Abstract
Background/Aim: We evaluated the incidence of radiation-induced hypothyroidism and its risk factors in patients with head and neck cancer who underwent radiotherapy using simultaneous integrated boost–volumetric-modulated arc therapy (SIB–VMAT). Patients and Methods: This retrospective study included 86 patients who received definitive radiotherapy using SIB–VMAT for head and neck cancer. The incidence of ≥ grade 2 hypothyroidism was evaluated. We also evaluated the relationships between hypothyroidism development and clinical factors and thyroid dose–volume parameters. Results: During a median follow-up period of 17 months (range=3-65 months), 31 patients (36.0%, 31/86) developed grade 2 hypothyroidism requiring hormone replacement therapy. No patients experienced ≥ grade 3 hypothyroidism. The cumulative incidences of hypothyroidism at 1 and 2 years after radiation therapy were 24.5% and 38.7%, respectively, with a median onset time of 10.0 months (range=3.0-35.0 months). Thyroid volume (p=0.003), volume of the thyroid spared at 60 Gy (VS60; cut-off value, 5.16 ml; p=0.009), VS70 (cut-off value, 8.0 ml; p=0.007), VS60 equivalent dose in 2 Gy fraction (EQD2; cut-off value, 7.78 ml; p=0.001), and VS70EQD2 (cut-off value, 10.59 ml; p=0.008) were significantly associated with the development of radiation-induced hypothyroidism. Conclusion: Radiation-induced hypothyroidism is not rare in patients with head and neck cancer undergoing radiotherapy using SIB–VMAT. Radiation dose–volume parameters detected in this study may be useful indicators to prevent this complication.
Head and neck cancer is the seventh most common type of cancer worldwide, with >660,000 patients newly diagnosed annually worldwide (1). Radiotherapy provides an important definitive therapy in these patients, by preserving larynx function when used in combination with concurrent chemotherapy (2).
Volumetric-modulated arc therapy (VMAT) has recently been widely used for the treatment of head and neck cancers, with the advantages of decreased monitor units and shorter treatment time compared with conventional intensity-modulated radiation therapy (IMRT) (3). The simultaneous integrated boost (SIB) technique, which can offer the simultaneous delivery of different dose levels to different target volumes within a single treatment fraction, is preferentially used in VMAT for the treatment of head and neck cancers (4).
Hypothyroidism is a common late complication after radiotherapy in patients with head and neck cancer (5-17) and breast cancer (18), requiring lifelong medication (19). In addition, hypothyroidism can cause various complications, such as dementia, cardiovascular events, and cancer (19-21). It is therefore important to prevent the development of radiation-induced hypothyroidism.
The reported incidence of radiation-induced hypothyroidism in patients with head and neck cancer is 10%-69% (5-13, 22-26); however, information on the incidence of hypothyroidism after radiotherapy using SIB–VMAT is lacking, and the radiation dose–volume threshold for the thyroid using SIB–VMAT has not yet been determined.
In this retrospective study, we aimed to evaluate the incidence of radiation-induced hypothyroidism and the radiation dose–volume threshold causing hypothyroidism in patients with head and neck cancer who underwent radiotherapy using SIB–VMAT (5-13, 16, 17, 22-26).
Patients and Methods
Study design. This retrospective single-center study was conducted with approval from the Ethics Review Board of Hyogo Medical University (approval no. 4189). Written informed consent to perform radiotherapy for head and neck cancer was obtained from all patients before treatment. The need for informed consent to use each patient’s data was waived because of the retrospective nature of the study.
Patients. Ninety patients underwent definitive radiotherapy using SIB-VMAT for head and neck cancer during July 2016 to December 2021. Four patients were excluded because of pre-existing hypothyroidism (n=3) or thyroid hypertrophy (n=1), and 86 patients were therefore finally included. There were 69 men and 17 women with a median age of 69 years (range=37-87 years). Seventy-one patients (82.6%, 71/86) received concurrent chemotherapy and all patients were clinically euthyroid before treatment. The patient characteristics are summarized in Table I.
Characteristics of patients with head and neck cancer who received radiation treatment from July 2016 to December 2021 (n=86).
Radiotherapy. Radiotherapy with VMAT was performed using a Versa HD linear accelerator (Elekta, Stockholm, Sweden) and Elekta Synergy linear accelerator with 6 MV photon (Elekta). SIB was applied with prescribed radiation doses of 70.0, 59.4, and 54.1 Gy in 33 fractions for gross tumor volume, high-risk clinical target volume (CTV), and low-risk CTV, respectively. The target delineation for CTV was performed according to the Practical Guide for Conformal & Intensity-Modulated Radiation Therapy (27-29). SIB–VMAT was planned using a radiation treatment planning system (Monaco; Elekta CMS, Maryland Heights, MO, USA), with the X-ray Voxel Monte Carlo as the calculation algorithm.
Dosimetric evaluation. The dose–volume histogram on the Monaco radiation treatment planning system for each plan was used to evaluate the following dose–volume parameters: mean thyroid dose, maximum thyroid dose, minimum thyroid dose, percentage of whole thyroid receiving ≥50, 60, and 70 Gy (V50, 60, and 70), and volume of the thyroid spared from 50, 60, and 70 Gy (VS50, 60, and 70). These dose–volume parameters were evaluated according to the physical dose and biological effective dose (BED), based on a linear quadratic model with alpha/beta ratio (30). EQD2 was calculated using MIM maestro (MIM Software Inc., Cleveland, OH, USA), using the following formula:
Assessment. The incidence of radiation-induced hypothyroidism and the relationships between the development of radiation-induced hypothyroidism and clinical factors and radiation dose–volume parameters of the thyroid were evaluated.
Thyroid function was evaluated by measuring serum thyroid-stimulating hormone (TSH) and free thyroxine 4 (FT4) levels within two weeks before and every 3-6 months after radiation therapy. Thyroid replacement therapy was performed if the serum TSH level increased >10 μIU/ml and the FT4 level decreased to <0.9 ng/dl.
Thyroid volumetry was performed using computed tomography images acquired before radiotherapy. The incidence of ≥ grade 2 hypothyroidism according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 was evaluated.
Statistical analysis. The cumulative incidence of hypothyroidism was evaluated by Kaplan–Meier analysis. The relationships between the development of hypothyroidism and clinical factors were evaluated using univariable Cox proportional hazards regression analyses. For usefulness in clinical practice, cut-off values for continuous covariates were determined to maximize an approximated log-rank test statistic based on the Cox regression model (31). In addition, restricted cubic spline (RCS) functions were used as non-linear predictors to examine flexible associations between the development of hypothyroidism and continuous covariates including age and thyroid volume. The optimal model was chosen as the model with the maximum χ2 value – 2 degrees of freedom, from among the models with dichotomized continuous covariates and an RCS function with 3-5 knots (32). The examined categorical covariates are summarized in Table II.
Relationships between clinical factors and development of hypothyroidism.
The associations between the development of hypothyroidism and each dose–volume parameter for the thyroid were evaluated as for the continuous covariates above. The dose–volume parameters included the mean thyroid dose, V50, V60, V70, VS50, S60, VS70, V50EQD2, V60EQD2, V70EQD2, VS50EQD2, VS60EQD2, and VS70EQD2. Multivariable Cox proportional hazards regression analysis was carried out using clinical factors and dose–volume parameters extracted based on the above univariable analysis. The overall discriminative capability of the Cox regression model was assessed using Harrell’s concordance index (C-index) and the optimism-corrected C-index was calculated for internal validation (33). Time-dependent area under the curve (AUC) values were calculated as a measure of the fit of the Cox regression model for the 1- and 2-year incidences of hypothyroidism.
The data were summarized as median and range for continuous variables and frequency for categorical variables (Table II). All statistical analyses were performed using the graphical user interface for R, version 4.02 (The R Foundation for Statistical Computing, Vienna, Austria), and SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA).
Results
Incidence of hypothyroidism. Thirty-one of the 86 patients (36.0%) developed grade 2 hypothyroidism requiring hormone replacement therapy, during a median follow-up of 17.0 months (range=3.0-65.0 months). No patient experienced ≥ grade 3 hypothyroidism. The cumulative incidences of hypothyroidism at 1 and 2 years after radiation therapy were 24.5% [95% confidence interval (CI)=16.5-35.5%] and 38.7% (95%CI=28.1-51.5%), respectively (Figure 1). The median time to the onset of hypothyroidism was 10.0 months (range=3.0-35.0 months).
Cumulative incidence of grade 2 hypothyroidism (n=86). Overall incidences at 1 and 2 years were 24.5% and 38.7%, respectively.
Relationships between hypothyroidism and clinical factors. The relationships between radiation-induced hypothyroidism and clinical factors are shown in Table III. Thyroid volume ranged from 5.3-42.3 ml (median volume, 11.2 ml). Thyroid volume was the only significant clinical factor affecting the development of radiation-induced hypothyroidism [hazard ratio (95%CI)=0.30 (0.14-0.67); p=0.003].
Univariable Cox proportional hazards analysis for evaluating associations between development of radiation-induced hypothyroidism and clinical factors.
Relationships between hypothyroidism and radiation dose–volume parameters for thyroid. Suitable models for assessing the risk of developing hypothyroidism were selected from among the univariate Cox proportional hazards models with dose–volume parameters as dichotomized predictors with derived cut-off values, continuous-type covariates (linear predictors), and non-linear predictors based on the RCS function (Table II). Although we originally dichotomized the continuous dose–volume parameters for practicality, the dichotomized parameters were more suitable for assessing the risk of developing hypothyroidism than conventional linear or non-linear predictors based on the flexible RCS functions. The goodness of fit of each model was compared (Table IV), and VS60 (cut-off value, 5.16 ml; p=0.009), VS70 (cut-off value, 8.0 ml; p=0.007), VS60EQD2 (cut-off value, 7.78 ml; p=0.001), and VS70EQD2 (cut-off value, 10.59 ml; p=0.008) were strongly associated with the risk of developing hypothyroidism. The hazard ratio, C-index, and time-dependent AUC were calculated based on the above dichotomized dose–volume parameters (Table V). Among these risk factors, VS60EQD2 showed the strongest association with the development of hypothyroidism, with a significant difference in the cumulative incidence of hypothyroidism between patients with VS60EQD2 >7.78 ml (14.5%) and ≤7.78 ml (64.6%) at 2 years after radiotherapy (p<0.001) (Figure 2).
Optimal univariable Cox proportional hazards model among dichotomous, linear, and restricted cubic spline functions for each dose–volume parameter.
C-index and time-dependent area under the curve to assess overall discriminative capability and fitting of univariable and multivariable Cox regression models.
Cumulative incidences of grade 2 hypothyroidism in patients with VS60EQD2 >7.78 and ≤7.78 ml. The cumulative incidences at 2 years after radiation therapy were 14.5% and 64.6% in patients with VS60EQD2 >7.78 and ≤7.78 ml, respectively (p<0.001). VS60: Volume of thyroid spared from 60 Gy; EQD2: equivalent dose in 2 Gy fraction.
Discussion
This study showed that radiation-induced hypothyroidism requiring hormone replacement is not rare, with an incidence of 36.0%. Hypothyroidism was previously reported in 28.9%-61% of patients who underwent IMRT and 38.6%-52.0% who underwent three-dimensional conformal radiation therapy (3D-CRT) (5-13, 15-17, 22-29).
It is difficult to prevent radiation-induced hypothyroidism because of the location of the thyroid. It is recommended to include the level IV cervical lymph node region in the high- or low-risk clinical target volume in the 3D-treatment planning for definitive radiotherapy in patients with head and neck cancers (34); however, because the thyroid is close to the level IV nodes, it is difficult to exclude them from the planning target volume.
This study clearly showed the importance of thyroid volume and thyroid dose–volume, including VS60 with a cut-off value of 5.16 ml, VS70 with a cut-off value of 8.0 ml, VS60EQD2 with a cut-off value of 7.78 ml, and VS70EQD2 with a cut-off value of 10.59 ml. The median thyroid volume in this study (11.2 ml) was smaller than that in previous studies (13.1-20.49 ml) (5-13, 15-17, 22-28); however, the mean thyroid volume reported in healthy Japanese people is 12.0 ml (5.6-20.2 ml) (35), and this discrepancy may thus indicate a racial difference. However, in addition to the location of the thyroid close to the level IV nodes, the small volume of the thyroid also makes it difficult to avoid irradiating the healthy thyroid.
Previous studies also pointed out the importance of thyroid dose–volume in patients with head and neck cancer undergoing IMRT. VS45 ranged from roughly 38.8 ml of the thyroid, and VS60 was 10 ml (5, 13, 15, 24); however, to the best of our knowledge, there are no data on VS70. This study showed a smaller VS60 (5.16 ml) in patients with head and neck cancer who underwent SIB–VMAT. This may be attributed to a smaller thyroid volume in Japanese people.
The advantages of SIB–VMAT over IMRT include the ability to adjust the dose distribution, like the prescribed dose for low-risk CTV, and the potential to reduce the absorbed dose to the thyroid, thus helping to prevent radiation-induced hypothyroidism.
VS30 was roughly 7.43 ml of the thyroid after 3D-CRT (22). Although further studies are required, SIB–VMAT thus seems to be superior to 3D-CRT in terms of sparing the healthy thyroid.
The percentages of healthy thyroid volume protected for each radiation dose–volume parameter in the current study were 46% (5.16/11.2 ml) in VS60, 71.4% (8.0/11.2 ml) in VS70, 69.5% (7.78/11.2 ml) in VS60EQD2, and 94.6% (10.59/11.2 ml).
As noted above, BED was a better indicator predicting radiation-induced hypothyroidism than physical dose. Orlandi et al. also evaluated EQD2 as a dose–volume predictor causing hypothyroidism and reported that V35EQD2 (alpha/beta ratio 3) <58% was a predictor for radiation-induced hypothyroidism (4).
This study had some limitations. The sample size was relatively small. In addition, factors other than dose–volume factors, including clinical factors, such as age, sex, chemotherapy, T stage, race and primary site which have been reported as significant factors causing radiation-induced hypothyroidism (6-13, 15, 22-24, 26), were not significant in this study. These factors should therefore be evaluated in a larger patient series. Although this study identified BED as a stringent indicator predicting radiation-induced hypothyroidism, this should also be evaluated in a larger patient series.
Conclusion
Radiation-induced hypothyroidism is not rare in patients with head and neck cancer undergoing SIB–VMAT. The dose–volume parameters detected in this study may help to prevent the development of hypothyroidism in these patients.
Acknowledgements
The Authors thank Susan Furness, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
Footnotes
Authors’ Contributions
N. Yoshimura; Conceptualization, Data curation, Formal analysis, Visualization and Writing – original draft. M. Fujiwara; Methodology and Supervision. M. Igeta; Formal analysis. H. Suzuki, R. Kunimoto, T. Terada, Y. Shinoda and J. Fukutake; Investigation. K. Yamakado and H. Takaki; Writing - review & editing. All Authors discussed the contents of the final manuscript.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
Funding
No funding was received to assist with the preparation of this manuscript.
- Received November 14, 2023.
- Revision received December 5, 2023.
- Accepted December 6, 2023.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
