Chemotherapy

Chemotherapy is the use of chemical substances to treat disease. In its modern-day use, it refers primarily to cytotoxicdrugs used to treat cancer.

In its non-oncological use, the term may also refer to antibiotics(antibacterial chemotherapy). In that sense, the first modern chemotherapeutic agent was Paul Ehrlich's arsphenamine, an arsenic compound discovered in 1909and used to treat syphilis. This was later followed by sulfonamidesdiscovered by Domagkand penicillinG discovered by Alexander Fleming.

Other uses of cytostatic chemotherapy agents (including the ones mentioned below) are the treatment of autoimmune diseasessuch as multiple sclerosis and rheumatoid arthritis, the treatment of some chronic viral infections such as Hepatitis, and the suppression of transplant rejections(see immunosuppressionand DMARDs).

History

Main article: history of cancer chemotherapy

The era of chemotherapy began in the 1940s with the first uses of nitrogen mustardsand folic acidinhibitors. Cancerdrug development since then has exploded into a multi-billion dollar industry. The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply.

Principles

Canceris the uncontrolled growth of cellsdue to damage to DNA(mutations) and, occasionally, due to an inheritedpropensity to develop certain tumours. Autoimmune diseasesarise from an overactive immune response of the body against substances and tissues normally present in the body - in other words, the body attacks its own cells. In a contrast, transplant rejectionhappens because a normal healthy human immune system can distinguish foreign tissues and attempts to destroy them. Also the reverse situation, called graft-versus-host disease, may take place.

Broadly, 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 "cell suicide").

Unfortunately, scientists have yet to be able to locate specific features of malignant and immune cells that would make them uniquely targetable (barring some recent examples, such as the Philadelphia chromosomeas targeted by imatinib). This means that other fast dividing cells such as those responsible for hairgrowth and for replacement of the intestinalepithelium(lining) are also affected. However, some drugs have a better side-effectprofile than others, enabling doctorsto adjust treatment regimens to the advantage of patients in certain situations.

As chemotherapy affects cell division, tumours with high growth fractions (such as acute myelogenous leukemiaand the lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell divisionat any time.

Chemotherapeutic drugs affect "younger" tumours (i.e. less differentiated) more effectively, because at a higher grade of differentiation, the propensity to growth usually decreases. Near the center of some solid tumours, cell division has effectively ceased, making them insensitive to chemotherapy. Another problem with solid tumours is the fact that the chemotherapeutic agent often does not reach the core of the tumour. Solutions to this problem include radiation therapy(both brachytherapyand teletherapy) and surgery.

Types

The majority of chemotherapeutic drugs can be divided in to: alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomeraseinhibitors, and antitumour agents. All of these drugs affect cell divisionor DNAsynthesis and function in some way.

Some newer agents don't directly interfere with DNA. These include the new tyrosine kinaseinhibitor imatinib mesylate (Gleevec® or Glivec®), which directly targets a molecular abnormality in certain types of cancer (chronic myelogenous leukemia, gastrointestinal stromal tumors).

In addition, some drugs may be used which modulate tumour cell behaviour without directly attacking those cells. Hormone treatments fall into this category of adjuvant therapies.

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

Alkylating agents (L01A)

See main article: alkylating agent

Alkylating agents are so named because of their ability to add alkyl groups to many electronegativegroups under conditions present in cells.

Anti-metabolites (L01B)

See main article: antimetabolite

Anti-metabolitesmasquerade as purine((azathioprine, mercaptopurine)) or pyrimidine- which become the building blocks of DNA. They prevent these substances 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 alkaloidsare derived from plantsand block cell division by preventing microtubulefunction. Microtubules are vital for cell division and without them it can not occur. The main examples are vinca alkaloidsand taxanes.

Vinca alkaloids (L01CA)

Vinca alkaloids bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules (M phaseof 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)

Podophyllotoxinis a plant-derived compound used to produce two other cytostatic drugs, etoposideand 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 still has to be elucidated.

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 recombinantively.

Taxanes (L01CD)

Taxanes are derived from the Pacific yew tree, Taxus brevifolia. Taxanes enhance stability of microtubules, preventing the separation of chromosomesduring anaphase. Taxanes include: -

• Paclitaxel
• Docetaxel

Topoisomerase inhibitors (L01CBand L01XX)

Topoisomerasesare essential enzymesthat maintain the topologyof DNA. Inhibition of type I or type II topoisomerases interferes with both transcriptionand replicationof DNA by upsetting proper DNA supercoiling.

• Some type I topoisomerase inhibitors include camptothecins: irinotecanand 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 mayapple (Podophyllum peltatum).

Antitumour antibiotics (L01D)

See main article: antineoplastic

The most important immunosuppressant from this group is dactinomycin, which is used to in kidney transplantations.

Hormonal therapy

Several malignancies responds to hormonal therapy. Strictly speaking, this is not chemotherapy. Cancer arising from certain tissues, including the mammary and prostate glands, may be inhibited or stimulated by appropriate changes in hormone balance.

• Steroids(often dexamethasone) can inhibit tumour growth or the associated edema(tissue swelling), and may cause regression of lymph node malignancies.
• Prostate canceris often sensitive to finasteride, an agent that blocks the peripheral conversion of testosteroneto dihydrotestosterone.
• Breast cancercells often highly express the estrogenand/or progesteronereceptor. Inhibiting the production (with aromatase inhibitors) or action (with tamoxifen) of these hormones can often be used as an adjunct to therapy.
• Gonadotropin-releasing hormone agonists (GnRH), such as goserelinpossess a paradoxic negative feedback effect followed by inhibition of the release of FSH (follicle-stimulating hormone) and LH (luteinizing hormone), when given continuously.

Some other tumours are also hormonedependent, although the specific mechanism is still unclear.

Dosage

Dosage of chemotherapy can be difficult: if the dose is too low, it will be ineffective against the tumor, while 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 malign diseases.

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

Delivery

Most chemotherapy is deliveredintravenously, although there are a number of agents that can be administered orally (e.g. melphalanand gemcitabine). Depending on the patient, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, IV chemotherapy may be given on either an inpatientor outpatientbasis. For continuous, frequent or prolonged IV chemotherapy administration, various systems may be surgically inserted into the vasculature to maintain access. Commonly used systems are the Hickman line, the Port-a-Cathor the PICC line. These have a lower infection risk, are much less prone to phlebitisor extravasation, and abolish the need for repeated insertion of peripheral cannulae.

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 therapyor surgery. Most cancers are now treated in this way. Combination chemotherapy is a similar practice which 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 aimed for shrinking 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 resistance developing 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.

Most chemotherapy regimens require that the patient is capable to undergo the treatment. Performance statusis often used as a measure to determine whether a patient can receive chemotherapy, or whether dose reduction is required.

Side-effects

The treatment can be physically exhausting for the patient. Current chemotherapeutic techniques have a range of side effects mainly affecting the fast-dividing cells of the body. Important common side-effects include (dependent on the agent):

• Hair loss
• Nauseaand vomiting
• Diarrheaor constipation
• Anemia
• Depression of the immune systemhence (potentially lethal) infectionsand sepsis
• Hemorrhage
• Secondary neoplasms
• Cardiotoxicity
• Hepatotoxicity
• Nephrotoxicity
• Ototoxicity

Immunosuppression and myelosuppression

Virtually all chemotherapeutic regimens can cause depression of the immune system, often by paralysing the bone marrowand leading to a decrease of white blood cells, red blood cellsand platelets. The latter two, when they occur, are improved with blood transfusion. Neutropenia(a decrease of the neutrophil granulocytecount below 0.5 x 10⁹/litre) can be improved with synthetic G-CSF(granulocyte-colony stimulating factor, e.g. filgrastim, lenograstim, Neupogen®, Neulasta®.)

In very severe myelosuppression, which occurs in some regimens, almost all the bone marrow stem cells(cells which produce whiteand red blood cells) are destroyed, meaning allogenic or autologous bone marrow cell transplantsare 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.

Nausea and vomiting

Nausea and vomiting caused by chemotherapy; stomach upset may trigger a strong urge to vomit, or forcefully eliminate what is in the stomach.

Stimulation of the vomiting center results in the coordination of responses from the diaphragm, salivary glands, cranial nerves, and gastrointestinal muscles to produce the interruption of respiration and forced expulsion of stomach contents known as retching and vomiting. The vomiting center is stimulated directly by afferent input from the vagal and splanchnic nerves, the pharynx, the cerebral cortex, cholinergic and histamine stimulation from the vestibular system, and efferent input from the chemoreceptor trigger zone (CTZ). The CTZ is in the area postrema, outside the blood-brain barrier, and is thus susceptible to stimulation by substances present in the blood or cerebral spinal fluid. The neurotransmitters dopamine and serotonin stimulate the vomiting center indirectly via stimulation of the CTZ.

The 5-HT3 inhibitors are the most effective antiemetics and constitute the single greatest advance in the management of nausea and vomiting in patients with cancer. These drugs are designed to block one or more of the signals that cause nausea and vomiting. The most sensitive signal during the first 24 hours after chemotherapy appears to be 5-HT3. Blocking the 5-HT3 signal is one approach to preventing acute emesis (vomiting), or emesis that is severe, but relatively short-lived. Approved 5-HT3 inhibitors include: dolasetron (Anzemet®), granisetron (Kytril®), and ondansetron (Zofran®). The newest 5-HT3 inhibitor, Aloxi® (palonosetron), has a distinct advantage over the other 5-HT3 inhibitors because, in addition to preventing acute nausea and vomiting, Aloxi® also prevents delayed nausea and vomiting, which occurs during the 2-5 days after treatment. Aloxi® is the only drug in its class that is approved by the FDA for the treatment of delayed nausea and vomiting.

Some studies^{[{{fullurl:Template:FULLPAGENAME}}#endnote_marijuana]} and patient groups claim that the use of cannabinoidsderived from marijuanaduring chemotherapy greatly reduces the associated nausea and vomiting, and enables the patient to eat. Some synthetic derivatives of the active substance in marijuana (tetrahydrocannabinolor THC) are in development for this indication.

Other side effects

In particularly large tumors, such as large lymphomas, some patients develop tumor lysis syndromefrom 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 which can lead to death if left untreated.

Chemotherapy may increase the risk of cardiovascular diseaseand occasionally leads to secondary cancer.

Some patients report attention deficitespecially when attempting tasks like driving a car that require continued concentration. The informal term "chemo head" is often used to describe the feeling. This may be a secondary symptom due to the effects of anemia.

See also

• Cancer
• Gene therapy
• Experimental cancer treatments
• Chemotherapy regimens

References

• ^  Tramer MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ2001;323:16-21. PMID 11440936.

External links

• Chemotherapy Regimens Database
• Chemocare.com chemotherapy drug information
• Chemotherapy.com Educational and support information about chemotherapy and associated side effects

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It uses material from the http://en.wikipedia.org/wiki/Chemotherapy Wikipedia article Chemotherapy.