carboplatin

Carboplatin is used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It may be used for some types of testicular cancer but cisplatin is generally more effective. It has also been used to treat triple-negative breast cancer. Carboplatin has also been used for adjuvant therapy of stage 1 seminomatous testicular cancer. Research has indicated that it is not less effective than adjuvant radiotherapy for this treatment, while having fewer side effects.{{cite journal | vauthors = Oliver RT, Mason MD, Mead GM, von der Maase H, Rustin GJ, Joffe JK, de Wit R, Aass N, Graham JD, Coleman R, Kirk SJ, Stenning SP | display-authors = 6 | title = Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial | journal = Lancet | volume = 366 | issue = 9482 | pages = 293–300 | year = 2005 | pmid = 16039331 | doi = 10.1016/S0140-6736(05)66984-X | s2cid = 6001898 | doi-access = free }} This has led to carboplatin based adjuvant therapy being generally preferred over adjuvant radiotherapy in clinical practice.{{cite journal | vauthors = Toner GC | title = Testicular cancer: Optimal management of stage I seminoma in 2015 | journal = Nature Reviews. Urology | volume = 12 | issue = 5 | pages = 249–251 | date = May 2015 | pmid = 25896179 | doi = 10.1038/nrurol.2015.85 | s2cid = 8072355 }}

Relative to cisplatin, the greatest benefit of carboplatin is its reduced side effects, particularly the elimination of nephrotoxic effects. Nausea and vomiting are less severe and more easily controlled.{{Cite book |title=Manual of Hematopoietic Cell Transplantation and Cellular Therapies |vauthors=Gulbis AM, Wallis WD |year=2023 |pages=125–143 |chapter=10 - Preparative Regimens Used in Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T-Cell Therapies |publisher=Elsevier |doi=10.1016/B978-0-323-79833-4.00010-3|isbn=9780323798334 }}

The main drawback of carboplatin is its myelosuppressive effect. This causes the blood cell and platelet output of bone marrow in the body to decrease quite dramatically, sometimes as low as 10% of its usual production levels. The nadir of this myelosuppression usually occurs 21–28 days after the first treatment, after which the blood cell and platelet levels in the blood begin to stabilize, often coming close to its pre-carboplatin levels. This decrease in white blood cells (neutropenia) can cause complications, and is sometimes treated with drugs like filgrastim. The most notable complication of neutropenia is increased probability of infection by opportunistic organisms, which necessitates hospital readmission and treatment with antibiotics.

Carboplatin differs from cisplatin in that it has a bidentate dicarboxylate (the ligand is cyclobutane dicarboxylate, CBDCA) in place of the two chloride ligands. Both drugs are alkylating agents. CBDCA and chloride are the leaving groups in these respective drugs Carboplatin exhibits slower aquation (replacement of CBDCA by water) and thus slower DNA binding kinetics, although it forms the same reaction products in vitro at equivalent doses with cisplatin. Unlike cisplatin, carboplatin may be susceptible to alternative mechanisms. Some results show that cisplatin and carboplatin cause different morphological changes in MCF-7 cell lines while exerting their cytotoxic behaviour.{{cite journal | vauthors = Natarajan G, Malathi R, Holler E | title = Increased DNA-binding activity of cis-1,1-cyclobutanedicarboxylatodiammineplatinum(II) (carboplatin) in the presence of nucleophiles and human breast cancer MCF-7 cell cytoplasmic extracts: activation theory revisited | journal = Biochemical Pharmacology | volume = 58 | issue = 10 | pages = 1625–1629 | date = November 1999 | pmid = 10535754 | doi = 10.1016/S0006-2952(99)00250-6 }} The diminished reactivity limits protein-carboplatin complexes, which are excreted. The lower excretion rate of carboplatin means that more is retained in the body, and hence its effects are longer lasting (a retention half-life of 30 hours for carboplatin, compared to 1.5-3.6 hours in the case of cisplatin).

Like cisplatin, carboplatin binds to and cross-links DNA, interfering with the replication and suppressing growth of the cancer cell.{{cite journal | vauthors = Noll DM, Mason TM, Miller PS | title = Formation and repair of interstrand cross-links in DNA | journal = Chemical Reviews | volume = 106 | issue = 2 | pages = 277–301 | date = February 2006 | pmid = 16464006 | pmc = 2505341 | doi = 10.1021/cr040478b }}{{Cite book |title=Encyclopedia of Respiratory Medicine |vauthors=Edelman MJ, Rupard EJ |year=2006 |pages=332–338 |chapter=TUMORS, MALIGNANT / Chemotherapeutic Agents |publisher=Academic Press |doi=10.1016/B0-12-370879-6/00409-9|isbn=9780123708793 }}

Prior to 1989, most carboplatin dosing used body surface area dosing as with other chemotherapy. However, toxicity from treatment was variable, and therefore Professor Hillary Calvert (University of Newcastle) developed a formula to dose carboplatin based on renal function.

Calvert's formula considers the creatinine clearance and the desired area under curve.{{cite web |url=http://www.mskcc.org/cancer-care/clinical-update/new-guidelines-carboplatin-dosing |title=New Guidelines for Carboplatin Dosing| vauthors = O'Cearbhaill R, Sabbatini PS |date=1 September 2012|publisher=Memorial Sloan Kettering Cancer Center|access-date=27 March 2014 |url-status=live |archive-url=https://web.archive.org/web/20141031014904/http://www.mskcc.org/cancer-care/clinical-update/new-guidelines-carboplatin-dosing |archive-date=31 October 2014 }} After 24 hours, close to 70% of carboplatin is excreted in the urine unchanged. This means that the dose of carboplatin must be adjusted for any impairment in kidney function.{{cite journal | vauthors = Calvert AH, Newell DR, Gumbrell LA, O'Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, Gore ME, Wiltshaw E | display-authors = 6 | title = Carboplatin dosage: prospective evaluation of a simple formula based on renal function | journal = Journal of Clinical Oncology | volume = 7 | issue = 11 | pages = 1748–1756 | date = November 1989 | pmid = 2681557 | doi = 10.1200/JCO.1989.7.11.1748 }}

Calvert formula: $\backslash mathrm\{Dose\}(\backslash mathrm\{mg\})=\; \backslash mathrm\{AUC\}\; \backslash cdot\; (\backslash mathrm\{GFR\}\; +\; 25)$

The typical area under the curve (AUC) for carboplatin ranges from 3-7 (mg/ml)*min. GFR (Glomerular Filtration Rate) is a measure or estimate of kidney function. This is either measured, by measuring clearance of a radioisotope or estimated using serum and (sometimes) urine creatine measurements.{{cite journal | vauthors = Donahue A, McCune JS, Faucette S, Gillenwater HH, Kowalski RJ, Socinski MA, Lindley C | title = Measured versus estimated glomerular filtration rate in the Calvert equation: influence on carboplatin dosing | journal = Cancer Chemotherapy and Pharmacology | volume = 47 | issue = 5 | pages = 373–379 | date = May 2001 | pmid = 11391850 | doi = 10.1007/s002800000260 }}

The Calvert formula was developed in 18 patients with GFR measurements up to 133ml/min. It's applicability at very high doses of carboplatin has been challenged{{cite journal | vauthors = Mazumdar M, Smith A, Tong WP, Motzer RJ | title = Calvert's formula for dosing carboplatin: overview and concerns of applicability in high-dose setting | journal = Journal of the National Cancer Institute | volume = 92 | issue = 17 | pages = 1434–1436 | date = September 2000 | pmid = 10974080 | doi = 10.1093/jnci/92.17.1434 }} and in the US the Food and Drug Administration has recommended capping GFR at 125ml/min.{{Cite web |work=Center for Drug Evaluation and Research (CDER) |title=Carboplatin dosing |url=http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm228974.htm |archive-url=https://web.archive.org/web/20170118084252/http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm228974.htm |archive-date=18 January 2017 |access-date=26 December 2024 |publisher=U.S. Food and Drug Administration |language=en |url-status=live }} This may be more important where dosing is based on calculations using more modern methods of creatinine measurement. The approach is not supported by all clinicians and certainly less so in those treating seminomas.{{cite journal | vauthors = Fehr M, Maranta AF, Reichegger H, Gillessen S, Cathomas R | title = Carboplatin dose based on actual renal function: no excess of acute haematotoxicity in adjuvant treatment in seminoma stage I | journal = ESMO Open | volume = 3 | issue = 3 | pages = e000320 | date = 2018 | pmid = 29531843 | pmc = 5844370 | doi = 10.1136/esmoopen-2018-000320 }}

Cisplatin reacts with silver nitrate and then cyclobutane-1,1-dicarboxylic acid to form carboplatin.{{Cite book |title=Synthesis of Essential Drugs |vauthors=Vardanyan RS, Hruby VJ |year=2006 |pages=389–418 |chapter=30 - Antineoplastics |publisher=Elsevier |doi=10.1016/B978-044452166-8/50030-3|isbn=9780444521668 }}

File:Carboplatin synthesis.png

Carboplatin, a cisplatin analogue, was developed by Bristol Myers Squibb and the Institute of Cancer Research in order to reduce the toxicity of cisplatin.{{Cite journal |vauthors=Lebwohl D, Canetta R |year=1998 |title=Clinical development of platinum complexes in cancer therapy: an historical perspective and an update |url=https://www.ejcancer.com/action/showPdf?pii=S0959-8049%2898%2900224-X |journal=Eur J Cancer |volume=34 |issue=10 |pages=1522–34 |doi=10.1016/s0959-8049(98)00224-x |pmid=9893623}}{{Cite web |title=Discovering early chemotherapy drugs |url=https://www.icr.ac.uk/about-us/our-achievements/our-scientific-discoveries/we-discovered-chemotherapeutic-agents-which-are-still-in-use-more-than-50-years-later |access-date=6 October 2023 |website=Institute of Cancer Research}} It gained U.S. Food and Drug Administration (FDA) approval for carboplatin, under the brand name Paraplatin, in March 1989. Starting in October 2004, generic versions of the drug became available.

{{Reflist}}

• {{cite journal | vauthors = Canetta R, Rozencweig M, Carter SK | title = Carboplatin: the clinical spectrum to date | journal = Cancer Treatment Reviews | volume = 12 Suppl A | issue = Suppl A | pages = 125–136 | date = September 1985 | pmid = 3002623 | doi = 10.1016/0305-7372(85)90027-1 }}
• {{cite journal | vauthors = Yang XL, Wang AH | title = Structural studies of atom-specific anticancer drugs acting on DNA | journal = Pharmacology & Therapeutics | volume = 83 | issue = 3 | pages = 181–215 | date = September 1999 | pmid = 10576292 | doi = 10.1016/S0163-7258(99)00020-0 }}

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