**3. Chemotherapy regimens in the neoadjuvant setting of malignant pleural mesothelioma**

Recently the use of neoadjuvant chemotherapy has been reported in 7 prospective and 3 retrospective published studies, with median overall survival ranging from 23 to 33 months in patients who completed the trimodality treatement (Table 1, 2). Preliminary data are available from other clinical trials, and some studies are still ongoing.

Neoadjuvant Chemotherapy in Malignant Pleural Mesothelioma 97

Van Schil et al., 2010

C-DDP + P X 3 C-DDP + P X 3 C-DDP + P X

54 Gy in 1.8 Gy fractions

TMT: 33

ITT: 13.9 months

months NR

Rea et al., 2011

3

54 Gy in 1.8 Gy fractions then emended to 50.4 Gy in 1.8 Gy fractions

ITT EFS: 6.9 months; ITT PFS: 8.6 months

Krug et al., 2009

4.3% 6.7% 4% 6.5% NR

54 Gy in 1.8 Gy fractions

CT+ EPP: 21.9 months: TMT: 29.1 months

ITT: 10.1 months; CT + EPP: 18.3 months

Reference Buduhan et al.,

CT

Perioperative mortality rate

RT

OS (EPP)

2009

C-DDP/Cb +P; C-DDP + MTX+ Vb; C-DDP+ G; other

EBRT 30 Gy in 1.8-2 Gy fractions + boost 9-18 Gy or IMRT 50 Gy + boost 24 Gy

CT + EPP: 24 months; TMT: 25 months

PFS NR NR

pleural mesothelioma has been changed.

de Perrot et al., 2009

C-DDP +Vn; C-DDP+ P; C-DDP + R; C-DDP + G X 2-6

50 Gy in 2 Gy fractions + boost 10 Gy; or IMRT 54 Gy in 1.8 Gy fractions

NR

**Table 2.** Summary of studies with pemetrexed plus a platinum compound as neoadjuvant

chemotherapy regimen (EPP: extrapleural pneumonectomy; TMT: trimodality treatment; ITT: intention to treat; NR: not reported; NA: not available; EBRT: external beam radiotherapy; IMRT: intensity modulated radiation therapy; EFS: event free survival; OS: overall survival; PFS: progression free survival; RR: response rate; CDDP: cisplatin; G: gemcitabine; Cb: Carboplatin; P: pemetrexed; Vb: vinblastine; Vn: vinorelbine; R: raltitrexed; MTX: methotrexate; CT: chemotherapy; RT: radiotherapy )

When we analyze those results, we should consider the heterogeneity in terms of patient selection, treatment regimens, and methods for follow-up and overall survival analysis.

Over the years standard chemotherapy regimens for systemic treatment of malignant

N° pts 55 60 77 58 54 Study type Retrospective Retrospective Prospective Prospective Prospective

RR NR NR 32.5% 43.9% 29.6% N° EPP 84% 75% 70.1% 72.4% 83.3%

TMT 69% 50% 52% 64.9% 40.7% OS (ITT) NR 14 months 16.8 months 18.4 months 15.5 months


**Table 1.** Summary of studies with gemcitabine plus a platinum compound as neoadjuvant chemotherapy regimen in malignant mesothelioma patients who underwent trimodality treatment. (EPP: extrapleural pneumonectomy; TMT: trimodality treatment; ITT: intention to treat; NR: not reported; IMRT: intensity modulated radiation therapy; OS: overall survival; PFS: progression free survival; RR: response rate; CDDP: cisplatin; G: gemcitabine; Cb: Carboplatin; P: pemetrexed; CT: chemotherapy; RT: radiotherapy )


**pleural mesothelioma** 

Reference Weder et al.,

CT

Perioperative mortality rate

RT

2004

C-DDP 80 mg/m2 d1 + G 1000 mg/m2 d 1,8,15 every 28 days X 3

30 Gy in 2 Gy fractions + site specific boost to 60 Gy

OS(EPP) NR CT + EPP: 23

months

PFS CT + EPP: 16.5

chemotherapy; RT: radiotherapy )

**3. Chemotherapy regimens in the neoadjuvant setting of malignant** 

N° pts 19 61 21 21 63 Study type Prospective Prospective Prospective Prospective Retrospective

RR 32% NR 33.3% 26% 32% N° EPP 84% 74% 80.9% 42% -

TMT 68% 59% 71% 42% - OS (ITT) 23 months 19.8 months 25.5 months 19 months NR

**Table 1.** Summary of studies with gemcitabine plus a platinum compound as neoadjuvant chemotherapy regimen in malignant mesothelioma patients who underwent trimodality treatment. (EPP: extrapleural pneumonectomy; TMT: trimodality treatment; ITT: intention to treat; NR: not reported; IMRT: intensity modulated radiation therapy; OS: overall survival; PFS: progression free survival; RR: response rate; CDDP: cisplatin; G: gemcitabine; Cb: Carboplatin; P: pemetrexed; CT:

available from other clinical trials, and some studies are still ongoing.

Weder et al.,

C-DDP 80 mg/m2 d1 + G 1000 mg/m2 d 1,8,15 every 28 days X 3

50-60 Gy in 2 Gy fractions

CT + EPP: 13.5 months

Recently the use of neoadjuvant chemotherapy has been reported in 7 prospective and 3 retrospective published studies, with median overall survival ranging from 23 to 33 months in patients who completed the trimodality treatement (Table 1, 2). Preliminary data are

2007 Rea et al., 2007 Flores et al.,

Cb AUC 5 d1 + G 1000 mg/m2 d 1,8,15 every 28 days X 3-4

0% 2.2% 0% 0% 3.2%

45 Gy in 1.8 Gy fractions + boost 10-14 Gy in 2 Gy fractions

months 27.5 months CT + EPP + RT:

CT + EPP: 16.3

<sup>2006</sup>Opitz et al., 2006

Before 2003: C-DDP 80 mg/m2 d1 + G 1000 mg/m2 d 1,8,15 every 28 days X 3; After 2003: C-DDP 80 mg/m2 d1 + P 500 mg/m2 d1 every 21 days X 3

30 Gy in 2 Gy fractions + boost 20 Gy or IMRT 45-55 Gy

C-DDP 75 mg/m2 d1 + G 1250 mg/m2 d1,8 every 21 days X 3

54 Gy in 1.8 fractions

months NR NR

33.5 months NR

**Table 2.** Summary of studies with pemetrexed plus a platinum compound as neoadjuvant chemotherapy regimen (EPP: extrapleural pneumonectomy; TMT: trimodality treatment; ITT: intention to treat; NR: not reported; NA: not available; EBRT: external beam radiotherapy; IMRT: intensity modulated radiation therapy; EFS: event free survival; OS: overall survival; PFS: progression free survival; RR: response rate; CDDP: cisplatin; G: gemcitabine; Cb: Carboplatin; P: pemetrexed; Vb: vinblastine; Vn: vinorelbine; R: raltitrexed; MTX: methotrexate; CT: chemotherapy; RT: radiotherapy )

When we analyze those results, we should consider the heterogeneity in terms of patient selection, treatment regimens, and methods for follow-up and overall survival analysis.

Over the years standard chemotherapy regimens for systemic treatment of malignant pleural mesothelioma has been changed.

On the basis of results in the metastatic disease, the association of carboplatin or cisplatin plus gemcitabine was considered as an effective treatment (Byrne et al.,1999; Nowak et al., 2002; Favaretto et al., 2003; Castagneto et al., 2005; Kalmadi et al., 2008).

Neoadjuvant Chemotherapy in Malignant Pleural Mesothelioma 99

The good toxicity profile of chemotherapy regimen and the efficacy and activity results, higher than with other trimodality approaches, suggested further investigation of such

The study investigated the feasibility of three cycles of cisplatin *plus* gemcitabine at the same doses previously adopted, followed by extrapleural pneumonectomy and adjuvant

Chemotherapy was administered to 95% of the patients, while the resection rate was 74%. Complete resection (R0-R1) was achieved in 37 (61%) of the 45 patients who underwent EPP. Trimodality treatment was completed by 36 (59%) patients, with an overall survival of 19.8 months in the intent-to-treat analysis and 23 months in patients who received both

Median time to progression was 13.5 months, while no radiologic response rate was reported in the study. No significant worsening of quality of life was showed during the multimodality treatement. The postoperative mortality (2.2%) and the morbidity rate (35%) were acceptable and underline the need for experienced centre to follow such approach.

Considering the risk of increasing perioperative complications and postoperative mortality with the use of neoadjuvant chemotherapy, the administration of a chemotherapy regimen

Since 1996, our italian group tested the activity of carboplatin plus gemcitabine in a phase II study in 50 mesothelioma patients (Favaretto et al., 2003). We observed partial response in 26% of the patients, a median overall survival and progression free survival of about 16 and

treatment in a Swiss multicenter study (Weder et al., 2007).

radiotherapy up to 60 Grey to the involved hemithorax, in 61 patients.

chemotherapy and surgery with or without adjuvant radiotherapy (Fig.1).

Quality of life assessment was one of the endpoints of the study.

with lower toxicity seemed attractive.

10 months respectively, and an acceptable toxicity profile.

**Figure 1.** Overall survival in the intention-to-treat population .

In 2003 and 2005 two phase III trials were published which reported striking results when cisplatin was associated to pemetrexed and raltitrexed respectively, compared to cisplatin as single agent in mesothelioma patients who were not eligible for curative surgery. Those regimens achieved a response rate of 30-40%, a median progression free and overall survival of approximately 6 and 12 months respectively [(Van Meerbeeck et al., 2005; Vogelzang et al., 2003) .

After the two studies, a combination of cisplatin and an antifolate has become the golden standard in the first line treatment of malignant pleural mesothelioma patients not suitable for surgery and, subsequently, also in neoadjuvant setting.

## **3.1. Doublet chemotherapy with gemcitabine combined to a platinum compound**

Since the end of the nineties, several groups analyzed the effectiveness and toxicity of gemcitabine combined to carboplatin or cisplatin in advanced mesothelioma patients (Byrne et al.,1999; Nowak et al., 2002; Favaretto et al., 2003; Castagneto et al., 2005; Kalmadi et al., 2008).

Those phase II trials showed a response rate ranging from 12% to 47%, an overall survival from 10 to 16 months, and a progression free survival from 6 to 10 months.

In the wake of the results by Byrne and colleagues in metastatic disease, in 2004 a Swiss group conducted a pilot study investigating neoadjuvant chemotherapy with cisplatin and gemcitabine followed by extrapleural pneumonectomy with or without adjuvant radiotherapy in 19 malignant pleural mesothelioma patients with resectable disease (Weder et al., 2004). Induction chemotherapy consisted of three cycles of cisplatin 80 mg/m2 on day 1 *plus* gemcitabine 1000 mg/m2 on day 1, 8, 15 every four weeks.

Extrapleural pneumonectomy was planned in all patients , while the total dose and fractionation of radiotherapy was decided according to resection margins and the target volume (hemitoracic three-dimensional conformal radiotherapy 30 to 60 Gy). 13 (68%) patients completed the entire trimodality treatment.

Response rate to neoadjuvant chemotherapy was 32%; median overall survival in the intention-to-treat population was 23 months and disease free survival in patients who received preoperative chemotherapy and extrapleural pneumonectomy was 16.5 months.

The authors observed a higher compliance to neoadjuvant compared to the adjuvant chemotherapy adopted in a previous study; in fact, the three cycles of chemotherapy were administered successfully in 95% of the patients. The preoperative systemic approach did not increase perioperative mortality rate, and the morbidity rate was in line with previous experience.

The good toxicity profile of chemotherapy regimen and the efficacy and activity results, higher than with other trimodality approaches, suggested further investigation of such treatment in a Swiss multicenter study (Weder et al., 2007).

The study investigated the feasibility of three cycles of cisplatin *plus* gemcitabine at the same doses previously adopted, followed by extrapleural pneumonectomy and adjuvant radiotherapy up to 60 Grey to the involved hemithorax, in 61 patients.

Quality of life assessment was one of the endpoints of the study.

98 Malignant Mesothelioma

al., 2003) .

2008).

experience.

On the basis of results in the metastatic disease, the association of carboplatin or cisplatin plus gemcitabine was considered as an effective treatment (Byrne et al.,1999; Nowak et al.,

In 2003 and 2005 two phase III trials were published which reported striking results when cisplatin was associated to pemetrexed and raltitrexed respectively, compared to cisplatin as single agent in mesothelioma patients who were not eligible for curative surgery. Those regimens achieved a response rate of 30-40%, a median progression free and overall survival of approximately 6 and 12 months respectively [(Van Meerbeeck et al., 2005; Vogelzang et

After the two studies, a combination of cisplatin and an antifolate has become the golden standard in the first line treatment of malignant pleural mesothelioma patients not suitable

**3.1. Doublet chemotherapy with gemcitabine combined to a platinum compound** 

Since the end of the nineties, several groups analyzed the effectiveness and toxicity of gemcitabine combined to carboplatin or cisplatin in advanced mesothelioma patients (Byrne et al.,1999; Nowak et al., 2002; Favaretto et al., 2003; Castagneto et al., 2005; Kalmadi et al.,

Those phase II trials showed a response rate ranging from 12% to 47%, an overall survival

In the wake of the results by Byrne and colleagues in metastatic disease, in 2004 a Swiss group conducted a pilot study investigating neoadjuvant chemotherapy with cisplatin and gemcitabine followed by extrapleural pneumonectomy with or without adjuvant radiotherapy in 19 malignant pleural mesothelioma patients with resectable disease (Weder et al., 2004). Induction chemotherapy consisted of three cycles of cisplatin 80 mg/m2 on day 1

Extrapleural pneumonectomy was planned in all patients , while the total dose and fractionation of radiotherapy was decided according to resection margins and the target volume (hemitoracic three-dimensional conformal radiotherapy 30 to 60 Gy). 13 (68%)

Response rate to neoadjuvant chemotherapy was 32%; median overall survival in the intention-to-treat population was 23 months and disease free survival in patients who received preoperative chemotherapy and extrapleural pneumonectomy was 16.5 months.

The authors observed a higher compliance to neoadjuvant compared to the adjuvant chemotherapy adopted in a previous study; in fact, the three cycles of chemotherapy were administered successfully in 95% of the patients. The preoperative systemic approach did not increase perioperative mortality rate, and the morbidity rate was in line with previous

from 10 to 16 months, and a progression free survival from 6 to 10 months.

*plus* gemcitabine 1000 mg/m2 on day 1, 8, 15 every four weeks.

patients completed the entire trimodality treatment.

2002; Favaretto et al., 2003; Castagneto et al., 2005; Kalmadi et al., 2008).

for surgery and, subsequently, also in neoadjuvant setting.

Chemotherapy was administered to 95% of the patients, while the resection rate was 74%. Complete resection (R0-R1) was achieved in 37 (61%) of the 45 patients who underwent EPP.

Trimodality treatment was completed by 36 (59%) patients, with an overall survival of 19.8 months in the intent-to-treat analysis and 23 months in patients who received both chemotherapy and surgery with or without adjuvant radiotherapy (Fig.1).

Median time to progression was 13.5 months, while no radiologic response rate was reported in the study. No significant worsening of quality of life was showed during the multimodality treatement. The postoperative mortality (2.2%) and the morbidity rate (35%) were acceptable and underline the need for experienced centre to follow such approach.

Considering the risk of increasing perioperative complications and postoperative mortality with the use of neoadjuvant chemotherapy, the administration of a chemotherapy regimen with lower toxicity seemed attractive.

Since 1996, our italian group tested the activity of carboplatin plus gemcitabine in a phase II study in 50 mesothelioma patients (Favaretto et al., 2003). We observed partial response in 26% of the patients, a median overall survival and progression free survival of about 16 and 10 months respectively, and an acceptable toxicity profile.

**Figure 1.** Overall survival in the intention-to-treat population .

Those results led us to evaluate the same chemotherapy combination in the neoadjuvant setting of a multimodality approach in 21 patients with resectable disease (Rea et al., 2007). Patients with stage I to III, epithelial or mixed mesothelioma underwent three to four cycles of chemotherapy with carboplatin [area under the concentration –time curve (AUC) 5] on day 1 and gemcitabine 1000 mg/m2 on days 1,8,15 every four weeks. Patients with complete or partial response or stable disease underwent to extrapleural pneumonectomy within 4-6 weeks. Postoperative radiotherapy consisted of 45 Grey in 25 fractions to the hemitorax, with a boost dose of 10-14 Grey to high risk areas.

Neoadjuvant Chemotherapy in Malignant Pleural Mesothelioma 101

From 2002 to 2004, 21 patients with locally advanced mesothelioma (stage III-IV) were entered into a phase II trial designed to test the feasibility of induction chemotherapy with cisplatin and gemcitabine followed by extrapleural pneumonectomy and external beam hemithoracic radiotherapy (EBRT). Chemotherapy included 4 cycles of gemcitabine 1250 mg/m2 on days 1,8 combined with cisplatin 75 mg/m2 on day 1 every 21 days. Extrapleural pneumonectomy was performed within 3-5 weeks, in those patients who had resectable disease, followed by EBRT 54 Gy/30F starting 3-6 weeks after surgery. 19 patients started chemotherapy and 53% of them completed 4 cycles. Eight patients underwent EPP followed

Response to chemotherapy were: 26% partial response, 32% stable disease, 42% progressive

Seven patients had grade 3 toxicity and one had grade 4 toxicity during chemotherapy, while only 2 (25%) grade 3 and no grade 4 surgical complications occurred. Median overall survival in the intent-to-treat population and in patients who completed also the surgical procedure and radiotherapy was 19 and 33.5 months respectively. The rationale of the trial was to test the multimodality approach in high-risk patients with advanced disease, to

The study was prematurely interrupted because of another prospective competitive trial

Those prospective studies adopting gemcitabine as the third-generation agent associated to platinum in the neoadjuvant setting agree that systemic treatment before surgery did not increase mortality and morbidity rate, provided that trimodality approach was managed by

A retrospective study on 63 mesothelioma patients published in 2006 by the Swiss group (Opitz et al., 2006) aimed at investigating the incidence of postoperative complications in the

Most of the patients (75%), who were included in the study before 2003, received three cycles of chemotherapy with cisplatin 80 mg/m2 on day 1 *plus* gemcitabine 1000 mg/m2 on day 1, 8, 15 every four weeks. Since 2003 the patients (25%) received induction chemotherapy based on three cycles of cisplatin 80 mg/m2 *plus* pemetrexed 500 mg/m2 on day 1 every three weeks.

Chemotherapy was followed by extrapleural pneumonectomy and radiotherapy (45 to 60

Morbidity and mortality rate were 62% and 3.2 % respectively. The most frequent postoperative complication was empyema (15.8%), which was often associated to a longer duration of surgery. Other complications were chylothorax, patch failure, bleeding, herniation. Those complications were successfully managed by the surgical equipe, thanks to an increasing expertise during the years. Furthermore, the authors could predict and earlier treat those patients at higher risk of postoperative complications according to EORTC

reduce the risk of systemic relapase and to improve the outcome of those patients.

by EBRT, thus 42% of patients who completed the trimodality treatement.

disease.

ongoing at the Center.

an experienced multidisciplinary team.

Grey to involved hemithorax including high risk areas).

context of trimodality treatment.

score, improving short-term outcome.

At the reassessment after induction chemotherapy, we observed 7 (33.3%) partial response and 14 (66.7%) stable disease.

The operability rate was about 81%, and 71% of the patients completed the trimodality protocol.

The median overall survival was 25.5 months in the intent-to-treat population, and 27.5 months in patients who received extrapleural pneumonectomy (Fig. 2). Median time to relapse was 16.3 months.

**Figure 2.** Overall survival in the intention to treat population and in patients who underwent extrapleural pneumonectomy for malignant pleural mesothelioma (Rea et al., 2007)

No intraoperative or perioperative morbidity was shown, while major complications were observed in 23.8% of the operated patients.

The absence of postoperative mortality characterizes another prospective study conducted at the Memorial Sloan-Kettering Cancer Center (Flores et al., 2006).

From 2002 to 2004, 21 patients with locally advanced mesothelioma (stage III-IV) were entered into a phase II trial designed to test the feasibility of induction chemotherapy with cisplatin and gemcitabine followed by extrapleural pneumonectomy and external beam hemithoracic radiotherapy (EBRT). Chemotherapy included 4 cycles of gemcitabine 1250 mg/m2 on days 1,8 combined with cisplatin 75 mg/m2 on day 1 every 21 days. Extrapleural pneumonectomy was performed within 3-5 weeks, in those patients who had resectable disease, followed by EBRT 54 Gy/30F starting 3-6 weeks after surgery. 19 patients started chemotherapy and 53% of them completed 4 cycles. Eight patients underwent EPP followed by EBRT, thus 42% of patients who completed the trimodality treatement.

100 Malignant Mesothelioma

with a boost dose of 10-14 Grey to high risk areas.

and 14 (66.7%) stable disease.

relapse was 16.3 months.

protocol.

Those results led us to evaluate the same chemotherapy combination in the neoadjuvant setting of a multimodality approach in 21 patients with resectable disease (Rea et al., 2007). Patients with stage I to III, epithelial or mixed mesothelioma underwent three to four cycles of chemotherapy with carboplatin [area under the concentration –time curve (AUC) 5] on day 1 and gemcitabine 1000 mg/m2 on days 1,8,15 every four weeks. Patients with complete or partial response or stable disease underwent to extrapleural pneumonectomy within 4-6 weeks. Postoperative radiotherapy consisted of 45 Grey in 25 fractions to the hemitorax,

At the reassessment after induction chemotherapy, we observed 7 (33.3%) partial response

The operability rate was about 81%, and 71% of the patients completed the trimodality

The median overall survival was 25.5 months in the intent-to-treat population, and 27.5 months in patients who received extrapleural pneumonectomy (Fig. 2). Median time to

**Figure 2.** Overall survival in the intention to treat population and in patients who underwent

No intraoperative or perioperative morbidity was shown, while major complications were

The absence of postoperative mortality characterizes another prospective study conducted

extrapleural pneumonectomy for malignant pleural mesothelioma (Rea et al., 2007)

at the Memorial Sloan-Kettering Cancer Center (Flores et al., 2006).

observed in 23.8% of the operated patients.

Response to chemotherapy were: 26% partial response, 32% stable disease, 42% progressive disease.

Seven patients had grade 3 toxicity and one had grade 4 toxicity during chemotherapy, while only 2 (25%) grade 3 and no grade 4 surgical complications occurred. Median overall survival in the intent-to-treat population and in patients who completed also the surgical procedure and radiotherapy was 19 and 33.5 months respectively. The rationale of the trial was to test the multimodality approach in high-risk patients with advanced disease, to reduce the risk of systemic relapase and to improve the outcome of those patients.

The study was prematurely interrupted because of another prospective competitive trial ongoing at the Center.

Those prospective studies adopting gemcitabine as the third-generation agent associated to platinum in the neoadjuvant setting agree that systemic treatment before surgery did not increase mortality and morbidity rate, provided that trimodality approach was managed by an experienced multidisciplinary team.

A retrospective study on 63 mesothelioma patients published in 2006 by the Swiss group (Opitz et al., 2006) aimed at investigating the incidence of postoperative complications in the context of trimodality treatment.

Most of the patients (75%), who were included in the study before 2003, received three cycles of chemotherapy with cisplatin 80 mg/m2 on day 1 *plus* gemcitabine 1000 mg/m2 on day 1, 8, 15 every four weeks. Since 2003 the patients (25%) received induction chemotherapy based on three cycles of cisplatin 80 mg/m2 *plus* pemetrexed 500 mg/m2 on day 1 every three weeks.

Chemotherapy was followed by extrapleural pneumonectomy and radiotherapy (45 to 60 Grey to involved hemithorax including high risk areas).

Morbidity and mortality rate were 62% and 3.2 % respectively. The most frequent postoperative complication was empyema (15.8%), which was often associated to a longer duration of surgery. Other complications were chylothorax, patch failure, bleeding, herniation. Those complications were successfully managed by the surgical equipe, thanks to an increasing expertise during the years. Furthermore, the authors could predict and earlier treat those patients at higher risk of postoperative complications according to EORTC score, improving short-term outcome.

#### **3.2. The advent of modern antifolate agents**

Pemetrexed is an antifolate agent which inhibits three target enzymes involved in purine and pyrimidine synthesis: dihydrofolate reductase, thymidylate synthase and glycinamide ribonucleotide formyltransferase.

Neoadjuvant Chemotherapy in Malignant Pleural Mesothelioma 103

During the study time frame, radiotherapy was administered according to two different modalities: conventional external beam radiotherapy (EBRT) to a median dose of 30 Gy in fractions of 1.8-2 Gy (63% of the patients) or intensity-modulated radiotherapy (IMRT) at the median dose of 50.4 Gy/28 F, with higher doses up to 60 Gy to the areas of residual disease

Trimodality treatment was completed by 69% of the initial cohort and median survival time for those patients was 25 months; nodal positivity and macroscopically positive margins

Postoperative mortality rate was 4.3%; major comorbidities were present in 80% of the patients who underwent extrapleural pneumonectomy. Recurrent disease occurred in half of the patients in the ipsilateral hemithorax and it was more common among patients

The main limitation of that study is the retrospective review of patients who started chemotherapy at different sites, so that it was not possible to determine which patients were

A mono-institutional experience was published during the same year (DePerrot et al., 2009), which retrospectively reviewed 60 cases of malignant pleural mesothelioma prospectively included in a trimodality protocol with induction chemotherapy, followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation up to at least 50 Gy.

**Figure 3.** Survival according to mediastinal lymphonodes involvement and completion of the

(34% of the patients).

were considered as predictors of worse survival.

selected for the trimodality treatment.

trimodality protocol, de Perrot et al., 2009

treated with EBRT compared to patients who received IMRT.

Patients with sarcomatoid mesothelioma were excluded.

On the basis of encouraging results of phase I trials in malignant pleural mesothelioma and a phase II study in non-small cell lung cancer, Vogelzang and colleagues conducted a phase III trial of pemetrexed, an antifolate agent, plus cisplatin compared to cisplatin as a single agent in 456 mesothelioma patients who were not elegible for curative surgery.

The doublet regimen achieved a significant improvement in terms of overall survival (12.1 *versus* 9.3 months, *p= 0.02*), time to progression (5.7 *versus* 3.9 months, *p=0.001*) and response rate (41.3% *versus* 16.7%, *p< 0.0001*) compared to single agent chemotherapy (Vogelzang et al., 2003).

Two years later, data from another phase III trial were published, which showed a benefit in terms of overall (11.4 *versus* 8.8 months, *p= 0.048*) and progression free survival (5.3 *versus*  4.0 months, *p= 0.058*), and response rate (23.6% *versus* 13.6%, *p= 0.056*) among patients treated with cisplatin plus raltitrexed, a different thymidylate synthase inhibitor, compared to cisplatin alone (Van Meerbeeck et al., 2005).

As previously mentioned, the combination of ciplatin to an antifolate agent became the golden standard in the systemic treatment of advanced malignant pleural mesothelioma.

More recent neoadjuvant trials have investigated the outcomes of trimodality treatment with this new regimen (Buduhan et al., 2009; De Perrot et al., 2009; Krug et al., 2009; Rea et al., 2011; Van Schil et al., 2010).

#### *3.2.1. Retrospective studies*

Two retrospective studies published in 2009 analyzed the outcomes of mesothelioma patients treated with neoadjuvant chemotherapy before surgery and radiotherapy. Chemotherapy regimen consisted of platinum-based doublet combined to different drugs, even if during the study time it was standardized to cisplatin plus pemetrexed.

The study by the Swedish Medical Center Institute (Buduhan et al., 2009), reviewed a consecutive group of 46 mesothelioma patients who were eligible for trimodality treatment. Preoperative chemotherapy administerd to the initial cohort of 55 patients was based on a platinum compound plus pemetrexed (44%), cisplatin plus methotrexate plus vinblastine (41%), cisplatin plus gemcitabine (9%), other (5%). Mediastinoscopy was performed within 3-5 weeks after completion of chemotherapy in those patients eligible for surgery, and the finding of malignant nodes was an absolute contraindication to extrapleural pneumonectomy. However, 44% of the patients were node positive at resection.

Extrapleural pneumonectomy was feasible in 46 patients (84%), followed by adjuvant radiotherapy in 38 patients within 6-8 weeks from surgery.

During the study time frame, radiotherapy was administered according to two different modalities: conventional external beam radiotherapy (EBRT) to a median dose of 30 Gy in fractions of 1.8-2 Gy (63% of the patients) or intensity-modulated radiotherapy (IMRT) at the median dose of 50.4 Gy/28 F, with higher doses up to 60 Gy to the areas of residual disease (34% of the patients).

102 Malignant Mesothelioma

al., 2003).

**3.2. The advent of modern antifolate agents** 

to cisplatin alone (Van Meerbeeck et al., 2005).

al., 2011; Van Schil et al., 2010).

*3.2.1. Retrospective studies* 

ribonucleotide formyltransferase.

Pemetrexed is an antifolate agent which inhibits three target enzymes involved in purine and pyrimidine synthesis: dihydrofolate reductase, thymidylate synthase and glycinamide

On the basis of encouraging results of phase I trials in malignant pleural mesothelioma and a phase II study in non-small cell lung cancer, Vogelzang and colleagues conducted a phase III trial of pemetrexed, an antifolate agent, plus cisplatin compared to cisplatin as a single

The doublet regimen achieved a significant improvement in terms of overall survival (12.1 *versus* 9.3 months, *p= 0.02*), time to progression (5.7 *versus* 3.9 months, *p=0.001*) and response rate (41.3% *versus* 16.7%, *p< 0.0001*) compared to single agent chemotherapy (Vogelzang et

Two years later, data from another phase III trial were published, which showed a benefit in terms of overall (11.4 *versus* 8.8 months, *p= 0.048*) and progression free survival (5.3 *versus*  4.0 months, *p= 0.058*), and response rate (23.6% *versus* 13.6%, *p= 0.056*) among patients treated with cisplatin plus raltitrexed, a different thymidylate synthase inhibitor, compared

As previously mentioned, the combination of ciplatin to an antifolate agent became the golden standard in the systemic treatment of advanced malignant pleural mesothelioma.

More recent neoadjuvant trials have investigated the outcomes of trimodality treatment with this new regimen (Buduhan et al., 2009; De Perrot et al., 2009; Krug et al., 2009; Rea et

Two retrospective studies published in 2009 analyzed the outcomes of mesothelioma patients treated with neoadjuvant chemotherapy before surgery and radiotherapy. Chemotherapy regimen consisted of platinum-based doublet combined to different drugs,

The study by the Swedish Medical Center Institute (Buduhan et al., 2009), reviewed a consecutive group of 46 mesothelioma patients who were eligible for trimodality treatment. Preoperative chemotherapy administerd to the initial cohort of 55 patients was based on a platinum compound plus pemetrexed (44%), cisplatin plus methotrexate plus vinblastine (41%), cisplatin plus gemcitabine (9%), other (5%). Mediastinoscopy was performed within 3-5 weeks after completion of chemotherapy in those patients eligible for surgery, and the finding of malignant nodes was an absolute contraindication to extrapleural

Extrapleural pneumonectomy was feasible in 46 patients (84%), followed by adjuvant

even if during the study time it was standardized to cisplatin plus pemetrexed.

pneumonectomy. However, 44% of the patients were node positive at resection.

radiotherapy in 38 patients within 6-8 weeks from surgery.

agent in 456 mesothelioma patients who were not elegible for curative surgery.

Trimodality treatment was completed by 69% of the initial cohort and median survival time for those patients was 25 months; nodal positivity and macroscopically positive margins were considered as predictors of worse survival.

Postoperative mortality rate was 4.3%; major comorbidities were present in 80% of the patients who underwent extrapleural pneumonectomy. Recurrent disease occurred in half of the patients in the ipsilateral hemithorax and it was more common among patients treated with EBRT compared to patients who received IMRT.

The main limitation of that study is the retrospective review of patients who started chemotherapy at different sites, so that it was not possible to determine which patients were selected for the trimodality treatment.

A mono-institutional experience was published during the same year (DePerrot et al., 2009), which retrospectively reviewed 60 cases of malignant pleural mesothelioma prospectively included in a trimodality protocol with induction chemotherapy, followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation up to at least 50 Gy. Patients with sarcomatoid mesothelioma were excluded.

**Figure 3.** Survival according to mediastinal lymphonodes involvement and completion of the trimodality protocol, de Perrot et al., 2009

Induction chemotherapy consisted of cisplatin combined with one of the following agents: vinorelbine (43%), pemetrexed (40%), raltitrexed (10%), gemcitabine (7%) for 2 to 6 cycles. Grade 3 (leucopenia) and 4 (pulmonary embolism) toxicity was described in 1(2%) and 3(5%) patients respectively.

Neoadjuvant Chemotherapy in Malignant Pleural Mesothelioma 105

patients. The postoperative mortality was 4% and the rate of postoperative complication

Median survival and progression free survival in the intent-to-treat population were 16.8 and 10.1 months respectively (Fig.4). Overall survival was higher in those patients who completed extrapleural pneumonectomy (21.9 months) and radiotherapy (29.1 months). Furthermore, radiologic response to induction chemotherapy was demonstrated as a significant prognostic factor: patients with complete or partial response had a median overall survival of 26 months compared to 13.9 months in patients with stable and progressive disease. Recurrences occurred in 40.4% of the patients who underwent

The study by Krug and colleagues was the largest prospective trial of trimodality treatment, and shows toxicity and efficacy data in line with previous studies. The authors emphasized the importance of patients selection and team experience in the management of early stage

**Figure 4.** Overall survival (A) and progression free survival (B) in the intention to treat population of

The combination of cisplatin and pemetrexed was the induction regimen adopted from 2005 to 2007 in the multicenter study by European Organization for Research and Treatment of

extrapleural pneumonectomy, with a median time to relapse of 18.3 months.

was in line with the studies we reported previously.

malignant pleural mesothelioma.

the study by Krug et al., 2009

Cancer (EORTC) (Van Schil et al., 2010).

45 patients (75%) underwent extrapleural pneumonectomy, without significant difference between the induction regimens, while only half of the study population completed the trimodality treatment.

Complete resection was shown in 91% of the patients undergoing surgery. The perioperative mortality rate was 6.7%.

Median overall survival in the intention-to-treat population was 14 months; chemotherapy regimen had no impact on overall survival, which was significantly better in patients without mediastinal node involvement who completed the trimodality treatment (59 months compared to 8 months in patients without node involvement but who did not complete the trimodality protocol). N2 involvement was a negative prognostic factor, without any difference between patients who completed or not the protocol. Nodal status showed a significant impact also on disease free survival (Fig.3).

Therefore, the conclusion of the study was to exclude patients with N2 disease from a trimodality protocol.

As well as in the study by Buduhan, also the retrospective analysis by de Perrot was limited by the administration of different chemotherapy regimens during the study time frame.

After the publication by Vogelzang, several prospective clinical trials which evaluated cisplatin plus pemetrexed as standard induction chemotherapy were designed.

#### *3.2.2. Prospective trials*

On the basis of the favourable results by Vogelzang, a multicenter phase II trial from the Memorial Sloan-Kettering Cancer Center group chose pemetrexed and cisplatin as induction chemotherapy regimen before extrapleural pneumonectomy and adjuvant radiotherapy, to assess the feasibility of such trimodality protocol (Krug et al., 2009).

A cohort of 77 patients was included in the protocol, but only 64 (83.1%) completed four cycles of neoadjuvant chemotherapy with pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on day 1 every three weeks. Extrapleural pneumonectomy was completed in 70.1% of the study population, while the trimodality protocol was completed by 40 (52%) patients.

Radiological response to induction chemotherapy was: 1 (1.3%) complete response, 24 (31.2%) partial response, 36 (46.8%) stable disease, 5 (6.5%) progressive disease and 11 (14.3%) patients with unknown or unavailable response.Three (5.3%) pathological complete response were reported. Grade 3-4 haematological toxicity was observed in 7.8% of the patients. The postoperative mortality was 4% and the rate of postoperative complication was in line with the studies we reported previously.

104 Malignant Mesothelioma

3(5%) patients respectively.

perioperative mortality rate was 6.7%.

showed a significant impact also on disease free survival (Fig.3).

trimodality treatment.

trimodality protocol.

*3.2.2. Prospective trials* 

frame.

Induction chemotherapy consisted of cisplatin combined with one of the following agents: vinorelbine (43%), pemetrexed (40%), raltitrexed (10%), gemcitabine (7%) for 2 to 6 cycles. Grade 3 (leucopenia) and 4 (pulmonary embolism) toxicity was described in 1(2%) and

45 patients (75%) underwent extrapleural pneumonectomy, without significant difference between the induction regimens, while only half of the study population completed the

Complete resection was shown in 91% of the patients undergoing surgery. The

Median overall survival in the intention-to-treat population was 14 months; chemotherapy regimen had no impact on overall survival, which was significantly better in patients without mediastinal node involvement who completed the trimodality treatment (59 months compared to 8 months in patients without node involvement but who did not complete the trimodality protocol). N2 involvement was a negative prognostic factor, without any difference between patients who completed or not the protocol. Nodal status

Therefore, the conclusion of the study was to exclude patients with N2 disease from a

As well as in the study by Buduhan, also the retrospective analysis by de Perrot was limited by the administration of different chemotherapy regimens during the study time

After the publication by Vogelzang, several prospective clinical trials which evaluated

On the basis of the favourable results by Vogelzang, a multicenter phase II trial from the Memorial Sloan-Kettering Cancer Center group chose pemetrexed and cisplatin as induction chemotherapy regimen before extrapleural pneumonectomy and adjuvant radiotherapy, to

A cohort of 77 patients was included in the protocol, but only 64 (83.1%) completed four cycles of neoadjuvant chemotherapy with pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on day 1 every three weeks. Extrapleural pneumonectomy was completed in 70.1% of the study

Radiological response to induction chemotherapy was: 1 (1.3%) complete response, 24 (31.2%) partial response, 36 (46.8%) stable disease, 5 (6.5%) progressive disease and 11 (14.3%) patients with unknown or unavailable response.Three (5.3%) pathological complete response were reported. Grade 3-4 haematological toxicity was observed in 7.8% of the

cisplatin plus pemetrexed as standard induction chemotherapy were designed.

population, while the trimodality protocol was completed by 40 (52%) patients.

assess the feasibility of such trimodality protocol (Krug et al., 2009).

Median survival and progression free survival in the intent-to-treat population were 16.8 and 10.1 months respectively (Fig.4). Overall survival was higher in those patients who completed extrapleural pneumonectomy (21.9 months) and radiotherapy (29.1 months). Furthermore, radiologic response to induction chemotherapy was demonstrated as a significant prognostic factor: patients with complete or partial response had a median overall survival of 26 months compared to 13.9 months in patients with stable and progressive disease. Recurrences occurred in 40.4% of the patients who underwent extrapleural pneumonectomy, with a median time to relapse of 18.3 months.

The study by Krug and colleagues was the largest prospective trial of trimodality treatment, and shows toxicity and efficacy data in line with previous studies. The authors emphasized the importance of patients selection and team experience in the management of early stage malignant pleural mesothelioma.

**Figure 4.** Overall survival (A) and progression free survival (B) in the intention to treat population of the study by Krug et al., 2009

The combination of cisplatin and pemetrexed was the induction regimen adopted from 2005 to 2007 in the multicenter study by European Organization for Research and Treatment of Cancer (EORTC) (Van Schil et al., 2010).

Neoadjuvant Chemotherapy in Malignant Pleural Mesothelioma 107

The predefined criteria of successful treatment were set looser, a higher number of patients reached the primary endpoint. The study remarked that trimodality treatment should be considered in centers with high levels of expertise and in the context of prospective clinical

A recent prospective phase II study presented at the latest ASCO (American Society of Clinical Oncology) meeting by our group evaluated neoadjuvant chemotherapy with pemetrexed plus cisplatin followed by extrapleural pneumonectomy (Rea et al., 2011) and

Chemotherapy was administered every three weeks for three cycles, at the following doses: cisplatin 75 mg/m2 and pemetrexed 500 mg/m2. Surgery was performed within 3 weeks after chemotherapy; radiotherapy maximum dose was changed during the study from 54 Gy to 50.4 Gy, and the local radiation was planned within 4-12 weeks after extrapleural pneumonectomy. Chemotherapy was completed in 96%of the study population, while the

Out of 54 patients, 16 (29.6%) showed partial response at the radiological assessment, 31

Median event free survival was 6.9 months, median progression free survival: 8.6 months; median overall survival: 15.5 months; 67% of the patients experienced grade 3-

In line with the previous studies in the same setting, the trimodality protocol presented in the study seemed feasible with manageable toxicity, provided that cardiopulmonary

What is the chance of extrapleural pneumonectomy in the management of malignant pleural mesothelioma? This was the big question from which the Mesothelioma And Radical

The aim of the study was to put an end to the debate between believers and doubters about that surgical procedure, through a randomization between induction chemotherapy followed by extrapleural pneumonectomy and induction chemotherapy without EPP.

Initially, to assess the patients' compliance and the recruitment rate, a feasibility exploratory analysis was performed which randomized 50 patients in 1 year between the two treatment arms. The randomization seemed to be feasible in 45% of the patients included in the study, and a larger trial was published two years later, with the aim of evaluating the clinical

The MARS study was a multicenter randomized controlled trial in 12 United Kingdom hospitals, with a two-stage consent process, before registration and before randomization

Surgery (MARS) trial rose in 2005 (Treasure et al.,2006, 2009, 2011) (Fig. 6).

trials for selected early stage malignant mesothelioma patients.

hemithoracic radiation in 54 mesothelioma patients.

trimodality treatment was completed in 22 (40.7%) patients.

4 toxicity.

(Fig.6).

function is closely monitored.

outcome in randomly assigned patients.

**3.3. The MARS trial** 

(57.4%) showed stable disease, 4 (7.4%) showed progressive disease.

**Figure 5.** Overall survival and progression free survival (B) in the study population by Van Schil et al., 2010)

The primary endpoint of the study was to evaluate the "success of treatment" of a trimodality protocol based on induction chemotherapy with three cycles of cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every three weeks followed by extrapleural pneumonectomy within 3-8 weeks after the last chemotherapy cycle and adjuvant hemithoracic radiotherapy (54 Gy/30 F).

Success of treatment was defined as the completion of the trimodality protocol within the defined time frames and a survival of 90 days without progression or grade 3-4 toxicity. Overall survival, progression free survival and toxicity were secondary endpoints.

58 patients were included in the study, 57 of them started chemotherapy and 55 (94%) completed three cycles of chemotherapy. Extrapleural pneumonectomy was performed in 72.4%of the eligible patients, while 63.8% received also radiotherapy and completed the trimodality protocol.

Grade 3-4 toxicity after chemotherapy was observed in 27.7% of the patients, and persisted in 5.7% of the study population 90 days after the end of the protocol.

Radiological response at the end of induction chemotherapy was: complete in 24.6%, partial in 19.3%, stable in 42.1%, progressive in 8.8% and not assessable in 5.3% of the patients. After surgery, postoperative complications were described in 82.6% of the patients, while postoperative mortality rate was 6.5%. The primary endpoint was reached in 42.1% of the patients, that was lower than the 60% success rate needed to further investigate the trimodality treatment.

Median overall survival in the intention-to-treat population and in patients who completed the trimodality protocol was 18.4 and 33 months respectively; progression free survival for 57 eligible patients was 13.9 months (Fig.5).

The predefined criteria of successful treatment were set looser, a higher number of patients reached the primary endpoint. The study remarked that trimodality treatment should be considered in centers with high levels of expertise and in the context of prospective clinical trials for selected early stage malignant mesothelioma patients.

A recent prospective phase II study presented at the latest ASCO (American Society of Clinical Oncology) meeting by our group evaluated neoadjuvant chemotherapy with pemetrexed plus cisplatin followed by extrapleural pneumonectomy (Rea et al., 2011) and hemithoracic radiation in 54 mesothelioma patients.

Chemotherapy was administered every three weeks for three cycles, at the following doses: cisplatin 75 mg/m2 and pemetrexed 500 mg/m2. Surgery was performed within 3 weeks after chemotherapy; radiotherapy maximum dose was changed during the study from 54 Gy to 50.4 Gy, and the local radiation was planned within 4-12 weeks after extrapleural pneumonectomy. Chemotherapy was completed in 96%of the study population, while the trimodality treatment was completed in 22 (40.7%) patients.

Out of 54 patients, 16 (29.6%) showed partial response at the radiological assessment, 31 (57.4%) showed stable disease, 4 (7.4%) showed progressive disease.

Median event free survival was 6.9 months, median progression free survival: 8.6 months; median overall survival: 15.5 months; 67% of the patients experienced grade 3- 4 toxicity.

In line with the previous studies in the same setting, the trimodality protocol presented in the study seemed feasible with manageable toxicity, provided that cardiopulmonary function is closely monitored.

## **3.3. The MARS trial**

106 Malignant Mesothelioma

2010)

endpoints.

trimodality protocol.

trimodality treatment.

57 eligible patients was 13.9 months (Fig.5).

hemithoracic radiotherapy (54 Gy/30 F).

**Figure 5.** Overall survival and progression free survival (B) in the study population by Van Schil et al.,

(A) (B)

The primary endpoint of the study was to evaluate the "success of treatment" of a trimodality protocol based on induction chemotherapy with three cycles of cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every three weeks followed by extrapleural pneumonectomy within 3-8 weeks after the last chemotherapy cycle and adjuvant

Success of treatment was defined as the completion of the trimodality protocol within the defined time frames and a survival of 90 days without progression or grade 3-4 toxicity. Overall survival, progression free survival and toxicity were secondary

58 patients were included in the study, 57 of them started chemotherapy and 55 (94%) completed three cycles of chemotherapy. Extrapleural pneumonectomy was performed in 72.4%of the eligible patients, while 63.8% received also radiotherapy and completed the

Grade 3-4 toxicity after chemotherapy was observed in 27.7% of the patients, and persisted

Radiological response at the end of induction chemotherapy was: complete in 24.6%, partial in 19.3%, stable in 42.1%, progressive in 8.8% and not assessable in 5.3% of the patients. After surgery, postoperative complications were described in 82.6% of the patients, while postoperative mortality rate was 6.5%. The primary endpoint was reached in 42.1% of the patients, that was lower than the 60% success rate needed to further investigate the

Median overall survival in the intention-to-treat population and in patients who completed the trimodality protocol was 18.4 and 33 months respectively; progression free survival for

in 5.7% of the study population 90 days after the end of the protocol.

What is the chance of extrapleural pneumonectomy in the management of malignant pleural mesothelioma? This was the big question from which the Mesothelioma And Radical Surgery (MARS) trial rose in 2005 (Treasure et al.,2006, 2009, 2011) (Fig. 6).

The aim of the study was to put an end to the debate between believers and doubters about that surgical procedure, through a randomization between induction chemotherapy followed by extrapleural pneumonectomy and induction chemotherapy without EPP.

Initially, to assess the patients' compliance and the recruitment rate, a feasibility exploratory analysis was performed which randomized 50 patients in 1 year between the two treatment arms. The randomization seemed to be feasible in 45% of the patients included in the study, and a larger trial was published two years later, with the aim of evaluating the clinical outcome in randomly assigned patients.

The MARS study was a multicenter randomized controlled trial in 12 United Kingdom hospitals, with a two-stage consent process, before registration and before randomization (Fig.6).

Neoadjuvant Chemotherapy in Malignant Pleural Mesothelioma 109

After the first informed consent and registration, 112 patients underwent mediastinoscopy and PET, then 94 received at least one cycle of chemotherapy; in particular 83 (74%) of them received three cycles of platinum-based chemotherapy. The most common chemotherapy regimen adopted was cisplatin and gemcitabine (40%), followed by cisplatin and pemetrexed (26%), cisplatin and mitomycin and vinblastine (21%). At the end of chemotherapy patients underwent CT scan and they were re-evaluated for the eligibility to

A second informed consent was provided to 50 patients before randomization. The proportion of patients who accepted to enter the registration phase was carefully

Patients in the control arm were eligible for any oncological treatment, which included

24 patients were assigned to extrapleural pneumonectomy, 26 to no EPP. Among patients in the first group, 16 (67%) completed extrapleural pneumonectomy; perioperative deaths occurred in 15.8% of the patients and perioperative complications in 69% of the patients. Half of the patients who underwent extrapleural pneumonectomy received

As far as the second group is concerned, further oncological treatment was administered to 32% of them; in particular, three patients received extrapleural pneumonectomy outside the trial. Among the 30 deaths within the first 24.7 months from randomization, 4 were perioperative events: 3 in the EPP arm, and 1 in the no EPP arm which occurred in a patient

Median survival from randomization was 14.4 months in patients addressed to EPP and 19.5 months in patients who did not undergo extrapleural pneumonectomy (p=0.016, after adjustment for prognostic factors). Median recurrence free survival in EPP group was 7.6

Median quality of life seemed better in those patients who did not undergo extrapleural pneumonectomy; the lowest scores in EPP group were observed shortly after surgery.

The MARS trial was the first study which randomized between extrapleural pneumonectomy and no extrapleural pneumonectomy in the management of malignant pleural mesothelioma. The study population was small but the conclusion of the trial raised the issue of a less invasive approach as suitable treatment of malignant pleural mesothelioma. Those results are supported by previous data from the surgical group of Flores where extrapleural pneumonectomy was compared to pleurectomy/decortication in a multi-institutional trial where 663 patients consecutively underwent one of the two surgical procedures. The mortality rate was higher in patients treated with extrapleural pneumonectomy (7%) compared to patients who underwent pleurectomy/decortication (4%)

months; median progression free survival in no EPP group was 9.0 months.

chemotherapy, radiotherapy, every surgical procedure but EPP, full supportive care.

extrapleural pneumonectomy.

who underwent EPP outside the clinical trial.

documented.

radiotherapy.

(Flores et al., 2008)..

**Figure 6.** Study design of the Mesothelioma And Radical Surgery (MARS) trial.

After the first informed consent and registration, 112 patients underwent mediastinoscopy and PET, then 94 received at least one cycle of chemotherapy; in particular 83 (74%) of them received three cycles of platinum-based chemotherapy. The most common chemotherapy regimen adopted was cisplatin and gemcitabine (40%), followed by cisplatin and pemetrexed (26%), cisplatin and mitomycin and vinblastine (21%). At the end of chemotherapy patients underwent CT scan and they were re-evaluated for the eligibility to extrapleural pneumonectomy.

108 Malignant Mesothelioma

**Figure 6.** Study design of the Mesothelioma And Radical Surgery (MARS) trial.

A second informed consent was provided to 50 patients before randomization. The proportion of patients who accepted to enter the registration phase was carefully documented.

Patients in the control arm were eligible for any oncological treatment, which included chemotherapy, radiotherapy, every surgical procedure but EPP, full supportive care.

24 patients were assigned to extrapleural pneumonectomy, 26 to no EPP. Among patients in the first group, 16 (67%) completed extrapleural pneumonectomy; perioperative deaths occurred in 15.8% of the patients and perioperative complications in 69% of the patients. Half of the patients who underwent extrapleural pneumonectomy received radiotherapy.

As far as the second group is concerned, further oncological treatment was administered to 32% of them; in particular, three patients received extrapleural pneumonectomy outside the trial. Among the 30 deaths within the first 24.7 months from randomization, 4 were perioperative events: 3 in the EPP arm, and 1 in the no EPP arm which occurred in a patient who underwent EPP outside the clinical trial.

Median survival from randomization was 14.4 months in patients addressed to EPP and 19.5 months in patients who did not undergo extrapleural pneumonectomy (p=0.016, after adjustment for prognostic factors). Median recurrence free survival in EPP group was 7.6 months; median progression free survival in no EPP group was 9.0 months.

Median quality of life seemed better in those patients who did not undergo extrapleural pneumonectomy; the lowest scores in EPP group were observed shortly after surgery.

The MARS trial was the first study which randomized between extrapleural pneumonectomy and no extrapleural pneumonectomy in the management of malignant pleural mesothelioma. The study population was small but the conclusion of the trial raised the issue of a less invasive approach as suitable treatment of malignant pleural mesothelioma. Those results are supported by previous data from the surgical group of Flores where extrapleural pneumonectomy was compared to pleurectomy/decortication in a multi-institutional trial where 663 patients consecutively underwent one of the two surgical procedures. The mortality rate was higher in patients treated with extrapleural pneumonectomy (7%) compared to patients who underwent pleurectomy/decortication (4%) (Flores et al., 2008)..

Overall survival was longer in those patients who were treated with pleurectomy/decortication; however gender, stage, histotype were significant factors which impacted the patients' outcome.

Neoadjuvant Chemotherapy in Malignant Pleural Mesothelioma 111

On the other side the delay of the surgical procedure is a disadvantage of neoadjuvant

Some authors reported the impairment of cardiorespiratory function as another detrimental effect of induction chemotherapy and showed an increased risk of perioperative morbidity

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

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

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

In 2005, data from 74 mesothelioma patients who underwent EPP were analyzed to assess

The authors identified three preoperative variables associated to perioperative

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

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

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.

chemotherapy, especially when chemotherapy is not effective

the incidence of perioperative complications (Stewart et al., 2005).

postoperative pneumonia and overall risk of perioperative mortality.

and mortality.

**and mortality** 

pneumonectomy.

complications.

performed.

the main target of chemotherapy.

In the future, a randomized study to evaluate the outcome of patients treated with pleurectomy/decortication is needed.
