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Prof.Usha Singh, Prof. Mangat R Dogra, Dr. Deeksha Katoch

Abstract:

Aim: To study the safety and efficacy of intraarterial chemotherapy in the management of intraocular retinoblastomas at a tertiary care institute. Methods: Clinical data, international classification, treatment outcomes and complications were studied in patients with the intraocular disease who underwent intraarterial chemotherapy. Results: There were twenty patients (23 eyes) with an average age of 19.75 months at presentation. Secondary treatment was given in 14. Each eye received 1 to 5 cycles of IAC, using melphalan, topotecan and/or carboplatin. Post IAC response of disease was evaluated in terms of tumor size, vitreous seeds, subretinal seeds, subretinal fluid and retinal detachment. Local complication included vascular occlusions in 3.  Overall globe salvage rate was 82.6% at a median follow up of 21.5 months. Conclusion: Intraarterial chemotherapy is safe and effective but vascular occlusion can lead to suboptimal vision.

INTRODUCTION

Intra-arterial chemotherapy (IAC) for retinoblastoma (RB), was first used in 1958, by administeringone injection of triethylenemelamine in the carotid artery which showed successful regression of the tumor.The purpose of IAC is to deliver concentrated chemotherapeutic drug into the eye and reduce its systemic toxicity. Later in 1987 the Japanese1delivered melphalan to the retinoblastoma eye via endovascular route after balloon occlusion of the distal internal carotid artery. With rapid advancement in endovascular techniques, this delivery became super selective in 2008 when Abramson et al2 did selective cannulation of the ophthalmic artery. Since then subsequent studies came up which concluded that IAC was safe, with globe salvage reaching 72-82% after primary IAC3,4.

MATERIAL AND METHODS

This study was a retrospective, nonrandomized, interventional case series. The clinical data review of all retinoblastoma patients treated with IAC at the Retinoblastoma Clinic, Advanced Eye Center of PGIMER was done between November2013 and May 2017 was done.

IAC catheterization procedure was performed by the interventional neuro-radiologist in the intervention room under general anesthesia. Data was analysed for clinical findings, management, complications, and outcomes. All pre and post IAC treatments to the eye and patient were recorded. Pre IAC ocular examination under anesthesia was performed to the assess patient for laterality, tumor growth pattern, number of tumors per eye, international classification of RB, intraocular pressure (Schiotz tonometer), and status of anterior and posterior chamber involvement. Ultrasound MRI and fundus imaging was done for all patients to diagnose, asses and group and or stage the disease. Complete blood counts and basic coagulation tests were done at baseline and blood counts repeated after every IAC.Informed consent was taken after explaining the pros and cons of IAC. Post IAC examination with retinal drawings and imaging was done to assess the response of the tumor. Each tumor was measured for greatest basal diameter and thickness, associated retinal detachment, subretinal seeds, and vitreous seeds. Local treatment (photocoagulation, cryotherapy) was applied if indicated. Globe salvage was defined as preservation of the globe with control of disease. Loss of eye leading to enucleation was considered a failure.

RESULTS

There were twenty patients (23 eyes) with average age of 19.75 months at presentation. There were 14 males and 6 females. Nine had unilateral disease, and none had family history of RB. Chief presenting complaint was white reflex in all. Duration of Symptoms ranged from 3 to 365 days (mean: 77.46 days). Eight eyes had group D disease,7 had group B, 4 had group C, 4 had group E and none had group A disease. Primary IAC was delivered to 6 eyes. Total 43 catheterisations were done of which 2 failed. Direct cannulation of ophthalmic artery ostium was done 24 times. Other arterial routes used were internal maxillary artery in 4, middle meningeal artery in 11 superficial temporal artery in 1 and by Japanese technique in 1. Each eye received 1 to 5 cycles of IAC, using melphalan and/or topotecan. Topotecan was given to two eyes in combination with melphalan. Two eyes received a combination of Melphalan, Topotecan and Carboplatin. One had intra-catheterization lung collapse but could be managed without any adverse sequalae. One had a difficult cannulation and ophthalmic artery stenosis was seen in one. Group wise response and reduction of the tumour mass, vitreous seeds, subretinal seeds and retinal detachment was seen in majority (Table 1). Local side effects were seen in the form of choroidal atrophy in 5, lid edema in 5, cheek swelling in 1 and development of new tumours were seen after IAC in 3 patients. Vascular occlusions were seen in 3, was complete (CRAO) in one leading to loss of sight. Post IAC additional treatment was received by 9 patients, of which 4 were enucleation, radiotherapy, laser photocoagulation, and Plaque in 1 each, Two also received Intravenous chemotherapy. The cause of enucleation in these 4 patients were regrowth after IAC in 2 and poor response leading to progression in two. Overall globe salvage rate was 82.6% at a follow-up of 21.5 (range 7-41) months.

Discussion:

Intraarterial chemotherapy is a newer endovascular technique in the armamentarium of retinoblastoma treatment modalities for achieving high globe salvage rates. With the current refinement of endovascular catheterisation, chemotherapeutic drug is directly delivered into the ophthalmic artery2. We retrospectively analysed the safety of this procedure and outcome in the treated eyes.

This study found response of the tumour and seeds when IAC is used as both primary and secondary treatment modality. Three eyes after IAC had poor response, which ultimately led to enucleation in all. Melphalan being the most effective with a short half-life was used in all patients. The reduction in tumour mass, subretinal seeds, vitreous seeds and retinal detachment rates ranged from 50-92% in majority (average 81.2%). Over all globe salvage rate in this series was high (82.6%). Literature meta-analysis of IAC for retinoblastoma in non-duplicative studies in 757 eyes has found a success rate of 66%5. In case the catheterisation of ophthalmic artery is inappropriate or difficult due to anatomic variations, alternative retrograde approach has been used6. We used alternative arterial route via middle meningeal, internal maxillary and superficial temporal arteries in 17 of the 43 catheterisations. Systemic complications after IAC such as stroke and neurological complications have been reported, however they were nil in our study, Unrelated complications were allergy to contrast in one and lung collapse in another. Serious local vascular complication was seen in 3 with one losing vision. Although literature does not address this issue, three eyes developed new lesions after IAC in our study.

The selection bias and moderate follow-up in our patient is a limitation. In order to study recurrence, metastasis and death longer follow-up is required as they can occur more than 5 years after treatment. Globe salvage is valuable after IAC only when it is achieved without major systemic complications and risk to life. Intraarterial chemotherapy is safe and effective but vascular occlusions can lead to suboptimal vision hence until well- established indications are laid down; it should be used with caution.

References:

  1. Yamane T, Kaneko A, Mohri M. The technique of ophthalmic arterial infusion therapy for patients with intraocular retinoblastoma. Int J Clin Oncol. 2004;9:69-73.
  2. 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;115:1398-404, 14041.
  3. Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH. Intra-arterial chemotherapy for the management of retinoblastoma: Four-year experience. Arch Ophthalmol. 2011;129:732-7.
  4. Shields CL, Manjandavida FP, Lally SE, Pieretti G, Arepalli SA, Caywood EH, et al. Intra-arterial chemotherapy for retinoblastoma in 70 eyes: Outcomes based on the international classification of retinoblastoma. Ophthalmology. 2014;121:1453-60.
  5. Yousef YA, Soliman SE, Astudillo P PP,Durairaj P, DimarasH,Chan HSL et al. Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. JAMA Ophthalmol. 2016;134(5):584-591. doi:10.1001/jamaophthlmol.2016.0244
  6. Saglam M, Sarici A, Anagnostakou V, Yildiz B, Kocer N, Islak C et al.An alternative technique of the super-selective catheterization of the ophthalmic artery for intra-arterial chemotherapy of the retinoblastoma: retrograde approach through the posterior communicating artery to the ophthalmic artery.2014;56: 751.

TABLES

Pre IAC Post IAC Globe Salvage % Round figure
Tumor size 13 12 12 92.3 92%
Vit Seeds 2 1 1 50 50
Subretinal seeds 9 8 8 88.88% 89
Subretinal fluid 9 8 8 88.88% 89
RD 7 6 6 85.7 86

Table 1: Response of tumor to Intra-arterial chemotherapy

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