The Emperor of All Maladies

by Siddhartha Mukherjee

  As you entered the new building, an oil painting of the man himself—with his characteristic half-scowling, half-smiling face—stared back at you in the foyer. Little bits and pieces of him, it seemed, were strewn everywhere. The corridor on the way to the fellows’ office was still hung with the cartoonish “portraits” that he had once commissioned for the Jimmy Fund: Snow White, Pinocchio, Jiminy Cricket, Dumbo. The bone marrow needles with which we performed our biopsies looked and felt as if they came from another age; perhaps they had been sharpened by Farber or one of his trainees fifty years ago. Wandering through these labs and clinics, you often felt as if you could stumble onto cancer history at any minute. One morning I did: bolting to catch the elevator, I ran headlong into an old man in a wheelchair whom I first took to be a patient. It was Tom Frei, a professor emeritus now, heading up to his office on the sixteenth floor.

  My patient that Wednesday morning was a seventy-six-year-old woman named Beatrice Sorenson. Bea, as she liked to be called, reminded me of one of those tiny insects or animals that you read about in natural-history textbooks that can carry ten times their weight or leap five times their height. She was almost preternaturally minuscule: about eighty-five pounds and four and a half feet tall, with birdlike features and delicate bones that seemed to hang together like twigs in winter. To this diminutive frame, however, she brought a fierce force of personality, the lightness of body counterbalanced by the heftiness of soul. She had been a marine and served in two wars. Even as I towered over her on the examination table, I felt awkward and humbled, as if she were towering over me in spirit.

  Sorenson had pancreatic cancer. The tumor had been discovered almost accidentally in the late summer of 2003, when she had had a bout of abdominal pain and diarrhea and a CT scan had picked up a four-centimeter solid nodule hanging off the tail of her pancreas. (In retrospect, the diarrhea may have been unrelated.) A brave surgeon had attempted to resect it, but the margins of the resection still contained some tumor cells. Even in oncology, a dismal discipline to begin with, this—unresected pancreatic cancer—was considered the epitome of the dismal.

  Sorenson’s life had turned upside down. “I want to beat it to the end,” she had told me at first. We had tried. Through the early fall, we blasted her pancreas with radiation to kill the tumor cells, then followed with chemotherapy, using the drug 5-fluorouracil. The tumor had grown right through all the treatments. In the winter, we had switched to a new drug called gemcitabine, or Gemzar. The tumor cells had shrugged the new drug off—instead mockingly sending a shower of painful metastases into her liver. At times, it felt as if we would have been better off with no drugs at all.

  Sorenson was at the clinic that morning to see if we could offer anything else. She wore white pants and a white shirt. Her paper-thin skin was marked with dry lines. She may have been crying, but her face was a cipher that I could not read.

  “She will try anything, anything,” her husband pleaded. “She is stronger than she looks.”

  But strong or not, there was nothing left to try. I stared down at my feet, unable to confront the obvious questions. The attending physician shifted uncomfortably in his chair.

  Beatrice finally broke the awkward silence. “I’m sorry.” She shrugged her shoulders and looked vacantly past us. “I know we have reached an end.”

  We hung our heads, ashamed. It was, I suspected, not the first time that a patient had consoled a doctor about the ineffectuality of his discipline.

  Two lumps seen on two different mornings. Two vastly different incarnations of cancer: one almost certainly curable, the second, an inevitable spiral into death. It felt—nearly twenty-five hundred years after Hippocrates had naively coined the overarching term karkinos—that modern oncology was hardly any more sophisticated in its taxonomy of cancer. Orman’s lymphoma and Sorenson’s pancreatic cancer were both, of course, “cancers,” malignant proliferations of cells. But the diseases could not have been further apart in their trajectories and personalities. Even referring to them by the same name, cancer, felt like some sort of medical anachronism, like the medieval habit of using apoplexy to describe anything from a stroke to a hemorrhage to a seizure. Like Hippocrates, it was as if we, too, had naively lumped the lumps.

  But naive or not, it was this lumping—this emphatic, unshakable faith in the underlying singularity of cancer more than its pluralities—that galvanized the Laskerites in the 1960s. Oncology was on a quest for cohesive truths—a “universal cure,” as Farber put it in 1962. And if the oncologists of the 1960s imagined a common cure for all forms of cancer, it was because they imagined a common disease called cancer. Curing one form, the belief ran, would inevitably lead to the cure of another, and so forth like a chain reaction, until the whole malignant edifice had crumbled like a set of dominoes.

  That assumption—that a monolithic hammer would eventually demolish a monolithic disease—surcharged physicians, scientists, and cancer lobbyists with vitality and energy. For the Laskerites, it was an organizing principle, a matter of faith, the only certain beacon toward which they all gravitated. Indeed, the political consolidation of cancer that the Laskerites sought in Washington (a single institute, a single source of funds, led by a single physician or scientist) relied on a deeper notion of a medical consolidation of cancer into a single disease, a monolith, a single, central narrative. Without this grand, embracing narrative, neither Mary Lasker nor Sidney Farber could have envisioned a systematic, targeted war.

  The illness that had brought Ben Orman to the clinic late that evening, Hodgkin’s lymphoma, was itself announced late to the world of cancer. Its discoverer, Thomas Hodgkin, was a thin, short, nineteenth-century English anatomist with a spadelike beard and an astonishingly curved nose—a character who might have walked out of an Edward Lear poem. Hodgkin was born in 1798 to a Quaker family in Pentonville, a small hamlet outside London. A precocious child, he grew quickly into an even more precocious young man, whose interests loped freely from geology to mathematics to chemistry. He apprenticed briefly as a geologist, then as an apothecary, and finally graduated from the University of Edinburgh with a degree in medicine.

  A chance event enticed Hodgkin into the world of pathological anatomy and led him toward the disease that would bear his name. In 1825, a struggle within the faculty of St. Thomas’ and Guy’s hospital in London broke up the venerable institution into two bickering halves: Guy’s hospital and its new rival, St. Thomas’. This divorce, like many marital spats, was almost immediately followed by a vicious argument over the partition of property. The “property” here was a macabre ensemble—the precious anatomical collection of the hospital: brains, hearts, stomachs, and skeletons in pickling jars of formalin that had been hoarded for use as teaching tools for the hospital’s medical students. St. Thomas’ hospital refused to part with its precious specimens, so Guy’s scrambled to cobble together its own anatomical museum. Hodgkin had just returned from his second visit to Paris, where he had learned to prepare and dissect cadaveric specimens. He was promptly recruited to collect specimens for Guy’s new museum. The job’s most inventive academic perk, perhaps, was his new title: the Curator of the Museum and the Inspector of the Dead.

  Hodgkin proved to be an extraordinary Inspector of the Dead, a compulsive anatomical curator who hoarded hundreds of samples within a few years. But collecting specimens was a rather mundane task; Hodgkin’s particular genius lay in organizing them. He became a librarian as much as a pathologist; he devised his own systematics for pathology. The original building that housed his collection has been destroyed. But the new museum, where Hodgkin’s original specimens are still on display, is a strange marvel. A four-chambered atrium located deep inside a larger building, it is an enormous walk-in casket-of-wonders constructed of wrought iron and glass. You enter a door and ascend a staircase, then find yourself on the top floor of a series of galleries that cascade downward. Along every wall are rows of formalin-filled jars: lungs in one gallery, hearts in another, brains, kidn
eys, bones, and so forth. This method of organizing pathological anatomy—by organ system rather than by date or disease—was a revelation. By thus “inhabiting” the body conceptually—by climbing in and out of the body at will, often noting the correlations between organs and systems—Hodgkin found that he could recognize patterns within patterns instinctually, sometimes without even consciously registering them.

  In the early winter of 1832, Hodgkin announced that he had collected a series of cadavers, mostly of young men, who possessed a strange systemic disease. The illness was characterized, as he put it, by “a peculiar enlargement of lymph glands.” To the undiscerning eye, this enlargement could easily have been from tuberculosis or syphilis—the more common sources of glandular swelling at that time. But Hodgkin was convinced that he had encountered an entirely new disease, an unknown pathology unique to these young men. He wrote up the case of seven such cadavers and had his paper, “On Some Morbid Appearances of the Absorbent Glands and Spleen,” presented to the Medical and Chirurgical Society.

  The story of a compulsive young doctor putting old swellings into new pathological bottles was received without much enthusiasm. Only eight members of the society reportedly attended the lecture. They filed out afterward in silence, not even bothering to record their names on the dusty attendance roster.

  Hodgkin, too, was a little embarrassed by his discovery. “A pathological paper may perhaps be thought of little value if unaccompanied by suggestions designed to assist in the treatment, either curative or palliative,” he wrote. Merely describing an illness, without offering any therapeutic suggestions, seemed like an empty academic exercise to him, a form of intellectual frittering. Soon after publishing his paper, he began to drift away from medicine altogether. In 1837, after a rather vicious political spat with his superiors, he resigned his post at Guy’s. He had a brief stint at St. Thomas’ hospital as its curator—a rebound affair that was doomed to fail. In 1844, he gave up his academic practice altogether. His anatomical studies slowly came to a halt.

  In 1898, some thirty years after Hodgkin’s death, an Austrian pathologist, Carl Sternberg, was looking through a microscope at a patient’s glands when he found a peculiar series of cells staring back at him: giant, disorganized cells with cleaved, bilobed nuclei—“owl’s eyes,” as he described them, glaring sullenly out from the forests of lymph. Hodgkin’s anatomy had reached its final cellular resolution. These owl’s-eye cells were malignant lymphocytes, lymph cells that had turned cancerous. Hodgkin’s disease was a cancer of the lymph glands—a lymphoma.

  Hodgkin may have been disappointed by what he thought was only a descriptive study of his disease. But he had underestimated the value of careful observation—by compulsively studying anatomy alone, he had stumbled upon the most critical revelation about this form of lymphoma: Hodgkin’s disease had a peculiar propensity of infiltrating lymph nodes locally one by one. Other cancers could be more unpredictable—more “capricious,” as one oncologist put it. Lung cancer, for instance, might start as a spicular nodule in the lung, then unmoor itself and ambulate unexpectedly into the brain. Pancreatic cancer was notoriously known to send sprays of malignant cells into faraway sites such as the bones and the liver. But Hodgkin’s—an anatomist’s discovery—was anatomically deferential: it moved, as if with a measured, ordered pace, from one contiguous node to another—from gland to gland and from region to region.

  It was this propensity to spread locally from one node to the next that poised Hodgkin’s uniquely in the history of cancer. Hodgkin’s disease was yet another hybrid among malignant diseases. If Farber’s leukemia had occupied the hazy border between liquid and solid tumors, then Hodgkin’s disease inhabited yet another strange borderland: a local disease on the verge of transforming into a systemic one—Halsted’s vision of cancer on its way to becoming Galen’s.

  In the early 1950s, at a cocktail party in California, Henry Kaplan, a professor of radiology at Stanford, overheard a conversation about the plan to build a linear accelerator for use by physicists at Stanford. A linear accelerator is an X-ray tube taken to an extreme form. Like a conventional X-ray tube, a linear accelerator also fires electrons onto a target to generate high-intensity X-rays. Unlike a conventional tube, however, the “linac” imbues massive amounts of energy into the electrons, pushing them to dizzying velocities before smashing them against the metal surface. The X-rays that emerge from this are deeply penetrating—powerful enough not only to pass through tissue, but to scald cells to death.

  Kaplan had trained at the NCI, where he had learned to use X-rays to treat leukemia in animals, but his interest had gradually shifted to solid tumors in humans—lung cancer, breast cancer, lymphomas. Solid tumors could be treated with radiation, he knew, but the outer shell of the cancer, like its eponymous crab’s carapace, needed to be penetrated deeply to kill cancer cells. A linear accelerator with its sharp, dense, knifelike beam might allow him to reach tumor cells buried deep inside tissues. In 1953, he persuaded a team of physicists and engineers at Stanford to tailor-make an accelerator exclusively for the hospital. The accelerator was installed in a vaultlike warehouse in San Francisco in 1956. Dodging traffic between Fillmore Street and Mission Hill, Kaplan personally wheeled in its colossal block of lead shielding on an automobile jack borrowed from a neighboring garage owner.

  Through a minuscule pinhole in that lead block, he could now direct tiny, controlled doses of a furiously potent beam of X-rays—millions of electron volts of energy in concentrated bursts—to lancinate any cancer cell to death. But what form of cancer? If Kaplan had learned one lesson at the NCI, it was that by focusing microscopically on a single disease, one could extrapolate into the entire universe of diseases. The characteristics that Kaplan sought in his target were relatively well defined. Since the linac could only focus its killer beam on local sites, it would have to be a local, not a systemic, cancer. Leukemia was out of the question. Breast and lung cancer were important targets, but both were unpredictable, mercurial diseases, with propensities for occult and systemic spread. The powerful oculus of Kaplan’s intellect, swiveling about through the malignant world, ultimately landed on the most natural target for his investigation: Hodgkin’s disease.

  “Henry Kaplan was Hodgkin’s disease,” George Canellos, a former senior clinician at the NCI told me, leaning back in his chair. We were sitting in his office while he rummaged through piles of manuscripts, monographs, articles, books, catalogs, and papers, pulling out occasional pictures of Kaplan from his files. Here was Kaplan, dressed in a bow tie, looking at sheaves of papers at the NCI. Or Kaplan in a white coat standing next to the linac at Stanford, its 5-million-volt probe just inches from his nose.

  Kaplan wasn’t the first doctor to treat Hodgkin’s with X-rays, but he was certainly the most dogged, the most methodical, and the most single-minded. In the mid-1930s, a Swiss radiologist named Rene Gilbert had shown that the swollen lymph nodes of Hodgkin’s disease could effectively and dramatically be reduced with radiation. But Gilbert’s patients had typically relapsed after treatment, often in the lymph nodes immediately contiguous to the original radiated area. At the Toronto General Hospital, a Canadian surgeon named Vera Peters had furthered Gilbert’s studies by broadening the radiation field even farther—delivering X-rays not to a single swollen node, but to an entire area of lymph nodes. Peters called her strategy “extended field radiation.” In 1958, analyzing the cohort of patients that she had treated, Peters observed that broad-field radiation could significantly improve long-term survival for early-stage Hodgkin’s patients. But Peters’s data was retrospective—based on the historical analysis of prior-treated patients. What Peters needed was a more rigorous medical experiment, a randomized clinical trial. (Historical series can be biased by doctors’ highly selective choices of patients for therapy, or by their counting only the ones that do the best.)

  Independently of Peters, Kaplan had also realized that extended field radiation could improve relapse-free survival, perh
aps even cure early-stage Hodgkin’s disease. But he lacked formal proof. In 1962, challenged by one of his students, Henry Kaplan set out to prove the point.

  The trials that Kaplan designed still rank among the classics of study design. In the first set, called the L1 trials, he assigned equal numbers of patients to either extended field radiation or to limited “involved field” radiation and plotted relapse-free survival curves. The answer was definitive. Extended field radiation—“meticulous radiotherapy” as one doctor described it—drastically diminished the relapse rate of Hodgkin’s disease.

  But Kaplan knew that a diminished relapse rate was not a cure. So he delved further. Two years later, the Stanford team carved out a larger field of radiation, involving nodes around the aorta, the large arch-shaped blood vessel that leads out of the heart. Here they introduced an innovation that would prove pivotal to their success. Kaplan knew that only patients that had localized Hodgkin’s disease could possibly benefit from radiation therapy. To truly test the efficacy of radiation therapy, then, Kaplan realized that he would need a strictly limited cohort of patients whose Hodgkin’s disease involved just a few contiguous lymph nodes. To exclude patients with more disseminated forms of lymphoma, Kaplan devised an intense battery of tests to stage his patients. There were blood tests, a detailed clinical exam, a procedure called lymphangiography (a primitive ancestor of a CT scan for the lymph nodes), and a bone marrow biopsy. Even so, Kaplan was unsatisfied: doubly careful, he began to perform exploratory abdominal surgery and biopsy internal nodes to ensure that only patients with locally confined disease were entering his trials.