Beyond tumor control: A protocol for multidimensional assessment of long-term effects of intensity-modulated radiotherapy on vision, patient well-being, and morbidity in head and neck cancer

Head and neck cancer (HNC) encompasses a group of neoplasms that affect the paranasal sinuses, nasal and oral cavities, pharynx, and larynx [1].  Although HNC accounts for only 4% of all cancer cases, its impact on the quality of life is disproportionately severe compared to malignancies in other regions [1]. The incidence and prevalence of HNC vary across continents, with the highest rates reported in Asia and northern Europe [2].

In Ghana, however, there is a lack of comprehensive registry data on HNC cases nationwide. Anecdotal evidence from the outpatient department records at the Ear, Nose, and Throat (ENT) department of the Korle-Bu Teaching Hospital (KBTH), the country’s largest teaching hospital, indicates annual cases of approximately 50 laryngeal cancers, 60 sinonasal tumors, 30 nasopharyngeal cancers, and 10 oropharyngeal cancers. Also, at the outpatient department records of the National Radiotherapy Oncology and Nuclear Medicine Centre (NRONMC), KBTH, the total number of new head and neck cancer cases in 2024 was 292, 11.1% of the total number of patients seen at the Centre that year.

Advancements in radiotherapy imaging techniques, particularly intensity-modulated radiotherapy (IMRT), have proven highly effective in minimizing normal tissue toxicity compared to conventional cancer management methods [3]. IMRT improves patient survival and reduces recurrence risks by targeting tumors with high radiation doses while sparing nearby healthy tissues [4,5]. Despite its benefits, IMRT may still lead to some degree of deterioration in adjacent tissues, as the globe and lacrimal system can be exposed to radiation doses exceeding normal tissue tolerance limits (30 Gy) [6,7]. Studies on the late effects of IMRT on eyes and periorbital tissues in HNC patients reveal that 26–62% experience complications such as dry eye syndrome, corneal issues, cataracts, glaucoma, retinal nerve fiber layer thinning, and decreased visual acuity, all significantly impairing their quality of life (QOL) [8,9].

In Ghana and sub-Saharan Africa, prospective research on radiation-induced ocular complications remains scarce due to variability in treatment protocols, radiation doses, fractionation schedules, and follow-up durations [10,11]. Beyond tumor control, this study advocates for the integration of ocular assessments during follow-up care for HNC patients, enabling early detection, timely intervention and improved quality of life. This study therefore aims to determine the visual outcomes and visual-related quality of life and late complications in patients with HNC treated with IMRT at the KBTH.

Methodology

Study design

This is a cohort study of adults ≥18 years with HNC scheduled to be treated with IMRT at the NRONMC of the KBTH.

Study sites

The study will be conducted at two departments within the KBTH in Ghana: The Lions International Eye Center (LIEC) and the National Radiotherapy, Oncology, and Nuclear Medicine Center (NRONMC).

Target population

Adult patients with HNC aged 18 years and above to be treated with IMRT at the radiotherapy department of the KBTH.

Inclusion criteria

Adult participants ≥18 years with HNC to be treated with IMRT will be included.

Exclusion criteria

Participants with chronic ocular surface disease e.g. allergic conjunctivitis, pterygium and other ocular complications such as cataract, glaucoma, dry eye disease, etc. will be excluded. Participants on short term (< 3 months) topical medications and those with previous ocular surface surgery will also be excluded. 

Primary outcome variables

Primary outcome variables in this study includes;

1. Vision-related acute and late complications such as dry eye disease assessed by the ocular surface disease index (OSDI), cataract, optic neuropathies and retinopathies, and visual acuity decline, among others at baseline, 3, 6 and 12 months post-IMRT [6,7].
2. Health and vision-related quality of life outcomes measured via the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Head and Neck 35 (EORTC QLQ-C35) and Vision Function-20 Quality of Life Questionnaire at baseline, 3, 6 and 12 months post-IMRT.  

Sample size

For this cohort study, the formula below was used in calculating the sample size [12]:

N = 2[Zα+ Zβ] [Zα+ Zβ][SD]^2 / [E][E]. Zβ = Represents the desired power (typically 0.84 for 80% power). Zα = Represents the desired level of statistical significance (typically 1.96). SD is the Standard deviation of the mean score for 6-months post-irradiation ocular surface disease index (OSDI) from a previous study = 4.3 [13]. E is the effect size (difference between mean pre- and post-6-months irradiation OSDI) = 8.6-3.1 = 5.5. Substituting the variables into the above equation and accounting for 15% loss to follow-up will yield; N = 60.6. Therefore, a minimum of 61 patients with HNC is required for this study.

Sampling technique

A consecutive sampling method will be utilized for this study. All consecutive patients diagnosed with HNC and scheduled for IMRT at the NRONMC of the KBTH will be eligible for selection. The Principal Investigator will work in collaboration with a designated Resident at the HNC Clinic to recruit participants who meet the inclusion criteria during each clinic session. The study objectives will be thoroughly explained to all potential participants, and written informed consent will be obtained before enrollment. Recruited participants will be guided by a Research Assistant from the NRONMC to the Eye Center, where ophthalmic and QOL assessments will be conducted. These assessments will take place at three specific intervals: prior to radiation therapy, six months post-treatment, and one-year post-treatment.

Study procedure

Selected participants who qualify to be part of the study will be contacted and informed consent will be obtained from them. They will be informed of the potential for minimum risks such as mild eye irritation or transient blurring of vision lasting a few minutes following the use of eye drops. These effects are expected to be self-limiting and will not require treatment. They will also be assured that the study will not be experimental and that their participation would be voluntary.

After consenting, participant’s demographic characteristics and detailed clinical history will be recorded on a data collection form (Multimedia Appendix 1). Information about the disease and treatment plan will be extracted from the medical record of HNC at the NRONMC.

Ocular Examination

Pre-IMRT clinical ocular examinations will include; best corrected visual acuity measurements using the Snellen chart, intraocular pressure (IOP) measurement using the applanation tonometer, administration of the Ocular Surface Disease Index (OSDI) questionnaire, slit lamp examination of the anterior segment of the eye with a Volk 66D Lens, Schirmer Test, Fluorescein Tear Break Up Time (FTBUT), Corneal Fluorescein Staining Pattern and fundus examination. Findings will be recorded on a data collection form. The OSDI and the study questionnaire will be administered for literate participants, and translated to the appropriate language for participants unable to read English. The OSDI is a 12-item questionnaire which assesses dry eye symptoms and its effects on vision-related function in the past week of the patient’s life. The questionnaire has 3 subscales: vision-related function (Questions 1–5), ocular symptoms (Questions 6–9), and environmental triggers (Questions 10-12) [14]. (For scoring procedures, translation/validation, and domains of interest, see Multimedia Appendix 1).

The Schirmer test (Surgitech Innovation, Haryana, India) will be done without topical anaesthesia. It will be done by placing a filter paper test strip (No. 41 Whatman Paper) folded 5 mm from one end in the lateral third of the lower eyelid after drying the inferior fornix. Patients will be instructed to blink and close the eye. The paper will be removed after 5 minutes and the length of the moistened portion of the strip will be measured from the fold. A reading of less than 10 mm will be regarded as abnormal and considered as indicative of dry eye disease.

To perform the Fluorescein Tearfilm Break Up Time test (FTBUT), fluorescein strips (Surgitech Innovation, Haryana, India) will be moistened with a drop of saline, the excess saline will be shaken off to instill a minimum volume and the strip applied to the lateral canthal area in up gaze to avoid ocular surface damage. Patients will be instructed to blink 3 times, and thereafter to cease blinking. The ocular surface will be viewed with the cobalt blue filter of the slit lamp (table-mounted, ZEISS SL 800, manufactured in Germany by ZEISS) and FTBUT will be timed with a stopwatch (Android clock, Google LLC). Two readings will be taken for each eye and the average recorded.

A complete ocular examination will be performed on each participant on the adnexa and anterior segment using the slit lamp, and dilated -fundus examination using Indirect ophthalmoscope with 20D lens and slit lamp biomicroscopy with 78D Volk Lens after instillation with 2.5% phenylephrine and 1% Tropicamide.

Vision- related quality of life assessment

The vision-related quality of life will be assessed using the World Health Organization/Prevention of Blindness and Deafness Vision Function-20 Questionnaire (WHO/PBD-VF20) which examines the impact of visual impairment in several domains including mental wellbeing, dependency and social functioning (Multimedia Appendix 2) [15]. (For scoring procedures, translation/validation, and domains of interest, see Multimedia Appendix 2).

Health-related quality of life assessment

Patients with HNC will have their health-related quality of life (HRQoL) assessed using the EORTC QLQ-H&N35 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Head and Neck 35) (For scoring procedures, translation/validation, and domains of interest, see in Multimedia Appendix 3). [16-18]. This validated, disease-specific tool is designed to evaluate HRQoL in HNC patients.

All the tests and examinations will be done before IMRT treatment and three (3), six (6) and twelve (12) months after IMRT treatment [6,7,13]. Completion of the eye examinations and filling of the questionnaire will take about 60 minutes.

Measures to Reduce Drop-Out Rates  

To reduce the rate of participants, drop out, a good rapport with study participants will be created and they will be reminded of their review appointments a day in advance by an Ophthalmic nurse and as an added incentive. The examination procedure will be planned in such a way that about five study participants will be scheduled to be seen daily to avoid undue delay for the non-participating patients. QOL assessment will be conducted by an ophthalmic nurse during the dilatation process to make better use of the participants’ time.  

Operational definitions

Late ocular complications will refer to eye complications occurring more than 3 months after receiving IMRT treatment [13]. Dry Eye Disease will be defined as an OSDI score of ≥ 13 with any one of Schirmer's test reading <10 mm, TBUT of <10 s and/or Corneal Fluorescein Staining > 5 corneal spots [19].

Data management, security, and quality assurance

Data collection will be done with the questionnaires by the principal investigator and the Research Assistants. All data will be entered into a Microsoft Access database and transferred into SPSS version 25 for analysis. Electronic data will be protected with password and accessible to the principal investigator and the institutional review board upon request. All information taken will be treated with confidentiality. Identities of respondents will not be included but codes will be used in identifying participants’ responses.

Missing data

Missing Data will be resolved using multiple imputation method and sensitivity analyses will be used in evaluating robustness.  

Data analysis

Data will be analysed with the SPSS software version 25. Descriptive data will be presented as means and standard deviation. Categorical data will be presented as counts and percentages. Mean pre-IMRT and post-IMRT tests for Schirmer, TBUT, and OSDI will be computed using the Analysis of variance (ANOVA) test. Chi-square and Fishers exact tests will be used for categorical variables and Student’s T-test for continuous variables. Repeated measure ANOVA test will be used to compare pre- and post-IMRT visual acuity outcomes. A linear mixed-effects model will be used to account for within-subject correlations, offer robust estimates even when data are unbalanced, and accommodate participants with incomplete follow-up data. The incidence of ocular complications will be calculated and presented as proportions. Ocular risk factors among participants will be analysed using logistic regression analysis. The health and visual-related QOL of participants will be analysed by scoring the questions in each of the four domains and converting the final scores into percentage. An overall score less than 70% will be classified as poor quality of life and scores ≥ 70% will be classified as better quality of life. P-values less than 0.05 will be considered statistically significant and odds ratios with 95% confidence intervals will be reported.

Results

Institutional approval for the study was obtained from the Korle Bu Teaching Hospital with registration number: KBTH-IRB/00082/2024. Funding for the project was received from the Ghana integRative Approach to Cancer rEsearch (GRACE) in January, 2025. Patient recruitment, clinical examination, and data collection commenced in February, 2025 and is expected to be completed in May, 2026. A total of 61 adults with HNC will be recruited. Currently, participant recruitment is on-going with a total of twelve (12) participants recruited. Data analysis will be completed by the end of July, 2026. Investigators plan to submit the results for publication by the end of October, 2026. Results will be reported in compliance with STROBE guidelines for observational studies.  

Results will be structured to align with the study’s multidimensional framework as follows:  

1. Demographic and clinical characteristics of study participants.
2. Vision Outcomes:

1. Pre- and post-IMRT visual acuity outcomes.
2. Incidence rates of ocular toxicities.
3. Acute and late ocular complications.
4. Mean pre-IMRT and post-IMRT tests for Schirmer, TBUT, and OSDI.
5. Ocular risk factors among participants using multiple logistic regression analysis and Hazard ratio.
6. Kaplan-Meier estimates for 1-year overall survival, locoregional control, and progression-free survival, stratified by tumor stage and HPV status.  

1. Patients’ well-being (health and visual-related quality of life):  

1. Mean changes in health and visual-related quality of life of participants over time.
2. Overall health and visual-related quality of life of participants over time.

Discussion:

While IMRT has revolutionized precision in targeting tumors and sparing critical structures, its long-term effects on vision, well-being, and morbidity remain underexplored especially in our sub-Saharan African population. This protocol proposes a multidimensional framework to systematically evaluate these outcomes, addressing critical gaps in survivorship care. It ensures rigorous and reproducible analysis of IMRT’s long-term impacts, paving the way for future refinements in HNC treatment.

Patients with orbital or sinonasal tumors treated with IMRT are at risk of dose exposure to sensitive structures such as the optic nerves, lacrimal glands, or retina [6-9]. Even subclinical doses exceeding 45 Gy may result in complications such as cataracts, dry eye syndrome, or retinopathy, impairing quality of life (QoL) and independence [8,9]. Vision impairment, though less studied, affects between 26% and 62% of patients with tumors near the orbit or optic pathways [8,9]. Conventional clinical trials often prioritize tumor control and acute toxicities (e.g., mucositis), neglecting long-term functional, aesthetic, and psychosocial outcomes. For example, while IMRT’s sparing of parotid glands reduces xerostomia, it fails to address downstream effects such as challenges with social eating or diminished self-esteem.

This protocol moves beyond the conventional "no evidence of disease" endpoint to address unmet rehabilitation needs. Identifying patients with ocular complications enables early ophthalmological referrals, potentially preventing irreversible vision loss. Findings from this study could guide refinements in IMRT protocols; for instance, correlating lacrimal gland doses with dry eye severity might lead to stricter dose constraints (e.g., Dmean <30 Gy), balancing tumor control with QoL.

This protocol re-defines success in HNC treatment by emphasizing survivorship alongside survival. It systematically evaluates vision, well-being, and morbidity to empower clinicians to mitigate the "cost of cure" while advocating for patient-centered radiotherapy approaches. Future work will focus on translating findings into survivorship guidelines and educational tools to ensure that advancements in IMRT improve both clinical and lived experiences.

The interdisciplinary collaboration between oncologists and ophthalmologists could institutionalize mandatory baseline and annual ophthalmic evaluations (e.g., OCT for retinal changes) for high-risk patients, preventing avoidable vision loss. Standardized ocular screenings in oncology clinics could ensure timely interventions that prevent disability and ease the burden on healthcare systems. Data on vision-related morbidity strengthens advocacy for funding HNC-specific low-vision services. By prioritizing multidimensional assessments, this protocol redefines success in HNC treatment, ensuring that advances in tumor control do not come at the cost of survivorship health. It calls for systemic shifts toward integrated, patient-centered care models addressing the full spectrum of IMRT’s long-term effects. Notwithstanding general resource constraints in Ghana, this study is feasible due to available infrastructure at Korle Bu Teaching Hospital, including OCT at LIEC-KBTH and IMRT capabilities at NRONMC, ensuring accurate assessment of IMRT-related ocular outcomes in the local context. Despite limitations in sample size, single-center design, and follow-up duration, this foundational Ghanaian protocol provides an essential basis for investigating ocular toxicities associated with IMRT. It fills a significant information gap in the region, makes use of Korle Bu's research capabilities, and encourages openness, scalability, and cooperation for upcoming multicenter studies throughout sub-Saharan Africa.