The COVANOS trial - insight into post-COVID olfactory dysfunction and the role of smell training.

BACKGROUND: Olfactory dysfunction is a cardinal symptom of COVID-19 infection, however, studies assessing long-term olfactory dysfunction are limited and no randomised-controlled trials (RCTs) of early olfactory training have been conducted. METHODOLOGY: We conducted a prospective, multi-centre study consisting of baseline psychophysical measurements of smell and taste function. Eligible participants were further recruited into a 12-week RCT of olfactory training versus control (safety information). Patient-reported outcomes were measured using an electronic survey and BSIT at baseline and 12 weeks. An additional 1-year follow-up was open to all participants. RESULTS: 218 individuals with a sudden loss of sense of smell of at least 4-weeks were recruited. Psychophysical smell loss was observed in only 32.1%; 63 participants were recruited into the RCT. The absolute difference in BSIT improvement after 12 weeks was 0.45 higher in the intervention arm. 76 participants completed 1-year follow-up; 10/19 (52.6%) of participants with an abnormal baseline BSIT test scored below the normal threshold at 1-year, and 24/29 (82.8%) had persistent parosmia. CONCLUSIONS: Early olfactory training may be helpful, although our findings are inconclusive. Notably, a number of individuals who completed the 1-year assessment had persistent smell loss and parosmia at 1-year. As such, both should be considered important entities of long-Covid and further studies to improve management are highly warranted.

An app with brief behavioural support to promote physical activity after a cancer diagnosis (APPROACH): study protocol for a pilot randomised controlled trial.

BACKGROUND: There are multiple health benefits from participating in physical activity after a cancer diagnosis, but many people living with and beyond cancer (LWBC) are not meeting physical activity guidelines. App-based interventions offer a promising platform for intervention delivery. This trial aims to pilot a theory-driven, app-based intervention that promotes brisk walking among people living with and beyond cancer. The primary aim is to investigate the feasibility and acceptability of study procedures before conducting a larger randomised controlled trial (RCT). METHODS: This is an individually randomised, two-armed pilot RCT. Patients with localised or metastatic breast, prostate, or colorectal cancer, who are aged 16 years or over, will be recruited from a single hospital site in South Yorkshire in the UK. The intervention includes an app designed to encourage brisk walking (Active 10) supplemented with habit-based behavioural support in the form of two brief telephone/video calls, an information leaflet, and walking planners. The primary outcomes will be feasibility and acceptability of the study procedures. Demographic and medical characteristics will be collected at baseline, through self-report and hospital records. Secondary outcomes for the pilot (assessed at 0 and 3 months) will be accelerometer measured and self-reported physical activity, body mass index (BMI) and waist circumference, and patient-reported outcomes of quality of life, fatigue, sleep, anxiety, depression, self-efficacy, and habit strength for walking. Qualitative interviews will explore experiences of participating or reasons for declining to participate. Parameters for the intended primary outcome measure (accelerometer measured average daily minutes of brisk walking (≥ 100 steps/min)) will inform a sample size calculation for the future RCT and a preliminary economic evaluation will be conducted. DISCUSSION: This pilot study will inform the design of a larger RCT to investigate the efficacy and cost-effectiveness of this intervention in people LWBC. TRIAL REGISTRATION: ISRCTN registry, ISRCTN18063498 . Registered 16 April 2021.

Neoadjuvant Chemotherapy in Locally Advanced Cervical Carcinoma - a Role in Patients with Para-aortic Lymph Node Involvement? A 10-year Institutional Experience.

AIMS: Overall survival and progression-free survival with concomitant chemoradiotherapy for locally advanced cervical carcinoma have been described as 66% and 58%, respectively, at 5 years. Para-aortic lymph node involvement significantly increases the risk of relapse and death. The role of additional chemotherapy in these patients is as yet undefined. This aim of the present study was to determine the outcome of a cohort of para-aortic lymph node-positive patients treated with neoadjuvant chemotherapy followed by extended-field chemoradiation compared with patients treated with extended-field chemoradiation without neoadjuvant chemotherapy. MATERIALS AND METHODS: We reviewed patients with International Federation of Gynaecology and Obstetrics (FIGO) 2014 stage IB1-IVA cervical carcinoma who received extended-field radiotherapy in addition to standard pelvic chemoradiotherapy with or without neoadjuvant chemotherapy, at University College London Hospital (January 2007 to January 2018). Patients in open clinical trials were excluded. RESULTS: Overall, 47 patients (15.8% of 298 eligible patients) with pelvic and/or para-aortic lymph node-positive cervical carcinoma received extended-field radiotherapy. Nineteen patients (40.4%) had both neoadjuvant chemotherapy (all received six cycles) and extended-field radiotherapy (median 44 days); 28 (59.6%) patients received extended-field radiotherapy alone (median 43 days). All patients completed radical radiotherapy within 49 days. We observed evidence that patients receiving neoadjuvant chemotherapy and extended-field radiotherapy had a lower risk of death (median follow-up 4.8 years, three deaths) compared with extended-field radiotherapy alone (median follow-up 3.0 years, 11 deaths; hazard ratio = 0.27, 95% confidence interval 0.08-1.00; P = 0.05). Three-year overall survival rates were 83.3% (95% confidence interval 66.1-100) and 64.6% (95% confidence interval 44.6-84.6), respectively. A PFS benefit was seen (hazard ratio 0.25, 95% confidence interval 0.08-0.77; P = 0.02), with 3-year PFS rates of 77.8% (95% confidence interval 58.6-97.0) and 35.0% (95% confidence interval 14.0-56.0), respectively. CONCLUSIONS: Our institutional experience suggests that the use of additional systemic therapy before chemoradiotherapy benefits patients with locoregionally advanced (FIGO 2018 IIIC2) cervical cancer. Neoadjuvant chemotherapy was associated with longer overall survival and PFS, without compromising definitive extended-field chemoradiation.

Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial.

BACKGROUND: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial. PATIENTS AND METHODS: The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I-IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated. RESULTS: 177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) n = 163, intravenous (IV) MTX n = 2, prophylaxis type unknown n = 11 and IT MTX and cytarabine n = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolated n = 11, with systemic relapse n = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a 'high-risk' extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively. CONCLUSION: Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence. CLINICALTRIALS.GOV: ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34.

The Impact of Cardiac Radiation Dosimetry on Survival After Radiation Therapy for Non-Small Cell Lung Cancer.

PURPOSE: The 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 MATERIALS: Dosimetric 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. RESULTS: 38% 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. CONCLUSIONS: We 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.

Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial.

BACKGROUND: There is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19-88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients ≥60 years treated on the R-CHOP14v21 trial with extended follow-up. PATIENTS AND METHODS: Six hundred and four R-CHOP14v21 patients ≥60 years were included in this subgroup analysis, with a median follow-up of 77.7 months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N = 217) and RICOVER-60 (N = 204) trials. RESULTS: Elderly DLBCL patients received high dose intensities with median total doses of ≥98% for all agents. Toxicities were similar in both arms with the exception of more grade ≥3 neutropenia (P < 0.0001) and fewer grade ≥3 thrombocytopenia (P = 0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65-73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR = 1.96; 95% CI: 1.22-3.16; P = 0.01) and DHL (HR = 2.21; 95% CI: 1.18-4.11; P = 0.01) on OS in the combined trial cohorts, independent of other prognostic factors. CONCLUSIONS: Our data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches. TRIAL NUMBERS: ISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).

Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control.

BACKGROUND: In stage III colon cancer, oxaliplatin/5-fluorouracil (5-FU)-based adjuvant chemotherapy (FOLFOX) improves disease-free survival (DFS) and overall survival (OS). In rectal adenocarcinoma following neoadjuvant chemoradiation (CRT), we examined the benefit of postoperative adjuvant capecitabine and oxaliplatin (XELOX) chemotherapy. METHODS: Eligible patients were randomly assigned following fluoropyrimidine-based CRT and curative resection to observation or six cycles of XELOX. The primary end point was DFS; secondary end points were acute toxicity and OS. 390 patients were required in each arm, to detect an improvement in 3-year DFS from 40% to 50.5%, with 85% power and two-sided 5% significance level. RESULTS: The study closed prematurely in 2008 because of poor accrual. Only 113 patients were randomly assigned to either observation (n = 59) or XELOX (n = 54). Compliance was poor, 93% allocated chemotherapy started and 48% completed six cycles. Protocolised dose reductions in XELOX were 39%, and levels of G3/G4 toxicity 40%. After a median follow-up of 44.8 months, 16 patients (27%) in the observation arm had relapsed or died compared with 12 patients (22%) in XELOX. The 3-year DFS rate was 78% with XELOX and 71% with observation [hazard ratio (HR) for DFS = 0.80; 95% confidence interval (CI) 0.38-1.69; P = 0.56]. The 3-year OS for XELOX and observation were 89% and 88%, respectively (HR for OS = 1.18; 95% CI 0.43-3.26; P = 0.75). CONCLUSIONS: The observed improvement in DFS for adjuvant XELOX and similar OS were not statistically significant, as expected given the small number of patients and consequent low power. Our findings support the need for trials that test the role of neoadjuvant chemotherapy. CLINICALTRIALSGOV IDENTIFIER: NCT00427713.

Platinum versus platinum-combination chemotherapy in platinum-sensitive recurrent ovarian cancer: a meta-analysis using individual patient data.

BACKGROUND: The majority of women with ovarian cancer develop recurrent disease. For patients with a platinum-free interval of >6 months, platinum-based chemotherapy is a treatment of choice. The benefit of platinum-based combination chemotherapy in randomized trials varies, and a meta-analysis was carried out to gain more secure information on the size of the benefit of this treatment. MATERIALS AND METHODS: We initiated a systematic review and meta-analysis following a pre-specified protocol to determine whether combination chemotherapy is superior to single-agent platinum chemotherapy in women with relapsed platinum-sensitive ovarian cancer. RESULTS: A total of five potentially eligible randomized trials were identified that had used combination-platinum chemotherapy versus single-agent platinum chemotherapy in women with relapsed platinum-sensitive ovarian cancer. For one trial (190 patients), adequate contact with the investigators could not be established. Therefore, four trials that randomly assigned 1300 patients were included, with a median follow-up of 36.1 months. Overall survival (OS) analyses were based on 865 deaths and demonstrated evidence for the benefit of combination-platinum chemotherapy (HR = 0.80; 95% CI, 0.64-1.00; P = 0.05). Progression-free survival (PFS) analyses were based on 1167 events and demonstrated strong evidence for the benefit of combination-platinum chemotherapy (HR = 0.68; 95% CI, 0.57-0.81; P < 0.001). There was no evidence of a difference in the relative effect of combination-platinum chemotherapy on either OS or PFS in patient subgroups defined by previous paclitaxel (Taxol) treatment (OS, P = 0.49; PFS, P = 0.66), duration of treatment-free interval (OS, P = 0.86; PFS, P = 0.48) or the number of previous lines of chemotherapy (OS, P = 0.21; PFS, P = 0.27). CONCLUSIONS: In this individual patient data (IPD) meta-analysis, we have demonstrated that combination-platinum chemotherapy improves OS and PFS across all subgroups. This provides the strongest evidence to date of the benefit of combination-platinum over single-agent platinum.

Phase II study of gemcitabine and bexarotene (GEMBEX) in the treatment of cutaneous T-cell lymphoma.

BACKGROUND: Both gemcitabine and bexarotene are established single agents for the treatment of cutaneous T-cell lymphoma (CTCL). We investigated the feasibility and efficacy of combining these drugs in a single-arm phase II study. METHODS: Cutaneous T-cell lymphoma patients who had failed standard skin-directed therapy and at least one prior systemic therapy were given four cycles of gemcitabine and concurrent bexarotene for 12 weeks. Responders were continued on bexarotene maintenance until disease progression or unacceptable toxicity. RESULTS: The median age was 65 years, stage IB (n=5), stage IIA (n=2), stage IIB (n=8), stage III (n=8) and stage IVA (n=12), 17 patients were erythrodermic, 17 patients were B1, and 10 patients were both erythrodermic and B1. Thirty (86%) patients completed four cycles of gemcitabine. In all, 80.0% of patients demonstrated a reduction in modified Severity-Weighted Assessment Tool (mSWAT) score although the objective disease response rate at 12 weeks was 31% (partial response (PR) 31%) and at 24 weeks 14% (PR 14%, stable disease (SD) 23%, progressive disease (PD) 54%, not evaluable 9%). Median progression-free survival was 5.3 months and median overall survival was 21.2 months. CONCLUSION: The overall response rate of the combination did not reach the specified target to proceed further and is lower than that previously reported for gemcitabine as a single agent.

Modelling psychiatric measures using Skew-Normal distributions.

Data from psychiatric research frequently exhibit departures from Normality. Methods which utilise the data optimally to model the distribution directly are available. We highlight the issue of modelling skewness, resulting from screening instruments where the majority of respondents are healthy individuals and few participants have a value reflecting particular disorders.