Contralateral Submandibular Gland Research Articles

Dosimetric comparison of postoperative interstitial high-dose-rate brachytherapy and modern external beam radiotherapy modalities in tongue and floor of the mouth tumours in terms of doses to critical organs.

The aim of the study was to dosimetrically compare interstitial high-dose-rate (HDR) brachytherapy (BT) and modern external beam radiotherapy modalities, as volumetric modulated arc therapy (VMAT) and stereotactic radiotherapy with Cyberknife (CK) of tumours of the tongue and floor of the mouth in terms of dose to the critical organs. In National Institute of Oncology, Budapest, between March 2013 and August 2022 twenty patients (11 male/9 female) with stage T1-3N0M0 tongue (n = 14) and floor of mouth (n = 6) tumours received postoperative radiotherapy because of close/positive surgical margin and/or lymphovascular and/or perineural invasion. High-dose-rate interstitial brachytherapy applying flexible plastic catheters with a total dose of 15 × 3 Gy was used for treatment. In addition to BT plans VMAT and stereotactic CK plans were also made in all cases, using the same fractionation scheme and dose prescription. As for the organs at risk, the doses to the mandible, the ipsilateral and the contralateral salivary glands were compared. The mean volume of the planning target volume (PTV) was 12.5 cm3, 26.5 cm3 and 17.5 cm3 in BT, VMAT and CK techniques, respectively, due to different safety margin protocols. The dose to the mandible was the most favourable with BT, as for the salivary glands (parotid and submandibular) the CK technique resulted in the lowest dose. The highest dose to the critical organs was observed with the VMAT technique. The mean values of D2cm3 and D0.1cm3 for the critical organs were as follows for BT, VMAT and CK plans: 47.4% and 73.9%, 92.2% and 101.8%, 68.4% and 92.3% for the mandible, 4.8% and 6.7%, 7.3% and 13.8%, 2.3% and 5.1% for the ipsilateral parotid gland, 3.5% and 4.9%, 6.8% and 10.9%, 1.5% and 3.3% for the contralateral parotid gland, 7.3% and 9.4%, 9.0% and 14.3%, 3.6% and 5.6% for the contralateral submandibular gland. The present results confirm that BT, despite being an invasive technique, is dosimetrically clearly beneficial in the treatment of oral cavity tumours and is a modality worth considering when applying radiotherapy, not only as definitive treatment, but also postoperatively. The use of the CK in the head and neck region requires further investigation.

NTCP modelling of xerostomia after radiotherapy for oropharyngeal cancer using the PRO-CTCAE and CTCAE scoring systems at different time-points post-RT

PurposeThis study aims at determining the parameter values of three normal tissue complication probability (NTCP) models for the contralateral parotid gland, contralateral submandibular gland (SMG) and contralateral salivary glands regarding the endpoint of xerostomia 6–24 months after radiotherapy for oropharynx cancer. MethodsThe treatment and outcome data of 231 patients with favorable risk, HPV-associated oropharyngeal squamous cell carcinoma are analyzed. 60 Gy intensity modulated radiotherapy was delivered to all the patients. The presence and severity of xerostomia was recorded (pre- and post- radiotherapy) by the PRO-CTCAE and the CTCAE scoring systems. In both scoring systems, patients with a change in symptom severity (from baseline) of ≥ 2 were considered responders. ResultsXerostomia was observed in 61.3 %, 39.2 %, 28.6 % and 27.0 % of the patients based on the PRO-CTCAE scoring system at 6-, 12-, 18- and 24-months post-RT, respectively. The AUCs of the contralateral salivary glands ranged between 0.58–0.64 in the LKB model with the gEUD ranging between 20.3 Gy and 24.7 Gy. ConclusionsBased on the PRO-CTCAE scores, mean dose < 22 Gy, V50 < 10 % for the contralateral salivary glands and mean dose < 18 Gy, V45 < 10 % for the contralateral parotid were found to significantly reduce by a factor of 2–3 the risk for radiation induced xerostomia that is observed at 6–24 months post-RT, respectively. Also, gEUD < 22 Gy to the contralateral salivary glands and < 18 Gy to the contralateral parotid was found to significantly reduce the risk for radiation induced xerostomia that is observed at 6–24 months post-RT by 2.0–2.3 times.

Use of Explainable AI Algorithm Revealing Longitudinal Changes in Practice Patterns and Toxicity Models

Dosimetric constraints evolve as clinicians implement practice changes, requiring modeling approaches to be dynamic. We applied a semi-automated explainable artificial intelligence (eAI) algorithm and dashboard visualizations to model dysphagia and xerostomia for head and neck cancer patients. We coupled a large, comprehensive, "real-world" database to the eAI for discovery of features with the strongest combined statistical and machine learning based evidence and to identify clinically actionable thresholds. Cohort included 758 patients treated 2017-2021 for HN cancer with conventional fractionation. Features included age, sex, diagnosis, staging, chemotherapy, smoking and alcohol status, BMI, weight loss, re-simulation, DVH curves, PTV and OAR volumes. Patients were scored for toxicity within 2 yrs of RT for dysphagia grade ≥ 3 and xerostomia grade ≥ 2. Bootstrap resampling of thresholds, ROC-AUC, PR-ROC, SN, SP, F1 and diagnostic odds ratio was used to statistically profile strength of evidence for candidate features. XGBoost models with 10-fold cross validation were repeated (n = 20) to identify mean and CIs for statistical measures of predictions. DVH metrics included standard template values and those with highest statistical evidence and low cross correlation with other features. Backward feature selection was used to identify the most relevant feature subset, where the least informative feature is iteratively removed from the model. This workflow was repeated by year and overall. Annual incidence of dysphagia averaged 0.13 ± 0.02 overall years. Xerostomia incidence decreased from 0.32 to 0.12 (2017-2021). Box-whisker plots by year showed consistent reductions in standard practice toxicity linked DVH metric values. Median dose to superior constrictors (PCM), contralateral parotid and contralateral submandibular gland (SMG) declined from 2017 to 2021 by 48 to 33 Gy, 17 to 10 Gy, and 28 to 22 Gy respectively. Statistics of XGBoost models of dysphagia for all years were ROC-AUC = 0.72 ± 0.05. Strongest overall years predictors were Oral Cavity (OC) D50%[Gy] < 32, inferior PCM Max [Gy] < 60, contralateral SMG D10%[Gy] < 53 and use of Paclitaxel. Xerostomia models were less predictive with ROC-AUC = 0.65 ± 0.05. Strongest predictors over each year were ipsilateral parotid D30%[Gy] < 35, contralateral SMG D96%[Gy] < 18.4, and overall staging < II. Predictive features varied substantially by year for both, showing the most consistency for SMG doses. For example, OC D50%[Gy] < 27 and contralateral SMG D96%[Gy] < 18 dominated xerostomia model in 2017 but not in 2021 when practice norms shifted to lower doses. As OAR doses were systematically reduced, statistical and AI models evidence highlighted contralateral SMG dose as important to both dysphagia and xerostomia for clinical practice change. The "real-world" database + eAI + visualization dashboards provided a method for continuous learning as clinical practice changes.

Clinical Implementation of an Automated IMRT/VMAT Treatment Planning Tool

To create an in-house automated treatment planning tool for IMRT/VMAT treatments and evaluate the dosimetric plan quality against manually generated plans. A scripting application programming interface is employed to interact with a commercial treatment planning system (TPS) to implement automatic plan evaluation and update optimization parameters by mimicking the human planning process. The automated planning performs in an iterative fashion until reaching an acceptable tradeoff among target coverage/dose homogeneity and sparing of critical organs at risk. In each iteration, the dose constraints, priorities, and optimization structures for are automatically updated based on the results of the current iteration. Twenty previously treated plans (10 prostate and 10 head and neck), were preliminarily used to evaluate the performance of the automated planning tool. The differences in target and organ-at-risk metrics from the manually generated clinical plans were analyzed using paired t-test to evaluate clinical acceptability of tour automated planning tool. The current in-house-developed automated planning solution is able to create plans for different disease sites, including head & neck, prostate, pelvis, and lung. So far, the VMAT plans for more than 150 different cases have been generated with the tool. The results for these were also evaluated. Compared to the manually generated clinical head and neck plans, all auto plans achieved PTV D95% coverage and critical organs at risk sparing without statistically significant change in average global Dmax (107.4% for manual vs 107.3% for automated plans). The auto-planning solution provided reduced maximum doses to brainstem and spinal cord (average reductions with standard deviations of 5.1 ± 2.6 Gy and 2.9 ± 1.4 Gy, respectively, all p <0.03), reduced average mean doses to contralateral parotid, ipsilateral parotid, contralateral submandibular gland, pharynx, esophagus, cochleae (reductions of 2.2 ± 2.9 Gy, 4.8 ± 4.7 Gy, 3.6 ± 5.2 Gy, 2.0 ± 7.1 Gy, 3.9 ± 2.6 Gy, 3.8 ± 5.0 Gy, respectively, all p < 0.045). Similar results were observed for the prostate plans. With the same PTV coverage and without statistically significant change in average global Dmax (106.5% for manual vs 106.8% for automated plans), the automated solution provided superior sparing for both bladder and rectum. Bladder V75, V70, V65 were reduced by 0.6% ± 2.1%, 0.8% ± 2.5%, and 0.9% ± 2.9% (all p <0.04), respectively. Rectum V75, V70, V65, V60 were reduced by 1.0% ± 2.3%, 1.2% ± 2.8%, 1.3% ± 3.2%, 1.6% ± 3.6% (all p < 0.01), respectively. Our automated treatment planning solution is capable of efficiently generating VMAT plans for different disease sites with superior dosimetric indices compared to manually generated plans. Our tool is integrated within a commercial TPS platform, so it has the advantage of seamless adoption into the standard workflow to improve plan quality and treatment planning efficiency in our clinic.

Evaluation of Late Toxicities in Postoperative Cases of Oral Cavity Cancer Treated by Intensity-Modulated Radiotherapy (IMRT): A Retrospective Cohort Study

Introduction: Surgical intervention serves as the primary treatment modality for operable oral cavity cancer. However, patients with locally advanced disease or unfavourable prognostic factors often require adjuvant Radiotherapy (RT) with or without concurrent Chemotherapy (CT). Advanced radiation techniques, such as Intensity-Modulated Radiotherapy (IMRT), have shown potential in minimising radiation-related toxicities while ensuring effective tumour control. Aim: To assess common late toxicities, namely xerostomia, dysphagia, and hoarseness, in patients with postoperative Squamous Cell Carcinoma (SCC) of the oral cavity, who received adjuvant RT or concurrent Chemo-Radiotherapy (CRT) utilising IMRT with a Simultaneous Integrated Boost (SIB) approach. Materials and Methods: A retrospective cohort study was conducted in the Department of Radiotherapy at IMS, BHU, Varanasi, Uttar Pradesh, India, from June 2018 to December 2021. Study was done using the medical records of 62 patients with SCC of the oral cavity and received adjuvant radiation by the IMRT technique with or without concurrent CT. Late toxicities were evaluated according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0). Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) software version 28.0, and a logistic regression model was used to establish the association between Organ-At-Risk (OAR) doses and the development of late toxicities. Results: The median age of the study participants was 45 years (range: 25-68), and 95.2% (n=59) of the patients were male. A total of 62 patients (59 male, 3 female) were included. The median follow-up duration was 21.5 months. At two years, the cumulative incidence of xerostomia, dysphagia, and hoarseness was 28.5% (n=8), 21.4% (n=6), and 28.5% (n=8), respectively. Logistic regression showed that both the D mean of &gt;26 Gy to the contralateral parotid (HR=4.32; 95% CI, 1.03- 18.05; p=0.045) and the D mean of &gt;26 Gy to the contralateral Submandibular Gland (SMG) (HR=6.41; 95% CI, 1.48-27.81; p=0.013) were significantly associated with the incidence of xerostomia. The D mean of &gt;47 Gy to the pharyngeal constrictors (HR=17.89; 95% CI, 3.15-101.62; p=0.001) and the D mean of &gt;50 Gy to the larynx (HR=5.77; 95% CI, 1.82-18.24; p=0.003) had a significantly high risk of dysphagia and hoarseness, respectively. Conclusion: Adjuvant IMRT resulted in acceptable rates of late toxicities in oral cancer. Doses to the contralateral parotid and SMGs, pharyngeal constrictors, and larynx had a significant impact on late xerostomia, dysphagia, and hoarseness, respectively.

Feasibility and safety of neck level IB-sparing radiotherapy in nasopharyngeal cancer: a long-term single institution analysis.

Nasopharyngeal cancer (NPC) has a higher prevalence of regional nodal metastasis than other head and neck cancers; however, level IB lymph node involvement is rare. We evaluated the safety and feasibility of level IB-sparing radiotherapy (RT) for NPC patients. We retrospectively reviewed 236 patients with NPC who underwent definitive intensity-modulated RT with or without chemotherapy between 2004 and 2018. Of them, 212 received IB-sparing RT, and 24 received non-IB-sparing RT. We conducted a propensity score matching analysis to compare treatment outcomes according to IB-sparing status. In addition, dosimetric analysis of the salivary glands was performed to identify the relationship between xerostomia and the IB-sparing RT. The median follow-up duration was 78 months (range, 7 to 194 months). Local, regional, and distant recurrences were observed in 11.9%, 6.8%, and 16.1% of patients, respectively. Of the 16 patients with regional recurrence, 14 underwent IB-sparing RT. The most common site categorization of regional recurrence was level II (75%), followed by retropharyngeal lymph nodes (43.8%); however, there was no recurrence at level IB. In the matched cohorts, IB-sparing RT was not significantly related to treatment outcomes. However, IB-sparing RT patients received a significantly lower mean ipsilateral and contralateral submandibular glands doses (all, p < 0.001) and had a lower incidence of chronic xerostomia compared with non-IB-sparing RT patients (p = 0.006). Our results demonstrated that IB-sparing RT is sufficiently safe and feasible for treating NPC. To reduce the occurrence of xerostomia, IB-sparing RT should be considered without compromising target coverage.

Short-term and bystander effects of radiation on murine submandibular glands.

Many patients treated for head and neck cancers experience salivary gland hypofunction due to radiation damage. Understanding the mechanisms of cellular damage induced by radiation treatment is important in order to design methods of radioprotection. In addition, it is crucial to recognize the indirect effects of irradiation and the systemic responses that may alter saliva secretion. In this study, radiation was delivered to murine submandibular glands (SMGs) bilaterally, using a 137Cs gamma ray irradiator, or unilaterally, using a small-animal radiation research platform (SARRP). Analysis at 3, 24 and 48 h showed dynamic changes in mRNA and protein expression in SMGs irradiated bilaterally. Unilateral irradiation using the SARRP caused similar changes in the irradiated SMGs, as well as significant off-target, bystander effects in the non-irradiated contralateral SMGs.

Dosimetric Impact of Simulated Daily Adaptive Radiotherapy with Significantly Reduced Setup Margins in the Definitive Treatment of Head and Neck Cancer

<h3>Purpose/Objective(s)</h3> Even when treating head and neck cancer (HNC) with daily image-guided radiation therapy, setup margins of 3-5 mm are required to ensure adequate coverage of disease due to setup error. These margins lead to additional normal tissue dose that may compromise acute and long-term quality-of-life. The use of daily adaptive radiotherapy (ART) using an online adaptive system significantly reduces the need for a PTV margin, since the targets and organs-at-risk (OAR) are recontoured each fraction. In this study, we hypothesized using daily ART (simulated) with 1 mm margins based on our involved nodal radiotherapy (INRT) paradigm would improve coverage and reduce OAR dose. <h3>Materials/Methods</h3> Ten patients with HNC treated on our institutional phase II INRT trial were selected for this study. Cone-beam CT scans were uploaded to the ETHOS emulator for daily adaptive replanning which was simulated using fractions 5, 10, 15, 20, 25, 30, and 35. Two plans were generated with a 1 mm (reduced) and a 5 mm (conventional) PTV expansion. The dose grid from the delivered, conventional margin plan was transposed onto the CBCT and adapted contours. Separately, a reduced target margin plan optimized on the online adaptive system was created. PTV coverage (70 Gy-gross/primary disease, 66.5 Gy-suspicious nodes, 63 Gy-extended volume surrounding the primary disease) and D1 were calculated for target structures along with the dose to OARs. Comparisons performed via paired two tailed t-test. <h3>Results</h3> Six patients with oropharynx cancer and four patients with larynx cancer were included. Median V100% coverage for 70 Gy (96% vs 95.6%), 66.5 Gy (98.5% vs 76.5%), and 63 Gy (98.9% vs 74.9%) were improved with the adaptive planning (all p-values<0.03). Plan homogeneity was improved in the ART plan (e.g., PTV70 median D1% 72.8 Gy vs 74.8 Gy, all p-values<0.02). The total median dose reduction was 10.8 Gy (interquartile range, IQR 8.0-12.6 Gy) for the ipsilateral submandibular gland (SMG), 12.2 Gy (IQR 7.3-23.5 Gy) for the contralateral SMG, 8.3 Gy (IQR 3.8-12.6 Gy) for the ipsilateral parotid, 8.1 Gy (IQR 4.4-11.0 Gy) for the contralateral parotid, 7.0 Gy (IQR 4.5-9.1 Gy) for larynx, 6.6 Gy (IQR 2.7-8.4 Gy) for oral cavity, and 8.6 Gy (IQR 5.9-12.1 Gy) for constrictors. <h3>Conclusion</h3> Simulated daily ART using a 1 mm PTV margin provided significant improvement over conventional PTV margins in coverage and critical OAR dosimetry. This small proof-of-concept study suggests this approach may lead to improved quality-of-life while preserving or improving tumor coverage. Further evaluation is needed to assess the resources needed to implement daily adaptations. A phase II randomized trial of daily ART is underway to determine if dosimetric improvements lead to similar gains in patient-reported outcomes.

Rare condition of unilateral submandibular gland aplasia and its diagnostic significance in oral cavity carcinoma

BackgroundThe unilateral submandibular gland aplasia (agenesis) is a rare, asymptomatic condition usually discovered incidentally on imaging. This is associated commonly with either compensatory hypertrophy of contralateral submandibular gland or sublingual glands.Case presentationWe report the case of a 34-year-old male with incidentally detected unilateral submandibular gland aplasia associated with hypertrophy of ipsilateral sublingual gland, demonstrated by imaging modalities, where we have highlighted the diagnostic significance of such rare findings in oncology, particularly in oral cavity carcinoma cases with metastatic submandibular lymph nodes (level IB) mimicking as submandibular gland. Hence, lymphadenopathy can be missed preoperatively which is an important part of staging and treatment planning.ConclusionsAim of the present report is to create awareness about such rare entity in both clinicians/radiologists and highlight the imaging features for correct identification and to avoid any diagnostic dilemmas.

Sural Nerve Vertical Cross-Face Graft for Lacrimal Gland Neurotization to Improve Tear Secretion in Neurodeprivative Dry Eye.

No specific interventions have been reported for the treatment of severe neurodeprivative dry eye disease owing to facial nerve palsy. We describe herein the feasibility of a novel surgical procedure to reinnervate the lacrimal gland and report the preliminary outcomes of the first series of patients who were treated accordingly. Prospective interventional case series including consecutive patients affected by facial palsy with absolute deficiency of tear secretion who underwent lacrimal gland neurotization. A sural nerve vertical cross-face graft was used to connect the lacrimal gland with the parasympathetic branch of the lingual nerve directed to the contralateral submandibular gland. Lacrimal neurotization was performed uneventfully in 10 patients (4 M, 6 F; mean age 47.1 ± 17.1 years). In all cases, the procedure was combined with facial reanimation, while corneal neurotization was performed in 4 cases. One year postoperatively, mean values of a Schirmer test increased significantly compared with baseline values (7.56 ± 7.84 vs. 0 ± 0 mm/5 min; P = 0.02), while the mean daily number of instillation of tear substitutes decreased significantly (21.8 ± 4.5 vs. 7.1 ± 2.2; P = 0.009). Overall, all patients were satisfied with surgery (very satisfied: n = 7 and satisfied: n = 2). No major postoperative complications occurred. Vertical cross-face using a sural nerve graft to connect the lacrimal gland with the contralateral submandibular gland is a novel technique for treating patients with facial nerve palsy and severe neurodeprivative dry eye disease. This surgery both performed alone and combined with corneal neurotization is able to improve tear secretion and decrease the need for frequent instillations of tear substitutes.

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.

Impact of Oral Cavity Dosimetry on Patient Reported Xerostomia and Dysgeusia in the Setting of Deintensified Chemoradiotherapy

PurposeTo determine the relationship between mean oral cavity (OC) dose (treated as a singular organ at risk) to patient reported xerostomia and dysgeusia. In addition, we will examine the relationship between oral cavity substructure doses to patient reported xerostomia and dysgeusia. All patients were treated in the setting of deintensification (60 Gy). Methods and MaterialsIn the study, 184 and 177 prospectively enrolled patients for de-escalated chemoradiotherapy (CRT) for human papillomavirus (HPV)-positive oropharyngeal cancer submitted PROs at 6 and 12 months, respectively using Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events questionnaire. Patient's OC consisting of the following substructures were segmented: oral tongue, base of tongue, floor of mouth, hard and soft palate, cheek mucosa, and upper and lower lip mucosa. Ordinal logistic regression (no/mild vs moderate vs severe/very severe symptoms) was used to compare organs at risk dosimetry to patient reported xerostomia and dysgeusia at 6 and 12 months. Multivariate ordinal logistic regression models were generated. ResultsMean dose to the contralateral parotid (P = .04), OC (P = .04), and baseline patient reported xerostomia (P = .009) were significantly associated with xerostomia severity at 6 months. Only baseline xerostomia (P = .02) and mean dose to the contralateral submandibular gland (P = .0001) were significantly associated with xerostomia severity at 12 months. The only significant factor related to dysgeusia at either time point was mean dose to the OC at 12 months (P = .009). On examining substructures, the mean dose to the floor of mouth was implicated for the dose relationship to 6-month xerostomia (P = .04), and the oral tongue was found to be implicated for the relationship for 12-month dysgeusia (P = .04). ConclusionsThe mean dose to the OC was found to relate to xerostomia symptoms at 6 months post-CRT and dysgeusia symptoms at 12 months post-CRT. The mean dose to the floor of mouth and oral tongue appeared to drive this relationship for xerostomia and dysgeusia symptoms, respectively. This work suggests the floor of mouth and oral tongue should be prioritized during planning over the rest of the OC. The effect of OC dose relative to other salivary structures for xerostomia appeared to depend on time post-CRT.

Submandibular gland extirpation during neck dissection, is it truly justified?

There is no oncologic basis for the extirpation of the submandibular gland (SMG) in early oral squamous cell carcinomas (OSCC) unless the SMG is truly infiltrated by the tumor. The study aimed at assessing the true involvement of SMG in OSCC and to determine whether the gland extirpation in all cases is justified. This study prospectively evaluated the pathological involvement of SMG by OSCC in 281 patients, who were diagnosed with OSCC and underwent wide local excision of the primary tumor with simultaneous neck dissection. Among 281 patients, 29 (10%) cases underwent bilateral neck dissection. A total of 310 SMG were evaluated. Involvement of SMG was seen in 5 (1.6%) cases. SMG metastases from Level Ib were seen in 3 (0.9%) of cases, whereas 0.6% showed direct SMG infiltration from the primary tumor. The advanced floor of mouth and lower alveolus cases had a higher tendency to infiltrate SMG. In none of the cases, bilateral or contralateral SMG was involved. The findings of this study show that the extirpation of SMG in all cases is truly irrational. Preserving the SMG is justified in early OSCC with no nodal metastasis. However, SMG preservation is case dependent and is an individual preference. Further studies are required to assess the locoregional control rate and salivary flow rate in postradiotherapy cases where SMG is preserved.

Clinical Use of A Priori Knowledge of Organ-At-Risk Sparing During Radiation Therapy Treatment for Oropharyngeal Cancer: Dosimetric and Patient Reported Outcome Improvements

PurposeThis study aimed to prospectively assess dosimetric and clinical effects of treatment planners having a priori knowledge of the maximum achievable dose sparing for organs at risk (OARs) for patients with oropharynx cancer receiving intensity modulated radiation therapy (RT). Methods and MaterialsWe examined patients with oropharynx cancer who were treated in prospective clinical trials between February 2012 and April 2019 at our institution. A tool generating estimates of maximum achievable dose sparing for OARs (feasibility dose-volume histogram [FDVH]) was used clinically starting July 2016. Patients were divided into 2 cohorts: Before (ie, baseline) and after (ie, FDVH-guided) FDVH. Doses received by various OARs were compared with those estimated to be achievable per FDVH, and that difference was defined as the excess of feasible dose (EFD). Patient-reported outcome (PRO) questionnaires were completed at 3, 6, and 12 months after treatment. The baseline and FDVH-guided cohorts were compared in terms of EFD, plan quality metrics, and post-RT PRO assessments. ResultsA total of 139 patients were included in the analysis (60 in the baseline cohort, 79 in the FDVH-guided cohort). The FDVH-guided cohort had lower EFD to the contralateral parotid by 4.1 Gy, the ipsilateral parotid by 10.6 Gy, the larynx by 4.3 Gy, the oral cavity by 1.5 Gy, and the contralateral submandibular gland by 0.4 Gy. Plan quality metrics were similar between the cohorts. Less variation of EFD was seen in the FDVH-guided cohort for the parotid glands and contralateral submandibular gland (P < .05). The average post-RT PROs were better in the FVHD cohort versus baseline (particularly at the 6-month timepoint for dry mouth frequency, sticky saliva, meal enjoyment, severity of pain, and Eating Assessment Tool 10 composite [swallowing]; P < .05). ConclusionsUse of FDVH was associated with improved and less variable OAR sparing for clinically delivered plans. FDVH-guided patients had improved PROs compared with baseline with a variety of outcomes significantly improved at 6 months after treatment.

A Priori Knowledge of Maximum Achievable Organ at Risk Sparing: Impact on Organ Doses and Patient Reported Outcomes

IMRT planning is challenging, at least in part, due to the essentially-infinite number of possibilities, and since the planner is never sure that they have gotten "the best", or at least "nearly the best" achievable plan. We prospectively assessed the impact of providing IMRT planners with a priori knowledge of the maximum achievable dose sparing for organs at risk (OARs) for patients on both dosimetric and clinical endpoints. We hypothesized that a priori knowledge of maximum achievable sparing would improve dosimetric and clinical (i.e., patient reported outcome) measures.We examined patients receiving IMRT for oropharynx cancer on prospective clinical trials from 2012-2019 at our institution. A tool that generates estimates of maximum achievable dose sparing for organs at risk was used starting July 2016. Patients treated pre-implementation (i.e., baseline) and post-implementation (i.e., experimental) were compared for the endpoints: (1) Doses received by various OARs MINUS doses achievable (per the tool), termed the 'excess of feasible dose'; (2) Plan quality metrics (e.g., target homogeneity and conformity), and (3) Patient reported outcomes (PRO) per questionnaires completed at 3-, 6- and 12-months post-treatment.139 patients were analyzed (60-baseline cohort, 79-experimental). (1) The excess of feasible dose was lower in the experimental (vs baseline) cohort, for the contralateral parotid (9.6 vs 5.5 Gy; P < 0.001), the ipsilateral parotid (17.6 vs 6.8 Gy; P < 0.001), larynx (12.5 vs 8.2 Gy; P = < 0.001), oral cavity by (15.8 vs 14.3 Gy; P = 0.002), and contralateral submandibular gland (17.4 vs 17 Gy; P = 0.40). Lesser variation of excess of feasible dose (i.e., more consistent sparing) was seen in the experimental (vs. baseline) cohort for the parotid and contralateral submandibular glands (P < 0.05). (2) Some small differences in target homogeneity and conformity were observed but not felt to be clinically significant. (3) The average post-RT PROs were significantly better in the experimental cohort vs baseline at 6 months post-RT. Dry mouth severity, sticky saliva, meal enjoyment, severity of pain, and EAT10 composite (swallowing) were all significantly improved; P < 0.05).Clinical plans aided by an a priori estimate of maximum achievable dose sparing for OARs was associated with improved (and more consistent) OAR sparing and better clinical outcomes (i.e., better post-RT PROs). Clinical implementation of this tool can yield quantifiable dosimetric and patient benefits.

Dosimetric, Volumetric, and Positional Stability After Submandibular Gland Transfer

Xerostomia and its effects are significant challenges for patients receiving radiation therapy (RT) for head and neck cancers (HNC). Submandibular gland (SMG) transfer has demonstrated promise in reduction of subjective and objective xerostomia. However, SMG transfer investigations have largely employed conventional RT or adjuvant RT, with little evaluation in patients treated with definitive modern RT. Furthermore, there has been no assessment of whether anatomic changes during RT may affect the potential benefits of SMG. We sought to characterize the preliminary dosimetric, volumetric, and positional stability of SMG transfer on an ongoing prospective case-control study.Previously untreated patients with oropharyngeal HNC, N0-N2b (unilateral neck disease) were enrolled. SMG transfers were performed by experienced surgeons per the Jha and Seikaly technique, transposing the gland anteriorly into the submental neck. Definitive VMAT plans were optimized according to institutional guidelines (goal mean SMG dose < 26 Gy), patients were treated to 70 Gy in 33-35 fractions. To assess the stability of planned dose and change in SMG volume and position, repeat CT simulation was performed at week 4. These were rigidly registered to the initial simulation centered about the mandible and hyoid, with the original dose superimposed. Glands were meticulously re-contoured on both scans. Statistical comparisons were by Wilcoxon paired rank tests or Mann-Whitney U tests.To date, 11 patients with SMG transfer and 5 controls have been treated, all male. In 3 cases, no re-simulation was available and a week 4 cone-beam CT was used. The mean time from gland transfer to RT start was 28.3 days. From simulation to week 4, transposed SMGs shrunk by a mean of 3.49 cc (27.6%), no different than corresponding contralateral SMGs at 2.37 cc (23.5%) or control SMGs (SMGs in control patients on the N0 side) at 1.71 cc (22.8%). There were no associations between SMG volume change and dose by linear regression or Spearman's rank correlation. Transposed SMGs had an average mean dose of 28.2 Gy on initial sim. At week 4, extrapolated to a full course, this increased to 32.8 Gy (P = 0.01). Average mean dose to control glands was 46 Gy, statistically greater than transposed glands (P = 0.03), with a non-significant 1.5 Gy increase at week 4. Mean change in geometric position was 0.45 cm for transposed glands, 0.37 cm for contralateral glands (P = .19), and 0.32 for control glands (P = .37).SMG transfer achieved significant reduction in dose compared to controls. While SMG shrinkage and movement were not separately different from contralateral or control glands, the higher dose at re-simulation indicates these factors may together have an effect, calling for careful SMG delineation, attention to daily position and image guidance, and planned re-simulation in order to maximize dosimetric benefits. Our trial is ongoing and clinical and QoL endpoints will be examined with these findings in mind.

Comprehensive Assessment of the Relationship Between Oral Cavity Dosimetry and Patient Reported Xerostomia and Dysgeusia

Xerostomia and dysgeusia are two common and severe complications for patients undergoing head and neck chemoradiotherapy (CRT). Literature suggests a relationship between mean oral cavity (OC) doses and worsening xerostomia and dysgeusia. However, limited data exists identifying which substructures of the oral cavity are most related to patient reported outcomes (PROs) or how oral cavity dosimetry should be prioritized in relationship to other salivary glands during planning. We hypothesized that only certain substructures of the OC will be related to patient reported xerostomia and dysgeusia and that OC dose will be less impactful than contralateral major salivary gland dose for patient reported xerostomia and dysgeusia.184 and 177 prospectively enrolled patients for de-escalated CRT for HPV-positive oropharyngeal cancer submitted PROs at 6 and 12 months, respectively using PRO-CTCAE questionnaire. Patient's OC consisting of the following substructures were segmented: oral tongue, base of tongue, floor of mouth, hard and soft palate, cheek mucosa, and upper and lower lip mucosa. Ordinal logistic regression (no/mild vs. moderate vs. severe/very severe symptoms) was used to compare OAR dosimetry to patient reported xerostomia and dysgeusia at 6 and 12 months. Multivariate ordinal logistic regression models were determined using forward/backward AIC minimization to minimize the number of predictive variables.Mean dose to the contralateral parotid (P = 0.04), OC (P = 0.04), and baseline patient reported xerostomia (P = 0.009) were significantly associated with xerostomia severity at 6 months. Only baseline xerostomia (P = 0.02) and mean dose to the contralateral submandibular gland (P = 0.0001) were significantly associated with xerostomia severity at 12 months. The only significant factor related to dysgeusia at either time point was mean dose to the OC at 12 months (P = 0.009). Upon examining substructures, the mean dose to the floor of mouth was implicated for the dose relationship to 6-month xerostomia (P = 0.04) and the oral tongue was found to be implicated for the relationship for 12-month dysgeusia (P = 0.04).The mean dose to the OC was found to relate to xerostomia symptoms at 6 months post-CRT and dysgeusia symptoms at 12 months post-CRT. The mean dose to the floor of mouth and oral tongue appeared to drive this relationship for xerostomia and dysgeusia symptoms, respectively. This work suggests the floor of mouth and oral tongue should be prioritized during planning over the rest of the OC. The impact of OC dose relative to other salivary structures for xerostomia appeared to depend on time post-CRT (comparable to contralateral parotid at 6 months and not significant at 12 months).

Prospective Study of the Impact of Artificial Intelligence Organ-at-risk Dose Prediction on Head and Neck Radiotherapy Plan Quality

Radiation treatment planning for head and neck cancer patients is complex, as the target and normal tissue anatomy are intertwined. The lowest achievable dose for each individual organ-at-risk (OAR) is unknown a priori. Artificial intelligence (AI) holds promise as an accurate predictor of the expected dose distribution for OARs. We prospectively studied a decision-support tool (DST) that leverages AI to predict OAR doses by identifying closely matched patients previously treated in an institutional database. The DST used an AI-based dose prediction model based on 376 volumetric modulated arc therapy (VMAT) plans previously treated at our institution. Under an IRB-approved prospective trial, the physician first generated a custom OAR directive for 50 consecutive patients (physician directive, PD) without engaging the DST. The treating physician then used the DST to identify the OAR doses from the closest matched patient (AI directive, AD), and the final Hybrid Directive (HD) for each OAR was the lower value of the AD and PD. The HD OAR metrics were used as the goals for treatment planning. A dose difference of 3 Gray (Gy) was considered clinically significant. Out of the 50 patients, the AD and PD estimates were within 3 Gy for 55% of all OARs, ranging from 27% (esophagus) to 78% (inferior constrictor). The AD was significantly lower for 23% of all estimates (ranging from 13% for the superficial parotid gland to 39% for superior constrictor dose), whereas the PD was lower in 22% of all estimates (ranging from 6% for inferior constrictor to 31% of the contralateral submandibular gland). When one directive was more than 3Gy lower than its comparison, the clinical plan typically met the lower constraint and the achieved average OAR dose reductions of 8.0Gy (AD >3Gy low and used) and 10.9Gy (PD >3Gy low and used). The reduction of OAR doses is mostly statistically significant (P<0.05). Use of the DST improved the final plan metrics in a significant percentage of patients (P<0.05, range 0.0001-0.046), but strictly relying on its estimates would have led to an inferior plan in an equal number of cases. While a more robust model informed by additional cases may further improve the accuracy of AI-based prediction tools, physician input is currently still imperative to generate an optimal plan.Abstract 197; TableOARPredictionAchieved PlanAD is LOWER than PD by > 3 Gy (%case)PD is LOWER than AD by > 3 Gy (%case)PD & AD within 3 Gy (%case)AD is LOWER than PD by > 3 GyPD is LOWER than AD by > 3 Gy%case AchievedAvg OAR reduction (Gy)%case AchievedAvg OAR reduction (Gy)Esophagus26%47%27%83%10.3*100%11.2*Larynx21%18%62%100%7.2*83%6.1*Constrictor_Sup39%17%44%100%7.5*100%13.6*Constrictor_Mid27%27%46%100%11.5*100%12.8*Constrictor_Inf16%6%78%60%8.1*50%6.6*Parotid_CL16%16%68%29%5.580%9.2*Sup_Parotid_IL13%10%77%100%6.9*100%12.3*SMG_CL15%31%54%100%7.2*100%19.4*Oral Cavity33%26%41%60%8.3*100%6.4**Statistical significance of the dose comparison, P < .05 Open table in a new tab

Modified technique of submandibular gland transfer followed by intensity modulated radiotherapy to reduce xerostomia in head and neck cancer patients.

Xerostomia is one of the most common long-term adverse effects of radiotherapy for head and neck cancer patients. Contralateral submandibular gland transfer (SMG-T) before radiotherapy was shown to reduce xerostomia compared to pilocarpine. We sought to evaluate a modification of this surgery preserving the ipsilateral facial artery and vein to simplify the SMG-T. Eighteen patients planned for head and neck intensity modulated radiotherapy to both necks were reviewed. Surgical complications were recorded. The grade of xerostomia was assessed after treatment completion. There were no minor or major complications resulting from the modified SMG-T. At 24.5-months follow up, the incidence of post-treatment moderate to severe xerostomia was 16.7%. No locoregional recurrence occurred. Only one patient had distant solitary lung metastasis. The modified SMG-T technique is a practical and effective method to reduce the dose of radiation to the contralateral SMG and limit post-treatment xerostomia.

Prediction model for tube feeding dependency during chemoradiotherapy for at least four weeks in head and neck cancer patients: A tool for prophylactic gastrostomy decision making.

Chemoradiation and bioradiation (CRT/BRT) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) often comes with high toxicity rates, interfering with oral intake and leading to temporary tube feeding (TF) dependency. High-quality scientific evidence for indicators of prophylactic gastrostomy insertion is not available. The aim of this retrospective cohort study was to develop a prediction model to identify patients who need prophylactic gastrostomy insertion, defined as the expected use of TF for at least four weeks. Four-hundred-fifty LAHNSCC patients receiving CRT/BRT with curative intent between 2013 and 2016 were included in the study. Primary outcome was TF-dependency for four weeks or longer. Patient, tumor, and treatment characteristics were extracted from the medical records and their effects on the use of TF were analyzed using univariable and multivariable analysis. The prediction model was internally validated using bootstrapping techniques. Sixty-five percent (294/450 patients) required TF for four weeks or longer. Variables included in the model were: body mass index and adjusted diet at start of CRT/BRT, percentage weight change at baseline, World Health Organization performance status, tumor subsite, TNM-classification, CRT/BRT, mean radiation dose on the contralateral submandibular and parotid gland. The corrected Area Under the Curve after internal validation was 72.3%, indicating good discriminative properties of the prediction model. We developed and internally validated a prediction model that is intended to estimate TF-dependency for at least four weeks in LAHNSCC patients treated with CRT/BRT. This model can be used as a tool to support personalized decision making on prophylactic gastrostomy insertion.