When the Mirror Doesn’t Reflect It at All
Authors: Stanley E. Order, Wayne Court, Felix E. de Jongh, Jaap Verweij, Alex Sparreboom
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.4.1144 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11844839 When the Mirror Doesn’t Reflect It at All Stanley E. OrderxStanley E. OrderSearch for articles by this author , Wayne CourtxWayne CourtSearch for articles by this author Felix E. de JonghxFelix E. de JonghSearch for articles by this author , Jaap VerweijxJaap VerweijSearch for articles by this author , Alex SparreboomxAlex SparreboomSearch for articles by this author Show More Center for Molecular Medicine, Garden City, NYRotterdam Cancer Institute (Daniel den Hoed Kliniek) and, University Hospital Rotterdam, Rotterdam, the Netherlands https://doi.org/10.1200/JCO.2002.20.4.1144 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15022002In Reply:We thank Drs Order and Court for responding to our article. Their most important issue is that measurement of plasma concentrations probably may not reflect drug exposure in the tumor very reliably. We certainly agree with this statement and indeed are conscious of the limitations of plasma pharmacokinetics.1 However, it has also been shown that the plasma area under the concentration-time curve of cisplatin correlates significantly with platinum DNA-adduct formation in peripheral-blood leukocytes and with antitumor activity.2 Furthermore, the statement that binding of cisplatin to plasma proteins results in drug inactivation is not necessarily true. It has been demonstrated that binding to plasma proteins (albumin) is a very complex process with many different binding sites involved. In vitro studies have demonstrated that albumin-cisplatin complexes are cytotoxic to cancer cells in culture. Infusion of preformed cisplatin-albumin complexes has exerted significant antitumor activity, whereas binding to serum albumin probably reduces cisplatin-related nephrotoxicity and ototoxicity.3 Colleagues Order and Court advocate a broader use of locoregional administration of cisplatin in order to obtain selectively higher activity against locally confined tumors, with less systemic toxicity. Although we acknowledge the advantages of local drug delivery, the most common clinical application of cisplatin remains treatment of patients with disseminated malignant disease, which necessitates the intravenous (IV) (systemic) route of administration. Another, more practical problem is the unavailability in most hospitals of equipment for radiopharmaceutical monitoring of intratumoral drug concentrations. Taken together, we believe that these issues present significant limitations to locoregional drug delivery in routine clinical practice for the near future, and that IV administration will remain the route of choice for cisplatin. The main message of our study is that the plasma clearance of IV-administered cisplatin is not reliably predicted by body-surface area, which challenges the routine use of body-surface area in dose calculation of cisplatin.41. Sparreboom A, Loos WJ, De Jonge MJA, et al: Clinical trial design: Incorporation of pharmacokinetic, pharmacodynamic, and pharmacogenetic principles, in Baguley BC, Kerr DJ (eds): Anticancer Drug Development. San Diego, CA, Academic Press, 2002, pp 329-351 (in press) Google Scholar2. Schellens JHM, Ma J, Planting AST, et al: Relationship between the exposure to cisplatin, DNA-adduct formation in leucocytes and tumour response in patients with solid tumours. Br J Cancer 73:: 1569,1996-1575, Crossref, Medline, Google Scholar3. Ivanov AI, Christodoulou J, Parkinson JA, et al: Cisplatin binding sites of human albumin. J Biol Chem 273:: 14721,1998-14730, Crossref, Medline, Google Scholar4. De Jongh FE, Verweij J, Loos WJ, et al: Body-surface area–based dosing does not increase accuracy of predicting cisplatin exposure. J Clin Oncol 19:: 3733,2001-3739, Link, Google Scholar