Radiation Environment and Medicine 2024 Vol.13, No.2 45–51

Regular Article

Risk Assessment of Cataract Development in Radiotherapy for Patientswith Brain Tumors and Head and Neck Cancer
Ryo Saga1*, Haruka Okabe2, Hideki Obara3, Fumio Komai3, Minoru Osanai1,
Masahiko Aoki4 and Yoichiro Hosokawa1
1

Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan2
Department of Radiological Technology, Hirosaki University School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan
3
Division of Radiology, Hirosaki University Hospital, 53 Hon-cho, Hirosaki, Aomori 036-8563, Japan
4
Department of Radiation Oncology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
Received 28 February, 2024; revised 15 May, 2024; accepted 10 June, 2024

The lens is one of the organs at risk (OAR) in radiotherapy for brain tumors and the head andneck cancer. The tolerable dose is low compared to other OARs, and in cases where the tumor isnear the lens, the tolerable dose will be exceeded. In this study, we retrospectively investigatedthe development of cataract after radiotherapy in patients with brain tumors and head and neckcancer. Among 76 patients with brain tumor, maxillary sinus cancer, orbital sarcoma, oral cavity
cancer, buccal mucosal cancer, and nasopharyngeal cancer, we reviewed follow-up records of 43
patients (86 lenses). These patients were treated in Hirosaki University Hospital. The lens dose
was estimated by dose volume histogram calculated using radiotherapy planning system. Amongthe 43 patients (86 lenses) investigated, 5 patients (6 lenses) developed cataracts (6.98%). Of which,four lenses were from patients with maxillary sinus cancer, one with orbital sarcoma, and one withnasopharyngeal cancer. The univariate analysis using Cox proportional hazards regression was
performed to examine the clinical features of cataract development. Sex, age, smoking, drinking
alcohol, and hypertension, which were reported to be associated with the onset of the cataract,
were not significantly correlated in this study. Only lens dose classified according to tolerable
dosage of 1,000 cGy was significantly associated (P = 0.048), with a hazard ratio of 8.830 (95% CI:
1.020–76.440). The cumulative incidence function indicated that the incidence was significantly
higher in the sub-group that exceeded the tolerable dose (P = 0.020). In addition, there was anegative correlation between lens dose and latent period (r = -0.521). The median lens dose was
the highest for orbital sarcoma (1973.2 cGy), followed by maxillary sinus cancer (1425.1 cGy).
Additionally, the median lens dose in brain tumors exceeded the tolerable dose (1243.4 cGy).
In comparison with the 3 dimensional-conformal radiotherapy, the lens dose was lower and nopatients developed cataract in the intensity modulated radiotherapy (IMRT) method. Radiotherapy
for tumors located in close proximity to the lens often results to a high lens dose, with many
instances exceeding the tolerable dose, thereby increasing the risk of developing cataracts.
Conversely, employing the IMRT technique has demonstrated the ability to reduce lens dose andrisk of cataract development.
Key words: lens, cataract, brain tumor, head and neck cancer*Ryo Saga: Department of Radiation Science, Hirosaki University Graduate Schoolof Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan
E-mail: sagar@hirosaki-u.ac.jp
https://doi.org/10.51083/radiatenvironmed.13.2_45
Copyright © 2024 by Hirosaki University. All rights reserved.

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1. Introduction
The lenses are one of organs at risk (OAR) in external
radiotherapy for brain tumor and head and neck cancer.
The tolerable dose of lens ranges from 2–10 Gy1), andis the lowest compared to peripheral OARs. Although
the absorbed dose to the lens is minimized by shielding
with multi-leaf collimator, radiotherapy for tumors thatdeveloped near the lens (e.g., brain tumor and head andneck cancer) tend to exceed the tolerable dose. According
to the International Commission on RadiologicalProtection (ICRP) guidelines, the threshold dose forcataract development (i.e., 1% incidence rate) is 0.5 Gy2).
The absorbed dose to the lens is considerably higher
than this threshold dose in radiotherapy, and developing
cataract is one of the most frequent complications. In
radiotherapy for orbital pseudotumor at 20 Gy (range, 4.8–
40 Gy), the incidence rate of was 10%3), 19.5% for primaryocular adnexal mucosa-associated lymphoid tissue
lymphoma at median dose 37.8 Gy (range, 30.6–45 Gy)4),
and 66.3% for proton beam therapy for uveal melanoma
at the lens dosage of 15–20 Cobalt Gray Equivalent 5).
While there are several reports on the development ofcataract after radiotherapy, there are few reports outsideof ophthalmology. Therefore, additional experience
regarding the development of lens cataract and absorbed
doses in radiotherapy needs to be reported. In this study,
we retrospectively evaluated the incidence of cataract
in patients with brain tumor and head and neck cancer
following radiotherapy, and the dose volume histogram(DVH) was used for dose assessment of the contoured
lenses.
2. Methods
2.1. Patients and retrospective analysis
A total of 76 patients (152 lenses) with brain tumor,
maxillary sinus cancer, orbital sarcoma, oral cavity
cancer, buccal mucosa cancer, or nasopharyngeal cancer
received external radiotherapy between 2011 and 2021
at Hirosaki University Hospital. Among the 76 patients,
24 patients (42 lenses) were unknown the absorbed doseof lens as the lens were not contoured in radiotherapy
planning system (RTPS). The treatment planning system
employed varied depending on the irradiation technique;for three-dimensional conformal radiotherapy (3D-CRT),
we used Monaco by Elekta, and for intensity modulated
radiotherapy (IMRT) and volumetric modulated ark
therapy (VMAT), we used Eclipse by Varian. Amongthe 76 patients, 9 patients (18 lenses) have no follow-up
records. Overall, the demographic and basic information(e.g., age, history of smoking, drinking alcohol,
hypertension) of 43 patients (86 lenses) were collectedby retrospective review of medical records, and theTable 1. Characteristics of the patients. Patient characteristics werereviewed based on medical records.
Characteristic

Number of patients(n = 43)

Sex
Male

27

Female16

brain tumor
maxillary sinus cancer
orbital sarcoma
oral cavity cancer
buccal mucosa cancer
nasopharyngeal cancer
Irradiation technique
3D-CRT
IMRT
VMAT
Prescribed dose for target (cGy)/fraction
3,000/15
5,000/25
5,040/28
6,000/30
6,600/33
7,000/35
Smoking
Yes
No
Drinking
Yes
No
Hypertension
Yes
No

10
14
2
2
6
9

Site

31
11
1
1
1
1
9
23
8
24
19
27
16
31
12

patients were evaluated for cataract development, latent
period of cataract development, irradiation technique, andtreatment regimens. Noted that if a history of cataract
was found in the medical records, the patient was judged
as cataract development. In addition, latent period was
defined the time span between completion of radiotherapy
and cataract development. The lens dose was estimatedusing DVH, with the lens dose represented by the meandose. This study was approved by the institutional review
board of Hirosaki University Graduate School of Medicine
Ethics Committee (approved number: 2023-001).
2.2. Statistical analysis
Univariate analysis was performed using Cox proportional
hazards regression to examine the association between
clinical features and cataract development. The age of thepatients and absorbed dose were classified into sub-groups
using the median value (i.e., 66 years old) and tolerable
dose of lens (i.e., 1,000 cGy), respectively. The cumulative
incidence function (CIF) curves were calculated and theRyo Saga et al. / Radiation Environment and Medicine 2024 Vol.13, No.2 45–51

47

Table 2. Characteristics of the patients who developed cataract. Five patients (six lenses) developed cataract. Note: Case no. 3 and 4 were the same
patient.
Case no.

Characteristic

1

2

3

4

5

6

Sex

Male

Male

Male

Male

FemaleMale

Age (y/o)

51

49

51

51

31

71

maxilalry sinus
6,600/33
3D-CRT
5,966.3

maxilalry sinus
6,600/33
3D-CRT
2,905.2

maxilalry sinus
6,600/33
3D-CRT
7,618.1

orbital3,000/15
3D-CRT
3,073.5

nasopharyngeal
6,600/33
3D-CRT
231

31
No
Yes
Yes

25
Yes
No
No

41
Yes
No
No

47
No
No
No

60
No
No
Yes

Site maxilalry sinus
Prescribed dose (cGy)/fraction
6,600/33
Irradiation technique
3D-CRT
Lens dose (cGy)
4,743.2
Latent period (months)
Smoking
Drinking
Hypertension

35
No
No
No

sub-groups were statistically compared using a Grayʼs
test. Welchʼs t-test was used to compare two groups, andmultiple comparisons were performed using Steel-Dwass
test after Kruskal-Wallis test. All statistical analyses were
performed using Easy R (EZR) version 1.52 (Saitama
Medical Center, Jichi Medical University). A P < 0.05
indicate a statistically significant difference.
3. Results
3.1. Patient characteristics and radiotherapy regimens
We identified 43 patients (86 lenses) who received
radiotherapy for brain tumor and head and neck cancer,
and their medical records were reviewed (Table 1).
The median age was 66 years (range, 17–83 years),
comprising 27 males and 16 females. The patientʼs ages
were distributed with seven under 40, five in their 50s,
twelve in their 60s, eighteen in their 70s, and one in their80s. Among them, 10 patients received radiotherapy
for brain tumor, 14 for maxillary sinus cancer, two for
orbital sarcoma, two for oral cavity cancer, six for buccal
mucosa cancer, and nine for nasopharyngeal cancer.
The radiotherapy regimens for a patient with orbitalsarcoma, maxillary sinus cancer, and brain tumor wasprescribed with a dosage of 3,000 cGy/15, 5,000 cGy/25,
and 5,040 cGy/28 fractions, respectively. The other ninepatients with brain tumor were prescribed with 6,000
cGy/30 fraction. Twenty-three patients including ninewith maxillary sinus cancer (one received IMRT), twowith oral cavity cancer, six with buccal mucosa cancer(one received IMRT), and six with nasopharyngeal cancer(two received IMRT) received 6,600 cGy/33 fraction. The
remaining eight patients, including four with maxillarysinus cancer, one with orbital sarcoma, and three withnasopharyngeal cancer received 7,000 cGy/35 fraction.
These eight patients were prescribed using the IMRT
technique, with one of them receiving VMAT.

3.2 Cataract development after radiotherapy correlatedwith lens doseAmong the 43 patients (86 lenses) included in theanalysis, five (six lenses) developed cataract (6.98%). This
comprises three patients (four lenses) with maxillarysinus cancer, one patient with ocular sarcoma, and one
patient with nasopharyngeal cancer. All patients whodeveloped cataract received 3D-CRT. The characteristicsof these patients were summarized in Table 2. The
median latent period was 38 months (range, 25 – 60
months), median age of 51 years (range 31 to 71 years),and median lens dose of 3908.4 cGy (range, 231.0 – 7,618.1
cGy). Only for patient (one lens) with nasopharyngeal
cancer has a lens dose below the tolerable dose (i.e., 231.0
cGy). Meanwhile, the lens dose in four patients (fivelenses) with maxillary sinus cancer and orbital sarcoma
was approximately equivalent to the prescribed dose to
the target.
To investigate the association between the patientcharacteristics and development of cataracts, univariate
analysis was performed using a Cox proportional
hazards regression model. Only lens dose was found tobe associated with the hazard ratio (HR) [8.830 (95% CI
1.020–76.44, P = 0.048, Table 3)]. These patients wereclassified based on a tolerable dosage of 1,000 cGy. In
addition, the CIF indicated that cataracts are significantly
induced in a sub-group, which exceeded the tolerable
dose (Fig. 1, P = 0.020), and the latent period was
negatively correlated with lens dose (Fig. 2, r = -0.512).
The lens dose for each disease site (Fig. 3) indicated thatthe lens dose of brain tumor (15 lenses, 75%), maxillarysinus cancer (23 lenses, 82%) and orbital sarcoma (2lenses, 50%) exceeded the tolerable dosage. Meanwhile,for prescribe targets located in the oral cavity site, thedose was maintained below the tolerable dose. When
comparing the lens dose by irradiation technique (Fig.
4), the median dose for IMRT/VMAT was 648.1 cGy

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Table 3. Univariate analysis of cataract incidence. Univariate analysis was performed
using cox hazard proportional regression model.
Parameters

HR (95% CI)

p-valueSex
Age > 66 y/o
Smoking
Drinking
Hypertension
Lens dose > 10 Gy

0.330 (0.038 to 2.835)
0.305 (0.036 to 2.622)
0.455 (0.083 to 2.503)
0.201 (0.023 to 1.727)
0.848 (0.153 to 4.712)
8.830 (1.020 to 76.440)

0.312
0.280
0.365
0.144
0.851
0.048

Fig. 1. CIF curves of cataract incidence. Patients were divided into
sub-groups based on excess or not excess tolerable dose of 1,000 cGy.
The black solid line indicates the > 1,000 cGy sub-group and the graysolid line indicates the < 1,000 cGy sub-group.

Fig. 2. The correlation between the latent period and lens dose.
The equation shows approximate formula, r is Pearsonʼs correlation
coefficient, and R2 is coefficient of determination.

Fig. 3. Lens dose of each disease site. The dot line indicatestolerable dosage of 1,000 cGy and horizontal lines indicate the mediandose. The asterisks represent significant differences of *P < 0.05,***P < 0.001, and ****P < 0.0001 between the two groups. P-value
was indicated by Steel-Dwass test.

(range, 157.2–4,127.5 cGy), which is lower than that for
3D-CRT (median dose 1,032.5 cGy; range, 6.6–7,618.1 cGy,
Fig. 4A). Meanwhile, 32 lenses (52%) and seven lenses(29%) exceeded the tolerable dose in 3D-CRT and IMRT/
VMAT, respectively. Lens doses were also comparedfor maxillary sinus and nasopharyngeal cancers, whichwere statistically comparable (Fig. 4B). While there was asignificant dose reduction in maxillary sinus cancer, it wasincreased in nasopharyngeal cancer in IMRT technique.
The maximum lens dose prescribed for nasopharyngeal
cancer with IMRT was 666.5 cGy, which was not excess
the tolerable dose. These results indicate that the patientswith brain tumor, maxillary sinus cancer and ocularsarcoma were at increased risk of developing cataracts.
The implementation of IMRT/VMAT may potentiallyreduce risk.
4. Discussion
We retrospectively investigated the lens cataract

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Fig. 4. Lens dose comparison by irradiation technique. Lens dose of (A) all disease sites and (B) maxillary sinus andnasopharyngeal cancer are shown. The gray dot line indicates tolerable dosage of 1,000 cGy and horizontal solid lines indicate
the median dose. The asterisks represent significant differences of **P < 0.01 between two groups. P-value was indicated by
Welchʼs t-test.

developments after radiotherapy for brain tumors andhead and neck cancer. The incidence rate of cataract
development was 6.98%, and is association only with lensdose. Regarding irradiation technique, all patients whodeveloped cataract were prescribed using 3D-CRT, andhad higher lens dose than IMRT/VMAT (Fig. 4). IMRT
can achieve a high probability of local control without
excessive risk for acute or late adverse events6). In
head and neck cancer, IMRT technique is employed to
avoid osteoradionecrosis, which is a severe side effect7).
In addition, IMRT for ocular adnexal lymphoma canreduce long-term late grade 2 toxicities (i.e., dry eye andcataract) compared with conventional procedures8). In thisretrospective study, cataract was not observed in patientswith head and neck cancer who were prescribed using
IMRT method. This suggests that IMRT/VMAT have an
advantage in reducing the risk of developing cataracts.
Radiation cataract is a tissue reaction and has athreshold dose. Some epidemiological studies haveshown HR or odds ratio (OR) per Gy. Little et al.
reported the risk of cataract incidence in a cohort of
US radiologic technologists, and exhibited an excess
HR/mGy of 0.69 ×10-3 (95% CI 0.27 ×10-3 to 1.16 ×10-3)9).
Allodji et al. investigated the risk of cataract afterradiotherapy for non-retinoblastoma solid cancer inchildhood, and the HR increased by 39-fold (95% CI, 12.0to 127.9-fold) at 10 Gy exposure to the eyes compared tothat in the no radiation exposure group10). In our results,
the HR was 8.830 (95% CI 1.020–76.44), and tended to
be lower than that in previous studies. This may be
attributed to the short follow-up period in this study(median follow-up of 39 months; range, 1–122 months)
compared with that in previous studies. The time ofdevelopment of radiation-induced cataract ranges from
6 months to several years, and typically diagnosed byophthalmologist within 2–3 years11). The cataract in thepresent study was determined based on the follow-up
medical records, and thus it cannot be detected unless thepatient had subjective symptoms such as obvious opacity.
In addition, markedly long-term follow-up is difficult
owing to the censoring depending on the prognosis due
to clinical stage of disease. Therefore, the incidence ratepresented in this study may be underestimated.
Moreover, we investigated the clinical features fordeveloping cataracts after radiotherapy and only lens dose
was associated with developing cataracts in this study.
Zetterberg et al. indicated that women are more likely tohave opaque lenses12). Meanwhile, Aina et al. highlighted
the correlation between estrogen and the developmentof cataracts, and that the incidence of cataract increases
af ter estrogen is decreased during menopause 13).
In terms of age, older people gradually develop more
severe and frequent cataracts14). Several reports indicatedthat smoking increases the risk of cataracts by 2–3
times15 -17). Additionally, drinking alcohol increases therisk of nuclear, cortical, and posterior subcapsularcataracts and pose a toxic ef fect on the lens 18, 19).
Regarding hypertension, early clinical studies of cataract
formation in diabetes mellitus indicated a high prevalenceof arterial hypertension 20). Moreover, hypertension,
which is associated with diabetes, induces cataract
development21, 22). In this study, we performed univariate
analysis including these clinical features, and foundthat only lens dose associated to cataract development(Table 2). This may be due to the small number of caseswith a history of cataract.

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This study has certain limitation, including the factthat we cannot rule out age-related cataracts. Multivariate
analysis can be used to examine the relationship between
age and cataract development, but this was not possible
due to the small number of developments. Radiationinduced cataract can be differentiated from age-related
cataract by the site of lens (i.e., posterior subcapsular
opacification)23, 24). However, there were no records ofthe cataract site of lenses. The prevalence of age-related
cataract among Japanese in their 50s is 37–54%, whichis considerably higher than the incidence rate reported
in this study (6.98%). Additionally, more than 70% of thepatients surveyed were over 60 years old (31 patients).
Therefore, it should be noted that there were too few
age-related cataracts in the patients investigated in thisstudy. Based on the lens dose dependence of latent
period (r = -0.512) and incidence rate (P < 0.05) (Figs. 1
and 2), radiation-induced cataracts are highly possible.
Meanwhile, the excess risk cannot be assessed.

5. Conclusion
In this study, we retrospectively investigated the cataract
incidence after radiotherapy for brain tumors and headand neck cancer. The incidence rate was 6.98%, which
is lower than that in previous studies that investigated
the adverse events after radiotherapy. This could be
attributed to the short follow-up period. The HR for thelens surpassing tolerable dose was 8.830, indicating an
increased risk of cataracts. The tolerable dose may be
exceeded for brain tumors, maxillary sinus cancer, andorbital sarcoma, particularly when the onsets are in close
proximity to the lens. Treating these targets requires anacceptance of risk, while opting for IMRT/VMAT can
reduce the dose of OARs and risk of developing cataract.
Conflict of Interest
The authors declare that they have no conflict of interest.

Data availability
The datasets generated and/or analysed during thecurrent study are available from the corresponding
author on reasonable request.
Ethics approval and consent to participate
The human data was recruited with the ethics approval(approval number: 2023-001) by Hirosaki University
Graduate School of Medicine Ethics Committee. Informed
consent was obtained from all subjects.
Consent to publish
All authors have consented for the publication of themanuscript.
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Author Contributions
R.S., M.O., M.A. and Y.H. designed the study, R.S.,
H.Okabe., H.Obara, F.K. performed retrospective analysis,
R.S. and H.Okabe performed statistical analysis. M.A.
diagnosed patients and gathered patient data. R.S.
and H.Okabe wrote the manuscript, M.O., M.A. and
Y.H. supervised the study. All authors reviewed themanuscript.
FundingNone.

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