PART THREE
Oft expectation fails, and most oft there
Where most it promises; and oft it hits
Where hope is coldest, and despair most sits
—William Shakespeare,
All’s Well That Ends Well
I have seen the moment of my greatness flicker
And I have seen the eternal Footman hold my coat, and snicker,
And in short, I was afraid.
—T. S. Eliot
You are absolutely correct, of course, when you say that we can’t go on asking for more money from the President unless we demonstrate progress.
—Frank Rauscher, director of
the National Cancer Program,
to Mary Lasker, 1974
“In God we trust.
All others [must] have data”
In science, ideology tends to corrupt; absolute ideology, [corrupts] absolutely.
—Robert Nisbet
Orthodoxy in surgery is like orthodoxy in other departments of the mind—it . . . begins to almost challenge a comparison with religion.
—Geoffrey Keynes
You mean I had a mastectomy for nothing?
—Rose Kushner
Farber was fortunate to have lived in the right time, but he was perhaps even more fortunate to have died at the right time. The year of his death, 1973, marked the beginning of a deeply fractured and contentious period in the history of cancer. Theories were shattered; drug discoveries stagnated; trials languished; and academic meetings degenerated into all-out brawls. Radiotherapists, chemotherapists, and surgeons fought viciously for power and information. The War on Cancer seemed, at times, to have devolved into a war within cancer.
The unraveling began at the very center of oncology. Radical surgery, Halsted’s cherished legacy, had undergone an astonishing boom in the 1950s and ’60s. At surgical conferences around the world, Halsted’s descendants—powerful and outspoken surgeons such as Cushman Haagensen and Jerome Urban—had stood up to announce that they had outdone the master himself in their radicalism. “In my own surgical attack on carcinoma of the breast,” Haagensen wrote in 1956, “I have followed the fundamental principle that the disease, even in its early stage, is such a formidable enemy that it is my duty to carry out as radical an operation as the . . . anatomy permits.”
The radical mastectomy had thus edged into the “superradical” and then into the “ultraradical,” an extraordinarily morbid, disfiguring procedure in which surgeons removed the breast, the pectoral muscles, the axillary nodes, the chest wall, and occasionally the ribs, parts of the sternum, the clavicle, and the lymph nodes inside the chest.
Halsted, meanwhile, had become the patron saint of cancer surgery, a deity presiding over his comprehensive “theory” of cancer. He had called it, with his Shakespearean ear for phrasemaking, the “centrifugal theory”—the idea that cancer, like a malevolent pinwheel, tended to spread in ever-growing arcs from a single central focus in the body. Breast cancer, he claimed, spun out from the breast into the lymph nodes under the arm (poetically again, he called these nodes “sentinels”), then cartwheeled mirthlessly through the blood into the liver, lungs, and bones. A surgeon’s job was to arrest that centrifugal spread by cutting every piece of it out of the body, as if to catch and break the wheel in midspin. This meant treating early breast cancer aggressively and definitively. The more a surgeon cut, the more he cured.
Even for patients, that manic diligence had become a form of therapy. Women wrote to their surgeons in admiration and awe, begging them not to spare their surgical extirpations, as if surgery were an anagogical ritual that would simultaneously rid them of cancer and uplift them into health. Haagensen transformed from surgeon to shaman: “To some extent,” he wrote about his patients, “no doubt, they transfer the burden [of their disease] to me.” Another surgeon wrote—chillingly—that he sometimes “operated on cancer of the breast solely for its effect on morale.” He also privately noted, “I do not despair of carcinoma being cured somewhere in the future, but this blessed achievement will, I believe, never be wrought by the knife of the surgeon.”
Halsted may have converted an entire generation of physicians in America to believe in the “blessed achievement” of his surgical knife. But the farther one got from Baltimore, the less, it seemed, was the force of his centrifugal theory; at St. Bartholomew’s Hospital in London, a young doctor named Geoffrey Keynes was not so convinced.
In August 1924, Keynes examined a patient with breast cancer, a thin, emaciated woman of forty-seven with an ulcerated malignant lump in her breast. In Baltimore or in New York, such a patient would immediately have been whisked off for radical surgery. But Keynes was concerned about his patient’s constitutional frailty. Rather than reaching indiscriminately for a radical procedure (which would likely have killed her at the operating table), he opted for a much more conservative strategy. Noting that radiation therapists, such as Emil Grubbe, had demonstrated the efficacy of X-rays in treating breast cancer, Keynes buried fifty milligrams of radium in her breast to irradiate her tumor and monitored her to observe the effect, hoping, at best, to palliate her symptoms. Surprisingly, he found a marked improvement. “The ulcer rapidly heal[ed],” he wrote, “and the whole mass [became] smaller, softer and less fixed.” Her mass reduced so rapidly, Keynes thought he might be able to perform a rather minimal, nonradical surgery on her to completely remove it.
Emboldened by his success, between 1924 and 1928, Keynes attempted other variations on the same strategy. The most successful of these permutations, he found, involved a careful mixture of surgery and radiation, both at relatively small doses. He removed the malignant lumps locally with a minor operation (i.e., without resorting to radical or ultraradical surgery). He followed the surgery with radiation to the breast. There was no stripping of nodes, no cracking or excavation of clavicles, no extirpations that stretched into six or eight hours. Nothing was radical, yet, in case after case, Keynes and his colleagues found that their cancer recurrence rate was at least comparable to those obtained in New York or Baltimore—achieved without grinding patients through the terrifying crucible of radical surgery.
In 1927, in a rather technical report to his department, Keynes reviewed his experience combining local surgery with radiation. For some cases of breast cancer, he wrote, with characteristic understatement, the “extension of [the] operation beyond a local removal might sometimes be unnecessary.” Everything about Keynes’s sentence was carefully, strategically, almost surgically constructed. Its implication was enormous. If local surgery resulted in the same outcome as radical surgery, then the centrifugal theory had to be reconsidered. Keynes had slyly declared war on radical surgery, even if he had done so by pricking it with a pin-size lancet.
But Halsted’s followers in America laughed away Keynes’s efforts. They retaliated, by giving his operation a nickname: the lumpectomy. The name was like a low-minded joke, a cartoon surgery in which a white-coated doctor pulls out a body part and calls it a “lump.” Keynes’s theory and operation were largely ignored by American surgeons. He gained fame briefly in Europe as a pioneer of blood transfusions during the First World War, but his challenge to radical surgery was quietly buried.
Keynes would have remained conveniently forgotten by American surgeons except for a fateful series of events. In 1953, a colleague of Keynes’s, on sabbatical from St. Bart’s at the Cleveland Clinic in Ohio, gave a lecture on the history of breast cancer, focusing on Keynes’s observations on minimal surgery for the breast. In the audience that evening was a young surgeon named George Barney Crile. Crile and Keynes had never met, but they shared old intellectual debts. Crile’s father, George Crile Sr., had pioneered the use of blood transfusions in America and written a widely read textbook on the subject. During the First World War, Keynes had learned to transfuse blood in sterilized, cone-shaped glass vessels—an apparatus devised, in part, by the elder Dr. Crile.
Political revolutions, the writer Amitav Ghosh writes, often occur in the courtyards of palaces, in spaces on the cusp of power, located neither outside nor inside. Scientific revolutions, in contrast, typically occur in basements, in buried-away places removed from mainstream corridors of thought. But a surgical revolution must emanate from within surgery’s inner sanctum—for surgery is a profession intrinsically sealed to outsiders. To even enter the operating theater, one must be soused in soap and water, and surgical tradition. To change surgery, one must be a surgeon.
The Criles, father and son, were quintessential surgical insiders. The elder Crile, an early proponent of radical surgery, was a contemporary of Halsted’s. The younger had learned the radical mastectomy from students of Halsted himself. The Criles were steeped in Halstedian tradition, upholding the very pole staffs of radical surgery for generations. But like Keynes in London, Crile Jr. was beginning to have his own doubts about the radical mastectomy. Animal studies performed in mice (by Skipper in Alabama, among others) had revealed that tumors implanted in animals did not behave as Halsted might have imagined. When a large tumor was grown in one site, microscopic metastatic deposits from it often skipped over the local nodes and appeared in faraway places such as the liver and the spleen. Cancer didn’t move centrifugally by whirling through larger and larger ordered spirals; its spread was more erratic and unpredictable. As Crile pored through Keynes’s data, the old patterns suddenly began to make sense: Hadn’t Halsted also observed that patients had died four or five years after radical surgery from “occult” metastasis? Could breast cancer in these patients also have metastasized to faraway organs even before radical surgery?
The flaw in the logic began to crystallize. If the tumor was locally confined to start with, Crile argued, then it would be adequately removed by local surgery and radiation, and manically stripping away extra nodes and muscles could add no possible benefit. In contrast, if breast cancer had already spread outside the breast, then surgery would be useless anyway, and more aggressive surgery would simply be more aggressively useless. Breast cancer, Crile realized, was either an inherently localized disease—thus curable by a smaller mastectomy—or an inherently systemic disease—thus incurable even by the most exhaustive surgery.
Crile soon gave up on the radical mastectomy altogether and, instead, began to operate in a manner similar to Keynes’s, using a limited surgical approach (Crile called it the “simple mastectomy”). Over about six years, he found that his “simple” operation was remarkably similar to Keynes’s lumpectomy+radiation combination in its impact: the survival rate of patients treated with either form of local surgery tended to be no different from that of those treated historically with the radical mastectomy. Separated by an ocean and forty years of clinical practice, both Keynes and Crile had seemingly stumbled on the same clinical truth.
But was it a truth? Keynes had had no means to prove it. Until the 1930s, clinical trials had typically been designed to prove positive results: treatment A was better than treatment B, or drug X superior to drug Y. But to prove a negative result—that radical surgery was no better than conventional surgery—one needed a new set of statistical measures.
The invention of that measure would have a profound influence on the history of oncology, a branch of medicine particularly suffused with hope (and thus particularly prone to unsubstantiated claims of success). In 1928, four years after Keynes had begun his lumpectomies in London, two statisticians, Jerzy Neyman and Egon Pearson, provided a systematic method to evaluate a negative statistical claim. To measure the confidence in a negative claim, Neyman and Pearson invoked a statistical concept called power. “Power” in simplistic terms, is a measure of the ability of a test or trial to reject a hypothesis. Intuitively, Neyman and Pearson reasoned that a scientist’s capacity to reject a hypothesis depends most critically on how intensively he has tested the hypothesis—and thus, on the number of samples that have independently been tested. If one compares five radical mastectomies against five conventional mastectomies and finds no difference in outcome, it is hard to make a significant conclusion about the result. But if a thousand cases of each produce precisely identical outcomes, then one can make a strong claim about a lack of benefit.
Right there, buried inside that dependence, lies one of the strangest pitfalls of medicine. For any trial to be adequately “powered,” it needs to recruit an adequate number of patients. But to recruit patients, a trialist has to convince doctors to participate in the trial—and yet these doctors are often precisely those who have the least interest in having a theory rejected or disproved. For breast cancer, a discipline immersed in the legacy of the radical surgery, these conflicts were particularly charged. No breast cancer trial, for instance, could have proceeded without the explicit blessing and participation of larger-than-life surgeons such as Haagensen and Urban. Yet these surgeons, all enraptured intellectual descendants of Halsted, were the least likely to sponsor a trial that might dispute the theory that they had so passionately advocated for decades. When critics wondered whether Haagensen had been biased in his evaluation by selecting only his best cases, he challenged surgeons to replicate his astounding success using their own alternative methods: “Go thou and do likewise.”
Thus even Crile—a full forty years after Keynes’s discovery—couldn’t run a trial to dispute Halsted’s mastectomy. The hierarchical practice of medicine, its internal culture, its rituals of practice (“The Gospel[s] of the Surgical Profession,” as Crile mockingly called it), were ideally arranged to resist change and to perpetuate orthodoxy. Crile found himself pitted against his own department, against friends and colleagues. The very doctors that he would need to recruit to run such a trial were fervently, often viciously, opposed to it. “Power,” in the colloquial sense of the word, thus collided with “power” in the statistical sense. The surgeons who had so painstakingly created the world of radical surgery had absolutely no incentive to revolutionize it.
It took a Philadelphia surgeon named Bernard Fisher to cut through that knot of surgical tradition. Fisher was brackish, ambitious, dogged, and feisty—a man built after Halsted’s image. He had trained at the University of Pittsburgh, a place just as steeped in the glorious Halstedian tradition of radical surgery as the hospitals of New York and Baltimore. But he came from a younger generation of surgeons—a generation with enough critical distance from Halsted to be able to challenge the discipline without undermining its own sense of credibility. Like Crile and Keynes, he, too, had lost faith in the centrifugal theory of cancer. The more he revisited Keynes’s and Crile’s data, the more Fisher was convinced that radical mastectomy had no basis in biological reality. The truth, he suspected, was quite the opposite. “It has become apparent that the tangled web of threads on the wrong side of the tapestry really represented a beautiful design when examined properly, a meaningful pattern, a hypothesis . . . diametrically opposite to those considered to be ‘halstedian,’” Fisher wrote.
The only way to turn the upside-down tapestry of Halstedian theory around was to run a controlled clinical trial to test the radical mastectomy against the simple mastectomy and lumpectomy+radiation. But Fisher also knew that resistance would be fierce to any such trial. Holed away in their operating rooms, their slip-covered feet dug into the very roots of radical surgery, most academic surgeons were least likely to cooperate.
But another person in that operating room was stirring awake: the long-silent, etherized body lying at the far end of the scalpel—the cancer patient. By the late 1960s, the relationship between doctors and patients had begun to shift dramatically. Medicine, once considered virtually infallible in its judgment, was turning out to have deep fallibilities—flaws that appeared to cluster pointedly around issues of women’s health. Thalidomide, prescribed widely to control pregnancy-associated “hysteria” and “anxiety,” was hastily withdrawn from the market in 1961 because of its propensity to cause severe fetal malformations. In Texas, Jane Roe (a pseudonym) sued the state for blocking her ability to abort her fetus at a medical clinic—launching the Roe v. Wade case on abortion and highlighting the complex nexus between the state, medical authority, and women’s bodies. Political feminism, in short, was birthing medical feminism—and the fact that one of the most common and most disfiguring operations performed on women’s bodies had never been formally tested in a trial stood out as even more starkly disturbing to a new generation of women. “Refuse to submit to a radical mastectomy,” Crile exhorted his patients in 1973.
And refuse they did. Rachel Carson, the author of Silent Spring and a close friend of Crile’s, refused a radical mastectomy (in retrospect, she was right: her cancer had already spread to her bones and radical surgery would have been pointless). Betty Rollin and Rose Kushner also refused and soon joined Carson in challenging radical surgeons. Rollin and Kushner—both marvelous writers: provocative, down-to-earth, no-nonsense, witty—were particularly adept at challenging the bloated orthodoxy of surgery. They flooded newspapers and magazines with editorials and letters and appeared (often uninvited) at medical and surgical conferences, where they fearlessly heckled surgeons about their data and the fact that the radical mastectomy had never been put to a test. “Happily for women,” Kushner wrote, “. . . surgical custom is changing.” It was as if the young woman in Halsted’s famous etching—the patient that he had been so “loathe to disfigure”—had woken up from her gurney and begun to ask why, despite his “loathing,” the cancer surgeon was so keen to disfigure her.
In 1967, bolstered by the activism of patients and the public attention swirling around breast cancer, Fisher became the new chair of the National Surgical Adjuvant Breast and Bowel Project (NSABP), a consortium of academic hospitals modeled self-consciously after Zubrod’s leukemia group that would run large-scale trials in breast cancer. Four years later, the NSABP proposed to test the operation using a systematic, randomized trial. It was, coincidentally, the eightieth “anniversary” of Halsted’s original description of the radical mastectomy. The implicit, nearly devotional faith in a theory of cancer was finally to be put to a test. “The clinician, no matter how venerable, must accept the fact that experience, voluminous as it might be, cannot be employed as a sensitive indicator of scientific validity,” Fisher wrote in an article. He was willing to have faith in divine wisdom, but not in Halsted as divine wisdom. “In God we trust,” he brusquely told a journalist. “All others [must] have data.”
It took Fisher a full ten years to actually gather that data. Recruiting patients for his study was an uphill task. “To get a woman to participate in a clinical trial where she was going to have her breast off or have her breast not taken off, that was a pretty difficult thing to do. Not like testing Drug A versus Drug B,” he recalled.
If patients were reluctant, surgeons were almost impossibly so. Immersed in the traditions of radical surgery, many American surgeons put up such formidable barriers to patient recruitment that Canadian surgeons and their patients were added to complete the study. The trial recruited 1,765 patients in thirty-four centers in the United States and Canada. Patients were randomized into three groups: one treated with the radical mastectomy, the second with simple mastectomy, and the third with surgery followed by radiation. Even with all forces in gear, it still took years to recruit adequate numbers. Crippled by forces within surgery itself, the NSABP-04 trial barely hobbled to its end.
In 1981, the results of the trial were finally made public. The rates of breast cancer recurrence, relapse, death, and distant cancer metastasis were statistically identical among all three groups. The group treated with the radical mastectomy had paid heavily in morbidity, but accrued no benefits in survival, recurrence, or mortality.
Between 1891 and 1981, in the nearly one hundred years of the radical mastectomy, an estimated five hundred thousand women underwent the procedure to “extirpate” cancer. Many chose the procedure. Many were forced into it. Many others did not even realize that it was a choice. Many were permanently disfigured; many perceived the surgery as a benediction; many suffered its punishing penalties bravely, hoping that they had treated their cancer as aggressively and as definitively as possible. Halsted’s “cancer storehouse” grew far beyond its original walls at Hopkins. His ideas entered oncology, then permeated its vocabulary, then its psychology, its ethos, and its self-image. When radical surgery fell, an entire culture of surgery thus collapsed with it. The radical mastectomy is rarely, if ever, performed by surgeons today.
“The smiling oncologist”
Few doctors in this country seem to be involved with the non-life-threatening side effects of cancer therapy. . . . In the United States, baldness, nausea and vomiting, diarrhea, clogged veins, financial problems, broken marriages, disturbed children, loss of libido, loss of self-esteem, and body image are nurses’ turf.
—Rose Kushner
And it is solely by risking life that freedom is obtained.
—Hegel
The ominous toppling of radical surgery off its pedestal may have given cancer chemotherapists some pause for reckoning. But they had their own fantasy of radicalism to fulfill, their own radical arsenal to launch against cancer. Surgery, the traditional battle-ax against cancer, was considered too primitive, too indiscriminate, and too weary. A “large-scale chemotherapeutic attack,” as one doctor put it, was needed to obliterate cancer.
Every battle needs its iconic battleground, and if one physical place epitomized the cancer wars of the late 1970s, it was the chemotherapy ward. It was “our trench and our bunker,” a chemotherapist recalls, a space marked indelibly in the history of cancer. To enter the ward was to acquire automatic citizenship—as Susan Sontag might have put it—into the kingdom of the ill.
The journalist Stewart Alsop was confined to one such ward at the NIH in 1973 for the treatment of a rare and unidentifiable blood cancer. Crossing its threshold, he encountered a sanitized vision of hell. “Wandering about the NIH clinical center, in the corridors or in the elevator, one comes occasionally on a human monster, on a living nightmare, on a face or body hideously deformed,” he wrote. Patients, even disguised in “civilian” clothes, could still be identified by the orange tinge that chemotherapy left on their skin, underneath which lurked the unique pallor of cancer-related anemia. The space was limbolike, with no simple means of egress—no exit. In the glass-paneled sanatorium where patients walked for leisure, Alsop recalled, the windows were covered in heavy wire mesh to prevent the men and women confined in the wards from jumping off the banisters and committing suicide.
A collective amnesia prevailed in these wards. If remembering was an essential requisite for survival, then so was forgetting. “Although this was a cancer ward,” an anthropologist wrote, “the word ‘cancer’ was actively avoided by staff and patients.” Patients lived by the regulations—“accepted roles, a predetermined routine, constant stimuli.” The artifice of manufactured cheer (a requirement for soldiers in battle) made the wards even more poignantly desolate: in one wing, where a woman lay dying from breast cancer, there were “yellow and orange walls in the corridors; beige and white stripes in the patients’ rooms.” At the NIH, in an attempt to inject optimism into the wards, the nurses wore uniforms with plastic yellow buttons with the cartoonish outline of a smiling face.
These wards created not just a psychological isolation chamber but also a physical microenvironment, a sterile bubble where the core theory of cancer chemotherapy—eradicating cancer with a death-defying bombardment of drugs—could be adequately tested. It was, undeniably, an experiment. At the NIH, Alsop wrote pointedly, “Saving the individual patient is not the essential mission. Enormous efforts are made to do so, or at least to prolong the patient’s life to the last possible moment. But the basic purpose is not to save that patient’s particular life but to find means of saving the lives of others.”
In some cases, the experiment worked. In 1976, the year that the NSABP-04 trial struggled to its midpoint, a novel drug, cisplatin, appeared in the cancer wards. Cisplatin—short for cis-platinum—was a new drug forged out of an old one. Its molecular structure, a central planar platinum atom with four “arms” extending outward, had been described back in the 1890s. But chemists had never found an application for cisplatin: the beautiful, satisfyingly symmetric chemical structure had no obvious human use. It had been shelved away in the laboratory in relative obscurity. No one had bothered to test its biological effects.
In 1965, at Michigan State University, a biophysicist, Barnett Rosenberg, began to investigate whether electrical currents might stimulate bacterial cell division. Rosenberg devised a bacterial flask through which an electrical current could be run using two platinum electrodes. When Rosenberg turned the electricity on, he found, astonishingly, that the bacterial cells stopped dividing entirely. Rosenberg initially proposed that the electrical current was the active agent in inhibiting cell division. But the electricity, he soon determined, was merely a bystander. The platinum electrode had reacted with the salt in the bacterial solution to generate a new growth-arresting molecule that had diffused throughout the liquid. That chemical was cisplatin. Like all cells, bacteria need to replicate DNA in order to divide. Cisplatin had chemically attacked DNA with its reactive molecular arms, cross-linking and damaging the molecule irreparably, forcing cells to arrest their division.
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 into 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.
But Huggins knew that certain forms of cancer did not obey this principle. Variants of thyroid cancer, for instance, continued to make thyroid hormone, the growth-stimulating molecule secreted by the normal thyroid gland; even though cancerous, these cells remembered their former selves. Huggins found that prostate cancer cells also retained a physiological “memory” of their origin. When he removed the testicles of prostate cancer–bearing dogs, thus acutely depriving the cancer cells of testosterone, the tumors also involuted within days. In fact, if normal prostate cells were dependent on testosterone for survival, then malignant prostate cells were nearly addicted to the hormone—so much so that the acute withdrawal acted like the most powerful therapeutic drug conceivable. “Cancer is not necessarily autonomous and intrinsically self-perpetuating,” Huggins wrote. “Its growth can be sustained and propagated by hormonal function in the host.” The link between the growth-sustenance of normal cells and of cancer cells was much closer than previously imagined: cancer could be fed and nurtured by our own bodies.
Surgical castration, fortunately, was not the only means to starve prostate cancer cells. If male hormones were driving the growth of these cancer cells, Huggins reasoned, then rather than eliminate the male hormones, what if one tricked the cancer into thinking that the body was “female” by suppressing the effect of testosterone?
In 1929, Edward Doisy, a biochemist, had tried to identify the hormonal factors in the estrous cycle of females. Doisy had collected hundreds of gallons of urine from pregnant women in enormous copper vats, then extracted a few milligrams of a hormone called estrogen. Doisy’s extraction had sparked a race to produce estrogen or its analogue in large quantities. By the mid-1940s, several laboratories and pharmaceutical companies, jostling to capture the market for the “essence of femininity,” raced to synthesize analogues of estrogen or find novel means to purify it efficiently. The two most widely used versions of the drug were diethylstilbestrol (or DES), an artificial estrogen chemically synthesized by biochemists in London, or Premarin, natural estrogen purified from horse’s urine in Montreal. (The synthetic analogue, DES, will return in a more sinister form in subsequent pages.)
Both Premarin (its name derived from pregnant mare urine) and DES were initially marketed as elixirs to cure menopause. But for Huggins, the existence of synthetic estrogens suggested a markedly different use: he could inject them to “feminize” the male body and stop the production of testosterone in patients with prostate cancer. He called the method “chemical castration.” And once again, he found striking responses. As with surgical castration, patients with aggressive prostate cancer chemically castrated with feminizing hormones responded briskly to the therapy, often with minimal side effects. (The most prominent complaint among men was the occurrence of menopause-like hot flashes.) Prostate cancer was not cured with these steroids; patients inevitably relapsed with cancer that had become resistant to hormone therapy. But the remissions, which often stretched into several months, proved that hormonal manipulations could choke the growth of a hormone-dependent cancer. To produce a cancer remission, one did not need a toxic, indiscriminate cellular poison (such as cisplatin or nitrogen mustard).
If prostate cancer could be starved to near-death by choking off testosterone, then could hormonal deprivation be applied to starve another hormone-dependent cancer? There was at least one obvious candidate—breast cancer. In the late 1890s, an adventurous Scottish surgeon named George Beatson, trying to devise new surgical methods to treat breast cancer, had learned from shepherds in the Scottish highlands that the removal of the ovaries from cows altered their capacity to lactate and changed the quality of their udders. Beatson did not understand the basis for this phenomenon (estrogen, the ovarian hormone, had not yet been discovered by Doisy), but intrigued by the inexplicable link between ovaries and breasts, Beatson had surgically removed the ovaries of three women with breast cancer.
In an age before the hormonal circuits between the ovary and the breast were even remotely established, this was unorthodox beyond description—like removing the lung to cure a brain lesion. But to Beatson’s astonishment, his three cases revealed marked responses to the ovarian removal—the breast tumors shrank dramatically. When surgeons in London tried to repeat Beatson’s findings on a larger group of women, though, the operation led to a more nuanced outcome: only about two-thirds of all women with breast cancer responded.
The hit-and-miss quality of the benefit mystified nineteenth-century physiologists. “It is impossible to tell beforehand whether any benefit will result from the operation or not, its effects being quite uncertain,” a surgeon wrote in 1902. How might the surgical removal of a faraway organ affect the growth of cancer? And why, tantalizingly, had only a fraction of cases responded? The phenomenon almost brought back memories of a mysterious humoral factor circulating in the body—of Galen’s black bile. But why was this humoral factor only active in certain women with breast cancer?
Nearly three decades later, Doisy’s discovery of estrogen provided a partial answer to the first question. Estrogen is the principal hormone secreted by the ovaries. As with testosterone for the normal prostate, estrogen was soon demonstrated to be a vital hormone for the maintenance and growth of normal breast tissue. Was breast cancer also fueled by estrogen from the ovaries? If so, what of Beatson’s puzzle: why did some breast cancers shrink with ovarian removal while others remained totally unresponsive?
In the mid-1960s, working closely with Huggins, a young chemist in Chicago, Elwood Jensen, came close to solving Beatson’s riddle. Jensen began his studies not with cancer cells but with the normal physiology of estrogen. Hormones, Jensen knew, typically work by binding to a receptor in a target cell, but the receptor for the steroid hormone estrogen had remained elusive. Using a radioactively labeled version of the hormone as bait, in 1968 Jensen found the estrogen receptor—the molecule responsible for binding estrogen and relaying its signal to the cell.
Jensen now asked whether breast cancer cells also uniformly possessed this receptor. Unexpectedly, some did and some did not. Indeed, breast cancer cases could be neatly divided into two types—ones with cancer cells that expressed high levels of this receptor and those that expressed low levels, “ER-positive” and “ER-negative” tumors.
Jensen’s observations suggested a possible solution to Beatson’s riddle. Perhaps the marked variation of breast cancer cells in response to ovarian removal depended on whether the cancer cells expressed the estrogen receptor or not. ER-positive tumors, possessing the receptor, retained their “hunger” for estrogen. ER-negative tumors had rid themselves of both the receptor and the hormone dependence. ER-positive tumors thus responded to Beatson’s surgery, Jensen proposed, while ER-negative tumors were unresponsive.
The simplest way to prove this theory was to launch an experiment—to perform Beatson’s surgery on women with ER-positive and ER-negative tumors and determine whether the receptor status of the cancer cells was predictive of the response. But the surgical procedure had fallen out of fashion. (Ovarian removal produced many other severe side effects, such as osteoporosis.) An alternative was to use a pharmacological means to inhibit estrogen function, a female version of chemical castration à la Huggins.
But Jensen had no such drug. Testosterone did not work, and no synthetic “antiestrogen” was in development. In their dogged pursuit of cures for menopause and for new contraceptive agents (using synthetic estrogens), pharmaceutical companies had long abandoned the development of an antiestrogen, and there was no interest in developing an antiestrogen for cancer. In an era gripped by the hypnotic promise of cytotoxic chemotherapy, as Jensen put it, “there was little enthusiasm about developing endocrine [hormonal] therapies to treat cancer. Combination chemotherapy was [thought to be] more likely to be successful in curing not only breast cancer but other solid tumors.” Developing an antiestrogen, an antagonist to the fabled elixir of female youth, was widely considered a waste of effort, money, and time.
Scarcely anyone paid notice, then, on September 13, 1962, when a team of talented British chemists from Imperial Chemical Industries (ICI) filed a patent for the chemical named ICI 46474, or tamoxifen. Originally invented as a birth control pill, tamoxifen had been synthesized by a team led by the hormone biologist Arthur Walpole and a synthetic chemist, Dora Richardson, both members of the “fertility control program” at the ICI. But even though structurally designed to be a potent stimulator of estrogen—its winged, birdlike skeleton designed to perch perfectly into the open arms of the estrogen receptor—tamoxifen had turned out to have exactly the opposite effect: rather than turning on the estrogen signal, a requirement for a contraceptive drug, it had, surprisingly, shut it off in many tissues. It was an estrogen antagonist—thus considered a virtually useless drug.
Yet the connection between fertility drugs and cancer preoccupied Walpole. He knew of Huggins’s experiments with surgical castration for prostate cancer. He knew of Beatson’s riddle—almost solved by Jensen. The antiestrogenic properties of his new drug raised an intriguing possibility. ICI 46474 may be a useless contraceptive, but perhaps, he reasoned, it might be useful against estrogen-sensitive breast cancer.
To test that idea, Walpole and Richardson sought a clinical collaborator. The natural site for such a trial was immediately apparent, the sprawling Christie Hospital in Manchester, a world-renowned cancer center just a short ride through the undulating hills of Cheshire from ICI’s research campus at Alderley Park. And there was a natural collaborator: Mary Cole, a Manchester oncologist and radiotherapist with a particular interest in breast cancer. Known affectionately as Moya by her patients and colleagues, Cole had a reputation as a feisty and meticulous physician intensely dedicated to her patients. She had a ward full of women with advanced, metastatic breast cancer, many of them hurtling inexorably toward their death. Moya Cole was willing to try anything—even an abandoned contraceptive—to save the lives of these women.
Cole’s trial was launched at Christie in the late summer of 1969. Forty-six women with breast cancer were treated with tablets of ICI 46474. Cole expected little from the drug—at best, a partial response. But in ten patients, the response was almost immediately obvious. Tumors shriveled visibly in the breast. Lung metastases shrank. Bone pain flickered away and lymph nodes softened.
Like Huggins’s prostate cancer patients, many of the women who responded to the drug eventually relapsed. But the success of the trial was incontrovertible—and the proof of principle historic. A drug designed to target a specific pathway in a cancer cell—not a cellular poison discovered empirically by trial and error—had successfully driven metastatic tumors into remission.
Tamoxifen’s journey came full circle in a little-known pharmaceutical laboratory in Shrewsbury, Massachusetts. In 1973, V. Craig Jordan, a biochemist working at the lab of the Worcester Foundation (a research institute involved in the development of new contraceptives), investigated the pattern behind cancers that did or did not respond to tamoxifen therapy. Jordan used a simple molecular technique to stain breast cancer cells for the estrogen receptor that Elwood Jensen had discovered in Chicago, and the answer to Beatson’s riddle finally leapt out of the experiment. Cancer cells that expressed the estrogen receptor were highly responsive to tamoxifen, while cells that lacked the estrogen receptor did not respond. The reason behind the slippery, hit-and-miss responses in women with breast cancer observed in England nearly a century earlier was now clear. Cells that expressed the estrogen receptor could bind tamoxifen, and the drug, an estrogen antagonist, shut off estrogen responsiveness, thus choking the cells’ growth. But ER-negative cells lacked the receptor for the drug and thus were insensitive to it. The schema had a satisfying simplicity. For the first time in the history of cancer, a drug, its target, and a cancer cell had been conjoined by a core molecular logic.
Halsted’s Ashes
I would rather be ashes than dust.
—Jack London
Will you turn me out if I can’t get better?
—A cancer patient to
her physician, 1960s
Moya Cole’s tamoxifen trial was initially designed to treat women with advanced, metastatic breast cancer. But as the trial progressed, Cole began to wonder about an alternative strategy. Typically, clinical trials of new cancer drugs tend to escalate inexorably toward sicker and sicker patients (as news of a novel drug spreads, more and more desperate patients lurch toward last-ditch efforts to save their lives). But Cole was inclined to journey in the opposite direction. What if women with earlier-stage tumors were treated with tamoxifen? If a drug could halt the progression of diffusely metastatic and aggressive stage IV cancers, might it work even better on more localized, stage II breast cancers, cancers that had spread only to the regional lymph nodes?
Unwittingly, Cole had come full circle toward Halsted’s logic. Halsted had invented the radical mastectomy based on the premise that early breast cancer needed to be attacked exhaustively and definitively—by surgically “cleansing” every conceivable reservoir of the disease, even when no visible cancer was present. The result had been the grotesque and disfiguring mastectomy, foisted indiscriminately on women with even small, locally restricted tumors to stave off relapses and metastasis into distant organs. But Cole now wondered whether Halsted had tried to cleanse the Augean stables of cancer with all the right intentions, but with the wrong tools. Surgery could not eliminate invisible reservoirs of cancer. But perhaps what was needed was a potent chemical—a systemic therapy, Willy Meyer’s dreamed-about “after-treatment” from 1932.
A variant of this idea had already gripped a band of renegade researchers at the NCI even before tamoxifen had appeared on the horizon. In 1963, nearly a decade before Moya Cole completed her experiments in Manchester, a thirty-three-year-old oncologist at the NCI, Paul Carbone, had launched a trial to see if chemotherapy might be effective when administered to women after an early-stage primary tumor had been completely removed surgically—i.e., women with no visible tumor remaining in the body. Carbone had been inspired by the patron saint of renegades at the NCI: Min Chiu Li, the researcher who had been expelled from the institute for treating women with placental tumors with methotrexate long after their tumors had visibly disappeared.
Li had been packed off in ignominy, but the strategy that had undone him—using chemotherapy to “cleanse” the body of residual tumor—had gained increasing respectability at the institute. In his small trial, Carbone found that adding chemotherapy after surgery decreased the rate of relapse from breast cancer. To describe this form of treatment, Carbone and his team used the word adjuvant, from the Latin phrase “to help.” Adjuvant chemotherapy, Carbone conjectured, could be the surgeon’s little helper. It would eradicate microscopic deposits of cancer left behind after surgery, thus extirpating any remnant reservoirs of malignancy in the body in early breast cancer—in essence, completing the Herculean cancer-cleansing task that Halsted had set for himself.
But surgeons had no interest in getting help from anyone—least of all chemotherapists. By the mid-1960s, as radical surgery became increasingly embattled, most breast surgeons had begun to view chemotherapists as estranged rivals that could not be trusted with anything, least of all improving surgical outcomes. And since surgeons largely dominated the field of breast cancer (and saw all the patients upon diagnosis), Carbone could not ramp up his trial because he could barely recruit any patients. “Except for an occasional woman who underwent a mastectomy at the NCI . . . the study never got off the ground,” Carbone recalled.
But Carbone found an alternative. Shunned by surgeons, he now turned to the surgeon who had shunned his own compatriots—Bernie Fisher, the man caught in the controversial swirl of testing radical breast surgery. Fisher was instantly interested in Carbone’s idea. Indeed, Fisher had been trying to run a trial along similar lines—combining chemotherapy with surgical mastectomy. But even Fisher could pick only one fight at a time. With his own trial, the NSABP-04 (the trial to test radical surgery versus nonradical surgery) barely limping along, he could hardly convince surgeons to join a trial to combine chemo and surgery in breast cancer.
An Italian team came to the rescue. In 1972, as the NCI was scouring the nation for a site where “adjuvant chemotherapy” after surgery could be tested, the oncologist Gianni Bonadonna came to Bethesda to visit the institute. Suave, personable, and sophisticated, impeccably dressed in custom-cut Milanese suits, Bonadonna made an instant impression at the NCI. He learned from DeVita, Canellos, and Carbone that they had been testing combinations of drugs to treat advanced breast cancer and had found a concoction that would likely work: Cytoxan (a cousin of nitrogen mustard), methotrexate (a variant of Farber’s aminopterin), and fluorouracil (an inhibitor of DNA synthesis). The regimen, called CMF, could be tolerated with relatively minimal side effects, yet was active enough in combination to thwart microscopic tumors—an ideal combination to be used as an adjuvant in breast cancer.
Bonadonna worked at a large cancer center in Milan called the Istituto Tumori, where he had a close friendship with the chief breast surgeon, Umberto Veronesi. Convinced by Carbone (who was still struggling to get a similar trial launched in America), Bonadonna and Veronesi, the only surgeon-chemotherapist pair seemingly on talking terms with each other, proposed a large randomized trial to study chemotherapy after breast surgery for early-stage breast cancer. They were immediately awarded the contract for the NCI trial.
The irony of that award could hardly have escaped the researchers at the institute. In America, the landscape of cancer medicine had become so deeply gashed by internal rifts that the most important NCI-sponsored trial of cytotoxic chemotherapy to be launched after the announcement of the War on Cancer had to be relocated to a foreign country.
Bonadonna began his trial in the summer of 1973. By the early winter that year, he had randomized nearly four hundred women to the trial—half to no treatment and half to treatment with CMF. Veronesi was a crucial supporter, but there was still little interest from other breast surgeons. “The surgeons were not just skeptical,” Bonadonna recalled. “They were hostile. [They] did not want to know. At the time there were very few chemotherapists, and they were not rated highly, and the attitude among surgeons was ‘chemotherapists deliver drugs in advanced disease [while] surgeons operate and we have complete remission for the entire life of the patient. . . . Surgeons rarely saw their patients again, and I think they didn’t want to hear about how many patients were being failed by surgery alone. It was a matter of prestige.’”
On an overcast morning in the winter of 1975, Bonadonna flew to Brussels to present his results at a conference of European oncologists. The trial had just finished its second year. But the two groups, Bonadonna reported, had clearly parted ways. Nearly half the women treated with no therapy had relapsed. In contrast, only a third of the women treated with the adjuvant regimen had relapsed. Adjuvant chemotherapy had prevented breast cancer relapses in about one in every six treated women.
The news was so unexpected that it was greeted by a stunned silence in the auditorium. Bonadonna’s presentation had shaken the terra firma of cancer chemotherapy. It was only on the flight back to Milan, ten thousand feet above the earth, that Bonadonna was finally inundated with questions about his trial by other researchers on his flight.
Gianni Bonadonna’s remarkable Milanese trial left a question almost begging to be answered. If adjuvant CMF chemotherapy could decrease relapses in women with early-stage breast cancer, then might adjuvant tamoxifen—the other active breast cancer drug established by Cole’s group—also decrease relapses in women with localized ER-positive breast cancer after surgery? Had Moya Cole been right about her instinct in treating early-stage breast cancer with antiestrogen therapy?
This was a question that Bernie Fisher, although embroiled in several other trials, could not resist trying to answer. In January 1977, five years after Cole had published her results on tamoxifen in metastatic cancer, Fisher recruited 1,891 women with estrogen receptor–positive (ER-positive) breast cancer that had spread only to the axillary nodes. He treated half with adjuvant tamoxifen and the other half with no tamoxifen. By 1981, the two groups had deviated sharply. Treatment with tamoxifen after surgery reduced cancer relapse rates by nearly 50 percent. The effect was particularly pronounced among women above fifty years old—a group most resistant to standard chemotherapy regimens and most likely to relapse with aggressive, metastatic breast cancer.
Three years later, in ’85, when Fisher reanalyzed the deviating curves of relapse and survival, the effect of tamoxifen treatment was even more dramatic. Among the five-hundred-odd women older than fifty assigned to each group, tamoxifen had prevented fifty-five relapses and deaths. Fisher had altered the biology of breast cancer after surgery using a targeted hormonal drug that had barely any significant side effects.
By the early 1980s, brave new paradigms of treatment had thus arisen out of the ashes of old paradigms. Halsted’s fantasy of attacking early-stage cancers was reborn as adjuvant therapy. Ehrlich’s “magic bullet” for cancer was reincarnated as antihormone therapy for breast and prostate cancer.
Neither method of treatment professed to be a complete cure. Adjuvant therapy and hormonal therapy typically did not obliterate cancer. Hormonal therapy produced prolonged remissions that could stretch into years or even decades. Adjuvant therapy was mainly a cleansing method to purge the body of residual cancer cells; it lengthened survival, but many patients eventually relapsed. In the end, often after decades of remission, chemotherapy-resistant and hormone-resistant cancers grew despite the prior interventions, flinging aside the equilibrium established during the treatment.
But although these alternatives did not offer definitive cures, several important principles of cancer biology and cancer therapy were firmly cemented in these powerful trials. First, as Kaplan had found with Hodgkin’s disease, these trials again clearly etched the message that cancer was enormously heterogeneous. Breast or prostate cancers came in an array of forms, each with unique biological behaviors. The heterogeneity was genetic: in breast cancer, for instance, some variants responded to hormonal treatment, while others were hormone-unresponsive. And the heterogeneity was anatomic: some cancers were localized to the breast when detected, while others had a propensity to spread to distant organs.
Second, understanding that heterogeneity was of deep consequence. “Know thine enemy” runs the adage, and Fisher’s and Bonadonna’s trials had shown that it was essential to “know” the cancer as intimately as possible before rushing to treat it. The meticulous separation of breast cancer into distinct stages, for instance, was a crucial prerequisite to the success of Bonadonna’s study: early-stage breast cancer could not be treated like late-stage breast cancer. The meticulous separation of ER-positive and ER-negative cancers was crucial to Fisher’s study: if tamoxifen had indiscriminately been tested on ER-negative breast cancer, the drug would have been discarded as having no benefit.
This nuanced understanding of cancer underscored by these trials had a sobering effect on cancer medicine. As Frank Rauscher, the director of the NCI, put it in 1985, “We were all more naive a decade ago. We hoped that a single application of drugs would result in a dramatic benefit. We now understand it’s much more complicated than that. People are optimistic but we’re not expecting home runs. Right now, people would be happy with a series of singles or doubles.”
Yet the metaphorical potency of battling and obliterating cancer relatively indiscriminately (“one cause, one cure”) still gripped oncology. Adjuvant chemotherapy and hormonal therapy were like truces declared in the battle—signs, merely, that a more aggressive attack was necessary. The allure of deploying a full armamentarium of cytotoxic drugs—of driving the body to the edge of death to rid it of its malignant innards—was still irresistible. So cancer medicine charged on, even if it meant relinquishing sanctity, sanity, or safety. Pumped up with self-confidence, bristling with conceit, and hypnotized by the potency of medicine, oncologists pushed their patients—and their discipline—to the brink of disaster. “We shall so poison the atmosphere of the first act,” the biologist James Watson warned about the future of cancer in 1977, “that no one of decency shall want to see the play through to the end.”
For many cancer patients caught in the first act, there was little choice but to see the poisonous play to its end.
“More is more,” a patient’s daughter told me curtly. (I had suggested to her delicately that for some patients with cancer, “Less might be more.”) The patient was an elderly Italian woman with liver cancer that had metastasized widely throughout her abdomen. She had come to the Massachusetts General Hospital seeking chemotherapy, surgery, or radiation—if possible, all three. She spoke halting, heavily accented English, often pausing between her words to catch her breath. Her skin had a yellow-gray tinge—a tinge, I was worried, that would bloom into a bright jaundice if the tumor obstructed her bile duct fully and her blood began to fill up with bile pigments. Exhausted, she drifted in and out of sleep even while I was examining her. I asked her to hold the palms of her hands straight upward, as if halting traffic, looking for signs of a subtle flapping motion that often predates liver failure. Thankfully, there was no tremor, but the abdomen had a dull, full sound of fluid building up inside it, likely full of malignant cells.
The daughter was a physician, and she watched me with intense, hawklike eyes while I finished the exam. She was devoted to her mother, with the reversed—and twice as fierce—maternal instinct that marks the poignant moment of midlife when the roles of mother and daughter begin to switch. The daughter wanted the best possible care for her mother—the best doctors, the best room with the best view of Beacon Hill, and the best, strongest, and toughest medicine that privilege and money could buy.
The elderly woman, meanwhile, would hardly tolerate even the mildest drug. Her liver had not failed yet but was on the verge of doing so, and subtle signs suggested her kidneys were barely functioning. I suggested that we try a palliative drug, perhaps a single chemotherapeutic agent that might just ameliorate her symptoms rather than pushing for a tougher regimen to try to cure an incurable disease.
The daughter looked at me as if I were mad. “I came here to get treatment, not consolations about hospice,” she finally said, glowering with fury.
I promised to reconsider by asking more experienced doctors to weigh in. Perhaps I had been too hasty in my caution. But in a few weeks, I learned that she and her daughter had found another doctor, presumably someone who had acquiesced more readily to their demands. I do not know whether the elderly woman died from cancer or its cure.
Yet a third voice of dissent arose in oncology in the 1980s, although this voice had skirted the peripheries of cancer for several centuries. As trial after trial of chemotherapy and surgery failed to chisel down the mortality rate for advanced cancers, a generation of surgeons and chemotherapists, unable to cure patients, began to learn (or relearn) the art of caring for patients.
It was a fitful and uncomfortable lesson. Palliative care, the branch of medicine that focuses on symptom relief and comfort, had been perceived as the antimatter of cancer therapy, the negative to its positive, an admission of failure to its rhetoric of success. The word palliate comes from the Latin palliare, “to cloak”—and providing pain relief was perceived as cloaking the essence of the illness, smothering symptoms rather than attacking disease. Writing about pain relief, a Boston surgeon thus reasoned in the 1950s: “If there is persistent pain which cannot be relieved by direct surgical attack on the pathological lesion itself . . ., relief can be obtained only by surgical interruption of sensory pathways.” The only alternative to surgery was more surgery—fire to fight fire. Pain-relieving opiate drugs such as morphine or fentanyl were deliberately denied. “If surgery is withheld,” the writer continued, “the sufferer is doomed to opiate addiction, physical deterioration or even suicide”—an ironic consideration, since Halsted himself, while devising his theory of radical surgery, had swiveled between his twin addictions to cocaine and morphine.
The movement to restore sanity and sanctity to the end-of-life care of cancer patients emerged, predictably, not from cure-obsessed America but from Europe. Its founder was Cecily Saunders, a former nurse who had retrained as a physician in England. In the late 1940s, Saunders had tended to a Jewish refugee from Warsaw dying of cancer in London. The man had left Saunders his life savings—£500—with a desire to be “a window in [her] home.” As Saunders entered and explored the forsaken cancer wards of London’s East End in the fifties, she began to decipher that cryptic request in a more visceral sense: she encountered terminally ill patients denied dignity, pain relief, and often even basic medical care—their lives confined, sometimes literally, to rooms without windows. These “hopeless” cases, Saunders found, had become the pariahs of oncology, unable to find any place in its rhetoric of battle and victory, and thus pushed, like useless, wounded soldiers, out of sight and mind.
Saunders responded to this by inventing, or rather resurrecting, a counterdiscipline—palliative medicine. (She avoided the phrase palliative care because care,she wrote, “is a soft word” that would never win respectability in the medical world.) If oncologists could not bring themselves to provide care for their terminally ill patients, she would leverage other specialists—psychiatrists, anesthesiologists, geriatricians, physical therapists, and neurologists—to help patients die painlessly and gracefully. And she would physically remove the dying from the oncology wards: in 1967, she created a hospice in London to care specifically for the terminally ill and dying, evocatively naming it St. Christopher’s—not after the patron saint of death, but after the patron saint of travelers.
It would take a full decade for Saunders’s movement to travel to America and penetrate its optimism-fortified oncology wards. “The resistance to providing palliative care to patients,” a ward nurse recalls, “was so deep that doctors would not even look us in the eye when we recommended that they stop their efforts to save lives and start saving dignity instead . . . doctors were allergic to the smell of death. Death meant failure, defeat—their death, the death of medicine, the death of oncology.”
Providing end-of-life care required a colossal act of reimagination and reinvention. Trials on pain and pain relief—trials executed with no less rigor or precision than those launched to test novel drugs and surgical protocols—toppled several dogmas about pain and revealed new and unexpected foundational principles. Opiates, used liberally and compassionately on cancer patients, did not cause addiction, deterioration, and suicide; instead, they relieved the punishing cycle of anxiety, pain, and despair. New antinausea drugs were deployed that vastly improved the lives of patients on chemotherapy. The first hospice in the United States was launched at Yale–New Haven Hospital in 1974. By the early 1980s, hospices for cancer patients built on Saunders’s model had sprouted up worldwide—most prominently in Britain, where nearly two hundred hospice centers were operating by the end of that decade.
Saunders refused to recognize this enterprise as pitted “against” cancer. “The provision of . . . terminal care,” she wrote, “should not be thought of as a separate and essentially negative part of the attack on cancer. This is not merely the phase of defeat, hard to contemplate and unrewarding to carry out. In many ways its principles are fundamentally the same as those which underlie all other stages of care and treatment, although its rewards are different.”
This, too, then, was knowing the enemy.
Counting Cancer
We must learn to count the living with that same particular attention with which we number the dead.
—Audre Lorde
Counting is the religion of this generation. It is its hope and its salvation.
—Gertrude Stein
In November 1985, with oncology caught at a pivotal crossroads between the sobering realities of the present and the hype of past promises, a Harvard biologist named John Cairns resurrected the task of measuring progress in the War on Cancer.
The word resurrection implies a burial, and since the Fortune article of 1937, composite assessments of the War on Cancer had virtually been buried—oddly, in an overwhelming excess of information. Every minor footfall and every infinitesimal step had been so obsessively reported in the media that it had become nearly impossible to discern the trajectory of the field as a whole. In part, Cairns was reacting to the overgranularity of the view from the prior decade. He wanted to pull away from the details and offer a bird’s-eye view. Were patients with cancer surviving longer in general? Had the enormous investments in the War on Cancer since 1971 translated into tangible clinical achievements?
To quantify “progress,” an admittedly hazy metric, Cairns began by revitalizing a fusty old record that had existed since World War II, the cancer registry, a state-by-state statistical record of cancer-related deaths subclassified by the type of cancer involved. “These registries,” Cairns wrote in an article in Scientific American, “yield a rather precise picture of the natural history of cancer, and that is a necessary starting point for any discussion of treatment.” By poring through that record, he hoped to draw a portrait of cancer over time—not over days or weeks, but over decades.
Cairns began by using the cancer registry to estimate the number of lives saved by the therapeutic advances in oncology since the 1950s. (Since surgery and radiation therapy preceded the 1950s, these were excluded; Cairns was more interested in advances that had emerged from the brisk expansion in biomedical research since the fifties.) He divided these therapeutic advances into various categories, then made numerical conjectures about their relative effects on cancer mortality.
The first of these categories was “curative” chemotherapy—the approach championed by Frei and Freireich at the NCI and by Einhorn and his colleagues at Indiana. Assuming relatively generous cure rates of about 80 or 90 percent for the subtypes of cancer curable by chemotherapy, Cairns estimated that between 2,000 and 3,000 lives were being saved overall every year—700 children with acute lymphoblastic leukemia, about 1,000 men and women with Hodgkin’s disease, 300 men with advanced testicular cancer, and 20 to 30 women with choriocarcinoma. (Variants of non-Hodgkin’s lymphomas, which were curable with polychemotherapy by 1986, would have added another 2,000 lives, bringing the total up to about 5,000, but Cairns did not include these cures in his initial metric.)
“Adjuvant” chemotherapy—chemotherapy given after surgery, as in the Bonadonna and Fisher breast cancer trials—contributed to another 10,000 to 20,000 lives saved annually. Finally, Cairns factored in screening strategies such as Pap smears and mammograms that detected cancer in its early stages. These, he estimated loosely, saved an additional 10,000 to 15,000 cancer-related deaths per year. The grand tally, generously speaking, amounted to about 35,000 to 40,000 lives per year.
That number was to be contrasted with the annual incidence of cancer in 1985—448 new cancer cases diagnosed for every 100,000 Americans, or about 1 million every year—and the mortality from cancer in 1985—211 deaths for every 100,000, or 500,000 deaths every year. In short, even with relatively liberal estimates about lives saved, less than one in twenty patients diagnosed with cancer in America, and less than one in ten of the total number of patients who would die of cancer, had benefited from the advances in therapy and screening.
Cairns wasn’t surprised by the modesty of that number; in fact, he claimed, no self-respecting epidemiologist should be. In the history of medicine, no significant disease had ever been eradicated by a treatment-related program alone. If one plotted the decline in deaths from tuberculosis, for instance, the decline predated the arrival of new antibiotics by several decades. Far more potently than any miracle medicine, relatively uncelebrated shifts in civic arrangements—better nutrition, housing, and sanitation, improved sewage systems and ventilation—had driven TB mortality down in Europe and America. Polio and smallpox had also dwindled as a result of vaccinations. Cairns wrote, “The death rates from malaria, cholera, typhus, tuberculosis, scurvy, pellagra and other scourges of the past have dwindled in the US because humankind has learned how to prevent these diseases. . . . To put most of the effort into treatment is to deny all precedent.”
Cairns’s article was widely influential in policy circles, but it still lacked a statistical punch line. What it needed was some measure of the comparative trends in cancer mortality over the years—whether more or less people were dying of cancer in 1985 as compared to 1975. In May 1986, less than a year after Cairns’s article, two of his colleagues from Harvard, John Bailar and Elaine Smith, provided precisely such an analysis in the New England Journal of Medicine.
To understand the Bailar-Smith analysis, we need to begin by understanding what it was not. Right from the outset, Bailar rejected the metric most familiar to patients: changes in survival rates over time. A five-year survival rate is a measure of the fraction of patients diagnosed with a particular kind of cancer who are alive at five years after diagnosis. But a crucial pitfall of survival-rate analysis is that it can be sensitive to biases.
To understand these biases, imagine two neighboring villages that have identical populations and identical death rates from cancer. On average, cancer is diagnosed at age seventy in both villages. Patients survive for ten years after diagnosis and die at age eighty.
Imagine now that in one of those villages, a new, highly specific test for cancer is introduced—say the level of a protein Preventin in the blood as a marker for cancer. Suppose Preventin is a perfect detection test. Preventin “positive” men and women are thus immediately counted among those who have cancer.
Preventin, let us further suppose, is an exquisitely sensitive test and reveals very early cancer. Soon after its introduction, the average age of cancer diagnosis in village 1 thus shifts from seventy years to sixty years, because earlier and earlier cancer is being caught by this incredible new test. However, since no therapeutic intervention is available even after the introduction of Preventin tests, the average age of death remains identical in both villages.
To a naive observer, the scenario might produce a strange effect. In village 1, where Preventin screening is active, cancer is now detected at age sixty and patients die at age eighty—i.e., there is a twenty-year survival. In village 2, without Preventin screening, cancer is detected at age seventy and patients die at age eighty—i.e., a ten-year survival. Yet the “increased” survival cannot be real. How can Preventin, by its mere existence, have increased survival without any therapeutic intervention?
The answer is immediately obvious: the increase in survival is, of course, an artifact. Survival rates seem to increase, although what has really increased is the time from diagnosis to death because of a screening test.
A simple way to avoid this bias is to not measure survival rates, but overall mortality. (In the example above, mortality remains unchanged, even after the introduction of the test for earlier diagnosis.)
But here, too, there are profound methodological glitches. “Cancer-related death” is a raw number in a cancer registry, a statistic that arises from the diagnosis entered by a physician when pronouncing a patient dead. The problem with comparing that raw number over long stretches of time is that the American population (like any) is gradually aging overall, and the rate of cancer-related mortality naturally increases with it. Old age inevitably drags cancer with it, like flotsam on a tide. A nation with a larger fraction of older citizens will seem more cancer-ridden than a nation with younger citizens, even if actual cancer mortality has not changed.
To compare samples over time, some means is needed to normalize two populations to the same standard—in effect, by statistically “shrinking” one into another. This brings us to the crux of the innovation in Bailar’s analysis: to achieve this scaling, he used a particularly effective form of normalization called age-adjustment.
To understand age-adjustment, imagine two very different populations. One population is markedly skewed toward young men and women. The second population is skewed toward older men and women. If one measures the “raw” cancer deaths, the older-skewed population obviously has more cancer deaths.
Now imagine normalizing the second population such that this age skew is eliminated. The first population is kept as a reference. The second population is adjusted: the age-skew is eliminated and the death rate shrunk proportionally as well. Both populations now contain identical age-adjusted populations of older and younger men, and the death rate, adjusted accordingly, yields identical cancer-specific death rates. Bailar performed this exercise repeatedly over dozens of years: he divided the population for every year into age cohorts—20–29 years, 30–39 years, 40–49, and so forth—then used the population distribution from 1980 (chosen arbitrarily as a standard) to convert the population distributions for all other years into the same distribution. Cancer rates were adjusted accordingly. Once all the distributions were fitted into the same standard demographic, the populations could be studied and compared over time.
Bailar and Smith published their article in May 1986—and it shook the world of oncology by its roots. Even the moderately pessimistic Cairns had expected at least a small decrease in cancer-related mortality over time. Bailar and Smith found that even Cairns had been overgenerous: between 1962 and 1985, cancer-related deaths had increased by 8.7 percent. That increase reflected many factors—most potently, an increase in smoking rates in the 1950s that had resulted in an increase in lung cancer.
One thing was frightfully obvious: cancer mortality was not declining in the United States. There is “no evidence,” Bailar and Smith wrote darkly, “that some thirty-five years of intense and growing efforts to improve the treatment of cancer have had much overall effect on the most fundamental measure of clinical outcome—death.” They continued, “We are losing the war against cancer notwithstanding progress against several uncommon forms of the disease [such as childhood leukemia and Hodgkin’s disease], improvements in palliation and extension of productive years of life. . . . Some thirty-five years of intense effort focused largely on improving treatment must be judged a qualified failure.”
That phrase, “qualified failure,” with its mincing academic ring, was deliberately chosen. In using it, Bailar was declaring his own war—against the cancer establishment, against the NCI, against a billion-dollar cancer-treatment industry. One reporter described him as “a thorn in the side of the National Cancer Institute.” Doctors railed against Bailar’s analysis, describing him as a naysayer, a hector, a nihilist, a defeatist, a crank.
Predictably, a torrent of responses appeared in medical journals. One camp of critics contended that the Bailar-Smith analysis appeared dismal not because cancer treatment was ineffective, but because it was not being implemented aggressively enough. Delivering chemotherapy, these critics argued, was a vastly more complex process than Bailar and Smith had surmised—so complex that even most oncologists often blanched at the prospect of full-dose therapy. As evidence, they pointed to a survey from 1985 that had estimated that only one-third of cancer doctors were using the most effective combination regimen for breast cancer. “I estimate that 10,000 lives could be saved by the early aggressive use of polychemotherapy in breast cancer, as compared with the negligible number of lives, perhaps several thousand, now being saved,” one prominent critic wrote.
In principle, this might have been correct. As the ’85 survey suggested, many doctors were indeed underdosing chemotherapy—at least by the standards advocated by most oncologists, or even by the NCI. But the obverse idea—that maximizing chemotherapy would maximize gains in survival—was also untested. For some forms of cancer (some subtypes of breast cancer, for instance) increasing the intensity of dosage would eventually result in increasing efficacy. But for a vast majority of cancers, more intensive regimens of standard chemotherapeutic drugs did not necessarily mean more survival. “Hit hard and hit early,” a dogma borrowed from the NCI’s experience with childhood leukemia, was not going to be a general solution to all forms of cancer.
A more nuanced critique of Bailar and Smith came, unsurprisingly, from Lester Breslow, the UCLA epidemiologist. Breslow reasoned that while age-adjusted mortality was one method of appraising the War on Cancer, it was by no means the only measure of progress or failure. In fact, by highlighting only one measure, Bailar and Smith had created a fallacy of their own: they had oversimplified the measure of progress. “The problem with reliance on a single measure of progress,” Breslow wrote, “is that the impression conveyed can vary dramatically when the measure is changed.”
To illustrate his point, Breslow proposed an alternative metric. If chemotherapy cured a five-year-old child of ALL, he argued, then it saved a full sixty-five years of potential life (given an overall life expectancy of about seventy). In contrast, the chemotherapeutic cure in a sixty-five-year-old man contributed only five additional years given a life expectancy of seventy. But Bailar and Smith’s chosen metric—age-adjusted mortality—could not detect any difference in the two cases. A young woman cured of lymphoma, with fifty additional years of life, was judged by the same metric as an elderly woman cured of breast cancer, who might succumb to some other cause of death in the next year. If “years of life saved” was used as a measure of progress on cancer, then the numbers turned far more palatable. Now, instead of losing the War on Cancer, it appeared that we were winning it.
Breslow, pointedly, wasn’t recommending one form of calculus over another; his point was to show that measurement itself was subjective. “Our purpose in making these calculations,” he wrote, “is to indicate how sensitive one’s conclusions are to the choice of measure. In 1980, cancer was responsible for 1.824 million lost years of potential life in the United States to age 65. If, however, the cancer mortality rates of 1950 had prevailed, 2.093 million years of potential life would have been lost.”
The measurement of illness, Breslow was arguing, is an inherently subjective activity: it inevitably ends up being a measure of ourselves. Objective decisions come to rest on normative ones. Cairns or Bailar could tell us how many absolute lives were being saved or lost by cancer therapeutics. But to decide whether the investment in cancer research was “worth it,” one needed to start by questioning the notion of “worth” itself: was the life extension of a five-year-old “worth” more than the life extension of a sixty-year-old? Even Bailar and Smith’s “most fundamental measure of clinical outcome”—death—was far from fundamental. Death (or at least the social meaning of death) could be counted and recounted with other gauges, often resulting in vastly different conclusions. The appraisal of diseases depends, Breslow argued, on our self-appraisal. Society and illness often encounter each other in parallel mirrors, each holding up a Rorschach test for the other.
Bailar might have been willing to concede these philosophical points, but he had a more pragmatic agenda. He was using the numbers to prove a principle. As Cairns had already pointed out, the only intervention ever known to reduce the aggregate mortality for a disease—any disease—at a population level was prevention. Even if other measures were chosen to evaluate our progress against cancer, Bailar argued that it was indubitably true that prevention, as a strategy, had been neglected by the NCI in its ever-manic pursuit of cures.
A vast majority of the institute’s grants, 80 percent, were directed toward treatment strategies for cancer; prevention research received about 20 percent. (By 1992, this number had increased to 30 percent; of the NCI’s $2 billion research budget, $600 million was being spent on prevention research.) In 1974, describing to Mary Lasker the comprehensive activities of the NCI, the director, Frank Rauscher, wrote effusively about its three-pronged approach to cancer: “Treatment, Rehabilitation and Continuing Care.” That there was no mention of either prevention or early detection was symptomatic: the institute did not even consider cancer prevention a core strength.
A similarly lopsided bias existed in private research institutions. At Memorial Sloan-Kettering in New York, for instance, only one laboratory out of nearly a hundred identified itself as having a prevention research program in the 1970s. When one researcher surveyed a large cohort of doctors in the early 1960s, he was surprised to learn that “not one” was able to suggest an “idea, lead or theory on cancer prevention.” Prevention, he noted drily, was being carried out “on a part-time basis.” *
This skew of priorities, Bailar argued, was the calculated by-product of 1950s-era science; of books, such as Garb’s Cure for Cancer, that had forecast impossibly lofty goals; of the Laskerites’ near-hypnotic conviction that cancer could be cured within the decade; of the steely, insistent enthusiasm of researchers such as Farber. The vision could be traced back to Ehrlich, ensconced in the semiotic sorcery of his favorite phrase: “magic bullet.” Progressive, optimistic, and rationalistic, this vision—of magic bullets and miracle cures—had admittedly swept aside the pessimism around cancer and radically transformed the history of oncology. But the notion of the “cure” as the singular solution to cancer had degenerated into a sclerotic dogma. Bailar and Smith noted, “A shift in research emphasis, from research on treatment to research on prevention, seems necessary if substantial progress against cancer is to be forthcoming. . . . Past disappointments must be dealt with in an objective, straightforward and comprehensive manner before we go much further in pursuit of a cure that always seems just out of reach.”
* Although this line of questioning may be intrinsically flawed since it does not recognize the interrelatedness of preventive and therapeutic research.