-
Biology of Blood and Marrow... Apr 2019Fludarabine with busulfan (FB) or melphalan (FM) are 2 more commonly used reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (HCT).We... (Meta-Analysis)
Meta-Analysis
Choosing a Reduced-Intensity Conditioning Regimen for Allogeneic Stem Cell Transplantation, Fludarabine/Busulfan versus Fludarabine Melphalan: A Systematic Review and Meta-Analysis.
Fludarabine with busulfan (FB) or melphalan (FM) are 2 more commonly used reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (HCT).We present a systematic review and meta-analysis of studies comparing these 2 RIC regimens. We searched electronic databases from inception through November 1, 2017 for literature searches to identify relevant studies. A DerSimonian random effects model was used to measure efficacy outcomes; hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) are reported. Seven studies, including a total of 1955 patients, met criteria for inclusion, of which 6 were included in the overall pooled analysis because of repetition of some patients in 2 studies. Three studies were included in the subgroup analysis of acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) and 2 in the subgroup analysis of lymphoid malignancies. Overall survival (OS) and progression-free survival were not statistically significantly different between the 2 RIC regimens in analysis of all studies. However, OS was better with FM in subgroup analysis of AML/MDS studies (HR, .83; 95% CI, .73 to .95). Nonrelapse mortality was lower with FB (HR, .64; 95% CI, .46 to .89), whereas relapse was lower with FM (HR, 1.52; 95% CI, 1.13 to 2.06) in the analysis of all studies. This meta-analysis shows that FB and FM are associated with a similar OS in patients undergoing HCT. Relapse rates are lower with FM but at the cost of higher nonrelapse mortality.
Topics: Busulfan; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Melphalan; Transplantation Conditioning; Transplantation, Homologous; Vidarabine
PubMed: 30471339
DOI: 10.1016/j.bbmt.2018.11.016 -
Journal of Comparative Effectiveness... May 2018A systematic literature review and network meta-analysis were conducted to determine the relative efficacy and safety of interventions for treatment-naive chronic... (Meta-Analysis)
Meta-Analysis
AIM
A systematic literature review and network meta-analysis were conducted to determine the relative efficacy and safety of interventions for treatment-naive chronic lymphocytic leukemia patients, as comparative evidence is scarce.
MATERIALS & METHODS
Relative treatment effects of progression-free survival, overall survival and safety outcomes were estimated via network meta-analysis based on data identified via systematic literature review.
RESULTS
Ibrutinib was superior in all pairwise comparisons for progression-free survival (probability to be better [P] range: overall population: 69-100%; fludarabine-ineligible population: 69-100%) and overall survival (P range: overall: 89-100%; fludarabine-ineligible: 91-100%) and had the highest probability of being best for all outcomes.
CONCLUSION
Ibrutinib provides superior benefit in survival and safety compared with other front-line treatments of chronic lymphocytic leukemia.
Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Network Meta-Analysis; Piperidines; Progression-Free Survival; Pyrazoles; Pyrimidines; Vidarabine
PubMed: 29210593
DOI: 10.2217/cer-2017-0086 -
Blood Nov 2017In chronic lymphocytic leukemia (CLL) patients with mutated , 3 recent studies have demonstrated prolonged progression-free survival (PFS) after treatment with... (Review)
Review
In chronic lymphocytic leukemia (CLL) patients with mutated , 3 recent studies have demonstrated prolonged progression-free survival (PFS) after treatment with fludarabine-cyclophosphamide-rituximab (FCR) chemoimmunotherapy. We performed a systematic review to assess the benefit of FCR for patients with CLL and identified 5 randomized trials that met our inclusion criteria. FCR improved complete remission, PFS and overall survival vs the comparator; median PFS was not reached in the subgroup of CLL patients with mutated .
Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Female; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Mutation; Remission Induction; Rituximab; Time Factors; Vidarabine
PubMed: 29025740
DOI: 10.1182/blood-2017-07-731588 -
Biology of Blood and Marrow... Apr 2016Oral mucositis (OM) is a debilitating early adverse effect of allogeneic hematopoietic stem cell transplantation (HSCT). The intensity of the conditioning regimen... (Review)
Review
Oral mucositis (OM) is a debilitating early adverse effect of allogeneic hematopoietic stem cell transplantation (HSCT). The intensity of the conditioning regimen correlates with the incidence and severity of OM, but no studies have analyzed this relationship among various conditioning regimens. We performed a systematic review on the incidence and outcomes of OM in allogeneic HSCT patients and analyzed this association. A comprehensive search of several databases (Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Cochrane CRCT, Cochrane DSR, Scopus) from 1990 to 2014 for studies of OM in allogeneic HSCT patients was conducted. Professional societies' meeting abstracts were also searched. Grade of OM was analyzed based on the World Health Organization (WHO) or National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events scales. Severe mucositis was defined as either grades 2 to 4 or grades 3 and 4, depending on the studies' definition of severity. Cohorts were analyzed based on regimen intensity; ie, reduced-intensity conditioning (RIC) (including nonmyeloablative) and myeloablative (MA). Random effect (RE) and standard logistic models weighted by the number of patients in each cohort were used for comparisons. A total of 624 studies were generated from the search. Of the 395 patients in 8 eligible MA regimen studies, 73.2% experienced any OM, whereas in 245 patients in the 6 eligible RIC regimen studies, 86.5% experienced any OM (chi-square P < .0001; RE, P = .05). Severe (grades 2 to 4) OM occurred among 79.7% of the WHO/NCI-graded MA patients and 71.5% of RIC patients (chi-square, P = .0421; RE, P < .01). In comparing graft-versus-host disease (GVHD) prophylaxis, only 55.4% of patients receiving nonmethotrexate regimens experienced OM; this was lower (chi-square, P < .0001; RE, P = .06) than that found among patients who received methotrexate (83.4%), either standard or reduced dose. Besides NCI and WHO grading scales, other scales included in the studies were Oral Mucositis Index, the Southwest Oncology Group Criteria, and Eastern Cooperative Oncology Group scale. To our knowledge, this is the first analysis on OM in allogeneic HSCT patients with respect to conditioning regimens, and we observed that RIC regimens led to a high incidence of OM similar to that of MA regimens. Clinical trials on treatment of OM are lacking, emphasizing the essential need for prospective studies in this arena. A significant variance in the criteria for grading OM underscores the importance of establishing a standard grading system for OM measurement in future allogeneic HSCT clinical trials.
Topics: Busulfan; Cyclophosphamide; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Methotrexate; Mouth Mucosa; Myeloablative Agonists; Severity of Illness Index; Stomatitis; Transplantation Conditioning; Transplantation, Homologous; Vidarabine
PubMed: 26409924
DOI: 10.1016/j.bbmt.2015.09.014 -
The Cochrane Database of Systematic... Jan 2015Eye disease due to herpes simplex virus (HSV) commonly presents as epithelial keratitis which, though usually self-limiting, may persist or progress without treatment. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Eye disease due to herpes simplex virus (HSV) commonly presents as epithelial keratitis which, though usually self-limiting, may persist or progress without treatment.
OBJECTIVES
To compare the relative effectiveness of antiviral agents, interferon, and corneal debridement in the treatment of HSV epithelial keratitis.
SEARCH METHODS
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 12), PubMed (January 1946 to 31 December 2014), EMBASE (January 1980 to 31 December 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to 31 December 2014), System for Information on Grey Literature in Europe (OpenGrey) (January 1995 to 31 December 2014), BIOSIS (January 1926 to 5 May 2014), Scopus (January 1966 to 31 December 2014), Japan Science and Technology Institute (J-Global) (January 1975 to 31 December 2014), China National Knowledge Infrastructure (CNKI) (January 1979 to 31 December 2014), British Library's Electronic Table of Contents (Zetoc) (January 1993 to 7 May 2014). We looked for trials listed on the the metaRegister of Controlled Trials (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en), Chinese Clinical Trial Registry, the U.S. Food and Drug Administration (FDA) (www.fda.gov/), National Institute for Health and Clinical Excellence (NICE) (www.
EVIDENCE
nhs.uk) and the European Medicines Agency (EMA) (www.ema.europa.eu/ema/) as of 31 December 2014. There were no language or date restrictions in the search for trials. We also culled literature digests and conference proceedings as of 15 April 2014. There were no language or date restrictions in the search for trials.
SELECTION CRITERIA
Randomised and quasi-randomised trials of HSV dendritic or geographic epithelial keratitis were included that reported the proportion of eyes healed at one week, two weeks, or both after enrolment.
DATA COLLECTION AND ANALYSIS
We tabulated data on study characteristics, risk of bias, and outcomes and used direct comparisons to estimate a risk ratio (RR) and, when feasible, a hazard ratio (HR) with a 95% confidence interval (CI). Heterogeneity was assessed by an inconsistency index. A multiple treatment comparison meta-analysis consolidated direct and indirect comparisons of relative healing at 14 days.
MAIN RESULTS
One hundred thirty-seven studies involving 8333 eyes met the inclusion criteria. Placebo-controlled studies were heterogeneous in comparison with idoxuridine (RR 1.74; 95% CI 1.03 to 2.91) and few in number for vidarabine (RR 1.81; 95% CI 1.09 to 3.01), interferon (RR 1.32; 95% CI 1.06 to 1.64), and debridement. Vidarabine (RR 1.13; 95% CI 1.02 to 1.25), trifluridine (RR 1.30; 95% CI 1.18 to 1.43), acyclovir (RR 1.23; 95% CI 1.14 to 1.34), and brivudine (RR 1.34; 95% CI 1.18 to 1.51) were more effective than idoxuridine. Trifluridine (RR 1.17; 95% CI 1.03 to 1.32) and acyclovir (RR 1.11; 95% CI 1.03 to 1.19) were more effective than vidarabine. No significant differences in healing emerged among trifluridine, acyclovir, brivudine, and foscarnet although few studies compared brivudine or foscarnet with other antivirals. Any potential advantage of ganciclovir compared to acyclovir was mitigated by study heterogeneity and possible publication bias. Only one study evaluated the joint use of two topical antivirals. In a limited number of studies, oral acyclovir (RR 0.92; 95% CI 0.79 to 1.07) or the combination of oral acyclovir with a topical antiviral (RR 1.36; 95% CI 0.68 to 2.74) appeared as effective as a single topical antiviral agent. Compared to topical antiviral monotherapy, the combination of an antiviral with either interferon or debridement had inconsistent effects on expediting healing and improving outcome.
AUTHORS' CONCLUSIONS
Placebo-controlled studies of HSV epithelial keratitis are limited to superseded interventions. Trifluridine and acyclovir are more effective than idoxuridine or vidarabine and similar in therapeutic effectiveness. Brivudine and foscarnet do not substantially differ in effectiveness from trifluridine or acyclovir. Ganciclovir is at least as effective as acyclovir. The addition of interferon to a nucleoside antiviral agent and the combination of debridement with antiviral treatment need to be further assessed to substantiate any possible advantage in healing.
Topics: Administration, Oral; Administration, Topical; Antiviral Agents; Combined Modality Therapy; Debridement; Humans; Interferons; Keratitis, Herpetic; Randomized Controlled Trials as Topic
PubMed: 25879115
DOI: 10.1002/14651858.CD002898.pub5 -
The Cochrane Database of Systematic... Nov 2012Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in western countries. Standard treatments include mono-... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in western countries. Standard treatments include mono- or polychemotherapies, usually combined with monoclonal antibodies such as rituximab or alemtuzumab. However, the impact of these agents remains unclear, as there are hints for increased risk of severe infections.
OBJECTIVES
The objectives of this review are to provide an evidence-based answer regarding the clinical benefits and harms of monoclonal anti-CD20 antibodies (such as rituximab, ofatumumab, GA101) compared to no further therapy or to other anti-leukaemic therapies in patients with CLL, irrespective of disease status.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 12, 2011), MEDLINE (from January 1990 to 4 January 2012), and EMBASE (from 1990 to 20 March 2009) as well as conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association and European Society of Medical Oncology) for randomised controlled trials (RCTs).
SELECTION CRITERIA
We included RCTs examining monoclonal anti-CD20 antibodies compared to no further therapy or to anti-leukaemic therapy such as chemotherapy or monoclonal antibodies in patients with newly diagnosed or relapsed CLL.
DATA COLLECTION AND ANALYSIS
We used hazard ratios (HR) as effect measures for overall survival (OS), progression-free survival (PFS) and time to next treatment, and risk ratios (RR) for response rates, treatment-related mortality (TRM) and adverse events (AEs). Two review authors independently extracted data and assessed quality of trials.
MAIN RESULTS
We screened a total of 1150 records. Seven RCTs involving 1763 patients were identified, but only five could be included in the two separate meta-analyses we performed. We judged the overall the quality of these trials as moderate to high. All trials were randomised and open-label studies. However, two trials were published as abstracts only, therefore we were unable to assess the potential risk of bias for these trials in detail.Three RCTs (N = 1421) assessed the efficacy of monoclonal anti-CD20 antibodies (i.e. rituximab) plus chemotherapy compared to chemotherapy alone. The meta-analyses showed a statistically significant OS (HR 0.78, 95% confidence interval (CI) 0.62 to 0.98, P = 0.03, the number needed to treat for an additional beneficial effect (NNTB) was 12) and PFS (HR 0.64, 95% CI 0.55 to 0.74, P < 0.00001) advantage for patients receiving rituximab. In the rituximab-arm occurred more AEs, World Health Organization (WHO) grade 3 or 4 (3 trials, N = 1398, RR 1.15, 95% CI 1.08 to 1.23, P < 0.0001; the number needed to harm for an additional harmful outcome (NNTH) was 9), but that did not lead to a statistically significant difference regarding TRM (3 trials, N = 1415, RR 1.19, 95% CI 0.70 to 2.01, P = 0.52).Two trials (N = 177) evaluated rituximab versus alemtuzumab. Neither study reported OS or PFS. There was no statistically significant difference between arms regarding complete response rate (CRR) (RR 1.21, 95% CI 0.94 to 1.58, P = 0.14) or TRM (RR 0.31, 95% CI 0.06 to 1.51, P = 0.15). However, the CLL2007FMP trial was stopped early owing to an increase in mortality in the alemtuzumab arm. More serious AEs occurred in this arm (43% with alemtuzumab versus 22% with rituximab; P = 0.006).Two trials assessed different dosages or time schedules of monoclonal anti-CD20 antibodies. One trial (N = 104) evaluated two different rituximab schedules (concurrent arm: fludarabine plus rituximab (Flu-R) plus rituximab consolidation versus sequential arm: fludarabine alone plus rituximab consolidation). The comparison of the concurrent versus sequential regimen of rituximab showed a statistically significant difference of the CRR with 33% in the concurrent-arm and 15% in the sequential-arm (P = 0.04), that did not lead to statistically significant differences regarding OS (HR 1.14, 95% CI 0.20 to 6.65, P = 0.30) or PFS (HR 0.96, 95% CI 0.43 to 2.15, P = 0.11). Furthermore results showed no differences in occurring AEs, except for neutropenia, which was more often observed in patients of the concurrent arm. The other trial (N = 61) investigated two different dosages (500 mg and 1000 mg) of ofatumumab in addition to FluC. The arm investigating ofatumumab did not assess OS and a median PFS had not been reached owing to the short median follow-up of eight months. It showed no statistically significant differences between arms regarding CRR (32% in the FCO500 arm versus 50% in the FCO1000 arm; P = 0.10) or AEs (anaemia, neutropenia, thrombocytopenia).
AUTHORS' CONCLUSIONS
This meta-analysis showed that patients receiving chemotherapy plus rituximab benefit in terms of OS as well as PFS compared to those with chemotherapy alone. Therefore, it supports the recommendation of rituximab in combination with FluC as an option for the first-line treatment as well as for the people with relapsed or refractory CLL. The available evidence regarding the other assessed comparisons was not sufficient to deduct final conclusions.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Randomized Controlled Trials as Topic; Rituximab; Vidarabine
PubMed: 23152253
DOI: 10.1002/14651858.CD008079.pub2 -
The Cochrane Database of Systematic... Feb 2012Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in Western countries. Standard treatment includes... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in Western countries. Standard treatment includes mono- or poly-chemotherapies. Nowadays, monoclonal antibodies are added, especially alemtuzumab and rituximab. However, the impact of these agents remains unclear, as there are hints of an increased risk of severe infections.
OBJECTIVES
To assess alemtuzumab compared with no further therapy, or with other anti-leukaemic therapy in patients with CLL.
SEARCH METHODS
We searched CENTRAL and MEDLINE (from January 1985 to November 2011), and EMBASE (from 1990 to 2009) as well as conference proceedings for randomised controlled trials (RCTs). Two review authors (KB, NS) independently screened search results.
SELECTION CRITERIA
We included RCTs comparing alemtuzumab with no further therapy or comparing alemtuzumab with anti-leukaemic therapy such as chemotherapy or monoclonal antibodies in patients with histologically-confirmed B-cell CLL. Both pretreated and chemotherapy-naive patients were included.
DATA COLLECTION AND ANALYSIS
We used hazard ratios (HR) as an effect measure for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) for response rates, treatment-related mortality (TRM) and adverse events. Two review authors independently extracted data and assessed the quality of trials.
MAIN RESULTS
Our search strategies led to 1542 potentially relevant references. Of these, we included five RCTs involving 845 patients. Overall, we judged the quality of the five trials as moderate. All trials were reported as randomised and open-label studies. However, two trials were published as abstracts only, therefore, we were unable to assess the potential risk of bias for these trials in detail. Because of the small number of studies in each analysis (two), the quantification of heterogeneity was not reliable.Two trials (N = 356) assessed the efficacy of alemtuzumab compared with no further therapy. One trial (N = 335), reported a statistically significant OS advantage for all patients receiving alemtuzumab (HR 0.65 (95% confidence interval (CI) 0.45 to 0.94; P = 0.021). However, no improvement was seen for the subgroup of patients in Rai stage I or II (HR 1.07; 95% CI 0.62 to 1.84; P = 0.82). In both trials, the complete response rate (CRR) (RR 2.61; 95% CI 1.26 to 5.42; P = 0.01) and PFS (HR 0.58; 95% CI 0.44 to 0.76; P < 0.0001) were statistically significantly increased under therapy with alemtuzumab. The potential heterogeneity seen in the forest plot could be due to the different study designs: One trial evaluated alemtuzumab additional to fludarabine as relapse therapy; the other trial examined alemtuzumab compared with no further therapy for consolidation after first remission.There was no statistically significant difference for TRM between both arms (RR 0.57; 95% CI 0.17 to 1.90; P = 0.36). A statistically significant higher rate of CMV reactivation (RR 10.52; 95% CI 1.42 to 77.68; P = 0.02) and infections (RR 1.32; 95% CI 1.01 to 1.74; P = 0.04) occurred in patients receiving alemtuzumab. Seven severe infections (64%) in the alemtuzumab arm in the GCLLSG CLL4B study led to premature closure.Two trials (N = 177), evaluated alemtuzumab versus rituximab. Neither study reported OS or PFS. We could not detect a statistically significant difference for CRR (RR 0.85; 95% CI 0.67 to 1.08; P = 0.18) or TRM (RR 3.20; 95% CI 0.66 to 15.50; P = 0.15) between both arms. However, the CLL2007FMP trial was stopped early due to an increase in mortality in the alemtuzumab arm. More serious adverse events occurred in this arm (43% versus 22% (rituximab), P = 0.006).One trial (N = 297), assessed the efficacy of alemtuzumab compared with chemotherapy (chlorambucil). For this trial, no HR is reported for OS. Median survival has not yet been reached, 84% of patients were alive in each arm at the data cut-off or at the last follow-up date (24.6 months). The TRM between arms shows no statistical significant difference (0.6% versus 2.0%; P = 0.34). Alemtuzumab statistically significantly improves PFS (HR 0.58; 95% CI 0.43 to 0.77; P = 0.0001), time to next treatment (23.3 compared with 14.7 months; P = 0.0001), ORR (83.2% versus 55.4%; P < 0.0001), CRR (24.2% versus 2.0%; P < 0.0001), and minimal residual disease rate (7.4% versus 0%; P = 0.0008) compared with chlorambucil. Statistically, significantly more asymptomatic (51.7% versus 7.4%) and symptomatic cytomegalovirus (CMV) infections (15.4% versus 0%) occurred in the patients treated with alemtuzumab.
AUTHORS' CONCLUSIONS
In summary, the currently available evidence suggests an OS, CRR and PFS benefit for alemtuzumab compared with no further therapy, but an increased risk for infections in general, CMV infections and CMV reactivations. The role of alemtuzumab versus rituximab still remains unclear, further trials with longer follow-up and overall survival as primary endpoint are needed to evaluate the effects of both agents compared with each other. Alemtuzumab compared with chlorambucil seems to be favourable in terms of PFS, but a longer follow-up period and trials with overall survival as primary endpoint are needed to determine whether this effect will translate into a survival advantage.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Chlorambucil; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Randomized Controlled Trials as Topic; Rituximab; Vidarabine
PubMed: 22336834
DOI: 10.1002/14651858.CD008078.pub2 -
The Cochrane Database of Systematic... Dec 2010Eye disease due to herpes simplex virus (HSV) commonly presents as epithelial keratitis. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Eye disease due to herpes simplex virus (HSV) commonly presents as epithelial keratitis.
OBJECTIVES
To compare the relative effectiveness of antiviral agents, interferon, and corneal débridement in the treatment of acute HSV epithelial keratitis.
SEARCH STRATEGY
We searched CENTRAL (The Cochrane Library 2010, Issue 4), MEDLINE (January 1950 to October 2010), EMBASE (January 1980 to October 2010), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to October 2010), Zetoc (British Library's Electronic Table of Contents), System for Information on Grey Literature in Europe (openSIGLE), Biosciences Information Service (BIOSIS), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), Japan Information Center of Science and Technology (JICST-EPlus), and China Academic Journals database (CAJ) via China National Knowledge Infrastructure (CNKI) with citations confirmed using China/Asia On Demand (COAD). There were no language or date restrictions in the search for trials. All databases except CNKI and COAD were last searched on 27 October 2010, CNKI and COAD were searched on 1 April 2010. We also searched literature digests, conference proceedings and reference lists.
SELECTION CRITERIA
Of 152 eligible studies,106 comparative treatment trials involving 5872 eyes with dendritic or geographic epithelial keratitis were analysed for corneal healing over two weeks.
DATA COLLECTION AND ANALYSIS
Interventions were compared at 14 days after trial enrolment by calculating a risk ratio (RR) that was adjusted with indirect RR, assessed by an inconsistency index (I(2) ) and supplemented by a seven-day RR and a hazard ratio (HR).
MAIN RESULTS
Idoxuridine, though uncertainly better in healing outcome than control because of few trials with 14-day follow up, allowed earlier corneal re-epithelialisation. Vidarabine resulted in a significantly better outcome than placebo in one trial (RR 1.96; 95% CI 1.10 to 3.49). Compared to idoxuridine, in combined direct and indirect analyses, vidarabine (RR 1.11; 95% CI 1.03 to 1.19), trifluridine (RR 1.31; 95% CI 1.20 to 1.42), acyclovir (RR 1.23; 95% CI 1.16 to 1.31), brivudine (RR 1.38; 95% CI 1.18 to 1.61), and ganciclovir (RR 1.40; 95% CI 1.25 to 1.57) were significantly more effective. Trifluridine (RR 1.12; 95% CI 1.04 to 1.21) and acyclovir (RR 1.11; 95% CI 1.05 to 1.19) appeared more effective than vidarabine. No significant differences were found in comparisons between acyclovir, trifluridine and brivudine. The comparison of ganciclovir to acyclovir was limited by heterogeneity and possible publication bias. The joint use of two topical antivirals (RR 1.00; 95% CI 0.89 to 1.12) and the use of oral acyclovir alone (RR 0.92; 95% CI 0.79 to 1.07) or combined with a topical antiviral (RR 1.08; 95% CI 0.99 to 1.17) appeared as effective as topical antiviral therapy. Compared to antiviral monotherapy, the combination of an antiviral with interferon (RR 1.03; 95% CI 0.99 to 1.07) or with débridement (RR 1.04; 95% CI 0.95 to 1.14) did not yield significantly better outcomes but may have accelerated healing. The corneal epithelial healing outcome was improved when antiviral therapy was added to débridement (RR 1.21; 95% CI 1.04 to 1.42).
AUTHORS' CONCLUSIONS
Trifluridine and acyclovir are more effective than idoxuridine or vidarabine, and similar in therapeutic effectiveness. Brivudine and ganciclovir are at least as effective as acyclovir. While not improving outcome, the combination of interferon and an antiviral agent may speed healing. The effectiveness of corneal epithelial débridement is improved by an antiviral agent.
Topics: Administration, Oral; Administration, Topical; Antiviral Agents; Combined Modality Therapy; Debridement; Humans; Interferons; Keratitis, Herpetic; Randomized Controlled Trials as Topic
PubMed: 21154352
DOI: 10.1002/14651858.CD002898.pub4 -
The Cochrane Database of Systematic... Jul 2009Herpes simplex virus (HSV) is a rare but serious neonatal pathogen. Prior to the availability of antiviral drugs the mortality associated with all but localised neonatal... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Herpes simplex virus (HSV) is a rare but serious neonatal pathogen. Prior to the availability of antiviral drugs the mortality associated with all but localised neonatal infection was high, with 85% of infants with disseminated HSV infection and 50% of infants with encephalitis dying by one year of age. The morbidity in the survivors of multiorgan infection was also high, with up to 50% experiencing long-term neurological sequelae.
OBJECTIVES
To determine the effect of antiviral agents in the treatment of neonatal HSV infections on mortality, progression of disease and neurodevelopmental sequelae at approximately one year. The secondary objective was to assess the effect of antiviral agents on major complications associated with the use of these agents including nephrotoxicity and bone marrow suppression.
SEARCH STRATEGY
Trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2008), MEDLINE (1996 - Nov 2008), EMBASE (1982 - Nov 2008) and reference lists of published trials.
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials of antiviral therapy in infants less than one month of age with virologically proven HSV infection were included.
DATA COLLECTION AND ANALYSIS
Data were extracted and the analyses performed independently by two review authors. Studies were analysed for methodological quality using the criteria of the Cochrane Neonatal Review Group. All data were analysed using RevMan 5.1. When possible, meta-analysis was performed to calculate typical relative risk, typical risk difference, along with their 95% confidence intervals (CI).
MAIN RESULTS
Two eligible studies of a total of 273 infants were included. Both studies were randomized controlled trials. One study treated 63 infants with vidarabine or placebo (Whitley 1980) and the other study treated 210 infants with aciclovir or vidarabine (Whitley 1991).In the study comparing vidarabine with placebo (Whitley 1980), infants with all forms of neonatal HSV disease were included [disseminated disease, central nervous system (CNS) disease alone, and skin, eye and mouth (SEM) disease].There was no significant reduction in the risk of mortality when analyzed as an entire group; however, mortality was significantly reduced when data from infants with CNS disease or disseminated disease were combined. There was no difference in the rate of neurological abnormalities in survivors at one year when analyzed as an entire group or by disease category.There was no difference between aciclovir and vidarabine (Whitley 1991) in preventing mortality from neonatal HSV disease, in preventing disease progression, in reducing the incidence of neurological abnormality at one year, or in the incidence of drug-induced renal or bone marrow toxicity. In infants with SEM disease, there was no significant difference in neurological outcome with aciclovir compared vidarabine treatment. Both drugs were well tolerated in the newborn period.
AUTHORS' CONCLUSIONS
There is insufficient trial evidence to evaluate the effects of antiviral agents with controls or with each other. The rarity of the condition makes effectively powered clinical trials difficult to perform. The efficacy of newer antiviral agents with better bioavailability (e.g. valaciclovir, valganciclovir) for the treatment of neonatal disease needs to be evaluated in randomised trials. The efficacy of oral formulations need to be evaluated as they may be useful for infants with skin, eye or mouth HSV disease or in the treatment of infants with recurrences after the neonatal period.
Topics: Acyclovir; Antiviral Agents; Developmental Disabilities; Disease Progression; Herpes Simplex; Humans; Infant, Newborn; Randomized Controlled Trials as Topic; Vidarabine
PubMed: 19588350
DOI: 10.1002/14651858.CD004206.pub2 -
The Cochrane Database of Systematic... Jul 2006Recent trials suggest improved response rates for purine antagonists compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Recent trials suggest improved response rates for purine antagonists compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a survival advantage.
OBJECTIVES
To determine if there is any advantage of purine antagonists compared to alkylating agents (alone or in combination) in the treatment of patients with previously untreated B-CLL.
SEARCH STRATEGY
Medical databases (Cochrane Library, MEDLINE, EMBASE), conference proceedings and internet-based trial registers were searched electronically and/or by hand (1990-2003). All references were checked for further trial information. We also contacted experts in the field and pharmaceutical companies.
SELECTION CRITERIA
Randomised controlled trials comparing purine antagonists as single agents with alkylator-based regimens in patients with previously untreated B-CLL were included. We included full-text and abstract publications as well as unpublished data.
DATA COLLECTION AND ANALYSIS
Data extraction and quality assessment were done in duplicate by two independent reviewers. Missing data were obtained from original authors. Endpoints included overall survival, overall response rate, rate of complete remissions, progression-free survival, treatment-related morbidity and mortality.
MAIN RESULTS
Five trials with 1838 randomised patients were included. There is some evidence for improved overall survival after treatment with purine antagonists compared to alkylators, but statistical significance was not reached (HR 0.89 [95% CI 0.78-1.01], 4 trials, n=1638). However, the relative risk for achieving an overall response (RR 1.22 [95% CI 1.13-1.31], 5 trials, n=1751) and complete remission (RR 1.94 [95% CI 1.65-2.28], 5 trials, n=1751) was significantly higher, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61-0.82], 4 trials, n=1638). Incidence of grade III/IV infections was significantly higher in patients receiving treatment with purine antagonists (RR 1.83 [95% 1.30-2.58], 4 trials, n=1620). There was no significant difference concerning the relative risk for grade III/IV neutropenia (RR 1.14 [95% CI 0.98-1.34], 4 trials, n=1620) and therapy-related mortality (RR 0.94 [95% CI 0.45-1.95]). Overall incidence of hemolytic anemia was low, but significantly increased in the purine antagonist group (RR 3.36 [95% CI 1.27-8.91], 3 trials, n=1258).
AUTHORS' CONCLUSIONS
Despite significantly increased overall response and complete remission rates and longer progression-free survival with first-line treatment of B-CLL patients with single-agent purine antagonists, we were not able to detect a statistically significant improvement of overall survival compared to alkylator-based regimens. Furthermore, the use of purine antagonists also augments the risk for grade III/IV infections and hemolytic anemia.
Topics: Antineoplastic Agents; Chlorambucil; Cladribine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Randomized Controlled Trials as Topic; Vidarabine
PubMed: 16856041
DOI: 10.1002/14651858.CD004270.pub2