Nearly 400 children in Malaysia are diagnosed with blood cancer every year, with the most frequent type being acute lymphoblastic leukaemia (ALL). One in 2,000 children aged below 15 years will be diagnosed with ALL in their lifetime.
Cancer is now the leading cause of death in children and adolescents in most developed countries. No one knows why children develop cancer, but recent studies in childhood ALL have generated interesting findings.
For example, cells carrying leukaemia-specific genetic changes are seen in one in 100 cord blood samples from healthy newborns. This suggests that the “seed” to develop ALL begins while the child is still in the mother’s womb.
Abnormalities in some genes can increase a child’s risk of developing leukaemia.
Yet, unlike Angelina Jolie, who inherited a faulty cancer gene from her mother (giving her an 80% chance of getting breast or ovarian cancer), 98% of children with ALL do not have an inherited risk for leukaemia and do not later pass the risk to their offspring.
Unlike many adult malignancies that result from habits such as smoking or poor diet, the cause of childhood cancer is largely unknown.
Interestingly, infection has been linked to the development of leukaemia. One hypothesis postulates that repeated early exposure to common viruses, usually from attending daycare facilities, protects against childhood leukaemia.
Strangely, late exposure to infections, i.e. after the age of two years, increases the risk of ALL.
In truth, there is no single way to prevent childhood cancer. However, the good news is that survival rates for children with cancer has improved tremendously over the last 50 years.
From a disease considered invariably fatal in the late 1960s, 85% of children with ALL are cured in most developed countries today.
But how has the story been for children in Malaysia?
In the 1970s, survival of children with ALL treated at the University of Malaya Medical Centre, one of the two centres providing childhood cancer care in the country at that time, was only 40%.
Protocols utilising intensive chemotherapy and radiation to the brain improved the survival rate to 56% in the mid-1980s.
Although more patients were cured, there were significant long-term side effects. The philosophy then was to deliver more intensive therapies to increase survival.
In 2002, a joint effort between the doctors of the University of Malaya (UM) and the National University of Singapore led to the founding of the Malaysia-Singapore (Ma-Spore) Leukaemia Study Group.
This brought together leading investigators from Malaysia and Singapore to tackle the problem of how to better treat ALL.
Bone marrow infiltrated by leukaemia cells: Despite almost identical morphology, leukaemia cells have heterogenous biology. Children with leukaemia require individualised therapy to achieve a balance between cure and toxicity.
The first collaborative clinical trial, called the Ma-Spore ALL 2003 protocol, incorporated specialised laboratory tests, which were previously unavailable in Malaysia, enabling risk-adapted therapy to be administered.
While most of the world used biomarkers to give more therapy with little gain, the Ma-Spore group focused on choosing the best patients and giving them less therapy.
When the trial closed in 2010, 556 children had been treated and overall survival had significantly improved to 81% – a landmark achievement for both countries.
Modern therapies have also elevated survival rates to 75%-80% for children with various other cancers such as Wilms’ tumour, lymphoma and hepatoblastoma.
However, these stellar achievements have come at a price. Many childhood cancer patients survive decades after completing treatment, but develop chronic health conditions earlier than their peers.
A phenomenon of accelerated ageing in these survivors with co-morbidities such as cardiovascular disease, diabetes mellitus and frailty in their early 40s, is particularly striking.
Our own studies on childhood cancer survivors have revealed similar concerns.
In a multi-ethnic Malaysian cohort of 101 long-term childhood cancer survivors followed up for 20 years or more at UM, we found that these young adults had evidence of cellular ageing similar to individuals three decades older.
One in five of our survivors had already developed overt metabolic syndrome, whereas 50% demonstrated one or more abnormal metabolic parameters, such as hypertension, dyslipidaemia or elevated blood glucose.
While a high survival rate is the aim and source of pride for every paediatric oncologist, an ever-increasing pool of young adult childhood cancer survivors with debilitating chronic co-morbidities necessitates serious reconsiderations of treatment philosophy.
Clearly, a “one-size-fits-all” business-like approach for childhood leukaemia therapy where survival percentage is the sole yardstick of success is no longer acceptable.
One of the key mitigation strategies is to improve how these children are treated; specifically, ensuring chemotherapy protocols are tweaked to be as personalised as possible to minimise long-term organ toxicities to a feasible extent.
Radiotherapy to the brain, once a standard component of childhood leukaemia therapy to prevent relapse, has been replaced by the chemotherapy drug methotrexate, which is given into the veins, as well as into the spinal fluid.
This spares the immature brain from radiation-associated late effects such as growth failure and drop in IQ.
Our current leukaemia trial, the Ma-Spore ALL 2010 protocol, which to date has recruited approximately 450 children, takes this one step further by excluding preventative brain irradiation altogether.
Additionally, children with low-risk ALL no longer receive any drugs that can cause their heart to fail.
One in five children with ALL has a loss of the Ikaros gene in their leukaemia cells.
The Ikaros gene controls the maturation of the normal B-cell. When lost, the leukaemia cells cannot mature and divide uncontrollably.
Those patients with Ikaros gene deletion have a 30% chance of relapse, double that of usual patients.
In the Ma-Spore ALL 2010 trial, more intensive therapy is given to this group of higher-risk patients, resulting in a reduction in relapse risk to 13%.
The Ma-Spore group is the first in the world to show that appropriately escalated therapy for Ikaros gene-deleted patients improves survival. This discovery was recently published in the prestigious Journal of Clinical Oncology.
One of the cross benefits of the Malaysia-Singapore collaboration has been the establishment of the UM Paediatric Oncology Research Laboratory; now in its 15th year of existence.
This facility, funded by a combination of charitable donations and research grants, provides the necessary laboratory support to advance collaborative clinical trials and serves as the research hub for the paediatric haemototology-oncology unit, whose main remit is to deliver high-quality therapies for Malaysian children with various malignancies.
The singular objective of curing a child with cancer at all costs is no longer adequate.
Today, we must look beyond merely searching for new cures, but instead ensure that a cure also means healthy adult lives for our children who survive cancer.
To this end, the Ma-Spore Group aims to continuously develop therapies for blood cancer that are not only effective, but also, more importantly, personalised, and hence, safer.
In the spirit of “Malaysia Boleh!”, we can help the world to better treat childhood leukaemia as the two innovative achievements of the Ma-Spore group have shown. All our children deserve the best care that we can provide.
Prof Dr Hany Ariffin is senior consultant and head of the paediatric haematology-oncology and bone marrow transplantation unit at UM Medical Centre. Ipoh-born Prof Dr Allen Yeoh Eng Juh is the Viva-Goh Foundation Associate Professor of Paediatric Oncology at the National University of Singapore.
In the end, it wasn’t easy for Aaron McQ to decide when to die.
The 50-year-old – a former world traveler, triathlete and cyclist – learned he had leukaemia five years ago, followed by an even grimmer diagnosis in 2016: a rare form of amyotrophic lateral sclerosis, or ALS.
An interior and urban designer in Seattle, United States, who legally changed his given name, McQ had been in pain and physical decline for years.
Then the disease threatened to shut down his ability to swallow and breathe. “It’s like waking up every morning in quicksand,” he said. “It’s terrifying.”
In the fall of 2017, McQ decided to use Washington state’s 2009 Death With Dignity law to end his suffering.
The practice, approved in seven American states and the District of Columbia, allows people with a projected six months or less to live to obtain lethal drugs to end their lives.
Although the option was legal, actually carrying it out was difficult for McQ, who agreed to discuss his deliberations with Kaiser Health News. He said he hoped to shed light on an often secretive and misunderstood practice.
“How does anyone get their head around dying?” he said, sitting in a wheelchair in his Seattle apartment in late January 2018.
More than 3,000 people in the US have chosen such deaths since Oregon’s law was enacted in 1997, according to state reports.
Even as similar statutes have expanded to more venues – including, this year, Hawaii – it has remained controversial.
California’s End of Life Option Act, which took effect in 2016, was suspended for three weeks this spring after a court challenge, leaving hundreds of dying patients briefly in limbo.
Supporters say the practice gives patients control over their own fate in the face of a terminal illness.
Detractors – including religious groups, disability rights advocates and some doctors – argue that such laws could put pressure on vulnerable people and that proper palliative care can ease end-of-life suffering.
Thin and wan, with silver hair and piercing blue eyes, McQ still could have passed for the photographer’s model he once was.
But his legs shook involuntarily beneath his dark jeans and his voice was hoarse with pain during a three-hour effort to tell his story.
In November 2017, doctors told McQ he had six months or less to live. The choice, he said, became not death over a healthy life, but a “certain outcome” now over a prolonged, painful – and “unknowable” – end.
“I’m not wanting to die,” he said. “I’m very much alive, yet I’m suffering. And I would rather have it not be a surprise.”
In late December 2017, a friend picked up a prescription for 100 tablets of the powerful sedative secobarbital. For weeks, the bottle holding the lethal dose sat on a shelf in his kitchen.
“I was not relaxed or confident until I had it in my cupboard,” McQ said.
At the time, he intended to take the drug in late February 2018. Or maybe mid-March. He had wanted to get past Christmas so that he didn’t ruin anyone’s holiday.
Then his sister and her family came for a visit. Then there was a friend’s birthday and another friend’s wedding.
“No one is ever really ready to die,” he said. “There will always be a reason not to.”
In late December 2017, a friend picked up McQ’s prescription for 100 tablets of secobarbital. For weeks, the bottle holding the lethal dose sat on a shelf in his kitchen.
Many people who opt for medical aid-in-dying are so sick that they take the drugs as soon as they can, impatiently enduring state-mandated waiting periods to obtain the prescriptions.
Data from Oregon show that the median time from first request to death is 48 days, or about seven weeks. But it has ranged from two weeks to more than 2.7 years, records show.
Neurodegenerative diseases like ALS are particularly difficult, said Dr Lonny Shavelson, a Berkeley, California, physician who has supervised nearly 90 aid-in-dying deaths in that state and advised more than 600 patients since 2016.
“It’s a very complicated decision week to week,” he said. “How do you decide? When do you decide? We don’t let them make that decision alone.”
Philosophically, McQ had been a supporter of aid-in-dying for years. He was the final caregiver for his grandmother, Milly, who, he said, begged for death to end pain at the end of her life.
By late spring 2018, his own struggle was worse, said Karen Robinson, his healthcare proxy and friend of two decades. He was admitted to home hospice care, but continued to decline.
When a nurse recommended that he transfer to a hospice facility to control his growing pain, he decided he’d rather die at home.
“There was part of him that was hoping there were some other alternative,” Robinson said.
McQ considered several dates – and then changed his mind, partly because of the pressure that such a choice imposed. “I don’t want to talk about it because I don’t want to feel like, now you gotta,” he said.
Along with the pain, the risk of losing the physical ability to administer the medication himself, a legal requirement, was growing.
“I talked with him about losing his window of opportunity,” said Gretchen DeRoche, a volunteer with the group End of Life Washington, who said she has supervised hundreds of aid-in-dying deaths.
Finally, McQ chose the day: April 10, 2018. Robinson came over early in the afternoon, as she had often done, to drink coffee and talk – but not about his impending death.
“There was a part of him that didn’t want it to be like this is the day,” she said.
DeRoche arrived exactly at 5:30pm, per McQ’s instructions. At 6pm, McQ took anti-nausea medication. Because the lethal drugs are so bitter, there is some chance patients won’t keep them down.
Four close friends gathered, along with Robinson. They sorted through McQ’s CDs, trying to find appropriate music.
“He put on Marianne Faithfull. She’s amazing, but it was too much,” Robinson said.
“Then he put on James Taylor for like, 15 seconds. It was You’ve Got a Friend. I vetoed that. I said, ‘Aaron, you cannot do that if you want us to hold it together.’”
DeRoche went into a bedroom to open the 100 capsules of 100mg secobarbital, one at a time, a tedious process. Then she mixed the drug with coconut water and some vodka.
Just then, McQ started to cry, DeRoche said. “I think he was just kind of mourning the loss of the life he had expected to live.”
After that, he said he was ready. he asked everyone but DeRoche to leave the room. She told him he could still change his mind.
“I said, as I do to everyone: ‘If you take this medication, you’re going to go to sleep and you are not going to wake up,’” she recalled.
McQ drank half the drug mixture, paused and drank water. Then he swallowed the rest.
His friends returned, but remained silent. “They just all gathered around him, each one touching him,” DeRoche said.
Very quickly, just before 7:30pm, it was over.
“It was just like one fluid motion,” DeRoche said. “He drank the medication, he went to sleep and he died in six minutes. I think we were all a little surprised he was gone that fast.”
The friends stayed until a funeral home worker arrived.
“Once we got him into the vehicle, she asked, ‘What kind of music does he like?’” Robinson recalled. “It was just such a sweet, human thing for her to say. He was driving away, listening to jazz.”
McQ’s friends gathered June 30, 2018, in Seattle for a “happy memories celebration” of his life, Robinson said.
She and a few others kayaked out into Lake Washington and left his ashes in the water, along with rose petals.
In the months since her friend’s death, Robinson has reflected on McQ’s decision to die. It was probably what he expected, she said, but not anything that he desired.
“It’s really tough to be alive and then not be alive because of your choice,” she said. “If he had his wish, he would have died in his sleep.” – Kaiser Health News/Tribune News Service