E xtrapleural pneumonectomy has been used in the treatment

Extrapleural Pneumonectomy in the Setting of a Multimodality Approach to Malignant Mesothelioma* David I. Sugarbaker, M.D., F.C.C.P; StevenJ. Mentzei M.D., F.C.C.P; Malcolm DeCamp, M.D.; Thomas j Ljnch, Jr., M.D.; and Gary M. Strauss, M.D. The use ofextrapleural pneumonectomy in a multimodality treatment setting for malignant pleural mesothelioma is described, presenting first the right-sided approach and then the left-sided. This technique used in a multimodality approach with CAP chemotherapy (cyclophosphamide 600 mg/rn, doxorubicin 60 mg/rn2, cisplatin 75 mg/rn2) 5 cycles at 3-week intervals, and radiotherapy (55 Gy radiation to sites of previous bulky disease or residual disease) to treat 44 patients with malignant pleural mesothelioma resulted in improved operative mortality and decreased length of hospital stay. (Chest 1993; 103:3775-815) E xtrapleural pneumonectomy has been used in the treatment of tuberculous empyema 3 and other pleural diseases including malignant pleural mesothelioma (MPM).-b6 Its initial use in the treatment ofmpm reportedly resulted in relatively high operative mortality6 compared with standard ee 7 At our institution, we have gained significant experience over the past 8 years treating diffuse MPM with a protocol including pleuropneumonectomy, CAP (cyclophosphamide/ doxorubicin/cisplatin) chemotherapy, and radiotherapy. Treatment results from a series of 44 patients indicate an advantage to identifying patients preoperatively who may derive survival benefit from such aggressive procedures within a multimodality treatment protocol. Our surgical technique, which includes resecting the lung, parietal and visceral pleura, pericardium, and diaphragm, has evolved over the 8 years, and the associated operative mortality and length of hospital stay have continued to decrease. Our technique, which will be discussed, varies depending on whether it is performed on the right or the left side, and differs from extrapleural pneumonectomy techniques described elsewhere 918 Patient Selection PATIENTS AND METHODS We base selection of patients for our procedure on the traditional parameters for defining operability in pneumonectomy patients. It is helpful to use forced expiratory volume in 1 second (FEy,) as well as other dynamic spirometry testing and functional oximetry in patient selection. In the case ofborderline patient eligibility, the use of quantitative ventilation perfusion scanning may be of significant benefit for predicting postoperative pulmonary function. *Fmm the Harvard Medical School (Dr. Lynch) and the Division of Thoracic Surgery (Drs. Sugarbaker, Mentzer, and DeCamp), and Department of Medicine (Dr. Strauss), Brigham and Women s Hospital, Boston. Reprint requests: Dr. Sugarbaker, Brigham & Women Hospital, 75 Francis Street, Boston 02115 Because patients ultimately receive doxorubicin as adjuvant chemotherap); we use preoperative echocardiography to define ventricular function. We have found the echocardiogram to be helpful in identifying patients who ll be able to tolerate not only the pneumonectomy but also the postoperative adjuvant treatments. Midway through the postoperative chemotherapy course, the baseline echocardiogram is used again to detect possible cardiac toxicity Preoperative chest magnetic resonance imaging (MRI) scanning has been useful for determining the extent of disease and particularlv for visualization of the sagittal planes, demonstrating evidence ofdisease in the paravertebral sulcus or disease extending through the diaphragm. Sagittal cuts also are significantly helpful for predicting mediastinal involvement of the cava, esophagus, or trachea; operative resection is precluded by any one of these findings. In cases where transdiaphragmatic involvement is suspeeted but not proven, limited laparotomy is used to inspect the liver for determination of actual invasion. Routine preoperative echocardiography and M RI are extremely helpful in decreasing the number of patients for whom resection is precluded at the time of surgical exploration. Patients Between 1980 and 1991, 44 patients were selected and enrolled in a protocol involving extrapleural pneumonectomy used as a means of control of the primary tumor. Participants included 35 men and 9 women, with a median age of54 years (range, 46 to 62). We perform resection only on patients with Butchart clinical stages I and II disease, and all study subjects in this trial were judged bs clinical preoperative criteria to have Butchart s stage I pleural MPM6 (tumor confined within the capsule of the parietal pleiira, 1#{128}, involving only ipsilateral lung, pericardium, and diaphragm, and thout regional node involvement). The treatment protocol used at the Brigham and Women s Hospital consisted of extrapleural pneumonectomy, including resection of pericardium and diaphragm, followed by CAP chemotherapy employing cyclophosphamide 600 mg/m2, doxorubicin 60 mg/m2, and cisplatin 75 mg/m2. Five chemotherapy cycles were given at 3-week intervals, followed in turn by 55 Gy radiation to previous sites of bulky disease or to sites of residual disease in the ipsilateral chest. At present, other adjuvant chemotherapy protocols are being developed in the United States and Europe. 2 Every attempt was made for as complete a cytoreductive procedure as possible, although clean surgical margins have not been shown to be beneficial in predicting survivors of MPM. 6 SUR(;ICAL TEChNIQuE An extended right thoracotomv along the course of the 6th rib is the incision for right-sided pleuropneumonectomy (Fig 1)! The incision is extended from the posteru)r aspect of the thorax, beginning midway between the posterior scapular ridge and the spine. The cut is carried along the bed of the 6th rib to the costochondral junction. At this juncture, a subperiosteal resection of the 6th rib is performed to create wider exposure and facilitate entrance into the extrapleural plane. The periosteum is then CHEST / 103 / 4 I APRIL, 1993 / Supplement 377$

reflection FIGURE 3. Dissection of the pleural envelope off the diaphragm. FIGURE 1. The extended right thoracotomy incision. From Sugarbaker et al, with permission. opened, and a broad-based dissection is begun superiorly toward the apex, using blunt and sharp techniques. The dissection is completed along the anterior lateral aspect superiorly and then begun in a similar fashion inferiorly and laterally to the diaphragm. We avoid dissection posteriorly to the azygous vein until wider exposure has been gained. Following placement of 2 chest retractors anteriorly and posteriorly, we continue blunt and sharp dissection up to the cupola of the lung. Care is taken to palpate the course of the subclavian artery and maintain the plane between the parietal pleura and these vessels. It also is important to preserve the internal mammary artery and vein, which often pass through the extrapleural plane superomedially. If mistaken for adhesions, these vessels can be avulsed from either the superior vena cava or the subclavian artery. Small adhesions are divided, staying close to the pleural plane in the extrapleural fat. Next, the dissection is performed immediately from the apex of the lung to the azygous vein. Dissection is continued extrapleurally until the right upper lobe and main stem bronchus are clearly identified (Fig 2). With sharp as well as blunt dissection, the cava and azygous vein are then dissected from the parietal pleural structures, again taking care to prevent avulsing the veins. The dissection is continued anteriorly and inferiorly to the circumferential diaphragmatic margin. The next step is placement of a nasogastnc tube, which facilitates Azygos vein Subclavian vessels Superior cava. Ce cc Right main bronchus / Peritoneum FIGURE 2. The right main stem bronchus identified. From Sugarbaker et al, with permission. FIGURE 4. The pentoneum wiped off the diaphragm with a sponge. 378$ Extrapleural Pneumonectomy in Malignant Mesothelioma (Sugarbaker eta!)

Pulmonary artery Diaphragm Parietal pleura Visceral pleura FIGURE 5. Diaphragm and pleural envelope divided lateral to inferior cava and esophagus. pal pation of the esophagus to preserve it from damage. The diaphragm is then opened posterolaterally in a radial fashion to the anterior medial aspect of the pericardium. We are careful to keep the pleural envelope intact, which, in some cases requires dissection of the pleural envelope off the diaphragm prior to its division (Fig 3). When dividing the diaphragm, care must be taken to preserve the underlying peritoneum. We use blunt dissection to wipe the peritoneum off the diaphragm, using a sponge stick (Fig 4). After the diaphragm has been divided anterolaterally to the pericardium, it is divided along the caval and esophageal hiatuses. To facilitate this dissection, one may enter the pericardium to define the course of the inferior vena cava through the diaphragm. The diaphragm and pleural envelope are then dissected just lateral to the inferior cava and esophagus (Fig 5), thereby completing removal of the diaphragm. At the next stage of the procedure, the pericardium is formally opened anteromedially to the phrenic nerve and the hilar vessels (Fig 6). At this point, care is taken to keep the panetal pleural FIGURE 7. The intrapericardial right pulmonary artery divided by two staple lines. envelope intact. The main pulmonary artery is divided free from the cava and underlying superior pulmonary vein, using two staple lines to divide the intrapericardial right pulmonary artery (Fig 7).22 After the pulmonary artery has been divided, the superior pulmonary veins are divided in the same manner. Next, the pericardium is divided posterior to the hilum, thereby completing the pericardial resection. The specimen is then elevated, and dissection continues posterior to the pericardium and lateral to the esophagus. Subcarinal node dissection is performed, and the main bronchus is dissected to the carina. It is stapled with a heavy gauge bronchial stapler (Fig 8),u and the specimen is removed. A pericardial fat pad is then raised into place over the bronchial stump, and the pericardium is closed with a prosthetic patch using a monofilament suture (Fig 9). In the right-sided procedure, the pericardium is always reconstructed to prevent the potentially fatal complication of cardiac herniation. Fenestrations are made in the patch to prevent tamponade. The next stage of the procedure is reconstruction of the diaphragm. We have found that the use of impermeable membranes welope enic I vessels nerve Pericardial incision -..----- Trachea._I::.:::: Stapler Right main bronchus 1 h i.riil FIGURE 6. The pericardium opened anteriorly, medial to the phrenic nerve and hilar vessels. From Sugarbaker et al,u with permission. FIGURE 8. The main bronchus dissected to the carina and stapled. CHEST / 103 I 4 / APRIL 1993 1 Supplement 379$

Fat pad Fenestrated patch FIGURE 9. A pericardial fat pad sewn to cover the bronchial stump; pericardium closed with a patch, and fenestratiorts made in the patch. From Sugarhaker et al, with permission. prevents rapid filling of the chest cavity by peritoneal fluid. Such rapid filling can produce mediastinal shift or tamponade in the early postoperative period, before mediastinal stabilization. If peritoneal covering remains intact after the dissection, multiple sutures of 0 vicryl are used in a reefing fashion (Fig 10) to provide strength to the overlying peritonetim. The sutures are anchored in the chest wall (Fig 10), and flo further reconstruction is needed. If, however, the peritoneum was not spared in the procedure, we place a prosthetic impermeable patch and sew it into place with a running monofilament 0 suture (Fig 11). Surgical specimens are assessed in the pathology suite for resection margins in multiple areas. An remaining gross disease, FIGURE 1 1. A prosthetic impermeable patch sewn into place where the peritoneum has been removed. From Sugarhaker et al, with permission. even if limited, is outlined with clips before wound closure for subsequent radiotherap The chest is then closed in multiple layers to assure watertight closure. A red rubber catheter is left in the chest until the skin is closed, and air (750 InI in women, 1,000 ml in men) is removed from the chest before the patient leaves the operating room. In the recover room, a chest x-ray is obtained and, ifthe mediastinum is midline, the catheter is removed. If a mediastinal shift is seen, air can be either instilled or removed to balance the mediastinum before removing the catheter. Alternatively, ifoozing is present, the chest tube can remain in place to waterseal overnight. The Left-Sided Procedure The approach for left-sided lesions is similar to that performed on the right side. Technically we find the left-sided procedure easier, due to the absence of the caval and esophageal hiatus. There are, however, subtle differences. Care must be taken to enter the correct plane in the preaortic region when dissecting the medial aspect of the specimen in the Cut edge of pericardium Pulmonary artery / Anchoring in chest wall suture Left lung FIGURE 10. Reconstruction of the diaphragm using multiple sutures of 0 vicryl in reefing fashion; the sutures are anchored to the chest wall. FIGURE 12. The pulmonary artery extrapericardial and extrapleural, read to be dissected. 380$ Extrapleural Pneumonectomy in Malignant Mesothelioma (Sugarbaker et a!)

posterior region. If an incorrect retroaortic plane is entered, bleeding will result from avulsion of the intercostal vessels. In addition, it is important that tumor involvement of the aorta be assessed at this time. Once the specimen has been circumferentially dissected from the chest wall, the diaphragm is divided along the left side in a radial fashion. Care must be taken to spare the aorta at the hiatus. The pericardium is then entered inferiorly, and the vessels are identified. In the left-sided procedure, unlike that used on the right, we prefer to dissect the extrapleural left main pulmonary artery as it leaves the pericardium and enters the left chest. Using two vascular staple lines, we divide the pulmonary artery in its extrapericardial, extrapleural position (Fig 12). The veins are taken from within the pericardium, and the pericardial resection is completed posteriorly. On the left side, the left main bronchus must be dissected for a greater distance to ensure a short bronchial stump. Just as in the right-sided procedure, the bronchial stump is covered, the diaphragm reconstructed, and the chest closed. The pericardium is not routinely reconstructed on the left side because the risk of cardiac herniation is low. At the end of the left-sided procedure, less air needs to be removed (500 ml in women, 750 ml in men). Hemostasis We encourage aggressive use of electrocautery because hemostasis is vital to successful completion ofextrapleural pneumonectomy. Following completion of dissection, rapid packing of areas also is undertaken. Following removal of the specimen, hemostatic sheets (Surgicel, Johnson & Johnson, Arlington, Tex) are placed over the raw chest-wall surface. Packs are then placed on them, and several minutes of tamponade is allowed to ensure a dry closure. CLINICAL RESULTS AND DISCUSSION The potential prognostic significance of various factors affecting patients with MPM were evaluated in a series of 44 consecutive patients undergoing multimodality protocol therapy between 1980 and 1991. Perioperative mortality was 4.6%, and morbidity was 30%. Survival of different patient groups was evaluated with Cox proportional hazards models. The following potential prognostic factors were not found to be statistically significant for survival: presence of gross residual tumor, microscopic tumor at the resection margin, tumor involving pericardium, and tumor involving diaphragm. These findings suggest that an aggressive multimodality regimen that includes pleural pneumonectomy can be accomplished with acceptable morbidity and mortality. Alternative treatment strategies, possibly involving neoadjuvant chemotherapy and/or intracavitary chemotherapy, could be considered in selected patients. 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