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Retinoblastoma: Intravenous Chemotherapy

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Clinical Ophthalmic Oncology

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Abstract

The last two decades have witnessed a dramatic evolution in the management of retinoblastoma including classification schemes, treatment modalities, genetic testing, and screening. The current treatment model for retinoblastoma is to save life, preserve the globe, and retain as much vision as possible. With the advent of intravenous chemotherapy, the use of radiation therapy has been largely abandoned. In the modern era, the rationale for neoadjuvant intravenous chemotherapy is reduction in intraocular tumor volume (chemoreduction) to allow better tumor cell killing with focal therapy (laser photocoagulation, cryotherapy, or brachytherapy). Eyes with Group A tumors are generally treated with focal therapy alone. Eyes with Group B tumors treated with three to six cycles of carboplatin, etoposide, and vincristine (CEV) in combination with focal therapy have resulted in ocular salvage rates of nearly 100%. Eyes with Group C or D tumors are treated with six cycles of CEV chemotherapy in combination with focal therapy. The recommended treatment for unilateral advanced tumors (particularly with extensive seeding) with negligible visual potential (Group D or E) is enucleation. The management of patients with high-risk histopathologic features has varied from close observation to, more commonly, chemoprophylaxis with six cycles of the low-dose CEV. Treatment options for extraocular retinoblastoma with overt orbital disease and preauricular or cervical lymph node extension include intravenous chemotherapy and external beam radiation therapy (EBRT). The prognosis of patients with metastatic retinoblastoma with CNS involvement is poor with conventional intravenous chemotherapy and radiation therapy alone; however, consolidation with high-dose chemotherapy with autologous hematopoietic stem cell rescue (AHSCR) is deemed as a promising strategy to improve survival outcomes. Lastly, extraocular retinoblastoma with CNS involvement (prechiasmatic lesion, CNS mass, and/or leptomeningeal dissemination) and trilateral retinoblastoma portend a poor prognosis despite aggressive multimodality treatment comprised of intensive induction chemotherapy followed by consolidation with high-dose chemotherapy and AHSCR. The contribution of EBRT is unclear.

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Abbreviations

AHSCR:

Autologous hematopoietic stem cell rescue

AJCC:

American Joint Committee on Cancer

AML:

Acute myeloid leukemia

CEV:

Carboplatin, etoposide, and vincristine

CHLA:

Children’s Hospital Los Angeles

CNS:

Craniospinal

COG:

Children’s Oncology Group

CTCAE:

Common Terminology Criteria for Adverse Events

EBRT:

External beam radiation therapy

EFS:

Event-free survival

IRSS:

International Retinoblastoma Staging System

MSKCC:

Memorial Sloan Kettering Cancer Center

OS:

Overall survival

R-E:

Reese-Ellsworth

TNM:

Tumor, node, metastasis

TTT:

Transpupillary thermotherapy

References

  1. Fabian ID, Onadim Z, Karaa E, et al. The management of retinoblastoma. Oncogene. 2018;37:1551–60.

    Google Scholar 

  2. Abramson DH, Ellsworth RM. The surgical management of retinoblastoma. Ophthalmic Surg. 1980;11:596–8.

    Google Scholar 

  3. Imhof SM, Mourits MP, Hofman P, et al. Quantification of orbital and mid-facial growth retardation after megavoltage external beam irradiation in children with retinoblastoma. Ophthalmology. 1996;103:263–8.

    Google Scholar 

  4. Kleinerman RA, Tucker MA, Tarone RE, et al. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol. 2005;23:2272–9.

    Google Scholar 

  5. 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;32:3284–90.

    Google Scholar 

  6. Shields CL, De Potter P, Himelstein BP, et al. Chemoreduction in the initial management of intraocular retinoblastoma. Arch Ophthalmol Chic Ill 1960. 1996;114:1330–8.

    Google Scholar 

  7. Murphree AL, Villablanca JG, Deegan WF, et al. Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol Chic Ill 1960. 1996;114:1348–56.

    Google Scholar 

  8. Dunkel IJ, Lee TC, Shi W, et al. A phase II trial of carboplatin for intraocular retinoblastoma. Pediatr Blood Cancer. 2007;49:643–8.

    Google Scholar 

  9. Rodriguez-Galindo C, Wilson MW, Haik BG, et al. Treatment of intraocular retinoblastoma with vincristine and carboplatin. J Clin Oncol. 2003;21:2019–25.

    Google Scholar 

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

    Google Scholar 

  11. Brennan RC, Qaddoumi I, Mao S, et al. Ocular salvage and vision preservation using a topotecan-based regimen for advanced intraocular retinoblastoma. J Clin Oncol. 2017;35:72–7.

    Google Scholar 

  12. 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.

    Google Scholar 

  13. Chantada GL, Guitter MR, Fandiño AC, et al. Treatment results in patients with retinoblastoma and invasion to the cut end of the optic nerve. Pediatr Blood Cancer. 2008;52:218–22.

    Google Scholar 

  14. Chantada G, Fandiño A, Casak S, et al. Treatment of overt extraocular retinoblastoma. Med Pediatr Oncol. 2003;40:158–61.

    Google Scholar 

  15. Antoneli CBG, Steinhorst F, de Cássia Braga Ribeiro K, et al. Extraocular retinoblastoma: a 13-year experience. Cancer. 2003;98:1292–8.

    Google Scholar 

  16. Antoneli CBG, Ribeiro KB, Rodriguez-Galindo C, et al. The addition of ifosfamide/etoposide to cisplatin/teniposide improves the survival of children with retinoblastoma and orbital involvement. J Pediatr Hematol Oncol. 2007;29:700–4.

    Google Scholar 

  17. Gallie BL, Budning A, DeBoer G, et al. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol. 1996;114:1321–8.

    Google Scholar 

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

    Google Scholar 

  19. Murphree AL. Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin. 2005;18:41–53.

    Google Scholar 

  20. Chantada G, Doz F, Antoneli CBG, et al. A proposal for an international retinoblastoma staging system. Pediatr Blood Cancer. 2006;47:801–5.

    Google Scholar 

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

    Google Scholar 

  22. Friedman DL, Himelstein B, Shields CL, et al. Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol. 2000;18:12–7.

    Google Scholar 

  23. Zhu D, Berry JL, Ediriwickrema L, et al. Long-term outcomes of group B eyes in patients with retinoblastoma treated with short-course chemoreduction: experience from Children’s Hospital Los Angeles/University of Southern California. Ocul Oncol Pathol. 2015;2:105–11.

    Google Scholar 

  24. Lumbroso-Le Rouic L, Aerts I, Hajage D, et al. Conservative treatment of retinoblastoma: a prospective phase II randomized trial of neoadjuvant chemotherapy followed by local treatments and chemothermotherapy. Eye. 2016;30:46–52.

    Google Scholar 

  25. Friedman DL, Krailo M, Villaluna D, et al. Systemic neoadjuvant chemotherapy for Group B intraocular retinoblastoma (ARET0331): a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2017;64

    Google Scholar 

  26. Chung CY, Medina CA, Aziz HA, et al. Retinoblastoma: evidence for stage-based chemotherapy. Int Ophthalmol Clin. 2015;55:63–75.

    Google Scholar 

  27. Shields CL, Honavar SG, Meadows AT, et al. Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation1. Am J Ophthalmol. 2002;133:657–64.

    Google Scholar 

  28. Abramson DH, Frank CM, Dunkel IJ. A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology. 1999;106:1947–50.

    Google Scholar 

  29. Berry JL, Shah S, Bechtold M, et al. Long-term outcomes of group D retinoblastoma eyes during the intravitreal melphalan era. Pediatr Blood Cancer. 2017;64:e26696.

    Google Scholar 

  30. Berry JL, Jubran R, Lee TC, et al. Low-dose Chemoreduction for infants diagnosed with retinoblastoma before 6 months of age. Ocul Oncol Pathol. 2015;1:103–10.

    Google Scholar 

  31. Uusitalo MS, Quill KRV, Scott IU, et al. Evaluation of chemoprophylaxis in patients with unilateral retinoblastoma with high-risk features on histopathologic examination. Arch Ophthalmol. 2001;119:41–8.

    Google Scholar 

  32. Honavar SG, Singh AD, Shields CL, et al. Postenucleation adjuvant therapy in high-risk retinoblastoma. Arch Ophthalmol. 2002;120:923–31.

    Google Scholar 

  33. Chantada GL, Dunkel IJ, de Dávila MT, et al. Retinoblastoma patients with high risk ocular pathological features: who needs adjuvant therapy? Br J Ophthalmol. 2004;88:1069–73.

    Google Scholar 

  34. Eagle RC Jr. High-risk features and tumor differentiation in retinoblastoma: a retrospective histopathologic study. Arch Pathol Lab Med. 2009;133:1203–9.

    Google Scholar 

  35. Kaliki S, Shields CL, Rojanaporn D, et al. High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes. Ophthalmology. 2013;120:997–1003.

    Google Scholar 

  36. Kaliki S, Shields CL, Shah SU, et al. Postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin for the treatment of high-risk retinoblastoma. Arch Ophthalmol. 2011;129:1422–7.

    Google Scholar 

  37. Chintagumpala MM, Langholz B, Eagle R, et al. A large prospective trial of children with unilateral retinoblastoma with and without histopathologic high-risk features and the role of adjuvant chemotherapy: a Children’s Oncology Group (COG) study. J Clin Oncol. 2012;30:9515.

    Google Scholar 

  38. Berry JL, Zolfaghari E, Chen A, et al. Optic nerve obscuration in retinoblastoma: a risk factor for optic nerve invasion? Ocul Oncol Pathol. 2017;3:283–91.

    Google Scholar 

  39. Armenian SH, Panigrahy A, Murphree AL, et al. Management of retinoblastoma with proximal optic nerve enhancement on MRI at diagnosis. Pediatr Blood Cancer. 2008;51:479–84.

    Google Scholar 

  40. Canturk S, Qaddoumi I, Khetan V, et al. Survival of retinoblastoma in less-developed countries impact of socioeconomic and health-related indicators. Br J Ophthalmol. 2010;94:1432–6.

    Google Scholar 

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

    Google Scholar 

  42. Chantada GL, Doz F, Orjuela M, et al. International Retinoblastoma Staging Working Group. World disparities in risk definition and management of retinoblastoma: a report from the International Retinoblastoma Staging Working Group. Pediatr Blood Cancer. 2008;50:692–4.

    Google Scholar 

  43. Kivelä T, Kujala E. Prognostication in eye cancer: the latest tumor, node, metastasis classification and beyond. Eye Lond Engl. 2013;27:243–52.

    Google Scholar 

  44. Hungerford J, Kingston J, Plowman N. Orbital recurrence of retinoblastoma. Ophthalmic Paediatr Genet. 1987;8:63–8.

    Google Scholar 

  45. Doz F, Khelfaoui F, Mosseri V, et al. The role of chemotherapy in orbital involvement of retinoblastoma. The experience of a single institution with 33 patients. Cancer. 1994;74:722–32.

    Google Scholar 

  46. Radhakrishnan V, Kashyap S, Pushker N, et al. Outcome, pathologic findings, and compliance in orbital retinoblastoma (International Retinoblastoma Staging System stage III) treated with neoadjuvant chemotherapy: a prospective study. Ophthalmology. 2012;119:1470–7.

    Google Scholar 

  47. Namouni F, Doz F, Tanguy ML, et al. High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: a SFOP and SFGM study 1. This work has been partially presented to the XXVIIth SIOP meeting in Montevideo, October 1995. Eur J Cancer. 1997;33:2368–75.

    Google Scholar 

  48. Matsubara H, Makimoto A, Higa T, et al. A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement. Bone Marrow Transplant. 2005;35:763–6.

    Google Scholar 

  49. Dunkel IJ, Aledo A, Kernan NA, et al. Successful treatment of metastatic retinoblastoma. Cancer. 2000;89:2117–21.

    Google Scholar 

  50. Dunkel IJ, Khakoo Y, Kernan NA, et al. Intensive multimodality therapy for patients with stage 4a metastatic retinoblastoma. Pediatr Blood Cancer. 2010;55:55–9.

    Google Scholar 

  51. Jubran RF, Erdreich-epstein A, Butturini A, et al. Approaches to treatment for extraocular retinoblastoma: Children’s Hospital Los Angeles experience. J Pediatr Hematol Oncol. 2004;26:31–4.

    Google Scholar 

  52. Dunkel IJ, Chan HSL, Jubran R, et al. High-dose chemotherapy with autologous hematopoietic stem cell rescue for stage 4B retinoblastoma. Pediatr Blood Cancer. 2010;55:149–52.

    Google Scholar 

  53. Kim JW, Jacobsen BH, Ko M, et al. Three presentations of CNS disease in patients with intraocular retinoblastoma at a tertiary medical center in the United States. Ophthalmic Genet. 2018;39:115–9.

    Google Scholar 

  54. Jakobiec FA, Tso MO, Zimmerman LE, et al. Retinoblastoma and intracranial malignancy. Cancer. 1977;39:2048–58.

    Google Scholar 

  55. De Potter P, Shields CL, Shields JA. Clinical variations of trilateral retinoblastoma: a report of 13 cases. J Pediatr Ophthalmol Strabismus. 1994;31:26–31.

    Google Scholar 

  56. de Jong MC, Kors WA, de Graaf P, et al. Trilateral retinoblastoma: a systematic review and meta-analysis. Lancet Oncol. 2014;15:1157–67.

    Google Scholar 

  57. Blach LE, McCormick B, Abramson DH, et al. Trilateral retinoblastoma--incidence and outcome: a decade of experience. Int J Radiat Oncol Biol Phys. 1994;29:729–33.

    Google Scholar 

  58. Finelli DA, Shurin SB, Bardenstein DS. Trilateral retinoblastoma: two variations. AJNR Am J Neuroradiol. 1995;16:166–70.

    Google Scholar 

  59. Katayama Y, Tsubokawa T, Yamamoto T, et al. Ectopic retinoblastoma within the 3rd ventricle: case report. Neurosurgery. 1991;28:158–61.

    Google Scholar 

  60. Dunkel IJ, Jubran RF, Gururangan S, et al. Trilateral retinoblastoma: potentially curable with intensive chemotherapy. Pediatr Blood Cancer. 2010;54:384–7.

    Google Scholar 

  61. Blommaert FA, van Dijk-Knijnenburg HC, Dijt FJ, et al. Formation of DNA adducts by the anticancer drug carboplatin: different nucleotide sequence preferences in vitro and in cells. Biochemistry (Mosc). 1995;34:8474–80.

    Google Scholar 

  62. Lambert MP, Shields C, Meadows AT. A retrospective review of hearing in children with retinoblastoma treated with carboplatin-based chemotherapy. Pediatr Blood Cancer. 2007;50:223–6.

    Google Scholar 

  63. Jehanne M, Lumbroso-Le Rouic L, Savignoni A, et al. Analysis of ototoxicity in young children receiving carboplatin in the context of conservative management of unilateral or bilateral retinoblastoma. Pediatr Blood Cancer. 2009;52:637–43.

    Google Scholar 

  64. Smith MA, Rubinstein L, Anderson JR, et al. Secondary leukemia or myelodysplastic syndrome after treatment with Epipodophyllotoxins. J Clin Oncol. 1999;17:569–77.

    Google Scholar 

  65. Correia JJ. Effects of antimitotic agents on tubulin-nucleotide interactions. Pharmacol Ther. 1991;52:127–47.

    Google Scholar 

  66. Rizzuti AE, Dunkel IJ, Abramson DH. The adverse events of chemotherapy for retinoblastoma: what are they? Do we know? Arch Ophthalmol. 2008;126:862–5.

    Google Scholar 

  67. Leahey A. A cautionary tale: dosing chemotherapy in infants with retinoblastoma. J Clin Oncol. 2012;30:1023–4.

    Google Scholar 

  68. 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.

    Google Scholar 

  69. Nishimura S, Sato T, Ueda H, et al. Acute myeloblastic leukemia as a second malignancy in a patient with hereditary retinoblastoma. J Clin Oncol. 2001;19:4182–3.

    Google Scholar 

  70. Turaka K, Shields CL, Meadows AT, et al. Second malignant neoplasms following chemoreduction with carboplatin, etoposide, and vincristine in 245 patients with intraocular retinoblastoma. Pediatr Blood Cancer. 2011;59:121–5.

    Google Scholar 

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Author information

Authors and Affiliations

  1. Division of Hematology, Oncology and Blood and Marrow Transplantation, Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Rachana Shah & Rima Fuad Jubran

  2. Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Rachana Shah

  3. Texas Children’s Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Rajkumar Venkatramani

  4. Department of Pediatrics, Keck School of Medicine, University of Southern California, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Rima Fuad Jubran

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  1. Rachana Shah
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  2. Rajkumar Venkatramani
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  3. Rima Fuad Jubran
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Corresponding author

Correspondence to Rachana Shah .

Editor information

Editors and Affiliations

  1. Associate Professor of Ophthalmology, Children’s Hospital Los Angeles, The USC Roski Eye Institute Keck School of Medicine, Los Angeles, CA, USA

    Jesse L. Berry

  2. Children’s Hospital Los Angeles, The USC Roski Eye Institute, Keck School of Medicine, Los Angeles, CA, USA

    Jonathan W. Kim

  3. University of Oxford, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK

    Bertil E. Damato

  4. Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA

    Arun D. Singh

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Shah, R., Venkatramani, R., Jubran, R.F. (2019). Retinoblastoma: Intravenous Chemotherapy. In: Berry, J., Kim, J., Damato, B., Singh, A. (eds) Clinical Ophthalmic Oncology. Springer, Cham. https://doi.org/10.1007/978-3-030-11123-6_13

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  • DOI: https://doi.org/10.1007/978-3-030-11123-6_13

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