BackgroundHuman papillomavirus-positive oropharyngeal squamous cell carcinoma is increasing in incidence worldwide. Current treatments are associated with high survival rates but often result in significant long-term toxicities. In particular, long-term dysphagia has a negative impact on patient quality of life and health. The aim of PATHOS is to determine whether reducing the intensity of adjuvant treatment after minimally invasive transoral surgery in this favourable prognosis disease will result in better long-term swallowing function whilst maintaining excellent disease-specific survival outcomes.Methods/DesignThe study is a multicentre phase II/III randomised controlled trial for patients with biopsy-proven Human papillomavirus-positive oropharyngeal squamous cell cancer staged T1-T3 N0-N2b with a primary tumour that is resectable via a transoral approach. Following transoral surgery and neck dissection, patients are allocated into three groups based on pathological risk factors for recurrence. Patients in the low-risk pathology group will receive no adjuvant treatment, as in standard practice. Patients in the intermediate-risk pathology group will be randomised to receive either standard dose post-operative radiotherapy (control) or reduced dose radiotherapy. Patients in the high-risk pathology group will be randomised to receive either post-operative chemoradiotherapy (control) or radiotherapy alone. The primary outcome of the phase II study is patient reported swallowing function measured using the MD Anderson Dysphagia Inventory score at 12 months post-treatment. If the phase II study is successful, PATHOS will proceed to a phase III non-inferiority trial with overall survival as the primary endpoint.DiscussionPATHOS is a prospective, randomised trial for Human papillomavirus-positive oropharyngeal cancer, which represents a different disease entity compared with other head and neck cancers. The trial aims to demonstrate that long-term dysphagia can be lessened by reducing the intensity of adjuvant treatment without having a negative impact on clinical outcome. The study will standardise transoral surgery and post-operative intensity-modulated radiotherapy protocols in the UK and develop a gold-standard swallowing assessment panel. An associated planned translational research programme, underpinned by tumour specimens and sequential blood collected as part of PATHOS, will facilitate further empirical understanding of this new disease and its response to treatment.Trial registrationThis study is registered with ClinicalTrials.gov identifier NCT02215265.

PurposeThe heart receives high radiation doses during radiation therapy of advanced-stage lung cancer. We have explored associations between overall survival, cardiac radiation doses, and electrocardiographic (ECG) changes in patients treated in IDEAL-CRT, a trial of isotoxically escalated concurrent chemoradiation delivering tumor doses of 63 to 73 Gy.Methods and MaterialsDosimetric and survival data were analyzed for 78 patients. The whole heart, pericardium, AV node, and walls of left and right atria (LA/RA-Wall) and ventricles (LV/RV-Wall) were outlined on radiation therapy planning scans, and differential dose-volume histograms (dDVHs) were calculated. For each structure, dDVHs were approximated using the average dDVH and the 10 highest-ranked structure-specific principal components (PCs). ECGs at baseline and 6 months after radiation therapy were analyzed for 53 patients, dichotomizing patients according to presence or absence of “any ECG change” (conduction or ischemic/pericarditis-like change). All-cause death rate (DR) was analyzed from the start of treatment using Cox regression.Results38% of patients had ECG changes at 6 months. On univariable analysis, higher scores for LA-Wall-PC6, Heart-PC6, “any ECG change,” and larger planning target volume (PTV) were significantly associated with higher DR (P=.003, .009, .029, and .037, respectively). Heart-PC6 and LA-Wall-PC6 represent larger volumes of whole heart and left atrial wall receiving 63 to 69 Gy. Cardiac doses ≥63 Gy were concentrated in the LA-Wall, and consequently Heart-PC6 was highly correlated with LA-Wall-PC6. “Any ECG change,” LA-Wall-PC6 scores, and PTV size were retained in the multivariable model.ConclusionsWe found associations between higher DR and conduction or ischemic/pericarditis-like changes on ECG at 6 months, and between higher DR and higher Heart-PC6 or LA-Wall-PC6 scores, which are closely related to heart or left atrial wall volumes receiving 63 to 69 Gy in this small cohort of patients.

Cleft lip and palate is the most common of the congenital conditions affecting the face and cranial bones and is associated with a raised risk of difficulties in infant-caregiver interaction; the reasons for such difficulties are not fully understood. Here, we report two experiments designed to explore how adults respond to infant faces with and without cleft lip, using behavioural measures of attractiveness appraisal (‘liking’) and willingness to work to view or remove the images (‘wanting’). We found that infants with cleft lip were rated as less attractive and were viewed for shorter durations than healthy infants, an effect that was particularly apparent where the cleft lip was severe. Women rated the infant faces as more attractive than men did, but there were no differences in men and women's viewing times of these faces. In a second experiment, we found that the presence of a cleft lip in domestic animals affected adults' ‘liking’ and ‘wanting’ responses in a comparable way to that seen for human infants. Adults' responses were also remarkably similar for images of infants and animals with cleft lip, although no gender difference in attractiveness ratings or viewing times emerged for animals. We suggest that the presence of a cleft lip can substantially change the way in which adults respond to human and animal faces. Furthermore, women may respond in different ways to men when asked to appraise infant attractiveness, despite the fact that men and women ‘want’ to view images of infants for similar durations.

PurposeTo report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer.Patients and MethodsPatients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumor doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined.ResultsEight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years.ConclusionsIDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.