NEW YORK – "I wish I did not have this hand anymore" said my 4 year old son when he…
NEW YORK – “I wish I did not have this hand anymore” said my 4 year old son when he woke up on a winter morning.
“Why, my love?”
“Because it’s not good,” he said, drawing to his almost left hand with his stronger partner.
Always tired of fear and worry about Natsa’s cascade of symptoms, I was afraid to hear him describe how his body betrayed him.
It was March 2017. During the previous year, the signs had mounted that something was wrong. First weakened Natan’s voice. He repeatedly became ill with pulmonary infections. Each transition week seemed to give a new warning. He choked when he was eating or drinking. His left foot subsided. He would travel and fall into play. His eyes moved quickly from side to side. When we talked to our bright boy, it was harder to connect, as if a heavy fog had settled between him and the world.
Now, Natan’s days were gone from a delicate operation to remove a part of the tumor that the doctor had finally grown, weed-like, from the spinal cord. It had invaded its brain stem and beyond, slowly suffocating nerves that control breathing, swallowing and movement. Left untrue, it can kill him.
But if successful, the operation would just be a stop-off goal, a starting point in a process that would drive our family to the forefront of medical science. There, the genomics revolution, as it is known, made it possible to understand and confront what drives some cancers and other diseases. With tissue taken from the tumor, doctors told us that they should determine if it was caused by a rare genetic mutation, which can radically change the treatment.
Just a few years earlier, that course had been cruel uncomplicated: more than a year of chemotherapy that can stop the tumor from growing. Patients like Nathan may need to repeat this punitive treatment several times in childhood and face a life of increased depression because the mass robbed them of their ability to breathe or go on their own. Now we were told that there was a slight chance Nathan could repel the tumor by just swallowing a pill twice a day, with few if any side effects.
During the 15 years since the researchers completed the first map of a person’s genomic sequence of DNA molecules, which is the unique genetic plan for each individual – the process has grown steadily faster and cheaper. With the information as such, tests on tumor cells, researchers develop drugs as target groups, one and one, specific disease-inducing genetic abnormalities, prolong and improve the lives of tens of thousands of people whose diseases were once a death sentence. And they have just begun.
“Forty years ago, we did not understand cancer, and we did not understand the drugs,” says Dr. Richard Schilsky, Chief Scientist at the American Society of Clinical Oncology. “Now we can actually study the patient’s cancer, gain insight into what drives it, and in some cases identify well-established, effective therapies that can target these drivers. That’s a big difference.”
These advances also bring new risks for patients already managing a devastating diagnosis, which may be encouraged to consider costly new treatments with some evidence of their effectiveness or safety. It is the subject of debate in the cancer community: How does the hope of some relieve the likelihood that most patients still can not find a response in these therapies.
“Most people do not benefit from it, but some do it, and that’s what drives the field forward,” said Schilsky.
In Natan, we learned that in one clinical study, one of the newer targeted therapies approved to treat aggressive adult cancers had worked under a small group of children with similar slowly growing tumors. If DNA sequencing came up with the relevant mutation, experts reported that Nathan would be a candidate for the drug.
I would not exclude a treatment for scarce evidence and one whose long-term effects were not known. As an American health editor for Reuters News for several years, I had worked on articles that chronized the promise and disappointments in so-called precision medicine. I knew to question claims about new drugs like “melting away” tumors.
The professional was now personal, so my and my as skeptical husband put out as much as possible about the options for Nathan. We consulted with family and friends in the medical field and lost reference networks in our Jewish community. We interviewed experts and read what research we could find. It was exhaustive, especially on the emotional and physical pathway to take care of a sick child, but we had no choice.
Our little boy’s survival was at stake.
Natan was a greeted baby and toddler, active and unpleasant in play with his older brother. Our only complaint was that he often woke up during the night, but there was always a reasonable explanation: feeding, dental care, growth powder.
Our first real panic struck spring 2016. Natan, then 3, woke up on a Sunday with a runny nose, but he seemed otherwise good. I went to the gym. During that time he spotted a high fever, and when I returned, my husband held him over the bathroom drain and sprinkled cold water on his face.
“He was sad, as if he was not breathed,” he said. “I’ve called an ambulance.”
Michele Gershberg speaks to memorial Sloan Kettering Cancer Center pediatrician Matthias Karajannis about the fall of the son and the field of targeted therapies.
After a few days at the hospital was treated for pneumonia, Natan bounced back. The rate of his deterioration worried us, but it seemed similar to other parents’ stories of scary but treatable respiratory diseases in young children and our own pre-school visits 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 hesitant.
The first medical visits showed nothing unusual. When someone recommended more in-depth tests, like a sleep study, my husband and I should be careful about unnecessary medical intervention, ask what practical difference the information could do.
Natan cried many mornings before school. “I am sick!” Would he say, even though his vital signs seemed normal.
Within months it became apparent that we needed more answers. When Nathan returned to preschool in September, his voice was barely audible to his teachers. He would sometimes seem to choke while eating or drinking. An ear infection gave way to a sinus infection that gave way to bronchitis. When he finished an antibiotic profile, he soon returned to his pediatrician or in the emergency room, struggling to breathe.
“There is no reason that a neurologically normal child should sound like that,” said a pulmonologist after listening to just a few breaths.
From Thanksgiving, the tests began to stack up, as did the drugs Natan needed daily. The list of “complaints” on his chart grew longer after each visit: noisy breathing, sleep disturbance, chronic bronchitis, asthma. He was in hospital again for pneumonia at Christmas. Nothing we did made him better, and that helplessness gave us anxiety.
Natan cried many mornings before school. “I am sick!” Would he say, even though his vital signs seemed normal. At work I was haunted by the feeling that his teacher or childmate would call a minute to say he had stopped breathing. When I picked him up from class I saw his heavy walk, how he stumbled forward as he walked and how his eyes seemed dulled.
Each new specialist who took the Nathan case identified another symptom, now more noticeable of a neurological disorder: the fast, involuntary eye movements, the weakness on the left side of his body. But we still had no explanation.
“What is the diagnosis?” My husband demanded every medical visit.
At the end of February 2017 we sat at the hospital cafeteria waiting to hear when Nathan had woken up from anesthesia for an MR scan. We tried to keep our worst fears in control.
“When it’s over, we’ll take the guys to the beach for a month. It’s the best medicine,” my husband said.
I watched the clock. The call from the nurse’s station had not come in, but more than enough time had passed, and I was appropriated.
“Let’s get up,” I said. Then my cell phone rang.
It was the neurologist who ordered MR. The scan showed something unusual: a major “infiltration” lesion centered in medullary oblongata, the structure of the lower stem of the brain that controls breathing and other involuntary functions. The thickest part was tightly packed into the cervical spine, with tentacles spinning at the waist and brain bone, which regulates balance and motor coordination.
“What does it mean?” Did I ask.
“You have to talk to a neuro oncologist,” she said, adding that she was trying to get us a meeting within a few days. “There is no sign of fluid build up in the brain, so you can take your son home.”
“Do you tell me my son has a huge brain tumor, but should go home now?” Did I ask.  We refused to leave until someone who could interpret the scan talked to us.
An hour later, an expert on pediatric brain tumors told that Natan’s injury was a rare, slow-growing type that occurs in about 100 cases a year in the United States. Nathan may even have been born with it, and only now it was big enough to break the nerves through his 4-year brain stem, a structure about the size of an adult thumb that connects the brain and spinal cord.  These dying nerves lost their ability to regulate Natan’s gait and fine motor movements, his breathing, swallowing and sleeping rhythms.
“At least you now have a diagnosis explaining everything,” said the doctor. “It may take some families a lot longer to arrive at this time.”
“I Want This Thumb”
As many people face a crisis, we called on all the resources we had at our disposal. We were lucky to have access to excellent doctors and world-renowned hospitals near the home. The health insurance provided by my employer covered almost all of our expenses.
Two weeks after we were diagnosed, Natan spent a six-hour operation at NewYork-Presbyterian / Weill Cornell Medical Center. Dr Mark Souweidane, Chief of Pediatric Neurological Surgery at Weill Cornell and Memorial Sloan Kettering Cancer Center, removed about 20 percent of the tumor, most of it in the cervix. Venturing further into the brain stem, where the tumor was more difficult to distinguish from healthy tissue, would have been too dangerous.
Within a few days, pathological tests confirmed the tumor type: a slow-growing ganglioglioma, a mixture of cells containing central nervous system components and supportive tissue.
The good news was that such low-grade gliomas are not malignant, which means that, unlike aggressive cancer, they do not grow rapidly and generally do not spread to other bodies. In many cases, they stop growing completely when patients reach their 20s. But the big size and location of the tumor had already hurt Nathan’s ability to swallow and breathe. This puts him at risk of inhalation of fluids and small pieces of food in his airways, leading to fatal pneumonia or suffocation.
It would take another two months to get sequencing results performed 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 hospitals and an emergency rehabilitation center.
Removing a portion of the tumor helped to improve some symptoms. The quick eye movements were almost gone. In daily treatment sessions, Nathan learned to use his left hand again and walk without stopping. However, we noticed or confirmed new problems: hearing impairment, severe sleep apnea, long elevations that are a hallmark of brain tumor tumors.
I tried to clamp on the idea that somehow the surgery would suffice for a few months or years before the tumor went on. I also hoped it would only stop growing on its own, as some doctors had suggested, and dreaded the new surprises that he would face in the treatment. Even without major complications after surgery, he was fragile, physically and emotionally.
My husband was worried about waiting to see if the tumor grew longer before starting any kind of therapy.
“It feels like we’re just sitting around waiting for a miracle to happen,” he said. “I want this tumor.”
The sequencing confirmed that a mutation called BRAF V600E, most commonly seen in adults with the fatal skin cancer genome, ran Natan’s tumor.
“I have something for you” Dr Matthias Karajannis, Sloan Kettering’s Chief of Pediatric Neurocarrals, told us when we met to review the test results. The “something” was a drug called dabrafenib, which is sold by Novartis AG under the trademark Tafinlar. It has helped to keep a significant proportion of melanic patients living after five years when used with a second drug, Mekinist, a major improvement in older therapies.
Karajannis recommended that we use Tafinlar to treat Natan. While chemotherapy is the most common first treatment for low-welded glioma that can not be removed surgically, early evidence showed that the new therapy could be much more effective.
In some cases, he said that the tumors just melted away. 
Roches Herceptin, or trastuzumab, was introduced in 1998, the first so-called “targeted” cancer therapy that interfered with growth-promoting protein found in about 20 percent of breast cancer patients. The drug has improved survival rates, especially among women with previous cancer.
Next major breakthrough came in 2001, with the approval of Novartis Gleevec or imatinib. Gleevec turned the lethal blood cancer called chronic myelogenous leukemia (CML) into a long-term manageable disease. For almost all CML patients, the diseased blood cells have a fusion of two genes that are usually separated. Gleevec blocks the activity of the digested genes and leaves healthy cells untouched – a major advancement of potentially fatal chemotherapy, which is toxic to both sick and healthy cells.
With Gleevec’s success, the race was to find other targeted therapies. any potentially new drug that meant that you first identified a divergent gene that burned a type of cancer and then developed a drug to counter this deviation.
The reality turns out to be much more complex, as researchers learn about the many influences at work in cancer cells. Many of the targeted therapies approved since Gleevec only help a small proportion of patients with any type of cancer, and often only a year or two before their tumor cells create new mutations to eradicate the drug.
“It was this feeling We will conquer cancer with these approaches,” said Dr. David Hyman, director of early drug development at Sloan Kettering, who conducts research on new targeted therapies. Now, the medical community has realized that cancer “is a series of rare diseases”, each with its unique biological mechanisms.
But the new drug detections can be changed for small groups of patients. U.S. The Food and Drug Administration has approved more than 30 therapies that are prescribed based on genomic test results. Most of these treatments have been introduced on the US market since 2012.
“Unfortunately, for many patients, we do not find the” magic bullet “but it is also an area under development,” Karajannis said in an interview. A few years ago, we had no treatment options. “
A study published in April in the JAMA Oncology magazine estimated that 15 percent of the nearly 610,000 advanced cancer patients in the United States could be considered as candidates for treatments informed by genomic sequencing, and that close to 7 percent would probably show some benefit.
Pfizer Xalkori and Roche’s Alecensa, such as target mutations occurring in about five percent of non-small cell lung cancer patients. At the end of November, newcomer Loxo Oncology USA received approval for Vitrakvi, a pill shown to shrink a variety of tumors driven by TRK fusion, a genetic anomaly found in less than one procedure. nt of all cancer patients.
Tafinlar side effects were much milder than chemos, said the specialists. But the long-term safety of children was – and still is – unknown.
Worldwide sales of such targeted treatments increased by $ 28 billion last year, according to research company GlobalData Plc.
Within the small community of low blood pressure children, the degree of glioma, 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 percent of the 1,000 American children diagnosed with low-grade gliomas each year. The research coincided with the development of Tafinlar, originally approved in 2013 for melanoma patients with the same BRAF mutation.
At a medical conference in Copenhagen in October 2016, just as we began to investigate Natan’s symptoms, Dr. Mark Kieran, when the director of the Dana-Farber Cancer Institute at the Dana-Farber Cancer Institute and the Boston Children’s Hospital presented 32 children treated with Tafinlar.
All children’s tumors were positive for the BRAF V600E mutation and nearly three quarters of them saw their tumors shrink or cease to grow on the drug. In two cases, the tumors vanished while 11 patients’ tumors shrunk more than half. The side effects were relatively minor rashes, fatigue, fever.
Less than a year later we read the results and wondered: Could there be enough evidence to use on our child?
DECISION  My husband and I made as many authoritative sources as possible. We especially wanted to hear more about treating children with a diagnosis identical to Natan: a brain ganglioglioma with a BRAF V600E mutation. We reached several leading pediatric neuro oncologists. Some had treated or carefully followed some tens of patients like Natan. Others had direct clinical experience of a handful or none.
They told us that chemotherapy and the new drug were both useful alternatives, but they differed from what they stressed. Some seemed more supportive for chemotherapy. The cited data collected for decades showing that 25 percent to 40 percent of low-grade gli patients saw their tumors stop growing after chemotherapy, which usually meant a year or more of weekly infusions of carboplatin and vincristine. Although the disease returned, a majority of children survived in adulthood, the studies showed.
Chemotherapy possible side effects while a patient was in treatment was tough, including neuropathy – nerve damage that can cause both debilitating pain and numbness – and the risk of bleeding or severe infection. However, there was no cognitive or other long-term injury afterwards.
Survival data climbed many varieties of low-grade gliomas, including tumors that were cured by surgical removal. Brainstem gangliogliomas like Natan represented a very small subset. Recent research and clinical experience suggested that chemotherapy was significantly less effective in children with brain tumors, especially those with a BRAF V600E mutation, resulting in repeated treatments and poor survival levels.
“Do not trust this tumor!” Sa Dr Eric Bouffet, Head of Neuroscience at the SickKids Hospital in Toronto and a co-author of the Tafinlar study. Bouffet knew many of the low-quality glioma patients in Canada. He and his colleagues continue to study their results and track data from other medical centers around the world.
The BRAF mutation seems to make the tumors more aggressive, told Bouffet during a telephone consultation. He told us about children, like Natan, whose brain tumors caused severe sleep apnea, a sudden respiratory arrest. A little boy died before he could get treatment, said Bouffet.
Tafinlar side effects were much milder, said the specialists and children who used the drug lacked the school as chemopathy. They could enjoy family holiday. But the long-term safety of children was – and is still – unknown and will take years to establish.
The medical literature was also small. One of the earliest published case studies, from 2014, told the heartbreaking story of a 21 year old whose brain strain gangliogliom had returned after several rounds of chemotherapy and radiation and left him in a wheelchair. His tumor shrank dramatically with Tafinlar, and he began to go again, only to experience a fatal brain bleed within a few weeks. His doctor questioned whether the rapid retreat of such a large tumor had contributed to bleeding.
A second report showed a hopeful result for an infant with a massive grimmed glioma that shrunk dramatically within two months of treatment and saves his life.
When we consulted with Kieran on the Nathan case, he recommended that we first treat chemotherapy with the security code and if failed, try Tafinlar. Previous treatment with chemotherapy had also been a requirement for enrollment of children in Novartis clinical trials.
There was good reason for caution. Even when drugs are tested on hundreds of patients, safety problems can take years to identify. Now regulators are more willing to approve targeted therapies, especially those treating advanced cancers, based on tests in smaller patient groups. For someone with a few months to live and no other choice, the risk may be worth it. But was the balance appropriate with a slow growing tumor?
We wanted to understand why Kieran, who led the clinical trial of Tafinlar, would not recommend using it from the outset. In June, as soon as we thought Nathan was on the trip, we took him to Boston. After reviewing our son and almost two hours of detailed discussion, Kieran nodded the new therapy.
In a new interview, he said that when we met, he had just begun discussing therapy as Novartis Tafinlar as the first line of treatment with other families, depending on the patient’s circumstances.
“The conversation I would have had with a family five years earlier would have been completely different,” he said. There is enough data to consider a BRAF therapy that is appropriate directly to the bat for patients like Natan, provided families recognize that the image may change when more data is available, he said.
Not all patients have the luxury to wait for the information: “You can not always say, let’s just wait for three years and see how data goes,” said Kieran. He recently left Dana-Farber to lead the development of pediatric cancer therapy at Bristol-Myers Squibb.
Through all our research and our consultation with experts, there was a detail: There was a chance that Tafinlar would actually shrink Natan’s tumor, an unlikely outcome with kemo. If so, his symptoms could be improved, provided that the nerves had not already been damaged irreparably. We needed to give him that chance.
Two weeks later, a pharmacist from Sloan Kettering showed me how to turn Tafinlar into a liquid for Nathan to cool safely. In our kitchen, I poured the white powder of Kool-Aid with lemonade flavor, as Novartis says is the only drink that can solve this advanced medicine. I tried hard not to spoil anyone. Our insurance covered almost all of the costs, but I was still paying attention at the expense of replacing only one pill, at almost 100 dollars.
During the first few weeks, we kept unusual reactions. One night, Nathan went almost without any obvious reason. Another night nailed its temperature to 105 degrees. It turned out to be a virus. For a few days the nostrils spread throughout the body. Again, a virus is suspected.
And we noticed something else. After just over a week, Natan’s voice, almost ceaseless for several months, resounded loudly. At first we doubted that it was true. But Nathan was so happy that he could hear and talk to his brother, that he would shout and sing spontaneously.
During the summer, the test confirmed that his hearing had returned. His time became steadier and stronger. With a glimpse in the eye, Nathan would take an extra deep breath for the nurse and look at the screen when the oxygen level crossed from 99 percent to 100. He was taken out of respiratory drugs and the antibiotics that had been head restraint for almost a year.
Natan next MR, in October 2017, showed a result far beyond what we had allowed ourselves to hope: Almost all of the detectable tumor was gone. “It almost looks like a normal brain,” says Karajannis.
My husband and I have asked if we could have noticed the symptoms earlier and if treatment at this stage would have saved Natan from the worst disease. However, given the rapid development of science, we now believe that the opposite is true in our case. If we had found the tumor earlier, Natan probably had chemotherapy infusions and their hard effects every week for more than a year, with little real benefit.
Nathan’s successes give no guarantees. No one can tell how long the medicine will work, whether to take the drug for an indefinite period or end, or if you either risk doing something.
Science is also continuing. Novartis begins testing Tafinlar plus Mekinist – the combination used to treat melanoma patients – compared to chemotherapy in children whose low glioma exhibits BRAF V600E mutations to see if the combination works better and longer. Drugmaker has also lost the requirement that patients have prior treatment with chemotherapy to register. A new generation of BRAF treatments from companies, including Array BioPharma and AstraZeneca, are available in clinical trials. Our hope is that if Tafinlar stops working for Natan at any time, a new therapy will take place.
It has been more than a year since Natan started treatment. He started running again, and jumped, and swim and climb. He is now in the first class, excited to come to school every day and see his friends.
Natan swallows her capsule with a sip of water and blinks a thumbs up every time. He has traveled on holiday, even abroad, without an accident. On our last trip, he chose a new T-shirt for himself. On the front it says: “Never give up.”
By Michele Gershberg
Photo Editing: Steve McKinley
Video: Jillian Kitchener, Craig Hettich, Mike Wood
Design: Pete Hausler
Edited by John Blanton