Ewing Tumor of Bone: Localized Tumors
Standard Treatment Options
Treatment Options Under Clinical Evaluation
Current Clinical Trials
Standard Treatment Options
Because most patients with apparently localized disease at diagnosis have
occult metastatic disease, multidrug chemotherapy as well as local disease
control with surgery and/or radiation is indicated in the treatment of all
patients.[1-8] Current regimens for the treatment of localized Ewing tumor of bone (ETB) achieve event-free survival (EFS) and overall survival (OS) of approximately 70% at 5 years after diagnosis.[9]
Current standard chemotherapy in the United States includes vincristine,
doxorubicin, and cyclophosphamide, also known as VAdriaC, alternating with ifosfamide and
etoposide.[9] The combination of ifosfamide and etoposide has shown activity in ETB, and a large randomized clinical trial and a nonrandomized trial demonstrated that outcome was improved when ifosfamide/etoposide was alternated with VAdriaC.[2,9,10] Dactinomycin is no longer used in the United States but continues to be used in the Euro-Ewing studies. Increased doxorubicin dose intensity during the initial months of therapy was associated with an improved outcome.[11]
The use of
high-dose VAdriaC has shown promising results in small numbers of patients.[11] Forty-four patients treated with high-dose VAdriaC and ifosfamide/etoposide had an 82% 4-year EFS.[12] However, in a trial of the former Children's Cancer Group (CCG), which compared a dose-intensified chemotherapy regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide with standard doses of the same regimen, no differences in outcome were observed.[13]
In a Children's Oncology Group (COG) trial, COG AEWS-0331, 568 patients with newly diagnosed localized extra-dural Ewing family of tumors (EFT) were randomized between the same chemotherapy (VAdriaC alternating with ifosfamide and etoposide) given every 2 weeks (interval compression) versus every 3 weeks (standard).
Patients randomized to the every 2-week interval of treatment had an improved 3-year EFS (76% vs 65%, p=0.028). There was no increase in toxicity observed with the every 2-week schedule. Despite the upper age limit, only 67 patients aged 18 years and older, were randomized on the trial.[14]
Local control can be achieved by surgery and/or radiation. Surgery is
generally the preferred approach if the lesion is resectable.[15,16] The
superiority of resection for local control has never been tested in a
prospective randomized trial. The apparent superiority may represent selection
bias. In past studies, smaller more peripheral tumors were more likely to be
treated by surgery, and larger, more central tumors were more likely to be
treated by radiation therapy.[17] An Italian retrospective study showed that surgery improved outcome only in extremity tumors, although the number of patients with central axis ETB who achieve adequate margins is small.[8] In a series of 39 patients treated at St. Jude Children's Research Hospital, who received both surgery and radiation, the 8-year local failure rate was 5% for patients with negative surgical margins and 17% for those with positive margins.[5] If a very young child has an ETB, surgery
may be a less morbid therapy than radiation therapy because of the retardation
of bone growth caused by radiation. Another potential benefit for surgical
resection of the primary tumor is information concerning the amount of necrosis
in the resected tumor. Patients with residual viable tumor in the resected
specimen have a worse outcome compared with those with complete necrosis. In the
French Ewing study (EW88), EFS for patients with less than 5%
viable tumor, 5% to 30% viable tumor, and more than 30% viable tumor was
75%, 48%, and 20%, respectively.[17] Currently, European investigators are
studying whether treatment intensification (i.e., high-dose chemotherapy with
stem cell rescue) will improve outcome for patients with a poor
histologic response. Radiation therapy should be employed for patients who do
not have a surgical option that preserves function and should be used for
patients whose tumors have been excised but with inadequate margins.
Pathologic fracture at the time of diagnosis does not preclude surgical resection and is not associated with adverse outcome.[18] Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture.[19]
Radiation therapy should be delivered in a setting in which stringent planning
techniques are applied by those experienced in the treatment of ETB. Such an approach will result in local control of the tumor with
acceptable morbidity in most patients.[1,2,20] The radiation dose may
be adjusted depending on the extent of residual disease after the initial surgical
procedure. Radiation therapy is generally administered in fractionated doses totaling approximately 55.8 Gy to the
prechemotherapy tumor volume. A randomized study of 40 patients with ETB using
55.8 Gy to the prechemotherapy tumor extent with a 2-cm margin compared with the
same total-tumor dose following 39.6 Gy to the entire bone showed no
difference in local control or EFS.[3] Hyperfractionated
radiation therapy has not been associated with improved local control or decreased morbidity.[1]
Higher rates of local failure are seen in patients older than 14 years who have tumors more than 8 cm in length.[19] When radiation therapy was utilized for local control, the presence of metastatic disease at initial presentation was associated with higher risk for local failure.[21] A retrospective analysis of patients with ETB of the chest wall compared patients who received hemithorax radiation therapy with those who received radiation therapy to the chest wall only. Patients with pleural invasion, pleural effusion, or intraoperative contamination were assigned to hemithorax radiation therapy. EFS was higher for patients who received hemithorax radiation, but the difference was not statistically significant. In addition, most patients with primary vertebral tumors did not receive hemithorax radiation and had a lower probability for EFS.[22]
For patients with residual disease following attempt at surgical resection, the Intergroup Ewing Sarcoma Study recommends 45 Gy to the original disease site plus a 10.8 Gy boost for patients with gross residual disease and 45 Gy plus a 5.4 Gy
boost for patients with microscopic residual disease. No radiation therapy is recommended for those who have no evidence of
microscopic residual disease following surgical resection.
Radiation therapy is associated with the development of second malignant neoplasms. A retrospective
study noted that those patients who received 60 Gy or more had an incidence
of second malignancy of 20%. Those who received 48 Gy to 60 Gy had an
incidence of 5%, and those who received less than 48 Gy did not develop a
second malignancy.[23]
Treatment Options Under Clinical Evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. For more information about clinical trials, please see the NCI Web site.
-
COG-AEWS07P1 is a pilot clinical trial that is investigating the addition of vincristine, topotecan, and cyclophosphamide (VTC) to a treatment regimen that uses interval compression of VAdriaC with ifosfamide and etoposide for patients with localized EFT. All chemotherapy cycles are 14 days duration. If feasible, this new regimen will become the experimental arm in a planned group-wide phase III clinical trial for patients with EFT.
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with localized Ewing sarcoma/peripheral primitive neuroectodermal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
References
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