Publications by authors named "Denis Maillet"

29 Publications

  • Page 1 of 1

Toxicity and Surgical Complication Rates of Neoadjuvant Atezolizumab in Patients with Muscle-invasive Bladder Cancer Undergoing Radical Cystectomy: Updated Safety Results from the ABACUS Trial.

Eur Urol Oncol 2021 Feb 18. Epub 2021 Feb 18.

Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London, UK. Electronic address:

Background: There are limited data on toxicity and surgical safety associated with neoadjuvant programmed death ligand 1 (PD-L1) inhibitors prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC).

Objective: To present a comprehensive safety analysis of the largest neoadjuvant series, with focus on timing and severity of toxicity and surgical complications occurring after neoadjuvant atezolizumab in patients with MIBC enrolled in the ABACUS trial.

Design, Setting, And Participants: ABACUS (NCT02662309) is an open-label, multicenter, phase II trial for patients with histologically confirmed (T2-T4aN0M0) MIBC, awaiting RC. Patients either were ineligible or refused cisplatin-based neoadjuvant chemotherapy.

Intervention: Two cycles of neoadjuvant atezolizumab (1200 mg, every 3 wk) followed by RC.

Outcome Measurements And Statistical Analysis: Description of atezolizumab toxicity profile in the neoadjuvant setting, impact on surgery, and delayed immune-mediated adverse events (AEs) were assessed.

Results And Limitations: Ninety-five patients received treatment. Of them, 44% (42/95) had atezolizumab-related AEs during the neoadjuvant period (fatigue [20%], decreased appetite [6%], and transaminases increased [6%]). Treatment-related grade 3-5 AEs occurred in 11% (10/95) of patients during the study. Of the patients, 21% (20/95) received only one cycle of atezolizumab due to AEs; 92% (87/95) underwent RC. No surgery was delayed due to atezolizumab-related toxicities. Surgical complications occurred in 62% (54/87) of patients. Of these patients, 43% (37/87) and 20% (17/87) had minor (grade 1-2) and major (grade 3-5) complications, respectively. Thirteen of 87 (15%) patients had post-RC atezolizumab-related AEs, including adrenal insufficiency and transaminases increased. Three deaths occurred during the period of study-related interventions (one non-treatment-related aspiration pneumonia, one immune-related myocardial infarction, and one cardiogenic shock after RC). Not all surgical safety parameters were available.

Conclusions: Two cycles of neoadjuvant atezolizumab are well tolerated and do not seem to impact surgical complication rates. Owing to the long half-life, AEs may occur in the postoperative period, including endocrine abnormalities requiring attention and intervention.

Patient Summary: Here, we report a comprehensive dataset of patients receiving neoadjuvant immune checkpoint inhibitors before radical cystectomy. Treatment with neoadjuvant atezolizumab is safe and does not seem to complicate surgery significantly.
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http://dx.doi.org/10.1016/j.euo.2020.11.010DOI Listing
February 2021

Association between immune-related adverse events and long-term survival outcomes in patients treated with immune checkpoint inhibitors.

Eur J Cancer 2020 06 22;132:61-70. Epub 2020 Apr 22.

Hospices Civils de Lyon, Oncology Department, Pierre-Bénite, France; Université de Lyon, F-69000 Lyon, France; Université Lyon 1, F-69100 Villeurbanne, France; ImmuCare (Immunology Cancer Research) Institut de Cancérologie des Hospices Civils de Lyon, Lyon, France; CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, F-69100 Villeurbanne, France.

Background: The impact of immune-related adverse events (irAE) on survival outcomes after single-agent immune checkpoint inhibitors (ICIs) remains unclear. We aimed to evaluate the association between irAEs and ICI efficacy in various malignancies.

Methods: All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective multicentric series. The primary objective was to assess the impact of all type grade ≥II irAEs on progression-free survival (PFS) and overall survival (OS). IrAEs were first considered as a fixed covariate and included in Cox-regression models. In addition, as irAEs are time-related events and can occur at any point during follow-up, we analysed the occurrence of irAEs as a time-varying covariate.

Results: In this cohort of 410 patients, the majority of patients (70%) were treated for non-small cell lung cancer. The ICI was an anti-PD(L)1 for 356 patients (82%) and an anti-CTLA4 for 79 patients (18%). In total 126 (29%) of the patients presented at least one grade ≥II irAEs. The first occurrence of a grade ≥II irAE had a positive impact on PFS and OS when considered as a fixed or as a time-varying covariate (hazard ratio [HR] for PFS = 0.63, 95% confidence interval [CI] 0.50-0.81; P = 0.00022; HR for OS = 0.57, 95% CI 0.43-0.74, P < 0.0001). This overall finding was confirmed in patients treated with an anti-PD(L)1 and among patients with lung cancer.

Conclusion: In this pooled multi-institutional cohort, the incidence of irAEs was associated with better long-term survival across different malignancies treated with ICI monotherapy.
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http://dx.doi.org/10.1016/j.ejca.2020.03.017DOI Listing
June 2020

[Checkpoint inhibitors-induced hypophysitis].

Bull Cancer 2020 Apr 19;107(4):490-498. Epub 2020 Mar 19.

Hospices civils de Lyon, fédération d'endocrinologie, 28, avenue Doyen-Lépine, 69677 Bron cedex, France; ImmuCare, institut de cancérologie des hospices civils de Lyon (IDCRC-HCL), Lyon, France; Université de Lyon, université Claude-Bernard-Lyon-1, Lyon, France.

Checkpoint inhibitors immunotherapy is more and more prescribed in oncology, causing new immune related endocrine adverse events. Hypophysitis occurs in approximately 10 % of patients treated with anti-CTLA4. It occurs two to three months after initiation of the immunotherapy. The initial presentation is characterized, in typical forms, by the association of headache, asthenia and hyponatremia. Hormonal exploration usually shows ACTH, gonadotropic and thyrotropic deficiencies. ACTH deficiency may be life-threatening and requires urgent supplementation, without awaiting for biological results. MRI is warranted in order to exclude differential diagnoses, such as pituitary metastases. Hypophysitis induced by anti-PD1/PDL1 seems to be a different nosologic entity characterized by a later onset and a less symptomatic presentation. Biologically ACTH deficiency seems to be constant and permanent, and often isolated. Treatment requires high-dose steroids only in case of severe tumor syndrome (resistant headache, visual disturbance) or acute decompensation of ACTH deficiency. Patients always need lifelong hormonal supplementation of pituitary deficits and must be followed and educated specifically. Immunotherapy can be delayed during the acute phase, but can be secondarily continued if there is an oncological benefit. As it is a pauci-symptomatic but potentially life-threatening complication, biological screening must be systematic in patients treated with checkpoint inhibitors.
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http://dx.doi.org/10.1016/j.bulcan.2020.01.012DOI Listing
April 2020

[Thyroid dysfunctions secondary to cancer immunotherapy].

Bull Cancer 2020 Feb 24;107(2):262-271. Epub 2019 Dec 24.

Hospices civils de Lyon, hôpital Lyon Sud, service d'endocrinologie diabète nutrition, 165, chemin du Grand Revoyet, 69310 Pierre-Bénite, France; ImmuCare, Institut de cancérologie des hospices civils de Lyon (IDCRC-HCL), 69003 Lyon, France; Université de Lyon, université Claude Bernard Lyon 1, 69100 Lyon, France.

The immune checkpoint inhibitors (CPI) such as anti-PD(L)1 or anti-CTLA4 had improved long-term patients' outcomes in different malignancies. Thyroid disorders are the most frequent endocrine side effects from CPI reported in clinical trials and in clinical routine practice. The incidence of thyroid dysfunction is variable according to ICP used (more frequent under anti-programmed cell death 1 (PD1) or anti-programmed cell death-ligand 1 (PDL1)). Most thyroid dysfunctions have been reported to occur 2 to 4 courses after CPI initiation. The clinical symptoms are generally nonspecific (asthenia, weight change, rarely cardiac rhythm disorder). These thyroid dysfunctions are commonly painless thyroiditis with a biphasic evolution: thyrotoxicosis followed by a secondary hypothyroidism frequently definitive. Diagnosis is made on a thyroid test (TSH and FT4). In most cases, no further exam is necessary. Beta blockers therapy is recommended in symptomatic thyrotoxicosis with palpitations. Thyroid hormones therapy will be introduced quickly in case of hypothyroidism. Thyroid dysfunctions are not a contra-indication to the continuation of immunotherapy. Due to the high frequency of these complications, close monitoring of the thyroid status is recommended under CPI.
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http://dx.doi.org/10.1016/j.bulcan.2019.10.005DOI Listing
February 2020

Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial.

Nat Med 2019 11 4;25(11):1706-1714. Epub 2019 Nov 4.

Department of Medical Oncology, Hospital 12 de Octubre, Madrid, Spain.

Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers. Biomarkers may facilitate identification of these responding tumors. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.
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http://dx.doi.org/10.1038/s41591-019-0628-7DOI Listing
November 2019

Improved Androgen Receptor Splice Variant 7 Detection Using a Highly Sensitive Assay to Predict Resistance to Abiraterone or Enzalutamide in Metastatic Prostate Cancer Patients.

Eur Urol Oncol 2019 Oct 29. Epub 2019 Oct 29.

Institut de Cancérologie des Hospices Civils de Lyon, Lyon, France; Centre de Recherche en Cancérologie de Lyon, INSERM 1052 CNRS UMR 5286, Centre Léon Berard, Université Claude Bernard Lyon 1, Lyon, France; Centre d'études, de Recherche et de Valorisation en Oncologie (CERVO), Faculté de Médecine et de Maïeutique Lyon Sud-Charles Mérieux, Pierre-Bénite, France; Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France; Service de Biochimie Biologie Moléculaire Sud, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France. Electronic address:

Background: In metastatic castration-resistant prostate cancer (mCRPC), androgen receptor splice variant 7 (AR-V7) expression is associated with a low response to androgen receptor signaling (ARS) inhibitors such as abiraterone or enzalutamide.

Objective: To perform a highly sensitive assay for detecting AR-V7 (hsAR-V7) in circulating tumor cells (CTCs) and evaluate its ability to predict response to ARS inhibitors.

Design, Setting, And Participants: From 41 mCRPC patients, CTCs were prospectively enriched using AdnaTest platform and analyzed for AR-V7 with and without the highly sensitive assay.

Outcome Measurements And Statistical Analysis: The first objective of the study was to compare AR-V7 detection rates with and without the highly sensitive assay. Next, we investigated how AR-V7 (detected without the highly sensitive assay) and hsAR-V7 status influenced prostate-specific antigen (PSA) response and long-term clinical outcomes (PSA progression-free survival [PFS] and radiological PFS) after ARS-inhibitor treatment. Finally, discriminatory abilities of the assays were assessed by C-index to compare their impact on long-term clinical outcomes.

Results And Limitations: AR-V7 detection rates increased from 22% to 56% when the highly sensitive assay was used. The discriminatory abilities of hsAR-V7 for PSA PFS (C-index, 0.74; 95% confidence interval [CI], 0.60-0.88) and radiological PFS (0.70; 95% CI, 0.55-0.85) were higher than those of AR-V7 detected without the highly sensitive assay (0.60, 0.51-0.72, and 0.56, 0.44-0.67, respectively). After ARS-inhibitor treatment, PSA response was lower in hsAR-V7 (53%) than in hsAR-V7 (93%) patients (p = 0.016). AR-V7 patients had shorter median PSA PFS (3.0 vs 10.6 mo, p = 0.032) and nonsignificantly shorter median radiological PFS (6.0 vs 14.8 mo, p = 0.24) compared with AR-V7 patients. The hsAR-V7 status was associated with shorter median PSA PFS (3.0 mo vs not reached, p = 0.0001) and radiological PFS (median, 6.0 mo vs not reached, p = 0.0026).

Conclusions: The hsAR-V7 assay achieved the highest AR-V7 detection rates among those reported in mCRPC. Discriminatory abilities for long-term clinical outcomes were better with hsAR-V7 assay.

Patient Summary: We prospectively analyzed circulating tumor cells from men with metastatic castration-resistant prostate cancer for androgen receptor splice variant 7 (AR-V7) status using a highly sensitive assay. It yielded higher AR-V7 detection rates and predicted resistance to androgen receptor signaling inhibitors with better discriminatory abilities for long-term clinical outcomes.
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http://dx.doi.org/10.1016/j.euo.2019.08.010DOI Listing
October 2019

Guillain-Barré Syndrome During Platinum-Based Chemotherapy: A Case Series and Review of the Literature.

Oncologist 2020 01 15;25(1):e194-e197. Epub 2019 Oct 15.

Assistance Publique Hôpitaux de Paris (APHP), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), Unité Mixte de Recherche (UMR) S975, Paris, France.

Platinum-based chemotherapy is commonly associated with toxic sensory neuropathies, but also, although rarely, with Guillain-Barré syndrome (GBS). We describe five patients who developed GBS while receiving platinum-based chemotherapy for a solid tumor and report the five cases published so far. Most patients had received cumulative platinum doses below known neurotoxic levels, and all of them had an optimal outcome after platinum discontinuation, associated in most cases with administration of intravenous immunoglobulin. Clinical presentation, electroneuromyography, and cerebrospinal fluid analysis help clinicians to differentiate GBS from toxic neuropathy. Platinum compounds are the only chemotherapeutic agents used for solid tumors that have been associated to GBS. Thus, we propose that GBS may constitute a non-dose-dependent side effect of platinum drugs and that awareness needs to be raised among oncologists on this rare but potentially life-threatening complication of platinum chemotherapy. IMPLICATIONS FOR PRACTICE: Many patients on platinum-based chemotherapy for solid tumors develop sensory neuropathy, a common dose-dependent side effect. The authors propose that Guillain-Barré syndrome may constitute an immune-mediated, non-dose-related side effect of platinum-based chemotherapy. Prompt diagnosis of Guillain-Barré syndrome and distinction from classical toxic neuropathy are crucial for optimal treatment. Platinum discontinuation, associated if needed to intravenous immunoglobulin administration, radically changes the course of the disease and minimizes neurological sequelae.
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http://dx.doi.org/10.1634/theoncologist.2019-0255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964130PMC
January 2020

Older and younger patients treated with immune checkpoint inhibitors have similar outcomes in real-life setting.

Eur J Cancer 2019 11 4;121:192-201. Epub 2019 Oct 4.

Hospices Civils de Lyon, Oncology Department, Pierre-Bénite, France; Université de Lyon, F-69000, Lyon, France; Université Lyon 1, F-69100, Villeurbanne, France; ImmuCare (Immunology Cancer Research) Institut de Cancérologie des Hospices Civils de Lyon, Lyon, France; CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, F-69100, Villeurbanne, France. Electronic address:

Background: Age-related immune dysfunction might impair the efficacy of immune checkpoint inhibitors (ICIs) in older patients. We aimed to evaluate the impact of age on clinical outcomes and tolerance of ICIs in a real-life setting.

Methods: All patients receiving a single-agent ICI (cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] or programmed death(ligand)1 [PD(L)-1] inhibitors) for the standard treatment of a locally advanced or metastatic cancer were included in this retrospective multicentric series. The primary end-point was overall survival (OS). Progression-free survival (PFS) and immune-related adverse events (irAEs) were secondary end-points. The impact of age was assessed using the threshold of 70 years.

Results: A total of 410 patients were included, for 435 lines of treatment, including 150 lines (34%) given to patients aged 70 years or older. The primary tumour types were lung cancer (n = 304, 74%), melanoma (n = 79, 19%) and urologic cancer (n = 27, 7%). Most of the administered treatments were PD(L)-1 inhibitors (n = 356, 82%). Median follow-up reached 46 months in the CTLA-4 cohort, and 20 months in the PD(L)-1 cohort. In both treatment cohorts, age did not impact OS (respectively, HR = 0.82, 95% CI 0.5-1.4; log-rank P = 0.49 and HR = 0.9, 95% CI 0.7-1.1; log-rank P = 0.27) or PFS (HR = 0.7, 95% CI 0.4-1.1; log-rank P = 0.13 and HR = 0.9, 95% CI 0.7-1.1; log-rank P = 0.19). Grade 3-4 irAEs rates were not statistically different between older and younger patients (11% vs 12%, P = 0.87).

Conclusion: In a large real-world series of patients treated by ICI monotherapy, the long-term clinical outcomes were not statistically different between older or younger patients, with no increased immune-related toxicity.
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http://dx.doi.org/10.1016/j.ejca.2019.08.027DOI Listing
November 2019

Clinical efficacy of the optimal biological dose in early-phase trials of anti-cancer targeted therapies.

Eur J Cancer 2019 10 31;120:40-46. Epub 2019 Aug 31.

Faculty of Medicine Lyon-Sud, Claude Bernard University Lyon 1, EMR UCBL/HCL 3738, University of Lyon, Lyon, France; Department of Medical Oncology, Cancerology Institute of Hospices Civils de Lyon (IC-HCL), CITOHL, Lyon-Sud Hospital, Lyon, France. Electronic address:

Background: Determining the optimal biological dose (OBD) has been described as an alternative strategy to the maximum tolerated doses (MTDs) for identifying the recommended phase II trial doses (RP2Ds) of phase I anti-cancer therapies. However, the clinical relevance is still unknown. An extensive review was performed to assess if the OBDs defined in early-phase trials were useful for subsequent drug development and approvals.

Methods: All the molecular targeted therapies approved by the Food and Drug Administration (FDA) in solid oncology or in haematological malignancies before July 2018 were listed through the National Cancer Institute Database. The early-phase trial publications investigating these drugs as single agents were retrieved and analysed to identify the drugs for which OBDs were reported. The publications of subsequent pivotal efficacy clinical trials leading to the approvals were retrieved, and OBDs compared with the final labelled doses and dosing schedules.

Results: A total of 87 early-phase trial publications were analysed, corresponding to 81 FDA-approved targeted therapies. OBDs were reported for 40% (32/81) of these drugs (19 small molecules, 13 monoclonal antibodies). MTDs were not identified for 59% (19/32) of molecules. When the OBDs were selected as the RP2Ds (18/32 molecules), the final FDA-approved doses were consistent with the OBDs for 83% of the drugs, which is much higher than the previously reported 58% rate when MTDs were chosen as the RP2Ds.

Conclusion: Although still poorly investigated, the OBD may be a relevant and complementary end-point for early-phase trials of targeted therapies.
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http://dx.doi.org/10.1016/j.ejca.2019.08.002DOI Listing
October 2019

[New drugs toxicities: A new fight].

Bull Cancer 2019 May;106(5):405-406

Centre hospitalier Lyon Sud, institut de cancérologie des hospices civils de Lyon, centre de recherche en cancérologie de Lyon-CRCL, oncologie médicale, UMR Inserm 1052, CNRS 5286, 165, chemin du Grand-Revoyet, 69310 Pierre Bénite, France.

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http://dx.doi.org/10.1016/j.bulcan.2019.04.002DOI Listing
May 2019

A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors.

Int J Cancer 2019 08 4;145(3):639-648. Epub 2019 Feb 4.

Department of Medical Oncology, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), Pierre-Bénite, France.

The advent of immune checkpoint-inhibitors (CPI) has transformed treatment for several cancer types. This review was performed to assess the rate of adverse events (AEs) associated with the use of CPI, alone or in combinations. A review of AEs reporting quality was also performed. All publications of Randomized Clinical Trials (RCTs) assessing CPI published before December 2017 were included. To investigate the quality of AEs reporting, a set of items was defined based on the 2004 CONSORT harms extension statement. Rates of Grade 5, serious, and study-withdrawal related AEs were collected in each treatment category. Specific immune related AEs (irAEs) were also collected when available. Pooled estimates of adverse event rates were calculated by using generalized linear mixed model. A total of 35 RCTs including 16,485 patients were included. The overall quality of AEs reporting was satisfactory, but items pertaining to methods of data collection and analysis were infrequently reported. Grade ≥ 3 AEs were reported for 14% (95% CI 12-16) of patients treated with PD(L)-1 inhibitors, 34% (95% CI 27-42) of patients treated with CTLA-4 inhibitors, 55% (95% CI 51-59) of patients on CPI combinations and 46% (95% CI 40-53) of patients on immunotherapy-chemotherapy combination. The profile of irAEs was different among the treatment categories. The use of CPI, especially in combination, is associated with significant rates of Grade ≥ 3 AEs. Healthcare planning should anticipate the expected high number of patients presenting with irAEs in the future.
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http://dx.doi.org/10.1002/ijc.32132DOI Listing
August 2019

Pure Seminoma and Concurrent Aggressive Lymphoma: Case Report of a Patient With Persistent Müllerian Duct Syndrome.

Clin Genitourin Cancer 2019 04 5;17(2):e369-e371. Epub 2018 Dec 5.

Department of Medical Oncology, Centre Hospitalier Lyon Sud, Institut de cancérologie des Hospices Civils de Lyon (IC-HCL), Pierre-Bénite, France; UMR INSERM 1052, CNRS 5286, Centre de recherche en cancérologie de Lyon (CRCL), Lyon, France. Electronic address:

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http://dx.doi.org/10.1016/j.clgc.2018.11.019DOI Listing
April 2019

Management of non-metastatic castrate-resistant prostate cancer: A systematic review.

Cancer Treat Rev 2018 Nov 21;70:223-231. Epub 2018 Sep 21.

Department of Oncology, Antoine-Lacassagne Center, Nice, France.

Management of non metastatic castrate resistant prostate cancer is challenging for clinicians due to the heterogeneity of the disease and to the scarce clinical data available in this setting. Recent results obtained with the new generation hormone therapies (NGHT) apalutamide and enzalutamide bring a new perspective for the treatment strategy. The authors present here a systematic review of the treatment options.
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http://dx.doi.org/10.1016/j.ctrv.2018.09.006DOI Listing
November 2018

The Ectodysplasin receptor EDAR acts as a tumor suppressor in melanoma by conditionally inducing cell death.

Cell Death Differ 2019 03 31;26(3):443-454. Epub 2018 May 31.

Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008, Lyon, France.

Ectodysplasin receptor EDAR is seen as a typical Tumor Necrosis Factor receptor (TNFR) family member known to interact with its ligand Eda-A1, and signaling mainly through the nuclear factor-kappaB (NF-κB) and c-jun N-terminal kinases pathways. Mutations in genes that encode proteins involved in EDAR transduction cascade cause anhidrotic ectodermal dysplasia. Here, we report an unexpected pro-apoptotic activity of EDAR when unbound to its ligand Eda-A1, which is independent of NF-κB pathway. Contrarily to other death receptors, EDAR does recruit caspase-8 to trigger apoptosis but solely upon ligand withdrawal, thereby behaving as the so-called dependence receptors. We propose that pro-apoptotic activity of unbound EDAR confers it a tumor suppressive activity. Along this line, we identified loss-of-pro-apoptotic function mutations in EDAR gene in human melanoma. Moreover, we show that the invalidation of EDAR in mice promotes melanoma progression in a B-Raf mutant background. Together, these data support the view that EDAR constrains melanoma progression by acting as a dependence receptor.
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http://dx.doi.org/10.1038/s41418-018-0128-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370843PMC
March 2019

Systemic treatments for high-risk localized prostate cancer.

Nat Rev Urol 2018 08;15(8):498-510

Department of Oncology, Antoine-Lacassagne Center, Nice, France.

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.
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http://dx.doi.org/10.1038/s41585-018-0017-xDOI Listing
August 2018

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

Crit Rev Oncol Hematol 2018 Feb 30;122:144-149. Epub 2017 Dec 30.

Department of Radiation therapy, Institut Bergonié, Bordeaux, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.critrevonc.2017.12.012DOI Listing
February 2018

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

Oncotarget 2017 Apr;8(14):23750-23759

Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.

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.
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http://dx.doi.org/10.18632/oncotarget.16077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410341PMC
April 2017

EVESOR, a model-based, multiparameter, Phase I trial to optimize the benefit/toxicity ratio of everolimus and sorafenib.

Future Oncol 2017 Apr 12;13(8):679-693. Epub 2017 Jan 12.

Medical Oncology, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), CITOHL, Centre Hospitalier Lyon-Sud, Lyon, France.

Aim: This novel multiparameter Phase I study aimed to optimize doses/dosing schedules of everolimus and sorafenib drug combination, based on modeling/simulation (NCT01932177).

Patients & Methods: About 26 patients with solid tumors were treated in four different dosing schedules. Everolimus once daily + sorafenib twice daily were given continuously in arms A and B, and intermittently in arms C (alternating every other week) and D (everolimus continuous and sorafenib 3 days on/4 days off).

Results: Continuous schedules exhibited higher toxicity risks than intermittent schedules (64.1 vs 35.9%; p < 0.0001), and trends for lower disease control rates (80 vs 100%). No significant pharmacokinetic interaction was identified.

Conclusion: Feasibility of EVESOR trial is demonstrated. Intermittent schedules might provide better tolerance and efficacy than continuous schedules.
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http://dx.doi.org/10.2217/fon-2016-0357DOI Listing
April 2017

BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas.

J Thorac Oncol 2017 04 27;12(4):724-733. Epub 2016 Dec 27.

Faculty of Medicine, Research Team 3738, Lyon1 University, Oullins, France; French National Network for the Treatment of Rare Peritoneal Surface Malignancies, University Hospital of Lyon and Lyon1 University, Lyon, France; Department of Pathology, University Hospital of Lyon and Lyon1 University, Lyon, France.

Introduction: Malignant mesothelioma is a deadly disease that is strongly associated with asbestos exposure. Peritoneal mesotheliomas account for 10% of all the cases. BRCA1 associated protein 1 (BAP1) is a deubiquitinating hydrolase that plays a key role in various cellular processes. Germline and somatic inactivation of BRCA1 associated protein 1 gene (BAP1) is frequent in pleural mesothelioma; however, little is known about its status in peritoneal mesothelioma.

Methods: Taking advantage of the extensive French National Network for the Diagnosis of Malignant Pleural Mesothelioma and Rare Peritoneal Tumors and the French National Network for the Treatment of Rare Peritoneal Surface Malignancies, we collected biological material and clinical and epidemiological data for 46 patients with peritoneal mesothelioma. The status of BAP1 was evaluated at the mutational and protein expression levels and combined with our previous data on copy number alterations assessed in the same samples.

Results: We detected mutations in 32% of the malignant peritoneal mesotheliomas analyzed. In addition, we have previously reported that copy number losses occurred in 42% of the samples included in this series. Overall, 73% of the malignant peritoneal mesotheliomas analyzed carried at least one inactivated BAP1 allele, but only 57% had a complete loss of its protein nuclear expression. Better overall survival was observed for patients with BAP1 mutations (p = 0.04), protein expression loss (p = 0.016), or at least one of these alterations (p = 0.007) independently of tumor histological subtype, age, and sex.

Conclusions: As in pleural mesothelioma, inactivation of BAP1 is frequent in peritoneal mesotheliomas. We found that BAP1 protein nuclear expression is a good prognostic factor and a more reliable marker for the complete loss of BAP1 activity than mutation or copy number loss.
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http://dx.doi.org/10.1016/j.jtho.2016.12.019DOI Listing
April 2017

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

Hum Pathol 2016 09 14;55:72-82. Epub 2016 May 14.

Department of Pathology, HCL Cancer Institute, Lyon 1 University, 69577 Bron, France; Equipe Mixte de Recherche 3738, Lyon 1 University, Faculty of Medicine, 69310 Pierre-Bénite, France; Réseau National de Prise en Charge des Tumeurs Rares du Péritoine (RENAPE), HCL Cancer Institute and Lyon 1 University, Lyon, 69310 Pierre-Bénite, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.humpath.2016.04.015DOI Listing
September 2016

Aggregated adverse-events outcomes in oncology phase III reports: A systematic review.

Eur J Cancer 2016 Jan 27;52:26-32. Epub 2015 Nov 27.

Medical Oncology Department, Centre Hospitalier Lyon-Sud, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), CITOHL, F-69310, Pierre-Bénite, France; Hospices Civils de Lyon, Biostatistics Unit, F-69003, Lyon, France; CNRS UMR 5558, Biometry and Evolutionary Biology Laboratory, Health and Biostatistics Team, Villeurbanne, France. Electronic address:

Background: Randomised controlled trials (RCTs) represent a major source of information on treatment-related adverse events (AEs). In this study, we reviewed the use and the reporting methods of aggregated-AEs (A-AEs) outcomes in RCTs reports published in oncology and compared that to the expectations of European Organisation for Research and Treatment of Cancer (EORTC) membership.

Methods: RCTs reports published between 2007 and 2011 were reviewed regarding the reporting of A-AEs-outcomes. A-AEs were defined as summary outcome combining several related AEs, usually grouped by organ system e.g. cardiac-AEs, dermatologic-AEs. Trial characteristics associated with the use of A-AEs outcomes were investigated. The expectation of EORTC members concerning A-AEs utilisation was queried through a survey.

Results: Among 325 RCTs published between 2007 and 2011, 94 (29%) included one or more A-AE outcomes. A clear description of the nature of AEs included in such aggregations was provided in 19 articles (20%). No description of A-AEs was conversely provided in the other 75 articles (80%). The most commonly used A-AEs-outcomes were dermatologic-AEs (45%) and cardiac-AEs (33%). In multivariate analysis, the use of A-AEs outcomes was more frequent when trials were conducted in Europe (p = 0.038) and in trials performed on colon/rectal cancers (p = 0.016). Finally, there is no consensus of EORTC members regarding the utilisation of A-AEs but a majority of them (88%) felt that a clear description of A-AEs should systematically be reported.

Conclusions: The use of A-AEs is infrequent in oncology RCT manuscripts although their use is accepted by most clinicians. However, a clear definition of A-AEs is strongly recommended if they are to be used in order to avoid a loss of important details about drug toxicities that is useful to clinicians.
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http://dx.doi.org/10.1016/j.ejca.2015.08.025DOI Listing
January 2016

DICER1 and FOXL2 mutations in ovarian sex cord-stromal tumours: a GINECO Group study.

Histopathology 2016 Jan 21;68(2):279-85. Epub 2015 Jul 21.

U1052 Inserm, UMR CNRS 5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Centre Léon Bérard, Lyon, France.

Aims: FOXL2 mutation has been consistently identified in adult granulosa cell tumours (A-GCTs). DICER1 mutations have been described predominantly in Sertoli-Leydig cell tumours (SLCTs). The prognostic implication of these mutations remains uncertain, as moderately sized studies have yielded variable outcomes. Our aim was to determine the implications of DICER1 and FOXL2 mutations in 156 ovarian sex cord-stromal tumours (SCSTs).

Methods And Results: FOXL2 mutations were found in 94% of pathologically confirmed A-GCTs (95/101), in one of eight juvenile granulosa cell tumours (J-GCTs), and in two of 19 SLCTs. DICER1 mutations in the RNase IIIb domain were found in six of 19 SLCTs, two of eight J-GCTs, and one of 12 undifferentiated SCSTs (Und-SCSTs). Comparison of DICER1-mutated SLCTs with DICER1-non-mutated SLCTs showed that patient age at diagnosis was lower and oestrogen receptor expression was more frequent in DICER1-mutated tumours. With a median follow-up of 22 months, two of five DICER1-mutated SLCTs relapsed, in contrast to none of eight DICER1-non-mutated tumours.

Conclusions: Our results suggest that, in contrast to FOXL2 mutations in A-GCT, DICER1 mutations in SLCT might be more useful for prognosis than for diagnosis. However, study of a larger cohort of patients is necessary to establish this. Identification of genetic alterations in SCST offers promising therapeutic options.
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http://dx.doi.org/10.1111/his.12747DOI Listing
January 2016

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

Eur J Cancer 2014 Jun 8;50(9):1602-9. Epub 2014 Apr 8.

Department of Medical Oncology, Georges Pompidou European Hospital, Paris, France. Electronic address:

Background: A 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.

Methods: Multicentre 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.

Results: Overall, 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).

Conclusion: The 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.
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http://dx.doi.org/10.1016/j.ejca.2014.03.015DOI Listing
June 2014

Impact of a second opinion using expression and molecular analysis of FOXL2 for sex cord-stromal tumors. A study of the GINECO group & the TMRO network.

Gynecol Oncol 2014 Jan 22;132(1):181-7. Epub 2013 Oct 22.

Roche SAS Scientific Partnerships, 92650 Boulogne Billancourt, France.

Objective: Ovarian sex cord-stromal tumors (SCSTs) are rare and their diagnosis is often difficult to establish. Recently, immunostaining and molecular analysis for Forkhead box L2 (FOXL2) have been developed in this pathology. This study aims to assess the benefit of an algorithm incorporating these new tools for a better diagnosis and classification of SCSTs

Methods: Seventy-two tumors with a potential diagnosis of SCSTs were addressed by 37 different pathologists to one French rare ovarian tumor expert center, member of the Rare Malignant Ovarian Tumor network (TMRO). Then a "second opinion" (SO) through an algorithm incorporating immunostaining (IHC) and molecular analysis of FOXL2 was performed for all these cases. This algorithm was then validated by all pathologists of the TMRO network.

Results: After a second opinion including molecular analysis and immunostaining for FOXL2 the initial diagnosis was changed in 15 of 72 samples (21%). FOXL2 mutation was present in 44 out of 47 adult granulosa cell tumors (94%), in 3 out of 8 Thecomas (37%), in 1 out of 10 Sertoli-Leydig cell tumors (SLSTs) (10%) and in 3 out of 5 undifferentiated-SCSTs (Und-SCSTs) (60%). Immunoexpression of FOXL2 was available in 45 cases of SCSTs: FOXL2 was expressed in 44 of them (98%).

Conclusions: A second opinion in an expert center for all cases of SCSTs is fundamental to get an optimal classification of these rare tumors. This second opinion could be performed with an algorithm which integrates FOXL2 mutation and expression status of FOXL2 in order to standardize the practice.
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http://dx.doi.org/10.1016/j.ygyno.2013.10.013DOI Listing
January 2014

Adherence to CONSORT adverse event reporting guidelines in randomized clinical trials evaluating systemic cancer therapy: a systematic review.

J Clin Oncol 2013 Nov 23;31(31):3957-63. Epub 2013 Sep 23.

Julien Péron, Denis Maillet, and Benoit You, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite; Julien Péron, Hospices Civils de Lyon; Julien Péron and Benoit You, Université de Lyon, Lyon; Julien Péron, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne; Benoit You, EMR UCBL/HCL 3738, Faculté de Médecine Lyon-Sud, Oullins, France; Hui K. Gan, Joint Austin-Ludwig Oncology Unit, Austin Hospital, Melbourne, Victoria, Australia; Eric X. Chen, Princess Margaret Hospital, University Health Network; and Eric X. Chen, University of Toronto, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1200/JCO.2013.49.3981DOI Listing
November 2013

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

Anticancer Drugs 2013 Mar;24(3):306-9

Department of Medical Oncology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, 69495 Pierre-Bénite, France.

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.
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http://dx.doi.org/10.1097/CAD.0b013e32835c3561DOI Listing
March 2013

Quality of reporting of modern randomized controlled trials in medical oncology: a systematic review.

J Natl Cancer Inst 2012 Jul 3;104(13):982-9. Epub 2012 Jul 3.

Service d'Oncologie Médicale, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, 165 chemin du grand Revoyet, Pierre-Bénite, France.

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.
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http://dx.doi.org/10.1093/jnci/djs259DOI Listing
July 2012