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Original Articles: General Thoracic

Survival of Patients With Unsuspected N2 (Stage IIIA) Nonsmall-Cell Lung Cancer

Division of Cardiothoracic Surgery, University of Alabama at Birmingham, Birmingham, Alabama

Accepted for publication April 7, 2008.

^_* Address correspondence to Dr Cerfolio, Department of Surgery, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, 703 19th St S, ZRB 739, Birmingham, AL 35294 (Email: rcerfolio{at}uab.edu).

Presented at the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2008.

General thoracic surgery: The Annals of Thoracic Surgery CME Program is located online at http://cme.ctsnetjournals.org. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal.

 

	Abstract

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Background: The objective of this study was to determine the survival of patients who have completely resected, nonsmall-cell, stage IIIA, lung cancer from unsuspected (nonimaged) N2 disease who received adjuvant chemotherapy.

Methods: This is a retrospective cohort study using a prospective database. All patients underwent positron emission tomography scan and computed tomography scan with contrast, R0 resection with complete thoracic lymphadenectomy, and had unsuspected, pathologic N2 NSCLC.

Results: Between June 1998 and December 2007, there were 148 patients (89 men). The most common pulmonary resection was right upper lobectomy in 67 patients (48%), and the most common lymph node station for unsuspected N2 diseased was 4R. One hundred and thirty-seven patients (93%) received adjuvant chemotherapy and 13% received postoperative radiation as well. The overall 2- and 5-year survivals were 58% and 35%, respectively. The 5-year survival for the 98 patients with single lymph node disease compared with patients with multiple nodal involvement was 40% versus 25%, respectively (p = 0.028). The number of lymph nodes involved (p = 0.032) was an independent predictors of survival on multivariate analysis. Median follow-up was 54 months.

Conclusions: The 5-year survival of patients with unsuspected N2 disease who undergo complete resection, followed by adjuvant therapy, is 35%. Patients with single station N2 disease fare better. The role for mediastinoscopy, endoscopic esophageal ultrasound with fine-needle aspirate, or endobronchial ultrasound in patients who are negative by positron emission tomography and computed tomography is unknown, since the benefit of neoadjuvant therapy in these patients is also unproven. A randomized study is needed.

The treatment of nonsmall-cell lung cancer (NSCLC) depends on the stage. Although some randomized studies suggest that neoadjuvant therapy is best for patients with stage IIIA disease from N2 mediastinal lymph node metastases, there are several different types of N2 disease [1, 2]. Pathologically, N2 disease has been referred to as bulky, multistationed, or fixed. In addition, after resection is has also been labeled as obvious, suspected, unsuspected or nonimaged, surprised or ignored [3].

Some general thoracic surgeons perform mediastinoscopy before any pulmonary resection for NSCLC irrespective of the size of the primary tumor or its location. We have shown in a prospective study that mediastinoscopy and endoscopic esophageal ultrasound with fine-needle aspirate (EUS-FNA) find unsuspected or nonimaged N2 disease in only 2.9% and 3.7%, respectively, of patients with NSCLC who are staged as N0 after both positron emission tomography (PET) and computed tomography (CT); thus, we do not recommend their routine use [4]. The advantage of preoperative chemotherapy or chemoradiotherapy before pulmonary resection over resection followed by adjuvant therapy is unknown for N2 disease that is radiographically silent and not fluorodeoxyglucose (FDG) avid. The only true way to answer this question is to perform a prospective randomized study. The objective or purpose of this study was to determine a baseline 5-year survival for patients who have undergone careful clinical staging before surgery with both CT and PET scans and are deemed N2 negative by both tests, and who then undergo R0 pulmonary resection with complete thoracic lymphadenectomy, and have unsuspected pN2 disease.

	Material and Methods

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Patients
This is a retrospective review of a prospective database from June 1998 to December 2007, from one general thoracic surgeon. Inclusion criteria mandated that all patients be older than 19 years old, have biopsy-proven NSCLC, and have been clinically staged as N0 or N1 using CT scan and FDG-PET scan before surgical resection, as previously described [5]. We excluded from this study any patient with suspected N2 disease on imaging or confirmed before resection. Integrated PET/CT instead of dedicated PET was employed after 2002. Patients had to have biopsy-proven NSCLC in an N2 lymph node station (as defined by the TNM staging classification system) [6]. The University of Alabama at Birmingham's Institutional Review Board approved this study as well as the electronic prospective database used for this study. Individual patient consent was obtained for use in the prospective database but was waived for inclusion in this particular study.

Staging
Staging was performed as previously described at length [5]. In brief, patients were pathologically staged after being clinically staged using FDG-PET or integrated PET/CT and CT scans. Patients with suspicious N2 or N3 disease (defined after PET as areas with a maximum standardized uptake value greater than 2.5, or after CT with an N2 lymph node greater than 1 cm in its greatest axis) were eliminated from this study, even if they underwent staging with mediastinoscopy or EUS-FNA [4] or endobronchial ultrasound-FNA that was negative for N2 disease. Biopsies of suspicious M1 sites were obtained before pulmonary resection.

Pulmonary resection was performed as previously described [5], and thoracotomy with lung palpation and complete thoracic lymphadenectomy was used for all patients. Complete thoracic lymphadenectomy was defined as the removal of all regional N1 nodes based on the lobe removed, and for right-sided lesions, lymph nodes from stations 2R, 4R, 7, 8, and 9. Left thoracotomy was used for left pulmonary resection, and the N2 lymph nodes removed were from stations 5, 6, 7, 8, and 9, and in most patients the 4L location as well. Pathologic review was performed using standard techniques, and immunohistochemical staining was employed when appropriate.

All patients had an R0 resection, which is defined as a margin negative resection of all tumor as well as resection of all of the mediastinal lymph nodes, and all had unsuspected (nonimaged preoperatively) N2 disease. All patients were referred to an oncologist postoperatively; however, the use of adjuvant chemotherapy was usually reserved for those with good performance status and for those younger than 80. Most patients received platinum-based adjuvant chemotherapy often with another chemotherapeutic agent. Some patients also received adjuvant radiotherapy after oncology consultation.

Statistics and Definitions
Analysis was conducted using SAS software 9.0 (SAS Institute, Cary, North Carolina). Continuous data are presented as medians, and categorical data are presented as percentages. Survival estimates were derived by Kaplan-Meier analysis, and Mantel-Haenszel log-rank tests were used to assess differences in survival among groups. Cox proportional-hazards stepwise modeling was used to investigate and adjust for major prognostic factors. A forward stepwise selection procedure was implemented, with a p value less than 0.10 in the univarate analysis. Variables in the univariate analysis included sex, histology, T stage, number of lymph node stations involved, and side of surgery. These variables were determined before the study. A two-sided p value of less than 0.05 was considered statistically significant and unlikely due to chance. Patients alive at the end of the study period were censored for purposes of data analysis.

Unsuspected N2 disease is defined as having pathologic evidence of metastatic NSLCC in at least one N2 lymph node after having surgery within 30 days of a contrast CT scan with 5-mm columinated cuts and an integrated PET/CT scan or CT scan. Operative mortality is defined as patients who died within 30 days of discharge or before hospital discharge. Death from any cause was used to determine the overall survival rate. Patients alive or disease free at the end of the follow-up period were censored. Follow-up consisted of chest and abdominal CT every 6 months for the first 2 years and yearly afterward. Data were obtained from multiple sources such as clinic letters, follow-up scans, hospital computer information systems, tumor registry, social security death index, telephone calls, and letters from oncologists and other physicians. All information was entered into our prospective database. The final date of follow-up was January 15, 2008.

	Results

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There were 148 patients (89 men) who met the entry criteria for this study. Patient characteristics are shown in Table 1, and tumor characteristics are shown in Table 2. The most common type of pulmonary resection was right upper lobectomy in 67 patients (48%). The most common lymph node station for unsuspected N2 diseased was station 4R (36% of patients) followed by station 5, 6 (32% of patients). One hundred and thirty-seven patients (93%) received adjuvant chemotherapy. The operative mortality was 3.3% (5 patients). Causes of death were myocardial infarction (2 patients), pneumonia (1 patient), hypoxia and respiratory distress (1 patient). The operative morbidity was 30.4%, and most common morbidity was transient atrial fibrillation.

View larger version (13K): [in this window] [in a new window]   Fig 1. The 5-year overall Kaplan-Meier survival for the 148 patients was 35% (this figure includes 13 patients with T4 disease).

View larger version (12K): [in this window] [in a new window]   Fig 2. The 5-year Kaplan-Meier survival for patients with single N2 disease (solid line) versus multiple N2 disease (dashed line) was 40% and 25%, respectively (includes 13 patients with T4 disease).

	Comment

Top Abstract Introduction Material and Methods Results Comment Discussion References

The true clinical problem is that most patients with NSCLC are not carefully staged before or even during surgery. Many physicians do not routinely use integrated PET/CT scan before resection even when it is readily available, and instead send their patients for dedicated FDG-PET. There have been two prospective randomized studies that have documented integrated PET/CT's superiority over dedicated PET for clinical staging [8, 9]. Even more troubling is that many patients are not staged intraoperatively. It is also not uncommon to see patients who have ostensibly undergone mediastinoscopy but no nodes were removed, or patients who have undergone pulmonary resection for cancer and have no or only one N2 station biopsied. These are the more important issues that we need to correct as surgical society to help improve the staging and survival of patients with NSCLC.

We have reported a 5-year survival of 35% for patients with this very specialized type of N2 disease. By comparison, the overall 5-year survival for patients with resected N2 disease has been reported to vary greatly, from 15% to 36% [10]. This is not surprising, given the large heterogeneity of N2 disease. Obviously patients with bulky N2 disease that is not resected have very poor survival rates when compared with the types of patients presented in this study. Deleyn and colleagues [11] in 1996 reported a 22% 5-year survival for patients with NSCLC with unsuspected subcarinal disease. Similarly, Inoue and coworkers [12] in 2004 reported a 5-year survival of 28% for patients with single station N2 disease. Our series is unique and presents an even more favorable group of patients with N2 disease. Unlike other series, all patients were integrated PET/CT negative, not just dedicate PET negative, and all underwent fourth-generation CT scans with contrast and with 5-mm cuts. Doing this further selects out even a more favorable subgroup of patients with N2 disease.

The strengths of this study include the meticulousness and homogenous staging of the patients preoperatively and intraoperatively. Also, thoracotomy was used exclusively and affords lung palpation, and thus unsuspected nodules can be felt and removed [13]. Complete thoracic lymphadenectomy was performed and not just biopsy of some lymph nodes. Confounders are minimized because one physician staged and operated on all patients. Limitations of this study include the fact that not all patients received adjuvant chemotherapy, and different types of chemotherapy and different doses were used. Some elderly patients (older than 70 years) were deemed ineligible to receive adjuvant chemotherapy after complete resection. In general, in our practice, adjuvant radiotherapy is considered for all patients with resected N2 disease, especially those with extracapsular N2 disease, but they are rarely PET negative. However, because we perform such an aggressive lymphadenectomy in all patients with NSCLC, it was not offered to the vast majority of patients in this study who had only microscopic or unsuspected N2 disease. Some patients with multistation N2 in this series did receive adjuvant radiotherapy in addition to their chemotherapy.

In conclusion, the 5-year survival of patients with integrated PET/CT unsuspected N2 disease who undergo complete resection, followed by adjuvant therapy, is 35%. Patients with single station N2 disease fare better than those with multistation N2 disease. The treatment algorithm for the discovery of microscopic N2 disease before thoracotomy is controversial, and thus the role of routine mediastinoscopy, EUS-FNA, or EBUS in patients who are negative on PET and CT scans for N2 negative remains unknown. Because the benefit of neoadjuvant therapy for these types of N2 patients is also unproven, a randomized study is needed to best answer this question.

	Discussion

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DR JOSEPH B. SHRAGER (Philadelphia, PA): I'm especially interested in the statement you made toward the end of your talk that there should be a trial of preoperative versus postoperative chemotherapy in these patients who have what might be called "nonbulky" N2 disease. At Penn, we actually did a meta-analysis of all of the randomized trials of neoadjuvant chemotherapy followed by surgery versus surgery alone for N2 disease, and what we found was that there is actually no significant difference in outcome between these two approaches. There is such an entrenched belief in neoadjuvant therapy in the oncology community, though, that we couldn't even get that published! The two markedly positive randomized trials on this issue have been very well publicized, to the point that in many institutions preoperative chemotherapy for less than bulky N2 nodal involvement is considered the standard of care. What most people don't realize is that there are other studies that showed no difference. Given that we now know that postoperative chemotherapy has some benefit in these patients, I don't think it is at all clear that preoperative chemotherapy is any better than postoperative chemotherapy. So I couldn't agree with you more that this should be a high priority area for study in an intergroup trial.

DR DAVID H. HARPOLE (Durham, NC): It's interesting that you brought that up because the issue was just the opposite. In fact, Dr Cerfolio and his group were leading accruers to SWOG 9900, which was a randomized surgery versus induction chemotherapy/surgery trial. It had to closed early because of poor accrual after the results of the adjuvant therapy trials came out and everyone wanted a treat out back. So this pendulum is swinging back and forth. I think it's a very important question. Let's see what Dr Bryant says about how this trial should be designed and carried out.

DR BRYANT: Well, such a trial would be multi-institutional, and would evaluate patients who are N2 negative by both CT scan and by integrated PET/CT, and then all get a med or an EUS-FNA and EBUS, and if they had unsuspected pathologic N2, they would be randomized—half would get surgery followed by adjuvant chemotherapy and the other half would get surgery alone.

DR MICHAEL LANUTI (Boston, MA): Perhaps you can explain your approach to left-sided pulmonary resections and the degree of lymphadenectomy that you perform. Do you typically take 4L, 5, 6, and 7 lymph nodes? Does everybody undergo preoperative staging with mediastinoscopy or EBUS/EUS FNA?

DR BRYANT: As described in the presentation, these patients had no targets suggested by PET or CT, so they did not all get routine mediastinoscopy. Doctor Cerfolio does not do a mediastinoscopy on all patients. In this series, since all patients were N2 negative by both CT and PET the only patients who got a mediastinoscopy, EBUS and EUS-FNA was those who had a centrally located tumor, a tumor that was large—greater than 4 cm—or they had an elevated maximum standardized uptake value of 8 or greater or evidence of N1 disease. Doctor Cerfolio does a complete and thorough lymphadenectomy, and that is why the incidence of unsuspected N2 is higher than in other series—on the right he takes all of the 2R, 4R, 7, 8, 9; and the N1s on the left, he takes all of the 5, 6, 7, 8, 9, and the 4Ls and the N1s.

DR ROBERT B. CAMERON (Los Angeles, CA): Back to the question of this randomized trial, I guess I'm totally confused. If you have what we used to call incidental N2 disease discovered only at surgery, how do you randomize those patients for preoperative chemotherapy?

DR HARPOLE: I think the issue would be using either mediastinoscopy or EUS-FNA. A CT/PET doesn't show bulky disease. So you take patients who would be suspicious, in other words, high maximum standardized uptake value, central tumors, where you think there is more than a 10% incidence, and you find histologic evidence of cancer when they really are negative. Rob, that's what you're talking about, right? And you do that up front, before.

DR BENEDICT D. T. DALY (Boston, MA): I have just a quick question and a quick comment. Do you have comparable results for patients treated with induction chemotherapy who had N2 disease preoperatively over the same period of time? A 37% 5-year survival at 5 years for patients with microscopic N2 disease is on the low side.

DR CERFOLIO: We just presented our results for patients with N2 disease who got neoadjuvant chemoradiotherapy yesterday. Yesterday, we showed a very highly select group of patients who had nonbulky, nonfixed N2 disease, of which there were 400, and then they got radiation and chemotherapy, and you're left with 200 who came back and got staged, and then you are left with about 150 of them, who went to resection; only 120 got R0 resections, and their survival in that very, very select group was great, about 40%. However, if you look at the overall survival for those 400 patients, it was miserable at 10%. So in this study of microscopic unsuspected N2 disease discovered after surgery, although 37% or 40% doesn't sound great, it's a heck of a lot better than the average number that oncologists quote for N2 disease, because this is also a highly select group of patients.

To answer your first question—how to do the—it would be a prospective multi-institutional study, people would have to be very carefully staged with CT scan, with 5-mm cuts with intravenous contrast, get an integrated PET-CT, not a dedicated PET, and we'd have them all done similarly at different institutions. They are eligible for the study if they are N2-negative clinically and then all would get a mediastinoscopy, and EBUS, and an EUS-FNA. If the mediastinoscopy or the EUS showed microscopic N2 disease, then they would be randomized to neoadjuvant therapy followed by surgery, which would be one group, and group B would get surgery followed by adjuvant therapy. That would be the study, and yes, it's a small group of patients.

DR LYALL A. GORENSTEIN (New York, NY): In your opening comments, you made reference that there were no data looking at this group of patients, with unsuspected N2 disease before surgery, who are found to have clinically occult N2 disease at surgery. I want to bring your attention to some older work published well over 25 years ago from the University of Toronto thoracic surgical division. In their large series of patients with N2 disease, there was a subgroup of patients who had negative mediastinoscopies but were found to have N2 disease at surgery, and the survival in that group of patients was approximately 25%. These patients did not receive adjuvant therapy, yet their survival was far better than the entire cohort of N2 patients. Survival in this group of patients is not all that dissimilar to what you have found. This would seem to imply a biologic difference to clinically occult N2 disease, be it a negative preoperative PET scan or a negative mediastinoscopy.

DR BRYANT: Thank you.

DR CERFOLIO: We are aware of that study but the CT scanners have come along way since then and there was no PET then as well, so this really is a very different group of clinically N2 negative patients.

	References

Top Abstract Introduction Material and Methods Results Comment Discussion References

 

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