Safety and Utility of Mediastinoscopy in Non-Small Cell Lung Cancer in a Complex Mediastinum

Transcription

1 Safety and Utility of Mediastinoscopy in Non-Small Cell Lung Cancer in a Complex Mediastinum Brian E. Louie, MD, Seema Kapur, MD, Alexander S. Farivar, MD, Samuel J. Youssef, MD, Jed Gorden, MD, Ralph W. Aye, MD, and Eric Vallières, MD Division of Thoracic Surgery and Department of Interventional Pulmonology, Swedish Cancer Institute and Medical Center, Seattle, Washington Background. Adequate mediastinal staging is crucial in patients with locally advanced non-small cell lung cancer. Mediastinoscopy is often omitted after induction therapy or prior mediastinoscopy because of concerns for potential morbidity, safety and unknown utility. We sought to determine the safety and utility of restaging mediastinoscopy before surgical resection. Methods. A retrospective review was made of nonsmall cell lung cancer patients who underwent mediastinoscopy with a complex mediastinum, defined as any or all of the following: previous mediastinoscopy or induction chemotherapy or mediastinal radiation. Results. Seventy-five patients underwent mediastinoscopy including 15 redo mediastinoscopies. In the non-redo group, 9 patients received induction chemotherapy, 16 received induction chemoradiotherapy (<46 Gy), 29 received definitive chemoradiotherapy (>50 Gy), and 6 received radiation alone. Two were aborted owing to fibrosis. Stations 4L, 4R, and 7 were accessed in 84% of patients, with confirmed nodal tissue in 88%. There was 1 azygos vein injury that required urgent thoracotomy and 2 recurrent nerve injuries. Resection ensued in 63 patients: 53 with negative mediastinoscopy, 8 with microscopic nodal metastases, and the 2 aborted cases. In patients with negative mediastinoscopy, 5 had N2 disease at thoracotomy: 3 in stations 4 and 7 and 2 in nodal stations inaccessible by mediastinoscopy. The sensitivity was 71%, specificity was 100%, and negative predictive value was 91%. Conclusions. In experienced hands, mediastinoscopy in a complex mediastinum is safe. Preclusive mediastinal fibrosis is rare. Expected lymph node stations can be accessed, and the results strongly correlate with postresection pathology. Mediastinoscopy is valuable to evaluate the nodal response to therapy in the setting of combined modality therapy. (Ann Thorac Surg 2011;92:278 83) 2011 by The Society of Thoracic Surgeons Treatment options for nonmetastatic non-small cell lung cancer (NSCLC) are largely based on the status of the mediastinal lymph nodes. Patients who do not have involvement of these lymph nodes may be considered for primary surgical resection. However, patients with mediastinal nodal involvement are often faced with a variety of management options including surgery, chemotherapy, radiation therapy, or some combination of these three modalities [1 3]. For limited volume mediastinal nodal involvement, our preferred approach remains induction chemotherapy with or without radiation therapy followed by surgical resection. In this strategy of induction therapy followed by resection, pathology confirmation of the mediastinal nodal involvement before therapy is strongly encouraged. Similarly, Accepted for publication Feb 4, Presented at the Fifty-seventh Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 3 6, Address correspondence to Dr Louie, Division of Thoracic Surgery, Swedish Cancer Institute and Medical Center, Ste 850, 1101 Madison St, Seattle, WA 98104; brian.louie@swedish.org. this nodal status after induction therapy is crucial to implement an appropriate treatment algorithm and avoid offering potentially morbid resections in patients who are unlikely to benefit and who could potentially be given additional radiation therapy to more definitive doses. Although computed tomography (CT) and positron emission tomography (PET) scanning are used to clinically assess the mediastinal nodes, patients who may otherwise be candidates for resection should have pathologic confirmation of their nodal status before treatment through either mediastinoscopy or endobronchial ultrasonography (EBUS) as the false positive rate of mediastinal imaging is not insignificant, particularly in the postinduction therapy setting [4]. The status of the mediastinal nodes after induction treatment is equally as important in determining whether to proceed with surgical resection because survival in patients with persistent nodal disease ranges from 10% to 20% [5-7]. However, mediastinoscopy is often omitted after induction therapy, and particularly after previous mediastinoscopy, because of potential morbidity, concerns for safety, and unknown utility [8]. We sought to determine the safety, 2011 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg LOUIE ET AL 2011;92: MEDIASTINOSCOPY IN A COMPLEX MEDIASTINUM 279 utility, and role of restaging mediastinoscopy before surgical resection. Patients and Methods A retrospective analysis was performed on consecutive patients with NSCLC who underwent mediastinoscopy from 1999 to 2009 by a single surgical group and who had a complex mediastinum. Data were obtained from patient charts, prospectively collected databases, operative reports, and the issued final pathology reports. Patients were assigned clinical or pathology stages based on the American Joint Committee on Cancer, 6th edition, staging system reflecting the time period of the study and the collected raw data. Clinical stages were determined using available radiologic investigations including CT, PET, CT/PET, and magnetic resonance imaging. Pathologic stages were only determined in patients undergoing resection. The Institutional Review Board of Swedish Cancer Institute and Medical Center approved this study. Complex Mediastinum All patients included in this study were deemed to have a complex mediastinum. We defined this as a patient who had undergone a previous mediastinoscopy, or had undergone induction chemotherapy with or without mediastinal radiation therapy. Patients in the latter two groups may not have undergone a prior mediastinoscopy. A mediastinoscopy was considered successful if all appropriate stations were reached and biopsies taken. This outcome was defined as feasible. A second factor defining success was if the pathologist determined on final histology evaluation that nodal tissue or cancer was identified. Surgical Procedure Mediastinoscopy was performed by standard technique using two different mediastinoscopes. In the earlier part of the study, a 17-cm Carlens direct viewing mediastinoscope (Richard Wolf, Freiburg, Germany) was used. Over time, a video-mediastinoscope ( Lerut Karl Storz, El Segundo, CA) was used primarily. For each mediastinoscopy, the superficial to deep layers were divided sharply with electrocautery or scissors. Once the trachea was identified, sharp dissection with the Metzenbaum scissors was used to divide the pretracheal fascia and establish a space in the correct plane. This sharp dissection was taken as low as possible under direct vision, well beyond the innominate artery. Once the scope was placed, a combination of blunt, sharp, and electrocautery dissection was used to advance the scope until the carina was identified. Care was then taken to identify the azygos vein and the space lateral to the left main stem bronchus and aortic arch and the right main stem. Systematic sampling of stations 4R, 4L, and 7 were carried out using standard mediastinoscopy biopsy forceps. Station 2 was left to the discretion of the surgeon but generally accessed when station 4 was positive before treatment. Simple bleeding was controlled with cauterization on the right side or in the subcarinal space, but never on the left, or gentle but firm sponge gauze packing was placed under direct vision of the mediastinoscope. Small sheets of polyanhydroglucuronic acid (Surgicel; Ethicon/ Johnson and Johnson, San Angelo, TX) were often applied to aid in hemostasis. Presumed vascular injuries were controlled by packing the mediastinum with two or more unrolled 4 8 sponge gauzes for 10 minutes. The sponges were then gently removed, and if further bleeding was noted, the area was repacked. If hemostasis was not achieved after several attempts or the patient became unstable, the mediastinoscopy was aborted and definitive control was established by open surgery. Surgical Resection Patients were offered surgical resection if the mediastinoscopy was negative or if the mediastinoscopy only revealed residual single station, micrometastatic disease, defined as disease confined within a lymph node but not extracapsular. Patients with persistent multiple N2 station or N3 positive nodes were not offered surgical resection. At the time of thoracotomy, a systematic lymphadenectomy was performed. On the right side, this included stations 2, 4, 7, 8, and 9. On the left, stations 4, 7, 8, and 9 were assessed with the addition of stations 5 and 6. Results A total of 774 mediastinoscopies for NSCLC were performed during the study period, of which 75 were on a complex mediastinum (Fig 1). There were 15 redo mediastinoscopies. When a primary mediastinoscopy was performed, 60% had received a combination of chemotherapy and radiotherapy before the mediastinoscopy. The median age of the patients was 62 years, and there were 39 (52%) men. There were no in-hospital or 30-day deaths from mediastinoscopy performed on a complex mediastinum. Ten patients (13%) experienced a single morbidity. Three were classified as major adverse events, and all three occurred in primary mediastinoscopies that had received induction chemoradiotherapy (1, less than 46 Gy; 2 more than 50 Gy). There was one vascular injury to the azygos Fig 1. Breakdown of mediastinoscopies (MEDS) in a complex mediastinum. (Chemo chemotherapy; CRT chemoradiation therapy; RT radiation therapy.)

3 280 LOUIE ET AL Ann Thorac Surg MEDIASTINOSCOPY IN A COMPLEX MEDIASTINUM 2011;92: vein that failed initial control by mediastinal packing and necessitated immediate and successful right thoracotomy and resection of the cancer without blood transfusion. Two permanent recurrent laryngeal nerve injuries were identified. Both patients underwent thyroplasty to restore voice and respiratory function. There were seven minor adverse events: temporary hoarseness (3 patients), atrial fibrillation, chyle leak, pneumonia, and skin bleed, all of which occurred in patients receiving radiation therapy. Overall, mediastinoscopy was feasible in accessing nodal stations 4R, 4L, and 7 in 84% of patients. Two mediastinoscopies (2.7%) were aborted owing to preclusive fibrosis related to prior definitive radiotherapy to a dose greater than 60 Gy. The feasibility was similar for redo mediastinoscopy (87%), redo mediastinoscopy after induction therapy (89%), prior induction therapy alone (83%), and after induction chemotherapy alone (81%). Of the biopsies taken, 88% contained either nodal tissue or cancer on final pathology. The median interval between completing radiation to mediastinoscopy was 4 months, with a range of 1 week to 33 months. This interval was significantly shorter for patients undergoing radiation doses less than 46 Gy (2.5 months) compared with patients undergoing radiation at doses greater than 50 Gy (5.3 months, p 0.038). Twentyone patients underwent radiation doses greater than 59 Gy, with mediastinoscopy being completed a median of 4 months after cessation of radiation. Two of the major adverse events (azygos injury and recurrent nerve) and both aborted mediastinoscopies occurred in this latter group (19%; Table 1). Sixty-three patients underwent surgical resection: 53 with a negative mediastinoscopy, 8 with limited microscopic nodal involvement in a single nodal zone at complex mediastinoscopy, and the 2 unsuccessful mediastinoscopies (Fig 2). In the final resection specimen, mediastinal (N2) lymph node metastases were found in 5 patients who had had negative mediastinoscopies. Three of these were found in nodal stations 4 and 7 accessible by the mediastinoscopy, whereas 2 were found in a nodal stations inaccessible by mediastinoscopy, namely, 5 and 9. This results in a sensitivity of 71%, specificity of 100%, and negative predictive value of 91% (Table 2), but when the stations inaccessible by mediastinoscopy are excluded, then the negative predictive value rises to 94%. Table 1. Complications in Patients Undergoing Mediastinoscopy After Radiation Subject Radiation (Gy) Interval Between Radiation and Mediastinoscopy (Months) Complication Aborted Recurrent nerve Azygos injury Recurrent nerve Aborted Fig 2. Distribution of mediastinoscopies (MED) in patients undergoing resection. (Stn station.) Comment The status of the mediastinal lymph nodes is pivotal to creating an appropriate treatment plan for patients with NSCLC. When the mediastinum is virgin untouched by surgery or unaltered by treatment the safety and utility of mediastinoscopy has been proven in numerous surgical series dating back to the late 1970s [9-13]. However, the mediastinum is increasingly being treated or accessed, and thus altered and rendered complex, in these patients by primary mediastinoscopy or the administration of chemotherapy or radiotherapy, or both. That occurs when presumed early stage lung cancers are found on primary mediastinoscopy to have N2 disease or when managing patients with NSCLC presenting with locally advanced disease (N2 or N3 positive). The mediastinum may also be altered in patients with lung cancer if they have previously been treated for an unrelated head-and-neck cancer or mediastinal lymphoma. This prior treatment or surgical incursion creates a complex mediastinum with potential fibrosis and treatment effect, and has proven to be a potential barrier for many physicians who treat these patients, ultimately resulting in patients not being offered a mediastinoscopy and appropriate restaging before surgical resection. Our study and those of others [14-19] have shown that concerns about safety and morbidity secondary to mediastinal fibrosis are not preclusive to a safe and successful mediastinoscopy, and that meticulous surgical technique does allow access to all three major mediastinal nodal stations: 4R, 4L, and 7. We believe, however, that complex Table 2. Lymph Nodes With or Without Metastases Found at Mediastinoscopy in Patients Undergoing Resection Positive Resection Negative Mediastinoscopy Positive 8 0 Negative 5 48 Sensitivity 8 of 13 73%; specificity 48 of %; negative predictive value 48 of 53 91%; false negative rate 5of53 9.4%.

4 Ann Thorac Surg LOUIE ET AL 2011;92: MEDIASTINOSCOPY IN A COMPLEX MEDIASTINUM 281 mediastinoscopy is a procedure that should be performed by persons who are very familiar and comfortable with simple mediastinoscopy and handling its potential complications. When compared with simple or first-time mediastinoscopy, the complex mediastinum does increase the risk of death and morbidity. For example, in two recent large series of first-time mediastinoscopy, the chance of mortality was 0.05% [9, 20], whereas the 1 death directly attributed to mediastinoscopy in the complex setting led to a mortality rate of 1% [21]. Although the chance of death remains similar, the rates of serious adverse events range from 3% to 8% [15, 22] in the complex setting versus 1% or less in the virgin mediastinum. The two most common adverse events cited are major venous injury and recurrent nerve injury, particularly on the left. Both of these injuries have been reported to occur in primary, noncomplex mediastinoscopy as well. However, it would appear that the likelihood of these injuries may be higher in the complex mediastinum. Moreover, most vascular injuries can be managed with packing the mediastinum, and when necessary, controlled at the time of definitive operation. The recurrent nerves, on the left side in particular because of its long intrathoracic course, may be damaged from minimal trauma. Although paresis is more common and usually recovers in 3 months, the paralyzed vocal cord can be temporarily or permanently medialized to avoid concomitant morbidities such as aspiration pneumonia. That is particularly important in patients who may be offered major pulmonary surgery soon after the injury. Even though most mediastinoscopies in a complex mediastinum will be completed, there are several studies that have shown that as many as 40% of attempted mediastinoscopies will be aborted because of preclusive fibrosis [23, 24]. These aborted mediastinoscopies have occurred when both prior mediastinoscopy and induction chemotherapy have been employed in N2 or N3 disease. It could be argued that the fibrosis in these cases is primarily due to the first mediastinoscopy, but other series of redo mediastinoscopy after induction chemotherapy show much higher rates of success [16, 21], suggesting that induction chemotherapy may play a role in creating a complex mediastinum. Because there has been no formal analysis to determine what additional risk factors (eg, lymph node status bulky, replaced, fixed, or micrometastatic type of chemotherapy, amount of radiation, or timing of mediastinoscopy after induction therapy) may play a role in the degree of fibrosis, we continue to believe any treatment can create a complex mediastinum. In this series, preclusive fibrosis leading to an aborted procedure or to an adverse outcome such as vascular injury seems to predominantly occur in the mediastinum that has received 60 Gy of irradiation and when the interval between the induction therapy and the mediastinoscopy is longer than 2 months. However, in our series and that of Lardinois and associates [15], there were aborted mediastinoscopies also occurring in patients undergoing primary mediastinoscopy after chemoradiotherapy with radiation doses at 45 Gy. That further suggests that treatment effect and other factors also likely play a role in creating fibrosis, and thus a complex mediastinum. Once access to stations 4R, 4L, and 7 has been established, nodal tissue or cancer can be confirmed with a high degree of certainty, Additionally, we found that our pathology findings on mediastinoscopy are largely indicative of the final pathology at thoracotomy. The false negative rate of 9% (5 of 53) in our series is among the lowest reported in the literature. Therefore, mediastinoscopy allows surgeons to accurately select which patients may benefit from thoracotomy after induction therapy while avoiding futile thoracotomy to inappropriate patients. Confirmation of persistent N3 or multiple station N2 disease at mediastinoscopy after induction therapy is not considered appropriate for resection. However, the absence of N2 disease or for highly selected patients with persistent, single station, intracapsular N2 disease, we have proceeded with resection. The decision to operate on persistent N2 disease remains controversial. In one series, patients with unsuspected N2 disease undergoing resection without induction therapy were shown to have more favorable survival if the N2 disease was confined to a single nodal station [25]. The improved survival of single station N2 disease has also been reported after induction chemotherapy as long as the station 7 nodes are not involved [18]. This observation is in contrast to that of Port and colleagues [5], who found that survival was surprisingly not influenced by multiple station N2 or extracapsular disease, although the small sample size likely prevented a definitive conclusion. One of the limitations of this paper is that it covers a 10-year period during which significant changes have occurred in mediastinal staging. During this period, CT-PET has become almost routine in lung cancer staging, and EBUS with fine-needle aspiration (EBUS-FNA) biopsy has been introduced and increasingly utilized. Even though these diagnostic tests have become more common, mediastinoscopy remains our procedure of choice, especially in the evaluation of a complex mediastinum. Moreover, CT- PET has had varied success in reassessing the mediastinum after induction therapy [4, 23, 26]. Similarly, in such a setting, the accuracy of EBUS-FNA is not as predictable, with reported false negative rates of 80%: negative EBUS-FNA after induction therapy still mandates mediastinoscopy [27]. With increasing experience in both EBUS-FNA and mediastinoscopy in a complex mediastinum, our strategy for suspected N2 disease is to proceed with EBUS to document nodal involvement at diagnosis. When these patients return after induction therapy (which has increasingly been with 60 Gy of radiation), for now, we prefer to go straight to mediastinoscopy for reevaluation [28]. We also try to keep the interval on this mediastinoscopy close to the completion of radiation in hopes of accessing the mediastinum before fibrosis becomes established. In patients who had presumed early stage NSCLC by imaging and in whom we identify positive N2 nodes at mediastinoscopy up front, similarly, after induction, we prefer to take them to redo mediastinoscopy.

5 282 LOUIE ET AL Ann Thorac Surg MEDIASTINOSCOPY IN A COMPLEX MEDIASTINUM 2011;92: In conclusion, in experienced hands, mediastinoscopy in the face of a complex mediastinum can be accomplished with acceptable morbidity. Preclusive mediastinal fibrosis is rare. All expected lymph node stations can be accessed, and the nodal information obtained strongly correlates with final postresection pathology results. Mediastinoscopy is an essential procedure for evaluating the nodal response to therapy when considering patients for resection in the setting of combined modality therapy. References 1. National Comprehensive Cancer Network. NCCN Guidelines Version , non-small cell lung cancer, Available at f_guidelines.asp. Accessed January 29, Albain KS. Induction chemotherapy with/without radiation followed by surgery in stage III non-small-cell lung cancer. Oncology 1997;11(Suppl 9): Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374: de Cabanyes Candela S, Detterbeck FC. A systematic review of restaging after induction therapy for stage IIIa lung cancer: prediction of pathologic stage. J Thorac Oncol 2010; 5: Port JL, Korst RJ, Lee PC, et al. Surgical resection for residual N2 disease after induction chemotherapy. Ann Thorac Surg 2005;79: Voltolini L, Luzzi L, Ghiribelli C, et al. Results of induction chemotherapy followed by surgical resection in patients with stage IIIA (N2) non-small cell lung cancer: the importance of the nodal down-staging after chemotherapy. Eur J Cardiothorac Surg 2001;20: Bueno R, Richards WG, Swanson SJ, et al. Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival. Ann Thorac Surg 2000;70: Palva T. Mediastinoscopy. Basal: Kargger, 1964: Lemaire A, Nikolic I, Petersen T, et al. 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Postinduction video-mediastinoscopy is as accurate and safe as videomediastinoscopy in patients without pretreatment for potentially operable nonsmall-cell lung cancer. Ann Thorac Surg 2003;75: Mateu-Navarro M, Rami-Porta R, Bastus-Piulats R, Cirera- Nogueras L, Gonzalez-Pont G. Remediastinoscopy after induction chemotherapy in nonsmall-cell lung cancer. Ann Thorac Surg 2000;70: Van Schil P, van der Schoot J, Poniewierski J, et al. Remediastinoscopy after neoadjuvant therapy for non-small cell lung cancer. Lung Cancer 2002;37: De Leyn P, Vansteenkiste J, Deneffe G, et al. Result of induction chemotherapy followed by surgery in patients with stage IIIA N2 NSCLC: importance of pre-treatment mediastinoscopy. Eur J Cardiothorac Surg 1999;15: Marra A, Hillejan L, Fechner S, Stamatis G. Remediastinoscopy in restaging of lung cancer after induction therapy. J Thorac Cardiovasc Surg 2008;135: Hammoud ZT, Anderson RC, Meyers BF, et al. 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Ann Thorac Surg 2002;74: Misthos P, Sepsas E, Kokotsakis J, Skottis I, Lioulias A. The significance of one-station N2 disease in the prognosis of patients with nonsmall-cell lung cancer. Ann Thorac Surg 2008;86: Hoekstra CJ, Stroobants SG, Smit EF, et al. Prognostic relevance of response evaluation using [18F]-2-fluoro-2- deoxy-d-glucose positron emission tomography in patients with locally advanced non-small-cell lung cancer. J Clin Oncol 2005;23: Herth FJ, Annema JT, Eberhardt R, et al. Endobronchial ultrasound with transbronchial needle aspiration for restaging the mediastinum in lung cancer. J Clin Oncol 2008;26: Page B, Blitz M, Louie BE, Aye RW, Vallieres E. Pulmonary resection of nonsmall cell lung cancer (NSCLC) can be performed safely following definitive chemoradiotherapy. J Thorac Oncol 2009;4(Suppl):301. DISCUSSION DR MARK J. KRASNA (Towson, MD): I enjoyed the presentation. I was a little bit confused about the definitions, but at the end I think you clarified it. In your group then, of those 65 patients, the 5 who were redos were included, but the other ones had no prior mediastinoscopy but had their mediastinoscopy after the chemoradiation, is that correct? DR LOUIE: Okay. DR KRASNA: So basically other than the redos, all your other patients had previous chemoradiation but did not have previous surgical staging. DR LOUIE: Correct.

6 Ann Thorac Surg LOUIE ET AL 2011;92: MEDIASTINOSCOPY IN A COMPLEX MEDIASTINUM 283 DR KRASNA: That is your definition? DR LOUIE: That is our definition of complex mediastinum. DR KRASNA: So I would just propose then, that anybody after high-dose chemoradiation who did not have a prior mediastinoscopy, should in fact get a mediastinoscopy, and I do think that it can be done safely, as you have shown. I would like to recommend, though, that for your small subgroup of the redos, the 6 and the 9 patients, one of the things and I think the publication came out this year by Mike Jaklitsch is to consider doing a video-assisted thoracoscopy (VATS) restaging in someone who has had a mediastinoscopy, followed by high-dose chemotherapy and radiation. I wonder if you or your colleagues have tried using that? So a patient who had a mediastinoscopy and then has a mediastinoscopy-positive treatment with highdose chemoradiation, to then go back and try to restage the mediastinum with VATS. DR LOUIE: As a group, we have not tackled the VATS nodal staging after a previous med and induction chemoradiotherapy. We have a fairly large VATS lobectomy program, we have done probably 450 as a group, but we have not tackled that nodal question in that fashion. We have seen the paper by Dr Jaklitsch and I think it is an intriguing one, but because we have had reasonable success with our data in this fashion, we have not gone down that pathway. DR KAMAL A. MANSOUR (Atlanta, GA): In the 2 patients you aborted, you did not do, what did do with them? Would you have considered, say, a positron emission tomography (PET) scan, would a PET scan be helpful, or VATS, as mentioned? DR LOUIE: When those 2 patients occurred, both had PET scans, but at that time the decision was made to go straight from there, the PET scan was negative at that time, so we made the decision to go straight to thoracotomy when we could not get in. DR MANSOUR: So what is the use of doing mediastinoscopy then? DR LOUIE: I think the utility of mediastinoscopy is to look for persistent N2 or N3 disease. DR SETH D. FORCE (Atlanta, GA): I have two questions. The first question, did all of these patients have a PET scan as restaging and have positive lymph nodes that you were targeting for on your mediastinoscopies? DR LOUIE: As you have seen, it is a long time frame, it is a decade-long series, so early on in the series not everybody got a PET scan at that time. In the latter half when PET scan became more useful, everybody has gotten a PET scan there. In general, we would target certain PET scan findings for a redo mediastinoscopy, for sure. DR FORCE: For this restaging after neoadjuvant therapy in patients who are PET negative, are you still doing mediastinoscopies on those patients? DR LOUIE: We are. DR FORCE: My second question kind of goes back to what Dr Krasna was saying with your definition of a complex mediastinum. So with regard to your patients, I will give you that the redo mediastinoscopies are certainly a complex mediastinum. I won t give you the neoadjuvant chemotherapy alone. So what I want to focus on is the neoadjuvant chemoradiation patients. As you pointed out, some are hard, some are not. My question is, how difficult were these? Are they really a complex mediastinum and they are difficult but can be done or are most of these not really that difficult after chemoradiation therapy? DR LOUIE: I think the vast majority of these were challenging, particularly the group that got more than 50 cgy. I will give you that the 12% that had induction chemotherapy probably is not the same as people who got 60 cgy of irradiation. In that 39% group, one of the things that we have been doing more recently is endobronchial ultrasonography staging up front, and then we give them full course definitive chemoradiation therapy, and then we take them for mediastinoscopy after that. Those are challenging. The fibrosis is reasonable. One of the things in the paper that will be written about is there has been no analysis in the redo mediastinoscopy papers about whether you have bulky N2 disease, did you have microscopic? The N2 envelope is a big group of people. Probably one of the things we need to do as we collect more data is figure out what is going to drive the fibrosis rate, which is the difficulty getting in. DR JOHN A. HOWINGTON (Evanston, IL): What is your timing for doing the mediastinoscopy after induction therapy? Are you waiting 4 to 6 weeks, or are you doing it immediately after radiation so the fibrosis hasn t set in and you can test the mediastinum? DR LOUIE: There probably are two time frames in this series. The first one, if we are worried and we are thinking we are going to go from 45 on to 60, we do the mediastinoscopy at the time. But, there are also half the patients in here who have been 3 or 4 weeks after the radiation is finished when they have had definitive radiotherapy, and we have waited until then or they were referred at that time.