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Context. —There is a substantial risk of a second cancer for persons with hereditary retinoblastoma, which is enhanced by radiotherapy. Objective. —To examine long-term risk of new primary cancers in survivors of childhood retinoblastoma and quantify the role of radiotherapy in sarcoma development. Design. —Cohort incidence study of patients with retinoblastoma followed for a median of 20 years, and nested case-control study of a radiation dose-response relationship for bone and soft tissue sarcomas. Setting/Participants. —A total of 1604 patients with retinoblastoma who survived at least 1 year after diagnosis, identified from hospital records in Massachusetts and New York during 1914 to 1984. Results. —Incidence of subsequent cancers was statistically significantly elevated only in the 961 patients with hereditary retinoblastoma, in whom 190 cancers were diagnosed, vs 6.3 expected in the general population (relative risk [RR], 30 [95% confidence interval, 26-47]). Cumulative incidence (±SE) of a second cancer at 50 years after diagnosis was 51.0% (±6.2%) for hereditary retinoblastoma, and 5.0% (±3.0%) for nonhereditary retinoblastoma. All 114 sarcomas of diverse histologic types occurred in patients with hereditary retinoblastoma. For soft tissue sarcomas, the RRs showed a stepwise increase at all dose categories, and were statistically significant at 10 to 29.9 Gy and 30 to 59.9 Gy. A radiation risk for all sarcomas combined was evident at doses above 5 Gy, rising to 10.7-fold at doses of 60 Gy or greater ( P Conclusions.— Genetic predisposition has a substantial impact on risk of subsequent cancers in retinoblastoma patients, which is further increased by radiation treatment. A radiation dose-response relationship is demonstrated for all sarcomas and, for the first time in humans, for soft tissue sarcomas. Retinoblastoma patients should be examined for new cancers and followed into later life to determine whether their extraordinary cancer risk extends to common cancers of adulthood.

Importance Intra-arterial chemotherapy has emerged as a treatment for intraocular retinoblastoma and has been quickly adopted by centers worldwide. Objective To conduct a systematic review and attempt a meta-analysis to summarize the reported outcomes of intra-arterial chemotherapy. Evidence Review In January 2015, we performed comprehensive searches in Medline, Embase, Cochrane, and Web of Science from inception through January 2015, including any peer-reviewed English-language publication that described outcomes related to toxicity or efficacy in at least 4 patients. Findings From a total of 208 identified publications, 28 met inclusion criteria. Twelve reports with discernable nonduplicative information were included, reporting 655 patients, 757 eyes, and 2350 catheterizations. All were single-arm case series, and 67% (8 of 12) were retrospective. Across all studies, globe salvage was achieved for 502 (66%) of all eyes. Most common reported toxicities were chorioretinal atrophy and vascular occlusions. There were at least 13 reports of children with metastases. After publication, 7 additional children had metastases. The 4 different classification systems used challenged the comparison of disease severity at presentation. Visual outcome was not addressed in most studies. Meta-analyses were not possible because no study had a comparative group. Assessment of risk of bias was not possible because no validated tool for single-arm studies was available. Conclusions and Relevance Intra-arterial chemotherapy is a promising new treatment associated with high rates of globe salvage. However, the literature is limited by the predominance of retrospective case series, absence of comparison groups, short median follow-up, heterogeneous definitions and tumor classifications, and frequent duplicate reporting. Metastases have been observed, and long-term follow-up is needed. Until the results of clinical, prospective studies are available, it is recommended that intra-arterial chemotherapy be offered selectively among other options, with fully informed discussion about all possible risks, benefits, and uncertainties.

The management of intraocular retinoblastoma is rapidly changing, and even recent reviews on the subject are behind existing practices. The 4 authors of this report collectively represent their management strategies with an emphasis on areas of agreement and disagreement. Ophthalmic artery chemosurgery and intravitreous chemotherapy have completely replaced external beam radiotherapy, reduced the use of systemic chemotherapy, and diminished enucleations by 90% without evidence of compromising patient survival.

The2013annualmeetingof theAmericanAssociationofOphthalmic Oncologists and Pathologists was dedicated to celebrating the life and work of my father, Lorenz E. Zimmerman, MD. Although many may know of his contributions to the field of ophthalmic pathology and oncology, the story of his personal challenges in the field is not widely known. After earning his bachelor of science degree in 1943 and hisdoctorofmedicinedegree in 1945, both fromGeorgeWashington University in Washington, DC, my father completed a pathologyresidencyatWalterReedGeneralHospital.TheArmy then sent him to Korea to run a mobile Army hospital laboratory. That facility supported Chinese and Korean prisonersofwar, and themajorityof specimensobtained there werebacteriologic, thusprovidinganexcellentopportunity for the development of an interest in the pathology of infectious diseases. When he returned from Korea in 1951, he was stationed at Walter Reed General Hospital’s Armed Forces Institute of Pathology (AFIP); his intention was to become an expert in thepathologyofmycoticdiseases.Fortunately,however, the Army had other plans for him, and the result was a 50-year renaissance in the field of ophthalmic pathology. Theevolutionofophthalmicpathology in theUnitedStates began at the ArmyMedical Museum, which later became the AFIP.Early in the20thcentury,most enucleatedeyeswerediscarded because therewas no one trained in ocular pathology. Dr George Callendar, the director of the AFIP in the 1920s, developed aprocess for examining all the enucleated eyes of patients from military institutions, and by World War II, all of these specimenswere sent to theAFIP forhistopathology.This process resulted in theAmericanRegistry of Pathology,where ophthalmic pathology became the first registry. In the early 1950s, few general pathologists were interested in ocular pathology; in 1953,my fatherwas assigned to theDepartment of Ophthalmic Pathology at theAFIP.His response: “I thought it was a stroke of real good fortune for me personally, not because I had anypreconceivednotions or interest in pathology of the eye, but I just knew that itwas a goldmine...in the figurative sense...in terms of having a wealth of material available andhaving this tremendous inflowof cases,notonly from military institutions, but from the civilian sector.”1 Becauseof WorldWar II and the resulting lack ofmanpower, a backlog of 5000 eye pathology cases had accumulated, and this abundance of clinical andhistopathologicmaterialwas the perfect background for the development of my father’s interest in ocular oncology. My father’s willingness and enthusiasm to pursue passionately a field in pathology, aboutwhich he had no prior interest, set the stage for a series of more than 50 years of professionalandpersonalchallenges inandcontributions toocular pathology andoncology, particularly in the fieldof retinoblastoma. In his first 15 years at the AFIP, he publishedmore than 50ocular oncology articles, someofwhichwere landmark initial descriptions.2 This work became intimately intertwined withmyfather’spersonal lifewhen, in1967,myparents’youngest child, Larry, received a diagnosis of bilateral retinoblastomaat4monthsof age.Thisbegana seriesof ironies andcontributions, includingseveral “firsts” in retinoblastomascience, nomenclature, and treatment by 3 generations of theZimmerman family. At the time of Larry’s birth, my father was involved in a reviewofall the casesof retinoblastomaat theAFIP.Therewas no Zimmerman family history of retinoblastoma, but Lorenz E. Zimmerman Jr (Larry) developed bilateral retinoblastoma. Could this havebeenamere coincidence?Larryhada large tumor involving the macula of the right eye and 3 small perimacular tumors in his left eye. Routine treatment at the time was to enucleate the eye with the more advanced tumor and radiate the other. My parents were not satisfied with this and wanted to find a way to salvage vision and the right eye. Larry’s initial treatment, by Drs Algernon Reese and RobertEllsworth inNewYork,wasan intracarotid injectionof chemotherapy.When thiswas ineffective, hewas treatedwithbilateral external beam radiotherapy. Both were experimental treatments at the time. Although bilateral external beam radiotherapy later saved thevisionof countlesspatientsover the years, owing to amore than 30% chance of secondary tumors in the field of radiation,3 better treatments have replaced it. Larry responded positively to the treatment of his retinoblastoma, andhis visionwas salvaged inbotheyes (visual acuitywas counting fingersODand 20/40OS); hewent on to a careerasabanker inManhattan.Hemarried,andafterundergoing genetic counseling and after the identification of hisRB gene, he andhiswife, Anne, decided tohave a child. Perrywas born healthy,butby7weeksof age, shehaddevelopedbilateral retinoblastoma.DrDavidAbramsonsuccessfully treated these tumorswith laser therapy; she had no recurrence of intraocular retinoblastoma. Larry andAnnebecame aware of a newassisted reproductivetechnology, thatofpreimplantationgeneticdiagnosis (PGD), and they sought consultation at the Institute for Reproductive Medicine at NewYorkHospital. The team there developed the mutationanalysisprocedure for the retinoblastomagene (RB1) Related articles pages 605, 614, 622, 630 and 651 Opinion

Objective To review the effectiveness and toxicity of periocular topotecan hydrochloride in fibrin sealant (Tisseel) for the control of intraocular retinoblastoma. Methods Retrospective medical record review of visually threatening or recurrent intraocular retinoblastoma treated with periocular topotecan. Results Eight children (10 eyes) received 1 to 4 injections of periocular topotecan in fibrin sealant, without or with concomitant laser and/or single freeze-thaw prechemotherapy cryotherapy. Median dose was 0.18 mg/kg (3.72 mg/m 2 ). The 6 children who responded to treatment had small discrete tumors (8 International Intraocular Retinoblastoma Classification group A or B eyes). Of these, prior primary treatment for 3 children (3 eyes) was laser; for 1 child (2 eyes), systemic chemotherapy with focal laser; and for 2 children (3 eyes), periocular topotecan. In 4 children (4 eyes), tumor regression was sufficient for effective focal therapy, but in 2 children (4 eyes), long-term control required systemic chemotherapy. The 2 children who did not respond each had an International Intraocular Retinoblastoma Classification group D eye treated primarily with systemic chemotherapy, focal laser, and cryotherapy and recurrent disease that was not controlled by periocular topotecan; both eyes were eventually enucleated. No ocular and minimal hematological toxic effects were observed. At 11 months' median follow-up after topotecan treatment (18 months since diagnosis), all 8 group A and B eyes were retained with ongoing focal therapy required in only 1 group B eye; the 2 group D eyes were enucleated. Conclusion Periocular topotecan in fibrin sealant can achieve volume reduction of small and recurrent retinoblastoma sufficient to allow successful focal therapy.

To determine the time course and extent of tumor reduction associated with systemic chemotherapy or external beam radiotherapy (EBRT) in the treatment of advanced intraocular retinoblastoma.Retrospective review of children with Reese-Ellsworth stages IV and V retinoblastoma undergoing primary globe-conserving therapy with either systemic chemoreduction or EBRT. Study variables were recorded at baseline, at monthly intervals for the first 6 months, and at 12 months after the initiation of treatment. Tumor volumes were calculated using basal area and height values determined by ultrasonography, physical examination, and fundus photographic review.Outcome measures included tumor volume, tumor reduction, regression pattern, treatment-related complications, metastases, and survival.Twenty-six eyes of 26 patients were evaluated for tumor response; 18 patients were treated with systemic chemotherapy and 8 patients were treated with EBRT. Median follow-up was 36 months. A mean 68% reduction in tumor volume occurred after 1 cycle of chemotherapy compared with a 12% reduction at a similar time point (1 month) after initiation of EBRT (P.004). There was no statistically significant difference in tumor volume reduction between treatment modalities at the 12-month follow-up visit. Both systemic chemoreduction and EBRT achieved 100% globe conservation and 100% patient survival in this series.Retinoblastoma reduction exhibits a differential time course based on the applied primary treatment. Systemic chemotherapy is associated with earlier tumor reduction than EBRT.

In reply Dr Hernandez addresses several issues we appreciate the opportunity to clarify. There are several clear reasons for using chemotherapy in addition to local modalities for RE group I and II tumors. 1. In the RE classification, group I tumors are less than 4 disc diameters (6 mm) in greatest diameter and are located posterior to the equator. Cryotherapy is not recommended for tumors posterior to the equator. 1 Traditional photocoagulation is recommended only for tumors no greater than 3 to 4 mm in diameter 2 away from visually important retina. Most group I tumors occur in the posterior pole of young infants with a family history of retinoblastoma. Because of their posterior location, EBR, not cryotherapy or laser photocoagulation, has been the most common treatment. 2 The risk of radiationinduced second malignant neoplasms in children younger than 1 year 3,4 led us to search for an alternative to

To investigate whether cryotherapy, which induces a serous effusion in retina, might increase access of systemic chemotherapy into the vitreous.The right eyes of 18 rabbits were treated with triple or single freeze-thaw cryotherapy at 1 or 2 locations, 1 day before administering intravenous carboplatin with or without cyclosporine. Control left eyes received no cryotherapy. The rabbits were killed 2 or 24 hours after chemotherapy, and carboplatin concentrations were measured in the vitreous of each eye and in blood.A significant increase was found in intravitreal carboplatin concentrations when cryotherapy was applied (P.001) or high-dose cyclosporine was administered (P.001) and if 2 locations were frozen compared with 1 location frozen (P = .02). Intravitreal carboplatin concentrations were always significantly greater after cryotherapy, either when the corresponding blood carboplatin concentrations were high (2 hours after completing treatment) or when they had dropped to much lower levels (at 24 hours). The triple freeze-thaw technique did not yield significantly better results than a single freeze-thaw technique.Cryotherapy administered 24 hours before chemotherapy significantly increased the intravitreal penetration of carboplatin, and this strategy may enhance the capacity of chemotherapy to cure intraocular retinoblastoma, particularly avascular tumors such as vitreous seeds.

Background: External beam radiotherapy is standard treatment for medium and large, or visually threatening, intraocular retinoblastoma but markedly increases the risk of cosmetic deformities and second malignant neoplasms in children with germline RB1 mutations. Large tumors and those with vitreous seeds do poorly despite radiotherapy. Chemotherapy traditionally is ineffective for intraocular retinoblastoma, perhaps because many retinoblastomas overexpress the multidrug resistance protein, P-glycoprotein. Objective: To avoid radiotherapy in the management of intraocular retinoblastoma by using chemotherapy and focal therapy. Interventions: We shrank retinoblastomas in 40 eyes of 31 patients that conventionally should be enucleated or receive radiotherapy by using chemotherapy (ie, vincristine-teniposide, 8 eyes; additional carboplatin, 32 eyes) combined with the administration of cyclosporine, a known multidrug—resistance-reversal agent. We then consolidated these responses to chemotherapy by subsequent 532- and 1064-nm laser therapy and cryotherapy. Results: At the median follow-up of 2/8 years (range, 1/10-43/4 years), the results of treatment were excellent. The actuarial relapse-free rate was 89% in patients not previously treated (91% for 28 eyes) and 67% in patients treated after relapse from previous therapy (70% for 12 eyes). For the eyes with the worst prognosis (ie, vitreous seeds), the relapse-free rate was 88%, better than previously reported. Cyclosporine is nontoxic and did not enhance the expected toxic effects of chemotherapy. Most eyes required laser therapy, cryotherapy, or both for consolidation of tumor control. Conclusions: This pilot study suggests that most retinoblastomas are curable by combining chemotherapy with cyclosporine therapy, laser therapy, and cryotherapy, without requiring external beam radiotherapy. We propose a randomized trial to clarify the role of cyclosporine.

Background: Chemoreduction is a method of reducing tumor volume to allow for more focused, less damaging therapeutic measures. Objective: To determine whether chemoreduction could be used to decrease the size of retinoblastoma so that enucleation or external beam radiotherapy could be avoided and more conservative modalities employed. Methods: A prospective pilot study was performed to assess the effectiveness of a 2-month chemoreduction regimen of vincristine sulfate, etoposide, and carboplatin in patients with retinoblastoma. The study included 20 patients with 54 tumors in 31 eyes. Results: At the initial examination, the mean tumor base was 12 mm and the thickness, 7 mm. Vitreous seeds were present in 14 eyes (45%). A secondary retinal detachment was present in 24 eyes (77%) and, when present, involved a mean of 71% of the retina. In 11 eyes (36%) the retina was totally detached with serous subretinal fluid. After 2 months of chemoreduction, all 54 tumors showed regression in size, and 48 (89%) showed evidence of calcification. The mean tumor base was 8 mm and the thickness, 4 mm. Overall, there was a mean 35% decrease in base and 49% decrease in thickness of the tumor at the end of the treatment period. A complete response was found in 25 tumors (46%) and a partial response in 29 (54%). The subretinal fluid had resolved completely in 50% of the cases (12/24 eyes), and, in the 11 eyes with total retinal detachment, the subretinal fluid had completely resolved, leaving flat retina, in 6 eyes (54%). The vitreous seeds demonstrated some degree of regression in all cases, and in 5 eyes there was 90% to 100% calcification of the seeds. Short-term systemic toxic effects were mild (transient bone marrow suppression). Enucleation was avoided in all cases; external beam radiotherapy was necessary in 9 eyes because of diffuse vitreous seeds. The remaining 22 eyes were treated with local methods after chemoreduction. Conclusion: Tumor shrinkage with chemoreduction may allow treatment with less invasive measures, such as cryotherapy, laser photocoagulation, thermotherapy, or plaque radiotherapy, thereby avoiding enucleation and external beam radiotherapy.