Strahlenther Onkol (2015) 191:133–140 DOI 10.1007/s00066-014-0740-z
O r i g i n a l a rt i c l e
Postoperative radiotherapy of patients with thymic epithelial tumors (TET) A retrospective analysis of outcome and toxicity Matthias Felix Häfner · Falk Roeder · Florian Sterzing · David Krug · Stefan A. Koerber · Jutta Kappes · Hans Hoffmann · Alla Slynko · Jürgen Debus · Marc Bischof Received: 7 February 2014 / Accepted: 16 July 2014 / Published online: 26 August 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose The purpose of this study was to evaluate postoperative radiotherapy regarding outcome and toxicity in patients with thymic epithelial tumors (TET) after surgery.
Dr. med. M. F. Häfner, M.D. () · PD Dr. med. F. Roeder, M.D. · PD Dr. med. F. Sterzing, M.D. · Dr. med. D. Krug, M.D. · Dr. med. S. A. Koerber, M.D. · Prof. Dr. med. Dr. rer. nat. J. Debus, M.D., Ph.D. · Prof. Dr. med. M. Bischof, M.D. Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany e-mail: [email protected] Dr. med. M. F. Häfner, M.D. · PD Dr. med. F. Roeder, M.D. · PD Dr. med. F. Sterzing, M.D. · Dr. med. D. Krug, M.D. · Dr. med. S. A. Koerber, M.D. · Prof. Dr. med. Dr. rer. nat. J. Debus, M.D., Ph.D. Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (dkfz), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Dr. med. J. Kappes, M.D. Department of Pneumology, Thoraxklinik Heidelberg, University of Heidelberg, Amalienstr. 5, 69126 Heidelberg, Germany Prof. Dr. med. H. Hoffmann, M.D. Department of Thoracic Surgery, Thoraxklinik Heidelberg, University of Heidelberg, Amalienstr. 5, 69126 Heidelberg, Germany Dr. rer. nat. A. Slynko, Ph.D. Biostatistics, German Cancer Research Center (dkfz), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Materials and methods We retrospectively analyzed medical records of 41 patients with TET treated with postoperative radiotherapy at our institution between 1995 and 2012. The impact of prognostic factors (e.g., Masaoka stage, histological subtype) was investigated and radiation-related toxicity was assessed. Results Median age was 59.8 years and median followup was 61 months. In 24.4 %, TETs were associated with paraneoplastic syndromes. The 5-year overall survival (OS) was 89.5 % and the 5-year disease-free survival (DFS) was 88.9 %. Masaoka stage had a significant impact on OS (p = 0.007). Locally limited stages I + II had a 5-year OS of 100 % compared to 80 % for stage III and 66.7 % for stage IV. The 5-year DFS was excellent with 100 % for both WHO groups A/AB/B1 and B2, respectively, and significantly (p = 0.005) differed from B3/C-staged patients with a 5-year DFS of 63.6 %. Resection status, paraneoplastic association, radiation dose, or tumor size did not influence survival. There were no high-grade acute or late side effects caused by radiotherapy. Conclusion Masaoka stage has a significant impact on OS as WHO type has on DFS in patients with TETs after surgery and adjuvant irradiation. Postoperative radiotherapy with doses around 50 Gy is safe and not likely to cause high-grade toxicity. Further prospective trials are necessary to separate patient subgroups that benefit from radiotherapy from those that do not. Keywords Radiotherapy, adjuvant · Thymoma · Thymic epithelial tumors · Postoperative care · Thyroid neoplasms
Prof. Dr. med. M. Bischof, M.D. Department of Radiation Oncology, SLK-Kliniken Heilbronn, Am Gesundbrunnen 20-26, 74076 Heilbronn, Germany
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Postoperative Strahlentherapie bei Patienten mit epithelialem Thymuskarzinom (TET) Eine retrospektive Analyse von Outcome und Toxizität Zusammenfassung Ziel Die vorliegende Studie hatte zum Ziel, die postoperative Radiotherapie von Patienten nach Resektion einer Thymusneoplasie epithelialen Ursprungs (Thymom, Thymuskarzinom, „thymic epithelial tumors“, TET) hinsichtlich prognostischer Relevanz und Nebenwirkungsprofil zu beurteilen. Material und methoden Wir analysierten retrospektiv die medizinischen Krankenakten von 41 Patienten mit TET, die zwischen 1995 und 2012 eine postoperative Radiotherapie in unserer Einrichtung erhielten. Hierbei untersuchten wir insbesondere mögliche Prognosefaktoren wie MasaokaStadium, histologischen Subtyp sowie weitere und erfassten radiogene Nebenwirkungen. Ergebnisse Das mediane Alter betrug 59,8 Jahre, das mediane Follow-up lag bei 61 Monaten. Bei 24,4 % aller Patienten trat ein paraneoplastisches Syndrom auf. Das 5-Jahres-Gesamtüberleben lag bei 89,5 %, das krankheitsfreie 5-Jahres-Übeleben bei 88,9 %. Das Masaoka-Stadium hatte signifikanten Einfluss auf das Gesamtüberleben (p = 0,007). Die lokal begrenzten Stadien I + II hatten ein 5-Jahres-Gesamtüberleben von 100 % im Vergleich zu 80 % bei Masaoka III und 66,7 % bei Masaoka IV. Das krankheitsfreie 5-Jahres-Übeleben war mit jeweils 100 % in den WHOGruppen A/AB/B1 bzw. B2 exzellent und damit signifikant besser (p = 0,005) im Vergleich zu 63,6 % bei Patienten mit B3/C. Resektionsstatus, Paraneoplasien, Bestrahlungsdosis oder Tumorgröße hatten keinen Einfluss auf das Überleben. Es traten keine höhergradigen, radiogenen Akut- oder Spätnebenwirkungen auf. Schlussfolgerung Das Masaoka-Stadium hat signifikanten Einfluss auf das Gesamtüberleben und der WHO-Subtyp auf das krankheitsfreie Überleben bei Patienten mit postoperativer Radiotherapie nach Resektion eines TET. Eine Bestrahlungsdosis von ca. 50 Gy kann hierbei sicher und ohne besonderes Risiko für höhergradige Nebenwirkungen appliziert werden. Allerdings werden weitere, prospektive Studien benötigt, um zu differenzieren, welche Patientensubgruppen von einer adjuvanten Radiotherapie profitieren und welche nicht. Schlüsselwörter Adjuvante Radiotherapie · Thymom · Epitheliales Thymuskarzinom · Postoperative Versorgung · Thymusneoplasie Thymic epithelial tumors (TET) are the most common neoplasm in the upper anterior mediastinal compartment.
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However, with an incidence of about 0.15 per 100,000 person–years they are rare compared to other malignant entities [1]. The group of TETs subsumes a heterogeneous collection of neoplasms arising from the thymic epithelium with different biological attributes. Surgical approaches have been established and are still considered the mainstay of therapy. The role of radiotherapy within multidisciplinary treatment concepts for thymic neoplasms remains unclear. The establishment of standardized treatment recommendations proves to be difficult because of a lack of evident scientific groundwork including prospective, randomized trials. Local invasiveness, biological subtypes, and resection status have turned out to be important for the patients’ prognosis and are increasingly the focus for further therapeutic considerations. In particular, complete resection has been identified as the leading prognostic factor and is superior to incomplete resection plus adjuvant radiotherapy [2–5]. However, patients with incomplete resection seem to benefit from postoperative irradiation [6]. The role of adjuvant irradiation after complete resection is controversially debated, particularly in patients with Masaoka stage II and III [7, 8]. In the present study, we retrospectively review our experience with postoperative radiation in the treatment of TET to investigate the influence of different factors on survival and disease control and to assess treatment-related side effects. Materials and methods Patient population We retrospectively reviewed records of patients with thymic epithelial tumors (TET) treated at the University Hospital of Heidelberg or the Clinical Cooperation Unit Radiation Oncology at the German Cancer Research Center between November 1995 and February 2012. Patients were included if they underwent complete or incomplete resection and received postoperative radiotherapy. Patients with incomplete records or with a follow-up period less than 6 months were not eligible and, thus, not included. A total of 41 patients met these criteria and were included in this analysis. Pathology Pathologic reports were reviewed for all patients. Evaluation of local invasiveness was performed according to the Masaoka staging system [9, 10]. Histopathological subtypes were determined based on the WHO classification [11, 12]. Surgical specimen before 1999 had been classified according to the system of Levine and Rosai [13]. In these cases a pathological review and reclassification according to the
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currently established WHO criteria was arranged. If there were two or more subtypes heterogeneously existing in one tumor specimen, we registered the assumedly most malignant component. Also we decided to simplify the histopathological characterization by summarizing patients into the categories A/AB/B1, B2, and B3/C according to a suggestion based on the meta-analysis by Marchevsky et al. [14]. Treatment All patients underwent primary tumor resection. Surgery was either performed as lateral thoracotomy (n = 29, 70.7 %), sternotomy (n = 9, 22.0 %) or video-assisted thoracoscopic (VATS) resection (n = 3, 7.3 %), and contained lobectomy or partial pleurectomy/pericardectomy if necessary. Most of the surgical interventions resulted in a complete resection (n = 32, 78 %); however, there were 8 cases with positive resection margins (19.5 %) and 1 patient with residual macroscopic tumor (2.4 %). After a median period of 44 days (range 20–151 days), postoperative radiotherapy of the mediastinum was initiated with a mean total dose of 51.7 Gy (range 49–60 Gy) and a daily dose of 2 Gy with 5 fractions per week. In most cases irradiation was delivered as 3D-conformal treatment or a combination of a 3D plan and opposed anteroposterior fields. Only 1 patient received intensity-modulated radiotherapy (IMRT). Clinical target volumes usually involved the upper mediastinum respecting preoperative tumor extent with an appropriate safety margin. In some patients after incomplete resection, a boost with a cumulative dose between 56 and 60 Gy was applied to residual tumor formations or close margin areas. One patient with thymic carcinoma received adjuvant chemotherapy consisting of four cycles of cisplatin plus etoposide. Apart from that chemotherapy was only delivered in case of progressive disease. Follow-up The follow-up period for this study ended on 30 June 2013. Medical follow-up included physical examination, chest radiography and/or thoracic CT scans as well as lung function testing on a regular basis. Acute toxicity and chronic side effects were classified according the National Cancer Institutes (NCI) Common Terminology Criteria of Adverse Events (CTCAE) Version 4 (v4.03). Statistical analysis All survival times were calculated starting from the date of surgery. Overall survival (OS) was defined as the time to death. Disease-free survival (DFS) was defined as the time to local recurrence or occurrence of metastases, depend-
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ing on which event occurred first. All patients who did not experience the event of interest were censored at the last follow-up date. The Kaplan–Meier method was applied to estimate OS and DFS for various group partitions. The logrank test was used to identify differences in survival experience between groups. The statistical analysis was performed using R version 3.0.2. Results Patient characteristics The study group consisted of 18 men (43.9 %) and 23 women (56.1 %). The median age was 59.8 years (range 19.8–76.2 years). In 9 cases (22 %), the TET was associated with myasthenia gravis (MG), 1 patient (2.4 %) presented a GOOD syndrome, a rare immunodeficiency associated with thymomas most commonly consisting of hypogammaglobulinemia and reduced or absent B or T cells. One patient with thymic carcinoma had lymph node metastasis. The median follow-up period was 61 months (range 15–174 months). Table 1 gives an overview over the characteristics of the collective. Survival Treatment failure was observed in 4 patients (9.8 %), all of them with tumors categorized as WHO C. One of these patients who was initially staged Masaoka II developed a local out-field relapse which was treated with re-irradiation and was alive at the end of the observation period. The other 3 patients had Masaoka III/IV TETs which failed locally (in-field relapse plus pleural carcinomatosis) or systemically (lung or bone metastases) and died due to the tumor disease. In the entire cohort, 8 patients died (19.5 %). Besides the 3 deaths directly related to recurring disease, 2 patients died due to complications indirectly associated with thymic disease (one with respiratory insufficiency after pleuropneumectomy and consecutive long-term artificial ventilation, the other due to recurring pulmonary infections because of GOOD syndrome). Three patients died from TET-independent cardiac comorbidity after 6, 10, and 13 years, respectively. The 5-year survival rates were 89.5 % [confidence interval (CI) 78.7–100 %] for OS and 88.9 % (CI 79–99.9 %) for DFS. Kaplan–Meier estimates for both OS and DFS for the entire study population are shown in Fig. 1. Masaoka stage had significant impact (p = 0.007) on OS as locally limited stages I + II had a 5-year OS of 100 % compared to 80 % (CI 51.6–100 %) for stage III and 66.7 % (CI 37.9–100 %) for stage IV (Fig. 2). There was no statistically significant difference in DFS according to local invasiveness (p = 0.1),
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136 Table 1 Summarized characteristics of the 41 patients Characteristic Number (%) Age (years) Median 59.3 Range 19.75–76.17 Sex Female 23 (56) Male 18 (44) Tumor size (mm) Median 80 Range 22–160 WHO classification A 5 (12) AB 11 (26) B1 6 (15) B2 8 (20) B3 0 (0) C 11 (26) Masaoka staging I 1 (2) II 28 (68) III 6 (15) IV 6 (15) Myasthenia gravis Yes 9 (22) No 32 (78) Surgery Thoracotomy 29 (71) Sternotomy 9 (22) VATS 3 (7) Resection status Complete 32 (78) Incomplete 9 (22) Period surgery to RT (days) Median 44 Range 22–151 Radiation technique APPA + 3D 5 (12) 3D 35 (86) IMRT 1 (2) Radiation dose (Gy) Median 50 Range 49–60 ≤ 50 Gy 27 (66) > 50 Gy 14 (34) Follow-up (months) Median 61 Range 15–174
although Kaplan–Meier curves may suggest a certain difference (Fig. 3). The 5-year DFS was excellent with 100 % for WHO groups A/AB/B1 and B2, respectively, and significantly (p = 0.005) differed from a DFS for B3/C-staged patients with a 5-year DFS of 63.6 % (CI 40.7–99.5 %) as demonstrated in Fig. 4. WHO type did not significantly affect OS in this cohort.
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Fig. 1 Kaplan–Meier estimates of overall survival and disease-free survival for the entire cohort
Fig. 2 Kaplan–Meier estimates of overall survival according to Masaoka stage
We found patients with complete resection to have a trend towards a better 5-year OS 91.1 % (CI 79.6–100 %) and DFS 89.1 % (CI 78.1–100 %) than patients with incomplete resection with an OS 85.7 % (CI 63.3–100 %) and DFS 87.5 % (CI 67.3–100 %). The same nonsignificant trend was observed for patients with MG with a 5-year OS and DFS of 100 %, respectively, compared to those without MG with an OS 87.1 % (CI 74.2–100 %) and a DFS 86.1 % (CI 74.3– 99.8 %). Differences in other potential prognostic factors
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Table 2 Overview: acute and late side effects with grading Acute Grade I, n (%) Grade II, n (%) Radiation dermatitis 12 (29) 1 (2) Pneumonitis 1 (2) 2 (5) Dyspnea 10 (24) 13 (32) Cough 11 (27) 0 Dysphagia 16 (39) 4 (10) Fatigue 5 (12) 0 Late Lung fibrosis 17 (41) 0 Cardiac 1 (2) 1 (2)
which two were treated due to clinical symptoms. Summarized toxicity data are shown in Table 2. Discussion Fig. 3 Kaplan–Meier estimates of disease-free survival according to Masaoka stage
Fig. 4 Kaplan–Meier estimates of disease-free survival according to WHO stage
such as radiation dosage or tumor size did not influence OS or DFS in our patient group. Toxicity We did not observe any high-grade acute or late side effects. Most common acute toxicities were mild to moderate dyspnea (n = 23, 56.1 %), dysphagia (n = 20, 48.8 %), mild radiation dermatitis (n = 13, 31.7 %), and cough (n = 11, 26.8 %). Only 3 patients (7.3 %) developed acute pneumonitis of
In this analysis, we retrospectively evaluated the therapeutic effectiveness of postoperative radiotherapy after resection of TETs and identified the rate and degree of side effects in the setting of a large, oncological center. The 5-year OS for our cohort was 89.5 % and the 5-year DFS was 88.9 %. These numbers correspond to the results of other, larger studies excluding thymic carcinoma [15] or even exceed them [16]. Other data including thymic carcinoma showed poorer results, e.g., Forquer et al. [6] in a large SEER-based analysis with a 5-year OS of 77.1 % or Kundel et al. [17] with a 5-year OS of 73 %. A reason for this difference may be advanced treatment options in our cohort as we included no patients treated before 1995 compared to study periods beginning in the early 1970s or 1980s in the majority of larger retrospective populations. The relevant literature has identified Masaoka stage in terms of local invasiveness as the most important prognostic factor regardless of histopathological criteria or treatment strategy. These findings apply to OS [3, 4, 15–22] and DFS [17–19, 22]. We did not find a noticeable impact on DFS; however, OS significantly differed between Masaoka groups. These results correspond to one of the largest study cohorts in literature of Kondo et al. [4] with 1320 patients who reported a 5-year OS of 100 % for stage I, 98.4 % for stage II, 88.7 % for stage III, and 70.6 and 52.8 % for stage IVa and b, respectively, though thymic carcinoma patients were excluded. There is coinstantaneous evidence that patients staged Masaoka I do not need adjuvant radiation since complete resection is achieved in most of all cases and relapse rate is very low. Although Patel et al. [16] showed a better OS and cause-specific survival (CSS) by trend for irradiated patients, most of the relevant studies did not find beneficial effects of postoperative radiation [2, 6, 23]. In contrast, Forquer et al. [6] found a significantly (p = 0.03) worse
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5-year CSS of 91 % for surgery plus radiation vs. 98 % for surgery alone. Masaoka II is probably the most disputed stage concerning the indication for postoperative radiotherapy. Several studies conclude that there is no benefit for an additional irradiation [2, 23–25]. In contrast, recent SEER-based studies have shown a positive impact of radiotherapy on survival data [6, 16]. Patel et al. [16] describe a superior 5-year/10year OS of 64/41 % for irradiated patients vs. 53/35 % for surgery only (p = 0.002), respectively. There was also a better CSS by trend. However, these works pooled Masaoka II + III patients. Even in locally advanced TETs with Masaoka stage III there is no clear-cut evidence in the literature concerning adjuvant irradiation. However, publications stating a benefit for adding postoperative radiotherapy [16, 26, 27] outbalance the skeptical positions [8, 28]. There is a lack of data considering patients with Masaoka stage IV TETs. However, in most of these patients a complete resection (R0) cannot be achieved. In this case, most studies focus on the analysis of resection status. There is a relationship between Masaoka stage and resection status as the probability of a complete resection declines with advancing local invasiveness. Complete resection is clearly associated with better survival [3, 4, 15, 17, 19, 21, 22, 29] and consequently remains the mainstay of all therapeutic efforts. The question is whether these patients require adjuvant radiation. There are some studies indicating better outcome for Masaoka III [26–27] or Masaoka II [5, 18] staged patients; however, there is also considerable evidence that radiotherapy might not be beneficial for this group [2, 8, 24, 25, 28]. For incompletely resected TETs, there is only poor data. In the large cohort SEER-based work by Forquer et al. [6], a better OS was shown for postoperative radiation after non-extirpative surgery in patients with Masaoka stage II and III. In contrast, Japanese data by Kondo et al. [4] did not reveal better survival or local control data despite including thymic carcinoma. Fuller et al. [7] outlined the recommendation for the postoperative management of patients with TETs in a review: radiotherapy is not beneficial in case of complete resection and Masaoka stage I and II, but should be generally considered in Masaoka stage III and IV and after incomplete resection. Considering data shown above these recommendations are rather cautious, especially regarding higher stages, and are a sign of a lack of reliable data. As there is doubtlessly a beneficial impact of complete resection on patient outcome, neoadjuvant concepts should be considered referring to convincing results of neoadjuvant regimens in other fields, e.g., rectal cancer [30, 31]. However, only a few, though encouraging approaches have been published so far [32, 33].
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Previous works have shown that it is admissible to subsummarize WHO categories into different groups. In our present analysis we adopted the classification proposed by Marchevsky et al. [14], but there are other, though quite similar grouping systems [19, 21]. WHO type has a measurable effect on patient outcome and may be considered a predictive prognostic factor [21, 22]. Yet, the impact is not as distinct as for Masaoka stage or resection status. Thymic carcinomas (WHO C) were mostly excluded from existing studies since there is a worse outcome [34, 35] and other treatment regimens including chemotherapy come to the fore. However, we decided to include these patients in our analysis to reflect practical clinical routine management of thymic tumors. As expected, WHO C patients showed a significantly worse DFS compared to WHO A and B thymomas, whereas there was no difference in OS in contrast to several other studies [19, 21, 22]. This mismatch may be due to some limitations of our present work. Differences between WHO A and B subtypes are ambiguous. Particularly, WHO B3 thymomas with the most malignant characteristics besides thymic carcinomas showed diverse results concerning impact on patients’ outcome [2, 27]. So far, there is no rationale for recommendations regarding postoperative irradiation depending on WHO type. In approximately 25 % of patients, TETs are associated with myasthenia gravis [15, 17, 19, 36]. In this regard, our cohort is representative with 22 % of patients showing MG. In some studies MG was associated with a better outcome [3, 17, 19, 22] which may assumedly be due to an earlier diagnosis because of corresponding symptoms. In the present work, we also described this difference by trend; however, this finding did not reach statistical significance and therefore matches results of many other studies [2, 15, 18, 21]. Ströbel et al. [21] observed that patients with MG had significantly smaller tumor size at the date of first diagnosis standing for an earlier detection compared to MG negative patients. Surprisingly, this effect did not translate into a better outcome for MG positive patients. The literature provides quite different results on radiation delivery. Studies proving a better outcome for higher radiation doses [3, 17, 19] are in opposition to others that did not find a dose relationship [15, 18, 26]. The very different dosage regimens are a further restriction for the comparison of study data. Target volume definition and radiation technique have hardly been part of the discussion so far. Fan et al. [26] showed a favorable trend of 3D/IMRT planning towards a better outcome compared to conventional techniques in Masaoka-III-staged patients. Again, the search of answers in this field is subject to restrictions due to the need of including very old data to create sufficiently large retrospective cohorts. In consideration of the fact that studies investigating advanced radiation techniques for other thoracic cancers have shown potential benefits in terms of spar-
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ing organs at risk or improving dosage regimens [37, 38], further research for the treatment of TETs with the help of these techniques seems not only worthwhile, but essential. The evaluation of toxicity data is complicated as many clinical symptoms after adjuvant radiation actually reflect perioperative morbidity. We found that most of the patients’ dyspnea was caused by lobectomy or diaphragm paresis due to injury of the nervus laryngeus recurrens, predominantly in patients with preexisting lung impairment due to COPD. Myasthenia gravis also disturbs the evaluation of radiationinduced toxicity as many patients reported dysphagia likely related to muscular dysfunction of the esophageal wall. Symptomatic pneumonitis occurred only in two patients and should be avoided as there is evidence for patients with mediastinal irradiation after surgery of non-small cell lung cancer that pneumonitis negatively affects survival [39]. Considering the good prognosis for TETs in lower stages the evaluation of late side effects is important. We did not find any high-grade late side effects; however, our followup period was rather short in this regard. Weksler et al. [27] described a 3–4 times higher risk of secondary malignancies for patients with TETs after mediastinal radiotherapy. Besides the retrospective, monocentric character the rather small number of patients is the major limitation of our analysis. This aspect might possibly be responsible for the fact that we did not see a significant impact of resection status on outcome. Furthermore, the median follow-up term was potentially rather short for TETs with a predominantly promising prognosis, especially concerning late toxicity. On the other hand, after the last publication about TETs from our institution [40] we present an entirely new group of patients in contrast to some other analyses originating from the same source [6, 16, 27]. Conclusion In this retrospective study we were able to show that tumor resection followed by postoperative radiotherapy results in appropriate 5-year survival data in patients diagnosed with thymoma or thymic carcinoma. Masaoka stage has a significant impact on OS as WHO type has on DFS. Adjuvant irradiation with doses around 50 Gy is safe and not likely to cause high-grade acute or late toxicity. Further randomized, prospective trials in a multi-institutional setting are necessary to identify patient subgroups that benefit from radiotherapy from those that do not. Compliance with ethical guidelines Conflict of interest M.F. Häfner, F. Roeder, F. Sterzing, D. Krug, S.A. Koerber, J. Kappes, H. Hoffmann, A. Slynko, J. Debus, and M.
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Bischof state that there are no conflicts of interest. All studies on patient data were carried out with approval of the institutional ethical review committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form).
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M. F. Häfner et al. 31. Calvo FA, Sole CV, Serrano J et al (2014) Preoperative chemoradiation with or without induction oxaliplatin plus 5-fluorouracil in locally advanced rectal cancer: long-term outcome analysis. Strahlenther Onkol 190:149–157 32. Kunitoh H, Tamura T, Shibata T et al (2010) A phase II trial of dose-dense chemotherapy, followed by surgical resection and/or thoracic radiotherapy, in locally advanced thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9606). Br J Cancer 103:6–11 33. Korst RJ, Bezjak A, Blackmon S et al (2014) Neoadjuvant chemoradiotherapy for locally advanced thymic tumors: a phase II, multiinstitutional clinical trial. J Thorac Cardiovasc Surg 147:36–44, 46 (e1) 34. Hsu HC, Huang EY, Wang CJ et al (2002) Postoperative radiotherapy in thymic carcinoma: treatment results and prognostic factors. Int J Radiat Oncol Biol Phys 52:801–805 35. Eng TY, Fuller CD, Jagirdar J et al (2004) Thymic carcinoma: state of the art review. Int J Radiat Oncol Biol Phys 59:654–664 36. Tormoehlen LM, Pascuzzi RM (2008) Thymoma, myasthenia gravis, and other paraneoplastic syndromes. Hematol Oncol Clin North Am 22:509–526 37. Fakhrian K, Oechsner M, Kampfer S et al (2013) Advanced techniques in neoadjuvant radiotherapy allow dose escalation without increased dose to the organs at risk: Planning study in esophageal carcinoma. Strahlenther Onkol 189:293–300 38. Song C, Pyo H, Kim J et al (2012) Superiority of conventional intensity-modulated radiotherapy over helical tomotherapy in locally advanced non-small cell lung cancer. A comparative plan analysis. Strahlenther Onkol 188:901–909 39. Butof R, Kirchner K, Appold S et al (2014) Potential clinical predictors of outcome after postoperative radiotherapy of non-small cell lung cancer. Strahlenther Onkol 190:263–269 40. Latz D, Schraube P, Oppitz U et al (1997) Invasive thymoma: treatment with postoperative radiation therapy. Radiology 204:859–864
O r i g i n a l a rt i c l e
Postoperative radiotherapy of patients with thymic epithelial tumors (TET) A retrospective analysis of outcome and toxicity Matthias Felix Häfner · Falk Roeder · Florian Sterzing · David Krug · Stefan A. Koerber · Jutta Kappes · Hans Hoffmann · Alla Slynko · Jürgen Debus · Marc Bischof Received: 7 February 2014 / Accepted: 16 July 2014 / Published online: 26 August 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose The purpose of this study was to evaluate postoperative radiotherapy regarding outcome and toxicity in patients with thymic epithelial tumors (TET) after surgery.
Dr. med. M. F. Häfner, M.D. () · PD Dr. med. F. Roeder, M.D. · PD Dr. med. F. Sterzing, M.D. · Dr. med. D. Krug, M.D. · Dr. med. S. A. Koerber, M.D. · Prof. Dr. med. Dr. rer. nat. J. Debus, M.D., Ph.D. · Prof. Dr. med. M. Bischof, M.D. Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany e-mail: [email protected] Dr. med. M. F. Häfner, M.D. · PD Dr. med. F. Roeder, M.D. · PD Dr. med. F. Sterzing, M.D. · Dr. med. D. Krug, M.D. · Dr. med. S. A. Koerber, M.D. · Prof. Dr. med. Dr. rer. nat. J. Debus, M.D., Ph.D. Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (dkfz), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Dr. med. J. Kappes, M.D. Department of Pneumology, Thoraxklinik Heidelberg, University of Heidelberg, Amalienstr. 5, 69126 Heidelberg, Germany Prof. Dr. med. H. Hoffmann, M.D. Department of Thoracic Surgery, Thoraxklinik Heidelberg, University of Heidelberg, Amalienstr. 5, 69126 Heidelberg, Germany Dr. rer. nat. A. Slynko, Ph.D. Biostatistics, German Cancer Research Center (dkfz), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Materials and methods We retrospectively analyzed medical records of 41 patients with TET treated with postoperative radiotherapy at our institution between 1995 and 2012. The impact of prognostic factors (e.g., Masaoka stage, histological subtype) was investigated and radiation-related toxicity was assessed. Results Median age was 59.8 years and median followup was 61 months. In 24.4 %, TETs were associated with paraneoplastic syndromes. The 5-year overall survival (OS) was 89.5 % and the 5-year disease-free survival (DFS) was 88.9 %. Masaoka stage had a significant impact on OS (p = 0.007). Locally limited stages I + II had a 5-year OS of 100 % compared to 80 % for stage III and 66.7 % for stage IV. The 5-year DFS was excellent with 100 % for both WHO groups A/AB/B1 and B2, respectively, and significantly (p = 0.005) differed from B3/C-staged patients with a 5-year DFS of 63.6 %. Resection status, paraneoplastic association, radiation dose, or tumor size did not influence survival. There were no high-grade acute or late side effects caused by radiotherapy. Conclusion Masaoka stage has a significant impact on OS as WHO type has on DFS in patients with TETs after surgery and adjuvant irradiation. Postoperative radiotherapy with doses around 50 Gy is safe and not likely to cause high-grade toxicity. Further prospective trials are necessary to separate patient subgroups that benefit from radiotherapy from those that do not. Keywords Radiotherapy, adjuvant · Thymoma · Thymic epithelial tumors · Postoperative care · Thyroid neoplasms
Prof. Dr. med. M. Bischof, M.D. Department of Radiation Oncology, SLK-Kliniken Heilbronn, Am Gesundbrunnen 20-26, 74076 Heilbronn, Germany
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Postoperative Strahlentherapie bei Patienten mit epithelialem Thymuskarzinom (TET) Eine retrospektive Analyse von Outcome und Toxizität Zusammenfassung Ziel Die vorliegende Studie hatte zum Ziel, die postoperative Radiotherapie von Patienten nach Resektion einer Thymusneoplasie epithelialen Ursprungs (Thymom, Thymuskarzinom, „thymic epithelial tumors“, TET) hinsichtlich prognostischer Relevanz und Nebenwirkungsprofil zu beurteilen. Material und methoden Wir analysierten retrospektiv die medizinischen Krankenakten von 41 Patienten mit TET, die zwischen 1995 und 2012 eine postoperative Radiotherapie in unserer Einrichtung erhielten. Hierbei untersuchten wir insbesondere mögliche Prognosefaktoren wie MasaokaStadium, histologischen Subtyp sowie weitere und erfassten radiogene Nebenwirkungen. Ergebnisse Das mediane Alter betrug 59,8 Jahre, das mediane Follow-up lag bei 61 Monaten. Bei 24,4 % aller Patienten trat ein paraneoplastisches Syndrom auf. Das 5-Jahres-Gesamtüberleben lag bei 89,5 %, das krankheitsfreie 5-Jahres-Übeleben bei 88,9 %. Das Masaoka-Stadium hatte signifikanten Einfluss auf das Gesamtüberleben (p = 0,007). Die lokal begrenzten Stadien I + II hatten ein 5-Jahres-Gesamtüberleben von 100 % im Vergleich zu 80 % bei Masaoka III und 66,7 % bei Masaoka IV. Das krankheitsfreie 5-Jahres-Übeleben war mit jeweils 100 % in den WHOGruppen A/AB/B1 bzw. B2 exzellent und damit signifikant besser (p = 0,005) im Vergleich zu 63,6 % bei Patienten mit B3/C. Resektionsstatus, Paraneoplasien, Bestrahlungsdosis oder Tumorgröße hatten keinen Einfluss auf das Überleben. Es traten keine höhergradigen, radiogenen Akut- oder Spätnebenwirkungen auf. Schlussfolgerung Das Masaoka-Stadium hat signifikanten Einfluss auf das Gesamtüberleben und der WHO-Subtyp auf das krankheitsfreie Überleben bei Patienten mit postoperativer Radiotherapie nach Resektion eines TET. Eine Bestrahlungsdosis von ca. 50 Gy kann hierbei sicher und ohne besonderes Risiko für höhergradige Nebenwirkungen appliziert werden. Allerdings werden weitere, prospektive Studien benötigt, um zu differenzieren, welche Patientensubgruppen von einer adjuvanten Radiotherapie profitieren und welche nicht. Schlüsselwörter Adjuvante Radiotherapie · Thymom · Epitheliales Thymuskarzinom · Postoperative Versorgung · Thymusneoplasie Thymic epithelial tumors (TET) are the most common neoplasm in the upper anterior mediastinal compartment.
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However, with an incidence of about 0.15 per 100,000 person–years they are rare compared to other malignant entities [1]. The group of TETs subsumes a heterogeneous collection of neoplasms arising from the thymic epithelium with different biological attributes. Surgical approaches have been established and are still considered the mainstay of therapy. The role of radiotherapy within multidisciplinary treatment concepts for thymic neoplasms remains unclear. The establishment of standardized treatment recommendations proves to be difficult because of a lack of evident scientific groundwork including prospective, randomized trials. Local invasiveness, biological subtypes, and resection status have turned out to be important for the patients’ prognosis and are increasingly the focus for further therapeutic considerations. In particular, complete resection has been identified as the leading prognostic factor and is superior to incomplete resection plus adjuvant radiotherapy [2–5]. However, patients with incomplete resection seem to benefit from postoperative irradiation [6]. The role of adjuvant irradiation after complete resection is controversially debated, particularly in patients with Masaoka stage II and III [7, 8]. In the present study, we retrospectively review our experience with postoperative radiation in the treatment of TET to investigate the influence of different factors on survival and disease control and to assess treatment-related side effects. Materials and methods Patient population We retrospectively reviewed records of patients with thymic epithelial tumors (TET) treated at the University Hospital of Heidelberg or the Clinical Cooperation Unit Radiation Oncology at the German Cancer Research Center between November 1995 and February 2012. Patients were included if they underwent complete or incomplete resection and received postoperative radiotherapy. Patients with incomplete records or with a follow-up period less than 6 months were not eligible and, thus, not included. A total of 41 patients met these criteria and were included in this analysis. Pathology Pathologic reports were reviewed for all patients. Evaluation of local invasiveness was performed according to the Masaoka staging system [9, 10]. Histopathological subtypes were determined based on the WHO classification [11, 12]. Surgical specimen before 1999 had been classified according to the system of Levine and Rosai [13]. In these cases a pathological review and reclassification according to the
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currently established WHO criteria was arranged. If there were two or more subtypes heterogeneously existing in one tumor specimen, we registered the assumedly most malignant component. Also we decided to simplify the histopathological characterization by summarizing patients into the categories A/AB/B1, B2, and B3/C according to a suggestion based on the meta-analysis by Marchevsky et al. [14]. Treatment All patients underwent primary tumor resection. Surgery was either performed as lateral thoracotomy (n = 29, 70.7 %), sternotomy (n = 9, 22.0 %) or video-assisted thoracoscopic (VATS) resection (n = 3, 7.3 %), and contained lobectomy or partial pleurectomy/pericardectomy if necessary. Most of the surgical interventions resulted in a complete resection (n = 32, 78 %); however, there were 8 cases with positive resection margins (19.5 %) and 1 patient with residual macroscopic tumor (2.4 %). After a median period of 44 days (range 20–151 days), postoperative radiotherapy of the mediastinum was initiated with a mean total dose of 51.7 Gy (range 49–60 Gy) and a daily dose of 2 Gy with 5 fractions per week. In most cases irradiation was delivered as 3D-conformal treatment or a combination of a 3D plan and opposed anteroposterior fields. Only 1 patient received intensity-modulated radiotherapy (IMRT). Clinical target volumes usually involved the upper mediastinum respecting preoperative tumor extent with an appropriate safety margin. In some patients after incomplete resection, a boost with a cumulative dose between 56 and 60 Gy was applied to residual tumor formations or close margin areas. One patient with thymic carcinoma received adjuvant chemotherapy consisting of four cycles of cisplatin plus etoposide. Apart from that chemotherapy was only delivered in case of progressive disease. Follow-up The follow-up period for this study ended on 30 June 2013. Medical follow-up included physical examination, chest radiography and/or thoracic CT scans as well as lung function testing on a regular basis. Acute toxicity and chronic side effects were classified according the National Cancer Institutes (NCI) Common Terminology Criteria of Adverse Events (CTCAE) Version 4 (v4.03). Statistical analysis All survival times were calculated starting from the date of surgery. Overall survival (OS) was defined as the time to death. Disease-free survival (DFS) was defined as the time to local recurrence or occurrence of metastases, depend-
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ing on which event occurred first. All patients who did not experience the event of interest were censored at the last follow-up date. The Kaplan–Meier method was applied to estimate OS and DFS for various group partitions. The logrank test was used to identify differences in survival experience between groups. The statistical analysis was performed using R version 3.0.2. Results Patient characteristics The study group consisted of 18 men (43.9 %) and 23 women (56.1 %). The median age was 59.8 years (range 19.8–76.2 years). In 9 cases (22 %), the TET was associated with myasthenia gravis (MG), 1 patient (2.4 %) presented a GOOD syndrome, a rare immunodeficiency associated with thymomas most commonly consisting of hypogammaglobulinemia and reduced or absent B or T cells. One patient with thymic carcinoma had lymph node metastasis. The median follow-up period was 61 months (range 15–174 months). Table 1 gives an overview over the characteristics of the collective. Survival Treatment failure was observed in 4 patients (9.8 %), all of them with tumors categorized as WHO C. One of these patients who was initially staged Masaoka II developed a local out-field relapse which was treated with re-irradiation and was alive at the end of the observation period. The other 3 patients had Masaoka III/IV TETs which failed locally (in-field relapse plus pleural carcinomatosis) or systemically (lung or bone metastases) and died due to the tumor disease. In the entire cohort, 8 patients died (19.5 %). Besides the 3 deaths directly related to recurring disease, 2 patients died due to complications indirectly associated with thymic disease (one with respiratory insufficiency after pleuropneumectomy and consecutive long-term artificial ventilation, the other due to recurring pulmonary infections because of GOOD syndrome). Three patients died from TET-independent cardiac comorbidity after 6, 10, and 13 years, respectively. The 5-year survival rates were 89.5 % [confidence interval (CI) 78.7–100 %] for OS and 88.9 % (CI 79–99.9 %) for DFS. Kaplan–Meier estimates for both OS and DFS for the entire study population are shown in Fig. 1. Masaoka stage had significant impact (p = 0.007) on OS as locally limited stages I + II had a 5-year OS of 100 % compared to 80 % (CI 51.6–100 %) for stage III and 66.7 % (CI 37.9–100 %) for stage IV (Fig. 2). There was no statistically significant difference in DFS according to local invasiveness (p = 0.1),
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136 Table 1 Summarized characteristics of the 41 patients Characteristic Number (%) Age (years) Median 59.3 Range 19.75–76.17 Sex Female 23 (56) Male 18 (44) Tumor size (mm) Median 80 Range 22–160 WHO classification A 5 (12) AB 11 (26) B1 6 (15) B2 8 (20) B3 0 (0) C 11 (26) Masaoka staging I 1 (2) II 28 (68) III 6 (15) IV 6 (15) Myasthenia gravis Yes 9 (22) No 32 (78) Surgery Thoracotomy 29 (71) Sternotomy 9 (22) VATS 3 (7) Resection status Complete 32 (78) Incomplete 9 (22) Period surgery to RT (days) Median 44 Range 22–151 Radiation technique APPA + 3D 5 (12) 3D 35 (86) IMRT 1 (2) Radiation dose (Gy) Median 50 Range 49–60 ≤ 50 Gy 27 (66) > 50 Gy 14 (34) Follow-up (months) Median 61 Range 15–174
although Kaplan–Meier curves may suggest a certain difference (Fig. 3). The 5-year DFS was excellent with 100 % for WHO groups A/AB/B1 and B2, respectively, and significantly (p = 0.005) differed from a DFS for B3/C-staged patients with a 5-year DFS of 63.6 % (CI 40.7–99.5 %) as demonstrated in Fig. 4. WHO type did not significantly affect OS in this cohort.
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Fig. 1 Kaplan–Meier estimates of overall survival and disease-free survival for the entire cohort
Fig. 2 Kaplan–Meier estimates of overall survival according to Masaoka stage
We found patients with complete resection to have a trend towards a better 5-year OS 91.1 % (CI 79.6–100 %) and DFS 89.1 % (CI 78.1–100 %) than patients with incomplete resection with an OS 85.7 % (CI 63.3–100 %) and DFS 87.5 % (CI 67.3–100 %). The same nonsignificant trend was observed for patients with MG with a 5-year OS and DFS of 100 %, respectively, compared to those without MG with an OS 87.1 % (CI 74.2–100 %) and a DFS 86.1 % (CI 74.3– 99.8 %). Differences in other potential prognostic factors
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Table 2 Overview: acute and late side effects with grading Acute Grade I, n (%) Grade II, n (%) Radiation dermatitis 12 (29) 1 (2) Pneumonitis 1 (2) 2 (5) Dyspnea 10 (24) 13 (32) Cough 11 (27) 0 Dysphagia 16 (39) 4 (10) Fatigue 5 (12) 0 Late Lung fibrosis 17 (41) 0 Cardiac 1 (2) 1 (2)
which two were treated due to clinical symptoms. Summarized toxicity data are shown in Table 2. Discussion Fig. 3 Kaplan–Meier estimates of disease-free survival according to Masaoka stage
Fig. 4 Kaplan–Meier estimates of disease-free survival according to WHO stage
such as radiation dosage or tumor size did not influence OS or DFS in our patient group. Toxicity We did not observe any high-grade acute or late side effects. Most common acute toxicities were mild to moderate dyspnea (n = 23, 56.1 %), dysphagia (n = 20, 48.8 %), mild radiation dermatitis (n = 13, 31.7 %), and cough (n = 11, 26.8 %). Only 3 patients (7.3 %) developed acute pneumonitis of
In this analysis, we retrospectively evaluated the therapeutic effectiveness of postoperative radiotherapy after resection of TETs and identified the rate and degree of side effects in the setting of a large, oncological center. The 5-year OS for our cohort was 89.5 % and the 5-year DFS was 88.9 %. These numbers correspond to the results of other, larger studies excluding thymic carcinoma [15] or even exceed them [16]. Other data including thymic carcinoma showed poorer results, e.g., Forquer et al. [6] in a large SEER-based analysis with a 5-year OS of 77.1 % or Kundel et al. [17] with a 5-year OS of 73 %. A reason for this difference may be advanced treatment options in our cohort as we included no patients treated before 1995 compared to study periods beginning in the early 1970s or 1980s in the majority of larger retrospective populations. The relevant literature has identified Masaoka stage in terms of local invasiveness as the most important prognostic factor regardless of histopathological criteria or treatment strategy. These findings apply to OS [3, 4, 15–22] and DFS [17–19, 22]. We did not find a noticeable impact on DFS; however, OS significantly differed between Masaoka groups. These results correspond to one of the largest study cohorts in literature of Kondo et al. [4] with 1320 patients who reported a 5-year OS of 100 % for stage I, 98.4 % for stage II, 88.7 % for stage III, and 70.6 and 52.8 % for stage IVa and b, respectively, though thymic carcinoma patients were excluded. There is coinstantaneous evidence that patients staged Masaoka I do not need adjuvant radiation since complete resection is achieved in most of all cases and relapse rate is very low. Although Patel et al. [16] showed a better OS and cause-specific survival (CSS) by trend for irradiated patients, most of the relevant studies did not find beneficial effects of postoperative radiation [2, 6, 23]. In contrast, Forquer et al. [6] found a significantly (p = 0.03) worse
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5-year CSS of 91 % for surgery plus radiation vs. 98 % for surgery alone. Masaoka II is probably the most disputed stage concerning the indication for postoperative radiotherapy. Several studies conclude that there is no benefit for an additional irradiation [2, 23–25]. In contrast, recent SEER-based studies have shown a positive impact of radiotherapy on survival data [6, 16]. Patel et al. [16] describe a superior 5-year/10year OS of 64/41 % for irradiated patients vs. 53/35 % for surgery only (p = 0.002), respectively. There was also a better CSS by trend. However, these works pooled Masaoka II + III patients. Even in locally advanced TETs with Masaoka stage III there is no clear-cut evidence in the literature concerning adjuvant irradiation. However, publications stating a benefit for adding postoperative radiotherapy [16, 26, 27] outbalance the skeptical positions [8, 28]. There is a lack of data considering patients with Masaoka stage IV TETs. However, in most of these patients a complete resection (R0) cannot be achieved. In this case, most studies focus on the analysis of resection status. There is a relationship between Masaoka stage and resection status as the probability of a complete resection declines with advancing local invasiveness. Complete resection is clearly associated with better survival [3, 4, 15, 17, 19, 21, 22, 29] and consequently remains the mainstay of all therapeutic efforts. The question is whether these patients require adjuvant radiation. There are some studies indicating better outcome for Masaoka III [26–27] or Masaoka II [5, 18] staged patients; however, there is also considerable evidence that radiotherapy might not be beneficial for this group [2, 8, 24, 25, 28]. For incompletely resected TETs, there is only poor data. In the large cohort SEER-based work by Forquer et al. [6], a better OS was shown for postoperative radiation after non-extirpative surgery in patients with Masaoka stage II and III. In contrast, Japanese data by Kondo et al. [4] did not reveal better survival or local control data despite including thymic carcinoma. Fuller et al. [7] outlined the recommendation for the postoperative management of patients with TETs in a review: radiotherapy is not beneficial in case of complete resection and Masaoka stage I and II, but should be generally considered in Masaoka stage III and IV and after incomplete resection. Considering data shown above these recommendations are rather cautious, especially regarding higher stages, and are a sign of a lack of reliable data. As there is doubtlessly a beneficial impact of complete resection on patient outcome, neoadjuvant concepts should be considered referring to convincing results of neoadjuvant regimens in other fields, e.g., rectal cancer [30, 31]. However, only a few, though encouraging approaches have been published so far [32, 33].
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Previous works have shown that it is admissible to subsummarize WHO categories into different groups. In our present analysis we adopted the classification proposed by Marchevsky et al. [14], but there are other, though quite similar grouping systems [19, 21]. WHO type has a measurable effect on patient outcome and may be considered a predictive prognostic factor [21, 22]. Yet, the impact is not as distinct as for Masaoka stage or resection status. Thymic carcinomas (WHO C) were mostly excluded from existing studies since there is a worse outcome [34, 35] and other treatment regimens including chemotherapy come to the fore. However, we decided to include these patients in our analysis to reflect practical clinical routine management of thymic tumors. As expected, WHO C patients showed a significantly worse DFS compared to WHO A and B thymomas, whereas there was no difference in OS in contrast to several other studies [19, 21, 22]. This mismatch may be due to some limitations of our present work. Differences between WHO A and B subtypes are ambiguous. Particularly, WHO B3 thymomas with the most malignant characteristics besides thymic carcinomas showed diverse results concerning impact on patients’ outcome [2, 27]. So far, there is no rationale for recommendations regarding postoperative irradiation depending on WHO type. In approximately 25 % of patients, TETs are associated with myasthenia gravis [15, 17, 19, 36]. In this regard, our cohort is representative with 22 % of patients showing MG. In some studies MG was associated with a better outcome [3, 17, 19, 22] which may assumedly be due to an earlier diagnosis because of corresponding symptoms. In the present work, we also described this difference by trend; however, this finding did not reach statistical significance and therefore matches results of many other studies [2, 15, 18, 21]. Ströbel et al. [21] observed that patients with MG had significantly smaller tumor size at the date of first diagnosis standing for an earlier detection compared to MG negative patients. Surprisingly, this effect did not translate into a better outcome for MG positive patients. The literature provides quite different results on radiation delivery. Studies proving a better outcome for higher radiation doses [3, 17, 19] are in opposition to others that did not find a dose relationship [15, 18, 26]. The very different dosage regimens are a further restriction for the comparison of study data. Target volume definition and radiation technique have hardly been part of the discussion so far. Fan et al. [26] showed a favorable trend of 3D/IMRT planning towards a better outcome compared to conventional techniques in Masaoka-III-staged patients. Again, the search of answers in this field is subject to restrictions due to the need of including very old data to create sufficiently large retrospective cohorts. In consideration of the fact that studies investigating advanced radiation techniques for other thoracic cancers have shown potential benefits in terms of spar-
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ing organs at risk or improving dosage regimens [37, 38], further research for the treatment of TETs with the help of these techniques seems not only worthwhile, but essential. The evaluation of toxicity data is complicated as many clinical symptoms after adjuvant radiation actually reflect perioperative morbidity. We found that most of the patients’ dyspnea was caused by lobectomy or diaphragm paresis due to injury of the nervus laryngeus recurrens, predominantly in patients with preexisting lung impairment due to COPD. Myasthenia gravis also disturbs the evaluation of radiationinduced toxicity as many patients reported dysphagia likely related to muscular dysfunction of the esophageal wall. Symptomatic pneumonitis occurred only in two patients and should be avoided as there is evidence for patients with mediastinal irradiation after surgery of non-small cell lung cancer that pneumonitis negatively affects survival [39]. Considering the good prognosis for TETs in lower stages the evaluation of late side effects is important. We did not find any high-grade late side effects; however, our followup period was rather short in this regard. Weksler et al. [27] described a 3–4 times higher risk of secondary malignancies for patients with TETs after mediastinal radiotherapy. Besides the retrospective, monocentric character the rather small number of patients is the major limitation of our analysis. This aspect might possibly be responsible for the fact that we did not see a significant impact of resection status on outcome. Furthermore, the median follow-up term was potentially rather short for TETs with a predominantly promising prognosis, especially concerning late toxicity. On the other hand, after the last publication about TETs from our institution [40] we present an entirely new group of patients in contrast to some other analyses originating from the same source [6, 16, 27]. Conclusion In this retrospective study we were able to show that tumor resection followed by postoperative radiotherapy results in appropriate 5-year survival data in patients diagnosed with thymoma or thymic carcinoma. Masaoka stage has a significant impact on OS as WHO type has on DFS. Adjuvant irradiation with doses around 50 Gy is safe and not likely to cause high-grade acute or late toxicity. Further randomized, prospective trials in a multi-institutional setting are necessary to identify patient subgroups that benefit from radiotherapy from those that do not. Compliance with ethical guidelines Conflict of interest M.F. Häfner, F. Roeder, F. Sterzing, D. Krug, S.A. Koerber, J. Kappes, H. Hoffmann, A. Slynko, J. Debus, and M.
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Bischof state that there are no conflicts of interest. All studies on patient data were carried out with approval of the institutional ethical review committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form).
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