Childhood Malignant Brain Tumors: Balancing the Bench and Bedside
Abstract
:Simple Summary
Abstract
1. Introduction
2. Medulloblastoma
2.1. Background
2.2. Histopathology
2.3. Molecular Classification
2.3.1. WNT Activated (WNT)
2.3.2. Sonic Hedgehog-Activated-Activated (SHH)
2.3.3. Group 3
2.3.4. Group 4
2.4. Prognostic Factors
2.5. Current Management/Clinical Trials
2.6. Novel Therapies
3. High-Grade Gliomas
3.1. Background
3.2. Histopathology
3.3. Molecular Classification
3.4. Prognostic Factors
3.5. Current Management/Clinical Trials
3.6. Novel Therapies
4. Ependymoma
4.1. Background
4.2. Histopathology
4.3. Molecular Classification
4.4. Prognostic Factors
4.5. Current Management/Clinical Trials
4.6. Novel Therapies
5. Conclusions
5.1. Clinical Trials and Therapeutic Protocols
5.2. Conventional and Novel Therapies
5.3. Future Challenges
Author Contributions
Funding
Conflicts of Interest
References
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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 |
Tumor Group | Future Clinical Challenge |
---|---|
ALL |
|
Medulloblastoma | |
WNT |
|
SHH |
|
Group 3 |
|
Group 4 |
|
High-grade gliomas |
|
Ependymoma | |
PF-A |
|
PF-B |
|
ST-ZFTA |
|
ST-YAP1 |
|
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Thorbinson, C.; Kilday, J.-P. Childhood Malignant Brain Tumors: Balancing the Bench and Bedside. Cancers 2021, 13, 6099. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13236099
Thorbinson C, Kilday J-P. Childhood Malignant Brain Tumors: Balancing the Bench and Bedside. Cancers. 2021; 13(23):6099. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13236099
Chicago/Turabian StyleThorbinson, Colin, and John-Paul Kilday. 2021. "Childhood Malignant Brain Tumors: Balancing the Bench and Bedside" Cancers 13, no. 23: 6099. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13236099