Ann Thorac Surg 2009;87:893-899. doi:10.1016/j.athoracsur.2008.11.073
© 2009 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Surgical Resection Is Justified in Non-Small Cell Lung Cancer Patients with Node Negative T4 Satellite Lesions
Arjun Pennathur, MDa,
Brenessa Lindeman, BSa,
Peter Ferson, MDa,
Mathew Ninan, MDc,
Irfan Quershi, MDa,
William E. Gooding, MSb,
Matthew Schuchert, MDa,
Neil A. Christie, MDa,
Rodney J. Landreneau, MDa,
James D. Luketich, MDa,*
a Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
b The University of Pittsburgh Cancer Institute Biostatistics Facility, Pittsburgh, Pennsylvania
c University of Tennessee Health Science Center, Knoxville, Tennessee
Accepted for publication November 24, 2008.
* Address correspondence to Dr Luketich, Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh, Pittsburgh, PA 15213 (Email: luketichjd{at}upmc.edu).
Presented at the Fifty-fourth Annual Meeting of the Southern Thoracic Surgical Association, Bonita Springs, FL, Nov 7–10, 2007.
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Abstract
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Background: The management of non-small cell lung cancer (NSCLC) depends on the stage, with a satellite nodule in the same lobe being classified as T4 stage IIIB even in node negative patients. Controversy exists as to the optimal management of these patients. Our objectives were to evaluate the outcomes in surgically resected patients with a T4 satellite lesion and to analyze the prognostic factors associated with outcome.
Methods: Patients who underwent resection for T4 (satellite nodule) N0-2M0 were identified. Patients with pure bronchoalveolar carcinoma were excluded. The primary endpoint studied was overall survival. Multiple covariates were analyzed for association with survival and recurrence.
Results: A total of 51 T4 N0-2 patients (men 22, women 29; median age 71 years [48 to 87]) underwent resection over a 7-year period. At a median follow-up of 26.4 months the estimated 5-year overall survival was 26% (95% confidence interval [CI] 14% to 50%; median survival 25.2 months). The estimated 5-year overall survival for T4 N0 patients was 40% (95% CI 23% to 68%; median survival 34.8 months). Size of the primary tumor, histology, and nodal status were significantly associated with overall survival; size and nodal status were significantly associated with disease-free survival.
Conclusions: Our results indicate that T4 (satellite nodule) N0 patients experienced excellent survival after surgical resection. These data support surgical resection in node negative patients. Size, histology, and nodal status were important prognostic variables associated with outcome. Consideration should be given to multimodality treatment in patients with adverse prognostic features. Further larger multiinstitutional studies are required to validate these findings.
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Introduction
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Lung cancer is the most common cause of cancer-related mortality in the United States. In 1997, the tumor-nodes-metastasis (TNM) staging was revised and in the current classification T4 tumors form a very heterogenous group [1]. The T4 descriptor comprises the following: (1) tumor of any size that invades one of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; (2) tumor with a malignant pleural or pericardial effusion; and (3) tumor with satellite tumor nodule(s) within the ipsilateral primary-tumor lobe of the lung [1]. These patients are classified as stage IIIB in the absence of metastatic disease, regardless of nodal status.
The management of non-small cell lung cancer (NSCLC) depends on the stage and IIIB lesions are typically treated by nonoperative therapy except in certain circumstances. Patients with one or more satellite nodules in the same lobe are classified as T4, stage IIIB even in node negative patients. Controversy exists as to the optimal management of these patients. Deslauriers and colleagues [2] in an early report evaluated satellite nodules as a prognostic factor after surgical resection. In this analysis, these authors compared 1,021 patients without satellite nodules to 84 patients with satellite nodules who were treated with surgical resection. The median survival in patients with satellite nodules was 15 months and median survival in those without satellite nodules was 30 months. In a subsequent meta-analysis by Urschel and colleagues [3], a 20% 5-year survival was noted in the group with satellite nodules, which was better than the reported survival for all patients with IIIB tumors. More recent reports have suggested that T4 satellite nodule patients, who are node negative, do better after surgical resection. However, many of these results are confounded by including patients with bronchoalveolar carcinoma (BAC), who have a more favorable prognosis [4, 5]. Therefore, in the current study, we excluded patients with confounding factors: patients with BAC and those who had undergone neoadjuvant therapy.
Our primary objectives for this study were to (1) evaluate the outcomes after surgical resection in patients with T4 satellite lesions and (2) analyze the clinical and pathologic prognostic factors associated with outcome in these patients.
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Material and Methods
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We retrospectively reviewed our experience with surgical resection for the treatment of T4 satellite lesions at the University of Pittsburgh from 1999 to July 2007. This study was approved by the Institutional Review Board of the University of Pittsburgh. Because this was a retrospective study, individual consent was waived.
Patients who underwent resection for T4 (by virtue of satellite nodule) N0-2M0 were identified from the University of Pittsburgh cancer registry. Satellite lesions were defined as those having the same histology and in the same lobe as primary cancer and no systemic metastases. All T4 satellite lesion patients (n = 51) included in this study were treated with curative intent by a lobectomy or pneumonectomy. Exclusion criteria were the following: (1) patients with pure bronchoalveolar carcinoma; (2) second primary lesions; (3) patients who received neoadjuvant therapy; (4) patients who underwent sublobar resection or incomplete resection; and (5) patients with metastatic disease. Detailed examination of the pathology reports were carried out to confirm the diagnosis and analyze prognostic factors. The specific endpoints studied were overall survival and recurrence. The primary endpoint studied was overall survival. Multiple covariates (number of satellite lesions, histology, size, angiolymphatic invasion, nodal status, and visceral pleural invasion) were analyzed for association with survival and recurrence.
Follow-up of Patients
Patients were followed up in the thoracic surgery clinic. Our current protocol is follow-up with clinical examinations, and computed tomographic scans at intervals of 4 to 6 months for the first 2 years and then yearly thereafter. Positron emission tomography scans were used selectively. In addition to the data derived from the University of Pittsburgh Lung Cancer Registry, the medical records were reviewed, and the Social Security Death Index was utilized to verify survival information.
Statistical Design and Analysis
The primary objectives of the study were to determine the outcomes of surgically resected patients with T4 satellite lesions and to assess clinical and pathologic factors that were associated with survival. Information on patient demographics, tumor characteristics, and treatment were collected. The primary endpoint studied was overall survival and the secondary endpoint studied was disease-free survival. Kaplan-Meier plots with Greenwood confidence intervals were constructed to estimate overall survival (OS) and disease-free survival (DFS). Recurrence-free (disease-free) time was computed as the time from resection to disease recurrence. For this analysis patients who died while disease-free were censored. A series of covariates were tested for their influence upon overall and disease-free survival including tumor size, histology, number of satellite lesions, angiolymphatic invasion, visceral pleural invasion, N stage, and gender. The log-rank test was used to analyze differences between the groups. The log-rank p values were adjusted by the step-down Bonferroni method.
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Results
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Patient Characteristics
A total of 51 patients (men 22, women 29) with a median age of 71 years (range, 48 to 87) with T4 (satellite lesion) N0-2 lesions treated who met the study criteria were identified over a 7-year period. Of these patients, the T4 N0 group was composed of 34 patients and the T4 N1-2 group was composed of 17 patients (N1 = 10; N2 = 7). Patient characteristics are summarized in Tables 1 and 2.
Preoperative Staging
The satellite nodule was identified preoperatively in 24 of 51 (47%) patients. The details of preoperative staging are summarized in Tables 1 and 2. Mediastinoscopy was performed in 17 patients (33%). Among patients with T4 N0 disease, the correct stage was identified preoperatively in 18 of 34 (53%). Patient characteristics of T4N0 patients are summarized in Table 2. The details of the staging procedures and surgical resection are summarized in Table 3.
Survival
The primary endpoint analyzed was overall survival. The median follow-up period of the entire cohort (n = 51) was 26.4 months (range, 0.3 to 85.2 months) and the estimated 5-year overall survival was 26% (95% confidence interval [CI] 14% to 50%) (Fig 1). The median survival was 25.2 months. The median follow-up period for the T4 N0 patients (n = 34) was 27.6 months (range, 14.4 months to 85.2 months) and the estimated 5-year overall survival was 40% (95% CI 23% to 68%). The median survival was 34.8 months (Fig 2).
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Fig 1. Kaplan-Meier Plot illustrating overall survival in the entire T4 N0-2 patients with confidence limits. The time shown is in x axis is in years from surgical resection. The dotted lines are 95% confidence bands for the probability of overall survival.
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Fig 2. Kaplan-Meier plot illustrating overall survival stratified by nodal status (T4 N0 vs node positive patients). The time shown is in x axis is in years from surgical resection. The numbers at risk are shown in the x axis.
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Recurrence
The estimated 3-year DFS for the entire cohort (T4 N0-2) was 56% (95% confidence interval 47% to 83%). The median DFS for the entire group has not been reached (2.5 to not reached). When we analyzed the node negative patients, the estimated 3-year DFS for the T4 N0 group was 69% (95% CI 51% to 93%). The median DFS for this group (T4 N0) has not been reached.
Analysis of Prognostic Factors Associated With Survival and Progression
Analysis of the association of the following covariates with overall survival and disease-free survival was performed: tumor size of the primary lesion, histology, number of satellite lesions, presence of angiolymphatic invasion, visceral pleural invasion, gender, and nodal status. Nodal status (N0), tumor size (<4 cm), and histology (adenocarcinoma) were associated with better overall survival. When stratified by node status, the median survival of node negative patients was 34.8 months, 20.4 months for N1 disease, and 22.8 months for N2 disease (Fig 2). After the log-rank p values were adjusted by the step-down Bonferroni method, size (<4 cm) was associated with better overall survival. These results are summarized in Table 4. When the analysis was limited to T4 N0 patients alone, tumor size (p < 0.0001) (Fig 3) and histology (p < 0.0225) were significantly associated with overall survival. These results are summarized in Table 5.
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Fig 3. Kaplan-Meier plot illustrating overall survival stratified by size in T4 N0 patients. The time shown in the x axis is in years from surgical resection. The numbers at risk are shown in the x axis.
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When the covariates associated with DFS were analyzed for the entire cohort (T4 N0-2; n = 51), size of the primary tumor (p = 0.0042) and nodal status (p = 0.03) were significantly associated. When T4 N0 (n = 34) patients were then separately analyzed, size was significantly associated with DFS (p < 0.0001).
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Comment
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The management of NSCLC depends on the stage and this is clearly one of the most important determinants of survival. Treatment decisions are made based on stage, and IIIB lesions are typically treated by nonoperative therapy except under certain circumstances. Patients who are classified as stage IIIB on the basis of one or more satellite nodules, in particular node negative patients, may be excellent candidates for surgical resection. In this article, we report the outcomes of node negative T4 satellite nodule patients and the prognostic variables associated with outcome. We excluded important confounding variables which may influence outcome including BAC, which is known to have a favorable prognosis, and administration of neoadjuvant therapy, which may have downstaged patients.
At a median follow-up of 26.4 months, the estimated 5-year overall survival was 26% and median survival was 25.2 months for the entire cohort. In patients who were node negative, the estimated 5-year overall survival was 40% with a median survival of 34.8 months. These results appear to be improved compared with the reported survival of stage IIIB patients.
Prognostic Factors Associated With Outcomes After Surgical Resection
In this series, we analyzed several prognostic variables which may influence outcomes. We found that tumor size (<4 cm), histology (adenocarcinoma), and negative nodal involvement (N0) were all associated with better overall survival. When the analysis was limited to T4 N0 patients alone, tumor size (Fig 3) and histology were significantly associated with overall survival. Similarly we found that size of the primary tumor and nodal status were significantly associated with DFS.
These findings argue in favor of accurate assessment of nodal status preoperatively. Patients who have nodal disease, larger lesions (>4 cm), and nonadeno histology appear to be at risk for worse outcomes. Identification of this high risk cohort may lead to development of protocols in the future to study neoadjuvant or adjuvant strategies in treatment of patients with adverse prognostic factors.
Other investigators have reported the results of patients who underwent resection of satellite nodules [2–9]. However, some of these series were confounded by addition of BAC patients. Recently, for instance, Rao and colleagues [4] reported the outcome after surgical resection in 35 patients with T4 satellite nodes, of which 18 patients were node negative. These investigators, however, included patients with BAC and reported an estimated 5-year survival of 57%. Similarly Bryant and colleagues [5] evaluated the results of 26 patients, which comprised 19% of patients with BAC, and reported a median survival of 27.6 months. However, similar to the current series, Port and colleagues [6], in a study of 53 patients with T4 satellite lesions, excluded patients with BAC. These investigators reported an estimated 58.4% 5-year overall survival in node negative patients. However, in contrast to our study these investigators identified only one variable, female gender, as a favorable factor.
In summary, although some of these studies had coexisting confounding variables, survival results in T4 N0 patients appeared encouraging. Our study differs from some of these series in that we have excluded many of the confounding variables and have identified important prognostic variables associated with survival.
Clinical Implications
One of the important clinical issues is the management of patients who have had satellite nodules identified during preoperative investigation. In our current study, 47% of patients had the diagnosis of satellite nodule identified preoperatively. This is in contrast to the study by Port and colleagues [6], where these satellite nodules were identified in only 15% of patients preoperatively. In one study, the majority of preoperative satellite lesions seen in imaging studies were benign [10] and it is important not to make an assumption of malignancy in these satellite nodules. Even if the satellite nodule was determined to be malignant, our results with a favorable prognosis in this group of patients when they are node negative argues in favor of surgical resection. In agreement with this approach is a recent review by Shen and colleagues [11] who have recommended resection in patients with T4 satellite lesions who are node negative. We have identified nodal status, size, and histology as important prognostic factors. These data support an accurate assessment of nodal status preoperatively.
This study has its strengths and limitations. The strengths of the current study include exclusion of patients with confounding variables, such as patients with BAC and those who received neoadjuvant therapy. In addition, we have performed an analysis of prognostic variables and have identified nodal status, size, and cell type as important variables associated with outcome. This analysis of prognostic variables may lead to development of protocols in the future to study neoadjuvant or adjuvant strategies in treatment of these patients.
The current study has the limitations which are inherent to retrospective studies, such as selection bias, and this is a single institution series. The patients treated in this study comprise a selected group of patients who underwent surgical resection. Longer follow-up for this cohort is required. Further, the full evaluation of survival endpoints will require greater maturity of time-to-event data.
Conclusion
In summary, our results indicate that T4 (on the basis of satellite nodule) node negative patients, although staged as IIIB, experience an excellent survival after surgical resection. These data support surgical resection in this group of patients. Nodal status, size, and histology are important prognostic variables associated with outcome. It is important to stage patients and determine nodal status accurately preoperatively. Consideration should be given to multimodality treatment in patients with adverse prognostic features. Further larger multiinstitutional studies are required to validate these findings.
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Discussion
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DR SHANDA HALEY BLACKMON (Houston, TX): Thank you very much for the opportunity to discuss this paper. I have two comments and only one question since you answered one that was in the presentation but not in the actual manuscript.
This current study retrospectively reviews completely resected intralobar multifocal disease. It mirrors two other 2007 Annals publications by Drs Port and Rao and colleagues, much like Dr Cerfolio's previous paper. Like Dr Altorki, you also excluded bronchioalveolar carcinoma, but your numbers are small. The abundance of these publications indicate a desire within the thoracic community to inevitably change the staging system, which should be coming. What might be more helpful is a more powerful analysis that is from a national database, such as the STS thoracic database, to strengthen conclusions on what appear to be a relatively small group in individual and numerous institutions. This could elicit differences, if they exist, among patients regarding nodal status, lymphatic invasion, numbers of satellite lesions, and stage or biology of the tumor.
Secondly, I would like to emphasize the importance of a thoracic surgical oncologist as a member of the multidisciplinary team making staging and treatment recommendations, especially when initial stage may prevent a surgical consultation in some centers.
My question for you is, in your manuscript it does not specify whether these patients were of clinical or pathologic T4 N0 satellite lesion or if this could be a node that is overwhelmed with tumor. How can you imply, as your title implies, that surgical resection for clinical T4 lung cancer in node negative satellite lesions is justified when you only retrospectively reviewed surgical specimens which are pathologic specimens? We judge resection candidates on clinical data and not on pathologic specimens.
DR PENNATHUR: Thank you, Dr Blackmon, for your comments and questions. That is an excellent question. In this particular series, approximately 50% of patients had the correct preoperative diagnosis of clinical stage III. So with at least this data, in approximately 50% of the patients, those are clinically staged preoperatively, and the results of surgical resection are good when compared to historical results of stage IIIB, as long as the nodal status is negative, which justifies surgical resection in this group of patients. But I think your point is well taken. I think that the path data cannot be immediately transposed to clinical data, and I think it will be interesting to see the outcomes of resection of clinical stage IIIb satellite nodule and this study was not restricted to this group of patients. I do agree with your comments that larger numbers are needed to confirm these findings, and also your comments with regard to accurate staging and thoracic surgical opinion in the management of these patients.
DR BLACKMON: I think the important clinical implication is to present that all of these satellite lesions are benign and continue resection and not make attempts to work up these benign lesions since we know unsuspected T4 satellite lesions do better.
DR PENNATHUR: Yes, they do better. A recent consensus statement by the ACCP [American College of Chest Physicians] essentially concluded that when there is a satellite lesion clinically seen, that they do not need any extra workup other than what is required for the primary tumor. And one of the premises under which the recommendation was made was a paper in the radiology literature looking at satellite nodules, which showed that many of these nodules were benign. Our analysis has shown important covariates associated with outcome in patients with T4 satellite lesion, in particular lymph node status. Therefore, it should be emphasized that these patients should be properly staged and accurate nodal staging is important. Nodal staging techniques such as mediastinoscopy should be an important component of the workup. Thank you for your excellent question and comments.
DR DOUGLAS E. WOOD (Seattle, WA): Arjun, I think what you have identified and emphasized is what many of us in thoracic surgery understand, which is that T4 N0 disease is a problem of anatomy rather than a problem of biology. This is where our medical oncology and pulmonary colleagues often get confused, since it gets labeled stage IIIb and lumped together with N3 disease. Yet it is quite clear when you add on to a T4 disease other surrogates for bad biology like nodal disease, which you have excluded, that the prognosis plummets. You excluded your N1 and N2 patients in the retrospective analysis I am presuming because their outcome was so poor. Do you have that information for us to confirm my impressions?
And my second question is, given the importance of nodal status in these patients with locally advanced T-stage, do you think that it would be important to perhaps be more vigorous in your nodal staging preoperatively? I note that only two-thirds of patients had PET scan and only 18% of patients had mediastinoscopy. I would allege that all of these patients that have the potential of resection for locally advanced disease probably deserve PET scans and all mediastinoscopy.
DR PENNATHUR: Thank you, Dr Wood. In terms of the survival rates for nodal disease, the median survival for N1 was 21 months and the median survival for N2 disease was about 23 months. So they were different when you compare the entire group. We have included these results in the manuscript. As to your point on staging, this study started in the late '90s and PET scan was not routinely obtained. These days we do obtain PET scan routinely. In terms of mediastinoscopy, we do mediastinoscopy for enlarged nodes and also PET positive nodes. And when you are dealing with a clinical satellite lesion, I think your point is an excellent one and well taken. Our analysis has shown that nodal status is an important predictor of outcome. Again, accurate nodal staging is important prior to committing these patients to a resection. We have discussed this in the manuscript also. We thank you for your questions and kind comments.
DR ARA VAPORCIYAN (Houston, TX): Whenever you are looking at a very small subgroup like this out of six, seven years of clinical work, one question that always comes up is this has got to be a very selective group. How many patients did you have in six, seven years with T4 satellite lesions who didn't get surgery? Have you looked at that number?
DR PENNATHUR: Patients with satellite lesions who did not need surgery? No, I do not have that number. Thank you for your question.
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Abstract
Introduction
