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Ann Thorac Surg 2005;80:268-275
© 2005 The Society of Thoracic Surgeons
a Division of Thoracic Surgery, University Hospital, Zurich
b Division of Thoracic Surgery, University Hospital, Bern
c Department of Oncology, University Hospital, Bern
d Department of Biostatistics, University of Zurich, Zurich
e Department of Thoracic and Vascular Surgery, CHUV, University Hospital, Lausanne, Switzerland
Accepted for publication February 1, 2005.
* Address reprint requests to Dr Lardinois, Division of Thoracic Surgery, University Hospital Zurich, Raemistrasse. 100 8091 Zurich, Switzerland (Email: didier.lardinois{at}usz.ch).
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: A consecutive series of one hundred patients with non-small-cell lung cancer, clinical stage T1-3 N0-1 after standardized staging, was divided into two groups of 50 patients each, according to the technique of intraoperative mediastinal lymph-node assessment (dissection versus sampling). Mediastinal lymph-node dissection consisted of removal of all lymphatic tissues within defined anatomic landmarks of stations 2–4 and 7–9 on the right side, and stations 4–9 on the left side according to the classification of the American Thoracic Society. Systematic mediastinal lymph-node sampling consisted of harvesting of one or more representative lymph nodes from stations 2–4 and 7–9 on the right side, and stations 4–9 on the left side.
RESULTS: All patients had complete resection. A mean follow-up time of 89 months was achieved in 92 patients. The two groups of patients were comparable with respect to age, gender, performance status, tumor stage, histology, extent of lung resection, and follow-up time. No significant difference was found between both groups regarding the duration of chest tube drainage, hospitalization, and morbidity. However, dissection required a longer operation time than sampling (179 ± 38 min versus 149 ± 37 min, p < 0.001). There was no significant difference in overall survival between the two groups; however, patients with stage I disease had a significantly longer disease-free survival after dissection than after sampling (60.2 ± 7 versus 44.8 ± 8 months, p < 0.03). Local recurrence was significantly higher after sampling than after dissection in patients with stage I tumor (12.5% versus 45%, p = 0.02) and in patients with nodal tumor negative mediastinum (N0/N1 disease) (46% versus 13%, p = 0.004).
CONCLUSION: Our results suggest that mediastinal lymph-node dissection may provide a longer disease-free survival in stage I non-small cell lung cancer and, most importantly, a better local tumor control than mediastinal lymph-node sampling after complete resection for N0/N1 disease without leading to increased morbidity.
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Introduction |
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The arguments in favor of MLND are improved intraoperative staging and better locoregional control due to resection of otherwise undetected micrometastases and skip lesions. Arguments against routine MLND are increased morbidity compared to sampling and the lack of evidence of improved staging or survival. The MLND requires a more extensive mediastinal dissection than MLNS and may be associated with longer hospitalization time and potential damage to mediastinal structures. In this study we compared MLND versus MLNS with respect to morbidity, duration of chest tube drainage and hospitalization, overall and disease-free survival, and local recurrence in a consecutive series of patients undergoing complete resection for stage T1-3 N0-1 NSCLC without mediastinal lymph-node involvement as assessed by mediastinoscopy.
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Material and Methods |
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Technique of MLNS and MLND
Lymph-node stations were defined according to the American Thoracic Society (ATS) [10, 11]. Lymph nodes of station 10 were considered as N1 lymph nodes according to the 1997 classification of Mountain (11).
The MLND was performed in a standardized manner as described by Martini (10) and was not dependent on the lobar location of the primary tumor. All the mediastinal fatty tissue containing the lymphatics was dissected and removed systematically and en bloc within anatomical landmarks. After removal, the different nodal stations were put in different vials with separate labeling. On the right side, the dissection systematically included the upper mediastinal nodes (ATS 2, 3, 4), the subcarinal nodes (ATS 7), and lower mediastinal nodes (ATS 8, 9). The highest mediastinal node was identified and separately labeled. The subcarinal nodes (ATS 7) were dissected along the posterior aspect of the carina and both main stem bronchi. The posterior aspect of the carina was freed and the contralateral main stem bronchus was dissected on a length of about 3 to 4 cm. The mediastinal tissue between the inferior pulmonary vein, the two main stem bronchi and the carina, the pericardium, and the esophagus was dissected en bloc. The inferior pulmonary ligament nodes (ATS 9) were dissected while the inferior pulmonary ligament was divided. The paraesophageal nodes (ATS 8) were removed between the esophagus and the pericardium from the diaphragm to the inferior pulmonary vein. The right paratracheal, pretracheal, and tracheobronchial nodes (ATS 2, 3, 4) were removed en bloc between the lateral and anterior border of the trachea, the ascending aorta, and the posterior aspect of the superior vena cava, and from the brachiocephalic artery to the right pulmonary artery after mobilization of the azygos vein. On the left side, MLND included the resection of the paraaortic nodes (ATS 6), the subaortic nodes (ATS 5), the caudal paratracheal lymph nodes (ATS 4), as well as the nodes ATS 7, 8, 9. Division of the ductus botalli allowing mobilization of the aortic arch and access to the high paratracheal nodes was not performed. The subaortic nodes (ATS 5) were removed en bloc between the aortic arch, the pulmonary artery, and the left main stem bronchus up to the tracheobronchial angle, while preserving the recurrent laryngeal nerve. The paraaortic nodes (ATS 6) were removed after dividing the mediastinal pleura between the vagus and phrenic nerve. The mediastinal fat containing the nodes was dissected from the innominate vein to the pulmonary artery. The highest mediastinal node was labeled individually.
The MLNS consisted of the removal of one or more lymph nodes guided by preoperative or intraoperative findings, which were thought to be representative of the different predetermined lymph-node stations. All the mediastinal fatty tissue containing the nodes of these nodal stations was not removed en bloc. In our study, the surgeon performed systematically a sampling of the lymph-node stations ATS 2, 3, 4, 7, 8, 9 on the right side and ATS 4, 5, 6, 7, 8, 9 on the left side. The number of the nodes removed was determined by the pathologist for both techniques.
Data Collection
The data of all patients were collected from the patient’s data files. The primary end point was disease-free survival, which was defined as time from surgery to first recurrence, either local or distant or both. The overall survival was calculated from the date of surgery.
Statistical Analysis
The Student’s t test for unpaired observation (bidirectional hypothesis) was used where appropriate. Overall and disease-free survival were estimated by use of the Kaplan-Meier life table analysis and compared with the log-rank test. Statistical significance was accepted at p less than 0.05.
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Results |
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Eight patients were lost to follow-up immediately after leaving the hospital. A mean follow-up time of 88.9 ± 6.6 months was achieved in 92 patients, including 24 patients with stage I, 12 patients with stage II, 13 patients with stage IIIA disease after MLND and 22, 11, and 10 patients with stage I, II, and III disease after MLNS, respectively. The pathological lymph-node status of these 92 patients was 26 N0, 12 N1, and 11 N2 after MLND versus 24 N0, 11 N1, and 8 N2 after MLNS.
Overall Survival
The median overall survival time was 51.7 ± 5.7 months after MLND and 50.9 ± 4.9 months after MLNS (p = 0.4). Overall survival, compared between different tumor stages and nodal involvement, was not significantly different between the groups (Fig 1).
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Comment |
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The argument against formal mediastinal lymph-node dissection is that MLND might be associated with a higher morbidity than less invasive mediastinal exploration such as MLNS. Potential complications, which have been attributed to MLND, are a higher risk of bronchopleural fistula due to interruption of the blood supply to the bronchial stump, phrenic and recurrent laryngeal nerve injury, and an increased risk of postoperative chylothorax and hemothorax [15]. However, our results did not reveal an increased morbidity after MLND compared to MLNS and endorse the findings of other reports in this respect [1, 16, 17]. However, MLND required a longer operating time than MLNS, which is in accordance with other results [2, 4]. The postoperative course was not different after the two techniques in terms of duration of chest tube drainage and hospitalization, which is in accordance with other authors [2, 4, 16, 17]. No bronchopleural fistula was observed in our patients. The argument in favor of MLND is that the clearance of all mediastinal lymphatics may lead to a more thorough intraoperative staging and eventually to a better local tumor control than a less extensive procedure such as MLNS, which might translate to a better long-term outcome of the patients.
The need for accurate intraoperative mediastinal lymph-node staging during resection in patients with NSCLC cannot be overemphasized. Despite improvements of preoperative mediastinal staging by positron emission tomography (PET) imaging, the nodal status frequently remains clinically understaged [7, 18, 19]. It has been shown that after negative PET and mediastinoscopy, about 10% to 20% of the patients will reveal pathological mediastinal lymph-node involvement depicted by MLND, even in patients with T1 tumors [7, 19–22]. Systematic MLNS and MLND both improve intraoperative mediastinal nodal staging as compared to less thorough mediastinal exploration. In a retrospective study, Bollen and colleagues [16] found a significantly higher rate of N2 disease after MLNS and MLND as compared to a less systematic exploration of the mediastinum. Although several studies have not shown a difference between MLNS and MLND [1, 4, 9], Keller and colleagues [1] and Izbicki and colleagues [4] both demonstrated a higher rate of N2 disease identified by MLND than by MLNS in patients with resectable NSCLC. Our results revealed a substantially higher number of mediastinal lymph nodes harvested by MLND as compared with MLNS (17.3 ± 5.3 vs 7.2 ± 2.5) indicating a more thorough mediastinal lymph-node assessment by use of MLND.
Whether or not a more extensive mediastinal exploration during resection for NSCLC will translate into better local tumor control and improved survival remains controversial at present [6]. Theoretically, a more extensive mediastinal dissection may allow for a more accurate staging of the disease. This highly accurate surgical staging obtained after MLND might allow a more precise selection of the patients in adjuvant therapy protocols with possible benefit in overall survival, since recent prospective randomized trials evaluating the role of cisplatin-based adjuvant chemotherapy in early stage NSCLC showed not only a significant better recurrence-free survival but also a significant better overall survival in the treated patients [23, 24].
Furthermore it may allow to eradicate otherwise undetected micrometastases which might result in better local tumor control and improved overall outcome of the patients [25]. On the other hand, it has been argued that extensive mediastinal dissection may release an increased amount of cytokines and growth factors, which are believed to stimulate tumor regrowth [26].
It has been shown that an increased number of resected lymph nodes correlates with improved survival in patients with early stage colorectal, breast, and bladder cancer [7, 27] but this might be explained by a stage migration phenomenon, which is related to the accuracy of intraoperative staging. Likewise, a more extensive mediastinal lymph-node dissection will detect more occult N2 disease in patients with resectable NSCLC and more patients will be assigned to stage IIIA disease after the operation. Several retrospective studies [28–30] reported no difference in long-term survival after MLND and MLNS. These authors considered a more extensive lymph-node dissection beneficial only for staging purposes but not for survival [19]. However, one study demonstrated a significantly lower 5-year and 10-year survival after MLNS than after MLND for stage I NSCLC [31], and a recent study [8], also focusing on patients with stage I NSCLC, found a correlation between the number of resected lymph nodes and the risk for recurrence and survival. However, two prospective randomized studies [4, 9] did not show improved overall and disease-free survival after MLND as compared to MLNS in patients undergoing resection for NSCLC.
Our results revealed no significant difference in overall survival between patients undergoing MLND or MLNS after complete resection for NSCLC after a mean follow-up time of 89 months. However, a significant better disease-free survival was observed in patients with pathological stage I disease after MLND compared to MLNS. However, caution in the interpretation of our data is indicated due to the nonrandomized design of our study and the relatively small sample size. Nevertheless, all patients were accurately staged by use of CT scan of the chest, abdomen, and brain, bone scintigraphy and mediastinoscopy, and the patients of both groups were comparable from the functional and oncological point of view.
Whether a more extensive mediastinal dissection might decrease the incidence of local recurrence after complete resection for NSCLC is a question that remains unanswered. Local recurrence after resection of NSCLC often leads to vexing clinical problems which are difficult to control and which are often independent of survival considerations. Despite its clinical impact, local recurrence and potential therapeutic maneuvers designed for its prevention are often not sufficiently considered in the management of patients with resectable NSCLC.
Our results indicate that the incidence of local recurrence was lower after MLND compared with MLNS after complete resection for NSCLC and after a mean follow-up time of 89 months. This holds especially true for N0/N1 disease without pathological mediastinal lymph node involvement after resection (13% for MLND and 46% after MLNS). The lower incidence of local recurrence after MLND compared with MLNS in patients without pathological mediastinal lymph-node involvement seems to be related to a better mediastinal clearance by MLND and a decreased risk of leaving residual microscopic disease behind. Noteworthy, only patients without mediastinal tumor involvement were enrolled in the study, as assessed by mediastinoscopy.
In conclusion, our results endorse the findings from previous reports that MLND does not lead to improved survival compared to MLNS in patients undergoing complete resection of NSCLC. However, local tumor control may be enhanced by MLND in patients with nodal negative mediastinum without conferring additional morbidity, but caution in the interpretation of the data is indicated due to the nonrandomized design of our study.
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Discussion |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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DR LARDINOIS: The follow-up of our patients after operation consisted of a chest x-ray and laboratory findings every 3 months during the first 3 years, every 6 months from the third to the fifth year, and then yearly. If local recurrence of the disease was suspected, a chest CT scan was performed. Local recurrence was defined by cytologically or histologically proven recurrence in the lymph nodes or in the lung parenchyma (same histological type than the primary). Most of the patients with local recurrence had nodal recurrence, and diagnosis was made by use of transbronchial biopsy. In some patients, recurrence of the disease was confirmed at autopsy.
DR ROBERT J. CERFOLIO (Birmingham, AL): Dr Lardinois, I would like to congratulate you on an extremely important study. I believe it was the best studies on the program until I heard you say that it wasn’t randomized. So my question to you would be—why didn’t you randomize these patients? Why didn’t you just put that in? Were there surgeons resistant to randomizing it? You could have had the best study on the whole program had you randomized it.
My second question would be, in the stage II, although you didn’t show a statistically significant difference, you only had 2 recurrences in one group and 6 in the other. Would you project for us what you think is possible with larger numbers. Of course, we’re all waiting for the ACOSOG Z30, which apparently is a few years away, but are you continuing to do this and following these patients so maybe you can present to us later that there is a statistically significant difference in stage II?
Thank you and congratulations on a critically important topic.
DR LARDINOIS: Thank you very much for your nice comments. Regarding your first question, the patients included in this series were operated from 1995 to 1996. Initially, we just wanted to compare the morbidity according to the technique of mediastinal lymphadenectomy. When we decided to analyze the outcome, a part of the patients of the series had already been operated on. We decided then to include 50 patients in each group according to the technique of lymph-node assessment. We showed that the patients of each group were comparable, and as I already said, the technique of lymphadenectomy was depending on the surgeon. Each surgeon always performed the same technique of lymphadenectomy, independently of the patients and of the clinical stage of the disease. In this respect and although the study was not randomized, we think that our results are reliable.
Regarding your second question, I totally agree with you. The number of patients with stage II disease was small, including 12 MLND patients and 11 MLNS patients. As we found a significant improvement of the outcome in patients with nodal negative mediastinum (N0, but also N1), MLND might significantly reduce the incidence of local recurrence in stage II disease in a larger series of patients. This study was a single center study and the inclusion of patients was discontinued, since MLND became the routine procedure of mediastinal lymphadenectomy.
DR GAIL E. DARLING (Toronto, Ontario, Canada): I enjoyed your paper very much. Thank you.
I have two questions. Yesterday we heard that in patterns of care in the United States, only 50% of patients having mediastinoscopy actually had any lymph nodes biopsied. Could you comment on which lymph node stations were biopsied at the time of mediastinoscopy?
The second question is, in the patients who had mediastinal lymph node dissection, how many of those patients had positive nodes in the dissected specimen? In other words, in the dissection group, what was the percentage of patients who had positive N2 nodes?
Thank you.
DR LARDINOIS: According to your first question, the stations which were systematically biopsied during mediastinoscopy were the stations 2, 4 on the right side, the station 4 on the left side, and the station 7. All the patients of this series underwent mediastinoscopy.
We observed 25 patients with pathological stage IIIA. From these 25 patients, 4 had a T3N1 disease. The 21 patients with stage IIIA N2 included 11/50 patients after MLND (22%) and 10/50 patients after MLNS (20%). In these patients, the tumor positive lymph nodes were localized in a single nodal station, which was not reachable by mediastinoscopy in about half of the cases (station 8, 9, 6).
DR JOHN A. HOWINGTON (Cincinnati, OH): In your stage I patients, under the sampling you had a 45% rate of local recurrence, which would be higher than most series with stage I cancers, so if you could address that. And then a follow-up on your last comment, what percentage of mediastinoscopy-negative/N2-positive were outside stations 2, 4, and 7? How many of those were level 8, level 9, or 5, 6?
Thank you.
DR LARDINOIS: In stage I disease, we observed 13% of local recurrence after MLND and 45% after MLNS. The high rate of 45% in patients who underwent MLNS might be due to a better mediastinal clearance and a decreased risk of leaving residual microscopic disease behind after MLND. Again, the rate of 45% has to be interpreted with caution to the relatively small sample size.
Regarding your second question, about half of the patients with negative mediastinoscopy and definitive pathological N2 disease had a nodal metastasis in level 5, 6, 8, or 9.
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Acknowledgments |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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