The Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) burden of care study: Analysis of local treatments for lung metastases and systemic chemotherapy in 220 patients in the PulMiCC cohort.

AIM: The aim of this work was to examine the burden of further treatments in patients with colorectal cancer following a decision about lung metastasectomy. METHOD: Five teams participating in the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) study provided details on subsequent local treatments for lung metastases, including the use of chemotherapy. For patients in three groups (no metastasectomy, one metastasectomy or multiple local interventions), baseline factors and selection criteria for additional treatments were examined. RESULTS: The five teams recruited 220 patients between October 2010 and January 2017. No lung metastasectomy was performed in 51 patients, 114 patients had one metastasectomy and 55 patients had multiple local interventions. Selection for initial metastasectomy was associated with nonelevated carcinoembryonic antigen, fewer metastases and no prior liver metastasectomy. These patients also had better Eastern Cooperative Oncology Group scores and lung function at baseline. Four sites provided information on chemotherapy in 139 patients: 79 (57%) had one to five courses of chemotherapy, to a total of 179 courses. The patterns of survival after one or multiple metastasectomy interventions showed evidence of guarantee-time bias contributing to an impression of benefit over no metastasectomy. After repeated metastasectomy, a significantly higher risk of death was observed, with no apparent reduction in chemotherapy usage. CONCLUSION: Repeated metastasectomy is associated with a higher risk of death without reducing the use of chemotherapy. Continued monitoring without surgery might reassure patients with indolent disease or allow response assessment during systemic treatment. Overall, the carefully collected information from the PulMICC study provides no indication of an important survival benefit from metastasectomy.

Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial.

BACKGROUND: Lung metastasectomy in the treatment of advanced colorectal cancer has been widely adopted without good evidence of survival or palliative benefit. We aimed to test its effectiveness in a randomised controlled trial (RCT). METHODS: Multidisciplinary teams in 13 hospitals recruited participants with potentially resectable lung metastases to a multicentre, two-arm RCT comparing active monitoring with or without metastasectomy. Other local or systemic treatments were decided by the local team. Randomisation was remote and stratified by site with minimisation for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, the number of metastases, and carcinoembryonic antigen level. The central Trial Management Group were blind to patient allocation until completion of the analysis. Analysis was on intention to treat with a margin for non-inferiority of 10%. RESULTS: Between December 2010 and December 2016, 65 participants were randomised. Characteristics were well-matched in the two arms and similar to those in reported studies: age 35 to 86 years (interquartile range (IQR) 60 to 74); primary resection IQR 16 to 35 months previously; stage at resection T1, 2 or 3 in 3, 8 and 46; N1 or N2 in 31 and 26; unknown in 8. Lung metastases 1 to 5 (median 2); 16/65 had previous liver metastases; carcinoembryonic antigen normal in 55/65. There were no other interventions in the first 6 months, no crossovers from control to treatment, and no treatment-related deaths or major adverse events. The Hazard ratio for death within 5 years, comparing metastasectomy with control, was 0.82 (95%CI 0.43, 1.56). CONCLUSIONS: Because of poor and worsening recruitment, the study was stopped. The small number of participants in the trial (N = 65) precludes a conclusive answer to the research question given the large overlap in the confidence intervals in the proportions still alive at all time points. A widely held belief is that the 5-year absolute survival benefit with metastasectomy is about 35%: 40% after metastasectomy compared to < 5% in controls. The estimated survival in this study was 38% (23-62%) for metastasectomy patients and 29% (16-52%) in the well-matched controls. That is the new and important finding of this RCT. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT01106261. Registered on 19 April 2010.

Patterns of peripheral joint involvement in psoriatic arthritis-Symmetric, ray and/or row?

OBJECTIVE: We sought to examine whether joint involvement in psoriatic arthritis (PsA) follows a symmetric, ray, and/or row pattern using longitudinal data. METHODS: Data on activity and clinical damage of the joints of the hands and feet were obtained from a PsA cohort. For each analysis (symmetry, ray or row) for each outcome (joint damage and activity) expected values for table cells under the null hypothesis that joints progress independently to damage or activity were calculated based on a logistic regression model with patient level random effects for the probability of involvement developing between clinic visits. To determine the consistency of observed with expected values, goodness-of-fit tests were performed. RESULTS: Data from 704 patients were available. The 511 (552) patients with no hand (foot) damage at clinic entry were used for analyses of hand (foot) damage. When considering joint damage, there was strong evidence against independence of joint involvement based on evident symmetric patterns. There was little suggestion of ray patterns of joint damage. There was considerable evidence for row pattern of involvement of joints. When considering joint activity, symmetric patterns were also evident but, unlike joint damage, there was evidence of ray patterns, most notably in the hands. There was also evidence for row pattern involvement. CONCLUSION: Patterns of peripheral joint involvement seen over time in PsA patients, demonstrate consistency with expected ray patterns of disease activity, especially in the hands, but there is also considerable evidence for symmetric and row patterns for both joint damage and activity.

Major Greenwood (1880-1949): the biography.

Background is provided on the discovery of an unpublished biography of Major Greenwood written by one of his sons. The motivation and preparation for online publication of the biography in Statistics in Medicine are outlined. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Major Greenwood (1880-1949): a biographical and bibliographical study.

Major Greenwood was the foremost medical statistician of the first half of the 20th century in the U.K. Trained in both medicine and statistics, his career extended over 45 years during which he published eight books, 23 extensive reports and over 200 papers. His classical education extended to Latin and Greek, and he was fluent in German and French. We provide an overview of his life including family background, training and his career subdivided according to the places where he worked. We describe in particular the key role he played with others in the development of medical statistics within the Medical Research Council, the General Register Office, the Department of Health and the Universities.

Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial.

OBJECTIVE: To determine whether intensive combinations of synthetic disease modifying drugs can achieve similar clinical benefits at lower costs to high cost biologics such as tumour necrosis factor inhibitors in patients with active rheumatoid arthritis resistant to initial methotrexate and other synthetic disease modifying drugs. DESIGN: Open label pragmatic randomised multicentre two arm non-inferiority trial over 12 months. SETTING: 24 rheumatology clinics in England. PARTICIPANTS: Patients with rheumatoid arthritis who were eligible for treatment with tumour necrosis factor inhibitors according to current English guidance were randomised to either the tumour necrosis factor inhibitor strategy or the combined disease modifying drug strategy. INTERVENTIONS: Biologic strategy: start tumour necrosis factor inhibitor; second biologic in six month for non-responders. Alternative strategy: start combination of disease modifying drugs; start tumour necrosis factor inhibitors after six months in non-responders. PRIMARY OUTCOME: reduction in disability at 12 months measured with patient recorded heath assessment questionnaire (range 0.00-3.00) with a 0.22 non-inferiority margin for combination treatment versus the biologic strategy. SECONDARY OUTCOMES: quality of life, joint damage, disease activity, adverse events, and costs. Intention to treat analysis used multiple imputation methods for missing data. RESULTS: 432 patients were screened: 107 were randomised to tumour necrosis factor inhibitors and 101 started taking; 107 were randomised to the combined drug strategy and 104 started taking the drugs. Initial assessments were similar; 16 patients were lost to follow-up (seven with the tumour necrosis factor inhibitor strategy, nine with the combined drug strategy); 42 discontinued the intervention but were followed-up (19 and 23, respectively). The primary outcome showed mean falls in scores on the health assessment questionnaire of -0.30 with the tumour necrosis factor inhibitor strategy and -0.45 with the alternative combined drug strategy. The difference between groups in unadjusted linear regression analysis favoured the alternative strategy of combined drugs. The mean difference was -0.14, and the 95% confidence interval (-0.29 to 0.01) was below the prespecified non-inferiority boundary of 0.22. Improvements at 12 months in secondary outcomes, including quality of life and erosive progression, were similar with both strategies. Initial reductions in disease activity were greater with the biologic strategy, but these differences did not persist beyond six months. Remission was seen in 72 patients (44 with biologic strategy; 36 with alternative strategy); 28 patients had serious adverse events (18 and 10, respectively); six and 10 patients, respectively, stopped treatment because of toxicity. The alternative strategy reduced health and social care costs per patient by £3615 (€4930, $5585) for months 0-6 and £1930 for months 6-12. CONCLUSIONS: In patients with active rheumatoid arthritis who meet English criteria for biologics an alternative strategy with combinations of intensive synthetic disease modifying drugs gives non-inferior outcomes to treatment with tumour necrosis factor inhibitors. Costs are reduced substantially.Trial Registration ISRCTN 37438295.

Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort.

BACKGROUND AND AIMS: We studied damage accrual and factors determining development and progression of damage in an international cohort of systemic lupus erythematosus (SLE) patients. METHODS: The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort recruited patients within 15 months of developing four or more 1997 American College of Rheumatology (ACR) criteria for SLE; the SLICC/ACR damage index (SDI) was measured annually. We assessed relative rates of transition using maximum likelihood estimation in a multistate model. The Kaplan-Meier method estimated the probabilities for time to first increase in SDI score and Cox regression analysis was used to assess mortality. RESULTS: We recruited 1722 patients; mean (SD) age 35.0 (13.4) years at cohort entry. Patients with damage at enrolment were more likely to have further worsening of SDI (SDI 0 vs ≥1; p<0.001). Age, USA African race/ethnicity, SLEDAI-2K score, steroid use and hypertension were associated with transition from no damage to damage, and increase(s) in pre-existing damage. Male gender (relative transition rates (95% CI) 1.48 (1.06 to 2.08)) and USA Caucasian race/ethnicity (1.63 (1.08 to 2.47)) were associated with SDI 0 to ≥1 transitions; Asian race/ethnicity patients had lower rates of new damage (0.60 (0.39 to 0.93)). Antimalarial use was associated with lower rates of increases in pre-existing damage (0.63 (0.44 to 0.89)). Damage was associated with future mortality (HR (95% CI) 1.46 (1.18 to 1.81) per SDI point). CONCLUSIONS: Damage in SLE predicts future damage accrual and mortality. We identified several potentially modifiable risk factors for damage accrual; an integrated strategy to address these may improve long-term outcomes.

Randomised controlled trial of tumour necrosis factor inhibitors against combination intensive therapy with conventional disease-modifying antirheumatic drugs in established rheumatoid arthritis: the TACIT trial and associated systematic reviews.

BACKGROUND: Rheumatoid arthritis (RA) is initially treated with methotrexate and other disease-modifying antirheumatic drugs (DMARDs). Active RA patients who fail such treatments can receive tumour necrosis factor inhibitors (TNFis), which are effective but expensive. OBJECTIVE: We assessed whether or not combination DMARDs (cDMARDs) give equivalent clinical benefits at lower costs in RA patients eligible for TNFis. DESIGN: An open-label, 12-month, pragmatic, randomised, multicentre, two-arm trial [Tumour necrosis factor inhibitors Against Combination Intensive Therapy (TACIT)] compared these treatment strategies. We then systematically reviewed all comparable published trials. SETTING: The TACIT trial involved 24 English rheumatology clinics. PARTICIPANTS: Active RA patients eligible for TNFis. INTERVENTIONS: The TACIT trial compared cDMARDs with TNFis plus methotrexate or another DMARD; 6-month non-responders received (a) TNFis if in the cDMARD group; and (b) a second TNFi if in the TNFi group. MAIN OUTCOME MEASURES: The Heath Assessment Questionnaire (HAQ) was the primary outcome measure. The European Quality of Life-5 Dimensions (EQ-5D), joint damage, Disease Activity Score for 28 Joints (DAS28), withdrawals and adverse effects were secondary outcome measures. Economic evaluation linked costs, HAQ changes and quality-adjusted life-years (QALYs). RESULTS: In total, 432 patients were screened; 104 started on cDMARDs and 101 started on TNFis. The initial demographic and disease assessments were similar between the groups. In total, 16 patients were lost to follow-up (nine in the cDMARD group, seven in the TNFi group) and 42 discontinued their intervention but were followed up (23 in the cDMARD group and 19 in the TNFi group). Intention-to-treat analysis with multiple imputation methods used for missing data showed greater 12-month HAQ score reductions with initial cDMARDs than with initial TNFis [adjusted linear regression coefficient 0.15, 95% confidence interval (CI) -0.003 to 0.31; p = 0.046]. Increases in 12-month EQ-5D scores were greater with initial cDMARDs (adjusted linear regression coefficient -0.11, 95% CI -0.18 to -0.03; p = 0.009) whereas 6-month changes in HAQ and EQ-5D scores and 6- and 12-month changes in joint damage were similar between the initial cDMARD group and the initial TNFi group. Longitudinal analyses (adjusted general estimating equations) showed that the DAS28 was lower in the initial TNFi group in the first 6 months (coefficient -0.63, 95% CI -0.93 to -0.34; p < 0.001) but there were no differences between the groups in months 6-12. In total, 36 patients in the initial cDMARD group and 44 in the initial TNFi group achieved DAS28 remission. The onset of remission did not differ between groups (p = 0.085 on log-rank test). In total, 10 patients in the initial cDMARD group and 18 in the initial TNFi group experienced serious adverse events; stopping therapy because of toxicity occurred in 10 and six patients respectively. Economic evaluation showed that the cDMARD group had similar or better QALY outcomes than TNFi with significantly lower costs at 6 and 12 months. In the systematic reviews we identified 32 trials (including 20-1049 patients) on early RA and 19 trials (including 40-982 patients) on established RA that compared (1) cDMARDs with DMARD monotherapy; (2) TNFis/methotrexate with methotrexate monotherapy; and (3) cDMARDs with TNFis/methotrexate. They showed that cDMARDs and TNFis had similar efficacies and toxicities. CONCLUSIONS: Active RA patients who have failed methotrexate and another DMARD achieve equivalent clinical benefits at a lower cost from starting cDMARDs or from starting TNFis (reserving TNFis for non-responders). Only a minority of patients achieve sustained remission with cDMARDs or TNFis; new strategies are needed to maximise the frequency of remission. TRIAL REGISTRATION: Current Control Trials ISRCTN37438295. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 66. See the NIHR Journals Library website for further project information.

Major Greenwood's early career and the first departments of medical statistics.

Major Greenwood was the foremost medical statistician of the first half of the 20th century in the UK and is often credited with founding the first department of medical statistics at the Lister Institute in London in 1910. Here, we examine in detail his career prior to this appointment, including his association with Karl Pearson. We also examine the remit of the Department of Medical Statistics at the London Hospital of which he was the founding Director in 1908, some 2 years earlier than his appointment at the Lister Institute. Supporting information consisting of further details about Major Greenwood's early career, biographical articles and obituaries for him, and a list of his publications to 1910 by year, is also provided.

Commentary: Dr John Brownlee MA, MD, DSc, DPH (Cantab), FRFPS, FSS, FRMetS (1868-1927), public health officer, geneticist, epidemiologist and medical statistician.

In July 1914 Dr John Brownlee was appointed head of the Statistical Department of the newly established Medical Research Committee. He had qualified in mathematics, natural philosophy and medicine at the University of Glasgow, and by 1914 had established a reputation as a public health officer, an expert in infectious diseases, and as a proponent of the Pearsonian school of the application of statistics and mathematics to medicine: an ideal background for his new position. In celebration of the centenary anniversary of the Medical Research Council and as a tribute to John Brownlee's involvement at the start, the International Journal of Epidemiology is reprinting in this issue one of his early papers on genetics. We comment on this paper, as well as Brownlee's background, achievements, research and his somewhat enigmatic though likeable character.

Hilda Mary Woods MBE, DSc, LRAM, FSS (1892-1971): reflections on a Fellow of the Royal Statistical Society.

We have previously described the content of a text by Woods and Russell, An Introduction to Medical Statistics, compared it with Principles of Medical Statistics by Hill and set both volumes against the background of vital statistics up until 1937. The two books mark a watershed in the history of medical statistics. Very little has been recorded about the life and career of the first author of the earlier textbook, who was a Fellow of the Royal Statistical Society for at least 25 years, an omission which we can now rectify with this paper. We describe her education, entry into medical statistics, relationship with Major Greenwood and her subsequent career and life in Ceylon, Kenya, Australia, England and South Africa.

Two-stage meta-analysis of survival data from individual participants using percentile ratios.

Methods for individual participant data meta-analysis of survival outcomes commonly focus on the hazard ratio as a measure of treatment effect. Recently, Siannis et al. (2010, Statistics in Medicine 29:3030-3045) proposed the use of percentile ratios as an alternative to hazard ratios. We describe a novel two-stage method for the meta-analysis of percentile ratios that avoids distributional assumptions at the study level.