Prevalence of Pituitary Hormone Dysfunction Following Radiotherapy for Sinonasal and Nasopharyngeal Malignancies.

BACKGROUND: There are limited studies and no surveillance protocols on pituitary dysfunction for adults who underwent anterior skull base radiation. METHODS: Cross-sectional study of 50 consecutive patients with sinonasal or nasopharyngeal cancer who underwent definitive radiotherapy. The mean radiation doses, prevalence of pituitary dysfunction, and associated factors were calculated. RESULTS: Pituitary hormone levels were abnormal in 23 (46%) patients, including 6 (12%) with symptomatic abnormalities requiring treatment. The most common hormonal abnormality was hyperprolactinemia (30%), central hypothyroidism (8%) and central hypogonadism (6%). Patients with abnormal pituitary hormone values received higher mean radiation doses to the pituitary gland (1143 cGy, P = 0.04), pituitary stalk (1129 cGy, P = 0.02), optic chiasm (1094 cGy, P = 0.01), and hypothalamus (900 cGy, P = 0.01). CONCLUSIONS: Nearly half of the patients had abnormal pituitary function, including over a tenth requiring treatment. There may be a dose-dependent association between hormonal dysfunction and radiation

Proton Image-guided Radiation Assignment for Therapeutic Escalation via Selection of locally advanced head and neck cancer patients [PIRATES]:A Phase I safety and feasibility trial of MRI-guided adaptive particle radiotherapy

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

Clinical Acceptability of Automatically Generated Lymph Node Levels and Structures of Deglutition and Mastication for Head and Neck Radiation Therapy

BACKGROUND AND PURPOSE: Auto-contouring of complex anatomy in computed tomography (CT) scans is a highly anticipated solution to many problems in radiotherapy. In this study, artificial intelligence (AI)-based auto-contouring models were clinically validated for lymph node levels and structures of swallowing and chewing in the head and neck. MATERIALS AND METHODS: CT scans of 145 head and neck radiotherapy patients were retrospectively curated. One cohort (n = 47) was used to analyze seven lymph node levels and the other (n = 98) used to analyze 17 swallowing and chewing structures. Separate nnUnet models were trained and validated using the separate cohorts. For the lymph node levels, preference and clinical acceptability of AI vs human contours were scored. For the swallowing and chewing structures, clinical acceptability was scored. Quantitative analyses of the test sets were performed for AI vs human contours for all structures using overlap and distance metrics. RESULTS: Median Dice Similarity Coefficient ranged from 0.77 to 0.89 for lymph node levels and 0.86 to 0.96 for chewing and swallowing structures. The AI contours were superior to or equally preferred to the manual contours at rates ranging from 75% to 91%; there was not a significant difference in clinical acceptability for nodal levels I-V for manual versus AI contours. Across all AI-generated lymph node level contours, 92% were rated as usable with stylistic to no edits. Of the 340 contours in the chewing and swallowing cohort, 4% required minor edits. CONCLUSIONS: An accurate approach was developed to auto-contour lymph node levels and chewing and swallowing structures on CT images for patients with intact nodal anatomy. Only a small portion of test set auto-contours required minor edits

Surgery After BRAF-Directed Therapy Is Associated with Improved Survival in BRAF

Supplementary Materials PMID: 3676294

Temporal Characterization of Acute Pain and Toxicity Kinetics During Radiation Therapy for Head and Neck Cancer A Retrospective Study

OBJECTIVES: Pain during Radiation Therapy (RT) for oral cavity/oropharyngeal cancer (OC/OPC) is a clinical challenge due to its multifactorial etiology and variable management. The objective of this study was to define complex pain profiles through temporal characterization of pain descriptors, physiologic state, and RT-induced toxicities for pain trajectories understanding. MATERIALS AND METHODS: Using an electronic health record registry, 351 OC/OPC patients treated with RT from 2013 to 2021 were included. Weekly numeric scale pain scores, pain descriptors, vital signs, physician-reported toxicities, and analgesics were analyzed using linear mixed effect models and Spearman\u27s correlation. Area under the pain curve (AUC RESULTS: Median pain scores increased from 0 during the weekly visit (WSV)-1 to 5 during WSV-7. By WSV-7, 60% and 74% of patients reported mouth and throat pain, respectively, with a median pain score of 5. Soreness and burning pain peaked during WSV-6/7 (51%). Median AUC CONCLUSION: This study provides insight on in-depth characterization and associations between dynamic pain, physiologic, and toxicity kinetics. Our findings support further needs of optimized pain control through temporal data-driven clinical decision support systems for acute pain management

Comparison of 3D Confromal Radiotherapy and Intensity Modulated Radiotherapy with or without Simultaneous Integrated Boost during Concurrent Chemoradiation for Locally Advanced Head and Neck Cancers

Objective: Radiotherapy techniques have evolved from 3D conformal radiotherapy (3D-CRT) to intensity modulated radiotherapy (IMRT) where boost fields are delivered either sequentially (IMRTseq) or with a simultaneous integrated boost (IMRT+SIB). Our goal was to compare the outcomes of patients treated with IMRT+SIB to traditional standards.Methods: We analyzed the efficacy and toxicity of patients treated with concurrent chemoradiation using 3D-CRT, IMRTseq or IMRT+SIB. Between 1993 and 2012, 379 patients with non-metastatic Stage III-IV head and neck squamous cell cancer were treated with concurrent chemoradiation using 3D-CRT (n = 125), IMRTseq (n = 120) and IMRT+SIB (n = 134).Results: Patients treated with any technique had similar rates of 2y local control, 2y regional control, 2y progression free survival and 2y overall survival. Patients treated with IMRT+SIB had lower rates acute toxicity according to Grade 3 or greater mucositis (3D-CRT: 44.0% vs. IMRTseq: 36.7% vs. IMRT+SIB: 22.4%; PPPPPConclusions: Compared to 3D-CRT and IMRTseq, IMRT+SIB provided similar outcomes and potentially less toxicity indicating it is a feasible technique for chemoradiation in locally advanced head and neck cancer.</p

Comparison of 3D confromal radiotherapy and intensity modulated radiotherapy with or without simultaneous integrated boost during concurrent chemoradiation for locally advanced head and neck cancers.

Radiotherapy techniques have evolved from 3D conformal radiotherapy (3D-CRT) to intensity modulated radiotherapy (IMRT) where boost fields are delivered either sequentially (IMRTseq) or with a simultaneous integrated boost (IMRT+SIB). Our goal was to compare the outcomes of patients treated with IMRT+SIB to traditional standards.We analyzed the efficacy and toxicity of patients treated with concurrent chemoradiation using 3D-CRT, IMRTseq or IMRT+SIB. Between 1993 and 2012, 379 patients with non-metastatic Stage III-IV head and neck squamous cell cancer were treated with concurrent chemoradiation using 3D-CRT (n = 125), IMRTseq (n = 120) and IMRT+SIB (n = 134).Patients treated with any technique had similar rates of 2y local control, 2y regional control, 2y progression free survival and 2y overall survival. Patients treated with IMRT+SIB had lower rates acute toxicity according to Grade 3 or greater mucositis (3D-CRT: 44.0% vs. IMRTseq: 36.7% vs. IMRT+SIB: 22.4%; P<.0001), dermatitis (3D-CRT: 44.0% vs. IMRTseq: 20.0% vs. IMRT+SIB: 7.5%; P<.0001) and feeding tube placement during radiotherapy (3D-CRT: 80.0% vs. IMRTseq: 50.8% vs. IMRT+SIB: 44.0%; P<.0001) as well as late toxicity as measured by feeding tube use (P<.0001) and tracheostomy use (P<.0001). On multivariate analysis, IMRT+SIB predicted for less mucositis, dermatitis and feeding tube use compared to 3D-CRT and for less dermatitis compared to IMRTseq.Compared to 3D-CRT and IMRTseq, IMRT+SIB provided similar outcomes and potentially less toxicity indicating it is a feasible technique for chemoradiation in locally advanced head and neck cancer

Loss of E2F1 Extends Survival and Accelerates Oral Tumor Growth in HPV-Positive Mice

The Human Papillomavirus (HPV) is associated with several human cancers, including head and neck squamous cell carcinomas (HNSCCs). HPV expresses the viral oncogene E7 that binds to the retinoblastoma protein (RB1) in order to activate the E2F pathway. RB1 can mediate contradictory pathways—cell growth and cell death via E2F family members. Here, we assessed the extent to which E2F1 mediates lethality of HPV oncogenes. Ubiquitous expression of the HPV oncogenes E6 and E7 caused lethality in mice that was associated with focal necrosis in hepatocytes and pancreatic tissues. Furthermore, all organs expressing HPV oncogenes displayed up-regulation of several E2F1 target genes. The E2F1 pathway mediated lethality in HPV-positive mice because deletion of E2F1 increased survival of mice ubiquitously expressing HPV oncogenes. E2F1 similarly functioned as a tumor suppressor in HPV-positive oral tumors as tumors grew faster with homozygous loss of E2F1 compared to tumors with heterozygous loss of E2F1. Re-expression of E2F1 caused decreased clonogenicity in HPV-positive cancer cells. Our results indicate that HPV oncogenes activated the E2F1 pathway to cause lethality in normal mice and to suppress oral tumor growth. These results suggest that selective modulation of the E2F1 pathway, which is activated in HPV tumors, may facilitate tumor regression