CompARE: study protocol for a phase III randomised controlled platform trial comparing alternative regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer.

BACKGROUND: Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. CompARE is designed to test alternative approaches to intensified treatment for these patients to improve survival. METHODS: CompARE is a pragmatic phase III, open-label, multicenter randomised controlled trial with an adaptive multi-arm, multi-stage design and an integrated QuinteT Recruitment Intervention. Eligible OPC patients include those with human papillomavirus (HPV) negative, T1-T4, N1-N3 or T3-4, N0, or HPV positive N3, T4, or current smokers (or ≥ 10 pack years previous smoking history) with T1-T4, N2b-N3. CompARE was originally designed with four arms (one control [arm 1] and three experimental: arm 2-induction chemotherapy followed by arm 1; arm 3-dose-escalated radiotherapy plus concomitant cisplatin; and arm 4-resection of primary followed by arm 1). The three original experimental arms have been closed to recruitment and a further experimental arm opened (arm 5-induction durvalumab followed by arm 1 and then adjuvant durvalumab). Currently recruiting are arm 1 (control): standard treatment of 3-weekly cisplatin 100 mg/m2 or weekly 40 mg/m2 with intensity-modulated radiotherapy using 70 Gy in 35 fractions ± neck dissection determined by clinical and radiological assessment 3 months post-treatment, and arm 5 (intervention): one cycle of induction durvalumab 1500 mg followed by standard treatment then durvalumab 1500 mg every 4 weeks for a total of 6 months. The definitive and interim primary outcome measures are overall survival time and event-free survival (EFS) time, respectively. Secondary outcome measures include quality of life, toxicity, swallowing outcomes, feeding tube incidence, surgical complication rates, and cost-effectiveness. The design anticipates that after approximately 7 years, 84 required events will have occurred to enable analysis of the definitive primary outcome measure for this comparison. Planned interim futility analyses using EFS will also be performed. DISCUSSION: CompARE is designed to be efficient and cost-effective in response to new data, emerging new treatments or difficulties, with the aim of bringing new treatment options for these patients. TRIAL REGISTRATION: ISRCTN ISRCTN41478539 . Registered on 29 April 2015.

Symptom burden, quality of life, functioning and emotional distress in survivors of human papillomavirus associated oropharyngeal cancer: An Australian cohort.

BACKGROUND: This cross-sectional study examines patient-reported outcomes and functioning-based subgroups in human papillomavirus-associated oropharyngeal cancer survivors treated with chemoradiotherapy ≥12 months prior. METHOD: Survivors completed EORTC QLQ-C30, MDASI-HN and PROMIS-Emotional distress questionnaires. Subgroups were identified via two-step clustering of QLQ-C30 functioning scales. RESULTS: 136 patients were enrolled. Clinicians' graded 19/136 (14%) patients as having at least one severe (Grade 3 CTCAE) toxicity, whereas 68/136 (50%) patients self-reported at least one toxicity in the severe range (MDASI-HN ≥ 7). QLQ-C30 Global health status score (mean 76, SD = 20) was comparable to population norms. Rates of moderate/severe anxiety (10%/1%) and depression (4%/1%) were low. Two functioning-based subgroups were formed based on auto-clustering statistics: high- (n = 93) and low-functioning (n = 41). Differences on all functioning scales were large (d: 1.57-2.29), as were differences on the remaining QLQ-C30 scales/items, most MDASI-HN symptom severity/interference scales, and PROMIS scales (d: 0.80-2.03). Differences and associations with patient/clinical characteristics were not significant. CONCLUSION: In this Australian cohort of HPV-OPC survivors there was significant discordance between clinician- and patient-reported toxicity. We observed population comparable global quality of life and low rates of emotional distress. However, we identified a low-functioning subgroup reporting significantly worse outcomes on a range of patient-reported measures who may benefit from targeted support.

Fear of Cancer Recurrence in Survivors of Human Papillomavirus-Associated Oropharyngeal Carcinoma.

PURPOSE: To estimate the prevalence of and characteristics associated with fear of cancer recurrence (FCR) among human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) survivors. METHODS AND MATERIALS: We conducted a cross-sectional study in HPV-OPC survivors ≥12 months from completion of definitive (chemo)radiation therapy (RT/CRT). Eligible patients completed the Fear of Cancer Recurrence Inventory short-form (FCRI-SF), the European Organisation for research and Treatment of Cancer QLQ-C30, MD Anderson Symptom Inventory-Head and Neck, and PROMIS Anxiety and Depression short forms. Associations between FCRI-SF scores and other variables were investigated using linear regression models. RESULTS: A total of 136 HPV-OPC survivors were enrolled; the median age was 61 years (range, 42-87 years), 84% were male, 72% were currently partnered, 83% were current nonsmokers, 67% were regular alcohol consumers, and the median time since treatment was 2.8 years (range, 1.0-5.5 years). Clinical levels of FCR (≥13) were observed in 72 of 135 patients (53%; 95% confidence interval [CI], 45%-62%). Characteristics significantly associated with increasing FCR scores were younger age (-0.9/5 years; 95% CI, -1.7 to -0.01; P = .031), lower global quality of life (-0.8/10 unit increase; 95% CI, -1.4 to -0.2; P = .012), higher symptom interference (0.8/unit increase; 95% CI, 0.1-1.5; P = .017), and a higher burden of anxiety (0.4/unit; 95% CI, 0.3-0.5; P <.001) and depression (0.3/unit; 95% CI, 0.1-0.4; P <.001). Other sociodemographic tumor- and treatment-related characteristics were not statistically significant. Compared with patients reporting nonclinical levels of FCR, significantly more patients reporting clinical levels of FCR than expected believed professional psychological assistance would have been beneficial (60% vs 33%; P = .002). CONCLUSIONS: Clinical levels of FCR were observed in approximately half of the HPV-OPC survivors. Survivors reporting higher FCR were younger with worse self-reported global quality of life and higher symptom interference and emotional distress. No other patient, tumor, or treatment factors were associated with higher FCR.

Sexual Health and Interpersonal Relationships After Chemoradiation Therapy for Human Papillomavirus-Associated Oropharyngeal Cancer: A Cross-sectional Study.

PURPOSE: To examine sexual health, including sexual satisfaction, and perceived changes in relationships and sexual relationships of human papillomavirus (HPV) oropharyngeal cancer (OPC) survivors ≥12 months after (chemo)radiation therapy. METHODS AND MATERIALS: We undertook a cross-sectional study of HPV-OPC survivors who had completed treatment ≥12 months prior. Eligible patients completed the EORTC QLQ-SHQ22, a customized relationship questionnaire, the EORTC QLQ-C30, MDASI-HN, and PROMIS Anxiety and Depression scales. RESULTS: We enrolled 136 survivors (median age, 61 years [range, 42-87 years]; male, 84%; currently partnered, 72%). The median time from (chemo)radiation therapy completion was 2.8 years (range, 1.0-5.5 years). Most patients (71/131; 60%) reported an active sex life as important; however, only 20% (26/133) reported significant recent sexual activity ("quite a bit"/"very much"). The mean sexual satisfaction score was 47/100 (interquartile range, 27-67; standard deviation 28). On univariable analysis, greater sexual satisfaction was positively associated with greater importance of sexual activity, stronger libido, greater relationship security, and more erection confidence (males). Lower sexual satisfaction was significantly associated with female sex (P = .04), more medical comorbidities (P = .008), and more time since treatment completion (P = .006). Only a few patients reported a change in their marital status (10/136; 7%). The majority (62/109; 57%) of patients partnered at diagnosis reported no change in their precancer relationship. Among those reporting a change, it was more frequently perceived as positive (29/109; 27%) than negative (16/109; 15%). Regarding their sexual relationship, 54 of 107 (50%) reported no change, 40 of 107 (37%) reported a negative change, and 8 of 107 (7%) reported a positive change. CONCLUSIONS: Although an active sex life is important to many HPV-OPC survivors, fewer reported significant recent sexual activity. Sexual satisfaction scores were moderate in this cohort. Although recall bias was possible, most patients reported either no change or a positive change in their interpersonal relationship. Prospective studies evaluating sexual health outcomes and addressing informational needs in HPV-OPC survivors are needed.

Patient-reported quality of life and toxicity in unilateral and bilateral radiotherapy for early-stage human papillomavirus associated tonsillar carcinoma.

PURPOSE: The purpose of this study was to compare self-reported health-related quality of life (QoL) and symptom burden in early stage tonsillar carcinoma patients treated with unilateral (URT) and bilateral radiotherapy (BRT). METHODS AND MATERIALS: This is a secondary analysis of a larger study assessing patient reported outcomes in human papillomavirus (HPV) oropharyngeal cancer (OPC) patients. Recruited patients were ≥12 months from completion of radiotherapy. This analysis included only patients with T1-2, N1-2b tonsil cancer and excluded patients with base of tongue involvement or recurrent disease. QoL and patient reported toxicity was measured using the EORTC QLQ-C30 module and the MDASI-HN. RESULTS: Patients were enrolled from November 2018 to May 2019. Of the 136 patients recruited to the main study, 43 were eligible for this substudy (22 URT, 21 BRT), with a median age and follow up of 58.2 and 3.0 years respectively. The two groups were balanced with respect to patient, tumor and treatment factors with the exception of higher rates of T2 disease (27% v 71%, p = 0.006) and more extensive GTV nodal volumes (11.0 v 25.5cc, p = 0.006) in the BRT group.BRT patients had lower global health status/QoL (84 v 69, p = 0.0005) and social functioning scores (93 vs 78, p = 0.033) on the EORTC QLQ-C30, and higher symptom severity (0.6 vs. 2.0, p = 0.001) and symptom interference scores (0.8 vs. 2.0, p = 0.010) on the MDASI-HN. Four of the six largest differences observed on MDASI-HN items were attributable to radiotherapy technique (dry mouth, mucous, difficulty swallowing/chewing and taste), with corresponding dose differences to the respective organs (contralateral parotid, oral cavity and pharyngeal constrictors). In every instance, severity of symptoms was worse on average for patients treated with BRT. CONCLUSIONS: In the highly conformal radiotherapy era, BRT in early HPV tonsillar cancer survivors has an enduring impact on long-term QoL and toxicity.

Setting the stage: Contemporary staging of non-melanomatous skin cancer and implementation of the new American Joint Committee on cancer eighth edition staging manual.

Non-melanomatous skin cancer (NMSC) generally refers to basal cell and squamous cell carcinoma of the skin. The majority of patients are curatively treated with simple excision. Only few present with locally advanced disease or have evidence of high-risk features, placing them at an elevated risk of relapse. In such cases, further investigations may guide the multidisciplinary management plan. There are no universally agreed on indications for recommending additional staging investigations, due to a lack of prospective data reporting their impact on patient outcomes. Some generally agreed upon indications are discussed in this review article. Most commonly, computed tomography (CT) and magnetic resonance imaging (MR) are used in cases of locally advanced NMSC for staging purposes and surgical planning. While Positron Emission Tomography (PET)/CT and sentinel lymph node biopsy have shown utility, data is lacking to establish their roles in the staging algorithm. An updated NMSC system was included in The American Joint Committee for Cancer eighth edition staging manual (AJCC8). Under AJCC8 the majority of patients with regional disease are upstaged by the presence of extranodal extension, however, this updated system appears to provide limited prognostic discrimination between the nodal categories and the overall TNM stages. This review article will explore the contemporary role of staging investigations, including evolving technologies, and review the changes implemented in AJCC8. It will also discuss the implications of the AJCC8 decision to assign patients with p16-positive cervical nodal SCC with an unknown primary to the oropharyngeal staging system, with particular relevance to clinicians working in areas of high NMSC incidence.

Dose to medium in head and neck radiotherapy: Clinical implications for target volume metrics.

BACKGROUND AND PURPOSE: In radiotherapy dose calculation, advanced type-B dose calculation algorithms can calculate dose to medium (Dm ), as opposed to Type-B algorithms which compute dose to varying densities of water (Dw ). We investigate the impact of Dm on calculated dose and target coverage metrics in head and neck cancer patients. METHODS AND MATERIALS: We reviewed 27 successfully treated (disease free at two-years post-(chemo)radiotherapy) human papillomavirus-associated (HPV) oropharyngeal cancer (ONC) patients treated with IMRT. Doses were calculated with Type-B and Linear Boltzman Transport Equation (LBTE) algorithms in a commercial treatment planning system, with the treated multi-leaf collimator patterns and monitor units. Coverage for primary Gross Tumour Volume (GTVp), high dose Planning Target Volume (PTV) (PTV_High), mandible within PTV_High (Mand ∩ PTV) and PTV_High excluding bone (PTV-bone) were compared between the algorithms. RESULTS: Dose to 95% of PTV_High with LBTE was on average 1.1 Gy/1.7% lower than with Type-B (95%CI 1.5-1.9%, p < 0.0001). This magnitude was inversely linearly correlated with the relative volume of the PTV_High containing bone (pearson r = -0.81). Dose to 98% of the GTVp was 0.9 Gy/1.3% lower with LBTE compared with Type-B (95%CI 1.1-1.5%, p < 0.05). Dose to 98% of Mand ∩ PTV was on average 3.4 Gy/5.0% lower with LBTE than with Type-B (95%CI 4.6-5.4%, p < 0.0001). CONCLUSION: In OPC treated with IMRT, Dm results in significant reductions in dose to bone in high dose PTVs. Reported GTVp dose was reduced, but by a lower magnitude. Reduced coverage metrics should be expected for OPC patients treated with IMRT, with dose reductions limited to regions of bone.

Improving Pre-emptive Prescribing to Relieve Patient Discomfort Occurring Out of Hours.

Junior doctors are commonly asked to prescribe simple medications for symptom relief for patients out of hours. Unfortunately, time constraints and other pressures may lead to delays before the medications are prescribed. A quality improvement project was conducted at a large university teaching hospital to establish the extent of the problem, with the aim of finding measures to improve preemptive prescribing for patients. Baseline data was gathered over three busy wards to calculate the total of new prescriptions made over the course of a weekend. There were 24 new prescriptions required over the weekend, a percentage increase of 14.9% compared to the existing prescriptions on a Friday. Following the first intervention this decreased to 10.2%, and by the second intervention the rate was 4.9%. Data collected several months later confirmed that the interventions remained successful, and preemptive prescribing continued. Overall, our interventions have shown that the number of new prescriptions required out of hours can be reduced by educating junior doctors on preemptive prescribing.

Buying time: The use of extracorporeal membrane oxygenation as a bridge to lung transplantation in pediatric patients.

To describe our experience to date of four children with end-stage lung disease who have been bridged with ECMO to successful lung transplantation in our institution. Between March 2006 and June 2012, a total of 21 pediatric patients successfully underwent lung transplantation within The Alfred's lung transplantation program. This included four children who were bridged on ECMO prior to transplantation according to the "ECMO bridge to transplant" protocol and whose clinical notes and outcomes were reviewed. Lung transplantation is an established life-saving treatment for patients with severe lung disease, but remains limited due to scarcity of suitable donor organs. This is a particular issue in the pediatric setting, where the smaller child waits disproportionately longer compared with adult patients for size-matched donor lungs. As ECMO has become more widely accepted, its use as a bridge to lung transplantation in pediatric patients with severe acute lung injury or end-stage chronic lung disease has been considered. The medical notes from the four pediatric patients were retrospectively reviewed. Our report describes excellent short- and medium-term outcomes in a small number of children who have been bridged to transplant on ECMO.