Assessment of Risk of Xerostomia After Whole-Brain Radiation Therapy and Association With Parotid Dose.

Importance: Whole-brain radiation therapy (WBRT) delivers a substantial radiation dose to the parotid glands, but the parotid glands are not delineated for avoidance and xerostomia has never been reported as an adverse effect. Minimizing the toxic effects in patients receiving palliative treatments, such as WBRT, is crucial. Objective: To assess whether xerostomia is a toxic effect of WBRT. Design, Setting, and Participants: This observational cohort study enrolled patients from November 2, 2015, to March 20, 2018, at 1 academic center (University of North Carolina Hospitals) and 2 affiliated community hospitals (High Point Regional Hospital and University of North Carolina Rex Hospital). Adult patients (n = 100) receiving WBRT for the treatment or prophylaxis of brain metastases were enrolled. Patients who had substantial baseline xerostomia or did not complete WBRT or at least 1 postbaseline questionnaire were prospectively excluded from analysis and follow-up. Patients received 3-dimensional WBRT using opposed lateral fields covering the skull and the C1 or C2 vertebra. Per standard practice, the parotid glands were not prospectively delineated. Main Outcomes and Measures: Patients completed the University of Michigan Xerostomia Questionnaire and a 4-point bother score at baseline, immediately after WBRT, at 1 month, at 3 months, and at 6 months. The primary end point was the 1-month xerostomia score, with a hypothesized worsening score of 10 points from baseline. Results: Of the 100 patients enrolled, 73 (73%) were eligible for analysis and 55 (55%) were evaluable at 1 month. The 73 patients included 43 women (59%) and 30 men (41%) with a median (range) age of 61 (23-88) years. The median volume of parotid receiving at least 20 Gy (V20Gy) was 47%. The mean xerostomia score was 7 points at baseline and was statistically significantly higher at each assessment period, including 21 points immediately after WBRT (95% CI, 16-26; P < .001), 23 points (95% CI, 16-30; P < .001) at 1 month, 21 points (95% CI, 13-28; P < .001) at 3 months, and 14 points (95% CI, 7-21; P = .03) at 6 months. At 1 month, the xerostomia score increased by 20 points or more in 19 patients (35%). The xerostomia score at 1 month was associated with parotid dose as a continuous variable and was 35 points in patients with parotid V20Gy of 47% or greater, compared with only 9 points in patients with parotid V20Gy less than 47% (P < .001). The proportion of patients who self-reported to be bothered quite a bit or bothered very much by xerostomia at 1 month was 50% in those with parotid V20Gy of 47% or greater, compared with only 4% in those with parotid V20Gy less than 47% (P < .001). At 3 months, this difference was 50% vs 0% (P = .001). Xerostomia was not associated with medication use. Conclusions and Relevance: Clinically significant xerostomia occurred by the end of WBRT, appeared to be persistent, and appeared to be associated with parotid dose. The findings from this study suggest that the parotid glands should be delineated for avoidance to minimize these toxic effects in patients who undergo WBRT and often do not survive long enough for salivary recovery.

Assessment of Parotid and Submandibular Glands With Shear Wave Elastography Following Radioactive Iodine Therapy for Papillary Thyroid Carcinoma.

OBJECTIVES: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy. Radioactive iodine (RAI) therapy is used for remnant ablation following thyroidectomy. Side effects such as dysphagia, xerostomia, and sialoadenitis may occur. We aimed to determine the differences in the parotid and submandibulary glands between healthy patients and patients with PTC who had undergone RAI therapy and have dry mouth symptoms using both shear wave elastography and ultrasonography. METHODS: We enrolled 30 patients with PTC who had undergone RAI therapy following surgery and 30 healthy controls. Ultrasonography and shear wave elastography of submandibular and parotid glands were performed. The volume of the submandibular glands and the thickness of parotid glands were determined. Ten independent measurements were obtained from each gland, with the region of interest placed at different points on the glands. The mean shear wave velocities (SWVs) were calculated and compared between the patients and controls. RESULTS: In the PTC group, there was a significant reduction in the volume of the submandibular glands (P < .05) and in the thickness of the parotid glands (P < .05) compared with the control group. The mean SWVs of the parotid glands and submandibular glands were significantly higher in the PTC group compared with the control group (P < .0001). The SWVs of the parotid glands were higher than the SWVs of the submandibular glands (P < .0001). CONCLUSIONS: Shear wave elastography could be a noninvasive and easy assessment method of parotid and submandibular glands in patients who had undergone RAI therapy and experience dry mouth.

The Needs and Benefits of Continuous Model Updates on the Accuracy of RT-Induced Toxicity Prediction Models Within a Learning Health System.

PURPOSE: Clinical data collection and development of outcome prediction models by machine learning can form the foundation for a learning health system offering precision radiation therapy. However, changes in clinical practice over time can affect the measures and patient outcomes and, hence, the collected data. We hypothesize that regular prediction model updates and continuous prospective data collection are important to prevent the degradation of a model's predication accuracy. METHODS AND MATERIALS: Clinical and dosimetric data from head and neck patients receiving intensity modulated radiation therapy from 2008 to 2015 were prospectively collected as a routine clinical workflow and anonymized for this analysis. Prediction models for grade ≥2 xerostomia at 3 to 6 months of follow-up were developed by bivariate logistic regression using the dose-volume histogram of parotid and submandibular glands. A baseline prediction model was developed with a training data set from 2008 to 2009. The selected predictor variables and coefficients were updated by 4 different model updating methods. (A) The prediction model was updated by using only recent 2-year data and applied to patients in the following test year. (B) The model was updated by increasing the training data set yearly. (C) The model was updated by increasing the training data set on the condition that the area under the curve (AUC) of the recent test year was less than 0.6. (D) The model was not updated. The AUC of the test data set was compared among the 4 model updating methods. RESULTS: Dose to parotid and submandibular glands and grade of xerostomia showed decreasing trends over the years (2008-2015, 297 patients; P < .001). The AUC of predicting grade ≥2 xerostomia for the initial training data set (2008-2009, 41 patients) was 0.6196. The AUC for the test data set (2010-2015, 256 patients) decreased to 0.5284 when the initial model was not updated (D). However, the AUC was significantly improved by model updates (A: 0.6164; B: 0.6084; P < .05). When the model was conditionally updated, the AUC was 0.6072 (C). CONCLUSIONS: Our preliminary results demonstrate that updating prediction models with prospective data collection is effective for maintaining the performance of xerostomia prediction. This suggests that a machine learning framework can handle the dynamic changes in a radiation oncology clinical practice and may be an important component for the construction of a learning health system.

Three-dimensional cluster formation and structure in heterogeneous dose distribution of intensity modulated radiation therapy.

PURPOSE: To investigate three-dimensional cluster structure and its correlation to clinical endpoint in heterogeneous dose distributions from intensity modulated radiation therapy. METHODS: Twenty-five clinical plans from twenty-one head and neck (HN) patients were used for a phenomenological study of the cluster structure formed from the dose distributions of organs at risks (OARs) close to the planning target volumes (PTVs). Initially, OAR clusters were searched to examine the pattern consistence among ten HN patients and five clinically similar plans from another HN patient. Second, clusters of the esophagus from another ten HN patients were scrutinized to correlate their sizes to radiobiological parameters. Finally, an extensive Monte Carlo (MC) procedure was implemented to gain deeper insights into the behavioral properties of the cluster formation. RESULTS: Clinical studies showed that OAR clusters had drastic differences despite similar PTV coverage among different patients, and the radiobiological parameters failed to positively correlate with the cluster sizes. MC study demonstrated the inverse relationship between the cluster size and the cluster connectivity, and the nonlinear changes in cluster size with dose thresholds. In addition, the clusters were insensitive to the shape of OARs. CONCLUSION: The results demonstrated that the cluster size could serve as an insightful index of normal tissue damage. The clinical outcome of the same dose-volume might be potentially different.

Prospective longitudinal assessment of parotid gland function using dynamic quantitative pertechnate scintigraphy and estimation of dose-response relationship of parotid-sparing radiotherapy in head-neck cancers.

PURPOSE: To estimate dose-response relationship using dynamic quantitative (99m)Tc-pertechnate scintigraphy in head-neck cancer patients treated with parotid-sparing conformal radiotherapy. METHODS: Dynamic quantitative pertechnate salivary scintigraphy was performed pre-treatment and subsequently periodically after definitive radiotherapy. Reduction in salivary function following radiotherapy was quantified by salivary excretion fraction (SEF) ratios. Dose-response curves were modeled using standardized methodology to calculate tolerance dose 50 (TD50) for parotid glands. RESULTS: Salivary gland function was significantly affected by radiotherapy with maximal decrease in SEF ratios at 3-months, with moderate functional recovery over time. There was significant inverse correlation between SEF ratios and mean parotid doses at 3-months (r = -0.589, p<0.001); 12-months (r = -0.554, p<0.001); 24-months (r = -0.371, p = 0.002); and 36-months (r=-0.350, p=0.005) respectively. Using a post-treatment SEF ratio <45% as the scintigraphic criteria to define severe salivary toxicity, the estimated TD50 value with its 95% confidence interval (95% CI) for the parotid gland was 35.1Gy (23.6-42.6Gy), 41.3Gy (34.6-48.8Gy), 55.9Gy (47.4-70.0Gy) and 64.3Gy (55.8-70.0Gy) at 3, 12, 24, and 36-months respectively. CONCLUSIONS: There is consistent decline in parotid function even after conformal radiotherapy with moderate recovery over time. Dynamic quantitative pertechnate scintigraphy is a simple, reproducible, and minimally invasive test of major salivary gland function.

Near Real-Time Assessment of Anatomic and Dosimetric Variations for Head and Neck Radiation Therapy via Graphics Processing Unit-based Dose Deformation Framework.

PURPOSE: The purpose of this study was to systematically monitor anatomic variations and their dosimetric consequences during intensity modulated radiation therapy (IMRT) for head and neck (H&N) cancer by using a graphics processing unit (GPU)-based deformable image registration (DIR) framework. METHODS AND MATERIALS: Eleven IMRT H&N patients undergoing IMRT with daily megavoltage computed tomography (CT) and weekly kilovoltage CT (kVCT) scans were included in this analysis. Pretreatment kVCTs were automatically registered with their corresponding planning CTs through a GPU-based DIR framework. The deformation of each contoured structure in the H&N region was computed to account for nonrigid change in the patient setup. The Jacobian determinant of the planning target volumes and the surrounding critical structures were used to quantify anatomical volume changes. The actual delivered dose was calculated accounting for the organ deformation. The dose distribution uncertainties due to registration errors were estimated using a landmark-based gamma evaluation. RESULTS: Dramatic interfractional anatomic changes were observed. During the treatment course of 6 to 7 weeks, the parotid gland volumes changed up to 34.7%, and the center-of-mass displacement of the 2 parotid glands varied in the range of 0.9 to 8.8 mm. For the primary treatment volume, the cumulative minimum and mean and equivalent uniform doses assessed by the weekly kVCTs were lower than the planned doses by up to 14.9% (P=.14), 2% (P=.39), and 7.3% (P=.05), respectively. The cumulative mean doses were significantly higher than the planned dose for the left parotid (P=.03) and right parotid glands (P=.006). The computation including DIR and dose accumulation was ultrafast (∼45 seconds) with registration accuracy at the subvoxel level. CONCLUSIONS: A systematic analysis of anatomic variations in the H&N region and their dosimetric consequences is critical in improving treatment efficacy. Nearly real-time assessment of anatomic and dosimetric variations is feasible using the GPU-based DIR framework. Clinical implementation of this technology may enable timely plan adaptation and improved outcome.

Texture analysis for the assessment of structural changes in parotid glands induced by radiotherapy.

BACKGROUND AND PURPOSE: During radiotherapy (RT) for head-and-neck cancer, parotid glands undergo significant anatomic, functional and structural changes which could characterize pre-clinical signs of an increased risk of xerostomia. Texture analysis is proposed to assess structural changes of parotids induced by RT, and to investigate whether early variations of textural parameters (such as mean intensity and fractal dimension) can predict parotid shrinkage at the end of treatment. MATERIAL AND METHODS: Textural parameters and volumes of 42 parotids from 21 patients treated with intensity-modulated RT for nasopharyngeal cancer were extracted from CT images. To individuate which parameters changed during RT, a Wilcoxon signed-rank test between textural indices (first and second RT week; first and last RT week) was performed. Discriminant analysis was applied to variations of these parameters in the first two weeks of RT to assess their power in predicting parotid shrinkage at the end of RT. RESULTS: A significant decrease in mean intensity (1.7 HU and 3.8 HU after the second and last weeks, respectively) and fractal dimension (0.016 and 0.021) was found. Discriminant analysis, based on volume and fractal dimension, was able to predict the final parotid shrinkage (accuracy of 71.4%). CONCLUSION: Textural features could be used in combination with volume to characterize structural modifications on parotid glands and to predict parotid shrinkage at the end of RT.

A quantitative assessment of volumetric and anatomic changes of the parotid gland during intensity-modulated radiotherapy for head and neck cancer using serial computed tomography.

To evaluate the change in volume and movement of the parotid gland measured by serial contrast-enhanced computed tomography scans in patients with head and neck cancer treated with parotid-sparing intensity-modulated radiotherapy (IMRT). A prospective study was performed on 13 patients with head and neck cancer undergoing dose-painted IMRT to 69.96Gy in 33 fractions. Serial computed tomography scans were performed at baseline, weeks 2, 4, and 6 of radiotherapy (RT), and at 6 weeks post-RT. The parotid volume was contoured at each scan, and the movement of the medial and lateral borders was measured. The patient's body weight was recorded at each corresponding week during RT. Regression analyses were performed to ascertain the rate of change during treatment as a percent change per fraction in parotid volume and distance relative to baseline. The mean parotid volume decreased by 37.3% from baseline to week 6 of RT. The overall rate of change in parotid volume during RT was-1.30% per fraction (-1.67% and-0.91% per fraction in≥31Gy and<31Gy mean planned parotid dose groups, respectively, p = 0.0004). The movement of parotid borders was greater in the≥31Gy mean parotid dose group compared with the<31Gy group (0.22% per fraction and 0.14% per fraction for the lateral border and 0.19% per fraction and 0.06% per fraction for the medial border, respectively). The median change in body weight was-7.4% (range, 0.75% to-17.5%) during RT. A positive correlation was noted between change in body weight and parotid volume during the course of RT (Spearman correlation coefficient, r = 0.66, p<0.01). Head and neck IMRT results in a volume loss of the parotid gland, which is related to the planned parotid dose, and the patient's weight loss during RT.

Protons in head-and-neck cancer: bridging the gap of evidence.

PURPOSE: To use Normal Tissue Complication Probability (NTCP) models and comparative planning studies to explore the (cost-)effectiveness of swallowing sparing intensity modulated proton radiotherapy (IMPT) compared with swallowing sparing intensity modulated radiotherapy with photons (IMRT) in head and neck cancer (HNC). METHODS AND MATERIALS: A Markov model was constructed to examine and compare the costs and quality-adjusted life years (QALYs) of the following strategies: (1) IMPT for all patients; (2) IMRT for all patients; and (3) IMPT if efficient. The assumption of equal survival for IMPT and IMRT in the base case analysis was relaxed in a sensitivity analysis. RESULTS: Intensity modulated proton radiation therapy and IMRT for all patients yielded 6.620 and 6.520 QALYs and cost €50,989 and €41,038, respectively. Intensity modulated proton radiation therapy if efficient yielded 6.563 QALYs and cost €43,650. The incremental cost-effectiveness ratio of IMPT if efficient versus IMRT for all patients was €60,278 per QALY gained. In the sensitivity analysis, IMRT was more effective (0.967 QALYs) and less expensive (€8218) and thus dominated IMPT for all patients. CONCLUSIONS: Cost-effectiveness analysis based on normal tissue complication probability models and planning studies proved feasible and informative and enables the analysis of individualized strategies. The increased effectiveness of IMPT does not seem to outweigh the higher costs for all head-and-neck cancer patients. However, when assuming equal survival among both modalities, there seems to be value in identifying those patients for whom IMPT is cost-effective.

Scintigraphic assessment of salivary function after intensity-modulated radiotherapy for head and neck cancer: correlations with parotid dose and quality of life.

OBJECTIVE: We investigated salivary function using quantitative scintigraphy and sought to identify functional correlations between parotid dose and quality of life (QoL) for head and neck cancer (HNC) patients receiving intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Between August, 2007 and June, 2008, 31 patients treated IMRT for HNC were enrolled in this prospective study. Salivary excretion function (SEF) was previously measured by salivary scintigraphy at annual intervals for 2 years after IMRT. A dose-volume histogram of each parotid gland was calculated, and the normal tissue complication probability (NTCP) was used to determine the tolerance dose. QoL was longitudinally assessed by the EORTC QLQ-C30 and H&N35 questionnaires prior to RT, and at one, three, 12 and 24 months after RT. RESULTS: A significant correlation was found between the reduction of SEF and the mean parotid dose measured at 1 year (correlation coefficient, R(2)=0.651) and 2 years (R(2)=0.310) after IMRT (p<0.001). The TD(50) of the parotid gland at 1 year after IMRT is 43.6 Gy, comparable to results from western countries. We further found that contralateral parotid and submandibular gland function preservation was correlated with reduced sticky saliva and a better QoL compared to the functional preservation of both parotid glands, as determined by the EORTC QLQ-H&N35 questionnaire. CONCLUSION: A significant correlation was found between the reduction of SEF and the mean parotid dose. Preservation of contralateral parotid and submandibular gland function predicts a better QoL compared to preservation of the function of both parotid glands.

Ultrasound histogram assessment of parotid gland injury following head-and-neck radiotherapy: a feasibility study.

Xerostomia (dry mouth), resulting from radiation damage to the parotid glands, is one of the most common and distressing side effects of head-and-neck cancer radiotherapy. A noninvasive, objective imaging method to assess parotid injury is lacking, but much needed in the clinic. Therefore, we investigated echo histograms to quantitatively evaluate the morphologic and microstructural integrity of the parotid glands. Six sonographic features were derived from the echo-intensity histograms to assess the echogenicity, homogeneity and heterogeneity of the parotid gland: (1) peak intensity value (I(peak)), (2) -3-dB intensity width (W(3-dB)), (3) the low (<50% I(peak)) intensity width (W(low)), (4) the high (>50% I(peak)) intensity width (W(high)), (5) the area of low intensity (A(low)) and (6) the area of high intensity (A(high)). In this pilot study, 12 post-radiotherapy patients and seven healthy volunteers were enrolled. Significant differences (p < 0.05) were observed in four sonographic features between 24 irradiated and 14 normal parotid glands. In summary, we developed a family of sonographic features derived from echo histograms and demonstrated the feasibility of quantitative evaluation of radiation-induced parotid-gland injury.

FDG-PET assessment of the effect of head and neck radiotherapy on parotid gland glucose metabolism.

PURPOSE: Functional imaging with [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) provides the opportunity to define the physiology of the major salivary glands before and after radiation therapy. The goal of this retrospective study was to identify the radiation dose-response relationship of parotid gland glucose metabolism in patients with head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Forty-nine adults with HNSCC were identified who had curative intent intensity-modulated radiation therapy (IMRT) and FDG-PET imaging before and after treatment. Using a graphical user interface, contours were delineated for the parotid glands on axial CT slices while all authors were blinded to paired PET slices. Average and maximal standard uptake values (SUV) were measured within these anatomic regions. Changes in SUV and volume after radiation therapy were correlated with parotid gland dose-volume histograms from IMRT plans. RESULTS: The average parotid gland volume was 30.7 mL and contracted 3.9 ± 1.9% with every increase of 10 Gy in mean dose (p = 0.04). However, within the first 3 months after treatment, there was a uniform reduction of 16.5% ± 7.3% regardless of dose. The average SUV(mean) of the glands was 1.63 ± 0.48 pretreatment and declined by 5.2% ± 2.5% for every increase of 10 Gy in mean dose (p = 0.04). The average SUV(max) was 4.07 ± 2.85 pretreatment and decreased in a sigmoid manner with mean dose. A threshold of 32 Gy for mean dose existed, after which SUV(max) declined rapidly. CONCLUSION: Radiation dose responses of the parotid glands can be measured by integrated CT/FDG-PET scans. Retrospective analysis showed sigmoidal declines in the maximum metabolism but linear declines in the average metabolism of the glands with dose. Future studies should correlate this decline in FDG uptake with saliva production to improve treatment planning.

Radiation injury of the parotid glands during treatment for head and neck cancer: assessment using dynamic contrast-enhanced MR imaging.

The parotid gland is an important organ at risk of complications of radiotherapy for head and neck cancer. In this study, we examined the potential of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for assessment of radiation injury to the parotid glands. DCE-MRI was performed before and 3 months after radiotherapy in patients treated for head and neck cancer. DCE-MRI was analyzed using the pharmacokinetic model proposed by Tofts and Kermode to produce three DCE parameters: k(trans), v(e) and v(p). These parameters were correlated with the dose of radiation delivered to the parotid glands and the degree of radiation-induced parotid atrophy. The mean radiation dose received by the parotid glands was 47.1 ± 6.6 Gy. All patients received concurrent chemotherapy. There was a significant rise in all three parameters after therapy (P < 0.0001). Baseline v(e) and v(p) and the post-treatment rise in v(e) correlated with parotid gland atrophy (P  =  0.0008, 0.0003 and 0.0022, respectively). DCE-MRI has the potential to be used as a non-invasive technique for predicting and assessing radiation injury in the parotid glands.

Ultrastructural assessment of the radioprotective effects of sodium selenite on parotid glands in rats.

The aim of this study was to assess the radioprotective effects of sodium selenite on parotid glands in rats by ultrastructural analysis of acinar cells. Four experimental groups were assessed; control, irradiated, selenium, and selenium/irradiated. The sodium selenite dose was 0.5 mg/kg, administered intraperitoneally 24 h before irradiation in the head and neck region with a single 15-Gy dose of gamma radiation. At 4, 8, 12, 48 and 72 h after irradiation, all animals were sacrificed and the parotid glands were removed. Radiation caused cellular changes from 4 h, and the organelles that presented the greatest alterations were the mitochondria and the secretion glands; nuclear alterations were also observed. Sodium selenite was found to have a radioprotective action, as the selenium/irradiated group presented with less damage when compared to the irradiated group. However, sodium selenite caused cellular alterations that were evident after 8 h, but with less damage when compared to those caused by radiation, which demonstrates a favorable risk-benefit for its use as a radioprotector. Thus, this research shows that sodium selenite has an effective radioprotective action in the parotid gland, which may contribute to the reduction of the adverse effects brought by the radiotherapy.

A pre-clinical assessment of an atlas-based automatic segmentation tool for the head and neck.

BACKGROUND AND PURPOSE: Accurate conformal radiotherapy treatment requires manual delineation of target volumes and organs at risk (OAR) that is both time-consuming and subject to large inter-user variability. One solution is atlas-based automatic segmentation (ABAS) where a priori information is used to delineate various organs of interest. The aim of the present study is to establish the accuracy of one such tool for the head and neck (H&N) using two different evaluation methods. MATERIALS AND METHODS: Two radiotherapy centres were provided with an ABAS tool that was used to outline the brainstem, parotids and mandible on several patients. The results were compared to manual delineations for the first centre (EM1) and reviewed/edited for the second centre (EM2), both of which were deemed as equally valid gold standards. The contours were compared in terms of their volume, sensitivity and specificity with the results being interpreted using the Dice similarity coefficient and a receiver operator characteristic (ROC) curve. RESULTS: Automatic segmentation took typically approximately 7min for each patient on a standard PC. The results indicated that the atlas contour volume was generally within +/-1SD of each gold standard apart from the parotids for EM1 and brainstem for EM2 that were over- and under-estimated, respectively (within +/-2SD). The similarity of the atlas contours with their respective gold standard was satisfactory with an average Dice coefficient for all OAR of 0.68+/-0.25 for EM1 and 0.82+/-0.13 for EM2. All data had satisfactory sensitivity and specificity resulting in a favourable position in ROC space. CONCLUSIONS: These tests have shown that the ABAS tool exhibits satisfactory sensitivity and specificity for the OAR investigated. There is, however, a systematic over-segmentation of the parotids (EM1) and under-segmentation of the brainstem (EM2) that require careful review and editing in the majority of cases. Such issues have been discussed with the software manufacturer and a revised version is due for release.

Longitudinal assessment of parotid function in patients receiving tomotherapy for head-and-neck cancer.

BACKGROUND AND PURPOSE: Conventional radiotherapy is associated with high doses to the salivary glands which causes xerostomia and adverse effects on quality of life. The study aims to investigate the potential of helical tomotherapy (Hi-Art Tomotherapy) to preserve parotid function in head-and-neck cancer patients. PATIENTS AND METHODS: Seven consecutive patients treated with helical tomotherapy at the UZ Brussel, Belgium, were included. During planning, priority was attributed to planning target volume (PTV) coverage: > or =95% of the dose must be delivered to > or =95% of the PTV. Elective nodal regions received 54 Gy (1.8 Gy/fraction). A dose of 70.5 Gy (2.35 Gy/fraction) was prescribed to the primary tumor and pathologic lymph nodes = simultaneous integrated boost scheme. If possible, the mean parotid dose was kept below 26 Gy. Salivary gland function was assessed by technetium scintigraphy. RESULTS: There was a significant dose-response relationship between mean parotid dose and functional recuperation. If the mean dose was kept <31 Gy, a recuperation of 75% can be expected at 12 months. The authors equally observed a significant correlation between salivary excretion (SE) and the percentage of parotid gland receiving a dose <26 Gy (V26%). In order to preserve 75% of SE, 46% of the parotid volume should receive a dose <26 Gy. CONCLUSION: With the use of heLical tomography the parotid gland function can largely be preserved since the mean dose to the entire gland as well as glandular volume receiving >26 Gy can be reduced.

Assessment of parotid gland dose changes during head and neck cancer radiotherapy using daily megavoltage computed tomography and deformable image registration.

PURPOSE: To analyze changes in parotid gland dose resulting from anatomic changes throughout a course of radiotherapy in a cohort of head-and-neck cancer patients. METHODS AND MATERIALS: The study population consisted of 10 head-and-neck cancer patients treated definitively with intensity-modulated radiotherapy on a helical tomotherapy unit. A total of 330 daily megavoltage computed tomography images were retrospectively processed through a deformable image registration algorithm to be registered to the planning kilovoltage computed tomography images. The process resulted in deformed parotid contours and voxel mappings for both daily and accumulated dose-volume histogram calculations. The daily and cumulative dose deviations from the original treatment plan were analyzed. Correlations between dosimetric variations and anatomic changes were investigated. RESULTS: The daily parotid mean dose of the 10 patients differed from the plan dose by an average of 15%. At the end of the treatment, 3 of the 10 patients were estimated to have received a greater than 10% higher mean parotid dose than in the original plan (range, 13-42%), whereas the remaining 7 patients received doses that differed by less than 10% (range, -6-8%). The dose difference was correlated with a migration of the parotids toward the high-dose region. CONCLUSIONS: The use of deformable image registration techniques and daily megavoltage computed tomography imaging makes it possible to calculate daily and accumulated dose-volume histograms. Significant dose variations were observed as result of interfractional anatomic changes. These techniques enable the implementation of dose-adaptive radiotherapy.

The impact of dose on parotid salivary recovery in head and neck cancer patients treated with radiation therapy.

PURPOSE: A common side effect experienced by head and neck cancer patients after radiation therapy (RT) is impairment of the parotid glands' ability to produce saliva. Our purpose is to investigate the relationship between radiation dose and saliva changes in the 2 years after treatment. METHODS AND MATERIALS: The study population includes 142 patients treated with conformal or intensity-modulated radiotherapy. Saliva flow rates from 266 parotid glands are measured before and 1, 3, 6, 12, 18, and 24 months after treatment. Measurements are collected separately from each gland under both stimulated and unstimulated conditions. Bayesian nonlinear hierarchical models were developed and fit to the data. RESULTS: Parotids receiving higher radiation produce less saliva. The largest reduction is at 1-3 months after RT followed by gradual recovery. When mean doses are lower (e.g., <25 Gy), the model-predicted average stimulated saliva recovers to pretreatment levels at 12 months and exceeds it at 18 and 24 months. For higher doses (e.g., >30 Gy), the stimulated saliva does not return to original levels after 2 years. Without stimulation, at 24 months, the predicted saliva is 86% of pretreatment levels for 25 Gy and <31% for >40 Gy. We do not find evidence to support that the overproduction of stimulated saliva at 18 and 24 months after low dose in 1 parotid gland is the result of low saliva production from the other parotid gland. CONCLUSIONS: Saliva production is affected significantly by radiation, but with doses <25-30 Gy, recovery is substantial and returns to pretreatment levels 2 years after RT.

Assessment of salivary function change in nasopharyngeal carcinoma treated by parotid-sparing radiotherapy.

PURPOSE: The purpose of this study was to evaluate function of major salivary glands, subjective xerostomia, and correlation between subjective and objective xerostomia scoring after precision-oriented radiotherapy for nasopharyngeal carcinoma. MATERIALS AND METHODS: From 2000 to 2002, 34 patients with histologically proven non-metastatic nasopharyngeal carcinoma received definitive therapy by parotid-sparing radiotherapy, which included intensity-modulated radiotherapy (33 patients>60 Gy), 3D-conformal radiotherapy, and brachytherapy boost. Salivary function was assessed by sialoscintigraphy pre-irradiation and post-irradiation at 1, 6, 12, and 18 months. The salivary stimulated secretion ratio (SSR) was used to evaluate function of submandibular and parotid glands. Subjective and objective xerostomia was monitored by the LENT/SOMA system. RESULTS: The median dose to parotid gland was 34.6 Gy (interquartile range, 32.9-36.5 Gy). The median dose to submandibular gland was 60.5 Gy (interquartile range, 58.1-61.5 Gy). Parotid-gland post-irradiation median SSR at 1 (0.01, P=0.000) and 6 (0.08, P=0.002) months showed significant reduction compared with pre-irradiation data (0.30). After 12 months, parotid-gland median SSR (12 months, 0.22, P = 0.734; 18 months, 0.16, P=0.885) lost significance compared with pre-irradiation data. Submandibular-gland post-irradiation median SSR at 1 (P=0.000), 6 (P=0.000), 12 (P=0.000), and 18 (P=0.000) months all showed significant reduction compared with pre-irradiation data. There were significant correlations between LENT/SOMA subjective and objective xerostomia scores at 6 months (r=0.657, P=0.000), 12 months (r=0.480, P=0.013), and 18 months (r=0.591, P=0.002). CONCLUSIONS: With parotid-sparing radiotherapy for nasopharyngeal carcinoma, gland function can recover significantly 12 months after radiotherapy. There were significant rank-order correlations between LENT/SOMA subjective and objective (analytic) grading scores at 6 to 18 months' follow-up.

A Bayesian mixture model relating dose to critical organs and functional complication in 3D conformal radiation therapy.

A goal of cancer radiation therapy is to deliver maximum dose to the target tumor while minimizing complications due to irradiation of critical organs. Technological advances in 3D conformal radiation therapy has allowed great strides in realizing this goal; however, complications may still arise. Critical organs may be adjacent to tumors or in the path of the radiation beam. Several mathematical models have been proposed that describe the relationship between dose and observed functional complication; however, only a few published studies have successfully fit these models to data using modern statistical methods which make efficient use of the data. One complication following radiation therapy of head and neck cancers is the patient's inability to produce saliva. Xerostomia (dry mouth) leads to high susceptibility to oral infection and dental caries and is, in general, unpleasant and an annoyance. We present a dose-damage-injury model that subsumes any of the various mathematical models relating dose to damage. The model is a nonlinear, longitudinal mixed effects model where the outcome (saliva flow rate) is modeled as a mixture of a Dirac measure at zero and a gamma distribution whose mean is a function of time and dose. Bayesian methods are used to estimate the relationship between dose delivered to the parotid glands and the observational outcome-saliva flow rate. A summary measure of the dose-damage relationship is modeled and assessed by a Bayesian chi(2) test for goodness-of-fit.