Neck Chemoradiation Research Articles

Dosimetric Parameters Correlate with Taste Alterations in Head and Neck Radiotherapy

Dysgeusia is an acute and chronic side effect of head and neck chemoradiation, with persistent taste dysfunction 1-2 years post radiotherapy occurring in 23-50% of patients. Several head and neck clinical trials set oral cavity mean doses between 30 to 40 Gy, however, there are no set guidelines accurately defining the composite structure and anatomic boundaries for the oral cavity or separating the tongue into specific quadrants. In this single institution cross sectional study, we sought to determine the effects of radiation doses to specific regions of the oral cavity and tongue on patient-reported long term dysgeusia. We hypothesize that radiation Dose to specific structures in the oral cavity will correlate with long-term dysgeusia in patients who have received head and neck radiotherapy. Patients with primary head and neck cancer receiving definitive intensity modulated radiation therapy (RT) completed quality of life assessments that included patient-reported gustatory function, 1 year post RT. Dosimetric data from RT plans were collected for specific regions and organs at risk within the oral cavity. These structures included the anterior, posterior, superior and inferior tongue (OT), pharyngeal constrictors (as a surrogate for the corda-tympani) and the oral cavity. A forward binary logistic regression model was performed using these data points with scoring from the QLQ-H&N43 questionnaire subsection on taste (Q45) to determine the most predictive values for dysgeusia and the OR for moderate/severe alterations in taste. A total of 78 patients were included in this study, of these patients, 63 had dosimetric data for the pharyngeal constrictors. The Oral Cavity Volume percentage receiving 50Gy (OC V50) and Pharyngeal Constrictors Volume percentage receiving 55Gy (PC V55) were the most predictive constraints for dysgeusia. (0.042, p = 0.011 and 0.041, p = 0.033). Holding all other variables constant in a forward binary logistic regression including 78 patients, the odds of having moderate to severe taste alterations increased by 56% (OR 1.045, 95% CI 1.012-1.079) for a 1% increase in OCV50. When analyzing the 68 patients with available pharyngeal constrictors data, taste alteration increased 20% for every 1% increase in PCV55 (OR 1.042, 95% CI 1.003-1.082). There was no correlation with taste alterations in any of the dose parameters tested (Dmax, mean and V50 up to V70) for superior, inferior, anterior or posterior regions of the tongue. Dosimetric parameters for the oral cavity (OC V50) and pharyngeal constrictors (PC V55) were positively correlated with taste alterations, however, no other specific regions within the oral tongue predicted taste disfunction. Normal tissue complication probability modeling curves to identify OC V50 and PC V55 constraints for dysgeusia are needed.

PO-1695 Biomechanical imaging biomarker to predict tumor progression after head and neck chemoradiotherapy

PO-1695 Biomechanical imaging biomarker to predict tumor progression after head and neck chemoradiotherapy

Efficacy of ketamine mouthwash in the management of oral and pharyngeal toxicity associated with head and neck chemoradiotherapy: protocol for a phase II, Simon’s two-stage trial

IntroductionCurative intent treatment of head and neck cancer (HNC) is frequently radiation therapy over 7 weeks with concurrent chemotherapy. This regimen is effective but carries a burden of toxicity leading...

PREVLAR: Phase 2a Randomized Trial to Assess the Safety and Efficacy of RRx-001 in the Attenuation of Oral Mucositis in Patients Receiving Head and Neck Chemoradiotherapy

No Food and Drug Administration-approved intervention exists for oral mucositis (OM) from chemoradiotherapy (CRT) used to treat head and neck cancers. RRx-001 is a hypoxia-activated, cysteine-directed molecule that affects key pathways involved in OM pathogenesis. This phase 2a, multi-institutional trial was designed to assess the safety and feasibility of 3 schedules of a fixed concentration of RRx-001; a standard-of-care arm was included to identify potential signals of efficacy for further study. This study enrolled patients with oral cavity and oropharynx squamous cell carcinoma receiving definitive or postoperative cisplatin-based CRT. Patients were randomized into 4 cohorts. In arms 1 to 3, RRx-001 was coinfused with patients' blood at differing intervals. Arm 4 was a control cohort of patients treated with CRT alone. Trained evaluators assessed OM using a standardized data collection instrument twice weekly during treatment and then until resolution. OM severity was scored centrally using World Health Organization criteria. Safety outcomes were assessed using National Cancer Institute - Common Terminology Criteriav4 benchmarks. Long-term tumor response was defined by Response evaluation criteria in solid tumors v1.1 criteria. Fifty-three patients were enrolled, with 46 and 45 individuals contributing safety and efficacy data, respectively. There were no severe adverse events attributed to the study drug. Across all 3 active arms, the study drug was infused fully per protocol in 86% of patients. All 3 RRx-001 treatment cohorts appeared to demonstrate a similar or lower OM duration relative to control; arm 1 had the lowest median duration of severe oral mucositis (SOM), 8.5 days versus 24 days in controls among patients who developed at least 1 day of SOM. There were no locoregional failures in any patient. Our results support the safety and feasibility of RRx-001 as an intervention to mitigate SOM. Additional studies are planned to confirm its efficacy.

A Case of Multiple Caries After Head and Neck Chemoradiotherapy and Difficulty with Oral Management

A Case of Multiple Caries After Head and Neck Chemoradiotherapy and Difficulty with Oral Management

Oral mucositis: Current knowledge and future directions

Oral mucositis secondary to head and neck chemoradiation displays a complex molecular pathogenesis involving epithelial and microvascular injury, release of pro-inflammatory cytokines, and host-microbiome communications. These processes lead to oxidative stress and the release of reactive oxygen species that stifle the structural integrity of the oral mucosa, with emergence of erosions and ulcers. The consequences are malnutrition, psychological/psychiatric symptoms, poor quality of life, and occurrence of opportunistic infections. The latter pose a major challenge due to the risk of interruption of anti-neoplastic therapy, tumour recurrence and, ultimately, death. This article aims to present the clinical characteristics, molecular pathogenesis, and an overview of the predisposing factors and current management of oral mucositis. It is anticipated that the future direction of the management of oral mucositis will focus on evidence-based prehabilitation and pre- and per-chemoradiation therapy monitoring.

Comprehensive Assessment of the Relationship Between Oral Cavity Dosimetry and Patient Reported Xerostomia and Dysgeusia

Xerostomia and dysgeusia are two common and severe complications for patients undergoing head and neck chemoradiotherapy (CRT). Literature suggests a relationship between mean oral cavity (OC) doses and worsening xerostomia and dysgeusia. However, limited data exists identifying which substructures of the oral cavity are most related to patient reported outcomes (PROs) or how oral cavity dosimetry should be prioritized in relationship to other salivary glands during planning. We hypothesized that only certain substructures of the OC will be related to patient reported xerostomia and dysgeusia and that OC dose will be less impactful than contralateral major salivary gland dose for patient reported xerostomia and dysgeusia.184 and 177 prospectively enrolled patients for de-escalated CRT for HPV-positive oropharyngeal cancer submitted PROs at 6 and 12 months, respectively using PRO-CTCAE 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 OAR dosimetry to patient reported xerostomia and dysgeusia at 6 and 12 months. Multivariate ordinal logistic regression models were determined using forward/backward AIC minimization to minimize the number of predictive variables.Mean dose to the contralateral parotid (P = 0.04), OC (P = 0.04), and baseline patient reported xerostomia (P = 0.009) were significantly associated with xerostomia severity at 6 months. Only baseline xerostomia (P = 0.02) and mean dose to the contralateral submandibular gland (P = 0.0001) 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 = 0.009). Upon examining substructures, the mean dose to the floor of mouth was implicated for the dose relationship to 6-month xerostomia (P = 0.04) and the oral tongue was found to be implicated for the relationship for 12-month dysgeusia (P = 0.04).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 impact of OC dose relative to other salivary structures for xerostomia appeared to depend on time post-CRT (comparable to contralateral parotid at 6 months and not significant at 12 months).

Feasibility of a collaborative palliative and oncology care intervention to improve symptoms and coping during head and neck chemoradiation.

73 Background: Patients receiving curative chemoradiation treatment (CRT) for head and neck cancer (HNC) undergo one of the most intensive treatments in oncology, resulting in immense physical and psychological symptoms. Integrated palliative care can improve symptoms and coping in patients with advanced cancer, but has not been evaluated in patients with curable solid tumors. Thus, we are conducting the first pilot study of a collaborative palliative and oncology care intervention among patients receiving CRT to assess feasibility and acceptability. Methods: Eligible participants include newly diagnosed HNC patients starting curative-intent CRT. The intervention entails weekly in-person palliative care (PC) visits integrated with standard oncology care during CRT, followed by 4 weekly phone calls after CRT ends. The PC visits are conducted primarily by a PC RN, with a supervising MD or NP available. Visits focus on coping and managing prominent symptoms during CRT. PC clinicians also receive a weekly patient-reported symptom assessment. Acceptability of the intervention is assessed at 1 month post CRT. The primary outcome is feasibility, defined as a >50% enrollment rate with >70% of participants attending at least half of the PC visits. Planned accrual is 20 patients. Results: We have enrolled 88% (14/16) of eligible patients to date. 11/14 (79%) have p16+ disease. All 14 have completed CRT and are evaluable for feasibility. Participants attended 98% (94/96) of all possible PC visits and completed 99% (95/96) of weekly symptom assessments. PC clinicians spent an average of 35.5 minutes (SD 15.1) per visit with participants. Among the 10 participants who completed the intervention and are evaluable for acceptability, 100% found the intervention “very helpful” and would “definitely recommend” it to others undergoing CRT. Conclusions: An integrated PC intervention to improve symptoms and coping during CRT for HNC is both feasible and acceptable with a high enrollment rate, excellent intervention compliance, and high patient satisfaction. Future studies will evaluate the effects of the integrated intervention on patient-reported outcomes and health care utilization. Clinical trial information: NCT03760471.

A preliminary Study on the Effect of Head and Neck Chemoradiotherapy on Systematic Immunity.

Background:This study was designed initially to explore the effect of chemoradiotherapy on patients diagnosed with head and neck cancer (HNC) with respect to the alteration of systematic immunity.Methods:We did a retrospective study enrolling patients received concurrent chemoradiotherapy (CCRT), with or without induction chemotherapy (IC). Blood tests were performed before IC, before and after CCRT. Flow cytometric analysis and turbidimetric inhibition immunoassay were used for detection.Results:A total number of 58 patients were included from April 1, 2018, to March 31, 2019. Levels of immunoglobulins (Ig), including IgA, IgG, and IgM, declined after 2 to 3 cycles of IC and CCRT, respectively. Serum level of total hemolytic complement (CH50) increased (P < .001) after IC, but kept stably post-CCRT. Natural killer (NK) cells decreased (P < .01) after IC and enhanced (P < .001) post-CCRT. The number of CD3+CD4+ T cells got increased (P < .01) after IC and decreased (P < .001) post-CCRT. Consistently, both IC and CCRT induced the increase in CD3+CD8+ T cells significantly (P < .001 vs P < .01).Conclusion:Both radiotherapy (RT) and chemotherapy (CT) induced dual effect of immune response. Concurrent chemoradiotherapy created an active immune response based on the effect induced by IC, suggesting that RT exerted a potential function on mobilizing immune system.

N-Acetylcysteine Rinse for Thick Secretion and Mucositis of Head and Neck Chemoradiotherapy (Alliance MC13C2): A Double-Blind Randomized Clinical Trial

ObjectiveTo determine whether N-acetylcysteine rinse was safe and could improve thickened secretions and dry mouth during and after radiotherapy. Patients and MethodsWe designed a prospective pilot double-blind, placebo-controlled randomized clinical trial (Alliance MC13C2). Adult patients (age ≥18 years) were enrolled if they underwent chemoradiotherapy (≥60 Gy). Patients initiated testing rinse within 3 days of starting radiotherapy. With swish-and-spit, they received 10% N-acetylcysteine (2500 mg daily) or placebo rinse solution 5 times daily during radiotherapy and 2 weeks postradiotherapy. The primary aim was to evaluate N-acetylcysteine in improvement of saliva viscosity with the Groningen Radiotherapy-Induced Xerostomia questionnaire. Secondary aims included evaluating xerostomia improvement by the same questionnaire and with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Head and Neck-35 Questions survey and adverse-event profiles. The type I error rate was 20%. ResultsThirty-two patients undergoing chemoradiotherapy were enrolled. Baseline characteristics were balanced for placebo (n=17) and N-acetylcysteine (n=15). N-acetylcysteine was better for improving sticky saliva (area under curve, P=.12). Scores of multiple secondary end points favored N-acetylcysteine, including sticky saliva daytime (P=.04), daytime and total xerostomia (both P=.02), pain (P=.18), and trouble with social eating (P=.15). Repeated measures models confirmed the findings. Taste was a major dissatisifer for N-acetylcysteine rinse; however, both testing rinses were safe and well tolerated overall. ConclusionOur pilot data showed that N-acetylcysteine rinse was safe and provided strong evidence of potential efficacy for improving thickened saliva and xerostomia by patient-reported outcome. A confirmatory phase 3 trial is required. Trial Registrationclinicaltrials.gov Identifier: NCT02123511

Therapeutic Benefit of Placentrex in the Management of Acute Chemo Radiation Induced Mucositis in Oral Cancer Patients

Background:A troublesome and usually unavoidable consequence of Head and Neck chemo radiation is oral mucositis which decreases patients’ compliance and negatively influences the outcome of therapy by increasing overall treatment time. Currently, no single effective recommended treatment exists for this problem and a variety of supportive care measures have been practiced with limited benefits. This study was done to evaluate the therapeutic benefit of Placentrex in the management of oral mucositis seen in oral cancer patients undergoing treatment with concurrent chemoradiation.Methodology:This study was carried out, as a retrospective analysis, on oral cancer patients undergoing concurrent chemoradiation with weekly Cisplatin regimen treated between Oct 2015 and July 2017. All the patients received 2ml of Inj Placentrex, once daily administered intramuscularly for 4 weeks, NSAIDs, topical analgesics, and mouth wash as treatment for oral mucositis. The results were compared with a historical control group of 40 oral cancer patients who had received treatment prior to the study period without receiving Inj Placentrex as a part of oral mucositis management.Results:Over 60% of the patients in both groups were older than 60 years of age. Buccal mucosa was the predominant sub site of the investigated cancer type. The addition of placentrex resulted in delay in the progression of mucositis, reduction of treatment breaks, regression of pain, and improvement of dysphagia while leading to no adverse effects (p<0.05).Conclusion:Placentrex appears to be a beneficial therapeutic option for the management of concurrent chemo-radiation induced acute oral mucositis in oral cancer patients.

Supersaturated Calcium Phosphate Rinse vs. Standard of Care for Mitigating Mucositis in Head and Neck Chemoradiation

Introduction: Oral mucositis (OM) can have a significant impact on patients’ quality of life, pain and treatment costs. Almost all patients receiving head and neck chemoradiation develop OM. Patients and Methods: Twenty patients were evaluated retrospectively for OM when undergoing head and neck chemoradiation. The control, soda/salt rinse, was compared to a powdered supersaturated calcium phosphate rinse (SSCPR), SalivaMAX. Results: The SSCPR group experienced a delay in the onset of OM, which was not statistically significant, and a marked reduction in peak OM that was statistically significant (p > 0.001). Conclusion: This retrospective study demonstrates that a powdered SSCPR is a safe and effective method of oral mucositis mitigation.

Diffusion-weighted magnetic resonance imaging for evaluation of salivary gland function in head and neck cancer patients treated with intensity-modulated radiotherapy

Background and purposesPermanent xerostomia as a result of radiation-induced salivary gland damage remains a common side effect of radiotherapy (RT) of the head and neck. The purpose of this study was to evaluate the usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI) in assessing the post-RT salivary gland function in patients with head and neck cancer (HNC). Materials and methodsIn this prospective study, 20 HNC patients scheduled for bilateral neck chemoradiotherapy (CRT) with weekly cisplatin went through diffusion-weighted magnetic resonance imaging (DW-MRI) and salivary gland scintigraphy (SGS) prior to and at a mean of six months after completing the treatment. The changes in apparent diffusion coefficient (ADC) before and after treatment were compared with ejection fraction (EF) measured with SGS and the radiation dose absorbed by the salivary glands. ResultsAs a result of gustatory stimulation with ascorbic acid, the ADC showed a biphasic response with an initial increase and subsequent decrease. This pattern was seen both before and after RT. Post-RT ADC increased as a function of RT dose absorbed by the salivary glands. A moderate statistical correlation between pre- and post-RT ADCs at rest and EF measured with SGS was found. ConclusionsDW-MRI seems a promising tool for detection of physiological and functional changes in major salivary glands after RT.

Exploratory Assessment of Swallowing Muscle Dose Volume Parameters With Chronic Dysphagia in Patients Receiving Head and Neck Chemoradiation Therapy

Exploratory Assessment of Swallowing Muscle Dose Volume Parameters With Chronic Dysphagia in Patients Receiving Head and Neck Chemoradiation Therapy

Phase 1 Trial of Bevacizumab With Concurrent Chemoradiation Therapy for Squamous Cell Carcinoma of the Head and Neck With Exploratory Functional Imaging of Tumor Hypoxia, Proliferation, and Perfusion

A phase 1 trial was completed to examine the safety and feasibility of combining bevacizumab with radiation and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC) treated with curative intent. Additionally, we assessed the capacity of bevacizumab to induce an early tumor response as measured by a series of biological imaging studies. All patients received a single induction dose of bevacizumab (15 mg/kg) delivered 3 weeks (±3 days) before the initiation of chemoradiation therapy.After the initial dose of bevacizumab, comprehensive head and neck chemoradiation therapy was delivered with curative intent to 70 Gy in 33 fractions with concurrent weekly cisplatin at 30 mg/m(2) and bevacizumab every 3 weeks (weeks 1, 4, 7) with dose escalation from 5 to 10 to 15 mg/kg. All patients underwent experimental imaging with [(18)F]fluorothymidine positron emission tomography (FLT-PET) (proliferation), [(61)Cu]Cu-diacetyl-bis(N4-methylthiosemicarbazone) PET (Cu-ATSM-PET) (hypoxia), and dynamic contrast-enhanced computed tomography (DCE-CT) (perfusion) at 3 time points: before bevacizumab monotherapy, after bevacizumab monotherapy, and during the combined therapy course. Ten patients were enrolled. All had stage IV HNSCC, all achieved a complete response to treatment, and 9 of 10 remain alive, with a mean survival time of 61.3 months. All patients experienced grade 3 toxicity, but no dose-limiting toxicities or significant bleeding episodes were observed. Significant reductions were noted in tumor proliferation (FLT-PET), tumor hypoxia (Cu-ATSM-PET), and DCE-CT contrast enhancement after bevacizumab monotherapy, with further decreases in FLT-PET and Cu-ATSM-PET during the combined therapy course. The incorporation of bevacizumab into comprehensive chemoradiation therapy regimens for patients with HNSCC appears safe and feasible. Experimental imaging demonstrates measureable changes in tumor proliferation, hypoxia, and perfusion after bevacizumab monotherapy and during chemoradiation therapy. These findings suggest opportunities to preview the clinical outcomes for individual patients and thereby design personalized therapy approaches in future trials.

Patient-Reported Outcomes: Correlation of MDASI-HN and Clinical Support Required for Patients Receiving Curative Head and Neck Chemoradiation Therapy

Patient-Reported Outcomes: Correlation of MDASI-HN and Clinical Support Required for Patients Receiving Curative Head and Neck Chemoradiation Therapy

Technical note: 9-month repositioning accuracy for functional response assessment in head and neck chemoradiotherapy

The use of thermoplastic immobilisation masks in head and neck radiotherapy is now common practice. The accuracy of these systems has been widely studied, but always within the context and time frame of the radiation delivery-some 6-8 weeks. There is growing current interest in the use of functional imaging to assess the response to treatment, particularly in the head and neck. It is therefore of interest to determine the accuracy with which functional images can be registered to baseline CT over the extended periods of time used for functional response assessment: 3-6 months after radiotherapy. In this study, repeated contrast-enhanced diagnostic quality CT and mid-quality localisation CT from a positron emission tomography/CT scanner were available for five time points over a period of 9 months (before, during and up to 6 months after chemoradiotherapy) for a series of eight patients enrolled in a clinical pilot study. All images were acquired using thermoplastic immobilisation masks. The overall set-up accuracy obtained from this 9-month study of 5.5 ± 3.2 mm (1 standard deviation) and 1.9 ± 1.3° (1 standard deviation) is in agreement with published data acquired over 6-8 weeks. No statistically significant change in set-up error was seen with time. This work indicates that thermoplastic immobilisation masks can be used to accurately align multimodality functional image data for assessment of the response to treatment in head and neck patients over extended follow-up periods.

Middle Ear Morbidity after Head and Neck Chemoradiation

Objective: Radiation therapy (RT) for head and neck cancers (HNC) has been associated with middle ear mobidity (MEM). The goal of this study is to evaluate the post-RT incidence of middle ear morbidity in HNCa patients receiving RT ± chemotherapy (chemo) and associated patient and treatment related factors. Method: Pre- and post-RT records of HNC patients were retrospectively assessed to estimate the incidence of chronic otitis media with effusion (OME), chronic suppurative otitis media (CSOM), tympanosclerosis, persistent tympanic membrane perforation (TMP), mastoiditis, dysgeusia, and corresponding radiation doses to the middle ear. Results: A total of 375 patients (750 ears) were evaluated. The rate of MEM included OME (31.5), CSOM (8.0), TMP with (7.0) and without (8.5) tympanostomy, tympanosclerosis (20.5), mastoiditis (5.5), middle ear fibrosis (6.0), dysgeusia (7.5). With a range of 0.25 to 6.5 years, the median times for detection of MEM varied from 0.95 to 2.3 years. Univariate and multivariate analyses indicated that dose to middle ear was significant for all MEM, but age (&gt;60 years), gender, and race were not. Significance of dose fractionation (daily/twice daily) for OME was marginal ( P = .0498). Adjuvant chemotherapy was significant for incidence of OME, TMP ( P &lt; .05). Conclusion: Incidence of post-RT MEM is proportional to the radiation dose received by middle ear. Adjuvant chemotherapy is associated with MEM, but further investigation into this risk factor is needed.

73 Effects of laser irradiation of blood for the treatment of acute coronary syndrome on the shape of erythrocytes and microcirculation

Our objective was to review the first 20 years of photobiomodulation (PBM) clinical studies for oral mucositis (OM) mitigation.A scoping review screened controlled clinical studies. The PBM devices, protocols, and clinical outcomes were analyzed.Seventy-five studies met the inclusion criteria. The first study dated from 1992, and the term “PBM” was first published in 2017. Public services, placebo-controlled randomized trials, and patients with head and neck chemoradiation were predominant among included studies. Prophylactic red intraoral laser protocols were mostly used. Comparing the outcomes of all protocols was unfeasible due to missing treatment parameters and nonhomogeneous measurements.The main barrier to optimizing clinical protocols of PBM for OM was the lack of standardization in clinical studies. Although PBM use is now globally present in oncology settings and generally marked by good outcomes reported, additional randomized clinical trials with well-described methods are necessary.

Easing acceleration of head and neck chemoradiotherapy

In the past 20 years, management of locoregionally advanced head and neck cancer has evolved from often devastating surgical resection towards radiotherapy, intensified either by altered fractionation1 or by addition of concurrent chemotherapy,2 with the aim of cure with functional preservation of organs. A key expectation was that intensification of radiotherapy would result in improved outcomes for patients, which would justify any extra morbidity.