Normal Tissue Complication Probability Modeling of Radiation-Induced Hypothyroidism After Head-and-Neck Radiation Therapy

doi:10.1016/j.ijrobp.2012.03.034

International Journal of Radiation OncologyBiologyPhysics

Volume 85, Issue 2, 1 February 2013, Pages 514-521

https://doi.org/10.1016/j.ijrobp.2012.03.034 Get rights and content

Purpose

To determine the dose-response relationship of the thyroid for radiation-induced hypothyroidism in head-and-neck radiation therapy, according to 6 normal tissue complication probability models, and to find the best-fit parameters of the models.

Methods and Materials

Sixty-five patients treated with primary or postoperative radiation therapy for various cancers in the head-and-neck region were prospectively evaluated. Patient serum samples (tri-iodothyronine, thyroxine, thyroid-stimulating hormone [TSH], free tri-iodothyronine, and free thyroxine) were measured before and at regular time intervals until 1 year after the completion of radiation therapy. Dose-volume histograms (DVHs) of the patients' thyroid gland were derived from their computed tomography (CT)-based treatment planning data. Hypothyroidism was defined as increased TSH (subclinical hypothyroidism) or increased TSH in combination with decreased free thyroxine and thyroxine (clinical hypothyroidism). Thyroid DVHs were converted to 2 Gy/fraction equivalent doses using the linear-quadratic formula with α/β = 3 Gy. The evaluated models included the following: Lyman with the DVH reduced to the equivalent uniform dose (EUD), known as LEUD; Logit-EUD; mean dose; relative seriality; individual critical volume; and population critical volume models. The parameters of the models were obtained by fitting the patients' data using a maximum likelihood analysis method. The goodness of fit of the models was determined by the 2-sample Kolmogorov-Smirnov test. Ranking of the models was made according to Akaike's information criterion.

Results

Twenty-nine patients (44.6%) experienced hypothyroidism. None of the models was rejected according to the evaluation of the goodness of fit. The mean dose model was ranked as the best model on the basis of its Akaike's information criterion value. The D₅₀ estimated from the models was approximately 44 Gy.

Conclusions

The implemented normal tissue complication probability models showed a parallel architecture for the thyroid. The mean dose model can be used as the best model to describe the dose-response relationship for hypothyroidism complication.

Introduction

Thyroid complications due to radiation, such as hypothyroidism, hyperthyroidism, benign adenoma, Graves' disease, and even thyroid cancer, have been reported in the literatures 1, 2, 3, 4, 5. The most common radiation late effect on the thyroid gland is primary hypothyroidism. This effect may be characterized as either clinical hypothyroidism (clinically overt) by low free thyroxin (FT4) and high thyroid-stimulating hormone (TSH), or subclinical hypothyroidism with normal FT4 and high TSH. Clinical symptoms such as hypercholesterolemia and accelerated atherosclerosis may be seen with subclinical hypothyroidism 1, 2, 5. On the other hand, overt hypothyroidism has well-known clinical symptoms, such as slowed mentation, depression, chronic fatigue, skin dryness, hair loss, hoarse voice, muscle aches, brittle nails, forgetfulness, weaker heart and slower heart rate, weight gain, cold intolerance, hypercholesterolemia, and accelerated atherosclerosis 1, 5. The incidence of hypothyroidism varies widely, from 3% to as much as 92%, but is most frequently in the range of 15%-48% after treatment for head-and-neck cancers 1, 2, 3, 4, 5. Emami et al (6) reported tolerance doses of 45, 60, and 70 Gy for incidence values of 8/5, 13/5, and 35/5 (incidence of clinical hypothyroidism in 8%, 13%, and 35% of patients at 5 years). In recent years, many studies have focused on modeling normal tissue complication probability (NTCP) for various anatomic sites and reporting known models parameters (7). Burman et al (8) reported fit parameters of the Lyman-Kutcher-Burman model for the clinical thyroiditis endpoint of thyroid gland. To our knowledge, there is no study describing NTCP of the thyroid gland for hypothyroidism endpoint after radiation therapy. In this study, the dose response of the thyroid gland for any hypothyroidism endpoint by 1-year follow-up after head-and-neck radiation therapy was used for modeling its NTCP using various phenomenologic or empirical models (Lyman with the dose-volume historgram [DVH] reduced to the equivalent uniform dose [LEUD] [9], mean dose [9], and Logit-EUD [LOGEUD] 10, 11), as well as tissue-architecture models (the relative seriality [RS] or Källman S [12] and 2 functional subunit [FSU]-based models known as the individual 13, 14, 15 and population [16] critical volume [CV] models). The aims of this study were to determine the best-fit parameters of these well-known and established NTCP models and introduce the model best describing the dose-response relationship of the thyroid gland for hypothyroidism endpoint by 1 year after radiation therapy.

Section snippets

Subjects

The study included prospective analysis of 65 consecutive head-and-neck patients treated with radiation therapy to investigate their thyroid toxicity after treatment at a hospital radiation therapy department in Tehran, Iran. The procedures were carried out in accordance with the ethical standards of the responsible committee on human experimentation and in compliance with the 1975 Helsinki Declaration and its revision in 2000. The study was prospective, consecutively enrolled research in which

Results

A summary of the demographic, clinical, and treatment characteristics of the patients is shown in Table 1. The mean dose to the thyroid gland in the patients and to the pituitary gland in patients with nasopharyngeal cancer was 42.21 and 31.11 Gy, respectively. The mean volume of the thyroid gland in the patients was 14.84 mL.

All patients had a complete follow-up lasting 1 year after their course of radiation therapy. All patients' glands had pre- and postradiation therapy thyroid functional

Discussion

The aim of this study was to determine the dose-response relationship of the thyroid gland for radiation-induced hypothyroidism in head-and-neck radiation therapy according to the 6 known NTCP models and find the best-fit parameters of the models. Our endpoint in this study was any hypothyroidism.

The D₅₀ calculated from the models was approximately 44 Gy when any hypothyroidism was regarded as the endpoint. However, when just clinical hypothyroidism was taken as the endpoint the estimated D₅₀

Conclusions

The results of the models implemented indicated an obvious volume effect, consistent with a parallel architecture for the thyroid gland for the endpoint considered in this study. The D₅₀ values ranged from 38.5 Gy-44.3 Gy when any hypothyroidism was taken as the endpoint and moved up to 60 Gy for clinical hypothyroidism alone. The mean dose (the most simple) and LEUD (the most frequently used) models were ranked as the best models according to the AIC index.

Acknowledgments

This article resulted from a PhD project carried out at Tarbiat Modares University in close collaboration with the Pars Radiotherapy Center in Tehran, Iran. The authors thank Tarbiat Modares University and Pars Radiotherapy Center for clinical and technical assistance; and Prof. Søren M. Bentzen, PhD, DSc, and Dr Peter van Luijk, PhD, for their useful comments and guidance.

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The analysis was conducted on retrospective data of 1259 patients with head and neck cancer treated at The University of Texas MD Anderson Cancer Center between 2005 and 2015. During a minimum 12-month posttherapy follow-up period, 173 patients in this cohort (13.7%) developed ORN (grades I to IV). The (structural) clusters of mandibular dose-volume histograms (DVHs) for these patients were identified using the K-means clustering method. A soft-margin support vector machine was used to determine the cluster borders and partition the dose-volume space. The risk of ORN for each dose-volume region was calculated based on incidence rates and other clinical risk factors.
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Radiation-induced hypothyroidism (RIHT) is a common but underestimated late effect in head and neck cancers. However, no consensus exists regarding risk prediction or dose constraints in RIHT. We aimed to develop a machine learning model for the accurate risk prediction of RIHT based on clinical and dose–volume features and to evaluate its performance internally and externally.
We retrospectively searched two institutions for patients aged >20 years treated with definitive radiotherapy for nasopharyngeal or oropharyngeal cancer, and extracted their clinical information and dose–volume features. One was designated the developmental cohort, the other as the external validation cohort. We compared the performances of machine learning models with those of published normal tissue complication probability (NTCP) models.
The developmental and external validation cohorts consisted of 378 and 49 patients, respectively. The estimated cumulative incidence rates of grade ≥1 hypothyroidism were 53.5% and 61.3% in the developmental and external validation cohorts, respectively. Machine learning models outperformed traditional NTCP models by having lower Brier scores at every time point and a lower integrated Brier score, while demonstrating a comparable calibration index and mean area under the curve. Even simplified machine learning models using only thyroid features performed better than did traditional NTCP algorithms. The machine learning models showed consistent performance between folds. The performance in a previously unseen external validation cohort was comparable to that of the cross-validation.
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: Financial support was provided by Tarbiat Modares University and the Pars Radiotherapy Center.

: The procedures carried out on the patients in this study were reviewed and approved by the Ethics Committee of Tarbiat Modares University in accordance with the standards set by the committee and in compliance with the 1975 Helsinki Declaration and its revision in 2000.

: Conflicts of interest: none.

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Physics ContributionNormal Tissue Complication Probability Modeling of Radiation-Induced Hypothyroidism After Head-and-Neck Radiation Therapy

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Subjects

Results

Discussion

Conclusions

Acknowledgments

Cancer Treat Rev

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Postradiotherapy hypothyroidism: radiation dose response and chemotherapeutic radiosensitization at less than 40 Gy

J Surg Oncol

Basic Clinical Radiobiology

Physics Contribution
Normal Tissue Complication Probability Modeling of Radiation-Induced Hypothyroidism After Head-and-Neck Radiation Therapy