Saturday, July 14, 2012
"Am I going to die?" Ms. Caton asked. "Is my baby going to have a mommy in five years?"
It is a question that plagues cancer patients. Doctors try to give survival odds based on a tumor's appearance and size, but often that is just an educated guess.
But Ms. Caton had a new option, something that became possible only in this new genetic age. She could have a genetic test of her tumor that could reveal her prognosis with uncanny precision. The test identifies one of two gene patterns in eye melanomas. Almost everyone in Class 1 — roughly half of patients — is cured when the tumor is removed. As for those in Class 2, 70 to 80 percent will die within five years. Their cancers will re-emerge as growths in the liver. For them, there is no cure and no way to slow the disease.
No test has ever been so accurate in predicting cancer outcomes, researchers said.
The data from studies of the test are "unbelievably impressive," said Dr. Michael Birrer, anovarian cancer specialist at Massachusetts General Hospital. "I would die to have something like that in ovarian cancer."
While for now the ocular melanoma test is in a class by itself, cancer researchers say it is a taste of what may be coming as they continue to investigate the genes of cancer cells. Similar tests, not always as definitive but nonetheless able to give prognostic information, are under development or starting to be used for other cancers, like cancers of the blood.
The eye test raises a similar choice, with an added twist. This is not a test offered to healthy people, but to patients who have just gotten the news that they have cancer. The results will either give them reassurance that they will survive the cancer — or near certainty that they will die from it.
Can patients in the throes of getting this terrifying news really make an informed choice about whether they want the test? Are they able to understand at such a fraught time that, for now at least, there is nothing that can save them if they get the bad prognosis?
Some doctors do not offer the test, reasoning that there is little to be gained.
But other doctors, including J. William Harbour of Washington University, who developed the test (but does not profit from its use), encourage patients to have it. And probably because of the way he describes it, Dr. Harbour says his patients almost always want it.
Ms. Caton was no exception. Without the test, doctors would have had to guess her outcome based on the size of her tumor. And the conventional wisdom is that people with growths as large as hers have a slim chance of surviving. But perhaps, her doctors hoped, the genetic test would come up with a different answer.
Heralding the Future
Dr. Harbour, a genial and burly man with salt-and-pepper hair, has a way about him that relaxes patients, makes them feel everything will be O.K.
"I give them as much information as I think they can handle," Dr. Harbour says.
And he's an optimist. The ocular melanoma test is just the beginning, he believes, of a new understanding of that cancer — and perhaps other cancers as well — and why they spread.
About 2,000 people a year, or about 5 percent of melanoma patients, have ocular melanoma, a tumor of the dark brown melanocytes that form a sheet much like a photographer's backdrop behind the retina. Those with very large tumors are most likely to have a bad prognosis, but patients with small tumors also can have the deadly type.
Often there are no symptoms; the tumor may be discovered by an ophthalmologist during a routine exam. Other patients, though, lose vision or see flashing lights or a sea of floaters in an eye, all signs of damage to the retina as the tumor encroaches.
Most get radiation, a highly radioactive disc placed on the surface of the eye that destroys the tumor in a few days and then is taken out. But those with huge tumors, like Ms. Caton, must have their eye removed.
Ocular melanoma specialists had long noticed that some patients did well and the rest did not, but Dr. Harbour wanted to know why.
Then he saw an opportunity. Ever since he came to Washington University in 1996, Dr. Harbour had been storing bits of tumors from ocular melanoma patients and keeping track of what happened to the patients. Working with his colleagues at the genome center, Dr. Harbour looked for genetic differences in tumors that spread and those that did not.
The genes themselves were no different. But a group of several hundred genes that looked the same in cells from patients in Class 1 and Class 2 were acting differently in the patients who did poorly. The genes were churning out many more proteins in the cells of patients in Class 2. Dr. Harbour found that he could look at the activity of 12 of those genes and predict how well a patient would do.
After a rigorous study to confirm that the test worked, the university licensed it to a small company, Castle Biosciences. They bill more than $6,000, with the price depending on the quality of the sample. But the company has programs to make sure that the poor or uninsured can receive the test, said Derek Maetzold, the company's president and chief executive.
Some cancer specialists, though, ask what is to be gained by using the test.
When it comes to dividing patients into two prognostic groups, "the data are really astonishing," said Dr. Keith Flaherty, a melanoma researcher at Massachusetts General. Yet, he added, "There is no treatment yet that will alter the natural history of the disease."
"Why would you want that information when we don't have anything we can do for you?" Dr. Flaherty asked. "That is the fundamental question that has caused people to pause."
For the majority treated with radiation, having the test requires a biopsy of the tumor before treatment. After going through that, those in Class 2 have no real options other than to wait for the inevitable.
Nothing has been shown to prolong the lives of Class 2 patients, said Dr. Evangelos S. Gragoudas, an ocular oncologist at Massachusetts Eye and Ear Infirmary. Not more frequent monitoring of the liver, not more aggressive or earlier chemotherapy. Nothing.
Dr. Gragoudas tells patients that the ocular melanoma test is available. Then, he said, "I tell them that I do not do it at the present time. But if you want it, there are people who will do it."
"I had only one patient tell me, 'I want to know,' " Dr. Gragoudas said.
Dr. Harbour has a different view, and conveys it to his patients. He tells them that if they are Class 2 he will monitor them closely, doing liver scans every six months and blood tests in between, and will treat metastases with chemotherapy, delivered to the site of the cancer's spread, as they occur.
Patients sometimes think that means they can be cured, Dr. Harbour confesses, adding that he makes a point of repeating the information about what the test results mean on several different visits to be sure it sinks in.
Dr. Harbour says he believes that frequent monitoring and prompt treatment of the cancer may be extending some patients' lives, although that has not been rigorously established. Dr. Gragoudas says a study he did found that early treatment made no difference.
But Dr. Harbour says his approach means patients have a different sort of death. Before the gene test was developed, patients would not know their cancer had spread until they were at the end stages of their disease. Then they would suddenly shed weight, lose their appetite, fall ill and their skin would turn yellow from liver failure. Within a few months they would be dead.
Now, by finding the cancer as soon as it spreads to the liver, it often can be controlled, at least for a while. The cancer then tends to spread to the lung or bones, where it can also be controlled. Death still tends to be from cancer in the liver, but even if it occurs at the same time, it may be less painful, Dr. Harbour says.
"Would you want a horrible death that is relatively short," he asks, "or a death that is slower?"
Dr. Harbour thinks there may be ways to impede the cancer's progress in Class 2 disease by blocking a gene, BAP 1, that seems to be driving the cancer's spread. That is his hope for clinical trials with one of two treatments: a class of drugs known as histone deacetylase inhibitors, which were developed to fight cancer and are being tested against a cancer of white blood cells, or valproic acid, an old drug used to treat epilepsy that subsequently was found to be a histone deacetylase inhibitor.
But then again, if Class 2 patients, most of whom are doomed anyway, find out about valproic acid, which is cheap and easily available, would they really wait for a clinical trial, taking a chance they could be randomly assigned to take a placebo? Yet without a rigorous study, it will be impossible to know if the drug helps Class 2 patients.
'Praying for a Miracle'
Cassie Caton and an older man came in for their biopsy and treatment on a frigid morning in early December. Both would have to have their eyes removed — their tumors were too large for radiation.
First was Joe Ritter, age 70.
"We are praying for a miracle," his wife, Judy, said that morning, as Mr. Ritter sat silently in his bed, waiting to be wheeled into the operating room.
At 11:30 that morning, Ms. Caton's surgery began. Dr. Harbour looked at her dilated eye. There, visible behind her blue pupil, was a brown halo, the melanoma.
He began to work, carefully and efficiently, preserving and pinning back the muscles that control her eye's movement.
About an hour into the surgery, Dr. Harbour removed Ms. Caton's eyeball, cutting the optic nerve with scissors. Her eye looked like a white marble with a blue pupil on top and a little white wicklike stalk on the end, the stub of the optic nerve. He took the eyeball to a metal table and cut it open. It was filled with what looked like slices of brown olives, the melanoma. A fluid squirted out, the vitreous. Normally it would be clear and jellylike. But cancer had made it liquid and the color of weak tea.
Some of that cancer tissue would go to Castle Biosciences for analysis. The rest would be stored for future research.
Then Dr. Harbour covered a plastic ball about the size of Ms. Caton's eyeball with the outer layer from a cadaver's eyeball, and put it into her eye socket so the ball would move like her eye. Finally, he carefully sewed the controlling muscles in place. In about six weeks, an artist would paint a thick contact lens to match Ms. Caton's remaining eye, giving her a prosthesis that would be all but indistinguishable from her healthy eye.
Mr. Ritter would also end up with a prosthetic eye that would look and move just like his healthy one.
Both Ms. Caton and Mr. Ritter would return in about a month to find out if they were Class 1 or Class 2.
Awaiting the Verdict
On Jan. 9, they arrived to hear their verdicts. Mr. Ritter went first, bringing his wife with him into the small windowless room.
After a few pleasantries, Dr. Harbour delivered the news.
"Based on what we found from your biopsy result, it was Class 2," he said.
Mrs. Ritter looked stricken, her eyes filled with tears. She crossed the room and hugged her husband. Mr. Ritter grinned nervously while Dr. Harbour explained how he would like to monitor him. And, he said, he planned to start some clinical trials to see if he could slow the cancer in Class 2 patients. Perhaps Mr. Ritter could join one.
Then Dr. Harbour stepped out of the room, allowing the Ritters to compose themselves.
Mr. Ritter reflected on how the news about his eye had steadily worsened.
"I started out thinking it was a cold in my eye," he said. "Then I thought it was a cataract. Then they told me it was a torn retina. That turned into a tumor. Now it's a Class 2."
Mrs. Ritter tried to be positive.
"Maybe we caught it in time," she said. "We've got a lot of prayers coming our way."
Ms. Caton and her stepfather came in next. He had driven three hours from his home in Kansas City and picked her up in Sedalia. The two had arrived in St. Louis the night before.
She had been too nervous to sleep.
With few preliminaries, Dr. Harbour told her what the test showed.
"Your test result," he said, "was very good." Her tumor was not only Class 1 but it was a subset of Class 1 that had an even better prognosis than Class 1 in general. It was Class 1a.
"That is very, very good news," Dr. Harbour said.
"In the old days, the size of a tumor was the best indicator," he told Ms. Caton. "People would have told you, you were at very high risk," he said. "Your tumor was almost an inch in its largest dimension. Pathologists' eyes widened when they saw it. But molecular testing trumps all of that."
"If you did not have this test you would have walked away being told you have a bad prognosis when you actually have a good prognosis," he added.
Ms. Caton could not stop smiling. Then, still grinning, the 18-year-old asked her next question.
"When can I wear eye makeup again?"
Wednesday, July 11, 2012
For a moment, an emergency room doctor stepped away from the scrum of people working on Rory Staunton, 12, and spoke to his parents.
"Your son is seriously ill," the doctor said.
"How seriously?" Rory's mother, Orlaith Staunton, asked.
The doctor paused.
"Gravely ill," he said.
How could that be?
Two days earlier, diving for a basketball at his school gym, Rory had cut his arm. He arrived at his pediatrician's office the next day, Thursday, March 29, vomiting, feverish and with pain in his leg. He was sent to the emergency room at NYU Langone Medical Center. The doctors agreed: he was suffering from an upset stomach and dehydration. He was given fluids, told to take Tylenol, and sent home.
Partially camouflaged by ordinary childhood woes, Rory's condition was, in fact, already dire. Bacteria had gotten into his blood, probably through the cut on his arm. He was sliding into a septic crisis, an avalanche of immune responses to infection from which he would not escape. On April 1, three nights after he was sent home from the emergency room, he died in the intensive care unit. The cause was severe septic shock brought on by the infection, hospital records say.
Because sepsis, a leading cause of death in hospitals, can at first look like less serious ailments, a campaign to aggressively identify it for early treatment has been undertaken by a consortium of 55 hospitals in the New York region, including NYU Langone.
Yet nowhere along Rory's journey, from boy with a bellyache on Thursday to gravely ill boy on Friday night, did anyone act on strong indications that he might be fighting for his life. Critical information gathered by his family doctor and during his first visit to NYU Langone either was not used, was not at hand or was not viewed as important when decisions were made about his care, records show.
Moments after an emergency room doctor ordered Rory's discharge believing fluids had made him better, his vital signs, recorded while still at the hospital, suggested that he could be seriously ill. Even more pointed signals emerged three hours later, when the Stauntons were at home: the hospital's laboratory reported that Rory was producing vast quantities of cells that combat bacterial infection, a warning that sepsis could be on the horizon.
The Stauntons knew nothing of his weak vital signs or abnormal lab results.
"Nobody said anything that night," Ms. Staunton said. "None of you followed up the next day on that kid, and he's at home, dying on the couch?"
NYU Langone declined to discuss any aspects of Rory's care or hospital procedures.
"Our deepest sympathies go out to the family at this difficult time," said Lisa Greiner, a hospital spokeswoman.
The Stauntons shared Rory's medical records with a reporter for The New York Times who had met the boy last summer in a social setting. A full airing of the case, along with a commitment to reforms, his parents said, could save lives. They have hired a lawyer, Thomas A. Moore, but have not decided how they will proceed.
Rory Staunton, 5 feet 9 inches tall and 169 pounds, was big for his age and a student of the world. "The most profound 12-year-old I had ever met," his debate coach, Kevin Burgoyne, said. For his birthday, his parents gave him flying lessons after Rory, who spent hours on a flight simulator, tracked down an aviation school that accepted students at 12. He devoured the memoir of Chesley B. Sullenberger III, the pilot who safely brought down an airliner on the Hudson River.
"I told him, 'Sully did some fast math landing that plane,' and for a short while, he was paying attention to math," said Ciaran Staunton, Rory's father. "Then he came back with, 'Yeah, but by the time I'm a pilot they'll have a faster way of doing it.' "
Rory and his sister, Kathleen, 10, grew up in Sunnyside Gardens, Queens, which their parents, Irish immigrants, regarded as a global village of sublime pleasures: shared courtyards, a rich brew of cultures and merry mobs of children rolling from house to house. Ms. Staunton, the former director of an international student exchange, said neighborhood kids formed their own country, Kidadelphia, designed a flag, and adapted the United States motto for their slogan: "In God and Fun We Trust." Rory was president. When he was 8, he raided his piggy bank to treat his parents to a Chinese dinner for their wedding anniversary. At the private Garden School in Jackson Heights, he was elected to the student council in seventh grade and led a campaign, Spread the Word to End the Word, to curtail the casual, derogatory use of the term "retarded."
Last summer, his uncle, a friend of this reporter, brought Rory, Kathleen and their mother to stay in my family's vacation home for two nights. Rory would go from barreling down a water slide backward to sizing up President Obama's prospects for re-election. Fascinated by North Korea, he tried to fathom how a country so afflicted by famine could afford a large army. (His parents recently found a note in his computer to the Swedish ambassador to North Korea.)
At home, said Mr. Staunton, a civic activist and bar owner, they would have nightly shouting matches over homework Rory had not done or dirty clothes he had not picked up, in between scoping out corners of global history.
During gym class on Wednesday, March 28, he dived for a ball and opened a cut on his arm. That night, Ms. Staunton said, Rory mentioned it: "How he presented it to me was, 'I fell in the gym. Mr. D, the athletic director, put the Band-Aids on. And, I got the ball.' "
Then he finished his homework and went to bed.
The bacteria Streptococcus pyogenes is part of the human ecosystem, normally dwelling in the throat or on the skin, areas where the body is well defended. Also known as Group A streptococcus, the strain typically causes strep throat or impetigo.
But if it is able to penetrate soft tissue or blood, "it moves very quickly," said Dr. Michael B. Edmond, the chairman of the division ofinfectious diseases at Virginia Commonwealth University. "The mortality rate is high. The clinical findings early in the infection can be relatively subtle."
The challenge for physicians is recognizing an invasive infection, whether from Group A strep or other pathogens, before the cascading damage of sepsis has picked up too much speed. The consortium of New York hospitals has a goal of starting antibiotics within an hour of spotting sepsis in the emergency room, according to officials with the Greater New York Hospital Association's Stop Sepsis program.
For every hour's delay in giving antibiotics after very low blood pressure had set in, a large study found, the survival rate decreased by 7.6 percent.
Shortly after midnight on March 29, Ms. Staunton heard Rory retching in the bathroom. "There wasn't a huge amount of vomit, but he kept saying, 'My leg, my leg, Mom,' " she recalled. Back in bed, he moaned. His mother rubbed his thigh. In the morning, he was weak, his leg still hurt, and his temperature was 104 degrees, his highest ever.
The parents began calling Dr. Susan Levitzky, who had been the family pediatrician for about five years. She saw Rory that evening.
"He was leaning on me as we were walking up to the office, because he could hardly stand from the weakness or pain in his leg," Ms Staunton said. In the waiting room, Rory vomited. When the doctor swabbed his throat, he vomited on her. The swab test, a rapid but not definitive detector of strep, was negative.
"We showed her the cut on his elbow, and I saw her follow up his arm from the cut," Ms. Staunton said. "She said, 'The cut's not an issue.' She focused on his stomach. We said, 'Although you see him throwing up, that's not what he's really complaining about.' Rory and I both said to her that it's the pain in his leg that's really bothering him."
The doctor told them that the leg pain might be from falling in the gym. "Rory said, 'It wasn't a fall, it was a skid,' " Ms. Staunton recalled.
The parents also remarked that Rory's skin became blotchy when they pressed a finger on it. Those concerns were well-founded, said Dr. Edmond, the infectious disease specialist, who was not involved in Rory's care: the mottling, which Dr. Levitzky made note of, could mean that vessels in his skin were constricting from low blood pressure; the leg pain could mean an invasive infection. Rory's temperature was 102 and his pulse was 140; he was breathing 36 times a minute. These, too, were "worrisome" observations, Dr. Edmond said.
Nevertheless, Ms. Staunton said, she did not recall being told that any of his vital signs were off: "She said, 'Make your way over to NYU, and get him rehydrated. He's vomiting now. He's going to feel better, and tomorrow, he'll have diarrhea.' "
In a brief phone conversation, Dr. Levitzky said she could not discuss the case. "I sent him to a major medical center," she said.
Rory arrived at NYU Langone, on First Avenue near 34th Street, at 7:14 that evening and was discharged about two hours later. Hospital records do not reflect any communication with Dr. Levitzky or her findings about the mottled skin.
Like Dr. Levitzky, the NYU physicians believed that Rory's discomfort was caused by a sick stomach and dehydration. His chart states that "labs, I.V.F., Zofran" were ordered. Zofran is an anti-nausea drug; two bags of intravenous fluids, or I.V.F., were administered; three vials of blood were drawn and sent to the hospital laboratory.
"They did the various checks, up, down, back and forth," Mr. Staunton said.
A screening tool in the Stop Sepsis program, used when a patient first arrives in the emergency room, calls special attention to a person with three symptoms of a possible eight. At the hospital, Rory showed two: he was breathing 20 times per minute and his pulse was 143.
Two hours later, though, he had three: his temperature had risen to 102, his pulse was 131 and his respiration rate was 22. But by the time those vital signs were recorded, at 9:26 p.m., they had no bearing on his treatment. In fact, the doctor had already decided that Rory was going home. Rory's "ExitCare" instructions, signed by his father, were printed 12 minutes before those readings.
To the pediatrician who examined and discharged Rory, it seemed that the fluids had done the trick. "Pt improved," the doctor, Camille Scribner, wrote, prescribing "home supportive care." There is no sign in the records that Dr. Scribner, described by a senior colleague as "hyper-conscientious," considered alternative explanations.
"They stated that it was a common flu that was going around," Mr. Staunton said. "It would start off as high temperature and throwing up, and would end up as diarrhea."
Dr. Scribner could not be reached for comment through the hospital.
As the Stauntons walked Rory onto First Avenue, the air temperature was in the mid-40s. "He was freezing," Ms. Staunton said. "He took my coat leaving the hospital. It has a little frilly thing around the collar."
"Not a thing that a boy of 12 would put on," Mr. Staunton said.
About three hours later, Rory's lab results were printed. He was producing neutrophils and bands, white blood cells, at rates that were "very abnormal and would suggest a serious bacterial infection," Dr. Edmond said.
The Stauntons said they heard nothing about it. In bed, Rory "was groaning in his sleep," Ms. Staunton said. "I felt the heat of the fever."
At 10 a.m. on Friday, the Stauntons began calling their pediatrician, Dr. Levitzky. "She told us to do a combination of Tylenol and Motrin," Ms. Staunton said.
Asked last month about the lab findings, Dr. Levitzky, who is associated with NYU Langone, said, "I never knew that testing was done."
Rory did have the predicted bout of diarrhea on Friday, which momentarily elated his family. Still, he could barely get to the bathroom. The doctor suggested fluids and crackers.
"'I told her, 'I'm not sure you're getting the picture, Dr. Levitzky,' " Mr. Staunton said. "'I can't even get him to sit up. I don't know how you expect me to get food into him.' "
Later, a slight touch would make him scream. "Around his nose was gone blue," Mr. Staunton said. "Down his body side was gone blue."
At that point, Dr. Levitzky told them to return to the emergency room. They supported him as he walked to the car. "All he said was, 'Can I please have a wheelchair when I get there?' " Ms. Staunton recalled.
In the intensive care unit, his parents tried to mask their worry, Mr. Staunton chatting lightly. But Ms. Staunton noticed her son's eyes following her. "He said, 'Mom, my toes are really, really cold,' " she said.
After extending an arm for blood to be drawn, "he thanked them when they were finished," Ms. Staunton said.
He had to be put on a ventilator. Just before he was sedated, Ms. Staunton said, "They told him, 'We need to figure some stuff out. There are some marks on your body, and you need a little bit of help breathing, so we're just going to intubate you and it'll be fine.' " First, though, they checked his mental status.
"Do you know what date it is?"
"I know it's March," Rory answered.
"Who's the president of the United States?"
He answered: "Barack Obama."
His mother smiled.
"Ah," she said, "but Rory, who is going to be the next one?"
"Barack Obama," he said.
As the next two days passed, doctors tried anything that might halt the shutdown of Rory's organs. "I can't say enough about the I.C.U.," Ms. Staunton said.
Relatives and a priest gathered bedside, talking of Irish football and tomfoolery and politics. Perhaps, one doctor whispered in a fleeting, hopeful aside, Rory might get away with losing his toes and nose. His skin blackened. He passed no urine. His blood would not clot. His heart had to be restarted twice. Three specialists who chronicled Rory's decline on his intensive care chart each noted that on Thursday night, when he was sent home from the emergency room, he had a fever and significant signs of infection in his blood.
On Sunday night, Dr. Mayer Sagy, who had not seen Rory on his first visit to the hospital but spent the weekend struggling to keep Rory alive, told the Stauntons that the team had been unable to resuscitate him a third time.
"I said to him, 'I brought him here to you the other night and you sent him home,' " Ms. Staunton said.
"He said, 'You have every right to be angry.' "
More than anything, the Stauntons said, NYU Langone owes an honest accounting of what happened. Racked with loss, they and othersremembered Rory as an unflinching champion of schoolyard underdogs.
"Above all," Ms. Staunton said, "we know that Rory would want no other child to go through what he went through."