Mean Parotid Gland Dose Research Articles

Effect of bilateral superficial parotid gland sparing IMRT on xerostomia and QOL: A prospective study

ABSTRACT Background: Superficial lobe constitutes 80% of the parotid and is situated lateral to mandible and can be better spared during intensity modulated radiation therapy (IMRT) for head and neck cancer (HNC). This study aimed to see the impact of bilateral superficial parotid gland (PG) sparing IMRT on xerostomia and quality of life (QOL) in patients with HNC receiving radiation. Study Design: Prospective, questionnaire-based study. Materials and Methods: Thirty-four patients with histopathologically proven non-nasopharyngeal non-oral cavity HNC were included in this study. IMRT technique was used and a constraint of 24 Gy was given to combined superficial PG. Physician- and patient-rated xerostomia and QOL scores were recorded at baseline and two weeks, three months, and six months post-radiation therapy (RT). The combined superficial PG dose correlated with xerostomia and QOL scores. Results: The combined superficial PG and combined whole PG mean dose was 18.71 Gy and 30 Gy, respectively, and the difference was statistically significant (P-< 0.001). At two weeks, three months, and six months post-RT, the odds of xerostomia scores were 0.11, 0.071, 0.042, respectively for a median dose of <18 Gy compared to >18 Gy and was statistically significant P=(0.001). Conclusion: Bilateral superficial PG sparing IMRT is beneficial in reducing xerostomia and translates to a better QOL.

Long-term follow-up of protective effects on salivary and swallowing structures and improvement of late xerostomia and dysphagia by level IIb optimisation in clinical target volume of nasopharyngeal carcinoma.

This study aimed to assess the long-term effect of level IIb clinical target volume (CTV) optimisation on survival, xerostomia, and dysphagia in patients with nasopharyngeal carcinoma (NPC). Clinical data of 415 patients with NPC treated with intensity-modulated radiotherapy between December 2014 and October 2018 were retrospectively analysed. The patients were categorised into modified and comparison groups. Late xerostomia and dysphagia were evaluated using Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer scoring. Survival analysis was performed using the Kaplan-Meier method. Differences in late toxicity and dose parameters between both groups were compared. Prognostic factors for survival and late toxicity were assessed using regression analyses. Patients in the modified group developed late xerostomia and dysphagia less frequently than those in the comparison group did (P < 0.001). The mean dose (Dmean) and V26 of parotid glands; Dmean and V39 of submandibular glands; and Dmean of sublingual glands, oral cavity, larynx, and superior, middle, and lower pharyngeal constrictor muscles were lower in the modified group than those in the comparison group (all P < 0.001). Both groups had no significant differences in overall, local recurrence-free, distant metastasis-free, or progression-free survival. The Dmean of the parotid and sublingual glands was a risk factor for xerostomia. The Dmean of the parotid and sublingual glands and middle pharyngeal constrictor muscle was a risk factor for dysphagia. Level IIb optimisation in NPC patients who meet certain criteria specially the exclusion of positive retropharyngeal nodes treated with intensity-modulated radiotherapy has the potential to better protect the salivary and swallowing structures, decreasing the development of late radiation-induced xerostomia and dysphagia while maintaining long-term survival.

Long-term outcomes of stimulated salivary flow and xerostomia after definitive intensity-modulated radiation therapy for patients with head and neck cancer†.

This retrospective study aimed to evaluate the time to recovery from xerostomia and analyze its predictors, along with long-term outcomes of stimulated salivary flow after intensity-modulated radiation therapy (IMRT) for head and neck cancer (HNC). We evaluated patients with HNC who had received IMRT with curative intent between 2012 and 2018 at our institution. The salivary recovery ratio (SRR) was defined as '(the stimulated salivary flow)/(pre-treatment salivary flow)'. The cutoff value of SRR in salivary recovery was estimated via the relationship between SRR and xerostomia grades. The salivary recovery time was defined as the time for SRR to exceed cutoff values from the end of radiotherapy. Fifty-seven patients were analyzed, with a 48-month median follow-up period of stimulated salivary flow. The cutoff value for SRR was 44.8%, and patients with a higher grade of xerostomia had a lower SRR (P < 0.001). The median salivary recovery time was 12months. The cumulative incidence rates of salivary recovery at two and four years were 84 (95% confidence interval [CI]: 53-79) and 92% (95% CI: 82-97), respectively, and these were significantly lower in patients with a higher mean parotid gland dose, mean oral cavity dose and stimulated salivary flow per parotid gland volume. Stimulated salivary flow and xerostomia recover over a long period after radiotherapy.

Identifying a Dose Constraint for the Parotid Ducts: Impact on Patient Reported Xerostomia and Comparison to Conventional Parotid Gland Mean Dose Sparing

(1) Identify a dose constraint for the parotid ducts to reduce patient reported xerostomia and compare effectiveness to QUANTEC constraint. (2) Determine if conventionally planned patients meet this constraint by using atlas-based duct segmentation. (1) 38 patients with oropharyngeal squamous cell carcinoma (OPSCC) were treated prospectively on trial with MRI sialography guided parotid duct sparing radiation therapy (parotid duct sparing cohort). These patients were compared to a historical cohort of 89 similar patients treated with conventional parotid gland mean dose sparing for salivary gland dosimetry and patient reported xerostomia (PRO-CTCAE ≥ Moderate). (2) A contour atlas comprised of 24 patients with MRI sialograms was created. Atlas-based segmentation was generated on the remaining 14 patients with MRI sialograms to assess for contour accuracy. Atlas-based parotid duct contours were generated on 111 patients treated with conventional parotid gland mean dose sparing to facilitate a dosimetric comparison to the parotid duct sparing cohort. (1) In the parotid duct sparing cohort, patients whose parotid ducts (bilateral) were planned for a mean dose <14 Gy reported significantly (p<0.01) lower rates of xerostomia compared to patients whose ducts were planned to receive >14 Gy (26% (5/19) versus 86% (12/14) at 6 months post-RT and 22% (4/18) versus 73% (8/11) at 12 months post-RT). This improvement compares favorably to the QUANTEC constraint of bilateral parotid glands < 25 Gy (see Table). (2) The atlas-based duct contours were found to have a mean distance-to-agreement of 5mm and an average absolute dose difference of 4.5 Gy compared to the MRI sialography defined duct contours. The average duct dose for those undergoing MRI sialography guided duct sparing was found to be 13.5 Gy compared to an estimated (via atlas-based segmentation) 22.3 Gy for those receiving conventional parotid gland mean dose sparing (p < 0.01). 20% (22/111) patients receiving conventional parotid gland mean dose sparing met the 14 Gy parotid duct constraint versus 60% of patients undergoing MRI sialography guided parotid duct sparing. Parotid duct sparing (parotid duct dose <14 Gy) was both more effective (∼50% [76% to 26%] absolute xerostomia reduction at 6mo and ∼24% [46% to 22%] absolute xerostomia reduction at 12 mo) and more achievable (∼60% of patients vs ∼35% patients) than mean dose parotid gland sparing per QUANTEC constraint. Atlas-based segmentation estimated that MRI sialography guided parotid duct sparing reduced the parotid duct dose by 9 Gy and that only 20% of patients met the parotid duct dose constraint (<14 Gy) with conventional parotid gland mean dose sparing.

Hippocampal-Sparing Radiotherapy in Primary Sinonasal and Cutaneous Head and Neck Malignancies: A Feasibility Study

Patients with primary sinonasal and cutaneous head and neck (H&N) malignancies often receive meaningful hippocampal doses, but the hippocampus is not a classic avoidance structure in radiation planning of these primary sites. This series characterizes the feasibility and tradeoffs of hippocampal-sparing radiotherapy (HSRT) for patients with primary sinonasal and cutaneous H&N malignancies. We retrospectively identified patients at a single institution treated definitively for primary sinonasal or cutaneous malignancies of the H&N. Each patient received (chemo)radiation and all received clinically-significant radiation dose to one or both hippocampi. We created new HSRT plans for each patient with intensity-modulated radiotherapy using original target and organ-at-risk (OAR) volumes. Hippocampi were contoured based on Radiation Therapy Oncology Group guidelines. Absolute and relative differences in radiation dose to the hippocampi, planning target volumes (PTV), and OARs were recorded. We used paired-samples t-tests to compare hippocampal and PTV dosimetric measures with and without HSRT. Thirty-seven patients were included (22 sinonasal, 11 cutaneous H&N, and 4 parotid primary tumors). Median prescription dose was 6600cGy (range: 5000-7440cGy). The most common fractionation regimens were 200cGy/fraction daily (51%, 19/37 patients) and 120cGy/fraction twice daily (41%, 15/37 patients). There were significant decreases in hippocampal Dmax and D100% using HSRT without compromising PTV coverage (Table 1). HSRT resulted in a relative increase of mean lacrimal gland dose by an average of 3.8%, optic chiasm Dmax by 1.3%, and whole brain Dmax of 1.2%. However, other OAR doses were lower with HSRT, including parotid gland mean dose, lens Dmax, optic nerve Dmax, cochlea mean dose, brainstem Dmax, and whole brain mean dose. HSRT is feasible and results in meaningful radiation dose reduction to the hippocampi without reducing PTV coverage or increasing dose to other OARs. The hippocampi should be regularly included as avoidance structures when treating primary sinonasal and cutaneous H&N tumors with radiation. We suggest target hippocampal constraints of Dmax < 1600cGy and D100% < 500cGy when feasible (without compromising PTV coverage). The clinical significance of HSRT in patients with primary H&N tumors should be investigated prospectively.

Evaluation of Deformable Image Registration-Based Dose Accumulation for Parotid Glands in Head and Neck Adaptive Radiotherapy and its Impact on Prediction of Xerostomia

<h3>Purpose/Objective(s)</h3> Deformable image registration (DIR) so far is the fundamental tool for dose accumulation despite the noticeable errors and uncertainty. Accurate dose and NTCP evaluation are crucial in adaptive radiotherapy (ART). The current study assessed the difference of mean dose (D_mean) between the accumulation by DIR and ground truth for parotid gland and the impact on NTCP of xerostomia. We aim to propose a method using DIR for fast and accurate dose and NTCP evaluation in ART. <h3>Materials/Methods</h3> A total of 123 head and neck cancer (HNC) patients who underwent photon radiotherapy and had at least 5 weekly in-treatment re-scan CTs (rCTs) were enrolled. Parotid glands were segmented on planning CT and each rCT by the same senior radiation oncologist with more than 10 years' experience in OAR segmentation. The original treatment plan (VMAT or IMRT) was re-calculated on each rCT to obtain the actual weekly mean dose (D_mean). was performed between planning CT (reference CT) and each rCT (target CT) and then used to warp the dose distribution of each rCT backward and accumulate on planning CT to obtain the DIR accumulated D_mean (D_{mean_DIR}). The ground truth D_mean (D_{mean_GT}) was defined as the average of the actual weekly D_mean. The planning D_mean, D_{mean_DIR} and D_{mean_GT} were all translated into NTCP for xerostomia (van den Bosch et al., 2021). NTCP of D_{mean_DIR} and planning D_mean were used to develop a liner multiple regression model to predict NTCP of D_{mean_GT}. All the combinations of coefficients within the 95% confidential interval were tested, the prediction error was defined as NTCP of D_{mean_GT} - prediction of NTCP. <h3>Results</h3> There is no statistically significant difference between D_mean difference of D_{mean_GT} (D_{mean_GT}- planning D_mean) and D_{mean_DIR} (D_{mean_DIR} - planning D_mean). The NTCP difference (NTCP based on D_{mean_DIR} – NTCP based on D_{mean_GT}) of xerostomia at the 6^th month after radiotherapy was 0.01 ± 0.96% (range: -3.94% to 2.63%, assumed Grade 0 baseline xerostomia) and 0.05 ± 1.17% (range: -3.71% to 2.99%, assumed Grade 1-2 baseline xerostomia). In both models, the p value of coefficients for NTCP of planning D_mean and D_{mean_DIR} were significant and <0.01. For cases showing increased NTCP during the course of RT >3 pp (NTCP of D_{mean_GT} vs. NTCP of planning D_mean), adjusting the coefficients within the 95% confidential interval could help to predict the NTCP of D_{mean_GT} within a deviation of -1.31% to 1.89% and -1.58% to 1.99% for baseline xerostomia of Grade0 and Grade 1-2, respectively. <h3>Conclusion</h3> The dose accumulation by deformable image registration could incur a prediction error up to 3.94 pp for NTCP of xerostomia. For patients showing increased NTCP of xerostomia more than 3 pp due to dose change, our model using the NTCP based on planning and DIR accumulated mean dose of parotid glands could be used for accurate prediction of the actual NTCP with a prediction error less than 2 pp.

Prospective assessment of sparing the parotid ducts via MRI sialography for reducing patient reported xerostomia

PurposeTo assess the impact of prospectively sparing the parotid ducts via MRI sialography on patient reported xerostomia for those receiving definitive radiotherapy (RT) for oropharyngeal squamous cell carcinoma. Methods and materialsThirty-eight patients with oropharynx cancer to be treated with definitive RT underwent pre-treatment MRI sialograms to localize their parotid ducts. The parotid ducts were maximally spared during treatment planning. Patients reported symptoms (PRO-CTCAE and QLQ-H&N35) were collected at 6 and 12 months post-RT and compared to a historical cohort who underwent conventional parotid gland mean dose sparing. Regression models were generated using parotid and submandibular gland doses with and without incorporating the dose to the parotid ducts to determine the impact of parotid duct dose on patient reported xerostomia. ResultsAt 6 months post-RT, 12/26 (46%) patients reported ≥moderate xerostomia when undergoing parotid ductal sparing compared to 43/61 (70%) in the historical cohort (p = 0.03). At 12 months post-RT, 8/22 (36%) patients reported ≥moderate xerostomia when undergoing parotid ductal sparing compared to 34/68(50%) in the historical cohort (p = 0.08). Using nested logistic regression models, the mean parotid duct dose was found to significantly relate to patient reported xerostomia severity at 6 months post-RT (p = 0.04) and trended towards statistical significance at 12 months post-RT (p = 0.09). At both 6 and 12 months post-RT, the addition of mean parotid duct dose significantly improved model fit (p < 0.05). ConclusionsMRI sialography guided parotid duct sparing appears to reduce the rates of patient-reported xerostomia. Further, logistic regression analysis found parotid duct dose to be significantly associated with patient reported xerostomia. A significant improvement in model fit was observed when adding mean parotid duct dose compared to models that only contain mean parotid gland dose and mean contralateral submandibular gland dose.

Functional Parotid Sparing: Does Sparing the Parotid Ducts Yield Improvements in Patient Reported Xerostomia?

Literature suggests that salivary gland stem cells, capable of regenerating salivary tissue, may preferentially reside in the large ducts of salivary glands. We conducted a prospective trial in patients receiving definitive chemoradiotherapy (CRT) for oropharyngeal cancer where we preferentially spared the major parotid ducts (localized via MRI sialography) during treatment planning. We hypothesized that (1) this technique would yield improvements in patient reported xerostomia (PRX) at 6- and 12-months post-CRT compared to a prospectively accrued cohort of similar patients, and (2) that parotid duct doses would be predictive for PRX.A total of 38 Patients were prospectively enrolled and underwent MRI sialography guided ductal sparing. 28/38 patients received de-escalated CRT (60Gy). PRX was classified as none/mild versus moderate to very severe. (1) PRX in the 28 de-escalated patients were compared using a fisher exact test to a cohort of 232 patients on the same clinical trials but who did not undergo ductal sparing. (2) Competing nested multivariate logistic models (+/- parotid duct doses) were assessed using dosimetric data from all 38 patients for their ability to predict PRX. Models included contralateral submandibular mean dose, mean parotid gland dose (both) +/- parotid duct mean dose (both). The two nested models were compared using a likelihood ratio test to determine if incorporating mean parotid duct doses significantly improved model fit.(1) Patients reporting moderate to very severe xerostomia was lower in patients with vs without parotid-ductal sparing at 6 months post-CRT (46% vs 67%, P = 0.03), and trended lower at 12 months post-CRT (32% vs 49%, P = 0.11). At 6 months post CRT, the mean parotid duct dose was the only covariate significantly associated with PRX (P = 0.047). At 12 months post CRT, no covariate was significantly associated with PRX but both mean contralateral submandibular dose and mean parotid duct dose approached significance (P = 0.06 and 0.07, respectively). (2) The models +/- parotid duct doses were compared and the addition of parotid ductal mean dose significantly improved model fit at 6- and 12-months post CRT (P = 0.030 and 0.047, respectively).The absolute rates of moderate to very severe patient reported xerostomia were approximately 20% lower for those undergoing MRI sialography guided parotid ductal sparing versus those without ductal sparing at 6- and 12-months post CRT. The significant improvement of model fit upon adding mean parotid ductal dose to the mean major salivary gland doses at 6 and 12 months suggests that the dose received by the parotid ducts relates to patient reported xerostomia severity even when considering traditional metrics such as mean parotid and contralateral submandibular dose.

First Application of Predictive Model to Assist Adaptive Proton Therapy

<h3>Purpose/Objective(s)</h3> To assess a model to predict anatomical changes in head and neck cancer patients and explore the applicability of the model as a tool for adaptive replanning in intensity-modulated proton therapy (IMPT). <h3>Materials/Methods</h3> 20 radiotherapy patients with nasopharyngeal cancer were included in this retrospective study. Each patient had a planning CT and weekly CTs during radiotherapy. To build the anatomical model, we deform the weekly CTs to planning CTs of our training population (n = 19) and obtain the average anatomical change per week. To predict a deformation for the remaining patient, the average deformation of the training population is applied to the patient's planning CT. The model is updated based on the patient's progression during treatment. K-fold cross validation (n = 5) was used to obtain a sample of 5 patients. For those 5 patients, we compare the accumulated dose of two adaptive IMPT strategies. 1) Predictive replan (PR): Replans were optimized on predicted images of weeks 3 and 5 and applied to week 3/4 and week 5/6 respectively. 2) Best-case replan (BcR): Adaptive replan on weekly CT is triggered when target coverage D95% criteria are not met and parotid gland mean dose deviation > 3 Gy (RBE). All plans (original plan, PR, BcR) were robustly optimized (+/-3 mm setup and +/-3.5% range uncertainty). Dosimetric goals: CTV D95(%) > 95% prescription dose in robust evaluation; maximum dose to spinal cord and brainstem < 45 Gy (RBE) and < 55 Gy (RBE), respectively. To ensure fairness of comparison, we kept dosimetric parameters between BcR and PR consistent. <h3>Results</h3> Accumulated dose differences from two adaptive strategies (PR-BcR) of our 5 testing patients are shown (tab 1). We observe a maximum dose difference of 2.2% in the CTV D₉₅, -1.35 Gy (RBE) in the brainstem D_max, and -1.24 Gy (RBE) in the parotid D_mean. The parentheses indicate the dose difference of the replans only (no accumulation). <h3>Conclusion</h3> A predictive model was applied to the replanning process for adaptive proton therapy and compared to a best-case replan strategy. Our suggested PR produces clinically acceptable plans, comparable to the best-case replan strategy, suggesting that the predictive models can be used for adaptive replanning. Application of predictive replanning provides the possibility to prepare adaptive plans in advance, streamlining the clinical workflow.

A Study to Assess the Dosimetric Impact of the Anatomical Changes Occurring in the Parotid Glands and Tumour Volume during Intensity Modulated Radiotherapy using Simultaneous Integrated Boost (IMRT-SIB) in Head and Neck Squamous Cell Cancers.

BackgroundAnatomical variations in head and neck cancer during IMRT leads to volume shrinkage, results in dosimetric variations in tumour and normal tissue including parotid glands, with a risk of radiation toxicities.Methods30 patients with a stage II–IV head and neck squamous cell carcinoma (HNSCC) were treated with definitive IMRT‐SIB and concomitant chemotherapy. Volumetric and dosimetric variations were evaluated during the period of IMRT by recalculating and obtaining dose‐volume histograms of re‐contoured target volumes and parotid glands on repeat CT scans taken multiple times during treatment (CT1, CT2, CT3 and CT4).ResultsResult showed significant (p < 0.001) mean decrease in both primary and nodal tumors volume with time whereas increase (p < 0.01 or p < 0.001) in respective V100 (%) and D2% (Gy). The mean parotid gland dose increased (p < 0.01 or p < 0.001) with time, whereas parotid gland volume and distance between plan isocenter and centre of mass of parotid glands decreased (p < 0.05 or p < 0.001) with time. Patient's mean weight and neck circumference both decrease (p < 0.001) with time whereas ECOG score increase (p < 0.001) with time. The mucosal toxicity increased significantly (p < 0.001) with time. The change in both weight and neck circumference showed significant (p < 0.001) and direct (positive correlation) association with change in parotid gland volume.ConclusionIf the PTV and normal anatomy are changing with time, adaptive IMRT would be beneficial radiation dose delivery where possible.

Examination of the best head tilt angle to reduce the parotid gland dose maintaining a safe level of lens dose in whole-brain radiotherapy using the four-field box technique.

The parotid gland is recognized as a major‐risk organ in whole‐brain irradiation; however, the beam delivery from the left and right sides cannot reduce the parotid gland dose. The four‐field box technique using a head‐tilting device has been reported to reduce the parotid gland dose by excluding it from the radiation field. This study aimed to determine the appropriate head tilt angle to reduce the parotid gland dose in the four‐field box technique. The bilateral, anterior, and posterior beams were set for each of ten patients. The orbitomeatal plane angle (OMPA) was introduced as an indicator that expresses the head tilt angle. Next, principal component analysis (PCA) was performed to understand the interrelationship between variables (dosimetric parameters of the lens and parotid gland and OMPA). In PCA, the angle between the OMPA vector and maximum lens dose or mean parotid gland dose vector was approximately opposite or close, indicating a negative or positive correlation [r = −0.627 (p < 0.05) or 0.475 (p < 0.05), respectively]. The OMPA that reduced the maximum lens dose to <10 Gy with a 95% confidence interval was approximately 14°. If the lens dose was not considered, the parotid gland dose could be reduced by decreasing the OMPA.

Comparison of CBCT-based dose calculation methods in head and neck cancer radiotherapy: from Hounsfield unit to density calibration curve to deep learning.

Anatomical variations occur during head and neck (H&N) radiotherapy treatment. kV cone-beam computed tomography (CBCT) images can be used for daily dose monitoring to assess dose variations owing to anatomic changes. Deep learning methods (DLMs) have recently been proposed to generate pseudo-CT (pCT) from CBCT to perform dose calculation. This study aims to evaluate the accuracy of a DLM and to compare this method with three existing methods of dose calculation from CBCT in H&N cancer radiotherapy. Forty-four patients received VMAT for H&N cancer (70-63-56Gy). For each patient, reference CT (Bigbore, Philips) and CBCT images (XVI, Elekta) were acquired. The DLM was based on a generative adversarial network. The three compared methods were: (a) a method using a density to Hounsfield Unit (HU) relation from phantom CBCT image (HU-D curve method), (b) a water-air-bone density assignment method (DAM), and iii) a method using deformable image registration (DIR). The imaging endpoints were the mean absolute error (MAE) and mean error (ME) of HU from pCT and reference CT (CTref ). The dosimetric endpoints were dose discrepancies and 3D gamma analyses (local, 2%/2mm, 30% dose threshold). Dose discrepancies were defined as the mean absolute differences between DVHs calculated from the CTref and pCT of each method. In the entire body, the MAEs and MEs of the DLM, HU-D curve method, DAM, and DIR method were 82.4 and 17.1HU, 266.6 and 208.9HU, 113.2 and 14.2HU, and 95.5 and -36.6HU, respectively. The MAE obtained using the DLM differed significantly from those of other methods (Wilcoxon, P≤0.05). The DLM dose discrepancies were 7±8cGy (maximum=44cGy) for the ipsilateral parotid gland Dmean and 5±6cGy (max=26cGy) for the contralateral parotid gland mean dose (Dmean ). For the parotid gland Dmean , no significant dose difference was observed between the DLM and other methods. The mean 3D gamma pass rate±standard deviation was 98.1±1.2%, 91.0±5.3%, 97.9±1.6%, and 98.8±0.7% for the DLM, HU-D method, DAM, and DIR method, respectively. The gamma pass rates and mean gamma results of the HU-D curve method, DAM, and DIR method differed significantly from those of the DLM. For H&N radiotherapy, DIR method and DLM appears as the most appealing CBCT-based dose calculation methods among the four methods in terms of dose accuracy as well as calculation time. Using the DIR method or DLM with CBCT images enables dose monitoring in the parotid glands during the treatment course and may be used to trigger replanning.

Predicting late radiation-induced xerostomia with parotid gland PET biomarkers and dose metrics

PurposeTo assess associations between parotid gland PET biomarkers and late radiation-induced xerostomia, and to validate improvement of xerostomia predictive models by adding pre-treatment PET features to models based on dose and pre-treatment xerostomia. Materials and MethodsIntensity PET features from 47 patients treated on institutional prospective clinical trials for HPV-associated oropharyngeal squamous cell carcinoma with uniform chemoRT were analyzed. Associations between 90th percentile of the parotid gland standardized uptake values (P90) from pre-treatment and post-treatment PET scans, mean parotid gland doses, and late xerostomia defined by the Xerostomia Questionnaire (XQ) and salivary flow rates were quantified. Multivariable analysis was applied for dose and PET features using penalized logistic regression for feature selection and generation of predictive models using the LASSO technique, and optimism bias was estimated by bootstrap resampling. ResultsSignificant associations between late xerostomia and both mean parotid gland dose and P90 were demonstrated, and were generally stronger for post-treatment PET scans. The addition of P90 from pre-treatment PET scans improved the prediction model for late moderate or severe xerostomia compared to the base model, from AUC = 0.74 to 0.78 (p-value <0.001) for XQ summary score and from 0.77 to 0.84 (p-value <0.001) for the single eating-related XQ item with the largest inter-patient variability; however, only the latter remained significant on cross validation (AUC = 0.69 to 0.70 and 0.73 to 0.80, respectively). ConclusionsThe addition of pre-treatment parotid gland PET biomarkers improved a predictive model for late patient-reported xerostomia over dose and pre-treatment xerostomia.

Implementation of an optimization method for parotid gland sparing during inverse planning for head and neck cancer radiotherapy

PurposeTo guide parotid gland (PG) sparing at the dose planning step, a specific model based on overlap between PTV and organ at risk (Moore et al.) was developed and evaluated for VMAT in head-and-neck (H&N) cancer radiotherapy. Materials and methodsOne hundred and sixty patients treated for locally advanced H&N cancer were included. A model optimization was first performed (20 patients) before a model evaluation (110 patients). Thirty cases were planned with and without the model to quantify the PG dose sparing. The inter-operator variability was evaluated on one case, planned by 12 operators with and without the model. The endpoints were PG mean dose (Dmean), PTV homogeneity and number of monitor units (MU). ResultsThe PG Dmean predicted by the model was reached in 89% of cases. Using the model significantly reduced the PG Dmean: −6.1±4.3Gy. Plans with the model showed lower PTV dose homogeneity and more MUs (+10.5% on average). For the inter-operator variability, PG dose volume histograms without the optimized model were significantly different compared to those with the model; the Dmean standard deviation for the ipsilateral PG decreased from 2.2Gy to 1.2Gy. For the contralateral PG, this value decreased from 2.9Gy to 0.8Gy. ConclusionDuring the H&N inverse planning, the optimized model guides to the lowest PG achievable mean dose, allowing a significant PG mean dose reduction of −6.1Gy. Integrating this method at the treatment-planning step significantly reduced the inter-patient and inter-operator variabilities.

Delta-radiomics features during radiotherapy improve the prediction of late xerostomia

The response of the major salivary glands, the parotid glands, to radiation dose is patient-specific. This study was designed to investigate whether parotid gland changes seen in weekly CT during treatment, quantified by delta-radiomics features (Δfeatures), could improve the prediction of moderate-to-severe xerostomia at 12 months after radiotherapy (Xer12m). Parotid gland Δfeatures were extracted from in total 68 planning and 340 weekly CTs, representing geometric, intensity and texture characteristics. Bootstrapped forward variable selection was performed to identify the best predictors of Xer12m. The predictive contribution of the resulting Δfeatures to a pre-treatment reference model, based on contralateral parotid gland mean dose and baseline xerostomia scores (Xerbaseline) only, was evaluated. Xer12m was reported by 26 (38%) of the 68 patients included. The most predictive Δfeature was the contralateral parotid gland surface change, which was significantly associated with Xer12m for all weeks (p < 0.04), but performed best for week 3 (ΔPG-surfacew3; p < 0.001). Moreover, ∆PG-surfacew3 showed a significant predictive contribution in addition to the pre-treatment reference model (likelihood-ratio test; p = 0.003), resulting in a significantly better model performance (AUCtrain = 0.92; AUCtest = 0.93) compared to that of the pre-treatment model (AUCtrain = 0.82; AUCtest = 0.82). These results suggest that mid-treatment parotid gland changes substantially improve the prediction of late radiation-induced xerostomia.

A hybrid approach for head and neck cancer using online image guidance and offline adaptive radiotherapy planning

AbstractBackgroundThis is a prospective study to evaluate the dosimetric benefits of treatment plan adaptation for patients who had undergone repeat computed tomography (ReCT)and re-planning due to treatment-induced anatomical changes during radiotherapy.Materials and MethodsThis study involved five head and neck cancer patients who had their treatment plan modified, based on weekly thrice imaging protocol. Impact of mid-course imaging was assessed in patients using ReCT and cone beam computed tomography (CBCT)-based dose verification. Patients were imaged, apart from their initial CT, during the course of their radiation therapy with a ReCT and on board imager CBCT (Varian Medical Systems Inc., Palo Alto, CA, USA). Each CBCT/CT series was rigidly registered to the initial CT in the treatment planning system Eclipse (Varian Medical Systems Inc.) using bony landmarks. The structures were copied to the current CBCT/CT series and, where needed, manually edited slicewise. The dose distribution from the treatment plan was viewed as of the current anatomy by applying the treatment plan the CBCT/CT series, and studying the corresponding dose–volume histograms for organs at risk doses.ResultsThe reduction of parotid volumes due to weight loss was observed in all patients, which means an increase in predicted mean doses of parotid when initial CT plan was re-calculated on ReCT and CBCT (Table 1). This explains the necessity of adaptive planning. The predicted mean dose of parotid glands was increased and constraints to spinal cord and skin were exceeded, so re-planning was performed.ConclusionsThe CBCT is a useful tool to view anatomic changes in patients and get an estimate of their impact on dose distribution. Re-planning based on imaging in head and neck patients during the course of radiotherapy is mandatory to reduce side effects.

Intensity-Modulated Proton Therapy with Dose Painting based on Hypoxia Imaging for Nasopharyngeal Cancer

In precision medicine, reducing recurrence rates and toxicities is necessary for nasopharyngeal cancer (NPC) patients. Hypoxia is a well-known risk factor for radioresistance. Radiation dose escalation (DE) to hypoxic regions is one strategy, especially for locally advanced cases in which tumor control may be unsuccessful. Radiation dose reduction is also a valuable approach. A clinical trial of dose de-escalation (DDE) for oropharyngeal cancer based on hypoxia status was recently reported. DDE may also be applicable for NPC patients with good prognostic characteristics. The purpose of this study was to investigate the feasibility of hypoxia-based dose painting for intensity-modulated proton therapy (IMPT) and intensity-modulated X-ray therapy (IMXT) with constraints on doses to organs at risk (OARs) and normal tissue complication probabilities (NTCPs) in DE and DDE scenarios. DE and DDE treatment plans for IMPT and IMXT were generated for ten NPC patients who underwent 18F-fluoromisonidazole (FMISO)-PET before definitive radiotherapy. In the DE scenario, 70 Gy was prescribed to the tumor in a standard manner, with DE to 84 Gy to FMISO-PET-positive (hypoxic) regions. In the DDE scenario, 70 Gy was prescribed to the hypoxic region, with DDE to 60 Gy to non-hypoxic regions. Prescribed doses to high- and low-risk areas were 63 and 56 Gy, respectively, in the DE scenario and 54 and 48 Gy, respectively, in the DDE scenario. The constraints for doses to OARs were a parotid gland mean dose (Dmean) <26 Gy and an oral cavity Dmean <39 Gy. The criterion for NTCP was probability ≤50% for all five toxicities: salivary flow reduction, xerostomia, dysphagia, tube feeding dependence and dysgeusia. The determined doses to hypoxic and non-hypoxic target volumes were prescribed in all IMPT and IMXT plans in the DE and DDE scenarios. The numbers of patients who satisfied the parotid gland, oral cavity and NTCP criteria were 7, 10 and 10, respectively, for IMPT and 0, 1 and 0, respectively, for IMXT in the DE scenario and 10, 10 and 10, respectively, for IMPT and 1, 2 and 5, respectively, for IMXT in the DDE scenario. Dmean for the contralateral parotid gland was 25.2±3.0 for IMPT and 36.3±3.4 for IMXT (p=0.0003) in the DE scenario and 21.4±2.6 for IMPT and 30.9±3.0 for IMXT (p=0.0003) in the DDE scenario. Dmean for the oral cavity was 28.8±7.3 for IMPT and 49.3±4.9 for IMXT (p=0.0003) in the DE scenario and 24.5±6.2 for IMPT and 41.3±4.3 for IMXT (p=0.0003) in the DDE scenario. For all toxicities, NTCPs were lower for IMPT than for IMXT for all patients. ΔNTCP, calculated as NTCPIMXT-NTCPIMPT, was more than 10% for 3 or more toxicities for 9 patients in the DE scenario and 8 patients in the DDE scenario. Compared with IMXT, IMPT satisfied parotid, oral cavity and NTCP criteria in more patients and reduced doses to OARs and NTCPs in both the DE and DDE scenarios. IMPT could be more useful than IMXT when conducting hypoxia-based dose painting while maintaining low toxicities.

The Association of Canonical Speech- and Swallow-Related Dosimetric Constraints with Patient-Reported Quality of Life Outcomes: Results from a Phase II Trial of Dose De-Escalated Chemoradiation for HPV-Associated, Locally-Advanced Oropharyngeal Carcinoma

Radiation dose de-escalation for patients with human papillomavirus (HPV)-related oropharyngeal carcinoma may improve quality of life. We conducted an exploratory exercise to examine potential relationships between canonical dosimetric parameters and speech- and swallow-related and overall patient-reported quality of life outcomes on a subset of patients treated on a phase II trial of de-escalated chemoradiation for HPV-related oropharyngeal carcinoma. An analysis was performed of 24 patients treated at a single-institution on a phase II, prospective study of induction chemotherapy followed by dose de-escalated chemoradiation for HPV-related, locally-advanced oropharyngeal carcinoma. Following two cycles of induction carboplatin/paclitaxel, reduced-dose chemoradiation with concurrent paclitaxel was administered to 54-60 Gy in 27-30 fractions. Intensity-modulated radiotherapy was used for all patients. Univariable logistic regression analysis was used to evaluate potential associations between multiple speech-and swallow-related dosimetric constraints and quality of life domains at 3 and 12 months post-treatment involving swallowing, chewing, speech, taste, and saliva, as well as overall quality of life, using the University of Washington Quality of Life instrument. Canonical models were constructed to analyze dosimetry to the temporomandibular joints, oral cavity, lips, parotid glands, submandibular glands, larynx, pharynx, cricopharyngeal inlet, and cervical esophagus, as analyzed by maximum, mean, and/or partial-volume parameters. The post-chemotherapy gross tumor volume, planning target volume (PTV) receiving the high, intermediate, and low dose levels, and combined volume of all PTV dose levels were also analyzed. Twenty-five percent of patients had T3-T4 tumors, and 13% had N2c nodal disease. Thirteen percent had >10 pack-year smoking history. At 12 months, a decreased taste domain score was significantly associated with a higher volume of high-dose level PTV (p=0.028). Also, a decreased health-related quality of life score at 12 months was significantly associated with a higher contralateral parotid gland mean dose (p=0.037), higher contralateral parotid gland V30Gy (p=0.046), and higher cricopharyngeal inlet mean dose (p=0.036). No dosimetric parameters were significantly associated with quality of life differences at 3 months (p>0.05, for all). For patients treated by de-escalated chemoradiation, canonical dosimetric constraints for conventional chemoradiation are poorly correlated with speech- and swallow-related and overall quality of life outcomes. While a smaller high-dose PTV, lower contralateral parotid gland dose, and lower cricopharyngeal inlet dose appear to be related to better quality of life outcomes, these require additional validation. Future studies of de-escalated chemoradiation may reveal new dosimetric constraints to help guide treatment planning.

A Novel Three Dimensional Conformal Radiation Therapy Technique to Decrease the Mean Parotid Gland Dose in Whole Brain Radiation Therapy

A Novel Three Dimensional Conformal Radiation Therapy Technique to Decrease the Mean Parotid Gland Dose in Whole Brain Radiation Therapy

18F-FDG PET image biomarkers improve prediction of late radiation-induced xerostomia

Background and purposeCurrent prediction of radiation-induced xerostomia 12months after radiotherapy (Xer12m) is based on mean parotid gland dose and baseline xerostomia (Xerbaseline) scores. The hypothesis of this study was that prediction of Xer12m is improved with patient-specific characteristics extracted from 18F-FDG PET images, quantified in PET image biomarkers (PET-IBMs). Patients and methodsIntensity and textural PET-IBMs of the parotid gland were collected from pre-treatment 18F-FDG PET images of 161 head and neck cancer patients. Patient-rated toxicity was prospectively collected. Multivariable logistic regression models resulting from step-wise forward selection and Lasso regularisation were internally validated by bootstrapping. The reference model with parotid gland dose and Xerbaseline was compared with the resulting PET-IBM models. ResultsHigh values of the intensity PET-IBM (90th percentile (P90)) and textural PET-IBM (Long Run High Grey-level Emphasis 3 (LRHG3E)) were significantly associated with lower risk of Xer12m. Both PET-IBMs significantly added in the prediction of Xer12m to the reference model. The AUC increased from 0.73 (0.65–0.81) (reference model) to 0.77 (0.70–0.84) (P90) and 0.77 (0.69–0.84) (LRHG3E). ConclusionPrediction of Xer12m was significantly improved with pre-treatment PET-IBMs, indicating that high metabolic parotid gland activity is associated with lower risk of developing late xerostomia. This study highlights the potential of incorporating patient-specific PET-derived functional characteristics into NTCP model development.