Surgical Management of Malignant Pleural Mesothelioma: From the Past to the Future

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a poor prognosis, principally caused by a prior asbestos exposure. Up to the present, multimodality protocols including surgery with chemotherapy (CT) and/or radiotherapy (RT) represent the therapeutic gold standard for selected patients (epithelial and early-stage MPM). In this context, the aim of surgery is to accomplish the macroscopic complete resection (MCR). There are two main surgical options to obtain MCR—extrapleural pneumonectomy (EPP) and pleurectomy/decortication (PD). The superiority of one surgical approach over the other is still discussed. To date, the decision to carry out one or the other in a multimodal setting is established on surgeons’ preference more than on strong scientific evidence. Due to the high morbidity, both surgical techniques should be achieved in tertiary referral centres. In summary, surgery, CT, and RT have failed as single modality therapies with no effects on patients survival. This aspect may be justified by the lack of randomized trials. Thus, novel therapeutic strategies, such as multimodality treatment and targeted agents, seem to prolong the survival and the quality of life. The aim of this chapter is to provide a complete overview of the current surgical approaches to MPM, discussing within the frameworks of pre-operative diagnostic evaluation and multimodality oncological treatments.

1. Introduction

MPM is a rare tumor that has become a world health issue due to its poor prognosis and its increasing incidence, largely due to prior asbestos exposure (the latency is about 20–40 years). Median overall survival (OS) is approximately 1 year in patients with MPM, and the 5-year OS rate is about 10% [1]. In recent years, there has been a notable advancement in the comprehension of MPM pathogenesis, leading to new promising drugs and therapeutic schemes [2, 3]. Particularly, recent trials including innovative drugs, such as targeted therapies or immunotherapies, have encouraged MPM patients [4]. Optimal treatment strategy in MPM has not yet been well established, consequently, current guidelines from the British Thoracic Society (BTS) [5], the American Society of Clinical Oncology (ASCO) [6], the National Comprehensive Cancer Network (NCCN) [1] and the European Society for Medical Oncology (ESMO) [7] have examined similar studies but reached different conclusions. Newly, a task force composed of the European Respiratory Society (ERS), the European Society of Thoracic Surgeons (ESTS), the European Association for Cardio-Thoracic Surgery (EACTS) and the European Society for Radiotherapy and Oncology (ESTRO) [8] proposed updated and practical guidelines on routine management of MPM, after a systematic review of the 2009–2018 literature, including new promising therapies and strategies. Up to the present, therapeutic strategies for MPM are still discussed; therefore, with a lack of a homogeneous consensus on this theme, physicians preferred to evaluate every single patient in a multidisciplinary team to adopt the best treatment based on the performance status of the patient and the stage of the tumor.

The current Eighth Edition of tumor, nodes, metastasis (TNM) classification for MPM [1] is reported in Tables 1 and 2. As stated in the aforementioned guidelines, at early stages (disease confined to the pleural envelope, without N2 lymph node involvement) with favorable histology (epithelial), a surgical approach with curative intent in a multimodal protocol appears to be indicated to enhance survival and quality of life. Instead, in advanced stages with distant spread palliative or supportive care must be preferred.

T	Primary tumor
TX	Primary tumor can not bed assessed
T0	No evidence of primary tumor
T1	Tumor limited to the ipsilateral pleural with or without the involvement of: Visceral pleura Mediastinal pleura Diaphragmatic pleura
T2	Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features: Involvement of diaphragmatic muscle Extension of tumor from visceral pleura into the underlying pulmonary parenchyma
T3	Locally advanced but potentially resectable tumor.; Tumor involving all ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura), with at least one of the following features: Involvement of the endothoracic fascia Extension into the mediastinal fat Solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall Nontransmural involvement of the pericardium
T4	Locally advanced technically unresectable tumor.; Tumor involving all ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura), with at least one of the following features: Diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction Direct transdiaphragmatic extension of the tumor to the peritoneum Direct transdiaphragmatic extension of the tumor to the contralateral pleura Direct transdiaphragmatic extension of the tumor to mediastinal organs Direct transdiaphragmatic extension of the tumor to the spine Tumor extending through to the internal surface of the pericardium with or without a pericardial effusion; or involving the myocardium
N	Regional lymph nodes
NX	Regional lymph nodes can not be assessed
N0	No regional lymph nodes metastases
N1	Metastases in the ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal) lymph nodes
N2	Metastases in the contralateral mediastinal, ipsilateral, or contralateral supraclavicular lymph nodes
M	Distant metastasis
M0	No distant metastasis
M1	Distant metastasis present

Table 1.

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

TNM: tumor nodes metastasis; MPM: malignant pleural mesothelioma.

Stage	T	N	M
IA	T1	N0	M0
IB	T2–T3	N0	M0
II	T1–T2	N1	M0
IIIA	T3	N1	M0
IIIB	T1–T3; T4	N2; Any N	M0; M0
IV	Any T	Any N	M1

Table 2.

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

MPM: malignant pleural mesothelioma; TNM: tumor nodes metastasis.

Because of the diffuse growth pattern and the lack of surgical margins, microscopic complete resection is theoretically impossible. Thus, a MCR should be the aim of the surgery, even though the optimal cytoreductive procedure is still controversial [9, 10]. There are two main surgical options to obtain MCR—EPP and PD; the superiority of one technique over the other is still debated [11]. Due to the high morbidity, both surgical techniques should be achieved only in tertiary referral centres with a wide experience in thoracic surgery [12]. Generally, surgery achieves only cytoreduction, hence it must be associated with induction CT (iCT) or adjuvant CT (aCT) with or without adjuvant RT (aRT) to achieve better outcomes in terms of survival and control of the disease.

The best combination of these different therapeutic approaches is still a matter of debate [13, 14]. Hence, the aim of this up-to-dated literature review is to provide a complete overview of the current surgical approaches to MPM, discussing within the frameworks of pre-operative diagnostic evaluation and multimodality oncological treatments.

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 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].

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 semi-automated 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, 24, 25, 26, 27, 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, 28, 29, 30].

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 video-assisted 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 non-insignificant 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].

Figure 1.

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

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 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).

Figure 2.

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

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

• Extended PD: the parietal and visceral pleurectomy associated with the resection of the pericardium and/or diaphragm;

• PD: the parietal and visceral pleurectomy without the removal of the diaphragm or pericardium;

• Partial pleurectomy (PP): the partial removal of the parietal and/or visceral pleura.

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].

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, argon-beam 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 post-operative 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].

2.5 Extracorporeal life support (ECLS) for life-threatening complications in MPM’s surgery: is it worthwhile?

In thoracic surgery, the use of ECLS in the postoperative period is augmented in the last decades [53]. Up to now, the unique absolute contraindication to extracorporeal membrane oxygenation (ECMO) is a pre-existing state incompatible with healing, such as an end-stage tumor [54]. Literature provides only a few reports on ECLS as a bridge to support oncological patients affected by complications of their illness [55], its therapy [56, 57] or cardiac arrest [58]. MPM is a locally aggressive tumor, with a very poor prognosis. The multimodality therapies including surgery offered to selected cases (early stages with epithelial histology) are often characterized by major and/or minor perioperative morbidities [13]. According to Burt et al., the EPP is burdened by a significantly higher rate of acute distress respiratory syndrome (ARDS) (8.4 vs. 0.8%) and 30-day mortality (10.5 vs. 3.1%), compared to the PD [52, 59]. Anyhow, in the case of perioperative complications after surgery for MPM the employment of ECLS represents an ethical dilemma due to the fatal nature of this malignancy.

Fica and collaborators mentioned the use of a single-site veno-venous ECMO to support ventilation in an early post-pneumonectomy broncho-pleural fistula [57], while Bellini and collaborators successfully used the veno-arterial (V-A) ECMO as cardiac support in two MPM patients (66%), conversely, the only case (33%) of V-A ECMO implanted primarily for respiratory support in pneumonia-associated ARDS of the residual lung had a negative outcome [60]. Similar results were reported in the literature; according to Gow and collaborators, patients with a better pulmonary reserve and cardiac indication for ECLS are the better oncological candidates for ECMO [61].

The disease process itself and/or the employed treatments lead patients with thoracic cancer to have less pulmonary reserve compared to adults generally demanding ECLS. Secondary infections and bleeding are the major problems for the use of ECLS for oncological patients [61], both potentially life-threatening. In this scenario, on one hand, we have potentially reversible complications not responsive to conventional therapies, while on the other hand frail and immunosuppressed patients with poor prognosis and at risk to develop life-threatening ECMO-related drawbacks.

In accordance with the aforementioned recent literature, in case of a potentially reversible condition especially if heart-related, ECLS could be used as a stopgap device until common therapies work, in very selected MPM patients, permitting the recovery and the completion of the multimodal protocol [60, 61].

2.6 Palliative surgery

The MesoVATS trial is an open-label randomized controlled trial conducted in 12 centres in the United Kingdom, that compared PP by VATS versus talc pleurodesis in patients with MPM [62]. There were no differences between groups in the OS at 1 year nor at 6 months of follow-up. Furthermore, the benefits of VATS-PP (better quality of life, less short-term pleural effusion) do not balance the inconveniences (surgical complications and longer hospital stay leading to more costs). Guidelines strongly recommend talc poudrage via thoracoscopy to control a recurrent MPM effusion as the first choice to achieve pleurodesis in patients with expanded lungs, while weakly suggest, with a low grade of recommendation, palliative VATS-PP to obtain pleural effusion control in symptomatic patients fit enough to undergo surgery who cannot benefit from (or after the failure of) chemical pleurodesis or indwelling catheter [8].

2.7 Surgery for MPM relapse

Recurrence of MPM after multimodality treatment is a common problem. Nevertheless, there has been no established therapy for relapse to date. Major studies about the treatment of recurrent MPM are reported in Tables 3 and 4. Over the literature, MPM with distant spread (associated or not with local relapse) is the most frequent pattern of recurrence, mostly in the EPP group, while the PD group showed a higher local-only failure rate [63, 64, 65, 66, 67, 68, 69, 70, 71]. A poor prognosis for recurrent MPM after multimodality treatment has been reported in the literature, with a median post-recurrence survival (PRS) after EPP ranging from 3 to 6.5 months [64, 65, 66, 72]. Newly, comfortable PRS were described after PD by Nakamura et al. and Kai and collaborators (14.4 and 20 months, respectively) [65, 67].

Author	Surgery, N	Multimodality, N	Relapse, N (%)	Pattern of recurrence, %
Kostron, 2016 [63]	EPP, 136	Bimodal, 47; Trimodal, 59	106 (77.9)	L 24.3; D 19.9; L + D 33.8
Takuwa, 2017 [64]	EPP, 59	Bimodal, 27; Trimodal, 12	39 (66.1)	NR
Kai, 2018 [65]	EPP, 29; PD, 15	Bimodal, 26; Trimodal, 18	32 (72.7)	L 18.2; D 27.3; L + D 27.3
Soldera, 2019 [66]	EPP, 93	Bimodal 43; Trimodal 10	53 (57.0)	L 5.4; D 38.7; L + D 12.9
Nakamura, 2020 [67]	PD, 90	Bimodal, 90	57 (63.3)	L 43; D 6.7; L + D 13.3
Politi, 2010 [68]	EPP, 8	NR	8 (100)	L 50; D 50
Okamoto, 2013 [69]	EPP, 10	NR	8 (80)	L 40; D 40
Burt, 2012 [70]	EPP, 32; PD, 15	NR	47 (100)	L 100
Bellini, 2021 [71]	EPP, 49; PD, 45	Bimodal, 18; Trimodal, 76	94 (100)	L, 28.7; D, 28.7; L + D, 42.6

Table 3.

Major studies about the treatment of recurrent MPM: Multimodality regimen and pattern of failure.

MPM: malignant pleural mesothelioma; EPP: extrapleural pneumonectomy; PD: pleurectomy/decortication; NR: not reported; L: local; D: distant; L + D: local+distant.

Author	Median DFS (m)	Relapse treatment, N (%)	Median PRS (m)	Median OS (m)
Kostron, 2016 [63]	9	None, 28 (26.4); Surgery, 16 (15.1); Medical treatment, 73 (68.9)	7	22^a
Takuwa, 2017 [64]	11.6	None, 12 (30.7); Medical treatment, 27 (69.2)	6.5	22
Kai, 2018 [65]	Overall, 14^b; EPP, 13^b; PD, 21^b	Medical treatment, 17 (53.1)	Overall, 5; EPP, 3; PD, 20	Overall, 22^b; EPP, 17^b; PD, 34^b
Soldera, 2019 [66]	NR	None, 27 (50.9); Medical treatment, 15 (28.3); NR, 11 (20.8)	4.8	NR
Nakamura, 2020 [67]	19	Surgery, 3 (5.3); Medical treatment, 40 (70.2); Best supportive care, 14 (24.5)	14.4	57^b
Politi, 2010 [68]	NR	Surgery, 8 (100)	14.5	NR
Okamoto, 2013 [69]	15.4	Surgery, 2 (25); Medical treatment, 6 (75)	17.8	49.6
Burt, 2012 [70]	16.1	Surgery, 47 (100)	Epithelial, 20.4; Biphasic, 7.0	44.9
Bellini, 2021 [71]	Overall, 14; EPP, 20; PD, 11	None, 13 (13.8); Surgery, 13 (13.8); Medical treatment, 68 (72.3)	Overall, 12; EPP, 14; PD, 8	Overall, 33; EPP, 38; PD, 23

Table 4.

Major studies about the treatment of recurrent MPM: Oncological outcomes.

MPM: malignant pleural mesothelioma; EPP: extrapleural pneumonectomy; PD: pleurectomy/decortication; NR: not reported; L: local; D: distant; L + D: local+distant; DFS: disease-free survival; PRS: post recurrence survival; OS: overall survival, calculated from the date of surgery, except (a) from the first cycle of neoadjuvant chemotherapy; (b) from the date of pleural biopsy.

Conversely, Bellini and collaborators recently noted that the type of surgical resection did not affect the PRS (14 and 8 months in the EPP and PD group, respectively) if patients are fit enough to receive post-recurrence treatments [71]. Across the literature, the post-recurrence treatment is the main predictor of better PRS [63, 65, 67], in particular, Bellini and co-authors found tailored medical therapies as the best strategy to face relapse, even in the case of local failure [71], in contrast with satisfactory PRS after redoing surgery, which was reported by Kostron et al. [63]. The Italian group cautiously hypothesized that the early local-only failure may likely reflect a less radical local resection that could benefit from timely systemic therapies, rather than redo surgery that is rarely radical in most of the cases [71]. Moreover, several authors reported a long disease-free survival (DFS) (≥12 months) as significantly associated with good survival [61, 67, 71], probably reflecting a slower tumor growth speed associated with a less aggressive recurrent disease. Furthermore, epithelial histology [65, 71] and local recurrence [71] resulted as a favorable prognostic factor for PRS, the latter may be due to a less deleterious effect on performance status and, consequently, on survival compared with distant spread [71]. In conclusion, in patients presenting with recurrence of MPM after an MCR procedure, radical surgery to resect the recurrent tumor could have a role in the improvement of survival in selected patients [73].

3. Multimodality treatment for MPM

3.1 Bimodal and trimodal therapy in MPM

The microscopic complete resection represents an unattainable goal for surgery alone in MPM disease. For this reason, in the last decades, the surgical approach is mainly used as cytoreduction with improved survival, but with the necessity at least to combine with a bimodal/trimodal treatment, although the income of the novel strategies as immunotherapy, are suggesting a multimodal approach [40, 62, 74, 75]. The debate regarding the possible surgical approach as the closest to the radicality for MPM is still opened [76, 77]. In particular, the believers for EPP as the most oncologically correct approach, strongly support the theory that a near-complete surgical resection associated with chemo-or high-dose aRT may be the best treatment for earlier stages [78]. Recent studies have shown improved survival with EPP associated with neoadjuvant or adjuvant chemoradiotherapy [79], in highly-selected patients, although this type of surgery is very aggressive and invasive and not far from postoperative complications with significant morbidity (25%) and mortality (4–15%) [5]. In 2011 the MARS-1 trial compared patients treated with EPP and patients without, defining this surgery as not effective for the high morbidity and 30-day mortality. Particularly, it was a feasibility multicentre randomized controlled trial carried on between October 2005 and November 2008 in 12 English Hospitals. It included 112 patients aged 18 years or older affected by MPM and fit enough to undergo trimodal treatment. In the pre-randomization registration phase, all patients underwent induction platinum-based CT, followed by a clinical revaluation. The main reasons for not proceeding to randomization were a progression of the disease (33 patients), inoperability (five patients), and patient choice (19 patients). Finally, 50 patients were randomly assigned (1:1): 24 to EPP followed by radical RT and 26 to no EPP. The EPP was completed in 16 patients (in five patients it was not started and in three it was abandoned). The clinical outcomes evaluated were the proportion of patients of the EPP group who completed the trimodal treatment; perioperative mortality; quality of life; OS; and disease-free survival. Of the 16 surgical treated patients, there were tw perioperative deaths, while eight completed the trimodal protocol receiving the radical RT. Serious adverse events were higher in the EPP group (n = 10) than in the no EPP group (n = 2). The median OS for the EPP and the no EPP group were 14.4 months and 19.5 months, respectively. The median DFS for the EPP and the no EPP group were 7.6 months and 9 months, respectively. There was a statistically significant difference in the survival outcomes, while a trend toward a lower quality of life in the EPP group was reported.

Following the MARS-1 trial, the scientific community and surgeons focused their attention on PD, which is for sure less invasive than EPP, but not less effective than EPP [80, 81]. In particular, in the last decades, some retrospective studies and systematic reviews described a comparable survival between the two procedures, but with less morbidity and mortality for the patients treated with PD [51, 74, 82, 83, 84, 85] with the association of improved quality of life [84, 85, 86], although there are also research groups showing no difference in morbidity and mortality [87, 88, 89]. For the fact that data are still extremely different [90], the most focused expert for MPM suggests that a multidisciplinary approach and randomized controlled trials need to be set to further define the best surgery in MPM [42, 90, 91, 92, 93, 94]. In particular, the MARS-2 trial is trying to set if PD plus iCT may offer an improvement of the survival than the only CT [48, 91, 95]. Regarding the most updated recommendation, several scientific societies use a trimodal approach (surgery, CT and RT) for MPM) [1, 6, 7, 96]. This has been also confirmed by the BTS and the European Respiratory Society for clinical trials [5, 97]; although the timing for this therapy is still unknown as well as also the sequences of each treatment [97]. However, even in the case of the trimodal approach, the long-term survival of these patients remains still poor and only 5% survive at 5 years [98]. The association of pemetrexed (folate antimetabolite) plus B12 and folic acid supplementation [1, 5, 6, 7, 97] is an association with the most standard platinum-based therapy, cisplatin, typically, or carboplatin [99, 100], seems to improve the survival by 2.8 months compared with single drug treatment, probably for the fact that B12 and folic acid supplementation reduce the toxicity, especially in elderly patients [101]. In a recent large phase III trial, MAPS, even the use of bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor in combination with pemetrexed/cisplatin is strongly recommended, which compares pemetrexed/cisplatin alone [102]. In particular, this trial showed improved survival of 2.7 months in unresectable MPM [102]. The ASCO has suggested vinorelbine as second-line treatment, although the NCCN suggested immunotherapy and CT as second-line treatment [1]. In particular, the second-line pemetrexed seems to have some effect against tumor, reducing the tumor progression, as described in a phase III trial [103]; for vinorelbine, the recent randomized controlled trials showed improved survival in patients treated with this drug [104] with good control of symptoms. There are other treatments as PD with intraoperative intracavitary hyperthermic CT, although more studies need to support and analyze concerning the long-term results [105, 106, 107, 108, 109, 110, 111, 112, 113]. The majority of studies that evaluate the trimodal approach are retrospective reviews [114, 115, 116, 117, 118, 119]. Since 2007, a multicentric clinical trial demonstrated that iCT plus EPP is feasible [41] showing an OS of 23 months compared with patients not treated with surgery with a survival of 19.8 months [41]. An Italian study published similar results [120]. The combination with neoadjuvant cisplatin/pemetrexed treatment has been discussed since 2009 in a multicentric phase II clinical trial in which patients in stage I-III MPM underwent 4 cycles of cisplatin/pemetrexed. Of these patients, who showed a good response to this medical treatment has been then underwent EPP followed by adjuvant hemithoracic radiation [121] with a median survival of 29.1 months with a 2-year survival of 61.2% [122]. These data let the researcher to conclude that a trimodal therapy may be effective and beneficial [122]. In 2010 the European Organization for Research and Treatment of Cancer (EORTC) published a similar multicentre phase II study [121], in which 65% of the patients underwent EPP 65% plus aRT showed a good result for the 42% of patients, although the neoadjuvant therapy associated with EPP, and adjuvant therapy have been shown to be challenging for the poor long term results [41, 116, 117, 118, 119]. With regards to the less invasive surgical treatment in MPM, represented by PD, few studies considered the use of trimodal therapy with PD. In particular, in 2012, a non-randomized prospective trial compared EPP to PD in trimodal approach [82] comparing 3 cycles of either cisplatin/gemcitabine or cisplatin/pemetrexed before EPP and aRT to PD with hyperthermic pleural lavage with povidone-iodine and aCT [82]. However, the median survival was 12.8 months for EPP patients, although a better survival of 23 months has been noted for the second group of patients. These results demonstrated that PD is a more feasible approach with better outcomes for MPM patients underwent trimodal therapy [82]. The role of adjuvant or neoadjuvant radiation therapy is not yet been clarified. In particular, the classic hemithoracic radiation of the entire pleural cavity after EPP is not a problem [123], although the lungs and the other organs cannot be spared from the radiation [124]. However, recent retrospective studies have shown an increased local recurrence in patients treated with adjuvant IMRT following EPP [125]. Recently, the SMART trial concluded the analysis about the role of neoadjuvant IMRT in T1–3N0 MPM followed by EPP, associated with aCT (cisplatin and an anti-folate) in case of mediastinal lymph nodes involvement, achieving encouraging survival results. The results were satisfying in consideration of a median OS of 42.8 months for the epithelial subtype, compared with 18 months for the biphasic one. The authors postulated that a probable mechanism for the distant spread is the spillage of the tumor cells into the coelomic cavities during EPP, hence the IMRT immediately before surgery could inactive these cells making them non-viable, preventing distant seeding with better survival outcomes. Probably the epithelial subtype is more sensible to the action of IMRT. Possible confounder factors for these promising survival results may be as follow: firstly, the criteria for inclusion in the trial were strict leading to a possible selection bias, secondly, the presence of BAP1 mutations (associated with better OS regardless of therapy) was not routinely investigated, so the potential inclusion of these patients in the trial could confound. [43]. In 2016 a group from Memorial Sloan Kettering Cancer Centre (MSKCC) showed the feasibility of IMRT and iCT and PD in IMPRINT phase II trial [126]; however, the same researcher’s group published a retrospective study comparing PD trimodal therapy with conventional RT to hemithoracic IMRT [126] with better survival for the patients treated with IMRT [127]. In US both ASCO and NCCN- guidelines strongly support the multimodality treatment for stages I-III epithelioid MPM [128]. The upcoming MARS-2 results may be very helpful to clarify the feasibility and benefits of the multimodality treatment [128]. Table 5 summarizes the main studies commented on in this paragraph.

Author, year, type of study	Type of surgery, N	Multimodal treatment, N	Median OS (m)
Spaggiari L, 2014, multicentre retrospective [79]	EPP, 518	iCT, 271; aRT, 213; aCT, 43; aRT+aCT, 117	18
Fahrner R, 2012, single centre retrospective [98]	EPP, 21	Port-site RT, 18; iCT, 19: platinum+gemcitabine, 15; platinum+pemetrexed, 4; aRT, 16	707 days
Katirtzoglou N, 2010, multicentre phase II[100]	Unresectable, 62	CT with carboplatin+pemetrexed	14
Zalcman G, 2016, multicentre randomized controlled open-label phase III [102]	Unresectable, 448	Cisplatin+bevacizumab, 223; Cisplatin only, 225	With bevacizumab: 18.8; Cisplatin only: 16.1
Muers MF, 2008, multicentre randomized [104]	Unresectable, 409	ASC alone (treatment could include steroids, analgesics drugs, bronchodilatators, palliative radiotherapy), 136; ASC plus mitomycin+vinblastine+cisplatin, 137; ASC plus vinorelbine, 136	ASC alone: 7.6; ASC plus CT: 8.5
Burt BM, 2018, single centre phase I [107]	EPP, 59; PD, 41; Debulking, 4	HIOC with gemcitabine added to cisplatin, 104; aCT, 45; aRT, 10	All 20.3; EPP 17.7; PD 38.8
Opitz I,. 2020, single centre phase I [109]	PD, 12	Intracavitary cisplatin-fibrin, 12	21
Ried M,. 2013, single centre prospective observational [111]	PD, 10	HIOC with cisplatin, 10	NR
Sugarbaker DJ, 2013, single centre retrospective [113]	EPP, 74 (53 HIOC group); PD, 29 (19 HIOC group)	HIOC with cisplatin, 72; No HIOC, 31	HIOC: 35.3; No HIOC: 22.8
Rusch VW, 2001, single centre phase II [114]	EPP, 62; PD, 5	aRT, 57 (54 EPP; 3 PD)	EPP: 17; Early stages 33.8; Advanced stages 10
de Perrot M, 2009, single centre retrospective [116]	EPP, 45; Unresectable, 15	iCT: Cisplatin+vinorelbine, 26; Cisplatin+pemetrexed, 24; Cisplatin+raltitrexed, 6; Cisplatin+gemcitabine, 4; aRT, 30	Trimodality completed 59
Thieke C, 2015, single centre retrospective [118]	EPP, 62	iCT, 62; cisplatin+pemetrexed, 30; carboplatin+pemetrexed, 23; cisplatin+gemcitabine, 9; aRT (IMRT), 62	20.4
Rea F, 2007, single centre prospective [120]	EPP, 17	iCT with carboplatin+gemcitabine, 21; aRT, 15	All 25.5; EPP, 27.5
Van Schil PE, 2009, multicentre phase II [121]	EPP, 42	iCT with cisplatin+pemetrexed, 55; aRT, 37	All 18.4; Trimodality completed 33
Krug LM, 2009, multicentre phase II [122]	EPP, 54	iCT, 77; aRT, 40	All 16.8; Trimodality completed 29.1
Cho BC, 2021, single centre phase II	EPP, 96; Epithelial, 83; Biphasic, 8; Unkown, 5	iRT (IMRT), 96	24.4; Epithelial: 42.8; Biphasic:18
Rimner A, 2016, multicentre phase II [126]	PD, 8; Partial pleurectomy, 13; Unresectable, 11	iCT, 45: Cisplatin+pemetrexed, 26; Carboplatin+pemetrexed, 18; Combination, 4; aRT (IMPRINT), 27	Trimodality completed 23.7
Shaikh F, 2016, single centre retrospective [127]	PD, 209	aRT: conventional, 131; IMPRINT, 78; Chemotherapy, 85 (15 conventional, 70 IMPRINT)	Conventional,12.3; IMPRINT, 20.2

Table 5.

Summary of the main studies commented in Section 3.1.

OS: overall survival; EPP: extrapleural pneumonectomy; iCT: induction chemotherapy; aRT: adjuvant radiotherapy; aCT: adjuvant chemotherapy; PD: pleurectomy/decortication; ASC: active symptom control; HIOC: heated intraoperative chemotherapy; NR: not reported; iRT: induction radiotherapy; IMPRINT: intensity-modulated pleural radiotherapy; IMRT: intensity-modulated radiotherapy.

3.2 New target therapies in MPM

Although the scientific community is studying genes and proteins which may be used to set new treatments against MPM, the targets for mesothelioma have not been clearly yet identified. Besides the fact that the common MPM treatments including surgery, CT and radiation therapies show a poor OS from 9 to 17 months from the diagnosis [120, 129, 130], new emerging treatments are setting from the scientific community to improve the quality of life and the survival. The most used approach in this field is immunotherapy which seems to play an important role in MPM for the connections and reactions with the patient immunity, driving immunoregulatory mechanisms with a direct good response [131, 132]. In particular, in patients with MPM showing a high infiltrate of cytotoxic CD8+ T associated with programmed death-ligand 1 (PDL-1) expression, the use of pembrolizumab and nivolumab, or nivolumab with the cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody ipilimumab showed very encouraging results [133, 134].

Several trials have been published showing the use of immunotherapy in advanced MPM alone or with standard CT. In particular, pembrolizumab seems to improve by 22%, the response rate compared with gemcitabine or vinorelbine which showed a 6% of response [135]. However, other immunotherapies have been analyzed in the last decades, for example, in MAPS2 open-label, phase 2 trial that has been studied in 21 French hospitals aiming to set nivolumab alone or combined with ipilimumab. This study showed a 12-weeks disease control in 44% of patients who received only nivolumab, compared with the 50% who underwent nivolumab plus ipilimumab [130]. In January of this year, the Checkmate 743 study was published in Lancet, which reported the superiority of the combination of nivolumab (3 mg/kg every 2 weeks) + ipilimumab (1 mg/kg every 6 weeks) over the above standard. With a significant advantage in the entire study population, particularly marked in the sarcomatoid subtype [136]. For patients progressing to the first line, however, no scheme has been shown to improve survival; however, these patients can be offered gemcitabine, vinorelbine or rechallenge with pemetrexed mono-CT, with unfortunately marginal benefits. Nivolumab, on the other hand, in a phase 3 study (CONFIRM) conducted against placebo in a heavily pretreated population, has shown efficacy in improving both progression-free survival and OS, but at the moment the drug is not approved in Italy. this indication [137].

From preclinical evidence, the role of angiogenesis in the development of this disease and the potential efficacy of inhibiting this mechanism appears to be relevant, although in lines subsequent to the first some antiangiogenic drugs have already been tested without success [138]. In particular, there is a strong rationale for angiogenesis inhibition in mesothelioma. VEGF plays an important role as an autocrine growth factor and strong mitogen in mesothelioma. Furthermore, the abnormal tumor vasculature increases the interstitial pressure and hypoxia, which may hinder the effect of the anticancer drugs against mesothelioma cells. Ramucirumab is a fully humanized monoclonal antibody directed against the VEGF receptor 2 (VEGFR-2), currently reimbursed in Italy for use in clinical practice in gastric cancer and tested in numerous other solid tumors [139]. VEGFR-2 is expressed not only in 90% of mesothelioma cells but also on the surface of macrophages present in the tumor microenvironment, considered to be responsible for the resistance to chemo- and immunotherapeutic treatments [140]. Inhibiting this receptor seems to allow the switch from a hypoxic and treatment-resistant environment to a more sensitive and immuno-permissive tumor milieu. In this context, the RAMES study was born, a multicentre, phase 2, randomized and double-blind trial [141]. In the study, which involved 26 Italian centres, patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2 and diagnosed with progressive MPM during or after a first-line with platinum and pemetrexed were enrolled. Patients were randomized to a second line with gemcitabine 1000 mg/m² on days 1 and 8 of every 21 plus placebo (in the control group) or ramucirumab (an anti-VEGFR2 antibody) at 10 mg/m² on day 1 of each cycle up to progression or severe toxicity. Central randomization was performed according to a minimization algorithm, using the following stratification factors: ECOG PS, age, histology and time to first-line progression (>/<6 months) [141]. The primary endpoint of the study was OS. Secondary aims were progression-free survival, objective response rate, disease control rate, drug safety, patient quality of life and the possible presence of predictive markers. It was planned to enroll 156 patients to obtain a power of 80% assuming a benefit of the experimental treatment of 13% at 1 year compared to the standard arm. From December 2016 to July 2018, 165 patients were enrolled, of whom 161 were correctly assigned and received treatment, 83 in the placebo arm and 81 in the experimental arm. The median age was 69, with about 40% over seventy in both arms. 74% of patients were male and 99% had an ECOG PS of 0–1 [141]. The database was closed in March 2020 and, after a median follow-up of 21.9 months, the observed OS was higher in the experimental arm (Hazard Ratio 0.71; p = 0.028). Specifically, in the ramucirumab arm, the median survival was 13.8 months versus only 7.5 months in the placebo arm and the one-year probability of survival improved from 33 to 56% with the addition of ramucirumab [141]. Progression-free survival was also higher in the experimental arm (median 6.4 versus 3.3 months), but without reaching statistical significance (p = 0.082). Disease control was achieved in 73% of patients treated in the ramucirumab group versus 52% in the placebo arm [141]. A post hoc analysis showed a duration of response of 8.4 months in the experimental arm versus 5.4 months in the standard arm [141]. The pre-specified analysis of the subgroups shows that the survival advantage was independent of the histological subtype and the time of progression of the tumor to the first line [141]. No unexpected toxicities occurred. Grade 3–4 adverse events were recorded in 44% of patients treated with gemcitabine + ramucirumab compared to 30% in the gemcitabine + placebo arm. In particular, the most frequent severe toxicities were neutropenia (20% and 12% in the experimental and standard arms, respectively), arterial hypertension (6% with ramucirumab, 0 with placebo) and fatigue (5% and 4% respectively) [141]. The authors conclude that the association between ramucirumab and gemcitabine significantly improved the OS of patients with progressive MPM following standard first-line CT, with a favorable safety profile. It is clear, however, that in light of the new standard of treatment with the immunotherapy brace nivolumab + ipilimumab, the scheme proposed by the RAMES study [141] is part of a therapeutic context that has changed from the one that had seen the start of the study: in particular, the scheme gemcitabine—ramucirumab has not been tested in patients who have received the combination of the 2 immunotherapies. In addition, the treatment landscape of pleural mesothelioma may still change, pending the results of randomized trials, following interesting phase 2 data for first-line chemo-immunotherapy (NCT02899195 and NCT04334759). Taking this into account, ramucirumab, given its action not only on cancer cells but also on the immune infiltrate and tumor microenvironment, could continue to play a role in patients progressing to chemo-immunotherapy, but further studies will need to be conducted.

Another important drug is the CTLA-4 inhibitor tremelimumab which has been studied in a randomized phase II trial (DETERMINE) in 571 patients with a median survival of 7.7 months compared with patients who underwent placebo with 7.3 months of survival: although its safety profile was consistent, tremelimumab did not significantly improve OS [142].

3.3 T-cell therapies

Adoptive T-cell therapy seems to be promising in MPM and this has been highlighted in a recent phase I trial studying the chimeric antigen receptor (CAR) T-cell therapy targeting mesothelin in MPM patients. Of 18 patients treated with a single dose of CD28-costimulated MSLN CAR-T cells plus the I-caspase-9 safety gene treated intrapleurally showed that in 14 patients, 2 had complete remission, 5 partial, and 4 patients showed the stability of the disease [143]. In the context of safety, no CAR-T cell-related toxicities have been noted. The most promising approach seems to be represented by the combination between CAR-T cells and anti- programmed death-1 (PD-1) therapy [144], although these considerations need to be further investigated.

3.4 Vaccines

One of the most considered new therapies against MPM is vaccine therapy. In particular, the Wilms tumor-1 (WT1) protein in MPM is highly expressed and it is considered a future target for the setting of a cancer vaccine. A recent phase II randomized trial evaluated a WT1 analogue peptide vaccine associated with immunologic adjuvants, showing an improved survival at 1 year (45%) compared with the control group with a 33% of survival rate. However, the OS for vaccinated patients was 22.8 months compared with patients not treated (18.3 months) [145].

Other new target agents as dendritic cells (DC) therapy started to be recently considered to investigate the anti-tumor immune response [146, 147].

3.5 Other investigational therapies

Besides the vaccines and the T-cells therapies which are coming up for the better control of MPM, the oncolytic viruses and other targets as some vascular endothelial growth factors receptors (VEGFR), the platelet-derived growth factor receptor (PDGFR), and the fibroblast growth factor receptor (FGFR) tyrosine-kinase inhibitor, are under consideration. Some phase I/II clinical trials are running at the moment to evaluate the safety of the biological effects [148, 149, 150, 151, 152].

4. Conclusions

In conclusion, the optimal treatment of MPM is still a matter of debate. Surgery, CT, and RT have failed as single modality therapies with no effects on patients’ survival. It is evident that optimal multidisciplinary care is fundamental in the management of MPM patients, as the best results are obtained when patients manage to undergo more complex treatment protocols, often consisting in trimodality approaches. New prospective studies are needed to provide high-quality evidence on the field. While it is reasonable to assume that surgery will remain a central component in the multimodality treatment of MPM, a great development is expected from novel treatment modalities such as targeted therapies, T-cell therapy, vaccines and other investigational therapies, leading to the possibility of prolonged control of the disease, increased survival rates, and better quality of life.