Swedish Working Group for Long-term
Follow-up after Childhood Cancer (SALUB)
Follow-up after
Childhood Cancer
V E R SION 5.0 2 010
SALUB 2010 5.0
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CONTENTS
Abbreviations 3
Introduction 4
1. Neurology and neuropsychology
5
2. Heart 7
3. Hearing10
4. Liver11
5. Kidneys12
6. Teeth, oral cavity and salivary glands
15
7. Eyes17
8. Blood and bone marrow
18
9. Lungs19
10. Gastro-intestinal canal
21
11. Endocrinology (non-gonads/fertility)
22
12. Gonads/fertility – girls
25
13. Gonads/fertility – boys
27
14. Metabolic syndrome
30
15. Mammary glands33
16. Skeleton, musculature and soft parts
34
17. Subsequent cancer38
Cytostatics register39
SALUB: Lars Hjorth (Chairman, VSTB, Lund), Christian Moëll (Lund), Birgitta Lannering (Gothenburg), Marianne Jarfelt
(Deputy, Gothenburg), Mikael Behrendtz (Secretary, Linköping), Stefan Söderhäll (SBLG, Stockholm), Johan Arvidson
(BMT, Uppsala), Per Frisk (Deputy, Uppsala), Per-Erik Sandström (VCTB, Umeå), Ulrika Norén-Nyström (Deputy, Umeå),
Cecilia Petersen (Deputy, Stockholm), Stanislaw Garwicz (Emeritus, Lund).
For the Swedish Working Group for Paediatric Radiotherapy: Jack Lindh (Umeå), Beatrice Melin (Umeå), Ulla Martinsson
(Uppsala), Anna-Lena Hjelm-Skog (Stockholm), Gunnar Adell (Linköping), Thomas Björk-Eriksson (Gothenburg/Lund),
Eva Ståhl (Lund), Per Bergström (Umeå).
Other participants: Ulf Thilén (Cardiologist, Lund), Eva Nylander (Clinical Physiologist, Linköping), Kirsi Jahnukainen
(Paediatric Oncologist, Helsinki), Ann-Charlotte Söderpalm (Orthopedic surgeon, Gothenburg), Richard Löfvenborg
(Orthopedic surgeon, Umeå), Petra Selin (Audiologist, Umeå), Mats Bågesund (Paedodontist, Linköping), Maria Elfving
(Paediatric Endocrinologist, Lund), Lars Hagenäs (Paediatric Endocrinologist, Stockholm).
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Abbreviations
ALL
Acute Lymphatic Leukemia
ARDS
Acute Respiratory Distress Syndrome
BMI
Body Mass Index
CNS
Central Nervous System
DEXA
Dual Energy X-ray Absorptiometry
ECGElectrocardiogram
GH
Growth Hormone
GVHD
Graft Versus Host Disease
GyGray
HR-CT
High Resolution Computerized Tomography
MR
Magnetic Resonance
NSAID
Non-Steroid Anti-Inflammatory Drugs
OAE
Oto-Acoustic Emissions
PEF
Peak Expiratory Flow
SBLG
Swedish Childhood Leukemia Group
TBI
Total Body Irradiation
VCTB
Swedish Working Group for CNS Tumours in Children
VSTB
Swedish Working Group for Solid Tumours in Children
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Introduction
The Swedish Working Group for Long-term Follow-up after Childhood Cancer (SALUB)
has the goal of linking a recommendation for follow-up of late complications to all future
treatment protocols, which will be carried out in collaboration with the Swedish Working
Group for Paediatric Radiotherapy.
As a part of this work, SALUB has compiled organ-related recommendations for follow-up,
depending on the treatment given. The aim is to provide all physicians responsible for
follow-up with documentation stating the follow-up that continues to be important when
the patient leaves paediatric oncology. This can to some extent direct the medical institution to which the patient is referred. However, there is no reason not to follow the recommendations earlier on in the process as well.
An overriding recommendation such as this shall function as a support in the planning
of follow-up and prevent important examinations from being missed or the patient being
exposed to unnecessary examinations. Each follow-up process must to some extent be
individually adapted. The physician with responsibility for care must also weigh in these
individual factors.
It is SALUB’s hope that all former childhood cancer patients get the opportunity to be
followed up in relation to late complications, with some form of feedback to a paediatric
cancer center.
This work does only in some cases bring up recommendations following total body
irradiation (TBI). For such treatment, please see separate recommendations for follow-up.
For further information, please contact any of the following:
Lund:
[email protected], [email protected]
Gothenburg: [email protected], [email protected]
Linköping:[email protected]
Stockholm: [email protected], [email protected]
Uppsala:
[email protected], [email protected]
Umeå:
[email protected], [email protected]
Radiotherapy issues: [email protected]
Date: January 1, 2007
Partially revised April 17, 2008 and April 1, 2010
Translated spring 2012
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1. NEUROLOGY AND NEUROPSYCHOLOGY
Peripheral nervous system
Background/Risk factors
Cytostatic treatment with vincristine often causes acute neuropathy, which in rare cases
can become permanent. If the patient has known or undiagnosed peripheral neuropathy,
even small doses of vincristine can cause neuropathy to become permanent.
The most noticeable motor feature is weakening or disappearance of peripheral reflexes
and awkward walk. Cranial nerve influence, where ptosis is the most common symptom,
can also occur, as can sensory effects, in particular pain/paresthesia.
Cytostatic treatment with cisplatin in high dosages, in particular in older children, can
in rare cases result in chronic sensory neuropathy.
Radiation treatment: permanent nerve damage rarely arises at dosages of <55 Gy.
Follow-up
If the patient does not have any symptoms after treatment is completed, no follow-up is
necessary. Peripheral neuropathy nearly always diminishes with time. If this does not
occur, the state becomes stationary, such as permanent disappearance of patellar reflexes.
Neurophysiological examination may come into question, as well as assessment by a
physiotherapist/occupational therapist.
Central nervous system
Background/Risk factors
The biggest risk group for neurological and neuropsychological long-term side effects
consists of children with CNS tumours, where the tumour itself, surgery, radiation treatment to the brain and cytostatic treatment each are contributing factors.
Other groups that may be affected, but with less severity, are children with leukemia
being treated with radiation therapy to the head and/or intrathecal cytostatics as well as
children going through bone marrow transplant with total body irradiation.
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Low age during radiation treatment increases the risk of permanent damage.
Other CNS conditions, such as postoperative complications and CNS infections, can in-
crease the risk of permanent neurological and neuropsychological problems.
Central neurological damage can result in permanent motor symptoms, such as hemiplegia, ataxia, cranial nerve damage or epilepsy. It can also cause neuropsychological
symptoms, i.e. disruption of various brain functions, such as memory, learning, attention, motivation, speed, flexibility and moods. Social problems in the form of exclusion
and isolation easily arise as a consequence of damage to these functions.
Follow-up
Children with remaining motor symptoms should be followed up within paediatric rehabilitation. Epilepsy should be followed up by a paediatric neurologist.
The neuropsychological damage usually becomes obvious after a few years, and can subsequently appear to deteriorate, as requirements on the child’s performance increase
with age.
It is recommended that all children who have received radiation treatment to the brain
should be the subject of a neuropsychological investigation within 1-2 years. Depending
on the result, this should be repeated at an interval of a few years. The neuropsychological
investigation should form the basis for the pedagogic support the child may need at
school. Children who have had only surgery on their tumours may in some cases have
neurological and neuropsychological complications that can require a similar type of
follow-up.
Apart from pedagogic support, the patient/family will usually need some form of psychological support, at least for some time, in order to adapt to the change that is entailed
in suffering from neuropsychological problems. Follow-up in adulthood should be assessed individually and on the basis of the local organization.
It is particularly important to exclude damage to vision and hearing, as these can worsen any neurological and neuropsychological disruptions.
CNS tumours often cause a number of other complications besides purely neuropsychological ones. Specific recommendations for follow-up of brain tumours developed by
VCTB are available from www.blf.net/onko/index.htm. (at present only in Swedish).
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2. HEART
Background
Once the heart of a fetus has developed completely, the number of myocytes cannot increase. During childhood, the heart grows with the child through development/growth
of the heart muscle cells and their organelles. The heart muscle cells contain much
mitochondria and contractile elements, which adapt with age to the adult myocyte. Heart
muscle cells contain, in relative terms, low levels of antioxidant enzymes, which is of importance for the anthracycline cardiotoxicity.
What is particularly feared is late cardiomyopathy (debut > 1 year after completed
therapy). This can debut after many years (cumulative incidence 15 years after completed
treatment is around 5%), is progressive and requires regular follow-up by a cardiologist
and possibly therapy.
Risk factors
The most important risk factors are the following:
1) Cytostatic treatment with anthracyclines
Doxorubicin equivalent dosage (see below).
a) Dose/dosage occasion or weekly dose (>45 mg/m²)
b) Accumulated dose (>300 mg/m²)
On the other hand, the infusion time does not appear to play the same role in children
as in adults.
Currently recommended maximum doses:
Doxorubicin: <2 years: 10 mg/kg, >2 years: 300 mg/m², adults: 450-550 mg/m²
Daunorubicin: 450-550 mg/m² (adults)
Epirubicin: 900 mg/m² (adults)
Idarubicin: 200 mg/m² (adults)
Mitoxantrone: 160 mg/m² (adults)
Dosage equivalent (roughly): Doxo-Dauno-Epi-Ida-Mitox : 1: 1: 0.5: 2: 2.5
2) Radiation treatment to the heart
(risk of myocardial fibrosis and cardiovascular changes).
At the same time, there is data indicating individual-dependent sensitivity (independent of dosage), gender-related sensitivity (girls > boys, possibly due to relatively higher
concentration levels due to differential fat distribution), age (more sensitive the younger
the patient is during treatment), ethnicity (blacks have increased inherent risk of other
cardiomyopathies), Trisomy 21 (concurrent hypothyroidism, pulmonary hypertension,
cardiac vitia excluded)
There is increased risk in patients in adulthood with metabolic syndrome, hypertension,
GH deficiency, pregnancy, competitive sports at elite level, radiation therapy solely to the
heart and heredity for early onset cardiovascular disease.
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Goal
The goal is to find those patients who after completed treatment with potentially cardiotoxic pharmaceuticals and/or radiation treatment to the heart have echo-cardiographical
changes that require regular follow-up by a cardiologist once the patient leaves the paediatric oncology setting due to age (after the age of 18).
Follow-up
Examination shall be carried out using ECG and echo-cardiography showing heart function in systole and diastole. The findings shall be compared to normal values for the age.
As a supplement to the examinations, a targeted medical history shall be compiled relating to subjective physical function levels and cardial symptoms, in particular arythmia.
Based on currently existing treatment protocols in use in Sweden, around 70% of patients treated with anthracyclines receive a cumulative dose of ≤210 mg/m², which means
that 30% receive ≥210 mg/m².
Anthracyclines and radiation treatment to the heart is given to a limited group of
patients. The group that only receives radiation treatment with the heart in the radiation
field is also limited.
Group 1
(Anthracycline treatment ≤210 mg/m², no radiation treatment to the heart):
1) Echo-cardiography within 6 months after completed anthracycline treatment.
2) Echo-cardiography in early puberty and at age 18 (before transfer to adult clinic/late
effect clinic). Some regard to the time interval between examination 1 and 2 depending
on age at diagnosis.
3) Echo-cardiography during adulthood is not recommended routinely.
4) For girls, heart assessment should be carried out in conjunction with pregnancy.
5) For both sexes, regular heart assessment should be carried out on participants in
competitive sport at elite level.
Group 2
(Anthracycline treatment ≥210 mg/m², no radiation treatment to the heart):
1) Echo-cardiography within 6 months after completed anthracycline treatment.
2) Echo-cardiography after 5 years, in early puberty and at age 18. Depending on the age
at diagnosis, the check-ups should be adjusted, but 2 echo-cardiographies should have
been carried out within a 10 year period.
3) Echo-cardiography regularly every 5 years during adulthood is recommended.
4) See points 4 and 5 for Group 1 above.
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Group 3
(Anthracycline treatment and radiation treatment with part of the heart in the radiation
field to >20 Gy):
1) Echo-cardiography within 6 months after completed anthracycline treatment.
2) Echo-cardiography after 5 years, in early puberty and at age 18 (before transfer to
adult clinic/follow-up clinic). Some reference to time interval between examination 1
and 2 depending on age when contracting disease.
3) Echo-cardiography and exercise tests are recommended every 5 years during
adulthood.
4) For girls, heart assessment in conjunction with pregnancy.
5) For both sexes, regular heart assessment should be carried out on participants in
competitive sport at elite level.
Group 4
(Radiation treatment with part of the heart in the radiation field):
If radiation dose >20 Gy, follow-up with echo-cardiography and excercise tests should be
carried out every 5 years.
Other
Patients with abnormal findings should be offered continuous check-ups with a cardiologist considering the risk of progressive symptom development and possible need for
treatment. This follow-up strategy should be planned by the cardiologist.
Others should be offered regular check-ups with or without echo-cardiography depending on group affiliation according to the foregoing.
Women should be assessed by a cardiologist in conjunction with pregnancy.
Participants in elite level sports who have previously received anthracycline treatment
should be assessed by a cardiologist.
If the echo-cardiography is normal at age 18, there is no cause for restrictions relating to
scuba-diving certificates.
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3. HEARING
Background
Impaired hearing after childhood cancer treatment affects the treble area in particular.
It should therefore be clear from any referral that an assessment of this area is particularly important. The method to be used in each individual case should be decided by the
responsible audiologist and depends on the child’s age and ability to cooperate during
the examination.
Audiometry is the method that best determines whether the treble hearing is normal.
For this reason it cannot be completely excluded that the treble hearing has been affected
before such an examination has been carried out.
Risk factors:
- Age below 5 at treatment.
- Cumulative dose of cisplatin or carboplatin.
- Combination of cisplatin/carboplatin and radiation treatment.
- Radiotherapy with fields that include the ear, including total body irradiation.
- Low Hb at treatment with cisplatin/carboplatin can be a risk factor.
Goal
The goal is to identify individuals with treatment-triggered hearing impairment and to
give them adequate follow-up/treatment via hearing care services.
Follow-up
A. Directly after completion of treatment.
B. 1 year after completion of treatment.
C. All children who have received treatment at an early age and who have only been
assessed with brain stem audiometry or OAE (oto-acoustic emissions) shall be
examined using conventional audiometry when the child can participate.
This normally occurs at the age of 4.
For normal hearing at B or C, a renewed hearing test should only be carried out following
clinically suspected hearing impairment.
For abnormal hearing at B or C, a renewed hearing test should be carried out in accordance with the assessment of a responsible audiologist.
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4. LIVER
Background:
Acute liver impairment is relatively common during childhood cancer treatment, but
chronic liver impairment is very seldom seen. It is important to remember that patients
whose liver function is affected by hepatitis are extra vulnerable to hepatotoxic treatment.
Risk factors
- Graft versus host disease (GVHD)
- Radiotherapy to the liver. Doses >20 Gy to the whole liver or >40 Gy to half the liver
entail increased risk for impaired function.
- Cytostatics can cause permanent liver damage. This is evaluated individually in
conjunction with therapy and completion of therapy.
- Blood transfusion with virus transfer.
Goal
The goal is to identify the individuals requiring specific follow-up after completion of
treatment.
Follow-up
Directly after completion of treatment, sampling for ASAT, ALAT, bilirubin, ALP and
hepatitis antibodies should be carried out.
For normal values
New testing should only be carried out on clinical suspicion of liver impairment, e.g.
hepatomegaly, icterus or ascites.
For abnormal values
Renewed testing carried out 1-2 times per year depending on abnormality.
For permanent abnormality
Contact a hepatologist to consider liver biopsy.
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5. KIDNEYS
Background
The glomerular filtration increases sharply after birth and reaches an even level before
the age of two, which remains until adulthood. For the tubular function, both reabsorption and secretion, as well as the concentration ability, are low at birth and then increases after weeks or months, depending on the filtered substance. Each kidney contains
approximately one million nephrons, which entail a large reserve capacity.
The ability of the kidneys to compensate for various anomalies is great, but once the
number of nephrons has been reduced sufficiently, or once the tubular function is sufficiently affected, the ability to compensate fully for various anomalies is reduced.
Risk factors
Some treatments can cause acute kidney damage, while others can cause chronic and
even progressive damage, which in the worst cases can entail need for dialysis and/or
kidney transplants.
Cytostatics
Of the greatest practical importance is any permanent kidney impairment that can be
seen after treatment with ifosfamide in particular and cisplatin to some extent. After completion of treatment, the kidney function may improve somewhat, but in some cases it can
deteriorate and lead to kidney insufficiency and impaired growth, among other effects.
There is data indicating that age < 5 years, dosages over a certain level or some combinations of individual cytostatics (ifosfamide, cisplatin, metotrexate, nitrosurea and high
dose treatment with carboplatin or mephalan) can affect the kidney function both acutely
and in the longer term.
Radiation treatment
The degree of late side effects following radiation treatment to the kidney – radiation
nephropathy – is dependent on total radiation dose, daily dose and irradiated kidney
volume. Radiation nephropathy can emerge after a long latency period and become clinically apparent only >10 years after the radiation treatment received.
- Age < 2 years during radiation treatment entails increased risk of complications.
- There is an increased risk of complications if nephrotoxic pharmaceuticals are given
in conjunction with (before, during and after) radiation treatment. This applies in particular to certain cytostatics, such as cisplatin, nitrosurea and anthracycline. It is more
unclear whether actinomycin, ifosfamide, carboplatin or metotrexate potentiate the
effect of radiation treatment. Nephrotoxic antibiotics, such as gentamycin and amphotericin as well as cyclosporin can also enhance the radiation effect.
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Tolerance dosages
At radiation dosages >25 Gy to the whole kidney there is great risk that the kidney function is knocked out entirely in the longer term. In order for the function of the remaining
kidney to be sufficient, 2/3 of it should have received <10 Gy.
If both kidneys are irradiated with a dose <15 Gy given in 7-8 fractions, the risk for serious late side effects should be small, unless treatment with nephrotoxic pharmaceuticals
has been given simultaneously.
Radiation treatment to a kidney and ipsilateral a. renalis can cause stenosis of the
renal artery, resulting in hypertonia, a so-called Goldblatt effect.
Surgery, nephrectomy
Goal
Correlation of Dose with Symptomatic
Radiation Nephropathy
% Incidence
Patienter med bara en kvarvarande njure löpPatients with only one remaining kidney are at
increased risk of clinically important kidney
damage, for example with recurrent UVI or
treatment with potentially nephrotoxic pharmaceuticals (gentamycin, NSAID, etc). This
must be particularly considered if the remaining kidney has been irradiated.
100
90
80
70
60
50
40
30
20
10
0
Thompson, et al.
Dewit, et al.
Avioli, et al.
0
500
1000
Luxton
LeBoutgeois; Dewit; Kim
Kim, et al.
1500 2000 2500
Dose (cGy)
3000
3500 4000
Fig. 4. Dose - response curve generated from data presented in
several series in the literature. An approximate threshold dose
of 15.0 Gy (conventional fractionation) is seen and a plateau is
noted beyond doses 30.0 + Gy.
I.J. Radiation Oncology Biol Phys., vol 31, no 5,
pp 1249-1256, 1995
- To identify patients with impaired
kidney function who require follow-up.
- To identify those patients who at the age of 18 with a long latency period are at risk of
developing kidney function impairment. These patients should be informed to be observant of future symptoms that may be renally related. If the risk is considered great,
regular check-ups should be recommended.
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Follow-up
The examinations should test both glomerular and tubular kidney function using methods that are available in all clinics, at least in regional hospitals. Extended testing should
be carried out in the event of pathological findings.
After completed nephrotoxic treatment
Kidney function: S-creatinine, S-Cystatine-C, GFR (glomerular filtration rate), S-elec-
trolyte status (Ca, PO4, Na, K, Mg), S-acid-alkali status, u-alpha-1-microglobuline, urine
dip-stick.
Other: blood pressure, height and weight.
Annually for 5 years after completed treatment
Kidney function: S-creatinine, S-Cystatine-C, urine dip-stick.
Other: blood pressure, height and weight (until fully grown).
>5 years after completed treatment if there is a high risk of renal complications
Kidney function: S-creatinine, S-Cystatine-C, urine dip-stick, blood pressure every 5 years.
High risk
Ifosfamide treatment (cumulative dose >60 g/m2 body surface)
Cisplatin treatment (cumulative risk dose not known)
Bilateral kidney irradiation >14 Gy
Unilateral kidney irradiation >25 Gy
Patients with abnormal findings should be offered regular examination by a nephrologist,
considering the risk of permanent damage and progressive disease development as well
as any need for treatment. Further follow-up strategy to be planned by the nephrologist.
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6. TEETH, ORAL CAVITY
AND SALIVARY GLANDS
Background
Oral health is important for perceived, complete quality of life. In order to minimize the
risk of oral complications, a paedodontist should be consulted already in conjunction
with the diagnosis being made, and preferably before any treatment starts. The paedodontist should provide a clinical and X-ray examination, advice and any odontological
measures as well as a plan for continued regular check-ups during and after the therapy.
The development of permanent teeth starts in uteri and is complete only at the age of
18-25. At birth, all tooth buds are complete, apart from those of the second molars
(6 months) and third molars (6 years). Calcification is complete at the age of 3, with the
exception of wisdom teeth (7-10 years). Mineralization of the crowns starts at birth and
is in principle complete by the age of around 8 (wisdom teeth 12-16 years). However,
dentine continues layering in towards the dental pulp for an additional number of years.
Root development continues until around 16 years (wisdom teeth 18-25 years).
Damage caused before the tooth buds are complete causes lack of teeth. Damage during calcification results in small/misshapen teeth. Enamel damage can either consist of
roughness in the enamel, which makes it easier for bacteria to gain a hold, or a generally
thinner enamel layer, which makes the teeth more sensitive to bacterial plaque. Root
damage results in the teeth becoming loose more easily.
Risk factors
Cytostatics can cause damage to teeth.
Radiation treatment
>4 Gy can cause damage to teeth.
>10 Gy can damage mature ameloblasts.
>30 Gy causes total stoppage of tooth development.
10-18 Gy in combination with cytostatics can probably cause root distortion.
Tooth damage becomes more pronounced in younger patients and at higher doses of
both cytostatics and radiation treatment.
Saliva protects the teeth against caries and lubricates and protects the oral mucus membrane. Both chemotherapy and radiation treatment affect saliva secretion negatively.
Saliva secretion is most impaired during the first couple of months after treatment.
After this, gradual recovery of the saliva secretion can be expected. If the salivary glands
have been exposed to radiation treatment, the reduced saliva secretion can become permanent. As it is unusual to irradiate all the salivary glands in children, later dryness of
mouth rarely becomes particularly prominent.
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Goal
The goal of the odontological treatment is to achieve and maintain oral health before,
during and after medical treatment.
Parents and patients should be sufficiently informed to understand the value of preventive measures and should – as applicable – carry out the recommended measures according to an individually drawn up program of measures.
Follow-up
During treatment and for at least one year after completion of medical treatment, the
patient should be checked up at least every 3 months by a paedodontist or general dentist
(following contact with a paedodontist). Special notice shall be taken of saliva status,
caries, osteitis, gingivitis, oral hygiene, plaque, sharp edges, eating habits, compliance
in relation to preventive measures, mucus membrane changes, jaw joint problems and
dentition development.
If there are any oral symptoms (dry mouth, pain, swelling or coating of the oral mucus
membrane), a dentist/paedodontist should be contacted as soon as possible in order to
start suitable therapy.
For any intervention in the oral cavity involving bleeding, antibiotic prophylaxis (single
dose) should be given during the first two years after completion of medical treatment
(and thereafter if the risk of infection is increased).
Panorama X-ray in order to investigate tooth development should be carried out 3 years
after completion of medical treatment, as needed and always before any orthodontic
treatment is started.
Orthodontic treatment should not be started until at least 2 years after completion of
medical treatment.
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7. EYES
Background
Cytostatic treatment in itself has no long-term direct toxic effect on eyes. However, radiation therapy can cause problems with vision and eyes in several ways.
Risk factors
The lens in the eye is sensitive to radiation. A very low radiation dose of 1-2 Gy to the lens
itself can hasten the development of cataracts, which leads to practical problems even at
a young age. The risk increases with increased radiation doses.
Very high doses can produce damage to the retina and/or optical nerve, but this is
unusual and constitutes a small practical problem.
Medium radiation doses to the eyelids can affect the glandula tarsa in the eyelids.
These glands produce a secretion that together with the lachrymal fluid reduces the friction in the eye. Symptoms: dry eyes that easily become irritated.
Those who are at increased risk in adulthood are patients who have received radiation
treatment to the head, eyes, eyelids, or who have received total body irradiation (TBI) as
a part of a stem cell transplant.
Goal
The goal is to identify the patients who after completed treatment have suffered, or risk
developing, changes that require regular follow-up by an ophthalmologist and to prepare
a plan for suitable long-term follow-up, even after the patient has left paediatrics.
Follow-up
The radiation dose to the eye shall be recorded in the medical notes, and a follow-up plan
shall be drawn up by the responsible physician in consultation with an ophthalmologist.
Patients who have not had this primary contact with an ophthalmologist shall be referred
to an ophthalmologist for examination by the physician responsible for the oncology
treatment. In these cases, it is normally sufficient with check-ups once every 1-2 years.
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8. BLOOD AND BONE MARROW
Background
The bone marrow, where in principle all blood is formed after the first few months of life,
is an organ with rapid cell division. This means that the factors that affect cell division
manifests as a reduction or increase of the cell type or types affected in the bone marrow
in the form of secondarily affected peripheral values.
Patients who have been treated with cytostatics or radiation therapy are traditionally
followed up using routine blood testing. In the first stage, this is done until the blood values have normalized during and after completion of treatment. After this, blood samples
are routinely taken in conjunction with other post-treatment check-ups.
Risk factors
The bone marrow is affected by both radiation and cytostatic treatment. During the acute
treatment, this is shown in the line of blood cells that is most affected in the individual
case. After completion of treatment, the primary risk is that the treatment given in the
long term can cause secondary bone marrow malignancy. This risk is linked to the cytostatic given.
For this reason, the pharmaceutical drugs, their dosages and combinations that are
known to give rise to such risks should be avoided if possible.
Patients who have been irradiated to large areas of the bone marrow, who have received large combined doses of alkylating cytostatics or frequent and/or total high doses
of etoposide are at increased risk of secondary bone marrow malignancy.
Goal
The goal is to inform patients with increased risk of affected bone marrow about the
symptoms that would lead to extra check-ups even before leaving paediatric oncology.
Follow-up
In normal cases there is no reason to take more blood samples during check-ups after
cancer treatment than would routinely be done for other reasons.
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9. LUNGS
Background
The post-natal development of the lungs has two phases. During the first phase, the formation of new alveoli that started during the fetal period continues, and is complete at
around the age of 2. During the second phase, the alveoli grow primarily in volume, in
parallel with the somatic growth, including the growth of the thorax. The lung volume
correlates primarily with the height, in such a way that taller individuals have bigger
lungs. The lung function is affected both by the type of damage and the time when it
occurs. This can lead to the development of alveoli and/or their growth being stunted –
direct through damage and/or indirect through the growth of the thorax being impeded.
Lung problems can arise at any time after treatment in principle (from dyspnea and
non-productive coughing to more serious symptoms).
Acute radiation pneumonitis is often self-limiting, with symptoms decreasing within
6-8 weeks. It can sometimes require treatment (cortisone, oxygen).
The risk of symptom-producing radiation pneumonitis increases with the dosage and
irradiated lung volume, and is considerable if the average lung dose exceeds 20 Gy or if
the part of the lung volume irradiated >20 Gy exceeds 30% in conventionally fractioned
radiation treatment (2 Gy/day).
There is a correlation between radiation pneumonitis and a later (within 1-2 years)
development of the second phase of the lung parenchyma damage, fibrosis, which is a
non-reversible, late radiation side effect, which leads to restrictive lung function impairment and lowered diffusion capacity.
Risk factors
Radiation treatment to the thorax (including mantle, mediastinal, spinal >30 Gy, TBI,
upper part of the abdomen): low age at irradiation, radiation dose, combination of pneumotoxic drugs, acute lung complications.
Cytostatics: total dose, combination of pneumotoxic drugs and lung irradiation.
Busulphan, BCNU, CCNU: risk of lung fibrosis.
Bleomycin: risk of interstitial pneumonitis, lung fibrosis, ARDS.
Toxic mechanisms: bleomycin, chlorambucil, nitrosurea.
Probable allergic mechanisms: cyclophosphamide, methotrexate, procarbazine, bleomycin.
Combined therapy is often given, which is why the individual contribution of the radiation treatment and various cytostatics to the lung damage is difficult to establish.
Surgery: (sequential thoracotomy) with lung metastases.
Infections: with impaired immune system.
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Goal
The goal is to find the patients who after completion of potentially pneumotoxic treatment have changes in lung function that require follow-up after they have left the paediatric oncology setting for reasons of age (on turning 18 years).
Follow-up
The diagnosis should be based on targeted medical history in relation to physical function level and symptoms from the airways, such as long-term non-productive cough,
exertion-triggered dyspnea and recurrent airway infections.
Patients with abnormal findings should be followed up in greater detail.
Irradiation of the lungs increases the risk of lung cancer, with a latency period of several decades. Smoking increases this risk considerably.
General follow-up recommendations:
Dynamic and static spirometry, DCLO (diffusion capacity) and PEF, on one occasion at
least 2 years after completion of treatment.
Continued follow-up with medical history and PEF, unless the history or the result
of the spirometry indicates closer follow-up. HR-CT gives better information about e.g.
lung parenchyma and fibrosis. Lung function tests are difficult to carry out on younger
children.
Special recommendations:
- Before anesthesia, if treated with bleomycin: spirometry; high doses of oxygen
can worsen bleomycin-triggered pulmonary fibrosis.
- Before scuba-diving: special medical assessment, including spirometry.
- Every influenza season: vaccination against influenza.
- Maintain vaccination protection against pneumococci.
- Councelling about not starting to smoke.
- Try to encourage smoking patients to quit.
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DATE: JANUARY 1, 2007
10. GASTRO-INTESTINAL CANAL
Background
Combination treatment with chemotherapy, surgery and radiation treatment increases the
risk of late complications, where the combination of the latter two entails the greatest risk.
Symptoms:
- Diarrhea and/or malabsorption as a result of impaired lymph drainage with protein
loss through the intestine wall, impaired fat absorption secondary to lack of gall salts,
and change in bacterial flora in the small intestine secondary to impaired intestinal
mobility due to stiff sections (blind loops).
- Pain, discomfort from the abdomen and vomiting as a sign of fibrotic adhesions with
chronic/sub-acute obstructions or acute obstruction.
- Fistulas, chronic ulceration and perforations secondary to mesenterial vessel
thrombosis.
Risk factors
Radiation treatment causes both damage to the mucus membrane (fibrosis and secondary stricturation) and also affects the lymphatic flow (secondary lymphangiectasis with
increased leakage into the intestinal lumen). This is reinforced by any previous surgery
with adhesions and reduced motility of the mesentery. Symptoms can arise acutely, but
they can also start several years after treatment has been given. Large radiation fields to
the abdomen increases the risk of late side effects at doses >20 Gy. Doses of 45-50 Gy to
1/3 of the small intestine volume can give rise to late complications. Fibrosis development
in the intestine in adults is seen increasingly frequently if the radiation dose is >50 Gy.
Goal
The goal is to identify, in consultation with the surgeon and radiotherapist, individuals
who are at risk of late complications in the gastro-intestinal canal.
Follow-up
1. During appointments, targeted questions relating to intestinal symptoms/malabsorp-
tion should be asked. Patients who display symptoms indicating late side effects should
be examined in consultation with a gastroenterologist/surgeon. Dietician to be consulted
as necessary.
2. Height and weight curves should be followed up annually. Puberty development.
3. Patients with verified late side effects should be followed up by a suitable specialist
based on the symptoms displayed.
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11. ENDOCRINOLOGY
(NON-GONADS/FERTILITY)
Background
A tumour disease can entail a risk for late endocrinological complications, both due to
the direct effect of the disease on endocrine organs and due to the treatment of the disease, i.e. operation, radiation treatment or cytostatic treatment. The most common cause
of these complications is radiation treatment.
Symptoms of hormone impairment can start early (at the onset of the disease or in
conjunction with treatment). In some cases, deficiency symptoms emerge much later (after several years).
Effect on hormones
Growth hormone (GH) is the hormone that is first affected by radiation treatment to the
hypothalamus/hypophysis area. Reduced secretion of GH is correlated to the radiation
dose given; higher doses have a greater effect.
Children who have received high radiation doses (>40-50 Gy) to the hypophysis usually have an explicit GH deficiency, which produces symptoms as early as during the
next few years after treatment. These patients need treatment with GH in order to grow
normally as children and to maintain a normal metabolic balance as adults.
Preventive CNS irradiation against ALL was previously given in moderate doses (1824 Gy) and often entailed a tendency in girls for early puberty and a relative GH deficiency, with impaired growth spurt during puberty.
More recent studies have shown that the majority of the patients (men and women)
treated with CNS radiation of 18-24 Gy have a GH deficiency in adulthood, 10-25 years
after irradiation. They also have an increased Body Mass Index, BMI, and raised levels of
plasma insulin, blood glucose and lipids in serum. These abnormalities can probably be
improved with GH treatment.
Symptoms: Impaired growth in height (children), tiredness, concentration difficulties, reduced performance ability, increased risk of cardiovascular disease, changes in fat
metabolism and reduced bone density.
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are less sensitive than
GH to the effects of radiation treatment to the hypothalamus/hypophysis area, and such
effects are usually only seen several years after treatment. The effect is dose-dependent.
Radiation doses >50 Gy cause a deficiency of LH/FSH and failure to develop puberty.
Lower doses (girls 18-50 Gy, boys 25-50 Gy), on the other hand, cause early and sometimes too early puberty.
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Adrenocorticotropic hormone (ACTH) is relatively insensitive to radiation treatment.
There are no clear-cut indications that total body irradiation or lower radiation doses to
CNS (18-24 Gy) produce any ACTH deficiency of clinical importance. Radiation doses
>50 Gy entail a considerable risk of developing ACTH deficiency after 10-15 years. This
deficiency is usually partial and may require substitution.
Symptoms: Tiredness, poor physical stamina, increased tiredness during infections.
Very low levels can be life-threatening.
Thyroidea-stimulating hormone (TSH) is regarded as the least radiation-sensitive of
the hypophysis hormones, and effects following radiation treatment are rarely seen. The
effect on the hypophysis’ secretion of TSH is very dependent on dosage and seems neither
to appear after prophylactic CNS irradiation (18-24 Gy) nor after total body irradiation
(10-12 Gy).
Symptoms: Impaired growth in height (children), tiredness, weight gain, sensitivity to
cold.
Prolactin, Anti-diuretic hormone (ADH) and Oxytocin are only affected to a small
degree by radiation treatment. The secretion of prolactin is normally impeded through
the secretion of dopamine from the hypothalamus. Radiation treatment affecting the
hypothalamus, with secondary reduction in LH and FSH, results in reduced secretion
of dopamine, which can cause a rise in prolactin secretion. The clinical importance is
generally small.
ADH deficiency, with accompanying diabetes insipidus, can arise after operations damaging the neuro-hypophysis. Radiation treatment does not have the same side effect.
Symptoms: Large amounts of urine, 4-6 liters per day, increased thirst.
Thyroidea hormone production (T4) is very sensitive to radiation treatment. Even at
relatively low radiation doses to the thyroidea there is great risk of developing impaired
function. The deficiency can arise after one or several decades.
There is also increased risk of developing secondary thyroid cancer. Radiation treatment
including thyroidea is given when treating certain CNS tumours, lymphoma, ALL and
primary tumours in the head/neck area.
Symptoms: Impaired growth in height (children), tiredness, weight gain, sensitivity to
cold.
Risk factors
The side effects of radiation treatment depend on the age of the child during treatment
and on the radiation dose to hormonal centers in the brain (total dose, fraction dose, total
radiation treatment time and dose rate).
The hypothalamus is more sensitive than the hypophysis. Patients with diseases of the
hypothalamus/hypophysis are more sensitive to radiation treatment than those without
any tumour in this region.
Radiation treatment to regions outside CNS, such as to the epipharynx, can produce
secondary effects on the hypothalamus/hypophysis.
Endocrinological disturbances after a tumour operation depend both on the spread of
the tumour and the scope of the operation. An operation in the hypothalamus/hypophysis area can give rise to effects that are comparable to the side effects of radiation therapy.
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Children with thyroidea cancer, who have had their thyroids removed completely, need
post-operative replacement therapy (over-substitution in order to reduce the risk of recurrence).
Sometime the parathyroid glands are damaged during the operation, which can entail
disturbance of the calcium balance requiring treatment.
Goal
The goal is to identify patients at risk of endocrinological deficiency symptoms at an early
stage and in consultation with an endocrinologist. These patients may require more detailed follow-up and subsequent treatment.
Follow-up
Height and weight should be documented at least twice yearly until the normal puberty
growth spurt is seen, and thereafter at least once yearly until full height has been reached.
Sitting height should be measured in children who have received cranio-spinal or total
body irradiation.
Puberty assessment according to Tanner and measurement of testicle size with an orchidometer should be carried out at each check-up, including after full height has been
achieved and puberty has fully developed.
Patients who have received radiation treatment to the thyroid gland (including mantle,
spinal and total body irradiation) should routinely be examined with palpation of the
thyroid gland and blood sampling (TSH and T4) in conjunction with medical examinations. Hypothyreosis can develop late, and these check-ups should be carried out regularly during a long period (up to 20 years after completion of treatment).
Targeted examination should be carried out in the event of clinical signs of other endocrinological dysfunction as per above.
An endocrinologist should assess:
- Patients who have been treated with total body irradiation (TBI) or radiation treatment
to CNS, in particular if the radiation field has included the hypothalamus/hypophysis.
- Short height (<-2SD), abnormal growth pattern or early puberty (girls <9 years, boys
<10 years).
- Patients with abnormal palpation findings of thyroidea with possible malignancy
(ultrasound treatment first).
- Patients with signs of other endocrinological dysfunction.
An adult endocrinologist should then follow up those who have been assessed by a paediatric endocrinologist and require continued endocrinological follow-up/treatment as
well as patients who in adulthood have abnormal palpation findings of the thyroidea
(malignancy) or late signs of other endocrinological dysfunction.
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12. GONADS/FERTILITY – GIRLS
Background
In girls, puberty starts with breast development (Tanner B 1-5) and a growth spurt at
around the age of 11, followed by the first menstruation, menarche, at an average age of
13. The ovaries’ estrogen production is dependent on functioning follicles.
Early puberty means development before the age of 9 and late puberty means a lack of
signs of puberty by the age of 15. The timing of puberty is directed by heredity, so puberty
development should be assessed in relation to the puberty of other members of the family.
Pubic and axillary hair growth is directed by the adrenal glands.
With increased fatty deposits in the breasts, which is common in overweight girls
(and boys), it can be difficult to determine whether actual mammary gland stimulation
actually exists. If there is no stimulated glandular tissue, a cavity can be felt in the tissue
under the areola (“donut sign”).
Regular menstruation indicates ovulation and fertility. For healthy normal girls, it
can take several years after menarche until ovulation and menstruation become regular.
Risk factors
The germinal cells of the ovaries are sensitive to radiation and can be damaged even by
low radiation doses given with spinal irradiation and abdominal irradiation. Pre-pubertal ovaries are considered to be slightly less sensitive than post-pubertal, which is probably due to them containing considerably more primordial follicles, i.e. that the “ovarian
reserve” is greater.
Radiation treatment
It has been shown that half of the girls may have remaining ovarian function after a prepubertal ovarian radiation >20 Gy. For women over 40, 5 Gy is sufficient to knock out all
ovarian activity. With significant germinal cell damage there is always a clear increase in
basal FSH – up to menopausal levels.
Abdominal and pelvic irradiation including the uterus increases the risk of endometrial and myometrial damage, with consequences for the ability to harbor a normal
pregnancy.
High radiation doses to the hypothalamus/hypophysis area entail a secondary lowering of LH and FSH and lack of pubertal development.
Following irradiation of the thorax including the mammary glands, these can be
damaged so that the ability to respond to estrogen stimulation decreases.
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Treatment with cytostatics can produce permanent damage to the oocytes and reduce
the number of primordial follicles. In this instance, alkylating cytostatics are the most
harmful. Treatment with busulfan usually entails permanent ovarian damage, irrespective of age. Other alkylators (cyclophosphamide, ifosfamide and procarbazine) often produce transient ovarian malfunction.
Even if a clear impact on puberty development, ovulation or menstruation cannot be seen,
it must be expected that the girls will have a reduced number of primordial follicles due
to the treatment, which can lead to a shorter period of fertility, early onset oligomenorrea
and early menopause. If menstruation does not return within two years after completion
of treatment, there is great risk that permanent ovarian damage has occurred.
The uterus is not damaged by cytostatic treatment.
Goal
-
To discover ovarian malfunction requiring hormonal substitution.
To evaluate the ovarian reserve in relation to fertility and risk of premature menopause.
To plan the follow-up of patients who have recovered from ovarian malfunction.
To give recommendations regarding fertility and pregnancy.
Follow-up
- Evaluate puberty development with particular notice taken of signs of estrogen effects,
as this is proof of ovarian activity. It is important to know when the mammary gland
growth starts and if there is any discharge as well as when menarche appears.
- Evaluate growth by plotting height measurements on the growth curve, preferably
every 6 months. Once puberty starts, the speed of growth increases – in girls from the
beginning of stage B2. For early or late puberty development, a skeletal age determination should be carried out.
- Basal values for LH and FSH can be followed annually during puberty development,
from 9-15 years. If so, girls who are being treated with contraceptive pills should stop
taking them for 1-2 months before samples are taken.
- The duration and regularity of menstruation should be registered. Irregular and ab
breviated periods may be a sign of approaching menopause.
- Even if no immediate ovarian damage can be seen, it is possible that several types of
cancer treatment can affect ovarian reserves. Girls should therefore be informed not to
delay any pregnancy unduly, as the chances of fertility can decrease even during the
early reproductive years. (However, mothers who have received cancer treatment in
childhood run no increased risk of bearing children with malformations or children
with increased risk of developing cancer in childhood.)
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13. GONADS/FERTILITY – BOYS
Background
Puberty is generally considered as started when the testicle volume is at least 4 ml, which
occurs on average at the age of 11 ½ years. Early puberty is defined as starting before the
age of 10 and late puberty as starting after the age of 14. As the age of puberty start is
directed by heredity, puberty development should be assessed in relation to the puberty
age of family members.
Growth of the penis and scrotum, including thinning of the scrotal skin, marks testosterone production by the testicles and functioning Leydig cells. A growth spurt of 7-10
cm per year in height also indicates pubertal sex hormone levels and a normal Leydig cell
function.
Growth of the testicles signals the start of spermatogenesis. The volume increase is almost entirely conditioned by a ripening germinal epithelium. At a testicle size of 10-12
ml, sperm is normally found in the urine (“spermarche”). Normal testicle size for an
adult man is 17-25 ml.
Isolated axillary and/or genital hair growth – without simultaneous noteworthy growth
of the genitals – is dependent on normal androgen production in the adrenal glands. The
levels of S-DHEAS and S-androstendion are raised in these cases, while the morning
level (before 9am) of testosterone is prepubertal (<1 nmol/liter).
Normal puberty development with full hair growth and penis growth indicates normal
Leydig cell function, irrespective of testicle size.
Cancer treatment damages spermatogenesis more often than the Leydig cell function.
Even if the testicle volume is normal, there may be a risk of sperm function being affected. A testicle size <10 ml – despite puberty development simultaneously being more
or less complete – is associated with defective sperm production. Serum levels for FSH is
in these cases clearly raised and have proven, in this situation, to correlate with testicle
size, as have the levels of Inhibin B.
Men who have received cancer treatment in childhood are not at increased risk of having
children with either malformations or increased risk of developing cancer.
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Risk factors
Radiation treatment
The germinal epithelium of the testicles, which produce sperms, is very sensitive to ionizing irradiation. Even very low doses during abdominal irradiation or spinal irradiation
can cause permanent damage to sperm production.
The Leydig cells, which produce testosterone, are not as sensitive to irradiation, but
doses >20 Gy to the testicles can cause permanent cell damage in the form of reduced or
cancelled testosterone production.
Cytostatics
Some cytostatic treatments can produce germinal cell damage, which sometimes becomes permanent, in particular treatment with so-called alkylators, such as procarbazine, busulfan and cyclophosphamide in high doses.
The ALL patients who have received the least intensive treatment (“standard risk ALL”)
are regarded from a fertility point of view as being at little risk of any effect. The effect of
other cytostatics which appear to be “safer” is not satisfactorily evaluated, however.
The Leydig cell function is rarely affected by cytostatic treatment, and normal puberty
development can therefore be expected.
Total body irradiation (TBI) and very high cyclophosphamide doses can produce compensated Leydig cell damage with normal puberty development and normal testosterone
levels, but a raised level of LH.
The development of gonad damage, as well as any return of normal germinal cell and
Leydig cell function, is usually slow.
Goal
- To show any Leydig cell dysfunction and, if so, to initiate hormonal substitution
treatment.
- To evaluate the germinal cells’ sperm production and, in the event of problems, to
check for any restitution of spermatogenesis and give advice about infertility treatment.
Follow-up
The sperm formation and hormone production of the testicles should be regarded as two
separate, but collaborating, physiological systems. The bodily examination should therefore include both an assessment of penis development and pubic hair growth (according
to Tanner) and also a measurement of testicle size using an orchidometer once a year
until puberty has been fully completed.
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Any testing of FSH and LH should be done in consultation with a paediatric endocrinologist.
Information about the risk of reduced fertility should preferably be given at the age of
18, when any fertility evaluation should also be done. Thereafter, an examination is done
with sperm samples at a fertility clinic.
Such an examination can be particularly important if the gonadotropines LH and FSH
are raised, if the testicle volume is smaller than expected or if the patient has received a
stem cell transplant. (Recovery can occur up to 10 years after total body irradiation. A
sperm sample should then be taken only after 4 years.)
If the sperm test shows azoospermia, it is worth repeating the test annually, as recovery
of surviving stem cells (spermatogonia) probably is not unusual.
A testis biopsy can provide important information about the degree and extent of any
germinal cell damage.
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14. METABOLIC SYNDROME
Background
Individuals who have received treatment for childhood cancer are at increased risk of
developing a changed body composition, with increased fat mass with central distribution (trunk obesity), with or without overweight, and subsequent insulin resistance and
dyslipidemia. These factors are included in the definition of the so-called metabolic syndrome, which is associated with increased risk of developing cardiovascular disease and
type 2 diabetes. A combination of the direct cardiovascular damage and the subsequent
cardiovascular risk factors (see chapter 2) constitutes a potentially serious late complication. There are a number of definitions relating to metabolic syndrome in adults, depending on the factors considered to be of the greatest importance. The definition from
IDF (International Diabetes Federation) is the one that currently exists for children and
young people.
Definition of metabolic syndrome in children and young people in
accordance with IDF (International Diabetes Federation).
Age 6 to <10 years
Obesity defined as waist measurement >90th percentile
Metabolic syndrome cannot be diagnosed, but further checks on the patient should be
carried out in the event of family medical history of metabolic syndrome, type 2 diabetes,
dyslipidemia, cardiovascular disease, hypertension or obesity.
Age 10 to <16 years
Obesity defined as waist measurement >90th percentile (or adult definition)
Triglycerides > 1.7 mmol/liter
Blood pressure systolic >130 mm Hg or diastolic >85 mm Hg
fP glucose > 5.6 mmol/liter (oral glucose loading recommended) or know
type 2 diabetes mellitus
Age >16 years
Use adult criteria
Central obesity (waist measurement >80 cm for women, >94 cm for men)
Also at least two of the following:
Triglycerides > 1.7 mmol/liter
HDL < 1.3 mmol/liter (women), < 1.0 mmol/liter (men)
BP >130/85 or anti-hypertensive treatment
fP glucose > 5.6 mmol/liter or reduced glucose tolerance or type 2 diabetes
Risk factors
The etiology of the metabolic changes is not clarified, and should be regarded as multifactorial, including treatments leading to endocrinological abnormalities, such as growth
hormone deficiency, testosterone or estrogen deficiency, hypothyroidism as well as
divergent body composition with or without overweight, disordered energy metabolism,
reduced physical activity and affected vascular endothelium function. The most important individual etiological factors appear to be hypothalamic damage following radiation
treatment/surgery.
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Radiation treatment/surgery
Impairment of the CNS following radiation treatment/surgery including the hypophysis/
hypothalamus area can result in great increase in weight via affected appetite regulation
and energy metabolism. This weight increase, which includes trunk obesity, regularly
leads to reduced insulin sensitivity, which results in reduced glucose tolerance and sometimes develops into type 2 diabetes. Overweight leads to the lipogenesis being affected,
with subsequent lipid disruption (raised triglycerides, raised LDL cholesterol, lowered
HDL cholesterol). Apart from the weight gain in itself leading to these consequences, it
has also been discussed whether reduced secretion of GH (growth hormone) can play
a role in the development of the metabolic syndrome. Adult individuals with GH deficiency have a changed body composition with increased fat mass, with trunk obesity
in particular and reduced muscle mass. At the same time, GH deficiency can result in
reduced insulin sensitivity, which has been found in adult individuals who were treated
in childhood for acute lymphoblastic leukemia (ALL).
Sex hormone deficiency, both centrally caused through damage to the hypophysis/hypothalamus and peripherally through irradiation/surgery to the gonads, can produce
a clinical image of metabolic syndrome, with both an increase in fat mass and reduced
muscle mass with subsequent reduced insulin sensitivity. The reduced muscle mass also
leads to reduced muscle power, which results in reduced physical activity and thus further weight gain.
Cytostatics/corticosteroids
Risk factors for inactivity include vincristine, which can lead to neuropathy and motor
dysfunction (see Chapter 1), and anthracyclines, which can lead to reduced heart muscle
function (see Chapter 2). Alkylating cytostatics can lead to estrogen deficiency (sometimes even testosterone deficiency) (see Chapter 12). A number of cytostatics have been
shown to disrupt endothelial function, but the long-term effects are unclear. Asparaginase can cause pancreatic insufficiency. Nephrotoxic cytostatics can produce increased
risk of hypertonia (see Chapter 5). During treatment, corticosteroids lead to a risk of
trunk obesity, increased insulin resistance and hypertonia. The long-term effects are unclear, but there is some evidence that girls in particular who have been treated for ALL
are at increased risk of obesity after treatment, even if they have not received radiation
treatment to the CNS.
Overweight/obesity
Although obesity is normally a feature of metabolic syndrome, it is important to underline that even individuals of normal weight can develop the syndrome. In large comparative studies, young adults who have received cancer treatment in childhood are, as
a group, instead more likely to be underweight. Overweight is seen in particular in the
group where the treatment has included CNS irradiation/surgery to the hypophysis/
hypothalamus area. It is more common to have a body composition with increased fat
mass with central distribution (trunk obesity) with or without overweight, and for this
reason the measurement of trunk obesity (waist measurement) should be included in the
follow-up as well as BMI.
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Goal
The goal is to identify the patients who are at increased risk of developing insulin
resistance, dyslipidemia and overweight, and who require follow-up. Cardiovascular risk
factors can be reduced with preventive measures and treatment, and are therefore important to identify at an early stage. Lifestyle changes including weight loss and increased
physical activity are the most important. There is no general treatment for the metabolic
syndrome. Instead, individual disparities are treated on their own, such as hormone substitution, anti-hypertensive drugs and lipid reducers.
Follow-up
For all: Medical history regarding heredity for cardiovascular disease, diabetes, obesity.
Before age of 18: Weight, height, BMI or alternatively age-related waist measurement.
If the BMI is above the overweight interval or waist measurement above the 90th percentile, the patient should be given active advice about diet and physical activity, or alternatively be referred to a dietician and physiotherapist. In teenage years, blood lipids may be
checked (in particular if there is heredity for early cardiovascular disease). For pathological values, a referral to a paediatric endocrinologist should be made.
At age of 18: Weight, height, BMI, waist measurement. If the waist measurement is over
the limit value (>80 cm for women, >94 cm for men), fB glucose, fS insulin, OGTT (oral
glucose tolerance test), fP cholesterol (total, LDL, HDL), fS triglycerides and blood pressure should be checked. If the patient has more than two components of the syndrome,
referral to a general practitioner should be made. Information about preventing smoking/help to quit smoking (if they have already started) should be provided.
Hormonal investigation
All patients who have received radiation treatment to the central nervous system in childhood should be followed up during childhood in respect of growth and be investigated
by a paediatric endocrinologist (see Chapter 11). Also patients who have received lower
radiation doses to the CNS (e.g. with prophylactic radiation treatment of ALL) shall be
referred to an adult endocrinologist for individual planning, even if they have not displayed any endocrinological disturbance during childhood.
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15. MAMMARY GLANDS
Background
Several large studies have shown an increased risk of secondary malignancy following
treatment of Hodgkin’s disease. It has been assumed to be caused primarily by the radiation treatment given. The risk of getting a second malignancy is particularly high for
breast cancer, and considerable studies have shown that this has arisen in a radiationtreated area.
Studies have also shown an increased risk of secondary cancer with time after the
radiation treatment. The risk increases in particular 15-30 years after receiving treatment, and is particularly great if the radiation treatment was given before the age of 30.
Radiation treatment before the mammary gland has developed results in increased
risk of later breast hypoplasia. This has been shown in a survey of patients receiving
radiation treatment for hemangioma located on the breast (50% risk).
Mammary gland tissue in young women (<50 years) is more dense, and conventional
mammography can therefore be an insufficient screening method. For this reason, the
examination of women with “dense mammary gland tissue” should be supplemented
with ultrasound or MR.
Risk factors
The radiation dose given is probably of importance for the risk of developing cancer.
However, there is no lower dosage level that is safe.
Goal
The goal is to find breast cancer at an early stage through planned, regular examination
of women who received radiation treatment of at least 20 Gy to the whole or parts of the
mammary gland tissue during the age of 10-18.
Follow-up
The follow-up starts 10 years after completion of the treatment, but at the age of 25 at
the earliest. The individual is encouraged to carry out monthly self-examination with
inspection and palpation.
An examination is made every 18 months, with the first involving both mammography and ultrasound. If the breast is very dense, the subsequent examinations should use
both methods, otherwise only mammography. Any decision about the need for ultrasound examination should be made by the mammographer.
The targeted check-ups can cease once the woman later is included in the general
mammography screening.
In the event of any breast hypoplasia, a referral should be made to a plastic surgeon.
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16. SKELETON, MUSCULATURE
AND SOFT TISSUE
Background
The skeleton is formed and develops differently in the axial skeleton and long tubular
bones. Skeletal growth occurs in the epiphyseal plates, and the epiphysis also grows sideways through enchondral growth. Growth is greatest at birth and during the growth
spurt in puberty. Once the epiphysis has closed, the bone ceases to grow. The bone mass
is built up during puberty and into the early 20s, when peak bone mass is achieved. For
a normally mineralized skeleton, not only does the bone growth during puberty and
early adulthood need to have been normal, but the relationship between break-down and
build-up of bone in adulthood has to be balanced.
The long-term consequences of tumour treatment on the skeleton and soft tissue can
be significant, and can be fully evaluated only several years after treatment or when the
child is fully grown, sometimes even later.
Secondary symptoms, such as aching, gait disruption and psychological effects are not
unusual. In some situations, orthopedic/surgical measures can reduce these consequences.
Risk factors
In children, the tissues are not fully developed. Late side effects therefore have more
serious consequences than in adults, as they can deteriorate during growth, more so the
younger the child is during treatment.
Radiation treatment
Non-ossified epiphyseal plates and tooth buds are particularly sensitive to radiation.
Doses of 10-20 Gy can cause permanent damage. The diaphysis of the bone is less radiation sensitive.
Risk of growth disruption exists at doses >15 Gy, asymmetric treatment of jaw joints in
the field, large radiation fields (thorax, spinal column, pelvis, extremities) and when
epiphysis/-es or joint/s are included in the radiation field. The effect on growth can give
rise to asymmetries, such as scoliosis, differential leg length and dentition disruption.
Avascular necrosis and risk of fracture emerge only at relatively high doses (>50 Gy).
Muscle atrophy is not rarely observed with therapeutic dosages of around 30 Gy and
above. Atrophies and lymphatic edema due to fibrosis are often related to the nature of
the operative measure, the radiation-treated locale and the radiation dose given in the
area. The risk is greater if the entire circumference of the extremity has been irradiated.
There is also increased risk of secondary benign and malignant tumours within the
irradiated area (skeleton, soft tissue and skin).
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Cytostatic treatment
Reduced bone density can be seen after treatment with methotrexate. The effect is dosedependent. Ifosfamide can affect the skeleton through loss of phosphate and calcium due
to impairment of the kidney function, which in turn leads to a breakdown of the skeleton via parathormone (PTH). Cisplatin and anthracyclines can also affect bone density
negatively.
Treatment with steroids
Reduced bone density/osteoporosis is a well-known side effect of long-term treatment. The
mechanism entails increased breakdown and reduced buildup. It is currently not clear
how bone density is affected in the long term by steroid treatment.
Avascular necrosis occurs during steroid treatment of children, in particular in those who
are receiving treatment at an older age (>10 years). It is most common in weight-bearing
skeleton parts, commonly with multifocal localization. Treatment with dexamethasone
entails a greater risk than with prednisolone.
Hormone deficiency
Reduced bone density/osteoporosis. Several studies have shown reduced bone mineralization secondary to GH deficiency. It is more pronounced in individuals who have GH
deficiency since childhood, probably due to a lower peak bone mass. The effect of GH
deficiency presenting in adulthood is slightly unclear. An estrogen deficiency due to
ovarian insufficiency in adult women reduces bone density. Studies indicate that young
women with premature ovarian insufficiency could be less affected. Hypogonadism in
boys affects bone density negatively.
Other factors that can affect bone density during/after the disease are long-term immobilization, nutrition problems and heredity for osteoporosis.
Goal
The goal is to identify those children who need specific follow-up due to the risk of complications in skeletal and/or soft tissue. This is done on a multi-disciplinary basis to ensure
adequate risk assessment.
Follow-up
Guidelines relating to growth abnormalities
Children who have received radiation treatment to areas where growth abnormalities
can cause sequele, such as scoliosis, abnormal dentition, differential leg length should
be followed up until they are fully grown. Patients who after the age of 18 are at risk of
having further complications should be informed and, if possible, monitored clinically.
Any need for preventive measures should also be assessed in consultation with a physiotherapist.
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The following clinical check-ups should be done annually, possibly more frequently during puberty.
- X-ray of any clinical abnormality.
- Orthopedic consultation for any abnormality (growth disruption or impaired
functionality).
- Assessment of any need for reconstructive surgery to avoid psychological sequel.
- For girls who have received pelvic irradiation, an assessment of any risk of childbirth
problems due to cephalopelvic disproportion after completed growth.
Guidelines for bone mineralization
Investigation and measures: Investigation with DEXA (with comparison according to
age-related z-score): <1 SD = osteopenia and should be followed up; <2.5 SD = osteoporosis and should lead to examination and treatment of any hormonal insufficiency. Treatment with calcium supplements and biphosphonates may also come into question. Annual follow-up is recommended in cases of reduced bone mineralization. It should be
investigated and treated by an endocrinologist.
Guidelines for avascular necrosis:
Investigation with X-ray and MRT of patients with symptoms. The patient shall be seen
by an orthopedic surgeon. Treatment with pressure relief, antiphlogistics and also surgical measures may be needed.
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In Sweden there is currently no generally accepted process for grading damage to normal
tissue caused by radiation treatment. At the Late Effect Concensus Conference in 1995, a
proposal for a grading scale of such side effects was presented, and a modified and simplified version has been published (see below). This can be applied in clinical practice and
form the basis for registering the damage as well as for guidelines for follow-up.
Modified LENT-SOMA* scale for growing skeleton, soft tissue and muscle
(Paulino et al. Int J Radiation Oncology Biol Phys, 2004, vol 60 pp 265-274).
Grade 1
Grade 2
Grade 3
Grade 4
Growing bone Mild curvature or
Length discrepancy
< 2cm
Moderate curvature
or length discrepancy
2-5 cm
Severe curvature
or length discrepancy
> 5 cm Epiphysidesis,
Severe functinal
deform.
Edema
Present/asymt
Symtomatic
Secondary dysfunction
Total dysfunct.
Atrophy
< 10% 10-20%
20-30%
> 50%
Mobility and Extremity funktion
Present/asymt
Symtomatic
Secondary dysfunction
Total dysfunct.
*) LENT =late effect normal tissue, SOMA: Subjective, Objective, Management, Analytic, Summary
Prognosticated or noted damage of grade 0-1 should be assessed by the treating physician in accordance with LENT-SOMA, in conjunction with routine tumour controls. Specific examinations or consultations should be carried out as necessary, depending on the
symptoms and treatment given. Side effects at prognosticated damage of grade 2-4 should
be assessed and followed up specifically, once a year, by a specialist team (see above).
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DATE: APRIL 17, 2008
17. SUBSEQUENT CANCER
Background
A number of studies have shown that patients who have had cancer during childhood
are at greater risk of developing a new cancer (second malignant neoplasm – SMN) than
individuals without previous cancer disease. The relative risk is around 4-6 times in population-based series and around 6-11 times in hospital-based series. In absolute terms,
however, this only means 1-2 and 2-3 extra cancer cases per 1000 persons/year respectively. After 20 years’ follow-up, the cumulative risk of SMN is 3-4% and 3-7% respectively. The most common forms of SMN are breast cancer in women as well as bone and soft
tissue sarcoma, CNS tumour and thyroidea cancer in both sexes. The latency period between the first and second cancer is 12 years on average, but the time lapse varies greatly.
It is shortest for leukemia (5 years) and longest for breast cancer (17 years) and tumours
in the gastro-intestinal canal (18 years) as SMN. The risk varies greatly depending on the
primary tumour and a number of risk factors.
Risk factors
Patients who have a genetic predisposition for developing childhood cancer, such as
hereditary retinoblastoma, neurofibromatosis type 1 or Li-Fraumeni syndrome, are at
increased risk of developing SMN, irrespective of treatment.
Of treatment-related factors, radiotherapy is by far the most important risk factor.
The relative risk increases already at low radiation doses, below 1 Gy. Chemotherapy
potentiates the cancerogenous effect of radiotherapy.
Certain cytostatics, such as alkylating preparations and epipodophylotoxins, increase
the risk of SMN, in particular acute non-lymphoblastic leukemia.
A combination of different risk factors, including the primary diagnosis, can lead to
significant risk for the individual of developing SMN in the longer term. For instance,
patients with Hodgkin’s lymphoma have a 12% cumulative risk of developing SMN after
25 years’ follow-up, and the risk of developing breast cancer is still considerably higher
for women who received mantle irradiation in childhood.
Goal
The goal of the follow-up is to limit the risk of developing SMN through secondary prevention, and to discover SMN arising at an early stage.
Follow-up
The follow-up should include general advice regarding healthy lifestyle, in particular
avoiding smoking and excessive exposure to sunlight, as well as checks that this advice
is complied with.
The follow-up should be drawn up on an individual basis, with consideration for the
risk factors above, and with knowledge about the natural history of SMN.
In general, the patient should be informed about symptoms and signs that may be
associated with the development of SMN. In addition, these symptoms should be asked
about at clinical check-ups. During physical examination, the skin should always be carefully inspected, and breasts and thyroid palpated, in view of the risk of SMN in these
organs. Particular attention should be paid to previous radiation fields.
Further examinations in order to discover breast cancer at an early stage in high risk
individuals is currently the subject of discussion.
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CYTOSTATICS – POTENTIAL LATE SIDE EFFECTS
Cytostatic given
All
Potential late side effect
Reduced quality of life
Chapter
Actomycin D
Liver dysfunction
4
Amsacrine
Heart dysfunction
2
Asparaginase
Pancreas dysfunction
BCNU (Carmustine)
Gonadal dysfunction
Respiratory dysfunction
Kidney dysfunction
Secondary leukemia
12+13
9
5
8, 17
Bleomycin
Respiratory dysfunction
9
Busulfan
Gonadal dysfunction
12+13
Respiratory dysfunction
9
Liver dysfunction
4
Secondary leukemia
8, 17
Cataract
7
Carboplatin
Hearing dysfunction
3
Kidney dysfunction
5
CCNU (Lomustine)
Gonadal dysfunction
Respiratory dysfunction
Kidney dysfunction
Secondary leukemia
12+13
9
5
8, 17
Chlorambucil
Gonadal dysfunction
Secondary leukemia
12+13
8, 17
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CYTOSTATICS – POTENTIAL LATE SIDE EFFECTS
Cytostatic given
Potential late side effect
Chapter
Cisplatin
Peripheral neuropathy
Hearing dysfunction
Kidney dysfunction
Gonadal dysfunction
Cardiovascular dysfunction
1
3
5
12+13
2
Cyclophosphamide
Gonadal dysfunction
Bladder dysfunction
Heart dysfunction
Secondary leukemia
12+13
5
2
8, 17
Cytarabine
Neuropsychological dysfunction
Gonadal dysfunction
1
12+13
Dacarbazine
Gonadal dysfunction
Secondary leukemia
Daunorubicin
Heart dysfunction
12+13
8, 17
2
Doxorubicin
Heart dysfunction
2
Epirubicin
Heart dysfunction
2
Estramustine
Gonadal dysfunction
Secondary leukemia
12+13
8, 17
Etoposide
Secondary leukemia
8, 17
Fludarabine
No known late effects
Hydroxyurea
No known late effects
Idarubicin
Heart dysfunction
2
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CYTOSTATICS – POTENTIAL LATE SIDE EFFECTS
Cytostatic given
Potential late side effect
Chapter
Ifosfamide
Gonadal dysfunction
Kidney dysfunction
Bladder dysfunction
Possibly reduced bone density
CNS dysfunction
Secondary leukemia
12+13
5
5
15
1
8, 17
Melfalan
Gonadal dysfunction
Kidney dysfunction
Secondary leukemia
12+13
5
8, 17
Mercaptopurine
No known late effects
Methotrexate
Neuropsychological dysfunction
Liver dysfunction
Kidney dysfunction
Possibly reduced bone density
1
4
5
15
Methyl-CCNU
(Semustine)
Mitoxantrone
Gonadal dysfunction
Kidney dysfunction
Secondary leukemia
12+13
5
8, 17
Heart dysfunction
2
Mustine
Gonadal dysfunction
Secondary leukemia
12+13
8, 17
Procarbazine
Gonadal dysfunction
Secondary leukemia
12+13
8, 17
Steroids
Reduced bone density
Cataracts
15
7
Teniposide
Secondary leukemia
8, 17
Thioguanine
Liver toxicity
4
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CYTOSTATICS – POTENTIAL LATE SIDE EFFECTS
Cytostatic given
Potential late side effect
Chapter
Thiotepa
Gonadal dysfunction
Secondary leukemia
12+13
8, 17
Vinblastine
Peripheral neuropathy
1
Vincristine
Peripheral neuropathy
1
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