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Clinical Trials in High-Risk Medulloblastoma: Comparison
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Please note this is a comparison between Version 2 by Vivi Li and Version 1 by Simon Bailey.

Medulloblastoma patients receive adapted therapies stratified according to their risk-profile. Favourable, standard, and high disease-risk groups are each defined by the status of clinical and pathological risk factors, alongside an evolving repertoire of diagnostic and prognostic biomarkers. Medulloblastoma clinical trials in Europe are coordinated by the International Society for Paediatric Oncology (SIOP-Europe) brain tumour group. Favourable and standard-risk patients are eligible for the SIOP-PNET5-MB clinical trial protocol. In contrast, therapies for high-risk disease worldwide have, to date, encompassed a range of different treatment philosophies, with no clear consensus on approach. Higher radiotherapy doses are typically deployed, delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. 

  • medulloblastoma
  • high-risk medulloblastoma
  • trial
  • CNS
  • brain tumour

1. High-Risk Medulloblastoma: Background, Challenges, and Basis for Clinical Trials

Medulloblastoma is the most common malignant brain tumour in children and young people, with approximately 650 new cases per year in the European Union (EU). These small, round, blue cell tumours of the posterior fossa account for 15–20% of all brain tumours in children. The median age of diagnosis is 7 years, but medulloblastoma occurs at all ages and into adulthood. The following variants of medulloblastoma are recognised in the World Health Organisation (WHO) classification of central nervous system (CNS) tumours (2016 and 2021) [1,2][1][2].
Medulloblastoma, Genetically Defined 
 
  • Medulloblastoma—WNT-activated;
  • Medulloblastom—SHH-activated and TP53-mutant;
  • Medulloblastoma—SHH-activated and TP53-wildtype;
  • Medulloblastoma—non-WNT/non-SHH (encompassing Group 3 and Group 4).
Medulloblastoma, Histologically Defined 
 
  • Classic medulloblastoma;
  • Desmoplastic/nodular medulloblastoma;
  • Medulloblastoma with extensive nodularity;
  • Large-cell/anaplastic medulloblastoma.
Our understanding of these variants and their clinical relevance is evolving and altering our understanding of prognosis and risk, creating a shifting scope of disease stratification [3,4,5][3][4][5]. Around 30% of MB patients are diagnosed as high-risk; currently defined clinically by the presence of one or more of the following high-risk factors: metastatic disease (i.e., M+), large cell/anaplastic (LCA) histology, MYC or MYCN amplification or significant residual disease post-surgery (i.e., R+).
High-risk medulloblastoma is associated with a 5-year, event-free survival (EFS) of about 60% [6,7,8,9,10,11][6][7][8][9][10][11]. Moreover, those patients that are cured have significant long-term toxicities (including neurocognitive and endocrinological toxicities) [12,13,14][12][13][14]. The median intelligence quotient (IQ) following therapy for medulloblastoma is in the order of 80 with significant effects on processing speed. This effect shows a linear relationship with a dose of radiotherapy (RT), memory and concentration, in addition to endocrinological, neurological, ototoxic and nephrotoxic effects, which have a significant effect on the quality of the rest of the patient. In many cases, independent living will not be possible and the ability to hold down a job unlikely. Initial studies indicate the severity of toxicity and late effects may be associated with the treatment received, clinico-biological disease features, and host genetic factors [7,12][7][12].

2. Definition of High-Risk Medulloblastoma: Trial Eligibility and Therapy Considerations

In current practice, high-risk disease is defined by the age of the patient, the presence of metastasis (Chang stages M1–M4; M+) and the amount of residual disease left following surgical resection (>1.5 cm2; R+). Histological, and now biological, factors refine the definition of risk. LCA pathology, tumour TP53 mutation (in sonic hedgehog (SHH) subgroup tumours) and MYC or MYCN amplification are all used as high-risk factors to exclude patients from standard-risk protocols. Furthermore, it is now accepted that wingless-type (WNT) subgroup tumours in patients under the age of 16 have a favourable prognosis [15]. Other favourable and poor prognostic subgroups are emerging, but are not yet clinically established; further studies are now required to consolidate these.

2.1. Metastatic Disease

Approximately 30% of medulloblastoma patients present with metastatic disease [1] and have a poorer prognosis. There is a clear worse outcome for image-defined intracranial disease dissemination (Chang stage M2) or spread to the spine (Chang Stage M3), but microscopic spread to the cerebrospinal fluid (CSF) (Chang stage M1) is independent of the presence of macroscopic metastasis [16,17][16][17]. Chang stages M1-M4 are thus considered high-risk [18]. Multicentre trials showed a significant rate of false staging of patients; described as not having metastasis on local imaging reports but revised on central review; this is reflected in a lower-than-expected survival in patients not undergoing central review [19,20][19][20]. Quality assurance thus mandates central review for all patients in this trial. M4 disease is exceptionally rare and the approach to its management must be individualised.

2.2. Histological Variants

The recognised histological variants of medulloblastoma in the WHO classification of CNS tumours (2016 and 2021) are as described above: classic medulloblastoma, desmoplastic/nodular medulloblastoma, medulloblastoma with extensive nodularity and large cell/anaplastic medulloblastoma [2]. Current treatment strategies use histology as a tool for risk-stratification. LCA medulloblastoma, although briefly classified separately as large-cell and anaplastic medulloblastoma, have now been re-grouped as one entity in the WHO 2016 classification due to the difficulty in differentiating these rare variants, which often show mixed phenotypes [1]. Large-cell medulloblastoma is characterised by predominant monomorphic cells with large, round vesicular nuclei, single prominent nucleoli and variable amounts of eosinophilic cytoplasm [21]. Highly aggressive behaviour has been described in several reports [22,23][22][23]. Severe cytological anaplasia is also recognised to be a negative prognostic factor [24].

2.3. Surgical Resection

The extent of resection is still currently considered as a prognostic variable in medulloblastoma when overt metastatic disease is excluded by initial staging; however, its influence on PFS and OS is not clear. Apart from the CCG-921 trial, undertaken in the pre-magnetic resonance imaging (MRI) era, there are roughly an equal number of studies that identify, or fail to identify, an association between the increased extent of resection and OS. In the biggest randomised trial so far reported for non-metastatic medulloblastoma patients by Packer et al. in 2006, the 15 patients with post-operative residual disease did not have a significantly worse prognosis than the others [20]. In the St Jude medulloblastoma-96 trial the “high” risk group represented by those six patients with only residual disease (non-metastatic) reported having 100% EFS/OS [7]. The presence of residual post-operative disease was prognostic in the SIOP PNET 4 trial [25], but more recent prognostic analyses of 184 medulloblastoma cases treated with HIT (German-speaking countries cooperative group) protocols did not reveal a role of residual disease in a multivariate evaluation [26]. In an analysis of 125 consecutive patients in a single Italian institution, the eight children with only residual disease did not have a statistically different EFS and OS from the patients without residual disease [27]. A recent report from the Paediatric Oncology Group (POG) 9631 protocol, exploring the role of concomitant oral etoposide during craniospinal irradiation, once again did not find residual disease as prognostic factor [28]. Furthermore, it is probable that the prognostic benefit of a total resection is attenuated after accounting for a molecular subgroup affiliation [4].
Considering all of these data, there is a paucity of supportive evidence that intensifying therapy to the craniospinal axis improves local control in the setting of subtotal resection. Presently, the SIOP-E group recommends that a residual tumour without any other high-risk factors should be treated similarly to standard-risk disease.

2.4. Molecular Biomarkers

The discovery of molecular disease subgroups represents the most fundamental recent advance in our biological understanding of medulloblastoma. The current international consensus recognises four subgroups—WNT, SHH, Group 3 and Group 4 [29] and further subtypes within these subgroups were recently described [3,5,30,31][3][5][30][31]. Each subgroup is defined empirically by genome-wide transcriptomic and DNA methylation patterns [5,32][5][32] and characterised by distinct clinico-pathological and molecular features. WNT and SHH are synonymous with WNT (wnt/wingless pathway) and SHH (sonic hedgehog pathway)-activating mutations, respectively [33,34][33][34]. Childhood WNT patients (<16 years at diagnosis) consistently show a favourable prognosis (>90% survival) [7,35,36,37][7][35][36][37]. In addition, significant biological heterogeneity is evident within each non-WNT subgroup, for instance, TP53 mutations associate with a poor outcome in SHH [5,38][5][38]. The loss of p53 function is thought to confer resistance to chemotherapy [39[39][40],40], and effective anti-tumoural treatments have yet to be established for this group, which represents approximately 10 patients in Europe per year. In contrast, Group 3 and Group 4 harbour few mutations but multiple DNA copy number alterations [34]. Importantly, subgrouping and TP53 status are now integral to the World Health Organization (WHO) MB classification and are considered the ‘standard-of-care’ [2]. In addition to WNT- and SHH/TP53-mutated tumours, the presence of MYC or MYCN amplification were consistently identified as independent prognostic factors in trials-based studies [14,35,40][14][35][40]. MYC/MYCN amplification is also significantly associated with metastasis and LCA histology [41]. Schema that incorporate these combined factors significantly outperform risk-stratification using clinical factors alone [4,35][4][35]. The prognostic significance of MYC/MYCN amplification and histology is likely to be relevant only in the context of molecular subgrouping (e.g., MYC amplification in Group 3 tumours; MYCN amplification in SHH but not Group 4 tumours); therefore, clearer risk groups may become apparent as these refined prognostic associations are validated [5,42][5][42].
MYCN amplification was considered a high-risk factor in the original SIOP-PNET5-MB protocol, based on its association with a poor prognosis in studies undertaken across the disease prior to the identification of the four consensus molecular subgroups [35,41][35][41]. Two large retrospective studies have since been undertaken which assessed the prognostic impact of MYCN amplification with reference to these subgroups [5,42][5][42]. In both studies, MYCN amplification was associated with the SHH and Group 4 subgroups and displayed different clinical outcomes in each. In SHH, MYCN amplification was associated with a poor prognosis and commonly co-occurred with other high-risk factors (LCA pathology, TP53 mutation, M+ disease). In contrast, MYCN amplification in Group 4 was not associated with a worse prognosis. These associations have since been validated in investigations of two groups of standard-risk patients (i.e., M− and R− with classic or desmoplastic pathology and no evidence of MYC amplification) from the HIT-SIOP-PNET4 clinical trial cohort and a UK research cohort [4,43][4][43].
Finally, emerging biological risk factors have the clear potential to further understand disease heterogeneity and improve the stratification of risk in medulloblastoma (e.g., novel molecular subgroups and/or whole-chromosome aberration patterns within Group 3/4 tumours [3,5,30,31,32][3][5][30][31][32] M+ in Group 4 tumours [4]). These require urgent evaluation and/or validation in the clinical trials setting, alongside biomarker discovery studies that focus on understanding heterogeneity within the high-risk medulloblastoma clinical group.

2.5. Familial/Germline Disease

Familial disease/germline mutations describe a notable proportion of medulloblastomas (5–10%); predominantly Gorlin (PTCH1/SUFU mutation in SHH patients), Turcot (Adenomatous-polyposis-coli (APC) in WNT patients), Li-Fraumeni (TP53 in SHH patients) and Fanconi’s Anaemia (BRCA2/PALB2, subgroup unknown); they are associated with systemic radio- and chemosensitivity and must also be considered in therapy selection [30].
Although SHH subgroup patients with somatic TP53 mutations are treated on high-risk protocols, chemotherapy-related toxicity and secondary malignancies are of great concern in patients with germline TP53 mutations [44]. Alkylating drugs especially seem to exert a high geno-toxic stress in TP53-deficient backgrounds [45]. In a historic cohort of n = 37 patients with SHH-activated, germline TP53-mutated medulloblastoma treated with surgery, chemotherapy and radiotherapy, 3- and 5-year EFS were 20% and 16%, respectively, and no long-term survivors were detected (Milde, personal communication). No difference in OS and PFS was detected when patients were treated with chemotherapy before RT as compared to RT immediately after surgery, suggesting that chemotherapy before radiotherapy (i.e., a delay of radiotherapy) does not significantly influence the outcome. Thus, there is currently no consensus on the treatment of SHH-activated, germline TP53-mutated medulloblastoma patients, and specific clinical studies are required for this patient group.
Children and young people currently eligible for trials of high-risk medulloblastoma are summarised in Table 1.
Table 1. Children older than 3 years at diagnosis are typically eligible for high-risk medulloblastoma trials based on current evidence. * Presence of at least one of these factors.
Molecular Features Histology Residual

Tumour		 Metastatic

Disease
TP53 mutant (somatic)

and/or MYCN amplified

(SHH subgroup only)		 any any any
any non-WNT subgroup LCA * any M+ *
WNT subgroup

(>16 years)		 LCA * any M+ *
MYC amplified

(any subgroup)		 any any any

3. Treatments for High-Risk Medulloblastoma and Future Potential

Prior to the 1990s, outcomes for high-risk medulloblastoma were poor, with 5-year EFS < 50% [17,46,47,48,49][17][46][47][48][49]. To improve survival, regimens looked to intensify treatment, either by increasing the dose of radiation, and through approaches including the use of high-dose or intensive chemotherapy, stem-cell rescue, or radiosensitisers. Since then, there have been several national or institutional trials that achieved 5-year EFS rates of around 60% (summarised in Table 2) [6,7,8,9,10,11][6][7][8][9][10][11]. The approaches used are dependent on national or institutional trials experience and include (i) high-dose chemotherapy prior to (or occasionally post-) craniospinal RT [6[6][7][8],7,8], (ii) HART (twice daily) [7[7][10][49],10,49], and (iii) conventional craniospinal RT (once daily), most commonly prior to maintenance chemotherapy [9,10][9][10].
Table 2. Summary of clinical trials in high-risk medulloblastoma. R+ = Residual disease > 1.5 cm2; M+ = metastatic disease; M1–3 = Chang metastatic staging.
Study [ref] Number of Patients Cohort Definition Radiotherapy Dose Chemotherapy Comments Toxic Deaths Progression on Treatment Event-Free Survival
SJMB96 [7] 48

(M0 = 6; M1 = 9; M2 = 6; M3 = 27)		 R+ or M1–M3 36–39.6 Gy 4× HD chemotherapy (cisplatin, cyclophosphamide and vincristine) post-radiation Single institute study; no randomization; part of a larger trial; 31/48 had additional pre-radiation topotecan window study.

Quality of survival data published.		 0 1 5-year EFS

70%
HART (UK) [50] 34

(M1 = 9; M2 = 3; M3 = 24)		 M+ 1.24 Gy fractions bd to 39.68 Gy Vincristine with radiation

Maintenance 8× cisplatin, CCNU, vincristine		 Toxicity feasibility study/not powered for survival.

Excluded patients requiring GA.		 1 0 3-year EFS

59%
COG 99,701
][11][50]. The improvement of modern radiotherapy techniques contributed to these clinical results, ensuring a more precise dose coverage of the whole neuraxis, reducing the risk of underdosage, and thus of the risk of relapse [51][53]. The gold standard radiotherapy for high-risk medulloblastoma, as described in the most recent clinical trials, is considered to be the delivery of craniospinal irradiation at a dose of 36–39.6 Gy with a conventional fractionation of 1.8–2 Gy per fraction, plus a boost up to 54 Gy to the primary site.
High-dose-intensity regimens, containing chemotherapy as well as radiotherapy, may result in an increase in significant long-term toxicities, particularly neurological and neurocognitive toxicities, as compared to less intensive regimens adopted for standard-risk medulloblastoma. However, in the most recent published series showing an increase in EFS, the impact of new, intensive treatment strategies, in particular high-dose cranio-spinal irradiation, on long term side-effects, including quality of life, was not assessed in detail.
Altered fractionation schedules of irradiation represent a possible approach to limit or reduce the impact of high-dose radiotherapy on the developing nervous tissue without compromising medulloblastoma control. The hyperfractionated-accelerated radiotherapy regimen (HART), as investigated by the Milan group [8], seems to be the most effective non-conventional schedule tested in the HRMB clinical setting. HART offers potential radiobiological advantages and was shown to be feasible in a UK study [50]. Hyperfractionation exploits the differences in repair capacity between normal and tumour cells and acceleration (larger doses per fraction, reduced length of treatment, hence increased treatment intensity); it has the potential to reduce tumour cell repopulation [52][54].
The Milan group showed that, in a prospective series of 33 children with metastatic medulloblastoma, HART, combined with sequential high-dose chemotherapy and consolidation myeloablative chemotherapy in selected cases, improved event-free survival (70% ± 8% standard error (SE) at 5 years) as compared with most historical series. In this single institution series, toxicity was acceptable considering the improved outcome, and it was detailed in two papers [53,55][51][55]. The HART regimen adopted, based on the linear quadratic model [56], was originally defined in the attempt to improve the therapeutic results without exacerbating the late sequelae of the conventional treatment, delivering 1.8 Gy daily fractions up to 36 Gy to the neuraxis and 54 Gy to the posterior fossa. Table 3 reports the extrapolated response dose for the tumour (ERD T) and for late-responding tissue (ERD L), according to the Dale equation, of the two schedules, HART and conventional fractionation (CF). As shown in Table 3, the HART regimen, increasing the dose intensity of irradiation, implies a potential improvement of radiotherapy efficacy in a tumour (ERD T) of about 5.8 and 4 points for CSI and tumour bed boost, respectively (ERD T column) as compared to conventional fractionation, while the late response of normal tissue is substantially equivalent between the two radiotherapy modalities (ERD L column).
Table 3. Extrapolated response dose for tumour (ERD T) and for late responding tissue (ERD L), according to the Dale equation, comparing HART and conventional fractionation (CF). HART = Hyperfractionated Accelerated Radiation Therapy; CF = Conventionally Fractionated radiotherapy.
RT Volume Schedule Total Dose Dose/Fraction Fractions/Day No. Fractions ERD T ERD L
None reported
5 (pre-radiation)


2 (on maintenance therapy)
CSI HART 39 Gy 1.3 Gy 2 30
[
9] 161

(M0 = 5; M1 = 18; M2 = 10; M3 = 49)		 R+, M+ or supratentorial PNET 36 Gy Carboplatin and vincristine during radiation

Maintenance with 6× cyclophosphamide and vincristine +/− cisplatin		 Phase I/II carboplatin as radiosensitizer; no quality of survival data published. 0
5-year EFS


70%
31.47 55.9
CF 36 Gy 1.8 Gy 1 20 25.68 57.6 4

(all long-term survivors, likely pseudo-progression)		 5-year EFS

M1 = 77%

M2 = 50%

M3 = 67%
Tumour Bed/Brain Metastasis boost HART 20.8 Gy 1.3 Gy 2 16 16.78 29.8 POG 9031 [10] 224

 28.8
Spine metastasis boost HART Institut Gustave Roussy (France)
CF(M1 = 29; M2 = 36; M3 = 34; M4 = 9) T3b/T4, M+ or R+ 35.2–40.0 Gy 18 Gy 1.8 GyRandomised 3x cisplatin and etoposide before or after radiation; Maintenance with 7× cyclophosphamide and vincristine 72 were Chang Stage T3b/T4, M0, R-; no quality of survival data published. None reported 12 in the CT 1st arm 5-year EFS

66% CT 1st

70% RT 1st
1 10 12.84 Milan [8,53][8][51] 33

(M1 = 9; M2 = 6;

M3 = 17; M4 = 1)		 M+ 7.8 GyHART

31.2–39 Gy		 1.3 Gy10 weeks chemotherapy pre-radiation (methotrexate, vincristine, etoposide, cyclophosphamide, carboplatin);

post-radiation 2× HD chemotherapy (Thiotepa]) or maintenance with 12 months CCNU and vincristine		 Limited centre study; Subsequent neuro toxicity reported. Quality of life data reported. 2 6 6.29 11.2

[6]		 24

(M0 = 5; M1 = 0;

M2 = 4; M3 = 15)		 R+, M+, MYCN amplification or supratentorial PNET 18 Gy (1)

25 Gy (2)

36 Gy (19)

40 Gy (1)

54 Gy focal [1 sPNET]		 2× carboplatin and etoposide pre-radiation;

2× HD chemotherapy (Thiotepa); Maintenance with temozolomide		 Single institute study; neurocognitive data reported. 0 0 5-year EFS

65%

CF72% in M+
9 Gy 1.8 Gy 1 5 6.42 14.4 HIT 2000

(Germany) [11]		 123

(M1 = 36; M2/M3 = 87)		 M+ HFRT 40 Gy 2× cycles of pre-radiation chemotherapy (cyclophosphamide, vincristine, methotrexate, carboplatin, etoposide and intraventricular methotrexate); maintenance with 4 cycles cisplatin, CCNU, vincristine Well-tolerated. 0 14 (pre-radiation)

1 (after radiation)

31 (during maintenance or at end of treatment)		 5-year EFS

62%
PNET HR+5

(France) [54][52]		 51

(M0 = 14; M1 = 3; M2/3 = 34)		 R+, M+, MYC/N amplification, LCA histology 36 Gy CSI

Unless Residual disease alone post surgery with no other high risk features then 23.4 Gy CSI		 2× carboplatin/etoposide; 2× thiotepa HD; 6× temozolomide maintenance French national study.     5-year EFS

76%

5-year OS 76%
Recent improvements in outcomes for patients with high-risk medulloblastoma are related to the systematic use of intensive chemotherapy regimens, including stem-cell rescue and the delivery of increasing doses of irradiation [6,7,8,9,10,11,50][6][7][8][9][10

4. Evolution of Medulloblastoma Clinical Trials by the SIOP-Europe Group

4.1. SIOP-E and First Trials

The International Society for Paediatric Oncology (SIOP) was established in 1969 with the intention of promoting clinical trials of novel therapies in a wide range of children’s cancers. The European branch of SIOP (SIOP-E) and its Brain Tumour Committee demonstrated its capacity to deliver clinical trials by running the first two medulloblastoma trials, SIOP-1 and SIOP-2, in the 1970s and 1980s [56,57][56][57].

4.2. UKCCSG-SIOP-PNET3 (1993–2000)

The next SIOP-E medulloblastoma trial demonstrated a significant survival benefit of the addition of chemotherapy to adjuvant radiotherapy, provided tumour samples and patient cohorts for biological studies, and developed integral post-treatment quality-of-life studies as added measures [58,59][58][59]. In contrast to children without macroscopic metastases (M0/M1), pre-irradiation chemotherapy did not show apparent improvements in outcome for patients with macroscopic metastases (M2/3) when compared with earlier multi-institutional series [48].

4.3. HIT-SIOP-PNET4 (2000–2006)

This subsequent study assessed the relative benefits of standard and hyper-fractionated radiotherapy regimes in children with non-metastatic medulloblastoma from 9 European countries, demonstrating equivalent outcomes using these approaches [37]. LCA pathology was the only biological parameter used for stratification at that time, as this risk factor became a non-inclusion criterion through an amendment. HIT-SIOP-PNET4 continued the embedded SIOP-E principles of collecting tissues and survivorship data to support critical research co-studies [11,36,37][11][36][37].

4.4. First Biologically Driven Trials—SIOP-PNET5-MB (2014–2022)

UKCCSG-SIOP-PNET3 and HIT-SIOP-PNET4 permitted the investigation of tumour biology and its clinical impact on homogeneously treated trial cohorts. This establishment of bio-characterisation strategies within SIOP-E trials, complementing careful pathological, imaging and surgical staging systems, provided the critical framework for advances in prognostication, risk-stratification and risk-adapted treatment selection. UKCCSG-SIOP-PNET3 biological studies first identified the WNT subgroup and its favourable prognosis [32,57][32][57] and subsequently developed integrated schemes for the stratification of patients into three risk-groups using combined clinical, pathological and molecular factors: favourable-risk (WNT subgroup), high-risk (non-WNT tumours with M+, R+, LCA pathology or MYC/MYCN amplification) and standard-risk (all remaining patients) [3]. HIT-SIOP-PNET4 subsequently validated and refined risk stratification; limiting the favourable prognosis of WNT patients to those under 16 years at diagnosis and the poor prognosis of MYCN amplification to SHH subgroup patients, alongside the discovery of novel prognostic subgroups (i.e., favourable-risk, non-WNT/non-SHH patients characterised by a whole-chromosome aberration phenotype) for further investigation [36].
These schemes form the basis of patient selection and therapy selection for the current SIOP-E trial for children with favourable-risk and standard-risk medulloblastoma (SIOP-PNET5-MB; NCT 02066220). Favourable-risk patients (SIOP-PNET5-MB-LR) receive reduced-intensity chemo- and radiotherapy that aims to maintain survival rates while limiting therapy-associated late effects; standard-risk patients received the randomised addition of concomitant carboplatin (SIOP-PNET5-MB-SR). High-risk patients, identified through the criteria and the national real-time molecular diagnostics and pathology review systems established for SIOP-PNET5-MB [58], represent eligible candidates for trials of high-risk medulloblastoma; facilitating patient work-up for all trials using common pathways.
SIOP-E medulloblastoma trials, from SIOP-1 through to SIOP-PNET5-MB and SIOP-HR-MB, were all conducted for children older than 3–5 years at diagnosis. For their younger counterparts, specific SIOP-E trials are currently being developed for the first time (YCMB-LR and YCMB-HR).

References

  1. Louis, D.N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.; Kleihues, P.; Ellison, D.W. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary. Acta Neuropathol. 2016, 131, 803–820.
  2. Louis, D.N.; Perry, A.; Wesseling, P.; Brat, D.J.; Cree, I.A.; Figarella-Branger, D.; Hawkins, C.; Ng, H.K.; Pfister, S.M.; Reifenberger, G.; et al. The 2021 WHO Classification of Tumors of the Central Nervous System: A summary. Neuro Oncol. 2021, 23, 1231–1251.
  3. Cavalli, F.M.G.; Remke, M.; Rampasek, L.; Peacock, J.; Shih, D.J.H.; Luu, B.; Garzia, L.; Torchia, J.; Nor, C.; Morrissy, A.S.; et al. Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell 2017, 31, 737–754.e6.
  4. Ramaswamy, V.; Remke, M.; Bouffet, E.; Bailey, S.; Clifford, S.C.; Doz, F.; Kool, M.; Dufour, C.; Vassal, G.; Milde, T.; et al. Risk stratification of childhood medulloblastoma in the molecular era: The current consensus. Acta Neuropathol. 2016, 131, 821–831.
  5. Schwalbe, E.C.; Lindsey, J.C.; Nakjang, S.; Crosier, S.; Smith, A.J.; Hicks, D.; Rafiee, G.; Hill, R.M.; Iliasova, A.; Stone, T.; et al. Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: A cohort study. Lancet Oncol. 2017, 18, 958–971.
  6. Dufour, C.; Kieffer, V.; Varlet, P.; Raquin, M.A.; Dhermain, F.; Puget, S.; Valteau-Couanet, D.; Grill, J. Tandem high-dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high-risk medulloblastoma or supratentorial primitive neuro-ectodermic tumors. Pediatr. Blood Cancer 2014, 61, 1398–1402.
  7. Gajjar, A.; Chintagumpala, M.; Ashley, D.; Kellie, S.; Kun, L.E.; Merchant, T.E.; Woo, S.; Wheeler, G.; Ahern, V.; Krasin, M.J.; et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): Long-term results from a prospective, multicentre trial. Lancet Oncol. 2006, 7, 813–820.
  8. Gandola, L.; Massimino, M.; Cefalo, G.; Solero, C.; Spreafico, F.; Pecori, E.; Riva, D.; Collini, P.; Pignoli, E.; Giangaspero, F.; et al. Hyperfractionated accelerated radiotherapy in the Milan strategy for metastatic medulloblastoma. J. Clin. Oncol. 2009, 27, 566–571.
  9. Jakacki, R.I.; Burger, P.C.; Zhou, T.; Holmes, E.J.; Kocak, M.; Onar, A.; Goldwein, J.; Mehta, M.; Packer, R.J.; Tarbell, N.; et al. Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: A Children’s Oncology Group Phase I/II study. J. Clin. Oncol. 2012, 30, 2648–2653.
  10. Tarbell, N.J.; Friedman, H.; Polkinghorn, W.R.; Yock, T.; Zhou, T.; Chen, Z.; Burger, P.; Barnes, P.; Kun, L. High-risk medulloblastoma: A pediatric oncology group randomized trial of chemotherapy before or after radiation therapy (POG 9031). J. Clin. Oncol. 2013, 31, 2936–2941.
  11. von Bueren, A.O.; Kortmann, R.D.; von Hoff, K.; Friedrich, C.; Mynarek, M.; Müller, K.; Goschzik, T.; Zur Mühlen, A.; Gerber, N.; Warmuth-Metz, M.; et al. Treatment of Children and Adolescents With Metastatic Medulloblastoma and Prognostic Relevance of Clinical and Biologic Parameters. J. Clin. Oncol. 2016, 34, 4151–4160.
  12. Câmara-Costa, H.; Bull, K.S.; Kennedy, C.; Wiener, A.; Calaminus, G.; Resch, A.; Kieffer, V.; Lalande, C.; Poggi, G.; von Hoff, K.; et al. Quality of survival and cognitive performance in children treated for medulloblastoma in the PNET 4 randomized controlled trial. Neurooncol. Pract. 2017, 4, 161–170.
  13. Mulhern, R.K.; Palmer, S.L.; Merchant, T.E.; Wallace, D.; Kocak, M.; Brouwers, P.; Krull, K.; Chintagumpala, M.; Stargatt, R.; Ashley, D.M.; et al. Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J. Clin. Oncol. 2005, 23, 5511–5519.
  14. Schreiber, J.E.; Gurney, J.G.; Palmer, S.L.; Bass, J.K.; Wang, M.; Chen, S.; Zhang, H.; Swain, M.; Chapieski, M.L.; Bonner, M.J.; et al. Examination of risk factors for intellectual and academic outcomes following treatment for pediatric medulloblastoma. Neuro Oncol. 2014, 16, 1129–1136.
  15. Ellison, D.W.; Dalton, J.; Kocak, M.; Nicholson, S.L.; Fraga, C.; Neale, G.; Kenney, A.M.; Brat, D.J.; Perry, A.; Yong, W.H.; et al. Medulloblastoma: Clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol. 2011, 121, 381–396.
  16. Miralbell, R.; Bieri, S.; Huguenin, P.; Feldges, A.; Morin, A.M.; Garcia, E.; Wagner, H.P.; Wacker, P.; von der Weid, N.; Swiss Pediatric Oncology Group. Prognostic value of cerebrospinal fluid cytology in pediatric medulloblastoma. Ann. Oncol. 1999, 10, 239–241.
  17. Zeltzer, P.M.; Boyett, J.M.; Finlay, J.L.; Albright, A.L.; Rorke, L.B.; Milstein, J.M.; Allen, J.C.; Stevens, K.R.; Stanley, P.; Li, H.; et al. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: Conclusions from the Children’s Cancer Group 921 randomized phase III study. J. Clin. Oncol. 1999, 17, 832–845.
  18. Fouladi, M.; Gajjar, A.; Boyett, J.M.; Walter, A.W.; Thompson, S.J.; Merchant, T.E.; Jenkins, J.J.; Langston, J.W.; Liu, A.; Kun, L.E.; et al. Comparison of CSF cytology and spinal magnetic resonance imaging in the detection of leptomeningeal disease in pediatric medulloblastoma or primitive neuroectodermal tumor. J. Clin. Oncol. 1999, 17, 3234–3237.
  19. Oyharcabal-Bourden, V.; Kalifa, C.; Gentet, J.C.; Frappaz, D.; Edan, C.; Chastagner, P.; Sariban, E.; Pagnier, A.; Babin, A.; Pichon, F.; et al. Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: A French Society of Pediatric Oncology Study. J. Clin. Oncol. 2005, 23, 4726–4734.
  20. Packer, R.J.; Gajjar, A.; Vezina, G.; Rorke-Adams, L.; Burger, P.C.; Robertson, P.L.; Bayer, L.; LaFond, D.; Donahue, B.R.; Marymont, M.H.; et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J. Clin. Oncol. 2006, 24, 4202–4208.
  21. Giangaspero, F.; Rigobello, L.; Badiali, M.; Loda, M.; Andreini, L.; Basso, G.; Zorzi, F.; Montaldi, A. Large-cell medulloblastomas. A distinct variant with highly aggressive behavior. Am. J. Surg. Pathol. 1992, 16, 687–693.
  22. Brown, H.G.; Kepner, J.L.; Perlman, E.J.; Friedman, H.S.; Strother, D.R.; Duffner, P.K.; Kun, L.E.; Goldthwaite, P.T.; Burger, P.C. “Large cell/anaplastic” medulloblastomas: A Pediatric Oncology Group Study. J. Neuropathol. Exp. Neurol. 2000, 59, 857–865.
  23. McManamy, C.S.; Lamont, J.M.; Taylor, R.E.; Cole, M.; Pearson, A.D.; Clifford, S.C.; Ellison, D.W. Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J. Neuropathol. Exp. Neurol. 2003, 62, 627–632.
  24. Eberhart, C.G.; Kepner, J.L.; Goldthwaite, P.T.; Kun, L.E.; Duffner, P.K.; Friedman, H.S.; Strother, D.R.; Burger, P.C. Histopathologic grading of medulloblastomas: A Pediatric Oncology Group study. Cancer 2002, 94, 552–560.
  25. Lannering, B.; Rutkowski, S.; Doz, F.; Pizer, B.; Gustafsson, G.; Navajas, A.; Massimino, M.; Reddingius, R.; Benesch, M.; Carrie, C.; et al. Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: Results from the randomized multicenter HIT-SIOP PNET 4 trial. J. Clin. Oncol. 2012, 30, 3187–3193.
  26. Pietsch, T.; Schmidt, R.; Remke, M.; Korshunov, A.; Hovestadt, V.; Jones, D.T.; Felsberg, J.; Kaulich, K.; Goschzik, T.; Kool, M.; et al. Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort. Acta Neuropathol. 2014, 128, 137–149.
  27. Massimino, M.; Antonelli, M.; Gandola, L.; Miceli, R.; Pollo, B.; Biassoni, V.; Schiavello, E.; Buttarelli, F.R.; Spreafico, F.; Collini, P.; et al. Histological variants of medulloblastoma are the most powerful clinical prognostic indicators. Pediatr. Blood Cancer 2013, 60, 210–216.
  28. Esbenshade, A.J.; Kocak, M.; Hershon, L.; Rousseau, P.; Decarie, J.C.; Shaw, S.; Burger, P.; Friedman, H.S.; Gajjar, A.; Moghrabi, A. A Phase II feasibility study of oral etoposide given concurrently with radiotherapy followed by dose intensive adjuvant chemotherapy for children with newly diagnosed high-risk medulloblastoma (protocol POG 9631): A report from the Children’s Oncology Group. Pediatr. Blood Cancer 2017, 64, e26373.
  29. Taylor, M.D.; Northcott, P.A.; Korshunov, A.; Remke, M.; Cho, Y.J.; Clifford, S.C.; Eberhart, C.G.; Parsons, D.W.; Rutkowski, S.; Gajjar, A.; et al. Molecular subgroups of medulloblastoma: The current consensus. Acta Neuropathol. 2012, 123, 465–472.
  30. Northcott, P.A.; Robinson, G.W.; Kratz, C.P.; Mabbott, D.J.; Pomeroy, S.L.; Clifford, S.C.; Rutkowski, S.; Ellison, D.W.; Malkin, D.; Taylor, M.D.; et al. Medulloblastoma. Nat. Rev. Dis. Primers 2019, 5, 11.
  31. Sharma, T.; Schwalbe, E.C.; Williamson, D.; Sill, M.; Hovestadt, V.; Mynarek, M.; Rutkowski, S.; Robinson, G.W.; Gajjar, A.; Cavalli, F.; et al. Second-generation molecular subgrouping of medulloblastoma: An international meta-analysis of Group 3 and Group 4 subtypes. Acta Neuropathol. 2019, 138, 309–326.
  32. Schwalbe, E.C.; Hayden, J.T.; Rogers, H.A.; Miller, S.; Lindsey, J.C.; Hill, R.M.; Nicholson, S.L.; Kilday, J.P.; Adamowicz-Brice, M.; Storer, L.; et al. Histologically defined central nervous system primitive neuro-ectodermal tumours (CNS-PNETs) display heterogeneous DNA methylation profiles and show relationships to other paediatric brain tumour types. Acta Neuropathol. 2013, 126, 943–946.
  33. Kool, M.; Jones, D.T.; Jäger, N.; Northcott, P.A.; Pugh, T.J.; Hovestadt, V.; Piro, R.M.; Esparza, L.A.; Markant, S.L.; Remke, M.; et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 2014, 25, 393–405.
  34. Northcott, P.A.; Jones, D.T.; Kool, M.; Robinson, G.W.; Gilbertson, R.J.; Cho, Y.J.; Pomeroy, S.L.; Korshunov, A.; Lichter, P.; Taylor, M.D.; et al. Medulloblastomics: The end of the beginning. Nat. Rev. Cancer 2012, 12, 818–834.
  35. Ellison, D.W.; Kocak, M.; Dalton, J.; Megahed, H.; Lusher, M.E.; Ryan, S.L.; Zhao, W.; Nicholson, S.L.; Taylor, R.E.; Bailey, S.; et al. Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J. Clin. Oncol. 2011, 29, 1400–1407.
  36. Clifford, S.C.; Lannering, B.; Schwalbe, E.C.; Hicks, D.; O’Toole, K.; Nicholson, S.L.; Goschzik, T.; Zur Mühlen, A.; Figarella-Branger, D.; Doz, F.; et al. Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial. Oncotarget 2015, 6, 38827–38839.
  37. Ellison, D.W.; Onilude, O.E.; Lindsey, J.C.; Lusher, M.E.; Weston, C.L.; Taylor, R.E.; Pearson, A.D.; Clifford, S.C. β-Catenin status predicts a favorable outcome in childhood medulloblastoma: The United Kingdom Children’s Cancer Study Group Brain Tumour Committee. J. Clin. Oncol. 2005, 23, 7951–7957.
  38. Zhukova, N.; Ramaswamy, V.; Remke, M.; Pfaff, E.; Shih, D.J.; Martin, D.C.; Castelo-Branco, P.; Baskin, B.; Ray, P.N.; Bouffet, E.; et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J. Clin. Oncol. 2013, 31, 2927–2935.
  39. Royds, J.A.; Iacopetta, B. p53 and disease: When the guardian angel fails. Cell Death Differ. 2006, 13, 1017–1026.
  40. Hientz, K.; Mohr, A.; Bhakta-Guha, D.; Efferth, T. The role of p53 in cancer drug resistance and targeted chemotherapy. Oncotarget 2017, 8, 8921–8946.
  41. Ryan, S.L.; Schwalbe, E.C.; Cole, M.; Lu, Y.; Lusher, M.E.; Megahed, H.; O’Toole, K.; Nicholson, S.L.; Bognar, L.; Garami, M.; et al. MYC family amplification and clinical risk-factors interact to predict an extremely poor prognosis in childhood medulloblastoma. Acta Neuropathol. 2012, 123, 501–513.
  42. Shih, D.J.; Northcott, P.A.; Remke, M.; Korshunov, A.; Ramaswamy, V.; Kool, M.; Luu, B.; Yao, Y.; Wang, X.; Dubuc, A.M.; et al. Cytogenetic prognostication within medulloblastoma subgroups. J. Clin. Oncol. 2014, 32, 886–896.
  43. Goschzik, T.; Schwalbe, E.C.; Hicks, D.; Smith, A.; Zur Muehlen, A.; Figarella-Branger, D.; Doz, F.; Rutkowski, S.; Lannering, B.; Pietsch, T.; et al. Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: A retrospective, molecular analysis of the HIT-SIOP PNET 4 trial. Lancet Oncol. 2018, 19, 1602–1616.
  44. Bougeard, G.; Renaux-Petel, M.; Flaman, J.M.; Charbonnier, C.; Fermey, P.; Belotti, M.; Gauthier-Villars, M.; Stoppa-Lyonnet, D.; Consolino, E.; Brugières, L.; et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J. Clin. Oncol. 2015, 33, 2345–2352.
  45. Zerdoumi, Y.; Kasper, E.; Soubigou, F.; Adriouch, S.; Bougeard, G.; Frebourg, T.; Flaman, J.M. A new genotoxicity assay based on p53 target gene induction. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 2015, 789–790, 28–35.
  46. Hoff, K.V.; Hinkes, B.; Gerber, N.U.; Deinlein, F.; Mittler, U.; Urban, C.; Benesch, M.; Warmuth-Metz, M.; Soerensen, N.; Zwiener, I.; et al. Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomised multicentre trial HIT’91. Eur. J. Cancer 2009, 45, 1209–1217.
  47. Kortmann, R.D.; Kühl, J.; Timmermann, B.; Mittler, U.; Urban, C.; Budach, V.; Richter, E.; Willich, N.; Flentje, M.; Berthold, F.; et al. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: Results of the German prospective randomized trial HIT ‘91. Int. J. Radiat. Oncol. Biol. Phys. 2000, 46, 269–279.
  48. Packer, R.J.; Sutton, L.N.; Elterman, R.; Lange, B.; Goldwein, J.; Nicholson, H.S.; Mulne, L.; Boyett, J.; D’Angio, G.; Wechsler-Jentzsch, K. Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J. Neurosurg. 1994, 81, 690–698.
  49. Taylor, R.E.; Bailey, C.C.; Robinson, K.J.; Weston, C.L.; Walker, D.A.; Ellison, D.; Ironside, J.; Pizer, B.L.; Lashford, L.S. Outcome for patients with metastatic (M2-3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. Eur. J. Cancer 2005, 41, 727–734.
  50. Taylor, R.E.; Howman, A.J.; Wheatley, K.; Brogden, E.E.; Large, B.; Gibson, M.J.; Robson, K.; Mitra, D.; Saran, F.; Michalski, A.; et al. Hyperfractionated Accelerated Radiotherapy (HART) with maintenance chemotherapy for metastatic (M1-3) Medulloblastoma--a safety/feasibility study. Radiother. Oncol. 2014, 111, 41–46.
  51. Veneroni, L.; Boschetti, L.; Barretta, F.; Clerici, C.A.; Simonetti, F.; Schiavello, E.; Biassoni, V.; Spreafico, F.; Gandola, L.; Pecori, E.; et al. Quality of life in long-term survivors treated for metastatic medulloblastoma with a hyperfractionated accelerated radiotherapy (HART) strategy. Childs Nerv. Syst. 2017, 33, 1969–1976.
  52. Dufour, C.; Foulon, S.; Geoffray, A.; Masliah-Planchon, J.; Figarella-Branger, D.; Bernier-Chastagner, V.; Padovani, L.; Guerrini-Rousseau, L.; Faure-Conter, C.; Icher, C.; et al. Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR+5. Neuro Oncol. 2021, 23, 1163–1172.
  53. Carrie, C.; Grill, J.; Figarella-Branger, D.; Bernier, V.; Padovani, L.; Habrand, J.L.; Benhassel, M.; Mege, M.; Mahé, M.; Quetin, P.; et al. Online quality control, hyperfractionated radiotherapy alone and reduced boost volume for standard risk medulloblastoma: Long-term results of MSFOP 98. J. Clin. Oncol. 2009, 27, 1879–1883.
  54. Wheldon, T.E.; O’Donoghue, J.A.; Barrett, A. Kinetic considerations in the choice of treatment schedules for neuraxis radiotherapy. Br. J. Radiol. 1993, 66, 61–66.
  55. Spreafico, F.; Gandola, L.; Marchianò, A.; Simonetti, F.; Poggi, G.; Adduci, A.; Clerici, C.A.; Luksch, R.; Biassoni, V.; Meazza, C.; et al. Brain magnetic resonance imaging after high-dose chemotherapy and radiotherapy for childhood brain tumors. Int. J. Radiat. Oncol. Biol. Phys. 2008, 70, 1011–1019.
  56. Dale, R.G. Time-dependent tumour repopulation factors in linear-quadratic equations--implications for treatment strategies. Radiother. Oncol. 1989, 15, 371–381.
  57. Clifford, S.C.; Lusher, M.E.; Lindsey, J.C.; Langdon, J.A.; Gilbertson, R.J.; Straughton, D.; Ellison, D.W. Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis. Cell Cycle 2006, 5, 2666–2670.
  58. Crosier, S.; Hicks, D.; Schwalbe, E.C.; Williamson, D.; Leigh Nicholson, S.; Smith, A.; Lindsey, J.C.; Michalski, A.; Pizer, B.; Bailey, S.; et al. Advanced molecular pathology for rare tumours: A national feasibility study and model for centralised medulloblastoma diagnostics. Neuropathol. Appl. Neurobiol. 2021, 47, 736–747.
  59. Chang, C.H.; Housepian, E.M.; Herbert, C. An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 1969, 93, 1351–1359.
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