diagnostics

Review
Evolution of Systemic Therapy in Medulloblastoma Including
Irradiation-Sparing Approaches
Naureen Mushtaq 1 , Rahat Ul Ain 2 , Syed Ahmer Hamid 3 and Eric Bouffet 4, *

1 Division of Pediatric Oncology, Department of Oncology, Aga Khan University, Karachi 74800, Pakistan;
naureen.mushtaq@aku.edu
2 Department of Pediatric Hematology/Oncology & Bone Marrow Transplant, University of Child Health
Sciences, Children’s Hospital, Lahore 54600, Pakistan; dr.rkashif@yahoo.com
3 Department of Pediatric Hematology and Oncology, Indus Hospital & Health Network,
Karachi 74800, Pakistan; sahmerhamid@gmail.com
4 Global Neuro-Oncology Program, Department of Global Pediatric Medicine, St. Jude Children’s Research
Hospital, St. Jude Global, Memphis, TN 38105, USA
* Correspondence: er.bouffet@gmail.com

Abstract: The management of medulloblastoma in children has dramatically changed over the past
four decades, with the development of chemotherapy protocols aiming at improving survival and
reducing long-term toxicities of high-dose craniospinal radiotherapy. While the staging and treatment
of medulloblastoma were until recently based on the modified Chang’s system, recent advances in
the molecular biology of medulloblastoma have revolutionized approaches in the management of
this increasingly complex disease. The evolution of systemic therapies is described in this review.

Keywords: medulloblastoma; subgrouping; chemotherapy; high-dose chemotherapy

1. Introduction
Described for the first time nearly 100 years ago, medulloblastoma is the most common
Citation: Mushtaq, N.; Ul Ain, R.; malignant brain tumor in the pediatric population. In their seminal report in 1925, Percival
Hamid, S.A.; Bouffet, E. Evolution of Bailey and Harvey Cushing described 29 medulloblastoma patients with only 4 radical
Systemic Therapy in
resections (14%) and 2 survivors (7%) at the time of the publication [1]. The management
Medulloblastoma Including
of medulloblastoma has largely evolved over the past century and has been transformed
Irradiation-Sparing Approaches.
with the introduction of craniospinal irradiation in the 1950s and chemotherapy in the
Diagnostics 2023, 13, 3680. https://
1970s. Currently, 5-year survival rates for patients with average-risk medulloblastoma in
doi.org/10.3390/diagnostics13243680
high-income countries are above 80%, while they range between 60 and 70% for patients
Academic Editors: Dario Marchetti with high-risk disease [2].
and Sang Kun Lee Over the past decade, advancements in molecular classification have provided new
insights into the landscape of this complex disease. The discovery of four different sub-
Received: 20 September 2023
Revised: 11 December 2023
groups (Sonic Hedgehog, WNT, subgroup 3, and subgroup 4) has been a critical milestone,
Accepted: 13 December 2023
opening the prospect of new clinical trials based on the molecular profile [3,4]. However,
Published: 16 December 2023 the implementation of these protocols has been relatively slow, and most patients are still
treated according to the modified Chang classification based on the extent of postoperative
residual tumor and subarachnoid dissemination [5].
Recent protocols in North America and in Europe have contributed to the further re-
Copyright: © 2023 by the authors. finement of medulloblastoma into molecular subtypes, offering the opportunity to identify
Licensee MDPI, Basel, Switzerland. specific groups of patients who may benefit from treatment de-escalation, sparing them
This article is an open access article adverse effects, but also to select patients who may be candidates for more intensive treat-
distributed under the terms and
ments. In this context, protocols for medulloblastoma patients are becoming increasingly
conditions of the Creative Commons
complex and will require national/international collaboration to achieve their objectives.
Attribution (CC BY) license (https://
This review summarizes the current knowledge of systemic therapies for medulloblastoma.
creativecommons.org/licenses/by/
4.0/).

Diagnostics 2023, 13, 3680. https://doi.org/10.3390/diagnostics13243680 https://www.mdpi.com/journal/diagnostics

Diagnostics 2023, 13, 3680 2 of 18

2. The Subgrouping of Medulloblastoma

Medulloblastoma is composed of four distinct molecular and clinical variants: WNT,
Sonic Hedgehog (SHH), group 3, and group 4 (often termed non-WNT, non-SHH). The WHO
2016 classification for CNS tumors additionally divided SHH medulloblastomas according to
their TP53 status due to their different clinicopathological characteristics [6]. Methylation and
“omics” studies have further identified new subgroups and currently, there are two different
WNT subgroups, four different SHH subgroups, and eight subgroups of non-WNT/non-SHH
medulloblastoma [7,8]. While gene expression and methylation profiling are the gold standard
for defining the molecular groups of medulloblastoma, they are not universally accessible. In
the absence of these techniques, immunohistochemistry assays can be used to identify specific
subgroups. GAB1 characterizes only SHH tumors and nuclear immunoreactivity for β-catenin
only WNT tumors. There is currently no reliable immunohistochemistry assay for group 3
and 4 tumors [9]. This new classification of medulloblastoma has recently been integrated
in clinical trials, and the management of this disease is becoming increasingly complex and
technical. Importantly, there is a before and an after. Most clinical trials conducted before the
period 2000–2010 did not include subgrouping, and the comparison of these trials with most
recent ones is therefore challenging.

3. Principles of the Management of Pediatric Medulloblastoma

The first step in the management of medulloblastoma is surgery. The importance of
the resection has been established [10], and the recommendation is to achieve a complete
“safe” resection. The value of this statement has been re-assessed in the context of the
subgrouping of medulloblastoma, suggesting that there is no definitive benefit to gross
total resection (GTR) compared with near-total resection, when the likelihood of neuro-
logical morbidity is high in achieving GTR [11]. Postoperative treatment in the pediatric
population differs according to the age of the patient. Due to the devastating consequences
of craniospinal irradiation in infants and young children, there is a general consensus to use
a radiation-sparing approach in this age group. Postoperative treatment is therefore based
on intensive/high-dose chemotherapy associated in some protocols with intraventricular
injections of chemotherapy via an Ommaya reservoir [12]. In older children, postoperative
treatment consists of a combination of craniospinal irradiation and chemotherapy. The cut-
off between young and older children has traditionally been at the age of 3 [13]. However,
recently, several protocols and cooperative groups have considered different cut-offs, either
at the age of 4 [14], 5 [15], and even 6 [16].

4. Evolution of Systemic Therapies in Medulloblastoma

The first reports on chemotherapy can be found in the early 1960s, when vincristine,
methotrexate (intrathecal and systemic), and nitrosourea were introduced in the manage-
ment of recurrent and newly diagnosed brain tumors, including medulloblastoma [17]. In
the absence of modern imaging, the benefit of these treatments was essentially assessed
clinically [18]. The development of large clinical trials by the SIOP (International Society
of Paediatric Oncology) and the CCG (Children’s Cancer Group) was the first attempt
to systematically evaluate the impact of chemotherapy in medulloblastoma [19,20]. Both
SIOP1 and CCG942 trials had a similar design, comparing craniospinal irradiation (CSI)
with a boost to the posterior fossa and metastatic deposits with or without the addition of
chemotherapy. The SIOP1 protocol used a combination of CCNU and vincristine, whereas
the CCG942 trial used prednisone in addition to CCNU and vincristine. These trials failed
to demonstrate a significant benefit of nitrosourea-based chemotherapy. However, sub-
group analyses identified a benefit of the addition of chemotherapy in patients with bulky
or advanced disease in the CCG trial [19]. These trials also contributed to identify prog-
nostic factors that were eventually used for stratification in subsequent clinical trials. The
introduction of platinum compounds in the management of medulloblastoma has been
associated with a significant increase in survival rates, as illustrated in the SEER Statisti-
cal Report [21]. However, this finding may also be the joint result of improved surgical
Diagnostics 2023, 13, 3680 3 of 18

management, an improvement in radiotherapy techniques, as well as the incorporation

of intensive chemotherapy protocols into clinical practice. Progressively, the manage-
ment of medulloblastoma has witnessed the emergence of two different approaches, one
for older children, with the use of craniospinal irradiation associated with multiagent
chemotherapy, and one for younger children, who are treated with a chemotherapy-only
and radiation-sparing strategy. Over the past decades, several clinical trials have been
conducted in young and older children using different regimens. However, the discovery
of four subgroups of medulloblastomas, with a further refinement in the subgrouping using
molecular and cytogenetic data, has made the interpretation of the results of old protocols
difficult and obsolete. We are currently witnessing an extensive re-assessment of classical
risk criteria in the context of this subgrouping [4,22]. As a result, the concept of high-risk
factors such as residual disease, anaplasia, or even metastatic disease has recently been
challenged [4,11,23].
As far as chemotherapy agents are concerned, protocols for older children in the
upfront setting have shown little change and include a limited number of agents, mostly
cisplatin, cyclophosphamide, vincristine, and lomustine in North America [24,25], whereas
European protocols also use etoposide, carboplatin, ifosfamide, and high-dose methotrex-
ate [26–28]. In younger children, in addition to these drugs, thiotepa is often part of high-
dose chemotherapy regimens [29]. Protocols for young children and in some cooperative
groups for metastatic patients use repeated injections of intraventricular chemotherapy [26].

5. Current Considerations for Older Medulloblastoma Patients

• Average risk medulloblastoma patients (Table 1)

Table 1. Average risk trials.

Dose of Dose Posterior

5-Year PFS
Average Risk MB Population Number Craniospinal/ Fossa or Tumor Chemotherapy Regimen
and/or OS
Fractionation Bed
Protocol
(Reference)
RT followed by maintenance
M0 45 35.2 Gy/1.6 Gy Boost 20 PF Gy/2.0 Gy chemotherapy with lomustine, 5-year PFS 83%
cisplatin, and vincristine (eight cycles).
“Sandwich chemotherapy” with
ifosfamide, etoposide, high-dose MTX,
HIT91 [30,31] cisplatin, and cytarabine (one or two
cycles according to response) before
M0 69 35.2 Gy/1.6 Gy Boost PF 20 Gy/2.0 Gy 5-year PFS 53%
RT followed by maintenance
chemotherapy after RT with lomustine,
cisplatin, and vincristine if incomplete
response.
Pre-radiotherapy chemotherapy with
alternating courses of vincristine;
Boost PF up to carboplatin, etoposide, and 5-year PFS
M0/1 90 35 Gy/1.67 Gy
55 Gy/1.67 Gy vincris-tine, and etoposide and 74.2%
PNET3 [32] cyclophos-phamide (a total of four
cycles).
Boost PF up to 5-year PFS
M0/1 89 35 Gy/1.67 Gy No chemotherapy.
55 Gy/1.67 Gy 59.8%
Six doses of vincristine (1.5 mg/m2 )
during radiotherapy; eight cycles of
Boost PF up to cisplatin (70 mg/m2 ) lomustine 5-year PFS 80%
M0 193 23.4 Gy/1.8 Gy
55.8 Gy/1.8 Gy (75 mg/m2 ) and vincristine 5-year OS 85%
(1.5 mg/m2 day 1, 8 and 15) post
COG9961 [24] radiotherapy.
Six doses of vincristine (1.5 mg/m2 )
during radiotherapy; eight cycles of
Boost PF up to cisplatin (70 mg/m2 ) 5-year PFS 82%
M0 186 39.6 Gy/1.8 Gy
55.8 Gy/1.8 Gy cyclophosphamide (1000 mg/m2 Day 5-year OS 87%
1 and 2) and vincristine (1.5 mg/m2
day 1, 8 and 15) post radiotherapy.
Diagnostics 2023, 13, 3680 4 of 18

Table 1. Cont.

Dose of Dose Posterior

5-Year PFS
Average Risk MB Population Number Craniospinal/ Fossa or Tumor Chemotherapy Regimen
and/or OS
Fractionation Bed
Protocol
(Reference)
Four cycles of post radiotherapy
Boost PF up to chemotherapy with cyclophosphamide
SJMB96 [33] M0 86 23.4 Gy/1.8 Gy 36 Gy/1.8 Gy and TB (4 g/m2 ), cisplatin (75 mg/m2 ), and 5-year PFS 83%
up to 55.8 Gy/1.8 Gy vincristine (1.0 mg/m2 ) with
autologous stem cell rescue.
Boost TB up to
M0 169 23.4 Gy/1.8 Gy Eight doses of vincristine (1.5 mg/m2 ) 5-year PFS 78%
55.8 Gy/1.8 Gy
during radiotherapy; eight cycles of
Boost posterior fossa
cisplatin (70 mg/m2 ) lomustine
PNET4 [34] up to 60 Gy/1.0 Gy
(75 mg/m2 ) and vincristine
M0 169 36 Gy/1.0 Gy (BID) (BID) and up to 5-year PFS 81%
(1.5 mg/m2 on day 1, 8, and 15) post
68 Gy/1.0 Gy (BID)
radiotherapy.
tumor bed

M0 110 23.4 Gy/1.8 Gy Boost PF or TB Six doses of vincristine (1.5 mg/m2 ) 5-year PFS
during radiotherapy; six cycles of (A) 82.9% (23.4 Gy)
M0 116 18 Gy/1.8 Gy Boost PF or TB
cisplatin (70 mg/m2 ), lomustine versus 71.4%
(75 mg/m2 ), and vincristine (18 Gy)
TB boost up to 5-year PFS
ACNS0331 [25] M0 227 18 or 23.4 Gy/1.8 Gy
55.8 Gy/1.8 Gy (1.5 mg/m2 on day 1, 8, and 15), and
three cycles of (B) vincristine 82.5% (TB
PF boost up to (1.5 mg/m2 on day 1 and 8), and boost) versus
Mo 237 18 or 23.4 Gy/1.8 Gy
55.8 Gy/1.8 Gy cyclophosphamide (1000 mg/m2 on 80.5% (PF
day 1 and 2) post radiotherapy, with a boost)
cycle schedule AABAABAAB.
Four cycles of post-radiotherapy
chemotherapy with cyclophosphamide 5-year PFS
Boost to tumor bed up
SJMB03 [23] M0 227 23.4 Gy/1.8 Gy (4 g/m2 ), cisplatin (75 mg/m2 ), and 82.3%
to 55.8 Gy/1.8 Gy
vincristine (1.0 mg/m2 ) with 5-year OS 88%
autologous stem cell rescue.
PFS: progression free survival; OS: overall survival. Gy: Gray; PF posterior fossa; TB: tumor bed; MTX: methotrexate.

Classically, the term average risk medulloblastoma defined a situation where the
patient did not show evidence of metastatic disease and underwent a complete or subtotal
resection, with a size of residual ≤1.5 cm2 . In some cooperative groups, an additional
requirement concerns the absence of anaplasia. However, recent evidence shows that the
prognostic value of anaplasia is group-specific, and the presence of anaplasia does not
affect survival in group 4 patients [23].
For this group of patients, the consensus is to proceed to upfront craniospinal ra-
diotherapy, if possible, within 4 to 5 weeks following surgical resection. Most protocols
include a weekly administration of vincristine during the 6 weeks of radiotherapy, al-
though this practice has been abandoned in the SJMB protocols without clear evidence
of negative impact on survival [23,33]. Post-radiation chemotherapy consists of several
cycles of chemotherapy. Protocol 9961 was a randomized trial comparing eight cycles of
cisplatin, CCNU, and vincristine versus eight cycles of cisplatin, cyclophosphamide, and
vincristine [24]. This trial has been pivotal in demonstrating the feasibility and safety of
reduced-dose craniospinal radiotherapy in a selected group of patients with average-risk
features. While before 2000, most protocols in Europe and North America were considering
a craniospinal dose of 36 Gy for all patients [10,32], regardless of their staging characteris-
tics, protocol 9961 has been the trigger for a new generation of protocols for average-risk
patients treated with doses of craniospinal radiotherapy of 18–23.4 Gy [25,34,35]. In pro-
tocol 9961, there was no significant difference in survival between the two chemotherapy
regimens. However, ototoxicity was identified as a major concern [36], and the subsequent
protocol, ACNS0331, reduced the number of courses of cisplatin-CCNU and vincristine to
six cycles (A), with the addition of three cycles of vincristine and cyclophosphamide (B) in
a AABAABAAB sequence [25]. The ongoing protocol of the Children’s Oncology Group,
ACNS2031 (NCT05382338) (https://clinicaltrials.gov/study/NCT05382338, accessed on 19
September 2023), is using the same schedule, with the introduction of sodium thiosulfate,
with the aim to reduce the risk of ototoxicity.
Diagnostics 2023, 13, 3680 5 of 18

The SJMB group has run three consecutive trials over the last 25 years. SJMB96 and
SJMB03 had a similar design for average-risk patients and consisted of four consecutive
courses of high-dose chemotherapy with stem cell rescue one month apart, administered
after craniospinal irradiation. The cumulative dose of cisplatin was 300 mg/m2 , while
the cumulative dose of cyclophosphamide was 16 g/m2 . This approach showed a 5-year
progression-free survival rate of 83.2% in average-risk patients, while the 5-year progression-
free survival rate of patients treated with standard dose CSI in ACNS0331 was 82.9% [23,37].
However, SJMB was reporting more concerning side effects, including a high risk of
ovarian failure in a high proportion of female patients [38]. SJMB12 (NCT01878617) (https:
//clinicaltrials.gov/study/NCT01878617, accessed on 19 September 2023) has a complex
design, based on tumor subgrouping and risk stratification. In this protocol, patients
with WNT and SHH medulloblastoma receive four cycles of cyclophosphamide, cisplatin,
and vincristine. Post-pubertal patients with SHH medulloblastoma receive a Vismodegib
maintenance. Average-risk patients with non SHH-non WNT medulloblastoma receive
four to seven cycles of chemotherapy. Patients with predefined high-risk features (MYC
or MYCN amplification) receive three cycles of gemcitabine and pemetrexed, in addition
to four cycles of vincristine-cyclophosphamide-cisplatin. The use of the gemcitabine-
pemetrexed combination is based on preclinical data [39]; however, no phase II trial has
demonstrated its activity in newly diagnosed or recurrent medulloblastoma. The final
results of SJMB12 are pending.
Due to the excellent prognosis of patients with WNT medulloblastoma, two pilot
studies have attempted to avoid the use of craniospinal radiotherapy. One protocol used
adjuvant chemotherapy as per the protocol ACNS0331, and recruited six patients [40]. The
first two enrolled patients experienced early local and leptomeningeal relapse and were
salvaged with craniospinal irradiation. In view of these early failures, two patients received
radiotherapy immediately after completing chemotherapy. One patient was removed
from the study to receive intensification with high-dose chemotherapy. A sixth patient
experienced early relapse and succumbed to disease progression despite craniospinal
irradiation. Another clinical trial, conducted at Tata Memorial Hospital (India), evaluated
the efficacy of focal radiotherapy to the tumor bed followed by six cycles of cisplatin,
cyclophosphamide, and vincristine [41]. The trial was closed after 2 years, after three of
the seven enrolled patients experienced disseminated relapse. Both studies suggest that
conventional chemotherapy only is not an alternative to craniospinal irradiation, even
in very good-risk WNT patients. Ongoing studies in Europe and North America are
exploring the possibility to reduce the dose of craniospinal irradiation to 18 or even 15 Gy
in average-risk WNT medulloblastoma patients.
Another interesting observation concerning WNT patients concerns the type of chemother-
apy administered. In a review of 93 molecularly confirmed WNT medulloblastomas, Nobre et al.
identified 15 relapses. Maintenance chemotherapy with high cumulative doses of cyclophos-
phamide was a significant predictor of improved survival, suggesting that in this subgroup, the
type of chemotherapy administered deserves careful consideration [42].
The SHH subgroup accounts for approximately 30% of all medulloblastomas. In SHH
medulloblastoma, there is a constitutive activation of hedgehog signaling, often due to
inactivating mutations of PTCH1. The inhibition of the hedgehog pathway by smoothened
homologue inhibitors such as cyclopamine and HhAntag results in the regression of
medulloblastoma tumors in PTCH1 mutant mice. This led to the development of SHH
inhibitors, in particular vismodegib and sonidegib [43,44]. When the antitumor activity
of these inhibitors in SHH medulloblastoma patients was first reported, there was a great
hope that the introduction of these agents would be the first step of a progressive transition
toward the use of targeted therapies. However, the overall response rate in clinical trials
has been relatively modest [44,45] and the bone toxicity of SHH inhibitors, particularly the
risk of irreversible growth plate fusion, precludes their use in prepubertal children [46].
Attempts are ongoing to develop alternative routes of administration to minimize or avoid
these side effects [47].
Diagnostics 2023, 13, 3680 6 of 18

• High-risk medulloblastoma patients (Table 2)

Table 2. High-risk trials.

Dose of
Dose Posterior
Risk Category Number Craniospinal/ Chemotherapy Regimen 5 Year-PFS
Fossa
Fractionation
Protocol
M1 31 36 Gy/1.8 Gy Boost 18 Gy/1.8 Gy Randomization: two cycles of 57.0%
M2 12 36 Gy/1.8 Gy Boost 18 Gy/1.8 Gy eight drugs in one day before RT
and eight cycles after versus eight
CCG921 [10] cycles or weekly vincristine
M3 37 36 Gy/1.8 Gy Boost 18 Gy/1.8 Gy during XRT and eight cycles of 40.0%
vincristine, lomustine, and
prednisone after XRT.
M1 29 35.5 Gy/1.6 Gy Total dose 54.4 Gy Randomization: three cycles of 64.9%
M2 36 40 Gy/1.6 Gy Total dose 54.4 Gy cisplatin-etoposide before or after 69.2%
POG9031 [48] RT; consolidation: seven cycles of
M3 34 40 Gy/1.6 Gy Total dose 54.4 Gy 61.6%
cyclophosphamide-vincristine.
M1 35.2 Gy/1.6 Gy Boost 20 Gy/2.0 Gy Randomization “sandwich
M2 35.2 Gy/1.6 Gy Boost 20 Gy/2.0 Gy chemotherapy” with ifosfamide,
etoposide, high-dose MTX,
cisplatin, cytarabine (one or two
cycles according to response)
before RT followed by
HIT91 [30] maintenance chemotherapy after
M3 35.2 Gy/1.6 Gy Boost 20 Gy/2.0 Gy RT with lomustine, cisplatin, and 62.5%
vincristine if incomplete response
versus RT followed by
maintenance chemotherapy with
lomustine, cisplatin, and
vincristine (eight cycles).
M1 11 39.6 Gy/1.8 Gy Boost 16.2/1.8 Gy Daily etoposide (day 1–21 and All patients 70.2%
M2 6 39.6 Gy/1.8 Gy Boost 16.2/1.8 Gy 29–49) during radiation. M0 91.7%
Maintenance with three courses of
POG9631 [49] cisplatin-etoposide, followed by
M1 62.7%
M3 18 39.6 Gy/1.8 Gy Boost 16.2/1.8 Gy eight courses of
No data on M2-3
cyclophosphamide and
vincristine.
Boost Vincristine and phase I dose
M1 18 36 Gy/1.8 Gy 77.0%
19.8 Gy/1.8 Gy escalation of carboplatin during
Boost radiation Six cycles of
M2 10 36 Gy/1.8 Gy 50.0%
19.8 Gy/1.8 Gy post-radiotherapy chemotherapy
CCG99701 [50]
with cyclophosphamide and
Boost vincristine (Regimen A) or
M3 49 36 Gy/1.8 Gy 67.0%
19.8 Gy/1.8 Gy cyclophosphamide, vincristine,
and cisplatin (Regimen B).
Boost Four courses of post-radiotherapy
M1 9 36 Gy/1.8 Gy
19.8 Gy/1.8 Gy chemotherapy with high-dose
M2 6 39.6 Gy/1.8 Gy Boost 16.2/1.8 Gy 66.0%
SJMB96 [33] cyclophosphamide, vincristine,
M3 27 39.6 Gy/1.8 Gy Boost 16.2/1.8 Gy and cisplatin with autologous
stem cell transplant.
Boost up to Two courses of eight drugs in one
M1 25 30.6 or 36 Gy/18 Gy 56.0%
54 Gy/1.8 Gy day and two courses of
etoposide-carboplatin before
SFOP [51] radiotherapy; two cycles of eight
30.6 or Boost up to
M2/3 63 drugs in one day (course 1 and 3) 44.2%
36 Gy/1.8 Gy 54 Gy/1.8 Gy
and etoposide-carboplatin (course
2 and 4) after radiotherapy.

Boost 28 Gy/1 Gy Two cycles of

M1 35 40 Gy/1 Gy BID 61.0%
BID cyclophosphamide-vincristine, 2
× HDMTX-vincristine,
carboplatin-etoposide, and
HIT2000 [52] intraventricular MTX before
Boost 28 Gy/1 Gy radiotherapy; four courses of
M2/3 84 40 Gy/1 Gy BID 60.0%
BID maintenance chemotherapy with
lomustine, cisplatin, and
vincristine post radiotherapy.
Diagnostics 2023, 13, 3680 7 of 18

Table 2. Cont.

Dose of
Dose Posterior
Risk Category Number Craniospinal/ Chemotherapy Regimen 5 Year-PFS
Fossa
Fractionation
M1 9 31.2 Gy (if CR and Boost up to 59.7 Four courses of high-dose MTX 78.4%
age <10 years old) ((less than 10 years (course 1), high-dose etoposide
M2 6
or 39 Gy (other old) to (course 2), high-dose
cases)/1.3 Gy BID 60 Gy/1.5 Gy BID cyclophosphamide (course 3), and
carboplatin (course 4) before XRT;
HART Milan [53] if complete remission before RT,
M3 17 maintenance with six courses of 70.0%
lomustine-vincristine; if no
complete response, intensification
with two courses of high-dose
thiotepa.
39.68 Gy/1.24 Gy 22.32 Gy/1.24 Gy
M1 9
BID BID Weekly vincristine during RT;
39.68 Gy/1.24 Gy 22.32 Gy/1.24 Gy maintenance: eight cycles of
HART CCLG [54] M2 3 59% at 3 years
BID BID lomustine, cisplatin, and
39.68 Gy/1.24 Gy 22.32 Gy/1.24 Gy vincristine.
M3 22
BID BID
M0 2 36 Gy/1.8 Gy Boost to TB up to Four cycles of cyclophosphamide
M1 17 36 Gy/1.8 Gy 55.8–59.4 Gy Boost (4 g/m2 ), cisplatin (75 mg/m2 ),
to metastatic sites > 5 years PFS 56.7%
SJMB03 [23] M2 28 39.6 Gy/1.8 Gy and vincristine (1.0 mg/m2 ) with
0.5 cm up to 5 years OS 69.5%
M3 56 39.6 Gy/1.8 Gy autologous stem cell rescue.
50.4–59.4 Gy
M0 72 36 Gy/1.8 Gy Boost up to 55.8 Gy Randomization:
M1 33 36 Gy/1.8 Gy Boost up to 55.8 Gy carboplatin-vincristine versus 5-year PFS 62.9%
M2 41 36 Gy/1.8 Gy Boost up to 55.8 Gy vincristine during radiotherapy. 5-year OS 73.4%
All patients received six courses of For group 3 M+
ACNS0332 [37] post-radiation cyclophosphamide- patients, 5-year PFS
cisplatin-vincristine. A second was 64.3% with
M3 115 36 Gy/1.8 Gy Boost up to 55.8 Gy randomization to isotretinoin carboplatin versus
maintenance was discontinued in 40.3% without
2015 for futility.
Boost up to Two courses of
M0 14 23.4 Gy/1.8 Gy
54 Gy/1.8 Gy etoposide-carboplatin followed by
Boost up to two courses of thiotepa
M1 3 36 Gy/1.8 Gy
54 Gy/1.8 Gy (600 mg/m2 ) with PBSC rescue, 5-year PFS and OS
PNET HR + 5 3 weeks apart. Patients then 76%
Boost up to proceeded to
M2/3 34 36 Gy/1.8 Gy
54 Gy/1.8 Gy radiotherapy—maintenance with
six courses of temozolomide.
PFS: progression free survival; OS: overall survival; Gy: Gray; TB: tumor bed; MTX: methotrexate; XRT: radiother-
apy; CR: complete response; HDMTX: High dose methotrexate.

The evolution of systemic therapies for high-risk patients has been more complex, and
there are still numerous controversies concerning optimal management. North American
protocols essentially use upfront radiotherapy followed by adjuvant chemotherapy [10].
By contrast, most European protocols use pre-radiotherapy chemotherapy [27,28].
In North America, one major focus has been the administration of chemotherapy con-
currently with craniospinal radiotherapy. The phase II study POG 9631 enrolled 47 patients
with high-risk medulloblastoma, including 35 with metastatic disease. The patients received
craniospinal radiotherapy at a dose of 36 Gy with concomitant oral etoposide [49]. The
trial was amended after the inclusion of the first 12 patients, as the daily dose of 50 mg/m2
was associated with a high rate of dysphagia/esophagitis. The dose was therefore reduced
to 35 mg/m2 . The design of the trial was planning a comparison with the response rate
observed in the POG 9031 protocol (radiation therapy followed by adjuvant chemother-
apy) [48]. As the 2- and 5-year progression-free and overall survival rates were not different
between this trial and POG 9031, no further development was planned. Another phase I/II
study evaluated the feasibility of administering carboplatin as a radiosensitizer during CSI
to high-risk medulloblastoma patients. The patients were to receive daily carboplatin at a
dose of 35 mg/m2 , 1 to 4 h before each session of radiotherapy and a weekly administration
of vincristine. The patients initially received 15 doses of carboplatin (3 weeks). The number
of doses of carboplatin was progressively increased to 20, 25, and 30, and the dose of carbo-
platin was increased in increments of 5 mg/m2 /dose up to 50 mg/m2 /dose. Following
CSI, patients received six courses of adjuvant chemotherapy. The maximum recommended
Diagnostics 2023, 13, 3680 8 of 18

phase II dose of carboplatin was 35 mg/m2 for 30 sessions, with myelosuppression the dose
limiting toxicity [50]. Subsequently, a randomized trial compared this chemo-radiation
design with CSI and weekly vincristine followed in both arms by the administration of
six courses of adjuvant cyclophosphamide, cisplatin, and vincristine. The trial included a
second randomization with or without maintenance isotretinoin after the completion of
chemotherapy [37]. Overall, this trial did not show a significant survival benefit associated
with the administration of carboplatin during CSI, with a 5-year overall survival of 77.6%
with carboplatin versus 68.8% for the control arm (p = 0.28). However, subgroup analyses
identified an effect of carboplatin on outcome exclusively in group 3 patients, with a 5-year
event-free survival of 73.2% with carboplatin versus 53.7% without carboplatin (p = 0.047).
For patients with metastatic group 3 medulloblastoma, 5-year PFS was 64.3% with carbo-
platin versus 40.3% without. The randomization to isotretinoin was discontinued following
an interim futility analysis that demonstrated that the addition of isotretinoin was unlikely
to show significant event-free survival differences. The result of this trial is setting a new
standard for group 3 high-risk medulloblastoma patients. However, this requires a timely
and reliable subgrouping of tumor samples prior to the initiation of radiotherapy, which is
currently unrealistic in many centers worldwide.
Three North American initiatives also explored the use of high-dose chemotherapy
given after CSI. Protocol ACNS99702 included one course of chemotherapy prior to CSI to
allow peripheral blood stem cell (PBSC) collection to support subsequent consolidation
therapy [55]. Following CSI, patients received three courses of consolidation with high-dose
chemotherapy and PBSC rescue. Courses 1 and 3 included the administration of high-
dose thiotepa. The study was closed early due to an unacceptable rate of veno-occlusive
disease of the liver. SJMB96 and SJMB03 both used a combination of cisplatin, high-dose
cyclophosphamide, and vincristine with autologous PBSC transplant for four courses after
dose-adapted CSI (23.4 Gy in average-risk patients, 36 Gy in high-risk patients) [23,33].
There was no case of veno-occlusive disease reported and the 5-year event-free survival of
high-risk patients in SJMB03 was 56.7%, with large differences between subgroups (25% for
SHH medulloblastoma patients, 100% for WNT medulloblastoma patients). Although this
experience did not suggest a survival advantage with this approach [56], it allowed a better
identification of high-risk patients such as patients with metastatic disease or subtype III or
medulloblastoma with MYC amplification.
In Europe, a unicentric pilot study from the Milan group reported the results of a pro-
tocol combining HART (hyperfractionated accelerated radiotherapy) with intensive sequen-
tial chemotherapy [53]. Prior to HART, patients received a 7-week course of chemotherapy
combining high-dose methotrexate, vincristine, etoposide, cyclophosphamide, and carbo-
platin. Following HART, patients in complete response received maintenance chemother-
apy with vincristine and CCNU, while incomplete responders received two courses of
high-dose thiotepa with PBCS rescue. The toxicity of this approach was manageable, and
the 3- and 5-year progression-free survival was 80% and 72%, respectively. However, a
UK attempt to reproduce these results in a multicenter setting failed and showed a lower
complete response rate (16/34 patients versus 30/33 patient in the Milan experience) as
well as a lower 3-year event-free survival of 56% [54].
The French group conducted a phase II trial that included two courses of postoperative
induction chemotherapy with etoposide and carboplatin, followed by two courses of high-
dose thiotepa (600 mg/m2 ) with hematological stem cell support [28]. The PBSC collection
was planned after the first or second course of etoposide and carboplatin. Patients with
metastatic medulloblastoma then received a 36 Gy dose of CSI, whereas high-risk non-
metastatic patients (with anaplasia or postoperative residue >1.5 cm2 ) received a lower
dose of CSI (23.4 Gy). The patients then received maintenance chemotherapy with six
courses of oral temozolomide. The trial accrued 51 patients (37 with metastatic disease),
and 33 completed the whole scheduled program. Twenty-five patients achieved a complete
response before radiotherapy, thirteen a partial response, eight had stable disease, and
three had progressive disease (two were not assessed). Twelve patients were unable to
Diagnostics 2023, 13, 3680 9 of 18

receive the maintenance chemotherapy due to persistent thrombocytopenia. At a median

follow-up of 7.1 years, the 3- and 5-year progression-free survival rates were 78% and 76%,
and the 3- and 5-year overall survival rates were 84% and 76%, respectively. All WNT and
group 4 medulloblastoma patients were alive at the time of publication.
The German group reported the result of the multicenter HIT2000 trial for metastatic
medulloblastoma patients. This trial included a pre-radiation induction chemotherapy fol-
lowed by CSI using hyperfractionation and maintenance chemotherapy [27]. The induction
used two cycles of the SKK-HIT protocol, i.e., a combination of intravenous cyclophos-
phamide, vincristine, high-dose methotrexate, carboplatin, and etoposide, and concomitant
intraventricular methotrexate. The maintenance consisted of four courses of cisplatin,
CCNU, and vincristine. In this cohort of 123 eligible patients, the 5-year event-free survival
and overall survival rates were 62% and 74%. Non-responders after one cycle of induction
chemotherapy had a significantly poorer outcome. There was no clear association between
patients with non-responding tumors and MYCC/MYCN status, histologic subtype, or
molecular subtype. Subgrouping was available for 69 patients. The study did not detect an
overall difference among the four subgroups.
Overall, high-risk protocols for older patients have contributed to improve knowl-
edge. In particular, the interpretation of these results in the context of medulloblastoma
subgrouping has shown that not all high-risk/metastatic patients are similar, opening the
prospect of risk-adapted protocols for high-risk patients [57]. The SIOPE group has already
opened a de-escalation trial for metastatic WNT patients who are receiving a reduced dose
of CSI (23.4 Gy) followed by adjuvant chemotherapy [35]. The same group has also opened
a specific stratum for patients with TP53-mutated SHH medulloblastoma, as these patients
have been identified to have a particularly poor prognosis, with a significant proportion
of these tumors occurring in the context of Li–Fraumeni syndrome [58,59]. The patients
receive two cycles of HIT-SKK-like induction, followed by focal radiotherapy when the
disease is localized or CSI in the context of metastatic disease. A “light” maintenance then
consists of the administration of vinblastine for 24 weeks. The SIOP-Europe HR-MB trial
for high-risk patients is currently open and enrolling. The design of this trial is complex,
and the primary objective is to compare the outcome of patients treated according to three
different modalities: daily conventional fractionation of radiotherapy, HART radiotherapy,
and high-dose chemotherapy followed by conventional radiotherapy. The trial will also
evaluate the benefits of two different maintenance chemotherapy regimens. This trial is
programmed to recruit over 800 patients in 16 countries across Europe [52].

6. Radiation-Sparing Approaches in Younger Children (Table 3)

The devastating consequences of craniospinal radiotherapy in infants and young
children have been extensively described, and there is a consensus that this treatment
modality should be avoided, due to its lifelong consequences. Walter et al. described the
neurocognitive outcome of 14 infants and young children successfully treated with adjuvant
or salvage radiotherapy [60]. The median age of these children at the time of radiotherapy
was 3.0 years old. With a follow-up of 4.8 years, the median IQ of these survivors was
62 (range 44–86), with an average annual decline of IQ of −3.9. However, while the
benefit of this radiation sparing approach in terms of neurocognitive outcome has been
demonstrated, the results of treatments in young children with medulloblastoma treated
with postoperative chemotherapy only are inferior to those reported in older children
treated with surgery, craniospinal irradiation, and chemotherapy [12].
Diagnostics 2023, 13, 3680 10 of 18

Table 3. Infant studies.

Radiotherapy/ Outcome
Infant MB Risk Category Number Chemotherapy Regimen 5-Year PFS Others
Fractionation DMB/MBEN
Protocol
Four courses of induction
chemotherapy
(cyclophosphamide, vincristine,
18 to 23.4 Gy (PF)
cisplatin, and etoposide)
and boost up to
COG 9934 [61] M0 74 (39 DMB) followed by focal PF 4-year PFS 58% 4-year PFS 23%
50.4–54 Gy/1.8 Gy
radiotherapy and four cycles of
TB
cyclophosphamide and
vincristine followed by oral
etoposide.
SKK-HIT: three cycles of 7-year PFS 85% 7-year PFS 34%
alternating courses of (1)
cyclophosphamide-vincristine,
43 (20 (2 and 3) high-dose MTX and
SKK91 [26] M0/1/2/3 None vincristine, and (4) 7-year OS 95% 7-year OS 41%
DMB/MBEN)
carboplatin-etoposide. Patients
received intraventricular MTX
during each course.
After 2006, patients
with classic or LCA 5-year PFS 93%
5-year PFS 37%
87 (42 MB in incomplete Three cycles of HIT-SKK with 5-year OS 100%
SKK 2000 [14,62] M0 5-year OS 62%. No
DMB/MBEN) remission received intraventricular MTX. 5-year CSI-free OS
impact of XRT
54 Gy focal 91%
radiotherapy
Five cycles of induction
chemotherapy (three cycles of
cisplatin, vincristine,
cyclophosphamide, etoposide,
83 Focal if local
and high-dose MTX, alternating 5-year PFS and OS 5-year PFS classic
56 residual (55.8 Gy),
with two cycles of 89% MB 26%
Head Start 3 [16] M0/1/2/3 ≤3 years old CSI if residual
cyclophosphamide, etoposide, 5-year 5-year PFS LCA MB
27 dissemination
vincristine, and temozolomide; radiation-free 78% 38%
DMB/MBEN (23.4 Gy)
consolidation with high-dose
carboplatin, thiotepa, and
etoposide, and stem cell
transplant.
≈ 23 (16 SHH) PF radiotherapy to Five cycles of cisplatin,
54 Gy/1.8 Gy vincristine, etoposide,
cyclophosphamide, and MTX
(only for metastatic patients),
5-year PFS SHHδ
followed by focal radiotherapy
Baroni [63] 100% 5-year PFS Group 3
(children > 18 months) with
M+ 4 (1 SHH) 5-year PFS SHHβ 50%
concomitant temozolomide,
56%
then maintenance with
carboplatin, vincristine,
cyclophosphamide, and
etoposide (four 56-day cycles).
Low risk 9 None Four cycles of high-dose MTX,
Intermediate vincristine, cisplatin, and
6 Focal XRT to TB cyclophosphamide. High-risk
risk
patients also received
vinblastine (five 5-year PFS M +
doses/cycle)—consolidation is SHH-II 100%
5-year PFS
risk-specific (low-risk 5-year PFS M0
intermediate-risk
SJYC07 [64] carboplatin-etoposide- SHH-II 72%
24.6%
cyclophosphamide ×2; 5-year PFS M +
5-year PFS high-risk
High risk 27 CSI (optional) intermediate: radiotherapy; SHH-I 25%
16.7%
high-risk: either CSI or IV 5-year PFS M0
topotecan-cyclophosphamide); SHH-II 28%
all risk groups then receive six
cycles of oral maintenance with
cyclophosphamide, topotecan,
and erlotinib.
2-year PFS SHH1
SKK-HIT without 30%
ACNS1221 [65] M0 25 DMB No
intraventricular MTX. 2-year PFS SHH2
66.7%
MB: medulloblastoma; DMB: desmoplastic medulloblastoma; MBEN: medulloblastoma with extensive nodularity;
LCA: large cell/anaplastic medulloblastoma; PFS: progression-free survival; OS: overall survival; Gy: Gray; PF:
posterior fossa; TB: tumor bed; CSI: craniospinal; XRT: radiotherapy; MTX: methotrexate. SHH: Sonic hedgehog;
SKK HIT: Säuglinge und Kleinkinder mit Hirntumoren.
Diagnostics 2023, 13, 3680 11 of 18

Evidence that young children can be successfully treated with surgery followed by
chemotherapy without radiotherapy stems from the so-called Baby POG1 protocol [13]. In
this trial, children less than 3 years of age were treated with a four-drug regimen (courses
of vincristine-cyclophosphamide and etoposide-cisplatin). Medulloblastoma patients were
to receive CSI at the age of 3. However, the parents of 13 children who had no evidence
of residual tumor at the end of the chemotherapy treatment declined treatment with ra-
diation. Eleven patients were disease-free at a median of 1 year following the completion
of chemotherapy. Based on this evidence and with increasing awareness of the devas-
tating effects of CSI in young patients, subsequent protocols in North America and in
Europe avoided radiation as a first-line treatment. However, the results of these trials
were disappointing. In the CCG9921 trial that randomized two regimens of induction
chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide versus vincristine,
carboplatin, ifosfamide, and etoposide), only 20 of 92 infants and young children with
medulloblastoma were alive radiation-free at 5 years [66]. A major breakthrough was the
publication of a study by Rutkowski et al. in 2005, who described 43 infants and young
children treated with an intensive regimen involving three cycles of multiagent chemother-
apy (cyclophosphamide, vincristine, high-dose methotrexate, carboplatin, and etoposide)
and the administration of intraventricular methotrexate [26]. Children who had a complete
resection and no metastatic disease had 5-year progression-free and overall survival rates
of 82 ± 9% and 93 ± 6%. Children with localized disease and incomplete resection and chil-
dren with metastatic disease had a 5-year progression-free and overall survival of 50 ± 13%
and 56 ± 14%, and 33 ± 14% and 38 ± 15%, respectively. Importantly, this trial identified
desmoplastic histology as a major prognostic factor, and the 5-year event-free survival
of 20 patients with desmoplastic histology was 85% versus 34% for patients with classic
histology. The role of histology was subsequently confirmed in a large meta-analysis of
European and North American trials. Interestingly, this meta-analysis showed that national
protocols were independent risk factors for event-free and overall survival, with higher
survival rates in the German and North American (HeadStart) protocols, while the UK
protocol had the lowest survival rates. A subsequent trial of the German group, HIT-SKK
2000, confirmed the high survival rate of patients with desmoplastic medulloblastoma
(DMB) and medulloblastoma with extensive nodularity (MBEN). This protocol also showed
that all DMB/MBEN assessed by DNA methylation profiling belonged to the subgroup of
infantile Sonic Hedgehog (SHH) medulloblastoma [14]. In infants and young children with
non-SHH medulloblastoma, the 5-year progression-free survival was 37% and the CSI-free
survival was 39%. The addition of local radiotherapy in this subgroup of patients did not
improve survival.
As intraventricular chemotherapy was potentially associated with a risk of encephalopa-
thy, and due to the lack of randomized evidence of its benefit, two North American trials
were developed simultaneously. Their objective was to reproduce the results of the HIT-SKK
91 and 2000 protocols without the use of intraventricular chemotherapy. ACNS1221 was a
multicenter COG trial for patients less than 4 years old with non-metastatic DMB/MBEN
medulloblastoma [65]. This trial closed early, due to a high rate of relapses (13 out of 25 pa-
tients), with a 2-year event-free survival rate of 52%. Interestingly, none of the patients with
MBEN and/or less than 12 months of age experienced a relapse. SJYC07 was a risk-adapted
trial for children up to the age of 5, depending on clinical and histological criteria [64]. This
trial also omitted intraventricular methotrexate and similarly showed a high rate of relapses
in DMB/MBEN patients. The outcome of patients without metastatic disease and classic
histology was also disappointing despite the use of focal radiotherapy (24.7% 5-year event-free
survival). By subgroups, patients in group 3 had a 5-year event-free survival of 8.3% versus
13.3% in group 4 and 51.1% in the SHH subgroup.
Another radiation-sparing approach for this vulnerable group of patients has been
the use of high-dose chemotherapy with bone marrow or peripheral stem cell transplant.
HeadStart protocols I, II, and III were pivotal trials that demonstrated the feasibility of high-
dose chemotherapy as a consolidation following an intensive induction regimen [16,29,67].
Diagnostics 2023, 13, 3680 12 of 18

However, the lack of central histology review and more recently the lack of subgrouping
in HeadStart III make the interpretation of these trials challenging. In HeadStart III,
patients were initially treated with five courses of induction. Courses 1, 3, and 5 included
vincristine, cyclophosphamide, cisplatin, etoposide, and high-dose methotrexate, whereas
courses 2 and 4 included cyclophosphamide, vincristine, oral etoposide, and temozolomide.
The consolidation consisted of one course of high, dose chemotherapy with carboplatin,
etoposide, and thiotepa, followed by stem cell rescue. The 5-year radiation-free survival for
patients with DMB/MBEN medulloblastoma was 78% compared to 21% for patients with
other histologies [16].
Over the past 20 years, sequential high-dose chemotherapy has been introduced in
the management of brain tumor in infants. Protocol CCG99703 was a phase I study that
demonstrated the feasibility of three courses of high-dose thiotepa containing chemotherapy
with a maximum dose of thiotepa of 20 mg/kg per course [68]. This trial enrolled 36 infants
and young children with medulloblastoma and reported a 5-year EFS of 60%. However,
the interpretation of these results is flawed as this trial was not designed to investigate the
role of radiotherapy, and data on additional radiotherapy treatments were not collected. A
retrospective review of patients treated off-protocol with the same approach showed a 5-year
progression-free survival (PFS) and overall survival (OS) of 69.6% and 76.1%, respectively [69].
Patients with SHH medulloblastoma had a 5-year PFS of 86% compared to 49% for group
3 patients, and the 5-year radiation free survival for group 3 patients was 46.4%. Such results
are promising for group 3 patients, who account for the largest subgroup of medulloblastoma
in this age group along with the SHH subgroup. The ACNS0334 protocol is comparing
two different three-course induction regimens with and without high-dose methotrexate,
followed by three courses of high-dose chemotherapy with carboplatin and thiotepa, and stem
cell rescue in children <3 years of age with high-risk medulloblastoma (metastatic disease
and/or postoperative residual >1.5 cm2 ). Early reports have suggested a higher response
rate and better event-free and overall survival in the group of patients treated with high-dose
methotrexate [70]. The final results of this trial are awaited.
Overall, current options for infant and young children with medulloblastoma include
a “HIT-SKK” approach for patients with DMB/MBEN histology or SHH subgrouping. The
evidence that SHH includes different subtypes with different behaviors [64,71] has not
translated in the design of clinical trials. The benefit of high-dose chemotherapy in this
category of patients needs to be investigated, and an international randomized study is
planned to compare the HIT/SKK protocol and a high-dose chemotherapy approach with
survival and neurocognitive outcomes as the primary endpoints. For infants and young
children with non-SHH medulloblastoma, the results of radiation-sparing protocols are
still disappointing, with a 5-year EFS ranging between 20 and 35%. The results of protocols
using sequential high-dose chemotherapy are encouraging, and this approach needs to
be studied further [68,69]. This is the objective of the HeadStart IV trial (NCT02875314)
that is comparing one consolidation versus three consolidations in this group of patients.
Finally, the management of infants and young children with metastatic medulloblastoma
is still a major challenge. While metastatic disease does not seem to affect the outcome
of patients with DMB/MBEN histology, the radiation-free survival of metastatic patients
with classic histology is dismal. In a review of 74 patients with non-WNT, non-SHH
metastatic medulloblastoma treated with a radiation-sparing approach including high-dose
chemotherapy, Mynarek reported a 5-year CSI-free survival of 8% [72]. New strategies are
definitely needed for this group of patients.

7. Chemotherapy as a Salvage Treatment

Very few prospective trials have been conducted in the recurrent setting, and there is no
consensus on the optimal management of recurrent medulloblastoma. For young patients
initially treated with a radiation-sparing approach, the use of craniospinal irradiation is
a logical option. The choice of the dose of CSI is still a matter of debate. A recent review
has shown that for patients who received a reduced dose of CSI (<35 Gy), the addition of
Diagnostics 2023, 13, 3680 13 of 18

systemic chemotherapy was associated with improved progression-free survival compared

to CSI alone (55% 3-year survival versus 38%; p = 0.007) [73].
For medulloblastoma patients who relapse after a CSI-containing regimen, studies
conducted in the 1990s have suggested a survival benefit with high-dose chemotherapy
followed by bone marrow or peripheral stem cell transplant [74–76]. As a result, this
approach has become a standard of care that is still used in some institutions. However, the
role of high-dose chemotherapy in this setting has been eventually questioned by coopera-
tive groups or in institutional reviews [77–80]. The recent evidence that medulloblastoma
subgrouping influences survival both at the time of diagnosis and after recurrence suggests
that most long-term survivors of early reports on high-dose chemotherapy were probably
group 4 patients [81].
There is an increasing interest in metronomic, low-dose chemotherapy for patients
with recurrent medulloblastoma. The MEMMAT protocol has provided promising results in
selected patients [82,83]. This protocol combines chemotherapy agents (cyclophosphamide,
etoposide, intraventricular etoposide, and cytarabine), bevacizumab and oral thalidomide,
fenofibrate and celecoxib. In a phase II trial of 40 patients with recurrent medulloblastoma
from several institutions in Europe and North America treated with this approach, Peyrl
et al. reported six complete responses (15.0%), nine partial responses (22.5%), and five stable
diseases (12.5%) The 5-year survival rate of patients who had no evidence of progression at
12 months was 66.7% [84].
A phase II trial from the COG compared the outcome of patients with recurrent medul-
loblastoma treated with temozolomide and irinotecan with or without bevacizumab [85].
This trial showed a significantly longer progression-free survival with the addition of beva-
cizumab (9 versus 6 months). This trial did not analyze outcomes according to subgrouping,
and the specific impact of the addition of bevacizumab in this context remains unknown.

8. Medulloblastoma Management in Countries with Limited Resources

Prospective clinical trials in the LMIC setting are few. Most information relies on retro-
spective studies, limiting a critical evaluation of the role of systemic chemotherapy in this
context. In addition, LMICs face significant challenges such as limited access to appropriate
facilities (imaging, neurosurgical, pathology, and radiotherapy), a lack of universal health
care coverage, a high rate of abandonment, and a high incidence of treatment refusal [86,87].
When it relates to the current WHO classification, gene sequencing and methylation are
unaffordable in most institutions, and the subgrouping—when it is done—most often relies
on immunohistochemical staining. However, some experiences are noteworthy. Gupta
et al. (Tata Memorial Hospital, India) reported the feasibility and efficacy of the addition
of carboplatin during craniospinal irradiation in a series of 97 high-risk medulloblastoma
patients, including 45 metastatic patients, with a 5-year EFS and OS of 60.2% and 62.1%,
respectively [88]. Baroni et al. (Argentina) reported the outcome of 29 young children
treated with a craniospinal irradiation-sparing strategy [63]. The children were treated
with five cycles of induction chemotherapy that consisted of a combination of cisplatin,
etoposide, cyclophosphamide, and vincristine. Patients with metastatic disease or high-risk
features (postoperative residue > 1.5 cm2 ) also received high-dose methotrexate. Patients
older than 18 months received focal radiotherapy to the posterior fossa, with concomitant
daily temozolomide. Patients younger than 18 months received maintenance chemotherapy
until the age of 18 months. Maintenance chemotherapy consisted of four 56-day cycles
of carboplatin, vincristine, cyclophosphamide, and oral etoposide. In this experience, the
5-year PFS was 70.4% and the 5-year OS was 77.8%. These experiences suggest that the
implementation of modern strategies is possible in LMICs. Considering the relative suc-
cess rate of MEMMAT as a salvage treatment [84], the affordably of the drugs, and the
possibility to manage patients in the outpatient setting, MEMMAT would be an interesting
option for patients with medulloblastoma in LMICs in the first-line setting. However,
Ommaya reservoir insertion is not routine in many LMICs. Several additional factors that
Diagnostics 2023, 13, 3680 14 of 18

are beyond the scope of this review impact on the management of medulloblastoma in
LMICs, including late diagnoses, late referrals, and a lack of multidisciplinary care.

9. The Future
While the benefit of chemotherapy in the management of patients with medulloblas-
toma has been questioned for decades, there is now a worldwide consensus that adjuvant
chemotherapy is an important component of medulloblastoma protocols. The introduction
of subgrouping in new protocols opens new perspectives, with treatments based on specific
risk stratifications. There is still an urgent need to explore new therapies, in particular
for high-risk and very high-risk patients. This includes patients with group 3 metastatic
disease, patients with Myc-amplified medulloblastoma, patients with SHH TP53-mutated
medulloblastoma, and infants and young children with non-SHH metastatic medulloblas-
toma. For these patients, intensive and high-dose chemotherapy protocols have failed to
demonstrate a benefit, and there is an urgent need to identify alternatives to a standard
chemoradiation approach.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No new data were created or analyzed in this study. Data sharing is
not applicable to this article.
Conflicts of Interest: The authors declare no conflict of interest.

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