Abstract and Introduction
The role of surgery for malignant pleural mesothelioma encompasses the need for rapid diagnosis, preoperative staging and surgical resection, and also the need for a greater biological understanding of this rare and aggressive malignancy. In the multimodality treatment paradigm, the goal of surgery is to provide a macroscopic complete resection (i.e., complete removal of all grossly visible tumor). Two operations have evolved: extrapleural pneumonectomy and pleurectomy/decortication. The former is indicated for patients with advanced locally invasive disease; the latter for patients with more superficial spread of tumor that spares the lung and fissures. If critical mediastinal structures (e.g., aorta and vertebral bodies) are found to be involved at thoracotomy, the tumor is classified as T4, and pleurectomy/decortication is recommended. Despite having more advanced disease, a subset of patients with favorable prognostic factors can experience extended survival by undergoing trimodality therapy with extrapleural pneumonectomy, chemotherapy and/or radiation. The influence of surgery goes beyond diagnosis and resection. Much of what we know about the biology of mesothelioma has been gleaned from studying the surgical pathophysiology, including the delineation of histopathologic subtypes, disease stage stratification with survival, the propensity for local (in contrast to systemic) recurrence, as well as the prognostic effect of epithelial versus nonepithelial cell type, extrapleural nodal involvement, tumor bulk and surgical margins. Pending the discovery of new drugs, the focus of clinical research over the next 5 years will emphasize refinements in patient selection, pathologic staging, molecular staging and other novel adjuvant therapies.
The development of surgical treatments for mesothelioma has followed a path similar to that of other solid tumors. The functional approach to treating solid tumors is a two-step process: remove all gross evidence of the primary malignancy and then treat microscopic residual disease with adjuvant therapy. In mesothelioma, however, the Halsteadian notion of complete tumor removal cannot be followed in the sense of an R0 resection. Some microscopic disease is always left behind owing to the irregular anatomy of the pleura and thoracic cavity. Nevertheless, we proceed with resection because it is the fastest, least morbid method, and in many situations, the only possible way of reducing the bulk of the tumor to microscopic levels. This R1 resection is called macroscopic complete resection in surgery for mesothelioma. Adjuvant therapy then completes the process by eliminating microscopic disease at the surgical margins to prevent local recurrence or widespread hematogenous or lymphangitic dissemination. These concepts form the basis of the multimodality treatment strategy for malignant mesothelioma. Failure to eradicate residual micrometastatic foci of disease through some form of adjuvant therapy hastens the recurrence of cancer and shortens survival.
The first phase of development of a surgical treatment for mesothelioma began with an operation that had been used in the mid-20th Century to treat patients with tuberculous empyema. The operation was called, alternately, pleuropneumonectomy or extrapleural pneumonectomy. The first attempts to apply this operation to mesothelioma were made in the 1970s when the specter of mesothelioma began to produce deaths among symptomatic patients who had been exposed to asbestos many years earlier. Unfortunately, the mortality associated with extrapleural pneumonectomy at that time was high (e.g., as high as 31%), leading many to conclude that surgical therapy for mesothelioma was completely untenable. Procedure redesign along with advances in perioperative care and anesthesia in the 1980s allowed surgeons to refine that surgery for mesothelioma, bringing morbidity and mortality rates in line with those of other major surgical resections for solid tumors.
Extrapleural pneumonectomy is a technically challenging operation. To achieve a macroscopic resection in most patients with operable mesothelioma, the affected parietal and visceral pleurae, underlying lung, ipsilateral diaphragm and ipsilateral pericardium must be resected, followed by repair or patch reconstruction of the diaphragm and pericardium. The chief complication of this operation is reversible atrial fibrillation, which occurred in 44.2% of patients in our previously reported series. Other major causes of morbidity are myocardial infarction (1.5%), epicarditis (2.7%), pulmonary complications (7.9%), thrombosis (6.4%), empyema (2.4%), technical (6.1%) and gastrointestinal complications (0.9%). When performed at an experienced, high-volume center, extrapleural pneumonectomy is associated with a perioperative mortality of between 2.2 and 7%,[4–10] comparable to mortality for other oncologic surgeries, for example, esophagectomy, pancreaticoduodenectomy[12,13] and hepatectomy.
Recent studies using validated quality-of-life questionnaires have demonstrated sustained improvement in quality of life after extrapleural pneumonectomy. Particularly in cases where there is chest wall invasion or poor lung function, resection can palliate symptoms of chest wall pain or shortness of breath due to ventilation/perfusion mismatch. In our experience, patients who tolerate pneumonectomy resume normal baseline functional status once they have recovered from extrapleural pneumonectomy.
As the technical details of extrapleural pneumonectomy were being modified, there was a resurgence of interest in pleurectomy/decortication, a lung-sparing procedure, to discern if it too could achieve cytoreduction. With pleurectomy/decortication, the visceral and parietal pleurae are dissected off the surface of the lung and the lung is left in place. The chief complications of pleurectomy/decortication are hemorrhage and prolonged air leak. However, the same cardiac, pulmonary, infectious, renal and hematologic complications that apply to other extensive thoracic procedures may also result from pleurectomy/decortication. Perioperative mortality for pleurectomy ranged from 1 to 5% in recent series, with prolonged air leak occurring in 4–10% of patients.[10,18]
Mesothelioma has a distinct pattern of failure. Unlike other solid tumors, in which hematogenous and lymphangitic metastases are the common sources of recurrence, the majority of patients with mesothelioma recur locally within the same tissue margins visited during the primary resection. The abdomen is the most common site and probably represents regional spread by local invasion. It is rare for the tumor to metastasize via hematogenous spread to the contralateral chest. The patterns of recurrence do differ between extrapleural pneumonectomy and pleurectomy/decortication and have been well described in a paper by Flores et al. (see Table 2 in that paper). In this multicenter study of 663 consecutive patients who underwent surgery for mesothelioma, Flores and colleagues found that 31% of patients who underwent extrapleural pneumonectomy experienced recurrence in the ipsilateral chest, whereas 63% of patients who underwent pleurectomy/decortication recurred in this location.
There is a common misperception that these operations are interchangeable. In fact, the selection of operation for a particular patient depends on the characteristics of the patient's tumor. Pleurectomy/decortication may improve survival in patients with early-stage disease, provided that there is no involvement of tumor in the lung fissures and that all gross visible tumor can be removed (macroscopic complete resection). Pleurectomy/decortication should not be performed simply for palliation. Extrapleural pneumonectomy is indicated for more advanced, bulky tumors, provided that the patient can tolerate a pneumonectomy.
The difference in biologic impact between these two procedures is the amount of residual tissue interface that was once in intimate association with the tumor that is left behind in the patient. With extrapleural pneumonectomy these potential sites for recurrence are limited to the resection margins of the diaphragm and pericardium, the lateral anterior and posterior chest walls and, to a certain extent, the upper mediastinum and apex. With pleurectomy, the surface area is essentially tripled, leaving a much broader field for potential recurrence, although the benefit of sparing the lung from removal may offset this disadvantage. A potential advantage of extrapleural pneumonectomy is that removing the lung facilitates radiation of the empty hemithorax. Radiation has effectively prevented recurrent disease in many solid tumors. After weighing the pros and cons of each operation, the decision rests on the characteristics of the individual tumor, whether the patient can tolerate the surgery and which procedure can deliver a macroscopic complete resection.
Thus, with respect to cytoreduction, the target goals have been met in two well-developed operative techniques that can be performed safely with acceptable morbidity and mortality by an experienced team (see Figures 1–3 for extrapleural pneumonectomy and Figures 4–6 for pleurectomy/decortication). By improving the techniques for preoperative staging, anesthesia, resection, reconstruction and perioperative management of procedure-related complications, we have substantially reduced the mortality of extrapleural pneumonectomy at our center to 3.4%.
Extrapleural pneumonectomy: chest retractors are placed to increase the initial exposure of the tumor.
Reprinted with permission from .
Extrapleural pneumonectomy: a nasogastric tube is inserted in the esophagus to prevent injury while the tumor is being resected off the esophagus.
Reprinted with permission from .
Extrapleural pneumonectomy: the diaphragm is avulsed or bluntly separated from the chest wall muscular attachments.
Reprinted with permission from .
Pleurectomy/decortication: visceral pleurectomy (decortication) is accomplished in two stages.
First, the tumor is incised posteriorly to the hilum and a plane is developed between the visceral pleura and the underlying lung parenchyma. Reprinted with permission from .
Pleurectomy/decortication: the fully decorticated lung is retracted out of the lower tumor shell.
The tumor shell is then resected and removed from the operative field. Reprinted with permission from .
Pleurectomy/decortication: appearance of the decorticated lung after the visceral and parietal pleurae have been resected (with diaphragm intact).
To achieve macroscopic complete resection for a tumor that invades the diaphragm, a split-thickness, partial or complete hemi-diaphragmatic resection may be required. In the case of partial resection, primary repair or autologous reconstruction may be possible, but in the case of complete resection, a patch is created similar to the technique of extrapleural pneumonectomy, which has previously been described .
The long-term results of multimodality therapy have been expressed by various measures. Overall median survival or disease-free progression interval are most commonly used. The overall median survival for patients undergoing surgery-based multimodality therapy at our institution is 1–2 years. Median overall survival with extrapleural pneumonectomy-based multimodality therapy in recent studies is 10–35 months.[5,7,9,19,22–24] Median survival with pleurectomy/decortication-based multimodality therapy is 8–22 months.[10,24–29] By contrast, the median survival range for patients who receive cisplatin chemotherapy alone or in combination with pemetrexed is 9.3–13.3 months, respectively, and for historical palliative controls, 7 months.[31,32]
It is unlikely that selection bias alone accounts for the longer survival observed in surgery-based multimodality series compared with chemotherapy series since patients with poor prognostic factors contributed to the higher median survivals reported in the surgical series. For example, 80 out of 183 (41%) of the patients described in our institution's first published series on multimodality therapy had nonepithelial (less favorable) tumors and their data contributed to the overall median survival of 19 months in this series. Also, in a recently published series, two thirds of 354 patients with epithelial tumors treated with extrapleural pneumonectomy between 1988 and 2005 were International Union Against Cancer and the American Joint Committee on Cancer (UICC/AJCC) Stage III and 19% were UICC/AJCC Stage IV, with 18.9 and 12.6 months median survival, respectively.
Given the natural history of mesothelioma, adjuvant therapy is critical to reduce the risk of recurrent disease. Failure to address residual foci of micrometastatic disease after surgical cytoreduction continues to be the chief barrier to long-term survival. A variety of locoregional techniques are being considered, some of which have been more widely accepted than others.
The role of adjuvant radiation therapy for pleurectomy/decortication is constrained by the presence of exposed lung parenchyma in the radiation field. The clinical benefit of adjuvant radiation after extrapleural pneumonectomy, however, has been established. Three approaches have been used in this setting: moderate-dose photon technique, high-dose matched photon/electron technique and high-dose intensity modulated radiation therapy.[35,36] The latter focuses more intensely on the target with less scatter and has the potential to achieve excellent control of the disease, however, some groups have experienced problems with pulmonary toxicity due to low-dose radiation exposure to the contralateral lung.[38,39] This topic has recently been reviewed.
Several groups have published their experiences with photodynamic therapy to treat pleural tumors, including mesothelioma. Photodynamic therapy is a light-based treatment that has been approved for several oncologic targets but remains experimental in the treatment of mesothelioma.[42,43] A primary advantage of this approach is that it can be administered in conjunction with lung-sparing pleurectomy. A number of experimental drug-delivery systems are being investigated, including nano-delivery systems that are being engineered to target, deliver and deploy cytotoxic agents directly into the nucleus of the malignant cell.
Heated intraoperative chemotherapy lavage is a treatment approach that we offer in both clinical practice and Phase II clinical trials at our institution.[44–46] This approach to adjuvant chemotherapy bathes the hemithorax in chemotherapy immediately after extrapleural pneumonectomy at a time when the residual cancer cells are most vulnerable.
Finally, systemic chemotherapy warrants its own discussion. Identifying a systemic chemotherapeutic agent that can control the resurgence of tumor cells after primary resection, alone or in combination with other sensitizing drugs or biologics, would represent a true breakthrough in mesothelioma treatment. Unfortunately, mesothelioma is highly resistant to standard chemotherapy and biologic agents, and current options remain limited.
Cisplatin-based regimens have provided the most benefit, particularly when combined with an antifolate agent, such as pemetrexed, which is thought to sensitize tumor cells to cisplatin. Sirolimus, which inhibits the mTOR, a cell signaling pathway that is involved in many human cancers, has also been shown to boost the efficacy of cisplatin in human mesothelioma cell lines. Cisplatin in combination with pemetrexed is considered by many to represent the current first-line combination for adjuvant or neoadjuvant chemotherapy. However, gemcitabine, an intravenous pyrimidine analog, has also demonstrated efficacy in combination with cisplatin according to a number of reports,[50–52] and was shown to produce equivalent median survival to cisplatin plus pemetrexed in a recent retrospective review. Vinorelbine, a semisynthetic vinca alkaloid, has delivered results when combined with cisplatin similar to the other platinum-based doublets described. These and other options for targeted therapies have been recently reviewed.
As previously mentioned, patients treated with chemotherapy alone have a median predicted survival of 9.3–13.3 months, in comparison with historical controls treated with palliative therapy, whose median predicted survival is only 7 months.[31,32] Chemotherapy tolerance is variable and many patients are unable to complete the minimum four cycles recommended. In Vogelzang's Phase III trial, depending on the subgroup, 41–96% of patients completed at least four cycles of chemotherapy.
Whether therapy should be administered before or after cytoreductive surgery for mesothelioma has been a subject of debate. The largest body of experience is with extrapleural pneumonectomy followed by adjuvant therapy. Data demonstrating improved survival with neoadjuvant therapy for stage III non-small-cell lung cancer (NSCLC) have prompted others to apply this approach to mesothelioma. Weder and colleagues showed good outcomes using this approach, but the patient numbers in their series are small and the duration of follow-up for this approach has been too short to draw meaningful conclusions regarding its potential benefit.[7,55] We have several concerns about this approach. Patients with aggressive tumor may progress to more advanced disease while undergoing neoadjuvant chemotherapy and ultimately be denied the opportunity for surgery. Other patients with tumor adjacent to the hilar vessels may be rendered unresectable because the effects of chemotherapy alter the dissection planes. These patients also may lose the potential opportunity for successful resection by undergoing neoadjuvant therapy. Consequently, we have adopted a more circumspect approach in our practice, reserving neoadjuvant chemotherapy for patients with high platelet counts, evidence of paraneoplastic syndrome, hormonally active tumors, intense chest pain with concern for diffuse chest wall invasion or mediastinal node involvement detected by cervical mediastinoscopy.
Surgery has contributed immensely to our improved understanding of the biology of mesothelioma. Much of what we know about this disease has been gleaned by studying the surgical pathology of patients undergoing extrapleural pneumonectomy.[56–58] This knowledge has formed the basis for dialog on disease staging and is particularly important for a rare malignancy, in which pooled data are used to derive statistical comparisons. Pooled data must be interpreted with caution as many series have failed to report prognostic factors that correlate with outcome, or have grouped patients with varying tumor histology and differing surgical procedures.
The WHO currently classifies mesothelioma as four distinct histologic categories based on immunohistochemical staining: epithelial, sarcomatoid, mixed and desmoplastic. The biology and clinical behavior of the epithelial versus nonepithelial subtypes is quite different. Patients with mixed or sarcomatous tumors have a higher mitotic index, more aggressive disease and shorter survival. By contrast, patients with epithelial tumors tend to have a longer natural history and a better response to surgery followed by adjuvant treatments.
The development of a universal staging system is challenged by the diverse biological behavior of the histopathologic types of mesothelioma and the sheer number of adjuvant therapies currently being investigated to prevent local recurrence. Consequently, several staging systems have evolved. These staging systems were developed by applying various treatments in patients with different prognostic factors and then comparing survival. A certain amount of surgical resection is necessary to correlate prognostic factors with outcomes. Two pathologic staging systems (Butchart and Brigham) were created specifically to stratify prognosis for patients undergoing extrapleural pneumonectomy. A separate system established by the International Mesothelioma Interest Group (IMIG), endorsed by UICC/AJCC, is based on the tumor–node–metastasis descriptors used for lung cancer staging. The latter system is limited in that it fails to provide optimal survival stratification or stage distribution among patients treated surgically. Much of the difficulty in stratifying patient survival is that these staging systems were developed by combining patients with both epithelial and nonepithelial subtypes, which display a widely variant prognosis, as described above. Recently, our group proposed adjustments to the IMIG system applicable to patients with epithelial disease treated by extrapleural pneumonectomy. These adjustments improve stratification of survival by disease stage. We hope that others will support similar adjustments driven by the application of other adjuvant treatments. An effective staging system that accurately predicts response to specific therapeutic interventions would improve the clinician's ability to select patients who will benefit most from surgery or some other form of treatment.
Expert Rev Resp Med. 2010;4(3):363-372. © 2010 Expert Reviews Ltd.
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