Comparison of radiotherapy techniques in patients with thymic epithelial tumor who underwent postoperative radiotherapy

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Radiat Oncol J. 2024;42(1):43-49

Publication date (electronic) : 2023 December 15

doi : https://doi.org/10.3857/roj.2023.00360

Hyunseok Lee, Dongryul Oh, Yong Chan Ahn, Hongryull Pyo, Kyungmi Yang, Jae Myoung Noh

Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

Correspondence: Jae Myoung Noh Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-gu, Seoul 06351, Republic of Korea. Tel: +82-2-3410-2612, E-mail: rodrno@skku.edu

Received 2023 April 29; Revised 2023 October 2; Accepted 2023 October 24.

Abstract

Introduction

Thymic epithelial tumor (TET), which originates from the anterior mediastinum, includes thymoma, thymic carcinoma, and thymic neuroendocrine tumors [1,2]. Although TET is the most common tumor of the anterior mediastinum, it is a rare disease with an age-standardized incidence rate of 0.50 per 100,000 individuals in the Republic of Korea [1-3]. However, the incidence of TET shows increasing trends in Korea [1]. According to the National Comprehensive Cancer Network guidelines [4], the standard treatment for resectable TET is upfront surgery. Patients with TET who have close surgical margins or those at an advanced stage are treated with postoperative radiotherapy (PORT) to eradicate microscopic cancer cells [5-12].

While PORT reduces locoregional recurrence and increases overall survival (OS) in patients with TET [5-12], mediastinal irradiation can cause several acute and late complications in adjacent normal organs, such as the lungs, esophagus, and heart [13-17]. Various complications including radiation pneumonitis, esophagitis, pericarditis, myocardial infarction, and congestive heart failure have been reported in patients with different malignancies who received chest radiation therapy (RT) [13-17]. In addition, considering the relatively younger age of onset of TET compared to that of other cancers [3], radiation-related secondary malignancies should be considered for long-term observation.

Proton beam therapy (PBT), due to its characteristic “Bragg peak” phenomenon, is expected to show decreased radiation exposure to nearby normal tissues [18]. Some studies have already analyzed dosimetric parameters and clinical outcomes of PBT in patients with TET [19-23]. However, only a few studies have compared PBT against other RT techniques, such as three-dimensional conformal RT (3D-CRT) and intensity-modulated RT (IMRT) [23]. Therefore, the purpose of the present study was to compare dose profiles and clinical outcomes between RT techniques in patients with TET.

Materials and Methods

Results

1. Patients' characteristics

The median age of all patients was 55 years (range, 28 to 79 years), and 57 patients (56.4%) were men. The baseline characteristics of the 101 patients are shown in Table 1. The majority of patients were Masaoka-Koga stage II (n = 54, 53.5%) or III (n = 34, 33.7%). In terms of WHO classification, WHO B type (n = 45, 44.5%) was the most common histological finding, followed by WHO C type (n = 37, 36.6%).

Table 1.

Baseline patient characteristics (n = 101)

Of the total number of patients, the 3D-CRT, IMRT, and PBT groups included 59 patients (58.4%), 23 (22.8%), and 19 (18.8%), respectively. The patients' characteristics according to RT technique are summarized in Table 2. The PBT group included patients of the youngest age (mean age, 45.4 ± 11.8 years) compared to those in the 3D-CRT (56.0 ± 10.9 years) and IMRT groups (58.4 ± 10.7 years; p < 0.001). In the 3D-CRT and PBT group, the most common histological types were Masaoka-Koga stage II and WHO B type, while in IMRT group, Masaoka-Koga stage III and WHO C type were the most frequent histological types.

Table 2.

Patients’ characteristics according to RT techniques

2. Dosimetric parameters

The median radiation dose was 52.8 Gy (range, 48.4 to 66.0 Gy), and the median fraction dose was 2.2 Gy (range, 2.0 to 3.0 Gy). The median clinical target volume (CTV) was 60.3 mL (range, 6.9 to 439.3 mL). The median mean lung dose, mean heart dose, and mean esophageal dose were 7.6 Gy, 8.1 Gy, and 8.3 Gy, respectively. The dosimetric parameters of patients according to RT technique are shown in Table 3. The IMRT group had the largest CTV (mean, 149.6 ± 95.6 mL) compared to the PBT (90.1 ± 105.7 mL) and 3D-CRT groups (56.5 ± 42.6 mL; p < 0.001). The PBT group had a lower mean lung dose (4.4 Gy vs. 7.6 Gy vs. 10.9 Gy, respectively; p < 0.001), lower mean heart dose (5.4 Gy vs. 10.0 Gy vs. 13.1 Gy, respectively; p = 0.003), and lower mean esophageal dose than the 3D-CRT and IMRT groups (6.3 Gy vs. 9.8 Gy vs. 13.5 Gy, respectively; p = 0.011). In addition, there was positive correlation between CTV and dosimetric parameters. The coefficients of correlation with CTV were 0.396 for mean lung dose (p < 0.001), 0.367 for mean heart dose (p < 0.001), and 0.625 for mean esophageal dose (p < 0.001).

Table 3.

Dosimetric parameters

3. Clinical outcome

The median follow-up duration was 43.4 months (range, 7.7 to 77.2 months). During that period, 20 patients (19.8%) showed recurrence, and seven patients (6.9%) died. Among the patients with recurrence, local, regional, and distant recurrence were detected in 2 patients (2.0%), 13 (12.9%), and 10 (9.9%), respectively. The most common regional and distant recurrence site was the pleura (n = 12), followed by the lungs (n = 4), and the supraclavicular lymph nodes (n = 3). In terms of PORT target volume, all recurrences (n = 20) included out-field failure. Sixteen patients experienced only out-field failure. In-field and marginal recurrences occurred in two patients each, which were accompanied with out-field failure. The failure patterns according to ITMIG guidelines are summarized in Table 4.

Table 4.

. Failure patterns according to International Thymic Malignancy Interest Group guidelines

The 3-year OS and 3-year DFS rates for all patients were 95.7% and 80.9%, respectively (Fig. 1). When comparing survival outcomes, there was no statistically significant difference between RT techniques. The 3-year OS rates for the 3D-CRT, IMRT, and PBT groups were 98.1%, 90.6%, and 94.4%, respectively (p = 0.255). The 3-year DFS rates for the 3D-CRT, IMRT, and PBT groups were 85.9%, 67.0%, and 82.5%, respectively (p = 0.147) (Fig. 2).

Fig. 1.

Kaplan-Meier survival curve of all patients: (A) overall survival and (B) disease-free survival.

Fig. 2.

Comparison of survival outcomes according to radiotherapy technique: (A) overall survival and (B) disease-free survival. PBT, proton beam therapy; 3D-CRT, three-dimensional conformal radiation therapy; IMRT, intensity-modulated radiation therapy.

4. Toxicity

Toxic events were developed in 78 patients (77.2%). Radiation-related complications for all patients and subgroups are summarized in Table 5. Most toxicities were grade 1 or 2, except for one patient who received PBT and experienced grade 3 dermatitis. More than half of the patients (n = 59, 58.4%) showed radiation dermatitis, which was mostly a grade 1 (n = 54, 53.5%) toxicity. Radiation pneumonitis and radiation esophagitis were observed in 18 patients (17.8%) and 35 (34.7%), respectively. The IMRT group showed a higher incidence rate for grade ≥2 pneumonitis (13.0%) and grade ≥2 esophagitis (34.8%) in comparison to the rates shown by the 3D-CRT (5.1% and 18.6%, respectively) and PBT groups (5.3% and 10.5%, respectively).

Table 5.

Radiation-related toxicities

Discussion and Conclusion

The current study analyzed dose profiles and clinical outcomes of three different RT techniques in patients with TET from a single tertiary institution. As reported in earlier studies [19-23], nearby organs were exposed to lower radiation dose during PBT than during other RT techniques. However, the survival outcome was not statistically different between the three groups.

Based on the number of patients who underwent each RT technique, 3D-CRT may be primarily considered in treatment planning for patients with TET. As patients in the PBT group were younger than those in other groups, PBT may be chosen for young patients, because of the lower possibility to develop short- and long-term toxicities due to excellent dose distribution. PBT provided a significantly lower mean lung dose, lung V₂₀ (the percentage of normal lung receiving at least 20 Gy), mean heart dose, mean/maximum esophagus dose, and maximum spinal cord dose than other RT techniques in the current study.

Compared to other groups, the IMRT group showed the largest CTV and the highest dose exposure to organs at risk. Patients in the IMRT group also showed lower survival rates (although not statistically significant) and tended to experience more radiation-related toxicities than patients in other groups. Masaoka-Koga stage III and WHO type C were the most common histological types in patients in the IMRT group. On the other hand, Masaoka-Koga stage II and WHO type B were the most frequent histological types in patients in the 3D-CRT and PBT groups. According to Masaoka-Koga staging system, stage III suggests macroscopic invasion into adjacent organs, compared to a mere microscopic invasion in stage II. WHO classification C type, also known as thymic carcinoma, has more aggressive features and poorer prognosis than other subtypes of TET [30]. Therefore, the IMRT group consisted of patients with more advanced stage of TET, who required extensive target volume and were expected to have dismal prognosis. These factors may account for the relatively unfavorable dose distribution, survival rates, and toxicities observed in this group.

Although both 3-year OS and 3-year DFS rates were highest in the 3D-CRT group and lowest in IMRT group, the differences between the three groups were not statistically significant. This could be due to several reasons. First, it is possible that the effect of different RT techniques on patients’ survival may be limited because of the relatively high survival rate of patients with TET. Second, since patients were not randomly assigned to each RT technique, but by the physician’s decision, the 3D-CRT group included relatively low-risk patients, while the IMRT group included high-risk patients. Third, due to the low number of patients in PBT group, the survival outcomes in this group may have been underestimated.

Although approximately 80% of patients experienced treatment-related toxicities, complications were limited to grade 1 or 2, except for one PBT-treated patient who underwent grade 3 radiation dermatitis. PBT, due to its high entrance dose, might cause more radiation dermatitis than 3D-CRT or IMRT. The other toxic events observed in the present study were comparable with those observed in other studies [6,20]. Due to the above-mentioned selection bias between RT groups, patients in the IMRT group tended to experience more toxicities compared to those in the other groups. Additionally, as the PBT group comprised patients who were relatively younger, with more favorable dose profiles, fewer long-term complications, such as cardiac events and secondary malignancy, may be expected in this group than in other groups. Some studies predicted a lower risk of radiation-induced malignant neoplasms in patients with TET treated using PBT than in patients using other RT techniques [31-33]. All patients with recurrence (n = 20, 19.8%) experienced out-field failures. The pattern of recurrence in the present study was similar to that in another study that reviewed failure patterns of thymic carcinoma in our institution [27].

This study has some limitations. First, the selection bias, owing to the retrospective nature of the study, interfered with proper statistical analysis. Second, the insufficient number of patients in the PBT group, due to the inherent weakness of a single-center study, may have distorted the clinical outcomes of the PBT group. Multivariate analyses to find out independent prognostic factors for survival outcomes were tried but not feasible due to the limited numbers of patients and events. Additionally, the follow-up duration was not sufficient to compare survival outcomes and long-term toxicities. Further study with larger sample size and longer follow-up might be helpful to overcome the limitation of the current study.

In conclusion, in comparison to other treatments, PBT resulted in a lower dose of exposure to adjacent organs at risk. This lower exposure may be related with fewer long-term radiation-related complications and quality of life in the PBT group. When deciding which RT technique is more appropriate for patients with TET, individual factors, such as age and disease status, should be considered for proper treatment selection. Moreover, prospective studies with long-term follow-up comparing PBT with other RT techniques are required to further examine the clinical outcomes of PBT-treated patients with TET.

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