Intravitreal Melphalan Injections Research Articles

INTRAVITREOUS CHEMOTHERAPY FOR ACTIVE VITREOUS SEEDING FROM RETINOBLASTOMA: Outcomes After 192 Consecutive Injections. The 2015 Howard Naquin Lecture.

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.

Cytopathological Evaluation of Ocular Surface and Needle Washings Following Intravitreal Melphalan Injections for Retinoblastoma.

There is concern that injections into eyes with retinoblastoma are dangerous and allow tumor escapement. This study attempted to determine this risk by investigating the presence of malignant cells in ocular surface and needle washings of eyes with retinoblastoma receiving intravitreal injections. Two hundred ocular surface and 202 needle washings were obtained from 280 injections into eyes with retinoblastoma. Each specimen underwent cytopathlogical assessment for the presence of malignant cells. Cytopathological results revealed no malignant cells in all 200 ocular surface and 202 needle washing specimens. In the ocular surface washings, squamous cells, red blood cells, and inflammatory cells were found in 15, 2, and 2 specimens, respectively. In the needle washings, 4 specimens contained squamous cells but no red blood cells or inflammatory cells were found in any specimen. With this injection and evaluation technique, no malignant cells were recovered, highlighting the low risk of the procedure. [J Pediatr Opthalmol Strabismus. 20XX;XX(XX):XX-XX.].

Combined intravitreal melphalan and intravenous/intra-arterial chemotherapy for retinoblastoma with vitreous seeds.

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 20-30μg 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.

Intravitreal chemotherapy in advanced retinoblastoma: results and complications

PurposeTo describe the technique and evaluate the efficacy of intravitreal melphalan in advanced retinoblastoma with focal or diffuse vitreous seedingMethodsThis is a retrospective non‐comparative study. Our analysis was conducted at our referral center of retinoblastoma, Siena, Italy. The study included 19 eyes of 19 patients with naïve, persistent or recurrent vitreous seeding in advanced retinoblastoma. All eyes received intravitreal injection (20 μg) of melphalan under general anaesthesia .Outcome measures included vitreous seeding control and eyeball preservation, treatment complications and drug toxicityResultsWe used concomitant therapy, including systemic chemotherapy, intra‐arterial chemotherapy and peribulbar chemotherapy. All patients are alive without evidence of extraocular dissemination and global salvage was attained in 83% of cases. Complications included central vein thrombosisConclusionsThis study suggests that intravitreal melphalan injection for naïve, persistent and recurrent vitreous seeding can provide seeding control and avoid enucleation with minimal toxicity and complications.

Intravitreal injection of melphalan for intraocular retinoblastoma.

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.

The Classification of Vitreous Seeds in Retinoblastoma and Response to Intravitreal Melphalan

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.

Local and Systemic Toxicity of Intravitreal Melphalan for Vitreous Seeding in Retinoblastoma: A Preclinical and Clinical Study

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.

Intravitreal Melphalan for Persistent or Recurrent Retinoblastoma Vitreous Seeds

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.

Intravitreal and subconjunctival melphalan for retinoblastoma in transgenic mice.

Purpose. To measure the chemotherapeutic effects of focal melphalan (intravitreal and subconjunctival) on tumor burden, hypoxia, and vasculature in LHBETATAG murine retinoblastoma model. Methods. LHBETATAG transgenic mice were treated with a single 1 mcg intravitreal injection of melphalan, 100 mcg subconjunctival injection, or semiweekly 10 mcg subconjunctival injections for 3 weeks. At 1 or 3 weeks, eyes were enucleated, serially sectioned, and processed with haematoxylin and eosin (H&E) for tumor burden measurements and probed with immunofluorescence to analyze tumor hypoxia and vasculature. Results. Focal melphalan significantly reduced retinal tumor size (P < 0.02) when given intravitreally or subconjunctivally. Eyes treated with a one-time intravitreal injection of 1 mcg melphalan had significantly smaller tumors at both 1 week (P = 0.017) and at 3 weeks after injection (P = 0.005). Intratumoral hypoxia showed a significant decline in hypoxia at 1 week following intravitreal injection and after maximum dosage of subconjunctival melphalan. Total vasculature was not significantly affected following intravitreal administration. Conclusion. Focal delivery of melphalan via intravitreal or subconjunctival injection has a significant effect on reducing tumor burden, hypoxia, and vasculature, in the treatment of murine retinoblastoma tumors.

Pathological findings in enucleated eyes after intravitreal melphalan injection

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.

Intravitreal chemotherapy: Indications and results

AbstractThe presence of active vitreous seeding following state‐of‐the‐art conservative treatment of intraocular retinoblastoma leads in the vast majority of cases to either external beam irradiation (EBR) and/or enucleation. Intravitreal chemotherapy (IVC) is theoretically the best route for delivering the highest vitreous concentration of a chemotherapeutic drug, over intravenous, periocular and ophthalmic artery chemotherapy. This makes IVC the best candidate for treatment of diffuse vitreous disease in eyes with retinoblastoma, but it has remained highly controversial, as considered an invasive procedure associated with the risk of tumor exteriorization. We retrospectively reviewed all consecutive patients with vitreous disease found eligible and then treated by intravitreal injections of melphalan. IVC was performed every 7 to 10 days up to 8 injections of Melphalan (20‐30 g) per event, using a novel injection technique characterized by the prevention of vitreous reflux and sterilization of the needle track. The results appear promising in terms of safety (with no evidence of exteriorization), and efficacy with unprecedented salvage rate over 85%. Control of vitreous seeding was achieved without EBR in all cases.

Intravitreal injection of melphalan in the treatment of retinoblastoma with vitreous cavity seeding

Intravitreal injection of melphalan in the treatment of retinoblastoma with vitreous cavity seeding

Persistence of retinal function after intravitreal melphalan injection for retinoblastoma

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 6months 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 17months 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 20μg. After 6months 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.

Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications

BackgroundTumour control of vitreous seeds remains challenging owing to their resistance to radiation and systemic chemotherapy.ObjectiveTo describe the short-term efficacy of intravitreal melphalan for vitreous disease in retinoblastoma using a...

Superselective ophthalmic artery infusion of melphalan for intraocular retinoblastoma: preliminary results from 140 treatments

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.

Japanese contributions to ocular oncology

Important studies by Japanese ocular oncologists are reviewed. These include investigations of mortality from malignant neoplasms of the eye in Japan and 17 other countries; the incidence of retinoblastoma, malignant melanoma of the eye, and lacrimal gland cancer; photodynamic therapy for retinoblastoma, using argon laser and hematoporphyrin derivatives; chemosensitivity profiles of retinoblastoma; chemo-thermotherapy, using melphalan; selective ophthalmic arterial infusion, using a balloon catheter; intravitreal injection of melphalan for the treatment of vitreous seeding of retinoblastoma; and stereotactic radiotherapy for choroidal melanoma.