Outcomes of Group D Retinoblastoma With Resistant Vitreous Seeds After Integration of Intravitreal Chemotherapy to the Treatment Protocol

Retinoblastoma is the most common paediatric ocular tumour, which appears in the retina. Without treatment, retinoblastoma grows and destroys the internal ocular globe architecture, even leading to metastasis. When treated, overall survival is close to 97%, the alkylating drug melphalan being the most extensively used chemotherapeutic agent in localised treatment. The aim of this study is to describe the implementation of a new intravitreal chemotherapy retinoblastoma treatment protocol for children implanting vitreous seeds through intravitreal melphalan injections and to evaluate the patients’ health outcomes treated with it. Between December 2014 and July 2018, seven patients were treated with this protocol. They received a mean of 3.3 cycles of intravitreal melphalan with standard doses of 30 mcg per cycle. In the seven eyes treated in our hospital, the response was as expected; three eyes with vitreous seedings (43%) were successfully treated. The main adverse effects presented by all patients were scars at cryogenisation points. In two patients, the appearance of ‘salt and pepper’ retinopathy was reported. Oncology pharmacists, as part of the treatment team, can provide information about recommended doses, expected adverse effects, stability of preparations, most appropriate method of processing, packaging, and methods of drug administration, to ensure efficacy and especially safety in the administration of these drugs.

Download Full-text

Safety and Efficacy of Intravitreal Chemotherapy (Melphalan) to Treat Vitreous Seeds in Retinoblastoma

Frontiers in Pharmacology ◽

10.3389/fphar.2021.696787 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yacoub A. Yousef ◽

Mays Al Jboor ◽

Mona Mohammad ◽

Mustafa Mehyar ◽

Mario D. Toro ◽

...

Keyword(s):

Tumor Response ◽

Standard Dose ◽

Complete Response ◽

Complete Regression ◽

Safety And Efficacy ◽

Intravitreal Chemotherapy ◽

Lost To Follow Up ◽

Group D ◽

Vitreous Seeds

Background: Active vitreous seeds in eyes with retinoblastoma (Rb) adversely affects the treatment outcome. This study aimed to investigate the safety and efficacy of intravitreal melphalan chemotherapy (IViC) as a treatment for recurrent and refractory vitreous seeds in patients with Rb.Methods: We used a retrospective non-comparative study of patients with intraocular Rb who had vitreous seeds and were treated by IViC (20–30 μg of melphalan) using the safety-enhanced anti-reflux technique. Tumor response, ocular toxicity, demographics, clinical features, and survival were analyzed.Results: In total, 27 eyes were treated with 108 injections for recurrent (16 eyes) or refractory (11 eyes) vitreous seeds after failed systemic chemotherapy. A total of 15 (56%) were males, and 20 (74%) had bilateral disease. At diagnosis, the majority (n = 21) of the injected eyes were group D, and n = 6 were group C. Vitreous seeds showed complete regression in 21 (78%) eyes; 100% (n = 10) for eyes with focal seeds; 65% (n = 11/17 eyes) for eyes with diffuse seeds (p = 0.04); 7 (64%) eyes with refractory seeds; and 14 (87%) eyes with recurrent seeds showed complete response (p = 0.37). In total, 16 (59%) eyes developed side effects: retinal toxicity (48%), pupillary synechiae (15%), cataracts (30%), iris atrophy (7%), and retinal and optic atrophy (4%). Only one child was lost to follow-up whose family refused enucleation and none developed orbital tumor recurrence or distant metastasis.Conclusion: IViC with melphalan is effective (more for focal than diffuse seeding) and a relatively safe treatment modality for Rb that can improve the outcomes of eye salvage procedures. However, unexpected toxicity can occur even with the standard dose of 20–30 μg.

Download Full-text

Primary Intra-Arterial Chemotherapy for Retinoblastoma in the Intravitreal Chemotherapy Era: Five Years of Experience

Ocular Oncology and Pathology ◽

10.1159/000491580 ◽

2018 ◽

Vol 5 (2) ◽

pp. 139-146 ◽

Cited By ~ 13

Author(s):

Lauren A. Dalvin ◽

Mamta Kumari ◽

Vera Adobea Essuman ◽

Shormin Shohelly Shipa ◽

David Ancona-Lezama ◽

...

Keyword(s):

Adjuvant Therapy ◽

Retrospective Review ◽

Tumor Control ◽

Primary Therapy ◽

Years Of Experience ◽

Intravitreal Chemotherapy ◽

Group B ◽

Group D ◽

Unilateral Group ◽

Vitreous Seeds

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.

Download Full-text

Secondary intra-arterial chemotherapy and/or intravitreal chemotherapy as salvage treatment for retinoblastoma

European Journal of Ophthalmology ◽

10.1177/1120672120957587 ◽

2020 ◽

pp. 112067212095758

Author(s):

Ibadulla Mirzayev ◽

Ahmet Kaan Gündüz ◽

Kıvılcım Yavuz ◽

Mehmet Zahid Şekkeli ◽

Funda Seher Özalp Ateş ◽

...

Keyword(s):

Survival Rates ◽

Primary Treatment ◽

Salvage Treatment ◽

External Radiotherapy ◽

Intravitreal Chemotherapy ◽

The Mean ◽

Group B ◽

Group D

Purpose: To evaluate the results of secondary intra-arterial chemotherapy (IAC) and/or intravitreal chemotherapy (IVC) as a salvage treatment for retinoblastoma (RB). Materials and Methods: 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. Results: 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. Discussion: 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.

Download Full-text

Intravitreal topotecan in the management of refractory and recurrent vitreous seeds in retinoblastoma

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2017-310641 ◽

2017 ◽

Vol 102 (4) ◽

pp. 490-495 ◽

Cited By ~ 20

Author(s):

Raksha Rao ◽

Santosh G Honavar ◽

Vishal Sharma ◽

Vijay Anand P Reddy

Keyword(s):

Visual Acuity ◽

Intravitreal Injection ◽

Primary Treatment ◽

Complete Regression ◽

Intravenous Chemotherapy ◽

Systemic Complications ◽

Group D ◽

Vitreous Seeds

Background/aimTo evaluate the efficacy of intravitreal topotecan for refractory or recurrent vitreous seeds in retinoblastoma.MethodsIntravitreal injection of topotecan hydrochloride (30 µg/0.15 mL) was provided every 3 weeks by the safety enhanced technique.ResultsThe study included 17 consecutive patients with retinoblastoma with refractory or recurrent vitreous seeds. Five eyes (29%) belonged to International Classification of Retinoblastoma group C and 12 eyes (71%) belonged to group D. Primary treatment included triple drug intravenous chemotherapy for a mean of 10 cycles (median, 9 cycles; range, 6–18 cycles). Fifteen patients (88%) had undergone 56 periocular carboplatin injections with a mean of 4 injections (median, 3 injections; range, 1–8 injections), concurrent with intravenous chemotherapy. A total of 53 intravitreal topotecan injections were performed in 17 eyes of 17 consecutive patients with refractory or recurrent vitreous seeds with a mean of 3 injections (median, 3 injections; range, 2–6 injections). Complete regression of vitreous seeds was achieved in 17 of 17 eyes (100%). At a mean follow-up of 23.8 months (median, 24 months; range, 15.1–34.1 months), one eye (6%) with a recurrent retinal tumour needed enucleation, and the rest of the 16 eyes (94%) maintained complete regression. Final visual acuity could be reliably assessed in all 16 eyes (100%), of whom 12 eyes (75%) had visual acuity ≥20/200. None of the patients developed ocular or systemic complications.ConclusionThree-weekly intravitreal topotecan appears effective and safe in controlling focal or diffuse refractory or recurrent vitreous seeds in retinoblastoma.

Download Full-text

Artesunate induces mitochondria-mediated apoptosis of human retinoblastoma cells by upregulating Kruppel-like factor 6

Cell Death and Disease ◽

10.1038/s41419-019-2084-1 ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 1

Author(s):

Ying Yang ◽

Nandan Wu ◽

Yihui Wu ◽

Haoting Chen ◽

Jin Qiu ◽

...

Keyword(s):

Tumor Growth ◽

Cell Apoptosis ◽

Underlying Mechanism ◽

Dependent Manner ◽

Chemotherapeutic Drug ◽

Sprague Dawley ◽

Fundus Fluorescein Angiography ◽

Intravitreal Chemotherapy ◽

Vitreous Seeds

Abstract Retinoblastoma (RB) is the most common primary intraocular malignancy in children. Intravitreal chemotherapy achieves favorable clinical outcomes in controlling RB vitreous seeds, which are a common reason for treatment failure. Thus, a novel, effective and safe intravitreal chemotherapeutic drug is urgently required. The malaria drug artesunate (ART) recently demonstrated remarkable anticancer effects with mild side effects. The purpose of this study is to investigate the anti-RB efficacy, the underlying mechanism and the intraocular safety of ART. Herein, we verified that ART inhibits RB cell viability and induces cell apoptosis in a dose- and time-dependent manner. Microarray analysis revealed that Kruppel-like factor 6 (KLF6) was upregulated after ART treatment, and this was further confirmed by real-time PCR and western blot assays. Silencing of KLF6 expression significantly reversed ART-induced RB cell growth inhibition and apoptosis. Furthermore, ART activated mitochondria-mediated apoptosis of RB cells, while silencing KLF6 expression significantly inhibited this effect. In murine xenotransplantation models of RB, we further confirmed that ART inhibits RB tumor growth, induces tumor cell apoptosis and upregulates KLF6 expression. In addition, KLF6 silencing attenuates ART-mediated inhibition of tumor growth in vivo. Furthermore, we proved that intravitreal injection of ART in Sprague-Dawley (SD) rats is safe, with no obvious retinal function damage or structural disorders observed by electrophysiology (ERG), fundal photographs, fundus fluorescein angiography (FFA) or optical coherence tomography (OCT) examinations. Collectively, our study revealed that ART induces mitochondrial apoptosis of RB cells via upregulating KLF6, and our results may extend the application of ART to the clinic as an effective and safe intravitreal chemotherapeutic drug to treat RB, especially RB with vitreous seeds.

Download Full-text

Effectiveness of intravitreal chemotherapy-assisted endoresection in monocular patients with group D retinoblastoma

10.21203/rs.3.rs-35648/v2 ◽

2020 ◽

Author(s):

Xiling Yu ◽

Xueke Li ◽

Yue Xing ◽

Siduo Lu ◽

Silvia Tanumiharjo ◽

...

Keyword(s):

Pars Plana Vitrectomy ◽

Case Series ◽

Repeated Treatment ◽

Retrospective Case ◽

Promising Alternative ◽

Tumour Control ◽

Intravitreal Chemotherapy ◽

Pars Plana ◽

Group D

Abstract Background: This study aimed to determine the efficacy and complications of intravitreal chemotherapy-assisted endoresection for refractory International Classification of Retinoblastoma (ICRB) group D retinoblastoma in monocular patients.Methods: In this retrospective case series, intravitreal chemotherapy-assisted endoresection by pars plana vitrectomy was performed in 11 eyes with refractory ICRB group D retinoblastoma unresponsive to standard therapies in monocular patients.Results: Across a mean follow-up period of 42.7 months, globe salvage was attained in all 11 eyes (100%). There were no cases of extra-ocular tumour seeding or remote metastasis. In 9 eyes (81.8%), tumour control was achieved with one pars plana vitrectomy; in 2 cases (18.2%), repeated treatment, such as laser therapy, intravitreal chemotherapy or a second pars plana vitrectomy, was needed. Retinal reattachment was achieved in all 4 eyes (100%) with previous retinal detachment. Four eyes (36.4%) required subsequent cataract surgery due to secondary cataract. Ten eyes (90.9%) had improvement in best-corrected visual acuity at the last follow-up.Conclusion: Intravitreal chemotherapy-assisted endoresection appears to be a safe and effective globe-salvaging method for refractory group D retinoblastoma. It is a promising alternative to enucleation and a supplementary therapeutic strategy for those unresponsive to standard therapies, especially for the monocular retinoblastoma patients.

Download Full-text

Precision Intravitreal Chemotherapy for Localized Vitreous Seeding of Retinoblastoma

Ocular Oncology and Pathology ◽

10.1159/000491432 ◽

2018 ◽

Vol 5 (4) ◽

pp. 284-289 ◽

Cited By ~ 3

Author(s):

Michael D. Yu ◽

Lauren A. Dalvin ◽

R. Joel Welch ◽

Carol L. Shields

Keyword(s):

Retinal Pigment ◽

Tumor Control ◽

Injection Technique ◽

Complete Control ◽

Intravitreal Chemotherapy ◽

Pars Plana ◽

Direct Delivery ◽

Vitreous Seeds ◽

Vitreous Seeding

Purpose: To describe and evaluate the effectivity of a novel precision intravitreal injection technique for select cases of localized vitreous seeding in retinoblastoma. Methods: Patients with localized vitreous seeds from retinoblastoma received intravitreal chemotherapy via a precision injection technique (P-IVitC) intended to optimize local delivery of melphalan to target seeds. The needle was inserted trans-pars plana and chemotherapy deposited within 3 mm of the target seed(s) under indirect ophthalmoscopic guidance. Without subsequent globe manipulation, the head was then positioned to promote gravity-dependent settling of chemotherapy. Results: There were 8 eyes of 8 patients treated with P-IVitC for active vitreous seeds following adequate solid tumor control with intravenous chemotherapy (n = 3, 38%) or intra-arterial chemotherapy (n = 5, 63%). Viable vitreous seeds were primarily solitary spheres (n = 6, 75%) and measured an average of 2.7 mm in diameter. Vitreous seed resolution (n = 8, 100%) was noted after a mean of 2.6 injections (median 2; range 1–3) of 20 μg melphalan. There was no recurrence at a mean follow-up of 10.0 months. Only 1 eye had an associated complication (focal retinal pigment epithelial mottling, n = 1, 13%). Conclusions: With direct delivery of chemotherapy to within 3–4 mm of vitreous seed activity, P-IVitC provided complete control of localized vitreous seeds with minimal toxicity.

Download Full-text

Changes in Treatment Patterns and Globe Salvage Rate of Advanced Retinoblastoma in Korea: Efficacy of Intra-Arterial Chemotherapy

Journal of Clinical Medicine ◽

10.3390/jcm10225421 ◽

2021 ◽

Vol 10 (22) ◽

pp. 5421

Author(s):

Dong Hyun Lee ◽

Jung Woo Han ◽

Seung Min Hahn ◽

Byung Moon Kim ◽

Chuhl Joo Lyu ◽

...

Keyword(s):

Primary Treatment ◽

Treatment Patterns ◽

Treatment Pattern ◽

Intravenous Chemotherapy ◽

Intravitreal Chemotherapy ◽

Group 4 ◽

Excellent Safety Profile ◽

Group D ◽

Control Study ◽

Salvage Rate

(1) Background: To analyze changes in treatment patterns for advanced retinoblastoma over time and differences in globe salvage rates; (2) Methods: Retrospective, observational case-control study of 97 eyes of 91 patients with advanced retinoblastoma (Group D and E).; (3) Results: Patients were divided into two groups based on whether they were treated before or after intraarterial chemotherapy (IAC) was introduced in our center in 2010. Before 2010, primary treatment pattern was enucleation, which was performed in 57.6% of cases, whereas primary treatment pattern after 2010 was IAC combined with intravenous chemotherapy (IVC), which was performed in 78.1%. Intravitreal chemotherapy (IVitC) has been performed to treat vitreous and subretinal seeding since 2015. The 5-year globe salvage rate of IVC alone was 24.0% for Group D and 0% for Group E, whereas that of IVC–IAC was 50.4% for Group D and 49.7% for Group E. Whether IVitC was performed or not did not significantly contribute to globe salvage rate. There was one metastatic death in the IVC alone group.; (4) Conclusions: Primary treatment pattern changed from enucleation to IAC-based treatment, which can now save nearly half of eyes with advanced retinoblastoma with excellent safety profile and survival rate.

Download Full-text

Effectiveness of Intravitreal Chemotherapy-Assisted Endoresection in Monocular Patients with Group D Retinoblastoma

10.21203/rs.3.rs-35648/v1 ◽

2020 ◽

Author(s):

Xiling Yu ◽

Xueke Li ◽

Yue Xing ◽

Siduo Lu ◽

Silvia Tanumiharjo ◽

...

Keyword(s):

Pars Plana Vitrectomy ◽

Case Series ◽

Tumor Control ◽

Repeated Treatment ◽

Promising Alternative ◽

Tumor Seeding ◽

Intravitreal Chemotherapy ◽

Pars Plana ◽

Group D

Abstract Background: To determine the efficacy and complications of intravitreal chemotherapy-assisted endoresection for refractory group D retinoblastoma in monocular patients.Methods: In this retrospective case series, intravitreal chemotherapy-assisted endoresection by pars plana vitrectomy was performed in 11 eyes with refractory ICRB group D retinoblastoma unresponsive to standard therapies in monocular patients.Results: Across a mean follow-up period of 42.7 months, globe salvage was attained in all 11 eyes (100%). There was no case of extra-ocular tumor seeding or remote metastasis. In 9 eyes (81.8%), tumor control was achieved with one-time pars plana vitrectomy, whereas in 2 cases (18.2%), repeated treatment such as laser, intravitreal chemotherapy or second pars plana vitrectomy were needed. Retinal reattachment was achieved in all 4 eyes (100%) with previous retinal detachment. 4 eyes (36.4%) required subsequent cataract surgery due to secondary cataract. 10 eyes (90.9%) had improvement in best-corrected visual acuity at the last follow-up.Conclusion: Intravitreal chemotherapy-assisted endoresection appears to be a safe and effective globe-salvaging method for refractory group D retinoblastoma. It is a promising alternative to enucleation and a supplementary therapeutic strategy for those unresponsive to standard therapies, especially for the monocular retinoblastoma patients.

Download Full-text