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In case of relapse, the prognosis of Ewing sarcoma (ES) is poor (5-y-OS 10-20%). No standard treatment is clearly defined, but the most common attitude remains to carry out a second-line palliative chemotherapy. In selected situations, aggressive strategies including Busulfan-Melphalan-based high dose chemotherapy (Bu-Mel-HDCT) have been reported. Regarding the efficiency of both Bu-Mel-HDCT and whole lung irradiation (WLI), the question whether this combination may be efficient and safe in case of lung relapse ES is still under debate and not evaluated yet. The main objective of this study is to evaluate both efficacy and toxicity of this therapeutic sequence in ES patients with pulmonary relapse.

All eligible pediatric ES patients (1991-2020) identified in SFCE departments were retrospectively reviewed. Patients were (1) diagnosed with a pulmonary relapse, isolated or not, (2) naïve from both HCDT and WLI during the first-line treatment (3) treated by the salvage sequence of conventional chemotherapy, Bu-Mel-HDCT followed by WLI. The main endpoint was OS evaluation. Acute and late WLI toxicities were scored according to the CTC-V5.

Seven patients, median age 15 years, met the inclusion criteria. Four patients had only lung metastasis at the time of relapse, three others had lung/other metastatic sites. Figure I presents salvage treatment details combining a second-line chemotherapy, lung surgery (6/7 patients), and Bu-Mel-HDCT followed by WLI. With a median follow-up of 13 years after the relapse, 5/7 patients are alive in complete remission. One patient died of metastatic lung progression 1.75 years after the end of WLI and one died of lung toxicity. Table 1 presents the results. Calculated 10y-OS and 10y-EFS are 71.4%.

Regarding WLI toxicity, one chest radio-dermatitis grade (gr) 1 was reported. Three patients experienced transitory radio-induced pneumopathy (RIP) (2 gr 2, 1 gr 3) with a median time of 6.2 months following WLI. A fourth patient developed RIP (gr 3), 3 months after WLI, associated with pneumocystis infection, and finally progressive lung fibrosis leading to death 2.8 years after WLI without sign of disease progression. 

With a long median follow-up, this short series reports ES patients treated for lung metastatic relapses using an aggressive strategy including Bu-Mel-HDCT followed by WLI with favorable survival results compared to data in the literature. Regarding the lung complication risk, only patients with adequate pulmonary function tests should be treated by the combination Bu-Mel-HDCT/WLI. The interval between Bu-Mel-HDCT and WLI should be longer than 60 days and WLI dose may probably be limited to 15 Gy in 10 fractions regarding recent literature data. Further prospective studies are needed to confirm our preliminary results.