Japanese Journal of Ophthalmology

, Volume 59, Issue 3, pp 164–172 | Cite as

Intravitreal injection of melphalan for intraocular retinoblastoma

  • Shigenobu Suzuki
  • Yukiko Aihara
  • Miyuki Fujiwara
  • Shuichi Sano
  • Akihiro Kaneko
Clinical Investigation



To investigate the safety and efficacy of intravitreal injection of melphalan for retinoblastoma.


A retrospective chart review of all patients who were administered intravitreal injections of melphalan for retinoblastoma between 1990 and 2011. A total of 264 eyes of 250 patients were included. All ocular adverse events, systemic prognosis, ocular prognosis, and visual acuity were investigated.


The total number of intravitreal injections administered was 1,067; each eye received between one and 25 injections. A postoperative subconjunctival tumor developed in one eye. None of the eyes suffered infections or uveitis, and all other adverse events including chorioretinal atrophy displayed incidences of less than 1.5 %. At 5 postoperative years, the cumulative incidence of cataract surgery was 3.1 % among the eyes that were treated without ocular hyperthermia. Distant metastasis or intracranial invasion occurred in 11 patients, all of whom had high-risk pathological factors for metastasis such as optic nerve invasion, but refused to receive adjuvant chemotherapy. Sixty-eight percent of the eyes achieved complete vitreous seed remission, but recurrence occurred in 19 % of these eyes after 10.0 ± 4.9 months. In addition, 47 and 27 % of the eyes without primary macular tumors retained visual acuity of >0.5 and >1.0, respectively.


The risk of extraocular tumor spreading following intravitreal injections is low, and other adverse events are rare. Sixty-eight percent of the treated eyes achieved complete vitreous seed remission, and about half of them retained practical levels of vision. The intravitreal injection of melphalan is a safe and effective treatment for vitreous seeds.


Intravitreal injection Melphalan Retinoblastoma Vitreous seeds 



This study was supported by the National Cancer Center Research and Development Fund (26-A-25).

Conflicts of interest

S. Suzuki, None; Y. Aihara, None; M. Fujiwara, None; S. Sano, None; A. Kaneko, None.


  1. 1.
    Kaneko A, Suzuki S. Eye-preservation treatment of retinoblastoma with vitreous seeding. Jpn J Clin Oncol. 2003;33:601–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Sobin LH, Gospodarowics MK, Wittekind C, editors. Retinoblastoma. In: TNM classification of malignant tumors. 7th ed. UK: Wiley-Blackwell; 2010. p. 291–7.Google Scholar
  3. 3.
    Abramson DH, Beaverson KL, Chang ST, Dunkel IJ, McCormick B. Outcome following initial external beam radiotherapy in patients with Reese-Ellsworth group Vb retinoblastoma. Arch Ophthalmol. 2004;122:1316–23.CrossRefPubMedGoogle Scholar
  4. 4.
    Shields CL, Honavar SG, Meadows AT, Shields JA, Demirci H, Singh A, et al. Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation. Am J Ophthalmol. 2002;133:657–64.CrossRefPubMedGoogle Scholar
  5. 5.
    Shields CL, Mashayekhi A, Au AK, Czyz C, Leahey A, Meadows AT, et al. The international classification of retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113:276–80.Google Scholar
  6. 6.
    Shields CL, Bianciotto CG, Jabbour P, Ramasubramanian A, Lally SE, Griffin GC, et al. Intra-arterial chemotherapy for retinoblastoma: report No. 1, control of retinal tumors, subretinal seeds, and vitreous seeds. Arch Ophthalmol. 2011;129:1399–406.CrossRefPubMedGoogle Scholar
  7. 7.
    Abramson DH, Marr BP, Dunkel IJ, Brodie S, Zabor EC, Driscoll SJ, 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.CrossRefPubMedGoogle Scholar
  8. 8.
    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. 2014 [Epub ahead].Google Scholar
  9. 9.
    Wilson TW, Chan HS, Moselhy GM, Heydt DD Jr, Frey CM, Gallie BL. Penetration of chemotherapy into vitreous is increased by cryotherapy and cyclosporine in rabbits. Arch Ophthalmol. 1996;114:1390–5.CrossRefPubMedGoogle Scholar
  10. 10.
    Abramson DH, Frank CM, Dunkel IJ. A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology. 1999;106:1947–50.CrossRefPubMedGoogle Scholar
  11. 11.
    Eljarrat-Binstock E, Domb AJ, Orucov F, Dagan A, Frucht-Pery J, Pe’er J. In vitro and in vivo evaluation of carboplatin delivery to the eye using hydrogel-iontophoresis. Curr Eye Res. 2008;33:269–75.CrossRefPubMedGoogle Scholar
  12. 12.
    Chévez-Barrios P, Chintagumpala M, Mieler W, Paysse E, Boniuk M, Kozinetz C, et al. Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir. J Clin Oncol. 2005;23:7927–35.CrossRefPubMedGoogle Scholar
  13. 13.
    Aiello LP, Bruchker AJ, Chang S, Cunningham ET Jr, D’Amico DJ, Flynn HW Jr, et al. Evolving guidelines for intravitreous injections. Retina. 2004;24:S3–19.CrossRefPubMedGoogle Scholar
  14. 14.
    Kivelä T, Eskelin S, Paloheimo M. Intravitreal methotrexate for retinoblastoma. Ophthalmology. 2011;118:1689–90.CrossRefPubMedGoogle Scholar
  15. 15.
    Ghassemi F, Shields CL. Intravitreal melphalan for refractory or recurrent vitreous seeding from retinoblastoma. Arch Ophthalmol. 2012;130:1268–71.CrossRefPubMedGoogle Scholar
  16. 16.
    Smith SJ, Pulido JS, Salomao DR, Smith BD, Mohney B. Combined intravitreal and subconjunctival carboplatin for retinoblastoma with vitreous seeds. Br J Ophthalmol. 2012;96:1073–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Munier FL, Gaillard MC, Balmer A, Soliman S, Podilsky G, Moulin AP, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol. 2012;96:1078–83.CrossRefPubMedGoogle Scholar
  18. 18.
    Munier FL, Soliman S, Moulin AP, Gaillard MC, Balmer A, Beck-Popovic M. Profiling safety of intravitreal injections for retinoblastoma using an anti-reflux procedure and sterilisation of the needle track. Br J Ophthalmol. 2012;96:1084–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Smith SJ, Smith BD, Mohney BG. Ocular side effects following intravitreal injection therapy for retinoblastoma: a systematic review. Br J Ophthalmol. 2014;98:292–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Shields CL, Manjandavida FP, Arepalli S, Kaliki S, Lally SE, Shields JA. Intravitreal melphalan for persistent or recurrent retinoblastoma vitreous seeds: preliminary results. JAMA Ophthalmol. 2014;132:319–25.CrossRefPubMedGoogle Scholar
  21. 21.
    Suzuki S, Yamane T, Mohri M, Kaneko A. Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis. Ophthalmology. 2011;118:2081–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Kaneko Akihiro. Management of retinoblastoma—how to preserve eyeballs of children with retinoblastoma [in Japanese]. J Eye. 2002;19:585–91.Google Scholar
  23. 23.
    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.PubMedGoogle Scholar
  24. 24.
    Ueda M, Tanabe J, Inomata M, Kaneko A, Kimura T. Study on conservative treatment of retinoblastoma—effect of intravitreal injection of melphalan on the rabbit retina. Nippon Ganka Gakkai Zasshi. 1995;99:1230–5 [in Japanese].PubMedGoogle Scholar
  25. 25.
    Brodie SE, Munier FL, Francis JH, Marr B, Gobin YP, Abramson DH. Persistence of retinal function after intravitreal melphalan injection for retinoblastoma. Doc Ophthalmol. 2013;126:79–84.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Ophthalmological Society 2015

Authors and Affiliations

  • Shigenobu Suzuki
    • 1
  • Yukiko Aihara
    • 1
  • Miyuki Fujiwara
    • 1
  • Shuichi Sano
    • 1
  • Akihiro Kaneko
    • 1
    • 2
  1. 1.Department of Ophthalmic OncologyNational Cancer Center HospitalTokyoJapan
  2. 2.Department of OphthalmologyYokohama City University HospitalKanagawaJapan

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