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Ann Thorac Surg 2009;87:1641-1647. doi:10.1016/j.athoracsur.2008.11.022
© 2009 The Society of Thoracic Surgeons
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Adjuvant Radiotherapy for Thymic Epithelial Tumors: A Systematic Review and Meta-Analysis

Robert J. Korst, MDa,b,*, Amanda L. Kansler, MPHa, Paul J. Christos, MPH, MSc, Sanjay Mandal, MDa

a Daniel and Gloria Blumenthal Cancer Center, Paramus, New Jersey
b Division of Thoracic Surgery, Department of Surgery, Valley Hospital/Valley Health System, Ridgewood, New Jersey
c Division of Biostatistics and Epidemiology, Department of Public Health, Weill Medical College of Cornell University, New York, New York

* Address correspondence to Dr Korst, Daniel and Gloria Blumenthal Cancer Center, Thoracic Surgery, Valley Hospital/Valley Health System, 1 Valley Health Plaza, Paramus, NJ 07652 (Email: korsro{at}valleyhealth.com).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Adjuvant radiotherapy after complete resection of localized, invasive thymic epithelial tumors is considered by many to be the standard of care, despite little supporting literature. We hypothesized that individual studies may lack statistical power to demonstrate a reduction in recurrence with this approach, but meta-analysis of published data may allow for more adequate statistical evaluation. Analysis of data from 592 patients with completely resected stage II or III thymic epithelial tumors, however, revealed no statistically significant reduction in recurrence after adjuvant radiotherapy (odds ratio 1.05; 95% confidence interval: 0.63 to 1.75; p = 0.840). Additionally, the majority of publications suggest that the most common sites of recurrence are the lung, pleura, and diaphragm, even when incompletely resected patients are included.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Thymic epithelial tumors (TET), although uncommon, are the most frequently diagnosed neoplasm in the anterior mediastinal compartment and are best treated with complete surgical resection [1]. The malignant potential of these tumors varies widely, and depends on both tumor stage as well as histologic subtype. Currently, TET are staged according to the system proposed by Masaoka and colleagues [2] in 1981 that relies on both operative and pathologic findings for stage assignment.

Recurrence after complete resection of localized TET (stages I to III) correlates with the extent of tumor invasion [1–5]. Briefly, stage I TET represent encapsulated, noninvasive lesions, and recurrence after complete resection of a stage I TET is rare [1]. When the tumor invades through the capsule, either microscopically or grossly into surrounding mediastinal fat (stage II), recurrence is more frequent after complete resection [1]. When the surgeon finds it necessary to resect surrounding mediastinal structures at the time of excision (blood vessels, pericardium, nerves, lung) to perform complete resection, tumors are classified as stage III. Even after complete resection with negative surgical margins, recurrence rates are significant for stage III lesions, ranging from approximately 20% to 50% [1].

Given that the ability to completely resect stage III lesions is only approximately 50% [6, 7], combined with the apparent radiosensitivity of TET [8] as well as the significant recurrence rate even after complete resection [6, 7], adjuvant (postoperative) radiotherapy is utilized by many clinicians and investigators. Although more controversial, adjuvant radiotherapy has also been advocated after resection of stage II lesions [9–11]. Despite these practice patterns, published literature supporting the use of adjuvant radiotherapy after complete resection of invasive, localized TET is sparse. One clear problem is the rarity of these lesions, with existing publications describing only small cohorts of patients, rendering statistical comparisons invalid, or in the least, difficult to perform.

Given that the majority of studies that address the role of adjuvant radiotherapy for invasive, localized TET are small and statistically underpowered, we hypothesized that combining these studies statistically using meta-analysis would be more likely to demonstrate a benefit to the use of adjuvant radiotherapy after complete resection of these tumors. To this end, we performed a comprehensive, systematic review of the published literature with meta-analysis aimed at determining the effect of adjuvant radiotherapy on recurrence rates after complete resection of stage II and III TET. In addition, we objectively scored the quality of published studies and reviewed recurrence patterns in patients with completely resected, localized, invasive TET.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Literature Search and Selection of Studies
A search of the English literature from 1981 to present was performed using the Cochrane, Embase, and Medline computerized databases. These databases were searched between the dates of May 7, 2008, and May 16, 2008. The year 1981 was chosen as the earliest time limit of the search to allow for evaluation according to Masaoka stage, which was first published at that time [2]. The search headings used were "thymoma," combined with any of the following headings: "complete resection," "adjuvant radiation therapy," "survival," "prognosis," "staging," "postoperative radiation therapy," "recurrence," and "radiotherapy." In addition, titles of abstracts from the American Society of Clinical Oncology (ASCO) and the American Association of Thoracic Surgery (AATS) were searched for the word "thymoma" on their respective websites. All resulting abstracts were reviewed, and studies were selected that met all of the following inclusion criteria: reported on two cohorts of patients—complete resection alone, versus complete resection with adjuvant radiotherapy, inclusive of thymic carcinoma (World Health Organization histologic type C); and reported on stage II or III TET, or both, either as distinct cohorts or individual patients.

Of note, no attempt was made to search for unpublished literature, and studies published solely in foreign languages were excluded. If Masaoka stage was not explicitly stated, operative and pathologic data had to be provided so that an accurate Masaoka stage could be assigned to either individual patients or cohorts of patients. Studies that combined adjuvant radiotherapy with chemotherapy, either preoperatively or postoperatively, were excluded.

The full text of selected abstracts was obtained, and reference lists were comprehensively evaluated and cross checked to determine if any other data sources were available. In addition, general review articles on thymoma were examined to identify additional potentially relevant original articles. To avoid bias generated by multiple publications from the same institution (duplication bias), only a single study from a given institution was selected. Usually, this represented the latest (most recent) study. However, priority was given to studies (regardless of chronology) that contained data extractable for the meta-analysis.

Scoring of Study Quality and Extraction of Data
In compliance with standard methodology for performing a Cochrane systematic review [12], the quality of each selected study was assessed using a modified Newcastle–Ottawa scale for assessing the quality of nonrandomized studies in meta-analyses [13]. Briefly, this scale assesses variables including patient selection and comparability between cohorts, as well as outcome measurement. Individual elements involved in scoring included the listing of selection criteria for radiotherapy, the robustness of the data source (eg, prospective, specific thymoma database versus tumor registry), the statement of clear-cut methodology (eg, was there a blinded pathology and chart review with multiple reviewers), matching of the two cohorts (resection alone versus resection plus radiotherapy), the number of patients in each study, how patients were followed, the length of follow-up, and the adequacy of follow-up. Each author independently scored each study, and then each study was discussed as a group, and a consensus score was arrived upon. Using this scoring system, a higher score was indicative of higher study quality. Although the lowest possible score was zero, there was no "limit" to the highest possible score.

Summary or individual patient data, or both, were extracted from all available studies that included the number of patients in each cohort (complete resection versus complete resection plus adjuvant radiotherapy), Masaoka stage (only stage II and III included), and the number of recurrences. Recurrence was defined as any recurrence, local, regional, or distant. These data were used in the meta-analysis. Data were not extracted for the meta-analysis if a "pure" cohort of completely resected patients in either stage II or stage III could not be obtained. In addition, data pertaining to recurrence patterns, survival, dose of radiotherapy, and patient demographics were also extracted, but owing to inconsistent reporting, no statistical analysis was able to be performed on these latter data elements.

Statistical Analysis
Meta-analysis was performed, and forest plots were generated with the extracted data and recurrence information from all eligible studies that met the above criteria, using STATA, version 10.0 (StataCorp, College Station, TX). This analysis was performed on stage II and stage III patients independently, as well as combined stage II and III patients. The study-specific odds ratios in the forest plots represent the odds of recurring when given adjuvant radiotherapy compared with complete resection alone. A pooled fixed effects or random effects odds ratio was then calculated using data from all eligible studies, and this pooled summary estimate was statistically compared with a null odds ratio of 1.0.

Heterogeneity among studies was assessed by using the {chi}2 test for heterogeneity (STATA, version 10.0). A p value of less than 0.05 assumed that there was significant heterogeneity across the studies and that random effects modeling should be used to calculate the combined odds ratio; otherwise, a fixed effects model was used. Additionally, a funnel plot was created to assess publication bias. Publication bias exists when studies are performed, but not reported in the literature, usually because of lack of a treatment effect. The significance of publication bias was evaluated using an adjusted rank correlation test (STATA, version 10.0).

The {chi}2 test was used to calculate if a significant difference existed in the proportion of stage II patients receiving adjuvant radiotherapy compared with stage III patients.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Selection and Characteristics of Studies
The literature search identified 22 studies that met the selection criteria [6, 9, 14–33]. All selected studies were retrospective cohort studies. No published randomized clinical trials exist in either the English or foreign language literature that evaluate the role of adjuvant radiotherapy after complete resection of invasive TET. In several instances, multiple studies were published from the same institution, and incorporated many of the same patients [7, 14, 18, 20, 24, 34, 35]. Duplication bias was avoided in these instances, as described above in the Methods section. As an example, although one recent publication addressed adjuvant radiotherapy for stage III TET [34], an earlier study from the same institution was selected because it contained extractable data for the meta-analysis [20], whereas the latter publication did not.

Details regarding the dose of adjuvant radiotherapy were commented upon to some extent in 16 of the 22 publications [6, 9, 14–20, 22, 25, 28–31, 33]; however, only one study listed a uniform dose for all patients [25], with the remaining 15 studies citing a range of radiation dosages administered.

The quality of the selected studies was assessed using a modified Newcastle–Ottawa scale for assessing the quality of nonrandomized studies in meta-analyses. As shown in Table 1, three of the four highest ranked publications exclusively reported on stage II TET.


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  		Table 1 Selected Publications With Corresponding Quality Score and Recurrence Data Used for Meta-Analysis
 
Meta-Analysis of Recurrence After Complete Resection of Invasive TET
Of the 22 selected studies, 13 had data that were able to be extracted for meta-analysis [9, 14–24, 33]. From these studies, data for a total of 592 patients were obtained, with 342 patients (57.8%) having undergone complete resection alone, and 250 (42.2%) receiving adjuvant radiotherapy in addition to complete resection. In the surgery-alone cohort, 273 patients had stage II disease, whereas 69 had stage III. In the cohort that received adjuvant radiotherapy, 197 patients had stage II and 53 had stage III disease. Recurrence of TET was reported in 79 of the 592 patients (13.3%). Recurrence rates in the studies evaluating completely resected stage II TET ranged from 0% to 62% in patients undergoing complete resection alone, and 0% to 25% with the addition of adjuvant radiotherapy. For stage III disease, recurrence rates ranged from 13% to 80% in patients undergoing complete resection alone, versus 0% to 64% with the addition of adjuvant radiotherapy. There was no significant difference in the percentage of patients undergoing surgery alone in stage II (273 of 470 [58.1%]) compared with stage III patients (69 of 122 [56.6%]; p = 0.875).

Table 1 shows individual recurrence data extracted from each of the 13 studies where data were extractable. As shown in Figure 1, the pooled odds ratio (OR) of recurring after complete resection with adjuvant radiotherapy compared with complete resection alone for both stage II and III combined was 1.05 (95% confidence interval [95% CI]: 0.63 to 1.75; p = 0.840). When stratified by stage (Figs 2 and 3), Go adjuvant radiation still had no significant effect on recurrence when compared with surgery alone: stage II, OR 0.87 (95% CI: 0.44 to 1.71; p = 0.677) and stage III, OR 0.87 (95% CI: 0.18 to 4.13; p = 0.856).


Figure 1
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  		Fig 1. Forest plot generated using extracted recurrence data for patients with stage II and III thymic epithelial tumors. The squares represent the odds ratios of the individual studies, and the size of the squares reflect the calculated weight of the study in the meta-analysis. The horizontal bars running through each square represent the 95% confidence interval (CI). The diamond at the bottom of the plot illustrates the combined odds ratio using a fixed effects model. (White boxes = stage II; gray boxes = stages II and III; black boxes = stage III.)

 

Figure 2
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  		Fig 2. Forest plot generated using extracted recurrence data for patients with stage II thymic epithelial tumors. The squares represent the odds ratios of the individual studies, and the size of the squares reflect the calculated weight of the study in the meta-analysis. The horizontal bars running through each square represent the 95% confidence interval (CI). The diamond at the bottom of the plot illustrates the combined odds ratio using a fixed effects model.

 

Figure 3
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  		Fig 3. Forest plot generated using extracted recurrence data for patients with stage III thymic epithelial tumors. The squares represent the odds ratios of the individual studies, and the size of the squares reflect the calculated weight of the study in the meta-analysis. The horizontal bars running through each square represented the 95% confidence interval (CI). The diamond at the bottom of the plot illustrates the combined odds ratio using a random effects model.

 
Test for Heterogeneity
The {chi}2 test for heterogeneity was used to detect the degree of heterogeneity between studies. Given that there was significant heterogeneity (p = 0.023) among the six studies for stage III patients, the random effects model was used to calculate the combined odds ratio to account for this variation between studies. A fixed effects model was used for analyzing stage II and the combined stage II/III data, as these tests for heterogeneity were not significant (p = 0.660 and p = 0.132, respectively).

Assessment for Publication Bias
The funnel plot (Fig 4) is a graphical representation of the log of the odds ratio plotted against the standard error of the log of the odds ratio for all of the studies used in the meta-analysis. The rank correlation test for publication bias was nonsignificant (p = 0.669) when all 13 studies included in the meta-analysis were analyzed in this fashion.


Figure 4
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  		Fig 4. Funnel plot incorporating all selected studies used in the meta-analysis. The black dots represent individual studies, and the dotted lines represent 95% confidence interval. (Ln OR = log of the odds ratio; S.E. = standard error.)

 
Effect of Adjuvant Radiotherapy on Survival of Completely Resected Patients With Invasive TET
Although 16 studies made a statistical survival comparison between the group of patients who underwent resection alone compared with the group who received adjuvant radiotherapy, only 10 of these included only patients who underwent complete resection of stage II or stage III disease, or both [6, 9, 14, 18, 19, 24–27, 33], with the other six analyzing mixed cohorts of completely and incompletely resected patients or stages [16, 17, 20–23]. However, meta-analysis of pooled data from these 10 studies was not possible with survival as the endpoint because individual survival data were infrequently listed. Of these 10 individual analyses, one detected a statistically significant survival advantage in the cohort that received adjuvant radiotherapy, eight could not detect a statistically significant survival difference between cohorts, and one found a significant survival advantage for the nonirradiated cohort.

Eralp and coworkers [25] retrospectively analyzed 36 patients with TET, 28 of whom received adjuvant radiotherapy. A benefit in progression-free survival was found favoring adjuvant radiotherapy in completely resected patients. This benefit was found to be statistically significant (p < 0.0001); however, individual patient data and details of this analysis were not included in this report. In addition, a multivariate analysis was not performed.

In contrast, Ruffini and colleagues [24] analyzed 266 patients with completely resected TET. For patients with stage II and III disease, multivariate analysis revealed that overall survival was significantly worse for patients who received adjuvant radiotherapy after complete resection, compared with patients who underwent complete resection alone (p = 0.04). The authors speculated that selection bias could be responsible for the higher recurrence rate seen after adjuvant radiotherapy.

Recurrence Patterns of Resected Invasive TET
Of the 22 selected studies, 12 (55%) listed details regarding the specific location of recurrent disease [6, 9, 14, 17–20, 24, 26–28, 30]. However, comprehensive data from exclusively completely resected patients stratified by the presence or absence of adjuvant radiotherapy were only available from three publications, all dealing with stage II TET [14, 18, 19]. One hundred forty-five patients were treated in these three studies, with recurrences classified as local (mediastinum), regional (lung or pleura/diaphragm or both), or distant. Of the 86 patients undergoing complete resection alone, 1 recurred locally, and 2 recurred regionally. Similarly, of the 59 patients who underwent complete resection with adjuvant radiotherapy, 1 recurred locally, and 2 recurred regionally. There were no distant recurrences in either group.

Interestingly, of the 12 studies listing details regarding patterns of recurrence, the most common site of recurrence in nine of these publications (75%) were the lung, pleura, or diaphragm, even though many of these studies grouped incompletely resected patients along with the patients undergoing complete resection. A clear exception is the study published by Curran and colleagues [9], in which no patient undergoing complete resection had recurrence in the pleura or lung, which is in clear contradistinction to all of the other publications. In this study, the authors listed the site of first recurrence, stating that "... additional patients subsequently developed intrathoracic dissemination following mediastinal failure ..." [9].


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
At first glance, the administration of adjuvant radiotherapy after complete resection of localized, invasive TET makes intuitive sense for at least two reasons. First, TET seem to be sensitive to radiation therapy, and second, the main threat from these lesions tends to be local invasion, as opposed to distant metastasis. Given these observations, it is not surprising that adjuvant radiotherapy has achieved adoption even after complete resection. Despite this, evidence to support this strategy is difficult to find in the published literature. As the present review details, the vast majority of studies are small, retrospective case series that lack the statistical power to make a clear statement regarding the utility of adjuvant radiotherapy.

A meta-analysis, such as that performed in this study, is a potentially useful tool in this situation because pooling of data can result in a very powerful study, as opposed to the results obtained from smaller, individual studies. In this regard, we sought to perform a systematic literature review of postoperative radiotherapy in preventing recurrence after complete resection of localized, invasive TET. In an attempt to overcome the statistical limitations of the small, individual publications on this topic, and to add a quantitative measurement to this review, recurrence data from individual studies were pooled, and a meta-analysis was performed. Surprisingly, despite the theoretical benefits of adjuvant radiotherapy outlined above, pooling of data from a large number of patients in this meta-analysis suggests that the addition of postoperative radiotherapy does not affect recurrence rates after complete resection of stage II and/or III TET. In addition, the most commonly reported sites of recurrence are the lung, pleura, and diaphragm, as opposed to the mediastinum.

Study Limitations
Several limitations of the present study exist. First, the 22 studies included in this review do not represent the entire body of literature regarding the use of adjuvant radiotherapy after complete resection. To be included in the present review and meta-analysis, studies had to contain both a surgery-alone group, in addition to a surgery-plus-radiotherapy group. However, multiple publications exist that represent series of patients who underwent exclusively surgical resection plus adjuvant radiotherapy, but with no "control" group of patients who underwent resection alone [36–39]. We chose to include only studies that provided data on both strategies because surgical technique and quality would be similar in studies in which two cohorts are presented, potentially reducing any bias based on surgical technique.

A second limitation is the quality of the supporting literature. No randomized trials exist that address the question of adjuvant radiotherapy, and all of the published data were obtained from retrospective, cohort studies. Multiple inconsistencies exist between studies related to important variables including but not limited to length of follow-up, proof of recurrence, technique and dose of radiotherapy, and tumor invasiveness. Perhaps most important is the selection bias introduced in retrospective studies, where the decision to give adjuvant radiotherapy is variable, and may depend on each individual surgeon's operative impression as well as the histologic type. We attempted to minimize some of these inconsistencies by incorporating data from studies after 1981 when Masaoka stage could definitively be determined and the radiotherapy techniques were more consistent. However, given the retrospective nature of the literature, these biases will always exist.

A third limitation is the statistically significant heterogeneity between the studies that evaluated stage III TET, and the relatively small number of patients with completely resected stage III disease included in the meta-analysis (122 total stage III patients). Given this heterogeneity, the random effects model was used to generate the forest plot for stage III disease (Fig 4). Causes of heterogeneity among the stage III studies could be related to the inherent heterogeneity of stage III lesions. As an example, a TET that is deemed stage III due to pericardial invasion may behave differently than a stage III lesion invading the superior vena cava. Another potential cause for heterogeneity among the stage III studies is that the determination of stage III is made by intraoperative assessment of macroscopic invasion into surrounding structures, a determination that is, at best, subjective and will vary between surgeons. Masaoka had recognized this potential difficulty in his 1981 publication that first elucidated the staging system, where it is stated: "It is sometimes difficult during surgery to distinguish accurately the infiltration of tumor from fibrous adhesion" [2].

A final limitation of the present analysis is that all types of recurrences were included in the meta-analysis, local (mediastinal), regional (lung, pleura, diaphragm), and distant. That was unavoidable because the vast majority of studies did not provide specific data on patterns of recurrence as related to the administration of adjuvant radiotherapy. This is potentially relevant because adjuvant radiotherapy probably will not affect recurrences outside of the radiation port. Despite this, given that the overall incidence of recurrence does not appear to be altered by the administration of adjuvant radiotherapy, it seems unlikely that survival will be affected by reduction of local (mediastinal) recurrence alone.

Assessment of Bias
Several types of bias are potentially introduced when performing a systematic review that are related to the literature search process. Publication bias exists when data are not published, usually as a result of a study performed with negative results. In the present study, this was assessed by the generation of a funnel plot (Fig 3), which failed to demonstrate significant publication bias. Additionally, the existence of unpublished, negative data would only strengthen the results of this meta-analysis, which failed to show a benefit for adjuvant radiotherapy. Duplication bias exists when multiple publications exist that characterize the same patients. This bias was avoided in the present review by scrutinizing individual studies and including only a solitary manuscript from each institution as outlined in the Methods section. Language bias exists when publications in foreign languages are excluded from the analysis, implying that studies conducted by foreign countries may not be included. Although the present review only contains English language studies, only seven of the 22 selected studies originated from the United States, suggesting that exclusion of data from foreign countries may not be significant.

Clinical Applications and Future Directions
The present meta-analysis suggests that the addition of adjuvant radiotherapy after complete resection of stage II and III TET does not affect overall recurrence rates. This finding, in combination with the fact that the most commonly reported sites of recurrence after resection of invasive TET are the lung, diaphragm, and pleura, suggests that the role of adjuvant mediastinal radiotherapy needs to be questioned, as it has been in several previously published single-institution studies [7, 17–19, 34]. Owing to inconsistently reported survival data, no statement can be made regarding whether or not adjuvant radiotherapy affects survival from this review with meta-analysis.

Mediastinal radiation is not without adverse effects, both short and long term, that include but are not limited to secondary malignancies, pulmonary fibrosis, esophageal strictures, coronary artery disease, cardiac valvular fibrosis, and pericardial disease [40, 41]. Given these potential problems, combined with the aforementioned results of this literature review and meta-analysis, an argument can be made that adjuvant radiotherapy should not be routinely administered after complete resection of stage II and III TET. Another potential benefit of withholding adjuvant radiotherapy in this scenario is that radiotherapy can be "reserved" should a recurrence develop in the future. Adjuvant radiotherapy can then be delivered after re-resection without the potential restrictions imposed by prior mediastinal irradiation.

Another avenue for investigation consists of the use of entire hemithoracic radiation therapy after complete resection of invasive TET. This approach potentially addresses the issue of pleural recurrence in this disease. In this regard, Uematsu and colleagues [37] published a small, retrospective analysis of a series of patients who received this modality, and found lower recurrence rates compared with those patients receiving mediastinal radiation alone. Yet another strategy may be to administer neoadjuvant radiotherapy combined with chemotherapy for locally invasive lesions, with the goal of enhancing the possibility of performing a complete resection, which is the most consistently demonstrated prognostic factor for this disease. This approach is currently being evaluated in a phase II multi-institutional prospective clinical trial [42]. One overwhelmingly clear message from this review is that prospectively collected data on patients with resectable thymoma are scarce, underscoring the need for such future prospective clinical trials.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

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