melphalan and Retinoblastoma

Retinoblastoma is the most common primary malignant intraocular tumor in children. Seeding, specifically the dispersion of the tumor into the adjacent compartments, represents a  major parameter determining the degree of retinoblastoma according to the International Classification of Retinoblastoma. In this article we focused on vitreous seeding, one of the main limiting factors in the successful "eye preservation treatment" of retinoblastoma. This article presents an overview of the history of vitreous seeding of retinoblastoma, established treatment procedures and new-research modalities. The introduction of systemic chemotherapy in the treatment of retinoblastoma at the end of the 1990s represented a  significant breakthrough, which enabled the progressive abandonment of radiotherapy with its attendant side effects. However, the attained concentrations of chemotherapeutics in the vitreous space during systemic chemotherapy are not sufficient for the treatment of vitreous seeding, and the toxic effects of systemic chemotherapy are not negligible. A significant change came with the advent of chemotherapy in situ, with the targeted administration of chemotherapeutic drugs, namely intra-arterial and intravitreal injections, contributing to the definitive eradication of external radiotherapy and a reduction of systemic chemotherapy. Although vitreous seeding remains the most common reason for the failure of intra-arterial chemotherapy, this technique has significantly influenced the original treatment regimen of children with retinoblastoma. However, intravitreal chemotherapy has made the greatest contribution to increasing the probability of preservation of the eyeball and visual functions in patients with advanced findings. Novel local drug delivery modalities, gene therapy, oncolytic viruses and immunotherapy from several ongoing preclinical and clinical trials may represent promising approaches in the treatment of vitreous retinoblastoma seeding, though no clinical trials have yet been completed for routine use.

Topics: Antineoplastic Agents, Alkylating; Child; Humans; Intravitreal Injections; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Vitreous Body

Topics: Antineoplastic Agents; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Retinal Neoplasms; Retinoblastoma

Retinoblastoma is the most common primary intraocular tumor of childhood. Accurate diagnosis at an early stage is important to maximize patient survival, globe salvage, and visual acuity. Management of retinoblastoma is individualized based on the presenting clinical and imaging features of the tumor, and a multidisciplinary team is required to optimize patient outcomes. The neuroradiologist is a key member of the retinoblastoma care team and should be familiar with characteristic diagnostic and prognostic imaging features of this disease. Furthermore, with the adoption of intra-arterial chemotherapy as a standard of care option for globe salvage therapy in many centers, the interventional neuroradiologist may play an active role in retinoblastoma treatment. In this review, we discuss the clinical presentation of retinoblastoma, ophthalmic imaging modalities, neuroradiology imaging features, and current treatment options.

Topics: Humans; Infusions, Intra-Arterial; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Salvage Therapy

Intra-arterial chemotherapy is a new retinoblastoma treatment associated with high rates of globe salvage that has been widely adopted for primary treatment of retinoblastoma but is less frequently used as secondary treatment for refractory retinoblastoma. This systematic review aims to summarize the reported outcomes of intra-arterial chemotherapy for refractory retinoblastoma.. We conducted a systematic review of studies published on PubMed, Medline, and Embase from 2011 to 2021 reporting globe salvage rates following intra-arterial chemotherapy for secondary treatment of refractory retinoblastoma.. Our search yielded 316 studies, and 24 met inclusion criteria. The 24 included studies were comprised of 1366 patients and 1757 eyes. Among these, 1184 (67%) eyes received secondary indication treatment, and globe salvage was achieved for 776 of these 1184 eyes (64%). Sixteen studies reported cannulation success rates from 71.8 to 100%. Pooled analysis of subjects revealed 21 patients (2.6%) with metastatic disease and 26 deaths (3%) during study follow-up periods (7-74 months). The most common ocular complications were vitreous hemorrhage (13.2%), loss of eyelashes (12.7%), and periocular edema (10.5%). The most common systemic complications were nausea/vomiting (20.5%), neutropenia (14.1%), fever (8.2%), and bronchospasm (6.2%).. Intra-arterial chemotherapy is associated with high rates of globe salvage and low rates of serious complications in patients with refractory retinoblastoma. Unfortunately, current literature is predominantly comprised of retrospective case studies, and further high-quality evidence is necessary to inform clinical practice.

Topics: Antineoplastic Agents; Bronchial Spasm; Carboplatin; Drug Resistance, Neoplasm; Edema; Eyelashes; Febrile Neutropenia; Humans; Infusions, Intra-Arterial; Melphalan; Methotrexate; Nausea; Retinal Neoplasms; Retinoblastoma; Salvage Therapy; Topotecan; Vitreous Hemorrhage; Vomiting

Intra-arterial chemotherapy for retinoblastoma has been adopted as a first-line treatment option by numerous tertiary centers. The effect of intra-arterial chemotherapy on future rates of metastatic disease as well as on globe salvage in advanced eyes remains relatively unknown.. A search of PubMED, MEDLINE, EMBASE, and Web of Science electronic databases was conducted from inception until January 2019 for studies with a minimum of 10 patients reporting outcomes and complications following intra-arterial chemotherapy for retinoblastoma.. A total of 20 studies met the inclusion criteria for analysis, comprising 873 patients and 1467 eyes. Only one study was comparative; there was substantial heterogeneity in reported outcomes and several overlapping patient cohorts that were published. Across all studies, 174 of 1467 eyes were enucleated (11.8%). Metastatic disease occurred in 8 of 513 patients (1.6%). Globe salvage was achieved in 318 of 906 (35.6%) cases of advanced retinoblastoma. The most common ocular complication was retinal detachment, occurring in 23% of eyes, and the most common systemic complications were transient fever and nausea/vomiting.. There is a paucity of higher-level evidence with adequate follow-up surrounding the long-term safety of intra-arterial chemotherapy and effect on metastasis in retinoblastoma. Studies to date have been limited by short-term follow-up. Longitudinal prospective studies could provide greater insight into the ability of intra-arterial chemotherapy to reduce the risk of retinoblastoma metastasis.

Topics: Antineoplastic Agents; Child, Preschool; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Prospective Studies; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Salvage Therapy

Topics: Antineoplastic Agents; Biocompatible Materials; Delayed-Action Preparations; Drug Delivery Systems; Drug Implants; History, 20th Century; History, 21st Century; Humans; Melphalan; Ophthalmology; Polymers; Retinoblastoma

To review preclinical and clinical pharmacokinetic studies of the three most important chemotherapy drugs used for intraocular retinoblastoma and the contribution of the reported results to optimize treatment.. Systemic review of pharmacokinetic studies identified by a literature search at Pubmed using the keywords carboplatin, melphalan, topotecan, intravitreal, ophthalmic artery chemosurgery, pharmacokinetics, and retinoblastoma.. A total of 21 studies were reviewed for assessing the preclinical and clinical pharmacokinetics of carboplatin, topotecan, and melphalan delivered by intravenous, periocular, ophthalmic artery, and intravitreal routes. Some preclinical studies were done before translation to the clinics. Others, despite encouraging preclinical data as reported for periocular topotecan did not correlate with clinical use. In addition, as was the case for melphalan after ophthalmic artery chemosurgery and despite nonfavorable preclinical information, some routes of drug delivery are clinically effective. Besides topotecan, complete knowledge of the pharmacokinetics of melphalan and carboplatin is still lacking.. Pharmacokinetic knowledge of chemotherapy may aid to guide retinoblastoma treatment in favor of safety and efficacy. Nonetheless, results obtained in preclinical models should be translated with care to the clinics.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Infusions, Intra-Arterial; Injections, Intraocular; Melphalan; Retinal Neoplasms; Retinoblastoma; Topotecan

To describe the ocular side effects in patients receiving intravitreal injection therapy (IViT) for retinoblastoma.. PubMed (1946-present), Scopus (all years), Science Citation Index (1900-present) and Conference Proceedings Citation Index-Science (1990-present) electronic databases were searched to identify all published reports of therapeutic intravitreal injections for retinoblastoma in humans.. Ten studies with original IViT ocular side effect data were included in this systematic review. In these combined reports, a total of 1287 intravitreal injections were given to 306 eyes of 295 patients, with a mean follow-up of 74.1 months. Two hundred sixty-one (88.5%) patients received comparatively standard melphalan IViT doses (8-30 mcg). Ocular side effects occurred in 38 patients (17 significant, 21 minor). The proportion of patients experiencing potentially significant ocular side effects following standard melphalan IViT regimens was 0.031 (8/261; 95% CI 0.013 to 0.06). The side effects of these eight included iris atrophy in three, two each with chorioretinal atrophy and vitreous haemorrhage and one with retinal detachment. Of the other nine patients with significant complications, five experienced sight-threatening complications following dramatic dose escalations (four with melphalan, one with thiotepa), three experienced complications that are commonly associated with concurrent therapies given to these patients and one had a retinal detachment. Of the 61 patients receiving IViT via safety-enhancing injection techniques, all six significant side effects were either attributed to the therapeutic dose or confounded by concurrent treatments.. Significant ocular complications following IViT for retinoblastoma are uncommon, and this risk may be reduced further by the use of careful injection technique and standard dosing regimens. Care must be taken in the dosing of intravitreal treatments to avoid potentially irreversible vision loss.

Topics: Antineoplastic Agents, Alkylating; Atrophy; Corneal Dystrophies, Hereditary; Humans; Intravitreal Injections; Iris; Melphalan; Retinal Detachment; Retinal Neoplasms; Retinoblastoma; Vitreous Hemorrhage

The tools for managing retinoblastoma have been increasing in the past decade. While globe-salvage still relies heavily on intravenous chemotherapy, tumors in advanced stage that failed chemotherapy are now referred for intra-arterial chemotherapy (IAC) to avoid enucleation. However, IAC still has many obstacles to overcome. We present an update on the indications, complications, limitations, success, and technical aspects of IAC. Given its safety and high efficacy, it is expected that IAC will replace conventional strategies and will become a first-line option even for tumors that are amenable for other strategies.

Topics: Antineoplastic Agents; Child; Eye Enucleation; Humans; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Salvage Therapy; Treatment Outcome

Retinoblastoma is a deadly eye cancer in children, leading to death in 50%-70% of children in undeveloped nations who are diagnosed with it. This malignancy is the most common intraocular tumor in childhood worldwide. The good prognosis in developed nations is related to early detection and advanced treatments. With the advent of intraarterial chemotherapy, neurosurgeons have taken a central role in the treatment of this pediatric condition. Intraarterial chemotherapy is a novel treatment for retinoblastoma whereby chemotherapeutic agents are precisely delivered into the ophthalmic artery, minimizing systemic toxicity. This procedure has shown impressive results and has allowed a dramatic decrease in the rate of enucleation (eye removal) in advanced and refractory retinoblastoma. Recent reports have raised some concerns about the risk of ocular vasculopathy, radiation-related toxicity, and the potential for metastatic disease after intraarterial chemotherapy. In the authors' experience of more than 3 years, tumor control is excellent with globe salvage at 67% and vascular events less than 5%, mostly related to improvement in technique. The role of this novel approach in the management of retinoblastoma has yet to be defined. As more centers are adopting the technique, the topic will decidedly become the focus of intensive future research. In this paper, the authors review and discuss current data regarding intraarterial chemotherapy for retinoblastoma.

Topics: Antineoplastic Agents, Alkylating; Eye Enucleation; Humans; Injections, Intra-Arterial; Melphalan; Neoplasm Seeding; Ophthalmic Artery; Research Design; Retinal Neoplasms; Retinoblastoma

Retinoblastoma with vitreous seeding has been one of the most challenging conditions for eye-preservation therapy. Several modalities for treating vitreous seeding were reviewed in order to analyze the problems associated with them. External beam radiotherapy has been the most reliable method to treat vitreous seeding. However, recurrence after external beam radiotherapy needs other types of treatments to preserve the eyeballs. Due to the progress of investigations concerning retinoblastoma, chemotherapy has become the most promising method to cure not only recurrence but also primary tumors. Systemic chemotherapy can rarely cure vitreous seeding, but local chemotherapy using vitreous injections of melphalan can preserve about 50% of the eyeballs with vitreous seeding. Currently, animal experiments are being conducted to study the efficacy and safety of vitreous surgery combined with infusion of anticancer drugs for eradication of vitreous seeds and maintenance of visual function.

Topics: Animals; Antineoplastic Agents, Alkylating; Brachytherapy; Combined Modality Therapy; Humans; Injections; Melphalan; Neoplasm Seeding; Rabbits; Retinal Neoplasms; Retinoblastoma; Thiotepa; Vitreous Body

To determine the safety and toxicity profile of intravitreal carboplatin as salvage treatment for retinoblastoma with vitreous disease.. Single-institution, interventional prospective clinical trial.. Patients with progressive or recurrent vitreous seeds after completion of primary treatment for intraocular retinoblastoma.. Eligible eyes received an intravitreal injection of carboplatin every 14 to 21 days with simultaneous focal therapy (laser, thermotherapy, and brachytherapy) provided at the discretion of the ocular oncologist. The evaluation with examination under anesthesia, ultrasound biomicroscopy, and electroretinography (ERG) were performed before each injection to assess for tumor response and drug-related toxicity. A serious adverse event resulted in dose recalculation and ultimately early closure of the study.. Regression pattern of vitreous disease and incidence of dose-limiting toxicities.. Four patients were enrolled at an initial dose of 0.3 mg. Complete regression of vitreous seeds was noted in all patients after 5, 2, 2, and 1 injections (respectively). Two patients developed recurrent vitreous disease at 3 and 25 months after complete regression and ultimately required enucleation. A serious adverse event occurred in 1 patient who developed acute vision loss with extinguished ERG response 72 hours after the second injection; ultimately, this eye developed a cataract and required enucleation. After temporary suspension and dose modification, 3 patients were enrolled at an injection dose of 3 μg and treated with a total of 5, 2, and 1 injections, respectively. Complete regression of vitreous disease was not achieved in any patient though ERG amplitudes remained stable. After removal from protocol, all 3 patients had a complete response to intravitreal melphalan. Concern for dose escalation and further toxicity in the setting of an effective and safe alternative (melphalan) led to the termination of the study.. Intravitreal carboplatin may be effective in treating progressive vitreous seeding at higher doses, but permanent retinal toxicity was observed. Other alternative agents should be considered.. Proprietary or commercial disclosure may be found after the references.

Topics: Carboplatin; Humans; Melphalan; Prospective Studies; Retinal Neoplasms; Retinoblastoma; Salvage Therapy; Vitreous Body

Access to intra-arterial chemotherapy for retinoblastoma in low- and middle-income countries (LMICs) is limited. There is a need to optimize the efficacy of systemic chemotherapy for advanced intraocular retinoblastoma, particularly in LMICs. The aim was to compare the efficacy of standard versus higher dose carboplatin-based intravenous chemotherapy for group D and E retinoblastoma.. Thirty-two eyes of 30 patients were analyzed: 17 group D and 15 group E eyes. The tumor response to chemotherapy with regards to regression pattern (p = .72), tumor shrinkage (diameter: p = .11, height: p = .96), subretinal seeds (p = .91), and vitreous seeds (p = .9) were comparable between the two treatment arms. The globe salvage (group D [82% vs. 67%; p = .58]; group E [12.5% vs. 29%; p = .57]) and salvage of meaningful vision (group D [100% vs. 75%; p = .13]; group E [100% vs. 50%; p = .48]) were comparable between standard and higher dose arms. No excess treatment-related toxicity was observed in the higher dose arm.. Higher dose carboplatin-based intravenous chemotherapy did not result in superior globe or vision salvage in group D or E retinoblastoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Humans; Infant; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Treatment Outcome

To determine prospectively the efficacy and to assess potential side effects of melphalan selective ophthalmic artery chemotherapy (SOAC) as first-line treatment for unilateral retinoblastoma.. Phase 2 nonrandomized, prospective study.. Patients with unilateral retinoblastoma group B, C, or D of the International Classification for Intraocular Retinoblastoma (IRC). Group D eyes with massive vitreous seeding were not eligible.. Melphalan SOAC associated with diode laser thermotherapy, cryotherapy, or both at 4-week intervals (3-6 cycles). For persistent vitreous seeding, intravitreal melphalan chemotherapy also was used.. The primary outcome was globe preservation rate. Secondary outcomes were tumor relapse rate, occurrence of ocular or systemic adverse events, and measurement of the dose area product (DAP).. This first prospective trial demonstrated that SOAC with melphalan alone as first-line treatment for retinoblastoma is efficient and well tolerated with no metastatic events, although ocular ischemic complications were observed.

Topics: Antineoplastic Agents, Alkylating; Child; Child, Preschool; Combined Modality Therapy; Cryotherapy; Disease Management; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Injections, Intra-Arterial; Magnetic Resonance Imaging; Male; Melphalan; Neoplasm Staging; Ophthalmic Artery; Prospective Studies; Retinal Neoplasms; Retinoblastoma; Time Factors; Treatment Outcome

To report the efficacy and complications of intra-ophthalmic artery melphalan (IAM) for treatment of patients with advanced intra-ocular retinoblastoma.. Patients with newly diagnosed, unilateral, group D retinoblastoma were included in a phase II protocol. Children with relapsed-refractory disease after systemic chemoreduction were later treated under the same guidelines.Melphalan (3–5 mg/procedure) was injected through a 1.2 F microcatheter placed into the ophthalmic artery every 21 days.. Eleven patients (12 eyes, eight as primary treatment) received 33 IAM procedures. The phase II protocol closed prematurely because of low accrual. The IAM technique was overall safe and could be performed successfully in 31 of 33(94%) attempts. After the second administration of IAM, very good partial response was achieved in all treated eyes. With a median follow-up time of 29.5 months (range 6–57), ocular salvage was achieved in 7 of 12 (58%) eyes. No systemic adverse events were observed. Two patients developed diffuse arteriolar sclerosis, hyperpigmentation of the retinal pigment epithelium and partial retinal atrophy after the second IAM. Both eyes were preserved with no tumour activity, good motility and perception of light, 56 and 30 months after the last IAM treatment. Multinucleated macrophages with intracytoplasmic foreign material were found in the choroid and the retina in 2 of 5 enucleated eyes.. Our study reports the activity and reproducibility of IAM in advanced retinoblastoma but also underlines the challenges of performing prospective studies on this treatment modality. Toxicity was limited to only ocular vascular events.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Dose-Response Relationship, Drug; Female; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; Humans; Infant; Infant, Newborn; Injections, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Prospective Studies; Retinal Neoplasms; Retinoblastoma; Time Factors; Treatment Outcome

High-dose chemotherapy (HDC) followed by autologous stem cell rescue (ASCR) is the only curative treatment for metastatic retinoblastoma, but its feasibility in developing countries is unknown. We report 11 consecutive children (six unilateral) treated in three South-American middle-income countries with HDC-ASCR. One patient had metastatic retinoblastoma at diagnosis and the remaining ones had a metastatic relapse. Metastatic sites included BM=6, bone=4, orbit=5 and central nervous system (CNS)=4. All patients received induction with conventional chemotherapy achieving CR at a median of 5.7 months from the diagnosis of metastasis. Conditioning regimens included carboplatin and etoposide with thiotepa in six or with CY in four or melphalan in one patient. All patients engrafted after G-CSF-mobilized peripheral blood ASCR and no toxic deaths occurred. Two children received post-ASCR CNS radiotherapy. Seven children have disease-free survival (median follow-up 39 months). CNS relapse, isolated (n=3) or with systemic relapse (n=1), occurring at a median of 7 months after ASCT was the most common event. In the same period, five children with metastatic retinoblastoma did not qualify for HDC-ASCR and died. We conclude that HDC-ASCR is a feasible and effective treatment for children with metastatic retinoblastoma in middle-income countries.

Topics: Antineoplastic Agents; Carboplatin; Child, Preschool; Etoposide; Female; Humans; Infant; Male; Melphalan; Neoplasm Metastasis; Retinoblastoma; South America; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

To report on our 3-year experience with the use of superselective ophthalmic artery infusion of chemotherapy as initial, primary treatment for intraocular retinoblastoma.. Prospective, institutional review board-approved clinical trial.. Twenty-eight eyes of 23 newly diagnosed retinoblastoma patients (Reese-Ellsworth [RE] group V, 25 eyes; RE IV, 1 eye; RE III, 1 eye; RE II, 1 eye), ages 3-88 months (mean, 22; median, 11) followed for 3-37 months (mean, 15; median, 14).. Cannulation of 1 or both ophthalmic arteries in young children with retinoblastoma was performed via the femoral artery under general anesthesia on an outpatient basis and chemotherapy (melphalan [n = 12], melphalan plus topotecan [n = 7], melphalan plus topotecan and carboplatin [n = 3], or melphalan plus carboplatin [n = 1]) infused.. Patient survival, eye survival, systemic toxicity, complete blood counts, ophthalmic examination, retinal photography, and electroretinograms.. We treated 23 newly diagnosed retinoblastoma patients initially with 75 separate intra-arterial chemotherapy infusions (range, 1-6 treatments; mean, 3.2) over a 3-year period. All children survived. Only 1 of the 28 eyes came to enucleation (for progressive disease). No eye was enucleated for ocular complications of the procedure and the only adverse ophthalmic findings were occasional transient lid edema, forehead hyperemia, and loss of nasal lashes. Kaplan-Meier enucleation free was 100% at 12 months and 89% at 2 years (95% confidence interval, 43%-98%). There were no deaths, strokes, or transfusions of any blood products; no effect on red cell count; 9 cycles of grade 3 and 1 cycle of grade 4 neutropenia; and no hospitalizations, episodes of fever/neutropenia, or complications at the site of femoral artery puncture.. The ophthalmic artery(s) of children can safely be repeatedly canulated in very young children and high concentrations (but low doses) of chemotherapy infused on an outpatient basis. When used as initial therapy superselective chemotherapy delivered through the ophthalmic artery prevented enucleation, primary radiation or the use of systemic chemotherapy in 27 of 28 eyes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Electroretinography; Female; Fluorescein Angiography; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Prospective Studies; Retinal Neoplasms; Retinoblastoma; Topotecan; Treatment Outcome; Visual Acuity

To develop a technique that would allow us to cannulate repeatedly the ophthalmic artery of young children with advanced retinoblastoma, to find a dose of melphalan that would be tolerable and tumoricidal for retinoblastoma when given intraarterially, and to study the local ocular and systemic side effects of intraarterial melphalan in these children.. Phase I/II clinical trial.. Ten children with advanced retinoblastoma (Reese-Ellsworth V) eyes who were indicated for enucleation were entered into an institutional review board-approved protocol of ophthalmic artery infusion of melphalan to avoid enucleation.. Cannulation of the ophthalmic artery was performed by a femoral artery approach using microcatheters while the children were under anesthesia and anticoagulated. Chemotherapy (melphalan) was infused into the artery over a 30-minute period.. Ophthalmic examinations, retinal photography, and electroretinograms were used to document local toxicity, whereas physical examinations and complete blood counts were used to measure systemic toxicity.. The ophthalmic arteries were successfully cannulated in 9 cases (total, 27 times), as many as 6 times in 1 patient. Dramatic regression of tumors, vitreous seeds, and subretinal seeds were seen in each case. No severe systemic side effects (sepsis, anemia, neutropenia, fever, or death) occurred. No transfusions were required (red cells or platelets). Three patients developed conjunctival and lid edema that resolved without treatment. There was no toxicity to the cornea, anterior segment, pupil, or motility. One (previously irradiated) eye developed retinal ischemia; another eye had no toxicity after intraarterial chemotherapy but did develop a radiationlike retinopathy after brachytherapy. Vision stabilized or improved in all but 1 patient after treatment. Electroretinograms were generally poor (advanced eyes were treated), but in 2 cases, the electroretinogram improved after treatment (and resolution of a retinal detachment). Seven eyes avoided enucleation. Two intraarterially treated eyes were enucleated, with no viable tumors identified pathologically.. We developed a technique of direct ophthalmic artery infusion of melphalan for children with retinoblastoma. The technique had minimal systemic side effects (one patient had grade 3 neutropenia) and minimal local toxicity. Among the first 9 cases treated with this technique, 7 eyes destined to be enucleated were salvaged.

Topics: Antineoplastic Agents, Alkylating; Blood Cell Count; Catheterization; Child, Preschool; Electroretinography; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Photography; Retinal Neoplasms; Retinoblastoma

Intra-arterial chemotherapy (IA) as a treatment to salvage the eye with advanced retinoblastoma is increasingly utilized based on successes reported by institutions around the world mainly through retrospective studies.. To study the feasibility of delivering melphalan directly into the ophthalmic artery in a multi-institutional prospective study in children with newly diagnosed unilateral group D retinoblastoma.. The Children's Oncology Group (COG) initiated study ARET12P1 in 2014 and was open to nine institutions. Eligible patients older than six months of age were enrolled. The feasibility of delivering three injections of melphalan into the ophthalmic artery every 28 days was assessed.. Nine institutions participated in this trial. Fourteen patients were enrolled, two of whom were unevaluable for feasibility. Four patients experienced a feasibility failure. In two patients, the ophthalmic artery could not be accessed for the second IA injection, in one the artery could not be accessed for the first injection, and one patient experienced grade 4 hypotension during the procedure.. Delivery of prescribed therapy within the context of this study did not meet the feasibility goals of the study with only a 67% feasibility success rate. These results should caution centers that plan to initiate this treatment and suggest investment in training to achieve technical expertise or referral to centers with expertise.

Topics: Child; Feasibility Studies; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Prospective Studies; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Treatment Outcome

Intra-arterial chemotherapy (IAC) for retinoblastoma is a minimally invasive and chemotherapeutic approach resulting in eye salvage and vision restoration or preservation. Moreover, IAC has proven to effectively treat advanced retinoblastoma while not compromising patient survival. Our institutional experience with IAC for retinoblastoma has included over 500 patients and over 2400 intra-arterial infusions. Each infusion is completed with the use of a micropuncture for arterial access and microcatheter for infusion, eliminating the need for guide catheters and related complications (video 1). This treatment modality has resulted in >95% ocular survival and reduces enucleation to <5% for this population. In addition to local therapy, including cryotherapy, intravitreal chemotherapy, or laser treatments, by the ophthalmologist, IAC has become an important component of comprehensive multidisciplinary and multimodal therapy for this disease. For what used to require a possibly vision-sacrificing procedure, retinoblastoma treated with IAC minimizes the need for enucleation while maximizing both patient and ocular survival.DC1SP110.1136/neurintsurg-2022-018957.supp1Supplementary data neurintsurg;15/3/303/V1F1V1Video 1 .

Topics: Humans; Infusions, Intra-Arterial; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Treatment Outcome

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Infant; Infusions, Intra-Arterial; Lasers; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies

To analyze the outcomes of salvage intra-arterial chemotherapy (IAC) for recurrent or persistent intraocular retinoblastoma after failure with other treatment modalities.. Retrospective study.. Twenty-four eyes of 23 patients.. Intra-arterial chemotherapy.. Globe salvage, metastasis, and death.. The mean age at the time of salvage IAC was 41 months (median, 36 months; range, 14-86 months). All patients (n = 23) received IV chemotherapy (IVC) as the primary treatment. The mean number of IVC cycles before salvage IAC was 10 (median, 12; range, 6-18). The indications for salvage IAC were tumor recurrence (n = 17; 71%) or persistent tumor (n = 7; 29%) post-IVC. The mean number of salvage IAC cycles was 3 (median, 3; range, 1-6). Of 24 eyes, 17 eyes (71%) achieved tumor regression with salvage IAC, whereas 7 (29%) eyes displayed poor response. Of these 17 eyes with initial tumor regression, 9 (38%) eyes sustained good response, whereas 8 (33%) eyes displayed tumor recurrence over a mean follow-up period of 21 months (median, 21 months; range, 6-44 months). The mean interval between IAC and tumor recurrence (n = 8) was 4 months (median, 3 months; range, 1-14 months). Of these 8 eyes, globe salvage was achieved in 5 (21%) eyes with additional alternate treatment. Of the 7 eyes with poor response to IAC, globe salvage was achieved in 1 (4%) eye with additional alternate treatment. Overall, globe salvage was achieved in 15 (63%) eyes.. Salvage IAC is an effective treatment for recurrent and persistent retinoblastoma, enabling globe salvage in 63% cases.. The authors have no proprietary or commercial interest in any materials discussed in this article.

Topics: Child, Preschool; Humans; Infusions, Intra-Arterial; Melphalan; Neoplasm Recurrence, Local; Retinal Neoplasms; Retinoblastoma; Retrospective Studies

To describe a patient with retinoblastoma and subsequent maculopathy unrelated to the tumor but related to intra-arterial melphalan documented by pattern electroretinography.. Comprehensive ophthalmic evaluation, treatment with intra-arterial chemotherapy and subsequent follow-up including electroretinography to assess for macular dysfunction.. A 3-year-old child was evaluated with electrophysiological investigations following treatment of unilateral Group D retinoblastoma with intra-arterial and intravitreal chemotherapy with melphalan. Pattern reversal visual evoked potential amplitude and P100 latency were normal in the left eye, but abnormal and delayed in the right eye. Pattern electroretinograms (pERGs) were abnormal on the right eye. Flash electroretinograms (fERGs) were normal on both eyes. Visual acuity dysfunction of 20/50 attributed to melphalan was seen on the right eye vs 20/40 on the left eye.. Our case report demonstrates that pERG rather than fERG should be used to monitor baseline macular function and potential toxicity in children undergoing chemotherapy for retinoblastoma using skin electrodes when corneal electrodes are not tolerated.

Topics: Child, Preschool; Electroretinography; Evoked Potentials, Visual; Follow-Up Studies; Humans; Infusions, Intra-Arterial; Melphalan; Retinal Neoplasms; Retinoblastoma; Vision Disorders

Intra-arterial chemotherapy (IAC) for the treatment of intraocular retinoblastoma has gained recognition as a method to improve ocular salvage; however, there is a paucity of evidence supporting treatment factors prognosticating ocular survival.. All patients with retinoblastoma treated with IAC at a single institution between December 2008 and December 2019 were evaluated. Patient demographics, tumor classification, prior treatments, procedural data, other non-IAC therapies, adverse reactions, procedural complications, ocular outcomes, and overall survival were assessed via retrospective chart review. Factors suggestive of increased ocular survival were identified via univariate and multivariate analyses. The impact of accrued treatment experience was evaluated by grouping eyes by the respective year, IAC treatment was initiated.. Forty-nine eyes of 43 patients were treated for retinoblastoma with IAC (256 total procedures). At least grade 3 neutropenia was observed following 19% of IAC procedures. The risk of neutropenia was not statistically different between single or multidrug IAC. Comparing those who received balloon-assisted intra-arterial chemotherapy (bIAC) in more than two-thirds of cycles to those who did not, the risk of arterial access site complications was not statistically different. Multivariate analysis revealed a significantly lower risk of enucleation associated with treatment era in years (hazard ratio [HR] = 0.52-1.00, p < .05) and laser therapies (HR = 0.02-0.60, p < .05).. Ocular survival rates in patients treated with IAC for retinoblastoma at our institution have increased over time. Accrued treatment experience and programmatic changes have likely contributed. Larger, prospective series may lead to a better understanding of factors that consistently contribute to better ocular salvage.

Topics: Humans; Infant; Infusions, Intra-Arterial; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Treatment Outcome

To evaluate the efficacy and toxicity of intravitreal carboplatin plus melphalan for the treatment of vitreous seeds in eyes with retinoblastoma (RB).. This retrospective series at a tertiary referral center included 22 consecutive RB patients who had received intravitreal carboplatin (16 μg per 0.05 ml) combined with melphalan (30 μg in 0.03 ml) [IVi (Ca-Me)] for treatment of vitreous seeds. Tumor control and drug toxicities were recorded.. There were 22 eyes of 22 patients, divided into primary group (n = 13) without history of previous intravitreal chemotherapy (IViC) and refractory group (n = 9) with history of previous IViC using melphalan and/or topotecan. The demographics and clinical findings of the primary and refractory groups did not differ significantly. The 6-month follow-up revealed complete vitreous seed control (77% vs. 89%, p = 0.47). Vitreous seed recurrence was detected in 1 eye of each group at 6 months. During the next 18-month follow-up period, no recurrence of seed was observed. The response to IVi (Ca-Me) was not significantly influenced by previous IViC (p = 0.70), primary systemic or intra-arterial chemotherapy (p = 0.45), or the type of regression (p = 0.35). The most common tumor treatment complications were retinal detachment (RD) (n = 2), early hypotony (n = 2) and late hypotony (n = 4, unrelated), cataract (n = 2), and severe pigment dispersion (n = 1). Enucleation was performed in 8 eyes, for total RD (n = 1), phthisis bulbi (n = 5), and extensive solid tumor recurrence (n = 2). There was no case of orbital invasion, systemic metastasis, or death.. Based on this interventional case series for primary and refractory vitreous RB seeds, carboplatin plus melphalan therapy may be effective with few toxic side effects.

Topics: Antineoplastic Agents, Alkylating; Carboplatin; Humans; Infant; Intravitreal Injections; Melphalan; Neoplasm Recurrence, Local; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Vitreous Body

Topics: Developing Countries; Humans; Melphalan; Retinal Neoplasms; Retinoblastoma

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Neoplasm Recurrence, Local; Neoplasm, Residual; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Treatment Outcome

Retinoblatoma is now the pediatric cancer with the highest cure rate. More than any other ocular malignancy the approach to this cancer has changed dramatically in the past 10 years. Most of the things taught to the majority of all Ophthalmology residents is out of date. Because few Ophthalmologists deal with retinoblastoma they are not aware of these seismic changes so this summary of my Curtin lectures outlines some of the major changes all Ophthalmologists should be familiar with.

Topics: Antineoplastic Agents, Alkylating; Child; Humans; Internship and Residency; Intravitreal Injections; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies

To examine the outcome of salvage intra-arterial chemotherapy (IAC) for patients with recurrent retinoblastoma after the initial course of IAC and determine the factors influencing clinical outcome.. A total of 73 eyes of 71 patients with recurrent retinoblastoma undergoing salvage IAC after initial successfully IAC between May 2014 and May 2019 were retrospectively reviewed for clinical outcomes. Ocular survival and progression-free survival were used to examine the efficacy of salvage IAC. The factors influencing clinical outcomes were determined using univariate and multivariate analyses.. The salvage IAC was delivered at mean 9.4 months (median 7, range 2.1-38.3 months) following the last cycle of initial IAC. 86.5% (64/73) eyes relapsed 16 months after the initial IAC. After the salvage IAC, 57 eyes (78.1%) were salvaged, and no further-line therapies were required for 36 eyes (49.3%). The 2-year Kaplan-Meier ocular survival and progression-free survival estimates after salvage IAC were 66.4% (95% CI, 31.5-42.1%) and 38.2% (95% CI, 17.8-28.8%), respectively. Univariate and multivariate analyses showed that the ocular survival and progression-free survival after salvage IAC were significantly associated with the history of vitreous seeds (p = 0.02 and p = 0.03, respectively).. Salvage IAC is effective for the management of recurrent retinoblastoma after the initial successful IAC. Eyes with a history of vitreous seeds in the course of the disease are more likely to relapse and with worse ocular survival. A close follow-up strategy is imperative to treat the recurrent tumour after salvage IAC.

Topics: Humans; Infant; Infusions, Intra-Arterial; Melphalan; Neoplasm Recurrence, Local; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Treatment Outcome

Retinoblastoma is the most common primary intraocular malignancy in infancy with a metastases-related death risk. However, a safe and convenient treatment without enucleation is still an unmet clinical need. In this work, a cell-penetrating peptide, 89WP, was conjugated with melphalan (89WP-Mel), which achieved high tumor inhibition effects as intravitreally injected melphalan via topical instillation for the first time. Notably, the "outside-in" diffusion of instilled 89WP-Mel created a protective shield surrounding the eye, efficiently preventing tumor metastases, while the mice treated with intravitreally injected melphalan suffered more brain metastases related death. The ocular absorption of 89WP-conjugated melphalan and other small molecules, both hydrophobic and hydrophilic, occurred via non-corneal pathway with high safety and a prolonged residence duration in retina up to 24 h. The present work paves a new avenue for simultaneous intraocular tumor inhibition and extraocular metastases prevention in a safe and convenient way via topical instillation.

Topics: Animals; Antineoplastic Agents, Alkylating; Cell-Penetrating Peptides; Melphalan; Mice; Retinal Neoplasms; Retinoblastoma

Retinoblastoma (RB) is the most common intraocular pediatric malignancy. Advancements in intra-arterial chemotherapy (IAC) for treatment of RB have resulted in dramatic improvement in eye salvage rates. Data regarding IAC outcomes and associated hematologic toxicities are limited. The objective of this retrospective study was to analyze baseline characteristics, efficacy, and hematologic complications associated with IAC treatment in children with RB at a single international referral institution. Ninety-five sessions of IAC were performed in 28 patients. Mean age at RB diagnosis was 12.5 months (SD, 9.2 mo). Fourteen patients had bilateral RB. IAC agents included melphalan, carboplatin, and topotecan. The most common regimens were triple-agent IAC and single-agent melphalan (66.3% and 15.8%, respectively). Median number of IAC sessions was 3 (mean: 3.39, range: 1 to 9). Eye salvage rate was 83.7% with an overall survival rate of 100% at a median follow-up of 29 months (mean: 29.8 mo, range: 1 to 63 mo). A total of 26 patients (92.9%) experienced at least 1 hematologic toxicity during their treatment course Prevalence of neutropenia, anemia, and thrombocytopenia were 89.3%, 85.7%, and 25%, respectively. While IAC is effective in salvaging most eyes with advanced intraocular RB, over half of patients experienced clinically significant neutropenia and anemia. Clinicians should be vigilant in monitoring patients for IAC-related complications.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Neutropenia; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Treatment Outcome

Retinal retinoblastoma growth phenotypes can be endophytic, exophytic, diffuse infiltrating or anterior diffuse. Herein, we describe a novel tumor growth pattern in two patients.. Imaging with spectral-domain optical coherence tomography (SD-OCT).. Both cases were diagnosed with unilateral group D retinoblastoma treated with first-line or bridge intra-arterial chemotherapy (IAC). Case 1 had a new intravitreal/epiretinal relapse 3 months after brachytherapy and intravitreal chemotherapy. SD-OCT showed a disruption of the inner limiting membrane (INL) underneath a parapapillary epiretinal seed. The intravitreal/epiretinal disease completely regressed with intravitreal melphalan. Three months later, an isolated intraretinal growth was documented on SD-OCT at the site of previously INL disruption, which was treated by thermotherapy. He remained disease-free at 1-year follow-up with 0.6 visual acuity. Case 2 was seen 2 months after treatment interruption due to the COVID-19 pandemic. Fundus examination showed a massive intravitreal/epipapillary invasion completely obscuring the papilla. Salvage treatment of this seeing eye consisted of combined intra-arterial and intravitreal melphalan and topotecan injections. An infraclinical papillary regrowth 4 months later was treated with additional IAC. Six months later, enucleation was performed due to an infraclinical papillary relapse with suspicion of intralaminar invasion. Histopathology showed retrolaminar optic nerve invasion with tumor-free surgical section. The child received four cycles of adjuvant chemotherapy and remained disease-free at 1-year follow-up.. Epiretinal/epipapillary vitreous seeding can be the source of a secondary intraretinal/optic nerve head relapse. SD-OCT is instrumental to follow such cases. Enucleation remains the safest option if secondary optic nerve invasion is suspected.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; COVID-19; Humans; Intravitreal Injections; Male; Melphalan; Neoplasm Recurrence, Local; Optic Nerve; Pandemics; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Tomography, Optical Coherence

Since 2006, ophthalmic artery chemosurgery (OAC) has been used for ocular-sparing treatment of retinoblastoma. Systemic exposure to melphalan is known to cause ovarian dysfunction, but the effect of melphalan-based OAC has not yet been determined. Here, we assess biochemical and symptomatic measures of ovarian function in a cohort of pubertal female survivors of retinoblastoma treated with melphalan-based OAC. These 13 patients all had normal gonadotropins at a median age of 11.1 years, 9.6 years from the completion of therapy. None had symptoms of ovarian dysfunction. This study provides initial evidence that ovarian function remains intact after melphalan-based OAC.

Topics: Carboplatin; Child; Electroretinography; Female; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Survivors; Topotecan; Treatment Outcome

In this case report we report our experience with rescue intra-arterial chemotherapy in a case of multi-relapsed peripapillary Retinoblastoma (RB) and the importance of high resolution MRI in detecting possible optic disc infiltration.. In 2007, a 14 month-old caucasian girl was referred to our ocular oncology unit for leukocoria. Only left eye was interested, with a single mass of the posterior pole. Patient underwent six cycles of systemic chemotherapy and focal laser consolidation. Several relapses occurred during follow-up. Selective intra-arterial chemotherapy (SIAC) with Melphalan was performed and type IV remission was achieved. A new relapse occurred next to the optic disc. MRI was performed and we decided to try to save the globe with a rescue cycle of SIAC.. MRI has demonstrated to be useful in decision making in RB, giving us a last chance to save the globe.

Topics: Decision Making; Female; Humans; Infant; Infusions, Intra-Arterial; Magnetic Resonance Imaging; Melphalan; Neoplasm Recurrence, Local; Retinal Neoplasms; Retinoblastoma; Treatment Outcome

Current melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort.. Rabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 μg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction.. retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan.. Intravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC. Taken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.

Topics: Animals; Antineoplastic Agents, Alkylating; Humans; Intravitreal Injections; Melphalan; Neoplasm Seeding; Rabbits; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan; Vitreous Body

To explore the risk factors for ophthalmic artery (OA) stenosis and occlusion after intra-arterial chemotherapy (IAC) with selective ophthalmic artery catheterisation (OAC) in the treatment of retinoblastoma.. Retrospective, single centre case-control study.. The study was conducted including consecutive patients with unilateral or bilateral intraocular retinoblastoma undergoing IAC between June 2016 and June 2019 with a follow-up time of 4 years. Main outcomes are rate of IAC-induced OA occlusion and OA diameter.. 346 attempted OAC infusions were successful. The total incidence of OA occlusion was 15.89%. The occlusion and control groups were similar in patients' age, sex and disease stage. Median OA diameter was 0.49 mm in those with OA occlusion, and 0.66 mm in those without occlusion. In the occlusion group, the OA diameter difference was significantly larger between the first IAC and the final IAC (0.22mm vs 0.12mm, p=0.001). In both groups, the median number of IAC treatments was 3. Multivariate Cox regression models included initial OA diameter (OR: 0.005, p=0.001), ratio of OA orifice diameter differences between first and last IAC to the initial OA orifice diameter (OR: 4.661, p=0.003), and number of IAC (OR: 1.538, p=0.042) as clinical features significantly associated with OA occlusion.. The OA diameter at first IAC treatment, the ratio of OA orifice diameter differences between first and last IAC to the initial OA orifice diameter and total number of IAC treatments may be three main clinical predictors for OA occlusion after IAC for retinoblastoma.

Topics: Case-Control Studies; Constriction, Pathologic; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Risk Factors; Treatment Outcome

To report our experience in the management of cataracts presumably due to intravitreal chemotherapy administration in eyes with vitreous disease associated with retinoblastoma.. This retrospective study consisted of a cohort of five eyes of five retinoblastoma patients who developed cataracts secondary to intravitreal chemotherapy administration and who then underwent cataract surgery. All patients underwent lensectomy and anterior vitrectomy with/without intraocular lens implantation via clear corneal approach. All cases were administered intraoperative intravitreal melphalan (35-40 mcg) and topotecan (10-20 mcg) at the end of cataract surgery as a preventive measure against retinoblastoma spread. Injections were repeated as needed in monthly follow-ups. Main outcome measures were enucleation rate and disease-free survival time.. The age at surgery ranged between 5 and 10 years. Follow-up time varied from 12 to 16 months. Treatment-free period before surgery ranged between 3 and 20 months. Time from last injection to cataract detection was: 2, 2, 10, 6, and 7 months; and time from last injection to cataract surgery was: 8, 3, 20, 7, and 15 months in cases 1-5, respectively. None of the eyes required enucleation. Tumor control was achieved in all patients at the end of follow-up.. Injection of melphalan and topotecan into anterior parts of the vitreous may lead to cataract formation. This can be safely managed with lensectomy and anterior vitrectomy and the use of intravitreal administration of melphalan and topotecan at the conclusion of the surgery as a precautionary measure against the potential risk of extraocular spread.

Topics: Antineoplastic Agents, Alkylating; Cataract; Child; Child, Preschool; Humans; Infant; Intravitreal Injections; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan; Vitreous Body

Topics: Antineoplastic Agents, Alkylating; Hemorrhage; Humans; Infant; Intravitreal Injections; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Carboplatin; Child, Preschool; Drug Therapy, Combination; Humans; Infusions, Intra-Arterial; Magnetic Resonance Imaging; Male; Melphalan; Ophthalmic Artery; Orbital Neoplasms; Retinal Neoplasms; Retinoblastoma; Topoisomerase I Inhibitors; Topotecan

Current melphalan-based regimens for intravitreal chemotherapy for retinoblastoma vitreous seeds are effective but toxic to the retina. Thus, alternative agents are needed. Based on the known biology of histone deacetylases (HDACs) in the retinoblastoma pathway, we systematically studied whether the HDAC inhibitor belinostat is a viable, molecularly targeted alternative agent for intravitreal delivery that might provide comparable efficacy, without toxicity.. In vivo pharmacokinetic experiments in rabbits and in vitro cytotoxicity experiments were performed to determine the 90% inhibitory concentration (IC90). Functional toxicity by electroretinography and structural toxicity by optical coherence tomography (OCT), OCT angiography, and histopathology were evaluated in rabbits following three injections of belinostat 350 µg (2× IC90) or 700 µg (4× IC90), compared with melphalan 12.5 µg (rabbit equivalent of the human dose). The relative efficacy of intravitreal belinostat versus melphalan to treat WERI-Rb1 human cell xenografts in rabbit eyes was directly quantified. RNA sequencing was used to assess belinostat-induced changes in RB cell gene expression.. The maximum nontoxic dose of belinostat was 350 µg, which caused no reductions in electroretinography parameters, retinal microvascular loss on OCT angiography, or retinal degeneration. Melphalan caused severe retinal structural and functional toxicity. Belinostat 350 µg (equivalent to 700 µg in the larger human eye) was equally effective at eradicating vitreous seeds in the rabbit xenograft model compared with melphalan (95.5% reduction for belinostat, P < 0.001; 89.4% reduction for melphalan, P < 0.001; belinostat vs. melphalan, P = 0.10). Even 700 µg belinostat (equivalent to 1400 µg in humans) caused only minimal toxicity. Widespread changes in gene expression resulted.. Molecularly targeted inhibition of HDACs with intravitreal belinostat was equally effective as standard-of-care melphalan but without retinal toxicity. Belinostat may therefore be an attractive agent to pursue clinically for intravitreal treatment of retinoblastoma.

Topics: Animals; Annexin A5; Antineoplastic Agents, Alkylating; Disease Models, Animal; Electroretinography; Fluorescein Angiography; Histone Deacetylase Inhibitors; Hydroxamic Acids; Intravitreal Injections; Maximum Tolerated Dose; Melphalan; Neoplasm Seeding; Rabbits; Retina; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Sulfonamides; Tomography, Optical Coherence; Vitreous Body; Xenograft Model Antitumor Assays

To compare retinal toxicity as measured by electroretinogram, ocular, and patient survival in retinoblastoma treated with intravitreal melphalan at two concentrations (25 vs. 30 µg).. Single-center, retrospective analysis of retinoblastoma eyes receiving 25-µg or 30-µg intravitreal melphalan from September 2012 to January 2019. Ocular toxicity was measured by electroretinogram of evaluable injections in 449 injections in 136 eyes. A repeated-measures linear mixed model with a random intercept and slope was applied to account for repeated measures for each eye.. Average decline in electroretinogram after each additional injection was -4.9 µV (95% confidence interval -6.3 to -3.4); electroretinogram declined by -4.6 µV (95% confidence interval -7.0 to -2.2) after 25-µg injections and -5.2 µV (95% confidence interval -6.6 to -3.8) after 30-µg injections (P = 0.66). Injection at a new clock site hour was associated with a -3.91-µV lower average (95% confidence interval -7.8 to -0.04).. Electroretinogram-measured toxicity in retinoblastoma eyes treated with intravitreal injections was not found to be different across 25-µg and 30-µg injections. There were no cases of extraocular extension or metastatic deaths in our patient population.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Child; Child, Preschool; Electroretinography; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Treatment Outcome; Vitreous Body

Intravitreal injections of topotecan are used in the management of retinoblastoma with vitreous seeds. This study evaluated whether intravitreal topotecan was associated with retinal toxicity.. Retrospective cohort study of patients with retinoblastoma who were treated with intravitreal topotecan at Memorial Sloan Kettering Cancer Center between December 2014 and May 2019. Electroretinogram (ERG) responses under anaesthesia were measured immediately before treatment with intravitreal topotecan and at the next visitor approximately one-month. Ocular toxicity was defined by a decrease in the ERG response at 30 Hz at follow-up.. Ocular toxicity was evaluated by ERG on 50 evaluable injections administered to 28 eyes. 22 (44.0%) injections were performed with concurrent intravitreal melphalan. The median time to ERG measurement following an injection was 27 days. By using a paired t-test, intravitreal topotecan combined with melphalan (n=22) at a dose of 25 μg or 30 μg was associated with a significant decrease in ERG amplitude at follow-up (p=0.046, 95% CI -20.4 μV to -0.2 μV). Among eyes that only received topotecan (n=28) at doses of 20 μg or 30 μg, there was not a significant difference in ERG amplitude measured (p=0.85, 95% CI -7.0 μV to 5.8 μV).. Intravitreal topotecan combined with intravitreal melphalan was associated with a decrease in ERG amplitude; there was not a significant decrease in ERG amplitude observed in patients who received topotecan alone. These findings suggest that intravitreal topotecan injections at doses of 20 μg or 30 μg are not associated with retinal toxicity in patients with retinoblastoma.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Electroretinography; Female; Follow-Up Studies; Humans; Infant; Intravitreal Injections; Male; Melphalan; Retina; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topoisomerase I Inhibitors; Topotecan

The "cavitary" form of retinoblastoma has historically demonstrated minimal treatment response with intravenous chemoreduction, showing less robust regression and less reduction in tumor size. Intra-arterial chemotherapy (IAC) has been reported to more effectively treat retinoblastoma, allowing many previously unsalvageable eyes to now be saved. The purpose was to report treatment response of cavitary retinoblastoma tumors to IAC.. Retrospective case series.. Patients presenting with cavitary retinoblastoma who were treated with IAC.. Retrospective case series of all patients presenting with cavitary retinoblastoma between August 2014 and January 2019 who were treated with primary IAC.. Tumor regression, recurrence, resolution of vitreous and subretinal seeds, number of treatments required, globe salvage, metastasis, and death.. Eight cavitary retinoblastoma tumors in 6 eyes of 4 patients were treated with IAC. One hundred percent of the cavitary tumors regressed (8/8 tumors, in 6/6 eyes), and 100% of vitreous and subretinal seeds regressed, with 100% globe salvage. None of the tumors recurred, no patients developed metastases, and no patients died. Eyes were treated with a median of 4.5 cycles of IAC (range, 1-7), with fewer IAC treatments used in the later patients (1-3 treatments per eye for the most recent 3 eyes, compared with 6-7 treatments per eye for the earliest 3 eyes). Mean reduction in thickness was 73.4% (range, 59.7%-84.6%). Mean reduction in basal diameter was 45.5% (range, 24.8%-56.0%).. Treatment with IAC results in regression of cavitary retinoblastoma, often with greater reduction in tumor size than has been reported previously with intravenous chemotherapy (IVC). Using up-front triple therapy (e.g., melphalan 0.4 mg/kg, carboplatin 50 mg, and topotecan 2 mg) and noting certain subtle signs of early regression can help to minimize unnecessary additional cycles of treatment.

Topics: Antineoplastic Agents; Carboplatin; Female; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Time Factors; Topoisomerase I Inhibitors; Topotecan; Treatment Outcome; Ultrasonography

To identify risk factors for acute choroidal ischemia (ACI) after intra-arterial chemotherapy (IAC) for retinoblastoma.. Retrospective cohort study.. Two hundred twenty patients (248 eyes) treated with IAC in Lausanne between November 2008 and September 2019 (665 procedures). All patients were evaluated on a monthly basis with fundus photography and fluorescein angiography before and after each IAC injection.. Acute choroidal ischemia, defined as any new choroidal ischemia clinically diagnosed within 35 days after an IAC injection, were noted. Eyes with choroidal complications diagnosed later than 35 days after the last IAC injection (n = 7) or those for which the status of the choroid was not assessable (n = 35) were excluded. Specific procedure parameters and treatment regimens were compared between the group of eyes with and without ACI.. Procedure-related risk factors for ACI after IAC injection and visual acuity assessment in the group of eyes with ACI.. Acute choroidal ischemia developed in 35 of 206 included eyes after a mean of 2 injections. No differences were found between the two study groups regarding age at first IAC injection, disease grouping at diagnosis, previously administered treatments, number of IAC injections, drug dose, mean injection time, injection method (pulsatile vs. continuous), or concomitant intravitreal melphalan use. Treatment regimen (melphalan vs. combined melphalan plus topotecan; P < 0.05), catheterization route (internal carotid artery vs. external carotid or posterior communicating artery; P < 0.001), and catheterization type (occlusive into the ophthalmic artery [OA] vs. nonocclusive; P < 0.001) were included in multivariate analysis, and occlusive catheterization was identified as an independent risk factor for ACI (P < 0.001). In the subgroup undergoing an occlusive procedure, placement of the catheter tip into the OA distal third versus medial and proximal thirds (P = 0.04) and a mean catheter diameter-to-OA lumen ratio of 0.6 or more (P < 0.001) were correlated significantly with ACI. Complete vision loss was noted in 27% of the eyes with ACI that were old enough for visual assessment (n = 9/33), whereas 33% maintained a useful vision ranging between 0.1 and 0.8 (n = 11/33).. Catheterization of the OA should be attempted from an ostial position or an external carotid approach to minimize the risk of potentially vision-threatening choroidal complications.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Agents, Alkylating; Catheterization; Child; Choroid; Female; Fluorescein Angiography; Humans; Incidence; Infusions, Intra-Arterial; Ischemia; Male; Melphalan; Middle Aged; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Risk Factors; Visual Acuity

To evaluate the effect of adding topotecan to melphalan for the treatment of retinoblastoma using intra-arterial chemotherapy (IAC).. Single-center, consecutive case series.. All eyes treated with IAC at the University of Siena, Siena, Italy, from 2008 to 2019.. Eyes were treated via IAC with either melphalan monotherapy or melphalan plus topotecan. The characteristics and outcomes of these 2 groups were compared.. The main outcome measure was globe salvage rate. Additionally, a complete summary of all adverse events for all eyes was compared between groups and included local, regional, and systemic events causing both transient and permanent effects.. A total of 193 patients and 208 eyes were treated with IAC between April 2008 and October 2019. Melphalan alone (MA) was used to treat 44 patients and 50 eyes for a total of 191 procedures. The combination of melphalan plus topotecan (MPT) was used to treat 149 patients and 158 eyes for a total of 780 procedures. Groups were similar in terms of age at presentation. The MPT group included more advanced eyes (P < 0.001) and had shorter follow-up time (mean 47 vs. 120 months in the MA group, P < 0.001). The MPT group required less laser and cryotherapy after treatment (32% of eyes vs. 50% of eyes in the MA group, P < 0.001); there was no other difference in the number of adjuvant treatments required between groups. There was no difference in the number of acute adverse events, both systemic and local, between groups. There was no difference in the number of transient or permanent intraocular side effects between groups. Kaplan-Meier survival analysis estimated a better globe salvage rate in the MPT group (66%) compared with the MA group (58%, P = 0.05).. In this case series, the addition of topotecan to melphalan did not alter the IAC side effect profile and may contribute to improved globe salvage.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; Humans; Infant; Injections, Intra-Arterial; Male; Melphalan; Prospective Studies; Retina; Retinal Neoplasms; Retinoblastoma; Topoisomerase I Inhibitors; Topotecan; Treatment Outcome

Selective ophthalmic artery infusion chemotherapy has improved ocular outcomes in children with retinoblastoma. Our aim was to correlate quantitative tumor reduction and dichotomous therapeutic response with technical and adjunctive factors during selective ophthalmic artery infusion chemotherapy for retinoblastoma. An understanding of such factors may improve therapeutic efficacy.. All patients with retinoblastoma treated by selective ophthalmic artery infusion chemotherapy at a single center during a 9-year period were reviewed. Only first-cycle treatments for previously untreated eyes were studied. Adjunctive factors (intra-arterial verapamil, intranasal oxymetazoline external carotid balloon occlusion) and technical factors (chemotherapy infusion time, fluoroscopy time) were documented by medical record review. Quantitative tumor reduction was determined by blinded comparison of retinal imaging acquired during examination under anesthesia before and 3-4 weeks after treatment. The dichotomous therapeutic response was classified according to quantitative tumor reduction as satisfactory (≥ 50%) or poor (<50%).. Twenty-one eyes met the inclusion criteria. Patients ranged from 2 to 59 months of age. Adjuncts included intra-arterial verapamil in 15, intranasal oxymetazoline in 14, and external carotid balloon occlusion in 14. Quantitative tumor reduction ranged from 15% to 95%. Six showed poor dichotomous therapeutic response. A satisfactory dichotomous therapeutic response was correlated with intra-arterial verapamil (. Intra-arterial verapamil during selective ophthalmic artery infusion chemotherapy is correlated with an improved therapeutic response, particularly when treating with lower doses of single-agent melphalan.

Topics: Antineoplastic Agents, Alkylating; Child; Child, Preschool; Cohort Studies; Female; Fluoroscopy; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Treatment Outcome; Vasodilator Agents; Verapamil

Topics: Antineoplastic Agents, Alkylating; Choroid; Humans; Infant; Injections, Intra-Arterial; Melphalan; Neoplasm Invasiveness; Ophthalmic Artery; Retinoblastoma

The use of intravitreal chemotherapy has revolutionized the treatment of advanced intraocular retinoblastoma, as intravitreal melphalan has enabled difficult-to-treat vitreous tumor seeds to be controlled, leading to many more eyes being saved. However, melphalan hydrochloride (MH) degrades rapidly in solution, increasing logistical complexity with respect to time between medication preparation and administration for intravitreal administration under anesthesia for retinoblastoma. A new propylene glycol-free melphalan (PGFM) formulation has greater stability and could therefore improve access and adoption of intravitreal chemotherapy, allowing more children to retain their eye(s). We compared the efficacy and toxicity of both formulations, using our rabbit xenograft model and clinical patient experience. Three weekly 12.5 μg intravitreal injections of MH or PGFM (right eye), and saline (left eye), were administered to immunosuppressed rabbits harboring human WERI-Rb1 vitreous seed xenografts. Residual live cells were quantified directly, and viability determined by TUNEL staining. Vitreous seeds were reduced 91% by PGFM (p = 0.009), and 88% by MH (p = 0.004; PGFM vs. MH: p = 0.68). All residual cells were TUNEL-positive (non-viable). In separate experiments to assess toxicity, three weekly 12.5 μg injections of MH, PGFM, or saline were administered to non-tumor-bearing rabbits. Serial electroretinography, optical coherence tomography (OCT) and OCT-angiography were performed. PGFM and MH both caused equivalent reductions in electroretinography amplitudes, and loss of retinal microvasculature on OCT-angiography. The pattern of retinal degeneration observed on histopathology suggested that segmental retinal toxicity associated with all melphalan formulations was due to a vitreous concentration gradient-effect. Efficacy and toxicity were assessed for PGFM given immediately (within 1 h of reconstitution) vs. 4 h after reconstitution. Immediate- and delayed-administration of PGFM showed equivalent efficacy and toxicity. In addition, we evaluated efficacy and toxicity in patients (205 eyes) with retinoblastoma vitreous seeds, who were treated with a total of 833 intravitreal injections of either MH or PGFM as standard of care. Of these, we analyzed 118 MH and 131 PGFM monotherapy injections in whom serial ERG measurements were available to model retinal toxicity. Both MH and PGFM caused reductions in electroretinography amplitudes, but with no statistical differ

Topics: Animals; Antineoplastic Agents, Alkylating; Electroretinography; Female; Fluorescein Angiography; Humans; In Situ Nick-End Labeling; Infant; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Pharmaceutical Preparations; Rabbits; Retina; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Tomography, Optical Coherence; Treatment Outcome; Tumor Cells, Cultured; Vitreous Body; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents, Alkylating; Edema; Female; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Orbital Diseases; Retinal Neoplasms; Retinoblastoma; Tomography, X-Ray Computed

To evaluate tumor control and globe salvage following intra-arterial chemotherapy (IAC) for retinoblastoma based on International Classification of Retinoblastoma (ICRB) and patient demographics.. The medical records of 313 patients (341 eyes) treated with IAC were reviewed retrospectively. Chemotherapy agents included melphalan, topotecan, and carboplatin. Comparative analysis was performed for tumor control and globe salvage based on ICRB and patient demographics including age (≤12 vs >12 months), race (white vs nonwhite), and sex.. Of the 341 eyes treated with 1,292 consecutive infusions of IAC as primary or secondary therapy for retinoblastoma, Kaplan-Meier 5-year estimates of globe salvage was 74%. Of those treated with IAC as primary therapy (n = 160 eyes; 655 infusions), 5-year globe salvage overall was 76%: and more specifically, 100% for groups B and C, 86% for group D, and 55% for group E. Of those treated with IAC as secondary therapy (n = 207 eyes; 859 infusions), 5-year globe salvage was 71%. Comparative analysis by race and sex demonstrated no differences in outcomes, but analysis by age revealed that younger patients had a higher rate of globe salvage (77% vs 72%; P < 0.001). Complications (per catheterization) included retina ischemia (1%), choroidal ischemia (1%), neovascularization of the disk, retina, iris (NVI), glaucoma (about 1% each), and central/peripheral systemic ischemia (<1%). Younger patients showed less NVI (P = 0.028), white patients showed less retinal ischemia (P = 0.037), and no difference by sex. There were no patients with metastatic disease or death.. Our results suggest that IAC provides substantial tumor control for advanced and/or recurrent retinoblastoma with a high rate of globe salvage and few complications. There was little difference in outcomes per age, race, and sex.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Neoplasm Recurrence, Local; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Treatment Outcome

To demonstrate histopathological findings in retinoblastoma eyes enucleated after intra-arterial chemotherapy (IAC) with special emphasis on vascular toxicity and local tumour control.. Retrospective study with a consecutive series of 23 retinoblastoma eyes enucleated after IAC where histopathological work-up was available.. From November 2010 to June 2019 23 eyes were enucleated after the attempt of eye salvaging therapy with IAC using melphalan. IAC was the first line treatment in nine and salvage treatment in 14 eyes. Doses of melphalan ranged from 3 to 7.5 mg, whereby a strict protocol with age-appropriate dosage was not used until 2015. The mean number of treatment cycles was 1.8. The main indications for enucleation were poor treatment response or tumour progression in 14 eyes, severe vascular complications in five eyes and a total exudative retinal detachment with amaurosis in the remaining four eyes. We found active disease in 15 eyes with an indication for adjuvant chemotherapy due to high risk factors for metastases in four eyes. To date none of these patients developed metastatic disease. Concerning vascular toxicity, we detected a central retinal artery occlusion in three eyes, severe vasculitis in another three, ischaemic outer retina atrophy and choroidal ischaemia in seven eyes with one eye developing a severe proliferative retinopathy.. IAC is a highly effective treatment option for advanced retinoblastoma, but the described potential risks should be kept in mind. These include severe vascular complications, as well as the possibility of persisting vital tumour cells fulfilling high-risk criteria for adjuvant chemotherapy.

Topics: Antineoplastic Agents, Alkylating; Brachytherapy; Child, Preschool; Cryotherapy; Eye Enucleation; Female; Fluorescein Angiography; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Salvage Therapy

Retinoblastoma is a rare intraocular malignancy in children. Current treatments have many adverse effects. New therapeutic approaches like intravitreal injections of chemotherapies are currently being developed but their toxicities need to be evaluated on animal models. This study compares the efficacy and toxicity of intravitreal melphalan, topotecan and carboplatin, alone or in combination (sequential administration), in the LHBetaTag retinoblastoma mice.. Mice were divided into nine groups: control, carboplatin 1.5 and 4 μg, melphalan 0.1 and 1 μg, topotecan 0.1 and 1 μg, carboplatin 4 μg/topotecan 0.1 μg and melphalan 1 μg/topotecan 0.1 μg. The follow-up was performed using fundus imaging and optical coherence tomography combined with histopathological analysis. Absence of tumour and presence of calcified tumours were the criteria for therapeutic response assessment. Ocular complications were assessed after four weekly injections. Retinal toxicity was defined by the decrease of retinal thickness and of the number of retinal layers.. Topotecan was inactive on retinal tumours. Melphalan (1 μg) led to a complete tumour control in 91.7% of eyes. Carboplatin strongly decreased the tumour burden (85.7-93.8% of eyes without retinal tumour). The intravitreal injection itself led to ocular complications (25% of media opacities and 45.7% of retinal detachment). Only melphalan at 1 μg showed a strong retinal toxicity. The two combinations showed a good efficacy in reducing the number of eyes with retinal tumours with a reduced retinal toxicity.. This preclinical study suggests that intravitreal injection of carboplatin has a low toxicity and could be evaluated in clinical practice to treat patients suffering from retinoblastoma.

Topics: Animals; Carboplatin; Humans; Intravitreal Injections; Melphalan; Mice; Retina; Retinal Neoplasms; Retinoblastoma; Retrospective Studies

This study determined the outcomes of selective intraarterial chemotherapy (IAC) for the treatment of Retinoblastoma in Pakistan. Single centre, prospective, interventional case series of three consecutive eyes were diagnosed as unilateral Retinoblastoma. Patients underwent IAC with Melphalan (0.5mg/kg) at Lahore General Hospital from July 2017 to January 2018. Selective ophthalmic arterial infusion was carried out in all 3 cases. Patients were evaluated on 1st, 3rd and 10th postoperative day and then at 4 weeks interval, till date. Among three eyes, 2(66.6%) were of stage C and 1(33.3%) of stage D. After 3 cycles of intra-arterial chemotherapy, full regression of the lesion was observed in all the eyes (100%). Complete regression and calcification of tumour was seen in 1 (33.3%) eye at 1 month post-treatment and 2 eyes at 2 months post-treatment. Globe was preserved in all 3 (100%) cases. Notable complications included eyelid oedema, orbital congestion and skin hyperaemia. None of the patients had any systemic side effects. Intra-arterial chemotherapy (IAC) is an effective modality for the treatment of Retinoblastoma and it plays a cardinal role in preservation of integrity of the globe.

Topics: Antineoplastic Agents; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Pakistan; Prospective Studies; Retinal Neoplasms; Retinoblastoma

Tractional retinal detachment with or without secondary tear is a rare complication reported in less than 0.5% of in eyes treated for retinoblastoma. Pars plana vitrectomy (PPV) in eyes with history of retinoblastoma has been associated with a significant risk for recurrence, extraocular spread, and systemic metastases. We report here the successful management by PPV under melphalan irrigation of 2 children presenting with tractional retinal detachment after retinoblastoma therapy and scleral buckle surgery.. A 7-year-old girl with a history of bilateral retinoblastoma (group D) presented with light perception best-corrected visual acuity (BCVA) and tractional retinal detachment (RD) in her left eye, 3 years after the last intra-arterial chemotherapy (IAC) injection. Moreover, she had history of left eye rhegmatogenous RD treated by scleral buckle 1 month after the last IAC and cataract surgery 12 months later. PPV associated with retinectomy, laser photocoagulation and silicone oil tamponade was performed. Silicone oil was removed 4 months later. Fifteen months after PPV, BCVA had increased to 20/32 without recurrence of RD and no evidence of tumor activity. A 7-year-old boy with a history of unilateral retinoblastoma (group D) in his left eye presented with rhegmatogenous RD 21 months after the last treatment for retinoblastoma. Scleral buckle surgery was performed, but 3 weeks later the patient presented with tractional RD associated with proliferative vitreo-retinopathy. BCVA was counting fingers. PPV associated with membrane peel, laser photocoagulation and silicone oil tamponade was performed. Silicone oil was removed after 5 months followed by cataract surgery 5 months later. Twenty months after PPV, BCVA was 20/20 and there was no sign of tumor recurrence.. PPV under melphalan irrigation, with retinectomy, if necessary, and silicone oil tamponade, allows anatomical and functional improvement in eyes with history of retinoblastoma and scleral buckling developing tractional RD.

Topics: Child; Child, Preschool; Female; Humans; Male; Melphalan; Myeloablative Agonists; Retinal Detachment; Retinal Neoplasms; Retinoblastoma; Therapeutic Irrigation; Tomography, Optical Coherence; Vitrectomy

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.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Humans; Infant; Intravitreal Injections; Melphalan; Pharmacists; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Vitreous Body

Although intra-arterial chemotherapy (IAC) is commonly used for treating intraocular retinoblastoma, it is not a systemic therapy. We aimed to investigate whether the addition of intravenous chemotherapy (IVC) before IAC administration had any effects (whether beneficial or adverse) on patient outcomes.. This multicenter retrospective cohort study included 213 patients with advanced intraocular retinoblastoma who received IVC plus IAC (n = 103) or IAC alone (n = 110) between April 2009 and January 2017. Eyes were grouped according to the International Intraocular Retinoblastoma Classification. Kaplan-Meier and Cox regression analyses were performed to compare survival outcomes between the two groups. Moreover, details regarding enucleation were recorded.. The 3-year ocular survival rates were 62% in the IVC plus IAC group and 68% in the IAC group (hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.55-1.43, P = 0.61). Moreover, the corresponding 3-year overall survival rates were 97% and 93%, respectively (HR 1.56, 95% CI 0.41-5.90, P = 0.51), while the 3-year event-free survival rates were 76% and 72%, respectively (HR 0.96, 95% CI 0.56-1.65, P = 0.89).. Within a 3-year follow-up period, IVC plus IAC produced no additional benefit over primary IAC for treating advanced intraocular retinoblastoma in terms of local tumor control and extending survival. Longer follow-up periods are required to assess long-term efficacy.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Etoposide; Female; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; Infusions, Intravenous; Intraocular Pressure; Male; Melphalan; Middle Aged; Prognosis; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Survival Rate; Vincristine; Young Adult

To report our first three-and-a-half years' experience with intra-arterial chemotherapy (IAC) in managing retinoblastoma (RB).. Single institution, retrospective, interventional case series of 14 retinoblastoma patients managed with IAC from December 2014 to June 2018. Demographics were described. Outcomes measures were tumor response, treatment complications and globe salvage.. Subjects' mean age at the first administration of IAC was 31.4 months. 57.1% of the eyes were Group D and E retinoblastoma, while 79% were bilateral disease. 93% of the eyes were as secondary treatment. Of 32 IAC cannulations performed, 23 (71.8%) were successful and received chemotherapy drug melphalan. Each eye received a mean of 1.8 (range 1-4) IAC injections. 53% of the eyes showed regression post treatment. After a mean follow up period of 19 months, globe salvage rate was 38%. Most of the adverse effects experienced were localized and transient.. IAC has provided an added recourse in the armamentarium of retinoblastoma treatment in our center. IAC treatment is a viable alternative in the treatment of retinoblastoma to salvage globe, for eyes that would conventionally require enucleation especially in bilateral disease.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Female; Humans; Infant; Infusions, Intra-Arterial; Malaysia; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Salvage Therapy; Treatment Outcome

To evaluate clinical outcomes and enucleation rates after intravitreal melphalan (IVM) alone and after IVM combined with intravitreal topotecan (IVT) for the treatment of vitreous disease, and to a lesser extent subretinal and retrohyaloid seeds, in patients with retinoblastoma.. A retrospective analysis of 77 eyes of 72 consecutive patients.. Demographic data, classification of tumors, seed type (dust, sphere or cloud) before injection and at the end of follow-up, injection type (IVM or IVM+IVT), doses of IVM and IVT, number of injections, follow-up time, enucleation status and side effects were recorded. Cox regression analysis and log-rank test for Kaplan-Meier curves were performed.. Of 77 eyes, 40 received IVM alone (group 1) and 37 received IVM+IVT (group 2). Enucleation rates were 62.5% (n=25) in group 1 and 10.8% (n=4) in group 2 (p=0.001). Median eye survival was 23.6 months in group 1 and 25.6 months in group 2. Mantel-Cox test revealed statistically significant differences between Kaplan-Meier curves of group 1 and 2 (p=0.022). Multiple Cox regression analysis showed a significantly elevated enucleation rate associated with: IVM only treatment group (p=0.019) and pre-injection cloud type of seeding (p=0.014).. The combined use of intravitreal melphalan and topotecan provides significantly better results in terms of avoiding enucleation and vitreal and subretinal seed control.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Drug Therapy, Combination; Eye Diseases; Eye Enucleation; Female; Follow-Up Studies; Humans; Infant; Intravitreal Injections; Kaplan-Meier Estimate; Male; Melphalan; Neoplasm Seeding; Proportional Hazards Models; Retinal Diseases; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topoisomerase I Inhibitors; Topotecan; Treatment Outcome; Vitreous Body

To evaluate the treatment outcomes of an alternative retrograde superselective ophthalmic artery catheterization (intra-arterial chemotherapy [IAC]), while treating retinoblastoma patients.. A retrospective review of IAC for 21 treatment-naïve eyes (21 patients, primary group) and 10 eyes of previously treated 9 patients (secondary group). Statistical analysis was performed using Number Cruncher Statistical System 2007, Kaplan-Meier survival analysis, and Fisher's exact test.. Total fluoroscopy time ranged from 3 to 12 minutes. Globe salvage was 71.4% (15/21 eyes) and 80% (8/10 eyes) in the primary and secondary groups, respectively. Globe salvage rates were recorded as 100%, 100%, 70%, and 0% for group B, C, D, and E patients, respectively.. Retrograde IAC is effective in tumour control with shorter fluoroscopy time and acceptable complication rates both for naïve and treated patients. Furthermore, controlling retinoblastoma in advanced group D eyes was efficacious.

Topics: Humans; Infant; Infusions, Intra-Arterial; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Tertiary Care Centers

Intra-arterial chemotherapy for retinoblastoma has dramatically altered the natural history of the disease. The remarkable outcomes associated with a high safety profile have pushed the envelope to offer treatment for patients weighing ≤10 kg. The purpose was to determine the efficacy and safety of IAC infusions performed in infants weighing ≤10 kg with intraocular retinoblastoma.. A retrospective chart review was performed for patients diagnosed with retinoblastoma and managed with intra-arterial chemotherapy.. The total study cohort included 207 retinoblastoma tumors of 207 eyes in 196 consecutive patients who underwent 658 intra-arterial chemotherapy infusions overall. Of these, patient weights were ≤10 kg in 69 (35.2%) and >10 kg in 127 (64.8%) patients. Comparison (≤10 kg versus >10 kg) revealed that the total number of intra-arterial chemotherapy infusions was 222 versus 436. Periprocedural complications were not significantly different (2 [0.9%] versus 2 [0.5%];. Intra-arterial chemotherapy in patients weighing ≤10 kg is a safe and effective treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan; Treatment Outcome

Intravitreal melphalan injections are commonly used in the treatment for intraocular retinoblastoma. This study compares retinal toxicity and ocular survival between two formulations, with and without propylene glycol (Alkeran vs. Evomela, respectively).. A retrospective cohort study of retinoblastoma patients who received intravitreal injections of Alkeran and Evomela at 30 μg from September 2012 to January 2019 at a single tertiary care center were enrolled. Retinal toxicity was measured using electroretinogram (ERG) and compared using a multivariate analysis of 338 injections in 101 eyes of 96 patients. Ocular survival of 163 eyes in 150 patients was compared across formulations using Cox proportional hazards model. Eyes were censored at the time a patient received a dose other than 30 μg.. Overall, ERG decline (mean, 95% CI) for each injection was -5.58 μV (-7.17, -3.99). No significant differences in ERG decrement were found between Alkeran (with alcohol) -5.52uV (-6.99, -4.05). and Evomela (without alcohol) -5.65uV (-8.31 to -2.98) formulations (p = 0.93). Ocular survival at 24 months was 93.6% (95% CI 86.2, 97.1) with alcohol and 91.7% (95% CI 53.9, 98.8) without alcohol. The hazard ratio (HR) for without vs with alcohol was 0.50 (95% CI 0.06 to 4.07); no significant difference in ocular survival was found between formulations (p = 0.52).. No differences were found in retinal toxicity and ocular survival between 30 μg intravitreal injections of Alkeran or Evomela for intraocular retinoblastoma. Given the increased stability of Evomela, intravitreal treatment could be expanded to centers without the ability to supply Alkeran due to its shorter safety window; however, Alkeran is less expensive. For those with existing infrastructure, Alkeran is a comparable, cost-effective alternative.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Child; Child, Preschool; Humans; Infant; Intravitreal Injections; Melphalan; Retina; Retinal Neoplasms; Retinoblastoma; Treatment Outcome

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Female; Humans; Infant; Intravitreal Injections; Macular Edema; Male; Melphalan; Retina; Retinal Neoplasms; Retinoblastoma; Tomography, Optical Coherence; Visual Acuity

Survivin stands out as one of the most specific cancer targets discovered to date. Although single inhibition, e.g. through small interfering RNA (siRNA), has shown modest results in clinical trials, its combination with drugs holds promise to sensitize cancer cells to chemotherapeutics. In this study, we propose a sequential treatment of siRNA survivin followed by chemotherapy. Firstly, we demonstrated that siRNA-loaded switchable lipid nanoparticles (siLNP) silence survivin in a panel of cancer cell lines. Subsequently, we selected retinoblastoma (RB) as our model to screen four chemotherapeutic agents: carboplatin, topotecan, melphalan or teniposide. The effect of drugs on survivin expression and caspase-3 was investigated by RT-qPCR. The best drug combination was selected measuring the viability, survivin expression and the selectivity of the treatment. Our stepwise method revealed that siRNA delivery by switchable LNP sensitized Y79, but not the healthy APRE-19 cell line, to carboplatin and melphalan cytotoxicity. This ability was validated on primary human RB cells. Finally, the distinct behavior of the drugs demonstrated that a diligent screening of drugs should be envisioned when looking for synergy with survivin. Our sequential approach highlighted carboplatin and melphalan as agents to be investigated in future survivin-associated in vivo testing to tackle RB.

Topics: Apoptosis; Carboplatin; Cell Line, Tumor; Humans; Inhibitor of Apoptosis Proteins; Melphalan; Retinal Neoplasms; Retinoblastoma; RNA, Small Interfering; Survivin

Topics: Antineoplastic Agents, Alkylating; Cell Line, Tumor; Cell Survival; Drug Liberation; Humans; Magnetic Resonance Spectroscopy; Melphalan; Micelles; Models, Biological; Polymers; Retinoblastoma

Intra-arterial chemotherapy (IAC) has emerged as an effective treatment for retinoblastoma (RB) however, little information exists regarding its use in older patients (>5 years). In the present study, we evaluate the use of IAC (2008-2018) for RB in older patients and compare the outcomes to those in the prechemotherapy (<1994) and intravenous chemotherapy (IVC) (1994-2007) eras.. A retrospective analysis of all patients older than 5 years treated with IAC for RB from 2008-2018. Comparisons were made to 26 active RB cases in older children treated in the prechemotherapy era and to 12 active RB cases treated in the IVC era.. There were 13 eyes with RB in 13 older patients treated in the IAC era. The median patient age was 6.8 years. Tumor response was achieved in all 13 eyes at a median interval of 1.1 months from first IAC. Globe salvage was achieved in eight eyes with five eyes requiring enucleation. At 14 months, median follow-up after IAC, there was no metastasis or death. Compared to the prechemotherapy era, those in the IAC era demonstrated significant reduction in need for enucleation (P < 0.001) and EBRT or enucleation (P < 0.001). Compared to the IVC era, there was significant reduction in need for EBRT (P = 0.02) and EBRT or enucleation (P = 0.03) and similar avoidance of metastasis (P > 0.99) and death (P > 0.99).. Older patients with RB managed in the IAC era demonstrated reduced need for EBRT or enucleation compared to those managed in the IVC or prechemotherapy eras, with no instance of metastasis or death.

Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Carboplatin; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Intravitreal Injections; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topoisomerase I Inhibitors; Topotecan; Treatment Outcome; Young Adult

Ophthalmic artery chemosurgery (OAC) has changed the face of retinoblastoma treatment and led to a higher rate of globe salvage. The introduction of intravitreal chemotherapy (IVitC) has further enhanced globe salvage with increased success in treatment of intravitreal seeds. Our group has seen success at treating non-vitreous disease that is refractory to OAC using IVitC. This study was undertaken to quantify and report on this success.. A retrospective review was used to identify patients treated with IVitC for indications other than vitreous seeds from two centres. The indication, prior and concurrent treatment, response time and duration of treatment were documented. Kaplan-Meier estimates were used to evaluate ocular and recurrence-free survival. Ocular toxicity was evaluated using the 30 Hz flicker electroretinogram (ERG). Continuous and categorical variables were compared with Student's t-test and χ. Fifty-six eyes from 52 retinoblastoma patients were identified. There were no disease-related or treatment-related deaths. One patient developed a second primary malignancy (pinealoblastoma) and subsequent leptomeningeal spread. Ninety-eight per cent of the eyes showed clinical regression. Recurrence was seen in 14.3%. Of the recurrences, five occurred in retinal tumours and three in subretinal seeds. The Kaplan-Meier estimated risk of recurrence in all patients treated was 83.5% (95% CI 7.9 to 14.1) at 10 months. The mean change in ERG over treatment course was -17.7 μV.. Intravitreal chemotherapy is successful for the treatment of subretinal seeds and recurrent retinal tumours and could be considered as adjunctive therapy in globe-sparing treatment of retinoblastoma.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Child; Drug Implants; Electroretinography; Female; Follow-Up Studies; Humans; Incidence; Intravitreal Injections; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Ophthalmoscopy; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Slit Lamp Microscopy; Treatment Outcome; United States; Young Adult

To determine whether treatment order affects ophthalmic vascular event rates after intra-arterial chemotherapy (IAC) for retinoblastoma.. Patients who received IAC as primary or secondary treatment for retinoblastoma from January 2009 to January 2018 were included. All eyes were imaged with fundus photography and fluorescein angiography. Patient characteristics and vascular event rates were compared using t-test and Fisher's exact test.. There were 196 patients treated with 682 infusions of IAC, divided into primary (no previous therapy, 98 eyes of 98 patients, 328 infusions) and secondary (after other therapy, 105 eyes of 98 patients, 354 infusions) treatment. Overall, ophthalmic vascular events were found after 5% of infusions (17% eyes). A comparison of ophthalmic vascular events (primary vs. secondary IAC), with mean three infusions per eye (median 3, range 1-7), revealed no difference in overall percentage of eyes affected (18% vs. 15%, P = 0.57). Adverse vascular events per eye included retinal vasculature attenuation (1% vs. 0%, P = 0.99), peripheral retinal pruning (1% vs. 0%, P = 0.99), branch retinal artery occlusion (0% vs. 1%, P = 0.99), central retinal artery occlusion (0% vs. 1%, P = 0.99), macular ischemia (0% vs. 2%, P = 0.51), vitreous hemorrhage (2% vs. 3%, P = 0.92), subretinal hemorrhage (1% vs. 0%, P = 0.99), retinal pigment epithelium atrophy (6% vs. 3% P = 0.43), choroidal atrophy (4% vs. 2%, P = 0.92), optic disk pallor (1% vs. 0%, P = 0.99), and ophthalmic artery occlusion (9% vs. 6%, P = 0.35).. Ophthalmic vascular events after IAC for retinoblastoma affect only 5% of eyes per infusion (17% of treated eyes). Vascular event risk per eye is similar when using IAC as primary or secondary treatment.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Choroid; Female; Fluorescein Angiography; Humans; Infant; Infant, Newborn; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retinal Diseases; Retinal Neoplasms; Retinal Vessels; Retinoblastoma; Retrospective Studies; Topotecan; Young Adult

To report the use of anti-vascular endothelial growth factor in the management of retinoblastoma.. Retrospective review of 35 eyes (33 patients) treated with at least one intravitreal anti-vascular endothelial growth factor (ranibizumab and/or aflibercept) for new iris (n = 26) and/or retinal neovascularization (n = 21) after intravenous chemotherapy and/or intraarterial chemotherapy.. Most eyes (n = 31/35, 89%) were Group D or E. Previous treatments were salvage intraarterial chemotherapy after intravenous chemotherapy (n = 21/35, 60%), first-line intraarterial chemotherapy (n = 7/35, 20%), and first-line intravenous chemotherapy (n = 7/35, 20%). Associated clinical features were retinal ischemia (94%), retinal detachment (51%), active tumor (34%), intravitreal hemorrhage (43%), and/or glaucoma (17%). Mean 1.6 anti-vascular endothelial growth factor injections/eye were given; 28 eyes received ranibizumab, 2 aflibercept, and 5 both agents. Eight eyes underwent complementary treatments of ischemic retina. Resolution of neovascularization was observed in 28 eyes (n = 28/35, 80%). Globe salvage was achieved in 51% (n = 18/35), including 25% of those with active tumor (n = 3/12). One eye became phthisic. Sixteen eyes were enucleated, nine for tumor relapse/progression. Five eyes had high-risk histopathologic risk factors and received adjuvant intravenous chemotherapy. All patients are alive with no extraocular extension nor metastases (mean follow-up 3.7 years, range 1.1-7.6).. Intravitreal anti-vascular endothelial growth factor contributed to a globe salvage rate of 51% by providing conditions to continue conservative treatment.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Fluorescein Angiography; Humans; Infant; Infusions, Intra-Arterial; Infusions, Intravenous; Intravitreal Injections; Male; Melphalan; Microscopy, Acoustic; Ranibizumab; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Retinal Neoplasms; Retinal Neovascularization; Retinoblastoma; Retrospective Studies; Topotecan; Vascular Endothelial Growth Factor A

In the last 10 years, intra-arterial chemotherapy (IAC) has been increasingly used in the clinical management of retinoblastoma. It is reported to provide tumor control even in advanced stage disease that might have previously required enucleation. In our clinical experience, there are three conditions that may impair the use of IAC: (1) significant collaterals to meningeal arteries, (2) technical failure of ophthalmic artery catheterization, or (3) retina blood supply from collaterals different to the ophthalmic artery. In the current study, we assessed the rate of IACs that could not be carried out in our institution due to these three reasons.. All patients admitted for IAC in our hospital were retrospectively assessed by chart review. Non-application rate of IAC was assessed and classified according to the three abovementioned criteria. Complication rate of both finalized and interrupted interventions was recorded.. Ninety-eight patients (median age 21.4 months, range 5.3 months-10.5 years) were identified. IAC was performed in 69 (70.4%) patients and interrupted in 12 (12.2%) cases because of meningeal collaterals, in 8 (8.2%) because of technical failure to cannulate the ophthalmic artery, and in 9 (9.2%) because of alternative blood supply of the retina.. The rather defensive approach that is pursued in our center resulted in an overall non-application rate of IAC around 30%. The relatively high probability of conditions that impair the use of IAC needs to be addressed adequately in the patient conversation prior to the procedure. Our rate of 8% of abstention from IAC due to technical limitations might be reduced by the application of more rigorous therapeutic approaches such as balloon occlusion of the distal internal carotid artery. More research is finally needed to determine if IAC can be safely performed in the presence of meningeal collaterals and via branches of the external carotid artery.

Topics: Antineoplastic Agents, Alkylating; Cerebral Angiography; Child; Child, Preschool; Collateral Circulation; Contrast Media; Feasibility Studies; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Meningeal Arteries; Neoplasm Staging; Ophthalmic Artery; Retinoblastoma; Retrospective Studies; Treatment Outcome; Ultrasonography, Interventional

Predictions of visual outcomes are useful in clinical and family decisions regarding treatment for retinoblastoma. Very little has been published on the association of post-treatment visual acuity with pre-treatment electroretinography (ERG), which can be performed on infants too young to reliably quantify visual acuity.. To report associations of pre-treatment ERG with post-treatment visual acuity in eyes with advanced retinoblastoma treated with ophthalmic artery chemosurgery (OAC).. Retrospective case-control study of eyes treated from 2006 through 2017, with mean follow-up of 51 months (range 2.3-150 months).. Single large academic center.. Group D and E eyes treated with OAC at Memorial Sloan Kettering Cancer Center with recorded visual acuity and ERG (30Hz flicker).. Snellen visual acuity (uncorrected) compared to initial 30Hz flicker ERG.. This study included 157 Group D and E eyes. Results of the Jonckheere-Terpstra test for trend were statistically significant and indicated that eyes with lower pre-treatment ERG readings tended to have more visual impairment post-treatment. Among eyes with initial ERG 75+ μV, 11 of 32 eyes (34%) had visual acuity 20/40 or better. Among eyes with ERG 0 μV, 44 of 46 (96%) had visual acuity of 20/200 or worse.. Eyes with advanced intraocular retinoblastoma treated with OAC can achieve excellent visual acuity, but poor ERG at initial visit is associated with poor visual acuity after treatment in the majority of eyes. Expectations regarding visual potential may influence decisions about treatment.

Topics: Carboplatin; Case-Control Studies; Child; Child, Preschool; Electroretinography; Female; Humans; Infant; Infant, Newborn; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan; Visual Acuity

Melphalan is an efficient chemotherapeutic agent that is currently used to treat retinoblastoma (Rb); however, the inherent risk of immunogenicity and the hazardous integration of this drug in healthy cells is inevitable. MicroRNAs are short non-coding single-stranded RNAs that affect a vast range of biological processes. Previously, we focused on the regulatory role of miR-181a during cancer development and progression. In this manuscript, 171 nm switchable lipid nanoparticles (LNP) co-delivered melphalan and miR-181a with encapsulation efficiencies of 93%. Encapsulation of melphalan in LNP significantly improved its therapeutic efficiency. Gene analysis shows that miR-181a decreases the expression of anti-proliferative gene MAPK1 and anti-apoptotic gene Bcl-2, but significantly increased the expression of pro-apoptotic gene BAX. Our results suggest that the two agents have a complementary effect in reducing the viability of cultured Rb cells (primary and cell line) and decreasing Rb cell counts in an in-vivo xenograft Rb model in rats. Our results suggest that the proposed co-delivery technique significantly increases the therapeutic impact, allows for lower administration of melphalan, and consequently, could minimize the cytotoxic side-effects of this drug.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Lipids; Male; Melphalan; MicroRNAs; Nanoparticles; Rats; Rats, Sprague-Dawley; Retinal Neoplasms; Retinoblastoma; Xenograft Model Antitumor Assays

To evaluate the efficacy, complications, and clinical characteristics, including the ocular toxicity, of intravitreal melphalan(IVM) treatment for vitreous seeding in Chinese retinoblastoma patients.. This was a retrospective, non-comparative analysis including 30 consecutive eyes of 23 patients with viable persistent or recurrent vitreous seeding following retinoblastoma treatment. All of the eyes received IVM injections (20-33 μg). Vitreous seeding control, determination of the ocular toxicity, and the clinical characteristics of intravitreal melphalan treatments were observed.. The mean patient age at the time of the injection was 28 months (median = 22 months, range = 12-50 months). In total, 80 injections were administered in 30 eyes, the overall enucleation-free survival rate was 83.3% (25/30). The complications included retinal pigment epithelium (RPE) and choroidal atrophy (19/30, 63.3%), pupillary synechiae (13/30, 43.3%), iris atrophy (12/30, 40%), retinal vascular occlusion (12/30, 40.0%), optic atrophy (6/30, 20%), vitreous hemorrhage (3/30, 10%), persistent hypotonia and phthisis bulbi (4/30 13.3%), and cataracts (8/30, 26.6%). Twelve eyes demonstrated grade 3 or greater IVM-associated retinal or anterior segment toxicity post injection. Mean dosage given showed significant difference between the groups. There were no significant differences in the retinal toxicity grades regarding the seed classification or seed regression patterns.. Intravitreal melphalan is an effective treatment for refractory vitreous seeding from retinoblastoma, but exhibits both anterior and posterior segment toxicity in Chinese patients.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Female; Humans; Infant; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Vitreous Body

To use our intra-arterial chemotherapy (IAC) rabbit model to assess the impact of IAC procedure, drug, dose, and choice of technique on ocular structure and function, to study the nature and etiology of IAC toxicity, and to compare to observations in patients.. Rabbits received IAC melphalan (0.4-0.8 mg/kg), carboplatin (25-50 mg), or saline, either by direct ophthalmic artery cannulation, or with a technique emulating nonocclusion. Ocular structure/function were assessed with examination, electroretinography (ERG), fundus photography, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography, prior to and 5 to 6 weeks after IAC. Blood counts were obtained weekly. We reviewed our last 50 IAC treatments in patients for evidence of ocular or systemic complications.. No toxicity was seen in the saline control group. With standard (0.4 mg/kg) melphalan, no vascular/microvascular abnormalities were seen with either technique. However, severe microvascular pruning and arteriolar occlusions were seen occasionally at 0.8 mg/kg doses. ERG reductions were dose-dependent. Histology showed melphalan dose-dependent degeneration in all retinal layers, restricted geographically to areas of greatest vascular density. Carboplatin caused massive edema of ocular/periocular structures. IAC patients experienced occasional periocular swelling/rash, and only rarely experienced retinopathy or vascular events/hemorrhage in eyes treated multiple times with triple (melphalan/carboplatin/topotecan) therapy. Transient neutropenia occurred after 46% of IAC procedures, generally after triple therapy.. IAC toxicity appears to be related to the specific drug being used and is dose-dependent, rather than related to the IAC procedure itself or the specific technique selected. These rabbit findings are corroborated by our clinical findings in patients.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Carboplatin; Dose-Response Relationship, Drug; Electroretinography; Female; Fluorescein Angiography; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Models, Animal; Ophthalmic Artery; Rabbits; Retina; Retinal Diseases; Retinal Neoplasms; Retinal Vessels; Retinoblastoma; Retrospective Studies; Tomography, Optical Coherence

A 35-month-old boy was diagnosed with retinoblastoma and underwent combination intra-arterial (IAC) and intravitreal chemotherapy. His course was complicated by anaphylactic reaction to IAC, yet he continued to improve with sustained intravitreal therapy. Eight months into treatment, the affected eye developed exudative retinal detachment, which resolved with sub-Tenon's steroid administration. As the management of retinoblastoma evolves, treaters need to be aware of potential complications of therapy. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:248-252.].

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Drug Therapy, Combination; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; Humans; Injections, Intraocular; Intravitreal Injections; Macula Lutea; Male; Melphalan; Retinal Detachment; Retinal Neoplasms; Retinoblastoma; Topoisomerase I Inhibitors; Topotecan; Triamcinolone Acetonide; Ultrasonography

The goal of this work was to design and assess the ability of unmodified and surface-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to enhance cell association, provide efficacy in retinoblastoma cells, and overcome current administration challenges, including hydrolysis and precipitation, of intravitreal administration.. A single emulsion method was used to encapsulate Coumarin 6, to enable NP visualization via fluorescence microscopy. Melphalan NPs were synthesized using an adapted double-emulsion method to reduce melphalan loss during fabrication. Melphalan loading and release were quantified against a free melphalan standard. The cellular association and internalization of unmodified and surface-modified NPs were determined using flow cytometry, and the efficacy of melphalan NPs was quantified in retinoblastoma cells.. The highest cell association was observed with TET1 and MPG-NPs after 24 hours administration; however, a significant fraction of NPs were associated with the cell surface, instead of undergoing internalization. MPG-NPs fabricated with the low saturation process were most efficacious, while all surface-modified NPs improved efficacy relative to unmodified NPs when formulated using the highly saturated process. Similar effects were observed as a function of NP dose, with TET1 and MPG-NPs particularly efficacious.. Surface-modified NPs achieved enhanced association and efficacy in retinoblastoma cells relative to unmodified NPs, with MPG and surface-modified NPs exhibiting the strongest efficacy relative to other NP groups. In future work we seek to assess the ability of these NPs to improve transport in the vitreous, where we expect a more dramatic impact on efficacy as a function of surface modification.

Topics: Antineoplastic Agents, Alkylating; Coumarins; Drug Delivery Systems; Flow Cytometry; Humans; Intravitreal Injections; Melphalan; Microscopy, Electron, Scanning; Nanoparticles; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer; Retinal Neoplasms; Retinoblastoma; Thiazoles; Tumor Cells, Cultured

Topics: Antineoplastic Agents, Alkylating; Child; Child, Preschool; Female; Humans; Infant; Intravitreal Injections; Male; Melphalan; Retina; Retinal Neoplasms; Retinoblastoma; Tomography, Optical Coherence

Intravitreal chemotherapy is recognized as an effective treatment for retinoblastoma with vitreous (and occasionally subretinal) seeding refractory to intravenous or intra-arterial chemotherapy. However, this treatment carries with it the risk of toxicity to both the posterior and anterior segments of the eye, including retinal pigment epithelial mottling, ischemic/hemorrhagic retinopathy, posterior synechia, cataract, scleral necrosis, and focal iris depigmentation. We report 2 cases of iris heterochromia secondary to profound iris stromal depigmentation following intravitreal melphalan and topotecan injections.

Topics: Diagnosis, Differential; Drug Therapy, Combination; Female; Humans; Infant; Intravitreal Injections; Iris Diseases; Melphalan; Pigmentation Disorders; Retinal Neoplasms; Retinoblastoma; Tomography, Optical Coherence; Topotecan

Intravitreal injection of chemotherapy in retinoblastoma eyes with vitreous seeds may lead to a risk of extraocular tumour dissemination that has not been assessed so far.. To develop a sensitive and clinically feasible technique to assess for potential retinoblastoma cell reflux after intravitreal injection of melphalan.. Filter papers were cut in 6 mm diameter circles and sterilised before use. Eyes with retinoblastoma vitreous seeds (group D, International Classification) received weekly intravitreal melphalan injections (20 µg or 30 µg/dose) followed by cryotherapy as part of local treatment. Immediately after finishing the injection and cryotherapy, filter papers were placed on the injection site and on the cryoprobe tip to assess for the expression of the cone-rod homeobox gene (CRX) by real-time qPCR as a surrogate of retinoblastoma RNA. The assay was developed and validated to determine sensitivity, linearity, recovery, repeatability and reproducibility.. The assay for quantitation of CRX expression was linear in the range of 1 to 1000 cells. The lowest limit of detection was one retinoblastoma cell and allowed to recover 100% of the cell load in external supplementation. A total of 14 eyes received 22 cycles of intravitreal melphalan and were evaluated for potential extraocular tumour cell dissemination using the developed technique. None of the cycles were positive for CRX in samples from the scar or from the cryoprobe tip.. A sensitive and simple method of tumour cell assessment has been developed that can be used in the clinics to assess for potential extraocular dissemination after intravitreal injections to assure its performance.

Topics: Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Cryotherapy; Homeodomain Proteins; Humans; Intravitreal Injections; Melphalan; Neoplasm Seeding; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; RNA, Neoplasm; Trans-Activators; Tumor Cells, Cultured

To report the occurrence and management of secondary choroidal infiltration in two retinoblastoma (rb) patients.. Fundus examination and imaging with spectral domain optical coherence tomography (SD-OCT), B-scan ultrasonography (B-scan), and ultrasound biomicroscopy (UBM).. Case 1: A 19-month-old girl with multifocal unilateral group B rb pretreated with intravenous chemotherapy (IVC) was referred for further management. At 3.5 years of age, routine 3-Tesla magnetic resonance imaging (3T-MRI) revealed an asymptomatic pinealoblastoma that underwent resection and adjuvant intensive IVC. Concomitant ophthalmic follow-up revealed a recurrence 8.3 × 2.8 mm at the posterior pole nasally to the optic disc on B-scan, localized within the choroid on SD-OCT and 3T-MRI. With high dose IVC ongoing, total regression of the choroidal mass was confirmed on SD-OCT already after 3 weeks. At 6-month follow-up, choroidal and pineal tumors were in complete remission. Sadly, the child died of intravascular disseminated coagulation-like disease after the 5th IVC. Case 2: A heavily pretreated 20-month-old girl with bilateral rb was referred for persistent vitreous seeding in her remaining eye (OD). Three months after intravitreal chemotherapy and chemothermotherapy, a hemorrhagic mass was observed inferior to the primary tumor. Two weeks later, an underlying peripheral choroidal mass 16 × 6 mm was documented by UBM and confirmed by 3T-MRI. Complete resolution was achieved 3 weeks after combined intra-arterial chemotherapy (IAC) of melphalan-topotecan. No recurrence or metastasis was observed at 34-month follow-up.. Isolated massive choroidal invasion can be treated conservatively with IVC or IAC in selected cases. SD-OCT, UBM, and B-scan ultrasonography are instrumental in the detection and follow-up of choroidal lesions.

Topics: Antineoplastic Combined Chemotherapy Protocols; Choroid Neoplasms; Conservative Treatment; Fatal Outcome; Female; Fluorescein Angiography; Humans; Infant; Infusions, Intra-Arterial; Magnetic Resonance Imaging; Melphalan; Microscopy, Acoustic; Neoplasm Recurrence, Local; Retinal Neoplasms; Retinoblastoma; Tomography, Optical Coherence; Topotecan

Topics: Adolescent; Anterior Chamber; Antineoplastic Agents, Alkylating; Child; Child, Preschool; Female; Humans; Infant; Male; Melphalan; Microscopy, Acoustic; Neoplasm Invasiveness; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Salvage Therapy

Background and purpose The purpose of this article is to estimate the distribution of superselective intra-arterial chemotherapy (IAC) delivery to ocular target tissue using quantitative digital subtraction angiography (qDSA). Materials and methods From March 2010 to January 2016, 50 ophthalmic artery contrast DSAs obtained immediately prior to IAC infusions in 22 patients were analyzed. This study was conducted under a retrospective review IRB (no. 10-01862). Parametric color-coded DSAs (iFlow, Siemens Medical) were post-processed (MATLAB, The Mathworks Inc.) using two methods: two box regions of interest (pre-retina and globe) and four custom regions of interest (ROIs-ophthalmic artery, choroid, supraclinoid internal carotid artery (ICA), cavernous ICA). Mean interobserver reliability of custom ROI selection is presented as a 95% confidence interval of interclass correlation, and fractional chemotherapy delivery to selected ROIs as means ± standard deviation in this study. Results The estimated fraction of chemotherapy delivered to the globe with the first method was 79.5%. Percentage regional delivery using the second method was as follows: ophthalmic artery, 85.8%; choroid, 60.5%; supraclinoid ICA, 14.2%. The cavernous ICA ROI (encompassing distal catheter and potential reflux) gave a signal equivalent to 9.3% of total delivery. Conclusion Parametric color-coded qDSA can estimate the fraction of IAC delivered to the retina and other orbital structures in ocular retinoblastoma patients. This information can inform delivery location and dosing strategies on a patient-specific basis.

Topics: Angiography, Digital Subtraction; Antineoplastic Agents, Alkylating; Carotid Artery, Internal; Child, Preschool; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies

Current intra-arterial chemotherapy (IAC) drug regimens for retinoblastoma have ocular and vascular toxicities. No small-animal model of IAC exists to test drug efficacy and toxicity in vivo for IAC drug discovery. The purpose of this study was to develop a small-animal model of IAC and to analyze the ocular tissue penetration, distribution, pharmacokinetics, and treatment efficacy.. Following selective ophthalmic artery (OA) catheterization, melphalan (0.4 to 1.2 mg/kg) was injected. For pharmacokinetic studies, rabbits were euthanized at 0.5, 1, 2, 4, or 6 hours following intra-OA infusion. Drug levels were determined in vitreous, retina, and blood by liquid chromatography tandem mass spectrometry. To assess toxicity, angiograms, photography, fluorescein angiography, and histopathology were performed. For in situ tissue drug distribution, matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) was performed. The tumor model was created by combined subretinal/intravitreal injection of human WERI-Rb1 retinoblastoma cells; the tumor was treated in vivo with intra-arterial melphalan or saline; and induction of tumor death was measured by cleaved caspase-3 activity.. OA was selectively catheterized for 79 of 79 (100%) eyes in 47 of 47 (100%) rabbits, and melphalan was delivered successfully in 31 of 31 (100%) eyes, without evidence of vascular occlusion or retinal damage. For treated eyes, maximum concentration (Cmax) in the retina was 4.95 μM and area under the curve (AUC0→∞) was 5.26 μM·h. Treated eye vitreous Cmax was 2.24 μM and AUC0→∞ was 4.19 μM·h. Vitreous Cmax for the treated eye was >100-fold higher than for the untreated eye (P = 0.01), and AUC0→∞ was ∼50-fold higher (P = 0.01). Histology-directed MALDI-IMS revealed highest drug localization within the retina. Peripheral blood Cmax was 1.04 μM and AUC0→∞ was 2.07 μM·h. Combined subretinal/intravitreal injection of human retinoblastoma cells led to intra-retinal tumors and subretinal/vitreous seeds, which could be effectively killed in vivo with intra-arterial melphalan.. This first small-animal model of IAC has excellent vitreous and retinal tissue drug penetration, achieving levels sufficient to kill human retinoblastoma cells, facilitating future IAC drug discovery.

Topics: Animals; Antineoplastic Agents, Alkylating; Disease Models, Animal; Electroretinography; Fluorescein Angiography; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Rabbits; Retina; Retinal Neoplasms; Retinoblastoma; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tissue Distribution; Treatment Outcome; Vitreous Body

The feasibility and results of intraarterial chemotherapy, also termed ophthalmic artery chemosurgery (OAC), for retinoblastoma in less developed countries have seldom been reported.. A retrospective evaluation of a program of OAC in Argentina from 2010 to 2015.. Ninety-seven eyes from 81 patients (61 bilateral) were analyzed. In 35 eyes, OAC was given as primary therapy and in 62 it was used for the treatment of tumors with partial response or those relapsing after systemic chemoreduction with focal therapy or external-beam radiotherapy. Twenty-two primarily treated eyes had group D and 13 groups B/C. A total of 400 procedures were carried out. Chemotherapy used included combinations of melphalan, carboplatin, and topotecan. There was no mortality associated with OAC. Toxicity included fever and neutropenia in five (1.25%), hypotension and bradycardia during anesthesia in two and femoral thrombosis in one, eyelid edema in nine, and neutropenia or thrombocytopenia in 28 cycles. With a median follow-up of 48.7 months (range 12-79), the 3-year probability of event-free survival (pEFS) (enucleation and/or radiotherapy were considered events) was comparable for patients who received first-line therapy and those treated at relapse (0.65 vs. 0.63, P = 0.5). In the former, the pEFS was 0.91 and 0.43 for groups B/C and D, respectively (P = 0.01). Two patients died of extraocular dissemination after refusal of enucleation.. OAC was feasible with low toxicity. pEFS improved in all groups compared to the previous experience with systemic chemotherapy reducing the use of radiotherapy. The overall mortality associated with OAC is comparable to our previous experience with systemic chemoreduction.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Argentina; Carboplatin; Child; Child, Preschool; Conservative Treatment; Disease-Free Survival; Feasibility Studies; Female; Humans; Infusions, Intra-Arterial; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan; Young Adult

To report on the rate and timing of retinal reattachment and outcomes for retinoblastoma children who have total retinal detachments at presentation to our center and were treated with intra-arterial chemotherapy (ophthalmic artery chemosurgery, OAC).. Single-center retrospective review of retinoblastoma patients who presented with total retinal detachments and were subsequently treated with OAC at MSKCC between May 2006 and July 2016. Endpoints were retinal detachment resolution, visual function, ERG amplitude, ocular survival, and patient survival from metastases.. 87 eyes of 84 retinoblastoma patients were included. Using a survival multistate model, by 36 months of follow-up, there was a 54% cumulative probability of complete retinal reattachment and a 76% probability of partial reattachment. 24% of eyes that completely reattached received only OAC without any prior or adjuvant treatments. Eyes that completely reattached were significantly more likely to have been diagnosed at a younger age (p<0.0001) and to have greater initial ERG values (p = 0.006). At final follow-up, 14% of eyes had gained at least 25 μV of ERG activity, and 8.0% had achieved hand motion vision or better, including one to 20/60. 13% of eyes were enucleated. No patient died from metastatic disease, and only one developed metastases.. OAC can successfully treat previously considered "non-salvageable" retinoblastoma eyes with total retinal detachments, promote retinal reattachment in the majority of eyes, and preserve ocular and patient survival.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child, Preschool; Electroretinography; Female; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retina; Retinal Detachment; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Survival Analysis; Topotecan; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Combined Modality Therapy; Cryotherapy; Dasatinib; Eye Enucleation; Humans; Infant; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Light Coagulation; Male; Melphalan; Neoplasms, Multiple Primary; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Radiotherapy, Adjuvant; Remission Induction; Retinoblastoma

Although studies from pediatric cancers (largely acute lymphoblastic leukemia) have shown that patients undergoing systemic chemotherapy may experience decreased growth velocity during the treatment phase, no such data exist for retinoblastoma patients treated with systemic chemotherapy or ophthalmic artery chemosurgery (OAC). The purpose of this study is to report growth patterns of our retinoblastoma (Rb) population who were treated with OAC in a retrospective, single center (Memorial Sloan Kettering Cancer Center) review of 341 patients treated between 2006 and 2016. Children who only received OAC were classified as naive; those who were treated initially with systemic chemotherapy and subsequently presented to our center for OAC were termed secondary; and a small group of patients who received single-agent systemic chemotherapy prior to OAC were labeled bridge. For all patients, height and weight were recorded at monthly intervals during OAC (short-term) and then annually during a follow-up period (long-term) up to 3 years after treatment. Excluded from this study were children who received external radiation therapy and those with genetic syndromes, which are independently associated with growth derangements. During OAC, there was no significant difference in growth velocity between the naïve and secondary groups. In either group, number of treatments also did not affect growth rate. Three years after the end of OAC, naïve patients were in the 68th percentile by height (95% CI 61.30, 74.63) compared to secondary patients in the 61st percentile (95% CI 51.1, 71.47). Both groups were in the same weight percentiles during the first two years of follow-up but at the three-year follow-up period, naïve patients were in the 63rd percentile (95% CI 57.4, 69.4) and secondary patients were in the 60th percentile (95% CI 50.4, 69.7). OAC for retinoblastoma does not appear to impact short-term growth velocity, weight gain during the treatment period or after three years.

Topics: Adolescent; Cancer Survivors; Carboplatin; Child; Child, Preschool; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retinoblastoma; Retrospective Studies; Treatment Outcome

To assess risk factors for ophthalmic vascular events after intra-arterial chemotherapy (IAC) for retinoblastoma.. Retrospective cohort study.. Patients who received unilateral IAC as primary treatment for retinoblastoma from January 1, 2009, to November 30, 2017, at a single center.. Records were reviewed for patient demographics, tumor features, IAC parameters, and treatment-related vascular events in the early IAC era (2009-2011) compared with the recent era (2012-2017) using the t test and Fisher exact test. Change in event rates over time was assessed using Poisson regression analysis, with Spearman's rho used to test correlation.. Rate of IAC-induced ophthalmic vascular events.. There were 243 chemotherapy infusions in 76 eyes of 76 patients, divided into early (22 eyes, 57 infusions) and recent (54 eyes, 186 infusions) eras. Intra-arterial chemotherapy consisted of melphalan (243 infusions), topotecan (124 infusions), and carboplatin (9 infusions). A comparison (early vs. recent era) revealed fewer mean number of infusions (2.6 vs. 3.4, P = 0.02) with similar mean patient age and presenting tumor features. Event rates decreased over time (P < 0.01), with fewer ophthalmic vascular events (early era vs. recent era) in the recent era (59% vs. 9% per eye, 23% vs. 3% per infusion, P < 0.01), including peripheral retinal nonperfusion (5% vs. 2% per eye, P = 0.50), vitreous hemorrhage (9% vs. 2%, P = 0.20), subretinal hemorrhage (0% vs. 2%, P = 0.99), branch retinal vein occlusion (5% vs. 0%, P = 0.29), choroidal ischemia (14% vs. 4%, P = 0.14), and ophthalmic artery spasm/occlusion (27% vs. 0%, P < 0.01). Events did not correlate to patient age (P = 0.75), tumor diameter (P = 0.32), tumor thickness (P = 0.59), or cumulative dosage of melphalan (P = 0.13) or topotecan (P = 0.59). There were no IAC-induced vascular events in 72 infusions of 21 consecutively treated eyes in 2016 to 2017.. Ophthalmic vascular events after IAC have decreased from the early era (2009-2011) through the current era (2012-2017) at this center. Experience performing this highly specialized procedure could be an important factor predicting IAC-related vascular events.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Female; Fluorescein Angiography; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmoscopy; Retinal Diseases; Retinal Neoplasms; Retinal Vessels; Retinoblastoma; Retrospective Studies; Risk Factors; Topotecan; Ultrasonography; Young Adult

Patients with retinoblastoma and central nervous system (CNS) involvement are rarely curable with available treatments. We designed a high-dose intra-arterial regimen targeting the ophthalmic artery and chiasm combined with intrathecal chemotherapy to treat a 4-year-old patient with retinoblastoma metastasized to the CNS. After three cycles of this regimen, including carboplatin, melphalan, and intrathecal topotecan, a partial response of the orbital tumor mass and chiasmatic lesion, and complete response in the cerebrospinal fluid and bone marrow were achieved. This new treatment strategy may be explored as a treatment component for patients with overt extraocular retinoblastoma and CNS dissemination.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Central Nervous System Neoplasms; Child, Preschool; Humans; Infusions, Intra-Arterial; Injections, Spinal; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Topotecan

Intra-arterial chemotherapy (IAC) has become an essential technique for the management of advanced intraocular retinoblastoma (RB). In this study, the aim of this article is to describe the clinical results and the short-term complications of IAC performed in our hospital.We retrospectively analyzed patients with newly diagnosed unilateral advanced intraocular (group D or E) RB undergoing IAC from October 2016 to December 2017 in our hospital. We recorded the data including age, gender, cycles of IAC, pathway of arteries approached (ophthalmic artery or middle meningeal artery), ocular and systematic complications, globe salvage.Sixty-one patients underwent IAC performing 189 procedures with a median of 3.1 sessions per eye (range, 1-5 sessions). The overall globe salvage rate is 78.7% (Group D (84.2%), and Group E (69.6%) and followed-up. Short-term ocular complications include eyelid edema (15 cases), ptosis (5 cases), forehead congestion (3 cases), retina hemorrhage (5 cases), choroid atrophy (2 cases), phthisis bulbi (1 case), bradycardia and hypotension during the procedure (7cases), myelosuppressions (6 cases), and nausea and vomiting (5cases).IAC is safe and effective for the treatment of unilateral advanced intraocular RB with a very low complication rate.

Topics: Antineoplastic Agents; Child, Preschool; Eye; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Meningeal Arteries; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan; Treatment Outcome

Persistent or recurrent retinoblastoma (RB) is associated with the presence of vitreous or/and subretinal seeds in advanced RB and represents a major cause of therapeutic failure. This necessitates the development of novel therapies and thus requires a model of advanced RB for testing candidate therapeutics. To this aim, we established and characterized a three-dimensional, self-organizing organoid model derived from chemotherapy-naïve tumors. The responses of organoids to drugs were determined and compared to relate organoid model to advanced RB, in terms of drug sensitivities. We found that organoids had histological features resembling retinal tumors and seeds and retained DNA copy-number alterations as well as gene and protein expression of the parental tissue. Cone signal circuitry (M/L

Topics: Antineoplastic Agents; Carcinogenesis; Child, Preschool; DNA Copy Number Variations; Gene Expression Regulation, Neoplastic; Humans; Infant; Melphalan; Models, Biological; Neoplasm Staging; Organoids; Retinal Neoplasms; Retinoblastoma; Topotecan

The aim of this study is to describe treatment outcomes and complications of selective intra-arterial chemotherapy (IAC) for intraocular retinoblastoma (RB).. A retrospective, interventional series of 10 eyes with RB which underwent IAC using melphalan (5 mg/7.5 mg) and topotecan (1 mg), or melphalan (5 mg/7.5 mg) alone. Treatment outcomes were evaluated in terms of tumor control, vitreous seeds (VS) and subretinal seeds (SRS) control, and globe salvage rates.. Ten eyes of 10 patients underwent 38 IAC sessions (mean = 3.8; median = 4; range = 3-5 sessions). Following IAC, complete regression of main tumor was seen in 9 eyes (90%) and partial regression in 1 (10%). All four eyes with SRS showed complete regression (100%). Of 5 eyes with VS, 3 eyes (60%) showed complete regression, 1 eye (20%) showed relapse, while 1 eye (20%) showed no response. Globe salvage was achieved in 8 of 10 eyes (80%). Complications included transient ophthalmic artery narrowing (n = 2), branched retinal vein occlusion (n = 1), forehead skin pigmentation (n = 1), and vitreous hemorrhage (n = 2). There was no case of stroke, hemiplegia, metastasis, or death. Transient hematological changes included relative pancytopenia (n = 4), relative leukopenia (n = 5), and relative thrombocytopenia (n = 4). Mean follow-up was 26 months (median = 28, range = 13-36) from the initiation of first IAC.. IAC is an effective therapy for globe preservation in eyes with intraocular RB, in the setting of a developing country like India. Larger studies with longer follow-up are required to validate these results.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Incidence; India; Infant; Injections, Intra-Arterial; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Time Factors; Topoisomerase I Inhibitors; Topotecan; Treatment Outcome; Ultrasonography

To compare the efficacy and toxicity of treating class 3 retinoblastoma vitreous seeds with ophthalmic artery chemosurgery (OAC) alone versus OAC with intravitreous chemotherapy.. Retrospective cohort study.. Forty eyes containing clouds (class 3 vitreous seeds) of 40 retinoblastoma patients (19 treated with OAC alone and 21 treated with OAC plus intravitreous and periocular chemotherapy).. Ocular survival, disease-free survival and time to regression of seeds were estimated with Kaplan-Meier estimates. Ocular toxicity was evaluated by clinical findings and electroretinography: 30-Hz flicker responses were compared at baseline and last follow-up visit. Continuous variables were compared with Student t test, and categorical variables were compared with the Fisher exact test.. Ocular survival, disease-free survival, and time to regression of seeds.. There were no disease- or treatment-related deaths and no patient demonstrated externalization of tumor or metastatic disease. There was no significant difference in the age, laterality, disease, or disease status (treatment naïve vs. previously treated) between the 2 groups. The time to regression of seeds was significantly shorter for eyes treated with OAC plus intravitreous chemotherapy (5.7 months) compared with eyes treated with OAC alone (14.6 months; P < 0.001). The 18-month Kaplan-Meier estimates of disease-free survival were significantly worse for the OAC alone group: 67.1% (95% confidence interval, 40.9%-83.6%) versus 94.1% (95% confidence interval, 65%-99.1%) for the OAC plus intravitreous chemotherapy group (P = 0.05). The 36-month Kaplan-Meier estimates of ocular survival were 83.3% (95% confidence interval, 56.7%-94.3%) for the OAC alone group and 100% for the OAC plus intravitreous chemotherapy group (P = 0.16). The mean change in electroretinography responses was not significantly different between groups, decreasing by 11 μV for the OAC alone group and 22 μV for the OAC plus intravitreous chemotherapy group (P = 0.4).. Treating vitreous seed clouds with OAC and intravitreous and periocular chemotherapy, compared with OAC alone, resulted in a shorter time to regression and was associated with fewer recurrences requiring additional treatment and fewer enucleations. The toxicity to the retina does not seem to be significantly worse in the OAC plus intravitreous chemotherapy group.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child, Preschool; Cohort Studies; Disease-Free Survival; Electroretinography; Female; Humans; Infusions, Intra-Arterial; Intravitreal Injections; Kaplan-Meier Estimate; Male; Melphalan; Neoplasm Seeding; Ophthalmic Artery; Retina; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan; Vitreous Body

To evaluate outcomes of Group D retinoblastoma (Rb) eyes during the intravitreal melphalan era.. Retrospective chart review of patients diagnosed with Group D Rb from 2011 to 2016 was done. Overall, 76 Group D eyes of 68 patients were included; salvage therapy included systemic chemoreduction with vincristine, etoposide, and carboplatin with local consolidation, followed by intravitreal injection of melphalan for recurrent or persistent seeding. External beam radiation was not used as a treatment modality. Primary outcome measurement was globe salvage.. Of 76 Group D eyes, 24 were enucleated primarily and 52 were treated with intent to salvage the globe. Systemic chemoreduction salvaged 25 of 52 eyes (48%). Tumor recurrences were diagnosed in 27 eyes (52%); five with massive retinal recurrences underwent enucleation and 22 were treated with intravitreal melphalan injection. Of the 22 injected eyes, 14 (64%) were salvaged and eight required enucleation primarily for retinal recurrences. Success in eradicating vitreous seeds was 100%. The Kaplan-Meier 3-year survival estimate for treated eyes is 76.5% (95% CI: 61.4-86.3). Median follow-up for the group of 76 Group D eyes was 29.5 months (SD 17.9 months).. During a 6-year period that included the initiation of intravitreal melphalan at our institution, the salvage rate of treated Group D eyes was 75% (39/52 eyes). Intravitreal melphalan was utilized for ocular salvage in 42% (22/52 eyes). Systemic chemoreduction combined with intravitreal melphalan for seeding demonstrated a high overall salvage rate for Group D eyes in this cohort.

Topics: Antineoplastic Agents, Alkylating; Child; Child, Preschool; Female; Humans; Infant; Intravitreal Injections; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Salvage Therapy; Treatment Outcome

Intravitreal chemotherapy has emerged as an important modality for treating vitreous seeding in retinoblastoma. A classification system has been described as predictive of response to intravitreal melphalan (IVM) in patients treated predominantly with primary intra-arterial chemotherapy. The objective of this study is to evaluate the outcomes of retinoblastoma treated with intravenous chemotherapy and IVM as salvage for vitreous seeding, and further to determine whether vitreous seed classification (dust, spheres, cloud) is predictive of the total number and dose of IVM injections required for treatment in this cohort.. A nonrandomized retrospective review.. Retinoblastoma patients treated at a single center with intravenous chemotherapy and IVM.. Retrospective review of patients with vitreous seeding from retinoblastoma treated with intravenous chemotherapy and IVM from 2012 to 2016.. Primary outcome measure was eradication of seeds and globe salvage. Secondary measures included IVM-associated toxicity and complications.. Overall, 28 eyes of 25 patients were included, with a total of 110 IVM injections. By seed classification, eyes with dust (n = 15) required a median of 3 injections, spheres (n = 8) required 4 injections, and clouds (n = 5) required 6 injections. Spherical seeds were only seen in recurrent vitreous seeding. Of the 28 treated eyes, 9 were enucleated, 6 for recurrent retinal disease, resulting in an overall globe salvage rate of 68%. The salvage rate secondary to active retinoblastoma was 79%. Dust classification was the most prevalent seeding type of the 9 enucleated eyes. There was 100% regression of vitreous seeds after intravitreal injection and no eye was treated with radiation or enucleated for seeding. Twelve eyes demonstrated grade 3 or greater IVM-associated retinal or anterior segment toxicity post injection. Mean follow-up was 33 months (range, 9-51 months).. IVM is an effective treatment for vitreous seeding after intravenous chemotherapy for retinoblastoma. As with eyes treated with intra-arterial chemotherapy, seed classification is predictive of the total number and dose of IVM injections in eyes treated with intravenous chemotherapy. Eyes with clouds required significantly more injections than eyes with dust or spheres.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Cryotherapy; Etoposide; Female; Follow-Up Studies; Humans; Infant; Infusions, Intravenous; Intravitreal Injections; Laser Coagulation; Male; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Salvage Therapy; Vincristine; Vitreous Body

Topics: Humans; India; Infant; Melphalan; Retinal Neoplasms; Retinoblastoma

The risk of extraocular extension from injecting chemotherapy into eyes with retinoblastoma is minimally understood; however, understanding this risk is important because of the increasing use of intravitreous chemotherapy.. To evaluate the risk of extraocular extension in eyes with retinoblastoma that have received intravitreous chemotherapy injections.. This retrospective cohort study was performed in 655 patients at 10 retinoblastoma centers in North and South American, European, Israeli, and Chinese centers. Physicians at the retinoblastoma centers administered more than 120 intravitreous chemotherapy injections in eyes with retinoblastoma from February 1, 1999, through February 28, 2017.. Risk of extraocular extension with secondary observational variables, including injection and precautionary techniques.. A total of 3553 intravitreous chemotherapy injections (3201 melphalan hydrochloride, 335 topotecan hydrochloride, and 17 methotrexate sodium) were administered to 704 eyes in 655 patients with retinoblastoma (mean [SD] age of patients at the time of the initial injections, 31.6 [11.6] months; 348 male [53.1%]). There were no extraocular tumor events related to prior intravitreous injections. This finding resulted in a calculated proportion of zero extraocular events per eye. According to the rule of 3, the risk is no greater than 0.08% injections. All 10 centers included in this study used at least 2 presumed precautionary injection methods (lowering of intraocular pressure, cryotherapy, ocular surface irrigation, ultrasonic biomicroscopy surveillance of the injection site, and subconjunctival chemotherapy deposition).. With use of at least 2 presumed precautionary safety methods, no extraocular extension of tumor events occurred. According to the rule of 3, this finding suggests that the risk is no greater than 0.08% injections.

Topics: Antineoplastic Agents; Child, Preschool; Cryotherapy; Female; Humans; Infant; Intravitreal Injections; Male; Melphalan; Methotrexate; Microscopy, Acoustic; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Risk Factors; Topotecan

To report retinal function outcomes after ophthalmic artery chemosurgery (OAC) for advanced retinoblastoma (RB) in eyes with minimal pretreatment retinal function.. For 72 advanced RB eyes with baseline electroretinograms (ERGs) indistinguishable from noise ('extinguished') or flicker ERG amplitudes <25 µV ('poor'), ERGs were obtained before OAC and at 3 months, 1 year and 2 years after OAC. Presence of baseline retinal detachments (RDs) and their subsequent resolution or persistence was also noted.. Minimal baseline ERGs do not preclude significant recovery of retinal function after OAC. Good correlation exists between ERG outcomes at 3 months and those at subsequent follow-ups, suggesting that ERG amplitudes at 3-month post-OAC can prognosticate longer term retinal function, and that improvement is durable. For eyes presenting with RD, RD resolution is necessary but not sufficient for significant (≥25 μV) increases in ERG amplitudes.

Topics: Antineoplastic Agents; Child; Disease-Free Survival; Electroretinography; Female; Humans; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retinal Detachment; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Salvage Therapy

The introduction of intra-arterial chemotherapy (IAC) as salvage treatment has improved the prognosis for eye conservation in group D retinoblastoma. The aim of this study was to compare the outcomes of consecutive patients with advanced unilateral disease treated with either first-line intravenous chemotherapy (IVC) or first-line IAC.. This is a retrospective mono-centric comparative review of consecutive patients.. Sporadic unilateral retinoblastoma group D cases treated conservatively at Jules-Gonin Eye Hospital and CHUV between 1997 and 2014. From January 1997 to August 2008, IVC, combined with focal treatments, was the primary treatment approach. From September 2008 to October 2014, IAC replaced IVC as first-line therapy.. 48 patients met the inclusion criteria, receiving only either IAC or IVC as primary treatment modality.. Outcomes of 23 patients treated by IVC were compared with those of 25 treated by IAC; mean follow-up was 105.3 months (range 29.2-218.6) and 41.7 months (range 19.6-89.5), respectively. Treatment duration was significantly shorter in the IAC group (p<0.001). Ten eyes in the IVC group underwent enucleation. Recordable visual acuity of the salvaged eyes was significantly better in the IAC group (0.9 vs 1.4 logarithm of the minimum angle of resolution, p<0.01). No extraocular disease, metastases or long-term systemic complications were observed in either group.. The difference in the time frame between treatment groups had an impact on the availability of intravitreal chemotherapy treatment. Despite this, the results reported here imply that eyes treated with first-line IAC will have shorter treatment period, better ocular survival and visual acuity than first-line IVC.

Topics: Aftercare; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Etoposide; Humans; Infant; Infusions, Intra-Arterial; Infusions, Intravenous; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Salvage Therapy; Treatment Outcome; Vision Disorders

To investigate the efficacy and toxicity of intravitreous melphalan for treatment of retinoblastoma, as a single agent or with concomitant topotecan.. A total of 130 eyes of 120 patients with retinoblastoma receiving 630 intravitreous (melphalan, topotecan) or topotecan periocular injections. A total of 83 (64%) of these eyes were treated with concomitant ophthalmic artery chemosurgery (OAC).. Retrospective cohort study.. Indirect ophthalmoscopy and clinical imaging were used to evaluate clinical response. Ocular survival and disease-free survival were estimated using Kaplan-Meier methods in 130 eyes. Ocular toxicity was evaluated by clinical findings and electroretinography (ERG) on 244 evaluable injections in 63 patients using 30-Hz flicker responses. Analysis was performed using linear mixed effects models with a random intercept and slope for each patient and a fixed effect for number of injections, in addition to any other fixed effect of interest.. Ocular survival, disease-free survival, ERG: peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation.. There were no disease- or treatment-related deaths, and no patient developed externalization of tumor or metastatic disease. Two-year Kaplan-Meier estimates of ocular survival and disease-free survival were 94.2% (95% confidence interval, 89.2-99.4) and 86.2% (95% confidence interval, 78.7-94.5), respectively. There was a significant association between the number of injections and diminished ERG responses, such that on average each intravitreous melphalan injection was associated with a 5.3-μV decrease in ERG amplitude (P < 0.001). Concomitant intra-arterial chemotherapy (P = 0.01) and greater inherent ocular pigment also were significantly associated with a reduction in ERG (P = 0.045). Patient age and weight, new injection site location, addition of topotecan, concomitant focal treatment, and time interval between injections were not significantly associated with toxicity.. Intravitreous melphalan is an effective treatment for vitreous seeding in retinoblastoma, resulting in high rates of ocular survival and disease-free survival. However, in this study, each injection of melphalan was associated, on average, with a decrement in ERG response. The findings suggest increased toxicity (1) when OAC is given within 1 week of the intravitreous injection and (2) in more deeply pigmented eyes.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Cohort Studies; Disease-Free Survival; Electroretinography; Female; Humans; Infant; Injections, Intraocular; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Ophthalmic Artery; Ophthalmoscopy; Retina; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topoisomerase I Inhibitors; Topotecan; Treatment Outcome; Vitreous Body

To investigate the impact of intravitreal chemotherapy on intraocular pressure (IOP) in children with retinoblastoma.. This was a retrospective study of 10 eyes of 10 patients with retinoblastoma (7 males, 3 females, mean age: 33.6 ± 9.4 months) with vitreous seeding injected with intravitreal melphalan and topotecan. IOP was measured with Tonopen (Reichert, Inc., Buffalo, NY) at baseline prior to injecting and then repeatedly following each intravitreal injection.. Mean pre-injection IOP was 8.2 ± 2.3 mm Hg (range: 4 to 12 mm Hg). Mean IOP 1 to 30 seconds after intravitreal melphalan (first injection) was 45.4 ± 14.3 mm Hg. The IOP of 89.5% of patients declined to 29 mm Hg or less in a mean 153.3 ± 97.5 seconds. Mean IOP 1 to 30 seconds after intravitreal topotecan (second injection) was 44.5 ± 11.0 mm Hg, which decreased to 31.0 ± 5.0 mm Hg by 150 seconds after injection. No significant relationship was found between age and post-injection IOP elevation. IOP exceeded the calculated mean arterial perfusion pressure in four encounters.. Intravitreal chemotherapy caused a transient rise in IOP. Post-injection IOP elevations can reach levels that may exceed mean arterial pressure. [J Pediatr Ophthalmol Strabismus. 2017;54(3):185-190.].

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Intraocular Pressure; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topoisomerase I Inhibitors; Topotecan; Treatment Outcome; Vitreous Body; Young Adult

To evaluate the therapeutic outcome of intravitreal melphalan injection in the management of vitreous disease in patients with retinoblastoma. We particularly aimed to assess whether higher melphalan dose with lower number of injections was more effective and associated with fewer side effects.. This retrospective, interventional, noncomparative, and nonrandomized study included 39 eyes of 37 patients. Vitreous seeds were classified as dust, sphere, and cloud types. Intravitreal injections were performed through pars plana free of any visible tumor using 30-G needle. Response of the seeds (disappearance, conversion into inactive debris, or progression) and enucleation rate were determined as outcome measures.. All patients previously received systemic or intra-arterial chemotherapy. Vitreous seeding was primary in 54% of eyes and secondary in 46% of eyes. Vitreous seeds were classified as dust in 9 (23.1%) eyes, sphere in 24 (61.5%) eyes, and cloud in 6 (15.4%) eyes. Melphalan dose varied between 20 and 40 µg and 20 (51.3%) eyes received >30 µg. The total number of injections was 70 (range 1-5, mean 1.8 per eye). Various types of regression were obtained in 27 (69.2%) eyes. Sphere-type seeds were the most responsive to melphalan. Nonresponse and disease progression were noted in 12 (30.8%) eyes. After a mean follow-up of 11.8 months, 17 (44%) eyes were enucleated. Vitreous hemorrhage (18%) and retinal pigment epithelial alterations (8%) were the most common side effects.. Intravitreal melphalan at 30-40 µg in 1 or 2 injections proved effective in 69.2% of eyes with vitreous disease.

Topics: Antineoplastic Agents, Alkylating; Child; Child, Preschool; Disease Progression; Female; Humans; Infant; Intravitreal Injections; Logistic Models; Male; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Vitreous Body; Vitreous Hemorrhage

Reports on retinoblastoma relapse at the optic nerve head (ONH) are anecdotal and include only treatments by external beam radiotherapy (EBRT) or enucleation. We aimed to describe such cases, termed secondary epipapillary retinoblastoma, diagnosed and monitored with the assistance of hand-held spectral domain optical coherence tomography (HHSD-OCT) and treated with intraophthalmic artery chemotherapy (IAC) and/or intravitreous chemotherapy (IViC).. A retrospective analysis of secondary epipapillary retinoblastoma cases treated conservatively.. Four males and two females were included, diagnosed with secondary epipapillary retinoblastoma at a median time of 8.6 months (mean 24.0) from initial retinoblastoma diagnosis. HHSD-OCT was used in all cases for accurate diagnosis; in 2/6, the epipapillary relapse was detected only by means of HHSD-OCT. Treatments for secondary epipapillary retinoblastoma included IAC and IViC (n=4), IAC alone (n=1) and IViC alone (n=1). HHSD-OCT demonstrated complete epipapillary tumour regression in all cases, achieved in a median time of 1.6 months (mean 1.8). The median time from secondary epipapillary retinoblastoma resolution to last visit was 29.2 months (mean 27.5). At last visit, all eyes were tumour-free and no cases of metastasis recorded.. Cases of retinoblastoma relapse at the ONH show common clinical features and represent specific diagnostic and therapeutic challenge; hence, we propose to consider this condition as a subset of retinoblastoma, termed secondary epipapillary retinoblastoma. HHSD-OCT is an invaluable diagnostic tool in the initial diagnosis as well as in monitoring these lesions, and IAC and IViC are efficient modalities for this clinical scenario, obviating the need for EBRT or enucleation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Carboplatin; Child, Preschool; Cryotherapy; Female; Humans; Hyperthermia, Induced; Infant; Infusions, Intra-Arterial; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Tomography, Optical Coherence; Topotecan

To evaluate the effects of intra-arterial chemotherapy on retrobulbar blood flow parameters in patients with retinoblastoma.. 20 eyes of 10 patients with unilateral retinoblastoma that were treated with intra-arterial chemotherapy were evaluated using colour Doppler imaging. The peak systolic and end-diastolic velocities of the ophthalmic, central retinal and posterior ciliary arteries were determined. The pulsatility and resistance indices were calculated automatically. The treated eye was compared with the untreated (control) eye and with itself before and after intra-arterial chemotherapy.. When comparing the retinoblastoma-containing eyes with the contralateral normal eyes, the peak systolic and end-diastolic velocities of the central retinal artery were significantly higher in the tumorous eyes than in the normal eyes before intra-arterial chemotherapy. Moreover, the peak systolic and end-diastolic velocities in the posterior ciliary and central retinal arteries were significantly decreased after intra-arterial chemotherapy in the tumorous eyes (p<0.05). There were no statistically significant differences in the other parameters.. Our results suggest that intra-arterial chemotherapy has a measurable effect on the retrobulbar blood flow, which can cause a decrease in the peak systolic and end-diastolic velocities in the posterior ciliary and central retinal arteries.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Flow Velocity; Carboplatin; Child, Preschool; Ciliary Arteries; Echocardiography, Doppler, Color; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Orbit; Pulsatile Flow; Regional Blood Flow; Retinal Artery; Retinal Neoplasms; Retinoblastoma

Topics: Antineoplastic Combined Chemotherapy Protocols; Catgut; Eye Enucleation; Fluorescein Angiography; Foreign-Body Reaction; Granuloma, Foreign-Body; Humans; Infant; Intravitreal Injections; Magnetic Resonance Imaging; Male; Melphalan; Neoplasm Staging; Orbital Diseases; Orbital Implants; Retinal Neoplasms; Retinoblastoma; Suture Techniques; Topotecan

We aimed to evaluate the therapeutic effect and complications of combined intravitreal melphalan and intravenous/intra-arterial chemotherapy as a primary approach for retinoblastoma with vitreous seeds.. In this retrospective case series, eight eyes from eight retinoblastoma patients with vitreous seeds were included. All eyes received 20-30 μg of intravitreal melphalan accompanied by intravenous and intra-arterial chemotherapy. Triple freeze-thaw cryotherapy was performed when withdrawing the needle from the eye to prevent tumor dissemination.. Tumors and vitreous seeds regressed in all eyes. The mean number of intravitreal melphalan injections was 3.25 (median 3.50, range 2-4). Globe salvage was attained in seven of eight eyes (87.5 %). Enucleation was performed in one case, in which the pathologic section showed no residual tumor and tumor-free resection margins. Serous retinal detachment was observed in four eyes (50 %), and vitreous hemorrhage developed in two (25 %). Retinal pigment epithelium atrophy or mottling was found in three eyes (37.5 %). There were no cases of extraocular tumor extension or remote metastasis.. Combined intravitreal melphalan and intravenous/intra-arterial chemotherapy was effective for tumor and vitreous seeding control, but vision-threatening complications such as vitreous hemorrhage or serous retinal detachment occurred in half the cases.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Combined Modality Therapy; Female; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Vitreous Body

Selective ophthalmic artery infusion chemotherapy (SOAIC) is increasingly used to treat retinoblastoma. We report the toxicities and outcome of 19 eyes in 17 patients with retinoblastoma receiving SOAIC treatment between 2008 and 2013. From the 87 treatments, mild local reactions were common. Myelosuppression was more common after triple-agent SOAIC (melphalan, carboplatin, and topotecan) than single-agent melphalan. Ocular salvage was achieved in 11 of 19 eyes and associated with triple-agent therapy. SOAIC is a effective therapy for some retinoblastoma with manageable toxicity; however, systemic toxicity increases with increasing therapeutic intensity of SOAIC.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan

This case series highlights the novel use of intravitreal melphalan for nonvitreous retinoblastoma. It assesses the efficacy and toxicity of intravitreal melphalan for nonvitreous retinoblastoma.. This observational small case series investigates three patients treated with intravitreal melphalan for nonvitreous retinoblastoma that was refractory to multiple-course ophthalmic artery chemosurgery. Patients' demographics, response to treatment, and toxicity of treatment as clinically evaluated are measured by electroretinogram.. Three eyes of three patients received a median of 7 weekly intravitreal melphalan injections (30 μg/0.07 cc) for persistent retinal or subretinal tumors refractory to treatment with multiple-course ophthalmic artery chemosurgery.. Eyes remain tumor free at a median of 14-month follow-up. One eye was enucleated because of a vitreous hemorrhage that obscured fundus details. One eye had extinguished electroretinogram recordings before injections and two eyes had a decrease in electroretinogram responses over the intravitreal treatment course. The eye with subretinal seeding demonstrated marked retinopathy by ophthalmoscopy and fluorescein angiography and one eye was enucleated because of the development of a vitreous hemorrhage.. This small case series highlights that nonvitreous disease that is, refractory or persistent despite previous ophthalmic artery chemosurgery can regress with intravitreal melphalan. However, this treatment may result in retinal toxicity.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Female; Humans; Infant; Intravitreal Injections; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Salvage Therapy; Treatment Outcome

To investigate on the safety and efficacy of intravitreous chemotherapy for retinoblastoma seeding in a relatively large cohort and provide information on the necessary number of injections and long-term control.. Retrospective interventional case series of 40 consecutive eyes with viable vitreous seeding after standard treatment of retinoblastoma. All eyes received intravitreal melphalan injection (20-30 μg) and additional topotecan (20 μg) as needed using the trans pars plana route with triple freeze-thaw cryotherapy at needle withdrawal for prevention of extraocular seeding for planned six cycles.. The mean patient age at presentation was 36 months, and interval to need for vitreous injection was 14 months. Viable vitreous (n = 40 eyes) and additional subretinal (n = 2 eyes) seeds were documented. There was a total of 192 injections using melphalan (n = 148) and/or topotecan (n = 44) with mean number of injections per eye of melphalan at 4 (median, 4; range, 1-6) and topotecan at 3 (median, 3; range, 1-5). Fewer than six planned melphalan injections (n = 31 cases, 78%) were necessary because of rapid and complete vitreous seed control (n = 30 eyes) or melphalan allergy (n = 1 eye). Fewer than six planned topotecan injections (n = 14 cases, 100%) were necessary because of rapid and complete vitreous seed control in all cases. At median 3-year follow-up, therapeutic success with continued seed regression was observed in all 40 eyes (100%). Globe salvage was attained in 35 cases (88%), and enucleation (n = 5) was necessary for extensive recurrent subretinal seeds (n = 2), neovascular glaucoma with vitreous hemorrhage (n = 2), and hemorrhagic retinal necrosis (n = 1). Side effects included focal retinal pigment epithelial mottling at the site of injection (n = 12), minor focal paraxial lens opacity (not requiring cataract surgery) (n = 11), transient focal vitreous hemorrhage (n = 5), transient hypotony (n = 3), transient retinal hemorrhage (n = 2), optic disc edema (n = 1), and hemorrhagic retinal necrosis (n = 1). There was no case of endophthalmitis, extraocular tumor extension, metastasis, or death.. Intravitreal melphalan and/or topotecan injection for retinoblastoma vitreous seeding provides lasting tumor control at 3 years with approximately 4 injections.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Eye Neoplasms; Female; Follow-Up Studies; Humans; Infant; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan; Vitreous Body

Topics: Antineoplastic Agents, Alkylating; Eye Neoplasms; Humans; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Vitreous Body

Topics: Antineoplastic Agents, Alkylating; Eye Neoplasms; Humans; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Vitreous Body

Controlling retinoblastoma with seeding is challenging despite advances in treatment modalities. Intravitreal melphalan is an alternative to external beam radiation or enucleation for recurrent or refractory vitreous seeds. Significant ocular side effects following intravitreal melphalan injections are uncommon. Complications have been reported in eyes receiving higher concentrations of melphalan and repetitive injections. We report a case in which diffuse chorioretinal atrophy was developed at the injection site after a single, standard low-dose intravitreal melphalan injection.. A 12-month-old female child without a family history of retinoblastoma presented with unilateral group C retinoblastoma in her right eye. A solitary tumour with retinal breaks on the tumour surface, and vitreous seeds overlying the tumour were observed at the 8 o'clock position of the retina. After two cycles of intra-arterial chemotherapy with melphalan, the main tumour displayed significant regression, but the vitreous seeds overlying the main tumour were still active. Because of the persistence of vitreous seeds and the inadequate response to intra-arterial melphalan treatment, intravitreal melphalan (8 μg in 0.05 mL) was injected using a 32-gauge needle 2.5 mm from the 5 o'clock position of the limbus, the meridian opposite to the vitreous seeds. After 1 month, the retina around the injection site demonstrated diffuse retinal pigment epithelium alterations with dense hard exudates. Although the main retinal mass, and vitreous seeds resolved, the hard exudates persisted for more than 2 years after the single low-dose melphalan injection.. Intravitreal melphalan injections should be cautiously used for eyes with refractory seeds, particularly when multiple injections are required to control retinoblastoma seeds. Dose- related retinal toxicity could occur in pre-treated eyes even when a relatively low standard dose is used. Such patients should be followed up closely to monitor the treatment response and to assess potential delayed toxicity.

Topics: Antineoplastic Agents, Alkylating; Atrophy; Female; Humans; Infant; Intravitreal Injections; Melphalan; Retina; Retinal Dystrophies; Retinal Neoplasms; Retinoblastoma

To evaluate the patient, disease, and tumor characteristics of the 3 morphologically distinct groups of vitreous seeds in retinoblastoma presenting for treatment with ophthalmic artery chemosurgery (OAC): dust (class 1), spheres (class 2), and clouds (class 3) in primary and recurrent vitreous seeds.. Retrospective cohort study of patients treated for vitreous seeds at Memorial Sloan Kettering Cancer Center between May 2006 and March 2015.. A total of 135 eyes with active vitreous seeds, presenting for primary treatment with OAC or with recurrent vitreous disease.. Vitreous seeds were classified into 3 groups: dust, spheres, and clouds. Indirect ophthalmoscopy, fundus photography, ultrasonography, and ultrasonic biomicroscopy were used to locate and evaluate the extent of retinal and vitreous disease. Patient and disease characteristics (age, laterality of disease, treatment status) were compared among classification groups. A 2-tailed Fisher exact test and paired Student t test were used for statistical analysis.. Age of patient, laterality of disease, location of retinal disease, extent of vitreous disease, and treatment status.. Primary treated disease: Patients with eyes containing class 3 (cloud) vitreous seeds were significantly older than patients with class 1 or 2 seeds (P < 0.05). The median age of patients with class 1, 2, and 3 seeds was 11, 15.5, and 32 months, respectively. Eyes containing class 3 seeds were significantly more likely to occur in the equator-ora region of the fundus (P < 0.0001), in a diffuse pattern (P < 0.0001), and in patients with unilateral disease (P < 0.05), compared with class 1 and 2 seeds. Recurrent disease: Recurrent vitreous seeds were significantly more common to class 2 (P < 0.05), occurring in a diffuse pattern (P = 0.01) and in patients with bilateral disease (P < 0.001).. The 3 classes of vitreous seeds have distinct clinical characteristics associated with the age of patient, laterality of disease, and extent and location of tumor-producing seeds. Furthermore, recurrent vitreous seeds appear to have a unique clinical profile compared with seeds receiving primary treatment.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Female; Humans; Infant; Male; Melphalan; Neoplasm Recurrence, Local; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Vitreous Body

Topics: Antineoplastic Agents, Alkylating; Cerebral Infarction; Humans; Infant; Infusions, Intra-Arterial; Magnetic Resonance Angiography; Male; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child, Preschool; Etoposide; Eye Enucleation; Fluorescein Angiography; Humans; Infusions, Intra-Arterial; Intravitreal Injections; Magnetic Resonance Imaging; Male; Melphalan; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Seeding; Optic Nerve Neoplasms; Retinal Neoplasms; Retinoblastoma; Treatment Failure

BACKGROUND Retinoblastoma (RB) is the most common malignant tumor of the eye in childhood. The objective of this paper was to investigate carboplatin (CAR)- and melphalan (MEL)-induced dynamic module changes in RB based on multiple (M) differential networks, and to generate systems-level insights into RB progression. MATERIAL AND METHODS To achieve this goal, we constructed M-differential co-expression networks (DCNs), assigned a weight to each edge, and identified seed genes in M DCNs by ranking genes based on their topological features. Starting with seed genes, a module search was performed to explore candidate modules in CAR and MEL condition. M-DMs were detected according to significance evaluations of M-modules, which originated from refinement of candidate modules. Further, we revealed dynamic changes in M-DM activity and connectivity on the basis of significance of Module Connectivity Dynamic Score (MCDS). RESULTS In the present study, M=2, a total of 21 seed genes were obtained. By assessing module search, refinement, and evaluation, we gained 18 2-DMs. Moreover, 3 significant 2-DMs (Module 1, Module 2, and Module 3) with dynamic changes across CAR and MEL condition were determined, and we denoted them as dynamic modules. Module 1 had 27 nodes of which 6 were seed genes and 56 edges. Module 2 was composed of 28 nodes and 54 edges. A total of 28 nodes interacted with 45 edges presented in Module 3. CONCLUSIONS We have identified 3 dynamic modules with changes induced by CAR and MEL in RB, which might give insights in revealing molecular mechanism for RB therapy.

Topics: Carboplatin; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Melphalan; Retinoblastoma

To report our 4-year experience in Turkey, with advanced intra-ocular retinoblastoma managed primarily with intra-arterial chemotherapy (IAC).. From October 2011 to September 2015, 26 group D eyes of 24 treatment-naïve retinoblastoma patients managed primarily with IAC were evaluated in this prospective study.. Of 76 procedures, ophthalmic artery cannulation failed in two patients with unilateral involvement. In the remaining 22 patients (24 eyes), the mean age at diagnosis was 18 months (range, 6-55 months). Each eye received a mean of 3 IAC sessions/eye (range, 2-5 sessions). After a median follow-up of 29 months (range, 6-55 months), complete regression of the main tumour was achieved in 23 of 24 eyes. One eye with partial regression required enucleation due to ciliary body involvement by the tumour. Overall, 16 eyes (66.6%) were salvaged with primary IAC with or without additional local treatments, and eight (33.3%) required enucleation. The main IAC-related periocular complications included transient eyelid oedema (n = 13), ptosis (n = 6) and forehead hyperpigmentation (n = 3), each resolving in 2 weeks to 4 months. Intra-ocular complications included chorioretinal atrophy (n = 9), newly noted retinal detachment (n = 5) and vitreous haemorrhage (n = 1). Kaplan-Meier eye estimates of enucleation-free survival rates were 83.3% (95% CI, 68.4-98.1%), 69.1% (95% CI, 49.8-88.3%) and 62.9 (95% CI, 41.9-83.8%) at 6 months, 1 and 2 years, respectively, and stable thereafter.. Our first 4-year experience in Turkey showed that enucleation or external-beam radiotherapy could be avoided in two-thirds of eyes with advanced intra-ocular retinoblastoma managed primarily with IAC.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Female; Fluoroscopy; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Prospective Studies; Retinal Neoplasms; Retinoblastoma; Treatment Outcome; Turkey

Report on the 7-year experience with bilateral ophthalmic artery chemosurgery (OAC-Tandem therapy) for bilateral retinoblastoma.. Retrospective, single institution study.. 120 eyes of 60 children with bilateral retinoblastoma treated since March 2008.. Retrospective review of all children treated at Memorial Sloan Kettering with bilateral ophthalmic artery chemosurgery (Melphalan, Carboplatin, Topotecan, Methotrexate) delivered in the same initial session to both naïve and previously treated eyes.. Ocular survival, metastatic disease, patient survival from metastases, second cancers, systemic adverse effects, need for transfusion of blood products, electroretinogram before and after treatment.. 116 eyes were salvaged (4 eyes were enucleated: 3 because of progressive disease, 1 family choice). Kaplan Meier ocular survival was 99.2% at one year, 96.9% at 2 and 3 years and 94.9% for years 4 through 7. There were no cases of metastatic disease or metastatic deaths with a mean follow-up of 3.01 years. Two children developed second cancers (both pineoblastoma) and one of them died. Transfusion of blood products was required in 3 cases (4 transfusions), 1.9%. Two children developed fever/neutropenia requiring hospitalization (0.95%). ERGs were improved in 21.6% and unchanged after treatment in 52.5% of cases (increase or decrease of less than 25μV).. Bilateral ophthalmic artery chemosurgery is a safe and effective technique for managing bilateral retinoblastoma-even when eyes are advanced bilaterally, and if both eyes have progressed after systemic chemotherapy. Ocular survival was excellent (94.9% at 8 years), there were no cases of of metastatic disease and no deaths from metastatic disease, but children remain at risk for second cancers. In 21.6% of cases ERG function improved. Despite using chemotherapy in both eyes in the same session, systemic toxicity was low.

Topics: Carboplatin; Child; Child, Preschool; Electroretinography; Female; Humans; Kaplan-Meier Estimate; Male; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan

Topics: Antineoplastic Agents, Alkylating; Cell Transformation, Neoplastic; Child; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmoscopy; Retinal Neoplasms; Retinoblastoma

To describe the results of intra-arterial chemotherapy (IAC) for control of persistent or recurrent subretinal seeds (SRS) following previous chemotherapy for retinoblastoma.. We reviewed the medical records of patients with massive persistent or recurrent SRS after intravenous and/or intra-arterial chemotherapy and subsequently treated with superselective ophthalmic artery infusion of melphalan (3, 5, or 7.5 mg) and/or additional topotecan (1 mg) and/or carboplatin (20 or 30 mg) as necessary from January 2009 to March 2014. The main outcome measures were SRS control and globe salvage.. A total of 30 eyes of 29 patients were included. Mean patient age was 19 months (median, 14 months; range, 2-58 months). Previous treatments included intravenous chemotherapy (n = 28) and intra-arterial chemotherapy (n = 5). The SRS occupied a median of 6 clock hours. Retinal detachment was present in 5 eyes (17%). Each eye received a mean of 3 IAC sessions (median, 2; range, 1-7) on a monthly basis. After a mean follow-up of 24 months (median, 18; range, 1-71 months), 27 of eyes (90%) demonstrated complete SRS regression. Overall, globe salvage was achieved in 15 eyes (50%). Fifteen eyes were enucleated because of recurrent SRS (4 eyes), recurrent SRS and vitreous seeds (3 eyes), recurrent solid tumor (1 eye), and neovascular glaucoma from total retinal detachment and/or vitreous hemorrhage (7 eyes), none of which had active tumor.. IAC can be an effective second- or third-line therapy in the management of massive persistent or recurrent SRS from retinoblastoma following previous chemotherapy. All eyes in this study were all facing enucleation; lasting seed control was achieved in 70%.

Topics: Antineoplastic Agents; Carboplatin; Child, Preschool; Female; Humans; Infant; Male; Melphalan; Neoplasm Recurrence, Local; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan

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.].

Topics: Antineoplastic Agents, Alkylating; Child; Child, Preschool; Eye Enucleation; Female; Humans; Infant; Infusions, Intra-Arterial; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topoisomerase I Inhibitors; Topotecan

A 32-year-old man with active unilateral group D retinoblastoma that was recurrent following external beam radiotherapy was treated with intra-arterial chemotherapy, leading to tumor regression. Additional plaque radiotherapy and intravitreal chemotherapy were required for complete control. Final visual acuity was 20/40. In selected cases, adult-onset retinoblastoma can be managed with intra-arterial chemotherapy. [J Pediatr Ophthalmol Strabismus. 2016;53:e43-e46.].

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Combined Modality Therapy; Humans; Infusions, Intra-Arterial; Male; Melphalan; Neoplasm Recurrence, Local; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Topotecan; Ultrasonography; Visual Acuity; Vitreous Body

Topics: Antineoplastic Agents, Alkylating; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma

Topics: Antineoplastic Agents, Alkylating; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma

Topics: Antineoplastic Agents, Alkylating; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma

Topics: Antineoplastic Agents, Alkylating; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma

Retinoblastoma is the most common intraocular malignancy of childhood. Notch plays a key role in retinal cells from which retinoblastomas arise, and we therefore studied the role of Notch signaling in promoting retinoblastoma proliferation. Moderate or strong nuclear expression of Hes1 was found in 10 of 11 human retinoblastoma samples analyzed immunohistochemically, supporting a role for Notch in retinoblastoma growth. Notch pathway components were present in WERI Rb1 and Y79 retinoblastoma lines, with Jag2 and DLL4 more highly expressed than other ligands, and Notch1 and Notch2 more abundant than Notch3. The cleaved/active form of Notch1 was detectable in both lines. Inhibition of the pathway, achieved using a γ-secretase inhibitor (GSI) or by downregulating Jag2, DLL4 or CBF1 using short hairpin RNA, potently reduced growth, proliferation and clonogenicity in both lines. Upregulation of CXCR4 and CXCR7 and downregulation of PI3KC2β were identified by microarray upon Jag2 suppression. The functional importance of PI3KC2β was confirmed using shRNA. Synergy was found by combining GSI with Melphalan at their IC50. These findings indicate that Notch pathway is active in WERI Rb1 and Y79, and in most human retinoblastoma samples, and suggest that Notch antagonists may represent a new approach to more effectively treat retinoblastoma.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Class II Phosphatidylinositol 3-Kinases; Cyclic S-Oxides; Humans; Jagged-2 Protein; Melphalan; Receptors, Notch; Retinal Neoplasms; Retinoblastoma; Signal Transduction; Thiadiazoles

The prognosis of high-risk retinoblastoma (RB) with extraocular disease, relapse, or invasion of the cut end of the optic nerve is extremely poor. Following the discontinuation of thiotepa production in Japan, BU- and melphalan (Mel)-based regimens have been used, followed by the standard treatment for neuroblastoma. This study retrospectively analyzed 14 high-risk RB patients who underwent high-dose chemotherapy (HDC) and hematopoietic SCT; 8 received a BU/Mel conditioning regimen and 6 received other regimens. The disease status at HDC was relapse in 8 patients and extraocular involvement in 5. All patients received peripheral blood stem cell infusion >1.5 × 10(6)/kg. Engraftment occurred within a median of 11 days (BU/Mel: 10-13, others: 9-13). Primary toxicities included mucositis (⩾grade 3) in 9 patients (4 with BU/Mel, 5 with others). Veno-occlusive disease (VOD) occurred in two 1-year-old patients in the BU/Mel group. There were no treatment-related deaths. Of 4 (2 with BU/Mel, 2 with others) patients with central nervous system (CNS) relapse after HDC, 3 died. In conclusion, the BU/Mel regimen may be feasible for high-risk RB under careful monitoring for VOD, particularly in younger patients. CNS relapse associated with a lethal prognosis occurred after all regimens; therefore, further evaluation of HDC efficacy for high-risk RB is required.

Topics: Allografts; Busulfan; Child, Preschool; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Infant; Japan; Male; Melphalan; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Transplantation Conditioning

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Atrophy; Chemotherapy, Cancer, Regional Perfusion; Choroid; Choroid Diseases; Combined Modality Therapy; Diseases in Twins; Enophthalmos; Female; Fluorescein Angiography; Humans; Infant; Laser Coagulation; Magnetic Resonance Imaging; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Scleritis; Topoisomerase I Inhibitors; Topotecan; Twins, Monozygotic

To describe tumor response and complications after selective ophthalmic arterial injection (SOAI) of melphalan for treatment of intraocular retinoblastoma.. A retrospective review of 17 eyes (12 patients) treated with SOAI of melphalan from January 2010 through December 2013 at Chang Gung Memorial Hospital.. SOAI was successfully performed in 49 of 54 attempts. Six eyes underwent SOAI as the primary treatment and 11 eyes had previously been treated with other treatment modalities. Subsequent to SOAI, tumor regression was observed in 12 of 17 eyes, and vitreous seeding with complete or partial regression in ten of 15 eyes. Globe salvage was achieved in ten of 17 eyes, with three of four in group B and group C eyes, and seven of 13 in group D and group E eyes. Pancytopenia accompanied by neutropenic fever was observed in one case. Twelve eyes had local side effects, including lid edema (two eyes), third cranial nerve palsy (two eyes), sixth cranial nerve palsy (one eye), chorioretinal atrophy (six eyes), retinal arterial occlusion (three eyes), retinal detachment (one eye), and vitreous hemorrhage (seven eyes). Three cases with high-risk features, according to the histopathologic examination, had metastatic disease, and two of them died.. SOAI of melphalan is an effective treatment for intraocular retinoblastoma, achieving high globe salvage in cases of advanced disease, but can be associated with significant ocular complications. Repetitive SOAI with delayed enucleation could increase the risk of metastasis when used in high-risk cases. Therefore, clinicians should consider the benefits and potential risks and use this new technique with caution.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Injections, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies

Assess the usefulness of second-course ophthalmic artery chemosurgery (OAC) for patients with intraocular retinoblastoma that recurred after prior OAC. This study evaluated the efficacy and toxicity of second-course OAC.. Single-arm retrospective study of 29 eyes of 30 patients treated with second-course OAC at Memorial Sloan Kettering Cancer Center between May 2006 and July 2013, with a median follow-up of 25.9 months.. Retinoblastoma patients who underwent a course of OAC, with a minimum of 2 months of progression-free follow-up at monthly examinations, but who subsequently received additional OAC for recurrent tumor.. To determine efficacy, Kaplan-Meier survival estimates were generated and the Mantel-Cox test was used to compare curves. To determine toxicity, electroretinography (ERG) amplitudes were measured in response to 30-Hz photopic flicker stimulation before and after OAC treatment; systemic adverse events were graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0).. For efficacy, ocular progression-free survival, ocular event-free survival (e.g., enucleation, external-beam radiation, or intravitreal melphalan), and ocular survival. For toxicity, peak-to-peak comparisons between ERG studies before and after OAC treatment and CTCAE 4.0-graded systemic adverse events.. Fifty percent of all recurrences were within 4.4 months and 90% were within 16 months of completion of the first course of OAC. The 2-year Kaplan-Meier ocular survival, event-free survival, and progression-free survival estimates after second-course OAC were 82.8% (95% confidence interval [CI], 60.1%-93.2%), 57.3% (95% CI, 36.1%-73.7%), and 26.5% (95% CI, 11.0%-45.0%), respectively. All eyes without vitreous seeding were progression free, whereas eyes with vitreous seeding were associated significantly with worse ocular survival after second-course OAC (P = 0.03). After second-course OAC, 90% of eyes had stable or improved ERG responses. Of all evaluable cases, there was no increased risk of systemic toxicity during the second course compared with the initial course of OAC.. Retinoblastoma eyes requiring second-course OAC after initial OAC treatment have good salvage rates, and the treatment has an acceptable ocular and systemic toxicity profile. However, these eyes often require additional (third- or fourth-course) OAC or other treatment methods because of progression of disease after second-line OAC, particularly if vitreous seeds are present at the time of initial OAC failure.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Child; Child, Preschool; Disease-Free Survival; Electroretinography; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Neoplasm Recurrence, Local; Neoplasm Seeding; Ophthalmic Artery; Retina; Retinal Neoplasms; Retinoblastoma; Retreatment; Retrospective Studies; Salvage Therapy; Treatment Outcome; Vitreous Body

Topics: Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Eye Neoplasms; Female; Fovea Centralis; Humans; Infusions, Intra-Arterial; Intravitreal Injections; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Tomography, Optical Coherence; Topotecan; Vitreous Body

To evaluate the clinical characteristics of the 3 classifications of vitreous seeds in retinoblastoma-dust (class 1), spheres (class 2), and clouds (class 3)-and their responses to intravitreal melphalan.. Retrospective, bi-institutional cohort study.. A total of 87 patient eyes received 475 intravitreal injections of melphalan (median dose, 30 μg) given weekly, a median of 5 times (range, 1-12 times).. At presentation, the vitreous seeds were classified into 3 groups: dust, spheres, and clouds. Indirect ophthalmoscopy, fundus photography, ultrasonography, and ultrasonic biomicroscopy were used to evaluate clinical response to weekly intravitreal melphalan injections and time to regression of vitreous seeds. Kaplan-Meier estimates of time to regression and ocular survival, patient survival, and event-free survival (EFS) were calculated and then compared using the Mantel-Cox test of curve.. Time to regression of vitreous seeds, patient survival, ocular survival, and EFS.. The difference in time to regression was significantly different for the 3 seed classes (P < 0.0001): the median time to regression was 0.6, 1.7, and 7.7 months for dust, spheres, and clouds, respectively. Eyes with dust received significantly fewer injections and a lower median and cumulative dose of melphalan, whereas eyes with clouds received significantly more injections and a higher median and cumulative dose of melphalan. Overall, the 2-year Kaplan-Meier estimates for ocular survival, patient survival, and EFS (related to target seeds) were 90.4% (95% confidence interval [CI], 79.7-95.6), 100%, and 98.5% (95% CI, 90-99.7), respectively.. The regression and response of vitreous seeds to intravitreal melphalan are different for each seed classification. The vitreous seed classification can be predictive of time to regression, number, median dose, and cumulative dose of intravitreal melphalan injections required.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Child; Child, Preschool; Cohort Studies; Disease-Free Survival; Eye Neoplasms; Follow-Up Studies; Humans; Infant; Intravitreal Injections; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Survival Rate; Vitreous Body

To investigate the safety and efficacy of intravitreal injection of melphalan for retinoblastoma.. A retrospective chart review of all patients who were administered intravitreal injections of melphalan for retinoblastoma between 1990 and 2011. A total of 264 eyes of 250 patients were included. All ocular adverse events, systemic prognosis, ocular prognosis, and visual acuity were investigated.. The total number of intravitreal injections administered was 1,067; each eye received between one and 25 injections. A postoperative subconjunctival tumor developed in one eye. None of the eyes suffered infections or uveitis, and all other adverse events including chorioretinal atrophy displayed incidences of less than 1.5 %. At 5 postoperative years, the cumulative incidence of cataract surgery was 3.1 % among the eyes that were treated without ocular hyperthermia. Distant metastasis or intracranial invasion occurred in 11 patients, all of whom had high-risk pathological factors for metastasis such as optic nerve invasion, but refused to receive adjuvant chemotherapy. Sixty-eight percent of the eyes achieved complete vitreous seed remission, but recurrence occurred in 19 % of these eyes after 10.0 ± 4.9 months. In addition, 47 and 27 % of the eyes without primary macular tumors retained visual acuity of >0.5 and >1.0, respectively.. The risk of extraocular tumor spreading following intravitreal injections is low, and other adverse events are rare. Sixty-eight percent of the treated eyes achieved complete vitreous seed remission, and about half of them retained practical levels of vision. The intravitreal injection of melphalan is a safe and effective treatment for vitreous seeds.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Child; Child, Preschool; Female; Humans; Infant; Intravitreal Injections; Male; Melphalan; Neoplasm Recurrence, Local; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Vitreous Body; Young Adult

Intra-arterial melphalan chemotherapy (IAC) continues to demonstrate excellent utility in the treatment of retinoblastoma. We present the case of a 3-month-old boy diagnosed with with unilateral, advanced stage 5B retinoblastoma and a Coats' response in the right eye. After laser therapy he received 3 doses of IAC. Intraretinal hemorrhaging, first noted after the second dose and worsening after the third, preceded complex exudative retinal detachment. With little visual potential and evidence of atropy, the eye was enucleated. This case illustrates that intraretinal hemorrhage may serve as an early predictor of treatment failure.

Topics: Antineoplastic Agents, Alkylating; Eye Enucleation; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Neoplasm Seeding; Neoplasm Staging; Retinal Detachment; Retinal Hemorrhage; Retinal Neoplasms; Retinoblastoma; Treatment Failure; Visual Acuity; Vitreous Body

To determine the efficacy of rescue intra-arterial chemotherapy (IAC) for retinoblastoma recurrence following failed initial IAC.. Retrospective, non-comparative, interventional case series of 12 eyes in 12 patients.. Rescue IAC employed chemotherapy agents of melphalan (5mg, 7.5mg) alone or with additional topotecan (1mg).. Tumor control and globe salvage.. The median patient age at initial presentation was 16 months. At initial examination, the International Classification of Retinoblastoma grouping was group B (n=1), group D (n=7), or group E (n=4). The initial IAC was primary in 5 cases (42%) and secondary following failure of intravenous chemotherapy in 7 (58%). In all cases, initial IAC was delivered using melphalan 3mg (n=3), melphalan 5mg (n=7), or combination melphalan 5mg/topotecan 1mg (n=2) for a median of 3 cycles. The mean interval from initial IAC to recurrence necessitating rescue IAC was 5 months (median 4, range 2-10 months). Of the 12 patients, 3 (25%) had undergone previous enucleation of the opposite eye and the rescue IAC was planned for the only remaining eye. Rescue IAC was delivered for recurrent solid tumor (n=1), recurrent subretinal seeds (n=7), recurrent vitreous seeds (n=1), or combination recurrent subretinal/vitreous seeds (n=3). IAC was technically successful through the ophthalmic artery in 9 cases (75%) or the middle meningeal artery in 3 (25%). Rescue IAC involved median 3 cycles (mean 3, range 2-4 cycles) of higher dose melphalan in 4 cases (33%) or combination melphalan/topotecan in 8 (67%). At mean follow-up of 20 months (median 14 months, range 7-36 months), complete tumor control was achieved in 9 eyes (75%) and globe salvage in 8 eyes (67%). Of the 3 failure eyes, all were initially groups D or E, previously treated with initial IAC, and 2 had previous intravenous chemotherapy. There were 4 eyes that came to enucleation for persistent subretinal/vitreous seeds (n=3) or neovascular glaucoma without viable tumor (n=1). There was no case of cerebrovascular stroke, systemic metastasis, or death.. Rescue IAC following retinoblastoma recurrence after initial IAC provided tumor control in 75% of cases and globe salvage in 67%. Rescue IAC can be considered in children who fail initial IAC, especially if the opposite eye has been enucleated.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Child, Preschool; Eye Enucleation; Female; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Neoplasm Recurrence, Local; Retinal Neoplasms; Retinoblastoma; Retinoscopy; Retreatment; Salvage Therapy; Topotecan; Treatment Failure; Treatment Outcome

A 10-month old infant was referred for the study of a leukocoria of the left eye of one month onset. On examination, a retinoblastoma occupying the macular area was detected. Treatment with intra-arterial chemotherapy (melphalan 6 mg) was performed, with no further intervention required for disease control.. Melphalan is an effective chemotherapeutic agent. However, its use is limited by the systemic toxicity that may occur. Intra-arterial chemotherapy allows the selective release of melphalan into the ophthalmic artery, thus limiting its systemic toxicity. This combination of efficiency, safety and accuracy makes it an attractive therapeutic alternative for the management of retinoblastoma.

Topics: Antineoplastic Agents, Alkylating; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Radiography, Interventional; Remission Induction; Retinal Neoplasms; Retinoblastoma

To describe treatment outcomes and complications of selective intra-arterial chemotherapy (IAC) for retinoblastoma (RB) in Indian eyes.. Single center, retrospective interventional case series of 6 eyes with RB who underwent IAC using Melphalan (3 mg/5 mg/7.5 mg) and topetecan (1 mg) (n = 4) or melphalan (3 mg/5 mg/7.5 mg) alone (n = 2) between December 2013 and June 2014. In all, 17 IAC procedures were performed using selective ophthalmic artery cannulation. Treatment outcomes were evaluated in terms of tumor control, vitreous and subretinal seeds control and globe salvage rates.. IAC was employed as primary (n = 1) or secondary (n = 5) modality of treatment. Each eye received mean 3 IAC sessions (median: 3; range: 1-4 sessions). Eyes were classified according to international classification of RB as Group B (n = 1), C (n = 1), D (n = 2) and E (n = 2). Following IAC, complete regression of the main tumor was seen in 3 cases (50%), partial regression in 2 (33%), while 1 case (15%) showed no response. Of 4 eyes with subretinal seeds, 1 (25%) eye had complete regression while 3 (75%) eyes had partial regression. Of 5 eyes with vitreous seeds, 2 (40%) eyes had complete regression while 3 (60%) eyes had a partial response. Globe salvage was achieved in 5 of 6 eyes (83%). Diffuse choroidal atrophy and vitreous hemorrhage were observed in 1 (17%) eye, each. No hematologic toxicity or cerebro-vascular events were observed. Mean follow-up period was 5.5 months (median: 6 months, range: 1-6 months).. IAC is an effective therapy for globe preservation in eyes with RB. Larger studies with longer follow-up are required to validate these results.

Topics: Antineoplastic Agents; Carboplatin; Child, Preschool; Dose-Response Relationship, Drug; Female; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; Humans; Incidence; India; Infant; Injections, Intra-Arterial; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Time Factors; Topoisomerase I Inhibitors; Topotecan

Angiography is a powerful tool to identify intraorbital arteries. However, the incidence by which these vessels can be identified is unknown. Our purpose was to determine such incidence and which angiographic approach is best for the identification of each artery.. A retrospective study of 353 angiographic procedures (via ophthalmic artery and/or external carotid artery) carried out on 79 children affected by intraocular retinoblastoma was made to investigate the arterial anatomy in 87 orbits. For each intraorbital artery two parameters were calculated: the angiographic incidence, as the percentage of times a given artery was identified, and the visibility index, as the ratio between the angiographic incidence and the true anatomic incidence.. All collaterals of the ophthalmic artery could be spotted. Most of them were identified with a high angiographic incidence; some of them were less easily identified because too thin or because frequently shielded. The visibility index paralleled the angiographic incidence of most arteries. However, the lacrimal and meningolacrimal arteries had a higher visibility index suggesting that their identification was more frequent than the angiographic incidence alone could suggest. Statistical analysis demonstrated that the lacrimal artery and some muscular branches had higher chances to be identified if the angiography of the ophthalmic artery was accompanied by the study of the external carotid system.. This work provides an objective measure of how powerful angiography is to identify intraorbital arteries as well as useful references for professionals who need to operate in the orbit.

Topics: Angiography, Digital Subtraction; Antineoplastic Combined Chemotherapy Protocols; Carotid Artery, Internal; Child, Preschool; Humans; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Orbit; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan

Studies conducted in recent years have reported promising results regarding the treatment of retinoblastoma with the intra-arterial use of melphalan. In the present study, we intended to report the results of intra-arterial chemotherapy with melphalan (IACT) in the treatment of newly diagnosed or relapsed-refractory retinoblastoma patients at the Department of Pediatric Oncology of Hacettepe University, Ankara, Turkey.. This was a retrospective study of patients with intraocular retinoblastoma who were treated with IACT from December 2011 to May 2014. A total of 56 eyes of 46 consecutive patients (30 males and 16 females) were included in the study. Forty-four eyes received systemic chemotherapy upon diagnosis (systemic chemotherapy group, SCG), and 12 eyes were those of newly diagnosed patients (primary intra-arterial melphalan group, PIAG). The choice of the IACT dose was based on age. Tumor control and globe salvage with IACT were analyzed. Complete blood counts were examined 7 days after the IACT for systemic toxicity. Ocular toxicities such as proptosis, eyelid edema, ocular motility, and retinal and optic atrophy were assessed by an ocular oncologist with regular ophthalmologic examinations.. Enucleation was avoided overall in 66% (37/56) of the eyes, including 75% (9/12) in the PIAG and 64% (28/44) in the SCG patients. The 1-year enucleation-free survival rate was 56.7% at a median follow-up time of 11.9 months (range 0.27-27.6). IACT was administered in a total of 124 cycles (ranging from 1 to 7 cycles, mean 2.3). The responses were as follows: regression of the retinal tumor in 27 eyes and improvements in vitreous seeding in 5 of 15 eyes. The further treatment requirements after IACT were as follows: enucleation in 19 eyes (10 with vitreous seeding), radiotherapy in 3 eyes, systemic chemotherapy in 1 eye, and local therapy in 1 eye. No severe systemic side effects occurred. Transient swelling of the eyelids (22 patients), conjunctival chemosis (12 patients), upper eyelid ptosis (5 patients), redness over the frontal area (3 patients), limitation of ocular motility (3 patients) and mild proptosis (1 patient) were detected. Retinal pigment epithelial alterations (30 patients) and optic atrophy (3 patients) were seen in the late follow-up.. Globe salvage and avoidance of radiotherapy may be achieved by IACT with limited toxicity. This treatment is efficient, repeatable and safe.

Topics: Antineoplastic Agents, Alkylating; Child; Child, Preschool; Disease-Free Survival; Eye Enucleation; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Neoplasm Recurrence, Local; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Survival Rate

Intravitreous injections of melphalan hydrochloride are increasingly used in the treatment of vitreous seeding of retinoblastoma. Although this technique can save eyes otherwise destined for enucleation, ocular salvage may be accompanied by local toxic effects. Posterior segment toxic effects in this context are well established. This report describes the toxic effects on the anterior segment following intravitreous administration of melphalan.. Our clinic cohort included 76 patients who received intravitreous injections of melphalan at Memorial Sloan Kettering Cancer Center from September 12, 2012, through April 15, 2015; data analysis was performed from April 15 through May 15, 2015. We report a series of 5 patients from this cohort who developed anterior segment toxic effects. These abnormalities were found at the injection site or within the meridian of the injection and included a traumatic cataract following an injection at an outside hospital, iris depigmentation and thinning, iris recession with retinal necrosis and hypotony, a filtering conjunctival bleb, and focal scleromalacia with localized pigmentation.. Intravitreous injection of melphalan may result in toxic effects on the anterior segment of the eye, in addition to retinal abnormalities, and appears to be more common in the meridian of the injection where the drug concentration is highest.

Topics: Anterior Eye Segment; Antineoplastic Agents, Alkylating; Child, Preschool; Eye Diseases; Female; Humans; Infant; Intravitreal Injections; Male; Melphalan; Microscopy, Acoustic; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Tomography, Optical Coherence

To describe the efficacy of intravitreal chemotherapy (IViC) preceded by intra-arterial chemotherapy (IAC) for the treatment of advanced stage retinoblastoma. This non-comparative interventional case series retrospectively reviewed the medical records of six patients who presented within months of each other with unilateral retinoblastoma, Reese-Ellsworth stage Vb/D of ABC classification in the affected eye. After clinical and ophthalmoscopic evaluation, they underwent MRI to exclude local and CNS dissemination. The IAC was given to treat retinal masses and intravitreal injections to treat vitreous seeding. Patients had received two cycles (six infusions) of IAC, and from six up to ten melphalan injections into the vitreous, with an interval of 7-10 days between them. From one to four intravitreal injections were performed for partial remission or consolidation. No permanent complications of procedures have been reported. All patients underwent to bimonthly MRI examination, during treatment and every 3 months for 1 year after last injection, to exclude orbital dissemination. Successful control (100 %) of tumor masses and vitreous seeds was achieved in all cases at 12 months follow-up. Complications were posterior lens opacity, acute ischemic papillitis, partial CVR thrombosis, hypotonia (case 1), partial vitreous hemorrhage (case 4). No complications appeared in cases 2, 3, 5, and 6. No intraocular or orbital tumor recurrence or retinoblastoma metastases (follow-up range, 12-33 months) were observed. Sequential IAC and intravitreal melphalan for advanced retinoblastoma allowed to provide retinal and vitreous seed control.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Female; Humans; Infant; Injections, Intra-Arterial; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan

To illustrate the successful outcome of pars plana vitrectomy (PPV) with melphalan irrigation for vitreous hemorrhage (VH) with suspected viable retinoblastoma. Despite the high risk of intraocular surgery, it was performed to preserve the only potentially seeing eye with treated retinoblastoma.. Vitreous hemorrhage occurred in the only eye of a 4-year-old boy after treatment for recurrent multifocal group C retinoblastoma with systemic chemotherapy (carboplatin, etoposide, and cyclophosphamide; and vincristine, cyclophosphamide, and doxorubicin), ruthenium brachytherapy with plaque repositioning, cryotherapy, and external radiotherapy. The VH developed 8 months after repeated brachytherapy with subsequent intravitreal melphalan chemotherapy. The patient's parents refused to remove the eye. The fellow eye was enucleated earlier because of VH and secondary glaucoma, without histologic signs of a viable tumor. Pars plana lensectomy, 25-G vitrectomy with melphalan irrigation (5 μg/mL), and silicone oil tamponade were performed.. No ophthalmoscopic or morphologic signs of a viable tumor were detected. Four months later, the silicone oil was removed. Visual acuity was 20/200 with aphakic correction. Follow-up for 34 months revealed no signs of tumor recurrence or dissemination.. Despite the high risk of intraocular surgery, the need to preserve the only potentially seeing eye with treated retinoblastoma may require PPV. Thus, in unclear cases of VH with suspected viable tumor, PPV with intraocular melphalan irrigation, with caution, may be a reasonable procedure.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Carboplatin; Combined Modality Therapy; Cryotherapy; Cyclophosphamide; Dacarbazine; Endotamponade; Etoposide; Humans; Infant; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Silicone Oils; Therapeutic Irrigation; Vincristine; Visual Acuity; Vitrectomy; Vitreous Hemorrhage

The major cause of failure in the management of retinoblastoma is the persistence/recurrence of vitreous seeds (VS). This study reports the efficacy and complications of standard lower-dose (20 µg) intravitreal melphalan for VS.. Retrospective review of all patients with active VS treated with lower-dose intravitreal melphalan (20 µg/0.1 mL) on a monthly basis until complete VS regression was achieved.. A total of 14 injections were delivered to seven eyes of seven patients (range: 1-4; median: 2). At a median follow-up of 20 months (range: 12-32 months), complete regression of VS was achieved in all cases (100%), and globe salvage was achieved in six cases (86%). One eye required enucleation for solid tumor recurrence. Side effects of retinal pigment epithelium mottling at the site of injection was noted in two eyes (29%).. The 2-year results of this study suggest that standard lower-dose (20 µg) intravitreal melphalan is safe and highly effective for the management of viable VS from retinoblastoma.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Intravitreal Injections; Male; Melphalan; Neoplasm Recurrence, Local; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Vitreous Body

We report the case of a 15-month-old boy with retinoblastoma who developed exotropia secondary to a right medial rectus infarct after intra-arterial chemotherapy. He had unilateral sporadic group C tumor (International Classification of Retinoblastoma) and was treated with intra-arterial melphalan. One week after the first session of intra-ophthalmic arterial melphalan chemotherapy, he was noted to have orbital congestion, exotropia, and right adduction limitation. Magnetic resonance imaging was suggestive of a right medial rectus infarct. The tumor showed a good response to intra-arterial chemotherapy but the exotropia persisted.

Topics: Antineoplastic Agents, Alkylating; Edema; Exotropia; Fluorescein Angiography; Humans; Infant; Infarction; Infusions, Intra-Arterial; Ischemia; Magnetic Resonance Imaging; Male; Melphalan; Muscular Diseases; Oculomotor Muscles; Ophthalmic Artery; Papilledema; Radiography; Retinal Neoplasms; Retinoblastoma

The aim of this study is to evaluate the pathological findings of the eye after intravitreal melphalan for viable vitreous seeding from retinoblastoma. All enucleated eyes receiving an intravitreal injection of melphalan (10-50 μg in 0.05 cc) were evaluated for histological changes. Of 25 treated cases, 8 eyes needed enucleation because of phthisis, parent request, or new tumor development. One of the cases was excluded from the study because of a history of intra-arterial chemotherapy with melphalan. There was no case of needle-site scleral involvement by retinoblastoma cells. In two eyes receiving 50 μg melphalan, no viable retinoblastoma cell was detectable in the eye. Severe gliosis, vascular occlusion, retinal necrosis, hemorrhage and neovascularization were seen. Histologically, intravitreal melphalan for recalcitrant or recurrent vitreous seeds from retinoblastoma appears to provide acceptable vitreous seed control. It seems that higher doses could be destructive causing ischemic necrosis in the retina, severe gliosis and secondary neovascular changes as well as having a destructive effect on retinoblastoma cells.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Eye Enucleation; Humans; Infant; Intravitreal Injections; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Vitreous Body

Topics: Antineoplastic Agents, Alkylating; Drug Delivery Systems; Humans; Infant; Injections, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Tumor Burden

To assess the antitumor activity, toxicity, and plasma pharmacokinetics of the combination of melphalan and topotecan for superselective ophthalmic artery infusion (SSOAI) treatment of children with retinoblastoma.. Single-center, prospective, clinical pharmacokinetic study.. Twenty-six patients (27 eyes) with intraocular retinoblastoma.. Patients with an indication for SSOAI received melphalan (3-6 mg) and topotecan (0.5-1 mg; doses calculated by age and weight). Plasma samples were obtained for pharmacokinetic studies, and a population approach via nonlinear mixed effects modeling was used. Safety and efficacy were assessed and compared with historical cohorts of patients treated with melphalan single-agent SSOAI.. Melphalan and topotecan pharmacokinetic parameters and efficacy and safety parameters.. Twenty-seven eyes from 26 consecutive patients received 66 cycles of SSOAI melphalan and topotecan in combination. All 5 eyes treated as primary therapy responded to the combination chemotherapy and were preserved. Sixteen of the 22 eyes with relapsed or resistant tumors responded, but 3 of them ultimately underwent enucleation at a median of 8 months (range, 7.9-9.1 months). The incidence of grade III and IV neutropenia was 10.6% and 1.5%, respectively, which was comparable with historical controls of single-agent SSOAI melphalan. No episode of fever neutropenia was observed, and no patient required transfusion of blood products. The large variability in melphalan pharmacokinetics was explained by body weight (P <0.05). Concomitant topotecan administration did not influence melphalan pharmacokinetic parameters. There was no effect of the sequence of melphalan and topotecan administration in plasma pharmacokinetics.. A regimen combining melphalan and topotecan for SSOAI treatment of retinoblastoma is active and well tolerated. This combination chemotherapy previously showed synergistic pharmacologic activity, and we herein provide evidence of not increasing the hematologic toxicity compared with single-agent melphalan.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Chromatography, High Pressure Liquid; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Prospective Studies; Retinal Neoplasms; Retinoblastoma; Topotecan

Retinoblastoma (RB) is a rare malignancy affecting the pediatric population. Intravenous chemotherapy is the longstanding delivery method, although intra-arterial (IA) chemotherapy is gaining popularity given the reduced side effects compared with systemic chemotherapy administration. Given the sensitivity of the target organ, patient age, and secondary tumor susceptibility, a premium has been placed on minimizing procedural related radiation exposure.. To reduce patient x-ray dose during the IA infusion procedure, customized surgical methods and fluoroscopic techniques were employed. The routine fluoroscopic settings were changed from the standard 7.5 pulses/s and dose level to the detector of 36 nGy/pulse, to a pulse rate of 4 pulses/s and detector dose to 23 nGy/pulse. The angiographic dose indicators (reference point air kerma (Ka) and fluoroscopy time) for a cohort of 10 consecutive patients (12 eyes, 30 infusions) were analyzed. An additional four cases (five eyes, five infusions) were analyzed using dosimeters placed at anatomic locations to reflect scalp, eye, and thyroid dose.. The mean Ka per treated eye was 20.1±11.9 mGy with a mean fluoroscopic time of 8.5±4.6 min. Dosimetric measurements demonstrated minimal dose to the lens (0.18±0.10 mGy). Measured entrance skin doses varied from 0.7 to 7.0 mGy and were 73.4±19.7% less than the indicated Ka value.. Ophthalmic arterial melphalan infusion is a safe and effective means to treat RB. Modification to contemporary fluoroscopic systems combined with parsimonious fluoroscopy can minimize radiation exposure.

Topics: Antineoplastic Agents, Alkylating; Combined Modality Therapy; Female; Fluoroscopy; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Radiation Dosage; Retinal Neoplasms; Retinoblastoma

Topics: Antineoplastic Agents, Alkylating; Autonomic Nervous System; Female; Heart; Humans; Male; Melphalan; Ophthalmic Artery; Reflex; Respiratory Mechanics; Retinal Neoplasms; Retinoblastoma

Topics: Antineoplastic Agents, Alkylating; Autonomic Nervous System; Female; Heart; Humans; Male; Melphalan; Ophthalmic Artery; Reflex; Respiratory Mechanics; Retinal Neoplasms; Retinoblastoma

Recurrent or persistent vitreous seeds following treatment of retinoblastoma poses difficult management and often leads to enucleation.. To describe the technique and evaluate the efficacy and complications of intravitreal melphalan for vitreous seeding from retinoblastoma.. This retrospective noncomparative analysis was conducted at a tertiary referral center. The study included 11 consecutive eyes of 11 patients with viable persistent or recurrent vitreous seeds following treatment of retinoblastoma.. All eyes received intravitreal melphalan injection (20-30 µg) by transconjunctival pars plana route with concomitant triple-freeze cryotherapy at the injection site during needle withdrawal for prevention of extraocular seeding. Each patient was offered planned 6 monthly cycles.. Vitreous seed control and complications of therapy.. The mean patient age at vitreous injection was 37 months (median, 27 months; range, 16-82 months). Viable vitreous seeds involved 2 (n = 1), 3 (n = 4), or 4 (n = 6) quadrants. The solid intraretinal retinoblastoma and subretinal seeds showed regression in all eyes following intravenous chemotherapy (n = 6) or intra-arterial chemotherapy (n = 5). There were a total of 55 injections, with a mean number per patient of 5 (median, 6; range, 2-6). Fewer than 6 injections (n = 5) were delivered owing to complete vitreous seed control and parental desire to avoid more injections. By a mean of 9 months' follow-up (median, 9 months; range, 6-16 months), therapeutic success with complete vitreous seed regression was achieved in all 11 cases (100%). Globe salvage was attained in all cases (100%). Further vitreous seed development did not occur in any case. Complications included focal retinal pigment epithelial mottling near the site of chemotherapy injection (2 eyes) and nonaxial posterior lens opacity (2 eyes). There was no case of extraocular tumor extension, hypotony, or phthisis bulbi.. These preliminary short-term results suggest that intravitreal melphalan injection for persistent or recurrent vitreous retinoblastoma seeding can provide tumor control with minimal toxicity and complications.

Topics: Antineoplastic Agents, Alkylating; Child; Child, Preschool; Combined Modality Therapy; Cryotherapy; Eye Neoplasms; Female; Humans; Infant; Intravitreal Injections; Male; Melphalan; Neoplasm Recurrence, Local; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Vitreous Body

To report electroretinogram responses of retinoblastoma children under anesthesia before and after treatment with chemotherapeutic drugs (melphalan, topotecan, carboplatin) delivery by ophthalmic artery chemosurgery (OAC).. A cohort study of 81 patients with retinoblastoma treated with OAC. All patients treated with OAC at our center through May 2012 for whom the requisite ERG data were available are included in the analysis. This study recorded the ERG 30 Hz flicker amplitude response changes from baseline, at 3 and 12 months following OAC treatment completion. Both univariate and multivariate linear regression models were evaluated, with generalized estimating equations to correct for correlations within patients. Independent numerical variables included maximum doses and cumulative doses of melphalan, topotecan and carboplatin.. By univariate analysis, both melphalan and topotecan appear to be associated with changes in ERG amplitude at both 3 and 12 months; but for the most part, these changes are minimal and likely clinically insignificant. By multivariate analysis, maximum and cumulative melphalan have a modest, temporary effect on the ERG amplitude change, which is apparent at 3 months but no longer evident at 12 months after completing treatment. By multivariate analysis, topotecan and carboplatin do not appear to adversely effect the change in ERG response.. Melphalan has the strongest, and carboplatin the weakest association with reduction in ERG response amplitudes; but for the most part, these changes are minimal and likely clinically insignificant. These conclusions apply only over the dose ranges used here, and should be applied with caution.

Topics: Carboplatin; Electroretinography; Humans; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Topotecan; Treatment Outcome

To analyze our 5-year experience of intra-arterial chemotherapy (IAC) for retinoblastoma as primary or secondary therapy.. Retrospective interventional case series.. A total of 70 eyes of 67 patients.. Ophthalmic artery chemotherapy infusion under fluoroscopic guidance was performed using melphalan (3, 5, or 7.5 mg) in every case, with additional topotecan (1 mg) and/or carboplatin (30 or 50 mg) as necessary.. Tumor control and treatment complications.. The mean patient age at IAC was 30 months. The treatment was primary in 36 eyes and secondary in 34 eyes. Those primary therapy eyes were classified according to the International Classification of Retinoblastoma (ICRB) as group A (n = 0), B (n = 1), C (n = 4), D (n = 17), or E (n = 14). The secondary therapy eyes had failed previous intravenous chemotherapy (n = 34) in every case. Each eye received a mean of 3 IAC sessions per eye (median, 3; range, 1-7 sessions). After IAC with a mean follow-up of 19 months, globe salvage was achieved in 72% of primary-treated cases and in 62% of secondary-treated cases. Specifically, primary therapy achieved globe salvage for group B (100%), group C (100%), group D (94%), and group E (36%). Of all 70 eyes, complete regression was achieved for solid tumor in 48 of 51 eyes (94%), subretinal seeds in 40 of 42 eyes (95%), and vitreous seeds in 34 of 39 eyes (87%). After each catheterization (n = 198), the main complications included transient eyelid edema (5%), blepharoptosis (5%), and forehead hyperemia (2%). More lasting complications included vitreous hemorrhage (2%), branch retinal artery obstruction (1%), ophthalmic artery spasm with reperfusion (2%), ophthalmic artery obstruction (2%), partial choroidal ischemia (2%), and optic neuropathy (<1%). Over the past 3 years, the combined incidence of ophthalmic, retinal, and choroidal vascular ischemia was reduced to 1%. There was no patient with stroke, seizure, neurologic impairment, limb ischemia, secondary leukemia, metastasis, or death.. Five-year experience with IAC indicates that this technique is remarkably effective for the management of retinoblastoma as both a primary and a secondary treatment.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Female; Fluorescein Angiography; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; International Classification of Diseases; Male; Melphalan; Microscopy, Acoustic; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan; Treatment Outcome; Young Adult

Retinoblastoma is the most common primary intraocular malignancy worldwide. The known established standard therapies for bilateral disease, such as external beam radiation therapy or systemic chemotherapy often lead to a higher morbidity and increased risk of secondary malignancies, especially with radiation therapy. Therefore, new non-systemic chemotherapy strategies, such as the intra-arterial or intravitreal administration of melphalan are being revised with the aim of reducing systemic side effects.

Topics: Antineoplastic Agents, Alkylating; Drug Therapy; Forecasting; Humans; Injections, Intra-Arterial; Intravitreal Injections; Melphalan; Retinal Neoplasms; Retinoblastoma

Demonstrating the usefulness and complications of multiagent intravitreal chemotherapy is necessary for successful treatment in patients with recalcitrant vitreous seeding of retinoblastoma.. To determine the efficacy and complications of combined intravitreal chemotherapy (melphalan hydrochloride and topotecan hydrochloride) for viable vitreous seeding from retinoblastoma.. This retrospective study was conducted in a hospital setting. Trans-pars plana intravitreal injection of melphalan hydrochloride (40 µg in 0.04 mL of diluent) combined with topotecan hydrochloride (8-20 µg in 0.04 mL of balanced salt solution) was performed in 9 eyes, followed by injection site cryotherapy.. Complete regression of vitreous seeds of retinoblastoma.. Nine eyes, initially classified as group D (n = 6) or E (n = 3) according to International Classification of Retinoblastoma categorization, received a standard 6 cycles of intravenous chemotherapy and/or intra-arterial chemotherapy and subsequently developed recurrent viable vitreous seeds. Intravitreal administration of melphalan combined with topotecan produced complete control of vitreous seeds in all 9 eyes following a mean of 1.9 injections (median, 2; range, 1-3 injections). In 3 cases (33%), tumor control was achieved with a single injection, whereas in 6 (67%) cases, 2 or 3 injections were necessary. Three patients (33%) subsequently underwent enucleation because of recurrent tumor and persistent anterior chamber lesions. During a mean 15.2 months of follow-up (median, 16; range, 7-25 months), there was no recurrence of new tumor or vitreous seeds in the remaining 6 eyes. Complications included temporary hypotonia of 2 weeks or less (2 [22%]), temporary epithelial defect (1 [11%]), and vitreous hemorrhage (1 [11%]). There was no case of episcleral or orbital retinoblastoma extension or remote retinoblastoma metastasis. There was no change in the a and b waves of bright-flash electroretinograms.. Administration of combined intravitreal melphalan and topotecan in eyes not subsequently enucleated appears to be safe and effective for resistant or recurrent vitreous seeds from retinoblastoma. In 3 of the cases (33%), tumor control was achieved with a single injection.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Female; Humans; Infant; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Recurrence; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan; Vitreous Body

Topics: Antineoplastic Agents, Alkylating; Blue Toe Syndrome; Catheterization, Peripheral; Humans; Male; Melphalan; Retinal Neoplasms; Retinoblastoma

Topics: Antineoplastic Agents, Alkylating; Blue Toe Syndrome; Catheterization, Peripheral; Humans; Male; Melphalan; Retinal Neoplasms; Retinoblastoma

Intravitreal melphalan is emerging as an effective treatment for refractory vitreous seeds in retinoblastoma, but there is limited understanding regarding its toxicity. This study evaluates the retinal and systemic toxicity of intravitreal melphalan in retinoblastoma patients, with preclinical validation in a rabbit model.. Clinical and preclinical, prospective, cohort study.. In the clinical study, 16 patient eyes received 107 intravitreal injections of 30 μg melphalan given weekly, a median of 6.5 times (range, 5-8). In the animal study, 12 New Zealand/Dutch Belt pigmented rabbits were given 3 weekly injections of 15 μg of intravitreal melphalan or vehicle to the right eye.. Electroretinogram (ERG) responses were recorded in both humans and rabbits. For the clinical study, ERG responses were recorded at baseline, immediately before each injection, and at each follow-up visit; 82 of these studies were deemed evaluable. Median follow-up time was 5.2 months (range, 1-11). Complete blood counts (CBCs) were obtained on the day of injection at 46 patient visits. In the animal study, ERG responses were obtained along with fluorescein angiography, CBCs, and melphalan plasma concentration. After humane killing, the histopathology of the eyes was evaluated.. For the clinical study, we measured peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation with comparisons between ERG studies before and after intravitreal melphalan. For the animal study, we collected ERG parameters before and after intravitreal melphalan injections with histopathologic findings.. By linear regression analysis, over the course of weekly intravitreal injections in retinoblastoma patients, for every additional injection, the ERG amplitude decreased by approximately 5.8 μV. The ERG remained stable once the treatment course was completed. In retinoblastoma patients, there were no grade 3 or 4 hematologic events. One week after the second injection in rabbits, the a- and b-wave amplitude declined significantly in the melphalan treated eyes compared with vehicle-treated eyes (P<0.05). Histopathology revealed severely atrophic retina.. Weekly injections of 30 μg of melphalan can result in a decreased ERG response, which is indicative of retinal toxicity. These findings are confirmed at an equivalent dose in rabbit eyes by ERG measurements and by histopathologic evidence of severe retinal damage. Systemic toxicity with intravitreal melphalan at these doses in humans or rabbits was not detected.

Topics: Animals; Antineoplastic Agents, Alkylating; Blood Cell Count; Child; Child, Preschool; Drug Evaluation, Preclinical; Electroretinography; Female; Fluorescein Angiography; Humans; Infant; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Prospective Studies; Rabbits; Regression Analysis; Retinal Neoplasms; Retinoblastoma; Vitreous Body

To measure the choroidal thickness (CT) and analyze the morphologic features of chorioretinal structures using a portable handheld spectral domain-optical coherence tomography in patients with retinoblastoma after intraarterial chemotherapy.. This was a case-control study. Eighteen eyes of 9 patients with unilateral retinoblastoma treated with intraarterial chemotherapy were assessed by spectral-domain optical coherence tomography. Submacular CT was measured at the foveola and at points located 500 μm and 2 mm from the foveola. The treated eye was compared with the untreated (control) eye.. Mean submacular CT was 174 ± 111.1 μm in the treated eyes and 259 ± 42.2 μm in the control eyes (P = 0.054). Several point locations showed statistically significant differences comparing CT (treated eye vs. control eye), including subfoveolar (P = 0.030), nasal 0.5 mm (P = 0.037), nasal 2 mm (P = 0.049), and temporal 2 mm (P = 0.031). In 4 patients with ophthalmoscopically visible choroidal atrophy, submacular CT was reduced by 73.3 ± 14.1% compared with the control eye. In 5 patients with no ophthalmoscopically visible choroidal atrophy, submacular CT was reduced by 0.5 ± 11.9% compared with the control eye.. Intraarterial chemotherapy for retinoblastoma can cause reduction in subfoveolar CT. Spectral-domain optical coherence tomography confirmed choroid to be thinned in eyes with or without clinical evidence of choroidal atrophy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Atrophy; Case-Control Studies; Child; Child, Preschool; Choroid; Female; Fluorescein Angiography; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Organ Size; Retinal Neoplasms; Retinoblastoma; Tomography, Optical Coherence; Topotecan

Topics: Antineoplastic Agents, Alkylating; Biological Availability; Chromatography, High Pressure Liquid; Drug Stability; Drug Storage; Humans; Intravitreal Injections; Melphalan; Ophthalmic Solutions; Retinal Neoplasms; Retinoblastoma

Topics: Antineoplastic Agents, Alkylating; Humans; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Vitreous Body

A 12-month-old boy with a history of bilateral retinoblastoma refractory to systemic chemotherapy, laser therapy and cryotherapy, with excellent response to previous intra-arterial melphalan infusion, presents with active tumour deposits in the right eye. Repeat intra-arterial chemotherapy was recommended. Previous bilateral melphalan infusion was uneventful using flow-guided catheterisation technique. Direct catheterisation of the right ophthalmic artery was unsuccessful despite employment of several flow-guided and over-the-wire catheters. Superselective catheterisation of the ipsilateral middle meningeal artery was unable to identify an anastomotic connection to the ophthalmic artery; however, angiography of the anterior deep temporal artery identified an alternate route for chemotherapy infusion. The anterior deep temporal artery was successfully and safely catheterised to infuse chemotherapy into the ophthalmic artery. The anterior deep temporal artery is an important potential anastomotic connection to the ophthalmic artery that can be used safely and effectively for central retinal artery chemotherapy infusion for retinoblastoma treatment.

Topics: Angiography; Antineoplastic Agents, Alkylating; Catheterization; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retina; Retinal Neoplasms; Retinoblastoma; Temporal Arteries

Intra-arterial chemotherapy is a promising strategy for intra-ocular retinoblastoma. Neutropenia is the most commonly encountered systemic toxicity and in this study we aimed to determine the risk factors associated with the development of severe (≥ grade 3) neutropenia.. Retrospective review of 187 evaluable cycles of melphalan-containing intra-arterial chemotherapy from the first three cycles administered to 106 patients with intra-ocular retinoblastoma from May 2006 to June 2011. Cycles were considered to be evaluable if (1) blood count results were available in the 7 to 14 days post-treatment interval and (2) concurrent intravenous chemotherapy was not administered. Toxicity was assessed via the Common Terminology Criteria for Adverse Events version 4.0.. 54 cycles (29%) were associated with grade 3 (n = 43) or grade 4 (n = 11) neutropenia. Multivariate stepwise logistic regression revealed that a higher melphalan dose (>0.40 mg/kg) was significantly associated with severe neutropenia during all 3 cycles (odds ratio during cycle one 4.11, 95% confidence interval 1.33-12.73, p = 0.01), but the addition of topotecan and/or carboplatin were not. Prior treatment with systemic chemotherapy was not associated with severe neutropenia risk in any analysis.. Intra-arterial melphalan-based chemotherapy can cause severe neutropenia, especially when a dose of greater than 0.40 mg/kg is administered. Further study with a larger sample may be warranted.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Neutropenia; Neutrophils; Retina; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Risk Factors

Intra-arterial chemotherapy (IAC) has proved to be an effective treatment for retinoblastoma, but can be very expensive in developing countries. We report 2 patients from Chile in whom IAC resulted in globe salvation. Both patients had their medical care provided by the public health system and had failed standard therapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Chile; Cost-Benefit Analysis; Developing Countries; Drug Costs; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Topotecan

Treatment of vitreous seeds in retinoblastoma is challenging because of relatively poor chemotherapeutic drug penetration by standard intravenous or intra-arterial routes. Intravitreal monotherapy with melphalan is effective but has a narrow therapeutic window. The authors describe a case of massive vitreous seeding successfully controlled after combination intravitreal chemotherapy using melphalan and topotecan with preserved anatomic outcome.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Eye Neoplasms; Female; Humans; Intravitreal Injections; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Topotecan; Vitreous Body

Topics: Antineoplastic Agents, Alkylating; Child; Humans; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Vitreous Body

To describe our experience with superselective ophthalmic artery chemotherapy (SOAC) in retinoblastoma and to report the serious adverse cardio-respiratory reactions we have observed.. SOAC was performed using a standardized protocol for general anesthesia, ophthalmic artery catheterization, and pulsed infusion of melphalan. Adverse reactions were defined as those in which the patient required active treatment to maintain cardio-respiratory stability.. Between December 2008 and May 2012, 54 eyes in 52 patients were treated. 143 catheterization procedures were performed, with a technical success rate of 93% (n = 133). There were no deaths or major complications. Adverse cardio-respiratory reactions developed during 35 procedures (24%; 95% CI, 18-32%). All reactions occurred during second or subsequent catheterization procedures (39%; 95% CI, .29-49%) and were characterized by hypoxia, reduced lung compliance, systemic hypotension and bradycardia. Adverse events were successfully treated in all patients. One procedure was abandoned due to prolonged hemodynamic instability.. Adverse cardio-respiratory reactions are commonly observed in SOAC for retinoblastoma. We believe that the adverse clinical signs represent an autonomic reflex response, akin to the trigemino-cardiac or oculo-respiratory reflexes, and all patients should be considered at-risk. Reactions occur only during second or subsequent procedures and can be life-threatening. The routine use of intravenous atropine does not seem to have altered the incidence or severity of these reactions. Anesthetists and interventional neuroradiologists involved in SOAC must be vigilant to ensure adverse reactions, when they develop, are treated quickly and effectively.

Topics: Anesthesia, General; Anesthetics, Intravenous; Antineoplastic Agents, Alkylating; Atracurium; Autonomic Nervous System; Blood Pressure; Child; Child, Preschool; Electrocardiography; Female; Heart; Heart Rate; Hemodynamics; Humans; Infant; Male; Melphalan; Methyl Ethers; Neuromuscular Nondepolarizing Agents; Ophthalmic Artery; Propofol; Reflex; Respiratory Mechanics; Retinal Neoplasms; Retinoblastoma; Sevoflurane; Tryptases

Topics: Anticoagulants; Antineoplastic Agents, Alkylating; Blue Toe Syndrome; Catheterization, Peripheral; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Treatment Outcome

Topics: Antineoplastic Agents, Alkylating; Electroretinography; Humans; Infant; Infusions, Intra-Arterial; Ischemia; Male; Melphalan; Ophthalmic Artery; Retina; Retinal Artery Occlusion; Retinal Neoplasms; Retinal Vein Occlusion; Retinoblastoma

To determine the frequency and cause of visual loss following intra-arterial melphalan (IAM) in patients with retinoblastoma with age appropriate vision.. Assessment of patients with refractory retinoblastoma that had undergone systemic chemotherapy, with or without local treatment, and were subsequently treated with IAM. Eyes of patients with a healthy foveola were assessed. The main outcome measures included visual, macular (including Pattern Visual Evoked Potentials and Fundus Fluorescein Angiography) and retinal functions (Electroretinograms).. Five of twelve eyes (42%) demonstrated severe visual loss following IAM at last follow-up (median 21 months). This was due to either retinal detachment (1 eye, 20%) or choroidal ischaemia involving the foveola (4 eyes, 80%). All 3 eyes that had technical difficulties or vasospasm during catheterisation suffered visual loss. 8 out of 10 eyes that had a non-age adjusted dose of melphalan suffered visual loss. Electroretinograms post-IAM deteriorated in 4 of 8 eyes (50%) and Pattern Visual Evoked Potentials deteriorated in 3 (37%), though only one of these 3 showed concomitant visual acuity loss.. Structural and vascular damage to the foveola limited visual acuity. Complications associated with catheterisation and high doses of melphalan may be contributory factors to visual morbidity. Although visual loss is described, no patient developed metastases and most retained good vision.

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Child; Child, Preschool; Electroretinography; Female; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; Humans; Infusions, Intra-Arterial; Male; Melphalan; Middle Aged; Ophthalmic Artery; Prospective Studies; Retinal Neoplasms; Retinoblastoma; Treatment Outcome; Visual Acuity; Young Adult

To report our experience in superselective ophthalmic artery infusion of melphalan (SOAIM) for intraocular retinoblastoma..   From June 2008 to October 2010, 38 patients (18 women, 20 men; age range at first treatment, 7 months to 22 years) with 41 eyes with retinoblastoma were scheduled for SOAIM, for 17 newly diagnosed retinoblastomas Tumour, Node and Metastasis (TNM) 7th Edition 1a (n = 1), 1b (n = 1), 2a (n = 7), 2b (n = 4) and 3a (n = 4) and 24 retinoblastomas with partial remission/relapse TNM 7th Edition 1b (n = 13), 2a (n = 1) and 2b (n = 10). Eight patients (ten eyes) have been treated by SOAIM alone. Follow-up was 6-27 months in 28 patients (30 eyes).. Ophthalmic artery cannulation failed in two patients. Thirty-six patients underwent 140 treatments by internal (n = 112) or external (n = 28) carotid arteries. No major procedural complications occurred. Two patients have been lost to follow-up. Remaining 34 patients (37 eyes) had no metastatic disease. Four patients suffered permanent ocular complications: chorioretinal dystrophy (n = 2), ptosis (n = 1) and strabismus/exotropia (n = 1). Eight (22%) eyes in eight (24%) patients underwent enucleation: 7/16 (43%) newly diagnosed retinoblastomas and 1/22 (4.5%) retinoblastomas undergoing partial remission/relapse. For all treated eyes, Kaplan-Meier eye enucleation-free rates (K-M) were 85.4% (95% CI, 73.3-97.5%), 74.4% (95% CI, 57-91.8%) and still stable at 6, 12 months and 2 years, respectively. For eyes with partial remission/relapse, and eyes at presentation, K-M at 2 years were 95.5% (95% CI, 86.9-100%) and 45.6% (95% CI, 16.6-74.6%), respectively.. Superselective ophthalmic artery infusion of melphalan was safe and powerful, especially following other therapies. Superselective ophthalmic artery infusion of melphalan should be added to focal therapies spectrum. In selected cases, melphalan should be combined with other chemotherapeutic agents.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Child; Child, Preschool; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; Italy; Male; Melphalan; Neoplasm Staging; Ophthalmic Artery; Ophthalmoscopy; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Survival Rate; Treatment Outcome; Young Adult

Retinoblastoma is a relatively uncommon childhood tumor. If untreated, RB grows to fill the eye and destroys the ocular globe's internal architecture. Metastatic spread usually begins after the first 6 months, and death occurs within a matter of years. When treated, overall survival rounds 97%, the alkylating drug melphalan being the most extensively used chemotherapeutic agent in localized treatment. In our hospital, pediatric oncologists asked the Pharmacy Department for assessment in order to implement a new chemotherapy protocol for the treatment of advanced intraocular elegible retinoblastoma cases using melphalan administered directly through the ophthalmic artery. In this paper, we describe the protocol implementation carried out by our collaborative interdisciplinary team as well as the clinical outcomes of five cases treated with ophthalmic intra-arterial melphalan therapy. Oncology pharmacists can contribute with their knowledge to the implementation process of new collaborative practice protocols recommending doses, predicting possible adverse effects and assessing about drug stability and elaboration, packaging and administration methods.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Cooperative Behavior; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Patient Care Team; Pharmacists; Pharmacy Service, Hospital; Professional Role; Retinal Neoplasms; Retinoblastoma; Treatment Outcome

Treatment of eyes with retinoblastoma failing systemic chemoreduction and external beam radiotherapy is seldom efficacious. This study compares the efficacy and toxicity of intra-arterial ophthalmic artery chemotherapy (IAO) to our historical cohort of sequential periocular and systemic chemotherapy in such patients.. Eighteen eyes (15 consecutive patients) were retrospectively evaluated. Eight eyes received IAO for a median of four cycles (range: 2-9) including melphalan alone (n = 3) or after topotecan and carboplatin (n = 4) or topotecan and carboplatin without melphalan (n = 1). Ten eyes received a median of two cycles (range: 1-3) of periocular topotecan (n = 9) or carboplatin (n = 1) followed by intravenous topotecan and cyclophosphamide in three patients if at least stable disease was achieved. Both groups were comparable for disease extension and prior therapy.. No extraocular dissemination or second malignancy occurred and all patients are alive. The probability of enucleation-free eye survival at 12 months was 0.87 (95% CI: 0.42-0.97) for the IAO group, compared to 0.1 (95% CI: 0.06-0.35) for the periocular group (P < 0.01). Ocular toxicity was mild and similar in both groups (mostly mild orbital edema). Systemic toxicity was low for IAO and periocular injection, but children who received sequentially intravenous chemotherapy (n = 12 cycles) had five episodes of grade 4 neutropenia, three of which resulted in hospitalizations. No case in the IAO group presented these complications.. IAO is significantly superior to sequential periocular-intravenous topotecan-containing regimens in eyes with relapsed intraocular retinoblastoma with a more favorable toxicity profile.

Topics: Administration, Intravenous; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Female; Humans; Injections, Intra-Arterial; Injections, Intraocular; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Salvage Therapy; Topotecan; Treatment Outcome; Vincristine; Young Adult

The risk/benefit profile of intravitreal melphalan injection for treatment of active vitreous seeds in retinoblastoma remains uncertain. We report clinical and electroretinography results after 6 months of one patient who has shown a favorable initial clinical response to intravitreal melphalan injections for treatment of refractory vitreous seeds.. Clinical case report.. The patient presented at age 17 months with bilateral retinoblastoma [OD: International Classification (ICRB) group E, Reese-Ellsworth (R-E) class Vb; OS: ICRB D, R-E Vb] with no known prior family history. The right eye was enucleated primarily. The patient received systemic chemotherapy and extensive local treatment to the left eye. Ten months later, she presented with recurrent disease, including fine, diffuse vitreous seeds. Tumor control was established with intra-arterial chemotherapy and local treatment. Subsequent recurrence was treated with further intra-arterial chemotherapy, local treatment, and plaque radiotherapy with iodine-125. Persistent free-floating spherical vitreous seeds were treated with 4 cycles of intravitreal melphalan injection via the pars plana, with doses of 30, 30, 30, and 20 μg.. After 6 months of follow-up, the left eye remained free of active tumor. Visual acuity was 20/40. Photopic ERGs amplitudes were unchanged compared with those recorded prior to the intravitreal injection treatments.. Intravitreal melphalan injection for refractory spherical vitreous seeds of retinoblastoma with favorable tumor response is compatible with good central visual acuity and preservation of retinal function as indicated by photopic ERG recordings.

Topics: Antineoplastic Agents, Alkylating; Electroretinography; Female; Follow-Up Studies; Humans; Infant; Intravitreal Injections; Melphalan; Ophthalmoscopy; Retina; Retinal Neoplasms; Retinoblastoma

We present a description of retinoblastoma treated with supraselective intra-arterial chemotherapy, demonstrating selective delivery of the infused chemotherapeutic agent into the tumor bed by MRI. A 7-month-old presented with group E (international classification) unilateral retinoblastoma. We treated the patient with several rounds of intra-ophthalmic artery melphalan. Gadolinium was infused along with melphalan to visualize the distribution of this chemotherapeutic drug. Intraoperative MRI was obtained within 15 min after treatment and showed increased enhancement of the tumor and subretinal space. We demonstrate here that supraselective administration of chemotherapy into the ophthalmic artery appears to result in drug delivery to the tumor and subretinal space.

Topics: Antineoplastic Agents, Alkylating; Cerebral Angiography; Contrast Media; Drug Delivery Systems; Follow-Up Studies; Gadolinium; Humans; Infant; Injections, Intra-Arterial; Intraoperative Period; Magnetic Resonance Angiography; Male; Melphalan; Retinal Artery; Retinal Detachment; Retinal Neoplasms; Retinoblastoma; Treatment Outcome; Visual Acuity

A 3-year-old girl with a history of bilateral retinoblastoma presented with a new right lower periorbital mass that showed calcifications on ultrasound. She had previously undergone systemic and intra-arterial chemotherapy for retinoblastoma but had no evidence of active disease for at least 6 months previously. Her family and oncologists feared that this mass was an extraocular metastasis of her retinoblastoma. On excision, it was diagnosed as a pilomatrixoma, an uncommon benign neoplasm that originates from the matrix of the hair root. This is the first reported case of pilomatrixoma in a patient with retinoblastoma.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Eyelids; Female; Hair Diseases; Humans; Melphalan; Pilomatrixoma; Retinal Neoplasms; Retinoblastoma; Skin Neoplasms; Ultrasonography

Reversible cerebral vasoconstriction syndrome is a rare cause of headache and stroke in the pediatric population. Reversible vasoconstriction is reported in a 19-month-old girl with retinoblastoma who underwent selective ophthalmic artery infusion chemotherapy with melphalan. Procedure-related cerebral vasoconstriction was specifically triggered during coadministration of adjunctive medications, which included mydriatic eye drops containing phenylephrine, intranasal oxymetazoline, nebulized albuterol, intravenous hydrocortisone, and intravenous diphenhydramine. The course of cerebral vasospasm, which began with a severe hypertensive surge and resolved spontaneously within hours of blood pressure normalization, was documented by angiography in real time. Subsequent brain magnetic resonance imaging showed no evidence of perfusion abnormality, cerebral infarction, or cerebral hemorrhage, and the patient was discharged home without any neurologic sequelae. In this report, we highlight the potential risk of reversible cerebral vasoconstriction in children administered vasoactive drugs and discuss its relevance during treatment of retinoblastoma by intraarterial chemotherapy.

Topics: Antineoplastic Agents, Alkylating; Female; Humans; Infant; Melphalan; Phenylephrine; Retinal Neoplasms; Retinoblastoma; Sympathomimetics; Vasospasm, Intracranial

To assess the efficacy of less than 3 cycles of intra-arterial chemotherapy (IAC) for retinoblastoma.. Retrospective, nonrandomized, interventional case series.. Eight patients.. Intra-arterial chemotherapy.. Tumor control and globe salvage.. Eight patients received fewer than 3 cycles of IAC for retinoblastoma because there was complete tumor control with no residual viable tumor (n = 7) or poor response (n = 1) with little hope that further therapy would benefit the patient. In 3 cases, additional vascular compromise precluded further IAC. The treatment was primary in 6 cases and secondary after failure of other treatment in 2 cases. The 8 eyes were classified (International Classification of Retinoblastoma) as group C (n = 2), group D (n = 3), group E (n = 1), and secondary treatment (n = 2). At initial examination, the main tumor showed a mean basal diameter of 16 mm, a thickness of 8.6 mm, vitreous seeds (n = 2), subretinal seeds (n = 6), and iris neovascularization (n = 1). Three patients were treated with a single cycle of IAC, and 5 patients were treated with 2 cycles of IAC. After IAC, complete tumor response was found in 7 eyes (88%) and partial response was found in 1 eye (13%). Over a mean of 13 months follow-up, there was intraretinal tumor recurrence (n = 1), subretinal seed recurrence (n = 1), and no case of vitreous seed recurrence. Globe salvage was achieved in 2 of 2 group C eyes (100%), 3 of 3 group D eyes (100%), 0 of 1 group E eye (0%), and 1 of 2 secondary treatment eyes (50%). Globe salvage was achieved in 6 of 8 eyes (75%), and 2 of 8 eyes (25%) required enucleation.. One or 2 cycles of IAC can be sufficient for selected eyes with group C or D retinoblastoma, with remarkable tumor control.. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Eye Enucleation; Eye Neoplasms; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retreatment; Retrospective Studies; Salvage Therapy; Treatment Outcome; Vitreous Body

Retinoblastoma is a rare and curable malignancy affecting the pediatric population. For advanced stage intraocular retinoblastoma, enucleation remains the primary treatment modality, although the use of laser photocoagulation, cryotherapy, radiotherapy and chemotherapy are frequently used, particularly in the setting of bilateral disease. Intravenous chemotherapy is the long-standing method of delivery, but local administration (subtenon, intravitreal or intra-arterial) is gaining in popularity because of the reduced side effects related to systemic administration. Of these newer methods, intra-arterial infusion has demonstrated technical feasibility, few procedural complications and robust tumor response. A case is described where a collateral supply to the affected ophthalmic artery was via the zygomatico-orbital branch of the ipsilateral superficial temporal artery. Melphalan infusion was performed via this pathway without incident.

Topics: Child, Preschool; Humans; Infusions, Intra-Arterial; Male; Melphalan; Orbit; Radiography; Retinal Neoplasms; Retinoblastoma; Temporal Arteries; Zygoma

Intra-arterial infusion of chemotherapy into the ophthalmic artery for treatment of retinoblastoma has been realized after catheterization of the internal carotid and temporary balloon occlusion beyond the orifice of the ophthalmic artery, or more recently after superselective canulation of the ophthalmic artery by a microcatheter. The superselective catheterization of the ophthalmic artery could be cumbersome because of the implantation of the ostium on the carotid siphon or because of the tortuosity of the carotid siphon. We report our experience of using a retrograde approach through the posterior communicating artery that allows a more direct angle of access to the origin of the ophthalmic artery.

Topics: Antineoplastic Agents, Alkylating; Female; Fluoroscopy; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma

To evaluate fluorescein angiography (FA) findings after intra-arterial chemotherapy (IAC) for retinoblastoma.. Retrospective case series.. Twenty-four eyes of 24 patients.. Fifty-five IAC procedures for delivery of melphalan 5 mg and possible carboplatin 30 mg.. Vascular flow of iris, retina, and choroid after IAC.. All patients received melphalan 5 mg, whereas the first 6 patients also were treated with additional carboplatin 30 mg. The IAC was performed as primary treatment in 17 eyes and as secondary treatment (after systemic chemotherapy) in 7 eyes. Two patients also received external-beam radiotherapy before IAC. At presentation, FA revealed neovascularization of the iris (NVI) in 8 eyes, and after IAC, complete NVI regression was noted in 5 eyes (63%). After a mean follow-up of 13 months after IAC, FA depicted the main tumor with decreased fluorescence in 22 eyes (92%). After 55 ophthalmic artery catheterizations, retinal vascular abnormalities by FA were detected in 7 eyes (13%) and choroidal vascular abnormalities were detected in 6 eyes (11%). The retinal abnormalities included ophthalmic artery obstruction (n = 1), transient ophthalmic artery spasm (n = 1), central retinal artery obstruction (n = 1), branch retinal artery obstruction (n = 2), and peripheral retinal ischemia (n = 2). Additional retinal neovascularization was found in 1 patient. The choroidal abnormalities included sector (n = 5) or diffuse (n = 1) choroidal nonperfusion. New-onset iris neovascularization was found in 2 patients. Retinal vascular abnormalities were diagnosed after median of 1 month after the first IAC, whereas choroidal vascular abnormalities were found after median of 5 months after the first IAC.. Fluorescein angiography suggests that vascular perfusion to the retina and the choroid can be compromised after IAC for retinoblastoma. The most common vascular abnormality was choroidal sector or diffuse nonperfusion.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Choroidal Neovascularization; Female; Fluorescein Angiography; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Radiotherapy, Adjuvant; Retinal Neoplasms; Retinal Neovascularization; Retinal Vessels; Retinoblastoma; Retrospective Studies

To report the efficacy of super-selective intra-ophthalmic artery melphalan (IAM) for the treatment of refractory retinoblastoma and any associated complications of this treatment.. A prospective case series.. Eyes with retinoblastoma that had been treated with systemic chemotherapy or local therapy and had a relapse of their condition.. All patients receiving IAM between May 2009 and September 2010 were included in the study. Intra-ophthalmic artery melphalan was offered to patients who had failed to respond adequately to systemic chemotherapy and local treatment where appropriate or because of a new recurrence of retinoblastoma that could not be treated with local therapies. None of the patients were excluded because of central nervous system abnormalities. Patients received 2 treatments of IAM given 4 weeks apart. All patients received an orthoptic assessment 3 weeks after each treatment and an examination under anesthesia (EUA). A third treatment was given if an unsatisfactory response was observed on EUA after 2 treatments.. The response of the retinoblastoma tumor(s) and any associated local side effects from the treatment.. A total of 15 eyes in 14 patients were treated with IAM during the study period. The mean age at the time of IAM was 31.5 months (median 17.3, range 11.2-150.7 months), and the mean follow-up was 8.7 months (3-16.3 months). Tumor control was achieved in 12 eyes (80%), and 12 eyes (80%) had local side effects that included third cranial nerve palsy in 6 (40%), orbital edema in 3 (20%), permanent retinal detachment in 1 (7%), and vitreous hemorrhage in 4 (27%). Seven eyes (47%) developed significant retinal pigment epithelium changes.. Intra-ophthalmic artery melphalan is an effective treatment for retinoblastoma, achieving a high level of remission in refractory tumors. It can be associated with significant local side effects that can result in loss of vision and possible amblyogenesis. Clinicians and parents need to consider the benefits and potential local side effects before embarking on treatment.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Child; Child, Preschool; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Prospective Studies; Retinal Neoplasms; Retinoblastoma; Treatment Outcome

To review results of orbital angiography performed during intra-arterial chemotherapy (chemosurgery) for treatment of retinoblastoma to assess the association of angiographic variability in orbitovascular anatomy with tumor response and outcomes.. Medical records and 64 orbital angiograms were reviewed for 56 pediatric patients with retinoblastoma undergoing chemosurgery using a combination of melphalan hydrochloride, topotecan hydrochloride, or carboplatin. The major orbital arteries and capillary blush patterns were graded, and tumor response and recurrence were compared using the log-rank and Fisher exact tests.. Statistically significant variables for tumor response were lacrimal artery prominence (P = .001), previous treatment (P = .003), and lacrimal blush (P = .004). The only statistically significant variable for vitreous seed response was ciliary body blush (P = .03). Statistically significant variables influencing time to recurrence and time to enucleation were choroidal blush absence (P = .01) and lacrimal artery presence (P = .03), respectively.. The success of intra-arterial chemotherapy is dependent on delivery of drug to the target tumor within the eye via the ophthalmic artery. Because of the small volume of drug used (0.50-1.25 mL per treatment) and the selectivity of catheterization, variables affecting orbital blood flow greatly influence drug delivery and the success of chemosurgery.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Blood Flow Velocity; Carboplatin; Child; Child, Preschool; Female; Fluorescein Angiography; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Orbit; Regional Blood Flow; Retinal Neoplasms; Retinoblastoma; Topotecan; Young Adult

The preservation of globe integrity has always been a major concern during the treatment of retinoblastoma for fear of extraocular or metastatic spread. Intravitreal chemotherapy has been attempted as a desperate salvage therapy only for eyes with refractory retinoblastoma. Published data on the safety and efficacy of this route are, however, limited.. A modified technique of intravitreal injection in eyes with retinoblastoma is described. All children with retinoblastoma who received one or more intravitreal injections using this technique were retrospectively reviewed concerning ocular complications of the injection procedure as well as clinical or histopathological evidence of tumour spread.. 30 eyes of 30 children with retinoblastoma received a total of 135 intravitreal injections, with a median follw-up duration of 13.5 months. No extraocular spread was seen on clinical follow-up in any patients and there was no tumour contamination of the retrieved entry sites histopathologically analysed among the five enucleated eyes. No significant ocular side effects were observed except transient localised vitreous haemorrhage (3/135).. This technique is potentially safe and effective at a low cost and may play a promising role, especially in the treatment of recurrent and/or resistant vitreous disease in retinoblastoma, as an alternative to enucleation and/or external beam radiotherapy. However, this treatment should not replace the primary standard of care of retinoblastoma and should not be considered in group E eyes. Its application should be approved by an ophthalmological-oncological team and it should be performed by an experienced eye surgeon in a tertiary referral centre after careful selection of a tumour-free injection site.

Topics: Antineoplastic Agents; Carboplatin; Child, Preschool; Eye Neoplasms; Female; Humans; Infant; Infant, Newborn; Intravitreal Injections; Male; Melphalan; Microscopy, Acoustic; Neoplasm Seeding; Paracentesis; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Sterilization; Vitreous Body

The authors present a case of group D unilateral sporadic retinoblastoma treated with only two intra-arterial chemotherapy cycles using melphalan, which resulted in tumor regression, resolution of subretinal fluid, and, most importantly, salvage of the life, and the eye.

Topics: Antineoplastic Agents, Alkylating; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Treatment Outcome; Ultrasonography

Ophthalmic artery chemosurgery (OAC) for retinoblastoma was introduced by us 5 years ago for advanced intraocular retinoblastoma. Because the success was higher than with existing alternatives and systemic side effects limited we have now treated less advanced intraocular retinoblastoma (Reese-Ellsworth (RE) I-III and International Classification Retinoblastoma (ICRB) B and C).. Retrospective review of 5 year experience in eyes with Reese Ellsworth (Table 1) I (7 eyes), II (6 eyes) or III (6 eyes) and/or International Classification (Table 2) B (19 eyes) and C (11 eyes) treated with OAC (melphalan with or without topotecan) introduced directly into the ophthalmic artery. Patient survival was 100%. Ocular event-free survival was 100% for Reese-Ellsworth Groups I, II and III (and 96% for ICRB B and C) at a median of 16 months follow-up. One ICRB Group C (Reese-Ellsworth Vb) eye could not be treated on the second attempt for technical reasons and was therefore enucleated. No patient required a port and only one patient required transfusion of blood products. The electroretinogram (ERG) was unchanged or improved in 14/19 eyes.. Ophthalmic artery chemosurgery for retinoblastoma that was Reese-Ellsworth I, II and III (or International Classification B or C) was associated with high success (100% of treatable eyes were retained) and limited toxicity with results that equal or exceed conventional therapy with less toxicity.

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Child, Preschool; Disease-Free Survival; Eye; Follow-Up Studies; Humans; Infant; Melphalan; Ophthalmic Artery; Ophthalmologic Surgical Procedures; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan; Young Adult

Introduced in 1988 by Kaneko and colleagues, selective ophthalmic arterial infusion of chemotherapeutic drug has recently gained more interest among retinoblastoma experts worldwide. The report showed that the procedure could be repeated up to 12 treatments without serious side effects. We report a 4-year-old girl with bilateral retinoblastoma. The left eye was enucleated for the group E disease. The right eye started with 3 retinal tumors (group C) was treated with systemic chemotherapy plus local therapy. Seven months after the last cycle of chemotherapy, the tumor recurred close to the fovea. Systemic chemotherapy was reinitiated without success. To avoid aggressive cryotherapy and external-beam radiotherapy, selective ophthalmic arterial infusion of chemotherapeutic drugs was performed for 15 sessions. The tumor responded partially without evidence of drug-induced retinal toxicity by the electroretinogram. Minor irregularities of the inner wall of supraclinoid portion of the internal carotid artery were observed only at the sixth session. Narrowing of the vascular lumen occurred on the last 2 sessions. We demonstrate that this technique when performed repeatedly could result in the anatomic changes of the small blood vessel. Careful follow-up is necessary for early detection of any serious consequences.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child, Preschool; Cryotherapy; Electrophysiology; Electroretinography; Etoposide; Female; Humans; Infusions, Intra-Arterial; Melphalan; Neoplasm Recurrence, Local; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Treatment Outcome; Vincristine

To characterize melphalan pharmacokinetics after superselective ophthalmic artery infusion (SSOAI) in animals and children with retinoblastoma.. Vitreous and plasma samples of five Landrace pigs were obtained over a 4-hour period after SSOAI of melphalan (7 mg). Melphalan cytotoxicity was evaluated in retinoblastoma cell lines with and without topotecan. Plasma samples were obtained from 17 retinoblastoma patients after SSOAI of 3 to 6 mg of melphalan to one (n=14) or two eyes (n=3). Correlation between plasma pharmacokinetics and age, dosage, and systemic toxicity was studied in patients.. In animals, melphalan peak vitreous levels were greater than its IC50 and resulted in 3-fold vitreous-to-plasma exposure. In patients, a large variability in pharmacokinetic parameters was observed and it was explained mainly by body weight (P<0.05). A significantly higher systemic area under the curve was obtained in children receiving more than 0.48 mg/kg for bilateral tandem infusions (P<0.05). These children had 50% probability of grades 3-4 neutropenia. Plasma concentrations after 2 and 4 hours of SSOAI were significantly higher in these children (P<0.05). A synergistic cytotoxic effect of melphalan and topotecan was evident in cell lines.. Potentially active levels of melphalan after SSOAI were achieved in the vitreous of animals. Low systemic exposure was found in animals and children. Doses greater than 0.48 mg/kg, given for bilateral tandem infusions, were associated with significantly higher plasma levels and increased risk of neutropenia. Synergistic in vitro cytotoxicity between melphalan and topotecan favors combination treatment.

Topics: Animals; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Child; Child, Preschool; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Neoplasms, Experimental; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Swine; Vitreous Body

To assess the long-term results of chemotherapy for cavitary retinoblastoma.. Retrospective, nonrandomized, interventional case series of 26 cavitary retinoblastomas in 25 eyes of 24 patients. Retinoblastomas were treated with intravenous chemoreduction and/or intra-arterial chemotherapy. Main outcome measures included tumor control, globe salvage, and metastasis.. Of 24 patients with cavitary retinoblastoma, the mean age at diagnosis was 16 months. The mean number of cavitary tumors per eye was 1 (median, 1; range, 1-2), with a mean tumor basal diameter of 13 (median, 13; range, 7-24) mm and mean tumor thickness of 7 (median, 6; range, 3-17) mm. The mean number of cavities per tumor was 2 (median, 2; range, 1-5), with a mean cavity diameter of 3 (median, 2; range, 1-10) mm. Related features included vitreous seeds in 7 tumors (27%), subretinal seeds in 6 (23%), and subretinal fluid in 13 (50%). Intravenous chemoreduction was used in 23 tumors (88%); intra-arterial chemotherapy, in 2 (8%); and both, in 1 (4%). After treatment, the mean reduction in tumor base was 22% and mean reduction in tumor thickness was 29%. Despite minimal reduction, tumor recurrence was noted in only 1 eye (4%), globe salvage was achieved in 22 (88%), and there were no cases of metastasis or death during 49 (range, 6-189) months of follow-up.. Despite minimal visible tumor response to chemotherapy, cavitary retinoblastoma displays relatively stable long-term results.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child, Preschool; Etoposide; Female; Fluorescein Angiography; Follow-Up Studies; Humans; Infant; Infusions, Intra-Arterial; Infusions, Intravenous; Male; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Tomography, Optical Coherence; Treatment Outcome; Vincristine

Tumour control of vitreous seeds remains challenging owing to their resistance to radiation and systemic chemotherapy.. To describe the short-term efficacy of intravitreal melphalan for vitreous disease in retinoblastoma using a new injection technique and dose.. This study is a retrospective non-comparative review of 23 consecutive heavily pretreated patients (23 eyes) with active vitreous seeding and eligible for intravitreous chemotherapy (IViC). They received a total of 122 intravitreal injections of melphalan (20-30 μg) given every 7-10 days. The ocular status was objectively monitored under anaesthesia with fundus photography.. All patients are alive without evidence of extraocular spread (95% CI 82.19% to 100%). Concomitant treatments, including other chemotherapeutic modalities, were used until complete sterilisation of the retinal seeding source and subretinal seeds. Globe retention was achieved in 87% (20/23) of cases. All retained eyes were in complete remission after a median follow-up period of 22 months (range 9-31 months). The Kaplan-Meier estimate of ocular survival rates at 2 years was 84.14% (95% CI 62.48% to 95.28%). A localised peripheral salt-and-pepper retinopathy was noted in 10 eyes (43%) at the site of injection.. This study reports the first clinically documented case series of patients with retinoblastoma treated with IViC. Despite a possible confounding effect of concomitant chemotherapy prescription using other routes of administration in four of the successfully treated eyes (20%), IViC achieved an unprecedented success rate of tumour control in the presence of vitreous seeding. Of note, none of the treated eyes required external beam irradiation to control the vitreous seeding. Further studies are required to assess IViC retinal toxicity and to better delineate its role in the management of retinoblastoma.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Eye Neoplasms; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Intravitreal Injections; Male; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retreatment; Retrospective Studies; Treatment Outcome; Vitreous Body

To report outcomes with selective intra-arterial chemotherapy (SIAC) using simultaneous carboplatin, topotecan, and melphalan for advanced intraocular retinoblastoma.. A retrospective chart review was conducted of patients who received three-drug (melphalan, topotecan, and carboplatin) SIAC during 2006-2011.. Twenty-six eyes of 25 patients received the three-drug chemotherapy for treatment of advanced retinoblastoma. Reese-Ellsworth group was 5b in 21 eyes, 5a in 2, 4a in 2, and 3a in 1. Seventeen patients (68%) had recurrence after prior intravenous chemotherapy with or without radiotherapy. In the three-drug therapy, dose ranges were 2.5-7.5 mg for melphalan, 0.3-0.6 mg for topotecan, and 25-50 mg for carboplatin, and median infusions per eye was 2 (range 1-4). At a mean follow-up of 14 months (range 1-43 months), all patients are alive and no patient developed metastatic disease. Twenty-three of 26 eyes (88%) survived. Eleven of the 26 eyes (35%) developed recurrent disease and were treated with enucleation (n=3) or with focal therapy (n=8) with or without plaque brachytherapy (n=3). The Kaplan-Meier estimate of ocular survival at 24 months was 75% (95% CI). Electroretinogram showed improvement greater than 25 µV in 4 eyes (15%), loss greater than 25 µV in 12 eyes (46%), and no change greater than 25 µV in 10 eyes (39%).. Three-drug SIAC has been used successfully to rescue eyes after treatment failure of intravenous chemotherapy and/or single- or double-agent SIAC. Twenty-three of 26 eyes avoided both enucleation and external beam radiotherapy and retained electroretinogram function.

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Infusions, Intra-Arterial; Male; Melphalan; Middle Aged; Pilot Projects; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topoisomerase I Inhibitors; Topotecan; Treatment Outcome; Young Adult

Topics: Antineoplastic Agents, Alkylating; Catheters, Indwelling; Chemotherapy, Cancer, Regional Perfusion; Computer Systems; Fluorescein Angiography; Fluoroscopy; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Ophthalmoscopy; Retinal Neoplasms; Retinoblastoma

To evaluate the efficacy and complications of intravitreal chemotherapy for viable vitreous seeding from retinoblastoma.. Intravitreal injection of melphalan (8-50 μg in 0.05 mL) followed by injection site cryotherapy.. Among 12 treated cases, success with control of vitreous seeds was achieved in 10 of 12 cases at immediate follow-up (0-3 months), 8 of 10 cases at short-term follow-up (3-6 months), and 6 of 10 cases at long-term (>6 months) follow-up. Among those 8 cases that received an 8- to 10-μg dose, control was achieved in 6 of 8 cases at immediate follow-up, 5 of 7 cases at short-term follow-up, and 3 of 7 cases at long-term follow-up. Complications with the 8- to 10-μg dose were minor and included preretinal hemorrhage and retinal vasculitis with retinal pigment epithelial alterations. Of those 4 that received a 50-μg dose, immediate, short-term, and long-term control was 100%, but complications of cataract, vitreous hemorrhage, subretinal hemorrhage, severe hypotonia, and phthisis lead to enucleation in 2 cases. There was no case of orbital tumor recurrence or retinoblastoma metastasis (follow-up range, 8-66 months).. Intravitreal melphalan for recurrent vitreous seeds from retinoblastoma appears to provide vitreous seed control in some patients. A high dose (50 μg) of melphalan is toxic and should be avoided.

Topics: Antineoplastic Agents, Alkylating; Child; Child, Preschool; Follow-Up Studies; Humans; Infant; Intravitreal Injections; Melphalan; Neoplasm Recurrence, Local; Neoplasm Seeding; Radiotherapy, Adjuvant; Retinal Neoplasms; Retinoblastoma; Treatment Outcome; Vitreous Body

We present a description of retinoblastoma treated with supraselective intra-arterial chemotherapy, demonstrating selective delivery of the infused chemotherapeutic agent into the tumor bed by MRI. A 7-month-old presented with group E (international classification) unilateral retinoblastoma. We treated the patient with several rounds of intra-ophthalmic artery melphalan. Gadolinium was infused along with melphalan to visualize the distribution of this chemotherapeutic drug. Intraoperative MRI was obtained within 15 min after treatment and showed increased enhancement of the tumor and subretinal space. We demonstrate here that supraselective administration of chemotherapy into the ophthalmic artery appears to result in drug delivery to the tumor and subretinal space.

Topics: Antineoplastic Agents, Alkylating; Contrast Media; Gadolinium; Humans; Infant; Magnetic Resonance Imaging; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma

To investigate the safety of treatment with ophthalmic artery cannulation for intra-arterial chemotherapy (IAC) for children with intraocular retinoblastoma (RB).. In the RB Treatment Center of General Hospital of Armed Police Forces between January 2009 and September 2011, 42 patients who were diagnosed intraocular RB and treated with ophthalmic artery cannulation for IAC, 8 patients were treated 1 circle, 31 patients were treated 2 circles and 3 patients were treated 3 circles (total, 96 times). Each month had IAC once. The ophthalmic and the whole body evaluations were performed during IAC and after IAC for each circle, the blood cell count, alanine aminotransferase (ALT), serum creatinine (Scr), CK-MB content before and after IAC for 1 circle, 2 circles and 3 circles were determined.. (1) In 52 eyes of 42 patients, 44 eyes (84.6%) were in remission. (2) Successful IAC was achieved in all cases, no severe side effects occurred during IAC. (3) The main ophthalmic complications were eyelid edema and blepharoptosis after IAC, the incidence for 1 circle was 18% (2/11) and 9% (1/11); for 2 circles was 29% (11/38) and 21% (8/38); for 3 circles was all 100% (3/3). The rare complications were vitreous hemorrhage and heterotropia, the incidence was all 2% (1/42). The incidence of eyelid edema and blepharoptosis had no significant differences for 1 circle IAC compared with 2 circles (P > 0.05); the incidence of eyelid edema and blepharoptosis had significant differences for 3 circles IAC compared with 2 circles and 1 circle (P < 0.01). (4) No fever, septicemia and other systemic toxic effects occurred. (5) ALT of 19% patients (8/42) elevated temporarily and CK-MB of 24% patients (10/42) increased. The blood cell counts, ALT, Scr, and CK-MB content before IAC had no significant differences compared with that at 24 h after IAC for 1 circle, 2 circles and 3 circles (P > 0.05).. Ophthalmic artery cannulation for IAC is a safe and effective method in treating intraocular stage retinoblastoma.

Topics: Antineoplastic Agents, Alkylating; Catheterization; Child, Preschool; Female; Humans; Infant; Infusions, Intra-Arterial; Liver Function Tests; Male; Melphalan; Neoplasm Staging; Ophthalmic Artery; Postoperative Complications; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Treatment Outcome

Superselective ophthalmic artery chemotherapy (SOAC) has recently been proposed as an alternative to intravenous chemoreduction for advanced intraocular retinoblastoma. Preliminary results appear promising in terms of tumor control and eye conservation, but little is known regarding ocular toxicity and visual prognosis. In this study, we report on the vascular adverse effects observed in our initial cohort of 13 patients.. The charts of 13 consecutive patients with retinoblastoma who received a total of 30 injections (up to 3 injections of a single agent per patient at 3-week interval) of melphalan (0.35 mg/kg) in the ophthalmic artery between November 2008 and June 2010 were retrospectively reviewed. RetCam fundus photography and fluorescein angiography were performed at presentation and before each injection. Vision was assessed at the latest visit.. Enucleation and external beam radiotherapy could be avoided in all cases but one, with a mean follow-up of 7 months. Sectoral choroidal occlusive vasculopathy leading to chorioretinal atrophy was observed temporally in 2 eyes (15%) 3 weeks to 6 weeks after the beginning of SOAC and retinal arteriolar emboli in 1 eye 2 weeks after injection. There was no stroke or other clinically significant systemic side effects except a perioperative transient spasm of the internal carotid artery in one patient. Vision ranged between 20/1600 and 20/32 depending on the status of the macula.. Superselective ophthalmic artery chemotherapy was effective in all patients with no stroke or other systemic vascular complications. Unlike intravenous chemoreduction, SOAC is associated with potentially sight-threatening adverse effects, such as severe chorioretinal atrophy secondary to subacute choroidal occlusive vasculopathy or central retinal artery embolism, not to mention the risk of ophthalmic artery obstruction, which was not observed in this series. Further analysis of the risks and benefits of SOAC will define its role within the therapeutic arsenal. Meanwhile, we suggest that SOAC should be given in one eye only and restricted to advanced cases of retinoblastoma, as an alternative to enucleation and/or external beam radiotherapy.

Topics: Antineoplastic Agents, Alkylating; Atrophy; Chemotherapy, Cancer, Regional Perfusion; Child, Preschool; Choroid; Choroid Diseases; Fluorescein Angiography; Humans; Infant; Melphalan; Ophthalmic Artery; Photography; Retinal Artery Occlusion; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Visual Acuity

Retinoblastoma is the most common ocular neoplasm in children. Left untreated it spreads to the brain via the optic nerve. Traditional therapy is enucleation, and while this procedure is still the most common treatment worldwide, modern eye-preserving therapies can often spare the globe. However, patients with retinoblastoma often present in advanced stages of the disease when these globe-preserving strategies are often insufficient to prevent enucleation. In these challenging cases, direct infusion of chemotherapy into the ophthalmic artery has been attempted to achieve tumor control. The authors' aim in this study was to report on their initial experience with and clinical results for this approach.. The authors prospectively collected data on all cases of retinoblastoma treated with selective intraophthalmic melphalan at Bascom Palmer Eye Institute. All cases were classified as International Intraocular Retinoblastoma Classification (IIRC) Group D or Reese-Ellsworth Group Vb, had not responded to aggressive multimodal therapy consisting of chemotherapy and focal consolidating laser therapy, and were pending enucleation. Using digital subtraction angiography, a microcatheter was navigated under roadmap guidance into the ophthalmic artery, and melphalan was infused over 40 minutes. Early in the series, patients were treated with 3 or 5 mg of melphalan, but after low response rates occurred all eyes were treated with 7.5 mg of melphalan. All patients were examined with funduscopy while under anesthesia 3 weeks after treatment and every 3 months thereafter. Patients with persistent disease were retreated with repeat infusions of melphalan.. Twenty-six procedures were performed to treat 17 tumors in 15 patients. Successful cannulation of the ophthalmic artery was achieved in all cases. The follow-up ranged from 3 to 12 months, with a mean of 8.6 months. Overall, 76% of the tumors responded to therapy and these cases were spared enucleation. The average number of treatments was 1.5 per tumor. Of the responders, 54% responded to a single dose of melphalan. Treatment with the higher dose of 7.5 mg up front was associated with a lower enucleation rate (0% vs 36%) as compared with the lower starting dose. Delayed vitreous hemorrhage occurred after 4 (15%) of 26 treatments, and these cases were treated with enucleation.. In this challenging group of advanced retinoblastomas refractory to aggressive multimodal therapy, virtually 100% of eyes are generally enucleated. In contrast, the authors' protocol of infusing melphalan directly into the ophthalmic artery led to a dramatic decrease in the enucleation rate to 23.5%. While it is now the treatment of choice for refractory retinoblastoma at their center, its role in less advanced disease remains to be elucidated.

Topics: Antineoplastic Agents; Child; Child, Preschool; Eye Enucleation; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Ophthalmoscopy; Prospective Studies; Retinal Neoplasms; Retinoblastoma; Treatment Outcome

A 22-month-old girl with Group C unilateral retinoblastoma demonstrated dramatic tumor regression after two infusions of 5 mg of intra-arterial melphalan as primary therapy. Complete tumor control without recurrence was noted at 1 year. Retinal and choroidal perfusion was intact and the electroretinogram improved following therapy.

Topics: Antineoplastic Agents, Alkylating; Electroretinography; Female; Fluorescein Angiography; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Retina; Retinal Neoplasms; Retinoblastoma; Ultrasonography

To describe treatment complications following intra-arterial chemotherapy (IAC) for retinoblastoma.. A retrospective interventional series of ophthalmic artery cannulation for IAC injection (3 planned sessions at 1-month intervals) was undertaken. Thirty-eight catheterizations of 17 eyes of 17 patients were performed from September 2008 to September 2010. Fluoroscopy of the ophthalmic artery was performed before and immediately after treatment. Heparin was given during the procedure and aspirin (40 mg) was given orally for 1 week. The treatment complications were determined.. Only 17 of 190 children were selected for treatment with IAC during this period. Following successful ophthalmic artery cannulation in 16 cases, there was no evidence of metastasis, stroke, brain injury, or persistent systemic toxic effects. Fluoroscopy demonstrated patent ophthalmic artery immediately before and after IAC injection in each case. Following therapy, orbital and adnexal findings at 1 month included eyelid edema (n = 13), blepharoptosis (n = 10), cilia loss (n = 1), and orbital congestion with temporary dysmotility (n = 12). These findings resolved within 6 months in all cases. Following therapy, vascular findings included ophthalmic artery stenosis (permanent in 3 cases, temporary in 1 case), confirmed on fluoroscopy in 3 cases. Concomitant central or branch retinal artery occlusion was noted (permanent in 2 cases, temporary in 1 case). Subtle retinal pigment epithelial mottling in 9 cases that slowly evolved to later-onset underlying choroidal atrophy in 5 cases was noted.. Treatment with IAC for retinoblastoma can lead to mild and severe short-term ocular complications, including eyelid edema as well as potentially blinding vascular obstruction. This procedure should be used with caution.

Topics: Antineoplastic Agents, Alkylating; Blepharoptosis; Catheterization; Chemotherapy, Cancer, Regional Perfusion; Child; Child, Preschool; Edema; Eyelid Diseases; Female; Fluorescein Angiography; Fluoroscopy; Humans; Infant; Injections, Intra-Arterial; Male; Melphalan; Ocular Motility Disorders; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies

To describe tumor control following intra-arterial chemotherapy (IAC) for retinoblastoma.. A retrospective interventional series in which 17 patients were treated with ophthalmic artery injection of melphalan, 5 mg, was undertaken to determine retinoblastoma control.. Of 190 children with retinoblastoma, 17 (9%) were treated with IAC. Catheterization was successful in 37 of 38 attempts. The treatment was primary in 13 cases (1 failed catheterization) and secondary in 4. The median retinoblastoma base was 20 mm and the median retinoblastoma thickness was 9.0 mm. Iris neovascularization was present in 5 cases. Following IAC, complete response of the main tumor was found in 14 cases (88%) and partial response was found in 2 (12%). Eyes with complete response and followed up for a minimum of 1 year (n = 10) showed no solid tumor recurrence. Of 11 eyes with subretinal seeds, 9 (82%) had complete response, 1 (9%) had partial response, and 1 (9%) had recurrence. Of 9 eyes with vitreous seeds, 6 (67%) had complete response, 2 (22%) had partial response, and 1 (11%) had recurrence. Globe salvage was achieved in 8 of 12 eyes (67%) treated with primary IAC, including 2 of 2 group C eyes, 4 of 4 group D eyes, and 2 of 6 group E eyes according to the International Classification of Retinoblastoma. Globe salvage was achieved in 2 of 4 eyes (50%) treated secondarily after failure of other methods.. Of 12 eyes managed with IAC as primary treatment, globe salvage was achieved in 67%. Eyes classified as group C or D showed 100% globe salvage, whereas group E had 33% salvage. Of 4 eyes managed with IAC as secondary treatment, globe salvage was achieved in 50%.

Topics: Antineoplastic Agents, Alkylating; Cerebral Angiography; Chemotherapy, Cancer, Regional Perfusion; Child; Child, Preschool; Electroretinography; Eye Neoplasms; Female; Fluorescein Angiography; Fluoroscopy; Humans; Infant; Injections, Intra-Arterial; Male; Melphalan; Neoplasm Seeding; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Treatment Outcome; Vitreous Body

To report the success rate, adverse events, and long-term prognosis of selective ophthalmic arterial injection (SOAI) therapy for intraocular retinoblastoma.. Noncomparative case series.. A total of 408 eyes of 343 patients.. Retrospective chart review of patients with intraocular retinoblastoma treated with SOAI using a balloon catheter and melphalan between 1988 and 2007.. The technical success rate of SOAI (we defined success as the successful injection of melphalan into the ophthalmic artery), ocular adverse events, systemic adverse events, secondary neoplasms, eye survival, and visual acuity.. Selective ophthalmic arterial injection was successful in 1452 procedures of 1469 trials, and the success rate was 98.8%. Each eye received 1 to 18 rounds of SOAI. Two eyes (0.5%) developed severe orbital inflammation, and 2 eyes (0.5%) had diffuse chorioretinal atrophy. Transient periocular swelling or redness occurred in some cases. No severe systemic adverse events were detected. Transient bronchospasm occurred in 1 patient (0.3%), and transient vomiting occurred in several patients. Twelve secondary neoplasms occurred in 11 patients, and the cumulative incidence was 1.3% at 5 years, 4.8% at 10 years, and 5.8% at 15 years. The eye preservation rate was 100% in group A, 88% in group B, 65% in group C, 45% in group D, and 30% in group E according to the International Classification of Intraocular Retinoblastoma. Fifty-one percent of eyes had a visual acuity >0.5, and 36% of eyes had a visual acuity >1.0 at the last follow-up examination in cases without macular tumors.. Selective ophthalmic arterial injection using a balloon catheter and melphalan achieved a success rate of 98.8% and was associated with few severe adverse events, including secondary neoplasms. More than half of the treated eyes were preserved, and more than half of the eyes without macular tumors maintained a visual acuity >0.5. Selective ophthalmic arterial injection is an established treatment method. We did not detect severe eye damage or severe systemic events; secondary neoplasms were seen but no more frequently than would otherwise have been expected.. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Topics: Antineoplastic Agents, Alkylating; Catheterization; Combined Modality Therapy; Follow-Up Studies; Humans; Injections, Intra-Arterial; Melphalan; Ophthalmic Artery; Prognosis; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Visual Acuity

To describe histopathologic observations in eyes enucleated after intra-arterial chemotherapy (IAC) for retinoblastoma (Rb).. Retrospective histopathologic analysis of 8 eyes.. The eyes were enucleated for tumor viability (n = 4), neovascular glaucoma (n = 2), anaphylactic reaction from IAC (n = 1), and persistent retinal detachment with poor visualization of the tumor (n = 1). Of the 2 eyes judged clinically with complete tumor regression and the 5 with viable tumor, the findings were confirmed on histopathology. The Rb response ranged from minimal (n = 1) to moderate (n = 1) to extensive (n = 4) to complete regression (n = 2). Viable vitreous seeds (n = 4 eyes), invasion into the optic nerve (n = 3), reaching the lamina cribrosa in 2 cases, and invasion into the choroid (n = 1) were observed. Histopathologic evidence of ischemic atrophy involving the outer retina and choroid was found in 4 eyes. One eye treated at another center with IAC and enucleated by our team for recurrence was observed to have extensive choroidal and outer retinal atrophy. This case showed orbital vascular occlusion and subendothelial smooth muscle hyperplasia. Intravascular birefringent foreign material was observed in 5 cases within occluded vessels, stimulating a granulomatous inflammatory response. The foreign material comprised cellulose fibers (n = 3), synthetic fabric fibers (n = 1), or unknown composition (n = 2). Thrombosed blood vessels were identified in 5 eyes and involved ciliary arteries in the retrobulbar orbit (n = 5), scleral emissarial canals (n = 1), small choroidal vessels (n = 1), and central retinal artery (n = 1).. Retinoblastoma can be controlled with IAC, but histopathology of enucleated eyes reveals that ocular complications including thromboembolic events can occur.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Child; Child, Preschool; Choroid Neoplasms; Eye Diseases; Eye Enucleation; Female; Fluorescein Angiography; Fluoroscopy; Humans; Infant; Injections, Intra-Arterial; Male; Melphalan; Neoplasm Invasiveness; Neoplasm Seeding; Ophthalmic Artery; Optic Nerve Neoplasms; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Thromboembolism; Vitreous Body

Topics: Antineoplastic Agents, Alkylating; Choroid Diseases; Humans; Melphalan; Ophthalmic Artery; Retinal Artery Occlusion; Retinal Neoplasms; Retinoblastoma

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Eye Neoplasms; Female; Humans; Injections, Intra-Arterial; Male; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Vitreous Body

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Humans; Injections, Intra-Arterial; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma

Topics: Antineoplastic Combined Chemotherapy Protocols; Catheters, Indwelling; Electroretinography; Evoked Potentials, Visual; Female; Follow-Up Studies; Functional Laterality; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retina; Retinal Neoplasms; Retinoblastoma; Topotecan; Treatment Outcome

The purpose of this study was to report a case of a 7-year-old girl with unilateral, multifocal Reese Ellsworth Stage Vb retinoblastoma who was successfully treated using intraarterial chemotherapy infusion as the primary therapy.. This is an interventional case report. A 7-year-old girl presented with advanced unilateral retinoblastoma. The patient received intraarterial melphalan infusion therapy as the primary treatment.. Complete tumor resolution was seen at 1 month after intraarterial melphalan infusion.. This case of advanced retinoblastoma in a 7-year-old girl was successfully treated with intraarterial melphalan infusion alone. Treatment resulted in complete resolution of the tumor 1 month after treatment. In comparison with systemic chemotherapy, intraarterial melphalan infusion therapy may be a less toxic and more effective primary treatment option in the future management of advanced retinoblastoma.

Topics: Antineoplastic Agents, Alkylating; Child; Female; Humans; Infusions, Intra-Arterial; Melphalan; Neoplasm Staging; Remission Induction; Retinal Neoplasms; Retinoblastoma; Visual Acuity

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Eye Enucleation; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma

To assess potential retinal viability by electroretinography following selective ophthalmic artery chemotherapy infusion for retinoblastoma.. Uncontrolled prospective case series. Patients with advanced retinoblastoma were offered elective ophthalmic artery chemotherapy infusion treatment under an IRB-approved protocol as an alternative to enucleation. The ophthalmic artery was cannulated under fluoroscopic control, and chemotherapeutic agents (melphalan and occasionally carboplatin) were directly infused at doses resulting in very high local tissue concentrations, but low systemic drug levels. Eyes were examined under anesthesia at 1-month intervals, and re-treated as indicated, up to a maximum of six infusions. Electroretinograms were obtained during examination under anesthesia, using ERG-jet contact lens electrodes and a hand-held mini-ganzfeld stimulator. The ERG protocol was similar to ISCEV standards except for briefer adaptation times as necessary to reduce the total anesthesia duration.. We report initial results in the first ten patients attempted. Nine eyes were successfully cannulated and perfused. ERG data for these nine patients are reported. [Clinical results have been published elsewhere.] Follow up ranged from 3 to 14 months. Extensive, often total, retinal detachments were present in many of the treated eyes. While regression of tumor mass and vitreous seeds was observed in nearly all the patients, retinal detachment occasionally persisted. ERG responses were extinguished in these eyes. Eyes with largely attached retinas, notwithstanding the presence of large tumors at baseline, remained free of detachment after treatment. Normal or near-normal ERGs in these eyes were repeatedly obtained. Recovery of ERG amplitudes was observed in three patients following treatment.. Retinal function can persist and even recover following selective ophthalmic artery chemotherapy infusion for retinoblastoma. Further work is indicated to determine optimal dosing regimens, maximal tolerated dosage, and subsequent visual function in these patients.

Topics: Adult; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Carboplatin; Cohort Studies; Electroretinography; Follow-Up Studies; Fundus Oculi; Humans; Infant; Infusions, Intra-Arterial; Melphalan; Ophthalmic Artery; Retina; Retinal Detachment; Retinal Neoplasms; Retinoblastoma

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Combined Modality Therapy; Eye Enucleation; Female; Humans; Melphalan; Retinal Neoplasms; Retinoblastoma; Vitrectomy; Vitreous Body

Topics: Antineoplastic Agents, Alkylating; Arteries; Catheterization; Eye; Humans; Infant; Male; Melphalan; Retinal Neoplasms; Retinoblastoma; Treatment Outcome

The prognosis of patients with metastatic retinoblastoma is poor with conventional chemotherapy and radiation. Since retinoblastoma is highly chemosensitive, dose-escalation of chemotherapeutic agents with stem cell support should be promising. We report our experience with high-dose chemotherapy (HDC) and autologous stem cell transplantation (SCT) in patients with metastatic retinoblastoma. Five patients with metastatic retinoblastoma underwent HDC with autologous SCT following conventional chemotherapy and local radiation therapy. Stem cells (bone marrow in four and peripheral blood stem cells in one) were collected after marrow involvement was cleared. Melphalan was a key drug in all patients, and was administered in combination with other agents such as cisplatin, cyclophosphamide, carboplatin or thiotepa. Three patients are currently alive disease-free at 113, 107 and 38 months, respectively, from the time of SCT. They had no central nervous system (CNS) involvement. The two patients who died of disease had CNS involvement. No long-term sequelae of HDC have been noted. Our treatment strategy using HDC appears to be effective for treating metastatic retinoblastoma without CNS involvement.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Carboplatin; Central Nervous System; Child, Preschool; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Dose-Response Relationship, Drug; Eye Neoplasms; Female; Humans; Infant; Male; Melphalan; Neoplasm Metastasis; Nervous System Neoplasms; Prognosis; Retinoblastoma; Stem Cell Transplantation; Stem Cells; Thiotepa; Time Factors; Treatment Outcome

Recently, there has been increasing interest in treating intraocular retinoblastoma with systemic chemotherapy combined with focal laser therapy and cryotherapy instead of radiotherapy. We developed a system of selective ophthalmic arterial infusion (SOAI) therapy, administering melphalan, the agent which had the greatest effect on retinoblastoma in a clonogenic assay. The SOAI system consists of a combination of a micro-balloon, a guiding catheter, and a flushing hub. After selective catheterization to the cervical segment of the internal carotid artery by the guiding catheter, the micro-balloon was propelled to the portion just distal to the orifice of the ophthalmic artery. During temporary occlusion of the internal carotid artery, melphalan was infused from the introduced catheter tip. We treated 187 patients with intraocular retinoblastoma with SOAI; 563 SOAIs were performed for 610 eyes. The technical success rate was 97.51%. Fourteen examinations failed. No significant complication due to catheterization (including brain infarction) was detected. SOAI, using the balloon occlusion technique, is safe, and its use will prevent the side effects that occur with systemic chemotherapy, and eliminate the need for irradiation and enucleation.

Topics: Antineoplastic Agents, Alkylating; Child; Child, Preschool; Female; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retinal Neoplasms; Retinoblastoma; Treatment Outcome

Effects of an intravitreal injection of melphalan on the electroretinogram and on the retinal structure were studied in albino rabbits to establish the non-toxic dose for its intravitreal use. The a-wave, the b-wave, the c-wave, the oscillatory potential and the retinal structure remained unchanged after 10-micrograms injection, but moderately changed after 20-micrograms injection and greatly deteriorated after 90-micrograms injection. A 10-micrograms injection is equal to an intravitreal concentration of about 5.9 micrograms/ml, if evenly diffused in the rabbit vitreous. Considering that colony formation of in vitro retinoblastoma cells is completely suppressed by melphalan at 4 micrograms/ml concentration, an intravitreal application of melphalan could be used as a non-surgical treatment for retinoblastoma.

Topics: Animals; Antineoplastic Agents, Alkylating; Electroretinography; Eye Neoplasms; Injections; Melphalan; Rabbits; Retina; Retinoblastoma; Vitreous Body

The effect of melphalan (an alkylic anti-cancer drug) on rabbit and human in vitro ERGs was studied to establish the non-toxic concentration of melphalan in chemo-thermotherapy for retinoblastoma. The ERGs were recorded before and 15 min after the perfusate was changed from the control solution to a melphalan-containing solution. Melphalan 10 micrograms/ml and 40 micrograms/ml caused no significant effect on the a-wave, the b-wave, or the oscillatory potential in either the rabbit or the human in vitro ERG. Melphalan 50 micrograms/ml significantly reduced the b-wave, but the change was reversible. Considering the minimum inhibitory concentration of melphalan against retinoblastoma cells on colony assay (4 micrograms/ml), melphalan is one of the most effective drugs for the conservative treatment of retinoblastoma.

Topics: Animals; Combined Modality Therapy; Electroretinography; Eye Neoplasms; Hot Temperature; Humans; In Vitro Techniques; Melphalan; Rabbits; Retinoblastoma

Topics: Antineoplastic Agents; Child; Child, Preschool; Cyclophosphamide; Female; Humans; Hydroxyurea; Infant; Male; Melphalan; Neoplasm Metastasis; Retinoblastoma; Uracil Mustard; Vincristine

Topics: Adenocarcinoma; Ameloblastoma; Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Carcinoma; Carcinoma, Squamous Cell; Cyclophosphamide; Ethylenediamines; Facial Neoplasms; Fibrosarcoma; Glioma; Humans; Infusions, Parenteral; Mechlorethamine; Melanoma; Melphalan; Meningioma; Methotrexate; Osteosarcoma; Perfusion; Quinones; Retinoblastoma; Rhabdomyosarcoma; Sarcoma; Thiotepa