Effective local and systemic therapy is necessary for the cure of Ewing tumor Most chemotherapy regimens are a combination of cyclophosphamide,
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1 Ewing Tumor Perez Ewing tumor is the second most common primary tumor of bone in childhood, and also occurs in soft tissues Ewing tumor is uncommon before 8 years of age and after 25 years of age In the European Intergroup Cooperative Ewing Sarcoma Study group (EICESS), 24.7% of lesions presented in the pelvis, 16.4% in the femur, 16.7% below the knee, 12.1% in the ribs, 8.0% in the spine, and 4.8% in the humerus Approximately 95% of Ewing tumors have a translocation between the EWS gene on chromosome 22 and the FLI1 gene on chromosome 11 (t[11:22][q24:q12]) or the ERG gene on chromosome 21 (t[21;22][q22;q12]) (64,72) The most frequent presenting symptoms are pain and swelling Pain can wax and wane as the tumor progresses Symptoms of systemic disease occur at times, including low-grade fevers, malaise, and weakness Ewing tumor patients exhibit a mean lag time of 146 days between the onset of symptoms and diagnosis, the longest lag time of any pediatric solid tumor Lytic and blastic areas may be present; lytic areas are more commonly seen Subperiosteal reactive new bone may be present, producing an â œonion skinâ appearance MRI of the primary lesion will show the extent of bone marrow involvement and soft tissue invasion, whereas bone destruction is best seen using computed tomography (CT) The systemic work-up should include blood studies, a chest roentgenogram, a CT scan of the chest, a bone scan, and a bone marrow biopsy. Because few lesions <8 mm are detectable using PET imaging, CT scans are still more accurate for the screening of lung metastases Approximately 20% of patients present with metastatic disease. Of these patients, 44% present with lung metastases only; 51% have bone or bone marrow involvement (with or without lung metastases); and 5% present with metastases in other organs Metastases at diagnosis, a large or pelvic or truncal primary tumor, the presence of a large soft tissue mass, an older age at diagnosis, a poor response to induction chemotherapy, not using surgery as part of the treatment of the primary lesion, and a filigree histologic pattern have all been proposed as poor prognostic factors The presence of necrosis on pretreatment MRI scans has been linked to an increased risk of metastases at diagnosis Ewing tumors with p53, p16/p14arf alterations or the presence of vascular endothelial growth factor respond poorly to chemotherapy and have a poor prognosis
2 Effective local and systemic therapy is necessary for the cure of Ewing tumor Most chemotherapy regimens are a combination of cyclophosphamide, doxorubicin HCl (Adriamycin), vincristine, dactinomycin, ifosfamide, and etoposide Induction chemotherapy is preferred over starting the systemic therapy and local therapy concomitantly The biopsy should be performed in the same institution in which the treatment will be performed, and the biopsy specimen should only be taken from the soft tissue component, if present The biopsy should be performed in the same institution in which the treatment will be performed, and the biopsy specimen should only be taken from the soft tissue component, if present but amputation may be an option for younger patients with lesions of the fibula, tibia, and foot In older patients, lesions of the proximal fibula, ribs, scapula, clavicle, and wing of the ilium are easier to resect than other sites Lesions of the bones of the hands and feet may be resectable with a ray resection For gross disease, standard treatment is a total dose of 55.8 Gy at 1.8 Gy per day, with a field reduction at 45 Gy, although 36 Gy may be adequate for the initial field Three-dimensional treatment planning is essential The initial field should include the prechemotherapy tumor volume with a 2- to 4-cm margin The boost should be to the residual tumor volume at the time of radiotherapy plus a 1.5- to 2.0- cm margin Extremity lesions require sparing at least a 1- to 2-cm strip of tissue to prevent lymphedema This can be very difficult at times, particularly in arm lesions, although the arm is less likely to develop lymphedema than the leg may be necessary to consider surgery as an alternative if a strip of tissue cannot be spared. It is more important to cover the tumor adequately than to spare adjacent growth plates and joints With the high doses of cyclophosphamide or ifosfamide given in chemotherapy regimens for Ewing tumor, Radiation cystitis can be a significant risk even at doses as low as 20 Gy neoadjuvant chemotherapy allows additional bladder to be spared if good shrinkage is obtained A 2-cm medial margin on the residual disease at the time of treatment is adequate from the beginning of radiation therapy Rib lesions should be treated conformally with a minimum of lung and heart in the high-dose field. rib primary tumors often present with pleural effusions, and in the EICESS and Children's Oncology Group (COG) trials hemithorax irradiation was used, even for surgically resected lesions A dose of 15 Gy for patien
3 ts younger than 14 years and 20 Gy for older patients was given, corrected for lung transmission The standard dose for vertebral lesions in the United States is 45 Gy; it is not clear whether this decreases local control and survival rates The average dose used in the CESS 81, CESS 86, and EICESS 92 trials was 49.6 Gy, The indications for adjuvant radiotherapy with surgery are not completely defined postoperative radiotherapy should probably be given to all patients with marginal margins and all with a poor histologic res-ponse Intralesional surgery is not indicated as the EICESS trials showed no improvement in local control in patients with intrale-sional surgery plus radiotherapy versus radiotherapy alone In the COG trials, a dose of 50.4 Gy at 1.8 Gy once a day is given if postoperative radiotherapy is indicated Doses in the range of 30 to 44.8 Gy at 1.8 Gy a day have also been reported to be effective for subclinical disease Intralesional resections should be treated to the same dose as in patients receiving radiotherapy alone In a review of 153 patients treated with surgery followed by postoperative radiotherapy from CESS-86 and EICESS 92, Schuck et al. (69) showed that the interval between surgery and radiotherapy did not influence survival, although there was a slight trend for improved local control in patients receiving radiotherapy <90 days postoperatively Good results have also been reported with preoperative radiotherapy for patients with a poor response (<50% reduction of the evaluable soft tissue mass) after two cycles of chemotherapy ), Doses of 36 to 63 Gy have been used
4
5 Results of Therapy Patients who relapse only with lung metastases can sometimes be salvaged with additional chemotherapy and lung irradiation Resecting the lung metastases if there are fewer than four lesions may also be beneficial IESS-I showed that VACA chemotherapy (vincristine, dactinomycin, cyclophosphamide, and doxorubicin) produced superior 5-year relapse-free survival rates over a VAC (vincristine, dactinomycin, and cyclophosphamide) regimen alone The third arm combined bilateral whole-lung irradiation (WLI) with VAC and produced survival rates better than VAC alone but less than VACA, indicating that bilateral WLI is an effective adjuvant, although it has not been studied in any subsequent trial except in patients with lung metastases at diagnosis IESS-I also showed poorer survival rates in all arms for patients with pelvic tumors The 48-week vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide regimen was used as the standard arm, compared with the same drugs given in fewer cycles but with higher drug doses per cycle The second POG and CCG intergroup trial: There was no significant difference in survival rates in the two arms, with a 5-year event-free survival of 71% and an overall survival of 79% The prognosis of the patients with metastatic disease at diagnosis is poor the 5-year relapse-free survival for patients with lung metastases only was 29%; for patients with bone and bone marrow metastases, it was 19% the addition of ifosfamide-etoposide did not improve survival for patients with metastatic disease at diagnosis Bone metastases are usually irradiated if there are not too many. It is acceptable to delay the radiotherapy until close to the end of chemotherapy if a significant amount of bone marrow would be treated.
6 The CESS 81 and 86 studies also showed increasing survival rates with an increasing radiation dose to the lung fields, particularly with a dose of >18 Gy (corrected for lung transmission) at either 1.5 Gy once a day or 1.25 Gy twice a day intensifying systemic therapy for patients with high-risk localized disease has improved survival rates, whether the intensification is with an ablative approach or more intensive conventional chemotherapy Sequelae of Treatment The most common skeletal complication of radiotherapy is abnormal growth and development of the irradiated tissues typical radiotherapy doses to the knee in boys younger than 14 years of age and girls younger than 12 years of age will usually cause a severe enough leg-length discrepancy to require intervention Approximately 15% of long-bone lesions develop pathologic fractures at some time in their course, 5% at diagnosis and 10% after radiation therapy, the most common site is the femur, particularly the proximal femur. Radiotherapy-related fractures usually occur within 24 months after treatment, but can be much later. Doses below 40 Gy using once-a-day doses of 1.8 to 2.0 Gy appear to have a very low risk, as does a hyperfractionated approach using 1.2 Gy twice a day from 50.4 to 55.2 Gy The risk of secondary neoplasia, with an increased risk at doses >60 Gy Sarcomas, often osteosarcoma, are the most common second tumor, and the risk for megavoltage treatment has been reported as 1% to 4% at 20 years With more intensive chemotherapy regimens and the increased use of etoposide, the risk of secondary leukemia is about 2% Future Considerations almost half of all patients diagnosed with Ewing tumor die of it within 10 years carboplatin, and etoposide (ICE) appears to be useful for recurrent disease, but has not been thoroughly explored for newly diagnosed patients major improvements in the long-term survival rates will probably not occur until the development of better systemic agents or genetic therapy targeted at the unique translocations that produce these malignancies.
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