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Chemotherapy

Chemotherapy, in its most general sense, is the treatment of a disease by chemicals especially by killing micro-organisms or cancerous cells. In popular usage, it refers to antineoplastic drugs used to treat cancer or the combination of these drugs into a cytotoxic standardized treatment regimen. In its non-oncological use, the term may also refer to 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.

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-mylosuppression (decreased production of blood cells), mucositis (inflammation of the lining of digestive tract) and alopecia (hair loss).

Other uses of cytostatic chemotherapy agents (including the ones metioned below) are the treatment of autoimmune diseases such as multiple sclerosis, dermatomyositis, polymositis, lupus, rheumatoid arthritis and the suppression of transplant rejections (see immunosuppression and DMARDs). Newer anticancer drugs act directly against abnormal proteins in cancer cells; this is termed targeted therapy.

History

The use of minerals and plant-based medicines are 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 studied further during World War II. During a military operation in World War II, a group of people were accidentally exposed to mustard gas and were later found to have very low white blood cell counts. It was reasoned that an agent that damaged the rapidly growing white blood cells might have a similar effect on cancer. Therefore, in the 1940s, 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. That experience led researchers to look for other substances that might have similar effects against cancer. As a result, many other drugs have been developed to treat cancer, and drug development since then has exploded into a multibillion-dollar industry, although the principles and limitations of chemotherapy discovered by the early researchers still apply.

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 indentify 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 indentified 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, in currently ongoing. Medications to inhibit the function of p-glycorotein 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 cancer are now treated in this way. Combination chemotherapy is a similar practice that involves treating patient with a number of different drugs simultaneously. The drugs differ in their mechanism and side effects. The biggest advantage is minimizing the chances of resistance developing to any one agent.

In neoadjuvant chemotherapy (preoperative treatment) initial chemotherapy is designed to shrink the primary tumor, 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 tumor does develop. It is also useful in killing any cancerous cells which have spread to other part of the body. This is often effective as the newly growing tumors are fast-dividing, and therefore very susceptible.

Pallitive 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 antitumor 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 mylogenous leukemia, gastrointestinal stromal tumors). These are examples of targted therapies.

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

Wherer avaible, Anatomical Therapeutic Chemical Classification System codes are provided for the major categories.

Alkylating agents

Alkylating agents are so named bacause of their ability to alkylate many nucleophilic functional groups under conditions present in cells. Cesplatin and cerboplatin, 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, infosfamide. They work by chemically modifying a cell’s DNA.

Anti-metabolites

Anti-metabolites maspuerade as purine (azathioprine, mercaptopurine) or pyrimidine-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

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

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:

1. Vincristine
2. Vinblastine
3. Vinorelbine
4. Vindesine

Podophyllotoxin

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 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

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

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 super coiling.

1. Some type I topoisomerase inhibitors include camptothecins: irinotecan and topotecan.
2. 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).

Antineoplastics

Main article: Antineoplastic

These include the immunosuppressant dactinomycin (which is used in kidney transplantation), doxorubicin, epirubicin, bleomycin and others.

Newer and experimental approaches

Hematopoietic stem cell transplant approaches

Stem cell harvesting and autologous or hematopoietic stem cell transplantation has been used to allow for higher doses of chemotheraputic agents where dosages are primarily limited by hematopoietic damage. Years of research in treating solid tumors, particularly breast cancer, with hematopoeitic stem cell transplants, has yielded little proof of efficacy. Hematological malignacies such as myeloma, lymphoma, and leukemia remain the main indications for stem cell transplants.

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 level 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 tumor-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 or 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, and allows reduced use of the Cremophor vehicle usually found in paclitaxel. Nanoparticles made of magnetic material can also be used to concentrate agents at tumor sites using an externally applied magnetic field.

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 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 tumor sites without causing overwhelming systemic damage.

Depending on the patient, 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 phlebitic 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 uses. 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 gut and skin. This may manifest as systemic infections, such as sepsis, or as localized outbreaks, such as shingles. 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 (erythoropoietin), iron supplements, and blood transfusions.

• Tendency to bleed easily. Medications that kill rapidly dividing cell 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 to 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.

Immunosuppression and myelosuppression

Virtually all chemotherapeutic regimens can cause depression of the immune system, often by paralyzing 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 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. The United States’ top-ranked cancer hospital, the MD Anderson, has reported that polysaccharide-K (PSK; an extract from Trametes versicolor) is a “promising candidate for chemprevention due to the multiple effects on the malignant process, limited side effects and safety of daily oral doses for extended period of time.” PSK is already used in pharmaceuticals designed to complement chemotherapy such as MC-S. The MD Anderson has also reported that there are 40 human studies, 55 animal studies, 37 in vitro studies, and 11 reviews published concerning Trametes versicolor or its extract PSK.

Nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) is common with many treatments and some forms of cancer. However, some chemotherapy regimens do not have this side effect, and very effective drugs to stop or noticeably reduce this adverse effect are available.

A class of drugs called 5-HT3 antagonists are the most effective antiemetics and constitute the single greatest advance in the management of nausea and vomiting in patients with cancer. These drugs block one or more of the nerve signals that cause nausea and vomiting. During the first 24 hourse after chemotherapy, the most effective approach appears to be blocking the 5-HT3 nerve signal. Approved 5-HT3 inhibitors include dolasetron, granisetron, and ondansetron (zofran). The newest 5-HT3 inhibitor, palonosetron also prevents delayed nausea and vomiting, which occurs during the 2-5 days after treatment. Since some patients have trouble swallowing pills, these drugs are often availed by injection, as orally disintegrating tablets, or as transdermal patches.

The substance P inhibitor aprepitant, which became available in 2005, is also effective in controlling the nausea of cancer chemotherapy.

Some studies and patient groups say 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 (Terahydrocannabinol or THC) such as Marinol may be practical for the application. Natural jarijuana, known as medical cannabis is also used and recommended by some oncologists, though its use is regulated and not legal everywhere.

Secondary neoplasm

The development of secondary neoplasia after successful chemotherapy and or radiotherapy treatment has shown to exist. The most common secondary neoplasm is secondary acute myeloid leukemia, which develops primarily after treatment with alkylating agents or topoisomerase inhibitors. Other studies have shown a 13.5 fold increase from the general population in the incidence of secondary neoplasm occurrence after 30 years from treatment. Infertility

Some types of chemotherapy are gonadotoxic and may cause infertility. Chemotherapies with high risk include procarbazine and alkylating drugs such as cyclophosphamide, inosfamide, 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 bleomycinand dactinmycin 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, oocyter or embryos.

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

Some patients report fatigue or non-specific naurocognitive problems, such as an inability to concentrate; this is sometimes called post-chemotherapy cognitive impairment, referred to as “chemo brain” by patients’ groups.

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

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