The Emperor of All Maladies

Siddhartha Mukherjee · 2010

Thesis

Cancer is not one disease but many, rooted in the same machinery that lets normal cells grow, and the history of the fight against it, from radical surgery and toxic chemotherapy to prevention and drugs aimed at specific genetic faults, is a story of progress achieved only when doctors stopped relying on bold theories and began understanding the disease itself.

Strength of evidence: clinical consensus on the history it tells. Its account rests on the published trials and studies it narrates, but its treatment details date from 2010 and predate later advances.

The main ideas

Cancer is as old as recorded medicine, but it became a dominant disease as people lived longer and other causes of death declined.
For decades, treatment followed the logic of more: more extensive surgery, more toxic drugs, often without evidence that more was better.
Randomized trials, not authority, showed which treatments worked.
Prevention, above all ending smoking, has saved more lives than many treatments.
Cancer arises from mutations in normal genes that control cell growth.
Understanding those genes made possible drugs that target specific cancers precisely.
Ambition and public money can speed research, but promises of quick victory have repeatedly failed.

A biography of cancer

Siddhartha Mukherjee is an oncologist who studied at Stanford, Oxford and Harvard Medical School and trained in cancer medicine at Massachusetts General Hospital and the Dana-Farber Cancer Institute. The Emperor of All Maladies, published in 2010, won the 2011 Pulitzer Prize for General Nonfiction and became the basis of a six-hour PBS documentary produced with Ken Burns in 2015.

Its title comes from a phrase a nineteenth-century surgeon inscribed in a book: "the emperor of all maladies, the king of terrors."

The book is framed by a patient, Carla Reed, a kindergarten teacher from Ipswich, Massachusetts, diagnosed with leukemia in 2004. Her treatment runs through the book, while Mukherjee narrates the history behind each step of it, from ancient Egypt to the laboratories of the 2000s.

Implication: read the treatments offered for any disease as the latest chapter of a history, shaped by what was tried and what failed.

The oldest disease

Mukherjee traces the first recorded description of cancer to an Egyptian papyrus attributed to the physician Imhotep, who described a bulging mass in the breast and, under treatment, noted that there was none.

He also returns repeatedly to Atossa, a Persian queen described by the Greek historian Herodotus as having a mass in her breast, probably cancer. Mukherjee uses her as a recurring figure, imagining how she would have been treated in each era.

Cancer was rarer in the past partly because people died earlier of other causes. As life expectancy rose and infectious diseases were controlled, cancer, which becomes more common with age, emerged as a leading cause of death.

The mechanism is that the more medicine conquers other diseases, the more cancer it reveals.

Implication: rising cancer rates can partly reflect success elsewhere, so compare rates adjusted for age before concluding that a population's risk has worsened.

Radical surgery

In the late nineteenth century, William Stewart Halsted of Johns Hopkins developed the radical mastectomy, removing the breast, the chest muscles beneath it and the lymph nodes of the armpit. The theory was that cancer spread outward from the tumor, so cutting more widely would cure more patients. Surgeons extended the logic further over the following decades.

The theory went untested for nearly a century. In 1971, the surgeon Bernard Fisher began a randomized trial of 1,765 women, comparing the radical mastectomy with less extensive operations. It found no survival advantage for the radical surgery, and a 25-year follow-up confirmed the result. Later trials showed that removing only the tumor, followed by radiation, was comparable for many women.

The mechanism is that a plausible theory backed by revered authority can dictate practice for generations if no one tests it.

Implication: when a treatment is justified by its logic rather than by trial results, ask whether it has ever been compared with something less drastic.

Chemotherapy

In 1948, Sidney Farber, a pathologist in Boston, reported that a drug called aminopterin, which blocked the action of folic acid, had produced temporary remissions in 10 of 16 children with acute leukemia. It was the first sign that a drug could push back a cancer.

From this beginning came the era of chemotherapy. Researchers learned that combining several drugs could overcome the cancer's ability to resist any single one, and childhood leukemia became one of the first cancers that could often be cured with drugs.

The success encouraged a belief that more drugs at higher doses would cure other cancers. In the 1980s and 1990s, women with breast cancer were given extremely high doses of chemotherapy followed by bone marrow transplants. Trials eventually showed no benefit, and the most encouraging results, from the South African oncologist Werner Bezwoda, proved to have been fabricated.

The mechanism is that early success can harden into a doctrine, and a doctrine can persist long after the evidence for extending it has run out.

Implication: be skeptical when a treatment that works for one condition is pushed to its limits for others without new evidence.

The war on cancer

Mukherjee describes how Mary Lasker, a philanthropist and lobbyist, and Farber built a political movement for cancer research. Their campaign led to the National Cancer Act, signed by President Richard Nixon in December 1971, which greatly expanded federal funding and was presented as a war on cancer.

The money built institutions and research programs. But the promise of a swift victory rested on the assumption that cancer was a single enemy that enough money could defeat. Progress against most cancers proved far slower.

The mechanism is that political campaigns need simple goals and deadlines, while science advances through understanding that cannot be scheduled.

Implication: welcome public investment in research, but distrust promises of a cure by a set date.

Prevention

Some of the greatest gains came not from treatment but from prevention. In 1950, Ernst Wynder and Evarts Graham in the United States and Richard Doll and Austin Bradford Hill in Britain published studies linking smoking to lung cancer. The tobacco industry fought the evidence for decades, but the 1964 report of the U.S. Surgeon General, Smoking and Health, marked a turning point in public policy.

The mechanism is that identifying a cause can prevent cancers that would be very hard to cure once they had developed.

Implication: when weighing the fight against a disease, count the cases prevented as well as the patients treated.

Knowing the enemy

The decisive change came from understanding cancer's biology. Harold Varmus and J. Michael Bishop showed that src, a cancer-causing gene carried by a virus, was a version of a normal gene found in healthy cells. Cancer, it emerged, arises when genes that normally control cell growth are mutated, turning them into drivers of uncontrolled division.

This understanding made targeted drugs possible. Dennis Slamon at UCLA championed trastuzumab, sold as Herceptin, for breast cancers driven by a gene called HER2. Brian Druker led trials of imatinib, sold as Gleevec, for chronic myeloid leukemia, which caused dramatic remissions; the U.S. Food and Drug Administration approved it in 2001.

The mechanism is that a treatment designed around a cancer's specific genetic fault can attack it with far less harm to normal cells.

Implication: real progress against a complex problem usually comes from understanding its mechanism, not from applying more force.

Limits

It predates the immunotherapy era. Since 2010, drugs that release the immune system's brakes and engineered immune cells have changed treatment for several cancers, a story the book could not tell.
It concentrates on American medicine. Its history centers on American institutions, researchers and politics, with less attention to work elsewhere.
It is history, not a treatment guide. Its accounts of specific treatments reflect knowledge in 2010, and readers facing cancer need current advice.

Genius on the Edge — a biography of Halsted, whose radical mastectomy dominated cancer surgery for decades.
Agnotology — how the tobacco industry manufactured doubt about smoking and cancer.
Better + Complications — a surgeon on how medicine learns from its failures.