Julien Péron

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

BACKGROUND The 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. METHODS All 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. RESULTS A 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. CONCLUSION The 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

PURPOSE The 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. METHODS All 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. RESULTS A 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. CONCLUSION Our 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.

Benefit of adjuvant trastuzumab-based chemotherapy in T1ab node-negative HER2-overexpressing breast carcinomas: a multicenter retrospective series

BACKGROUND Randomized clinical trials showed the benefit of adjuvant trastuzumab-based chemotherapy (ATBC) for node-positive and/or >1 cm HER2+ breast carcinomas. No efficacy data have been published on ATBC in large series of pT1abN0 HER2+ tumors. PATIENTS AND METHODS This retrospective study evaluated 276 cases of pT1abN0 HER2+ breast tumors in eight French cancer centers. Factors associated with prognosis and ATBC prescription were analyzed. RESULTS A total of 129 cases (47%) were treated with ATBC (ATBC+), 19 with chemotherapy alone, 5 with trastuzumab alone, and 123 (45%) with neither trastuzumab nor chemotherapy (ATBC-). ATBC use was associated with the date of diagnosis (before or after June 2005) and with poor prognostic features. At a median follow-up of 44 months, there were 13 recurrences in the ATBC- group and 2 in the ATBC+ group. ATBC was associated with a significant survival benefit (99% 40-month disease-free survival for ATBC+ versus 93% for ATBC- cases; P = 0.018). Lack of hormone receptors (HRs) and the presence of lymphovascular invasion (LVI) were significantly associated with a poor prognosis and a greater benefit of ATBC. CONCLUSIONS ATBC was associated with a significantly reduced risk of recurrence in pT1abN0 HER2+ tumors, and was more beneficial in HR- and/or LVI+ tumors.

Adjuvant docetaxel/cyclophosphamide in breast cancer patients over the age of 70: results of an observational study.

This retrospective observational study was designed to describe feasibility and tolerance of adjuvant Taxotere®/cyclophosphamide (TC) chemotherapy in women aged over 70 years with early breast cancer. Data including geriatric evaluations were collected from the medical charts of 110 patients from 14 oncology institutions in France who had completed adjuvant systemic TC (91% received at least 4 cycles). Median age was 73 years (range 70-85), 51% of patients had breast conserving surgery, 42% had a tumor smaller than 2cm and 33% had positive nodes. Geriatric assessment was performed by oncologists in 88% of patients; 55% were considered fit, 5% had geriatric syndrome and 10% had more than three comorbidities. Neutropenia was reported in 15% of patients, including febrile neutropenia and/or grade 4 in 5% for each. Primary prophylactic G-CSF was given to 49% of patients. In a selected population of elderly patients, 4 cycles of adjuvant TC is feasible without major toxicity, confirming the US Oncology trial data.

Paclitaxel and cetuximab combination efficiency after the failure of a platinum-based chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma.

The addition of cetuximab (CTX) to the combination of cisplatin and 5-fluorouracil increases the overall survival (OS) in recurrent/metastatic head and neck squamous cell carcinoma. Only a few patients are eligible for this treatment because of its toxicity. The combination of CTX and paclitaxel (TXL) could be included in sequential treatment strategies. Patients were treated with CTX (400/250 mg/m2) and TXL (60–80 mg/m2) weekly until disease progression or unacceptable toxicity. Efficacy and safety outcomes were determined retrospectively. A total of 42 patients were included in this analysis. The overall response rate was 38% [95% confidence interval (CI); 23–53%]. The disease control rate with TXL and CTX combination was 74%. Seven (17%) patients progressed before the first evaluation. The median progression-free survival was 3.9 months [95% CI; 3.1–4.7 months] and the median OS was 7.6 months [95% CI; 5.3–9.9 months]. Neurotoxicity and skin rash were the most frequent grade≥2 toxicities, reported in 17 and 12% of patients, respectively. Previous chemotherapy seems to be associated with a lower response rate and progression-free survival but not with the OS. The combination of CTX and TXL was an active and well-tolerated treatment in this series of patients with a poor prognosis and who were mostly symptomatic.

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

BACKGROUND The 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. DESIGN All 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. RESULTS The 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. CONCLUSION Despite 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.BACKGROUND The 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. DESIGN All 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. RESULTS The 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. CONCLUSION Despite 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.

Inclusion Of Elderly Patients In Oncology Clinical Trials

BACKGROUND Physicians need clinical trials assessing benefits and harms of treatments to avoid under-treatment or over-treatment of elderly patients. The main objectives of this report were to examine how data regarding elderly oncology patients were presented in medical literature; and to assess the evolution of this presentation between two time periods. PATIENTS AND METHODS All phases I, II and III trials dedicated to the treatment of cancer among elderly patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. All phase III clinical trials assessing cancer treatments among adults in the same periods were also reviewed to evaluate potential subgroup analyses in elderly patients in these studies. Key characteristics of interest were extracted by two investigators before descriptive and comparative analyses were undertaken. RESULTS A total of 1084 trials were included: 366 and 718 from the first and second time period, respectively. Twenty-seven and 193 of these trials were phase I and II trials dedicated to elderly or frail patients, respectively. A large proportion of phase III trials published between 2011 and 2014 reported at least one analysis dedicated to elderly patients (46.7%) versus 19.3% during the first time period. The use of subgroup analyses of elderly patients in phase III trials was the most frequent source of information. Subgroup analyses were more frequent among trials with industrial funding, trials published in high impact factor journal, intercontinental trials and trials with large sample size. The age threshold defining the elderly subgroup increased over time. CONCLUSION Elderly patients have become a topic of interest during the past decade. However, data available are mostly extracted from subgroup analyses, which can only be regarded as preliminary evidence.

Nonoperative management of squamous-cell carcinoma of the rectum.

BACKGROUND: Radiochemotherapy without surgical resection has become the treatment of choice for anal squamous-cell carcinoma. The optimal treatment for rectal squamous-cell carcinoma is not well established. OBJECTIVE: The purpose of this work was to assess the efficacy of nonoperative strategies in the management of primary rectal squamous-cell carcinoma. DESIGN: We retrospectively reviewed data from all of the patients with documented rectal squamous-cell carcinoma who were treated with conservative strategies in a single institution. Concomitant radiochemotherapy was proposed to all except 1 patient. The remaining patient was treated by radiotherapy alone given his impaired functional status. All of the patients were treated with conformal or intensity-modulated radiation therapy. Surgical resection was reserved for persistent disease or relapse. SETTING: This study was conducted in a single tertiary institution. MAIN OUTCOME MEASURES: After a mean follow-up of 56 months, 2 patients experienced relapse and no patients died. RESULTS: Eleven patients were included in the series. The clinical response to radiotherapy was complete for 7 patients. The remaining 4 patients underwent salvage surgery. The pathologic response was incomplete for 2 of the 4 patients. One recurrence occurred outside the field of radiotherapy and was successfully treated by radiotherapy. The second was a local recurrence, which occurred on a patient who was treated with radiotherapy alone. LIMITATIONS: The number of patients included in this retrospective series was limited because of the rarity of the disease. Patients were treated with nonhomogeneous conservative strategies because of modification in the therapeutic strategy for anal squamous-cell carcinoma and of the adaptation of the treatment to patient comorbidities and functional status. CONCLUSIONS: This series demonstrates that good results can be obtained by using a rectum-conserving strategy. Close follow-up should be maintained, with the use of salvage surgery reserved only for persistent disease or relapse (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A155).

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

BACKGROUND Determination 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. MATERIALS AND METHODS RCTs 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. RESULTS Although 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). CONCLUSIONS These 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.