Chemotherapy
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Chemotherapy is the use of chemical substances to treat disease. In its modern-day use, it refers almost exclusively to cytostatic drugs 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 1909 and used to treat syphilis. This was later followed by sulfonamides discovered by Domagk and penicillin G discovered by Alexander Fleming.
Other uses of cytostatic chemotherapy agents (including the ones mentioned below) are the treatment of autoimmune diseases (DMARDs).
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History
Main article: history of cancer chemotherapy
The era of chemotherapy began in the 1940s with the first uses of nitrogen mustards and folic acid inhibitors. Cancer drug 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
Cancer is the uncontrolled growth of cells due to damage to DNA (mutations) and, occasionally, due to an inherited propensity to develop certain tumours.
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 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 those responsible for hair growth and for replacement of the intestinal epithelium (lining) are also 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, tumours with high growth fractions (such as acute myelogenous leukemia and the lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the tumour cells are undergoing cell division at 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 brachytherapy and teletherapy) and surgery.
Types and dosage
The majority of chemotherapeutic drugs can be divided in to: alkylating agents, anti-metabolites, plant alkaloids, topoisomerase inhibitors, and antitumour agents. All of these drugs affect cell division or DNA synthesis and function in some way.
Some newer agents don't directly interfere with DNA. These include the new tyrosine kinase inhibitor 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.
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 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.
Alkylating agents
Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumour growth by cross-linking guanine nucleobases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs acts mainly nonspecifically, some of them requires conversion into active substances in vivo (e.g. cyclophosphamide). Selected examples: cisplatin, carboplatin, ifosfamide, chlorambucil, busulfan, thiotepa.
Anti-metabolites
Anti-metabolites masquerade as purine 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. An important example is 5-fluorouracil (5FU), which inhibits thymidylate synthase. Fludarabine inhibits function of multiple DNA polymerases, DNA primase, DNA ligase I and is S phase-specific (since these enzymes are highly active during DNA replication). Methotrexate inhibits dihydrofolate reductase, an enzyme essential for purine and pyrimidine synthesis.
Plant alkaloids
These alkaloids are derived from plants and block cell division by preventing microtubule function. Microtubules are vital for cell division and without them it can not occur. The main examples are vinca alkaloids and taxanes.
Vinca alkaloids
Vinca alkaloids bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules. They are derived from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). The vinca alkaloids include: -
Taxanes
Taxanes are derived from the Pacific yew tree, Taxus brevifolia. Taxanes enhance stability of microtubules, preventing the separation of chromosomes during anaphase. Taxanes include: -
Topoisomerase inhibitors
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. The latter are semisynthetic derivatives of epipodophyllotoxins, alkaloids naturally occurring in the root of mayapple (Podophyllum peltatum) .
Antitumour antibiotics
There are many differing antitumour antibiotics, but generally they prevent cell division by several ways: (1) binding to DNA through intercalation between two adjacent nucleotide bases and making it unable to separate, (2) inhibiting ribonucleic acid (RNA), preventing enzyme synthesis, (3) interfering with cell replication. They are products of various strains of the soil fungus Streptomyces. Examples are anthracyclines (doxorubicin, daunorubicin and epirubicin, which also inhibit topoisomerase II), actinomycin, bleomycin, mitomycin and plicamycin. Bleomycin acts in unique way through oxidation of a DNA-bleomycin-Fe(II) complex and forming free radicals, which induce damage and chromosomal aberrations.
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 cancer is often sensitive to finasteride, an agent that blocks the peripheral conversion of testosterone to 5-hydroxy-testosterone.
- Breast cancer cells often highly express the estrogen and/or progesterone receptor. 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 goserelin possess 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 hormone dependent, although the specific mechanism is still unclear.
Delivery
Most chemotherapy is delivered intravenously, although there are a number of agents that can be administered orally (e.g. melphalan and 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 inpatient or outpatient basis. 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-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.
Treatment schemes
There are a number of strategies in the administration of chemotheraputic 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 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 status is 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 chemotheraputic 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
- nausea and vomiting
- diarrhea or constipation
- anaemia
- depression of the immune system hence (potentially lethal) infections and sepsis
- hemorrhage
- secondary neoplasms
- cardiotoxicity
- hepatotoxicity
- nephrotoxicity
- ototoxicity
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. The latter two, 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, Neupogen®, Neulasta®.)
In very severe myelosuppression, which occurs in some regimens, almost all the bone marrow stem cells (cells which 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.
Nausea and vomiting induced by chemotherapy can be alleviated with antiemetics. Usually metoclopramide, dexamethasone or 5 hydroxytryptamine 3 (5-HT3) receptor antagonists (dolasetron, granisetron, ondansetron) are used.
Some studies1 and patient groups claim that the use of cannabinoids derived from marijuana during chemotherapy greatly reduces the associated nausea and vomiting, and enables the patient to eat. Some synthetic derivatives of the active substance in marijuana (tetrahydrocannabinol or THC) are in development for this indication.
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 which can lead to death if left untreated.
Chemotherapy may increase the risk of cardiovascular disease and occasionally leads to secondary cancer.
See also
References
- Note 1: Tramer MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2001;323:16-21. PMID 11440936.
External links
- Chemotherapy Regimens Database (http://www.thedoctorslounge.net/oncolounge/regimens/index.htm)de:Chemotherapie
es:Quimioterapia fr:Chimiothérapie lt:Chemoterapija nl:Chemotherapie ja:化学療法 pl:Chemioterapia pt:Quimioterapia fi:Kemoterapia