The Emperor of All Maladies

The world has paid too little attention to cancer over the last two years. Following the onset of the Covid-19 pandemic in early 2020, many cancer screening centers closed for a period of months, and routine procedures were put off to prioritize Covid patients and reduce risk. Screenings in April 2020 at the Center for Disease Control’s National Breast and Cervical Cancer Early Detection Program declined by over 80 percent compared to that same month in previous years. In light of the anticipation of another wave of Covid cases this coming fall and winter and the realization that the virus has yet to recede in the rearview mirror, a look back at Siddhartha Mukherjee’s 2011 book on cancer is not only worthwhile, but timely.

The Emperor of All Maladies, an extraordinary book aptly subtitled “A Biography of Cancer,” is as deep a dive into a family of diseases and the millennia-old effort to understand, treat, and cure them as we are ever likely to see. Mukherjee, the Pulitzer Prize-winning author, is both a cancer clinician and a scholar of the disease. Fortunately, he is also a gifted storyteller with a poetic eye and ear for metaphor and analogy. Even so, the abundant detail and sheer bulk of his narrative are daunting.

More than four thousand years ago, an Egyptian physician named Imhotep identified a tumor; and, around 400 B.C., Hippocrates named the disease, noting its resemblance to Cancer, the astrological crab. But other than the Roman physician Galen’s mention of some bizarre medicines for “black bile,” Mukherjee finds little mention of the malady for almost two millennia, until Andreas Vesalius’ 16^th-century anatomical drawings. Since then, cancer’s signature sequence—invasion of a site, repulsion of putative cures, metastasis to other sites—has drawn the attention, even obsession, of generations of investigators from many different fields. Until very recently, they had precious little to show for their efforts.

In Mukherjee’s adroit hands, this centuries-old story of dogged trial-and-error efforts to treat this dimly perceived scourge—invariably followed by failure, spawning newer efforts based on fresh theories of causation and control—is inspiring. We glimpse the harsh discipline of science in the stories of these pioneers, whose lonely trails almost invariably led to dead ends.

Treatment efforts intensified in the 1860s with the development of antiseptics and anesthesia, which made more complex and radical surgery possible. William Stewart Halsted, a leading figure in this advance, described a cheap, accessible, foolproof, and easy-to-dose substance—cocaine—that became the “fast food of surgical anesthesia.” So alluring was it that Halsted himself became addicted to it while he expanded its use in attempting ever more radical mastectomies. The radical surgery, though it lacked proof of effectiveness, nevertheless “drew the blinds of circular logic around itself for nearly a century.”

Some putative advances, like radium, turned out to cause cancer, not cure it. Other innovations, like the development of chemical dyes, enabled better tracking of cancerous cells.

Genuine progress against cancer had to await a serious commitment to large-scale scientific research after World War II. Mukherjee, invoking Tocqueville’s paean to private civic energy, details the crusading organizational efforts of Mary Lasker and Dr. Sidney Farber, who together created remarkable momentum for a scientific war against cancer—first by orchestrating the anti-leukemia “Jimmy Fund,” showcased by Ted Williams and other baseball stars and modeled on the anti-polio March of Dimes. Mukherjee shows how they mobilized political entrepreneurship and quasi-religious zeal to produce the National Institutes of Health, the National Cancer Institute (NCI), and, in 1971, the National Cancer Act, likened to a “moon shot.” (While noting that many scientists opposed the act, he inexplicably fails to explain why.)

Pure happenstance also played a key role in the war on cancer, as exemplified in the work of Min Chiu Li, a fugitive researcher from wartime China, fired by NCI for using a chemical on a woman whose symptoms then disappeared. In other words, he effected the first chemotherapeutic cure of cancer in adults—and established a basic principle of oncology: cancer must be treated even after every visible sign of it has vanished. In the mid-1970s, Dr. Larry Einhorn stunned the cancer world by curing a solid organ tumor with chemotherapy.

But these victories, despite overhyping, were very limited; the individual battlefields were small. Genuine progress would require researchers to appreciate the “colossal diversity” of what was a “shape-shifting disease.” Such a comprehensive view, however, was impeded by practitioners’ commitment to radical surgery and their resistance to rigorously designed and controlled trials on appropriately selected groups of patients. Patients’ recruitment, unfortunately, had to come through their doctors, who were often “precisely those who have the least interest in having a theory rejected or disproved.”

For breast cancer, a condition embedded in a legacy of radical surgery, these conflicts were “particularly charged.” But maverick researchers increasingly believed that the traditional “mastectomy or lumpectomy-plus-radiation” approach had no scientific basis. Decisively, they were joined by a growing “medical feminism,” in which women increasingly resisted their surgeons’ preferences. But another major problem arose: Patients worried that in a rigorous blind trial, they might unknowingly receive the placebo (or no surgery) and thus lose the possibility of a cure. Accordingly, recruiting adequate numbers for a trial took years. But radical surgery had been discredited; and, when it was abandoned, an “entire culture of surgery … collapsed with it.” The radical mastectomy, Mukherjee notes, is “rarely, if ever, performed by surgeons today.”

Another unfulfilled hope that detection would lead to cure involved the screening technique of mammography—for which there was great initial enthusiasm, especially in Europe. Between 1976 and 1992, enormous parallel trials of mammography were launched there and in Canada. Mukherjee explains the design and procedural obstacles that confronted and ultimately undermined the scientific value of these trials. Sometimes rigorous controls were embedded into the trials, sometimes not. Even when controls were present by design, execution of the trials was scattershot or biased in ways that defeated the random assignment of patients.

One trial, for example, selectively removed high-risk patients from the mammography group; another trial did just the opposite. The Malmo study in Sweden was exceptionally well run and accurately detected early cancers; but it turned out to benefit only older women and then only modestly, a pattern that plagued later studies as well. The problems, Mukherjee concludes, were the complexity of early detection trials, the conundrum of over- and underdiagnosis, and the sensitivity of the results to the ages of the women involved. The limits on scientists’ knowledge about how carcinogenicity actually works were—and, to an extent, remain today—the root problems.

The scientific and political struggles over smoking occupy, appropriately, a substantial chunk of the book. It describes tobacco’s vast human toll even today: the massive legal and political struggles required to regulate the products, the relative roles of public health and legal reformers in exposing the peril, the industry’s political power, its many deceptions and evasions, and the long tail of the distribution of lethal risk. Mukherjee begins this knotted, tragic story with an 18^th-century surgeon, Percivall Pott, who inferred, epidemiologically, that cancer could be caused by environmental agents and thus was preventable. In a cruel irony, the ubiquitous use of tobacco made the causal relationship much harder to discern: Indeed, a leading epidemiologist, Richard Doll, first attributed it to road tar exposure.

The rest of the tobacco story is well known: a public health establishment of the 1950s that was “largely unperturbed” by the epidemiological evidence; the industry’s cynical deployment of geneticists and other “experts” as dupes; the conversion of Surgeon General Luther Terry; the regulation of cigarette advertising by a rejuvenated Federal Trade Commission; the warning label fiasco; the tireless, innovative legal campaigner John Banzhaf; the dramatic announcement by the dying actor William Talman that smoking was killing him; the consumer class actions and state litigation that culminated in the Master Settlement Agreement; the evasions of the agreement by the industry; the export of the tobacco scourge abroad; and the continuing toll among American smokers today, sixty years after the surgeon general’s report, a “devastation” that Mukherjee personally witnessed in the cancer wards he visited.

The rest of the book presents the evolution of our post-1970s scientific knowledge about the nature, detection, prevention, and treatment of various cancers, including the inspiring crusade against AIDS by the gay community. The passage of time has only revealed the extraordinary variety of causes of the many discrete types of cancers. The most important of these new discoveries concerns the plagues caused by viruses and bacteria. These exceedingly complex agents, Mukherjee explains, have vastly expanded our knowledge not only of cancer’s etiology but, crucially, of the fundamental nature of carcinogenicity itself. The most important windows into this world have been opened by advances in research on genes, DNA, RNA, proteins, enzymes, and their complex interactions. Mutagenicity—chemical changes in a cell’s DNA—plays a particularly critical role, as Berkeley bacteriologist Bruce Ames has established over the past fifty years.

This extraordinary book concludes on a characteristic note of cautious optimism. Mukherjee is taken with the figure of what he calls “the Red Queen syndrome” from Alice in Wonderland; she “moved incessantly,” he puts it, “just to keep in place.” This, he maintains, applies to screening, prevention, and every other aspect of the battle against cancer. Even smoking behavior exhibits this dynamic complexity: In the “smoking-network effect,” people smoke or refrain based on signals from their cohesive social groups. This helps explain why “even the most successful cancer-prevention strategies can lapse so swiftly.” As he illustrates with a final account of a beloved patient for whom he pulled out all the stops to no avail, we are never likely to find a definitive cure.

Peter H. Schuck, Baldwin Professor of Law Emeritus at Yale Law School, is Distinguished Scholar in Residence at NYU Law School and author of many articles and books on law, public policy, diversity, immigration, and other subjects.