Siddhartha Mukherjee - The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

  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.

  It was like watching someone locked in a chess game. Every time Germaine's disease moved, imposing yet another terrifying constraint on her, she made an equally assertive move in return. The illness acted; she reacted. It was a morbid, hypnotic game--a game that had taken over her life. She dodged one blow only to be caught by another. She, too, was like Carroll's Red Queen, stuck pedaling furiously just to keep still in one place.

  Germaine seemed, that evening, to have captured something essential about our struggle against cancer: that, to keep pace with this malady, you needed to keep inventing and reinventing, learning and unlearning strategies. Germaine fought cancer obsessively, cannily, desperately, fiercely, madly, brilliantly, and zealously--as if channeling all the fierce, inventive energy of generations of men and women who had fought cancer in the past and would fight it in the future. Her quest for a cure had taken her on a strange and limitless journey, through Internet blogs and teaching hospitals, chemotherapy and clinical trials halfway across the country, through a landscape more desolate, desperate, and disquieting than she had ever imagined. She had deployed every morsel of energy to the quest, mobilizing and remobilizing the last dregs of her courage, summoning her will and wit and imagination, until, that final evening, she had stared into the vault of her resourcefulness and resilience and found it empty. In that haunted last night, hanging on to her life by no more than a tenuous thread, summoning all her strength and dignity as she wheeled herself to the privacy of her bathroom, it was as if she had encapsulated the essence of a four-thousand-year-old war.

  --S.M., June 2010

  The first medical description of cancer was found in an Egyptian text originally written in 2500 BC: "a bulging tumor in [the] breast . . . like touching a ball of wrappings." Discussing treatment, the ancient scribe noted: "[There] is none."

  The anatomist Andreas Vesalius (1514-1564) tried to discover the source for black bile, the fluid thought to be responsible for cancer. Unable to find it, Vesalius launched a new search for cancer's real cause and cure.

  Medieval surgeons attacked cancer using primitive surgical methods. Johannes Scultetus (1595-1645) describes a mastectomy, the surgical removal of breast cancer, using fire, acid and leather bindings.

  Between 1800 and 1900, surgeons devised increasingly aggressive operations to attack the roots of cancer in the body. In the 1890s, William Stewart Halsted at Johns Hopkins University devised the radical mastectomy--an operation to extirpate the breast, the muscles beneath the breast and the associated lymph nodes.

  "The patient was a young lady whom I was loath to disfigure," Halsted wrote. In this etching, Halsted presented an idealized patient. Real cancer patients tended to be older women with larger tumors, far less able to withstand this radical attack.

  When radium was discovered by Marie and Pierre Curie, oncologists and surgeons began to deliver high doses of radiation to tumors. Yet radiation was itself carcinogenic: Marie Curie died from a leukemia caused by decades of X-ray exposure.

  During World War Two, hundreds of tons of mustard gas were released on the Bari harbor in Italy during an air raid. The gas decimated normal white blood cells in the body, leading pharmacologists to fantasize about using a similar chemical to kill cancers of white blood cells. Chemotherapy--chemical warfare on cancer cells--was inspired, literally, by war.

  In 1947, Sidney Farber discovered a folic acid analog called aminopterin that killed rapidly dividing cells in the bone marrow. Using aminopterin, Farber obtained brief, tantalizing remissions in acute lymphoblastic leukemia. One of Farber's first patients was two-year-old Robert Sandler.

  From her all-white apartment in New York City, Mary Lasker, a legendary entrepreneur, socialite, lobbyist and advocate, helped launch a national battle against cancer. Lasker would become the "fairy godmother" of cancer research; she would coax and strong-arm the nation to initiate a War on Cancer.

  Farber's patient, Einar Gustafson--known as "Jimmy"--a baseball fan, became the unofficial mascot for children's cancer. The Jimmy Fund, founded in 1948, was one of the most powerful cancer advocacy organizations, with Ted Williams a vocal supporter.

  Sidney Farber, Lasker's confidant, mentor and co-conspirator, provided medical legitimacy to the War on Cancer and oversaw the building of a new cancer ward in Boston.

  At the National Cancer Institute (NCI) in the 1960s physicians Emil Frei

  Emil Freireich forged a strategy to cure acute lymphoblastic leukemia using highly toxic drugs.

  Henry Kaplan, a physician-scientist, used radiation therapy to cure Hodgkin's lymphoma. The cures of lymphoblastic leukemia and Hodgkin's lymphoma invigorated the War on Cancer, raising the possibility of Farber's "universal cure."

  Inspired by the early victories of chemotherapy, cancer advocates, led by Lasker and Farber, urged the nation to launch a War on Cancer. In 1970, the Laskerites published a full-page advertisement in the New York Times, coaxing Nixon to support their war.

  Many scientists criticized the War on Cancer as premature, arguing that a political cure would not lead to a medical cure.

  Lasker's use of canny advertising and potent imagery still in
spires generations of advocates, including Greenpeace.

  In 1775, the London surgeon Percivall Pott observed that scrotal cancer occurred disproportionately in adolescent chimney sweeps, and proposed a link between soot and scrotal cancer, launching the hunt for preventable carcinogens in the environment.

  Innovative studies in the 1950s established the link between cigarette smoking and lung cancer. Yet early warning labels affixed on packages in the 1960s avoided the word "cancer." Explicit warning labels were not required until decades later.

  Although smoking rates have fallen in most developed nations, active marketing and bold political lobbying allows the tobacco industry to flourish in others, creating a new generation of smokers (and of future cancer victims).

  Harold Varmus and J. Michael Bishop discovered that cancer is caused not by exogenous viruses, but by the activation of endogenous precursor genes that exist in all normal cells. Cancer, Varmus wrote, is a "distorted version" of our normal selves.

  Working with collaborators across the globe, Robert Weinberg, of MIT, discovered distorted genes in mouse and human cancer cells.

  Scientists have sequenced the entire genome (all 23,000 genes), making it possible to document every genetic change (relative to normal genes). Dots represent mutations in genes found in colon cancer, with commonly mutated genes becoming "hills" and then "mountains."

  In the 1990s, Barbara Bradfield was among the first women to be treated with a drug, Herceptin, that specifically attacks breast cancer cells. She is the longest survivor of that treatment, with no hint of her cancer remaining.