Chemotherapy

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)
This article is about the cancer treatment. For antimicrobial chemotherapy, see Antimicrobial chemotherapy. For the journal, see Chemotherapy (journal).
"Anticancer drugs" and "Chemo" redirect here. For the journal, see Anti-Cancer Drugs. For other uses of chemo, see Chemo (disambiguation).

Chemotherapy
A woman being treated with docetaxel chemotherapy for breast cancer. Cold mittens and cold booties are placed on her hands and feet to reduce harm to her nails.
Other nameschemo, CTX, CTx

Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of

alkylating agents) as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent (which almost always involves combinations of drugs) or it may aim to prolong life or to reduce symptoms (palliative chemotherapy). Chemotherapy is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer, which is called medical oncology.[1][2]

The term chemotherapy has come to connote non-specific usage of intracellular poisons to inhibit mitosis (cell division) or induce DNA damage, which is why inhibition of DNA repair can augment chemotherapy.[3] The connotation of the word chemotherapy excludes more selective agents that block extracellular signals (signal transduction). The development of therapies with specific molecular or genetic targets, which inhibit growth-promoting signals from classic endocrine hormones (primarily estrogens for breast cancer and androgens for prostate cancer) are now called hormonal therapies. By contrast, other inhibitions of growth-signals like those associated with receptor tyrosine kinases are referred to as targeted therapy.

Importantly, the use of drugs (whether chemotherapy, hormonal therapy or targeted therapy) constitutes systemic therapy for cancer in that they are introduced into the blood stream and are therefore in principle able to address cancer at any anatomic location in the body. Systemic therapy is often used in conjunction with other modalities that constitute local therapy (i.e., treatments whose efficacy is confined to the anatomic area where they are applied) for cancer such as radiation therapy, surgery or hyperthermia therapy.

Traditional chemotherapeutic agents are

systemic lupus erythematosus, multiple sclerosis, vasculitis
and many others.

Treatment strategies

Common combination chemotherapy regimens[4]
Cancer type Drugs Acronym
Breast cancer
5-fluorouracil, vinorelbine
 CMF
Doxorubicin, cyclophosphamide AC
Hodgkin's lymphoma
 Docetaxel, doxorubicin, cyclophosphamide TAC
Doxorubicin, bleomycin, vinblastine, dacarbazine ABVD
Mustine, vincristine, procarbazine, prednisolone MOPP
Non-Hodgkin's lymphoma
 Cyclophosphamide, doxorubicin, vincristine, prednisolone CHOP, R-CVP
Germ cell tumor Bleomycin, etoposide, cisplatin BEP
Stomach cancer[5] Epirubicin, cisplatin, 5-fluorouracil ECF
Epirubicin, cisplatin, capecitabine ECX
Bladder cancer Methotrexate, vincristine, doxorubicin, cisplatin MVAC
Lung cancer Cyclophosphamide, doxorubicin, vincristine, vinorelbine CAV
Colorectal cancer
5-fluorouracil, folinic acid, oxaliplatin
 FOLFOX
Pancreatic cancer
5-fluorouracil
 FOLFOX
Bone cancer
 Doxorubicin, cisplatin, methotrexate, ifosfamide, etoposide MAP/MAPIE

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.

  • Induction chemotherapy is the first line treatment of cancer with a chemotherapeutic drug. This type of chemotherapy is used for curative intent.[1][6]: 55–59 
  • Combined modality chemotherapy is the use of drugs with other cancer treatments, such as surgery, radiation therapy, or hyperthermia therapy.
  • Consolidation chemotherapy is given after remission in order to prolong the overall disease-free time and improve overall survival. The drug that is administered is the same as the drug that achieved remission.[6]: 55–59 
  • Intensification chemotherapy is identical to consolidation chemotherapy but a different drug than the induction chemotherapy is used.[6]: 55–59 
  • Combination chemotherapy involves treating a person 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. Also, the drugs can often be used at lower doses, reducing toxicity.[6]: 55–59 [7]: 17–18 [5]
  • Neoadjuvant chemotherapy is given prior to a local treatment such as surgery, and is designed to shrink the primary tumor.[6]: 55–59  It is also given for cancers with a high risk of micrometastatic disease.[8]
    : 42 
  • micrometastases can be treated with adjuvant chemotherapy and can reduce relapse rates caused by these disseminated cells.[9]
  • Maintenance chemotherapy is a repeated low-dose treatment to prolong remission.[5][6]: 55–59 
  • Salvage chemotherapy or palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase life expectancy. For these regimens, in general, a better toxicity profile is expected.[6]: 55–59 

All chemotherapy regimens require that the recipient be capable of undergoing the treatment. Performance status is often used as a measure to determine whether a person 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.[10] Current chemotherapy regimens apply drug treatment in cycles, with the frequency and duration of treatments limited by toxicity.[11]

Effectiveness

The effectiveness of chemotherapy depends on the type of cancer and the stage. The overall effectiveness ranges from being curative for some cancers, such as some

non-melanoma skin cancers.[15]

Dosage

Dose response relationship of cell killing by chemotherapeutic drugs on normal and cancer cells. At high doses the percentage of normal and cancer cells killed is very similar. For this reason, doses are chosen where anti-tumour activity exceeds normal cell death.[4]

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) will be intolerable to the person receiving it.[4] The standard method of determining chemotherapy dosage is based on calculated body surface area (BSA). The BSA is usually calculated with a mathematical formula or a nomogram, using the recipient's weight and height, rather than by direct measurement of body area. This formula was originally derived in a 1916 study and attempted to translate medicinal doses established with laboratory animals to equivalent doses for humans.[16] The study only included nine human subjects.[17] When chemotherapy was introduced in the 1950s, the BSA formula was adopted as the official standard for chemotherapy dosing for lack of a better option.[18][19]

The validity of this method in calculating uniform doses has been questioned because the formula only takes into account the individual's weight and height. Drug absorption and clearance are influenced by multiple factors, including age, sex, metabolism, disease state, organ function, drug-to-drug interactions, genetics, and obesity, which have major impacts on the actual concentration of the drug in the person's bloodstream.[18][20][21] As a result, there is high variability in the systemic chemotherapy drug concentration in people dosed by BSA, and this variability has been demonstrated to be more than ten-fold for many drugs.[17][22] In other words, if two people receive the same dose of a given drug based on BSA, the concentration of that drug in the bloodstream of one person may be 10 times higher or lower compared to that of the other person.[22] This variability is typical with many chemotherapy drugs dosed by BSA, and, as shown below, was demonstrated in a study of 14 common chemotherapy drugs.[17]

5-FU dose management results in significantly better response and survival rates versus BSA dosing.[23]

The result of this pharmacokinetic variability among people is that many people do not receive the right dose to achieve optimal treatment effectiveness with minimized toxic side effects. Some people are overdosed while others are underdosed.[18][20][21][23][24][25][26] For example, in a randomized clinical trial, investigators found 85% of metastatic colorectal cancer patients treated with 5-fluorouracil (5-FU) did not receive the optimal therapeutic dose when dosed by the BSA standard—68% were underdosed and 17% were overdosed.[23]

There has been controversy over the use of BSA to calculate chemotherapy doses for people who are

overdosing.[27] In many cases, this can result in sub-optimal treatment.[27]

Several clinical studies have demonstrated that when chemotherapy dosing is individualized to achieve optimal systemic drug exposure, treatment outcomes are improved and toxic side effects are reduced.[23][25] In the 5-FU clinical study cited above, people whose dose was adjusted to achieve a pre-determined target exposure realized an 84% improvement in treatment response rate and a six-month improvement in overall survival (OS) compared with those dosed by BSA.[23]

Toxicity. Diarrhea. BSA-based dose, 18%. Dose-adjusted, 4%. Hematologic. BSA-based dose, 2%. Dose-adjusted, 0%.
5-FU dose management avoids serious side effects experienced with BSA dosing.[23]
5-FU dose management in the FOLFOX regimen increases treatment response significantly and improves survival by six months.[25]

In the same study, investigators compared the incidence of common 5-FU-associated grade 3/4 toxicities between the dose-adjusted people and people dosed per BSA.[23] The incidence of debilitating grades of diarrhea was reduced from 18% in the BSA-dosed group to 4% in the dose-adjusted group and serious hematologic side effects were eliminated.[23] Because of the reduced toxicity, dose-adjusted patients were able to be treated for longer periods of time.[23] BSA-dosed people were treated for a total of 680 months while people in the dose-adjusted group were treated for a total of 791 months.[23] Completing the course of treatment is an important factor in achieving better treatment outcomes.

Similar results were found in a study involving people with colorectal cancer who have been treated with the popular FOLFOX regimen.[25] The incidence of serious diarrhea was reduced from 12% in the BSA-dosed group of patients to 1.7% in the dose-adjusted group, and the incidence of severe mucositis was reduced from 15% to 0.8%.[25]

The FOLFOX study also demonstrated an improvement in treatment outcomes.[25] Positive response increased from 46% in the BSA-dosed group to 70% in the dose-adjusted group. Median progression free survival (PFS) and overall survival (OS) both improved by six months in the dose adjusted group.[25]

One approach that can help clinicians individualize chemotherapy dosing is to measure the drug levels in blood plasma over time and adjust dose according to a formula or algorithm to achieve optimal exposure. With an established target exposure for optimized treatment effectiveness with minimized toxicities, dosing can be personalized to achieve target exposure and optimal results for each person. Such an algorithm was used in the clinical trials cited above and resulted in significantly improved treatment outcomes.[28]

Oncologists are already individualizing dosing of some cancer drugs based on exposure. Carboplatin[29]: 4  and busulfan[30][31] dosing rely upon results from blood tests to calculate the optimal dose for each person. Simple blood tests are also available for dose optimization of methotrexate,[32] 5-FU, paclitaxel, and docetaxel.[33][34]

The serum albumin level immediately prior to chemotherapy administration is an independent prognostic predictor of survival in various cancer types.[35]

Types

Two DNA bases that are cross-linked by a nitrogen mustard. Different nitrogen mustards will have different chemical groups (R). The nitrogen mustards most commonly alkylate the N7 nitrogen of guanine (as shown here) but other atoms can be alkylated.[36]

Alkylating agents

Main article: Alkylating antineoplastic agent

Alkylating agents are the oldest group of chemotherapeutics in use today. Originally derived from mustard gas used in World War I, there are now many types of alkylating agents in use.[4] They are so named because of their ability to alkylate many molecules, including proteins, RNA and DNA. This ability to bind covalently to DNA via their alkyl group is the primary cause for their anti-cancer effects.[37] DNA is made of two strands and the molecules may either bind twice to one strand of DNA (intrastrand crosslink) or may bind once to both strands (interstrand crosslink). If the cell tries to replicate crosslinked DNA during cell division, or tries to repair it, the DNA strands can break. This leads to a form of programmed cell death called apoptosis.[36][38] Alkylating agents will work at any point in the cell cycle and thus are known as cell cycle-independent drugs. For this reason, the effect on the cell is dose dependent; the fraction of cells that die is directly proportional to the dose of drug.[39]

The subtypes of alkylating agents are the

phosphate groups in biologically important molecules.[41] Non-classical alkylating agents include procarbazine and hexamethylmelamine.[37][38]

Antimetabolites

Deoxycytidine (left) and two anti-metabolite drugs (center and right), gemcitabine and decitabine. The drugs are very similar but they have subtle differences in their chemical structure.
Main article: Antimetabolite

S-phase (the DNA synthesis phase). For this reason, at a certain dose, the effect plateaus and proportionally no more cell death occurs with increased doses. Subtypes of the anti-metabolites are the anti-folates, fluoropyrimidines, deoxynucleoside analogues and thiopurines.[37][42]

The anti-folates include

thioguanine and mercaptopurine.[37][42]

Anti-microtubule agents

Vinca alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. Both mechanisms cause defective mitosis.

β-tubulin. They are hollow, rod-shaped structures that are required for cell division, among other cellular functions.[45] Microtubules are dynamic structures, which means that they are permanently in a state of assembly and disassembly. Vinca alkaloids and taxanes are the two main groups of anti-microtubule agents, and although both of these groups of drugs cause microtubule dysfunction, their mechanisms of action are completely opposite: Vinca alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. By doing so, they can induce mitotic catastrophe in the cancer cells.[46] Following this, cell cycle arrest occurs, which induces programmed cell death (apoptosis).[37][47] These drugs can also affect blood vessel growth, an essential process that tumours utilise in order to grow and metastasise.[47]

Vinca alkaloids are derived from the

M-phase.[39]

Taxanes are natural and semi-synthetic drugs. The first drug of their class, paclitaxel, was originally extracted from Taxus brevifolia, the Pacific yew. Now this drug and another in this class, docetaxel, are produced semi-synthetically from a chemical found in the bark of another yew tree, Taxus baccata.[56]

Podophyllotoxin is an antineoplastic lignan obtained primarily from the American mayapple (Podophyllum peltatum) and Himalayan mayapple (Sinopodophyllum hexandrum). It has anti-microtubule activity, and its mechanism is similar to that of vinca alkaloids in that they bind to tubulin, inhibiting microtubule formation. Podophyllotoxin is used to produce two other drugs with different mechanisms of action: etoposide and teniposide.[57][58]

Topoisomerase inhibitors

Topoisomerase I and II Inhibitors
Main article: Topoisomerase inhibitor

Topoisomerase inhibitors are drugs that affect the activity of two enzymes:

topoisomerase II. When the DNA double-strand helix is unwound, during DNA replication or transcription, for example, the adjacent unopened DNA winds tighter (supercoils), like opening the middle of a twisted rope. The stress caused by this effect is in part aided by the topoisomerase enzymes. They produce single- or double-strand breaks into DNA, reducing the tension in the DNA strand. This allows the normal unwinding of DNA to occur during replication or transcription. Inhibition of topoisomerase I or II interferes with both of these processes.[59][60]

Two topoisomerase I inhibitors,

Camptotheca acuminata.[39] Drugs that target topoisomerase II can be divided into two groups. The topoisomerase II poisons cause increased levels enzymes bound to DNA. This prevents DNA replication and transcription, causes DNA strand breaks, and leads to programmed cell death (apoptosis). These agents include etoposide, doxorubicin, mitoxantrone and teniposide. The second group, catalytic inhibitors, are drugs that block the activity of topoisomerase II, and therefore prevent DNA synthesis and translation because the DNA cannot unwind properly. This group includes novobiocin, merbarone, and aclarubicin, which also have other significant mechanisms of action.[61]

Cytotoxic antibiotics

The cytotoxic

actinomycin.[62]

Among the anthracyclines,

free radicals that damage intercellular molecules and topoisomerase inhibition.[65]

Actinomycin is a complex molecule that intercalates DNA and prevents

RNA synthesis.[66]

Bleomycin, a

chemically reduced and reacts with oxygen.[67][6]
: 87 

Mitomycin is a cytotoxic antibiotic with the ability to alkylate DNA.[68]

Delivery

Two girls with acute lymphoblastic leukemia receiving chemotherapy. The girl on the left has a central venous catheter inserted in her neck. The girl on the right has a peripheral venous catheter. The arm board stabilizes the arm during needle insertion. Anti-cancer IV drip is seen at top right.

Most chemotherapy is delivered intravenously, although a number of agents can be administered orally (e.g., melphalan, busulfan, capecitabine). According to a recent (2016) systematic review, oral therapies present additional challenges for patients and care teams to maintain and support adherence to treatment plans.[69]

There are many intravenous methods of drug delivery, known as vascular access devices. These include the

implantable port. The devices have different applications regarding duration of chemotherapy treatment, method of delivery and types of chemotherapeutic agent.[7]
: 94–95 

Depending on the person, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, intravenous chemotherapy may be given on either an

PICC line. These have a lower infection risk, are much less prone to phlebitis or extravasation, and eliminate the need for repeated insertion of peripheral cannulae.[70]

Isolated limb perfusion (often used in melanoma),[71] or isolated infusion of chemotherapy into the liver[72] or the lung have been used to treat some tumors. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumor sites without causing overwhelming systemic damage.[73] 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.[citation needed
]

Topical chemotherapies, such as

non-melanoma skin cancer.[74]

If the cancer has

intrathecal chemotherapy may be administered.[4]

Adverse effects

Chemotherapeutic techniques have a range of side effects that depend on the type of medications used. The most common medications affect mainly the

fast-dividing cells of the body, such as blood cells and the cells lining the mouth, stomach, and intestines. Chemotherapy-related toxicities can occur acutely after administration, within hours or days, or chronically, from weeks to years.[6]
: 265 

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.

G-CSF (granulocyte-colony-stimulating factor, e.g., filgrastim, lenograstim, efbemalenograstim alfa).[75]

In very severe

bone marrow cell transplants are necessary. (In autologous BMTs, cells are removed from the person before the treatment, multiplied and then re-injected afterward; in allogenic BMTs, the source is a donor.) However, some people still develop diseases because of this interference with bone marrow.[76]

Although people receiving chemotherapy are encouraged to wash their hands, avoid sick people, and take other infection-reducing steps, about 85% of infections are due to naturally occurring microorganisms in the person's own

Herpesviridea.[78] The risk of illness and death can be reduced by taking common antibiotics such as quinolones or trimethoprim/sulfamethoxazole before any fever or sign of infection appears.[79] Quinolones show effective prophylaxis mainly with hematological cancer.[79] However, in general, for every five people who are immunosuppressed following chemotherapy who take an antibiotic, one fever can be prevented; for every 34 who take an antibiotic, one death can be prevented.[79] Sometimes, chemotherapy treatments are postponed because the immune system is suppressed to a critically low level.[citation needed
]

In

medicinal mushrooms like Trametes versicolor, to counteract depression of the immune system in people undergoing chemotherapy.[80]

Trilaciclib is an inhibitor of cyclin-dependent kinase 4/6 approved for the prevention of myelosuppression caused by chemotherapy. The drug is given before chemotherapy to protect bone marrow function.[81]

Neutropenic enterocolitis

Due to immune system suppression,

distended abdomen, fever, chills, or abdominal pain and tenderness.[83]

hemicolectomy to prevent recurrence.[84]

Gastrointestinal distress

typhlitis, a very serious and potentially life-threatening medical emergency that requires immediate treatment.[87]

Anemia

bleeding. Extremely low platelet counts may be temporarily boosted through platelet transfusions and new drugs to increase platelet counts during chemotherapy are being developed.[91][92][93][94]
Sometimes, chemotherapy treatments are postponed to allow platelet counts to recover.

solid tumours.[97]

Nausea and vomiting

Further information: Chemotherapy-induced nausea and vomiting

antiemetics have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to successfully manage these symptoms in many people. Effective mediation of these unpleasant and sometimes debilitating symptoms results in increased quality of life for the recipient and more efficient treatment cycles, due to less stoppage of treatment due to better tolerance and better overall health.[100]

Hair loss

Chemotherapy adverse effects on hair
Hair matting after few sessions of chemotherapy

Hair loss (alopecia) can be caused by chemotherapy that kills rapidly dividing cells; other medications may cause hair to thin. These are most often temporary effects: hair usually starts to regrow a few weeks after the last treatment, but sometimes with a change in color, texture, thickness or style. Sometimes hair has a tendency to curl after regrowth, resulting in "chemo curls." Severe hair loss occurs most often with drugs such as doxorubicin, daunorubicin, paclitaxel, docetaxel, cyclophosphamide, ifosfamide and etoposide. Permanent thinning or hair loss can result from some standard chemotherapy regimens.[101]

Chemotherapy induced hair loss occurs by a non-androgenic mechanism, and can manifest as alopecia totalis, telogen effluvium, or less often alopecia areata.[102] It is usually associated with systemic treatment due to the high mitotic rate of hair follicles, and more reversible than androgenic hair loss,[103][104] although permanent cases can occur.[105] Chemotherapy induces hair loss in women more often than men.[106]

Scalp cooling offers a means of preventing both permanent and temporary hair loss; however, concerns about this method have been raised.[107][108]

Secondary neoplasm

Development of secondary neoplasia after successful chemotherapy or radiotherapy treatment can occur. The most common

secondary neoplasm during the 30 years after treatment than the general population.[110]
Not all of this increase can be attributed to chemotherapy.

Infertility

Some types of chemotherapy are gonadotoxic and may cause infertility.[111] Chemotherapies with high risk include procarbazine and other alkylating drugs such as cyclophosphamide, ifosfamide, busulfan, melphalan, chlorambucil, and chlormethine.[111] Drugs with medium risk include doxorubicin and platinum analogs such as cisplatin and carboplatin.[111] 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-fluorouracil.[111]

primordial follicles.[112] This loss is not necessarily a direct effect of the chemotherapeutic agents, but could be due to an increased rate of growth initiation to replace damaged developing follicles.[112]

People may choose between several methods of fertility preservation prior to chemotherapy, including cryopreservation of semen, ovarian tissue, oocytes, or embryos.[113] As more than half of cancer patients are elderly, this adverse effect is only relevant for a minority of patients. A study in France between 1999 and 2011 came to the result that embryo freezing before administration of gonadotoxic agents to females caused a delay of treatment in 34% of cases, and a live birth in 27% of surviving cases who wanted to become pregnant, with the follow-up time varying between 1 and 13 years.[114]

Potential protective or attenuating agents include

GnRH analogs, where several studies have shown a protective effect in vivo in humans, but some studies show no such effect. Sphingosine-1-phosphate (S1P) has shown similar effect, but its mechanism of inhibiting the sphingomyelin apoptotic pathway may also interfere with the apoptosis action of chemotherapy drugs.[115]

In chemotherapy as a

conditioning regimen in hematopoietic stem cell transplantation, a study of people conditioned with cyclophosphamide alone for severe aplastic anemia came to the result that ovarian recovery occurred in all women younger than 26 years at time of transplantation, but only in five of 16 women older than 26 years.[116]

Teratogenicity

Chemotherapy is

first trimester, to the extent that abortion usually is recommended if pregnancy in this period is found during chemotherapy.[117] 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.[117]

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.

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 be screened.[117]

Peripheral neuropathy

Further information: Chemotherapy-induced peripheral neuropathy

Between 30 and 40 percent of people undergoing chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), a progressive, enduring, and often irreversible condition, causing pain, tingling, numbness and sensitivity to cold, beginning in the hands and feet and sometimes progressing to the arms and legs.[118] Chemotherapy drugs associated with CIPN include thalidomide, epothilones, vinca alkaloids, taxanes, proteasome inhibitors, and the platinum-based drugs.[118][119] Whether CIPN arises, and to what degree, is determined by the choice of drug, duration of use, the total amount consumed and whether the person already has peripheral neuropathy. Though the symptoms are mainly sensory, in some cases motor nerves and the autonomic nervous system are affected.[120] CIPN often follows the first chemotherapy dose and increases in severity as treatment continues, but this progression usually levels off at completion of treatment. The platinum-based drugs are the exception; with these drugs, sensation may continue to deteriorate for several months after the end of treatment.[121] Some CIPN appears to be irreversible.[121] Pain can often be managed with drug or other treatment but the numbness is usually resistant to treatment.[122]

Cognitive impairment

Some people receiving chemotherapy 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" in popular and social media.[123]

Tumor lysis syndrome

In particularly large tumors and cancers with high

cardiac arrhythmia. Although prophylaxis is available and is often initiated in people with large tumors, this is a dangerous side-effect that can lead to death if left untreated.[7]
: 202 

Organ damage

DNA damage. Other chemotherapeutic agents that cause cardiotoxicity, but at a lower incidence, are cyclophosphamide, docetaxel and clofarabine.[125]

liver fibrosis.[126][127]

Nephrotoxicity (kidney damage) can be caused by tumor lysis syndrome and also due direct effects of drug clearance by the kidneys. Different drugs will affect different parts of the kidney and the toxicity may be asymptomatic (only seen on blood or urine tests) or may cause acute kidney injury.[128][129]

vertigo.[130][131] Children treated with platinum analogues have been found to be at risk for developing hearing loss.[132][133][134]

Other side-effects

Less common side-effects include red skin (

pseudoallergic
reactions.

Specific chemotherapeutic agents are associated with organ-specific toxicities, including

MOPP therapy for Hodgkin's disease).[135]

Hand-foot syndrome is another side effect to cytotoxic chemotherapy.[136]

Nutritional problems are also frequently seen in cancer patients at diagnosis and through chemotherapy treatment. Research suggests that in children and young people undergoing cancer treatment, parenteral nutrition may help with this leading to weight gain and increased calorie and protein intake, when compared to enteral nutrition.[137]

Limitations

Chemotherapy does not always work, and even when it is useful, it may not completely destroy the cancer. People frequently fail to understand its limitations. In one study of people who had been newly diagnosed with incurable,

stage 4 cancer, more than two-thirds of people with lung cancer and more than four-fifths of people with colorectal cancer still believed that chemotherapy was likely to cure their cancer.[138]

The

alkylating agents such as lomustine or temozolomide are able to cross this blood–brain barrier.[139][140][141]

Blood vessels in tumors are very different from those seen in normal tissues. As a tumor grows, tumor cells furthest away from the blood vessels become low in oxygen (hypoxic). To counteract this they then signal for new blood vessels to grow. The newly formed tumor vasculature is poorly formed and does not deliver an adequate blood supply to all areas of the tumor. This leads to issues with drug delivery because many drugs will be delivered to the tumor by the circulatory system.[142]

Resistance

Resistance is a major cause of treatment failure in chemotherapeutic drugs. There are a few possible causes of resistance in cancer, one of which is the presence of small pumps on the surface of cancer cells that actively move chemotherapy from inside the cell to the outside. Cancer cells produce high amounts of these pumps, known as p-glycoprotein, in order to protect themselves from chemotherapeutics. Research on p-glycoprotein and other such chemotherapy efflux pumps is currently ongoing. Medications to inhibit the function of p-glycoprotein are undergoing investigation, but due to toxicities and interactions with anti-cancer drugs their development has been difficult.[143][144] Another mechanism of resistance is gene amplification, a process in which multiple copies of a gene are produced by cancer cells. This overcomes the effect of drugs that reduce the expression of genes involved in replication. With more copies of the gene, the drug can not prevent all expression of the gene and therefore the cell can restore its proliferative ability. Cancer cells can also cause defects in the cellular pathways of apoptosis (programmed cell death). As most chemotherapy drugs kill cancer cells in this manner, defective apoptosis allows survival of these cells, making them resistant. Many chemotherapy drugs also cause DNA damage, which can be repaired by enzymes in the cell that carry out DNA repair. Upregulation of these genes can overcome the DNA damage and prevent the induction of apoptosis. Mutations in genes that produce drug target proteins, such as tubulin, can occur which prevent the drugs from binding to the protein, leading to resistance to these types of drugs.[145] Drugs used in chemotherapy can induce cell stress, which can kill a cancer cell; however, under certain conditions, cells stress can induce changes in gene expression that enables resistance to several types of drugs.[146] In lung cancer, the transcription factor NFκB is thought to play a role in resistance to chemotherapy, via inflammatory pathways.[147][148][149]

Cytotoxics and targeted therapies

side effects are often less severe than that seen of cytotoxic chemotherapeutics, life-threatening effects can occur. Initially, the targeted therapeutics were supposed to be solely selective for one protein. Now it is clear that there is often a range of protein targets that the drug can bind. An example target for targeted therapy is the BCR-ABL1 protein produced from the Philadelphia chromosome, a genetic lesion found commonly in chronic myelogenous leukemia and in some patients with acute lymphoblastic leukemia. This fusion protein has enzyme activity that can be inhibited by imatinib, a small molecule drug.[151][152][153][154]

Mechanism of action

The four phases of the cell cycle. G1 – the initial growth phase. S – the phase in which DNA is synthesised. G2 – the second growth phase in preparation for cell division. M – mitosis; where the cell divides to produce two daughter cells that continue the cell cycle.

genetic mutations in oncogenes (genes that control the growth rate of cells) and tumor suppressor genes (genes that help to prevent cancer), which gives cancer cells their malignant characteristics, such as uncontrolled growth.[158]
: 93–94 

In the broad sense, most chemotherapeutic drugs work by impairing

fast-dividing cells. As these drugs cause damage to cells, they are termed cytotoxic. They prevent mitosis by various mechanisms including damaging DNA and inhibition of the cellular machinery involved in cell division.[39][159] One theory as to why these drugs kill cancer cells is that they induce a programmed form of cell death known as apoptosis.[160]

As chemotherapy affects cell division, tumors with high

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.[4] Heterogeneic tumours may also display varying sensitivities to chemotherapy agents, depending on the subclonal populations within the tumor.[161]

Cells from the immune system also make crucial contributions to the antitumor effects of chemotherapy.[162] For example, the chemotherapeutic drugs oxaliplatin and cyclophosphamide can cause tumor cells to die in a way that is detectable by the immune system (called immunogenic cell death), which mobilizes immune cells with antitumor functions.[163] Chemotherapeutic drugs that cause cancer immunogenic tumor cell death can make unresponsive tumors sensitive to immune checkpoint therapy.[164]

Other uses

Some chemotherapy drugs are used in diseases other than cancer, such as in autoimmune disorders,

myeloma such as lenalidomide have shown promise in treating AL amyloidosis.[172]

Chemotherapy drugs are also used in

hematopoietic stem cell transplant). Conditioning regimens are used to suppress the recipient's immune system in order to allow a transplant to engraft. Cyclophosphamide is a common cytotoxic drug used in this manner and is often used in conjunction with total body irradiation. Chemotherapeutic drugs may be used at high doses to permanently remove the recipient's bone marrow cells (myeloablative conditioning) or at lower doses that will prevent permanent bone marrow loss (non-myeloablative and reduced intensity conditioning).[173]
When used in non-cancer setting, the treatment is still called "chemotherapy", and is often done in the same treatment centers used for people with cancer.

Occupational exposure and safe handling

In the 1970s, antineoplastic (chemotherapy) drugs were identified as hazardous, and the American Society of Health-System Pharmacists (ASHP) has since then introduced the concept of hazardous drugs after publishing a recommendation in 1983 regarding handling hazardous drugs. The adaptation of federal regulations came when the U.S. Occupational Safety and Health Administration (OSHA) first released its guidelines in 1986 and then updated them in 1996, 1999, and, most recently, 2006.[174]

The National Institute for Occupational Safety and Health (NIOSH) has been conducting an assessment in the workplace since then regarding these drugs. Occupational exposure to antineoplastic drugs has been linked to multiple health effects, including infertility and possible carcinogenic effects. A few cases have been reported by the NIOSH alert report, such as one in which a female pharmacist was diagnosed with papillary transitional cell carcinoma. Twelve years before the pharmacist was diagnosed with the condition, she had worked for 20 months in a hospital where she was responsible for preparing multiple antineoplastic drugs.[175] The pharmacist did not have any other risk factor for cancer, and therefore, her cancer was attributed to the exposure to the antineoplastic drugs, although a cause-and-effect relationship has not been established in the literature. Another case happened when a malfunction in biosafety cabinetry is believed to have exposed nursing personnel to antineoplastic drugs. Investigations revealed evidence of genotoxic biomarkers two and nine months after that exposure.

Routes of exposure

Antineoplastic drugs are usually given through

subcutaneous administration. In most cases, before the medication is administered to the patient, it needs to be prepared and handled by several workers. Any worker who is involved in handling, preparing, or administering the drugs, or with cleaning objects that have come into contact with antineoplastic drugs, is potentially exposed to hazardous drugs. Health care workers are exposed to drugs in different circumstances, such as when pharmacists and pharmacy technicians prepare and handle antineoplastic drugs and when nurses and physicians administer the drugs to patients. Additionally, those who are responsible for disposing antineoplastic drugs in health care facilities are also at risk of exposure.[176]

Dermal exposure is thought to be the main route of exposure due to the fact that significant amounts of the antineoplastic agents have been found in the gloves worn by healthcare workers who prepare, handle, and administer the agents. Another noteworthy route of exposure is inhalation of the drugs' vapors. Multiple studies have investigated inhalation as a route of exposure, and although air sampling has not shown any dangerous levels, it is still a potential route of exposure. Ingestion by hand to mouth is a route of exposure that is less likely compared to others because of the enforced hygienic standard in the health institutions. However, it is still a potential route, especially in the workplace, outside of a health institute. One can also be exposed to these hazardous drugs through injection by needle sticks. Research conducted in this area has established that occupational exposure occurs by examining evidence in multiple urine samples from health care workers.[177]

Hazards

Hazardous drugs expose health care workers to serious health risks. Many studies show that antineoplastic drugs could have many side effects on the reproductive system, such as fetal loss, congenital malformation, and infertility. Health care workers who are exposed to antineoplastic drugs on many occasions have adverse reproductive outcomes such as spontaneous abortions, stillbirths, and congenital malformations. Moreover, studies have shown that exposure to these drugs leads to menstrual cycle irregularities. Antineoplastic drugs may also increase the risk of learning disabilities among children of health care workers who are exposed to these hazardous substances.[178]

Moreover, these drugs have carcinogenic effects. In the past five decades, multiple studies have shown the carcinogenic effects of exposure to antineoplastic drugs. Similarly, there have been research studies that linked alkylating agents with humans developing leukemias. Studies have reported elevated risk of breast cancer, nonmelanoma skin cancer, and cancer of the rectum among nurses who are exposed to these drugs. Other investigations revealed that there is a potential genotoxic effect from anti-neoplastic drugs to workers in health care settings.[175]

Safe handling in health care settings

As of 2018, there were no occupational exposure limits set for antineoplastic drugs, i.e., OSHA or the American Conference of Governmental Industrial Hygienists (ACGIH) have not set workplace safety guidelines.[179]

Preparation

NIOSH recommends using a ventilated cabinet that is designed to decrease worker exposure. Additionally, it recommends training of all staff, the use of cabinets, implementing an initial evaluation of the technique of the safety program, and wearing protective gloves and gowns when opening drug packaging, handling vials, or labeling. When wearing personal protective equipment, one should inspect gloves for physical defects before use and always wear double gloves and protective gowns. Health care workers are also required to wash their hands with water and soap before and after working with antineoplastic drugs, change gloves every 30 minutes or whenever punctured, and discard them immediately in a chemotherapy waste container.[180]

The gowns used should be disposable gowns made of polyethylene-coated polypropylene. When wearing gowns, individuals should make sure that the gowns are closed and have long sleeves. When preparation is done, the final product should be completely sealed in a plastic bag.[181]

The health care worker should also wipe all waste containers inside the ventilated cabinet before removing them from the cabinet. Finally, workers should remove all protective wear and put them in a bag for their disposal inside the ventilated cabinet.[176]

Administration

Drugs should only be administered using protective medical devices such as needle lists and closed systems and techniques such as priming of IV tubing by pharmacy personnel inside a ventilated cabinet. Workers should always wear personal protective equipment such as double gloves, goggles, and protective gowns when opening the outer bag and assembling the delivery system to deliver the drug to the patient, and when disposing of all material used in the administration of the drugs.[179]

Hospital workers should never remove tubing from an IV bag that contains an antineoplastic drug, and when disconnecting the tubing in the system, they should make sure the tubing has been thoroughly flushed. After removing the IV bag, the workers should place it together with other disposable items directly in the yellow chemotherapy waste container with the lid closed. Protective equipment should be removed and put into a disposable chemotherapy waste container. After this has been done, one should double bag the chemotherapy waste before or after removing one's inner gloves. Moreover, one must always wash one's hands with soap and water before leaving the drug administration site.[182]

Employee training

All employees whose jobs in health care facilities expose them to hazardous drugs must receive training. Training should include shipping and receiving personnel, housekeepers, pharmacists, assistants, and all individuals involved in the transportation and storage of antineoplastic drugs. These individuals should receive information and training to inform them of the hazards of the drugs present in their areas of work. They should be informed and trained on operations and procedures in their work areas where they can encounter hazards, different methods used to detect the presence of hazardous drugs and how the hazards are released, and the physical and health hazards of the drugs, including their reproductive and carcinogenic hazard potential. Additionally, they should be informed and trained on the measures they should take to avoid and protect themselves from these hazards. This information ought to be provided when health care workers come into contact with the drugs, that is, perform the initial assignment in a work area with hazardous drugs. Moreover, training should also be provided when new hazards emerge as well as when new drugs, procedures, or equipment are introduced.[179]

Housekeeping and waste disposal

When performing cleaning and decontaminating the work area where antineoplastic drugs are used, one should make sure that there is sufficient ventilation to prevent the buildup of airborne drug concentrations. When cleaning the work surface, hospital workers should use deactivation and cleaning agents before and after each activity as well as at the end of their shifts. Cleaning should always be done using double protective gloves and disposable gowns. After employees finish up cleaning, they should dispose of the items used in the activity in a yellow chemotherapy waste container while still wearing protective gloves. After removing the gloves, they should thoroughly wash their hands with soap and water. Anything that comes into contact or has a trace of the antineoplastic drugs, such as needles, empty vials, syringes, gowns, and gloves, should be put in the chemotherapy waste container.[183]

Spill control

A written policy needs to be in place in case of a spill of antineoplastic products. The policy should address the possibility of various sizes of spills as well as the procedure and personal protective equipment required for each size. A trained worker should handle a large spill and always dispose of all cleanup materials in the chemical waste container according to EPA regulations, not in a yellow chemotherapy waste container.[184]

Occupational monitoring

A

urine dipstick or microscopic examination, mainly looking for blood, as several antineoplastic drugs are known to cause bladder damage.[175]

Urinary mutagenicity is a marker of exposure to antineoplastic drugs that was first used by Falck and colleagues in 1979 and uses bacterial mutagenicity assays. Apart from being nonspecific, the test can be influenced by extraneous factors such as dietary intake and smoking and is, therefore, used sparingly. However, the test played a significant role in changing the use of horizontal flow cabinets to vertical flow biological safety cabinets during the preparation of antineoplastic drugs because the former exposed health care workers to high levels of drugs. This changed the handling of drugs and effectively reduced workers' exposure to antineoplastic drugs.[175]

Biomarkers of exposure to antineoplastic drugs commonly include urinary

5-fluorouracil. In addition to this, there are other drugs used to measure the drugs directly in the urine, although they are rarely used. A measurement of these drugs directly in one's urine is a sign of high exposure levels and that an uptake of the drugs is happening either through inhalation or dermally.[175]
 

Available agents

Main article: List of antineoplastic agents

There is an extensive list of antineoplastic agents. Several classification schemes have been used to subdivide the medicines used for cancer into several different types.[185][186]

History

Main article: History of cancer chemotherapy
Sidney Farber did pioneering work in chemotherapy.
Jane C. Wright pioneered the use of the drug methotrexate to treat breast cancer and skin cancer

The first use of

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.[191]

The term chemotherapy

The word chemotherapy without a modifier usually refers to cancer treatment, but its historical meaning was broader. The term was coined in the early 1900s by

usage, the sense "any treatment of disease with drugs" is often expressed with the word pharmacotherapy
. In terms of metaphorical language, 'chemotherapy' can be paralleled with the idea of a 'storm', as both can cause distress but afterwards may have a healing/cleaning effect.

Research

Scanning electron micrograph of mesoporous silica, a type of nanoparticle
used in the delivery of chemotherapeutic drugs
Main article:
Experimental cancer treatments

Targeted delivery vehicles

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 or reduced toxicity or both.[194]

Antibody-drug conjugates

endothelial cells. They bind to the tumor antigen and are internalised, where the linker releases the drug into the cell. These 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.[195] Reduced systemic toxicity means that they can also be used in people who are sicker and that they can carry new chemotherapeutic agents that would have been far too toxic to deliver via traditional systemic approaches.[196]

The first approved drug of this type was

anaplastic large cell lymphoma.[195]

Nanoparticles

receptor ligands) to preferentially target the nanoparticles to the tumor cells. There are many types of nanoparticle delivery systems, such as silica, polymers, liposomes[198] and magnetic particles. Nanoparticles made of magnetic material can also be used to concentrate agents at tumor sites using an externally applied magnetic field.[194] They have emerged as a useful vehicle in magnetic drug delivery for poorly soluble agents such as paclitaxel.[199]

Electrochemotherapy

Main article: 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.[200]

Clinical electrochemotherapy has been successfully used for treatment of cutaneous and subcutaneous tumors irrespective of their histological origin.[201][202] 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.[203][204] 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.[205][206]

Hyperthermia therapy

Hyperthermia therapy is heat treatment for cancer that can be a powerful tool when used in combination with chemotherapy (thermochemotherapy) or radiation for the control of a variety of cancers. The heat can be applied locally to the tumor site, which will dilate blood vessels to the tumor, allowing more chemotherapeutic medication to enter the tumor. Additionally, the tumor cell membrane will become more porous, further allowing more of the chemotherapeutic medicine to enter the tumor cell.

Hyperthermia has also been shown to help prevent or reverse "chemo-resistance." Chemotherapy resistance sometimes develops over time as the tumors adapt and can overcome the toxicity of the chemo medication. "Overcoming chemoresistance has been extensively studied within the past, especially using CDDP-resistant cells. In regard to the potential benefit that drug-resistant cells can be recruited for effective therapy by combining chemotherapy with hyperthermia, it was important to show that chemoresistance against several anticancer drugs (e.g. mitomycin C, anthracyclines, BCNU, melphalan) including CDDP could be reversed at least partially by the addition of heat.[207]

Other animals

Chemotherapy is used in veterinary medicine similar to how it is used in human medicine.[208]

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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Chemotherapy&oldid=1213451337"