65Radiotherapy dose fractionation Third edition
Background
Radiotherapy (RT) is an important modality of therapy in the local control of paediatric
malignancies and the majority of paediatric tumours are radiosensitive. However, for many
children, long-term survival comes at the price of long-term eects of treatment. Long-term
eects of radiotherapy include soft tissue hypoplasia, impaired bone growth, endocrine
dysfunction, impaired fertility, neuropsychological eects of irradiation of the central
nervous system (CNS) and radiation-induced malignancy.
Currently, 40–50% of children with cancer receive radiotherapy as part of their initial
treatment. It is extremely important that radiotherapy for children should be undertaken only
in specialised centres associated with the Children’s Cancer and Leukaemia Group (CCLG)
paediatric oncology centres. The paediatric radiotherapy team should include a specialist
paediatric therapy radiographer, specialist nurse and play specialist. The components of
the paediatric multidisciplinary team are described in The Royal College of Radiologists’
Good practice guidance for paediatric radiology.
1
Wherever possible parents of children requiring radiotherapy should be oered the
opportunity for their child to have treatment within an appropriate National Cancer
Research Institute (NCRI) portfolio or international trial.
Radiotherapy for children should only be carried out in designated departments associated
with CCLG centres. The current document summarises typical dose-fractionation policies
as applied in CCLG centres in the UK.
Leukaemia
The leukaemias account for the largest group of paediatric malignancies, with
approximately 80% having acute lymphoblastic leukaemia (ALL). The remainder have acute
non-lymphoblastic leukaemia (ANLL), usually acute myeloid leukaemia (AML) or, rarely,
chronic myeloid leukaemia (CML). Currently more than 85% with ALL and 65% with AML
are long-term survivors. During the 1960s and 1970s, the routine use of prophylactic whole-
brain radiotherapy (WBRT) and intrathecal methotrexate reduced the risk of CNS relapse
to less than 10%. In current protocols, the use of WBRT is no longer standard but may be
employed for patients who present with CNS involvement.
2
Recommendation
Whole brain radiotherapy childhood leukaemia:
24 Gray (Gy) in 15 fractions of 1.6 Gy daily over 3 weeks (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
Boys who suer a testicular relapse may be treated with testicular radiotherapy, generally
with electrons, encompassing a clinical target volume (CTV) which includes both testes,
scrotum and the inguinal canal supero-laterally as far as the deep inguinal ring.
4
9.
Paediatric cancer
66Radiotherapy dose fractionation Third edition
Recommendation
Testicular irradiation in childhood leukaemia:
24 Gy in 12 fractions of 2.0 Gy daily over 2.5 weeks (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
Total body irradiation (TBI)
As in the treatment of adults with haematological malignancies, TBI is an important
technique usually used together with high-dose cyclophosphamide (cyclo-TBI) as the
conditioning regimen prior to bone marrow transplantation (BMT). Individual techniques
for TBI have evolved in dierent departments, often depending on availability of
treatment machines. TBI planning may use CT and dosimetry is usually based on in vivo
measurements. For such a large and complex target volume, it is not feasible to adhere to
the International Commission on Radiation Units and Measurements (ICRU) 50 guidelines
of a range of -5% to +7%; a range of -10% to +10% is more realistic.
5–7
For children with CNS relapse in ALL, a cranial boost may be advised in addition to the TBI.
8
Recommendations
TBI in childhood leukaemia:
14.4 Gy in 8 fractions of 1.8 Gy twice daily with a minimum interfraction interval of 6
hours over 4 days (Level C)
12 Gy in 6 fractions of 2 Gy twice daily with a minimum interfraction interval of 6 hours
over 4 days (Level C)
Cranial boost where indicated after TBI:
5.4 Gy in 3 fractions of 1.8 Gy over 3 days (Level D)
TBI for bone marrow transplant (BMT) in benign haematological disorders, for
example, Fanconi’s anaemia and thalassaemia:
2–3 Gy single dose (Level D)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
Hodgkin lymphoma
The survival rate for children with Hodgkin lymphoma is approximately 90%. In current
protocols, the aims are to maintain this good overall survival rate and reduce long-term
eects.
9–11
Typically patients are selected for radiotherapy if their disease does not respond
well on 18F-uorodeoxyglucose (18F-FDG) positron emission tomography-computed
tomography (PET-CT) reassessment after initial chemotherapy. All sites initially involved are
usually treated.
67Radiotherapy dose fractionation Third edition
Recommendations
Hodgkin lymphoma: sites of initial involvement:
19.8 Gy in 11 fractions over 2.2 weeks. Where there is signicant residual disease
(Level B)
Hodgkin lymphoma: residual disease following chemotherapy or bulky sites:
Boost of 10 Gy in 5 fractions over 1 week (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
Neuroblastoma
Patients with neuroblastoma are risk-stratied at presentation by age, stage and molecular
pathology. External-beam radiotherapy to the primary tumour bed is indicated for all
patients with ‘high risk’ disease (for example, aged greater than one year with stage
M4 disease at presentation, patients with localised disease and MYCN amplication
at presentation, and selected patients with intermediate-risk disease). The intent is to
maximise the probability of local tumour control following chemotherapy and surgical
resection of the primary tumour.
12–14
Recommendation
Neuroblastoma: postoperative radiotherapy to the tumour bed:
21 Gy in 14 fractions over 3 weeks (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
Wilms’ tumour (nephroblastoma)
In Europe, the series of International Society of Paediatric Oncology (SIOP) studies have
been based on preoperative chemotherapy to ‘downstage’ the primary, reducing the
surgical morbidity, particularly the number who have tumour rupture at surgery and the
number who require ank radiotherapy. Initial treatment is with preoperative chemotherapy
with actinomycin-D and vincristine, with delayed nephrectomy after six weeks of
preoperative chemotherapy. Postoperative adjuvant therapy is based on subsequent
pathological staging and allocation of risk status (good risk versus intermediate risk versus
poor risk histology).
Postoperative chemotherapy is given using the drugs vincristine, actinomycin D and
sometimes other drugs; the number of drugs and duration are dependent upon the staging.
Postoperative ank radiotherapy is employed for stage III patients, that is, those with
incompletely resected primary tumours, pre- or perioperative tumour rupture or
histologically involved lymph nodes. Patients with gross pre- or perioperative tumour
68Radiotherapy dose fractionation Third edition
rupture or disseminated intra-abdominal disease should receive whole abdominal
radiotherapy.
15
Patients with lung metastases who do not achieve a complete response to
chemotherapy should receive whole lung radiotherapy.
16
Recommendations
Wilms’ tumour: postoperative radiotherapy to ank:
Intermediate risk: 14.4 Gy in 8 fractions of 1.8 Gy daily over 1.5 weeks (Level B)
High risk: 25.2 Gy in 14 fractions of 1.8 Gy over 2 weeks (Level B)
Wilms’ tumour: whole abdominal radiotherapy
Depending upon histopathological risk group:
15 Gy in 10 fractions over 2 weeks (Level B) or
21 Gy in 14 fractions of 1.5 Gy over 2 weeks (Level B)
Wilms’ tumour: whole lung radiotherapy
15 Gy in 10 fractions of 1.5 Gy over 2 weeks (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
Rhabdomyosarcoma
The basis of treatment has generally involved the use of intensive chemotherapy with
the aim of improving survival, and reducing the use of local therapy with surgery and/or
radiotherapy, thus minimising long-term eects. Treatment is stratied according to risk
groups based on parameters such as histological subtype (embryonal versus alveolar
histology), stage of disease and primary tumour site. Patients in the ‘low-risk’ category, that
is, those with localised tumours which are microscopically completely resected, are treated
with chemotherapy using actinomycin-D and vincristine for nine weeks.
17–19
Standard
risk tumours are those which are locally more extensive but at selected favourable sites,
for example, the vagina, uterus or paratestis, and are treated with ifosfamide, vincristine
and actinomycin-D. Poor responders switch to a six-drug combination. High-risk tumours
include other incompletely resected tumours, including all those arising in parameningeal
sites (nasopharynx, middle ear) and those with involved lymph nodes. These are treated
with further chemotherapy.
Brachytherapy, typically in conjunction with conservative surgery, may be considered for
very carefully selected patients such as those with localised embryonal bladder/prostate
and female genital tract rhabdomyosarcoma. Such patients should be referred to a
specialist centre with experience in this type of treatment.
69Radiotherapy dose fractionation Third edition
Recommendations
Embryonal rhabdomyosarcoma:
Post-chemotherapy, no surgery:
41.4 Gy in 23 fractions of 1.8 Gy following complete response to chemotherapy and
50.4 Gy in 28 fractions of 1.8 Gy for incomplete response (Level B)
Consider boost of 5.4 Gy in 3 fractions of 1.8 Gy for large tumours and/or poor
response to chemotherapy
Postoperative:
36 Gy in 20 fractions of 1.8 Gy (Level B)
Alveolar rhabdomyosarcoma:
Post-chemotherapy, no surgery:
50.4 Gy in 28 fractions of 1.8 Gy (Level B)
Consider boost of 5.4 Gy in 3 fractions of 1.8 Gy for large tumours and/or poor
response to chemotherapy
Postoperative:
41.4 Gy in 23 fractions of 1.8 Gy (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
Ewings sarcoma/peripheral primitive neuroectodermal tumour
(PPNET)
Initial treatment is with chemotherapy in conjunction with the appropriate use of local
therapy. The decision as to whether surgery, radiotherapy or both should be employed
for local control of the primary tumour demands careful multidisciplinary discussion. In
previous series, patients’ survival has been better following local treatment with surgery
compared with radiotherapy alone. However, these series are confounded by selection bias
with patients with smaller tumours selected for surgery.
20,21
70Radiotherapy dose fractionation Third edition
Recommendations
Ewings and PPNET:
Phase 1 and postoperative volume:
45 Gy in fractions of 1.8 Gy over 5 weeks (Level B)
Phase 2 for macroscopic disease:
9.6 Gy in fractions of 1.8–2.0 Gy (Level B)
Ewings and PPNET:
Whole lung radiotherapy:
15 Gy in 10 fractions over 2 weeks (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
Central nervous system tumours
Low-grade astrocytoma
These comprise the most common group of paediatric CNS tumours. Modern
management is based on the recognition that low-grade gliomas may undergo long
periods of ‘quiescence’ even when not completely resected. The current ve-year survival
rate is 85%, but late relapse is not uncommon.
Treatment is initially with surgical resection, as complete as is considered safe.
In the recently closed SIOP Low-Grade Glioma (LGG2) study, those over the age of seven
were treated with radiotherapy. Those aged seven or under received chemotherapy with
the aim of delaying radiotherapy.
22
Recommendation
Low-grade astrocytoma:
54 Gy in 30 fractions of 1.8 Gy daily over 6 weeks (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
For patients who present with spinal cord primary low-grade glioma, the management
policy will be similar.
Recommendation
Low-grade spinal astrocytoma:
50.4 Gy in 28 fractions of 1.8 Gy over 5.5 weeks (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
71Radiotherapy dose fractionation Third edition
High-grade astrocytoma
Unlike adults, high-grade astrocytomas are uncommon in childhood. However, in
common with adults, the outlook is generally poor. Survival is currently approximately
20% at ve years. Current management is based on surgical resection and postoperative
chemoradiotherapy with temozolomide.
23
Recommendation
High-grade astrocytoma:
Under 14 years: 54 Gy in 30 fractions over 6 weeks (Level B)
Over 14 years: 60 Gy in 30 fractions over 6 weeks (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
Ependymoma
The overall ve-year survival rate is approximately 50–60%. In the majority of studies,
prognostic factors include tumour grade and extent of resection. The predominant
site of relapse is within the local tumour bed. The majority of collaborative groups now
recommend an increased radiotherapy dose (59.4 Gy with conformal techniques) taking
care to limit the dose to the brainstem and other adjacent critical structures.
24
Recommendation
Ependymoma:
59.4 Gy in 33 fractions in 6.5 weeks (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
Medulloblastoma
Medulloblastoma is a primitive neuronal tumour which arises in the cerebellum. It is
notable for its propensity for metastatic spread via the craniospinal uid (CSF) and its
radiosensitivity. PNET arises elsewhere in the CNS, usually the supratentorial cerebral
cortex, where they are referred to as supratentorial PNET (StPNET). PNET arising in the
pineal area are referred to as pineoblastoma.
Standard therapy for medulloblastoma/PNET is initial maximal surgical resection followed
by craniospinal radiotherapy and a ‘boost’ to the primary site.
Current studies are based on the allocation of risk status. Standard-risk disease refers
to non-metastatic medulloblastoma with complete or near-complete surgical resection.
High-risk disease includes patients with medulloblastoma with metastases or postsurgical
residue and StPNET.
It is standard practice to employ adjuvant chemotherapy (vincristine, CCNU, cisplatin)
following radiotherapy for patients with standard-risk disease and more intensive
chemotherapy for high-risk disease.
25–27
72Radiotherapy dose fractionation Third edition
Recommendations
Medulloblastoma/PNET:
Standard-risk craniospinal:
23.4 Gy in 13 fractions over 2.5 weeks (Level B) followed by boost to tumour bed or
whole posterior fossa
30.6 Gy in 17 fractions in 3.5 weeks (Level B)
High-risk medulloblastoma and StPNET craniospinal
36.0 Gy in 20 fractions over 4 weeks (Level B)
39.6 Gy in 22 fractions over 4.4 weeks (St Jude’s regimen for M2–3) (Level B)
Followed by boost to primary site to a total of 54.0–55.8 Gy in 1.8 Gy fractions (Level B)
Boost to sites of metastases to a total of 50.4 Gy (spinal) and 54–55.8 Gy (intracranial)
in 1.8 Gy fractions (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
Intracranial germ cell tumours
Intracranial germ cell tumours account for approximately 30% of paediatric germ cell
tumours. For germinoma, although in the past craniospinal radiotherapy has been standard,
future trials will explore the role of chemotherapy and whole ventricular radiotherapy.
Patients with non-germinoma receive platinum based chemotherapy and radiotherapy,
either focal for non-metastatic disease or craniospinal for metastatic disease.
28,29
Recommendations
Germinoma – craniospinal radiotherapy, no chemotherapy:
24 Gy in 15 fractions over 3 weeks followed by boost to primary site (Level B)
16 Gy in 10 daily fractions over 2 weeks (Level B)
Germinoma – post-chemotherapy: whole ventricular radiotherapy:
24 Gy in 15 fractions over 3 weeks followed by boost to residual disease (Level B)
16 Gy in 10 daily fractions over 2 weeks (Level B)
Non-germinomatous tumours – primary tumour:
54 Gy in 30 fractions over 6 weeks (Level B)
Meningeal metastases – craniospinal axis:
30 Gy in 20 fractions over 4 weeks (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
73Radiotherapy dose fractionation Third edition
Brain stem glioma
This includes tumours arising in the midbrain, pons and medulla. Historically they were
regarded as a single entity. However, it is now clear that they can be subdivided into focal
(5–10%), dorsal exophytic (10–20%), cervico-medullary (5–10%) and diuse intrinsic
tumours (75–85%).
The majority of children with brain stem gliomas have diuse intrinsic pontine glioma
(DIPG), which are usually high-grade astrocytomas. Their prognosis is very poor with a
median survival of approximately nine months and very few long-term survivors.
30
Recommendation
Brain stem glioma:
54 Gy in 30 fractions over 6 weeks (Level B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
3
References
Further reading
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Williams & Wilkins, 2011.
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Thorp N, Taylor RE. Management of central nervous system tumours in children. Clin Oncol (R Coll Radiol)
2014; 26(7): 438–445.
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College of Radiologists, 2012.
2. Pui CH, Howard SC. Current management and challenges of malignant disease in the CNS in
paediatric leukaemia. Lancet Oncol 2008; 9(3): 257–268.
3. www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009 (last accessed
30/9/16)
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childhood: categories and inuence on survival. J Clin Oncol 1984; 2(8): 924–929.
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allogeneic bone marrow transplantation using a straightforward radiotherapy technique. Clin Oncol (R
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References
