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Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry
ORIGINAL ARTICLE
Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry Bryan M. Burt, MD,a,* Xiaopan Yao, MD,b Joseph Shrager, MD,c Alberto Antonicelli,b Sukhmani Padda, MD,c Jonathan Reiss, MD,d Heather Wakelee, MD,c Stacey Su, MD,e James Huang, MD,f Walter Scott, MDe a
Baylor College of Medicine, Houston, Texas Yale University, New Haven, Connecticut c Stanford University School of Medicine, Stanford, California d University of California Davis Medical Center, Sacramento, California e Fox Chase Cancer Center, Philadelphia, Pennsylvania f Memorial Sloan-Kettering Cancer Center, New York, New York b
Received 13 May 2016; revised 6 July 2016; accepted 15 August 2016 Available online - 23 August 2016
ABSTRACT Introduction: Minimally invasive thymectomy (MIT) is a surgical approach to thymectomy that has more favorable short-term outcomes for myasthenia gravis than open thymectomy (OT). The oncologic outcomes of MIT performed for thymoma have not been rigorously evaluated. We analyzed determinants of complete (R0) resection among patients undergoing MIT and OT in a large international database. Methods: The retrospective database of the International Thymic Malignancy Interest Group was queried. Chi-square and Wilcoxon rank sum tests, multivariate logistic regression models, and propensity matching were performed. Results: A total of 2514 patients underwent thymectomy for thymoma between 1997 and 2012; 2053 of them (82%) underwent OT and 461 (18%) underwent MIT, with the use of MIT increasing significantly in recent years. The rate of R0 resection among patients undergoing OT was 86%, and among those undergoing MIT it was 94% (p < 0.0001). In propensitymatched MIT and OT groups (n ¼ 266 in each group); however, the rate of R0 resection did not differ significantly (96% in both the MIT and OT groups, p ¼ 0.7). Multivariate analyses were performed to identify determinants of R0 resection. Factors independently associated with R0 resection were geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy. Surgical approach, whether minimally invasive or open, was not associated with completeness of resection. Conclusions: The use of MIT for resection of thymoma has been increasing substantially over time, and MIT can
achieve rates of R0 resection for thymoma similar to those achieved with OT. 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. Keywords: Thymoma; Thymectomy; Minimally invasive; Complete resection; R0
Introduction Minimally invasive surgical approaches for thymectomy have gained popularity for patients with nonthymomatous myasthenia gravis (MG), and a variety of single-institution studies suggest that that minimally invasive thymectomy (MIT) has improved short-term outcomes when compared with open thymectomy (OT). For example, when compared with OT, MIT has been associated with shorter hospital stays,1–7 shorter length of stay in the intensive care unit,1 lower operative blood loss,1,7,8 improved postoperative pulmonary function,9
*Corresponding author. Disclosure: The authors declare no conflict of interest. Address for correspondence: Bryan M. Burt, MD, One Baylor Place, BCM390, Baylor College of Medicine, Houston, Texas. E-mail: bryan. [email protected] ª 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2016.08.131
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decreased postoperative pain,10 and similar operating room times.1 Currently, there are few published oncologic outcomes data that support the adoption of MIT for patients with thymic malignancies. For resection of thymoma, MIT and OT could vary with respect to rates of R0 resection, extent of thymectomy, and risk of violation of the tumor capsule. It is well known that R0 resection is the most important long-term prognostic indicator in thymoma, and resection status at the time of thymectomy closely correlates with recurrence outcomes.11–15 Using the large international database of the International Thymic Malignancies Interest Group (ITMIG), we therefore set out to (1) determine whether MIT was associated with rates of incomplete resection equivalent to those with OT for thymoma and (2) identify factors that were independently associated with completeness of resection.
Materials and Methods The ITMIG database is a multi-institutional retrospective database with contributions from 43 institutions on four continents.16 All data were deidentified and considered exempt from institutional review board review. This database was queried to define a cohort of patients who underwent OT or MIT for thymoma from the date of the first MIT entry in January 1997 up until the date of last entry in December 2012. This study was conducted on the basis of the data available in the ITMIG database at the time of data harvest. For this project, OT was defined as either sternotomy or thoracotomy, and MIT was defined as either a video-assisted thoracoscopic surgery (VATS)- or robotic-assisted thoracoscopic surgery (RATS)-based approach. The thoracosternotomy and clamshell approaches, cervical thymectomy, and mediastinotomy approaches were intentionally excluded as they represented a minority of resection types, as well as to balance the OT and MIT comparison groups. Variables examined in our analyses are listed in Table 1 and each contained less than 5% missing data. The clinical stage variable was intentionally excluded because of 28% missing data. A total thymectomy was defined in the database as resection of the thymoma and the entire thymus gland, whereas a partial thymectomy was defined as resection of the thymoma with a margin of normal thymic tissue. The R0, R1, and R2 variables were defined in the database as being identified from surgical pathology reports. Conversion from MIT to OT data was not available from the retrospective ITMIG database. All statistical analyses were performed with SAS 9.3 software (SAS Institute, Inc., Cary, NC). Patient characteristics were compared between the MIT and OT groups
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using the chi-square test for categorical variables and the Wilcoxon rank sum test for continuous variables. Propensity matching was performed by the nearest available pair matching method, with utilization of all the variables in this study with the exception of completeness of resection. The patients undergoing MIT were ordered and sequentially matched to the nearest unmatched patients undergoing OT. If multiple patients in the OT group had propensity scores equally close to that of the patient in the MIT group, one of those patients in the OT group was selected at random. A p value less than 0.05 was used to determine significance. Univariate logistic regression analyses were used to investigate the relationship between resection status and clinical and patient characteristic variables, including age, sex, paraneoplastic syndrome, time period, WHO histologic type, pathologic Masaoka stage, tumor size, extent of thymectomy, surgical approach, and use of chemotherapy and radiotherapy. A multivariate logistic regression model was built to test the association between resection status and surgical approach (MIT versus OT), including other clinical factors and patient characteristics variables as covariates.
Results A total of 2514 patients underwent thymectomy for thymoma between January 1997 and December 2012. Of those patients, 2053 (82%) underwent OT (1751 [85%] by sternotomy and 302 [15%] by thoracotomy) and 461 (18%) underwent MIT (315 [68%] by VATS and 146 [32%] by RATS). The numbers of MIT and OT cases performed from 1997 to 2012 are shown graphically in Figure 1. The frequency of MIT cases was seen to increase from 2008 to 2012, at which time its frequency approached that of the of OT cases. The demographic, clinical, and pathologic characteristics of these cases are shown in Table 1. Most of the MIT cases were contributed from Asian institutions. Patients undergoing MIT were 2.1 years younger than those undergoing OT, and patients in the MIT group were more likely to be female (55%) than were those in the OT group (45%). Patients undergoing MIT had a more favorable World Health Organization (WHO) histologic type and less advanced pathologic Masaoka stage than patients undergoing OT. In the MIT group, the mean tumor size was 4.0 cm (range 0.4–15.5 cm) compared with 6.0 cm (range 0.1–28.0 cm) in the OT group. The rate of partial thymectomy was found to be higher in the MIT group (27%) than in the OT group (9%). Patients undergoing MIT were less likely to have received chemotherapy (3%) or radiotherapy (31%) than were those undergoing OT (16% and 37%, respectively), and most chemotherapy and radiotherapy was administered in the adjuvant setting.
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Table 1. Demographics and Clinicopathologic Characteristics of Study Cohort Variable Region Americas Asia Europe Time period 1997–2000 2001–2004 2005–2008 2009–2012 Median age (range), y Sex Male Female Paraneoplastic syndrome No Yes WHO histologic type A AB B1 B2 B3 Masaoka stage (pathologic) I II III IV Median tumor size (range), cm Extent of thymectomy Partial Total Resection status R0 R1/2 Chemotherapy None Neoadjuvant Adjuvant Radiotherapy None Neoadjuvant Adjuvant
All (N ¼ 2514)
MIT (n ¼ 461)
OT (n ¼ 2053)
p Value <0.0001
672 (27) 873 (35) 969 (39)
82 (18) 227 (49) 152 (33)
590 (29) 646 (31) 817 (40)
304 (12) 501 (20) 738 (29) 971 (39) 54 (8–88)
8 (2) 24 (5) 91 (20) 338 (73) 52 (15–85)
296 (14) 477 (23) 647 (32) 633 (31) 54 (8–88)
1239 (49) 1275 (51)
207 (45) 254 (55)
1032 (50) 1021 (50)
1480 (60) 1008 (41)
256 (56) 204 (44)
1224 (60) 804 (40)
256 575 437 599 413
59 (14) 105 (25) 80 (19) 126 (30) 55 (13)
197 470 357 473 358
868 (39) 838 (38) 371 (17) 142 (6) 5.5 (0.1–28.0)
199 (47) 186 (44) 27 (6) 12 (3) 4.0 (0.4–15.5)
669 (37) 652 (36) 344 (19) 130 (7) 6.0 (0.1–28.0)
291 (12) 2091 (88)
122 (27) 331 (73)
169 (9) 1760 (91)
2178 (88) 309 (12)
430 (94) 29 (6)
1748 (86) 280 (14)
2182 (87) 18 (7) 15 (6)
447 (97) 2 (0) 12 (3)
1735 (85) 179 (9) 139 (7)
1601 (64) 4 (1) 867 (35)
316 (69) 2 (0) 143 (31)
1268 (63) 34 (1) 735 (36)
<0.0001
0.002 0.04
0.06
0.01 (11) (25) (19) (26) (18)
(11) (25) (19) (26) (19) <0.0001
<0.0001 <0.0001
<0.0001
<0.0001
0.02
Note: Column percentages are shown in parentheses. p Values represent comparison of MIT and OT. MIT, minimally invasive thymectomy; OT, open thymectomy.
Eighty-eight percent of all thymectomies achieved complete (R0) resection, and R0 resection was achieved more frequently in patients undergoing MIT (94%) than in those undergoing OT (86%). There was a statistically significant relationship with R0 resection and more recent time period for all patients (p < 0.0001), and Figure 2 shows these relationships in the MIT (p ¼ 0.22) and OT (p ¼ 0.02) cohorts. Among MIT resections, the rate of R0 resection in VATS thymectomy was 95% and that in RATS thymectomy was 92% (p ¼ 0.2). To determine whether completeness of resection was independently associated
with surgical approach, propensity matching was performed between the MIT and OT groups. As shown in Table 2, the MIT and OT groups each contained 266 patients and were balanced with respect to all variables. The rate of R0 resection did not differ between the balanced MIT and OT groups; it was 96% in each group (p ¼ 0.7). A sensitivity analysis of patients with stage I–II thymoma was performed in 385 patients undergoing MIT and 1313 patients undergoing OT. This analysis demonstrated no significant difference in R0 resection between patients in the MIT group (96.6%) and OT group (95.1%) (p ¼ 0.19).
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Table 2. Propensity-Matched MIT and OT Groups Variable
Figure 1. The number of minimally invasive thymectomies (MITs) and open thymectomies (OTs) for thymoma by year.
To examine which factors were associated with R0 thymoma resection, univariate analyses were performed in all patients undergoing thymectomy (MIT and OT). Variables significantly associated with R0 resection included geographic region, later time period, female sex, less favorable WHO histologic type, less advanced Masaoka stage, total thymectomy, minimally invasive surgical approach, and no chemotherapy or radiotherapy received (Table 3). Multivariate analyses were next performed to determine which of these factors were independently associated with R0 resection status. In these analyses, surgical approach, minimally invasive or open, was not a predictor of R0 resection. Variables that were independently associated with R0 resection included region, more recent time period, less advanced Masaoka stage, total thymectomy, and no radiotherapy received (Table 4).
Discussion To advance the knowledge of thymic malignancies, the ITMIG has developed a centralized, international, retrospective database that currently represents the largest data set assembled for these relatively infrequent tumors.16 Because the oncologic effectiveness of MIT is essentially unknown, we utilized this data set to
Region Americas Asia Europe Time period 1997–2000 2001–2004 2005–2008 2009–2012 Mean age, y Sex Male Female Paraneoplastic syndrome No Yes WHO histologic type A AB B1 B2 B3 Masaoka stage (pathologic) I II III IV Mean tumor size, cm Extent of thymectomy Partial Total Chemotherapy None Neoadjuvant Adjuvant Radiotherapy None Neoadjuvant Adjuvant Resection status R0 R1/R2
MIT (n ¼ 266)
OT (n ¼ 266)
p Value 0.5
52 (20) 134 (50) 80 (30)
43 (16) 134 (50) 89 (34)
7 (3) 19 (7) 53 (20) 187 (70) 51.4
8 (3) 12 (5) 46 (17) 200 (75) 51.5
127 (48) 139 (52)
129 (49) 127 (51)
148 (56) 118 (44)
144 (54) 122 (46)
29 75 58 68 34
38 72 54 72 30
0.6
1.0 0.9
0.9
0.7 (11) (28) (22) (26) (14)
(14) (27) (20) (27) (11) 0.6
119 (45) 122 (46) 20 (8) 5 (2) 4.6
127 (48) 121 (46) 13 (5) 5 (2) 4.7
54 (20) 212 (80)
51 (19) 215 (81)
256 (96) 2 (1) 8 (3)
260 (98) 1 (0) 6 (2)
183 (69) 2 (1) 81 (30)
187 (70) 3 (1) 76 (29)
256 (96) 10 (4)
255 (96) 11 (4)
0.7 0.9
0.7
0.8
0.7
Note: Column percentages are shown in parentheses. p Values represent comparison of MIT and OT. MIT, minimally invasive thymectomy; OT, open thymectomy.
Figure 2. Percent of thymectomies achieving R0 resection analyzed by time period. MIT, minimally invasive thymectomy; OT, open thymectomy.
determine whether thymectomy performed by minimally invasive techniques has rates of complete thymoma resection equivalent to those of thymectomy performed by sternotomy or thoracotomy. Completeness of resection is a critically important oncologic outcome that is highly correlated with disease recurrence in thymoma.11–15 The study of disease recurrence can itself be challenging to evaluate after thymoma resection primarily because of the long (approximately 10-year) disease-free intervals seen after
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Table 3. Variables Associated with R0 Resection by Univariate Logistic Regression Variable Region Americas Asia Europe (ref) Time period 1997–2000 2001–2004 2005–2008 2009–2012 (ref) Median age (range), y Sex Male Female (ref) Paraneoplastic syndrome No Yes (ref) WHO histologic type A AB B1 B2 B3 (ref) Masaoka stage I (ref) II III IV Mean tumor size (range), cm Extent of thymectomy Partial Total (ref) Approach MIT OT (ref) Chemotherapy No Yes (ref) Radiotherapy No Yes (ref)
R0
R1/2
OR
95% CI
p Value
511 (24) 788 (36) 879 (40)
141 (46) 85 (27) 83 (27)
0.34 0.88
0.26–0.46 0.64–1.20
<0.0001
248 (11) 416 (19) 648 (30) 866 (40) 54 (8–88)
54 79 82 94 53
0.50 0.57 0.86
0.35–0.72 0.42–0.79 0.63–1.20
<0.001 <0.001 0.34
1.01
1.00–1.01
0.21
1058 (49) 1120 (51)
170 (55) 139 (45)
0.77
0.61–0.98
0.03
1276 (59) 879 (41)
186 (61) 121 (39)
0.94
0.74–1.21
0.65
243 540 397 506 316
11 33 37 87 93
6.50 4.82 3.16 1.71
3.41–12.52 3.16–7.34 2.10–4.75 1.24–2.37
<0.0001 <0.0001 <0.0001 0.001
0.09 0.02 0.01 0.92
0.04–0.19 0.01–0.05 0.00–0.01 0.88–0.95
<0.001 <0.001 <0.001 <0.0001
(12) (27) (20) (25) (16)
(17) (26) (27) (30) (9–87)
(4) (13) (14) (33) (36)
860 (44) 760 (39) 272 (14) 60 (3) 5.5 (0.1–28.0)
7 (3) 71 (28) 97 (38) 81 (32) 7.0 (0.5–21.5)
227 (11) 1843 (89)
59 (20) 232 (80)
0.48
0.35–0.67
<0.0001
430 (20) 1748 (80)
29 (9) 280 (91)
2.38
1.60–3.53
<0.0001
1970 (90) 208 (10)
191 (62) 118 (38)
5.85
4.47–7.67
<0.0001
1478 (68) 700 (32)
107 (35) 202 (65)
3.99
3.10–5.12
<0.0001
Note: Regression column percentages are shown in parentheses. CI, confidence interval; ref, reference; MIT, minimally invasive thymectomy; OT, open thymectomy.
thymectomy for thymoma. It is therefore not surprising that the several studies to have evaluated survival after minimally invasive resection of thymoma include relatively short follow-up periods ranging from 24 to 40 months,1,2,8,17 which are too truncated to draw definitive conclusions about survival and relapse after surgical resection of thymoma. Similarly, at the time of data harvest for our study, the number of recurrence events was insufficient to effectively study recurrence as a primary outcome variable. The performance of MIT and OT techniques with regard to rates of R0 resection has not been rigorously evaluated. In one previous single-institution study of 10 patients undergoing MIT for thymoma, MIT was
associated with a 100% rate of R0 resection.1 In our study, R0 resection was achieved in 94% of all MIT (n ¼ 461) and 86% of all OT procedures (n ¼ 2053, p < 0.0001). Whereas this difference was likely associated with allocation of more advanced thymoma tumors to the OT group, our propensity-matched analyses of balanced MIT and OT groups demonstrated equal rates of R0 resection in the MIT (96%) and OT groups (96%) (p ¼ 0.7). Further, in multivariate logistic regression analyses, surgical approach was not associated with completeness of resection. Taken together, these data support equivalence in the ability to achieve R0 thymoma resection by minimally invasive and open surgical approaches.
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Table 4. Variables Associated with R0 Resection by Multivariate Logistic Regression Variable Region Americas Asia Europe (ref) Time period 1997–2000 2001–2004 2005–2008 2009–2012 (ref) Median age (range), y Sex Male Female (ref) Paraneoplastic syndrome No Yes (ref) WHO histologic type A AB B1 B2 B3 (ref) Masaoka stage I (ref) II III IV Median tumor size (range), cm Extent of thymectomy Partial Total (ref) Approach MIT OT (ref) Chemotherapy No Yes (ref) Radiotherapy No Yes (ref)
OR
95% CI
p Value
0.13 0.75
0.08–0.22 0.44–1.27
0.76 0.48 0.91
0.37–1.52 0.29–0.79 0.57–1.45
1.00
0.98–1.01
0.62
0.97
0.66–1.40
0.85
1.27
0.84–1.94
0.26
2.16 1.29 1.60 1.17
0.84–5.57 0.70–2.40 0.86–2.97 0.73–1.90
<0.0001
0.03
0.43
<0.0001 0.06 0.02 0.004 0.96
0.02–0.19 0.006–0.07 0.001–0.01 0.90–1.02
0.15
0.22
0.12–0.40
<0.0001
1.32
0.67–2.61
0.42
1.31
0.82–2.09
0.27
2.02
1.33–3.09
0.001
CI, confidence interval; ref, reference; MIT, minimally invasive thymectomy; OT, open thymectomy.
Variables that were independently associated with R0 resection in our study included less advanced Masaoka stage, no radiotherapy received, more recent time period, the geographic region on which the thymectomy was performed, and total (versus partial) thymectomy. The relationship of Masaoka stage and radiotherapy to completeness of resection can be reasonably ascribed to invasiveness of the tumor. Further, it is likely that the relationship of more recent time period to completeness of resection, especially for MIT, can be attributed to evolving surgical technique. The finding that the rate of R0 resection was significantly
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lower in the Americas (predominantly in North America [98% in North America and 2% in South America]) than on other continents was interesting. Among all cases of thymectomy in North America, the R0 resection rate was 78%, which was lower than the rates of thymectomy performed in Asia (92%) and Europe (91%). Whereas this could possibly be due to a higher frequency of invasive thymoma resections being performed in North America compared with on other continents, thymectomy performed in North America was independently associated with R1/R2 resection in multivariate analyses, and the reasons for this are not known. Among all thymecotomies in this study, which included those performed for early- and advanced-stage tumors, total thymectomy (total resection of the thymus gland) was associated with R0 resection of the thymoma. Whereas some authors recommend total thymectomy for all cases of thymoma resection, including those cases involving only partial involvement of the thymus,18 there are few objective data to substantiate the assumption that this practice will result in more favorable cancerspecific outcomes, and it is certainly technically feasible to achieve R0 tumor resections of smaller thymomas by partial thymectomy. For example, one report of 61 patients undergoing thymectomy for thymoma demonstrated better overall survival after complete thymectomy than after resection of the tumor alone,19 although another study on 126 thymoma resections suggested that there was no difference between total and partial resection of the gland.14 In this study, 27% of patients in the MIT group underwent partial thymectomy compared with 9% of patients in the OT group. This could possibly be related to the unilateral surgical approaches that are most often performed in MIT, as opposed to the “bilateral” approach afforded by sternotomy. Until further data become available, we support total thymectomy for patients undergoing resection for thymoma. In patients with a thymoma who also have MG, an “extended” thymectomy, during which the entire gland is removed along with the contiguous right and left mediastinal pleura and mediastinal and pericardiophrenic adipose tissues and the aortopulmonary window is dissected, can also be considered.20 Unencapsulated lobules of thymus and microscopic foci of thymus can be widely and invisibly distributed in the pretracheal and anterior mediastinal fat, and a number of studies have suggested that removal of more thymic tissues is associated with improved remission rates for MG.21 Proponents of open approaches to thymectomy discuss the excellent visualization of the thymus and its surrounding structures as well as the ease of resection and reconstruction of involved structures in cases of advanced disease. A similar perspective would view the
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open approach as providing the most oncologically sound operation, decreasing the risk of capsule violation, and in cases of MG, facilitating removal of the entire thymus gland and associated mediastinal fat. Proponents of MIT endorse the improved visualization of the thymus gland and surrounding structures over that with OT, in particular, with regard to the magnification and advanced optics of current robotic technology, and they will cite improved and shorter recovery after the operation. A number of studies on thymectomy, predominantly for MG, have demonstrated favorable short-term advantages of MIT when compared with OT. These advantages include improved pain scores, shorter recovery, decreased blood loss, and shorter length of hospital and intensive care unit stays.1–10 In our study, of patients undergoing MIT, 68% underwent a procedure based on a thoracoscopic approach and 32% underwent procedure based on a robotic approach. Whereas many of the initial reports of MIT included thoracoscopic approaches, more contemporary series have evaluated both thoracoscopic and robotic techniques. The balance of these reports suggests that robotic-assisted approaches, albeit performed mostly for MG, are safe and can result in good short-term outcomes.22 The largest of these studies is a multi-institutional retrospective study of 79 robotic-assisted thymectomies from four European centers that reported a median hospital stay of 3 days and a 13% complication rate.17 Similarly, in a retrospective comparison of 79 thoracoscopic with 74 robotic thymectomies for MG, there were similarly low morbidity rates and rates of conversion between these two minimally invasive approaches.23 Certainly not all patients with a thymoma are suitable candidates for MIT. Suggested exclusion criteria for MIT include involvement of a phrenic nerve, innominate vein, or other major vessels.20 On the basis of a retrospective review of MIT performed with R0 resection of thymoma, one group has suggested that selection criteria for MIT include location of the tumor in the mediastinum, distinct fat planes between tumor and vital organs, tumor encapsulation, the existence of residual normal appearing thymic tissue, no mass compression effect, and unilateral tumor predominance.24 Bilateral MIT approaches, however, are well described and tumors without unilateral predominance can be approached in such a way. In our data set, the median size of the tumors resected by MIT was 5.5 cm (range 0.4–15.5 cm) and tumor size was not predictive of R0 resection, suggesting that size of thymoma is not as an important consideration in the decision to proceed with MIT as are other factors representing tumor invasion. Generally, patients in whom invasion of mediastinal structures is highly suspected are better served by OT. Furthermore, should
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minimally invasive resection at any time compromise basic oncologic principles, conversion to OT is necessary. The strengths of our study include the large size of the patient cohort and the multi-institutional, multinational database from which it was derived. Limitations of this study include its retrospective nature and associated selection and information biases. This study was additionally limited by some certain missing data, for example, the conversion of MIT to OT. These instances were likely coded as OT and could bias the R0 resection rate against OT. For reference, such published conversion rates range from 0% to 7%.1,8,17 Additionally, certain approaches to thymectomy (thoracosternotomy, clamshell, and cervical) were excluded from our analyses secondary to their relative rarity in our database. Certainly these approaches may be warranted and beneficial in certain cases. Indications for thymectomy are not available in the retrospective ITMIG database, and it is possible that smaller tumors were incidental findings of thymectomy for MG or other neoplastic syndrome. Lastly, although this is a large multi-institutional international database comprising select participants, it is difficult to precisely estimate its representation of the general population in the United States and the world. Our data demonstrate that worldwide adoption of MIT for thymoma has increased substantially in recent years. In our data set comprising data from 43 institutions in 15 countries, approximately half of all thymectomies performed in recent years for thymoma were performed by a minimally invasive technique. Our data demonstrate that R0 resection of thymoma can be performed at comparable rates by minimally invasive and OT operations. The long-term cancer-specific outcomes of MIT will be determined in future studies with maturation of the ITMIG database.
Acknowledgments The authors would like to thank Frank Detterbeck for critical review of data, appraisal of the manuscript, expert insight, and support for this project. The authors would also like to thank Elham Biaghoshi for administrative support for this manuscript and project.
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14. Nakagawa K, Asamura H, Matsuno Y, et al. Thymoma: a clinicopathologic study based on the new World Health Organization classification. J Thorac Cardiovasc Surg. 2003;126:1134–1140. 15. Regnard JF, Magdeleinat P, Dromer C, et al. Prognostic factors and long-term results after thymoma resection: a series of 307 patients. J Thorac Cardiovasc Surg. 1996;112:376–384. 16. Huang J, Ahmad U, Antonicelli A, et al. Development of the international thymic malignancy interest group international database: an unprecedented resource for the study of a rare group of tumors. J Thorac Oncol. 2014;9:1573–1578. 17. Marulli G, Rea F, Melfi F, et al. Robot-aided thoracoscopic thymectomy for early-stage thymoma: a multicenter European study. J Thorac Cardiovasc Surg. 2012;144: 1125–1130. 18. Venuta F, Rendina EA, Anile M, et al. Thymoma and thymic carcinoma. Gen Thorac Cardiovasc Surg. 2012;60:1–12. 19. Wang LS, Huang MH, Lin TS, et al. Malignant thymoma. Cancer. 1992;70:443–450. 20. Toker A, Sonett J, Zielinski M, et al. Standard terms, definitions, and policies for minimally invasive resection of thymoma. J Thorac Oncol. 2011;6:S1739– S1742. 21. Sonett JR, Jaretzki A, 3rd. Thymectomy for nonthymomatous myasthenia gravis: a critical analysis. Ann N Y Acad Sci. 2008;1132:315–328. 22. Ismail M, Swierzy M, Ruckert RI, et al. Robotic thymectomy for myasthenia gravis. Thorac Surg Clin. 2014;24: 189–195, v–vii. 23. Ruckert JC, Swierzy M, Ismail M. Comparison of robotic and nonrobotic thoracoscopic thymectomy: a cohort study. J Thorac Cardiovasc Surg. 2011;141: 673–677. 24. Cheng YJ, Hsu JS, Kao EL. Characteristics of thymoma successfully resected by videothoracoscopic surgery. Surg Today. 2007;37:192–196.
Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry Bryan M. Burt, MD,a,* Xiaopan Yao, MD,b Joseph Shrager, MD,c Alberto Antonicelli,b Sukhmani Padda, MD,c Jonathan Reiss, MD,d Heather Wakelee, MD,c Stacey Su, MD,e James Huang, MD,f Walter Scott, MDe a
Baylor College of Medicine, Houston, Texas Yale University, New Haven, Connecticut c Stanford University School of Medicine, Stanford, California d University of California Davis Medical Center, Sacramento, California e Fox Chase Cancer Center, Philadelphia, Pennsylvania f Memorial Sloan-Kettering Cancer Center, New York, New York b
Received 13 May 2016; revised 6 July 2016; accepted 15 August 2016 Available online - 23 August 2016
ABSTRACT Introduction: Minimally invasive thymectomy (MIT) is a surgical approach to thymectomy that has more favorable short-term outcomes for myasthenia gravis than open thymectomy (OT). The oncologic outcomes of MIT performed for thymoma have not been rigorously evaluated. We analyzed determinants of complete (R0) resection among patients undergoing MIT and OT in a large international database. Methods: The retrospective database of the International Thymic Malignancy Interest Group was queried. Chi-square and Wilcoxon rank sum tests, multivariate logistic regression models, and propensity matching were performed. Results: A total of 2514 patients underwent thymectomy for thymoma between 1997 and 2012; 2053 of them (82%) underwent OT and 461 (18%) underwent MIT, with the use of MIT increasing significantly in recent years. The rate of R0 resection among patients undergoing OT was 86%, and among those undergoing MIT it was 94% (p < 0.0001). In propensitymatched MIT and OT groups (n ¼ 266 in each group); however, the rate of R0 resection did not differ significantly (96% in both the MIT and OT groups, p ¼ 0.7). Multivariate analyses were performed to identify determinants of R0 resection. Factors independently associated with R0 resection were geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy. Surgical approach, whether minimally invasive or open, was not associated with completeness of resection. Conclusions: The use of MIT for resection of thymoma has been increasing substantially over time, and MIT can
achieve rates of R0 resection for thymoma similar to those achieved with OT. 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. Keywords: Thymoma; Thymectomy; Minimally invasive; Complete resection; R0
Introduction Minimally invasive surgical approaches for thymectomy have gained popularity for patients with nonthymomatous myasthenia gravis (MG), and a variety of single-institution studies suggest that that minimally invasive thymectomy (MIT) has improved short-term outcomes when compared with open thymectomy (OT). For example, when compared with OT, MIT has been associated with shorter hospital stays,1–7 shorter length of stay in the intensive care unit,1 lower operative blood loss,1,7,8 improved postoperative pulmonary function,9
*Corresponding author. Disclosure: The authors declare no conflict of interest. Address for correspondence: Bryan M. Burt, MD, One Baylor Place, BCM390, Baylor College of Medicine, Houston, Texas. E-mail: bryan. [email protected] ª 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ISSN: 1556-0864 http://dx.doi.org/10.1016/j.jtho.2016.08.131
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decreased postoperative pain,10 and similar operating room times.1 Currently, there are few published oncologic outcomes data that support the adoption of MIT for patients with thymic malignancies. For resection of thymoma, MIT and OT could vary with respect to rates of R0 resection, extent of thymectomy, and risk of violation of the tumor capsule. It is well known that R0 resection is the most important long-term prognostic indicator in thymoma, and resection status at the time of thymectomy closely correlates with recurrence outcomes.11–15 Using the large international database of the International Thymic Malignancies Interest Group (ITMIG), we therefore set out to (1) determine whether MIT was associated with rates of incomplete resection equivalent to those with OT for thymoma and (2) identify factors that were independently associated with completeness of resection.
Materials and Methods The ITMIG database is a multi-institutional retrospective database with contributions from 43 institutions on four continents.16 All data were deidentified and considered exempt from institutional review board review. This database was queried to define a cohort of patients who underwent OT or MIT for thymoma from the date of the first MIT entry in January 1997 up until the date of last entry in December 2012. This study was conducted on the basis of the data available in the ITMIG database at the time of data harvest. For this project, OT was defined as either sternotomy or thoracotomy, and MIT was defined as either a video-assisted thoracoscopic surgery (VATS)- or robotic-assisted thoracoscopic surgery (RATS)-based approach. The thoracosternotomy and clamshell approaches, cervical thymectomy, and mediastinotomy approaches were intentionally excluded as they represented a minority of resection types, as well as to balance the OT and MIT comparison groups. Variables examined in our analyses are listed in Table 1 and each contained less than 5% missing data. The clinical stage variable was intentionally excluded because of 28% missing data. A total thymectomy was defined in the database as resection of the thymoma and the entire thymus gland, whereas a partial thymectomy was defined as resection of the thymoma with a margin of normal thymic tissue. The R0, R1, and R2 variables were defined in the database as being identified from surgical pathology reports. Conversion from MIT to OT data was not available from the retrospective ITMIG database. All statistical analyses were performed with SAS 9.3 software (SAS Institute, Inc., Cary, NC). Patient characteristics were compared between the MIT and OT groups
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using the chi-square test for categorical variables and the Wilcoxon rank sum test for continuous variables. Propensity matching was performed by the nearest available pair matching method, with utilization of all the variables in this study with the exception of completeness of resection. The patients undergoing MIT were ordered and sequentially matched to the nearest unmatched patients undergoing OT. If multiple patients in the OT group had propensity scores equally close to that of the patient in the MIT group, one of those patients in the OT group was selected at random. A p value less than 0.05 was used to determine significance. Univariate logistic regression analyses were used to investigate the relationship between resection status and clinical and patient characteristic variables, including age, sex, paraneoplastic syndrome, time period, WHO histologic type, pathologic Masaoka stage, tumor size, extent of thymectomy, surgical approach, and use of chemotherapy and radiotherapy. A multivariate logistic regression model was built to test the association between resection status and surgical approach (MIT versus OT), including other clinical factors and patient characteristics variables as covariates.
Results A total of 2514 patients underwent thymectomy for thymoma between January 1997 and December 2012. Of those patients, 2053 (82%) underwent OT (1751 [85%] by sternotomy and 302 [15%] by thoracotomy) and 461 (18%) underwent MIT (315 [68%] by VATS and 146 [32%] by RATS). The numbers of MIT and OT cases performed from 1997 to 2012 are shown graphically in Figure 1. The frequency of MIT cases was seen to increase from 2008 to 2012, at which time its frequency approached that of the of OT cases. The demographic, clinical, and pathologic characteristics of these cases are shown in Table 1. Most of the MIT cases were contributed from Asian institutions. Patients undergoing MIT were 2.1 years younger than those undergoing OT, and patients in the MIT group were more likely to be female (55%) than were those in the OT group (45%). Patients undergoing MIT had a more favorable World Health Organization (WHO) histologic type and less advanced pathologic Masaoka stage than patients undergoing OT. In the MIT group, the mean tumor size was 4.0 cm (range 0.4–15.5 cm) compared with 6.0 cm (range 0.1–28.0 cm) in the OT group. The rate of partial thymectomy was found to be higher in the MIT group (27%) than in the OT group (9%). Patients undergoing MIT were less likely to have received chemotherapy (3%) or radiotherapy (31%) than were those undergoing OT (16% and 37%, respectively), and most chemotherapy and radiotherapy was administered in the adjuvant setting.
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Table 1. Demographics and Clinicopathologic Characteristics of Study Cohort Variable Region Americas Asia Europe Time period 1997–2000 2001–2004 2005–2008 2009–2012 Median age (range), y Sex Male Female Paraneoplastic syndrome No Yes WHO histologic type A AB B1 B2 B3 Masaoka stage (pathologic) I II III IV Median tumor size (range), cm Extent of thymectomy Partial Total Resection status R0 R1/2 Chemotherapy None Neoadjuvant Adjuvant Radiotherapy None Neoadjuvant Adjuvant
All (N ¼ 2514)
MIT (n ¼ 461)
OT (n ¼ 2053)
p Value <0.0001
672 (27) 873 (35) 969 (39)
82 (18) 227 (49) 152 (33)
590 (29) 646 (31) 817 (40)
304 (12) 501 (20) 738 (29) 971 (39) 54 (8–88)
8 (2) 24 (5) 91 (20) 338 (73) 52 (15–85)
296 (14) 477 (23) 647 (32) 633 (31) 54 (8–88)
1239 (49) 1275 (51)
207 (45) 254 (55)
1032 (50) 1021 (50)
1480 (60) 1008 (41)
256 (56) 204 (44)
1224 (60) 804 (40)
256 575 437 599 413
59 (14) 105 (25) 80 (19) 126 (30) 55 (13)
197 470 357 473 358
868 (39) 838 (38) 371 (17) 142 (6) 5.5 (0.1–28.0)
199 (47) 186 (44) 27 (6) 12 (3) 4.0 (0.4–15.5)
669 (37) 652 (36) 344 (19) 130 (7) 6.0 (0.1–28.0)
291 (12) 2091 (88)
122 (27) 331 (73)
169 (9) 1760 (91)
2178 (88) 309 (12)
430 (94) 29 (6)
1748 (86) 280 (14)
2182 (87) 18 (7) 15 (6)
447 (97) 2 (0) 12 (3)
1735 (85) 179 (9) 139 (7)
1601 (64) 4 (1) 867 (35)
316 (69) 2 (0) 143 (31)
1268 (63) 34 (1) 735 (36)
<0.0001
0.002 0.04
0.06
0.01 (11) (25) (19) (26) (18)
(11) (25) (19) (26) (19) <0.0001
<0.0001 <0.0001
<0.0001
<0.0001
0.02
Note: Column percentages are shown in parentheses. p Values represent comparison of MIT and OT. MIT, minimally invasive thymectomy; OT, open thymectomy.
Eighty-eight percent of all thymectomies achieved complete (R0) resection, and R0 resection was achieved more frequently in patients undergoing MIT (94%) than in those undergoing OT (86%). There was a statistically significant relationship with R0 resection and more recent time period for all patients (p < 0.0001), and Figure 2 shows these relationships in the MIT (p ¼ 0.22) and OT (p ¼ 0.02) cohorts. Among MIT resections, the rate of R0 resection in VATS thymectomy was 95% and that in RATS thymectomy was 92% (p ¼ 0.2). To determine whether completeness of resection was independently associated
with surgical approach, propensity matching was performed between the MIT and OT groups. As shown in Table 2, the MIT and OT groups each contained 266 patients and were balanced with respect to all variables. The rate of R0 resection did not differ between the balanced MIT and OT groups; it was 96% in each group (p ¼ 0.7). A sensitivity analysis of patients with stage I–II thymoma was performed in 385 patients undergoing MIT and 1313 patients undergoing OT. This analysis demonstrated no significant difference in R0 resection between patients in the MIT group (96.6%) and OT group (95.1%) (p ¼ 0.19).
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Table 2. Propensity-Matched MIT and OT Groups Variable
Figure 1. The number of minimally invasive thymectomies (MITs) and open thymectomies (OTs) for thymoma by year.
To examine which factors were associated with R0 thymoma resection, univariate analyses were performed in all patients undergoing thymectomy (MIT and OT). Variables significantly associated with R0 resection included geographic region, later time period, female sex, less favorable WHO histologic type, less advanced Masaoka stage, total thymectomy, minimally invasive surgical approach, and no chemotherapy or radiotherapy received (Table 3). Multivariate analyses were next performed to determine which of these factors were independently associated with R0 resection status. In these analyses, surgical approach, minimally invasive or open, was not a predictor of R0 resection. Variables that were independently associated with R0 resection included region, more recent time period, less advanced Masaoka stage, total thymectomy, and no radiotherapy received (Table 4).
Discussion To advance the knowledge of thymic malignancies, the ITMIG has developed a centralized, international, retrospective database that currently represents the largest data set assembled for these relatively infrequent tumors.16 Because the oncologic effectiveness of MIT is essentially unknown, we utilized this data set to
Region Americas Asia Europe Time period 1997–2000 2001–2004 2005–2008 2009–2012 Mean age, y Sex Male Female Paraneoplastic syndrome No Yes WHO histologic type A AB B1 B2 B3 Masaoka stage (pathologic) I II III IV Mean tumor size, cm Extent of thymectomy Partial Total Chemotherapy None Neoadjuvant Adjuvant Radiotherapy None Neoadjuvant Adjuvant Resection status R0 R1/R2
MIT (n ¼ 266)
OT (n ¼ 266)
p Value 0.5
52 (20) 134 (50) 80 (30)
43 (16) 134 (50) 89 (34)
7 (3) 19 (7) 53 (20) 187 (70) 51.4
8 (3) 12 (5) 46 (17) 200 (75) 51.5
127 (48) 139 (52)
129 (49) 127 (51)
148 (56) 118 (44)
144 (54) 122 (46)
29 75 58 68 34
38 72 54 72 30
0.6
1.0 0.9
0.9
0.7 (11) (28) (22) (26) (14)
(14) (27) (20) (27) (11) 0.6
119 (45) 122 (46) 20 (8) 5 (2) 4.6
127 (48) 121 (46) 13 (5) 5 (2) 4.7
54 (20) 212 (80)
51 (19) 215 (81)
256 (96) 2 (1) 8 (3)
260 (98) 1 (0) 6 (2)
183 (69) 2 (1) 81 (30)
187 (70) 3 (1) 76 (29)
256 (96) 10 (4)
255 (96) 11 (4)
0.7 0.9
0.7
0.8
0.7
Note: Column percentages are shown in parentheses. p Values represent comparison of MIT and OT. MIT, minimally invasive thymectomy; OT, open thymectomy.
Figure 2. Percent of thymectomies achieving R0 resection analyzed by time period. MIT, minimally invasive thymectomy; OT, open thymectomy.
determine whether thymectomy performed by minimally invasive techniques has rates of complete thymoma resection equivalent to those of thymectomy performed by sternotomy or thoracotomy. Completeness of resection is a critically important oncologic outcome that is highly correlated with disease recurrence in thymoma.11–15 The study of disease recurrence can itself be challenging to evaluate after thymoma resection primarily because of the long (approximately 10-year) disease-free intervals seen after
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Table 3. Variables Associated with R0 Resection by Univariate Logistic Regression Variable Region Americas Asia Europe (ref) Time period 1997–2000 2001–2004 2005–2008 2009–2012 (ref) Median age (range), y Sex Male Female (ref) Paraneoplastic syndrome No Yes (ref) WHO histologic type A AB B1 B2 B3 (ref) Masaoka stage I (ref) II III IV Mean tumor size (range), cm Extent of thymectomy Partial Total (ref) Approach MIT OT (ref) Chemotherapy No Yes (ref) Radiotherapy No Yes (ref)
R0
R1/2
OR
95% CI
p Value
511 (24) 788 (36) 879 (40)
141 (46) 85 (27) 83 (27)
0.34 0.88
0.26–0.46 0.64–1.20
<0.0001
248 (11) 416 (19) 648 (30) 866 (40) 54 (8–88)
54 79 82 94 53
0.50 0.57 0.86
0.35–0.72 0.42–0.79 0.63–1.20
<0.001 <0.001 0.34
1.01
1.00–1.01
0.21
1058 (49) 1120 (51)
170 (55) 139 (45)
0.77
0.61–0.98
0.03
1276 (59) 879 (41)
186 (61) 121 (39)
0.94
0.74–1.21
0.65
243 540 397 506 316
11 33 37 87 93
6.50 4.82 3.16 1.71
3.41–12.52 3.16–7.34 2.10–4.75 1.24–2.37
<0.0001 <0.0001 <0.0001 0.001
0.09 0.02 0.01 0.92
0.04–0.19 0.01–0.05 0.00–0.01 0.88–0.95
<0.001 <0.001 <0.001 <0.0001
(12) (27) (20) (25) (16)
(17) (26) (27) (30) (9–87)
(4) (13) (14) (33) (36)
860 (44) 760 (39) 272 (14) 60 (3) 5.5 (0.1–28.0)
7 (3) 71 (28) 97 (38) 81 (32) 7.0 (0.5–21.5)
227 (11) 1843 (89)
59 (20) 232 (80)
0.48
0.35–0.67
<0.0001
430 (20) 1748 (80)
29 (9) 280 (91)
2.38
1.60–3.53
<0.0001
1970 (90) 208 (10)
191 (62) 118 (38)
5.85
4.47–7.67
<0.0001
1478 (68) 700 (32)
107 (35) 202 (65)
3.99
3.10–5.12
<0.0001
Note: Regression column percentages are shown in parentheses. CI, confidence interval; ref, reference; MIT, minimally invasive thymectomy; OT, open thymectomy.
thymectomy for thymoma. It is therefore not surprising that the several studies to have evaluated survival after minimally invasive resection of thymoma include relatively short follow-up periods ranging from 24 to 40 months,1,2,8,17 which are too truncated to draw definitive conclusions about survival and relapse after surgical resection of thymoma. Similarly, at the time of data harvest for our study, the number of recurrence events was insufficient to effectively study recurrence as a primary outcome variable. The performance of MIT and OT techniques with regard to rates of R0 resection has not been rigorously evaluated. In one previous single-institution study of 10 patients undergoing MIT for thymoma, MIT was
associated with a 100% rate of R0 resection.1 In our study, R0 resection was achieved in 94% of all MIT (n ¼ 461) and 86% of all OT procedures (n ¼ 2053, p < 0.0001). Whereas this difference was likely associated with allocation of more advanced thymoma tumors to the OT group, our propensity-matched analyses of balanced MIT and OT groups demonstrated equal rates of R0 resection in the MIT (96%) and OT groups (96%) (p ¼ 0.7). Further, in multivariate logistic regression analyses, surgical approach was not associated with completeness of resection. Taken together, these data support equivalence in the ability to achieve R0 thymoma resection by minimally invasive and open surgical approaches.
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Table 4. Variables Associated with R0 Resection by Multivariate Logistic Regression Variable Region Americas Asia Europe (ref) Time period 1997–2000 2001–2004 2005–2008 2009–2012 (ref) Median age (range), y Sex Male Female (ref) Paraneoplastic syndrome No Yes (ref) WHO histologic type A AB B1 B2 B3 (ref) Masaoka stage I (ref) II III IV Median tumor size (range), cm Extent of thymectomy Partial Total (ref) Approach MIT OT (ref) Chemotherapy No Yes (ref) Radiotherapy No Yes (ref)
OR
95% CI
p Value
0.13 0.75
0.08–0.22 0.44–1.27
0.76 0.48 0.91
0.37–1.52 0.29–0.79 0.57–1.45
1.00
0.98–1.01
0.62
0.97
0.66–1.40
0.85
1.27
0.84–1.94
0.26
2.16 1.29 1.60 1.17
0.84–5.57 0.70–2.40 0.86–2.97 0.73–1.90
<0.0001
0.03
0.43
<0.0001 0.06 0.02 0.004 0.96
0.02–0.19 0.006–0.07 0.001–0.01 0.90–1.02
0.15
0.22
0.12–0.40
<0.0001
1.32
0.67–2.61
0.42
1.31
0.82–2.09
0.27
2.02
1.33–3.09
0.001
CI, confidence interval; ref, reference; MIT, minimally invasive thymectomy; OT, open thymectomy.
Variables that were independently associated with R0 resection in our study included less advanced Masaoka stage, no radiotherapy received, more recent time period, the geographic region on which the thymectomy was performed, and total (versus partial) thymectomy. The relationship of Masaoka stage and radiotherapy to completeness of resection can be reasonably ascribed to invasiveness of the tumor. Further, it is likely that the relationship of more recent time period to completeness of resection, especially for MIT, can be attributed to evolving surgical technique. The finding that the rate of R0 resection was significantly
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lower in the Americas (predominantly in North America [98% in North America and 2% in South America]) than on other continents was interesting. Among all cases of thymectomy in North America, the R0 resection rate was 78%, which was lower than the rates of thymectomy performed in Asia (92%) and Europe (91%). Whereas this could possibly be due to a higher frequency of invasive thymoma resections being performed in North America compared with on other continents, thymectomy performed in North America was independently associated with R1/R2 resection in multivariate analyses, and the reasons for this are not known. Among all thymecotomies in this study, which included those performed for early- and advanced-stage tumors, total thymectomy (total resection of the thymus gland) was associated with R0 resection of the thymoma. Whereas some authors recommend total thymectomy for all cases of thymoma resection, including those cases involving only partial involvement of the thymus,18 there are few objective data to substantiate the assumption that this practice will result in more favorable cancerspecific outcomes, and it is certainly technically feasible to achieve R0 tumor resections of smaller thymomas by partial thymectomy. For example, one report of 61 patients undergoing thymectomy for thymoma demonstrated better overall survival after complete thymectomy than after resection of the tumor alone,19 although another study on 126 thymoma resections suggested that there was no difference between total and partial resection of the gland.14 In this study, 27% of patients in the MIT group underwent partial thymectomy compared with 9% of patients in the OT group. This could possibly be related to the unilateral surgical approaches that are most often performed in MIT, as opposed to the “bilateral” approach afforded by sternotomy. Until further data become available, we support total thymectomy for patients undergoing resection for thymoma. In patients with a thymoma who also have MG, an “extended” thymectomy, during which the entire gland is removed along with the contiguous right and left mediastinal pleura and mediastinal and pericardiophrenic adipose tissues and the aortopulmonary window is dissected, can also be considered.20 Unencapsulated lobules of thymus and microscopic foci of thymus can be widely and invisibly distributed in the pretracheal and anterior mediastinal fat, and a number of studies have suggested that removal of more thymic tissues is associated with improved remission rates for MG.21 Proponents of open approaches to thymectomy discuss the excellent visualization of the thymus and its surrounding structures as well as the ease of resection and reconstruction of involved structures in cases of advanced disease. A similar perspective would view the
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open approach as providing the most oncologically sound operation, decreasing the risk of capsule violation, and in cases of MG, facilitating removal of the entire thymus gland and associated mediastinal fat. Proponents of MIT endorse the improved visualization of the thymus gland and surrounding structures over that with OT, in particular, with regard to the magnification and advanced optics of current robotic technology, and they will cite improved and shorter recovery after the operation. A number of studies on thymectomy, predominantly for MG, have demonstrated favorable short-term advantages of MIT when compared with OT. These advantages include improved pain scores, shorter recovery, decreased blood loss, and shorter length of hospital and intensive care unit stays.1–10 In our study, of patients undergoing MIT, 68% underwent a procedure based on a thoracoscopic approach and 32% underwent procedure based on a robotic approach. Whereas many of the initial reports of MIT included thoracoscopic approaches, more contemporary series have evaluated both thoracoscopic and robotic techniques. The balance of these reports suggests that robotic-assisted approaches, albeit performed mostly for MG, are safe and can result in good short-term outcomes.22 The largest of these studies is a multi-institutional retrospective study of 79 robotic-assisted thymectomies from four European centers that reported a median hospital stay of 3 days and a 13% complication rate.17 Similarly, in a retrospective comparison of 79 thoracoscopic with 74 robotic thymectomies for MG, there were similarly low morbidity rates and rates of conversion between these two minimally invasive approaches.23 Certainly not all patients with a thymoma are suitable candidates for MIT. Suggested exclusion criteria for MIT include involvement of a phrenic nerve, innominate vein, or other major vessels.20 On the basis of a retrospective review of MIT performed with R0 resection of thymoma, one group has suggested that selection criteria for MIT include location of the tumor in the mediastinum, distinct fat planes between tumor and vital organs, tumor encapsulation, the existence of residual normal appearing thymic tissue, no mass compression effect, and unilateral tumor predominance.24 Bilateral MIT approaches, however, are well described and tumors without unilateral predominance can be approached in such a way. In our data set, the median size of the tumors resected by MIT was 5.5 cm (range 0.4–15.5 cm) and tumor size was not predictive of R0 resection, suggesting that size of thymoma is not as an important consideration in the decision to proceed with MIT as are other factors representing tumor invasion. Generally, patients in whom invasion of mediastinal structures is highly suspected are better served by OT. Furthermore, should
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minimally invasive resection at any time compromise basic oncologic principles, conversion to OT is necessary. The strengths of our study include the large size of the patient cohort and the multi-institutional, multinational database from which it was derived. Limitations of this study include its retrospective nature and associated selection and information biases. This study was additionally limited by some certain missing data, for example, the conversion of MIT to OT. These instances were likely coded as OT and could bias the R0 resection rate against OT. For reference, such published conversion rates range from 0% to 7%.1,8,17 Additionally, certain approaches to thymectomy (thoracosternotomy, clamshell, and cervical) were excluded from our analyses secondary to their relative rarity in our database. Certainly these approaches may be warranted and beneficial in certain cases. Indications for thymectomy are not available in the retrospective ITMIG database, and it is possible that smaller tumors were incidental findings of thymectomy for MG or other neoplastic syndrome. Lastly, although this is a large multi-institutional international database comprising select participants, it is difficult to precisely estimate its representation of the general population in the United States and the world. Our data demonstrate that worldwide adoption of MIT for thymoma has increased substantially in recent years. In our data set comprising data from 43 institutions in 15 countries, approximately half of all thymectomies performed in recent years for thymoma were performed by a minimally invasive technique. Our data demonstrate that R0 resection of thymoma can be performed at comparable rates by minimally invasive and OT operations. The long-term cancer-specific outcomes of MIT will be determined in future studies with maturation of the ITMIG database.
Acknowledgments The authors would like to thank Frank Detterbeck for critical review of data, appraisal of the manuscript, expert insight, and support for this project. The authors would also like to thank Elham Biaghoshi for administrative support for this manuscript and project.
References 1. Jurado J, Javidfar J, Newmark A, et al. Minimally invasive thymectomy and open thymectomy: outcome analysis of 263 patients. Ann Thorac Surg. 2012;94:974–981 [discussion 981–972]. 2. Pennathur A, Qureshi I, Schuchert MJ, et al. Comparison of surgical techniques for early-stage thymoma: feasibility of minimally invasive thymectomy and comparison with open resection. J Thorac Cardiovasc Surg. 2011;141:694–701. 3. Meyer DM, Herbert MA, Sobhani NC, et al. Comparative clinical outcomes of thymectomy for myasthenia gravis
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