Developmental Delay and School Performance Among Retinoblastoma Survivors


The purpose of this study was to describe the academic performance of childhood retinoblastoma (RB) survivors.


Retrospective cohort study.


Retrospective chart review of children followed in a survivorship clinic.


A total of 73 patients with RB (median age at diagnosis: 9.97 months; range: 0.29-65.1) were followed for a median of 6.4 years (0.2-1.76). A total of 48 patients (65.8%) had unilateral RB; 43 patients (63.0%) received systemic chemotherapy; and 57 patients (78.1%) underwent enucleation. At last follow-up, 5 children (6.8%) had bilateral visual acuity (VA) <20/70. Seventeen subjects (23.3%) reported school difficulties, and 10 subjects (13.7%) had an individualized education program (IEP). Multivariate analysis revealed that a history of receiving chemotherapy” Multivariate analysis revealed that a history of receiving chemotherapy was associated with self-reported school difficulties (odds ratio [CI]: 5.44; 95% confidence interval [CI]: 1.36-21.69; P = .016), and undergoing an IEP (OR: 11.47; 95% CI: 1.34-98.16; P = .03). The degree of visual impairment and history of enucleation did not influence the risk of self-reported school difficulties or the implementation of an IEP. Among unilateral RB patients, chemotherapy was an independent risk factor for self-reported school difficulties (OR: 12.8; 95% CI: 1.45-113; P = .009) and implementation of an IEP (OR: 15.2; 95% CI: 0.78-292; P = .02).


Academic difficulties in childhood RB survivors are associated with chemotherapy treatment, a risk factor independent of VA.

R etinoblastoma (RB) is the most common primary intraocular malignancy of childhood, with approximately 350 cases diagnosed in the United States and 5,000-8,000 cases worldwide annually. Children with RB have an excellent prognosis, with survival exceeding 95% in developed countries, , but one-half of RB survivors have decreased unilateral or bilateral visual acuity (VA) due to the disease or treatment. It is well known that children with VA worse than 20/200 in their better seeing eye experience developmental delays and decreased school performance. The global development among these young children is further impacted by the effects of cancer therapy administered to treat the tumor. Cancer therapy can affect vision but may also cause disruptions in neurocognitive development. The standard chemotherapy regimen for RB patients (carboplatin/etoposide/vincristine) has not previously been associated with cognitive difficulties. Few data exist for the developmental or neurocognitive morbidity of RB survivors. This study retrospectively reviewed records of children who were followed after completion of their RB therapy for evidence of developmental delay or reported school difficulties to identify potential variables impacting cognitive function.


The medical records of all patients whose RB was diagnosed at St. Louis Children’s Hospital from 1995 to 2018, who are currently followed in our program and were 18 years of age and younger at the time of chart review were reviewed. Patients were identified by searching the medical records for relevant diagnostic codes (International Classification of Diseases Tenth Revision [ICD-10] code: Clinical Modification [CM] C69.20; or ICD-9 code: M9510-2/3 190.5). The study was approved by the Institutional Review Board at Washington University Medical School. Demographic characteristics, including sex and age at diagnosis, development, and medical and family history of RB were collected for each patient. Ocular data included laterality, macular involvement, best-corrected VA (BCVA) at last follow-up, and additional surgeries were required for inclusion in the analysis. The natural history of the disease with respect to progression, treatment modalities, and outcomes were also recorded. School difficulties were identified from a review of the medical records, collecting documentation of school difficulties, placement of a 504 Plan, or an individualized education plan (IEP).

Self-reported school difficulty was defined as documentation in the medical record that the child was having difficulty in school, as reported by the patient or parent. Patients are were followed in the Late Effects Clinic and ophthalmology clinic where school performance is part of the annual history obtained by providers. Any report of school difficulty during the follow-up period classified the child as having school difficulty. Placement of a 504 Plan was extracted from the chart. Section 504 of the Rehabilitation Act of 1972 is a federal law that protects the rights of individuals with disabilities to receive federal funding. To qualify, students must have “a physical or mental impairment substantially limiting one or more major life activities” that affect their education. To create this Plan, educators used information from providers about the student’s attention, concentration, learning, ability to walk, see, hear, communicate, and interact with others. Students who require more intensive services may qualify for special education through the Individuals with Disabilities Education Act (IDEA), which requires public schools to accommodate children through an IEP with specific, eligible disabilities including visual impairment, hearing impairment, and developmental delay. Charts were reviewed to determine if patients who had an IEP or 504 Plan continued to require services at last follow-up or were no longer in need of those services. We also reviewed charts to determine whether patients had developmental delay as documented by provider and defined as inability to perform age- appropriate milestones, motor delay, speech delay, or abnormal neuropsychiatric testing. Neuropsychiatric testing was typically performed by a licensed neuropsychologist at this institution, and results were documented in the medical record. Patients were excluded if they had not yet completed treatment for RB.

Descriptive statistics were performed (means, medians, range) to characterize the sample. Univariate and multivariate logistic regression models were constructed to determine variables were associated with increased morbidity; variables included in multivariate models were statistically significant in univariate analyses using SPSS statistical software (27, IBM, Armonk, New York, USA).


A total of 73 patients met inclusion criteria ( Figure 1 , Table 1 ). The median age of the patients at diagnosis was 9.97 months (range: 0.29-65.1 months). Median age at last follow-up was 8.0 years (range: 1.3-18.0). Patients were followed for a median of 6.4 years (range: 0.2-17.0) from diagnosis to last follow-up. A total of 48 patients (65.8%) had unilateral disease, and 25 patients had bilateral disease (34.2%); 46 patients (63.0%) were treated with systemic chemotherapy; 57 (78.1%) underwent enucleation; and 7 (9.6%) were treated with intra-arterial chemotherapy (6 unilateral; 1 bilateral). The chemotherapy regimen for RB (carboplatin/etoposide, and vincristine) was administered to this population as standard of care and has not varied significantly over the past 2 decades ( Table 2 ).

Figure 1



Baseline Demographic Characteristics for 73 RB Less Than 18 yrs of Age Followed Long-Term at St. Louis Children’s Hospital.

Age at study, yrs (min, max) 11.1 (2.0, 18.8)
Chemotherapy, number (%) 46 (63.0)
Number of intra-arterial chemotherapy procedures, number (%) 6 (8.2) unilateral; 1 (1.4) bilateral
Number of enucleations (%) Unilateral 57 (78.1); 1 bilateral (1.4)
Number of eye surgeries after RB treatment (%) a 10 (13.7)
Number of germline mutations (%) 34 (46.6)
Macular involvement (%) 54 unilateral (74.0); 10 bilateral (13.7)
LogMAR VA OU at last f/u (median range, Snellen equivalent) 0.0 (−0.12, 1.09) 20/20 range 20/15, 20/246
Number of other secondary malignancies (%) 1 (1.4)
Number of plaques (%) Unilateral 4 (5.5); bilateral 1 (1.4)
Number of orbital radiations (%) Unilateral 3 (4.1); bilateral 4 (5.5)
Number of intravitreal chemotherapy sessions (%) 4 (5.5)
Number laterality (%) Unilateral 48 (65.8); bilateral 25 (34.2)
Number of hearing impaired based on auditory brainstem response (%) 4 (5.5)
Age at diagnosis, months (median, range) 9.97 (0.29, 65.1)
Length of f/u, yrs (median, range) 6.4 (0.2, 17.6)

f/u = follow up; LogMAR = logarithm o the minimum angle of resolution; VA = visual acuity; RB = retinoblastoma.

a Surgeries included strabismus, cataracts, vitrectomy, and intravitreal injection for radiation retinopathy.


Chemotherapy Agents Received by Patients.

Agent Frequency
Etoposide, vincristine, carboplatin 41
Etoposide, vincristine, carboplatin, cyclosporine A 1
Etoposide, vincristine, carboplatin, cyclophosphamide 1
Etoposide, vincristine, carboplatin, cyclophosphamide, cisplatin 1
Etoposide, vincristine, carboplatin, cyclophosphamide, daunorubicin 1
Unknown (this patient was treated outside the United States prior to adoption) 1
No systemic chemotherapy 27

Review of their medical records revealed that these children experienced significant morbidity with regard to school performance ( Figure 2 ). A total of 26 patients (35.6%) experienced 1 or more of the defined morbidities. Nine patients experienced 1 morbidity, 7 patients experienced 2 morbidities, 3 patients experienced 3 morbidities, 5 patients experienced 4 morbidities, and 2 patients experienced 5 morbidities. One patient (1.4%) had a 504 Plan in place, 3 patients (4.1%) each had speech delay and were enrolled in a special education program, including 1 child outside the regular classroom for most subjects due to difficulty with schoolwork and 2 children attending a school for the blind. Six patients (8.2%) experienced motor delay; 7 (9.6%) had abnormal neuropsychiatric testing; 10 patients (13.7%) had developmental delay; and 17 patients (23.3%) had self-reported school difficulties. Ten patients (13.7%) had IEPs. Of these patients, 6 met criteria based on VA alone. Due to the retrospective nature of this review, it was unclear from the available records why patients were otherwise qualified for an IEP or a 504 Plan. Eight patients reported school difficulties who did not have an IEP or a 504 Plan in place. During the study period, no patients with a 504 Plan or an IEP stopped requiring these services.

Figure 2

Educational and developmental delay among 73 retinoblastoma survivors of a median age of 8.0 years (range: 1.3-18.0 years) followed for a median 6.4 years (range: 0.2-17.0 years) at St. Louis Children’s Hospital.

By univariate analysis, most school difficulties were correlated with a treatment history that included chemotherapy. Patients with developmental delay were more likely to have received chemotherapy (10 of 10 patients with developmental delay received chemotherapy versus 24 of 63 patients without developmental delay who received chemotherapy; odds ratio (OR): 14.49; 95% confidence interval [CI]: 0.81-259.1; P = .013) ( Table 3 ). Nine of 10 patients with an IEP versus 37 of 63 patients without an IEP underwent chemotherapy (OR: 6.324; 95% CI: 0.755-53.0; P = .057) ( Table 4 ). Finally, chemotherapy was a risk factor for self-reported school difficulty with 15 of 17 patients who reported school difficulty having received chemotherapy versus 31 of 56 children without self-reported school difficulty (OR: 6.04; 95% CI: 1.26-28.98; P = .014) ( Table 5 ). In contrast, macular involvement was protective against motor delay by univariate analysis (OR: 0.08; 95% CI: 0.01-0.69; P = .01) but not by multivariate analyses (Supplemental Table 1). By multivariate analysis, patients undergoing systemic chemotherapy were 5.4 times more likely to have self-reported school difficulty (OR: 5.44; 95% CI: 1.36-21.69; P = .016) and 11.5 times more likely to have an IEP in place (OR: 11.47; 95% CI: 1.34-98.16; P = .03) when controlling for logMAR VA and history of enucleation. History of enucleation ( P = .16) and logMAR VA ( P = .78) were not significantly correlated with school difficulties in this model.


Univariate and Multivariate Analysis Developmental Delay Among Childhood RB Survivors

Univariate OR (95% CI) P Multivariate OR (95% CI) P
Chemotherapy 14.49 (0.81-259.1) .13 0.0 (0.0) .998
Enucleation 2.29 (0.26-19.9) .67 0.37 (0.04-3.49) .38
Hearing loss 2.48 (0.23-27.2) .45
Germline 1.11 (0.29-4.23) .88
Laterality 1.3 (0.33-5.14) .71
Macular involvement 0.59 (0.06-5.99) .39
Eye surgery 0.83 (0.74-0.93) .16
LogMAR VA 0.265 (0.01-9.13) .46 0.19 (0.01-6.44) .35

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Dec 24, 2021 | Posted by in OPHTHALMOLOGY | Comments Off on Developmental Delay and School Performance Among Retinoblastoma Survivors

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