Intensive care doctors' preferences for arterial oxygen tension levels in mechanically ventilated patients.

BACKGROUND: Oxygen is liberally administered in intensive care units (ICUs). Nevertheless, ICU doctors' preferences for supplementing oxygen are inadequately described. The aim was to identify ICU doctors' preferences for arterial oxygenation levels in mechanically ventilated adult ICU patients. METHODS: In April to August 2016, an online multiple-choice 17-part-questionnaire was distributed to 1080 ICU doctors in seven Northern European countries. Repeated reminder e-mails were sent. The study ended in October 2016. RESULTS: The response rate was 63%. When evaluating oxygenation 52% of respondents rated arterial oxygen tension (PaO2 ) the most important parameter; 24% a combination of PaO2 and arterial oxygen saturation (SaO2 ); and 23% preferred SaO2 . Increasing, decreasing or not changing a default fraction of inspired oxygen of 0.50 showed preferences for a PaO2 around 8 kPa in patients with chronic obstructive pulmonary disease, a PaO2 around 10 kPa in patients with healthy lungs, acute respiratory distress syndrome or sepsis, and a PaO2 around 12 kPa in patients with cardiac or cerebral ischaemia. Eighty per cent would accept a PaO2 of 8 kPa or lower and 77% would accept a PaO2 of 12 kPa or higher in a clinical trial of oxygenation targets. CONCLUSION: Intensive care unit doctors preferred PaO2 to SaO2 in monitoring oxygen treatment when peripheral oxygen saturation was not included in the question. The identification of PaO2 as the preferred target and the thorough clarification of preferences are important when ascertaining optimal oxygenation targets. In particular when designing future clinical trials of higher vs lower oxygenation targets in ICU patients.

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.

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).

Establishment of a UK-wide network to facilitate the acquisition of quality assured FDG-PET data for clinical trials in lymphoma.

BACKGROUND: Multicentre trials are required to determine how [fluorine-18]-2-fluoro-2-deoxy-D-glucose-positron emission tomography imaging can guide cancer treatment. Consistency in quality control (QC), scan acquisition and reporting is mandatory for high-quality results, which are comparable across sites. METHODS: A national positron emission tomography (PET) clinical trials network (CTN) has been set up with a 'core laboratory' to coordinate QC and interpret scans. The CTN is involved in trials in Hodgkin's lymphoma [Randomised Phase III trial to determine the role of FDG-PET Imaging in Clinical Stages IA/IIA Hodgkin's Disease (RAPID) and Randomised Phase III trial to assess response adapted therapy using FDG-PET imaging in patients with newly diagnosed, advanced Hodgkin lymphoma (RATHL)] and diffuse large B-cell lymphoma [Blinded evaluation of prognostic value of FDG-PET after 2 cycles of chemotherapy in diffuse large B-cell Non-Hodgkins Lymphoma, a sub-study of the R-CHOP-21 vs R-CHOP-14 trial (R-CHOP PET substudy)]. Approval to join requires scanner validation and agreement to follow a standard QC protocol. Scans are transferred to the core laboratory and reported centrally according to predetermined criteria. RESULTS: The qualification procedure was carried out on 15 scanners. All scanners were able to demonstrate the necessary quantitative accuracy, and following modification of image reconstruction where necessary, scanners demonstrated comparable recovery coefficients (RCs) indicating similar performance. The average RC (±1 standard deviation) was 0.56 ± 0.095 for the 13-mm sphere. Reports from 444 of 473 (94%) patients in RAPID and 67 of 73 (92%) patients in RATHL were available for randomisation of therapy. CONCLUSIONS: The CTN has enabled consistent quality assured PET results to be obtained from multiple centres in time for clinical decision making. The results of trials will be significantly strengthened by this system.

A phase III trial comparing CHOP to PMitCEBO with or without G-CSF in patients aged 60 plus with aggressive non-Hodgkin's lymphoma.

The management of older patients with aggressive non-Hodgkin's lymphoma presents a challenge to the physician. Age is a poor prognostic indicator, due to reduced ability to tolerate and maintain dose-intensive chemotherapy. Generally, older patients demonstrate a lower response rate, reduced survival and increased toxicity, although the majority of large randomised trials exclude older patients. This randomised trial was conducted in patients 60 years or over to compare CHOP (cyclophosphamide 750 mg m(-2), doxorubicin 50 mg m(-2), vincristine 1.4 mg m(-2), prednisolone 100 mg) with PMitCEBO (mitoxantrone 7 mg m(-2), cyclophosphamide 300 mg m(-2), etoposide 150 mg m(-2), vincristine 1.4 mg m(-2), bleomycin 10 mg m(-2) and prednisolone 50 mg). Due to the myelosuppressive nature of these regimens, patients were also randomised to the addition of G-CSF. The formal results of this trial with long-term follow-up are now reported. Data were analysed to assess efficacy and toxicity. Overall response rate was 84% in the CHOP arm and 83% in the PMitCEBO arm, with overall response rates of 83% for the use of G-CSF and 84% for no G-CSF. At median 44 months follow-up, there was no significant difference in failure-free, progression-free or overall survival between the CHOP and PMitCEBO arms. At 3 years, the actuarial failure-free survival was 44% in CHOP recipients and 42% in PMitCEBO recipients and the 3-year actuarial overall survival was 46% and 45% respectively. There was no significant difference in the failure-free, progression-free or overall survival with the addition of G-CSF.

Effectiveness and cost-effectiveness of prognostic markers in prostate cancer.

This paper demonstrates how economic modelling can be used to derive estimates of the cost-effectiveness of prognostic markers in the management of clinically localised and moderately graded prostate cancer. The model uses a Markov process and is populated using published evidence and local data. The robustness of the results has been tested using sensitivity analysis. Three treatment policies of 'monitoring' (observation), radical prostatectomy, or a selection-based management policy using DNA-ploidy as an experimental marker, have been evaluated. Modelling indicates that a policy of managing these tumours utilising experimental markers has an estimated cost per quality-adjusted life year (QALY) of pound 12 068. Sensitivity analysis shows the results to be relatively sensitive to quality-of-life variables. If novel and experimental markers can achieve specificity in excess of 80%, then a policy of radical surgery for those identified as being at high risk and conservative treatment for the remainder would be both better for patients and cost-effective. The analysis suggests that a radical prostatectomy treatment policy for the moderately graded tumours (Gleason grades -7) modelled in this paper may be inferior to a conservative approach in the absence of reliable prognostic markers, being both more costly and yielding fewer QALYs.