when survival data were

The main limitation of the study was the retrospective data analysis which did not allow

In line with the results of the MARS study, a randomized trial which analyze the impact of pleurectomy/decortication on the overall survival of mesothelioma patients could define the

As already mentioned, the role of chemotherapy in the multimodality management of

So far, no randomized trial has compared different chemotherapy regimens in the induction

It is possible that the integration of less invasive treatments lead to a better outcome of

Carboplatin is often preferred to cisplatin in the systemic treatment of cancer because it shows a lower incidence of neurotoxicity, nephrotoxicity, nausea and vomiting. When carboplatin substituted cisplatin in malignant pleural mesothelioma patients not eligible for surgery, it showed comparable results in terms of activity (Castagneto et al., 2008; Ceresoli

Recently, our group retrospectively analyzed the feasibility of pemetrexed plus carboplatin or cisplatin as preoperative chemotherapy of malignant pleural mesothelioma (Pasello et al., 2011). 54 patients were consecutively included in a trimodality protocol based on preoperative chemotherapy followed by surgery and adjuvant radiotherapy; neoadjuvant chemotherapy was based on three cycles of pemetrexed (500 mg/m2) plus carboplatin (AUC5) on day 1 every three weeks in 30 patients; 24 patients received pemetrexed (500

treatment, while in P/D group, elderly patients and early stage tumors were included.

mortality in the patients who received pleurectomy/decortication was 4%.

analyzed in a multivariate analysis with other prognostic factors.

role of lung-sparing surgery within a trimodality protocol.

mg/m2) plus cisplatin (75 mg/ m2) on day 1 every 21 days.

any definitive conclusion about the outcome of the two surgical procedures.

malignant pleural mesothelioma aims at reducing distant recurrences.

intraoperative findings and tumor stage.

histology, and multimodality treatment.

phase of a trimodality protocol.

et al., 2006; Favaretto et al., 2003).

mesothelioma patients.

All the parameters estimated for the lung function and exercise tests improved after preoperative chemotherapy; in particular FEV1, oxygen pressure (PaO2) at rest and at the peak of exercise and VO2. A significant improvement of the lung volume indexes was observed in particular for those patients who achieved a partial response to induction chemotherapy; the results of the stratified analysis by response were explained by the cytoreductive effects of chemotherapy on the tumor mass, thus improving the lung expansion.

As already mentioned, chemotherapy could affect the lung function by decreasing the efficiency of alveolar-capillary membrane. In our study, gas exchange parameters were not impacted by induction chemotherapy, probably related to an improvement in alveolar volume. Preoperative chemotherapy seemed not to compromise the cardiopulmonary effectiveness to undergo EPP; such conclusion seems in line with the results of previous studies about trimodality treatment, which did not show increased perioperative mortality (table 1 and 2).
