Table 7.
Non-randomized clinical studies of proton versus photon radiation therapy – pediatric CNS cancer.
| Study | Cancer Type | Interventions | Dose | Number of patients | Accrual Period | Follow up | Clinical Outcomes (Proton therapy vs Photon therapy) |
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|---|---|---|---|---|---|---|---|---|---|
| (51) Kahalley et al. (2016) | Pediatric brain tumor | PSPT/IMPT vs 3D-CRT/IMRT | PSPT/IMPT: M 54 Gy (R 30-60 Gy) 3D-CRT/IMRT: M 54 Gy (R 30.6-59.4 Gy) |
90 PBT (81 PSPT, 9 IMPT), 60 3D-CRT/IMRT | PSPT/IMPT: 2007-2012 3D-CRT/IMRT 2002-2007 |
not specified | IQ: 3D-CRT/IMRT vs PSPT/IMPT (- 8.7 points average, P = 0.011)* |
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| (52) Kahalley et al. (2020) | pediatric medulloblastoma | PBT vs photon therapy with chemotherapy |
standard-dose 30.6-39.6 Gy or reduced dose 15.0-23.4 Gy to the whole brain and spine | 37 PBT, 42 photon therapy | 2007-2018 | not specified | Global IQ: P = 0.011* PIQ: P = 0.022* Working memory: P = 0.002* VIQ: P > 0.05 PSI: P > 0.05 |
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| (53) Eaton et al. (2021) | standard-risk Pediatric medulloblastoma | PSPT vs 3D-CRT/IMRT | CSI dose: PSPT: M 23.4Gy (R 18-27Gy), 3D-CRT/IMRT: M 23.4Gy (R 18-26.4Gy) | 25 PSPT, 25 3D-CRT/IMRT | 2000-2009 | PSPT: M 5.3y (R 1.0-11.4y), 3D-CRT/IMRT: M 4.6y (R 1.1-11.2y) | FSIQ: 99.6 vs 86.2* VIQ: 105.2 vs 88.6* PIQ: 103.1 vs 88.9* PSI: 82.9 vs 77.2 Working memory: 97.0 vs 92.7 |
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| (54) Gross et al. (2019) | pediatric brain tumor | PSPT/IMPT vs 3D-CRT/IMRT | not specified | 58 PBT (11 PSPT, 47 IMPT), 67 photon therapy (26 3D-CRT, 41 IMRT) |
1998-2017 | M 3.2y (IQR 1.8-4.7y) |
FSIQ/GAI: P = 0.048* PSI: P = 0.007* VIQ: P = 0.06 Adaptive functioning across domains: GAC P = 0.07 Conceptual: P = 0.09 Social: P = 0.07 Practical: P = 0.08 Focal irradiation: PSI: P = 0.01* CSI: FSIQ/GAI: P = 0.01* VIQ: P = 0.01* |
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| (55) Child et al. (2021) | pediatric primary brain tumor | PBT vs photon therapy | Focal PBT: M 50.4Gy (R 45.0–59.4Gy), Focal photon therapy: M 54.0Gy (R 48.6–59.4Gy), CSI PBT: M 54.0Gy (R 45.0–55.8Gy), CSI photon therapy: M 54.0Gy (R 30.6–55.8Gy) | 58 PBT, 30 photon therapy | PBT: 2007-2013, photon therapy: 2001-2006 | Focal PBT: M 6.3 ± 2.7y (R 1.2–10.6y), Focal photon therapy: M 8.7 ± 3.4y (R 4.0–15.3y), CSI PBT: M 5.9 ± 3.3y (R 1.2–11.1y), CSI photon therapy: M 9.8 ± 2.5y (R 5.8–13.9y) |
Focal irradiation:
FSIQ: 99.0 ± 2.7 vs 92.5 ± 4.3 VIQ: 101.8 ± 2.2 vs 101.4 ± 3.6 PIQ: 103.6 ± 3.2 vs 96.3 ± 5.1 Working memory: 96.4 ± 2.9 vs 95.8 ± 4.5 PSI: 87.9 ± 3.2 vs 78.5 ± 5.1 CSI: FSIQ: 86.3 ± 4.5 vs 71.3 ± 7.3 VIQ: 90.2 ± 4.4 vs 80.0 ± 7.1 PIQ: 92.7 ± 5.2 vs 76.9 ± 8.4 Working memory: 89.0 ± 4.4 vs 77.8 ± 7.1 PSI: 76.0 ± 2.8 vs 72.3 ± 4.4 |
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| (56) Bielamowicz et al. (2018) | Standard and high risk pediatric medulloblastoma | PSPT vs 3D-CRT+IMRT boost w/chemotherapy |
PSPT: M 55.8Gy (R 36-57Gy),3D-CRT+IMRT boost: M 55.8Gy (R 54-59.4Gy) | 41 PSPT, 54 3D-CRT+IMRT boost | 1997-2014 | PSPT: M 3.8y (R 1.0-8.8y),3D-CRT+IMRT boost: M 9.6y (R 1.0-15.8y) | Primary hypothyroidism: 7.3 vs 20.4% Central hypothyroidism: 9.8 vs 24.0% |
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| (57) Aldrich et al. (2021) | Pediatric medulloblastoma | PSPT vs 3D-CRT+IMRT boost | standard/low-risk: 15-23.4Gy, high risk: 36-39.6Gy | 64 PSPT, 54 3D-CRT+IMRT boost | 1997-2016 | M 5.6y (R 1.0-10.0y) | Primary hypothyroidism: 6% vs 28%* | ||
| (58) Eaton et al. (2016) | Standard risk pediatric medulloblastoma | PSPT vs 3D-CRT/IMRT w/chemotherapy |
54–55.8 Gy at 1.8Gy/fx, or 60Gy in 1.2Gy/fx | 40 PSPT, 37 photon therapy (13 3D-CRT, 24 IMRT) | 2000-2009 | PSPT: M 5.8y (R 3.4–9.9y), 3D-CRT/IMRT: M 7.0y (R 3.5–13.5y) | Hypothyroidism: 23% vs 69%* Sex hormone deficiency: 3% vs 19%* Endocrine replacement therapy requirement: 55% vs 78%* Height standard deviation score: 21.19 ( ± 1.22) vs 22 ( ± 1.35)* Growth hormone deficiency: 53% vs 57% Adrenal insufficiency: 5% vs 8% Precocious puberty: 18% vs 16% |
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| (59) Liu et al. (2021) | Pediatric medulloblastoma | DSPT vs photon therapy w/or w/o concurrent chemotherapy |
DSPT: M 54 Gy (R 54-55.8 Gy) Photon therapy: M 54 Gy (R 52.2-55.8 Gy) |
60 DSPT, 37 photon therapy |
2000-2017 | DSPT: M 8.1y (R 0.2-13.7y); Photon therapy: M 7.1y (R 0.2-17.5y) |
Hematologic toxicity:
Leukopenia: P = 0.044* Neutropenia: P = 0.762 Lymphopenia: P < 0.0001* Anemia: P = 0.011* Thrombocytopenia: P = 0.066 5y OS: 89.6% vs 93.4% |
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| (60) Song et al. (2014) | Pediatric brain tumor (mainly medulloblastoma) | PBT vs Photon therapy | PBT: mean 29.4 Gy (R 19.8-39.6 Gy) at 1.8 Gy/fx Photon therapy: mean 32.1 Gy (R 23.4-39.6 Gy) at 1.8 or 1.5 Gy/fx |
30 PBT, 13photon therapy |
PBT: 2008-2012 Photon therapy: 2003-2012 |
M: 22 mo (R 2-118 mo) |
GI toxicity:
Nausea: 33% vs 46% Dysphagia: 47% vs 15% Anorexia: 37% vs 31% Vomiting: 30% vs31% Diarrhoea: 0 vs 23%* Hematologic toxicity: Leukopenia: 64% vs 78% Anaemia: 0 vs 15% Thrombocytopenia: 23% vs 54%* Platelet transfusion: 17% vs 46%* RBC transfusion: 50% vs 39% WBC: -0.57 ± 2.22 vs -2.61 ± 2.27* Hb: +0.23 ± 1.04 vs -0.7 ± 1.89 Platelet: -0.49 ± 0.64 vs -1.37 ± 0.96* |
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| (61) Yoo et al. (2022) | Pediatric brain tumors | PBSPT vs 3D-CRT/helical tomotherapy | up to 30.6Gy at 1.5 or 1.8Gy/fx in M 13fx (R 10-17fx) | 36 PBSPT, 29 3D-CRT/1 helical tomotherapy | 2010-2019 | M 38 mo (R 1-114 mo) | Hb: P = 0.328 ALC: P = 0.018* PLT: P = 0.007* Diarrhea: 0 vs 3.3% Grade 3 anemia: 0 vs 13.3%* Grade 4 lymphopenia: 30.6% vs 43.3% Grade 3 thrombocytopenia: 11.1% vs 20% Platelet transfusion: 5.6% vs 13.3% 3y OS: 92.9% vs 93.2% |
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| (62) Paulino et al. (2021) | Pediatric medulloblastoma | PSPT vs 3D-CRT+IMRT boost w/chemotherapy |
CSI dose: 18.0-23.4Gy or 30.6-40Gy | 52 PSPT, 63 IMRT | 1996-2014 | PSPT: M 8.7y (R 0.4-13.4y), IMRT: M 12.8y (R 0.2-20.3y) | 5y OS: 80.3% vs 80% 10y OS: 72.4% vs 78.1% 5y SMN: 2.2% vs 0 10y SMN: 4.9% vs 8% |
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| (63) Eaton et al. (2016) | Pediatric standard risk medulloblastoma | PBT vs 3D-CRT/IMRT w/chemotherapy |
M 23.4 Gy (R 18-27 Gy), boost 30.6 Gy (R 27-37.8 Gy) |
45 PBT, 43 3D-CRT/IMRT |
2000-2009 | PBT: M 6.2 y (R 5.1-6.6 y) 3D-CRT/IMRT: M 7 y (R 5.8-8.9 y) |
6y OS: 82% vs 87.6% 6y RFS: 78.8% vs 76.5% Patterns of failure: 22.2% vs 23.3% |
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| (64) Paulino et al. (2018) | Pediatric medulloblastoma | PSPT vs 3D-CRT+IMRT boost w/chemotherapy |
18–23.4 Gy for standard-risk patients, 36–39.6 Gy for high-risk patients | 38 PSPT, 46 3D-CRT+IMRT boost | 1997-2013 | PSPT: M 56mo (R 13–101 mo), 3D-CRT+IMRT boost: M 66mo (R 13–163 mo) | Grade 3&4 hearing loss SIOP Boston scale: 20% vs 23.1% Brock scale: 9.3% vs 9% POG scale: 17.3% vs 20.9% CTCAE scale: 29.9% vs 28.3% |
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| (65) Trybula et al. (2021) | Pediatric medulloblastoma | PBT vs Photon therapy | PBT: 54.8Gy, Photon therapy: 54.2Gy | 49 PBT, 30 Photon therapy |
2003-2019 | PBT: 56.8 mo, Photon therapy: 105 mo | CM: 85.7% vs 86.7% | ||
| (66) Bishop et al. (2014) | Pediatric craniopharyngioma | PBT (mainly PSPT) vs IMRT | PBT and IMRT: 50.4-54 Gy at 1.8 Gy/fx | 21 PBT (18 PSPT), 31IMRT | 1996-2012 | M 59.6 mo |
Toxicities:
Cyst growth: 19% vs 42% at 3 mo; 19% vs 32% after 3 mo Vascular morbidity: 10% vs 10% Vision: 5% vs 13% Hypothalamic obesity: 19% vs 29% Endocrinopathy: 76% vs 77% 3y OS: 94.1% vs 96.8% 3y CFFS: 67% vs 76.8% 3y NFFS: 91.7% vs 96.4% |
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| (67) Sato et al. (2017) | Grade II-III pediatric intracranial ependymomas | PBT vs IMRT w/or wo/chemotherapy | PBT: M 55.8Gy (R 50.4-59.4Gy), IMRT: M 54Gy (R 50.4-59.4Gy) at 1.8Gy/fx in 28-33fx | 41 PBT, 38 IMRT | 2000-2013 | PBT: M 2.6y (R 0.6-7.2y), IMRT: M 4.9y (R 1.1-11.7y) | 3y PFS: 82% vs 60%* 3y OS: 97% vs 81% | ||
| (68) Yock et al. (2014) | Pediatric brain tumor |
PBT vs photon therapy | < 50Gy or 50-54Gy or > 54Gy | 57 PBT, 63 photon therapy | PBT: 2004-2009, photon therapy: 2001-2002 | PBT: M 3y, photon therapy: M 2.9y | QoL: 75.9 vs 65.4* | ||
Proton dose is RBE weighted.
*There is a statistically significant difference.
mo, month(s); y, year(s); fx, fraction(s); M, median; R, range; IQR, interquartile range; w, with; w/o, without; vs, versus; 3D-CRT, 3-D conformal radiation therapy; IMRT, intensity modulated radiotherapy; PBT, proton beam therapy; PSPT, passively scattering proton therapy; DSPT, double-scattering proton therapy; IMPT, intensity modulated proton therapy;
PBSPT, pencil beam scanning proton therapy; CNS, central nervous system; OS, overall survival; RFS, recurrence-free survival; CFFS, cystic failure-free survival; NFFS, nodular failure-free survival; GI, gastrointestinal; RBC, red blood cells; WBC, white blood cells; Hb, hemoglobin; CSI, craniospinal irradiation; IQ, intelligence quotient; FSIQ, full-scale intelligence quotient;
GAI, general ability index; VIQ, verbal reasoning; PIQ, perceptual reasoning; PSI, processing speed index; GAC, general adaptive composite; CM, cavernous malformations; ALC, absolute lymphocyte count; PLT, platelet count; PFS, progression-free survival; SMN, Secondary Malignant Neoplasms; QoL, quality of life; SIOP, International Society of Pediatric Oncology;
POG, Pediatric Oncology Group; CTCAE, Common Terminology Criteria for Adverse Events.