Mesothelioma Empowerment

Treatment of Malignant Pleural Mesothelioma by Surgery

Robert B. Cameron, MD

Introduction. Malignant pleural mesothelioma is a diffuse tumor of the pleural lining that,unlike many solid tumors, does not easily lend itself to complete surgical resection. The tumor abuts all 12 ribs and intercostal muscles, aorta, esophagus, vertebral bodies, diaphragm, pericardium, great vessels, thymus, and the entire visceral lung surface (figure 1). Removal of all these structures with true pathological clear margins (R0 resection) is not possible. Therefore, the use of surgery in this disease requires significant compromise of normal surgical oncology principles and a strategic plan to remediate the inherent deficiencies in an incomplete resection.

Mesothelioma Characteristics Favoring Surgery. Surgical resection of diffuse pleural disease from solid tumor epithelial malignancies, including lung, colon, esophageal, pancreatic, and breast cancer almost never can be achieved due to their physically invasive nature; however, specific mesothelioma characteristics make surgery not only feasible—but even potentially therapeutically beneficial. Due to the mesodermal origin of the mesothelium, mesothelioma behaves less like most other common solid tumors with endodermal origins and more like other “mesenchymal” tumors, such as sarcomas. Importantly, both mesotheliomas and sarcomas grow with “pushing” rather than “infiltrative” borders and have a pseudocapsule. This physical property allows surgeons to “pull” the tumor off all of the pleural-covered surfaces (like removing a sarcoma through its pseudocapsule), making operations for mesothelioma even possible. Further, the metastatic spread of the epithelioid subtype of mesothelioma (vs biphasic and sarcomatoid) is primarily locoregional with distant metastatic disease occurring late. Specifically, lymph node metastases occur in 50.4%-57.6% of epithelioid (1,2), 32%-41.7% of biphasic (1,3), and only in a few nodes in < 28% of sarcomatoid tumors (1). Interestingly, this is similar to the characteristics of epithelioid sarcomas. which commonly develop lymph node metastases in 22%-45% (4-7) while the incidence of lymph node involvement in more classical “spindle” sarcomas is low--only 3-4%.(8,9) However, it is the relatively low rate of distant hematogenous metastases with epithelioid tumors (vs biphasic and sarcomatoid tumors) that favors the use of locoregional therapies, such as surgery and radiation.

Mesothelioma Characteristics Against Surgery. Like virtually all mesenchymal tumors including the sarcomas, mesothelioma has a high incidence of wound seeding following invasive procedures (needle tracks and surgical incisions). The tendency for surgical site seeding does not particularly favor surgery and has two important implications. First, surgical biopsies should be minimized to avoid unnecessary areas of chest wall invasion and should be limited to an subsequently easily re-resectable area, such as the low lateral chest wall but never the visceral pleura to avoid invasion into the lung, mediastinal pleura, or pericardium. Secondly, “extended” surgical resections remove natural barriers to the spread of mesothelioma (ie., pericardium and diaphragm). This can unwittingly spread the tumor to new previously uninvolved body cavities, such as the pericardial space and peritoneum with marked treatment consequences.

Surgical Rationale. As noted above, surgical resection of pleural mesothelioma, no matter how radical, cannot provide a better oncologic result than an R1 resection--resection with microscopic residual disease. Such surgical results are almost never accepted with other solid tumors. The question is why do surgeons persist in “debulking” pleural mesothelioma? There are no randomized controlled trials to provide a rationale for this practice; however, there are several observations that seemingly support the use of surgery in this disease. First, surgery can remove all visible disease (R1 resection) in a high percentage of patients—116/121 (95.9%) in our UCLA experience(1)—equivalent to an otherwise rare complete response to systemic drug therapy. Secondly, the microscopic residual disease that remains following surgery is likely to be controlled more easily by adjuvant therapy than gross disease. Thirdly, the majority of mesothelioma patients still succumb to local rather than distant metastatic disease, supporting the use of more aggressive local therapies to prolong overall survival. Fourthly, most locally advanced solid tumors require multimodality therapy for any chance at cure. Fifth surgery provides a unique access to the entire locoregional tumor “bed.” Thus, surgery can provide physical access for intraoperative adjuvant therapies, such as photodynamic therapy; betadine lavage; hyperthermic chemotherapy; and gene, cytokine/chemokine, and stem cell therapies, which albeit remain unproven, are currently under investigation. Finally, multimodality therapy utilizing aggressive surgical resection at specialized centers like ours at UCLA, almost uniformly report long-term survival (5-15 years or more) in surgical patients. (1,10). Similar long-term survival following any other therapy combination is exceedingly rare, if it exists at all.

Types of Surgical Procedures. A variety of surgical procedures varying from thorascopic pleurodesis to radical extrapleural pneumonectomy (EPP) have been utilized in patients with malignant pleural mesothelioma. The individual procedures are outlined below:

Thorascopic Pleurodesis. The simplest procedure is a thorascopic (minimally-invasive) pleurodesis procedure. This procedure usually serves both a diagnostic and therapeutic function. Importantly, cytopathology and small percutaneous core needle biopsies do not provide adequate determination of histology subtype; and therefore an optimal biopsy often can only be provided by a thorascopic (or open pleural biopsy, if the pleural space is fused) procedure which can assess the extent of visceral and parietal involvement and obtain biopsy material for definitive diagnosis—preferably from the parietal surface near the lower chest wall (lung biopsies should be avoided at all costs). In addition, thorascopic procedures can most reliably achieve pleural symphysis, if at least the majority of the parietal and visceral pleurae surfaces can appose in order to prevent symptoms of recurrent pleural effusions. Although the most reliable method of pleurodesis, talc poudrage, alone has been associated with a reasonable median survival of 21 months (11,12), its accepted role remains strictly for symptomatic palliation only. It is imperative that any biopsy or port incisions are planned to be incorporated into a standard thoracotomy incision or chest tube site so as to prevent chest wall wound seeding outside the area of a planned definitive thoracotomy for resection.

Pleurectomy and Decortication (P/D). The resection of mesothelioma tumor tissue by complete removal of both the parietal and visceral pleural surfaces is termed pleurectomy and (or with) decortication. P/D has been used for decades, first reported in substantial series by Worn and then Martini.(13,14) Although P/D was equivalent to the more radical EPP in Worn’s series, many surgeons still focused on the more radical resection, undeterred by its early high mortality rate of 31%.(15) P/D essentially became a secondary procedure performed only when an EPP was not possible, and was referred to simply as a “debulking” (16) or “cytoreduction” procedure.(17) These terms both imply that portions of the tumor knowingly were left behind by the surgeon, a likely outcome particularly if staunch EPP advocates discovered intraoperatively that an EPP was not possible. The exact details and the extent of resections performed under the umbrella term, “P/D,” varies tremendously depending on surgeon and experience. The International Association for the Study of Lung Cancer (IASLC) and the International Mesothelioma Interest Group (IMIG) conducted a survey of surgeons’ concepts of various P/D procedures and made recommendations for definitions of specific P/D terminology:(17)

1. Pleurectomy and Decortication (P/D). This procedure consists of a parietal and visceral pleurectomy removing all gross tumor (R1 resection) but without diaphragm or pericardial resection.
2. Extended Pleurectomy and Decortication (Extended P/D). This procedure consists of a parietal and visceral pleurectomy removing all gross tumor (R1 resection) but with the addional resection of the diaphragm and/or pericardium.
3. Partial Pleurectomy: This procedure consists of a partial parietal and/or visceral pleurectomy leaving gross tumor behind (R2 resection), primarily for diagnostic or palliative purposes.
4. “Radical” is a term commonly used to indicate either the completeness of resection or extension of the resection to include additional tissues, such as the pericardium and diaphragm. Due to its ambiguity, this term was left out of the IASLC/IMIG nomenclature.

A P/D is performed by placing the patient in a standard lateral decubitus position, often with the operative table in flexion to expand the intercostal space and facilitate exposure. Peripheral venous access is preferred with only 2.5% of patients at UCLA requiring central venous access due to poor peripheral access or cardiac issues. A standard posterolateral thoracotomy incision is made, removing the 7^th rib (most surgeons). All prior biopsy and/or port sites with palpable disease undergo re-resection but routine “en bloc” resection as performed in EPP is not usually necessary. Then, an extrapleural dissection plane is created and extended to the thoracic apex, carefully avoiding injury to the great vessels and apical nerves (phrenic, vagus, sympathetic and T1 nerve root of the brachial plexus), as well as anteriorly and posteriorly, carefully preserving the internal mammary vessels and the azygous venous system or aorta depending on the side of the procedure. The extrapleural dissection then is carried down to the diaphragm and pericardium where these structures are either preserved or resected (see Extended P/D below). In our UCLA experience, resection of these two structures rarely was necessary (<10% of 121 patients); however, the weakened diaphragm should be reinforced with bovine pericardial sheets (or similar biological material) covering the majority of the central muscular and fibrous portions. Rarely, resection of esophageal longitudinal muscle or the aortic adventitia may be required due to tumor invasion. The parietal pleura then is mobilized to circumferentially around the pulmonary hilum. Level 7 and all other lymph nodes (levels 2, 4, 8, 9, 10, 11 and often 12 on the right; and levels 4, 5, 6, 8, 9, 10, 11, and often 12 on the left) are removed. To this point, the operation is essentially identical whether a P/D or EPP is performed. The lung is then re-inflated and placed on constant positive airway pressure (CPAP) and a scalpel (15 blade) is used to cut through both the parietal and visceral pleurae into the superficial lung parenchyma (figure 2). The visceral pleura is elevated gently off the lung parenchyma of each lobe serially. A variable number of septae, which interrupt the smooth parenchyma of the lung surface creating lobules, determine the difficulty of decortication which may be technically challenging in some patients, yet still achievable. Interestingly, the number of septae present in the fissure is almost always minimal making removal of the tumor in the pulmonary fissures almost uniformly simple and quick often taking just a few minutes. This conflicts with the finding in EPP series that tumor in the fissures is an indication for EPP since it cannot be removed. After complete excision of the tumor, the chest is vigorously irrigated to remove free microscopic cells and adjuvant therapies may be utilized. The chest is closed with multiple drainage catheters (usually at least 4) to prevent accumulation of loculated fluid collections. At UCLA, 93.4% of patients are extubated in the operating room and routinely transferred to a monitored floor with only 18.2% of patients in our 121 patient series requiring ICU care anytime during their hospitalization.(1) Epidural-related hypotension is the most frequent indication for ICU care. The mortality rate varies from 0-2.5% with prolonged air leaks (23.1-33.9% after 10 days) and atrial fibrillation (11.5%-31.4%) reported as the most frequent complications.(1,18) The mean/median length of stay is 8.1-10.0 days.(1,18)

Extended Pleurectomy and Decortication (Extended P/D). The complete resection of both the parietal and visceral pleural surfaces en bloc with the diaphragm and pericardium is termed an extended P/D. It is performed essentially the same as a P/D except the diaphragm and pericardium are removed en bloc instead of being preserved. A variety of materials can be used for reconstruction including Gortex but also a variety of biological materials as well.

Partial Pleurectomy. Partial resection of tumor tissue often only just enough to expand the lung and achieve pleurodesis is termed partial pleurectomy and has been used in many centers as the alternative procedure in patients who cannot undergo EPP with results that are not directly comparable to P/D, extended P/D, or EPP. Waller, et al. reported that thorascopic simple pleurectomy provided no benefit.(19)

Extrapleural Pneumonectomy (EPP). Although Butchart originally noted that “at first sight the margin of tumor clearance might not appear to be any greater with radical surgery than with palliative surgery,” EPP was felt to be superior due to the “superior” inherent clearance of tumor from the diaphragm and lung.(15, 16) Contradictory “truths” were claimed, including that “although it is possible to strip the peritoneum off the muscle of the diaphragm, it is quite impossible to do the same with the pleura.” This is despite the pleura and peritoneum having essentially the same histological relationship—one simply being above and the other below the diaphragmatic muscle.(15) Furthermore, Butchart felt that “diffuse malignant pleural mesothelioma of the pleura in the parietal pleura appears to behave quite differently from diffuse malignant pleural mesothelioma in the visceral pleura in terms of invasiveness.”(15) Visceral pleura was thought to be “inseparable from the lung,” but only more recently was complete visceral pleurectomy attempted and successfully performed. Instead areas of diseased visceral pleura were removed leaving behind areas of “normal” pleura. In our UCLA experience, however, it is virtually impossible to find any pathologically normal pleura even in areas that appear visibly normal. These concepts and attitudes persist even today with some surgeons insisting that pleurectomy “even with decortication” has to “leave tumor behind.”(15)

The initial “pleurectomy” portion of an extended P/D (see above) combined with an intra-pericardial pneumonectomy are the essential components of an EPP. Since both an extended P/D and EPP remove the pericardium, the pneumonectomy can be performed inside the pericardium and accomplished simply and expeditiously, rather than a more tedious and difficult decortication. Following removal of the lung and pleurae, again intra-operative adjuvants may be used. Following surgery, all patients initially are observed in the intensive care unit (ICU) with arterial and central venous catheters, fluid is restricted to 1 L/day, and they are not allowed oral intake until there is return of bowel function.(25) Similar to P/D, common morbidity includes atrial fibrillation (44.2%), prolonged intubated (7.9%), and deep venous thrombosis (6.4%), but there were slightly more vocal cord paralysis (6.7%) and technical complications (6.1%), such as diaphragm patch dehiscence.(25) Due to the pneumonectomy, there also were no prolonged air leaks and a low rate of bronchopleural fistulae (0.6%).

Outcomes and Survival. Survival comparisons are complicated by heterogeneous definitions and methods of reporting. Patient survival may be measured from the time of surgery, from the time of first chemotherapy (particularly with neoadjuvant chemotherapy), and even the date of study entry. Results can be compared in two ways: within the various techniques of P/D and between P/D and EPP. Patient outcomes for P/D, particularly as compared to EPP, are controversial and mired in significant variation in surgical technique as well as strong selection, center, and surgeon biases. Reported endpoints include disease-free survival, overall survival and frequently freedom from local versus distant recurrence. Yet, the absence of any well-designed, prospective, randomized clinical trials leaves all claims of surgical benefit open to debate.

1. Outcomes with partial pleurectomy, P/D, and extended P/D have been examined in detail by Cao, et al.(20) Contemporary studies with adequate reported follow-up were classified according to the IASLC-IMIG pleurectomy classification system. Morbidity results showed that P/D and extended P/D were nearly identical (13-48% vs 20-43%, respectively) while the morbidity of partial pleurectomy was slightly less (14-20%).(20) P/D and partial pleurectomy also were identical in terms of mortality, both ranging from 0 to between 7 and 8%, while extended P/D was slightly more risky (mortality = 0-11%).(20) Although survival statistics suggested a slight trend for longer disease-free survival in extended P/D versus P/D (range 6-7.4 mos vs 7.2-16 mos), there were no differences observed in median overall survival (range 8.3-26 mos vs 11.5-31.7 mos).(20); however an inferior overall median survival (7.1-14 mos) was observed in partial pleurectomy patients (disease-free survival not able to be measured).(20)
2. Outcomes with EPP have been reported by numerous authors with some excluding perioperative deaths and others reporting outcomes predominantly in selected favorable patient subsets potentially distorting the true outcomes for all patient groups. Although patients with epithelioid tumors, clear lymph nodes, complete resection, and completion of all multimodality therapy have the best prognosis, it is extremely difficult to preoperatively select these patients accurately. The only randomized trial reported was the pilot Mesothelioma And Radical Surgery (MARS) Trial performed in the U.K. This registered patients  for preoperative chemotherapy, re-evaluated ??? of them following induction therapy, and then randomized the remaining patients (50) to receive surgery (24) or best supportive care (26). The conclusions were heavily criticized due to the small patient numbers, high crossover rates in both directions (6/26 = 23.1% in the no surgery arm having surgery and 5/24 (20.8%) in the EPP group did not undergo surgery), high early EPP mortality (3/24=12.5% randomized patients or 3/19=15.8% operated patients), a low overall median EPP survival of 14.4 months (improves to 18 mos with chemotherapy time), and a high overall median survival in the no surgery group of 19.5 months. Despite these criticisms, the experience likely reflects the realities of treating general mesothelioma patients and not those attracted to specialized treatment centers. Furthermore, there was absolutely no data suggesting that EPP was beneficial; and in fact, showed a significant detriment in quality of life.
3. A number of retrospective reports have compared outcomes with P/D (all types) and EPP, but to date no prospective randomized trials comparing the two procedures exist. Regardless of practical or theoretical considerations(21), current evidence supports the claim that P/D produces similar or better outcomes than EPP. First, mortality (and morbidity) is greater with EPP. In a retrospective analysis of 663 patients pooled from 3 centers, Flores et al, showed that operative mortality was 27/385 (7%) for EPP while only 13/278 (4%) for P/D.(22) A recent meta-analysis suggested an improvement in perioperative mortality in both procedures but a difference in favor of P/D persisted (1.7% vs 4.5%; p<0.05).(23) Secondly, several studies suggest an overall survival benefit to P/D. For instance, Flores documented better median survival with P/D compared to EPP (16 mos vs 12 mos; p<0.001) even when operative deaths were excluded.(22) This persisted in the patients with early stage tumors (AJCC stage I and II) albeit the difference did not reach statistical significance (p=0.07). Although a scatter plot shows overlapping overall survival statistics reported in 17 P/D studies compared to those reported in 20 EPP series, most ranging from 8 to 21 mos (figure 3), two recent meta-analyses strongly suggested better outcomes with P/D over EPP.(23,24)
4. Recurrence Patterns. EPP enthusiasts have long claimed improved local control and increased distal disease recurrence from EPP, representing a “change in the natural history” of mesothelioma. Closer analysis of the data from the 663 patients reported by Flores, however, is instructive. In this collective experience from three centers, local recurrence rates (ipsilateral chest and pericardium) of 33% for EPP and 65% for P/D were reported and distant recurrence rates (contralateral pleura/lung, peritoneum, bone, brain, and other) of 66% for EPP and 35% for P/D claimed.(22) An explanation for the difference was proposed in that EPP patients more consistently received aggressive postoperative adjuvant radiation. Yet, the inclusion of peritoneum (EPP 57 vs P/D 24), peritoneum and chest (EPP 17 vs P/D 1), abdominal viscera (EPP 12 vs P/D4) and contralateral pleura (EPP 49 vs 14 P/D) as “distant” recurrences defies logic in the face of the surgical techniques. The diaphragm and pericardium are resected in all cases of EPP while not in many of the P/D patients. With resection of the diaphragm, the peritoneum itself becomes the new surgical margin as does the contralateral pericardial/pleural tissue with resection of the pericardium, making recurrences in these area more accurately classified as marginal “local” recurrences rather than biological “distant” recurrences. If corrected, the extended local recurrence rates become 208/219 (95%) for EPP and 129/133 (97%) for P/D. This actually suggests poor local control in both groups.

Summary. Current evidence strongly suggests that P/D is a better operation, both in terms of mortality and survival; however, no operation has been evaluated in a prospective randomized controlled clinical trial, although a planned Mesothelioma And Radical Surgery (MARS) 2 trial, a feasibility study comparing (extended) pleurectomy decortication to no surgery is in final planning stages in the U.K. Clearly, successful surgery for malignant pleural mesothelioma relies heavily on the addition of effective adjuvant therapies. With rapidly advancing knowledge of targeted and immunologically based treatments, successful multimodality therapy may very well be possible soon. Hope certainly exists for the future, and it appears that surgery will remain a part of mesothelioma treatment in the foreseeable future.

References:

1. Cameron RB, Olevsky OM, Selch M, Fishbein M, Abtin F, Wallace WD, Lai C,Suh R, and Rorie A. The timing of chemotherapy in the multimodality treatment of malignant pleural mesotheliom). IMIG 2012, September 12, 2012, Boston, MA.
2. Sugarbaker DJ, Richards WG, Bueno R. Extrapleural pneumonectomy in the treatment of epithelioid malignant pleural mesothelioma: novel prognostic implications of combined N1 and N2 nodal involvement based on experience in 529 patients. Ann Surg. 2014 Oct;260(4):577-80; discussion 580-2
3. Chirieac L, Richards WG, Sugarbaker DJ. Patterns of lymph node spread to N2 nodes predicts survival in patients with biphasic pelural malignant mesothelioma (MM). IMIG 2012, September 12, 2012, Boston, MA.
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12. Aelony Y, Yao JF. Prolonged survival after talc poudrage for malignant pleural mesothelioma: case series. Respirology. 2005 Nov;10(5):649-55.
13. Wörn H. [Chances and results of surgery of malignant mesothelioma of the pleura (author's transl)]. Thoraxchir Vask Chir. 1974 Oct;22(5):391-3.
14. Martini N, Bains MS, Beattie EJ Jr. Indications for pleurectomy in malignant effusion. Cancer. 1975 Mar;35(3):734-8.
15. Butchart EG, Ashcroft T, Barnsley WC, Holden MP. Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients. Thorax. 1976 Feb;31(1):15-24.
16. Butchart EG, Ashcroft T, Barnsley WC, Hoden MP. The role of surgery in diffuse malignant mesothelioma of the pleura. Semin Oncol. 1981 Sep;8(3):321-8.
17. Rice D, Rusch V, Pass H, Asamura H, Nakano T, Edwards J, Giroux DJ, Hasegawa S, Kernstine KH, Waller D, Rami-Porta R; International Association for the Study of Lung Cancer International Staging Committee and the International Mesothelioma Interest Group. Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the international association for the study of lung cancer international staging committee and the international mesothelioma interest group. J Thorac Oncol. 2011 Aug;6(8):1304-12
18. Burt BM, Cameron RB, Mollberg NM, Kosinski AS, Schipper PH, Shrager JB, Vigneswaran WT. Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality. J Thorac Cardiovasc Surg. 2014 Jul;148(1):30-5
19. Rintoul RC, Ritchie AJ, Edwards JG, Waller DA, Coonar AS, Bennett M, Lovato E, Hughes V, Fox-Rushby JA, Sharples LD; MesoVATS Collaborators. Efficacy and cost of video-assisted thoracoscopic partial pleurectomy versus talc pleurodesis in patients with malignant pleural mesothelioma (MesoVATS): an open-label, randomised, controlled trial. Lancet. 2014 Sep 20;384(9948):1118-27.
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22. Flores RM, Pass HI, Seshan VE, Dycoco J, Zakowski M, Carbone M, Bains MS, Rusch VW. Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg. 2008 Mar;135(3):620-26.
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Figure 1: This MRI shows diffuse mesothelioma essentially adjacent to every surface inside the chest including the ribs, intercostal muscles, aorta, esophagus, vertebral bodies, diaphragm, pericardium, great vessels, thymus, and lung

Figure 2: This intraoperative photograph shows an open thoracotomy incision with the uncovered inflated lung at the bottom left (with the visceral surface removed and normal lung parenchyma and alveoli exposed) and the mass of mesothelioma tumor at the upper right as it is almost completely extirpated from the intra-thoracic surfaces.

Figure 3: This graph compares the various studies of EPP versus P/D in terms of median survival. The range of median survivals (x axis) is slightly greater with EPP but overall there is no difference with the vast majority of studies for both showing a median survival of between 8 and 21 months