To the Editor: Ewing sarcoma (ES) is a highly malignant tumor that commonly arises in children, adolescents, and young adults. Prognosis depends on metastasis, with a 5-year event-free survival (EFS) rate of about 70% for localized and 20%–25% for metastatic disease. As ES is radiosensitive, surgery and radiation are often combined for local control. Whole lung irradiation (WLI) is widely used for pulmonary metastases but causes long-term toxicities. Proton WLI (PWLI) can reduce doses to normal tissues, though clinical reports remain limited. We describe the first Japanese case of ES with bilateral lung metastases and pleural dissemination treated with PWLI. An 11-year-old girl presented with chest pain and dyspnea. Physical examination showed a left chest mass, absent breath sounds in the left lung, and axillary lymphadenopathy. Computed tomography (CT) revealed a rib tumor with massive pleural effusion and dissemination, along with multiple bilateral lung and lymph node metastases (Figure 1A–C). Biopsy confirmed ES with the EWSR1::FLI1 fusion gene. F-18 fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) showed no extrathoracic disease. She was diagnosed with ES of the left fifth rib with bilateral lung and lymph node metastases. Five cycles of vincristine, doxorubicin, cyclophosphamide (VDC), and ifosfamide and etoposide (IE) markedly reduced lesions and resolved pleural effusion (Figure 1D,E). She subsequently underwent resection of the primary rib tumor and 18 metastatic lesions in the left lung, followed by chest wall reconstruction. Pathology revealed complete tumor necrosis with no viable cells. Despite the favorable response, multiple metastases at diagnosis indicated poor prognosis. Therefore, we adopted high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) and WLI. She received two additional cycles of vincristine/cyclophosphamide and IE, followed by thiotepa–melphalan HDC with ASCT. No severe HDC-related complications occurred. Pulmonary function before HDC showed a %vital capacity (%VC) of 67.2% and an FEV1/FVC ratio of 89.5%, indicating restrictive ventilatory impairment. Ovarian tissue cryopreservation was performed before HDC; numerous follicles remained despite prior chemotherapy. After HDC, residual right lung nodules were surgically resected, all showing complete necrosis. Consequently, she underwent PWLI of 15 GyE/10 fr to minimize radiation-related side effects, particularly to the heart, breast, and thyroid (Figure 2A–C). Treatment was well tolerated with no acute adverse events. Pulmonary function 15 months post-treatment was unchanged (%VC of 68.4%, FEV1/FVC ratio of 84.1%). She has remained in complete remission (CR) for over 25 months without complications. Although combined therapy has improved outcomes in localized ES, prognosis for metastatic disease remains poor, with EFS only 20%–25%. Our case demonstrates durable remission despite multiple metastases at presentation. Favorable response to initial chemotherapy may partly explain this outcome. A study of 57 metastatic cases identified response to first-line therapy, stem cell transplantation, and number of bone metastases as risk factors affecting overall survival (OS) 1. Recent molecular analyses have proposed new prognostic factors in ES. Co-expression of STAG2 and TP53 has been associated with poor prognosis and gain of 1q or loss of 16q with adverse OS 2, 3, whereas favorable molecular predictors remain rare. Future genomic analyses may clarify differences in treatment responses. HDC with ASCT has long been used for metastatic ES. Previous reports suggested HDC is particularly effective in patients showing a favorable response to first-line chemotherapy or achieving CR at HDC 1, 4. Our patient showed excellent response and tolerated HDC well, which likely contributed to sustained remission. WLI has also been associated with improved survival in patients with lung metastases. In one study involving 97 cases, a 4-year EFS of 40% was observed in the WLI group and 19% in the non-irradiation group, indicating a significant improvement in EFS favoring WLI 5. However, the benefit of combining HDC and WLI remains unclear. Given that bilateral multiple lung metastases with pleural dissemination indicated an extremely poor prognosis, we combined HDC, surgery, and WLI. We avoided busulfan–melphalan because of potential for pulmonary toxicity and selected thiotepa-based HDC, which has been reported to be effective 6. Conventional WLI causes not only pulmonary dysfunction but also cardiac and thyroid dysfunction, and thoracic growth impairment at relatively low radiation doses. Previous studies of pediatric chest irradiation have demonstrated increased risks of cardiotoxicity, secondary breast cancer, and thyroid dysfunction, highlighting the importance of minimizing radiation exposure to organs 7. Intensity modulated radiation therapy (IMRT) has reduced radiation to normal structures, and more recently PWLI further lowered exposure. PWLI (15 Gy in 11 cases, 18 Gy in 1 case) was performed in 12 patients with malignant tumors and lung metastases, including 9 ES. Compared with IMRT, PWLI significantly reduced exposure to heart, breast, esophagus, and thyroid 8. Reported toxicities were fatigue, cough, and nausea, all Grade 1 and transient. In our case, pulmonary function remained stable before and after PWLI, and no adverse events were observed, although long-term monitoring is warranted. In summary, a patient with ES presenting with multiple lung metastases and pleural dissemination was successfully treated with combination therapy, including PWLI, and has remained in remission for 25 months without severe complications. PWLI is an effective treatment option with minimal side effects for pulmonary metastases in ES; however, further studies are needed to evaluate its long-term efficacy and toxicity. All authors contributed to the collection and interpretation of clinical data. Satoshi Okada and Yoko Mizoguchi contributed to the conception and design of the report. Yusuke Imanaka drafted the manuscript. Yusuke Imanaka, Sho Kurihara, Shuhei Karakawa, and Yoko Mizoguchi performed the clinical work and collected data. Yukayo Terashita, Masataka Hasegawa, Hiroshi Taguchi, Seishin Takao, Takayuki Hashimoto, and Atsushi Manabe performed the treatment planning, delivery, and management of proton whole lung irradiation. All authors have revised the manuscript for important intellectual content and approved the final version. We thank the patient and her families and also thank the hospital staff for helpful discussions. The authors declare no conflicts of interest. The study was approved by the Ethics Committees and Institutional Review Board of Hiroshima University. Written informed consent was obtained from the patient's family.
Imanaka et al. (Sun,) studied this question.