Radiation therapy

Radiation therapy is usually employed in the following cases:

Radiation therapy is delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of Ewing sarcoma. Such an approach will result in local control of the tumor with acceptable morbidity in most patients.[1,2,24]

The radiation dose may be adjusted depending on the extent of residual disease after the initial surgical procedure. When no surgical resection is performed, 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 Ewing sarcoma using 55.8 Gy to the prechemotherapy tumor extent with a 2-cm margin compared with the same total-tumor dose after 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]

Preoperative radiation therapy is an approach that can be used when surgical resection is deemed possible but with the likelihood of microscopic residual disease. A panel of international expert clinicians used a three-stage modified Delphi technique to develop consensus statements about local treatment. The panel reached a strong consensus that preoperative radiation therapy may be given when an inadequate (marginal) margin at resection is foreseen on imaging.[25]

For patients with residual disease after an attempt at surgical resection, the Intergroup Ewing Sarcoma Study (INT-0091) recommended 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 was recommended for those who had no evidence of microscopic residual disease after surgical resection.[14]

For patients who are deemed to have unresectable disease after induction chemotherapy, radiation therapy is given, using the same doses as those administered for patients with partially resected disease.[26] Patients who have unresectable disease are typically those with extremity tumors that have persistent encasement of the neurovascular bundles and/or morbid surgical excision entailing loss of functionality. In a phase III randomized controlled clinical trial of patients with unresectable disease, patients were randomly assigned to receive either standard-dose radiation therapy (55.8 Gy in 1.8 Gy fractions) or escalated-dose radiation therapy (70.2 Gy in 1.8 Gy fractions).[26] From 2005 to 2015, the study accrued 47 patients who received standard-dose radiation therapy and 48 patients who received escalated-dose radiation therapy (interquartile age, 13–23 years). The median largest tumor dimension was 9.7 cm. At a median follow-up of 67 months, the 5-year local control rate was significantly better in the escalated arm than in the standard arm (76.4% vs. 49.4%; P = .02). The differences in disease-free survival (DFS) and OS at 5 years did not achieve statistical significance (DFS rates, 46.7% vs. 31.8%; P = .22; OS rates, 58.8% vs. 45.4%; P = .08), possibly because the rate of metastatic disease was not changed. A skin toxicity grade of more than 2 was greater in the high-dose arm (10.4% vs. 2.1%; P = .08).

In a single-institution nonrandomized study, patients who had primary tumors 8 cm or larger were treated with higher-dose radiation therapy (median dose, 64.8 Gy). The 5-year cumulative incidence of local failure rate was 6.6%, which compares favorably to other published local failure rates in this group of patients.[27]

Comparison of proton-beam radiation therapy and intensity-modulated radiation therapy (IMRT) treatment plans has shown that proton-beam radiation therapy can spare more normal tissue adjacent to Ewing sarcoma primary tumors than IMRT.[28] Follow-up remains relatively short, and there are no data to determine whether the reduction in dose to adjacent tissue will result in improved functional outcome or reduce the risk of secondary malignancy. Because patient numbers are small and follow-up is relatively short, it is not possible to determine whether the risk of local recurrence might be increased by reducing radiation dose in tissue adjacent to the primary tumor.

Higher rates of local failure are seen in patients older than 14 years who have tumors larger than 8 cm in length.[29] Among patients with pelvic tumors, a larger tumor volume, a periacetabular tumor site, and the use of definitive radiation therapy only (rather than a combined-modality approach) were associated with higher rates of local failure.[30] A retrospective analysis of patients with Ewing sarcoma 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 longer 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.[31]

Radiation therapy is associated with the development of subsequent neoplasms. A retrospective study noted that patients who received 60 Gy or more had an incidence of second malignancy of 20%. Patients 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.[32]