Cancer

For other uses, see Cancer (disambiguation).

Cancer
Specialty	Oncology

Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue through invasion or by implantation into distant sites by metastasis. Metastasis is defined as the stage in which cancer cells are transported through the bloodstream or lymphatic system. Cancer may affect people at all ages, but risk tends to increase with age, due to the fact that DNA damage becomes more apparent in aging DNA. It is one of the principal causes of death in developed countries. Cancer originated in Wigan, England in 333BC, and has since spread carried on the wings of migratory birds.

There are many types of cancer. Severity of symptoms depends on the site and character of the malignancy and whether there is metastasis. A definitive diagnosis usually requires the histologic examination of tissue by a pathologist. This tissue is obtained by biopsy or surgery. 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 the type of cancer pathology. Drugs that target specific cancers already exist for several cancers. If untreated, cancers may eventually cause illness and death, though this is not always the case.

The unregulated growth that characterizes cancer is caused by damage to DNA, resulting in mutations to genes that encode for proteins controlling cell division. Many mutation events may be required to transform a normal cell into a malignant cell. These mutations can be caused by chemicals or physical agents called carcinogens, by close exposure to radioactive materials, or by certain viruses that can insert their DNA into the human genome. Mutations occur spontaneously, and may be passed down from one generation to the next as a result of mutations within germ lines.

Many forms of cancer are associated with exposure to environmental factors such as tobacco smoke, radiation, alcohol and certain viruses. While some of these risk factors can be avoided or reduced, there is no known way to entirely avoid the disease.

History

Today, 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.

File:Cancer vs crab.jpg

Breast cancer in a mastectomy specimen (top). The cancerous tumour (pale yellow) resembles a crab (bottom photo, by Chouby, Flickr).

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 probably comes from the appearance of the cut surface of a solid malignant tumour, with a roundish hard center surrounded by pointy projections, vaguely resembling the shape of a crab (see photo). 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.

Though treatment remained the same, 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"). The use of surgery to treat cancer had poor results due to problems with hygiene. The renowned Scottish surgeon Alexander Monro (1697-1767) 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 WWII, 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.

Nomenclature and classification

The following closely related terms may be used to designate abnormal growths:

• Neoplasia and neoplasm are the scientific designations for cancerous diseases. This group contains a large number of different diseases. Neoplasms can be benign or malignant.
• Cancer is a widely used word that is usually understood as synonymous with malignant neoplasm. It is occasionally used instead of carcinoma, a sub-group of malignant neoplasms. Because of its overwhelming popularity relative to 'neoplasia', it is used frequently instead of 'neoplasia', even by scientists and physicians, especially when discussing neoplastic diseases as a group.
• Tumor in medical language simply means swelling or lump, either neoplastic, inflammatory or other. In common language, however, it is synonymous with 'neoplasm', either benign or malignant. This is inaccurate since some neoplasms usually do not form tumors, for example leukemia or carcinoma in situ.

Cancers are classified by the type of cell that resembles the tumor and, therefore, the tissue presumed to be the origin of the tumor. The following general categories are usually accepted:

• Carcinoma: malignant tumors derived from epithelial cells. This group represent the most common cancers, including the common forms of breast, prostate, lung and colon cancer.
• Lymphoma and Leukemia: malignant tumors derived from blood and bone marrow cells
• Sarcoma: malignant tumors derived from connective tissue, or mesenchymal cells
• Mesothelioma: tumors derived from the mesothelial cells lining the peritoneum and the pleura.
• Glioma: tumors derived from glia, the most common type of brain cell
• Germinoma: tumors derived from germ cells, normally found in the testicle and ovary
• Choriocarcinoma: malignant tumors derived from the placenta

Malignant tumors are usually named using the Latin or Greek root of the organ as a prefix and the above category name as the suffix. For instance, a malignant tumor of liver cells is called hepatocarcinoma; a malignant tumor 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 are named using -oma as a suffix. For instance, a benign tumor of the smooth muscle of the uterus is called leiomyoma (the common name of this frequent tumor is fibroid). This nomenclature is however somewhat inconsistent, since several "malignant" tumor growths also have this suffix in their names, e.g. neuroblastoma, lymphoma and melanoma.

Adult cancers

In the USA and other developed countries, cancer is presently responsible for about 25% of all deaths . On a yearly basis, 0.5% of the population is diagnosed with cancer.

The statistics below are for adults in the United States. These statistics vary substantially in other countries.

Male • most common	Male • cause of death	Female • most common	Female • cause of death
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%, uterus)	ovarian cancer (6%)
cutaneous melanoma (5%)	leukemia (4%)	non-Hodgkin's lymphoma (4%)	pancreatic cancer (6%)

Childhood cancers

Cancer can also occur in young children and adolescents, but it is rare. Some studies have concluded that pediatric cancers, especially leukemia, are on an upward trend.

The age of peak incidence of cancer in children occurs during the first year of life. Leukemia (usually ALL) is the most common infant malignancy (30%), followed by the central nervous system cancers and neuroblastoma. The remainder consists of Wilms' tumor, lymphomas, rhabdomyosarcoma (arising from muscle), retinoblastoma, osteosarcoma and Ewing's sarcoma.

Female and male infants have essentially the same overall cancer incidence rates, but white infants have substantially higher cancer rates than black infants for most cancer types. Relative survival for infants is very good for neuroblastoma, Wilms' tumor and retinoblastoma, and fairly good (80%) for leukemia, but not for most other types of cancer.

Causes and pathophysiology

Main article: Carcinogenesis

Origins of cancer

Cell division or cell proliferation is a physiological process that occurs in almost all tissues and under many circumstances. Normally the balance between proliferation and programmed cell death is tightly regulated to ensure the integrity of organs and tissues. Mutations in DNA that lead to cancer disrupt these orderly processes.

The uncontrolled and often rapid proliferation of cells can lead to either a benign tumor or a malignant tumor (cancer). Benign tumors do not spread to other parts of the body or invade other tissues, and they are rarely a threat to life unless they extrinsically compress vital structures. Malignant tumors can invade other organs, spread to distant locations (metastasize) and become life-threatening.

Molecular biology

Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.

Carcinogenesis, which means the initiation or generation of cancer, is the process of derangement of the rate of cell division due to damage to DNA. Cancer is, ultimately, a disease of genes. In order for cells to start dividing uncontrollably, genes which regulate cell growth must be damaged. Proto-oncogenes are genes which promote cell growth and mitosis, a process of cell division, and tumor suppressor genes discourage cell growth, or temporarily halt cell division in order to carry out DNA repair. Typically, a series of several mutations to these genes are required before a normal cell transforms into a cancer cell.

Proto-oncogenes promote cell growth through a variety of ways. Many can produce hormones, a "chemical messenger" between cells which encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. Some are responsible for the signal transduction system and signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. They often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with.

Mutations in proto-oncogenes can modify their expression and function, increasing the amount or activity of the product protein. When this happens, they become oncogenes, and thus cells have a higher chance to divide excessively and uncontrollably. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome as they are critical for growth, repair and homeostasis of the body. It is only when they become mutated that the signals for growth become excessive.

Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways which lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. Canonical tumor suppressors include the p53 protein, which is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.

Despite nearly half of all cancers may involve alterations in p53, its tumor suppressor function is poorly understood. It is clear it has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in cell cycle and division regulation and apoptosis.

The Warburg effect is the preferential use of glycolyisis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway. Synthesis of Cytochrome c Oxidase 2 (SCO2) has been recognized as the downstream mediator of this effect. SCO2 is critical for regulating the cytochrome c oxidase complex within the mitochondria, and p53 can disprutpt the SCO2 gene. P53 regulation of SCO2 and mitochondrial respiration may provide a possible explanation for the Warburg effect

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.

In general, mutations in both types of genes are required for cancer to occur. For example, a mutation limited to one oncogene would be suppressed by normal mitosis control and tumor suppressor genes, which was first hypothesised as the Knudson hypothesis. A mutation to only one tumor suppressor gene would not cause cancer either, due to the presence of many "backup" genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes, and enough tumor suppressor genes deactivated or damaged, that the signals for cell growth overwhelm the signals to regulate it, that cell growth quickly spirals out of control. Often, because these genes regulate the processes that prevent most damage to genes themselves, the rate of mutations increase as one gets older, because DNA damage forms a feedback loop. 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 phenomena 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.

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 mutation in one copy of a particular proto-oncogene is enough to make that gene a true oncogene, while usually loss of function mutation needs to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one loss of function copy of a tumor suppressor gene can render the other copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations.

Mutation of tumor suppressor genes that are passed on to the next generation of not merely cells, but their offspring can cause increased likelihoods for cancers to be inherited. Members within these families have increased incidence and decreased latency of multiple tumors. The mode of inheritance of mutant tumor suppressors is that affected member inherits a defective copy from one parent, and a normal copy from another. Because mutations in tumor suppressors act in a recessive manner (although there are exceptions), the loss of the normal copy creates the cancer phenotype. For instance, individuals who are heterozygous for p53 mutations are often victims of Li-Fraumeni syndrome, and those who are heterozygous for Rb mutations develop retinoblastoma. Similarly, mutations in the APC gene are linked to adenopolyposis colon cancer, with thousands of polyps in colon while young, while mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.

Cancer pathology is ultimately due to the accumulation of DNA mutations that negatively effect expression of tumour suppressor proteins or positivly effect the expression of proteins that drive the cell cycle. Substances that cause these mutations are known as mutagens, and mutagens that cause cancers are known as carcinogens. Particular substances have been linked to specific types of cancer. Tobacco smoking is associated with lung cancer. Prolonged exposure to radiation, particularly ultraviolet radiation from the sun, leads to melanoma and other skin malignancies. Breathing asbestos fibers is associated with mesothelioma. In more general terms, chemicals called mutagens and free radicals are known to cause mutations. Other types of mutations can be caused by chronic inflammation, as neutrophil granulocytes secrete free radicals that damage DNA. Chromosomal translocations, such as the Philadelphia chromosome, are a special type of mutation that involve exchanges between different chromosomes.

Many mutagens are also carcinogens, but some carcinogens are not mutagens. Examples of carcinogens that are not mutagens include alcohol and estrogen. These are thought to promote cancers through their stimulating effect on the rate of cell mitosis. Faster rates of mitosis increasingly leave less opportunities for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells receiving the wrong number of chromosomes, which leads to aneuploidy and may lead to cancer.

Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but also in humans, as viruses are responsible for 15% of human cancers worldwide. The main viruses associated with human cancers are human papillomavirus, hepatitis B virus, Epstein-Barr virus, and human T-lymphotropic virus. Experimental and epidemiologic data imply a causative role for viruses and they appear to be the second most important risk factor for cancer development in humans, exceeded only by tobacco usage The mode of virally-induced tumors can be divided into two, acutely-transforming or slowly-transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly-transforming viruses, the virus genome is inserted, especially as viral genome insertion is an obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements in turn cause overexpression of that proto-oncogene, which in turn induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly-transforming viruses have very long tumor latency compared to acutely-transforming viruses, which already carry the viral-oncogene.

It is impossible to tell the initial cause for any specific cancer. However, with the help of molecular biological techniques, it is possible to characterize the mutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting prognosis based on the spectrum of mutations in some cases. For example, some tumors have a defective p53 gene. This mutation is associated with poor prognosis, since those tumor cells are less likely to go into apoptosis or programmed cell death when damaged by therapy. Telomerase mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vessels to provide more nutrients, or to metastasize, spreading to other parts of the body.

Malignant tumors cells have distinct properties:

• evading apoptosis
• unlimited growth potential (immortalitization) due to overabundance of telomerase
• self-sufficiency of growth factors
• insensitivity to anti-growth factors
• increased cell division rate
• altered ability to differentiate
• no ability for contact inhibition
• ability to invade neighbouring tissues
• ability to build metastases at distant sites
• ability to promote blood vessel growth (angiogenesis)

A cell that degenerates into a tumor cell does not usually acquire all these properties at once, but its descendant cells are selected to build them. This process is called clonal evolution. A first step in the development of a tumor cell is usually a small change in the DNA, often a point mutation, which leads to a genetic instability of the cell. The instability can increase to a point where the cell loses whole chromosomes, or has multiple copies of several. Also, the DNA methylation pattern of the cell changes, activating and deactivating genes without the usual regulation. Cells that divide at a high rate, such as epithelials, show a higher risk of becoming tumor cells than those which divide less, for example neurons.

Morphology

Tissue can be organized in a continuous spectrum from normal to cancer.

Cancer tissue has a distinctive appearance under the microscope. Among the distinguishing traits are a large number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, loss of normal tissue organization, and a poorly defined tumor boundary. Immunohistochemistry and other molecular methods may characterise specific markers on tumor cells, which may aid in diagnosis and prognosis.

Biopsy and microscopical examination can also distinguish between malignancy and hyperplasia, which refers to tissue growth based on an excessive rate of cell division, leading to a larger than usual number of cells but with a normal orderly arrangement of cells within the tissue. This process is considered reversible. Hyperplasia can be a normal tissue response to an irritating stimulus, for example callus.

Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure. Often such cells revert to normal behavior, but occasionally, they gradually become malignant.

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 shows no propensity to invade other tissues. Nevertheless, carcinoma in situ may develop into an invasive malignancy and is usually removed surgically, if possible.

Heredity

Most forms of cancer are "sporadic", and have no basis in heredity. There are, however, a number of recognised syndromes of cancer with a hereditary component, often a defective tumor suppressor allele. Examples are:

• certain inherited mutations in the genes BRCA1 and BRCA2 are associated with an elevated risk of breast cancer and ovarian cancer
• tumors of various endocrine organs in multiple endocrine neoplasia (MEN types 1, 2a, 2b)
• Li-Fraumeni syndrome (various tumors such as osteosarcoma, breast cancer, soft-tissue sarcoma, brain tumors) due to mutations of p53
• Turcot syndrome (brain tumors and colonic polyposis)
• Familial adenomatous polyposis an inherited mutation of the APC gene that leads to early onset of colon carcinoma.
• Retinoblastoma in young children is an inherited cancer

Lifestyle factors

The incidence of lung cancer is highly correlated with smoking. Source:NIH.

The most consistent finding, over decades of research, is the strong association between tobacco use and cancers of many sites. Hundreds of epidemiological studies have confirmed this association. Further support comes from the fact that 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. Lifestyle choices cause cancer: tobacco, diet, exercise, sex, alcohol, and tanning choices are the major risks. "Most cancers are related to known lifestyle factors."

There is also a growing body of research that correlates cancer incidence with the lower levels of melatonin produced in the body when people spend more time in bright-light conditions, as happens typically in the well-lit nighttime environments of the more developed countries. This effect is compounded in people who sleep fewer hours and in people who work at night, two groups that are known to have higher cancer rates.

Epidemiology

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," in 1956), (otherwise known as the British doctors study). Richard Droll 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.

The biggest problem facing cancer epidemiology today is the changing concept of 'cancer incidence'. For example, a breast cancer tumor with a very slow growth rate may be found with a mammogram at 50 years, while the same tumor may have been found as a noteworthy 'lump' at 70 years, depending on the specific growth factors affecting that particular patient's case. As diagnostic tools improve, this has a direct impact on the epidemiological data.

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 neighboring 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.

Prevention

Cancer prevention is defined as active measures to decrease the incidence of cancer. This can be accomplished by avoiding carcinogens or altering their metabolism, pursuing a lifestyle or diet that modifies cancer-causing factors and/or medical intervention (chemoprevention, treatment of pre-malignant lesions).

Much of the promise for cancer prevention comes from observational epidemiologic studies that show associations between modifiable life style factors or environmental exposures and specific cancers. Evidence is now emerging from randomized controlled trials designed to test whether interventions suggested by the epidemiologic studies, as well as leads based on laboratory research, actually result in reduced cancer incidence and mortality.

Examples of modifiable cancer risk include alcohol consumption (associated with increased risk of oral, esophageal, breast, and other cancers), smoking (although 20% of women with lung cancer have never smoked, versus 10% of men [1]), physical inactivity (associated with increased risk of colon, breast, and possibly other cancers), and being overweight (associated with colon, breast, endometrial, and possibly other cancers). Based on epidemiologic evidence, it is now thought that avoiding excessive alcohol consumption, being physically active, and maintaining recommended body weight may all contribute to reductions in risk of certain cancers; however, compared with tobacco exposure, the magnitude of effect is modest or small and the strength of evidence is often weaker. Other lifestyle and environmental factors known to affect cancer risk (either beneficially or detrimentally) include certain sexual and reproductive practices , the use of exogenous hormones, exposure to ionizing radiation and ultraviolet radiation, certain occupational and chemical exposures, and infectious agents.

See Alcohol and cancer for more on that topic.

Diet and cancer

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, suggesting a link between diet and cancer rather than a genetic basis.

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.

The case of beta-carotene provides an example of the necessity 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 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.

However, Randomized Clinical Trials (RCTs) also have drawbacks in cancer prevention, particularly in micronutrient deficiencies, which are thought by some to be a major contributor to cancer. RCTs involve huge numbers of people, take many years to complete, and are therefore extremely expensive and complicated, and therefore few are done. In addition, these randomized clinical trials usually test only a single dose. An alternative, which is likely to be more useful, is to do shorter intervention trials focusing on other endpoints related to cancer, such as DNA damage. These trials can test a variety of doses on fewer people to determine what level of micronutrient intake (or, better, micronutrient concentration in blood) keeps DNA damage to a minimum.

Other chemoprevention agents

Daily use of tamoxifen, a selective estrogen receptor modulator, typically for 5 years, has been demonstrated to reduce the risk of developing breast cancer in high-risk women by about 50%. Cis-retinoic acid also has been shown to reduce risk of second primary tumors among patients with primary head and neck cancer. Finasteride, a 5-alpha reductase inhibitor, has been shown to lower the risk of prostate cancer. Other examples of drugs that show promise for chemoprevention include COX-2 inhibitors (which inhibit a cyclooxygenase enzyme involved in the synthesis of proinflammatory prostaglandins).

Genetic testing

Genetic testing for high-risk individuals, with enhanced surveillance, chemoprevention, or risk-reducing surgery for those who test positive, is already available for certain cancer-related genetic mutations.

Diagnosing cancer

Most cancers are initially recognized either because signs or symptoms appear or through screening. Neither of these lead to a definitive diagnosis, which usually requires the opinion of a pathologist.

Signs and symptoms

Roughly, cancer symptoms can be divided into three groups:

• Local symptoms: unusual lumps or swelling (tumor), hemorrhage (bleeding), pain and/or ulceration. Compression of surrounding tissues may cause symptoms such as jaundice.
• Symptoms of metastasis (spreading): enlarged lymph nodes, cough and hemoptysis, hepatomegaly (enlarged liver), bone pain, fracture of affected bones and neurological symptoms. Although advanced cancer may cause pain, it is often not the first symptom.
• Systemic symptoms: weight loss, poor appetite and cachexia (wasting), excessive sweating (night sweats), anemia and specific paraneoplastic phenomena, i.e. specific conditions that are due to an active cancer, such as thrombosis or hormonal changes.

Every single item 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.

Biopsy

A cancer may be suspected for a variety of reasons, but the definitive diagnosis of most malignancies must be confirmed by histological examination of the cancerous cells by a pathologist. Tissue can be obtained from a biopsy or surgery. Many biopsies (such as those of the skin, breast or liver) can be done in a doctor's office. Biopsies of other organs are performed under anesthesia and require surgery in an operating room.

The tissue diagnosis 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 choose the best treatment. Cytogenetics and immunohistochemistry may provide information about future behavior of the cancer (prognosis) and best treatment.

Screening

Cancer screening is an attempt to detect unsuspected cancers in the population. Screening tests suitable for large numbers of healthy people must be relatively affordable, safe, noninvasive procedures with acceptably low rates of false positive results. If signs of cancer are detected, more definitive and invasive follow up tests are performed to confirm the diagnosis.

Screening for cancer can lead to earlier diagnosis. Early diagnosis may lead to extended life. A number of different screening tests have been developed. Breast cancer screening can be done by breast self-examination. Screening by regular mammograms detects tumors even earlier than self-examination, and many countries use it to systematically screen all middle-aged women. 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 for by a digital rectal exam along with prostate specific antigen (PSA) blood testing.

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 a cancer, 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.

Canine cancer detection has shown promise, but is still in the early stages of research.

Treatment of cancer

Cancer can be treated by surgery, chemotherapy, radiation therapy, immunotherapy, monoclonal antibody therapy or other methods. The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient (performance status). A number of experimental cancer treatments are also under development.

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.

Because "cancer" refers to a class of diseases, it is unlikely that there will ever be a single "cure for cancer" any more than there will be a single treatment for all infectious diseases.

Surgery

In theory, cancers can be cured if entirely removed by surgery, but this is not always possible. When the cancer has metastasized to other sites in the body prior to surgery, complete surgical excision is usually impossible.

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.

Occasionally, surgery is necessary to control symptoms, such as spinal cord compression or bowel obstruction. This is referred to as palliative treatment.

Chemotherapy

Main article: Chemotherapy

See also: History of cancer chemotherapy

Chemotherapy is the treatment of cancer with drugs ("anticancer drugs") that can destroy cancer cells. It interferes 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. 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. 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 transplantation. Alternatively, bone marrow may be transplanted from a Matched Unrelated Donor.

Monoclonal antibody therapy

Main article: Monoclonal antibody therapy

Immunotherapy is the use of immune mechanisms against tumors. These are used in various forms of cancer, such as breast cancer (trastuzumab/Herceptin®) and leukemia (gemtuzumab ozogamicin/Mylotarg®). The agents are monoclonal antibodies directed against proteins that are characteristic to the cells of the cancer in question, or cytokines that modulate the immune system's response.

Immunotherapy

Other, more contemporary methods for generating non-specific immune response against tumours include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferon and interleukin. Vaccines to generate non-specific immune responses are the subject of intensive research for a number of tumours, notably malignant melanoma and renal cell carcinoma.

Radiation therapy

Main article: Radiation 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.

Hormonal suppression

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.

Symptom control

Although the control of the symptoms of cancer is not typically thought of as a treatment directed at the cancer, it is an important determinant of the quality of life of cancer patients, and plays an important role in the decision whether the patient is able to undergo other treatments. Although all practicing doctors have the therapeutic skills to control pain, nausea, vomiting, diarrhea, hemorrhage and other common problems in cancer patients, the multidisciplinary specialty of palliative care has arisen specifically in response to the symptom control needs of this group of patients.

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.

Treatment trials

Clinical trials, also called research studies, test new treatments in people with cancer. The goal of this research is to find better ways to treat cancer and help cancer patients. Clinical trials test many types of treatment such as new drugs, new approaches to surgery or radiation therapy, new combinations of treatments, or new methods such as gene therapy.

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(s) 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. Of course, there is no guarantee that a new treatment being tested or a standard treatment will produce good results. 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.

Cancer vaccines

Considerable research effort is now devoted to the development of vaccines (to prevent infection by oncogenic infectious agents, as well as to mount an immune response against cancer-specific epitopes) and to potential venues for gene therapy for individuals with genetic mutations or polymorphisms that put them at high risk of cancer.

As of October 2005, researchers found that an experimental vaccine for HPV types 16 and 18 was 100% successful at preventing infection with these types of HPV and, thus, are able to prevent the majority of cervical cancer cases.

Complementary and alternative medicine

Complementary and alternative medicine (CAM) treatments are the diverse group of medical and health care systems, practices, and products that are not presently considered to be effective by the standards of conventional medicine. Conventional medical practitioners may describe non-conventional treatment methods as a "complement" to conventional treatment, to provide comfort or lift the spirits of the patient, while others are offered as alternatives to be used instead of conventional treatments in hope of curing the cancer.

Some complementary measures include prayer or psychological approaches such as "imaging" or meditation to aid in pain relief, or improve mood. The benefits of these approaches have not been scientifically proven and therefore face skepticism. Other complementary approaches include traditional medicine like Traditional Chinese Medicine.

A wide range of alternative treatments have been offered for cancer over the last century. The appeal of alternative cures arises from the daunting risks, costs, or potential side effects of many conventional treatments, or in the limited prospect for cure. Proponents of these therapies are unable or unwilling to demonstrate effectiveness by conventional criteria. Alternative treatments have included special diets or dietary supplements (e.g., the "grape diet", "cabbage diet" or megavitamin therapy), electromagnetic therapy with electrical devices (e.g., "rhumart", "zappers"), specially formulated compounds (e.g., laetrile, and homeopathic remedies), unconventional use of conventional drugs (e.g., insulin), purges or enemas, physical manipulations of the body, various herbs or herbal preparations such as essiac. Some of these alternative treatments may be ineffective or dangerous. Using these modalities as sole treatment for potentially fatal conditions such as cancer are generally not recommended by the majority of medical professionals. The Ralph Moss Reports are a source of information on CAM and conventional cancer treatments from a biologically based, alternative medicine point of view with detailed reports on a variety of cancer types.

Coping with cancer

Many local organizations offer a variety of practical and support services to people with cancer. Support can take the form of support groups, counseling, advice, financial assistance, transportation to and from treatment, films or information about cancer. Neighborhood organizations, local health care providers, or area hospitals may have resources or services available.

While some people are reluctant to seek counseling, studies show that having someone to talk to reduces stress and helps people both mentally and physically. Counseling can also provide emotional support to cancer patients and help them better understand their illness. Different types of counseling include individual, group, family, self-help (sometimes called 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. Examples include: American Cancer Society, Lance Armstrong Foundation, BC Cancer Agency, Macmillan Cancer Relief , the Terry Fox Foundation, Cancer Research UK, Cancer Research Foundation, Canadian Cancer Society, International Agency for Research on Cancer, The Cancer Council Australia and the National Cancer Institute (US).

Social impact

Once referred to as "the C-word," cancer has a reputation for being a deadly disease . While this certainly applies to certain particular types, the truths behind the historical connotations of cancer are increasingly being overturned by advances in medical care. Some types of cancer have a prognosis that is substantially better than nonmalignant diseases such as heart failure and stroke.

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.

Cancer research

Cancer research is the intense scientific effort to understand disease processes and discover possible therapies. Although understanding of cancer has greatly increased since the last decades of the 20th century, few radically new therapies have been discovered.

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 molecules (such as the tyrosine kinase inhibitors imatinib and gefitinib) and monoclonal antibodies have proven to be a major step in oncological treatment. Targeted therapy can also involve small peptidic structures as ´homing device´ 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 (vide supra Radiation therapy). Especially oligo- or multimeris of these binding motifs are of great interest, since this can lead to enhanced tumor specificity and avidity.

See also

• Alcohol and cancer
• Oncology
• List of oncology-related terms
• European Organisation for Research and Treatment of Cancer (EORTC)

References

General references:

• The Basic Science of Oncology. Tannock IF, Hill RP et al (eds) 4th ed.2005 McGraw-Hill.
• Principles of Cancer Biology. Kleinsmith, LJ (2006). Pearson Benjamin Cummings.
• "A Special Message to Cancer Patients Seeking "Alternative" Treatments". Retrieved 2005-12-16.
• Parkin D, Bray F, Ferlay J, Pisani P. "Global cancer statistics, 2002". CA Cancer J Clin. 55 (2): 74–108. PMID 15761078.{{cite journal}}: CS1 maint: multiple names: authors list (link)Full text

External links

Professional and research

• The World Health Organisation's cancer site A review of worldwide strategies for the prevention and treatment of cancer.
• National Cancer Institute US Government agency responsible for conducting and supporting research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer, rehabilitation from cancer, and the continuing care of cancer patients and the families of cancer patients.
• National Comprehensive Cancer Network - Free guidelines for professionals and many pages of quality information for patients with all types of cancers
• The Institute of Cancer Research One of the world’s foremost independent cancer research organisations, based in the United Kingdom.
• Cancer: new treatment paradigms to transform the top 20 The top 20 cancer therapeutics were worth nearly $20.1 billion in sales in 2005 across the seven major markets, and this is set to rise to $27.4 billion by 2015 according to Pharmaceutical Business Review.
• EORTC European Organization for Research and Treatment of Cancer. A European non-profit organization that sets up and executes clinical trials.
• International Society for Biological Therapy of Cancer Society of medical professionals committed to investigating, developing and utilizing biologicals and biological therapy for the treatment of malignant disease.
• National Cancer Institute of Canada Longest-standing Canadian research organization devoted to advancing cancer control.
• Cancer Facts & Figures 2005 - 2005 United States Cancer Statistics
• Canadian Cancer Statistics 2006 - This publication reports cancer incidence and mortality in Canada, analyzed by gender, age and province/territory.
• Cancer Medicine, 6th Edition Textbook
• New Scientist (2006). "Everything you wanted to know about cancer". New Scientist. {{cite web}}: Unknown parameter |accessyear= ignored (|access-date= suggested) (help)
• Diet, Nutrition and the prevention of chronic diseases (including cancer) by a Joint WHO/FAO Expert consultation (2003). Summary by GreenFacts.
• University of Pittsburgh Supercourse
• Virtual Cancer Centre - information resource with the latest cancerous diseases news by professionals of Oncology, Haematology, Radiation Oncology and Palliative Care.

Support and advocacy

• Medbroadcast.com Information on cancer including a database of thousands of local community support groups.
• About Cancer Your Guide to Cancer
• American Cancer Society Patient advocate group
• Action Cancer Northern Ireland Cancer Charity providing screening and support
• Canadian Cancer Society Information on all types of cancer, ways to reduce your risk. Support for people living with cancer. Advocating for healthy public policy.
• American Association for Cancer Research
• The Leukemia and Lymphoma Society
• Cancer from MedlinePlus - provides links to news, general sites, diagnosis, treatment and alternative therapies, clinical trials, research, related issues, organizations, other MedlinePlus Cancers Topics and Living with Cancer, and more. Also, links to pre-formulated searches of the MEDLINE/PubMed database for recent research articles.
• Cancer Research UK - Cancer Resources - In-depth, up-to-date information for people with a professional or general interest in cancer and health.
• Cancer Council of Australia - Australia's national non-government cancer control organisation, involved in research, information, prevention, patient treatment and support.
• Sydney Children's Hospital: Centre for Cancer and Blood Disorders - Offers information on childhood cancer, treatment options, and support. [Australia].
• ACOR - Association of Cancer Online Resources ACOR is a unique collection of online communities designed to provide timely and accurate information in a supportive environment. ACOR offers access to mailing lists that provide support, information, and community to everyone affected by cancer and related disorders.