Parental nutrient intake and risk of retinoblastoma resulting from new germline RB1 mutation.

PURPOSE: We conducted a case-control study to examine the role of parents' nutrient intake before their child's conception in the child's risk of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation. METHODS: Parents of 206 cases from 9 North American institutions and 269 friend and relative controls participated; fathers of 182 cases and 223 controls and mothers of 202 cases and 260 controls provided useable information in telephone interviews on their diet in the year before the child's conception. We also asked parents about supplements, a significant source of nutrients in users. RESULTS: Father's intake of dairy-associated nutrients and his use of calcium supplements were associated with decreased risk, while his intake of copper, manganese, and vitamin E was associated with increased risk. Mother's use of multivitamins close to conception was associated with lower risk as was her intake of several micronutrients found in these supplements. In analyses to elucidate the primary factor from multiple correlated factors, the most robust findings were for father's calcium intake (adjusted OR = 0.46-0.63 for 700 mg increase) and calcium supplement use (OR = 0.35-0.41) and mother's multivitamin use (ORs 0.28-0.48). CONCLUSIONS: There are few directly relevant studies but some data indirectly support the biologic plausibility of the inverse associations with father's calcium intake and mother's use of multivitamins; however, we cannot rule out contributions of bias, confounding, or chance. Our findings provide a starting point for further investigation of diet in the etiology of retinoblastoma and new germline mutation generally.

Retinoblastoma regression patterns following chemoreduction and adjuvant therapy in 557 tumors.

OBJECTIVE: To evaluate retinoblastoma regression patterns following chemoreduction and adjuvant therapy. PARTICIPANTS: A total of 557 retinoblastomas. METHODS: A retrospective medical record review following 6 cycles of chemoreduction and tumor consolidation (thermotherapy or cryotherapy). Regression patterns included type 0 (no remnant), type 1 (calcified remnant), type 2 (noncalcified remnant), type 3 (partially calcified remnant), and type 4 (flat scar). MAIN OUTCOME MEASURES: Regression pattern. RESULTS: Retinoblastoma regressions were type 0 (n = 10), type 1 (n = 75), type 2 (n = 28), type 3 (n = 127), and type 4 (n = 317). Tumors with an initial thickness of 3 mm or less regressed most often to type 4 (92%), those 3 to 8 mm regressed to type 3 (34%) or type 4 (40%), and those thicker than 8 mm regressed to type 1 (40%) or type 3 (49%). Factors predictive of type 1 regression included larger tumor base and closer foveolar proximity. Factors predictive of type 3 included older age, larger tumor base, macular location, closer foveolar proximity, and lack of consolidation. Factors predictive of type 4 included familial hereditary pattern, smaller tumor base, greater foveolar distance, and tumor consolidation. CONCLUSIONS: Following chemoreduction, most small retinoblastomas result in a flat scar, intermediate tumors in a flat or partially calcified remnant, and large tumors in a more completely calcified remnant.

The International Classification of Retinoblastoma predicts chemoreduction success.

PURPOSE: To evaluate the reliability of the International Classification of Retinoblastoma (ICRB) for predicting treatment success with chemoreduction (CRD). DESIGN: Noncomparative interventional case series. PARTICIPANTS: Two hundred forty-nine consecutive eyes. METHODS: All eyes were treated with CRD and were classified according to the ICRB: group A included those eyes with retinoblastoma 3 mm, macular location, or minor subretinal fluid; group C included those eyes with retinoblastoma with localized seeds; group D included those eyes with retinoblastoma with diffuse seeds; group E included those eyes with massive retinoblastoma necessitating enucleation. The CRD regimen included vincristine, etoposide, and carboplatin for 6 cycles plus local consolidation with thermotherapy or cryotherapy. MAIN OUTCOME MEASURE: Chemoreduction success, defined as avoidance of external beam radiotherapy or enucleation. RESULTS: Of the 249 eyes, 23 (9%) were in group A, 96 (39%) were in group B, 21 (8%) were in group C, and 109 (44%) were in group D. In this series, group E eyes were managed with enucleation. Treatment success was achieved in 100% of group A, 93% of group B, 90% of group C, and 47% of group D eyes. CONCLUSIONS: The ICRB can be of assistance in predicting CRD success for retinoblastoma. Additional treatment methods are necessary to salvage more group D eyes.

Macular retinoblastoma managed with chemoreduction: analysis of tumor control with or without adjuvant thermotherapy in 68 tumors.

OBJECTIVE: To evaluate the effectiveness of chemoreduction alone and chemoreduction with thermotherapy for macular retinoblastoma. DESIGN: Prospective, nonrandomized, single-center case series. SETTING: Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University in conjunction with the Division of Oncology at the Children's Hospital of Philadelphia (Pa). PARTICIPANTS: There were 68 macular retinoblastomas in 62 eyes of 49 patients managed with chemoreduction from January 1995 through January 2003. Intervention All patients received 6 cycles of intravenous chemoreduction using vincristine, etoposide, and carboplatin. The patients were then treated according to 1 of 2 approaches: chemoreduction alone with no adjuvant focal therapy (group A) or chemoreduction combined with adjuvant foveal-sparing thermotherapy to each macular retinoblastoma (group B). Main Outcome Measure Tumor recurrence. RESULTS: Of the 68 tumors, 28 were in group A and 40 were in group B. A comparison of both groups revealed that the tumors were similar with regard to clinical features. The mean tumor basal dimension was 12.3 mm for group A and 12.1 mm for group B, and the mean tumor thickness was 6.8 mm for group A and 6.1 mm for group B. Tumors in group A occupied a mean of 71% of the macula, and those in group B occupied 74% of the macula. Following treatment, Kaplan-Meier estimates revealed that group A tumors showed recurrence in 25% by 1 year and 35% by 4 years whereas those in group B showed recurrence in 17% by 1 year and 17% by 4 years. All recurrences were treated with additional focal thermotherapy, cryotherapy, or plaque radiotherapy except for 1 that required external beam radiotherapy and 1 that required enucleation, both in group A. Univariate analysis revealed that predictors of tumor recurrence were intraretinal growth pattern (vs endophytic); small tumor basal dimension (less than 3 mm and occupying a smaller percentage of the macula); absence of subretinal fluid, subretinal seeds, and vitreous seeds; and chemoreduction response with less tumor calcification and tumor regression of type 0 (complete disappearance without a scar). By multivariate analysis, the most important factors predictive of tumor recurrence were smaller macular tumor size (judged by percentage of the macula occupied by the tumor), absence of subretinal or vitreous seeds, and unilateral disease. CONCLUSIONS: Treatment of macular retinoblastoma with chemoreduction plus adjuvant foveal-sparing thermotherapy provides tumor control of 83% by 4 years, and this is slightly more favorable than chemoreduction alone, which provides control of 65% by 4 years. Tumors most destined for recurrence are small tumors.

Continuing challenges in the management of retinoblastoma with chemotherapy.

The management of retinoblastoma has gradually changed over the past 10 years. Over 95% of children with retinoblastoma in the United States are cured with modern techniques. The challenge remains, however, in maintaining the eye and vision. There is a trend away from enucleation and external beam radiotherapy toward focal conservative treatments involving primary chemoreduction in conjunction with thermotherapy and cryotherapy. This is related to earlier detection of the disease, recognition of more effective chemotherapeutic agents, more focused local treatment modalities, and, most importantly, knowledge of the long-term risks of external beam radiotherapy. Enucleation is still preferable for retinoblastoma that fills most of the eye, especially when the disease is unilateral or when there is concern for tumor invasion into the optic nerve, choroid, or orbit. The orbital integrated implant is placed after enucleation and provides acceptable prosthesis motility and appearance. External beam radiotherapy is still vital for treating advanced retinoblastoma, especially when there is diffuse vitreous or subretinal seeding after failure of other methods and preservation of vision is a priority. The most important recent advance in the management of retinoblastoma is the use of intravenous chemotherapy for tumor reduction, a technique of neoadjuvant chemotherapy termed "chemoreduction." This is followed by tumor consolidation with focal measures such as thermotherapy, cryotherapy, and plaque radiotherapy. This strategy provides reduced tumor volume and often permits consolidation with methods other than radiotherapy. It appears that vision can be preserved in some cases with these methods, avoiding some of the local complications like radiation cataract or macular edema that have been found with radiotherapy techniques. External beam radiotherapy and enucleation can now be avoided in most cases of Reese-Ellsworth groups I (minimal disease) through IV (moderate disease) retinoblastoma. The most advanced stage of retinoblastoma, Reese-Ellsworth group V, continues to provide the greatest difficulty for management, and external beam radiotherapy and enucleation are often employed in addition to chemoreduction to save the child's life. A collaborative prospective study in North America is currently under way to further study the benefits and risks of chemoreduction for minimal, moderate, and advanced retinoblastoma.

Chemoreduction for retinoblastoma. Analysis of tumor control and risks for recurrence in 457 tumors.

PURPOSE: To evaluate retinoblastoma control following chemoreduction. DESIGN: Interventional case series. METHODS: Prospective. SETTING: Single center trial. PATIENT POPULATION: 457 retinoblastomas in 193 eyes of 125 patients. Nonrandomized, noncomparative study. INTERVENTION: All patients received intravenous vincristine, etoposide, and carboplatin,. The tumors were managed with chemoreduction alone (group W) or chemoreduction combined with thermotherapy (group X), cryotherapy (group Y), or both thermotherapy and cryotherapy (group Z). MAIN OUTCOME MEASURE: Tumor recurrence in each treatment group. RESULTS: Of 457 retinoblastomas, 63 (14%) were in group W, 256 (56%) in group X, 127 (28%) in group Y, and 11 (2%) in group Z. The tumor was located in the macula in 33 (52%) of group W, 109 (43%) of group X, 3 (2%) of group Y, and 9 (1%) of group Z. The mean tumor thickness at initial examination was 7 mm for group W, 4 mm for group X, 2 mm for group Y, and 3 mm for group Z. Using Kaplan-Meier estimates, recurrence of the individual retinoblastoma at 7 years was found in 45% of group W and 18% for combined groups X, Y, and Z. Risk factors predictive of tumor recurrence by multivariate analysis included macular tumor location for all groups and additionally female gender for group W and increasing tumor thickness for groups X, Y, and Z. CONCLUSIONS: Chemoreduction alone or combined with cryotherapy or thermotherapy is effective for treatment of retinoblastoma, but tumor recurrence rate is highest for those located in the macula and those with greater thickness.

Chemoreduction for retinoblastoma: analysis of tumor control and risks for recurrence in 457 tumors.

PURPOSE: To evaluate individual tumor control following chemoreduction for retinoblastoma. METHODS: Prospective nonrandomized single-center case series of 457 retinoblastomas managed with six cycles of chemoreduction (vincristine, etoposide, and carboplatin). The tumors were then managed with chemoreduction alone (group A) or chemoreduction combined with thermotherapy (group B), cryotherapy (group C), or both thermotherapy and cryotherapy (group D). The main outcome measure was development of tumor recurrence. RESULTS: Of 457 retinoblastomas, 63 (14%) were in group A, 256 (56%) in group B, 127 (28%) in group C, and 11 (2%) in group D. The tumor was located in the macula in 33 (52%) of group A, 109 (43%) of group B, 3 (2%) of group C, and 1 (9%) of group D. Using Kaplan-Meier analysis, recurrence of the individual retinoblastoma at 7 years was found in 45% of group A and in 18% of combined groups B, C, and D. Treatment of the 93 tumor recurrences included thermotherapy, cryotherapy, or plaque radiotherapy in 62 cases (67%) and external beam radiotherapy or enucleation in 31 cases (33%). Risk factors predictive of tumor recurrence by multivariate analysis included macular tumor location for all groups and, additionally, female sex for group A and increasing tumor thickness for groups B, C, and D. CONCLUSIONS: Chemoreduction alone or combined with cryotherapy and/or thermotherapy is effective for treatment of retinoblastoma, but tumor recurrence is greatest for those located in the macula and those with greater thickness. Globe salvage is usually achieved despite tumor recurrence.

Development of new retinoblastomas after 6 cycles of chemoreduction for retinoblastoma in 162 eyes of 106 consecutive patients.

OBJECTIVE: To evaluate the occurrence of new retinoblastomas in patients treated with 6 cycles of chemoreduction. DESIGN: Prospective nonrandomized single-center case series. SETTING: Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University, Philadelphia, Pa, in conjunction with the Division of Oncology at The Children's Hospital of Philadelphia. PARTICIPANTS: A total of 162 eyes of 106 patients with retinoblastoma treated with 6 cycles of chemoreduction between January 1, 1995, and May 31, 2002. INTERVENTION: All patients received intravenous chemoreduction with vincristine sulfate, etoposide, and carboplatin, combined with focal treatment (cryotherapy or thermotherapy) to each retinal tumor. MAIN OUTCOME MEASURE: Development of new intraretinal retinoblastoma during or after treatment with chemoreduction. Recurrent subretinal tumor seeds or vitreous seeds were excluded from this analysis, and only primary new intraretinal tumors were included. RESULTS: Of 28 patients with unilateral retinoblastoma, new intraretinal tumor development was found during or after chemoreduction in 2 (9%) of the 23 patients with sporadic disease and 4 (80%) of the 5 patients with familial disease. The new tumor was located in the macula in none, between the macula and equator in 7 (54%), and between the equator and ora serrata in 6 (46%). Of the 78 patients with bilateral retinoblastoma, new tumor development was found during or after chemoreduction in 11 (19%) of the 57 patients with sporadic disease and 8 (38%) of the 21 patients with familial disease. The new tumor was macula in 2 (4%), between the macula and equator in 30 (55%), and between the equator and ora serrata in 23 (42%). Overall, according to Kaplan-Meier analysis, new tumor development occurred in 23% of patients by 1-year follow-up and 24% by 5-year follow-up. By multivariate analysis, the most important risk factors for the development of new tumors was younger age at presentation (median age, 2 months with new tumor vs 9 months without new tumor) and family history of retinoblastoma (12 [48%] of patients with new tumor vs 14 [17%] without new tumor). CONCLUSIONS: Children with retinoblastoma treated with chemoreduction should be followed for new intraretinal tumor development, as it peaks at a mean interval of 5 months after initiation of chemoreduction and affects 24% of patients by 5 years of follow-up. New tumors are most commonly found in those who develop disease as young infants and those with a family history of retinoblastoma.

Chemoreduction for unilateral retinoblastoma.

OBJECTIVE: To evaluate conservative management of unilateral retinoblastoma using chemoreduction and focal treatment. DESIGN: Prospective nonrandomized single-center clinical trial. SETTING: Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University, Philadelphia, Pa, in conjunction with the Division of Oncology at The Children's Hospital of Philadelphia. PARTICIPANTS: Thirty eyes of 30 patients with unilateral retinoblastoma treated with chemoreduction between June 1, 1994, and August 31, 1999, that would otherwise have been managed with enucleation or external beam radiotherapy. INTERVENTION: All patients received treatment for retinoblastoma with a planned 6 cycles of chemoreduction using vincristine sulfate, etoposide, and carboplatin, combined with focal treatment (cryotherapy or thermotherapy) to each retinal tumor. MAIN OUTCOME MEASURES: The main outcome measure was the postchemoreduction need for external beam radiotherapy or enucleation. The cumulative probability of each outcome was estimated using Kaplan-Meier survival analysis. A secondary outcome measure was final visual acuity in the affected eye. The clinical features at the time of patient presentation were analyzed for their impact on the main outcomes using a series of Fisher exact tests and Cox proportional hazards regressions. RESULTS: Eighteen eyes (60%) were classified as having Reese-Ellsworth (RE) groups I through IV retinoblastoma and 12 eyes (40%), group V retinoblastoma. By using Kaplan-Meier estimates, we found a need for either external beam radiotherapy or enucleation in 68% of eyes by 5 years. In fact, 38% of those in groups I through IV required either treatment, whereas all of those in group V required the additional use of either treatment. Specifically, the need for external beam radiotherapy occurred in 27% of eyes by 5 years. Eleven percent of those in groups I through IV and 50% of group V required external beam radiotherapy by 5 years. The factors predictive of the need for external beam radiotherapy included RE group V disease, tumor thickness greater than 5 mm, and presence of vitreous seeds. The need for enucleation occurred in 47% of eyes by 5 years using Kaplan-Meier analysis. Specifically, 29% of those in groups I through IV and 67% of group V required enucleation by 5 years. The factors predictive of the need for enucleation included age at diagnosis older than 12 months, RE group V disease, tumor base diameter greater than 15 mm, and tumor thickness greater than 5 mm. At a mean follow-up of 29 months, the final visual acuity was 20/200 or better in 6 eyes (20%) and worse than 20/200 in 14 (47%); enucleation was needed in 10 (33%). Of the 26 eyes with initial macular involvement of retinoblastoma, final visual acuity was 20/200 or better in 6 (23%). No patient developed retinoblastoma metastasis, pinealoblastoma, or second malignant neoplasms. CONCLUSIONS: Chemoreduction is an option for selected eyes with unilateral retinoblastoma. Those with advanced RE group V retinoblastoma showed poorest results, while those with less advanced groups I through IV disease showed best results, maintaining the globe in 71% of eyes, sometimes with satisfactory functional visual acuity.

Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation.

PURPOSE: To report the results of chemoreduction and focal therapy for retinoblastoma with determination of factors predictive of the need for treatment with external beam radiotherapy or enucleation. DESIGN: Interventional case series. METHODS: One-hundred three patients with retinoblastoma (158 eyes with 364 tumors) at the Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University in conjunction with the Division of Oncology at Children's Hospital of Philadelphia from June 1994 to August 1999 were enrolled for this prospective clinical trial. The patients received treatment for retinoblastoma with six planned cycles (one cycle per month) of chemoreduction using vincristine, etoposide, and carboplatin combined with focal treatments (cryotherapy, thermotherapy, or plaque radiotherapy). The two main outcome measures after chemoreduction and focal therapy were the need for external beam radiotherapy and the need for enucleation. The clinical features at the time of patient presentation were analyzed for impact on the main outcome measures using a series of Cox proportional hazards regressions. RESULTS: Using Reese-Ellsworth (RE) staging for retinoblastoma, there were nine (6%) eyes with group I disease, 26 (16%) eyes with group II disease, 16 (10%) eyes with group III disease, 32 (20%) eyes with group IV disease, and 75 (48%) eyes with group V retinoblastoma. All eyes showed initial favorable response with tumor regression. The median follow-up was 28 months (range, 2-63 months). Failure of chemoreduction and need for treatment with external beam radiotherapy occurred in 25% of eyes at 1 year, 27% at 3 years, and no further increase at 5 years. More specifically, external beam radiotherapy was necessary at 5 years in 10% of RE groups I-IV eyes and 47% of RE group V eyes. Multivariate factors predictive of treatment with external beam radiotherapy included non-Caucasian race, male sex, and RE group V disease. Failure of chemoreduction and the need for treatment with enucleation occurred in 13% eyes at 1 year, 29% at 3 years, and 34% at 5 years. More specifically, enucleation was necessary in 15% of RE groups I-IV eyes at 5 years and in 53% of RE group V at 5 years. Multivariate factors predictive of treatment with enucleation included patient age older than 12 months, single tumor in eye, and tumor proximity to foveola within 2 mm. Overall, of the 158 eyes, 50% required external beam radiotherapy or enucleation and 50% were successfully managed without these treatments. No patient developed retinoblastoma metastasis, pinealoblastoma, or second malignant neoplasms over the 5-year follow up. CONCLUSIONS: Chemoreduction offers satisfactory retinoblastoma control for RE groups I-IV eyes, with treatment failure necessitating additional external beam radiotherapy in only 10% of eyes and enucleation in 15% of eyes at 5-year follow-up. Patients with RE group V eyes require external beam radiotherapy in 47% and enucleation in 53% at 5 years.

Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma.

OBJECTIVE: To identify the clinical features of eyes with retinoblastomas that predict the recurrence of retinal tumors, vitreous seeds, and subretinal seeds following treatment with chemoreduction. DESIGN: Prospective nonrandomized single-center clinical trial. SETTING: Ocular oncology service at Wills Eye Hospital of Thomas Jefferson University (Philadelphia, Pa) in conjunction with the division of oncology at Children's Hospital of Philadelphia. PARTICIPANTS: There were 158 eyes with 364 tumors in 103 consecutive patients with retinoblastoma managed with chemoreduction between June 1994 and August 1999. INTERVENTION: All patients received treatment for retinoblastoma with 6 cycles of chemoreduction using vincristine, etoposide, and carboplatin combined with focal treatment (cryotherapy, thermotherapy, or plaque radiotherapy) for each retinal tumor. MAIN OUTCOME MEASURES: The 3 main outcome measures included recurrence of retinal tumors, recurrence of vitreous seeds, and recurrence of subretinal seeds. The clinical features at the initial examination were analyzed for their association with the main outcome measures using a series of Cox proportional hazards regressions. RESULTS: All retinal tumors, vitreous seeds, and subretinal seeds showed an initial favorable response of regression during this treatment regimen. Using Kaplan-Meier estimates, at least 1 retinal tumor recurrence per eye was found in 37% of eyes at 1 year, 51% at 3 years, and no further increase at 5 years. By multivariate analysis, the only factor predictive of retinal tumor recurrence was the presence of tumor-associated subretinal seeds at the initial examination. Of the 54 eyes that had vitreous seeds at the initial examination, vitreous seed recurrence was found in 26% of eyes at 1 year, 46% at 3 years, and 50% at 5 years. By univariate analysis, the only factor predictive of vitreous seed recurrence was the presence of tumor-associated subretinal seeds at the initial examination. Of the 71 eyes that had subretinal seeds at the initial examination, subretinal seed recurrence was detected in 53% of eyes at 1 year, 62% at 3 years, and no further increase at 5 years. By multivariate analysis, factors predictive of subretinal seed recurrence included a tumor base greater than 15 mm and a patient age of 12 months or younger at diagnosis. There were no patients who developed retinoblastoma metastasis, pinealoblastoma, or second malignant neoplasms. CONCLUSIONS: Chemoreduction combined with focal therapy is effective for selected eyes with retinoblastomas. Eyes with subretinal seeds at initial examination are at particular risk for recurrence of retinal tumor and vitreous seeds. Younger patients with large tumors are at risk for recurrence of subretinal seeds. Retinal tumor and subretinal seed recurrence seems to manifest within 3 years of follow-up. Close follow-up of all patients treated with chemoreduction is warranted.