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Ann Thorac Surg 2005;80:1988-1993
© 2005 The Society of Thoracic Surgeons
Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Accepted for publication June 7, 2005.
* Address correspondence to Dr Rice, Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Box 445, 1515 Holcombe Blvd, Houston, TX77030 (Email: drice{at}mdanderson.org).
Presented at the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.
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Abstract |
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METHODS: One hundred eighteen patients with MPM, deemed clinically and radiologically resectable, underwent extended surgical staging. Mediastinoscopy was performed in 111 patients, laparoscopy in 109 patients, and peritoneal lavage in 78 patients.
RESULTS: Ten (9.2%) patients had gross evidence of transdiaphragmatic or peritoneal involvement. Peritoneal lavage was positive for metastatic MPM in 2 (2.6%) patients, neither of whom had obvious transdiaphragmatic invasion. Ipsilateral mediastinal nodes contained metastatic tumor in 10 of 62 (16.1%) patients. Contralateral nodes were positive in 4 of 111 (3.6%) patients. Of the patients who underwent biopsy of both ipsilateral and contralateral mediastinal nodes, and who had complete pathologic staging after extrapleural pneumonectomy (n = 46), 14 (30.4%) had N2-positive nodes. Only 5 of these patients were correctly identified by mediastinoscopy (sensitivity 36%, accuracy 80%). Extended surgical staging identified 16 (13.6%) patients who had contralateral nodal involvement, transdiaphragmatic invasion, or positive peritoneal cytology.
CONCLUSIONS: Extended surgical staging defines an important subset of patients with unresectable MPM not identified by imaging. Because of the potential morbidity associated with extrapleural pneumonectomy, we advocate that extended surgical staging be performed in all patients with MPM before resection.
Malignant pleural mesothelioma (MPM) is an uncommon neoplasm with an annual incidence of 2,000 to 3,000 cases in the United States [1]. Despite recent advances with chemotherapeutic regimens [2], the disease is usually fatal. Aggressive local treatment strategies using extrapleural pneumonectomy and postoperative hemithoracic radiation have demonstrated long-term survival benefits in select groups of patients [3]. Our institution has shown that the combination of extrapleural pneumonectomy with postoperative hemithoracic intensity-modulated radiation therapy can achieve greater than 90% local control of tumor [4, 5]. Such radical treatment strategies can be associated with significant morbidity and should be performed only in patients who are likely to benefit. Preoperative identification of patients who have advanced disease is, therefore, of great importance.
Currently, computed tomography (CT) scanning is the gold-standard staging modality for MPM but is frequently inaccurate at distinguishing between locally advanced primary tumors that are potentially resectable (T3) and those that are not (T4). In particular, the ability of CT to determine metastatic involvement of intrathoracic nodes or peritoneal metastases is poor [6]. Although magnetic resonance imaging has been advocated by some authors, Heelan and associates [7] demonstrated that magnetic resonance was superior to CT only in identifying single foci of chest wall invasion and invasion (but not penetration) of the diaphragm, neither of which precludes extrapleural pneumonectomy. The introduction of positron emission tomography has improved the ability to detect occult distant metastatic disease, but is inaccurate for tumor or nodal staging. A recent study by Flores and colleagues [8] showed that the sensitivity of positron emission tomography for determining T4 and nodal status was 19% and 11%, respectively. In an effort to improve staging accuracy we performed extended surgical staging (ESS) procedures on all patients considered candidates for extrapleural pneumonectomy. Extended surgical staging includes outpatient cervical mediastinoscopy, laparoscopy, and peritoneal lavage, all performed in a single outpatient setting. We present the results of this staging strategy on a group of 118 consecutive patients with MPM during a 5-year period.
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Patients and Methods |
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Extended surgical staging was performed as an outpatient procedure. In general, laparoscopy was performed first and followed by cervical mediastinoscopy (CM), provided that there was no evidence of transdiaphragmatic invasion or peritoneal metastases. At laparoscopy, the peritoneal cavity was entered under direct visualization through a supraumbilical incision, and a 10-mm camera port was placed. A pneumoperitoneum was established using warm carbon dioxide gas insufflation. Two additional 5-mm port sites were placed in the right and left subcostal regions. The entire abdominal cavity was inspected for evidence of peritoneal metastases, and special care was taken to meticulously examine the ipsilateral hemidiaphragm. To aid in inspection of the most posterior portions of the diaphragm, visualization was improved by placing the patient in Trendelenburg position, introducing saline into the subdiaphragmatic space, and then immersing the camera lens below the surface. Any abnormal appearing tissue was biopsied; however, if the peritoneal surfaces of the diaphragm were normal in appearance, blind biopsies were not performed. From 2001 onward we began performing routine peritoneal lavage at the outset of laparoscopy. Five hundred milliliters of normal saline solution was irrigated throughout the peritoneal cavity and approximately 100 mL was removed and examined for the presence of malignant cells. In select patients who had experienced significant weight loss, a jejunostomy feeding tube was placed at the time of laparoscopy to improve nutritional status before extrapleural pneumonectomy.
If laparoscopy was grossly negative, patients underwent CM, under the same anesthetic. This was performed in the standard fashion, as previously described [9]. Our institutional protocol involving extrapleural pneumonectomy followed by intensity-modulated radiation therapy did not exclude patients with positive ipsilateral (N2) mediastinal nodes, as these nodes resided within the target area for postoperative hemithoracic radiation. Therefore, although lymph nodes from the contralateral mediastinum (N3) were always examined and biopsied if present, ipsilateral and subcarinal lymph nodes (N2) were frequently, but not routinely, biopsied.
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Results |
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Cervical mediastinoscopy was performed in 111 patients, of which 62 (55.9%) patients had biopsies of both ipsilateral and contralateral nodes, and 49 (44.1%) patients had sampling of contralateral nodes only. Of 111 patients who had contralateral nodes examined, nodal metastases (N3) were identified in only 4 (3.6%) patients. In the patients who had biopsy of ipsilateral nodes (n = 62), 10 (16.1%) had nodal metastases (N2). Eighty-five (72%) patients underwent extrapleural pneumonectomy and had complete pathologic staging (Fig 1), of whom 46 (54.1%) had preoperative CM evaluation of both ipsilateral and contralateral nodes. Of these, 14 of 46 patients (30.4%) were found to have intrathoracic nodal metastases. However, only 5 of these patients had positive N2 nodes identified by CM. Of the remaining 9 patients with positive N2 nodes identified at extrapleural pneumonectomy, 5 had positive nodes at sites that were potentially accessible by CM (Naruke stations 2, 4, and 7), and 4 had positive nodes that were beyond the reach of the mediastinoscope (anterior mediastinal, prevascular, anterior diaphragmatic, and internal mammary nodes). In the group of patients who underwent CM biopsy of contralateral nodes only (n = 39), 20 (51.3%) patients had N2-positive nodes discovered at extrapleural pneumonectomy. Fourteen (70%) of these had positive N2 nodes in locations that potentially would have been accessible by CM (predominately the subcarinal station). The sensitivity, specificity, and accuracy of CM for detecting N2 disease were 36%, 100%, and 80%, respectively.
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Extended surgical staging was performed as an outpatient procedure in 98 (83%) patients. In 2 patients CM was performed at the time of extrapleural pneumonectomy. Eighteen patients were admitted to the hospital after ESS (median length of stay, 1.5 days; range, 1 to 16 days). Extended surgical staging–related morbidity occurred in 6 patients and included atelectasis (2 patients), splenic laceration (1 patient), urinary retention (1 patient), and ileus (1 patient). Eight patients who had significant preoperative weight loss underwent laparoscopic placement of a feeding jejunostomy tube at the time of ESS. The median interval between ESS and subsequent definitive surgery was 15 days.
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Comment |
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It has been suggested that CT may help determine which patients should undergo laparoscopic staging [13]. However, we found that 2 of 9 patients had low peridiaphragmatic disease burden on CT scan, and yet had transdiaphragmatic extension at laparoscopy. Therefore, we believe that CT scanning is not sensitive enough to stratify which patients should undergo laparoscopic staging.
Performing peritoneal lavage at the time of laparoscopy adds little to the surgical procedure in terms of time or cost and yielded positive results in 2 (2.6%) patients. The diagnosis of MPM from lavage specimens can be difficult, however, and relies on an expert cytologist. It should be noted that both patients who had positive lavage specimens succumbed relatively quickly to their disease and fortunately were identified and spared the morbidity of an extrapleural pneumonectomy. The significance of cellular atypia in lavage specimens is uncertain, but it is worrisome that it may be a harbinger of peritoneal metastases, as 2 of 6 patients with atypical cytology developed abdominal recurrences. Hopefully its true significance will be clarified when larger numbers of patients are available to analyze.
Large retrospective studies by Sugarbaker and colleagues [14] and Rusch and coworkers [15] have shown that up to 50% of patients who undergo extrapleural pneumonectomy for MPM present with intrathoracic nodal metastases, which confer a poor prognosis. These same studies also suggest that there are subgroups of patients who have a significant chance of 5-year survival, and in whom an aggressive multimodality approach is worthwhile. In our own experience, intrathoracic nodal metastases (N1 and N2) were present in 47% of patients undergoing extrapleural pneumonectomy. Unfortunately, we lack precise and accurate predictors of outcome that can be applied to individual patients. Although patients with N2-positive nodes as a group do poorly, there are occasional patients with N2 metastases who are cured with multimodality therapy [16]. Furthermore, newer, more-active preoperative chemotherapeutic regimens combined with improved postoperative radiation strategies, such as intensity-modulated radiation therapy, offer hope that survival of patients with nodal metastases can be improved. We currently treat patients with positive N2 nodes on a clinical protocol incorporating induction chemotherapy, extrapleural pneumonectomy, and intensity-modulated radiation therapy.
The efficacy of surgical staging of the mediastinum with CM is well established for non–small-cell lung cancer; however, only one study has evaluated staging of MPM with CM. Schouwink and associates [17] performed CM in 43 patients with MPM and compared the staging accuracy of CM with that of CT scanning. Sensitivity, specificity, and accuracy were 80%, 100%, and 93%, respectively, for CM compared with 60%, 71%, and 67% for CT. Mediastinoscopy failed to identify 9 (21%) patients who were found to have positive intrathoracic nodes at thoracotomy, despite the fact that 3 of these patients had positive nodes in sites that were potentially accessible by CM. No patients were identified with positive contralateral (N3) nodes. In contrast, we identified 4 (3%) patients with contralateral mediastinal nodes, which disqualified them for extrapleural pneumonectomy. We also found a significant proportion of patients with intrathoracic (N2) nodal metastases that were not identified by CM, which had a sensitivity of only 36% in our hands. Reasons for this low sensitivity may include incomplete sampling of all mediastinal nodal stations, heterogeneity of nodal involvement leading to sampling error, and the frequent presence of positive nodes in regions that are inaccessible to CM, including the prevascular, aortopulmonary, paracaval, paraesophageal, internal mammary, and anterior diaphragmatic regions. Despite these shortcomings, CM is a relatively safe procedure that can be performed on an outpatient basis and leads to improved staging accuracy compared with radiologic imaging alone. Initially we were concerned about the theoretical potential of ipsilateral CM to disrupt the mediastinal extrapleural plane, therefore complicating subsequent extrapleural dissection; however, we have not found this to be problematic. It is therefore appropriate that assessment of mediastinal nodal involvement be made, both to offer prognostic information to patients and to guide therapy and enrollment in clinical protocols.
In conclusion, the performance of ESS before extrapleural pneumonectomy identifies a significant number of patients (13.6%) with advanced MPM who are not accurately diagnosed by imaging alone. These patients can therefore be spared aggressive treatment regimens that they would not benefit from.
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Discussion |
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I would like you to answer a couple of questions. For the patients who had extensive laparoscopic staging, how many of those patients would have been excluded by the mediastinoscopy portion only?
Number two, although it is your protocol to operate on N2-positive patients, the results with N2-positive patients are equally dismal with N3 positivity, so why do you pursue operating on those patients if you know up front that N2 is positive?
Number three, all of the factors you identified show poor prognosis, but not significantly different than the surgically treated group as a whole. Identifying 75% of patients who had disease and then succumbed to it even though they had surgery: that's the average survival. So is there anything better, perhaps biologic, that would allow us to choose the subset of patients with epithelial malignant mesothelioma that should actually undergo surgery?
I admire your work and congratulate you.
DR RICE: To answer your first question, as it was our policy with respect to our institutional protocol of extrapleural pneumonectomy followed by hemithoracic intensity-modulated radiation therapy (IMRT), we did not exclude patients who had N2 disease. Patients with contralateral nodes were excluded, however. Therefore, only 4 patients who we did the mediastinoscopy on were actually excluded from surgery. Whether or not one should perform extrapleural pneumonectomy on patients with N2 disease is debatable. Certainly our results mirrored those of other major institutions, such as the Brigham group and the Sloan-Kettering group. However, it should be noted that we lack accurate predictive factors that be can be applied to the individual patient. There are patients who do have N2 disease in our series who are long-term survivors.
Secondly, our protocol involved a novel form of hemithoracic radiation, which was believed to be potentially more accurate than the standard three-dimensional conformal radiation techniques, and we did not know whether or not the addition of hemithoracic intensity-modulated radiation therapy would have a beneficial effect on N2 disease. Having performed extrapleural pneumonectomy and IMRT on over 50 patients with malignant pleural mesothelioma, I think our results show that N2 positivity is still a bad prognostic sign. There is a newer multiinstitutional protocol currently underway involving neoadjuvant treatment with cisplatin and pemetrexed (Alimta), and it is hoped that this will have some benefit on patients with N2 disease.
To answer your third question, regarding the refinement of predicting outcome, Dr Pass and Dr Bueno have both recently shown promising results using gene expression profiles. Using DNA microarray analysis, patterns of gene expression were observed that were predictive of survival, independent of nodal status or tumor histology. Further characterization of these genes and their putative roles in tumor progression is underway.
DR MARK J. KRASNA (Baltimore, MD): I enjoyed your paper. I want to applaud you for trying to get the best possible preoperative staging. I think that's a very laudable goal.
Just to follow Dr D'Amico's comments and take it a step further: question number one, I think you're doing your whole approach a disservice by only telling us that you have a 36% sensitivity when in fact that's because you only sampled half the patients with N2 disease. Obviously, had you sampled everyone, I bet that you would have a much higher sensitivity. But, of course, that begs Tommy's question, which is, if you know up front that the patient is N2 positive, either don't go ahead and do surgery, as it has been shown that that's the worst prognostic group, or, alternatively, as we are doing in Maryland with our esophageal cancer patients, use that information to direct your IMRT or other external therapy, and actually knowing the node status up front, then targeting those areas. So rather than not doing it and just treating anyone anyway, it's better to identify exactly where the lymph nodes that are involved are, and then you can even better construct your three-dimensional radiation fields.
My second question, again is about the biological factors; have you at the time when you're doing the peritoneal lavage looked at simple things, such as immunohistochemical markers, to see if there were those patients who were, although macroscopically negative, perhaps by not only cytology but by IHC were actually positive?
I enjoyed your paper.
DR RICE: To answer your latter question, we performed immunohistochemical (IHC) analysis on patients who had abnormal-looking cells, ie, atypical cells or cells that we thought had a potential to be mesothelioma cells. We did not do it routinely since typically the IHC markers present on mesothelioma cells are also present on normal mesothelial cells.
With respect to the planning of intensity-modulated radiation therapy, unfortunately a high percentage of the nodes that one finds to be N2 nodes are actually nodes in the paraesophageal region, the aorticopulmonary window, the prevascular space, intercostal nodes, or internal mammary nodes. These are not accessible by mediastinoscopy. Therefore, knowing this information up front I don't think would influence our intensity-modulated radiation target areas. What we do do is a very careful treatment planning after we have the complete pathologic staging back. Therefore, we know whether or not the tumor invaded the mediastinum; we know the interspaces that it may have invaded; we know where the positive nodes were. Since IMRT can be given only after extrapleural pneumonectomy anyway, preoperative knowledge of N2 nodal status will not influence radiation treatment planning. I believe that N2 positivity is probably not a marker of local recurrence but rather a marker of distant disease, and therefore probably indicates that systemic treatment is required Therefore, I'm hopeful that our current protocol involving neoadjuvant trimetrexate and cisplatin, followed by extrapleural pneumonectomy and IMRT, may have benefit for N2-positive patients, much the same way as preoperative chemotherapy has shown improved survival in some studies of patients with stage IIIA lung cancer.
Regarding the issue of sensitivity of mediastinoscopy, we looked at this only in the group of patients in whom bilateral mediastinal nodal stations were examined and in whom complete pathologic staging was known (ie, those who also underwent extrapleural pneumonectomy). In this group of patients the sensitivity was as described, 36%. It is possible, but unlikely, that by increasing the sample size that the sensitivity would have been improved.
DR FRANCIS C. NICHOLS (Rochester, MN): David, congratulations on an excellent presentation.
I just want to back up one second. You started with 300 patients and you eventually got down to 180. What are your criteria for accepting people for possible surgical resection? How did you arrive at that final 118 patients?
DR RICE: In general, patients have to be of reasonable performance status. Obviously, that's somewhat subjective. We do intensive physiologic screening on these patients. Patients have to have a postoperative predictive FEV1 (forced expiratory volume in 1 second) of greater than 0.8 L/min. They undergo extensive cardiac screening. Many patients are found in the interim to have metastatic disease. So all of these things are factored in. In addition, the fact that overall the results of local therapy for this disease are not great, and that there is significant morbidity associated with surgery, leads many patients to choose not to undergo aggressive therapy. It should be noted that we were fairly unselective with respect to tumor stage and that the majority of patients (66%) were AJCC stage III. Therefore we are not just choosing to operate on early-stage patients.
DR DAVID H. HARPOLE, JR (Durham, NC): I think this is a very nice study with your patients and I applaud you for doing this.
I have two points. First of all, it's not surprising that mediastinoscopies aren't necessarily positive because these patients are either recumbent or they're upright, and if you look at the disease burden of mesothelioma, it's usually on the diaphragm and posterior in the mediastinum. My point is that probably this is an ideal case for using endoscopic ultrasound (EUS)-directed biopsy because then you can get those nodes that are more likely going to be involved in the mediastinum, and it certainly may help your N2 studies if you're talking about looking specifically with that, with your extrapleural pneumonectomies and IMRT, that you would diagnose those patients ahead of time.
Secondly, I have not been doing the lavage but actually do the mediastinoscopy and then use the mediastinoscope in the abdomen because I don't have to insufflate. You just do a little 1.5-cm subcostal incision on the right or left side where you're going to do this. The mediastinoscope gives you a beautiful view of the whole hemidiaphragm from underneath, so you can see the whole dome and then you can biopsy any abnormalities, and, again, if you're doing it at one setting, you don't have the problem of a pneumonectomy patient who has a bellyful of CO2 afterwards. That's just a comment on a possibly helpful way of doing this.
Thanks.
DR RICE: That's an interesting technique. I'll have to try that. The addition of EUS biopsy of mediastinal nodes is also probably a very reasonable thing to do and would likely improve detection of nodal metastases.
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