**5. Potential benefits of a less aggressive approach in the management of malignant pleural mesothelioma: Which is the best chemotherapy regimen?**

Trimodality treatment is one of the more invasive approaches in cancer management, and patients might suffer from perioperative complications due to the impaired clinical conditions after induction treatments.

Two surgical techniques are applied to the removal of malignant pleural mesothelioma: extrapleural pneumonectomy and pleurectomy/decortication.

Extrapleural pneumonectomy consists of en bloc resection of the pleura, lung, diaphragm, and pericardium, while pleurectomy/decortication removes the involved pleura and makes the underlying lung free to expand and fill the pleural cavity.

Despite previous studies did not show a significant rising in mortality and morbidity within trimodality protocols (Buduhan et al., 2009; De Perrot et al., 2009; Flores et al., 2006; Krug et al., 2009; Opitz et al., 2006; Rea et al., 2007, 2011; Van Schil et al., 2010, Weder et al., 2004, 2007) extrapleural pneumonectomy is still a controversial approach, especially in the light of the MARS trial results (Treasure et al., 2011).

The choice of extrapleural pneumonectomy (EPP) rather than pleurectomy/decortication (P/D) is not based on scientific evidences but on the surgeon decision.

In 2008, Flores and his group analyzed the outcome of the two surgical procedures in 663 malignant pleural mesothelioma patients (Flores et al., 2008). 60% of the study population received extrapleural pneumonectomy with a perioperative mortality of 7%. Perioperative mortality in the patients who received pleurectomy/decortication was 4%.

112 Malignant Mesothelioma

expansion.

(table 1 and 2).

**regimen?** 

conditions after induction treatments.

extrapleural pneumonectomy and pleurectomy/decortication.

the underlying lung free to expand and fill the pleural cavity.

(P/D) is not based on scientific evidences but on the surgeon decision.

light of the MARS trial results (Treasure et al., 2011).

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

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

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

**5. Potential benefits of a less aggressive approach in the management of** 

Trimodality treatment is one of the more invasive approaches in cancer management, and patients might suffer from perioperative complications due to the impaired clinical

Two surgical techniques are applied to the removal of malignant pleural mesothelioma:

Extrapleural pneumonectomy consists of en bloc resection of the pleura, lung, diaphragm, and pericardium, while pleurectomy/decortication removes the involved pleura and makes

Despite previous studies did not show a significant rising in mortality and morbidity within trimodality protocols (Buduhan et al., 2009; De Perrot et al., 2009; Flores et al., 2006; Krug et al., 2009; Opitz et al., 2006; Rea et al., 2007, 2011; Van Schil et al., 2010, Weder et al., 2004, 2007) extrapleural pneumonectomy is still a controversial approach, especially in the

The choice of extrapleural pneumonectomy (EPP) rather than pleurectomy/decortication

In 2008, Flores and his group analyzed the outcome of the two surgical procedures in 663 malignant pleural mesothelioma patients (Flores et al., 2008). 60% of the study population

**malignant pleural mesothelioma: Which is the best chemotherapy** 

improved in 27.8%, was stable in 50% and worsened in 22.2% of the patients.

The decision to perform EPP rather than P/D was based on patients' clinical condition, intraoperative findings and tumor stage.

In the EPP group there was a higher proportion of patients who received a multimodality treatment, while in P/D group, elderly patients and early stage tumors were included.

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, histology, and multimodality treatment.

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 analyzed in a multivariate analysis with other prognostic factors.

The main limitation of the study was the retrospective data analysis which did not allow any definitive conclusion about the outcome of the two surgical procedures.

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 role of lung-sparing surgery within a trimodality protocol.

As already mentioned, the role of chemotherapy in the multimodality management of malignant pleural mesothelioma aims at reducing distant recurrences.

So far, no randomized trial has compared different chemotherapy regimens in the induction phase of a trimodality protocol.

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

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

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

We observed a higher incidence of grade 2-3 cumulative asthenia and worsening of performance status in the subgroup of patients who received cisplatin rather than carboplatin. Furthermore the postoperative mortality was 4% among patients treated with cisplatin compared to 0% among patients who received carboplatin in the induction chemotherapy regimen. We observed no difference in terms of disease control rate and progression free survival between the two treatment arms, while a longer overall survival (118 *versus* 66 weeks) was shown in patients treated with carboplatin rather than cisplatin. At the multivariate analysis, non-epithelial histology and cisplatin-based chemotherapy were associated to a worse prognosis. It is possible that a less aggressive chemotherapy regimen could improve the outcome of trimodality treatment, and allows second-line treatments to a higher proportion of patients. In our study, in fact, at the time of disease progression 37% of the patients previously treated with cisplatin received a second-line treatment, compared to 58% of the patients treated with carboplatin in the first-line.

Neoadjuvant Chemotherapy in Malignant Pleural Mesothelioma 115

The integration of systemic and local treatments in the multimodality approach seemed to reduce local and distant recurrences, and subsequently to improve the overall survival of

The optimal sequence of chemotherapy, radiotherapy and surgery has not been defined yet, even though trimodality protocols of neoadjuvant chemotherapy followed by extrapleural pneumonectomy and adjuvant radiotherapy achieved the best results, with overall survival

The lack of a randomized study in this setting and the variability among the available phase II studies does not allow to draw any conclusion about the best treatment for mesothelioma patients. Furthermore, those studies evaluated data from selected patients who were eligible for trimodality treatment, subsequently introducing a bias in the final

The role of EPP is still a matter of debate, and the recent results of the MARS trial suggests a

The optimal chemotherapy regimen in the induction phase is not defined, and prospective randomized studies assessing toxicity and survival data of different protocols should be

To improve the response rate to chemotherapy regimen, new biologic agents should be introduced in the clinical practice, so that the best results in terms of tumor shrinkage and

The optimal relationship between toxicity profile and clinical benefit should be investigated especially in the context of a trimodality approach, which implies a long-term treatment in

Buduhan, G., Menon, S., Aye, R., Louie, B., Mehta, V., & Vallières, E. (2009). Trimodality Therapy for Malignant Pleural Mesothelioma. *The Annals of Thoracic Surgery*, Vol.8,

Burdett, S., Stewart, L.A., & Rydzewska, L. (2006). A Systematic Review and Meta-analysis of the Literature: Chemotherapy and Surgery versus Surgery Alone in Non-small Cell Lung Cancer. *Journal of Thoracic Oncology,* Vol.1, No. 7, (September 2006), pp. 611-621,

potential role of a less invasive surgery, such as pleurectomy/decortication.

patients who are often elderly and with impaired performance status.

*Second Medical Oncology Dept., Istituto Oncologico Veneto, Italy* 

affected patients.

data analysis.

designed.

low toxicity could be achieved.

Giulia Pasello and Adolfo Favaretto

No.3, (September 2009), pp.870-876

ISSN 1556-0864/06/0107-0611

**Author details** 

**7. References** 

longer than 20 months in selected patients.

Second line chemotherapy could have an impact on overall survival of mesothelioma patients, as already shown by Manegold and colleagues in the retrospective analysis of patients from the phase III study by Vogelzang in 2003 (Manegold et al., 2005). Another explanation for the longer survival in patients treated with carboplatin might be the higher number of sarcomatoid mesothelioma patients in the subgroup of patients treated with cisplatin.

As far as the doublet carboplatin and pemetrexed doublet concerns, another group recently compared that regimens to cisplatin plus pemetrexed in 54 malignant pleural mesothelioma patients (Emri et al., 2011).

Chemotherapy consisted of pemetrexed plus carboplatin in 34 patients and plus cisplatin in 20 patients; median number of cycles was 6. Surgery was performed in 41% of the study population, and radiotherapy in 29 (54%) patients.

Median overall survival in all the 54 patients was 16 months. When the authors compared overall survival in the two treatment subgroups, they observed a significantly longer survival in patients treated with carboplatin (20 months compared to 15 months in cisplatinsubgroup), while no difference in terms of time to relapse and response rate was observed between the two arms.

On the basis of those results, prospective randomized clinical trials should be designed to evaluate toxicity profile, response rate, survival data of different chemotherapy regimens in the neoadjuvant treatement of malignant mesothelioma patients.

## **6. Conclusion**

Despite the improvement in diagnosis and treatment, malignant pleural mesothelioma patients still have a dismal prognosis, because of the low response rate to chemotherapy and the early relapses.

The integration of systemic and local treatments in the multimodality approach seemed to reduce local and distant recurrences, and subsequently to improve the overall survival of affected patients.

The optimal sequence of chemotherapy, radiotherapy and surgery has not been defined yet, even though trimodality protocols of neoadjuvant chemotherapy followed by extrapleural pneumonectomy and adjuvant radiotherapy achieved the best results, with overall survival longer than 20 months in selected patients.

The lack of a randomized study in this setting and the variability among the available phase II studies does not allow to draw any conclusion about the best treatment for mesothelioma patients. Furthermore, those studies evaluated data from selected patients who were eligible for trimodality treatment, subsequently introducing a bias in the final data analysis.

The role of EPP is still a matter of debate, and the recent results of the MARS trial suggests a potential role of a less invasive surgery, such as pleurectomy/decortication.

The optimal chemotherapy regimen in the induction phase is not defined, and prospective randomized studies assessing toxicity and survival data of different protocols should be designed.

To improve the response rate to chemotherapy regimen, new biologic agents should be introduced in the clinical practice, so that the best results in terms of tumor shrinkage and low toxicity could be achieved.

The optimal relationship between toxicity profile and clinical benefit should be investigated especially in the context of a trimodality approach, which implies a long-term treatment in patients who are often elderly and with impaired performance status.
