Purpose: This 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.Methods: The 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.Results: Xerostomia 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.Conclusions: Based 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.

Labile ctHPV16DNA clearance kinetics in patients with low ({less than or equal to}200 copies/mL) baseline ctHPVDNA levels

Primers, probes, plasmids and gBlocks used in the HPV assay

Multiplexed dPCR assay for non-16 HPV strains

Lack of correlation between ctHPV16DNA clearance at week 6 and persistent/recurrent disease

Baseline ctHPV16DNA levels stratified by AJCC 8th edition N staging

Specificity, sensitivity and linearity of HPV16 dPCR assay

PURPOSE:Dose escalation improves localized prostate cancer disease control, and moderately hypofractionated external beam radiation is noninferior to conventional fractionation. The evolving treatment approach of ultrahypofractionation with stereotactic body radiation therapy (SBRT) allows possible further biological dose escalation (biologically equivalent dose [BED]) and shortened treatment time.METHODS AND MATERIALS:The American Association of Physicists in Medicine Working Group on Biological Effects of Hypofractionated Radiation Therapy/SBRT included a subgroup to study the prostate tumor control probability (TCP) with SBRT. We performed a systematic review of the available literature and created a dose-response TCP model for the endpoint of freedom from biochemical relapse. Results were stratified by prostate cancer risk group.RESULTS:Twenty-five published cohorts were identified for inclusion, with a total of 4821 patients (2235 with low-risk, 1894 with intermediate-risk, and 446 with high-risk disease, when reported) treated with a variety of dose/fractionation schemes, permitting dose-response modeling. Five studies had a median follow-up of more than 5 years. Dosing regimens ranged from 32 to 50 Gy in 4 to 5 fractions, with total BED (α/β = 1.5 Gy) between 183.1 and 383.3 Gy. At 5 years, we found that in patients with low-intermediate risk disease, an equivalent doses of 2 Gy per fraction (EQD2) of 71 Gy (31.7 Gy in 5 fractions) achieved a TCP of 90% and an EQD2 of 90 Gy (36.1 Gy in 5 fractions) achieved a TCP of 95%. In patients with high-risk disease, an EQD2 of 97 Gy (37.6 Gy in 5 fractions) can achieve a TCP of 90% and an EQD2 of 102 Gy (38.7 Gy in 5 fractions) can achieve a TCP of 95%.CONCLUSIONS:We found significant variation in the published literature on target delineation, margins used, dose/fractionation, and treatment schedule. Despite this variation, TCP was excellent. Most prescription doses range from 35 to 40 Gy, delivered in 4 to 5 fractions. The literature did not provide detailed dose-volume data, and our dosimetric analysis was constrained to prescription doses. There are many areas in need of continued research as SBRT continues to evolve as a treatment modality for prostate cancer, including the durability of local control with longer follow-up across risk groups, the efficacy and safety of SBRT as a boost to intensity modulated radiation therapy (IMRT), and the impact of incorporating novel imaging techniques into treatment planning.

PURPOSE:Ultrahypofractionationed radiation therapy for prostate cancer is increasingly studied and adopted. The American Association of Physicists in Medicine Working Group on Biological Effects of Hypofractionated Radiotherapy therefore aimed to review studies examining toxicity and quality of life after stereotactic body radiation therapy (SBRT) for prostate cancer and model its effect.METHODS AND MATERIALS:We performed a systematic PubMed search of prostate SBRT studies published between 2001 and 2018. Those that analyzed factors associated with late urinary, bowel, or sexual toxicity and/or quality of life were included and reviewed. Normal tissue complication probability modelling was performed on studies that contained detailed dose/volume and outcome data.RESULTS:We found 13 studies that examined urinary effects, 6 that examined bowel effects, and 4 that examined sexual effects. Most studies included patients with low-intermediate risk prostate cancer treated to 35-40 Gy. Most patients were treated with 5 fractions, with several centers using 4 fractions. Endpoints were heterogeneous and included both physician-scored toxicity and patient-reported quality of life. Most toxicities were mild-moderate (eg, grade 1-2) with a very low overall incidence of severe toxicity (eg, grade 3 or higher, usually <3%). Side effects were associated with both dosimetric and non-dosimetric factors.CONCLUSIONS:Prostate SBRT appears to be overall well tolerated, with determinants of toxicity that include dosimetric factors and patient factors. Suggested dose constraints include bladder V(Rx Dose)Gy <5-10 cc, urethra Dmax <38-42 Gy, and rectum Dmax <35-38 Gy, though current data do not offer firm guidance on tolerance doses. Several areas for future research are suggested.

PIK3CA is the most frequently mutated gene in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Prognostic implications of such mutations remain unknown. We sought to elucidate the clinical significance of PIK3CA mutations in HPV-associated OPSCC patients treated with definitive chemoradiation (CRT). Seventy-seven patients with HPV-associated OPSCC were enrolled on two phase II clinical trials of deintensified CRT (60 Gy intensity-modulated radiotherapy with concurrent weekly cisplatin). Targeted next-generation sequencing was performed. Of the 77 patients, nine had disease recurrence (two regional, four distant, three regional and distant). Thirty-four patients had mutation(s) identified; 16 had PIK3CA mutations. Patients with wild-type-PIK3CA had statistically significantly higher 3-year disease-free survival than PIK3CA-mutant patients (93.4%, 95% confidence interval [CI] = 85.0% to 99.9% vs 68.8%, 95% CI = 26.7% to 89.8%; P = .004). On multivariate analysis, PIK3CA mutation was the only variable statistically significantly associated with disease recurrence (hazard ratio = 5.71, 95% CI = 1.53 to 21.3; P = .01). PIK3CA mutation is associated with worse disease-free survival in a prospective cohort of newly diagnosed HPV-associated OPSCC patients treated with deintensified CRT.

We recently reported an association between parotid dose and xerostomia in patients receiving whole brain radiation therapy (WBRT). The purpose of this analysis is to perform normal tissue complication probability (NTCP) modeling to further explore the parotid dosimetric indices associated with patient-reported xerostomia. Patients receiving WBRT (25-40 Gy in 10-20 fractions) for any diagnosis were enrolled on a prospective observational study. WBRT was delivered with 3D-conformal radiation therapy using standard opposed lateral fields covering C1. The parotids were not prospectively delineated, but retrospectively delineated and considered one structure for analysis. Patients completed the University of Michigan Xerostomia Questionnaire (Xerostomia score, scaled 0-100, higher is worse) and a 4-point dry mouth “bother” score (1-Not at all, 2-A little, 3-Quite a bit, 4-Very much) at baseline, conclusion of WBRT, 2 weeks, 1 month (primary endpoint), 3 months, and 6 months post-WBRT. The clinical data were fitted by the Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP models using outcomes at 1 month post-RT. We defined toxicity as a ≥20 point worsening in xerostomia score, or a ≥2 point worsening in bother score. 55 patients who reached the primary time point of 1 month were eligible for analysis. Median WBRT dose was 30 Gy in 10 fractions. Median parotid mean dose was 17Gy (Range, 11-28Gy) and median parotid V20Gy was 48% (Range, 24-84%). Xerostomia score increased by ≥20 in 19 patients (35%), and bother score increased by ≥2 points in 11 patients (20%). Parotid V5Gy-V20Gy were found to correlate best with toxicity, with AUC 0.68 for xerostomia score and 0.69 to 0.71 for bother score. AUC values for parotid mean dose were 0.64 and 0.65 for xerostomia score and bother score respectively. The values for the D50, m and n parameters of the Lyman-Kutcher-Burman model were 22.3Gy, 0.84 and 1.0, respectively for xerostomia score and 28.4Gy, 0.55 and 1.0 for bother score. Similarly, the values for the D50, γ and s parameters of the Relative Seriality model were 23.5Gy, 0.28 and 0.0001, respectively for xerostomia score and 32.0Gy, 0.45 and 0.0001 for bother score. A statistically significant toxicity Odds Ratio of 8.6 and 9.1 was observed in patients with parotid V20Gy > 48% for xerostomia score and bother score, respectively. Clinically significant xerostomia was fairly common after WBRT and correlated well with parotid V5Gy-V20Gy. The dose-response for xerostomia could be determined by fitting the clinical data with the LKB and RS NTCP models. These data support the need for minimization of parotid dose in patients receiving WBRT. Additionally, they can be very useful in prospective treatment plan optimization and evaluation.

e17552 Background: p16 immunohistochemistry (IHC) is a commonly used method for identifying HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). However, p16 overexpression in a minority of HPV negative OPSCC can give rise to false positive results. In contrast, HPV nucleic acid testing lacks adequate sensitivity for routine diagnostic testing. The goal of this study was to investigate whether a multiplexed digital PCR assay can detect and quantify HPV DNA in p16 positive OPSCC treated with definitive chemo-radiotherapy (CRT). Methods: Formalin-fixed paraffin embedded (FFPE) residual diagnostic biopsy specimens were collected from 57 patients. Macrodissection was performed to ensure tumor cellularity > 70%. Extracted genomic DNA was analyzed by next generation sequencing (NGS) using a hybrid capture assay (UNCSeq) targeting > 200 cellular genes and HPV 16/18 genomes. We also designed, validated, and implemented an multiplexed droplet digital PCR (dPCR) assay to detect and quantify HPV DNA (strains 16, 18, 31, 33 and 35) in tissue samples, relative to a genomic control locus (chromosome 6). Results: HPV strain 16 DNA was identified in 50 patients (87.7%), whereas 5 patients (8.8%) had HPV DNA from an alternative high-risk strain (18/31/33/35). HPV DNA was undetectable in 2 patients, indicating a false positive rate of 3.5% for p16 IHC testing in this cohort. HPV DNA copy number per diploid genome equivalent varied significantly across samples, with a median value of 19.7 (range 0.23-1712). A significant correlation was observed between the copies of HPV detected by dPCR and NGS (R2 = 0.5853, p < 0.0001). Evidence for HPV integration was detected by NGS in 23 out of 56 evaluable tumors (42%). There was a trend towards a higher prevalence of HPV integration in tumors with less than 10 HPV copies per diploid genome relative to cancers with > / = 10 HPV copy number (63% versus 34%, p = 0.07). Conclusions: Multiplexed digital PCR demonstrates excellent sensitivity for detection and typing of HPV DNA in diagnostic FFPE specimens from patients with p16 positive oropharyngeal cancer. HPV copy number varies significantly across samples, with a possible association with HPV integration status. Future investigations of potential correlation between HPV copy number, integration status, and clinical outcomes are warranted. Clinical trial information: NCT02281955, NCT03077243.

PURPOSETo report the results of a phase II clinical trial of de-intensified chemoradiotherapy for patients with human papillomavirus?associated oropharyngeal squamous cell carcinoma.MATERIALS AND METHODSMajor inclusion criteria were (1) having American Joint Committee on Cancer (AJCC) 7th edition T0-T3, N0-N2c, M0 (AJCC 8th edition T0-T3, N0-N2, M0), (2) being p16 positive, and (3) reporting minimal or remote smoking history. Treatment was limited to 60 Gy intensity-modulated radiotherapy with concurrent intravenous cisplatin 30 mg/m(2) once per week. Patients with T0-T2 N0-1 (AJCC 7th edition) did not receive chemotherapy. All patients had a 10- to 12-week post-treatment positron emission tomography/computed tomography to assess for neck dissection. The primary end point was 2-year progression-free survival. Secondary end points included 2-year local-regional control, distant metastasis-free survival and overall survival, and patient-reported outcomes (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire and the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events).RESULTSOne hundred fourteen patients were enrolled (median follow-up of 31.8 months), with 81% having a minimum follow-up of 2 years. Eighty percent of patients had 10 or fewer tobacco pack-years. Two-year local-regional control, distant metastasis-free survival, progression-free survival, and overall survival were as follows: 95%, 91%, 86%, and 95%, respectively. Mean pre- and 2-year post-treatment European Organisation for Research and Treatment of Cancer quality of life scores were as follows: global, 79/84 (lower worse); swallowing, 8/9 (higher worse); and dry mouth, 14/45 (higher worse). Mean pre- and 2-year post-treatment patient-reported outcomes version of the Common Terminology Criteria for Adverse Events scores (0 to 4 scale, higher worse) were as follows: swallowing, 0.5/0.7, and dry mouth, 0.4/1.3. Thirty-four percent of patients required a feeding tube (median, 10.5 weeks; none permanent). There were no grade 3 or higher late adverse events.CONCLUSIONClinical outcomes with a de-intensified chemoradiotherapy regimen of 60 Gy intensity-modulated radiotherapy with concurrent low-dose cisplatin are favorable in patients with human papillomavirus?associated oropharyngeal squamous cell carcinoma. Neither neoadjuvant chemotherapy nor routine surgery is needed to obtain favorable results with de-escalation.

Purpose: Dry eye is not typically considered a toxicity of whole brain radiation therapy (WBRT). We analyzed dry eye syndrome as part of a prospective study of patient-reported outcomes after WBRT. Methods and Materials: Patients receiving WBRT to 25 to 40 Gy were enrolled on a study with dry mouth as the primary endpoint and dry eye syndrome as a secondary endpoint. Patients received 3-dimensional WBRT using opposed lateral fields. Per standard practice, lacrimal glands were not prospectively delineated. Patients completed the Subjective Evaluation of Symptom of Dryness (SESoD, scored 0-4, with higher scores representing worse dry eye symptoms) at baseline, immediately after WBRT (EndRT), and at 1 month (1M), 3 months, and 6 months. Patients with baseline SESoD >= 3 (moderate dry eye) were excluded. The endpoints analyzed were >= 1-point and >= 2-point increase in SESoD score at 1M. Lacrimal glands were retrospectively delineated with fused magnetic resonance imaging scans. Results: One hundred patients were enrolled, 70 were eligible for analysis, and 54 were evaluable at 1M. Median bilateral lacrimal V20Gy was 79%. At 1M, 17 patients (32%) had a >= 1-point increase in SESoD score, and 13 (24%) a >= 2-point increase. Lacrimal doses appeared to be associated with an increase in SESoD score of both >= 1 point (V10Gy: P = .042, odds ratio [OR] 1.09/%; V20Gy: P = .071, OR 1.03/%) and >= 2 points (V10Gy: P = .038, OR 1.15/%; V20Gy: P = .063, OR 1.04/%). The proportion with increase in dry eye symptoms at 1M for lacrimal V20Gy >= 79% versus <79% was 46% versus 15%, respectively, for >= 1 point SESoD increase (P = .02) and 36% versus 12%, respectively, for >= 2 point SESoD increase (P = .056). Conclusions: Dry eye appears to be a relatively common, dose/volume-dependent acute toxicity of WBRT. Minimization of lacrimal gland dose may reduce this toxicity, and patients should be counseled regarding the existence of this potential side effect and treatments for dry eye. (C) 2019 Elsevier Inc. All rights reserved.

6022 Background: To report the mature results from a prospective phase II clinical trial of highly de-intensified chemoradiotherapy (CRT) for patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods: The major inclusion criteria were: 1) T0-T3, N0-N2, M0, 2) p16 positive, and 3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatin 30 mg/m2(second choice was cetuximab). Patients with T0-T2 N0-1 disease did not receive chemotherapy. All patients had a 10 to 12-week post-treatment PET/CT to determine need for planned neck dissection. The primary study endpoint was 2 year progression free survival (PFS). Secondary endpoint measures include 2 year local control (LC), regional control (RC), distant metastasis free survival (DMFS), cause specific survival (CSS) and overall survival (OS), and patient reported symptoms (PRO-CTCAE) and quality of life (EORTC QLQ-C30 & H&N35). Results: 114 patients were enrolled (median f/u of 28.8 months, range 2.6 to 51.4) with 84 having a minimum follow-up of 2 years. Smoking status was as follows: 47% never, 33% ≤ 10 pack years, and 19% > 10 pack years. Post-treatment PET/CT complete response rate was 93% at the primary site and 80% in the neck. Eleven patients had planned neck dissection with 4 having pathological residual disease. Two year LC, RC, DMFS, PFS, CSS, and OS were the following: 96%, 99%, 91%, 88%, 97%, and 95%. Neither smoking status nor receipt of cetuximab correlated with recurrence. Four patients with recurrent disease had PIK3CA mutations. Thirty four percent of patients required a feeding tube (none permanent) for a median of 10.5 weeks. Mean pre- and 2-year post-treatment EORTC QOL scores were: Global 79/83 (lower worse), Swallowing 8/9 (higher worse), Dry Mouth 14/45 (higher worse), and Sticky Saliva 9/28 (higher worse). Mean pre- and 2 year post-treatment PRO-CTCAE (0 to 4 scale, higher worse) scores were: Swallowing 0.5/0.7 and Dry mouth 0.4/1.4. There were no ≥ Grade 3 late adverse events. Conclusions: Clinical outcomes with a highly de-intensified CRT regimen of 60 Gy IMRT with concurrent low-dose cisplatin are excellent in patients with HPV-associated OPSCC. Clinical trial information: NCT02281955.

AbstractPurpose: To identify a profile of circulating tumor human papilloma virus (HPV) DNA (ctHPVDNA) clearance kinetics that is associated with disease control after chemoradiotherapy (CRT) for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Experimental Design: A multi-institutional prospective biomarker trial was conducted in 103 patients with (i) p16-positive OPSCC, (ii) M0 disease, and (iii) receipt of definitive CRT. Blood specimens were collected at baseline, weekly during CRT, and at follow-up visits. Optimized multianalyte digital PCR assays were used to quantify ctHPVDNA (types 16/18/31/33/35) in plasma. A control cohort of 55 healthy volunteers and 60 patients with non–HPV-associated malignancy was also analyzed. Results: Baseline plasma ctHPVDNA had high specificity (97%) and high sensitivity (89%) for detecting newly diagnosed HPV-associated OPSCC. Pretreatment ctHPV16DNA copy number correlated with disease burden, tumor HPV copy number, and HPV integration status. We define a ctHPV16DNA favorable clearance profile as having high baseline copy number (>200 copies/mL) and >95% clearance of ctHPV16DNA by day 28 of CRT. Nineteen of 67 evaluable patients had a ctHPV16DNA favorable clearance profile, and none had persistent or recurrent regional disease after CRT. In contrast, patients with adverse clinical risk factors (T4 or >10 pack years) and an unfavorable ctHPV16DNA clearance profile had a 35% actuarial rate of persistent or recurrent regional disease after CRT (P = 0.0049). Conclusions: A rapid clearance profile of ctHPVDNA may predict likelihood of disease control in patients with HPV-associated OPSCC patients treated with definitive CRT and may be useful in selecting patients for deintensified therapy.

6011 Background: PIK3CA is the most frequently mutated gene in HPV-associated oropharyngeal SCC (OPSCC), with a prevalence of 20-30%. While PIK3CA mutations have been associated with adverse outcomes in cervical cancer, their prognostic significance in HPV-associated OPSCC remains unknown. We sought to elucidate the significance of PIK3CA mutations in a prospective cohort of HPV-associated OPSCC patients treated with definitive chemoradiation (CRT). Methods: Seventy-eight patients with HPV-associated OPSCC were prospectively enrolled on three protocols: LCCC 1121 (NCT03161821) or two phase II clinical trials of de-intensified CRT (NCT02281955 / NCT03077243). De-intensified regimen was 60 Gy IMRT with concurrent cisplatin (30mg/m2). Next-generation sequencing of tumor samples was performed using a targeted panel-based assay (UNCSeq), including over 200 genes. We estimated disease-free survival (DFS) using the Kaplan-Meier method and compared treatment groups with two-sided log-rank test (Medcalc). Results: Sequencing was performed in 78 patients with a median follow-up of 24 months. Seventy-five patients received 60Gy; three patients received 70Gy. Ten patients had disease recurrence (2 regional only, 5 distant only, 3 regional and distant). Thirty-eight of 78 patients had at least one mutation identified (17 PIK3CA, 4 PTEN, 3 KRAS, 3 FBXW7, 3 FGFR3, 2 TP53, 2 prothrombin 20210, 1 NRAS, 1 BRCA1, 1 factor V Leiden, 1 FLT3, 1 RAD50, 1 PIK3R1). The most common site of PIK3CA mutation was the helical domain (E545K – 8/17, E542K – 2/17). Despite similar T/N staging and tobacco pack years, patients with WT-PIK3CA had significantly higher DFS (93%) compared with 65% for patients with PIK3CA mutations (p = 0.0009). Patients with mutations other than PIK3CA also had improved DFS relative to those with PIK3CA mutations (96% vs. 65%; p = 0.0147). Conclusions: PIK3CA mutation is associated with worse DFS in a prospective cohort of newly diagnosed HPV-associated OPSCC patients treated with definitive CRT. These findings suggest that patients with PIK3CA mutations may not be suitable for de-intensified therapy and investigation of novel treatment strategies may be appropriate.

Background We investigated the quality of life (QOL) impact of post-radiation therapy (RT) superselective/selective neck dissection after de-intensified chemoradiation for human papillomavirus-associated oropharynx cancer. Methods A total of 147 patients received 60 Gy and weekly low-dose cisplatin on two phase 2 trials with planned post-RT neck dissection or surveillance positron emission tomography with neck dissection reserved for salvage. UW-QOL Shoulder Score, EORTC H&N-35, and EAT-10 were assessed. Results In all, 48 of 147 patients had post-RT neck dissection. At 2 years, 37% and 13% of patients receiving post-RT neck dissection had Shoulder Score >= 1 (any shoulder symptoms) and >= 2 (symptoms affecting work/hobbies), respectively, versus only 16% and 3% of patients not receiving post-RT neck dissection. Post-RT neck dissection was associated with Shoulder Score >= 1 (P = 0.005) and Shoulder Score >= 2 (P = 0.03) at 2 years, but not H&N-35 or EAT-10 scores. Conclusions Post-RT superselective/selective neck dissection was associated with modest but persistent shoulder symptoms. These toxicities should be weighed against the probability of persistent disease when evaluating patients for post-RT neck dissection.

Patients with head & neck tumors are commonly treated with external radiation therapy. Due to the proximity of the parotids to the tumor they often receive high doses to a portion of their volume. We prospectively enrolled patients on an IRB-approved clinical trial to estimate the correlation between different normal tissue complication probability (NTCP) models and dosimetric indices of the parotid and submandibular glands with the patient reported severity of xerostomia 12 months post de-intensified chemoradiotherapy. 120 patients with favorable risk, HPV-associated oropharyngeal squamous cell carcinoma were treated with de-intensified chemoradiotherapy. 60Gy delivered with intensity modulated radiotherapy was prescribed to all patients, who also received concurrent weekly intravenous cancer-treating drugs (30 mg/m2). The dose constraints for contralateral parotid and submandibular glands were mean dose <26 and <35, respectively. The status of xerostomia was reported pre- and post-treatment using the patient reported outcome version of the CTCAE (PRO-CTCAE): none/mild/moderate/severe/very severe. We correlated individual patient dosimetric data from the contralateral parotid and contralateral glands (parotid and submandibular glands combined) with the changes in the severity of xerostomia at 12 month post-treatment. A change in severity (from baseline) of ≥ 2 was considered clinically meaningful. The clinical data were fitted by the Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP models. Xerostomia increased in 40 patients (33%). Median mean doses to the contralateral parotid and combined glands were 23Gy (range: 5.1-47.1Gy) and 28Gy (range: 6-50Gy), respectively. For both structures, the V15Gy and mean doses correlated best with the subsequent xerostomia (AUC = 0.68-0.70). The values for the D50, m and n parameters of the Lyman-Kutcher-Burman model are 67Gy, 0.58 and 0.01 for the contralateral parotid and 56Gy, 0.56 and 0.12 for the combined glands. The values for the D50, γ and s parameters of the Relative Seriality model are 31.0Gy, 0.46 and 1.0 for the contralateral parotid and 39Gy, 0.48 and 1.0 for the combined glands. The AUC values for the two NTCP models for the contralateral parotid and combined glands and were similar 0.65 and 0.64, respectively. A statistically significant Odds Ratio of 5.7 (95%CI: 2.0-16.1Gy) was found for the contralateral parotid at V15Gy ≤ 53% and 7.8 (95%CI: 2.2-27.5Gy) for the combined glands at V15Gy ≤ 61%. The dosimetric thresholds V15Gy ≤ 53% to the contralateral parotid and V15Gy ≤ 61% to the combined parotid and submandibular glands were found to significantly reduce the risk for xerostomia. The dose-response curve of xerostomia could be determined by fitting the clinical data with the LKB and RS NTCP models. These models can provide constraints, which can be very useful in prospective treatment plan optimization and evaluation.