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Background: Retinoblastoma can extend beyond the structures of the eye, where cells can enter the bloodstream and cause metastases. Various types of protocols for adjuvant treatment risk-adapted according to histopathological risk factors are used worldwide., Methods: Between 1997 and 2009, 420 children were diagnosed with retinoblastoma at the German Retinoblastoma Referral Centre and risk factors were assessed. Patients with post-laminar optic nerve infiltration or choroid or minor scleral invasion received six courses of adjuvant chemotherapy using vincristine, etoposide, carboplatin and cyclophosphamide (group 1). Patients with microscopic extension beyond the sclera to the resection margin of the optic nerve or potential spread due to vitrectomy received chemotherapy plus orbital radiotherapy (group 2). Neoadjuvant chemotherapy was performed in patients with local extraocular invasion detected on MRI., Results: Following this protocol, 42 of the 420 patients and 21 referred from other centres showed high-risk histopathological factors qualifying for adjuvant therapy (57 in group 1 and 6 in group 2). Seven of the 63 patients received neoadjuvant and adjuvant treatment. During a mean follow-up of 5.8 (range 0.4-15.4) years, one of six patients in group 2 developed metastases and died. No patients died from toxicity. The 5-year overall survival was 100% for group 1 and 80% for group 2., Conclusions: This retrospective single-site study reveals a 10% incidence of high-risk features in children with retinoblastoma diagnosed at the German Retinoblastoma Referral Centre. Overall survival rates of 98.3% underline the safety of this adjuvant chemotherapy protocol and its efficiency in preventing metastasis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Intravitreal injection therapy (IViT) for retinoblastoma has shown promise in the treatment of vitreous seeds; however, the potential for tumour dissemination following intravitreal penetration has limited its use. This review evaluates the risk of extraocular tumour spread in patients receiving therapeutic intravitreal injections for retinoblastoma., Methods: 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 IViT for retinoblastoma in humans., Results: 14 studies with original IViT data were included in this review. A total of 1304 intravitreal injections were given in 315 eyes of 304 patients, with one report of extraocular tumour spread and one patient in whom intravitreal treatment could not be excluded as a contributor to metastatic disease. The proportion of subjects with extraocular tumour spread potentially due to IViT in these combined reports was 0.007 (95% CI 0.0008 to 0.0236), with a mean follow-up of 72.1 months. In a subset of 61 patients receiving IViT via safety enhancing injection techniques (347 injections, 19.6 months mean follow-up), there were no reports of tumour spread., Conclusions: Local and systemic tumour spread following IViT in cases of retinoblastoma is rare, and this risk is potentially reduced by the use of safety enhancing injection techniques. These results suggest that the risk of tumour spread should not preclude IViT use for carefully selected patients as part of multi-modal globe salvaging therapy.

Background: Published findings on MRI results in retinoblastoma patients treated with neoadjuvant chemotherapy (NACT) are lacking. The present study evaluates the role of MRI in International Retinoblastoma Staging System (IRSS) stage III retinoblastoma treated with NACT., Methods: 28 consecutive IRSS stage III retinoblastoma patients underwent MRI at baseline and after three cycles of NACT prior to enucleation. MRI films were reviewed retrospectively by an ophthalmic radiologist who was masked to patient outcome. Optic nerves were staged based on their thickness, contrast enhancement and length of involvement on MRI. Response evaluation criteria were based on optic nerve staging and changes in the size of the orbital mass on MRI after NACT., Results: The proposed staging at baseline and after NACT was able to predict event-free-survival (EFS) (p=0.005 and p <0.001, respectively) and overall survival (OS) (p=0.002 and p=0.001, respectively) using the log-rank test for trends. Patients with complete or partial response according to the proposed response evaluation criteria had significantly better EFS (p<0.001) and OS (p=0.024) than those who had stable or progressive disease., Conclusions: The proposed MRI based optic nerve staging system and response evaluation criteria were able to predict EFS and OS at baseline and after NACT.

Background: Tumour control of vitreous seeds remains challenging owing to their resistance to radiation and systemic chemotherapy., Objective: To describe the short-term efficacy of intravitreal melphalan for vitreous disease in retinoblastoma using a new injection technique and dose., Methods: 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., Results: 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., Conclusions: 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.

Background: To describe the technique of intravitreal chemotherapy preceded by subconjunctival chemotherapy for the treatment of vitreous seeds in advanced stage retinoblastoma., Methods: This non-comparative interventional case series retrospectively reviewed the medical records and postenucleation histopathological findings of two patients who presented within weeks of each other with bilateral retinoblastoma, Reese-Ellsworth (R-E) stage Vb in the worse eye. Both patients had failed systemic chemotherapy prior to receiving a single treatment of 0.5 ml (5 mg per 0.5 ml) of subconjunctival carboplatin, through which 0.05 ml (3 mcg per 0.05 ml) of carboplatin was injected into the vitreous (Case 2 received 0.1 ml of intravitreal carboplatin). The subconjunctival chemotherapy was given to reduce the risk of orbital tumour seeding following intravitreal injection. Following enucleation, ocular toxicity and the presence or absence of viable tumour cells at the intravitreal injection site were recorded., Results: Histopathological examination did not reveal patency of the pars plana intravitreal penetration site in either case at 6 weeks post-treatment nor was malignant seeding detected in the area of injection. Examination of the two enucleated eyes did not demonstrate structural toxicity to the cornea, anterior segment, iris or retina. Additionally, both cases were followed for over 37 months post-treatment, without the occurrence of orbital malignancy., Conclusions: Injecting a bleb of subconjunctival chemotherapy prior to intravitreal drug delivery appeared to mitigate the risk of orbital tumour seeding in two patients with advanced stage retinoblastoma. Incorporating this technique may allow further investigation of intravitreal chemotherapy for the treatment of vitreous seeds in retinoblastoma.

Background: 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., Methods: 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., Results: 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)., Conclusion: 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.

Background/aims: To review the effectiveness of intra-arterial chemotherapy for advanced intra-ocular retinoblastoma with vitreous and/or subretinal seeds in naive (untreated) and previously treated eyes., Methods: Retrospective study, approved by the institutional review board, of 76 eyes of 67 patients with retinoblastoma with subretinal and/or vitreous seeding treated with intra-arterial chemotherapy at Memorial Sloan-Kettering Cancer Center between May 2006 and August 2010., Results: Despite advanced intraocular disease with seeding, the majority (56/76) of eyes were saved; 20/76 eyes were enucleated. Among treatment-naive eyes, the 2-year probability of ocular salvage was 83% (95% CI 27% to 97%) for eyes with subretinal seeding only, 64% (95% CI 24% to 87%) for eyes with vitreous seeding only, and 80% (95% CI 40% to 95%) for eyes with both. Among eyes that received previous treatment and had progressed, the 2-year probability of ocular salvage was 50% (95% CI 15% to 78%) for eyes with only subretinal seeding, 76% (95% CI 48% to 91%) for eyes with vitreous seeding only, and 54% (95% CI 20% to 79%) for eyes with both. Nine of 29 naive eyes (31%) were cured with intra-arterial (super-selective ophthalmic artery infusion of chemotherapy) chemotherapy alone., Conclusion: Unlike radiation or systemic chemotherapy, intra-arterial chemotherapy can usually prevent the need for enucleation in naive eyes with advanced intraocular retinoblastoma with seeding-especially if the seeding is subretinal. Treatment appears to be less effective in previously treated eyes when subretinal seeding is present (50% at 2 years), but may be more effective in eyes that failed to respond to previous systemic chemotherapy and have only vitreous seeding.

Background: Metastatic spread in retinoblastoma is a rare occurrence in developed countries but still associated with a poor prognosis., Patients and Methods: Medical records of all metastatic retinoblastoma diagnosed during a 20-year period were retrospectively reviewed., Results: Six patients out of 104 presented a metastatic disease with an incidence at diagnosis of 2%. Three had a metastatic disease at diagnosis, one patient a trilateral retinoblastoma and two a metastatic spread after enucleation. All but one were sporadic retinoblastoma. Central nervous system (CNS) involvement was reported in five patients, while one patient had an intraorbital lesion, and bone and bone marrow spread. Different treatment strategies were administered based on local treatment plus chemotherapy and radiotherapy with or without high-dose chemotherapy. An ifosfamide/carboplatin/etoposide regimen was administered in three patients resulting in a partial response. Out of six patients, four died, and two patients are alive at 60 and 63 months from diagnosis. Both children with a long follow-up were treated with high-dose chemotherapy. All but one of the patients with CNS involvement died; the survivor was a patient with pineal involvement., Conclusion: This retrospective review confirms a curable strategy based on local treatment and conventional plus high-dose chemotherapy. Patients with CNS involvement remain incurable.

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.

Aims: To evaluate rates of vitreous relapse among retinoblastoma patients treated with primary chemotherapy and assess diode laser as a potential risk factor for relapse., Methods: Retrospective review of all patients treated with primary chemotherapy at a large ocular oncology centre. Eyes that developed vitreous relapse were coded with regard to Reese-Ellsworth Group, laterality, time to relapse, type of relapse (vitreous base or non-vitreous base relapse), treatments used (including adjuvant diode laser), and ocular preservation. Individual tumour foci treated with laser hyperthermia were also coded for laser parameters including power settings, number of treatments, and concomitant administration of systemic chemotherapy (chemothermotherapy)., Results: 15 of 106 eyes (14.15%) developed vitreous relapse over a 6 year period. Mean time to relapse was 7.2 months after chemotherapy was completed. Five cases (33%) were of the vitreous base variety. Ocular salvage was attempted in 11 cases using a variety of methods; one patient was lost to follow up. Six of the remaining 10 eyes (60%) were salvaged. Eight of 38 eyes (21%) treated with systemic chemotherapy and laser hyperthermia developed vitreous relapse compared with seven of 68 eyes (10%) treated with primary chemotherapy alone (p<0.005). Laser settings, number of hyperthermia treatments, and the concomitant use of systemic chemotherapy (chemothermotherapy) were not associated with higher rates of vitreous relapse., Conclusion: Nearly one in seven eyes with retinoblastoma treated with primary chemotherapy may develop vitreous relapse. The administration of diode laser hyperthermia appears to increase this risk. Despite additional therapy a number of these eyes succumb to enucleation.

There is considerable debate about the significance of choroidal invasion of retinoblastoma with regard to metastatic disease. The charts of patients with retinoblastoma were reviewed over a 17 year period to determine the frequency of histopathological choroidal invasion of retinoblastoma and its risk for eventual metastatic disease. Sixty seven of 289 eyes (23%) enucleated for retinoblastoma had histopathological evidence of choroidal invasion. Those patients with choroidal invasion (with or without optic nerve invasion) were more likely to develop metastases than those without choroidal invasion (p = 0.0001). When considering those patients with isolated choroidal invasion of retinoblastoma, excluding those with associated optic nerve invasion, there was no significant risk but there was a trend towards the development of metastases (p = 0.10). The clinical factors found to be predictive for choroidal invasion from retinoblastoma from a univariate analysis included increased intraocular pressure (p = 0.04) and iris neovascularisation (p = 0.007) and, from a multivariate analysis, iris neovascularisation (p = 0.02). The histopathological factors statistically associated with choroidal invasion included the presence of optic nerve invasion (p = 0.002) and poorly differentiated retinoblastoma (p = 0.003). Factors not predictive for choroidal invasion included the age, race, and sex of the patient and the tumour laterality, inheritance, size, and growth pattern. Choroidal invasion of retinoblastoma is a risk for metastases, especially if it is associated with any degree of optic nerve invasion.

In a 9-month-old girl a subperiosteal metastasis of the maxillary bone developed in the contralateral orbit about one year after enucleation of a poorly differentiated retinoblastoma.

Five children with an orbital recurrence of retinoblastoma have been successfully treated by a combination of excision biopsy of the tumour mass, radical orbital radiotherapy, and systemic chemotherapy. Nine previous children, consecutive with the five presented here, died from disseminated retinoblastoma after failure of earlier treatment programmes for orbital recurrence. An aggressive therapeutic approach is justified by this improvement in survival.

Three cases of local extraocular extension of retinoblastoma following intraocular surgery via a transscleral approach have been seen in one centre during a 12-month period. This number represents a significant increase on the previous incidence of this serious complication, which may be related to more widespread use of vitrectomy techniques. Orbital and local lymph node recurrence of retinoblastoma have been associated with a very poor survival rate in the past, and steps must be taken to limit the chance of this happening should an intraocular surgical procedure be performed inadvertently on an eye containing a retinoblastoma. Early enucleation without implant is advised, and adjuvant orbital radiotherapy is strongly recommended, even when there is no histopathological evidence of local extraocular tumour spread.