Abstract
Objective
This study aimed to evaluate and conduct a meta-analysis on the efficacy and safety of proton beam therapy (PBT) for rhabdomyosarcoma (RMS).
Methods
We searched for articles using PubMed, Embase, Cochrane Library, and Web of Science databases from their inception to December 22, 2022. Two researchers independently screened literature and extracted data. Statistical analyses were performed using STATA version 14.0.
Results
We got 675 candidate articles, of which 11 studies were included in our study according to the inclusion and exclusion criteria. Of the 544 RMS patients who received PBT. The local control (LC) rate at 1, 2, 3, 4, and 5 years were 96% (95% confidence interval (CI) 0.91–1.01), 93% (95% CI 0.86–1.00), 78% (95% CI 0.71–0.85), 85% (95% CI 0.78–0.92), and 84% (95% CI 0.74–0.95), respectively. The progression-free survival (PFS) rate at 1, 2, 3, 4, and 5 years were 82% (95% CI 0.72–0.92), 73% (95% CI 0.61–0.84), 63% (95% CI 0.47–0.79), 64% (95% CI 0.54–0.74), and 76% (95% CI 0.59–0.94), respectively. The overall survival (OS) rate at 1, 2, 3, 4, and 5 years were 93% (95% CI 0.86–1.00), 85% (95% CI 0.76–0.95), 80% (95% CI 0.63–0.96), 71% (95% CI 0.62–0.80), and 82% (95% CI 0.71–0.94), respectively. Acute and late toxicities were mainly grades 1 to 2 in all studies.
Conclusion
As an advantageous RT technique, PBT is an emerging option for patients with RMS, particularly children and adolescents patients. The data showed that PBT is a feasible, safe, and effective modality for RMS, showing promising LC, OS, PFS, and lower acute and late toxicities.
PROSPERO registration number: CRD42022329154.
Keywords: Particle, Proton therapy, Rhabdomyosarcoma, systematic review, Meta-analysis
Introduction
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. It is a heterogeneous disease both in presentation and histology, accounting for approximately 5% of all pediatric malignancies [1, 2]. RMS treatment requires multiple modalities, including systemic chemotherapy (CT), local therapy (surgery and radiotherapy), or both. Radiotherapy (RT) is an important treatment strategy for some patients with RMS in unfavorable sites, such as the head, neck, and genitourinary [3–5]. However, radiation oncologists are often very cautious in treating children and adolescents patient with RMS using photon therapy due to long-term toxicity, especially growth retardation and radiation-induced cancer [6–9].
In recent years, advanced radiation modalities have been developed, including proton beam therapy (PBT). They can deposit majority dose in the “Bragg peak” region, providing a more favorable dose-distribution than photons. PBT can deliver a higher dose to the tumor area while protecting the organ at risk from radiation-induced toxicities [10]. As one of the more advanced RT modalities, PBT is a promising treatment strategy for RMS [10].
Clinical studies on PBT for RMS were mainly case series; however, the sample size was small, and the efficacy and safety were not clear and definite. Therefore, this study aimed to systematically evaluate and analyze comprehensive evidence for PBT treatment of RMS and provide the latest evidence for PBT clinical treatment, guideline formulation, and policy implementation.
Materials and methods
Literature identification
This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The review protocol was registered in PROSPERO (CRD42022329154).
Search strategy
Our search strategy followed the PRISMA guidelines and recommendations [11]. We searched for articles using Cochrane Library, Embase, PubMed, and Web of Science databases from their dates-of-inception to December 22, 2022. Only literature written in English was considered. The search terms were as follows: (“Rhabdomyosarcoma” AND (“Proton therapy OR Proton OR Proton Therap* OR Proton Beam Therap* OR Proton Beam OR Proton Beam Radiation Therapy”)). Simultaneously, the references included in the study were traced to obtain relevant information not found in the above retrieval.
Inclusion and exclusion criteria
Two researchers (MD and QZ) independently screened all retrieved articles. The inclusion criteria were as follows: (a) studies wherein patients were clinically or pathologically diagnosed with primary or recurrent RMS, and (b) clinical studies reporting incidence of survival outcomes and toxicity in patients who received PBT. In addition, the survival outcome data of these studies were required to identify the overall survival (OS), local control (LC), and progression-free survival (PFS) rates from the initial diagnosis. The exclusion criteria were as follows: (a) studies on patients receiving treatment using only photons, carbon ion RT, brachytherapy, and other particles; (b) duplicate publications; (c) case reports, reviews, meta-analyses, abstracts, letters, comments, and protocols; (d) re-irradiation studies; (e) lack of detailed data; (f) clinical studies with < 10 patients; and (g) other irrelevant topics.
Data extraction
Literature screening and data extraction of the selected studies were performed by two reviewers (RW and QZ) independently, and the results were checked by a third reviewer (DW). If there was any disagreement, the three investigators discussed it together until a consensus was reached. Data extraction included the following: (a) first author, journal, publication year, country, research institution, study design, and study period; (b) number of patients, age, sex, tumor site, histology, tumor status, stage, intergroup RMS study (IRS) group, risk group, tumor size, total treatment dose, fractions, fraction dose, and follow-up time; (c) the primary outcome was OS, and secondary outcomes were LC, PFS, and toxicity; and (d) evaluation indicators of quality and bias assessments.
Quality and bias assessments
In our systematic review, each included article was a case series evaluated using the Joanna Briggs Institute (JBI) critical appraisal tool for case series [12]. Literature quality and bias assessments were independently completed by two researchers (QZ and MD). Disputes were resolved by a third reviewer (DW) with answers as yes, no, unclear, or not applicable. The evaluation indicators and outcomes are presented in Table 1.
Table 1.
Assessment of risk of bias in included studies
| References | Criterion | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| a | b | c | d | e | f | g | h | i | j | |
| USA | ||||||||||
| Ladra et al. [13] | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | No | Yes |
| Indelicato et al. [14] | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | No | Yes |
| Ludmir et al. [15] | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | No | Yes |
| Bradley et al. [16] | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | No | Yes |
| Indelicato et al. [17] | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | No | Yes |
| Buszek et al. [18] | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | No | Yes |
| Parekh et al. [19] | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | No | Yes |
| Japan | ||||||||||
| Mizumoto et al. [20] | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | No | Yes |
| Suzuki et al. [21] | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | No | Yes |
| Switzerland | ||||||||||
| Leiser et al. [22] | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | No | Yes |
| Weber et al. [23] | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | No | Yes |
(a) Were there clear criteria for inclusion in the case series?; (b) Was the condition measured in a standard, reliable way for all participants included in the case series?; (c) Were valid methods used for identification of the condition for all participants included in the case series?; (d) Did the case series have consecutive inclusion of participants?; (e) Did the case series have complete inclusion of participants?; (f) Was there clear reporting of the demographics of the participants in the study?; (g) Was there clear reporting of clinical information of the participants?; (h) Were the outcomes or follow-up results of cases clearly reported?; (i) Was there clear reporting of the presenting sites’/clinics’ demographic information?; (j) Was statistical analysis appropriate?
Statistical analysis
Descriptive statistics were used to summarize the baseline variables and incidence of toxicity. Data descriptions included frequencies and percentages for dichotomous data and means with standard deviations or medians with interquartile ranges for continuous data. The case series studies were conducted under different conditions. Thus, we used a random effects model to provide an overall summary estimate. We computed the proportions with 95% confidence intervals (CIs) to estimate the effect sizes for continuous outcomes. All analyses were performed using STATA version 14.0 (StataCorp, College Station, Texas, USA).
Results
Study selected and characteristics
As shown in Fig. 1, the systematic search yielded 675 potential articles for inclusion. After title and abstract reviews, 369 duplicates were removed, resulting in 306 remaining reports. We screened 58 related studies for full-text article eligibility. We eliminated another 47 items, including 19 abstracts, 24 with no detailed data, 3 overlapping cohorts, and 1 re-irradiation, and eventually included 11 articles. These 11 studies originated from 3 countries: the United States (n = 7), Japan (n = 2), and Switzerland (n = 2) [13–23]. The study design included eight prospective and three retrospective studies (Table 2). Only 544 patients with RMS underwent PBT in the studies. These studies reported the survival and toxicity after PBT. Overall, the median sample size was 46 patients (range 24–94), the median age ranged from 15.6 to 69.6 months, the female proportion was 44.1%, and the median follow-up time ranged from 11.52 to 61.2 months (Table 2).
Fig. 1.
Search results per the PRISMA guidelines
Table 2.
Baseline characteristics and clinical features of all included studies
| References | Study type | No. of patients | Median age (months) | Male/female | Median follow-up (months) | Histology | IRS group | TNM stage | Risk group | Tumor site (favorable*/unfavorable**) | Tumor size (cm) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Ladra et al. [13] | Prospective | 57 | 42 (7.2–235) | 27/30 | 47 (14–102) | Alveolar = 16; Embryonal = 41 |
Group I = 1; Group II = 7 Group III = 47; Group IV = 2 |
Stage 1 = 18; Stage 2 = 14 Stage 3 = 23; Stage 4 = 2 |
Low = 15; High = 0 Intermediate = 42 |
Favorable = 19; Unfavorable = 38 | ≤ 5 cm (n = 36); > 5 cm (n = 21) |
| Indelicato et al. [14] | Prospective | 30 | 57.6 (12–136.8) | 19/11 | 48 (6–114) | Embryonal = 30 | Group III = 30 | Stage 1 = 30 | NR | Favorable = 30; Unfavorable = 0 |
3.4 cm (range, 2.2–6.1 cm)£ 2.3 cm (range, 0.1–4.0 cm)ǂ |
| Ludmir et al. [15] | Prospective | 46 | 64.8 (8.4–188.4) | 20/26 | 46.8 (12–106.8) | Alveolar = 14; Embryonal = 32 |
Group I = 1; Group II = 5 Group III = 35; Group IV = 5 |
Stage 1 = 20; Stage 2 = 7 Stage 3 = 14; Stage 4 = 5 |
Low = 13; High = 5 Intermediate = 28 |
Favorable = 21; Unfavorable = 25 | ≤ 5 cm (n = 33); > 5 cm (n = 13) |
| Bradley et al. [16] | Prospective | 24 | 42 (12–243.6) | 12/12 | 11.52 (3.6–67.2) | Alveolar = 24 | Group II = 1; Group III = 23 | Stage 2 = 4; Stage 3 = 20 | NR | Favorable = 0; Unfavorable = 24 | 5.5 cm (range, 1.8–9.0 cm) |
| Indelicato et al. [17] | Prospective | 31 | 31.2 (12–240) | 24/7 | 12 (12–116.4) | Alveolar = 7; Embryonal = 24 | Group III = 31 |
Stage 1/2 = 24 Stage 3 = 7; Stage 4 = 0 |
NR | Favorable = 0; Unfavorable = 31 | ≤ 5 cm (n = 6); > 5 cm (n = 25) |
| Buszek et al. [18] | Prospective | 94 | 39.6 (1.2–187.2) | 50/44 | 48 (4.4–135.6) |
Alveolar = 22; Embryonal = 71 Not specified = 1 |
Group I = 6; Group II = 14 Group III = 62; Group IV = 12 |
Stage 1 = 25; Stage 2 = 24 Stage 3 = 33; Stage 4 = 12 |
Low = 19; High = 12 Intermediate = 63 |
Favorable = 33; Unfavorable = 61 |
≤ 5 cm (n = 59); > 5 cm (n = 33) Unknown (n = 2) |
| Parekh et al. [19] | Prospective | 37 | 15.6 (1.2–22.8) | 24/13 | 61.2 (8.4–26.4) | Alveolar = 12; Embryonal = 25 |
Group I = 1; Group II = 3 Group III = 33; Group IV = 0 |
Stage 1 = 4; Stage 2 = 5 Stage 3 = 28; Stage 4 = 0 |
Low = 4; High = 0 Intermediate = 33 |
Favorable = 9; Unfavorable = 28 | ≤ 5 cm (n = 13); > 5 cm (n = 24) |
| Mizumoto et al. [20] | Retrospective | 55 | 60 (0–228) | 35/20 | 24.5 (1.5–320.3) |
Alveolar = 18; Embryonal = 31 Others = 6 |
Group I = 1; Group II = 11 Group III = 37; Group IV = 6 |
NR |
Low = 9; High = 7 Intermediate = 39 |
Favorable = 37; Unfavorable = 18 | NR |
| Suzuki et al. [21] | Retrospective | 48 | 45.6 (2.4–181.2) | 26/22 | 39.6 (4.8–141.6) | Alveolar = 22; Embryonal = 26 | NR | NR |
Low = 0; High = 6 Intermediate = 42 |
Favorable = 25; Unfavorable = 23 | NR |
| Leiser et al. [22] | Prospective | 83 | 54 (9.6–186) | 46/37 | 44 (0.9–126.3) | Alveolar = 9; Embryonal = 74 |
Group I = 2; Group II = 5 Group III = 65; Group IV = 11 |
Stage 1 = 22; Stage 2 = 16 Stage 3 = 34; Stage 4 = 11 |
Low = 20; High = 11 Intermediate = 52 |
Favorable = 24; Unfavorable = 59 | ≤ 5 cm (n = 42); > 5 cm (n = 41) |
| Weber et al. [23] | Retrospective | 39 | 69.6 (14.4–193.2) | 21/18 | 41 (9–106) |
Embryonal = 38 Undifferentiated = 1 |
Group I = 0; Group II = 1 Group III = 33; Group IV = 5 |
Stage 1/2/3 = 34 Stage 4 = 5 |
NR | Favorable = 0; Unfavorable = 39 | ≤ 5 cm (n = 11); > 5 cm(n = 28) |
NR no reported, IRS intergroup rhabdomyosarcoma study group
*Orbital, Head and neck (non-parameningial), Perinea, Biliary, Urogenital (non-bladder/prostate)
**Parameningeal, Bladder/prostate, Extremities, Chest/abdomen, Perianal, Trunk or thorax
£The median maximum tumor size at the time of diagnosis
ǂThe median maximum tumor size at the time of radiation
Clinical features
Of the 11 included articles, all patients were diagnosed with RMS. The histology included 392 patients with embryonal, 144 patients with alveolar, and 8 patients with other conditions. Sixty-four percent (n = 346) of the tumors arose in unfavorable sites, and 36 (n = 198) were in favorable sites. The main details of tumor size, stage, risk group, surgery, IRS group, and chemotherapy regimens are shown in Tables 2 and 3.
Table 3.
Treatment regimens main results of all included studies
| References | Surgery n (%) | Chemotherapy n (%) | Beam-delivery | Median total dose (Gy RBE) | Fractions (n) | Dose/fraction GyRBE |
|---|---|---|---|---|---|---|
| Ladra et al. [13] | NR |
54 (100%) 18 (31.6%)c; 18 (31.5%)f; 16 (28.1%)e; 3 (5.3%)h; 2 (3.5%)d |
Passive scanning |
50.4 (36.0–50.4) |
NR | NR |
| Indelicato et al. [14] | NR | 30 (100%)e/h | Passive scanning | 45 | 25 | 1.8 |
| Ludmir et al. [15] | 1 (2.2%) |
46 (100%) 21 (45.7%)f; 10 (21.7%)e; 7 (15.2%)o; 5 (10.9%)h; 3 (6.5%)g |
Passive scanning Active scanning |
50.4 (36.0–50.8) |
28 | 1.8–2.0 |
| Bradley et al. [16] | 1 (4.2%) |
24 (100%) 15 (62.5%)h; 8 (33.3%)f; 1 (4.2%)i |
Passive scanning |
50.4 (41.4–59.4) |
28 | 1.8 |
| Indelicato et al. [17] | 14 (45.2%) |
31 (100%) 19 (61.3%)a; 12 (38.7%)b |
Passive scanning |
50.4 (36.0–59.4) |
28 | 1.8 |
| Buszek et al. [18] | 60 (63.8%) |
94 (100%) 51 (31.6%)f; 15 (31.5%)e; 10 (28.1%)g; 9 (5.3%)a; 6 (3.5%)0; 3 (3.5%)c |
Passive scanning Active scanning |
50.4 (36.0–50.8) |
28 | 1.8–2.0 |
| Parekh et al. [19] | 20 (54.1%) |
37 (100%) 18 (48.7%)a; 17 (45.9%)b; 2 (5.4%)o |
Passive scanning |
50.4 (36.0–55.8) |
28 | 1.8 |
| Mizumoto et al. [20] | 41 (74.5%) | 53 (96.4%)NR | NR |
50.4 (36.0–60.0) |
NR | NR |
| Suzuki et al. [21] | 21 (43.8%) |
46 (95.8%) 40 (83.3%)j; 6 (12.5%)k |
NR |
50.4 (41.4–59.4) |
NR | NR |
| Leiser et al. [22] | 55 (66.3%) |
83 (100%) 59 (71.1%)l; 14 (16.9%)a; 5 (6.0%)m; 3 (3.6%)f; 1 (1.2%)c; 1 (1.2%)n |
Active scanning |
54 (41.4–64.8) |
30 | 1.8–2.0 |
| Weber et al. [23] | NR |
39 (100%) 28 (71.8%)l; 5 (12.8%)a; 3 (7.7%)b; 3 (7.7%)m |
Active scanning |
54 (50.4–55.8) |
30 | 1.8–2.0 |
EpSSG European Pediatric Soft Tissue Sarcoma Study Group, COG Children’s Oncology Group, NR no reported, RMS Rhabdomyosarcoma, CWS Cooperative Weichteilsarkom Studies, MSKCC Memorial Sloan Kettering Cancer Center, RBE Relative Biologic Effectiveness
aEpSSG regimens; b: COG regimens; c: COG-D9803; d: D9602; e: COG-ARST0331; f: COG-ARST0531; g: COG-ARST0431; h: EpSSG 2005; i: St Jude RMS 13; j: VC (vincristine and cyclophosphamide); k: Irinotecan-containing regimen; l: CWS (2002P/ Guidance 2006/2007 HR/ Guidance 2009/ DOK IV 2004); m: SIOP-MMT-95; n: MSKCC 03,099; o: other regimens
Proton beam therapy
In terms of PBT, each research center used a different beam delivery system (Table 3). Passive scanning is mainly performed in the United States, whereas active scanning is mainly performed in Switzerland. Regarding the total dose, each research center used different dose fractions (Table 3).
LC, PFS, and OS rate outcomes of PBT
In our systematic review, the LC incidence at 1, 2, 3, 4, and 5 years in these studies were 96% (95% CI 0.91–1.01), 93% (95% CI 0.86–1.00), 78% (95% CI 0.71–0.85, I2 = 0%), 85% (95% CI 0.78–0.92), and 84% (95% CI 0.74–0.95, I2 = 91.1%), respectively (Fig. 2) [13–23]. In ten studies reported the PFS rate outcomes of PBT for RMS (Fig. 3) [13–21, 23]. The PFS rate at 1, 2, 3, 4, and 5 years in these studies were 82% (95% CI 0.72–0.92), 73% (95% CI 0.61–0.84), 63% (95% CI 0.47–0.79, I2 = 74.1%), 64% (95% CI 0.54–0.74), and 76% (95% CI 0.59–0.94, I2 = 94.6%), respectively (Fig. 3) [13–21, 23]. As shown in Fig. 4, after undergoing PBT for 1, 2, 3, 4, and 5 years, the OS rates for RMS were 93% (95% CI 0.86–1.00), 85% (95% CI 0.76–0.95), 80% (95% CI 0.63–0.96, I2 = 84.9%), 71% (95% CI 0.62–0.80), and 82% (95% CI 0.71–0.94, I2 = 92.2%), respectively [13–23].
Fig. 2.
The pooled incidences of LC after PBT for RMS
Fig. 3.
The pooled incidences of PFS after PBT for RMS
Fig. 4.
The pooled incidences of OS after PBT for RMS
Toxicity
Across all studies, the incidence of acute and late toxicities were mainly grades 1 to 2 (Table 4). Acute toxicity grade 3 was observed in 6 studies. The incidence of which was 9–25% [13, 15, 16, 20–22]. Late toxicity grade 3 was observed in 7 articles, with an incidence of 2.1–26% [13, 15–17, 19, 22, 23]. Acute toxicity of orbital embryonal RMS were mild. Serious late toxicities included cataracts (n = 18), permanently reduced visual acuity (n = 4), and chronic sinusitis (n = 1) [14]. Two studies of parameningial RMS (PM-RMS) identified grade 3 late toxicity of unilateral cataracts and hearing impairment; however, the incidence was 8% [16, 23]. The study of head and neck RMS (H&N-RMS) identified grade 3 acute and late toxicity; the incidence were 9%, and 26%, respectively [15]. Regarding RMS in the pelvis, we observed grade 2 acute toxicity and grade 3 late toxicity, the incidence of which were 16% and 6%, respectively [17]. Dysfunction was reported in three studies, including unilateral hearing loss, cognitive disturbance, and skeletal muscle defect; however, grade 3 dysfunction occurred in only one case [13, 15, 20]. In addition, two studies reported secondary malignancy (radiation-induced); the incidence of which were 1.8% (n = 1) and 2.4% (n = 2), respectively [20, 22].
Table 4.
Survival outcomes, toxicity incidence and prognostic factors on patients of all included studies
| References | Local failure n (%) | Regional failure n (%) | Metastasis n (%) | Radiation induced cancer n (%) | Local control | Progress-free survival | Overall survival | Toxicity | Prognostic factors |
|---|---|---|---|---|---|---|---|---|---|
| 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 diagnosisd; 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); Sexa; 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 rhabdomyosarcomad |
| 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 groupa,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 |
Boldface indicates statistically significant difference
NR no reported, IRS Intergroup Rhabdomyosarcoma Study, EpSSG European Pediatric Soft Tissue Sarcoma Study Group, COG Children’s Oncology Group, PM Parameningial, RMS Rhabdomyosarcoma, RBE Relative Biologic Effectiveness, PBS-PT Pencil-beam Scanning Proton Beam Therapy, PSPT Passivescattered Proton Beam Therapy
ǂRadiation- induced toxicities (including mucositis and dermatitis)
aFactor significantly correlated with local control (LC) (p ≤ 0.05); bfactor significantly correlated with overall survival (OS) (p ≤ 0.05); cfactor significantly correlated with progress-free survival (PFS) (p ≤ 0.05); dfactor significantly correlated with local failure (LF) (p ≤ 0.05); efactor significantly correlated with freedom from metastases (p ≤ 0.05); ffactor significantly correlated with disease-free survival (p ≤ 0.05)
Prognostic factors of PBT effectiveness
In our systematic review, nine studies reported the prognostic factors of PBT effectiveness. The following factors were evaluated: age, sex, race, tumor size, surgery, risk group, histology, IRS group, lymph nodal stage, intracranial extension, beam delivery system, interval time between RT and CT, CT regimens or dose, and total dose. Table 4 (Boldface indicates statistically significant difference) shows the main details of the prognostic factors of PBT effectiveness in all the included studies [13, 15–20, 22, 23].
Discussion
In the past 40 years, significant advances have been made in treating RMS, with a 3-year OS rate of approximately 80% in high-risk patients [24]. RT is an important part of the current pretreatment strategy for RMS, and the absence of RT for high-risk RMS leads to a poor prognosis. According to previous studies, PBT was used to treat various malignancies. The supposed decrease of toxicity and better therapeutic effect with proton therapy are not strictly confirmed but strongly supported according to dosimetric comparisons [25]. We analyzed all available studies on PBT for treating RMS, including efficacy, safety, and prognostic factors. Our study found that PBT is safe and effective for RMS, showing promising results for LC, PFS, and OS and acceptable acute and late toxicities.
In our systematic review, patients with RMS were treated using PBT. The median total dose was 45–50.4 GyRBE; most research institutions used a median total dose of 50.4 GyRBE (Table 3). In terms of included patients, pooled probabilities of LC, PFS, and OS were 85%, 72%, and 82%, respectively (Figs. 2, 3, 4). According to previous clinical outcomes based on photon RT, LC rates were 62–88%. Therefore, compared with previous clinical reports, the efficacy of PBT for RMS is comparable to that of photon RT [5, 24, 26–28].
PM-RMS is a mesenchymal tumor that usually invades the leptomeninges into the brain, leading to neoplastic meningitis [29]. PM-RMS accounts for approximately 40% of H&N tumors and 15% of all RMS in children and is a refractory RMS [3, 30]. In two studies on PM-RMS with PBT in our review (Table 4), the 5 years LC, PFS, and OS were 77%, 72%, and 73%, respectively [23]. In terms of X-ray RT for PM-RMS, Merks et al. reported a study of 862 patients who received RT [31]. The event-free survival (EFS) rates at 5 and 10 years for all patients were 64.9% and 62.6%, respectively; the OS rates at 5 and 10 years for all patients were 69.5% and 66.1%, respectively. In addition, their study also showed that patients with PM-RMS who did not receive RT had worse OS rates (5 years OS 49.6% versus 71.4%; 10 years OS 40.8% versus 68.5%) [31]. These studies showed that proton and photon therapies have similar clinical outcomes for both disease control and survival.
In patients with RMS, unfavorable tumor sites often predict poorer disease control and survival [19, 22]. These usually include parameninges, bladder/prostate, extremities, chest/abdomen, perianal, and trunk or thorax. In contrast, favorable tumor sites include the orbital, head, neck (non-parameningeal), perineal, biliary, and urogenital (non-bladder/prostate). We included three studies with unfavorable disease sites (Table 2) [16, 17, 23]. The LC, PFS and OS incidence at 3 years in these studies were 66%, 40%, and 58%, respectively; the LC, PFS and OS incidence at 5 years in these studies were 77–83%, 72–80%, and 73–84%, respectively (Table 4) [16, 17, 23]. These results suggest that, despite irradiating unfavorable sites of RMS with a higher median total dose of PBT (50.4–54 GyRBE), local failure is expected to occur within 3 or 5 years in 13–25% of the cases [16, 17, 23]. Regarding favorable sites of RMS, Indelicato et al. reported orbital RMS treated with PBT. The LC, PFS, and OS rates at 5 years were 97%, 97%, and 100%, respectively [14]. The results of this study suggest that 45 GyRBE PBT for favorable RMS sites maybe achieve satisfactory disease control and survival.
Balancing disease control with toxicity remains a significant challenge for radiation oncologists since it is the most common soft tissue sarcoma in children and adolescents. In our systematic review, the incidence of acute and late toxicities was mainly grade 1 to grade 2 (Table 4). The most common event was an acute skin or mucous membrane reaction [13–15, 20–22], with an incidence of grade 3 acute toxicity at 4–9% and 2–12%, respectively [13, 15, 20, 22]. No grade 4 or higher skin and mucosal acute reactions were observed in any of the studies. Gaito et al. reported radiation-induced skin toxicity (RIST) profile of photon radiotherapy versus PBT in patients with RMS and Ewing sarcoma [32]. With regards to acute RIST, 47.9% of photon radiotherapy patients and 48.4% of PBT patients had acute grade 2/3 toxicity. When it comes to late RIST, 17.5% of photon radiotherapy patients and 29.0% of PBT patients had grade 1/2 toxicity. This difference in grade 1/2 toxicity between photon radiotherapy and PBT was not statistically significant (P = 0.25) [32]. In terms of late toxicity, grade 3 was observed in 7 articles, with an incidence of 5–26% [13, 15–17, 19–23]. RMS of the H&N did not present with more than grade 3 early and late toxicities [14–16, 23]. One study of pelvic RMS had grade 3 late toxicity, including gonadal failure, stress fracture of S1, and leg length discrepancy; however, the incidence was 6% [17]. Parekh et al. reported 37 cases of infant RMS (˂ 24 months) without acute toxicity; however, grade 3 late toxicity was observed in 6 patients, including cataract (11%), eyelid entropion (3%), and scoliosis (3%) [19]. Dysfunction was reported in three studies, including unilateral hearing loss, cognitive disturbance, and skeletal muscle defect; however, only one case of grade 3 dysfunction was observed [13, 15, 20]. Additionally, two studies reported secondary malignancy (radiation-induced); the incidence were 1.8% (n = 1) and 2.4% (n = 2), respectively [20, 22]. Although the toxicity of PBT was low and acceptable, late toxicity, especially dysfunction and secondary malignancy (radiation-induced) required larger samples and long-term follow-up.
In our systematic review, nine studies reported the prognostic factors of PBT effectiveness (Table 4) [13, 15–20, 22, 23]. The following factors were evaluated: age, sex, race, tumor size, surgery, risk profile, histology, IRS group, lymph nodal stage, intracranial extension, beam-delivery system, interval time between RT and CT, CT regimens or dose, and total dose. Prognostic factors varied widely among the selected studies. Overall, most studies showed that risk group, tumor size, tumor site, stage, and intracranial extension are common significant prognostic factors for RMS. Furthermore, younger age, shorter interval time between RT and CT, and negative lymph nodal stage were significantly associated with better LC, PFS, and OS. According to Kubo et al., the PAX3/7-FOXO1 fusion gene may be a potential unfavorable prognostic factor [33]. There were three articles reporting about the PAX3/7-FOXO1 fusion gene in our study, but no correlation was found with survival prognosis [15, 16, 19].
This systematic review and meta-analysis had several limitations. First, grey literature were not included, and there may be publication bias. Second, our search results showed that 64% of the literature on PBT for RMS was from the United States, 18% was from Japan, and 18% was from Switzerland. Therefore, reporting bias may be present. In addition, all studies were case series reports without randomized controlled studies and included small sample sizes. This may affect the reliability of the conclusions of this systematic review. Third, due to limited data, conducting a subgroup analysis of disease control and survival for different histology, IRS group, stage, and risk group was difficult. However, all study designs were reasonable, the missed follow-up rates were low, and the strength of the endpoints was high, with all studies evaluating LC, PFS, and OS as specific outcomes.
As an advantageous RT technique, PBT has shown promising efficacy and acceptable toxicity in RMS treatment. However, there are still some areas of insufficient PBT for RMS. First, previous studies on PBT for RMS often involved different age groups, sites, IRS groups, risk groups, and stages. Different types of RMS may have inconsistent optimal dose patterns, and individualized PBT requires further study. Second, although PBT for RMS has achieved good LC and PFS, integrated treatment modalities, including CT regimens, anti-angiogenic therapy, and immunotherapy, require further study. Third, the number of patients treated with PBT for RMS was too small, although a potential role of protons in improving LC and PFS at low toxicity was found. In addition, the relatively short follow-up period of the current study limits the reliability of the long-term toxicity evaluation of proton therapy for RMS, such as recurrence, functional deficits, growth and development, and secondary cancer. Lastly, whether PBT is superior to other RT technologies needs to be determined with high-quality prospective randomized controlled clinical trials in patients with RMS.
Conclusion
As an advantageous RT technique, PBT is an emerging option for patients with RMS, particularly children and adolescents patients. The data showed that PBT is a feasible, safe, and effective modality for RMS, showing promising LC, OS, PFS, and lower acute and late toxicities. However, whether PBT is superior to other RT technologies needs to be determined using high-quality prospective randomized controlled clinical trials.
Acknowledgements
We would like to thank Qiuning Zhang for her support during the search strategy.
Abbreviations
- PBT
Proton beam therapy
- RMS
Rhabdomyosarcoma
- LC
Local control
- CI
Confidence interval
- PFS
Progress-free survival
- OS
Overall survival
- CT
Chemotherapy
- RT
Radiotherapy
- H&N-RMS
Head and neck rhabdomyosarcoma
- PRISMA
Preferred Reporting Items for Systematic Reviews and Meta-analysis
- IRS
Intergroup rhabdomyosarcoma study
- RBE
Relative biological effectiveness
- JBI
Joanna Briggs Institute
- CI(s)
Confidence interval(s)
- PM-RMS
Parameningial rhabdomyosarcoma
Author contributions
Conception/design: XW, MD. Provision of study material or patients: MD, JW, QZ. Collection and/or assembly of data: RW, QZ, DW, YW. Data analysis and interpretation: MD, RL, RW, QZ, HL, DW, YW, JC, YO. Manuscript writing: MD, JW, QZ. Final approval of manuscript: XW, QZ. All authors read and approved the final manuscript.
Funding
The systematic review was supported by National Key Research and Development Program of China (No. 2022YFC2401505); Science and Technology Plan Project of Chengguan District of Lanzhou (No.2020-2-2-5); Talent innovation and venture project of Lanzhou city (No. 2017-RC-23); Talent innovation and venture project of Lanzhou city (No. 2020-RC-113); Key R&D Program of Science and Technology Department of Gansu Province (No. 20YF8FA116); The authorized project of Lanzhou KejinTaiji Corporation, Ltd (No. BMP-B-02-002).
Availability of data and materials
All data are provided.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests for this article.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Meng Dong and Jianrong Wu contributed equally to this study
Contributor Information
Qiuning Zhang, Email: zhangqn@impcas.ac.cn.
Xiaohu Wang, Email: xhwang@impcas.ac.cn.
References
- 1.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. doi: 10.3322/caac.21442. [DOI] [PubMed] [Google Scholar]
- 2.Egas-Bejar D, Huh WW. Rhabdomyosarcoma in adolescent and young adult patients: current perspectives. Adolesc Health Med Ther. 2014;5:115–125. doi: 10.2147/AHMT.S44582. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Crist WM, Anderson JR, Meza JL, et al. Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol. 2001;19:3091–3102. doi: 10.1200/JCO.2001.19.12.3091. [DOI] [PubMed] [Google Scholar]
- 4.Rodeberg DA, Anderson JR, Arndt CA, et al. Comparison of outcomes based on treatment algorithms for rhabdomyosarcoma of the bladder/prostate: combined results from the Children's Oncology Group, German Cooperative Soft Tissue Sarcoma Study, Italian Cooperative Group, and International Society of Pediatric Oncology Malignant Mesenchymal Tumors Committee. Int J Cancer. 2011;128:1232–1239. doi: 10.1002/ijc.25444. [DOI] [PubMed] [Google Scholar]
- 5.Arndt CA, Stoner JA, Hawkins DS, et al. Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: children's oncology group study D9803. J Clin Oncol. 2009;27:5182–5188. doi: 10.1200/JCO.2009.22.3768. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Ferrari A, Casanova M, Bisogno G, et al. Rhabdomyosarcoma in infants younger than one year old: a report from the Italian Cooperative Group. Cancer. 2003;97:2597–2604. doi: 10.1002/cncr.11357. [DOI] [PubMed] [Google Scholar]
- 7.Malempati S, Rodeberg DA, Donaldson SS, et al. Rhabdomyosarcoma in infants younger than 1 year: a report from the Children's Oncology Group. Cancer. 2011;117:3493–3501. doi: 10.1002/cncr.25887. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Orbach D, Rey A, Oberlin O, et al. Soft tissue sarcoma or malignant mesenchymal tumors in the first year of life: experience of the International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Committee. J Clin Oncol. 2005;23:4363–4371. doi: 10.1200/JCO.2005.12.009. [DOI] [PubMed] [Google Scholar]
- 9.Fukushima H, Fukushima T, Suzuki R, et al. Comorbidity and quality of life in childhood cancer survivors treated with proton beam therapy. Pediatr Int. 2017;59:1039–1045. doi: 10.1111/ped.13323. [DOI] [PubMed] [Google Scholar]
- 10.Munck af Rosenschold P, Engelholm SA, Brodin PN, et al. A retrospective evaluation of the benefit of referring pediatric cancer patients to an external proton therapy center. Pediatr Blood Cancer. 2016;63:262–269. doi: 10.1002/pbc.25768. [DOI] [PubMed] [Google Scholar]
- 11.Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097. doi: 10.1371/journal.pmed.1000097. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Munn Z, Barker TH, Moola S, et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI Evid Synth. 2020;18:2127–2133. doi: 10.11124/JBISRIR-D-19-00099. [DOI] [PubMed] [Google Scholar]
- 13.Ladra MM, Szymonifka JD, Mahajan A, et al. Preliminary results of a phase II trial of proton radiotherapy for pediatric rhabdomyosarcoma. J Clin Oncol. 2014;32:3762–3770. doi: 10.1200/JCO.2014.56.1548. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Indelicato DJ, Rotondo RL, Mailhot Vega RB, et al. 45 GyRBE for group III orbital embryonal rhabdomyosarcoma. Acta Oncol. 2019;58:1404–1409. doi: 10.1080/0284186X.2019.1627412. [DOI] [PubMed] [Google Scholar]
- 15.Ludmir EB, Grosshans DR, McAleer MF, et al. Patterns of failure following proton beam therapy for head and neck rhabdomyosarcoma. Radiother Oncol. 2019;134:143–150. doi: 10.1016/j.radonc.2019.02.002. [DOI] [PubMed] [Google Scholar]
- 16.Bradley JA, Indelicato DJ, Uezono H, et al. Patterns of failure in parameningeal alveolar rhabdomyosarcoma. Int J Radiat Oncol Biol Phys. 2020;107:325–333. doi: 10.1016/j.ijrobp.2020.01.035. [DOI] [PubMed] [Google Scholar]
- 17.Indelicato DJ, Rotondo RL, Krasin MJ, et al. Outcomes following proton therapy for Group III pelvic rhabdomyosarcoma. Int J Radiat Oncol Biol Phys. 2020;106:968–976. doi: 10.1016/j.ijrobp.2019.12.036. [DOI] [PubMed] [Google Scholar]
- 18.Buszek SM, Ludmir EB, Grosshans DR, et al. Disease control and patterns of failure after proton beam therapy for rhabdomyosarcoma. Int J Radiat Oncol Biol Phys. 2021;109:718–725. doi: 10.1016/j.ijrobp.2020.09.050. [DOI] [PubMed] [Google Scholar]
- 19.Parekh AD, Indelicato DJ, Vega RBM, et al. Proton radiotherapy for infant rhabdomyosarcoma: rethinking young age as an adverse prognostic factor. Radiother Oncol. 2021;163:215–220. doi: 10.1016/j.radonc.2021.05.017. [DOI] [PubMed] [Google Scholar]
- 20.Mizumoto M, Murayama S, Akimoto T, et al. Preliminary results of proton radiotherapy for pediatric rhabdomyosarcoma: a multi-institutional study in Japan. Cancer Med. 2018;7:1870–1874. doi: 10.1002/cam4.1464. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Suzuki R, Fukushima H, Okuwaki H, et al. Proton beam therapy with concurrent chemotherapy is feasible in children with newly diagnosed rhabdomyosarcoma. Rep Pract Oncol Radiother. 2021;26:616–625. doi: 10.5603/RPOR.a2021.0082. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Leiser D, Calaminus G, Malyapa R, et al. Tumour control and Quality of Life in children with rhabdomyosarcoma treated with pencil beam scanning proton therapy. Radiother Oncol. 2016;120:163–168. doi: 10.1016/j.radonc.2016.05.013. [DOI] [PubMed] [Google Scholar]
- 23.Weber DC, Ares C, Albertini F, et al. Pencil beam scanning proton therapy for pediatric parameningeal rhabdomyosarcomas: clinical outcome of patients treated at the Paul Scherrer Institute. Pediatr Blood Cancer. 2016;63:1731–1736. doi: 10.1002/pbc.25864. [DOI] [PubMed] [Google Scholar]
- 24.Bisogno G, Jenney M, Bergeron C, et al. Addition of dose-intensified doxorubicin to standard chemotherapy for rhabdomyosarcoma (EpSSG RMS 2005): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet Oncol. 2018;19:1061–1071. doi: 10.1016/S1470-2045(18)30337-1. [DOI] [PubMed] [Google Scholar]
- 25.Sakurai H, Ishikawa H, Okumura T. Proton beam therapy in Japan: current and future status. Jpn J Clin Oncol. 2016;46:885–892. doi: 10.1093/jjco/hyw102. [DOI] [PubMed] [Google Scholar]
- 26.Ladra MM, Mandeville HC, Niemierko A, et al. Local failure in parameningeal rhabdomyosarcoma correlates with poor response to induction chemotherapy. Int J Radiat Oncol Biol Phys. 2015;92:358–367. doi: 10.1016/j.ijrobp.2015.01.049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Hawkins DS, Chi YY, Anderson JR, et al. Addition of vincristine and irinotecan to vincristine, dactinomycin, and cyclophosphamide does not improve outcome for intermediate-risk rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2018;36:2770–2777. doi: 10.1200/JCO.2018.77.9694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Curtis AE, Okcu MF, Chintagumpala M, Teh BS, Paulino AC. Local control after intensity-modulated radiotherapy for head-and-neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys. 2009;73:173–177. doi: 10.1016/j.ijrobp.2008.03.029. [DOI] [PubMed] [Google Scholar]
- 29.Wharam MD., Jr Rhabdomyosarcoma of parameningeal sites. Semin Radiat Oncol. 1997;7:212–216. doi: 10.1016/S1053-4296(97)80005-7. [DOI] [PubMed] [Google Scholar]
- 30.Crist W, Gehan EA, Ragab AH, et al. The third intergroup rhabdomyosarcoma study. J Clin Oncol. 1995;13:610–630. doi: 10.1200/JCO.1995.13.3.610. [DOI] [PubMed] [Google Scholar]
- 31.Merks JH, De Salvo GL, Bergeron C, et al. Parameningeal rhabdomyosarcoma in pediatric age: results of a pooled analysis from North American and European cooperative groups. Ann Oncol. 2014;25:231–236. doi: 10.1093/annonc/mdt426. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Gaito S, Abravan A, Richardson J, et al. Skin toxicity profile of photon radiotherapy versus proton beam therapy in paediatric and young adult patients with sarcomas. Clin Oncol (R Coll Radiol) 2021;33:507–516. doi: 10.1016/j.clon.2021.03.009. [DOI] [PubMed] [Google Scholar]
- 33.Kubo T, Shimose S, Fujimori J, Furuta T, Ochi M. Prognostic value of PAX3/7-FOXO1 fusion status in alveolar rhabdomyosarcoma: systematic review and meta-analysis. Crit Rev Oncol Hematol. 2015;96:46–53. doi: 10.1016/j.critrevonc.2015.04.012. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data are provided.