For child cancer patients, survival is just the first step to a better later life

Survival rates for paediatric, or child, cancers have risen dramatically over the decades, thanks to major advances in treatments and decades of clinical trials.

With treatment, which often includes chemotherapy, over 60-70% of young patients will survive into adulthood, with a decent chance at leading happy, productive lives.

However, despite the survival rate, many of these children often suffer the late effects of chemotherapy treatment.

Says senior consultant paediatric oncologist Prof Dr Hany Mohd Ariffin: “Success has mostly been achieved by using very old, general chemotherapy, which has its own costs.

“Many children spend time hospitalised as a consequence of the side effects of treatment, rather than from the cancer itself.

“Following cure, over two-thirds of childhood cancer survivors have been reported to have significant health problems arising from the therapies that cured their cancer.”

Treatment stress, disturbance of the gut microbiome and exposure to agents that damage their organs affect many of their body systems, which increases the risk of health challenges in adulthood.

As these children were exposed to such substances at a time when they were rapidly growing, their healthy cells can be damaged.

Prof Hany explains: “Cancer therapies increase cellular senescence – it makes the cells old and reduces their ability to repair, and that causes prolonged inflammation that goes on in the background.

“So, while outwardly they may be free of their disease, they have a pocket of cells that is causing constant inflammation inside.

“This accelerates the (ageing) processes that usually take 20-30 years to achieve.

“It has been recognised that children who survive cancer have many problems.

“Hence, if they had cancer at six years old and survived, they may start developing heart disease, high blood pressure, diabetes, osteoporosis, etc, in their late 20s and early 30s.

“It’s as if they have aged prematurely and this acceleration is something we need to address, so we’re trying to make therapies safer for a better quality of survival.”

The benchmark is no longer about curing these young children of cancer, but to ensure that when they grow up, they are not encumbered by chronic health problems usually seen in older age groups.

The red ‘hot’ medicine

According to The Malaysian Society of Paediatric Haematology and Oncology, the incidence of paediatric cancer is about 77.4 per one million children aged less than 15 years old.All children who survive childhood cancer should have a good quality of adult life.All children who survive childhood cancer should have a good quality of adult life.

The most common childhood cancer is acute lymphoblastic leukaemia (ALL), a type of cancer in which the bone marrow makes too many immature lymphocytes (a type of white blood cell).

In Malaysia, approximately 400 children are diagnosed with ALL annually and survival rates have risen from 55% two decades ago to approximately 80% currently.

Chemotherapy is the main treatment for ALL where several medicines are given at different times over a period of two years.

It’s often done in cycles, with rest periods in between.

Up until the late 1990s, children also routinely received radiation therapy to the head to prevent the leukaemia from relapsing in the central nervous system.

This has since been phased out unless the child suffers a relapse in the brain.

One class of drugs used for chemotherapy are anthracyclines, which are derived from the Streptomyces bacterium.

Examples include daunorubicin, doxorubicin and idarubicin.

These drugs have been an important component in treating childhood leukaemia since the 1960s, as well as adult cancers such as breast, stomach and uterine cancer, and sarcoma and lymphoma.

Anthracyclines are delivered intravenously and all child patients will recall it vividly because it is red in colour.

“When they see the red medicine, they know it is ‘hot’ and will cause mouth ulcers – they still remember it as adults.

“Indeed, it is a good drug, but it has been implicated in many late effects and has been associated with damage of the heart muscles (cardiomyopathy), high blood pressure, stroke and second cancers in survivors when they reach adulthood.

“The damage is irreversible and can be associated with mortality rates of up to 24% in 10 years,” Prof Hany points out.

Due to this, the Universiti Malaya Medical Centre’s Paediatric Haematology-Oncology and Bone Marrow Transplantation Unit head and her team of researchers set out to find strategies to reduce the detrimental effects of anthracyclines.

Reducing to none

In 2003, they designed the Malaysia-Singapore ALL 2003 study and conducted clinical trials on newly-diagnosed ALL patients aged one to nine.

“Children with ALL are categorised into different risk groups based on factors such as age, genetic abnormalities of the cancer cells and the rapidity of response to chemotherapy.

“Those in the low-risk group may receive less intensive treatment compared to those in the high-risk group, thus reducing the potential for late effects.

“The way individuals metabolise drugs is influenced by their genetic make-up.

“Patients with mutations in the TPMT or NUDT15 genes, which regulate the way we metabolise certain chemotherapeutic agents, may be sensitive to certain drugs,” says Prof Hany.

They can suffer severe oral ulcers and episodes of sepsis if standard doses are not reduced.

In the study, the dose of anthracycline was reduced to 120 milligrammes per metre (mg/m) for low-risk patients (167) and substituted with other drugs without any long-term side effects.

The usual cumulative anthracycline dose is around 180mg/m of body surface area.

Results showed the six-year survival rate was 97.6%, while the incidence of relapse was 3.6%.

Similar studies have also been carried out worldwide, but despite dosage restrictions, the incidence of anthracycline-induced heart dysfunction remains prevalent.

No researcher has been willing to experiment with a treatment regime that completely omits anthracyclines.

That is, until Prof Hany and her group decided to brave it with another clinical trial.

“On one hand, we don’t want to cut the drugs until the child doesn’t survive, but at the same time, we need to find a balance to cure them, yet reduce drug toxicity,” she says.

In 2010, the team embarked on another Malaysia-Singapore ALL clinical trial.

This time, they completely removed anthracyclines for low-risk patients (202), who accounted for 42% of the participants.

A total of 1,100 children were enrolled into both studies from July 2002 to December 2019.

“We were confident as in our previous trial, we had slowly reduced the amount and saw good outcome,” she says.

Here are some of the potential health problems child cancer survivors may suffer from later in life due to the detrimental effects of chemotherapy. Here are some of the potential health problems child cancer survivors may suffer from later in life due to the detrimental effects of chemotherapy.

It works!

The second clinical trial concluded in 2020, and when compared with the 2003 one, the six-year overall survival was 99%, while the relapse rate was 2.6%.

Additionally, the omission of anthracyclines also led to a significant reduction in bacterial infections, intensive care admissions and treatment interruptions.

The team was thrilled as this is the first study in the world to show that it is possible to remove anthracyclines from ALL treatment without affecting survival rates, thus, making it possible to design safer treatments for childhood cancer with reduced toxic effects.

The study, titled Anthracycline-free Protocol for Favorable-Risk Childhood Acute Lymphoblastic Leukemia: A non-inferiority comparison between Malaysia-Singapore ALL2003 and ALL2010 studies, was recently published in the Journal of Clinical Oncology.

An elated Prof Hany says: “It’s a work in progress – we have removed one (and the worst) component, (but) further research is required to make things as safe as possible so that our children who survive childhood cancer have a better chance at adult life.

“Patients who are high-risk ALL, i.e. the cancer is tougher to get rid of, may have to be given anthracyclines, but this is where we need to find a balance.

“The concept is different from adult cancer patients because they may be in their 40s or 50s, and perhaps this drug can prolong survival by 12 or 18 months.

“But here, we are looking at childhood cancer survivors – 50 years on, they must have a good quality of life.”

She emphasises that the decision to use reduced therapies depends on various factors, including the specific type and stage of ALL, individual patient characteristics, and the risk- benefit analysis conducted by the medical team.

“We have a survival clinic so we will be monitoring them closely since late effects come later in life,” she says.

Over the course of her career, Prof Hany has seen female ALL survivors get pregnant and collapse due to heart failure.

“Some young ALL survivors were fine, and then they may join a marathon or competitive sport and it’s too strenuous for the heart.

“Suddenly, they collapse from a heart attack and people are wondering why – it’s because of the anthracyclines.

“They won’t know until they push themselves – but now, we may have eliminated that cardiovascular risk.”

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