NEW YORK – "I wish I could not have that hand," my 4-year-old son said as he woke up one winter morning.
"Why my love?"
"Because it's no good," he said, pulling the almost lifeless fingers of his left hand with his stronger partner.
Already tired of the fear and concern with the cascade of Nathan's symptoms, I was sad to hear him describe how his body was cheating on him.
It was March 2017. The year before, the signs indicated something was wrong. First, Natan's voice weakened. He repeatedly became ill with lung infections. Each passing week seemed to bring a new warning. He choked when he ate or drank. His left foot crawled. He would stumble and fall in the game. His eyes moved rapidly from side to side. When we spoke to our bright boy, it was more difficult to connect, as if a heavy fog had settled between him and the world.
Now Natan was within days of delicate surgery to remove some of the tumor the doctors had just found growing like weeds from his spinal cord. He had invaded his brain stem and beyond, slowly choking the nerves that control breathing, swallowing and movement. Left unmarked, I could kill him.
But even if it was successful, surgery would be only a temporary measure, a starting point in a process that would propel our family to the advanced frontiers of medical science. There, the revolution of genomics, as it is known, made it possible to understand and confront what drives some types of cancer and other diseases. With tissue removed from the tumor, doctors said, they would determine if it was caused by a rare genetic mutation that could radically change the course of their treatment.
Just a few years earlier, this course would have been grimly simple: over a year of chemotherapy that could prevent tumor growth. Patients like Natan may need to repeat this punitive treatment several times in childhood and face a life of growing commitment as the mass has robbed them of their ability to breathe or walk on their own. Now, we were told, there was a small chance that Natan could defeat the tumor by simply swallowing a pill twice a day with few side effects.
In the 15 years since scientists completed the first map of a person's genome – the sequence of DNA molecules that is the unique genetic plan of each individual – the process has become faster and cheaper. With information from such tests on tumor cells, researchers are developing drugs to target disease-specific genetic abnormalities one by one, prolonging and improving the lives of tens of thousands of people whose diseases have already been sentenced to death. And they just started.
"Forty years ago, we did not understand cancer and we did not understand drugs," said Dr. Richard Schilsky, medical director of the American Society of Clinical Oncology. "Now we are really capable of studying a patient's cancer, gaining some insight into what it is driving, and in some cases identifying effective and well-established therapies that can be targeted at these drivers. That's a huge difference.
These advances also bring new risks to patients, already dealing with a devastating diagnosis, who may be encouraged to consider expensive new treatments with little evidence of their efficacy or safety. It is a matter of debate in the cancer community: how to moderate the hope of some against the likelihood that most patients still do not find a response in these therapies.
"Most people do not benefit, but some do, and that's what drives the field," Schilsky said.
In Natan's case, we learned that in one clinical trial, one of the newer, targeted therapies approved to treat aggressive cancers in adults had worked wonders on a small group of children with similar slow-growing tumors. If DNA sequencing revealed the relevant mutation, the experts told us that Natan would be a candidate for the drug.
I was not about to accept, without question, treatment with scant evidence, and one whose long-term effects were not known. As a US health editor for Reuters News several years ago, I worked on articles about the promises and disappointments of so-called precision medicine. I knew how to question allegations about new drugs that "melted" tumors.
The professional was now personal, so my husband and I, equally skeptical, began to learn as much as we could about the options for Natan. We consult family and friends in the medical field and use reference networks in our Jewish community. We interviewed specialists and read what research we could find. It was exhausting, especially upon the emotional and physical toll of caring for a sick child, but we had no choice.
Our boy's survival was at stake.
Natan was a healthy little baby, active and mischievous playing with his older brother. Our only complaint was that he often woke up during the night, but in those years, there was always a reasonable explanation: feeding, teething, growth spurts.
Our first real panic occurred in the spring of 2016. Nathan, then 3, woke up Sunday with a runny nose, but otherwise he looked fine. I went out to the gym. At that time, he vomited a high fever, and when I returned, my husband was holding him over the bathroom sink, pouring cold water on his face.
"He got limp, like he was not breathing," he said. "I called an ambulance."
After a few days at the hospital being treated for pneumonia, Natan recovered. The speed of its deterioration worried us, but it seemed quite similar to the stories of other parents about scary but treatable respiratory illnesses in young children and our own preschool outbreaks with pneumonia and bronchitis.
Soon we began to wonder why his sleep was still so disturbed and why his voice had begun to sound soft and husky.
The first visits to the doctor did not give anything abnormal. When someone recommended deeper tests, such as a sleep study, my husband and I, suspicious of unnecessary medical interventions, asked what practical difference the information might bring.
Natan now cried many mornings before school. "I'm sick!" He said, even though his vital signs seemed normal.
In a few months, it became clear that we needed more answers. When Natan returned to preschool in September, his voice was barely audible to his teachers. He sometimes seems to choke while eating or drinking. An ear infection gave way to a sinus infection that gave rise to bronchitis. When he finished a course of antibiotics, he was soon back to the pediatrician's office or the emergency room, struggling to breathe.
"There is no reason why a neurologically normal child sounds like this," said a pulmonologist after only a few breaths.
Since Thanksgiving, tests began to pile up, just like the medications Nathan needed every day. The list of "complaints" on his chart became longer after each visit: noisy breathing, respiratory sleep disorder, chronic bronchitis, asthma. He was hospitalized again for pneumonia at Christmas. Nothing we were doing made it any better, and that helplessness fueled our anxiety.
Natan now cried many mornings before school. "I'm sick!" He said, even though his vital signs seemed normal. At work, I was haunted by the feeling that his teacher or nanny would call at any moment to say that he stopped breathing. When I picked him up from class, I noticed his heavy gait as he stumbled forward as he walked and how his eyes seemed numb.
Each new specialist brought in the case of Natan identified another symptom, now more suggestive of a neurological disorder: quick and involuntary eye movements, weakness on the left side of his body. But we still had no explanation.
"What's the diagnosis?", My husband demanded at every medical appointment.
In late February 2017, the two of us sat in the hospital dining room, waiting to know when Natan had left the anesthesia for an MRI. We try to keep our worst fears under control.
"When this is over, we should take the boys to the beach for a month. It's the best medicine, "my husband said.
I glanced at my watch. The call of the nurses' station had not arrived, though more than enough time had passed, and I was impatient.
"Let's go upstairs," I said. Then my cell phone rang.
It was the neurologist who ordered the MRI. The examination showed something unusual: a large "infiltrating" lesion centered on the medulla oblongata, the structure at the lower end of the brainstem that controls breathing and other involuntary functions. The thickest part was compacted firmly into the cervical spine, with tentacles snaking into the midbrain and cerebellum, which regulates balance and motor coordination.
"What does that mean?" I asked.
"You need to talk to a neuro-oncologist," she said, adding that she was trying to score us in a few days. "There are no signs of fluid accumulation in the brain, so you can take your child home."
"You're telling me that my son has a huge brain tumor, but should he go home now?" I asked.
We refused to leave until someone who could interpret the scan spoke to us.
An hour later, a pediatric brain tumor specialist told us that Natan's injury was probably a rare type of slow growth, appearing in about 100 cases a year in the United States. Natan may even have been born with it, and it was only now big enough to crush the nerves that went through the 4-year-old brain stem, a structure the size of an adult thumb that connects the brain and spinal cord.
These agonizing nerves were losing their ability to regulate Natan's walking and motor movements, their breathing, swallowing, and sleep rhythms.
"At least you now have a diagnosis that explains everything," said the doctor. "It may take a few families much longer to get to this point."
"I want this TUMOR OUT"
Like many people facing a crisis, we turn to all the resources we have at our disposal. We were lucky enough to have access to excellent doctors and world-renowned hospitals close to home. The health insurance provided by my employer covered almost all our expenses.
Two weeks after we received the diagnosis, Natan underwent a six-hour operation at NewYork-Presbyterian / Weill Cornell Medical Center. Dr. Mark Souweidane, director of pediatric neurological surgery at Weill Cornell and Memorial Sloan Kettering Cancer Center, removed about 20 percent of the tumor, mostly in the cervical spine. Venturing further into the brainstem, where the tumor was more difficult to distinguish from healthy tissue, would have been very dangerous.
In a few days, pathology tests confirmed the tumor type: a slow-growing ganglioglioma, a mixture of cells that includes central nervous system components and supportive tissue.
The good news is that these low-grade gliomas are not malignant, which means that, unlike aggressive cancers, they do not grow rapidly and usually do not spread to other organs. In many cases, they stop growing completely when patients reach the age of 20. But the large size and location of the tumor had already significantly damaged Natan's ability to swallow and breathe. This put him at risk of inhaling liquids and small pieces of food into his airways, leading to fatal or choking pneumonia.
It would take another two months to obtain sequencing results conducted separately by Weill Cornell and Sloan Kettering, where we sought a second confirmation of the tumor's genetic profile.
At that time, we focused on Natan's recovery from surgery, with weeks spent in the hospital and an acute rehabilitation center.
Removing part of the tumor helped to improve some of the symptoms. The quick movements of his eyes almost disappeared. In the daily therapy sessions, Natan was learning to use his left hand again and walking without stumbling. But we were noticing or confirming new problems: hearing loss, severe sleep apnea, long periods of hiccups that are a hallmark of brain stem tumors.
I tried to cling to the idea that somehow the surgery would suffice for a few months, or years, before the tumor progressed further. I even hoped he'd stop growing on his own, as some doctors suggested, and feared the new surprises he'd face in treatment. Even without major complications after surgery, he was fragile, both physically and emotionally.
My husband was uncomfortable waiting to see if the tumor grew more before starting some kind of therapy.
"It looks like we're sitting waiting for a miracle to happen," he said. "I want this tumor."
Sequencing confirmed that a mutation known as BRAF V600E, most commonly seen in adults with fatal skin cancer melanoma, was driving the Natan tumor.
"I have something for you," said Dr. Matthias Karajannis, chief of pediatric neuro-oncology at Sloan Kettering, when we met to review the test results. This "something" was a drug called dabrafenib, sold by Novartis AG under the brand name Tafinlar. It helped keep a significant percentage of melanoma patients alive after five years when used with a second medicine, Mekinist, a major improvement on older therapies.
Karajannis recommended that we use Tafinlar to treat Nathan. Although chemotherapy is the first standard treatment for low-grade gliomas that can not be removed surgically, early evidence has shown that the new therapy could be much more effective.
In some cases, he said, "the tumors just disappeared."
Roche's Herceptin, or trastuzumab, launched in 1998, was the first "target" cancer therapy, interfering with a growth-promoting protein found in about 20% of breast cancer patients. The drug has improved overall survival rates, particularly among women with early-stage cancer.
The next major breakthrough came in 2001, with the approval of Novartis's Gleevec, or imatinib. Gleevec has transformed the deadly blood cancer known as chronic myelogenous leukemia (CML) into a long-term manageable disease. For almost all patients with CML, diseased blood cells show a fusion of two genes that are normally separated. Gleevec blocks the activity of fused genes and leaves healthy cells untouched – a breakthrough in potentially lethal chemotherapy, which is toxic to both diseased and healthy cells.
With the success of Gleevec, the race was in search of other targeted therapies: for each new potential drug, this meant first identifying an aberrant gene that would fuel a type of cancer and then crafting a drug to counteract that aberration.
Reality is proving to be much more complex as researchers learn about the multiple influences at work on cancer cells. Many of the target therapies approved since Gleevec help only a small percentage of patients with any type of cancer, and often only for a year or two before tumor cells create new mutations to overcome the drug.
"There was this feeling that we were going to beat cancer with these approaches," said Dr. David Hyman, head of drug development at the beginning of Sloan Kettering, who leads the research on new targeted therapies. Now the medical community has recognized that cancer "is a series of rare diseases," each with its unique biological mechanisms.
However, these new drug discoveries can change the lives of small groups of patients. The US Food and Drug Administration has approved more than 30 prescribed therapies based on genomic test results. Most of these treatments have been introduced in the US market since 2012.
"For many patients, unfortunately, we did not find the" magic ", but it's also a developing area," Karajannis said in an interview. "Just a few years ago, we had no treatment options."
A study published in April in the journal JAMA Oncology estimated that 15% of the nearly 610,000 advanced cancer patients in the United States could be considered candidates for treatments informed by genomic sequencing, and that almost 7% would likely have some benefit.
Xalkori from Pfizer and Alecensa from Roche, for example, target mutations that occur in about five percent of patients with non-small cell lung cancer. In late November, newcomer Loxo Oncology received US approval for Vitrakvi, a pill shown to shrink a wide variety of TRK fusion-driven tumors, a genetic anomaly found in less than one percent of all cancer patients.
The side effects of Tafinlar were much milder than those of chemotherapy, experts said. But long-term safety in children was – and still is – unknown.
Global sales of these targeted treatments reached $ 28 billion last year, according to research firm GlobalData Plc.
Within the small community of children with low grade gliomas, the potential for a targeted approach emerged almost a decade ago when two different BRAF abnormalities were identified in these tumors. The BRAF V600E mutation appears in about 10% of the 1,000 US children diagnosed with low grade gliomas each year. The research coincided with the development of Tafinlar, originally approved in 2013 for patients with melanoma with the same BRAF mutation.
At a medical conference in Copenhagen in October 2016, when we began investigating Natan's symptoms, Dr. Mark Kieran, director of the pediatric brain tumor program at the Dana-Farber Cancer Institute and Boston Children's Hospital, presented data on 32 children treated with Tafinlar. .
All of the children's tumors were positive for the BRAF V600E mutation, and nearly three-quarters of them saw their tumors shrink or stop growing with the drug. In two cases, the tumors disappeared, while the tumors of 11 patients decreased by more than half. The side effects were relatively minor – rash, fatigue, fever.
Less than a year later, we read about these results and wonder: would that be enough proof to use on our son?
My husband and I have analyzed as many sources as possible. We wanted to know more specifically about the treatment of children with a diagnosis identical to that of Natan: a brainstem ganglioglioma with a BRAF V600E mutation. We contacted several pediatric neuro-oncologists. Some had treated or closely followed a few dozen patients like Nathan. Others had direct clinical experience with a handful or none.
They told us that chemotherapy and the new drug were viable options, but they differed in what they emphasized. Some looked more conducive to chemotherapy. They cited data collected over decades showing that 25% to 40% of patients with low-grade glioma saw their tumors stop growing after chemotherapy, which usually resulted in a year or more of weekly infusions of carboplatin and vincristine. Even if the disease returned, most children survived into adulthood, studies show.
Potential side effects of chemotherapy while a patient was being treated were harsh, including neuropathy – nerve damage that can cause both debilitating pain and numbness – and the risk of bleeding or severe infection. But there was no cognitive damage or other damage in the long run afterwards.
Survival data pooled many varieties of low grade gliomas, including tumors cured by surgical removal. Gangliogliomas of the brainstem like the one of Natan represented a very small subset. New research and clinical trials have suggested that chemotherapy was much less effective in children with brain stem tumors, particularly those with a mutation in BRAF V600E, leading to repeat treatments and worse survival rates.
"Do not trust this tumor!" Said Dr. Eric Bouffet, chief of neuro-oncology at the Hospital for Sick Children (SickKids) in Toronto and co-author of the Tafinlar study. Bouffet was familiar with many of the patients with low grade glioma in Canada. He and his colleagues continue to study their results and track data from other medical centers around the world.
The BRAF mutation appears to make tumors more aggressive, Bouffet said during a telephone consultation. He told us about children, like Natan, whose brain stem tumors caused severe sleep apnea, a sudden stop in the breath. A boy died in his sleep before receiving therapy, Bouffet said.
The side effects of Tafinlar were much milder, experts said, and the children who used the drug were not missing school, like chemotherapy patients. They could enjoy a family vacation. But their long-term safety in children was – and still is – unknown and will take years to establish.
Medical literature was also scarce. One of the first published case studies of 2014 told the painful story of a 21-year-old whose brainstem ganglioglioma returned after several rounds of chemotherapy and radiation, leaving him in a wheelchair. His tumor shrank drastically with Tafinlar and he started walking again, only to experience a fatal brain hemorrhage in a few weeks. His doctors questioned whether the rapid withdrawal of such a large tumor had contributed to the bleeding.
A second report showed a promising outcome for a child with a low-grade massive glioma who declined dramatically within two months of treatment, saving his life.
When we consulted Kieran on Natan's case, he recommended that we consider chemotherapy first, given his safety record, and if that fails, try Tafinlar. Previous treatment with chemotherapy was also a requirement for enrolling children in the Novartis clinical trial.
There were good reasons for caution. Even when drugs are tested on hundreds of patients, safety issues can take years to identify. Now, regulators are more willing to approve targeted therapies, particularly those that treat advanced cancers, based on testing in smaller groups of patients. For someone with a few months to live and no other options, the risk may be worth it. But was the trade-off appropriate with a slow-growing tumor?
We wanted to understand why Kieran, who led the Tafinlar clinical trial, would not recommend using it from the start. In June, as soon as we thought Natan was ready for the trip, we took him to Boston. After examining our son and almost two hours of detailed discussion, Kieran gave a nod to the new therapy.
In a recent interview, he said that by the time we met, he had started discussing therapies like Novartis's Tafinlar as first-line treatment with other families, depending on the circumstances of the patient.
"The conversation I would have had with a family five years ago would have been completely different," he said. There is enough data now to consider appropriate BRAF therapy for patients like Natan as long as families recognize that the condition could change as more data comes in, he said.
Not every patient has the luxury of waiting for this information: "You can not always say, let's just wait for three years and see how the data goes," Kieran said. He recently left Dana-Farber to lead the development of pediatric cancer therapy at Bristol-Myers Squibb.
Throughout our research and our consultations with experts, one detail stood out: there was a chance that Tafinlar would actually shrink Natan's tumor, an unlikely result with chemotherapy. If he did, his symptoms might improve, assuming the nerves were no longer irreparably damaged. We needed to give him this chance.
Two weeks later a pharmacist from Sloan Kettering showed me how to turn Tafinlar into liquid so Natan swallowed safely. In our kitchen, I poured the white powder from the capsule into Kool-Aid lemonade-flavored, which Novartis says is the only drink that can dissolve this advanced remedy. I tried not to spill anything. Our insurance covered almost the entire cost, but I was still aware of the expense of replacing just one pill for almost $ 100 of retail.
In the first few weeks, we are attentive to unusual reactions. One night, Natan almost fainted for no obvious reason. Another night, his temperature rose to 105 degrees. It turned out to be a virus. For a few days, hives erupted all over the body. Again, a virus was suspected.
And we notice something else. After just over a week, Natan's voice, barely audible for months, was ringing out loud. At first we doubted it was real. But Natan was so pleased that he could now hear himself and talk about his brother, whom he would scream and sing spontaneously.
During the summer, tests confirmed that his hearing had returned. His gait grew stronger and stronger. With a twinkle in his eyes, Natan breathed too deep for the nurse and watched the monitor as his oxygen levels rose from 99% to 100. He was taken from the respiratory remedies and the antibiotics that had been one of the pillars for nearly a year.
The next magnetic resonance of Nathan in October 2017 showed a result far beyond what we had allowed ourselves to wait: almost all of its detectable tumor disappeared. "It looks almost like a normal brain," Karajannis said.
My husband and I wondered if we could have noticed the symptoms earlier, and whether the treatment at that stage would have spared Natan from the worst of his illness. But given the rapidity with which science has developed, we now think otherwise in our case: if we had found the tumor earlier, Natan would probably have undergone chemotherapy infusions and its hard effects every week for over a year with little real benefit .
The success of Natan treatment offers no guarantees. No one can say how long the remedy will work, whether it should take the remedy indefinitely or stop, or whether both present some risk.
Science is also moving forward. Novartis is starting to test Tafinlar plus Mekinist – the combination used to treat patients with melanoma – versus chemotherapy in children whose low-grade gliomas exhibit mutations in the BRAF V600E to see if the combination works better and longer. The drugmaker also dropped the requirement that patients have chemotherapy treatment to enroll. A new generation of BRAF therapies from companies like Array BioPharma and AstraZeneca are in clinical trials. Our hope is that if Tafinlar stops working for Natan at some point, a new therapy will be there to take his place.
It's been over a year since Natan started treatment. He started running again, jumping, swimming, and climbing. He is now in the first grade, excited to go to school every day and see his friends.
Natan now swallows his capsule with a sip of water, blinking one thumb up each time. He traveled on vacation, even abroad, with no setbacks. On our last trip, he chose a new T-shirt for himself. At the front, he says, "Never give up."
Photo Editing: Steve McKinley
Video: Jillian Kitchener, Craig Hettich and Mike Wood
Design: Pete Hausler
Edited by John Blanton