Staging algorithm for diffuse malignant pleural mesothelioma

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1 doi: /icvts Interactive CardioVascular and Thoracic Surgery 10 (2010) report - Pulmonary Staging algorithm for diffuse malignant pleural mesothelioma a, a a b c Marcin Zieliński *, Jolanta Hauer, Lukasz Hauer, Juliusz Pankowski, Tomasz Nabialek, Artur Szlubowski d a Department of Thoracic Surgery, Pulmonary Hospital, Ul. Gladkie { 1, Zakopane, Poland b Department of Pathology, Pulmonary Hospital, Zakopane, Poland c Department of Anesthesiology and Intensive Care, Pulmonary Hospital, Zakopane, Poland d Bronchoscopy Unit, Pulmonary Hospital, Zakopane, Poland Progress Abstract Received 2 June 2009; received in revised form 13 September 2009; accepted 15 September 2009 An algorithm of preoperative mediastinal nodal staging with endobronchialyendoesophageal ultrasonography (EBUSyEUS) and transcervical extended mediastinal lymphadenectomy (TEMLA) combined with laparoscopyyperitoneal lavage and cytology was analyzed to establish the realistic criteria for radical multimodality treatment of malignant pleural mesothelioma (MPM). The algorithm included computed tomography (CT), thoracoscopy with multiple pleural biopsies and talc pleurodesis, EBUSyEUS and one-stage TEMLA and laparoscopyy peritoneal lavage and cytology of the fluid. Forty-two patients were diagnosed from 1 January 2004 to 31 December There were 16 women and 26 men in ages ranging from 43 to 77 years (mean 57.8); 31 epithelioid, 2 sarcomatoid and 9 biphasic type MPM. 21y42 patients were considered possible candidates for multimodality treatment. Three patients who received neoadjuvant chemotherapy were excluded from this study. EBUSyEUS was performed to stage the mediastinal nodes. In 3y18 patients metastatic nodes were discovered. In the rest of the 15 patients simultaneous TEMLA and laparoscopyyperitoneal lavage and cytology of the fluid were performed. In three patients TEMLA was positive, in six patients laparoscopy was positive and in two patients both TEMLA and laparoscopy were positive. Finally, 4y42 (9.5%) patients underwent thoracotomy with one exploration (chest wall infiltration) and three pleuropneumonectomies with the subsequent chemo- and radiotherapy. The proposed algorithm of preoperative staging spared the majority of MPM patients from futile surgery Published by European Association for Cardio-Thoracic Surgery. All rights reserved. Keywords: Malignant mesothelioma; Pleura; Staging 1. Introduction The prognosis of malignant pleural mesothelioma (MPM) is dismal with mean survival without treatment ranging from 4 to 12 months with no single treatment modality (surgery, radiotherapy, chemotherapy, immunotherapy and photodynamic therapy) proved to have any impact on the results of treatment w1, 2x. In the beginning of the 1990s Sugarbaker et al. reported the encouraging results of multimodality treatment including extrapleural pneumonectomy (EPP) with adjuvant chemotherapy and radiotherapy, with 45% five-year survival for a subgroup of patients with early stage disease and epithelioid histology w3x. In our institution, we started to treat patients with MPM with multimodality treatment from We performed 35 EPPs overall, with a postoperative mortality rate of 2.9% (1y35 patients). The patients were referred to adjuvant chemoradiotherapy afterwards. However, during follow-up it was found that all but one of these patients finally succumbed from the recurrence of the disease. In all patients who survived two years after EPP, the cause of death was the Presented at the 17th European Conference on General Thoracic Surgery, Krakow, Poland, May 31 June 3, *Corresponding author. Tel.: (q48) ; fax: (q48) address: marcinz@mp.pl (M. Zieliński) Published by European Association for Cardio-Thoracic Surgery recurrence localized intraabdominally, not intrathoracically. This experience stimulated us to develop the preoperative staging algorithm to offer such aggressive treatment as EPP combined with chemoradiotherapy more selectively. In this article, we analyze a value of the algorithm of preoperative mediastinal nodal staging with endobronchialy endoesophageal ultrasonography (EBUSyEUS) and transcervical extended mediastinal lymphadenectomy (TEMLA) combined with laparoscopyyperitoneal lavage and cytology. 2. Material and methods All patients with unequivocal diagnosis of MPM established with histopathological examination of the biopsies obtained during thoracoscopy were analyzed. Histological studies were performed with hematoxillin eosin (HE) staining and immunohistochemistry. The patients with pleural disease other than MPM or diagnosed without thoracoscopyypleural biopsy were excluded. Initial selection was made to choose patients who were possible candidates for multimodality treatment based on patient s general condition, co-morbidities and clinical stage of MPM, which was established on the results of chest computed tomography (CT), abdominal ultrasound and thoracoscopy findings. Patient s clinical stage was assessed with the use of international tumor Case

2 186 M. Zieliński et al. / Interactive CardioVascular and Thoracic Surgery 10 (2010) nodes metastasis (TNM) staging system w4x. Positron emission tomography (PET)yCT has not been used in any patient of the study group. In the patients who were not excluded at this point, the staging algorithm consisting of initial EBUS andyor EUS to discover metastatic mediastinal nodes was applied in all but four patients who underwent TEMLA without EBUSyEUS. If the results of these studies were negative, the next step was laparoscopy with peritoneal lavage and cytologic examination of the fluid and TEMLA. The EBUS was performed using the BF-UC160F-OL8 videobronchoscope (Olympus Medical Systems Corporation, Tokyo, Japan). The technique of EBUS was described in detail elsewhere w5x. In brief, the mediastinal nodal stations 2R, 4R, 2L, 4L, 7 and bilateral stations 10 and 11 were visualized and biosied in case of suspected pathology. The EUS was performed using the GF-UCT160-OL5 videogastroscope (Olympus Medical Systems Corporation, Tokyo, Japan). The technique of EUS was described in detail elsewhere w6x. In brief, the mediastinal nodal stations 2L, 4L, 7, 8, 9 and 5 could be visualized, as well as the heart, left lobe of the liver and the left adrenal gland. TEMLA and laparoscopy were performed under one general anesthesia with laparoscopy starting first to check if there were any macroscopic infiltrations intraabdominally. In such cases TEMLA was not performed. The laparoscopy was performed with the use of two 5 mm ports, with the first one used as camera port inserted above the umbilicus, and the second one inserted beneath the right costal arch. A thorough search was done to discover any signs of abdominal dissemination and to take biopsies of any suspicion areas. Abdominal lavage was performed in case of normal looking abdomen; 500 ml 0.9% NaCl was injected and sucked back and sent for cytological examination. TEMLA included bilateral dissection of all mediastinal nodes except from the station 9. The use of the Rochard frame (Aesculap AG) mounted on the operating table for retraction and elevation of the sternal manubrium, enabled good access to the mediastinal structures and safe dissection of lymph nodes. The technique of the TEMLA was described in detail elsewhere w7x. In brief, the operation is performed through the limited collar incision in the neck. The dissection is performed in the open fashion with removal of the whole nodal stations along with the surrounding fatty tissue. All patients who were not suitable for multimodality treatment due to co-morbidities or whose results of any staging steps were positive were referred to oncologicaly palliative treatment. The patients with negative results were offered multimodality treatment consisting of the initial EPP followed by adjuvant chemotherapy and radiotherapy. Adjuvant chemotherapy schedule was chosen individually by oncologists, generally cisplatin based chemotherapy was used before 2006, after cisplatin-pemetrexed chemotherapy afterwards, when in 2006 registration of pemetrexed in our country was completed. 3. Statistical analysis Statistical calculation was carried out using Statistics TM software (Statsoft Inc, USA). Table 1 Reasons for exclusion of the patients with MPM from the invasive staging Age )75 years 2 Respiratory insufficiency 7 Cardiovascular insufficiency 4 Stage IIIyIV disease 7 Other 1 MPM, malignant pleural mesothelioma. 4. Forty-two consecutive patients hospitalized in our institution, since 1 January 2004 to 31 December 2008, with diagnosis of MPM were analyzed. There were 16 women of mean age 62 (47 80) years and 26 men of mean age 57.8 (43 77) years. There were 12 left-sided lesions and 30 right-sided lesions. There was a significant difference between the incidence of the right-sided and left-sided lesions (Ps0.0002). All patients underwent thoracoscopy with pleural biopsy and talc pleurodesis. The histological type of MPM was as follows: 31 epithelioid, 2 sarcomatoid and 9 biphasic. There were 21y42 patients who were found unfit for EPP due to co-morbidities andyor advanced clinical stage IIIyIV (Table 1). There were three other patients who were referred to neoadjuvant chemotherapy after positive thoracoscopic pleural biopsy and restaged afterwards; these patients were excluded from the current study. The other 18 patients with stage ci and cii disease without contraindications to multimodality treatment who were regarded candidates for multimodality treatment starting from EPP underwent further staging studies. The first step of staging procedure was EBUS or EUS to assess the mediastinal lymph nodes. EBUS was performed in 14 patients and the metastatic nodes were found in two patients (station 4R in one patient and stations 4R and 7 in the other one). EUS was performed in three patients with metastatic nodes found in one patient (stations 7 and 8). After exclusion of three patients after positive EBUS and EUS the other 15 patients underwent laparoscopy with diagnostic peritoneal lavage and TEMLA at the same general anesthesia. 1y18 patients underwent TEMLA without previous EBUSyEUS. In one patient macroscopic neoplastic infiltration was found intraperitoneally and in this patient TEMLA was not performed. In the other 14 patients no abnormalities were found during laparoscopy and the diagnostic lavage with subsequent TEMLA was performed. In five patients the result of cytological examination of the peritoneal lavage fluid discovered malignant cells. On TEMLA, metastatic nodes were found in five patients (station 4R in three patients, station 2R in one patient and stations 5 and 7 in the other patient). In two patients, both TEMLA and cytology of the peritoneal fluid were positive. The results of staging studies are shown in Table 2. After exclusion of 14 patients with laparoscopy and TEMLA, the other four patients underwent thoracotomy in attempt to perform EPP. In three patients R0 radical EPP could be completed, in the other one patient only exploratory thoracotomy was possible because of the extensive chest wall infiltration, omitted on the preoperative CT. All patients who underwent EPP were subsequently referred to adjuvant chemoradiotherapy, the same as the patient after explor-

3 M. Zieliński et al. / Interactive CardioVascular and Thoracic Surgery 10 (2010) Table 2 of staging of 18 patients with MPM regarded potential candidates for multimodality treatment Type of the study Number of Number of patients with patients positive results studied EBUS 14 2 (stations 4R and 4Rq7) EUS 3 1 (stations 7 and 8) Laparoscopy with 15 1 macroscopically positive intraabdominal lavage 7 macroscopically negative and cytologically positive TEMLA 14 5 (station 4R in 3 patients, station 2R in 1 patient, and station 5 and 7 in 1 patient) Overall (in 2 patients both laparoscopy and TEMLA were positive) MPM, malignant pleural mesothelioma; EBUS, endobronchial ultrasonography; EUS, endoesophageal ultrasonography; TEMLA, transcervical extended mediastinal lymphadenectomy. atory thoracotomy. There was no mortality in the whole group of 42 patients. There was no morbidity in any patient who underwent EBUS and EUS and laparoscopy. In 2y3 patients who underwent EPP there was arterial hypotonia necessitating catecholamine infusion and atrial fibrillation (66.7% morbidity). After five years of follow-up, 1y3 patients who underwent multimodality treatment with EPP was alive and without recurrence. The other two patients died from the intraabdominal recurrence of MPM after 17 months and 24 months after EPP. All patients who were excluded from multimodality treatment or underwent neoadjuvant chemotherapy ultimately died during followup. Finally, 1y42 patients survived five years without recurrence of MPM. Our preoperative staging algorithm for MPM is shown in Fig Discussion Currently, it has been proven that even such an extensive operation like EPP can be performed safely with a mortality rate below 5% and acceptable morbidity rate w3, 8x. Late results of multimodality treatment and the number of patients surviving five years without recurrence has still been the open issue, however. The results of our institution with only 2.9% disease-free five-year survival rate are much worse than those reported by Sugarbaker et al. who had 18% five-year survival rate w3x. The question how to explain such a big difference cannot be answered easily. There were at least two peculiar features of our group of patients with MPM that have not Progress Fig. 1. Staging algorithm for MPM. Case

4 188 M. Zieliński et al. / Interactive CardioVascular and Thoracic Surgery 10 (2010) been reported by any other authors. This was a vast majority of right-sided lesions in comparison to the leftsided ones, with significant difference between these subgroups. The second interesting finding was that in all our patients who survived more than two years after EPP and finally developed a recurrence, the localization of this recurrence was the abdomen not the chest. Does it mean that the biology of MPM in our country is different than in the other countries is an open question. Nevertheless, such poor late results forced us to look for the better selection criteria, sparing unnecessary aggressive multimodality treatment to the patients with advanced disease. The first issue was to have proven pathological diagnosis of MPM. Our practice was to perform thoracoscopy with multiple biopsies and subsequent talc pleurodesis to achieve palliation of hydrothorax. The same as other authors, we regarded a needle biopsy to be a less reliable technique w1, 9x. The aim to our staging algorithm was to discover any metastatic mediastinal nodes and any signs of intraabdominal dissemination of MPM. Both these factors were found to indicate for very poor prognosis. The invasive staging protocol of mediastinal nodal staging was generally started with minimally invasive endoscopic ultrasound studies EBUS and EUS and followed by TEMLA in case EBUS and EUS were negative. Laparoscopy with intrabdominal lavage and TEMLA were performed with the use of one anesthesia with laparoscopy being performed first. In case of a macroscopically positive result of laparoscopy TEMLA was not performed. The combination of EBUS, EUS, laparoscopy with intraabdominal lavage and TEMLA enabled to discover metastases in 14y18 (77.7%) patients regarded potential candidates for multimodality treatment with the use of EPP. The rate of mediastinal metastases and intraabdominal dissemination was 44.4% (8y18 patients) and 44.4% (8y21 patients), respectively. The rate pn2 metastatic nodes found after EPP was 30.4% in the study of Rice et al., 38% in the study of Edwards et al., and 32% in the study of de Perrot et al. w10 12x. Sorensen et al. found metastatic N2 nodes in 20% of patients on mediastinoscopy and in an additional 17% after EPP, and Schouwink et al. found metastatic N2 nodes in 26% of patients on mediastinoscopy and in an additional 14% after EPP w13, 14x. The rate of intraabdominal dissemination (44.4%) discovered in our study is higher than in the study of Rice et al. who found gross evidence of transdiaphragmatic or peritoneal involvement in 9.2% and positive cytological lavage in the other 2.6% patients without obvious transdiaphragmatic invasion. Overall, we were able to avoid non-curative surgery in 14y 18 (77.7%) of the patients regarded potential candidates for multimodality treatment. We excluded three patients who underwent neoadjuvant chemotherapy. In 2y3 of these patients gross invasion of the chest wall was found despite negative results of chest CT precluding curative EPP. In our opinion, restaging of T factor after neoadjuvant chemotherapy is beyond the scope of this study. We have not used PETyCT in our patients because this study was hardly available until recent time, however, the other authors found PETyCT useful and recommend its use in MPM w15x. In conclusion, we strongly recommend the use of detailed staging algorithm including EBUS, EUS, laparoscopy with peritoneal lavage and TEMLA in all patients regarded potential candidates for multimodality treatment to avoid noncurative surgery. References w1x Paul S, Neragi-Miandoab S, Jaklitsch MT. Preoperative assessment and therapeutic options for patients with malignant pleural mesothelioma. Thorac Surg Clin 2004;14: w2x Metinas M, Ak G, Erginel S, Alatas F, Yildrim H, Kurt E, Metinas S. A retrospective analysis of malignant pleural mesothelioma patients treated either with chemotherapy or best supportive care between 1990 and A single institution experience. Lung Cancer 2007;55: w3x Sugarbaker DJ, Garcia JP, Richards WG, Harpole DH Jr, Baldini HE, DeCamp MM Jr, Mentzer SJ, Liptay MJ, Strauss GM, Swanson SJ. Extrapleural pneumonectomy in the multimodality therapy of malignant pleural mesothelioma. in 120 consecutive patients. Ann Surg 1996;224: w4x Rusch VW. A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group. Chest 1995;108: w5x Szlubowski A, Kuzdzal { J, Kolodziej { M, Soja J, Pankowski J, Obrochta A, Kopiński P, Zieliński M. Endobronchial ultrasound-guided needle aspiration in the non-small cell lung cancer staging. Eur J Cardiothorac Surg 2009;35: w6x Tournoy KG, Burgers SA, Annema JT, Vermassen F, Praet M, Smits M, Klomp HM, van Meerbeeck JP, Baas P. Transesophageal endoscopic ultrasound with fine needle aspiration in the preoperative staging of malignant pleural mesothelioma. Clin Cancer Res 2008;14: w7x Kuzdzal J, Zieliński M, Papla B, Szlubowski A, Hauer L, { Nabialek { T, Sośnicki W, Pankowski J. Transcervical extender mediastinal lymphadenectomy the new operative technique and early results in lung cancer staging. Eur J Cardiothorac Surg 2005;27: w8x Sagarbaker DJ, Flores RM, Jaklitsch M, Richards WG, Strauss GM, Corson JM, DeCamp MM, Swanson SJ, Bueno R, Lukanich JM, Baldini EH, Mentzer SJ. Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg 1999;117: w9x Bueno R, Reblando J, Glickman J, Jaklitsch MT, Lukanich J, Sugarbaker DJ. Pleural biopsy: a reliable method for determining the diagnosis but not subtype in mesothelioma. Ann Thorac Surg 2004;78: w10x Rice DC, Erasmus JJ, Stevens CW, Vaporciyan AA, Wu JS, Tsao AS, Walsh GL, Swisher SG, Hofstetter WL, Ordonez NG, Smythe WR. Extended surgical staging for potentially respectable malignant pleural mesothelioma. Ann Thorac Surg 2005;80: w11x Edwards J, Stewart DJ, Martin-Ucar A, Muller S, Richards C, Waller D. The pattern of lymph node involvement influences outcome after extrapleural pneumonectomy for malignant mesothelioma. J Thorac Cardiovasc Surg 2006;131: w12x de Perrot M, Uy K, Anraku M, Tsao MS, Darling G, Waddell TK, Pierre AF, Bezjak A, Keshavjee S, Johnston MR. Impact of lymph node metastasis on outcome after extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2007;133: w13x Sorensen JB, Ravn J, Loft A, Brenoe J, Berthelsen AK. Preoperative staging of mesothelioma by 18F-fluoro-2-deoxy-D-glucose positron emission tomographyyct fused imaging and mediastinoscopy compared to pathological findings after extrapleural pneumonectomy. Eur J Cardiothorac Surg 2008;34: w14x Schouwink JH, Kool LS, Rutgers EJ, Zoetmulder FA, Van Zandwijk N, Vijver MJ, Baas P. The value of chest computer tomography and cervical mediastinoscopy in the preoperative assessment of patients with malignant pleural mesothelioma. Ann Thorac Surg 2003;75: w15x Erasmus JJ, Truong MT, Smythe WR, Munden RF, Marom EM, Rice DC, Vaporciyan AA, Walsh GL, Sabloff, Broemeling LD, Stevens CW, Pisters KM, Podoloff DA, Macapinlac HA. Integrated computed tomographypositron emission tomography in patients with potentially respectable malignant pleural mesothelioma: staging implications. J Thorac Cardiovasc Surg 2005;129:

5 M. Zieliński et al. / Interactive CardioVascular and Thoracic Surgery 10 (2010) Conference discussion Dr. L. Lampl (Augsburg, Germany): Thank you very much for this very interesting presentation of a very restrictive policy in patient selection for any operative procedure in malignant pleural mesothelioma. According to my opinion, this is really a very good basis for discussion. My question is, you did not mention pleurectomyydecortication as an alternative for all these patients with lymph node involvement. Dr. Hauer: We did not perform pleurectomyydecortication. We have very good symptom control with thoracoscopy and talc pleurodesis, and all these patients were referred to oncologists and they have chemoradiotherapy. Dr. Lampl: And you do not believe or mention that so-called debulking or reduction of tumor mass would have a benefit for the patients prior to chemoradiotherapy? Dr. Hauer: Well, perhaps, but in our institution we do not perform this kind of operation. We rely on thoracoscopy and talc pleurodesis, and the only operation with curative intention we perform in the department is EPP. Dr. H. Eid (Dubai, UAE): In spite of your algorithm, you have two cases of thoracotomy without a found nodule in the chest. So your staging technique in these two cases was not desirable to reach your staging. This is one point. The second thing, what is the prognosis in the patients you did extrapleural pneumonectomy? Have you followed these patients? Have you any results, mortality? Can you give any clue what happened to these patients? Dr. Hauer: Indeed, we have a very hard time to stage the T stage of these patients, and the results at the end of our staging policy, we have seven patients. They were all each epithelioid type; they have a good performance status. What we know about these patients, we do not confirm N2 disease and we do not confirm intraabdominal disease, and we do not have strong evidence of chest wall infiltration. That is why we proceed to thoracotomy. And perhaps we need some more investigation, some more modalities to better stage the T stage of the patients. And maybe it would be helpful to use MRI, but I am not sure of the clinical data. Regarding the second question, one patient is still alive after five years from the procedure. The second patient died because of heart infarct. It was two years after the procedure. And two patients had recurrence: one was intrathoracic, and, as far as I remember, it was 17 months after the procedure, and the other one was 24 months after the procedure and it was intraabdominal recurrence. Dr. W. Weder (Zurich, Switzerland): I have a comment and a question. The role of N2 disease in malignant pleural mesothelioma is not yet solved. There are several studies showing that survival in patients with N2 disease who undergo induction therapy and EPP does not differ from those with N1. In the new staging system, and we had a preliminary meeting on this, N2 disease might be defined differently. I am surprised to see this high number of positive malignant cells in the abdominal fluid in your study. Could you tell us something about the tumor burden you had on the diaphragm? Did all these patients present with a lot of tumor on the diaphragm, or was this also observed in very early stages as well? Dr. Hauer: We were surprised by our results, too, so many cytologic positive intraperitoneal lavage, and it was eight such positive patients. One patient had only macroscopic evidence of the disease. So a biopsy from the suspicious areas was taken. And on the other side, the peritoneum looked absolutely normal. So we inserted 500 ml of saline, we performed lavage, then sent it to cytology, and in all these seven patients we do not see any disease in the peritoneal cavity. Dr. Weder: That was not exactly the answer to my question. Was the tumor load on the diaphragm as assessed in the CT-scan in all these cases very advanced? Did you observe that the tumor was infiltrating through the diaphragm or was a positive cytology also seen in cases with minimal disease in the chest? Dr. Hauer: All these patients who underwent an invasive staging procedure were in stage I or stage II, and not necessarily it was the involvement of the diaphragm. Dr. M.A. Paul (Amsterdam, Netherlands): I would like to ask one maybe last question. We tend to make the whole selection process bigger, longer and more sophisticated. You even talked about adding MRIs. So now we have CT-scan, PET scan, maybe ultrasonography, laparoscopy, MRI added. Now, having your results and looking back at the first chest X-ray, can you sometimes predict, looking back, by a simple way, say, by seeing the shrinking hemithorax, by asking about the amount of pain, we can more or less with simple methods predict which one will be operable and which one will not? Dr. Hauer: This is what we did in our study, and looking back at CTs, there was no strong evidence of chest wall infiltration in all seven patients who underwent thoracotomy, and that is why we go for it, I would say, because it was all seven patients in good performance status, epithelioid type, we do not confirm N2 disease, intraabdominal disease, and there was no strong evidence of chest wall infiltration. We in case of doubt perform chest wall sonography, and there was no evidence of chest wall infiltration. That is why we proceed to thoracotomy. Dr. Paul: So no simple shortcut, I am sorry. Progress Case