External-beam RT (EBRT)

Site of primary tumor.

Histological subtype/fusion status.

Postsurgical amount of residual disease (none vs. microscopic vs. macroscopic), if surgery was performed.

Presence of involved lymph nodes.

A prospective, phase II trial compared proton-beam therapy with IMRT in pediatric rhabdomyosarcoma.[27]

A prospective, phase II trial compared proton-beam therapy with IMRT in pediatric rhabdomyosarcoma.[27]

Target coverage was comparable between proton-beam therapy and IMRT plans. However, the mean integral dose for IMRT was 1.8 to 3.5 times higher than with proton therapy, depending on the site. Proton radiation may lower the radiation dose in the uninvolved tissue surrounding the tumor and, thus, improves normal tissue sparing when compared with IMRT.

A prospective, phase II trial compared proton-beam therapy with IMRT in pediatric rhabdomyosarcoma.[27]

Follow-up of treated patients remains short, and there are no data available to determine whether the reduction in dose to adjacent tissue will result in improved functional outcomes or reduce the risk of secondary malignancy or other toxicities.

A retrospective review of patients with intermediate-risk rhabdomyosarcoma compared 3-dimensional conformal RT with IMRT.[28][Level of evidence B4]

A retrospective review of patients with intermediate-risk rhabdomyosarcoma compared 3-dimensional conformal RT with IMRT.[28][Level of evidence B4]

IMRT improved the target coverage but did not show a difference in local failure rate or EFS.

In a study on the patterns of failure in 11 of 66 children with nonmetastatic rhabdomyosarcoma who were treated with proton RT, the following results were observed:[29]

In a study on the patterns of failure in 11 of 66 children with nonmetastatic rhabdomyosarcoma who were treated with proton RT, the following results were observed:[29]

The 2-year local control rate was 88%.

In a study on the patterns of failure in 11 of 66 children with nonmetastatic rhabdomyosarcoma who were treated with proton RT, the following results were observed:[29]

All 11 children with local recurrences were Group III (gross residual disease) and experienced relapse in the radiation field, suggesting that the conformality of the proton field did not lead to out-of-field failures. The radiation dose was 41.4 Gy (relative biological effectiveness [RBE]) to the prechemotherapy tumor volume and 50.4 Gy (RBE) to the visible disease at the time of RT.

In a study on the patterns of failure in 11 of 66 children with nonmetastatic rhabdomyosarcoma who were treated with proton RT, the following results were observed:[29]

Eight patients with local recurrences had tumors larger than 5 cm at diagnosis. The COG ARST1431 (NCT02567435) protocol is testing escalated doses to 59.4 Gy for these patients.

In a study on the patterns of failure in 11 of 66 children with nonmetastatic rhabdomyosarcoma who were treated with proton RT, the following results were observed:[29]

This study did not delineate whether the recurrence was in the 41.4 Gy or 50.4 Gy irradiated volumes.

In the COG ARST0531 (NCT00354835) trial, local failure rates were similar among patients who were treated with proton and photon radiation therapy.[30]

Group II. In general, patients with microscopic residual disease (Group II) receive 36 Gy of RT if they do not have involved lymph nodes and 41.4 Gy in the presence of involved nodes.[12,31] Low-risk patients (embryonal histology and favorable sites with microscopic residual disease) treated in a COG study had excellent local control with 36 Gy, which was comparable to historical controls who received 41.4 Gy.[9] For Group II patients, 36 Gy of RT is recommended to the prechemotherapy involved site, and 41.4 Gy to involved nodes.

Group III. IRS-II patients with gross residual disease (Group III) who received 40 Gy to more than 50 Gy had locoregional relapse rates greater than 30%, but higher doses of radiation (>60 Gy) were associated with unacceptable long-term toxic effects.[32,33] Group III patients on the standard treatment arm of the IRS-IV study received 50.4 Gy to 59.4 Gy, with 5-year progression-free survival (PFS) rates of 55% to 75% and local control rates of 85% to 88%.[34] Select COG subgroups with Group III disease received somewhat reduced radiation doses of 36 Gy after delayed gross-total resection with negative margins (R0 resection), and 41.4 Gy if the margins were microscopically involved (R1 resection) or the nodes were positive. In the COG-D9602 study, a limited number of low-risk patients had a greater than 85% likelihood of local control with 36 Gy.[9] Similarly, the intermediate-risk studies for patients with Group III disease investigated the paradigm of delayed resection in amenable patients (anticipated complete resection with no loss of form or function at select sites such as bladder, prostate, extremity, trunk, peritoneum, intrathoracic, perineum, and perianal), with a subsequent reduced dose of RT (36 Gy for R0 resections or 41.4 Gy for R1 resections). The study demonstrated that patients who received reduced doses of RT had outcomes equivalent to patients who were treated with full-dose RT of 50.4 Gy.[8,10]

Group IV. Radiation therapy is appropriate treatment for sites of metastatic disease (technique, timing, and volume discussed below). The European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) examined 102 patients with metastatic rhabdomyosarcoma (97 analyzed). Patients received radical RT (all metastatic sites except those completely resected), partial RT, or no RT. The OS was superior in patients treated with radical RT than partial RT (HR, 0.245; P = .039); however, it should be noted that some component of the difference in survival likely relates to the patients selected to receive radical versus partial RT rather than the type of RT administered. The 3-year OS rate was 84% for patients who received radical RT, 54% for patients who received partial RT, and 23% for patients who received no RT.[35] Patients with lung metastases who were enrolled in four COG studies (D9802, D9803, ARST08P1, and ARST0431) were retrospectively analyzed. All four protocols required whole-lung irradiation therapy for patients with rhabdomyosarcoma and lung metastases. In 143 patients, 65 (45.5%) received whole-lung irradiation and 78 (54.5%) did not receive whole-lung irradiation, despite protocol mandates.[36] In this retrospective study, there was no statistically significant differences in known prognostic factors between those who did and did not receive whole-lung irradiation. The prognostic factors included patient age, tumor histology, FOXO1 gene fusion status, primary tumor site, tumor size, lymph node status, number of metastatic sites, and Oberlin score. The 5-year EFS rate was 38.3% (95% CI, 24.8%–51.8%) for patients who received whole-lung irradiation and 25.2% (95% CI, 13.8%–36.6%) for patients who did not receive whole-lung irradiation (P = .0496). The 5-year OS rate was 45.5% (95% CI, 31.8%–59.3%) for patients who received whole-lung irradiation and 32.4% (95% CI, 20.4%–44.4%) for patients who did not receive whole-lung irradiation (P = .08). These results highlight the potential importance of whole-lung irradiation.