PDF Summary:The Emperor of All Maladies, by Siddhartha Mukherjee

The Emperor of All Maladies by Siddhartha Mukherjee is an overview and rough timeline of the fight against cancer. The book’s subtitle, A Biography of Cancer, reflects Mukherjee’s feeling that cancer is a living and evolving entity that fought modern medicine to a stalemate for centuries. Mukherjee, a doctor and biologist specializing in immunology (the study of the immune system) and oncology (the study of cancer), has spent much of his career on the front line of that fight. Though the book was first published in 2010, cancer remains a frightening disease that doctors are still working to understand and treat.

Our guide provides context and background information for Mukherjee’s book, helping you to understand the more technical aspects of cancer and cancer treatment, as well as the significance behind major events in the fight against cancer.

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1. Automatic mitosis. Cancer cells don’t need chemical signals to divide; they’re always “on.”
2. Non-responsive to antigrowth signals. Cancer cells do not respond to chemical signals that normally stop cell division.
3. “Immortality.” Cancer cells do not respond to chemical signals that normally trigger cell death (called apoptosis).
4. Limitless replication. Normal cells can divide a limited number of times; cancer cells bypass this limit, allowing for apparently infinite cell division.
5. Self-sustaining. Cancer cells induce nearby blood vessels to grow into the tumor, sustaining the tumor with oxygen and nutrients.
6. Mobility. Cancer cells can travel through the bloodstream and attach to other areas of the body (this is called metastasis).

Refining the Definition of Cancer

Although Weinberg and Hanahan aimed to provide clear guidelines for recognizing and understanding cancer, their list wasn’t comprehensive. For example, the National Cancer Institute now recognizes several other qualities of cancer cells that Weinberg and Hanahan’s list didn’t include:

• Invade other tissue types. Most cells stop dividing when they encounter other types of cells—for example, bone cells don’t normally try to grow into and through muscle tissue—but cancer cells invade any body part they encounter.

• Manipulate the immune system. The body’s immune system normally finds and kills abnormal cells, but some cancerous cells can hide from it; in some cases, they can even trick the immune system into protecting a tumor rather than destroying it.

• Use different nutrients and chemical pathways. Cancer cells don’t rely on the same nutrients as normal cells—for example, while the amino acid glutamine is a preferred energy source for all types of cells, cancer cells can substitute several different amino acids for it, making them less reliant on that particular nutrient. Furthermore, cancer cells often process those nutrients differently and more quickly than healthy cells, allowing them to grow and multiply more quickly.

Cancer Cell Genomes and Pathways

The next major development came in 2006, when a project called the Cancer Genome Atlas began sequencing the genomes (complete DNA sequences) of various cancer cells, looking for the specific collections of mutations that give rise to cancer. Early results commonly showed anywhere from five to 80 mutated genes, depending on the type of cancer. Mukherjee says these results mean that cancer cells are extremely diverse, and finding the exact mutations in any given cancer patient to inform treatment would be difficult and time-consuming.

(Shortform note: The Cancer Genome Atlas is still active today, and it contains data from some 20,000 genetic samples, making it an invaluable resource for cancer researchers. The Atlas also boasts (accurately) that it has increased our knowledge of cancer, driven improvements in genetic sequencing technology, and improved patient outcomes with targeted treatments.)

However, Mukherjee adds that a much less daunting approach would be to identify which biological pathways are affected in an individual patient and repair those, which would theoretically cure any form of cancer. Most biological processes happen through pathways—numerous genes working together to produce a single effect—and therefore many different mutations can lead to the same outcome because they all affect the same pathway. Researchers believe that the typical cancer cell has anywhere from 11 to 15 disrupted pathways, with an average of 13.

Understanding cancer at the microscopic level—through the Cancer Genome Atlas as well as other research methods—can also help scientists identify possible carcinogens; they can directly test whether particular chemicals activate cancer-related genetic pathways.

(Shortform note: Some carcinogens, including certain metals forms of radiation, inhibit pathways that repair DNA damage and activate pathways that are likely to produce errors in DNA repair, leading to cancer-causing mutations.)

Advancements in Treatment

Chemotherapy is a cornerstone of cancer treatment even today. Many of the major advancements in recent decades have centered around making chemotherapy more effective—more reliably sending patients into remission, as well as preventing relapses.

Mukherjee says that the first case of chemotherapy truly curing cancer happened in 1956. An oncologist named Min Chiu Li tracked the progress of a patient’s cancer by measuring a chemical the cancer cells secreted, rather than observing visible tumors.

Li continued treatment until that chemical marker was completely gone, which required many more doses over a much longer time period than treatment based on tumor observation. Although other doctors argued that he was being cruel and hurtful—continuing to administer nauseating and toxic drugs for no reason—Li’s patient never relapsed.

Several new discoveries showed that curing cancer usually requires—at minimum—using a combination of different treatments, and continuing the treatment regimen until all signs of cancer are gone.

A series of trials from 1957-1962 showed that drug cocktails (mixtures of multiple drugs) are significantly more effective than individual drugs. Unfortunately, according to Mukherjee, using multiple drugs also increases the danger to the patient: Drugs don’t discriminate between cancerous cells and healthy ones, so more potent treatments kill more of both types of cells.

Mukherjee writes that, in addition to combining drugs in chemo cocktails, doctors began using chemotherapy and radiation therapy together. Sidney Farber—the pathologist who studied childhood leukemia—was the first to try this approach, in 1958. He treated Wilms’ tumor (a type of kidney cancer that often spreads to the lungs) with a combination of X-rays and a drug called actinomycin D. Farber found that the combination was significantly more effective than using either treatment alone.

Around the same time, a researcher named Howard Skipper discovered that chemotherapy kills cancer cells in clear fractions of whatever remains: For instance, the first treatment might take the number of cancer cells in a patient from 1000 to 100, the second from 100 to 10, the third from 10 to 1, and a fourth round of chemotherapy finally takes the number to zero (remember that even a single surviving cancer cell can rapidly divide and cause the patient to relapse).

How Does Chemotherapy Work?

Given that chemotherapy can’t distinguish between diseased cells and healthy ones, it would be reasonable to ask how it can cure cancer without killing the patient as well. In simple terms, it works because cancer cells grow and divide so rapidly—chemotherapy targets cells at particular stages of their life cycles, and the cancerous cells go through those cycles much more quickly than (most) healthy cells. Therefore, the diseased cells die off sooner than the healthy ones.

Incidentally, this also explains many of chemotherapy’s side effects. Cells that normally reproduce quickly also die off, such as white blood cells (leading to immunosuppression) and intestinal cells (leading to nausea and digestive problems).

Chemotherapy-Resistant Cancer and the Rise of Total Therapy

Despite advancements in chemotherapy, doctors found that some cancers are resistant to the treatment. In 1962, trials of a new drug cocktail called VAMP sent leukemia patients into remission. However, most patients relapsed after approximately a year with leukemia cells in their spines and brains. Mukherjee explains that the blood-brain barrier—a protective layer of densely packed cells that separates the brain’s blood vessels from the actual brain tissue—makes the central nervous system (the brain and spine) impervious to most chemotherapy.

(Shortform note: The blood-brain barrier (BBB) is a strong, yet selective barrier: It allows necessary things like oxygen and nutrients to pass through to the brain tissue, while blocking out germs and toxins that would infect or damage the brain. Unfortunately, that barrier protects cancer cells in the central nervous system just as effectively as it protects the healthy ones.)

In 1962, a year after becoming the director of St. Jude Children’s Research Hospital, oncologist Donald Pinkel began developing a comprehensive course of treatment for childhood leukemia that he called “total therapy.” This development was based on four key innovations:

1. More elaborate drug cocktails, carefully mixing up to eight different drugs to maximize effectiveness while keeping toxicity to survivable levels
2. Bypassing the blood-brain barrier by injecting the drugs directly into the spinal fluid
3. Using X-ray radiation therapy to directly kill cancerous cells in the brain
4. Continuing treatment long after visible signs of cancer are gone—potentially for years—in order to make sure that every trace of cancer is scoured from the patient

(Shortform note: Pinkel’s total therapy regimen was extremely effective, and hospitals still use revised versions of it today. St. Jude Children’s Research Hospital—one of the world’s foremost facilities for treating childhood cancer—reports that improved technology and refined techniques have pushed the survival rate for childhood leukemia up to 94% at their hospitals.)

In 1998, researchers made another step in treating chemotherapy-resistant cancers when they developed two cancer antibodies—drugs designed to specifically target cancer cells—that sent patients into remission during clinical trials. Mukherjee says that these two drugs show that it is possible to treat cancer by targeting key genes and proteins that the disease relies on to survive. In the decade following these trials, the National Cancer Institute listed 24 drugs similar to those two as targeted cancer therapies: treatments that pinpoint a particular type of cell, as opposed to killing cells indiscriminately.

How Antibody Drugs Work

We mentioned earlier that cancer cells often hide from the immune system or, worse, manipulate it into protecting the tumor rather than destroying it. Antibody drugs are lab-grown immune system cells designed to help the immune system fight cancerous cells.

The Mayo Clinic explains that different antibody drugs have various effects, including:

• Marking cancer cells for destruction. Some antibody drugs act like flags, helping the immune system “see” the cancer cells they bind to.

• Delivering other treatments. Some antibodies can carry other treatments like chemotherapy or radiation therapy. They deliver those treatments directly to the cancerous cells, which helps to preserve healthy cells and minimize side effects of the treatment.

• Preventing cell growth. Certain antibody drugs block cancer cells from interacting with proteins that they need to continue growing, or they stop blood vessels from growing through the tumor to provide it with nutrients.

• Destroying cancer cells directly. Some types of antibody drugs cause deadly reactions inside the cells they bind to.

The Social Aspects of Cancer

Although a lot of The Emperor of All Maladies is about the history of cancer research and treatment, Mukherjee says that we mustn’t focus so much on the disease that we lose sight of the people. After all, curing cancer isn’t just an interesting puzzle to solve—fighting cancer is about helping people.

Considering the Person, Not Just the Disease

In the 1950s, an English physician named Cecily Saunders introduced the idea of palliative medicine to cancer treatment: end-of-life care designed to preserve comfort and dignity, rather than cure the disease at any cost.

Mukherjee says that, despite its name, palliative medicine was more of a social advancement than a medical one. Many doctors had refused to even consider palliative care because it felt like admitting defeat; furthermore, many people fought for the slightest chance that their loved ones could be healed, no matter the cost or the impact on the patient. However, Saunders argued that subjecting patients to painful and nauseating treatments with little hope of curing them did more harm than good—that there came a time when doctors and loved ones should let the patient stop suffering and die peacefully.

Saunders opened the world’s first modern hospice center in England in 1967. In 1974, the first American hospice opened at Yale-New Haven Hospital. By the early 1980s, hospice centers based on Saunders’s model could be found all over the world.

Misconceptions About Hospice

The purpose of hospice is to relieve patients’ symptoms and allow them to live out what remains of their lives as comfortably as possible. However, many people aren’t comfortable with the idea of hospice, often because they misunderstand what hospice does or how it works.

Here are a few common misconceptions and truths about hospice care:

• Hospice is only for elderly people. In reality, people of any age can enter into hospice care.

• Hospice must be given on an inpatient basis. In reality, many patients receive hospice care in the comfort of their own homes.

• Once you’re in hospice care, you can’t leave. In reality, patients can decide at any time to go back to the hospital or the emergency room.

• You won’t be able to see your usual doctor. In reality, hospice works with your regular physician to make sure you receive the best possible care.

The Social Aspects of the Fight Against Cancer

Mukherjee observes that fighting cancer is as much a social battle as a medical one. Funding cancer research requires people to first acknowledge that cancer exists (an unpleasant topic that many prefer to ignore), and then recognize that doctors and researchers need vast amounts of funding and resources to combat it.

Furthermore, preventing cancer often requires us to change our lifestyles and laws: For example, giving up alcohol (a personal change) and carefully regulating pesticides (a legal change) both help reduce the risk of cancer. People are often reluctant to make the necessary changes, or even to believe that they are necessary. Therefore, alongside the scientific and technological advances in cancer research, Mukherjee describes a series of social advances (and setbacks) that helped shape the fight against cancer over the years.

(Shortform note: In Creativity, Inc., Ed Catmull and Amy Wallace argue that people often resist change because they’re afraid to acknowledge that something’s wrong in the first place. They offer three tips for alleviating that fear of change: 1. Discuss why change is necessary. 2. Assess the current situation and its problems honestly. 3. Embrace the fact that the change may not go smoothly at first, and accept that there will be mistakes.)

The National Cancer Institute and the American Cancer Society

In 1937, US president Franklin Roosevelt created the National Cancer Institute (NCI), a federally funded organization intended to coordinate and lead a national effort to cure cancer. Mukherjee says that this was the first time cancer had been in the national spotlight. However, America entered World War II in 1941, just a few years later. As a result, funds and resources (as well as public attention) unfortunately were redirected from the fight against cancer to the fight against the Axis.

(Shortform note: While Mukherjee implies that the NCI fell by the wayside because of World War II, the organization continued its fight against cancer throughout the war—albeit with reduced funding—and is still active today as part of the National Institutes of Health.)

However, Mukherjee says that the distraction didn’t last long. In 1943—before the war was even over—Reader’s Digest published a series of articles on detecting and screening for cancer, thereby bringing the disease back into the public eye.

In 1944, a group of professional businesspeople took advantage of the renewed interest in cancer to take over the American Society for the Control of Cancer (ASCC). Mukherjee describes the old ASCC as a small and ineffective nonprofit group staffed by medical professionals: people whose skills lay in medicine, not in business or public relations. The new board renamed the ASCC to the American Cancer Society (ACS) and began an aggressive campaign of public education and fundraising. Donations to the ACS increased exponentially, from around $300,000 in 1943 to over $12 million in 1947.

(Shortform note: The ACS is still active today, and it is dedicated to fighting cancer on numerous fronts: helping cancer patients find and afford treatment, preventing cancer through education and screening, funding scientific research, and pushing for laws and policies that support the fight against cancer.)

The Fight Against Tobacco Advertising

In 1964, a scientific report conclusively showed that smoking cigarettes increases the risk of lung cancer. According to Mukherjee, the Federal Trade Commission (FTC) proposed that an explicit warning be put on every package of cigarettes to dissuade people from smoking. However, Congress severely weakened the FTC’s suggested warning in order to protect the tobacco industry. The final warning, which went into effect in 1965, read, “Caution: Cigarette smoking may be hazardous to your health.” That vague, watered-down message didn’t have nearly the impact on smoking rates that the FTC had hoped for.

A few years later, in 1968, a landmark court case ruled that anti-tobacco ads had to be given proportional airtime with pro-tobacco ads on TV. As a result, Mukherjee says, public opinion began to swing against the tobacco industry, and tobacco use in America steadily declined starting in 1974.

However, Mukherjee adds that—for that generation—the damage from a lifetime of smoking and tobacco addiction was already done. It would take decades to see a corresponding drop in rates of lung cancer, because that drop would mostly occur in the next generation.

(Shortform note: Although there are no longer tobacco ads on TV, tobacco companies in the US still spend billions of dollars per year advertising cigarettes, e-cigs, and other products, and they heavily target young people with their ads. E-cigarette companies also came under fire for targeting kids and teens with flavors like lemonade and candy, leading the US Food and Drug Administration to ban flavors besides tobacco and menthol in 2020. Most smokers today smoke their first cigarette before the age of 18, and the Centers for Disease Control and Prevention (CDC) attributes that—at least in part—to such marketing.)

The National Cancer Act

In 1971, President Nixon signed the National Cancer Act, committing a total of $1.5 billion to cancer research over three years. However, Mukherjee says that many scientists and advocates were disappointed with the bill, which heavily prioritized clinical drug trials—testing specific drugs and treatments—at the expense of further research into the nature of cancer and other possible methods of treatment.

In 1985, a biologist named John Cairns assembled a comprehensive report on the progress of cancer treatments since the National Cancer Act of 1971. That report, along with a 1986 report by his colleagues John Bailar and Elaine Smith, showed that cancer-related deaths had actually increased during that time period.

According to Mukherjee, Cairns’s explanation was that the extreme focus on cancer treatment was misguided. Citing precedents like cholera, scurvy, and tuberculosis, Cairns argued that the greatest results always came from preventing diseases, and the same principle must be applied to cancer.

The National Cancer Act, 50 Years Later

2021 marked the 50th anniversary of the National Cancer Act. However, as Nature magazine says, many challenges still remain in the field of cancer treatment.

When Nixon signed the act into law in 1971, cancer was the second-leading cause of death in America (behind heart disease). In 2021, that fact hadn’t changed: Cancer was still the second-leading cause of death in the country. Furthermore, there’s a major problem that the National Cancer Act didn’t address: cost. In 2021, 42% of Americans with cancer reported suffering extreme financial difficulties within two years of being diagnosed.

However, as we’ll discuss, the news isn’t all bad. While there are still challenges to overcome, the last 50 years have brought huge advances in how we understand and treat cancer, and those advancements show in greatly reduced mortality rates.

The Good News

Cancer is a difficult topic with a bleak history, but Mukherjee does have some good news for us: From 1990-2005, cancer mortality declined by about 1% per year—an unprecedented 15% decrease overall. Mukherjee says that this decrease was the result of earlier advancements in cancer prevention, screening, and treatment, such as the pushback against the tobacco industry in the 1960s and 1970s.

Advancements Since Publication

Mukherjee included data only up to 2005 because that was all that was available at the time The Emperor of All Maladies was published in 2010, but the steady decline in cancer mortality has continued. According to the CDC’s most recent data (above), in 2018, about 149 per 100,000 Americans died from cancer, or about 0.149%—in 1990, that number was 214 per 100,000, or about 0.214%. In other words, from 1990 to 2018 we’ve seen a 30% decrease in cancer mortality rates.

There have also been numerous advancements in cancer treatment, including better ways to detect the disease in its early stages, new and more effective drugs, and improved methods of delivering those drugs to historically chemo-resistant types of cancer.