Initial management of malignant pleural mesothelioma | ПРЕЦИЗИОННАЯ ОНКОЛОГИЯ

Initial management of malignant pleural mesothelioma

UpToDate, 2015


Introduction

Malignant pleural mesothelioma (MPM) is a rare neoplasm that typically arises from the mesothelial surfaces of the pleural cavity. Mesotheliomas may also arise from the peritoneal surface, the tunica vaginalis, or pericardium.

MPM has a poor prognosis. The median survival of patients is between 6 and 18 months, and the outlook has not been substantially improved by newer therapeutic interventions. However, carefully selected patients with localized disease who receive aggressive multimodality therapy have relatively prolonged survival.

Data supporting current treatment recommendations are derived from observational studies. The benefits of incorporating surgery and radiation therapy (RT) into the initial treatment have not been demonstrated in randomized trials.

Initial evaluation and clinical approach

Most patients with MPM present with the gradual onset of pulmonary symptoms (dyspnea, cough, chest pain). Symptoms generally are present only once extensive intrathoracic disease has developed.

Diagnosis

Typical findings on chest imaging combined with a history of asbestos exposure may raise the suspicion of MPM. However, the diagnosis of MPM requires an adequate tissue sample from the tumor.

Thoracentesis for cytology and closed pleural biopsy are generally the initial procedures and may be sufficient to establish the diagnosis in some cases. However, typically only epithelial cells are shed into the pleural effusion, and thus cytology does not exclude a diagnosis of mixed histology. If this is not diagnostic, video thoracoscopy can establish the definitive diagnosis in patients with localized or free-flowing pleural effusion suspected of having mesothelioma.

Larger tissue samples may be required for accurate subtype classification, which may be useful for prognostic purposes. In a study comparing histologic subtype as determined preoperatively with that based upon a definitive surgical resection specimen, open pleural biopsy or thoracotomy was more accurate than either thoracoscopy or imaging-guided core or needle biopsy (83 versus 74 and 44%, respectively) [1,2].

Staging

The most widely used staging system is the tumor (T), node (N), metastasis (M) staging system that is used by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) (table 1) [3].

The initial staging evaluation will often identify patients with extensive disease who are not candidates for a combined modality approach that includes definitive surgery. Such patients will require palliative treatment that may include management of a malignant pleural effusion and/or systemic therapy.

Clinical approach

A multidisciplinary treatment plan is based upon the assessment of the extent of disease, the patient’s overall condition including cardiopulmonary function and other comorbidities, and their desire for aggressive treatment. Chemotherapy with pemetrexed plus a platinum compound (cisplatin or carboplatin) is the standard approach for MPM, but approximately 20% of patients with MPM may be candidates for surgery with a macroscopic complete resection (MCR, ie, an R0 or R1 resection) as part of a combined modality approach.

Whether resection as part of a combined modality approach actually improves survival is uncertain and has not been established in a prospective randomized trial. If surgery is to be used as part of the initial treatment, the goal is an MCR, regardless of the specific surgical approach (lung-sparing versus lung sacrificing):

Surgical candidates – For patients who have surgically resectable disease limited to one hemithorax and have no medical contraindication to surgery, we use a combined modality approach that incorporates surgery aimed at MCR with chemotherapy and/or radiation therapy (RT).

Non surgical candidates – For patients who have disease in which an MCR is not feasible and for those who are not candidates for definitive surgery because of age, inadequate cardiopulmonary reserve, or other comorbidities, systemic chemotherapy and/or symptom directed treatment may be beneficial.

Surgery-based therapy

A combined modality approach is often used in patients with a surgically resectable tumor when there is access to a center with adequate expertise in all aspects of the management of MPM. Therapy in this setting includes a definitive surgical procedure (extrapleural pneumonectomy [EPP] or pleurectomy/decortication [P/D]), combined with radiation therapy (RT) to enhance local disease control and chemotherapy (systemic, either preoperative or postoperative, or intraoperative) to reduce the risk of local recurrence and systemic metastases.

Although an overall survival advantage has not been demonstrated with these approaches in randomized trial, this approach has been associated with relatively prolonged survival compared with chemotherapy alone for patients in contemporary surgery-based series.

Patient selection

Although surgery is not considered the standard of care treatment for MPM, there seem to be patients who benefit from a surgery-based approach beyond what would otherwise be expected. These aggressive procedures should be limited to surgeons and centers with appropriate expertise in these procedures and in the management of MPM. Identifying the subset of patients who might be good surgical candidates is an area of active research.

Many surgeons consider histologic subtype the single most important oncologic selection criterion although it is not currently part of the staging system, and thus they only offer surgery-based treatment to patients with epithelial subtype. The histologic subtype should be established with a biopsy, not cytology, since other cell types are not typically shed into the pleural fluid. Across nearly all surgical series the benefit of surgery appears to be limited to patients with pure epithelial subtype. Patients with mixed or pure sarcomatous variants often have overall survivals that are the same or shorter than what would be expected with nonoperative therapy [4].

Other factors associated with a worse prognosis for surgery include age >50 years, male gender, platelet count >400,000/uL, or white blood cell count >15,000/uL [4,5]. Chest wall pain at presentation is a worrisome feature that prevents many experienced surgeons from attempting surgery. Tumor volume, as measured by computed tomography (CT), is also associated with a worse prognosis [6]. The common variable here seems to be the bulk of solid tumor on presentation; although increased tumor bulk may have a negative impact on survival it does not preclude a successful macroscopic complete resection (MCR) with reasonable overall survival in the context of a multimodality approach.

Given the morbidity and potential mortality associated with surgery, the use of EPP or a lung sparing P/D procedure should be limited to situations in which surgery will result in a complete resection of all gross tumor. Assessment of operability begins with drainage of a pleural effusion, if present, in order to improve dyspnea or cough and to assess the extent of disease. Whether pleurodesis prior to surgery makes subsequent surgery more difficult or whether it may actually facilitate resection is controversial.

Assessment of patient-specific factors by an experienced surgeon will be required to determine the appropriate procedure for each individual patient. An experienced surgeon generally will not knowingly explore a patient for “palliation,” and most so-called palliative mesothelioma resections are the result of a failed attempt at an MCR.

Patient-specific factors that need to be considered include the following:

  • There should be no imaging evidence of disseminated disease outside the involved hemithorax (clinical stage I-III) (table 1).
  • The patient should have adequate cardiopulmonary function such that he/she will be able to tolerate the procedure.
  • The patient should have no serious comorbidity, and patients with an ECOG performance status 2 or worse are generally excluded.
  • Patients need to be fully informed that there is no uniformly accepted standard of care for MPM and that a surgery-based approach is only one option; expert consultation should be obtained if available.

Surgical procedure nomenclature

There has been considerable variability in the nomenclature used to describe MCR procedures. Based upon a survey of surgeons experienced with surgical management of MPM, the Mesothelioma Domain of the International Association for the Study of Lung Cancer (IASLC) recommended the following uniform definitions for MPM resections [7]:

  • EPP – En bloc resection of the parietal and visceral pleura with the ipsilateral lung, pericardium, and diaphragm. In cases where the pericardium and/or diaphragm are not involved by tumor, these structures may be left intact.
  • Extended P/D – Parietal and visceral pleurectomy to remove all gross tumor with resection of the diaphragm and/or pericardium.
  • P/D – Parietal and visceral pleurectomy to remove all gross tumor without diaphragm or pericardial resection.
  • Partial pleurectomy – Partial removal of parietal and/or visceral pleura for diagnostic or palliative purposes but leaving gross tumor behind when an R0 or R1 resection does not prove to be feasible.

Surgery

The role of definitive surgery (MCR, ie, an R0 or R1 resection) for MPM is controversial. Whether resection actually is responsible for an improvement in survival in some patients is uncertain and has not been established in a prospective randomized trial. When surgery is undertaken, the goal should be the removal of all visible or palpable tumor, regardless of whether that involves EPP or a lung-preserving operation (P/D).

MCR procedures are associated with substantial morbidity and potential mortality. Early reports using EPP reported mortality rates as high as 31% [8]. However, subsequent studies, which relied upon improved strict functional criteria for patient selection, as well as improvement in techniques, have resulted in mortality rates less than 5%. Despite careful selection of the patients who are to undergo MCR, there are no prognostic predictors that accurately determine which patients will recur rapidly after surgery and therefore derive no benefit.

After induction chemotherapy, EPP has been feasible in approximately 70 to 90% of cases in most series, and the operative mortality rates have ranged from 0 to 7% (table 2). In combining these three modalities, chemotherapy has been given both prior to surgery [9,10] and as an adjuvant following surgery [11]. Lung sparing procedures (P/D) have also been combined with chemotherapy and RT.

For patients who are candidates for MCR, the optimal procedure to be performed (ie, EPP versus P/D) is uncertain, and there are no data from randomized trials comparing different approaches. In addition, there are no randomized trials that define the optimal approach for the integration of other modalities (chemotherapy, RT) before and/or after surgery.

Extrapleural pneumonectomy (EPP)

With increasing experience and better patient selection, the morbidity and mortality associated with EPP decreased and survival results improved at centers with adequate expertise. Whether these improved results reflect a patient selection bias, decreased mortality from the procedure, or a benefit of surgery is not clear.

Contemporary large retrospective series from high volume centers have reported median survivals of approximately 18 months for patients whose treatment included EPP as part of a combined modality approach [12-14]. Long-term results are significantly worse, with 5- and 10-year survival rates of 14 and 4%, respectively in one series of 529 patients [12]. In an older systematic review of the use of EPP for MPM, overall perioperative mortality rates ranged from 0 to 12%, and the perioperative morbidity rates ranged from 22 to 82%. Key factors contributing to the improved results include improvements in preoperative staging, anesthesia, resection, reconstruction, and perioperative management of procedure-related complications [15].

The morbidity associated with EPP is illustrated by a large single institution experience that included over 300 cases, in which the mortality rate was 3.4% [16]. The most frequent complication was reversible atrial fibrillation, which occurred in 44% of patients. Other causes of serious morbidity included myocardial infarction, epicarditis, pulmonary complications, thrombosis, empyema, and technical and gastrointestinal complications (2, 3, 8, 6, 2, 6, and 1%, respectively). Observed technical issues included herniation of the heart due to failure of the pericardial patch, herniation of abdominal contents into the pleural space secondary to dehiscence of the diaphragmatic repair, vocal cord dysfunction secondary to recurrent laryngeal nerve injury, bronchopleural fistula, empyema, and prolonged respiratory failure.

Pleurectomy/decortication (Ps/D)

The morbidity and mortality with EPP led to the development of P/D as an alternative MCR procedure for carefully selected patients. In addition, P/D offers the potential to preserve lung parenchyma.

Studies presenting outcomes in patients managed with P/D are summarized in the table (table 3). In these studies, the achievement of MCR using P/D was associated with a significantly better overall survival compared with historical studies of palliative P/D.

EPP versus P/D

The choice of a specific procedure – EPP versus P/D – is a function of the surgeon’s expertise and judgement on the ability to achieve an MCR with the respective approaches and multimodal treatment protocols within that institution. There are no randomized trials that compare EPP versus P/D, but retrospective analyses suggest that survival outcomes are similar.

The most extensive data comparing EPP versus P/D come from a retrospective review of 663 consecutive patients who underwent surgery at three mesothelioma centers in the United States [17]. The operative mortality was greater for EPP than for P/D (27 of 385 [7%] versus 13 of 278 [4%]). EPP was associated with a worse overall survival (median 12 versus 16 months); this difference was statistically significant on multivariate analysis controlling for histology, stage, gender, and use of multimodality therapy. When the data were analyzed based upon clinical stage, there was no statistically significant difference for any stage. This study was the first to postulate that patients who underwent pleurectomy/decortication could have comparable survival to those who underwent extrapleural pneumonectomy; however, the reasons for such a conclusion were multifactorial and subject to selection bias. The morbidity and mortality conclusions from this study have recently been validated by a study from the Society of Thoracic Surgeons Database [18].

Additional observational data from series at four other centers comparing EPP versus P/D are presented in the table (table 4). In all studies P/D seems to have less mortality, less morbidity, and a comparable overall survival to EPP. Contemporary studies, however, have shown that satisfactory morbidity and mortality can be achieved after induction therapy with EPP [19].

Radiation therapy

The pattern of spread of MPM poses unique challenges to a radiation oncologist. Since the disease most often is confined to the ipsilateral pleura, local control is the primary concern. However, treating the entire pleura requires a large radiation field, which increases the risk of toxicity. The choice of surgical intervention (EPP versus P/D) and the clinical setting will dictate how RT is delivered. RT may also be used prophylactically to chest wall intervention sites.

Although the data using RT following surgery with either EPP or P/D suggest that RT improves local control, the available data from retrospective series do not suggest that there is a significant improvement in overall survival (table 4).

RT after EPP

Advances in RT techniques have led to the widespread application of highly conformal, three-dimensional techniques, such as intensity-modulated RT (IMRT), in patients with MPM having EPP.

Historically, adjuvant RT after EPP was given through anterior and posterior fields that encompassed the entire involved hemithorax. This simple approach has the advantage of avoiding oblique angles that could expose the contralateral lung to low doses of radiation. Sparing of organs in the RT field (eg, heart, liver, kidneys, or stomach) is achieved by blocking those areas and adding an electron boost to the anterior and posterior chest wall to compensate for the missing dose. This invariably leads to dose uncertainties along the edges of blocked areas as well as under- and overdosing of the pleural space and chest wall. Also, tolerance limits require blocking the spine after 4140 cGy, often leading to underdosing of the medial pleura and mediastinum/hilum [20].

A phase II trial exploring high-dose hemithoracic RT to 54 Gy following EPP demonstrated high rates of local control, with only two isolated locoregional failures in 54 patients and a median survival of 17 months [21] (stage I and II tumors, 33.8 months; stage III or IV, 10 months). Multiple subsequent studies incorporated this technique into a multimodality approach combining chemotherapy, EPP, and hemithoracic radiation [9,22-24].

However, with conventional RT there may be radiation underdosing near regions that are blocked. This has the potential to lead to increased risk of local failure in approximately 10 to 15% of patients [25].

IMRT is a highly conformal radiation technique that allows more effective sparing of normal tissues, providing an opportunity for safer, less toxic treatments and increased efficacy by enabling higher radiation doses to the tumor target. It comes with a much higher level of dosimetric control leading to better target coverage than conventional techniques [26]. Areas of potential under- or overdosing are readily recognizable in the planning phase and thus can be corrected.

A potential disadvantage of IMRT is the dose of radiation delivered to the contralateral lung, which increases the risk of pneumonitis. Several groups reported significantly increased toxicity and even deaths from radiation pneumonitis in patients treated with IMRT after EPP [27-29]. A higher mean lung dose and the volume of lung receiving 5, 10, or 20 Gy have been associated with a greater risk for lung toxicity [28-30]. Strict dosimetric guidelines, particularly on the contralateral lung, are therefore critical. Increasing experience with IMRT has led to improved target coverage and has decreased rates of toxicity [30-33].

RT after P/D

The use of IMRT and related contemporary three dimensional conformal RT techniques in conjunction with P/D is expanding in an effort to improve local control while minimizing toxicity [34-37].

Older approaches using two-dimensional (anterior-posterior) techniques were limited since the ipsilateral lung remained in situ after P/D. Even though blocks were used to protect the heart and central part of the lungs and an electron field was added to boost the dose, this technique resulted in a disappointing one-year local control rate of 42% and a median survival of 13.5 months [25].

The results using IMRT are illustrated by the single institution experience in 67 patients with two intact lungs treated at Memorial Sloan-Kettering Cancer Center between 2004 and 2013 [34,37]. In this cohort, 42 patients (63%) underwent P/D prior to RT, while 25 (37%) were unresectable and underwent definitive hemithoracic pleural IMRT. Median follow-up was 24 months. Treatment was delivered in 1.8 Gy fractions to a total dose of 50.4 Gy [34]. The total delivered dose was based upon normal tissue constraints, to give a median lung dose <21 Gy. The one- and two-year overall survival rates were 85 and 50%, respectively. Increasing experience over time led to fewer marginal failures and decreased toxicity, consistent with an improvement in target delineation and RT planning.

A pattern of failure analysis in patients who had undergone P/D found that the majority of local failures occurred in sites of gross disease, supporting the role of a macroscopically complete surgical resection when feasible [37]. Local (in field) failure occurred in 43 cases (64%), and 32 of these (74%) occurred at sites of previous gross disease. Furthermore, when patients who had had been treated with P/D followed by IMRT were compared with those treated with IMRT alone, there was a significantly prolonged time to in-field recurrence (14 versus 6 months).

Chemotherapy

Even if disease can be controlled locally with surgery and/or RT, most patients develop systemic metastases. Combinations of active agents, such as cisplatin plus pemetrexed, have been shown to prolong overall survival in patients with unresectable disease and have been integrated into combined modality approaches with surgery and/or RT. In these regimens, chemotherapy has been given both prior to surgery [9,10] and as an adjuvant following surgery [11].

The feasibility of integrating neoadjuvant chemotherapy with surgery and RT was illustrated by a multicenter phase II study [9]. In this trial, 77 patients were treated with neoadjuvant pemetrexed plus cisplatin, which was to be followed by EPP and then adjuvant RT. Overall, EPP was attempted in 57 patients and completed in 54, while radiation was initiated in 44 cases and was able to be completed in 40 patients. The median overall survival for the entire cohort was 17 months. For those who were able to complete chemotherapy, surgery, and RT, median survival was 29 months, with a 61% two-year survival rate.

In addition, intraoperative intracavitary chemotherapy has been studied in an effort to improve local disease control. In a series of 92 patients, hyperthermic intracavitary perfusion with cisplatin (225 mg/m2) was performed following EPP [38]. Recurrence of pleural mesothelioma was seen in 47 patients (51%), and was ipsilateral in 16 cases (17%). Intracavitary chemotherapy remains experimental and should be limited to formal clinical studies.

Randomized trials

There are no adequately powered randomized trials that have defined the benefit of combining surgery using an MCR with chemotherapy and RT in patients with localized MPM.

Although the Mesothelioma and Radical Surgery (MARS) trial was originally designed with adequate statistical power to assess the role of EPP, accrual difficulties led to its transformation into a feasibility study. In the feasibility trial, 112 patients were treated with induction chemotherapy. Subsequently 50 patients were randomly assigned to EPP or no EPP, which was to be followed by RT [39]. There were no statistically significant differences in survival at 6, 12, or 18 months, and median survivals for EPP and no EPP were 14.4 and 19.5 months, respectively.

The authors concluded that combined modality therapy did not offer any benefit. However, the study was severely underpowered to detect any difference between the two treatment approaches, with an original power calculation indicating that 670 patients would be required. Furthermore, the operative mortality was 18%, compared with 3% in contemporary single institution phase II studies, and there were several other issues in the conduct of the trial that compromise any conclusions.

As a result of this trial, and the interest in lung preservation in mesothelioma, a randomized trial comparing radical pleurectomy with photodynamic therapy and postoperative chemotherapy to radical pleurectomy with postoperative chemotherapy will be initiated at University of Pennsylvania (NCT02153229). In Europe, plans for a comparison of preoperative versus postoperative chemotherapy with lung sparing surgery for mesothelioma are being formulated.

Nonsurgical approaches

Many patients with localized MPM are not candidates for a surgically-based approach due to the extent of their disease, age, underlying comorbidities, or other factors. In these situations, systemic chemotherapy and the management of the malignant pleural effusion may prolong life or provide significant symptom palliation.

Pleural effusions

Large pleural effusions can cause persistent dyspnea, which, along with pain, is the most common symptom in patients with MPM. Although dyspnea can be relieved by thoracentesis, most such effusions recur relatively rapidly and a more definitive procedure may be required.

Multiple approaches have been used to manage such effusions:

  • Pleurodesis – Pleurodesis can often control symptoms from pleural effusions by obliterating the pleural space and causing adhesions between the visceral and parietal pleura. Complete drainage of the pleural effusion by tube thoracostomy or video thoracoscopy followed by introduction of an irritative agent into the pleural space to produce pleural symphysis, or obliteration of the pleural space, often provides palliation in this setting.

The most widely used compound for pleurodesis is sterile, asbestos-free talc, either insufflated as a powder or instilled via chest tube as a slurry [40]. However, the presence of bulky tumor in the pleural space or a thick visceral pleural peel of tumor can preclude successful pleurodesis because the lung may not completely expand to allow for visceral and parietal pleural contact. Talc should not be used as a sclerosant unless the lung fully expands; talc is a permanent foreign body, which can serve as a nidus for an intractable empyema if the residual pleural space (due to the lung entrapment) gets infected.

Pleurodesis may not be the optimal approach to a pleural effusion in patients who present with MPM that is mainly effusive and do not have much bulky disease. The patient’s options must be considered, and if the patient is a candidate for non-surgical catheter-based intrapleural therapies, symphysis of the pleura may not be desired. However, more recently, with the advanced use of P/D, some surgeons feel that pleurodesis prior to the operation allows easier and more complete visceral pleurectomy. After more extensive evaluation these patients may be candidates for definitive surgery using lung sparing techniques, and the ability to perform such a procedure could be compromised by fusion of the pleura.

  • Tunneled catheters – Some patients with entrapped lungs and sizable effusions can get relief from a tunneled catheter even though the lung does not expand. The mechanism of this may be relieving pressure on the diaphragm. Patients may report an improvement in their breathing, decreased pain, and/or an improvement in early satiety.
  • VATS pleurectomy – Video assisted thoracoscopic subtotal (VATS) pleurectomy may also have a role in the palliative management of pleural effusions in patients with MPM. However, VATS pleurectomy does not improve overall survival in patients with MPM. In the randomized MesoVATS trial, VATS pleurectomy provided better control of pleural effusion at one and six months, but not at 3 and 12 months compared with pleurodesis [41]. VATS pleurectomy has not been directly compared with the use of indwelling valved catheters.

Tumor seeding at the operative site

Prophylactic radiation therapy (RT) has been advocated as a way to prevent tumor seeding at the site of a diagnostic or therapeutic intervention [42]. However, trial results have yielded conflicting results, and there is currently no standard of care regarding the use of prophylactic radiation.

  • In one randomized trial, 40 patients who had had invasive diagnostic procedures (cytology, needle biopsy, thoracoscopy, or chest tube placement) were randomly assigned to either 21 Gy in three fractions or no treatment [43]. There were no chest wall recurrences in the RT patients, but a 40% incidence in the patients who did receive treatment (p<0.001).
  • However, two other randomized trials did not show a statistically significant difference in recurrence between the two arms, and the risk of chest wall recurrence without treatment ranged from 10 to 13% [44,45].

A phase III trial is currently recruiting patients in which patients are randomly assigned to prophylactic irradiation (21 Gy in three fractions) or to no prophylactic irradiation to prevent chest wall tract recurrences (NCT01604005). The trial is limited to patients who are not undergoing definitive surgery.

Chemotherapy

For patients who cannot tolerate aggressive trimodality therapy, combination chemotherapy with a platinum-based doublet such as cisplatin plus pemetrexed has been shown to prolong survival in patients with unresectable MPM.

Radiation therapy

There are only limited data available on the role of RT in combination with systemic therapy in patients with two intact lungs who are not candidates for extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D). At least one report has reported that this approach is feasible using IMRT [34,36], but additional study is required.

Summary and recommendations

  • Patients with malignant pleural mesothelioma (MPM) generally present with locally extensive disease. Surgery, radiation therapy (RT), and systemic chemotherapy each may be beneficial as single modalities in selected situations, but the prognosis for prolonged survival is poor.
  • For patients with MPM limited to one hemithorax, a detailed evaluation is indicated to assess whether disease is amenable to a macroscopic complete resection (MCR), whether there is adequate cardiopulmonary function to tolerate such a procedure, and whether there are any medical contraindications.
  • For surgical candidates, we suggest a combined modality approach that includes chemotherapy (generally a platinum plus pemetrexed), surgery (MCR) with either pleurectomy/decortication (P/D) or radical extrapleural pneumonectomy, and RT. (Grade 2C). Although this approach has not been demonstrated to improve overall survival in randomized trials, carefully selected patients may have relatively prolonged survival.
  • For patients who are not surgical candidates, management of symptoms from any pleural effusion, systemic chemotherapy, and palliative RT may all have a role.

TNM staging system for diffuse malignant pleural mesothelioma

Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor limited to the ipsilateral parietal pleura with or without mediastinal pleura and with or without diaphragmatic pleural involvement
T1a No involvement of the visceral pleura
T1b Tumor also involving the visceral pleura
T2 Tumor involving each of the ipsilateral pleural surface (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following:
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 of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following:
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 of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following:
Diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction
Direct transdiaphragmatic extension of tumor to the peritoneum
Direct extension of tumor to the contralateral pleura
Direct extension of tumor to mediastinal organs
Direct extension of tumor into the spine
Tumor extending through to the internal surface of the pericardium with or without a pericardial effusion or tumor involving the myocardium
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes
N2 Metastases in the subcarinal or the ipsilateral mediastinal lymph nodes including the ipsilateral internal mammary and peridiaphragmatic nodes
N3 Metastases in the contralateral mediastinal, contralateral internal mammary, ipsilateral or contralateral supraclavicular lymph nodes
Distant metastasis (M)
M0 No distant metastasis
MI Distant metastasis present
Anatomic stage/prognostic groups
Stage I T1 N0 M0
Stage IA T1a N0 M0
Stage IB T1b N0 M0
Stage II T2 N0 M0
Stage III T1, T2 N1 M0
T1, T2 N2 M0
T3 N0, N1, N2 M0
Stage IV T4 Any N M0
Any T N3 M0
Any T Any N M1

Note: cTNM is the clinical classification, pTNM is the pathologic classification.

Trimodality studies in pleural malignant pleural pneumonectomy

Ref n Chemotherapy RR
(percent)
EPP done
(percent)
Mortality
(percent)
Completed trimodal
(percent)
OS (ITT) months OS: Subsets months PFS months
Weder[1] 19 32 84 0 68 23 NR CT + EPP: 16.5
Weder[2] 61 NR 74 2.2 59 19.8 CT + EPP: 23 CT + EPP: 13.5
Rea[3] 21 33 81 0 71 25.5 27.5 CT + EPP: 16.3
Flores[4] 21 26 42 0 42 19 CT + EPP + RT: 33.5 NR
Opitz[5] 63 32 3.2 NR NR NR
Buduhan[6] 55 NR 84 4.3 69 NR CT + EPP: 24
TMT: 25
NR
de Perrot[7] 60 NR 75 6.7 50 14 NR NR
Krug[8] 77 32 70 4 52 16.8 CT + EPP: 21.9
TMT: 29.1
ITT: 10.1
CT + EPP: 18.3
Van Schil[9] 58 43 72 6.5 65 18.4 TMT: 33 ITT: 13.9
Rea[10] 54 29 83 NR 41 15.5 NR ITT PFS: 8.6
Bille[11] 25 NR 88 4 71 12.8 NR NR
Okada[12] 27 NR 100 3.7 63 13 23 (chemoRT after EPP) NR

RR: response rate; EPP: extrapleural pneumonectomy; OS: overall survival; PFS: progression free survival; CT: chemotherapy; TMT: trimodality therapy; ITT: intent to treat; NR: not recorded.

Pleurectomy decortication as maximal cytoreductive surgery of pleural mesothelioma

Ref n Rx MCR P/D done
(percent)
Mortality
(percent)
Completed trimodal
(percent)
OS (ITT) months OS: Subsets months PFS months
Sugarbaker[1] 64 Palliative P/D 3.1 9.4 Epith: 21.7
Non-epith: 5.8
Waller[2] 102 P/D, radical 51 5.9 65 15.3 25.4 Epith
Non-radical 51 9.8 26 7.1 10.2 Epith
Butchart[3] 24 P/D CT + RT 24 1.1 24 26
Shahin[4] 26 P/D, radical 13 CT: 54
RT: 46
16.9
Non-radical 13 CT: 54
RT: 15
6.8
Bolukbas[5] 88 P/D, RT, CT NR 2.3 84 26 13
Cameron[6] 121 P/D, RT ± CT 100 NR NR 13.8 19.7 P/D and RT NR
Friedberg[7] 44 P/D, PDT, CT 97 2.3 100 ~33 Epith: 37-57 9.6
Non-epith: 6.8
Lang-Lazdunski[8] 65 P/D, HPov, RT, CT NR 0 100 5 y: 33.4 9

Rx: treatment protocol; MCR: maximal cytoreductive surgery; OS: overall survival; P/D: pleurectomy decortication; PFS: progression free survival; RT: radiation therapy; CT: chemotherapy; PDT: photodynamic therapy; HPov: hyperthermic povidone; NR: not reported.

Multimodality data comparing pleurectomy/decortication and extrapleural pneumonectomy

Ref Procedure n 30 d mortality
(percent)
Morbidity
(percent)
Median fu (months) Median OS (months) 2 year
(percent)
5 year
(percent)
Lang-Lazdunski[1] P/D
(V/P/dgm/peri)
54 0 28 15.7 23 49 30.1
EPP 22 4.5 68 12.9 12.8 18.2 9
Rena[2] P/D
(? extended)
37 0 24 2-45 25 55 NA
EPP 40 5 62 10-41 20 35 NA
Sorensen[3] P/D 34 0 NR 28.4 27
EPP 28 0 NR 31.9 16
Pass[4] P/D
(all stages, 24 extended)
78 1.3 22 22
(0-204)
23 46 19
EPP 102 4.9 57 12
(0-118)
12 23 5
  P/D Stage I/II
(11 extended)
38 2 20 35
(0-204)
44 66 35
EPP Stage I/II 20 5 30 27.5
(0-105)
25 55 29
 Bovolato[5]
 
P/D 204 2.6 10 80 20.5 40 10
EPP 301 4.1 22 80 18.8 37 12
 Flores[6] P/D 278 4 17 16
EPP  385 7 17 12
 Burt[7] P/D 130 3.1 4
EPP 95 10.5 24

OS: overall survival; P/D: pleurectomy decortication; V/P: visceral/parietal; dgm: diaphragm; peri: pericardium; fu: followup.

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