Retinoblastoma is a rare form of eye cancer that usually develops in early childhood, typically before the age of 5 years.1,2 It is aggressive and life-threatening if untreated, but curable if detected at an early stage.3 The tumor can be unilateral, occurring in only one of the eyes, or bilateral, occurring in both eyes.
Leukocoria and strabismus are the most frequent clinical manifestations of retinoblastoma. Some other signs may be observed, including iris rubeosis, hypopyon, hyphema, buphthalmia, orbital cellulitis, and exophthalmia.4 Diagnosis is determined by funduscopy, ultrasound, and magnetic resonance imaging, contributing to both the diagnosis and assessment of the extension of the disease. Early diagnosis and prompt treatment are vital to preserve the patient's life and useful vision.5
The treatment of intraocular retinoblastoma has progressed to a more risk-adapted strategy that intends to minimize systemic exposure to drugs, optimize ocular drug delivery, and conserve useful vision. For cases of extraocular retinoblastoma, treatment with intensive chemotherapy is indicated and includes consolidation with high-dose chemotherapy and autologous hematopoietic stem cell rescue.6
Retinoblastoma-related deaths can be a consequence of second malignant neoplasms, trilateral retinoblastoma, and metastases. In the United States, due to improvement in the diagnosis and management of primary retinoblastoma, mortality is more commonly associated with trilateral retinoblastoma and second malignant neoplasms rather than metastases.7–9 Onset of metastasis typically takes place within 2 years of diagnosis and portends a poor prognosis, with death occurring within 6 months of the diagnosis of metastatic retinoblastoma.8 Trilateral retinoblastoma alludes to an ectopic intracranial tumor in patients with germline retinoblastoma developing within the first 5 years of life.10 The establishment of second malignant neoplasms occurs secondary to effects of germline retinoblastoma mutation, which can be augmented by external radiation.
Previous studies show that treatment has shifted toward increased use of chemotherapy and less radiation therapy, with surgical therapy remaining the predominant treatment method. Radiotherapy treatment indication has decreased in an effort to minimize local radiation-induced effects (ie, cataract, radiation-induced retinopathy, temporal bone atrophy, and sicca syndrome) and the risk of developing second malignant neoplasms.8,11 Current treatment designs for retinoblastoma predominantly include intravenous chemotherapy, which results in positive oncologic outcomes and may also minimize the risk of pineoblastoma in children with hereditary retinoblastoma.12 More recently, the use of intra-arterial chemotherapy via the ophthalmic artery has shown oncologic efficacy and safety by delivering localized chemotherapy and decreasing systemic toxicity related to intravenous toxicity.13
The initial surveillance of retinoblastoma in the United States dates from 1973 with the creation of the Surveillance, Epidemiology, and End Results (SEER) Program (National Cancer Institute, Rockville, MD). The coverage of the SEER Program has expanded from 9 to 18 population-based cancer registries for cases diagnosed since 1973 (9 registries), 1992 (13 registries), and 2000 (18 registries).14 The 9 original SEER registries included Atlanta, Georgia; San Francisco–Oakland, California; Detroit, Michigan; Seattle–Puget Sound, Washington; and Connecticut, Hawaii, Iowa, New Mexico, and Utah. The 13 SEER registries included the 9 original registries with the addition of Los Angeles and San Jose–Monterey, California; rural Georgia; and the Alaska Natives registry. The 18 SEER registries added Kentucky, Louisiana, and New Jersey, and the rest of California and Georgia.
A previous study using SEER data from 1973 to 2002 found a retinoblastoma incidence rate of 11.8 cases per 1 million children 4 years or younger in the United States, but did not evaluate the survival rate of these patients.15
The current study aimed to determine the incidence rate of retinoblastoma in the United States during a 40-year period ranging from 1973 to 2012 and to characterize the 5-year overall survival rate of patients diagnosed as having retinoblastoma through a review of existing databases.
The SEER Program is the only comprehensive source of population-based information on cancer incidence and survival rates in the United States. The SEER Program's overall coverage is approximately 28% of the country and the population covered is comparable to the general U.S. population. In our study, 9 historical SEER registries were used because these were the only registries collecting data for the entire period from 1973 to 2012. These registries cover approximately 9% of the U.S. population.14
Patients and Methods
The National Cancer Institute SEER Public Use CD-ROM for the period of 1973 to 2012 was used.16 Nine historical SEER registries were analyzed. For both morphology (retinoblastoma = 9,510 to 9,513) and topography (retinoblastoma included retina and eye [C69.2, C69.9]), International Classification of Oncology (ICDO-3) codes were used to define the cases for the study.17
Descriptive statistics evaluated the number of cases and deaths in different categories of sex, age at diagnosis, laterality, decade of diagnosis, race, origin, and surgical procedure (ie, enucleation).
The incidence rates of retinoblastoma were calculated per 1 million children using the U.S. Census Bureau 2010 data as the standard population,18 applying a relative correction of 9% considering the coverage of the 9 SEER registries.16 The significance of trend in the incidence rate over time was determined using the chi-square test, and 95% confidence intervals (CIs) were calculated.
Hazard ratios with a 95% CI were estimated for variables associated with overall mortality by using univariate and multivariate Cox regression models. Seven variables (sex, age at diagnosis, decade of diagnosis, laterality, race, origin, and surgery intervention) were analyzed in the multivariate model. Survival rates were calculated using the Kaplan–Meier method and compared among the different levels of the 7 variables.
The Cox proportional hazard regression was used for the analysis of retinoblastoma survival rates. The Hosmer–Lemeshow purposeful selection of variables was the strategy used for modeling.
Data analysis was performed using Statistical Analysis Software (version 9.4; SAS Institute, Inc., Cary, NC). A two-tailed P value of less than .05 was considered significant.
This study used a de-identified public database from the SEER Program. Because it did not involve the use of personal identifying information or interaction with human patients, informed consent from the SEER registered cases was not required and the authors obtained a Limited-Use Data Agreement from the SEER Program.
A total of 879 cases of retinoblastoma in the period of 1973 to 2012 were identified using the 9 original SEER registries. The retinoblastoma cases represented 6.1% of all registered childhood cancers of patients younger than 9 years.
The descriptive analysis presented in Table 1 shows an even distribution of cases among males and females (49% and 51%, respectively) and a higher incidence of unilateral retinoblastoma (71.1%). Most cases were diagnosed before the age of 4 years (96%) and occurred among white patients (71.5%). The most frequent reporting sources were hospitals (98.8%).
Descriptive Characteristics of Retinoblastoma Cases in the United States from 1973 to 2012
Age-specific incidence rates were calculated due to important differences in the distribution of disease between two age groups: 4 years or younger and between 5 and 9 years. The mean annual incidence of retinoblastoma was 12.14 cases per 1 million children 4 years or younger (95% CI: 11.32 to 12.96) and 0.49 cases per 1 million children between the ages of 5 and 9 years (95% CI: 0.36 to 0.65). There was no significant trend over time in incidence rates for children 4 years or younger (chi-square test = 35.455; P =.632) or between the ages of 5 and 9 years (chi-square test = 32.247; P = .769) (Figure 1). The proportion of bilateral (28.9%) versus unilateral cases (71.1%) remained stable across the 40-year period (chi-square test = 30.032; P = .848).
Incidence of retinoblastoma in the United States by age group from 1973 to 2012.
The analyses indicate a significant effect of age at diagnosis, laterality of tumor, and decade of diagnosis on survival rates. The model with age at diagnosis, laterality of tumor, and decade of diagnosis fits well (Akaike information criterion = 587.947). The hazard ratios and 95% CIs for death, adjusted for age at diagnosis, laterality of tumor, and decade of diagnosis, are presented in Table 2.
Data From Patients Who Died of Retinoblastoma
Patients diagnosed between the ages of 1 and 2 years were 2.53 (95% CI: 1.135 to 5.648) times more likely to die than those diagnosed before 1 year of age. Patients diagnosed between the ages of 2 and 3 years were 4.24 (95% CI: 1.732 to 10.395) times more likely to die than those diagnosed before 1 year of age. No significant statistical differences were found between the survival rates of patients diagnosed after 3 years of age compared to those diagnosed before 1 year of age (hazard ratios = 1.11; 95% CI: 0.292 to 4.321). Patients with bilateral cases were 2.65 (95% CI: 1.406 to 4.983) times more likely to die than patients who had unilateral cases. Cases from the 1990s and 2000s were significantly less likely to result in the death of a patient than cases from the 1970s (P < .0001).
The 5-year overall survival rate was 95.18%. The Kaplan–Meier survival rate curves by time period show differences in survival time according to the age at diagnosis, decade of diagnosis, and laterality of tumor (Figure 2). The 5-year overall survival rates were 97.6% for those diagnosed before 1 year of age, 92.7% for those diagnosed between the ages of 1 and 2 years, 91.1% for those diagnosed between the ages of 2 and 3 years, and 96.4% for those diagnosed after 3 years of age (P = .0136). The 5-year overall survival rates were 92.5% for bilateral and 96.3% for unilateral (P = .0116) cases. The 5-year overall survival rates were 90.8%, 92.5%, 97.6%, and 97.3% for increasing time periods (1973 to 1979, 1980 to 1989, 1990 to 1999, and 2000 to 2012, respectively; P = .0017).
Kaplan–Meier cumulative survival for retinoblastoma cases in the United States by (A) age of diagnosis, (B) tumor laterality, and (C) decade of diagnosis.
The 5-year overall survival rates show no significant differences across sex, race, origin, or surgery intervention (P = .57, .61, .53, and .19, respectively).
The retinoblastoma incidence of 12.1 cases per 1 million children 4 years or younger is comparable to the previously published incidences in the United States15,19 and other countries, such as the Netherlands,20 northern Europe,21 and Singapore.22 The incidence of retinoblastoma in the United States has remained constant during the past 40 years, extending previous observations from the 1980s,19 1990s,23 and 2000s.15 Stability of the incidence of retinoblastoma has also been observed in the United Kingdom,24,25 the Netherlands,20 northern Europe,21 and Singapore.22
In our analysis, survival rates showed improvement from the 1970s to 2000s, with 91% to 97% 5-year survival rates, which follows similar trends previously reported using SEER data.8,9,26 The improvement in survival rates over time parallels the shift in therapy toward chemotherapy and a decline in radiation therapy. This improvement in survival rates may be due to the decreased incidence of second malignant neoplasms as a consequence of the decreased use of radiation therapy.15 In a previous SEER evaluation combined with individual treatment information data, the risk of second malignant neoplasms was 7-fold higher in patients who received radiation therapy compared to those who did not.8
The 5-year survival rate in the United States is higher than the 5-year survival rates reported in developing countries and regions (ie, 80% in Taiwan,27 83.1% in Iran,28 and 81% in other developing countries such as Argentina, Brazil, Turkey, Jordan, and Venezuela).29 The survival rate calculated in the United States is significantly higher than those reported for less developed regions, such as in East Africa (30%)30 and Central America (48%).31
We found that the survival rate of patients with unilateral retinoblastoma was significantly higher than that of patients with bilateral cases, which is in accordance with previous studies.32 Bilateral cases were more likely to develop secondary malignant neoplasms and, therefore, presented a higher risk of mortality.33 Other studies found no significant difference in survival rates between unilateral and bilateral retinoblastoma34; however, the short-term follow-up periods of the cases could explain the conflicting results.
In terms of age, we observed that children diagnosed after 3 years of age had no statistical differences in survival rates when compared to those diagnosed before 1 year of age. It should be considered that the children evaluated were more likely to have had a tumor developed later as opposed to a late diagnosis. Previous studies indicate that retinoblastomas developed in older children are unilateral, sporadic (no family history of retinoblastoma), and have mainly an endophytic pattern of growth; therefore the likelihood of survival could be higher if diagnosed early.35
In the current study, no significant differences in survival rates were found between Hispanic and non-Hispanic children. However, this single measure is not sufficient when evaluating disparities because vulnerable populations might be affected in many other ways.36 As shown in previous studies, although origin does not have a significant effect on the survival of children with retinoblastoma, the extent of the disease (and thus the intensity of the treatment received) and the chances of eye preservation and ultimate effect on vision and quality of life differ significantly.37
The SEER database allows us to assess incidence and survival rates of patients with retinoblastoma in the general population. However, there are inherent limitations in this study. The dataset was retrospectively collected and is vulnerable to the intrinsic biases associated with data collection. In particular, differences in reporting over time that may have been enhanced with more contemporary patients could have artificially inflated recent incidence rates of retinoblastoma. Information regarding radiotherapy and chemotherapy were not available for the current analysis. We observed a significant decrease of surgical intervention through the decades, but a more detailed characterization of retinoblastoma treatment strategies was achievable in this study. Additionally, information regarding hereditary/inherited diseases and quality of life and vision preservation was not provided in the dataset. Finally, follow-up of the pediatric patient cohort is a challenge because many are lost to follow-up as they move out of geographic areas not covered by SEER registries. However, the SEER Program uses the National Death Index to count deaths due to a lack of follow-up, which increases the precision of the database.9
The incidence rate of retinoblastoma in the United States has remained stable for the 40-year period ranging from 1973 to 2012. The survival rate analysis indicates a significant effect of age at diagnosis, laterality of tumor, and decade of diagnosis. Overall, survival rates in patients with retinoblastoma continue to remain favorable. The current study demonstrates the improvement of survival rates in contemporary time periods, which parallels the improvement in early detection and a shift in therapy for retinoblastoma.
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- Li SY, Chen SC, Tsai CF, Sheu SM, Yeh JJ, Tsai CB. Incidence and survival of retinoblastoma in Taiwan: a nationwide population-based study 1998–2011. Br J Ophthalmol. 2016;100:839–842. doi:10.1136/bjophthalmol-2015-307211 [CrossRef]
- PDQ Pediatric Treatment Editorial Board. Retinoblastoma Treatment (PDQ®): Health Professional Version. National Cancer Institute Web site. https://www.cancer.gov/types/retinoblastoma/hp/retinoblastoma-treatment-pdq. Updated September 19, 2017.
- Brichard B, De Bruycker JJ, De Potter P, Neven B, Vermylen C, Cornu G. Combined chemotherapy and local treatment in the management of intraocular retinoblastoma. Med Pediatr Oncol. 2002;38:411–415. doi:10.1002/mpo.1355 [CrossRef]
- Shinohara ET, DeWees T, Perkins SM. Subsequent malignancies and their effect on survival in patients with retinoblastoma. Pediatr Blood Cancer. 2014;61:116–119. doi:10.1002/pbc.24714 [CrossRef]
- Tamboli D, Topham A, Singh N, Aingh AD. Retinoblastoma: a SEER dataset evaluation for treatment patterns, survival, and second malignant neoplasms. Am J Ophthalmol. 2015;160:953–958. doi:10.1016/j.ajo.2015.07.037 [CrossRef]
- Paulino AC. Trilateral retinoblastoma. Cancer. 1999;86:135–141. doi:10.1002/(SICI)1097-0142(19990701)86:1<135::AID-CNCR19>3.0.CO;2-0 [CrossRef]
- Wong FL, Boice JD Jr, Abramson DH, et al. Cancer incidence after retinoblastoma: radiation dose and sarcoma risk. JAMA. 1997;278:1262–1267. doi:10.1001/jama.1997.03550150066037 [CrossRef]
- Shields CL, Shields JA. Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin Ophthalmol. 2010;21:203–212. doi:10.1097/ICU.0b013e328338676a [CrossRef]
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- Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1973–2012. National Cancer Institute Web site. https://seer.cancer.gov/archive/csr/1975_2012/. Published April 2015. Updated November 18, 2015.
- Broaddus E, Topham A, Singh AD. Incidence of retinoblastoma in the USA: 1975–2004. Br J Ophthalmol. 2009;93:21–23. doi:10.1136/bjo.2008.138750 [CrossRef]
- SEER*Stat Databases: November 2014 Submission: Incidence: SEER 9 Regs Research Data, Nov 2014 Sub (1973–2012) <Katrina/ Rita Population Adjustment>. Rockville, MD: National Cancer Insititute; 2014. https://seer.cancer.gov/data/seerstat/nov2014/. Accessed April 9, 2017.
- Fritz A, Percy C, Jack A, , eds. International Classification of Diseases for Oncology, 3rd ed. Geneva, Switzerland: World Health Organization; 2000.
- Howden LM, Meyer JA. Age and Sex Composition: 2010 Census Briefs. https://www.census.gov/prod/cen2010/briefs/c2010br-03.pdf. Published May 2011. Accessed December 11, 2017.
- Tamboli A, Podgor MJ, Horm JW. The incidence of retinoblastoma in the United States: 1974 through 1985. Arch Ophthalmol. 1990;108:128–132. doi:10.1001/archopht.1990.01070030134045 [CrossRef]
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Descriptive Characteristics of Retinoblastoma Cases in the United States from 1973 to 2012
|Characteristic||No. of Children (%)||No. of Deaths (%)|
| Males||431 (49.0%)||24 (51.1%)|
| Females||448 (51.0%)||23 (48.9%)|
|Age at diagnosis (y)|
| 0 to 1||385 (43.9%)||13 (27.7%)|
| 1 to 2||206 (23.4%)||16 (34.0%)|
| 2 to 3||146 (16.6%)||12 (25.5%)|
| 3 to 9||142 (16.1%)||6 (12.8%)|
| Unilateral||624 (71.0%)||24 (51.1%)|
| Bilateral||255 (29.0%)||23 (48.9%)|
|Decade of diagnosis|
| 1970s||120 (13.6%)||14 (29.8%)|
| 1980s||204 (23.2%)||18 (38.3%)|
| 1990s||253 (28.8%)||8 (17.0%)|
| 2000s||302 (34.4%)||7 (14.9%)|
| White||630 (71.7%)||30 (63.8%)|
| Black||136 (15.5%)||8 (17.2%)|
| Native American||60 (6.8%)||5 (10.5%)|
| Pacific Islander||35 (4.0%)||3 (6.4%)|
| Other||18 (2.0%)||1 (2.1%)|
| Hispanic||94 (10.7%)||7 (14.9%)|
| Non-Hispanic||776 (88.3%)||40 (85.1%)|
| Undetermined||9 (1.0%)||0 (0%)|
| Yes||759 (86.4%)||38 (80.8%)|
| No||88 (10.0%)||1 (2.2%)|
| Undetermined||32 (3.6%)||8 (17.0%)|
Data From Patients Who Died of Retinoblastoma
|Variable||Univariate Cox Regressiona||Multivariate Cox Regressionb|
|HR (95% CI)||P||HR (95% CI)||P|
| Male||1.196 (0.637 to 2.246)||.578||–|
|Age at diagnosis (y)|
| 0 to 1||Reference||Reference|
| 1 to 2||2.004 (0.914 to 4.392)||.082||2.532 (1.135 to 5.678)||.023|
| 2 to 3||2.598 (1.146 to 5.888)||.022||4.244 (1.732 to 9.395)||.002|
| 3 to 9||0.620 (0.175 to 2.196)||.458||1.110 (0.292 to 4.221)||.878|
| Bilateral||2.479 (1.322 to 4.647)||.005||3.779 (1.870 to 7.637)||.001|
|Decade of diagnosis|
| 1980s||0.732 (0.337 to 1.589)||.430||0.837 (0.371 to 1.888)||.669|
| 1990s||0.280 (0.109 to 0.720)||.008||0.263 (0.102 to 0.681)||.006|
| 2000s||0.265 (0.098 to 0.717)||.009||0.253 (0.092 to 0.693)||.007|
| Black||1.722 (0.767 to 3.869)||.188||–|
| Native American||2.813 (0.661 to 9.966)||.161||–|
| Pacific Islander||2.605 (0.986 to 6.880)||.063||–|
| Other||2.283 (0.537 to 9.708)||.264||–|
| Non-Hispanic||1.353 (0.529 to 3.461)||.528||–|
| No||3.792 (0.520 to 27.652)||.189||–|