Severe Xerostomia Research Articles

(P30) Prospective Outcomes of Xerostomia-Related quality of Life in Oropharyngeal Carcinoma Patients Treated With Proton Therapy

Proton therapy plays an important role in the management of head and neck cancer, where the challenging anatomy benefits from dosimetric advantages of protons. The reduction of treatment-related morbidity is significant for oropharyngeal cancer, as increasingly younger, HPV-positive patients with more favorable prognoses are treated. Patient-reported outcome (PRO) instruments such as the MD Anderson Symptom Inventory (MDASI) have described the response profile of symptoms experienced by patients. Focusing on xerostomia-related quality-of-life outcomes in oropharyngeal carcinoma patients, we prospectively explore xerostomia severity during and after proton therapy, as well as patient- and treatment-specific factors influencing xerostomia. We analyzed xerostomia-related quality-of-life in oropharyngeal carcinoma patients receiving proton therapy between May 1, 2012 and December 31, 2016 at the University of Texas MD Anderson Cancer Center. Inclusion criteria were AJCC 7th Edition Stage III/IV, M0 oropharyngeal carcinoma with documented baseline and at least one response at the primary intervals of interest (6 weeks on treatment, 10 week-, 6-month-, 12-month-, and 24-month follow up). Patients with Stage I/II or M1 disease, or lacking a response at primary intervals above were excluded. The Xerostomia-Related Quality-of-Life Scale (XQ) consists of 15 items scored on a 0-5 Likert scale with higher scores corresponding to more severe symptoms. Piecewise linear mixed effects modeling was used to analyze the mean global XQ response from baseline through 2 years. Our database included 112 patients with oropharyngeal carcinoma treated with proton therapy, with 69 patients satisfying the inclusion criteria. The mean global XQ response was 0.24 at baseline, 2.00 at 6 weeks on treatment, and 1.03, 0.97, 0.82, and 0.70 at 10 weeks, 6 months, 1 year, and 2 years post-treatment, respectively. Furthermore, all changes from baseline were significant (p<0.001) at each of the five respective follow-up time points. The peak XQ response occurred at 6 weeks on treatment, with patients reporting significant improvement by 10 weeks post-treatment. The mean global XQ response after 2 years remained significantly greater than at baseline (n=69); however, less than half of patients contributed information at 2 years (n=26). Similar trends were observed for individual sub-domain scores. Univariate analyses demonstrated significant associations between XQ score and time (p<0.0001 for each time interval) and baseline score (p<0.0001). There were no significant associations between XQ score and age at diagnosis (p=0.223), gender (p=0.659), receipt of chemotherapy (p=0.751), smoking history (p=0.543), or primary disease site (p=0.620). Results from the mixed effects model suggested that baseline global XQ response was significantly associated with global XQ responses measured during treatment and recovery phases. We report prospective outcomes on xerostomia in oropharyngeal cancer patients receiving proton therapy. Patients reported the most severe xerostomia at 6 weeks on treatment with significant recovery by 10 weeks post-treatment; however, xerostomia remained significantly above baseline after 2 years. Xerostomia was associated with time and baseline xerostomia, while no association was detected with age at diagnosis, gender, receipt of chemotherapy, smoking history, or primary disease site. Ongoing studies will establish functional imaging correlates of symptom severity and comparison with conventional photon therapy.

Early Prediction of Acute Xerostomia During Radiation Therapy for Head and Neck Cancer Based on Texture Analysis of Daily CT

To investigate radiation-induced changes of computed tomography (CT)textures in parotid glands (PG) to predict acute xerostomia during radiotherapy (RT) for head and neck cancer (HNC). Daily or fraction kilovoltage CTs acquired using diagnostic CT scanners (eg, in-room CTs) during intensity-modulated RT for 59 HNC patients at 3 institutions were analyzed. The PG contours were generated on selected daily/fraction CTs. A series of histogram-based texture features, including the mean CT number (MCTN) in Hounsfield units, volume, standard deviation, skewness, kurtosis, and entropy for PGs were calculated for each fraction. Correlations between the changes of the texture features, radiation dose, and observed acute xerostomia were analyzed. A classifier model and the incurred CT-based xerostomia score (CTXS) were introduced to predict xerostomia based on combined changes of MCTN and volume of PGs. The t test and Spearman and Pearson correlation tests were used in the analyses. Substantial changes in various CT texture features of PGs were observed during RT delivery. The changes of PG MCTN or volume are not strongly correlated with the observed xerostomia grades if they are considered separately. The CTXS showed a significant correlation to the observed xerostomia grades (r=0.71, P<.00001). The CTXS-based classifier can predict the xerostomia severity with a success rate ranging from 79% to 98%. The xerostomia severity at the end of treatment can be predicted based on the CTXS determined at the fifth week with a precision and sensitivity of 100%. Significant changes in the CT histogram features of the parotid glands were observed during RT of HNC. A practical method of using the changes of MCTN and volume of PGs is proposed to predict radiation-induced acute xerostomia, which may be used to help design adaptive treatment.

Submandibular function recovery after IMRT in head and neck cancer: A prospective dose modelling study

PurposeTo estimate the dose response relationship for submandibular gland (SMG) recovery using salivary scintigraphy in patients diagnosed with head and neck cancer treated with curative image guided chemoradiation. Material and methodsNinety newly diagnosed head and neck cancer patients (T1-3, N0-2c, M0) treated with intensity modulated radiotherapy on a prospective clinical trial were assessed for salivary toxicity at predefined intervals using dynamic salivary scintigraphy. The SMG function was measured using salivary excretion fraction (SEF) ratios at baseline and 6 monthly. Tolerance dose (TD) 50 for submandibular gland was estimated from dose response curves. ResultsThe mean SEF ratio of 180 SMGs decreased at 6 months with a nadir at 12 months after treatment (SEF ratio 15%) and progressively recovered over time reaching 38% over 24 months. There was significant inverse correlation between SEF ratio and mean SMG dose at 6 months (r = −0.18, p = 0.04); 12-months (r = −0.36, p < 0.001); 18-months (r = −0.48, p < 0.001); 24-months (r = −0.42, p < 0.001); and more than 24-months (r = −0.56, p < 0.001). The estimated TD 50 values at 1 year and 2 year post treatment were 36 Gy and 44 Gy respectively with SEF ratio of ≤45% used to define severe xerostomia. For every 1 Gy reduction in mean dose below 54 Gy, there is 2–2.5% reduction in the probability of severe xerostomia. ConclusionThe submandibular gland function declines after radiotherapy with a nadir at 12 months and there is incomplete recovery over time with continued improvement over 24 months. The TD 50 at 1 year and 2 year was 36 Gy and 44 Gy with a 2–2.5% reduction in the probability of severe xerostomia for every 1 Gy reduction in mean dose.

Oral and maxillofacial symptoms of patients with IgG4-related disease: The meaning of a labial minor salivary gland biopsy

ObjectiveWe examined the symptoms in the oral and maxillofacial regions of patients with IgG4-related disease (IgG4-RD) and considered the meaning of a labial minor salivary gland (LMSG) biopsy in such patients. MethodsSixty-three patients diagnosed with IgG4-RD in our hospital, were examined for symptoms in the oral and maxillofacial regions. Out of the 24 patients who were referred to our department, 20 underwent immunohistochemical analysis of the LMSG for IgG and IgG4. ResultsSymptoms in the oral and maxillofacial region were observed in 18 of the 63 patients. Out of the 18 patients, 15 had swelling of the submandibular glands, 5 had severe xerostomia, 4 had swelling of the parotid glands, and 2 experienced irritation and pain while eating. IgG4-positive plasma cells in the LMSG biopsy samples were observed in 19 of the 20 patients examined (95%). In 6 patients, more than 40% of the infiltrated plasma cells were positive for IgG4; in 2 patients, more than 30% of the plasma cells were positive; in 3 patients, more than 20% of the plasma cells were positive; in 7 patients, more than 10% of the plasma cells were positive; in 1 patient, more than 5% of the plasma cells were positive. ConclusionsOut of the 63 patients, only 18 (29%) had symptoms in the oral and maxillofacial regions. Infiltration of IgG4-positive plasma cells, regardless of their intensity in the non-symptomatic LMSG, might be considered as one of the important symptoms of IgG4-RD.

Correlation of Salivary Gland Dose to Volume Changes Noted During Adaptive Replanning of Head and Neck Radiation Therapy

Salivary gland shrinkage is known to occur with radiation therapy (RT) for head and neck cancer. Adaptive Radiation Therapy (ART) is commonly performed during the course of Intensity-Modulated Radiation Therapy (IMRT) due to weight loss and/or tumor shrinkage. Our goal was to investigate changes in parotid (PG) and submandibular gland (SMG) volumes measured on initial and replanning CT. We hypothesize that dose received by gland at the time of replan predicts for quantitative gland volume reduction. Replanning thus has the potential to reduce this effect which ultimately may reduce severity of xerostomia. We analyzed 100 patients who underwent adaptive re-planning (200 plans) between December 2014 to August 2017. Volumetric Modified Arc Therapy (VMAT) based IMRT was used in all. All patients had an initial CT simulation scan (Plan 1) used for radiation planning and a subsequent new CT simulation for adaptive replan (Plan 2). Dose-volume histograms were used to measure mean and maximum doses to right and left PG and SMG. We then correlated these doses to PG and SMG volume changes noted at the time of replan (PG1-PG2; SMG1-SMG2). Univariate and multivariate analyses were performed to identify factors contributing to gland volume changes. Tumor site included 9 oral cavity, 50 oropharynx, 14 Larynx, 7 Nasopharynx, and 20 others. Treatments were definitive chemo-RT in 67%, adjuvant chemo-RT in 20%, or adjuvant RT alone in 10%. Chemo used was Cisplatin-based 36%, Carboplatin-based 22%, or Cetuximab-based in 28%. Median total RT dose was 70 Gy (60-70 Gy in 30-35 daily fractions). Median time to performing replan was at fraction #21 (42 Gy) and around day 37 of therapy (13-66 days). Mean weight loss at time of replan was -4.3% (-21.3 to +17.5%). Analysis included 181 PG and 116 SMG. Mean dose received at time of replan with corresponding volume change: RPG = 1548 cGy, -13.6%; LPG = 1647 cGy, -14.6%; RSMG = 3359 cGy, -12.7%; LSMG = 3366 cGy, -14.4%. The correlation values of dose received and volume change: RPG r = 0.17, LPG r = -0.21, RSMG r = -0.33, and LSMG r = -0.27 (all with P<.05 except RPG, P=.13). Anatomic changes during radiation can result in increased doses to normal tissues and increased risk of toxicity. Our results show a significant change in gland volume in 3 of 4 salivary glands at the time of replanning with a direct correlation to dose received to the gland. Adaptive replan has the potential to reduce salivary gland doses.

Relationship between radiation-induced xerostomia and the volume of parotid glands exposed in radiotherapy for nasopharyngeal carcinoma

Objective To evaluate the relationship between the volume of parotid glands and radiation-induced xerostomia in patients with nasopharyngeal carcinoma (NPC). Methods A total of 199 patients with NPC who were admitted to our hospital from 2015 to 2016 were enrolled as subjects. According to the initial volume of parotid glands, all patients were divided into large parotid group and small parotid group. The incidence of xerostomia after radiotherapy and dosimetric parameters were compared between the two groups. Comparison of categorical data was made by χ2 test. Comparison of continuous data was made by t-test or nonparametric test. Comparison of dose-volume histogram index was made by nonparametric test. Results There was no difference in the severity of xerostomia between the two groups at 3 and 6 months after radiotherapy. At one year after radiotherapy, the large parotid group had significantly milder xerostomia than the small parotid group (P=0.035). The small parotid group had a higher dose delivered to both parotid glands than the large parotid group. There was no difference in the mean dose to the submandibular gland between the two groups. Conclusions The initial volume of parotid glands is one of the influencing factors for the grade of xerostomia after radiotherapy. Patients with large parotid glands have better recovery from xerostomia after radiotherapy than those with small parotid glands. For patients with small parotid glands, more attention should be paid to reducing the dose to protect parotid glands. Key words: Nasopharyngeal neoplasms/intensity-modulated radiotherapy; Radiation-induce dxerostomia; Dosimetry

Texture analysis as a predictor of radiation-induced xerostomia in head and neck patients undergoing IMRT.

Image texture analysis (TA) is a heterogeneity quantifying approach that cannot be appreciated by the naked eye, and early evidence suggests that TA has great potential in the field of oncology. The aim of this study is to evaluate parotid gland texture analysis (TA) combined with formal dosimetry as a factor for predicting severe late xerostomia in patients undergoing radiation therapy for head and neck cancers. We performed a retrospective analysis of patients treated at our Radiation Oncology Unit between January 2010 and December 2015, and selected the patients whose normal dose constraints for the parotid gland (mean dose<26Gy for the bilateral gland) could not be satisfied due to the presence of positive nodes close to the parotid glands. The parotid gland that showed the higher V30 was contoured on CT simulation and analysed with LifeX Software©. TA parameters included features of grey-level co-occurrence matrix (GLCM), neighbourhood grey-level dependence matrix (NGLDM), grey-level run length matrix (GLRLM), grey-level zone length matrix (GLZLM), sphericity, and indices from the grey-level histogram. We performed a univariate and multivariate analysis between all the texture parameters, the volume of the gland, the normal dose parameters (V30 and Mean Dose), and the development of severe chronic xerostomia. Seventy-eight patients were included and 25 (31%) developed chronic xerostomia. The TA parameters correlated with severe chronic xerostomia included V30 (OR 5.63), Dmean (OR 5.71), Kurtosis (OR 0.78), GLCM Correlation (OR 1.34), and RLNU (OR 2.12). The multivariate logistic regression showed a significant correlation between V30 (0.001), GLCM correlation (p: 0.026), RLNU (p: 0.011), and chronic xerostomia (p<0.001, R2:0.664). Xerostomia represents an important cause of morbidity for head and neck cancer survivors after radiation therapy, and in certain cases normal dose constraints cannot be satisfied. Our results seem promising as texture analysis could enhance the normal dose constraints for the prediction of xerostomia.

Impact of 1% malic acid spray on the oral health-related quality of life of patients with xerostomia.

Dry mouth sensation, also known as xerostomia, is a common clinical problem with an increasing prevalence. Although recent studies have reported promissory results of malic acid, none have evaluated the impact of malic acid on the oral health-related quality of life (OHRQoL) of patients with xerostomia. Thus, this study aimed to evaluate the impact of 1% malic acid, combined with fluoride and xylitol, on the OHRQoL of patients with xerostomia. We enrolled 70 patients and randomly allocated them into two groups: the intervention group (applied topical sialogogue with 1% malic acid) and the control group (applied a placebo). We assessed the OHRQoL and severity of xerostomia before and after treatment with the Spanish version of the Oral Health Impact Profile-14 questionnaire (OHIP-14sp) and a visual analogue scale (VAS), respectively. In addition, stimulated and non-stimulated salivary flow rates before and after treatments were also measured. In total, 60 patients completed the study. According to the VAS, both sprays significantly improved dry mouth sensation (P < 0.001). However, OHIP-14sp total scores decreased significantly in the intervention group from 20.8 ± 10.4 to 16.5 ± 9.5 (P < 0.001), indicating an improvement in the OHRQoL. No significant differences were observed in the control group (P > 0.05). Furthermore, non-stimulated salivary flow rates significantly increased in the intervention group from 0.25 ± 0.22 to 0.33 ± 0.33 mL/min (P < 0.001). Overall, this study demonstrated that malic acid improves the OHRQoL and dry mouth sensation in patients with xerostomia.

Comparison three-dimensional conformal radiotherapy versus intensity modulated radiation therapy in local control of head and neck cancer.

About 74% of head and neck cancer (HNC) patients need to undergo either definitive or postoperative radiation therapy because of aggressive nature of disease. The transition from two-dimensional conventional radiotherapy to three-dimensional conformal radiotherapy (3D-CRT) and further technological evolutions led to the successful clinical implementation of intensity modulated radiation therapy (IMRT), which constitutes an evolution of 3D-CRT. The IMRT technique gives the ability to create treatment fields with varying beam intensity using inverse planning and optimization algorithms to treat irregularly shaped target volumes with high precision. IMRT is in existence in clinical practice since 1995. Since then, presuming its clinical benefit a significant amount of patients has been treated by this technique. PARSPORT was the first multi-institutional prospective trial comparing IMRT with conventional RT in the treatment of HNC. It has shown a reduction in severe xerostomia but no difference in other toxicity and locoregional control after 24 months' follow or overall survival. Except for early T1, 2 N0 stages, the prognosis for patients with oral cavity cancer (OCC) is dismal than for carcinoma in other sites of the head and neck (HNC). The aim of this study was to assess the outcome of OCC following IMRT. Between January 2013 and January 2015, 40 patients of carcinoma buccal mucosa and carcinoma alveolus were treated by postoperative (19) or definitive (21) radiation therapy by IMRT technique. Of these, 28 patients (70%) presented with locally advanced T3/4 or recurrent tumor. Total radiation doses delivered was between 60 and 70 Gray at 2 Gray/fraction. Of these 31 patients (78%) has received concurrent cisplatin-based chemotherapy. Another group of 42 similar patients treated by 3D-CRT as definitive or postoperative adjuvant treatment over the same period has been selected. Comparisons were performed between these two groups. Data were entered into Excel spreadsheet and expressed as mean and standard deviation for deriving P value, and unpaired t-test was used to calculate 95% confidence interval. Local control (LC) was analyzed using Kaplan-Meier curve. Of all assessed treatment subgroups, LC rate was highest for patients treated with postoperative IMRT (89% LC at 2 years) followed by postoperative 3D-CRT patients (79% LC at 2 years); and finally, poorest LC rates (43% and 32% at 2 years) were seen in definitively irradiated patients with IMRT and 3D-CRT, respectively. LC rate for T1 stage (83%, n = 6) was significantly higher, than that for T2-4 (LC 55%, n = 76) as expected. Postoperative IMRT of carcinoma buccal mucosa and alveolus resulted in the highest LC rate of all the treatment subgroups assessed hence should be generously recommended in such cases especially ones with unfavorable features such as close resection margin, nodal involvement, locally advanced tumor (>T1N0), or recurrent disease, respectively. Despite definitive IMRT, locoregional control in carcinoma buccal mucosa and alveolus remain unsatisfactory, comparable to that following definitive 3D-CRT.

Evaluation of Salivary Gland Function Using Diffusion-Weighted Magnetic Resonance Imaging for Follow-Up of Radiation-Induced Xerostomia.

ObjectiveTo investigate the value of diffusion-weighted magnetic resonance imaging (DW-MRI) as a noninvasive tool to assess salivary gland function for follow-up of patients with radiation-induced xerostomia.Materials and MethodsThis study included 23 patients with nasopharyngeal carcinoma who had been treated with parotid-sparing radiotherapy (RT). Salivary function was assessed by DW-MRI pre-treatment and one week and one year post-RT, respectively. The maximum apparent diffusion coefficient (ADC) of parotid glands (pADCmax) and the time to peak ADC of parotid glands (pTmax) during stimulation were obtained. Multivariate analysis was used to analyze factors correlated with the severity of radiation-induced xerostomia.ResultsThe ADCs of parotid and submandibular glands (1.26 ± 0.10 × 10−3 mm2/s and 1.32 ± 0.07 × 10−3 mm2/s pre-RT, respectively) both showed an increase in all patients at one week post-RT (1.75 ± 0.16 × 10−3 mm2/s, p < 0.001 and 1.70 ± 0.16 × 10−3 mm2/s, p < 0.001, respectively), followed by a decrease in parotid glands at one year post-RT(1.57 ± 0.15 × 10−3 mm2/s, p < 0.001) but not in submandibular glands (1.69 ± 0.18 × 10−3 mm2/s, p = 0.581). An improvement in xerostomia was found in 13 patients at one year post-RT. Multivariate analysis revealed 4 significant predictors for the improvement of xerostomia, including dose to parotid glands (p = 0.009, odds ratio [OR] = 0.639), the ADC of submandibular glands (p = 0.013, OR = 3.295), pADCmax (p = 0.024, OR = 0.474), and pTmax (p = 0.017, OR = 0.729) at one week post-RT.ConclusionThe ADC value is a sensitive indicator for salivary gland dysfunction. DW-MRI is potentially useful for noninvasively predicting the severity of radiation-induced xerostomia.

CRISPR-Cas9 HDR system enhances AQP1 gene expression.

Ionizing radiation (IR) isthe primarytherapeutic tool to treat patients with cancerous lesions located in the head and neck. In many patients, IR results in irreversible and severe salivary gland dysfunction or xerostomia. Currently there are no effective treatment options to reduce the effects of xerostomia. More recently, salivary gland gene therapy utilizing the water-specific protein aquaporin 1 (AQP1) has been of great interest to potentially correct salivary dysfunction. In this study, we used CRISPR-Cas9 gene editing along with the endogenous promoter of AQP1 within theHEK293 and MDCK cell lines. The successful integration of the cytomegalovirus (CMV) promoterresultedin a significant increase of AQP1 gene transcription and translation. Additionalfunctional experiments involvingthe MDCK cell line confirmedthat over-expressed AQP1increasedtransmembrane fluid flux indicative of increased intracellular fluid flux. The off-target effect of designed guided RNA sequence was analyzed and demonstrateda high specificity for the Cas9 cleavage. Considering the development of new methods for robust DNA knock-in, our results suggest that endogenous promoter replacement may be a potential treatment forsalivary gland dysfunction.

Trismus and reduced quality of life in patients with oral squamous cell carcinoma who received postoperative radiotherapy alone or combined with chemotherapy.

222 Background: Patients, who receive radiotherapy (RT) for head and neck cancer, develop chronic functional abnormalities and reduced mouth opening-trismus, surviving with reduced quality of life (QoL). We aimed to study trismus and QoL in patients with oral cancer, who received post-operative radiotherapy or chemoradiotherapy. Methods: Patients, who receive radiotherapy (RT) for head and neck cancer, develop chronic functional abnormalities and reduced mouth opening-trismus, surviving with reduced quality of life (QoL). We aimed to study trismus and QoL in patients with oral cancer, who received post-operative radiotherapy or chemoradiotherapy. Results: Mean RT dose was 64.3 Gray. Six patients received chemoradiotherapy. Severe mucositis, pain and xerostomia were recorded in 6 and 5 patients respectively. MMO was reduced in all patients. The mean MMO (34 mm) reached the level of trismus. The total number of symptoms increased from 3.1 to 6.3 in C-30 and from 3.1 to 8.8 per patient in the H/N35. Severe fatigue, pain, limitations at work, weakness, sad feelings, family problems, sleeping problems, anorexia, financial difficulties, tense/irritable, constipation, nausea, vomiting and depression were most often reported with C-30. Most patients reported poor to moderate quality of life. Severe oral, jaw and neck pain, swallowing problems, taste alterations, sticky saliva, dry mouth, coarseness, dental problems, feeling sick and reduced interest in life/sex were the most common symptoms reported with N/H35. Conclusions: The observed trismus, the 2- to 3-fold increase of symptoms and poorer quality of life highlighted the need for support of oral cancer patients, who receive postoperative radiotherapy or chemoradiotherapy. Reduced systemic health, financial difficulties and family problems could be some of the main reasons for the inadequate compliance of our patients to the study, as shown by others, too. The strength of our study was the homogeneous group of patients: all had oral squamous cell carcinoma and all received post-operative radiotherapy or chemoradiotherapy. The small number of patients represents a weakness.

Comparative evaluation of the doses received by the parotid glands as predictors of xerostomia be 3D-CRT, IMRT and VMAT irradiation techniques in local advanced nasopharynx cancer

Xerostomia is commonly associated with the radio-chemotherapy treatment of the head and neck cancers. The risk increases with increasing doses received by the parotid. Severe xerostomia (defined as long-term salivary function of < 25% of baseline) may be avoided if at least one parotid gland receives less than 20 Gy. The combined treatment with cisplatin regarded as bringing a significant benefit in survival with concurrent radiotherapy is associated with increased risk of late toxicity. Intensity-modulated radiotherapy (IMRT) is considered the radio-therapeutic standard in the management of head and neck cancer. Purpose: to evaluate the possibility of modern techniques to reduce radiation doses to parotid glands compared to conventional 3D-CRT radiotherapy even if the parotid glands are not delineated as organs at risk (OAR) and dosimetric constraints are not applied. Methods: For 10 locally advanced nasopharyngeal cancer cases treated by radiotherapy with curative intent using 3D-CRT technique, alternative IMRT and VMAT plans were proposed without applying dosimetric constraints for parotid glands. Results: IMRT and VMAT techniques reduce the maximum dose (Dmax) and the mean dose (Dmean) for both parotid glands compared to the 3D-CRT technique. The treatment plans were comparatively analyzed in terms of doses received by both parotid glands. Conclusions: Modern radiotherapy techniques implementation can reduce the dose received by the parotids even in the absence of contouring them as organs at risk, reducing xerostomia and ensuring a better quality of life for the nasopharynx cancer radio-treated patients.

Dose–volume toxicity modeling for de-intensified chemo-radiation therapy for HPV-positive oropharynx cancer

Background and purposeThe aim is to determine the radiobiological parameters of four popular normal tissue complication probability (NTCP) models that describe the dose–response relations of salivary glands and pharyngeal constrictors to the severity of patient reported xerostomia and dysphagia, respectively 6 and 12months post chemo-radiotherapy, furthermore, to evaluate the goodness-of-fit of the NTCP models for different combinations of glands and constrictors. Material and methodsForty-three patients were treated on a prospective multi-institutional phase II study (ClinicalTrials.gov, NCT01530997) assessing the efficacy of de-intensified chemoradiotherapy in patients with favorable risk, HPV-associated oropharyngeal squamous cell carcinoma. All patients received 60Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatinum. All patients reported severity of their xerostomia and dysphagia (pre- and post-treatment) using the patient reported outcome version of the CTCAE (PRO-CTCAE). A change in severity (from baseline) of ≥2 was considered clinically meaningful. The Lyman–Kutcher–Burman (LKB), Relative Seriality (RS), Logit, and Relative Seriality Logit (RSL) NTCP models were used to fit the patients’ dose/volume data to changes in PRO-CTCAE severity of xerostomia and dysphagia (from baseline to 6 and 12months post-treatment). The correlation of the models with the patient outcomes was performed for different combinations of salivary glands and different sections of pharyngeal constrictors. The goodness-of-fit of the different models was assessed through the area under the receiver operating characteristic curve (AUC), maximum of the log-likelihood function, normal error distribution and Akaike information criterion (AIC). ResultsThe dose/volume metrics of the combined contralateral (parotid+submandibular) glands appear to correlate best with xerostomia, at both 6- and 12-months. Among the different sections of pharyngeal constrictors, the dose/volume metrics of the superior pharyngeal constrictors appear to correlate best with dysphagia at 6months. The AUC values ranged from 0.72 to 0.85 in the case of xerostomia and 0.73 to 0.74 in the case of dysphagia over the different models. The four NTCP models showed similar goodness-of-fit. The differences in AIC between the different models were less than 2 and ranged within 0.7 and 0.8 in the cases of xerostomia and dysphagia, respectively. The calculated parameters of the LKB model were D50=26.9Gy, m=0.63, n=1.0 for the combined contralateral glands at 12months and D50=62.0Gy, m=0.10, n=0.49 for the superior pharyngeal constrictors at 6months. ConclusionsThe values of the parameters of four NTCP models were determined for salivary glands and pharyngeal constrictors. All four models could fit the clinical data equally well. The NTCP predictions of the combined contralateral glands and superior pharyngeal constrictors showed the best correlation with the patient reported outcomes of xerostomia and dysphagia, respectively.

Trismus and reduced quality of life in patients with oral squamous cell carcinoma, who received post-operative radiotherapy alone or combined with chemotherapy

Abstract Background Patients, who receive radiotherapy (RT) for head and neck cancer, develop chronic functional abnormalities and survive with reduced quality of life. Purpose We aimed to study patients with oral cancer, who received post-operative radiotherapy or chemoradiotherapy. Patients Ten patients (mean age 63.8 years) were included. Methods Oral mucositis, pain and xerostomia, maximum mouth opening (MMO) and functional abnormalities before and after RT were recorded. The 35 mm MMO or less was accepted as trismus. Patients completed the EORTC QLQ C-30 and Head/Neck35 questionnaires. Results Mean RT dose was 64.3 Gray. Six patients received chemoradiotherapy. Severe mucositis, pain and xerostomia were recorded in 6 and 5 patients respectively. MMO was reduced in all patients. The mean MMO (34 mm) reached the level of trismus. The total number of symptoms increased from 3.1 to 6.3 in C-30 and from 3.1 to 8.8 per patient in the H/N35. Severe fatigue, pain, limitations at work, weakness, sad feelings, family problems, sleeping problems, anorexia, financial difficulties, tense/irritable, constipation, nausea, vomiting and depression were most often reported with C-30. Most patients reported low to moderate quality of life. Severe oral, jaw and neck pain, swallowing problems, taste alterations, sticky saliva, dry mouth, coarseness, dental problems, feeling sick and reduced interest in life/sex were the most common symptoms reported with N/H35. Conclusions The observed trismus, 2- to 3-fold increase of symptoms and poorer quality of life highlighted the need for support of oral cancer patients, who receive postoperative radiotherapy or chemoradiotherapy.

Oral symptoms and salivary findings in oral lichen planus, oral lichenoid lesions and stomatitis

BackgroundTo examine if patients with oral lichen planus, oral lichenoid lesions and generalised stomatitis and concomitant contact allergy have more frequent and severe xerostomia, lower unstimulated and chewing-stimulated saliva and citric-acid-stimulated parotid saliva flow rates, and higher salivary concentration of total protein and sIgA than cases without contact allergy and healthy controls.MethodsForty-nine patients (42 women, aged 61.0 ± 10.3 years) and 29 healthy age- and gender-matched subjects underwent a standardised questionnaire on general and oral health, assessment of xerostomia, clinical examination, sialometry, mucosal biopsy and contact allergy testing.ResultsNineteen patients had oral lichen planus, 19 patients had oral lichenoid lesions and 11 patients had generalised stomatitis. 38.8% had contact allergy. Xerostomia was significantly more common and severe in patients (46.9%) than in healthy controls, whereas the saliva flow rates did not differ. The patients had higher sIgA levels in unstimulated and chewing-stimulated saliva than the healthy controls. The total protein concentration in saliva was lower in the unstimulated saliva samples whereas it was higher in the chewing stimulated saliva samples from patients when compared to healthy controls. The differences were not significant and they were irrespective of the presence of contact allergy.ConclusionXerostomia is prevalent in patients with oral lichen planus, lichenoid lesions and generalised stomatitis, but not associated with salivary gland hypofunction, numbers of systemic diseases or medications, contact allergy, age, or gender. Salivary sIgA levels were higher in patients than in healthy controls, but did not differ between patient groups. The total salivary protein concentration was lower in unstimulated saliva samples and higher in chewing-stimulated saliva samples in patients than in healthy controls, but did not differ between patient groups. Our findings do not aid in the discrimination between OLP and OLL and these conditions with or without contact allergic reactions.

Use of Electrical Impedance Spectroscopy in vivo to Distinguish Active and Rest Stages of Salivary Glands

Xerostomia, or dry mouth syndrome, is one of the radiation therapy (RT)-induced side effects experienced by head and neck cancer patients. Measuring the severity of xerostomia can be performed by several techniques such as measuring the differential weight of dental rolls placed in the mouth for a fixed time period, measuring the electromyographic activity of musculus digastricus, using parotid cup, and electrophysiological measurements by electrical impedance. The present study focuses on detecting the change in bioimpedance around the oral cavity when salivation is induced using lime juice on healthy human subjects. In this study, impedance changes between stimulated and resting states of the salivary glands for 31 healthy volunteers were measured and analyzed. Pre- and post-stimulation impedance measurement was performed on healthy volunteer subjects using impedance spectroscopy over 50 frequencies ranging from 10 kHz to 1 MHz. The electrical properties of salivary glands were extracted by fitting the measured admittance data to the well-known Cole model. Comparison of measured electrical properties of gland at the resting and stimulated states reveals the changes in the intra- and extra-cellular spaces of salivary gland as a result of saliva secretion. Statistical analysis of the spectroscopy data collected shows that there is a significant difference in electrical properties of tissue between resting and stimulated states of the salivary activity. These electrical impedance spectroscopy measurements will be used to benchmark changes of impedance due to salivary gland stimulation.

Parotid gland mean dose as a xerostomia predictor in low-dose domains

Purpose: Xerostomia is a common side effect of radiotherapy resulting from excessive irradiation of salivary glands. Typically, xerostomia is modeled by the mean dose-response characteristic of parotid glands and prevented by mean dose constraints to either contralateral or both parotid glands. The aim of this study was to investigate whether normal tissue complication probability (NTCP) models based on the mean radiation dose to parotid glands are suitable for the prediction of xerostomia in a highly conformal low-dose regime of modern intensity-modulated radiotherapy (IMRT) techniques.Material and methods: We present a retrospective analysis of 153 head and neck cancer patients treated with radiotherapy. The Lyman Kutcher Burman (LKB) model was used to evaluate predictive power of the parotid gland mean dose with respect to xerostomia at 6 and 12 months after the treatment. The predictive performance of the model was evaluated by receiver operating characteristic (ROC) curves and precision-recall (PR) curves.Results: Average mean doses to ipsilateral and contralateral parotid glands were 25.4 Gy and 18.7 Gy, respectively. QUANTEC constraints were met in 74% of patients. Mild to severe (G1+) xerostomia prevalence at both 6 and 12 months was 67%. Moderate to severe (G2+) xerostomia prevalence at 6 and 12 months was 20% and 15%, respectively. G1 + xerostomia was predicted reasonably well with area under the ROC curve ranging from 0.69 to 0.76. The LKB model failed to provide reliable G2 + xerostomia predictions at both time points.Conclusions: Reduction of the mean dose to parotid glands below QUANTEC guidelines resulted in low G2 + xerostomia rates. In this dose domain, the mean dose models predicted G1 + xerostomia fairly well, however, failed to recognize patients at risk of G2 + xerostomia. There is a need for the development of more flexible models able to capture complexity of dose response in this dose regime.

The effect of submandibular gland preservation during level 1B neck dissection on postoperative xerostomia

ObjectiveCompare the presence and degree of postoperative xerostomia following preservation or excision of the submandibular gland (SMG) during level IB neck dissection (ND) without adjuvant radiation. MethodsRetrospective review with patient questionnaire administered to patients with pT1-2N0 oral squamous cell carcinoma (SCC) who underwent resection and ND with SMG preservation or SMG excision without postoperative radiation from 2011 to 2015. We analyzed an additional control group that was age and gender-matched and had not undergone oral resection or SMG excision. We compared the scores reported by the three groups from three questionnaires: University of Michigan Xerostomia Quality of Life (XeQoL), Short Form-8 (SF-8), and a xerostomia severity scale (XSS). Dry mouth severity (DMS) was calculated based on XSS scores among those complaining of any xerostomia. ResultsEleven SMG preservation group, 14 SMG excision group and 15 control group patients completed the survey. Complication and recurrence rates were comparable among experimental groups. No differences were identified between the two experimental groups for the XeQoL, SF-8, and XSS questionnaires (p=0.96, 0.87, 0.7). Control patients reported less xerostomia on XeQoL (p=0.046) and XSS (p=0.01) compared to the experimental groups combined with no statistical difference in SF-8 scores (p=0.25). No patients in either group developed regional recurrence in level IB. ConclusionSMG preservation, though technically and oncologically sound, does not appear in this study to reduce xerostomia. Oral resection with ND may result in some degree of xerostomia perception.

Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding.

The aim of this study was to develop a treatment protocol for 225Ac-PSMA-617 α-radiation therapy in advanced-stage, metastatic castration-resistant prostate cancer patients with prostate-specific membrane antigen (PSMA)-positive tumor phenotype. Methods: A dosimetry estimate was calculated on the basis of time-activity curves derived from serially obtained 177Lu-PSMA-617 scans extrapolated to the physical half-life of 225Ac, assuming instant decay of unstable daughter nuclides. Salvage therapies empirically conducted with 50 (n = 4), 100 (n = 4), 150 (n = 2), and 200 kBq/kg (n = 4) of 225Ac-PSMA-617 were evaluated retrospectively regarding toxicity and treatment response. Eight of 14 patients received further cycles in either 2- or 4-mo intervals with identical or deescalated activities. Results: Dosimetry estimates for 1 MBq of 225Ac-PSMA-617 assuming a relative biologic effectiveness of 5 revealed mean doses of 2.3 Sv for salivary glands, 0.7 Sv for kidneys, and 0.05 Sv for red marrow that are composed of 99.4% α, 0.5% β, and 0.1% photon radiation, respectively. In clinical application, severe xerostomia became the dose-limiting toxicity if treatment activity exceeded 100 kBq/kg per cycle. At 100 kBq/kg, the duration of prostate-specific antigen decline was less than 4 mo, but if therapy was repeated every 2 mo patients experienced additive antitumor effects. Treatment activities of 50 kBq/kg were without toxicity but induced insufficient antitumor response in these high-tumor-burden patients. Remarkable antitumor activity by means of objective radiologic response or tumor marker decline was observed in 9 of 11 evaluable patients. Conclusion: For advanced-stage patients, a treatment activity of 100 kBq/kg of 225Ac-PSMA-617 per cycle repeated every 8 wk presents a reasonable trade-off between toxicity and biochemical response.