Editors

KirsiJahnukainen

Problems of Childhood or Adolescence Cancer Survivors in Adulthood

Essentials

Currently, approximately 1-2‰ of young adults have been treated for cancer in their childhood. Only one in three of these will not develop any long-term sequelae related to the disease or its treatment.
Modern radiotherapy, when targeted well, decreases long-term effects in the future. There will be, however, patients with extensive damage in follow-up for a long time.
As follow-up by the treating unit ends, a treatment summary should be produced for the young patient and an estimate made of the need for late follow-up in adulthood.
Late follow-up in adulthood should be based on individual risk assessment (table T1). Early identification of some late sequelae may improve health and quality of life. The aim of late follow-up in adulthood is to screen for such sequelae.
Find out about local organization and coordination of late monitoring, as well as about relevant age limits. Primary care may have a central role in the implementation of late monitoring.
- In Finland, for example, each university hospital has a team responsible for coordinating late monitoring in adulthood in its area. The patients are monitored by the late monitoring clinic in general until the age of 40.

International risk classification of late sequelae of cancer treatment received during the period of growth

Risk of late sequela	Type of cancer treatment
Low	Just surgery No radiotherapy Light cytostatic therapy not including alkylating agents, anthracyclines, bleomycin or epipodophyllotoxins
Moderate	Low/moderate-dose alkylating agents, anthracyclines, bleomycin or epipodophyllotoxins Low/moderate-dose radiotherapy Autologous stem cell transplantation (first-line treatment)
High	High-dose alkylating agents (such as ifosfamide 60 g/m² ), anthracyclines (300 mg/m² ), bleomycin (400 U/m² ) or epipodophyllotoxins (2 g/m² ) High-dose radiotherapy (20-30 Gy or more, depending on the field) Allogeneic stem cell transplantation

Modified from: Skinner R, Wallace WH, Levitt GA; UK Children's Cancer Study Group Late Effects Group. Long-term follow-up of people who have survived cancer during childhood. Lancet Oncol. 2006 Jun;7(6):489-98. Alkylating agents include, for example, cyclophosphamide, ifosfamide and busulphan. Anthracyclines include, for example, doxorubicin, daunorubicin and idarubicin. Epipodophyllotoxins include, for example, etoposide.

Endocrine system

Cranial and cervical irradiation and total body irradiation are associated with a risk of decreasing growth hormone secretion.
- Growth hormone deficiency commonly occurs if the pituitary is exposed to a radiation dose exceeding 30 Gy.
- Such deficiency may develop slowly over the years even if lower (18-24 Gy) doses are applied.
- Even in the absence of growth hormone deficiency, adult height may be affected by radiotherapy extending widely to the vertebrae or growth plate area.
- Growth hormone deficiency can be treated during the period of growth by giving growth hormone.
- Growth hormone therapy may also be needed in adulthood to improve the quality of life and to treat metabolic problems, such as dyslipidaemia.
A radiation dose exceeding 30 Gy to the pituitary gland, or damage caused by the tumour or the surgical operation may lead to insufficient gonadotropin secretion.
- In adult patients, this causes decreased sex hormone secretion and infertility.
- Nevertheless, hypogonadism is more commonly due to the damaging effect of cancer therapy on the gonad.
Hypothyroidism is the most common form of hormone deficiency due to cancer therapy.
- A radiation dose exceeding 30 Gy to the pituitary gland may lead to decreasing thyrotropin (TSH) secretion.
- Irradiation of the thyroid gland is a more common reason for hypothyroidism developing after cancer therapy. The thyroid gland is often within the field being irradiated, or it may be affected by irradiation scattered from radiotherapy of the head and neck, the area of the mediastinum, the spinal cord or total body.
- Cytostatic treatment with busulfan and cyclophosphamide may cause mild or transient hypothyroidism.
- Hypothyroidism has also been observed after treatment with tyrosine kinase inhibitors.
- Hypothyroidism caused through an immunological mechanism with autoimmune thyroiditis is sometimes seen after allogeneic stem cell transplantation.
- Thyroxine treatment is needed if free T4 levels are below the reference range and TSH levels are elevated. Treatment of subclinical compensated hypothyroidism (elevated TSH, free T4 within the reference range) may be justified because it decreases thyroid masses.
Hyperthyroidism is rare after cancer therapy. Autoimmune thyroiditis leading to hyperthyroidism can sometimes be seen after radiotherapy of the neck and spinal cord.
Decreased ACTH secretion with resulting cortisol deficiency may develop after more than 30 Gy radiation to the pituitary gland or as a result of injury caused by a tumour or its surgical treatment.
- The risk of hypocortisolism increases in long-term follow-up and is more common in patients with other pituitary hormone deficiencies.
Immuno-oncological treatment with immune checkpoint inhibitors can cause autoimmune-based hyper- or hypothyroidism, hypophysitis, adrenocortical insufficiency and diabetes. These endocrinological adverse effects are usually permanent.

Fertility and the gonads

Irradiation of the ovaries and cytostatic therapy including alkylating agents may damage the ovaries, leading to delayed pubertal development or premature ending of fertility in climacterium praecox.
Depletion of the ovarian reserve will simultaneously lead to infertility and the need for oestrogen replacement.
The sterilizing effect of radiotherapy and alkylating agents is age-dependent.
- Children have a bigger ovarian reserve than adult women, and their ovaries can therefore tolerate more potent gonadotoxic therapy without developing ovarian insufficiency.
- The period of fertility will still be shortened.
In both children and young adults, more than 20 Gy radiation to the ovaries usually has a sterilizing effect.
- In patients above 25 years of age, ovarian reserve can be assessed based on blood anti-Müller hormone (AMH) and gonadotropin concentrations.
Irradiation of the abdomen with radiation to the uterus may prevent the growth of the uterus, increasing the risk of miscarriage and preterm birth.
Sperm production in the testes ends quickly after the beginning of any cytostatic treatment.
- However, it will recover it the stem cells that produce sperm are not damaged.
- Stem cells may be permanently damaged by more than 6 Gy of radiation to the testes or by cytostatic therapy with high-dose alkylating agents.
- Even after such treatment, slow recovery of sperm production may be possible (this has been observed when patients have been followed up for decades).
- Radiation to the testes exceeding 12 Gy usually has a sterilizing effect.
- The existence of sperm in semen is probable if the size of the patient's testis in adulthood is larger than 15 ml.
- Everyone who has received cancer treatment should be offered a possibility to check sperm production from a semen sample in young adulthood.
In men, pubertal development and testosterone production usually remain normal after less than 12 Gy radiation to the testes and cytostatic treatments.
- Men who have had more than 12 Gy radiation to their testes and show symptoms of testosterone deficiency or have a morning blood testosterone below the reference range should be referred to an endocrinologist.

Nervous system

Cranial irradiation for the treatment of a cerebral tumour or relapsing leukaemia may have late neurocognitive effects, particularly if given in early childhood.
- The most common such effects are decreased IQ, learning problems, speech and executive problems and memory and attention problems.
Neurocognitive symptoms of patients with brain tumours are also caused by the tumour and its surgical treatment.
- The risk of late neurocognitive sequelae is increased by:
  - infratentorial location of tumour
  - large size of tumour
  - large area of radiotherapy
  - high-dose irradiation.
- Radiotherapy of the whole head is most damaging.
- Young age increases the damaging effect of irradiation.
- Neurological effects of radiotherapy advance with age, and the decrease in IQ may not stop even after decades.
Replacing prophylactic cranial radiotherapy in the treatment of lymphoblastic leukaemia by intrathecal antimetabolite treatments has decreased the neurocognitive effects of the treatment of leukaemia.
- In spite of this, high-dose antimetabolite treatments are associated with impaired intelligence, memory and concentration, to which a young age (below 5 years) and female sex predispose.
The incidence of meningiomas is increased several years after the treatment of leukaemia, if radiotherapy directed at the head area has been a part of the treatment regime.
Permanent damage to the peripheral nervous system, seen as disturbances in fine and gross motor functions, has been found after the treatment of childhood lymphoblastic leukaemia.

Cardiovascular system

Patients treated with anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin), mitoxantrone or thoracic irradiation have an increased risk of developing cardiac failure.
- It has been estimated that one in eight patients receiving such treatment will develop a life-threatening heart disease by the age of 30 years.
- There is a genetic tendency associated with the development of heart failure that is insufficiently understood so far.
Patients with a risk of left ventricular failure are recommended follow-up of systolic cardiac function by echocardiography every 5 years throughout adulthood. This concerns patients who have:
- been exposed to a cumulative anthracycline dose exceeding 250 mg/m²
- received more than 35 Gy thoracic irradiation or
- been exposed to a cumulative anthracycline dose exceeding 100 mg/m² combined with thoracic irradiation exceeding 15 Gy.
Women diagnosed in early pregnancy with asymptomatic impaired left ventricular function will need follow-up by a cardiologist during pregnancy and childbirth.
Radiotherapy is associated with accelerated vascular ageing and risk of atherosclerosis, predisposing patients to coronary and cerebrovascular stenosis.
- Vascular changes are most often seen in areas subjected to irradiation but also outside the irradiated field.
- So far, there is no reliable clinical follow-up method to observe such vascular changes.
Patients exposed to anthracyclines with hypertension or diabetes have a particular risk of cardiovascular disease.
- Classical cardiovascular risk factors, such as elevated blood lipid and glucose levels and hypertension must be treated with particular care in patients who have been given cardiotoxic treatment in childhood.
- Patients should be instructed in a healthy lifestyle, for example by encouraging weight management, non-smoking life and maintenance of good physical condition.
For hypertension, see Kidneys here

Metabolic syndrome

If the hypothalamus is damaged by, for example, a tumour or the operation to treat the tumour, severe obesity often ensues.
Adulthood obesity associated with cranial radiotherapy and glucocorticoid treatment is also common among those who have recovered from acute lymphoblastic leukaemia.
Even normal-weight cancer survivors may show patterns of glucose and fat metabolism that resemble those of overweight persons.
- As many as half of normal-weight patients who have received stem cell transplantation show disturbances of glucose metabolism.
- Impaired glucose tolerance and hyperinsulinaemia are associated with low HDL levels.
- Disturbances of glucose metabolism in patients who have undergone stem cell transplantation is partly explained by the total body irradiation reducing muscle bulk and affecting fat distribution in the body. Abdominal radiation may also impair pancreatic insulin production.

Lungs

Lung irradiation in association with bleomycin, dactinomycin, cyclophosphamide and doxorubicin use may predispose to radiation pneumonitis.
Fibrosis and delayed interstitial pneumonia are possible.
However, lung problems are usually mild and mostly restrictive (the mobility of the chest is restricted by the disease and its treatment).
The patients should be encouraged to avoid smoking.

Kidneys

Radiotherapy, ifosfamide and cisplatin may cause both glomerular and tubular damage. Usually the damage does not progress after the end of the treatment.
Hypertension associated with mild renal failure has been described in patients who have received stem cell transplantation in childhood or multiple cisplatin treatments.
- Radiotherapy directed to the kidney region may also predispose to elevated blood pressure later on. Hypertension must be treated with particular care in patients who have been given treatment affecting the kidneys in childhood.

Bones, teeth and soft tissues

Radiotherapy targeted at the spine damages the vertebral growth plates and results in shorther adulthood height.
Osteoporosis increases the risk of fractures. It occurs after stem cell transplantation, as well as after the treatment of brain tumours and acute lymphoblastic leukaemia. Glucocorticoid treatment, radiation injury of bones and the direct effect of leukaemia on bones predispose patients to osteoporosis.
The effect of cancer therapy on bone mineral density decreases with time and, in adulthood, hormone deficiencies, insufficient exercise and poor muscle condition become more significant.
The clinical condition of the bones and the occurrence of possible scoliosis should be checked annually in patients who have received radiotherapy to the spinal area.
Osteoporosis can be treated with hormone and calcium replacement therapy, as necessary. Bisphosphonate therapy may be used in adulthood if needed.
Sufficient intake of calcium and vitamin D should be ensured, and the patient should be instructed to maintain good physical condition.
Prolonged glucocorticoid treatment is associated with a risk of osteonecrosis.
- The risk is increased by young age (> 10 years), female sex and the treatment of lymphoblastic leukaemia and lymphoma.
- Osteonecrosis occurs in large weight-bearing joints, such as the hips and knees, and is often multifocal.
Missing or small size of permanent teeth and underdevelopment of the roots is seen especially after stem cell transplantation performed before the age of 10 years. Enamel damage increases the risk of dental caries.

Teratogenicity

The offspring of survivors of cancer do not have a significantly increased risk of cancer, with the exception of certain hereditary cancer syndromes (such as retinoblastoma or Li-Fraumeni syndrome).
There is no strong evidence of a higher incidence of congenital abnormalities among the offspring of survivors of childhood cancer compared with other children.

Secondary malignancies

People who have survived cancer are at an increased risk of developing other cancers or leukaemia. Childhood cancer survivors have a more than double risk of developing another malignant tumour by the age of 40 years.
Radiotherapy increases the risk of cancer dose-dependently.
- The risk of breast cancer, malignant brain tumour, thyroid cancer and bone cancer may be five times as high in patients who have been given radiotherapy compared to the control population.
- The risk is increased by young age during radiotherapy and genetic tendency.
Secondary tumours usually manifest themselves more than 10 years after cancer treatment, and they still continue to emerge 30 years after termination of treatment. Secondary leukaemia usually develops earlier than secondary tumours, only a few years after the treatment.
Cytostatic treatment with alkylating agents, topomerase inhibitors (etoposide) and anthracyclines is associated with a risk of solid tumours, leukaemia and myelodysplastic syndromes.
Patients who have been given radiotherapy to the thoracic region in childhood or youth have an increased risk of breast cancer.
- Regular breast cancer screening is recommended for all whose chest has been exposed to radiotherapy exceeding 20 Gy at an age below 30 years.
- Regular annual breast cancer screening should be started at the age of 25 years or when at least 8 years have elapsed since radiotherapy. The follow-up is organized through late monitoring clinics. Country-specific variation may exist. Find out about local policies and practices.
Good lifestyle choices can reduce the risk of cancer. All cancer survivors should be advised to refrain from smoking, to protect their skin from sunburn and to seek prompt treatment if they observe any abnormal changes.

Psychosocial situation

Most of those who receive cancer therapy in their childhood or youth will recover to become mentally healthy adults.
However, cancer survivors show slightly more depression and delayed psychosocial maturation compared to their siblings. They get married more rarely and stay with their parents more often than their siblings.
- The risk of late psychosocial sequelae is increased by the treatment of brain tumour and by cancer treatment associated with physical injury.
Consideration of psychosocial wellbeing and offering of timely support during cancer treatment, already, identification and treatment of late neuropsychological sequelae, support for going to school, provision of information on late sequelae and psychological support in adulthood reduce late psychosocial sequelae in cancer survivors.
If more than 5 years have elapsed since the cancer, military service is possible if the person is otherwise found to be fit for service.

Premature ageing

Radiotherapy and cytostatic treatment in childhood have been found to accelerate the biological ageing process.
- Muscle strength, speed and fatigability at the age of 30 years have been found to be on the level of 65-year-old healthy controls.
- In addition, childhood cancer survivors are diagnosed with ageing-related diseases at a younger age.
- These findings suggest premature ageing in childhood cancer survivors.
As physical exercise increases muscle bulk and strength, as well as contraction speed, it reduces frailty associated with old-age. Fitness training is recommended for all cancer survivors.

References

Chemaitilly W, Li Z, Huang S et al. Anterior hypopituitarism in adult survivors of childhood cancers treated with cranial radiotherapy: a report from the St Jude Lifetime Cohort study. J Clin Oncol 2015;33(5):492-500. [PubMed]
Clement SC, Schouten-van Meeteren AY, Boot AM et al. Prevalence and Risk Factors of Early Endocrine Disorders in Childhood Brain Tumor Survivors: A Nationwide, Multicenter Study. J Clin Oncol 2016;34(36):4362-4370. [PubMed]
van Kalsbeek RJ, van der Pal HJH, Kremer LCM, et al. European PanCareFollowUp Recommendations for surveillance of late effects of childhood, adolescent, and young adult cancer. Eur J Cancer 2021;154:316-328. [PubMed]
Krull KR, Hardy KK, Kahalley LS et al. Neurocognitive Outcomes and Interventions in Long-Term Survivors of Childhood Cancer. J Clin Oncol 2018;36(21):2181-2189. [PubMed]
Mogensen SS, Harila-Saari A, Mäkitie O et al. Comparing osteonecrosis clinical phenotype, timing, and risk factors in children and young adults treated for acute lymphoblastic leukemia. Pediatr Blood Cancer 2018;65(10):e27300. [PubMed]

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