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  5. FP1061 : Intra-arterial chemotherapy for retinoblastoma: Three-year follow-up

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Dr. Pukhraj Rishi, R08659, Dr. Ashutosh Agarwal, Dr. Tarun Sharma

Introduction

            Treatment of retinoblastoma (RB) is rapidly evolving and ever changing. Management options include enucleation, radiotherapy, chemotherapy and focal therapy. The four routes for delivering chemotherapy are intra-venous (IVC), intra-arterial (IAC),peri-ocular, and intra-vitreal (IVitC). Focal therapy includes laser photocoagulation, trans-pupillary thermotherapy (TTT), and cryotherapy.  External beam radiotherapy (EBRT) has now become obsolete due to the risk of secondary non-ocular tumors and was replaced by intravenous chemotherapy (IVC) in the 1990s.(1),(2),(3)Enucleation rates have steadily declined as high rates of globe salvage can now be achieved using various forms of chemotherapy. Still, enucleation remains an important option in advanced RB, especially in developing countries of Asia and Africa.(4),(5) Even in ICRB (International Classification of Retinoblastoma) Group E eyes, intra-arterial chemotherapy (IAC) and IVC are offered as options to save the eye. In unilateral, non-germline Group B to group E RB, IAC is now considered as a primary option in select cases. Secondary IAC is used for recurrent tumors, subretinal seeds, and vitreous seeds. IVC is used as first line treatment modality for bilateral, familial RB (germline RB) for intraocular tumor control and prevention of metastasis. Intravitreal chemotherapy is used for recurrent vitreous seeding.(6) IAC offers the advantage to reduce systemic chemotherapy related complications like neutropenia, anemia and secondary neoplasms.(7) It decreases the duration of hospital stay and allows delivery of high dose chemotherapy directly to the tumor bed.(8) Reduced systemic absorption also allows the use of melphalan, which has been found to be the most effective chemotherapeutic agent in RB.(9) Concerns with the use of IAC include its efficacy in advanced Group E tumors and recurrence rates in tumors with vitreous seeding; high economic burden especially in developing countries; rates of useful vision salvage despite high globe salvage and complications. Complications in IAC can occur due to the technique of the injection itself and from the use of a high dose of chemotherapeutic agents which can lead to ocular and systemic toxicity.

We have previously reported the one-year and two-year efficacy and complications of IAC for RB. In this study, we seek to share our three-year experience of IAC for RB at a tertiary eye-care hospital in India.

Materials and methods  

            This is a retrospective, interventional case series which includes 15 eyes of 15 patients with RB treated by IAC at the Oncology Service between November 2013 and July 2017. Institutional Review Board approval was sought. Written informed consent was taken from the parents of all patients after a detailed explanation of the risks and potential benefits of treatment. The tenets of the Declaration of Helsinki were adhered to. The study included subjects with unilateral or bilateral Group B to E retinoblastoma. The patients may or may not have received prior systemic chemotherapy. Data collection included demographic details, details of presenting features, clinical findings, management, complications, and outcomes. Relevant family history was noted. History of past ocular and systemic treatment was taken. A comprehensive ophthalmic examination was performed under anesthesia. Details of the ophthalmic examination, ancillary and systemic investigations have been described by us in a previous study. Documentation of retinal findings was done with fundus drawing and fundus photography with RetCam camera (Massey Industries, Dublin, CA, USA). The international classification of retinoblastoma (ICRB) was used to group the tumors. The IAC catheterization procedure, chemotherapy dosing and follow-up schedule have been described by us previously. Primary outcome measures included tumor regression, VS and SRS control, globe salvage at final follow up. Secondary outcome measures were best corrected visual acuity (BCVA) at final follow up and treatment complications.

Results: 

The mean age of the patients at treatment was 30.4 months (median: 24, range: 11-94 months). All 15 patients had sporadic RB. The various modes of presentation were leukocoria (n = 7), strabismus (n = 1), both (n = 4), diminished vision (n=1) and redness of the eye (n = 2). Mean duration of symptoms at presentation was 9.1 weeks (median: 3, range: 0–48 weeks). Eyes with RB were grouped as per the international classification of RB (ICRB) as Group A (n=0), Group B (n = 1), C (n = 3), D (n = 9) and E (n = 2). Baseline tumor characteristics at first EUA were noted. The mean tumor base at baseline was 17.1 mm (median: 18, range: 6–24 mm) and the mean tumor thickness was 7.4 mm (median: 8.2, range: 2.6-11.5 mm). Vitreous seeds (VS) were present at baseline in 12 eyes with involvement of 1 quadrant (n = 1), 2 quadrants (n=5), 3 quadrants (n = 1) or all 4 quadrants (n = 5). Subretinal seeds (SRS) were present at baseline in 6 eyes involving 2 quadrants (n = 2), 3 quadrants (n = 2) or all 4 quadrants (n = 2). Optic nerve was visible in seven eyes, partially visible in one eye and obscured due to tumor overhang in seven eyes. Exudative retinal detachment secondary to the tumor was present in six eyes (15-100%). Six eyes had a single tumor at presentation. Of the remaining nine eyes that had multiple tumors, the number of tumors per eye ranged from 1 (n = 6), 2 (n = 5), 3 (n = 2), 4 (n=1) or 5 (n = 1). Eight eyes (53.3%) had predominantly exophytic tumors while seven eyes (46.7%) had predominantly endophytic tumors. Mean proximity of tumor to optic disc was 1.5 mm (median: 0, range: 0–16 mm) and to the foveola was 2.1 mm (median: 0, range: 0–20 mm). IAC was employed as either primary (n = 6) or secondary (n = 9) modality of systemic therapy. Nine of 15 patients had bilateral RB. Of these, fellow eye of 6 patients underwent enucleated for Group E tumor. Prior treatment with intravenous chemotherapy using vincristine, etoposide and carboplatin (VEC) is as follows: 1 cycle (n=1), 3 cycles (n=2), 4 cycles (n=1), 6 cycles (n=2), 7 cycles (n=1), 9 cycles (n=1) or 11 cycles (n=1). Local treatments included cryotherapy (n = 10), transpupillary thermotherapy (n = 5), external beam radiotherapy (n=1) and combination intravitreal chemotherapy with melphalan and topotecan (n = 1; Case 9)

Tumor characteristics before IAC, treatment details, ocular complications and outcomes are mentioned in Table 2. Each eye received mean 3.53 IAC sessions (median: 3; range: 1–5 sessions). Additional systemic chemotherapy included VEC for 2 cycles (n = 2), 3 cycles (n = 1), 5 cycles (n = 1), 6 cycles (n=4) or 8 cycles (n=1). Local therapy included cryotherapy (n = 14), transpupillary thermotherapy (n = 11) and combination intravitreal chemotherapy with melphalan and topotecan (n = 5).

At the last follow-up following IAC, complete regression of the main tumor was seen in 8 eyes (53.3%), partial regression in 4 eyes (26.7%), persistence of tumor in one eye (6.7%), and recurrence in two eyes (13.3%). Twelve eyes had active VS at baseline, of which six eyes (50%) showed complete regression, one eye (16.7%) showed partial regression, two eyes (8.3%) showed persistence, while 3 eyes (25%) showed recurrence. Six eyes had subretinal seeds at baseline. Of these, five (83.3%) had completely regressed after the last IAC session, while one eye (16.7%) showed recurrence. Globe salvage was achieved in 12 of 15 (80%) eyes and three eyes underwent enucleation during the course of treatment (Case I,II and XII); case I due to dense vitreous haemorrhage after fourth IAC session; case II and XII due to development of retinal detachment and recurrence of tumor. Kaplan Meier survival curve showed 91% globe survival rate at 18 months after the first IAC session, 82% at the end of 18 months, 70% at the end of 24 months and remained stable at 70% at the end of 36 months. Histopathologic examination revealed poorly differentiated RB with choroidal invasion more than 3 mm in all three cases. There was involvement of post-laminar optic nerve and ciliary body infiltration in Case 2 and anterior sclera involvement in case XII. All cases underwent adjuvant chemotherapy using VEC.

Complications included transient ophthalmic artery narrowing (n=2), branched retinal vein occlusion (n = 1), vitreous hemorrhage (n=3), sclerosed vessels (n = 1), toxic optic neuropathy (n=1), optic atrophy (n=1), iris atrophy with posterior synechiae (n=1), posterior subcapsular cataract (n = 2), forehead skin pigmentation (n = 1) and allergic skin reaction (n=1). There was no stroke, hemiplegia, metastasis or death in any patient. Transient hematological changes included relative pancytopenia (n = 4), relative leukopenia (n = 5), relative thrombocytopenia (n = 4), eosinophilia(n=2) and relative lymphocytopenia(n=1). None of the patients had metastasis or death.

In summary, we describe the outcomes of IAC for RB at 3 years from a single, tertiary eye-care centre in India. IAC is effective in achieving higher rates of globe salvage in eyes with intraocular retinoblastoma.

References:

  1. Shields CL, De Potter P, Himelstein BP, Shields JA, Meadows AT, Maris JM. Chemoreduction in the initial management of intraocular retinoblastoma. Arch Ophthalmol Chic Ill 1960. 1996 Nov;114(11):1330–8.
  2. Murphree AL, Villablanca JG, Deegan WF, Sato JK, Malogolowkin M, Fisher A, et al. Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol Chic Ill 1960. 1996 Nov;114(11):1348–56.
  3. Gallie BL, Budning A, DeBoer G, Thiessen JJ, Koren G, Verjee Z, et al. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol Chic Ill 1960. 1996 Nov;114(11):1321–8.
  4. Kivelä T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol. 2009 Sep;93(9):1129–31.
  5. Rodriguez-Galindo C, Wilson MW, Chantada G, Fu L, Qaddoumi I, Antoneli C, et al. Retinoblastoma: one world, one vision. Pediatrics. 2008 Sep;122(3):e763-770.
  6. Shields CL, Fulco EM, Arias JD, Alarcon C, Pellegrini M, Rishi P, et al. Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Eye. 2013 Feb;27(2):253–64.
  7. Shields CL, Shields JA. Intra-arterial chemotherapy for retinoblastoma: the beginning of a long journey. Clin Experiment Ophthalmol. 2010 Aug;38(6):638–43.
  8. Zanaty M, Barros G, Chalouhi N, Starke RM, Manasseh P, Tjoumakaris SI, et al. Update on intra-arterial chemotherapy for retinoblastoma. ScientificWorldJournal. 2014;2014:869604.
  9. Jabbour P, Chalouhi N, Tjoumakaris S, Gonzalez LF, Dumont AS, Chitale R, et al. Pearls and pitfalls of intraarterial chemotherapy for retinoblastoma. J NeurosurgPediatr. 2012 Sep;10(3):175–81.
  10. Rishi P, Sharma T, Sharma M, Maitray A, Dhami A, Aggarwal V, Munusamy S, Ravikumar R, Ramamurthy S. Intra-arterial chemotherapy for retinoblastoma: Two-year results from tertiary eye-care center in India.Indian J Ophthalmol. 2017 Apr;65(4):311-315.
  11. Rishi P, Sharma T, Koundanya V, Bansal N, Saravanan M, Ravikumar R, Ramamurthy S. Intra-arterial chemotherapy for retinoblastoma: First Indian report.Indian J Ophthalmol. 2015 Apr;63(4):331-4.

 

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