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Non-small cell lung cancer: When to offer sublobar resection
Lung Cancer 86 (2014) 115–120
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Review
Non-small cell lung cancer: When to offer sublobar resection Alan D.L. Sihoe a , Paul Van Schil b,∗ a Division of Cardiothoracic Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China b Department of Thoracic and Vascular Surgery, Antwerp University Hospital, Wilrijkstraat 10, Edegem, B-2650 Antwerp, Belgium
a r t i c l e
i n f o
Article history: Received 2 September 2014 Accepted 7 September 2014 Keywords: Lung cancer Segmentectomy Sublobar resection Wedge resection Surgery Thoracotomy Video assisted thoracic surgery
a b s t r a c t Sublobar resection for lung cancer – whether non-anatomic wedge resection or anatomic segmentectomy – has emerged as a credible alternative to lobectomy for the surgical treatment of selected patients with lung cancer. Sublobar resection promises to cause less pulmonary compromise in such patients. Emerging evidence suggests that sublobar resection may offer survival outcomes approaching that of lobectomy for lung cancer patients whose disease meets the following criteria: stage IA disease only; tumor up to 2–3 cm diameter; peripheral location of tumor in the lung; and predominantly ground-glass (non-solid) appearance on CT imaging. The best results are obtained with segmentectomy (as opposed to wedge resection) and complete lymph node dissection. Nevertheless, the evidence is currently still limited, and the above criteria are met only in a minority of patients. Large randomized trials are underway to define the clinical role of sublobar resections, and results are eagerly anticipated. Until that time, lobectomy should still be regarded as the mainstay of surgical therapy for patients with early stage lung cancer at present. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Only some 50-odd years ago, the pneumonectomy was considered the surgical procedure offering the best chance of curing a patient with lung cancer [1,2]. It took decades before the lobectomy gradually became the default operation for lung cancer. Recently, the question arose whether sublobar resection comprising a non-anatomic resection of a wedge of lung parenchyma (wedge resection or excision) or removal of an anatomic segment of the lung (segmentectomy), is an oncologically valid procedure. Such a sublobar resection would leave the patient with less respiratory compromise, and (at least with wedge resection) would be a technically simpler operation that ideally complements minimally invasive surgical approaches. Over the years, clinical evidence has generally supported the latter argument. Most thoracic surgeons today would acknowledge that the lobectomy still offers a better chance of curing lung cancer than any form of sublobar resection. But that situation is gradually evolving. Clinical evidence is emerging to show that sublobar resection may have an important role to play in a subset of patients with non-small cell lung cancer (NSCLC).
This article will look at some of the evidence for sublobar resection for NSCLC. Technical aspects of how wedge resections and segmentectomies are performed are beyond the scope of this article, but can be easily read about elsewhere [3]. 2. Evidence from the surgical literature Sublobar resection as a concept is not new. As early as 1973, an actuarial 5-year survival rate of 56% was reported in a series of 69 patients undergoing segmentectomy for bronchogenic carcinoma [4]. In the 1990s, further retrospective studies found no difference in survival when lobectomy and sublobar resections for NSCLC were compared [5,6]. In 1995, the only randomized trial of sublobar resection versus lobectomy for clinical T1N0 NSCLC was published by the Lung Cancer Study Group [7]. In this study, 122 patients with sublobar resection (including 82 segmentectomies) were compared with 125 lobectomies. The death rate per year was 30% higher in the sublobar group with borderline statistical significance (p = 0.08). Moreover, the locoregional recurrence rate in the sublobar group was 300% higher than in the lobectomy group (p = 0.008), with relatively worse results after wedge resection than after segmentectomy. 2.1. Evidence for reduced morbidity?
∗ Corresponding author. Tel.: +32 3 8214360; fax: +32 3 8214396. E-mail addresses: [email protected], [email protected] (P. Van Schil). http://dx.doi.org/10.1016/j.lungcan.2014.09.004 0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
In the Lung Cancer Study Group randomized trial, it was found that the mean drop in Forced Expiratory Volume in one second
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(FEV1) at 12–18 months after a sublobar resection was 5.2% compared to 11.1% after lobectomy (p = 0.04). Since that time, further studies have confirmed that sublobar resection better preserves lung function [8,9]. In addition to lung function preservation, overall morbidity may also be reduced by sublobar resection [10,11]. De Zoysa [12] conducted a systematic literature review on the topic. In three studies morbidity after sublobar resection was reduced – with lower complication rates, shorter hospital stays and better preservation of pulmonary function.
2.2. Evidence for equivalent survival to lobectomy? In the Lung Cancer Study Group randomized trial, sublobar resection was associated with a loco-regional recurrence rate of over 17% [7]. Studies since then have consistently shown locoregional recurrence rates with segmentectomy to be only 2–8% [6,13–16]. Fernando [17] compared outcomes of 124 patients after sublobar resection with those of 167 patients after lobar resection. For tumors smaller than 2 cm, there was no difference in survival. Okada [18] concluded that the 5-year cancer-specific survival rates of patients with stage I disease with a tumor of 20 mm or less were no different if a lobectomy, segmentectomy or wedge resection was performed. In a study of 107 patients undergoing complete (R0) resection for stage IA NSCLC 1 cm or less, Schuchert [19] found no difference in recurrence rates or estimated 5-year survival between patients receiving lobectomy, segmentectomy or wedge resections. In a subsequent retrospective review of 785 consecutive patients undergoing anatomic segmentectomy for solitary pulmonary nodules, the same group found that for patients ultimately found to have pathologic stage IA NSCLC, there was no difference in recurrence rates (14.5% vs 13.9%) or 5-year freedom from recurrence estimates (78% in each group, p = 0.74) when comparing segmentectomy and lobectomy [20]. A study by Kates [21] used the Surveillance, Epidemiology, and End Results (SEER) registry in the United States comparing 688 patients who underwent sublobar resection with 1402 who underwent lobectomy for stage I NSCLC up to 1 cm in size. Overall and lung cancer-specific survival rates were not statistically different. This result seems to support sublobar resection for smaller tumors. Most recently, Altorki [22] identified 347 patients who underwent lobectomy (n = 294) or sublobar resection (n = 53) for NSCLC manifesting as a solid nodule found on CT screening as part of the International Early Lung Cancer Action Program. The 10-year survival rates for sublobar resection and lobectomy were 85% and 86%, respectively (p = 0.86). For those with cancers 20 mm or less, the 10-year survival rates were 88% versus 84%, respectively (p = 0.45). However, there have been reports not so favorable to sublobar resection. Another study using the same SEER database failed to corroborate the earlier findings by Kates [21,23]. Looking at an even larger cohort of 14,473 patients with stage I NSCLC, Whitson found that patients who underwent lobectomy had superior overall and cancer-specific survival rates [23]. Another study by Kraev also demonstrated that patients who underwent lobectomy for tumors <3 cm in size had better survival times compared to those who underwent wedge resection [24]. In 2005, Nakamura published the only major meta-analysis of the results of sublobar resection to date [25]. Sublobar resection was performed in a total of 903 patients, while conventional lobectomy was performed in 1887 patients. The combined survival differences between sublobar resection and lobectomy at 1, 3, and 5 years after resection were 0.7, 1.9, and 3.6%, respectively. Although these differences were all in favor of lobectomy, none of these combined survival differences were statistically significant. In conclusion, therefore, the published data demonstrated that survival
after sublobar resection for stage I lung cancer was comparable to lobectomy. In the systematic review by De Zoysa [12] the authors noted that three studies showed a decreased survival in sublobar resection patients. However, further analysis showed that these patients tended to be older and have limited node sampling. After adjusting for those variables, the authors found no significant difference in survival. However, when considering the published evidence for sublobar resection, caution in its interpretation is advisable [26]. As most of the studies were non-randomized, there may also have been selection bias in terms of pre-operative patient risk factors, tumors of different histological types or different sized tumors in the study arms. 3. Prognostic factors for sublobar resection From the above evidence, it would appear that if sublobar resection is offered to selected patients, cancer treatment of equivalent efficacy as lobectomy may be achievable in selected patients. In the study by Donahue [16] certain factors were potentially associated with better survival after sublobar resection: tumor size <2 cm; ensuring margin adequacy; performing segmentectomy rather than wedge resection; and inclusion of nodal dissection during any sublobar resection. 3.1. Staging First and foremost, it must be remembered that all clinical evidence supporting the use of sublobar resection relates specifically to patients with stage I NSCLC only. Therefore, every effort must be made to ensure accurate staging to rule out metastasis. Positron emission tomographic (PET) scanning is certainly advisable. In many patients, mediastinoscopy and/or endobronchial ultrasonography (EBUS) may prove helpful for mediastinal staging prior to committing to a sublobar resection. 3.2. Size of tumor In the systematic review by De Zoysa [12], the authors noted that sublobar resection offered comparable survival to lobectomy only for tumors up to 2 cm in diameter. In the study by Fernando [17], for tumors smaller than 2 cm, there was no difference in survival between the sublobar resection and lobar resection groups. Okada [18] found equivalent survival between sublobar resection and lobectomy for smaller tumors. However, for tumors larger than 30 mm in diameter, the 5-year cancer-specific survivals were 81.3% after lobectomy compared to only 62.9% after segmentectomy (p = 0.005). Okumura [27] looked at patients with stage I, II, or III disease NSCLC who underwent a segmentectomy (n = 144) and compared them with patients who underwent a lobectomy during the same period (n = 1241). In patients with pT1N0M0 (stage IA) disease and a tumor smaller than 2 cm, except for large cell carcinomas, the 5and 10-year survival rates were 83% and 83%, respectively, after a segmentectomy, and 81% and 64%, respectively, after a lobectomy (p = 0.66). More recently, Varlotto [28] looked at 93 patients undergoing sublobar resection for stage I NSCLC and confirmed that local recurrence was correlated with tumor size greater than 2 cm. Incidentally, this study was also one of the only to identify high tumor grade as a factor predictive of recurrence after sublobar resection. 3.3. Adequacy of resection margin The best evidence for the importance of an adequate margin comes from the study of El-Sherif [29] that looked at 55 wedge and
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26 segmental resections performed for patients with NSCLC. In 6 of 41 patients (14.6%) with a resection margin of less than 1 cm, local recurrence developed. This compared with local recurrence in 3 of 40 patients (7.5%) in the group with a resection margin of equal to or more than 1 cm (p = 0.04). 3.4. Segmentectomy versus wedge resection The most widely appreciated prognostic factor for sublobar resection in recent years appears to be the performance of segmentectomy instead of wedge resection. In a study of 87 patients with stage IA NSCLC, wedge resection was performed in 31 patients and segmentectomy in 56 patients [30]. There were significantly less loco-regional recurrences (p = 0.001), and a better cancer-related survival (p = 0.016) following segmentectomy compared to wedge resection. Nakamura [31] recently looked at a cohort of 411 patients with clinical stage I NSCLC who underwent resections by VideoAssisted Thoracic Surgery (VATS), including lobectomy in 289, segmentectomy in 38, and wedge resection in 84. Survival was poorer in the wedge resection patients. The hazard ratio of wedge resection relative to lobectomy was 4.30. Koike [32] compared wedge resection and segmentectomy and determined the hazard ratios for local recurrence and for poorer disease-specific survival with the former to be 5.8 and 3.2, respectively. In a systematic review Chamogeorgakis [33] found that wedge resection is not comparable to lobectomy for stage IA NSCLC. However, segmental resection is comparable to lobectomy for small peripheral tumors. With increasing experience with VATS worldwide, it has been well demonstrated that segmentectomy can be performed using this minimally invasive approach [34,35]. There is growing evidence that for segmentectomies, VATS allows lower morbidity rates and shorter chest drain durations and lengths of stay than thoracotomy [36,37]. Other authors have shown that robotic surgical systems can also be used to perform segmentectomy [38]. A novel technique of using 3-dimensional virtual images reconstructed from CT data to guide bronchoscopic multiple marking on the lung surface has been recently described [39]. 3.5. Lymph node dissection In a recent study, Wolf [40] looked at 154 patients who received sublobar resection and 84 who had lobectomy for NSCLC where the primary tumor was 2 cm or less in diameter. Overall, the results did not favor sublobar resection. However, if only those 45 sublobar resection patients who also had mediastinal lymph node sampling during surgery were compared with the lobectomy patients, these differences were found to be no longer present. A study on 223 patients receiving segmentectomy for small (2 cm or less) peripheral NSCLC by Koike [41] found that lymphatic permeation was the only independent predictor for both a poor prognosis and recurrence. As already mentioned, De Zoysa [12] found that when the adequacy of nodal dissection was accounted for, there was no appreciable difference between the lobectomy and sublobar resection study arms in terms of survival. The current challenge is that failure to examine lymph nodes was found to occur in up to 51% of all cases of sublobar resection in a recent retrospective analysis of NSCLC resections in the US SEER database from 1998 to 2009 [42]. Unfortunately, such patients with non-examination of lymph nodes were found to be a high risk subset, with survival approximating pathologic N1, not N0. However, in contrast, a study by Tsutani [43] of 618 patients with sublobar resection for clinical stage IA lung adenocarcinoma seems to suggest an opposite view. This study found that no patient having solid tumor size of less than 0.8 cm on high-resolution CT, or maximum
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standardized uptake value of less than 1.5 on PET/CT was found to have any pathological lymph node metastasis. 3.6. 2011 IASLC/ATS/ERS adenocarcinoma classification In 2011, a new classification of lung adenocarcinoma was introduced by a joint working group of the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS) [44]. This classification introduces the new categories of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) that represent small (≤3 cm), solitary adenocarcinomas consisting purely of lepidic growth without invasion or with ≤0.5 cm invasion, respectively. These two new categories have essentially replaced the term ‘bronchioloalveolar carcinoma’ (BAC). These new categories are reportedly associated with 100% or near-100% 5-year disease-free survival, respectively, if completely resected [45]. Over the years, BAC has been well linked to an appearance of ‘ground glass opacity’ (GGO) on CT scanning. Clinical studies correlating imaging and histopathology have consistently linked many GGOs with pre-invasive, noninvasive or early forms of neoplastic growth, namely AIS or MIA [46,47]. In a recent prospective study, a CT finding of a GGO of ≤2 cm diameter with ≤0.25 consolidated component by volume was even used to define a radiological diagnosis of noninvasive peripheral lung adenocarcinoma or AIS [48]. Lobectomy is still considered the standard surgical treatment for tumors that have a solid appearance on chest CT (even if smaller than 2 cm) because such tumors are likely to be invasive carcinomas. However, recent guidelines and evidence from a large, randomized trial suggest that small nodules of ≤10 mm or ≤500 mm3 that are clearly 100% pure GGO lesions on chest CT may be considered as AIS or MIA, and hence may be suitable for close follow-up or sublobar resection rather than immediate lobectomy [49,50]. In a recent review by Rami-Porta and Tsuboi [51], nine case series were identified in which lobectomy or sublobar resection was performed for small localized BACs detected by CT as pure GGO with no nodal involvement. These are the lesions which are now classified as AIS or MIA. For these lesions, 5-year survival rates were 100% in all but one of the series and there was no recurrence at follow-up. Another systematic review by the Lung Cancer Study Group also concluded that tumors less than 2 cm and with greater than 50% density of GGOs are unlikely to have N1 or N2 lymph node metastasis [52]. One recent study from Japan shows that the above recommendations can be put into routine practice [53]. Recently, Tsutani [54] looked at 610 patients with stage IA adenocarcinoma who underwent surgical resection. For those 239 patients with a GGOdominant (less solid) primary tumor, there was no significant difference in 3-year recurrence-free survival among patients who underwent lobectomy (96.4%), segmentectomy (96.1%), and wedge resection (98.7%). However, despite the impact of adenocarcinoma subtyping on prognosis, a recent study by Dembitzer [55] suggests that this factor is still not as important as tumor size in terms of influencing survival outcomes after sublobar resection. 3.7. Adjuvant therapy Because of concern over the potential of loco-regional recurrence after sublobar resection, adjuvant therapy has always been a topic of interest in this field. However, after sublobar resection for stage I NSCLC, the use of external beam radiation therapy was associated with significantly worse median overall and disease-specific survival compared with no additional locoregional therapy [56].
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Intra-operative brachytherapy has also been evaluated. Fernando [17] applied brachytherapy to 60 (48%) out of 124 patients receiving sublobar resection for stage I NSCLC. After a mean follow-up of 34.5 months, the brachytherapy decreased local recurrence rate significantly from 17.2% to 3.3% (p = 0.012). Birdas [57] looked at 167 stage Ib NSCLC patients, comparing those 126 who underwent lobectomy with those 41 who had sublobar resection with iodine 125 brachytherapy over the resection staple line. They found that use of sublobar resection plus brachytherapy conferred similar rates of locoregional recurrence, disease-free survival and overall survival as lobectomy. In a recent multicenter randomized trial specifically looking at patients with stage I NSCLC who had poor lung function pre-operatively, those who had sublobar resection with intra-operative brachytherapy were compared with those who had sublobar resection alone [58,59]. After a median follow-up of 4.4 years local progression occurred in only 7.7% of patients. Three-year overall survival rate was 71% and similar for both groups. Brachytherapy did not reduce local recurrence rate after sublobar resection [60]. It has been suggested that use of a robotic surgical system for placement of brachytherapy seeds may allow more precise delivery and dosing [61]. 4. Patient factors The other major consideration in the workup of the candidate for sublobar resection is his/her fitness for surgery. Patients being considered for sublobar resection are often in that position paradoxically because they are deemed unfit or at high risk for a lobectomy. This is most often due to poor pre-existing lung function or advanced patient age [25,62]. 4.1. Lung function considerations Complete lung function testing is mandatory, including spirometry, arterial blood gas analysis, and preferably assessment of the carbon monoxide diffusion capacity (DLCO) [63]. If doubts remain regarding the patient’s lung function, split-lung ventilation/perfusion nuclear scintigraphic assessment (VQ scan) should be used to assess the relative contribution to the patient’s respiration of the segment planned to be removed. It has been shown that the VATS approach can be used to perform segmentectomy [34–37] but recent reports suggest that lobectomy can be performed with acceptable morbidity and mortality even in patients deemed to have ‘marginal pulmonary function’ [64,65]. In favor of sublobar resection, on the other hand, Martin-Ucar [66] reported a study of patients with predicted post-operative FEV1 of less than 40% who underwent resections for stage I NSCLC. The authors individually case-matched 17 patients who underwent anatomical segmentectomy to 17 patients operated by lobectomy. There were no significant differences in hospital mortality, complications or hospital stay. There was preservation of pulmonary function after segmentectomy (median gain of 12%) compared to lobectomy (median loss of 12%) (p = 0.02). In patients in whom a second primary lung cancer develops after the resection of a previous primary lung cancer, there is often insufficient pulmonary function to undergo another anatomic lobectomy. In a study of 40 such patients with a second lung cancer, Bae [67] found that sublobar resection gave comparable overall survival and disease-free survival compared with the patients who underwent anatomic lobectomy, but sublobar resection also gave better operative outcome in terms of peri-operative mortality and morbidity. Zuin [68] looked at 121 such patients with a second
lung cancer, including 60 with sublobar resections. Lobectomy offered better 5-year survival than sublobar resection (57.5 and 36%, respectively, p = 0.016). Another sub-group of patients that may benefit from sublobar resection may be those with synchronous multiple primary lung cancers. A study by Kocaturk [69] of 26 patients in such situations has shown that multiple sublobar resections did not result in any survival disadvantage and hence could be a viable alternative to multiple lobectomies or a pneumonectomy. 4.2. Elderly patients In addition to lung function preservation, overall morbidity may also be reduced by sublobar resection. Kilic reported that in patients older than 75 years, segmentectomy could reduce the postoperative major complication rate from 25.5% (with lobectomy) to just 11.5% (p = 0.02). In another study, Okami [11] compared the outcomes of 79 standard lobectomies and 54 sublobar resections for stage IA NSCLC in elderly patients aged 75 years or more. No significant differences were found. More recently, Dell’Amore [70] reported 319 patients aged ≥75 years who underwent intended curative lung resection for lung cancer. While patients with pneumonectomy had significantly worse outcomes, there was no difference in overall survival between patients who had sublobar resection and those who had lobectomy. 5. Future directions Much of the evidence for sublobar resection comes from retrospective case series only [71]. The limited power of the results being published is a potential barrier to greater acceptance of sublobar resections. To address this issue, a Cancer and Lymphoma Group B trial (CALBG 140503) is underway, recruiting over 1200 patients in a multi-center, randomized study comparing lobectomy and sublobar resection for stage IA NSCLC with peripheral tumors that are no larger than 2 cm in diameter [72]. Another major randomized trial currently in progress is the Japan Clinical Oncology Group and the West Japan Oncology Group trial (JCOG0802/WJOG4607L) [73]. This is broadly similar to the CALGB trial, and also aims to recruit over 1100 patients with small-sized (diameter no larger than 2 cm) peripheral NSCLC. Sublobar resection is not the only alternative to lobectomy for treating NSCLC. Stereotactic body radiation therapy (SBRT) and ablative therapies - such as radiofrequency ablation (RFA) and microwave ablation (MWA) – have emerged as further options in selected patients [74–76]. These modalities are essentially non-operative and non-resectional in nature. Published studies currently offer a great spread of disparate conclusions regarding survival after sublobar resection versus RFA/MWA versus SBRT [77,78]. A recent systematic review was performed by Mahmood [79] comparing sublobar resection with SBRT for patients with stage I NSCLC considered too high risk for lobectomy. Overall 3-year survival was higher following sublobar resection than following SBRT (87.1 vs 45.1–57.1%). A prospective, multi-center, randomized trial the ACOSOG Z4099 trial has been initiated in the USA but was recently closed due to poor accrual [80]. Regardless of any published survival data, however, RFA/MWA and SBRT will be fundamentally limited by two issues [77]. Firstly, with the non-resectional modalities, there is no reliable method of ensuring that 100% of the tumor has been destroyed and secondly, with the non-resectional modalities, no histopathological assessment of the lymph nodes is performed which may give rise to understaging.
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6. Conclusions Lobectomy remains firmly entrenched as the treatment of choice for early stage NSCLC [62,81]. The quantity and quality of available evidence regarding sublobar resection is currently insufficient to support a paradigm shift in clinical practice for managing NSCLC. At present, sublobar resection remains a useful treatment alternative for a very select population of NSCLC patients. From the evidence discussed above, such a population is defined by: I. Confirmed stage IA disease only; II. Small tumors up to 2–3 cm diameter; III. Peripheral location of tumor in the lung (and hence wide resection margins achievable); IV. Predominantly GGO appearance on CT imaging. Predictors reported for successful sublobar resection on preoperative CT include: location within the outer third of the lung parenchyma; lesion smaller than 3 cm; and no evidence of endobronchial involvement [62]. Attempting sublobar resections if these conditions are not fulfilled potentially increases the risk of inadequate resection margins, staple line dehiscence, and distortion of the remaining parenchyma of the lung resulting after stapling. At least one study also suggests that large cell carcinoma may be associated with poorer results after sublobar resection [26]. From a patient factors perspective, advanced age and poor lung function are not absolute contra-indications and may conversely be the very reasons why sublobar resection is being considered. Considering surgeon factors, the best results from sublobar resection are potentially obtained if segmentectomy is performed (as opposed to wedge resection), and if complete lymph node dissection is performed. Brachytherapy is probably not useful as adjuvant therapy. It is also not yet clear whether sublobar resections offer ‘less morbidity’ than lobectomy. Sublobar resection should be compared to therapies a patient ineligible for lobectomy would otherwise receive: radiotherapy/SBRT, ablative therapies or palliative management alone. In this context, the current role of sublobar resection is to offer resectional therapy to those patients who would otherwise traditionally have had none. Conflict of interest statement The authors declare no conflict of interest. References [1] Horn L, Johnson DH, Evarts A. Graham and the first pneumonectomy for lung cancer. J Clin Oncol 2008;26:3268–75. [2] Ochsner A, DeBakey M. Primary pulmonary malignancy: treatment by total pneumonectomy – analysis of 79 collected cases and presentation of 7 personal cases. Surg Gyn Obst 1939;68:435–51. [3] Sihoe ADL, Yim APC. Video-assisted pulmonary resections. In: Patterson GA, Cooper JD, Deslauriers J, Lerut AEMR, Luketich JD, Rice TW, Pearson FG, editors. Thoracic surgery. 3rd ed. Philadelphia, USA: Elsevier; 2008. p. 970–88. [4] Jensik RJ, Faber LP, Milloy FJ, Monson DO. Segmental resection for lung cancer – a fifteen-year experience. J Thorac Cardiovasc Surg 1973;66:563–72. [5] Read R, Yoder G, Schaeffer R. Survival after conservative resection for T1 N0 M0 non-small cell lung cancer. Ann Thorac Surg 1990;49:391–8. [6] Kodama K, Doi O, Higashiyama M, Yokouchi H. Intentional limited resection for selected patients with T1 N0 M0 non-small-cell lung cancer: a single-institution study. J Thorac Cardiovasc Surg 1997;114:347–53. [7] Ginsberg R, Rubinstein L. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615–22. [8] Keenan RJ, Landreneau RJ, Maley Jr RH, Singh D, Macherey R, Bartley S, et al. Segmental resection spares pulmonary function in patients with stage I lung cancer. Ann Thorac Surg 2004;78:228–33. [9] Harada H, Okada M, Sakamoto T, Matsuoka H, Tsubota N. Functional advantage after radical segmentectomy versus lobectomy for lung cancer. Ann Thorac Surg 2005;80:2041–5. [10] Kilic A, Schuchert MJ, Pettiford BL. Anatomic segmentectomy for stage I nonsmall cell lung cancer in the elderly. Ann Thorac Surg 2009;87:1662–6.
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[61] Blasberg JD, Belsey SJ, Schwartz GS. Robotic brachytherapy and sublobar resection for T1 non-small cell lung cancer in high-risk patients. Ann Thorac Surg 2010;89:360–7. [62] Pettiford B, Landreneau RJ. Role of sublobar resection (segmentectomy and wedge resection) in the surgical management of non-small cell lung cancer. In: Patterson GA, Cooper JD, Deslauriers J, Lerut AEMR, Luketich JD, Rice TW, Pearson FG, editors. Thoracic surgery. 3rd ed. Philadelphia, USA: Elsevier; 2008. p. 869–78. [63] Iizasa T, Suzuki M, Yasufuku K, Iyoda A, Otsuji M, Yoshida S, et al. Preoperative pulmonary function as a prognostic factor for stage I non-small cell carcinoma. Ann Thorac Surg 2004;77:1896–903. [64] Garzon JC, Ng CSH, Sihoe ADL, Manlulu AV, Wong RHL, Lee TW, et al. Videoassisted thoracic surgery pulmonary resection for lung cancer in patients with poor lung function. Ann Thorac Surg 2006;81:1996–2003. [65] Taylor MD, LaPar DJ, Isbell JM. Marginal pulmonary function should not preclude lobectomy in selected patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 2014;147:738–44. [66] Martin-Ucar A, Nakas A, Pilling JE. 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. [67] Bae MK, Byun CS, Lee CY. The role of surgical treatment in second primary lung cancer. Ann Thorac Surg 2011;92:256–63. [68] Zuin A, Andriolo LG, Marulli G. Is lobectomy really more effective than sublobar resection in the surgical treatment of second primary lung cancer? Eur J Cardiothorac Surg 2013;44:e120–5. [69] Kocaturk CI, Gunluoglu MZ, Cansever L. Survival and prognostic factors in surgically resected synchronous multiple primary lung cancers. Eur J Cardiothorac Surg 2011;39:160–6. [70] Dell’Amore A, Monteverde M, Martucci N. Early and long-term results of pulmonary resection for non-small-cell lung cancer in patients over 75 years of age: a multi-institutional study. Interact Cardiovasc Thorac Surg 2013;16:250–6. [71] Detterbeck FC. Are limited resections appropriate in non-small cell lung cancer? No. Chest 2012;141:590–2. [72] Cancer, Leukemia Group B. Comparison of different types of surgery in treating patients with stage IA non-small cell lung cancer. NCT00499330. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2007. http:// clinicaltrials.gov/ct2/show/NCT00499330?term=CALGB+140503&rank=1 [19.04.12]. [73] Nakamura K, Saji H, Nakajima R. A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L). Jpn J Clin Oncol 2010;40:271–4. [74] Fernandez FG, Crabtree TD, Liu J, Meyers BF. Sublobar resection versus definitive radiation in patients with stage IA non-small cell lung cancer. Ann Thorac Surg 2012;94:354–61. [75] Fernando HC. Radiofrequency ablation to treat non-small cell lung cancer and pulmonary metastases. Ann Thorac Surg 2008;85:S780–4. [76] Cesarati JA, Pennathur A, Rosenstein BS. Stereotactic radiosurgery for thoracic malignancies. Ann Thorac Surg 2008;85:S785–91. [77] Fernando HC, Schuchert M, Landreneau R, Daly BT. Approaching the high-risk patient: sublobar resection, stereotactic body radiation therapy, or radiofrequency ablation. Ann Thorac Surg 2010;89:S2123–7. [78] Senan S, Verstegen NE, Palma D, Rodrigues G, Lagerwaard FJ, van der Elst A, et al. Stages I–II non-small cell lung cancer treated using either lobectomy by video-assisted thoracoscopic surgery (VATS) or stereotactic ablative radiotherapy (SABR): outcomes of a propensity score-matched analysis. J Clin Oncol 2012;30 [suppl; abstr 7009]. [79] Mahmood S, Bilal H, Faivre-Finn C, Shah R. Is stereotactic ablative radiotherapy equivalent to sublobar resection in high-risk surgical patients with Stage I nonsmall-cell lung cancer? Interact Cardiovasc Thorac Surg 2013;17:845–53. [80] Fernando HC, Timmerman R. American College of Surgeons Oncology Group Z4099/Radiation Therapy Oncology Group 1021: a randomized study of sublobar resection compared with stereotactic body radiotherapy for high risk stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 2012;144:S35–8. [81] Zwischenberger JB. Wedge resection: when a little is not enough. Chest 2007;131:6–7.
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Review
Non-small cell lung cancer: When to offer sublobar resection Alan D.L. Sihoe a , Paul Van Schil b,∗ a Division of Cardiothoracic Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China b Department of Thoracic and Vascular Surgery, Antwerp University Hospital, Wilrijkstraat 10, Edegem, B-2650 Antwerp, Belgium
a r t i c l e
i n f o
Article history: Received 2 September 2014 Accepted 7 September 2014 Keywords: Lung cancer Segmentectomy Sublobar resection Wedge resection Surgery Thoracotomy Video assisted thoracic surgery
a b s t r a c t Sublobar resection for lung cancer – whether non-anatomic wedge resection or anatomic segmentectomy – has emerged as a credible alternative to lobectomy for the surgical treatment of selected patients with lung cancer. Sublobar resection promises to cause less pulmonary compromise in such patients. Emerging evidence suggests that sublobar resection may offer survival outcomes approaching that of lobectomy for lung cancer patients whose disease meets the following criteria: stage IA disease only; tumor up to 2–3 cm diameter; peripheral location of tumor in the lung; and predominantly ground-glass (non-solid) appearance on CT imaging. The best results are obtained with segmentectomy (as opposed to wedge resection) and complete lymph node dissection. Nevertheless, the evidence is currently still limited, and the above criteria are met only in a minority of patients. Large randomized trials are underway to define the clinical role of sublobar resections, and results are eagerly anticipated. Until that time, lobectomy should still be regarded as the mainstay of surgical therapy for patients with early stage lung cancer at present. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Only some 50-odd years ago, the pneumonectomy was considered the surgical procedure offering the best chance of curing a patient with lung cancer [1,2]. It took decades before the lobectomy gradually became the default operation for lung cancer. Recently, the question arose whether sublobar resection comprising a non-anatomic resection of a wedge of lung parenchyma (wedge resection or excision) or removal of an anatomic segment of the lung (segmentectomy), is an oncologically valid procedure. Such a sublobar resection would leave the patient with less respiratory compromise, and (at least with wedge resection) would be a technically simpler operation that ideally complements minimally invasive surgical approaches. Over the years, clinical evidence has generally supported the latter argument. Most thoracic surgeons today would acknowledge that the lobectomy still offers a better chance of curing lung cancer than any form of sublobar resection. But that situation is gradually evolving. Clinical evidence is emerging to show that sublobar resection may have an important role to play in a subset of patients with non-small cell lung cancer (NSCLC).
This article will look at some of the evidence for sublobar resection for NSCLC. Technical aspects of how wedge resections and segmentectomies are performed are beyond the scope of this article, but can be easily read about elsewhere [3]. 2. Evidence from the surgical literature Sublobar resection as a concept is not new. As early as 1973, an actuarial 5-year survival rate of 56% was reported in a series of 69 patients undergoing segmentectomy for bronchogenic carcinoma [4]. In the 1990s, further retrospective studies found no difference in survival when lobectomy and sublobar resections for NSCLC were compared [5,6]. In 1995, the only randomized trial of sublobar resection versus lobectomy for clinical T1N0 NSCLC was published by the Lung Cancer Study Group [7]. In this study, 122 patients with sublobar resection (including 82 segmentectomies) were compared with 125 lobectomies. The death rate per year was 30% higher in the sublobar group with borderline statistical significance (p = 0.08). Moreover, the locoregional recurrence rate in the sublobar group was 300% higher than in the lobectomy group (p = 0.008), with relatively worse results after wedge resection than after segmentectomy. 2.1. Evidence for reduced morbidity?
∗ Corresponding author. Tel.: +32 3 8214360; fax: +32 3 8214396. E-mail addresses: [email protected], [email protected] (P. Van Schil). http://dx.doi.org/10.1016/j.lungcan.2014.09.004 0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
In the Lung Cancer Study Group randomized trial, it was found that the mean drop in Forced Expiratory Volume in one second
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(FEV1) at 12–18 months after a sublobar resection was 5.2% compared to 11.1% after lobectomy (p = 0.04). Since that time, further studies have confirmed that sublobar resection better preserves lung function [8,9]. In addition to lung function preservation, overall morbidity may also be reduced by sublobar resection [10,11]. De Zoysa [12] conducted a systematic literature review on the topic. In three studies morbidity after sublobar resection was reduced – with lower complication rates, shorter hospital stays and better preservation of pulmonary function.
2.2. Evidence for equivalent survival to lobectomy? In the Lung Cancer Study Group randomized trial, sublobar resection was associated with a loco-regional recurrence rate of over 17% [7]. Studies since then have consistently shown locoregional recurrence rates with segmentectomy to be only 2–8% [6,13–16]. Fernando [17] compared outcomes of 124 patients after sublobar resection with those of 167 patients after lobar resection. For tumors smaller than 2 cm, there was no difference in survival. Okada [18] concluded that the 5-year cancer-specific survival rates of patients with stage I disease with a tumor of 20 mm or less were no different if a lobectomy, segmentectomy or wedge resection was performed. In a study of 107 patients undergoing complete (R0) resection for stage IA NSCLC 1 cm or less, Schuchert [19] found no difference in recurrence rates or estimated 5-year survival between patients receiving lobectomy, segmentectomy or wedge resections. In a subsequent retrospective review of 785 consecutive patients undergoing anatomic segmentectomy for solitary pulmonary nodules, the same group found that for patients ultimately found to have pathologic stage IA NSCLC, there was no difference in recurrence rates (14.5% vs 13.9%) or 5-year freedom from recurrence estimates (78% in each group, p = 0.74) when comparing segmentectomy and lobectomy [20]. A study by Kates [21] used the Surveillance, Epidemiology, and End Results (SEER) registry in the United States comparing 688 patients who underwent sublobar resection with 1402 who underwent lobectomy for stage I NSCLC up to 1 cm in size. Overall and lung cancer-specific survival rates were not statistically different. This result seems to support sublobar resection for smaller tumors. Most recently, Altorki [22] identified 347 patients who underwent lobectomy (n = 294) or sublobar resection (n = 53) for NSCLC manifesting as a solid nodule found on CT screening as part of the International Early Lung Cancer Action Program. The 10-year survival rates for sublobar resection and lobectomy were 85% and 86%, respectively (p = 0.86). For those with cancers 20 mm or less, the 10-year survival rates were 88% versus 84%, respectively (p = 0.45). However, there have been reports not so favorable to sublobar resection. Another study using the same SEER database failed to corroborate the earlier findings by Kates [21,23]. Looking at an even larger cohort of 14,473 patients with stage I NSCLC, Whitson found that patients who underwent lobectomy had superior overall and cancer-specific survival rates [23]. Another study by Kraev also demonstrated that patients who underwent lobectomy for tumors <3 cm in size had better survival times compared to those who underwent wedge resection [24]. In 2005, Nakamura published the only major meta-analysis of the results of sublobar resection to date [25]. Sublobar resection was performed in a total of 903 patients, while conventional lobectomy was performed in 1887 patients. The combined survival differences between sublobar resection and lobectomy at 1, 3, and 5 years after resection were 0.7, 1.9, and 3.6%, respectively. Although these differences were all in favor of lobectomy, none of these combined survival differences were statistically significant. In conclusion, therefore, the published data demonstrated that survival
after sublobar resection for stage I lung cancer was comparable to lobectomy. In the systematic review by De Zoysa [12] the authors noted that three studies showed a decreased survival in sublobar resection patients. However, further analysis showed that these patients tended to be older and have limited node sampling. After adjusting for those variables, the authors found no significant difference in survival. However, when considering the published evidence for sublobar resection, caution in its interpretation is advisable [26]. As most of the studies were non-randomized, there may also have been selection bias in terms of pre-operative patient risk factors, tumors of different histological types or different sized tumors in the study arms. 3. Prognostic factors for sublobar resection From the above evidence, it would appear that if sublobar resection is offered to selected patients, cancer treatment of equivalent efficacy as lobectomy may be achievable in selected patients. In the study by Donahue [16] certain factors were potentially associated with better survival after sublobar resection: tumor size <2 cm; ensuring margin adequacy; performing segmentectomy rather than wedge resection; and inclusion of nodal dissection during any sublobar resection. 3.1. Staging First and foremost, it must be remembered that all clinical evidence supporting the use of sublobar resection relates specifically to patients with stage I NSCLC only. Therefore, every effort must be made to ensure accurate staging to rule out metastasis. Positron emission tomographic (PET) scanning is certainly advisable. In many patients, mediastinoscopy and/or endobronchial ultrasonography (EBUS) may prove helpful for mediastinal staging prior to committing to a sublobar resection. 3.2. Size of tumor In the systematic review by De Zoysa [12], the authors noted that sublobar resection offered comparable survival to lobectomy only for tumors up to 2 cm in diameter. In the study by Fernando [17], for tumors smaller than 2 cm, there was no difference in survival between the sublobar resection and lobar resection groups. Okada [18] found equivalent survival between sublobar resection and lobectomy for smaller tumors. However, for tumors larger than 30 mm in diameter, the 5-year cancer-specific survivals were 81.3% after lobectomy compared to only 62.9% after segmentectomy (p = 0.005). Okumura [27] looked at patients with stage I, II, or III disease NSCLC who underwent a segmentectomy (n = 144) and compared them with patients who underwent a lobectomy during the same period (n = 1241). In patients with pT1N0M0 (stage IA) disease and a tumor smaller than 2 cm, except for large cell carcinomas, the 5and 10-year survival rates were 83% and 83%, respectively, after a segmentectomy, and 81% and 64%, respectively, after a lobectomy (p = 0.66). More recently, Varlotto [28] looked at 93 patients undergoing sublobar resection for stage I NSCLC and confirmed that local recurrence was correlated with tumor size greater than 2 cm. Incidentally, this study was also one of the only to identify high tumor grade as a factor predictive of recurrence after sublobar resection. 3.3. Adequacy of resection margin The best evidence for the importance of an adequate margin comes from the study of El-Sherif [29] that looked at 55 wedge and
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26 segmental resections performed for patients with NSCLC. In 6 of 41 patients (14.6%) with a resection margin of less than 1 cm, local recurrence developed. This compared with local recurrence in 3 of 40 patients (7.5%) in the group with a resection margin of equal to or more than 1 cm (p = 0.04). 3.4. Segmentectomy versus wedge resection The most widely appreciated prognostic factor for sublobar resection in recent years appears to be the performance of segmentectomy instead of wedge resection. In a study of 87 patients with stage IA NSCLC, wedge resection was performed in 31 patients and segmentectomy in 56 patients [30]. There were significantly less loco-regional recurrences (p = 0.001), and a better cancer-related survival (p = 0.016) following segmentectomy compared to wedge resection. Nakamura [31] recently looked at a cohort of 411 patients with clinical stage I NSCLC who underwent resections by VideoAssisted Thoracic Surgery (VATS), including lobectomy in 289, segmentectomy in 38, and wedge resection in 84. Survival was poorer in the wedge resection patients. The hazard ratio of wedge resection relative to lobectomy was 4.30. Koike [32] compared wedge resection and segmentectomy and determined the hazard ratios for local recurrence and for poorer disease-specific survival with the former to be 5.8 and 3.2, respectively. In a systematic review Chamogeorgakis [33] found that wedge resection is not comparable to lobectomy for stage IA NSCLC. However, segmental resection is comparable to lobectomy for small peripheral tumors. With increasing experience with VATS worldwide, it has been well demonstrated that segmentectomy can be performed using this minimally invasive approach [34,35]. There is growing evidence that for segmentectomies, VATS allows lower morbidity rates and shorter chest drain durations and lengths of stay than thoracotomy [36,37]. Other authors have shown that robotic surgical systems can also be used to perform segmentectomy [38]. A novel technique of using 3-dimensional virtual images reconstructed from CT data to guide bronchoscopic multiple marking on the lung surface has been recently described [39]. 3.5. Lymph node dissection In a recent study, Wolf [40] looked at 154 patients who received sublobar resection and 84 who had lobectomy for NSCLC where the primary tumor was 2 cm or less in diameter. Overall, the results did not favor sublobar resection. However, if only those 45 sublobar resection patients who also had mediastinal lymph node sampling during surgery were compared with the lobectomy patients, these differences were found to be no longer present. A study on 223 patients receiving segmentectomy for small (2 cm or less) peripheral NSCLC by Koike [41] found that lymphatic permeation was the only independent predictor for both a poor prognosis and recurrence. As already mentioned, De Zoysa [12] found that when the adequacy of nodal dissection was accounted for, there was no appreciable difference between the lobectomy and sublobar resection study arms in terms of survival. The current challenge is that failure to examine lymph nodes was found to occur in up to 51% of all cases of sublobar resection in a recent retrospective analysis of NSCLC resections in the US SEER database from 1998 to 2009 [42]. Unfortunately, such patients with non-examination of lymph nodes were found to be a high risk subset, with survival approximating pathologic N1, not N0. However, in contrast, a study by Tsutani [43] of 618 patients with sublobar resection for clinical stage IA lung adenocarcinoma seems to suggest an opposite view. This study found that no patient having solid tumor size of less than 0.8 cm on high-resolution CT, or maximum
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standardized uptake value of less than 1.5 on PET/CT was found to have any pathological lymph node metastasis. 3.6. 2011 IASLC/ATS/ERS adenocarcinoma classification In 2011, a new classification of lung adenocarcinoma was introduced by a joint working group of the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS) [44]. This classification introduces the new categories of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) that represent small (≤3 cm), solitary adenocarcinomas consisting purely of lepidic growth without invasion or with ≤0.5 cm invasion, respectively. These two new categories have essentially replaced the term ‘bronchioloalveolar carcinoma’ (BAC). These new categories are reportedly associated with 100% or near-100% 5-year disease-free survival, respectively, if completely resected [45]. Over the years, BAC has been well linked to an appearance of ‘ground glass opacity’ (GGO) on CT scanning. Clinical studies correlating imaging and histopathology have consistently linked many GGOs with pre-invasive, noninvasive or early forms of neoplastic growth, namely AIS or MIA [46,47]. In a recent prospective study, a CT finding of a GGO of ≤2 cm diameter with ≤0.25 consolidated component by volume was even used to define a radiological diagnosis of noninvasive peripheral lung adenocarcinoma or AIS [48]. Lobectomy is still considered the standard surgical treatment for tumors that have a solid appearance on chest CT (even if smaller than 2 cm) because such tumors are likely to be invasive carcinomas. However, recent guidelines and evidence from a large, randomized trial suggest that small nodules of ≤10 mm or ≤500 mm3 that are clearly 100% pure GGO lesions on chest CT may be considered as AIS or MIA, and hence may be suitable for close follow-up or sublobar resection rather than immediate lobectomy [49,50]. In a recent review by Rami-Porta and Tsuboi [51], nine case series were identified in which lobectomy or sublobar resection was performed for small localized BACs detected by CT as pure GGO with no nodal involvement. These are the lesions which are now classified as AIS or MIA. For these lesions, 5-year survival rates were 100% in all but one of the series and there was no recurrence at follow-up. Another systematic review by the Lung Cancer Study Group also concluded that tumors less than 2 cm and with greater than 50% density of GGOs are unlikely to have N1 or N2 lymph node metastasis [52]. One recent study from Japan shows that the above recommendations can be put into routine practice [53]. Recently, Tsutani [54] looked at 610 patients with stage IA adenocarcinoma who underwent surgical resection. For those 239 patients with a GGOdominant (less solid) primary tumor, there was no significant difference in 3-year recurrence-free survival among patients who underwent lobectomy (96.4%), segmentectomy (96.1%), and wedge resection (98.7%). However, despite the impact of adenocarcinoma subtyping on prognosis, a recent study by Dembitzer [55] suggests that this factor is still not as important as tumor size in terms of influencing survival outcomes after sublobar resection. 3.7. Adjuvant therapy Because of concern over the potential of loco-regional recurrence after sublobar resection, adjuvant therapy has always been a topic of interest in this field. However, after sublobar resection for stage I NSCLC, the use of external beam radiation therapy was associated with significantly worse median overall and disease-specific survival compared with no additional locoregional therapy [56].
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Intra-operative brachytherapy has also been evaluated. Fernando [17] applied brachytherapy to 60 (48%) out of 124 patients receiving sublobar resection for stage I NSCLC. After a mean follow-up of 34.5 months, the brachytherapy decreased local recurrence rate significantly from 17.2% to 3.3% (p = 0.012). Birdas [57] looked at 167 stage Ib NSCLC patients, comparing those 126 who underwent lobectomy with those 41 who had sublobar resection with iodine 125 brachytherapy over the resection staple line. They found that use of sublobar resection plus brachytherapy conferred similar rates of locoregional recurrence, disease-free survival and overall survival as lobectomy. In a recent multicenter randomized trial specifically looking at patients with stage I NSCLC who had poor lung function pre-operatively, those who had sublobar resection with intra-operative brachytherapy were compared with those who had sublobar resection alone [58,59]. After a median follow-up of 4.4 years local progression occurred in only 7.7% of patients. Three-year overall survival rate was 71% and similar for both groups. Brachytherapy did not reduce local recurrence rate after sublobar resection [60]. It has been suggested that use of a robotic surgical system for placement of brachytherapy seeds may allow more precise delivery and dosing [61]. 4. Patient factors The other major consideration in the workup of the candidate for sublobar resection is his/her fitness for surgery. Patients being considered for sublobar resection are often in that position paradoxically because they are deemed unfit or at high risk for a lobectomy. This is most often due to poor pre-existing lung function or advanced patient age [25,62]. 4.1. Lung function considerations Complete lung function testing is mandatory, including spirometry, arterial blood gas analysis, and preferably assessment of the carbon monoxide diffusion capacity (DLCO) [63]. If doubts remain regarding the patient’s lung function, split-lung ventilation/perfusion nuclear scintigraphic assessment (VQ scan) should be used to assess the relative contribution to the patient’s respiration of the segment planned to be removed. It has been shown that the VATS approach can be used to perform segmentectomy [34–37] but recent reports suggest that lobectomy can be performed with acceptable morbidity and mortality even in patients deemed to have ‘marginal pulmonary function’ [64,65]. In favor of sublobar resection, on the other hand, Martin-Ucar [66] reported a study of patients with predicted post-operative FEV1 of less than 40% who underwent resections for stage I NSCLC. The authors individually case-matched 17 patients who underwent anatomical segmentectomy to 17 patients operated by lobectomy. There were no significant differences in hospital mortality, complications or hospital stay. There was preservation of pulmonary function after segmentectomy (median gain of 12%) compared to lobectomy (median loss of 12%) (p = 0.02). In patients in whom a second primary lung cancer develops after the resection of a previous primary lung cancer, there is often insufficient pulmonary function to undergo another anatomic lobectomy. In a study of 40 such patients with a second lung cancer, Bae [67] found that sublobar resection gave comparable overall survival and disease-free survival compared with the patients who underwent anatomic lobectomy, but sublobar resection also gave better operative outcome in terms of peri-operative mortality and morbidity. Zuin [68] looked at 121 such patients with a second
lung cancer, including 60 with sublobar resections. Lobectomy offered better 5-year survival than sublobar resection (57.5 and 36%, respectively, p = 0.016). Another sub-group of patients that may benefit from sublobar resection may be those with synchronous multiple primary lung cancers. A study by Kocaturk [69] of 26 patients in such situations has shown that multiple sublobar resections did not result in any survival disadvantage and hence could be a viable alternative to multiple lobectomies or a pneumonectomy. 4.2. Elderly patients In addition to lung function preservation, overall morbidity may also be reduced by sublobar resection. Kilic reported that in patients older than 75 years, segmentectomy could reduce the postoperative major complication rate from 25.5% (with lobectomy) to just 11.5% (p = 0.02). In another study, Okami [11] compared the outcomes of 79 standard lobectomies and 54 sublobar resections for stage IA NSCLC in elderly patients aged 75 years or more. No significant differences were found. More recently, Dell’Amore [70] reported 319 patients aged ≥75 years who underwent intended curative lung resection for lung cancer. While patients with pneumonectomy had significantly worse outcomes, there was no difference in overall survival between patients who had sublobar resection and those who had lobectomy. 5. Future directions Much of the evidence for sublobar resection comes from retrospective case series only [71]. The limited power of the results being published is a potential barrier to greater acceptance of sublobar resections. To address this issue, a Cancer and Lymphoma Group B trial (CALBG 140503) is underway, recruiting over 1200 patients in a multi-center, randomized study comparing lobectomy and sublobar resection for stage IA NSCLC with peripheral tumors that are no larger than 2 cm in diameter [72]. Another major randomized trial currently in progress is the Japan Clinical Oncology Group and the West Japan Oncology Group trial (JCOG0802/WJOG4607L) [73]. This is broadly similar to the CALGB trial, and also aims to recruit over 1100 patients with small-sized (diameter no larger than 2 cm) peripheral NSCLC. Sublobar resection is not the only alternative to lobectomy for treating NSCLC. Stereotactic body radiation therapy (SBRT) and ablative therapies - such as radiofrequency ablation (RFA) and microwave ablation (MWA) – have emerged as further options in selected patients [74–76]. These modalities are essentially non-operative and non-resectional in nature. Published studies currently offer a great spread of disparate conclusions regarding survival after sublobar resection versus RFA/MWA versus SBRT [77,78]. A recent systematic review was performed by Mahmood [79] comparing sublobar resection with SBRT for patients with stage I NSCLC considered too high risk for lobectomy. Overall 3-year survival was higher following sublobar resection than following SBRT (87.1 vs 45.1–57.1%). A prospective, multi-center, randomized trial the ACOSOG Z4099 trial has been initiated in the USA but was recently closed due to poor accrual [80]. Regardless of any published survival data, however, RFA/MWA and SBRT will be fundamentally limited by two issues [77]. Firstly, with the non-resectional modalities, there is no reliable method of ensuring that 100% of the tumor has been destroyed and secondly, with the non-resectional modalities, no histopathological assessment of the lymph nodes is performed which may give rise to understaging.
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6. Conclusions Lobectomy remains firmly entrenched as the treatment of choice for early stage NSCLC [62,81]. The quantity and quality of available evidence regarding sublobar resection is currently insufficient to support a paradigm shift in clinical practice for managing NSCLC. At present, sublobar resection remains a useful treatment alternative for a very select population of NSCLC patients. From the evidence discussed above, such a population is defined by: I. Confirmed stage IA disease only; II. Small tumors up to 2–3 cm diameter; III. Peripheral location of tumor in the lung (and hence wide resection margins achievable); IV. Predominantly GGO appearance on CT imaging. Predictors reported for successful sublobar resection on preoperative CT include: location within the outer third of the lung parenchyma; lesion smaller than 3 cm; and no evidence of endobronchial involvement [62]. Attempting sublobar resections if these conditions are not fulfilled potentially increases the risk of inadequate resection margins, staple line dehiscence, and distortion of the remaining parenchyma of the lung resulting after stapling. At least one study also suggests that large cell carcinoma may be associated with poorer results after sublobar resection [26]. From a patient factors perspective, advanced age and poor lung function are not absolute contra-indications and may conversely be the very reasons why sublobar resection is being considered. Considering surgeon factors, the best results from sublobar resection are potentially obtained if segmentectomy is performed (as opposed to wedge resection), and if complete lymph node dissection is performed. Brachytherapy is probably not useful as adjuvant therapy. It is also not yet clear whether sublobar resections offer ‘less morbidity’ than lobectomy. Sublobar resection should be compared to therapies a patient ineligible for lobectomy would otherwise receive: radiotherapy/SBRT, ablative therapies or palliative management alone. In this context, the current role of sublobar resection is to offer resectional therapy to those patients who would otherwise traditionally have had none. Conflict of interest statement The authors declare no conflict of interest. References [1] Horn L, Johnson DH, Evarts A. Graham and the first pneumonectomy for lung cancer. J Clin Oncol 2008;26:3268–75. [2] Ochsner A, DeBakey M. Primary pulmonary malignancy: treatment by total pneumonectomy – analysis of 79 collected cases and presentation of 7 personal cases. Surg Gyn Obst 1939;68:435–51. [3] Sihoe ADL, Yim APC. Video-assisted pulmonary resections. In: Patterson GA, Cooper JD, Deslauriers J, Lerut AEMR, Luketich JD, Rice TW, Pearson FG, editors. Thoracic surgery. 3rd ed. Philadelphia, USA: Elsevier; 2008. p. 970–88. [4] Jensik RJ, Faber LP, Milloy FJ, Monson DO. Segmental resection for lung cancer – a fifteen-year experience. J Thorac Cardiovasc Surg 1973;66:563–72. [5] Read R, Yoder G, Schaeffer R. Survival after conservative resection for T1 N0 M0 non-small cell lung cancer. Ann Thorac Surg 1990;49:391–8. [6] Kodama K, Doi O, Higashiyama M, Yokouchi H. Intentional limited resection for selected patients with T1 N0 M0 non-small-cell lung cancer: a single-institution study. J Thorac Cardiovasc Surg 1997;114:347–53. [7] Ginsberg R, Rubinstein L. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615–22. [8] Keenan RJ, Landreneau RJ, Maley Jr RH, Singh D, Macherey R, Bartley S, et al. Segmental resection spares pulmonary function in patients with stage I lung cancer. Ann Thorac Surg 2004;78:228–33. [9] Harada H, Okada M, Sakamoto T, Matsuoka H, Tsubota N. Functional advantage after radical segmentectomy versus lobectomy for lung cancer. Ann Thorac Surg 2005;80:2041–5. [10] Kilic A, Schuchert MJ, Pettiford BL. Anatomic segmentectomy for stage I nonsmall cell lung cancer in the elderly. Ann Thorac Surg 2009;87:1662–6.
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