Previous studies have investigated the prevalence of ocular complications in childhood cancer survivors, often targeting specific disease populations (18
). The current study adds new information by providing risk estimates for the occurrence of eye-related late effects 5 or more years post-diagnosis, with follow-up spanning up to 25 years. The availability of detailed treatment information, including radiation dosimetry to the eye and optic nerve, allowed for investigation of treatment-related risk factors, which can directly inform guideline-based recommendations for long-term follow-up.
The large size, prolonged follow-up period, and diverse diagnosis and treatment characteristics of the CCSS cohort provide a unique opportunity to characterize and quantify the risk of ocular late effects. With the large number of survivors in the cohort it was necessary to rely upon self-reported ocular outcomes. While well-defined ocular outcomes were selected for inclusion in the questionnaire, and self-reported data from survivors were compared to self-reported data from the sibling cohort, it is important to acknowledge that the potential exists for misclassification (I.e., either under- or over-reporting) of outcomes.
The lens is the most sensitive structure of the eye to the effects of ionizing radiation (21
). Early studies in adults found that a single dose of 200 cGy or multiple, fractionated doses of radiation at a minimum total dose of 400 cGy could lead to cataract formation (10
). We found that even low doses of radiation to the eye resulted in an increased risk of cataract formation, which increased with increasing dose. Previous reports have found that latency period and severity of cataracts after total body irradiation is also influenced by other factors, such as steroid treatment for graft versus host disease (GVHD) (18
). The mechanism triggering the formation of posterior subcapsular cataracts due to chronic high doses glucocorticoid use is controversial (24
). One opinion is the oxidation of lens proteins and changes to lens hydration by steroids will induce cataract formation. Other theories include glucocorticoid receptor activation leading to changes in transcription of specific genes, such as RGC32 protein, which has been reported to induce cellular proliferation (24
). While our study found that prednisone was associated with cataract formation, we found no increased risk of cataracts in survivors treated with dexamethasone, possibly due to the small number of survivors in the CCSS cohort exposed to dexamethasone.
A known complication of radiation to the orbit is severe dry eyes, also known as keratoconjunctivitis sicca, with symptoms increasing when the dose to the eye is > 4000 cGy (26
). Radiation may damage the lacrimal apparatus through various mechanisms, including scarring of the canaliculi and puncta and failure of the lacrimal pump due to decreased eyelid mobility (10
). This complication was observed in our survivors with as little as 500 cGy radiation to the eye. Other factors within CCSS survivors could also account the increased risk of severe dry eyes. For example, 6.8% of CCSS survivors who reported late onset dry eyes had received total body irradiation, presumably as part of a preparative regimen for a bone marrow transplant. This subset would be at risk for the development of chronic GVHD, which frequently affects the eye and manifests as keratoconjunctivitis sicca (22
). Specific information on type of transplant was not collected for the original CCSS cohort, but will be available for the CCSS cohort expansion that is currently underway and may provide more insight into the risk of ocular complications after transplant.
Our analysis identified two associations that require further investigation. The first is the reported late onset of diplopia. Double vision may be secondary to ocular and brain conditions, including cataracts, retinal detachment, cranial nerve palsies, astigmatism, or uncorrected refractory errors (29
). We found a modest correlation between diplopia and other reported ocular conditions, with 6% of survivors with cataracts also reporting double vision. Second, is the risk of reported late-onset legal blindness. A small percentage of survivors with late onset blindness also reported cataracts, which may have contributed to vision loss in 22 out of 107 survivors. In addition, 20 survivors who reported a recurrence of their primary CNS malignancy or developed a second malignant neoplasm located in the CNS reported vision loss occurring 5 or more years after initial diagnosis. The underlying etiology of the reported blindness however, is not clear.
Glucocorticoids appear to have a protective effect against development of some ocular conditions, such as legal blindness or diplopia. Other studies have noted the beneficial anti-inflammatory effects of steroids with respect to some eye-related conditions such as keratitis and macular degeneration (30
). This finding may be reflective of the underlying cancer diagnosis, and should be pursued in future research endeavors.
We found no increase in risk of glaucoma among survivors treated with glucocorticoid therapy. Some reports suggest an increased risk of open angle glaucoma after steroid use due to alterations in the trabecular meshwork, resulting in impaired aqueous outflow (32
). Other studies have found that increased intraocular pressure after prolonged oral glucocorticoid therapy is rare (22
). It is possible we may have underestimated the true incidence of glaucoma in survivors, as it is often an asymptomatic condition, difficult to diagnose unless routine eye exams include measuring intraocular pressure. Additional follow-up may uncover increased risk of glaucoma in childhood cancer survivors treated with steroid therapy
In summary, survivors of childhood cancer are at increased risk for ocular late effects, related to both glucocorticoid and radiationx exposure. This analysis demonstrates that self-reported eye-related complications continue to manifest more than 5 years after diagnosis. While some of these effects have a minor impact on survivors’ quality of life, others, such as blindness and cataracts, may have significant consequences. Continued medical follow-up of survivors is essential for early detection to minimize the effects of ocular complications, and to optimizing survivors’ quality of life.