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

by Siddhartha Mukherjee

  I would like to see myself at my wife's side awaiting the miraculous moment of my daughter's birth as most fathers do. But in truth I was gowned and gloved like a surgeon, with a blue, sterile sheet spread out in front of me, and a long syringe in my hands, poised to harvest the maroon gush of blood cells from the umbilical cord. When I cut that cord, part of me was the father, but the other part an oncologist. Umbilical blood contains one of the richest known sources of blood-forming stem cells--cells that can be stored away in cryobanks and used for a bone marrow transplant to treat leukemia in the future, an intensely precious resource often flushed down a sink in hospitals after childbirth.

  The midwives rolled their eyes; the obstetrician, an old friend, asked jokingly if I ever stopped thinking about work. But I was too far steeped in the study of blood to ignore my instincts. In the bone-marrow-transplant rooms across that very hallway were patients for whom I had scoured tissue banks across the nation for one or two pints of these stem cells that might save their lives. Even in this most life-affirming of moments, the shadows of malignancy--and death--were forever lurking on my psyche.

  But not everything was involuting into death. Something transformative was also happening in the fellows' clinics in the summer of 2005: many of my patients, whose faces had so fixedly been pressed up against the glass of their mortality, began to glimpse an afterlife beyond cancer. February, as I said before, had marked the midpoint of an abysmal descent. Cancer had reached its full, lethal bloom that month. Nearly every week had brought news of a mounting toll, culminating chillingly with Steve Harmon's arrival in the emergency room and his devastating spiral into death thereafter. Some days I dreaded walking by the fax machines outside my office, where a pile of death certificates would be waiting for my signature.

  But then, like a poisonous tide receding, the bad news ebbed. The nightly phone calls from the hospitals or from ERs and hospice units around Boston bringing news of yet another death ("I'm calling to let you know that your patient arrived here this evening with dizziness and difficulty breathing") suddenly ceased. It was as if the veil of death had lifted--and survivors had emerged from underneath.

  Ben Orman had been definitively cured of Hodgkin's lymphoma. It had not been an effortless voyage. His blood counts had dropped calamitously during the midcycle of chemotherapy. For a few weeks it had appeared that the lymphoma had ceased responding--a poor prognostic sign portending a therapy-resistant, fatal variant of the disease. But in the end the mass in his neck, and the larger archipelago of masses in his chest, had all melted away, leaving just minor remnants of scar tissue. The formality of his demeanor had visibly relaxed. When I last saw him in the summer of 2005, he spoke about moving away from Boston to Los Angeles to join a law firm. He assured me that he would visit to follow up, but I wasn't convinced. Orman epitomized the afterlife of cancer--eager to forget the clinic and its bleak rituals, like a bad trip to a foreign country.

  Katherine Fitz could also see a life beyond cancer. For Fitz, with the lung tumor wrapped ominously around her bronchus, the biggest hurdle had been the local control of her cancer. The mass had been excised in an incredibly meticulous surgery; she had then finished adjuvant chemotherapy and radiation. Nearly twelve months after the surgery, there was no sign of a local relapse. Nor was there any sign of the woman who had come to the clinic several months earlier, nearly folded over in fear. Tumor out, chemotherapy done, radiation behind her, Fitz's effervescence poured out of every spigot of her soul. At times, watching her personality emerge as if through a nozzle, it seemed abundantly clear why the Greeks had thought of disease as pathological blockades of humors.

  Carla returned to see me in July 2005, bringing pictures of her three growing children. She refused to let another doctor perform her bone marrow biopsy, so I walked over from the lab on a warm morning to perform the procedure. She looked relieved when she saw me, greeting me with her anxious half-smile. We had developed a ritualistic relationship; who was I to desecrate a lucky ritual? The biopsy revealed no leukemia in the bone marrow. Her remission, for now, was still intact.

  I have chosen these cases not because they were "miraculous" but because of precisely the opposite reason. They represent a routine spectrum of survivors--Hodgkin's disease cured with multidrug chemotherapy; locally advanced lung cancer controlled with surgery, chemotherapy, and radiation; lymphoblastic leukemia in a prolonged remission after intensive chemotherapy. To me, these were miracles enough. It is an old complaint about the practice of medicine that it inures you to the idea of death. But when medicine inures you to the idea of life, to survival, then it has failed utterly. The novelist Thomas Wolfe, recalling a lifelong struggle with illness, wrote in his last letter, "I've made a long voyage and been to a strange country, and I've seen the dark man very close." I had not made the journey myself, and I had only seen the darkness reflected in the eyes of others. But surely, it was the most sublime moment of my clinical life to have watched that voyage in reverse, to encounter men and women returning from the strange country--to see them so very close, clambering back.

  Incremental advances can add up to transformative changes. In 2005, an avalanche of papers cascading through the scientific literature converged on a remarkably consistent message--the national physiognomy of cancer had subtly but fundamentally changed. The mortality for nearly every major form of cancer--lung, breast, colon, and prostate--had continuously dropped for fifteen straight years. There had been no single, drastic turn but rather a steady and powerful attrition: mortality had declined by about 1 percent every year. The rate might sound modest, but its cumulative effect was remarkable: between 1990 and 2005, the cancer-specific death rate had dropped nearly 15 percent, a decline unprecedented in the history of the disease. The empire of cancer was still indubitably vast--more than half a million American men and women died of cancer in 2005--but it was losing power, fraying at its borders.

  What precipitated this steady decline? There was no single answer but rather a multitude. For lung cancer, the driver of decline was primarily prevention--a slow attrition in smoking sparked off by the Doll-Hill and Wynder-Graham studies, fueled by the surgeon general's report, and brought to its full boil by a combination of political activism (the FTC action on warning labels), inventive litigation (the Banzhaf and Cipollone cases), medical advocacy, and countermarketing (the antitobacco advertisements).

  For colon and cervical cancer, the declines were almost certainly due to the successes of secondary prevention--cancer screening. Colon cancers were detected at earlier and earlier stages in their evolution, often in the premalignant state, and treated with relatively minor surgeries. Cervical cancer screening using Papanicolaou's smearing technique was being offered at primary-care centers throughout the nation, and as with colon cancer, premalignant lesions were excised using relatively minor surgeries.

  For leukemia, lymphoma, and testicular cancer, in contrast, the declining numbers reflected the successes of chemotherapeutic treatment. In childhood ALL, cure rates of 80 percent were routinely being achieved. Hodgkin's disease was similarly curable, and so, too, were some large-cell aggressive lymphomas. Indeed, for Hodgkin's disease, testicular cancer, and childhood leukemias, the burning question was not how much chemotherapy was curative, but how little: trials were addressing whether milder and less toxic doses of drugs, scaled back from the original protocols, could achieve equivalent cure rates.

  Perhaps most symbolically, the decline in breast cancer mortality epitomized the cumulative and collaborative nature of these victories--and the importance of attacking cancer using multiple independent prongs. Between 1990 and 2005, breast cancer mortality had dwindled an unprecedented 24 percent. Three interventions had potentially driven down the breast cancer death rate--mammography (screening to catch early breast cancer and thereby prevent invasive breast cancer), surgery, and adjuvant chemotherapy (chemotherapy after surgery to remove remnant cancer cells). Donald Berry, a statistician in Houston, Texas, set out to answer a controve
rsial question: How much had mammography and chemotherapy independently contributed to survival? Whose victory was this--a victory of prevention or of therapeutic intervention?*

  Berry's answer was a long-due emollient to a field beset by squabbles between the advocates of prevention and the proponents of chemotherapy. When Berry assessed the effect of each intervention independently using statistical models, it was a satisfying tie: both cancer prevention and chemotherapy had diminished breast cancer mortality equally--12 percent for mammography and 12 percent for chemotherapy, adding up to the observed 24 percent reduction in mortality. "No one," as Berry said, paraphrasing the Bible, "had labored in vain."

  These were all deep, audacious, and meaningful victories borne on the backs of deep and meaningful labors. But, in truth, they were the victories of another generation--the results of discoveries made in the fifties and sixties. The core conceptual advances from which these treatment strategies arose predated nearly all the significant work on the cell biology of cancer. In a bewildering spurt over just two decades, scientists had unveiled a fantastical new world--of errant oncogenes and tumor suppressor genes that accelerated and decelerated growth to unleash cancer; of chromosomes that could be decapitated and translocated to create new genetic chimeras, of cellular pathways corrupted to subvert the death of cancer. But the therapeutic advances that had led to the slow attrition of cancer mortality made no use of this novel biology of cancer. There was new science on one hand and old medicine on the other. Mary Lasker had once searched for an epochal shift in cancer. But the shift that had occurred seemed to belong to another epoch.

  Mary Lasker died of heart failure in 1994 in her carefully curated home in Connecticut--having removed herself physically from the bristling epicenters of cancer research and policymaking in Washington, New York, and Boston. She was ninety-three years old. Her life had nearly spanned the most transformative and turbulent century of biomedical science. Her potent ebullience had dimmed in her last decade. She spoke rarely about the achievements (or disappointments) of the War on Cancer. But she had expected cancer medicine to have achieved more during her lifetime--to have taken a more assertive step toward Farber's "universal cure" for cancer and marked a more definitive victory in the war. The complexity, the tenacity--the sheer magisterial force of cancer--had made even its most committed and resolute opponent seem circumspect and humbled.

  In 1994, a few months after Lasker's death, the cancer geneticist Ed Harlow captured both the agony and the ecstasy of the era. At the end of a weeklong conference at the Cold Spring Harbor Laboratory in New York pervaded by a giddy sense of anticipation about the spectacular achievements of cancer biology, Harlow delivered a sobering assessment: "Our knowledge of . . . molecular defects in cancer has come from a dedicated twenty years of the best molecular biology research. Yet this information does not translate to any effective treatments nor to any understanding of why many of the current treatments succeed or why others fail. It is a frustrating time."

  More than a decade later, I could sense the same frustration in the clinic at Mass General. One afternoon, I watched Tom Lynch, the lung cancer clinician, masterfully encapsulate carcinogenesis, cancer genetics, and chemotherapy for a new patient, a middle-aged woman with bronchoalveolar cell cancer. She was a professor of history with a grave manner and a sharp, darting mind. He sat across from her, scribbling a picture as he spoke. The cells in her bronchus, he began, had acquired mutations in their genes that had allowed them to grow autonomously and uncontrollably. They had formed a local tumor. Their propensity was to acquire further mutations that might allow them to migrate, to invade tissues, to metastasize. Chemotherapy with Carboplatin and Taxol (two standard chemotherapy drugs), augmented with radiation, would kill the cells and perhaps prevent them from migrating to other organs to seed metastases. In the best-case scenario, the cells carrying the mutated genes would die, and her cancer would be cured.

  She watched Lynch put his pen down with her quick, sharp eyes. The explanation sounded logical and organized, but she had caught the glint of a broken piece in the chain of logic. What was the connection between this explanation and the therapy being proposed? How, she wanted to know, would Carboplatin "fix" her mutated genes? How would Taxol know which cells carried the mutations in order to kill them? How would the mechanistic explanation of her illness connect with the medical interventions?

  She had captured a disjunction all too familiar to oncologists. For nearly a decade, practicing cancer medicine had become like living inside a pressurized can--pushed, on one hand, by the increasing force of biological clarity about cancer, but then pressed against the wall of medical stagnation that seemed to have produced no real medicines out of this biological clarity. In the winter of 1945, Vannevar Bush had written to President Roosevelt, "The striking advances in medicine during the war have been possible only because we had a large backlog of scientific data accumulated through basic research in many scientific fields in the years before the war."

  For cancer, the "backlog of scientific data" had reached a critical point. The boil of science, as Bush liked to imagine it, inevitably produced a kind of steam--an urgent, rhapsodic pressure that could only find release in technology. Cancer science was begging to find release in a new kind of cancer medicine.

  * Jimmy began chemo in the Children's Hospital in 1948, but was later followed and treated in the Jimmy Fund Building in 1952.

  * Surgery's contribution could not be judged since surgery predated 1990, and nearly all women are treated surgically.

  New Drugs for Old Cancers

  In the story of Patroclus

  No one survives, not even Achilles

  Who was nearly a god.

  Patroclus resembled him; they wore

  The same armor

  --Louise Gluck

  The perfect therapy has not been developed. Most of us believe that it will not involve toxic cytotoxic therapy, which is why we support the kinds of basic investigations that are directed towards more fundamental understanding of tumor biology. But . . . we must do the best with what we now have.

  --Bruce Chabner to Rose Kushner

  In the legend, Achilles was quickly dipped into the river Styx, held up only by the tendon of his heel. Touched by the dark sheath of water, every part of his body was instantly rendered impervious to even the most lethal weapon--except the undipped tendon. A simple arrow targeted to that vulnerable heel would eventually kill Achilles in the battlefields of Troy.

  Before the 1980s, the armamentarium of cancer therapy was largely built around two fundamental vulnerabilities of cancer cells. The first is that most cancers originate as local diseases before they spread systemically. Surgery and radiation therapy exploit this vulnerability. By physically excising locally restricted tumors before cancer cells can spread--or by searing cancer cells with localized bursts of powerful energy using X-rays--surgery and radiation attempt to eliminate cancer en bloc from the body.

  The second vulnerability is the rapid growth rate of cancer cells. Most chemotherapy drugs discovered before the 1980s target this second vulnerability. Antifolates, such as Farber's aminopterin, interrupt the metabolism of folic acid and starve all cells of a crucial nutrient required for cell division. Nitrogen mustard and cisplatin chemically react with DNA, and DNA-damaged cells cannot duplicate their genes and thus cannot divide. Vincristine, the periwinkle poison, thwarts the ability of a cell to construct the molecular "scaffold" required for all cells to divide.

  But these two traditional Achilles' heels of cancer--local growth and rapid cell division--can only be targeted to a point. Surgery and radiation are intrinsically localized strategies, and they fail when cancer cells have spread beyond the limits of what can be surgically removed or irradiated. More surgery thus does not lead to more cures, as the radical surgeons discovered to their despair in the 1950s.

  Targeting cellular growth also hits a biological ceiling because normal cells must grow as well. Growth may be the hallmark of can
cer, but it is equally the hallmark of life. A poison directed at cellular growth, such as vincristine or cisplatin, eventually attacks normal growth, and cells that grow most rapidly in the body begin to bear the collateral cost of chemotherapy. Hair falls out. Blood involutes. The lining of the skin and gut sloughs off. More drugs produce more toxicity without producing cures, as the radical chemotherapists discovered to their despair in the 1980s.

  To target cancer cells with novel therapies, scientists and physicians needed new vulnerabilities that were unique to cancer. The discoveries of cancer biology in the 1980s offered a vastly more nuanced view of these vulnerabilities. Three new principles emerged, representing three new Achilles' heels of cancer.

  First, cancer cells are driven to grow because of the accumulation of mutations in their DNA. These mutations activate internal proto-oncogenes and inactivate tumor suppressor genes, thus unleashing the "accelerators" and "brakes" that operate during normal cell division. Targeting these hyperactive genes, while sparing their modulated normal precursors, might be a novel means to attack cancer cells more discriminately.

  Second, proto-oncogenes and tumor suppressor genes typically lie at the hubs of cellular signaling pathways. Cancer cells divide and grow because they are driven by hyperactive or inactive signals in these critical pathways. These pathways exist in normal cells but are tightly regulated. The potential dependence of a cancer cell on such permanently activated pathways is a second potential vulnerability of a cancer cell.

  Third, the relentless cycle of mutation, selection, and survival creates a cancer cell that has acquired several additional properties besides uncontrolled growth. These include the capacity to resist death signals, to metastasize throughout the body, and to incite the growth of blood vessels. These "hallmarks of cancer" are not invented by the cancer cell; they are typically derived from the corruption of similar processes that occur in the normal physiology of the body. The acquired dependence of a cancer cell on these processes is a third potential vulnerability of cancer.