Ocular and systemic toxicity of high-dose intravitreal topotecan in rabbits: Implications for retinoblastoma treatment.

Although many more eyes of children with retinoblastoma are salvaged now compared to just 10 years ago, the control of vitreous seeding remains a challenge. The introduction of intravitreal injection of melphalan has enabled more eyes to be salvaged safely but with definite retinal toxicity. Intensive treatment with high-dose intravitreal topotecan may be a strategy to control tumor burden because of its cell cycle-dependent cytotoxicity and the proven safety in humans. Therefore, we evaluated the ocular and systemic safety of repeated high-dose intravitreal injections of topotecan in rabbits. Systemic and ocular toxicity was assessed in non-tumor-bearing rabbits after four weekly injections of three doses of topotecan (10 µg, 25 µg, and 50 µg) or vehicle alone. Animals were evaluated weekly for general and ophthalmic clinical status. One week after the last injection, vitreous and plasma samples were collected for drug quantification and the enucleated eyes were subjected to histological assessment. Weight, hair loss, or changes in hematologic values were absent during the study period across all animal groups. Eyes injected with all topotecan doses or vehicle showed no signs of anterior segment inflammation, clinical or histologic evidence of damage to the retina, and ERG parameters remained unaltered throughout the study. Vitreous and plasma topotecan lactone concentrations were undetectable. Four weekly intravitreal injections of topotecan up to 50 µg in the animal model or a 100 µg human equivalent dose were not toxic for the rabbit eye. High doses of topotecan may show promising translation to the clinic for the management of difficult-to-treat retinoblastoma vitreous seeds.

Breast cancer risk after radiotherapy for heritable and non-heritable retinoblastoma: a US-UK study.

BACKGROUND: Retinoblastoma is a rare childhood eye cancer caused by germline or somatic mutations in the RB1 gene. Previous studies observed elevated breast cancer risk among retinoblastoma survivors. However, there has been no research on breast cancer risk in relation to radiation (primarily scatter radiation from the primary treatment) and genetic susceptibility of retinoblastoma survivors. METHODS: Two groups of retinoblastoma survivors from the US and UK were selected, and breast cancer risk analysed using a case-control methodology, nesting within the respective cohorts, matching on heritability (that is to say, having bilateral retinoblastoma or being unilateral cases with at least one relative with retinoblastoma), and using exact statistical methods. There were a total of 31 cases and 77 controls. RESULTS: Overall there was no significant variation of breast cancer risk with dose (P>0.5). However, there was a pronounced and significant (P=0.047) increase in the risk of breast cancer with increasing radiation dose for non-heritable retinoblastoma patients and a slight and borderline significant (P=0.072) decrease in risk of breast cancer with increasing radiation dose for heritable retinoblastoma patients, implying significant (P=0.024) heterogeneity in radiation risk between the heritable and non-heritable retinoblastoma groups; this was unaffected by the blindness status. There was no significant effect of any type of alkylating-agent chemotherapy on breast cancer risk (P>0.5). CONCLUSIONS: There is significant radiation-related risk of breast cancer for non-heritable retinoblastoma survivors but no excess risk for heritable retinoblastoma survivors, and no significant risk overall. However, these results are based on very small numbers of cases; therefore, they must be interpreted with caution.

Intra-arterial chemotherapy as a treatment for intraocular retinoblastoma: alternatives to direct ophthalmic artery catheterization.

BACKGROUND AND PURPOSE: Intra-arterial chemotherapy is a very effective treatment option for intraocular retinoblastoma. However, direct catheterization of the OA is not always possible. The purpose of this work was to report our initial results with intra-arterial chemotherapy for intraocular retinoblastoma when delivery of the drug was not via direct catheterization of the OA. MATERIALS AND METHODS: Retrospective review of 110 eyes (89 patients) undergoing a total of 351 intra-arterial treatments at our institution between 2006 and 2010 identified 18 eyes (14 patients) that received at least 1 infusion via a vascular route other than direct OA catheterization. Alternatives included catheterization of the orbital branch of the MMA and temporary balloon occlusion of the ICA. RESULTS: Tumor control was observed in 17 of 18 eyes at a mean follow-up of 18.9 months (median, 17.5 months; range, 8-36 months). The mean number of intra-arterial infusions was 3.7 per eye (median, 3; range, 2-9). Treatment routes included the following: MMA only, 3 eyes; MMA + OA, 4 eyes; MMA + balloon, 2 eyes; balloon only, 1 eye; balloon + OA, 7 eyes; balloon + OA + MMA, 1 eye. Intra-arterial chemotherapies included melphalan, topotecan, and carboplatin. Complications were all transient. ERG readings were the following: stable, 10 eyes; improved, 3 eyes; reduced, 5 eyes. One patient died from a second malignancy (pinealoblastoma). CONCLUSIONS: This initial experience shows that when direct OA catheterization is not possible, using alternative routes of intra-arterial chemotherapy saves eyes and preserves vision with acceptable side effects.

Survival of retinoblastoma in less-developed countries impact of socioeconomic and health-related indicators.

BACKGROUND: The survival of retinoblastoma in less-developed countries (LDCs) and the impact of socioeconomic variables on survival are not widely available in the literature. METHODS: A systematic review of publications from LDCs was performed. Articles were from multiple databases and written in seven languages. Results were correlated with socioeconomic indicators. Lower-income countries (LICs) and middle-income countries (MICs) were included in our analyses. RESULTS: An analysis of 164 publications including 14,800 patients from 48 LDCs was performed. Twenty-six per cent of the papers were written in languages other than English. Estimated survival in LICs was 40% (range, 23-70%); in lower MICs, 77% (range, 60-92%) and in upper MICs, 79% (range, 54-93%; p = 0.001).Significant differences were also found in the occurrence of metastasis: in LICs, 32% (range, 12-45); in lower MICs, 12% (range, 3-31) and in upper MICs, 9.5% (range, 3-24; p = 0.04). On multivariate analysis, physician density and human development index were significantly associated with survival and metastasis. Maternal mortality rate and per capita health expenditure were significantly associated with treatment refusal. CONCLUSIONS: Important information from LDCs is not always available in English or in major databases. Indicators of socioeconomic development and maternal and infant health were related with outcome.

Orbital recurrence of retinoblastoma following enucleation.

BACKGROUND/AIMS: To determine the incidence, clinical presentation and histopathological profile of patients developing orbital recurrence following enucleation for retinoblastoma. METHODS: A cohort of 1674 consecutive patients undergoing enucleations between 1914 and 2006 was retrospectively reviewed to identify cases of orbital recurrence. A detailed chart review of all identified patients with orbital recurrence following enucleation was performed. The main outcome measures were histopathological features of the enucleated globe, clinical presentation, status of metastatic disease and clinical outcomes of treatment at last follow-up. RESULTS: There were 71 cases of orbital recurrence identified in the study, for an incidence of 4.2% (71 of 1674 cases). The diagnosis of orbital recurrence was made between 1 and 24 months after enucleation (mean 6 months), with 69 of the 71 patients (97%) being diagnosed within the first 12 months. Over a follow-up period of 3-208 months (mean 34.8 months), 60 of 71 patients developed metastatic disease (85%), and 53 of 71 patients died from metastatic retinoblastoma (75%). For the subgroup of cases diagnosed as having orbital recurrences after 1984, 10 of 11 patients (91%) are alive and well. CONCLUSIONS: All patients undergoing enucleation for retinoblastoma need to be followed carefully for the first 2 years after surgery for the possibility of orbital relapse. The majority of retinoblastoma patients with orbital tumour recurrence develop systemic metastatic disease, although mortalities appear to be improving in the modern era.

Systemic carboplatin for retinoblastoma: change in tumour size over time.

BACKGROUND/AIM: Chemotherapy for intraocular retinoblastoma is used to shrink individual retinal tumours to a size amenable to focal treatments. Quantitative data regarding retinal tumour response following treatment with primary systemic carboplatin are reported. METHODS: Changes in area and largest basal diameter of tumours that were exposed to carboplatin, had no concomitant focal treatment, and had digital funduscopic photography performed before and after treatment, were measured. Response was evaluated. RESULTS: 36 tumours were measured following one treatment: 34/36 (94.4%) responded, with a 37.1% mean decrease in area (median = 37.0%; range 4.0%-76.7%). Mean reduction in basal diameter was 21.3% (med = 21.0%; -7.9%-52.5%). 20 tumours were treated with a second cycle: 15/20 (75.0%) responded. Mean decrease in area was 17.8% (med = 15.3%; -7.0%-49.7%). The mean cumulative decrease in area after two treatments was 55.1% (med = 56.2%; 33.0%-74.5%). Mean cumulative reduction in basal diameter was 33.6% (med = 33.6%; 10.9%-53.2%). 12 tumours were treated with a third cycle: 3/12 (25.0%) responded, 8/12 were stable, and one progressed. Mean decrease in area was 5.4% (med = 7.2%; -17.7%-20.6%). Cumulative decrease in area after three treatments was 58.1% (med = 57.3%; 34.8%-77.2%). Mean cumulative reduction in basal diameter was 38.8% (med = 38.2%; 19.1%-54.1%). CONCLUSIONS: Carboplatin caused measurable shrinkage of retinoblastoma tumours. Response was greatest following the initial treatment and decreased with subsequent treatments.

Retinoblastoma patients with high risk ocular pathological features: who needs adjuvant therapy?

AIMS: To describe the outcome of patients with non-metastatic unilateral retinoblastoma with high risk histopathological features after primary enucleation, and to clarify the need and results of adjuvant therapy. PATIENTS AND METHODS: From 1980 to 2001 adjuvant therapy was recommended only to patients with scleral involvement, post-laminar optic nerve involvement (PLONI) with either a positive margin or associated choroidal involvement, or (before 1994) isolated PLONI. RESULTS: 108 of 224 patients had at least one high risk feature (choroidal, scleral, anterior chamber, and/or PLONI). Patients with isolated choroidal (n = 55) or anterior chamber (n = 2) invasion, and most with PLONI without other risk factors (n = 21) were not treated; three relapsed but are long term survivors after intensive therapy. Four with isolated PLONI received adjuvant chemotherapy and none relapsed. Three of 11 with PLONI and concomitant choroidal or scleral involvement who received adjuvant therapy relapsed, versus two of four not treated. Two of five with scleral disease relapsed. All 12 with cut end involvement received adjuvant treatment and none relapsed. In the total group, all four patients who relapsed after adjuvant therapy died. CONCLUSIONS: Relapsing patients can be rescued with intensive therapy. Those with isolated choroidal or PLONI have a good prognosis without adjuvant therapy. Patients with PLONI with a positive margin have a good prognosis if treated with combined therapy. Those with scleral involvement or PLONI with concomitant choroid disease may benefit from adjuvant therapy.

Third (fourth and fifth) nonocular tumors in survivors of retinoblastoma.

OBJECTIVE: This study aimed to investigate the incidence, timing, pattern, and distribution of, as well as survival as a result of, third, fourth, and fifth primary tumors in survivors of retinoblastoma. DESIGN: This study was a retrospective case series of patients diagnosed with retinoblastoma and a second malignant neoplasm. Records were examined for demographic, prior treatment, and second tumor information, as well as any evidence of the development of a third, fourth, or fifth nonocular tumor. When possible, telephone inquiries were conducted for follow-up. PARTICIPANTS: The study included 1506 patients followed in the Ophthalmic Oncology Center at New York-Presbyterian Hospital, New York Weill Cornell Medical Center, 211 of whom developed a second tumor and had sufficient treatment data to be useful for analysis. MAIN OUTCOME MEASURES: The development of third and additional nonocular tumors and survival from these tumors were the primary outcome measures. RESULTS: Of 211 second-tumor patients, 142 died before an additional malignancy developed (median survival time, 1.8 +/- 0.3 years) and in 28, third tumors developed (5-year incidence rate, 11%; 10-year incidence rate, 22%; median time to third tumor development, 5.8 +/- 8.3 years). The 5- and 10-year survival rates for this group were 41% and 30%, respectively (median survival time, 4.1 +/- 1.0 years). Of 28 patients in whom third tumors developed, 27 (96%) had received radiation therapy for their retinoblastoma. The most common sites for third tumors were soft tissues of the head (36% of all third tumors) and skin (36% of all third tumors). In six patients, a fourth tumor developed, and in two patients a fifth tumor developed. All fourth and fifth tumors were found in the soft tissues of the head, the skin, or the bones. CONCLUSIONS: Survivors of retinoblastoma in whom second malignant neoplasms develop are at a higher risk for the development of additional tumors than they were for the development of a second tumor. The locations and expected ages at which additional tumors develop are consistent with the patterns we have seen in second tumors.

Collaborative ocular melanoma study (COMS) randomized trial of I-125 brachytherapy for medium choroidal melanoma. I. Visual acuity after 3 years COMS report no. 16.

OBJECTIVE: To report visual acuity during the first three years after iodine 125 (I(125)) brachytherapy for medium-sized choroidal melanoma and to identify important baseline and treatment factors associated with posttreatment visual acuity in a group of patients who were treated and observed prospectively as part of a large, randomized clinical trial. DESIGN: Observational case series within a randomized, multicenter study. PARTICIPANTS: Patients enrolled in the Collaborative Ocular Melanoma Study randomized trial of I(125) brachytherapy versus enucleation had choroidal melanoma of at least 2.5 mm but no more than 10.0 mm in apical height, and no more than 16.0 mm in largest basal dimension. One thousand three hundred seventeen patients enrolled from February 1987 through July 1998; 657 patients were assigned to I(125) brachytherapy. Visual acuity data for 623 patients who received I(125) brachytherapy as randomly assigned and who have been observed for at least 1 year were analyzed for this report. METHODS: Under study protocol, an ophthalmic evaluation, including best-corrected visual acuity measurement of each eye, was performed at baseline, every 6 months thereafter for 5 years, and once yearly thereafter. Two poor vision outcomes, visual acuity of 20/200 or worse that was confirmed at the next follow-up examination and loss of six lines or more of visual acuity from baseline that was confirmed at the next follow-up examination, were analyzed to identify baseline and treatment characteristics that were associated with posttreatment visual acuity. RESULTS: At baseline, median visual acuity in the eye with choroidal melanoma was 20/32, with 70% of eyes having 20/40 or better and 10% of eyes having 20/200 or worse visual acuity. Three years after I(125) brachytherapy, median visual acuity was 20/125, with 34% having 20/40 or better and 45% having 20/200 or worse visual acuity, including eyes that were enucleated within 3 years of treatment. Life-table estimates of percentages of patients who lost six or more lines of visual acuity from baseline, a quadrupling of the minimum angle of resolution, with this finding confirmed at the next 6-month follow-up examination, were 18% by 1 year, 34% by 2 years, and 49% by 3 years after treatment. Life-table estimates of percentages of patients with baseline visual acuity better than 20/200 whose visual acuity decreased to 20/200 or worse, confirmed at the next follow-up examination, were 17% by 1 year, 33% by 2 years, and 43% by 3 years after treatment. As soon as a poor vision outcome was observed, improvement of visual acuity to a level that no longer met the definition for a poor vision outcome was rare. Greater baseline tumor apical height and shorter distance between the tumor and the foveal avascular zone (FAZ) were the factors most strongly associated with loss of six or more lines of visual acuity after treatment. These two factors and baseline visual acuity also were strongly associated with visual acuity 20/200 or worse after treatment. Patient history of diabetes, presence of tumor-associated retinal detachment, and tumors that were not dome shaped also were associated with greater risk for both of the poor vision outcomes. CONCLUSIONS: Forty-three percent to 49% of treated eyes had substantial impairment in visual acuity by 3 years after I(125) brachytherapy, defined as a loss of six or more lines of visual acuity from the pretreatment level (49% of eyes) or visual acuity of 20/200 or worse (43% of eyes) that was confirmed at the next 6-month examination. Patients with a history of diabetes and patients whose eyes had thicker tumors, tumors close to or beneath the FAZ, tumor-associated retinal detachment, or tumors that were not dome shaped were those most likely to have a poor visual acuity outcome within 3 years after I(125) brachytherapy.

Successful treatment of metastatic retinoblastoma.

BACKGROUND: In the past, patients with metastatic retinoblastoma have had a poor prognosis when treated with conventional modalities. In the current study, the authors evaluated the use of combined intensive conventional chemotherapy, high dose chemotherapy with autologous stem cell rescue (ASCR), and radiation therapy. METHODS: Four patients with metastatic retinoblastoma were treated. All had orbital and bone marrow metastases. In addition, three patients had bone metastases and two patients had liver metastases. None had central nervous system disease. Patients received intensive conventional chemotherapy that included vincristine, cyclophosphamide, etoposide, and either cisplatin or carboplatin. Stem cells were harvested after bone marrow disease was no longer detectable. High dose chemotherapy with carboplatin (500 mg/m(2)/day x 3 days or area under the curve = 7 via the Calvert formula) and thiotepa (300 mg/m(2)/day x 3 days) with (n = 3 patients) or without (n = 1 patient) etoposide (250 mg/m(2)/day x 3 days) was administered with ASCR. Sites that originally harbored bulky disease were irradiated after recovery from the high dose chemotherapy. RESULTS: The therapy was associated with substantial acute hematopoietic and mucosal toxicities. At last follow-up, all four patients had survived event free from 46-80 months after the diagnosis of metastatic disease. CONCLUSIONS: The treatment strategy described in the current study is effective for patients with metastatic retinoblastoma that does not involve the central nervous system. However, a multicenter trial should be considered to evaluate it in a larger group of patients.

Presence of human papilloma virus in tumor tissue from children with retinoblastoma: an alternative mechanism for tumor development.

Epidemiological studies have shown that the use of barrier methods of contraception is associated with a decreased incidence of papilloma virus infection and reduced risk of having a child with retinoblastoma. Thirty-nine primary retinoblastomas were analyzed for the presence of papilloma virus sequences. Tumor tissue sections were also used to assess the expression of the retinoblastoma protein and proliferative index. Papilloma sequences were detected in 14 of 39 (36%) tumors. Tumors in which viral sequences were detected were associated with a lower proliferative index (68% versus 78%; P = 0.015). Children with tumors containing viral sequences had a lower risk of extraocular disease (odds ratio, 9.0; 95% confidence interval, 1.6-49; P = 0.008) and a lower birth weight (2.9 versus 3.5 kg; P = 0.030). Based on these data, it is our hypothesis that papilloma viruses may play a role in the development of sporadic retinoblastoma. Detection of papilloma virus sequences and retinoblastoma protein in certain primary lesions suggests an alternative mechanism of tumor development for sporadic retinoblastoma.

Engraftment and growth of patient-derived retinoblastoma tumour in severe combined immunodeficiency mice.

The development of an in vivo model of retinoblastoma could be important for studying its biological behaviour and developing novel therapeutic strategies. We examined the ability of patient-derived retinoblastoma cells to grow and disseminate in severe combined immunodeficiency CB-17-SCID mice after subcutaneous (s.c.) inoculation without conditioning treatment. 24/30 (80%) of patient-derived tumours engrafted and grew as s.c. nodules in SCID mice. Whilst most xenografted tumours appeared to be localised, by PCR assay a positive DNA band of human minisatellite region (YNZ.22) was determined in the bone marrow of 19/25 (76%), in the spleen of 14/25 (56%) and in the liver of 16/25 (64%) mice, respectively, indicating dissemination to distant organs. Cytogenetic analysis demonstrated i(6p) in 5/12 (42%) and trisomy 1 or 1q abnormalities in 8/12 (67%) of the xenografted tumour samples studied, respectively, suggesting that retinoblastoma tumour cells maintain their cytogenetic abnormalities following adoptive growth in SCID mice. In this report we demonstrate the ability to propagate human primary retinoblastoma cells in SCID mice after s.c. inoculation and suggest the possibility of using the SCID mouse model to study the intrinsic biological behaviour of human retinoblastoma and to develop novel therapeutic strategies in the treatment of this disease.

A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma.

PURPOSE: To evaluate the efficacy and toxicity of subconjunctival carboplatin for intraocular retinoblastoma. DESIGN: A phase I/II clinical trial (noncomparative case series). PARTICIPANTS: Eleven children with bilateral retinoblastoma who had 13 eyes containing active tumor. METHODS: Subconjunctival carboplatin (1.4-2.0 ml of a 10-mg/ml solution) was administered. Ophthalmologic examinations with the patient under anesthesia were performed before each injection, and response and toxicity were assessed. MAIN OUTCOME MEASURES: Tumor response and toxicities. RESULTS: A median of three injections per eye was administered (range, 1-7 injections per eye) at a median interval of 21 days between injections (range, 14-35 days). The median dose was 20 mg/injection (range, 14-20 mg). Toxicities included transient periorbital edema in four eyes and optic atrophy in one eye that also received laser photocoagulation and cryotherapy. No nonocular toxicities were noted. Three of five eyes with vitreous disease that could be evaluated had major responses. Two of five eyes with retinal tumors had a response, but neither eye with subretinal disease responded. CONCLUSIONS: Subconjunctival carboplatin as used in this protocol is effective for intraocular retinoblastoma. It appears to be safe, but additional study and longer follow-up are required, particularly to determine the risk of optic atrophy.

Intraocular carboplatin concentrations following intravenous administration for human intraocular retinoblastoma.

Previous studies of the penetration of carboplatin into the vitreous have depended on unaffected animals or on animal models for other cancers. The objective of this study was to determine the intraocular levels of carboplatin following intravenous administration of carboplatin in the treatment of human intraocular retinoblastoma. Eight patients with bilateral intraocular retinoblastoma were treated in a consistent fashion with intravenous carboplatin. One additional patient was similarly treated, but enucleated one month later. Samples were taken from those nine eyes after enucleation one to two hours after the administration of 18.7 mg/kg (560 mg/m( 2) for patients more than 12 kg) of intravenous carboplatin, and carboplatin concentrations in the aqueous and vitreous were then measured by atomic absorption spectrometry. The mean concentration measured in the aqueous was 5.13 microg/ml and in the vitreous 4.05 microg/ml, and vitreal concentrations were an average of 80% of aqueous concentrations. In one patient, a vitreous concentration of carboplatin was detected after an interval of one month that was 10% of the levels found in the samples enucleated one hour post-administration. These concentrations are much higher than previous animal studies would predict, and are similar to levels measured in unaffected animals when the drug is given after the use of cryotherapy. The concentration also approaches levels previously shown to be toxic to the retina. This elevation in carboplatin concentration may be due to disruption of the blood-vitreous barrier by active tumor.

Visual outcomes in children with bilateral retinoblastoma.

BACKGROUND: Retinoblastoma is the most common primary intraocular tumor of childhood. Although studies have explored trends in retinoblastoma management and prognosis, few have addressed visual outcome. METHODS: A retrospective chart review was performed on children in whom bilateral retinoblastoma was diagnosed at New York Hospital-Cornell Medical College. A total of 74 children were included in the study. All children underwent radiation to the eyes that were studied. Fundus drawings done at the time of diagnosis were evaluated to determine the location of tumors on presentation and the Reese-Ellsworth classification. Visual outcome was classified into 3 groups: group 1 represented visual acuity of 20/20 to 20/40; group 2, 20/50 to 20/400, and group 3, <20/400. RESULTS: A total of 74 children were studied. Forty-six (62%) underwent enucleation of 1 eye. The visual acuity of the remaining 102 eyes was divided into groups 1, 2, and 3. Fifty-eight percent of these eyes were in group 1, 31% in group 2, and 9% in group 3. Two percent underwent subsequent enucleation after treatment. The tumors were analyzed on the basis of Reese-Ellsworth classification, location, size, and distance from the macula. Excluding Reese-Ellsworth group VB, there was no correlation between Reese-Ellsworth classification and final visual outcome. Tumors involving the macula were in 7 (78%) of 9 eyes with poor visual outcome (group 3), and 16 (33%) of 48 eyes with excellent vision (group 1) had macular tumors. Paradoxically, 2 (22%) of 9 eyes in group 3 did not have tumors involving the macula. CONCLUSIONS: Children with retinoblastoma now have an excellent prognosis for life. Although correlated with tumor location, visual outcome is not always easily predicted on the basis of the initial presentation. Final acuity is excellent in most cases but may be influenced by multiple factors that must be considered when caring for these children and families.