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Oncotarget Dec 2016A meta-analysis was conducted to estimate the risk of wound-healing complications in patients who treated with neoadjuvant-adjuvant bevacizumab in various oncological... (Meta-Analysis)
Meta-Analysis Review
A meta-analysis was conducted to estimate the risk of wound-healing complications in patients who treated with neoadjuvant-adjuvant bevacizumab in various oncological indications. We searched PUBMED, EMBASE and the Cochrane Library through June 2016 to identify randomized controlled trials of bevacizumab and wound-healing complications. Seven RCTs studies involving 5,147 participants were included in the analysis. Compared with routine therapy, bevacizumab increased the incidence of wound-healing complications for various cancers. The pooled estimate of odds ratio (OR) was 2.32, and the 95 % confidence intervals (CI) was 1.43 to 3.75. (P < 0.001). Subgroup analyses revealed the similar result in colon carcinoma patients. In conclusion, bevacizumab increases the incidence of wound-healing complications for cancers especially for colon neoplasms patients. However, the adverse effect is not appeared in breast cancer, metastatic renal cell carcinoma, non-small-cell lung cancer and gastro-oesophageal adenocarcinoma. Due to the findings relying chiefly on data from single or two studies, hence, further research is required to assess the wound-healing complications risk of bevacizumab in each oncological indication.
Topics: Angiogenesis Inhibitors; Bevacizumab; Chemotherapy, Adjuvant; Chi-Square Distribution; Humans; Neoadjuvant Therapy; Neoplasms; Odds Ratio; Randomized Controlled Trials as Topic; Risk Factors; Wound Healing
PubMed: 27756883
DOI: 10.18632/oncotarget.12666 -
Frontiers in Pharmacology 2023According to the 2023 guidelines for treating non-small-cell lung cancer (NSCLC), first-line treatment and recently developed agents for the treatment of epidermal...
Comparison of the efficacy and safety of first-line treatments for of advanced EGFR mutation-positive non-small-cell lung cancer in Asian populations: a systematic review and network meta-analysis.
According to the 2023 guidelines for treating non-small-cell lung cancer (NSCLC), first-line treatment and recently developed agents for the treatment of epidermal growth factor (EGFR) mutation-positive locally advanced or metastatic NSCLC were compared in this meta-analysis. Treatment regimens involved in the included studies included first, second, and third-generation tyrosine kinase inhibitors (TKIs), TKIs plus chemotherapy, TKIs plus angiogenesis inhibitors, and platinum-containing doublet chemotherapy with or without bevacizumab. Considering the varying efficacy and safety of drugs in people of different ethnic origins, the optimal regimen should be determined, and the safety of first-line treatments should be assessed in the Asian population specifically. PubMed, Embase, the Cochrane Library, Web of Science, and the China National Knowledge Infrastructure (CNKI) were systematically searched to retrieve reports on randomized controlled trials (RCTs) with research data published from inception to 1 February 2023. Adopting Asian patient populations as the target (including studies in which Asian patients accounted for more than 50% of the sample), a network meta-analysis (NMA) was conducted for comparison of treatment regimens and treatments were ranked based on the surface under the cumulative ranking curve (SUCRA). A total of 19 RCTs involving 5,824 patients and covering 14 treatment regimens were included. The primary outcome measure examined in this study was progression-free survival (PFS); other outcome measures examined were overall survival (OS), disease control rate (DCR), objective response rate (ORR), occurrence of any adverse events (AE), occurrence of adverse events of grade 3 or above (≥3AE), and occurrence of serious adverse events (SAE). In terms of PFS, all regimens including TKIs (as a monotherapy or in combination with other therapies), as well as bevacizumab (Bev) plus chemotherapy (Ch) were found to be significantly superior to basic chemotherapy (HRs: 0.09-0.61, < 0.05 in all cases compared with Ch alone). The highest-ranking therapies were erlotinib (Erl) plus Bev (SUCRA: 0.94) and Erl plus ramucirumab (Ram) (SUCRA: 0.93). Regarding OS, no significant differences was observed between first-line treatment strategies; the top four treatments based on SUCRA, in rank order, were Bev + Ch (0.87), gefitinib (Gef) plus Ch (0.81), dacomitinib (Dac) (0.79), and osimertinib (Osi) (0.69). Additionally, there were no significant differences between first-line treatment strategies in terms of DCR. Regarding ORR, the top three treatments based on SUCRA were Erl + Bev (0.85), Erl + Ram (0.76), and Gef + Ch (0.74). No significant difference between first-line treatment strategies was observed in terms of the risk of AE. However, based on SUCRA, Erl ranked highest on avoidance of ≥ 3AE (0.97), and Osi ranked highest on avoidance of SAE (0.91). Based on these analyses of survival benefits, tumor burden response, and safety, furmonertinib (Fur), Osi, and aumolertinib (Aum) may represent the best treatment regimen options for Asian patients, significantly prolonging survival (as measured by median PFS/OS), eliciting a greater tumor burden response, and exposing patients to a lower risk of adverse events. Although Erl + Bev and Erl + Ram are associated with the best survival benefits in terms of PFS, further clinical studies are still needed to identify ways to reduce the risk of adverse events. https://www.crd.york.ac.uk/prospero/display_record.php? ID=CRD42023407994, identifier CRD42023407994.
PubMed: 37484016
DOI: 10.3389/fphar.2023.1212313 -
Frontiers in Immunology 2023Previous studies revealed that Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus anti-angiogenic agents had extensive... (Meta-Analysis)
Meta-Analysis
The benefit and risk of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small-cell lung cancer: a systematic review and single-arm meta-analysis of prospective clinical trials.
BACKGROUND
Previous studies revealed that Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus anti-angiogenic agents had extensive anti-tumor activities. However, almost all studies on the efficacy and safety of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small cell lung cancer are non-randomized controlled trials with small sample sizes, which might lead to a lack of effective metrics to assess the effectiveness and safety of the therapeutic regimen. Here, this meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small cell lung cancer.
METHODS
A single-arm meta-analysis was performed, and published literature from PubMed, Web of Science and Embase databases as of January 13, 2023, was systematically retrieved. We used the Cochrane risk of bias tool and methodological index for non-randomized studies (MINORS) Methodological items to evaluate the quality of eligible clinical trials. Outcomes including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were extracted for further analysis. The random effect model is used to calculate the pooled parameters.
RESULTS
19 studies (16 were non-comparative single-arm clinical trials and 3 were randomized controlled trials) were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 22.4% (95% CI, 16.6-28.1%) and 76.8% (95% CI, 72.6-81.1%), respectively. With regard to survival analysis, the pooled PFS and OS were 5.20 (95% CI, 4.46-5.93) months and 14.09 (95% CI, 13.20-14.97) months, respectively. The pooled grade ≥3 adverse effect (AE) rate was 47.6% (95% CI, 33.1-62.0%).
CONCLUSION
PD-1/PD-L1 inhibitors plus anti-angiogenic agents has promising efficacy and safety as second or later-line treatment in patients with advanced non-small cell lung cancer.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD42023407559.
Topics: Humans; Angiogenesis Inhibitors; Carcinoma, Non-Small-Cell Lung; Immune Checkpoint Inhibitors; Lung Neoplasms; Programmed Cell Death 1 Receptor; Prospective Studies; Clinical Trials as Topic
PubMed: 37614237
DOI: 10.3389/fimmu.2023.1218258 -
Diagnostics (Basel, Switzerland) Mar 2023(1) Background: Among new anti-angiogenesis agents being developed and ever-changing guidelines indications, the question of the benefits/safety ratio remains unclear.... (Review)
Review
(1) Background: Among new anti-angiogenesis agents being developed and ever-changing guidelines indications, the question of the benefits/safety ratio remains unclear. (2) Methods: We performed a systematic review combined with a meta-analysis of 23 randomized controlled trials (12,081 patients), evaluating overall survival (OS), progression free survival (PFS) and toxicity (grade ≥ 3 toxic effects, type, and number of all adverse effects. (3) Results: The analysis showed improvement of pooled-PFS (HR, 0.71; 95% CI, 0.64-0.78; I = 77%; < 0.00001) in first-line (HR, 0.85; 95% CI, 0.78-0.93; = 0.0003) or recurrent cancer (HR, 0.62; 95% CI, 0.56-0.70; < 0.00001) and regardless of the type of anti-angiogenesis drug used (Vascular endothelial growth factor (VEGF) inhibitors, VEGF-receptors (VEGF-R) inhibitors or angiopoietin inhibitors). Improved OS was also observed (HR, 0.95; 95% CI, 0.90-0.99; = 0.03). OS benefits were only observed in recurrent neoplasms, both platinum-sensitive and platinum-resistant neoplasms. Grade ≥ 3 adverse effects were increased across all trials. Anti-angiogenetic therapy increased the risk of hypertension, infection, thromboembolic/hemorrhagic events, and gastro-intestinal perforations but not the risk of wound-related issues, anemia or posterior leukoencephalopathy syndrome. (4) Conclusions: Although angiogenesis inhibitors improve PFS, there are little-to-no OS benefits. Given the high risk of severe adverse reactions, a careful selection of patients is required for obtaining the best results possible.
PubMed: 36980348
DOI: 10.3390/diagnostics13061040 -
European Review For Medical and... Nov 2022Triplet regimens based on pomalidomide and dexamethasone have been applied to treat relapsed/refractory multiple myeloma, but the safety and efficacy are not yet very... (Meta-Analysis)
Meta-Analysis
The efficacy and safety of triplet regimens based on pomalidomide and dexamethasone for treatment of relapsed/refractory multiple myeloma: a systematic review and meta-analysis.
OBJECTIVE
Triplet regimens based on pomalidomide and dexamethasone have been applied to treat relapsed/refractory multiple myeloma, but the safety and efficacy are not yet very clear. This meta-analysis aimed at comparing the safety and efficacy of different triplet therapies and analyzing the best therapy regimen.
MATERIALS AND METHODS
A comprehensive literature search identified a total of 615 studies, and 22 studies assessing 1,889 subjects met the inclusion criteria of this meta: phase II/III trial, over 2 median lines of prior therapy, and detailed efficacy outcomes like overall response rate (ORR), overall survival, and progression-free survival (PFS). All statistical analyses were performed by Revman version 5.3, and the heterogeneity was tested by I2 (25% indicating low heterogeneity, 50% moderate, and 75% high). For those with less heterogeneity, fixed-effect model was used. With a significant high heterogeneity, a random-effect model was used.
RESULTS
Pooled analysis showed ORR 66.2% across all triplet regimens based on pomalidomide and dexamethasone. Among all triplet regimens, therapy containing bortezomib showed the highest ORR (90.3%), and the one containing elotuzumab showed the lowest ORR (41.2%). The pooled ORRs for the remaining treatment regimens are as follows: cyclophosphamide (70.1%), isatuximab (66.3%), daratumumab (61.2%), clarithromycin (60.0%), pembrolizumab (47.3%). A total of 21 adverse events appeared in the included studies, with neutropenia being the highest incidence of hematologic adverse events (32.1%) and cough being the highest incidence of non-hematologic adverse events (43.3.%).
CONCLUSIONS
Three-drug regimens based on pomalidomide and dexamethasone could yield excellent overall response rate to relapsed/refractory multiple myeloma, but there are still various adverse events; therefore, consequent studies should address these adverse events.
Topics: Humans; Multiple Myeloma; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Thalidomide
PubMed: 36394758
DOI: 10.26355/eurrev_202211_30162 -
PloS One 2016Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and adjuvant temozolomide. However, disease recurs in almost all patients, and the optimal salvage treatment for recurrent GBM remains unclear. We conducted a systematic review and meta-analysis of published clinical trials to assess the efficacy and toxicities of angiogenesis inhibitors alone as salvage treatment in these patients.
METHODS
Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). Demographic data, treatment regimens, objective response rate (ORR), median progression-free survival (PFS), median overall survival (OS), 6-months PFS rate, 1-year OS and grade 3/4 toxicities were extracted. We also compared the main outcomes of interest between bevacizumab and other angiogenesis inhibitors. All analyses were performed using Comprehensive Meta Analysis software (Version 2.0).
RESULTS
A total of 842 patients were included for analysis: 343 patients were treated with bevacizumab, 386 with other angiogenesis inhibitors and 81 with thalidomide. The pooled ORR, 6-months PFS, and 1-year OS for recurrent GBM patients receiving angiogenesis inhibitors was 20.1%, 19.5% and 29.3%, respectively. The use of single agent bevacizumab in recurrent GBM significantly improved ORR and 6-months PFS when compared to other angiogenesis inhibitors [relative risk (RR) 2.93, 95% CI 1.38-6.21; p = 0.025; and RR 2.36 95% CI 1.46-3.82; p<0.001, respectively], while no significant difference in 1-year OS was found between the two groups (p = 0.07). when compared to thalidomide, bevacizumab treatment in recurrent GBM significantly improved ORR (RR 6.8, 95%CI: 2.64-17.6, p<0.001), but not for 6-months PFS (p = 0.07) and 1-year OS (p = 0.31). As for grade 3/4 toxicities, the common toxicity was hypertension with pooled incidence of 12.1%, while high-grade thromboembolic events (2.2%), hemorrhage (5.1%) and GI perforation (2.8%) associated with angiogenesis inhibitors were relatively low.
CONCLUSIONS
In comparison with other angiogenesis inhibitors and thalidomide, the use of single agent bevacizumab as salvage treatment for recurrent GBM patients improve ORR and 6-months PFS, but not for 1-year OS.
Topics: Angiogenesis Inhibitors; Bevacizumab; Glioblastoma; Humans; Recurrence; Salvage Therapy; Thalidomide
PubMed: 27007828
DOI: 10.1371/journal.pone.0152170 -
Biomolecules Jun 2023Invasive dental treatment in patients exposed to antiresorptive and antiangiogenic drugs can cause medication-related osteonecrosis of the jaw (MRONJ). Currently, the... (Review)
Review
BACKGROUND
Invasive dental treatment in patients exposed to antiresorptive and antiangiogenic drugs can cause medication-related osteonecrosis of the jaw (MRONJ). Currently, the exact pathogenesis of this disease is unclear.
METHODS
In March 2022, Medline (Ovid), Embase (Ovid), Scopus, and Web of Science were screened to identify eligible in vitro studies investigating the effects of antiresorptive and antiangiogenic compounds on orally derived cells.
RESULTS
Fifty-nine articles met the inclusion criteria. Bisphosphonates were used in 57 studies, denosumab in two, and sunitinib and bevacizumab in one. Zoledronate was the most commonly used nitrogen-containing bisphosphonate. The only non-nitrogen-containing bisphosphonate studied was clodronate. The most frequently tested tissues were gingival fibroblasts, oral keratinocytes, and alveolar osteoblasts. These drugs caused a decrease in cell proliferation, viability, and migration.
CONCLUSIONS
Antiresorptive and antiangiogenic drugs displayed cytotoxic effects in a dose and time-dependent manner. Additional research is required to further elucidate the pathways of MRONJ.
Topics: Humans; Bone Density Conservation Agents; Bisphosphonate-Associated Osteonecrosis of the Jaw; Denosumab; Diphosphonates; Zoledronic Acid; Angiogenesis Inhibitors
PubMed: 37371553
DOI: 10.3390/biom13060973 -
The Cochrane Database of Systematic... Apr 2023Neovascular glaucoma (NVG) is a potentially blinding, secondary glaucoma. It is caused by the formation of abnormal new blood vessels, which prevent normal drainage of... (Review)
Review
BACKGROUND
Neovascular glaucoma (NVG) is a potentially blinding, secondary glaucoma. It is caused by the formation of abnormal new blood vessels, which prevent normal drainage of aqueous from the anterior segment of the eye. Anti-vascular endothelial growth factor (anti-VEGF) medications are specific inhibitors of the primary mediators of neovascularization. Studies have reported the effectiveness of anti-VEGF medications for the control of intraocular pressure (IOP) in NVG.
OBJECTIVES
To assess the effectiveness of intraocular anti-VEGF medications, alone or with one or more types of conventional therapy, compared with no anti-VEGF medications for the treatment of NVG.
SEARCH METHODS
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register); MEDLINE; Embase; PubMed; and LILACS to 19 October 2021; metaRegister of Controlled Trials to 19 October 2021; and two additional trial registers to 19 October 2021. We did not use any date or language restrictions in the electronic search for trials.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) of people treated with anti-VEGF medications for NVG.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed the search results for trials, extracted data, and assessed risk of bias, and the certainty of the evidence. We resolved discrepancies through discussion.
MAIN RESULTS
We included five RCTs (356 eyes of 353 participants). Each trial was conducted in a different country: two in China, and one each in Brazil, Egypt, and Japan. All five RCTs included both men and women; the mean age of participants was 55 years or older. Two RCTs compared intravitreal bevacizumab combined with Ahmed valve implantation and panretinal photocoagulation (PRP) with Ahmed valve implantation and PRP alone. One RCT randomized participants to receive an injection of either intravitreal aflibercept or placebo at the first visit, followed by non-randomized treatment according to clinical findings after one week. The remaining two RCTs randomized participants to PRP with and without ranibizumab, one of which had insufficient details for further analysis. We assessed the RCTs to have an unclear risk of bias for most domains due to insufficient information to permit judgment. Four RCTs examined achieving control of IOP, three of which reported our time points of interest. Only one RCT reported our critical time point at one month; it found that the anti-VEGF group had a 1.3-fold higher chance of achieving control of IOP at one month (RR 1.32, 95% 1.10 to 1.59; 93 participants) than the non-anti-VEGF group (low certainty of evidence). For other time points, one RCT found a three-fold greater achievement in control of IOP in the anti-VEGF group when compared with the non-anti-VEGF group at one year (RR 3.00; 95% CI:1.35 to 6.68; 40 participants). However, another RCT found an inconclusive result at the time period ranging from 1.5 years to three years (RR 1.08; 95% CI: 0.67 to 1.75; 40 participants). All five RCTs examined mean IOP, but at different time points. Very-low-certainty evidence showed that anti-VEGFs were effective in reducing mean IOP by 6.37 mmHg (95% CI: -10.09 to -2.65; 3 RCTs; 173 participants) at four to six weeks when compared with no anti-VEGFs. Anti-VEGFs may reduce mean IOP at three months (MD -4.25; 95% CI -12.05 to 3.54; 2 studies; 75 participants), six months (MD -5.93; 95% CI -18.13 to 6.26; 2 studies; 75 participants), one year (MD -5.36; 95% CI -18.50 to 7.77; 2 studies; 75 participants), and more than one year (MD -7.05; 95% CI -16.61 to 2.51; 2 studies; 75 participants) when compared with no anti-VEGFs, but such effects remain uncertain. Two RCTs reported the proportion of participants who achieved an improvement in visual acuity with specified time points. Participants receiving anti-VEGFs had a 2.6 times (95% CI 1.60 to 4.08; 1 study; 93 participants) higher chance of improving visual acuity when compared with those not receiving anti-VEGFs at one month (very low certainty of evidence). Likewise, another RCT found a similar result at 18 months (RR 4.00, 95% CI 1.33 to 12.05; 1 study; 40 participants). Two RCTs reported the outcome, complete regression of new iris vessels, at our time points of interest. Low-certainty evidence showed that anti-VEGFs had a nearly three times higher chance of complete regression of new iris vessels when compared with no anti-VEGFs (RR 2.63, 95% CI 1.65 to 4.18; 1 study; 93 participants). A similar finding was observed at more than one year in another RCT (RR 3.20, 95% CI 1.45 to 7.05; 1 study; 40 participants). Regarding adverse events, there was no evidence that the risks of hypotony and tractional retinal detachment were different between the two groups (RR 0.67; 95% CI: 0.12 to 3.57 and RR 0.33; 95% CI: 0.01 to 7.72, respectively; 1 study; 40 participants). No RCTs reported incidents of endophthalmitis, vitreous hemorrhage, no light perception, and serious adverse events. Evidence for the adverse events of anti-VEGFs was low due to limitations in the study design due to insufficient information to permit judgments and imprecision of results due to the small sample size. No trial reported the proportion of participants with relief of pain and resolution of redness at any time point.
AUTHORS' CONCLUSIONS
Anti-VEGFs as an adjunct to conventional treatment could help reduce IOP in NVG in the short term (four to six weeks), but there is no evidence that this is likely in the longer term. Currently available evidence regarding the short- and long-term effectiveness and safety of anti-VEGFs in achieving control of IOP, visual acuity, and complete regression of new iris vessels in NVG is insufficient. More research is needed to investigate the effect of these medications compared with, or in addition to, conventional surgical or medical treatment in achieving these outcomes in NVG.
Topics: Female; Humans; Male; Middle Aged; Bevacizumab; Glaucoma, Neovascular; Ranibizumab; Vascular Endothelial Growth Factor A
PubMed: 37010901
DOI: 10.1002/14651858.CD007920.pub4 -
Current Oncology (Toronto, Ont.) Sep 2023Serous epithelial ovarian cancer, classified as either high-grade (90%) or low-grade (10%), varies in molecular, histological, and clinicopathological presentation.... (Review)
Review
Serous epithelial ovarian cancer, classified as either high-grade (90%) or low-grade (10%), varies in molecular, histological, and clinicopathological presentation. Low-grade serous ovarian cancer (LGSOC) is a rare histologic subtype that lacks disease-specific evidence-based treatment regimens. However, LGSOC is relatively chemo-resistant and has a poor response to traditional treatments. Alternative treatments, including biologic therapies such as bevacizumab, have shown some activity in LGSOC. Thus, the objective of this systematic review is to determine the effect and safety of bevacizumab in the treatment of LGSOC. Following PRISMA guidelines, Medline ALL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase all from the OvidSP platform, ClinicalTrials.gov, International Clinical Trials Registry Platform, International Standard Randomised Controlled Trial Number Registry were searched from inception to February 2022. Articles describing bevacizumab use in patients with LGSOC were included. Article screening, data extraction, and critical appraisal of included studies were completed by two independent reviewers. The effect of bevacizumab on the overall response rate, progression-free survival, overall survival, and adverse effects were summarized. The literature search identified 3064 articles, 6 of which were included in this study. A total of 153 patients were analyzed; the majority had stage IIIC cancer (56.2%). The overall median response rate reported in the studies was 47.5%. Overall, bevacizumab is a promising treatment for LGSOC, with response rates higher than traditional treatment modalities such as conventional chemotherapy, and is often overlooked as a treatment tool. A prospective clinical trial evaluating the use of bevacizumab in LGSOC is necessary to provide greater evidence and support these findings.
Topics: Humans; Female; Bevacizumab; Prospective Studies; Carcinoma, Ovarian Epithelial; Cystadenocarcinoma, Serous; Peritoneal Neoplasms; Ovarian Neoplasms
PubMed: 37754507
DOI: 10.3390/curroncol30090592 -
The Cochrane Database of Systematic... Sep 2017Myelodysplastic syndrome (MDS) is one of the most frequent haematologic malignancies of the elderly population and characterised by progenitor cell dysplasia with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Myelodysplastic syndrome (MDS) is one of the most frequent haematologic malignancies of the elderly population and characterised by progenitor cell dysplasia with ineffective haematopoiesis and a high rate of transformation to acute myeloid leukaemia (AML). Thrombocytopenia represents a common problem for patients with MDS. ranging from mild to serious bleeding events and death. To manage thrombocytopenia, the current standard treatment includes platelet transfusion, unfortunately leading to a range of side effects. Thrombopoietin (TPO) mimetics represent an alternative treatment option for MDS patients with thrombocytopenia. However, it remains unclear, whether TPO mimetics influence the increase of blast cells and therefore to premature progression to AML.
OBJECTIVES
To evaluate the efficacy and safety of thrombopoietin (TPO) mimetics for patients with MDS.
SEARCH METHODS
We searched for randomised controlled trials in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (January 2000 to August 2017), trials registries (ISRCTN, EU clinical trials register and clinicaltrials.gov) and conference proceedings. We did not apply any language restrictions. Two review authors independently screened search results, disagreements were solved by discussion.
SELECTION CRITERIA
We included randomised controlled trials comparing TPO mimetics with placebo, no further treatment or another TPO mimetic in patients with MDS of all risk groups, without gender, age or ethnicity restrictions. Additional chemotherapeutic treatment had to be equal in both arms.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed the quality of trials, disagreements were resolved by discussion. Risk ratio (RR) was used to analyse mortality during study, transformation to AML, incidence of bleeding events, transfusion requirement, all adverse events, adverse events >= grade 3, serious adverse events and platelet response. Overall survival (OS) and progression-free survival (PFS) have been extracted as hazard ratios, but could not be pooled as results were reported in heterogenous ways. Health-related quality of life and duration of thrombocytopenia would have been analysed as standardised mean differences, but no trial reported these outcomes.
MAIN RESULTS
We did not identify any trial comparing one TPO mimetic versus another. We analysed six eligible trials involving 746 adult patients. All trials were reported as randomised and double-blind trials including male and female patients. Two trials compared TPO mimetics (romiplostim or eltrombopag) with placebo, one trial evaluated eltrombopag in addition to the hypomethylating agent azacitidine, two trials analysed romiplostim additionally to a hypomethylating agent (azacitidine or decitabine) and one trial evaluated romiplostim in addition to the immunomodulatory drug lenalidomide. There are more data on romiplostim (four included, completed, full-text trials) than on eltrombopag (two trials included: one full-text publication, one abstract publication). Due to small sample sizes and imbalances in baseline characteristics in three trials and premature termination of two studies, we judged the potential risk of bias of all included trials as high.Due to heterogenous reporting, we were not able to pool data for OS. Instead of that, we analysed mortality during study. There is little or no evidence for a difference in mortality during study for thrombopoietin mimetics compared to placebo (RR 0.97, 95% confidence interval (CI) 0.73 to 1.27, N = 6 trials, 746 patients, low-quality evidence). It is unclear whether the use of TPO mimetics induces an acceleration of transformation to AML (RR 1.02, 95% CI 0.59 to 1.77, N = 5 trials, 372 patients, very low-quality evidence).Thrombopoietin mimetics probably improve the incidence of all bleeding events (RR 0.92, 95% CI 0.86 to 0.99, N = 5 trials, 390 patients, moderate-quality evidence). This means that in the study population, 713 out of 1000 in the placebo arm will have a bleeding event, compared to 656 of 1000 (95% CI 613 to 699) in the TPO mimetics arm. There is little or no evidence for a difference that TPO mimetics significantly diminish the rate of transfusion requirement (RR 0.83, 95% CI 0.66 to 1.05, N = 4 trials, 358 patients, low-quality evidence). No studies were found that looked at quality of life or duration of thrombocytopenia.There is no evidence that patients given TPO mimetics suffer more all adverse events (RR 1.01, 95% CI 0.96 to 1.07, N = 5 trials, 390 patients, moderate-quality evidence). There is uncertainty whether the number of serious adverse events decrease under therapy with TPO mimetics (RR 0.89, 95% CI 0.54 to 1.46, N = 4 trials, 356 patients, very low-quality evidence).We identified one ongoing study and one study marked as completed (March 2015), but without publication of results for MDS patients (only results reported for AML and MDS patients together). Both studies evaluate MDS patients receiving eltrombopag in comparison to placebo.
AUTHORS' CONCLUSIONS
No trial evaluated one TPO mimetic versus another.Six trials including adult patients analysed one TPO mimetic versus placebo, sometimes combined with standard therapy in both arms. Given the uncertainty of the quality of evidence, meta-analyses show that there is little or no evidence for a difference in mortality during study and premature progress to AML. However, these assumptions have to be further explored. Treatment with TPO mimetics resulted in a lower number of MDS patients suffering from bleeding events.There is no evidence for a difference between study groups regarding transfusion requirement. Enlarged sample sizes and a longer follow-up of future trials should improve the estimate of safety and efficacy of TPO mimetics, moreover health-related quality of life should be evaluated. As two ongoing studies currently investigate eltrombopag (one already completed, but without published results), we are awaiting results for this drug.
Topics: Adult; Azacitidine; Benzoates; Blood Transfusion; Decitabine; Female; Hemorrhage; Humans; Hydrazines; Lenalidomide; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Pyrazoles; Quality of Life; Randomized Controlled Trials as Topic; Receptors, Fc; Recombinant Fusion Proteins; Thalidomide; Thrombocytopenia; Thrombopoietin
PubMed: 28962071
DOI: 10.1002/14651858.CD009883.pub2