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

by Siddhartha Mukherjee

  After San Antonio, the early-phase trials gathered speed. Emboldened by the positive response, Peters pushed for evaluating STAMP not just for metastatic breast cancer, but as an adjuvant therapy for high-risk patients with locally advanced cancer (patients with more than ten cancer-afflicted lymph nodes). Following Peters's initial observations, several groups across the nation also hotly pursued megadose chemotherapy with bone marrow transplantation. Two years later, with early-phase trials completed successfully, a randomized, blinded, Phase III trial was needed. Peters approached the Cancer and Leukemia Group B (CALGB), the centralized group that acted as a clearinghouse for clinical trials, to sponsor a definitive multicenter, randomized clinical trial.

  On a winter afternoon, Peters flew up from Duke to Boston to detail a STAMP trial to the CALGB for its approval. As expected, vicious arguments broke out in the room. Some clinicians still contended that STAMP was, in fact, no different from cytotoxic chemotherapy taken to its extreme brink--stale wine being sold in a new bottle. Others contended that the chemotherapeutic battle against cancer needed to be taken to the brink. The meeting stretched hour upon hour, each side hotly debating its points. In the end, the CALGB agreed to sponsor the trial. Peters left the conference room on the sixth floor of the Massachusetts General Hospital feeling bewildered but relieved. When the hinged saloon door of the room swung closed behind him, it was as if he had just emerged out of a nasty barroom brawl.

  * The notion of using a "cocktail" of drugs against HIV was borrowed from oncology--although it would be several years before anti-HIV drugs were available.

  The Map and the Parachute

  Oedipus: What is the rite of purification? How shall it be done?

  Creon: By banishing a man, or expiation of blood by blood.

  --Sophocles, Oedipus the King

  William Peters was trying to convince himself, using a strict randomized trial, that megadose chemotherapy worked. But others were already convinced. Many oncologists had long assumed that the regimen was so obviously effective that no trial could possibly be needed. After all, if the deepest reservoirs of the marrow could be depleted by the searing doses of drugs, how could cancer possibly resist?

  By the late 1980s, hospitals and, increasingly, private clinics offering marrow transplantation for breast cancer had sprouted up all around America, Great Britain, and France with waiting lists that stretched into several hundreds of women. Among the most prominent and successful of the megadose transplanters was Werner Bezwoda, an oncologist at the University of Witwatersrand in Johannesburg, South Africa, who was recruiting dozens of women into his trial every month. Transplant was big business: big medicine, big money, big infrastructure, big risks. At large academic centers, such as the Beth Israel hospital in Boston, entire floors were refitted into transplant units, with case volumes that ran into several dozens each week. Minimizing the risks of the procedure using creative phrasing became a cottage industry. As private clinics lined up to perform transplants on women, they christened the procedure a "minitransplant" or "transplant lite" or even "drive-thru transplant." Transplanters, as one oncologist put it, "became gods at hospitals."

  This frantic landscape was tipped into further disarray as patients began to file requests for insurance providers to pay for the procedure, priced anywhere between $50,000 to $400,000 per patient. In the summer of 1991, a public-school teacher named Nelene Fox in Temecula, California, was diagnosed with advanced breast cancer. Fox was thirty-eight years old, the mother of three children. When she relapsed with metastatic breast cancer after exhausting all conventional therapies, her doctors suggested an autologous bone marrow transplant as a last resort. Fox lunged at the suggestion. But when she applied to Health Net, her insurance provider, to pay for the transplant, Health Net refused, stating that the procedure was still "investigational" and thus not covered by the HMO's standard list of clinically proven protocols.

  In another decade and with any other disease, Fox's case may have garnered scarcely any public attention. But something fundamental about the relationship between patients and medicine had changed in the aftermath of AIDS. Until the late 1980s, an experimental drug or procedure had been considered precisely that, experimental, and therefore unavailable for general public use. But AIDS activism had transformed that idea. An investigational agent, AIDS activists insisted, was no longer a hothouse flower meant to be cultivated only in the rarefied greenhouses of academic medicine, but rather a public resource merely waiting in the warming antechamber of science while doctors finished clinical trials that would, in the end, prove the efficacy of said drugs or procedures anyway.

  Patients, in short, had lost patience. They did not want trials; they wanted drugs and cures. ACT UP, parading on the streets of New York and Washington, had made the FDA out to be a woolly bureaucratic grandfather--exacting but maddeningly slow, whose sole purpose was to delay access to critical medicines. Health Net's denial of Nelene Fox's transplant thus generated a visceral public reaction. Furious and desperate, Fox decided to raise the money privately by writing thousands of letters. By mid-April 1992, an enormous fund-raising effort to pay for Fox's transplant had swung into gear. Temecula, a quiet hamlet of golf courses and antique shops, was gripped by a mission. Money poured in from softball matches and pie sales; from lemonade stands and car washes; from a local Sizzler restaurant; from a yogurt shop that donated a portion of its profits. On June 19, a retinue of Fox's supporters, chanting, "Transplant, transplant," and Fox's name, staged a rally outside Health Net's corporate headquarters. A few days later, Fox's brother, an attorney named Mark Hiepler, filed a lawsuit against Health Net to force the HMO to pay for his sister's transplant. "You marketed this coverage to her when she was well," Hiepler wrote. "Please provide it now that she is ill."

  In the late summer of 1992, when Health Net refused yet another request for coverage, once again citing lack of clinical evidence, Fox chose to go ahead on her own. By then, she had raised $220,000 from nearly twenty-five hundred friends, neighbors, relatives, coworkers, and strangers--enough to afford the transplant on her own.

  In August 1992, Nelene Fox thus underwent high-dose chemotherapy and a bone marrow transplant for metastatic breast cancer, hoping for a new lease on her life.

  In the gleaming new wards of the Norris Center in Los Angeles, where Fox was undergoing her transplant, the story of Werner Bezwoda's remarkable success with megadose chemotherapy was already big news. In Bezwoda's hands, everything about the regimen seemed to work like a perfectly cast spell. A stocky, intense, solitary man capable, Oz-like, of inspiring both charm and suspicion, Bezwoda was the self-styled wizard of autologous transplantation who presided over an ever-growing clinical empire at Witwatersrand in Johannesburg with patients flying in from Europe, Asia, and Africa. As Bezwoda's case series swelled, so, too, did his reputation. By the mid-1990s, he was regularly jetting up from South Africa to discuss his experience with megadose chemotherapy at meetings and conferences organized all around the world. "The dose-limiting barrier," Bezwoda announced audaciously in 1992, had been "overcome"--instantly rocketing himself and his clinic into stratospheric fame.

  Oncologists, scientists, and patients who thronged to his packed seminars found themselves mesmerized by his results. Bezwoda lectured slowly and dispassionately, in a bone-dry, deadpan drone, looking occasionally at the screen with his characteristic sideways glance, delivering the most exhilarating observations in the world of clinical oncology as if reading the Soviet evening news. At times the ponderous style seemed almost deliberately mismatched, for even Bezwoda knew that his results were astounding. As the lights flickered on for the poster session at the annual oncology meeting held in San Diego in May 1992, clinicians flocked around him, flooding him with questions and congratulations. In Johannesburg, more than 90 percent of women treated with the megadose regimen had achieved a complete response--a rate that even the powerhouse academic centers in the United States had been unable to achieve. Bezwoda, it seemed, was go
ing to lead oncology out of its decades-long impasse with cancer.

  Nelene Fox, though, was not so fortunate. She soldiered through the punishing regimen of high-dose chemotherapy and its multiple complications. But less than one year after her transplant, breast cancer relapsed explosively all over her body, in her lungs, liver, lymph nodes, and, most important, in her brain. On April 22, eleven months after Bezwoda's poster was hung up in nearby San Diego, Fox passed away in her home in a shaded cul-de-sac in Temecula. She was only forty years old. She left behind a husband and three daughters, aged four, nine, and eleven. And a lawsuit against Health Net, now winding its way through the California court system.

  Juxtaposed against Bezwoda's phenomenal results, Fox's agonizing struggle and untimely death seemed an even more egregious outcome. Convinced that the delayed transplant--not cancer--had hastened his sister's demise, Hiepler broadened his claims against Health Net and vigorously pushed for a court trial. The crux of Hiepler's case rested on the definition of the word "investigational." High-dose chemotherapy could, he argued, hardly be considered an "investigational" procedure if nearly every major clinical center in the nation was offering it to patients, both on and off trial. In 1993 alone, 1,177 papers in medical journals had been written on the subject. In certain hospitals, entire wards were dedicated to the procedure. The label "experimental" was slapped on, Hiepler contended, by HMOs to save money by denying coverage. "If all you have is a cold or the flu, sure, they will take good care of you. But when you get breast cancer, what happens? Out comes 'investigative.' Out comes 'experimental.'"

  On the morning of December 28, 1993, Mark Hiepler spent nearly two hours in the courtroom describing the devastating last year of his sister's life. The balconies and benches overflowed with Fox's friends and supporters and with patients, many of them weeping with anger and empathy. The jury took less than two hours to deliberate. That evening, it returned a verdict awarding Fox's family $89 million in damages--the second-highest amount in the history of litigation in California and one of the highest ever awarded in a medical case in America.

  Eighty-nine million dollars was largely symbolic (the case was eventually settled out of court for an undisclosed smaller amount), but it was also the kind of symbolism that any HMO could readily understand. In 1993, patient advocacy groups urged women to battle similar cases around the country. Understandably, most insurers began to relent. In Massachusetts, Charlotte Turner, a forty-seven-year-old nurse diagnosed with metastatic breast cancer, lobbied ferociously for her transplant, rushing on a wheelchair from one legislator's office to another with sheaves of medical articles in her arms. In late 1993, as a result of Turner's efforts, the Massachusetts state legislature enacted the so-called Charlotte's Law, mandating coverage for transplantation for eligible patients within the state. By the mid-1990s, seven states required HMOs to pay for bone marrow transplantation, with similar legislation pending in seven additional states. Between 1988 and 2002, eighty-six cases were filed by patients against HMOs that had denied transplants. In forty-seven instances, the patient won the case.

  That this turn of events--aggressive chemotherapy and marrow transplantation mandated by law--was truly extraordinary was not lost on many observers. It was, at face value, a liberating moment for many patients and patient advocates. But medical journals ran rife with scorching critiques of the protocol. It is a "complicated, costly and potentially dangerous technology," one article complained pointedly. The litany of complications was grim: infections, hemorrhage, blood clots in the arteries and the liver, heart failure, scarring of lungs, skin, kidneys, and tendons. Infertility was often permanent. Patients were confined to the hospital for weeks, and most ominous perhaps, between 5 and 10 percent of women ran the risk of developing a second cancer or precancerous lesion as a result of the treatment itself--cancers doggedly recalcitrant to any therapy.

  But as autologous transplantation for cancer exploded into a major enterprise, the scientific evaluation of the protocol fell further and further behind. Indeed the trials were caught in an old and perverse quagmire. Everyone--patients, doctors, HMOs, advocacy groups--wanted trials in principle. But no one wanted to be in trials, in practice. The more health insurance plans opened their floodgates for bone marrow transplantation, the more women fled from clinical trials, fearing that they might be assigned to the nontreatment arm by what amounted to a coin flip.

  Between 1991 and 1999, roughly forty thousand women around the world underwent marrow transplantation for breast cancer, at an estimated cost of between $2 billion and $4 billion (at the higher estimate, about twice the yearly budget of the NCI). Meanwhile, patient accrual for the clinical trials, including Peters's trial at Duke, nearly trickled to a halt. The disjunction was poignant. Even as clinics overflowed with women being treated with high-dose chemotherapy and wards filled their beds with transplanted patients, the seminal measure to test the efficacy of that regimen was pushed aside, almost as if it were an afterthought. "Transplants, transplants, everywhere," as Robert Mayer put it, "but not a patient to test."

  When Bezwoda returned to the annual cancer meeting in Atlanta in May 1999, he was clearly triumphant. He rose to the podium confidently, feigning irritation that his name had been mispronounced during the introduction, and flashed his opening slides. As Bezwoda presented the data--his monotone voice washing over the vast sea of faces in front of him--a spell of silence fell over the audience. The wizard of Wits had worked magic again. At Witwatersrand hospital, young women with high-risk breast cancer treated with bone marrow transplants had showed staggeringly successful results. At eight and a half years, nearly 60 percent of patients in the megadose/transplant arm were still alive, versus only 20 percent in the control arm. For patients treated with the Bezwoda regimen, the line of survival had plateaued at about seven years with no further deaths, suggesting that many of the remaining patients were not just alive, but likely cured. Applause broke out among transplanters.

  But Bezwoda's triumph felt odd, for although the Witwatersrand results were unequivocally spectacular, three other trials presented that afternoon, including Peters's, were either equivocal or negative. At Duke, embarrassingly enough, the trial had not even been finished because of low accrual. And while it was too soon to assess the survival benefits of transplantation, its darker face was readily evident: of the three-hundred-odd patients randomized to the transplant arm, thirty-one women had died of complications--of infections, blood clots, failed organs, and leukemias. The news from Philadelphia was even more grim. The megadose chemotherapy regimen had not produced a hint of benefit, not "even a modest improvement," as the investigators glumly informed the audience. A complex and tangled trial from Sweden, with patients divided into groups and subgroups, was also headed inexorably toward failure with no obvious survival benefit in sight.

  How, then, to reconcile these vastly disparate results? The president of the American Society of Clinical Oncology (ASCO) had asked a panel of discussants to try to hammer all the contradictory data into a single cohesive shape, but even the experts threw up their hands. "My goal here," one discussant began, frankly befuddled, "is to critique the data just presented, to maintain some credibility in the field, and to continue to remain friends with both the presenters and the discussants."

  But even that would be a tall order. On and off the stage, the presenters and discussants bickered about small points, hurling critiques at each other's trials. Nothing was resolved and certainly no friendships were made. "People who like to transplant will continue to transplant, and people who don't will continue not to," Larry Norton, the powerful breast oncologist and president of the National Alliance of Breast Cancer Organizations (NABCO), told a journalist from the New York Times. The conference had been a disaster. As the exhausted audience trickled out of the massive auditorium in Atlanta, it was already dark outside and the warm, muggy blast of air provided no relief.

  Bezwoda left the Atlanta meeting in a hurry, leaving behind a field awash with confu
sion and tumult. He had underestimated the impact of his data, for it was now the sole fulcrum on which an entire theory of cancer therapy, not to mention a $4 billion industry, rested. Oncologists had come to Atlanta for clarity. They left exasperated and confused.

  In December 1999, with the benefits of the regimen still uncertain and thousands of women clamoring for treatment, a team of American investigators wrote to Bezwoda at Witwatersrand to ask if they could travel to Johannesburg to examine the data from his trial in person. Bezwoda's transplants were the only ones that had succeeded. Perhaps important lessons could be learned and brought back to America.

  Bezwoda readily agreed. On the first day of the visit, when the investigators requested the records and logbooks of the 154 patients in his study, Bezwoda sent them only 58 files--all, oddly, from the treatment arm of the trial. When the team pressed for records from the control arm, Bezwoda claimed that they had been "lost."

  Mystified, the team probed further, and the picture began to turn disturbing. The records provided were remarkably shoddy: scratched-out, one-page notes with random scribbles written almost as an afterthought, summarizing six or eight months of supposed care. Criteria for eligibility for the trial were virtually always missing in the records. Bezwoda had claimed to have transplanted equal numbers of black and white women, yet nearly all the records belonged to poor, barely literate black women treated at the Hillbrow Hospital in Johannesburg. When the reviewers asked for consent forms for a procedure known to have deadly consequences, no such forms could be found. The hospital's review boards, meant to safeguard such protocols, certainly had no copies. No one, it seemed, had approved the procedure or possessed even the barest knowledge of the trial. Many of the patients counted as "alive" had long been discharged to terminal-care facilities with advanced, fungating lesions of breast cancer, presumably to die, with no designated follow-up. One woman counted in the treatment arm had never been treated with any drugs. Another patient record, tracked back to its origin, belonged to a man--obviously not a patient with breast cancer.