The Emperor of All Maladies

by Siddhartha Mukherjee

  But our goals could be more modest. Above the door to Richard Peto’s office in Oxford hangs one of Doll’s favorite aphorisms: “Death in old age is inevitable, but death before old age is not.” Doll’s idea represents a far more reasonable proximal goal to define success in the War on Cancer. It is possible that we are fatally conjoined to this ancient illness, forced to play its cat-and-mouse game for the foreseeable future of our species. But if cancer deaths can be prevented before old age, if the terrifying game of treatment, resistance, recurrence, and more treatment can be stretched out longer and longer, then it will transform the way we imagine this ancient illness. Given what we know about cancer, even this would represent a technological victory unlike any other in our history. It would be a victory over our own inevitability—a victory over our genomes.

  To envision what such a victory might look like, permit a thought experiment. Recall Atossa, the Persian queen with breast cancer in 500 BC. Imagine her traveling through time—appearing and reappearing in one age after the next. She is cancer’s Dorian Gray: as she moves through the arc of history, her tumor, frozen in its stage and behavior, remains the same. Atossa’s case allows us to recapitulate past advances in cancer therapy and to consider its future. How has her treatment and prognosis shifted in the last four thousand years, and what happens to Atossa later in the new millennium?

  First, pitch Atossa backward in time to Imhotep’s clinic in Egypt in 2500 BC. Imhotep has a name for her illness, a hieroglyph that we cannot pronounce. He provides a diagnosis, but “there is no treatment,” he says humbly, closing the case.

  In 500 BC, in her own court, Atossa self-prescribes the most primitive form of a mastectomy, which is performed by her Greek slave. Two hundred years later, in Thrace, Hippocrates identifies her tumor as a karkinos, thus giving her illness a name that will ring through its future. Claudius Galen, in AD 168, hypothesizes a universal cause: a systemic overdose of black bile—trapped melancholia boiling out as a tumor.

  A thousand years flash by; Atossa’s entrapped black bile is purged from her body, yet the tumor keeps growing, relapsing, invading, and metastasizing. Medieval surgeons understand little about Atossa’s disease, but they chisel away at her cancer with knives and scalpels. Some offer frog’s blood, lead plates, goat dung, holy water, crab paste, and caustic chemicals as treatments. In 1778, in John Hunter’s clinic in London, her cancer is assigned a stage—early, localized breast cancer or late, advanced, invasive cancer. For the former, Hunter recommends a local operation; for the latter, “remote sympathy.”

  When Atossa reemerges in the nineteenth century, she encounters a new world of surgery. In Halsted’s Baltimore clinic in 1890, Atossa’s breast cancer is treated with the boldest and most definitive therapy thus far—radical mastectomy with a large excision of the tumor and removal of the deep chest muscles and lymph nodes under the armpit and the collarbone. In the early twentieth century, radiation oncologists try to obliterate the tumor locally using X-rays. By the 1950s, yet another generation of surgeons learns to combine the two strategies, although tempered by moderation. Atossa’s cancer is treated locally with a simple mastectomy, or a lumpectomy followed by radiation.

  In the 1970s, new therapeutic strategies emerge. Atossa’s surgery is followed by adjuvant combination chemotherapy to diminish the chance of a relapse. Her tumor tests positive for the estrogen receptor. Tamoxifen, the antiestrogen, is also added to prevent a relapse. In 1986, her tumor is further discovered to be Her-2 amplified. In addition to surgery, radiation, adjuvant chemotherapy, and tamoxifen, she is treated with targeted therapy using Herceptin.

  It is impossible to enumerate the precise impact of these interventions on Atossa’s survival. The shifting landscape of trials does not allow a direct comparison between Atossa’s fate in 500 BC and her fate in 1989. But surgery, chemotherapy, radiation, hormonal therapy, and targeted therapy have likely added anywhere between seventeen and thirty years to her survival. Diagnosed at forty, say, Atossa can reasonably be expected to celebrate her sixtieth birthday.

  In the mid-1990s, the management of Atossa’s breast cancer takes another turn. Her diagnosis at an early age and her Achaemenid ancestry raise the question of whether she carries a mutation in BRCA-1 or BRCA-2. Atossa’s genome is sequenced, and indeed, a mutation is found. She enters an intensive screening program to detect the appearance of a tumor in her unaffected breast. Her two daughters are also tested. Found positive for BRCA-1, they are offered either intensive screening, prophylactic bilateral mastectomy, or tamoxifen to prevent the development of invasive breast cancer. For Atossa’s daughters, the impacts of screening and prophylaxis are dramatic. A breast MRI identifies a small lump in one daughter. It is found to be breast cancer and surgically removed in its early, preinvasive stage. The other daughter chooses to undergo a prophylactic bilateral mastectomy. Having excised her breasts preemptively, she will live out her life free of breast cancer.

  Move Atossa into the future now. In 2050, Atossa will arrive at her breast oncologist’s clinic with a thumb-size flash drive containing the entire sequence of her cancer’s genome, identifying every mutation in every gene. The mutations will be organized into key pathways. An algorithm might identify the pathways that are contributing to the growth and survival of her cancer. Therapies will be targeted against these pathways to prevent a relapse of the tumor after surgery. She will begin with one combination of targeted drugs, expect to switch to a second cocktail when her cancer mutates, and switch again when the cancer mutates again. She will likely take some form of medicine, whether to prevent, cure, or palliate her illness, for the rest of her life.

  This, indubitably, is progress. But before we become too dazzled by Atossa’s survival, it is worthwhile putting it into perspective. Give Atossa metastatic pancreatic cancer in 500 BC and her prognosis is unlikely to change by more than a few months over twenty-five hundred years. If Atossa develops gallbladder cancer that is not amenable to surgery, her survival changes only marginally over centuries. Even breast cancer shows a marked heterogeneity in outcome. If Atossa’s tumor has metastasized, or is estrogen-receptor negative, Her-2 negative, and unresponsive to standard chemotherapy, then her chances of survival will have barely changed since the time of Hunter’s clinic. Give Atossa CML or Hodgkin’s disease, in contrast, and her life span may have increased by thirty or forty years.

  Part of the unpredictability about the trajectory of cancer in the future is that we do not know the biological basis for this heterogeneity. We cannot yet fathom, for instance, what makes pancreatic cancer or gallbladder cancer so markedly different from CML or Atossa’s breast cancer. What is certain, however, is that even the knowledge of cancer’s biology is unlikely to eradicate cancer fully from our lives. As Doll suggests, and as Atossa epitomizes, we might as well focus on prolonging life rather than eliminating death. This War on Cancer may best be “won” by redefining victory.

  Atossa’s tortuous journey also raises a question implicit in this book: if our understanding and treatment of cancer keep morphing so radically in time, then how can cancer’s past be used to predict its future?

  In 1997, the NCI director, Richard Klausner, responding to reports that cancer mortality had remained disappointingly static through the nineties, argued that the medical realities of one decade had little bearing on the realities of the next. “There are far more good historians than there are good prophets,” Klausner wrote. “It is extraordinarily difficult to predict scientific discovery, which is often propelled by seminal insights coming from unexpected directions. The classic example—Fleming’s discovery of penicillin on moldy bread and the monumental impact of that accidental finding—could not easily have been predicted, nor could the sudden demise of iron-lung technology when evolving techniques in virology allowed the growth of poliovirus and the preparation of vaccine. Any extrapolation of history into the future presupposes an environment of static discovery—an oxymoron.”

  In a limited sense, Klausner is
right. When truly radical discoveries appear, their impact is often not incremental but cataclysmic and paradigm-shifting. Technology dissolves its own past. The speculator who bought stock options in an iron-lung company before the discovery of the polio vaccine, or the scientist who deemed bacterial pneumonias incurable just as penicillin was being discovered, were soon shown to be history’s fools.

  But with cancer, where no simple, universal, or definitive cure is in sight—and is never likely to be—the past is constantly conversing with the future. Old observations crystallize into new theories; time past is always contained in time future. Rous’s virus was reincarnated, decades later, in the form of endogenous oncogenes; George Beatson’s observation that removing ovaries might slow the growth of breast cancer, inspired by a Scottish shepherds’ tale, roars back in the form of a billion-dollar drug named tamoxifen; Bennett’s “suppuration of blood,” the cancer that launches this book, is also the cancer that ends this book.

  And there is a subtler reason to remember this story: while the content of medicine is constantly changing, its form, I suspect, remains astonishingly the same. History repeats, but science reverberates. The tools that we will use to battle cancer in the future will doubtless alter so dramatically in fifty years that the geography of cancer prevention and therapy might be unrecognizable. Future physicians may laugh at our mixing of primitive cocktails of poisons to kill the most elemental and magisterial disease known to our species. But much about this battle will remain the same: the relentlessness, the inventiveness, the resilience, the queasy pivoting between defeatism and hope, the hypnotic drive for universal solutions, the disappointment of defeat, the arrogance and the hubris.

  The Greeks used an evocative word to describe tumors, onkos, meaning “mass” or “burden.” The word was more prescient than they might have imagined. Cancer is indeed the load built into our genome, the leaden counterweight to our aspirations for immortality. But if one looks back even further behind the Greek to the ancestral Indo-European language, the etymology of the word onkos changes. Onkos arises from the ancient word nek. And nek, unlike the static onkos, is the active form of the word load. It means to carry, to move the burden from one place to the next, to bear something across a long distance and bring it to a new place. It is an image that captures not just the cancer cell’s capacity to travel—metastasis—but also Atossa’s journey, the long arc of scientific discovery—and embedded in that journey, the animus, so inextricably human, to outwit, to outlive and survive.

  Late one evening in the spring of 2005, toward the end of the first year of my fellowship, I sat in a room on the tenth floor of the hospital with a dying woman, Germaine Berne. She was a vivacious psychologist from Alabama. In 1999, she had been struck by nausea, a queasiness so sudden and violent that it felt as if it had been released from a catapult. Even more unsettling, the nausea had been accompanied by a vague sense of fullness, as if she were perpetually stuck devouring a large meal. Germaine had driven herself to the Baptist Hospital in Montgomery, where she had undergone a barrage of tests until a CAT scan had revealed a twelve-centimeter solid mass pushing into her stomach. On January 4, 2000, a radiologist had biopsied the mass. Under the microscope, the biopsy had revealed sheets of spindlelike cells dividing rapidly. The tumor, which had invaded blood vessels and bucked the normal planes of tissue, was a rare kind of cancer called a gastrointestinal stromal tumor, or simply, a GIST.

  The news quickly became worse. Her scans showed spots in her liver, swellings in her lymph nodes, and a spray of masses peppering the left lung. The cancer had metastasized all over her body. A surgical cure was impossible, and in 2000, no chemotherapy was known to be effective against her kind of sarcoma. Her doctors in Alabama cobbled together a combination of chemotherapeutic drugs, but they were essentially biding their time. “I signed my letters, paid my bills, and made my will,” she recalled. “There was no doubt about the verdict. I was told to go home to die.”

  In the winter of 2000, handed her death sentence, Germaine stumbled into a virtual community of cosufferers—GIST patients who spoke to each other through a website. The site, like most of its bloggers, was a strange and moribund affair, with desperate folks seeking desperate remedies. But in late April, news of a novel drug began to spread like wildfire through this community. The new drug was none other than Gleevec—imatinib—the same chemical that Druker had found to be active against chronic myelogenous leukemia. Gleevec binds and inactivates the Bcr-abl protein. But serendipitously, the chemical inactivates another tyrosine kinase, called c-kit. Just as activated Bcr-abl drives cancer cells to divide and grow in CML, c-kit is a driver gene in GIST. In early trials, Gleevec had turned out to be remarkably clinically active against c-kit, and hence against GIST.

  Germaine pulled strings to get enrolled in one of these trials. She was, by nature, effortlessly persuasive, able to cajole, badger, wheedle, pester, beg, and demand—and her illness had made her bold. (“Cure me, Doc, and I’ll send you to Europe,” she told me once—an offer that I politely declined.) She worked her way into a teaching hospital where patients were being given the drug on trial. Just as she was being enrolled, Gleevec had turned out to be so effective that doctors could no longer justify treating GIST patients with a placebo pill. Germaine started on the drug in August 2001. A month later, her tumors began to recede at an astonishing rate. Her energy returned; her nausea vanished. She was resurrected from the dead.

  Germaine’s recovery was a medical miracle. Newspapers in Montgomery picked up the story. She doled out advice to other cancer victims. Medicine was catching up on cancer, she wrote; there was reason for hope. Even if no cure was in sight, a new generation of drugs would control cancer, and another generation would round the bend just as the first one failed. In the summer of 2004, as she was celebrating the fourth anniversary of her unexpected recovery, the cells of Germaine’s tumor suddenly grew resistant to Gleevec. Her lumps, having remained dormant for four years, sprouted vengefully back. In months, masses appeared in her stomach, lymph nodes, lungs, liver, spleen. The nausea returned, just as powerfully as the first time. Malignant fluid poured into the cisterns of her abdomen.

  Resourceful as usual, Germaine scoured the Web, returning to her makeshift community of GIST patients for advice. She discovered that other drugs—second-generation analogues of Gleevec—were in trial in Boston and in other cities. In 2004, on a telephone halfway across the country, she enrolled in a trial of one such analogue called SU11248 that had just opened up at the Farber.

  The new drug produced a temporary response, but did not work for long. By February 2005, Germaine’s cancer had spiraled out of control, growing so fast that she could record its weight, in pounds, as she stood on the scales every week. Eventually her pain made it impossible for her to walk even from her bed to the door and she had to be hospitalized. My meeting with Germaine that evening was not to discuss drugs and therapies, but to try to make an honest reconciliation between her and her medical condition.

  As usual, she had already beaten me to it. When I entered her room to talk about next steps, she waved her hand in the air with a withering look and cut me off. Her goals were now simple, she told me. No more trials. No more drugs. The six years of survival that she had eked out between 1999 and 2005 had not been static, frozen years; they had sharpened, clarified, and cleansed her. She had severed her relationship with her husband and intensified her bond with her brother, an oncologist. Her daughter, a teenager in 1999 and now a preternaturally mature sophomore at a Boston college, had grown into her ally, her confidante, her sometime nurse, and her closest friend. (“Cancer breaks some families and makes some,” Germaine said. “In my case, it did both.”) Germaine realized that her reprieve had finally come to an end. She wanted to get to Alabama, to her own home, to die the death that she had expected in 1999.

  When I recall that final conversation with Germaine, embarrassingly enough, the objects seem to stand out more vividly than the words: a hospital room,
with its sharp smell of disinfectant and hand soap; the steely, unflattering overhead light; a wooden side table on wheels, piled with pills, books, newspaper clippings, nail polish, jewelry, postcards. Her room, wallpapered with pictures of her beautiful house in Montgomery and of her daughter holding some fruit picked from her garden; a standard-issue plastic hospital pitcher filled with a bunch of sunflowers perched on a table by her side. Germaine, as I remember her, was sitting by the bed, one leg dangling casually down, wearing her usual eccentric and arresting combination of clothes and some large and unusual pieces of jewelry. Her hair was carefully arranged. She looked formal, frozen and perfect, like a photograph of someone in a hospital waiting to die. She seemed content; she laughed and joked. She made wearing a nasogastric tube seem effortless and dignified.

  Only years later, in writing this book, could I finally put into words why that meeting left me so uneasy and humbled; why the gestures in that room seemed larger-than-life; why the objects seemed like symbols; why Germaine herself seemed like an actor playing a part. Nothing, I realized, was incidental. The characteristics of Germaine’s personality that had once seemed spontaneous and impulsive were, in fact, calculated and almost reflexive responses to her illness. Her clothes were loose and vivid because they were decoys against the growing outline of the tumor in her abdomen. Her necklace was distractingly large so as to pull attention away from her cancer. Her room was topsy-turvy with baubles and pictures—the hospital pitcher filled with flowers, the cards tacked to the wall—because without them it would devolve into the cold anonymity of any other room in any other hospital. She had dangled her leg at that precise, posed angle because the tumor had invaded her spine and begun to paralyze her other leg, making it impossible to sit any other way. Her casualness was studied, the jokes rehearsed. Her illness had tried to humiliate her. It had made her anonymous and seemingly humorless; it had sentenced her to die an unsightly death in a freezing hospital room thousands of miles away from home. She had responded with vengeance, moving to be always one step ahead, trying to outwit it.