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1.  Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial 
The Lancet Oncology  2012;13(5):549-558.
Summary
Background
Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE—an international, open-label, randomised controlled trial—uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A).
Methods
Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544.
Findings
2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·98 (95% CI 0·90–1·06). 2-year FFS was 51% (95% CI 46–56) in arm A and 51% (95% CI 43–58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20–27] patients in arm A and 64 [25%, 19–30] in arm D). The most common grade 3–5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee.
Interpretation
Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival.
Funding
Cancer Research UK, Pfizer, Novartis, Sanofi-Aventis, Medical Research Council (London, UK).
doi:10.1016/S1470-2045(12)70088-8
PMCID: PMC3398767  PMID: 22452894
3.  The need for a cultural shift from two-arm to multi-arm RCTS 
Trials  2013;14(Suppl 1):O3.
doi:10.1186/1745-6215-14-S1-O3
PMCID: PMC3981643
4.  Late Gastrointestinal Toxicity After Dose-Escalated Conformal Radiotherapy for Early Prostate Cancer: Results From the UK Medical Research Council RT01 Trial (ISRCTN47772397) 
Purpose
In men with localized prostate cancer, dose-escalated conformal radiotherapy (CFRT) improves efficacy outcomes at the cost of increased toxicity. We present a detailed analysis to provide further information about the incidence and prevalence of late gastrointestinal side effects.
Methods and Materials
The UK Medical Research Council RT01 trial included 843 men with localized prostate cancer, who were treated for 6 months with neoadjuvant radiotherapy and were randomly assigned to either 64-Gy or 74-Gy CFRT. Toxicity was evaluated before CFRT and during long-term follow-up using Radiation Therapy Oncology Group (RTOG) grading, the Late Effects on Normal Tissue: Subjective, Objective, Management (LENT/SOM) scale, and Royal Marsden Hospital assessment scores. Patients regularly completed Functional Assessment of Cancer Therapy--Prostate (FACT-P) and University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) questionnaires.
Results
In the dose-escalated group, the hazard ratio (HR) for rectal bleeding (LENT/SOM grade ≥2) was 1.55 (95% CI, 1.17–2.04); for diarrhea (LENT/SOM grade ≥2), the HR was 1.79 (95% CI, 1.10–2.94); and for proctitis (RTOG grade ≥2), the HR was 1.64 (95% CI, 1.20–2.25). Compared to baseline scores, the prevalence of moderate and severe toxicities generally increased up to 3 years and than lessened. At 5 years, the cumulative incidence of patient-reported severe bowel problems was 6% vs. 8% (standard vs. escalated, respectively) and severe distress was 4% vs. 5%, respectively.
Conclusions
There is a statistically significant increased risk of various adverse gastrointestinal events with dose-escalated CFRT. This remains at clinically acceptable levels, and overall prevalence ultimately decreases with duration of follow-up.
doi:10.1016/j.ijrobp.2009.05.052
PMCID: PMC2937212  PMID: 19836155
Prostate cancer; Conformal radiotherapy; Dose escalation; Late gastrointestinal toxicity; Phase III trial
5.  Flexible trial design in practice - stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial 
Trials  2012;13:168.
Background
Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) is a randomized controlled trial that follows a novel multi-arm, multi-stage (MAMS) design. We describe methodological and practical issues arising with (1) stopping recruitment to research arms following a pre-planned intermediate analysis and (2) adding a new research arm during the trial.
Methods
STAMPEDE recruits men who have locally advanced or metastatic prostate cancer who are starting standard long-term hormone therapy. Originally there were five research and one control arms, each undergoing a pilot stage (focus: safety, feasibility), three intermediate ‘activity’ stages (focus: failure-free survival), and a final ‘efficacy’ stage (focus: overall survival). Lack-of-sufficient-activity guidelines support the pairwise interim comparisons of each research arm against the control arm; these pre-defined activity cut-off becomes increasingly stringent over the stages. Accrual of further patients continues to the control arm and to those research arms showing activity and an acceptable safety profile. The design facilitates adding new research arms should sufficiently interesting agents emerge. These new arms are compared only to contemporaneously recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is subject to adequate recruitment rates to support the overall trial aims.
Results
(1) Stopping Existing Therapy: After the second intermediate activity analysis, recruitment was discontinued to two research arms for lack-of-sufficient activity. Detailed preparations meant that changes were implemented swiftly at 100 international centers and recruitment continued seamlessly into Activity Stage III with 3 remaining research arms and the control arm. Further regulatory and ethical approvals were not required because this was already included in the initial trial design.
(2) Adding New Therapy: An application to add a new research arm was approved by the funder, (who also organized peer review), industrial partner and regulatory and ethical bodies. This was all done in advance of any decision to stop current therapies.
Conclusions
The STAMPEDE experience shows that recruitment to a MAMS trial and mid-flow changes its design are achievable with good planning. This benefits patients and the scientific community as research treatments are evaluated in a more efficient and cost-effective manner.
Trial registration
ISRCTN78818544, NCT00268476
First patient into trial: 17 October 2005
First patient into abiraterone comparison: 15 November 2011
doi:10.1186/1745-6215-13-168
PMCID: PMC3466132  PMID: 22978443
Novel design; Multi-arm multi-stage design; Implementation; Prostate cancer; Methodology; Randomized controlled trial
6.  Presence of chemotherapy-induced toxicity predicts improved survival in patients with localised extremity osteosarcoma treated with doxorubicin and cisplatin: A report from the European Osteosarcoma Intergroup 
European Journal of Cancer  2012;48(5):703-712.
Aim
Chemotherapy-induced toxicity is an independent prognostic indicator in several cancers. We aimed to determine whether toxicity was related to survival and histological response in high-grade localised extremity osteosarcoma. We undertook a retrospective analysis of patients treated within three consecutive randomised controlled trials (RCTs) of the European Osteosarcoma Intergroup.
Methods
Between 1982 and 2002, 533 patients were randomised to six cycles of doxorubicin 75 mg/m2 and cisplatin 100 mg/m2. Toxicity data were collected prospectively and graded according to the World Health Organisation (WHO) criteria. Standard univariate and multivariate models were constructed to examine the relationship between reported toxicity, survival, and histological response.
Results
Five- and 10-year overall survival was 57% (95% confidence interval (CI) 52–61%) and 53% (49–58%), respectively. Grades 3–4 oral mucositis (hazard ratio (HR) 0.51, 95% CI 0.29–0.91), grades 1–2 nausea/vomiting (HR 0.37, 95% CI 0.16–0.85), grades 1–2 thrombocytopenia (HR 0.49, 95% CI 0.27–0.87), good histological response (HR 0.42, 95% CI 0.27–0.65), and distal tumour site (HR 0.45, 95% CI 0.28–0.71) were associated with improved survival in multivariate analysis. The only factors that were independently associated with histological response were older age (odds ratio (OR) 0.18, 95% CI 0.04–0.72) and chondroblastic tumour (OR 0.28, 95% CI 0.10–0.77), both being associated with a significantly lower chance of achieving a good response.
Conclusion
Chemotherapy-induced toxicity predicts survival in patients with localised extremity osteosarcoma. Investigation of the pharmacogenomic mechanisms of constitutional chemosensitivity underlying these observations will present opportunities for personalising treatment and could lead to improved outcomes.
doi:10.1016/j.ejca.2011.09.012
PMCID: PMC3657154  PMID: 22036088
Osteosarcoma; Toxicity; Survival; Chemotherapy
7.  Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial 
Lancet  2011;378(9809):2104-2111.
Summary
Background
Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer.
Methods
Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65–69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633.
Results
Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4–8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70–78 vs 66%, 60–70; hazard ratio [HR] 0·77, 95% CI 0·61–0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups).
Interpretation
The benefits of combined modality treatment—ADT and RT—should be discussed with all patients with locally advanced prostate cancer.
Funding
Canadian Cancer Society Research Institute, US National Cancer Institute, and UK Medical Research Council.
doi:10.1016/S0140-6736(11)61095-7
PMCID: PMC3243932  PMID: 22056152
9.  Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials 
The Lancet Oncology  2009;10(9):872-876.
Summary
Background
Bisphosphonates might modulate the development of symptomatic bone metastases in men with prostate cancer. The Medical Research Council (MRC) PR05 and PR04 randomised controlled trials assessed the use of sodium clodronate, an oral, first-generation bisphosphonate. We report the final analyses of long-term survival data with additional follow-up in both trials.
Methods
311 men with metastatic disease were recruited to PR05 between 1994 and 1998, and 508 men with non-metastatic disease were recruited to PR04 from 1994 to 1997. All men were treated according to the recruiting site's standard practice at the time: for metastatic disease, all men were starting or responding to long-term hormone therapy; for non-metastatic disease, most men had radiotherapy, hormone therapy, or both. Men were randomly assigned to take four tablets per day of sodium clodronate (2080 mg) or matching placebo for up to 3 years (metastatic disease) or 5 years (non-metastatic). Long-term overall survival was assessed on an intention-to-treat basis in all men at sites in England and Wales using data from the National Health Service Information Centre, which held data for 278 of 311 men in the PR05 trial and 471 of 508 men in the PR04 trial. These studies are registered International Standardised Randomised Controlled Trials, numbers ISRCTN38477744 (PR05) and ISRCTN61384873 (PR04).
Findings
Of the 278 men with metastatic disease, 258 (93%) were reported to have died. Evidence of a benefit for those with metastatic disease from use of sodium clodronate compared with placebo was seen in overall survival (hazard ratio [HR] 0·77, 95% CI 0·60–0·98; p=0·032). Of the 471 men with non-metastatic disease, 281 (60%) were reported to have died, with no evidence of improvement in overall survival with clodronate compared with placebo (HR 1·12, 0·89–1·42; p=0·94).
Interpretation
Long-term data from these trials show that a first-generation bisphosphonate, sodium clodronate, improves overall survival in men with metastatic prostate cancer who are starting hormone therapy, but there is no evidence of an effect in men with non-metastatic prostate cancer.
Funding
UK MRC; and an education grant and free drug from Roche Products Ltd.
doi:10.1016/S1470-2045(09)70201-3
PMCID: PMC2748902  PMID: 19674936
10.  Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial 
Trials  2009;10:39.
Background
The multi-arm multi-stage (MAMS) trial is a new paradigm for conducting randomised controlled trials that allows the simultaneous assessment of a number of research treatments against a single control arm. MAMS trials provide earlier answers and are potentially more cost-effective than a series of traditionally designed trials. Prostate cancer is the most common tumour in men and there is a need to improve outcomes for men with hormone-sensitive, advanced disease as quickly as possible. The MAMS design will potentially facilitate evaluation and testing of new therapies in this and other diseases.
Methods
STAMPEDE is an open-label, 5-stage, 6-arm randomised controlled trial using MAMS methodology for men with prostate cancer. It is the first trial of this design to use multiple arms and stages synchronously.
Results
The practical and statistical issues faced by STAMPEDE in implementing MAMS methodology are discussed and contrasted with those for traditional trials. These issues include the choice of intermediate and final outcome measures, sample size calculations and the impact of varying the assumptions, the process for moving between trial stages, stopping accrual to each trial arm and overall, and issues around perceived trial complexity.
Conclusion
It is possible to use the MAMS design to initiate and undertake large scale cancer trials. The results from STAMPEDE will not be known for some years but the lessons learned from running a MAMS trial are shared in the hope that other researchers will use this exciting and efficient method to perform further randomised controlled trials.
Trial registration
ISRCTN78818544, NCT00268476
doi:10.1186/1745-6215-10-39
PMCID: PMC2704188  PMID: 19519885
11.  Using Implicit Information to Identify Smoking Status in Smoke-blind Medical Discharge Summaries 
As part of the 2006 i2b2 NLP Shared Task, we explored two methods for determining the smoking status of patients from their hospital discharge summaries when explicit smoking terms were present and when those same terms were removed. We developed a simple keyword-based classifier to determine smoking status from de-identified hospital discharge summaries. We then developed a Naïve Bayes classifier to determine smoking status from the same records after all smoking-related words had been manually removed (the smoke-blind dataset). The performance of the Naïve Bayes classifier was compared with the performance of three human annotators on a subset of the same training dataset (n = 54) and against the evaluation dataset (n = 104 records). The rule-based classifier was able to accurately extract smoking status from hospital discharge summaries when they contained explicit smoking words. On the smoke-blind dataset, where explicit smoking cues are not available, two Naïve Bayes systems performed less well than the rule-based classifier, but similarly to three expert human annotators.
doi:10.1197/jamia.M2440
PMCID: PMC2274867  PMID: 17947620
12.  Practical methods for incorporating summary time-to-event data into meta-analysis 
Trials  2007;8:16.
Background
In systematic reviews and meta-analyses, time-to-event outcomes are most appropriately analysed using hazard ratios (HRs). In the absence of individual patient data (IPD), methods are available to obtain HRs and/or associated statistics by carefully manipulating published or other summary data. Awareness and adoption of these methods is somewhat limited, perhaps because they are published in the statistical literature using statistical notation.
Methods
This paper aims to 'translate' the methods for estimating a HR and associated statistics from published time-to-event-analyses into less statistical and more practical guidance and provide a corresponding, easy-to-use calculations spreadsheet, to facilitate the computational aspects.
Results
A wider audience should be able to understand published time-to-event data in individual trial reports and use it more appropriately in meta-analysis. When faced with particular circumstances, readers can refer to the relevant sections of the paper. The spreadsheet can be used to assist them in carrying out the calculations.
Conclusion
The methods cannot circumvent the potential biases associated with relying on published data for systematic reviews and meta-analysis. However, this practical guide should improve the quality of the analysis and subsequent interpretation of systematic reviews and meta-analyses that include time-to-event outcomes.
doi:10.1186/1745-6215-8-16
PMCID: PMC1920534  PMID: 17555582

Results 1-12 (12)