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Highlights • The PIRATES protocol is a novel tumor radiation dose-escalation approach. • PIRATES integrates proton therapy, image guided RT and hybrid hyper-fractionation. • It targets only head and neck cancer patients at high risk of treatment failure. • This Phase I trial aims to test the feasibility and safety of PIRATES., Introduction Radiation dose-escalation for head and neck cancer (HNC) patients aiming to improve cure rates is challenging due to the increased risk of unacceptable treatment-induced toxicities. With “Proton Image-guided Radiation Assignment for Therapeutic Escalation via Selection of locally advanced head and neck cancer patients” (PIRATES), we present a novel treatment approach that is designed to facilitate dose-escalation while minimizing the risk of dose-limiting toxicities for locally advanced HPV-negative HNC patients. The aim of this Phase I trial is to assess the safety & feasibility of PIRATES approach. Methods The PIRATES protocol employs a multi-faceted dose-escalation approach to minimize the risk of dose-limiting toxicities (DLTs): 1) sparing surrounding normal tissue from extraneous dose with intensity-modulated proton therapy, 2) mid-treatment hybrid hyper-fractionation for radiobiologic normal tissue sparing; 3) Magnetic Resonance Imaging (MRI) guided mid-treatment boost volume adaptation, and 4) iso-effective restricted organ-at-risk dosing to mucosa and bone tissues. The time-to-event Bayesian optimal interval (TITE-BOIN) design is employed to address the challenge of the long DLT window of 6 months and find the maximum tolerated dose. The primary endpoint is unacceptable radiation-induced toxicities (Grade 4, mucositis, dermatitis, or Grade 3 myelopathy, osteoradionecrosis) occurring within 6 months following radiotherapy. The second endpoint is any grade 3 toxicity occurring in 3–6 months after radiation. Discussion The PIRATES dose-escalation approach is designed to provide a safe avenue to intensify local treatment for HNC patients for whom therapy with conventional radiation dose levels is likely to fail. PIRATES aims to minimize the radiation damage to the tissue surrounding the tumor volume with the combination of proton therapy and adaptive radiotherapy and within the high dose tumor volume with hybrid hyper-fractionation and not boosting mucosal and bone tissues. Ultimately, if successful, PIRATES has the potential to safety increase local control rates in HNC patients with high loco-regional failure risk. Trial registration: ClinicalTrials.gov ID: NCT04870840; Registration date: May 4, 2021. Netherlands Trial Register ID: NL9603; Registration date: July 15, 2021.

Background Recurrent head and neck cancer has poor prognosis. Stereotactic body radiotherapy (SBRT) may improve outcomes by delivering ablative radiation doses. Methods We reviewed patients who received definitive-intent SBRT reirradiation at our institution from 2013 to 2020. Patterns of failure, overall survival (OS), and toxicities were analyzed. Results One hundred and thirty-seven patients were evaluated. The median OS was 44.3 months. The median SBRT dose was 45 Gy and median target volume 16.9 cc. The 1-year local, regional, and distant control was 78%, 66%, and 83%, respectively. Systemic therapy improved regional (p = 0.004) and distant control (p = 0.04) in nonmetastatic patients. Grade 3+ toxicities were more common at mucosal sites (p = 0.001) and with concurrent systemic therapy (p = 0.02). Conclusions In a large cohort of SBRT reirradiation for recurrent, small volume head and neck cancers, a median OS of 44.3 months was observed. Systemic therapy improved regional and distant control. Toxicities were modulated by anatomic site and systemic therapy.

Purpose To evaluate the clinical outcomes and treatment related toxicities of charged particle-based re-irradiation (reRT; protons and carbon ions) for the definitive management of recurrent or second primary skull base and head and neck tumors. Materials and Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied for the conduct of this systematic review. Published work in English language evaluating the role of definitive charged particle therapies in the clinical setting of reRT for recurrent or second primary skull base and head and neck tumors were eligible for this analysis. Results A total of 26 original studies (15 protons, 10 carbon ions, and 1 helium/neon studies) involving a total of 1,118 patients (437 with protons, 670 with carbon ions, and 11 with helium/neon) treated with curative-intent charged particle reRT were included in this systematic review. All studies were retrospective in nature, and the majority of them (n=23, 88 %) were reported as single institution experiences (87% for protons, and 90% for carbon ion-based studies). The median proton therapy reRT dose was 64.5 Gy (RBE 1.1) (range, 50.0 – 75.6 Gy ), while the median carbon ion reRT dose was 53.8 Gy (RBE 2.5 – 3.0) (range, 44.8 – 60 Gy ). Induction and/or concurrent chemotherapy was administered to 232 (53%) of the patients that received a course of proton reRT, and 122 (18%) for carbon ion reRT patients. ReRT with protons achieved 2-year local control rates ranging from 50% to 86%, and 41% to 92% for carbon ion reRT. The 2-year overall survival rates for proton and carbon ion reRT ranged from 33% to 80%, and 50% to 86% respectively. Late ≥ G3 toxicities ranged from 0% to 37%, with brain necrosis, ototoxicity, visual deficits, and bleeding as the most common complications. Grade 5 toxicities for all treated patients occurred in 1.4% (n= 16/1118) with fatal bleeding as the leading cause. Conclusions Based on current data, curative intent skull base and head and neck reRT with charged particle radiotherapy is feasible and safe in well-selected cases, associated with comparable or potentially improved local control and toxicity rates compared to historical reRT studies using photon radiotherapy. Prospective multi-institutional studies reporting oncologic outcomes, toxicity, and dosimetric treatment planning data are warranted to further validate these findings and to improve the understanding of the clinical benefits of charged particle radiotherapy in the reRT setting.

Purpose To report clinical outcomes in terms of disease control and toxicity in patients with major salivary gland cancers (SGCs) treated with proton beam therapy. Materials and Methods Clinical and dosimetric characteristics of patients with SGCs treated from August 2011 to February 2020 on an observational, prospective, single-institution protocol were abstracted. Local control and overall survival were calculated by the Kaplan-Meier method. During radiation, weekly assessments of toxicity were obtained, and for patients with ≥ 90 days of follow-up, late toxicity was assessed. Results Seventy-two patients were identified. Median age was 54 years (range, 23-87 years). Sixty-three patients (88%) received postoperative therapy, and nine patients (12%) were treated definitively. Twenty-six patients (36%) received concurrent chemotherapy. Nine patients (12%) had received prior radiation. All (99%) but one patient received unilateral treatment with a median dose of 64 GyRBE (relative biological effectiveness) (interquartile range [IQR], 60-66), and 53 patients (74%) received intensity-modulated proton therapy with either single-field or multifield optimization. The median follow-up time was 30 months. Two-year local control and overall survival rates were 96% (95% confidence interval [CI] 85%-99%) and 89% (95% CI 76%-95%], respectively. Radiation dermatitis was the predominant grade-3 toxicity (seen in 21% [n = 15] of the patients), and grade ≥ 2 mucositis was rare (14%; n = 10 patients). No late-grade ≥ 3 toxicities were reported. Conclusion Proton beam therapy for treatment of major SGCs manifests in low rates of acute mucosal toxicity. In addition, the current data suggest a high rate of local control and minimal late toxicity.

Purpose To report patient-reported outcomes (PROs) derived from the Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN) tool, in patients with oropharynx cancer (OPC) treated with intensity-modulated proton therapy (IMPT) in the context of first-course irradiation. Materials and Methods Patients with locally advanced OPC treated with radical IMPT between 2011 and 2018 were included in a prospective registry. FACT-HN scores were measured serially during and 24 months following IMPT. PRO changes in the FACT-HN scores over time were assessed with mixed-model analysis. Results Fifty-seven patients met inclusion criteria. Median age was 60 years (range, 41-84), and 91% had human papillomavirus-associated disease. In total, 28% received induction chemotherapy and 68% had concurrent chemotherapy. Compliance to FACT-HN questionnaire completion was 59%, 48%, and 42% at 6, 12, and 24 months after treatment, respectively. The mean FACT-General (G), FACT-Total, and FACT-Trial Outcome Index (TOI) score changes were statistically and clinically significant relative to baseline from week 3 of treatment up to week 2 after treatment. Nadir was reached at week 6 of treatment for all scores, with maximum scores dropping by 15%, 20%, and 39% compared to baseline for FACT-G, FACT-Total, and FACT-TOI, respectively. Subdomain scores of physical well-being, functional well-being, and head and neck additional concerns decreased from baseline during treatment and returned to baseline at week 4 after treatment. Conclusions IMPT was associated with a favorable PRO trajectory, characterized by an acute decline followed by rapid recovery to baseline. This study establishes the expected acute, subacute, and chronic trajectory of PROs for patients undergoing IMPT for OPC.

Purpose We compared work outcomes in patients with oropharyngeal cancer (OPC), randomized to intensity-modulated proton (IMPT) versus intensity-modulated photon therapy (IMRT) for chemoradiation therapy (CRT). Patients and Methods In 147 patients with stage II-IVB squamous cell OPC participating in patient-reported outcomes assessments, a prespecified secondary aim of a randomized phase II/III trial of IMPT (n = 69) versus IMRT (n = 78), we compared absenteeism, presenteeism (i.e., the extent to which an employee is not fully functional at work), and work productivity losses. We used the work productivity and activity impairment questionnaire at baseline (pre-CRT), at the end of CRT, and at 6 months, 1 year, and 2 years. A one-sided Cochran-Armitage test was used to analyze within-arm temporal trends, and a χ2 test was used to compare between-arm differences. Among working patients, at each follow-up point, a 1-sided Wilcoxon rank-sum test was used to compare work-productivity scores. Results Patient characteristics in IMPT versus IMRT arms were similar. In the IMPT arm, within-arm analysis demonstrated that an increasing proportion of patients resumed working after IMPT, from 60% (40 of 67) pre-CRT and 71% (30 of 42) at 1 year to 78% (18 of 23) at 2 years (P = 0.025). In the IMRT arm, the proportion remained stable, with 57% (43 of 76) pre-CRT, 54% (21 of 39) at 1 year, and 52% (13 of 25) working at 2 years (P = 0.47). By 2 years after CRT, the between-arm difference between patients who had IMPT and those who had IMRT trended toward significance (P = 0.06). Regardless of treatment arm, among working patients, the most severe work impairments occurred from treatment initiation to the end of CRT, with significant recovery from absenteeism, presenteeism, and productivity impairments by the 2-year follow-up (P Conclusion In patients with OPC receiving curative CRT, patients randomized to IMPT demonstrated increasing work and productivity recovery trends. Studies are needed to identify mechanisms underlying head and neck CRT treatment causing work disability and impairment.

BACKGROUND AND PURPOSE: Sarcopenia is associated with decreased survival in head and neck cancer patients treated with radiotherapy. This study sought to determine whether in-clinic multifrequency bioelectrical impedance analysis (BIA) can identify survival-associated sarcopenia in patients with head and neck cancer. MATERIALS AND METHODS: This prospective observational study enrolled 50 patients with head and neck cancer undergoing radiation therapy. Baseline BIA measures of skeletal muscle (SM) mass, fat-free mass (FFM), and fat mass (FM) were compared to CT-based estimates using linear regression. Sex-specific BIA-derived thresholds for sarcopenia were defined by the maximum Youden Index on receiver operator characteristic (ROC) curves. Patients were stratified by sarcopenia status and OS was compared using the Kaplan-Meier method and log-rank test. RESULTS: Among 48 evaluable patients, BIA measures of body composition were strongly correlated with CT measures: SM mass (r = 0.97; R(2) = 0.94; p < 0.0001), FFM (r = 0.97; R(2) = 0.94; p < 0.0001) and FM (r = 0.95; R(2) = 0.90; p < 0.0001). SM mass index < 9.19 kg/m(2) identified sarcopenia men with high sensitivity (91.7%) and specificity (92.9%), whereas in women SM mass index < 6.53 kg/m(2) was sensitive for sarcopenia (100%), but not specific. Patients with sarcopenia, defined by either CT or BIA, exhibited decreased OS (HR=not estimable; CT p = 0.009; BIA p = 0.03). CONCLUSION: BIA provides accurate estimates of body composition in head and neck cancer patients. Implementation of BIA in clinical practice may identify patients with sarcopenia at risk for poor survival.

Background Squamous cell carcinoma is the most common type of sinonasal malignancy. Despite improvements in surgical resection and adjuvant therapy, which are considered the standard of care, the outcome for patients with locoregionally advanced disease remains poor. The objective of this study was to investigate the role of induction chemotherapy in patients with locoregionally advanced sinonasal squamous cell carcinoma and to determine the oncologic outcomes in those patients. Methods The study included 123 consecutive patients with previously untreated, locoregionally advanced (stage III and IV) sinonasal squamous cell carcinoma who were treated with curative intent at The University of Texas MD Anderson Cancer Center between 1988 and 2017 with induction chemotherapy followed by definitive local therapy. Patient demographics, tumor staging, treatment details, and oncologic outcomes were reviewed. The outcomes of this study included response to induction chemotherapy, recurrence, organ preservation, and survival. Results The median follow-up was 32.6 months (range, 12.4-240 months). Of the 123 patients, 110 (89%) had T4 disease, and 13 (11%) had T3 disease. Lymph node metastasis at the time of presentation was observed in 36 patients (29.3%). The overall stage was stage IV in 111 patients (90.2%) and stage III in 12 patients (9.8%). The chemotherapy regimen consisted of the combination of a platinum and taxanes in most cases (109 patients; 88.6%), either as a doublet (41 patients) or in combination with a third agent, such as 5-fluorouracil (34 patients), ifosfamide (26 patients), or cetuximab (8 patients). After induction chemotherapy, 71 patients (57.8%) achieved at least a partial response, and 6 patients had a complete response. Subsequent treatment after induction chemotherapy was either: 1) definitive chemoradiation or radiation followed by surgical salvage for any residual disease, or 2) surgery followed by adjuvant radiation or chemoradiation. Overall, 54 patients (49.5%) underwent surgical resection. The 2-year overall and disease-free survival rates for the whole cohort were 61.4% and 67.9%, respectively. The rate of orbital preservation was 81.5%. The recurrence rate was 26.8% (33 patients), and distant metastases occurred in 8 patients (6.5%). Patients who had at least a partial response or stable disease had significantly better overall and disease-free survival than those who had progressive disease (P = .028 and P = .021, respectively). Conclusions The current results indicate that a high proportion of patients with sinonasal squamous cell carcinoma achieved a favorable response to induction chemotherapy. The data suggest that response to induction chemotherapy is associated with an improved outcome and a good chance of organ preservation. The oncologic outcomes in this cohort with locally advanced (mostly T4) disease are better than those historically reported in the literature. Further study of induction chemotherapy in patients with advanced sinonasal squamous carcinoma is warranted.

Purpose To determine the optimal dose‐volume constraint for laryngeal sparing using three commonly employed intensity modulated radiation therapy (IMRT) approaches in patients with oropharyngeal cancer treated to the bilateral neck. Materials and methods Thirty patients with stage II‐IVA oropharynx cancers received definitive radiotherapy with split‐field IMRT (SF‐IMRT) to the bilateral neck between 2008 and 2013. Each case was re‐planned using whole‐field IMRT (WF‐IMRT) and volumetric modulated arc therapy (VMAT) and plan quality metrics and dose to laryngeal structures was evaluated. Two larynx volumes were defined and compared on the current study: the Radiation Therapy Oncology Group (RTOG) larynx as defined per the RTOG 1016 protocol and the MDACC larynx defined as the components of the larynx bounded by the superior and inferior extent of the thyroid cartilage. Results Target coverage, conformity, and heterogeneity indices were similar in all techniques. The RTOG larynx mean dose was lower with WF‐IMRT than SF‐IMRT (22.1 vs 25.8 Gy; P

Introduction Tongue-deviating oral stents (TDOS) are commonly used during unilateral neck radiation therapy to reduce unnecessary dose to nontarget oral structures. Their benefit in the setting of highly conformal treatment techniques, however, is not defined. The goal of this study was to investigate the potential benefit of TDOS use on dosimetric parameters in unilateral intensity modulated radiation therapy (IMRT) and intensity modulated proton therapy (IMPT). Methods A total of 16 patients with T1-2 tonsil cancer treated at a single institution were selected, of which 8 were simulated/treated with a TDOS and 8 without a TDOS. All received definitive unilateral IMRT to a dose of 66 Gy in 30 fx. IMPT plans were generated for each patient for study purposes and optimized according to standard institutional practice. Results For IMRT plans, the presence of a TDOS (vs without) was associated with a significantly lower oral mucosa mean dose (31.4 vs 35.3 Gy; P = .020) and V30 (42.7% vs 57.1%; P = .025). For IMPT plans, the presence of TDOS (vs without) was not associated with any improvement in oral mucosa mean dose (18.3 vs 19.9 Gy; P = .274) or V30 (25.0% vs 26.2%; P = .655). IMPT plans without TDOS compared with IMRT plans with TDOS demonstrated reduced oral mucosa mean dose (P < .001) and V30 (P < .001). Conclusion The use of a TDOS for the unilateral treatment of well-lateralized tonsil cancers was associated with oral mucosa sparing for IMRT, but not for IMPT. Moreover, mucosa sparing was improved for IMPT plans without a TDOS compared to IMRT plans with a TDOS.

Background This study aimed to evaluate the prognostic value of pre-treatment NLR in patients with oropharyngeal cancer. Methods Patients who completed definitive radiotherapy (RT) for oropharyngeal cancer and had blood counts taken pre-RT from 2002 to 2013 were included. NLR was calculated as total neutrophil/lymphocytes. Survival rates were estimated using the Kaplan–Meier method. Univariable and multivariable analyses were conducted with linear and Cox regression methods. NLR was analysed posteriori and dichotomised on the discovered median. Results Eight hundred and forty-eight patients were analysed. The median pre-RT NLR was 3. Patients with NLR of p p = 0.011; HPV-negative p = 0.003). Freedom from any recurrence (FFR), locoregional control (LRC) and freedom of distant recurrence (FDR) were better in those with NLR p = 0.001), FFR (HR = 1.6, p = 0.006) and LRC (HR = 1.8, p = 0.005) remained significant on multivariable analysis. Conclusions Pre-RT NLR is an independent prognostic factor in patients with oropharyngeal cancer regardless of HPV status. Patients with lower NLR had more favourable OS and disease control.

Background and purpose To characterize patterns and outcomes of brain MR image changes after proton therapy (PT) for skull base head and neck cancer (HNC). Material and methods Post-treatment MRIs ≥6 months were reviewed for radiation-associated image changes (RAIC) in 127 patients. All patients had received at least a point dose of 40 Gy(RBE) to the brain. The MRIs were rigidly registered to planning CTs and RAIC lesions were contoured both on T1 weighted (post-contrast) and T2 weighted sequences, and dose–volume parameters extracted. Probability of RAIC was calculated using multistate survival analysis. Univariate/multivariate analyses were performed using Cox Regression. Recursive partitioning analysis was used to investigate dose–volume correlates of RAIC development. Results 17.3% developed RAIC. All RAIC events were asymptomatic and occurred in the temporal lobe (14), frontal lobe (6) and cerebellum (2). The median volume of the contrast enhanced RAIC lesion was 0.5 cc at their maximum size. The RAIC resolved or improved in 45.5% of the patients and were stable or progressed in 36.4%. The 3-year actuarial rate of developing RAIC was 14.3%. RAIC was observed in 63% of patients when V67 Gy(RBE) of the brain ≥0.17 cc. Conclusion Small RAIC lesions after PT occurred in 17.3% of the patients; the majority in nasopharyngeal or sinonasal cancer. The estimated dose–volume correlations confirm the importance of minimizing focal high doses to brain when achievable.

Background The incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the US is rapidly increasing, driven largely by the epidemic of human papillomavirus (HPV)-mediated OPSCC. Although survival for patients with HPV mediated OPSCC (HPV+ OPSCC) is generally better than that of patients with non-virally mediated OPSCC, this effect is not uniform. We hypothesized that tobacco exposure remains a critical modifier of survival for HPV+ OPSCC patients. Methods We conducted a retrospective analysis of 611 OPSCC patients with concordant p16 and HPV testing treated at a single institute (2002–2013). Survival analysis was performed using Kaplan-Meier analysis and Cox regression. Recursive partitioning analysis (RPA) was used to define tobacco exposure associated with survival (p Results Tobacco exposure impacted overall survival (OS) for HPV+ patients on univariate and multivariate analysis (p = 0.002, p = 0.003 respectively). RPA identified 30 pack-years (PY) as a threshold at which survival became significantly worse in HPV+ patients. OS and disease-free survival (DFS) for HPV+ > 30 PY patients didn’t differ significantly from HPV- patients (p = 0.72, p = 0.27, respectively). HPV+ > 30 PY patients had substantially lower 5-year OS when compared to their ≤30 PYs counterparts: 78.4% vs 91.6%; p = 0.03, 76% vs 88.3%; p = 0.07, and 52.3% vs 74%; p = 0.05, for stages I, II, and III (AJCC 8th Edition Manual), respectively. Conclusions Tobacco exposure can eliminate the survival benefit associated with HPV+ status in OPSCC patients. Until this effect can be clearly quantified using prospective datasets, de-escalation of treatment for HPV + OPSCC smokers should be avoided.

Purpose Here we provide an analysis of the set-up and positioning accuracy of SABR for skull base malignancies to evaluate the use of site- or axis-specific margins to reduce field size. Methods and Materials Data were prospectively collected on 63 patients who received 304 fractions of SABR for recurrent/previously irradiated skull base tumors. Using our custom cushion-mask-bite-block immobilization system combined with ExacTrac x-ray and cone beam computed tomography (CBCT), set-up, residual, CBCT-positioning agreement, and intrafractional errors were measured. The resulting planning target volume (PTV) margins were estimated across 4 skull base subsites: anterior (group 1), central (group 2), posterolateral (group 3), and skull base–associated sites (eg, nasopharynx/retropharyngeal, cervical vertebrae 1-2, occiput) (group 4). Results On initial set-up, 66% of treatment courses required shifts of >2 mm or >2°, necessitating 4.9 mm PTV margins without image guidance. After correction, only 6 of 304 treatment sessions had residual errors >1 mm. CBCT-ExacTrac agreement was ≤1 mm in 89.1% of treatments and ≤1.5 mm in all but 1 session. Group 4 showed a higher rate of >1 mm or >1° CBCT-positioning differences compared with other groups (24.5% vs 7.8%; P = .0001), and the greatest variations occurred in the craniocaudal translational and the pitch rotational axes. Overall calculated PTV margins (based on intrafractional error) were 1.5 mm across subsites except for group 4, which required 2.0 mm margins. Conclusions The use of 2.0 mm PTV margins for skull base SABR appears feasible using ExacTrac x-ray as the sole imaging modality for most subsites. However, PTVs were not uniformly equal, and the use of a site-specific nonuniform margin reduction to optimize critical-organ dose sparing may be feasible for select cases. These findings warrant clinical investigation.

Objective Temporal bone osteoradionecrosis (TBORN) is a rare, chronic complication of head and neck radiation. Initial treatment consists of conservative management, with surgical resection of necrotic bone indicated for cases of severe, symptomatic, or progressive disease. Pentoxifylline-tocopherol (PENTO) has demonstrated usefulness for osteoradionecrosis of other head and neck subsites. Herein, we report five TBORN cases utilizing this protocol. Study design Retrospective case series. Setting Tertiary referral center. Patients This case series describes five TBORN cases in which the PENTO protocol was used in conjunction with conservative management. All patients were women and average age was 61 ± 8 years. Intervention All patients received a daily dose of 800 mg of pentoxifylline and 1 g of tocopherol. Four of the five patients received systemic and/or ototopical antibiotics as an antimicrobial regimen before and/or during the PENTO protocol. Main outcome measures Details regarding the total duration of protocol, improvement in symptoms, exposed bone and radiographic changes, and duration until first improvement of exposed bone were collected retrospectively. Results The average duration of PENTO protocol was 302 ± 166 days. Four of the five (80%) patients demonstrated a decrease in exposed ear canal bone. Three of the five (60%) patients had stable or improvement in otologic symptoms of TBORN. One patient progressed to diffuse TBORN. The average duration until first improvement in exposed bone was 193 ± 137 days. Conclusions The PENTO protocol may be a useful adjunct to conservative measures in the management of localized TBORN. We recommend trialing the protocol for at least 12 months.

Highlights • Large head and neck volume irradiation is feasible using Multileaf Collimator-based robotic technology. • Proton beam therapy had superior conformity, but homogeneity and dose gradient of robotic and proton plans were similar. • Conventionally fractionated robotic stereotactic radiotherapy is an alternative for large volume head and neck re-irradiation., Purpose To report on the feasibility and performance of conventionally fractionated multileaf collimator (MLC)-based robotic stereotactic body re-irradiation of the head and neck region using MLC-based Cyberknife (CK) technology. Methods Patients treated for recurrent or second primary head and neck cancer (HNC) with curative proton therapy to a target volume > 30 cm3 between 2011 and 2015 were included. MLC-based CK plans were generated using the CK M6 InCise2 MLC system. Dose statistics from MLC-based CK plans were compared to proton beam therapy (PBT) plans according to the following metrics: target coverage, target homogeneity index, gradient index, Paddick conformity index (CI), prescription isodose volume (PIV), treatment time (tTime) for one fraction as well as doses to organs at risk (OAR). Wilcoxon signed-rank test was used to compare dose metrics. Results Eight patients were included; the tumor sites included: salivary glands, pharynx (oropharynx, hypopharynx and retropharynx) and sinonasal cavities. Five of 8 patients were treated with multifield optimisation intensity modulated proton therapy, 3 were treated with passive scattering proton therapy. Median dose was 67 Gy (range 60–70) in 32 fractions (range 30–35). The median high-dose planning target volume (PTV) was 45.4 cm3 (range 2.4 – 130.2 cm3) and the median elective PTV was 91.9 cm3 (range 61.2 – 269.7 cm3). Overall, the mean target coverage (mean 98.3% vs. 96.2% for CK vs. PBT, respectively), maximum dose to PTV (mean 111% vs. 111%, p = 0.2) and mean dose to PTV (mean 104% vs. 104%) were similar across modalities. Highly conformal plans were achieved with both modalities, but mean CI was better with PBT (0.5 vs. 0.6 for CK vs. PBT, p = 0.04). Homogeneity and gradient indexes were similar between the 2 modalities; mean tTime with PBT and CK was 17 vs. 18 min, respectively (p = 0.7). Case-based study revealed that CK and PBT plans allowed for excellent sparing of OAR, with some clinical scenarios associated with better performance of CK while others with better performance of PBT. Conclusion Our study has demonstrated the dosimetric performance of large volume head and neck re-irradiation using MLC-based CK in various clinical scenarios. While conformity was generally better achieved with PBT, MLC-based CK allowed for high dose gradient leading to rapid dose drop-off and sparing of OAR. Conventionally fractionated MLC-based CK could be a competitive alternative in large volume head and neck re-irradiation that deserves further investigation in the clinical setting.

Purpose: In oropharyngeal squamous cell carcinoma (OPC), high CD8+ tumor-infiltrating lymphocyte (CD8+TIL) density confers improved prognosis. We compared neoadjuvant durvalumab (PD-L1 inhibitor) with durvalumab + tremelimumab (CTLA-4 inhibitor) in terms of impact on CD8+TIL density, safety, and efficacy in patients with OPC. Patients and Methods: Patients with newly diagnosed stage II–IVA OPC or locoregionally recurrent OPC amenable to resection were included. Patients were randomized to two cycles of durvalumab or durvalumab + tremelimumab before surgery. The primary endpoint was change between baseline and resection specimen in CD8+TIL density between arms. Secondary endpoints included safety, response rate per RECIST, major pathologic response (MPR; ≤10% viable tumor cells) rate, and patient-reported outcomes. Results: Of 28 eligible patients (14/arm), 20 (71%) had newly diagnosed OPC, and 24 (86%) were p16-positive. The posttreatment to pretreatment median CD8+TIL density ratio was 1.31 for durvalumab and 1.15 for combination treatment (P = 0.97; 95% CI: −1.07–2.28). In each group, 6 patients (43%, 95% CI: 17.66–71.14) had a response. Eight patients (29%) had a MPR at the primary tumor and/or nodal metastases. Neither baseline CD8+TIL density nor PD-L1 expression level correlated with overall response, but a trend toward greater CD8+TIL change in patients with a MPR was seen (P = 0.059; 95% CI: −0.33–3.46). Four patients (14%) had grade ≥3 adverse events. At median follow-up time of 15.79 months, all patients were alive, and one had an additional recurrence. Conclusions: Durvalumab + tremelimumab did not increase CD8+TIL density more than durvalumab alone did. The observed safety and activity support further investigation of neoadjuvant checkpoint inhibitor for OPC.

Background and purpose With an enlarging population of long-term oropharyngeal cancer survivors, dysphagia is an increasingly important toxicity following oropharynx cancer treatment. While lower doses to normal surrounding structures may be achieved with intensity modulated proton therapy (IMPT) compared to photon-based radiation, the clinical benefit is uncertain. Methods and materials Seventy-one patients with stage III/IV oropharyngeal cancer (AJCC 7th edition) undergoing definitive IMPT on a longitudinal prospective cohort study who had completed the MD Anderson Dysphagia Inventory (MDADI) at pre-specified time points were included. Results The majority of patients had HPV-positive tumors (85.9%) and received bilateral neck radiation (81.4%) with concurrent systemic therapy (61.8%). Mean composite MDADI scores decreased from 88.2 at baseline to 59.6 at treatment week 6, and then increased to 74.4 by follow up week 10, 77.0 by 6 months follow up, 80.5 by 12 months follow up, and 80.1 by 24 months follow up. At baseline, only 5.6% of patients recording a poor composite score (lower than 60), compared to 61.2% at treatment week 6, 19.1% at follow up week 10, 13.0% at 6 months follow up, 13.5% at 1 year follow up, and 11.1% at 2 years follow up. Conclusions Patient reported outcomes following IMPT for oropharyngeal cancer demonstrates decreased swallowing function at completion of treatment with relatively rapid recovery by 10 weeks follow up and steady improvement through 2 years. The results are comparable to similar longitudinal studies of photon-based radiotherapy for oropharynx cancer, and suggest that IMPT confers no additional excess toxicity related to swallowing.

Background and purpose To report physician-assessed toxicities (PATs) and patient-reported outcomes (PROs) in a prospective cohort of patients treated using proton beam therapy (PBT). Methods and materials From 2011 to 2019, PBT-treated patients with a sinonasal malignancy were enrolled with a primary endpoint of toxicity assessment. PATs and PROs were assessed at baseline, acute (during PBT), subacute (within 90 days after PBT), and chronic time points. PATs were graded with the Common Terminology Criteria for Adverse Events V4.0. PROs were assessed with the Xerostomia-Related Quality-of-Life Scale (XeQoLS), MD Anderson Dysphagia Inventory (MDADI), and Functional Assessment of Cancer Therapy (FACT). PRO changes from baseline to follow-up were defined as significantly different based on a paired t-test plus a minimal clinically important difference. Results Sixty-four patients had a median follow-up time of 33 months (interquartile range: 10–52 months). The most common histology was olfactory neuroblastoma (28%) and most patients had T4 disease (46%). One acute G3 neurologic PAT (blurred vision) resolved, and no late G3–4 neurologic PATs were observed. Feeding tube placement occurred in 6% of patients. No significant changes were noted in PROs from baseline to the chronic period. Significant worsening from baseline was noted in the XeQoLS acute-subacute physical functioning, pain, personal/psychological distress, and social function; acute-subacute MDADI physical function; and acute-subacute FACT head/neck subscale. The 3-year local control, disease-free survival, and overall survival rates were 88%, 76%, and 82%, respectively. Conclusions We demonstrate low grade ≥3 toxicity and encouraging disease outcomes with PBT. PROs suggest significant changes in the acute-subacute period but no chronic sequelae.

BACKGROUND We report outcomes for patients with T2N0M0 glottic squamous cell carcinoma (SCC) treated with radiation therapy (RT). METHODS Patients who received definitive RT for T2 glottic SCC from 2000 through 2013 were retrospectively reviewed. RESULTS One hundred and thirteen patients were analyzed (median follow-up time 91 months; 85 patients received three-dimensional conformal radiotherapy [3D-CRT] and 28 received intensity-modulated radiation therapy [IMRT]). Fractionation was conventional (58%) or altered (42%); 20 patients (18%) received concurrent chemotherapy. Five-year local control was 83% for the 3D-CRT vs 81% for the IMRT group (P = .76). The ultimate locoregional control at 5 years was 100% for IMRT vs 91% for 3D-CRT (P = .1). The 5-year overall survival (OS) was 78% for 3D-CRT vs 81% for IMRT (P = .83). On multivariate analysis, younger age was the only independent predictor of improved OS (P = .0002). CONCLUSIONS Oncologic and survival outcomes were excellent for patients with T2N0 glottic cancer. Patients treated with IMRT and 3D-CRT had no statistically significant differences in all investigated endpoints.

Highlights • GTVs on the 60 kV and 140 kV from DECT, and the T1c and T2 from MRI were compared. • Delineation was the most consistent using T1c (no interobserver difference in DSC). • T1c MRI provided higher interobserver agreement for skull base tumors. • 60 kV DECT provided higher interobserver agreement for non-skull base tumors., In treatment planning, multiple imaging modalities can be employed to improve the accuracy of tumor delineation but this can be costly. This study aimed to compare the interobserver consistency of using dual energy computed tomography (DECT) versus magnetic resonance imaging (MRI) for delineating tumors in the head and neck cancer (HNC) re-irradiation scenario. Twenty-three patients with recurrent HNC and had planning DECT and MRI were identified. Contoured tumor volumes by seven radiation oncologists were compared. Overall, T1c MRI performed the best with median DSC of 0.58 (0–0.91) for T1c. T1c MRI provided higher interobserver agreement for skull base sites and 60 kV DECT provided higher interobserver agreement for non-skull base sites.

Background Metastatic head and neck cancers (HNCs) predominantly affect the lungs and have a two-year overall survival (OS) of 15% to 50%, if amenable for pulmonary metastasectomy. Methods Retrospective review of the two-year local control (LC), local-regional control (LRC) within the same lobe, OS, and toxicity rates in consecutive patients with metastatic pulmonary HNC who underwent stereotactic ablative radiotherapy (SABR) January 2007 to May 2018. Results Evaluated 82 patients with 107 lung lesions, most commonly squamous cell carcinoma (SCC; 64%). Median follow-up was 20 months (range: 9.0-97.6). Systemic therapy administered in 34%. LC, LRC, and OS rates were 94%, 90%, and 62%. Patients with oligometastatic disease had a higher OS than polymetastatic disease, 72% vs 44% (HR = 0.30, 95% CI: 0.14-0.64; P = .008). OS in oligometastatic non-SCC and SCC were 100% and 66% (P = .03). There were no grade ≥3 toxicities. Conclusions Metastatic pulmonary HNCs after SABR have a two-year OS rate comparable to pulmonary metastasectomy.

Recurrent or previously irradiated head and neck cancers (HNC) are therapeutically challenging and may benefit from high-dose, highly accurate radiation techniques, such as stereotactic ablative radiation therapy (SABR). Here, we compare set-up and positioning accuracy across HNC subsites to further optimize the treatment process and planning target volume (PTV) margin recommendations for head and neck SABR.We prospectively collected data on 405 treatment fractions across 79 patients treated with SABR for recurrent/previously irradiated HNC. First, interfractional error was determined by comparing ExacTrac x-ray to the treatment plan. Patients were then shifted and residual error was measured with repeat x-ray. Next, cone beam computed tomography (CBCT) was compared with ExacTrac for positioning agreement, and final shifts were applied. Lastly, intrafractional error was measured with x-ray before each arc. Results were stratified by treatment site into skull base, neck/parotid, and mucosal.Most patients (66.7%) were treated to 45 Gy in 5 fractions (range, 21-47.5 Gy in 3-5 fractions). The initial mean ± standard deviation interfractional errors were -0.2 ± 1.4 mm (anteroposterior), 0.2 ± 1.8 mm (craniocaudal), and -0.1 ± 1.7 mm (left-right). Interfractional 3-dimensional vector error was 2.48 ± 1.44, with skull base significantly lower than other sites (2.22 vs 2.77; P = .0016). All interfractional errors were corrected to within 1.3 mm and 1.8°. CBCT agreed with ExacTrac to within 3.6 mm and 3.4°. CBCT disagreements and intrafractional errors of1 mm or1° occurred at significantly lower rates in skull base sites (CBCT: 16.4% vs 50.0% neck, 52.0% mucosal, P.0001; intrafractional: 22.0% vs 48.7% all others, P.0001). Final PTVs were 1.5 mm (skull base), 2.0 mm (neck/parotid), and 1.8 mm (mucosal).Head and neck SABR PTV margins should be optimized by target site. PTV margins of 1.5 to 2 mm may be sufficient in the skull base, whereas 2 to 2.5 mm may be necessary for neck and mucosal targets. When using ExacTrac, skull base sites show significantly fewer uncertainties throughout the treatment process, but neck/mucosal targets may require the addition of CBCT to account for positioning errors and internal organ motion.

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

PURPOSE: To report cancer control outcomes and health-related quality of life (HRQoL) outcomes after highly conformal skull-based re-irradiation (re-RT). METHODS: Patients planned for curative intent re-RT to a recurrent or new skull base tumor were enrolled. HRQoL were assessed using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) and the anterior skull base surgery quality of life (ASBQ) questionnaires. RESULTS: Thirty-nine patients were treated with stereotactic body RT or intensity modulated RT. Median follow-up was 14 months. Progression free survival was 71% at 1-year. There was mild clinically significant worsening of fatigue, lack of appetite and drowsiness (MDASI-BT), and physical function (ASBQ) at the end of RT, followed by recovery to baseline on subsequent follow-ups. Subjective emotions were clinically improved at 12 months, with patients reporting feeling less tense/nervous. CONCLUSION: Conformal skull base re-RT is associated with mild immediate deterioration in physical function followed by rapid and sustained recovery.

Cancer is a growing burden globally. Radiotherapy has proven to be a critical and cost-effective treatment modality for a cure in greater than 50% of cancer patients. There are numerous obstacles and challenges in establishing new radiotherapy facilities and programs, especially in low- and middle-income countries. It is known that the clinical aspect, as well as procedure related to the physical and technical aspect of patient treatment, needs to be subjected to careful planning in order to ensure safe and high-quality radiotherapy. This process required the engagement of various professionals from different backgrounds.This chapter aims to define radiotherapy value, assessing a radiation facility’s clinical, infrastructure, and resources need to establish a new radiotherapy facility.

Objectives/hypothesis Olfactory neuroblastoma (ONB) is a rare sinonasal malignant neoplasm that is known to develop late recurrence. The aim of this study is to evaluate the long-term outcomes of patients with ONB and to determine the factors associated with prognosis. Study design Retrospective study. Methods A retrospective review of the medical records of 139 patients diagnosed with ONB at MD Anderson Cancer Center was performed between 1991 and 2016. Descriptive statistics were calculated, and Kaplan-Meier curves were utilized to assess survival. Results Median follow-up time was 75 months. Overall, 129 patients (92.8%) had surgery as part of their treatment and 82 (58.9%) patients received postoperative radiation therapy (PORT) or concurrent chemoradiotherapy. Endoscopic approaches were utilized for 72 patients, 69.4% of whom had pure endoscopic endonasal approaches. Five-year overall survival and disease-specific survival were 85.6% and 93.4%, respectively. Recurrence rate was 39.6% with a median time to recurrence of 42 months. Among the 31 patients who received elective nodal irradiation (ENI), two patients developed neck recurrence (6.4%) compared with 20 who developed neck recurrence when ENI was omitted (34.4%) (P = .003). Advanced Kadish stage, orbital invasion, intracranial invasion, and presence of cervical lymphadenopathy at the time of presentation were significantly associated with poor survival. Conclusion ONB has an excellent survival. Surgical resection with PORT when indicated is the mainstay of treatment. Endoscopic approaches can be used as a good tool. Elective neck irradiation reduces the risk of nodal recurrence among patients with clinically N0 neck. Despite the excellent survival, recurrence rate remains high and delayed, highlighting the need for long-term surveillance. Level of evidence Level 4 Laryngoscope, 2021.

Purpose To introduce a contouring guideline for the taste bud bearing tongue mucosa for head and neck cancer patients receiving radiotherapy. Methods and Materials CT simulation images of oropharyngeal cancer patients were used to delineate both the whole tongue (extrinsic/intrinsic tongue muscles, floor of mouth) and the taste bud bearing tongue mucosa (method A: adaptation of the whole tongue structure; method B: axial adaptation of a mid-sagittal contour). Volumetric and dosimetric parameters of the whole tongue and the two methods of mucosal delineation, spatial overlap between methods A and B, and inter-observer variability for method B were calculated. Results The study cohort was comprised of 70 patients with T1–4 N0–1 tonsillar (83%) and base of tongue (17%) cancers. Most of the comparative parameters between the whole tongue and mucosa (method A) significantly differed (mean, minimum, and maximum dose, V5–V70, D40–D90). The mean dose calculated for the whole tongue deviated on average 3.77 Gy compared to method A. No significant differences were found between methods A and B of the taste bud bearing tongue mucosa structure, and none of the dosimetric parameters differed more than 1.03 Gy on average. The mean Dice similarity coefficient for both mucosal structures was 0.79 ± 0.05, and 0.63 ± 0.12 for the inter-observer analysis of method B. Conclusions We defined two methods for delineating the taste bud bearing mucosa and both are equally satisfactory procedures. Either method is preferable over delineation of the whole tongue as organ at risk for taste impairment.

Second primary malignancy (SPM) may occur after index head and neck cancer (HNC) treatment. This study evaluated the prevalence and outcome of SPM in patients with HNC treated with definitive radiotherapy. Eligible patients include those with index mucosal HNC treated with definitive radiotherapy between 2000 and 2010. SPM was defined as an invasive cancer at a noncontiguous site diagnosed at least 6 months after completion of radiotherapy. Clinical data were collected, and the Kaplan–Meier method was used to estimate overall survival. In total, 1512 patients were studied. The majority of patients had index oropharyngeal cancer (86%). In all, 130 (9%) patients developed a SPM. The risk of SPM increased exponentially with time with 5-, 10-, and 15-year rates of 4, 10, and 25%. Half of SPMs were within the head and neck or thoracic regions. SPM rates were significantly higher (p

Background: When achieved, complete surgical resection improves outcomes in anaplastic thyroid carcinoma (ATC). However, most ATC patients present with advanced inoperable disease, often with impending airway obstruction, increased hemorrhage risk, and significant dysphagia. Novel treatment strategies are critically needed to improve disease control and decrease locoregional morbidity. The objective of this study was to determine the feasibility and effectiveness of a neoadjuvant regimen by using dabrafenib with trametinib followed by surgical resection in patients with initially unresectable BRAFV600E-mutated ATC. Methods: Case series of six consecutive patients with BRAFV600E-mutated ATC diagnosed between January 2017 and February 2018. Pathologic confirmation of ATC was obtained before treatment. BRAFV600E status was ascertained via immunohistochemistry or sequencing of circulating tumor DNA. All patients received dabrafenib and trametinib (DT) followed by surgical resection and adjuvant chemoradiation. Three patients also received pembrolizumab. Results: Complete surgical resection was achieved in all patients. Histopathologic analyses of resected specimens showed high pathologic response rates with significantly decreased ATC viability and residual papillary thyroid carcinoma components. Overall survival at six months and one year was 100% and 83%, respectively. Locoregional control rate was 100%. Two patients died of distant metastases without evidence of locoregional disease at 8 and 14 months from diagnosis. The remaining four patients had no evidence of disease at the last follow-up. Conclusions: We report the first series in the literature of BRAFV600E-mutated ATC patients with locoregionally advanced disease treated with DT followed by surgical resection. We demonstrated feasibility of complete resection, decreased need for tracheostomy, high pathologic response rates, and durable locoregional control with symptom amelioration.

PURPOSE: Local/systemic symptoms during cancer therapy may be exacerbated by dysregulated inflammation and its downstream toxic effects. Minocycline can suppress proinflammatory cytokine release; therefore, we investigated its potential to reduce patient-reported symptom severity during radiotherapy (RT) for head and neck cancer (HNC). METHODS: Eligible patients for this blinded, placebo–controlled trial were adults with T0–3, N-any, and M0 HNC receiving single-modality RT. Participants were randomized 1:1 to either minocycline (200 mg/day) or placebo during RT. The primary endpoint was the area under the curve (AUC) of 5 prespecified symptoms (pain, fatigue, disturbed sleep, poor appetite, difficulty swallowing/chewing) during RT, assessed with the MD Anderson Symptom Inventory for HNC (MDASI-HN). RESULTS: We analyzed data from 20 evaluable patients per arm. Overall, 75% had oropharyngeal cancer and 78% were male. No grade 3+ adverse events potentially related to study medication were observed. Two minocycline patients required a feeding tube during RT vs 5 placebo patients (P = 0.21). The average daily AUC during RT for the 5 MDASI-HN symptoms was 3.1 (SD =1.0) for minocycline and 3.7 (SD = 1.7) for placebo (P = 0.16); the 0.37 effect size was less than our 0.70 target. AUC comparisons for several individual symptoms and symptom interference favored minocycline but were not statistically significant. The greatest numerical differences occurred for systemic symptoms, larger toward treatment end, and in early post-RT recovery. CONCLUSIONS: Minocycline was feasible, well tolerated, and achieved a positive signal toward reducing patient-reported symptom severity during RT for HNC, particularly for systemic symptoms. This justifies additional study and informs future trial design.

Highlights • Early stage tonsillar cancers may be treated with unilateral neck radiotherapy (RT). • We performed a dosimetric study comparing three common radiotherapy modalities. • No significant differences in target coverage existed between all plans. • Laryngeal doses were reduced using whole-field intensity modulated RT and VMAT. • Shorter treatment times and required monitor units were also associated with VMAT., Background and purpose Minimizing radiation dose exposure to nearby organs is key to limiting clinical toxicities associated with radiotherapy. Several treatment modalities such as split- or whole-field intensity-modulated radiotherapy (SF-IMRT, WF-IMRT) and volumetric modulated arc therapy (VMAT) are being used to treat tonsillar cancer patients with unilateral neck radiotherapy. Herein, we provide a modern dosimetric comparison of all three techniques. Materials and methods Forty patients with tonsillar cancer treated with definitive, ipsilateral neck SF-IMRT were evaluated. Each patient was re-planned with WF-IMRT and VMAT techniques, and doses to selected organs-at-risk (OARs) including the larynx, esophagus, and brainstem were compared. Results No significant differences in target coverage existed between plans; however, the heterogeneity index improved using WF-IMRT and VMAT relative to SF-IMRT. Compared to SF-IMRT, WF-IMRT and VMAT plans had significantly lower mean doses to the supraglottic larynx (31 Gy, 18.5 Gy, 17 Gy; p

OBJECTIVEThe objective of this study was to assess outcomes after Gamma Knife radiosurgery (GKRS) re-irradiation for palliation of patients with trigeminal pain secondary to recurrent malignant skull base tumors.METHODSFrom 2009 to 2016, 26 patients who had previously undergone radiation treatment to the head and neck received GKRS for palliation of trigeminal neuropathic pain secondary to recurrence of malignant skull base tumors. Twenty-two patients received single-fraction GKRS to a median dose of 17 Gy (range 15–20 Gy) prescribed to the 50% isodose line (range 43%–55%). Four patients received fractionated Gamma Knife Extend therapy to a median dose of 24 Gy in 3 fractions (range 21–27 Gy) prescribed to the 50% isodose line (range 45%–50%). Those with at least a 3-month follow-up were assessed for symptom palliation. Self-reported pain was evaluated by the numeric rating scale (NRS) and MD Anderson Symptom Inventory–Head and Neck (MDASI-HN) pain score. Frequency of as-needed (PRN) analgesic use and opioid requirement were also assessed. Baseline opioid dose was reported as a fentanyl-equivalent dose (FED) and PRN for breakthrough pain use as oral morphine-equivalent dose (OMED). The chi-square and Student t-tests were used to determine differences before and after GKRS.RESULTSSeven patients (29%) were excluded due to local disease progression. Two experienced progression at the first follow-up, and 5 had local recurrence from disease outside the GKRS volume. Nineteen patients were assessed for symptom palliation with a median follow-up duration of 10.4 months (range 3.0–34.4 months). At 3 months after GKRS, the NRS scores (n = 19) decreased from 4.65 ± 3.45 to 1.47 ± 2.11 (p < 0.001); MDASI-HN pain scores (n = 13) decreased from 5.02 ± 1.68 to 2.02 ± 1.54 (p < 0.01); scheduled FED (n = 19) decreased from 62.4 ± 102.1 to 27.9 ± 45.5 mcg/hr (p < 0.01); PRN OMED (n = 19) decreased from 43.9 ± 77.5 to 10.9 ± 20.8 mg/day (p = 0.02); and frequency of any PRN analgesic use (n = 19) decreased from 0.49 ± 0.55 to 1.33 ± 0.90 per day (p = 0.08). At 6 months after GKRS, 9 (56%) of 16 patients reported being pain free (NRS score 0), with 6 (67%) of the 9 being both pain free and not requiring analgesic medications. One patient treated early in our experience developed a temporary increase in trigeminal pain 3–4 days after GKRS requiring hospitalization. All subsequently treated patients were given a single dose of intravenous steroids immediately after GKRS followed by a 2–3-week oral steroid taper. No further cases of increased or new pain after treatment were observed after this intervention.CONCLUSIONSGKRS for palliation of trigeminal pain secondary to recurrent malignant skull base tumors demonstrated a significant decrease in patient-reported pain and opioid requirement. Additional patients and a longer follow-up duration are needed to assess durability of symptom relief and local control.

Background The current study was performed to assess the efficacy of surveillance imaging in patients with head and neck cancer (HNC) who are treated definitively with radiotherapy. Methods Eligible patients included those with a demonstrable disease-free interval (≥1 follow-up imaging procedure without evidence of disease and a subsequent visit/imaging procedure) who underwent treatment of HNC from 2000 through 2010. Results A total of 1508 patients were included. The median overall survival was 99 months, with a median imaging follow-up period of 59 months. Of the 1508 patients, 190 patients (12.6%) experienced disease recurrence (107 patients had locoregional and 83 had distant disease recurrence). A total of 119 patients (62.6%) in the group with disease recurrence were symptomatic and/or had an adverse clinical finding associated with the recurrence. Approximately 80% of patients with locoregional disease recurrences presented with a clinical finding, whereas 60% of distant disease recurrences were detected by imaging in asymptomatic patients. Despite the earlier detection of disease recurrence via imaging, those patients in the group of patients with clinically detected disease recurrence were significantly more likely to undergo salvage therapy compared with those whose recurrence was detected on imaging (odds ratio, 0.35). There was no difference in overall survival noted between those patients with disease recurrences that were detected clinically or with imaging alone. Approximately 70% of disease recurrences occurred within the first 2 years. In those patients who developed disease recurrence after 2 years, the median time to recurrence was 51 months. After 2 years, the average number of imaging procedures per patient for the detection of a salvageable recurrence for the imaging-detected group was 1539. Conclusions Surveillance imaging in asymptomatic patients with HNC who are treated definitively with radiotherapy without clinically suspicious findings beyond 2 years has a low yield and a high cost. Physicians ordering these studies must use judicious consideration and discretion.

OBJECTIVE To evaluate long-term global and site-specific health-related quality of life (HRQoL) in patients treated for sinonasal and nasopharyngeal malignancies. STUDY DESIGN Cross-sectional. METHODS One hundred fourteen patients with sinonasal and nasopharyngeal malignancies received surgery, radiation, systemic chemotherapy, or a combination thereof, with curative intent. Validated global ([EuroQol-5D] Visual Analogue Scale [EQ-5D VAS]) and disease-specific instruments (MD Anderson Symptom Inventory-Head and Neck [MDASI-HN], Anterior Skull Base Questionnaire [ASBQ]) were administered to patients who were both free of disease and had completed treatment at least 12 months previously. Associations between instruments, instrument domains, and specific clinical parameters were analyzed. RESULTS The median age was 55 years. The mean EQ-5D VAS, MDASI-22 composite score, and ASBQ score were 74 (standard deviation [SD] 21), 48 (SD 36), and 130 (SD 27), respectively. The most frequently reported high-severity items in MDASI-HN were dry mouth and difficulty tasting food. The most frequently reported high-severity items in ASBQ were difficulty with smell and nasal secretions. Advanced Tumor (T) classification was associated with worse overall ASBQ sum score (P = 0.02). ASBQ performance at home and MDASI-HN drowsy symptom items independently predicted worse global HRQoL as measured by the EQ-5D VAS (P

BACKGROUND: The objective of the current study was to characterize the incidence, pattern, and impact on oncologic outcomes of retropharyngeal lymph node (RPLN) involvement in HPV-associated oropharyngeal cancer (OPC). METHODS: Data regarding patients with HPV-associated OPC who were treated at The University of Texas MD Anderson Cancer Center with intensity-modulated radiotherapy from 2004 through 2013 were analyzed retrospectively. RPLN status was determined by reviewing pretreatment imaging and/or reports. Outcomes analysis was restricted to patients with lymph node-positive (+) disease. Kaplan-Meier survival estimates were generated and survival curves were compared using the log-rank test. Bayesian information criterion assessed model performance changes with the addition of RPLN status to current American Joint Committee on Cancer staging. Competing risk analysis compared modes of disease recurrence. RESULTS: The incidence of radiographic RPLN involvement was 9% (73 of 796 patients) and was found to vary by primary tumor site. The 5-year rates of freedom from distant metastases (FDM) and overall survival were lower in patients with RPLN(+) status compared with those with RPLN-negative (−) status (84% vs 93% [P = .0327] and 74% vs 87% [P = .0078], respectively). RPLN(+) status was not found to be associated with outcomes on multivariate analysis. Bayesian information criterion analysis demonstrated that current American Joint Committee on Cancer staging was not improved with the inclusion of RPLN. Locoregional and distant disease recurrence probabilities for those patients with RPLN(+) status were 8% and 13%, respectively, compared with 10% and 6%, respectively, for those with RPLN(−) status. RPLN(+) status portended worse 5-year FDM in the low-risk subgroup (smoking history of

Purpose: Fractionated stereotactic radiosurgery (FSRS) can be given with at least three modalities: Gamma Knife, with the noninvasive frameless extend system (GKE); linear accelerator-based volumetric modulated arc therapy (VMAT); and intensity-modulated proton therapy (IMPT). We extracted treatment plans for patients who had received FSRS with GKE for recurrent skull base or intracranial tumors, created corresponding plans for VMAT and IMPT, and compared the quality of the three sets of plans. Methods and materials: Plans were extracted for 9 patients with recurrent malignant skull-base tumors (n = 6) or large intracranial tumors (n = 3) who had received FSRS with GKE (median dose 24 Gy in 3 fractions) in 2013 through 2015. Plans for VMAT were generated with a TrueBeam STx LINAC machine using 6-MV photons, and plans for IMPT were generated with multi-field optimization. The optimized VMAT and IMPT plans were normalized to achieve the best possible target coverage while meeting the same dose-volume constraints on organs at risk (OARs) as the GKE plans. Plans were evaluated on the basis of target coverage, conformity index, homogeneity index, gradient index, and treatment efficiency. Results: The median target volume was 10.2 cm3 (range 1.9 - 33.8 cm3). The VMAT and IMPT plans met all OAR constraints, and target coverage and conformity were comparable among all plans. VMAT and IMPT plans showed significantly better target uniformity and treatment delivery efficiency (P < 0.001). The gradient index and low-dose-bath were superior in the GKE plans (P < 0.001), indicating smaller irradiated volumes. When inverse planning was used, VMAT plans could achieve a similar or steeper dose drop-off at the target-OAR boundary than GKE plans. Conclusion: FSRS for skull base and large intracranial lesions delivered by VMAT and IMPT can achieve comparable target coverage, conformity, and sparing of critical structure as the GKE while providing superior target uniformity and treatment delivery efficiency. The GKE had superior high-dose gradients outside the target and thus better protected surrounding normal structures.

PURPOSE/OBJECTIVE(S) Given the historical toxicity of radiotherapy for head & neck cancer, there has been an emphasis on de-escalation for patients with favorable disease features. The use of unilateral radiation to cervical nodes is a prominent de-escalation strategy in well-lateralized tonsil cancers. However, the safety of this approach for patients with AJCC-7 N2b disease was less well-established in the landmark studies guiding its use. The study hypothesis was that unilateral radiation for AJCC-7 T1-2N2b tonsillar cancer results in a low rate of contralateral nodal failure. MATERIALS/METHODS This study was a retrospective chart review of 66 patients treated from 2005 to 2016 at two academic institutions. Eligible patients had AJCC-7 T1-2N2b squamous cell carcinoma of the tonsil and were treated with unilateral radiation therapy. The primary endpoint was the rate of contralateral nodal failure at the time of last follow-up. Ipsilateral recurrence rates and overall survival were additional endpoints of interest. When available, data were collected regarding the presence of clinical extracapsular extension (ECE). Human papillomavirus/p16 status was also assessed. RESULTS The median age at diagnosis was 55.5 years and 53 patients (80.3%) were male. 38 patients (57.6%) had T1 disease and 28 patients (42.4%) had T2 disease based upon AJCC-7 staging. Of the 52 patients who had information on tumor HPV status, all were positive. In regards to systemic therapy, 18 patients (27.3%) had induction therapy, 26 (39.4%) had concurrent therapy, and 4 (6.1%) had both. The median time to last post-radiation follow-up was 80.9 months; 87.9% of patients remained alive at last follow-up and median OS was not reached. Contralateral nodal failure occurred in 2/66 (3.0%) patients at 3.6 and 20.9 months, respectively. Both patients underwent salvage treatment. The first survived an additional 65 months and the second remains alive at last follow-up 37 months after recurrence. Sixteen patients (24.2%) were felt to have extracapsular extension by clinical exam, radiology, or pathology; one of the two contralateral recurrences occurred in this group. Two patients (3%) experienced recurrence at the treated primary site and/or neck. Overall locoregional control at both 2 and 5 years was 93.9% and the median duration of control was not reached. CONCLUSION The use of unilateral radiation for AJCC-7 T1-2N2b tonsillar cancer resulted in low rates of contralateral nodal failure. This outcome demonstrates the safety of considering unilateral treatment in patients with a high ipsilateral nodal burden. Further assessments are needed to determine the impact of radiation volume reduction on patient quality of life.

Purpose/Objective(s) Stereotactic body radiotherapy (SBRT) is an emerging modality for the reirradiation of head and neck cancers (HNC). The need to use smaller reirradiation volumes to limit severe toxicity concerns represents a challenge in determining optimal target coverage. Herein, we investigate the associated patterns of failure after SBRT using previously defined spatial and dosimetric analysis (Mohamed et al, Radiat Oncol. 2017). Materials/Methods SBRT reirradiation HNC cases treated between 2014-2019 and surveilled by CT, PET/CT, and/or MRI were reviewed retrospectively in this IRB approved study. Patients with radiographic evidence of recurrence within the head and neck region after SBRT were identified. Multifocal disease was defined as any non-contiguous FDG-avid or biopsy positive disease seen on imaging. Diagnostic scans were co-registered with planning CT scans (pCT) for manual segmentation of recurrent gross volumes (rGTV). rGTVs were then deformed to co-registered pCTs for failure classification. The classification followed a granular typology of 5 failure categories: central high-dose (type A or “in-field”), peripheral high-dose (type B), central low-dose (type C), peripheral low-dose (type D or “marginal”), and extraneous-dose (type E or “out of field”). Each type was determined based on the centroid location of rGTV relative to the planning target volumes plus the dose received by 95% of rGTV volume. Results A total of 106 SBRT cases were reviewed out of which 34 patients (32%) recurred after SBRT; 27 (79%) patients had squamous cell carcinomas, 7 (21%) received postoperative SBRT, and 24 (71%) received concurrent systemic therapy. Twenty-three (68%) patients received 42.5-45 Gy in 5 fractions (Fx) and 7 (21%) patients received 36 Gy in 6 Fx. Median time to failure was 5.5 months (range, 1-22 months). Twenty-two recurrences (65%) were out-of-field type E failures, 6 (18%) type A, 3 (9%) type C, and 3 (9%) type D. Fourteen of 16 (88%) multifocal SBRT reirradiation cases had Type E failures compared to 8 of 18 (44%) unifocal SBRT cases. Among the 6 in-field failures, 3 received 36 Gy in 6 Fx and 3 received 42.5-45 Gy in 5 Fx. Conclusion Post SBRT reirradiation recurrences were seen in one-third of cases with the majority of failures being Type E (outside the treatment field), particularly in patients who were treated for multifocal disease. The use of 42.5-45 Gy in 5 Fx appears to be an effective biological dose for local tumor control. Marginal (Type C and D) failures may be reduced with larger margins, but limit feasibility of SBRT. Therefore, future reirradiation strategies should aim to improve patient selection, multimodal therapy, and margin definition in the HNC SBRT reirradiation setting.

Purpose Patients with p16/human papilloma virus (HPV)–associated oropharyngeal squamous cell carcinoma have a favorable outcome after treatment. In this group of patients who could have a long life expectancy, the optimal surveillance strategy and modality is not well established. We aim to determine the ability of a negative postradiation positron emission tomography (PET)/computed tomography scan to predict the risk of subsequent relapse in these patients. Materials and Methods A retrospective analysis of patients with p16/HPV-associated oropharyngeal squamous cell carcinoma who completed definitive (chemo)radiation therapy and had a posttreatment PET/computed tomography scan from 2006 to 2013 was performed. Patient, tumor, and treatment characteristics and clinical outcomes were recorded. Tumors were considered HPV/p16 positive if either HPV (by in situ hybridization) or p16 (by immunohistochemistry) was positive. Disease-free survival and overall survival rates were estimated using the Kaplan-Meier method. Results In our study, 327 patients were evaluated. The median age was 57 years. The most common primary sites were base of tongue (50%) and tonsil (48%). Of the patients evaluated, 291 (89%) had a negative posttreatment PET scan. For these 291 patients who had a complete metabolic response after treatment, the 5-year disease-free survival and overall survival rates were 91% and 89%, respectively. The median time to development of recurrence was 16 months. Of the 291 patients, 24 patients (8%) had disease recurrence; 13 recurrences were locoregional, and 13 were distant. Eleven (4%) patients with recurrence had further surgery or radiation, and 8 patients (3%) were without disease as of the last follow-up. Conclusions Patients who achieve a complete metabolic response on posttreatment PET imaging have an excellent prognosis, and the risk of developing a recurrence in the future is very low. Therefore, a more cost effective surveillance program should be considered for this subgroup of patients.

Highlights • Treatment de-escalation in HPV+ oropharynx cancer is an active area of research. • A Bayesian phase II trial of MR-guided radiotherapy dose adaptation is proposed. • High dose volume will be adapted on weekly MRI based on tumor response. • The non-inferiority of dose adaptation compared to standard IMRT will be assessed., Background Current standard radiotherapy for oropharynx cancer (OPC) is associated with high rates of severe toxicities, shown to adversely impact patients’ quality of life. Given excellent outcomes of human papilloma virus (HPV)-associated OPC and long-term survival of these typically young patients, treatment de-intensification aimed at improving survivorship while maintaining excellent disease control is now a central concern. The recent implementation of magnetic resonance image – guided radiotherapy (MRgRT) systems allows for individual tumor response assessment during treatment and offers possibility of personalized dose-reduction. In this 2-stage Bayesian phase II study, we propose to examine weekly radiotherapy dose-adaptation based on magnetic resonance imaging (MRI) evaluated tumor response. Individual patient’s plan will be designed to optimize dose reduction to organs at risk and minimize locoregional failure probability based on serial MRI during RT. Our primary aim is to assess the non-inferiority of MRgRT dose adaptation for patients with low risk HPV-associated OPC compared to historical control, as measured by Bayesian posterior probability of locoregional control (LRC). Methods Patients with T1-2 N0-2b (as per AJCC 7th Edition) HPV-positive OPC, with lymph node

Opinion statementThe rise in the incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPC), the relatively young age at which it is diagnosed, and its favorable prognosis necessitate the use of treatment techniques that reduce the likelihood of side effects during and after curative treatment. Intensity-modulated proton therapy (IMPT) is a form of radiotherapy that de-intensifies treatment through dose de-escalation to normal tissues without compromising dose to the primary tumor and involved, regional lymph nodes. Preclinical studies have demonstrated that HPV-positive squamous cell carcinoma is more sensitive to proton radiation than is HPV-negative squamous cell carcinoma. Retrospective studies comparing intensity-modulated photon (X-ray) radiotherapy to IMPT for OPC suggest comparable rates of disease control and lower rates of pain, xerostomia, dysphagia, dysgeusia, gastrostomy tube dependence, and osteoradionecrosis with IMPT—all of which meaningfully affect the quality of life of patients treated for HPV-associated OPC. Two phase III trials currently underway—the “Randomized Trial of IMPT versus IMRT for the Treatment of Oropharyngeal Cancer of the Head and Neck” and the “TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer (TORPEdO)” trial—are expected to provide prospective, level I evidence regarding the effectiveness of IMPT for such patients.

Background Patients with locoregionally advanced oral cavity squamous cell carcinoma (OCSCC) have a poor survival outcome. Treatment involves extensive surgery, adjuvant radiation, or chemoradiation and results in high morbidity. In this study, the authors' objective was to evaluate their experience with induction chemotherapy (IC) in the treatment of locoregionally advanced OCSCC. Methods A retrospective review of the medical records of all patients with locoregionally advanced (stage III and IV) OCSCC who received IC followed by definitive local therapy was conducted. Outcomes included response to IC and survival. Results In total, 120 patients were included in the study. The overall stage was stage IV in 79.2% of patients. After 2 cycles of IC, 76 patients (63.3%) achieved at least a partial response, including 13 who had a complete response. Stable disease was observed in 30 patients (25%), and 14 patients (11.7%) had progressive disease. Among responders, 16 patients received definitive chemoradiation or radiation therapy, and 60 underwent surgical resection, of whom 15 had less extensive surgery than was originally planned. Overall, organ preservation was achieved in 40.8% of patients who had a favorable response to IC. The 5-year overall and disease-specific survival rates were 51.4% and 66.9%, respectively. Patients who had at least a partial response had better 5-year overall survival (60.1%) and disease-specific survival (78.5%) compared with nonresponders (33.8% and 46.4%, respectively). Conclusions The results demonstrate a response rate to IC in patients with advanced OCSCC similar to what has been observed in patients with cancer in other head and neck subsites. Patients who achieved at least a partial response to IC had a more favorable outcome, with ensuing organ preservation. Further studies are warranted.

Background Risk of recurrence among patients with oropharyngeal cancer (OPC) who survive 5 years is low. The goal of this study was to assess long-term survival of patients with OPC alive without recurrence 5 years after diagnosis. Methods This study included newly diagnosed patients with OPC, who had been treated with radiation and were alive without recurrence 5 years after diagnosis. Overall survival (OS) probabilities beyond 5 years were estimated using the Kaplan-Meier method. Factors associated with OS were determined using Bayesian piecewise exponential survival regression. Standardized mortality ratios for all-cause death were estimated controlling for study year, age, and sex in the US general population. Results Among 1699 patients, the additional 2-year, 5-year, and 10-year OS probabilities were 94%, 83%, and 63%, respectively, and were lower than those in the general population. Patients who were older, were current or former smokers, had other than tonsil or base of tongue tumors, or had T4 tumors had a higher risk of death. Patients who had base of tongue tumors and had received intensity-modulated radiation therapy (IMRT) or lower-radiation doses had a lower risk of death. Standardized mortality ratios were higher among current and heavy smokers and lower among recipients of IMRT and lower radiation doses. Conclusions In this large cohort, long-term survival among patients with OPC was good but lower than predicted for the general population. Patients treated with IMRT and those with less tobacco exposure had better outcomes.

Head and neck squamous cell carcinoma (HNSCC) treatment response relies heavily on macroscopic clinical findings. Blood monitoring of circulating markers during treatment may improve earlier detection of responders versus non-responders during radiotherapy. In this study, patients with intact tumour of HNSCC were enrolled in the prospective PREDICT-HN study. Pre-, after first treatment, weekly, and post-treatment blood samples were collected. CTC was enumerated using the CellSearch system. cfDNA was quantified from cfNA isolated at pre-, mid- and post-treatment timepoints. Blood samples were collected from 45 patients. Of the 339 samples analysed for CTC, 31% had detectable CTCs. Nine patients had detectable CTCs (1-3/7.5ml blood) in pre-treatment samples. After 1 fraction, 16 patients had CTCs detected, with 12 who had no pre-treatment CTC. Sixteen (36%) patients had detectable CTC in final week of treatment. There was no correlation between cancer stage, nodal status and tumour burden with CTC. cfDNA levels increased during treatment, with its highest level in the final week and lowest at post-treatment. Our results showed in HNSCC that CTCs can be detected during radiotherapy, suggesting mobilization into circulation during treatment, with as-yet-unknown viability. cfDNA kinetics during treatment correlated with CTC release, and may indicate apoptotic change.Simple SummaryHead and neck squamous cell carcinoma (HNSCC) treatment response relies heavily on macroscopic clinical findings. Blood monitoring of circulating markers such as circulating tumour cell (CTC) and cell-free DNA (cfDNA) during treatment may improve earlier detection of responders versus non-responders during definitive radiotherapy. Although the detection of CTCs and cfDNA in patients with HNSCC has been described, there is minimal data on the kinetics of CTC counts and cfDNA levels during radiotherapy in patients with HNSCC. Here, our study prospectively describes the changes in CTC and cfDNA enumeration during radiotherapy in patients with HNSCC. Our results showed, for the first time to our knowledge, in HNSCC, that CTCs can be detected during radiotherapy, suggesting mobilization into peripheral circulation during treatment, with as-yet-unknown viability. cfDNA kinetics during treatment correlated with CTC release, may indicate apoptotic change during radiotherapy. Combined cfDNA-CTC as an early marker of treatment response should be investigated further.

OBJECTIVES To evaluate the incidence of histopathologic diagnostic discrepancy for patients referred to our institution, identify pathologies susceptible to diagnostic error, and assess the impact on survival of histopathologic diagnostic discrepancies. METHODS Three hundred ninety-seven patients with sinonasal cancers were identified, and discordance between the outside pathologic report and MD Anderson Cancer Center pathologic report was assessed. Overall survival and disease-specific survival were analyzed using Kaplan-Meier and log rank methods. RESULTS Discordance of major histopathologic diagnoses was present in 24% (97 of 397) of reports, with sinonasal undifferentiated carcinoma, sarcoma, neuroendocrine carcinoma, and poorly differentiated carcinoma pathologies having the highest change in diagnosis (P

Highlights • The use of oral stents during RT was associated with reduced late morbidity. • OPC patients with bilateral RT and tongue-depressing stents had less dysphagia. • Patients with unilateral RT and tongue-deviating stent had better taste/appetite., Objectives To evaluate whether the use of oral stents during intensity modulated radiation therapy (IMRT) for oropharyngeal cancer (OPC) is associated with long-term patient reported symptoms. Materials and methods Data was obtained from a prospective observational study of disease-free head and neck cancer survivors. Radiation-associated patient reported symptoms were assessed using the MD Anderson Symptom Inventory Head and Neck module (MDASI-HN). Scores of ≥5 (11-point Likert scale, 0-10) were considered moderate/severe. Stratification was performed regarding IMRT volume (uni- versus bilateral neck) and stent utilization, with non-parametric analyses between groups. Results 462 OPC survivors formed the cohort (54% tonsil, 46% base of tongue primaries). A tongue-deviating stent was used in 17%, tongue-depressing stent in 46%, and no stent in 37%. Median prescribed dose to the high dose clinical target volume was 66.0 Gy. Median follow-up from RT to MDASI-HN assessment was 68 months. Twenty percent had received unilateral neck RT (all had tonsil primaries), in whom a significant improvement in the proportion of patients with moderate/severe taste impairment (2% vs. 15%, p = 0.047) and lack of appetite (0% vs. 9%, p = 0.019) was associated with the use of tongue-deviating stents compared to no oral stent. In those who had received bilateral neck RT, a significant improvement in the proportion of patients with moderate/severe difficulty swallowing/chewing was associated with use of a tongue-depressing stent (21% vs. 31% without oral stent, p = 0.013). Conclusion Disease-site specific select use of oral stents during IMRT was associated with reduced long-term patient reported symptoms in OPC survivors.

Background and purposeTo characterize patterns and outcomes of brain MR image changes after proton therapy (PT) for skull base head and neck cancer (HNC).Material and methods127 patients treated with PT for HNC who had received at least 40 Gy(RBE) to the brain and had ≥ 1 follow-up MRI > 6 months after PT were analyzed. MRIs were reviewed for radiation- associated image changes (RAIC). MRIs were rigidly registered to planning CTs, and RAIC were contoured on T1 (post-contrast) and T2 weighted sequences, and dose-volume parameters extracted. Probability of RAIC over time was calculated using multistate analysis. Univariate/multivariate analyses were performed using Cox Regression. Recursive partitioning analysis was used to investigate dose-volume correlates of RAIC development.Results17.3% developed RAIC. All RAIC events were asymptomatic and occurred in the temporal lobe (14), frontal lobe (6) and cerebellum (2). The median volume of the RAIC on post-contrast T1 was 0.5 cc at their maximum size. The RAIC spontaneously resolved in 27.3%, progressed in 27.3% and improved or were stable in 29.6% of patients. The 3-year actuarial rate of developing RAIC was 14.3%. Brain and RAIC lesion doses were generally higher for temporal lobe RAIC compared to frontal lobe RAIC. RAIC was observed in 63% of patients when V67 Gy(RBE) of the brain ≥ 0.17 cc.ConclusionRAIC lesions after PT were asymptomatic and either resolved or regressed in the majority of the patients. The estimated dose–volume correlations confirm the importance of minimizing focal high doses to brain when achievable.