Search

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. Using a living systematic review approach, to assess whether hyperimmune immunoglobulin therapy is effective and safe in the treatment of people with COVID-19; and to maintain the currency of the evidence.

Background Diffuse large B‐cell lymphoma (DLBCL) is an aggressive cancer of the lymphatic system. About 30% to 40% of people with DLBCL experience relapse and 10% are refractory to first‐line treatment usually consisting of R‐CHOP chemotherapy. Of those eligible for second‐line treatment, commonly consisting of salvage chemotherapy followed by autologous stem‐cell transplantation (ASCT), around 50% experience relapse. With a median overall survival of less than six to 12 months, the prognosis of individuals who relapse or are refractory (r/r) to advanced lines of treatment or of those who are ineligible for ASCT, is very poor. With the introduction of chimeric antigen receptor (CAR) T‐cell therapy, a novel treatment option for these people is available. Objectives To assess the benefits and harms of chimeric antigen receptor (CAR) T‐cell therapy for people with relapsed or refractory (r/r) DLBCL. Search methods An experienced information specialist performed a systematic database search for relevant articles on CENTRAL, MEDLINE and Embase until September 11th, 2020. We also searched trial registries and reference lists of identified studies up to this date. All search results were screened by two authors independently and a third author was involved in case of discrepancies. Selection criteria We included prospectively planned trials evaluating CAR T‐cell therapy for people with r/r DLBCL. We had planned to include randomised controlled trials (RCTs) and we flexibly adapted eligibility criteria to the most reliable study designs available. We excluded studies involving fewer than 10 participants with r/r DLBCL and studies with a proportion of participants with r/r DLBCL below 70%, unless data were reported separately for this subgroup. Data collection and analysis Two review authors extracted data and performed risk of bias ratings independently. A third author was involved in case of disagreements. As our search did not yield any completed RCTs, prospective controlled non‐randomised studies of interventions (NRSIs) or prospective observational studies with a control group, we did not meta‐analyse data and reported all results narratively. We adopted the GRADE approach to assess the certainty of the evidence for prioritised outcomes. Main results We identified 13 eligible uncontrolled studies evaluating a single or multiple arms of CAR T‐cell therapies. We also identified 38 ongoing studies, including three RCTs. Ten studies are awaiting classification due to completion with no retrievable results data or insufficient data to justify inclusion. The mean number of participants enrolled, treated with CAR T‐cell therapy and evaluated in the included studies were 79 (range 12 to 344; data unavailable for two studies), 61 (range 12 to 294; data unavailable for one study) and 52 (range 11 to 256), respectively. Most studies included people with r/r DLBCL among people with other haematological B‐cell malignancies. Participants had received at least a median of three prior treatment lines (data unavailable for four studies), 5% to 50% had undergone ASCT (data unavailable for five studies) and, except for two studies, 3% to 18% had undergone allogenic stem‐cell transplantation (data unavailable for eight studies). The overall risk of bias was high for all studies, in particular, due to incomplete follow‐up and the absence of blinding. None of the included studies had a control group so that no adequate comparative effect measures could be calculated. The duration of follow‐up varied substantially between studies, in particular, for harms. Our certainty in the evidence is very low for all outcomes. Overall survival was reported by eight studies (567 participants). Four studies reported survival rates at 12 months which ranged between 48% and 59%, and one study reported an overall survival rate of 50.5% at 24 months. The evidence is very uncertain about the effect of CAR T‐cell therapy on overall survival. Two studies including 294 participants at baseline and 59 participants at the longest follow‐up (12 months or 18 months) described improvements of quality of life measured with the EuroQol 5‐Dimension 5‐Level visual analogue scale (EQ‐5D‐5L VAS) or Function Assessment of Cancer Therapy‐Lymphoma (FACT‐Lym). The evidence is very uncertain about the effect of CAR T‐cell therapy on quality of life. None of the studies reported treatment‐related mortality. Five studies (550 participants) reported the occurrence of adverse events among participants, ranging between 99% and 100% for any grade adverse events and 68% to 98% for adverse events grade ≥ 3. In three studies (253 participants), 56% to 68% of participants experienced serious adverse events, while in one study (28 participants), no serious adverse events occurred. CAR T‐cell therapy may increase the risk of adverse events and serious adverse events but the evidence is very uncertain about the exact risk. The occurrence of cytokine release syndrome (CRS) was reported in 11 studies (675 participants) under use of various grading criteria. Five studies reported between 42% and 100% of participants experiencing CRS according to criteria described in Lee 2014. CAR T‐cell therapy may increase the risk of CRS but the evidence is very uncertain about the exact risk. Nine studies (575 participants) reported results on progression‐free survival, disease‐free survival or relapse‐free survival. Twelve‐month progression‐free survival rates were reported by four studies and ranged between 44% and 75%. In one study, relapse‐free survival remained at a rate of 64% at both 12 and 18 months. The evidence is very uncertain about the effect of CAR T‐cell therapy on progression‐free survival. Thirteen studies (620 participants) provided data on complete response rates. At six months, three studies reported complete response rates between 40% and 45%. The evidence is very uncertain about the effect of CAR T‐cell therapy on complete response rates. Authors' conclusions The available evidence on the benefits and harms of CAR T‐cell therapy for people with r/r DLBCL is limited, mainly because of the absence of comparative clinical trials. The results we present should be regarded in light of this limitation and conclusions should be drawn very carefully. Due to the uncertainty in the current evidence, a large number of ongoing investigations and a risk of substantial and potentially life‐threatening complications requiring supplementary treatment, it is critical to continue evaluating the evidence on this new therapy.

Background Monoclonal antibodies (mAbs) are laboratory‐produced molecules derived from the B cells of an infected host. They are being investigated as a potential therapy for coronavirus disease 2019 (COVID‐19). Objectives To assess the effectiveness and safety of SARS‐CoV‐2‐neutralising mAbs for treating patients with COVID‐19, compared to an active comparator, placebo, or no intervention. To maintain the currency of the evidence, we will use a living systematic review approach. A secondary objective is to track newly developed SARS‐CoV‐2‐targeting mAbs from first tests in humans onwards. Search methods We searched MEDLINE, Embase, the Cochrane COVID‐19 Study Register, and three other databases on 17 June 2021. We also checked references, searched citations, and contacted study authors to identify additional studies. Between submission and publication, we conducted a shortened randomised controlled trial (RCT)‐only search on 30 July 2021. Selection criteria We included studies that evaluated SARS‐CoV‐2‐neutralising mAbs, alone or combined, compared to an active comparator, placebo, or no intervention, to treat people with COVID‐19. We excluded studies on prophylactic use of SARS‐CoV‐2‐neutralising mAbs. Data collection and analysis Two authors independently assessed search results, extracted data, and assessed risk of bias using the Cochrane risk of bias tool (RoB2). Prioritised outcomes were all‐cause mortality by days 30 and 60, clinical progression, quality of life, admission to hospital, adverse events (AEs), and serious adverse events (SAEs). We rated the certainty of evidence using GRADE. Main results We identified six RCTs that provided results from 17,495 participants with planned completion dates between July 2021 and December 2031. Target sample sizes varied from 1020 to 10,000 participants. Average age was 42 to 53 years across four studies of non‐hospitalised participants, and 61 years in two studies of hospitalised participants. Non‐hospitalised individuals with COVID‐19 Four studies evaluated single agents bamlanivimab (N = 465), sotrovimab (N = 868), regdanvimab (N = 307), and combinations of bamlanivimab/etesevimab (N = 1035), and casirivimab/imdevimab (N = 799). We did not identify data for mortality at 60 days or quality of life. Our certainty of the evidence is low for all outcomes due to too few events (very serious imprecision). Bamlanivimab compared to placebo No deaths occurred in the study by day 29. There were nine people admitted to hospital by day 29 out of 156 in the placebo group compared with one out of 101 in the group treated with 0.7 g bamlanivimab (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.02 to 1.33), 2 from 107 in the group treated with 2.8 g (RR 0.32, 95% CI 0.07 to 1.47) and 2 from 101 in the group treated with 7.0 g (RR 0.34, 95% CI 0.08 to 1.56). Treatment with 0.7 g, 2.8 g and 7.0 g bamlanivimab may have similar rates of AEs as placebo (RR 0.99, 95% CI 0.66 to 1.50; RR 0.90, 95% CI 0.59 to 1.38; RR 0.81, 95% CI 0.52 to 1.27). The effect on SAEs is uncertain. Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Bamlanivimab/etesevimab compared to placebo There were 10 deaths in the placebo group and none in bamlanivimab/etesevimab group by day 30 (RR 0.05, 95% CI 0.00 to 0.81). Bamlanivimab/etesevimab may decrease hospital admission by day 29 (RR 0.30, 95% CI 0.16 to 0.59), may result in a slight increase in any grade AEs (RR 1.15, 95% CI 0.83 to 1.59) and may increase SAEs (RR 1.40, 95% CI 0.45 to 4.37). Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Casirivimab/imdevimab compared to placebo Casirivimab/imdevimab may reduce hospital admissions or death (2.4 g: RR 0.43, 95% CI 0.08 to 2.19; 8.0 g: RR 0.21, 95% CI 0.02 to 1.79). We are uncertain of the effect on grades 3‐4 AEs (2.4 g: RR 0.76, 95% CI 0.17 to 3.37; 8.0 g: RR 0.50, 95% CI 0.09 to 2.73) and SAEs (2.4 g: RR 0.68, 95% CI 0.19 to 2.37; 8.0 g: RR 0.34, 95% CI 0.07 to 1.65). Mortality by day 30 and clinical progression/improvement of symptoms or development of severe symptoms were not reported. Sotrovimab compared to placebo We are uncertain whether sotrovimab has an effect on mortality (RR 0.33, 95% CI 0.01 to 8.18) and invasive mechanical ventilation (IMV) requirement or death (RR 0.14, 95% CI 0.01 to 2.76). Treatment with sotrovimab may reduce the number of participants with oxygen requirement (RR 0.11, 95 % CI 0.02 to 0.45), hospital admission or death by day 30 (RR 0.14, 95% CI 0.04 to 0.48), grades 3‐4 AEs (RR 0.26, 95% CI 0.12 to 0.60), SAEs (RR 0.27, 95% CI 0.12 to 0.63) and may have little or no effect on any grade AEs (RR 0.87, 95% CI 0.66 to 1.16). Regdanvimab compared to placebo Treatment with either dose (40 or 80 mg/kg) compared with placebo may decrease hospital admissions or death (RR 0.45, 95% CI 0.14 to 1.42; RR 0.56, 95% CI 0.19 to 1.60, 206 participants), but may increase grades 3‐4 AEs (RR 2.62, 95% CI 0.52 to 13.12; RR 2.00, 95% CI 0.37 to 10.70). 80 mg/kg may reduce any grade AEs (RR 0.79, 95% CI 0.52 to 1.22) but 40 mg/kg may have little to no effect (RR 0.96, 95% CI 0.64 to 1.43). There were too few events to allow meaningful judgment for the outcomes mortality by 30 days, IMV requirement, and SAEs. Hospitalised individuals with COVID‐19 Two studies evaluating bamlanivimab as a single agent (N = 314) and casirivimab/imdevimab as a combination therapy (N = 9785) were included. Bamlanivimab compared to placebo We are uncertain whether bamlanivimab has an effect on mortality by day 30 (RR 1.39, 95% CI 0.40 to 4.83) and SAEs by day 28 (RR 0.93, 95% CI 0.27 to 3.14). Bamlanivimab may have little to no effect on time to hospital discharge (HR 0.97, 95% CI 0.78 to 1.20) and mortality by day 90 (HR 1.09, 95% CI 0.49 to 2.43). The effect of bamlanivimab on the development of severe symptoms at day 5 (RR 1.17, 95% CI 0.75 to 1.85) is uncertain. Bamlanivimab may increase grades 3‐4 AEs at day 28 (RR 1.27, 95% CI 0.81 to 1.98). We assessed the evidence as low certainty for all outcomes due to serious imprecision, and very low certainty for severe symptoms because of additional concerns about indirectness. Casirivimab/imdevimab with usual care compared to usual care alone Treatment with casirivimab/imdevimab compared to usual care probably has little or no effect on mortality by day 30 (RR 0.94, 95% CI 0.87 to 1.02), IMV requirement or death (RR 0.96, 95% CI 0.90 to 1.04), nor alive at hospital discharge by day 30 (RR 1.01, 95% CI 0.98 to 1.04). We assessed the evidence as moderate certainty due to study limitations (lack of blinding). AEs and SAEs were not reported. Authors' conclusions The evidence for each comparison is based on single studies. None of these measured quality of life. Our certainty in the evidence for all non‐hospitalised individuals is low, and for hospitalised individuals is very low to moderate. We consider the current evidence insufficient to draw meaningful conclusions regarding treatment with SARS‐CoV‐2‐neutralising mAbs. Further studies and long‐term data from the existing studies are needed to confirm or refute these initial findings, and to understand how the emergence of SARS‐CoV‐2 variants may impact the effectiveness of SARS‐CoV‐2‐neutralising mAbs. Publication of the 36 ongoing studies may resolve uncertainties about the effectiveness and safety of SARS‐CoV‐2‐neutralising mAbs for the treatment of COVID‐19 and possible subgroup differences.

Background Different bone-modifying agents like bisphosphonates and receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors are used as supportive treatment in men with prostate cancer and bone metastases to prevent skeletal-related events (SREs). SREs such as pathologic fractures, spinal cord compression, surgery and radiotherapy to the bone, and hypercalcemia lead to morbidity, a poor performance status, and impaired quality of life. Efficacy and acceptability of the bone-targeted therapy is therefore of high relevance. Until now recommendations in guidelines on which bone-modifying agents should be used are rare and inconsistent. Objectives To assess the effects of bisphosphonates and RANKL-inhibitors as supportive treatment for prostate cancer patients with bone metastases and to generate a clinically meaningful treatment ranking according to their safety and efficacy using network meta-analysis. Search methods We identified studies by electronically searching the bibliographic databases Cochrane Controlled Register of Trials (CENTRAL), MEDLINE, and Embase until 23 March 2020. We searched the Cochrane Library and various trial registries and screened abstracts of conference proceedings and reference lists of identified trials. Selection criteria We included randomized controlled trials comparing different bisphosphonates and RANKL-inihibitors with each other or against no further treatment or placebo for men with prostate cancer and bone metastases. We included men with castration-restrictive and castration-sensitive prostate cancer and conducted subgroup analyses according to this criteria. Data collection and analysis Two review authors independently extracted data and assessed the quality of trials. We defined proportion of participants with pain response and the adverse events renal impairment and osteonecrosis of the jaw (ONJ) as the primary outcomes. Secondary outcomes were SREs in total and each separately (see above), mortality, quality of life, and further adverse events such as grade 3 to 4 adverse events, hypocalcemia, fatigue, diarrhea, and nausea. We conducted network meta-analysis and generated treatment rankings for all outcomes, except quality of life due to insufficient reporting on this outcome. We compiled ranking plots to compare single outcomes of efficacy against outcomes of acceptability of the bone-modifying agents. We assessed the certainty of the evidence for the main outcomes using the GRADE approach. Main results Twenty-five trials fulfilled our inclusion criteria. Twenty-one trials could be considered in the quantitative analysis, of which six bisphosphonates (zoledronic acid, risedronate, pamidronate, alendronate, etidronate, or clodronate) were compared with each other, the RANKL-inhibitor denosumab, or no treatment/placebo. By conducting network meta-analysis we were able to compare all of these reported agents directly and/or indirectly within the network for each outcome. In the abstract only the comparisons of zoledronic acid and denosumab against the main comparator (no treatment/placebo) are described for outcomes that were predefined as most relevant and that also appear in the 'Summary of findings' table. Other results, as well as results of subgroup analyses regarding castration status of participants, are displayed in the Results section of the full text. Treatment with zoledronic acid probably neither reduces nor increases the proportion of participants with pain response when compared to no treatment/placebo (risk ratio (RR) 1.46, 95% confidence interval (CI) 0.93 to 2.32; per 1000 participants 121 more (19 less to 349 more); moderate-certainty evidence; network based on 4 trials including 1013 participants). For this outcome none of the trials reported results for the comparison with denosumab. The adverse event renal impairment probably occurs more often when treated with zoledronic acid compared to treatment/placebo (RR 1.63, 95% CI 1.08 to 2.45; per 1000 participants 78 more (10 more to 180 more); moderate-certainty evidence; network based on 6 trials including 1769 participants). Results for denosumab could not be included for this outcome, since zero events cannot be considered in the network meta-analysis, therefore it does not appear in the ranking. Treatment with denosumab results in increased occurrence of the adverse event ONJ (RR 3.45, 95% CI 1.06 to 11.24; per 1000 participants 30 more (1 more to 125 more); high-certainty evidence; 4 trials, 3006 participants) compared to no treatment/placebo. When comparing zoledronic acid to no treatment/placebo, the confidence intervals include the possibility of benefit or harm, therefore treatment with zoledronic acid probably neither reduces nor increases ONJ (RR 1.88, 95% CI 0.73 to 4.87; per 1000 participants 11 more (3 less to 47 more); moderate-certainty evidence; network based on 4 trials including 3006 participants). Compared to no treatment/placebo, treatment with zoledronic acid (RR 0.84, 95% CI 0.72 to 0.97) and denosumab (RR 0.72, 95% CI 0.54 to 0.96) may result in a reduction of the total number of SREs (per 1000 participants 75 fewer (131 fewer to 14 fewer) and 131 fewer (215 fewer to 19 fewer); both low-certainty evidence; 12 trials, 5240 participants). Treatment with zoledronic acid and denosumab likely neither reduces nor increases mortality when compared to no treatment/placebo (zoledronic acid RR 0.90, 95% CI 0.80 to 1.01; per 1000 participants 48 fewer (97 fewer to 5 more); denosumab RR 0.93, 95% CI 0.77 to 1.11; per 1000 participants 34 fewer (111 fewer to 54 more); both moderate-certainty evidence; 13 trials, 5494 participants). Due to insufficient reporting, no network meta-analysis was possible for the outcome quality of life. One study with 1904 participants comparing zoledronic acid and denosumab showed that more zoledronic acid-treated participants than denosumab-treated participants experienced a greater than or equal to five-point decrease in Functional Assessment of Cancer Therapy-General total scores over a range of 18 months (average relative difference = 6.8%, range -9.4% to 14.6%) or worsening of cancer-related quality of life. Authors' conclusions When considering bone-modifying agents as supportive treatment, one has to balance between efficacy and acceptability. Results suggest that Zoledronic acid likely increases both the proportion of participants with pain response, and the proportion of participants experiencing adverse events However, more trials with head-to-head comparisons including all potential agents are needed to draw the whole picture and proof the results of this analysis.

Background: Chronic lymphocytic leukaemia (CLL) is the most common cancer of the lymphatic system in Western countries. Several clinical and biological factors for CLL have been identified. However, it remains unclear which of the available prognostic models combining those factors can be used in clinical practice to predict long‐term outcome in people newly‐diagnosed with CLL. Objectives: To identify, describe and appraise all prognostic models developed to predict overall survival (OS), progression‐free survival (PFS) or treatment‐free survival (TFS) in newly‐diagnosed (previously untreated) adults with CLL, and meta‐analyse their predictive performances. Search methods: We searched MEDLINE (from January 1950 to June 2019 via Ovid), Embase (from 1974 to June 2019) and registries of ongoing trials (to 5 March 2020) for development and validation studies of prognostic models for untreated adults with CLL. In addition, we screened the reference lists and citation indices of included studies. Selection criteria: We included all prognostic models developed for CLL which predict OS, PFS, or TFS, provided they combined prognostic factors known before treatment initiation, and any studies that tested the performance of these models in individuals other than the ones included in model development (i.e. 'external model validation studies'). We included studies of adults with confirmed B‐cell CLL who had not received treatment prior to the start of the study. We did not restrict the search based on study design. Data collection and analysis: We developed a data extraction form to collect information based on the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS). Independent pairs of review authors screened references, extracted data and assessed risk of bias according to the Prediction model Risk Of Bias ASsessment Tool (PROBAST). For models that were externally validated at least three times, we aimed to perform a quantitative meta‐analysis of their predictive performance, notably their calibration (proportion of people predicted to experience the outcome who do so) and discrimination (ability to differentiate between people with and without the event) using a random‐effects model. When a model categorised individuals into risk categories, we pooled outcome frequencies per risk group (low, intermediate, high and very high). We did not apply GRADE as guidance is not yet available for reviews of prognostic models. Main results: From 52 eligible studies, we identified 12 externally validated models: six were developed for OS, one for PFS and five for TFS. In general, reporting of the studies was poor, especially predictive performance measures for calibration and discrimination; but also basic information, such as eligibility criteria and the recruitment period of participants was often missing. We rated almost all studies at high or unclear risk of bias according to PROBAST. Overall, the applicability of the models and their validation studies was low or unclear; the most common reasons were inappropriate handling of missing data and serious reporting deficiencies concerning eligibility criteria, recruitment period, observation time and prediction performance measures. We report the results for three models predicting OS, which had available data from more than three external validation studies: CLL International Prognostic Index (CLL‐IPI) This score includes five prognostic factors: age, clinical stage, IgHV mutational status, B2‐microglobulin and TP53 status. Calibration: for the low‐, intermediate‐ and high‐risk groups, the pooled five‐year survival per risk group from validation studies corresponded to the frequencies observed in the model development study. In the very high‐risk group, predicted survival from CLL‐IPI was lower than observed from external validation studies. Discrimination: the pooled c‐statistic of seven external validation studies (3307 participants, 917 events) was 0.72 (95% confidence interval (CI) 0.67 to 0.77). The 95% prediction interval (PI) of this model for the c‐statistic, which describes the expected interval for the model's discriminative ability in a new external validation study, ranged from 0.59 to 0.83. Barcelona‐Brno score Aimed at simplifying the CLL‐IPI, this score includes three prognostic factors: IgHV mutational status, del(17p) and del(11q). Calibration: for the low‐ and intermediate‐risk group, the pooled survival per risk group corresponded to the frequencies observed in the model development study, although the score seems to overestimate survival for the high‐risk group. Discrimination: the pooled c‐statistic of four external validation studies (1755 participants, 416 events) was 0.64 (95% CI 0.60 to 0.67); 95% PI 0.59 to 0.68. MDACC 2007 index score The authors presented two versions of this model including six prognostic factors to predict OS: age, B2‐microglobulin, absolute lymphocyte count, gender, clinical stage and number of nodal groups. Only one validation study was available for the more comprehensive version of the model, a formula with a nomogram, while seven studies (5127 participants, 994 events) validated the simplified version of the model, the index score. Calibration: for the low‐ and intermediate‐risk groups, the pooled survival per risk group corresponded to the frequencies observed in the model development study, although the score seems to overestimate survival for the high‐risk group. Discrimination: the pooled c‐statistic of the seven external validation studies for the index score was 0.65 (95% CI 0.60 to 0.70); 95% PI 0.51 to 0.77. Authors' conclusions: Despite the large number of published studies of prognostic models for OS, PFS or TFS for newly‐diagnosed, untreated adults with CLL, only a minority of these (N = 12) have been externally validated for their respective primary outcome. Three models have undergone sufficient external validation to enable meta‐analysis of the model's ability to predict survival outcomes. Lack of reporting prevented us from summarising calibration as recommended. Of the three models, the CLL‐IPI shows the best discrimination, despite overestimation. However, performance of the models may change for individuals with CLL who receive improved treatment options, as the models included in this review were tested mostly on retrospective cohorts receiving a traditional treatment regimen. In conclusion, this review shows a clear need to improve the conducting and reporting of both prognostic model development and external validation studies. For prognostic models to be used as tools in clinical practice, the development of the models (and their subsequent validation studies) should adapt to include the latest therapy options to accurately predict performance. Adaptations should be timely.

BACKGROUND: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with respiratory virus diseases, and are currently being investigated in trials as a potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required. OBJECTIVES: To assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19. SEARCH METHODS: The protocol was pre-published with the Center for Open Science and can be accessed here: osf.io/dwf53 We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trials registries to identify ongoing studies and results of completed studies on 23 April 2020 for case-series, cohort, prospectively planned, and randomised controlled trials (RCTs). SELECTION CRITERIA: We followed standard Cochrane methodology and performed all steps regarding study selection in duplicate by two independent review authors (in contrast to the recommendations of the Cochrane Rapid Reviews Methods Group). We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulins. DATA COLLECTION AND ANALYSIS: We followed recommendations of the Cochrane Rapid Reviews Methods Group regarding data extraction and assessment. To assess bias in included studies, we used the assessment criteria tool for observational studies, provided by Cochrane Childhood Cancer. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality at hospital discharge, improvement of clinical symptoms (7, 15, and 30 days after transfusion), grade 3 and 4 adverse events, and serious adverse events. MAIN RESULTS: We included eight studies (seven case-series, one prospectively planned, single-arm intervention study) with 32 participants, and identified a further 48 ongoing studies evaluating convalescent plasma (47 studies) or hyperimmune immunoglobulin (one study), of which 22 are randomised. Overall risk of bias of the eight included studies was high, due to: study design; small number of participants; poor reporting within studies; and varied type of participants with different severities of disease, comorbidities, and types of previous or concurrent treatments, including antivirals, antifungals or antibiotics, corticosteroids, hydroxychloroquine and respiratory support. We rated all outcomes as very low certainty, and we were unable to summarise numerical data in any meaningful way. As we identified case-series studies only, we reported results narratively. Effectiveness of convalescent plasma for people with COVID-19 The following reported outcomes could all be related to the underlying natural history of the disease or other concomitant treatment, rather than convalescent plasma. All-cause mortality at hospital discharge All studies reported mortality. All participants were alive at the end of the reporting period, but not all participants had been discharged from hospital by the end of the study (15 participants discharged, 6 still hospitalised, 11 unclear). Follow-up ranged from 3 days to 37 days post-transfusion. We do not know whether convalescent plasma therapy affects mortality (very low-certainty evidence). Improvement of clinical symptoms (assessed by respiratory support) Six studies, including 28 participants, reported the level of respiratory support required; most participants required respiratory support at baseline. All studies reported improvement in clinical symptoms in at least some participants. We do not know whether convalescent plasma improves clinical symptoms (very low-certainty evidence). Time to discharge from hospital Six studies reported time to discharge from hospital for at least some participants, which ranged from four to 35 days after convalescent plasma therapy. Admission on the intensive care unit (ICU) Six studies included patients who were critically ill. At final follow-up the majority of these patients were no longer on the ICU or no longer required mechanical ventilation. Length of stay on the ICU Only one study (1 participant) reported length of stay on the ICU. The individual was discharged from the ICU 11 days after plasma transfusion. Safety of convalescent plasma for people with COVID-19 Grade 3 or 4 adverse events The studies did not report the grade of adverse events after convalescent plasma transfusion. Two studies reported data relating to participants who had experienced adverse events, that were presumably grade 3 or 4. One case study reported a participant who had moderate fever (38.9 °C). Another study (3 participants) reported a case of severe anaphylactic shock. Four studies reported the absence of moderate or severe adverse events (19 participants). We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low-certainty evidence). Serious adverse events One study (3 participants) reported one serious adverse event. As described above, this individual had severe anaphylactic shock after receiving convalescent plasma. Six studies reported that no serious adverse events occurred. We are very uncertain whether or not convalescent plasma therapy affects the risk of serious adverse events (very low-certainty evidence). AUTHORS' CONCLUSIONS: We identified eight studies (seven case-series and one prospectively planned single-arm intervention study) with a total of 32 participants (range 1 to 10). Most studies assessed the risks of the intervention; reporting two adverse events (potentially grade 3 or 4), one of which was a serious adverse event. We are very uncertain whether convalescent plasma is effective for people admitted to hospital with COVID-19 as studies reported results inconsistently, making it difficult to compare results and to draw conclusions. We identified very low-certainty evidence on the effectiveness and safety of convalescent plasma therapy for people with COVID-19; all studies were at high risk of bias and reporting quality was low. No RCTs or controlled non-randomised studies evaluating benefits and harms of convalescent plasma have been completed. There are 47 ongoing studies evaluating convalescent plasma, of which 22 are RCTs, and one trial evaluating hyperimmune immunoglobulin. We will update this review as a living systematic review, based on monthly searches in the above mentioned databases and registries. These updates are likely to show different results to those reported here.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: This review aims to determine benefits and harms of daratumumab in addition to antineoplastic therapy compared to antineoplastic therapy only for adults with newly diagnosed multiple myeloma ineligible for transplant.

Background: Multiple myeloma is a bone marrow‐based hematological malignancy accounting for approximately two per cent of cancers. First‐line treatment for transplant‐ineligible individuals consists of multiple drug combinations of bortezomib (V), lenalidomide (R), or thalidomide (T). However, access to these medicines is restricted in many countries worldwide. Objectives: To assess and compare the effectiveness and safety of multiple drug combinations of V, R, and T for adults with newly diagnosed transplant‐ineligible multiple myeloma and to inform an application for the inclusion of these medicines into the World Health Organization's (WHO) list of essential medicines. Search Methods: We searched CENTRAL and MEDLINE, conference proceedings and study registries on 14 February 2019 for randomised controlled trials (RCTs) comparing multiple drug combinations of V, R and T for adults with newly diagnosed transplant‐ineligible multiple myeloma. Selection Criteria: We included RCTs comparing combination therapies of V, R, and T, plus melphalan and prednisone (MP) or dexamethasone (D) for first‐line treatment of adults with transplant‐ineligible multiple myeloma. We excluded trials including adults with relapsed or refractory disease, trials comparing drug therapies to other types of therapy and trials including second‐generation novel agents. Data Collection and Analysis: Two review authors independently extracted data and assessed risk of bias of included trials. As effect measures we used hazard ratios (HRs) for overall survival (OS) and progression‐free survival (PFS) and risk ratios (RRs) for adverse events. An HR or RR < 1 indicates an advantage for the intervention compared to the main comparator MP. Where available, we extracted quality of life (QoL) data (scores of standardised questionnaires). Results quoted are from network meta‐analysis (NMA) unless stated. Main Results: We included 25 studies (148 references) comprising 11,403 participants and 21 treatment regimens. Treatments were differentiated between restricted treatment duration (treatment with a pre‐specified amount of cycles) and continuous therapy (treatment administered until disease progression, the person becomes intolerant to the drug, or treatment given for a prolonged period). Continuous therapies are indicated with a "c". Risk of bias was generally high across studies due to the open‐label study design. Overall Survival (OS) Evidence suggests that treatment with RD (HR 0.63 (95% confidence interval (CI) 0.40 to 0.99), median OS 55.2 months (35.2 to 87.0)); TMP (HR 0.75 (95% CI 0.58 to 0.97), median OS: 46.4 months (35.9 to 60.0)); and VRDc (HR 0.49 (95% CI 0.26 to 0.92), median OS 71.0 months (37.8 to 133.8)) probably increases survival compared to median reported OS of 34.8 months with MP (moderate certainty). Treatment with VMP may result in a large increase in OS, compared to MP (HR 0.70 (95% CI 0.45 to 1.07), median OS 49.7 months (32.5 to 77.3)), low certainty). Progression‐Free Survival (PFS) Treatment withRD (HR 0.65 (95% CI0.44 to 0.96), median PFS: 24.9 months (16.9 to 36.8)); TMP (HR 0.63 (95% CI 0.50 to 0.78), median PFS:25.7 months (20.8 to 32.4)); VMP (HR 0.56 (95% CI 0.35 to 0.90), median PFS: 28.9 months (18.0 to 46.3)); and VRDc (HR 0.34 (95% CI 0.20 to 0.58), median PFS: 47.6 months (27.9 to 81.0)) may result in a large increase in PFS (low certainty) compared to MP (median reported PFS: 16.2 months). Adverse Events The risk of polyneuropathies may be lower with RD compared to treatment with MP (RR 0.57 (95% CI 0.16 to 1.99), risk for RD: 0.5% (0.1 to 1.8), mean reported risk for MP: 0.9% (10 of 1074 patients affected), low certainty). However, the CIs are also compatible with no difference or an increase in neuropathies. Treatment with TMP (RR 4.44 (95% CI1.77 to 11.11), risk: 4.0% (1.6 to 10.0)) and VMP (RR 88.22 (95% CI 5.36 to 1451.11), risk: 79.4% (4.8 to 1306.0)) probably results in a large increase in polyneuropathies compared to MP (moderate certainty). No study reported the amount of participants with grade ≥ 3 polyneuropathies for treatment with VRDc. VMP probably increases the proportion of participants with serious adverse events (SAEs) compared to MP (RR 1.28 (95% CI 1.06 to 1.54), risk for VMP: 46.2% (38.3 to 55.6), mean risk for MP: 36.1% (177 of 490 patients affected), moderate certainty). RD, TMP, and VRDc were not connected to MP in the network and the risk of SAEs could not be compared. Treatment with RD (RR 4.18 (95% CI 2.13 to 8.20), NMA‐risk: 38.5% (19.6 to 75.4)); and TMP (RR 4.10 (95% CI 2.40 to 7.01), risk: 37.7% (22.1 to 64.5)) results in a large increase of withdrawals from the trial due to adverse events (high certainty) compared to MP (mean reported risk: 9.2% (77 of 837 patients withdrew)). The risk is probably slightly increased with VMP (RR 1.06 (95% CI 0.63 to 1.81), risk: 9.75% (5.8 to 16.7), moderate certainty), while it is much increased with VRDc (RR 8.92 (95% CI 3.82 to 20.84), risk: 82.1% (35.1 to 191.7), high certainty) compared to MP. Quality of Life QoL was reported in four studies for seven different treatment regimens (MP, MPc, RD, RMP, RMPc, TMP, TMPc) and was measured with four different tools. Assessment and reporting differed between studies and could not be meta‐analysed. However, all studies reported an improvement of QoL after initiation of anti‐myeloma treatment for all assessed treatment regimens. Authors' Conclusions: Based on our four pre‐selected comparisons of interest, continuous treatment with VRD had the largest survival benefit compared with MP, while RD and TMP also probably considerably increase survival. However, treatment combinations of V, R, and T also substantially increase the incidence of AEs, and lead to a higher risk of treatment discontinuation. Their effectiveness and safety profiles may best be analysed in further randomised head‐to‐head trials. Further trials should focus on consistent reporting of safety outcomes and should use a standardised instrument to evaluate QoL to ensure comparability of treatment‐combinations.

Background Health literacy, defined as all skills and capabilities that enable a person to access, understand, appraise and apply health information, is a key factor regarding disease management, health outcomes, and health-decision-making. Internationally, migrants have been identified as a high-risk group for limited health literacy. However, it remains unclear if female and male migrants process health information differently. This systematic review aims to analyze gender differences in the health literacy of first and second generation migrants. Methods We performed a systematic review according to PRISMA guidelines. We searched OVID (MEDLINE), PsychInfo and CINAHL for original articles providing extractable data on the health literacy of male and/or female migrants. Two reviewers independently reviewed abstracts and full text articles for according to predefined inclusion criteria, including the use of a validated health literacy measurement tool, applying it to first and/or second generation adult migrants. We adapted a data extraction sheet from the Cochrane Collaboration for extracting relevant data. The included studies were evaluated against a standardized set of quality criteria. Results Our search yielded 3411 records. We included 48 studies, of which 37 were conducted in the USA and Canada, with 22 focusing Hispanic and Asian immigrants’ functional health literacy; the nine European studies examined a variety of work migrants and refugees using a comprehensive approach (e.g. measured by the HLS-EU-Q47). Thus, a strong heterogeneity in defining and measuring health literacy and in the populations examined can be stated. 15 studies exclusively examined the health literacy of women; none dealt with men only. Conclusions The heterogeneity in defining and measuring health literacy in migrants as well as the diversity of the populations studied make it difficult to compare international research in this area. There is a lack of research focusing male migrants. Key messages International research on health literacy with gender-specific data on migrants reveals a strong heterogeneity in defining and measuring health literacy. International research on health literacy with gender-specific data on migrants reveals a lack of studies regarding male migrants’ health literacy.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of different bone‐modifying agents for women with breast cancer in early or locally advanced stages. Using a network meta‐analysis, we will generate a clinically meaningful ranking of these agents according to safety and efficacy.

Background Breast cancer is the most common cancer in women. Diagnosis and treatment may drastically affect quality of life, causing symptoms such as sleep disorders, depression and anxiety. Mindfulness-based stress reduction (MBSR) is a programme that aims to reduce stress by developing mindfulness, meaning a non-judgmental, accepting moment-by-moment awareness. MBSR seems to benefit patients with mood disorders and chronic pain, and it may also benefit women with breast cancer. Objectives To assess the effects of mindfulness-based stress reduction (MBSR) in women diagnosed with breast cancer. Search methods In April 2018, we conducted a comprehensive electronic search for studies of MBSR in women with breast cancer, in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and two trial registries (World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov). We also handsearched relevant conference proceedings. Selection criteria Randomised clinical trials (RCTs) comparing MBSR versus no intervention in women with breast cancer. Data collection and analysis We used standard methodological procedures expected by Cochrane. Using a standardised data form, the review authors extracted data in duplicate on methodological quality, participants, interventions and outcomes of interest (quality of life, fatigue, depression, anxiety, quality of sleep, overall survival and adverse events). For outcomes assessed with the same instrument, we used the mean difference (MD) as a summary statistic for meta-analysis; for those assessed with different instruments, we used the standardised mean difference (SMD). The effect of MBSR was assessed in the short term (end of intervention), medium term (up to 6 months after intervention) and long term (up to 24 months after intervention). Main results Fourteen RCTs fulfilled our inclusion criteria, with most studies reporting that they included women with early breast cancer. Ten RCTs involving 1571 participants were eligible for meta-analysis, while four studies involving 185 participants did not report usable results. Queries to the authors of these four studies were unsuccessful. All studies were at high risk of performance and detection bias since participants could not be blinded, and only 3 of 14 studies were at low risk of selection bias. Eight of 10 studies included in the meta-analysis recruited participants with early breast cancer (the remaining 2 trials did not restrict inclusion to a certain cancer type). Most trials considered only women who had completed cancer treatment.MBSR may improve quality of life slightly at the end of the intervention (based on low-certainty evidence from three studies with a total of 339 participants) but may result in little to no difference up to 6 months (based on low-certainty evidence from three studies involving 428 participants). Long-term data on quality of life (up to two years after completing MBSR) were available for one study in 97 participants (MD 0.00 on questionnaire FACT-B, 95% CI -5.82 to 5.82; low-certainty evidence).In the short term, MBSR probably reduces fatigue (SMD -0.50, 95% CI -0.86 to -0.14; moderate-certainty evidence; 5 studies; 693 participants). It also probably slightly reduces anxiety (SMD -0.29, 95% CI -0.50 to -0.08; moderate-certainty evidence; 6 studies; 749 participants), and it reduces depression (SMD -0.54, 95% CI -0.86 to -0.22; high-certainty evidence; 6 studies; 745 participants). It probably slightly improves quality of sleep (SMD -0.38, 95% CI -0.79 to 0.04; moderate-certainty evidence; 4 studies; 475 participants). However, these confidence intervals (except for short-term depression) are compatible with both an improvement and little to no difference.In the medium term, MBSR probably results in little to no difference in medium-term fatigue (SMD -0.31, 95% CI -0.84 to 0.23; moderate-certainty evidence; 4 studies; 607 participants). The intervention probably slightly reduces anxiety (SMD -0.28, 95% CI -0.49 to -0.07; moderate-certainty evidence; 7 studies; 1094 participants), depression (SMD -0.32, 95% CI -0.58 to -0.06; moderate-certainty evidence; 7 studies; 1097 participants) and slightly improves quality of sleep (SMD -0.27, 95% CI -0.63 to 0.08; moderate-certainty evidence; 4 studies; 654 participants). However, these confidence intervals are compatible with both an improvement and little to no difference.In the long term, moderate-certainty evidence shows that MBSR probably results in little to no difference in anxiety (SMD -0.09, 95% CI -0.35 to 0.16; 2 studies; 360 participants) or depression (SMD -0.17, 95% CI -0.40 to 0.05; 2 studies; 352 participants). No long-term data were available for fatigue or quality of sleep.No study reported data on survival or adverse events. Authors' conclusions MBSR may improve quality of life slightly at the end of the intervention but may result in little to no difference later on. MBSR probably slightly reduces anxiety, depression and slightly improves quality of sleep at both the end of the intervention and up to six months later. A beneficial effect on fatigue was apparent at the end of the intervention but not up to six months later. Up to two years after the intervention, MBSR probably results in little to no difference in anxiety and depression; there were no data available for fatigue or quality of sleep.

BACKGROUND: Although people with haematological malignancies have to endure long phases of therapy and immobility, which is known to diminish their physical performance level, the advice to rest and avoid intensive exercises is still common practice. This recommendation is partly due to the severe anaemia and thrombocytopenia from which many patients suffer. The inability to perform activities of daily living restricts them, diminishes their quality of life and can influence medical therapy. OBJECTIVES: In this update of the original review (published in 2014) our main objective was to re‐evaluate the efficacy, safety and feasibility of aerobic physical exercise for adults suffering from haematological malignancies considering the current state of knowledge. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2018, Issue 7) and MEDLINE (1950 to July 2018) 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 (RCTs) comparing an aerobic physical exercise intervention, intending to improve the oxygen system, in addition to standard care with standard care only for adults suffering from haematological malignancies. We also included studies that evaluated aerobic exercise in addition to strength training. We excluded studies that investigated the effect of training programmes that were composed of yoga, tai chi chuan, qigong or similar types of exercise. We also excluded studies exploring the influence of strength training without additive aerobic exercise as well as studies assessing outcomes without any clinical impact. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, extracted data and assessed the quality of trials. We used risk ratios (RRs) for adverse events, mortality and 100‐day survival, standardised mean differences (SMD) for quality of life (QoL), fatigue, and physical performance, and mean differences (MD) for anthropometric measurements. MAIN RESULTS: In this update, nine trials could be added to the nine trials of the first version of the review, thus we included eighteen RCTs involving 1892 participants. Two of these studies (65 participants) did not provide data for our key outcomes (they analysed laboratory values only) and one study (40 patients) could not be included in the meta‐analyses, as results were presented as changes scores only and not as endpoint scores. One trial (17 patients) did not report standard errors and could also not be included in meta‐analyses. The overall potential risk of bias in the included trials is unclear, due to poor reporting. The majority of participants suffered from acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), malignant lymphoma and multiple myeloma, and eight trials randomised people receiving stem cell transplantation. Mostly, the exercise intervention consisted of various walking intervention programmes with different duration and intensity levels. Our primary endpoint overall survival (OS) was only reported in one of these studies. The study authors found no evidence for a difference between both arms (RR = 0.67; P = 0.112). Six trials (one trial with four arms, analysed as two sub‐studies) reported numbers of deceased participants during the course of the study or during the first 100 to 180 days. For the outcome mortality, there is no evidence for a difference between participants exercising and those in the control group (RR 1.10; 95% CI 0.79 to 1.52; P = 0.59; 1172 participants, low‐certainty evidence). For the following outcomes, higher numbers indicate better outcomes, with 1 being the best result for the standardised mean differences. Eight studies analysed the influence of exercise intervention on QoL. It remains unclear, whether physical exercise improves QoL (SMD 0.11; 95% CI ‐0.03 to 0.24; 1259 participants, low‐certainty evidence). There is also no evidence for a difference for the subscales physical functioning (SMD 0.15; 95% CI ‐0.01 to 0.32; 8 trials, 1329 participants, low‐certainty evidence) and anxiety (SMD 0.03; 95% CI ‐0.30 to 0.36; 6 trials, 445 participants, very low‐certainty evidence). Depression might slightly be improved by exercising (SMD 0.19; 95% CI 0.0 to 0.38; 6 trials, 445 participants, low‐certainty evidence). There is moderate‐certainty evidence that exercise probably improves fatigue (SMD 0.31; 95% CI 0.13 to 0.48; 9 trials, 826 patients). Six trials (435 participants) investigated serious adverse events. We are very uncertain, whether additional exercise leads to more serious adverse events (RR 1.39; 95% CI 0.94 to 2.06), based on very low‐certainty evidence. In addition, we are aware of four ongoing trials. However, none of these trials stated, how many patients they will recruit and when the studies will be completed, thus, potential influence of these trials for the current analyses remains unclear. AUTHORS' CONCLUSIONS: Eighteen, mostly small RCTs did not identify evidence for a difference in terms of mortality. Physical exercise added to standard care might improve fatigue and depression. Currently, there is inconclusive evidence regarding QoL, physical functioning, anxiety and SAEs . We need further trials with more participants and longer follow‐up periods to evaluate the effects of exercise intervention for people suffering from haematological malignancies. To enhance comparability of study data, development and implementation of core sets of measuring devices would be helpful.

Bone-modifying agents like bisphosphonates and receptor activator of nuclear factor kappaβ ligand (RANK-L) inhibitors are used as supportive treatments in breast cancer patients with bone metastases to prevent skeletal-related events (SREs). Due to missing head-to-head comparisons, a network meta-analysis was performed to provide a hierarchy of these therapeutic options. Through a systematic literature search, 21 randomized controlled trials (RCTs) that fulfilled the inclusion criteria were identified. To prevent SREs, the ranking through P-scores showed denosumab (RR: 0.62; 95%CI: 0.50-0.76), zoledronic acid (RR: 0.72; 95%CI: 0.61-0.84) and pamidronate (RR: 0.76; 95%CI: 0.67-0.85) to be significantly superior to placebo. Due to insufficient or heterogeneous data, overall survival, quality of life, pain response and adverse events were not able to be analyzed within the network. Although data were sparse on adverse events, the risk of significant adverse events appeared low. The results of this review can therefore be used to formulate clinical studies more precisely in order to standardise and focus on patient-relevant outcomes.

Background Hodgkin's lymphoma (HL) is a cancer of the lymphatic system, and involves the lymph nodes, spleen and other organs such as the liver, lung, bone or bone marrow, depending on the tumour stage. With cure rates of up to 90%, HL is one of the most curable cancers worldwide. Approximately 10% of people with HL will be refractory to initial treatment or will relapse; this is more common in people with advanced stage or bulky disease. Standard of care for these people is high-dose chemotherapy and autologous stem cell transplantation (ASCT), but only 55% of participants treated with high-dose chemotherapy and ASCT are free from treatment failure at three years, with an overall survival (OS) of about 80% at three years. Checkpoint inhibitors that target the interaction of the programmed death (PD)-1 immune checkpoint receptor, and its ligands PD-L1 and PD-L2, have shown remarkable activity in a wide range of malignancies. Nivolumab is an anti-(PD)-1 monoclonal antibody and currently approved by the US Food and Drug Administration (FDA) for the treatment of melanoma, non-small cell lung cancer, renal cell carcinoma and, since 2016, for classical Hodgkin's lymphoma (cHL) after treatment with ASCT and brentuximab vedotin. Objectives To assess the benefits and harms of nivolumab in adults with HL (irrespective of stage of disease). Search methods We searched CENTRAL, MEDLINE, Embase, International Pharmaceutical Abstracts, conference proceedings and six study registries from January 2000 to May 2018 for prospectively planned trials evaluating nivolumab. Selection criteria We included prospectively planned trials evaluating nivolumab in adults with HL. We excluded trials in which less than 80% of participants had HL, unless the trial authors provided the subgroup data for these participants in the publication or after we contacted the trial authors. Data collection and analysis Two review authors independently extracted data and assessed potential risk of bias. We used the software RobotReviewer to extract data and compared results with our findings. As we did not identify any randomised controlled trials (RCTs) or non-RCTs, we did not meta-analyse data. Main results Our search found 782 potentially relevant references. From these, we included three trials without a control group, with 283 participants. In addition, we identified 14 ongoing trials evaluating nivolumab, of which two are randomised. Risk of bias of the three included studies was moderate to high. All of the participants were in relapsed stage, most of them were heavily pretreated and had received at least two previous treatments, most of them had also undergone ASCT. As we did not identify any RCTs, we could not use the software RobotReviewer to assess risk of bias. The software identified correctly that one study was not an RCT and did not extract any trial data, but extracted characteristics of the other two studies (although also not RCTs) in a sufficient way. Two studies with 260 participants evaluated OS. After six months, OS was 100% in one study and median OS (the timepoint when only 50% of participants were alive) was not reached in the other trial after a median follow-up of 18 months (interquartile range (IQR) 15 to 22 months) (very low certainty evidence, due to observational trial design, heterogenous patient population in terms of pretreatments and various follow-up times (downgrading by 1 point)). In one study, one out of three cohorts reported quality of life. It was unclear whether there was an effect on quality of life as only a subset of participants filled out the follow-up questionnaire (very low certainty evidence). Three trials (283 participants) evaluated progression-free survival (PFS) (very low certainty evidence). Six-month PFS ranged between 60% and 86%, and median PFS ranged between 12 and 18 months. All three trials (283 participants) reported complete response rates, ranging from 12% to 29%, depending on inclusion criteria and participants' previous treatments (very low certainty evidence). One trial (243 participants) reported drug-related grade 3 or 4 adverse events (AEs) only after a median follow-up of 18 months (IQR 15 to 22 months); these were fatigue (23%), diarrhoea (15%), infusion reactions (14%) and rash (12%). The other two trials (40 participants) reported 23% to 52% grade 3 or 4 AEs after six months' follow-up (very low certainty evidence). Only one trial (243 participants) reported drug-related serious AEs; 2% of participants developed infusion reactions and 1% pneumonitis (very low certainty evidence). None of the studies reported treatment-related mortality. Authors' conclusions To date, data on OS, quality of life, PFS, response rate, or short- and long-term AEs are available from small uncontrolled trials only. The three trials included heavily pretreated participants, which had previously undergone regimens of BV or ASCT. For these participants, median OS was not reached after follow-up times of at least 16 months (more than 50% of participants with a limited life expectancy were alive at this timepoint). Only one cohort out of three only reported quality of life, with limited follow-up data so that meaningful conclusions were not possible. Serious adverse events occurred rarely. Currently, data are too sparse to make a clear statement on nivolumab for people with relapsed or refractory HL except for heavily pretreated people, which had previously undergone regimens of BV or ASCT. When interpreting these results, it is important to consider that proper RCTs should confirm these findings. As there are 14 ongoing trials evaluating nivolumab, of which two are RCTs, it is possible that an update of this review will be published in the near future and that this update will show different results to those reported here.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of bisphosphonates and RANK‐ligand (RANKL)‐inhibitors for supportive treatment in prostate cancer with bone metastases and to generate a clinically meaningful treatment ranking according to their safety and efficacy.

R-CHOP-21 has remained the standard chemotherapy for aggressive non-Hodgkin's lymphoma. It was suggested that decreasing the treatment interval from three weeks (CHOP-21) to two weeks (CHOP-14) may improve survival and disease control of patients with aggressive lymphoma.To evaluate the effect of CHOP-like-14 (with or without rituximab) compared to standard CHOP-like -21 on overall survival (OS), disease control and toxicity of patients with aggressive non-Hodgkin lymphoma.Systematic review and meta-analysis of RCTs. In October 2014 we searched The Cochrane Library, MEDLINE, LILACS, conference proceedings, and databases of ongoing trials. Authors were contacted for complementary data. The primary outcome was OS.We identified seven trials (4073 patients), conducted between the years 1999 and 2008. Trials were at low or unclear risk for selection bias, and at low or unclear risk of attrition bias. CHOP-like-14 improved OS of patients with aggressive lymphoma compared to the same regimen given every 21 days (all trials): HR of death 0.86, 95% confidence interval (CI) 0.77-0.97. There was no OS difference between rituximab-CHOP-like 14 to rituximab-CHOP-like-21 (3 trials): HR 0.93 95% CI 0.78-1.10. The rates of progression or death, complete response, treatment-related mortality, grade 3-4 infection, and discontinuation were similar between groups.R-CHOP-21 remains the standard of care for patient with aggressive B-cell lymphoma. CHOP-14 can be considered as in case rituximab is omitted.

Treatment intensification to maximize disease control and reduced intensity approaches to minimize the risk of late sequelae have been evaluated in newly diagnosed Hodgkin lymphoma. The influence of these interventions on the risk of secondary malignant neoplasms, progression-free survival and overall survival is reported in the meta-analysis herein, based on individual patient data from 9498 patients treated within 16 randomized controlled trials for newly diagnosed Hodgkin lymphoma between 1984 and 2007. Secondary malignant neoplasms were meta-analyzed using Peto's method as time-to-event outcomes. For progression-free and overall survival, hazard ratios derived from each trial using Cox regression were combined by inverse-variance weighting. Five study questions (combined-modality treatment vs. chemotherapy alone; more extended vs. involved-field radiotherapy; radiation at higher doses vs. radiation at 20 Gy; more vs. fewer cycles of the same chemotherapy protocol; standard-dose chemotherapy vs. intensified chemotherapy) were investigated. After a median follow-up of 7.4 years, dose-intensified chemotherapy resulted in better progression-free survival rates (P=0.007) as compared with standard-dose chemotherapy, but was associated with an increased risk of therapy-related acute myeloid leukemia/myelodysplastic syndromes (P=0.0028). No progression-free or overall survival differences were observed between combined-modality treatment and chemotherapy alone, but more secondary malignant neoplasms were seen after combined-modality treatment (P=0.010). For the remaining three study questions, outcomes and secondary malignancy rates did not differ significantly between treatment strategies. The results of this meta-analysis help to weigh up efficacy and secondary malignancy risk for the choice of first-line treatment for Hodgkin lymphoma patients. However, final conclusions regarding secondary solid tumors require longer follow-up.

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.

Background Efficacy and the risk of severe late effects have to be well-balanced in treatment of Hodgkin lymphoma (HL). Late adverse effects include secondary malignancies which often have a poor prognosis. To synthesise evidence on the risk of secondary malignancies after current treatment approaches comprising chemotherapy and/or radiotherapy, we performed a meta-analysis based on individual patient data (IPD) from patients treated for newly diagnosed HL. Objectives We investigated several questions concerning possible changes in the risk of secondary malignancies when modifying chemotherapy or radiotherapy (omission of radiotherapy, reduction of the radiation field, reduction of the radiation dose, use of fewer chemotherapy cycles, intensification of chemotherapy). We also analysed whether these modifications affect progression-free survival (PFS) and overall survival (OS). Search methods We searched MEDLINE and Cochrane CENTRAL trials databases comprehensively in June 2010 for all randomised trials in HL since 1984. Key international trials registries were also searched. The search was updated in March 2015 without collecting further IPD (one further eligible study found) and again in July 2017 (no further eligible studies). Selection criteria We included randomised controlled trials (RCTs) for untreated HL patients which enrolled at least 50 patients per arm, completed recruitment by 2007 and performed a treatment comparison relevant to our objectives. Data collection and analysis Study groups submitted IPD, including age, sex, stage and the outcomes secondary malignant neoplasm (SMN), OS and PFS as time-to-event data. We meta-analysed these data using Petos method (SMN) and Cox regression with inverse-variance pooling (OS, PFS) for each of the five study questions, and performed subgroup and sensitivity analyses to assess the applicability and robustness of the results. Main results We identified 21 eligible trials and obtained IPD for 16. For four studies no data were supplied despite repeated efforts, while one study was only identified in 2015 and IPD were not sought. For each study question, between three and six trials with between 1101 and 2996 participants in total and median follow-up between 6.7 and 10.8 years were analysed. All participants were adults and mainly under 60 years. Risk of bias was assessed as low for the majority of studies and outcomes. Chemotherapy alone versus same chemotherapy plus radiotherapy. Omitting additional radiotherapy probably reduces secondary malignancy incidence (Peto odds ratio (OR) 0.43, 95% confidence interval (CI) 0.23 to 0.82, low quality of evidence), corresponding to an estimated reduction of eight-year SMN risk from 8% to 4%. This decrease was particularly true for secondary acute leukemias. However, we had insufficient evidence to determine whether OS rates differ between patients treated with chemotherapy alone versus combined-modality (hazard ratio (HR) 0.71, 95% CI 0.46 to 1.11, moderate quality of evidence). There was a slightly higher rate of PFS with combined modality, but our confidence in the results was limited by high levels of statistical heterogeneity between studies (HR 1.31, 95% CI 0.99 to 1.73, moderate quality of evidence). Chemotherapy plus involved-field radiation versus same chemotherapy plus extended-field radiation (early stages) . There is insufficient evidence to determine whether smaller radiation field reduces SMN risk (Peto OR 0.86, 95% CI 0.64 to 1.16, low quality of evidence), OS (HR 0.89, 95% C: 0.70 to 1.12, high quality of evidence) or PFS (HR 0.99, 95% CI 0.81 to 1.21, high quality of evidence). Chemotherapy plus lower-dose radiation versus same chemotherapy plus higher-dose radiation (early stages). There is insufficient evidence to determine the effect of lower-radiation dose on SMN risk (Peto OR 1.03, 95% CI 0.71 to 1.50, low quality of evidence), OS (HR 0.91, 95% CI 0.65 to 1.28, high quality of evidence) or PFS (HR 1.20, 95% CI 0.97 to 1.48, high quality of evidence). Fewer versus more courses of chemotherapy (each with or without radiotherapy; early stages). Fewer chemotherapy courses probably has little or no effect on SMN risk (Peto OR 1.10, 95% CI 0.74 to 1.62), OS (HR 0.99, 95% CI 0.73 to1.34) or PFS (HR 1.15, 95% CI 0.91 to 1.45).Outcomes had a moderate (SMN) or high (OS, PFS) quality of evidence. Dose-intensified versus ABVD-like chemotherapy (with or without radiotherapy in each case). In the mainly advanced-stage patients who were treated with intensified chemotherapy, the rate of secondary malignancies was low. There was insufficient evidence to determine the effect of chemotherapy intensification (Peto OR 1.37, CI 0.89 to 2.10, low quality of evidence). The rate of secondary acute leukemias (and for younger patients, all secondary malignancies) was probably higher than among those who had treatment with standard-dose ABVD-like protocols. In contrast, the intensified chemotherapy protocols probably improved PFS (eight-year PFS 75% versus 69% for ABVD-like treatment, HR 0.82, 95% CI 0.7 to 0.95, moderate quality of evidence). Evidence suggesting improved survival with intensified chemotherapy was not conclusive (HR: 0.85, CI 0.70 to 1.04), although escalated-dose BEACOPP appeared to lengthen survival compared to ABVD-like chemotherapy (HR 0.58, 95% CI 0.43 to 0.79, moderate quality of evidence). Generally, we could draw valid conclusions only in terms of secondary haematological malignancies, which usually occur less than 10 years after initial treatment, while follow-up within the present analysis was too short to record all solid tumours. Authors' conclusions The risk of secondary acute myeloid leukaemia and myelodysplastic syndrome (AML/MDS) is increased but efficacy is improved among patients treated with intensified chemotherapy protocols. Treatment decisions must be tailored for individual patients. Consolidating radiotherapy is associated with an increased rate of secondary malignancies; therefore it appears important to define which patients can safely be treated without radiotherapy after chemotherapy, both for early and advanced stages. For early stages, treatment optimisation methods such as use of fewer chemotherapy cycles and reduced field or reduced-dose radiotherapy did not appear to markedly affect efficacy or secondary malignancy risk. Due to the limited amount of long-term follow-up in this meta-analysis, further long-term investigations of late events are needed, particularly with respect to secondary solid tumours. Since many older studies have been included, possible improvement of radiotherapy techniques must be considered when interpreting these results.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To compare the effects of antiemetics on the prevention of acute, delayed and overall chemotherapy‐induced nausea and vomiting in adults with solid cancer or haematological malignancies receiving moderately or highly emetogenic chemotherapy and to generate a clinically meaningful treatment ranking according to their safety and efficacy.

Background There are two different international standards for the treatment of early unfavourable and advanced stage Hodgkin lymphoma (HL): chemotherapy with escalated BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone) regimen and chemotherapy with ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) regimen. Objectives To determine the advantages and disadvantages of chemotherapy including escalated BEACOPP compared to chemotherapy including ABVD in the treatment of early unfavourable or advanced stage HL as first-line treatment. Search methods We searched for randomised controlled trials in MEDLINE, CENTRAL and conference proceedings (January 1985 to July 2013 and for the update to March 2017) and Embase (1985 to November 2008). Moreover we searched trial registries (March 2017; www.controlled-trials.com, www.clinicaltrialsregister.eu/ctr-search/search, clinicaltrials.gov, www.eortc.be, www.ghsg.org, www.ctc.usyd.edu.au, www.trialscentral.org/index.html) Selection criteria We included randomised controlled trials examining chemotherapy including at least two cycles of escalated BEACOPP regimens compared with chemotherapy including at least four cycles of ABVD regimens as first-line treatment for patients with early unfavourable stage or advanced stage HL. Data collection and analysis The effect measures we used were hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS) and freedom from first progression. We used risk ratios (RRs) relative risks to analyse harms: treatment-related mortality, secondary malignancies (including myeloid dysplastic syndrome (MDS) or acute myeloid leukaemia (AML)), infertility and adverse events. Quality of life was not reported in any trial, therefore not analysed. Two review authors independently extracted data and assessed quality of trials. Main results We screened 1796 records and identified five eligible trials in total i.e. one trial could be added on the previous review. These trials included only adults (16 to 65 years of age). We included all five trials with 3427 people in the meta-analyses: the HD9 and HD14 trials were co-ordinated in Germany, the HD2000 and GSM-HD trials were performed in Italy and the EORTC 20012 was conducted in Belgium. The overall risk of performance and detection bias was low for overall survival (OS), but was high for other outcomes, as therapy blinding was not feasible. The remaining 'Risk of bias' domains were low and unclear. All trials reported results for OS and progression-free survival (PFS). In contrast to the our first published review (2011) the addition of results from the EORTC 20012 BEACOPP escalated increases OS (3142 participants; HR 0.74 (95% confidence interval (CI) 0.57 to 0.97; high-quality evidence). This means that only 90 (70 to 117) patients will die after five years in the BEACOPP escalated arm compared to 120 in the ABVD arm. This survival advantage is also reflected in an increased PFS with BEACOPP escalated (3142 participants; HR 0.54 (95% CI 0.45 to 0.64); moderate-quality evidence), meaning that after five years only 144 (121 to 168) patients will experience a progress, relapse or death in the BEACOPP escalated arm compared to 250 in the ABVD arm. There is no evidence for a difference for treatment-related mortality (2700 participants, RR 2.15 (95% CI = 0.93 to 4.95), low-quality evidence). Although the occurrence of MDS or AML may increase with BEACOPP escalated (3332 participants, RR 3.90 (95% CI 1.36 to 11.21); low-quality evidence)), there is no evidence for a difference between both regimens for overall secondary malignancies (3332 participants, RR 1.00 (95% CI 0.68 to 1.48), low-quality evidence). However, the observation time of the studies included in the review is too short to be expected to demonstrate differences with respect to second solid tumours which would not be expected to show significance until around 15 years after treatment. We are very uncertain how many female patients will be infertile due to chemotherapy and which arm might be favoured (106 participants, RR 1.37 (95% CI 0.83 to 2.26), very low-quality evidence). This is a very small sample, and the age of the patients was not detailed. No analysis of male fertility was provided. Five trials reported adverse events and the analysis shows that the escalated BEACOPP regimens probably causes more haematological toxicities WHO grade III or IV ((anaemia: 2425 participants, RR 10.67 (95% CI 7.14 to 15.93); neutropenia: 519 participants, RR 1.80 (95% CI 1.52 to 2.13); thrombocytopenia: 2425 participants, RR 18.12 (95% CI 11.77 to 27.92); infections: 2425 participants, RR 3.73 (95% CI 2.58 to 5.38), all low-quality evidence). Only one trial (EORTC 20012) planned to assess quality of life, however, no results were reported. Authors' conclusions This meta-analysis provides moderate- to high-quality evidence that adult patients between 16 and 60 years of age with early unfavourable and advanced stage HL benefit regarding OS and PFS from first-line chemotherapy including escalated BEACOPP. The proven benefit in OS for patients with advanced HL is a new finding of this updated review due to the inclusion of the results from the EORTC 20012 trial. Furthermore, there is only low-quality evidence of a difference in the total number of secondary malignancies, as the follow-up period might be too short to detect meaningful differences. Low-quality evidence also suggests that people treated with escalated BEACOPP may have a higher risk to develop secondary AML or MDS. Due to the availability of only very low-quality evidence available, we are unable to come to a conclusion in terms of infertility. This review does for the first time suggest a survival benefit. However, it is clear from this review that BEACOPP escalated may be more toxic that ABVD, and very important long-term side effects of second malignancies and infertility have not been sufficiently analysed yet.

Background Combined modality treatment consisting of chemotherapy followed by localised radiotherapy is the standard treatment for patients with early stage Hodgkin lymphoma (HL). However, due to long- term adverse effects such as secondary malignancies the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication. Objectives To assess the effects of chemotherapy alone compared to chemotherapy plus radiotherapy in adults with early stage HL . Search methods For the or i ginal version of this review, we searched MEDLINE, Embase and CENTRAL as well as conference proceedings (American Society of Hematology, American Society of Clinical Oncology and International Symposium of Hodgkin Lymphoma) from January 1980 to November 2010 for randomised controlled trials (RCTs) comparing chemotherapy alone versus chemotherapy regimens plus radiotherapy. For the updated review we searched MEDLINE, CENTRAL and conference proceedings to December 2016. Selection criteria We included RCTs comparing chemotherapy alone with chemotherapy plus radiotherapy in patients with early stage HL. We excluded trials with more than 20% of patients in advanced stage. As the value of radiotherapy in addition to chemotherapy is still not clear, we also compared to more cycles of chemotherapy in the control arm. In this updated review, we also included a second comparison evaluating trials with varying numbers of cycles of chemotherapy between intervention and control arms, same chemotherapy regimen in both arms assumed. We excluded trials evaluating children only, therefore only trials involving adults are included in this updated review. Data collection and analysis Two review authors independently extracted data and assessed the quality of trials. We contacted study authors to obtain missing information. As effect measures we used hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RR) for response rates. Since not all trials reported PFS according to our definitions, we evaluated all similar outcomes (e.g. event-free survival) as PFS/tumour control. Main results Our search led to 5518 potentially relevant references. From these, we included seven RCTs in the analyses involving 2564 patients. In contrast to the first version of this review including five trials, we excluded trials randomising children. As a result, we excluded one trial from the former analyses and we identified three new trials. Five trials with 1388 patients compared the combination of chemotherapy alone and chemotherapy plus radiotherapy, with the same number of chemotherapy cycles in both arms. The addition of radiotherapy to chemotherapy has probably little or no difference on OS (HR 0.48; 95% confidence interval (CI) 0.22 to 1.06; P = 0.07, moderate- quality evidence), however two included trials had potential other high risk of bias due to a high number of patients not receiving planned radiotherapy. After excluding these trials in a sensitivity analysis, the results showed that the combination of chemotherapy and radiotherapy improved OS compared to chemotherapy alone (HR 0.31; 95% CI 0.19 to 0.52; P

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The objectives are to systematically review the effect of intravenous iron or no iron in combination with erythropoiesis‐stimulating agents (ESAs) on the prevention or alleviation of anaemic cancer patients and to generate a clinically meaningful treatment ranking according to their safety and efficacy.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the benefits and harms of nivolumab in adult individuals with Hodgkin lymphoma (HL).

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The main objective of this systematic review is to evaluate the efficacy and safety of low dose cytarabine for patients with MDS.

Background Myelodysplastic syndromes (MDS) are a heterogeneous group of haematological diseases which are characterised by a uni- or multilineage dysplasia of haematological stem cells. Standard treatment is supportive care of the arising symptoms including red blood cell transfusions or the administration of erythropoiesis-stimulating agents (ESAs) in the case of anaemia or the treatment with granulocyte (G-CSF) and granulocyte-macrophage colony stimulating factors (GM-CSF) in cases of neutropenia. Objectives The objective of this review is to assess the evidence for the treatment of patients with MDS with G-CSF and GM-CSF in addition to standard therapy in comparison to the same standard therapy or the same standard therapy and placebo. Search methods We searched MEDLINE (from 1950 to 3 December 2015) and CENTRAL (Cochrane Central Register of Controlled Trials until 3 December 2015), as well as conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association, European Society of Medical Oncology) for randomised controlled trials (RCTs). Two review authors independently screened search results. Selection criteria We included RCTs examining G-CSF or GM-CSF in addition to standard therapy in patients with newly diagnosed MDS. Data collection and analysis We used hazard ratios (HR) as effect measure for overall survival (OS), progression-free survival (PFS) and time to progression, and risk ratios for response rates, adverse events, antibiotic use and hospitalisation. Two independent review authors extracted data and assessed risk of bias. Investigators of two trials were contacted for subgroup information, however, no further data were provided. G-CSF and GM-CSF were analysed separately. Main results We screened a total of 566 records. Seven RCTs involving 486 patients were identified, but we could only meta-analyse the two evaluating GM-CSF. We judged the potential risk of bias of these trials as unclear, mostly due to missing information. All trials were randomised and open-label studies. However, three trials were published as abstracts only, therefore we were not able to assess the potential risk of bias for these trials in detail. Overall, data were not reported in a comparable way and patient-related outcomes like survival, time to progression to acute myeloid leukaemia (AML) or the incidence of infections was reported in two trials only. Five RCTs (N = 337) assessed the efficacy of G-CSF in combination with standard therapy (supportive care, chemotherapy or erythropoietin). We were not able to perform meta-analyses for any of the pre-planned outcomes due to inconsistent and insufficient reporting of data. There is no evidence for a difference for overall survival (hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.44 to 1.47), progression-free survival (only P value provided), progression to AML, incidence of infections and number of red blood transfusions (average number of 12 red blood cell transfusions in each arm). We judged the quality of evidence for all these outcomes as very low, due to very high imprecision and potential publication bias, as three trials were published as abstracts only. Data about quality of life and serious adverse events were not reported in any of the included trials. Two RCTs (N = 149) evaluated GM-CSF in addition to standard therapy (chemotherapy). For mortality (two RCTs; HR 0.88, 95% CI 0.62 to 1.26), we found no evidence for a difference (low-quality evidence). Data for progression-free survival and serious adverse events were not comparable across both studies, without evidence for a difference between both arms (low-quality evidence). For infections, red blood cell and platelet transfusions, we found no evidence for a difference, however, these outcomes were reported by one trial only (low-quality evidence). Time to progression to AML and quality of life were not reported at all. Moreover, we identified two cross-over trials, including 244 patients and evaluating GM-CSF versus placebo, without publishing results for each arm before crossing over. In addition, we identified two ongoing studies, one of which was discontinued due to withdrawal of pharmaceutical support, the other was terminated early, both without publishing results. Authors' conclusions Although we identified seven trials with a total number of 486 patients, and two unpublished, prematurely finished studies, this systematic review mainly shows that there is a substantial lack of data, which might inform the use of G-CSF and GM-CSF for the prevention of infections, prolonging of survival and improvement of quality of life. The impact on progression to AML remains unclear.

Reason for Withdrawal Authors have made no progress with this protocol in several years. New authors are being sought to take over this protocol. To view the published versions of this article, please click the 'Other versions' tab.

Reason for Withdrawal The completion of the last task is overdue for more than one year. New authors are being sought to take over this protocol. To view the published versions of this article, please click the 'Other versions' tab.

This is the protocol for a review and there is no abstract. The objectives are as follows: In order to evaluate the therapeutical benefit of idiotype vaccination in the treatment of NHL we will particularly analyse overall survival (OS) as the primary endpoint; as well as progression-free survival (PFS), response rate, treatment-related mortality, adverse events and quality of life as secondary endpoints. We will analyse these outcome parameters critically and systematically with respect to different vaccine formulations, dosages or time schedules in the experimental arm and placebo or no other treatment in the control arm.

Reason for Withdrawal Authors have made no progress with this protocol in two years. New authors are being sought to take over this protocol. To view the published versions of this article, please click the 'Other versions' tab.

Reason for Withdrawal Authors have made no progress with this protocol in two years. New authors are being sought to take over this protocol. To view the published versions of this article, please click the 'Other versions' tab.

Reason for Withdrawal Authors have made no progress with this protocol in two years. New authors are being sought to take over this protocol. To view the published versions of this article, please click the 'Other versions' tab.

This 13th biannual report of the Cochrane Hematological Malignancies Group highlights recently published randomized controlled trials (RCTs) in the field of hemato-oncology, covering the publication period from July 2010 to February 2011. Implications for clinical practice and methodological aspects are the main principles for selecting trials for this report. Studies were identified by an electronic search of MEDLINE using a broad search filter that covers all topics in hemato-oncology combined with a highly sensitive search filter for randomized trials (Cochrane Handbook for Systematic Reviews of Interventions). The electronic search of the OVID MEDLINE database was conducted on February 28, 2011. In this summary of key features of recent RCTs, we focus on multiple myeloma (MM). Of the 62 identified RCTs, 15 evaluated different treatment approaches in patients with MM. Five of these 15 trials are selected and presented in detail [three in long version (1–3) and two in short version (4,5)]. Three further RCTs of clinical importance are also presented in less detail (6–8).

BACKGROUND Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment-related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (macrophage) colony-stimulating factors (G(M)-CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony-stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken. OBJECTIVES To compare the efficacy and safety of G(M)-CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy. SEARCH METHODS We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full-text and abstract publications. Two review authors independently screened search results. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)-CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full-text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross-over trials, quasi-randomised trials and post-hoc retrospective trials. DATA COLLECTION AND ANALYSIS Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician. MAIN RESULTS In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high-dose chemotherapy and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics.We judge the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.For the trial comparing G-CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection-related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM-CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM-CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non-haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. AUTHORS' CONCLUSIONS As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.

Background Autologous stem cell transplantation is widely used to restore functioning bone marrow in people with malignant lymphoma or multiple myeloma after myeloablative chemotherapy. Results of some clinical trials indicate that plerixafor in addition to granulocyte colony-stimulating factors (G-CSF) compared to G-CSF only could lead to an increased mobilisation and release of CD34-positive cells, facilitating effective apheresis. Objectives To evaluate the efficacy and safety of additional plerixafor to G-CSF for haematopoietic stem cell mobilisation in people with malignant lymphoma or multiple myeloma. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1990 to September 2015), as well as conference proceedings (American Society of Hematology; American Society of Clinical Oncology; European Hematology Association; American Society for Blood and Marrow Transplantation; European Group for Blood and Marrow Transplantation) for studies. Two review authors independently screened search results. Selection criteria We included randomised controlled trials (RCTs) comparing plerixafor in addition to G-CSF compared to G-CSF only for stem cell mobilisation in people with malignant lymphoma or multiple myeloma of all stages and ages. We included full text as well as abstracts and unpublished data if sufficient information on study design, participant characteristics, interventions, and outcomes was available. We excluded cross-over trials, quasi-randomised trials, and post-hoc retrospective trials. Data collection and analysis Two review authors independently screened the results of the search strategies, extracted data, assessed quality, and analysed data according to standard Cochrane methods. We performed final interpretation with an experienced clinician. Main results We identified four RCTs fitting the inclusion criteria. However, two of these closed prematurely due to low recruitment and did not report results. The remaining two trials evaluated 600 participants with multiple myeloma or non-Hodgkin lymphoma. In both studies the experimental group received G-CSF plus plerixafor and the control group received G-CSF plus placebo. The meta-analysis showed no evidence for differences between plerixafor and placebo group regarding mortality at 12 months (600 participants; risk ratio (RR) 1.00, 95% confidence interval (CI) 0.59 to 1.69; P = 1.00; moderate-quality evidence) and adverse events during stem cell mobilisation and collection (593 participants; RR 1.02, 95% CI 0.99 to 1.06; P = 0.19; high-quality evidence). Regarding the outcome successful stem cell collection, the meta-analysis showed an advantage for those participants randomised to the plerixafor group (600 participants; RR 2.42, 95% CI 1.98 to 2.96; P < 0.00001; high-quality evidence). As there was high heterogeneity between studies for the number of transplanted participants, we did not meta-analyse these data. In the multiple myeloma study, 95.9% (142 participants) in the plerixafor arm and 88.3% (136 participants) in the placebo arm underwent transplantation (RR 1.09, 95% CI 1.02 to 1.16); in the non-Hodgkin lymphoma trial, 90% (135 participants) in the plerixafor group versus 55.4% (82 participants) in the placebo group could be transplanted (RR 1.62, 95% CI 1.39 to 1.89). In both trials there was no evidence for a difference between participants in the plerixafor and placebo group in terms of time to neutrophil and platelet engraftment in transplanted participants. None of the trials reported on the outcomes quality of life and progression-free survival. Authors' conclusions The results of the analysed data suggest that additional plerixafor leads to increased stem cell collection in a shorter time. There was insufficient evidence to determine whether additional plerixafor affects survival or adverse events. The two trials included in the meta-analysis, both of which were conducted by the Genzyme Corporation, the manufacturer of plerixafor, were published several times. Two more RCTs examining the addition of plerixafor to a G-CSF mobilisation regimen terminated early without publishing any outcome. The trials included nine and five participants, respectively. Another RCT with 100 participants was recently completed, but has not yet published outcomes. Due to the unpublished RCTs, it is possible that our review is affected by publication bias, even though two trials failed to recruit a sufficient number of participants to analyse any data.

Background Haematological malignancies are malignant neoplasms of the myeloid or lymphatic cell lines including leukaemia, lymphoma and myeloma. In order to manage physical and psychological aspects of the disease and its treatment, complementary therapies like yoga are coming increasingly into focus. However, the effectiveness of yoga practice for people suffering from haematological malignancies remains unclear. Objectives To assess the effects of yoga practice in addition to standard cancer treatment for people with haematological malignancies. Search methods Our search strategy included the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950 to 4th February 2014), databases of ongoing trials (controlled-trials.com; clinicaltrials.gov), conference proceedings of the American Society of Clinical Oncology, the American Society of Hematology, the European Haematology Association, the European Congress for Integrative Medicine, and Global Advances in Health and Medicine. We handsearched references of these studies from identified trials and relevant review articles. Two review authors independently screened the search results. Selection criteria We included randomised controlled trials (RCTs) of yoga in addition to standard care for haematological malignancies compared with standard care only. We did not restrict this to any specific style of yoga. Data collection and analysis Two review authors independently extracted data for eligible studies and assessed the risk of bias according to predefined criteria. We evaluated distress, fatigue, anxiety, depression and quality of sleep. Further outcomes we planned to assess were health-related quality of life (HRQoL), overall survival (OS) and adverse events (AE), but data on these were not available. Main results Our search strategies led to 149 potentially relevant references, but only a single small study met our inclusion criteria. The included study was published as a full text article and investigated the feasibility and effect of Tibetan Yoga additional to standard care (N = 20; 1 person dropped out before attending any classes and no data were collected) compared to standard care only (N = 19). The study included people with all stages of Hodgkin and non-Hodgkin's lymphoma, with and without current cancer treatment. The mean age was 51 years. We judged the overall risk of bias as high as we found a high risk for performance, detection and attrition bias. Additionally, potential outcome reporting bias could not be completely ruled out. Following the recommendations of GRADE, we judged the overall quality of the body of evidence for all predefined outcomes as 'very low', due to the methodical limitations and the very small sample size. The influence of yoga on HRQoL and OS was not reported. There is no evidence that yoga in addition to standard care compared with standard care only can improve distress in people with haematological malignancies (mean difference (MD) -0.30, 95% confidence interval (CI) -5.55 to 4.95; P = 0.91). Similarly, there is no evidence of a difference between either group for fatigue (MD 0.00, 95% CI -0.94 to 0.94; P = 1.00), anxiety (MD 0.30, 95% CI -5.01 to 5.61; P = 0.91) or depression (MD -0.70, 95% CI -3.21 to 1.81; P = 0.58). There is very low quality evidence that yoga improves the overall quality of sleep (MD -2.30, 95% CI -3.78 to -0.82; P = 0.002). The yoga groups' total score for the Pittsburgh Sleep Quality Index (PSQI) was 5.8 (± 2.3 SD) and better than the total score (8.1 (± 2.4 SD)) of the control group. A PSQI total score of 0 to 5 indicates good sleep whereas PSQI total score 6 to 21 points towards significant sleep disturbances. The occurrence of AEs was not reported. Authors' conclusions The currently available data provide little information about the effectiveness of yoga interventions for people suffering from haematological malignancies. The finding that yoga may be beneficial for the patients' quality of sleep is based on a very small body of evidence. Therefore, the role of yoga as an additional therapy for haematological malignancies remains unclear. Further high-quality randomised controlled trials with larger numbers of participants are needed to make a definitive statement.

Treatment for Hodgkin lymphoma is effective for about 85% of the patients. A gold-standard for the 15% of relapsing patients is still missing. High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) has shown efficacy and safety for patients, but up to date no survival benefit revealed. After systematic literature search we identified three randomised controlled trials from 1663 total hits. Meta-analysis of two trials (157 patients) showed a statistically significant increase in progression-free survival (hazard ratio 0.55, 95% confidence interval 0.35–0.86) for patients treated with HDCT and ASCT compared to conventional chemotherapy, but no difference in overall survival nor increased adverse events. The third trial (241 patients) showed an statistically significant increase in infections and 5% more treatment-related mortalities following sequential HDCT plus HDCT and ASCT compared to HDCT plus ASCT, without differences in the efficacy endpoints overall survival or progression-free survival.

BACKGROUND Hodgkin lymphoma (HL) is one of the most common malignancies in young adults and has become curable for the majority of patients, even in advanced stage. After first-line therapy, 15% to 20% do not respond to treatment and relapse. For those patients, high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is a frequently used therapy option. OBJECTIVES To find the best available treatment with HDCT followed by ASCT for patients with relapsed or refractory HL after first-line treatment. SEARCH METHODS We searched the Central Register of Controlled Trials (CENTRAL), MEDLINE, and relevant conference proceedings up to January 2013 for randomised controlled trials (RCTs). We also contacted experts for unpublished data. SELECTION CRITERIA We included RCTs comparing HDCT followed by ASCT versus conventional chemotherapy without ASCT, or versus additional sequential HDCT (SHDCT) followed by ASCT. We also included RCTs with different HDCT regimens before ASCT in patients with relapsed or primary refractory HL after any first-line therapy. DATA COLLECTION AND ANALYSIS Two review authors (MR, NS) independently selected relevant studies, extracted data and assessed trial quality. We used hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS), and we calculated risk ratios (RR) for the other outcomes. We presented all measures with 95% confidence intervals (CI).We assessed the quality of evidence using GRADE methods. MAIN RESULTS Our search resulted in 1663 potentially relevant references, of which we included three trials with 14 publications, assessing 398 patients. Overall, we judged the quality of the trials as moderate. The trials were all reported as randomised controlled and open-label. We included two RCTs assessing the effect of HDCT followed by ASCT compared with conventional chemotherapy in a meta-analysis. The number of studies was very low, therefore, the quantification of heterogeneity was not reliable. We included one further RCT (one assessing additional SHDCT followed by ASCT versus HDCT followed by ASCT), which was not compatible with our meta-analysis. For this trial, we performed further analyses.Two trials showed a non-statistically significant trend that HDCT followed by ASCT compared to conventional chemotherapy increases OS (HR 0.67; 95% CI 0.41 to 1.07; P value = 0.10, 157 patients, moderate quality of evidence). However, the increase in PFS was statistically significant for people treated with HDCT followed by ASCT (HR 0.55; 95% CI 0.35 to 0.86; P value = 0.009, 157 patients, moderate quality of evidence). Adverse events were reported in one trial only and did not differ statistically significant between the treatment arms. We were not able to draw conclusions regarding treatment-related mortality (TRM) because of insufficient evidence (RR 0.61; 95% CI 0.16 to 2.22; P value = 0.45, 157 patients, moderate quality of evidence).For the second comparison, SHDCT plus HDCT followed by ASCT versus HDCT followed by ASCT there was no difference between the treatment arms regarding OS (HR 0.93; 95% CI 0.5 to 1.74; P value = 0.816, three-year OS: 80% SHDCT versus 87% HDCT, 241 patients), or PFS (HR 0.87; 95% CI 0.58 to 1.30; P value = 0.505, 241 patients). Seven patients died in the SHDCT arm and one in the HDCT arm due to increased toxicity of the treatment. Adverse events were increased with SHDCT plus HDCT followed by ASCT after two cycles of dexamethasone plus high-dose cytarabine plus cisplatin (DHAP) (88% SHDCT versus 45% HDCT, 223 patients, P value < 0.00001). Overall, more statistically significant World Health Organization (WHO) grade 3/4 infections occurred with SHDCT (48% SHDCT versus 33% HDCT; P value = 0.002, 223 patients). AUTHORS' CONCLUSIONS The currently available evidence suggests a PFS benefit for patients with relapsed or refractory HL after first-line therapy, who are treated with HDCT followed by ASCT compared to patients treated with conventional chemotherapy. In addition, data showes a positive trend regarding OS, but more trials are needed to detect a significant effect.Intensifying the HDCT regime before HDCT followed by ASCT did not show a difference as compared to HDCT followed by ASCT, but was associated with increased adverse events.

Background Primary central nervous system lymphoma (PCNSL) is a variant of extranodal non-Hodgkin lymphoma (NHL) that accounts for about 2% to 5% of all primary intracranial tumours with immunocompetent patients. It appears at a median age of 62 years. A standard of care for PCNSL patients has not been defined yet, but high-dose methotrexate (HD-MTX) is considered to be a beneficial chemotherapy in PCNSL treatment. Currently, HD-MTX is combined with numerous other chemotherapy drugs to improve outcomes of HD-MTX monotherapy. However, the impact of additional chemotherapy remains unclear, as there is evidence of a higher risk of adverse events (AEs) such as infective complications. Objectives We performed a systematic review of randomised controlled trials (RCTs) to assess the efficacy and safety of additional chemotherapy to HD-MTX in the treatment of immunocompetent PCNSL patients. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5) and MEDLINE (from 1950 to May 2012) as well as conference proceedings for RCTs. Two review authors (NB, NS) independently screened search results. Selection criteria We included RCTs comparing HD-MTX in combination with additional chemotherapy to mono-chemotherapy with HD-MTX in immunocompetent patients off all ages in first-line treatment of PCNSL. Data collection and analysis As an effect measure we used hazard ratios (HR) and 95% confidence intervals (CI) for overall survivals (OS) and progression-free survival (PFS). For effect measure of complete remission rate (CRR), partial response rate (PRR), treatment-related mortality (TRM) and AEs we used risk ratios (RR). Two review authors (NB, NS) independently extracted data and assessed the quality of trials. Main results Our search strategies led to 699 potentially relevant references. Of these, one RCT involving 79 patients was included. We judged the quality of the trial as moderate. The study was reported as a randomised open-label study and published as a full-text article.Even though PFS was statistically significantly improved for patients treated with HD-MTX plus cytarabine (HR 0.54; 95% CI 0.31 to 0.92; P = 0.01), this did not translate to a statistical significant OS benefit (HR 0.65; 95% CI 0.38 to 1.13; P = 0.07). AEs, especially infective complications, hepatotoxicity and haematological toxicities, were assessed more often in patients undergoing HD-MTX therapy combined with cytarabine. However, there were no statistically significant differences in terms of TRM (RR 3.08; 95% CI 0.33 to 28.32; P = 0.35). Authors' conclusions Owing to the small number of included trials and patients, the findings in this review remain uncertain. In summary, the presently available evidence (one small trial) showed a benefit in terms of PFS, ORR and CRR but no statistically significant difference regarding OS for patients with PCNSL treated with HD-MTX plus cytarabine compared to HD-MTX alone. However, the risk of severe infections and toxicity was significantly higher in patients treated with combined chemotherapy. More RCTs with additional chemotherapy to HD-MTX therapy with higher numbers of patients and longer follow-up periods are needed to confirm the results of this review and determine whether the PFS benefit will translate into an OS advantage. At least the one included study shows that RCTs of moderate quality and with valuable outcomes for this malignant disease are feasible.

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.

Background There are two different international standards for the treatment of early unfavourable and advanced stage Hodgkin lymphoma (HL): chemotherapy with escalated BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone) regimen and chemotherapy with ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) regimen. Objectives To provide an evidence-based answer regarding the advantages and disadvantages of chemotherapy including escalated BEACOPP compared to chemotherapy including ABVD. Search methods We searched for randomised controlled trials in MEDLINE, CENTRAL and conference proceedings (January 1985 to November 2010) and EMBASE (1985 to November 2008). Selection criteria We included randomised controlled trials examining chemotherapy including at least two cycles of escalated BEACOPP regimens compared to chemotherapy including at least four cycles of ABVD regimens as first-line treatment for patients with early unfavourable stage or advanced stage HL. Data collection and analysis Effect measures used were hazard ratios (HR) for overall survival (OS), progression-free survival (PFS) and freedom from first progression. Relative risks were used to analyse complete response rate, treatment-related mortality and adverse events. Two independent review authors extracted data and assessed quality of trials. Main results A total of 790 records were screened. Five eligible trials (four published, one ongoing), were identified. These trials included only adult patients (16 to 60 years of age). Four trials with 2868 patients were included in the meta-analyses: the HD9 and HD14 trials from Germany, the HD2000 and GSM-HD trials from Italy. All trials reported results for PFS and OS. PFS was statistically significantly longer for escalated BEACOPP: HR was 0.53 (95% confidence interval (CI) 0.44 to 0.64, I2 = 0%). There was no statistically significant difference in OS between the comparators: HR was 0.80 (95% CI 0.59 to 1.09, I2 = 0%). Three trials reported adverse events: the escalated BEACOPP regimens caused statistically significantly more haematological toxicities WHO grade III or IV (anaemia P < 0.00001, neutropenia P = 0.007, thrombocytopenia P < 0.00001), infections (P < 0.00001)) and occurrence of myeloid dysplastic syndrome (MDS) or acute myeloid leukemia (AML) (P = 0.05). There were no differences between both regimens for secondary malignancies, treatment-related mortality or infertility. Authors' conclusions This meta-analysis showed that adult patients between 16 and 60 years of age with early unfavourable or advanced stage HL benefited from chemotherapy including escalated BEACOPP regarding PFS, but there was no significant difference in OS. Longer follow-up and the inclusion of the EORTC 20012 trial will lead to a more definitive answer with respect to OS.

For this biannual report, the electronic search of the OVID MEDLINE database (gateway.ut.ovid.com) was undertaken on June 30, 2010. We identified 145 randomized controlled trials and selected four that evaluated tyrosine kinase inhibitors (imatinib, nilotinib, or dasatinib) in patients with chronic myeloid leukemia (CML) to present in detail and four further clinically important randomized controlled trials to present in less detail. After a short overview of the clinical relevance and the selection of patients in each trial, we discussed important methodological aspects of each trial (eg, randomization, loss to follow-up, and statistical analysis). Results of the primary efficacy endpoints and safety analysis were presented. The main objective of this article was to provide busy practitioners with easily interpretable knowledge about tyrosine kinase inhibitors and CML. A summary of the latest Cochrane reviews and protocols as developed by the Cochrane Haematological Malignancies Group was also included.

Combined modality treatment (CMT) of chemotherapy followed by localized radiotherapy is standard treatment for patients with early stage Hodgkin's lymphoma. However, the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication. We thus performed a systematic review with meta-analysis of randomized controlled trials comparing chemotherapy alone with CMT in patients with early stage Hodgkin's lymphoma with respect to response rate, tumor control and overall survival (OS). We searched Medline, EMBASE and the Cochrane Library as well as conference proceedings from January 1980 to February 2009 for randomized controlled trials comparing chemotherapy alone versus the same chemotherapy regimen plus radiotherapy. Progression free survival and similar outcomes were analyzed together as tumor control. Effect measures used were hazard ratios for OS and tumor control as well as relative risks for complete response (CR). Meta-analyses were performed using RevMan5. Five randomized controlled trials involving 1,245 patients were included. The hazard ratio (HR) was 0.41 (95% confidence interval (CI) 0.25 to 0.66) for tumor control and 0.40 (95% CI 0.27 to 0.59) for OS for patients receiving CMT compared to chemotherapy alone. CR rates were similar between treatment groups. In sensitivity analyses another 6 trials were included that did not fulfill the inclusion criteria of our protocol but were considered relevant to the topic. These trials underlined the results of the main analysis. In conclusion, adding radiotherapy to chemotherapy improves tumor control and OS in patients with early stage Hodgkin's lymphoma.