Editing Chemotherapy (section)

=== Dosage ===
[[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.<ref name=Corrie />]]
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.<ref name=Corrie /> 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.<ref>{{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 }}</ref> The study only included nine human subjects.<ref name="dosing strategies">{{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 }}</ref> 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.<ref name="pmid17305252">{{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 }}</ref><ref>{{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 }}</ref>

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.<ref name="pmid17305252" /><ref name="pmid11953888">{{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 }}</ref><ref name="pmid22965963">{{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 }}</ref> 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.<ref name="dosing strategies" /><ref name="role of body">{{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 }}</ref> 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.<ref name="role of body" /> 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.<ref name="dosing strategies" />

[[File:Improvement in Response Rate.jpg|thumb|180px|right|5-FU dose management results in significantly better response and survival rates versus BSA dosing.<ref name="individual fluorouracil" />]]
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.<ref name="pmid17305252" /><ref name="pmid11953888" /><ref name="pmid22965963" /><ref name="individual fluorouracil">{{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 }}</ref><ref>{{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 }}</ref><ref name="dose adjustment">{{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 }}</ref><ref>{{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 }}</ref> 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.<ref name="individual fluorouracil" />

There has been controversy over the use of BSA to calculate chemotherapy doses for people who are [[obese]].<ref name="dosing chemotherapy">{{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 }}</ref> Because of their higher BSA, clinicians often arbitrarily reduce the dose prescribed by the BSA formula for fear of [[overdosing]].<ref name="dosing chemotherapy" /> In many cases, this can result in sub-optimal treatment.<ref name="dosing chemotherapy" />

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.<ref name="individual fluorouracil" /><ref name="dose adjustment" /> 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.<ref name="individual fluorouracil" />

[[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.<ref name="individual fluorouracil" />]]
{{multiple image
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| image1            = Response 1.jpg
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| caption2          = 5-FU dose management in the FOLFOX regimen increases treatment response significantly and improves survival by six months.<ref name="dose adjustment" />
}}
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.<ref name="individual fluorouracil" /> 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.<ref name="individual fluorouracil" /> Because of the reduced toxicity, dose-adjusted patients were able to be treated for longer periods of time.<ref name="individual fluorouracil" /> 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.<ref name="individual fluorouracil" /> Completing the course of treatment is an important factor in achieving better treatment outcomes.

Similar results were found in a study involving people with colorectal cancer who have been treated with the popular [[FOLFOX]] regimen.<ref name="dose adjustment" /> 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%.<ref name="dose adjustment" />

The FOLFOX study also demonstrated an improvement in treatment outcomes.<ref name="dose adjustment" /> 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.<ref name="dose adjustment" />

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.<ref>{{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 }}</ref>

Oncologists are already individualizing dosing of some cancer drugs based on exposure. [[Carboplatin]]<ref name=Hanna2008>{{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}}</ref>{{rp|4}} and [[busulfan]]<ref>{{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 }}</ref><ref>{{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 }}</ref> 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]],<ref>{{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}}</ref> 5-FU, [[paclitaxel]], and [[docetaxel]].<ref>{{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}}</ref><ref>{{cite web|url=http://bettercancercare.com|title=A Brief History of BSA Dosing|publisher=My Care Diagnostics}}</ref>

The serum albumin level immediately prior to chemotherapy administration is an independent prognostic predictor of survival in various cancer types.<ref>{{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 }}</ref>