Radiotherapy For Diffuse Brainstemglioma in Children and Young Adults (Review)

Cochrane Database of Systematic Reviews
Radiotherapy for diffuse brainstem glioma in children and

young adults (Review)
Hu X, Fang Y, Hui X, Jv Y, You C
Hu X, Fang Y, Hui X, Jv Y, You C.

Radiotherapy for diffuse brainstem glioma in children and young adults.
Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD010439.
DOI: 10.1002/14651858.CD010439.pub2.
www.cochranelibrary.com
Radiotherapy for diffuse brainstem glioma in children and young adults (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 21
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Analysis 1.1. Comparison 1 Hyperfractionated radiotherapy versus conventional radiotherapy, Outcome 1 Overall
survival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Analysis 1.2. Comparison 1 Hyperfractionated radiotherapy versus conventional radiotherapy, Outcome 2 Event-free
survival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Analysis 1.3. Comparison 1 Hyperfractionated radiotherapy versus conventional radiotherapy, Outcome 3 Radiological
response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Analysis 1.4. Comparison 1 Hyperfractionated radiotherapy versus conventional radiotherapy, Outcome 4 Toxicities. 38
Analysis 2.1. Comparison 2 Hypofractionated radiotherapy versus conventional radiotherapy, Outcome 1 Overall
survival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Analysis 2.2. Comparison 2 Hypofractionated radiotherapy versus conventional radiotherapy, Outcome 2 Progression-free
survival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Analysis 2.3. Comparison 2 Hypofractionated radiotherapy versus conventional radiotherapy, Outcome 3 Toxicities. 42
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 47
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Radiotherapy for diffuse brainstem glioma in children and young adults (Review) i
[Intervention Review]
Radiotherapy for diffuse brainstem glioma in children and

young adults
Xin Hu1 , Yuan Fang1 , Xuhui Hui1 , Yan Jv1 , Chao You1
1 Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
Contact address: Chao You, Department of Neurosurgery, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu,
610041, China. youchao_nswc@163.com. doctoryouchao@163.com.
Editorial group: Cochrane Childhood Cancer Group.

Publication status and date: New, published in Issue 6, 2016.
Review content assessed as up-to-date: 19 August 2015.
Citation: Hu X, Fang Y, Hui X, Jv Y, You C. Radiotherapy for diffuse brainstem glioma in children and young adults. Cochrane
Database of Systematic Reviews 2016, Issue 6. Art. No.: CD010439. DOI: 10.1002/14651858.CD010439.pub2.
ABSTRACT
Background
Diffuse brainstem glioma is a devastating disease with very poor prognosis. The most commonly used radiological treatment is
conventional fractionated radiation. So far, there is no meta-analysis or systematic review available that assesses the benefits or harms
of radiation in people with diffuse brainstem glioma.
Objectives
To assess the effects of conventional fractionated radiotherapy (with or without chemotherapy) versus other therapies (including different
radiotherapy techniques) for newly diagnosed diffuse brainstem gliomas in children and young adults aged 0 to 21 years.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed, and EMBASE to 19 August
2015. We scanned conference proceedings from the International Society for Paediatric Oncology (SIOP), International Symposium
on Paediatric Neuro-Oncology (ISPNO), Society of Neuro-Oncology (SNO), and European Association of Neuro-Oncology (EANO)
from 1 January 2010 to 19 August 2015. We searched trial registers including the International Standard Randomised Controlled Trial
Number (ISRCTN) Register, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and
the register of the National Institutes of Health to 19 August 2015. We imposed no language restrictions.
Selection criteria
All randomised controlled trials (RCTs), quasi-randomised trials (QRCTs), or controlled clinical trials (CCTs) that compared conven-
tional fractionated radiotherapy (with or without chemotherapy) versus other therapies (including different radiotherapy techniques)
for newly diagnosed diffuse brainstem glioma in children and young adults aged 0 to 21 years.
Data collection and analysis
Two review authors independently screened studies for inclusion, extracted data, assessed the risk of bias in each eligible trial, and
conducted GRADE assessment of included studies. We resolved disagreements through discussion. We performed analyses according
to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.
Radiotherapy for diffuse brainstem glioma in children and young adults (Review) 1
Main results
We identified two RCTs that fulfilled our inclusion criteria. The two trials tested different comparisons.
One multi-institutional RCT included 130 participants and compared hyperfractionated radiotherapy (six-week course with twice
a day treatment of 117 cGy per fraction to a total dose of 7020 cGy) with conventional radiotherapy (six-week course with once a
day treatment of 180 cGy per fraction to a total dose of 5400 cGy). The median time overall survival (OS) was 8.5 months in the
conventional group and 8.0 months in the hyperfractionated group. We detected no clear evidence of effect on OS or event-free survival
(EFS) in participants receiving hyperfractionated radiotherapy compared with conventional radiotherapy (OS: hazard ratio (HR) 1.07,
95% confidence interval (CI) 0.75 to 1.53; EFS: HR 1.26, 95% CI 0.83 to 1.90). Radiological response (risk ratio (RR) 0.94, 95% CI
0.54 to 1.63) and various types of toxicities were similar in the two groups. There was no information on other outcomes. According
to the GRADE approach, we judged the quality of evidence to be low (i.e. further research is very likely to have an important impact
on our confidence in the estimate of effect and is likely to change the estimate) for OS and EFS, and very low (i.e. we are very uncertain
about the estimate) for radiological response and toxicities.
The second RCT included 71 participants and compared hypofractionated radiotherapy (39 Gy in 13 fractions over 2.6 weeks, 3 Gy
per fraction) with conventional radiotherapy (54 Gy in 30 fractions over six weeks, 1.8 Gy per fraction). This trial reported a median OS
of 7.8 months for the hypofractionated group and 9.5 months for the conventional group. It reported a progression-free survival (PFS)
of 6.3 months for the hypofractionated group and 7.3 months for the conventional group. We found no clear evidence of effect on
OS (HR 1.03, 95% CI 0.53 to 2.01) or PFS (HR 1.19, 95% CI 0.63 to 2.22) in participants receiving hypofractionated radiotherapy
when compared with participants receiving conventional radiotherapy. The mainly observed adverse effect was local erythema and
dry desquamation especially behind the auricles. There were some other toxicities, but there was no statistically significant difference
between treatment groups. There was no information on other outcomes. We judged the quality of evidence to be moderate (i.e. further
research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) for OS, and low
for PFS and toxicities. It should be mentioned that the sample size in this RCT was small, which could lead to insufficient statistical
power for a clinically relevant outcome.
Authors’ conclusions
We could make no definitive conclusions from this review based on the currently available evidence. Further research is needed to
establish the role of radiotherapy in the management of newly diagnosed diffuse brainstem glioma in children and young adults. Future
RCTs should be conducted with adequate power and all relevant outcomes should be taken into consideration. Moreover, international
multicentre collaboration is encouraged. Considering the potential advantage of hypofractionated radiotherapy to decrease the treatment
burden and increase the quality of remaining life, we suggest that more attention should be paid to hypofractionated radiotherapy.
PLAIN LANGUAGE SUMMARY

Radiotherapy for diffuse brainstem glioma in children and young adults
Review question
To assess the effects of conventional radiotherapy (with or without chemotherapy) versus other therapies (including different radiotherapy
techniques) for newly diagnosed diffuse brainstem gliomas in children and young adults aged 0 to 21 years.
Background
Diffuse brainstem glioma typically occurs in the pons (part of the brainstem) and expands and infiltrates at least 50% of the pons, with
a characteristic appearance on magnetic resonance imaging (MRI). The prognosis is very poor, with a median overall survival (OS;
time from cancer diagnosis, or treatment, to death from any cause) ranges from 8 to 11 months. So far, there is no analysis or review
available that assessed the benefits or harms of radiation for newly diagnosed diffuse brainstem glioma in children and young adults
aged 0 to 21 years.
Study characteristics
Through comprehensive search and screening of medical databases, we found two clinical studies that tested different treatments. One
study, with 130 participants included, compared hyperfractionated radiotherapy (six-week course with treatment twice a day ) with
conventional radiotherapy (six-week course with treatment once a day ). The second study, with 71 participants included, compared
hypofractionated radiotherapy (three-week course with treatment once a day ) with conventional radiotherapy.
Key results
For the comparison of hyperfractionated radiotherapy and conventional radiotherapy, there was no clear evidence of effect on OS,
event-free survival (EFS; time from diagnosis, study entry, or treatment to disease progression, disease relapse, a second tumour, or
death), radiological response (a reduction in tumour size of more than 50%), and toxicities (damage to the body due to radiotherapy).
For the comparison of hypofractionated radiotherapy and conventional radiotherapy, there was no clear evidence of effect on OS,
progression-free survival (PFS; time from diagnosis, study entry, or treatment to disease progression), and side effects.
Quality of the evidence
For the hyperfractionated radiotherapy, when compared with conventional therapy, the quality of evidence was low for OS and EFS,
and very low for radiological response and toxicities.
For the hypofractionated radiotherapy, when compared with conventional therapy, the quality of evidence was moderate for OS, and
low for PFS and toxicities.
Radiotherapy for diffuse brainstem glioma in children and young adults (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Hyperfractionated radiotherapy compared with conventional radiotherapy for diffuse brainstem glioma in children and young adults
Patient or population: children and young adults with dif f use brainstem gliom a
Settings: hospital setting in USA and Canada
Intervention: hyperf ractionated radiotherapy
Comparison: conventional radiotherapy
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
Conventional radio- Hyperfractionated ra-

therapy diotherapy
Overall survival See com m ents See com m ents HR 1.07 (0.75 to 1.53) 130 (1 study) ⊕⊕ Tim e-to-event data; no
low 2,3 assum ed risk could be
calculated
Participants were en-
rolled between June
1992 and M arch 1996.
All participants were
f ollowed until death or
October 1997 except 5
participants who were
lost during f ollow-up
Progression- free sur- See com m ent See com m ent Not estim able - See com m ent No adequate inf orm a-
vival tion on this outcom e
was provided
Event- free survival See com m ent See com m ent HR 1.26 (0.83 to 1.90) 130 (1 study) ⊕⊕ Tim e-to-event data; no
low 2,4 assum ed risk could be
calculated
4
Quality of life See com m ent See com m ent Not estim able - See com m ent No inf orm ation on this
outcom e was provided
Neurological response See com m ent See com m ent Not estim able - See com m ent No adequate inf orm a-
tion on this outcom e
was provided
Radiological response 333 per 1000 1 313 per 1000 RR 0.94 (0.54 to 1.63) 108 ⊕ -
def ined as the num - (180 to 543) (1 study) very low 2,5
ber of participants with
a reduction in tum our
size > 50%
Follow-up: 4 or 8 weeks
(m edian 4 weeks) post
treatm ent
Toxicities See com m ent See com m ent See com m ents 112 or 113 ⊕ Various types of tox-
(1 study) very low 2,5 icities were evaluated
(see text)
No signif icant dif f er-
ences in exam ined tox-
icities between the 2
groups
For f ungal stom atitis,
112 participants were
available while f or the
other toxicities, 113
participants were avail-
able
* The basis f or the assumed risk (e.g. the m edian control group risk across studies) is provided in f ootnotes. The corresponding risk (and its 95% conf idence interval) is
based on the assum ed risk in the com parison group and the relative effect of the intervention (and its 95% CI).
CI: conf idence interval; HR: hazard ratio; RR: risk ratio.
5
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our conf idence in the estim ate of ef f ect.
M oderate quality: Further research is likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and m ay change the estim ate.
Low quality: Further research is very likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and is likely to change the estim ate.
Very low quality: We are very uncertain about the estim ate.
1 The assum ed risk is based on the prevalence in the control group of the included study.
2
Sm all sam ple size with a total num ber of events f ewer than 300 (the threshold rule-of -thum b value stated in the GRADEpro
sof tware).
3 Presence of selection bias and other bias was unclear.
4 Presence of selection bias, detection bias, and other bias was unclear.
5 Presence of selection bias, detection bias, and other bias was unclear; high risk of attrition bias.
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6
consistently shown clinical and radiographic improvement in peo-
BACKGROUND
ple with DBG (Khatua 2011).
Gliomas located in the brainstem account for 10% to 20% of all
brain tumours in children (Stiller 1994; Jallo 2004). Many classi- Without radiation, median survival is approximately 20 weeks
fication schemes have been devised for brainstem tumours (Jallo (Langmoen 1991). The most commonly used radiological treat-
2003). Currently, radiographic findings and clinical symptoms are ment is conventional fractionated radiation, with local field radi-
used to categorise brainstem gliomas into four groups, namely: ation for a total dose of 54 to 60 Gy delivered in 30 fractions (1.8
diffuse (widely distributed), focal, exophytic (growing outwards to 2 Gy per fraction per day) over a period of six weeks (Albright
from the epithelium), and cervicomedullary (within the organ) 2004; Donaldson 2006). Preclinical studies have shown that initial
(Roonprapunt 2002). Focal tumours are defined as demarcated radiation effects are mediated through direct vascular effects on the
lesions less than 2 cm in diameter without associated oedema; dor- endothelium (i.e. thin layer of cells that lines the interior surface
sally exophytic brainstem gliomas are a group of tumours arising of blood vessels) and through cytokine (i.e. small cell-signalling
from the subependymal glial tissue; and cervicomedullary brain- protein molecules that are secreted by cells) activation, with at-
stem gliomas are similar to intramedullary spinal cord gliomas. Fo- tendant oedema and disruption of the blood-brain barrier. Doses
cal and dorsally exophytic brainstem gliomas comprise about 15% delivered within the therapeutic range result in progressive, diffuse
to 20% of brainstem tumours; they are low-grade astrocytomas changes in white matter as part of a continuous, dynamic series of
(i.e. arise from embryonic tissue that forms the nervous system) events, including direct and indirect effects on glial (brain tissue
that have characteristic clinical features, growth patterns of low- that does not conduct electrical impulses) and neuronal elements,
grade glial tumours, and generally follow an indolent course (i.e. as well as on small vessels (Tofilon 2000; Coderre 2006). Studies
cause no trouble or pain). Most of the remaining 80% of tumours reported no toxicity in children with brainstem glioma (treated
are diffuse brainstem gliomas (DBG) (Maria 1993); usually a fib- with opposed lateral fields that encompassed the majority of the
rillary (World Health Organization (WHO) grade 2) or malig- brainstem) to doses of 54 to 60 Gy at 2 Gy per fraction, 75.6 Gy
nant (WHO grade 3 or 4) astrocytoma (Freeman 1998). DBGs at 1.26 Gy twice daily, or 78 Gy at 1 Gy twice daily (Freeman
are the most aggressive subgroup of brainstem tumours, and typi- 1993; Packer 1994; Mayo 2010). Radiotherapy induces neurolog-
cally occur in the pons (part of the brainstem) with a characteristic ical improvement, allows reduction or discontinuation of steroids,
appearance on magnetic resonance imaging (MRI) of a T1 hy- and is associated with the radiological response.
pointensity and T2 hyperintensity diffuse tumour, which expands
Researchers attempted to seek more effective radiotherapeutic ap-
and infiltrates at least 50% of the pons. The encasement of the
proaches given the evidence of transient response to radiation,
basilar artery is one of the most common findings in typical diffuse
the tumours’ tendencies to progress locally (Donahue 1998), and
intrinsic pontine gliomas (DIPG) (Hargrave 2008). The typical
the radiation dose-response relationship observed for DBGs (Hibi
clinical presentation includes a neurological signs triad: multiple
1992). These regimens were designed to increase the dose-inten-
cranial nerve deficits (cranial neuropathy), long tract signs (hyper-
sity by delivering a higher total dose in the same time (hyperfrac-
reflexia, a Babinski sign, and weakness), and ataxia (problems with
tionated regimen) (Freeman 1991; Freeman 1993; Packer 1994;
muscular co-ordination) (Donaldson 2006; Khatua 2011).
Prados 1995), or a higher daily dose given over a shorter period of
Diffuse pontine (i.e. relating to the pons) gliomas rarely affect time (hypofractionated regimen) (Janssens 2009; Negretti 2011).
children younger than three years old. Broniscer et al. suggested In hyperfractionated regimens, two fractions are delivered each
that DBG in children below the age of three years may be distinct day, with a reduced dose per fraction equal to 1.1 to 1.2 Gy. The
biologically from similar tumours in older age groups (Broniscer reduction of the dose per fraction might reduce the risk of late toxi-
2008). The difference between children aged below three years and city, despite the increased total dose. In 1984, the Pediatric Oncol-
older children with diffuse pontine glioma is unclear. In addition, ogy Group began a phase I/II study to test the efficacy and toxicity
most contemporary clinical trials for children with diffuse pontine of sequentially escalated doses of hyperfractionated (twice daily)
glioma are restricted to children aged three years and older. radiation in children with brainstem gliomas (Freeman 1988).
The final results of this study revealed that there appeared to be
Despite collaborative efforts to improve treatments, DBGs carry a trend towards increased survival and time to progression with
the worst prognosis of all brainstem gliomas. Survival has re- an increase in the dose level from 6600 to 7020 cGy (Freeman
mained dismal since the mid-1990s with the median overall sur- 1991). The next dose escalation level of 7560 cGy did not result
vival (OS) ranging from 8 to 14 months (Kaplan 1996; Mandell in an improvement in survival over that observed with the second
1999; Vanan 2015). Various interventions have been investigated dose level (Freeman 1993); this observation was corroborated by
including radiation, surgical resection, chemotherapy, radiation other investigators who used hyperfractionated radiotherapy to 78
sensitisers, and biological agents (Epstein 1988; Pierre-Kahn 1993; Gy (Packer 1994; Prados 1995). In hypofractionated regimens a
Hargrave 2006; Jansen 2012). However, most of them showed total dose of 45 Gy is delivered in daily fractions of 3 to 5.5 Gy
disappointing efficacy. Radiotherapy is the only treatment that has over three weeks (Janssens 2009; Negretti 2011). The advantages
of hypofractionated radiotherapy include the shorter overall treat- Types of outcome measures
ment time with a reduction in the associated economic burden,
reduced supportive care, limited toxicity, and the same efficacy as
conventionally fractionated radiotherapy. Primary outcomes
• Overall survival (OS), defined as time from tumour
So far, there is no meta-analysis or systematic review available diagnosis, or treatment, to death from any cause.
that assesses the benefits or harms of radiation in people with
DBG. This review aimed to evaluate the existing evidence on
radiotherapy in treating children and young adults aged 0 to 21 Secondary outcomes
years with newly diagnosed DBG. • Progression-free survival (PFS): progression defined
clinically or radiologically (or both) as an increase of 25% or
more in the size of the tumour on imaging, or as the appearance
of a new lesion (or both). PFS defined as time from diagnosis,
OBJECTIVES study entry, or treatment to progression.
To assess the effects of conventional fractionated radiotherapy • Event-free survival (EFS): defined as time from diagnosis,
(with or without chemotherapy) versus other therapies (includ- study entry, or treatment to disease progression, disease relapse, a
ing different radiotherapy techniques) for newly diagnosed diffuse second malignant neoplasm, or death from any cause.
brainstem gliomas in children and young adults aged 0 to 21 years. • Quality of life (QoL) (as defined by the trial authors).
• Neurological response: defined as the number of
participants with improved neurological function.
• Radiological response: defined as the number of
METHODS participants with a reduction in tumour size of more than 50%
(Gnekow 1995).
• Toxicity (as defined by the trial authors).
Criteria for considering studies for this review

Search methods for identification of studies
Types of studies
We included all randomised controlled trials (RCTs) and quasi- Electronic searches
randomised trials (QRCTs) or controlled clinical trials (CCTs), We searched the following electronic databases:
as defined by the Cochrane Handbook for Systematic Reviews of In- • the Cochrane Central Register of Controlled Trials
terventions (Higgins 2011), that compared conventional fraction- (CENTRAL) (2015, Issue 7);
ated radiotherapy (with or without chemotherapy) versus other • MEDLINE/PubMed (1945 to 19 August 2015);
therapies (including different radiotherapy techniques). We did • EMBASE/Ovid (1980 to 19 August 2015).
not include uncontrolled observational trials.
The appendices show the search strategies for the different elec-
tronic databases (using a combination of controlled vocabulary
and text words) (Appendix 1; Appendix 2; Appendix 3).
Types of participants
Participants met the following criteria:
Searching other resources
• aged of 0 to 21 years at treatment;
• diagnosis of DBG made as described in the original studies; We searched the reference lists of relevant articles and review arti-
• DBG was newly diagnosed and previously untreated with cles to identify potentially eligible citations.
radiotherapy. We scanned the following conference proceedings electronically,
from 1 January 2010 to 19 August 2015 (Appendix 4):
• International Society for Paediatric Oncology (SIOP);
Types of interventions • International Symposium on Paediatric Neuro-Oncology
(ISPNO);
Conventional fractionated radiotherapy (with or without chemo-
• Society of Neuro-Oncology (SNO);
therapy) versus other therapies (including different radiotherapy
• European Association of Neuro-Oncology (EANO).
techniques). Trials differed only in respect of radiotherapy modali-
ties. The denition of conventional radiotherapy was external-beam We searched the following trials registers to 19 August 2015 (
radiotherapy and local field radiotherapy. Appendix 5):
• International Standard Randomised Controlled Trial Participants
Number (ISRCTN) Register (www.isrctn.com/); • Sampling.
• the World Health Organization (WHO) International • Total number and number in comparison groups.
Clinical Trials Registry Platform (ICTRP, apps.who.int/ • Sex.
trialsearch); • Age.
• the register of the National Institutes of Health (NIH) ( • Trial inclusion and exclusion criteria.
clinicaltrials.gov/) for ongoing trials. • Withdrawals and losses to follow-up (with reasons and
descriptions).
We did not impose any language restrictions and we will update
• Subgroups.
the searches every two years.
Outcomes
• Outcomes specified above that are included in the trial
Data collection and analysis
report(s).
• Length of follow-up.
• Quality of reporting of outcomes.
Selection of studies
If there were differences in data extraction, we resolved them by
Two review authors independently screened the titles and abstracts discussion, referring back to the original paper, or by consultation
of studies identified through the searches, and selected trials that with a third review author. In addition, we contacted authors about
possibly met the inclusion criteria. We retrieved full-text articles information missing from their trial reports, if necessary.
for further assessment. We used discussion and consultation with
a third review author to resolve any disagreements.
Assessment of risk of bias in included studies
Two review authors assessed the methodological quality of in-
Data extraction and management cluded RCTs, QRCTs, and CCTs using the Cochrane ’Risk of
For included studies, two review authors extracted the following bias’ tool (Higgins 2011). The tool considered six domains of
information independently, using a standard form. bias: sequence generation, allocation concealment, blinding, in-
complete outcome data, selective outcome reporting, and other
issues. For each domain, the study method was described using
General information verbatim quotes (i.e. quotations from the original paper(s)) and
• Title. judged for adequacy (’Yes’ (adequate), ’No’ (inadequate), ’Unclear’
• Authors. (insufficient information to decide ’Yes’ or ’No’)). A judgement of
• Whether trial was published or unpublished. ’Yes’ indicated low risk of bias, while ’No’ indicated high risk of
• Year of publication. bias. We added items for the assessment of risk of bias as described
• Language of publication. in the module of the Cochrane Childhood Cancer Group (Kremer
• Duplicate publications. 2014). We resolved any disagreements by discussion, or by using
• Study design. a third-party arbitrator, and presented the results in the ’Risk of
• Country. bias’ table, and in both graphical and written summary form.
• Reference/source.
• Contact address. Measures of treatment effect
• Sponsor(s). For time-to-event data (e.g. OS, EFS and PFS), we used hazard
• Setting. ratios (HR) with 95% confidence intervals (CI). If HRs were not
• Funding. explicitly presented in the study, we used Parmar’s method (Parmar
• Declaration of interest. 1998).
For dichotomous outcomes (e.g. radiological and neurological re-
sponse to treatment, toxicities), we calculated risk ratios (RR) with
Intervention
95% CI for each trial.
• Radiation techniques. For continuous outcomes (e.g. QoL), we evaluated mean differ-
• Dose. ence (MD) or standardised mean difference (SMD) with 95% CI.
• Duration. We used the MD between the treatment arms at the end of follow-
• Control intervention. up if all trials measured the outcome on the same scale, otherwise,
• Concomitant therapy and timing. we used the SMD.
Dealing with missing data radiological response, and toxicities. Two review authors indepen-
During our review, we tried to contact authors of both included dently assessed the quality of the evidence using the five GRADE
studies to clarify or gather missing data with regard to our study considerations, that is, study limitations, inconsistency, indirect-
selection, risk of bias assessment, and data extraction. We success- ness, imprecision, and publication bias.
fully contacted Dr. Peter C. Adamson, chair of the Children’s On-
cology Group, and the corresponding author of Zaghloul 2014 for Subgroup analysis and investigation of heterogeneity
additional information. If appropriate, we performed intention- If possible, we planned to carry out the following subgroup anal-
to-treat analyses. yses:
• age at onset of radiotherapy (less than three years old versus
three years old or older);
Assessment of heterogeneity
• different radiation techniques;
We planned to assess heterogeneity both by visual inspection of • different concomitant therapies.
the forest plots and by a formal statistical test for heterogeneity,
the I2 statistic. In the absence of significant heterogeneity (I2 less
Sensitivity analysis
than 50%) (Higgins 2011), we planned to use a fixed-effect model
for the estimation of treatment effects. Otherwise, we intended to Since for each comparison we found only one study, sensitivity
explore possible reasons for the occurrence of heterogeneity and analyses were not applicable.
take appropriate measures, such as using a random-effects model.
However, assessment of heterogeneity was not applicable since, for
each comparison, only one study was available.
RESULTS
Assessment of reporting biases

We evaluated reporting bias as described in the ’Assessment of risk Description of studies
of bias’ section. We planned to construct a funnel plot for reporting
See: Characteristics of included studies; Characteristics of excluded
bias evaluation when there were a sufficient number of included
studies; Characteristics of ongoing studies tables.
studies (i.e. at least 10 studies included in a meta-analysis) because
otherwise the power of the test is too low to distinguish chance
from real asymmetry (Higgins 2011). Since pooling of results was Results of the search
not possible, this was not applicable. The initial search identified 3414 records, 112 from CENTRAL,
771 from MEDLINE/PubMed, 2180 from EMBASE, 71 from
trials registers (45 from the NIH register; 10 from the WHO regis-
Data synthesis ter; 16 from the ISRCTN register), 279 from conference abstracts
We carried out data synthesis and analyses using Review Manager (69 from SIOP, 128 from ISPNO, 62 from SNO, and 20 from
5 (RevMan 2011). For time-to-event data, we used the generic EANO), and 1 identified by screening reference lists (Janssens
inverse variance function of Review Manager 5 to combine logs 2013). Figure 1 shows the process of study selection. After ex-
of the HRs. We used Pamar’s method to obtain the necessary data cluding 379 duplicating records, we screened the titles and ab-
(Parmar 1998). Dichotomous outcomes were related to risk using stracts of the remaining 3035 records. We subsequently excluded
the RR. We used the fixed-effect model throughout the review. another 3022 records as they did not meet the inclusion criteria.
Since the two included studies tested different comparisons, pool- We obtained the full-text publications of the remaining 13 stud-
ing of results was not possible. ies (including one conference abstract and one ongoing trial) and
For each comparison, we prepared a ’Summary of findings’ table read them thoroughly to assess eligibility. Finally, we considered
using the GRADE profiler software, in which we presented the two studies (Mandell 1999; Zaghloul 2014) and one ongoing trial
following outcomes: OS, EFS, PFS, QoL, neurological response, (NCT01878266) eligible in this review.
Figure 1. Study flow diagram.
Gy (details in Characteristics of included studies table). No che-
Included studies
motherapy was administered during or after radiation. The dose
of steroids was reduced in a tapering way identically in the two
groups. The median follow-up period was 9.0 months (range 1.3
See: Characteristics of included studies table.
to 25 months). Only one participant in the conventional radio-
Only two trials were eligible for inclusion, both of which were
therapy group was lost to follow-up. We contacted the correspond-
RCT design (Mandell 1999; Zaghloul 2014).
ing author of this trial and were informed about exclusion criteria,
The Mandell 1999 trial was a multi-institutional phase III RCT.
funding, and conflicts of interest.
This study focused on the comparison between conventional ra-
diotherapy versus hyperfractionated radiotherapy. A total of 132
children and young adults were enrolled between June 1992 and Excluded studies
March 1996. Two participants were considered ineligible due to
See: Characteristics of excluded studies table.
an error in diagnosis. Diagnosis of diffuse brainstem tumour was
We excluded 10 studies: two studies were retrospective design (
based on clinical and radiological findings. Histological diagno-
Negretti 2011; Sun 2013), five were cohort studies (Packer 1990;
sis was established in 22 participants, 10 in the conventional ra-
Freeman 1993; Kretschmar 1993; Packer 1993; Packer 1994), one
diotherapy group and 12 in the hyperfractionated radiotherapy
was matched-cohort analysis (Janssens 2013), one was a comment
group. Median age was 78 months in the conventional radiother-
letter (Roos 2014), and one was a conference abstract (Ahmed
apy group, and 74 months in the hyperfractionated radiotherapy
2012) that was reported in full-text (Zaghloul 2014).
group. The treatment was initiated within 28 days of diagnosis,
consisting of a six-week course of local field radiotherapy with ei-
ther conventional regimen or hyperfractionated regimen (details Ongoing studies
in Characteristics of included studies table). Cisplatin was added See: Characteristics of ongoing studies table.
as a potential radiosensitiser in all participants. All participants re- One RCT is ongoing comparing two hypofractionated radiother-
ceived steroid medication during radiotherapy. Participants were apy regimens versus conventional radiotherapy in children with
followed until death or October 1997, and five were lost to follow- newly diagnosed DIPG.
up.
The second RCT included 71 eligible participants from July
2007 to July 2011 in Children’s Cancer Hospital, Egypt (CCHE)
Risk of bias in included studies
(Zaghloul 2014). Diagnosis of diffuse brainstem tumour was based Figure 2 shows the risk of bias on seven items for each in-
on clinical and radiological findings. Participants were randomised cluded trial. The ’Risk of bias’ table details judgement of bias (see
to receive hypofractionated radiotherapy or conventional radio- Characteristics of included studies table). We contacted Dr. Pe-
therapy. Mean (± standard deviation (SD)) age was 8.3 ± 3.8 years ter C. Adamson, chair of the Children’s Oncology Group, who
in the hypofractionated radiotherapy group and 7.5 ± 4.1 years provided the study protocol of Mandell 1999. We contacted the
in the conventional radiotherapy group. Treatment was initiated corresponding author of Zaghloul 2014, who provided informa-
within two weeks of diagnosis. Hypofractionated radiotherapy was tion about random sequence generation, allocation concealment,
delivered over 2.6 weeks to a total dose of 39 Gy. Conventional blinding of outcome assessment, incomplete outcome data, fol-
radiotherapy was delivered over six weeks to a total dose of 54 low-up time, and median age.
Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.
Allocation
fractions), Thus, we considered both trials to have a high risk of
For evaluating selection bias, we assessed random sequence gener- performance bias.
ation and allocation concealment. The risk was unclear in Mandell For evaluating detection bias, we assessed the blinding of outcome
1999 and low in Zaghloul 2014. assessors for each separate outcome. For OS, we considered both
Mandell 1999 and Zaghloul 2014 to have a low risk of detection
bias since this outcome was unlikely to be affected by assessors’
knowledge of the assignment status. Mandell 1999 also reported
Blinding
radiological response and toxicities: risk of detection bias for these
For evaluating performance bias, we assessed the blinding of par- outcomes was unclear. Zaghloul 2014 also reported toxicities: risk
ticipants and personnel. Although neither of the studies clearly of detection bias for these outcomes was high.
stated whether blinding was done, it was impossible to blind the
participants or personnel, considering the different nature of the
intervention (conventional: daily for 30 fractions; hyperfraction-
Incomplete outcome data
ated: twice a day for 60 fractions; hypofractionated: daily for 13
For evaluating attrition bias, we assessed incomplete outcome data See: Summary of findings for the main comparison
for each separate outcome. Both studies reported OS: the risk of Hyperfractionated radiotherapy compared with conventional
attrition bias was low. Both studies reported toxicities: the risk of radiotherapy for diffuse brainstem glioma in children and young
attrition bias was high in Mandell 1999 and low in Zaghloul 2014. adults; Summary of findings 2 Hypofractionated radiotherapy
Mandell 1999 reported radiological response: the risk of attrition compared with conventional radiotherapy for diffuse brainstem
bias was high. glioma in children and young adults
See: Summary of findings for the main comparison; Summary of
findings 2.
Selective reporting We did not combine the data of these two RCTs using meta-
analysis since they reported different comparisons. Instead, we
For evaluating reporting bias, we assessed selective reporting. The
presented results for each trial separately.
risk of bias was unclear for Mandell 1999 and low for Zaghloul
2014.
Comparison 1: hyperfractionated radiotherapy versus
conventional radiotherapy
Other potential sources of bias Only one RCT compared hyperfractionated radiotherapy versus
For evaluating other potential sources of bias, we assessed the fol- conventional radiotherapy (Mandell 1999).
lowing items: block randomisation in unblinded trials, baseline
imbalance between treatment groups related to outcome (prior
chemotherapy and radiotherapy, age, sex), and difference in length Overall survival
of follow-up between treatment arms. The risk was unclear for The analysis included all 130 participants (66 for conventional
Mandell 1999. Zaghloul 2014 did not conduct block randomi- radiotherapy and 64 for hyperfractionated radiotherapy). Mandell
sation; baseline characteristics were balanced; and there was no 1999 reported that the median time to death was 8.5 months
significant difference in length of follow-up between treatment (range 3 to 24 months) for participants receiving conventional ra-
groups. Taken together, we considered there was low risk of other diotherapy, and 8 months (range 1 to 23 months) for participants
bias for Zaghloul 2014, receiving hyperfractionated radiotherapy. We detected no signifi-
cant difference in OS between the groups (one study, 130 partic-
ipants, HR 1.07, 95% CI 0.75 to 1.53, P value = 0.70; Figure 3;
Effects of interventions Analysis 1.1).
Figure 3. Forest plot of comparison: 1 Hyperfractionated radiotherapy versus conventional radiotherapy,

outcome: 1.1 Overall survival.
Progression-free survival
The Mandell 1999 trial did not assess PFS.
Event-free survival
The analysis included all 130 participants (66 for conventional
radiotherapy and 64 for hyperfractionated radiotherapy). Mandell
1999 reported that the median EFS was six months (range 2 to
15 months) for participants receiving conventional radiotherapy,
and five months (range 1 to 12 months) for participants receiving
hyperfractionated radiotherapy. We detected no significant differ-
ence in EFS between the participants who received hyperfraction-
ated radiotherapy and participants who received conventional ra-
diotherapy (one study, 130 participants, HR 1.26, 95% CI 0.83
to 1.90, P value = 0.27; Figure 4; Analysis 1.2).

outcome: 1.2 Event-free survival.
Mandell 1999 were available for review of post-treatment MRI.

Quality of life
For the conventional radiotherapy group, the authors reported that
The Mandell 1999 trial did not assess QoL. there was complete response in one participant, partial response
(greater than 50% decrease in size) in 18 participants, stable re-
sponse in 25 participants, and progressive response (increase in
Neurological response
size of disease on MRI) in 13 participants. For the hyperfraction-
Mandell 1999 reported the neurological response for the whole ated radiotherapy group, the authors observed complete response
group of participants rather than for treatment groups. Thus, we in one participant, partial response in 15 participants, stable re-
could not calculate RR for corresponding neurological response. sponse in 23 participants, and progressive response in 12 partici-
pants. There is no evidence of difference in radiological response
between the two groups (RR 0.94, 95% CI 0.54 to 1.63, P value
Radiological response
= 0.83; Figure 5; Analysis 1.3).
Only 108/130 participants (57 in the conventional radiotherapy
group and 51 in the hyperfractionated radiotherapy group) in
outcome: 1.3 Radiological response.
3.16, 95% CI 0.34 to 29.51, P value = 0.31), infection NOS/

Toxicities
UNK (RR 1.05, 95% CI 0.22 to 5.00, P value = 0.95), sepsis
Mandell 1999 presented various types of toxicities, most of which and bacteria (RR 2.11, 95% CI 0.20 to 22.61, P value = 0.54),
were both recorded in both the conventional radiotherapy group upper respiratory infection/otitis (RR 1.05, 95% CI 0.43 to 2.61,
(58 participants, unless otherwise stated (NOS)) and hyperfrac- P value = 0.91), abscess (RR 2.11, 95% CI 0.20 to 22.61, P value
tionated radiotherapy group (55 participants). This trial graded = 0.54), other bacterial (RR 1.05, 95% CI 0.15 to 7.23, P value
the toxicities into six categories (i.e. 1 to 5 and unknown (UNK)). = 0.96), fungal NOS/UNK (RR 0.35, 95% CI 0.04 to 3.28, P
All the observed toxicities were minimal to mild. There was no value = 0.36), fungal stomatitis (RR 1.24, 95% CI 0.40 to 3.84,
grade 4 or 5 toxicity of hearing loss or renal dysfunction. Given P value = 0.70; 57 participants in the conventional radiotherapy
the fact that the distribution of each reported toxicity in both group), alopecia (RR 1.76, 95% CI 0.44 to 7.01, P value = 0.42),
groups was similar, we combined the count in each grade for spe- decrease of magnesium (electrolyte imbalance) (RR 0.41, 95% CI
cific toxicity item, with the aim of transferring it to dichotomous 0.15 to 1.06, P value = 0.07), decrease of sodium (electrolyte im-
variable (i.e. toxicity and non-toxicity). There was no evidence of balance) (RR 2.11, 95% CI 0.20 to 22.61, P value = 0.54), hear-
difference between the hyperfractionated radiotherapy group and ing (subjective) (RR 2.11, 95% CI 0.20 to 22.61, P value = 0.54),
the conventional radiotherapy group with regards to platelets (RR and hearing (objective) (RR 1.51, 95% CI 0.62 to 3.68, P value
1.58, 95% CI 0.27 to 9.11, P value = 0.61), haemoglobin (RR = 0.37) (see: Figure 6; Analysis 1.4).
outcome: 1.4 Toxicities.
fects with the last observation carried forward (not as best or worst
Subgroup analysis
case).
We did not perform a subgroup analysis due to lack of data from
the included study.
Overall survival
The analysis included 71 participants (36 in the conventional ra-
Comparison 2: hypofractionated radiotherapy versus diotherapy group and 35 in the hypofractionated radiotherapy
conventional radiotherapy group). For the hypofractionated radiotherapy group, Zaghloul
Only one RCT compared hypofractionated radiotherapy versus 2014 reported a median OS of 7.8 months. For the conventional
conventional radiotherapy (Zaghloul 2014). In this trial, one par- radiotherapy group, Zaghloul 2014 reported a median OS of 9.5
ticipant in the conventional radiotherapy was lost to follow-up. months. There was no significant difference between the groups
The corresponding author from Zaghloul 2014 stated that the (one study, 71 participants, HR 1.03, 95% CI 0.53 to 2.01, P
participant lost for follow-up was enrolled in OS and adverse ef- value = 0.93; Figure 7; Analysis 2.1).
Figure 7. Forest plot of comparison: 2 Hypofractionated radiotherapy versus conventional radiotherapy,

outcome: 2.1 Overall survival.
Progression-free survival
The analysis included 71 participants (36 in the conventional ra-
diotherapy group and 35 in the hypofractionated radiotherapy
group). For the hypofractionated radiotherapy group, Zaghloul
2014 reported a median PFS of 6.3 months (range 3.7 to 8.8
months). For the conventional radiotherapy group, Zaghloul 2014
reported a median PFS of 7.3 months (range 5.5 to 9.2 months).
There was no significant difference between groups (one study,
71 participants, HR 1.19, 95% CI 0.63 to 2.22, P value = 0.60;
Figure 8; Analysis 2.2).

outcome: 2.2 Progression-free survival.
Toxicities
Event-free survival
The trial reported information on adverse effects for all included
The Zaghloul 2014 trial did not assess EFS.
participants. The most frequent adverse effect was local erythema
and dry desquamation, especially behind the auricles, with 16
Quality of life participants in the hyperfractionated radiotherapy group and 17
participants in conventional radiotherapy group. The difference
The Zaghloul 2014 trial did not assess QoL
was not significant (RR 0.97, 95% CI 0.59 to 1.60, P value = 0.90).
For other less frequent adverse effects, there were no differences in
Neurological response hearing (RR 1.54, 95% CI 0.27 to 8.68, P value = 0.62), decreased
The Zaghloul 2014 trial did not assess neurological response. appetite (RR 1.54, 95% CI 0.27 to 8.68, P value = 0.62), dysphagia
(RR 1.37, 95% CI 0.33 to 5.69, P value = 0.66), fatigue (RR 1.10,
95% CI 0.63 to 1.93, P value = 0.73), insomnia (RR 0.69, 95%
Radiological response CI 0.12 to 3.86, P value = 0.67), night mares (RR 1.03, 95% CI
The Zaghloul 2014 trial did not assess radiological response. 0.15 to 6.90, P value = 0.98), or seizures (RR 0.34, 95% CI 0.01
to 8.14, P value = 0.51) (see: Figure 9; Analysis 2.3).
outcome: 2.3 Toxicities.
Subgroup analysis
We did not perform a subgroup analysis due to lack of data from
the included study.
Radiotherapy for diffuse brainstem glioma in children and young adults (Review) A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
Hypofractionated radiotherapy compared with conventional radiotherapy for diffuse brainstem glioma in children and young adults
Patient or population: children and young adults with dif f use brainstem gliom a
Settings: Children’s Cancer Hospital, Egypt
Intervention: hypof ractionated radiotherapy
Comparison: conventional radiotherapy
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
Conventional radio- Hypofractionated ra-

therapy diotherapy
Overall survival See com m ent See com m ent HR 1.03 (0.53 to 2.01) 71 ⊕⊕⊕ Tim e-to-event data; no
Follow up: m ean 9 (1 study) m oderate 1 assum ed risk could be
m onths calculated
Progression- free sur- See com m ent See com m ent HR 1.19 (0.63 to 2.22) 71 ⊕⊕ Tim e-to-event data; no
vival (1 study) low 1,2 assum ed risk could be
calculated
Event- free survival See com m ent See com m ent Not estim able - See com m ent No inf orm ation on this
Quality of life See com m ent See com m ent Not estim able - See com m ent No inf orm ation on this
Neurological response See com m ent See com m ent Not estim able - See com m ent No inf orm ation on this
Radiological response See com m ent See com m ent Not estim able - See com m ent No inf orm ation on this
22
Toxicities See com m ent See com m ent See com m ents 71 ⊕⊕ Various types of tox-
(1 study) low 1,2 icities were evaluated
(see text)
No signif icant dif f er-
ences in exam ined tox-
icities between the 2
groups
* The basis f or the assumed risk (e.g. the m edian control group risk across studies) is provided in f ootnotes. The corresponding risk (and its 95% conf idence interval) is
based on the assum ed risk in the com parison group and the relative effect of the intervention (and its 95% CI).
CI: conf idence interval; HR: hazard ratio.
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our conf idence in the estim ate of ef f ect.
M oderate quality: Further research is likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and m ay change the estim ate.
Low quality: Further research is very likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and is likely to change the estim ate.
Very low quality: We are very uncertain about the estim ate.
1 Sm all sam ple size with a total num ber of events f ewer than 300 (the threshold rule-of -thum b value stated in the GRADEpro
sof tware).
2 High risk of detection bias.
23
DISCUSSION ment group; they reported that all participants received steroid
medication during radiotherapy but presented no more details.
Summary of main results Instead of taking the neurological symptoms as a whole, Zaghloul
2014 compared each symptom along the course of therapy be-
This systematic review included two RCTs that investigated the tween the hypofractionated radiotherapy group and the conven-
benefits and harms of two different radiotherapy techniques (com- tional radiotherapy group. They reported a non-significant trend
pared with conventional radiotherapy) in children and young towards more rapid improvement in cranial nerve palsy by the
adults aged 0 to 21 years with newly diagnosed DBG. Mandell hyperfractionated radiotherapy group.
1999, a multi-institutional RCT, enrolled 130 participants and It is noteworthy that Mandell 1999 recommended conventional
compared hyperfractionated radiotherapy with conventional ra- rather than hyperfractionated radiotherapy as the radiotherapeu-
diotherapy. We detected no clear evidence of effect on OS or tic regimen of choice due to the similar outcome and there being
EFS in participants received hyperfractionated radiotherapy when less treatment burden for the participant and family as well as the
compared with participants received conventional radiotherapy. radiation oncology department. Furthermore, one participant in
Radiological response and various types of toxicities were similar the hyperfractionated radiotherapy group in this study was histo-
between the two groups. There were no severe toxicities. The sec- logically diagnosed as hemangioblastoma, which is not a diagnosis
ond trial included 71 participants and compared hypofractionated of interest for this review and which might have a more favourable
radiotherapy with conventional radiotherapy (Zaghloul 2014). prognosis. Moreover, only 22 of the 130 participants had a his-
Based on this trial, we found no clear evidence of effect on OS or tological diagnosis. Therefore, it is possible that there are more
PFS in participants who received hypofractionated radiotherapy ineligible participants included. These confounding factors could
compared with participants who received conventional radiother- influence the applicability of its results to current clinical practice.
apy. The main adverse effect was local erythema and dry desqua- However, some studies shifted their aim to decrease the treatment
mation, especially behind the auricles, with a similar proportion burden and increase the quality of remaining life (Janssens 2009;
in the two groups. There were other toxicities, but there was no Negretti 2011; Janssens 2013; Zaghloul 2014). Effect of hypofrac-
statistically significant different between the treatment groups. tionated radiotherapy for DIPG was thus examined.
Since only two RCTs were eligible and only one RCT was included
for each specific comparison with limited sample size, combined
Overall completeness and applicability of with the limitation mentioned above, we could not draw conclu-
evidence sions or make any recommendations. It should also be noted that
’no evidence of effect’, as identified in this review, is not the same
We attempted to identify all relevant studies. We are confident that
as ’evidence of no effect’.
majority of published trials are included in this review. In both in-
cluded RCTs, the diagnosis of DBG was established based on MRI
findings (in Mandell 1999, at least two-thirds of the diffuse lesion
was intrinsic to the pons; in Zaghloul 2014, diffuse infiltration of
more than 50% of the pons with or without extension to the mid-
Quality of the evidence
brain or medulla oblongata (or both)) and clinical findings (at least We used the GRADE approach to assess the quality of evidence,
two of the three typical brainstem symptoms, cranial nerve deficit, and our judgements are presented in Summary of findings for the
long tract signs, and ataxia). However, in our protocol, we also main comparison and Summary of findings 2.
specified the T1 and T2 findings from MRI as one of the diagnos- For the hyperfractionated radiotherapy versus conventional ra-
tic criteria, which were actually unavailable in both included stud- diotherapy comparison, we included only one multi-institutional
ies. Therefore, we modified the diagnostic criteria as ’Diagnosis RCT. This trial was well organised. Although the risk of bias was
of DBG made as described in the original studies’. EFS, focusing high for blinding of participants and personnel, it was accept-
on time to disease progression, disease relapse, a second malignant able since these two treatment modalities are very different from
neoplasm, or death from any cause, could also provide valuable each other. The quality of evidence was low for OS and EFS, and
information regarding the treatment outcome. Therefore, it was very low for radiological response and toxicities. The main reason
included in this review although we did not include it as secondary for downgrading was that only one trial with a small sample size
outcome in prior protocol. Both included studies reported the was eligible. The sample size in Mandell 1999 (130 participants)
primary outcome. For the secondary outcomes, only toxicity was was estimated based on the assumption that there could be 80%
reported in both included studies; only Mandell 1999 reported power (one sided, P value = 0.05) to detect a 15% improvement
EFS and radiological response; only Zaghloul 2014 reported PFS. in two-year survival in hyperfractionated radiotherapy over the
Neither study included QoL and neurological response. It should 15% expected on the conventional radiotherapy. In addition, the
be noted that Mandell 1999 provided information about neuro- process of randomisation sequence generation and allocation con-
logical response for all available participants rather than per treat- cealment was not described. Furthermore, for the outcomes radi-
ological response and toxicities, the incomplete outcome data also different, with that reported in studies focusing on hypofraction-
contributed to downgrading. ated radiotherapy (Janssens 2009; Negretti 2011; Janssens 2013).
For the hypofractionated radiotherapy versus conventional radio- Based on only one available RCT (Zaghloul 2014), Zaghloul rec-
therapy comparison, we included only one RCT. This trial was ommended hypofractionated radiotherapy as standard radiother-
well organised, with protocol available, sample size estimation per- apy due to the findings that the child and his/her family could
formed, and allocation concealed. The risk of bias was high for spend less than 10% of his/her remaining survival time on treat-
blinding of participants and personnel, but was reasonable since ment, while conventional radiotherapy needs more than double
these two treatment modalities are very different from each other. this time, with minimal affection of survival rates (Zaghloul 2015).
The quality of evidence was moderate for OS and low for PFS and In addition, we are waiting for the result from an important on-
toxicities. The quality was downgraded mainly because only one going RCT comparing two hypofractionated radiotherapy regi-
trial with a small sample size was found for this comparison. In mens versus conventional radiotherapy in children with newly di-
Zaghloul 2014, the sample size estimation was based on non-infe- agnosed DIPG (NCT01878266).
riority test. However, it should be noted that the small sample size There are no reviews available discussing the effects of radiother-
(only 71 children were included) might generate wider CI values. apy (compared between different radiotherapy techniques or with
Furthermore, for PFS and toxicities, the presence of high risk of other therapies) based on RCTs, QRCTs, or CCTs.
detection bias also contribute to the consideration of downgrad-
ing.
AUTHORS’ CONCLUSIONS
Potential biases in the review process
We followed a well-designed search strategy to identify potentially Implications for practice
eligible studies, with no restriction on language, publication status, We identified only two randomised controlled trials (RCTs) evalu-
or sample size. Two review authors independently conducted the ating radiotherapy in newly diagnosed diffuse brainstem glioma in
study selection and data extraction processes. Therefore, we made children and young adults aged 0 to 21 years. One RCT compared
every attempt to minimise bias during the review process. hyperfractionated versus conventional radiotherapy and was con-
ducted from 1992 to 1997 (Mandell 1999). There was no clear
evidence of effect of hyperfractionated radiotherapy with regard
Agreements and disagreements with other to overall survival (OS), event-free survival (EFS), radiological re-
studies or reviews sponse, and various types of toxicities. Considering the similar out-
comes and treatment burden for participant and family as well as
Both RCTs used well-specified eligibility criteria: at least two of the
radiation oncology department, Mandell et al. recommended con-
three typical brainstem symptoms with a clinical history of symp-
ventional radiotherapy as standard radiotherapy strategy. The sec-
toms less than six months for Mandell 1999 and no longer than
ond study compared hypofractionated versus conventional radio-
three months for Zaghloul 2014; extent of pontine involvement
therapy and was conducted from 2007 to 2013 (Zaghloul 2014).
of tumour on MRI was required (greater than 66% for Mandell
There was no clear evidence of effect of hypofractionated radio-
1999 and 50% or greater for Zaghloul 2014). Median age and age
therapy on OS, progression-free survival (PFS), or toxicities. Based
range in both studies were in agreement with many other clinical
on the results of this most recent trial, Zaghloul et al. recom-
trials according to previous critical reviews (Hargrave 2006; Jansen
mended hypofractionated radiotherapy instead of conventional
2012). In addition, according to the reported baseline characteris-
radiotherapy as standard radiotherapy due to the lesser time spent
tics, neither study included children younger than three years. For
on treatment with minimal effect on survival rates. Neither study
Zaghloul 2014, a Karnofsky/Lansky play status of 50% or greater
reported information on quality of life (QoL) and neurological
was required. For Mandell 1999, median OS in the hyperfraction-
response, and only one study reported radiological response. It
ated radiotherapy group (8.0 months) was within the range (8.0 to
should be noted that no evidence of effect, as identified in this
10.5 months) in studies assessing hyperfractionated radiotherapy
review, is not the same as evidence of no effect.
with specified clinical and radiological eligibility criteria applied
(Hargrave 2006). For Zaghloul 2014, the median OS and PFS
in the hypofractionated radiotherapy group (7.8 months for OS
Implications for research
and 6.3 months for PFS) were within the range (7 to 14 months Further research is needed to establish the role of radiotherapy in
for median OS and 5 to 8 months for median PFS) reported in management of diffuse brainstem glioma in children and young
studies with specified MRI criteria for DIPG (greater than 50% adults. Future RCTs should be conducted with adequate power
pontine involvement) (Jansen 2012). Furthermore, the median and all relevant outcomes should be taken into consideration, in-
OS and PFS in Zaghloul 2014 appeared similar, although slightly cluding OS, EFS, PFS, QoL, neurological response, radiological
response, toxicities, and steroid consumption. Given the incidence ment of the search strategy; running the searches in CENTRAL,
of this rare entity, international multicentre collaboration is en- MEDLINE/PubMed, and EMBASE; and providing us with ti-
couraged. Considering the potential advantage of hypofraction- tles/abstracts. Dr. Edith Leclercq also provided us with valuable
ated radiotherapy to decrease the treatment burden and increase suggestions for searching conference abstracts. We are also grateful
the quality of remaining life, we suggest that more attention should to other members from the editorial base of the Cochrane Child-
be given to hypofractionated radiotherapy. hood Cancer group for their kind review and valuable suggestions
for our work. The Stichting Kinderen Kankervrij (KiKa) funds
the editorial base of Cochrane Childhood Cancer Group. We are
grateful to Dr. Zaghloul and Dr. Peter C. Adamson for providing
ACKNOWLEDGEMENTS additional information of the included studies. We are also grate-
ful to the peer reviewers, Dr E. Bouffet and Prof. D.N. Sharma.
We are grateful to Dr. Edith Leclercq for helping with the develop-
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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Mandell 1999
Methods Phase III prospective RCT
Participants Sample: 130 participants (aged 37-266 months; 57 boys and 73 girls; conventional
radiotherapy group: 30 boys and 36 girls; median age 78 months (range 40-266 months)
; hyperfractionated radiotherapy: 27 boys and 37 girls; median age 74 months (range
37-212 months))
Setting: multi-institutional; USA (Departments of Radiation Oncology and Pediatrics,
Mount Sinai Medical Center; Children’s Hospital of San Diego; Zeneca Pharmaceuti-
cals; Department of Radiation Oncology, Harper Hospital; Department of Neurology,
Buffalo Children’s Hospital; MACC Fund Research Center; Department of Pathology,
Johns Hopkins Hospital, Baltimore; Semmes-Murphy Clinic, Memphis, TN University
of Florida; Department of Pediatrics, Duke University Medical School; Department of
Radiation Oncology, St. Jude Children’s Research Hospital) and Canada (Department
of Radiation Oncology, McGill University)
Period of trial conducted: June 1992 to October 1997
Inclusion criteria: aged 3-21 years; newly diagnosed brainstem tumour based on radio-
logical and clinical findings; at least two-thirds of the lesion was intrinsic to the pons on
MRI; clinical history of < 6 months; at least 2 of the neurological triad (cranial nerve
deficit, long tract signs, and ataxia); no prior chemotherapy and radiotherapy; life ex-
pectancy > 6 weeks; adequate haematological and renal function
Exclusion criteria: not mentioned
Interventions Treatment was initiated within 28 days of diagnosis and consisted of a 6-week course of
local field radiotherapy
Conventional radiotherapy (66 participants): once a day treatment of 180 cGy per
fraction to a total dose of 5400 cGy for a 6-week course
Hyperfractionated radiotherapy (64 participants): twice a day regimen of 117 cGy per
fraction to a total dose of 7020 cGy for a 6-week course
Treatment volume was to include a 2-cm margin around MRI-visualised abnormalities
in all directions. All participants received 3 courses of cisplatin (delivered by continuous
infusion over 120 hours, beginning on the first day of radiotherapy on weeks 1, 3, and
5). All participants received steroid medication during radiotherapy
Outcomes Overall survival (defined as time from diagnosis to time of death)

Event-free survival (defined as time from diagnosis to off-study) (off-study criteria: pro-
gressive or recurrent disease; death) (based on the study protocol provided by Peter C.
Adamson)
Radiological response (number of participants with > 50% decrease in size on MRI)
Toxicity (graded by standard National Cancer Institute common toxicity criteria; includ-
ing platelets, haemoglobin, infection NOS/UNK, sepsis, bacteria, URI/otitis, abscess,
other bacterial, fungal NOS/UNK, fungal stomatitis, alopecia, magnesium decrease,
sodium decrease, hearing - subjective, hearing - objective considering grade ≥ 1 toxici-
ties)
Mandell 1999 (Continued)
Notes Sponsor: National Cancer Institute

Funding and declaration of interest: not mentioned
The study stated that 130 participants were finally eligible. However, in a figure caption it
was presented that there were 66 participants in the conventional radiotherapy group and
65 participants in the hyperfractionated radiotherapy group (so total of 131 participants)
. We were unable to contact the author to clarify this. We considered that this was possibly
a typographical error
Some toxicities were not reported for both groups and we were unsure if that meant that
the participants did not have that toxicity. Therefore, we did not include these toxicities
in the review
Histological diagnosis was confirmed in 22/130 participants. 1 participant in the hyper-
fractionated radiotherapy group was diagnosed as having a hemangioblastoma, which is
not a diffuse brainstem glioma and thus ineligible for this review
According to the protocol (provided by Peter C. Adamson) and full-text of this study,
the eligible participants should be between 3 and 21 years of age. However, the age range
of participants in conventional radiotherapy group was 40-266 months
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Unclear risk Quote: “prospective randomized trial”
bias) Comment: no description of sequence generation process
Allocation concealment (selection bias) Unclear risk Quote: “prospective randomized trial”
Comment: no information regarding allocation conceal-
ment provided
Blinding of participants and personnel High risk Comment: not mentioned. Considering different nature
(performance bias) of the intervention, we assumed that participants and care
All outcomes providers were not blinded
Blinding of outcome assessment (detection Low risk Comments: although no information was provided, we
bias) judged this as a low risk of bias considering that this out-
Overall survival come is unlikely to be affected by the participant’s or per-
sonnel’s knowledge of the assignment status
Blinding of outcome assessment (detection Unclear risk Comment: insufficient information to judge
bias)
Event-free survival
bias)
Radiological response
bias)
Toxicities
Mandell 1999 (Continued)
Incomplete outcome data (attrition bias) Low risk Comment: all participants were analysed
Overall survival
Incomplete outcome data (attrition bias) Low risk Comment: all participants were analysed
Event-free survival
Incomplete outcome data (attrition bias) High risk Quote: “available for review in 108 of the 130 patients”
Radiological response Comment: status of radiological response was not available
in 22 participants
Incomplete outcome data (attrition bias) High risk Quote: “Toxicity reported among 58 patients evaluable for
Toxicities Treatment 01 (180 cGy/d to 5400)” (conventional radio-
therapy) and “Toxicity reported among 55 patients evalu-
able for Treatment 02 (117 cGy/d to 7020)” (hyperfrac-
tionated radiotherapy); for fungal stomatitis toxicity, grade
was unknown for 1 additional participant in the conven-
tional radiotherapy group
Comment: toxicities was not reported in 17 or 18 partici-
pants
Selective reporting (reporting bias) Low risk Comment: protocol provided by Dr. Peter C. Adamson;
the outcomes were reported accordingly
Other bias Unclear risk Block randomisation in unblinded trials: unclear (not men-
tioned)
Baseline imbalance between treatment arms related to out-
come (prior chemotherapy and radiotherapy, age, sex): low
(age and sex was similar between the 2 arms; all partici-
pants received no prior chemotherapy and radiotherapy)
Difference in length of follow-up between treatment arms:
unclear (not mentioned)
Central review: copies of all clinical, pathological, and ra-
diological data were to be gathered centrally and reviewed
by the study co-ordinators
Zaghloul 2014
Methods Phase III RCT
Participants Sample: 71 participants (median age 7.9 years; 37 boys and 34 girls; conventional ra-
diotherapy group: 18 boys and 18 girls; median age 7.7 years (range 3.9-12.0 years);
hypofractionated radiotherapy group: 19 boys and 16 girls; median age 8.1 years (range
4.0-14.2 years))
Setting: Radiation Oncology Department, Children’s Cancer Hospital, Egypt
Period of trial conducted: July 2007 to Jan 2013;
Inclusion criteria: aged < 18 years; MRI showing diffuse infiltration of > 50% of the pons
with or without extension to the midbrain or medulla oblongata (or both); at least 2 of
the 3 typical brainstem symptoms; clinical history no longer than 3 months; Karnofsky/
Zaghloul 2014 (Continued)
Lansky play status ≥ 5, unless the reason for decrease in status was a direct result of
neurological involvement; no prior chemotherapy or radiotherapy
Exclusion criteria: opposite of the inclusion criteria (provided by the corresponding
author)
Interventions Treatment was initiated as soon as possible and within 2 weeks of diagnosis
Hypofractionated radiotherapy (35 participants): total dose of 39 Gy in 13 daily fractions
of 3 Gy each, given over 2.6 weeks
Conventional radiotherapy (36 participants): 54 Gy in 30 fractions over 6 weeks, 1.8
Gy per fraction
No chemotherapy was administered during or after radiation
Steroids were allowed and usually initiated before radiation treatment was started
Outcomes Overall survival (calculated from time of diagnosis to death or time of reporting)
Progression-free survival (calculated from time of diagnosis to time of documented failure)
(documented failure: clinical or radiological progression on MRI)
Toxicity (recorded according to Radiation Therapy Oncology Group criteria; including
skin, hearing, decreased appetite, dysphagia, fatigue, insomnia, night mares, seizures;
considering grade ≥ 1 toxicities)
Notes Sponsor: Children’s Cancer Hospital Egypt 57357

Funding and declaration of interest: funded by Children’s Cancer Hospital Egypt and
no conflict of interest to declare (provided by the corresponding author)
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Low risk Quote: “simple randomisation, sequence of numbers was com-
bias) puter generated” (provided by the corresponding author)
Allocation concealment (selection bias) Low risk Quote: “Concealment of randomization was performed using
sequential, sealed opaque envelopes” (provided by the corre-
sponding author)
Blinding of participants and personnel High risk Comment: this trial was open-label (NCT01635140)
(performance bias)
All outcomes
Blinding of outcome assessment (detection Low risk Comment: although no information was provided, we judged
bias) this as a low risk of bias considering that this outcome is unlikely
Overall survival to be affected by the participant’s or personnel’s knowledge of
the assignment status
Blinding of outcome assessment (detection High risk Quote: “assessment of progression-free survival was not blinded
bias) on the clinical examination level” (provided by the correspond-
Progression-free survival ing author)
Zaghloul 2014 (Continued)
Blinding of outcome assessment (detection High risk Quote: “assessment of side-effects was not blinded on the clinical
bias) examination level” (provided by the corresponding author)
Toxicities
Incomplete outcome data (attrition bias) Low risk Comment: all participants were analysed (provided by the cor-
Overall survival responding author)
Incomplete outcome data (attrition bias) Low risk Comment: progression-free survival was assessed in all partici-
Progression-free survival pants (provided by the corresponding author)
Incomplete outcome data (attrition bias) Low risk Comment: toxicities were assessed in all participants (provided
Toxicities by the corresponding author)
Selective reporting (reporting bias) Low risk Quote: “The study was registered in Clinical Trial. Gov
(NCT01635140)”
Comment: prospectively registered protocol available and out-
comes reported accordingly
Other bias Low risk Block randomisation in unblinded trials: used simple randomisa-
tion (provided by the corresponding author)
Baseline imbalance between treatment groups related to outcome
(prior chemotherapy and radiotherapy, age, sex): low (age and
sex were similar between the 2 groups; all participants received
no prior chemotherapy or radiotherapy). In addition to the items
defined by us as being important for baseline imbalance, this
study also reported that signs and symptoms, site, Karnofsky/
Lanesky status, shunt application, and steroid needs were similar
between the 2 groups
Difference in length of follow-up between treatment groups: no sig-
nificant difference (provided by the corresponding author)
Central review: this was a single-centre RCT, so central review is
not needed
MRI: magnetic resonance imaging; NOS: not otherwise specified; RCT: randomised controlled trial; UNK: unknown; URI; upper
respiratory infection.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Ahmed 2012 Conference abstract was in a full-text report
Freeman 1993 Not an RCT, quasi-RCT, or CCT; cohort study
(Continued)
Janssens 2013 Not an RCT, quasi-RCT, or CCT; matched-cohort study
Kretschmar 1993 Not an RCT, quasi-RCT, or CCT; cohort study
Negretti 2011 Not an RCT, quasi-RCT, or CCT; retrospective studies
Packer 1990 Not an RCT, quasi-RCT, or CCT; cohort study
Packer 1993 Not an RCT, quasi-RCT, or CCT; cohort study
Packer 1994 Not an RCT, quasi-RCT, nor CCT; cohort study
Roos 2014 Not an RCT, quasi-RCT, nor CCT; comment letter
Sun 2013 Not an RCT, quasi-RCT, nor CCT; retrospective study
CCT: controlled clinical trial; quasi-RCT; quasi-randomised controlled trial; RCT: randomised controlled trial.
Characteristics of ongoing studies [ordered by study ID]
NCT01878266
Trial name or title Prospective Randomized Trial of Two Hypofractionated Radiotherapy Regimens Versus Conventional Ra-
diotherapy in Pediatric Diffuse Brainstem Glioma
Methods Randomised
Participants Children aged 2-18 years with newly diagnosed diffuse intrinsic brainstem glioma
Estimated enrolment: 119
Interventions Hypofractionated radiotherapy: total dose of 39 Gy in daily fractions of 3 Gy, 5 fractions per week
Hypofractionated radiotherapy: total dose to 4500 cGy in 15 fractions in 3 weeks
Conventional radiotherapy: total dose of 54 Gy in 30 fractions giving 1.8 Gy per fraction
Outcomes Primary outcome: median overall survival (time frame: 3 years)

Secondary outcome: progression-free survival (time frame: 3 years)
Starting date February 2013
Contact information Children’s Cancer Hospital Egypt 57357, Cairo, Egypt, 11441 (Mohamed S Zaghloul)
www.clinicaltrials.gov (NCT01878266)
Notes The status of this study is ’Recruiting’ (last checked 4 April 2016), although the estimated completion date
was “December 2013”
DATA AND ANALYSES
Comparison 1. Hyperfractionated radiotherapy versus conventional radiotherapy
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Overall survival 1 130 Hazard Ratio (Fixed, 95% CI) 1.07 [0.75, 1.53]
2 Event-free survival 1 130 Hazard Ratio (Fixed, 95% CI) 1.26 [0.83, 1.90]
3 Radiological response 1 108 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.54, 1.63]
4 Toxicities 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
4.1 Platelets 1 113 Risk Ratio (M-H, Fixed, 95% CI) 1.58 [0.27, 9.11]
4.2 Haemoglobin 1 113 Risk Ratio (M-H, Fixed, 95% CI) 3.16 [0.34, 29.51]
4.3 Infection (not otherwise 1 113 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.22, 5.00]
specified/unknown)
4.4 Sepsis, bacteria 1 113 Risk Ratio (M-H, Fixed, 95% CI) 2.11 [0.20, 22.61]
4.5 Upper respiratory 1 113 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.43, 2.61]
infection/otitis
4.6 Abscess 1 113 Risk Ratio (M-H, Fixed, 95% CI) 2.11 [0.20, 22.61]
4.7 Other bacterial 1 113 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.15, 7.23]
4.8 Fungal (not otherwise 1 113 Risk Ratio (M-H, Fixed, 95% CI) 0.35 [0.04, 3.28]
specified/unknown)
4.9 Fungal stomatitis 1 112 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [0.40, 3.84]
4.10 Alopecia 1 113 Risk Ratio (M-H, Fixed, 95% CI) 1.76 [0.44, 7.01]
4.11 Decrease of magnesium 1 113 Risk Ratio (M-H, Fixed, 95% CI) 0.41 [0.15, 1.06]
(electrolyte imbalance)
4.12 Decrease of sodium 1 113 Risk Ratio (M-H, Fixed, 95% CI) 2.11 [0.20, 22.61]
(electrolyte imbalance)
4.13 Hearing (subjective) 1 113 Risk Ratio (M-H, Fixed, 95% CI) 2.11 [0.20, 22.61]
4.14 Hearing (objective) 1 113 Risk Ratio (M-H, Fixed, 95% CI) 1.51 [0.62, 3.68]
Comparison 2. Hypofractionated radiotherapy versus conventional radiotherapy
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Overall survival 1 71 Hazard Ratio (Fixed, 95% CI) 1.03 [0.53, 2.01]
2 Progression-free survival 1 71 Hazard Ratio (Fixed, 95% CI) 1.19 [0.63, 2.22]
3 Toxicities 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
3.1 Skin 1 71 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.59, 1.60]
3.2 Hearing 1 71 Risk Ratio (M-H, Fixed, 95% CI) 1.54 [0.27, 8.68]
3.3 Decreased appetite 1 71 Risk Ratio (M-H, Fixed, 95% CI) 1.54 [0.27, 8.68]
3.4 Dysphagia 1 71 Risk Ratio (M-H, Fixed, 95% CI) 1.37 [0.33, 5.69]
3.5 Fatigue 1 71 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.63, 1.93]
3.6 Insomnia 1 71 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.12, 3.86]
3.7 Night mares 1 71 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.15, 6.90]
3.8 Seizures 1 71 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.01, 8.14]
Analysis 1.1. Comparison 1 Hyperfractionated radiotherapy versus conventional radiotherapy, Outcome 1
Overall survival.
Review: Radiotherapy for diffuse brainstem glioma in children and young adults
Comparison: 1 Hyperfractionated radiotherapy versus conventional radiotherapy
Outcome: 1 Overall survival
Study or subgroup Hyperfractionated Conventional log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio
N N (SE) IV,Fixed,95% CI IV,Fixed,95% CI
Mandell 1999 64 66 0.07 (0.18) 100.0 % 1.07 [ 0.75, 1.53 ]
Total (95% CI) 64 66 100.0 % 1.07 [ 0.75, 1.53 ]

Heterogeneity: not applicable
Test for overall effect: Z = 0.39 (P = 0.70)
Test for subgroup differences: Not applicable
0.02 0.1 1 10 50
Favours hyperfractionated Favours conventional

Event-free survival.
Outcome: 2 Event-free survival
Study or subgroup Hyperfractionated Conventional log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio
Mandell 1999 64 66 0.23 (0.21) 100.0 % 1.26 [ 0.83, 1.90 ]
Total (95% CI) 64 66 100.0 % 1.26 [ 0.83, 1.90 ]

0.01 0.1 1 10 100

Radiological response.
Outcome: 3 Radiological response
Study or subgroup Hyperfractionated Conventional Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Mandell 1999 16/51 19/57 100.0 % 0.94 [ 0.54, 1.63 ]
Total (95% CI) 51 57 100.0 % 0.94 [ 0.54, 1.63 ]

Total events: 16 (Hyperfractionated), 19 (Conventional)
0.01 0.1 1 10 100

Toxicities.
Outcome: 4 Toxicities

1 Platelets
Mandell 1999 3/55 2/58 100.0 % 1.58 [ 0.27, 9.11 ]
Subtotal (95% CI) 55 58 100.0 % 1.58 [ 0.27, 9.11 ]

2 Haemoglobin
Mandell 1999 3/55 1/58 100.0 % 3.16 [ 0.34, 29.51 ]
Subtotal (95% CI) 55 58 100.0 % 3.16 [ 0.34, 29.51 ]

3 Infection (not otherwise specified/unknown)
Mandell 1999 3/55 3/58 100.0 % 1.05 [ 0.22, 5.00 ]
Subtotal (95% CI) 55 58 100.0 % 1.05 [ 0.22, 5.00 ]

4 Sepsis, bacteria
Mandell 1999 2/55 1/58 100.0 % 2.11 [ 0.20, 22.61 ]
Subtotal (95% CI) 55 58 100.0 % 2.11 [ 0.20, 22.61 ]

5 Upper respiratory infection/otitis
Mandell 1999 8/55 8/58 100.0 % 1.05 [ 0.43, 2.61 ]
Subtotal (95% CI) 55 58 100.0 % 1.05 [ 0.43, 2.61 ]

6 Abscess
Mandell 1999 2/55 1/58 100.0 % 2.11 [ 0.20, 22.61 ]
Subtotal (95% CI) 55 58 100.0 % 2.11 [ 0.20, 22.61 ]
0.005 0.1 1 10 200

(Continued . . . )
(. . . Continued)
7 Other bacterial
Mandell 1999 2/55 2/58 100.0 % 1.05 [ 0.15, 7.23 ]
Subtotal (95% CI) 55 58 100.0 % 1.05 [ 0.15, 7.23 ]

8 Fungal (not otherwise specified/unknown)
Mandell 1999 1/55 3/58 100.0 % 0.35 [ 0.04, 3.28 ]
Subtotal (95% CI) 55 58 100.0 % 0.35 [ 0.04, 3.28 ]

9 Fungal stomatitis
Mandell 1999 6/55 5/57 100.0 % 1.24 [ 0.40, 3.84 ]
Subtotal (95% CI) 55 57 100.0 % 1.24 [ 0.40, 3.84 ]

10 Alopecia
Mandell 1999 5/55 3/58 100.0 % 1.76 [ 0.44, 7.01 ]
Subtotal (95% CI) 55 58 100.0 % 1.76 [ 0.44, 7.01 ]

11 Decrease of magnesium (electrolyte imbalance)

Mandell 1999 5/55 13/58 100.0 % 0.41 [ 0.15, 1.06 ]
Subtotal (95% CI) 55 58 100.0 % 0.41 [ 0.15, 1.06 ]

12 Decrease of sodium (electrolyte imbalance)

Mandell 1999 2/55 1/58 100.0 % 2.11 [ 0.20, 22.61 ]
Subtotal (95% CI) 55 58 100.0 % 2.11 [ 0.20, 22.61 ]

13 Hearing (subjective)
Mandell 1999 2/55 1/58 100.0 % 2.11 [ 0.20, 22.61 ]
0.005 0.1 1 10 200

(Continued . . . )
(. . . Continued)
Subtotal (95% CI) 55 58 100.0 % 2.11 [ 0.20, 22.61 ]
14 Hearing (objective)
Mandell 1999 10/55 7/58 100.0 % 1.51 [ 0.62, 3.68 ]
Subtotal (95% CI) 55 58 100.0 % 1.51 [ 0.62, 3.68 ]

0.005 0.1 1 10 200

Analysis 2.1. Comparison 2 Hypofractionated radiotherapy versus conventional radiotherapy, Outcome 1

Overall survival.
Comparison: 2 Hypofractionated radiotherapy versus conventional radiotherapy
Outcome: 1 Overall survival
Study or subgroup Hypofractionated Conventional log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio
Zaghloul 2014 35 36 0.03 (0.34) 100.0 % 1.03 [ 0.53, 2.01 ]
Total (95% CI) 35 36 100.0 % 1.03 [ 0.53, 2.01 ]

0.005 0.1 1 10 200

Favours hypofractionated Favours conventional
Progression-free survival.
Outcome: 2 Progression-free survival
Study or subgroup Hypofractionated Conventional log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio
Zaghloul 2014 35 36 0.17 (0.32) 100.0 % 1.19 [ 0.63, 2.22 ]
Total (95% CI) 35 36 100.0 % 1.19 [ 0.63, 2.22 ]

0.01 0.1 1 10 100

Toxicities.
Outcome: 3 Toxicities
Study or subgroup Hypofractionated Conventional Risk Ratio Weight Risk Ratio

1 Skin
Zaghloul 2014 16/35 17/36 100.0 % 0.97 [ 0.59, 1.60 ]
Subtotal (95% CI) 35 36 100.0 % 0.97 [ 0.59, 1.60 ]

Total events: 16 (Hypofractionated), 17 (Conventional)
2 Hearing
Zaghloul 2014 3/35 2/36 100.0 % 1.54 [ 0.27, 8.68 ]
Subtotal (95% CI) 35 36 100.0 % 1.54 [ 0.27, 8.68 ]

3 Decreased appetite
Zaghloul 2014 3/35 2/36 100.0 % 1.54 [ 0.27, 8.68 ]
Subtotal (95% CI) 35 36 100.0 % 1.54 [ 0.27, 8.68 ]

4 Dysphagia
Zaghloul 2014 4/35 3/36 100.0 % 1.37 [ 0.33, 5.69 ]
Subtotal (95% CI) 35 36 100.0 % 1.37 [ 0.33, 5.69 ]

5 Fatigue
Zaghloul 2014 15/35 14/36 100.0 % 1.10 [ 0.63, 1.93 ]
Subtotal (95% CI) 35 36 100.0 % 1.10 [ 0.63, 1.93 ]

6 Insomnia
Zaghloul 2014 2/35 3/36 100.0 % 0.69 [ 0.12, 3.86 ]
Subtotal (95% CI) 35 36 100.0 % 0.69 [ 0.12, 3.86 ]
0.002 0.1 1 10 500

(Continued . . . )
(. . . Continued)
Study or subgroup Hypofractionated Conventional Risk Ratio Weight Risk Ratio
7 Night mares
Zaghloul 2014 2/35 2/36 100.0 % 1.03 [ 0.15, 6.90 ]
Subtotal (95% CI) 35 36 100.0 % 1.03 [ 0.15, 6.90 ]

8 Seizures
Zaghloul 2014 0/35 1/36 100.0 % 0.34 [ 0.01, 8.14 ]
Subtotal (95% CI) 35 36 100.0 % 0.34 [ 0.01, 8.14 ]

0.002 0.1 1 10 500

APPENDICES
Appendix 1. Search strategy for Cochrane Central Register of Controlled Trials (CENTRAL)
1. ForGlioma, we used the following text words:
glioma OR gliomas OR glioma* OR Glial Cell Tumors OR Glial Cell Tumor OR Tumor, Glial Cell OR Tumors, Glial Cell OR Mixed
Glioma OR Glioma, Mixed OR Gliomas, Mixed OR Mixed Gliomas OR Malignant Glioma OR Glioma, Malignant OR Gliomas,
Malignant OR Malignant Gliomas OR brain stem glioma OR brainstem glioma OR brain stem tumor OR brain stem tumors OR
brainstem tumor OR brainstem tumors OR brain stem tumour OR brainstem tumour OR brain stem tumours OR brainstem tumours
OR brain stem neoplasm OR brain stem neoplasms OR pons neoplasm
2. For Radiotherapy, we used the following text words:
Radiotherapy OR radiotherap* OR radiotherapies OR Targeted Radiotherapies OR Targeted Radiotherapy OR adjuvant radiotherapy
OR radiation oncology OR radiation OR radiation* OR radiation therapy OR radiation therap* OR “radiotherapy fractionation” OR
irradiation or irradiation* OR chemoradiotherapy OR chemoradiotherap* OR chemoradiotherapies OR Combined Modality Therapy
OR Multimodal Treatment OR Multimodal Treatments OR Combined Modality Therapies OR hyperfractionated radiotherapy OR
hyperfractionated radiotherap* OR hyperfractionated radiotherapies OR hyperfractionated radiation OR hyperfractionated radiation*
OR hyperfractionated irradiation OR hyperfractionated irradiation* OR accelerate* hyperfractionate* OR hyperfractionation OR
radiotherapy dosage OR Radiotherapy Dosages OR Radiation Dose-Response Relationship OR Radiation Dose-Response Relationships
OR dose fractionation OR Dose Fractionations OR Radiotherapy Dose Fractionation OR Radiotherapy Dose Fractionations
3. For Children and young adults, we used the following text words:
infant OR infan* OR newborn OR newborn* OR new-born* OR baby OR baby* OR babies OR neonat* OR perinat* OR postnat*
OR child OR child* OR schoolchild* OR schoolchild OR school child OR school child* OR kid OR kids OR toddler* OR adolescent
OR adoles* OR teen* OR boy* OR girl* OR minors OR minors* OR underag* OR under ag* OR juvenil* OR youth* OR kindergar*
OR puberty OR puber* OR pubescen* OR prepubescen* OR prepuberty* OR pediatrics OR pediatric* OR paediatric* OR peadiatric*
OR schools OR nursery school* OR preschool* OR pre school* OR primary school* OR secondary school* OR elementary school*
OR elementary school OR high school* OR highschool* OR school age OR schoolage OR school age* OR schoolage* OR infancy
OR young adult OR young adults OR young adult*
Final search: 1 AND 2 AND 3
[*=zero to many characters]
Appendix 2. Search strategy for PubMed

1. ForGlioma, we used the following MeSH headings and text words:
glioma OR gliomas OR glioma* OR Glial Cell Tumors OR Glial Cell Tumor OR Tumor, Glial Cell OR Tumors, Glial Cell OR Mixed
Glioma OR Glioma, Mixed OR Gliomas, Mixed OR Mixed Gliomas OR Malignant Glioma OR Glioma, Malignant OR Gliomas,
Malignant OR Malignant Gliomas OR brain stem glioma OR brainstem glioma OR brain stem tumor OR brain stem tumors OR
brainstem tumor OR brainstem tumors OR brain stem tumour OR brainstem tumour OR brain stem tumours OR brainstem tumours
OR brain stem neoplasm OR brain stem neoplasms OR pons neoplasm OR pons neoplasms
2. ForRadiotherapy, we used the following MeSH headings and text words:
Radiotherapy OR radiotherap* OR radiotherapies OR Radiotherapy, Targeted OR Radiotherapies, Targeted OR Targeted Radiother-
apies OR Targeted Radiotherapy OR radiotherapy[sh] OR adjuvant radiotherapy OR radiation oncology OR radiation[tiab] OR radi-
ation* OR radiation therapy[tiab] OR radiation therap* OR “radiotherapy fractionation” OR (radiotherapy AND fractionation[tiab])
OR irradiation OR irradiation* OR chemoradiotherapy OR chemoradiotherap* OR chemoradiotherapies OR Combined Modality
Therapy OR Multimodal Treatment OR Multimodal Treatments OR Treatment, Multimodal OR Treatments, Multimodal OR Ther-
apy, Combined Modality OR Combined Modality Therapies OR Modality Therapies, Combined OR Modality Therapy, Combined
OR Therapies, Combined Modality OR hyperfractionated radiotherapy OR hyperfractionated radiotherap* OR hyperfractionated ra-
diotherapies OR hyperfractionated radiation OR hyperfractionated radiation* OR hyperfractionated irradiation OR hyperfractionated
irradiation* OR accelerate* hyperfractionate* OR hyperfractionation OR radiotherapy dosage OR Dosage, Radiotherapy OR Dosages,
Radiotherapy OR Radiotherapy Dosages OR dose-response relationship, radiation OR Dose Response Relationship, Radiation OR
Dose-Response Relationships, Radiation OR Radiation Dose-Response Relationship OR Radiation Dose-Response Relationships OR
Relationship, Radiation Dose-Response OR Relationships, Radiation Dose-Response OR dose fractionation OR Dose Fractionations
OR Fractionation, Dose OR Fractionations, Dose OR Radiotherapy Dose Fractionation OR Dose Fractionation, Radiotherapy OR
Dose Fractionations, Radiotherapy OR Fractionation, Radiotherapy Dose OR Fractionations, Radiotherapy Dose OR Radiotherapy
Dose Fractionations
3. ForChildren and young adults, we used the following MeSH headings and text words:
infant OR infan* OR newborn OR newborn* OR new-born* OR baby OR baby* OR babies OR neonat* OR perinat* OR postnat*
OR child OR child* OR schoolchild* OR schoolchild OR school child OR school child* OR kid OR kids OR toddler* OR adolescent
OR adoles* OR teen* OR boy* OR girl* OR minors OR minors* OR underag* OR under ag* OR juvenil* OR youth* OR kindergar*
OR puberty OR puber* OR pubescen* OR prepubescen* OR prepuberty* OR pediatrics OR pediatric* OR paediatric* OR peadiatric*
OR schools OR nursery school* OR preschool* OR pre school* OR primary school* OR secondary school* OR elementary school*
OR elementary school OR high school* OR highschool* OR school age OR schoolage OR school age* OR schoolage* OR infancy
OR schools, nursery OR infant, newborn OR young adult OR young adults OR young adult*
4. Forrandomised controlled trials (RCTs) and controlled clinical trials (CCTs), we used the following MeSH headings and text
words:
(randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR
randomly[tiab] OR trial[tiab] OR groups[tiab]) AND humans[mh]
Final search: 1 AND 2 AND 3 AND 4

[pt = publication type; tiab = title, abstract; sh = subheading; mh = MeSH term; * = zero to many characters; RCT = randomized
controlled trial; CCT = controlled clinical trial]
Appendix 3. Search strategy for EMBASE (Ovid)
1 For Glioma, we used the following Emtree terms and text words:
1. exp glioma/ or exp pontine glioma/
2. (glioma or gliomas or glioma$).mp.
3. (Glial Cell Tumor or Glial Cell Tumors).mp.
4. (Mixed Glioma or Mixed Gliomas).mp.
5. (Malignant Glioma or Malignant Gliomas).mp.
6. (brain stem glioma or brain stem gliomas or brainstem glioma or brainstem gliomas).mp.
7. exp brain stem tumor/
8. (brain stem tumor or brain stem tumors or brainstem tumor or brainstem tumors or brain stem tumour or brainstem tumour or
brain stem tumours or brainstem tumours).mp.
9. brain neoplasm.mp.
10. (brain stem neoplasm or brain stem neoplasms).mp.
11. (pons neoplasm or pons neoplasms).mp.
12. or/1-11
2. For Radiotherapy, we used the following Emtree terms and text words:
1. exp Radiotherapy/ or exp Cancer Radiotherapy/
2. (radiotherapy or radiotherapies or radiotherap$).mp.
3. (targeted radiotherapy or targeted radiotherapies or targeted radiotherap$).mp.
4. radiotherapy.sh.
5. adjuvant radiotherapy.mp.
6. radiation oncology.mp.
7. (radiation or radiation therapy).ti,ab.
8. (radiation$ or radiation therap$).mp.
9. exp Radiation Dose Fractionation/ or radiotherapy fractionation.mp.
10. (radiotherapy and fractionation).ti,ab.
11. (irradiation or irradiation$).mp.
12. (chemoradiotherapy or chemoradiotherap$ or chemoradiotherapies).mp.
13. Combined Modality Therapy.mp. or exp Multimodality Cancer Therapy/
14. (multimodal treatment or multimodal treatments).mp.
15. combined modality therapies.mp.
16. (hyperfractionated radiotherapy or hyperfractionated radiotherap$ or hyperfractionated radiotherapies).mp.
17. (hyperfractionated radiation or hyperfractionated radiation$).mp.
18. (hyperfractionated irradiation or hyperfractionated irradiation$).mp.
19. accelerate$ hyperfractionate$.mp.
20. hyperfractionation.mp.
21. radiotherapy dosage.mp. or exp Radiation Dose/ or exp Radiation Dose Distribution/
22. radiotherapy dosages.mp.
23. (radiation dose-response relationship or radiation dose-response relationships).mp.
24. (dose fractionation or dose fractionations).mp.
25. (radiotherapy dose fractionation or radiotherapy dose fractionations).mp.
26. or/1-25
3. For Children and young adults, we used the following Emtree terms and text words:
1. infant/ or infancy/ or newborn/ or baby/ or child/ or preschool child/ or school child/
2. adolescent/ or juvenile/ or boy/ or girl/ or puberty/ or prepuberty/ or pediatrics/ or female/
3. primary school/ or high school/ or kindergarten/ or nursery school/ or school/
4. or/1-3
5. (infant$ or newborn$ or (new adj born$) or baby or baby$ or babies or neonate$ or perinat$ or postnat$).mp.
6. (child$ or (school adj child$) or schoolchild$ or (school adj age$) or schoolage$ or (pre adj school$) or preschool$).mp.
7. (kid or kids or toddler$ or adoles$ or teen$ or boy$ or girl$).mp.
8. (minors$ or (under adj ag$) or underage$ or juvenil$ or youth$ or young adult or young adults or young adult$).mp.
9. (puber$ or pubescen$ or prepubescen$ or prepubert$).mp.
10. (pediatric$ or paediatric$ or peadiatric$).mp.
11. (school or schools or (high adj school$) or highschool$ or (primary adj school$) or (nursery adj school$) or (elementary adj school)
or (secondary adj school$) or kindergar$).mp.
12. or/5-11
13. 4 or 12
4. For randomised controlled trials (RCTs) and controlled clinical trials (CCTs), we used the following Emtree terms and text
words:
1. Randomized Controlled Trial/
2. Controlled Clinical Trial/
3. randomized.ti,ab.
4. placebo.ti,ab.
5. randomly.ti,ab.
6. trial.ti,ab.
7. groups.ti,ab.
8. drug therapy.sh.
9. or/1-8
10. Human/
11. 9 and 10
Final search: 1 and 2 and 3 and 4
[mp = title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer; $= zero
or more characters; /= Emtree term; sh = subheading; ti,ab = title or abstract]
Appendix 4. Search strategy for conference abstracts (Embase.com)

1.’international society of paediatric oncology’:nc AND [embase]/lim
2.’international society of pediatric oncology’:nc AND [embase]/lim
3.’international symposium on pediatric neuro-oncology’:nc AND [embase]/lim
4.’society for neuro-oncology’:nc AND [embase]/lim
5.’european association of neuro-oncology’:nc AND [embase]/lim
6.’european association of neurooncology’:nc AND [embase]/lim
7.#1 OR #2 OR #3 OR OR #4 OR #5 OR #6 AND [1-1-2010]/sd NOT [19-8-2015]/sd
8.pons OR pontine OR brainstem OR ’brain stem’ AND [embase]/lim
9.glioma* OR tumor* OR neoplasm* AND [embase]/lim
10.radiotherap* OR radiation AND [embase]/lim
11.#7 AND #8 AND #9 AND #10
[nc = conference name; lim = limit; sd = since date; * = zero or more characters]
Appendix 5. Search strategy for ongoing trial registers

1. www.isrctn.com (ISRCTN register)
Search terms were: glioma
2. apps.who.int/trialsearch (WHO register)
In advanced search page, search terms were glioma ORtumor ORneoplasm for Conditions, radiotherapy OR radiation for Inter-
ventions, brainstem OR brain stem OR pontine OR pons for Titles.
3. https://clinicaltrials.gov (NIH registered)
In advanced search page, search terms were glioma ORtumor ORneoplasm for Conditions, radiotherapy OR radiation for Inter-
ventions, brainstem OR brain stem OR pontine OR pons for Titles.
CONTRIBUTIONS OF AUTHORS
X Hu: selection of trials, risk of assessment of trials, data extraction, data analyses, GRADE assessment, preparation of the Summary
of Findings tables, contributed to the results and discussion, and developed the draft of the review.
Y Fang: protocol and review development; searching for trials, selection of trials, data extraction, data analyses, GRADE assessment,
preparation of the Summary of Findings tables , and contributed to the results and discussion.
X Hui: protocol and review development, searching for trials, risk of bias assessment of trials, data extraction, data analyses, and review
development.
Y Jv: protocol development, searching for trials, and contributed to discussion.
C You: organization of the revision process, and contributed to the discussion.
DECLARATIONS OF INTEREST
None known.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

In the protocol, we specified that diagnostic criteria for diffuse brainstem glioma should be made by magnetic resonance imaging (MRI)
or histological tests. Furthermore, the MRI criteria for the diagnosis of diffuse brainstem glioma was a T1 isointense or hypointense,
T2 hyperintense tumour originating in the pons, with at least 50% involvement of the pontine region. In our review, both included
studies performed MRI but neither mentioned T1 or T2. If the diagnostic criteria remained unchanged as the protocol, neither of
the included study could be considered as eligible and important information might have been missed. Therefore, we modified the
diagnostic criteria as ’Diagnosis of diffuse brainstem glioma made as described in the original studies’.
Our previous definition of the neurological response (i.e. defined as the number of participants with a complete or partial remission)
was actually in duplicate with that of radiological response (i.e. number of participants with a reduction in tumour size of more than
50%). Therefore, we changed the definition of the neurological response into ’the number of participants with improved neurological
function’.
In the protocol, PFS was defined as time from study entry to progression. However, the starting time point for PFS calculation varied
among different studies. Therefore, in this review, definition of PFS has been changed and PFS was calculated from time of diagnosis,
study entry, or treatment to progression.
We added ’event-free survival’ as one of the secondary outcome since some studies measure event-free survival while some measured
progression-free survival and some measured both parameters.
We did not mention ’Summary of findings’ tables in the protocol. We reconsidered this and decided that ’Summary of findings’ tables
were necessary and would help the reader to obtain the important information quickly. Therefore, we added the tables to the review.
INDEX TERMS
Medical Subject Headings (MeSH)
∗ Brain Stem; ∗ DoseFractionation; Brain Neoplasms [mortality; pathology; ∗ radiotherapy]; Glioma [mortality; pathology;
∗ radiotherapy]; Neoplasm Invasiveness; Randomized Controlled Trials as Topic
MeSH check words

Adolescent; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Young Adult

Radiotherapy For Diffuse Brainstemglioma in Children and Young Adults (Review)

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Cochrane Database of Systematic Reviews

Radiotherapy for diffuse brainstem glioma in children and

Hu X, Fang Y, Hui X, Jv Y, You C

Hu X, Fang Y, Hui X, Jv Y, You C.

Radiotherapy for diffuse brainstem glioma in children and

1 Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China

Editorial group: Cochrane Childhood Cancer Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Assumed risk Corresponding risk

Conventional radio- Hyperfractionated ra-

GRADE Working Group grades of evidence

Criteria for considering studies for this review

Assessment of reporting biases

Figure 3. Forest plot of comparison: 1 Hyperfractionated radiotherapy versus conventional radiotherapy,

Figure 4. Forest plot of comparison: 1 Hyperfractionated radiotherapy versus conventional radiotherapy,

Mandell 1999 were available for review of post-treatment MRI.

3.16, 95% CI 0.34 to 29.51, P value = 0.31), infection NOS/

Figure 7. Forest plot of comparison: 2 Hypofractionated radiotherapy versus conventional radiotherapy,

Figure 8. Forest plot of comparison: 2 Hypofractionated radiotherapy versus conventional radiotherapy,

Assumed risk Corresponding risk

Conventional radio- Hypofractionated ra-

GRADE Working Group grades of evidence

Freeman 1998 Khatua 2011

Parmar 1998 Vanan 2015

Characteristics of included studies [ordered by study ID]

Methods Phase III prospective RCT

Outcomes Overall survival (defined as time from diagnosis to time of death)

Notes Sponsor: National Cancer Institute

Bias Authors’ judgement Support for judgement

Methods Phase III RCT

Notes Sponsor: Children’s Cancer Hospital Egypt 57357

Bias Authors’ judgement Support for judgement

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Ahmed 2012 Conference abstract was in a full-text report

Freeman 1993 Not an RCT, quasi-RCT, or CCT; cohort study

Janssens 2013 Not an RCT, quasi-RCT, or CCT; matched-cohort study

Kretschmar 1993 Not an RCT, quasi-RCT, or CCT; cohort study

Negretti 2011 Not an RCT, quasi-RCT, or CCT; retrospective studies

Packer 1990 Not an RCT, quasi-RCT, or CCT; cohort study

Packer 1993 Not an RCT, quasi-RCT, or CCT; cohort study

Packer 1994 Not an RCT, quasi-RCT, nor CCT; cohort study

Roos 2014 Not an RCT, quasi-RCT, nor CCT; comment letter

Sun 2013 Not an RCT, quasi-RCT, nor CCT; retrospective study

Characteristics of ongoing studies [ordered by study ID]

Outcomes Primary outcome: median overall survival (time frame: 3 years)

Starting date February 2013

Comparison 1. Hyperfractionated radiotherapy versus conventional radiotherapy

Comparison 2. Hypofractionated radiotherapy versus conventional radiotherapy

Comparison: 1 Hyperfractionated radiotherapy versus conventional radiotherapy

Outcome: 1 Overall survival

Mandell 1999 64 66 0.07 (0.18) 100.0 % 1.07 [ 0.75, 1.53 ]

Total (95% CI) 64 66 100.0 % 1.07 [ 0.75, 1.53 ]

Analysis 1.2. Comparison 1 Hyperfractionated radiotherapy versus conventional radiotherapy, Outcome 2

Comparison: 1 Hyperfractionated radiotherapy versus conventional radiotherapy

Outcome: 2 Event-free survival

Mandell 1999 64 66 0.23 (0.21) 100.0 % 1.26 [ 0.83, 1.90 ]

Total (95% CI) 64 66 100.0 % 1.26 [ 0.83, 1.90 ]

0.01 0.1 1 10 100

Comparison: 1 Hyperfractionated radiotherapy versus conventional radiotherapy

Outcome: 3 Radiological response

Study or subgroup Hyperfractionated Conventional Risk Ratio Weight Risk Ratio