'Kids are not little adults'

Tom Hinds remembers every detail about his daughter, Ella. He remembers the day in 2005 she was born and how she was “just a joy.” He remembers her soft strawberry-blond hair and her beloved flock of stuffed geese, each one named Gossie.

And he remembers how, shortly after she turned 1, her balance sometimes faltered and she just seemed “out of it.”

After a string of misdiagnoses, doctors finally discovered she had a cancer called medulloblastoma that reached from her brain down her spine.

The only treatment option the California family found for Ella, Hinds remembers, was a clinical trial testing modified dosages of drugs that had already been around for decades.

“We kept a positive attitude and we did everything we could,” says Hinds, who spoke to doctors across the country in his search for options for his daughter. “There was no other treatment. There was no other solution.”

It’s a problem that is too common for the youngest cancer patients. The challenge of finding the right drugs and dose for a child with cancer is constant, say oncologists. 

Dr. Jim Olson, a pediatric oncologist and scientist at Fred Hutchinson Cancer Research Center, says he has an arsenal of dozens of cancer-killing drugs to treat his young patients with brain cancer. But only one is actually approved by the U.S. Food and Drug Administration for treating children, he says.

A relative lack of research in children hampers the growth of knowledge about the diseases that affect them, and the best drugs to help them.

As a result, some children with cancer are treated with regimens developed from research in the adult version of the disease, which may have a completely different biology than the pediatric disease of the same name. Or, they may have a type of cancer that simply does not affect adults, making it so rare that little research has been conducted on treatment options. Meanwhile, pediatric doctors must balance the knife’s edge between the curative power of cancer-killing therapies and the effects that such intensive treatments can have on young bodies and minds that are still growing, brimming with the potential of decades of living ahead.

For the children and families affected by cancer, and the doctors who have dedicated their lives to helping them, it’s been a tough road. But as technology is accelerating and barriers to research are falling, hope is rising.

A lack of funding, a lack of knowledge

Fewer than one third of drugs prescribed to children, across all areas of medicine, were actually approved by the FDA for pediatric use, according to a 2008 report by the University of Michigan C.S. Mott Children’s Hospital’s National Poll on Children’s Health. It’s a fact most parents don’t realize. More than 80 percent of them believed that the last medication prescribed for their child was FDA approved for kids, the report found.

The medical community has long been aware that the biology of a child’s body is quite different than that of an adult. They break down, absorb and excrete drugs differently than adults, for instance, and their immune systems are relatively immature. Also, a child’s body is proportioned differently and every part of it is changing rapidly with growth and maturation.

“One of the first things I learned when I was getting my Ph.D. in pharmacology is that kids are not simply little adults,” Olson says. “You shouldn’t divide the weight of a kid into the weight of an adult and adjust the dose accordingly.”

Research is the only way to know for sure the right dose of a medication in infants and children. Olson pointed to well-designed studies in his field, conducted through federally funded research networks, that have helped doctors find safe pediatric doses of adult cancer medications, for example.

Let’s make it clear that pediatric cancer is rare and most children with cancer will survive it. Over the past several decades, survival rates have improved dramatically.

But the fact of these cancers’ rarity also means it’s tough to conduct research to continue making improvements. And some types of pediatric cancers, such as Ella Hinds’ medulloblastoma, are even rarer in adults. According to the National Cancer Institute, approximately 10,000 children through age 14 are diagnosed with cancer every year, compared with over 1.5 million adults. From the perspective of a pharmaceutical company that must focus on the bottom line, an expensive study is a tough sell when a new drug’s eventual market share will be tiny. (Among governmental and private funders too, pediatric cancer accounts for a small fraction of total cancer research funding.)

One name, multiple diseases

Unlike some pediatric cancers, acute myeloid leukemia at first glance seems to be different: AML occurs across the lifespan, from birth through old age. Decades ago, the chemotherapy regimen that became the long-time standard of care for AML was first developed from studies in older adults, in whom the disease is most common.

But having the same name doesn’t mean that the biology is the same, says Dr. Soheil Meshinchi, a physician and researcher at Fred Hutch who has made pediatric AML the focus of his career.

The types of genetic changes that cause the cancer are quite different across the age span: In the old, a lifetime of exposures to carcinogens and accumulating errors in the endless process of repairing and replicating DNA leads to a collection of critical single-letter changes in the DNA code that makes blood cells go rogue and become leukemic. In babies with AML, however, researchers have found evidence of a “catastrophic change in utero,” Meshinchi says: whole chunks of DNA sequences that have been moved from their proper locations in one chromosome to entirely different regions where they do not belong.

In fact, he and collaborators have looked for the two most common cancer-driving mutations in adult AML in numerous children with the disease, and they have never found them.

“In the world of target discovery and targeted therapies, one cannot expect for the targeted therapies developed against targets discovered in adults to trickle down and benefit younger patients,” Meshinchi says.

Toxic tools

Meshinchi is motivated to figure out what makes pediatric AML tick to guide the development of better treatments that target the unique causes of the disease in children ― but that also have less of an impact on the child’s growing body and the rest of their life.

“Our goal is to cure children with AML,” Meshinchi says ― unlike what is often the case in older adults, where the goal of treatment is to prolong life. “But unfortunately, the tools that are available to us are so toxic that we may cure their disease but really damage our patients, so much that the quality of life or the life expectancy drops quite a bit.”

For example, he says, recent data show that nearly a quarter of children who survive AML develop heart failure within 20 years of their diagnosis due to the cardiac toxicity of an effective chemotherapy that became the standard of care in adults and is used routinely in children.

These longer-term toxicities, which might not be big concerns for patients already of advanced age, can have a huge impact on young lives.

“A 20-year-old who needs a heart transplant because he was treated for AML when he was 5 — now that is significant,” Meshinchi says.

A recent large study of childhood cancer survivors found that children have a better chance than ever of surviving cancer, but survivors’ self-reported overall health has not seen the same gains, as they face the long-term effects of their cancer and its treatment. 

The trade-off between cure and long-term quality of life in pediatric cancer became far too real to Hinds. Ella was ineligible to receive radiation therapy for her brain tumor, Hinds says, because she was under age 3 ― an age that demarcates the upper limit of a particularly dramatic period of brain growth. The collateral damage of the radiation would have devastated her ability to function for the rest of her life, even if it had cured her tumor.

Brain cancer expert Olson (who did not treat Ella) says that when the pediatric brain cancer field learned about the terrible long-term effects of radiation to the brain in children under age 3, survival rates for these children plummeted as radiation came off the table in an effort to spare children’s brains the collateral damage of this treatment. Pioneered by researchers like Olson’s mentor Dr. Russ Geyer at Seattle Children’s Hospital, better chemotherapy regimens have since improved matters, Olson says, but they bring long-term challenges of their own.

“We are slowly getting back up to reasonable survival rates using chemo-only regimens, but these can also have serious long-term side effects, including permanent neurocognitive damage,” Olson says.

Dr. Marie Bleakley of Fred Hutch, who treats advanced leukemia in children, also grapples with the challenges of treating children in this critical developmental window. When someone has very serious leukemia, often the only thing that can save their life is a transplant of blood-forming cells. In the youngest children, however, the intensive, cell-destroying, pre-transplant preparative regimens have profound negative effects on later growth and cognitive function.

Even just staving off transplant for a year or two could have a huge impact, Bleakley says. She is exploring whether engineered, tumor-targeting immune cells would allow doctors to push a transplant back, out of this critical window, or just avoid the most toxic transplantation regimens.

“Probably they’ll still need one, but it’s a different ballpark if you could delay transplant from when they are less than 1 to when they’re 3,” Bleakley says. The goal, she says, is to “transplant smarter” in young patients who are still growing and developing.

‘Heartening progress’

The good news is that the need for more research on therapies for children has not gone unnoticed.

Federal legislation over the past decades has helped to increase the number studies of new treatments in children by creating incentives for drug companies to study therapies in children and giving the FDA more power to request pediatric studies. A 2008 report by the Institute of Medicine, for example, cited improvements in dosing and safety information for medications used in children and the development of new pediatric formulations of medications as positive results of the previous decade’s legislation.

Instead of a drug company, Olson has partnered on the early development of new targeted therapies with the families and friends of children who had suffered brain cancer ― people who are acutely aware of the need for new treatments. Crowdfunding helped to make possible his team’s initial development of BLZ-100 Tumor Paint, now in clinical trials in adults and children, that is designed to help surgeons distinguish between cancer and healthy tissue by lighting up cancerous cells.

Emerging data on the molecular basis of rare diseases like childhood cancers is also helping to turn the tide, pediatric leukemia expert Meshinchi says. He and collaborators are poised to kick off a study in pediatric AML, funded by a drug company, that tests a medication that the company already has on the market for a different disease. His research had discovered that the cancer cells of almost a third of children with AML display the molecule that is targeted by this drug.

“If you can match an existing drug with a target in your population, you’ve functionally truncated that [drug development] process by 10 to 15 years,” Meshinchi says. The fact that the drug already exists vastly reduces costs and gives the company an opening into a new market.

Once they proved that the most common AML mutations in adults are not found in children with the disease, Meshinchi and colleagues succeeded in getting federal funding for a five-year initiative called TARGET AML that is uncovering new knowledge about the genetic signatures of this disease in children, adolescents and young adults. A new effort kicked off at the Hutch and funded by philanthropists, called Target Pediatric AML, seeks to sequence the genome of every child diagnosed with AML in the U.S. through the nationwide cooperative research network in pediatric oncology.

Armed with these emerging data and philanthropic support, Meshinchi and Bleakley are setting off on a project to develop immunotherapies that employ genetically engineered immune cells to kill the unique variants of AML that occur in children. They hope that the eventual therapy that results from their project will not only be effective in treating this cancer, it will minimize the kinds of toxic side effects that are especially impactful on young lives.

The Hutch Holiday Gala, to be held Dec. 3, will raise money to make the biggest investment ever in pediatric cancer researchers at Fred Hutch who focus on developing safe, effective therapies for children.

Ella Hinds, whose dad will always remember her as “a gentle, smiley kid,” died at the age of 2 in 2007. In the years since, Tom Hinds says he’s seen a number of such targeted strategies begin to emerge from cancer research that give him hope that someday there will be more options for children like her.

“I think there’s been a lot of really heartening progress. But there’s a lot more to go,” Hinds says. “I think we’re years, not decades, away from finding a good treatment.”