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Published in: Cancer Chemotherapy and Pharmacology 1/2011

01-07-2011 | Original Article

Difluorodeoxyuridine plasma concentrations after low-dose gemcitabine during chemoradiation in head and neck cancer patients

Authors: P. Specenier, G. Guetens, J. Dyck, G. De Boeck, J. Weyler, D. Van den Weyngaert, K. Aelbrecht, J. B. Vermorken

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2011

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Abstract

Purpose

The aim of this study was to investigate whether relevant plasma levels of dFdU could be detected during concurrent chemoradiation (CRT) with low doses of dFdC administered in patients with head and neck cancer and to assess the toxicity related to dose.

Methods

dFdC was administered at doses of 5 mg/m² twice weekly or 10, 50, or 100 mg/m² weekly. Plasma concentrations of dFdU were determined daily for 7 days after the first administration and before each administration, thereafter. A high-performance liquid chromatographic method was used. During CRT, skin and mucosal toxicity were scored weekly according to the RTOG toxicity scoring system.

Results

Eight patients were sampled at the 10–50 mg/m² dose and nine at the 5–100 mg/m² dose. dFdU levels were in the micromolar range, inducing RS in vitro. There was a strong correlation between the area under the curve of dFdU and the dose of dFdC (r = 0.803, P < 0.001) and a weak correlation between trough concentrations and total dose of dFdC (r = 0.408, P = 0.017). Duration of severe mucositis correlated with dFdC dose.

Conclusions

During CRT with 10–100 mg/m2 of dFdC weekly or 5 mg/m2 twice weekly, dFdU remains detectable at potentially radiosensitizing concentrations.
Literature
1.
go back to reference Heinemann V, Hertel LW, Grindey GB, Plunkett W (1988) Comparison of the cellular pharmacokinetics and toxicity of 2′,2′-difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine. Cancer Res 48:4024–4031PubMed Heinemann V, Hertel LW, Grindey GB, Plunkett W (1988) Comparison of the cellular pharmacokinetics and toxicity of 2′,2′-difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine. Cancer Res 48:4024–4031PubMed
2.
go back to reference Catimel G, Vermorken JB, Clavel M et al (1994) A phase II study of Gemcitabine (LY 188011) in patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 5:543–547PubMed Catimel G, Vermorken JB, Clavel M et al (1994) A phase II study of Gemcitabine (LY 188011) in patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 5:543–547PubMed
3.
go back to reference Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W (1991) Action of 2′,2′-difluorodeoxycytidine on DNA synthesis. Cancer Res 51(22):6110–6117PubMed Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W (1991) Action of 2′,2′-difluorodeoxycytidine on DNA synthesis. Cancer Res 51(22):6110–6117PubMed
4.
go back to reference van Ruiz Haperen VW, Veerman G, Vermorken JB, Peters GJ (1993) 2′,2′-Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines. Biochem Pharmacol 46:726–762 van Ruiz Haperen VW, Veerman G, Vermorken JB, Peters GJ (1993) 2′,2′-Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines. Biochem Pharmacol 46:726–762
5.
go back to reference Bergman AM, Pinedo HM, Peters GJ (2002) Determinants of resistance to 2′,2′-difluorodeoxycytidine (gemcitabine). Drug Resist Updat 5:19–33PubMedCrossRef Bergman AM, Pinedo HM, Peters GJ (2002) Determinants of resistance to 2′,2′-difluorodeoxycytidine (gemcitabine). Drug Resist Updat 5:19–33PubMedCrossRef
6.
go back to reference van der Wilt CL, Kroep JR, Bergman AM, Loves WJ, Alvarez E, Talianidis I, Eriksson S, van Groeningen CJ, Pinedo HM, Peters GJ (2000) The role of deoxycytidine kinase in gemcitabine cytotoxicity. Adv Exp Med Biol 486:287–290PubMedCrossRef van der Wilt CL, Kroep JR, Bergman AM, Loves WJ, Alvarez E, Talianidis I, Eriksson S, van Groeningen CJ, Pinedo HM, Peters GJ (2000) The role of deoxycytidine kinase in gemcitabine cytotoxicity. Adv Exp Med Biol 486:287–290PubMedCrossRef
7.
go back to reference Kroep JR, Loves WJ, van der Wilt CL, Alvarez E, Talianidis I, Boven E, Braakhuis BJ, van Groeningen CJ, Pinedo HM, Peters GJ (2002) Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity. Mol Cancer Ther 1:371–376PubMed Kroep JR, Loves WJ, van der Wilt CL, Alvarez E, Talianidis I, Boven E, Braakhuis BJ, van Groeningen CJ, Pinedo HM, Peters GJ (2002) Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity. Mol Cancer Ther 1:371–376PubMed
8.
go back to reference Pauwels B, Korst AEC, Lardon F, Vermorken JB (2005) Combined modality therapy of gemcitabine and radiation. Oncologist 10:34–51PubMedCrossRef Pauwels B, Korst AEC, Lardon F, Vermorken JB (2005) Combined modality therapy of gemcitabine and radiation. Oncologist 10:34–51PubMedCrossRef
9.
go back to reference Pauwels B, Vermorken JB, Wouters A, Ides J, Van Laere S, Lambrechts HA, Pattyn GG, Vermeulen K, Meijnders P, Lardon F (2009) The role of apoptotic cell death in the radiosensitising effect of gemcitabine. Br J Cancer 101:628–636PubMedCrossRef Pauwels B, Vermorken JB, Wouters A, Ides J, Van Laere S, Lambrechts HA, Pattyn GG, Vermeulen K, Meijnders P, Lardon F (2009) The role of apoptotic cell death in the radiosensitising effect of gemcitabine. Br J Cancer 101:628–636PubMedCrossRef
10.
go back to reference Morgan MA, Parsels LA, Parsels JD, Mesiwala AK, Maybaum J, Lawrence TS (2005) Role of checkpoint kinase 1 in preventing premature mitosis in response to gemcitabine. Cancer Res 65:6835–6842PubMedCrossRef Morgan MA, Parsels LA, Parsels JD, Mesiwala AK, Maybaum J, Lawrence TS (2005) Role of checkpoint kinase 1 in preventing premature mitosis in response to gemcitabine. Cancer Res 65:6835–6842PubMedCrossRef
11.
go back to reference Wachters FM, van Putten JW, Maring JG, Zdzienicka MZ, Groen HJ, Kampinga HH (2003) Selective targeting of homologous DNA recombination repair by gemcitabine. Int J Radiat Oncol Biol Phys 57:553–625PubMedCrossRef Wachters FM, van Putten JW, Maring JG, Zdzienicka MZ, Groen HJ, Kampinga HH (2003) Selective targeting of homologous DNA recombination repair by gemcitabine. Int J Radiat Oncol Biol Phys 57:553–625PubMedCrossRef
12.
go back to reference Robinson BW, Shewach DS (2001) Radiosensitization by gemcitabine in p53 wild-type and mutant MCF-7 breast carcinoma cell lines. Clin Cancer Res 7:2581–2589PubMed Robinson BW, Shewach DS (2001) Radiosensitization by gemcitabine in p53 wild-type and mutant MCF-7 breast carcinoma cell lines. Clin Cancer Res 7:2581–2589PubMed
13.
go back to reference Robinson BW, Im MM, Ljungman M, Praz F, Shewach DS (2003) Enhanced radiosensitization with gemcitabine in mismatch repair-deficient HCT116 cells. Cancer Res 63:6935–6941PubMed Robinson BW, Im MM, Ljungman M, Praz F, Shewach DS (2003) Enhanced radiosensitization with gemcitabine in mismatch repair-deficient HCT116 cells. Cancer Res 63:6935–6941PubMed
14.
go back to reference Cranea CH, Varadhachary G, Settlea SH, Fleming JB, Evans DB, Wolff RA (2009) The integration of chemoradiation in the care of patient with localized pancreatic cancer. Cancer Radiother 13:123–143 Cranea CH, Varadhachary G, Settlea SH, Fleming JB, Evans DB, Wolff RA (2009) The integration of chemoradiation in the care of patient with localized pancreatic cancer. Cancer Radiother 13:123–143
15.
go back to reference Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW, Vauthey JN, Wang H, Cleary KR, Staerkel GA, Charnsangavej C, Lano EA, Ho L, Lenzi R, Abbruzzese JL, Wolff RA (2008) Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol 26:3496–3502PubMedCrossRef Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW, Vauthey JN, Wang H, Cleary KR, Staerkel GA, Charnsangavej C, Lano EA, Ho L, Lenzi R, Abbruzzese JL, Wolff RA (2008) Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol 26:3496–3502PubMedCrossRef
16.
go back to reference Rose PG, Degeest K, McMeekin S, Fusco N (2007) A phase I study of gemcitabine followed by cisplatin concurrent with whole pelvic radiation therapy in locally advanced cervical cancer: a Gynecologic Oncology Group study. Gynecol Oncol 107:274–279PubMedCrossRef Rose PG, Degeest K, McMeekin S, Fusco N (2007) A phase I study of gemcitabine followed by cisplatin concurrent with whole pelvic radiation therapy in locally advanced cervical cancer: a Gynecologic Oncology Group study. Gynecol Oncol 107:274–279PubMedCrossRef
17.
go back to reference Dueñas-González A, Zarba JJ, Alcedo JC, Pattarunataporn P, Beslija S, Patel F, Casanova L, Barraclough H, Orlando M (2009) A phase III study comparing concurrent gemcitabine (Gem) plus cisplatin (Cis) and radiation followed by adjuvant Gem plus Cis versus concurrent Cis and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 27: 18s (suppl; abstr CRA5507) Dueñas-González A, Zarba JJ, Alcedo JC, Pattarunataporn P, Beslija S, Patel F, Casanova L, Barraclough H, Orlando M (2009) A phase III study comparing concurrent gemcitabine (Gem) plus cisplatin (Cis) and radiation followed by adjuvant Gem plus Cis versus concurrent Cis and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 27: 18s (suppl; abstr CRA5507)
18.
go back to reference Eisbruch A, Shewach DS, Bradford CR, Littles JF, Teknos TN, Chepeha DB, Marentette LJ, Terrell JE, Hogikyan ND, Dawson LA, Urba S, Wolf GT, Lawrence TS (2001) Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study. J Clin Oncol 19:792–799PubMed Eisbruch A, Shewach DS, Bradford CR, Littles JF, Teknos TN, Chepeha DB, Marentette LJ, Terrell JE, Hogikyan ND, Dawson LA, Urba S, Wolf GT, Lawrence TS (2001) Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study. J Clin Oncol 19:792–799PubMed
19.
go back to reference Specenier PM, Van den Weyngaert D, Van Laer C, Weyler J, Van den Brande J, Huizing MT, Dyck J, Schrijvers D, Vermorken JB (2007) Phase II feasibility study of concurrent radiotherapy and gemcitabine in chemonaive patients with squamous cell carcinoma of the head and neck: long-term follow up data. Ann Oncol 18:1856–1860PubMedCrossRef Specenier PM, Van den Weyngaert D, Van Laer C, Weyler J, Van den Brande J, Huizing MT, Dyck J, Schrijvers D, Vermorken JB (2007) Phase II feasibility study of concurrent radiotherapy and gemcitabine in chemonaive patients with squamous cell carcinoma of the head and neck: long-term follow up data. Ann Oncol 18:1856–1860PubMedCrossRef
20.
go back to reference Specenier PM, Weyler J, Van Laer C, Van den Weyngaert D, Van den Brande J, Huizing MT, Altintas S, Vermorken JB (2009) A non-randomized comparison of gemcitabine-based chemoradiation with or without induction chemotherapy for locally advanced squamous cell carcinoma of the head and neck. BMC Cancer 9:273PubMedCrossRef Specenier PM, Weyler J, Van Laer C, Van den Weyngaert D, Van den Brande J, Huizing MT, Altintas S, Vermorken JB (2009) A non-randomized comparison of gemcitabine-based chemoradiation with or without induction chemotherapy for locally advanced squamous cell carcinoma of the head and neck. BMC Cancer 9:273PubMedCrossRef
21.
go back to reference Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Satterlee W, Raber MN (1991) A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491–498PubMed Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Satterlee W, Raber MN (1991) A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491–498PubMed
22.
go back to reference Peters GJ, Clavel M, Noordhuis P, Geyssen GJ, Laan AC, Guastalla J, Edzes HT, Vermorken JB (2007) Clinical phase I and pharmacology study of gemcitabine (2′,2′-difluorodeoxycytidine) administered in a two-weekly schedule. J Chemother 19:212–221PubMed Peters GJ, Clavel M, Noordhuis P, Geyssen GJ, Laan AC, Guastalla J, Edzes HT, Vermorken JB (2007) Clinical phase I and pharmacology study of gemcitabine (2′,2′-difluorodeoxycytidine) administered in a two-weekly schedule. J Chemother 19:212–221PubMed
23.
go back to reference Pauwels B, Korst AEC, Lambrechts AEJ, Pattyn GGO, de Pooter CMJ, Lardon F, Vermorken JB (2006) The radiosensitising effect of difluorodeoxyuridine, a metabolite of gemcitabine, in vitro. Cancer Chemother Pharmacol 58:219–228PubMedCrossRef Pauwels B, Korst AEC, Lambrechts AEJ, Pattyn GGO, de Pooter CMJ, Lardon F, Vermorken JB (2006) The radiosensitising effect of difluorodeoxyuridine, a metabolite of gemcitabine, in vitro. Cancer Chemother Pharmacol 58:219–228PubMedCrossRef
25.
go back to reference Mini E, Nobili S, Caciagli B, Landini I, Mazzei T (2006) Cellular pharmacology of gemcitabine. Ann Oncol 17(Suppl 5):v7–v12PubMedCrossRef Mini E, Nobili S, Caciagli B, Landini I, Mazzei T (2006) Cellular pharmacology of gemcitabine. Ann Oncol 17(Suppl 5):v7–v12PubMedCrossRef
26.
go back to reference Wong A, Soo RA, Yong WP, Innocenti F (2009) Clinical pharmacology and pharmacogenetics of gemcitabine. Drug Metab Rev 41:77–88PubMedCrossRef Wong A, Soo RA, Yong WP, Innocenti F (2009) Clinical pharmacology and pharmacogenetics of gemcitabine. Drug Metab Rev 41:77–88PubMedCrossRef
27.
go back to reference Danesi R, Altavilla G, Giovannetti E, Rosell R (2009) Pharmacogenomics of gemcitabine in non-small-cell lung cancer and other solid tumors. Pharmacogenomics 10:69–80PubMedCrossRef Danesi R, Altavilla G, Giovannetti E, Rosell R (2009) Pharmacogenomics of gemcitabine in non-small-cell lung cancer and other solid tumors. Pharmacogenomics 10:69–80PubMedCrossRef
28.
go back to reference Ueno H, Kiyosawa K, Kaniwa N (2007) Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy? Br J Cancer 97:145–151PubMedCrossRef Ueno H, Kiyosawa K, Kaniwa N (2007) Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy? Br J Cancer 97:145–151PubMedCrossRef
29.
go back to reference Kim SR, Saito Y, Maekawa K, Sugiyama E, Kaniwa N, Ueno H, Okusaka T, Ikeda M, Morizane C, Yamamoto N, Yoshida T, Kamatani N, Furuse J, Ishii H, Saijo N, Ozawa S, Sawada J (2008) Twenty novel genetic variations and haplotype structures of the DCK gene encoding human deoxycytidine kinase (dCK). Drug Metab Pharmacokinet 23:379–384PubMedCrossRef Kim SR, Saito Y, Maekawa K, Sugiyama E, Kaniwa N, Ueno H, Okusaka T, Ikeda M, Morizane C, Yamamoto N, Yoshida T, Kamatani N, Furuse J, Ishii H, Saijo N, Ozawa S, Sawada J (2008) Twenty novel genetic variations and haplotype structures of the DCK gene encoding human deoxycytidine kinase (dCK). Drug Metab Pharmacokinet 23:379–384PubMedCrossRef
30.
go back to reference Giovannetti E, Laan AC, Vasile E, Tibaldi C, Nannizzi S, Ricciardi S, Falcone A, Danesi R, Peters GJ (2008) Correlation between cytidine deaminase genotype and gemcitabine deamination in blood samples. Nucleosides Nucleotides Nucleic Acids 27:720–725PubMedCrossRef Giovannetti E, Laan AC, Vasile E, Tibaldi C, Nannizzi S, Ricciardi S, Falcone A, Danesi R, Peters GJ (2008) Correlation between cytidine deaminase genotype and gemcitabine deamination in blood samples. Nucleosides Nucleotides Nucleic Acids 27:720–725PubMedCrossRef
31.
go back to reference Sugiyama E, Kaniwa N, Kim S-R, Kikura-Hanajiri R, Hasegawa R, Maekawa K, Saito Y, Ozawa S, Sawada J-I, Kamatani N, Furuse J, Ishii H, Yoshida T, Ueno H, Okusaka T, Saijo N (2007) Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. J Clin Oncol 25:32–42PubMedCrossRef Sugiyama E, Kaniwa N, Kim S-R, Kikura-Hanajiri R, Hasegawa R, Maekawa K, Saito Y, Ozawa S, Sawada J-I, Kamatani N, Furuse J, Ishii H, Yoshida T, Ueno H, Okusaka T, Saijo N (2007) Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. J Clin Oncol 25:32–42PubMedCrossRef
33.
go back to reference Koolen SL, Huitema AD, Jansen RS, van Voorthuizen T, Beijnen JH, Smit WM, Schellens JH (2009) Pharmacokinetics of gemcitabine and metabolites in a patient with double-sided nephrectomy: a case report and review of the literature. Oncologist 14:944–948PubMedCrossRef Koolen SL, Huitema AD, Jansen RS, van Voorthuizen T, Beijnen JH, Smit WM, Schellens JH (2009) Pharmacokinetics of gemcitabine and metabolites in a patient with double-sided nephrectomy: a case report and review of the literature. Oncologist 14:944–948PubMedCrossRef
34.
go back to reference Kiani A, Köhne CH, Franz T, Passauer J, Haufe T, Gross P, Ehninger G, Schleyer E (2003) Pharmacokinetics of gemcitabine in a patient with end-stage renal disease: effective clearance of its main metabolite by standard hemodialysis treatment. Cancer Chemother Pharmacol 51:266–270PubMed Kiani A, Köhne CH, Franz T, Passauer J, Haufe T, Gross P, Ehninger G, Schleyer E (2003) Pharmacokinetics of gemcitabine in a patient with end-stage renal disease: effective clearance of its main metabolite by standard hemodialysis treatment. Cancer Chemother Pharmacol 51:266–270PubMed
Metadata
Title
Difluorodeoxyuridine plasma concentrations after low-dose gemcitabine during chemoradiation in head and neck cancer patients
Authors
P. Specenier
G. Guetens
J. Dyck
G. De Boeck
J. Weyler
D. Van den Weyngaert
K. Aelbrecht
J. B. Vermorken
Publication date
01-07-2011
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 1/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-010-1471-1

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