Denis Maillet

Quality of Reporting of Modern Randomized Controlled Trials in Medical Oncology: A Systematic Review

BACKGROUNDnThe Consolidated Standards of Reporting Trials (CONSORT) guidelines were developed in the mid-1990s for the explicit purpose of improving clinical trial reporting. However, there is little information regarding the adherence to CONSORT guidelines of recent publications of randomized controlled trials (RCTs) in oncology.nnnMETHODSnAll phase III RCTs published between 2005 and 2009 were reviewed using an 18-point overall quality score for reporting based on the 2001 CONSORT statement. Multivariable linear regression was used to identify features associated with improved reporting quality. To provide baseline data for future evaluations of reporting quality, RCTs were also assessed according to the 2010 revised CONSORT statement. All statistical tests were two-sided.nnnRESULTSnA total of 357 RCTs were reviewed. The mean 2001 overall quality score was 13.4 on a scale of 0-18, whereas the mean 2010 overall quality score was 19.3 on a scale of 0-27. The overall RCT reporting quality score improved by 0.21 points per year from 2005 to 2009. Poorly reported items included method used to generate the random allocation (adequately reported in 29% of trials), whether and how blinding was applied (41%), method of allocation concealment (51%), and participant flow (59%). High impact factor (IF, P = .003), recent publication date (P = .008), and geographic origin of RCTs (P = .003) were independent factors statistically significantly associated with higher reporting quality in a multivariable regression model. Sample size, tumor type, and positivity of trial results were not associated with higher reporting quality, whereas funding source and treatment type had a borderline statistically significant impact.nnnCONCLUSIONnThe results show that numerous items remained unreported for many trials. Thus, given the potential impact of poorly reported trials, oncology journals should require even stricter adherence to the CONSORT guidelines.

Adherence to CONSORT Adverse Event Reporting Guidelines in Randomized Clinical Trials Evaluating Systemic Cancer Therapy: A Systematic Review

PURPOSEnThe Consolidated Standards of Reporting Trials (CONSORT) guidance was extended in 2004 to provide a set of 10 specific and comprehensive guidelines regarding adverse event (AE) reporting in randomized clinical trials (RCTs). Limited data exist regarding adherence to these guidelines in publications of oncology RCTs.nnnMETHODSnAll phase III RCTs published between 2007 and 2011 were reviewed using a 16-point AE reporting quality score (AERQS) based on the 2004 CONSORT extension. Multivariable linear regression was used to identify features associated with improved reporting quality.nnnRESULTSnA total of 325 RCTs were reviewed. The mean AERQS was 10.1 on a 16-point scale. The most common items that were poorly reported were the methodology of AE collection (adequately reported in only 10% of studies), the description of AE characteristics leading to withdrawals (15%), and whether AEs are attributed to trial interventions (38%). Even when reported, the methods of AE collection and analysis were highly heterogeneous. The multivariable regression model revealed that industry funding, intercontinental trials, and trials in the metastatic setting were predictors of higher AERQS. The quality of AE reporting did not improve significantly over time and was not better among articles published in journals with a high impact factor.nnnCONCLUSIONnOur findings show that some methodologic aspects of AE collection and analysis were poorly reported. Given the importance of AEs in evaluating new treatments, authors should be encouraged to adhere to the 2004 CONSORT guidelines regarding AE reporting.

Prostate-specific antigen flare induced by cabazitaxel-based chemotherapy in patients with metastatic castration-resistant prostate cancer

BACKGROUNDnA prostate-specific antigen (PSA) flare occurs in about 15% of metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel. This flare has no standard definition. Its impact on treatment efficacy is unclear. We sought to evaluate the incidence and characteristics of PSA flare on cabazitaxel, and its impact on survival.nnnMETHODSnMulticentre retrospective review of consecutive patients treated with cabazitaxel second-line chemotherapy for mCRPC. Collection of baseline characteristics, disease history and PSA levels before and during cabazitaxel therapy. Overall survival (OS) and radiological/clinical progression-free survival (PFS) for patient groups corresponding to different definitions of PSA flare estimated by the Kaplan-Meier method and compared using the log-rank test.nnnRESULTSnOverall, 125 patients were included. Median PFS and OS were 6.5 and 13.3 months, respectively. Depending upon the definition used, flare incidence ranged from 8.3% to 30.6%. The flare lasted <2.6 months. A PSA flare followed by a ⩾ 50% decrease was associated with a median PFS and OS of 11.2 and 25.2 months, respectively. Median PFS and OS for a ⩾ 30% rather than ⩾ 5 0% decrease were 10.4 and 16.5 months. These outcomes were not significantly different from those in patients with immediate PSA decreases of ⩾ 50% or ⩾ 30% from baseline, but were significantly better than in patients experiencing no PSA decrease (p = 0.006 and 0.015, respectively, for OS).nnnCONCLUSIONnThe PSA response to cabazitaxel, with or without initial flare, was associated with a strong survival benefit. The taxane-induced flare during the first 12 weeks of therapy can be ignored when evaluating PSA response.

Poor patient-reported outcomes reporting according to CONSORT guidelines in randomized clinical trials evaluating systemic cancer therapy

BACKGROUNDnThe Consolidated Standards of Reporting Trials (CONSORT) guidance was extended in 2013 to provide a set of specific recommendations regarding patient-reported outcomes (PROs) reporting in randomized clinical trials (RCTs). There is limited data regarding how well current publications of oncology RCTs report PROs if assessed using these guidelines.nnnDESIGNnAll phase III medical oncology RCTs published between 2007 and 2011 were reviewed according to the 2013 PROs CONSORT recommendations and an 11-point PROs reporting quality score (PRORQS) was defined based on the criteria.nnnRESULTSnThe majority of trials did not report on PROs at all (201 of 325; 62%). Of the remaining 124 trials, the mean PRORQS score was 5.0 on an 11-point scale. The items related to methods of PROs collection and analysis were poorly reported (Description of the prespecified PRO hypothesis: 26% of RCTs; methods for PRO data collection (paper, telephone, electronic, other): 16%; statistical approaches for managing missing data: 37%). The only factor significantly associated with improved PROs reporting was where PROs reporting was the subject of a dedicated secondary manuscript, as was the case in 36 of the 124 (29%) of RCTs.nnnCONCLUSIONnDespite their clinical relevance, our findings show that some aspects of PROs reporting may greatly be improved, especially critical methodological aspects of PROs collection and analysis. The exceptions were where PROs were described in PROs-specific secondary publication. Use of the 2013 PROs CONSORT extensions should be encouraged and their effects on PROs reporting subsequently reassessed.BACKGROUNDnThe Consolidated Standards of Reporting Trials (CONSORT) guidance was extended in 2013 to provide a set of specific recommendations regarding patient-reported outcomes (PROs) reporting in randomized clinical trials (RCTs). There is limited data regarding how well current publications of oncology RCTs report PROs if assessed using these guidelines.nnnDESIGNnAll phase III medical oncology RCTs published between 2007 and 2011 were reviewed according to the 2013 PROs CONSORT recommendations and an 11-point PROs reporting quality score (PRORQS) was defined based on the criteria.nnnRESULTSnThe majority of trials did not report on PROs at all (201 of 325; 62%). Of the remaining 124 trials, the mean PRORQS score was 5.0 on an 11-point scale. The items related to methods of PROs collection and analysis were poorly reported (Description of the prespecified PRO hypothesis: 26% of RCTs; methods for PRO data collection (paper, telephone, electronic, other): 16%; statistical approaches for managing missing data: 37%). The only factor significantly associated with improved PROs reporting was where PROs reporting was the subject of a dedicated secondary manuscript, as was the case in 36 of the 124 (29%) of RCTs.nnnCONCLUSIONnDespite their clinical relevance, our findings show that some aspects of PROs reporting may greatly be improved, especially critical methodological aspects of PROs collection and analysis. The exceptions were where PROs were described in PROs-specific secondary publication. Use of the 2013 PROs CONSORT extensions should be encouraged and their effects on PROs reporting subsequently reassessed.

Genomic copy number alterations in 33 malignant peritoneal mesothelioma analyzed by comparative genomic hybridization array

Malignant peritoneal mesotheliomas (MPM) are rare, accounting for approximately 8% of cases of mesothelioma in France. We performed comparative genomic hybridization (CGH) on frozen MPM samples using the Agilent Human Genome CGH 180 K array. Samples were taken from a total of 33 French patients, comprising 20 men and 13 women with a mean (range) age of 58.4 (17-76) years. Asbestos exposure was reported in 8 patients (24.2%). Median (range) overall survival (OS) was 39 (0-119) months. CGH analysis demonstrated the presence of chromosomal instability in patients with MPM, with a genomic pattern that was similar to that described for pleural mesothelioma, including the loss of chromosomal regions 3p21, 9p21, and 22q12. In addition, novel genomic copy number alterations were identified, including the 15q26.2 region and the 8p11.22 region. Median OS was associated with a low peritoneal cancer index (P=.011), epithelioid subtype (P=.038), and a low number of genomic aberrations (P=.015), all of which constitute good prognostic factors for MPM. Our results provide new insights into the genetic and genomic background of MPM. Although pleural and peritoneal mesotheliomas have different risk factors, different therapeutics, and different prognosis; these data provide support to combine pleural and peritoneal mesothelioma in same clinical assays.

The reporting of adverse events in oncology phase III trials: a comparison of the current status versus the expectations of the EORTC members

BACKGROUNDnDetermination of drug safety and tolerability is usually based on the frequency of certain key adverse events (AEs) rather than the frequency of all-grade toxicities. We assessed the reporting of key AEs in oncology randomized, controlled trials (RCTs) and compared that with the expectations of the European Organization for Research and Treatment of Cancer (EORTC) membership.nnnMATERIALS AND METHODSnRCTs reports published between 2007 and 2011 were reviewed regarding the reporting of key AEs, namely: grade 3/4 AEs, grade 5 AEs, and AEs resulting in study withdrawal or in dose reduction. Study characteristics associated with better reporting of key AEs were investigated. Finally, a survey was conducted among the EORTC membership to determine their expectations on key AEs reporting.nnnRESULTSnAlthough the frequency of grade 3/4 was reported in most reports (96%), only 17% of them described the reporting threshold above which grade 3/4 AEs were included for reporting, raising the possibility that important but less frequent grade 3/4 AEs might be underreported. Frequency and nature of grade 5 AEs were adequately reported in 161 (50%) of manuscripts; AEs leading to study withdrawal in 61 manuscripts (19%); and AEs leading to dose reduction in 43 manuscripts (13%). In contrast, most EORTC members expected a comprehensive reporting of grade 5 AEs (96% of EORTC members responses), AEs leading to study withdrawal (86%) and AEs leading to dose reduction (70%). In multivariate analysis, frequencies of grade 5 AEs were less frequently reported in European trials (P = 0.004). Frequencies of AEs leading to withdrawals were more frequently reported in trials funded by industry (P = 0.005) and in trials including patients with breast or urological cancers (P = 0.006).nnnCONCLUSIONSnThese findings suggest that current practice of key AEs reporting remains highly variable and sometimes inadequate in oncology RCTs reports. Current standards for safety reporting in RCTs should be revised to emphasize the importance of key AEs reporting.

Ephrin-B3 supports glioblastoma growth by inhibiting apoptosis induced by the dependence receptor EphA4

EphA4, an Ephrins tyrosine kinase receptor, behaves as a dependence receptor (DR) by triggering cell apoptosis in the absence of its ligand Ephrin-B3. DRs act as conditional tumor suppressors, engaging cell death based on ligand availability; this mechanism is bypassed by overexpression of DRs ligands in some aggressive cancers. The pair EphA4/Ephrin-B3 favors survival of neuronal progenitors of the brain subventricular zone, an area where glioblastoma multiform (GBM) are thought to originate. Here, we report that Ephrin-B3 is highly expressed in human biopsies and that it inhibits EphA4 pro-apoptotic activity in tumor cells. Angiogenesis is directly correlated with GBM aggressiveness and we demonstrate that Ephrin-B3 also supports the survival of endothelial cells in vitro and in vivo. Lastly, silencing of Ephrin-B3 decreases tumor vascularization and growth in a xenograft mice model. Interference with EphA4/Ephrin-B3 interaction could then be envisaged as a relevant strategy to slow GBM growth by enhancing EphA4-induced cell death.EphA4, an Ephrins tyrosine kinase receptor, behaves as a dependence receptor (DR) by triggering cell apoptosis in the absence of its ligand Ephrin-B3. DRs act as conditional tumor suppressors, engaging cell death based on ligand availability; this mechanism is bypassed by overexpression of DRs ligands in some aggressive cancers. The pair EphA4/Ephrin-B3 favors survival of neuronal progenitors of the brain subventricular zone, an area where glioblastoma multiform (GBM) are thought to originate. Here, we report that Ephrin-B3 is highly expressed in human biopsies and that it inhibits EphA4 pro-apoptotic activity in tumor cells. Angiogenesis is directly correlated with GBM aggressiveness and we demonstrate that Ephrin-B3 also supports the survival of endothelial cells in vitro and in vivo. Lastly, silencing of Ephrin-B3 decreases tumor vascularization and growth in a xenograft mice model. Interference with EphA4/Ephrin-B3 interaction could then be envisaged as a relevant strategy to slow GBM growth by enhancing EphA4-induced cell death.

Loco-regional treatment for castration-resistant prostate cancer: Is there any rationale? A critical review from the AFU-GETUG

Emerging evidence from population-based and retrospective series suggests a potential improvement of clinical outcomes in metastatic prostate cancer. Moreover, metastasis-directed treatment has shown encouraging results in this setting. There is an increasing interest in exploring the potential of local therapies in advanced prostate cancer, but this has rarely been specifically addressed in the castration-resistant state, whether non-metastatic or metastatic. A review of relevant articles was performed on the oncologic benefit of local treatment of the primary tumor or metastasis-targeted treatment in castration-resistant prostate cancer patients. The main goal of this strategy is to delay introduction of a new systemic agent to maintain quality of life and potentially to limit resistance. Further investigation is required to provide high-level evidence for the oncologic benefit of this treatment modality.

Influence of statistician involvement on reporting of randomized clinical trials in medical oncology.

Ideally, statisticians should be involved in the design, analysis, and reporting of randomized clinical trials (RCTs). This study assessed the impact of a statistician involvement in published medical oncology RCTs between 2005 and 2009. The reporting quality of each publication was rated using the Overall Reporting Quality Score on the basis of either 2001 or 2010 Consolidated Standards of Reporting Trials criteria. A four-question email survey on the statistical design and analysis was sent to the corresponding authors of each trial. Nonresponders were approached a maximum of three times. Overall, 107 responses were received from 357 solicited authors (30%). Corresponding authors from industry-funded RCTs were less likely to respond (51 vs. 65%, P=0.013). The same person was responsible for statistical design and analyses in 47% of cases. Overall, the statistician involved held a PhD (or equivalent) in statistics in most cases. The statisticians responsible for the statistical design and analysis were listed as coauthors in 68 and 81% of RCT manuscripts. There was no statistically significant impact on manuscript reporting quality of the degree of statistician involvement in manuscript preparation. Fewer trials were reported as positive when the responsible statistician was listed as a coauthor. It is possible that RCTs included in this review are in general of higher quality or were more likely to have a greater level of statistician involvement than smaller, single-arm, or unpublished studies. This imbalance could explain the lack of significant difference observed in the Overall Reporting Quality Score between trials where statisticians were listed as coauthors or not.

Systemic treatments for high-risk localized prostate cancer

The majority of patients with prostate cancer who later develop lethal metastatic disease have high-risk localized disease at presentation, emphasizing the importance of effective treatment strategies at this stage. Multimodal treatment approaches that combine systemic and local therapies offer a promising strategy for improving the clinical outcomes of patients with high-risk localized prostate cancer. Combinations of neoadjuvant and adjuvant chemotherapy, hormonal therapy, or chemohormonal therapy are considered to be the standard of care in most solid tumours and should be investigated in the future for the treatment of prostate cancer to improve patient outcomes. However, although the combination of androgen deprivation therapy and radiotherapy is a standard of care in high-risk localized or locally advanced prostate cancer, the benefit of chemotherapy or chemohormonal therapy has yet to be demonstrated outside of the metastatic setting. Moreover, the benefit of neoadjuvant and/or adjuvant systemic therapies in combination with radical prostatectomy has not been proved. The development of next-generation hormonal agents, which have been approved for the treatment of castration-resistant prostate cancer, offers further therapeutic possibilities that are being assessed in early-phase clinical trials.Patients with high-risk localized prostate cancer have a poor prognosis, and appropriate treatments are therefore imperative. Herein, the authors present the current clinical evidence of the benefit of neoadjuvant and adjuvant systemic therapies for the treatment of these patients.Key pointsPatients with high-risk localized prostate cancer have a poor prognosis and require an appropriate treatment strategy that considers a multimodal approach and includes both local and systemic therapies.No benefit has been proved for any neoadjuvant or adjuvant hormonal therapy in the case of radical prostatectomy.No benefit has been proved for chemotherapy administered before or after radical prostatectomy.Long-term androgen deprivation therapy in combination with radiotherapy was shown to markedly improve survival outcomes and should therefore be proposed for patients with high-risk localized prostate cancer.Additional evidence of the benefit of chemohormonal therapy in combination with radiotherapy is required in the neoadjuvant and adjuvant settings.Next-generation hormone therapies are still under investigation in the neoadjuvant or adjuvant settings.