Array ( [0] => {{short description|Treatment of cancer using drugs that inhibit cell division or kill cells}} [1] => {{About|the cancer treatment|antimicrobial chemotherapy|Antimicrobial chemotherapy|the journal|Chemotherapy (journal){{!}}''Chemotherapy'' (journal)}} [2] => {{Redirect2|Anticancer drugs|Chemo|the journal|Anti-Cancer Drugs{{!}}''Anti-Cancer Drugs''|other uses of chemo|Chemo (disambiguation)}} [3] => {{Use dmy dates|date=October 2021}} [4] => {{Infobox medical intervention (new) [5] => | name = Chemotherapy [6] => | image = Chemotherapy with acral cooling.jpg [7] => | caption = 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. [8] => | alt = [9] => | pronounce = [10] => | synonyms = chemo, CTX, CTx [11] => | ICD10 = [12] => | ICD9 = [13] => | ICD9unlinked = [14] => | MeshID = [15] => | LOINC = [16] => | other_codes = [17] => | MedlinePlus = [18] => | eMedicine = [19] => }} [20] => [21] => '''Chemotherapy''' (often abbreviated to '''chemo''' and sometimes '''CTX''' or '''CTx''') is a type of [[cancer treatment]] that uses one or more anti-cancer drugs ([[list of chemotherapeutic agents|chemotherapeutic agents]] or [[alkylating agent]]s) as part of a standardized [[chemotherapy regimen]]. Chemotherapy may be given with a [[cure|curative]] intent (which almost always involves combinations of drugs) or it may aim to prolong life or to [[Palliative care|reduce symptoms]] ([[Palliative care|palliative]] chemotherapy). Chemotherapy is one of the major categories of the medical discipline specifically devoted to [[pharmacotherapy]] for [[cancer]], which is called [[oncology#Specialties|''medical oncology'']].{{cite journal | vauthors = Alfarouk KO, Stock CM, Taylor S, Walsh M, Muddathir AK, Verduzco D, Bashir AH, Mohammed OY, Elhassan GO, Harguindey S, Reshkin SJ, Ibrahim ME, Rauch C | display-authors = 6 | title = Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp | journal = Cancer Cell International | volume = 15 | issue = 1 | pages = 71 | date = 15 July 2015 | pmid = 26180516 | pmc = 4502609 | doi = 10.1186/s12935-015-0221-1 | doi-access = free }}{{cite journal | vauthors = Johnstone RW, Ruefli AA, Lowe SW | title = Apoptosis: a link between cancer genetics and chemotherapy | journal = Cell | volume = 108 | issue = 2 | pages = 153–64 | date = January 2002 | pmid = 11832206 | doi = 10.1016/S0092-8674(02)00625-6 | s2cid = 7429296 | doi-access = free }} [22] => [23] => The term ''chemotherapy'' has come to connote non-specific usage of intracellular [[poison]]s to inhibit [[mitosis]] (cell division) or induce [[DNA damage (naturally occurring)|DNA damage]], which is why inhibition of [[DNA repair]] can augment chemotherapy.{{cite journal | vauthors = Rajman L, Chwalek K, Sinclair DA | title = Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence | journal = [[Cell Metabolism]] | volume = 27 | issue=3 | pages = 529–547 |date=2018 | doi = 10.1016/j.cmet.2018.02.011 | pmc =6342515 | pmid = 29514064}} 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 [[estrogen]]s for breast cancer and [[androgen]]s for prostate cancer) are now called [[hormonal therapy (oncology)|hormonal therapies]]. By contrast, other inhibitions of growth-signals like those associated with [[receptor tyrosine kinase]]s are referred to as [[targeted therapy]]. [24] => [25] => 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]]. [26] => [27] => Traditional chemotherapeutic agents are [[cytotoxicity|cytotoxic]] by means of interfering with cell division (mitosis) but cancer cells vary widely in their susceptibility to these agents. To a large extent, chemotherapy can be thought of as a way to damage or stress cells, which may then lead to cell death if [[apoptosis]] is initiated. Many of the side effects of chemotherapy can be traced to damage to normal cells that divide rapidly and are thus sensitive to anti-mitotic drugs: cells in the [[bone marrow]], [[digestive tract]] and [[hair follicle]]s. This results in the most common side-effects of chemotherapy: [[myelosuppression]] (decreased production of blood cells, hence that also [[immunosuppression]]), [[mucositis]] (inflammation of the lining of the digestive tract), and [[alopecia]] (hair loss). Because of the effect on immune cells (especially lymphocytes), chemotherapy drugs often find use in a host of diseases that result from harmful overactivity of the immune system against self (so-called [[autoimmunity]]). These include [[rheumatoid arthritis]], [[systemic lupus erythematosus]], [[multiple sclerosis]], [[vasculitis]] and many others. [28] => [29] => {{TOC limit|3}} [30] => [31] => == Treatment strategies == [32] => {| class="wikitable" style="float: right;" [33] => |+ Common combination [[chemotherapy regimen]]s [34] => ! scope="col" | Cancer type [35] => ! scope="col" | Drugs [36] => ! scope="col" | Acronym [37] => |- [38] => ! scope="row" rowspan="2" |[[Breast cancer]] [39] => | [[Cyclophosphamide]], [[methotrexate]], [[5-fluorouracil]], [[vinorelbine]] || CMF [40] => |- [41] => | [[Doxorubicin]], [[cyclophosphamide]]|| AC [42] => |- [43] => ! scope="row" rowspan="3" |[[Hodgkin's lymphoma]] [44] => | [[Docetaxel]], [[doxorubicin]], [[cyclophosphamide]] [45] => |TAC [46] => |- [47] => |[[Doxorubicin]], [[bleomycin]], [[vinblastine]], [[dacarbazine]] [48] => |ABVD [49] => |- [50] => |[[Chlormethine|Mustine]], [[vincristine]], [[procarbazine]], [[prednisolone]] [51] => |MOPP [52] => |- [53] => ! scope="row" | [[Non-Hodgkin's lymphoma]] [54] => |[[Cyclophosphamide]], [[doxorubicin]], [[vincristine]], [[prednisolone]]|| CHOP, R-CVP [55] => |- [56] => ! scope="row" | [[Germ cell tumor]] [57] => |[[Bleomycin]], [[etoposide]], [[cisplatin]]|| BEP [58] => |- [59] => ! scope="row" rowspan="2" |[[Stomach cancer]]{{cite journal | vauthors = Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC, Ho J, Unverzagt S | title = Chemotherapy for advanced gastric cancer | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD004064 | date = August 2017 | issue = 8 | pmid = 28850174 | pmc = 6483552 | doi = 10.1002/14651858.cd004064.pub4 }} [60] => | [[Epirubicin]], [[cisplatin]], [[Fluorouracil|5-fluorouracil]]|| ECF [61] => |- [62] => |[[Epirubicin]], [[cisplatin]], [[capecitabine]]|| ECX [63] => |- [64] => ! scope="row" | [[Bladder cancer]] [65] => | [[Methotrexate]], [[vincristine]], [[doxorubicin]], [[cisplatin]]|| MVAC [66] => |- [67] => ! scope="row" | [[Lung cancer]] [68] => | [[Cyclophosphamide]], [[doxorubicin]], [[vincristine]], [[vinorelbine]]|| CAV [69] => |- [70] => ! scope="row" | [[Colorectal cancer]] [71] => | [[5-fluorouracil]], [[folinic acid]], [[oxaliplatin]] || [[FOLFOX]] [72] => |- [73] => ! scope="row" | [[Pancreatic cancer]] [74] => | [[Gemcitabine]], [[5-fluorouracil]] || FOLFOX [75] => |- [76] => ![[Bone cancer]] [77] => |[[Doxorubicin]], [[cisplatin]], [[methotrexate]], [[ifosfamide]], [[etoposide]] [78] => |MAP/MAPIE [79] => |- [80] => |} [81] => [82] => There are a number of strategies in the administration of chemotherapeutic drugs used today. Chemotherapy may be given with a [[cure|curative]] intent or it may aim to prolong life or to [[Palliative care|palliate symptoms]]. [83] => * Induction chemotherapy is the first line treatment of cancer with a chemotherapeutic drug. This type of chemotherapy is used for curative intent.{{cite book |author=Rachel Airley|title=Cancer chemotherapy |publisher=Wiley-Blackwell|year=2009 |isbn=978-0-470-09254-5}}{{rp|55–59}} [84] => * Combined modality chemotherapy is the use of drugs with other [[Cancer#Treatments|cancer treatments]], such as [[surgery]], [[radiation therapy]], or [[hyperthermia therapy]]. [85] => * 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.{{rp|55–59}} [86] => * Intensification chemotherapy is identical to consolidation chemotherapy but a different drug than the induction chemotherapy is used.{{rp|55–59}} [87] => * [[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.{{rp|55–59}}{{cite book | last1 = Wood | first1 = Miriam | first2 = David | last2 = Brighton | name-list-style = vanc |title=The Royal Marsden Hospital handbook of cancer chemotherapy: a guide for the multidisciplinary team|publisher=Elsevier Churchill Livingstone|location=St. Louis, Mo |year=2005|isbn=978-0-443-07101-0}}{{rp|17–18}} [88] => * [[Neoadjuvant]] chemotherapy is given prior to a local treatment such as surgery, and is designed to shrink the primary tumor.{{rp|55–59}} It is also given for cancers with a high risk of micrometastatic disease.{{cite book |author=Perry, Michael J. |title=The Chemotherapy source book |publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins|location=Philadelphia |year=2008|isbn=978-0-7817-7328-7}}{{rp|42}} [89] => * [[Adjuvant chemotherapy]] is given after a local treatment (radiotherapy or surgery). It can be used when there is little evidence of cancer present, but there is risk of recurrence.{{rp|55–59}} It is also useful in killing any cancerous cells that have spread to other parts of the body. These [[micrometastases]] can be treated with adjuvant chemotherapy and can reduce relapse rates caused by these disseminated cells.{{cite journal | vauthors = Epstein RJ | title = Maintenance therapy to suppress micrometastasis: the new challenge for adjuvant cancer treatment | journal = Clinical Cancer Research | volume = 11 | issue = 15 | pages = 5337–41 | date = August 2005 | pmid = 16061845 | doi = 10.1158/1078-0432.CCR-05-0437 | doi-access = free }} [90] => * Maintenance chemotherapy is a repeated low-dose treatment to prolong remission.{{rp|55–59}} [91] => * 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.{{rp|55–59}} [92] => [93] => All [[chemotherapy regimen]]s 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.{{cite book |name-list-style=vanc |last1=Skeel |first1=R. T. |year=2003 |title=Handbook of Cancer Chemotherapy (paperback) |publisher=Lippincott Williams & Wilkins |edition=6th |isbn=978-0-7817-3629-9 |url-access=registration |url=https://archive.org/details/handbookofcancer00rola }} Current chemotherapy regimens apply drug treatment in cycles, with the frequency and duration of treatments limited by toxicity.{{cite book | vauthors = Chabner B, Longo DL |year=2005 | edition=4th |title= Cancer Chemotherapy and Biotherapy: Principles and Practice| url = https://archive.org/details/cancerchemothera0000unse_v1m4 | url-access = registration |location= Philadelphia |publisher= Lippincott Willians & Wilkins |isbn= 978-0-7817-5628-0}} [94] => [95] => === Effectiveness === [96] => 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 [[leukemias]],{{cite journal | vauthors = Nastoupil LJ, Rose AC, Flowers CR | title = Diffuse large B-cell lymphoma: current treatment approaches | journal = Oncology | volume = 26 | issue = 5 | pages = 488–95 | date = May 2012 | pmid = 22730604 }}{{cite journal | vauthors = Freedman A | title = Follicular lymphoma: 2012 update on diagnosis and management | journal = American Journal of Hematology | volume = 87 | issue = 10 | pages = 988–95 | date = October 2012 | pmid = 23001911 | doi = 10.1002/ajh.23313 | s2cid = 35447562 | doi-access = free }} to being ineffective, such as in some [[brain tumors]],{{cite journal | vauthors = Rampling R, James A, Papanastassiou V | title = The present and future management of malignant brain tumours: surgery, radiotherapy, chemotherapy | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 75 | issue = Suppl 2 | pages = ii24-30 | date = June 2004 | pmid = 15146036 | pmc = 1765659 | doi = 10.1136/jnnp.2004.040535 }} to being needless in others, like most [[non-melanoma skin cancer]]s.{{cite journal | vauthors = Madan V, Lear JT, Szeimies RM | title = Non-melanoma skin cancer | journal = Lancet | volume = 375 | issue = 9715 | pages = 673–85 | date = February 2010 | pmid = 20171403 | doi = 10.1016/S0140-6736(09)61196-X | pmc = 3339125 }} [97] => [98] => === Dosage === [99] => [[File:Chemotherapy dose response graph.png|thumb|left|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.]] [100] => 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 ([[adverse effect|side-effects]]) will be intolerable to the person receiving it. 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.{{cite journal | vauthors = Du Bois D, Du Bois EF | title = A formula to estimate the approximate surface area if height and weight be known. 1916 | journal = Nutrition | volume = 5 | issue = 5 | pages = 303–11; discussion 312–3 | year = 1989 | pmid = 2520314 }} The study only included nine human subjects.{{cite journal | vauthors = Felici A, Verweij J, Sparreboom A | title = Dosing strategies for anticancer drugs: the good, the bad and body-surface area | journal = European Journal of Cancer | volume = 38 | issue = 13 | pages = 1677–84 | date = September 2002 | pmid = 12175683 | doi = 10.1016/s0959-8049(02)00151-x }} 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.{{cite journal | vauthors = Kaestner SA, Sewell GJ | title = Chemotherapy dosing part I: scientific basis for current practice and use of body surface area | journal = Clinical Oncology | volume = 19 | issue = 1 | pages = 23–37 | date = February 2007 | pmid = 17305252 | doi = 10.1016/j.clon.2006.10.010 | hdl = 10026.1/3714 | hdl-access = free }}{{cite journal | vauthors = Pinkel D | title = The use of body surface area as a criterion of drug dosage in cancer chemotherapy | journal = Cancer Research | volume = 18 | issue = 7 | pages = 853–6 | date = August 1958 | pmid = 13573353 }} [101] => [102] => 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.{{cite journal | vauthors = Gurney H | title = How to calculate the dose of chemotherapy | journal = British Journal of Cancer | volume = 86 | issue = 8 | pages = 1297–302 | date = April 2002 | pmid = 11953888 | pmc = 2375356 | doi = 10.1038/sj.bjc.6600139 }}{{cite journal | vauthors = Beumer JH, Chu E, Salamone SJ | title = Body-surface area-based chemotherapy dosing: appropriate in the 21st century? | journal = Journal of Clinical Oncology | volume = 30 | issue = 31 | pages = 3896–7 | date = November 2012 | pmid = 22965963 | doi = 10.1200/JCO.2012.44.2863 | doi-access = free }} 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.{{cite journal | vauthors = Baker SD, Verweij J, Rowinsky EK, Donehower RC, Schellens JH, Grochow LB, Sparreboom A | title = Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001 | journal = Journal of the National Cancer Institute | volume = 94 | issue = 24 | pages = 1883–8 | date = December 2002 | pmid = 12488482 | doi = 10.1093/jnci/94.24.1883 | doi-access = free }} 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. 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. [103] => [104] => [[File:Improvement in Response Rate.jpg|thumb|180px|right|5-FU dose management results in significantly better response and survival rates versus BSA dosing.]] [105] => 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.{{cite journal | vauthors = Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, Dorval E, Piot G, Morel A, Boisdron-Celle M | s2cid = 9557055 | title = Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer | journal = Journal of Clinical Oncology | volume = 26 | issue = 13 | pages = 2099–105 | date = May 2008 | pmid = 18445839 | doi = 10.1200/jco.2007.13.3934 | doi-access = free }}{{cite journal | vauthors = Saam J, Critchfield GC, Hamilton SA, Roa BB, Wenstrup RJ, Kaldate RR | title = Body surface area-based dosing of 5-fluoruracil results in extensive interindividual variability in 5-fluorouracil exposure in colorectal cancer patients on FOLFOX regimens | journal = Clinical Colorectal Cancer | volume = 10 | issue = 3 | pages = 203–6 | date = September 2011 | pmid = 21855044 | doi = 10.1016/j.clcc.2011.03.015 }}{{cite journal | vauthors = Capitain O, Asevoaia A, Boisdron-Celle M, Poirier AL, Morel A, Gamelin E | title = Individual fluorouracil dose adjustment in FOLFOX based on pharmacokinetic follow-up compared with conventional body-area-surface dosing: a phase II, proof-of-concept study | journal = Clinical Colorectal Cancer | volume = 11 | issue = 4 | pages = 263–7 | date = December 2012 | pmid = 22683364 | doi = 10.1016/j.clcc.2012.05.004 }}{{cite journal | vauthors = Kaldate RR, Haregewoin A, Grier CE, Hamilton SA, McLeod HL | title = Modeling the 5-fluorouracil area under the curve versus dose relationship to develop a pharmacokinetic dosing algorithm for colorectal cancer patients receiving FOLFOX6 | journal = The Oncologist | volume = 17 | issue = 3 | pages = 296–302 | year = 2012 | pmid = 22382460 | pmc = 3316912 | doi = 10.1634/theoncologist.2011-0357 }} 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. [106] => [107] => There has been controversy over the use of BSA to calculate chemotherapy doses for people who are [[obese]].{{cite journal | vauthors = Hunter RJ, Navo MA, Thaker PH, Bodurka DC, Wolf JK, Smith JA | title = Dosing chemotherapy in obese patients: actual versus assigned body surface area (BSA) | journal = Cancer Treatment Reviews | volume = 35 | issue = 1 | pages = 69–78 | date = February 2009 | pmid = 18922643 | doi = 10.1016/j.ctrv.2008.07.005 }} Because of their higher BSA, clinicians often arbitrarily reduce the dose prescribed by the BSA formula for fear of [[overdosing]]. In many cases, this can result in sub-optimal treatment. [108] => [109] => 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. 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. [110] => [111] => [[File:Toxicity.png|thumb|180px|left|alt=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.]] [112] => {{multiple image [113] => | align = right [114] => | direction = vertical [115] => | width = 100 [116] => | image1 = Response 1.jpg [117] => | image2 = Survival 1.png [118] => | caption2 = 5-FU dose management in the FOLFOX regimen increases treatment response significantly and improves survival by six months. [119] => }} [120] => 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. 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. Because of the reduced toxicity, dose-adjusted patients were able to be treated for longer periods of time. 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. Completing the course of treatment is an important factor in achieving better treatment outcomes. [121] => [122] => Similar results were found in a study involving people with colorectal cancer who have been treated with the popular [[FOLFOX]] regimen. 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%. [123] => [124] => The FOLFOX study also demonstrated an improvement in treatment outcomes. 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. [125] => [126] => 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.{{Cite journal |last1=Canal |first1=P. |last2=Chatelut |first2=E. |last3=Guichard |first3=S. |date=1998 |title=Practical treatment guide for dose individualisation in cancer chemotherapy |url=https://pubmed.ncbi.nlm.nih.gov/9878990/ |journal=Drugs |volume=56 |issue=6 |pages=1019–1038 |doi=10.2165/00003495-199856060-00006 |issn=0012-6667 |pmid=9878990|s2cid=36211632 }} [127] => [128] => Oncologists are already individualizing dosing of some cancer drugs based on exposure. [[Carboplatin]]{{cite book |editor3=Fergus Macbeth |editor1=Hanna, Louise |editor2=Crosby, Tom |title=Practical clinical oncology |publisher=Cambridge University Press |location=Cambridge, UK |year=2008|isbn=978-0-521-61816-8}}{{rp|4}} and [[busulfan]]{{cite journal | vauthors = Buffery PJ, Allen KM, Chin PK, Moore GA, Barclay ML, Begg EJ | title = Thirteen years' experience of pharmacokinetic monitoring and dosing of busulfan: can the strategy be improved? | journal = Therapeutic Drug Monitoring | volume = 36 | issue = 1 | pages = 86–92 | date = February 2014 | pmid = 24299921 | doi = 10.1097/FTD.0b013e31829dc940 | s2cid = 28646787 }}{{cite journal| vauthors = Bartelink IH, Bredius RG, Belitser SV, Suttorp MM, Bierings M, Knibbe CA, Egeler M, Lankester AC, Egberts AC, Zwaveling J, Boelens JJ | display-authors = 6 |title=Association Between Busulfan Exposure and Outcome in Children Receiving Intravenous Busulfan Before Hematopoietic Stem Cell Transplantation|journal=Ther Drug Monit|volume=36|issue=1|pages=93–99| pmid = 24061446 | year = 2014 | doi = 10.1097/FTD.0b013e3182a04fc7 | s2cid = 21072472 }} 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]],{{cite web|url=http://ark-tdm.com/DB_methotrexate.html|title=ARK Methotrexate Assay|publisher=Ark Diagnostics|access-date=28 April 2014|archive-url=https://web.archive.org/web/20140428150337/http://ark-tdm.com/DB_methotrexate.html|archive-date=28 April 2014|url-status=dead}} 5-FU, [[paclitaxel]], and [[docetaxel]].{{cite web|url=http://mycaretests.com|title=Customizing Chemotherapy for Better Cancer Care|publisher=My Care Diagnostics|access-date=25 November 2018|archive-url=https://web.archive.org/web/20140428135326/http://www.mycaretests.com/|archive-date=28 April 2014|url-status=dead}}{{cite web|url=http://bettercancercare.com|title=A Brief History of BSA Dosing|publisher=My Care Diagnostics}} [129] => [130] => The serum albumin level immediately prior to chemotherapy administration is an independent prognostic predictor of survival in various cancer types.{{cite journal | vauthors = Asher V, Lee J, Bali A | title = Preoperative serum albumin is an independent prognostic predictor of survival in ovarian cancer | journal = Medical Oncology | volume = 29 | issue = 3 | pages = 2005–9 | date = September 2012 | pmid = 21735143 | doi = 10.1007/s12032-011-0019-5 | s2cid = 19558612 }} [131] => [132] => === Types === [133] => [[File:Cross-linked DNA by nitrogen mustard.png|thumb|left| 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.]] [134] => [135] => ==== Alkylating agents ==== [136] => {{Main|Alkylating antineoplastic agent}} [137] => 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. They are so named because of their ability to [[alkylation|alkylate]] many molecules, including [[protein]]s, [[RNA]] and [[DNA]]. This ability to bind [[covalent bond|covalently]] to DNA via their [[alkyl group]] is the primary cause for their anti-cancer effects.{{cite journal|last1=Lind M.J.|title=Principles of cytotoxic chemotherapy|journal=Medicine|year=2008|volume=36|issue=1|pages=19–23|doi=10.1016/j.mpmed.2007.10.003|first1=M.J.}} 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]].{{cite book | vauthors = Siddik ZH |year=2005|publisher=John Wiley & Sons, Ltd|doi=10.1002/0470025077.chap84b|title=The Cancer Handbook|isbn=978-0470025062|chapter=Mechanisms of Action of Cancer Chemotherapeutic Agents: DNA-Interactive Alkylating Agents and Antitumour Platinum-Based Drugs}} 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. [138] => [139] => The subtypes of alkylating agents are the [[nitrogen mustard]]s, [[nitrosoureas]], [[tetrazine]]s, [[aziridines]],{{cite journal | vauthors = Giorgi-Renault S, Renault J, Baron M, Gebel-Servolles P, Delic J, Cros S, Paoletti C | year = 1988 | title = Heterocyclic quinones XIII. Dimerization in the series of 5,8-quinazolinediones: Synthesis and anti tumor effects of bis(4-amino-5,8-quinazolinediones) | journal = Chem. Pharm. Bull. | volume = 36 | issue = 10| pages = 3933–3947 | doi=10.1248/cpb.36.3933| pmid = 3245973 | doi-access = free }} [[cisplatin]]s and derivatives, and non-classical alkylating agents. Nitrogen mustards include [[mechlorethamine]], [[cyclophosphamide]], [[melphalan]], [[chlorambucil]], [[ifosfamide]] and [[busulfan]]. Nitrosoureas include [[N-Nitroso-N-methylurea]] (MNU), [[carmustine]] (BCNU), [[lomustine]] (CCNU) and [[semustine]] (MeCCNU), [[fotemustine]] and [[streptozotocin]]. Tetrazines include [[dacarbazine]], [[mitozolomide]] and [[temozolomide]]. Aziridines include [[thiotepa]], [[mytomycin]] and diaziquone (AZQ). Cisplatin and derivatives include [[cisplatin]], [[carboplatin]] and [[oxaliplatin]].{{cite journal | vauthors = Damia G, D'Incalci M | title = Mechanisms of resistance to alkylating agents | journal = Cytotechnology | volume = 27 | issue = 1–3 | pages = 165–73 | date = September 1998 | pmid = 19002790 | pmc = 3449574 | doi = 10.1023/A:1008060720608 }} They impair cell function by forming [[covalent bond]]s with the [[amino group|amino]], [[carboxyl group|carboxyl]], [[sulfhydryl group|sulfhydryl]], and [[phosphate group]]s in biologically important molecules.{{cite book | vauthors = Takimoto CH, Calvo E | chapter-url = http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628 | chapter = Principles of Oncologic Pharmacotherapy | veditors = Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ | title = Cancer Management: A Multidisciplinary Approach | edition = 11th | date = 2008 | access-date = 18 June 2009 | archive-date = 15 May 2009 | archive-url = https://web.archive.org/web/20090515221337/http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628 | url-status = dead }} Non-classical alkylating agents include [[procarbazine]] and hexamethylmelamine. [140] => [141] => ==== Antimetabolites ==== [142] => [[File:Deoxcytidine, Gemcitidine and Decitabine.png|thumb|[[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]].]] [143] => {{Main|Antimetabolite}} [144] => [[Anti-metabolite]]s are a group of molecules that impede DNA and RNA synthesis. Many of them have a similar structure to the building blocks of DNA and RNA. The building blocks are [[nucleotide]]s; a molecule comprising a [[nucleobase]], a sugar and a [[phosphate group]]. The nucleobases are divided into [[purine]]s ([[guanine]] and [[adenine]]) and [[pyrimidine]]s ([[cytosine]], [[thymine]] and [[uracil]]). Anti-metabolites resemble either nucleobases or nucleosides (a nucleotide without the phosphate group), but have altered [[chemical group]]s.{{cite journal | vauthors = Parker WB | title = Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer | journal = Chemical Reviews | volume = 109 | issue = 7 | pages = 2880–93 | date = July 2009 | pmid = 19476376 | pmc = 2827868 | doi = 10.1021/cr900028p }} These drugs exert their effect by either blocking the enzymes required for DNA synthesis or becoming incorporated into DNA or RNA. By inhibiting the enzymes involved in DNA synthesis, they prevent mitosis because the DNA cannot duplicate itself. Also, after misincorporation of the molecules into DNA, [[DNA damage]] can occur and programmed cell death ([[apoptosis]]) is induced. Unlike alkylating agents, anti-metabolites are cell cycle dependent. This means that they only work during a specific part of the cell cycle, in this case [[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 [[antifolate|anti-folates]], fluoropyrimidines, deoxynucleoside analogues and [[thiopurine]]s. [145] => [146] => The anti-folates include [[methotrexate]] and [[pemetrexed]]. Methotrexate inhibits [[dihydrofolate reductase]] (DHFR), an enzyme that regenerates [[tetrahydrofolate]] from [[dihydrofolate]]. When the enzyme is inhibited by methotrexate, the cellular levels of folate coenzymes diminish. These are required for [[thymidylate]] and purine production, which are both essential for DNA synthesis and cell division.{{rp|55–59}}{{rp|11}} Pemetrexed is another anti-metabolite that affects purine and pyrimidine production, and therefore also inhibits DNA synthesis. It primarily inhibits the enzyme [[thymidylate synthase]], but also has effects on DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase and [[glycinamide ribonucleotide formyltransferase]].{{cite journal | vauthors = Adjei AA | title = Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent | journal = Clinical Cancer Research | volume = 10 | issue = 12 Pt 2 | pages = 4276s–4280s | date = June 2004 | pmid = 15217974 | doi = 10.1158/1078-0432.CCR-040010 | s2cid = 31467685 }} The fluoropyrimidines include [[fluorouracil]] and [[capecitabine]]. Fluorouracil is a nucleobase analogue that is metabolised in cells to form at least two active products; 5-fluourouridine monophosphate (FUMP) and 5-fluoro-2'-deoxyuridine 5'-phosphate (fdUMP). FUMP becomes incorporated into RNA and fdUMP inhibits the enzyme thymidylate synthase; both of which lead to cell death.{{rp|11}} Capecitabine is a [[prodrug]] of 5-fluorouracil that is broken down in cells to produce the active drug.{{cite journal | vauthors = Wagstaff AJ, Ibbotson T, Goa KL | title = Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer | journal = Drugs | volume = 63 | issue = 2 | pages = 217–36 | year = 2003 | pmid = 12515569 | doi = 10.2165/00003495-200363020-00009 }} The deoxynucleoside analogues include [[cytarabine]], [[gemcitabine]], [[decitabine]], [[azacitidine]], [[fludarabine]], [[nelarabine]], [[cladribine]], [[clofarabine]], and [[pentostatin]]. The thiopurines include [[thioguanine]] and [[mercaptopurine]]. [147] => [148] => ==== Anti-microtubule agents ==== [149] => [[File:Microtubules and alkaloids.png|thumb|left|''Vinca'' alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. Both mechanisms cause defective mitosis.]] [150] => [[Anti-microtubule agent]]s are [[plant]]-derived chemicals that block cell division by preventing [[microtubule]] function. Microtubules are an important cellular structure composed of two proteins, [[α-tubulin]] and [[β-tubulin]]. They are hollow, rod-shaped structures that are required for cell division, among other cellular functions.{{cite journal | vauthors = Rowinsky EK, Donehower RC | title = The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics | journal = Pharmacology & Therapeutics | volume = 52 | issue = 1 | pages = 35–84 | date = October 1991 | pmid = 1687171 | doi = 10.1016/0163-7258(91)90086-2 }} Microtubules are dynamic structures, which means that they are permanently in a state of assembly and disassembly. [[Vinca alkaloid|''Vinca'' alkaloids]] and [[taxane]]s 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.{{Cite journal |last1=Vitale |first1=Ilio |last2=Galluzzi |first2=Lorenzo |last3=Castedo |first3=Maria |last4=Kroemer |first4=Guido |date=June 2011 |title=Mitotic catastrophe: a mechanism for avoiding genomic instability |url=https://www.nature.com/articles/nrm3115 |journal=Nature Reviews Molecular Cell Biology |language=en |volume=12 |issue=6 |pages=385–392 |doi=10.1038/nrm3115 |pmid=21527953 |s2cid=22483746 |issn=1471-0072}} Following this, cell cycle arrest occurs, which induces programmed cell death ([[apoptosis]]). These drugs can also affect [[Angiogenesis|blood vessel growth]], an essential process that tumours utilise in order to grow and metastasise.{{cite journal | vauthors = Yue QX, Liu X, Guo DA | title = Microtubule-binding natural products for cancer therapy | journal = Planta Medica | volume = 76 | issue = 11 | pages = 1037–43 | date = August 2010 | pmid = 20577942 | doi = 10.1055/s-0030-1250073 | doi-access = free }} [151] => [152] => ''Vinca'' alkaloids are derived from the [[Madagascar periwinkle]], ''Catharanthus roseus'',{{cite book|vauthors = Hirata K, Miyamoto K, Miura Y|chapter = ''Catharanthus roseus'' L. (Periwinkle): Production of Vindoline and Catharanthine in Multiple Shoot Cultures|title = Biotechnology in Agriculture and Forestry 26|series = Medicinal and Aromatic Plants|volume = VI|veditors = Bajaj YP|publisher = [[Springer-Verlag]]|year = 1994|pages = [https://archive.org/details/medicinalaromati0006unse/page/46 46–55]|chapter-url = https://books.google.com/books?id=e64hCDBddowC&pg=PA47|isbn = 9783540563914|url = https://archive.org/details/medicinalaromati0006unse/page/46}}{{cite journal | vauthors = van Der Heijden R, Jacobs DI, Snoeijer W, Hallard D, Verpoorte R | title = The Catharanthus alkaloids: pharmacognosy and biotechnology | journal = Current Medicinal Chemistry | volume = 11 | issue = 5 | pages = 607–28 | date = March 2004 | pmid = 15032608 | doi = 10.2174/0929867043455846 }} formerly known as ''Vinca rosea''. They bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules. The original ''vinca'' alkaloids are [[natural product]]s that include [[vincristine]] and [[vinblastine]].{{cite book|title = Metal Catalyzed Reductive C—C Bond Formation: A Departure from Preformed Organometallic Reagents|volume = 279|series = Topics in Current Chemistry|pages = 25–52|year = 2007|chapter = Reductive C—C bond formation after epoxide opening via electron transfer| vauthors = Gansäuer A, Justicia J, Fan CA, Worgull D, Piestert F |doi = 10.1007/128_2007_130|chapter-url = https://books.google.com/books?id=A5xcVmT9iIQC&pg=PA25|editor-link1=Michael J. Krische|editor-first = Michael J.|editor-last = Krische|publisher = [[Springer Science & Business Media]]|isbn = 9783540728795}}{{cite book|chapter = Africa's gift to the world|pages = 46–51|chapter-url = https://books.google.com/books?id=aXGmCwAAQBAJ&pg=PA46|title = Botanical Miracles: Chemistry of Plants That Changed the World|first1 = Raymond|last1 = Cooper|first2 = Jeffrey John|last2 = Deakin | name-list-style = vanc |publisher = [[CRC Press]]|year = 2016|isbn = 9781498704304}}{{cite journal | vauthors = Keglevich P, Hazai L, Kalaus G, Szántay C | title = Modifications on the basic skeletons of vinblastine and vincristine | journal = Molecules | volume = 17 | issue = 5 | pages = 5893–914 | date = May 2012 | pmid = 22609781 | pmc = 6268133 | doi = 10.3390/molecules17055893 | doi-access = free }}{{cite book|last = Raviña|first = Enrique|title = The evolution of drug discovery: From traditional medicines to modern drugs|year = 2011|publisher = [[John Wiley & Sons]]|isbn = 9783527326693|pages = 157–159|chapter = Vinca alkaloids|chapter-url = https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA157}} Following the success of these drugs, semi-synthetic ''vinca'' alkaloids were produced: [[vinorelbine]] (used in the treatment of [[non-small-cell lung cancer]]{{cite journal | vauthors = Faller BA, Pandit TN | title = Safety and efficacy of vinorelbine in the treatment of non-small cell lung cancer | journal = Clinical Medicine Insights: Oncology | volume = 5 | pages = 131–44 | year = 2011 | pmid = 21695100 | pmc = 3117629 | doi = 10.4137/CMO.S5074 }}{{cite journal | vauthors = Ngo QA, Roussi F, Cormier A, Thoret S, Knossow M, Guénard D, Guéritte F | title = Synthesis and biological evaluation of vinca alkaloids and phomopsin hybrids | journal = Journal of Medicinal Chemistry | volume = 52 | issue = 1 | pages = 134–42 | date = January 2009 | pmid = 19072542 | doi = 10.1021/jm801064y }}), [[vindesine]], and [[vinflunine]]. These drugs are [[cell cycle]]-specific. They bind to the tubulin molecules in [[S-phase]] and prevent proper microtubule formation required for [[M-phase]]. [153] => [154] => 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]]''.{{Cite journal |last1=Croteau |first1=Rodney |last2=Ketchum |first2=Raymond E. B. |last3=Long |first3=Robert M. |last4=Kaspera |first4=Rüdiger |last5=Wildung |first5=Mark R. |date=2006 |title=Taxol biosynthesis and molecular genetics |journal=Phytochemistry Reviews |volume=5 |issue=1 |pages=75–97 |doi=10.1007/s11101-005-3748-2 |issn=1568-7767 |pmc=2901146 |pmid=20622989|bibcode=2006PChRv...5...75C }} [155] => [156] => [[Podophyllotoxin]] is an antineoplastic [[lignan]] obtained primarily from the [[Podophyllum|American mayapple]] (''Podophyllum peltatum'') and [[Sinopodophyllum|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]].{{cite journal | vauthors = Damayanthi Y, Lown JW | title = Podophyllotoxins: current status and recent developments | journal = Current Medicinal Chemistry | volume = 5 | issue = 3 | pages = 205–52 | date = June 1998 | doi = 10.2174/0929867305666220314204426 | pmid = 9562603 | s2cid = 247493530 }}{{cite journal |vauthors=Liu YQ, Yang L, Tian X |title=Podophyllotoxin: current perspectives |journal=Current Bioactive Compounds |year=2007 |volume=3 |issue=1 |pages=37–66 |doi=10.1016/j.jallcom.2006.06.070 }} [157] => [158] => ==== Topoisomerase inhibitors ==== [159] => [[File:Topoisomerase Inhibitor.JPG|thumb|Topoisomerase I and II Inhibitors]] [160] => {{Main|Topoisomerase inhibitor}} [161] => Topoisomerase inhibitors are drugs that affect the activity of two enzymes: [[topoisomerase I]] and [[topoisomerase II]]. When the DNA double-strand helix is unwound, during DNA replication or [[transcription (biology)|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 [[DNA replication|replication]] or transcription. Inhibition of topoisomerase I or II interferes with both of these processes.{{cite book |vauthors=Lodish H, Berk A, Zipursky SL |title=Molecular Cell Biology. 4th edition. The Role of Topoisomerases in DNA Replication|year=2000|publisher=New York: W. H. Freeman|url=https://www.ncbi.nlm.nih.gov/books/NBK21703/|display-authors=etal }}{{cite journal | vauthors = Goodsell DS | title = The molecular perspective: DNA topoisomerases | journal = Stem Cells | volume = 20 | issue = 5 | pages = 470–1 | year = 2002 | pmid = 12351817 | doi = 10.1634/stemcells.20-5-470 | s2cid = 9257158 | doi-access = free }} [162] => [163] => Two topoisomerase I inhibitors, [[irinotecan]] and [[topotecan]], are semi-synthetically derived from [[camptothecin]], which is obtained from the Chinese ornamental tree ''[[Camptotheca acuminata]]''. 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.{{cite journal | vauthors = Nitiss JL | title = Targeting DNA topoisomerase II in cancer chemotherapy | journal = Nature Reviews. Cancer | volume = 9 | issue = 5 | pages = 338–50 | date = May 2009 | pmid = 19377506 | pmc = 2748742 | doi = 10.1038/nrc2607 }} [164] => [165] => ==== Cytotoxic antibiotics ==== [166] => The cytotoxic [[antibiotic]]s are a varied group of drugs that have various mechanisms of action. The common theme that they share in their chemotherapy indication is that they interrupt [[cell division]]. The most important subgroup is the [[anthracycline]]s and the [[bleomycin]]s; other prominent examples include [[mitomycin C]] and [[actinomycin]].{{cite book |url=https://books.google.com/books?id=iwwo5gx8aX8C&pg=PA155 |title=Encyclopedia of Molecular Pharmacology | vauthors = Offermanns S, Rosenthal W |date=2008-08-14 |publisher=Springer Science & Business Media |isbn=9783540389163 | page = 155 }} [167] => [168] => Among the anthracyclines, [[doxorubicin]] and [[daunorubicin]] were the first, and were obtained from the [[bacterium]] ''[[Streptomyces peucetius]]''.{{Cite book |url=https://books.google.com/books?id=iwwo5gx8aX8C&pg=PA91 |title=Encyclopedia of Molecular Pharmacology | vauthors = Offermanns S, Rosenthal W |date=2008-08-14 |publisher=Springer Science & Business Media |isbn=9783540389163 |pages=91ff }} Derivatives of these compounds include [[epirubicin]] and [[idarubicin]]. Other clinically used drugs in the anthracycline group are [[pirarubicin]], [[aclarubicin]], and [[mitoxantrone]].{{cite journal | pmid = 3048848| year = 1988| vauthors = Koeller J, Eble M | title = Mitoxantrone: A novel anthracycline derivative| journal = Clinical Pharmacy| volume = 7| issue = 8| pages = 574–81 }} The mechanisms of anthracyclines include [[DNA intercalation]] (molecules insert between the two strands of DNA), generation of highly reactive [[free radicals]] that damage intercellular molecules and topoisomerase inhibition.{{cite journal | vauthors = Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L | s2cid = 13138853 | title = Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity | journal = Pharmacological Reviews | volume = 56 | issue = 2 | pages = 185–229 | date = June 2004 | pmid = 15169927 | doi = 10.1124/pr.56.2.6 }} [169] => [170] => Actinomycin is a complex molecule that intercalates DNA and prevents [[RNA synthesis]].{{cite journal | vauthors = Sobell HM | title = Actinomycin and DNA transcription | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 16 | pages = 5328–31 | date = August 1985 | pmid = 2410919 | pmc = 390561 | doi = 10.1073/pnas.82.16.5328 | bibcode = 1985PNAS...82.5328S | doi-access = free }} [171] => [172] => Bleomycin, a [[glycopeptide]] isolated from ''[[Streptomyces verticillus]]'', also intercalates DNA, but produces [[free radical]]s that damage DNA. This occurs when bleomycin binds to a [[metal ion]], becomes [[reduction (chemistry)|chemically reduced]] and reacts with [[oxygen]].{{cite journal | vauthors = Dorr RT | title = Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics | journal = Seminars in Oncology | volume = 19 | issue = 2 Suppl 5 | pages = 3–8 | date = April 1992 | pmid = 1384141 }}{{rp|87}} [173] => [174] => Mitomycin is a cytotoxic antibiotic with the ability to alkylate DNA.{{cite journal | vauthors = Verweij J, Pinedo HM | title = Mitomycin C: mechanism of action, usefulness and limitations | journal = Anti-Cancer Drugs | volume = 1 | issue = 1 | pages = 5–13 | date = October 1990 | pmid = 2131038 | doi = 10.1097/00001813-199010000-00002 }} [175] => [176] => === Delivery === [177] => [[File:Pediatric patients receiving chemotherapy.jpg|thumb|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.]] [178] => Most chemotherapy is [[Route of administration|delivered]] [[intravenous therapy|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.{{cite journal | vauthors = Greer JA, Amoyal N, Nisotel L, Fishbein JN, MacDonald J, Stagl J, Lennes I, Temel JS, Safren SA, Pirl WF | display-authors = 6 | title = A Systematic Review of Adherence to Oral Antineoplastic Therapies | journal = The Oncologist | volume = 21 | issue = 3 | pages = 354–76 | date = March 2016 | pmid = 26921292 | pmc = 4786357 | doi = 10.1634/theoncologist.2015-0405 }} [179] => [180] => There are many intravenous methods of drug delivery, known as vascular access devices. These include the [[Winged infusion set|winged infusion device]], [[peripheral venous catheter]], midline catheter, [[peripherally inserted central catheter]] (PICC), [[central venous catheter]] and [[implantable port]]. The devices have different applications regarding duration of chemotherapy treatment, method of delivery and types of chemotherapeutic agent.{{rp|94–95}} [181] => [182] => 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 [[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.{{rp|113–118}} Commonly used systems are the [[Hickman line]], the [[Port-a-Cath]], and the [[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.{{Cite journal |last1=O'Grady |first1=Naomi P. |last2=Alexander |first2=Mary |last3=Burns |first3=Lillian A. |last4=Dellinger |first4=E. Patchen |last5=Garland |first5=Jeffrey |last6=Heard |first6=Stephen O. |last7=Lipsett |first7=Pamela A. |last8=Masur |first8=Henry |last9=Mermel |first9=Leonard A. |last10=Pearson |first10=Michele L. |last11=Raad |first11=Issam I. |last12=Randolph |first12=Adrienne G. |last13=Rupp |first13=Mark E. |last14=Saint |first14=Sanjay |date=2011-05-01 |title=Guidelines for the Prevention of Intravascular Catheter-related Infections |journal=Clinical Infectious Diseases|volume=52 |issue=9 |pages=e162–e193 |doi=10.1093/cid/cir257 |issn=1058-4838 |pmc=3106269 |pmid=21460264}} [183] => [184] => [[Isolated limb perfusion]] (often used in [[melanoma]]),{{cite journal | vauthors = Moreno-Ramirez D, de la Cruz-Merino L, Ferrandiz L, Villegas-Portero R, Nieto-Garcia A | title = Isolated limb perfusion for malignant melanoma: systematic review on effectiveness and safety | journal = The Oncologist | volume = 15 | issue = 4 | pages = 416–27 | year = 2010 | pmid = 20348274 | pmc = 3227960 | doi = 10.1634/theoncologist.2009-0325 }} or isolated infusion of chemotherapy into the liver{{cite journal | vauthors = Verhoef C, de Wilt JH, ten Hagen TL, Eggermont AM | title = Isolated hepatic perfusion for the treatment of liver tumors: sunset or sunrise? | journal = Surgical Oncology Clinics of North America | volume = 17 | issue = 4 | pages = 877–94, xi | date = October 2008 | pmid = 18722924 | doi = 10.1016/j.soc.2008.04.007 }} 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.{{cite journal | vauthors = Hendriks JM, Van Schil PE | title = Isolated lung perfusion for the treatment of pulmonary metastases | journal = Surgical Oncology | volume = 7 | issue = 1–2 | pages = 59–63 | year = 1998 | pmid = 10421507 | doi = 10.1016/S0960-7404(98)00028-0 }} These approaches can help control solitary or limited metastases, but they are by definition not systemic, and, therefore, do not treat distributed metastases or [[micrometastasis|micrometastases]].{{citation needed|date=December 2021}} [185] => [186] => Topical chemotherapies, such as [[5-fluorouracil]], are used to treat some cases of [[non-melanoma skin cancer]].{{cite journal | vauthors = Chitwood K, Etzkorn J, Cohen G | title = Topical and intralesional treatment of nonmelanoma skin cancer: efficacy and cost comparisons | journal = Dermatologic Surgery | volume = 39 | issue = 9 | pages = 1306–16 | date = September 2013 | pmid = 23915332 | doi = 10.1111/dsu.12300 | s2cid = 597295 }} [187] => [188] => If the cancer has [[central nervous system]] involvement, or with meningeal disease, [[intrathecal]] chemotherapy may be administered. [189] => [190] => == Adverse effects == [191] => 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.{{rp|265}} [192] => [193] => === Immunosuppression and myelosuppression === [194] => 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 cell]]s, [[red blood cell]]s, and [[platelet]]s. [195] => [[Anemia]] and [[thrombocytopenia]] may require [[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]], [[efbemalenograstim alfa]]).{{Cite journal |last1=Estcourt |first1=Lise J |last2=Stanworth |first2=Simon J |last3=Hopewell |first3=Sally |last4=Doree |first4=Carolyn |last5=Trivella |first5=Marialena |last6=Massey |first6=Edwin |date=2016-04-29 |title=Granulocyte transfusions for treating infections in people with neutropenia or neutrophil dysfunction |journal=The Cochrane Database of Systematic Reviews |volume=2016 |issue=4 |pages=CD005339 |doi=10.1002/14651858.CD005339.pub2 |issn=1469-493X |pmc=4930145 |pmid=27128488}} [196] => [197] => In very severe [[myelosuppression]], which occurs in some regimens, almost all the bone marrow [[stem cell]]s (cells that produce [[white blood cells|white]] and [[red blood cell]]s) are destroyed, meaning ''allogenic'' or ''[[autologous]]'' [[bone marrow transplant|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.{{Cite journal |last1=Léger |first1=Chantal S. |last2=Nevill |first2=Thomas J. |date=2004-05-11 |title=Hematopoietic stem cell transplantation: a primer for the primary care physician |journal=Canadian Medical Association Journal |volume=170 |issue=10 |pages=1569–1577 |doi=10.1503/cmaj.1011625 |issn=0820-3946 |pmid=15136552|pmc=400723 }} [198] => [199] => 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 [[Human gastrointestinal tract|gastrointestinal tract]] (including [[oral cavity]]) and skin.{{cite book | name-list-style = vanc | last1 = Huang | first1 = Elbert S. | title = Internal medicine: handbook for clinicians, resident survival guide | year = 2000 | publisher = Scrub Hill Press | location = Arlington, VA | isbn = 978-0-9645467-5-2 | page = 130}}{{rp|130}} This may manifest as systemic infections, such as [[sepsis]], or as localized outbreaks, such as [[Herpes simplex]], [[shingles]], or other members of the [[human herpes virus|Herpesviridea]].{{cite journal | vauthors = Elad S, Zadik Y, Hewson I, Hovan A, Correa ME, Logan R, Elting LS, Spijkervet FK, Brennan MT | title = A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea | journal = Supportive Care in Cancer | volume = 18 | issue = 8 | pages = 993–1006 | date = August 2010 | pmid = 20544224 | doi = 10.1007/s00520-010-0900-3 | s2cid = 2969472 }} The risk of illness and death can be reduced by taking common antibiotics such as [[Quinolone antibiotic|quinolone]]s or [[trimethoprim/sulfamethoxazole]] before any fever or sign of infection appears.{{cite journal | vauthors = Gafter-Gvili A, Fraser A, Paul M, Vidal L, Lawrie TA, van de Wetering MD, Kremer LC, Leibovici L | title = Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD004386 | date = January 2012 | issue = 1 | pmid = 22258955 | pmc = 4170789 | doi = 10.1002/14651858.CD004386.pub3 }} Quinolones show effective prophylaxis mainly with hematological cancer. 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. Sometimes, chemotherapy treatments are postponed because the immune system is suppressed to a critically low level.{{cn|date=March 2023}} [200] => [201] => In [[Japan]], the government has approved the use of some [[medicinal mushrooms]] like ''[[Trametes versicolor]]'', to counteract depression of the immune system in people undergoing chemotherapy.{{cite web |url=http://www.cancer.org/docroot/ETO/content/ETO_5_3X_Coriolous_Versicolor.asp |title=Coriolus Versicolor |publisher=Cancer.org |date=2008-06-10 |access-date=7 August 2012 |archive-date=25 June 2010 |archive-url=https://web.archive.org/web/20100625052416/http://www.cancer.org/docroot/ETO/content/ETO_5_3X_Coriolous_Versicolor.asp |url-status=dead }} [202] => [203] => [[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.{{Cite web|last=Commissioner|first=Office of the|date=2021-02-12|title=FDA Approves Drug to Reduce Bone Marrow Suppression Caused by Chemotherapy|url=https://www.fda.gov/news-events/press-announcements/fda-approves-drug-reduce-bone-marrow-suppression-caused-chemotherapy|access-date=2021-03-09|website=FDA|language=en}} [204] => [205] => === Neutropenic enterocolitis === [206] => Due to immune system suppression, [[neutropenic enterocolitis]] (typhlitis) is a "life-threatening gastrointestinal complication of chemotherapy."{{cite journal | vauthors = Davila ML | title = Neutropenic enterocolitis | journal = Current Opinion in Gastroenterology | volume = 22 | issue = 1 | pages = 44–7 | date = January 2006 | pmid = 16319675 | doi = 10.1097/01.mog.0000198073.14169.3b | s2cid = 25479771 }} [[Typhlitis]] is an intestinal infection which may manifest itself through symptoms including [[nausea]], [[vomiting]], [[diarrhea]], a [[distended abdomen]], [[fever]], [[chills]], or [[abdominal pain]] and tenderness.{{Cite journal |last=Sinicrope |first=Frank A. |date=2003 |title=Typhlitis |url=https://www.ncbi.nlm.nih.gov/books/NBK12821/ |journal=Holland-Frei Cancer Medicine. 6th Edition |language=en}} [207] => [208] => [[Typhlitis]] is a [[medical emergency]]. It has a very poor [[prognosis]] and is often fatal unless promptly recognized and aggressively treated.{{cite journal | vauthors = Keidan RD, Fanning J, Gatenby RA, Weese JL | title = Recurrent typhlitis. A disease resulting from aggressive chemotherapy | journal = Diseases of the Colon and Rectum | volume = 32 | issue = 3 | pages = 206–9 | date = March 1989 | pmid = 2920627 | doi = 10.1007/BF02554529 | s2cid = 46090832 }} Successful treatment hinges on early diagnosis provided by a high index of suspicion and the use of CT scanning, nonoperative treatment for uncomplicated cases, and sometimes elective right [[hemicolectomy]] to prevent recurrence. [209] => [210] => === Gastrointestinal distress === [211] => [[Nausea]], [[vomiting]], [[Anorexia (symptom)|anorexia]], [[diarrhea]], abdominal cramps, and [[constipation]] are common side-effects of chemotherapeutic medications that kill fast-dividing cells.{{cite journal | vauthors = Gibson RJ, Keefe DM | title = Cancer chemotherapy-induced diarrhoea and constipation: mechanisms of damage and prevention strategies | journal = Supportive Care in Cancer | volume = 14 | issue = 9 | pages = 890–900 | date = September 2006 | pmid = 16604351 | doi = 10.1007/s00520-006-0040-y | s2cid = 109778 }} [[Malnutrition]] and [[dehydration]] can result when the recipient does not eat or drink enough, or when the person vomits frequently, because of gastrointestinal damage. This can result in rapid weight loss, or occasionally in weight gain, if the person eats too much in an effort to allay nausea or heartburn. Weight gain can also be caused by some steroid medications. These side-effects can frequently be reduced or eliminated with [[antiemetic]] drugs. Low-certainty evidence also suggests that probiotics may have a preventative and treatment effect of diarrhoea related to chemotherapy alone and with radiotherapy.{{cite journal | vauthors = Wei D, Heus P, van de Wetering FT, van Tienhoven G, Verleye L, Scholten RJ | title = Probiotics for the prevention or treatment of chemotherapy- or radiotherapy-related diarrhoea in people with cancer | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | pages = CD008831 | date = August 2018 | issue = 8 | pmid = 30168576 | pmc = 6513393 | doi = 10.1002/14651858.cd008831.pub3 }} However, a high index of suspicion is appropriate, since diarrhoea and bloating are also symptoms of [[typhlitis]], a very serious and potentially life-threatening [[medical emergency]] that requires immediate treatment.{{Cite journal |last1=Rodrigues |first1=Fabio G |last2=Dasilva |first2=Giovanna |last3=Wexner |first3=Steven D |date=2017-01-07 |title=Neutropenic enterocolitis |journal=World Journal of Gastroenterology |volume=23 |issue=1 |pages=42–47 |doi=10.3748/wjg.v23.i1.42 |issn=1007-9327 |pmc=5221285 |pmid=28104979 |doi-access=free }} [212] => [213] => === Anemia === [214] => [[Anemia]] can be a combined outcome caused by myelosuppressive chemotherapy, and possible cancer-related causes such as [[bleeding]], [[blood cell]] destruction ([[hemolysis]]), hereditary disease, kidney dysfunction, nutritional deficiencies or [[anemia of chronic disease]]. Treatments to mitigate anemia include hormones to boost blood production ([[erythropoietin]]), [[iron supplement]]s, and [[blood transfusion]]s.{{cite journal | vauthors = Groopman JE, Itri LM | title = Chemotherapy-induced anemia in adults: incidence and treatment | journal = Journal of the National Cancer Institute | volume = 91 | issue = 19 | pages = 1616–34 | date = October 1999 | pmid = 10511589 | doi = 10.1093/jnci/91.19.1616 | doi-access = free }}{{cite journal | vauthors = Henry DH | title = The role of intravenous iron in cancer-related anemia | journal = Oncology | volume = 20 | issue = 8 Suppl 6 | pages = 21–4 | date = July 2006 | pmid = 16925107 }}{{cite journal | vauthors = Rodgers GM, Becker PS, Bennett CL, Cella D, Chanan-Khan A, Chesney C, Cleeland C, Coccia PF, Djulbegovic B, Garst JL, Gilreath JA, Kraut EH, Lin WC, Matulonis U, Millenson M, Reinke D, Rosenthal J, Sabbatini P, Schwartz RN, Stein RS, Vij R | title = Cancer- and chemotherapy-induced anemia | journal = Journal of the National Comprehensive Cancer Network | volume = 6 | issue = 6 | pages = 536–64 | date = July 2008 | pmid = 18597709 | doi = 10.6004/jnccn.2008.0042}} Myelosuppressive therapy can cause a tendency to bleed easily, leading to anemia. Medications that kill rapidly dividing cells or blood cells can reduce the number of [[platelet]]s in the blood, which can result in [[Hematoma|bruises]] and [[Hemorrhage|bleeding]]. Extremely low platelet counts may be temporarily boosted through [[platelet transfusion]]s and new drugs to increase platelet counts during chemotherapy are being developed.{{cite journal | vauthors = Vadhan-Raj S | title = Management of chemotherapy-induced thrombocytopenia: current status of thrombopoietic agents | journal = Seminars in Hematology | volume = 46 | issue = 1 Suppl 2 | pages = S26-32 | date = January 2009 | pmid = 19245931 | doi = 10.1053/j.seminhematol.2008.12.007 }}{{cite journal | vauthors = Sekhon SS, Roy V | s2cid = 16527763 | title = Thrombocytopenia in adults: A practical approach to evaluation and management | journal = Southern Medical Journal | volume = 99 | issue = 5 | pages = 491–8; quiz 499–500, 533 | date = May 2006 | pmid = 16711312 | doi = 10.1097/01.smj.0000209275.75045.d4 }}{{cite journal | vauthors = Estcourt L, Stanworth S, Doree C, Hopewell S, Murphy MF, Tinmouth A, Heddle N | title = Prophylactic platelet transfusion for prevention of bleeding in patients with haematological disorders after chemotherapy and stem cell transplantation | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD004269 | date = May 2012 | pmid = 22592695 | doi = 10.1002/14651858.CD004269.pub3 | collaboration = Cochrane Haematological Malignancies Group | url = https://ora.ox.ac.uk/objects/uuid:552b24c8-5ce8-4f0c-8d08-2516e6c355b5/download_file?safe_filename=Estcourt%2Bet%2Bal%2C%2B%2BProphylactic%2Bplatelet%2Btransfusion%2Bfor%2Bprevention%2Bof%2Bbleeding%2Bin%2Bpatients%2Bwith%2Bhaematological%2Bdisorders.pdf&file_format=application%2Fpdf&type_of_work=Journal+article }}{{cite journal | vauthors = Estcourt LJ, Stanworth SJ, Doree C, Hopewell S, Trivella M, Murphy MF | title = Comparison of different platelet count thresholds to guide administration of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation | journal = The Cochrane Database of Systematic Reviews | issue = 11 | pages = CD010983 | date = November 2015 | volume = 2015 | pmid = 26576687 | doi = 10.1002/14651858.CD010983.pub2 | pmc = 4717525 | collaboration = Cochrane Haematological Malignancies Group }} Sometimes, chemotherapy treatments are postponed to allow platelet counts to recover. [215] => [216] => [[Cancer-related fatigue|Fatigue]] may be a consequence of the cancer or its treatment, and can last for months to years after treatment. One physiological cause of fatigue is anemia, which can be caused by chemotherapy, [[surgery]], [[radiotherapy]], primary and metastatic disease or nutritional depletion.{{cite journal | vauthors = Berger AM, Abernethy AP, Atkinson A, Barsevick AM, Breitbart WS, Cella D, Cimprich B, Cleeland C, Eisenberger MA, Escalante CP, Jacobsen PB, Kaldor P, Ligibel JA, Murphy BA, O'Connor T, Pirl WF, Rodler E, Rugo HS, Thomas J, Wagner LI | s2cid = 70400559 | title = NCCN Clinical Practice Guidelines Cancer-related fatigue | journal = Journal of the National Comprehensive Cancer Network | volume = 8 | issue = 8 | pages = 904–31 | date = August 2010 | pmid = 20870636 | doi = 10.6004/jnccn.2010.0067| doi-access = free }}{{cite journal | vauthors = Franklin DJ, Packel L | title = Cancer-related fatigue | journal = Archives of Physical Medicine and Rehabilitation | volume = 87 | issue = 3 Suppl 1 | pages = S91–3; quiz S94–5 | date = March 2006 | pmid = 16500197 | doi = 10.1016/j.apmr.2005.12.015 }} [[Aerobic exercise]] has been found to be beneficial in reducing fatigue in people with [[solid tumour]]s.{{cite journal | vauthors = Cramp F, Byron-Daniel J | title = Exercise for the management of cancer-related fatigue in adults | journal = The Cochrane Database of Systematic Reviews | volume = 11 | pages = CD006145 | date = November 2012 | issue = 9 | pmid = 23152233 | doi = 10.1002/14651858.CD006145.pub3 | pmc = 8480137 | editor1-last = Cramp | editor1-first = Fiona }} [217] => [218] => === Nausea and vomiting === [219] => {{Further|Chemotherapy-induced nausea and vomiting}} [220] => [[Nausea]] and [[vomiting]] are two of the most feared cancer treatment-related side-effects for people with cancer and their families. In 1983, Coates et al. found that people receiving chemotherapy ranked nausea and vomiting as the first and second most severe side-effects, respectively.{{Citation |last=PDQ Supportive and Palliative Care Editorial Board |title=Nausea and Vomiting Related to Cancer Treatment (PDQ®): Health Professional Version |date=2002 |url=http://www.ncbi.nlm.nih.gov/books/NBK66056/ |work=PDQ Cancer Information Summaries |place=Bethesda (MD) |publisher=National Cancer Institute (US) |pmid=26389491 |access-date=2022-11-08}} Up to 20% of people receiving highly emetogenic agents in this era postponed, or even refused potentially curative treatments.{{cite journal | title = Nausea and Vomiting in the Cancer Patient | year = 2006 | journal = Oncology | pages = 1482–1496 | doi = 10.1007/0-387-31056-8_83 | quote = Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. | last1 = Gill | first1 = Paula | last2 = Grothey | first2 = Axel | last3 = Loprinzi | first3 = Charles | name-list-style = vanc | isbn = 978-0-387-24291-0 }} Chemotherapy-induced nausea and vomiting (CINV) are common with many treatments and some forms of cancer. Since the 1990s, several novel classes of [[antiemetics]] have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to successfully manage these symptoms in 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.{{Cite journal |last1=Sanger |first1=Gareth J. |last2=Andrews |first2=Paul L. R. |date=2018-09-04 |title=A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research |journal=Frontiers in Pharmacology |volume=9 |pages=913 |doi=10.3389/fphar.2018.00913 |issn=1663-9812 |pmc=6131675 |pmid=30233361|doi-access=free }} [221] => [222] => === Hair loss === [223] => [[File:Hair matting after few sessions of chemotherapy.jpg|alt=Chemotherapy adverse effects on hair|thumb|Hair matting after few sessions of chemotherapy]] [224] => [[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.{{Cite web |title=Chemotherapy-Related Hair Loss (Alopecia) in Children - Health Encyclopedia - University of Rochester Medical Center |url=https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=90&contentid=P02732 |access-date=2022-11-08 |website=www.urmc.rochester.edu}} [225] => [226] => Chemotherapy induced hair loss occurs by a non-androgenic mechanism, and can manifest as [[alopecia totalis]], telogen effluvium, or less often [[alopecia areata]].{{cite journal | vauthors = Chadha V, Shenoi SD | title = Hair loss in cancer chemotherapeutic patients | journal = Indian Journal of Dermatology, Venereology and Leprology | volume = 69 | issue = 2 | pages = 131–2 | year = 2003 | pmid = 17642856 }} It is usually associated with systemic treatment due to the high mitotic rate of hair follicles, and more reversible than androgenic hair loss,{{cite journal | vauthors = Lemieux J | title = Reducing chemotherapy-induced alopecia with scalp cooling | journal = Clinical Advances in Hematology & Oncology | volume = 10 | issue = 10 | pages = 681–2 | date = October 2012 | pmid = 23187775 }}{{cite journal | vauthors = Shapiro J, Price VH | title = Hair regrowth. Therapeutic agents | journal = Dermatologic Clinics | volume = 16 | issue = 2 | pages = 341–56 | date = April 1998 | pmid = 9589208 | doi = 10.1016/S0733-8635(05)70017-6 }} although permanent cases can occur.{{cite journal | vauthors = Al-Mohanna H, Al-Khenaizan S | title = Permanent alopecia following cranial irradiation in a child | journal = [[Journal of Cutaneous Medicine and Surgery]] | volume = 14 | issue = 3 | pages = 141–3 | year = 2010 | pmid = 20487675 | doi = 10.2310/7750.2010.09014 | s2cid = 43583651 }} Chemotherapy induces hair loss in women more often than men.{{cite journal | vauthors = Can G, Demir M, Erol O, Aydiner A | title = A comparison of men and women's experiences of chemotherapy-induced alopecia | journal = [[European Journal of Oncology Nursing]] | volume = 17 | issue = 3 | pages = 255–60 | date = June 2013 | pmid = 22901547 | doi = 10.1016/j.ejon.2012.06.003 }} [227] => [228] => [[Hypothermia cap|Scalp cooling]] offers a means of preventing both permanent and temporary hair loss; however, concerns about this method have been raised.{{cite journal | vauthors = Trüeb RM | title = Chemotherapy-induced alopecia | journal = Seminars in Cutaneous Medicine and Surgery | volume = 28 | issue = 1 | pages = 11–4 | date = March 2009 | pmid = 19341937 | doi = 10.1016/j.sder.2008.12.001 }}{{cite journal | vauthors = Chon SY, Champion RW, Geddes ER, Rashid RM | title = Chemotherapy-induced alopecia | journal = Journal of the American Academy of Dermatology | volume = 67 | issue = 1 | pages = e37-47 | date = July 2012 | pmid = 22178150 | doi = 10.1016/j.jaad.2011.02.026 }} [229] => [230] => === Secondary neoplasm === [231] => Development of secondary neoplasia after successful chemotherapy or radiotherapy treatment can occur. The most common [[secondary neoplasm]] is secondary acute myeloid leukemia, which develops primarily after treatment with alkylating agents or topoisomerase inhibitors.{{Cite book |title=Secondary neoplasias following chemotherapy, radiotherapy and immunosuppression |date=2000 |publisher=Karger |isbn=9783318006155 |volume=55 |location=Basel |oclc=606559421}} Survivors of [[childhood cancer]] are more than 13 times as likely to get a [[secondary neoplasm]] during the 30 years after treatment than the general population.{{cite journal | vauthors = Hijiya N, Hudson MM, Lensing S, Zacher M, Onciu M, Behm FG, Razzouk BI, Ribeiro RC, Rubnitz JE, Sandlund JT, Rivera GK, Evans WE, Relling MV, Pui CH | title = Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia | journal = JAMA | volume = 297 | issue = 11 | pages = 1207–15 | date = March 2007 | pmid = 17374815 | doi = 10.1001/jama.297.11.1207 | doi-access = free }} Not all of this increase can be attributed to chemotherapy. [232] => [233] => === Infertility === [234] => Some types of chemotherapy are gonadotoxic and may cause [[infertility]].{{cite journal | vauthors = Brydøy M, Fosså SD, Dahl O, Bjøro T | title = Gonadal dysfunction and fertility problems in cancer survivors | journal = Acta Oncologica | volume = 46 | issue = 4 | pages = 480–9 | year = 2007 | pmid = 17497315 | doi = 10.1080/02841860601166958 | s2cid = 20672988 }} Chemotherapies with high risk include procarbazine and other alkylating drugs such as cyclophosphamide, ifosfamide, busulfan, melphalan, chlorambucil, and chlormethine. Drugs with medium risk include doxorubicin and platinum analogs such as cisplatin and carboplatin. On the other hand, therapies with low risk of gonadotoxicity include plant derivatives such as vincristine and vinblastine, [[antibiotic]]s such as bleomycin and dactinomycin, and antimetabolites such as methotrexate, mercaptopurine, and 5-fluorouracil. [235] => [236] => [[Female infertility]] by chemotherapy appears to be secondary to [[premature ovarian failure]] by loss of [[primordial follicles]].{{cite journal | vauthors = Morgan S, Anderson RA, Gourley C, Wallace WH, Spears N | title = How do chemotherapeutic agents damage the ovary? | journal = Human Reproduction Update | volume = 18 | issue = 5 | pages = 525–35 | year = 2012 | pmid = 22647504 | doi = 10.1093/humupd/dms022 | doi-access = free | hdl = 1842/9543 | hdl-access = free }} 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. [237] => [238] => People may choose between several methods of [[fertility preservation]] prior to chemotherapy, including [[cryopreservation]] of semen, ovarian tissue, oocytes, or embryos.{{cite journal | vauthors = Gurgan T, Salman C, Demirol A | title = Pregnancy and assisted reproduction techniques in men and women after cancer treatment | journal = Placenta | volume = 29 Suppl B | pages = 152–9 | date = October 2008 | pmid = 18790328 | doi = 10.1016/j.placenta.2008.07.007 }} 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.{{cite journal | vauthors = Courbiere B, Decanter C, Bringer-Deutsch S, Rives N, Mirallié S, Pech JC, De Ziegler D, Carré-Pigeon F, May-Panloup P, Sifer C, Amice V, Schweitzer T, Porcu-Buisson G, Poirot C | title = Emergency IVF for embryo freezing to preserve female fertility: a French multicentre cohort study | journal = Human Reproduction | volume = 28 | issue = 9 | pages = 2381–8 | date = September 2013 | pmid = 23832792 | doi = 10.1093/humrep/det268 | doi-access = free }} [239] => [240] => Potential protective or attenuating agents include [[GnRH analog]]s, 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#Apoptosis|sphingomyelin apoptotic pathway]] may also interfere with the [[apoptosis]] action of chemotherapy drugs.{{cite journal | vauthors = Roness H, Kalich-Philosoph L, Meirow D | title = Prevention of chemotherapy-induced ovarian damage: possible roles for hormonal and non-hormonal attenuating agents | journal = Human Reproduction Update | volume = 20 | issue = 5 | pages = 759–74 | year = 2014 | pmid = 24833728 | doi = 10.1093/humupd/dmu019 | doi-access = free }} [241] => [242] => 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.{{cite journal | vauthors = Tichelli A, Rovó A | title = Fertility issues following hematopoietic stem cell transplantation | journal = Expert Review of Hematology | volume = 6 | issue = 4 | pages = 375–88 | date = August 2013 | pmid = 23991924 | doi = 10.1586/17474086.2013.816507 | s2cid = 25139582 }} [243] =>
In turn citing: {{cite journal | vauthors = Sanders JE, Hawley J, Levy W, Gooley T, Buckner CD, Deeg HJ, Doney K, Storb R, Sullivan K, Witherspoon R, Appelbaum FR | title = Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation | journal = Blood | volume = 87 | issue = 7 | pages = 3045–52 | date = April 1996 | pmid = 8639928 | doi = 10.1182/blood.V87.7.3045.bloodjournal8773045 | doi-access = free }} [244] => [245] => === Teratogenicity === [246] => Chemotherapy is [[teratogenic]] during [[pregnancy]], especially during the [[first trimester]], to the extent that [[abortion]] usually is recommended if pregnancy in this period is found during chemotherapy.{{cite journal | vauthors = Arnon J, Meirow D, Lewis-Roness H, Ornoy A | title = Genetic and teratogenic effects of cancer treatments on gametes and embryos | journal = Human Reproduction Update | volume = 7 | issue = 4 | pages = 394–403 | year = 2001 | pmid = 11476352 | doi = 10.1093/humupd/7.4.394 | doi-access = free }} 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. [247] => [248] => In males previously having undergone chemotherapy or radiotherapy, there appears to be no increase in genetic defects or congenital malformations in their children conceived after therapy. The use of [[assisted reproductive technologies]] and [[micromanipulation technique]]s might increase this risk. In females previously having undergone chemotherapy, miscarriage and congenital malformations are not increased in subsequent conceptions. However, when [[in vitro fertilization]] and [[embryo cryopreservation]] is practised between or shortly after treatment, possible genetic risks to the growing oocytes exist, and hence it has been recommended that the babies be screened. [249] => [250] => === Peripheral neuropathy === [251] => {{further|Chemotherapy-induced peripheral neuropathy}} [252] => 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.{{cite journal | vauthors = del Pino BM | date = 23 February 2010 | journal = NCI Cancer Bulletin | volume = 7 | issue = 4 | page = 6 | title = Chemotherapy-induced Peripheral Neuropathy | url = http://www.cancer.gov/cancertopics/research/chemotherapy-induced-peripheral-neuropathy}} Chemotherapy drugs associated with CIPN include [[thalidomide]], [[epothilone]]s, ''vinca'' alkaloids, taxanes, [[proteasome inhibitor]]s, and the platinum-based drugs.{{cite journal|url=http://www.kup.at/kup/pdf/10376.pdf |archive-url=https://web.archive.org/web/20120812155252/http://www.kup.at/kup/pdf/10376.pdf |archive-date=2012-08-12 |url-status=live| vauthors =Grisold W, Oberndorfer S, Windebank AJ|journal=European Association of Neurooncology Magazine|title=Chemotherapy and polyneuropathies|year=2012|volume=12|issue=1}} 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 nerve]]s and the [[autonomic nervous system]] are affected.{{cite journal | vauthors = Beijers AJ, Jongen JL, Vreugdenhil G | title = Chemotherapy-induced neurotoxicity: the value of neuroprotective strategies | journal = The Netherlands Journal of Medicine | volume = 70 | issue = 1 | pages = 18–25 | date = January 2012 | pmid = 22271810 | url = http://www.njmonline.nl/njm/getarticle.php?v=70&i=1&p=18 }} 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.{{cite journal | vauthors = Windebank AJ, Grisold W | title = Chemotherapy-induced neuropathy | journal = Journal of the Peripheral Nervous System | volume = 13 | issue = 1 | pages = 27–46 | date = March 2008 | pmid = 18346229 | doi = 10.1111/j.1529-8027.2008.00156.x | s2cid = 20411101 }} Some CIPN appears to be irreversible. Pain can often be managed with drug or other treatment but the numbness is usually resistant to treatment.{{cite journal | vauthors = Savage L | title = Chemotherapy-induced pain puzzles scientists | journal = Journal of the National Cancer Institute | volume = 99 | issue = 14 | pages = 1070–1 | date = July 2007 | pmid = 17623791 | doi = 10.1093/jnci/djm072 | doi-access = free }} [253] => [254] => === Cognitive impairment === [255] => 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.{{cite journal | vauthors = Tannock IF, Ahles TA, Ganz PA, Van Dam FS | title = Cognitive impairment associated with chemotherapy for cancer: report of a workshop | journal = Journal of Clinical Oncology | volume = 22 | issue = 11 | pages = 2233–9 | date = June 2004 | pmid = 15169812 | doi = 10.1200/JCO.2004.08.094 | doi-access = free }} [256] => [257] => === Tumor lysis syndrome === [258] => In particularly large tumors and cancers with high [[white cell count]]s, such as [[lymphoma]]s, [[teratoma]]s, and some [[leukemia]]s, some people develop [[tumor lysis syndrome]]. The rapid breakdown of cancer cells causes the release of chemicals from the inside of the cells. Following this, high levels of [[hyperuricemia|uric acid]], [[hyperkalemia|potassium]] and [[hyperphosphatemia|phosphate]] are found in the blood. High levels of phosphate induce secondary hypoparathyroidism, resulting in low levels of calcium in the blood.{{Citation |last1=Adeyinka |first1=Adebayo |title=Tumor Lysis Syndrome |date=2022 |url=http://www.ncbi.nlm.nih.gov/books/NBK518985/ |work=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30085527 |access-date=2022-11-08 |last2=Bashir |first2=Khalid}} This causes kidney damage and the high levels of potassium can cause [[Cardiac dysrhythmia|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.{{rp|202}} [259] => [260] => === Organ damage === [261] => [[Cardiotoxicity]] (heart damage) is especially prominent with the use of [[anthracycline]] drugs ([[doxorubicin]], [[epirubicin]], [[idarubicin]], and [[liposomal doxorubicin]]). The cause of this is most likely due to the production of [[free radical]]s in the cell and subsequent [[DNA damage]]. Other chemotherapeutic agents that cause cardiotoxicity, but at a lower incidence, are [[cyclophosphamide]], [[docetaxel]] and [[clofarabine]].{{cite journal | vauthors = Shaikh AY, Shih JA | title = Chemotherapy-induced cardiotoxicity | journal = Current Heart Failure Reports | volume = 9 | issue = 2 | pages = 117–27 | date = June 2012 | pmid = 22382639 | doi = 10.1007/s11897-012-0083-y | s2cid = 35723897 }} [262] => [263] => [[Hepatotoxicity]] (liver damage) can be caused by many cytotoxic drugs. The susceptibility of an individual to liver damage can be altered by other factors such as the cancer itself, [[viral hepatitis]], [[immunosuppression]] and [[nutritional deficiency]]. The liver damage can consist of damage to liver cells, [[Hepatic veno-occlusive disease|hepatic sinusoidal syndrome]] (obstruction of the veins in the liver), [[cholestasis]] (where bile does not flow from the liver to the intestine) and [[liver fibrosis]].{{cite journal | vauthors = Thatishetty AV, Agresti N, O'Brien CB | title = Chemotherapy-induced hepatotoxicity | journal = Clinics in Liver Disease | volume = 17 | issue = 4 | pages = 671–86, ix–x | date = November 2013 | pmid = 24099024 | doi = 10.1016/j.cld.2013.07.010 }}{{cite journal | vauthors = King PD, Perry MC | title = Hepatotoxicity of chemotherapy | journal = The Oncologist | volume = 6 | issue = 2 | pages = 162–76 | year = 2001 | pmid = 11306728 | doi = 10.1634/theoncologist.6-2-162 | s2cid = 39518402 | url = http://theoncologist.alphamedpress.org/content/6/2/162.full.pdf }} [264] => [265] => [[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]].{{cite journal | vauthors = de Jonge MJ, Verweij J | title = Renal toxicities of chemotherapy | journal = Seminars in Oncology | volume = 33 | issue = 1 | pages = 68–73 | date = February 2006 | pmid = 16473645 | doi = 10.1053/j.seminoncol.2005.11.011 }}{{cite journal | vauthors = Humphreys BD, Soiffer RJ, Magee CC | title = Renal failure associated with cancer and its treatment: an update | journal = Journal of the American Society of Nephrology | volume = 16 | issue = 1 | pages = 151–61 | date = January 2005 | pmid = 15574506 | doi = 10.1681/ASN.2004100843 | doi-access = free }} [266] => [267] => [[Ototoxicity]] (damage to the inner ear) is a common side effect of platinum based drugs that can produce symptoms such as dizziness and [[Vertigo (medical)|vertigo]].{{cite journal | vauthors = Brock PR, Knight KR, Freyer DR, Campbell KC, Steyger PS, Blakley BW, Rassekh SR, Chang KW, Fligor BJ, Rajput K, Sullivan M, Neuwelt EA | display-authors = 6 | title = Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale | journal = Journal of Clinical Oncology | volume = 30 | issue = 19 | pages = 2408–17 | date = July 2012 | pmid = 22547603 | pmc = 3675696 | doi = 10.1200/JCO.2011.39.1110 }}{{cite journal | vauthors = Rybak LP, Mukherjea D, Jajoo S, Ramkumar V | title = Cisplatin ototoxicity and protection: clinical and experimental studies | journal = The Tohoku Journal of Experimental Medicine | volume = 219 | issue = 3 | pages = 177–86 | date = November 2009 | pmid = 19851045 | pmc = 2927105 | doi = 10.1620/tjem.219.177 }} Children treated with platinum analogues have been found to be at risk for developing hearing loss.{{cite journal | vauthors = van As JW, van den Berg H, van Dalen EC | title = Different infusion durations for preventing platinum-induced hearing loss in children with cancer | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD010885 | date = January 2020 | issue = 1 | pmid = 31961948 | pmc = 6984653 | doi = 10.1002/14651858.CD010885.pub5 }}{{cite journal | vauthors = van As JW, van den Berg H, van Dalen EC | title = Platinum-induced hearing loss after treatment for childhood cancer | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD010181 | date = August 2016 | volume = 2019 | pmid = 27486906 | pmc = 6466671 | doi = 10.1002/14651858.cd010181.pub2 }}{{cite journal | vauthors = van As JW, van den Berg H, van Dalen EC | title = Medical interventions for the prevention of platinum-induced hearing loss in children with cancer | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | pages = CD009219 | date = May 2019 | issue = 5 | pmid = 31063591 | pmc = 6504134 | doi = 10.1002/14651858.cd009219.pub5 }} [268] => [269] => === Other side-effects === [270] => Less common side-effects include red skin ([[erythema]]), dry skin, damaged fingernails, a dry mouth ([[xerostomia]]), [[Water retention (medicine)|water retention]], and [[sexual impotence]]. Some medications can trigger [[allergic]] or [[pseudoallergic]] reactions. [271] => [272] => Specific chemotherapeutic agents are associated with organ-specific toxicities, including [[cardiovascular disease]] (e.g., [[doxorubicin]]), [[interstitial lung disease]] (e.g., [[bleomycin]]) and occasionally [[secondary neoplasm]] (e.g., [[MOPP (medicine)|MOPP]] therapy for Hodgkin's disease).{{Cite book |last=Shannon |first=Vickie R. |title=Oncologic Critical Care |chapter=Cancer Treatment-Related Lung Injury |date=2019-07-09 |pages=531–556 |doi=10.1007/978-3-319-74588-6_52 |pmc=7123056|isbn=978-3-319-74587-9 }} [273] => [274] => [[Chemotherapy-induced acral erythema|Hand-foot syndrome]] is another side effect to cytotoxic chemotherapy.{{Cite journal |last1=Kwakman |first1=Johannes J.M. |last2=Elshot |first2=Yannick S. |last3=Punt |first3=Cornelis J.A. |last4=Koopman |first4=Miriam |date=2020-05-13 |title=Management of cytotoxic chemotherapy-induced hand-foot syndrome |journal=Oncology Reviews |volume=14 |issue=1 |pages=442 |doi=10.4081/oncol.2020.442 |issn=1970-5565 |pmc=7232019 |pmid=32431787}} [275] => [276] => 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.{{cite journal | vauthors = Ward EJ, Henry LM, Friend AJ, Wilkins S, Phillips RS | title = Nutritional support in children and young people with cancer undergoing chemotherapy | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD003298 | date = August 2015 | volume = 2015 | pmid = 26301790 | doi = 10.1002/14651858.cd003298.pub3 | pmc = 8752126 }} [277] => [278] => == Limitations == [279] => 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|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.{{cite journal | vauthors = Weeks JC, Catalano PJ, Cronin A, Finkelman MD, Mack JW, Keating NL, Schrag D | title = Patients' expectations about effects of chemotherapy for advanced cancer | journal = The New England Journal of Medicine | volume = 367 | issue = 17 | pages = 1616–25 | date = October 2012 | pmid = 23094723 | pmc = 3613151 | doi = 10.1056/NEJMoa1204410 }} [280] => [281] => The [[blood–brain barrier]] poses an obstacle to delivery of chemotherapy to the [[brain]]. This is because the brain has an extensive system in place to protect it from harmful chemicals. Drug transporters can pump out drugs from the brain and brain's blood vessel cells into the [[cerebrospinal fluid]] and blood circulation. These transporters pump out most chemotherapy drugs, which reduces their efficacy for treatment of brain tumors. Only small [[lipophilic]] [[alkylating agents]] such as [[lomustine]] or [[temozolomide]] are able to cross this blood–brain barrier.{{cite journal | vauthors = Deeken JF, Löscher W | title = The blood-brain barrier and cancer: transporters, treatment, and Trojan horses | journal = Clinical Cancer Research | volume = 13 | issue = 6 | pages = 1663–74 | date = March 2007 | pmid = 17363519 | doi = 10.1158/1078-0432.CCR-06-2854 | doi-access = free }}{{cite journal | vauthors = Agarwala SS, Kirkwood JM | title = Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma | journal = The Oncologist | volume = 5 | issue = 2 | pages = 144–51 | year = 2000 | pmid = 10794805 | doi = 10.1634/theoncologist.5-2-144 | s2cid = 25331035 | doi-access = free }}{{cite journal | vauthors = Gerstner ER, Fine RL | title = Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm | journal = Journal of Clinical Oncology | volume = 25 | issue = 16 | pages = 2306–12 | date = June 2007 | pmid = 17538177 | doi = 10.1200/JCO.2006.10.0677 }} [282] => [283] => [[Blood vessel]]s 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 ([[Tumor hypoxia|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]].{{cite journal | vauthors = Minchinton AI, Tannock IF | title = Drug penetration in solid tumours | journal = Nature Reviews. Cancer | volume = 6 | issue = 8 | pages = 583–92 | date = August 2006 | pmid = 16862189 | doi = 10.1038/nrc1893 | s2cid = 42818461 }} [284] => [285] => == Resistance == [286] => [[Drug 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.{{cite journal | vauthors = Goldman B | title = Multidrug resistance: can new drugs help chemotherapy score against cancer? | journal = Journal of the National Cancer Institute | volume = 95 | issue = 4 | pages = 255–7 | date = February 2003 | pmid = 12591977 | doi = 10.1093/jnci/95.4.255 | doi-access = free }}{{cite book | vauthors = Crowley E, McDevitt CA, Callaghan R |title=Multidrug Resistance in Cancer. Generating Inhibitors of P-Glycoprotein: Where to, Now?|year=2009|publisher=Springer Protocols|pages=405–432}} Another mechanism of resistance is [[gene duplication|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 [[enzyme]]s 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.{{cite journal | vauthors = Luqmani YA | title = Mechanisms of drug resistance in cancer chemotherapy | journal = Medical Principles and Practice | volume = 14 | pages = 35–48 | year = 2005 | issue = Suppl 1 | pmid = 16103712 | doi = 10.1159/000086183 | doi-access = free }} 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.{{cite journal | vauthors = Moschovi M, Critselis E, Cen O, Adamaki M, Lambrou GI, Chrousos GP, Vlahopoulos S | title = Drugs acting on homeostasis: challenging cancer cell adaptation | journal = Expert Review of Anticancer Therapy | volume = 15 | issue = 12 | pages = 1405–17 | year = 2015 | pmid = 26523494 | doi = 10.1586/14737140.2015.1095095 | s2cid = 28992964 }} In [[lung cancer]], the transcription factor [[NF-κB|NFκB]] is thought to play a role in resistance to chemotherapy, via inflammatory pathways.{{cite journal | vauthors = Heavey S, Godwin P, Baird AM, Barr MP, Umezawa K, Cuffe S, Finn SP, O'Byrne KJ, Gately K | display-authors = 6 | title = Strategic targeting of the PI3K-NFκB axis in cisplatin-resistant NSCLC | journal = Cancer Biology & Therapy | volume = 15 | issue = 10 | pages = 1367–77 | date = October 2014 | pmid = 25025901 | pmc = 4130730 | doi = 10.4161/cbt.29841 }}{{cite journal | vauthors = Ryan SL, Beard S, Barr MP, Umezawa K, Heavey S, Godwin P, Gray SG, Cormican D, Finn SP, Gately KA, Davies AM, Thompson EW, Richard DJ, O'Byrne KJ, Adams MN, Baird AM | display-authors = 6 | title = Targeting NF-κB-mediated inflammatory pathways in cisplatin-resistant NSCLC | journal = Lung Cancer | volume = 135 | pages = 217–227 | date = September 2019 | pmid = 31446998 | doi = 10.1016/j.lungcan.2019.07.006 | s2cid = 199025494 | url = https://eprints.qut.edu.au/200933/1/__qut.edu.au_Documents_StaffHome_StaffGroupH%24_henderm5_Desktop_1-s2.0-S016950021930529X-main.pdf }}{{cite journal | vauthors = Godwin P, Baird AM, Heavey S, Barr MP, O'Byrne KJ, Gately K | title = Targeting nuclear factor-kappa B to overcome resistance to chemotherapy | journal = Frontiers in Oncology | volume = 3 | pages = 120 | date = 2013 | pmid = 23720710 | pmc = 3655421 | doi = 10.3389/fonc.2013.00120 | doi-access = free }} [287] => [288] => == Cytotoxics and targeted therapies == [289] => [[Targeted therapy|Targeted therapies]] are a relatively new class of cancer drugs that can overcome many of the issues seen with the use of cytotoxics. They are divided into two groups: small molecule and antibodies. The massive toxicity seen with the use of cytotoxics is due to the lack of cell specificity of the drugs. They will kill any rapidly dividing cell, tumor or normal. Targeted therapies are designed to affect cellular proteins or processes that are utilised by the cancer cells.{{Cite journal |last1=Vanneman |first1=Matthew |last2=Dranoff |first2=Glenn |date=2012-03-22 |title=Combining Immunotherapy and Targeted Therapies in Cancer Treatment |journal=Nature Reviews. Cancer |volume=12 |issue=4 |pages=237–251 |doi=10.1038/nrc3237 |issn=1474-175X |pmc=3967236 |pmid=22437869}} This allows a high dose to cancer tissues with a relatively low dose to other tissues. Although the [[adverse effects|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.{{cite journal | vauthors = Gerber DE | title = Targeted therapies: a new generation of cancer treatments | journal = American Family Physician | volume = 77 | issue = 3 | pages = 311–9 | date = February 2008 | pmid = 18297955 }}{{cite journal | vauthors = Allen TM | title = Ligand-targeted therapeutics in anticancer therapy | journal = Nature Reviews. Cancer | volume = 2 | issue = 10 | pages = 750–63 | date = October 2002 | pmid = 12360278 | doi = 10.1038/nrc903 | s2cid = 21014917 }}{{cite journal | vauthors = Chen HX, Cleck JN | title = Adverse effects of anticancer agents that target the VEGF pathway | journal = Nature Reviews. Clinical Oncology | volume = 6 | issue = 8 | pages = 465–77 | date = August 2009 | pmid = 19581909 | doi = 10.1038/nrclinonc.2009.94 | s2cid = 30482752 | url = https://zenodo.org/record/1233504 }}{{cite journal | vauthors = Zhang J, Yang PL, Gray NS | title = Targeting cancer with small molecule kinase inhibitors | journal = Nature Reviews. Cancer | volume = 9 | issue = 1 | pages = 28–39 | date = January 2009 | pmid = 19104514 | doi = 10.1038/nrc2559 | s2cid = 17934366 }} [290] => [291] => == Mechanism of action == [292] => [[File:Cell cycle simple.png|thumb|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.]] [293] => [[Cancer]] is the uncontrolled growth of [[cell (biology)|cells]] coupled with [[malignant]] behaviour: invasion and [[metastasis]] (among other features).{{cite journal | vauthors = Hanahan D, Weinberg RA | title = The hallmarks of cancer | journal = Cell | volume = 100 | issue = 1 | pages = 57–70 | date = January 2000 | pmid = 10647931 | doi = 10.1016/S0092-8674(00)81683-9 | s2cid = 1478778 | doi-access = free }} It is caused by the interaction between [[gene]]tic susceptibility and environmental factors.{{cite journal | vauthors = Hodgson S | title = Mechanisms of inherited cancer susceptibility | journal = Journal of Zhejiang University Science B | volume = 9 | issue = 1 | pages = 1–4 | date = January 2008 | pmid = 18196605 | pmc = 2170461 | doi = 10.1631/jzus.B073001 }}{{cite journal | vauthors = Perera FP | title = Environment and cancer: who are susceptible? | journal = Science | volume = 278 | issue = 5340 | pages = 1068–73 | date = November 1997 | pmid = 9353182 | doi = 10.1126/science.278.5340.1068 | bibcode = 1997Sci...278.1068P }} These factors lead to accumulations of [[genetic mutation]]s in [[oncogene]]s (genes that control the growth rate of cells) and [[tumor suppressor gene]]s (genes that help to prevent cancer), which gives cancer cells their malignant characteristics, such as uncontrolled growth.{{cite book |editor1-last=Hoskins |editor1-first=William J. |editor2-last=Perez |editor2-first=Carlos A. |editor3-last=Young|editor3-first=Robert C.|editor4-last=Barakat|editor4-first=Richard R.|editor5-last=Markman|editor5-first=Maurie|editor6-last=Randall|editor6-first=Marcus E. | name-list-style = vanc |title=Principles and practice of gynecologic oncology|date=2005|publisher=Lippincott Williams & Wilkins|location=Baltimore, Md.|isbn=978-0-7817-4689-2|edition = 4th }}{{rp|93–94}} [294] => [295] => 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''. They prevent mitosis by various mechanisms including damaging DNA and inhibition of the cellular machinery involved in cell division.{{cite journal | vauthors = Malhotra V, Perry MC | title = Classical chemotherapy: mechanisms, toxicities and the therapeutic window | journal = Cancer Biology & Therapy | volume = 2 | issue = 4 Suppl 1 | pages = S2-4 | year = 2003 | pmid = 14508075 | doi = 10.4161/cbt.199 | doi-access = free }}{{cite journal | vauthors = Kehe K, Balszuweit F, Steinritz D, Thiermann H | title = Molecular toxicology of sulfur mustard-induced cutaneous inflammation and blistering | journal = Toxicology | volume = 263 | issue = 1 | pages = 12–9 | date = September 2009 | pmid = 19651324 | doi = 10.1016/j.tox.2009.01.019 }} One theory as to why these drugs kill cancer cells is that they induce a programmed form of cell death known as [[apoptosis]].{{cite journal | vauthors = Makin G, Hickman JA | title = Apoptosis and cancer chemotherapy | journal = Cell and Tissue Research | volume = 301 | issue = 1 | pages = 143–52 | date = July 2000 | pmid = 10928287 | doi = 10.1007/s004419900160 | bibcode = 1994RSPTB.345..319H | s2cid = 22909070 }} [296] => [297] => As chemotherapy affects cell division, tumors with high [[proliferative index|growth rates]] (such as [[acute myelogenous leukemia]] and the aggressive [[lymphoma]]s, 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.{{cite journal|last1=Corrie PG|title=Cytotoxic chemotherapy: clinical aspects|journal=Medicine|year=2008|volume=36|issue=1|pages=24–28|doi=10.1016/j.mpmed.2007.10.012|first1=Pippa G.}} [[Tumour heterogeneity|Heterogeneic tumours]] may also display varying sensitivities to chemotherapy agents, depending on the subclonal populations within the tumor.{{Cite journal |last1=Fisher |first1=R |last2=Pusztai |first2=L |last3=Swanton |first3=C |date=2013-02-19 |title=Cancer heterogeneity: implications for targeted therapeutics |journal=British Journal of Cancer |volume=108 |issue=3 |pages=479–485 |doi=10.1038/bjc.2012.581 |issn=0007-0920 |pmc=3593543 |pmid=23299535}} [298] => [299] => Cells from the [[immune system]] also make crucial contributions to the antitumor effects of chemotherapy.{{cite journal | vauthors = Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G | title = Immunological aspects of cancer chemotherapy | journal = Nature Reviews. Immunology | volume = 8 | issue = 1 | pages = 59–73 | date = January 2008 | pmid = 18097448 | doi = 10.1038/nri2216 | s2cid = 205490545 | doi-access = free }} 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.{{cite journal | vauthors = Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G | title = Immunogenic cell death in cancer and infectious disease | journal = Nature Reviews. Immunology | volume = 17 | issue = 2 | pages = 97–111 | date = February 2017 | pmid = 27748397 | doi = 10.1038/nri.2016.107 | s2cid = 4045072 }} Chemotherapeutic drugs that cause cancer immunogenic tumor cell death can make unresponsive tumors sensitive to [[immune checkpoint]] therapy.{{cite journal | vauthors = Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, Yamazaki T, Poirier-Colame V, Newton A, Redouane Y, Lin YJ, Wojtkiewicz G, Iwamoto Y, Mino-Kenudson M, Huynh TG, Hynes RO, Freeman GJ, Kroemer G, Zitvogel L, Weissleder R, Pittet MJ | title = Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy | journal = Immunity | volume = 44 | issue = 2 | pages = 343–54 | date = February 2016 | pmid = 26872698 | pmc = 4758865 | doi = 10.1016/j.immuni.2015.11.024 }} [300] => [301] => == Other uses == [302] => Some chemotherapy drugs are used in diseases other than cancer, such as in autoimmune disorders, and noncancerous [[plasma cell dyscrasia]]. In some cases they are often used at lower doses, which means that the side effects are minimized,{{cite journal | vauthors = Ben-Ari ET | title = Dual purpose: some cancer therapies used to treat autoimmune diseases | journal = Journal of the National Cancer Institute | volume = 96 | issue = 8 | pages = 577–9 | date = April 2004 | pmid = 15100330 | doi = 10.1093/jnci/96.8.577 | doi-access = free }} while in other cases doses similar to ones used to treat cancer are used. [[Methotrexate]] is used in the treatment of [[rheumatoid arthritis]] (RA),{{cite journal | vauthors = Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH | title = Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis | journal = Annals of the Rheumatic Diseases | volume = 60 | issue = 8 | pages = 729–35 | date = August 2001 | pmid = 11454634 | pmc = 1753808 | doi = 10.1136/ard.60.8.729 }} [[psoriasis]],{{cite journal | vauthors = Montaudié H, Sbidian E, Paul C, Maza A, Gallini A, Aractingi S, Aubin F, Bachelez H, Cribier B, Joly P, Jullien D, Le Maître M, Misery L, Richard MA, Ortonne JP | title = Methotrexate in psoriasis: a systematic review of treatment modalities, incidence, risk factors and monitoring of liver toxicity | journal = Journal of the European Academy of Dermatology and Venereology | volume = 25 | pages = 12–8 | date = May 2011 | issue = Suppl 2 | pmid = 21388454 | doi = 10.1111/j.1468-3083.2011.03991.x | s2cid = 13015911 }} [[ankylosing spondylitis]]{{cite journal | vauthors = Chen J, Veras MM, Liu C, Lin J | title = Methotrexate for ankylosing spondylitis | journal = The Cochrane Database of Systematic Reviews | volume = 2 | issue = 2 | pages = CD004524 | date = February 2013 | pmid = 23450553 | doi = 10.1002/14651858.CD004524.pub4 | editor1-last = Chen | editor1-first = Junmin }} and [[multiple sclerosis]]. The anti-inflammatory response seen in RA is thought to be due to increases in [[adenosine]], which causes [[immunosuppression]]; effects on immuno-regulatory [[cyclooxygenase]]-2 enzyme pathways; reduction in pro-inflammatory [[cytokine]]s; and anti-proliferative properties. Although methotrexate is used to treat both multiple sclerosis and ankylosing spondylitis, its efficacy in these diseases is still uncertain.{{cite journal | vauthors = Gray O, McDonnell GV, Forbes RB | title = Methotrexate for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD003208 | year = 2004 | volume = 2010 | pmid = 15106195 | doi = 10.1002/14651858.CD003208.pub2 | pmc = 9006525 | editor1-last = Gray | editor1-first = Orla }}{{cite journal | vauthors = Gray OM, McDonnell GV, Forbes RB | title = A systematic review of oral methotrexate for multiple sclerosis | journal = Multiple Sclerosis | volume = 12 | issue = 4 | pages = 507–10 | date = August 2006 | pmid = 16900766 | doi = 10.1191/1352458506ms1299oa | s2cid = 46120577 }} [[Cyclophosphamide]] is sometimes used to treat [[lupus nephritis]], a common symptom of [[systemic lupus erythematosus]].{{cite journal | vauthors = Ntali S, Bertsias G, Boumpas DT | title = Cyclophosphamide and lupus nephritis: when, how, for how long? | journal = Clinical Reviews in Allergy & Immunology | volume = 40 | issue = 3 | pages = 181–91 | date = June 2011 | pmid = 20107927 | doi = 10.1007/s12016-009-8196-0 | s2cid = 11902371 }} [[Dexamethasone]] along with either [[bortezomib]] or [[melphalan]] is commonly used as a treatment for [[AL amyloidosis]]. Recently, bortezomid in combination with [[cyclophosphamide]] and dexamethasone has also shown promise as a treatment for AL amyloidosis. Other drugs used to treat [[myeloma]] such as [[lenalidomide]] have shown promise in treating AL amyloidosis.{{cite web|title=NCCN Guidelines: Systemic Light Chain Amyloidosis|url=http://williams.medicine.wisc.edu/amyloidosis.pdf|publisher=National Comprehensive Cancer Network|access-date=25 February 2015|archive-date=25 June 2021|archive-url=https://web.archive.org/web/20210625164616/http://williams.medicine.wisc.edu/amyloidosis.pdf|url-status=dead}} [303] => [304] => Chemotherapy drugs are also used in [[conditioning regimen]]s prior to bone marrow transplant ([[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).{{cite journal | vauthors = Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, Apperley J, Slavin S, Pasquini M, Sandmaier BM, Barrett J, Blaise D, Lowski R, Horowitz M | title = Defining the intensity of conditioning regimens: working definitions | journal = Biology of Blood and Marrow Transplantation | volume = 15 | issue = 12 | pages = 1628–33 | date = December 2009 | pmid = 19896087 | pmc = 2861656 | doi = 10.1016/j.bbmt.2009.07.004 }} 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. [305] => [306] => == Occupational exposure and safe handling == [307] => {{manual|section|date=June 2023}} [308] => 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.{{cite journal | vauthors = Sorsa M, Hämeilä M, Järviluoma E | title = Handling anticancer drugs: from hazard identification to risk management? | journal = Annals of the New York Academy of Sciences | volume = 1076 | issue = 1 | pages = 628–34 | date = September 2006 | pmid = 17119240 | doi = 10.1196/annals.1371.008 | bibcode = 2006NYASA1076..628S | s2cid = 7081365 }} [309] => [310] => 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.{{Cite journal|url=http://theoncologypharmacist.com/top-issues/2014-issues/february-2014-vol-7-no-1/16084-chemotherapy-biomarkers-of-exposure-effect-reproductive-hazards-and-cancer|title=Chemotherapy: Biomarkers of Exposure, Effect, Reproductive Hazards, and Cancer|journal=The Oncology Pharmacist|date=March 2014|last1=Thomas h. Connor|first1=PhD|access-date=22 November 2018|archive-date=25 June 2021|archive-url=https://web.archive.org/web/20210625164339/http://theoncologypharmacist.com/top-issues/2014-issues/february-2014-vol-7-no-1/16084-chemotherapy-biomarkers-of-exposure-effect-reproductive-hazards-and-cancer|url-status=dead}} 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. [311] => [312] => === Routes of exposure === [313] => Antineoplastic drugs are usually given through [[Intravenous therapy|intravenous]], [[Intramuscular injection|intramuscular]], [[Intrathecal administration|intrathecal]], or [[Subcutaneous injection|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.{{cite document|title=Personal protective equipment for health care workers who work with hazardous drugs |date=October 2008 |doi=10.26616/NIOSHPUB2009106|publisher=NIOSH |doi-access=free }} [314] => [315] => 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 [[Needlestick injury|needle sticks]]. Research conducted in this area has established that occupational exposure occurs by examining evidence in multiple urine samples from health care workers.{{Cite book|title=Antineoplastic drugs: Occupational exposure and health risks | year=2006|isbn=978-90-393-4331-9}} [316] => [317] => === Hazards === [318] => 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.{{Cite journal |last1=Connor |first1=Thomas H. |last2=Lawson |first2=Christina C. |last3=Polovich |first3=Martha |last4=McDiarmid |first4=Melissa A. |date=2014 |title=Reproductive Health Risks Associated with Occupational Exposures to Antineoplastic Drugs in Health Care Settings: A Review of the Evidence |journal=Journal of Occupational and Environmental Medicine |volume=56 |issue=9 |pages=901–910 |doi=10.1097/JOM.0000000000000249 |issn=1076-2752 |pmc=4569003 |pmid=25153300}} [319] => [320] => Moreover, these drugs have [[carcinogen]]ic 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 [[Genotoxicity|genotoxic]] effect from anti-neoplastic drugs to workers in health care settings. [321] => [322] => === Safe handling in health care settings === [323] => As of 2018, there were no [[occupational exposure limit]]s set for antineoplastic drugs, i.e., OSHA or the [[American Conference of Governmental Industrial Hygienists]] (ACGIH) have not set workplace safety guidelines.{{Cite web|url=https://www.cdc.gov/niosh/docs/2004-165/pdfs/2004-165.pdf |archive-url=https://web.archive.org/web/20040913063413/http://www.cdc.gov/niosh/docs/2004-165/pdfs/2004-165.pdf |archive-date=2004-09-13 |url-status=live|title=preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings }} [324] => [325] => ==== Preparation ==== [326] => NIOSH recommends using a [[Engineering controls|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.{{Cite web|url=https://www.lni.wa.gov/Safety/Topics/AtoZ/HazardousDrugs/ProgramGuides.asp|title=Hazardous Drugs Program Guides|website=lni.wa.gov|access-date=2018-11-22|archive-date=27 October 2019|archive-url=https://web.archive.org/web/20191027005510/http://www.lni.wa.gov/Safety/Topics/AtoZ/HazardousDrugs/ProgramGuides.asp|url-status=dead}} [327] => [328] => 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.{{Cite journal |last=Kilinc |first=F. Selcen |date=2015 |title=A Review of Isolation Gowns in Healthcare: Fabric and Gown Properties |journal=Journal of Engineered Fibers and Fabrics |volume=10 |issue=3 |pages=180–190 |doi=10.1177/155892501501000313 |issn=1558-9250 |pmc=4791533 |pmid=26989351}} [329] => [330] => 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. [331] => [332] => ==== Administration ==== [333] => 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. [334] => [335] => 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.{{Cite book|title=Infectious and Medical Waste Management|isbn=9781315894430|last1=Reinhardt|first1=Peter A.|date=29 November 2017|publisher=CRC Press }}{{page needed|date=December 2018}} [336] => [337] => ==== Employee training ==== [338] => 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. [339] => [340] => ==== Housekeeping and waste disposal ==== [341] => 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.{{Cite web|url=http://www.searo.who.int/srilanka/documents/safe_management_of_wastes_from_healthcare_activities.pdf?ua=1|title=Safe management of wastes from health-care activities |website=WHO}} [342] => [343] => ==== Spill control ==== [344] => 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.{{cite journal | vauthors = DeJoy DM, Smith TD, Woldu H, Dyal MA, Steege AL, Boiano JM | title = Effects of organizational safety practices and perceived safety climate on PPE usage, engineering controls, and adverse events involving liquid antineoplastic drugs among nurses | journal = Journal of Occupational and Environmental Hygiene | volume = 14 | issue = 7 | pages = 485–493 | date = July 2017 | pmid = 28326998 | doi = 10.1080/15459624.2017.1285496 | s2cid = 3879822 }} [345] => [346] => === Occupational monitoring === [347] => A [[Workplace health surveillance|medical surveillance]] program must be established. In case of exposure, occupational health professionals need to ask for a detailed history and do a thorough physical exam. They should test the urine of the potentially exposed worker by doing a [[urine dipstick]] or microscopic examination, mainly looking for blood, as several antineoplastic drugs are known to cause bladder damage. [348] => [349] => 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. [350] => [351] => Biomarkers of exposure to antineoplastic drugs commonly include urinary [[platinum]], [[methotrexate]], urinary [[cyclophosphamide]] and [[ifosfamide]], and urinary metabolite of [[5-Fluorouracil|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.   [352] => [353] => == Available agents == [354] => {{Main|List of antineoplastic agents}} [355] => 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.{{cite book|author=Ian Olver|title=The MASCC Textbook of Cancer Supportive Care and Survivorship|url=https://books.google.com/books?id=fPzO59tmdBoC&pg=PA351|date=19 October 2010|publisher=Springer Science & Business Media|isbn=978-1-4419-1225-1|page=351}}{{cite book| first1 = James F. | last1 = Holland | first2 = Raphael E. | last2 = Pollock | name-list-style = vanc |title=Holland-Frei Cancer Medicine 8|url=https://books.google.com/books?id=R0FbhLsWHBEC&pg=PA1758|year=2010|publisher=PMPH-USA|isbn=978-1-60795-014-1|page=1758}} [356] => [357] => == History == [358] => {{Main|History of cancer chemotherapy}} [359] => [[File:Sidney Farber nci-vol-1926-300.jpg|thumb|150px|[[Sidney Farber]] did pioneering work in chemotherapy.]] [360] => [[File:Jane_Cooke_Wright.jpg|thumb|150px|[[Jane C. Wright]] pioneered the use of the drug methotrexate to treat breast cancer and skin cancer]] [361] => The first use of [[small-molecule drug]]s to treat cancer was in the early 20th century, although the specific chemicals first used were not originally intended for that purpose. [[Mustard gas]] was used as a [[chemical warfare]] agent during [[World War I]] and was discovered to be a potent suppressor of [[hematopoiesis]] (blood production).{{cite journal |author=Krumbhaar EB |title=Role of the blood and the bone marrow in certain forms of gas poisoning |journal=JAMA |volume=72 |pages=39–41 |year=1919 |doi=10.1001/jama.1919.26110010018009f |url=https://zenodo.org/record/1423423 }} A similar family of compounds known as [[nitrogen mustards]] were studied further during [[World War II]] at the [[Yale School of Medicine]].{{cite journal | vauthors = Fenn JE, Udelsman R | title = First use of intravenous chemotherapy cancer treatment: rectifying the record | journal = Journal of the American College of Surgeons | volume = 212 | issue = 3 | pages = 413–7 | date = March 2011 | pmid = 21247779 | doi = 10.1016/j.jamcollsurg.2010.10.018 }} It was reasoned that an agent that damaged the rapidly growing white blood cells might have a similar effect on cancer. Therefore, in December 1942, several people with advanced [[lymphomas]] (cancers of the lymphatic system and lymph nodes) were given the drug by vein, rather than by breathing the irritating gas. Their improvement, although temporary, was remarkable.{{cite journal | vauthors = Chabner BA, Roberts TG | title = Timeline: Chemotherapy and the war on cancer | journal = Nature Reviews. Cancer | volume = 5 | issue = 1 | pages = 65–72 | date = January 2005 | pmid = 15630416 | doi = 10.1038/nrc1529 | s2cid = 205467419 }} Concurrently, during a military operation in World War II, following a German [[Air raid on Bari|air raid]] on the Italian harbour of [[Bari]], several hundred people were accidentally exposed to mustard gas, which had been transported there by the [[Allies of World War II|Allied forces]] to prepare for possible retaliation in the event of German use of chemical warfare. The survivors were later found to have very low white blood cell counts.{{cite book | name-list-style = vanc |last = Faguet|first = Guy B.|title = The War on Cancer| url = https://archive.org/details/waroncanceranato00fagu | url-access = limited |publisher = Springer|year = 2005|page = [https://archive.org/details/waroncanceranato00fagu/page/n75 71]|isbn = 978-1-4020-3618-7}} After WWII was over and the reports declassified, the experiences converged and led researchers to look for other substances that might have similar effects against cancer. The first chemotherapy drug to be developed from this line of research was [[mustine]]. Since then, many other drugs have been developed to treat cancer, and drug development has exploded into a multibillion-dollar industry, although the principles and limitations of chemotherapy discovered by the early researchers still apply.{{cite journal | vauthors = Joensuu H | title = Systemic chemotherapy for cancer: from weapon to treatment | journal = The Lancet. Oncology | volume = 9 | issue = 3 | pages = 304 | date = March 2008 | pmid = 18308256 | doi = 10.1016/S1470-2045(08)70075-5 }} [362] => [363] => === The term ''chemotherapy'' === [364] => 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 [[Paul Ehrlich]] as meaning any use of chemicals to treat any disease (''[[wikt:chemo-|chemo]]-'' + ''[[wikt:-therapy|-therapy]]''), such as the use of [[antibiotic]]s (''antibacterial chemotherapy'').{{cite journal | vauthors = DeVita VT, Chu E | title = A history of cancer chemotherapy | journal = Cancer Research | volume = 68 | issue = 21 | pages = 8643–53 | date = November 2008 | pmid = 18974103 | doi = 10.1158/0008-5472.CAN-07-6611 | doi-access = free }} Ehrlich was not optimistic that effective chemotherapy drugs would be found for the treatment of cancer. The first modern chemotherapeutic agent was [[arsphenamine]], an arsenic compound discovered in 1907 and used to treat [[syphilis]].{{cite journal | vauthors = Nichols HJ, Walker JE | journal = The Journal of Experimental Medicine | volume = 37 | issue = 4 | pages = 525–42 | date = March 1923 | pmid = 19868743 | pmc = 2128372 | doi = 10.1084/jem.37.4.525 | title = Experimental Observations on the Prophylaxis and Treatment of Syphilis }} This was later followed by [[Sulfonamide (medicine)|sulfonamides]] (sulfa drugs) and [[penicillin]]. In today's [[usage]], the [[word sense|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. [365] => [366] => == Research == [367] => [[File:Mesoporous silica SEM.jpg|thumb|[[Scanning electron micrograph]] of [[mesoporous silica]], a type of [[nanoparticle]] used in the delivery of chemotherapeutic drugs]] [368] => {{Main|Experimental cancer treatments}} [369] => [370] => === Targeted delivery vehicles === [371] => 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.{{cite journal | vauthors = Chidambaram M, Manavalan R, Kathiresan K | title = Nanotherapeutics to overcome conventional cancer chemotherapy limitations | journal = Journal of Pharmacy & Pharmaceutical Sciences | volume = 14 | issue = 1 | pages = 67–77 | year = 2011 | pmid = 21501554 | doi = 10.18433/J30C7D | doi-access = free }} [372] => [373] => ==== Antibody-drug conjugates ==== [374] => [[Antibody-drug conjugate]]s (ADCs) comprise an [[antibody]], drug and a linker between them. The antibody will be targeted at a preferentially expressed protein in the tumour cells (known as a [[tumor antigen]]) or on cells that the tumor can utilise, such as blood vessel [[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.{{cite journal | vauthors = Teicher BA, Chari RV | title = Antibody conjugate therapeutics: challenges and potential | journal = Clinical Cancer Research | volume = 17 | issue = 20 | pages = 6389–97 | date = October 2011 | pmid = 22003066 | doi = 10.1158/1078-0432.CCR-11-1417 | doi-access = free }} 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.{{Cite journal |last1=Mokhtari |first1=Reza Bayat |last2=Homayouni |first2=Tina S. |last3=Baluch |first3=Narges |last4=Morgatskaya |first4=Evgeniya |last5=Kumar |first5=Sushil |last6=Das |first6=Bikul |last7=Yeger |first7=Herman |date=2017-03-30 |title=Combination therapy in combating cancer |journal=Oncotarget |volume=8 |issue=23 |pages=38022–38043 |doi=10.18632/oncotarget.16723 |issn=1949-2553 |pmc=5514969 |pmid=28410237}} [375] => [376] => The first approved drug of this type was [[gemtuzumab ozogamicin]] (Mylotarg), released by [[Wyeth]] (now [[Pfizer]]). The drug was approved to treat [[acute myeloid leukemia]].{{cite journal | vauthors = Sievers EL, Linenberger M | title = Mylotarg: antibody-targeted chemotherapy comes of age | journal = Current Opinion in Oncology | volume = 13 | issue = 6 | pages = 522–7 | date = November 2001 | pmid = 11673694 | doi = 10.1097/00001622-200111000-00016 | s2cid = 27827980 }} Two other drugs, [[trastuzumab emtansine]] and [[brentuximab vedotin]], are both in late clinical trials, and the latter has been granted accelerated approval for the treatment of [[refractory]] [[Hodgkin's lymphoma]] and systemic [[anaplastic large cell lymphoma]]. [377] => [378] => ==== Nanoparticles ==== [379] => [[Nanoparticles]] are 1–1000 [[nanometer]] (nm) sized particles that can promote tumor selectivity and aid in delivering low-[[solubility]] drugs. Nanoparticles can be targeted passively or actively. Passive targeting exploits the difference between tumor blood vessels and normal blood vessels. Blood vessels in tumors are "leaky" because they have gaps from 200 to 2000 nm, which allow nanoparticles to escape into the tumor. Active targeting uses biological molecules ([[Antibody|antibodies]], [[protein]]s, [[DNA]] and [[receptor ligand]]s) to preferentially target the nanoparticles to the tumor cells. There are many types of nanoparticle delivery systems, such as [[mesoporous silica|silica]], [[polymer]]s, [[liposome]]s{{cite journal | vauthors = Taléns-Visconti R, Díez-Sales O, de Julián-Ortiz JV, Nácher A | title = Nanoliposomes in Cancer Therapy: Marketed Products and Current Clinical Trials | journal = International Journal of Molecular Sciences | volume = 23 | issue = 8 | pages = 4249 | date = Apr 2022 | doi = 10.3390/ijms23084249 | pmid = 35457065 | pmc = 9030431 | doi-access = free }} and magnetic particles. Nanoparticles made of magnetic material can also be used to concentrate agents at tumor sites using an externally applied magnetic field. They have emerged as a useful vehicle in [[magnetic drug delivery]] for poorly soluble agents such as [[paclitaxel]].{{cite journal | vauthors = Vines T, Faunce T | title = Assessing the safety and cost-effectiveness of early nanodrugs | journal = Journal of Law and Medicine | volume = 16 | issue = 5 | pages = 822–45 | date = May 2009 | pmid = 19554862 }} [380] => [381] => === Electrochemotherapy === [382] => {{Main|Electrochemotherapy}} [383] => 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.{{Cite journal |last1=Larkin |first1=John O. |last2=Collins |first2=Christopher G. |last3=Aarons |first3=Simon |last4=Tangney |first4=Mark |last5=Whelan |first5=Maria |last6=O'Reily |first6=Seamus |last7=Breathnach |first7=Oscar |last8=Soden |first8=Declan M. |last9=O'Sullivan |first9=Gerald C. |date=2007 |title=Electrochemotherapy |journal=Annals of Surgery |volume=245 |issue=3 |pages=469–479 |doi=10.1097/01.sla.0000250419.36053.33 |issn=0003-4932 |pmc=1877027 |pmid=17435555}} [384] => [385] => Clinical electrochemotherapy has been successfully used for treatment of cutaneous and subcutaneous tumors irrespective of their histological origin.{{cite journal | vauthors = Larkin JO, Collins CG, Aarons S, Tangney M, Whelan M, O'Reily S, Breathnach O, Soden DM, O'Sullivan GC | title = Electrochemotherapy: aspects of preclinical development and early clinical experience | journal = Annals of Surgery | volume = 245 | issue = 3 | pages = 469–79 | date = March 2007 | pmid = 17435555 | pmc = 1877027 | doi = 10.1097/01.sla.0000250419.36053.33 }}{{cite journal | vauthors = Testori A, Tosti G, Martinoli C, Spadola G, Cataldo F, Verrecchia F, Baldini F, Mosconi M, Soteldo J, Tedeschi I, Passoni C, Pari C, Di Pietro A, Ferrucci PF | title = Electrochemotherapy for cutaneous and subcutaneous tumor lesions: a novel therapeutic approach | journal = Dermatologic Therapy | volume = 23 | issue = 6 | pages = 651–61 | year = 2010 | pmid = 21054709 | doi = 10.1111/j.1529-8019.2010.01370.x | s2cid = 46534637 | doi-access = free }} 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.{{cite journal |vauthors=Marty M, Sersa G, Garbay JR, Gehl J, Collins CG, Snoj M, Billard V, Geertsen PF, Larkin JO, Miklavcic D, Pavlovic I, Paulin-Kosir SM, Cemazar M, Morsli N, Soden DM, Rudolf Z, Robert C, O'Sullivan GC, Mir LM |year=2006 |title=Electrochemotherapy – An easy, highly effective and safe treatment of cutaneous and subcutaneous metastases |journal=Eur J Cancer Suppl |volume=4 |issue=11 |pages=3–13 |doi=10.1016/j.ejcsup.2006.08.002}}{{cite journal |vauthors=Mir LM, Gehl J, Sersa G, Collins CG, Garbay JR, Billard V, Geertsen PF, Rudolf Z, O'Sullivan GC, Marty M |title=Standard operating procedures of the electrochemotherapy: Instructions for the use of bleomycin or cisplatin administered either systemically or locally and electric pulses delivered by the Cliniporator™ by means of invasive or non-invasive electrodes |journal=Eur J Cancer Suppl |volume=4 |issue=11 |pages=14–25 |year=2006 |doi=10.1016/j.ejcsup.2006.08.003 }} 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.{{cite journal | vauthors = Soden DM, Larkin JO, Collins CG, Tangney M, Aarons S, Piggott J, Morrissey A, Dunne C, O'Sullivan GC | title = Successful application of targeted electrochemotherapy using novel flexible electrodes and low dose bleomycin to solid tumours | journal = Cancer Letters | volume = 232 | issue = 2 | pages = 300–10 | date = February 2006 | pmid = 15964138 | doi = 10.1016/j.canlet.2005.03.057 }}{{cite journal | vauthors = Miklavcic D, Snoj M, Zupanic A, Kos B, Cemazar M, Kropivnik M, Bracko M, Pecnik T, Gadzijev E, Sersa G | title = Towards treatment planning and treatment of deep-seated solid tumors by electrochemotherapy | journal = BioMedical Engineering OnLine | volume = 9 | issue = 1 | pages = 10 | date = February 2010 | pmid = 20178589 | pmc = 2843684 | doi = 10.1186/1475-925X-9-10 | doi-access = free }} [386] => [387] => === Hyperthermia therapy === [388] => [[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. [389] => [390] => 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.{{cite journal| vauthors = Issels R |title=Hyperthermia Combined with Chemotherapy – Biological Rationale, Clinical Application, and Treatment Results |journal=Onkologie |year=1999 |volume=22 |issue=5 |pages=374–381 |doi=10.1159/000026986 |s2cid=37581171 |url=http://nbn-resolving.de/urn:nbn:de:bvb:19-epub-16495-8 }} [391] => [392] => == Other animals == [393] => Chemotherapy is used in veterinary medicine similar to how it is used in human medicine.{{cite journal | vauthors = McKnight JA | s2cid = 39060053 | title = Principles of chemotherapy | journal = Clinical Techniques in Small Animal Practice | volume = 18 | issue = 2 | pages = 67–72 | date = May 2003 | pmid = 12831063 | doi = 10.1053/svms.2003.36617 }} [394] => [395] => == See also == [396] => {{columns-list|colwidth=20em| [397] => * [[Anti-Cancer Drugs (journal)|''Anti-Cancer Drugs'' (journal)]] [398] => * [[Chemotherapy (journal)|Antimicrobial chemotherapy]] [399] => * [[Cancer and nausea]] [400] => * [[Cancer-related fatigue]] [401] => * [[Chemo brain]] [402] => * [[Chemotherapy regimens]] [403] => * [[Cytostasis]] [404] => * [[Experimental cancer treatment]]s [405] => * [[Hazardous drugs#Safe handling|Safe Handling of Hazardous Drugs]] [406] => * [[Drug delivery]] [407] => * [[Hyperthermia therapy]] [408] => * [[Immunotherapy]] [409] => * [[National Comprehensive Cancer Network]] [410] => * [[Radiation induced cognitive decline]] [411] => * [[Radiotherapy]] [412] => * [[Virotherapy]] [413] => }} [414] => [415] => == References == [416] => {{reflist}} [417] => [418] => == External links == [419] => {{sisterlinks|d=Q974135|c=Category:Chemotherapy|n=no|b=no|v=no|voy=no|q=no|s=no|m=no|mw=no|species=no}} [420] => * [https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy.html Chemotherapy], [[American Cancer Society]] [421] => * [https://www.cdc.gov/niosh/topics/hazdrug/default.html Hazardous Drug Exposures in Health Care], [[National Institute for Occupational Safety and Health]] [422] => * [[National Institute for Occupational Safety and Health|NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016, National Institute for Occupational Safety and Health]] [423] => [424] => {{Tumors}} [425] => {{Targeted cancer therapeutic agents}} [426] => {{Major Drug Groups}} [427] => {{Authority control}} [428] => [429] => [[Category:Chemotherapy| ]] [430] => [[Category:Antineoplastic drugs]] [431] => [[Category:Oncology]] [432] => [[Category:Cancer treatments]] [433] => [[Category:Occupational safety and health]] [] => )
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Chemotherapy

Chemotherapy is a widely used treatment method in the field of oncology, aimed at treating cancer by administering drugs that kill rapidly dividing cells. This Wikipedia page provides an overview of chemotherapy, including its history, mechanisms of action, types, and applications.

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This Wikipedia page provides an overview of chemotherapy, including its history, mechanisms of action, types, and applications. The page begins with a brief introduction explaining the concept of chemotherapy and its significance in treating cancer. It then delves into the historical background, tracing the origins of chemotherapy from ancient times to its development into a systematic treatment method in the 20th century. The mechanisms of action section highlights how chemotherapy drugs target and interfere with various stages of cell division, ultimately leading to the death of cancer cells. The page then explores the different types of chemotherapy agents, including cytotoxic drugs, targeted therapy drugs, immunomodulatory drugs, and hormonal agents. Each category is explained in detail, with examples of commonly used drugs provided. Next, the page discusses the administration routes of chemotherapy, such as oral, intravenous, and intrathecal methods. It also covers various treatment regimens and schedules, depending on the type and stage of cancer. This section also addresses the side effects associated with chemotherapy, which are often the result of the drugs' effects on normal healthy cells. The page further explores the applications of chemotherapy in different types of cancer, such as breast, lung, and colon cancer, among others. It provides specific examples of chemotherapy drugs commonly used in each cancer type, highlighting their efficacy and limitations. Moreover, the page analyzes the potential complications and risks associated with chemotherapy, including drug resistance, long-term side effects, and the need for supportive care during treatment. The Wikipedia page concludes with information about ongoing research and advancements in chemotherapy, as well as emerging therapies, such as immunotherapy and personalized medicine. It also provides references and external links for further reading and exploration of the topic. Overall, the Wikipedia page on chemotherapy comprehensively covers the history, mechanisms, types, applications, side effects, and future directions of chemotherapy in cancer treatment.

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