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

by Siddhartha Mukherjee

  For patients such as John Cleland, cisplatin came to epitomize the new breed of aggressive chemotherapeutics of the 1970s. In 1973, Cleland was a twenty-two-year-old veterinary student in Indiana. In August that year, two months after his marriage, he discovered a rapidly expanding lump in his right testis. He saw a urologist on a Tuesday afternoon in November. On Thursday, he was whisked off to the operating room for surgery. He returned with a scar that extended from his abdomen to his breastbone. The diagnosis was metastatic testicular cancer--cancer of the testes that had migrated diffusely into his lymph nodes and lungs.

  In 1973, the survival rate from metastatic testes cancer was less than 5 percent. Cleland entered the cancer ward at Indiana University and began treatment with a young oncologist named Larry Einhorn. The regimen, a weather-beaten and toxic three-drug cocktail called ABO that had been derived from the NCI's studies in the 1960s--was only marginally effective. Cleland lived in and out of the hospital. His weight shrank from 158 to 106 pounds. One day in 1974, while he was still receiving chemo, his wife suggested that they sit outside to enjoy the afternoon. Cleland realized, to his utter shame, that he was too weak to stand up. He was carried to his bed like a baby, weeping with embarrassment.

  In the fall of 1974, the ABO regimen was stopped. He was switched to another equally ineffective drug. Einhorn suggested a last-ditch effort: a new chemical called cisplatin. Other researchers had seen some responses in patients with testicular cancer treated with single-agent cisplatin, although not durable ones. Einhorn wanted to combine cisplatin with two other drugs to see if he could increase the response rate.

  There was the uncertainty of a new combination and the certainty of death. On October 7, 1974, Cleland took the gamble: he enrolled as "patient zero" for BVP, the acronym for a new regimen containing bleomycin, vinblastine, and cisplatin (abbreviated P for "platinum"). Ten days later, when he returned for his routine scans, the tumors in his lungs had vanished. Ecstatic and mystified, he called his wife from a hospital phone. "I cannot remember what I said, but I told her."

  Cleland's experience was typical. By 1975, Einhorn had treated twenty additional patients with the regimen and found dramatic and sustained responses virtually unheard of in the history of this disease. Einhorn presented his data at the annual meeting of oncologists held in Toronto in the winter of 1975. "Walking up to that podium was like my own walk on the moon," he recalled. By the late winter of 1976, it was becoming progressively clearer that some of these patients would not relapse at all. Einhorn had cured a solid cancer by chemotherapy. "It was unforgettable. In my own naive mind I thought this was the formula that we had been missing all the while."

  Cisplatin was unforgettable in more than one sense. The drug provoked an unremitting nausea, a queasiness of such penetrating force and quality that had rarely been encountered in the history of medicine: on average, patients treated with the drug vomited twelve times a day. (In the 1970s, there were few effective antinausea drugs. Most patients had to be given intravenous fluids to tide them through the nausea; some survived by smuggling marijuana, a mild antiemetic, into the chemotherapy wards.) In Margaret Edson's play Wit, a scathing depiction of a woman's battle with ovarian cancer, an English professor undergoing chemotherapy clutches a nausea basin on the floor of her hospital ward, dry-heaving in guttural agony (prompting her unforgettable aside, "You may think my vocabulary has taken a turn for the Anglo-Saxon"). The pharmacological culprit lurking unmentioned behind that scene is cisplatin. Even today, nurses on oncology floors who tended to patients in the early 1980s (before the advent of newer antiemetics that would somewhat ease the effect of the drug) can vividly recollect the violent jolts of nausea that suddenly descended on patients and brought them dry-heaving to the ground. In nursing slang, the drug came to be known as "cisflatten."

  These side effects, however revolting, were considered minor dues to pay for an otherwise miraculous drug. Cisplatin was touted as the epic chemotherapeutic product of the late 1970s, the quintessential example of how curing cancer involved pushing patients nearly to the brink of death. By 1978, cisplatin-based chemotherapy was the new vogue in cancer pharmacology; every conceivable combination was being tested on thousands of patients across America. The lemon-yellow chemical dripping through intravenous lines was as ubiquitous in the cancer wards as the patients clutching their nausea basins afterward.

  The NCI meanwhile was turning into a factory of toxins. The influx of money from the National Cancer Act had potently stimulated the institute's drug-discovery program, which had grown into an even more gargantuan effort and was testing hundreds of thousands of chemicals each year to discover new cytotoxic drugs. The strategy of discovery was empirical--throwing chemicals at cancer cells in test tubes to identify cancer killers--but, by now, unabashedly and defiantly so. The biology of cancer was still poorly understood. But the notion that even relatively indiscriminate cytotoxic agents discovered largely by accident would cure cancer had captivated oncology. "We want and need and seek better guidance and are gaining it," Howard Skipper (Frei and Freireich's collaborator on the early leukemia studies) admitted in 1971, "but we cannot afford to sit and wait for the promise of tomorrow so long as stepwise progress can be made with tools at hand today." Ehrlich's seductive phrase--"magic bullet"--had seemingly been foreshortened. What this war needed was simply "bullets," whether magical or not, to annihilate cancer.

  Chemicals thus came pouring out of the NCI's cauldrons, each one with a unique personality. There was Taxol, one gram purified from the bark of a hundred Pacific yew trees, whose molecular structure resembled a winged insect. Adriamycin, discovered in 1969, was bloodred (it was the chemical responsible for the orange-red tinge that Alsop had seen at the NCI's cancer ward); even at therapeutic doses, it could irreversibly damage the heart. Etoposide came from the fruit of the poisonous mayapple. Bleomycin, which could scar lungs without warning, was an antibiotic derived from a mold.

  "Did we believe we were going to cure cancer with these chemicals?" George Canellos recalled. "Absolutely, we did. The NCI was a charged place. The chief [Zubrod] wanted the boys to move into solid tumors. I proposed ovarian cancer. Others proposed breast cancer. We wanted to get started on the larger clinical problems. We spoke of curing cancer as if it was almost a given."

  In the mid-1970s, high-dose combination chemotherapy scored another sentinel victory. Burkitt's lymphoma, the tumor originally discovered in southern Africa (and rarely found in children and adolescents in America and Europe), was cured with a cocktail of seven drugs, including a molecular cousin of nitrogen mustard--a regimen concocted at the NCI by Ian Magrath and John Ziegler.* The felling of yet another aggressive tumor by combination chemotherapy even more potently boosted the institute's confidence--once again underscoring the likelihood that the "generic solution" to cancer had been found.

  Events outside the world of medicine also impinged on oncology, injecting new blood and verve into the institute. In the early 1970s, young doctors who opposed the Vietnam War flooded to the NCI. (Due to an obscure legal clause, enrollment in a federal research program, such as the NIH, exempted someone from the draft.) The undrafted soldiers of one battle were thus channeled into another. "Our applications skyrocketed. They were brilliant and energetic, these new fellows at the institute," Canellos said. "They wanted to run new trials, to test new permutations of drugs. We were a charged place." At the NCI and in its academic outposts around the world, the names of regimens evolved into a language of their own: ABVD, BEP, C-MOPP, ChlaVIP, CHOP, ACT.

  "There is no cancer that is not potentially curable," an ovarian cancer chemotherapist self-assuredly told the media at a conference in 1979. "The chances in some cases are infinitesimal, but the potential is still there. This is about all that patients need to know and it is about all that patients want to know."

  The greatly expanded coffers of the NCI also stimulated enormous, expensive, multi-institutional trials, allowing academic centers to trot out ever more powerful
permutations of cytotoxic drugs. Cancer hospitals, also boosted by the NCI's grants, organized themselves into efficient and thrumming trial-running machines. By 1979, the NCI had recognized twenty so-called Comprehensive Cancer Centers spread across the nation--hospitals with large wards dedicated exclusively to cancer--run by specialized teams of surgeons and chemotherapists and supported by psychiatrists, pathologists, radiologists, social workers, and ancillary staff. Hospital review boards that approved and coordinated human experimentation were revamped to allow researchers to bulldoze their way through institutional delays.

  It was trial and error on a giant human scale--with the emphasis, it seemed at times, distinctly on error. One NCI-sponsored trial tried to outdo Einhorn by doubling the dose of cisplatin in testicular cancer. Toxicity doubled, although there was no additional therapeutic effect. In another particularly tenacious trial, known as the eight-in-one study, children with brain tumors were given eight drugs in a single day. Predictably, horrific complications ensued. Fifteen percent of the patients needed blood transfusions. Six percent were hospitalized with life-threatening infections. Fourteen percent of the children suffered kidney damage; three lost their hearing. One patient died of septic shock. Yet, despite the punishing escalation of drugs and doses, the efficacy of the drug regimen remained minimal. Most of the children in the eight-in-one trial died soon afterward, having only marginally responded to chemotherapy.

  This pattern was repeated with tiresome regularity for many forms of cancer. In metastatic lung cancer, for instance, combination chemotherapy was found to increase survival by three or four months; in colon cancer, by less than six months; in breast, by about twelve. (I do not mean to belittle the impact of twelve or thirteen months of survival. One extra year can carry a lifetime of meaning for a man or woman condemned to death from cancer. But it took a particularly fanatical form of zeal to refuse to recognize that this was far from a "cure.") Between 1984 and 1985, at the midpoint of the most aggressive expansion of chemotherapy, nearly six thousand articles were published on the subject in medical journals. Not a single article reported a new strategy for the definitive cure of an advanced solid tumor by means of combination chemotherapy alone.

  Like lunatic cartographers, chemotherapists frantically drew and redrew their strategies to annihilate cancer. MOPP, the combination that had proved successful in Hodgkin's disease, went through every conceivable permutation for breast, lung, and ovarian cancer. More combinations entered clinical trials--each more aggressive than its precursor and each tagged by its own cryptic, nearly indecipherable name. Rose Kushner (by then, a member of the National Cancer Advisory Board) warned against the growing disconnect between doctors and their patients. "When doctors say that the side effects are tolerable or acceptable, they are talking about life-threatening things," she wrote. "But if you just vomit so hard that you break the blood vessels in your eyes . . . they don't consider that even mentionable. And they certainly don't care if you're bald." She wrote sarcastically, "The smiling oncologist does not know whether his patients vomit or not."

  The language of suffering had parted, with the "smiling oncologist" on one side and his patients on the other. In Edson's Wit--a work not kind to the medical profession--a young oncologist, drunk with the arrogance of power, personifies the divide as he spouts out lists of nonsensical drugs and combinations while his patient, the English professor, watches with mute terror and fury: "Hexamethophosphacil with Vinplatin to potentiate. Hex at three hundred mg per meter squared. Vin at one hundred. Today is cycle two, day three. Both cycles at the full dose."

  * Many of these NCI-sponsored trials were carried out in Uganda, where Burkitt's lymphoma is endemic in children.

  Knowing the Enemy

  It is said that if you know your enemies and know yourself, you will not be imperiled in a hundred battles; if you do not know your enemies but do know yourself, you will win one and lose one; if you do not know your enemies nor yourself, you will be imperiled in every single battle.

  --Sun Tzu

  As the armada of cytotoxic therapy readied itself for even more aggressive battles against cancer, a few dissenting voices began to be heard along its peripheries. These voices were connected by two common themes.

  First, the dissidents argued that indiscriminate chemotherapy, the unloading of barrel after barrel of poisonous drugs, could not be the only strategy by which to attack cancer. Contrary to prevailing dogma, cancer cells possessed unique and specific vulnerabilities that rendered them particularly sensitive to certain chemicals that had little impact on normal cells.

  Second, such chemicals could only be discovered by uncovering the deep biology of every cancer cell. Cancer-specific therapies existed, but they could only be known from the bottom up, i.e., from solving the basic biological riddles of each form of cancer, rather than from the top down, by maximizing cytotoxic chemotherapy or by discovering cellular poisons empirically. To attack a cancer cell specifically, one needed to begin by identifying its biological behavior, its genetic makeup, and its unique vulnerabilities. The search for magic bullets needed to begin with an understanding of cancer's magical targets.

  The most powerful such voice arose from the most unlikely of sources, a urological surgeon, Charles Huggins, who was neither a cell biologist nor even a cancer biologist, but rather a physiologist interested in glandular secretions. Born in Nova Scotia in 1901, Huggins attended Harvard Medical School in the early 1920s (where he intersected briefly with Farber) and trained as a general surgeon in Michigan. In 1927, at age twenty-six, he was appointed to the faculty of the University of Chicago as a urological surgeon, a specialist in diseases of the bladder, kidney, genitals, and prostate.

  Huggins's appointment epitomized the confidence (and hubris) of surgery: he possessed no formal training in urology, nor had he trained as a cancer surgeon. It was an era when surgical specialization was still a fluid concept; if a man could remove an appendix or a lymph node, the philosophy ran, he could certainly learn to remove a kidney. Huggins thus learned urology on the fly by cramming a textbook in about six weeks. He arrived optimistically in Chicago, expecting to find a busy, flourishing practice. But his new clinic, housed inside a stony neo-Gothic tower, remained empty all winter. (The fluidity of surgical specialization was, perhaps, not as reassuring to patients.) Tired of memorizing books and journals in an empty, drafty waiting room, Huggins changed tracks and set up a laboratory to study urological diseases while waiting for patients to come to his clinic.

  To choose a medical specialty is also to choose its cardinal bodily liquid. Hematologists have blood. Hepatologists have bile. Huggins had prostatic fluid: a runny, straw-colored mixture of salt and sugar meant to lubricate and nourish sperm. Its source, the prostate, is a small gland buried deep in the perineum, wrapped around the outlet of the urinary tract in men. (Vesalius was the first to identify it and draw it into human anatomy.) Walnut-shaped and only walnut-sized, it is yet ferociously the site of cancer. Prostate cancer represents a full third of all cancer incidence in men--sixfold that of leukemia and lymphoma. In autopsies of men over sixty years old, nearly one in every three specimens will bear some evidence of prostatic malignancy.

  But although an astoundingly common form of cancer, prostate cancer is also highly variable in its clinical course. Most cases are indolent--elderly men usually die with prostate cancer than die of prostate cancer--but in other patients the disease can be aggressive and invasive, capable of exploding into painful lesions in the bones and lymph nodes in its advanced, metastatic form.

  Huggins, though, was far less interested in cancer than in the physiology of prostatic fluid. Female hormones, such as estrogen, were known to control the growth of breast tissue. Did male hormones, by analogy, control the growth of the normal prostate--and thus regulate the secretion of its principal product, prostatic fluid? By the late 1920s, Huggins had devised an apparatus to collect precious drops of prostatic fluid from dogs. (He diverted urine away by inserting a catheter i
nto the bladder and stitched a collection tube to the exit of the prostate gland.) It was the only surgical innovation that he would devise in his lifetime.

  Huggins now had a tool to measure prostatic function; he could quantify the amount of fluid produced by the gland. He found that if he surgically removed the testicles of his dogs--and thereby depleted the dogs of the hormone testosterone--the prostate gland involuted and shriveled and the fluid secretion dried up precipitously. If he injected the castrated dogs with purified testosterone, the exogenous hormone saved the prostate from shriveling. Prostate cells were thus acutely dependent on the hormone testosterone for their growth and function. Female sexual hormones kept breast cells alive; male hormones had a similar effect on prostate cells.

  Huggins wanted to delve further into the metabolism of testosterone and the prostate cell, but his experiments were hampered by a peculiar problem. Dogs, humans, and lions are the only animals known to develop prostate cancer, and dogs with sizable prostate tumors kept appearing in his lab during his studies. "It was vexatious to encounter a dog with a prostatic tumor during a metabolic study," he wrote. His first impulse was to cull the cancer-afflicted dogs from his study and continue single-mindedly with his fluid collection, but then a question formed in his mind. If testosterone deprivation could shrink normal prostate cells, what might testosterone deprivation do to cancer cells?

  The answer, as any self-respecting cancer biologist might have informed him, was almost certain: very little. Cancer cells, after all, were deranged, uninhibited, and altered--responsive only to the most poisonous combinations of drugs. The signals and hormones that regulated normal cells had long been flung aside; what remained was a cell driven to divide with such pathological and autonomous fecundity that it had erased all memory of normalcy.