4 I DISCUSSION
Our study describes the incidence of 4 ocular complications - cataract,
dry eyes, retinopathy, and glaucoma, in early follow-up after cranial
proton radiation. It also provides a snapshot of visual function for
childhood brain tumor survivors after completion of treatment that
includes proton radiation. For patients who receive whole brain
radiation, as a part of CSI, the incidence of bilateral cataracts is
significant, even with limited follow-up. Nearly two-thirds of patients
in our cohort who received this volume of radiation, developed
cataracts. In addition, nearly a quarter of these patients developed dry
eyes during or shortly after CSI. Multivariable analysis identified CSI
radiation volume as a significant risk factor for the development of
cataract and ocular complications overall (cataract and dry eyes). In
contrast, patients who did not receive whole-brain radiation, did not
have ocular complications that could be attributed to radiation. Only 1
patient who received IFRT for craniopharyngioma, developed retinal
scarring and bilateral cataracts, but had to be excluded due to having
received both photon and proton radiation. No other patient was found to
have retinal scarring, and none had glaucoma.
Infratentorial tumor location and the use of radiosensitizer
chemotherapy were also found to be significant risk factors for the
development of cataract and ocular complications overall. However, all
patients with these 2 variables, who developed cataract or dry eyes,
also received CSI radiation volume, making them likely confounding
factors, although this could not be tested statistically. For whole
brain radiation (CSI), the proton beam enters through the posterior
aspect of the brain and ends at the eyes, to ensure adequate coverage of
the planning target volume. Hence the lenses of the eyes receive some
radiation. The relative biological effectiveness (RBE) for protons is
postulated to be 1.1 compared to photons. However, depending on the area
relative to the Bragg peak, it is possible that the RBE might be higher,
with an increased linear energy transfer (LET), and potentially higher
doses to tissues in the vicinity of the target
volume.20 Our finding of significantly increased risk
of cataracts with whole brain radiation, is consistent with the
literature. A study of long-term survivors in the Childhood Cancer
Survivor Study (CCSS), reported an increased risk for cataracts with
radiation dose to the lens greater than, as little as 200 cGy, with a
relative risk of 3.2, compared to their siblings.9Steroid treatment has been described to be significantly associated with
an increased risk for cataracts in leukemia survivors who received TBI,
while other literature has shown a lack of significant risk in the
absence of CNS irradiation.11,21 Busulfan in the
setting of conditioning for bone marrow transplant, with TBI, has also
been reported to increase the risk for cataracts.14,22None of the patients in our cohort received Busulfan. However, all
patients in our cohort who received CSI for embryonal tumors, also
received dexamethasone as an anti-emetic prior to chemotherapy, making
it a confounding factor.
At last follow-up, after completion of all treatment, nearly three in
four patients in our cohort had a visual acuity in their best eye,
better than 20/60. Only 3 patients had VA in both eyes, worse than
20/100. In the Childhood Cancer Survivor Study (CCSS), any radiation
dose to the posterior fossa, more than 3000 cGy to the temporal lobe and
more than 500 cGy to the lenses, were associated with increased risk of
legal blindness at a median of 1 year from cancer
diagnosis.9 However, the patients in the CCSS cohort
received radiation prior to the advent of more targeted techniques like
intensity modulated radiation therapy (IMRT), and the use of protons.
That study also had a much larger number of patients, with more
heterogeneous diagnoses and longer follow-up.
Our study had several limitations. Our study was retrospective and
relied on data recorded in medical records, with missing or limited
details. All patients received radiation and oncology care at a single
institution, limiting the generalizability of our findings. Most
patients in our cohort, did not have ophthalmology exam data from prior
to radiation. Most patients’ ocular complications were detected at their
first formal eye exam post-radiation. Hence the true time to develop
these complications could not be accurately determined, and they were
presumed to have occurred after radiation. While our study provides a
glimpse of ocular function in childhood brain tumor survivors after
treatment, the absence of pre-treatment visual acuity data for most
patients precluded the analysis of the change of visual function with
treatment. Very few patients had eye exam data during or shortly after
radiation, limiting the analysis of the true incidence of dry eyes, as
an acute adverse effect of radiation. Parsons et al. reported a
significant increase in the risk of severe dry eyes at ocular radiation
doses higher than 40 Gy.23,24 In the CCSS study, the
median time to the development of dry eyes was 7.2 years, with a
cumulative incidence of over 5% for survivors of primary CNS
malignancies.9 The long-term incidence of dry eyes
after protons could not be elucidated in our study due to the limited
duration of follow-up.
Nearly half the patients in our cohort of consecutive patients who
received protons for brain tumors, did not have ophthalmology data
available, which creates the potential for inclusion bias. Our
statistical analysis, however, suggests the excluded patients were
similar to study patients in gender, age at radiation, tumor location
and volume of radiation. The ophthalmology follow-up for our cohort was
relatively short, and hence our results do not provide insight into the
incidence of more delayed ocular complications after radiation. In the
CCSS cohort, patients who received more than 500 cGy to the lens, the
incidence of cataracts continued to increase up to 20 years after
diagnosis.9 The lack of long-term follow-up also
limited our analysis of the functional outcomes for patients who
developed ocular complications.
Our study findings highlight the need for larger prospective,
multi-institutional pediatric CNS tumor trials, to include regular,
formal ophthalmology exams prior to and after radiation, with longer
follow-up, to determine the true incidence of these complications and
their impact on visual function for these children. This would help
inform ophthalmology screening guidelines for these patients, and also
radiation planning to mitigate the risk of these adverse effects when
possible.