- Email: [email protected]
Oncologic Outcomes After Surgical Resection of Subcentimeter Non-Small Cell Lung Cancer
Matthew J. Schuchert, MD, Arman Kilic, BS, Arjun Pennathur, MD, Katie S. Nason, MD, David O. Wilson, MD, James D. Luketich, MD, and Rodney J. Landreneau, MD Division of Thoracic and Foregut Surgery, Heart, Lung and Esophageal Surgery Institute, University of Pittsburgh Medical Center Health System, and Division of Pulmonary Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Background. The recent initiation of screening protocols and greater utilization of computed tomography has led to an increasing proportion of non-small cell lung cancer (NSCLC) patients presenting with subcentimeter stage IA tumors. The aim of this study was to compare the oncologic outcomes of lobectomy, segmentectomy, and wedge resection in patients with NSCLC tumors 1 cm or less in diameter. Methods. Data were extracted from medical records of patients undergoing surgical resection for stage IA NSCLC and a pathologically confirmed tumor diameter measuring 1 cm or less. Primary oncologic outcomes were disease recurrence and disease-free survival. Statistical comparisons were performed using Fisher’s exact test and unpaired t test. Kaplan-Meier curves were compared using the log rank test. Significance was defined as a two-tailed p value less than 0.05. Results. A total of 107 patients underwent complete (R0) surgical resection for stage IA NSCLC 1 cm or less in
diameter (lobectomy, 32; segmentectomy, 40; wedge, 35). Age, sex distribution, tumor size, and histology were similar between groups. There was 1 perioperative mortality in the lobectomy group (3%). At a mean follow-up of 42.5 months, overall disease recurrence was equivalent, occurring in 3 lobectomy patients (9%), 4 segmentectomy patients (10%), and 3 wedge resection patients (9%; p ⴝ 0.99). Estimated 5-year disease-free survival was comparable among cohorts (lobectomy, 87%; segmentectomy, 89%; wedge, 89%; p >0.402). Conclusions. Sublobar resections are associated with oncologic outcomes that are comparable to those of lobectomy for subcentimeter stage IA NSCLC, suggesting that they may be appropriate surgical interventions in this patient cohort. The validity of these observations needs to be assessed in a prospective setting.
A
less in size. Primary outcome variables include tumor recurrence and patient survival. Secondary outcome variables include hospital course, morbidity, and mortality.
natomic lung resection remains the mainstay of therapy in the setting of early-stage non-small cell lung cancer (NSCLC) [1]. Lobectomy is the accepted standard, and has been shown to minimize the recurrence risk and optimize the chances of long-term survival [2]. With technical advances in thoracic imaging and the introduction of computed tomography (CT) screening protocols in patient groups at high risk for lung cancer, smaller and smaller tumors are being identified (Fig 1) [3, 4]. This has led many surgeons to question the necessity of lobectomy in all cases. Emerging data from Japan, Europe, and the United States have suggested that sublobar resection techniques (segmentectomy, wedge resection) can achieve outcomes similar to those of lobectomy for smaller, peripheral tumors [5, 6]. In the current study, we compare the outcomes of 107 patients undergoing lobectomy, anatomic segmentectomy, or extended wedge resection for NSCLC of 1 cm or
Accepted for publication Jan 4, 2011. Presented at the Forty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 25–27, 2010. Address correspondence to Dr Schuchert, Heart, Lung and Esophageal Surgery Institute, Shadyside Medical Bldg, Ste 715, 5200 Centre Ave, Pittsburgh, PA 15232; e-mail: [email protected].
© 2011 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2011;91:1681– 8) © 2011 by The Society of Thoracic Surgeons
Patients and Methods Patients Approval for this study was provided by the Institutional Review Board of the University of Pittsburgh, and individual patient consent was waived given the retrospective nature of the analysis. We performed a review of 107 consecutive patients undergoing resection for stage IA NSCLC 1 cm or smaller in size at the University of Pittsburgh from 1999 to 2008. Lobectomy was performed in 32 patients (11 video-assisted thoracoscopic surgery [VATS], 21 open), segmentectomy in 40 (23 VATS, 17 open), and extended wedge resection in 35 patients (27 VATS, 8 open). Patients with multicentric disease at the time of presentation, and patients with preoperative radiation or chemotherapy, were excluded. Patients were identified from the Lung Cancer Database and billing records of the Heart, Lung and Esophageal Surgery Institute as well as the Lung Cancer Registry at the University of Pittsburgh. Patient demographics and tumor characteristics are detailed in Table 1. 0003-4975/$36.00 doi:10.1016/j.athoracsur.2011.01.010
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Oncologic Outcomes After Surgical Resection of Subcentimeter Non-Small Cell Lung Cancer
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Fig 1. Subcentimeter non-small cell lung cancer. (A) A spiculated 8-mm lesion situated in the tip of the superior segment of the left lower lobe was managed with extended wedge resection. (B) A rounded 7-mm nodule within the upper division of the left upper lobe was treated with anatomic segmentectomy.
Preoperative Evaluation All patients underwent careful preoperative staging with CT scan, with or without positron emission tomography (PET) within 6 weeks of surgery as well as pulmonary function testing. Preoperative PET scans were performed in 16 of 35 patients (46%) undergoing wedge resection, 27 of 40 (68%) undergoing segmentectomy, and 15 of 32 (47%) undergoing lobectomy. Indications for the use of PET scanning included assessment of the primary lesion to determine if there was any associated 18Ffluorodeoxyglucose uptake, evaluation of mediastinal lymph nodes (mediastinal staging), and to ascertain whether there were any distant foci of disease (secondary lesions or metastases). Additional diagnostic testing (brain magnetic resonance imaging, bone scan) was performed at the discretion of the individual surgeon, based
on patient symptoms and clinical findings. Mediastinoscopy was not used routinely in the preoperative evaluation of this group of patients.
Operative Technique As a general rule, lobectomy is viewed as the gold standard in the surgical management of NSCLC [2]. Anatomic segmentectomy, however, is emerging as a reasonable alternative to lobectomy in the setting of small (⬍2 cm) tumors that are confined to a discrete bronchopulmonary segment, when amenable to resection with adequate margins that are ideally equal to the tumor size [7]. This approach may be particularly beneficial in elderly patients and patients deemed to be at high risk from the cardiopulmonary standpoint [8, 9]. Wedge resection is viewed as a potentially compromised
Table 1. Patient and Tumor Characteristics Lobectomy (n ⫽ 32)
Segmentectomy (n ⫽ 40)
Wedge (n ⫽ 35)
66.1 45–81 17/15
68.5 54–83 21/19
68.1 50–87 10/25
0.45
14 (44) 12 (38) 8 (25) 7 (22) 4 (13) 10 (31) 9 (28)
20 (50) 16 (40) 9 (23) 5 (13) 7 (18) 5 (13) 6 (15)
14 (40) 11 (31) 10 (29) 4 (11) 5 (14) 12 (34) 5 (14)
0.68 0.74 0.83 0.42 0.83 0.06 0.26
2.52 (92) 17.2 (71)
1.97 (72) 14.7 (65)
1.70 (71) 15.3 (72)
0.03 0.53
24 (68) 3 (9) 8 (23)
0.69 0.26 0.41
Age, years Mean Range Sex, male/female Comorbidities (%) Hypertension Hyperlipidemia Coronary artery disease Diabetes mellitus Peripheral vascular disease Prior cancer history Gastroesophageal reflux PFTs, preoperatively (%) FEV1, L Dlco, mL · min⫺1 · mm Hg⫺1 Histology (%) Adenocarcinoma Squamous cell carcinoma Other Tumor size Mean, cm Range, cm Dlco ⫽ lung diffusion capacity for carbon monoxide;
23 (72) 5 (16) 4 (12) 0.8 0.2–1.0
25 (63) 9 (22) 6 (15.0) 0.8 0.3–1.0
FEV1 ⫽ forced expiratory volume in 1 second;
0.8 0.3–1.0 PFT ⫽ pulmonary function test.
p Value
0.06
0.84
procedure in the setting of NSCLC [5]. Wedge resection was utilized in cases where the clinical diagnosis remained in doubt (benign or deferred frozen section evaluation at the time of surgery), in cases that have undergone prior anatomic lung resection (parenchymal preservation), where metastatic disease from another nonpulmonary primary was suspected, in the setting of bronchoalveolar carcinoma (low metastatic potential), and in cases of severe cardiopulmonary compromise deemed at high risk for lobectomy. A VATS approach was utilized in 61 (57%) of the patients, with thoracotomy performed in 46 patients (43%). Choice of procedure was determined based upon patient and tumor characteristics as well as surgeon preference. Open lung resection was performed by either a muscle-sparing axillary thoracotomy, posterolateral minithoracotomy, or anterior thoracotomy [10]. The VATS approach was performed as described previously [11]. Lymph node sampling is the preferred method of mediastinal lymph node assessment among the authors. There were no cases of formal lymph node dissection in this series. Among lobectomies, all patients underwent mediastinal lymph node sampling (32 of 32, 100%). Lymph node sampling was performed in 23 of 35 patients (66%) undergoing wedge resection, and in 33 of 40 (83%) undergoing segmentectomy. The most common reasons for no lymph node sampling were negative/deferred frozen section result of the primary tumor at the time of surgery (n ⫽ 7; 3 wedges, 4 segments), the possibility of metastatic disease from another site (n ⫽ 5; all wedges), bronchoalveolar carcinoma (n ⫽ 2), and unknown (n ⫽ 6; 3 wedges, 3 segments).
Follow-Up Perioperative data were collected from the hospital chart, anesthesia, and operating room records as well as the electronic medical record for each patient. Major complications were defined to include the following: cardiac (myocardial infarction and cardiac arrest); pulmonary (pneumonia, empyema, bronchopleural fistula, respiratory failure requiring reintubation, and tracheostomy); and other (septicemia, pulmonary embolism, stroke). All patients were followed up postoperatively at 2 weeks and at 4-month to 6-month intervals for the first 2 years, then yearly thereafter with CT scans. Locoregional recurrence was defined as evidence of tumor within the same lobe, the hilum, or the mediastinal lymph nodes. Distant recurrences were defined as evidence of tumor in another lobe, the pleural space, or elsewhere outside the hemithorax. Follow-up data were updated continuously in the Lung Cancer Database of the Heart, Lung and Esophageal Surgery Institute. The endpoints for this analysis were perioperative outcomes, recurrence rates, and disease-free and overall survival. Perioperative mortality was defined as any patient who died within the first 30 days after surgery. Mean follow-up was 45.2 months (range, 0.1 to 151.6 months).
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Statistical Analysis Comparisons of lobectomy, anatomic segmentectomy, and wedge resection cohorts were performed on the basis of clinical, demographic, and pathologic data. Student’s t test was used to compare the distributions of continuous data (age, tumor size, number of lymph nodes removed, operative time, estimated blood loss), and Fisher’s exact test was used to compare the frequencies of categorical measures (sex, histology, stage, and so forth) between groups. All comparisons were two-tailed. One-way analysis of variance was utilized to compare means of continuous data among the three groups. Comparisons of proportions among the three groups were performed utilizing the Fisher-Freeman-Halton test [12]. 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 survival curves were estimated with the Kaplan-Meier method. Significance was assessed with the log rank test.
Results Patient and Tumor Characteristics Patient and tumor characteristics are summarized in Table 1. There were no significant differences in age, sex, preoperative patient comorbidities, histology, or tumor size when comparing the lobectomy, segmentectomy, and wedge resection groups. There was a significant reduction in preoperative forced expiratory volume in 1 second among patients undergoing sublobar resection (segmentectomy, wedge) compared with the lobectomy cohort (Table 1). No significant differences were noted in preoperative lung diffusion capacity for carbon monoxide. Adenocarcinoma was the most commonly encountered histology, comprising two thirds of all cases.
Perioperative Outcomes A VATS approach was more commonly employed in the sublobar resection groups, and an open approach was more frequently utilized during lobectomy (p ⫽ 0.002; Table 2). Sublobar resection techniques were associated with reduced median operative time (lobectomy, 272 minutes; segmentectomy, 115 minutes; wedge, 116 minutes; p ⬍ 0.001) and estimated blood loss (lobectomy, 225 cc; segmentectomy, 100 cc; wedge, 45 cc; p ⬍ 0.001). When stratifying for surgical approach (VATS versus open), however, significant differences remained for operative time, estimated blood loss, and lymph nodes harvested, suggesting that mode of surgical access did not contribute significantly to the differences appreciated in these variables. Fewer lymph nodes were harvested, on average, during wedge and segmentectomy compared with lobectomy (5 nodes, 2 nodes, and 12 nodes, respectively; p ⫽ 0.003). Importantly, the decreased lymph node numbers during sublobar resection in this series do not appear to be the result of either a VATS or open approach (p ⫽ 0.32), but appear to correlate most closely
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Table 2. Perioperative Outcomes
Approach (%) VATS Open Operative time, minutes Estimated blood loss, cc Lymph nodes harvested Length of stay, days Complications (%) Overall Major Pulmonary Mortality, 30-day
Lobectomy (n ⫽ 32)
Segmentectomy (n ⫽ 40)
Wedge (n ⫽ 35)
11 (34) 21 (66) 221 225 12 6
23 (58) 17 (42) 126 100 5 6
27 (77) 8 (23) 116 45 2 4
⬍0.001 ⬍0.001 ⬍0.001 0.027
12 (38) 8 (25) 6 (19) 1 (3)
9 (23) 6 (15) 8 (20) 0 (0)
7 (20) 4 (11) 4 (11) 0 (0)
0.21 0.31 0.58 0.44
p Value 0.002
VATS ⫽ video-assisted thoracic surgery.
with the extent of hilar dissection and the size of the resected specimen. The median number of lymph node stations sampled was 3 in each group. Wedge resection was associated with a shorter length of stay compared with segmentectomy or lobectomy (4 days, 6 days, and 6 days, respectively; p ⫽ 0.027). There was 1 perioperative death in the lobectomy group (3%). No perioperative mortality was encountered in the sublobar resection groups. There was a trend toward a reduction in perioperative morbidity with sublobar resection techniques (Table 2). Major perioperative complications were reduced by more than 50% in the wedge resection group compared with lobectomy, although these differences did not attain statistical significance. The most common minor complication encountered was atrial fibrillation, which occurred in 6 patients (5.6%). There were 10 conversions (9%) from VATS to an open approach in this study. In the wedge resection group, 5 cases were converted to an open approach secondary to inability to palpate or localize the target lesion. The remaining 5 cases (3 segmentectomy, 2 lobectomy) underwent conversion secondary to hemorrhage (n ⫽ 3) or dense adhesions (n ⫽ 2). Importantly, in the lobectomy group, there were 10 patients (29%) who underwent thoracoscopic wedge resection followed by planned open lobectomy during the same procedure once the diagnosis of cancer was confirmed. Over the last several years, our group has adapted the VATS approach
for both anatomic segmentectomy and lobectomy, with more than 95% of cases being accomplished thoracoscopically in the setting of early-stage NSCLC.
Recurrence Patterns and Survival There were 10 recurrences during the follow-up period (9%)—3 locoregional and 7 distant. Mean time to recurrence was 19.3 months (range, 5.2 to 35.8 months). Overall recurrence rates were similar for lobectomy (9%), segmentectomy (10%), and wedge resection (9%) groups (Table 3). Of note, there was no difference noted in the incidence of locoregional recurrence when comparing lobectomy with anatomic segmentectomy (3% versus 3%) or wedge resection (3% versus 3%). No significant difference was noted in recurrence rates when comparing VATS (6 of 61: 2 local, 4 distant) or open approaches (4 of 46: 1 local, 3 distant; p ⫽ 0.99). Among patients with locoregional recurrence, disease developed in the ipsilateral hilum in 2 patients, and in the ipsilateral paratracheal lymph nodes in 1 patient. There were no instances of bronchial stump or staple line recurrences among these patients. Among the 10 patients with recurrence, 5 had PET scans preoperatively and 5 did not. Among those with preoperative PET imaging who went on to have recurrence, the preoperative PET scan did not predict the site of first recurrence in any case (4 distant,1 locoregional). The mean maximum standardized uptake
Table 3. Recurrence and Survival Patterns
No evidence of disease (%) Overall recurrence (%) Locoregional Distant Cancer deaths (%) Percent disease-free survival, 5 years
Lobectomy (n ⫽ 32)
Segmentectomy (n ⫽ 40)
Wedge (n ⫽ 35)
p Value
29 (91) 3 (9) 1 (3) 2 (6) 2 (6) 87
36 (90) 4 (10) 1 (3) 3 (8) 4 (10) 89
32 (91) 3 (9) 1 (3) 2 (6) 3 (9) 89
0.99 0.99 0.99 0.99 0.69 ⬎0.25
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Fig 2. Recurrence-free survival after wedge resection (blue line), anatomic segmentectomy (green line), and lobectomy (red line) in the setting of subcentimeter stage 1A non-small cell lung cancer.
value of the primary tumor among patients with recurrence was only 1.5 (range, 0.9 to 2.5). Deaths due to cancer were found to be similar between groups (Table 3). There was no difference in recurrencefree survival (Fig 2) or overall survival (Fig 3) when comparing lobectomy with anatomic segmentectomy and extended wedge resection. Recurrence-free survival estimates at 5 years were 87% for lobectomy and 89% for both anatomic segmentectomy and extended wedge resection. Angiolymphatic invasion was evident in 9 cases
(8%). Interestingly, this pathologic finding was associated with an increased risk of tumor recurrence (4 of 9, 44%).
Comment Anatomic lobar resection has been established as the procedure of choice in early-stage NSCLC. Several recent reports have demonstrated that sublobar resection (anatomic segmentectomy, in particular) may be associated with equivalent recurrence and survival in this setting. Fig 3. Overall survival after wedge resection (blue line), anatomic segmentectomy (green line), and lobectomy (red line) in the setting of subcentimeter stage 1A non-small cell lung cancer.
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Okada and coworkers [13] compared the results of extended segmentectomy to lobectomy in patients with T1N0 tumors, documenting equivalent 5-year survival of 87% among the segmentectomy patients compared with 88% in the lobectomy group. Fernando and associates [14] reported no difference in survival in those patients undergoing lobar or sublobar resection for tumors less than 2 cm. Bando and colleagues [15] reported a series of 74 patients with T1N0 NSCLC, and noted locoregional recurrence in only 2% of the patients with tumors of 2 cm or less. Schuchert and associates [7] similarly found no difference in morbidity, mortality, locoregional recurrence, or survival, when comparing anatomic segmentectomy with lobectomy for stage I NSCLC. Considering even smaller tumors, Kondo and associates [16] analyzed outcomes in 57 patients with tumors less than 1 cm in diameter, including 23 lobectomies, 13 segmentectomies, and 21 wedge resections. There was no difference in cancer-free survival regardless of the mode of resection, with an overall 5-year survival of 97%. Miller and colleagues [17] reviewed the outcomes of 100 patients (71 lobectomies, 12 segmentectomies, and 13 wedge resections) with subcentimeter lung cancer and reported an 18% overall recurrence rate. In this study, lobectomy was associated with improved recurrence-free and overall survival compared with limited resection. This result appeared to be driven by significantly reduced disease-free (42%) and overall (27%) survival in the wedge resection group. Of note, no significant differences in recurrence-free or overall survival were seen comparing the lobectomy and segmentectomy groups [17]. Other reports examining sublobar resection in the setting of subcentimeter tumors document no difference in local recurrence or survival [18, 19]. In the present analysis, the overall recurrence rate was found to be 9%. Locoregional recurrence was 3%, much lower than that seen with tumors greater than 1 cm in diameter. In addition, we have found that extent of resection (wedge, segment, or lobe) does not appear to have a significant impact on recurrence-free or overall survival rates. In the absence of a meaningful difference in oncologic outcome, the reduced operative time, estimated blood loss, length of stay (in the case of wedge resection), and mortality risk associated with sublobar resection techniques supports the validity of these techniques in the management of small, peripheral tumors. The chosen approach should be tailored to individual patient and tumor characteristics, as well as surgeon experience and judgment. Several factors may be influencing these encouraging results, including the low rate of regional nodal involvement encountered in patients with subcentimeter tumors. We have noted only 3 cases of nodal involvement in such patients over a 10-year span. These findings are similar to the reports of Ohta and coworkers [20] and Sawabata and associates [21], who have documented a markedly decreased risk of nodal involvement in tumors less than 1 cm. Risk of nodal involvement in this setting ranges from 0% to 11% in the reported literature [17, 22, 23]. The risk of nodal involvement or distant metastases may increase in the presence of adverse pathologic variables such as angiolym-
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phatic invasion or pleural invasion [24]. Although the incidence of angiolymphatic invasion was rare in our study (8%), its presence was associated with an increased risk of recurrence (44%), as demonstrated previously in the setting of early-stage NSCLC [25]. The increased incidence of well-differentiated adenocarcinoma and bronchoalveolar carcinoma in this cohort compared with tumors greater than 1 cm may also be contributing to the diminished risk of recurrence seen in these patients. Small (⬍1 cm) ground-glass opacities detected on CT imaging are associated with in-situ and early cancers that are particularly amenable to sublobar resection when confined to a discrete bronchopulmonary segment [26]. Sublobar resection in this setting allows complete excision of the lesion, while preserving parenchyma in patients who might require future resections [27], and can achieve exceptional (⬎90%) 5-year survival [28, 29]. There are several limitations with the current analysis. The retrospective design introduces the possibility of surgical and selection bias. The small sample sizes inherent to the disease process in question (subcentimeter NSCLC) limit the statistical power as well as the ability to perform propensity-matched comparisons. Care should be taken in extrapolating these data to other management strategies, including ablative therapy approaches such as radiofrequency ablation or stereotactic radiosurgery. The data presented here represent a cohort of pathologically confirmed, completely resected subcentimeter tumors. The importance of obtaining an accurate tissue diagnosis, complete excision with adequate tissue margins, and regional nodal staging must be emphasized. Taken together, these data suggest that sublobar resection is safe and effective in the setting of subcentimeter NSCLC. It can be performed with reduced operative time, blood loss, and length of stay. Extent of resection is not associated with a discernable difference in recurrence-free or overall survival in this setting. A VATS approach is currently preferred in the significant majority of cases. The use of anatomic segmentectomy may be particularly useful in cases where a nonpalpable lesion is localized radiographically to a discrete bronchopulmonary segment. In the era of “emerging” image-guided ablation modalities, sublobar resection for small tumors maintains the advantage of complete resection with adequate margins and an opportunity for regional nodal staging, and provides tissue for pharmacogenomic assessment. Prospective studies (ACOSOG Z4032; CALGB 140503) will be necessary to validate the potential benefits of sublobar resection in this setting.
The authors wish to acknowledge the important contribution of Peg Reamer and Judy Forster in clinical trial enrollment. We would also like to recognize Lorraine Ickes of the Thoracic Surgery Tumor Registry for her assistance in database management and analysis. We would also like to thank Kimberly Burke, Lauren Matteo, Patricia Williams, Diane Sabilla, and Maria Haffely for their assistance in organizing and analyzing hospital charts, and providing timely updates regarding patient follow-up.
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16. Kondo D, Yamada K, Kitayama Y, et al. Peripheral lung adenocarcinomas: 10 mm or less in diameter. Ann Thorac Surg 2003;76:350 –5. 17. Miller DL, Rowland CM, Deschamps C, et al. Surgical treatment of nonsmall-cell lung cancer 1 cm or less in diameter. Ann Thorac Surg 2002;73:1545–51. 18. Martin-Ucar AE, Nakas A, Pilling JE, et al. A case-matched study of anatomical segmentectomy versus lobectomy for stage I lung cancer in high-risk patients. Eur J Cardiothorac Surg 2005;27:675–9. 19. Okada M, Koike T, Higashiyama M, et al. Radical sublobar resection for small-sized non-small cell lung cancer: a multicenter study. J Thorac Cardiovasc Surg 2006;132:769 –75. 20. Ohta Y, Oda M, Wu J, et al. Can tumor size be a guide for limited surgical intervention in patients with peripheral non-small cell lung cancer? Assessment from the point of view of nodal micrometastases. J Thorac Cardiovasc Surg 2001;122:900 – 6. 21. Sawabata N, Ohta M, Matsumura A, et al. Optimal distance of malignant negative margin in excision of nonsmall-cell lung cancer: a multicenter, prospective study. Ann Thorac Surg 2004;77:415–20. 22. Kishi K, Homma S, Kurosaki A, et al. Small lung tumors with the size of 1 cm or less in diameter: clinical, radiological, and histopathological characteristics. Lung Cancer 2004;44:43–51. 23. Koike T, Togashi K, Shirato T, et al. Limited resection for noninvasive bronchoalveolar carcinoma diagnosed by intraoperative pathologic examination. Ann Thorac Surg 2009;88: 1106 –11. 24. Suzuki K, Nagai K, Yoshida J, Nishimura M, Nishiwaki Y. Predictors of lymph node and intrapulmonary metastasis in clinical stage IA nonsmall-cell lung cancer. Ann Thorac Surg 2001;72:352– 6. 25. Bodendorf MO, Haas V, Laberke HG, Blumenstock G, Wex P, Graeter T. Prognostic value and therapeutic consequences of vascular invasion in non-small cell lung carcinoma. Lung Cancer 2009;64:71– 8. 26. Moriya Y, Iyoda A, Hiroshima K, et al. Clinicopathological analysis of clinical N0 peripheral lung cancers with a diameter of 1 cm or less. Thorac Cardiovasc Surg 2004;52: 196 –9. 27. Yoshida J, Nagai K, Yokose T, et al. Limited resection trial for pulmonary ground-glass opacity nodules: fifty case experiences. J Thorac Cardiovasc Surg 2005;129:991– 6. 28. Roberts PF, Stranicka M, Lara PN, et al. Resection of multifocal non-small cell lung cancer when the bronchoalveolar subtype is involved. J Thorac Cardiovasc Surg 2003;126:1597– 602. 29. Kodama K, Higashiyama M, Takami K, et al. Treatment strategy for patients with small peripheral lung lesion(s): intermediate-term results of prospective study. Eur J Cardiothorac Surg 2008;34:1068 –74.
DISCUSSION DR SCOTT J. SWANSON (Boston, MA): I have two questions. One, what percentage of patients had nodal disease? Second, I assume these data would be supportive, and I assume you’re interested in the CALGB 140503 study, so I think we all have to keep that in mind when we find these little lesions, that we should get them on that trial. It’s an important trial and it’s always teetering on the brink of marginal accrual. If everyone can adopt that, it would be helpful. But what about the nodal disease? DR SCHUCHERT: In our analysis of subcentimeter patients, we found only 3 patients who had nodal disease. There was one N1 and two N2 tumors.
DR SWANSON: And which subgroups were those? DR SCHUCHERT: They were all in the segmentectomy subgroup. There was no N1 or N2 nodal disease in lobectomy, even with the enhanced nodal harvest.
DR ANDREW J. E. SEELY (Ottawa, Ontario, Canada): Thank you very much for that nice presentation. My question is about margins. Did you assess what the margins were, the closest margins in the wedge resection, and what do you consider to be an adequate margin?
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DR SCHUCHERT: In this group, margin distance from tumor was not associated with the risk for recurrence. The average margin size was 2.6 cm in all of the recurrences. For sublobar resection in general, especially for larger tumors, we found a tumor size/margin ratio of 1 to be useful, so that you want your margin to approximate the tumor size to help minimize the risk of recurrence, but it didn’t seem to apply in these subcentimeter cases. DR JIRO OKAMI (Osaka, Japan): Thank you for your excellent presentation. I may have missed your slide, but for what reasons did you select sublobar resections? DR SCHUCHERT: That’s an excellent question. Sublobar resection was based on surgical judgment of an individual case. In reading all of the operative reports, one of the most common reasons was due to concerns regarding preoperative pulmonary function. That was commonly discussed in the operative reports. I don’t have a specific percentage to give you or the specific rationale behind it, but I think patients were more likely to get a wedge if they had impaired pulmonary function. Now, having said that, we have a very strong interest in anatomic segmentectomy as primary therapy for non-small cell lung cancer even in good-risk patients, especially for small tumors like this. So I think it comes down to surgeon judgment and experience. DR MARK I. BLOCK (Hollywood, FL): I really enjoyed the presentation. I have two questions. First, I noticed that there seemed to be a greater proportion of the segmentectomies done by VATS than lobectomy, 60% versus 35%, which is a bit peculiar from my thinking because I think a segmentectomy by VATS is much harder than a lobectomy by VATS. So certainly early in your experience, why would you see more segmentectomies done in that way than lobectomies? The second question is relative to the point of Dr Swanson about the trial. Given your experience and your findings, do you now have equipoise for that trial? Would you be willing to randomize a patient to lobectomy? DR SCHUCHERT: Thank you very much. I think some of the differences in distribution of VATS versus open has to do with the expertise of the specific surgeons involved in this study. Doctor Landreneau being extremely experienced with VATS techniques has particular interest in segmentectomy, so there is a very high proportion of VATS segmentectomies. Also, I would say there has been an evolution at our center toward using VATS increasingly, even in lobectomies, over the last 4 years, such that more than 75% of our resections for stage I lung cancer are now performed by VATS, whether lobectomy or segmentectomy. I do want to underscore the importance of this study, the CALGB study, which compares sublobar resection, either segmentectomy or extended wedge, versus lobectomy for tumors less than 2 cm. I think this question really does need to be addressed with a prospective study so we know how best to approach patients just like this.
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DR STEPHEN R. HAZELRIGG (Springfield, IL): I have two questions. One, I assume the majority of these were peripheral lesions, which I think most of us would feel comfortable with, but the deeper, smaller lesions that result in closer margins create a little bit less comfort. Secondly, with these data in hand, would you personally feel comfortable now saying that a wedge or a segmentectomy is perfectly adequate treatment in your patients you’re going to see next week versus a lobectomy if they have a peripheral lesion under 1 cm? DR SCHUCHERT: That’s an excellent point. I think the majority of these tumors are smaller peripheral tumors, though I don’t have the specific numbers in our dataset to give you a percentage, but I would estimate that there would be probably a higher percent of more central tumors that went on to lobectomy. I know that if you have a middle third tumor that is lying in a discrete bronchopulmonary segment, we would probably perform a segmentectomy as opposed to a deep wedge in those cases. So we individualize the decision based on tumor size and location. With our experience in sublobar resection, I would feel comfortable treating patients primarily with sublobar resection, especially with small subcentimeter disease, based on our experience in segmentectomy and now this analysis of our wedge data. DR SEBASTIAN DEFRANCHI (Buenos Aires, Argentina): Congratulations on a very nice presentation. There could probably be some concerns about doing a wedge resection for lung cancer because it’s not an anatomical resection. Daniel Miller published a paper some years ago with the Mayo Clinic experience treating lesions less than 1 cm in diameter with lobectomy, segmentectomy, or wedge resection. He found a lower 5-year survival rate when you do nonanatomic resections compared with anatomic resections. You did not find the same; do you have any explanation for this? Did you have a significant number of patients with BAC who have a better 5-year survival rate? DR SCHUCHERT: I think that’s a great point. One of the salient features of his study was the incidence of nodal disease, which was 7% in that analysis. In our experience, it’s less than 3%. So it’s hard to know if resecting much more territory is going to have a significant impact on survival. We do know from this analysis that the significant majority of recurrences were distant, and so, again, I don’t know if resecting more lung or taking out more lymph nodes will be saving these patients who have systemic disease. DR SWANSON: How many patients had mediastinoscopy? DR SCHUCHERT: A very low number, probably less than 10%. I don’t have an exact number for you, but it was an extremely small number.
Background. The recent initiation of screening protocols and greater utilization of computed tomography has led to an increasing proportion of non-small cell lung cancer (NSCLC) patients presenting with subcentimeter stage IA tumors. The aim of this study was to compare the oncologic outcomes of lobectomy, segmentectomy, and wedge resection in patients with NSCLC tumors 1 cm or less in diameter. Methods. Data were extracted from medical records of patients undergoing surgical resection for stage IA NSCLC and a pathologically confirmed tumor diameter measuring 1 cm or less. Primary oncologic outcomes were disease recurrence and disease-free survival. Statistical comparisons were performed using Fisher’s exact test and unpaired t test. Kaplan-Meier curves were compared using the log rank test. Significance was defined as a two-tailed p value less than 0.05. Results. A total of 107 patients underwent complete (R0) surgical resection for stage IA NSCLC 1 cm or less in
diameter (lobectomy, 32; segmentectomy, 40; wedge, 35). Age, sex distribution, tumor size, and histology were similar between groups. There was 1 perioperative mortality in the lobectomy group (3%). At a mean follow-up of 42.5 months, overall disease recurrence was equivalent, occurring in 3 lobectomy patients (9%), 4 segmentectomy patients (10%), and 3 wedge resection patients (9%; p ⴝ 0.99). Estimated 5-year disease-free survival was comparable among cohorts (lobectomy, 87%; segmentectomy, 89%; wedge, 89%; p >0.402). Conclusions. Sublobar resections are associated with oncologic outcomes that are comparable to those of lobectomy for subcentimeter stage IA NSCLC, suggesting that they may be appropriate surgical interventions in this patient cohort. The validity of these observations needs to be assessed in a prospective setting.
A
less in size. Primary outcome variables include tumor recurrence and patient survival. Secondary outcome variables include hospital course, morbidity, and mortality.
natomic lung resection remains the mainstay of therapy in the setting of early-stage non-small cell lung cancer (NSCLC) [1]. Lobectomy is the accepted standard, and has been shown to minimize the recurrence risk and optimize the chances of long-term survival [2]. With technical advances in thoracic imaging and the introduction of computed tomography (CT) screening protocols in patient groups at high risk for lung cancer, smaller and smaller tumors are being identified (Fig 1) [3, 4]. This has led many surgeons to question the necessity of lobectomy in all cases. Emerging data from Japan, Europe, and the United States have suggested that sublobar resection techniques (segmentectomy, wedge resection) can achieve outcomes similar to those of lobectomy for smaller, peripheral tumors [5, 6]. In the current study, we compare the outcomes of 107 patients undergoing lobectomy, anatomic segmentectomy, or extended wedge resection for NSCLC of 1 cm or
Accepted for publication Jan 4, 2011. Presented at the Forty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 25–27, 2010. Address correspondence to Dr Schuchert, Heart, Lung and Esophageal Surgery Institute, Shadyside Medical Bldg, Ste 715, 5200 Centre Ave, Pittsburgh, PA 15232; e-mail: [email protected].
© 2011 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2011;91:1681– 8) © 2011 by The Society of Thoracic Surgeons
Patients and Methods Patients Approval for this study was provided by the Institutional Review Board of the University of Pittsburgh, and individual patient consent was waived given the retrospective nature of the analysis. We performed a review of 107 consecutive patients undergoing resection for stage IA NSCLC 1 cm or smaller in size at the University of Pittsburgh from 1999 to 2008. Lobectomy was performed in 32 patients (11 video-assisted thoracoscopic surgery [VATS], 21 open), segmentectomy in 40 (23 VATS, 17 open), and extended wedge resection in 35 patients (27 VATS, 8 open). Patients with multicentric disease at the time of presentation, and patients with preoperative radiation or chemotherapy, were excluded. Patients were identified from the Lung Cancer Database and billing records of the Heart, Lung and Esophageal Surgery Institute as well as the Lung Cancer Registry at the University of Pittsburgh. Patient demographics and tumor characteristics are detailed in Table 1. 0003-4975/$36.00 doi:10.1016/j.athoracsur.2011.01.010
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Oncologic Outcomes After Surgical Resection of Subcentimeter Non-Small Cell Lung Cancer
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Fig 1. Subcentimeter non-small cell lung cancer. (A) A spiculated 8-mm lesion situated in the tip of the superior segment of the left lower lobe was managed with extended wedge resection. (B) A rounded 7-mm nodule within the upper division of the left upper lobe was treated with anatomic segmentectomy.
Preoperative Evaluation All patients underwent careful preoperative staging with CT scan, with or without positron emission tomography (PET) within 6 weeks of surgery as well as pulmonary function testing. Preoperative PET scans were performed in 16 of 35 patients (46%) undergoing wedge resection, 27 of 40 (68%) undergoing segmentectomy, and 15 of 32 (47%) undergoing lobectomy. Indications for the use of PET scanning included assessment of the primary lesion to determine if there was any associated 18Ffluorodeoxyglucose uptake, evaluation of mediastinal lymph nodes (mediastinal staging), and to ascertain whether there were any distant foci of disease (secondary lesions or metastases). Additional diagnostic testing (brain magnetic resonance imaging, bone scan) was performed at the discretion of the individual surgeon, based
on patient symptoms and clinical findings. Mediastinoscopy was not used routinely in the preoperative evaluation of this group of patients.
Operative Technique As a general rule, lobectomy is viewed as the gold standard in the surgical management of NSCLC [2]. Anatomic segmentectomy, however, is emerging as a reasonable alternative to lobectomy in the setting of small (⬍2 cm) tumors that are confined to a discrete bronchopulmonary segment, when amenable to resection with adequate margins that are ideally equal to the tumor size [7]. This approach may be particularly beneficial in elderly patients and patients deemed to be at high risk from the cardiopulmonary standpoint [8, 9]. Wedge resection is viewed as a potentially compromised
Table 1. Patient and Tumor Characteristics Lobectomy (n ⫽ 32)
Segmentectomy (n ⫽ 40)
Wedge (n ⫽ 35)
66.1 45–81 17/15
68.5 54–83 21/19
68.1 50–87 10/25
0.45
14 (44) 12 (38) 8 (25) 7 (22) 4 (13) 10 (31) 9 (28)
20 (50) 16 (40) 9 (23) 5 (13) 7 (18) 5 (13) 6 (15)
14 (40) 11 (31) 10 (29) 4 (11) 5 (14) 12 (34) 5 (14)
0.68 0.74 0.83 0.42 0.83 0.06 0.26
2.52 (92) 17.2 (71)
1.97 (72) 14.7 (65)
1.70 (71) 15.3 (72)
0.03 0.53
24 (68) 3 (9) 8 (23)
0.69 0.26 0.41
Age, years Mean Range Sex, male/female Comorbidities (%) Hypertension Hyperlipidemia Coronary artery disease Diabetes mellitus Peripheral vascular disease Prior cancer history Gastroesophageal reflux PFTs, preoperatively (%) FEV1, L Dlco, mL · min⫺1 · mm Hg⫺1 Histology (%) Adenocarcinoma Squamous cell carcinoma Other Tumor size Mean, cm Range, cm Dlco ⫽ lung diffusion capacity for carbon monoxide;
23 (72) 5 (16) 4 (12) 0.8 0.2–1.0
25 (63) 9 (22) 6 (15.0) 0.8 0.3–1.0
FEV1 ⫽ forced expiratory volume in 1 second;
0.8 0.3–1.0 PFT ⫽ pulmonary function test.
p Value
0.06
0.84
procedure in the setting of NSCLC [5]. Wedge resection was utilized in cases where the clinical diagnosis remained in doubt (benign or deferred frozen section evaluation at the time of surgery), in cases that have undergone prior anatomic lung resection (parenchymal preservation), where metastatic disease from another nonpulmonary primary was suspected, in the setting of bronchoalveolar carcinoma (low metastatic potential), and in cases of severe cardiopulmonary compromise deemed at high risk for lobectomy. A VATS approach was utilized in 61 (57%) of the patients, with thoracotomy performed in 46 patients (43%). Choice of procedure was determined based upon patient and tumor characteristics as well as surgeon preference. Open lung resection was performed by either a muscle-sparing axillary thoracotomy, posterolateral minithoracotomy, or anterior thoracotomy [10]. The VATS approach was performed as described previously [11]. Lymph node sampling is the preferred method of mediastinal lymph node assessment among the authors. There were no cases of formal lymph node dissection in this series. Among lobectomies, all patients underwent mediastinal lymph node sampling (32 of 32, 100%). Lymph node sampling was performed in 23 of 35 patients (66%) undergoing wedge resection, and in 33 of 40 (83%) undergoing segmentectomy. The most common reasons for no lymph node sampling were negative/deferred frozen section result of the primary tumor at the time of surgery (n ⫽ 7; 3 wedges, 4 segments), the possibility of metastatic disease from another site (n ⫽ 5; all wedges), bronchoalveolar carcinoma (n ⫽ 2), and unknown (n ⫽ 6; 3 wedges, 3 segments).
Follow-Up Perioperative data were collected from the hospital chart, anesthesia, and operating room records as well as the electronic medical record for each patient. Major complications were defined to include the following: cardiac (myocardial infarction and cardiac arrest); pulmonary (pneumonia, empyema, bronchopleural fistula, respiratory failure requiring reintubation, and tracheostomy); and other (septicemia, pulmonary embolism, stroke). All patients were followed up postoperatively at 2 weeks and at 4-month to 6-month intervals for the first 2 years, then yearly thereafter with CT scans. Locoregional recurrence was defined as evidence of tumor within the same lobe, the hilum, or the mediastinal lymph nodes. Distant recurrences were defined as evidence of tumor in another lobe, the pleural space, or elsewhere outside the hemithorax. Follow-up data were updated continuously in the Lung Cancer Database of the Heart, Lung and Esophageal Surgery Institute. The endpoints for this analysis were perioperative outcomes, recurrence rates, and disease-free and overall survival. Perioperative mortality was defined as any patient who died within the first 30 days after surgery. Mean follow-up was 45.2 months (range, 0.1 to 151.6 months).
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Statistical Analysis Comparisons of lobectomy, anatomic segmentectomy, and wedge resection cohorts were performed on the basis of clinical, demographic, and pathologic data. Student’s t test was used to compare the distributions of continuous data (age, tumor size, number of lymph nodes removed, operative time, estimated blood loss), and Fisher’s exact test was used to compare the frequencies of categorical measures (sex, histology, stage, and so forth) between groups. All comparisons were two-tailed. One-way analysis of variance was utilized to compare means of continuous data among the three groups. Comparisons of proportions among the three groups were performed utilizing the Fisher-Freeman-Halton test [12]. 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 survival curves were estimated with the Kaplan-Meier method. Significance was assessed with the log rank test.
Results Patient and Tumor Characteristics Patient and tumor characteristics are summarized in Table 1. There were no significant differences in age, sex, preoperative patient comorbidities, histology, or tumor size when comparing the lobectomy, segmentectomy, and wedge resection groups. There was a significant reduction in preoperative forced expiratory volume in 1 second among patients undergoing sublobar resection (segmentectomy, wedge) compared with the lobectomy cohort (Table 1). No significant differences were noted in preoperative lung diffusion capacity for carbon monoxide. Adenocarcinoma was the most commonly encountered histology, comprising two thirds of all cases.
Perioperative Outcomes A VATS approach was more commonly employed in the sublobar resection groups, and an open approach was more frequently utilized during lobectomy (p ⫽ 0.002; Table 2). Sublobar resection techniques were associated with reduced median operative time (lobectomy, 272 minutes; segmentectomy, 115 minutes; wedge, 116 minutes; p ⬍ 0.001) and estimated blood loss (lobectomy, 225 cc; segmentectomy, 100 cc; wedge, 45 cc; p ⬍ 0.001). When stratifying for surgical approach (VATS versus open), however, significant differences remained for operative time, estimated blood loss, and lymph nodes harvested, suggesting that mode of surgical access did not contribute significantly to the differences appreciated in these variables. Fewer lymph nodes were harvested, on average, during wedge and segmentectomy compared with lobectomy (5 nodes, 2 nodes, and 12 nodes, respectively; p ⫽ 0.003). Importantly, the decreased lymph node numbers during sublobar resection in this series do not appear to be the result of either a VATS or open approach (p ⫽ 0.32), but appear to correlate most closely
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Table 2. Perioperative Outcomes
Approach (%) VATS Open Operative time, minutes Estimated blood loss, cc Lymph nodes harvested Length of stay, days Complications (%) Overall Major Pulmonary Mortality, 30-day
Lobectomy (n ⫽ 32)
Segmentectomy (n ⫽ 40)
Wedge (n ⫽ 35)
11 (34) 21 (66) 221 225 12 6
23 (58) 17 (42) 126 100 5 6
27 (77) 8 (23) 116 45 2 4
⬍0.001 ⬍0.001 ⬍0.001 0.027
12 (38) 8 (25) 6 (19) 1 (3)
9 (23) 6 (15) 8 (20) 0 (0)
7 (20) 4 (11) 4 (11) 0 (0)
0.21 0.31 0.58 0.44
p Value 0.002
VATS ⫽ video-assisted thoracic surgery.
with the extent of hilar dissection and the size of the resected specimen. The median number of lymph node stations sampled was 3 in each group. Wedge resection was associated with a shorter length of stay compared with segmentectomy or lobectomy (4 days, 6 days, and 6 days, respectively; p ⫽ 0.027). There was 1 perioperative death in the lobectomy group (3%). No perioperative mortality was encountered in the sublobar resection groups. There was a trend toward a reduction in perioperative morbidity with sublobar resection techniques (Table 2). Major perioperative complications were reduced by more than 50% in the wedge resection group compared with lobectomy, although these differences did not attain statistical significance. The most common minor complication encountered was atrial fibrillation, which occurred in 6 patients (5.6%). There were 10 conversions (9%) from VATS to an open approach in this study. In the wedge resection group, 5 cases were converted to an open approach secondary to inability to palpate or localize the target lesion. The remaining 5 cases (3 segmentectomy, 2 lobectomy) underwent conversion secondary to hemorrhage (n ⫽ 3) or dense adhesions (n ⫽ 2). Importantly, in the lobectomy group, there were 10 patients (29%) who underwent thoracoscopic wedge resection followed by planned open lobectomy during the same procedure once the diagnosis of cancer was confirmed. Over the last several years, our group has adapted the VATS approach
for both anatomic segmentectomy and lobectomy, with more than 95% of cases being accomplished thoracoscopically in the setting of early-stage NSCLC.
Recurrence Patterns and Survival There were 10 recurrences during the follow-up period (9%)—3 locoregional and 7 distant. Mean time to recurrence was 19.3 months (range, 5.2 to 35.8 months). Overall recurrence rates were similar for lobectomy (9%), segmentectomy (10%), and wedge resection (9%) groups (Table 3). Of note, there was no difference noted in the incidence of locoregional recurrence when comparing lobectomy with anatomic segmentectomy (3% versus 3%) or wedge resection (3% versus 3%). No significant difference was noted in recurrence rates when comparing VATS (6 of 61: 2 local, 4 distant) or open approaches (4 of 46: 1 local, 3 distant; p ⫽ 0.99). Among patients with locoregional recurrence, disease developed in the ipsilateral hilum in 2 patients, and in the ipsilateral paratracheal lymph nodes in 1 patient. There were no instances of bronchial stump or staple line recurrences among these patients. Among the 10 patients with recurrence, 5 had PET scans preoperatively and 5 did not. Among those with preoperative PET imaging who went on to have recurrence, the preoperative PET scan did not predict the site of first recurrence in any case (4 distant,1 locoregional). The mean maximum standardized uptake
Table 3. Recurrence and Survival Patterns
No evidence of disease (%) Overall recurrence (%) Locoregional Distant Cancer deaths (%) Percent disease-free survival, 5 years
Lobectomy (n ⫽ 32)
Segmentectomy (n ⫽ 40)
Wedge (n ⫽ 35)
p Value
29 (91) 3 (9) 1 (3) 2 (6) 2 (6) 87
36 (90) 4 (10) 1 (3) 3 (8) 4 (10) 89
32 (91) 3 (9) 1 (3) 2 (6) 3 (9) 89
0.99 0.99 0.99 0.99 0.69 ⬎0.25
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Fig 2. Recurrence-free survival after wedge resection (blue line), anatomic segmentectomy (green line), and lobectomy (red line) in the setting of subcentimeter stage 1A non-small cell lung cancer.
value of the primary tumor among patients with recurrence was only 1.5 (range, 0.9 to 2.5). Deaths due to cancer were found to be similar between groups (Table 3). There was no difference in recurrencefree survival (Fig 2) or overall survival (Fig 3) when comparing lobectomy with anatomic segmentectomy and extended wedge resection. Recurrence-free survival estimates at 5 years were 87% for lobectomy and 89% for both anatomic segmentectomy and extended wedge resection. Angiolymphatic invasion was evident in 9 cases
(8%). Interestingly, this pathologic finding was associated with an increased risk of tumor recurrence (4 of 9, 44%).
Comment Anatomic lobar resection has been established as the procedure of choice in early-stage NSCLC. Several recent reports have demonstrated that sublobar resection (anatomic segmentectomy, in particular) may be associated with equivalent recurrence and survival in this setting. Fig 3. Overall survival after wedge resection (blue line), anatomic segmentectomy (green line), and lobectomy (red line) in the setting of subcentimeter stage 1A non-small cell lung cancer.
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Okada and coworkers [13] compared the results of extended segmentectomy to lobectomy in patients with T1N0 tumors, documenting equivalent 5-year survival of 87% among the segmentectomy patients compared with 88% in the lobectomy group. Fernando and associates [14] reported no difference in survival in those patients undergoing lobar or sublobar resection for tumors less than 2 cm. Bando and colleagues [15] reported a series of 74 patients with T1N0 NSCLC, and noted locoregional recurrence in only 2% of the patients with tumors of 2 cm or less. Schuchert and associates [7] similarly found no difference in morbidity, mortality, locoregional recurrence, or survival, when comparing anatomic segmentectomy with lobectomy for stage I NSCLC. Considering even smaller tumors, Kondo and associates [16] analyzed outcomes in 57 patients with tumors less than 1 cm in diameter, including 23 lobectomies, 13 segmentectomies, and 21 wedge resections. There was no difference in cancer-free survival regardless of the mode of resection, with an overall 5-year survival of 97%. Miller and colleagues [17] reviewed the outcomes of 100 patients (71 lobectomies, 12 segmentectomies, and 13 wedge resections) with subcentimeter lung cancer and reported an 18% overall recurrence rate. In this study, lobectomy was associated with improved recurrence-free and overall survival compared with limited resection. This result appeared to be driven by significantly reduced disease-free (42%) and overall (27%) survival in the wedge resection group. Of note, no significant differences in recurrence-free or overall survival were seen comparing the lobectomy and segmentectomy groups [17]. Other reports examining sublobar resection in the setting of subcentimeter tumors document no difference in local recurrence or survival [18, 19]. In the present analysis, the overall recurrence rate was found to be 9%. Locoregional recurrence was 3%, much lower than that seen with tumors greater than 1 cm in diameter. In addition, we have found that extent of resection (wedge, segment, or lobe) does not appear to have a significant impact on recurrence-free or overall survival rates. In the absence of a meaningful difference in oncologic outcome, the reduced operative time, estimated blood loss, length of stay (in the case of wedge resection), and mortality risk associated with sublobar resection techniques supports the validity of these techniques in the management of small, peripheral tumors. The chosen approach should be tailored to individual patient and tumor characteristics, as well as surgeon experience and judgment. Several factors may be influencing these encouraging results, including the low rate of regional nodal involvement encountered in patients with subcentimeter tumors. We have noted only 3 cases of nodal involvement in such patients over a 10-year span. These findings are similar to the reports of Ohta and coworkers [20] and Sawabata and associates [21], who have documented a markedly decreased risk of nodal involvement in tumors less than 1 cm. Risk of nodal involvement in this setting ranges from 0% to 11% in the reported literature [17, 22, 23]. The risk of nodal involvement or distant metastases may increase in the presence of adverse pathologic variables such as angiolym-
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phatic invasion or pleural invasion [24]. Although the incidence of angiolymphatic invasion was rare in our study (8%), its presence was associated with an increased risk of recurrence (44%), as demonstrated previously in the setting of early-stage NSCLC [25]. The increased incidence of well-differentiated adenocarcinoma and bronchoalveolar carcinoma in this cohort compared with tumors greater than 1 cm may also be contributing to the diminished risk of recurrence seen in these patients. Small (⬍1 cm) ground-glass opacities detected on CT imaging are associated with in-situ and early cancers that are particularly amenable to sublobar resection when confined to a discrete bronchopulmonary segment [26]. Sublobar resection in this setting allows complete excision of the lesion, while preserving parenchyma in patients who might require future resections [27], and can achieve exceptional (⬎90%) 5-year survival [28, 29]. There are several limitations with the current analysis. The retrospective design introduces the possibility of surgical and selection bias. The small sample sizes inherent to the disease process in question (subcentimeter NSCLC) limit the statistical power as well as the ability to perform propensity-matched comparisons. Care should be taken in extrapolating these data to other management strategies, including ablative therapy approaches such as radiofrequency ablation or stereotactic radiosurgery. The data presented here represent a cohort of pathologically confirmed, completely resected subcentimeter tumors. The importance of obtaining an accurate tissue diagnosis, complete excision with adequate tissue margins, and regional nodal staging must be emphasized. Taken together, these data suggest that sublobar resection is safe and effective in the setting of subcentimeter NSCLC. It can be performed with reduced operative time, blood loss, and length of stay. Extent of resection is not associated with a discernable difference in recurrence-free or overall survival in this setting. A VATS approach is currently preferred in the significant majority of cases. The use of anatomic segmentectomy may be particularly useful in cases where a nonpalpable lesion is localized radiographically to a discrete bronchopulmonary segment. In the era of “emerging” image-guided ablation modalities, sublobar resection for small tumors maintains the advantage of complete resection with adequate margins and an opportunity for regional nodal staging, and provides tissue for pharmacogenomic assessment. Prospective studies (ACOSOG Z4032; CALGB 140503) will be necessary to validate the potential benefits of sublobar resection in this setting.
The authors wish to acknowledge the important contribution of Peg Reamer and Judy Forster in clinical trial enrollment. We would also like to recognize Lorraine Ickes of the Thoracic Surgery Tumor Registry for her assistance in database management and analysis. We would also like to thank Kimberly Burke, Lauren Matteo, Patricia Williams, Diane Sabilla, and Maria Haffely for their assistance in organizing and analyzing hospital charts, and providing timely updates regarding patient follow-up.
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16. Kondo D, Yamada K, Kitayama Y, et al. Peripheral lung adenocarcinomas: 10 mm or less in diameter. Ann Thorac Surg 2003;76:350 –5. 17. Miller DL, Rowland CM, Deschamps C, et al. Surgical treatment of nonsmall-cell lung cancer 1 cm or less in diameter. Ann Thorac Surg 2002;73:1545–51. 18. Martin-Ucar AE, Nakas A, Pilling JE, et al. A case-matched study of anatomical segmentectomy versus lobectomy for stage I lung cancer in high-risk patients. Eur J Cardiothorac Surg 2005;27:675–9. 19. Okada M, Koike T, Higashiyama M, et al. Radical sublobar resection for small-sized non-small cell lung cancer: a multicenter study. J Thorac Cardiovasc Surg 2006;132:769 –75. 20. Ohta Y, Oda M, Wu J, et al. Can tumor size be a guide for limited surgical intervention in patients with peripheral non-small cell lung cancer? Assessment from the point of view of nodal micrometastases. J Thorac Cardiovasc Surg 2001;122:900 – 6. 21. Sawabata N, Ohta M, Matsumura A, et al. Optimal distance of malignant negative margin in excision of nonsmall-cell lung cancer: a multicenter, prospective study. Ann Thorac Surg 2004;77:415–20. 22. Kishi K, Homma S, Kurosaki A, et al. Small lung tumors with the size of 1 cm or less in diameter: clinical, radiological, and histopathological characteristics. Lung Cancer 2004;44:43–51. 23. Koike T, Togashi K, Shirato T, et al. Limited resection for noninvasive bronchoalveolar carcinoma diagnosed by intraoperative pathologic examination. Ann Thorac Surg 2009;88: 1106 –11. 24. Suzuki K, Nagai K, Yoshida J, Nishimura M, Nishiwaki Y. Predictors of lymph node and intrapulmonary metastasis in clinical stage IA nonsmall-cell lung cancer. Ann Thorac Surg 2001;72:352– 6. 25. Bodendorf MO, Haas V, Laberke HG, Blumenstock G, Wex P, Graeter T. Prognostic value and therapeutic consequences of vascular invasion in non-small cell lung carcinoma. Lung Cancer 2009;64:71– 8. 26. Moriya Y, Iyoda A, Hiroshima K, et al. Clinicopathological analysis of clinical N0 peripheral lung cancers with a diameter of 1 cm or less. Thorac Cardiovasc Surg 2004;52: 196 –9. 27. Yoshida J, Nagai K, Yokose T, et al. Limited resection trial for pulmonary ground-glass opacity nodules: fifty case experiences. J Thorac Cardiovasc Surg 2005;129:991– 6. 28. Roberts PF, Stranicka M, Lara PN, et al. Resection of multifocal non-small cell lung cancer when the bronchoalveolar subtype is involved. J Thorac Cardiovasc Surg 2003;126:1597– 602. 29. Kodama K, Higashiyama M, Takami K, et al. Treatment strategy for patients with small peripheral lung lesion(s): intermediate-term results of prospective study. Eur J Cardiothorac Surg 2008;34:1068 –74.
DISCUSSION DR SCOTT J. SWANSON (Boston, MA): I have two questions. One, what percentage of patients had nodal disease? Second, I assume these data would be supportive, and I assume you’re interested in the CALGB 140503 study, so I think we all have to keep that in mind when we find these little lesions, that we should get them on that trial. It’s an important trial and it’s always teetering on the brink of marginal accrual. If everyone can adopt that, it would be helpful. But what about the nodal disease? DR SCHUCHERT: In our analysis of subcentimeter patients, we found only 3 patients who had nodal disease. There was one N1 and two N2 tumors.
DR SWANSON: And which subgroups were those? DR SCHUCHERT: They were all in the segmentectomy subgroup. There was no N1 or N2 nodal disease in lobectomy, even with the enhanced nodal harvest.
DR ANDREW J. E. SEELY (Ottawa, Ontario, Canada): Thank you very much for that nice presentation. My question is about margins. Did you assess what the margins were, the closest margins in the wedge resection, and what do you consider to be an adequate margin?
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DR SCHUCHERT: In this group, margin distance from tumor was not associated with the risk for recurrence. The average margin size was 2.6 cm in all of the recurrences. For sublobar resection in general, especially for larger tumors, we found a tumor size/margin ratio of 1 to be useful, so that you want your margin to approximate the tumor size to help minimize the risk of recurrence, but it didn’t seem to apply in these subcentimeter cases. DR JIRO OKAMI (Osaka, Japan): Thank you for your excellent presentation. I may have missed your slide, but for what reasons did you select sublobar resections? DR SCHUCHERT: That’s an excellent question. Sublobar resection was based on surgical judgment of an individual case. In reading all of the operative reports, one of the most common reasons was due to concerns regarding preoperative pulmonary function. That was commonly discussed in the operative reports. I don’t have a specific percentage to give you or the specific rationale behind it, but I think patients were more likely to get a wedge if they had impaired pulmonary function. Now, having said that, we have a very strong interest in anatomic segmentectomy as primary therapy for non-small cell lung cancer even in good-risk patients, especially for small tumors like this. So I think it comes down to surgeon judgment and experience. DR MARK I. BLOCK (Hollywood, FL): I really enjoyed the presentation. I have two questions. First, I noticed that there seemed to be a greater proportion of the segmentectomies done by VATS than lobectomy, 60% versus 35%, which is a bit peculiar from my thinking because I think a segmentectomy by VATS is much harder than a lobectomy by VATS. So certainly early in your experience, why would you see more segmentectomies done in that way than lobectomies? The second question is relative to the point of Dr Swanson about the trial. Given your experience and your findings, do you now have equipoise for that trial? Would you be willing to randomize a patient to lobectomy? DR SCHUCHERT: Thank you very much. I think some of the differences in distribution of VATS versus open has to do with the expertise of the specific surgeons involved in this study. Doctor Landreneau being extremely experienced with VATS techniques has particular interest in segmentectomy, so there is a very high proportion of VATS segmentectomies. Also, I would say there has been an evolution at our center toward using VATS increasingly, even in lobectomies, over the last 4 years, such that more than 75% of our resections for stage I lung cancer are now performed by VATS, whether lobectomy or segmentectomy. I do want to underscore the importance of this study, the CALGB study, which compares sublobar resection, either segmentectomy or extended wedge, versus lobectomy for tumors less than 2 cm. I think this question really does need to be addressed with a prospective study so we know how best to approach patients just like this.
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DR STEPHEN R. HAZELRIGG (Springfield, IL): I have two questions. One, I assume the majority of these were peripheral lesions, which I think most of us would feel comfortable with, but the deeper, smaller lesions that result in closer margins create a little bit less comfort. Secondly, with these data in hand, would you personally feel comfortable now saying that a wedge or a segmentectomy is perfectly adequate treatment in your patients you’re going to see next week versus a lobectomy if they have a peripheral lesion under 1 cm? DR SCHUCHERT: That’s an excellent point. I think the majority of these tumors are smaller peripheral tumors, though I don’t have the specific numbers in our dataset to give you a percentage, but I would estimate that there would be probably a higher percent of more central tumors that went on to lobectomy. I know that if you have a middle third tumor that is lying in a discrete bronchopulmonary segment, we would probably perform a segmentectomy as opposed to a deep wedge in those cases. So we individualize the decision based on tumor size and location. With our experience in sublobar resection, I would feel comfortable treating patients primarily with sublobar resection, especially with small subcentimeter disease, based on our experience in segmentectomy and now this analysis of our wedge data. DR SEBASTIAN DEFRANCHI (Buenos Aires, Argentina): Congratulations on a very nice presentation. There could probably be some concerns about doing a wedge resection for lung cancer because it’s not an anatomical resection. Daniel Miller published a paper some years ago with the Mayo Clinic experience treating lesions less than 1 cm in diameter with lobectomy, segmentectomy, or wedge resection. He found a lower 5-year survival rate when you do nonanatomic resections compared with anatomic resections. You did not find the same; do you have any explanation for this? Did you have a significant number of patients with BAC who have a better 5-year survival rate? DR SCHUCHERT: I think that’s a great point. One of the salient features of his study was the incidence of nodal disease, which was 7% in that analysis. In our experience, it’s less than 3%. So it’s hard to know if resecting much more territory is going to have a significant impact on survival. We do know from this analysis that the significant majority of recurrences were distant, and so, again, I don’t know if resecting more lung or taking out more lymph nodes will be saving these patients who have systemic disease. DR SWANSON: How many patients had mediastinoscopy? DR SCHUCHERT: A very low number, probably less than 10%. I don’t have an exact number for you, but it was an extremely small number.