Descriptive characteristics of the retinoblastoma survivors are shown in . The median age of the combined cohort at the end of follow-up was 30 years (range = 1–79 years). At the end of follow-up, 720 (65.9%) hereditary retinoblastoma survivors and 660 (86.6%) nonhereditary retinoblastoma survivors were alive, 346 (31.7%) hereditary retinoblastoma survivors and 77 (10.1%) nonhereditary retinoblastoma survivors were deceased, and 26 (2.4%) hereditary retinoblastoma survivors and 25 (3.3%) nonhereditary retinoblastoma survivors were lost to follow-up (). The median duration of follow-up since retinoblastoma diagnosis was 28.5 years (range = 1–69 years) for hereditary survivors and 29.6 years (range = 1–77 years) for nonhereditary retinoblastoma survivors. Radiotherapy—either alone or in combination with chemotherapy—was used to treat 87.5% of hereditary retinoblastoma survivors and 17.7% of nonhereditary retinoblastoma survivors (). The majority (75.2%) of the nonhereditary retinoblastoma survivors were treated with surgery only. The cause of death could not be determined for 16 deceased survivors, all of whom were from cohort 1. Among the 407 retinoblastoma survivors whose cause of death was known, 186 (45.7%) died from retinoblastoma.
Selected characteristics of 1-year survivors of retinoblastoma*
In cohort 1, there were 393 deaths from a known cause (322 among hereditary retinoblastoma survivors and 71 among nonhereditary retinoblastoma survivors). During the 13 years since the last mortality report for this cohort (6
), there were 70 additional deaths due to subsequent malignant neoplasms in cohort 1, of which 33 (47.1%) were cancers of the bone and connective tissue. We have previously reported five incident cases of pineoblastoma in our earlier incidence study of cohort 1 survivors (9
). However, we noted that the cause of death of these pineoblastoma patients was attributable to other causes, including three deaths that were attributed to retinoblastoma, one to malignant brain tumor, and one to an external cause. In cohort 2, there were 14 deaths from a known cause (11 among hereditary retinoblastoma survivors and three among nonhereditary retinoblastoma survivors), including three deaths from bone cancers, eight from retinoblastoma, one from pineoblastoma, one from sequelae of chronic liver disease, and one from non–drug-induced interstitial lung disease. In the combined cohort, 151 deaths due to subsequent malignant neoplasms occurred among 1092 hereditary retinoblastoma survivors (SMR = 35, 95% CI = 30 to 41) compared with 12 such deaths among 762 nonhereditary retinoblastoma survivors (SMR = 2.5, 95% CI = 1.3 to 4.4) (). In hereditary retinoblastoma survivors, the most common subsequent malignant neoplasms included sarcomas of the bone and connective tissue, melanoma, and cancers of the brain and other parts of the nervous system (including four cancers of the sympathetic nervous system, one of which was an esthesioneuroblastoma in the ethmoid sinus and three were unspecified neuroblastoma). Among the hereditary retinoblastoma survivors, substantial elevations in SMRs (ie, SMRs > 10) were also observed for cancers of the lung, corpus uteri, nasal cavities, and buccal cavity and pharynx (due to nasopharyngeal cancer in two cases). Among the nonhereditary retinoblastoma survivors, statistically significantly elevated mortality from subsequent malignant neoplasms was found for deaths due to cancers of the breast (n = 3 deaths; SMR = 5.7, 95% CI = 1.2 to 17). In addition, among the nonhereditary retinoblastoma survivors, the SMR for subsequent malignant neoplasms was statistically significantly elevated for those who received radiotherapy (n = 6 deaths; SMR = 7.3, 95% CI = 2.7 to 15.8) but not for those who did not or whose radiotherapy status was uncertain (n = 6 deaths; SMR = 1.5, 95% CI = 0.6 to 3.3).
Causes of death other than retinoblastoma in 1-year survivors of retinoblastoma, by hereditary status*
We found an apparent excess mortality from benign tumors in hereditary retinoblastoma survivors (n = 9; SMR = 72, 95% CI = 33 to 137); these deaths included one from spinal meningioma (ICD-8 225.4), one from benign neoplasm of the pituitary gland and caniopharyngeal duct (ICD-8 226.2), and seven from unspecified brain tumors (ICD-8 238.1).
Compared with the general population, neither hereditary nor nonhereditary retinoblastoma survivors experienced elevated mortality from non-neoplastic causes (). The only exception was an excess mortality from mental disorders among three nonhereditary retinoblastoma survivors (SMR = 9.7, 95% CI = 2.0 to 28), including one death from alcohol addiction and two from drug dependence ().
Among hereditary retinoblastoma survivors, mortality from subsequent malignant neoplasms was statistically significantly elevated compared with that in the general population in all time intervals investigated (). However, among hereditary retinoblastoma survivors, compared with those younger than 25 years, those aged 25 years or older had a statistically significantly lower SMR for subsequent malignant neoplasms but a higher absolute excess risk of death (). The extended follow-up revealed that excess mortality from sarcomas, melanoma, and cancers of the brain and other parts of the nervous system among the hereditary retinoblastoma survivors extended beyond 40 years after retinoblastoma diagnosis. Among the hereditary retinoblastoma survivors, cancers of the bone and connective tissue accounted for 76.5% of all deaths from subsequent malignant neoplasms before an attained age of 25 years (48 deaths from bone cancer, 14 deaths from connective tissue cancer), whereas they accounted for 35.7% of all deaths from subsequent malignant neoplasms at age 25 years or older (eight deaths from bone, 17 deaths from connective tissue cancer). At age 25 years or older, excess mortality from cancers of the following sites began to emerge: lung (n = 7 deaths; SMR = 11, 95% CI = 4.3 to 22), corpus uteri (n = 5 deaths, including three from leiomyosarcoma, one from carcinoma, and one from mixed Müllerian tumor; SMR = 162, 95% CI = 52 to 378), and digestive organs and peritoneum (n = 3 deaths, including one from colon cancer and two from retroperitoneal tissue cancer; SMR = 5.2, 95% CI = 1.04 to 15). The majority of deaths due to melanoma occurred at age 25 years or older (n = 10 deaths; SMR = 75, 95% CI = 36 to 139), although the SMR was also elevated among those younger than 25 years at death (n = 3; SMR = 212, 95% CI = 43 to 618).
Mortality from subsequent malignant neoplasms in 1-year survivors of retinoblastoma, by selected characteristics*
Among hereditary retinoblastoma survivors, those who were irradiated had an SMR for all malignant neoplasms other than retinoblastoma that was 3.4 times that of nonirradiated survivors (). Among the hereditary retinoblastoma survivors who died of a subsequent malignant neoplasm, the median age at death among the 140 irradiated survivors was less (20.5 years, range = 1–67 years) than the median age at death for the 11 nonirradiated survivors (44 years, range = 10–64 years). With the exception of lung cancer, SMRs for specific sites were consistently higher among hereditary retinoblastoma survivors who were irradiated than among those who were not (). The highest SMRs (ie, SMR > 100) were observed for cancers in heavily irradiated organs (≥1 Gy) near or in the radiation treatment field, with the exception of cancer of the corpus uteri, a lightly irradiated organ (<0.4 Gy).
Mortality from subsequent malignant neoplasms in 1-year survivors of hereditary retinoblastoma, by radiotherapy status*
Among irradiated hereditary retinoblastoma survivors, those who were aged 12 months or younger at irradiation were 2.2 times more likely to die of subsequent malignant neoplasms than those who were older than 12 months at irradiation (mean = 23.15 months, range = 12.01–102 months) (SMR = 59 [95% CI = 48 to 73] vs 27 [95% CI = 20 to 35]; P
< .001). The absolute excess risk for subsequent malignant neoplasm mortality was 1.3 times higher among survivors irradiated at age 12 months or younger than among those older than 12 months at irradiation (62.9 per 10
000 person-years vs 47.5 per 10
Among survivors with hereditary retinoblastoma who were irradiated, there was no statistically significant difference by sex in the SMRs for all subsequent malignant neoplasms combined (). An analysis of mortality by years since retinoblastoma diagnosis revealed that females generally had higher SMRs and absolute excess risks from all subsequent malignant neoplasms combined than males up to 39 years after retinoblastoma diagnosis. At 40 years or more of follow-up, both the SMR and the absolute excess risk for subsequent malignant neoplasms were higher in males than in females, but the differences were not statistically significant. For all latency intervals combined, females had statistically significantly higher SMRs compared with males for cancers of certain heavily irradiated sites such as the brain and other parts of the nervous system and the buccal cavity and pharynx (). In addition, females had higher SMRs than males for melanoma (n = 7, SMR = 158 [95% CI = 63 to 325] vs n = 4, SMR = 55 [95% CI = 15 to 140]; P = .07) and for cancer of the nasal cavities (n = 4, SMR = 2012 [95% CI = 542 to 5153] vs n = 1, SMR = 322 [95% CI = 4.2 to 1790]; P = .07), but those differences were not statistically significant.
Mortality from subsequent malignant neoplasms following radiotherapy for hereditary retinoblastoma, by sex*
Radiotherapy for retinoblastoma was associated with increased subsequent malignant neoplasm mortality for both hereditary and nonhereditary retinoblastoma survivors (). The lower relative rate of death associated with radiation among hereditary survivors (RR = 2.46, 95% CI = 1.39 to 4.84) than among nonhereditary survivors (RR = 7.19, 95% CI = 2.21 to 23.37) may reflect a higher background rate for subsequent malignant neoplasms among hereditary survivors due to their genetic susceptibility to subsequent malignant neoplasms (5
). Among hereditary retinoblastoma survivors, other statistically significant risk factors for subsequent malignant neoplasm mortality included female sex, retinoblastoma diagnosis before 1960, and longer latency since retinoblastoma diagnosis (). A retinoblastoma diagnosis at age 12 months or younger marginally increased the risk of subsequent malignant neoplasm mortality but not statistically significantly ().
Multivariable Poisson regression model of relative rate of mortality from subsequent malignant neoplasms in 1-year survivors of retinoblastoma, by hereditary status*
To evaluate the interaction between hereditary status and treatment with radiotherapy, a multivariable Poisson regression model was fitted for hereditary and nonhereditary survivors combined. With nonirradiated nonhereditary retinoblastoma survivors as the referent group, the relative rates of mortality from subsequent malignant neoplasms were 7.12 (95% CI = 2.70 to 20.7), 7.20 (95% CI = 2.25 to 23.0), and 17.9 (95% CI = 8.55 to 45.8) for nonirradiated hereditary retinoblastoma survivors, irradiated nonhereditary retinoblastoma survivors, and irradiated hereditary retinoblastoma survivors, respectively. However, the interaction term did not reach statistical significance (P = .12, likelihood ratio test).
The cumulative mortality from subsequent malignant neoplasms at 50 years after retinoblastoma diagnosis after adjusting for competing risks of death from other causes was 25.5% (95% CI = 20.8% to 30.2%) for hereditary retinoblastoma survivors and 1.0% (95% CI = 0.2% to 1.8%) for nonhereditary retinoblastoma survivors (). Among hereditary retinoblastoma survivors, the cumulative mortality from subsequent malignant neoplasms at 50 years after retinoblastoma diagnosis was 26.8% (95% CI = 21.6% to 32.0%) for those who received radiotherapy and 17.2% (95% CI = 5.4% to 28.9%) for those who did not ().
Figure 1 Cumulative mortality due to SMNs following diagnosis of retinoblastoma. A) Cumulative mortality by hereditary status. B) Cumulative mortality among hereditary retinoblastoma survivors by radiotherapy status. SMN = subsequent malignant neoplasm; CI = confidence (more ...)