Combination of brachytherapy and intravitreal chemotherapy in the treatment of retinoblastoma with vitreous seeding

Purpose: To report the efficacy of combined intravitreal chemotherapy (IVC) and ruthenium-106 brachytherapy in retinoblastoma, either as first line or second line treatment following systemic chemoreduction or intraarterial chemotherapy. Methods: Retrospective data collection of 18 eyes from 18 patients treated with IVC and brachytherapy from August 2014 to December 2019. Results: The method described was our first line therapy in 6 patients, whereas it was used as second line treatment after chemoreduction in the remaining 12 patients. The eyes showed the following classification at initial presentation: 2 group B eyes, 3 group C eyes and 13 group D eyes. The mean follow-up was 19.5 months (range 2 – 53 months). Mean patient age at brachytherapy was 34.0 months (range 15 – 83 months). Median prescribed dose at the tumour base and apex was 574.5 ± 306.7Gy and 88.5 ± 12.2Gy, respectively. The ocular retention rate was 66.7%. Six eyes had to be enucleated due to uncontrollable subretinal and recurrent vitreous seeding, tumour relapse, recurrence of a solid tumour elsewhere in the eye and persistent vitreous bleeding with loss of tumour control. The mean number of intravitreal injections of Melphalan was 5.0. Two patients received a simultaneous injection of Topotecan for insufficient therapeutic response. With regard to radiogenic complications, we could observe temporary retinal and vitreous bleeding (27.8%), serous retinal detachment (44.4%) and radiogenic maculopathy and retinopathy (11.1%). None of the children showed metastatic disease during follow up. Conclusion: Ruthenium-106 plaque therapy in combination with intravitreal chemotherapy is an effective local therapy with good tumour control rates even in advanced eyes. Overall, the analysed therapeutic approach shows an acceptable side effect profile, especially when considering that EBRT and systemic polychemotherapy, or at least the number of cycles needed, with their increased incidence of adverse events can thus be avoided.

Primary laser therapy as monotherapy for discrete retinoblastoma

Background/aimLaser photocoagulation is less invasive than chemotherapy (systemic, intra-arterial or periocular) and brachytherapy. We studied the safety and efficacy of laser as primary monotherapy for discrete retinoblastoma with well-defined borders and attached retina.MethodsA single-institution retrospective non-comparative review (2004–2018) of discrete retinoblastoma tumours managed with primary laser (532 or 810 nm wavelength, 0.5–1 s duration and power titrated until desired tumour whitening). Efficacy was evaluated by tumour long-term stability avoiding non-laser therapies. Safety was evaluated by frequency of laser-related complications and uncontrollable tumour progression.ResultsEligible were 112 tumours in 55 eyes of 44 patients. Laser monotherapy (median 2 sessions) achieved initial remission in 95/112 (85%) tumour. Initial encircling only laser photocoagulation was associated with tumour progression (9/11, one tumour had vitreous seeding) compared with direct or combined photocoagulation techniques (0/94 and 0/7 tumours, respectively, p<0.001). Direct laser had no vitreous seeding, haemorrhage or injury to vital structures. Tumour recurrences developed in 52/112 (46%) tumour but repeat laser achieved long-term stability, except five tumour recurrences that required invasive therapy. Receiver operating characteristic analysis identified threshold largest basal diameter of 3 disc diameters (DD) for successful laser monotherapy, where 92/106 (87%) of tumours ≤3 DD and 0/6>3 DD achieved long-term stability with laser monotherapy (p<0.001). Overall, 35/55 (64%) eyes and 24/44 (55%) patients achieved long-term stability with laser monotherapy. No eye was enucleated for uncontrollable tumour progression.ConclusionsDiscrete retinoblastoma ≤3 DD can be effectively and safely managed with laser monotherapy, sparing a significant proportion of patients/eyes from more invasive therapies.

Intravenous Chemotherapy for Retinoblastoma in the Era of Intravitreal Chemotherapy: A Systematic Review

<b><i>Purpose:</i></b> The published data on ocular survival following intravenous chemotherapy of retinoblastoma (RB) seems to be skewed by evolving practice patterns induced by use of intravitreal chemotherapy (iVitc). We aimed to explore potential role of iVitc for vitreous seeding for patients treated with intravenous chemotherapy (IVC). <b><i>Methods:</i></b> A literature search was performed to identify cases of RB treated with primary IVC prior to advent of iVitc by various search engines (PubMed, Medline, and Google) from 1992 to 2018. Studies were excluded if number of cases were less than 40 or lacked data related to type of recurrence and its treatment. Rates and patterns of recurrence and its management were categorized. <b><i>Results:</i></b> Out of 15 studies identified, only 10 studies (797 eyes) met the inclusion criteria. The mean age at presentation was 15.3 months (range 0–192.8 months). Unilateral cases represented 25% of the cohort. The ocular survival rate with primary IVC was 63% (500/797 eyes). Of the 297 eyes (37%) that failed IVC therapy, additional 99 eyes could be salvaged with EBRT (599/797 eyes, 75%). Remaining 198 eyes were enucleated (198/797 eyes 25%). K-M survival analysis could not be done due lack of sufficient data. Recurrences that occurred (mean 12.2 months) after completion of primary IVC included relapse of retinal tumor (143 eyes [48%]), vitreous seeding (73 eyes [25%]), subretinal seeding (49 eyes [16%]), or any combination (103 eyes [35%]). Out of 73 eyes with vitreous seeding, additional 66 eyes (90%) would have been salvaged with iVitc, potentially improving ocular survival rates to 71% (500 + 66/797). <b><i>Conclusions:</i></b> Evolving practice patterns of RB treatment have unfavorably skewed published ocular survival rates following IVC. With incorporation of iVitc, the ocular survival rates with IVC can be potentially improved to be non-inferior to those achieved with intra-arterial chemotherapy.

Proteomic Profiling of Retinoblastoma-Derived Exosomes Reveals Potential Biomarkers of Vitreous Seeding

Retinoblastoma (RB) is the most common tumor of the eye in early childhood. Although recent advances in conservative treatment have greatly improved the visual outcome, local tumor control remains difficult in the presence of massive vitreous seeding. Traditional biopsy has long been considered unsafe in RB, due to the risk of extraocular spread. Thus, the identification of new biomarkers is crucial to design safer diagnostic and more effective therapeutic approaches. Exosomes, membrane-derived nanovesicles that are secreted abundantly by aggressive tumor cells and that can be isolated from several biological fluids, represent an interesting alternative for the detection of tumor-associated biomarkers. In this study, we defined the protein signature of exosomes released by RB tumors (RBT) and vitreous seeding (RBVS) primary cell lines by high resolution mass spectrometry. A total of 5666 proteins were identified. Among these, 5223 and 3637 were expressed in exosomes RBT and one RBVS group, respectively. Gene enrichment analysis of exclusively and differentially expressed proteins and network analysis identified in RBVS exosomes upregulated proteins specifically related to invasion and metastasis, such as proteins involved in extracellular matrix (ECM) remodeling and interaction, resistance to anoikis and the metabolism/catabolism of glucose and amino acids.

Intravitreal Melphalan for Retinoblastoma: The Impact of Toxicity on Recurrence and Ultimate Globe Salvage

<b><i>Introduction:</i></b> Intravitreal melphalan (IVM) has emerged as an efficacious treatment for vitreous seeding in retinoblastoma. Although rarely severe, IVM-related toxicity may be treatment limiting. There is paucity of data on the impact of IVM toxicity on new tumor formation and ultimate globe salvage. <b><i>Objectives:</i></b> To investigate whether the grade of retinal toxicity post-IVM impacts retinal and seeding tumor recurrence, as well as the overall ability to salvage the eye. <b><i>Methods:</i></b> A single-institution retrospective chart review was performed on 47 eyes of 42 patients who received systemic intravenous chemotherapy followed by IVM as salvage treatment for persistent or recurrent vitreous seeding. Chorioretinal toxicity was graded from 0 to 5. <b><i>Results:</i></b> Toxicity grade was inversely associated with the risk of recurrence, where a one-unit increase in toxicity grade correlated with nearly a 54% reduction in the odds of tumor recurrence (OR 0.46 [0.25–0.84], <i>p</i> = 0.01). Similarly, toxicity grade was related to enucleation, where a one-unit increase in toxicity grade was associated with a 31% reduction in the odds of undergoing enucleation (OR 0.69 [0.40–1.18], <i>p</i> = 0.17). <b><i>Conclusions:</i></b> While retinoblastoma therapy aims to limit toxicity, especially visually significant toxicity, eyes with higher grades of post-IVM toxicity are less likely to have retinal and seeding tumor recurrence.