Adverse events related to abiraterone and enzalutamide treatment: analysis of the EudraVigilance database and meta-analysis of registrational phase III studies

2019 ◽  
Vol 23 (2) ◽  
pp. 199-206 ◽  
Author(s):  
Cosimo De Nunzio ◽  
Riccardo Lombardo ◽  
Giorgia Tema ◽  
Olivia Voglino ◽  
Angela Sica ◽  
...  
Keyword(s):  
Adverse Events ◽  
Meta Analysis ◽  
Phase Iii ◽  
Treatment Analysis ◽  
Phase Iii Studies

scholarly journals Bevacizumab and Breast Cancer: A Meta-Analysis of First-Line Phase III Studies and a Critical Reappraisal of Available Evidence

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
José R. Rossari ◽  
Otto Metzger-Filho ◽  
Marianne Paesmans ◽  
Kamal S. Saini ◽  
Alessandra Gennari ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fixed Effects ◽  
Meta Analysis ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Statistical Estimates ◽  
Treatment Indications ◽  
Phase Iii Studies

Background. Randomized studies have shown different magnitude of bevacizumab benefit in the treatment of advanced breast cancer. Regulatory agencies have modified bevacizumab treatment indications across different regions. In this study, we perform a meta-analysis of phase III studies aiming to interrogate the magnitude of bevacizumab benefit for the treatment of first-line HER2-negative metastatic breast cancer (MBC).Methods. Data from studies E2100, AVADO and RIBBON-1 were used to calculate the benefit of bevacizumab in terms of tumor overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicities. Combined statistical estimates of hazard ratios (HR) and odds ratios were calculated using fixed-effects or random-effects models.Results. A total of 2,695 patients were evaluated. Combining bevacizumab with different chemotherapy backbones resulted in a 30% risk reduction of PFS events (HR = 0.70; 95% confidence interval [CI], 0.57–0.86) and increased ORR (odds ratio 1.81; 95% CI, 1.53–2.14). No OS benefit could be demonstrated (HR = 0.95; 95% CI, 0.85–1.06). Bevacizumab significantly increased the incidence of adverse events such as proteinuria, hypertension and cardiovascular events.Conclusions. Bevacizumab combined with chemotherapy in the first-line treatment of MBC significantly improved ORR and PFS, but also increased grade 3-4 toxicities. No significant OS advantage was observed.

scholarly journals Benefits and harms of pregabalin in the management of neuropathic pain: a rapid review and meta-analysis of randomised clinical trials

BMJ Open ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. e023600 ◽  
Author(s):  
Igho J Onakpoya ◽  
Elizabeth T Thomas ◽  
Joseph J Lee ◽  
Ben Goldacre ◽  
Carl J Heneghan
Keyword(s):  
Neuropathic Pain ◽  
Adverse Events ◽  
Meta Analysis ◽  
Peripheral Oedema ◽  
Phase Iii ◽  
Rapid Review ◽  
Secondary Outcome ◽  
Cord Injury ◽  
Quality Evidence

ObjectiveTo assess the benefits and harms of pregabalin in the management of neuropathic pain.DesignRapid review and meta-analysis of phase III, randomised, placebo-controlled trials.ParticipantsAdults aged 18 years and above with neuropathic pain defined according to the International Association for the Study of Pain criteria.InterventionsPregabalin or placebo.Primary and secondary outcome measuresOur primary outcomes were pain (as measured using validated scales) and adverse events. Our secondary outcomes were sleep disturbance, quality of life, Patient Global Impression of Change, Clinician Global Impression scale, anxiety and depression scores, overall discontinuations and discontinuations because of adverse events.ResultsWe included 28 trials comprising 6087 participants. The neuropathic pain conditions studied were diabetic peripheral neuropathy, postherpetic neuralgia, herpes zoster, sciatica (radicular pain), poststroke pain and spinal cord injury-related pain. Patients who took pregabalin reported significant reductions in pain (numerical rating scale (NRS)) compared with placebo (standardised mean difference (SMD) −0.49 (95% CI −0.66 to −0.32, p<0.00001), very low quality evidence). Pregabalin significantly reduced sleep interference scores (NRS) compared with placebo (SMD −0.38 (95% CI −0.50 to −0.26, p<0.00001), moderate quality evidence. Pregabalin significantly increased the risk of adverse events compared with placebo (RR 1.33 (95% CI 1.23 to 1.44, p<0.00001, low quality evidence)). The risks of experiencing weight gain, somnolence, dizziness, peripheral oedema, fatigue, visual disturbances, ataxia, non-peripheral oedema, vertigo and euphoria were significantly increased with pregabalin. Pregabalin was significantly more likely than placebo to lead to discontinuation of the drug because of adverse events (RR 1.91 (95% CI 1.54 to 2.37, p<0.00001), low quality evidence).ConclusionPregabalin has beneficial effects on some symptoms of neuropathic pain. However, its use significantly increases the risk of a number of adverse events and discontinuation due to adverse events. The quality of the evidence from journal publications is low.

Meta-analysis of anti-VEGF class adverse events from three double-blind (db), placebo (pbo)-controlled phase III trials with IV aflibercept (Afl).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3579-3579 ◽  
Author(s):  
Josep Tabernero ◽  
Carmen Joseph Allegra ◽  
Philippe R Rougier ◽  
Giorgio Scagliotti ◽  
Philip Agop Philip ◽  
...  
Keyword(s):  
Adverse Events ◽  
Metastatic Cancer ◽  
Meta Analysis ◽  
Safety Data ◽  
Dose Intensity ◽  
Phase Iii ◽  
Double Blind ◽  
Anti Vegf ◽  
Increased Risk ◽  
Grade 3

3579 Background: Three db, pbo-controlled studies were conducted with IV Afl in metastatic cancer patients (pts) (colorectal [CRC], Afl + FOLFIRI [WCGC 2011, abstract O-0024]; lung [LC], Afl + docetaxel [WCLC 2011, abstract 511]; and pancreatic [PC], Afl + gemcitabine [WCGC 2009 abstract O-0006]). Each study used the same weekly Afl dose intensity (4 mg/kg q2w for CRC and PC; 6 mg/kg q3w for LC). A safety meta-analysis of anti-VEGF class adverse events (AEs) was performed on data from these studies. Methods: A fixed-effect logistic regression model was used, including study, treatment, and study-by-treatment interaction factors as covariates to test the consistency of treatment effect across studies for each of the considered AE. When no evidence of heterogeneity of treatment effects was found across studies, relative risks (RRs) and 95% confidence intervals (CIs) were estimated. Summary incidences (% of pts) and RR are presented for NCI grade 3-4 events. Results: Safety data from a total of 2662 pts (Afl, 1333; pbo, 1329) were included for analysis. Among pts treated with Afl, 0.4 and 0.5% experienced grade 4 hypertension and nephrotic syndrome, respectively. Conclusions: The addition of Afl to concurrent chemotherapies did not increase the risk of VTE. The risk of grade 3-4 anti-VEGF class AEs was increased when adding Afl to concurrent chemotherapies. This increased risk was statistically significant only for hypertension, proteinuria, and hemorrhage. Further analyses, when more data are available, should improve the precision of these results. [Table: see text]

Discontinuation of poly(adenosine diphosphate-ribose) polymerase inhibitors due to adverse events in patients with recurrent ovarian cancer: A meta-analysis of three phase III trials.

2018 ◽  
Vol 36 (34_suppl) ◽  
pp. 118-118
Author(s):  
Kyaw Zin Thein ◽  
Anita Sultan ◽  
Myo Zaw ◽  
Sriman Swarup ◽  
Myat M. Han ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Adverse Events ◽  
Dose Reduction ◽  
Meta Analysis ◽  
Adenosine Diphosphate ◽  
Recurrent Ovarian Cancer ◽  
Treatment Interruption ◽  
Parp Inhibitors ◽  
Treatment Discontinuation ◽  
Phase Iii

118 Background: Ovarian cancer is the fifth leading cause of cancer-related death among women. Poly adenosine diphosphate ribose polymerase (PARP) inhibitors maintenance has shown to improve survival in patients with recurrent ovarian cancer. Yet, there are notable adverse events which led to treatment discontinuation, interruption, or dose reduction. We conducted a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of PARP inhibitors discontinuation due to adverse events. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through June 2018 were queried. Phase III RCTs which employed PARP inhibitors maintenance in ovarian cancer and mentioned treatment interruption, dose reduction and treatment discontinuation due to adverse events were included. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: Three phase III RCTs with a total of 1,401 patients with recurrent ovarian cancer were eligible. The study arm used olaparib or niraparib or rucaparib while the control arm utilized placebo. The randomization ratio was 2:1 in all studies. The incidence of treatment interruption due to adverse events was 578 (61.8%) in study group versus 46 (9.8%) in control arm. The relative risk for treatment interruption was statistically significant at 5.87 (95% CI: 2.24 – 15.36, P < 0.001). The reduction in dose was reported in 496 (53.1%) in PARP inhibitors arm versus 37 (7.9%) in control group. The pooled RR for dose reduction was 7.49 (95% CI: 3.44 – 16.29, P < 0.001). The treatment discontinuation rate was 11.4% higher with PARP inhibitors than with control arm (RR - 6.84; 95% CI: 3.51 – 13.34, P < 0.001). Conclusions: Our study showed that patients on PARP inhibitors experienced some adverse events which led to significant drop outs although the definitive advantage to PARP inhibitors is still shown in the studies. Preemptive measures with proper supportive care will aide in reducing those toxicities, improve patients’ quality of life and may probably affect patients’ compliance.

scholarly journals Immune Checkpoints Inhibitors and Chemotherapy as First-Line Treatment for Metastatic Urothelial Carcinoma: A Network Meta-Analysis of Randomized Phase III Clinical Trials

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1484
Author(s):  
Hsiao-Ling Chen ◽  
Vinson Wai-Shun Chan ◽  
Yu-Kang Tu ◽  
Erica On-Ting Chan ◽  
Hsiu-Mei Chang ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Adverse Events ◽  
Urothelial Carcinoma ◽  
Safety Profile ◽  
Survival Benefit ◽  
Meta Analysis ◽  
Phase Iii ◽  
Immune Checkpoints ◽  
Metastatic Urothelial Carcinoma ◽  
Grade 3

Immune checkpoints inhibitors (ICIs) were considered as second-line treatments in metastatic urothelial carcinoma (mUC) based on better survival benefit and safety profile than chemotherapy (CTX). We aimed to assess different ICIs regimens in the efficacy and safety for front-line treatments in mUC patients. A comprehensive literature search was performed and Phase II-III randomized controlled trials (RCTs) on ICIs for patients with mUC were included. The outcome was evaluated by overall survival (OS), progression of free survival (PFS), objective response rate (ORR), and grade 3–5 adverse events. Network meta-analysis was used to estimate the effect size. Surface under cumulative ranking curves (SUCRAs) were applied to rank the included treatments for each outcome. Results: The survival benefit of a single ICI was non-inferiority to chemotherapy (CTX). Although no superior effects were indicated, combination therapy (either ICIs plus CTX or ICIs plus ICIs) presented better OS compared with CTX alone. In terms of PFS, combination therapy produced a noticeable benefit over CTX. Regarding the SUCRA ranking, atezolizumab plus CTX was associated with the best ranking for OS and pembrolizumab plus CTX was the best in PFS. In terms of safety, a single ICI had better safety profile than CTX and combination therapy had a similar risk of grade 3–5 adverse events with CTX. Conclusions: Our NMA results revealed that combination therapy has better ranking compared with monotherapy in OS and acceptable AEs. ICIs alone present non-inferior OS but a lower incidence of AEs compared with CTX.

Early closure of clinical trials: The experience of the National Cancer Institute of Canada Clinical Trials Group

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6053-6053 ◽  
Author(s):  
W. Parulekar ◽  
J. L. Pater
Keyword(s):  
Clinical Trials ◽  
Meta Analysis ◽  
Phase Iii ◽  
External Information ◽  
Efficacy Analysis ◽  
Time Period ◽  
Number Of Patients ◽  
Early Closure ◽  
Phase Iii Studies ◽  
Over Time

6053 Background: Phase III studies require a significant commitment on behalf of researchers and patients. Closure of a study before the originally planned number of patients have been enrolled may be due to a number of reasons such as poor accrual, information within the study that precludes continuation such as excess toxicity, an interim futility or extreme efficacy analysis or data from outside sources that render the study question obsolete. Methods: We reviewed the phase III activity of our group since inception. Reasons for early closure were classified in the following manner: accrual failure (AF), external information (EI), internal information (II). Studies were grouped by site and time period of study activation to demonstrate any trends over time. Results: 94 phase III studies led by our group were identified from our roster. Reasons for early closure are presented below. Other sites include brain with an early closure due to AF, head/neck where 1 of 3 studies closed due to AF, melanoma where 1 of 3 studies closed due to EI and sarcoma where 2 studies were successfully completed. Several of the studies that closed for accrual failure were nevertheless published either singly or as part of a meta-analysis. Conclusions: Slightly over one third of studies closed prior to achievement of the targeted sample size. Accrual failure continues to be the main cause of early study closure (27/34 or 80%) with a trend towards decreasing frequency of occurrence over time. Emerging data within or external to a study leading to study closure are important but relatively rare reasons for early closure. [Table: see text] No significant financial relationships to disclose.

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