Long Term Complications of Childhood, Adolescent and Young Adult Cancers

Over the last 50 years remarkable progress has been made in the treatment and survival of childhood, adolescent and young adult (CTYA) cancers; with up to 80% now surviving longer than ten years (1). Despite this success, however, childhood and teenage cancers still rank as the 6th leading cause of total cancer burden worldwide and are associated with significant long-term morbidities (2). Studies suggest that these long-term complications range from the development of secondary cancers to other chronic physical and psychological comorbidities, including endocrine, reproductive, educational and mental health problems(3-7). Management of these complications is an ongoing concern for young people with cancer, who, in a recent national survey, highlighted this area of research as one of their top ten research priorities(8). There are major gaps in our understanding of late effects, with a pressing call for studies to investigate 1) when and why these complications arise, 2) who is affected, and 3) ultimately what subsequent strategies can be put in place for most effective risk-based surveillance. Indeed, this is in line with the National Health Service (NHS) Long Term Plan (2019)(9), the National Cancer Survivorship Initiative (NCSI)(10), and Childhood Cancer and Leukaemia Group (CCLG) Strategic Plan (2020)(11).
Exploring long term complications of surviving CTYA cancer has been a subject of research interest over the last two decades. Although early studies suffered from having small sample sizes and being statistically underpowered, the generation of large multi-centre and national cohorts of CTYA cancer survivors in North America and Europe have provided clearer insight. These studies suggest that survivors experience significantly poorer health and social outcomes overall compared to siblings and healthy controls (12, 13). Similar registry-based studies have been carried out in the United Kingdom (UK), which has given us invaluable insight into long-term complications (5-7, 14-18). Despite the large sample sizes in the UK-based studies, they have been limited by: 1) exploring outcomes using only secondary care data, which is likely to capture only more severe outcomes and underestimate the burden of disease within the survivor population, 2) their data covers historic study periods, which does not fully reflect contemporary treatments strategies, 3) risk factors such as treatment data (which requires linkage through the National Cancer Registry) and diagnostic intervals (which requires access to primary care data), have not been explored in detail.
We have the unique opportunity to overcome these limitations and provide further insight using QResearch Database. QResearch is linked not only to secondary care data (Hospital Episode Statistics) but also the National Cancer Registry, which provides detailed data on tumour type, stage and treatments. This will allow us to comprehensively explore disease burden across the CTYA survivor population in the United Kingdom (UK), providing more contemporary risk estimates and exploring potential mediators in more detail.
In this study, we will investigate three common and pressing physical and social outcomes experienced by survivors of CTYA cancer, which are more likely to present to general practice and can be captured through primary care data. These will be: 1) endocrine disorders, 2) mental health problems and 3) special educational needs. By adding further to the current understanding of these outcomes, our goal is to drive appropriate clinical services and implement policy changes to support survivors.

Demographics:
1) Year of birth,
2) sex,
3) ethnicity,
4) Townsend Deprivation Score,
5) GP-practice,
6) date of registration and leaving practice
7) family history (initially to check for completeness of dataset and will be used if recorded consistently)


Part 1: Exploring Endocrine Disorders

The following Read Codes:
1. Thyroid disorders: hypothyroidism, hyperthyroidism.
2. Diabetes: Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus
3. Pubertal Disorders: delayed puberty, precocious puberty, disorders of puberty.
4. Infertility & Related Disorders: infertile, infertility external to reproductive organs, infertility (female to include anovulatory infertility, pituitary hypothalamic infertility, tubal infertility, uterine, vaginal and cervical infertility), infertility (male to include aspermia, azoospermia, oligospermia, pituitary hypothalamic infertility)
5. Referral to secondary/hospital/tertiary care related to above conditions.

The following ICD 10 codes:

1. Thyroid disorders: E01-E07
2. Diabetes: E10-E14
3. Pubertal Disorders: E30
4. Infertility & Related Disorders: E28, E29.


The following prescription (Fixed BNF codes) codes:

1. Thyroid disorders: thyroid and anti-thyroid drugs (ID 889 & 891), thyroid hormones (ID 890), excision of thyroid gland (B08)
2. Diabetes: drugs used in diabetes (ID 879), insulins (ID 880-882),
3. Pubertal and Infertility Disorders: female sex hormones (ID 896), male sex hormones and antagonists (ID 901), hypothalamic and pituitary hormones and anti-oestrogen (ID 903-4), GnRH antagonists (ID 1865)



Part 2: Exploring Mental Health Diagnoses

The following Read Codes:
1. Depression: mild-severe depression, recurrent depression, psychotic depression, deliberate/intentional self-harm
2. Generalised Anxiety Disorder: Anxiety disorders
3. Acute psychotic episodes: psychotic illness, acute psychotic disorder, schizophrenia, bipolar affect disorder, mania.
4. Referral to secondary/hospital/tertiary care related to above conditions.

The following ICD 10 codes:
1. Depression: F32-39
2. Generalised Anxiety Disorder: F40-F42
3. Acute psychotic episodes: F20-F31

The following prescription (Fixed BNF codes) codes:
1. Depression: antidepressant drugs (ID 811- 815)
2. Generalised Anxiety Disorder: anxiolytics and hypnotics (ID 801, 803)
3. Acute psychotic episodes: antipsychotic drugs and depots (ID 807-808)

Part 3: Exploring Special Educational Needs (SEN)

The following Read Codes:
Child with special educational needs, Statement of special educational needs, special educational need with type (e.g. learning difficulty, visual impairment, hearing impairment etc.).
2. Referral to secondary/hospital/tertiary care related to above condition.
Child with the following read codes: cerebral palsy, developmental coordination disorder, autism spectrum disorder, ADD/ADHD, blindness, deafness, dyslexia.
The following ICD 10 codes:
Educational maladjustment and problems related to education (Z55)


Exploratory Variables:

1. Type of cancer
• Clinical diagnostic codes (ICD 9 & 10)
ICD10 (C70.0, C70.1, C70.9, C71.0-C71.9, C72.0-C72.9, C79.0-C79.9, C81.0-C81.9, C82.0-C82.9, C83.0-C83.9, C84.0-
C84.9, C85.0-C85.9, C86.0-C86.6, C88.0-88.9, C91.0- C91.9 C91.A, C91.Z, C92.0- C92.9 C92.A, C92.Z, C93.0-C93.9,
C93.Z, C94.0-4,6,8, C95.0 C95.1,C95.9)
ICD-9 (191 (all clauses), 192 (all clauses), 196-199 (all clauses), 200-208 (all clauses)), 171.9, 170.9.

2. Diagnostic time interval
The following will be included:

• Coded symptoms (as per symptoms listed in NICE guidelines)
For Leukemias:
Abdominal mass, enlarged abdominal organ
Abdominal pain
Hepatomegaly
Splenomegaly
Hepato-splenomegaly
Fever and lymphadenopathy/splenomegaly
Lymphadenopathy, enlarged lymph node, painless lymph nodeBleeding
Bruising
Petechiae
Pallor, pale
Bone pain
Unexplained fever/weight loss/ night sweats
For Lymphomas:
Splenomegaly
Lymphadenopathy, enlarged lymph node, painless lymph node
Fever and lymphadenopathy/splenomegaly
Pruritus, itching
Shortness of breath
Unexplained fever/weight loss/ night sweats
For CNS tumours:
Headache
Vomiting (persistent)
Abnormal gait
Loss of coordination
Changes in sight (visual problems) - double vision, blurred vision, loss of vision
Any abnormal new-onset neurological sign
For Sarcomas:
Lumps on body
Bone pain

Professor Julia Hippisley-Cox - University of Oxford

Professor Anthony Harnden - University of Oxford