University College London study links paediatric cancer with increased illness later in life

Pixel-Shot child nurse cancer

Childhood cancer currently has long-term survival rates over 80%. However, survivors are known to face high risks of ill health in adulthood. A new study led by scientists from University College London (UCL) has for the first time examined how these late effects may vary according to cancer type and treatment modality.

‘This is the first life course atlas of cancer survivorship,’ the researchers say. They found that survivors who developed late effects had significant premature mortality compared with those without late effects.

The researchers call for these long-term health effects to be taken into consideration at the outset when young people and their families discuss treatment options with their healthcare team. They point out that, although late effects of treatment modalities such as chemotherapy or radiotherapy are well-recognised, their burden may be proportionately greater in children, who have potentially longer to live to experience them.

The study, published in The Lancet Regional Health - Europe, found that adult survivors of childhood cancer had five times as many GP or hospital visits for cardiovascular disease by age 45 as a matched control group. Survivors also had many more visits for infections, immune system disorders, and subsequent malignancies. 

The consequences of late effects were considerable. Survivors who developed cardiovascular disease lost an average of 10 years of life compared with those who did not; those who succumbed to immune disorders or infections lost on average 6.7 years, and those who developed subsequent cancer lost on average 11 years. Years of life lost were highest among survivors with haematological comorbidities.

When the figures were broken down by treatment type, late health effects were highest for children treated with both chemotherapy and radiotherapy, and lowest for those who had only surgery. 

So, for example, by age 45 adult survivors who had been treated with chemotherapy plus radiotherapy had more than twice the total number of hospital admissions compared with those who had surgery alone. They also had seven times the number of GP or hospital visits for cardiovascular disease and an increased risk of a further cancer and of metastatic cancer.

Lead author Wai Hoong Chang, from the UCL Institute of Health Informatics, commented in a press release: ‘Combined chemotherapy and radiotherapy is effective at saving lives, but is associated with a lower quality of life in the long term. Our study suggests using lower doses could reduce these long-term effects.’

Linked databases

The researchers aimed systematically to quantify the cumulative burden of late effects across all cancer subtypes, treatment modalities, and chemotherapy drug classes. They extracted anonymised primary care records and linked to hospital records, death, and cancer registries from 1998 to 2020 for 3466 people in England who had been diagnosed with cancer before the age of 25 and who survived for at least 5 years—representing an 85% survival rate from the total 4063 patients diagnosed with cancer before age 25.

Survivors were compared with a birth-year- and sex-matched community control group of 13,517 people who had not had childhood cancer. The team assessed the total GP or hospital visits for each of 183 physical and mental conditions by people in each group. They then stratified the burden of these different diseases by cancer type, treatment received and, where relevant, treatment dosage.

In terms of cancer type, the cumulative burden of late effects at age 45 was highest in survivors of leukaemia (an average of 29.79 episodes per individual) and lowest in survivors of germ cell tumours (9.07 episodes). In comparison, the relevant figure was 7.19 for the control population. 

Immunological conditions and infections imparted the highest cumulative burden, with a mean of 3.27 episodes by age 45, followed by cardiovascular conditions at 3.08, versus 1.12 and 0.61 respectively in the control group.

Cancer survivors also experienced a high burden of mental health conditions, with an average of 3.19 events per person by age 45, compared with 2.68 for community controls.

Looking at treatment modality, survivors who received both chemotherapy and radiotherapy had the highest disease burden and the highest hospitalisation burden (mean 10.43 episodes by age 45), whereas the lowest burdens were seen among those who received surgery only.

Regression analyses revealed that survivors who had been treated by surgery alone had lower risks of developing cardiovascular (adjusted odds ratio [OR] 0.73), haematological (0.51), immunology and infection (0.84), and renal (0.51) late effects. By contrast, the opposite trend was observed in survivors who received chemotherapy plus radiotherapy. 

Treatment with antimetabolites was associated with the highest disease and hospitalisation burden, compared with the lowest in those receiving anti-tumour antibiotics. 

Increased cumulative dose of antimetabolites, alkylating agents, plant alkaloids, and anti-tumour antibiotics were associated with increased risks of subsequent cancer, infection and immunological conditions, renal, endocrine, pulmonary, and neurological conditions. Similarly, increased radiation dose and field were associated with increased risks of subsequent neoplasm and neurological conditions.

Experts advocate early discussion of late effects 

The authors point out that despite a general shift towards a cancer-as-chronic-disease care model, the risks of late effects are often raised only during counselling sessions after completion of therapy.

‘Most teenagers and young adults with cancer desire information about what could happen to them after cancer therapy, and many want to be included in treatment decision-making at early stages,’ they say. ‘Yet, because their information needs regarding potential late effects are often unmet, participation in survivorship monitoring and care may be affected, hence causing impairments in long-term psychosocial and physical well-being.

Speaking to Medscape UK, senior author Dr Alvina Lai, from the UCL Institute of Health Informatics, said: ‘Initially, the focus is on deciding and getting started on treatment. Long-term effects are not much discussed, and young people are not involved in decision-making.

‘That should definitely change, because over 80% of children survive cancer and they go on to live a very long life, and they suffer from these late effects in the long term.’

How can clinicians get the balance right between the most efficacious cancer treatment and minimising the risks of long-term effects?

‘The balance is difficult,’ Dr Lai said. ‘Children are very resilient, and we want to be able to target the cancer quite aggressively but, at the same time, if children are subjected to both chemotherapy and radiation, they have a significantly higher risk of developing many, many different late effects.’

Clinicians might explore treatment options that are associated with less risk, for example just surgery, or just chemotherapy alone.‘It really depends on the type of cancer—some cancers are very aggressive and there is not much choice but to treat them very aggressively.

‘But having really close discussions with the young person involved is very important—they have to face the treatment and they have to face the long term effects.

‘We need to inform them about the types of condition that they could potentially experience down the line, making them aware of the symptoms of those conditions— because a lot of them are very treatable, for example hypertension or some heart conditions, and mental health conditions. We can encourage them to have conversations with their doctors and not be afraid to seek help.’

Helen Gravestock, Director of Policy, Influencing, and Voice at Young Lives vs Cancer commented: ‘We believe that all children and young people facing a cancer diagnosis should be given timely information and advice on how to manage long term consequences of their treatment.
 
‘When a child receives a cancer diagnosis, we believe they must be listened to. Input from teenage and young adult specialists is important so that young people have access to age-appropriate information, which can lead them to make an informed decision about the treatment they receive and the impact it will have on them beyond.’

Future hopes

The researchers conclude: ‘This trade-off between anti-tumour efficacy and late effects must be considered when designing front-line therapy.’ Furthermore, given that most childhood cancer patients survive well into adulthood, and that mental health conditions are common late effects, teenagers and young adults should be involved in initial decision-making with their parents.

’Patient empowerment and psychological support at early stages are crucial for improving survivorship.’

The study may also contribute to the development of guidelines for screening of childhood cancer survivors to enable earlier identification of and intervention for late effects.

In future the team hope to investigate how cancer therapies might be designed to minimise the incidence of late effects.

This article originally appeared on Medscape UK, part of the Medscape Professional Network.

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