Summary

METHODS
The study comprised 28 patients who received RT at the Radiation Oncology Department of Eskişehir Osmangazi University Faculty of Medicine between 2010 and 2021. Each patient received RT (3DCRT/ IMRT/VMAT).

RESULTS
The median overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) at a median follow-up of 74 months were 76 (3?201), 29, and 57 (0?198) months, respectively. The median RT dose was 50 Gy (44?66). While there was no statistically significant difference between DFS and RT doses (p=0.88), there was a statistically significant difference between PFS and OS and 50 Gy and higher doses (p=0.03 vs. p=0.02).

CONCLUSION
Post-operative RT has been proven to be beneficial in cases of incomplete resection, even if the role of adjuvant RT in patients with complete resection remains debatable. It is well established that primary unresectable thymic tumors can be treated safely and successfully with neoadjuvant or definitive chemoradiotherapy.

Introduction

The World Health Organization (WHO) classification is based on the ratios of lymphocytes to non-malignant thymic epithelial cells (A, AB, B1, B2, B3, and C), whereas the MASAOKA staging system is based on the localization of pertinent areas and the macroscopic and microscopic extension of the tumor (Stage I, II, III, and IV).[3] The evaluation of the tumor"s radical resectability serves as the cornerstone of the treatment for thymic malignancies. After resection, its histological degree and capsular invasion status can be used to assess whether adjuvant therapy is necessary.[4] Patients are usually diagnosed while investigating myasthenia gravis or having a thorax computed tomography (CT) scan for another reason. Up to 70% of thymomas are associated with paraneoplastic syndromes. Depending on the size of the tumor and how it affects the surrounding organs, clinical symptoms may include cough, chest pain, dyspnea, hoarseness, superior vena cava syndrome, and tumor hemorrhage. Although less frequently, symptoms of anorexia, dysphagia, and weight loss can also be seen.[5,6]

The clinical diagnosis is made through CT and positron emission tomography-CT (PET-CT), despite the fact that it coincidentally presents on direct chest radiographs as anterior mediastinum enlargement. There are several techniques for histological diagnosis, including thoracoscopic biopsy, true-cut biopsy, anterior parasternal mediastinotomy, and fine-needle aspiration biopsy.[7]

There are surgical, chemotherapy (ChT), and radiotherapy (RT) alternatives for treatment (RT). The MASAOKA stage and resectability are the most significant variables influencing the prognosis (R0, R1, R2). Anemia, serum lactate dehydrogenase, serum leukocyte, performance status, weight loss, coexisting disorders, tumor size, involvement of the pericardium, and lymph node metastatic status are additional factors.[8,9] Yan et al.[10] found no evidence that adjuvant RT improved overall survival (OS) or progression-free survival (PFS) in 88 stage I-II thymoma patients; however, adjuvant RT improved OS and PFS in Stage III?IV.

In this study, we examined the disease-free survival (DFS), PFS, and OS rates of patients who received adjuvant or definitive RT at Radiation Oncology Department of the Faculty of Medicine, Eskişehir Osmangazi University.

Methods

Treatment Protocol
In the supine position, the patients were immobilized hands above the head with the Wingboard. Using the Somatom Definition AS? CT simulator device, planning CT was examined at 3?5 mm cross-sectional intervals. Image fusion was carried out using FDG/PET and thorax CT scans taken at the time of diagnosis. Surgery reports, post-operative thorax CT, PET-CT, and surgical clips were used for contouring in patients undergoing adjuvant RT. In patients receiving definitive RT, gross tumor volume was contoured using visible gross tumors and surgical clips, if present. In patients with PET-CT, planning CT and PET-CT fusion were carried out. In our study, the planned target volume (PTV) margin was determined as 3?5 mm, while the clinical target volume (CTV) margin was determined as 5?10 mm. In patients receiving adjuvant RT, the CTV was determined to comprise the whole thymus (in partially resected individuals), surgical clips, and possible residual disease areas. In patients scheduled for adjuvant RT, PTV was created by giving an 8?10 mm margin to the CTV, and RT was administered at a dose of 1.8-2 Gy/day, with a median dose of 50 Gy (44?60) using the 3DCRT/IMRT/VMAT technique with Varian Trilogy™/TrueBeam™ and Elekta Precise™ devices. When definitive RT was anticipated, concomitant ChT was scheduled while taking into account the Karnofsky Performance Status (KPS), comorbid conditions, and blood parameters.

Patient Follow-up
Patients were assessed for response to therapy through physical examination, anamnesis, and thorax CT during the 1^st month following treatment. Patients underwent thoracic CT scans, physical examinations, and anamnesis as part of patient follow-up setting, and cases with suspected recurrence were discussed in a multidisciplinary council every 3 months for the first 2 years, every 6 months for up to 5 years, and every year after 5 years.

Statistical Methods
The data were analyzed using the Statistical Program for the Social Sciences version 26 package program (IBM Corp., Armonk, NY, USA), with summary values of qualitative variables displayed as frequency and percentage and quantitative variables shown as mean±standard deviation. Shapiro-Wilk test was used to assess the compatibility of quantitative variables to normal distribution. Because there was no normal distribution in the comparisons of the two groups, Mann-Whitney U-test was performed. Because no normal distribution was seen in group comparisons of more than two groups, Kruskal-Wallis test was used. For survival analysis, Kaplan- Meier approach was utilized. Cases with p<0.05 as a result of the analysis were considered significant.

Results

Table 1: Patient, tumor, and treatment characteristics

The MASAOKA stage of the patients is given in Table 2. When the stage and OS were evaluated, no statistically significant differences were detected (p=0.48). When the resection status of 23 patients undergoing adjuvant RT was evaluated, it was seen that 11 (47.8%) patients had R0, 9 (39.1%) patients had R1, and 3 (13.1%) patients had R2 resection. No statistically significant relationship between resection status and OS has been established (p=0.84). When evaluated in terms of OS, DFS, and PFS, it was observed that the median OS duration was 76 (3-201) months, the median DFS 29 months (0-195) months, and the median PFS duration was 57 (0-198) months. Statistically significant differences in OS were not observed between patients receiving adjuvant and definitive RT (p=0.38). In the RT dose and survival assessment of patients, the median PFS and OS periods were 28.5 months and 37 months, respectively, in the group with <50 Gy RT; and median PFS and OS periods with doses ≥50 Gy above were 95 and 99 months, respectively. Statistically significant differences in PFS and OS were observed between groups with <50 Gy and ?50 Gy RT (p=0.03). No statistically significant differences were observed between DFS and RT dose (p=0.88). OS is indicated in the sequence of the DFS and PFS times with the delivered RT dose in Figure 1a-c. After treatment at the median follow-up of 74 months, complete response (71.4%) was monitored in 20 patients, partial response (14.3%) in 4 patients, stable response (10.7%) in 3 patients, and progression in 1 patient (3,6). During the median follow-up of 74 months, 17 cases were alive and 13 cases died. Of the 13 cases with ex, 6 died due to thymic tumor, and the remaining 7 died due to non-tumor causes.

Fig. 1: (a) Overall survival and radiotherapy dose relationship. (b) Disease-free survival and radiotherapy dose relationship. (c) Progression- free survival and radiotherapy dose relationship.

RT: Radiotherapy; Gy: Gray.

Table 2: The MASAOKA stage of the patients

Discussion

In a study conducted between 2001 and 2016, Fukui et al.[14] evaluated the clinicopathological features and prognosis of 153 patients with stage I thymic epithelial tumors and underwent complete resection, and the 5-year OS and recurrence-free survival rates were found to be 94% and 80%, respectively. In multivariate analysis, patients with tumor size >5 cm were associated with a higher risk of recurrence (p=0.027). In our study, however, no statistically significant relationship was found between tumor size and OS, DFS, and PFS (p=0.20, p=0.54, p=0.33).

Jackson et al.[15] investigated the contribution of adjuvant RT to survival in 4056 patients with thymic tumors between 2004 and 2012 using National Cancer Database data. In multivariate analysis, parameters such as patient age, WHO histological subtype, Masaoka Stage, surgical margins, and ChT application were used in the evaluation of OS. Improvement in OS was observed in patients who received adjuvant RT in the early stage (p=0.001). In our study, regardless of the stage of the disease, the median DFS was 51 months in patients receiving adjuvant RT, and the median DFS was 0 months in patients receiving definitive RT, and a statistically significant relationship was found by using Kaplan Meier method (p=0.01), but no significant relationship was found in terms of OS and PFS (p=0.30, p=0.50). Similarly, Tateishi et al.[16] in a meta-analysis consisting of five separate studies, 4746 patients with thymoma with Masaoka Stage II-III were included in the study, and 2408 of these patients received adjuvant RT and their survival rates were evaluated. OS rates were observed to be better with adjuvant RT (p<0.001), but no statistically significant relationship was found with DFS (p=0.83).

Although the adjuvant RT dose in thymic tumors is known as 45-55 Gy, the surgical resection status is important in making this decision. For adjuvant treatment, the radiation dose consists of 45-50 Gy for clear/close margins and 54 Gy for microscopically positive resection margins. A total dose of 60-70 Gy should be given to patients with gross residual disease (similar to patients with unresectable disease).[17-19] While adjuvant RT is not recommended after complete resection in Stage I cases, RT can be applied to Stage II cases with R1 and R2 resections or capsule invasion. In patients with stage III-IV thymic tumors, the contribution of adjuvant RT to survival is evident. In some selected cases, definitive CRT can be tried in cases where surgery cannot be performed due to proximity or invasion of vascular structures. In a study by Urgesi et al.[20] on 77 patients with Stage IIIIV thymic tumors between 1970 and 1987, the adjuvant RT dose was 1.8-2 Gy/day, a total of 39.6-46 Gy was administered, and the 10-year OS was found to be 58.3%. Ogawa et al.[21] administered adjuvant RT dose <40 Gy to 19 patients, 40 Gy to 45 patients, and >40 Gy to 39 patients in 103 patients with complete resection of thymoma, and no dose-response correlation was observed. Again, between 1981 and 1995, in a study conducted by Latz et al.,[22] local control analysis was performed with adjuvant RT in 43 (23 total, 20 subtotal resection) patients with thymic tumor after surgery. In this study, a local control rate of 74% (32 patients) was obtained.

In our study, 44?60 Gy (median 50 Gy) RT was applied to the patients, and the 5 and 10-year OS rates were found to be 50% and 10%, respectively. In this study, improvement in PFS and OS was observed at doses of 50 Gy and above (p=0.03 vs. p=0.02). We recommend that dosing 50 Gy and above because of thymic tumors are radiosensitive tumors and complete response with surgery alone is difficult. Dose applications under 50 Gy can be considered palliative.

The limitations of our study are that this study is single- centered, retrospective, limited number of patients, evaluation of surgical and non-surgical cases, and ex cases due to comorbid disease and COVID pneumonia.

Due to the fact that thymic tumors are very rare tumors and difficulties in calculating real survival rates during the COVID-19 pandemic period, multicenter studies with more patients are needed.

Conclusion

Peer-review: Externally peer-reviewed.

Conflict of Interest: All authors declared no conflict of interest.

Ethics Committee Approval: The study was approved by the Eskişehir Osmangazi University Non-Interventional Clinical Research Ethics Committee (no: E-25403353- 050.99-392767, date: 04/10/2022).

Financial Support: None declared.

Authorship contributions: Concept - D.E., M.Ç.Y., D.K.; Design - D.E., M.Ç.Y., D.K.; Supervision - D.E., M.Ç.Y., D.K.; Funding - D.E., M.Ç.Y., D.K.; Materials - D.E., M.Ç.Y., D.K., E.D.; Data collection and/or processing - D.E., M.Ç.Y., D.K., E.D.; Data analysis and/or interpretation - D.E., M.Ç.Y., D.K.; Literature search ? D.E., M.Ç.Y., D.K., E.D.; Writing - D.E., M.Ç.Y., D.K.; Critical review - D.E., M.Ç.Y., D.K.

References

1) Scorsetti M, Leo F, Trama A, D"Angelillo R, Serpico D, Macerelli M, et al. Thymoma and thymic carcinomas. Crit Rev Oncol Hematol 2016;99:332-50.

2) Lombe DC, Jeremic B. A review of the place and role of radiotherapy in thymoma. Clin Lung Cancer 2015;16(6):406?12.

3) Weissferdt A, Moran CA. Staging of thymic epithelial neoplasms: Thymoma and thymic carcinoma. Pathol Res Pract 2015;211(1):2-11.

4) Conforti F, Marino M, Vitolo V, Spaggiari L, Mantegazza R, Zucali P, et al. Clinical management of patients with thymic epithelial tumors: The recommendations endorsed by the Italian Association of Medical Oncology (AIOM). ESMO Open 2021;6(4):100188.

5) Ritter JH, Wick MR. Primary carcinomas of the thymus gland. Semin Diagn Pathol 1999;16(1):18-31.

6) Konstantinov IE, Saxena P, Koniuszko M, Ghosh S, Low VH, Khor TS, et al. Superior vena cava obstruction by tumour thrombus in invasive thymoma: Diagnosis and surgical management. Heart Lung Circ 2007;16(6):462-4.

7) Detterbeck FC, Zeeshan A. Thymoma: Current diagnosis and treatment. Chin Med J Engl 2013;126(11):2186-91.

8) Knetki-Wróblewska M, Kowalski DM, Olszyna-Serementa M, Krzakowski M, Szo?kowska M. Thymic epithelial tumors: Do we know all the prognostic factors? Thorac Cancer. 2021;12(3):339-48.

9) Chiappetta M, Aprile V, Lococo F, Zanfrini E, Nachira D, Meacci E, et al. Prognostic factors for survival in advanced thymomas: The role of the number of involved structures. J Surg Oncol 2021;124(5):858-66.

10) Yan J, Liu Q, Moseley JN, Baik CS, Chow LQ, Goulart BH, et al. Adjuvant radiotherapy for stages II and III resected thymoma: A single-institutional experience. Am J Clin Oncol 2016;39(3):223-7.

11) Marx A, Chan JK, Coindre JM, Detterbeck F, Girard N, Harris NL, et al. The 2015 World Health Organization classification of tumors of the thymus: Continuity and changes. J Thorac Oncol 2015;10(10):1383-95.

12) Chiappetta M, Lococo F, Pogliani L, Sperduti I, Tabacco D, Bria E, et al. Masaoka-Koga and TNM Staging System in thymic epithelial tumors: Prognostic comparison and the role of the number of involved structures. Cancers Basel 2021;13(21):5254.

13) Xu C, Zhang Y, Wang W, Wang Q, Li Z, Song Z, et al. Chinese expert consensus on the diagnosis and treatment of thymic epithelial tumors. Thorac Cancer 2023;14(12):1102-17.

14) Fukui T, Kadomatsu Y, Tsubouchi H, Nakanishi K, Ueno H, Sugiyama T, et al. Prognostic factors of stage I thymic epithelial tumors. Gen Thorac Cardiovasc Surg 2021;69(1):59-66.

15) Jackson MW, Palma DA, Camidge DR, Jones BL, Robin TP, Sher DJ, et al. The impact of postoperative radiotherapy for thymoma and thymic carcinoma. J Thorac Oncol 2017;12(4):734-44.

16) Tateishi Y, Horita N, Namkoong H, Enomoto T, Takeda A, Kaneko T. Postoperative radiotherapy for completely resected Masaoka/Masaoka-Koga stage II/III thymoma improves overall survival: An updated meta-analysis of 4746 patients. J Thorac Oncol 2021;16(4):677-85.

17) Mornex F, Resbeut M, Richaud P, Jung GM, Mirabel X, Marchal C, et al. Radiotherapy and chemotherapy for invasive thymomas: A multicentric retrospective review of 90 cases. The FNCLCC trialists. Fédération Nationale des Centres de Lutte Contre le Cancer. Int J Radiat Oncol Biol Phys 1995;32(3):651-9.

18) Myojin M, Choi NC, Wright CD, Wain JC, Harris N, Hug EB, et al. Stage III thymoma: Pattern of failure after surgery and postoperative radiotherapy and its implication for future study. Int J Radiat Oncol Biol Phys 2000;46(4):927-33.

19) Rimner A, Yao X, Huang J, Antonicelli A, Ahmad U, Korst RJ, et al. Postoperative radiation therapy is associated with longer overall survival in completely resected Stage II and III thymoma - An analysis of the International Thymic Malignancies Interest Group retrospective database. J Thorac Oncol 2016;11(10):1785-92.

20) Urgesi A, Monetti U, Rossi G, Ricardi U, Casadio C. Role of radiation therapy in locally advanced thymoma. Radiother Oncol 1990;19(3):273-80.

21) Ogawa K, Uno T, Toita T, Onishi H, Yoshida H, Kakinohana Y, et al. Postoperative radiotherapy for patients with completely resected thymoma: A multi-institutional, retrospective review of 103 patients. Cancer 2002;94(5):1405-13.

22) Latz D, Schraube P, Oppitz U, Kugler C, Manegold C, Flentje M, et al. Invasive thymoma: Treatment with postoperative radiation therapy. Radiology 1997;204(3):859-64.