The Emperor of All Maladies

by Siddhartha Mukherjee

  The procedure had to be put to a test by following patients longitudinally in time. So, in the mid-1890s, at the peak of his surgical career, Halsted began to collect long-term statistics to show that his operation was the superior choice. By then, the radical mastectomy was more than a decade old. Halsted had operated on enough women and extracted enough tumors to create what he called an entire “cancer storehouse” at Hopkins.

  Halsted would almost certainly have been right in his theory of radical surgery: that attacking even small cancers with aggressive local surgery was the best way to achieve a cure. But there was a deep conceptual error. Imagine a population in which breast cancer occurs at a fixed incidence, say 1 percent per year. The tumors, however, demonstrate a spectrum of behavior right from their inception. In some women, by the time the disease has been diagnosed the tumor has already spread beyond the breast: there is metastatic cancer in the bones, lungs, and liver. In other women, the cancer is confined to the breast, or to the breast and a few nodes; it is truly a local disease.

  Position Halsted now, with his scalpel and sutures, in the middle of this population, ready to perform his radical mastectomy on any woman with breast cancer. Halsted’s ability to cure patients with breast cancer obviously depends on the sort of cancer—the stage of breast cancer—that he confronts. The woman with the metastatic cancer is not going to be cured by a radical mastectomy, no matter how aggressively and meticulously Halsted extirpates the tumor in her breast: her cancer is no longer a local problem. In contrast, the woman with the small, confined cancer does benefit from the operation—but for her, a far less aggressive procedure, a local mastectomy, would have done just as well. Halsted’s mastectomy is thus a peculiar misfit in both cases; it underestimates its target in the first case and overestimates it in the second. In both cases, women are forced to undergo indiscriminate, disfiguring, and morbid operations—too much, too early for the woman with local breast cancer, and too little, too late, for the woman with metastatic cancer.

  On April 19, 1898, Halsted attended the annual conference of the American Surgical Association in New Orleans. On the second day, before a hushed and eager audience of surgeons, he rose to the podium armed with figures and tables showcasing his highly anticipated data. At first glance, his observations were astounding: his mastectomy had outperformed every other surgeon’s operation in terms of local recurrence. At Baltimore, Halsted had slashed the rate of local recurrence to a bare few percent, a drastic improvement on Volkmann’s or Billroth’s numbers. Just as Halsted had promised, he had seemingly exterminated cancer at its root.

  But if one looked closely, the roots had persisted. The evidence for a true cure of breast cancer was much more disappointing. Of the seventy-six patients with breast cancer treated with the “radical method,” only forty had survived for more than three years. Thirty-six, or nearly half the original number, had died within three years of the surgery—consumed by a disease supposedly “uprooted” from the body.

  But Halsted and his students remained unfazed. Rather than address the real question raised by the data—did radical mastectomy truly extend lives?—they clutched to their theories even more adamantly. A surgeon should “operate on the neck in every case,” Halsted emphasized in New Orleans. Where others might have seen reason for caution, Halsted only saw opportunity: “I fail to see why the neck involvement in itself is more serious than the axillary [area]. The neck can be cleaned out as thoroughly as the axilla.”

  In the summer of 1907, Halsted presented more data to the American Surgical Association in Washington, D.C. He divided his patients into three groups based on whether the cancer had spread before surgery to lymph nodes in the axilla or the neck. When he put up his survival tables, a pattern became apparent. Of the sixty patients with no cancer-afflicted nodes in the axilla or the neck, the substantial number of forty-five had been cured of breast cancer at five years. Of the forty patients with such nodes, only three had survived.

  The ultimate survival from breast cancer, in short, had little to do with how extensively a surgeon operated on the breast; it depended on how extensively the cancer had spread before surgery. As George Crile, one of the most fervent critics of radical surgery, later put it, “If the disease was so advanced that one had to get rid of the muscles in order to get rid of the tumor, then it had already spread through the system”—making the whole operation moot.

  But if Halsted came to the brink of this realization in 1907, he just as emphatically shied away from it. He relapsed to stale aphorisms. “But even without the proof which we offer, it is, I think, incumbent upon the surgeon to perform in many cases the supraclavicular operation,” he advised in one paper. By now the perpetually changing landscape of breast cancer was beginning to tire him out. Trials, tables, and charts had never been his forte; he was a surgeon, not a bookkeeper. “It is especially true of mammary cancer,” he wrote, “that the surgeon interested in furnishing the best statistics may in perfectly honorable ways provide them.” That statement—almost vulgar by Halsted’s standards—exemplified his growing skepticism about putting his own operation to a test. He instinctively knew that he had come to the far edge of his understanding of this amorphous illness that was constantly slipping out of his reach.

  The 1907 paper was to be Halsted’s last and most comprehensive discussion on breast cancer. He wanted new and open anatomical vistas where he could practice his technically brilliant procedures in peace, not debates about the measurement and remeasurement of end points of surgery. Never having commanded a particularly good bedside manner, he retreated fully into his cloistered operating room and into the vast, cold library of his mansion. He had already moved on to other organs—the thorax, the thyroid, the great arteries—where he continued to make brilliant surgical innovations. But he never wrote another scholarly analysis of the majestic and flawed operation that bore his name.

  Between 1891 and 1907—in the sixteen hectic years that stretched from the tenuous debut of the radical mastectomy in Baltimore to its center-stage appearances at vast surgical conferences around the nation—the quest for a cure for cancer took a great leap forward and an equally great step back. Halsted proved beyond any doubt that massive, meticulous surgeries were technically possible in breast cancer. These operations could drastically reduce the risk for the local recurrence of a deadly disease. But what Halsted could not prove, despite his most strenuous efforts, was far more revealing. After nearly two decades of data gathering, having been levitated, praised, analyzed, and reanalyzed in conference after conference, the superiority of radical surgery in “curing” cancer still stood on shaky ground. More surgery had just not translated into more effective therapy.

  Yet all this uncertainty did little to stop other surgeons from operating just as aggressively. “Radicalism” became a psychological obsession, burrowing its way deeply into cancer surgery. Even the word radical was a seductive conceptual trap. Halsted had used it in the Latin sense of “root” because his operation was meant to dig out the buried, subterranean roots of cancer. But radical also meant “aggressive,” “innovative,” and “brazen,” and it was this meaning that left its mark on the imaginations of patients. What man or woman, confronting cancer, would willingly choose nonradical, or “conservative,” surgery?

  Indeed, radicalism became central not only to how surgeons saw cancer, but also in how they imagined themselves. “With no protest from any other quarter and nothing to stand in its way, the practice of radical surgery,” one historian wrote, “soon fossilized into dogma.” When heroic surgery failed to match its expectations, some surgeons began to shrug off the responsibility of a cure altogether. “Undoubtedly, if operated upon properly the condition may be cured locally, and that is the only point for which the surgeon must hold himself responsible,” one of Halsted’s disciples announced at a conference in Baltimore in 1931. The best a surgeon could do, in other words, was to deliver the most technically perfect operation. Curing cancer was someone else’s proble
m.

  This trajectory toward more and more brazenly aggressive operations—“the more radical the better”—mirrored the overall path of surgical thinking of the early 1930s. In Chicago, the surgeon Alexander Brunschwig devised an operation for cervical cancer, called a “complete pelvic exenteration,” so strenuous and exhaustive that even the most Halstedian surgeon needed to break midprocedure to rest and change positions. The New York surgeon George Pack was nicknamed Pack the Knife (after the popular song “Mack the Knife”), as if the surgeon and his favorite instrument had, like some sort of ghoulish centaur, somehow fused into the same creature.

  Cure was a possibility now flung far into the future. “Even in its widest sense,” an English surgeon wrote in 1929, “the measure of operability depend[s] on the question: ‘Is the lesion removable?’ and not on the question: ‘Is the removal of the lesion going to cure the patient?’” Surgeons often counted themselves lucky if their patients merely survived these operations. “There is an old Arabian proverb,” a group of surgeons wrote at the end of a particularly chilling discussion of stomach cancer in 1933, “that he is no physician who has not slain many patients, and the surgeon who operates for carcinoma of the stomach must remember that often.”

  To arrive at that sort of logic—the Hippocratic oath turned upside down—demands either a terminal desperation or a terminal optimism. In the 1930s, the pendulum of cancer surgery swung desperately between those two points. Halsted, Brunschwig, and Pack persisted with their mammoth operations because they genuinely believed that they could relieve the dreaded symptoms of cancer. But they lacked formal proof, and as they went further up the isolated promontories of their own beliefs, proof became irrelevant and trials impossible to run. The more fervently surgeons believed in the inherent good of their operations, the more untenable it became to put these to a formal scientific trial. Radical surgery thus drew the blinds of circular logic around itself for nearly a century.

  The allure and glamour of radical surgery overshadowed crucial developments in less radical surgical procedures for cancer that were evolving in its penumbra. Halsted’s students fanned out to invent new procedures to extirpate cancers. Each was “assigned” an organ. Halsted’s confidence in his heroic surgical training program was so supreme that he imagined his students capable of confronting and annihilating cancer in any organ system. In 1897, having intercepted a young surgical resident, Hugh Hampton Young, in a corridor at Hopkins, Halsted asked him to become the head of the new department of urological surgery. Young protested that he knew nothing about urological surgery. “I know you didn’t know anything,” Halsted replied curtly, “but we believe that you can learn”—and walked on.

  Inspired by Halsted’s confidence, Young delved into surgery for urological cancers—cancers of the prostate, kidney, and bladder. In 1904, with Halsted as his assistant, Young successfully devised an operation for prostate cancer by excising the entire gland. Although called the radical prostatectomy in the tradition of Halsted, Hampton’s surgery was rather conservative by comparison. He did not remove muscles, lymph nodes, or bone. He retained the notion of the en bloc removal of the organ from radical surgery, but stopped short of evacuating the entire pelvis or extirpating the urethra or the bladder. (A modification of this procedure is still used to remove localized prostate cancer, and it cures a substantial portion of patients with such tumors.)

  Harvey Cushing, Halsted’s student and chief surgical resident, concentrated on the brain. By the early 1900s, Cushing had found ingenious ways to surgically extract brain tumors, including the notorious glioblastomas—tumors so heavily crisscrossed with blood vessels that they could hemorrhage any minute, and meningiomas wrapped like sheaths around delicate and vital structures in the brain. Like Young, Cushing inherited Haslted’s intaglio surgical technique—“the slow separation of brain from tumor, working now here, now there, leaving small, flattened pads of hot, wrung-out cotton to control oozing”—but not Halsted’s penchant for radical surgery. Indeed Cushing found radical operations on brain tumors not just difficult, but inconceivable: even if he desired it, a surgeon could not extirpate the entire organ.

  In 1933, at the Barnes Hospital in St. Louis, yet another surgical innovator, Evarts Graham, pioneered an operation to remove a lung afflicted with cancer by piecing together prior operations that had been used to remove tubercular lungs. Graham, too, retained the essential spirit of Halstedian surgery: the meticulous excision of the organ en bloc and the cutting of wide margins around the tumor to prevent local recurrences. But he tried to sidestep its pitfalls. Resisting the temptation to excise more and more tissue—lymph nodes throughout the thorax, major blood vessels, or the adjacent fascia around the trachea and esophagus—he removed just the lung, keeping the specimen as intact as possible.

  Even so, obsessed with Halstedian theory and unable to see beyond its realm, surgeons sharply berated such attempts at nonradical surgery. A surgical procedure that did not attempt to obliterate cancer from the body was pooh-poohed as a “makeshift operation.” To indulge in such makeshift operations was to succumb to the old flaw of “mistaken kindness” that a generation of surgeons had tried so diligently to banish.

  The Hard Tube and the Weak Light

  We have found in [X-rays] a cure for the malady.

  —Los Angeles Times, April 6, 1902

  By way of illustration [of the destructive power of X-rays] let us recall that nearly all pioneers in the medical X-ray laboratories in the United States died of cancers induced by the burns.

  —The Washington Post, 1945

  In late October 1895, a few months after Halsted had unveiled the radical mastectomy in Baltimore, Wilhelm Röntgen, a lecturer at the Würzburg Institute in Germany, was working with an electron tube—a vacuum tube that shot electrons from one electrode to another—when he noticed a strange leakage. The radiant energy was powerful and invisible, capable of penetrating layers of blackened cardboard and producing a white phosphorescent glow on a barium screen accidentally left on a bench in the room.

  Röntgen whisked his wife, Anna, into the lab and placed her hand between the source of his rays and a photographic plate. The rays penetrated through her hand and left a silhouette of her finger bones and her metallic wedding ring on the photographic plate—the inner anatomy of a hand seen as if through a magical lens. “I have seen my death,” Anna said—but her husband saw something else: a form of energy so powerful that it could pass through most living tissues. Röntgen called his form of light X-rays.

  At first, X-rays were thought to be an artificial quirk of energy produced by electron tubes. But in 1896, just a few months after Röntgen’s discovery, Henri Becquerel, the French chemist, who knew of Röntgen’s work, discovered that certain natural materials—uranium among them—autonomously emitted their own invisible rays with properties similar to those of X-rays. In Paris, friends of Becquerel’s, a young physicist-chemist couple named Pierre and Marie Curie, began to scour the natural world for even more powerful chemical sources of X-rays. Pierre and Marie (then Maria Skłodowska, a penniless Polish immigrant living in a garret in Paris) had met at the Sorbonne and been drawn to each other because of a common interest in magnetism. In the mid-1880s, Pierre Curie had used minuscule quartz crystals to craft an instrument called an electrometer, capable of measuring exquisitely small doses of energy. Using this device, Marie had shown that even tiny amounts of radiation emitted by uranium ores could be quantified. With their new measuring instrument for radioactivity, Marie and Pierre began hunting for new sources of X-rays. Another monumental journey of scientific discovery was thus launched with measurement.

  In a waste ore called pitchblende, a black sludge that came from the peaty forests of Joachimsthal in what is now the Czech Republic, the Curies found the first signal of a new element—an element many times more radioactive than uranium. The Curies set about distilling the boggy sludge to trap that potent radioactive source in its purest form. From several tons of pitchblende,
four hundred tons of washing water, and hundreds of buckets of distilled sludge waste, they finally fished out one-tenth of a gram of the new element in 1902. The metal lay on the far edge of the periodic table, emitting X-rays with such feverish intensity that it glowered with a hypnotic blue light in the dark, consuming itself. Unstable, it was a strange chimera between matter and energy—matter decomposing into energy. Marie Curie called the new element radium, from the Greek word for “light.”

  Radium, by virtue of its potency, revealed a new and unexpected property of X-rays: they could not only carry radiant energy through human tissues, but also deposit energy deep inside tissues. Röntgen had been able to photograph his wife’s hand because of the first property: his X-rays had traversed through flesh and bone and left a shadow of the tissue on the film. Marie Curie’s hands, in contrast, bore the painful legacy of the second effect: having distilled pitchblende into a millionth part for week after week in the hunt for purer and purer radioactivity, the skin in her palm had begun to chafe and peel off in blackened layers, as if the tissue had been burnt from the inside. A few milligrams of radium left in a vial in Pierre’s pocket scorched through the heavy tweed of his waistcoat and left a permanent scar on his chest. One man who gave “magical” demonstrations at a public fair with a leaky, unshielded radium machine developed swollen and blistered lips, and his cheeks and nails fell out. Radiation would eventually burn into Marie Curie’s bone marrow, leaving her permanently anemic.