**2. Surgery for MPM**

#### **2.1 The importance of the MCR in the surgery for MPM**

The MPM is characterized by a singular growth along the pleural surface, representing a challenge for its surgical resection to provide a microscopic free margin (R0 resection) avoiding its direct manipulation. Hence, the best surgical result is a MCR with microscopic positive margins (R1 resection) [9, 10, 15, 16]. For this reason, MCR came to be the main principle of surgery for MPM, based on retrospective data

*Surgical Management of Malignant Pleural Mesothelioma: From the Past to the Future DOI: http://dx.doi.org/10.5772/intechopen.103686*


#### **Table 1.**

*Definitions for TNM for MPM (according to the current eighth edition).*

showing longer survival for MCR when compared to R2 resection [15, 17, 18]. As claimed by the literature, 30% of the patients addressed to surgery is found unresectable in the operating room [15]. Basically, it is important to improve the preoperative identification of an unresectable disease to prevent a futile explorative thoracotomy (ET), promote enrolment to medical therapies, and avoid expensive and not necessary costs [19].


#### **Table 2.**

*Prognostic group for MPM (according to the current eighth edition).*

#### **2.2 The pre-operative role of computed tomography (CT) and spirometry**

Across the literature, the most common factor precluding MCR is the diffuse chest wall invasion (DCWI), which is frequently associated with the contraction of the ipsilateral hemithorax in the CT scan [15, 20]. Growing up, MPM conducts to a restrictive syndrome and reduces the thoracic cage expansion and the diaphragmatic contraction, leading to a respiratory pump failure, as a necessary consequence [21, 22].

Recently, few authors analyzed the thoracic cage volume (TCV), the aerated lung volumes and the pleural thickness according to Response Evaluation Criteria in Solid Tumors (RECIST) modified criteria (the radiological parameters that correlated with the contracted hemithorax) and the pulmonary functions tests (PFTs), particularly the total lung capacity (TLC) (an indicator of the restrictive syndrome), as possible preoperative predictors of unresectability. Particularly, Burt et al. created a novel three-dimensional radiographic metric of the TCV, based on a fully manual segmentation, and demonstrated that a 5% decrease in TCV compared with the contralateral side was significantly associated with unresectability due to DCWI [15], while Bellini and co-workers used two methods already codified in the literature: the semiautomated segmentation of the aerated lung volumes [23] and the RECIST modified criteria measuring pleural thickness (the sum of the two maximum tumor thicknesses, perpendicular to the chest wall or mediastinum, measured at three levels, was reported as the disease burden) [24]. The Italian group found the TLC and the disease burden as independent predictors of unresectability in the multivariable analysis, with an optimal cut-off value of <77.5% and >120.5 mm, respectively; whereas the aerated lung volumes were significantly associated with ET only in the univariable analysis, probably due to the strong correlation with the disease burden. The PFTs seems to be an additional tool to better improve the preoperative identification of MPM disease not amenable to MCR [20], besides to be indicators of cytoreductive efficacy of iCT, as previously demonstrated by Marulli and collaborators [21, 22]. Moreover, both lung volumes and pleural thickness according to RECIST modified criteria play an important and consolidated prognostic role in MPM survival [23–28]. In particular, the pleural thickness has been recently reported as a useful prognostic indicator of MPM —there is joint approval of the Eighth Edition of the tumor, node and metastasis (TNM) staging system and a recommendation to prospectively evaluate the importance of tumor volume or an approximation by tumor thickness [27–30].

*Surgical Management of Malignant Pleural Mesothelioma: From the Past to the Future DOI: http://dx.doi.org/10.5772/intechopen.103686*

### **2.3 Surgical indications**

Early stages MPM (stage I to IIIA according to Eighth Edition TNM staging system) in patients with epithelial subtype and good performance status represents the best indication for surgery. Conversely, absolute contraindications are patients with sarcomatoid or sarcomatoid-predominant histology, pN2 disease (according to Eighth Edition TNM staging system) and/or stage IV, unless in the context of clinical trials [1, 8, 30, 31]. Despite the overall poor prognosis of biphasic histology, according to recent multicentre analyses, a multimodal approach, including cancer-directed surgery, seems to be associated with improved long-term results in very selected patients with biphasic MPM [31, 32], mostly in patients with a lower proportion of sarcomatoid disease [33]. The ipsilateral nodal disease is not an absolute contraindication for surgery, in fact, the pattern of lymphatic drainage of the pleura does not follow the same pathway as for the lung parenchyma; mediastinal nodes may be the initial site of metastases before the lung parenchyma is involved. The International Association for the Study of Lung Cancer (IASLC) staging project recently reported no survival difference between traditional pN1 and pN2. Therefore, clinical and pathological N1 and N2 are combined into a single N1 category including all ipsilateral, intrathoracic nodal metastases, conversely, contralateral or all extrathoracic nodal metastases (N2 category) represent an absolute contraindication for surgery [34]. Before radical surgery, it is recommended to have a diagnosis not only based on cytology, because of the high risk of diagnostic error, but also on tissue confirmation by pleural biopsy (by either videoassisted thoracoscopy (VATS) or by mini-thoracotomy in the presence of fused pleural space, minimizing the number and size of incisions due to the risk of recurrence in the port-sites) to confirm the presence of microscopic subpleural fat tissue invasion and to allow for adequate immunohistochemical analysis [30].

### **2.4 Surgical procedures with curative intent: EPP vs. PD, which one to choose?**

To obtain MCR there are two main surgical options with curative intent—EPP and PD. Both often allows to obtain only cytoreduction, hence surgical resection must be incorporated in multimodality regimens which include CT and/or RT in the neoadjuvant or adjuvant setting, to achieve better outcomes in term of survival and control of the disease [12, 13]. The EPP is a well-standardized procedure, based on the en bloc resection of the parietal and visceral pleura, ipsilateral lung, pericardium, and hemidiaphragm [35]; it has been deemed for many decades the best technique to achieve MCR with its survival benefits [9]. Conversely, PD is a lung-sparing approach, first reported in 1975 [36] and not yet homogenized in all centres: its description has changed according to the surgical technique, curative intent, and clinical indications [37]. Originally, it was suggested as a cytoreductive substitute in patients with a reduced cardiorespiratory reserve, which cannot tolerate the resection of the entire lung. In 2011, the International Mesothelioma Interest Group (IMIG) and the IASLC recommended that surgical procedures for MPM should be classified into three categories—(1) extended PD (EPD), (2) PD, and (3) partial pleurectomy [38], while mediastinal node sampling should be performed with a goal to obtain at least three nodal stations [1].

Both EPP and EPD required diaphragm and pericardial resections and reconstructions. Due to the lack of consistent guidelines, different materials (alloplastic and autologous) and techniques are available according to surgeons' preferences, with the aim to maximize the strength of the patch and to decrease the complications rate. The most frequent complications after diaphragmatic and pericardial reconstructions are the patch dehiscence with abdominal herniation (mostly in the left side), inferior vena cava (IVC) stenosis, cardiac herniation, cardiac tamponade and infection [39].

The most popular material for diaphragmatic reconstruction is the 2 mm-thick expanded polytetrafluroethylene (e-PTFE), often in its dual mesh formulation (with the 2 different surfaces both reduce the adhesion of abdominal organs and facilitate the proliferation of cells in the thoracic side.), fixed with interrupted non-absorbable stitches across the ribs. The use of a synthetic alloplastic material on one hand permits an improvement in resistance, but on the other hand, it is characterized by a noninsignificant risk of infection (2.4%), while the herniation risk oscillates from 3.8– 12%, in particular, the left posterior mediastinum represents the area with the highest incidence of patch dehiscence [39]. To reduce the risk of gastric herniation, it may help leave a small rim (maximus 2 cm) of autologous diaphragm next to the aortic arch and oesophagal hiatus to anchor the patch. On the right side, the herniation of the abdominal organs is less common because of the presence of the liver. However, surgeons should pay attention to preventing the IVC stenosis from leaving a short rim of diaphragmatic tissue or fixing the diaphragmatic mesh to the pericardium edge or the pericardium patch [39].

Similar to a diaphragmatic replacement, synthetic patches are preferred for the repair of the pericardium: among the non-permeable group, the most used is the 0.1 mm-thick e-PTFE, while in the permeable group the polyester and polypropylene prosthesis. The patch is generally sutured with interrupted non-absorbable stitches beginning from the deeper posterior part, while in the inferior side it might be fixed to the diaphragmatic mesh increasing the pericardial space. In fact, the purpose of the pericardial reconstruction is to allow a normal cardiac function, preventing tamponade or diastolic dysfunction. It could be helpful both the fenestration of the mesh or its anchorage leaving unfixed it's superior part for the regular outflow of the pericardial fluid in the directions of the pleural space [39].

*EPP* involves en bloc resection of the visceral and parietal pleura, lung and, if necessary, ipsilateral hemidiaphragm, and pericardium (**Figure 1**). The lung removal allows administrating a higher dose of RT with no risk of radiation pneumonitis, improving the local control of the disease. This procedure was first employed in 1976 [40], becoming the treatment of choice for potentially resectable MPM. In 1999, Sugarbaker and colleagues reported a 5-year OS rate of 46% and a low mortality rate for patients affected by an early stage epithelial MPM, underwent EPP in a multimodal regimen [12]. Subsequently, there have been different series demonstrating a similar trend with a OS of 20–24 months [35, 41]. One decade ago, in a European survey composed of 802 thoracic surgeons, EPP was considered more efficacious than PD and the supplementation with aCT or other associations of multimodal treatments were deemed to enhance the possibility of cure [42]. Nevertheless, its survival advantages, EPP is charged by some disadvantages: it is a debilitating surgical procedure, associated with a morbidity rate of almost 50% and a mortality rate of 5% even in tertiary referral centres, with high expertise in the surgical management of MPM [41].

In particular, it is associated with a reduction in quality of life, a worsening of postoperative cardiorespiratory function, and difficulties in administration, tolerance, and compliance of adjuvant therapy. A single centre trial (Surgery for Mesothelioma After Radiation Therapy, SMART) embraced a novel protocol, consisting in EPP after intensity-modulate radiation therapy (IMRT) (a short hemi-thoracic high dose technique), with good early and long-term results [43]. However, the employment of EPP as part of the multimodal treatment of MPM has been recently debated after the

*Surgical Management of Malignant Pleural Mesothelioma: From the Past to the Future DOI: http://dx.doi.org/10.5772/intechopen.103686*

#### **Figure 1.**

*(a and b) En bloc resection of the lung, parietal, and visceral pleural with diaphragm and pericardium after extrapleural pneumonectomy.*

Mesothelioma and Radical Surgery (MARS)-1 trial reports. This wide randomized trial, comparing EPP with no surgery in terms of survival and quality of life, concluded that "EPP within trimodal therapy offers no benefit and possibly harms patient" [44]. Anyhow, these results were controversial because survival was not the primary outcome of the study, the sample size was small, and the surgical mortality was higher than expected—this trial, in fact, faced several problems in the enrolment of patients with few cases treated by few centres with a not acceptable high mortality rate in the EPP arm that finally conditioned the survival results [45].

*PD* involves the total resection of both the parietal and visceral pleura, while the lung is spared (**Figure 2**).

As claimed by the IMIG classification, it is categorized in [38]:


The first employment of pleurectomy for MPM was in 1975 by Martin and collaborators, who reported a median OS of 16 months in a series of 14 patients [36], extended the year later with 33 MPM patients with a median OS of 21 months [46].

**Figure 2.** *(A and B) Pleurectomy/decortication (PD). (C) Pathological specimen (visceral and parietal pleura) after PD.*

#### *Surgical Management of Malignant Pleural Mesothelioma: From the Past to the Future DOI: http://dx.doi.org/10.5772/intechopen.103686*

Since then, several non-randomized studies have demonstrated the feasibility and safety of PD with various multimodality schemes involving induction and adjuvant treatments [37, 47, 48]. The preservation of the ipsilateral lung is the main advantage of PD compared to EPP, in fact, it allows a surgical treatment even in patients with a marginal cardiopulmonary reserve, making more feasible adjuvant therapies. The efficacy and radicality of PD in advanced MPM are controversial, however, data from literature are divergent [49]. Almost one decade ago, in an editorial Raja Flores [50] underlined the general trend of thoracic surgeons moving from EPP to PD, due to the lack of solid evidence about a significant survival difference between the aforementioned two surgical procedures [51]. According to the author, the main goal of surgery is the removal of as much tumor as possible preventing pneumonectomy with a consequent reduction in perioperative morbidity and mortality.

On the basis of the currently available data the equation tips in favor of PD rather than EPP. The MARS-2 trial [48], a phase III study of 328 patients with resectable MPM of any sub-type, recently completed the recruitment and, in a little over 2 years, will address the question of whether PD adds any survival benefit to systemic CT alone. While awaiting the results of MARS-2, we are justified in offering surgery as part of multimodality treatment to those with the best prognostic factors, ie, epithelioid with no clinical evidence of nodal disease [30]. The correct surgical strategy must be planned with the intention to accomplish MCR opting for the less invasive technique, basically, surgeons should enter the operating room with the intention to perform PD, except in case of extensive lung invasion. With the lack of randomized controlled trials comparing the two intended to treat techniques, it is still debatable which one provides better long-term outcomes. This is the reason why until now there is not a unique therapeutic approach for MPM and physicians base their decision according to their expertise, the performance status of the patient and the characteristic of the neoplasm. Anyhow, it is important that the sick person and his relatives acquire satisfactory information about both the disease and the available treatments [52].

Among the major complications after both surgical techniques, haemothorax is one of the most frequent, mostly after EPP (1–20.6%) than PD (0–4%). In fact, the extensive pleurectomy and the creation of a post-pneumonectomy cavity increase the risk of bleeding. Surgeons should meticulously verify the hemostasis at the end of the procedure in presence of a normal blood pressure, often using tissue sealants, argonbeam coagulation or oxidized regenerated cellulose products.

Empyema is a frequent complication after surgery for MPM (EPP 1.5–29.7%, PD 4–6.8%), often consequently the development of a bronchopleural fistula (BPF) after EPP (1–12%) in debilitated patients, because of the neoadjuvant treatments and the surgical procedure itself. To prevent the development of such life-threatening complication, it is mandatory keeping the bronchial stump as short as possible, to avoid blind-end secretion retention, and prevent excessive devascularisation of the bronchus. To date, there is no evidence that the preventive use of bronchial stump coverage decreases the rate of BPF after EPP. Late empyema could also occur, several weeks after the intervention, in this case often not associated with BPF.

The peculiar and commonest complication after PD is the prolonged air leakage (3.5–57%), consequently the peeling of the visceral pleura with the underlined lung damage. This kind of complication could also cause an empyema due to ascending infection through the longtime chest drain. Surgeons should carefully reduce the postoperative air leaks, mending the lung with stapling device, sutures and sealant. Most of the time conservative management is a correct strategy with the removal of the active suction as soon as possible and the preservation of the chest tube until the resolution of the air leaks with a satisfactory lung expansion, which may take even 2–3 weeks. The post-operative management after PD is not well standardized among the centres—to prevent bleeding and air leakage, some centres prefer to keep patients on mechanical ventilation with positive and expiratory pressure (up to 48 h) to maintain the maximal lung inflation, which aids both the parietal hemostasis by compression and the closure of the parenchymal wounds; other centres prefer to reduce positive pressure ventilation to minimize the air leaks by extubating the patient as soon as possible [37].
