Chemotherapy

Chemotherapy (sometimes cancer chemotherapy) is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen.

Most commonly, chemotherapy acts by killing cells that divide rapidly, one of the main properties of most cancer cells. This means that it also harms cells that divide rapidly under normal circumstances: cells in the bone marrow, digestive tract and hair follicles. This results in the most common side effects of chemotherapy: myelosuppression (decreased production of blood cells, hence also immunosuppression), mucositis (inflammation of the lining of the digestive tract), and alopecia (hair loss).

Newer anticancer drugs act directly against abnormal proteins in cancer cells; this is termed targeted therapy and is technically not chemotherapy.

History
The use of minerals and plant-based medicines to treat diseases is believed to date back to prehistoric medicine.

The first use of drugs to treat cancer, however, was in the early 20th century, although it was not originally intended for that purpose. Mustard gas was used as a chemical warfare agent during World War I and was discovered to be a potent suppressor of hematopoiesis (blood production). A similar family of compounds known as nitrogen mustards were studied further during World War II at Yale University. It was reasoned that an agent that damaged the rapidly growing white blood cells might have a similar effect on cancer. Therefore, in December 1942, several patients with advanced lymphomas (cancers of certain white blood cells) were given the drug by vein, rather than by breathing the irritating gas. Their improvement, although temporary, was remarkable. Concurrently, during a military operation in World War II, following a German air raid on the Italian harbour of Bari, several hundred people were accidentally exposed to mustard gas, transported there by the allied forces to prepare for possible retaliation in the event of German use of chemical warfare. The survivors were later found to have very low white blood cell counts. After WWII was over and the reports declassified, the experiences converged and led researchers to look for other substances that might have similar effects against cancer. The first chemotherapy drug to be developed from this line of research was mustine. Since then, many other drugs have been developed to treat cancer, and drug development has exploded into a multibillion-dollar industry, although the principles and limitations of chemotherapy discovered by the early researchers still apply. '''

The term chemotherapy
The word "chemotherapy" without a modifier nowadays usually refers to cancer treatment, but its historical meaning is broader. In the most simple sense, chemotherapy is the treatment of an ailment by chemicals especially by killing micro-organisms. As such, the term has been used for non-oncological use, such as the use of antibiotics (antibacterial chemotherapy). In that sense, the first modern chemotherapeutic agent was arsphenamine, an arsenic compound discovered in 1909 and used to treat syphilis. This was later followed by sulfonamides (sulfa drugs) and penicillin. Other uses that have been termed chemotherapy are the treatment of autoimmune diseases such as multiple sclerosis, dermatomyositis, polymyositis, lupus, rheumatoid arthritis (See DMARDs) and the suppression of transplant rejections (see immunosuppression).

Principles
Cancer is the uncontrolled growth of cells coupled with malignant behavior: invasion and metastasis. Cancer is thought to be caused by the interaction between genetic susceptibility and environmental toxins.

In the broad sense, most chemotherapeutic drugs work by impairing mitosis (cell division), effectively targeting fast-dividing cells. As these drugs cause damage to cells they are termed cytotoxic. Some drugs cause cells to undergo apoptosis (so-called "self programmed cell death").

Scientists have yet to identify specific features of malignant and immune cells that would make them uniquely targetable (barring some recent examples, such as the Philadelphia chromosome as targeted by imatinib). This means that other fast-dividing cells, such as those responsible for hair growth and for replacement of the intestinal epithelium (lining), are also often affected. However, some drugs have a better side effect profile than others, enabling doctors to adjust treatment regimens to the advantage of patients in certain situations.

As chemotherapy affects cell division, tumors with high growth fractions (such as acute myelogenous leukemia and the aggressive lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell division at any time. Malignancies with slower growth rates, such as indolent lymphomas, tend to respond to chemotherapy much more modestly.

Drugs affect "younger" tumors (i.e., more differentiated) more effectively, because mechanisms regulating cell growth are usually still preserved. With succeeding generations of tumor cells, differentiation is typically lost, growth becomes less regulated, and tumors become less responsive to most chemotherapeutic agents. Near the center of some solid tumors, cell division has effectively ceased, making them insensitive to chemotherapy. Another problem with solid tumors is the fact that the chemotherapeutic agent often does not reach the core of the tumor. Solutions to this problem include radiation therapy (both brachytherapy and teletherapy) and surgery.

Over time, cancer cells become more resistant to chemotherapy treatments. Recently, scientists have identified small pumps on the surface of cancer cells that actively move chemotherapy from inside the cell to the outside. Research on p-glycoprotein and other such chemotherapy efflux pumps, is currently ongoing. Medications to inhibit the function of p-glycoprotein are undergoing testing as of June, 2007 to enhance the efficacy of chemotherapy.

Treatment schemes
There are a number of strategies in the administration of chemotherapeutic drugs used today. Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms.

Combined modality chemotherapy is the use of drugs with other cancer treatments, such as radiation therapy or surgery. Most cancers are now treated in this way. Combination chemotherapy is a similar practice that involves treating a patient with a number of different drugs simultaneously. The drugs differ in their mechanism and side effects. The biggest advantage is minimising the chances of resistance developing to any one agent.

In neoadjuvant chemotherapy (preoperative treatment) initial chemotherapy is designed to shrink the primary tumour, thereby rendering local therapy (surgery or radiotherapy) less destructive or more effective.

Adjuvant chemotherapy (postoperative treatment) can be used when there is little evidence of cancer present, but there is risk of recurrence. This can help reduce chances of developing resistance if the tumour does develop. It is also useful in killing any cancerous cells which have spread to other parts of the body. This is often effective as the newly growing tumours are fast-dividing, and therefore very susceptible.

Palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase life expectancy. For these regimens, a better toxicity profile is generally expected.

All chemotherapy regimens require that the patient be capable of undergoing the treatment. Performance status is often used as a measure to determine whether a patient can receive chemotherapy, or whether dose reduction is required. Because only a fraction of the cells in a tumor die with each treatment (fractional kill), repeated doses must be administered to continue to reduce the size of the tumor. Current chemotherapy regimens apply drug treatment in cycles, with the frequency and duration of treatments limited by toxicity to the patient.

Types
The majority of chemotherapeutic drugs can be divided in to alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, and other antitumour agents. All of these drugs affect cell division or DNA synthesis and function in some way.

Some newer agents do not directly interfere with DNA. These include monoclonal antibodies and the new tyrosine kinase inhibitors e.g. imatinib mesylate (Gleevec or Glivec), which directly targets a molecular abnormality in certain types of cancer (chronic myelogenous leukemia, gastrointestinal stromal tumors). These are examples of targeted therapies.

In addition, some drugs that modulate tumor cell behaviour without directly attacking those cells may be used. Hormone treatments fall into this category.

Where available, Anatomical Therapeutic Chemical Classification System codes are provided for the major categories.

Alkylating agents (L01A)
Alkylating agents are so named because of their ability to alkylate many nucleophilic functional groups under conditions present in cells. Cisplatin and carboplatin, as well as oxaliplatin, are alkylating agents. They impair cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules.

Other agents are mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide. They work by chemically modifying a cell's DNA.

Anti-metabolites (L01B)
Anti-metabolites masquerade as purines ((azathioprine, mercaptopurine)) or pyrimidines—which become the building blocks of DNA. They prevent these substances from becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. They also affect RNA synthesis. Due to their efficiency, these drugs are the most widely used cytostatics.

Plant alkaloids and terpenoids (L01C)
These alkaloids are derived from plants and block cell division by preventing microtubule function. Microtubules are vital for cell division, and, without them, cell division cannot occur. The main examples are vinca alkaloids and taxanes.

Vinca alkaloids (L01CA)
Vinca alkaloids bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules (M phase of the cell cycle). They are derived from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). The vinca alkaloids include:
 * Vincristine
 * Vinblastine
 * Vinorelbine
 * Vindesine

Podophyllotoxin (L01CB)
Podophyllotoxin is a plant-derived compound which is said to help with digestion as well as used to produce two other cytostatic drugs, etoposide and teniposide. They prevent the cell from entering the G1 phase (the start of DNA replication) and the replication of DNA (the S phase). The exact mechanism of its action is not yet known.

The substance has been primarily obtained from the American Mayapple (Podophyllum peltatum). Recently it has been discovered that a rare Himalayan Mayapple (Podophyllum hexandrum) contains it in a much greater quantity, but, as the plant is endangered, its supply is limited. Studies have been conducted to isolate the genes involved in the substance's production, so that it could be obtained recombinantly.

Taxanes (L01CD)
The prototype taxane is the natural product paclitaxel, originally known as Taxol and first derived from the bark of the Pacific Yew tree. Docetaxel is a semi-synthetic analogue of paclitaxel. Taxanes enhance stability of microtubules, preventing the separation of chromosomes during anaphase.

Topoisomerase inhibitors (L01CB and L01XX)
Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling.


 * Some type I topoisomerase inhibitors include camptothecins: irinotecan and topotecan.


 * Examples of type II inhibitors include amsacrine, etoposide, etoposide phosphate, and teniposide. These are semisynthetic derivatives of epipodophyllotoxins, alkaloids naturally occurring in the root of American Mayapple (Podophyllum peltatum).

Cytotoxic antibiotics (L01D)
These include:
 * actinomycin.
 * anthracyclines
 * doxorubicin
 * daunorubicin
 * valrubicin
 * idarubicin
 * epirubicin, which also inhibit topoisomerase II)
 * other cytotoxic antibiotics
 * bleomycin . Bleomycin acts in unique way through oxidation of a DNA-bleomycin-Fe(II) complex and forming free radicals, which induce damage and chromosomal aberrations.
 * plicamycin
 * mitomycin

Isolated infusion approaches
Isolated limb perfusion (often used in melanoma), or isolated infusion of chemotherapy into the liver or the lung have been used to treat some tumours. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumor sites without causing overwhelming systemic damage. These approaches can help control solitary or limited metastases, but they are by definition not systemic, and, therefore, do not treat distributed metastases or micrometastases.

Targeted delivery mechanisms
Specially targeted delivery vehicles aim to increase effective levels of chemotherapy for tumor cells while reducing effective levels for other cells. This should result in an increased tumor kill and/or reduced toxicity.

Specially targeted delivery vehicles have a differentially higher affinity for tumor cells by interacting with tumor-specific or tumour-associated antigens.

In addition to their targeting component, they also carry a payload - whether this is a traditional chemotherapeutic agent, or a radioisotope or an immune stimulating factor. Specially targeted delivery vehicles vary in their stability, selectivity, and choice of target, but, in essence, they all aim to increase the maximum effective dose that can be delivered to the tumor cells. Reduced systemic toxicity means that they can also be used in sicker patients, and that they can carry new chemotherapeutic agents that would have been far too toxic to deliver via traditional systemic approaches.

Nanoparticles
Nanoparticles have emerged as a useful vehicle for poorly soluble agents such as paclitaxel. Protein-bound paclitaxel (e.g., Abraxane) or nab-paclitaxel was approved by the U.S. Food and Drug Administration (FDA) in January 2005 for the treatment of refractory breast cancer. This formulation of paclitaxel uses human albumin as a vehicle and not the Cremophor vehicle used in Taxol. Nanoparticles made of magnetic material can also be used to concentrate agents at tumour sites using an externally applied magnetic field.

Electrochemotherapy
Electrochemotherapy is the combined treatment in which injection of a chemotherapeutic drug is followed by application of high voltage electric pulses locally to the tumor. The treatment enables the chemotherapeutic drugs, which otherwise cannot or hardly go through the membrane of cells (such as bleomycin and cisplatin), to enter the cancer cells. Hence greater effectiveness of antitumor treatment is achieved. Clinical electrochemotherapy has been successfully used for treatment of cutaneous and subcutaneous tumors irrespective of their histological origin  	. The method has been reported as safe, simple and highly effective in all reports on clinical use of electrochemotherapy. According to the ESOPE project (European Standard Operating Procedures of Electrochemotherapy), the Standard Operating Procedures (SOP) for electrochemotherapy were prepared, based on the experience of the leading European cancer centres on electrochemotherapy. Recently, new electrochemotherapy modalities have been developed for treatment of internal tumors using surgical procedures, endoscopic routes or percutaneous approaches to gain access to the treatment area.

Dosage
Dosage of chemotherapy can be difficult: If the dose is too low, it will be ineffective against the tumor, whereas, at excessive doses, the toxicity (side effects, neutropenia) will be intolerable to the patient. This has led to the formation of detailed "dosing schemes" in most hospitals, which give guidance on the correct dose and adjustment in case of toxicity. In immunotherapy, they are in principle used in smaller dosages than in the treatment of malignant diseases.

In most cases, the dose is adjusted for the patient's body surface area, a measure that correlates with blood volume. The BSA is usually calculated with a mathematical formula or a nomogram, using a patient's weight and height, rather than by direct measurement.

Delivery
Most chemotherapy is delivered intravenously, although a number of agents can be administered orally (e.g., melphalan, busulfan, capecitabine). In some cases, isolated limb perfusion (often used in melanoma), or isolated infusion of chemotherapy into the liver or the lung have been used. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumour sites without causing overwhelming systemic damage.

Depending on the patient, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, intravenous chemotherapy may be given on either an inpatient or an outpatient basis. For continuous, frequent or prolonged intravenous chemotherapy administration, various systems may be surgically inserted into the vasculature to maintain access. Commonly used systems are the Hickman line, the Port-a-Cath or the PICC line. These have a lower infection risk, are much less prone to phlebitis or extravasation, and abolish the need for repeated insertion of peripheral cannulae.

Harmful and lethal toxicity from chemotherapy limits the dosage of chemotherapy that can be given. Some tumors can be destroyed by sufficiently high doses of chemotherapeutic agents. However, these high doses cannot be given because they would be fatal to the patient.

Adverse effects
Chemotherapeutic techniques have a range of side effects that depend on the type of medications used. The most common medications mainly affect the fast-dividing cells of the body, such as blood cells and the cells lining the mouth, stomach, and intestines. Common side effects include:


 * Depression of the immune system, which can result in potentially fatal infections. Although patients are encouraged to wash their hands, avoid sick people, and to take other infection-reducing steps, about 85% of infections are due to naturally occurring microorganisms in the patient's own gastrointestinal tract (including oral cavity) and skin.  This may manifest as systemic infections, such as sepsis, or as localized outbreaks, such as Herpes simplex, shingles, or other members of the Herpesviridea. Sometimes, chemotherapy treatments are postponed because the immune system is suppressed to a critically low level.
 * Fatigue. The treatment can be physically exhausting for the patient, who might already be very tired from cancer-related fatigue.  It may produce mild to severe anemia.  Treatments to mitigate anemia include hormones to boost blood production (erythropoietin), iron supplements, and blood transfusions.
 * Tendency to bleed easily. Medications that kill rapidly dividing cells or blood cells are likely to reduce the number of platelets in the blood, which can result in bruises and bleeding.  Extremely low platelet counts may be temporarily boosted through platelet transfusions.  Sometimes, chemotherapy treatments are postponed to allow platelet counts to recover.
 * Gastrointestinal distress. Nausea and vomiting are common side effects of chemotherapeutic medications that kill fast-dividing cells.  This can also produce diarrhea or constipation.  Malnutrition and dehydration can result when the patient doesn't eat or drink enough, or when the patient vomits frequently, because of gastrointestinal damage.  This can result in rapid weight loss, or occasionally in weight gain, if the patient eats too much in an effort to allay nausea or heartburn.  Weight gain can also be caused by some steroid medications.  These side effects can frequently be reduced or eliminated with antiemetic drugs.  Self-care measures, such as eating frequent small meals and drinking clear liquids or ginger tea, are often recommended.  This is a temporary effect, and frequently resolves within a week of finishing treatment.
 * Hair loss. Some medications that kill rapidly dividing cells cause dramatic hair loss; other medications may cause hair to thin.  These are temporary effects:  hair usually starts growing back a few weeks after the last treatment, sometimes with a tendency to curl that may be called a "chemo perm".

Damage to specific organs may occur, with resultant symptoms:
 * Cardiotoxicity (heart damage)
 * Hepatotoxicity (liver damage)
 * Nephrotoxicity (kidney damage)
 * Ototoxicity (damage to the inner ear), producing vertigo
 * Encephalopathy (brain dysfunction)

Immunosuppression and myelosuppression
Virtually all chemotherapeutic regimens can cause depression of the immune system, often by paralysing the bone marrow and leading to a decrease of white blood cells, red blood cells, and platelets. Anemia and thrombocytopenia when they occur, are improved with blood transfusion. Neutropenia (a decrease of the neutrophil granulocyte count below 0.5 x 109/litre) can be improved with synthetic G-CSF (granulocyte-colony stimulating factor, e.g., filgrastim, lenograstim).

In very severe myelosuppression, which occurs in some regimens, almost all the bone marrow stem cells (cells that produce white and red blood cells) are destroyed, meaning allogenic or autologous bone marrow cell transplants are necessary. (In autologous BMTs, cells are removed from the patient before the treatment, multiplied and then re-injected afterwards; in allogenic BMTs the source is a donor.) However, some patients still develop diseases because of this interference with bone marrow.

In Japan the government has approved the use of some medicinal mushrooms like Trametes versicolor, to counteract depression of the immune system in patients undergoing chemotherapy.

Chemotherapy-induced nausea and vomiting (CINV)
Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy ranked nausea and vomiting as the first and second most severe side effects, respectively. Up to 20% of patients receiving highly emetogenic agents in this era postponed, or even refused, potentially curable treatments. Chemotherapy-induced nausea and vomiting (CINV) is common with many treatments and some forms of cancer. Since the 1990s, several novel classes of antiemetics have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to successfully manage these symptoms in a large portion of patients. Effective mediation of these unpleasant and sometimes crippling symptoms results in increased quality of life for the patient and more efficient treatment cycles, due to less stoppage of treatment due to better tolerance by the patient, and due to better overall health of the patient.

Secondary neoplasm
Development of secondary neoplasia after successful chemotherapy and/or radiotherapy treatment can occur. The most common secondary neoplasm is secondary acute myeloid leukemia, which develops primarily after treatment with alkylating agents or topoisomerase inhibitors. Survivors of childhood cancer are more than 13 times as likely to get a secondary neoplasm during the 30 years after treatment than the general population. Not all of this increase can be attributed to chemotherapy.

Infertility
Some types of chemotherapy are gonadotoxic and may cause infertility. Chemotherapies with high risk include procarbazine and other alkylating drugs such as cyclophosphamide, ifosfamide, busulfan, melphalan, chlorambucil and chlormethine. Drugs with medium risk include doxorubicin and platinum analogs such as cisplatin and carboplatin. On the other hand, therapies with low risk of gonadotoxicity include plant derivatives such as vincristine and vinblastine, antibiotics such as bleomycin and dactinomycin and antimetabolites such as methotrexate, mercaptopurine and 5-fluoruracil.

Patients may choose between several methods of fertility preservation prior to chemotherapy, including cryopreservation of semen, ovarian tissue, oocytes or embryos. As more than half of cancer patients are elderly, this adverse effect is only relevant for a minority of patients.

Teratogenicity
Chemotherapy is potentially teratogenic during pregnancy, especially during the first trimester, to the extent that abortion usually is recommended if pregnancy in this period is found during chemotherapy. Second- and third-trimester exposure does not usually increase the teratogenic risk and adverse effects on cognitive development, but it may increase the risk of various complications of pregnancy and fetal myelosuppression.

In males previously having undergone chemotherapy or radiotherapy, there appears to be no increase in genetic defects or congenital malformations in their children conceived after therapy. The use of assisted reproductive technologies and micromanipulation techniques might increase this risk. In females previously having undergone chemotherapy, miscarriage and congenital malformations are not increased in subsequent conceptions. However, when in vitro fertilization and embryo cryopreservation is practised between or shortly after treatment, possible genetic risks to the growing oocytes exist, and hence it has been recommended that the babies should be screened.

Neurological adverse effects
Reported are cytotoxic-induced neuropathy causing pain or paralysis. Some patients report fatigue or non-specific neurocognitive problems, such as an inability to concentrate; this is sometimes called post-chemotherapy cognitive impairment, referred to as "chemo brain" by patients' groups.

Other side effects
In particularly large tumors, such as large lymphomas, some patients develop tumor lysis syndrome from the rapid breakdown of malignant cells. Although prophylaxis is available and is often initiated in patients with large tumors, this is a dangerous side effect that can lead to death if left untreated.

Less common side effects include red skin (erythema), dry skin, damaged fingernails, a dry mouth (xerostomia), water retention, and sexual impotence. Some medications can trigger allergic or pseudoallergic reactions.

Specific chemotherapeutic agents are associated with organ-specific toxicities, including cardiovascular disease (e.g., doxorubicin), interstitial lung disease (e.g., bleomycin) and occasionally secondary neoplasm (e.g., MOPP therapy for Hodgkin's disease).

Efficacy
Chemotherapy is highly effective in some cancers, useless in others, and unnecessary in still others.

Taking all forms of cancer together, people who receive chemotherapy increase their odds of living five years after diagnosis by about two percentage points (e.g., from about 61% being alive after five years to about 63% of them being alive after five years). However, this overall rate obscures the wide variation. Cytotoxic chemotherapy produces much larger gains for some forms of cancer, including testicular cancer (about 40% of the men who live five years after diagnosis are alive because of chemotherapy), lymphomas (about 13%), and cervical cancer (12%). By contrast, chemotherapy is essentially useless in other cancers, including prostate cancer, melanoma of the skin, multiple myeloma, bladder cancer, kidney cancer, and pancreatic cancer: people who receive chemotherapy for these conditions are just as likely to die within five years as people who do not. Chemotherapy only slightly improves survival for some of the most common forms of cancer, including breast cancers (1.5%) and lung cancers (1.5%).

Occupational precautions
For the healthcare workers that are exposed to antineoplastic agents as part of their work practice, precautions should be taken to eliminate or reduce exposure as much as possible. There already is a limitation in cytotoxics dissolution in Australia and the United States to 20 dissolutions per pharmacist/nurse, since pharmacists that prepare these drugs or nurses that may prepare and/or administer them are the two occupational groups with the highest potential exposure to antineoplastic agents. In addition, physicians and operating room personnel may also be exposed through the treatment of patients. Hospital staff, such as shipping and receiving personnel, custodial workers, laundry workers, and waste handlers, all have potential exposure to these drugs during the course of their work. The increased use of antineoplastic agents in veterinary oncology also puts these workers at risk for exposure to these drugs.

In other animals
Chemotherapy is used in veterinary medicine similar to in human medicine.