Dr Robert Legg and Dr Jaya Sujatha Gopal-Kothandapani

Introduction:

Each year, approximately 1900 children in the UK are diagnosed with cancer, with 1 in 600 children receiving a life-changing diagnosis by the age of 15.  However, survival rates have improved significantly, with more than 80% of children surviving 5 years, and more than 75% surviving beyond 10 years.  Although undoubtedly positive this increasing population of survivors of childhood cancer still go on to have a higher premature death rate, and later health complications compared to the general population with 40% experiencing late effects of their disease or treatment.  Endocrine complications comprise a significant proportion of these effects.

In 2013, the Scottish Intercollegiate Guideline Network (SIGN) produced a guideline aiding primary and secondary clinicians in the surveillance and monitoring of survivors of childhood cancer.  This advice has been supplemented by guidelines from the UK Children’s Cancer Study Group, and the Children’s Oncology Group in the US.  There are limited trials/studies in this area, and so many of the recommendations are based on extrapolations of existing studies, or on expert advice, yet they provide a framework for standardised management.

Risk stratification

SIGN 132 recommends that all children should receive long term follow up.  A significant proportion of that will be delivered outside of tertiary centres – but for whom?

Survivors of childhood cancer are classified into three risk groups, based on what treatment they received, as the risk of long-term effects is more dependent on the treatment than the cancer type (figure 1):

All patients should have any potential endocrine symptoms reviewed and an assessment of growth and puberty that includes weight, height, height velocity and Tanner pubertal staging. 

Further assessments are dependent on the type of cancer and treatment they received.

Care should entail the following for each patient:

• Co-ordination via an integrated MDT approach
• A designated key-worker
• A ‘patient-held’ record, containing a summary of their treatment (should they transfer services, or move out of area)
• Counselling (for family too) on the lifelong risks, and the importance of early review if symptoms develop.

Using a few illustrative cases, we will cover some key endocrine complications (there are others beyond those below), and how they can be assessed in the primary/secondary setting. In part one, we will look at puberty/fertility and growth issues.

Puberty & Fertility

Jan is 12 years old and has ALL. He is due to receive cyclophosphamide and total body irradiation in preparation for bone marrow transplant. Emma is also 12 and has received the same diagnosis and management plan.  How might these two situations differ?

All cytotoxic treatments carry a risk to puberty and fertility, and this must be discussed with the child/family prior to commencement of treatment, along with fertility counselling.  Risk to future fertility is dependent on the agent and dose of exposure, pubertal status in both sexes, and for girls the age at exposure.  There are methods available for gonadal protection and future fertility preservation exquisitely summarised in this recent article. Gonadal shielding may be a possibility in both these cases. 

Pubertal progress should also be monitored annually until sexual maturation in both cases.

Jan’s main risk is subfertility as his treatment will affect his Sertoli cells more than his Leydig cells.  He may thus progress through puberty normally but still be subfertile later in life.  His puberty, however, should still be monitored, inducing it with testosterone if needed.  He should also be offered semen cryopreservation if appropriate (or if he were older) for later conception.  Semen analysis, FSH, and inhibin B levels can be later used to assess subfertility with referral to assisted reproductive services if necessary.

Emma has risks to both pubertal progression and fertility as ovarian follicles provide both functions.  She is also at a further pubertal stage and therefore at a higher risk.  Emma may develop pubertal arrest or, at a later age, secondary amenorrhoea, both of which can indicate future subfertility. Puberty can be induced under the guidance of a paediatric endocrinologist but fertility treatment options are more limited. Oocyte collection and ovary cryopreservation have limited evidence bases in the pre-pubertal setting and can result in delaying cancer treatment.  However, they may be appropriate for a post-pubertal child.

Emma should be referred for fertility testing later in life.  Should she become pregnant, exposure to radiotherapy can still impact these pregnancies (leading to low birth weight, stillbirth, etc), and she should be advised to give birth in a centre for high-risk pregnancies.

Equally puberty is not always delayed but can be precocious in children with cancer. For example, Bethany is 7 years old and has received cranial irradiation for craniopharyngioma. This may induce precocious puberty in her, which should be regularly monitored and treated with GnRH analogues appropriately. The younger she has been treated, the more at risk she is thus in need of close surveillance.

Growth

The impact on growth in survivors of childhood cancer are multifactorial – the effects of the disease itself (particularly suprasellar disease), complications (e.g. infection), immediate effects of treatment (e.g. nausea) and late effects all play a role.  Patients that have cancer or treatment that affects the hypothalamic-pituitary axis are particularly at risk as growth hormone deficiency is the most likely form of pituitary dysfunction in such cases, though 1 in 3 children will develop other endocrine abnormalities (figure 2).  Children who receive craniospinal irradiation are also at high risk of growth arrest.

How do these risk factors affect our patients?

• Jan and Emma are at lower risk, as, although they received TBI and high dose chemotherapy, they were older when treatment started, and ALL patients are more likely to have final heights in the normal adult range. 
• Bethany is at higher risk, as she is younger and had direct cranial radiotherapy. All patients with cranio +/- spinal radiotherapy are at a high risk of growth disorders. Bethany is also likely to have had some pre-treatment impact from her craniopharyngioma.

All of our cases should have their height (sitting and standing), height velocity and BMI checked regularly (6 monthly to yearly) until final height is achieved.  If growth appears impaired, refer to a paediatric endocrinologist and test to check pituitary function (and regularly so in craniopharyngioma).  Also consider dietary interventions.

Growth hormone replacement can be given if a child is shown to be growth hormone deficient post-treatment.  This should be given early in cases of craniopharyngioma (as growth is often affected at presentation) and spinal irradiation.  In children for whom the cause of impaired growth is uncertain, a trial of growth hormone may also be appropriate.  Patients/parents should be counselled that growth hormone does not increase cancer recurrence risk.

Next, part 2, in which we turn our focus to other endocrine issues (bone health, metabolic syndrome, and thyroid function)…

Abbreviations: ACTH: Adrenocorticotrophic Hormone ALL: Acute Lymphoblastic Leukaemia BMD: Bone Mineral Density BMI: Body Mass Index DXA: Dual energy X-ray Absorptiometry FSH: Follicle Stimulating Hormone GH: Growth Hormone SIGN: Scottish Intercollegiate Guideline Network TBI: Total Body Irradiation TSH: Thyroid Stimulating hormone