[Show abstract][Hide abstract] ABSTRACT: Background:
Results from large randomised controlled trials combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer have emerged. In order to investigate the effects of these therapies and to respond to emerging evidence, we aimed to systematically review all relevant trials using a framework for adaptive meta-analysis.
For this systematic review and meta-analysis, we searched MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomised controlled trials (published, unpublished, and ongoing) comparing either standard of care with or without docetaxel or standard of care with or without bisphosphonates for men with high-risk localised or metastatic hormone-sensitive prostate cancer. For each trial, we extracted hazard ratios (HRs) of the effects of docetaxel or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) from published trial reports or presentations or obtained them directly from trial investigators. HRs were combined using the fixed-effect model (Mantel-Haenzsel).
We identified five eligible randomised controlled trials of docetaxel in men with metastatic (M1) disease. Results from three (CHAARTED, GETUG-15, STAMPEDE) of these trials (2992 [93%] of 3206 men randomised) showed that the addition of docetaxel to standard of care improved survival. The HR of 0·77 (95% CI 0·68-0·87; p<0·0001) translates to an absolute improvement in 4-year survival of 9% (95% CI 5-14). Docetaxel in addition to standard of care also improved failure-free survival, with the HR of 0·64 (0·58-0·70; p<0·0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI 12-19). We identified 11 trials of docetaxel for men with locally advanced disease (M0). Survival results from three (GETUG-12, RTOG 0521, STAMPEDE) of these trials (2121 [53%] of 3978 men) showed no evidence of a benefit from the addition of docetaxel (HR 0·87 [95% CI 0·69-1·09]; p=0·218), whereas failure-free survival data from four (GETUG-12, RTOG 0521, STAMPEDE, TAX 3501) of these trials (2348 [59%] of 3978 men) showed that docetaxel improved failure-free survival (0·70 [0·61-0·81]; p<0·0001), which translates into a reduced absolute 4-year failure rate of 8% (5-10). We identified seven eligible randomised controlled trials of bisphosphonates for men with M1 disease. Survival results from three of these trials (2740 [88%] of 3109 men) showed that addition of bisphosphonates improved survival (0·88 [0·79-0·98]; p=0·025), which translates to 5% (1-8) absolute improvement, but this result was influenced by the positive result of one trial of sodium clodronate, and we found no evidence of a benefit from the addition of zoledronic acid (0·94 [0·83-1·07]; p=0·323), which translates to an absolute improvement in survival of 2% (-3 to 7). Of 17 trials of bisphosphonates for men with M0 disease, survival results from four trials (4079 [66%] of 6220 men) showed no evidence of benefit from the addition of bisphosphonates (1·03 [0·89-1·18]; p=0·724) or zoledronic acid (0·98 [0·82-1·16]; p=0·782). Failure-free survival definitions were too inconsistent for formal meta-analyses for the bisphosphonate trials.
The addition of docetaxel to standard of care should be considered standard care for men with M1 hormone-sensitive prostate cancer who are starting treatment for the first time. More evidence on the effects of docetaxel on survival is needed in the M0 disease setting. No evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease, and any potential benefit is probably small.
Medical Research Council UK.
Full-text · Article · Dec 2015 · The Lancet Oncology
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010.
To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival.
We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations.
We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment.
We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status.
We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low.
Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.
Full-text · Article · Mar 2015 · Cochrane database of systematic reviews (Online)
[Show abstract][Hide abstract] ABSTRACT: Guidance concerning TKIs for patients with wild-type EGFR and advanced non-small cell lung cancer (NSCLC) following first-line treatment is unclear.Materials and Methods
We assessed the effect of TKIs as second-line therapy and maintenance therapy following first-line chemotherapy in two systematic reviews and meta-analyses, focusing on patients without EGFR mutations. Systematic searches were completed and data extracted from eligible RCTs. Three analytical approaches were used to maximise available data.ResultsFourteen trials of second-line treatment (4388 patients) were included. Results showed the effect of TKIs on progression-free survival (PFS) depended on EGFR status (interaction HR=2·69, p=0·004). Chemotherapy benefitted patients with wild-type EGFR (HR=1.31, p<0·0001), TKIs benefitted patients with mutations (HR=0·34, p=0·0002). Based on 12 trials (85% of randomised patients) the benefits of TKIs on PFS decreased with increasing proportions of patients with wild-type EGFR (p=0.014). Six trials of maintenance therapy (2697 patients) were included. Results showed that whilst the effect of TKIs on PFS depended on EGFR status (interaction HR=3.58, p<0·0001), all benefitted from TKIs (wild-type EGFR: HR=0.82, p=0.01; mutated EGFR: HR=0.24, p<0·0001). There was a suggestion that benefits of TKIs on PFS decreased with increasing proportions of patients with wild-type EGFR (p=0.11).Conclusions
Chemotherapy should be standard second-line treatment for patients with advanced NSCLC and wild-type EGFR. TKIs may be unsuitable for unselected patients. TKIs appear to benefit all patients when compared with no active treatment as maintenance treatment, however direct comparisons with chemotherapy are needed.
Full-text · Article · Nov 2014 · Clinical Lung Cancer
[Show abstract][Hide abstract] ABSTRACT: Background Individual participant data meta-analyses of postoperative chemotherapy have shown improved survival for patients with non-small-cell lung cancer (NSCLC). We aimed to do a systematic review and individual participant data meta-analysis to establish the effect of preoperative chemotherapy for patients with resectable NSCLC. Methods We systematically searched for trials that started after January, 1965. Updated individual participant data were centrally collected, checked, and analysed. Results from individual randomised controlled trials (both published and unpublished) were combined using a two-stage fixed-effect model. Our primary outcome, overall survival, was defined as the time from randomisation until death (any cause), with living patients censored on the date of last follow-up. Secondary outcomes were recurrence-free survival, time to locoregional and distant recurrence, cause-specific survival, complete and overall resection rates, and postoperative mortality. Prespecified analyses explored any variation in effect by trial and patient characteristics. All analyses were by intention to treat. Findings Analyses of 15 randomised controlled trials (2385 patients) showed a significant benefit of preoperative chemotherapy on survival (hazard ratio [HR] 0.87, 95% CI 0.78-0.96, p=0.007), a 13% reduction in the relative risk of death (no evidence of a difference between trials; p=0.18, I-2 =25%). This finding represents an absolute survival improvement of 5% at 5 years, from 40% to 45%. There was no clear evidence of a difference in the effect on survival by chemotherapy regimen or scheduling, number of drugs, platinum agent used, or whether postoperative radiotherapy was given. There was no clear evidence that particular types of patient defined by age, sex, performance status, histology, or clinical stage benefited more or less from preoperative chemotherapy. Recurrence-free survival (HR 0.85, 95% CI 0.76-0.94, p=0.002) and time to distant recurrence (0.69, 0.58-0.82, p<0.0001) results were both significantly in favour of preoperative chemotherapy although most patients included were stage IB-IIIA. Results for time to locoregional recurrence (0.88, 0.73-1.07, p=0.20), although in favour of preoperative chemotherapy, were not statistically significant. Interpretation Findings, which are based on 92% of all patients who were randomised, and mainly stage IB-IIIA, show preoperative chemotherapy significantly improves overall survival, time to distant recurrence, and recurrence-free survival in resectable NSCLC. The findings suggest this is a valid treatment option for most of these patients. Toxic effects could not be assessed.
[Show abstract][Hide abstract] ABSTRACT: Background
The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels.
We analysed individual patients' data from 15 071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints.
In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ2=0·83, 95% CI 0·83–0·83 in trials without radiotherapy, and 0·87, 0·87–0·87 in trials with radiotherapy) and excellent at trial level (R2=0·92, 95% CI 0·88–0·95 in trials without radiotherapy and 0·99, 0·98–1·00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ2 range 0·77–0·85, dependent on the regimen being assessed) and trial level (R2 range 0·89–0·97). In studies with data on locoregional control, individual-level correlations were good (ρ2=0·71, 95% CI 0·71–0·71 for concurrent chemotherapy and ρ2=0·61, 0·61–0·61 for modified vs standard radiotherapy) and trial-level correlations very good (R2=0·85, 95% CI 0·77–0·92 for concurrent chemotherapy and R2=0·95, 0·91–0·98 for modified vs standard radiotherapy).
We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted.
Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis.
Full-text · Article · Jun 2013 · The Lancet Oncology
[Show abstract][Hide abstract] ABSTRACT: To evaluate the reliability of risk of bias assessments based on published trial reports, for determining trial inclusion in meta-analyses.
Reliability evaluation of risk of bias assessments. DATA SOURCES : 13 published individual participant data (IPD) meta-analyses in cancer were used to source 95 randomised controlled trials. REVIEW METHODS : Risk of bias was assessed using the Cochrane risk of bias tool (RevMan5.1) and accompanying guidance. Assessments were made for individual risk of bias domains and overall for each trial, using information from either trial reports alone or trial reports with additional information collected for IPD meta-analyses. Percentage agreements were calculated for individual domains and overall (<66%=low, ≥66%=fair, ≥90%=good). The two approaches were considered similarly reliable only when agreement was good.
Percentage agreement between the two methods for sequence generation and incomplete outcome data was fair (69.5% (95% confidence interval 60.2% to 78.7%) and 80.0% (72.0% to 88.0%), respectively). However, percentage agreement was low for allocation concealment, selective outcome reporting, and overall risk of bias (48.4% (38.4% to 58.5%), 42.1% (32.2% to 52.0%), and 54.7% (44.7% to 64.7%), respectively). Supplementary information reduced the proportion of unclear assessments for all individual domains, consequently increasing the number of trials assessed as low risk of bias (and therefore available for inclusion in meta-analyses) from 23 (23%) based on publications alone to 66 (66%) based on publications with additional information.
Using cancer trial publications alone to assess risk of bias could be unreliable; thus, reviewers should be cautious about using them as a basis for trial inclusion, particularly for those trials assessed as unclear risk. Supplementary information from trialists should be sought to enable appropriate assessments and potentially reduce or overcome some risks of bias. Furthermore, guidance should ensure clarity on what constitutes risk of bias, particularly for the more subjective domains.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: As part of a broader methodological programme of work around clinical trial monitoring, we wanted to evaluate the existing evidence for the effectiveness of different monitoring techniques. PURPOSE: To identify and evaluate prospective studies of the effectiveness of different monitoring strategies. METHODS: A systematic search of MEDLINE from 1950 onwards, using free-text terms to identify relevant published studies. We intended to extract data on details of comparative techniques, monitoring findings identified by different techniques, and recommendations or identification of areas in need of further research made by authors. RESULTS: A total of 1222 published abstracts were identified and reviewed. Of these, nine articles described methods for quality control (QC) of clinical trial activities, and one article was identified that compared the same monitoring technique at two timepoints. None included a direct comparison of different monitoring techniques and findings. LIMITATIONS: The search strategy was limited to MEDLINE. However, MEDLINE includes all the journals that tend to report trial methodological research. CONCLUSIONS: There is a lack of published empirical data that compare monitoring strategies prospectively. Assessment of the usefulness and cost-effectiveness of monitoring techniques in a variety of clinical trial settings and indications is needed. Clinical Trials 2012; 0: 1-4 http://ctj.sagepub.com.
[Show abstract][Hide abstract] ABSTRACT: Aspirin inhibits the enzyme cyclooxygenase (Cox), and there is a significant body of epidemiological evidence demonstrating that regular aspirin use is associated with a decreased incidence of developing cancer. Interest focussed on selective Cox-2 inhibitors both as cancer prevention agents and as therapeutic agents in patients with proven malignancy until concerns were raised about their toxicity profile. Aspirin has several additional mechanisms of action that may contribute to its anti-cancer effect. It also influences cellular processes such as apoptosis and angiogenesis that are crucial for the development and growth of malignancies. Evidence suggests that these effects can occur through Cox-independent pathways questioning the rationale of focussing on Cox-2 inhibition alone as an anti-cancer strategy. Randomised studies with aspirin primarily designed to prevent cardiovascular disease have demonstrated a reduction in cancer deaths with long-term follow-up. Concerns about toxicity, particularly serious haemorrhage, have limited the use of aspirin as a cancer prevention agent, but recent epidemiological evidence demonstrating regular aspirin use after a diagnosis of cancer improves outcomes suggests that it may have a role in the adjuvant setting where the risk:benefit ratio will be different.
Full-text · Article · Aug 2011 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Clinical researchers have often preferred to use a fixed effects model for the primary interpretation of a meta-analysis. Heterogeneity is usually assessed via the well known Q and I2 statistics, along with the random effects estimate they imply. In recent years, alternative methods for quantifying heterogeneity have been proposed, that are based on a 'generalised' Q statistic.
We review 18 IPD meta-analyses of RCTs into treatments for cancer, in order to quantify the amount of heterogeneity present and also to discuss practical methods for explaining heterogeneity.
Differing results were obtained when the standard Q and I2 statistics were used to test for the presence of heterogeneity. The two meta-analyses with the largest amount of heterogeneity were investigated further, and on inspection the straightforward application of a random effects model was not deemed appropriate. Compared to the standard Q statistic, the generalised Q statistic provided a more accurate platform for estimating the amount of heterogeneity in the 18 meta-analyses.
Explaining heterogeneity via the pre-specification of trial subgroups, graphical diagnostic tools and sensitivity analyses produced a more desirable outcome than an automatic application of the random effects model. Generalised Q statistic methods for quantifying and adjusting for heterogeneity should be incorporated as standard into statistical software. Software is provided to help achieve this aim.
Full-text · Article · Apr 2011 · BMC Medical Research Methodology
[Show abstract][Hide abstract] ABSTRACT: The previous individual patient data meta-analyses of chemotherapy in locally advanced non-small-cell lung cancer (NSCLC) showed that adding sequential or concomitant chemotherapy to radiotherapy improved survival. The NSCLC Collaborative Group performed a meta-analysis of randomized trials directly comparing concomitant versus sequential radiochemotherapy.
Systematic searches for trials were undertaken, followed by central collection, checking, and reanalysis of updated individual patient data. Results from trials were combined using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival; secondary outcomes were progression-free survival, cumulative incidences of locoregional and distant progression, and acute toxicity.
Of seven eligible trials, data from six trials were received (1,205 patients, 92% of all randomly assigned patients). Median follow-up was 6 years. There was a significant benefit of concomitant radiochemotherapy on overall survival (HR, 0.84; 95% CI, 0.74 to 0.95; P = .004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. For progression-free survival, the HR was 0.90 (95% CI, 0.79 to 1.01; P = .07). Concomitant treatment decreased locoregional progression (HR, 0.77; 95% CI, 0.62 to 0.95; P = .01); its effect was not different from that of sequential treatment on distant progression (HR, 1.04; 95% CI, 0.86 to 1.25; P = .69). Concomitant radiochemotherapy increased acute esophageal toxicity (grade 3-4) from 4% to 18% with a relative risk of 4.9 (95% CI, 3.1 to 7.8; P < .001). There was no significant difference regarding acute pulmonary toxicity.
Concomitant radiochemotherapy, as compared with sequential radiochemotherapy, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control, but at the cost of manageable increased acute esophageal toxicity.
Full-text · Article · Mar 2010 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: SummaryBackground Many randomised controlled trials have investigated the effect of adjuvant chemotherapy in operable non-small-cell lung cancer. We undertook two comprehensive systematic reviews and meta-analyses to establish the effects of adding adjuvant chemotherapy to surgery, or to surgery plus radiotherapy.Methods We included randomised trials, not confounded by additional therapeutic differences between the two groups and that started randomisation on or after Jan 1, 1965, which compared surgery plus adjuvant chemotherapy versus surgery alone, or surgery plus adjuvant radiotherapy and chemotherapy versus surgery plus adjuvant radiotherapy. Updated individual patient data were collected, checked, and included in meta-analyses stratified by trial. The primary endpoint was overall survival, defined as time from randomisation until death by any cause. All analyses were by intention to treat.Findings The first meta-analysis of surgery plus chemotherapy versus surgery alone was based on 34 trial comparisons and 8447 patients (3323 deaths). We recorded a benefit of adding chemotherapy after surgery (hazard ratio [HR] 0·86, 95% CI 0·81-0·92, p<0·0001), with an absolute increase in survival of 4% (95% CI 3-6) at 5 years (from 60% to 64%). The second meta-analysis of surgery plus radiotherapy and chemotherapy versus surgery plus radiotherapy was based on 13 trial comparisons and 2660 patients (1909 deaths). We recorded a benefit of adding chemotherapy to surgery plus radiotherapy (HR 0·88, 95% CI 0·81-0·97, p=0·009), representing an absolute improvement in survival of 4% (95% CI 1-8) at 5 years (from 29% to 33%). In both meta-analyses we noted little variation in effect according to the type of chemotherapy, other trial characteristics, or patient subgroup.Interpretation The addition of adjuvant chemotherapy after surgery for patients with operable non-small-cell lung cancer improves survival, irrespective of whether chemotherapy was adjuvant to surgery alone or adjuvant to surgery plus radiotherapy.Funding
[Show abstract][Hide abstract] ABSTRACT: A National Cancer Institute (NCI) clinical announcement recommended i.p. therapy for women with optimally debulked ovarian cancer. Its basis was a summary of eight randomised controlled trials and two systematic reviews, which appear to indicate benefit of i.p. therapy. However, the systematic reviews that inform the recommendations have been inappropriately presented and interpreted. The systematic reviews inappropriately pooled results from 'confounded' trials in which different drugs and different doses of drugs were given in the control and i.p. treatment arms. Therefore, it is not possible to assess which component of treatment is responsible for improving outcome. In addition, none of the trials use a control arm of the internationally accepted standard of care. Using just the unconfounded trials, indirect comparisons show that the magnitude of benefit observed when i.p. regimens are compared with older i.v. regimens [hazard ratio (HR) for overall survival (OS) 0.75; 95% confidence interval (CI) 0.60-0.92, P = 0.006] is smaller than the magnitude of benefit achieved with modern day standard of i.v. treatment compared with the same i.v. regimen used as control in the unconfounded i.p. trials (HR for OS 0.68; 95% CI 0.58-0.80, P < 0.001). A further difficulty is that the reviews cannot recommend an i.p. regimen for standard use. Drug-related toxicity and catheter complications that occur with i.p. therapy are considerable. The NCI recommendations have major implications for the treatment of women with ovarian cancer and for the next generation of clinical trials. We do not believe that the body of evidence currently available supports the recommendation that i.p. therapy should form part of routine care. The choice of treatment of women with newly diagnosed, optimally debulked, ovarian cancer, where therapy has the best chance of influencing OS, is too important to be left with this uncertainty. A clinical trial that investigates a practical and acceptable regimen which gives some or all chemotherapy by the i.p. route and compares this with standard i.v. chemotherapy should be a priority for those who wish to promote its use.
Full-text · Article · Apr 2008 · Annals of Oncology