Intravitreal Chemotherapy in Retinoblastoma: Current Trends and Future Directions.

Here Comes the Sun … for Retinoblastoma.

Retinoblastoma outcomes: a global perspective

To compare outcomes of intra-arterial chemotherapy for retinoblastoma as primary therapy before (Era I) and during (Era II) the intravitreal chemotherapy era. In this retrospective interventional case series at a tertiary referral center, 66 eyes of 66 patients with untreated unilateral retinoblastoma were used. intraarterial chemotherapy into the ophthalmic artery under fluoroscopic guidance was performed using melphalan in every case, with additional topotecan as necessary. Intravitreal chemotherapy using melphalan and/or topotecan was employed as needed for active vitreous seeding. Globe salvage was measured based on the International Classification of Retinoblastoma (ICRB) during two eras. The two eras encompassed 2008 to 2012 (intraarterial chemotherapy alone, Era I) and 2012 to 2015 (intraarterial chemotherapy plus intravitreal chemotherapy, Era II). Over this period, there were 66 patients with unilateral untreated retinoblastoma treated with primary intra-arterial chemotherapy. A comparison of features (Era I vs Era II) revealed no significant difference in mean patient age (24 vs 24 months), ICRB groups, mean largest tumor diameter (19 vs 17 mm), mean largest tumor thickness (10 vs 10 mm), vitreous seed presence (56% vs 59%), subretinal seed presence (67% vs 62%), retinal detachment (70% vs 66%), or vitreous hemorrhage (0% vs 5%). There was no significant difference in mean number of intra-arterial chemotherapy cycles (3 vs 3.1) or intraarterial chemotherapy dosages. Following therapy, there was a significant difference (Era I vs Era II) in the need for enucleation overall (44% vs 15%, P = .012), especially for group E eyes (75% vs 27%, P = .039). Four of the eyes that initiated therapy in Era I later required intravitreal chemotherapy during Era II. The enucleation rate was 0% for groups B and C in both eras and non-significant for group D (23% vs 13%). There were no patients with stroke, seizure, limb ischemia, extraocular tumor extension, secondary leukemia, metastasis, or death. The current era of retinoblastoma management using intra-arterial chemotherapy plus additional intravitreal chemotherapy (as needed for vitreous seeding) has improved globe salvage in eyes with advanced retinoblastoma. [J Pediatr Ophthalmol Strabismus. 2016;53(5):275-284.].

Intravitreal chemotherapy (IVitC) in the management of retinoblastoma has increased the rate of globe salvage, specifically in patients with recurrent disease and associated vitreous seeds. A significant number of children with retinoblastoma in developing countries present late, resulting in higher intraocular tumour-stage at presentation. Treatment requirements for such tumours usually include intravenous chemotherapy (IVC) and/or intra-arterial chemotherapy (IAC). While IVC has a long usage track record and a good efficacy, it has been reported to be associated with higher recurrence rates in a significant number of patients. Intra-arterial chemotherapy has the advantage of lower recurrence rates but requires personnel with advanced interventional radiology skills and has limited efficacy in treating intravitreal seeds. Intravitreal chemotherapy has gained popularity recently, largely because of its superior efficacy in the management of vitreous seeds, subretinal seeds and recurrent retinal tumour. An 8-month-old male infant initially presented with bilateral retinoblastoma, International Classification System for Intraocular Retinoblastoma (ICRB) Group E in the right eye and Group B on the left eye. The right eye was enucleated and currently has a prosthesis. The left eye had tumours that initially responded to brachytherapy and transpupillary thermotherapy (TTT). Approximately two years later his tumours recurred with vitreous seeds and were successfully managed with the use of cryotherapy and intravitreal chemotherapy. The simplicity of the technique of IVitC and its efficacy in controlling vitreous seeds and recurrent retinal tumours makes this route of regional chemotherapy a viable one in areas with limited expertise and resources such as South Africa.

Simple SummaryIntravenous chemoreduction (IVCRD) has been the standard of care for treatment of retinoblastoma (RB). Since survival rates exceed 95–98%, the goals of treatment have now shifted to emphasize eye salvage and vision preservation in addition to patient survival. Consequently, there has been a shift towards combining standard IVCRD with intravitreal chemotherapy or altogether replacing IVCRD with intra-arterial chemotherapy. As more data from intravitreal chemotherapy and intra-arterial chemotherapy are being published, there are claims of improved globe salvage rates resulting in more widespread use of these newer treatment modalities. However, there are no published randomized controlled trials comparing these to IVCRD head-to-head. To evaluate the relative efficacy of these new therapies, it is critical to determine the true success rates of IVCRD regimens alone. Therefore, it is both timely and essential to determine the baseline IVCRD success rates so that an evidence-based assessment of new and emerging therapies can be determined.To evaluate the relative efficacy of novel retinoblastoma treatments, eye classification-specific success rates for current standard-of-care intravenous chemotherapy regimens must be known. This meta-analysis included studies if: (1) patients received intravenous chemotherapy for retinoblastoma, (2) globe salvage data was reported, (3) only intravenous chemoreduction (with/without local consolidation) was used. The outcome measure was globe salvage success without need for salvage radiotherapy, subdivided by disease classification and chemotherapy regimen. Data from 27 studies (1483 eyes) were pooled. By Reese–Ellsworth classification, globe salvage rates were 85% (95%CI:73–92%) for Group I, 78% (95%CI:70–85%) for Group II, 68% (95%CI:56–78%) for Group III, 47% (95%CI:34–60%) for Group IV, and 35% (95%CI:26–45%) for Group V (Va: 35% [95%CI:21–54%]; Vb: 42% [95%CI:29–56%]; those without sub-classification: 31% [95%CI:19–47%]). By International Classification, globe salvage rates were 93% (95%CI:80–97%) for Group A, 83% (95%CI:73–89%) for Group B, 73% (95%CI:54–86%) for Group C, 40% (95%CI:31–51%) for Group D, and 19% (95%CI:5–50%) for Group E. Standard carboplatin-etoposide-vincristine out-performed two-drug regimens (odds ratio (OR) = 1.9 (95%CI:1.3–3.0) for Groups I-IV and OR = 2.1 (95%CI:1.3–3.4) for Group V; p = 0.002 for each). For eyes with diffuse vitreous seeds (Vb), an enhanced regimen out-performed standard chemotherapy (OR = 2.4 [95%CI:1.3–4.7]; p = 0.004). In conclusion, two-drug regimens were less effective for all eyes, whereas enhanced regimens were more effective for eyes with vitreous seeds. Novel therapies can now be compared to these baseline globe salvage rates.

To evaluate the results of secondary intra-arterial chemotherapy (IAC) and/or intravitreal chemotherapy (IVC) as a salvage treatment for retinoblastoma (RB). The medical records of 31 (20 male, 11 female) cases (with 38 eyes) who underwent secondary IAC and/or IVC between February 2010 and June 2019 were retrospectively reviewed. Thirteen (41.9%) cases had unilateral and 18 (58.1%) had bilateral RB. According to the International Classification of RB, 6 (15.8%) eyes had group B, 9 (23.7%) eyes had group C, 16 (42.1%) eyes had group D, and 7 (18.4%) eyes had group E RB at diagnosis. All patients underwent six-cycle intravenous chemotherapy as primary treatment and 8 eyes received external radiotherapy before IAC/IVC. Secondary IAC was performed in 21 (55.3%) eyes, IVC in 10 (26.3%) eyes, and IAC + IVC in 7 (18.4%) eyes. External radiotherapy was applied in 2 (5.3%) eyes after IAC/IVC, one of which was later enucleated. In total, 17 (44.7%) eyes undergoing secondary IAC/IVC treatments were enucleated. Metastasis and death were not observed in any case during the mean follow-up period of 59.3 (median 61, range: 10-98) months. Although 60.5% of the eyes undergoing IAC/IVC consisted of groups D and E RB, globe salvage and survival rates were 55.3% and 100.0%, respectively. External radiotherapy was required in 5.3% of the eyes after IAC/IVC. In conclusion, IAC and IVC are safe and effective treatment methods in eyes with RB unresponsive to other eye-preserving treatments and those demonstrating recurrence.

Retinoblastoma is a complex eye tumor manifesting in children below the age of 3 years. Over the years, the management of retinoblastoma has undergone drastic changes, thus improving the outcomes. The primary goal of management of retinoblastoma is life salvage, and secondary and tertiary goals include globe salvage and vision salvage, respectively, and thus improvement of the quality of life of the child. The choice of treatment of retinoblastoma depends on multiple factors including patients’ age, general condition, family desires, tumor laterality, tumor classification, tumor location, associated ocular features, radiological findings, and patient compliance to treatment. Smaller tumors can be managed with focal treatment like transpupillary thermotherapy or cryotherapy, while larger tumors need intravenous chemotherapy or intra-arterial chemotherapy. Enucleation is needed in very advanced tumors. External beam radiotherapy is rarely used except in cases with extraocular extension of retinoblastoma. Other supplemental treatments with subtenon’s chemotherapy, intravitreal chemotherapy, and plaque radiotherapy improve the outcomes further.

Purpose: To report our 5-year experience with intra-arterial chemotherapy (IAC) in the intravitreal chemotherapy (IvitC) era. Methods: Retrospective review of retinoblastoma treated with primary unilateral IAC in the IvitC era (2012–2017). Results: There were 34 eyes treated with IAC alone versus 20 eyes treated with IAC plus IvitC for vitreous seeds. IAC (IAC alone vs. IAC plus IvitC) consisted of melphalan (41 vs. 10%) or melphalan plus topotecan (59 vs. 90%, p = 0.03). IvitC consisted of melphalan (60%) or melphalan plus topotecan (40%). Tumor control and globe salvage were achieved in 100% of group B and C eyes without IvitC. Despite more extensive vitreous seeds in the IvitC group (p < 0.01), comparison of IAC alone versus IAC plus IvitC revealed no difference in tumor control for group D (88 vs. 69%, p = 0.36) or group E (67 vs. 100%, p = 0.25) and no difference in globe salvage for group D (88 vs. 69%, p = 0.36) or group E (58 vs. 57%, p = 0.39). Conclusions: IAC is effective as primary therapy for unilateral group B, C, D, and E retinoblastoma. IvitC is an important adjuvant therapy to achieve comparable globe salvage rates for group D and E eyes with persistent active vitreous seeds.

The management of retinoblastoma is complex. With increasing treatment modalities and increasing experience with each treatment modality, the globe salvage rates have drastically improved with time. Aqueous seeding in an eye with retinoblastoma is classified as group E based on International Classification of Intraocular Retinoblastoma, and most group E eyes were enucleated a decade earlier. Newer modalities of treatment have improved the globe salvage rates in group E eyes including those with aqueous seeding. Various globe salvage treatment modalities attempted for the management of aqueous seeds include external beam radiotherapy, plaque radiotherapy, intra-arterial chemotherapy, periocular chemotherapy, intravitreal chemotherapy and intracameral chemotherapy. Of all treatment modalities, intracameral chemotherapy holds promise for the management of aqueous seeds in selected patients, but it should be done with the utmost care by a trained ocular oncologist. Enucleation is still the preferred modality of treatment for eyes with advanced retinoblastoma and anterior segment invasion. This review focuses on the current evidence on aqueous seeding, highlighting the pathogenesis, classification, clinical presentation, treatment and outcomes.

10062 Background: Retinoblastoma (RB) is the most common childhood eye tumor. Intraocular RB cure rates approach 100%. Therefore, treatment now focuses on globe salvage and preserving functional vision. The Research into Visual Endpoints and RB Health Outcomes After Treatment (RIVERBOAT) consortium was established to examine patient outcomes in the transitional era from systemic to intraocular therapy. Methods: Patients with RB treated at 13 North American centers from 2008-2022 were identified. Medical record abstraction was performed for disease presentation, visual acuity, treatment, globe salvage and functional outcome. Enrollment on the study included submission of retrospective data and prospective data on newly diagnosed patients as well as retrospective data from chart reviews. Results: 830 patients (68% white race, 77% non-Hispanic ethnicity) were enrolled. In 420 of these, data was limited to chart review. Median age at diagnosis of the 830 patients (1165 eyes) was 1 year (0 - 16.3) and at enrollment was 7.8 years (0 - 28.6). 60% had unilateral disease and the eye group distribution (International Intraocular Retinoblastoma Classification) was 10% A, 16% B, 12% C, 31% D, 27% E, and 4% unknown (UK). Of the 1165 affected eyes, major treatment modalities included primary enucleation (15%), systemic chemotherapy (SC) (36%), intraarterial chemotherapy (IAC) (10%), SC followed by IAC in 9%, and intravitreal chemotherapy in combination in 6%. SC only was used in 55-59% of those with A-C eyes compared to 29% of D eyes. IAC only was used in 20% of D eyes and 16% of C eyes. Secondary enucleation occurred in 151 eyes (14%): 63/416 (15%) of SC; 34/120 (28%) of IAC; 25/106 (24%) of SC followed by IAC; 29/523 (6%) other treatments. The overall globe salvage rate was 86%. Second malignancies occurred in 5, metastatic disease in 8 and pineoblastoma in 3 patients. Eleven patients died of RB (1%). Visual acuity after treatment was reported in 229 eyes: 106 (eye group 24 A, 37 B, 22 C, 19 D, 3 E, 1 UK) had normal vision (20/20-20/40). 38 eyes, (6 A, 11 B, 4 C, 10 D, 5 E, 2 UK) had moderate vision loss ( &gt; 20/40 – 20/70). Twenty-five eyes (5 B, 2 C, 16 D, 2 E) had low vision ( &gt; 20/70 &lt; 20/200), and 60 eyes (12 B, 7 C, 32 D, 8 E, 1 UK) were legally blind (&gt;20/200). In those treated with IAC only, normal vision was found in 30% of eyes, moderate vision loss in 22%, low vision in 13%, and legal blindness in 35%. In those treated with SC only, normal vision was noted in 53% of eyes, moderate vision loss in 11%, low vision in 11%, and legal blindness in 25%. In those treated with SC followed by IAC, normal vision was reported in 32%, moderate vision in 26%, low vision in 5% and legal blindness in 37%. Conclusions: We demonstrate the significant benefits witnessed by the evolution of RB therapy. Cure rates remain high, with a very low incidence of second malignancies, metastatic disease or trilateral RB. Eye salvage rate was excellent, avoiding low vision or legal blindness in two-thirds of the patients.

In this report, we explore retinoblastoma diagnostic accuracy and review chemotherapy alternatives for retinoblastoma using intravenous, intra-arterial, periocular, and intravitreal routes. A review of 2775 patients referred for management of retinoblastoma, disclosed 78% with confirmed retinoblastoma and 22% with simulating lesions, termed pseudoretinoblastomas. Children ≤2 years old showed leading pseudoretinoblastomas of persistent fetal vasculature, Coats disease, and vitreous haemorrhage, whereas those >5 years showed simulators of Coats, toxocariasis, and familial exudative vitreoretinopathy. The diagnosis of retinoblastoma should be established before planning therapeutic strategy. Chemotherapy strategy depends on tumour laterality and stage of disease. If bilateral retinoblastoma, intravenous chemotherapy (IVC) is important as first-line therapy for control of intraocular disease, prevention of metastasis, and reduction in prevalence of pinealoblastoma and long-term second malignant neoplasms. Bilateral groups D and E retinoblastoma receive additional subtenon's carboplatin boost for improved local control. If unilateral disease is present, then intra-arterial chemotherapy (IAC) is often considered. IAC can be salvage therapy following chemoreduction failure. Unilateral retinoblastoma of groups D and E are managed with enucleation or globe-conserving IVC and/or IAC. Intravitreal chemotherapy is cautiously reserved for recurrent vitreous seeds following other therapies. In conclusion, the strategy for retinoblastoma management with chemotherapy depends on tumour laterality and stage of disease. Bilateral retinoblastoma is most often managed with IVC and unilateral retinoblastoma with IAC, but if advanced stage, combination IVC plus IAC or enucleation.

Intra-arterial chemotherapy for retinoblastoma in 341 consecutive eyes (1,292 infusions): comparative analysis of outcomes based on patient age, race, and sex

We aimed to analyze our 4-year experience of intra-arterial chemotherapy (IAC) for retinoblastoma (RB) and to examine the tumor response, globe salvage, mortality, and safety profile of IAC in the Malaysian profile. This was a retrospective, interventional case series. A total of 22 eyes of 20 patients with RB who underwent IAC using melphalan and topotecan from January 2018 to December 2021 in Hospital Kuala Lumpur were retrospectively reviewed. Tumor response, globe salvage, mortality, and safety profile of IAC were compared based on the International Classification of Retinoblastoma. The mean patient age at IAC was 21.3 months. An overall globe salvage rate of 63.6% was observed: more specifically, 100% for Group A, 75% for Groups B and C, 66.7% for Group D, and 42.9% for Group E. Poor tumor response after IAC was significantly associated with a lesser chance of globe salvage (P = 0.045). The overall rate of good tumor response following IAC was 77.3%. Specifically, rates of good tumor response in each group were 100%, 75%, 75%, 83.3% and 71.4% in group A, B, C, D and E, respectively. The mortality rate was 5%. Complications (per-catheterization) included cerebral infarct (2.2%), oxygen desaturation (2.2%), vomiting (26.1%), periorbital edema (8.8%), ptosis (6.5%), fever, femoral hematoma, and hyperpigmentation over lid (4.4% each). Four-year experience showed that IAC is a safe and effective method for RB management. Patients with a poor response after IAC may have a lower chance of globe salvage. Careful patient selection is of utmost importance to achieve the best outcome in a setting of limited health-care resources.

Purpose:To describe a series of sight-threatening ocular and adnexal involvement associated with dengue hemorrhagic fever and their treatment options.Methods:Retrospective, interventional, non-comparative case series. Medical records of patients who presented with ocular symptoms attributed to dengue hemorrhagic fever were reviewed. Demography, presenting features, and treatment outcomes were recorded. Outcome measures assessed included globe salvage, vision salvage, and visual improvement. The outcome was deemed as favorable if vision salvage was possible and unfavorable if the vision was lost.Results:Twenty-nine eyes of 23 patients were included. Bilateral ocular involvement was seen in 6 (26%) patients. The mean age was 37.62 ± 18.68 years (range: 14 to 81 years). Coexistent diabetes mellitus and enteric fever were present in three patients. History of blood transfusion was present in nine (40%) and thrombocytopenia in eight (35%) patients at the time of presentation with ocular complaints. Presenting features included endophthalmitis in 11 (38%), panophthalmitis in 10 (35%), orbital cellulitis with panophthalmitis in four (14%), isolated corneal or scleral melt in three (10%), and orbital hemorrhage with panophthalmitis in one (3%) patient. Globe salvage was achieved in 21/29 eyes (72.4%), vision salvage in 6/29 eyes (20.68%), and improvement in visual acuity was noted in 5/29 eyes (17.24%). Logistic regression analysis revealed no significant effect of any clinical-microbiological factors on globe salvage, vision salvage, and visual improvement. However, visual improvement and globe salvage were possible in eyes that underwent early endoscopic vitrectomy.Conclusion:Dengue fever can present with sight-threatening ocular and adnexal inflammation resulting in endophthalmitis and panophthalmitis, orbital cellulitis, corneal and scleral melt, and orbital hemorrhage. Early vitrectomy may improve vision and globe salvage in cases with significant vitritis.

The management of retinoblastoma (RB) has dramatically changed over the past two decades from previous radiotherapy methods to current chemotherapy strategies. RB is a remarkably chemotherapy-sensitive tumor. Chemotherapy is currently used as a first-line approach for children with this malignancy and can be delivered by intravenous, intra-arterial, periocular, and intravitreal routes. The choice of route for chemotherapy administration depends upon the tumor laterality and tumor staging. Intravenous chemotherapy (IVC) is used most often in bilateral cases, orbital RB, and as an adjuvant treatment in high-risk RB. Intra-arterial chemotherapy (IAC) is used in cases with group C or D RB and selected cases of group E tumor. Periocular chemotherapy is used as an adjunct treatment in eyes with group D and E RB and those with persistent/recurrent vitreous seeds. Intravitreal chemotherapy is reserved for eyes with persistent/recurrent vitreous seeds. In this review, we describe the various forms of chemotherapy used in the management of RB. A database search was performed on PubMed, using the terms “RB,” and “treatment,” “chemotherapy,” “systemic chemotherapy,” “IVC,” “IAC,” “periocular chemotherapy,” or “intravitreal chemotherapy.” Relevant English language articles were extracted, reviewed, and referenced appropriately.