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.

Ayurvedic versus conventional dietary and lifestyle counseling for mothers with burnout-syndrome: A randomized controlled pilot study including a qualitative evaluation.

OBJECTIVES: Ayurveda claims to be effective in the treatment of psychosomatic disorders by means of lifestyle and nutritional counseling. DESIGN: In a randomized controlled study mothers with burnout were randomized into two groups: Ayurvedic nutritional counseling (according to tradition), and conventional nutritional counseling (following the recommendations of a family doctor). Patients received five counseling sessions over twelve weeks. MAIN OUTCOME MEASURES: Outcomes included levels of burnout, quality of life, sleep, stress, depression/anxiety, and spirituality at three and six months. It also included a qualitative evaluation of the communication processes. RESULTS: We randomized thirty four patients; twenty three participants were included in the per protocol analysis. No significant differences were observed between the groups. However, significant and clinically relevant intra-group mean changes for the primary outcome burnout, and secondary outcomes sleep, stress, depression and mental health were only found in the Ayurveda group. The qualitative part of the study identified different conversational styles and counseling techniques between the two study groups. In conventional consultations questions tended to be category bound, while counseling-advice was predominantly admonitory. The Ayurvedic practitioner used open-ended interrogative forms, devices for displaying understanding, and positive re-evaluation more frequently, leading to an overall less asymmetrical interaction. CONCLUSIONS: We found positive effects for both groups, which however were more pronounced in the Ayurvedic group. The conversational and counseling techniques in the Ayurvedic group offered more opportunities for problem description by patients as well as patient-centered practice and resource-oriented recommendations by the physician. TRIAL REGISTRATION: NCT01797887.

Interpreting small treatment differences from quality of life data in cancer trials: an alternative measure of treatment benefit and effect size for the EORTC-QLQ-C30.

BACKGROUND: The EORTC-QLQ-C30 is a widely used health related quality of life (HRQoL) questionnaire in lung cancer patients. Small HRQoL treatment effects are often reported as mean differences (MDs) between treatments, which are rarely justified or understood by patients and clinicians. An alternative approach using odds ratios (OR) for reporting effects is proposed. This may offer advantages including facilitating alignment between patient and clinician understanding of HRQoL effects. METHODS: Data from six CRUK sponsored randomized controlled lung cancer trials (2 small cell and 4 in non-small cell, in 2909 patients) were used to HRQoL effects. Results from Beta-Binomial (BB) standard mixed effects were compared. Preferences for ORs vs MDs were determined and Time to Deterioration (TD) was also compared. RESULTS: HRQoL effects using ORs offered coherent interpretations: MDs >0 resulted in ORs >1 and vice versa; effect sizes were classified as 'Trivial' if the OR was between 1 ± 0.05 (i.e. 0.95 to 1.05); 'Small': for 1 ± 0.1; 'Medium': 1 ± 0.2 and 'Large': OR <0.8 or >1.20. Small HRQoL effects on the MD scale may translate to important treatment differences on the OR scale: for example, a worsening in symptoms (MD) by 2.6 points (p = 0.1314) would be a 17 % deterioration (p < 0.0001) with an OR. Hence important differences may be missed with MD; conversely, small ORs are unlikely to yield large MDs because methods based on OR model skewed data well. Initial evidence also suggests oncologists prefer ORs over MDs since interpretation is similar to hazard ratios. CONCLUSION: Reporting HRQoL benefits as MDs can be misleading. Estimates of HRQoL treatment effects in terms of ORs are preferred over MDs. Future analysis of QLQ-C30 and other HRQoL measures should consider reporting HRQoL treatment effects as ORs.

[Repeated cold water stimulations (hydrotherapy according to Kneipp) in patients with COPD]. / Serielle Kaltwasserreize (Kneipp'scher Oberguss) bei Patienten mit chronisch obstruktiver Bronchitis (COPD).

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often suffer from exacerbations caused by infections of the bronchial tract. OBJECTIVE: What effects do hydrotherapeutic applications according to Kneipp have on lung function, blood gases, immune system and quality of life of patients with COPD? PATIENTS AND METHODS: 20 patients with COPD (17 males, 3 females); mean age: 64; forced expiratory volume (FEV1): 62 of 100% (on average); no acute exacerbations, no oral corticosteroids. Measurements were performed (I) at 10 weeks pre-treatment, (II) immediately before therapy (I-II: baseline-period), (III) after 10 weeks treatment with 3 cold affusions and 2 cold washings of the upper part of the body (self-treatment) per week each, (IV) 3 months after completion of the treatment (follow- up). The following parameters were measured: lung function, blood gases, routine lab, experimental lab (interleukines, lymphocytes), maximal expiratory flow (PEF), quality of life and respiratory infections. RESULTS: The pH increased over the course of the study. PEF and the number of lymphocytes significantly increased over the treatment (II-III). Intracellular expression of IL-4 by T lymphocytes decreased. However, the expression of IFN-gamma increased. Frequency of infections was lower during follow-up (IV) than before and during therapy. Quality of life after treatment was estimated to be good in all patients. CONCLUSIONS: Repeated cold stimulations (affusions) can influence the frequency of respiratory infections and improve subjective well-being. It may cause an immunological modulation in terms of the Th1-type pattern.

Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study.

UNLABELLED: A 3-year prospective, randomized, placebo-controlled trial of oral clodronate 800 mg showed that the incidence of clinical fractures was decreased by 20% in 5596 elderly women unselected for osteoporosis. The effect occurred in the absence of systematic calcium and vitamin D supplementation and was observed across a wide range of BMDs. INTRODUCTION: To date, most studies with bisphosphonates have reported on their use in individuals selected to be at high risk for fracture usually by the presence of low BMD or a prior fragility fracture, usually of the spine. We wished to determine the effect of the bisphosphonate, clodronate, on the rate of fractures in women > or =75 years of age living in the community. MATERIALS AND METHODS: Women > or =75 years of age living in the general community in South Yorkshire and North Derbyshire, identified from general practice registers, were recruited by letter of invitation to a randomized, double-blind, controlled trial of 800 mg oral clodronate (Bonefos) or matching placebo daily over 3 years. The main outcomes were the incidences of hip and any clinical fracture. RESULTS: Of the 5579 elderly women included in the intention-to-treat analysis of efficacy, 114 had a new hip fracture during the 3-year treatment phase: 56 (2.0%) women in the clodronate group and 58 (2.1%) women in the placebo group (hazard ration [HR], 1.02; 95% CI, 0.71-1.47). Clodronate did, however, decrease the incidence of any clinical fracture by 20% (264 women [9.5%] versus 337 [12.1%] in the placebo group; HR, 0.80; 95% CI, 0.68-0.94). The incidence of osteoporosis-associated nonhip fractures was also significantly decreased by 29% (5.2% versus 7.4%; HR, 0.71; 95% CI, 0.57-0.87). The ability of clodronate to reduce the risk of osteoporotic fracture was independent of baseline BMD, but the number needed-to-treat was lower in the presence of osteoporosis. CONCLUSIONS: Oral daily clodronate can prevent fractures without significant adverse effects in elderly women living in the general community. The effect on hip fracture risk is not significant, but an effect similar to that at other nonvertebral sites cannot be excluded. This study suggests that antiresorptive therapies can reduce fracture incidence in high-risk individuals even in the presence of a normal or osteopenic BMD.