Table 4 Survival outcomes, toxicity incidence and prognostic factors on patients of all included studies

Ladra et al. (2014) [13]

10 (18%)

4 (7%)

5 (9%)

0

3-y (81%)

5-y (81%)

3-y (73%)

5-y (69%)

3-y (81%)

5-y (78%)

Acute: ≤ G3 (G3 = 23%)

Late: ≤ G3 (G3 = 5%)

Age (˂ 2 y vs 2–10 y vs > 10 y); Tumor size (> 5 cm vs ≤ 5 cm); Stage (1 to 2 vs 3 to 4) ^b; Risk group (Low vs Intermediate) ^b; Histology (Embryonal/botryoid vs Alveolar/undifferentiated); Group (I to II vs III to IV); Site (Favorable vs Unfavorable)

Indelicato et al. [14]

1 (3%)

0

0

0

5-y (97%)

5-y (97%)

5-y (100%)

Acute: Mild

Late: Unable to evaluate

NR

Ludmir et al. [15]

7 (15%)

9 (20%)

4 (9%)

0

5-y (84%)

5-y (57%)

5-y (76%)

Acute: ≤ G3 (G3 = 9%)

Late: ≤ G3 (G3 = 26%)

Primary tumor size (> 5 cm vs ≤ 5 cm)^d; The presence of intracranial extension at diagnosis^d; Primary tumor site; Age; Histology; Study protocol; Post-surgical IRS risk group; Cyclophosphamide equivalent dose; PBS-PT vs PSPT; Radiotherapy dose; Radiotherapy timing

Bradley et al. [16]

6 (25%)

0

7 (29%)

0

3-y (66%)

3-y (40%)

3-y (58%)

Acute: ≤ G3

Late: ≤ G3

Age (˂ 4 y vs ≥ 4 y)^e; Weeks from chemotherapy to radiation therapy (˂ 14 weeks vs ≥ 14 weeks); Elapsed days (˂ 39 vs ≥ 39); Intracranial extension ^b,e; Nodal stage (0 vs 1)^b,e,f; Primary tumor size (˂ 5 cm vs ≥ 5 cm)^e; Race (White vs Other); Sex^a; Total dose (˂ 50.4 GyRBE vs ≥ 50.4 GyRBE)

Indelicato et al. [17]

4 (13%)

0

2 (6%)

0

5-y (83%)

5-y (80%)

5-y (84%)

Acute: ≤ G2 (G2 = 16%)

Late: ≤ G3 (G3 = 6%)

Age (0–2 y vs ≥ 3 y)^a; Sex; Ethnicity (White vs Other); Histology (Alveolar vs Embryonal)^b; Regional lymph nodes (Positive vs Negative); Chemotherapy regimen (EpSSG vs COG); Median duration between chemotherapy and start of radiation (˂ Median vs ≥ Median); Total dose (> 50.4GyRBE vs ≤ 50.4GyRBE); Maximum size at diagnosis (˂ 5 cm vs 5-8 cm vs > 8 cm); Volume at diagnosis (˂ 92cm³ vs 93-382cm³ vs > 383cm³); Surgery (Resected vs Unresected)

Buszek et al. [18]

12 (13%)

20 (21%)

7 (7%)

0

4-y (85%)

4-y (63%)

4-y (71%)

Acute: NR

Late: NR

Tumor size (≤ 5 cm vs > 5 cm)^a,b,c; Timing of radiotherapy to chemotherapy (≤ 13 weeks vs > 13 weeks)^a,b,c; Cyclophosphamide dose; Intermediate-risk rhabdomyosarcoma^d

Parekh et al. [19]

8 (22%)

0

1 (3%)

0

5-y (83%)

5-y (78%)

5-y (83%)

Acute: No

Late: ≤ G3 (G3 = 16%)

Age (12 months vs > 12 months); Gender; Site (Favorable vs Unfavorable)^a,b,c; Histology (Alveolar vs Embryonal)^a,b; Size (5 cm vs > 5 cm); Stage (I/II vs III)^b,c; Nodal disease (N0 vs N1); Chemotherapy (COG vs Other); Timing of radiotherapy to chemotherapy (≤ 12 weeks vs > 12 weeks)

Mizumoto et al. [20]

5 (9%)

0

8 (15%)

1 (1.8%)

1-y (96%)

2-y (93%)

1-y (82%)

2-y (72%)

1-y (92%)

2-y (85%)

Acute: ≤ G3 (G3 = 16%)^ǂ

Late: ≤ G2 (G2 = 15%)

COG Risk group^a,b

Suzuki et al. [21]

9 (19%)

0

3 (6%)

0

3-y (79%)

3-y (69%)

3-y (94%)

Acute: ≤ G3 (G3 = 25%)

Late: Unable to evaluate

NR

Leiser et al. [22]

20 (24%)

0

4 (5%)

2 (2.4%)

5-y (79%)

NR

5-y (81%)

Acute: ≤ G3 (G3 = 15%)

Late: ≤ G3 (G3 = 18%)

Age at first diagnosis (≥ 4.5y); Age at first diagnosis (≤ 10y); Gender; Tumour site (Other vs PM)^a; IRS Group (≥ IIIb)^a; COG Stage (≥ 3)^a; COG Risk group (High vs low/int.)^a; Histology of disease (Alveolar vs Embryonal); Size at diagnosis (> 5 cm)^a; Positive lymph node at diagnosis; Total dose (≥ 54 GyRBE); In PM RMS (Intracranial extension)^a

Weber et al. [23]

9 (23%)

0

2 (5%)

0

5-y (77%)

5-y (72%)

5-y (73%)

Acute: NR

Late: ≤ G3 (G3 = 8%)

Interval time (IT) between the start of the neoadjuvant chemotherapy and start of the proton therapy (> 13 weeks) ^c