Ewing sarcoma
Current standard of care for ES has evolved over decades through randomized trials into just-tolerated, prolonged intensive chemotherapy regimens through the addition of cytotoxic agents, (notably- doxorubicin, ifosfamide and etoposide) to vincristine, dactinomycin and cyclophosphamide (VAC).45-50 Randomized trials by risk group for newly diagnosed ES are shown in Table I. More recently, the focus has shifted to dose-intensity of the alkylating agents and through several large, randomized trials, a clearer international consensus has emerged. The most recent prospective COG trial randomized patients <50years with localized ES to receive alternating vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) every 3 weeks (standard) compared to every 2 weeks, facilitated by the use of granulocyte colony stimulating factor (intensive).51,52 5y EFS was superior in the intensified regimen compared with the standard arm, (73% vs 65%, (P =0.048)), with no difference in toxicity (P = 0.056).52 The Euro Ewing 2012 trial demonstrated a superior outcome for VDC/IE compared to the previous European standard, VIDE/VAI in patients with localized and metastatic ES: a Bayesian analysis demonstrated hazard ratios (HRs) of 0.70 for EFS and 0.64 for overall survival and a 98% posterior probability in favor of VDC/IE.53,54 The 3-year EFS for VIDE/ VAI was 61% compared to 68% for VDC/IE and there was a similar difference in overall survival, with no excess acute toxicity with VDC/IE.54 On the basis of these results, interval compressed VDC/IE therapy has become the international current standard of care for localized and metastatic ES. Dexrazoxane cardioprotection with short infusion doxorubicin allows for safe intensification of treatment without affecting tumor response.55 The addition of chemotherapeutic agents to VDC/IE -such as vincristine-cyclophosphamide-topotecan in the COG trial AEWS1031 or irinotecan temozolomide showed no survival benefit in non-metastatic patients.56,57
Recurrent ES, which is mostly systemic relapse, occurs in 30-40% of primary localized disease and 60-80% of metastatic ES.58 Survival is less than 25% overall for patients with relapsed ES, better in later relapses >2y after treatment.59,60 The management of patients with primary refractory or recurrent ES is less well defined with several combinations of chemotherapy in use, largely dependent on institutional experience. An ongoing randomized multi-arm European trial (rEECur) is recruiting relapsed ES patients between ages 4 and 50, to multiple chemotherapy arms to determine a standard of care. Interim analyses suggest irinotecan plus temozolomide and gemcitabine and docetaxel are inferior to high dose ifosfamide and cyclophosphamide/ topotecan combination.61,62 The median PFS across all cohorts was 4.7 months with overall survival of 13.7 months across all therapies.61
Local management of the primary tumor in ES includes surgery or RT or a combination of both. Complete surgical resection with clear margins (R0) remains the most important goal for local control. 5 year local failure rates after RT alone, surgery only, and surgery combined with RT were 15.3%, 3.9% and 6.6% respectively in 956 patients treated on COG protocols.63 The failure rate after RT alone is higher in pelvic and extremity tumors reflecting patients with often locally advanced tumors unsuitable for surgery.63,64Indications for combination treatment include the expectation or confirmation of inadequate resection margins, large tumors and poor response to induction chemotherapy.65,66 Definitive RT is recommended where surgery would result in unacceptable morbidity.44,63,67-72 RT dose ranges from 45Gy to 66Gy depending on anatomical location, tumor size and timing of RT in relation to surgery.72,73 Whole lung RT may be used to consolidate the response of lung metastases after chemotherapy and is well tolerated although the benefit has not been unequivocally demonstrated.74