Dose intensity and outcomes of VDC/IE chemotherapy for adolescent and adult patients with Ewing’s family sarcoma.
Authors: Klingberg Danielle , Bae Susie , Zhou Deborah , Sim Hao-Wen , Cai Ruilin , Anazodo Antoinette , Grimison Peter S. , Lewis Craig R. , Lee Yeh Chen 
Published: June 2022

11570

Background: Ewing’s family sarcoma (EFS) is a rare and aggressive malignancy with peak incidence in the second decade of life. Treatment is multimodal, involving local surgery and/or radiotherapy, and chemotherapy, typically with VDC/IE (Vincristine, Doxorubicin, Cyclophosphamide alternating with Ifosfamide, Etoposide). There is paucity of data in the adult setting, with treatment protocols extrapolated mainly from the paediatric setting. We assessed chemotherapy dose intensity and outcomes across four Australian sarcoma centres (three adult and one paediatric centre). Methods: Using the Australia New Zealand Sarcoma Association national database (ACCORD) and medical records, we identified patients aged ≥10 years diagnosed with EFS between 2010-2020. Clinical characteristics, treatment and survival information were collected for those receiving Ewing protocol with VDC/IE backbone. Received Dose Intensity (RDI) of chemotherapy was calculated using planned and actual doses received and time taken. RDI ≥85% was considered acceptable, consistent with published literature. We compared survival outcomes based on RDI. Clinical predictors of achieving an acceptable RDI were explored using logistic regression. Results: Of 146 patients with EFS identified, 76 received VDC/IE (59% male). The median age was 25 years, with age distribution 24% aged 10-19, 58% aged 20-39, and 18% aged 40-59. Majority had extraskeletal Ewing’s (57%), non-extremity primary site (64%) and localised disease (stage, II 37%; III 28%; IV 28%). Treatment received included surgery (74%), radiotherapy (66%) and chemotherapy (100%). Over two-thirds (70%) completed their scheduled chemotherapy and 57% achieved an acceptable RDI (67% aged 10-19, 61% aged 20-39, 29% aged 40-59). Compared to those aged 10-19, the odds ratio (OR) of an acceptable RDI for patients aged 20-39 was 0.79 (95% CI 0.24-2.46, p = 0.70) and for patients aged 40-59 was 0.20 (95% CI 0.04-0.86, p = 0.04). The median number of chemotherapy cycles was 14 (range, 2-17). Dose reductions were mostly within 20% cumulative target dose (91%), and were predominantly for neutropenia (47%), thrombocytopenia (30%) and/or anaemia (28%), and less frequently for cardiotoxicity (7%). Median follow-up was 37.3 months. Two-year progression-free survival (PFS) rates were 56% for acceptable RDI, compared to 30% for low RDI (p = 0.001), with two-year overall survival (OS) rates respectively 88% versus 49% (p < 0.001). After adjustment for age, gender, Ewing’s type, primary site and stage, RDI remained an important prognostic factor (PFS HR 0.39, 95% CI 0.18-0.82; OS HR 0.25, 95% CI 0.10-0.63). Conclusions: Survival outcomes in EFS were contingent on achieving an acceptable RDI. It was more difficult to maintain VDC/IE chemotherapy dose intensity in adults aged over 40 years, due to myelosuppression. Optimal treatment strategy for older adults remains to be defined.