What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis.

Background: Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies. Methods: Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed. Results: We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability). Conclusions: Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

A framework for identifying treatment-covariate interactions in individual participant data network meta-analysis.

BACKGROUND: Stratified medicine seeks to identify patients most likely to respond to treatment. Individual participant data (IPD) network meta-analysis (NMA) models have greater power than individual trials to identify treatment-covariate interactions (TCIs). Treatment-covariate interactions contain "within" and "across" trial interactions, where the across-trial interaction is more susceptible to confounding and ecological bias. METHODS: We considered a network of IPD from 37 trials (5922 patients) for cervical cancer (2394 events), where previous research identified disease stage as a potential interaction covariate. We compare 2 models for NMA with TCIs: (1) 2 effects separating within- and across-trial interactions and (2) a single effect combining within- and across-trial interactions. We argue for a visual assessment of consistency of within- and across-trial interactions and consider more detailed aspects of interaction modelling, eg, common vs trial-specific effects of the covariate. This leads us to propose a practical framework for IPD NMA with TCIs. RESULTS: Following our framework, we found no evidence in the cervical cancer network for a treatment-stage interaction on the basis of the within-trial interaction. The NMA provided additional power for an across-trial interaction over and above the pairwise evidence. Following our proposed framework, we found that the within- and across-trial interactions should not be combined. CONCLUSION: Across-trial interactions are susceptible to confounding and ecological bias. It is important to separate the sources of evidence to check their consistency and identify which sources of evidence are driving the conclusion. Our framework provides practical guidance for researchers, reducing the risk of unduly optimistic interpretation of TCIs.

Strategies to improve retention in randomised trials: a Cochrane systematic review and meta-analysis.

OBJECTIVE: To quantify the effect of strategies to improve retention in randomised trials. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Sources searched: MEDLINE, EMBASE, PsycINFO, DARE, CENTRAL, CINAHL, C2-SPECTR, ERIC, PreMEDLINE, Cochrane Methodology Register, Current Controlled Trials metaRegister, WHO trials platform, Society for Clinical Trials (SCT) conference proceedings and a survey of all UK clinical trial research units. REVIEW METHODS: Included trials were randomised evaluations of strategies to improve retention embedded within host randomised trials. The primary outcome was retention of trial participants. Data from trials were pooled using the fixed-effect model. Subgroup analyses were used to explore the heterogeneity and to determine whether there were any differences in effect by the type of strategy. RESULTS: 38 retention trials were identified. Six broad types of strategies were evaluated. Strategies that increased postal questionnaire responses were: adding, that is, giving a monetary incentive (RR 1.18; 95% CI 1.09 to 1.28) and higher valued incentives (RR 1.12; 95% CI 1.04 to 1.22). Offering a monetary incentive, that is, an incentive given on receipt of a completed questionnaire, also increased electronic questionnaire response (RR 1.25; 95% CI 1.14 to 1.38). The evidence for shorter questionnaires (RR 1.04; 95% CI 1.00 to 1.08) and questionnaires relevant to the disease/condition (RR 1.07; 95% CI 1.01 to 1.14) is less clear. On the basis of the results of single trials, the following strategies appeared effective at increasing questionnaire response: recorded delivery of questionnaires (RR 2.08; 95% CI 1.11 to 3.87); a 'package' of postal communication strategies (RR 1.43; 95% CI 1.22 to 1.67) and an open trial design (RR 1.37; 95% CI 1.16 to 1.63). There is no good evidence that the following strategies impact on trial response/retention: adding a non-monetary incentive (RR=1.00; 95% CI 0.98 to 1.02); offering a non-monetary incentive (RR=0.99; 95% CI 0.95 to 1.03); 'enhanced' letters (RR=1.01; 95% CI 0.97 to 1.05); monetary incentives compared with offering prize draw entry (RR=1.04; 95% CI 0.91 to 1.19); priority postal delivery (RR=1.02; 95% CI 0.95 to 1.09); behavioural motivational strategies (RR=1.08; 95% CI 0.93 to 1.24); additional reminders to participants (RR=1.03; 95% CI 0.99 to 1.06) and questionnaire question order (RR=1.00, 0.97 to 1.02). Also based on single trials, these strategies do not appear effective: a telephone survey compared with a monetary incentive plus questionnaire (RR=1.08; 95% CI 0.94 to 1.24); offering a charity donation (RR=1.02, 95% CI 0.78 to 1.32); sending sites reminders (RR=0.96; 95% CI 0.83 to 1.11); sending questionnaires early (RR=1.10; 95% CI 0.96 to 1.26); longer and clearer questionnaires (RR=1.01, 0.95 to 1.07) and participant case management by trial assistants (RR=1.00; 95% CI 0.97 to 1.04). CONCLUSIONS: Most of the trials evaluated questionnaire response rather than ways to improve participants return to site for follow-up. Monetary incentives and offers of monetary incentives increase postal and electronic questionnaire response. Some strategies need further evaluation. Application of these results would depend on trial context and follow-up procedures.

Use of strategies to improve retention in primary care randomised trials: a qualitative study with in-depth interviews.

OBJECTIVE: To explore the strategies used to improve retention in primary care randomised trials. DESIGN: Qualitative in-depth interviews and thematic analysis. PARTICIPANTS: 29 UK primary care chief and principal investigators, trial managers and research nurses. METHODS: In-depth face-to-face interviews. RESULTS: Primary care researchers use incentive and communication strategies to improve retention in trials, but were unsure of their effect. Small monetary incentives were used to increase response to postal questionnaires. Non-monetary incentives were used although there was scepticism about the impact of these on retention. Nurses routinely used telephone communication to encourage participants to return for trial follow-up. Trial managers used first class post, shorter questionnaires and improved questionnaire designs with the aim of improving questionnaire response. Interviewees thought an open trial design could lead to biased results and were negative about using behavioural strategies to improve retention. There was consensus among the interviewees that effective communication and rapport with participants, participant altruism, respect for participant's time, flexibility of trial personnel and appointment schedules and trial information improve retention. Interviewees noted particular challenges with retention in mental health trials and those involving teenagers. CONCLUSIONS: The findings of this qualitative study have allowed us to reflect on research practice around retention and highlight a gap between such practice and current evidence. Interviewees describe acting from experience without evidence from the literature, which supports the use of small monetary incentives to improve the questionnaire response. No such evidence exists for non-monetary incentives or first class post, use of which may need reconsideration. An exploration of barriers and facilitators to retention in other research contexts may be justified.

Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy?

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.

A critical review of methods for the assessment of patient-level interactions in individual participant data meta-analysis of randomized trials, and guidance for practitioners.

OBJECTIVE: Treatments may be more effective in some patients than others, and individual participant data (IPD) meta-analysis of randomized trials provides perhaps the best method of investigating treatment-covariate interactions. Various methods are used; we provide a comprehensive critique and develop guidance on method selection. STUDY DESIGN AND SETTING: We searched MEDLINE to identify all frequentist methods and appraised them for simplicity, risk of bias, and power. IPD data sets were reanalyzed. RESULTS: Four methodological categories were identified: PWT: pooling of within-trial covariate interactions; OSM: "one-stage" model with a treatment-covariate interaction term; TDCS: testing for difference between covariate subgroups in their pooled treatment effects; and CWA: combining PWT with meta-regression. Distinguishing across- and within-trial information is important, as the former may be subject to ecological bias. A strategy is proposed for method selection in different circumstances; PWT or CWA are natural first steps. The OSM method allows for more complex analyses; TDCS should be avoided. Our reanalysis shows that different methods can lead to substantively different findings. CONCLUSION: The choice of method for investigating interactions in IPD meta-analysis is driven mainly by whether across-trial information is considered for inclusion, a decision, which depends on balancing possible improvement in power with an increased risk of bias.

One-stage parametric meta-analysis of time-to-event outcomes.

Methodology for the meta-analysis of individual patient data with survival end-points is proposed. Motivated by questions about the reliance on hazard ratios as summary measures of treatment effects, a parametric approach is considered and percentile ratios are introduced as an alternative to hazard ratios. The generalized log-gamma model, which includes many common time-to-event distributions as special cases, is discussed in detail. Likelihood inference for percentile ratios is outlined. The proposed methodology is used for a meta-analysis of glioma data that was one of the studies which motivated this work. A simulation study exploring the validity of the proposed methodology is available electronically.

Substantial improvement in UK cervical cancer survival with chemoradiotherapy: results of a Royal College of Radiologists' audit.

AIMS: To compare survival and late complications between patients treated with chemoradiotherapy and radiotherapy for locally advanced cervix cancer. MATERIALS AND METHODS: A Royal College of Radiologists' audit of patients treated with radiotherapy in UK cancer centres in 2001-2002. Survival, recurrence and late complications were assessed for patients grouped according to radical treatment received (radiotherapy, chemoradiotherapy, postoperative radiotherapy or chemoradiotherapy) and non-radical treatment. Late complication rates were assessed using the Franco-Italian glossary. RESULTS: Data were analysed for 1243 patients from 42 UK centres. Overall 5-year survival was 56% (any radical treatment); 44% (radical radiotherapy); 55% (chemoradiotherapy) and 71% (surgery with postoperative radiotherapy). Overall survival at 5 years was 59% (stage IB), 44% (stage IIB) and 24% (stage IIIB) for women treated with radiotherapy, and 65% (stage IB), 61% (stage IIB) and 44% (stage IIIB) for those receiving chemoradiotherapy. Cox regression showed that survival was significantly better for patients receiving chemoradiotherapy (hazard ratio=0.77, 95% confidence interval 0.60-0.98; P=0.037) compared with those receiving radiotherapy taking age, stage, pelvic node involvement and treatment delay into account. The grade 3/4 late complication rate was 8% (radiotherapy) and 10% (chemoradiotherapy). Although complications continued to develop up to 7 years after treatment for those receiving chemoradiotherapy, there was no apparent increase in overall late complications compared with radiotherapy alone when other factors were taken into account (hazard ratio=0.94, 95% confidence interval 0.71-1.245; P=0.667). DISCUSSION: The addition of chemotherapy to radiotherapy seems to have improved survival compared with radiotherapy alone for women treated in 2001-2002, without an apparent rise in late treatment complications.

Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data.

BACKGROUND: 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: UK Medical Research Council, Institut Gustave-Roussy, Programme Hospitalier de Recherche Clinique (AOM 05 209), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Concomitant and neoadjuvant chemotherapy for cervical cancer.

In the past, women with early-stage cervical cancer have been treated with radical radiotherapy or radical surgery, and women with locally advanced disease with radical radiotherapy, each offering a good chance of cure. Numerous trials have investigated whether giving cytotoxic chemotherapy alongside radiotherapy or before local treatment could augment the established benefits of these therapies. There is a strong basis for the use platinum-based chemoradiotherapy, the current standard of care, but little convincing evidence as to the therapeutic benefits of using concomitant hydroxyurea. Chemoradiotherapy based on other non-platinum agents may offer alternatives. The effect of chemoradiotherapy seems to vary according to the stage of disease, but all types of women benefit. Neoadjuvant chemotherapy before radiotherapy could jeopardise survival and should be avoided unless perhaps a 'quick', dose-intense regimen is used. Neoadjuvant chemotherapy before surgery may be beneficial, but the approach will remain controversial until it is tested against platinum-based chemoradiotherapy. Future studies many include combinations of other cytotoxics, such as topotecan, with cisplatin-based concomitant chemoradiotherapy or the addition of agents targeted against specific receptors, such as epidermal growth factor receptor.

Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration.

BACKGROUND: Cytotoxic chemotherapy has a limited place in the management of advanced or recurrent endometrial cancer. Commonly used agents include cisplatin and doxorubicin, but the side-effect profile may be unacceptable for many patients. The feasibility of administration of combination chemotherapy is limited in many patients on account of significant co-morbidity. While early-stage endometrial adenocarcinoma is a common gynaecological cancer with a favourable prognosis, advanced or recurrent disease presents a difficult management problem. The platinum and anthracycline compounds have been widely used for many years, but their impact on progression-free survival (PFS) and overall survival (OS) is not clear. This systematic review aimed to evaluate both the benefits and adverse effects of cytotoxic chemotherapy in these women. PATIENTS AND METHODS: We carried out systematic searches for randomised controlled trials (RCTs) comparing chemotherapy with another intervention. Data were extracted from trial reports or supplied by investigators. Where possible, hazard ratios (HRs) were calculated for OS and PFS and odds ratios (ORs) were calculated for acute toxicity. The impact of more versus less intensive chemotherapy on OS, PFS and acute toxicity was assessed in a meta-analysis. RESULTS: Eleven eligible RCTs were identified that recruited 2288 patients. A meta-analysis of six of these trials found that PFS [HR = 0.80, 95% confidence interval (CI) 0.71-0.90; P = 0.004], but not OS (HR = 0.90, 95% CI 0.80-1.03; P = 0.12), was significantly improved when more intensive chemotherapy was compared with less intensive chemotherapy. OS was improved when doxorubicin, cisplatin and other drugs were compared with doxorubicin and cisplatin. Toxicity was generally higher with more chemotherapy. There was insufficient evidence to assess the effect of chemotherapy on symptom control or quality of life (QoL). Platinums, anthracyclines and taxanes were the most studied in phase II trials and combinations gave the best responses, but patient selection and pre-treatment was very variable. CONCLUSIONS: More intense combination chemotherapy significantly improves the disease-free survival and the data indicate a modest improvement in OS. The addition of anthracyclines (e.g. doxorubicin) or the taxanes [e.g. paclitaxel (Taxol)] to cisplatin increases the response rate. More intensive regimens are associated with the gain in survival. However, grade 3 and 4 myelosuppression and gastrointestinal toxicity are also increased. Future developments are likely to exploit specific molecular characteristics of endometrial cancers, including their hormone dependence, growth factor target overexpression and PTEN loss. While no one drug or regimen offers a clear benefit for women with advanced endometrial cancer, platinum drugs, anthracyclines and paclitaxel seem the most promising agents. Future trials should address the impact of such agents on QoL and symptom control in addition to survival. Chemotherapy and endocrine therapy need to be compared directly in an RCT.

Preoperative radiotherapy for esophageal carcinoma.

BACKGROUND: The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. OBJECTIVES: This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery and whether or not any pre-defined patient subgroups benefit more or less from preoperative radiotherapy SEARCH STRATEGY: MEDLINE and CancerLit searches were supplemented by information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists, organisations and industry. The search strategy was run again in MEDLINE, EMBASE and the Cochrane Library on 30th April 2001, two years after original publication. No new trials were found. The search strategy was re-run August 2002 and August 2003 on MEDLINE, EMBASE , CancerLit and The Cochrane Library, and July 2004 and 2005 on MEDLINE, EMBASE and the Cochrane Library. No new relevant trials were identified on any of these occasions. SELECTION CRITERIA: Trials were eligible for inclusion in this meta-analysis provided they randomized patients with potentially resectable carcinoma of the esophagus (of any histological type) to receive radiotherapy or no radiotherapy prior to surgery. Trials must have used a randomization method which precluded prior knowledge of treatment assignment and completed accrual by December 1993, to ensure sufficient follow-up by the time of the first analysis (September 1995). DATA COLLECTION AND ANALYSIS: A quantitative meta-analysis using updated data from individual patients from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. This approach was used to assess whether preoperative radiotherapy improves overall survival and whether it is differentially effective in patients defined by age, sex and tumour location. MAIN RESULTS: With a median follow-up of 9 years, in a group patients with mostly squamous carcinomas, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p=0.062). No clear differences in the size of the effect by sex, age or tumor location were apparent. AUTHORS' CONCLUSIONS: Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients (90% power, 5% significance level) would be needed to reliably detect such an improvement (from 15 to 20%).

Concomitant hydroxyurea plus radiotherapy versus radiotherapy for carcinoma of the uterine cervix: a systematic review.

We identified eight randomised control trials of hydroxyurea and radiation versus radiotherapy alone (six published in full and two abstracts). Most concluded that outcomes were improved by use of hydroxyurea. However, methodological problems associated with these trials included small sample size, a large number of patient exclusions post randomisation, differing outcome definitions, subgroup analyses of already small numbers of patients and questionable rules for censoring, particularly a failure to include treatment related deaths in the survival analysis. All but two studies were of less than 50 patients. Patients were excluded from some analyses for treatment related reasons. The exclusion of such patients undoubtedly altered the conclusions of the studies. Even if there was a survival advantage attributed to hydroxyurea, overall survival was somewhat poor. We found the evidence regarding the use of hydroxyurea and radiotherapy to be inadequate for assessing its role in the treatment of cervical cancer.

Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis.

BACKGROUND: The US National Cancer Institute alert in February, 1999, stated that concomitant chemotherapy and radiotherapy should be considered for all patients with cervical cancer. Our aim was to review the effects of chemoradiotherapy on overall and progression-free survival, local and distant control, and acute and late toxicity in patients with cervical cancer. METHODS: With the methodology of the Cochrane Collaboration, we did a systematic review of all known randomised controlled trials done between 1981 and 2000 (17 published, two unpublished) of chemoradiation for cervical cancer. FINDINGS: The trials included 4580 randomised patients, and 2865-3611 patients (62-78%) were available for analysis. Cisplatin was the most common agent used. The findings suggest that chemoradiation improves overall survival (hazard ratio 0.71, p<0.0001), whether platinum was used (0.70, p<0.0001) or not (0.81, p=0.20). A greater beneficial effect was seen in trials that included a high proportion of stage I and II patients (p=0.009). An improvement in progression-free survival was also seen with chemoradiation (0.61, p<0.0001). Thus, the absolute benefit in progression-free and overall survival was 16% (95% CI 13-19) and 12% (8-16), respectively. A significant benefit of chemoradiation on both local (odds ratio 0.61, p<0.0001) and distant recurrence (0.57, p<0.0001) was also recorded. Grade 3 or 4 haematological (odds ratio 1.49-8.60) and gastrointestinal (2.22) toxicities were significantly greater in the concomitant chemoradiation group than the control group. There was insufficient data to establish whether late toxicity was increased in the concomitant chemoradiation group. INTERPRETATION: Concomitant chemotherapy and radiotherapy improves overall and progression-free survival and reduces local and distant recurrence in selected patients with cervical cancer, which may give a cytotoxic and sensitisation effect.

Preoperative radiotherapy for esophageal carcinoma.

BACKGROUND: The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. OBJECTIVES: This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery and whether or not any pre-defined patient subgroups benefit more or less from preoperative radiotherapy SEARCH STRATEGY: Medline and CancerLit searches were supplemented by information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists, organisations and industry. The search strategy was run again in Medline, Embase and the Cochrane Library on 2nd May 2000, one year after original publication. No new trials were found. SELECTION CRITERIA: Trials were eligible for inclusion in this meta-analysis provided they randomized patients with potentially resectable carcinoma of the esophagus (of any histological type) to receive radiotherapy or no radiotherapy prior to surgery. Trials must have used a randomization method which precluded prior knowledge of treatment assignment and completed accrual by December 1993, to ensure sufficient follow-up by the time of the first analysis (September 1995). DATA COLLECTION AND ANALYSIS: A quantitative meta-analysis using updated data from individual patients from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. This approach was used to assess whether preoperative radiotherapy improves overall survival and whether it is differentially effective in patients defined by age, sex and tumour location. MAIN RESULTS: With a median follow-up of 9 years, in a group patients with mostly squamous carcinomas, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p=0.062). No clear differences in the size of the effect by sex, age or tumor location were apparent. REVIEWER'S CONCLUSIONS: Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients (90% power, 5% significance level) would be needed to reliably detect such an improvement (from 15 to 20%).

Is there bias in the publication of individual patient data meta-analyses?

OBJECTIVE: There is increasing empirical evidence for the existence of bias in the publication of primary clinical research, with statistically significant results being published more readily, more quickly, and in higher impact journals. Meta-analysis of individual patient data (IPD) may represent a gold standard of "secondary" clinical research, giving the best possible summary of current evidence for a particular question, but publication of these may also be subject to bias. This study aimed to explore which factors might be associated with publication of IPD meta-analyses and to identify potential sources of bias. METHODS: For all known IPD meta-analysis projects in cancer, the responsible investigator was surveyed by means of a questionnaire to determine descriptive characteristics of the meta-analysis, the nature of the results, and details of the publication history. RESULTS: There is no good evidence that overall publication status of meta-analyses in cancer is dependent on the statistical or clinical significance of the results. However, those meta-analyses with nonsignificant results did seem to take longer to publish and were published in lower impact journals compared with those with more striking results. CONCLUSIONS: Based on the current data, there seems to be no strong association between the results of IPD meta-analyses in cancer and publication.

Preoperative radiotherapy for esophageal carcinoma. Oeosphageal Cancer Collaborative Group.

BACKGROUND: The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. OBJECTIVES: This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery and whether or not any pre-defined patient subgroups benefit more or less from preoperative radiotherapy SEARCH STRATEGY: Medline and CancerLit searches were supplemented by information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists, organisations and industry. SELECTION CRITERIA: Trials were eligible for inclusion in this meta-analysis provided they randomized patients with potentially resectable carcinoma of the esophagus (of any histological type) to receive radiotherapy or no radiotherapy prior to surgery. Trials must have used a randomization method which precluded prior knowledge of treatment assignment and completed accrual by December 1993, to ensure sufficient follow-up by the time of the first analysis (September 1995). DATA COLLECTION AND ANALYSIS: A quantitative meta-analysis using updated data from individual patients from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. This approach was used to assess whether preoperative radiotherapy improves overall survival and whether it is differentially effective in patients defined by age, sex and tumour location. MAIN RESULTS: With a median follow-up of 9 years, in a group patients with mostly squamous carcinomas, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p=0.062). No clear differences in the size of the effect by sex, age or tumor location were apparent. REVIEWER'S CONCLUSIONS: Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients (90% power, 5% significance level) would be needed to reliably detect such an improvement (from 15 to 20%).

Can the published data tell us about the effectiveness of neoadjuvant chemotherapy for locally advanced cancer of the uterine cervix?

The effect of neoadjuvant chemotherapy on survival of patients with locally advanced cervical cancer was investigated by conducting a systematic review and meta-analysis of the published data. Of the 21 randomised trials that we identified, only 15 were published. Furthermore, 2-year survival data could be extracted from only seven trial reports and 3-year survival from only nine trial reports. Meta-analyses of the published data at 2 and 3 years are neither clearly in favour of neoadjuvant chemotherapy nor control (2 years: odds ratio (OR) = 1.09, 95% confidence interval (CI) = 0.83-1.45, P = 0.37; 3 years: OR = 0.96, 95% confidence interval (CI) = 0.73-1.25, P = 0.45). Being restricted to only some of the data from a relatively small fraction of the randomised trials, these analyses potentially suffer from a number of biases and are therefore inconclusive. The only reliable way to judge the value of neoadjuvant chemotherapy in this disease is to perform a meta-analysis of centrally collected, updated, individual data on all patients from all known randomised trials. Such an analysis is currently being carried out by an international collaborative group.

Preoperative radiotherapy in esophageal carcinoma: a meta-analysis using individual patient data (Oesophageal Cancer Collaborative Group).

PURPOSE: The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery. METHODS AND MATERIALS: This quantitative meta-analysis included updated individual patient data from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. RESULTS: With a median follow-up of 9 years, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p = 0.062). No clear differences in the size of the effect by sex, age, or tumor location were apparent. CONCLUSION: Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients would be needed to reliably detect such an improvement (15-->20%).