Practice Guidelines

Long term follow-up of survivors of childhood cancer: summary of updated SIGN guidance

BMJ 2013; 346 doi: (Published 27 March 2013) Cite this as: BMJ 2013;346:f1190
  1. W H B Wallace, professor of paediatric oncology 1,
  2. L Thompson, programme manager2,
  3. R A Anderson, professor of clinical reproductive science, University of Edinburgh3
  4. on behalf of the Guideline Development Group
  1. 1Department of Haematology and Oncology, Royal Hospital for Sick Children, Edinburgh EH9 1LF, UK
  2. 2Scottish Intercollegiate Guidelines Network, Healthcare Improvement Scotland, Edinburgh EH12 9EB, UK
  3. 3MRC Centre for Reproductive Health, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh EH16 4TJ, UK
  1. Correspondence to: W H B Wallace hamish.wallace{at}

Cancer is diagnosed in 1600 children each year in the United Kingdom, and for teenagers cancer is the leading cause of death after accidents (unintentional injury, including road traffic incidents). The five year survival rate has improved over recent decades, from 30% to 80%; this increased survival has led to a rapidly increasing population of adult survivors, with an estimated 33 000 childhood cancer survivors now living in the UK.1 These survivors have higher premature death rates than the general population and are at increased risk of a range of physical and psychosocial problems.2 Late effects of treatment may occur soon after the treatment ends or many years later.

Healthcare practitioners need guidance about potential late effects and the lifelong needs of survivors of childhood cancer. This article summarises the most recently updated recommendations from SIGN.3


SIGN recommendations are based on systematic reviews of best available evidence. The strength of the evidence is graded as A, B, C, or D (figure), but the grading does not reflect the clinical importance of the recommendations. Recommended best practice (“good practice points”), based on the clinical experience of the Guideline Development Group, is also indicated (as GPP). The group appraised the current evidence for new or completely revised sections on subsequent primary cancers, fertility, cardiac and bone health, and metabolic effects; for the remaining sections the group did not re-appraise the original supporting evidence.


Fig 1 Explanation of SIGN grades of recommendations

Subsequent primary cancers (all new recommendations)

  • Be aware that survivors of childhood cancer are at particular and lifelong increased risk of developing a subsequent primary cancer (C).

  • As those who have been treated with radiotherapy are at risk of subsequent primary cancer arising within the radiation field, adopt a high level of awareness when assessing health concerns (C). The risk of a subsequent primary cancer increases through life.

  • Be aware that exposure to chemotherapy, especially to alkylating agents (such as cyclophosphamide) and epipodophyllotoxins (such as etoposide), is associated with increased risk of subsequent primary cancers (C).

  • The guideline group was unable to make specific recommendations on subsequent primary cancer screening or surveillance as it identified no relevant studies that explored any benefits or harms of specific screening programmes or entering national screening programmes (such as mammography for breast cancer) at an earlier age than for the general population.

Fertility (all new recommendations)

In both girls and boys, the prepubertal gonad is not protected against the adverse effects of chemotherapy or radiotherapy.

  • Good links are required between paediatric and adolescent oncology units and fertility services to promote rapid referral and pretreatment assessment of young patients who may benefit from fertility preservation (GPP).

  • Consider the potential impact of cytotoxic treatment in young male cancer patients in discussion with patients and parents, and offer appropriate fertility preservation options, such as semen cryopreservation (D).

  • Consider cryopreservation of ovarian tissue (in the context of a clinical trial) in girls at high risk of premature ovarian insufficiency (D). Cryopreservation of ovarian tissue in girls and testicular tissue in prepubertal boys remains experimental. In post-pubertal girls, oocyte cryopreservation may be an option.

  • Monitor pubertal onset closely in boys who have received radiotherapy to the testes (D) and in girls who have received abdominopelvic radiotherapy or cytotoxic treatment (D).

  • Pubertal induction with appropriate sex steroid replacement treatment should be managed by a paediatric endocrinologist (GPP).

  • For females who have received abdominopelvic radiotherapy or cytotoxic treatment, offer assessment of ovarian function in adulthood (D).

  • Women who have had radiotherapy treatment to a field that included the uterus are at increased risk of adverse outcome in pregnancy, including late miscarriage, premature delivery, and low birth weight. Preconception counselling may be appropriate; advise women that pregnancy needs to be supervised in a high risk obstetric unit (C).

  • Reassure survivors of childhood cancer that their offspring are not at increased risk of congenital abnormality (C).

Cardiac problems (all new recommendations)

  • Reassure survivors of childhood cancer who did not receive anthracyclines or radiation to a field that included the heart that the lifelong risk of cardiac problems related to treatment is very low (D).

  • Individualise the frequency of echocardiographic surveillance to the risk of cardiotoxicity induced by anthracycline, with a maximum interval of five years for those at low risk (cumulative anthracycline doses <250 mg/m2) (GPP). For patients at high risk of anthracycline induced cardiotoxicity (cumulative anthracycline doses >250 mg/m2) or who have also received radiotherapy to a field that includes the heart, screen every two to three years (GPP).

  • Patients with asymptomatic left ventricular dysfunction after cancer treatment need long term echocardiographic monitoring as prognosis is uncertain (GPP).

  • Treat patients who develop heart failure according to evidence based guidelines for treating heart failure (GPP).

  • Inform patients about the importance of a healthy lifestyle, particularly smoking behaviour, exercise, and avoidance of overweight or obesity (GPP).

  • Monitor risk factors associated with coronary heart disease, such as hypertension and hyperlipidaemia, as these may modulate the heart’s susceptibility to the development of heart failure (GPP).

Bone health (all new recommendations)

  • Children treated for cancer during the period of normal accrual of bone mass may be at risk of reduced peak bone mass owing to the disease process itself or the treatment received.

  • Those who have had the following interventions are at high risk of low bone mineral density (BMD) and should have a baseline BMD evaluation about two years after completion of treatment (D):

    • -High cumulative doses of steroids

    • -High cumulative doses of methotrexate

    • -Cranial irradiation

    • -Bone marrow transplantation.

  • Evaluate BMD in survivors whose treatment has resulted in endocrine dysfunction (most commonly hypogonadism) (D).

  • In patients with results in the normal range, do not repeat BMD measures unless the clinical situation changes (GPP).

  • When interpreting BMD measurements, consider whether a patient’s final height is compromised and the possibility of pubertal delay (GPP).

Metabolic syndrome (all new recommendations)

Metabolic syndrome is associated with premature death as a result of macrovascular disease and diabetes and is characterised by features that usually include, as well as insulin resistance, the triad of central adiposity or obesity; hypertension; and dyslipidaemia.

  • Advise survivors of childhood cancer (particularly those who have been treated for acute lymphoblastic leukaemia or brain tumours) that they may be at higher risk of developing metabolic syndrome than the general population (D).

  • The guideline group was unable to make a specific recommendation on surveillance in childhood cancer survivors owing to lack of evidence, although consensus guidelines recommend annual assessment of blood pressure and body mass index.4

Recommendations from SIGN 76, not updated5

The following recommendations are still valid, although not updated.

Thyroid dysfunction

  • For those who have had radiotherapy to the neck, spine, or brain, check thyroid function after completion of treatment and regularly thereafter for life (B).

Growth and endocrine problems

  • Measure height regularly in all children until they reach final adult height (B). Refer children with impaired growth velocity to a paediatric endocrinologist for measurement of growth hormone levels (C).

Dental problems

  • Treatment for cancer in childhood causes disturbances in the mineralisation and development of crowns and roots of teeth. Specialist paediatric dentists should have a role in the care of these children (D).

Neurological and psychosocial problems

  • Regularly review neurological and cognitive function as part of normal follow-up, as treatment of childhood cancer may affect this function in later life, particularly if irradiation of the brain occurred at a young age. If a problem is suspected, refer to a psychologist for a neuropsychological assessment (D).

  • Survivors are at an increased risk of low mood, anxiety, or post-traumatic stress disorder or phobias associated with previous medical treatments.6 Regularly review for possible educational and psychosocial dysfunction, as treatment of childhood cancer may affect such function in later life. If a problem is suspected, refer the patient appropriately (D).

Overcoming barriers

Guideline implementation requires investment in long term follow-up that is led by nurses with supervision from doctors. Lifelong follow-up of survivors will necessitate multidisciplinary collaboration between patients and their families, oncologists, and other health professionals (including primary care practitioners) for appropriate counselling, early diagnosis of late effects, and where possible, timely appropriate treatments.

To improve care of survivors of childhood cancer, the guideline recommends that each survivor has access to an appropriate designated key worker who will coordinate care, and that a training programme and career structure should be developed for nurse practitioners specialising in long term follow-up.

The National Cancer Survivorship Initiative has also developed a risk stratification process to identify for each patient which care pathway is most suitable.7 The process is based on the level of risk associated with the disease, the treatment, the patient’s ability to manage, and therefore what level of professional involvement will be needed.

Further information on the guidance

Late effects related to treatment for cancer may occur soon after treatment is completed or may not present for many years or decades, so lifelong follow-up of survivors and multidisciplinary collaboration is needed. Primary care practitioners will need guidance to increase knowledge of late effects and the needs of survivors of childhood cancer whose health behaviours and socioeconomic circumstances, such as access to work and education, may be adversely affected by their experiences. This patient group may benefit from interventions to encourage healthy lifestyle behaviours, with emphasis on diet, exercise, maintenance of a healthy weight, and avoidance of smoking.

This guideline updates SIGN 76 which was published in 2004.5 The recommendations presented here include the new and the updated topic areas: subsequent primary cancers, fertility problems, cardiac effects, bone health, and the metabolic syndrome.


The development of the guideline followed established SIGN methodology based on a systematic review of the evidence. SIGN is a collaborative network of clinicians, other healthcare professionals, and patient organisations and is part of Healthcare Improvement Scotland. Further details about SIGN and the guideline development methods are contained in SIGN 50: A Guideline Developer’s Handbook ( This guideline was issued in 2013 and will be considered for review in three years. Any updates to the guideline in the interim period will be noted on the SIGN website.

Future research and remaining uncertainties
  • What is the optimal age at which survivors of childhood cancer should enter current national screening programmes for subsequent primary cancers, and their benefits and harms? For example, will the childhood cancer survivors who received high doses of radiation to a field that includes the breast benefit from early mammographic screening?

  • Does annual screening of weight and blood pressure improve long term health of childhood cancer survivors? Should specific cardiovascular screening programmes be developed for this patient group?


Cite this as: BMJ 2013;346:f1190


  • This is one of a series of BMJ summaries of new guidelines based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists.

  • The members of the Guideline Development Group are W Hamish Wallace (chair), professor and consultant in paediatric oncology, Royal Hospital for Sick Children, Edinburgh; Richard Anderson (vice-chair), professor of clinical reproductive science, University of Edinburgh; Juliet Brown, evidence and information scientist, SIGN; Susan Buck, general practitioner, Edinburgh; Janet Burns, consultant cardiologist, Royal Hospital for Sick Children, Edinburgh; Fiona Cowie, consultant oncologist, Beatson West of Scotland Cancer Centre, Glasgow; Ian Craigie, associate specialist paediatrician, Greater Glasgow and Clyde Children’s Diabetes Service, Glasgow; Angela Edgar, consultant paediatric oncologist, Royal Hospital for Sick Children, Edinburgh; Musab Elmantaser, PhD student, Royal Hospital for Sick Children, Glasgow; Brenda Gibson, consultant paediatric haematologist, Royal Hospital for Sick Children, Glasgow; Nicholas Heaney, consultant in adolescent haematology, Royal Hospital for Sick Children, Glasgow; Jen Layden, programme manager, SIGN; Caroline McManus, childhood cancer survivor, Edinburgh; John Murphy, consultant haematologist, Monklands Hospital, Airdrie; Dzung Nguyen, consultant paediatrician, St John’s Hospital, Livingston; Stephen Rogers, consultant haematologist, Victoria Hospital, Kirkcaldy; Guftar Shaikh, paediatric endocrinologist, Royal Hospital for Sick Children, Glasgow; Ailsa Stein, programme manager, SIGN; Lorna Thompson, programme manager, SIGN.

  • Contributors: All authors contributed to planning, drafting, revising, and final approval of this article. WHBW is the guarantor.

  • Competing interests: All authors declare that we have read and understood the BMJ Group policy on declaration of interests and we have no relevant interests to declare.

  • Provenance and peer review: Commissioned; not externally peer reviewed.