Oral health-related quality of life after radiation therapy for head and neck cancer: the OraRad study.

PURPOSE: Head and neck cancer (HNC) treatment results in morbidity impacting quality of life (QOL) in survivorship. This analysis evaluated changes in oral health-related QOL (OH-QOL) up to 2 years after curative intent radiation therapy (RT) for HNC patients and factors associated with these changes. METHODS: 572 HNC patients participated in a multicenter, prospective observational study (OraRad). Data collected included sociodemographic, tumor, and treatment variables. Ten single-item questions and 2 composite scales of swallowing problems and senses problems (taste and smell) from a standard QOL instrument were assessed before RT and at 6-month intervals after RT. RESULTS: The most persistently impacted OH-QOL variables at 24 months included: dry mouth; sticky saliva, and senses problems. These measures were most elevated at the 6-month visit. Aspects of swallowing were most impacted by oropharyngeal tumor site, chemotherapy, and non-Hispanic ethnicity. Problems with senses and dry mouth were worse with older age. Dry mouth and sticky saliva increased more among men and those with oropharyngeal cancer, nodal involvement, and use of chemotherapy. Problems with mouth opening were increased by chemotherapy and were more common among non-White and Hispanic individuals. A 1000 cGy increase in RT dose was associated with a clinically meaningful change in difficulty swallowing solid food, dry mouth, sticky saliva, sense of taste, and senses problems. CONCLUSIONS: Demographic, tumor, and treatment variables impacted OH-QOL for HNC patients up to 2 years after RT. Dry mouth is the most intense and sustained toxicity of RT that negatively impacts OH-QOL of HNC survivors. GOV IDENTIFIER: NCT02057510; first posted February 7, 2014.

Mature results of a prospective study of deintensified chemoradiotherapy for low-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma.

BACKGROUND: The purpose of the current study was to determine quality of life and tumor control from a prospective phase 2 clinical trial evaluating deintensified chemoradiotherapy for favorable risk, human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma. METHODS: Patients with T0-T3, N0-N2c, M0, p16-positive disease and a minimal smoking history were treated with 60 grays of intensity-modulated radiotherapy with concurrent weekly intravenous cisplatin (30 mg/m2 ). The primary study endpoint was the pathologic complete response rate based on biopsy of the primary site and dissection of pretreatment positive lymph node regions. The pathologic complete response rate as previously reported was 86%. Herein, the authors report secondary endpoint measures of local control, regional control, cause-specific survival, distant metastasis-free survival, and overall survival, and patient-reported outcomes (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [EORTC QLQ-C30] and the Patient-Reported Outcomes version of Common Terminology Criteria for Adverse Events [PRO-CTCAE]). RESULTS: A total of 44 patients enrolled with a median follow-up of 36 months (88% with ≥2 years). The 3-year local control, regional control, cause-specific survival, distant metastasis-free survival, and overall survival rates were 100%, 100%, 100%, 100%, and 95%, respectively. The mean before and 3-year after EORTC QOL scores were: global: 80 of 78; swallowing: 11 of 11; dry mouth: 16 of 41; and sticky saliva: 6 of 29. The mean before and 3-year after PRO-CTCAE scores were: swallowing: 0.4 of 0.7; and dry mouth: 0.4 of 1.4. Approximately 39% of patients required a feeding tube (median duration, 15 weeks; none were permanent). There were no ≥grade 3 late adverse events reported. CONCLUSIONS: For patients with favorable-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma, a substantially decreased intensity of therapy with 60 grays of intensity-modulated radiotherapy and weekly low-dose cisplatin produced better preservation of quality of life compared with standard therapies while maintaining excellent 3-year tumor control and survival. Cancer 2018;124:2347-54. © 2018 American Cancer Society.

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

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

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

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

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

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

Prospective Assessment of Patient-Reported Dry Eye Syndrome After Whole Brain Radiation.

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.

Phase II Trial of De-Intensified Chemoradiotherapy for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

PURPOSE: To 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 METHODS: Major 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/m2 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). RESULTS: One 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. CONCLUSION: Clinical 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.

Quality of Life for Patients With Favorable-Risk HPV-Associated Oropharyngeal Cancer After De-intensified Chemoradiotherapy.

PURPOSE: Oropharynx cancers associated with human papillomavirus (HPV) have a favorable prognosis, but current treatment approaches carry significant long-term morbidity. Strategies to de-intensify treatment in this population are under investigation, but the impact of these approaches on quality of life (QOL) is not well understood. We present patient-reported outcomes from 2 prospective studies examining de-intensified chemoradiotherapy. METHODS AND MATERIALS: This study included patients enrolled in 2 prospective phase 2 trials of de-intensified chemoradiotherapy in patients with HPV-associated oropharynx cancer who had at least 1 year of follow-up. Treatment included concurrent radiation therapy (60 Gy) and chemotherapy (weekly cisplatin, 30 mg/m2). Patients reported QOL and symptoms using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, the European Organisation for Research and Treatment of Cancer Head and Neck Cancer Module-35, and the Eating Assessment Tool-10 instruments before treatment and at regular intervals thereafter. Changes in QOL and individual symptoms were examined over time, and multivariate analysis was used to identify clinical factors associated with recovery to baseline symptom levels. RESULTS: Of the 154 patients enrolled, 126 patients had at least 1 year of follow-up and were included in this study (median follow-up, 25 months). Global QOL, functional indices, and most individual symptoms returned to baseline 3 to 6 months after treatment. Swallowing (Eating Assessment Tool-10 score) returned to baseline function by 2 years, but dry mouth, sticky saliva, and taste/senses did not return to baseline levels. However, from 1 to 2 years, continued improvement occurred in dry mouth score (55 vs 48), sticky saliva score (35 vs 27), and senses score (24 vs 20). On multivariate analysis, unilateral radiation therapy was associated with returning to baseline level of swallowing and sticky saliva. CONCLUSIONS: The use of de-intensified chemoradiotherapy in HPV-associated oropharynx cancer led to favorable patient-reported outcomes, with early recovery of QOL and continued improvement of xerostomia and dysphagia beyond 1-year posttreatment.

Clear cell odontogenic carcinoma of the maxilla: a case report and literature review.

BACKGROUND: Clear cell odontogenic carcinoma (CCOC) is a rare tumor of odontogenic origin. It was first described as a clinicopathological entity in 1985, and since then, several case reports have been published. METHODS: We present a patient with CCOC treated at the University of Florida and review the pertinent literature. RESULTS: We treated a 52-year-old woman with CCOC of the maxilla. She received a maxillectomy and postoperative radiotherapy (RT). She developed pulmonary metastases 2 years after treatment. She remains alive and asymptomatic 7 years after completing treatment and has not required additional therapy. The literature search yielded 48 other case reports. The median age at presentation was 53 years (mean, 55 years), the female-to-male ratio was 2:1, and the most common site of presentation was the mandible. Three patients presented with submandibular lymphadenopathy. Most patients had a surgical resection (35 patients, 71%); the remainder underwent curettage. Six (12%) patients received postoperative RT. Eighty percent of patients who were initially treated with curettage developed a local recurrence. Local and/or regional recurrences occurred in 34% of patients who underwent surgical resection. Six patients developed distant metastatic disease; the most common site of the metastases was the lung. Seven patients died from or with the disease, and 3 are alive with the disease. CONCLUSIONS: Clear cell odontogenic carcinoma is a rare tumor of the mandible and maxilla that has the propensity for local destruction and the potential for lymphatic and hematogenous metastases. We recommend radical excision as the primary treatment and that adjuvant RT be added for those who have close or positive margins as well as those with lymph node metastases.

Incidence of, and risk factors for, mandibular osteoradionecrosis in patients with oral cavity and oropharynx cancers.

OBJECTIVES: To evaluate the incidence of, and risk factors associated with, mandibular osteoradionecrosis (MORN) following radiation therapy (RT) for oral cavity and oropharyngeal cancers. MATERIALS AND METHODS: Patient and treatment records of 252 consecutive patients with oral cavity or oropharynx cancers treated with RT by a single radiation oncologist at a high volume academic institution from August 2009 to December 2015 were retrospectively reviewed. A Cox regression model was used to assess factors associated with the development of MORN. RT dosimetry was compared between patients with MORN and a matched cohort of patients without MORN. RESULTS: MORN developed in 14 patients (5.5%), occurring 3-40 (median 8) months post-RT. Factors associated with MORN on univariable analysis included primary diagnosis of oral cavity vs oropharynx cancer (hazard ratio [HR]: 3.0, p=0.04), smoking at the time of RT (HR: 3.1, p=0.04), mandibular invasion of the primary (HR: 3.7, p=0.04), pre-RT tooth extraction (HR: 4.52, p=0.01), and treatment with 3D-conformal RT vs intensity-modulated RT (HR: 5.1, p=0.003). On multivariable analysis, pre-RT tooth extractions and RT technique remained significant. A dosimetric comparison between patients with and without MORN showed no significant differences. CONCLUSIONS AND RELEVANCE: The incidence of MORN is low in the modern era at a high volume academic center. Modifiable risk factors including pre-RT tooth extractions, smoking, and RT technique are associated with MORN, and the risk should be minimized with appropriate dental evaluation and treatment, smoking cessation efforts, and the use of intensity-modulated RT.

Prognostic significance of bone invasion for oral cavity squamous cell carcinoma considered T1/T2 by American joint committee on cancer size criteria.

BACKGROUND: It is unclear whether bone invasion in small oral cavity squamous cell carcinomas (OCSCC) results in worse prognosis. METHODS: Two hundred fifty-four patients with OCSCC were identified and divided into 3 cohorts: (1) ≤4 cm with no bone invasion; (2) ≤4 cm with bone invasion; and (3) ≥4 cm or other factors (eg, skin invasion, deep muscle invasion) that would qualify for American Joint Committee on Cancer (AJCC) T4 classification aside from bone invasion. Depth of bone invasion (none, cortical, or medullary) was also recorded. RESULTS: Cohorts 1 and 2 had similar outcomes. Cohort 3 had lower rates of regional control (p = .04), disease-specific survival (DSS; p < .01), and overall survival (OS; p < .01). On multivariate analysis, margin status and medullary bone invasion were associated with worse outcomes. CONCLUSION: Bone invasion does not seem to significantly influence outcomes in patients with small primary tumors treated with surgery/radiation. Medullary bone invasion seems to result in reduced rates of control and survival.

Recommended patient-reported core set of symptoms to measure in head and neck cancer treatment trials.

We identified a standard core set of patient-reported symptoms and health-related quality-of-life (HRQOL) domains to be assessed in head and neck (H&N) cancer clinical trials. The core symptom and HRQOL domain scores were used to guide recommendations by a working group of experts as part of a National Cancer Institute Symptom Management and HRQOL Clinical Trials Planning Meeting. A PubMed search was conducted using the search terms of "health-related quality of life" and "head & neck cancer," limited to publications from January 1, 2000, to December 31, 2010. Fifty-four articles were used to guide the choice of recommendations. Twenty-nine symptoms and nine domains were identified, from which 12 H&N-specific core symptoms and HRQOL domains were recommended: swallowing, oral pain, skin changes, dry mouth, dental health, opening mouth/trismus, taste, excess/thick mucous/saliva, shoulder disability/motion, voice/hoarseness, social domain, and functional domain. This core set of 12 H&N-specific, patient-reported symptoms and HRQOL domains should be assessed in future H&N cancer clinical trials.