FP832 : Outcomes of Triple Drug Intra- Arterial Chemotherapy (IAC) for Retinoblastoma as Secondary Therapy

Dr. Sonal Chaugule, C14278, Dr. Santosh G Honavar

Abstract:

Purpose: To study the technique and outcomes of triple drug intra-arterial chemotherapy (IAC) in retinoblastoma (RB) as a secondary treatment modality.

Materials and Methods: This was a retrospective interventional case series involving 12 eyes of 11 patients with residual and recurrent RB. Triple drug (Topotecan, Melphalan and Carboplatin) intra-arterial chemotherapy infusion was performed under radiological guidance. Outcome measures were successful catheterization, tumor regression, eye salvage, local complications and systemic toxicity.

Results: The mean age was 33 (range 13-80) months. Secondary therapy was performed in cases with residual RB in 4 (33%) and recurrent in 8 (67%) eyes with previous intravenous chemotherapy (mean 12.6; range 6-23, cycles). Intraarterial therapy involved a mean of 2 (median 3, range 1-3) cycles of IAC. The mean duration of follow up after IAC was 13 (median, 15.5; range 10-18) months. Of secondary therapy eyes, regression of the solid tumor noted in 10 (n=12, 83%), subretinal seeds in 7 (n=9, 78%), and vitreous seeds in 7(n=9, 78%) eyes. Eye salvage was achieved in 10 (77%) of primary therapy eyes, and in 7 (58%) of secondary therapy eyes. Common transient external complications included ptosis (n=1), scalp alopecia (n=2), eyelid hyperemia (n=2). No intraocular or neurological complications were noted.

Conclusion: Triple drug IAC holds promise as a secondary treatment option for residual or recurrent retinoblastoma. 

Introduction:

Retinoblastoma is the most common primary intraocular malignancy of childhood. It is also believed to be perhaps the ‘most curable pediatric cancer’.^[1]  The management of retinoblastoma has evolved from external beam radiotherapy and enucleation (1950); to more conservative systemic chemotherapy or intravenous chemotherapy (IVC) with adjuvant focal thermotherapy, photocoagulation, cryotherapy (1990), periocular chemotherapy (1995); to the recent selective intra-arterial chemotherapy (IAC) (2003).^[2] The aim has been to achieve higher rates of globe as well as functional vision salvage. Enucleation is still a preferred option for eyes with ICRB group E disease with clinical risk factors namely neovascular glaucoma, buphthalmos, anterior chamber invasion, vitreous hemorrhage and phthisis bulbi according to experts. ^[1]

Intra-arterial chemotherapy has assumed an important role in management of retinoblastoma since its commencement. This targeted therapy involves delivery of the potent chemotherapy drugs directly into the ophthalmic artery of the eye to increase their intraocular concentration to treat intraocular tumor and minimize the systemic absorption.^[3] The method of chemotherapy delivery has evolved over time from the initial Japanese technique of catheterization with balloon obstruction to the American technique of selective ophthalmic artery catheterization for the delivery of chemotherapeutic agents directly into the vascular tree that serves the eye and tumor.^[4-9]

IAC has mostly replaced systemic chemotherapy as standard-of-care first line treatment for management for ICRB group D eyes and selected group E eyes in centers in developed countries. ^[1,3,7] Systemic chemotherapy with adjuvant focal measures like photocoagulation, thermotherapy, cryotherapy is still the first line of management as an organ salvage measure, in developing countries like India. Rishi et al have published their first report of IAC for residual and recurrent retinoblastoma from India in 2015 (n=6) using Melphalan alone or Melphalan plus Topotecan thus far.^[10]

We report our single center results of triple drug (Melphalan, Topotecan and Carboplatin) intra-arterial chemotherapy as secondary treatment modality in retinoblastoma.

Materials and Methods:

This was a retrospective, non-randomized, non-comparative, interventional case series. The medical records of all patients diagnosed with residual and recurrent retinoblastoma undergoing IAC between September 2015 to February 2017 were reviewed. Institutional Review Board (IRB) approval was taken for the study. Twelve eyes of 11 cases who underwent IAC using age adjusted doses of Melphalan (3mg/ 5mg/ 7.5mg), Topotecan (0.5mg/ 1 mg) and Carboplatin (30mg) were included. (Table 1) The IAC catheterization procedure was performed by skilled interventional radiologist in operation theatre under general anesthesia. The patient data was reviewed for the demographic characteristics, clinical features, primary and secondary management, complications and outcomes.

Pre-IAC tumor data:

IAC was carried out for defined number of cycles at the interval of 3 weeks preceded by detailed examination under anesthesia of the child. Anterior chamber was examined for any infiltration/ seeds. Intraocular pressure was measured with Perkin’s contact tonometry and recorded. Posterior segment was examined with help of indirect ophthalmoscopy aided with indentation to assess the laterality, number of tumors per eye, location, dimensions and extent. Baseline ultrasound B scan was performed on all eyes. Complete blood counts and basic coagulation studies were performed.

Each tumor was measured for its greatest basal diameter and thickness, proximity to optic nerve and fovea (mm), associated retinal detachment (number of quadrants involved), subretinal and vitreous seeds (absent/ present- quadrants involved). The Examination findings were documented at each visit by fundus drawings and imaging by RetCam 3 (Clarity)^TM camera. The risk and benefits of intra-arterial chemotherapy, appropriate treatment options were discussed with parents and family. A signed written informed consent was obtained prior to each procedure.

Triple drug Intra-arterial Chemotherapy Technique:

IAC catheterization was performed in the operating theatre under general anesthesia using sterile techniques by an interventional radiologist. The chemotherapy drug preparation was done as explained in Table 1. Intravenous heparin (50IU/Kg) was used initially for anticoagulation. Through right trans-femoral approach, the ipsilateral internal carotid artery was catheterized with pediatric neuro-catheter. The arterial anatomy was studied with serial angiograms. The drug delivery was possible by one of the following methods:

1. Catheterization of ophthalmic artery ostium selectively with the pediatric neuro-catheter. The determined concentration of drug was diluted in 30 ml of diluent solution. The drug infusion was carried out slowly, in a non-laminar manner without any reflux over 90 minutes. (30 minutes for each drug)
2. In cases where selective catheterization was not possible (n=6) due to reasons like anatomic variation (n=2) or stenosed ostium (n=4), the internal carotid artery was occluded with balloon inflation distal to origin of ophthalmic artery. The drugs were injected in their primary dilution and volume over short period of time (60-120 seconds). The balloon was deflated after the drug infusion. The carotid flow was checked with an angiogram.

The intracranial blood perfusion was checked with an angiogram at the end of each procedure to ensure uninterrupted blood flow. At conclusion of the infusion, the catheter was withdrawn, the femoral sheath was removed, and hemostasis of the femoral artery was achieved by manual compression. The child was observed overnight and discharged the next day. Topical antibiotic-steroid drops and cycloplegic were advised for 3 weeks post the procedure.

The complete blood count was repeated on day 7, 14 and 21. The child was examined at the end of 3^rd week under anesthesia before commencing with next IAC cycle.

Follow-up visit examination:

External ocular examination for periocular changes with detailed anterior chamber and posterior segment was carried out. The IAC cycle was repeated every 3-weekly. The number of cycles for eyes receiving IAC as secondary modality was decided after monitoring tumor response after each cycle.

Secondary systemic chemotherapy, intravitreal chemotherapy and/ or adjuvant thermotherapy, cryotherapy was administered after evaluation of the tumor post IAC as indicated. During follow up, each eye was evaluated for regression of solid tumor, subretinal seeds, vitreous seeds and subretinal fluid. Tumor recurrence was documented. Other subsequent treatment modalities administered were recorded and the data was analyzed.

Main outcome measures:

Outcome measures were successful catheterization, tumor regression, subretinal and vitreous seeds regression, eye salvage, local complications and systemic toxicity. 

Results:

The demographic features are described in Table 2. Secondary IAC was administered in 12 eyes after suboptimal response from prior treatment with systemic chemotherapy (mean, 12.6; range, 6-23) with residual disease in 4 (33%); recurrence of solid tumor in 8 (67%), subretinal seeds in 6 (50%), vitreous seeds in 5 (42%), sometimes in combination. The clinical findings and outcome are described in Table 3. After mean 2.2 (median, 3; range, 1-3) cycles of IAC, regression of the solid tumor was noted in 10 (n=12, 83%), subretinal seeds in 7 (n=9, 78%), and vitreous seeds in 7(n=9, 78%) eyes. Globe salvage was possible in 7 (58%) cases. Five (42%) eyes had to be enucleated for single or combination of reasons, including residual viable solid tumor (n=2), recurrence of subretinal seeds (n=3), persistent vitreous seeds (n=2), extensive vitreous hemorrhage (n=1), neovascular glaucoma (n=1).

After each IAC procedure, common side effects included transient eyelid edema (n=2), ptosis (n=1), eyelid and forehead hyperemia (n=1). Hematological events like transient neutropenia was observed in 10 (90%) cases and blood transfusion was required in 5 (20%). (Table 4) All systemic complications were timely and appropriately treated and were followed by remission. No patient was found to have stroke, seizures, limb ischemia suggesting any long term neurological damage. No regional lymph node or distant systemic metastasis was noted with the mean follow up of 13 (median, 15.5; range, 6-18 months)

Discussion:

With increased number of treatment modalities and advances in methods of chemotherapy delivery, management of retinoblastoma has entered a new era. Retinoblastoma carries a high fatality rate, with projected patient death in approximately 42% of cases worldwide. ^[3] The mortality varies region wise. Developed countries from North America and Europe have achieved promising outcomes with only 3-5% mortality as opposed to 50-70% mortality in developing countries like Africa. ^[2,3] The Mortality is projected to be 40-50 % in India. The reasons for this gap are multifaceted. They include delay in diagnosis, advanced disease at presentation, deficiency of trained tertiary centers, cost of advanced treatment modalities and low socio-economic status.

Intra-arterial chemotherapy is being practiced since its start in 1958, by centers worldwide. ^[11-19] In 2008, Abramson et al reported use of Melphalan and salvage of 7 out of the 9 treated eyes with minimal systemic complications and local toxicity.^[6] In 2011, Gobin et al reported their results with injection of Melphalan with or without Topotecan in 95 eyes with unilateral RB. They concluded by saying that IAC is safe and effective in the treatment of advanced intraocular retinoblastoma. ^[9]

Shields et al published their outcomes of IAC in 70 eyes with Melphalan with additional Topotecan and/ or Carboplatin, giving globe salvage of 72% for primary-treated eyes and 62% in secondary-treated eyes with minimal systemic and local side effects.^[3] In a recent publication, Shields et al, while describing the ICRB dependent outcomes of systemic intravenous chemotherapy (IVC) versus IAC in unilateral retinoblastoma, concluded that for unilateral retinoblastoma, IAC provided significantly superior globe salvage as compared to IVC for group D eyes. In addition, it also provided superior control of solid tumor, subretinal and vitreous seeds. ^[20]

Advanced retinoblastoma (ICRB group D and E) are a constant challenge to manage. They are commonly destined for systemic chemotherapy or enucleation. With systemic intravenous chemotherapy, globe salvage of 47% for group D and 23% for group E eyes has been reported.^[2,21,22]We treated 12 eyes with IAC as secondary therapy, all had failed to improve with prior chemotherapy and were being considered for enucleation. By using IAC, globe salvage was possible in 7 (58%) of those eyes. Also; tumor control was achieved in 10 (n=12, 83%), regression of recurrent subretinal seeds in 7 (n=9, 78%), and vitreous seeds was achieved in 7 (n=9, 78%) eyes.

The findings of our study should be considered along with its limitations; which are retrospective nature, small sample size and relatively shorter follow up. An analysis of long follow up with larger number of patients in future would be beneficial to reinforce our findings. Considering the barriers of large cost and requirement of skilled personnel to perform the procedure; our study demonstrates improvement in globe salvage for eyes with advanced retinoblastoma having residual or recurrent disease. Triple drug intra-arterial chemotherapy requires 3 median number of cycles; as opposed to 6 for standard systemic chemotherapy cycles to cause complete or partial tumor regression. This reduces the treatment duration as well as the number of cycles of examination under anesthesia needed by the child. Though systemic and intravitreal chemotherapy are indispensable for complete control in a retinoblastoma eyes, triple drug IAC is a promising modality in eyes with advanced disease.

To summarize, triple drug intra-arterial chemotherapy is effective and has modest success as secondary modality in treating retinoblastoma. Eyes that have massive residual or recurrent tumor following intravenous chemotherapy and optimal focal therapy are often destined to enucleation. Our series shows that the use of triple drug intra-arterial chemotherapy with a combination of Topotecan + Melphalan + Carboplatin as secondary treatment provides a chance for eye salvage in such patients.

Table: 1: Age adjusted dose for Triple drug intra-arterial chemotherapy

Sr no	Drug	Age	Dose
1	Topotecan	0-2 years	0.5 mg
		≥2 years	1 mg
2	Melphalan	0-2 years	3mg
		2-5 years	5mg
		≥5 years	7.5mg
3	Carboplatin	All ages	30mg

Table 2: Demographic details

Sr No	Feature at the time of IAC	Numbers
1	Mean agein months(n= 11) Median Range	33 29 13 – 80
2	Ethnicity (number, percentage) Asian Arab African	10 (91%) 0 (0%) 1 (9%)
3	Sex (n= 11) (number, percentage) Male Female	9 (81%) 2 (19%)
4	Hereditary (n=11) (number, percentage) Sporadic Familial	10 (91%) 1 (9%)
5	Laterality (n=11) (number, percentage) Unilateral Bilateral	3 (27%) 8 (73%)
6	Eye undergoing treatment (n=12) (number, percentage) Right Left	7 (63%) 5 (37%)

Table 3: Clinical findings and outcomes of retinoblastoma eyes undergoing Secondary Triple drug IAC

Sr no	Features	Number
1.	Indications for IAC* (n=12), Number (percentage) Residual tumor Recurrent tumor Recurrent subretinal seeds Recurrent vitreous seeds	4 (33%) 8 (67%) 6 (50%) 5 (42%)
2	Review of treatment before IAC (n=12), Number (percentage) Systemic chemotherapy IAC (elsewhere) EBRT Plaque radiotherapy	12 (100%) 2 (17%) 1 (8.3%) 0 (0%)
3	Tumor control after IAC (n=12), Number (percentage) Regression of: Solid tumor (n=12) Subretinal seeds (n=9) Vitreous seeds (n=9) Subretinal fluid (n=11)	10 (83%) 7 (78%) 7 (78%) 10 (91%)
4	Globe outcome (n=12), Number (percentage) Eye salvage Enucleation	7 (58%) 5 (42%)

* – One or more indications could have been found in same eye.

Table: 4 Treatment complications

Sr No	Complications	Number (percentage)
1	External findings Eyelid edema Ptosis Eyelid erythema Forehead hyperemia Scalp alopecia	2 (18%) 1 (9%) 1 (9%) 1 (9%) 0 (0%)
2	Intraocular findings Raised IOP Ophthalmic artery occlusion Ophthalmic artery spasm Central retinal artery occlusion (CRAO) Branch retinal artery occlusion (BRAO) Choroidal vascular occlusion Optic neuropathy Vitreous hemorrhage	2 (18%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (9%)
3	Globe related findings Phthisis bulbi	0 (0%)
4	Central nervous system findings Stroke Seizures Neurological impairment	0 (0%) 0 (0%) 0 (0%)
5	Hematological findings Neutropenia Need for blood transfusion Febrile illness Respiratory tract infection Gastrointestinal disturbances Limb ischemia	10 (90%) 3 (27%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
6	Metastasis Regional lymph node spread Systemic spread	0 (0%) 0 (0%)

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