The History of Cancer

What is cancer?
Cancer begins when cells in a part of the body start to grow out of control. There are
many kinds of cancer, but they all start because of out-of-control growth of abnormal
cells. To learn more about how cancer forms and grows, see our document What Is
Cancer?.
Cancer is the second leading cause of death in the United States. Half of all men and one-
third of all women in the US will develop cancer during their lifetimes. Today, millions
of people are living with cancer or have had cancer.

Oldest descriptions of cancer

Human beings have had cancer throughout recorded history. So it is no surprise that from
the dawn of history people have written about cancer. Some of the earliest evidence of
cancer is found among fossilized bone tumors, human mummies in ancient Egypt, and
ancient manuscripts. Bone remains of mummies have revealed growths suggestive of the
bone cancer, osteosarcoma. Bony skull destruction as seen in cancer of the head and neck
has been found, too.
Our oldest description of cancer (although the word cancer was not used) was discovered
in Egypt and dates back to about 1600 B.C. It is called the Edwin Smith Papyrus, and is a
copy of part of an ancient Egyptian textbook on trauma surgery. It describes 8 cases of
tumors or ulcers of the breast that were treated by cauterization, with a tool called the fire
drill. The writing says about the disease, "There is no treatment."

Origin of the word cancer

The origin of the word cancer is credited to the Greek physician Hippocrates (460–370
B.C.), considered the "Father of Medicine." Hippocrates used the terms carcinos and
carcinoma to describe non-ulcer forming and ulcer-forming tumors. In Greek, these
words refer to a crab, most likely applied to the disease because the finger-like spreading
projections from a cancer called to mind the shape of a crab. The Roman physician,
Celsus (28-50 B.C.), later translated the Greek term into cancer, the Latin word for crab.
Galen (130-200 A.D.), another Roman physician, used the word oncos (Greek for
swelling) to describe tumors. Although the crab analogy of Hippocrates and Celsus is still
used to describe malignant tumors, Galen's term is now used as a part of the name for
cancer specialists -- oncologists.

Renaissance period
During the Renaissance, beginning in the 15th century, scientists in Italy developed a
greater understanding of the human body. Scientists like Galileo and Newton began to
use the scientific method, which later was used to study disease. Autopsies, done by
Harvey (1628), allowed an understanding of the circulation of blood through the heart
and body that had until then been a mystery.
In 1761, Giovanni Morgagni of Padua was the first to do something which has become
routine today -- he did autopsies to relate the patient's illness to the pathologic findings
after death. This laid the foundation for scientific oncology, the study of cancer.
The famous Scottish surgeon John Hunter (1728–1793) suggested that some cancers
might be cured by surgery and described how the surgeon might decide which cancers to
operate on. If the tumor had not invaded nearby tissue and was "moveable," he said,
"There is no impropriety in removing it."
A century later the development of anesthesia allowed surgery to flourish and the classic
cancer operations such as radical mastectomy were developed.

Nineteenth century
The 19th century saw the birth of scientific oncology with use of the modern microscope
in studying diseased tissues. Rudolf Virchow, often called the founder of cellular
pathology, provided the scientific basis for the modern pathologic study of cancer. As
Morgagni had linked autopsy findings seen with the unaided eye with the clinical course
of illness, so Virchow correlated the microscopic pathology.
This method not only allowed a better understanding of the damage cancer had done, but
also laid the foundation for the development of cancer surgery. Body tissues removed by
the surgeon could now be examined and a precise diagnosis made. The pathologist could
also tell the surgeon whether the operation had completely removed the cancer.

Cancer causes: Theories throughout history

From the earliest times, physicians have puzzled over the causes of cancer. The
Egyptians blamed cancers on the gods.
Humoral theory: Hippocrates believed that the body had 4 humors (body fluids) --
blood, phlegm, yellow bile, and black bile. When the humors were balanced, a person
was healthy. Too much or too little of any of them caused disease. An excess of black
bile in various body sites was thought to cause cancer. This theory of cancer was passed
on by the Romans and was embraced by the influential doctor Galen’s medical teaching,
which remained the unchallenged standard through the Middle Ages for over 1300 years.
During this period, the study of the body, including autopsies, was prohibited for
religious reasons, thus limiting knowledge.
Lymph theory: Among theories that replaced the humoral theory of cancer was cancer's
formation by another fluid, lymph. Life was believed to consist of continuous and
appropriate movement of the fluid parts through solids. Of all the fluids, the most
important were blood and lymph. Stahl and Hoffman theorized that cancer was composed
of fermenting and degenerating lymph varying in density, acidity, and alkalinity. The
lymph theory gained rapid support. The eminent surgeon John Hunter (1723–1792)
agreed that tumors grow from lymph constantly thrown out by the blood.
Blastema theory: In 1838, German pathologist Johannes Muller demonstrated that
cancer is made up of cells and not lymph, but he believed that cancer cells did not arise
from normal cells. Muller proposed that cancer cells arose from budding elements
(blastema) between normal tissues. His student, Rudolph Virchow (1821–1902), the
famous German pathologist, determined that all cells, including cancer cells, are derived
from other cells.
Chronic irritation theory: Virchow proposed that chronic irritation was the cause of
cancer, but he falsely believed that cancers "spread like a liquid." A German surgeon,
Karl Thiersch, showed that cancers metastasize through the spread of malignant cells and
not through some unidentified fluid.
Trauma theory: Despite advances in the understanding of cancer, from the late 1800s
until the 1920s, trauma was thought by some to cause cancer. This belief was maintained
despite the failure of injury to cause cancer in experimental animals.
Parasite theory: In the 17th and 18th centuries, some believed that cancer was
contagious. In fact, the first cancer hospital in France was forced to move from the city in
1779 because of the fear of the spread of cancer throughout the city. Although human
cancer, itself, is not contagious, we now know that certain viruses, bacteria, and parasites
can increase a person's risk of developing cancer.

Modern knowledge and cancer cause

By the middle of the 20th century, scientists had in their hands the instruments needed to
begin solving the complex problems of chemistry and biology. James Watson and Francis
Crick, who received a Nobel Prize in 1962 for their work, had discovered the exact
chemical structure of DNA, the basic material in genes.
DNA was found to be the basis of the genetic code that gives orders to all cells. After
learning how to translate this code, scientists were able to understand how genes worked
and how they could be damaged by mutations (changes or mistakes in genes). These
modern techniques of chemistry and biology answered many complex questions about
cancer.
Scientists already knew that cancer could be caused by chemicals, radiation, and viruses,
and that sometimes cancer seemed to run in families. But as the understanding of DNA
and genes increased, they learned that it was the damage to DNA by chemicals and
radiation, or the introduction of new DNA sequences by viruses that often led to the
development of cancer. It became possible to pinpoint the exact site of the damage to a
specific gene.
Scientists discovered that sometimes defective genes are inherited, and sometimes these
inherited genes are defective at the same points that chemicals exerted their effect. In
other words, most of the things that caused cancer (carcinogens) caused genetic damage
(mutations), these mutations led to abnormal groups of cells (called clones), the mutant
clones evolved to even more malignant clones over time, and the cancer progressed by
more and more genetic damage and mutations. Normal cells with damaged DNA die;
cancer cells with damaged DNA do not. The discovery of this critical difference
answered many questions that have troubled scientists for many years.
During the 1970s, scientists discovered 2 important families of genes: oncogenes and
tumor suppressor genes.
Oncogenes are mutated forms of genes that cause normal cells to grow out of control and
become cancer cells. They are mutations of certain normal genes of the cell called proto-
oncogenes. Proto-oncogenes are the genes that normally control how often a cell divides
and the degree to which it differentiates (or specializes).
Tumor suppressor genes are normal genes that slow down cell division, repair DNA
mistakes, and tell cells when to die (a process known as apoptosis or programmed cell
death). When tumor suppressor genes don’t work properly, cells can grow out of control,
which can lead to cancer.
It may be helpful to think of a cell as a car. For it to work properly, there need to be ways
to control how fast it goes. A proto-oncogene normally functions in a way that is similar
to a gas pedal -- it helps the cell grow and divide. An oncogene could be compared to a
gas pedal that is stuck down, which causes the cell to divide out of control. A tumor
suppressor gene is like the brake pedal on a car. It normally keeps the cell from dividing
too quickly just as a brake keeps a car from going too fast. When something goes wrong
with the gene, such as a mutation, cell division can get out of control.
Slowly, medical scientists are identifying the oncogenes and tumor suppressor genes that
are damaged by chemicals or radiation and the genes that, when inherited, can lead to
cancer. For example, the discovery during the 1990s of 2 genes that cause some breast
cancers, BRCA1 and BRCA2, represents considerable promise because these genes can
be used to identify people who have a higher probability of developing breast cancer.
Other genes have been discovered that are associated with some cancers that run in
families, such as cancers of the colon, rectum, kidney, ovary, thyroid, pancreas, and skin
melanoma. Familial cancer is not nearly as common as spontaneous cancer. It is less than
15% of all cancers. Still, it is important to understand these cancers because with
continued research in genetics we may be able to identify people at very high risk.
Once researchers recognized the importance of specific genetic changes in cancer, they
soon began working to develop targeted therapies (drugs or substances that interfere with
specific molecules) to overcome the effects of these changes in tumor suppressor genes
and especially in oncogenes.

Viral and chemical carcinogens

In 1915 cancer was induced in lab animals for the first time by a chemical, coal tar,
applied to rabbit skin at Tokyo University by Katsusaburo Yamagiwa and Koichi
Ichikawa. One hundred and fifty years had passed since clinician John Hill of London
recognized tobacco as a carcinogen (a substance known or believed to cause cancer in
humans). Many more years passed before tobacco was "rediscovered" as the most
destructive source of chemical carcinogens known to man.
Today we recognize and avoid many specific substances that cause cancer: coal tars and
their derivatives (like benzene), some hydrocarbons, aniline (a substance used to make
dyes), asbestos, and others. Radiation from a variety of sources, including the sun, is
known to cause cancer. To ensure the public's safety, the government has set standards
for many substances, including benzene, asbestos, hydrocarbons in the air, arsenic in
drinking water, and radiation.
In 1911, Peyton Rous at the Rockefeller Institute in New York, described a type of cancer
(sarcoma) in chickens caused by what later became known as the Rous sarcoma virus. He
was awarded the Nobel Prize for that work in 1968. Several viruses are now linked to
cancer in humans, too:
• Long-standing liver infection with the hepatitis B or C viruses can lead to cancer of
the liver.
• A variety of the herpes virus, the Epstein-Barr virus, causes infectious mononucleosis
and has been linked to non-Hodgkin lymphomas and nasopharyngeal cancer.
• The human immunodeficiency virus (HIV) is associated with an increased risk of
developing several cancers, especially Kaposi sarcoma and non-Hodgkin lymphoma.
• Human papilloma viruses (HPVs) have been linked to many cancers, especially those
of the cervix, vulva, vagina, and penis. Some head and neck cancers (mostly the
tongue and tonsils) may be related to the high-risk types of HPV, too. A test for HPV
types linked to cervical cancer was approved by the FDA for clinical use in cervical
cancer screening in 2003. The first vaccine (Gardasil®) to prevent infection with 2
cancer-associated HPV types was approved by the FDA in 2006 for cancer
prevention. A second vaccine (Cervarix®) was approved in 2009.
As of 2010, the World Health Organization's International Agency for Research on
Cancer (IARC) has identified more than 100 chemical, physical, and biological
carcinogens. Many of these associations were recognized long before scientists
understood much about how cancer develops. Today, ongoing research is discovering
new carcinogens, explaining how they cause cancer, and providing insight into ways to
prevent cancer.

Cancer epidemiology
During the 18th century, 3 important observations were made that launched the field of
cancer epidemiology (the study of causes, distribution, and control of diseases).
• In 1713, Bernardino Ramazzini, an Italian doctor, reported the virtual absence of
cervical cancer and relatively high incidence of breast cancer in nuns and wondered if
this was in some way related to their celibate lifestyle. This observation was an
important step toward identifying and understanding the importance of hormones
(like the changes that come with pregnancy) and sexually-transmitted infections and
cancer risk.
• In 1775, Percival Pott of Saint Bartholomew's Hospital in London described an
occupational cancer in chimney sweeps, cancer of the scrotum, which was caused by
soot collecting under the scrotum. This research led to many more studies that
identified a number of occupational carcinogenic exposures and led to public health
measures to reduce a person's cancer risk at work.
• John Hill of London was the first to recognize the dangers of tobacco. In 1761, only a
few decades after tobacco became popular in London, he wrote a book entitled
Cautions Against the Immoderate Use of Snuff.
• Results of epidemiologic research published during the 1950s and early 1960s
showed that smoking is a cause of lung cancer, and led to the US Surgeon General's
1964 report Smoking and Health.
Epidemiologists continue their search for factors that cause cancer (like tobacco use,
obesity, ultraviolet radiation) as well as those offering protection against cancer (such as
physical activity and a healthy diet). This research provides evidence to guide public
health recommendations and regulations. As molecular biologists learn more about how
factors cause or prevent cancer, this information is used in studies of molecular
epidemiology, which study the interactions between genes and external factors.

Cancer screening and early detection

Screening refers to tests and exams used to find a disease, such as cancer, in people who
do not have any symptoms. The first screening test to be widely used for cancer was the
Pap test. The test was developed by George Papanicolaou as a research method in
understanding the menstrual cycle. Papanicolaou soon recognized its potential for
detecting cervical cancer early and presented his findings in 1923. At first, most doctors
were skeptical, and it was not until the American Cancer Society promoted the test during
the early 1960s that this test was widely used. Since that time, the cervical cancer death
rate in the United States has declined by about 70%.
Modern mammography methods were developed late in the 1960s and first officially
recommended by the ACS in 1976.
Current American Cancer Society guidelines include methods for early detection of
cancers of the cervix, breast, colon and rectum, endometrium, and prostate, as well as a
cancer-related check-up which, depending on a person's age and gender, might include
exams for cancers of the thyroid, oral cavity, skin, lymph nodes, testes, and ovaries.

Cancer treatments: Surgery

Ancient physicians and surgeons knew that cancer would usually come back after it was
removed by surgery. The Roman physician Celsus wrote, "After excision, even when a
scar has formed, none the less the disease has returned."
Galen was a 2nd-century Roman doctor whose books were preserved for centuries and
who was thought to be the highest medical authority for over a thousand years. Galen
viewed cancer much as Hippocrates had, and his views set the pattern for cancer
management for centuries: he considered the patient incurable after a diagnosis of cancer
had been made.
Even though medicine progressed and flourished in some ancient civilizations, there was
little progress in cancer treatment. The approach to cancer was Hippocratic (or Galenic)
for the most part. To some extent this view that cancer cannot be cured has persisted even
into the 20th century. This has served to fuel the fear people have of the disease. Some
people, even today, consider all cancer incurable and put off seeing a doctor until it is too
late for optimal treatment.
Cancer treatment has gone through a slow process of development. The ancients
recognized that there was no curative treatment once a cancer had spread and that
intervention might be more harmful than no treatment at all. Galen did write about
surgical cures for breast cancer if the tumor could be completely removed at an early
stage. Surgery then was very primitive with many complications, including blood loss. It
wasn't until the 19th and early 20th centuries that major advances were made in general
surgery and cancer surgery.
There were great surgeons before the discovery of anesthesia. John Hunter, Astley
Cooper, and John Warren achieved lasting acclaim for their swift and precise surgery.
But when anesthesia became available in 1846, great surgeons emerged whose work so
rapidly advanced the art that the next hundred years became known as "the century of the
surgeon."
Three surgeons stand out because of their contributions to the art and science of cancer
surgery: Bilroth in Germany, Handley in London, and Halsted in Baltimore. Their work
led to "cancer operations" designed to remove all of the tumor along with the lymph
nodes in the region where the tumor was located.
William Stewart Halsted, professor of surgery at Johns Hopkins University, developed
the radical mastectomy during the last decade of the 19th century. His work was based in
part on that of W. Sampson Handley, the London surgeon who believed that cancer
spread outward by invasion from the original growth.
Halsted did not believe that cancers usually spread through the bloodstream: "Although it
undoubtedly occurs, I am not sure that I have observed from breast cancer, metastasis
which seemed definitely to have been conveyed by way of the blood vessels." He
believed that adequate local removal of the cancer would cure it -- if the cancer later
appeared elsewhere, it was a new process. That belief led him to develop the radical
mastectomy for breast cancer. This became the basis of cancer surgery for almost a
century until the 1970s, when modern clinical trials demonstrated that less extensive
surgery is equally effective for most women with breast cancer. Today, a radical
mastectomy is almost never done and the "modified radical mastectomy" is performed
less frequently than before; most women with breast cancer undergo local removal of the
primary tumor (lumpectomy) coupled with radiation therapy.
At the same time Halsted and Handley were developing their radical operations, another
surgeon was asking, "What is it that decides which organs shall suffer in a case of
disseminated cancer?" Stephen Paget, an English surgeon, concluded that cancer cells
spread by way of the bloodstream to all organs in the body but were able to grow only in
a few organs. In a brilliant leap of logic he drew an analogy between cancer metastasis
and seeds that "are carried in all directions, but they can only live and grow if they fall on
congenial soil."
Paget's conclusion that cells from a primary tumor spread through the bloodstream but
could grow only in certain, and not all, organs was an accurate and highly sophisticated
hypothesis that was confirmed by the techniques of modern cellular and molecular
biology almost a hundred years later. This understanding of metastasis became a key
element in recognizing the limitations of cancer surgery. It eventually allowed doctors to
develop systemic treatments used after surgery to destroy cells that had spread throughout
the body and to use less mutilating operations, for example, in treating many types of
cancer. Today these systemic treatments may also be used before surgery.
During the final decades of the 20th century, surgeons developed greater technical
expertise in minimizing the amounts of normal tissue removed during cancer operations.
Like the trend from radical mastectomy to lumpectomy, progress was also made in
removing bone and soft tissue tumors of the arms and legs without the need for
amputation in most cases, and in avoiding a colostomy for most patients with rectal
cancer. This progress depended not only on understanding cancer better as a disease and
on better surgical instruments, but also on combining surgery with chemotherapy and/or
radiation.
Until the end of the 20th century, diagnosing cancer required "exploratory surgery" to
open the abdomen (belly) or chest so the surgeon could take tissue samples to be tested
for cancer. Starting in the 1970s, progress in ultrasound (sonography), computed
tomography (CT scans), magnetic resonance imaging (MRI scans), and positron emission
tomography (PET scans) have replaced most exploratory operations. CT scans and
ultrasound can be used to guide biopsy needles into tumors.
Instruments that use fiberoptic technology and miniature video cameras let doctors look
inside the body. Surgeons can use special surgical instruments operated through tubes put
into the body. Endoscopic surgery can remove tumors through tubes put through body
openings to reach the colon, esophagus, or bladder. Similar instruments can also be put
through small cuts in the skin to look and work inside the abdomen (laparoscopic
surgery) or chest (thorascopic surgery).
Less invasive ways of destroying tumors without removing them are being studied and/or
used. Cryosurgery (also called cryotherapy or cryoablation) uses liquid nitrogen spray or
a very cold probe to freeze and kill abnormal cells. Lasers can be used to cut through
tissue (instead of using a scalpel) or to vaporize (burn and destroy) cancers of the cervix,
larynx (voice box), liver, rectum, skin and other organs. Radiofrequency ablation
transmits radio waves to a small antenna placed in the tumor to kill cancer cells by
heating them.

Cancer treatments: Hormone therapy

Another 19th century discovery laid the groundwork for an important modern method to
treat and prevent breast cancer. Thomas Beatson graduated from the University of
Edinburgh in 1874 and developed an interest in the relation of the ovaries to milk
formation in the breasts, probably because he grew up near a large sheep farm in rural
Scotland. In 1878 he discovered that the breasts of rabbits stopped producing milk after
he removed the ovaries. He described his results to the Edinburgh Medico-Chirurgical
Society in 1896: "This fact seemed to me of great interest, for it pointed to one organ
holding control over the secretion of another and separate organ."
Because the breast was "held in control" by the ovaries, Beatson decided to test removal
of the ovaries (oophorectomy) in advanced breast cancer. He found that oophorectomy
often resulted in improvement for breast cancer patients. He also suspected that "the
ovaries may be the exciting cause of carcinoma" of the breast. He had discovered the
stimulating effect of the female ovarian hormone (estrogen) on breast cancer, even before
the hormone itself was discovered. His work provided a foundation for the modern use of
hormone therapy, such as tamoxifen, to treat and prevent breast cancer.
A half century after Beatson’s discovery, a urologist at the University of Chicago,
Charles Huggins, reported dramatic regression of metastatic prostate cancer after the
testicles were removed. Later, drugs that blocked male hormone were found to be
effective treatment for prostate cancer. Today these drugs are being studied to determine
if they have a role in preventing prostate cancer.
New classes of drugs (such as aromatase inhibitors, LHRH [luteinizing hormone-
releasing hormone] analogs and inhibitors, and others) have greatly changed the way
prostate and breast cancers are treated. Research to better understand how hormones
influence cancer growth has guided progress in developing and prescribing new drugs for
cancer treatment. It is also helping researchers look at new ways to use drugs to reduce
the risk of developing breast and prostate cancer.

Cancer treatments: Radiation

As the 19th century was drawing to a close, in 1896 a German physics professor,
Wilhelm Conrad Roentgen, presented a remarkable lecture entitled "Concerning a New
Kind of Ray." Roentgen called it the "X-ray", with "X" being the algebraic symbol for an
unknown quantity. There was immediate worldwide excitement. Within months, systems
were being devised to use X-rays for diagnosis, and within 3 years radiation was used in
to treat cancer.
In 1901 Roentgen received the first Nobel Prize awarded in physics. Radiation therapy
began with radium and with relatively low-voltage diagnostic machines. In France a
major breakthrough took place when it was discovered that daily doses of radiation over
several weeks would greatly improve the patient's chance for a cure . The methods and
the machines for delivery of radiation therapy have steadily improved. Today, radiation is
delivered with great precision to destroy malignant tumors while limiting damage to
nearby normal tissues.
At the beginning of the 20th century, shortly after radiation began to be used for
diagnosis and therapy, it was discovered that radiation could cause cancer as well as cure
it. Many early radiologists used the skin of their arms to test the strength of radiation
from their radiotherapy machines, looking for a dose that would produce a pink reaction
(erythema) that looked like sunburn. They called this the "erythema dose," and this was
considered an estimate of the proper daily fraction of radiation. In retrospect, it is no
surprise that many developed leukemia.
Advances in radiation physics and computer technology during the last quarter of the
20th century made it possible to aim radiation more precisely. Conformal radiation
therapy (CRT) uses CT images and special computers to very precisely map the location
of a cancer in 3 dimensions. The patient is fitted with a plastic mold or cast to keep the
body part still. The radiation beams are matched to the shape of the tumor and delivered
to the tumor from several directions. Intensity-modulated radiation therapy, is like CRT
but along with aiming photon beams from several directions, the intensity (strength) of
the beams can be adjusted. This gives even more control over decreasing the radiation
reaching normal tissue while delivering a higher dose to the cancer.
A related technique, conformal proton beam radiation therapy, uses a similar approach to
focusing radiation on the cancer. But instead of using x-rays, this technique uses proton
beams. Protons are parts of atoms that cause little damage to tissues they pass through but
are very effective in killing cells at the end of their path. This means that proton beam
radiation can deliver more radiation to the cancer while reducing damage to nearby
normal tissues.
Stereotactic radiosurgery and stereotactic radiation therapy are terms that describe
several techniques used to deliver a large, precise radiation dose to a small tumor. The
term surgery may be confusing because no cut (incision) is actually made. The most
common site being treated with this technique is the brain. The linear accelerator, or a
special machine known as a Gamma Knife, can be used to deliver this treatment.
Research is being done to produce delivery systems to treat sites other than the brain.
Intraoperative radiation therapy (IORT) is a form of treatment that delivers radiation at
the time of surgery. The radiation can be given directly to the cancer or to the adjacent
tissues after the cancer has been removed. It is more commonly used in abdominal or
pelvic cancers and in cancers that tend to recur (return after treatment). IORT minimizes
the amount of tissue that is exposed to radiation because normal tissues can be moved out
of the way during surgery and shielded, allowing a higher dose of radiation to the cancer.
Chemical modifiers or radiosensitizers are substances that make cancer more sensitive to
radiation. The goal of research into these types of substances is to develop agents that
will make the tumor more sensitive without affecting normal tissues. Research is also
looking for substances that may protect normal cells from radiation.

Cancer treatments: Chemotherapy

During World War II, naval personnel who were exposed to mustard gas as a result of a
military action were found to have toxic effects on the bone marrow cells that develop
into blood cells. During that same period, the US Army was studying a number of
chemicals related to mustard gas in order to develop more effective agents and develop
protective measures. In the course of that work, a compound called nitrogen mustard was
studied and found to work against a cancer of the lymph nodes called lymphoma. This
agent served as the model for a long series of similar but more effective agents (called
alkylating agents) that killed rapidly growing cancer cells by damaging their DNA.
Not long after the discovery of nitrogen mustard, Sidney Farber of Boston demonstrated
that aminopterin, a compound related to the vitamin, folic acid, produced remission in
children with acute leukemia. Aminopterin blocked a critical chemical reaction needed
for DNA replication. That drug was the predecessor of methotrexate, a cancer treatment
drug used commonly today. Since then, other researchers discovered drugs that blocked
different functions involved in cell growth and replication. The era of chemotherapy had
begun. Metastatic cancer was first cured in 1956 when methotrexate was used to treat a
rare tumor called choriocarcinoma.
Over the years, the development and use of chemotherapy drugs (chemo) have resulted in
the successful treatment of many people with cancer. Long-term remissions and even
cures of many patients with Hodgkin disease and childhood ALL (acute lymphoblastic
leukemia) with chemo were first reported during the 1960s. Cures of testicular cancer
were seen during the next decade. Many other cancers can be controlled with chemo for
long periods of time, even if they are not cured. Today, several approaches are being
studied to improve the activity and reduce the side effects of chemotherapy. These
include:
• New drugs, new combinations of drugs, and new delivery techniques
 • Novel approaches to targeting drugs more specifically at the cancer cells (such as
liposomal therapy and monoclonal antibody therapy) to produce fewer side effects
• Drugs to reduce side effects, like colony-stimulating factors, chemoprotective agents
(such as dexrazoxane and amifostine), and anti-emetics (to reduce nausea and
vomiting)
• Agents that overcome multi-drug resistance
Liposomal therapy is a new technique that puts chemo drugs inside liposomes (synthetic
fat globules). The liposome, or fatty coating, helps them penetrate the cancer cells more
selectively and decreases possible side effects (like hair loss, nausea, and vomiting).
Examples of liposomal drugs are Doxil (the encapsulated form of doxorubicin) and
Daunoxome (the encapsulated form of daunorubicin).
Early in the 20th century, only cancers small and localized enough to be completely
removed by surgery were curable. Later, radiation was used after surgery to control small
tumor growths that were not surgically removed. Finally, chemotherapy was added to
destroy small tumor growths that had spread beyond the reach of the surgeon and
radiotherapist. The use of chemotherapy after surgery to destroy the few remaining
cancer cells in the body is called adjuvant therapy. Adjuvant therapy was tested first in
breast cancer and found to be effective. It was later used in colon cancer, cancer of the
testis, and others.
A major discovery was the advantage of using multiple chemotherapy drugs (known as
combination chemotherapy) over single agents. Some types of very fast-growing
leukemias and lymphomas (tumors involving the cells of the bone marrow and lymph
nodes, respectively) responded very well to combination chemotherapy, and clinical trials
led to gradual improvement of the drug combinations used. Many of these tumors can be
cured today by appropriate combination chemotherapy.
The approach to patient treatment has become more scientific with the introduction of
clinical trials on a wide basis throughout the world. These clinical trials compare new
treatments to standard treatments and contribute to a better understanding of treatment
benefits and risks. Clinical trials test theories about cancer learned in the basic science
laboratory and also test ideas derived from the clinical observations on cancer patients.
They are necessary for continued progress.

Cancer treatments: Immunotherapy

Better understanding of the biology of cancer cells has led to the development of biologic
agents that mimic some of the natural signals that the body uses to control growth.
Clinical trials have shown that this cancer treatment, called biological response modifier
(BRM) therapy, biologic therapy, biotherapy, or immunotherapy, is effective for several
cancers.
Some of these biologic agents, which occur naturally in the body, can now be made in the
lab. Examples are interferons, interleukins, and other cytokines. These agents are given to
patients to imitate or influence the natural immune response either by directly altering the
cancer cell growth or acting indirectly to help healthy cells control the cancer.
One of the most exciting applications of biologic therapy has come from identifying
certain tumor targets, called antigens, and aiming an antibody at these targets. This
method was first used to find tumors for diagnosis and more recently has been used to
attack cancer cells. Using technology first developed during the 1970s, scientists can
mass produce monoclonal antibodies that are specifically targeted to chemical
components of cancer cells. Refinements to these methods, using recombinant DNA
technology, have improved the effectiveness and decreased the side effects of these
treatments. The first therapeutic monoclonal antibodies, rituximab (Rituxan) and
trastuzumab (Herceptin) were approved during the late 1990s for treating lymphoma and
breast cancer, respectively. Studies are now being done to see if and how well these drugs
work in other cancers, too. At least 9 monoclonal antibodies now are being used for
cancer treatment, and many more are being studied.
Scientists are also studying vaccines that boost the body’s immune response to cancer
cells. For instance, a 2009 lymphoma study looked at personalized vaccines made from
tissue from each patient's tumor. Encouraging results showed that patients who received
the vaccine lived longer disease-free than those who did not.

Cancer treatments: Targeted therapy

Until the late 1990s nearly all drugs used in cancer treatment (with the exception of
hormone treatments) worked by killing cells that were in the process of replicating their
DNA and dividing to form 2 new cells. These chemotherapy drugs also killed some
normal cells but, fortunately, had a greater effect on cancer cells.
Targeted therapies work by influencing the processes that control growth, division, and
spread of cancer cells, as well as the signals that cause cancer cells to die naturally (the
way normal cells do when they are too old). Targeted therapies work in several ways.
Growth signal inhibitors: Growth factors are hormone-like substances that help tell
cells when to grow and divide. Their role in fetal growth and repair of injured tissue was
first recognized during the 1960s. Later it was realized that abnormal forms or
abnormally high levels of the same factors contribute to the growth and spread of cancer
cells. Researchers have also started to understand how cells recognize these factors, and
how that recognition leads to signals inside the cells that cause the abnormal features of
cancer cells. Changes in these signal pathways have also been recognized as causing the
abnormal behavior of cancer cells.
During the 1980s, scientists found that many of the growth factors and other substances
responsible for growth factor recognition and signaling are actually products of
oncogenes. Among the earliest targeted therapies that block growth signals are
trastuzumab (Herceptin), gefitinib (Iressa), imatinib (Gleevec), and cetuximab (Erbitux).
Current research has shown great promise for these treatments in some of the more
difficult to treat and deadly forms of cancer, such as non-small cell lung cancer, advanced
kidney cancer, and glioblastoma.
Angiogenesis inhibitors: Angiogenesis is the creation of new blood vessels. The term
comes from 2 Greek words: angio, meaning "blood vessel," and genesis, meaning
"beginning." Normally, this is a healthy process. New blood vessels, for instance, help
the body heal wounds and repair damaged tissues. But in a person with cancer, this same
process creates new, very small blood vessels that give a tumor its own blood supply and
allow it to grow. Anti-angiogenesis is a form of targeted therapy that uses drugs or other
substances to stop tumors from making the new blood vessels they need to continue
growing. This concept was first proposed by Judah Folkman in the early 1970s, but it
wasn't until 2004 that the first angiogenesis inhibitor, bevicizumab (Avastin) was
approved for clinical use. Currently used to treat advanced colorectal, breast, and lung
cancers, bevicizumab is being studied as treatment for many other types of cancer, too.
Apoptosis-inducing drugs: Apoptosis is a natural process through which cells with
DNA too damaged to repair -- such as cancer cells -- can be forced to die. Many anti-
cancer treatments (including radiation and chemotherapy) cause cell changes that
eventually lead to apoptosis. But targeted drugs in this group are different, because they
are aimed specifically at the cell substances that control cell survival and death.

Cancer survivorship
Only a few decades ago, the prognosis (outlook) for people facing cancer was not nearly
as favorable as it is today. During the 1970s, about 1 of 2 people diagnosed with cancer
survived at least 5 years. Now, more than 2 of 3 survive that long. Today there are more
than 11 million cancer survivors in the United States alone.
Now that more people are surviving cancer, more attention than ever is focused on the
quality of life and long-term outcomes of cancer survivors. Behavioral researchers are
working to learn more about the problems survivors face. Some of these problems are
medical, such as permanent side effects of treatment, the possibility of second cancers
caused by treatment, and the need for long-term medical follow-up. Other problems are
emotional or social challenges, like getting health insurance, discrimination by
employers, relationship changes that may result from life-threatening illness, or learning
to live with the possibility of cancer coming back.
Cancer was once a word that people were afraid to speak in public, and people rarely
admitted to being a cancer survivor. Now, many celebrities and national leaders have
very openly discussed their cancer experiences.

The twenty-first century and beyond

The growth in our knowledge of cancer biology has led to remarkable progress in cancer
prevention, early detection, and treatment in recent years. Scientists have learned more
about cancer in the last 2 decades than has been learned in all the centuries preceding.
This does not change the fact, however, that all scientific knowledge is based on the
knowledge already acquired by the hard work and discovery of our predecessors -- and
we know that there is still a lot more to learn.
Cancer research is currently advancing on so many fronts that it is difficult to choose the
ones to highlight here.
More targeted therapies: As more is learned about the molecular biology of cancer,
researchers will have more targets for their new drugs. Along with more monoclonal
antibodies and small signaling pathway inhibitors, researchers are developing new classes
of molecules such as antisense oligodeoxynucleotides and small interfering RNA
(siRNA).
An example of this is a new class of targeted therapies called PARP inhibitors. (PARP is
short for poly (ADP-ribose) polymerase enzymes.) Cancer cells use PARP to repair DNA
damage, including the damage caused by cancer treatment. Recent studies in breast
cancer have shown that blocking PARP can make cancer cells more sensitive to treatment
and promote cell death.
Nanotechnology: New technology for producing materials that form extremely tiny
particles is leading to very promising imaging tests that can more accurately show the
location of tumors, as well as new ways to deliver drugs more specifically and effectively
to cancer cells.
Robotic surgery: This term refers to manipulation of surgical instruments remotely by
robot arms and other devices controlled by a surgeon. Robotic systems have been used
for several types of cancer surgery; radical prostatectomy is among the most common
uses in surgical oncology. As mechanical and computer technology improve, some
researchers expect future systems will be able to remove tumors more completely and
with less surgical trauma.
RNA expression profiling and proteomics: RNA expression profiling lets scientists
determine relative amounts of hundreds or even thousands of RNA molecules at one
time. Knowing what proteins or RNA molecules are present in cells can tell scientists a
lot about how the cell is behaving. In cancer, it can help distinguish more aggressive
cancers from less aggressive ones, and can often help predict which drugs the tumor is
likely to respond to. Proteomic methods are also being tested for cancer screening. For
most types of cancer, measuring the amount of one protein in the blood is not very good
at finding early cancers. But researchers are hopeful that comparing the relative amounts
of many proteins may be more useful, and that knowing certain proteins are abnormally
abundant and others are less abundant can provide accurate, useful information. This is
an exciting area of research and early results in lung and colorectal cancer studies have
been promising.

Additional resources
Encyclopedia Britannica. See entries on Medicine, History of Cancer.
Lyons AS, Petrucelli RJ. Medicine: An Illustrated History. New York: Harry N. Abrams
Publishers; 1978.
Shimkin MB. Contrary to Nature: Cancer. For sale by the Superintendent of Documents,
US Printing Office, Washington D.C. 20401. DHEW Publication No (NIH) 76-720;
1976.

References
American Society of Clinical Oncology. Clinical Cancer Advances 2009: Major Research
Advances in Cancer Treatment, Prevention and Screening. Accessed at
www.cancer.net/patient/ASCO%20Resources/Research%20and%20Meetings/CCA_2009
.pdf on March 5, 2010.
Contran R, Kumar V, Robbins S. Robbins Pathologic Basis of Disease, 4th ed.
Philadelphia, Pa: WB Saunders; 1989.
Diamandopoulus GT. Cancer: An historical perspective. Anticancer Res. 1996;16:1595–
1602.
Gallucci BB. Selected concepts of cancer as a disease: From the Greeks to 1900. Oncol
Nurs Forum. 1985;12:67–71.
Harvey AM. Early contributions to the surgery of cancer: William S. Halsted, Hugh H.
Young and John G. Clark. Johns Hopkins Med J. 1974;135:399–417.
Kardinal C, Yarbro J. A conceptual history of cancer. Semin Oncol. 1979;6:396–408.
Timeline: Milestones in Cancer Treatment. CureToday Web site. Accessed at
www.curetoday.com/index.cfm/fuseaction/article.show/id/2/article_id/631 on February
19, 2010.
Progress Against Cancer. Cancer.Net Web site. Accessed at
www.cancer.net/patient/Advocacy%20and%20Policy/Treatment_Advances_Timeline.pd
f on February 19, 2010.
The History of Cancer. Institut Jules Bordet Web site. Accessed at
www.bordet.be/en/presentation/history/cancer_e/cancer1.htm on February 19, 2010.

Last Medical Review: 3/22/2010

Last Revised: 3/22/2010

2010 Copyright American Cancer Society