What is cancer?

Cancer develops when cells in a part of the body begin to grow out of control. Even though there are many kinds of cancer, they all start because of abnormal cells that grow out of control.

Normal body cells grow, divide, and die in an orderly fashion. During the early years of a person's life, normal cells divide more rapidly until the person becomes an adult. After that, cells in most parts of the body divide only to replace worn-out or dying cells and to repair injuries.

Because cancer cells continue to grow and divide, they are different from normal cells. Instead of dying, they outlive normal cells and continue to form new abnormal cells.

Cancer cells often travel to other parts of the body where they begin to grow and replace normal tissue. This process, called metastasis, occurs as the cancer cells get into the bloodstream or lymph vessels of our body. When cells from a cancer like breast cancer spread to another organ like the liver, the cancer is still called breast cancer, not liver cancer.

Cancer cells develop because of damage to DNA. This substance is in every cell and directs all its activities. Most of the time when DNA becomes damaged the body is able to repair it. In cancer cells, the damaged DNA is not repaired. People can inherit damaged DNA, which accounts for inherited cancers. Many times though, a person’s DNA becomes damaged by exposure to something in the environment, like smoking.

Cancer usually forms as a solid tumor. Some cancers, like leukemia, do not form tumors. Instead, these cancer cells involve the blood and blood-forming organs and circulate through other tissues where they grow.

Not all tumors are cancerous. Benign (non-cancerous) tumors do not spread to other parts of the body (metastasize) and, with very rare exceptions, are not life threatening.

Different types of cancer can behave very differently. For example, lung cancer and breast cancer are very different diseases. They grow at different rates and respond to different treatments. That is why people with cancer need treatment that is aimed at their particular kind of 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 United States will develop cancer during their lifetimes. Today, millions of people are living with cancer or have had cancer. The risk of developing most types of cancer can be reduced by changes in a person's lifestyle, for example, by quitting smoking and eating a better diet. The sooner a cancer is found and treatment begins, the better are the chances for living for many years.

Oldest descriptions of cancer

Cancer has afflicted humans throughout recorded history. 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. In other cases, bony skull destruction as seen in cancer of the head and neck has been found.

Our oldest description of cancer (although the term cancer was not used) was discovered in Egypt and dates back to approximately 1600 B.C. The Edwin Smith Papyrus, or writing, 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 such as Galileo and Newton began to use the scientific method, which later began to be used to study disease. Autopsies, performed by Harvey (1628), allowed an understanding of the circulation of blood through the heart and body that had remained a mystery.

In 1761, Giovanni Morgagni of Padua was the first to do something considered routine today. He performed 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 the discovery and use of the modern microscope. Rudolf Virchow, often called the founder of cellular pathology, provided the scientific basis for the modern pathologic study of cancer. As Morgagni had correlated the autopsy findings observed 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 to a patient 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. In addition, the pathologist could tell the surgeon whether the operation had completely removed the tumor.

Cancer causes

From the earliest times, physicians have wondered about the cause of cancer. The Egyptians blamed cancers on the Gods.

Humoral theory: Hippocrates believed that the body contained 4 humors (body fluids) -- blood, phlegm, yellow bile, and black bile. A balance of these fluids resulted in a state of health. Any excesses or deficiencies caused disease. An excess of black bile collecting 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 Hofman theorized that cancer was composed of fermenting and degenerating lymph varying in density, acidity, and alkalinity. The lymph theory gained rapid support. 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 was of the opinion 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: 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: Despite advances in the understanding of cancer, from the late 1800s until the 1920s, cancer was thought by some to be caused by trauma. This belief was maintained despite the failure to cause cancer in experimental animals by injury.

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.

A Nobel Prize was wrongly awarded in 1926 for scientific research documenting stomach cancer being caused by a certain worm. Scientists were unable to confirm this research, so they lost interest in the parasite theory.

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 presented by cancer. 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 our understanding of DNA and genes increased, we learned that it was the damage to DNA by chemicals and radiation or 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.

Further, scientists discovered that sometimes defective genes are inherited and that sometimes these inherited genes are defective at the same points that chemicals exerted their effect. In other words, most carcinogens caused genetic damage (mutations), mutations led to abnormal groups of cells (called clones), 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 recent discovery of this critical difference answers 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 many people who have a higher probability of developing breast cancer can now be identified

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, causing less than 15% of all cancers, but it is important to understand these cancers because with continued research in genetics we may be able to identify persons at very high risk.

Modern day carcinogens

More recently, other causes of cancer were discovered and documented. 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. In 1915 cancer was induced in laboratory animals for the first time by a chemical, coal tar, applied to rabbit skin at Tokyo University. One hundred and fifty years had passed since the most destructive source of chemical carcinogens known to man, tobacco, was first identified in London by the astute clinician John Hill. It was to be many years until tobacco was "rediscovered" as a carcinogen (a substance known or believed to cause cancer in humans).

Today we recognize and avoid many specific substances that cause cancer: coal tars and their derivatives such as 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 lead to cancer. To ensure the public's safety, the government has set standards for many substances, such as benzene, asbestos, hydrocarbons in the air, arsenic in drinking water, radiation, and so on.

Several viruses are now linked to cancer:

• 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 implicated in 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 several cancers, especially those of the cervix, vulva, and penis. A test for types HPV types linked to cervical cancer was approved by the FDA for clinical use in cervical cancer screening in 2003. A vaccine that prevents infection with 2 cancer-associated HPV types was approved by the FDA in 2006 for use in cancer prevention.

As of 2008, 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 the mechanism by which the cancer was produced, but continuing 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.

• Bernardino Ramazzini, an Italian doctor, reported in 1713 the virtual absence of cervical cancer and relatively high incidence of breast cancer in nuns and wondered whether this was in some way related to their celibate lifestyle. This observation was an important step toward identifying and understanding the importance of hormonal factors such as pregnancy and infections related to sexual contact in modifying cancer risk.

• Percival Pott of Saint Bartholomew's Hospital in London described in 1775 an occupational cancer in chimney sweeps, cancer of the scrotum, caused by soot collecting under their scrotum. This research led to many additional studies that identified a number of occupational carcinogenic exposures and led to public health measures to reduce cancer risk.

• 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 demonstrate that smoking is a cause of lung cancer, and lead to the US Surgeon General's 1964 report Smoking and Health.

Epidemiologists continue their search for factors that cause cancer (such as tobacco use, obesity, ultraviolet radiation) as well as those offering protection against cancer (such as physical activity, healthful diet). This research provides evidence to guide pubic health recommendations and regulations. As molecular biologists learn more about how factors cause of 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 first developed by George Papanicolaou as a research method in understanding the menstrual cycle. Papanicolaou soon recognized its potential for early detection of cervical cancer and presented his findings in 1923. Most doctors were initially skeptical, and it was not until the American Cancer Society promoted the test during the early 1960 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 checkup 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 patients have of the disease. Some people, even today, consider all cancer incurable and delay consulting a doctor until it is too late.

Treatments for cancer went 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 specifically in 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, there emerged the great surgeons 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 at Johns Hopkins. Their work led to "cancer operations" designed to remove all of the tumor together 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 be curative -- 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, the radical mastectomy is almost never performed 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 of 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 twentieth 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 better understanding of cancer as a disease and on better surgical instruments, but also on combining surgery with chemotherapy and/or radiation.

Until the end of the twentieth century, cancer diagnosis required "exploratory surgery" to open the abdomen 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 of internal organs.

Instruments that use fiberoptic technology and miniature video cameras permit doctors to view the inside of the body. Surgeons can use special surgical instruments operated through tubes inserted into the body. Endoscopic surgery can remove tumors through tubes inserted through body openings to reach the colon, esophagus, or bladder. Similar instruments can also be inserted through small incisions to reach the abdomen (laporscopic 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 the improvement of 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, for the treatment and prevention of 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 following removal of the testes. Later, drugs that blocked male hormone were found to be effective treatment for prostate cancer, and these drugs are now being studied to determine if they have a role in prevention of prostate cancer.

New classes of drugs (such as aromatase inhibitors, LHRH analogs and inhibitors, and others) have substantially changed treatment of prostate and breast cancer. Ongoing research to better understand how hormones influence growth of some forms of cancer has guided progress in developing and prescribing new drugs for cancer treatment as well as for reducing 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 the treatment of 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 therapeutic response. The methods and the machines for delivery of radiation therapy have steadily improved. Today, radiation is delivered with great precision in order to destroy malignant tumors while minimizing damage to adjacent normal tissue.

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 are making it possible to aim radiation more precisely than in the past. 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 side effects of nearby normal tissues.

Stereotactic surgery 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 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 ongoing 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 directly to the cancer or the adjacent tissues after the cancer has been removed. It is more commonly used in abdominal or pelvic cancers and in cancers that have a tendency to return. 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, thus 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 ongoing to find substances that may protect normal cells from radiation.

Cancer treatments: Chemotherapy

The century of the surgeon had begun with the discovery of anesthesia in 1846. Fifty years later, in 1896, Roentgen presented his famous paper on the X-ray. 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 U.S Army was studying a number of agents related to mustard gas in order to develop more effective agents and to develop protective measures. In the course of that work, a compound called nitrogen mustard was studied and found to have substantial activity 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 proliferating 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 acute leukemia in children. Aminopterin blocked a critical chemical reaction needed for DNA replication. That drug was the predecessor of methotrexate, a commonly used cancer treatment drug today. Since then, other researchers discovered drugs that blocked different functions involved in cell growth and replication. The era of chemotherapy had begun. The first cure of metastatic cancer was obtained in 1956 when methotrexate was used to treat a rare tumor called choriocarcinoma.

Over the years, the development and use of chemotherapy drugs 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 acute lymphoblastic leukemia with chemotherapy were first reported during the 1960s, with testicular cancer following during the next decade. Many other cancers can be controlled for long periods of time, even if not cured, although even the most chemosenstive forms of cancer are not always curable. Now several approaches are being studied to improve the activity and reduce the undesirable 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 antiemetics (to reduce nausea and vomiting)

• hematopoietic stem cell transplantation

• agents that overcome multidrug resistance

Liposomal therapy is a new technique that uses chemotherapy drugs that have been packaged inside liposomes (synthetic fat globules). This liposome, or fatty coating, helps them penetrate the cancer cells more selectively and decreases possible side effects (such as hair loss, nausea, and vomiting). Examples of liposomal medications are Doxil (the encapsulated form of doxorubicin) and Daunoxome (the encapsulated form of daunorubicin).

Early in the 20th century, the only curable cancers were small and localized enough to be completely removed by surgery. 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 multiple chemotherapeutic agents (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 extremely 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 essential to continued progress.

Cancer treatments: immunotherapy

Scientists’ 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 regulate growth. This cancer treatment, called biological response modifier (BRM) therapy, biologic therapy, biotherapy, or immunotherapy, has proven effective for several cancers through the clinical trial process.

Some of these biologic agents, occurring naturally in the body, can now be produced in the laboratory. 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 localize tumors in the body 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. At least 9 monoclonal antibodies are already used for cancer treatment, and many more are being studied.

Scientists are also studying vaccines to would boost the body’s immune response to cancer cells.

Cancer treatments: Targeted therapies

Until the late 1990s nearly all drugs used in cancer treatment (with the notable exception of hormonal 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.

On the other hand, 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 naturally die (in the way normal cells when they are too old). These 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 on, they 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 these factors are recognized by cells, and how that recognition leads to signals inside the cells resulting in the abnormal features of cancer cells. Changes in these signal pathways have also been recognized as causing the abnormal behavior of cancerous cells. During the 1980s, scientists recognized 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).

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 body tissues. But in a person with cancer, this same process creates new, very small blood vessels that provide a tumor with 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 new the 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.

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 anticancer 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, the 1 out of 2 people diagnosed with cancer survived at least five years. Now, more than 2 out of 3 survive that long. Today there are about 11 million cancer survivors in the United States.

Now that more people are surviving cancer, more attention than ever is focused on the quality of life for cancer survivors. Behavioral researchers have conducted studies to learn more about the problems survivors face. Some of these problems are medical ones, such as permanent side effects of treatment. Others are emotional or social challenges, like problems getting healthcare insurance, discrimination by employers, or that some people avoid cancer survivors because they just don’t know what to say and are afraid to ask.

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 two 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 that much more remains to be learned.

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 at which to aim their new drugs. In addition to more monoclonal antibodies and small signaling pathway inhibitors, researchers are developing new classes of molecules such as antisense oligodeoxynucleotides and small interfering RNA (siRNA).

Nanotechnology: New technology for producing new materials that form extremely tiny particles is leading to very promising methods for diagnostic imaging to more accurately demonstrate the location of tumors, and for delivering drugs more specifically and effectively into cancer cells.

Robotoic surgery: This term refers to manipulation of surgical instruments remotely by robotic 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 application 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 than an unaided surgeon could.

RNA expression profiling and proteomics: RNA expression profiling permits scientists to determine relative amounts of hundreds or even thousands or 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 the case of 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 accurate at finding early cancers. But researchers are hopeful that comparing the relative amounts of many proteins may be more useful, and that knowing particular proteins are abnormally abundant and others are less abundant can provide accurate information.

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, U.S. Printing Office, Washington D.C. 20401. DHEW Publication No (NIH) 76-720; 1976.

References

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 http://www.curetoday.com/index.cfm/fuseaction/article.show/id/2/article_id/631 on February 15, 2009.

Progress against cancer. Cancer.Net Web site. Accessed at http://www.cancer.net/patient/Advocacy%20and%20Policy/Treatment_Advances_Timeline.pdf on February 15, 2009.

The history of cancer. Institut Jules Bordet Web site. Accessed at http://www.bordet.be/en/presentation/history/cancer_e/cancer1.htm on February 15, 2009.

Last Medical Review: 03/09/2009
Last Revised: 03/09/2009