I. Overview
Ewing sarcoma is a malignant tumor of small round cell proliferation in bone. Recent cytomolecular genetic studies have shown that Ewing sarcoma is one of a family of tumors that includes primary neuroectodermal tumors (PNET), peripheral neuroepithelial tumors, Askin’s tumor of the chest wall, and Ewing’s sarcoma of the extraosseous bone.? The use of multiple chemotherapeutic agents and chemotherapy regimens has increased the five-year survival rate for Ewing’s sarcoma from 5-10% 20 years ago to over 70%. Chemotherapy for Ewing’s sarcoma began in the 1960s, and the first organized Ewing sarcoma study (IESS-1) began in 1973. It included 3 major research groups (CCSG, SWOG and CALBG) and 84 institutes that were in the process of joining. Chemotherapy was based on vincristine, actinomycin D and cyclophosphamide (VAC) and patients were divided into three groups: VAC only group, VAC plus adriamycin group and VAC plus radiotherapy group. The survival rate of patients receiving VAC only was only 28%, the 5-year relapse-free survival rate of patients treated with VAC plus adriamycin was 60%, and the survival rate of patients receiving VAC plus radiotherapy was 53%, a result that demonstrates the effectiveness of adriamycin. In the subsequent IESS-2 trial, intermittent high-dose chemotherapy was superior to continuous moderate dose chemotherapy. From the above trials, we can see that dose intensity, especially adriamycin, is an important factor in chemotherapy.
In recent years more interest has focused on the application of isocyclophosphamide and VP16, showing both drugs effective in phase II trials, however these drugs showed only a small increase in survival compared to the traditional 4 drugs: adriamycin, vincristine, actinomycin and cyclophosphamide. A large study from the Rizzoli Institute found only a 4% increase in disease-free survival, a result that was not statistically significant. Early data from a recent large randomized CCG/POG study including 398 patients showed more encouraging results, with a 5-year disease-free survival rate increasing from 52% to 69%.
In recent years attempts have been made to classify patients into two categories: high risk and standard risk. High risk usually includes metastatic cases (lung, bone and/or bone marrow), cases of spread and primary tumors at poor sites and large tumors. Large tumors are diagnosed as having a maximum diameter of >8 cm or a volume >100 ml. standard risk includes tumors of the medial bone or pelvis. The prognosis is not necessarily poor in high-risk cases, and tumors of the humerus or femur have a better prognosis than tumors of the midshaft bone or pelvis.
Chemotherapy regimen
1.Rosen et al.’s VACA regimen
Actinomycin D (Dactinomycin): 400ug/m2 i.v. Day 1-5
Adriamycin (Doxorubicin):20mg/m2 i.v. Days 20-22, 37-39
Cyclophophamide:1,200mg/m2 i.v. Days 54, 68
Vincristine: 1.5mg/m2 i.v. days 54, 61, 68, 75
Each treatment course is 2 weeks apart for 2 years
(Adjuvant radiotherapy added for primary tumor)
2. Risk-based regimen – CESS 86 regimen
It consists of VACA/VAIA, surgery and radiotherapy
1) For tumors of the limb with a volume less than 100 ml:
VACA regimen.
Phase 1 Phase 2 Phase 3
Cyclophosphamide 1200mg/m2 i.v. 400mg/ m2 i.v. 1200mg/ m2 i.v.
Day 1 Days 1-3 Day 1
Adriamycin 30mg/ m2 i.v. — 30mg/ m2 i.v.
Day 1-2 Day 1-2
Actinomycin D — 0.5mg/ m2 i.v. —
(maximum amount 0.8mg)
Day 1-3
2) In case of limb tumor volume greater than 100 ml or mesial bone tumor.
VAIA regimen.
Phase 1 Phase 2 Phase 3
Isocyclophosphamide 3000mg/ m2 i.v. 3000mg/ m2 i.v. 3000mg/ m2 i.v.
Day 1-2 Day 1-2 Day 1-2 Day 1-2
Adriamycin 30mg/ m2 i.v. — 30mg/ m2 i.v.
Day 1-2 Day 1-2
Actinomycin D — 0.5mg/ m2 i.v. —
(maximum amount 0.8mg)
Day 1-3
Vincristine 1.5mg/ m2 i.v. 1.5mg/ m2 i.v. —
(Maximum amount 2mg) (Maximum amount 2mg)
Days 1, 8, 15 Day 1
All four courses of VACA regimen or VAIA regimen will take a total of 9-10 months.
Doses may be adjusted accordingly.