CANCER IS A prehistoric disease, recognized since the time of the ancient Egyptians. The Edwin Smith Papyrus, translated in 1930, contained the medical teachings of the Egyptian physician Imhotep, who lived around 2625 BC. It describes a case of a “bulging mass in the breast” that was cool and hard to the touch.
Infections and abscesses are typically inflamed, and warm and painful when touched. By contrast, this mass was firm, cool, and not painful—something much worse. As for suggested treatment, the author had none. The Greek historian Herodotus, writing around 440 BC, describes Atossa, the queen of Persia, who likely suffered from inflammatory breast cancer. In a thousand-year-old grave site in Peru, mummified remains show a bone tumor, preserved by the dry desert climate. A two-million-year-old human jawbone unearthed by archeologist Louis Leakey showed evidence of lymphoma, an unusual cancer of the blood.1 Cancer dates back at least to the dawn of humanity.
Cancer has walked this earth at least as long as we have as an ever-present adversary. Its longevity makes it unique among diseases. Maladies have come and gone. Smallpox and the Black Death once devastated the world, but have largely disappeared from the modern pantheon of health concerns. But cancer? Cancer was there in the beginning. It was there in the middle. It’s still here now, worse than ever.
Despite several thousand years of advancing medical knowledge, cancer still ravages us. Cancer was likely rare in ancient times because it is a disease of aging, and life expectancy was low. If people are dying young from famine, pestilence, and war, then cancer is not a big concern.
The Greek physician Hippocrates (ca. 460 BC–ca. 370 BC), who is often called the father of modern medicine, may have appropriately named our ancient foe using the word karkinos, meaning “crab.” This is a surprisingly astute and accurate description of cancer. Examined microscopically, cancer extends multiple spicules (a spikelike tendril) out of the main body to grab tenaciously on to adjacent tissue. Like miniature versions of its namesake, cancer distinguishes itself from other deadly diseases by its ability to scuttle around the body from one location to another. A cut on your thigh does not metastasize into a cut on your head, but a cancer in your lung can easily become a cancer in your liver.
In the second century AD, the Greek physician Galen used the term oncos, meaning “swelling,” to describe cancer, as it was often detected as a hard nodule. From this root, the words oncology (the science of cancer), oncologist (cancer specialist), and oncologic (related to cancer) are all derived. Galen also used the suffix -oma to denote a cancer. Thus, a hepatoma is a cancer in the liver. A sarcoma is a cancer of the soft tissues. A melanoma is a cancer of the melanin-containing skin cells. Celsus (ca. 25 BC–ca. AD 50), a Roman encyclopedist who wrote the medical text De Medicina, translated the Greek term karkinos into the English word cancer. The word tumor is used to describe any localized growth of abnormal cells, which can be benign or malignant.
Cancer was first understood as an exuberant, unregulated, and uncontrolled growth of tissue. Normal tissues have well-defined growth patterns. A normal kidney, for example, grows from birth until adulthood and then stops. It then simply maintains its size, unless other diseases intervene. A normal kidney does not continue growing throughout life until it is so big that it takes up the entire abdominal space. Cancer cells, however, will continue growing until they die or you do.
Cancers are usually divided into benign and malignant varieties. Benign cancers grow, but they don’t metastasize. Some examples are lipomas and basal cell carcinomas of the skin. These may become huge, but we aren’t overly concerned about benign cancers, because they are rarely deadly. It is the ability to move and spread, or metastasize, that is responsible for the majority of cancer deaths.
Malignant cancer is what we usually think of as cancer, and in this book, we consider only malignant cancers. The many types of cancers (breast, colorectal, prostate, lung, myeloma, etc.) are generally named for their cell of origin. There are likely as many types of cancers as types of cells in the body. These cancers both continue growing without limit and have the ability to leave the site of origin to reestablish at a distant site.
All cancers are derived from normal cells. Breast cancer originates from normal breast cells. Prostate cancer originates from normal prostate cells. Skin cancer originates from normal skin cells. This is the particularly vexing and unusual part of cancer—that it originally derives from ourselves. Cancer is not a foreign invader. It’s an internal uprising. The war on cancer is a war on ourselves.
While all types of cancer are different, this book attempts to discuss the origins of cancer as a whole, looking at the similarities among cancers rather than the differences. This is the fundamental question of this book: What turns normal cells into cancer cells in some people in some situations, but not others? In other words, what causes cancer?
The ancient Greeks believed in the humoral theory of disease, which posited that all diseases resulted from an imbalance in the four humors: blood, phlegm, yellow bile, and black bile. Inflammation was the result of too much blood; pustules, from too much phlegm; jaundice, from too much yellow bile. Cancer was considered an internal excess of black bile. Local accumulations of black bile manifested as tumors that could be palpated as nodules. However, the disease itself was a systemic excess involving the whole body.
Treatment of cancer was therefore aimed at removing this excess black bile, and included those oldies but goodies: bloodletting, purging, and laxatives. Local excision of the tumor would not work, because cancer was understood to be a systemic disease. This was yet another surprisingly astute observation from ancient physicians, and it spared many a cancer patient from surgery, which was a pretty gruesome thing in ancient times. In the absence of antiseptics, anesthetics, and analgesics, you were more likely to die of surgery than of cancer.
The humoral theory of cancer endured for centuries, but there was a big problem with it. Three of the four humors were identified—blood, lymph, and yellow bile—but where was the black bile? Doctors looked and looked, but could not find any black bile. Tumors, believed to be local outcroppings of black bile, were examined, but there was none to be found. If black bile caused cancer, where was it?
By the 1700s, lymph theory had replaced humoral theory. Cancer was believed to be caused by fermentation and degeneration of stagnant lymph that did not properly circulate. Once again, while the theory was incorrect, it contained some surprisingly astute observations about the nature of cancer. First, it recognized that cancer cells are derived from the body’s own normal cells that have somehow become perverted. Second, it recognized cancer’s natural tendency to spread along lymphatic drainage routes and lymph nodes.
The development of microscopes and reliable dyes to stain tissue samples allowed another major scientific leap forward. By 1838, the focus had shifted to cells rather than fluids, with the blastema theory. The German pathologist Johannes Müller showed that cancer was not caused by lymph, but instead originated from cells. Cancer, he believed, derived from the budding elements, or “blastema,” between these cells. That same year, the pathologist Robert Carswell, examining several widespread cancers, was among the first to suggest that cancer may move through the bloodstream.
Cancers were simply cells, albeit bizarre-looking cells with unregulated growth. This is what I call cancer paradigm 1.0, the first great modern paradigm of understanding cancer. It is a disease of excessive growth. If the problem is too much growth, then the obvious solution is to kill it. This logic gave us surgery, radiation, and chemotherapy, and is still the basis of many of our cancer treatment protocols today.
Surgical treatment of cancer dates back to the second century AD, when Leonidas of Alexandria described a logical, stepwise surgery for breast cancer by removing all cancerous tissue and a margin of healthy tissue. Even with cautery to stanch the expected bleeding, surgery was fraught with danger. Surgical instruments were not sterilized. If you developed a postsurgical infection, there were no antibiotics. Most of us would not let these ancient surgeons cut our hair, let alone our bodies. One particularly macabre invention from 1653 was the breast guillotine, for amputation of the affected breast.
The advent of modern anesthesia and antisepsis transformed surgery from a barbaric, ritualistic sacrifice to a fairly reasonable medical procedure. The ancient Greeks treated cancer as a systemic disease, but nineteenth-century physicians increasingly viewed cancer as a local disease, amenable to surgery. The obvious solution, then, was simply to cut it all out—and they did. As surgical technology and knowledge grew, local tumor excision became an option in almost all cases. Whether such a procedure was useful was a different matter entirely.
Cancer inevitably recurred, usually at the incision site. Again, cancer is like a crab, sending invisible microscopic pincers out into adjoining tissue. These minuscule remnants of cancer inevitably lead to a relapse. And so, physicians began to subscribe to a new theory: if a little bit surgery is good, then perhaps a lot of surgery is even better.
In the early 1900s, Dr. William Halsted championed increasingly radical surgeries to purge breast cancer “root and stem.” The word radical, as in a “radical mastectomy” or “radical prostatectomy,” is derived from the Latin word meaning “root.” In addition to the affected breast, Halsted removed a wide margin of normal tissue, including almost the entire chest wall, the pectoral muscles, and associated lymph nodes that might possibly contain the seeds of cancer. The complications were horrific, but thought to be worth it. A radical mastectomy might be disfiguring and painful, but the alternative, if cancer recurred, was death. Less invasive surgery, Halsted believed, was a misguided kindness. This became the standard surgical treatment of breast cancer for the next fifty years, making the breast guillotine look almost humane by comparison.
Halsted’s results were both very good and very bad. Patients with localized cancer fared extremely well. Patients with metastatic cancer fared extremely poorly. After cancers had metastasized, the extent of the surgery was largely irrelevant, because it was a local treatment for a systemic disease. By 1948, researchers showed that less invasive surgery achieved similar local control of disease as Halsted’s method, with a fraction of the surgical complications.
By the 1970s, preoperative X-rays and CT scans allowed earlier detection of metastasis, which prevented unnecessary surgery. In addition, the location of the tumor could be ascertained and the extent of surgical invasion necessary could now be precisely delineated before doctors whipped out the scalpel. Today we know that such targeted surgery is potentially curative—if the cancer is caught early. Modern technological advances have steadily reduced operative complications, and surgical deaths have dropped by over 90 percent2 since the 1970s. Surgery remains an important weapon against cancer, but only at the proper time and in the proper situation.
In 1895, German physicist Wilhelm Röntgen identified X-rays, high-energy forms of electromagnetic radiation, a discovery for which he would receive the 1901 Nobel Prize. These invisible X-rays could damage and kill living tissue. Barely one year later, an American medical student, Emil Grubbe, pioneered the specialty of radiation oncology by irradiating a patient with advanced breast cancer.3 Grubbe, also a manufacturer of vacuum tubes, had exposed his own hand to this new X-ray technology, causing an inflammatory rash, which he showed to a senior physician. Noting the tissue damage, the physician suggested that these newfangled X-rays may have other therapeutic uses, suggesting lupus or cancer as likely candidates. Fortuitously, Grubbe was caring for a patient suffering with both lupus and breast cancer at that very moment. On January 29, 1896, he exposed the breast cancer to the X-ray source for one hour. One hour! Modern X-ray treatments take seconds. Recalling the damage to his own hand, Grubbe did thoughtfully protect the areas around the breast cancer with the lead sheet lining from a nearby Chinese tea chest. One shudders to think of what could have happened if he had not been a tea drinker.
Meanwhile, that same year in France, physicist Henri Becquerel, along with the legendary scientists Marie and Pierre Curie, discovered spontaneous emission of radiation; the three would share a Nobel Prize for their work. In 1901, while carrying a tube of pure radium (yikes!) in his waistcoat pocket, Becquerel noted a severe burn on his skin underneath the tube. Researchers at the Hôpital Saint-Louis in Paris used his radium to develop more powerful and precise X-ray treatments. By 1903, researchers claimed to have cured a case of cervical cancer through radium treatment.4 In 1913, the “hot-cathode tube” was used to control the quality and quantity of radiation, allowing dosing for the first time, instead of the haphazard blasting of X-rays willy-nilly against a suspected lesion.
The early period of radiation oncology, from 1900 to 1920, was dominated by the efficient Germans, who favored treatment with a few large, caustic doses of radiation. There were some impressive remissions and some impressive side effects, but few lasting cures. Burns and damage to the body were inevitable, and by 1927, French scientists realized that a single huge dose of radiation harmed the overlying skin without much affecting the cancer underneath. Instead, a smaller dose of radiation delivered over multiple days (called fractionated radiotherapy) could hit the buried target without so much surface collateral damage. This is because cancer cells are more sensitive to damage from X-rays than the surrounding normal tissue.
Fractionated radiotherapy exploits this difference in sensitivity to preferentially kill cancer cells while only injuring normal cells, which have a chance to recover. This is still the preferred method of radiation therapy today. By the 1970s, President Nixon’s war on cancer supplied much-needed funds for the development of this high-tech modality.
But the biggest problem with both surgery and radiation is that they are inherently local treatments. If a cancer remained localized, then these treatments were effective, but if a cancer had metastasized, these local treatments offered little hope of recovery. Luckily, development of a more systemic treatment using chemicals (drugs) had continued concurrently.
The logical solution for a widespread cancer was to deliver “chemotherapy,” a systemic, selective toxin, to destroy cancer cells wherever they hid but leave normal cells relatively unscathed. In 1935, the Office of Cancer Investigations, which would later be merged into the National Cancer Institute, set up a methodical program for cancer drug screening involving more than three thousand chemical compounds. Only two made it to clinical trials, and both eventually failed due to excessive toxicity. Finding a selective toxin was no easy task.
A breakthrough came from an unlikely source: the deadly poisonous gases used in World War I. Nitrogen mustard gas, named for its faint peppery smell, was first used in 1917 by Germany. Developed by Fritz Haber, the brilliant chemist and winner of the 1918 Nobel Prize, this deadly gas is absorbed through the skin, blistering and burning the lungs. Victims died slowly, taking up to six weeks to complete the deadly journey.
Interestingly, mustard gas has a peculiar predilection for only destroying certain parts of the bone marrow and the white blood cells.5 In other words, it is a selective poison. In 1929, an Israeli researcher named Isaac Berenblum, studying the carcinogenic effect of tar, applied mustard gas in an attempt to provoke cancer by adding its irritant effects—but paradoxically, cancer regressed.6
Two doctors at Yale University hypothesized that this selective poison could be used therapeutically to kill the abnormal white blood cells in a cancer known as non-Hodgkin’s lymphoma. After successful animal trials, they tested their theory on a human volunteer, now known only by his initials, J.D. This forty-eight-year-old man suffered from advanced, radiation-resistant lymphoma, with tumors in his jaw and chest so large that he couldn’t swallow or cross his arms. With no other options, he agreed to the secret experimental treatment.
In August 1942, J.D. received the first dose of the mustard gas, then known only as “substance X.”7 By day four, he began to show signs of improvement. By day ten, the cancer had all but disappeared.8 The recovery was almost miraculous, but one month later, the lymphoma relapsed, and J.D.’s medical record on December 1, 1942, contained one entry: “Died.” Nevertheless, it was a great start, proving that the concept could be effective. The treatment known as chemotherapy had just been born, although war restrictions meant that the results were not published until 1946. Derivatives of mustard gas, such as chlorambucil and cyclophosphamide, are still in use today as chemotherapy drugs.
Another form of chemotherapy took advantage of folic acid metabolism. Folic acid is one of the essential B vitamins and is required for new cell production. When the body is deficient in it, new cells cannot be produced, which affects fast-growing cells like cancers. By 1948, Sidney Farber, a pathologist at the Harvard Medical School, pioneered the use of folic acid–blocking drugs in the treatment of certain types of childhood leukemia.9 The remissions were spectacular, with cancer simply melting away. Alas, it would always come back.
The development of chemotherapy pressed onward. The 1950s witnessed some notable successes against some rare cancers. Dr. Min Chiu Li, a researcher with the National Cancer Institute, reported in 1958 that a regimen of chemotherapies had cured several cases of choriocarcinoma, a tumor of the placenta.10 Few scientists believed him, and he was asked to leave his position at the NCI when he persisted in using his “crazy” newfangled treatments. He returned to Memorial Sloan-Kettering Hospital in New York, where his insights into chemotherapy would later be vindicated for choriocarcinoma and also metastatic testicular cancer.
The development of multiple types of chemotherapy drugs allowed more options. If one poison was not enough, why not combine multiple poisons into a chemical cocktail that no cancer cell could withstand? By the mid-1960s, Drs. Emil Freirich and Emil Frei were applying their combination of four drugs to children with leukemia, eventually increasing the remission rate to a then-unheard-of 60 percent.11 The remission rate for advanced Hodgkin’s disease rocketed from nearly zero to almost 80 percent.12 By 1970, Hodgkin’s lymphoma was considered a largely curable disease. Things were looking up. Chemotherapy had made the respectability leap from “poison” to “drug treatment.”
Most chemotherapy drugs are selective poisons, preferentially killing fast-growing cells. Because cancer cells are fast growing, they are particularly susceptible to chemotherapy. If you were lucky, you could kill the cancer before you killed the patient. Fast-growing normal cells, like hair follicles and the lining of the stomach and intestines, also sustained collateral damage, leading to the well-known side effects of baldness and nausea/vomiting. Newer medications, such as many of the targeted antibodies, are not often referred to as “chemotherapy” because of the negative connotations associated with the classic medications.
The first great paradigm of cancer, what I call cancer paradigm 1.0, deems cancer an unregulated growth of cells. If the problem is too much growth, then the solution is to kill. In order to kill, you need weapons of cellular mass destruction for cutting (surgery), burning (radiation), and poisoning (chemotherapy). For localized cancer, you could use locally destructive methods (surgery or radiation). For metastatic cancers, you need systemic poisons (chemotherapy).
Cancer paradigm 1.0 was a huge medical advance, but it did not answer the most fundamental questions: What was causing this uncontrolled cell growth? What was the root cause of cancer? To understand this, we need to know: what is cancer?