Guideline 76: Long term follow up care or survivors of childhood cancer

Long term follow up of survivors of childhood cancer
Section 3: Growth problems

3.1 Growth impairment following therapy for childhood cancer

There is a large body of evidence showing that survivors of childhood cancer may have impaired growth before, during or after successful treatment for their cancer. A number of factors are responsible for this, including the disease process itself, complications of treatment (infection), direct effects during treatment (anorexia, vomiting) and direct and indirect late effects attributable to therapy.

Cranial radiotherapy can cause growth hormone deficiency and growth retardation, which in turn may be compounded by other pituitary hormone deficiencies, particularly adrenocorticotrophin (ACTH), follicle stimulating hormone (FSH), luteinising hormone (LH) and thyroid stimulating hormone (TSH).^{6,
7, 8,
9, 10,
11, 12}

Localised tumour treatments may affect growth and function of individual organs. For example, spinal growth is adversely affected by spinal irradiation and may result in skeletal disproportion. Abdominal surgery and/or radiotherapy may cause sex hormone deficiencies and secondary effects on growth and pubertal development.

Chemotherapy alone may also have significant effects on growth.¹³

The particular risks of growth impairment for any individual survivor depend upon the cancer type, the treatment given and the age at presentation.

3.2 Special groups at risk of growth impairment

3.2.1 SURVIVORS OF CRANIOPHARYNGIOMA

The majority of children with craniopharyngioma have symptoms of abnormal pituitary function at presentation,¹⁴ most commonly growth impairment and/or pubertal delay. Treatment includes surgery and/or radiotherapy. Evidence level 2+

3.2.2 SURVIVORS OF BRAIN TUMOURS REMOTE FROM THE PITUITARY-HYPOPHYSEAL REGION

Cranial or craniospinal radiotherapy following surgical excision of brain tumours leaves survivors at high risk of growth hormone deficiency.^{6,
7, 8,
9, 10,
11, 12} Radiation involving the spine will result in reduced spinal growth and disproportionate short stature which can be detected by sitting height measurements. Without growth hormone replacement, virtually all such patients will have a final height below the third centile. In a significant minority there will be additional pituitary hormone deficiencies, which contribute to reduced growth. In addition, both boys and girls may have an early onset of puberty, which may be precocious in girls. The younger the age at irradiation, the earlier the onset of puberty.^{11,
15} Evidence level 2+

3.2.3 SURVIVORS OF ACUTE LYMPHOBLASTIC LEUKAEMIA TREATED WITH PROPHYLACTIC LOW-DOSE (18-25 GY) CRANIAL RADIOTHERAPY

There are multiple longitudinal and cross-sectional studies in this treatment group. These demonstrate consistently poor growth during chemo- and radiotherapy treatment, followed by catch-up growth after treatment cessation. Up to 50% may have growth hormone deficiency on testing.^{16,
17} Overall, final height in the majority is less than predicted, but almost all fall within the normal adult range.^{18,
19, 20,
21, 22,
23, 24,
25, 26,
27, 28,
29} Some studies show a dose dependent effect, with a higher frequency of growth problems at 24-25 Gy than at 18 Gy, but others do not. Evidence level 2++,2+

Children who have received additional cranial or craniospinal radiotherapy tended to have more significant growth problems.^{17,
30, 31} Evidence level 2++,2+

Some survivors have additional pituitary hormone deficiencies, but the frequency is much less than with high-dose radiotherapy. Evidence level 2++,2+

The effects on growth are age dependent, with a poorer outcome the younger the age at diagnosis.^{7,
32, 33} Evidence level 2++,2+

In survivors with normal growth before the onset of puberty there may be an attenuated growth spurt in puberty associated with growth hormone insufficiency.³⁴ Evidence level 2++,2+

A significant minority of girls, but not boys, will have premature or precocious puberty.^{23,
27, 35} Evidence level 2++,2+

3.2.4 SURVIVORS WHO HAVE RECEIVED BONE MARROW TRANSPLANTS

Conditioning for bone marrow transplants for leukaemias has usually included total body irradiation, whereas that for severe aplastic anaemia has not. Comparison of these two groups has shown significant loss of height in the leukaemia group.^{24,
31, 36,
37, 38,
39, 40} Many of these children however attain adult height within the normal range. Evidence level 2++,2+

Recipients of bone marrow transplants for neuroblastoma, who had received abdominal radiotherapy prior to transplant, had very poor growth.⁴¹ In contrast, survivors of acute myeloid leukaemia, who received no radiotherapy prior to bone marrow transplant, had no growth impairment.⁴² Evidence level 2++,2+

3.2.5 OTHERS

More recently, prophylaxis in acute lymphoblastic leukaemia has not included radiotherapy. Some of these children show impaired growth, but final height is usually normal, and growth hormone deficiency is much less common.^{16,
25, 28,
43} Similar results are seen with children with solid tumours.^{44,
45}

3.3 Monitoring for growth problems

All children who have survived childhood cancer should have their height measured regularly until they reach final adult height. Sitting height should also be measured in children who have received craniospinal irradiation.

Children with impaired growth velocity should be referred to a paediatric endocrinologist for growth hormone level measurement.

Causes of poor growth, other than growth hormone deficiency, including potential deficiencies of other pituitary hormones or problems related to early or delayed puberty, should be considered and treated as necessary.

Children with craniopharyngioma should be tested at presentation for growth and other pituitary hormone deficiencies, and at regular intervals thereafter.

Prepubertal girls receiving cranial radiotherapy should be closely monitored for clinical signs of precocious puberty (see section 4).

Growth assessment requires integration of information including height measurements, bone age and puberty staging, all of which should be plotted onto growth charts.

Healthcare professionals should be aware that puberty growth can be mistaken for catch-up growth.

3.4 Obesity

There is accumulating evidence that childhood cancer survivors, particularly those who have had leukaemia, are at increased risk of obesity with its associated morbidity, in adolescence and in adult life.⁴⁶ This problem is worse in girls.^{21,
23, 47,
48} In a study of 1,765 adult survivors of childhood ALL, cranial radiotherapy £20 Gy was found to be associated with an increased prevalence of obesity, especially in females diagnosed at up to 4 years of age.⁴⁹ The management of obesity in children and young people is discussed in detail in SIGN guideline number 69.⁴⁶ Evidence level 2+

Regular growth monitoring should include evaluation of body mass index and be related to growth charts.

Advice on healthy eating and exercise should be given early and reinforced regularly.

Healthcare professionals should be aware that obesity can result in normal growth at the expense of inappropriately rapid bone age advancement resulting in reduced height prognosis.

3.5 Treatment with growth hormone

3.5.1 EFFECTIVENESS

Growth hormone replacement therapy has shown varying rates of success in growth impaired cancer survivors.^{13,
20, 30,
50, 51,
52, 53,
54, 55,
56, 57,
58, 59,
60, 61} In survivors of craniopharyngioma a growth response similar to that in children with idiopathic growth hormone deficiency is seen.⁶² Evidence level 2++,2+

On confirmation of growth hormone deficiency, growth hormone replacement therapy is indicated. For children with craniopharyngioma, the need for growth hormone replacement may be from presentation.

If the cause of growth impairment is unclear, a trial of growth hormone treatment may be appropriate.

3.5.2 SAFETY

Doubts have been expressed about the safety of recombinant growth hormone replacement therapy for childhood cancer survivors, based on the theoretical possibility that it may cause unwanted effects on any remaining cancer cells after treatment. Patients on growth hormone therapy in the USA, Canada and Europe are registered and closely monitored, allowing large studies to address the rate of cancer recurrence. The evidence supports the view that there is no increased risk of cancer recurrence.^{52,
62, 63,
64, 65,
66} Other adverse effects in survivors of craniopharyngioma are common and include headache, seizures and water retention. These effects are likely to be due to the tumour and/or surgery, rather than the growth hormone.⁶² No increase in melanocytic naevi was detected in children receiving growth hormone.^{67,
68} A single large cohort study of growth hormone recipients with various diagnoses found double the population risk of leukaemia and lymphoma in growth hormone recipients, but this was only statistically significant at extended follow up, and the absolute risk remains very small.⁶⁹ Evidence level 2++,2+

Survivors of childhood cancer should be informed that current evidence indicates that there is no increased risk of cancer recurrence from growth hormone replacement therapy.

Growth hormone should be prescribed under the supervision of a paediatrician with an expertise in growth disorders. Detailed and comprehensive shared care protocols should be available, with prescribing normally done by the General Practitioner.

In most circumstances, it is safe and appropriate to start growth hormone therapy when it is indicated. Growth hormone is important both to maximise growth potential and for bone mineralisation. Bone accretion is not complete until young adulthood.

3.6 Dental and facial problems

With the increasing survival of children after treatment for cancer, the potential clinical impact on orofacial and dental development is considerable. Facial deformity and developmental defects of the crowns of teeth can affect appearance and require advanced restorative care. If there are arrested or short roots, the usefulness of orthodontic treatment to straighten teeth is limited and the consequence of periodontal disease will be greater. Whilst there are insufficient follow up data to estimate effects into adulthood the implication is that specialist treatment may be required.

3.6.1 PROBLEMS WITH OROFACIAL AND DENTAL GROWTH

Studies have been carried out to investigate the effects of treatment for cancer in childhood on dental development and the findings consistently demonstrated disturbances in the mineralisation and development of crowns and roots of teeth.^{70,
71, 72,
73, 74,
75, 76} The younger the age of the child at treatment, the greater the chance of later dental problems.^{70,
71, 72,
73, 77,
78, 79} The magnitude of effect is difficult to estimate since the evidence base is from selected groups of patients with few studies extending beyond early adulthood. Evidence level 2+

Studies comparing levels of decay as an outcome consistently found no difference between case and control groups.^{75,
77, 78,
79, 80,
81, 82,
83, 84,
85, 86} Evidence level 2+

In survivors of head and neck cancer treated with radiotherapy both facial and dental problems were found. Facial asymmetry due to disturbance in the growth of the mandible and maxilla were more severe the younger the child at diagnosis and treatment.^{75,
81} Orbital growth, cataracts and otological hearing loss have been reported for children receiving radiation of eyes and ears.^{75,
78} Dental crown defects and root foreshortening are more prevalent the younger the child and more severe with increasing doses of radiation.^{72,
73, 75} For survivors of acute lymphoblastic leukaemia the evidence suggests that more severe disturbances are evident in children treated with prophylactic cranial radiotherapy.^{70,
71, 74} Survivors who have received bone marrow transplants experience disturbances in dental development that are greater the younger the child and are more severe than in children receiving chemotherapy alone.^{76,
77, 79,
80} Evidence level 2+

Evidence from studies of children treated for a range of cancers, and followed for between one to ten years, suggests that the growth of orofacial structures and teeth are affected. Results demonstrate disturbances in the mineralisation and development of crowns and roots of teeth. Facial growth and temporo-mandibular function can also be affected. Levels of decay were no different from control groups.

Children undergoing cancer treatment would benefit from being seen, as close to diagnosis as possible, by a specialist in paediatric dentistry who will carry out a full oral and dental examination and formulate a treatment plan in liaison with the paediatric oncologist. Restorable teeth should be filled and teeth of poor prognosis removed. A targeted preventative programme to include toothbrushing instruction, topical fluoride application in addition to the use of toothpaste, and antibacterial mouthwash to reduce the amount and adherence of plaque will help to reduce oral morbidity during treatment.⁸⁷ Evidence level 4

Children undergoing cancer treatment, and their parents/carers, should be advised about the possible effects on orofacial and dental development. Specialist paediatric dentists should have a role in the care of these children.

Children undergoing cancer treatment should see a specialist in paediatric dentistry and be advised to attend for routine dental monitoring as recommended for every child.