Skip to main content

Advertisement

SpringerLink
Log in

Age affects pegylated liposomal doxorubicin elimination and tolerability in patients over 70 years old

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Pegylated liposomal doxorubicin (PLD) is often used in elderly people, due to its improved tolerability. However, clinical and pharmacological data in the subset of patients over 70 are scanty.

Methods

PLD safety was evaluated in 35 patients (aged ≥70 years) who were treated with PLD as a single agent for 165 cycles. Doxorubicin plasma levels, leukocyte DNA breaks and monocyte count variations were measured as markers of drug exposure, DNA repair capability and reticuloendothelial system activation, respectively. A correlation between these markers and age was sought.

Results

Treatment was generally well tolerated. Skin erythrodysesthesia was the most frequent side effect, and no severe (G4) toxicity occurred. PLD plasma half-life generally correlated with age (P < 0.001) and was particularly prolonged in octogenarians (P = 0.005). Doxorubicin clearance significantly declined up to 70 % at cycle 7. DNA breaks increased over the first two cycles (P = 0.007) and were inversely correlated with age (P = 0.007) and directly with clearance (P = 0.006). Pre-treatment monocyte counts increased over cycles (P < 0.001) and were associated with an increase in clearance at cycle 3 (P = 0.015). The hand–foot–skin syndrome was significantly more severe in patients of advanced age or longer PLD half-life.

Conclusions

This study showed (1) increased systemic drug exposure over subsequent cycles; (2) association of age with increased drug exposure, reduced DNA repair capability and worse skin toxicity; (3) a relation between monocyte count and drug clearance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Biganzoli L, Coleman R, Minisini A, Hamilton A, Aapro M, Therasse P, Mottino G, Bogaerts J, Piccart M (2007) A joined analysis of two European Organization for the Research and Treatment of Cancer (EORTC) studies to evaluate the role of pegylated liposomal doxorubicin (Caelyx) in the treatment of elderly patients with metastatic breast cancer. Crit Rev Oncol Hematol 61:84–89

    Article  PubMed  Google Scholar 

  2. Minisini AM, Andreetta C, Fasola G, Pugliesi F (2008) Pegylated liposomal doxorubicin in elderly patients with metastatic breast cancer. Expert Rev Anticancer Ther 8:331–342

    Article  CAS  PubMed  Google Scholar 

  3. Basso U, Roma A, Brunello A, Falci C, Fiduccia P, Banzato A, Bononi A, Gusella M, Vamvakas L, Zagonel V, Monfardini S (2013) By-weekly liposomal doxorubicin for advanced breast cancer in elderly women (≥70 years). J Geriatr Oncol 4:340–345

    Article  PubMed  Google Scholar 

  4. Sostelly A, Henin E, Chauvenet L, Hardy-Bessard AC, Jestin-Le Tallec V, Kirsher S et al (2013) Can we predict chemo-induced hematotoxicity in elderly patients treated with pegylated liposomal doxorubicin? Results of a population-based model derived from the DOGMES phase II trial of the GINECO. J Geriatr Oncol 4:48–57

    Article  PubMed  Google Scholar 

  5. Falandry C, Brain E, Bonnefoy M, Mefti F, Jovenin N, Rigal O et al (2013) Impact of geriatric risk factors on pegylated liposomal doxorubicin tolerance and efficacy in elderly metastatic breast cancer patients: final results of the DOGMES multicentre GINECO trial. Eur J Cancer 49:2806–2814

    Article  CAS  PubMed  Google Scholar 

  6. Gabizon A, Shmeeda H, Barenholz Y (2003) Pharmacokinetics of pegylated liposomal doxorubicin: review of animal and human studies. Clin Pharmacokinet 42:419–436

    Article  CAS  PubMed  Google Scholar 

  7. La-Beck NM, Zamboni BA, Gabizon A et al (2012) Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients. Cancer Chemother Pharmacol 69:43–50

    Article  CAS  PubMed  Google Scholar 

  8. Lyass O, Uziely B, Ben-Yosef R et al (2000) Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer 89:1037–1047

    Article  CAS  PubMed  Google Scholar 

  9. Richly H, Grubert M, Scheulen ME, Hilger RA (2009) Plasma and cellular pharmacokinetics of doxorubicin after intravenous infusion of Caelyx/Doxil in patients with hematological tumors. Int J Clin Pharmacol Ther 47:55–57

    Article  CAS  PubMed  Google Scholar 

  10. Gabizon A, Isacson R, Rosengarten O, Tzemach D, Shmeeda H, Sapir R (2008) An open-label study to evaluate dose and cycle dependence of the pharmacokinetics of pegylated liposomal doxorubicin. Cancer Chemother Pharmacol 61:695–702

    Article  CAS  PubMed  Google Scholar 

  11. Ongrádi J, Kövesdi V (2010) Factors that may impact on immunosenescence: an appraisal. Immun Ageing 7:7–21

    Article  PubMed Central  PubMed  Google Scholar 

  12. Hamaker ME, Jonker JM, de Rooij SE, Vos AG, Smorenburg CH, van Munster BC (2012) Frailty screening methods for predicting outcome of a comprehensive geriatric assessment in elderly patients with cancer: a systematic review. Lancet Oncol 13:e437–e444

    Article  PubMed  Google Scholar 

  13. Huober J, Fett W, Nusch A et al (2010) A multicentric observational trial of pegylated liposomal doxorubicin for metastatic breast cancer. BMC Cancer 10:2

    Article  PubMed Central  PubMed  Google Scholar 

  14. Al-Batran SE, Meerpohl HG, von Minckwitz G et al (2006) Reduced incidence of severe palmar–plantar erythrodysesthesia and mucositis in a prospective multicenter phase II trial with pegylated liposomal doxorubicin at 40 mg/m2 every 4 weeks in previously treated patients with metastatic breast cancer. Oncology 70:141–146

    Article  CAS  PubMed  Google Scholar 

  15. Briasoulis E, Karavasilis V, Tzamakou E et al (2004) Interaction pharmacokinetics of pegylated liposomal doxorubicin (Caelyx) on coadministration with paclitaxel or docetaxel. Cancer Chemother Pharmacol 53:452–457

    Article  CAS  PubMed  Google Scholar 

  16. Amantea MA, Forrest A, Northfelt DW, Mamelok R (1997) Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi’s sarcoma. Clin Pharmacol Ther 61:301–311

    Article  CAS  PubMed  Google Scholar 

  17. Hazlehurst LA (2009) Detection of DNA damage induced by topoisomerase II inhibitors, gamma radiation and crosslinking agents using the comet assay. Methods Mol Biol 523:169–176

    Article  CAS  PubMed  Google Scholar 

  18. Collins AR (2004) The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol 26:249–261

    Article  CAS  PubMed  Google Scholar 

  19. Marina NM, Cochrane D, Harney E et al (2002) Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors: a pediatric oncology group study. Clin Cancer Res 8:413–418

    CAS  PubMed  Google Scholar 

  20. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229

    Article  CAS  PubMed  Google Scholar 

  21. Gajewski E, Gaur S, Akman SA, Matsumoto L, van Balgooy JN, Doroshow JH (2007) Oxidative DNA base damage in MCF-10A breast epithelial cells at clinically achievable concentrations of doxorubicin. Biochem Pharmacol 73:1947–1956

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Wei Q, Matanoski GM, Farmer ER, Hedayati MA, Grossman L (1993) DNA repair and aging in basal cell carcinoma: a molecular epidemiology study. Proc Natl Acad Sci USA 90:1614–1618

    Article  CAS  PubMed  Google Scholar 

  23. Garm C, Moreno-Villanueva M, Bürkle A, Petersen I, Bohr VA, Christensen K, Stevnsner T (2013) Age and gender effects on DNA strand break repair in peripheral blood mononuclear cells. Aging Cell 12(1):58–66

    Article  CAS  PubMed  Google Scholar 

  24. Ishida T, Harada M, Wang XY, Ichihara M, Irimura K, Kiwada H (2005) Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes. J Control Release 105:305–317

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr. Eros Ferrazzi for critical review of the paper and the nurses at the Oncology Unit of Rovigo General Hospital for caring for the patients in this trial. This research was partly funded by CARIPARO Foundation, Italy.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Oncology, ULSS 18-Rovigo, S Maria della Misericordia Hospital, Rovigo General Hospital, Viale Tre Martiri 140, 45100, Rovigo, Italy

    Milena Gusella, Antonio Bononi, Yasmina Modena, Daniela Menon, Carmen Barile, Giorgio Crepaldi, Alessandro Inno & Felice Pasini

  2. Laboratory of Pharmacology and Molecular Biology, Department of Oncology, ULSS 18-Rovigo, San Luca Hospital, Viale Grisetti 265, 45027, Trecenta, Rovigo, Italy

    Milena Gusella, Laura Bertolaso, Paola Franceschetti, Elisa Pezzolo & Caterina Bolzonella

  3. Clinical Pharmacology Section, Department of Medicine DIMED, University of Padova, Via Giustiniani 2, 35128, Padua, Italy

    Roberto Padrini

Authors
  1. Milena Gusella
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antonio Bononi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasmina Modena
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura Bertolaso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paola Franceschetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniela Menon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elisa Pezzolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carmen Barile
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giorgio Crepaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Caterina Bolzonella
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alessandro Inno
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Roberto Padrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Felice Pasini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Milena Gusella.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gusella, M., Bononi, A., Modena, Y. et al. Age affects pegylated liposomal doxorubicin elimination and tolerability in patients over 70 years old. Cancer Chemother Pharmacol 73, 517–524 (2014). https://doi.org/10.1007/s00280-014-2378-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-014-2378-z

Keywords

Search

Navigation