by Sid Holt
Yet even though many men and women with relapsed Hodgkin’s lymphoma responded to immunological treatments, there were some who remained deeply resistant. “These patients were the hardest to treat,” O’Connor continued. “Their tumors seemed to be unique—a category of their own.”
Lorenzo Falchi, a fellow training with O’Connor and me, was intrigued by these resistant patients. Falchi came to our hospital from Italy, where he specialized in treating leukemias and lymphomas; his particular skill, gleaned from his experience with thousands of patients, is to look for patterns behind seemingly random bits of data. Rooting about in Columbia’s medical databases, Falchi made an astonishing discovery: The men and women who responded most powerfully to the immune-boosting therapies had invariably been pretreated with another drug called azacitidine, rarely used in lymphoma patients. A thirty-five-year-old woman from New York with relapsed lymphoma saw her bulky nodes melt away. She had received azacitidine as part of another trial before moving on to the immunotherapy. A man, with a similar stage of cancer, had not been pretreated. He had only a partial response, and his disease grew back shortly thereafter.
Falchi and O’Connor will use this small “training set” to begin a miniature trial of patients with relapsed Hodgkin’s disease. “We will try it on just two or three patients,” Falchi told me. “We’ll first use azacitidine—intentionally, this time—and then chase it with the immune activators. I suspect that we’ll reproduce the responses that we’ve seen in our retrospective studies.” In lung cancer too, doctors have noted that pretreating patients with azacitidine can make them more responsive to immunological therapy. Falchi and O’Connor are trying to figure out why patients respond if they are pretreated with a drug that seems, at face value, to have nothing to do with the immune system. Perhaps azacitidine makes the cancer cells more recognizably foreign, or perhaps it forces immune cells to become more aggressive hunters.
Falchi and O’Connor are mixing and matching unexpected combinations of medicines based on previous responses—departing from the known world of chemotherapy. Even with the new combination, Falchi suspects, there will be resistant patients, and so he will divide these into subsets, and root through their previous responses, to determine what might make these patients resistant—grinding the data into finer and finer grains until he’s down to individualized therapy for every variant of lymphoma.
• • •
Suppose every cancer is, indeed, unique, with its own permutation of genes and vulnerabilities—a sole, idiosyncratic “mind.” It’s obviously absurd to imagine that we’ll find an individual medicine to treat each one: There are fourteen million new cases of cancer in the world every year, and several million of those patients will present with advanced disease, requiring more than local or surgical treatment. Trying to individualize treatment for those cases would shatter every ceiling of cost.
But while the medical costs of personalized therapy are being debated in national forums in Washington, the patients in my modest waiting room in New York are focused on its personal costs. Insurance will not pay for “off-label” uses of medicines: It isn’t easy to convince an insurance company that you intend to use Lipitor to treat a woman with pre-leukemia—not because she has high cholesterol but because the cancer cells depend on cholesterol metabolism for their growth (in one study of a leukemia subtype, the increasing cells were highly dependent on cholesterol, suggesting that high doses of Lipitor-like drugs might be an effective treatment).
In exceptional cases, doctors can requisition pharmaceutical companies to provide the medicines free—for “compassionate use,” to use the language of the pharma world—but this process is unpredictable and time-consuming. I used to fill out such requests once every few months. Now it seems I ask for such exceptions on a weekly basis. Some are approved. A majority, unfortunately, are denied.
So doctors like Falchi and O’Connor do what they can—using their wiles not just against cancer but against a system that can resist innovation. They create minuscule, original clinical trials involving just ten or twenty patients, a far cry from the hundred-thousand-patient trials of the eighties and nineties. They study these patients with monastic concentration, drawing out a cosmos of precious data from just that small group. Occasionally, a patient may choose to pay for the drugs out of his or her own pockets—but it’s a rare patient who can afford the tens of thousands of dollars that the drugs cost.
But could there be some minimal number of treatments that could be deployed to treat a majority of these cancers effectively and less expensively? More than any other scientist, perhaps, Bert Vogelstein, a cancer geneticist at Johns Hopkins University, has tackled that conundrum. The combination of genetic mutations in any individual cancer is singular, Vogelstein acknowledges. But these genetic mutations can still act through common pathways. Targeting pathways, rather than individual genes, might reorganize the way we perceive and treat cancer.
Imagine, again, the cell as a complex machine, with thousands of wheels, levers, and pulleys organized into systems. The machine malfunctions in the cancer: Some set of levers and pulleys gets jammed or broken, resulting in a cell that continues to divide without control. If we focus on the individual parts that are jammed and snapped, the permutations are seemingly infinite: Every instance of a broken machine seems to have a distinct fingerprint of broken cogs. But if we focus, instead, on systems that malfunction, then the seeming diversity begins to collapse into patterns of unity. Ten components function, say, in an interconnected loop to keep the machine from tipping over on its side. Snap any part of this loop, and the end result is the same: a tipped-over machine. Another twenty components control the machine’s internal thermostat. Break any of these twenty components, and the system overheats. The number of components—ten and twenty—are deceptive in their complexity and can have endless permutations. But viewed from afar, only two systems in this machine are affected: stability and temperature.
Cancer, Vogelstein argues, is analogous. Most of the genes that are mutated in cancer also function in loops and circuits—pathways. Superficially, the permutations of genetic flaws might be boundless, but lumped into pathways, the complexity can be organized along the archetypal, core flaws. Perhaps these cancer pathways are like Hollywood movies; at first glance, there seems to be an infinite array of plot lines in an infinite array of settings—gold-rush California, the Upper West Side, a galaxy far, far away. But closer examination yields only a handful of archetypal narratives: boy meets girl, stranger comes to town, son searches for father.
How many such pathways, or systems, operate across a subtype of cancer? Looking at one cancer, pancreatic, and mapping the variations in mutated genes across hundreds of specimens, Vogelstein’s team proposed a staggeringly simple answer: twelve. (One such “core pathway,” for instance, involves genes that enable cells to invade other tissues. These genes normally allow cells to migrate through parts of the body—but in cancer, migration becomes distorted into invasion.) If we could find medicines that could target these twelve core pathways, we might be able to attack most pancreatic cancers, despite their genetic diversity. But that means inventing twelve potential ways to block these core paths—an immense creative challenge for scientists, considering that they haven’t yet figured out how to target more than, at best, one or two.
Immunological therapies provide a second solution to the impasse of unlimited diversity. One advantage of deploying a patient’s own immune system against cancer is that immunological cells are generally agnostic to the mutations that cause a particular cancer’s growth. The immune system was designed to spot differences in the superficial features of a diseased or foreign cell, thereby identifying and killing it. It cares as little about genes as an intercontinental ballistic missile cares about the e-mail addresses or dietary preferences of the population that it has been sent to destroy.
• • •
A few years ago, in writing a history of cancer, I interviewed Emil Freireich. Freireich
, working with Emil Frei at the National Cancer Institute in the 1960s and 1970s, stumbled on the idea of deploying multiple toxic drugs simultaneously to treat cancer—combination chemotherapy. They devised one of the first standard protocols—vincristine, Adriamycin, methotrexate, and prednisone, known as VAMP—to treat pediatric leukemias. Virtually nothing about the VAMP protocol was individualized (although doses could be reduced if needed). In fact, doctors were discouraged from trying alternatives to the formula.
Yet as Freireich recalled, long before they came up with the idea for a protocol, there were small, brave experiments; before trials, there was trial and error. VAMP was brought into existence through grit, instinct, and inspired lunges into the unknown. Vincent T. DeVita Jr., who worked with Freireich in the 1960s, wrote a book, The Death of Cancer, with his daughter, Elizabeth DeVita-Raeburn. In it, he recalled a time when the leukemic children in Freireich’s trial were dying of bacterial meningitis during treatment. The deaths threatened the entire trial: If Freireich couldn’t keep the children alive during the therapy, there would be no possibility of remission. They had an antibiotic that could kill the microbe, but the medicine wouldn’t penetrate the blood-brain barrier. So Freireich decided to try something that pushed the bounds of standard practice. He ordered DeVita, his junior, to inject it directly into the spinal cords of his patients. It was an extreme example of off-label use of the drug: The medicine was not meant for use in the cord. DeVita writes:
The first time Freireich told me to do it, I held up the vial and showed him the label, thinking that he’d possibly missed something. “It says right on there, ‘Do not use intrathecally,’ ” I said. Freireich glowered at me and pointed a long, bony finger in my face. “Do it!” he barked. I did it, though I was terrified. But it worked every time.
When I asked Freireich about that episode and about what he would change in the current landscape of cancer therapy, he pointed to its extreme cautiousness. “We would never have achieved anything in this atmosphere,” he said. The pioneer of protocols pined for a time before there were any protocols.
Medicine needs standards, of course; otherwise it can ramble into dangerous realms, compromising safety and reliability. But cancer medicine also needs a healthy dose of Freireich: the desire to read between the (guide)lines, to reimagine the outer boundaries, to perform the experiments that become the standards of the future. In January, President Obama introduced an enormous campaign for precision medicine. Cancer is its molten centerpiece: Using huge troves of data, including gene sequences of hundreds of thousands of specimens and experiments performed in laboratories nationwide, the project’s goal is to find individualized medicines for every patient’s cancer. But as we wait for that decades-long project to be completed, oncologists still have to treat patients now. To understand the minds of individual cancers, we are learning to mix and match these two kinds of learning—the standard and the idiosyncratic—in unusual and creative ways. It’s the kind of medicine that so many of us went to medical school to learn, the kind that we’d almost forgotten how to practice.
The New Yorker
FINALIST—FEATURE WRITING
“Nothing embodied the manic, angry spirit of the phenomenon known as Donald Trump more than his campaign rallies,” said the Ellie judges. “And no one was better suited to capture that reality than George Saunders.” Trump, Saunders wrote during the summer before the election, “was not trying to persuade, detail, or prove: he [was] trying to thrill, agitate, be liked, be loved.” The nomination of “Trump Days” was the seventh for Saunders’s work but his first in the Feature Writing category. His short stories won Ellies for Fiction in 1994, 1996, 2000, and 2004 and were also nominated for the Fiction award in 1999 and 2010. “Trump Days” was soon followed by the publication of Saunders’s first novel, the widely acclaimed Lincoln in the Bardo.
George Saunders
Trump Days
He Appears
Trump is wearing the red baseball cap, or not. From this distance, he is strangely handsome, well proportioned, puts you in mind of a sea captain: Alan Hale from Gilligan’s Island, say, had Hale been slimmer, richer, more self-confident. We are afforded a side view of a head of silver-yellow hair and a hawklike orange-red face, the cheeks of which, if stared at steadily enough, will seem, through some optical illusion, to glow orange-redder at moments when the crowd is especially pleased. If you’ve ever, watching The Apprentice, entertained fantasies of how you might fare in the boardroom (the Donald, recognizing your excellent qualities with his professional businessman’s acumen, does not fire you but, on the contrary, pulls you aside to assign you some important non-TV, real-world mission), you may, for a brief, embarrassing instant, as he scans the crowd, expect him to recognize you.
He is blessing us here in San Jose, California, with his celebrity, promising never to disappoint us, letting us in on the latest bit of inside-baseball campaign strategy: “Lyin’ Ted” is no longer to be Lyin’ Ted; henceforth he will be just “Ted.” Hillary, however, shall be “Lyin’ Crooked.” And, by the way, Hillary has to go to jail. The statute of limitations is five years, and if he gets elected in November, well … The crowd sends forth a coarse blood roar. “She’s guilty as hell,” he snarls.
He growls, rants, shouts, digresses, careens from shtick nugget to shtick nugget, rhapsodizes over past landslides, name-drops Ivanka, Melania, Mike Tyson, Newt Gingrich, Bobby Knight, Bill O’Reilly. His right shoulder thrusts out as he makes the pinched-finger mudra with down-swinging arm. His trademark double-eye squint evokes that group of beanie-hatted street-tough Munchkin kids; you expect him to kick gruffly at an imaginary stone. In person, his autocratic streak is presentationally complicated by a Ralph Kramdenesque vulnerability. He’s a man who has just dropped a can opener into his wife’s freshly baked pie. He’s not about to start groveling about it, and yet he’s sorry—but, come on, it was an accident. He’s sorry, he’s sorry, OK, but do you expect him to say it? He’s a good guy. Anyway, he didn’t do it.
Once, Jack Benny, whose character was known for frugality and selfishness, got a huge laugh by glancing down at the baseball he was supposed to be first-pitching, pocketing it, and walking off the field. Trump, similarly, knows how well we know him from TV. He is who he is. So sue me, OK? I probably shouldn’t say this, but oops—just did. (Hillary’s attack ads? “So false. Ah, some of them aren’t that false, actually.”) It’s oddly riveting, watching someone take such pleasure in going so much farther out on thin ice than anyone else as famous would dare to go. His crowds are ever hopeful for the next thrilling rude swerve. “There could be no politics which gave warmth to one’s body until the country had recovered its imagination, its pioneer lust for the unexpected and incalculable,” Norman Mailer wrote in 1960.
The speeches themselves are nearly all empty assertion. Assertion and bragging. Assertion, bragging, and defensiveness. He is always boasting about the size of this crowd or that crowd, refuting some slight from someone who has treated him “very unfairly,” underscoring his sincerity via adjectival pile-on (he’s “going to appoint beautiful, incredible, unbelievable Supreme Court Justices”). He lies, bullies, menaces, dishes it out but can’t seem to take it, exhibits such a muddy understanding of certain American principles (the press is free, torture illegal, criticism and libel two different things) that he might be a seventeenth-century Austrian prince time-transported here to mess with us. Sometimes it seems that he truly does not give a shit, and you imagine his minders cringing backstage. Other times you imagine them bored, checking their phones, convinced that nothing will ever touch him. Increasingly, his wild veering seems to occur against his will, as if he were not the great, sly strategist we have taken him for but, rather, someone compelled by an inner music that sometimes produces good dancing and sometimes causes him to bring a bookshelf crashing down on an old Mexican lady. Get more, that inner music seems to be telling him. Get, finally, enough. Refute a lifetime of critics. Create a pile of unprecedented testimonia
ls, attendance receipts, polling numbers, and pundit gasps that will, once and for all, prove—what?
Apply Occam’s razor: if someone brags this much, bending every ray of light back to himself, what’s the simplest explanation?
“We’re on the cover of every newspaper, every magazine,” he says in San Jose in early June. “Time magazine many times. I just learned they’re doing yet another cover on Trump—I love that. You know, Time magazine’s a good magazine. You grow up reading Time magazine—who ever thought you’d be on the cover of Time magazine? Especially so much?”
It’s considered an indication of authenticity that he doesn’t generally speak from a teleprompter but just wings it. (In fact, he brings to the podium a few pages of handwritten bullet points, to which he periodically refers as he, mostly, wings it.) He wings it because winging it serves his purpose. He is not trying to persuade, detail, or prove: he is trying to thrill, agitate, be liked, be loved, here and now. He is trying to make energy. (At one point in his San Jose speech, he endearingly fumbles with a sheaf of “statistics,” reads a few, fondly but slightingly mentions the loyal, hapless statistician who compiled them, then seems unable to go on, afraid he might be boring us.)
And make energy he does. It flows out of him, as if channeled in thousands of micro wires, enters the minds of his followers: their cheers go ragged and hoarse, chanting erupts, a look of religious zeal may flash across the face of some nonchanter, who is finally getting, in response to a question long nursed in private, exactly the answer he’s been craving. One such person stays in my memory from a rally in Fountain Hills, Arizona, in March: a solidly built man in his midforties, wearing, in the crazy heat, a long-sleeved black shirt, who, as Trump spoke, worked himself into a state of riveted, silent concentration-fury, the rally equivalent of someone at church gazing fixedly down at the pew before him, nodding, Yes, yes, yes.
