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Ann Thorac Surg 2006;82:408-416
© 2006 The Society of Thoracic Surgeons
a Department of Surgery, Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
b Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
c Cancer Registry, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
d Department of Cardiothoracic Surgery, Boston Medical Center, Boston, Massachusetts
Accepted for publication February 4, 2006.
* Address correspondence to Dr Landreneau, Division of Thoracic and Foregut Surgery, Department of Surgery, Shadyside Medical Bldg, 5200 Centre Ave, Suite 715, Pittsburgh, PA 15232 (Email: landreneaurj{at}upmc.edu).
Presented at the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.
| 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.
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Abstract |
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METHODS: The outcomes of all stage I non–small cell lung cancer patients (n = 784) undergoing resection were analyzed from our lung cancer registry from 1990 to 2003. Lobectomy was the standard of care for patients with adequate cardiopulmonary reserve. Sublobar resection was reserved for patients with cardiopulmonary impairment prohibiting lobectomy. Predictors of overall survival and disease-free survival were evaluated. Statistical analyses included Kaplan–Meier estimates of survival, log-rank tests of survival differences, and multivariate Cox proportional hazards models.
RESULTS: Lobectomy was used for 577 patients and sublobar resection for 207 patients. The median age was 70 years (range, 31 to 107 years). The median follow-up of patients remaining alive was 31 months. Compared with lobectomy, sublobar resection had no significant impact on disease-free survival, with a hazard ratio of 1.20 (95% confidence interval, 0.90 to 1.61; p = 0.24). Sublobar resection had a statistically significant association with overall survival when compared with lobectomy, with an increased hazard ratio of 1.39 (95% confidence interval, 1.11 to 1.75; p = 0.004). Twenty-eight percent of lobectomy patients experienced disease recurrence in that time compared with 29% of the sublobar patients. Seventy-two percent of the recurrences in the lobectomy cohort were distant metastasis versus 52% of the sublobar group recurrences (p = 0.0204).
CONCLUSIONS: Although sublobar resection is thought to be associated with increased incidence of local recurrence when compared with lobectomy, we found no difference in disease-free survival between the two types of resection for stage IA patients but slightly worse disease-free survival for stage IB.
| Dr Luketich discloses that he has a financial relationship with US Surgical, Stryker and Berchtold.
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Surgical resection remains the mainstay of therapy for stage I non–small cell lung cancer (NSCLC), providing the best opportunity for cure. The extent of pulmonary resection required to achieve complete eradication of the malignancy has been a hotly debated issue [1]. Many patients presenting with resectable early stage disease are unable to tolerate pulmonary resection because of compromised cardiopulmonary function. It has been suggested that more than 20% of patients who are diagnosed with stage I or II NSCLC do not undergo operation because of comorbid health factors [2]. The use of sublobar resection with adequate surgical margins in this setting may provide a comparable survival advantage to such patients along with preservation of pulmonary function [3].
Additionally, computed tomographic scan surveillance efforts directed to patients with a higher risk for lung cancer have identified small peripheral cancers amenable to sublobar resection with generous margins of parenchymal resection. Many surgeons have questioned the necessity of total lobectomy for the management of such lesions [4–6].
The purpose of this investigation was to evaluate the patterns of recurrence, postoperative morbidity differences, and survival differences between patients with stage I NSCLC treated by either sublobar resection or anatomic lobectomy. This period (from 1990 through 2003) of surgical experience with stage I NSCLC was chosen for analysis as computed tomographic clinical staging and follow-up were routinely applied. Additionally, this was also a period of increased surgical experience with patients having significant impairment in cardiopulmonary reserve as our group was actively involved in the initial efforts with minimally invasive thoracic surgery, lung-volume reduction surgery, and the National Emphysema Treatment Trial [7]. These experiences influenced the nature of our lung cancer referral; accordingly, many patients found to have peripheral small lung cancers with significant cardiopulmonary impairment were considered for surgical resection. Many of these cancer patients were thought to be at risk for unacceptable pulmonary functional loss associated with lobectomy, and thus sublobar resection was chosen as the primary resectional therapy. The evaluation of this mature experience with surgical resection of stage I NSCLC by either lobectomy or sublobar resection follows.
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Material and Methods |
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The demographic data of patients' age and sex were collected as well as tumor histology, size, number of lymph nodes sampled, length of stay, and operative and perioperative mortality data. Perioperative mortality included patients who died within the first 30 days after surgery.
End points of the analysis included the incidence of disease recurrence (locoregional and distant), disease-free survival, and overall survival. Locoregional recurrence was defined as any recurrence within the same lobe of the lung, or interlobar and hilar lymph nodes (N1 nodes). All other metastases were classified as distant recurrence.
The two cohorts, lobectomy and sublobar resection, were compared on the basis of clinical, demographic, and pathologic data. Both the Student's t test and the Wilcoxon test [9] were used to compare the distributions of continuous data (age, tumor size), and the 
2 test or Fisher's exact test [10] was used to compare the frequencies of categorical measures (sex, histology, stage, vascular pleural invasion, and number of lymph nodes removed). In cases with low cell counts, the exact 2 test was used in place of the usual (asymptotic) test. All comparisons were two-tailed.
Disease-free survival was defined as the time from surgery to the first diagnosis of local, regional, or distant disease recurrence, or until last follow-up. Overall survival was defined as the time from surgery to death or last follow-up. Disease-free and overall survivals were estimated with the Kaplan–Meier method [11] with the Greenwood formula for estimation of standard errors. Individual predictors such as sex, histology, stage tumor size, and type of surgery (lobe versus sublobe) were compared with the log-rank test and Cox regression. To fully assess the effect of sublobar resection, Cox proportional hazards models [12] were constructed to evaluate the independent effect of sublobar resection while adjusting for other prognostic variables, including age, stage, tumor size, and number of resected lymph nodes.
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Results |
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Mean ages were slightly different between the two groups, and the sex ratio was equal (Table 1). Lung cancer histologic diagnosis was also well balanced between the cohorts (Table 1, Fig 3). Patients receiving sublobar resection tended to have smaller tumors (1.8 cm versus 2.8 cm; p < 0.0001) and were more likely to be stage IA rather than IB (78% stage 1A versus 27% stage IB; p < 0.0001), but among the 46 stage IB patients having sublobar resection, 35 of them (76%) had visceral pleural invasion (p < 0.0001).
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2, p < 0.0001).
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Disease-Free Survival
All 784 patients were followed until disease recurrence or death or until loss of follow-up in the tumor registry (Table 3). The median follow-up for patients who were alive and were disease-free at their last review was 2.7 years, with a range of less than 1 month to 14 years. Twenty-eight percent of lobectomy patients experienced disease recurrence in that time compared with 29% of the sublobar patients. Although the proportion of patients found with disease recurrence was the same in both groups, there is a suggestion that the recurrence patterns differ, as 72% of the recurrences in the lobectomy cohort were distant metastasis versus 52% of the sublobar group recurrences. This difference was significant (exact 2 test, p = 0.0204).
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Comment |
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Although we could not study this difference in comorbid conditions between the two groups given the retrospective analysis and the limitations of the lung registry, we can only speculate based on our standard approach of lobectomy for stage I disease in patients with good risk.
This effect of comorbid disease in evaluating survival from coronary artery disease has been recently analyzed and emphasized by a group from Duke [13]. In this analysis of coronary artery disease survival, the survival influence of comorbidities such as chronic obstructive pulmonary disease or peripheral vascular disease in 1,471 patients was equivalent to poor left ventricular function in affecting patient survival. The effect of comorbidity on older lung cancer patients' survival after lung resection has also been documented in a report by Birim and coworkers [14]. The authors assessed the risk factors of survival in 126 consecutive patients with NSCLC who were older than 70 years of age and underwent resection. During a period of 12 years, the patient survival was compared with the yearly expected survival rates of the general population. The study showed a 5- and 10-year survival rate of 37% and 15%, respectively. Smoking (odds ratio, 2.3) and chronic obstructive pulmonary disease (odds ratio, 2.1) were identified as risk factors for long-term survival. The observed survival was lower than the expected survival related to the natural history of their comorbid disease and the patient age. The recent subanalysis of the medical treatment arm of the National Emphysema Treatment Trial further emphasized the importance of the natural history of moderate to severe chronic obstructive pulmonary disease [7]. The mortality among patients with predominant upper lobe emphysema and poor exercise tolerance was 34% at 2 years. Even among patients with the least chronic obstructive pulmonary disease limitations (lower lobe predominance and good exercise tolerance), the mortality was 13% at 2 years.
The possible effect of erroneous "understaging" of a significant number of the patients undergoing sublobar resection related to the thoracic lymph node sampling differences observed in this study could have also led to disparate survival results between lobectomy and sublobar resection patients.
The Lung Cancer Study Group conducted the only randomized study comparing sublobar resection with lobectomy for stage IA NSCLC patients [15]. Importantly, all patients considered for the study had to be considered functional candidates for lobectomy if necessary. In this study, the intraoperative nodal staging requirements were limited to sampling a single mediastinal, hilar and interlobar node before randomization to the mode of surgical resection. Distant recurrence rate was unaffected by the method of resection used. There was no difference in hospital mortality between the two groups of patients; however, patients who underwent lobectomies did have significantly more postoperative pulmonary complications requiring mechanical ventilatory support. A significant threefold increase in local recurrence was seen with sublobar resection; however, there was no difference in overall survival or cancer-related survival between sublobar resection and lobectomy.
Although all patients in this report were staged as stage I on the basis of pathologic staging, we think there may be an artificial tumor understaging of patients undergoing sublobar resection as a consequence of disproportionate dissection between lobectomy and sublobar resection techniques. Our analysis showed a 2% decrease in the risk of dying for every node that was resected (p = 0.0075); this resulted in a bias in survival favoring lobectomy. Our results are consistent with the recent data from the ACOSOG (American College of Surgeons Oncology Group) Z0030 trial presented at the Annual Meeting of The Society of Thoracic Surgeons in Tampa, Florida, in January 2005, and published in 2006 [16]. This study included 1,111 randomized patients undergoing anatomic resection of stage I NSCLC. The report showed a 4% increase in number of positive lymph nodes when lymph node sampling was compared with lymph node dissection. Interestingly, an 18% stage shift from stage I to stage II and III was seen when one compares the preoperative clinical staging to the intraoperative or postoperative pathologic staging.
Recent investigations from Japan comparing extended segmentectomy with thorough thoracic lymph node staging for small peripheral stage I lesions have reported equivalent survival to that of lobectomy [17]. These reports may be considered an expected consequence to the lung cancer computed tomographic screening programs begun in that country more than a decade ago. Many thoracic surgeons began to selectively use sublobar resection as the primary therapy for small peripheral NSCLC in lieu of lobectomy. An interesting report of sublobar management of small peripheral NSCLC came from Swanson and coworkers [18] and Mery and associates [19]. These investigators reported their experience among patients undergoing wedge resection as primary therapy for subcentimeter peripheral lung cancers.
Kondo and colleagues [20] reviewed the outcome of 104 patients with peripheral stage IA adenocarcinomas of the lung. They specifically analyzed the survival among 57 of these patients with lesions less than 1 cm in diameter. These patients with subcentimeter lesions underwent the following procedures: 23 lobectomies, 13 segmentectomies, and 21 wedge resections. Interestingly, the authors found that the mode of resection used for these small peripheral lung cancers did not affect postoperative cancer-related survival. The 5-year survival for the group was 97%.
These investigators also advocated the use of the Noguchi's histologic classification for these small peripheral tumors to aid in predicting the risk of nodal metastasis [21]. This system identifies small ground-glass opacities with bronchioalveolar histology as having a very minimal chance of nodal metastasis and also an extremely favorable prognosis with sublobar wedge resection alone. In contrast, lesions with more characteristic glandular adenocarcinoma histologic appearance had greater than 10% chance of nodal metastasis. Because of this occult lymph node metastasis risk, Kondo and associates [20] advocated anatomic resection, preferably lobectomy, for such lesions.
An interesting recent report by Okada and colleagues [6] looked at the effect of tumor size on prognosis after resection in 1,272 patients. There was no statistical difference in the 5-year cancer-specific survival between lobectomy and segmentectomy in patients with tumors 20 mm or less in diameter (92.4% versus 96.7%, respectively). In addition, tumors 20 to 30 mm in diameter had no significant difference between lobectomy and segmentectomy in the 5-year cancer-specific survival (87.4% versus 84.6%, respectively). The authors suggested segmentectomy was an acceptable operation for stage I disease 2 cm or less in diameter.
A summary of the studies comparing sublobar with lobar resection for stage I NSCLC is shown in Table 6.
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Online Discussion Forum |
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Once the article selected for discussion is published in the online version of The Annals, we will post a notice on the CTSNet home page (http://www.ctsnet.org) with a FREE LINK to the full-text article. Readers wishing to comment can post their own commentary in the discussion forum for that article, which will be informally moderated by The Annals Internet Editor. We encourage all surgeons to participate in this interesting exchange and to avail themselves of the other valuable features of the CTSNet Discussion Forum and Web site.
For August, the article chosen for discussion under the Adult Cardiac Dilemma Section of the Discussion forum is: Reduction Ascending Aortoplasty: Midterm Follow-Up and Predictors of Redilatation
Gianluca Polvani, MD, Fabio Barili, MD, Luca Dainese, MD, Veli K. Topkara, MD, Faisal H. Cheema, MD, Eleonora Penza, MD, Sandro Ferrarese, MD, Alessandro Parolari, MD, PhD, Francesco Alamanni, MD, and Paolo Biglioli, MD
Tom R. Karl, MD
The Annals Internet Editor
UCSF Children's Hospital
Pediatric Cardiac Surgical Unit
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San Francisco, CA
94143-0118
Phone: (415) 476-3501
Fax: (212) 202-3622
e-mail: karlt{at}surgery.ucsf.edu
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Discussion |
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DR EL-SHERIF: Thank you, Dr Swanson, we analyzed the 10-year follow-up period as a means of evaluating overall recurrence. Accordingly, we did not find a difference between the sublobar resection and lobectomy groups with regard to overall tumor recurrence. Most local recurrences will be identified within the first 2 years after resection. The relative understaging seen between lobectomy and sublobar resection patients related to the difference in lymph node yield may confound the accuracy in comparing tumor recurrence. This would potentially bias against the sublobar resection patients who had significantly fewer lymph nodes sampled as a group. These sublobar resection patients also were physiologically more impaired than the lobectomy patients, which would also potentially affect the overall survival time owing to death from unrelated disease.
DR FRANK C. DETTERBECK (Chapel Hill, NC): I was surprised by the number of sublobar resections you had. It was about a third as many as the lobectomy patients, and I'm wondering what your criteria for poor cardiopulmonary reserve are that preclude lobectomy. They seem to be fairly liberal, I think.
Secondly, I think that in comparing the patients, what would probably be best is if you could compare the same patients by clinical stage and tumor size, in other words, clinical stage I, peripheral 2-cm tumor, in both groups as opposed to what we have here, which are probably discrepant stages and, of course, the whole issue of the accuracy of your postoperative pathologic staging, which is obviously different in the two groups. So if you look at clinical staging, can you give us a subset of your lobe resection patients and compare those two groups?
DR EL-SHERIF: Thank you, Dr Detterbeck, our standard of surgical care for the good risk stage I non–small cell lung cancer patient was lobectomy during the entire period reviewed for this investigation. However, we do see many patients with poor preoperative functional reserve for whom we do not recommend lobectomy but who could potentially obtain an important survival advantage with a sublobar resection that they could tolerate. The criteria to utilize sublobar resection was variable among surgeons in our group.
There were multiple factors affecting the decision to recommend sublobar resection. The patient's pulmonary function was a primary determinant for many patients; however, other important medical comorbidities and advanced patient age were also important variables leading to the decision to perform less than lobectomy for these stage I lung cancer patients.
We did not look at the patterns of recurrence between resection groups among patients with small, less than 2-cm tumors. We will be investigating this subset of patients in the future.
DR SUDISH C. MURTHY (Cleveland, OH): This is just to get back to Dr Swanson's question. You must be careful when you're comparing a group of very high-risk patients from a medical standpoint to a group of more fit patients. Because of this type of analysis, you often have to normalize the data for the competing risk of non-cancer death (which is likely much higher in the patients undergoing limited resection). By not accounting for this, you may be overestimating the impact of your intervention. This is just a suggestion for your additional analyses. I enjoyed your presentation.
DR EL-SHERIF: You are absolutely correct.
DR DAVID RICE (Houston, TX): You alluded to the Japanese literature, and I think a point that I would make is that a significant number of patients in these trials have very early-stage bronchoalveolar cancer (BAC) or ground-glass opacities. What was the percentage of BAC in both groups in your study?
DR EL-SHERIF: Twelve percent, without a differential between resection groups.
DR RICE: Thank you.
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