(P 442) LONG-TERM OUTCOME AND RELAPSE PATTERNS IN EWING SARCOMA PATIENTS WITH EXTENSIVE LUNG/PLEURAL METASTASES AFTER A COMPLETE RESPONSE TO SYSYEMIC THERAPY

Objective: Ewing sarcoma (ES) is sensitive to systemic therapy, including chemotherapy and anti-angiogenesis Tyrosine Kinase Inhibitors(aaTKIs). However, the prognosis of patients with metastatic disease remains poor. Recurrence or distant metastasis after a complete response (CR) or near-CR due to systemic therapy is not rare.There have been numerous clinical trials aiming at the prognosis of R2pulm group or recurrent/relapsed (RR) ES patients. However, for those who had extensive lung/pleural metastasis (L/Pmeta), then completely responded to chemotherapy and got whole lung irradiation as maintenance therapy, there is insufficient high quality data to answer the following questions: 1. How much portion of these patients could be cured at last? 2. If not, what are the relapse patterns in these former responders? To answer these questions, we carried out this retrospective study and reviewed ES patients from one institutes in China.

Methods: Patients
We conducted an Institutional Review Board-approved review of all patients with complete medical records diagnosed with ES and treated at Peking University People’s Hospital and Peking University Shougang Hospital between 2014 and 2019. Inclusion criteria were: 1. Histologically-confirmed EWS; 2.Extensive L/Pmeta with no chance of radical radiotherapy (RT) or resection before multi-drug chemotherapy. Extensive L/Pmeta was defined when it fulfilled at least one of the following criteria: 1) Multiple pulmonary nodules in both lungs, and the largest nodule ≥ 0.5 cm (More than 5 nodules were defined as “multiple” in this study). 2) Pleural effusion and/or multiple pleural nodules; 3. Experiencing a complete response or nearly completely response (CR/nCR)] recorded and then confirmed after 6-8 weeks of multi-drug systemic therapy based on chemotherapy with or without aa-TKIs. CR was defined according to the Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1) guidelines. nCR was defined as each nodule < 3 mm.
Treatment
Alternating vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide (VDC/IE) q2w were administered as first-line chemotherapy. Irinotecan-based regimens such as vincristine/irinotecan/temozolomide (VIT), or anlotinib, an aa-TKI plus vincristine and irinotecan was used as second-line chemotherapy in recurrent or refractory patients (NCT03359005 and NCT03416517).
WLI was given at the end for patients with first-line chemotherapy, or if all pulmonary lesions were < 3 mm in two consecutive CT scans for recurrent or relapsed patients. WLI was given by the 3DCRT technique. The median dose of prescribed radiation was 15 Gy/1.5 Gy/F, once per day; with the dose changing according to the hospital treatment policy from 12 Gy earlier to 15 Gy more recently. Notably, no patients received a boost dose.
Outcomes
EFS was defined from the date of first confirmation of CR/nCR to the first reported event (recurrence, progression, or death). Patients without an event were censored at the date of last follow-up. OS was defined from the date of first confirmation of CR/nCR to death or the date that they were last known to be alive. Chest computed tomography (CT) images were reviewed by two doctors to define the exact location of each recurrent lesion, compared with the primary L/P lesion before chemotherapy, and the relapse pattern was then summarized according to the following criteria:
Pattern 1= All recurrent lesions completely coincide with the original metastatic lesions before chemotherapy (Figure 1)
Pattern 2= Some of the recurrent lesions coincide with the original lesions, but also with some new lesions
Pattern 3= All recurrent lesions are completely new lesions

Results: Patient Characteristics
17 pts and 21 cases of CR/nCR were finally analyzed. 2 patients experienced CR/nCR twice and 1 patient experienced CR/nCR a third time. Of these patients, 23.8% had primary extensive L/Pmeta, while 19.0% suffered L/Pmeta within 12 months of the initial diagnosis, and 57.1% after more than 12 months. The median time from extensive L/Pmeta to first confirmation of CR/nCR was 5.2 months. Median follow-up of surviving patients was 39.6 months.
Treatment details and survival
82.4% patients received WLI. At last assessment, 3 patients had no evidence of disease, 6 were still alive with disease and 8 had already died of disease (DOD). For 8 DOD patients, 4 died of recurrent lung/pleural metastases, while 4 of them died of distant metastases other than lung/pleual lesions. The median EFS and OS were 9.3 months and 37.5 months. The 2-year EFS was 19%. The 2-year OS was 70.6%. In all 17 patients, 12 were relapsed cases while the other 5 were initially metastatic cases. For the 12 relapsed cases, all of them joined clinical trial NCT03416517 (AVI for relapsed or recurrent EWS). The median EFS and OS were 6.5 months and 37.5 months. The 2-year EFS was 16.7% and OS was 66.7%.
Patterns of relapse
Lung/pleural relapse occurred in 71.4% (15/21) of CR/nCR cases. Most notably, in 9 of the 15 recurrent cases, the locations of all recurrent lesions exactly coincided with the original metastatic lesions (i.e. exactly in situ). This was the major relapse pattern; however, 4/9 cases also had distant metastases, while the other 5 cases had no lesions outside the lung/pleura. In 2 of the 15 cases with lung/pleural recurrence, some of the recurrent lesions were exactly in situ, but some new lesions in the lungs were also noted. Neither patient had distant metastases concurrently. For the last 4, all recurrent lung/pleural lesions were completely new, and two also had distant metastases as well. For the whole cohort, 42.9% had distant metastases outside of the L/P.

Conclusion: Survival of ES patients with extensive L/Pmeta remains poor, even after they have a complete response to systemic therapy. Recurrence exactly in situ is the major relapse pattern. WLI is not sufficient to prevent local recurrence in lung or pleura. More aggressive local treatment for metastatic lesions is warranted.