Table 1.

Multinational collaborative clinical trials in pediatric medulloblastoma, high-grade gliomas and ependymoma, published since 2000.

Year	Trial	Treatment Strategy	Inclusion Criteria	No. Patients	Results
Medulloblastoma
1992– 2000	SIOP PNET III [50]	Randomization Arm 1: RT alone (35 Gy CSI + 20 Gy PF boost) Arm 2: 4 cycles alternating Carbo/VP16 and Cyclo/VP16 followed by RT	Age 3–16 yrs Standard-risk MB	179	5 yr EFS 59.8% vs. 74.2% RT + chemotherapy superior
1996– 2000	COG A9961 [3]	Radiotherapy: 23.4 Gy CSI + 32.4 Gy PF boost + weekly VCR Continuation chemotherapy randomization: Arm 1: CCNU/Cis/VCR Arm 2: Cis/Cyclo/VCR	Age 3–21 yrs Standard-risk MB	421	10 yr EFS 74% vs. 78% None superior
2001– 2006	HIT-SIOP PNET-4 [51]	Radiotherapy randomization Arm 1: HFRT (36 Gy CSI, 24 Gy PF boost, 8 Gy TB boost) Arm 2: STRT (23.4 Gy CSI, 30 Gy PF boost) Continuation chemotherapy 8 cycles Cis/CCNU/VCR	Age 4–<22 years Standard-risk MB	340	5 yr EFS 77% vs. 78 None superior
2004– 2016	COG ACNS0331 [52]	Radiotherapy Children aged 3–7 years randomized: Randomization 1: CSI: Low-dose (LDCSI) 18 Gy vs. Standard dose (SDCSI) 23.4 Gy Randomization 2: Involved field RT boost vs. Standard volume boost Children ≥ 8 yrs receive CSI 23.4 Gy, then randomized: Randomization 3: Involved field RT boost (IFRT) vs. Arm 2: Standard volume boost (PFRT) Continuation chemotherapy 9 cycles (6 × CCNU/Cis/VCR, 3 × Cytoxan/VCR)	Age 3–<21 yrs Standard-risk MB	513	5 yr EFS/OS LDCSI 72.1%/78.1% SDCSI 82.6%/85.9% LDCSI higher event rates and worse survival PFRT 80.8%/85.2% IFRT 82.2%/84.1% None superior
1990– 1996	POG 9031 [49]	Arm 1: 3 cycles Cis/VP16, followed by RT (CSI 35.2–44.0 Gy, PF dose 53.2–54.4 Gy) then 7 cycles VCR/Cyclo continuation chemotherapy Arm 2: RT (CSI 35.2–44.0 Gy, PF dose 53.2–54.4 Gy) followed by 3 cycles Cis/VP16 and 7 cycles VCR/Cyclo continuation chemotherapy	Age 3–18 yrs High-risk MB	224	5 yr EFS/OS: 66%/73.1% vs. 70%/76.1% None superior
1996– 2007	SJMB96 [48]	Radiotherapy Risk Stratified: SR: 23.4 Gy, 36 Gy PF dose and 55.8 Gy TB dose; HR: 36–39.6 Gy and 55.8 Gy TB dose (50.4 Gy dose to metastatic sites) Chemotherapy 4 × Cis/Cyclo/VCR with stem cell rescue	Age 3–20 yrs Standard and High-risk MB	134	5 yr EFS/OS: SR 83%/85% HR 70%/70%
2007– 2017	SJYC07 [38]	Induction chemotherapy LR and IR: MTX/VCR/Cis/Cyclo HR: MTX/VCR/Cis/Cyclo + Vinblastine Consolidation therapy LR: 2 cycles Carbo/Cyclo/VP16 IR ≥ 12 mths old: Focal RT (54 Gy TB dose); IR < 12 months old: 2 × cycles Carbo/Cyclo/VP16 HR < 3 years old: Topo/Cyclo (8 weeks); HR ≥3 years old: could opt for CSI (23.4–39.6 Gy) Continuation chemotherapy All Groups: 6 cycles oral Cyclo/Topo/Erlotinib	Age < 3 yrs newly diagnosed MB OR Age 3–5 yrs -non-metastatic -no high-risk features	81	LR: 1 yr EFS 78.3%, (accrual suspended as EFS below stopping rule). 5 yr EFS/OS: LR 55.3%/85.9% IR: 24.6%/52.8% HR: 16.7%/41%
2013– 2016	ACNS1221 [39]	Induction chemotherapy 3 cycles Cyclo/VCR/MTX/VP16/Carbo Reassessment CR/CCR: No further treatment PRD: Second look surgery + 2 cycles Cyclo/VCR/Carbo/VP16	Age < 4 yrs Localized ND or MBEN	25	2 yr PFS/OS 52%/92% Failed to achieve 2 yr PFS target of 90%; study closed early
2007– 2018	ACNS0332 [53]	Randomization Arm 1: Standard treatment (CSI 36 Gy, PF 55.8 Gy + 6 cycles Cis/Cyclo/VCR maintenance) Arm 2: Standard treatment + RT with Carbo Arm 3: Standard treatment + isotretinoin during maintenance Arm 4: Standard treatment + RT with Carbo + isotretinoin during maintenance	3–21 yrs High-risk MB	261	Survival advantage for Grp 3 MB receiving RT with carboplatin. 5 yr EFS/OS: 73.2%/82.3% vs. 53.7%/63.7% Isotretinoin therapy futile
High-Grade Gliomas
2004– 2005	ACNS0126 [54]	RT (HGG 54 Gy, DIPG 59.4 Gy) + concomitant low-dose TMZ, followed by 10 cycles of higher dose TMZ continuation therapy	Age 3–≤22 yrs	HGG = 107 DIPG = 63	1 yr EFS/OS 14%/40% No improvement vs. historical controls
2005– 2007	ACNS0423 [55]	RT (GTR 54 Gy, STR 59.4 Gy, spinal cord lesions 50.4–54 Gy) + concomitant low-dose TMZ, followed by up to 6 cycles of higher dose TMZ + CCNU continuation	Age 3–≤22 yrs	108	3 yr EFS/OS 22%/19% Improved vs. ACNS0126
2007– 2008	ACNS0222 [56]	RT (54 Gy) with motexafin-gadolinium as a potent radiosensitizer	Age ≤ 21 yrs Unifocal DIPG	60	1 yr EFS/OS 18%/53% No Improvement
2011– 2015	HERBY [57]	Randomization Arm 1: RT (54 Gy) + low-dose TMZ, continuation high-dose TMZ 12 months Arm 2: RT (54 Gy) + low-dose TMZ + Bev, continuation high-dose TMZ + Bev 12 mnths	Age ≥ 3–≤18 yrs Non–brainstem	116	1 yr median EFS 11.8 vs. 8.2 mnths No improvement
2014– 2020	BIOMEDE 1 [58]	Randomization Arm 1: RT + Everolimus Arm 2: RT + Dasatinib Arm 3: RT + Erlotinib	Age 6 mths–25 yrs DIPG	193	Median OS Arms 1, 2, 3 10.9, 9.5 and 9 mnths No improvement
Ependymoma
2003– 2007	ACNS0121 [59]	Stratum 1: Completely resected differentiated, ST ependymoma undergo observation Stratum 2: Incompletely resected ependymoma undergo chemotherapy, second surgery and RT Stratum 3: Near-total or macroscopic GTR undergo conformal RT Stratum 4: Microscopic GTR undergo conformal RT, excluding differentiated, ST lesions	Age 1–21 yrs	356	5 yr EFS/OS Strata 1: 61%/100% Strata 2: 37.2%/70.2% Strata 3: 67%/83.3% Strata 4: 70%/88.3%
2010– 2017	ACNS0831 [60]	PF tumours gross/near total resection: randomization Arm 1: RT alone Arm 2: RT + 4 cycles VCR/Cis/Cyclo/VP16	Age 1–21 yrs	451	3 yr EFS 71% vs. 80% ? chemotherapy superior

RT: radiotherapy; CSI: craniospinal irradiation; PF: posterior fossa; Carbo: carboplatin; VP16: etoposide; Cyclo: cyclophosphamide; MB; medulloblastoma; EFS: event-free survival; VCR; vincristine; CCNU: lomustine; Cis: cisplatin; HFRT: hyper-fractionated radiotherapy; STRT: standard radiotherapy; TB: tumor bed; OS: overall survival; SR: standard risk; HR: high risk; MTX: methotrexate; LR: low risk; IR: intermediate risk; Topo: topotecan; CR: complete response; CCR: continuous complete response; PRD: persistent residual disease; Ifos: ifosfamide; GTR: gross total resection; DIPG: diffuse intrinsic pontine glioma; yrs: years; mnths: months.