Mean Parotid Research Articles

Clinical Experience With an Offline Adaptive Radiation Therapy Head and Neck Program: Dosimetric Benefits and Opportunities for Patient Selection

PurposeTo develop a LINAC-based adaptive radiotherapy (ART) workflow for head and neck that is informed by automated image tracking to identify major anatomic changes warranting adaptation. In this study we report our initial clinical experience with the program and an investigation into potential trigger signals for ART. Methods and MaterialsOffline ART was systematically performed on patients receiving radiotherapy for head and neck cancer on C-arm LINACs. Adaptations were performed at a single timepoint during treatment with resimulation approximately 3 weeks into treatment. Throughout treatment, all patients were tracked using an automated image tracking system called the IN_HOUSE_SOFTWARE*. IN_HOUSE_SOFTWARE measures volumetric changes in gross tumor volumes (GTV) and selected normal tissues via cone-beam computed tomography (CBCT) scans and deformable registration. The benefit of ART was determined by comparing adaptive plan dosimetry and normal tissue complication probabilities (NTCP) against the initial plans recalculated on resimulation CT scans. Dosimetric differences were then correlated with IN_HOUSE_SOFTWARE-measured volume changes to identify patient-specific triggers for ART. Candidate trigger variables were evaluated using receiver operator characteristic (ROC) analysis. ResultsN=46 patients received ART in this study. Amongst these patients, we observed a significant decrease in dose to the submandibular glands (mean ± standard deviation: -219.2±291.2cGy, p-value<10−5), parotids (-68.2±197.7cGy, p-value=0.001) and oral cavity (-238.7±206.7cGy, p-value<10−5) with the adaptive plan. NTCPs for xerostomia computed from mean parotid doses also decreased significantly with the adaptive plans (p-value=0.008). We also observed systematic intra-treatment volume reductions (ΔV) for GTVs and normal tissues. Candidate triggers were identified which did predict significant improvement with ART including parotid ΔV=7%, neck ΔV=2%, and nodal GTV ΔV=29%. ConclusionsSystematic offline head and neck ART was successfully deployed on conventional LINACs and reduced doses to critical salivary structures and oral cavity. Automated CBCT tracking provided information regarding anatomic changes that may aid patient-specific triggering for ART. (*Anonymized for review)

Results of a Multi-institutional Randomized Phase 3 Trial of Parotid-Sparing Whole Brain Radiotherapy

Observational studies have reported that xerostomia is common after conventional whole brain radiotherapy (WBRT) and associated with parotid dose. In this multi-institutional, single-blind randomized controlled trial, we hypothesized that patient-reported xerostomia is reduced in patients randomized to parotid-sparing vs. standard WBRT fields. Between 2018 and 2021, patients receiving conventional WBRT (30-35 Gy in 10-15 fractions) for any diagnosis were enrolled at 3 academic institutions. Patients were randomized between standard WBRT fields covering the C1 vertebra with no prospective parotid delineation (control) vs. parotid-sparing fields without C1 coverage (experimental). Patients completed the University of Michigan Xerostomia Questionnaire (Scored 0-100, higher is worse) at baseline, EndRT, 2 weeks, 1 month, 3 months, and 6 months. Patients were excluded from toxicity analyses if baseline xerostomia score was >50 or if they did not complete any post-baseline questionnaires. The primary endpoint was proportion of patients with ≥15 point absolute increase in xerostomia score from baseline to 1 month; 108 patients were needed for an 80% power to detect a 22% absolute difference (1-sided significance of 0.05). The secondary endpoint was the rate of marginal failures. The study closed early after 56 patients were randomized. Median survival was 4.6 months. 46 patients (23 in each arm) were eligible for analysis. Mean parotid dose was 17 vs. 10 Gy in the standard vs. parotid-sparing arms, respectively. The table below shows mean xerostomia score and proportion of patients with ≥15 increase in xerostomia score at each time point. There was no difference in the proportion of patients experiencing ≥15 increase in xerostomia score at 1 month, though there was a trend toward lower xerostomia score at 1 month in patients randomized to parotid-sparing fields (p = 0.07, Table). Xerostomia rates were also significantly improved in the parotid-sparing arm at EndRT (p = 0.03), but no longer-term difference was observed with greater attrition at 3 and 6 months. On linear regression, there was a trend toward association between mean parotid dose and xerostomia score at 1 month (p = 0.06). There were no reported marginal failures in either arm. Parotid-sparing without coverage of the C1 vertebra appears safe and may meaningfully reduce acute xerostomia in patients with limited life expectancy who are candidates for conventional WBRT, although the study was underpowered to detect a significant difference at 1 month.

Mid-treatment 18F-FDG PET imaging changes in parotid gland correlates to radiation-induced xerostomia

BackgroundThe aim of this study was to measure functional changes in parotid glands using mid-treatment FDG-PET/CT and correlate early imaging changes to subsequent xerostomia in mucosal head and neck squamous cell carcinoma patients undergoing radiotherapy. Materials and Methods56 patients from two prospective imaging biomarker studies underwent FDG-PET/CT at baseline and during radiotherapy (week 3). Both parotid glands were volumetrically delineated at each time point. PET parameter SUVmedian were calculated for ipsilateral and contralateral parotid glands.Absolute and relative change (Δ) in SUVmedian were correlated to moderate-severe xerostomia (CTCAE grade ≥ 2) at 6 months. Four predictive models were subsequently created using multivariate logistic regression using clinical and radiotherapy planning parameters. Model performance was calculated using ROC analysis and compared using Akaike information criterion (AIC) Results29 patients (51.8%) developed grade ≥ 2 xerostomia. Compared to baseline, there was an increase in SUVmedian at week 3 in ipsilateral (8.4%) and contralateral (5.5%) parotid glands. Increase in ipsilateral parotid Δ SUVmedian (p = 0.04) and contralateral mean parotid dose (p = 0.04) were correlated to xerostomia.The reference ‘clinical’ model correlated to xerostomia (AUC 0.667, AIC 70.9). Addition of ipsilateral parotid Δ SUVmedian to the clinical model resulted in the highest correlation to xerostomia (AUC 0.777, AIC 65.4). ConclusionOur study shows functional changes occurring in the parotid gland early during radiotherapy. We demonstrate that integration of baseline and mid-treatment FDG-PET/CT changes in the parotid gland with clinical factors has the potential to improve xerostomia risk prediction which could be utilised for personalised head and neck radiotherapy.

A Prospective Cohort Study Analyzing Radiation-Induced Xerostomia and Quality of Life of Head and Neck Cancer Patients Treated With Intensity-Modulated Radiotherapy and 3D Conformal Radiotherapy Techniques at a Tertiary Cancer Center in Eastern India.

Introduction Cancer of the head and neck is one of the most common cancers in India. Radiotherapy (RT) plays a vital role in the management of head and neck cancer both as a curative and adjuvant modality. Xerostomia is the most common acute and late toxicity. Therefore, this study aimed to analyzeradiation-induced xerostomia and the quality of life of patients treated with intensity-modulated radiotherapy (IMRT) and three-dimensional (3D) conformal radiotherapy (3DCRT). Objectives We aimto evaluate radiation-induced acute xerostomia both subjectively and objectively at three-monthand one-year post-radiotherapy follow-up period in patients who received radiotherapy in conformal technique (IMRT) to the head and neck region and compare it with those who received the 3DCRT technique. We also aim to assess the recovery of salivary flowin the third month post-radiotherapy by measuring the parotid scintigraphy excretion fraction. Materials and methods Forty patients with head and neck squamous cell carcinoma (SCC) were randomly assigned to the IMRT and 3DCRT arms. Xerostomia during radiation and at three-monthand one-year post-radiotherapy follow-up was assessed subjectively using the xerostomia-related quality of life (XeQOL)questionnaire and objectively by measuring the salivary flow rate and parotid scintigraphy. Results The result is analyzed using an independent t-test, Mann-Whitney U test, and Fisher's exact test. The analysis showed that patients treated with radiation by IMRT showed better XeQOL scores (43.40±2.326 in IMRT and 52.10±2.573 in 3DCRT, p<0.001) and Eating Assessment Tool-10 (EAT-10) score (27.65±2.796 in IMRT and 33.80±1.936 in 3DCRT, p<0.001) compared to those treated with 3DCRT. Analysis of the excretion fraction (EF%) of parotid scintigraphy depicted improvement in EF% for both right and left parotids in the IMRT arm with statisticalsignificance (for right parotid, 25.22±12.98 in IMRT and 19.60±10.17 in 3DCRT, p=0.136, and for left parotid, 28.03±12.51 in IMRT and 15.35±11.49 in 3DCRT, p=0.0019). The mean rate of flow (ROF) of saliva showed a declining trend during the end of radiotherapy treatment compared to baseline, but the mean ROF of saliva was better in IMRT compared to 3DCRT, and the difference was statistically significant. The ROF of saliva starts improving during the one-year post-radiotherapy follow-up period. Pearson's chi-square test was used to analyzethe correlation between mean parotid dose with EF% of parotid scintigraphy,and it showed a negative correlation, which is statistically significant for both 3DCRT and IMRT arms. Conclusion Xerostomia can be reduced by precision radiotherapies such as the parotid-sparing IMRT technique in head and neck cancer patients, hence improving the quality of life.

Development of prediction model for mean parotid dose of HNC undergoing radiotherapy - A single institutional study

Development of prediction model for mean parotid dose of HNC undergoing radiotherapy - A single institutional study

Can Superficial Parotid Sparing Alone Reduce Xerostomia? A Retrospective Study Correlating Type of Tobacco Use, Chronic Xerostomia and Parotid Sparing

<h3>Purpose/Objective(s)</h3> Head and neck cancer is one of the most common cancers in India. Tobacco chewing is the most widespread form of tobacco consumption. Majority of the patients present in locally advanced stage and achieving parotid sparing with IMRT in these patients can be challenging. We aimed to correlate the incidence of chronic xerostomia with the type of tobacco use and parotid volumes. <h3>Materials/Methods</h3> Patients with squamous carcinomas of head and neck region treated with conventionally fractionated curative-intent radiotherapy (bilateral neck) to a dose of 60-70 Gy between June 2017 and March 2020 were included in the study. The superficial and deep lobes of parotid were contoured retrospectively and the dosimetric data along with physician-assessed Radiation Therapy Oncology Group (RTOG) xerostomia toxicity grades at one year were retrieved. The individual, superficial and deep lobe parotids were considered spared if the mean dose was less than 26Gy. Patients were divided into five groups: Group 1 constituted bilateral parotid-spared, Group 2 of contralateral parotid-spared, Group 3 of contralateral superficial parotid-spared, Group 4 of bilateral superficial parotid-spared, and Group 5 where no sparing could be achieved. The groups were compared using chi-square test. <h3>Results</h3> 174 patients were included in the study. The median age was 59 years (IRQ 20 - 89). Chewing (40%), followed by smoking (35%) were the most frequent forms of tobacco consumption. The most common subsite was oropharynx (30.5%) followed by hypopharynx (26.4%), and about 83% had locally advanced disease. The mean bilateral parotid volume was 55.9 cc (18-130 cc). Tobacco chewers had significantly smaller mean parotid (53cc vs 60cc, p=0.02) and submandibular gland volumes (6cc vs 14cc, p<0.001) as compared to smokers. Bilateral or contralateral parotid sparing was achieved in 62.7%, bilateral or contralateral superficial lobe in 27.6%, and no sparing in 9.8% of patients. At one year, grade 0/I xerostomia was reported by 89.5%, and ≥grade II xerostomia in 11.5%. The grade of xerostomia was similar in smokers and chewers (p=0.95). The ipsilateral (26.5 Gy vs 37.8 Gy, p <0.001) and contralateral (23.3 Gy vs 34.1 Gy, p <0.001) superficial parotid mean dose in patients with grade 0/I and ≥grade II xerostomia was significantly different. Patients with bilateral or contralateral superficial lobe sparing had lower rates of grade II/III xerostomia compared to no sparing group (p<0.001). <h3>Conclusion</h3> Tobacco chewers have smaller parotid and submandibular glands compared to smokers. This did not impact the sparing of glands or the severity of xerostomia. Contralateral or bilateral superficial parotid sparing translated into superior salivary gland function at 1 year.

Dosimetric Comparison of Intensity Modulated Radiotherapy (IMRT) and Intensity Modulated Proton Therapy (IMPT) for Novel Oral Tongue Avoidance Concept in Low-Risk Squamous Cell Carcinoma of the Oral Tongue

<h3>Purpose/Objective(s)</h3> A subset of favorable oral tongue squamous cell carcinoma patients who undergo adequate surgical resection are at low risk of local recurrence to the primary site. Since irradiation of the primary site is the major cause of treatment morbidity during adjuvant radiotherapy, avoidance of this target while still treating the at-risk lymph nodes including the intervening lymphatics between the tongue and neck is an attractive potential treatment strategy. Prior to initiation of an investigator-initiated trial, we sought to quantify the dosimetric advantage of this strategy, hypothesizing intensity modulated proton therapy (IMPT) may further reduce dose to organs at risk (OAR) when avoiding the oral tongue compared to intensity modulated radiation therapy (IMRT). <h3>Materials/Methods</h3> Five consecutive patients with oral tongue cancer treated with postoperative radiation therapy from 8/2020 to 9/2021 were retrospectively reviewed. Novel Clinical Target Volume (CTV) contours were generated that excluded the oral tongue while maintaining coverage of at-risk lymph nodes. Comparison IMRT (X) and IMPT (PBT) plans were generated using both standard treatment volumes (Control) and oral tongue avoidance volumes (Study) (n=4 plans per patient). Dosimetric variables for critical OARs were compared using the paired t-test. <h3>Results</h3> Patients had T1-2 and N0-N2b disease with complete margin-negative partial or hemiglossectomy and bilateral neck dissections. The prescribed dose was 60 Gy in 30 fractions. D95% CTV coverage was similar between X and PBT plans for both Control and Study target volumes. Comparing Control to Study plans, both X (58.9 Gy vs. 38.3 Gy, p=0.007) and PBT (60.2 Gy vs. 26.1 Gy, p<0.001) decreased the mean dose to the oral cavity (OC). Similar results were demonstrated for mean pharyngeal constrictor dose with X (47.7 Gy vs. 44.6 Gy, p=0.003) and PBT (45.0 Gy vs. 34.9 Gy, p=0.001). There was no difference between Control and Study plans for larynx (p>0.19) or parotid (p>0.11) mean dose, or mandible max dose (p>0.59). Comparing the Study plans alone, PBT resulted in a significant reduction in mean OC dose (38.3 Gy vs. 26.1 Gy, p=0.007) and reduction in mean parotid dose (23.3 Gy vs.19.3 Gy, p=0.03) compared to X. For Control plans, there was no difference in OC dose using PBT compared to X but an improvement in mean parotid dose (26.6 Gy vs 19.7 Gy, p=0.02). <h3>Conclusion</h3> This study quantifies the dosimetric advantage of avoiding the oral tongue while still treating the at-risk intervening lymphatics and the bilateral necks during adjuvant radiotherapy for oral tongue cancer. The dosimetric difference between PBT and X was most prominent with an oral tongue avoidance strategy. Prospective studies are warranted to evaluate the clinical efficacy of oral tongue avoidance for favorable oral tongue cancer patients with indications for elective nodal irradiation.

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.

Recurrence and Quality-of-Life Following Involved Node Radiotherapy for Head and Neck Squamous Cell Carcinoma: Initial Results From the Phase II INRT-Air Trial

Elective neck irradiation (ENI) has long been considered mandatory when treating head and neck squamous cell carcinoma (HNSCC) with definitive radiotherapy (RT). However, ENI is often responsible for the majority of the dose to the salivary glands and swallowing organs-at-risk (OAR), and recent prospective studies have supported reduced elective neck volume and dose. Moreover, with sensitive staging studies and artificial intelligence (AI), our ability to identify occult lymphadenopathy is greatly improving. In this prospective phase II study, we investigated the efficacy and tolerability of eliminating ENI and strictly treating involved and suspicious lymph nodes (LN) with intensity modulated radiation therapy.Patients with newly-diagnosed squamous cell carcinoma of the oropharynx, larynx and hypopharynx were eligible for enrollment, excluding stage I-II glottic larynx. Each LN was characterized as involved or suspicious based on CT (e.g., cross-sectional size, enhancement pattern) and PET criteria and an in-house AI-based classification model. Gross disease and the primary clinical target volume were irradiated to 70 and 63 Gy in 35 fractions, respectively, and suspicious LN were treated to 66.5 Gy. Concurrent chemotherapy was required for stage T3N0-1 and IVA/B patients. The primary endpoint of the study was risk of solitary elective volume LN recurrence (i.e., LN recurrence in a classic ENI field without synchronous in-field or distant failure), with secondary endpoints including patterns-of-failure and patient reported outcomes.Sixty-seven patients were enrolled, with 18 larynx/hypopharynx and 49 oropharynx cancer (88% p16+). In total, 10% and 90% of patients were treated with accelerated RT and chemoRT, respectively. Average contralateral/ipsilateral mean parotid and contralateral submandibular doses were 11.9/18.4 Gy and 34.1 Gy, respectively, and average mean larynx/inferior constrictor/esophagus doses for oropharynx patients were 18.9/12.2/6.7 Gy. With a median follow-up of 12.8 months for surviving patients, there have been no solitary elective volume LN recurrences. Four patients have died from unrelated causes, and one died from in-field local progression. Gastrostomy was placed in 14 (21%), with median removal after 2.8 months for disease-free patients; only one patient is still dependent. Grade 1/2 dermatitis was seen in 90%/10% patients. There was no significant difference in MDADI score between baseline and months 3 and 6 post-RT; for patients with baseline MDADI score > 75, the scores at 3/6 months were 84/83.Preliminary results suggest that eliminating ENI is oncologically sound for HNSCC, with highly favorable OAR dosimetry and promising quality-of-life outcomes. Longer follow-up is needed to confirm these results.

Serum MicroRNAs as Xerostomia Biomarkers in Patients With Oropharyngeal Cancer Undergoing Radiation Therapy

Severe xerostomia is noted in the majority of patients irradiated for oropharyngeal cancer. Extracellular microRNAs (miRNAs) may serve as effective tools allowing prediction of radiation-related toxicity. The aim of this study was to create an efficient prognostic miRNA-based test for severe, patient-rated xerostomia 3 months after primary treatment. This prospective study enrolled patients with oropharyngeal cancer treated between 2016 and 2018 in 3 centers in Poland. The primary endpoint was severe (grade ≥3) xerostomia as assessed by the European Organisation for Research and Treatment of Cancer H&N-35 questionnaires. Initially, a group of 10 patients with severe xerostomia was randomly selected and matched with a comparative group of 10 patients without severe xerostomia. Samples were collected before radiation therapy, after receiving 20 Gy, and within 24 hours after treatment completion. Quantitative real-time polymerase chain reaction arrays (QIAGEN, Hilden, Germany) were used to quantify expression levels of 752 miRNAs in the serum at all timepoints. The resulting logistic-regression based model was validated in additional 60 patients: 30 with grade >3 xerostomia and 30 without. Of 152 eligible patients, we successfully recruited 111 patients. Severe xerostomia 3 months after treatment was reported by 63 patients (56.8%). Mean dose delivered to parotid glands was higher in both the exploratory and validation cohort. The model based on miR-185-5p and miR-425-5p expression levels measured before the start of radiation therapy had an area under the curve of 0.96 (95% confidence interval, 0.88-1.00). The model based on the same miRNAs remained robust when parameters were measured after 20 Gy (area under the curve 0.90; 95% confidence interval, 0.75-1.00). These results were confirmed in the validation group. In the validation group, preradiation therapy model application yielded 73.3% sensitivity and 80.0% specificity. In the samples taken after 20 Gy, the same 2 miRNAs yielded 67.7% sensitivity and 72.4% specificity. The model including pretreatment miR-185-5p and miR-425-5p levels together with mean parotid dose yielded 90.0% sensitivity and 80.0% specificity. In the validation cohort, this model yielded 80.6% sensitivity and 55.2% specificity. The model based on miRNA levels measured after 20 Gy and mean parotid dose had 80.0% sensitivity and 100% specificity in the exploratory group. In the validation cohort its performance fell to 71.0% sensitivity and 58.6% specificity. Serum expression levels of miR-425-5p and miR-185-5p measured before the start of radiation therapy or during therapy (after 20 Gy) had significant prognostic value for the occurrence of severe xerostomia 3 months after treatment completion. The variability explained by miRNAs appears to be, at least partially, independent from that related to the dosimetric data.

Salivary and Dental Complications in Childhood Cancer Survivors Treated With Radiation Therapy to the Head and Neck: A PENTEC Comprehensive Review

Radiation therapy (RT) to the head and neck (H&N) region is critical in the management of various pediatric malignancies; however, it may result in late toxicity. This comprehensive review from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative focused on salivary dysfunction and dental abnormalities in survivors who received RT to the H&N region as children. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. Of the 2,164 articles identified through a literature search, 40 were included in a qualitative synthesis and 3 were included in a quantitative synthesis. The dose-toxicity data regarding salivary function demonstrate that a mean parotid dose of 35 to 40 Gy is associated with a risk of acute and chronic grade ≥2 xerostomia of approximately 32% and 13% to 32%, respectively, in patients treated with chemo-radiation therapy. This risk increases with parotid dose; however, rates of xerostomia after lower dose exposure have not been reported. Dental developmental abnormalities are common after RT to the oral cavity. Risk factors include higher radiation dose to the developing teeth and younger age at RT. This PENTEC task force considers adoption of salivary gland dose constraints from the adult experience to be a reasonable strategy until more data specific to children become available; thus, we recommend limiting the parotid mean dose to ≤26 Gy. The minimum toxic dose for dental developmental abnormalities is unknown, suggesting that the dose to the teeth should be kept as low as possible particularly in younger patients, with special effort to keep doses <20 Gy in patients <4 years old.

Significance of site-specific radiation dose and technique for success of implant-based prosthetic rehabilitation in irradiated head and neck cancer patients-A cohort study.

Radiotherapy aggravates implant-based prosthetic rehabilitation in patients with head and neck cancer. To evaluate the impact of radiation dose at implant and parotid gland site for prosthetic rehabilitation. The retrospective study includes 121 irradiated head and neck cancer patients with 751 inserted implants. Radiation doses on implant bed and parotid gland site were recorded by 3-dimensional modulated radiation plans. Implant success was clinically and radiographically evaluated according to modified Albrektsson criteria and compared to treatment- and patient-specific data. Implant overall survival after 5 years was 92.4% with an implant success rate of 74.9%. Main reasons for implant failure were marginal bone resorption (20.9%), implant not in situ or unloaded (9.6%) and peri-implantitis (7.5%). A mean radiation dose of 62.6Gy was applied with a mean parotid dose of 35 Gy. Modulating radiation techniques went along with lower grades of xerostomia (p < 0.001). At implant site mean doses of 57.5, 42.0, and 32.3Gy were recorded for oral, oropharyngeal, and hypopharyngeal/laryngeal carcinoma, respectively. Implant success inversely correlated to radiation dose at implant site. Strong predictors for implant failure in uni- and multivariate analysis were implant-specific dose >50 Gy (HR 7.9), parotid dose >30 Gy (HR 2.3), bone (HR 14.5) and soft tissue (HR 4.5) transplants, bad oral hygiene (HR 3.8), nonmodulated radiation treatment planning (HR 14.5), and nontelescopic prosthetics (HR 5.2). Radiotherapy impedes implant success in a dose-dependent manner at implant site. Modern radiation techniques effectively reduce xerostomia favoring implant-based prosthetic rehabilitation. Implantation in bone grafts is more critical and telescopic-retained overdentures should be preferred.

Dosimetric impact of volumetric modulated arc therapy for nasopharyngeal cancer treatment

The purpose of the study was to evaluate the toxicity and outcome of nasopharyngeal carcinoma patients treated using 3-dimensional conformal radiotherapy (3DCRT) or volumetric modulated arc therapy (VMAT) technique. 68 patients treated between 2006 and 2018 were retrospectively analysed. Since 2009 patients received 3DCRT with 50/70 Gy to the elective/boost volumes in 35 fractions; from then, VMAT with simultaneous integrated boost (SIB) with 54.45/69.96 Gy in 33, or 54/66 Gy in 30 fractions. Induction chemotherapy was administered in 74% of the patients, concomitant cisplatinum in 87%. Acute and late toxicity data, progression-free survival PSF and overall survival OS, and toxicity correlations with dose metrics were reported. With a median follow-up of 64 months, complete remission at the last evaluation was in 68% of the patients, while 28% and 9% had locoregional relapse and distant disease, respectively. The 5- and 10-year progression free survival (PFS) rates were 62.7 ± 6.5% and 53.2 ± 8.7%, respectively. The 5- and 10-year OS rates were 78.9 ± 5.5% and 61.4 ± 9.2%, respectively. At the multivariate Cox analysis TNM stage (p = 0.02) and concomitant chemotherapy (p = 0.01) resulted significant for PFS, concomitant chemotherapy (p = 0.04) for OS.Improvements in acute toxicity were presented for VMAT patients due to its ability to spare OARs. Odds ratio (OR) for acute salivary toxicity, between VMAT and 3DCRT, was 4.67 (p = 0.02). Dosimetrically, salivary toxicity correlated with mean parotid dose (p = 0.05), dysphagia with laryngeal (p = 0.04) and mean oral cavity (p = 0.06) doses, when dose-volume histograms (DVHs) are corrected for fractionation. This study is a proof of a significant benefit of the VMAT technique compared with 3DCRT in terms of side effects in nasopharynx patients, and adds dosimetric correlations.

Mean parotid dose prediction model using machine learning regression method for intensity-modulated radiotherapy in head and neck cancer.

Parotids are considered one of the major organs at risk in Head and Neck (HN) intensity-modulated radiotherapy (IMRT). Achieving proper target coverage with reduced mean parotid dose demands an elaborate time-consuming IMRT plan optimization. A parotid mean dose prediction model based on a machine-learning linear regression was developed and validated in this study. The model was developed using independent variables, such as parotid to PTV overlapping volume, dose coverage of the overlapping PTV, the ratio of overlapping parotid volume to total parotid volume, and volume of parotid overlapping with isotopically expanded PTV contours. The Pearson correlation coefficients between these independent variables and the mean parotid dose were calculated. Multicollinearity of the independent variables was checked by calculating the Variance Inflation Factor (VIF). All variables are having VIF less than ten were taken for the model. Fifty IMRT patient plans were used to develop the model. The mean parotid dose predicted by the model was in good agreement with the obtained mean parotid dose. The model is having a Root Mean Square Error (RMSE) of 2.89 Gy and an R-square of 0.7695. The model was successfully validated using the fivefold cross-validation method, resulting R-square value of 0.6179 and an RMSE of 2.93 Gy. The normality of the model's residuals was tested using Quartile-Quartile (Q-Q) plot and Shapiro Wilk test (p = 0.996, for null hypothesis ``residuals were normally distributed''). The data points in the Q-Q plot are falling approximately along the reference line. This model can be used in clinics to help the planner in the preplanning phase for efficient plan optimization.

Recurrence and Quality-of-Life Following Elective Nodal Volume and Dose De-Escalation for Oropharyngeal and Laryngeal Cancer: Initial Results from the Infield Trial

The required elective nodal dose and volumes for head and neck intensity-modulated radiotherapy (IMRT) have largely been extrapolated from conventional radiotherapy fields. The combination of CT and PET-CT imaging with surgically established patterns-of-nodal-spread provides an opportunity to meaningfully reduce the elective dose and volume, with a significant gain in acute and long-term morbidity. In this prospective phase II study, we investigated the efficacy and tolerability of reduced elective nodal volume and dose in oropharyngeal and laryngeal squamous cell carcinoma. Patients with newly-diagnosed squamous cell carcinoma of the oropharynx and larynx were eligible for enrollment; only stage I-II glottic larynx were excluded. In collaboration with a nuclear radiologist, each lymph node was characterized as involved or suspicious based on anatomic and PET criteria. Lymph nodes whose cross-sectional diameter was at least 17 mm and/or nodes with FDG uptake greater than the adjacent blood pool were considered suspicious. For oropharynx cancer, only involved nodal stations plus one adjacent station (and retropharynx) were treated to 40 Gy in 20 fractions. In larynx patients, at least bilateral levels II and III were treated to 40 Gy, with level IV treated only if level III was involved. Involved and suspicious nodes were then boosted with 30 Gy and 24 Gy in 15 fractions, respectively. The primary gross tumor and clinical target volumes were irradiated to 70 and 64 Gy, respectively, in the same fractionation. Concurrent chemotherapy was required for stage T3N0-1 and IVA/B patients. The primary endpoint of the study was solitary elective volume recurrence, with secondary endpoints including patterns-of-failure and patient reported outcomes. A total of 72 patients completed treatment on this trial from January 2017 through November 2018. The study was composed of 19 larynx and 53 oropharyngeal patients, 77% of whom were p16-positive. The stages at presentations were 5, 17, and 50 stage I-II, III, and IV, respectively, with 8% and 92% treated with accelerated radiotherapy and chemoradiotherapy, respectively. Average contralateral mean parotid and SMG doses for non-N2c patients were 16.5 Gy and 36.7 Gy, respectively. With a median follow-up of 11.9 months for surviving patients, there have been no recurrences in the 40 Gy or untreated elective nodal stations. Gastrostomy was placed in 32 (44%), with median removal after 2.9 months for disease-free patients; only one disease-free patient is still dependent. At 3 months, the mean composite MDADI score was 79, and the mean EORTC HN35 dry mouth and sticky saliva scores were 59 and 40, respectively. Preliminary results suggest that elective dose and volume reduction is oncologically sound for oropharyngeal and laryngeal cancer treated with IMRT, with promising quality-of-life outcomes. Longer follow-up is needed to confirm these results.

Risk of Acute and Late Xerostomia in Pediatric Head and Neck Cancer Patients Treated with Radiotherapy: Initial Results from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) Initiative

Radiation-induced xerostomia is a relatively common complication of definitive radiotherapy (RT) of the head and neck in the pediatric cancer population. The PENTEC head and neck (HN) task force aims to quantify radiation dose effects and the impact of critical risk factors. Through a systematic review of available literature, we analyzed the relationship between RT dose and this toxicity. A PubMed search of peer-reviewed literature was performed for articles published between January 1964 and June 2017, that evaluated xerostomia and dental effects among pediatric cancer patients who received radiotherapy. Of 2201 abstracts identified, only four reports had quantitative dosimetric and xerostomia data that could be used for mathematical modeling. The incidence of toxicity was modeled employing a normal tissue complication probability (NTCP) model using a two-parameter logistic fit. Three papers with 75 children treated for nasopharyngeal cancer reported dosimetric parameters and development of grade ≥ 2 xerostomia. Acute and late grade ≥ 2 xerostomia incidence along with dosimetric data (median dose, D50% and D80% to parotid glands) from 36 patients treated with RT (Laskar 2008) were used to determine the model parameters. About half of the patients were treated with 3-D conformal RT (mean parotid dose 57 Gy) and the rest with IMRT (mean parotid dose 38.3 Gy) with an incidence of acute grade ≥ 2 xerostomia of 88.2% and 31.6% and late grade ≥ 2 xerostomia of 64.7% and 15.8% respectively. The two other reports validate these results. In a paper with 34 patients whose right and left parotid glands received a mean dose of 35.8 and 35.3 Gy, the acute and late grade ≥ 2 xerostomia rates were 32.4% and 8.8% (Tao 2013). In another paper of 5 patients whose mean parotid doses were ≤ 26 Gy, 1 developed a late grade 2 xerostomia (Louis 2007). Another paper with 133 patients that received RT to the salivary glands for mostly Hodgkin lymphoma and rhabdomyosarcoma reported acute and late ≥ grade 1 xerostomia and median maximal doses consistent with the logistic model parameterized using Laskar data (Bolling 2015). In the same paper, children who received concurrent chemotherapy had more acute (p = 0.005) and late xerostomia (p = 0.026) compared to those not receiving concurrent chemotherapy. In this report we were able to build a logistic model based on quantitative dose and toxicity data from the current literature, and it demonstrates a dose response for acute and late xerostomia in pediatric patients treated with RT. Due to the variability and scarcity of data, it was not possible to establish other risk factors such as age and sex. PENTEC acknowledges logistical support from American Association of Physicists in Medicine

Predicting Late Radiation-Induced Xerostomia with Parotid PET Biomarkers and Dose Metrics

Xerostomia is a common long-term toxicity from head and neck radiotherapy that is only partially predicted by delivered dose to salivary glands. Associations between parotid gland imaging biomarkers and late radiation-induced xerostomia have recently been shown. The aim of this study was to assess predictive models for late xerostomia incorporating pre-treatment parotid PET biomarkers compared to a base model using parotid dose alone in a homogeneous group of patients treated for orophangeal cancer. 47 patients with p16+ oropharyngeal squamous cell carcinoma were treated on two prospective institutional protocols with 70 Gy IMRT and concurrent carboplatin/paclitaxel. The 90th percentile of standardized uptake value (SUV-P90) was generated from each parotid gland on pre and 3-month post-RT PET scans. Late xerostomia (12-months post-RT) was defined by the patient-reported University of Michigan Xerostomia Questionnaire (XQ), and parotid-specific salivary flow rate (SFR). XQ outcomes included both the summary score (XQ-sum12m) and the most variable eating-related item as determined by principal component analysis: frequency of sipping fluids to aid in swallowing food (XQ-sip12m). Univariate analysis was applied to dose and SUV-P90 features as predictors of late xerostomia using both continuous and discrete scales. Multivariate analysis was applied for dose only and combined dose and SUV-P90 using penalized logistic regression for feature selection and model prediction based on the LASSO technique. Mean parotid dose and SUV-P90 from both pre and post-RT PET scans were significantly associated with patient-reported xerostomia and stimulated SFR (Stim12m) but not unstimulated SFR. Associations were stronger for SUV-P90 from the contralateral parotid (SUV-P90CL) than the ipsilateral parotid, and from 3-month PET scans relative to pre-treatment scans. On multivariate analysis, the addition of pre-treatment SUV-P90CL and an interaction term for dose and SUV to the model significantly improved the prediction for late moderate or severe xerostomia compared to the base model, from AUC = 0.70 to 0.74 for XQ-sum12m and from 0.74 to 0.84 for XQ-sip12m. The improvements remained statistically significant upon cross-validation. The addition of pre-treatment parotid PET biomarkers significantly improved a predictive model for late patient-reported xerostomia over a model based on parotid dose alone. The improvement was greatest for the single eating-related item with the largest inter-patient variability (XQ-sip12m). Correlation between SUV-P90 from 3-month post-RT PET scans and late xerostomia was even higher than those from pre-treatment scans, suggesting that mid-treatment scans should be further explored for a potential role in adaptive radiotherapy.Abstract 121; Table 1SUV-P90CL (3m)Mean XQ-Sum12mMean XQ-Sip12mMean Stim12m< 1.551.37.50.171.5 - 2.029.04.40.392.0 - 2.521.92.80.48> 2.510.81.30.80 Open table in a new tab

Xerostomia-related quality of life for patients with oropharyngeal carcinoma treated with proton therapy

PurposeWe report longitudinal patient-reported quality-of-life (QoL) outcomes related to xerostomia in patients with oropharyngeal cancer treated with intensity-modulated proton therapy (IMPT). Materials and methodsPatients treated from May 2012 through December 2016 at a single institution for AJCC7 stage III-IV, M0 oropharyngeal cancer were given the 15-item Xerostomia-Related QoL Scale (XeQoLS) before, during, and for up to 2 years after treatment. We evaluated the evolution of xerostomia-related QoL over that time, and examined potential associations between those measures with clinical characteristics. ResultsSixty-nine patients had XeQoLS scores at baseline and at least once either during or after treatment. The mean (±SD) XeQoLS score (0–4) was 0.24 ± 0.57 at baseline. Subsequent scores were 2.00 ± 1.01 at 6 weeks on treatment, and 1.03 ± 0.76, 0.97 ± 0.78, 0.82 ± 0.69, and 0.70 ± 0.75 at 10 weeks, 6 months, 1 year, and 2 years after treatment, respectively. All were statistically different from baseline (p < 0.001). Univariate analyses demonstrated associations between XeQoLS score and time (p < 0.0001 for each interval), baseline XeQoLS score (p < 0.0001), stage (p = 0.008), N status (p = 0.006), and mean oral cavity dose (p = 0.038), but not for age, sex, T status, receipt of chemotherapy, smoking history, disease site, laterality of neck irradiation, mean parotid dose, or mean submandibular dose. Multivariate analysis suggested that baseline XeQoLS scores, phase of treatment, and N status were associated with XeQoLS scores measured during treatment and recovery. ConclusionsPatients receiving IMPT reported the greatest xerostomia-related QoL impairment at 6 weeks on treatment, with a 49% improvement by 10 weeks after treatment; however, XeQoLS scores remained above baseline after 2 years. As we aim to establish the value of IMPT in oropharyngeal tumors to de-intensify treatment over conventional therapy, these data help inform discussions about xerostomia-related quality of life for patients with oropharyngeal cancer treated with IMPT.

Omitting Elective Irradiation of the Contralateral Retropharyngeal Nodes in Oropharyngeal Squamous Cell Carcinoma Treated with Intensity-modulated Radiotherapy.

Introduction: The use of intensity-modulated radiation therapy (IMRT) in head and neck cancers has allowed for selective sparing of low-risk or uninvolved lymph nodes. In oropharyngeal cancers, the benefits and risks of omitting contralateral retropharyngeal lymph nodes (RPLN) remain uncertain. This study examines the outcomes of elective coverage of contralateral RPLN in oropharyngeal cancer treated with definitive IMRT.Methods: We analyzed 54 patients with newly diagnosed unilateral tonsil or base of tongue squamous cell carcinoma with at most unilateral neck involvement (cN0-N2b) and no RPLN involvement. These patients had no prior head and neck irradiation and were treated with definitive radiotherapy or chemoradiotherapy between 2012 and 2017. Cumulative incidences of local/regional/distant failure were estimated using competing risks methodology, and overall survival (OS) was estimated using the Kaplan-Meier method.Results: All patients received elective nodal coverage to the ipsilateral RPLN, and 38 (62%) patients did not receive elective treatment of the contralateral RPLN. There were no significant differences in baseline characteristics. There were no contralateral RPLN failures observed. When comparing patients who received contralateral RP treatment with those who did not, there were no significant differences in two-year local failure (23% vs. 9%, p = 0.09), regional failure (18% vs. 4%, p = 0.12), or distant failure (15% vs. 9%, p = 0.62). Two-year OS was 89%. Mean parotid dose was not significantly lower after sparing vs. treating the contralateral RPLN (median 25.6 vs. 32.7 Gy, p = 0.15).Conclusions: The omission of contralateral RPLN irradiation in tonsil or tongue base carcinomas with unilateral neck involvement is safe without compromising disease control.

Effectiveness of Multi-Criteria Optimization-based Trade-Off exploration in combination with RapidPlan for head & neck radiotherapy planning

BackgroundA new strategy is introduced combining the use of Multi-Criteria Optimization-based Trade-Off Exploration (TO) and RapidPlan™ (RP) for the selection of optimisation parameters that improve the trade-off between sparing of organs at risk (OAR) and target coverage for head and neck radiotherapy planning. Using both approaches simultaneously; three different workflows were proposed for the optimisation process of volumetric-modulated arc therapy (VMAT) plans. The generated plans were compared to the clinical plans and the plans that resulted using RP and TO individually.MethodsTwenty clinical VMAT plans previously administered were selected. Five additional plans were created for each patient: a clinical plan further optimised with TO (Clin+TO); two plans generated by in-house built RP models, RP_1 with the model built with VMAT clinical plans and RP_TO with the model built with VMAT plans optimised by TO. Finally, these last two plans were additionally optimised with TO for the creation of the plans RP_1 + TO and RP_TO+ respectively. The TO management was standardised to maximise the sparing of the parotid glands without compromising a clinically acceptable PTV coverage. Resulting plans were inter-compared based on dose-volume parameters for OAR and PTVs, target homogeneity, conformity, and plans complexity and deliverability.ResultsThe plans optimised using TO in combination with RP showed significantly improved OAR sparing while maintaining comparable target dose coverage to the clinical plans. The largest OAR sparing compared to the clinical plans was achieved by the RP_TO+ plans, which reported a mean parotid dose average of 15.0 ± 4.6 Gy vs 22.9 ± 5.5 Gy (left) and 17.1 ± 5.0 Gy vs 24.8 ± 5.8 Gy (right). However, at the same time, RP_TO+ showed a slight dose reduction for the 99% volume of the nodal PTV and an increase for the 95% (when comparing to the clinical plans 76.0 ± 1.2 vs 77.4 ± 0.6 and 80.9 ± 0.9 vs 79.7 ± 0.4) but remained within clinical acceptance. Plans optimised with RP and TO combined, showed an increase in complexity but were proven to be deliverable.ConclusionThe use of TO combined with RP during the optimisation of VMAT plans enhanced plan quality the most. For the RP_TO+ plans, acceptance of a slight deterioration in nodal PTV allowed the largest reduction in OAR dose to be achieved.