Loss of contact inhibition accounts for two other characteristics of cancer cells: invasiveness of surrounding tissues, and metastasis, or spreading via the lymph system or blood to other tissues and organs. Whereas normal cells have a limited lifespan controlled by the telomere gene, which signals the end of the cell line, cancer cells contain telomerase, an enzyme that alters the telomere gene and allows the cell to continue to divide. Cancer tissue, growing without limits, competes with normal tissue for nutrients, eventually killing normal cells by nutritional deprivation. Cancerous tissue can also cause secondary effects, in which the expanding malignant growth puts pressure on surrounding tissue or organs or the cancer cells metastasize and invade other organs.
Virtually all organs and tissues are susceptible to cancer. Cancers are usually named for their site of origin. Cancer cells that spread to other organs are similar to those of the original tumor, therefore these secondary (metastatic) cancers are still named for their primary site even though they may have invaded a different organ. For example, lung cancer that has spread to the brain is called metastatic lung cancer, rather than brain cancer. Carcinoma in situ refers to a cancer that has not spread. (See neoplasm for more on cancer nomenclature.)
Cancer is the second leading cause of death in the United States. Lung cancer is the leading cause of cancer death in adults; leukemia is the most common cancer in children. Other common types of cancer include breast cancer (in women), prostate cancer (in men), and colon cancer (see also Hodgkin's disease). The incidence of particular cancers varies around the world and sometimes according to ethnic group. For instance, African Americans have comparatively higher cancer rates and cancer mortality rates. It is unclear whether this is due to differences in exposure or to biological susceptibility. The number of diagnosed cases of cancer rose steadily in the United States for decades, but in 1998 it was announced that the number of new cases had begun to decline.
Cancer results from mutations of certain genes that allow the cells to begin their uncontrolled growth. These mutations are either inherited or acquired. Acquired mutations are caused by repeated insults from triggers (e.g., cigarette smoke or ultraviolet rays) referred to as carcinogens. There is usually a latency period of years or decades between exposure to a carcinogen and the appearance of cancer. This, combined with the individual nature of susceptibility to cancer, makes it very difficult to establish a cause for many cancers.
The most significant avoidable carcinogens are the chemical components of tobacco smoke (see smoking). Dietary components, like excessive consumption of alcohol or of foods high in fat and low in fiber rather than fruits and vegetables that contain antioxidants and necessary micronutrients, have also been linked with various cancers. Some cancers may be triggered by hormone imbalances. For example, some daughters of mothers who had been given DES (diethylstilbestrol) during pregnancy to prevent miscarriage developed vaginal adenocarcinomas as young women. Aflatoxins are natural mold byproducts that can cause cancer of the liver.
Certain carcinogens present occupational hazards. For example, in the asbestos industry, workers have a high probability of developing lung and colon cancer or a particularly virulent cancer of the mesothelium (the lining of the chest and abdomen). Benzene and vinyl chloride are other known industrial carcinogens.
X rays and radioactive elements are also carcinogenic; the high incidence of leukemia and other cancers in Japanese survivors of the atomic bombing of Hiroshima and Nagasaki and the increased incidence of thyroid cancer after the Chernobyl nuclear disaster give evidence of this. Exposure to the ultraviolet radiation of sunlight is the leading cause of skin cancer.
Many other substances have been identified as carcinogenic to a greater or lesser extent, including chemicals in pesticides that leave residues on foods. The Delaney clause, an amendment (1958) to the U.S. Food, Drug, and Cosmetic Act that prohibits even minuscule amounts of carcinogens in the food supply, has provided the impetus for the investigation of many such chemicals but has also been a source of controversy between industry and environmentalists.
In the early 20th cent., the American virologist Peyton Rous showed that certain sarcomas affecting fowl could be transmitted by injection of an agent invisible under the microscope and later indentified as an RNA-containing virus. Other research uncovered oncogenic, or tumor-causing, viruses, first in experimental animals and then in humans. The Epstein-Barr virus, a member of the herpesvirus group, has been linked with a number of human cancers, including the lymphomas that often occur in immunosuppressed people, such as people with AIDS. Several human papillomaviruses (HPV) have also been shown to initiate cancers. For example, some types of HPV cause genital warts known as condylomata acuminata, which can lead to invasive cancer of the cervix, vulva, vagina, or penis, and another human papillomavirus has been associated with some forms of Kaposi's sarcoma. In addition, hepatitis B has been shown to increase the risk of liver cancer. Bacteria have also been associated with cancer. For example, the Helicobacter pylori bacterium that causes many ulcers is also associated with an increased risk of stomach cancer.
Risk to humans from carcinogens depends upon the dose and a person's biologic susceptibility. Factors influencing a person's biological susceptibility to cancer include age, sex, immune status, nutritional status, genetics, and ethnicity. Only 5% of all cancers in the United States are thought to be explained by inherited genetic mutations. Known genes associated with hereditary cancer include the aberrant BRCA1 and BRCA2 genes that increase breast cancer risk and the HNPCC gene that is linked with colon cancer. In hereditary forms, it is often the normal gene of the allele that is injured or destroyed, leaving the abnormal inherited gene in control. Nonhereditary cancers sometimes involve the same gene mutations that hereditary forms have.
Most bodily insults by carcinogens come to nothing because DNA has built-in repair mechanisms, but repeated insults can eventually result in mutations or altered gene expression in key genes called oncogenes and tumor-suppressor genes. Oncogenes produce growth factors, substances that signal a cell to grow and divide into daughter cells; tumor-suppressor genes (such as the p16, p53, and BRCA1 genes) normally produce a negative growth factor that tells a cell when to stop dividing. The abnormally inactivated tumor-suppressor gene or the abnormally activated oncogene is inherited by each of the cell's daughter cells, and a tumor develops. In many cases tumors remain small and in one place (in situ) for years, but some develop their own blood vessels (a process known as angiogenesis) and begin to grow and spread.
The classic symptoms of cancer are rapid weight loss; a change in a wart or mole; a sore that does not heal; difficulty swallowing; chronic hoarseness, blood in phlegm, urine, or stool (a consequence of angiogenesis); chronic abdominal pain; a change in size or shape of the testes; a change in bowel habits; a lump in the breast; and unusual vaginal bleeding. Many of these and other symptoms are often nonspecific, e.g., weakness, loss of appetite, and weight loss, and thus are not obvious in the early stages. Sometimes the side effects of tumor growth are more severe than the actual effects of the malignancy; for example, some tumors secrete materials such as serotonin and histamine that can cause drastic vascular changes. Conversely, cancers that destroy tissue may also have serious effects, e.g., malignant destruction of bone tissue may raise the blood level of calcium.
As more has been learned about cancer, emphasis on prevention and early detection has increased. Cessation of smoking and other tobacco use is the most important controllable means of prevention; smoking causes about 30% of the cancer deaths in the United States. A diet low in fat and high in fiber, including a variety of fruits and vegetables (especially those high in antioxidants), is also recommended. Effective protection against the rays of the sun is recommended to avoid skin cancer. Another preventive approach is vaccination against cancer-causing viruses, such as the hepatitis B virus.
Cancers caught early, before metastasis, have the best cure rates. A number of screening tools are now available to allow early detection and treatment. Among these are monthly breast self-examinations and regular mammography and Pap tests for women, regular self-examination of the testes for young men, and, for older men, regular examination of the prostate gland with blood tests for prostate-specific antigen (PSA) tumor marker (a substance in the body that heralds an increased cancer risk). Colonoscopy plus physical examination and laboratory tests for carcinoembryonic antigen (CEA) are recommended for detection of colon cancer. Self-examination of the skin is important for the early detection of skin cancers. Suspicion of a tumor may be confirmed by X-ray study, endoscopy (see endoscope), blood tests for various tumor markers, and biopsy from which the cells are examined by a pathologist for malignancy.
Developments in the treatment of cancer have led to greatly improved survival and quality of life for cancer patients in the past three decades. Traditionally, cancer has been treated by surgery, chemotherapy, and radiation therapy. In recent years immunotherapy has been added to that list. New drugs and techniques are constantly being researched and developed, such as antiangiogenic agents (e.g., angiostatin and endostatin), genetically engineered monoclonal antibodies, retinoid agents, and vaccine agents (stimulating the immune system).
For most kinds of cancer, surgery remains the primary treatment. It is most effective if the cancer is caught while still localized. Some cancers that spread to the lymph system are sometimes treated by extensive surgical removal of tissue, but the trend is toward more conservative procedures (see mastectomy). Cryosurgery, the use of extreme cold, and electrodessication, the use of extreme heat, are also being used to kill cancerous tissue and the surrounding blood supply. If the cancer has metastasized, surgery is often replaced by or followed by radiation therapy (which is a localized therapy) and chemotherapy (which is a system-wide therapy).
For some cancers, radiation therapy—either from an external beam or from implanted radioactive pellets—is the primary treatment. The usual forms are X rays and gamma rays. Use of radioactive elements specific for particular target organs, such as radioactive iodine specific for the thyroid gland, is effective in treating malignancies of those organs.
Cytotoxic chemotherapy is used as a primary treatment for some cancers, such as lymphomas and leukemias or as an addition to surgery or radiation therapy. Cytotoxic drugs (drugs that are toxic to cells) are aimed at rapidly proliferating cells and interfere with nucleic acid and protein synthesis in the cancer cell, but they are often toxic to normal rapidly proliferating cells, such as bone marrow and hair cells. Often a combination of cytotoxic drugs is used. Drugs that reduce side effects may be added to the treatment, such as antinausea agents.
Hormonal chemotherapy is based upon the fact that the growth of some malignant tumors (specifically those of the reproductive organs) is influenced by reproductive hormones. Tamoxifen is a naturally occurring estrogen inhibitor used to prevent breast cancer recurrences. Flutamide is sometimes used in prostate cancer to inhibit androgen uptake. Sex-hormone related drugs such as DES and tamoxifen, which may be carcinogenic under some conditions, have proven to be protective under others.
More specifically targeted drug therapies have begun to be explored as a better understanding of the molecular biology of individual cancers has been developed. Such drugs are designed to kill only cancer cells while having fewer side effects. Gleevec (STI-571), which is used to treat chronic myelogenous leukemia and some other cancers, inhibits certain kinase receptors that become hyperactive in cancer cells, resulting in the cells' rapid reproduction.
Immunotherapy (sometimes called biological therapy) uses substances that help the body mobilize its immune defenses. Some attack the tumor itself, while others bolster the body's ability to withstand conventional chemotherapy treatment. Other new or experimental therapies include drugs that inhibit angiogenesis and photodynamic therapy, in which a patient is given a drug to make the tumor light-sensitive, after which the tumor is exposed to bright laser light. The best choice of treatment will increasingly be influenced by the growing field of molecular pathology, in which characteristics of individual cancers (e.g., virulence or resistance to a particular treatment) can be revealed by analysis of their genetic characteristics rather than by the microscope.
Besides treatment of the cancer itself, progress has been made in the management of the chronic pain that often accompanies cancer and in the education of patients and physicians in such techniques as biofeedback, acupuncture, and meditation and the appropriate use of narcotics and other medications. Because of improvements in early detection and treatment, many more people are now living with cancer. Over half of all people with cancer now survive for five or more years.
See S. S. Lang and R. B. Patt, You Don't Have to Suffer (1994); P. Greenwald et al., Cancer Prevention and Control (1995); M. Dollinger et al., Everyone's Guide to Cancer Therapy (3d ed. 1997); C. N. Coleman, Understanding Cancer (1998). See also publications of the National Cancer Institute and the American Cancer Society.
Malignant tumour of the uterus. Cancers affecting the lining of the uterus (endometrium) are the most common cancers of the female reproductive tract. Risk factors include absence of pregnancy, early age of first menstruation (before age 12), late onset of menopause (after age 52), obesity, diabetes, and estrogen replacement therapy. Additional risk factors are a personal history of breast or ovarian cancer, age (over age 40), and a family history of uterine cancer. Whites are more likely to develop uterine cancer than are blacks. The major symptom is vaginal bleeding or discharge. Treatment may begin with simple or radical hysterectomy. Some uterine cancers are treated in part by hormonal therapy, radiation therapy, or chemotherapy.
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Malignant tumour of the testis, or testicle. Although relatively rare, testicular cancer is the most common malignancy for men between the ages of 20 and 34. It typically affects men between 15 and 39 years old. A developmental abnormality of males in which one or both testes fail to descend into the scrotum about the time of birth increases the risk of developing the cancer later in life. The most notable symptom of testicular cancer is the formation of a painless lump in either testis. Treatment usually consists of the surgical removal of the cancerous testis, followed by radiation therapy or chemotherapy if the cancer has metastasized.
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Malignant tumour of the stomach. The main risk factors include a diet high in salted, smoked, or pickled foods; Helicobacter pylori infection; tobacco and alcohol use; age (over age 60); and a family history of stomach cancer. Males develop stomach cancer at approximately twice the rate of females. Symptoms may be abdominal pain or swelling, unexplained weight loss, vomiting, and poor digestion. Surgery is the only method for treating stomach cancer, although radiation therapy or chemotherapy may be used in conjunction with surgery or to relieve symptoms.
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Malignant tumour of the skin, including some of the most common human cancers. Though recognizable at an early stage, it has a significant death rate. Light-skinned people have the highest risk but can reduce it by limiting exposure to sunlight and to ionizing radiation. The most common types arise in the epidermis (outer skin layer) and have become more frequent with the thinning of the atmosphere's ozone layer. The most serious form is melanoma, which is frequently fatal if not treated early with surgery. Cancers arising from the dermis are rare; the best-known is Kaposi sarcoma.
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Malignant tumour of the prostate gland. Prostate cancer commonly occurs in men over age 50. Symptoms include frequent or painful urination, blood in the urine, sexual dysfunction, swollen lymph nodes in the groin, and pain in the pelvis, hips, back, or ribs. The likelihood of developing prostate cancer doubles if there is a family history. Treatment may include surgery, radiation therapy, hormone therapy, chemotherapy, or a combination of two or more of these approaches.
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Malignant tumour of the pancreas. Risk factors include smoking, a diet high in fat, exposure to certain industrial products, and diseases such as diabetes and chronic pancreatitis. Pancreatic cancer is more common in men. Symptoms often do not appear until pancreatic cancer is advanced; they include abdominal pain, unexplained weight loss, and difficulty digesting fatty foods. Surgery, radiation therapy, chemotherapy, or some combination of these may be used to treat the disease.
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Malignant tumour of the ovaries. Risk factors include early age of first menstruation (before age 12), late onset of menopause (after age 52), absence of pregnancy, presence of specific genetic mutations, use of fertility drugs, and personal history of breast cancer. Symptoms such as abdominal swelling, pelvic pressure or pain, and unusual vaginal bleeding often do not appear until ovarian cancer is advanced. Surgery, sometimes followed by chemotherapy or radiation therapy, is an effective treatment for most ovarian cancers.
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Malignant tumour of the lung. Four major types (squamous-cell carcinoma, adenocarcinoma, large-cell carcinoma, and small-cell carcinoma) have roughly equal prevalence. Most cases are due to long-term cigarette smoking. Heavy smoking and starting smoking earlier in life increase the risk. Passive inhalation (“secondhand smoke”) is linked to lung cancer in nonsmokers. Other risk factors include exposure to radon or asbestos. Symptoms, including coughing (sometimes with blood), chest pain, and shortness of breath, seldom appear until lung cancer is advanced, when treatment with surgery, chemotherapy, and radiation or some combination of the three is less effective. Most patients die within a year of diagnosis.
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Malignant tumour of the larynx. The larynx is affected by both benign and malignant tumours. Squamous-cell carcinoma, the most common laryngeal malignancy, is associated with smoking and alcohol consumption; it is more common in men. Prolonged hoarseness without pain is the major symptom and should always be investigated. Radiation therapy or surgery may be used to treat tumours.
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Malignant tumour of the large intestine (colon) or rectum. Risk factors include age (after age 50), family history of colorectal cancer, chronic inflammatory bowel diseases, benign polyps, physical inactivity, and a diet high in fat. Many of the symptoms are associated with abnormal digestion and elimination. Colorectal cancer is treated by surgery, chemotherapy, or radiation therapy.
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Uncontrolled multiplication of abnormal cells. Cancerous cells and tissues have abnormal growth rates, shapes, sizes, and functioning. Cancer may progress in stages from a localized tumour (confined to the site of origin) to direct extension (spread into nearby tissue or lymph nodes) and metastasis (spread to more distant sites via the blood or lymphatic system). This malignant growth pattern distinguishes cancerous tumours from benign ones. Cancer is also classified by grade, the extent to which cell characteristics remain specific to their tissue of origin. Both stage and grade affect the chances of survival. Genetic factors and immune status affect susceptibility. Triggers include hormones, viruses, smoking, diet, and radiation. Cancer can begin in almost any tissue, including blood (see leukemia) and lymph (see lymphoma). When it metastasizes, it remains a cancer of its tissue of origin. Early diagnosis and treatment increase the chance of cure. Treatment may include chemotherapy, surgery, and radiation therapy. Seealso bladder cancer; breast cancer; carcinogen; colorectal cancer; Kaposi sarcoma; laryngeal cancer; lung cancer; ovarian cancer; pancreatic cancer; prostate cancer; skin cancer; stomach cancer; uterine cancer.
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Malignant tumour in a breast, usually in women after menopause. Risk factors include family history of breast cancer, prolonged menstruation, late first pregnancy (after age 30), obesity, alcohol use, and some benign tumours. Most breast cancers are adenocarcinomas. Any lump in the breast needs investigation because it may be cancer. Treatment may begin with radical or modified mastectomy or lumpectomy (in which only the tumour is removed), followed by radiation therapy, chemotherapy, or removal of the ovaries or adrenal glands.
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Malignant tumour of the bladder. The most significant risk factor associated with bladder cancer is smoking. Exposure to chemicals called arylamines, which are used in the leather, rubber, printing, and textiles industries, is another risk factor. Most bladder cancers are diagnosed after the age of 60; men are affected more than women. Symptoms include blood in the urine, difficulty urinating, excessive urination, or, more rarely, painful urination. Bladder cancer can be treated with surgery, radiation therapy, or chemotherapy.
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Parallel of latitude approximately 23°27' north of the terrestrial Equator. It is the northern boundary of the tropics and marks the northernmost latitude at which the Sun can be seen directly overhead at noon.
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(Latin: “Crab”) In astronomy, the constellation lying between Leo and Gemini; in astrology, the fourth sign of the zodiac, governing approximately the period June 22–July 22. It is represented as a crab (or crayfish), a reference to the crab in Greek mythology that pinched Heracles while he was fighting the Lernaean hydra. Heracles crushed the crab, but his enemy Hera rewarded it by placing it in the sky as a constellation.
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Cancer (medical term: malignant neoplasm) is a class of diseases in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, do not invade or metastasize. Most cancers form a tumor but some, like leukemia, do not. The branch of medicine concerned with the study, diagnosis, treatment, and prevention of cancer is oncology.
Cancer may affect people at all ages, even fetuses, but the risk for most varieties increases with age. Cancer causes about 13% of all deaths. According to the American Cancer Society, 7.6 million people died from cancer in the world during 2007. Cancers can affect all animals.
Nearly all cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may be randomly acquired through errors in DNA replication, or are inherited, and thus present in all cells from birth. The heritability of cancers are usually affected by complex interactions between carcinogens and the host's genome. New aspects of the genetics of cancer pathogenesis, such as DNA methylation, and microRNAs are increasingly recognized as important.
Genetic abnormalities found in cancer typically affect two general classes of genes. Cancer-promoting oncogenes are typically activated in cancer cells, giving those cells new properties, such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Tumor suppressor genes are then inactivated in cancer cells, resulting in the loss of normal functions in those cells, such as accurate DNA replication, control over the cell cycle, orientation and adhesion within tissues, and interaction with protective cells of the immune system.
Diagnosis usually requires the histologic examination of a tissue biopsy specimen by a pathologist, although the initial indication of malignancy can be symptoms or radiographic imaging abnormalities. Most cancers can be treated and some cured, depending on the specific type, location, and stage. Once diagnosed, cancer is usually treated with a combination of surgery, chemotherapy and radiotherapy. As research develops, treatments are becoming more specific for different varieties of cancer. There has been significant progress in the development of targeted therapy drugs that act specifically on detectable molecular abnormalities in certain tumors, and which minimize damage to normal cells. The prognosis of cancer patients is most influenced by the type of cancer, as well as the stage, or extent of the disease. In addition, histologic grading and the presence of specific molecular markers can also be useful in establishing prognosis, as well as in determining individual treatments.
The following terms can be used to describe a cancer:
Cancers are classified by the type of cell that resembles the tumor and, therefore, the tissue presumed to be the origin of the tumor. Examples of general categories include:
Malignant tumors (cancers) are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ of origin as the root. For instance, a cancer of the liver is called hepatocarcinoma; a cancer of the fat cells is called liposarcoma. For common cancers, the English organ name is used. For instance, the most common type of breast cancer is called ductal carcinoma of the breast or mammary ductal carcinoma. Here, the adjective ductal refers to the appearance of the cancer under the microscope, resembling normal breast ducts.
Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as the root. For instance, a benign tumor of the smooth muscle of the uterus is called leiomyoma (the common name of this frequent tumor is fibroid). Unfortunately, some cancers also use the -oma suffix, examples being melanoma and seminoma.
|most common (by occurrence)||most common (by mortality)||most common (by occurrence)||most common (by mortality)|
|prostate cancer (33%)||lung cancer (31%)||breast cancer (32%)||lung cancer (27%)|
|lung cancer (13%)||prostate cancer (10%)||lung cancer (12%)||breast cancer (15%)|
|colorectal cancer (10%)||colorectal cancer (10%)||colorectal cancer (11%)||colorectal cancer (10%)|
|bladder cancer (7%)||pancreatic cancer (5%)||endometrial cancer (6%)||ovarian cancer (6%)|
|cutaneous melanoma (5%)||leukemia (4%)||non-Hodgkin lymphoma (4%)||pancreatic cancer (6%)|
There is a reasonable doubt that children living near nuclear facilities face an increased risk of cancer.
The age of peak incidence of cancer in children occurs during the first year of life, in infants. The average annual incidence in the United States, 1975-1995, was 233 per million infants. Several estimates of incidence exist. According to SEER, in the United States:
According to another study:
Teratoma (a germ cell tumor) often is cited as the most common tumor in this age group, but most teratomas are surgically removed while still benign, hence not necessarily cancer. Prior to the widespread routine use of prenatal ultrasound examinations, the incidence of sacrococcygeal teratomas diagnosed at birth was 25 to 29 per million births.
Female and male infants have essentially the same overall cancer incidence rates, a notable difference compared to older children.
White infants have higher cancer rates than black infants. Leukemias accounted for a substantial proportion of this difference: the average annual rate for white infants (48.7 per million) was 66% higher than for black infants (29.4 per million).
Every symptom in the above list can be caused by a variety of conditions (a list of which is referred to as the differential diagnosis). Cancer may be a common or uncommon cause of each item.
The tissue diagnosis given by the pathologist indicates the type of cell that is proliferating, its histological grade and other features of the tumor. Together, this information is useful to evaluate the prognosis of this patient and to choose the best treatment. Cytogenetics and immunohistochemistry are other types of testing that the pathologist may perform on the tissue specimen. These tests may provide information about future behavior of the cancer (prognosis) and best treatment.
Complete removal of the cancer without damage to the rest of the body is the goal of treatment. Sometimes this can be accomplished by surgery, but the propensity of cancers to invade adjacent tissue or to spread to distant sites by microscopic metastasis often limits its effectiveness. The effectiveness of chemotherapy is often limited by toxicity to other tissues in the body. Radiation can also cause damage to normal tissue.
Examples of surgical procedures for cancer include mastectomy for breast cancer and prostatectomy for prostate cancer. The goal of the surgery can be either the removal of only the tumor, or the entire organ. A single cancer cell is invisible to the naked eye but can regrow into a new tumor, a process called recurrence. For this reason, the pathologist will examine the surgical specimen to determine if a margin of healthy tissue is present, thus decreasing the chance that microscopic cancer cells are left in the patient.
In addition to removal of the primary tumor, surgery is often necessary for staging, e.g. determining the extent of the disease and whether it has metastasized to regional lymph nodes. Staging is a major determinant of prognosis and of the need for adjuvant therapy.
Radiation therapy (also called radiotherapy, X-ray therapy, or irradiation) is the use of ionizing radiation to kill cancer cells and shrink tumors. Radiation therapy can be administered externally via external beam radiotherapy (EBRT) or internally via brachytherapy. The effects of radiation therapy are localised and confined to the region being treated. Radiation therapy injures or destroys cells in the area being treated (the "target tissue") by damaging their genetic material, making it impossible for these cells to continue to grow and divide. Although radiation damages both cancer cells and normal cells, most normal cells can recover from the effects of radiation and function properly. The goal of radiation therapy is to damage as many cancer cells as possible, while limiting harm to nearby healthy tissue. Hence, it is given in many fractions, allowing healthy tissue to recover between fractions.
Radiation therapy may be used to treat almost every type of solid tumor, including cancers of the brain, breast, cervix, larynx, lung, pancreas, prostate, skin, stomach, uterus, or soft tissue sarcomas. Radiation is also used to treat leukemia and lymphoma. Radiation dose to each site depends on a number of factors, including the radiosensitivity of each cancer type and whether there are tissues and organs nearby that may be damaged by radiation. Thus, as with every form of treatment, radiation therapy is not without its side effects.
Chemotherapy is the treatment of cancer with drugs ("anticancer drugs") that can destroy cancer cells. In current usage, the term "chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy (see below). Chemotherapy drugs interfere with cell division in various possible ways, e.g. with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can. Hence, chemotherapy has the potential to harm healthy tissue, especially those tissues that have a high replacement rate (e.g. intestinal lining). These cells usually repair themselves after chemotherapy.
Because some drugs work better together than alone, two or more drugs are often given at the same time. This is called "combination chemotherapy"; most chemotherapy regimens are given in a combination.
The treatment of some leukaemias and lymphomas requires the use of high-dose chemotherapy, and total body irradiation (TBI). This treatment ablates the bone marrow, and hence the body's ability to recover and repopulate the blood. For this reason, bone marrow, or peripheral blood stem cell harvesting is carried out before the ablative part of the therapy, to enable "rescue" after the treatment has been given. This is known as autologous stem cell transplantation. Alternatively, hematopoietic stem cells may be transplanted from a matched unrelated donor (MUD).
Targeted therapy, which first became available in the late 1990s, has had a significant impact in the treatment of some types of cancer, and is currently a very active research area. This constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors imatinib and gefitinib.
Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (Herceptin) used in breast cancer, and the anti-CD20 antibody rituximab, used in a variety of B-cell malignancies.
Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to this peptides (e.g. RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. Especially oligo- or multimers of these binding motifs are of great interest, since this can lead to enhanced tumor specificity and avidity.
Photodynamic therapy (PDT) is a ternary treatment for cancer involving a photosensitizer, tissue oxygen, and light (often using lasers). PDT can be used as treatment for basal cell carcinoma (BCC) or lung cancer; PDT can also be useful in removing traces of malignant tissue after surgical removal of large tumors.
Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumours include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients. Vaccines to generate specific immune responses are the subject of intensive research for a number of tumours, notably malignant melanoma and renal cell carcinoma. Sipuleucel-T is a vaccine-like strategy in late clinical trials for prostate cancer in which dendritic cells from the patient are loaded with prostatic acid phosphatase peptides to induce a specific immune response against prostate-derived cells.
Allogeneic hematopoietic stem cell transplantation ("bone marrow transplantation" from a genetically non-identical donor) can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a phenomenon known as graft-versus-tumor effect. For this reason, allogeneic HSCT leads to a higher cure rate than autologous transplantation for several cancer types, although the side effects are also more severe.
The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial.
Pain medication, such as morphine and oxycodone, and antiemetics, drugs to suppress nausea and vomiting, are very commonly used in patients with cancer-related symptoms. Improved antiemetics such as ondansetron and analogues, as well as aprepitant have made aggressive treatments much more feasible in cancer patients.
Chronic pain due to cancer is almost always associated with continuing tissue damage due to the disease process or the treatment (i.e. surgery, radiation, chemotherapy). Although there is always a role for environmental factors and affective disturbances in the genesis of pain behaviors, these are not usually the predominant etiologic factors in patients with cancer pain. Furthermore, many patients with severe pain associated with cancer are nearing the end of their lives and palliative therapies are required. Issues such as social stigma of using opioids, work and functional status, and health care consumption are not likely to be important in the overall case management. Hence, the typical strategy for cancer pain management is to get the patient as comfortable as possible using opioids and other medications, surgery, and physical measures. Doctors have been reluctant to prescribe narcotics for pain in terminal cancer patients, for fear of contributing to addiction or suppressing respiratory function. The palliative care movement, a more recent offshoot of the hospice movement, has engendered more widespread support for preemptive pain treatment for cancer patients.
Fatigue is a very common problem for cancer patients, and has only recently become important enough for oncologists to suggest treatment, even though it plays a significant role in many patients' quality of life.
A clinical trial is one of the final stages of a long and careful cancer research process. The search for new treatments begins in the laboratory, where scientists first develop and test new ideas. If an approach seems promising, the next step may be testing a treatment in animals to see how it affects cancer in a living being and whether it has harmful effects. Of course, treatments that work well in the lab or in animals do not always work well in people. Studies are done with cancer patients to find out whether promising treatments are safe and effective.
Patients who take part may be helped personally by the treatment they receive. They get up-to-date care from cancer experts, and they receive either a new treatment being tested or the best available standard treatment for their cancer. At the same time, new treatments also may have unknown risks, but if a new treatment proves effective or more effective than standard treatment, study patients who receive it may be among the first to benefit. There is no guarantee that a new treatment being tested or a standard treatment will produce good results. In children with cancer, a survey of trials found that those enrolled in trials were on average not more likely to do better or worse than those on standard treatment; this confirms that success or failure of an experimental treatment cannot be predicted.
Progressive and disseminated malignant disease has a substantial impact on a cancer patient's quality of life, and many cancer treatments (such as chemotherapy) may have severe side-effects. In the advanced stages of cancer, many patients need extensive care, affecting family members and friends. Palliative care solutions may include permanent or "respite" hospice nursing.
Counseling can provide emotional support to cancer patients and help them better understand their illness. Different types of counseling include individual, group, family, peer counseling, bereavement, patient-to-patient, and sexuality.
Many governmental and charitable organizations have been established to help patients cope with cancer. These organizations often are involved in cancer prevention, cancer treatment, and cancer research.
Cancer is a diverse class of diseases which differ widely in their causes and biology. The common thread in all known cancers is the acquisition of abnormalities in the genetic material of the cancer cell and its progeny. Research into the pathogenesis of cancer can be divided into three broad areas of focus. The first area of research focuses on the agents and events which cause or facilitate genetic changes in cells destined to become cancer. Second, it is important to uncover the precise nature of the genetic damage, and the genes which are affected by it. The third focus is on the consequences of those genetic changes on the biology of the cell, both in generating the defining properties of a cancer cell, and in facilitating additional genetic events, leading to further progression of the cancer.
Many mutagens are also carcinogens, but some carcinogens are not mutagens. Alcohol is an example of a chemical carcinogen that is not a mutagen. Such chemicals may promote cancers through stimulating the rate of cell division. Faster rates of replication leaves less time for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a mutation.
Decades of research has demonstrated the link between tobacco use and cancer in the lung, larynx, head, neck, stomach, bladder, kidney, oesophagus and pancreas. Tobacco smoke contains over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons. Tobacco is responsible for about one in three of all cancer deaths in the developed world, and about one in five worldwide. Indeed, lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking followed by decreases in lung cancer death rates in men. However, the numbers of smokers worldwide is still rising, leading to what some organizations have described as the tobacco epidemic.
Radio-frequency radiation from mobile phones has been proposed as a cause of cancer, but there is little evidence of such a link. Nevertheless, some experts caution against prolonged exposure.
Hepatitis viruses, including hepatitis B and hepatitis C, can induce a chronic viral infection that leads to liver cancer in 0.47% of hepatitis B patients per year (especially in Asia, less so in North America), and in 1.4% of hepatitis C carriers per year. Liver cirrhosis, whether from chronic viral hepatitis infection or alcoholism, is associated with the development of liver cancer, and the combination of cirrhosis and viral hepatitis presents the highest risk of liver cancer development. Worldwide, liver cancer is one of the most common, and most deadly, cancers due to a huge burden of viral hepatitis transmission and disease.
Advances in cancer research have made a vaccine designed to prevent cancer available. In 2006, the US FDA approved a human papilloma virus vaccine, called Gardasil. The vaccine protects against four HPV types, which together cause 70% of cervical cancers and 90% of genital warts. In March 2007, the US CDC Advisory Committee on Immunization Practices (ACIP) officially recommended that females aged 11-12 receive the vaccine, and indicated that females as young as age 9 and as old as age 26 are also candidates for immunization.
In addition to viruses, researchers have noted a connection between bacteria and certain cancers. The most prominent example is the link between chronic infection of the wall of the stomach with Helicobacter pylori and gastric cancer. Although only a minority of those infected with Helicobacter go on to develop cancer, since this pathogen is quite common it is probably responsible for the majority of these cancers.
In the United States every year, approximately 3,500 pregnant women have a malignancy, and transplacental transmission of acute leukaemia, lymphoma, melanoma and carcinoma from mother to fetus has been observed.
The development of donor-derived tumors from organ transplants is exceedingly rare. The main cause of organ transplant associated tumors seems to be malignant melanoma, that was undetected at the time of organ harvest.
Cancer is fundamentally a disease of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, genes which regulate cell growth and differentiation must be altered. Genetic changes can occur at many levels, from gain or loss of entire chromosomes to a mutation affecting a single DNA nucleotide. There are two broad categories of genes which are affected by these changes. Oncogenes may be normal genes which are expressed at inappropriately high levels, or altered genes which have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes which inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Typically, changes in many genes are required to transform a normal cell into a cancer cell.
There is a diverse classification scheme for the various genomic changes which may contribute to the generation of cancer cells. Most of these changes are mutations, or changes in the nucleotide sequence of genomic DNA. Aneuploidy, the presence of an abnormal number of chromosomes, is one genomic change which is not a mutation, and may involve either gain or loss of one or more chromosomes through errors in mitosis.
Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.
Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants.
Mutations in proto-oncogenes, which are the normally quiescent counterparts of oncogenes, can modify their expression and function, increasing the amount or activity of the product protein. When this happens, the proto-oncogenes become oncogenes, and this transition upsets the normal balance of cell cycle regulation in the cell, making uncontrolled growth possible. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, even if this were possible, as they are critical for growth, repair and homeostasis of the organism. It is only when they become mutated that the signals for growth become excessive.
One of the first oncogenes to be defined in cancer research is the ras oncogene. Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours. Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only was this gene present in the human genome but that, when ligated to a stimulating control element, could induce cancers in cell line cultures.
Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis.
The Warburg hypothesis is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway.
However, a mutation can damage the tumor suppressor gene itself, or the signal pathway which activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.
Mutations of tumor suppressor genes that occur in germline cells are passed along to offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant p53 allele (and are therefore heterozygous for mutated p53) can develop melanomas and pancreatic cancer, known as Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include Rb mutations, linked to retinoblastoma, and APC gene mutations, linked to adenopolyposis colon cancer. Adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to colon cancer at a relatively early age. Finally, inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.
Development of cancer was proposed in 1971 to depend on at least two mutational events. In what became known as the Knudson two-hit hypothesis, an inherited, germ-line mutation in a tumor suppressor gene would only cause cancer if another mutation event occurred later in the organism's life, inactivating the other allele of that tumor suppressor gene.
Usually, oncogenes are dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a tumor suppressor gene can render the other, wild-type copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations.
Knudson’s two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by haploinsufficiency usually have a later age of onset when compared with those by a two hit process.
Often, the multiple genetic changes which result in cancer may take many years to accumulate. During this time, the biological behavior of the pre-malignant cells slowly change from the properties of normal cells to cancer-like properties. Pre-malignant tissue can have a distinctive appearance under the microscope. Among the distinguishing traits are an increased number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, and loss of normal tissue organization. Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. These early neoplastic changes must be distinguished from hyperplasia, a reversible increase in cell division caused by an external stimulus, such as a hormonal imbalance or chronic irritation.
The most severe cases of dysplasia are referred to as "carcinoma in situ." In Latin, the term "in situ" means "in place", so carcinoma in situ refers to an uncontrolled growth of cells that remains in the original location and has not shown invasion into other tissues. Nevertheless, carcinoma in situ may develop into an invasive malignancy and is usually removed surgically, if possible.
The completion of these multiple steps would be a very rare event without :
These biological changes are classical in carcinomas; other malignant tumor may not need all to achieve them all. For example, tissue invasion and displacement to distant sites are normal properties of leukocytes; these steps are not needed in the development of leukemia. The different steps do not necessarily represent individual mutations. For example, inactivation of a single gene, coding for the p53 protein, will cause genomic instability, evasion of apoptosis and increased angiogenesis. Not all the cancer cells are dividing. Rather, a subset of the cells in a tumor, called cancer stem cells, replicate themselves and generate differentiated cells.
Observational epidemiological studies that show associations between risk factors and specific cancers mostly serve to generate hypotheses about potential interventions that could reduce cancer incidence or morbidity. Randomized controlled trials then test whether hypotheses generated by epidemiological trials and laboratory research actually result in reduced cancer incidence and mortality. In many cases, findings from observational epidemiological studies are not confirmed by randomized controlled trials.
About a third of the twelve most common cancers worldwide are due to nine potentially modifiable risk factors. Men with cancer are twice as likely as women to have a modifiable risk factor for their disease. The nine risk factors are tobacco smoking, excessive alcohol use, diet low in fruit and vegetables, limited physical exercise, human papillomavirus infection (unsafe sex), urban air pollution, domestic use of solid fuels, and contaminated injections (hepatitis B and C).
Every year, at least 200,000 people die worldwide from cancer related to their workplace. Millions of workers run the risk of developing cancers such as lung cancer and mesothelioma from inhaling asbestos fibers and tobacco smoke, or leukemia from exposure to benzene at their workplaces. Currently, most cancer deaths caused by occupational risk factors occur in the developed world. It is estimated that approximately 20,000 cancer deaths and 40,000 new cases of cancer each year in the U.S. are attributable to occupation.
See alcohol and cancer for more on that topic.
The consensus on diet and cancer is that obesity increases the risk of developing cancer. Particular dietary practices often explain differences in cancer incidence in different countries (e.g. gastric cancer is more common in Japan, while colon cancer is more common in the United States). Studies have shown that immigrants develop the risk of their new country, often within one generation, suggesting a substantial link between diet and cancer. Whether reducing obesity in a population also reduces cancer incidence is unknown.
Despite frequent reports of particular substances (including foods) having a beneficial or detrimental effect on cancer risk, few of these have an established link to cancer. These reports are often based on studies in cultured cell media or animals. Public health recommendations cannot be made on the basis of these studies until they have been validated in an observational (or occasionally a prospective interventional) trial in humans.
Proposed dietary interventions for primary cancer risk reduction generally gain support from epidemiological association studies. Examples of such studies include reports that reduced meat consumption is associated with decreased risk of colon cancer, and reports that consumption of coffee is associated with a reduced risk of liver cancer. Studies have linked consumption of grilled meat to an increased risk of stomach cancer, colon cancer, breast cancer, and pancreatic cancer, a phenomenon which could be due to the presence of carcinogens such as benzopyrene in foods cooked at high temperatures.
A 2005 secondary prevention study showed that consumption of a plant-based diet and lifestyle changes resulted in a reduction in cancer markers in a group of men with prostate cancer who were using no conventional treatments at the time. These results were amplified by a 2006 study in which over 2,400 women were studied, half randomly assigned to a normal diet, the other half assigned to a diet containing less than 20% calories from fat. The women on the low fat diet were found to have a markedly lower risk of breast cancer recurrence, in the interim report of December, 2006.
Recent studies have also demonstrated potential links between some forms of cancer and high consumption of refined sugars and other simple carbohydrates. Although the degree of correlation and the degree of causality is still debated, some organizations have in fact begun to recommend reducing intake of refined sugars and starches as part of their cancer prevention regimens.
In November 2007, the American Institute for Cancer Research (AICR), in conjunction with the World Cancer Research Fund (WCRF), published Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective', "the most current and comprehensive analysis of the literature on diet, physical activity and cancer". The WCRF/AICR Expert Report lists 10 recommendations that people can follow to help reduce their risk of developing cancer, including the following dietary guidelines: (1) reducing intake of foods and drinks that promote weight gain, namely energy-dense foods and sugary drinks, (2) eating mostly foods of plant origin, (3) limiting intake of red meat and avoiding processed meat, (4) limiting consumption of alcoholic beverages, and (5) reducing intake of salt and avoiding mouldy cereals (grains) or pulses (legumes).
Epidemiological studies have shown that low vitamin D status is correlated to increased cancer risk. However, the results of such studies need to be treated with caution, as they cannot show whether a correlation between two factors means that one causes the other (i.e. correlation does not imply causation). The possibility that Vitamin D might protect against cancer has been contrasted with the risk of malignancy from sun exposure. Since exposure to the sun enhances natural human production of vitamin D, some cancer researchers have argued that the potential deleterious malignant effects of sun exposure are far outweighed by the cancer-preventing effects of extra vitamin D synthesis in sun-exposed skin. In 2002, Dr. William B. Grant claimed that 23,800 premature cancer deaths occur in the US annually due to insufficient UVB exposure (apparently via vitamin D deficiency). This is higher than 8,800 deaths occurred from melanoma or squamous cell carcinoma, so the overall effect of sun exposure might be beneficial. Another research group estimates that 50,000–63,000 individuals in the United States and 19,000 - 25,000 in the UK die prematurely from cancer annually due to insufficient vitamin D.
The case of beta-carotene provides an example of the importance of randomized clinical trials. Epidemiologists studying both diet and serum levels observed that high levels of beta-carotene, a precursor to vitamin A, were associated with a protective effect, reducing the risk of cancer. This effect was particularly strong in lung cancer. This hypothesis led to a series of large randomized clinical trials conducted in both Finland and the United States (CARET study) during the 1980s and 1990s. This study provided about 80,000 smokers or former smokers with daily supplements of beta-carotene or placebos. Contrary to expectation, these tests found no benefit of beta-carotene supplementation in reducing lung cancer incidence and mortality. In fact, the risk of lung cancer was slightly, but not significantly, increased by beta-carotene, leading to an early termination of the study.
Results reported in the Journal of the American Medical Association (JAMA) in 2007 indicate that folic acid supplementation is not effective in preventing colon cancer, and folate consumers may be more likely to form colon polyps.
Daily use of tamoxifen, a selective estrogen receptor modulator (SERM), typically for 5 years, has been demonstrated to reduce the risk of developing breast cancer in high-risk women by about 50%. A recent study reported that the selective estrogen receptor modulator raloxifene has similar benefits to tamoxifen in preventing breast cancer in high-risk women, with a more favorable side effect profile.
Raloxifene is a SERM like tamoxifen; it has been shown (in the STAR trial) to reduce the risk of breast cancer in high-risk women equally as well as tamoxifen. In this trial, which studied almost 20,000 women, raloxifene had fewer side effects than tamoxifen, though it did permit more DCIS to form.
Finasteride, a 5-alpha-reductase inhibitor, has been shown to lower the risk of prostate cancer, though it seems to mostly prevent low-grade tumors. The effect of COX-2 inhibitors such as rofecoxib and celecoxib upon the risk of colon polyps have been studied in familial adenomatous polyposis patients and in the general population. In both groups, there were significant reductions in colon polyp incidence, but this came at the price of increased cardiovascular toxicity.
|BRCA1, BRCA2||Breast, ovarian, pancreatic||Commercially available for clinical specimens|
|MLH1, MSH2, MSH6, PMS1, PMS2||Colon, uterine, small bowel, stomach, urinary tract||Commercially available for clinical specimens|
As reported above, a preventive human papillomavirus vaccine exists that targets certain sexually transmitted strains of human papillomavirus that are associated with the development of cervical cancer and genital warts. The only two HPV vaccines on the market as of October 2007 are Gardasil and Cervarix.
Screening for cancer can lead to earlier diagnosis in specific cases. Early diagnosis may lead to extended life, but may also falsely prolong the lead time to death through lead time bias or length time bias.
A number of different screening tests have been developed for different malignancies. Breast cancer screening can be done by breast self-examination, though this approach was discredited by a 2005 study in over 300,000 Chinese women. Screening for breast cancer with mammograms has been shown to reduce the average stage of diagnosis of breast cancer in a population. Stage of diagnosis in a country has been shown to decrease within ten years of introduction of mammographic screening programs. Colorectal cancer can be detected through fecal occult blood testing and colonoscopy, which reduces both colon cancer incidence and mortality, presumably through the detection and removal of pre-malignant polyps. Similarly, cervical cytology testing (using the Pap smear) leads to the identification and excision of precancerous lesions. Over time, such testing has been followed by a dramatic reduction of cervical cancer incidence and mortality. Testicular self-examination is recommended for men beginning at the age of 15 years to detect testicular cancer. Prostate cancer can be screened using a digital rectal exam along with prostate specific antigen (PSA) blood testing, though some authorities (such as the US Preventive Services Task Force) recommend against routinely screening all men.
Screening for cancer is controversial in cases when it is not yet known if the test actually saves lives. The controversy arises when it is not clear if the benefits of screening outweigh the risks of follow-up diagnostic tests and cancer treatments. For example: when screening for prostate cancer, the PSA test may detect small cancers that would never become life threatening, but once detected will lead to treatment. This situation, called overdiagnosis, puts men at risk for complications from unnecessary treatment such as surgery or radiation. Follow up procedures used to diagnose prostate cancer (prostate biopsy) may cause side effects, including bleeding and infection. Prostate cancer treatment may cause incontinence (inability to control urine flow) and erectile dysfunction (erections inadequate for intercourse). Similarly, for breast cancer, there have recently been criticisms that breast screening programs in some countries cause more problems than they solve. This is because screening of women in the general population will result in a large number of women with false positive results which require extensive follow-up investigations to exclude cancer, leading to having a high number-to-treat (or number-to-screen) to prevent or catch a single case of breast cancer early.
Cervical cancer screening via the Pap smear has the best cost-benefit profile of all the forms of cancer screening from a public health perspective as, being largely caused by a virus, it has clear risk factors (sexual contact), and the natural progression of cervical cancer is that it normally spreads slowly over a number of years therefore giving more time for the screening program to catch it early. Moreover, the test itself is easy to perform and relatively cheap.
For these reasons, it is important that the benefits and risks of diagnostic procedures and treatment be taken into account when considering whether to undertake cancer screening.
Use of medical imaging to search for cancer in people without clear symptoms is similarly marred with problems. There is a significant risk of detection of what has been recently called an incidentaloma - a benign lesion that may be interpreted as a malignancy and be subjected to potentially dangerous investigations. Recent studies of CT scan-based screening for lung cancer in smokers have had equivocal results, and systematic screening is not recommended as of July 2007. Randomized clinical trials of plain-film chest X-rays to screen for lung cancer in smokers have shown no benefit for this approach.
Canine cancer detection has shown promise, but is still in the early stages of research.
Cancer epidemiology is the study of the incidence of cancer as a way to infer possible trends and causes. The first such cause of cancer was identified by British surgeon Percivall Pott, who discovered in 1775 that cancer of the scrotum was a common disease among chimney sweeps. The work of other individual physicians led to various insights, but when physicians started working together they could make firmer conclusions.
A founding paper of this discipline was the work of Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health. Her ground-breaking work on cancer epidemiology was carried on by Richard Doll and Austin Bradford Hill, who published "Lung Cancer and Other Causes of Death In Relation to Smoking. A Second Report on the Mortality of British Doctors" followed in 1956 (otherwise known as the British doctors study). Richard Doll left the London Medical Research Center (MRC), to start the Oxford unit for Cancer epidemiology in 1968. With the use of computers, the unit was the first to compile large amounts of cancer data. Modern epidemiological methods are closely linked to current concepts of disease and public health policy. Over the past 50 years, great efforts have been spent on gathering data across medical practise, hospital, provincial, state, and even country boundaries, as a way to study the interdependence of environmental and cultural factors on cancer incidence.
Cancer epidemiology must contend with problems of lead time bias and length time bias. Lead time bias is the concept that early diagnosis may artificially inflate the survival statistics of a cancer, without really improving the natural history of the disease. Length bias is the concept that slower growing, more indolent tumors are more likely to be diagnosed by screening tests, but improvements in diagnosing more cases of indolent cancer may not translate into better patient outcomes after the implementation of screening programs. A similar epidemiological concern is overdiagnosis, the tendency of screening tests to diagnose diseases that may not actually impact the patient's longevity. This problem especially applies to prostate cancer and PSA screening.
Some cancer researchers have argued that negative cancer clinical trials lack sufficient statistical power to discover a benefit to treatment. This may be due to fewer patients enrolled in the study than originally planned.
State and regional cancer registries are organizations that abstract clinical data about cancer from patient medical records. These institutions provide information to state and national public health groups to help track trends in cancer diagnosis and treatment. One of the largest and most important cancer registries is SEER, administered by the US Federal government. Health information privacy concerns have led to the restricted use of cancer registry data in the United States Department of Veterans Affairs and other institutions.
In some Western countries, such as the USA, and the UK cancer is overtaking cardiovascular disease as the leading cause of death. In many Third World countries cancer incidence (insofar as this can be measured) appears much lower, most likely because of the higher death rates due to infectious disease or injury. With the increased control over malaria and tuberculosis in some Third World countries, incidence of cancer is expected to rise; this is termed the epidemiologic transition in epidemiological terminology.
Cancer epidemiology closely mirrors risk factor spread in various countries. Hepatocellular carcinoma (liver cancer) is rare in the West but is the main cancer in China and neighbouring countries, most likely due to the endemic presence of hepatitis B and aflatoxin in that population. Similarly, with tobacco smoking becoming more common in various Third World countries, lung cancer incidence has increased in a parallel fashion.
Today, the Greek term carcinoma is the medical term for a malignant tumor derived from epithelial cells. It is Celsus who translated carcinos into the Latin cancer, also meaning crab. Galen used "oncos" to describe all tumours, the root for the modern word oncology.
Hippocrates described several kinds of cancers. He called benign tumours oncos, Greek for swelling, and malignant tumours carcinos, Greek for crab or crayfish. This name comes from the appearance of the cut surface of a solid malignant tumour, with the veins stretched on all sides as the animal the crab has its feet, whence it derives its name (see picture). He later added the suffix -oma, Greek for swelling, giving the name carcinoma. Since it was against Greek tradition to open the body, Hippocrates only described and made drawings of outwardly visible tumors on the skin, nose, and breasts. Treatment was based on the humor theory of four bodily fluids (black and yellow bile, blood, and phlegm). According to the patient's humor, treatment consisted of diet, blood-letting, and/or laxatives. Through the centuries it was discovered that cancer could occur anywhere in the body, but humor-theory based treatment remained popular until the 19th century with the discovery of cells.
Our oldest description and surgical treatment of cancer was discovered in Egypt and dates back to approximately 1600 B.C. The Papyrus describes 8 cases of 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."
Another very early surgical treatment for cancer was described in the 1020s by Avicenna (Ibn Sina) in The Canon of Medicine. He stated that the excision should be radical and that all diseased tissue should be removed, which included the use of amputation or the removal of veins running in the direction of the tumor. He also recommended the use of cauterization for the area being treated if necessary.
In the 16th and 17th centuries, it became more acceptable for doctors to dissect bodies to discover the cause of death. The German professor Wilhelm Fabry believed that breast cancer was caused by a milk clot in a mammary duct. The Dutch professor Francois de la Boe Sylvius, a follower of Descartes, believed that all disease was the outcome of chemical processes, and that acidic lymph fluid was the cause of cancer. His contemporary Nicolaes Tulp believed that cancer was a poison that slowly spreads, and concluded that it was contagious.
With the widespread use of the microscope in the 18th century, it was discovered that the 'cancer poison' spread from the primary tumor through the lymph nodes to other sites ("metastasis"). This view of the disease was first formulated by the English surgeon Campbell De Morgan between 1871 and 1874. The use of surgery to treat cancer had poor results due to problems with hygiene. The renowned Scottish surgeon Alexander Monro saw only 2 breast tumor patients out of 60 surviving surgery for two years. In the 19th century, asepsis improved surgical hygiene and as the survival statistics went up, surgical removal of the tumor became the primary treatment for cancer. With the exception of William Coley who in the late 1800s felt that the rate of cure after surgery had been higher before asepsis (and who injected bacteria into tumors with mixed results), cancer treatment became dependent on the individual art of the surgeon at removing a tumor. During the same period, the idea that the body was made up of various tissues, that in turn were made up of millions of cells, laid rest the humor-theories about chemical imbalances in the body. The age of cellular pathology was born.
When Marie Curie and Pierre Curie discovered radiation at the end of the 19th century, they stumbled upon the first effective non-surgical cancer treatment. With radiation came also the first signs of multi-disciplinary approaches to cancer treatment. The surgeon was no longer operating in isolation, but worked together with hospital radiologists to help patients. The complications in communication this brought, along with the necessity of the patient's treatment in a hospital facility rather than at home, also created a parallel process of compiling patient data into hospital files, which in turn led to the first statistical patient studies.
Cancer patient treatment and studies were restricted to individual physicians' practices until World War II, when medical research centers discovered that there were large international differences in disease incidence. This insight drove national public health bodies to make it possible to compile health data across practises and hospitals, a process that many countries do today. The Japanese medical community observed that the bone marrow of bomb victims in Hiroshima and Nagasaki was completely destroyed. They concluded that diseased bone marrow could also be destroyed with radiation, and this led to the discovery of bone marrow transplants for leukemia. Since WWII, trends in cancer treatment are to improve on a micro-level the existing treatment methods, standardize them, and globalize them as a way to find cures through epidemiology and international partnerships.
Cancer research is the intense scientific effort to understand disease processes and discover possible therapies. The improved understanding of molecular biology and cellular biology due to cancer research has led to a number of new, effective treatments for cancer since President Nixon declared "War on Cancer" in 1971. Since 1971 the United States has invested over $200 billion on cancer research, that total includes money invested by public and private sectors and foundations.