Skip to main content

Pharmacokinetics of Chemotherapy Delivered by Ophthalmic Artery Chemosurgery

  • Chapter
Recent Advances in Retinoblastoma Treatment

Part of the book series: Essentials in Ophthalmology ((ESSENTIALS))

  • 886 Accesses

Abstract

Super-selective ophthalmic artery infusion of chemotherapy is a powerful treatment option for intraocular retinoblastoma. However, the dose and schedule for drug administration are selected empirically. Knowledge of the amount of chemotherapy that effectively targets the ocular structures after local delivery and the availability in the bloodstream that correlates with toxicity may provide guidance towards a more scientific approach. The pharmacokinetics of a chemotherapy agent after local delivery is an important concept that has many clinical implications and varies according to drug type and method of delivery. Pharmacokinetic studies have been carried out in different animal models and patients with retinoblastoma. In the present chapter we will discuss general concepts of pharmacokinetics and specifically, we will overview the current knowledge about topotecan and melphalan pharmacokinetics after super-selective ophthalmic artery infusion and the relationship with pharmacodynamic parameters in animals and patients. Differences, advantages and disadvantages of each model will be discussed for a better understanding.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abramson DH. Periocular chemotherapy for retinoblastoma: success with problems? Arch Ophthalmol. 2005;123:128–9.

    Article  PubMed  Google Scholar 

  • Abramson DH. Retinoblastoma: saving life with vision. Annu Rev Med. 2014;65:171–84.

    Article  CAS  PubMed  Google Scholar 

  • Abramson DH, Dunkel IJ, Brodie SE, et al. A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology. 2008;115:1398–404.

    Article  PubMed  Google Scholar 

  • Abramson DH, Dunkel IJ, Brodie SE, Marr B, Gobin YP. Bilateral superselective ophthalmic artery chemotherapy for bilateral retinoblastoma: tandem therapy. Arch Ophthalmol. 2010;128:370–2.

    Article  PubMed  Google Scholar 

  • Abramson DH, Marr BP, Dunkel IJ, et al. Intra-arterial chemotherapy for retinoblastoma in eyes with vitreous and/ or subretinal seeding: 2-year results. Br J Ophthalmol. 2012;96:499–502.

    Article  PubMed  Google Scholar 

  • Athale UH, Stewart C, Kuttesch JF, et al. Phase I study of combination topotecan and carboplatin in pediatric solid tumors. J Clin Oncol. 2002;20:88–95.

    Article  CAS  PubMed  Google Scholar 

  • Carcaboso AM, Bramuglia GF, Chantada GL, et al. Topotecan vitreous levels after periocular or intravenous delivery in rabbits: an alternative for retinoblastoma chemotherapy. Invest Ophthalmol Vis Sci. 2007;48:3761–7.

    Article  PubMed  Google Scholar 

  • Chantada GL, Fandino AC, Casak SJ, et al. Activity of topotecan in retinoblastoma. Ophthalmic Genet. 2004;25:37–43.

    Article  CAS  PubMed  Google Scholar 

  • Chantada GL, Fandino AC, Carcaboso AM, et al. A phase I study of periocular topotecan in children with intraocular retinoblastoma. Invest Ophthalmol Vis Sci. 2009;50:1492–6.

    Article  PubMed  Google Scholar 

  • Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70:440–6.

    Article  CAS  PubMed  Google Scholar 

  • Cunha-Vaz JG. The blood retinal barriers system. Basic concepts and clinical evaluation. Exp Eye Res. 2004;78:715–21.

    Article  CAS  PubMed  Google Scholar 

  • Dondelinger RF, Ghysels MP, Brisbois D, et al. Relevant radiological anatomy of the pig as a training model in interventional radiology. Eur Radiol. 1998;8:1254–73.

    Article  CAS  PubMed  Google Scholar 

  • Dyer MA, Rodriguez-Galindo C, Wilson MW. Use of preclinical models to improve treatment of retinoblastoma. PLoS Med. 2005;2:e332.

    Article  PubMed Central  PubMed  Google Scholar 

  • Francis JH, Gobin YP, Dunkel IJ, et al. Carboplatin +/- topotecan ophthalmic artery chemosurgery for intraocular retinoblastoma. PLoS One. 2013;8:e72441.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Francis JH, Schaiquevich P, Buitrago E, et al. Local and systemic toxicity of intravitreal melphalan for vitreous seeding in retinoblastoma: a preclinical and clinical study. Ophthalmology. 2014;121:1810–7.

    Article  PubMed  Google Scholar 

  • Gaudana R, Jwala J, Boddu SH, et al. Recent perspectives in ocular drug delivery. Pharm Res. 2009;26:1197–216.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gobin YP, Dunkel IJ, Marr BP, et al. Combined, sequential intravenous and intra-arterial chemotherapy (bridge chemotherapy) for young infants with retinoblastoma. PLoS One. 2012;7:e44322.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gombos DS, Hungerford J, Abramson DH, et al. Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology. 2007;114:1378–83.

    Article  PubMed  Google Scholar 

  • Hartmann O, Oberlin O, Lemerle J, et al. Acute leukemia in two patients treated with high-dose melphalan and autologous marrow transplantation for malignant solid tumors. J Clin Oncol. 1984;2:1424–5.

    CAS  PubMed  Google Scholar 

  • Herben VMM, ten Bokkel HW, Beihnen JH. Clinical pharmacokinetics of topotecan. Clin Pharmacokinet. 1996;31:85–102.

    Article  CAS  PubMed  Google Scholar 

  • Hobbie WL, Ginsberg JP, Ogle SK, Carlson CA, Meadows AT. Fertility in males treated for Hodgkins disease with COPP/ABV hybrid. Pediatr Blood Cancer. 2005;44:193–6.

    Article  PubMed  Google Scholar 

  • Hocht C, Opezzo JA, Taira CA. Microdialysis in drug discovery. Curr Drug Discov Technol. 2004;1:269–85.

    Article  PubMed  Google Scholar 

  • Hosoya K, Kyoko H, Toyooka N, et al. Evaluation of amino acid mustard transport as L-type amino acid transporter 1 (LAT1)-mediated alkylating agents. Biol Pharm Bull. 2008;31:2126–30.

    Article  CAS  PubMed  Google Scholar 

  • Inomata M, Kaneko A. Chemosensitivity profiles of primary and cultured human retinoblastoma cells in a human tumor clonogenic assay. Jpn J Cancer Res. 1987;78:858–68.

    CAS  PubMed  Google Scholar 

  • Kaneko A, Suzuki S. Eye-preservation treatment of retinoblastoma with vitreous seeding. Jpn J Clin Oncol. 2003;33:601–7.

    Article  PubMed  Google Scholar 

  • Klaase JM, Kroon BB, Beijnen JH, et al. Melphalan tissue concentrations in patients treated with regional isolated perfusion for melanoma of the lower limb. Br J Cancer. 1994;70:151–3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Laurie NA, Gray JK, Zhang J, et al. Topotecan combination chemotherapy in two new rodent models of retinoblastoma. Clin Cancer Res. 2005;11:7569–78.

    Article  CAS  PubMed  Google Scholar 

  • Marr BP, Brodie SE, Dunkel IJ, Gobin YP, Abramson DH. Three-drug intra-arterial chemotherapy using simultaneous carboplatin, topotecan and melphalan for intraocular retinoblastoma: preliminary results. Br J Ophthalmol. 2012;96:1300–3.

    Article  PubMed  Google Scholar 

  • Moren H, Undren P, Gesslein B, et al. The porcine retinal vasculature accessed using an endovascular approach: a new experimental model for retinal ischemia. Invest Ophthalmol Vis Sci. 2009;50:5504–10.

    Article  PubMed  Google Scholar 

  • Munier FL, Gaillard MC, Balmer A, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol. 2012;96:1078–83.

    Article  PubMed  Google Scholar 

  • Nath CE, Shaw PJ, Montgomery K, Earl JW. Population pharmacokinetics of melphalan in paediatric blood or marrow transplant recipients. Br J Clin Pharmacol. 2007;64:151–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nemeth KM, Federico S, Carcaboso AM, et al. Subconjunctival carboplatin and systemic topotecan treatment in preclinical models of retinoblastoma. Cancer. 2011;117:421–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Palioura S, Gobin YP, Brodie SE, et al. Ophthalmic artery chemosurgery for the management of retinoblastoma in eyes with extensive (>50%) retinal detachment. Pediatr Blood Cancer. 2012;59:859–64.

    Article  PubMed  Google Scholar 

  • Panetta JC, Schaiquevich P, Santana VM, et al. Using pharmacokinetic and pharmacodynamic modeling and simulation to evaluate importance of schedule in topotecan therapy for pediatric neuroblastoma. Clin Cancer Res. 2008;14:318–25.

    Article  CAS  PubMed  Google Scholar 

  • Pritchard J, Cotterill SJ, Germond SM, et al. Jones DR. High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatr Blood Cancer. 2005;44:348–57.

    Article  PubMed  Google Scholar 

  • Qaddoumi I, Billups CA, Tagen M, et al. Topotecan and vincristine combination is effective against advanced bilateral intraocular retinoblastoma and has manageable toxicity. Cancer. 2012;118:5663–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ritschel WA, Kearns GL, editors. Handbook of basic pharmacokinetics including clinical applications. American Pharmacist Association: Washington, DC; 2004.

    Google Scholar 

  • Santana VM, Zamboni WC, Kirstein MN, et al. A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors. Clin Cancer Res. 2003;9:633–40.

    CAS  PubMed  Google Scholar 

  • Saylors 3rd RL, Stine KC, Sullivan J, et al. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001;19:3463–9.

    CAS  PubMed  Google Scholar 

  • Schaiquevich P, Buitrago E, Ceciliano A, et al. Pharmacokinetic analysis of topotecan after superselective ophthalmic artery infusion and periocular administration in a porcine model. Retina. 2012a;32:387–95.

    Article  CAS  PubMed  Google Scholar 

  • Schaiquevich P, Buitrago E, Taich P, et al. Pharmacokinetic analysis of melphalan after super-selective ophthalmic artery infusion in preclinical models and retinoblastoma patients. Invest Ophthalmol Vis Sci. 2012b;53:4205–12.

    Article  CAS  PubMed  Google Scholar 

  • Schaiquevich P, Ceciliano A, Millan N, et al. Intra-arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma. Pediatr Blood Cancer. 2013;60:766–70.

    Article  CAS  PubMed  Google Scholar 

  • Schaiquevich P, Carcaboso AM, Buitrago E, et al. Ocular pharmacology of topotecan and its activity in retinoblastoma. Retina. 2014;34:1719–27.

    Article  CAS  PubMed  Google Scholar 

  • Schrijvers D, Pronk L, Highley M, et al. Pharmacokinetics of ifosfamide are changed by combination with docetaxel: results of a phase I pharmacologic study. Am J Clin Oncol. 2000;23:358–63.

    Article  CAS  PubMed  Google Scholar 

  • Taich P, Ceciliano A, Buitrago E, et al. Clinical pharmacokinetics of intra-arterial melphalan and topotecan combination in patients with retinoblastoma. Ophthalmology. 2014;121:889–97.

    Article  PubMed  Google Scholar 

  • Tse BC, Steinle JJ, Johnson D, Haik BG, Wilson MW. Super selective intraophthalmic artery chemotherapy in a nonhuman primate model: histopathologic findings. JAMA Ophthalmol. 2013;131:903–11.

    Article  PubMed Central  PubMed  Google Scholar 

  • Tubergen DG, Stewart CF, Pratt CB, et al. Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: a Pediatric Oncology Group Study. J Pediatr Hematol Oncol. 1996;18:352–61.

    Article  CAS  PubMed  Google Scholar 

  • Wahlin A, Roos G, Rudolphi O, Holm J. Melphalan-related leukemia in multiple myeloma. Acta Med Scand. 1982;211:203–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Financial Support: This work was supported by Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, PIP Nr 11220090100343); Hospital JP Garrahan, Buenos Aires, Argentina; Agencia Nacional de Promoción Científica (PICT 2010-2271); Fund for Ophthalmic Knowledge (GLC, ACF), New York, NY, USA.

Compliance with Ethical Requirements: Dr. Schaiquevich and Dr. Chantada declare that they have no conflict of interest.

The present study followed the tenets of the Declaration of Helsinki and institutional review board approval was obtained. Written informed consent was obtained from the parent/guardian for being included in the study.

All experiments adhered the tenets of Hospital Garrahan Institutional Committee for Animal Care and the ARVO Statement for the use of animals in ophthalmic and vision research. Also, all institutional and national guidelines for the care and use of laboratory animals were followed.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paula Schaiquevich Ph.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Schaiquevich, P., Chantada, G.L. (2015). Pharmacokinetics of Chemotherapy Delivered by Ophthalmic Artery Chemosurgery. In: Francis, J., Abramson, D. (eds) Recent Advances in Retinoblastoma Treatment. Essentials in Ophthalmology. Springer, Cham. https://doi.org/10.1007/978-3-319-19467-7_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-19467-7_6

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-19466-0

  • Online ISBN: 978-3-319-19467-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics