By Erin Digitale
Photography by Misha Gravenor
Isabelle’s parents were worried. Their toddler was vomiting every morning and regressing developmentally — forgetting words she’d known days before. So Heather and Derek Wagner convinced their pediatrician to investigate.
When an MRI revealed a malignant, golf-ball-sized tumor at the base of Isabelle’s brain, “we started living life in segments of time,” Derek says of the unforgettable period in 2006. Even in the two days after the MRI she declined further, crying in pain and needing to be held continuously. “Things changed by the minute.”
Derek and Heather soon learned that the tumor was a medulloblastoma, which meant Isabelle had relatively good odds for surviving. More than half of the 350 U.S. patients diagnosed each year are cured.
Isabelle was immediately scheduled for surgery with Michael Edwards, MD, chief of pediatric neurosurgery at Lucile Packard Children’s Hospital. He operated two days after her diagnosis and was able to remove all the visible tumor.
“Instantly she was in better shape,” Derek says.
“In the hospital, she cracked a joke for the first time ever,” Heather says, recalling her amazement. Before surgery, she had thought Isabelle was introverted. “She’s not; she’s really outgoing.”
In tears, Heather pauses.
“She couldn’t be herself. She had this thing in her head.”
On Feb. 10, 2011, Isabelle passed the five-year anniversary of her surgery. It’s a significant milestone in a journey that included 14 months of chemotherapy and radiation.
“It’s fantastic,” says Derek. “And yet there’s a bit of holding back, the feeling that this isn’t over.”
The Wagners’ mixed feelings reflect a larger truth about pediatric cancer. Today, nearly 80 percent of childhood malignancies are cured. But reaching the five-year landmark — when doctors first use the word “cure” — does not mean a child’s medical journey is over.
Isabelle, like most cancer survivors, faces lifelong risks for side effects from her treatment. Complicating risk assessment further, the available research findings on childhood cancer survivors don’t always apply to newly cured kids like Isabelle. A generation ago her diagnosis was almost always fatal, and the few who survived to be studied as adults received therapies that are now outmoded.
The only large-scale study on young people treated for a variety of childhood malignancies has shown that the first pediatric cancer cures came at a significant cost. Patients treated in the 1970s and early ’80s suffered blows to their long-term physical and emotional health and social functioning.
However, pediatric oncologists are working to minimize the harm the therapies cause and help patients manage long-term challenges of survival. And the original survivorship studies will soon be updated with findings from recently cured children, which should give new patients a better sense of what to expect.
Still, no one can be certain what the future holds for a 7-year-old who is five years past what was at the time a new therapy. So, as they try to help Isabelle enjoy her childhood and live with the aftereffects of cancer treatment, the Wagners are stepping into the unknown.
The first big effort to study pediatric cancer survivors began around the same time as the 1989 premiere of Doogie Howser, MD, a hit TV show whose teenage-doctor protagonist was a leukemia survivor. In the preceding 30 years, childhood cancer had gone from being almost universally fatal to having cure rates that exceeded 50 percent. But no one knew what life was like for the growing population of survivors, and physicians worried that as these young adults lost touch with their childhood oncologists, their experiences and concerns were being lost, too.
“We decided that to really understand long-term effects, we had to go directly to survivors themselves,” says Les Robison, PhD, who started the Childhood Cancer Survivor Study, a wide-ranging research project funded primarily by the National Cancer Institute. In the late 1980s, Robison, an epidemiologist now at St. Jude Children’s Research Hospital in Memphis, Tenn., called on North American pediatric oncology programs to enroll their survivors in the new study.
“We said, we need to ask what’s bothering them and find out what they’re experiencing,” says Sarah Donaldson, MD, a Stanford professor of radiation oncology who helped design the study.
Since it launched, CCSS has produced more than 140 peer-reviewed publications on 20,000 pediatric cancer survivors treated between 1970 and 1986. Data on participants’ diagnoses and treatments have been paired with extensive surveys about their physical health, emotional well-being and social functioning. The study, which uses 4,000 cancer survivors’ siblings as its control group, has documented everything from participants’ struggles to obtain health insurance to their rate of second malignancies.
“The thing that’s most surprising is the true magnitude of the negative health consequences” experienced by cancer survivors, says Robison.
Major brain surgery is a risky operation — and the younger the child or bigger the tumor, the higher the risk. But physicians can quickly ascertain the neurocognitive effects of surgery. And its payoff for patients like Isabelle, who came through without significant neurologic deficits, is quick and dramatic.
“Every day she had five new words,” Heather says of the first month after Isabelle’s surgery.
In contrast, aftereffects of chemotherapy and radiation can crop up decades after treatment, sometimes long after the recurrence risk for the original cancer has dropped to nil. That’s the situation Isabelle is in now, Edwards explains. If medulloblastoma is going to reappear, it usually comes back within a period equal to the patient’s age at diagnosis plus nine months. For Isabelle, diagnosed at 20 months, the risky period was the first 29 months after her surgery, and a return of her tumor now, more than five years later, is “very, very unlikely,” Edwards says.
But she still faces potential late effects of chemotherapy and radiation, which vary depending on treatment doses, the specific drugs, the physical site of radiotherapy and the age of the patient.
For the CCSS patients treated in the 1970s and ’80s, the long-term damage was often severe.
One major CCSS paper, published in 2006, found chronic ailments in 62 percent of survivors versus 37 percent of siblings. Survivors were eight times more likely than siblings to have a severe or life-threatening condition such as blindness, deafness, a second malignancy, congestive heart failure or stroke. These problems appeared before the survivors reached middle age — survivors were, on average, 27 years old at the time of the study and 17 years past their original cancer diagnosis.
Equally worrying, the majority of adults who survived pediatric cancer had not received adequate follow-up. A 2008 CCSS paper shows less than one-third get “survivor-focused care” that addresses specific health problems arising from cancer treatment.
While, at first blush, these numbers are depressing, oncologists see reasons for hope. The study has led to new recommendations for maintaining survivors’ health and to less-risky cancer treatments. For instance, girls who receive chest radiation are now cautioned to be extra-vigilant about breast cancer screening — they need annual mammograms or MRIs starting at age 25.
And, with cure rates high, many cancer researchers can now focus on fine-tuning established cures to reduce their late effects.
Isabelle benefited directly from one such fine-tuning. After her surgery, she was part of the first group of young medulloblastoma patients in the world to receive radiation only at the site of the tumor, as opposed to the standard procedure — irradiating the whole brain and spinal column. The radiation therapy was augmented by four chemotherapy drugs, which she received in intervals over a 14-month period following her surgery.
“We wanted to tailor her treatment such that we could cure her but also not devastate her,” says Isabelle’s oncologist, Paul Fisher, MD, chief of neurology at Packard Children’s.
The new therapy appears to have spared Isabelle’s brain function. Young children who receive radiation to the entire brain and spinal cord inevitably experience significant developmental delays. Isabelle, in contrast, is now a creative, outgoing little girl who recently completed first grade in a regular classroom.
“Isabelle really is in the vanguard of lesser treatment to create better long-term outcomes,” Fisher says, noting that the treatment she received is now widely used.
But being in the vanguard isn’t simple. “It is a very different world once you’re in it,” Heather says. Because so few patients make it as far as Isabelle, the family feels they are in “uncharted territory,” she says.
“Isabelle really is in the vanguard of lesser treatment to create better long-term outcomes.”
To help future childhood cancer patients get a better sense of what lies ahead, the Childhood Cancer Survivor Study team is focusing on a new cohort of survivors. The researchers are recruiting 14,000 childhood cancer survivors treated between 1986 and 1999, plus 4,000 of their siblings; they expect to begin studying the new group in 2012. About 400 of the survivors in the new cohort will be former Stanford or Packard Children’s patients, says Neyssa Marina, MD, the pediatric oncologist who is the principal investigator for the Stanford arm of the study.
Marina expects the new cohort will demonstrate, on a large scale, the benefit of the lowered radiation exposure that helped Isabelle. Smaller radiation fields and doses have been adopted not just for brain tumors but also for many other diagnoses, she points out. “And we think a lot more about which patients get radiation.”
With its focus on survivors, the CCSS gathers no data on the newest therapies, but it still makes a huge contribution to treating new childhood cancer patients, Robison says. Pediatric oncologists can now tell their patients that most will be cured, and work from day one to educate them about long-term health effects.
“When a patient is first diagnosed,” says Robison, “we start talking about the future.”
Now that Isabelle has graduated to survivorship, she receives annual monitoring with Fisher’s comprehensive neuro-oncology team. Packard Children’s cancer survivors who had non-brain-tumor diagnoses get similar care at the hospital’s Health After Therapy clinic, which educates people who have lived through pediatric cancer. Such clinics exist across the country, another indirect outcome of the CCSS research.
Each HAT clinic visit lasts 90 minutes to two hours. Arun Rangaswami, MD, and nurse practitioner Verna Mitchell question patients about all aspects of their lives.
“We tell them that the clinic’s purpose is not just to point out potential late effects,” Mitchell says. “It’s to say, you have your life, your health. Make the best of it that you can.”
After years of being in battle mode against cancer, this is a significant shift of view for many patients.
Nutrition and exercise are a focus at the clinic — many survivors received drugs that raise obesity and heart disease risk, or were left with sedentary habits after long hospitalizations. The team also ensures patients are checked for specific physical problems linked to their treatments: for instance, cisplatin, a drug given to Isabelle, may cause deafness. (Fortunately for Isabelle, her hearing is normal.) They educate patients about possible side effects that may be years away, such as early strokes, impaired fertility and secondary cancers.
Mitchell also questions closely about psychological and school performance issues: information-processing problems, poor attention span and focus, difficulties with reading and math. Are patients sleeping enough? Do they experience anxiety?
“We don’t accept, ‘I’m doing well in school,’” Mitchell says. The HAT clinic team wants to hear the fine details so they can refer the patients properly for additional treatment. The team also points patients to resources that can help them navigate situations in which they might face discrimination. For instance, early CCSS research showed that many pediatric cancer survivors had problems obtaining health insurance once they grew too old to be covered by their parents’ insurance.
“That story came back over and over again,” Donaldson says. “And boys who wanted to enlist in the military wouldn’t be accepted because they had previously had cancer … it went on and on and on.”
Though most patients are grateful for the HAT team’s efforts, Mitchell says, some never come back after the first visit.
“It’s hard for them,” she adds. “Across the board, these families have been affected for the rest of their lives. Some don’t want to face it again.”
For Derek and Heather Wagner, life may never be back to normal, but it is good. Though their old family photos show a tiny bald girl with a feeding tube, the newer pictures are happier: the family at Disneyland; Isabelle and her little brother, Ryan, dressed in red, white and blue for the Fourth of July; Isabelle with a snowman that she and her grandmother built at Lake Tahoe.
“Our measurements of time are stretching out,” Derek says.
For Isabelle, who has no memories of her diagnosis, surgery, chemotherapy or radiation, her illness is abstract. At home with her mom, she describes what she knows about her illness: Follow-up MRIs are notable mostly for the cherry-flavored anesthetic gas she inhales beforehand; going under the anesthetic makes it feel like things around her are vibrating; Fisher is a good audience for the pictures she draws when she’s sitting in his waiting room.
Discussing family photos of an early hospitalization, Isabelle sounds momentarily upset as she asks Heather, “Why did I have to go in the baby crib?”
“You were a baby,” Heather says, calm and matter-of-fact.
And that’s that. Isabelle is quickly on to more important 7-year-old concerns: showing off a skinned knee; telling an animated story about her music teacher (“He’s super funny!”); describing plans for her upcoming birthday party.
The family is keeping a close eye on Isabelle’s school progress, as they want to address any cognitive problems as soon as possible. She struggles a bit with speed-based math quizzes, which hints that she may have deficits in processing speed.
“There are a few things we’re concerned about, but clearly, relative to what she had and to what other patients go through, she’s phenomenally well,” Derek says. “We’re really grateful for that.”
And Isabelle’s stubborn streak is serving her well in school, Heather adds. “She’s determined. She keeps trying.”
Most important, Isabelle has the support system she needs to make sure that complications can be caught early and treated aggressively.
The weight of the CCSS results has helped make it easier for childhood cancer survivors to obtain services under the Americans with Disabilities Act, such as individualized education plans that are part of special education programs. Isabelle benefited from this change when she was enrolled in a preschool program that included physical therapy for her floppy feet, a common side effect of vincristine, one of her chemotherapy drugs. And she will receive extensive cognitive testing this summer.
Meanwhile, Derek and Heather are still feeling their way forward.
“We wonder if we have to worry about leukemia — it’s one of the more common side effects of the treatment Isabelle got,” Heather says. She and Derek don’t want to focus too heavily on a bad outcome, but they want to be well-informed about all the possibilities.
“You have to really become the advocate for your child,” Derek says, adding that such advocacy requires not just fact-finding but also a “defensive posture” — the ability to step in and protect Isabelle from the scariest information about her medical situation until she is ready to handle it.
“I just want her to be able to feel like there isn’t anything she can’t do,” says Heather.
The family got an unexpected boost to their outlook at a July 2009 follow-up visit at Packard Children’s. Fisher was absent, so the Wagners saw neuro-oncologist Sonia Partap, MD. After answering a long list of questions, Heather recalls, Partap said, “‘I hope you’re not worrying about all this stuff. You are in a really special category of people; there are not a lot of people where you are.’”
They’d known this, of course, but until this conversation with an outside observer it hadn’t sunk in, Heather says.
“That’s when we realized that Isabelle is one of the lucky ones.”
This worldwide clinical trial group for studying childhood cancer offers long-term follow-up guidelines on its website.
The National Cancer Institute’s overview of the study’s findings so far.