The 1995 publication from the Lung Cancer Study. Sublobar Resection. A Movement from the Lung Cancer Study Group REVIEW ARTICLE

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1 REVIEW ARTICLE A Movement from the Lung Cancer Study Group Justin D. Blasberg, MD,* Harvey I. Pass, MD, and Jessica S. Donington, MD Abstract: The 1995 Lung Cancer Study Group consensus recommending lobectomy for stage I non-small cell lung cancer (NSCLC) has directed lung cancer resections since its publication. However, enhancements in imaging technology over the last decade have produced larger cohorts of patients presenting with localized, earlystage disease. Today, multislice computer tomography is widely available, capable of detecting NSCLC at smaller sizes, with improved spatial resolution, and is used in screening programs for high-risk individuals. Furthermore, the maturation of minimally invasive surgical resection (video-assisted thoracoscopic surgery) has reduced perioperative morbidity and mortality, improved postoperative lung function, and demonstrated equivalent oncologic effectiveness to open surgery. The mandatory use of lobectomy for patients with small stage IA NSCLC is now being challenged. Numerous single-institution trials have demonstrated that wellselected use of sublobar resection can afford comparable survival and recurrence rates to lobectomy, particularly in high-risk patients. Currently, a prospective, randomized multi-institutional phase III trial is being conducted by the Cancer and Lymphoma Group B (CALGB ) to determine whether patients with small ( 2 cm) peripheral NSCLC tumors can safely undergo sublobar resection while maintaining rates of survival and recurrence that are comparable to lobectomy. This review summarizes the literature from the past 15 years to assist in applying those conclusions to future research innovation. Key Words: Non-small cell lung cancer, Surgery, Lobectomy, Sublobar resection, Segmentectomy, Wedge resection. (J Thorac Oncol. 2010;5: ) The 1995 publication from the Lung Cancer Study Group s (LCSG) prospective randomized trial of lobectomy versus limited resection for stage IA non-small cell lung cancer (NSCLC) reinforced the need for formal *Department of Surgery, St. Luke s-roosevelt Medical Center, New York, NY; Departments of Surgery and Cardiothoracic Surgery, NYU School of Medicine, New York, NY; and Department of Thoracic Surgery, Bellevue Hospital, New York, NY. Disclosure: The authors declare no conflicts of interest. Address for correspondence: Jessica S. Donington, MD, Department of Cardiothoracic Surgery, NYU School of Medicine, 530 First Avenue, Suite 9V, New York, NY jessica.donington@med.nyu.edu Copyright 2010 by the International Association for the Study of Lung Cancer ISSN: /10/ lobectomy in early-stage patients. Demonstrating an increased risk for local/regional recurrence, reduced 5-year mortality, and no statistical evidence for preservation of pulmonary function, this study disproved speculation that sublobar resection had comparable outcome to lobectomy. 1,2 Since that time, the utility of spiral computer tomography (CT) imaging has refined the presentation and diagnosis of early-stage NSCLC. 3,4 Improved spatial resolution, detection of ground glass opacities (GGOs) associated with favorable histology, and increased screening of high-risk individuals has created a growing cohort of patients with smaller tumors than those assessed in the LCSG trial. Concurrent improvements in adjuvant chemotherapy and radiation therapy techniques, as well as a growing population of older patients with significant medical comorbidities that preclude larger operations, have further driven research to determine the effectiveness of limited resection. Theoretical advantages of sublobar resection include preservation of pulmonary function, improved perioperative morbidity and mortality, and increased potential for a second resection with a subsequent primary tumor. 1,5 10 Multiple single-institution studies have demonstrated equivalent rates of survival and recurrence for patients with small, early-stage tumors that lack gross evidence of lymph node involvement. Increased utilization of minimal access surgical techniques in conjunction with innovation in adjuvant therapy, including the application of brachytherapy, are recent improvements that strengthen the likelihood of sublobar resection affording equivalent survival and rates of recurrence compared with lobectomy. This review of the literature from the last 15 years serves to summarize the clinical research investigating the use sublobar resection in early-stage NSCLC. We will focus on the importance of tumor size, extent of resection ( resection versus segmentectomy), adequate surgical margins, bronchioloalveolar histology, and adjuvant brachytherapy on freedom from recurrence and survival. HISTORY Considerable interest in sublobar resection arose in the 1970s and 1980s when the international community demonstrated the feasibility of limited resection for patients with compromised cardiopulmonary reserve. 11 At that time, 5-year survival data and recurrence rates were deemed inferior to lobectomy, and sublobar resection was Journal of Thoracic Oncology Volume 5, Number 10, October

2 Blasberg et al. Journal of Thoracic Oncology Volume 5, Number 10, October 2010 restricted to patients with impaired cardiac function or significant comorbidities precluding conventional lobectomy. Early work by Warren and Faber 12 in 173 patients with stage I NSCLC demonstrated decreased survival and increased recurrence for sublobar resection versus lobectomy. Continued speculation about the prospects of limited resection prompted the large prospective randomized LCSG trial in 247 patients with stage IA NSCLC comparing limited resection with lobectomy. This study demonstrated a 39% increase in local recurrence and a nonsignificant decrease in overall survival after sublobar resection. 1,2 It included patients with tumors up to 3 cm and a significant number of nonanatomic resections (1 of 3 sublobar procedures). In retrospect, both these parameters may have significantly limited the effectiveness of sublobar resection. 1 Shortly after the LCSG, investigators from the University of Pittsburgh published a prospective, multicenter, nonrandomized study that demonstrated equivalent 1-year survival and 5-year actual survival favoring lobectomy (70% versus 58%). The increased rate of death after limited resection was due almost entirely to non-lung cancer causes (38% versus 18% after lobectomy) and was attributed to poor cardiopulmonary reserve in that cohort. Higher rates of local/regional recurrence after sublobar resection were also demonstrated (18% versus 4%). 13 Since these landmark publications, numerous singleinstitution reviews have recapitulated these results, demonstrating an overall survival advantage for lobectomy. Sienel et al. 14 established poorer cancer-related 5-year survival and increased local/regional recurrence after segmental resection compared with lobectomy for stage IA cancer (16% versus 5%), attributing worse outcome to tumor size and width of resection margin. Kraev et al. 15 demonstrated that lobectomy for stage IA tumors had significantly better 10-year survival than resection, recognizing size as an important prognostic variable to consider when planning sublobar resection. A review by Chang et al. 16 of data from the Surveillance, Epidemiology, and End Result Program (SEER) also demonstrated inferior survival with sublobar resection compared with lobectomy (44% versus 61%) for stage IA disease. Limited resection was associated with fewer dissected mediastinal lymph nodes, reinforcing the importance of lymph node assessment in staging and prognosis. Risk for recurrence in these evaluations was independent of histology. Recent single-institution retrospective investigations evaluating the equivalency of sublobar resection to lobectomy in patients with limited cardiopulmonary reserve contradict earlier results and have demonstrated that stage I disease portends a survival advantage regardless of the extent of surgical resection or histologic subtype (Table 1). The majority of these studies assessed patients preoperatively by CT alone, without mediastinoscopy or positron emission tomography (PET), and performed anatomic segmentectomy with intraoperative mediastinal lymph sampling or dissection and demonstrated comparable 5-year survival between lobectomy and sublobar resection. Campione et TABLE 1. 5-yr Survival Data for Lobectomy vs. for NSCLC Overall 5-yr Survival (%) Sublobar Resection p Lobectomy Evaluation Type of Sublobar Resection vs. Intentional Operative Approach Patients Preoperative Staging Stage Study Trial Design 100% IA 100% thoracotomy I 67% segment, 33% LCSG 1 Prospective 247 CXR, bronchoscopy, selective CT scan 65% Koike et al. 75 Prospective 233 CT Scan IA N/R I 81% segment, 19% Campione et al. 58 Retrospective 120 CT scan and bone scan IA 100% thoracotomy C 100% segment 100% Marin-Ucar et al. 18 Retrospective 34 CT scan IA and IB 76% thoracotomy, C 100% segment 100% N/R 24% VATS % sublobar, 97% lobe El-Sherif et al 19 Retrospective 784 CT scan IA and IB N/R C 41% segment, 59% 100% Mixed 100% extended segment Iwasaki et al. 25 Retrospective 86 CT scan I, II, IIIA 77% thoracotomy, 23% VATS C 100% segment 100% IA and IB 69% thoracotomy, 31% VATS Kilic et al. 6 Retrospective 184 CT scan, selective PET, and mediastinoscopy C, compromised; I, intentional; CT, computerized tomography; PET, positron emission tomography; segment, segmentectomy;, resection; lobe, lobectomy; N/R, not recorded; VATS, video-assisted thoracoscopic surgery Copyright 2010 by the International Association for the Study of Lung Cancer

3 Journal of Thoracic Oncology Volume 5, Number 10, October 2010 al. 17 found no significant difference in survival between lobectomy and anatomic segmentectomy in a series of 121 stage IA patients (median survival: 98 months for lobectomy versus 104 months for sublobar resection). Martin- Ucar et al. 18 retrospectively matched 17 stage IA lobectomy patients to an equal number of segmentectomy patients based on age, gender, use of video-assisted thoracoscopic surgery (VATS), tumor location, and respiratory function and found no difference in morbidity, mortality, 5-year survival, or recurrence. The group from the University of Pittsburgh retrospectively assessed outcomes in 784 stage IA patients and found equivalent disease-free survival and rates of recurrence regardless of resection technique; average tumor size in their sublobar cohort was 1.8 cm, stressing the importance tumor size as a prognostic variable. 19 In a subsequent analysis of 184 patients with stage I NSCLC older than 75 years, the Pittsburgh group demonstrated that segmentectomy was associated with fewer perioperative complications, similar length of hospitalization, and equivalent overall and 5-year disease-free survival compared with lobectomy, even when used in a medically compromised population. 6 These studies and others have outlined specific prognostic factors that play an important role in determining survival and recurrence after sublobar resection: (1) tumor size, (2) lymph node assessment, (3) anatomic versus nonanatomic resection techniques, and (4) adequate surgical margins. These parameters, in addition to the growing body of work from Japan highlighting the utility of sublobar resection for bronchioloalveolar carcinoma (BAC), have become the focus of investigation into the appropriate use of limited resection for NSCLC. 6,20,21 TUMOR SIZE Warren s 1994 series provided early evidence that tumor size carried important prognostic relevance, with a distinct survival advantage and decreased rates of recurrence for tumors less than 2 cm. 12 These results have been replicated by multiple large surgical series including two independent reviews of the SEER database by Chang et al. and Mery et al. 16,22 Each found a significant survival improvement for stage IA tumors more than 2 cm compared with those 2 to 3 cm in size. Approximately 25% of patients with tumors less than 2 cm were successfully treated by limited resection in these reviews. 16,23 Port et al. 24 and Birim et al. 5 also reported improved survival and local control in resected stage IA tumors less than 2 cm compared with those 2 to 3 cm in size. Several modern trials examining sublobar resection have stratified tumors that are larger and smaller than 2 cm and demonstrate a reproducible difference in outcome based on tumor size irrespective of gender, use of invasive preoperative mediastinal staging, minimally invasive or open surgical resection, or performance of segmentectomy versus (Table 2). Bando et al., 26,27 Fernando et al., 2 and Okada et al. 28 each evaluated the impact of tumor size less than 2 cm as an independent predictor of recurrence and survival after sublobar resection. Although these three TABLE 2. Evidence for Increased Survival After Resection for Tumors 2 cm Local Regional Recurrence (%) Tumor >2 cm Tumor <2 cm Overall 5-yr Survival (%) Tumor <2 cm Tumor >2 cm Adjuvant Therapy Evaluation Type of Sublobar Resection vs. Intentional Preoperative Staging Stage Patients Study Bando et al CT pia 55% I, 45% C Segment 100% I, 0% C Oral UFT 1yr a 4.4 a 50.6-mo median survival 55.8-mo median survival 100% 48% brachytherapy Fernando et al N/R pia C 59% segment, 41% N/R N/R 87 segment, % None 97 segment, 92 Okada et al N/R pia N/R 80% segment, 20% a Brachytherapy used more frequently in larger tumors. C, compromised; I, intentional; CT, computerized tomography; UFT, tegafur/uracil; N/R, not recorded; segment, segmentectomy;, resection. Copyright 2010 by the International Association for the Study of Lung Cancer 1585

4 Blasberg et al. Journal of Thoracic Oncology Volume 5, Number 10, October 2010 series contained a mixed population of healthy and medically compromised patients, a distinct survival advantage for tumors less than 2 cm compared with tumors 2 to 3 cm in size was demonstrated. A follow-up evaluation by Bando et al. also investigated the impact of size on survival and recurrence and correlated these findings with the expression of specific tumor markers. Patients were at significantly higher risk for local/regional recurrence after resection of tumors 2 to 3 cm in size, particularly when a concurrent increase in expression of carcinoembryonic antigen, squamous cell carcinoma-related antigen, or fragment of cytokeratin was demonstrated. For tumors less than 2 cm without elevated tumor markers, no recurrence was reported, and 5-year survival was 92%. 27 The findings from these trials mirror data from the recent lung cancer staging project headed by the International Association for the Study of Lung Cancer with respect to the importance of stratifying tumors around a 2 cm cutoff. In this project, tumors less than 2 cm and those 2 to 3 cm were found to have statistically significant differences in 5-year survival (77% versus 71%) and lead to the reclassification of T1 tumors in the revised staging system. In this revision, tumors less than 2 cm are denoted as T1a and tumors between 2 and 3 cm as T1b. 29 Tumor size is an important independent predictor of outcome in NSCLC. Although the LCSG alluded to a survival advantage based on tumor size, more recent literature has successfully characterized tumors less than 2 cm as a distinct entity with improved outcome and may represent the population in whom sublobar resection should be contemplated and the equivalency of resection evaluated. This is particularly relevant to patients with BAC and will be discussed further. SEGMENTECTOMY VERSUS WEDGE RESECTION Although imaging refinements have revolutionized our ability to diagnose early-stage NSCLC, surgical technology has also advanced with improvements in the operative techniques available for limited resection in medically compromised patients. VATS, which was not practiced during the era of the LCSG trial, is now widely performed. Equivalent long-term survival for VATS and open surgical resection for NSCLC have been validated specifically for stage IA disease ( 2 cm tumors), as have the advantages of reduced blood loss, faster recovery, preserved pulmonary function, and shorter hospitalization for VATS. 7,30 32 Wedge resection by VATS is frequently used in sublobar operations because of the technical ease and favorable perioperative morbidity and mortality. Frequently, patients presenting for limited resection have coexisting cardiopulmonary impairment; resection by VATS in this setting is desirable because of reduced operative times and reduced postoperative pain. 10,21,33 35 However, overwhelming data suggest that nonanatomic resections are an inferior oncologic approach compared with anatomic segmentectomy. Higher recurrence rates associated with resection are attributed to important intralobar lymph node basins in the remaining lung tissue. 27 Anatomic segmentectomy has the theoretical advantage of a more comprehensive resection, reduced technical limitations for achieving appropriate margins, and wider resection of draining lymphatics including intersegmental planes commonly referenced as a source of residual cancer cells. 26,32 The dissection also allows en bloc removal of adjacent anatomic segments based on tumor size and invasion, 27,32,36 which mirrors many of the important characteristics of lobectomy. 6,36 Newer techniques, such as jet ventilation of individual segments, further enhances identification of intersegmental planes. 37 Separating data on anatomic segmentectomy from nonanatomic resection and analyzing the survival and recurrence rates for each procedure is important when evaluating sublobar resection for NSCLC. Yoshikawa et al. 38 demonstrated equivalent 5-year survival (82%) for extended open segmentectomy and mediastinal lymph node dissection as an intentional resection protocol for patients with tumors less than 2 cm to historical controls for lobectomy. Studies that report the results of versus segmentectomy independently are outlined in Table 3. In each, patients were staged preoperatively by CT scan and underwent intraoperative mediastinal lymph node sampling or dissection to properly identify involved lymph node basins (N2). A study by Miller et al. from the Mayo Clinic specifically examining outcomes in tumors 1 cm analyzed outcome differences among lobectomy, segmentectomy, and. Although there was a distinct survival advantage favoring lobectomy, subdivision of limited resection patients uncovered a statistically significant survival advantage and improved local control with segmentectomy compared with resection even in these very small tumors. 39 Okada et al. 28 and El-Sherif et al. 40 each reported a critical difference in recurrence based on the extent of resection in large retrospective reviews. Increased local/regional recurrence after resection was attributed to the technical limitations of achieving an appropriate margin and incomplete dissection of intraparenchymal and hilar lymph nodes with. In a review from Europe of sublobar resection in stage IA patients with cardiopulmonary insufficiency, Sienel et al. also found significantly less local/regional recurrence (55% versus 16%) and improved cancer-specific survival (71% versus 48%) after anatomic segmentectomy with systematic nodal dissection compared with resection with selective nodal sampling. In their multivariate analysis, the type of resection, tumor size, and age were significant prognostic indicators. 41 VATS segmentectomy, similar to VATS lobectomy, is now more widely performed but requires longer operative time and greater technical expertise compared with open procedures. 30 Experience with VATS segmentectomy continues to expand in some series, demonstrating equivalent oncologic effectiveness to VATS lobectomy. In a recent assessment by Shapiro et al. specifically comparing the equivalency of VATS segmentectomy for compro Copyright 2010 by the International Association for the Study of Lung Cancer

5 Journal of Thoracic Oncology Volume 5, Number 10, October 2010 TABLE 3. Survival and Recurrence Rates After Wedge Resection and Anatomic Segmentectomy for NSCLC Local Recurrence Rate (%) 5-yr Cancer-Specific Survival (%) Wedge Segment Wedge Segment Evaluation (%) Histology vs. Intentional Resection Type Preoperative Staging Patients Stage Study Miller et al I III CT C 12 segment, adeno, 26 squam, 19 BAC, 3 other N/R N/R 92 ( 2 cm), 85 (2 3 cm), 63 ( 3 cm) 97 ( 2 cm), 39 (2 3 cm), 0( 3 cm) Okada et al I III N/R N/R 285 segment, adeno, 456 squam, 34 LC N/R N/R 15 4 El-Sherif et al IA and IB CT C 26 segment, adeno, 26 squam, 13 LC, 9 BAC adeno, 26 squam, 23 other Sienel et al IA CT C 56 segment, segment selective in C, compromised; I, intentional; CT, computerized tomography; N/R, not recorded;, resection; segment, segmentectomy; adeno, adenocarcinoma; squam, squamous cell carcinoma; LC, large cell carcinoma; BAC, Bronchoalveolar carcinoma. mised patients to VATS lobectomy for tumors less than 3 cm, the number of resected lymph nodes, chest tube duration, complications, recurrence rates (17.6% versus 16.7%), and overall 2-year survival were similar between modalities. Mean tumor size was less than 2 cm for both groups. 10 The survival advantage and decreased rates of local/ regional recurrence after segmentectomy demonstrated in these series are likely related to three key features inherent to the technique: (1) resection along anatomic planes, (2) wider resection margins, and (3) resection of intraparenchymal draining lymphatics. Primary sources of local recurrence after NSCLC resection include remnant tumors of intrapulmonary metastasis, intralobar lymph node metastasis, and an incomplete resection with positive margins. 26,42 Anatomic segmentectomy is regarded as an oncologically superior procedure compared with resection because it more definitively addresses these tumor basins. However, regardless of the extent of resection, thorough mediastinal lymph node assessment is suggested for completeness of staging and to appropriately compare outcome data with lobectomy. 6,8,10,37 BRONCHIOLOALVEOLAR CARCINOMA BAC is a noninvasive variant of adenocarcinoma with unique clinical and radiologic features that distinguish it from other forms of NSCLC. It is reported in up to 24% of pathology specimens after resection of lung tumors less than 2 cm. The incidence of BAC has increased substantially over the past 20 years following the World Health Organization reclassification to include tumors with pure lepidic spread and no evidence of stromal, vascular, or pleural invasion. 43 A survival advantage conferred by BAC was initially characterized in the United States after an evaluation by the LCSG of 1635 patients with resected adenocarcinomas less than 3 cm. A total of 235 specimens demonstrated pure BAC histology, which correlated with better overall survival and decreased risk for recurrence compared with the invasive adenocarcinoma cohort. Additional studies, including a Japanese review of 236 patients with peripheral adenocarcinomas less than 2 cm, demonstrated that tumor histology with minimal stromal response and no invasion (Noguchi type A or B) was associated with 100% 5-year survival. 44 The use of limited resection for patients with pure or mixed BAC has been assessed in a variety of retrospective Japanese trials (Table 4). In each of these studies, patients with BAC had prolonged survival and lower recurrence after resection than those with other subtypes of NSCLC. 45,46 Reviews by Yamada and Kohno and Yamato et al., 45,47 using intentional limited resection in patients with pure ground glass opacities (GGOs) less than 2 to 3 cm, demonstrated 100% survival and no evidence of recurrence at median follow-up of 30 months. In another assessment of long-term recurrence and survival by Watanabe et al., patients with suspected BAC underwent intentional resection with intraoperative pathologic evaluation. No recurrence and 100% survival at 5 years Copyright 2010 by the International Association for the Study of Lung Cancer 1587

6 Blasberg et al. Journal of Thoracic Oncology Volume 5, Number 10, October 2010 TABLE 4. Survival and Recurrence for for Bronchioloalveolar Carcinoma Rate of Local Recurrence (%) Overall Disease- Free Survival (%) Evaluation (%) Histology vs. Intentional Surgical Approach Resection Type Tumor Size Preoperative Staging Patients Gender Study 0 BAC, N/R adeno Sakurai et al M, 72 F CT 3 cm I 100% thoracotomy 7 segment, 101 lobe BAC, 83 adeno 100 BAC, 64 adeno 0 (median F/U of 30 mo) 8 AAH, 31 BAC 100 (median F/U of 30 mo) 0, 100 segment/lobe Yamada and Kohno 46 4 lobe M, 22 F CT 3 cm I 100% VATS 31, 4 segment, 0 (median F/U of 30 mo) BAC 100 (median F/U of 30 mo) Yamato et al M, 18 F CT 2 cm I 100% thoracotomy 34, 2 segment, 6 lobe 0 (median F/U of 32 mo) 14, 3 segment 0 17 BAC 100 (median F/U of 32 mo) Watanabe et al M,13F CT 3 cm I 82% VATS, 18% thoracotomy C, compromised; I, intentional; CT, computerized tomography; VATS, video-assisted thoracoscopic surgery;, resection; segment, segmentectomy; lobe, lobectomy; adeno, adenocarcinoma; BAC, bronchoalveolar carcinoma; AAH, atypical adenomatous hyperplasia; F/U, follow-up. was seen in patients with confirmed BAC histology on intraoperative pathologic analysis, despite the fact that intraoperative lymph node evaluation was not performed. 48,49 Sugi et al. analyzed the utility of intentional VATS sublobar resection compared with VATS lobectomy in 159 clinical stage IA patients from Japan. The extent of resection was based on tumor size, achievable resection margins, and ratio of GGO on preoperative imaging. VATS resection was used only for peripheral tumors less than 1.5 cm with GGO ratio of more than 75%, indicating a high likelihood of pure BAC histology. Five-year recurrence-free survival in this group was 100%. Central tumors or those 1.5 to 2 cm in size with a high GGO ratio were resected by VATS segmentectomy with mediastinal lymph node sampling, with 5-year recurrence-free survival of 90.5%. The remaining patients, with tumors 2 to 3 cm or low GGO ratio, underwent VATS lobectomy with 5-year recurrence-free survival of 94.5%. 50 There was no statistical survival difference between the groups, highlighting the importance of size, favorable CT appearance with high GGO ratio, and adequate resection margins to achieve oncologic equivalency between sublobar resection and lobectomy. Two similar series by Kodama et al. and Okada et al. used the same principles of tumor size, GGO ratio, and need for wide resection margins to determine the extent of resection in patients with small ( 2 cm) peripheral tumors. Each series reported equivalent survival and recurrence rates among lobectomy, segmentectomy, and when utilizing this resection algorithm, recognizing high GGO ratio as predictor of decreased recurrence after sublobar resection. 28,51 It is becoming apparent that pure GGOs on diagnostic imaging represent BAC without areas of invasive adenocarcinoma, whereas tumors with mixed ground glass and solid appearance are likely mixtures of both BAC and invasive adenocarcinoma. 52 In addition, tumors less than 2 cm with greater than 50% density of GGOs are unlikely to have N1 or N2 lymph node metastasis. Five-year survival after limited resection in these tumors is approximately 100% with no incidence of recurrence. 53 These patients may ultimately prove to be the most appropriate candidates for intentional limited resection However, extrapolation of these results to the use of intentional sublobar resection for larger tumors and those with less than 50% GGO ratio remains unproven. 45,58,59 THE ROLE OF ADEQUATE MARGINS Cancer surgery demands specific universal standards that are critical for survival and low recurrence rates. One of the most important of these regards the role of adequate resection. Inadequate resection margins have been attributed to recurrence in a multitude of solid tumors including NSCLC. Technical limitations that preclude negative surgical margins are a more challenging issue for sublobar resection than conventional lobectomy. Reliance on intraoperative frozen section has traditionally been the sole 1588 Copyright 2010 by the International Association for the Study of Lung Cancer

7 Journal of Thoracic Oncology Volume 5, Number 10, October 2010 modality for assurance that negative margins were achieved; however, these results can be flawed. Several molecular techniques have been developed, which are useful for intraoperative margin assessment. Higashiyama et al. 60 described a cytologic lavage of surgical staplers as a more sensitive tool to uncover positive margins after resection. Ten percent of patients with negative margins by frozen section had positive cytology on stapler lavage for malignancy. Sawabata et al. evaluated the use of glass slide brushings of staple lines after resection to uncover residual malignant cells. Those with residual disease detected at the staple line had nearly a 50% increased risk of local recurrence, whereas negative cytology nearly excluded recurrence. 61 Masasyesva et al. found a strong association between K-ras mutations sequenced from DNA isolated at the tumor resection margin and recurrence. Sixty-seven percent of patients with K-ras mutations at histologically negative resection margins developed local/regional recurrence, whereas a lack of K-ras mutation was associated with 0% recurrence. 62 These techniques are useful adjuncts for establishing negative margins after limited resection. Inadequate surgical margins portend a significantly higher risk of local/regional recurrence regardless of the type of resection. It is uncertain how significantly this affects long-term survival in patients with limited cardiopulmonary reserve and high noncancer-specific mortality. When sublobar resection is used in medically fit patients who would otherwise tolerate conventional lobectomy, increased local/regional recurrence rates are more likely to affect long-term survival, enhancing the importance of adequate surgical margins. There is growing evidence that negative cytologic margins alone are not adequate to reduce the risk of local recurrence in NSCLC, and that a tumor margin of at least 2 cm may be needed. A review of sublobar resection in 81 stage IA patients from the University of Pittsburgh reported recurrence in 15% of patients with margins less than 1 cm and only 8% of patients with more than 1-cm margins. 40 Two independent series from Sawabata et al. and Schuchert et al. identified a margin distance greater than 2 cm and greater than the maximal tumor diameter as favorable indicators for decreased recurrence after sublobar resection. 9,63 Much of the literature over the last 10 years supports anatomic segmentectomy over resection because it can more effectively achieve the goal of 2-cm margins. Regardless of the procedure performed, achieving adequate margin distance is extremely important when considering sublobar resection, especially when used as an alternative to lobectomy in a medically fit population. ADJUVANT BRACHYTHERAPY Inadequate surgical margins are strongly associated with recurrence after sublobar resection. As such, unacceptable levels of local/regional recurrence, as demonstrated by the LCSG and others, have driven improvements in localized adjuvant therapy. Iodine-125 ( 125 I) brachytherapy seed placement is an ideal technology for sublobar resection, specifically for compromised patients with limited cardiopulmonary reserve. Medically compromised patients undergoing limited resection often survive long enough to be at risk for cancer recurrence. Implantation of brachytherapy seeds at the time of resection allows for the delivery of a concentrated dose of radiation to the resection margin in a quick and precise manner with little exposure to the surrounding lung. 64 This technique is a significant advancement over adjuvant external beam radiation used in the 1980s and 1990s, both in its effectiveness and lack of associated treatment morbidity. 65 d Amato et al. 66 first reported on the feasibility of intraoperative brachytherapy in 14 medically compromised patients undergoing VATS sublobar resection, demonstrating no additional morbidity or mortality after seed placement. Multiple small, prospective series have reported favorable recurrence rates for sublobar resection with brachytherapy in medically compromised cohorts (Table 5). In a prospective analysis of medically compromised patients with stage I NSCLC, Lee et al. reported a 10.5% local recurrence rate after resection with brachytherapy and 77% 5-year cancer-specific survival for tumors less than 3 cm, which was comparable with a matched lobectomy cohort. In patients with tumors more than 3 cm, local recurrence was higher and survival decreased compared with patients undergoing lobectomy. 67 A review by Santos et al. specifically compared recurrence and survival between sublobar resection with and without adjuvant brachytherapy in a series of 203 patients with poor cardiopulmonary reserve and stage I NSCLC. Local recurrence was reduced from 18.6 to 2% with the addition of brachytherapy. No difference in operative mortality, distant recurrence, or 4-year overall survival (60% versus 67%, respectively) was found. Failure to demonstrate an improvement in survival was likely due to underlying medical comorbidities. 68 Dosimetric analysis of this population reported by Johnson et al. 65 confirmed that 125 I seeds resulted in limited radiation fields at the resection margin while sparing surrounding normal lung tissue and concluded that brachytherapy was superior to external beam radiation on parameters of cardiac toxicity, lung fibrosis, and loss of pulmonary function. A multi-institutional series of sublobar resection by Fernando et al. reported on a subgroup of 60 patients who received 125 I seeds to resected staple lines and compared survival and local recurrence to 64 sublobar resection patients without brachytherapy. The type of sublobar resection was not specified, but local recurrence was reduced from 17.2 to 3.3% with the application of brachytherapy seeds. 69 Birdas et al. reviewed 167 patients with resected stage IB NSCLC and found that sublobar resection with 125 I brachytherapy to have local recurrence rates to the equivalent of lobectomy (3.2 and 4.8%, respectively). They also reported similar rates of disease-free and overall survival, despite decreased preoperative cardiopulmonary function in the sublobar resection group. 70 Sublobar resection with brachytherapy for patients with medical contraindications to lobectomy seems to be a Copyright 2010 by the International Association for the Study of Lung Cancer 1589

8 Blasberg et al. Journal of Thoracic Oncology Volume 5, Number 10, October 2010 TABLE 5. Recurrence and Survival for with Brachytherapy Overall Survival (%) Sublobar Resection Brachytherapy Local Recurrence (%) Resection Alone Resection Brachytherapy Resection Alone Evaluation Histology vs. Intentional Surgical Approach Resection Type Preoperative Staging Stage Patients Study 58% N/R N/A 6 N/A 47 (5 yr) IA and IB C Thoracotomy 31, 2 segment, 1 lobe Lee et al CT (mediastinoscopy in 3) Santos et al CT IA and IB C 89 VATS, 114 thoracotomy N/R Selective use N/R (4 yr) 67 (4 yr) Fernando et al N/R IA C N/R 51, 73 segment 100% N/R N/R N/R Birdas et al CT IB C 11 VATS, 30 thoracotomy 14, 27 segment N/R 18 squam, 18 adeno, N/A 4.8 N/A 54 (4 yr) 1LC McKenna et al. 66a 48 CT I, II, IIIa C VATS Wedge 100% 7 squam, 32 adeno, N/A 6.3 N/A 79 (1 yr) 3 BAC, 2 LC, 4 other CT, computerized tomography; C, compromised; I, intentional; VATS, video-assisted thoracoscopic surgery;, resection; segment, segmentectomy; lobe, lobectomy; adeno, adenocarcinoma; squam, squamous cell carcinoma; BAC, Bronchoalveolar carcinoma; LC, large cell carcinoma; N/A, not applicable; N/R, not recorded. reasonable alternative. An ongoing multicenter, phase II trial sponsored by the American College of Surgeons Oncology Group (ACOSOG Z4032) is prospectively evaluating the use of sublobar resection with adjuvant 125 I brachytherapy seed placement in high-risk patients with stage IA NSCLC. Local recurrence and survival are the primary end points. All patients in this study undergo cytologic analysis to ensure negative margins. Survival will be compared between patients with and without brachytherapy and ultimately matched to historical lobectomy outcome data for analysis. INTENTIONAL SUBLOBAR RESECTION It is incredibly important when evaluating survival after sublobar resection to differentiate between those resections performed in a compromised situation for a medically unfit population and those performed intentionally in patients who would otherwise tolerate lobectomy. Improved detection of small peripheral tumors and GGOs associated with favorable histology has led to the increased use of sublobar resection in many centers to include patients with adequate physiologic reserve. 4 Both American and Japanese series have demonstrated that small BAC, which is identified preoperatively by high GGO ratio, represents an entity with improved survival and reduced rates of metastatic disease to lymph nodes. 4,71,72 Additional parameters such as the absence of pleural invasion, 73 lack of spiculation, 74 or lack of elevations of tumor markers have also been shown to have prognostic significance in early-stage NSCLC. 27 Selection of medically fit patients with very favorable tumors for intentional limited resection is gaining acceptance in the international community. An early nonrandomized Japanese trial from Kodama et al. compared recurrence and survival in medically fit patients with stage IA NSCLC undergoing intentional segmentectomy with lymph node dissection to standard lobectomy and to a small cohort of medically unfit patients undergoing a compromised sublobar resection. Fiveyear survival after intentional limited resection was 87% and comparable with lobectomy at 86%. Local/regional recurrence was also comparable with lobectomy at 4.3%. The intentional sublobar group had improved overall and cancer-specific survival and local/regional control compared with the compromised group. Percentage of patients in each group with BAC in this older series was not reported, but results suggest that segmentectomy with appropriate lymph node dissection may be a viable intentional alternative for healthy patients with stage I disease, especially for tumors less than 2 cm. 74 Bando et al., 26,27 Koike et al., 75 and Okada et al. 76 reported similar outcome data for intentional sublobar resection in well-selected patients with small peripheral NSCLC tumors. Each series demonstrated equivalent local control and survival compared with lobectomy (Table 6). These studies establish the foundation for future research that views sublobar resection as a means of maintaining lung volume without an increased risk of 1590 Copyright 2010 by the International Association for the Study of Lung Cancer

9 Journal of Thoracic Oncology Volume 5, Number 10, October 2010 TABLE 6. Study Recurrence and Survival for Intentional s Patients Preoperative Staging Stage vs. Intentional Surgical Approach Resection Type Evaluation (%) 5-yr Actual Survival (%) Rate of Local Recurrence (%) Kodama et al CT IA I Thoracotomy Segment Bando et al CT IA I Thoracotomy Segment Koike et al CT IA I Thoracotomy 60 segment, Okada et al CT, bone scan IA, 2 cm I Thoracotomy 230 segment, 30 CT, computerized tomography; C, compromised; I, intentional;, resection; segment, segmentectomy TABLE 7. Tumor, Resection, and Patient Characteristics Associated with Improved Survival After for NSCLC Improved Prognosis Poor Prognosis Tumor characteristics Size 2 cm 2 cm CT appearance Pure GGO Solid, spiculated Histology Noninvasive, BAC Invasive Location Peripheral 1/3 Central 1/3 Resection specifications Extent Anatomic Nonanatomic, segmentectomy Resection margin 2 cm, diameter of tumor 2 cm, diameter of tumor Adjuvant Used Not used brachytherapy nodal evaluation Performed Not performed Patient characteristics Cardiopulmonary status Fit, could tolerate lobectomy CT, computerized tomography; GGO, ground glass opacity; BAC; Bronchoalveolar carcinoma. local/regional recurrence for selected patients with small peripheral, early-stage NSCLC. Currently, a prospective, randomized, multi-institutional phase III trial is being conducted by the Cancer and Lymphoma Group B (CALGB ) to determine the effectiveness of an intentional sublobar resection protocol for small peripheral tumors ( 2 cm). Conventional lobectomy is being compared with sublobar resection ( or segmentectomy). All patients will undergo intraoperative mediastinal lymph node dissection to ensure negative involvement before randomization. 32 Results will likely provide important contributions to the role of intentional resection for small, peripheral stage IA tumors. CONCLUSION The future use of sublobar resection for NSCLC needs to be founded on the long-standing principles of surgical oncology, with selective use for small tumors and those with favorable histologic profile, assurance of adequate surgical margins, proper evaluation of hilar and mediastinal lymph nodes, and the use of adjuvant therapy. Each of these components has been independently associated with improved outcome. When selected appropriately, early-stage patients, either healthy or with significant comorbidities, seem to have the potential for comparable survival and recurrence to their lobectomy counterparts with the thoughtful and appropriate use of sublobar resection. Patient and tumor characteristics and resection specifications that have been associated with improved survival and reduced local recurrence after sublobar resection for NSCLC are summarized in Table 7. Ultimately, the utility of limited resection will be dependent on a system of experienced thoracic surgeons, with an early detection/ screening protocol for high-risk individuals and a multidisciplinary approach to diagnosis, surgery, and adjuvant therapy. Under those conditions, comparable survival is a likely reality. REFERENCES 1. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60: ; discussion Lederle FA. Lobectomy versus limited resection in T1 N0 lung cancer. Ann Thorac Surg 1996;62: Henschke CI, Yankelevitz DF, Altorki NK. The role of CT screening for lung cancer. Thorac Surg Clin 2007;17: Koike T, Togashi K, Shirato T, et al. Limited resection for noninvasive bronchioloalveolar carcinoma diagnosed by intraoperative pathologic examination. Ann Thorac Surg 2009;88: Keenan RJ, Landreneau RJ, Maley RH Jr, et al. Segmental resection spares pulmonary function in patients with stage I lung cancer. Ann Thorac Surg 2004;78: ; discussion Kilic A, Schuchert MJ, Pettiford BL, et al. Anatomic segmentectomy for stage I non-small cell lung cancer in the elderly. Ann Thorac Surg 2009;87: ; discussion Oizumi H, Kanauchi N, Kato H, et al. Total thoracoscopic pulmonary segmentectomy. Eur J Cardiothorac Surg 2009;36: ; discussion Pettiford BL, Schuchert MJ, Santos R, et al. Role of sublobar resection (segmentectomy and resection) in the surgical management of non-small cell lung cancer. Thorac Surg Clin 2007;17: Schuchert MJ, Pettiford BL, Keeley S, et al. Anatomic segmentectomy in the treatment of stage I non-small cell lung cancer. Ann Thorac Surg 2007;84: ; discussion Shapiro M, Weiser TS, Wisnivesky JP, et al. Thoracoscopic segmentectomy compares favorably with thoracoscopic lobectomy for patients with small stage I lung cancer. J Thorac Cardiovasc Surg 2009;137: Jensik RJ, Faber LP, Milloy FJ, et al. Segmental resection for lung Copyright 2010 by the International Association for the Study of Lung Cancer 1591

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