Skip to main content

Advertisement

Log in

The role for intra-arterial chemotherapy for refractory retinoblastoma: a systematic review

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

Intra-arterial chemotherapy is a new retinoblastoma treatment associated with high rates of globe salvage that has been widely adopted for primary treatment of retinoblastoma but is less frequently used as secondary treatment for refractory retinoblastoma. This systematic review aims to summarize the reported outcomes of intra-arterial chemotherapy for refractory retinoblastoma.

Methods

We conducted a systematic review of studies published on PubMed, Medline, and Embase from 2011 to 2021 reporting globe salvage rates following intra-arterial chemotherapy for secondary treatment of refractory retinoblastoma.

Results

Our search yielded 316 studies, and 24 met inclusion criteria. The 24 included studies were comprised of 1366 patients and 1757 eyes. Among these, 1184 (67%) eyes received secondary indication treatment, and globe salvage was achieved for 776 of these 1184 eyes (64%). Sixteen studies reported cannulation success rates from 71.8 to 100%. Pooled analysis of subjects revealed 21 patients (2.6%) with metastatic disease and 26 deaths (3%) during study follow-up periods (7–74 months). The most common ocular complications were vitreous hemorrhage (13.2%), loss of eyelashes (12.7%), and periocular edema (10.5%). The most common systemic complications were nausea/vomiting (20.5%), neutropenia (14.1%), fever (8.2%), and bronchospasm (6.2%).

Conclusions

Intra-arterial chemotherapy is associated with high rates of globe salvage and low rates of serious complications in patients with refractory retinoblastoma. Unfortunately, current literature is predominantly comprised of retrospective case studies, and further high-quality evidence is necessary to inform clinical practice.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097

Similar content being viewed by others

References

  1. Berry JL, Kogachi K, Murphree AL, Jubran R, Kim JW. A review of recurrent retinoblastoma: Children’s Hospital Los Angeles classification and treatment guidelines. Int Ophthalmol Clin. 2019;59(2):65–75.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Grigorovski N, Lucena E, Mattosinho C, et al. Use of intra-arterial chemotherapy for retinoblastoma: results of a survey. Int J Ophthalmol. 2014;7(4):726–30.

    PubMed  PubMed Central  Google Scholar 

  3. Dimaras H, Corson TW, Cobrinik D, et al. Retinoblastoma. Nat Rev Dis Primers. 2015;1:15021.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Broaddus E, Topham A, Singh AD. Survival with retinoblastoma in the USA: 1975–2004. Br J Ophthalmol. 2009;93(1):24–7.

    Article  CAS  PubMed  Google Scholar 

  5. Reese AB, Ellsworth RM. The evaluation and current concept of retinoblastoma therapy. Trans Am Acad Ophthalmol Otolaryngol. 1963;67:164–72.

    CAS  PubMed  Google Scholar 

  6. Murphree AL. Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin N Am. 2005;18(1):41–53.

    Article  Google Scholar 

  7. Shields CL, Mashayekhi A, Au AK, et al. The international classification of retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113(12):2276–80.

    Article  PubMed  Google Scholar 

  8. Edge SB, Edge SB, American Joint Committee on C. AJCC cancer staging manual. 8th ed. New York: Springer; 2017.

    Google Scholar 

  9. Tomar AS, Finger PT, Gallie B, et al. A multicenter, international collaborative study for American Joint Committee on cancer staging of retinoblastoma: part i: metastasis-associated mortality. Ophthalmology. 2020;127(12):1719–32.

    Article  PubMed  Google Scholar 

  10. Chintagumpala M, Chevez-Barrios P, Paysse EA, Plon SE, Hurwitz R. Retinoblastoma: review of current management. Oncologist. 2007;12(10):1237–46.

    Article  PubMed  Google Scholar 

  11. Francis JH, Roosipu N, Levin AM, et al. Current treatment of bilateral retinoblastoma: the impact of intraarterial and intravitreous chemotherapy. Neoplasia. 2018;20(8):757–63.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kim JY, Park Y. Treatment of retinoblastoma: the role of external beam radiotherapy. Yonsei Med J. 2015;56(6):1478–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jairam V, Roberts KB, Yu JB. Historical trends in the use of radiation therapy for pediatric cancers: 1973–2008. Int J Radiat Oncol Biol Phys. 2013;85(3):e151-155.

    Article  PubMed  Google Scholar 

  14. Wong JR, Morton LM, Tucker MA, et al. Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy. J Clin Oncol. 2014;32(29):3284–90.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wong FL, Boice JD Jr, Abramson DH, et al. Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. Jama. 1997;278(15):1262–7.

    Article  CAS  PubMed  Google Scholar 

  16. Abramson DH, Frank CM. Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age effect on radiation-related risk. Ophthalmology. 1998;105(4):573–9 (Discussion 579–580).

    Article  CAS  PubMed  Google Scholar 

  17. Mouw KW, Sethi RV, Yeap BY, et al. Proton radiation therapy for the treatment of retinoblastoma. Int J Radiat Oncol Biol Phys. 2014;90(4):863–9.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Krengli M, Hug EB, Adams JA, Smith AR, Tarbell NJ, Munzenrider JE. Proton radiation therapy for retinoblastoma: comparison of various intraocular tumor locations and beam arrangements. Int J Radiat Oncol Biol Phys. 2005;61(2):583–93.

    Article  PubMed  Google Scholar 

  19. Shields CL, Shields JA, De Potter P, et al. Plaque radiotherapy in the management of retinoblastoma. Use as a primary and secondary treatment. Ophthalmology. 1993;100(2):216–24.

    Article  CAS  PubMed  Google Scholar 

  20. Schueler AO, Flühs D, Anastassiou G, Jurklies C, Sauerwein W, Bornfeld N. Beta-ray brachytherapy of retinoblastoma: feasibility of a new small-sized ruthenium-106 plaque. Ophthalmic Res. 2006;38(1):8–12.

    Article  PubMed  Google Scholar 

  21. Rao R, Honavar SG. Retinoblastoma. Indian J Pediatr. 2017;84(12):937–44.

    Article  PubMed  Google Scholar 

  22. Mendoza PR, Grossniklaus HE. Therapeutic options for retinoblastoma. Cancer Control. 2016;23(2):99–109.

    Article  PubMed  Google Scholar 

  23. Chawla B, Jain A, Azad R. Conservative treatment modalities in retinoblastoma. Indian J Ophthalmol. 2013;61(9):479–85.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ancona-Lezama D, Dalvin LA, Shields CL. Modern treatment of retinoblastoma: a 2020 review. Indian J Ophthalmol. 2020;68(11):2356–65.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Shields CL, Lally SE, Leahey AM, et al. Targeted retinoblastoma management: when to use intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Curr Opin Ophthalmol. 2014;25(5):374–85.

    Article  PubMed  Google Scholar 

  26. Manjandavida FP, Stathopoulos C, Zhang J, Honavar SG, Shields CL. Intra-arterial chemotherapy in retinoblastoma—a paradigm change. Indian J Ophthalmol. 2019;67(6):740–54.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ghassemi F, Shields CL, Ghadimi H, Khodabandeh A, Roohipoor R. Combined intravitreal melphalan and topotecan for refractory or recurrent vitreous seeding from retinoblastoma. JAMA Ophthalmol. 2014;132(8):936–41.

    Article  PubMed  Google Scholar 

  28. Shields CL, Douglass AM, Beggache M, Say EA, Shields JA. Intravitreous chemotherapy for active vitreous seeding from retinoblastoma: outcomes after 192 consecutive injections. The 2015 Howard Naquin Lecture. Retina. 2016;36(6):1184–90.

    Article  CAS  PubMed  Google Scholar 

  29. Yamane T, Kaneko A, Mohri M. The technique of ophthalmic arterial infusion therapy for patients with intraocular retinoblastoma. Int J Clin Oncol. 2004;9(2):69–73.

    Article  PubMed  Google Scholar 

  30. Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol. 2011;129(6):732–7.

    Article  PubMed  Google Scholar 

  31. Peterson EC, Elhammady MS, Quintero-Wolfe S, Murray TG, Aziz-Sultan MA. Selective ophthalmic artery infusion of chemotherapy for advanced intraocular retinoblastoma: initial experience with 17 tumors. J Neurosurg. 2011;114(6):1603–8.

    Article  PubMed  Google Scholar 

  32. Suzuki S, Yamane T, Mohri M, Kaneko A. Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis. Ophthalmology. 2011;118(10):2081–7.

    Article  PubMed  Google Scholar 

  33. Muen WJ, Kingston JE, Robertson F, Brew S, Sagoo MS, Reddy MA. Efficacy and complications of super-selective intra-ophthalmic artery melphalan for the treatment of refractory retinoblastoma. Ophthalmology. 2012;119(3):611–6.

    Article  PubMed  Google Scholar 

  34. Thampi S, Hetts SW, Cooke DL, et al. Superselective intra-arterial melphalan therapy for newly diagnosed and refractory retinoblastoma: results from a single institution. Clin Ophthalmol. 2013;7:981–9.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Shields CL, Manjandavida FP, Lally SE, et al. Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the international classification of retinoblastoma. Ophthalmology. 2014;121(7):1453–60.

    Article  PubMed  Google Scholar 

  36. Gonzalez LF, Albuquerque FC, McDougall CG. Neurointerventional techniques : tricks of the trade. Thieme; 2015.

  37. Dilenge D, Ascherl GF Jr. Variations of the ophthalmic and middle meningeal arteries: relation to the embryonic stapedial artery. Am J Neuroradiol. 1980;1(1):45–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Abramson DH, Marr BP, Francis JH, et al. Simultaneous bilateral ophthalmic artery chemosurgery for bilateral retinoblastoma (tandem therapy). PLoS One. 2016;11(6):e0156806.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Yousef YA, Soliman SE, Astudillo PPP, et al. Intra-arterial chemotherapy for retinoblastoma: a systematic review. JAMA Ophthalmol. 2016;134(5):584–91.

    Article  PubMed  Google Scholar 

  40. Abramson DH, Dunkel IJ, Brodie SE, Kim JW, Gobin YP. A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology. 2008;115(8):1398-1404.e1391.

    Article  PubMed  Google Scholar 

  41. Povirk LF, Shuker DE. DNA damage and mutagenesis induced by nitrogen mustards. Mutat Res. 1994;318(3):205–26.

    Article  CAS  PubMed  Google Scholar 

  42. Shah NV, Pham DG, Murray TG, et al. Intravitreal and subconjunctival melphalan for retinoblastoma in transgenic mice. J Ophthalmol. 2014;2014:829879.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Esma F, Salvini M, Troia R, Boccadoro M, Larocca A, Pautasso C. Melphalan hydrochloride for the treatment of multiple myeloma. Expert Opin Pharmacother. 2017;18(11):1127–36.

    Article  CAS  PubMed  Google Scholar 

  44. Kuczma M, Ding ZC, Zhou G. Immunostimulatory effects of melphalan and usefulness in adoptive cell therapy with antitumor CD4+ T cells. Crit Rev Immunol. 2016;36(2):179–91.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Francis JH, Levin AM, Zabor EC, Gobin YP, Abramson DH. Ten-year experience with ophthalmic artery chemosurgery: ocular and recurrence-free survival. PLoS One. 2018;13(5):e0197081.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Gombos DS, Hungerford J, Abramson DH, et al. Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology. 2007;114(7):1378–83.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Taich P, Ceciliano A, Buitrago E, et al. Clinical pharmacokinetics of intra-arterial melphalan and topotecan combination in patients with retinoblastoma. Ophthalmology. 2014;121(4):889–97.

    Article  PubMed  Google Scholar 

  50. Gerson SL, Caimi PF, William BM, Creger RJ, et al. Chapter 57—pharmacology and molecular mechanisms of antineoplastic agents for hematologic malignancies. In: Hoffman R, Benz EJ, Silberstein LE, et al., editors. Hematology. 7th ed. Amsterdam; 2018. p. 849–912.

  51. Hagner N, Joerger M. Cancer chemotherapy: targeting folic acid synthesis. Cancer Manag Res. 2010;2:293–301.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Munier FL, Beck-Popovic M, Balmer A, Gaillard MC, Bovey E, Binaghi S. Occurrence of sectoral choroidal occlusive vasculopathy and retinal arteriolar embolization after superselective ophthalmic artery chemotherapy for advanced intraocular retinoblastoma. Retina. 2011;31(3):566–73.

    Article  CAS  PubMed  Google Scholar 

  53. Venturi C, Bracco S, Cerase A, et al. Superselective ophthalmic artery infusion of melphalan for intraocular retinoblastoma: preliminary results from 140 treatments. Acta Ophthalmol. 2013;91(4):335–42.

    Article  CAS  PubMed  Google Scholar 

  54. Ghassemi F, Ghanaati H, Karkhaneh R, Boujabadi L, Tabatabaie SZ, Rajabi MT. Outcome of retinoblastoma following limited sessions of intra-arterial chemotherapy in Iran. Iran J Radiol. 2014;11(3):e16958.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Akyüz C, Kıratlı H, Şen H, Aydın B, Tarlan B, Varan A. Intra-arterial chemotherapy for retinoblastoma: a single-center experience. Ophthalmologica. 2015;234(4):227–32.

    Article  PubMed  Google Scholar 

  56. Ong SJ, Chao AN, Wong HF, Liou KL, Kao LY. Selective ophthalmic arterial injection of melphalan for intraocular retinoblastoma: a 4-year review. Jpn J Ophthalmol. 2015;59(2):109–17.

    Article  CAS  PubMed  Google Scholar 

  57. Michaels ST, Abruzzo TA, Augsburger JJ, Corrêa ZM, Lane A, Geller JI. Selective ophthalmic artery infusion chemotherapy for advanced intraocular retinoblastoma: CCHMC early experience. J Pediatr Hematol Oncol. 2016;38(1):65–9.

    Article  CAS  PubMed  Google Scholar 

  58. Chen M, Jiang H, Zhang J, et al. Outcome of intra-arterial chemotherapy for retinoblastoma and its influencing factors: a retrospective study. Acta Ophthalmol. 2017;95(6):613–8.

    Article  CAS  PubMed  Google Scholar 

  59. Reddy MA, Naeem Z, Duncan C, et al. Reduction of severe visual loss and complications following intra-arterial chemotherapy (IAC) for refractory retinoblastoma. Br J Ophthalmol. 2017;101(12):1704–8.

    Article  PubMed  Google Scholar 

  60. Rishi P, Sharma T, Sharma M, et al. Intra-arterial chemotherapy for retinoblastoma: two-year results from tertiary eye-care center in India. Indian J Ophthalmol. 2017;65(4):311–5.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Funes S, Sampor C, Villasante F, et al. Feasibility and results of an intraarterial chemotherapy program for the conservative treatment of retinoblastoma in Argentina. Pediatr Blood Cancer. 2018;65(8):e27086.

    Article  PubMed  Google Scholar 

  62. Hua J, Gang S, Yizhou J, Jing Z. Intra-arterial chemotherapy as second-line treatment for advanced retinoblastoma: a 2-year single-center study in China. J Cancer Res Ther. 2018;14(1):106–10.

    Article  PubMed  Google Scholar 

  63. Rojanaporn D, Chanthanaphak E, Boonyaopas R, Sujirakul T, Hongeng S, Ayudhaya SSN. Intra-arterial chemotherapy for retinoblastoma: 8-year experience from a Tertiary Referral Institute in Thailand. Asia Pac J Ophthalmol (Phila). 2019;8(3):211–7.

    CAS  Google Scholar 

  64. Rishi P, Agarwal A, Chatterjee P, et al. Intra-arterial chemotherapy for retinoblastoma: four-year results from Tertiary Center in India. Ocul Oncol Pathol. 2020;6(1):66–73.

    Article  PubMed  Google Scholar 

  65. Leal-Leal CA, Asencio-López L, Higuera-Calleja J, et al. Globe salvage with intra-arterial topotecan-melphalan chemotherapy in children with a single eye. Rev Invest Clin. 2016;68(3):137–42.

    CAS  PubMed  Google Scholar 

  66. Liu CC, Mohmood A, Hamzah N, Lau JH, Khaliddin N, Rahmat J. Intra-arterial chemotherapy for retinoblastoma: our first three-and-a-half years’ experience in Malaysia. PLoS One. 2020;15(5):e0232249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Abramson DH, Shields CL, Jabbour P, et al. Metastatic deaths in retinoblastoma patients treated with intraarterial chemotherapy (ophthalmic artery chemosurgery) worldwide. Int J Retina Vitreous. 2017;3:40.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Tuncer S, Sencer S, Kebudi R, Tanyıldız B, Cebeci Z, Aydın K. Superselective intra-arterial chemotherapy in the primary management of advanced intra-ocular retinoblastoma: first 4-year experience from a single institution in Turkey. Acta Ophthalmol. 2016;94(7):e644–51.

    Article  PubMed  Google Scholar 

  69. Ravindran K, Dalvin LA, Pulido JS, Brinjikji W. Intra-arterial chemotherapy for retinoblastoma: an updated systematic review and meta-analysis. J Neurointerv Surg. 2019;11(12):1266–72.

    Article  PubMed  Google Scholar 

  70. Lim LS, Dalvin LA, Ancona-Lezama D, Yu MD, Jabbour P, Shields CL. Retinoblastoma vascular perfusion and intra-arterial chemotherapy cycle requirements. Clin Exp Ophthalmol. 2019;47(9):1164–72.

    Article  PubMed  Google Scholar 

Download references

Funding

The authors have not received any funding for this work from any organization.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J. Runnels.

Ethics declarations

Conflict of interest

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Ethical approval and informed consent

This article was exempt from IRB approval requirements due to it's nature as a review article. All reviewed retrospective and prospective articles were conducted with necessary ethical approval and informed consents.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Runnels, J., Acosta, G., Rose, A. et al. The role for intra-arterial chemotherapy for refractory retinoblastoma: a systematic review. Clin Transl Oncol 23, 2066–2077 (2021). https://doi.org/10.1007/s12094-021-02610-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-021-02610-z

Keywords

Navigation