Intra-arterial chemotherapy in refractory and advanced intraocular retinoblastoma

Abstract

Purpose:

To evaluate the efficacy of secondary and salvage intra-arterial chemotherapy (IAC) as a globe salvage treatment modality in advanced and refractory intraocular retinoblastoma.

Methods:

A retrospective chart review of advanced intraocular retinoblastoma (groups D and E International Classification of Retinoblastoma [ICRB] classification) patients refractory to intravenous chemotherapy (IVC) and undergoing IAC as the secondary and salvage treatment modality between December 2018 and June 2021 was carried out. All patients underwent the IAC procedure by super-selective ophthalmic artery catheterization and with triple-drug chemotherapeutic agents of melphalan, topotecan, and carboplatin. Data were collected about tumor regression, eye salvage, metastasis, and survival outcome at follow-up.

Results:

Out of 13 patients, 12 patients received secondary IAC after being primarily treated with IVC and focal therapies and one patient received rescue IAC after recurrence following primary IAC. Mean number of IAC cycles administered was 2. Overall, globe salvage rate was 53.84%, with a mean follow-up of 17.53 months (range 6–37 months), three patients had enucleation for residual tumor or tumor recurrence. One patient developed metastasis post enucleation and two patients who were lost to follow-up after enucleation advice for residual tumor developed orbital tumor extension and eventually died of metastasis.

Conclusion:

Secondary triple-drug IAC following failure of IVC, along with other adjunct treatment modalities might a be a cost-effective option for eye salvage in advanced intraocular retinoblastoma patients who refuse enucleation, with a globe salvage rate of 53.84%. It can also be an effective approach to improve treatment compliance and can help in addressing the barrier of treatment refusal when enucleation is advised.

Retinoblastoma (RB) is the most common primary intraocular malignancy in children. Systemic intravenous chemotherapy (IVC) along with focal therapy in the form of laser and cryotherapy have shown very favorable results in salvaging the eyes of nearly 100% of groups A, B, and C tumors.[1-3] However, IVC in cases of advanced Group D and Group E RB with diffuse vitreous seeds (VS) and subretinal seeds (SRS) has shown limited results in terms of eye salvage.[4] Over the past decade, targeted treatment in the form of intravitreal chemotherapy (IVitC) and intra-arterial chemotherapy (IAC) has completely changed the treatment paradigm for advanced cases of RB and also dramatically improved eye salvage rates in advanced cases.[5,6] IAC is a super-selective technique of chemotherapy meant to deliver chemotherapeutic agents directly to the eyes at the tumor site through the ophthalmic artery. In recent times, IVitC has gained popularity in the management of advanced intraocular RB with VS and has shown improved eye salvage rates. Many patients in low-middle countries still present at an advanced stage of the disease due to a lack of awareness about early warning signs, poor access to health-care facilities, and delayed referral. Group D/E RB accounts for 78.7% of cases in the intraocular group, and enucleation is often the mainstay of treatment in such cases.[7] Shields et al. have shown globe salvage in 57% of eyes with secondary IAC post-IVC in advanced RB (groups D and E), which otherwise is an indication for enucleation.[8] Shields et al. also highlighted the importance of rescue IAC in managing RB recurrence after initial IAC, with tumor control in 75% of cases and globe salvage in 67% of cases.[9]

A few studies from India have shown promising results in the management of RB using newer modalities like IAC and IVitC.[10-12] In this study, we share our 3-year experience of managing advanced groups D and E RB with secondary and rescue IAC and eye salvage and survival outcomes.

Methods

This is a retrospective, nonrandomized, interventional case series of advanced intraocular RB patients refractory to IVC, who underwent IAC procedures between 2018 and 2021. The institutional review board approval was obtained before the study. Written informed consent was taken from the parents of all patients before the procedure. This study included only patients with unilateral or bilateral Group D or Group E RB according to the International Classification of Retinoblastoma (ICRB), who underwent secondary and rescue IAC after incomplete tumor regression with IVC during the above-mentioned period. Baseline imaging with magnetic resonance imaging (MRI) brain and orbits was done for all patients, and metastatic workup including bone marrow aspiration and cerebrospinal fluid (CSF) cytology was done for all Group E patients before starting IVC.

Data collected included demographic details, age (in months), gender (male or female), clinical findings at presentation, tumor characteristics, treatment data, complications, and outcomes. Previous treatment details, additional treatment modalities, and family history were also recorded. The primary outcome was measured in terms of tumor regression and globe salvage. Data about the visual outcome was also collected in patients with globe salvage, metastasis, and mortality. Tumor regression patterns along with the status of VS and SRS were recorded. Retinal findings were documented with fundus drawing and fundus photography at every visit during examination under anesthesia.

Before the IAC procedure, each patient was tested for a complete hematological profile, including coagulation profile, and this was repeated 2 weeks after the IAC procedure. Nasal vasoconstrictor was used preoperatively to minimize chemotherapy flow into the nose on the day of the procedure. The IAC catheterization procedure was performed by an experienced interventional neuroradiologist under fluoroscopic guidance in a neurointerventional lab. Intravenous heparin (50 IU/kg) was used for anticoagulation. The groin area was prepared and draped, and a 4-French arterial sheath was placed in the femoral artery region. Under fluoroscopic guidance, a micro-catheter was guided into the ipsilateral ophthalmic artery. Serial arteriograms were obtained to evaluate the cerebral vasculature and identify the vascular branches. A choroidal blush was identified in the angiogram. After ensuring the placement of the catheter at the ophthalmic artery ostium with an angiogram, chemotherapeutic drugs diluted in 30 ml of normal saline were infused gradually over 30 min in a pulsatile fashion to maintain a homogeneous drug delivery to the target. In every patient, a repeat angiogram was performed after the procedure to exclude any central nervous system (CNS) thromboembolic event. Chemotherapeutic agents used were injection melphalan hydrochloride (50 mg/10 ml), injection topotecan hydrochloride (2.5 mg/2.5 ml), and injection carboplatin (150 mg/15 ml). In all patients, a triple-drug regimen was used, except in one where the injection of the third drug could not be completed due to an intraoperative vasospasm episode. The dose of drugs was decided according to the age and weight of the patients. All patients who were under 2 years of age or weighed less than 10 kg received drugs in doses of topotecan 0.5 mg, melphalan 3 mg, and carboplatin 30 mg, and patients weighing more than 10 kg or of age >2 years received topotecan 1 mg, melphalan 5 mg, and carboplatin 30 mg. Post procedure, femoral artery hemostasis was maintained by manual compression followed by a compressive bandage. Patients were discharged on the same day after observation for 4–6 h. Oral analgesics and topical steroids were advised for 1 week postoperatively. Cold compress was also recommended for any swelling around the eyes. After completion of the IAC procedure, all patients were scheduled for examination under anesthesia at an interval of 3–4 weeks. Retinal and vitreous findings were noted, including the status of the tumor, SRS, and VS. Posttreatment complications, including those in the immediate postoperative period, were also recorded. All patients were monitored with regular Examination under anesthesia (EUA) after completion of treatment, to detect any recurrence. Visual acuity was noted at every follow-up visit. Relevant history and general physical examination including evaluation for reginal lymphadenopathy was done at every follow-up visit. For patients who received more than one cycle of IAC, the cycles were repeated at 4-weekly interval.

Results

In this series, 14 patients with group D and E RB were planned for secondary or rescue IAC following residual tumor or tumor recurrence after previous IVC or IAC. In one patient, cannulation could not be carried out in view of the anomalous origin of the ophthalmic artery. Out of the 13 patients, 12 patients had received secondary IAC after being primarily treated with IVC and focal therapies and one patient had received rescue IAC for tumor recurrence after primary IAC. The mean patient age at diagnosis was 33 months (range 0.5–108 months). There were seven female patients and six male patients. Except for one patient, all have had IAC for the right eye tumor. All demographic details, baseline tumor characteristics, and history of previous treatment are shown in Table 1.

Table 1.

Demographic and pre-IAC treatment data of the study patients

Age at diagnosis (months)	Gender	Baseline BCVA	Laterality	ICRB classification	Fellow eye	Systemic treatment before IAC
24	Male	FFL	Bilateral	Group D	Group D RB	VEC×12
24	Female	FFL	Bilateral	Group E	Group E RB	VEC×10
24	Female	PL+	Unilateral	Group E	WNL	VEC×6
108	Male	FFL	Unilateral	Group D	WNL	VEC×6
48	Female	PL+	Bilateral	Group D	Group B RB	VEC×14
48	Female	PL+	Unilateral	Group E	WNL	VEC×9
12	Male	FFL	Bilateral	Group D	Enucleated	VEC×12
48	Female	20/200	Unilateral	Group D	WNL	VEC×12
24	Male	FFL	Bilateral	Group D	Enucleated	VEC×6
0.5	Female	FFL	Bilateral	Group E	Enucleated	VEC×9
6	Female	PL+	Unilateral	Group E	WNL	Nil
12	Male	FFL	Bilateral	Group E	Enucleated	VEC×5
36	Male	PL+	Unilateral	Group E	WNL	VEC×6

PL=Perception of light, BCVA=best corrected visual acuity, FFL=fixing and following light, IAC=intra-arterial chemotherapy, ICRB=International Classification of Retinoblastoma, RB=retinoblastoma, VEC=vincristine, etoposide, and carboplatin, WNL=Within normal limits

RB was bilateral in seven patients (53.84%) and unilateral in six patients (46.15%). Out of the seven patients of bilateral RB, four were monocular after enucleation of the opposite eye for advanced RB. All eyes were classified as either Group D (n = 7) or Group E (n = 6), according to the ICRB classification. Viable VS were noted in seven of 13 eyes (53.84%) and SRS were noted in seven of 13 eyes (53.84%). All patients had components of active solid retinal tumors. Three patients had active tumors along with overlying preretinal and subretinal hemorrhage.

Out of 13 patients, 12 patients received a mean number of IVCs of 9 (range 6–14 before IAC). One patient had received six cycles of primary single-drug IAC with melphalan elsewhere and presented with a recurrence of tumor and dispersed vitreous hemorrhage along with diffuse SRS. The child was managed with two cycles of triple-drug IAC as rescue IAC, along with cryotherapy and laser therapy. Following this, complete regression was noted. The mean number of IAC cycles given was 2 (range 1–4). Twelve patients received additional focal therapy with transpupillary thermotherapy (TTT) or cryotherapy to the active component of the tumor [Fig. 1]. Five patients have received IvitC as adjunct chemotherapy for the management of persistent VS [Fig. 2]. Three patients received plaque-brachytherapy for the management of residual active solid retinal tumors post IAC [Fig. 3]. Overall, tumor regression was achieved in seven of 13 eyes (53.84%) and tumor was persistent in five of 13 eyes (38.46%) and recurrent in one of 13 eyes (7.69%). Among the five patients with persistent tumor following IAC, three patients developed retinal detachment after IAC [Fig. 4]. Three patients with persistent tumor post IAC underwent enucleation in that eye, and two patients lost follow-up on enucleation advice. One patient with persistent tumor post IAC who underwent enucleation developed a contralateral massive tumor recurrence with vitreous and anterior chamber seeding at 6 months follow-up. This recurrence was refractory to all forms of treatment, including IVC, IVitC, intracameral chemotherapy, and plaque brachytherapy, and the child was advised enucleation for the contralateral eye, which the family refused. The patient was lost to follow-up and presented after 1 year with stage 4 disease and succumbed to the disease. The second patient who refused enucleation for persistent tumor after IAC was lost to follow-up and presented at stage 4 disease after 1.5 years and died due to disease. Tumor recurrence with vitreous hemorrhage post IAC developed in one patient, who was lost to follow-up for 1 year during coronavirus disease (COVID) lockdown. The family refused enucleation, and tumor control was not possible with rescue IAC and IVitC. The eye was subsequently enucleated, which was followed by adjuvant chemotherapy for the high-risk factors on histopathology. The child developed CNS metastasis 6 months after treatment completion and died due to disease. At a mean of 17.53 months (range 6–37 months) follow-up, seven patients had globe salvage, three had enucleation, and three patients had events ranging from death following loss to follow-up after enucleation advice and following tumor recurrence during COVID lockdown. Globe salvage outcome was 57.14% (four out of seven eyes) in Group D eyes and 50% (three out of six) in Group E eyes. Visual acuity at the last follow-up visit in patients with globe salvage ranged from no light perception in two patients (28.5%) to fixing and following light in two patients (28.5%) and counting fingers at 1 m in two patients (28.5%) and 20/400 in one patient (14.2%). The treatment details, procedure-related complications, and treatment and visual outcomes are presented in Table 2.

Figure 1.

Unilateral group E RB in a child presenting with retinal detachment (a) and tumor filling the vitreous cavity on B scan (b). Appearance after IVC showing residual active retinal tumor and subretinal seeds and vitreous seeds (c). Appearance after triple-drug IAC and add-on focal and IVitC at 2-year follow-up showing complete tumor regression (d). Massive retinal tumor recurrence with dispersed vitreous hemorrhage in the left eye of a bilateral RB child post fellow eye enucleation and IVC (e and f). Appearance after the first cycle of triple-drug IAC (g) and appearance after four cycles of IAC and add-on focal therapy at 9-month follow-up showing complete tumor regression and disk pallor (h). IAC = intra-arterial chemotherapy, IVC = intravenous chemotherapy, IVitC = intravitreal chemotherapy, RB = retinoblastoma

Figure 2.

Group D RB in the worse eye of a child with bilateral RB showing diffuse vitreous seeds and solid retinal tumor and diffuse subretinal seeds (a and b). Appearance after IVC showing partial tumor regression and residual active vitreous seeds and subretinal seeds (c and d). Complete regression of vitreous seeds and retinal tumor after one cycle of triple-drug IAC followed by IVitC and cryotherapy (e and f). IAC = intra-arterial chemotherapy, IVC = intravenous chemotherapy, IVitC = intravitreal chemotherapy, RB = retinoblastoma

Figure 3.

Unilateral Group E RB with tumor filling the vitreous cavity (a). Appearance after six cycles of IVC showing partial tumor regression (b). Appearance at 10 months follow-up after IAC and plaque brachytherapy showing complete tumor regression (c). Group D RB in a child with bilateral RB with fellow eye enucleated for Group E RB (d). Appearance after six cycles of IVC showing partial regression of tumor with residual active retinal tumor and vitreous seeds (e). Complete tumor regression at 1 year follow-up after one cycle of triple-drug IAC followed by plaque brachytherapy, IVitC, and focal therapy (f). IAC = intra-arterial chemotherapy, IVC = intravenous chemotherapy, IVitC = intravitreal chemotherapy, RB = retinoblastoma

Figure 4.

Unilateral Group D RB in a 9-year-old child presenting with diffuse vitreous seeds, subretinal seeds, and subretinal fluid (a). Appearance after six cycles of IVC and three cycles of triple-drug IAC showing good response with regression of subretinal fluid and minimal residual active tumor at the periphery (b). Patient was continued on focal therapy and at 2 months follow-up, developed total rhegmatogenous retinal detachment with residual active subretinal seeds and underwent enucleation for the same (c). IAC = intra-arterial chemotherapy, IVC = intravenous chemotherapy, RB = retinoblastoma

Table 2.

IAC treatment details and outcome of 13 eyes

No. of IAC cycles	Drugs used for each cycle of IAC (mg)	Outcome at the last follow-up	Additional treatment (no. of cycles)	Adverse effects and treatment complications	BCVA at the last follow-up
2	C (30) + T (1)	Dead due to disease	TTT (8), ICG TTT (2) Cryo (1), periocular topotecan (3)	Cerebral thromboembolism episode (reversible), eyelid swelling	No PL
1	M (5) + C (30) + T (1)	Dead due to disease	TTT (8), Cryo (3), periocular topotecan (1)	Eyelid swelling, posterior subcapsular cataract, retinal detachment	No PL
1	M (5) + C (30) + T (1)	Regressed	IVitC (3), TTT (2), Cryo (2)	Eyelid swelling, CRA atrophy	PL +
3	M (5) + C (30) + T (1)	Enucleated	TTT (2), Cryo (3)	Eyelid swelling, retinal detachment	No PL
1	M (5) + C (30) + T (1)	Regressed	TTT (2), IVitC (2)	CRA changes	20/2000
3	M (5) + C (30) + T (1)	Enucleated	TTT (4) + IVitC (1)	CRA changes	No PL
2	M (5) + C (30) + T (1)	Regressed	Periocular topotecan (5) + TTT (2) + IVitC (3)	Eyelid swelling, retinal detachment	PL +
3	M (5) + C (30) + T (1)	Enucleated, dead due to disease	TTT (10) + Cryo (2) + IVC (6)	Vitreous hemorrhage	No PL
1	M (5) + C (30) + T (1)	Regressed	IVitC (1) + Cryo (1) + TTT (2) + plaque brachytherapy	Pre-retinal and vitreous hemorrhage, CRA changes	20/2000
4	M (3) + C (30) + T (0.5)	Regressed	TTT (2) + IVitC (2)	Eyelid swelling, retinal artery occlusion, pigment dispersion in vitreous, CRA changes	No PL
2	M (5) + C (30) + T (1)	Regressed	Cryo (1) + IVitC (2)	Forehead pigmentation, posterior subcapsular cataract, CRA changes	20/400
1	M (5) + C (30) + T (1)	Enucleated	TTT (5) + plaque brachytherapy + IVitC (1)	Vitreous hemorrhage	No PL
3	M (5) + C (30) + T (1)	Regressed	TTT (4) + IVitC (2) + plaque brachytherapy	CRA changes, optic atrophy	PL +

BCVA=best corrected visual acuity, C=carboplatin, CRA=chorioretinal atrophy, IAC=intra-arterial chemotherapy, IVC=intravenous chemotherapy, IVitC=intravitreal chemotherapy, M=melphalan, T=topotecan, TTT=transpupillary thermotherapy, ICG=Indocyanine green

Discussion

IAC is an established treatment modality for intraocular RB and is increasingly becoming the preferred initial treatment modality for intraocular RB patients. The overall success rate in terms of eye salvage has been reported to be in the range of 52%–97% for intraocular RB.[1-6] Shields et al.[5] have reported 5-year globe salvage rate of 100% in group B and C eyes, 86% in Group D eyes, and 55% in Group E eyes. The eye salvage rates in group A–C eyes are comparable to those of IVC and is almost 100% in most studies. The figures for globe salvage in group D and E eyes are variable. Shields et al.[5] reported 91% eye salvage in Group D eyes and Munier et al.[11] reported 100% eye salvage, while Abramson et al.[7] reported an estimated 2-year eye salvage of 64% for Group D eyes. However, in most studies with advanced intraocular disease like group D and E eyes, IAC has been found to be more effective in eye salvage, compared to IVC. Rojanaporn et al.,[4] in their series of 27 eyes with 8 years follow-up, have reported an eye salvage rate of 75% in Group D yes and 9% in Group E eyes. Lee et al.,[12] in their series from Korea, have reported a globe salvage of 50.4% in Group D and 49.7% in Group E tumors in patients treated with IVC followed by IAC. Data from the Indian subcontinent on IAC for RB is scarce. Rishi et al.,[10] in their series, have reported a globe salvage rate of 67% in Group D eyes and 50% in Group E eyes at 4-year follow-up. Better eye salvage rates have been reported with primary IAC compared to secondary IAC, with the overall globe salvage reported to be between 76% and 80.2% in primary IAC, compared to 58.2%–71% in the secondary IAC group.[5,11] The use of adjunct IVitC along with IAC improves the globe salvage rates further, and Shield et al.[12] reported overall enucleation in 44% eyes treated with IAC alone, compared to 15% in eyes treated with a combination of IAC and IVitC chemo. Enucleation could be avoided in 73% of Group E eyes treated with combined therapy.

In our series, all patients had Group D (n = 7) and Group E (n = 6) tumor and received secondary IAC after the failure of IVC or recurrence of tumor following IVC and focal therapy and in Group E tumors following chemoreduction where the family did not consent for primary or secondary enucleation. Four patients were monocular with contralateral eye enucleated for Group E tumor and two patients had group E and D tumor in the contralateral eye. Tumor was unilateral in six patients (Group D in two eyes and Group E in four eyes) and they received IVC as the first-line treatment as financial constraints did not allow IAC as the first-line treatment modality. One patient with Group D tumor received rescue IAC after tumor recurrence following primary IAC. The overall eye salvage rate in our series of secondary IAC was 53.4%. Eye salvage was 57.14% for Group D eyes and 50% for Group E eyes, which is comparable to previous studies. In a study from India, Rishi et al. have reported 67% and 50% eye salvage at 4-year follow-up for group D and E tumor, respectively, in their series of 15 eyes.[10] However, only two patients in that series had Group E tumor and IAC was done as the secondary treatment in only nine eyes (60%). In contrast, 46% (n = 6) patients in our series had Group E tumors and all patients in our series received secondary IAC.

Refusal of enucleation as treatment is a major cause of poor treatment compliance and poor outcome and extraocular tumor extension leading to death in RB. Data from India reports treatment noncompliance in 28% patients leading to eventual mortality in 68%, apprehension about enucleation being the main reason for treatment abandonment.[15] Most RB children in India present with advanced intraocular disease, and Chawla et al.,[16] in their study from North India, have reported 78% patients having group D and E tumors at presentation. Enucleation is the standard treatment modality for advanced intraocular disease and at most of the treating centers in the country, chemoreduction is offered to patients who refuse enucleation. Secondary IAC in these advanced eyes can ensure treatment compliance by ensuring eye salvage in a proportion of these patients, and thus provides improved survival outcome. Primary IAC has shown to be more effective in eye salvage even for group D and E tumors, compared to secondary IAC. However, in resource-constraint settings like India where the majority of RB patients belong to poor socioeconomic strata, primary IAC might not be a feasible treatment option for all patients. In these scenarios, an initial attempt at chemoreduction followed by secondary IAC along with add-on focal and IVitC might be an optimal approach for additional eye salvage for advanced tumor and also ensure treatment compliance. Globe salvage following secondary IAC combined with IVitC has been reported in 55.3% of group D and E eyes by Mirzayev et al.[17] from Turkey. The average cost of one cycle of IAC can be about 40,000 USD, making it prohibitive for most patients in developing countries.[18,19] Though the average cost of a cycle of IAC in the Indian context is approximately 2000–3000 USD, this is still high compared to the average cost of one cycle of IVC (approximately 100–200 USD). This 10–15-fold cost difference might make repeated IAC for advanced tumors unaffordable for most patients, especially in India where universal government health coverage is still not available for all patients, and patients have to bear the treatment cost out of pocket. Initial IVC can also reduce the need for multiple cycles of IAC. Our patients received an average of two cycles of secondary IAC. The only patient in our series with Group D tumor who received primary IAC received six cycles of IAC for tumor control. This makes the treatment more cost-effective.

In our study, we used triple-drug combination of melphalan, topotecan, and carboplatin for all patients except one. Most of the primary and secondary IAC reported in literature, especially for early intraocular RB, have used either single or two-drug combination. However, single drug is not effective in complete tumor control in all patients, especially in advanced tumors where the disease burden requires a higher dose of the drug. Increasing the dose of single drug can increase systemic toxicity profile and drug resistance. IVC is usually given with a combination of drugs with different mechanisms of action to minimize development of drug resistance and to increase efficacy via synergistic effect of the drug combination. All patients in our series had advanced tumor, and hence, a triple-drug combination was chosen. Marr et al.[20] have used triple-drug combination for 26 eyes with advanced intraocular RB to minimize systemic toxicity and improve efficacy and have reported a disease-free ocular survival of 75% at 2 years and retained electroretinogram function. Also, resource constraints in our setting limit the number of IAC cycles which can be given to patients, and hence, a triple-drug combination was used to have the maximum benefit from each cycle and reduce the need for multiple cycles of IAC.

Additional treatment modalities used in our series included TTT in 11 eyes, cryotherapy in seven eyes, IVitC in seven eyes, and plaque brachytherapy in three eyes. Tumor recurrence developed in two eyes after the initial response, both having Group E tumor at presentation. Repeat IAC was done for both eyes with three drugs and one eye showed poor response and tumor progression requiring enucleation. Complete tumor regression was noted in the other patient with additional one cycle of triple-drug IAC. Tumor recurrence following triple-drug IAC has been reported in 38.4% of Group D eyes and 3.8% of Group E eyes following IAC, with three eyes requiring enucleation in this series for recurrent vitreous seeding.[20] In our patients, recurrence developed in two eyes (23.07%) at a mean of follow-up of 8.5 months (range 3–12 months), requiring enucleation. Three eyes (23.07%) developed total retinal detachment following IAC with significant residual tumor and were advised enucleation. Two of these three patients refused enucleation and were lost to follow-up; they came back with metastatic disease at 1 and 1.5 years follow-up and eventually succumbed to the disease. In one eye, massive vitreous hemorrhage and secondary glaucoma developed at 8 months follow-up after IAC and subsequent plaque brachytherapy and required enucleation.

Overall, six patients (46.15%) in our series required enucleation for poor response to IAC or tumor recurrence, out of which four were compliant with treatment. Two patients refused enucleation and succumbed to the disease following orbital recurrence. One patient developed systemic metastasis following enucleation and adjuvant chemotherapy for high-risk histopathology risk factors and died due to disease.

Metastasis following IAC has been reported to vary from 1.14% to 25% in various series.[21-23] Ong et al.,[23] in their series of 12 IAC patients, have reported 25% systemic metastasis rate over a 4-year follow-up period. All patients, except one, who developed metastasis had Group E tumor at presentation and had high-risk features on histopathology following enucleation for tumor recurrence post IAC. In our series, one patient who developed metastasis following IAC and enucleation had high-risk histopathology features and received adjuvant chemotherapy for the same. Hence, clinical findings of advanced intraocular RB predictive of high-risk factors for metastasis on histopathology, like prolonged duration of symptoms, secondary glaucoma, hyphema, pseudohypopyon, and orbital cellulitis, should not receive IAC as the preferred chemotherapy modality.[24,25] Metastasis developed in two other patients in our series, both of whom were not compliant with enucleation advice and were lost to follow-up for more than 1 year. None of the other patients who were complaint with treatment developed systemic metastasis over the follow-up period.

The complications of the procedure in our study included chorioretinal atrophy changes in seven eyes (53.8%), transient eyelid edema and erythema in six eyes (46.15%), vitreous and preretinal hemorrhage in three eyes (23.07%), retinal detachment in three eyes (23.07%), posterior subcapsular cataract in two eyes (15.3%), forehead skin pigmentation in one patient (7.7%), reversible intraoperative cerebrovascular thromboembolic episode in one eye (7.7%), retinal vascular occlusion in one eye (7.7%), and optic atrophy in one eye (7.7%). None of our patients had postoperative neutropenic episodes. Diffuse retinal pigment epithelial changes were noted in all eyes; however, Electroretinogram(ERG) was not done in any of our patients to quantify the changes. One of the seven patients with eye salvage had no light perception in the treated eyes, which was due to retinal artery occlusion post IAC. The suboptimal vision in the other patients was due to extensive macular scarring following tumor regression, as the primary tumor involved the macula in all patients.

Our study had follow-up duration of 17.53 months (range 6–37 months). Tumor recurrence and metastasis can develop in the long term and might affect the glove salvage status and survival outcome. Hence, a longer follow-up will provide data on the outcome of IAC and its suitability in eye salvage for advanced intraocular group D and E tumors resistant to the conventional treatment modality of IVC.

Conclusion

In conclusion, salvage IAC with triple-drug regimen along with other adjunct treatment modalities like IVitC, cryotherapy, laser thermotherapy, and plaque brachytherapy might be a cost-effective and safe option for eye salvage in selected patients of advanced intraocular Rb following failure of IVC, with a globe salvage rate of 53.84%. It can also be an effective approach to improve treatment compliance and can help in addressing the barrier of treatment refusal to enucleation and consequently improve the survival outcome. This approach might be a cost-effective approach in the Indian setting, where the majority of RB patients belong to poor socioeconomic strata and present with an advanced stage of disease, have poor acceptance of enucleation, and cannot afford multiple cycles of IAC as the primary treatment modality.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.