The Emperor of All Maladies: A Biography of Cancer

date Apr 17, 2019
authors Siddhartha Mukherjee
reading time 16 mins

Reading this book not only gave me an insights into cancer, but also the appreciation on how medical cures are found after many trials, tests, and collection of data. And not to mention, the cure for the patients equally involves the mental and emotional.

Science is often described as an iterative and cumulative process, a puzzle solved piece by piece, with each piece contributing a few hazy pixels of a much larger picture. But the arrival of a truly powerful new theory in science often feels far from iterative. Rather than explain one observation or phenomenon in a single, pixelated step, an entire field of observations suddenly seems to crystallize into a perfect whole. The effect is almost like watching a puzzle solve itself.

Definition of Cancer

Cancer is

Cancer, we now know, is a disease caused by the uncontrolled growth of a single cell. This growth is unleashed by mutations—changes in DNA that specifically affect genes that incite unlimited cell growth. In a normal cell, powerful genetic circuits regulate cell division and cell death. In a cancer cell, these circuits have been broken, unleashing a cell that cannot stop growing.

Cells’ drive to grow

Looking at cancerous growths through his microscope, Virchow discovered an uncontrolled growth of cells — hyperplasia in its extreme form. As Virchow examined the architecture of cancers, the growth often seemed to have acquired a life of its own, as if the cells had become possessed by a new and mysterious drive to grow.

History

Oldest diesease

discovered a jawbone dating from two million years ago from a nearby site that carried the signs of a peculiar form of lymphoma found endemically in southeastern Africa (although the origin of that tumor was never confirmed pathologically). If that finding does represent an ancient mark of malignancy, then cancer, far from being a “modern” disease, is one of the oldest diseases ever seen in a human specimen—quite possibly the oldest.

Cancer has always existed

In most ancient societies, people didn’t live long enough to get cancer. Men and women were long consumed by tuberculosis, dropsy, cholera, smallpox, leprosy, plague, or pneumonia. If cancer existed, it remained submerged under the sea of other illnesses… Indeed, cancer’s emergence in the world is the product of a double negative: it becomes common only when all other killers themselves have been killed… The link was correct, but the causality was not: civilization did not cause cancer, but by extending human life spans—civilization unveiled it.

Process

Science, counting and measuring

And despite its many idiosyncrasies, leukemia possessed a singularly attractive feature: it could be measured. Science begins with counting. To understand a phenomenon, a scientist must first describe it; to describe it objectively, he must first measure it. If cancer medicine was to be transformed into a rigorous science, then cancer would need to be counted somehow—measured in some reliable, reproducible way.

Organising mundane tasks

But collecting specimens was a rather mundane task; Hodgkin’s particular genius lay in organizing them. He became a librarian as much as a pathologist; he devised his own systematics for pathology.

Being a scientist is like being a bookkeeper with skepticism

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.

Randomising trials

Hill’s proposed solution was to remove such biases by randomly assigning patients to treatment with streptomycin versus a placebo. By “randomizing” patients to each arm, any doctors’ biases in patient assignment would be dispelled. Neutrality would be enforced—and thus a hypothesis could be strictly tested. Hill’s randomized trial was a success.

Cure

Surgery or radiation

To cure cancer (if it could be cured at all), doctors had only two strategies: excising the tumor surgically or incinerating it with radiation—a choice between the hot ray and the cold knife.

Relapse

But there was always the same catch. After a few months of remission, the cancer would inevitably relapse, ultimately flinging aside even the most potent of Yella’s drugs. The cells would return in the bone marrow, then burst out into the blood, and even the most active antifolates would not keep their growth down.

Stomach cancer reduced, but lung cancer increased

With the introduction of modern refrigeration (and possibly changes in public hygiene that have diminished the rate of endemic infection), the stomach cancer epidemic seems to have abated. In contrast, lung cancer incidence in men increased dramatically in the 1950s as a result of an increase in cigarette smoking during the early twentieth century.

Over-use of surgery

By 1898, it had transformed into a profession booming with self-confidence, a discipline so swooningly self-impressed with its technical abilities that great surgeons unabashedly imagined themselves as showmen. The operating room was called an operating theater, and surgery was an elaborate performance often watched by a tense, hushed audience of observers from an oculus above the theater. To watch Halsted operate, one observer wrote in 1898, was to watch the “performance of an artist”

How is survival rate calculated? Longitudinal test

To determine whether Halsted had truly cured breast cancer, one needed to track not immediate survival, or even survival over five or ten months, but survival over five or ten years… The procedure had to be put to a test by following patients longitudinally in time.

What cancer treatment looks like

Test came after test. Seven months into her course, Carla had now visited the clinic sixty-six times, had had fifty-eight blood tests, seven spinal taps, and several bone marrow biopsies.

Recruiting for trials

For any trial to be adequately “powered,” it needs to recruit an adequate number of patients. But to recruit patients, a trialist has to convince doctors to participate in the trial—and yet these doctors are often precisely those who have the least interest in having a theory rejected or disproved.

Controlled trials for radical surgery

The only way to turn the upside-down tapestry of Halstedian theory around was to run a controlled clinical trial to test the radical mastectomy against the simple mastectomy and lumpectomy+radiation. But Fisher also knew that resistance would be fierce to any such trial.

Experience != Scientific validity

“The clinician, no matter how venerable, must accept the fact that experience, voluminous as it might be, cannot be employed as a sensitive indicator of scientific validity,” Fisher wrote in an article. He was willing to have faith in divine wisdom, but not in Halsted as divine wisdom. “In God we trust,” he brusquely told a journalist. “All others [must] have data.”

Combining surgery and chemotherapy

In his small trial, Carbone found that adding chemotherapy after surgery decreased the rate of relapse from breast cancer. To describe this form of treatment, Carbone and his team used the word adjuvant, from the Latin phrase “to help.”

Different treatment for different stages of cancer

The meticulous separation of breast cancer into distinct stages, for instance, was a crucial prerequisite to the success of Bonadonna’s study: early-stage breast cancer could not be treated like late-stage breast cancer.

Death meant failure as opposed to palliative care

The resistance to providing palliative care to patients,” a ward nurse recalls, “was so deep that doctors would not even look us in the eye when we recommended that they stop their efforts to save lives and start saving dignity instead… doctors were allergic to the smell of death. Death meant failure, defeat—their death, the death of medicine, the death of oncology.”

Early detection tests saved lives

Finally, Cairns factored in screening strategies such as Pap smears and mammograms that detected cancer in its early stages. These, he estimated loosely, saved an additional 10,000 to 15,000 cancer-related deaths per year. The grand tally, generously speaking, amounted to about 35,000 to 40,000 lives per year.

How to measure success rate of cancer?

A young woman cured of lymphoma, with fifty additional years of life, was judged by the same metric as an elderly woman cured of breast cancer, who might succumb to some other cause of death in the next year. If “years of life saved” was used as a measure of progress on cancer, then the numbers turned far more palatable. Now, instead of losing the War on Cancer, it appeared that we were winning it.

3 approaches to cancer

Frank Rauscher, wrote effusively about its three-pronged approach to cancer: “Treatment, Rehabilitation and Continuing Care.” That there was no mention of either prevention or early detection was symptomatic: the institute did not even consider cancer prevention a core strength.

Types of cancer

Link between scrotal cancer and soot!

But as cases streamed into his London clinic, he noticed a larger trend. His patients were almost invariably chimney sweeps or “climbing-boys”—poor, indentured orphans apprenticed to sweeps and sent up into chimneys to clean the flues of ash, often nearly naked and swathed in oil. The correlation startled Pott.

External agents causing cancer

The implication of Pott’s work was far-reaching. If soot, and not some mystical, numinous humor (à la Galen), caused scrotal cancer, then two facts had to be true. First, external agents, rather than imbalances of internal fluids, had to lie at the root of carcinogenesis!… Second, if a foreign substance was truly the cause, then cancer was potentially preventable.

How lunch cancer spread

By 1855, English, Russian, and French soldiers were all puffing their tobacco rations rolled up in paper. When these soldiers returned from the war, they brought their habits, like viruses again, to their respective homelands with them.

Linking lung cancer with smoking

By May 1, 1948, 156 interviews had come in. And as Doll and Hill sifted through the preliminary batch of responses, only one solid and indisputable statistical association with lung cancer leapt out: cigarette smoking. As more interviews poured in week after week, the statistical association strengthened… In the middle of the survey, sufficiently alarmed, he gave up smoking.

Smoking and lung cancer

Piece by piece, a highly incontrovertible and consistent picture emerged. The relationship between smoking and lung cancer, the committee found, was one of the strongest in the history of cancer epidemiology—remarkably significant, remarkably conserved between diverse populations, remarkably durable over time, and remarkably reproducible in trial after trial.

Curable cancer

The Pap smear had, in effect, pushed the clock of cancer detection forward by nearly two decades, and changed the spectrum of cervical cancer from predominantly incurable to predominantly curable.

Biology and cells

Carcinogenesis

Varmus and Bishop’s theory—that oncogenes were activated cellular genes—was recognized to be widely true for many forms of cancer. And the two-hit hypothesis—that tumor suppressors were genes that needed to be inactivated in both chromosomes—was also found to be widely applicable in cancer. A rather general conceptual framework for carcinogenesis was slowly becoming apparent.

Cause of diesease explanation

Koch had postulated that for an agent to be identified as the “cause” of a disease, it must (1) be present in the diseased organism, (2) be capable of being isolated from the diseased organism, and (3) re-create the disease in a secondary host when transferred from the diseased organism. Oncogenes had met the first two criteria. They had been found to be present in cancer cells and they had been isolated from cancer cells. But no one had shown that a cancer gene, in and of itself, could create a bona fide tumor in an animal.

Pre-cancer cells were discovered to be everywhere

This was a relief. In the decade between 1980 and 1990, proto-oncogenes and tumor suppressor genes had been discovered in such astonishing numbers in the human genome—at last count, about one hundred such genes—that their abundance raised a disturbing question: if the genome was so densely littered with such intemperate genes—genes waiting to push a cell toward cancer as if at the flick of a switch—then why was the human body not exploding with cancer every minute?… First, proto-oncogenes need to be activated through mutations, and mutations are rare events. Second, tumor suppressor genes need to be inactivated, but typically two copies exist of each tumor suppressor gene, and thus two independent mutations are needed to inactivate a tumor suppressor, an even rarer event.

Cancer is all genetics

Cancer, in short, was not merely genetic in its origin; it was genetic in its entirety. Abnormal genes governed all aspects of cancer’s behavior. Cascades of aberrant signals, originating in mutant genes, fanned out within the cancer cell, promoting survival, accelerating growth, enabling mobility, recruiting blood vessels, enhancing nourishment, drawing oxygen—sustaining cancer’s life.

We suggest that the vast catalog of cancer cell genotypes is a manifestation of six essential alterations in cell physiology that collectively dictate malignant growth.

  1. Self-sufficiency in growth signals
  2. Insensitivity to growth-inhibitory (antigrowth) signals
  3. Evasion of programmed cell death (apoptosis)
  4. Limitless replicative potential
  5. Sustained angiogenesis
  6. Tissue invasion and metastasis

Future of cancer cure

Hope

The mortality for nearly every major form of cancer — lung, breast, colon, and prostate — had continuously dropped for fifteen straight years. There had been no single, drastic turn but rather a steady and powerful attrition: mortality had declined by about 1 percent every year. The rate might sound modest, but its cumulative effect was remarkable: between 1990 and 2005, the cancer-specific death rate had dropped nearly 15 percent, a decline unprecedented in the history of the disease.

What caused the decline in deaths?

What precipitated this steady decline? There was no single answer but rather a multitude. For lung cancer, the driver of decline was primarily prevention… For colon and cervical cancer, the declines were almost certainly due to the successes of secondary prevention — cancer screening… For leukemia, lymphoma, and testicular cancer, in contrast, the declining numbers reflected the successes of chemotherapeutic treatment… Perhaps most symbolically, the decline in breast cancer mortality epitomized the cumulative and collaborative nature of these victories—and the importance of attacking cancer using multiple independent prongs (mammography, surgery, chemotherapy).

It’s not a one-time cure, but an ongoing process

Our bodies, our cells, our genes are thus being immersed and reimmersed in a changing flux of molecules—pesticides, pharmaceutical drugs, plastics, cosmetics, estrogens, food products, hormones, even novel forms of physical impulses, such as radiation and magnetism. Some of these, inevitably, will be carcinogenic. We cannot wish this world away; our task, then, is to sift through it vigilantly to discriminate bona fide carcinogens from innocent and useful bystanders.

Cell phone scare about cancer was totally false

The cell phone case is a sobering reminder of the methodological rigor needed to evaluate new carcinogens. It is easy to fan anxiety about cancer. Identifying a true preventable carcinogen, estimating the magnitude of risk at reasonable doses and at reasonable exposures, and reducing exposure through scientific and legislative intervention—keeping the legacy of Percivall Pott alive—is far more complex.

Cancer Genome Atlas

The Human Genome Project, the full sequence of the normal human genome, was completed in 2003. In its wake comes a far less publicized but vastly more complex project: fully sequencing the genomes of several human cancer cells. Once completed, this effort, called the Cancer Genome Atlas, will dwarf the Human Genome Project in its scope… As of 2009, the genomes of ovarian cancer, pancreatic cancer, melanoma, lung cancer, and several forms of leukemia have been sequenced, revealing the full catalog of mutations in each tumor type.

Identifying preventable carcinogens

But important preventable carcinogens might escape detection by either strategy. Subtle risk factors for cancer require enormous population studies; the subtler the effect, the larger the population needed. Such vast, unwieldy, and methodologically challenging studies are difficult to fund and launch.

Philosophical

Survival

Perhaps cancer defines the inherent outer limit of our survival. As our cells divide and our bodies age, and as mutations accumulate inexorably upon mutations, cancer might well be the final terminus in our development as organisms.

Progress must be balanced with nihilism and over-optimism

There is a very clear place that lies between the nihilism that has been reported in the media lately and the over-optimism—or the hype that existed thirty years ago. To lean in one direction while neglecting the other does a disservice to the progress that has been made.

Cancer patient

To take care of cancer patients is an enormous privilege, but it also involves deploying everything in your toolbox: the emotional, the psychological, the scientific, the epidemiologic. There’s laboratory science, history, clinical trials, and palliative medicine. Every aspect of medicine is involved, and the difference that you can make to a person’s life as an oncologist is incredible.

Areas of improvements

There are four significant areas. The first is the role of the immune system in certain kinds of cancer… The second area is cancer metabolism… The third area of interest is the role of gene regulation in cancer cells… The final area of promising investigation is the role of the microenvironment of cancer cells, and its relationship with growth, invasion, and metastasis.

Possible changes in lifestyle

We should avoid exposure to tobacco and avoid or reduce our exposure to alcohol. We could eat low-meat, fiber-rich diets, we could avoid exposure to UV and to ionizing radiation.