Post-radiation primary hypothyroidism in patients with head and neck cancer: External validation of thyroid gland dose-volume constraints with long-term endocrine outcomes.

BACKGROUND: Post-radiation primary hypothyroidism is a common late complication in head and neck cancer (HNC) survivors. No radiation dose-volume constraint of the thyroid gland has been externally validated for predicting long-term thyroid function outcomes. MATERIALS AND METHODS: This external validation study evaluated the diagnostic properties of 22 radiation dose-volume constraints of the thyroid gland proposed in the literature. Radiation dosimetric data from 488 HNC patients who underwent neck irradiation from January 2013 to December 2015 at two tertiary oncology centers were reviewed. The diagnostic metrics of candidate constraints were computed by inverse probability of censoring weighting and compared using time-dependent receiver operating characteristic (ROC) curves with death designated as a competing event. Multivariable regression analyses were performed using the Fine-Gray sub-distribution hazard model. RESULTS: Over a median follow-up period of 6.8 years, 205 (42.0 %) patients developed post-radiation primary hypothyroidism. The thyroid volume spared from 60 Gy (VS60) had the largest area under ROC curve of 0.698 at 5 years after radiotherapy. Of all evaluated constraints, VS60 at a cutoff value of 10 cc had the highest F-score of 0.53. The 5-year hypothyroidism risks of patients with thyroid VS60 ≥ 10 cc and < 10 cc were 14.7 % and 38.2 %, respectively (p < 0.001). The adjusted sub-hazard ratio for post-radiation primary hypothyroidism for VS60 < 10 cc was 1.87 (95 % confidence interval, 1.22-2.87; p < 0.001). CONCLUSION: Thyroid VS60 is the best radiation dose-volume parameter to predict the long-term risk of primary hypothyroidism in patients with HNC who underwent neck irradiation. VS60 ≥ 10 cc is a robust constraint that limits the 5-year primary hypothyroidism risk to less than 15 % and should be routinely employed during radiotherapy optimization.

Dose-volume predictors of post-radiation primary hypothyroidism in head and neck cancer: A systematic review.

BACKGROUND AND PURPOSE: This systematic review aims to identify radiation dose-volume predictors of primary hypothyroidism after radiotherapy in patients with head and neck cancer (HNC). MATERIALS AND METHODS: We performed a systematic literature search of Medline, EMBASE and Web of Science from database inception to July 1, 2021 for articles that discuss radiation dose-volume predictors of post-radiation primary hypothyroidism in patients with HNC. Data on the incidence, clinical risk factors and radiation dose-volume parameters were extracted. A meta-analysis was performed using the random-effects model to estimate the pooled odds ratio (OR) of thyroid volume as a predictor of the risk of post-radiation hypothyroidism, adjusted for thyroid radiation dosimetry. RESULTS: Our search identified 29 observational studies involving 4,530 patients. With median follow-up durations ranging from 1.0 to 5.3 years, the average crude incidence of post-radiation primary hypothyroidism was 41.4 % (range, 10 %-57 %). Multiple radiation dose-volume parameters were associated with post-radiation primary hypothyroidism, including the thyroid mean dose (Dmean), minimum dose, V25, V30, V35, V45, V50, V30-60, VS45 and VS60. Thyroid Dmean and V50 were the most frequently proposed dosimetric predictors. The pooled adjusted OR of thyroid volume on the risk of post-radiation primary hypothyroidism was 0.89 (95 % confidence interval, 0.85-0.93; p < 0.001) per 1 cc increment. CONCLUSION: Post-radiation primary hypothyroidism is a common late complication after radiotherapy for HNC. Minimizing inadvertent exposure of the thyroid gland to radiation is crucial to prevent this late complication. Radiation dose-volume constraints individualized for thyroid volume should be considered in HNC radiotherapy planning.

A practical methodology to improve the dosimetric accuracy of MR-based radiotherapy simulation for brain tumors.

PURPOSE: To investigate the dosimetric accuracy of synthetic computed tomography (sCT) images generated by a clinically-ready voxel-based MRI simulation package, and to develop a simple and feasible method to improve the accuracy. METHODS: 20 patients with brain tumor were selected to undergo CT and MRI simulation. sCT images were generated by a clinical MRI simulation package. The discrepancy between planning CT and sCT in CT number and body contour were evaluated. To resolve the discrepancies, an sCT specific CT-relative electron density (RED) calibration curve was used, and a layer of pseudo-skin was created on the sCT. The dosimetric impact of these discrepancies, and the improvement brought about by the modifications, were evaluated by a planning study. Volumetric modulated arc therapy (VMAT) treatment plans for each patient were created and optimized on the planning CT, which were then transferred to the original sCT and the modified-sCT for dose re-calculation. Dosimetric comparisons and gamma analysis between the calculated doses in different images were performed. RESULTS: The average gamma passing rate with 1%/1 mm criteria was only 70.8% for the comparison of dose distribution between planning CT and original sCT. The mean dose difference between the planning CT and the original sCT were -1.2% for PTV D95 and -1.7% for PTV Dmax, while the mean dose difference was within 0.7 Gy for all relevant OARs. After applying the modifications on the sCT, the average gamma passing rate was increased to 92.2%. Mean dose difference in PTV D95 and Dmax were reduced to -0.1% and -0.3% respectively. The mean dose difference was within 0.2 Gy for all OAR structures and no statistically significant difference were found. CONCLUSIONS: The modified-sCT demonstrated improved dosimetric agreement with the planning CT. These results indicated the overall dosimetric accuracy and practicality of this improved MR-based treatment planning method.

Application of hypoglossal nerve constraint in definitive radiotherapy for nasopharyngeal carcinoma: A dosimetric feasibility study.

PURPOSE: Radiation-induced hypoglossal nerve palsy is an infrequent but debilitating late complication after definitive radiotherapy for head and neck cancers. D1cc < 74 Gy (equivalent dose in 2 Gy fractions, EQD2) has been proposed as a potential dose constraint that limits 8-year palsy risk to < 5%. This study sets to perform detailed dosimetric assessments on the applicability of this novel dose constraint in advanced nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: This is a retrospective single-institution dosimetry study. NPC radiotherapy plans were identified from an institutional database, with an aim to select 10 eligible cases. Bilateral hypoglossal nerves were retrospectively contoured following a standard atlas. Cases with either one, or both, hypoglossal nerves D1cc exceeded 74 Gy EQD2 were included. Dosimetry of hypoglossal nerves, planning target volumes (PTV) and normal structures before and after application of the new hypoglossal nerve constraint were compared and analyzed. RESULTS: Ten NPC cases were replanned. All hypoglossal nerve contours overlapped with high-dose PTV, predominantly at regions of gross nodal diseases. D1cc in 15 out of 20 hypoglossal nerves exceeded 74G y EQD2 at initial plans. All nerves fulfilled the pre-specified constraint of 74Gy EQD2 after re-plan. Median hypoglossal nerve D1cc reduced from 74.8Gy (range, 74.1 to 77.4Gy) to 73.5Gy (range, 72.4 to 74.0Gy) (p < 0.001), corresponded to a projected reduction in 8-year palsy risk from 5%-14% to 3%-5%. PTV V100 was maintained above 95% in all cases. Dose increments in near-maximum (D2) and decrements in near-minimum (D98) were < 1 Gy. Safety dosimetric parameters of standard head and neck organs-at-risk showed no significant changes. CONCLUSIONS: Hypoglossal nerve D1cc < 74 Gy EQD2 is a dosimetrically feasible constraint in definitive radiotherapy for NPC. Tumor target coverage and normal organ dosimetry were not compromised with its usage. Its routine application should be considered in definitive radiotherapy for head and neck cancers.

Radiation-induced hypoglossal nerve palsy after definitive radiotherapy for nasopharyngeal carcinoma: Clinical predictors and dose-toxicity relationship.

BACKGROUND AND PURPOSE: Radiation-induced hypoglossal nerve palsy is a debilitating and irreversible late complication after definitive radiotherapy for nasopharyngeal carcinoma (NPC) and other skull base tumors. This study sets to evaluate its incidence and clinical predictive factors, and to propose relevant dosimetric constraints for this structure to guide radiotherapy planning. MATERIALS AND METHODS: We undertook a retrospective review of 797 NPC patients who underwent definitive intensity-modulated radiotherapy (IMRT) between 2003 and 2011. Cumulative incidence and clinical predictors for radiation-induced hypoglossal nerve palsy were evaluated. Archived radiotherapy plans were retrieved and 330 independent hypoglossal nerves were retrospectively contoured following standardized atlas. Optimal threshold analyses of dosimetric parameters (Dmax, D0.5cc, D1cc, D2cc, Dmean) were conducted using receiver operating characteristic curves. Normal tissue complication probability was generated with logistic regression modeling. RESULTS: With a median follow-up of 8.1 years, sixty-nine (8.7%) patients developed radiation-induced hypoglossal nerve palsy. High radiotherapy dose, premorbid diabetes, advanced T-stage and radiological hypoglossal canal involvement were independent clinical risk factors. Maximum dose received by 1 cc volume (D1cc) was the best predictor for the development of radiation-induced nerve palsy (AUC = 0.826) at 8 years after IMRT. Hypoglossal nerves with D1cc of 74 Gy EQD2 had an estimated palsy risk of 4.7%. Nerves with D1cc <74 Gy EQD2 had significantly lower risk of palsy than those ≥74 Gy EQD2 (2.4% vs 20.8%, p <0.001). CONCLUSION: Incidence of radiation-induced hypoglossal nerve palsy was high after definitive IMRT for NPC. D1cc <74 Gy EQD2 can serve as a useful dose constraint to adopt during radiotherapy planning to limit palsy risk to <5% at 8 years after IMRT.

Diffusion tensor imaging (DTI) of rodent brains in vivo using a 1.5T clinical MR scanner.

PURPOSE: To evaluate the feasibility of using a clinical 1.5T MR scanner to perform magnetic resonance (MR) diffusion tensor imaging (DTI) on in vivo rodent brains and to trace major rodent neuronal bundles with anatomical correlation. MATERIALS AND METHODS: Two normal adult Sprague Dawley (SD) rats were anesthetized and imaged in a 1.5T MR scanner with a microscopic coil. DTI was performed at a resolution of 0.94 mm x 0.94 mm x 0.5 mm (reconstructed to 0.47 mm x 0.47 mm x 0.5 mm, with b-factors of 600 seconds/mm2 and 1000 seconds/mm2) and a higher resolution of 0.63 mm x 0.63 mm x 0.5 mm (reconstructed to 0.235 mm x 0.235 mm x 0.5 mm, with a b-factor of 1500 seconds/mm2). The fiber-tracking results were correlated with corresponding anatomical sections stained to visualize neuronal fibers. The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of the neuronal fibers were measured and compared with results in published reports. RESULTS: Several major neuronal fiber tracts, including the corticospinal cord, corpus callosum, and anterior commissure, were identified in all DTI data sets. Stained anatomical sections obtained from the rats confirmed the location of these fibers. The ADC values (0.6-0.8 +/- 10(-3) mm2/second) of the fibers were similar to published figures. However, the FA values (0.3-0.35) were lower than those obtained in previous studies of white matter in rodent spinal cord. CONCLUSION: We have demonstrated the feasibility of using a 1.5T clinical MR scanner for neuronal fiber tracking in rodent brains. The technique will be useful in rodent neuroanatomy studies. Further investigation is encouraged to verify the FA values generated by DTI with such techniques.

Vertebral bone mineral density, marrow perfusion, and fat content in healthy men and men with osteoporosis: dynamic contrast-enhanced MR imaging and MR spectroscopy.

PURPOSE: To prospectively use hydrogen 1 (1H) magnetic resonance (MR) spectroscopy and dynamic contrast material-enhanced MR imaging to measure vertebral body marrow fat content and bone marrow perfusion in older men with varying bone mineral densities as documented with dual x-ray absorptiometry (DXA). MATERIALS AND METHODS: This study had institutional review board approval, and all participants provided informed consent. DXA, 1H MR spectroscopy, and dynamic contrast-enhanced MR imaging of the lumbar spine were performed in 90 men (mean age, 73 years; range, 67-101 years). Vertebral marrow fat content and perfusion (maximum enhancement and enhancement slope) were compared for subject groups with differing bone densities (normal, osteopenic, and osteoporotic). The t test was used for comparisons between groups, and the Pearson test was used to determine correlation between marrow fat content and perfusion indexes. RESULTS: Eight subjects were excluded, yielding a final cohort of 82 subjects (mean age, 73 years; range, 67-101 years) that included 42 subjects with normal bone density (mean T score, 0.8 +/- 1.1 [standard deviation]), 23 subjects with osteopenia (mean T score, -1.6 +/- 0.4), and 17 subjects with osteoporosis (mean T score, -3.2 +/- 0.5). Vertebral marrow fat content was significantly increased in subjects with osteoporosis (mean fat content, 58.23% +/- 7.8) (P = .002) or osteopenia (mean fat content, 55.68% +/- 10.2) (P = .034) compared with that in subjects with normal bone density (50.45% +/- 8.7). Vertebral marrow perfusion indexes were significantly decreased in osteoporotic subjects (mean enhancement slope, 0.78%/sec +/- 0.3) compared with those in osteopenic subjects (mean enhancement slope, 1.15%/sec +/- 0.6) (P = .007) and those in subjects with normal bone density (mean enhancement slope, 1.48%/sec +/- 0.7) (P < .001). CONCLUSION: Subjects with osteoporosis have decreased vertebral marrow perfusion and increased marrow fat compared with these parameters in subjects with osteopenia. Similarly, subjects with osteopenia have decreased vertebral marrow perfusion and increased marrow fat compared with these parameters in subjects with normal bone density.

Osteoporosis is associated with increased marrow fat content and decreased marrow fat unsaturation: a proton MR spectroscopy study.

PURPOSE: To use proton magnetic resonance spectroscopy ((1)H-MRS) to evaluate vertebral marrow fat, and to determine whether bone density correlates with fat content and fat unsaturation levels in postmenopausal women. MATERIALS AND METHODS: Fifty-three women (mean age = 70 years) underwent dual energy x-ray absorptiometry and (1)H-MRS, and 12 young female controls (mean age = 28 years) underwent (1)H-MRS of the lumber spine. Water and lipid peak amplitudes were measured to calculate fat content and fat unsaturation index. Spearman's correlation tests and a t-test comparison of means were applied. RESULTS: (1)H-MRS was successful in 15 normal, 15 osteopenic, and 20 osteoporotic subjects, and in all controls. Marrow fat content was significantly elevated in osteoporotic (65.5% +/- 10%) and osteopenic (63.5% +/- 9.3%) subjects compared to normal subjects (56.3% +/- 11.2%) and young controls (29% +/- 9.6%). The fat unsaturation index was significantly decreased in osteoporotic (0.091 +/- 0.013) and osteopenic (0.097 +/- 0.014) subjects compared to normal subjects (0.114 +/- 0.016) and young controls (0.127 +/- 0.031). A good inverse correlation was observed between the fat content and the unsaturation index (r(s) = -0.53, P < 0.0001). CONCLUSION: Osteoporosis is associated with increased marrow fat. As marrow fat increases, saturated lipids appear to increase preferentially to unsaturated lipids.

Segmentation of nasopharyngeal carcinoma (NPC) lesions in MR images.

PURPOSE: An accurate and reproducible method to delineate tumor margins from uninvolved tissues is of vital importance in guiding radiation therapy (RT). In nasopharyngeal carcinoma (NPC), tumor margin may be difficult to identify in magnetic resonance (MR) images, making the task of optimizing RT treatment more difficult. Our aim in this study is to develop a semiautomatic image segmentation method for NPC that requires minimal human intervention and is capable of delineating tumor margins with good accuracy and reproducibility. METHODS AND MATERIALS: The segmentation algorithm includes 5 stages: masking, Bayesian probability calculation, smoothing, thresholding and seed growing, and finally dilation and overlaying of results with different thresholds. The algorithm is based on information obtained from the contrast enhancement ratio of T1-weighted images and signal intensity of T2-weighted images. The algorithm is initiated by the selection of a valid anatomical seed point within the tumor by the user. The algorithm was evaluated on MR images from 7 NPC patients and was compared against the radiologist's reference outline. RESULTS: The algorithm was successfully implemented on all 7 subjects. With a threshold of 1, the average percent match is 78.5 +/- 3.86 (standard deviation) %, and the correspondence ratio is 66.5 +/- 7%. DISCUSSION: The segmentation algorithm presented here may be useful for diagnosing NPC and may guide RT treatment planning. Further improvement will be desirable to improve the accuracy and versatility of the method.