Comparison of first-line chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for people with early unfavourable or advanced stage Hodgkin lymphoma.

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.

Bortezomib for the treatment of multiple myeloma.

BACKGROUND: Multiple myeloma is a malignancy of plasma cells accounting for approximately 1% of cancers and 12% of haematological malignancies. The first-in-class proteasome inhibitor, bortezomib, is commonly used to treat newly diagnosed as well as relapsed/refractory myeloma, either as single agent or combined with other therapies. OBJECTIVES: We conducted a systematic review and meta-analysis to assess the effects of bortezomib on overall survival (OS), progression-free survival (PFS), response rate (RR), health-related quality of life (HRQoL), adverse events (AEs) and treatment-related death (TRD). SEARCH METHODS: We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE (till 27 January 2016) as well as conference proceedings and clinical trial registries for randomised controlled trials (RCTs). SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared i) bortezomib versus no bortezomib with the same background therapy in each arm; ii) bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s) and iii) bortezomib dose comparisons and comparisons of different treatment administrations and schedules. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted outcomes data and assessed risk of bias. We extracted hazard ratios (HR) and their confidence intervals for OS and PFS and odds ratios (OR) for response rates, AEs and TRD. We contacted trial authors to provide summary statistics if missing. We estimated Logrank statistics which were not available. We extracted HRQoL data, where available. MAIN RESULTS: We screened a total of 3667 records, identifying 16 relevant RCTs involving 5626 patients and included 12 trials in the meta-analyses. All trials were randomised and open-label studies. Two trials were published in abstract form and therefore we were unable to assess potential risk of bias in full.There is moderate-quality evidence that bortezomib prolongs OS (four studies, 1586 patients; Peto OR 0.77, 95% CI 0.65 to 0.92) and PFS (five studies, 1855 patients; Peto OR 0.65, 95% CI 0.57 to 0.74) from analysing trials of bortezomib versus no bortezomib with the same background therapy in each arm.There is high-quality evidence that bortezomib prolongs OS (five studies, 2532 patients; Peto OR 0.76, 95% CI 0.67 to 0.88) but low-quality evidence for PFS (four studies, 2489 patients; Peto OR 0.67, 95% CI 0.61 to 0.75) from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s).Four trials (N = 716) examined different doses, methods of administrations and treatment schedules and were reviewed qualitatively only.We identified four trials in the meta-analysis that measured time to progression (TTP) and were able to extract and analyse PFS data for three of the studies, while in the case of one study, we included TTP data as PFS data were not available. We therefore did not analyse TTP separately in this review.Patients treated with bortezomib have increased risk of thrombocytopenia, neutropenia, gastro-intestinal toxicities, peripheral neuropathy, infection and fatigue with the quality of evidence highly variable. There is high-quality evidence for increased risk of cardiac disorders from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or versus other agents. The risk of TRD in either comparison group analysed is uncertain due to the low quality of the evidence.Only four trials analysed HRQoL and the data could not be meta-analysed.Subgroup analyses by disease setting revealed improvements in all outcomes, whereas for therapy setting, an improved benefit for bortezomib was observed in all outcomes and subgroups except for OS following consolidation therapy. AUTHORS' CONCLUSIONS: This meta-analysis found that myeloma patients receiving bortezomib benefited in terms of OS, PFS and response rate compared to those who did not receive bortezomib. This benefit was observed in trials of bortezomib versus no bortezomib with the same background therapy and in trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s). Further evaluation of newer proteasome inhibitors is required to ascertain whether these agents offer an improved risk-benefit profile, while more studies of HRQoL are also required.

Meditation for adults with haematological malignancies.

BACKGROUND: Malignant neoplasms of the lymphoid or myeloid cell lines including lymphoma, leukaemia and myeloma are referred to as haematological malignancies. Complementary and alternative treatment options such as meditation practice or yoga are becoming popular by treating all aspects of the disease including physical and psychological symptoms. However, there is still unclear evidence about meditation's effectiveness, and how its practice affects the lives of haematologically-diseased patients. OBJECTIVES: This review aims to assess the benefits and harms of meditation practice as an additional treatment to standard care for adults with haematological malignancies. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 8, 2015), MEDLINE (1950 to August 2015), databases of ongoing trials, the metaRegister of Controlled Trials (mRCT) (http://www.controlled-trials.com/mrct/), conference proceedings of annual meetings of: the American Society of Hematology; American Society of Clinical Oncology; European Hematology Association; European Congress for Integrative Medicine; and Global Advances in Health and Medicine (2010 to 2015). SELECTION CRITERIA: We included randomised controlled trials (RCTs) using meditation practice for adult patients with haematological malignancies. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from eligible studies and assessed the risk of bias according to predefined criteria. We evaluated quality of life and depression. The other outcomes of overall survival, anxiety, fatigue, quality of sleep and adverse events could not be evaluated, because they were not assessed in the included trial. MAIN RESULTS: We included only one small trial published as an abstract article. The included study investigated the effects of meditation practice on patients newly hospitalised with acute leukaemia. Ninety-one participants enrolled in the study, but only 42 participants remained in the trial throughout the six-month follow-up period and were eligible for analysis. There was no information provided about the average age and sex of the study population. We found a high risk for attrition bias and unclear risk for reporting bias, performance and detection bias because of missing data due to abstract publication only, thus we judged the overall risk of bias as high. According to the GRADE criteria, we judged the overall quality of the body of evidence for all predefined outcomes as 'very low', due to the extent of missing data on the study population, and the small sample size.As the abstract publication did not provide numbers and results except P values, we are not able to give more details.Meditation practice might be beneficial for the quality of life of haematologically-diseased patients, with higher scores for participants in the mediation arms compared to the participants in the usual care control group (low quality of evidence). Levels of depression decreased for those practising meditation in both the spiritually-framed meditation group and the secularly-focused meditation group in comparison to the usual care control group, whose levels of depression remained constant (low quality of evidence). The influence of meditation practice on overall survival, fatigue, anxiety, quality of sleep and adverse events remained unclear, as these outcomes were not evaluated in the included trial. AUTHORS' CONCLUSIONS: To estimate the effects of meditation practice for patients suffering from haematological malignancies, more high quality randomised controlled trials are needed. At present there is not enough information available on the effects of meditation in haematologically-diseased patients to draw any conclusion.

Aerobic physical exercise for adult patients with haematological malignancies.

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: To evaluate the efficacy, safety and feasibility of aerobic physical exercise for adults suffering from haematological malignancies. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2014, Issue 1) and MEDLINE (1950 to January 2014) as well as conference proceedings for randomised controlled trials (RCTs). SELECTION CRITERIA: We included 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. Additionally, we excluded 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 and 100-day survival, standardised mean differences for quality of life (QoL), fatigue, and physical performance, and mean differences for anthropometric measurements. MAIN RESULTS: Our search strategies identified 1518 potentially relevant references. Of these, we included nine RCTs involving 818 participants. The potential risk of bias in these 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 six 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 of overall survival (OS) was not analysed in any of the included trials, but three trials reported deceased participants during the course of the study or during the first 100 days. There is no evidence for a difference between participants exercising and those in the control group (RR 0.93; 95% CI 0.59 to 1.47; P = 0.75; 3 trials, 269 participants, moderate quality of evidence).Four trials analysed the influence of exercise intervention on quality of life (QoL). Excluding one trial with serious baseline imbalances, physical exercise improves QoL (SMD 0.26; 95% CI 0.03 to 0.49; P = 0.03; 3 trials, 291 participants, low quality of evidence). This positive effect of exercise was also found in the subscales physical functioning (SMD 0.33; 95% CI 0.13 to 0.52; P = 0.0009; 4 trials, 422 participants, moderate quality of evidence) and depression (SMD 0.25; 95% CI -0.00 to 0.50; P = 0.05; 3 trials, 249 participants, low quality of evidence). However, there is no evidence for a difference between additional exercise and standard treatment for the subscale anxiety (SMD -0.18; 95% CI -0.64 to 0.28; P = 0.45; 3 trials, 249 participants, low quality of evidence). Seven trials (692 participants) evaluated fatigue. There is moderate quality of evidence that exercise improves fatigue (SMD 0.24; 95% CI 0.08 to 0.40; P = 0.003).Eight studies evaluated various aspects of physical performance (e.g. aerobic capacity, cardiovascular fitness), but none of them could be pooled in a meta-analysis. In seven trials there is a tendency or statistically significant effect favouring the exercise group (very low quality of evidence).Three trials (266 participants) investigated serious adverse events (SAEs) (e.g. bleeding, fever, pneumonia, deep vein thrombosis, and infection), and one trial (122 participants) assessed adverse events (AEs). There is no evidence for a difference between arms in terms of SAEs (RR 1.44; 95% CI 0.96 to 2.18; P = 0.06) or AEs (RR 7.23; 95% CI 0.38 to 137.05; P = 0.19); both findings are based on low quality of evidence. AUTHORS' CONCLUSIONS: There is no evidence for differences in mortality between the exercise and control groups. Physical exercise added to standard care can improve quality of life, especially physical functioning, depression and fatigue. Currently, there is inconclusive evidence regarding anxiety, physical performance, serious adverse events and adverse events.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. Furthermore, we need trials with overall survival as the primary outcome to determine whether the suggested benefits will translate into a survival advantage. To enhance comparability of study data, development and implementation of core sets of measuring devices would be helpful.

Sixteenth biannual report of the Cochrane Haematological Malignancies Group: focus on Non-Hodgkin's lymphoma.

This sixteenth biannual report of the Cochrane Haematological Malignancies Group highlights recently published randomized controlled trials (RCTs) in the field of hemato-oncology, with special focus on non-Hodgkin's lymphoma. The report covers the publication period June 2012 to July 2013. Trials are selected regarding their methodology and implication for clinical practice. Studies were identified by 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). Four RCTs are presented in detail, followed by two further RCTs of high importance in a short version. The report is finalized with an overview of new and updated Cochrane Reviews.

Fifteenth biannual report of the Cochrane Haematological Malignancies Group--focus on non-Hodgkin's lymphoma.

This fifteenth biannual report of the Cochrane Haematological Malignancies Group (CHMG) highlights recently published randomized controlled trials (RCTs) in the field of hemato-oncology, covering the publication period from October 2011 to May 2012. Implications for clinical practice and methodological aspects are the main principles for selecting trials for this report. Studies were identified by 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).

Use of anterior tibial translation in the management of patellofemoral pain syndrome in older patients: a case series.

The currently most plausible pathophysiologic theory for the etiology of pain in patients with patellofemoral pain syndrome involves abnormal mechanical stress to the patellofemoral joint. At this time, there is no consensus nor is there a sufficient body of research evidence to guide management of patients with patellofemoral pain syndrome. This means that clinicians have to rely to some extent on a mechanism-based approach. Decreased quadriceps flexibility and muscular endurance have been identified as possibly relevant impairments in patients with patellofemoral pain syndrome. Surgical anterior translation of the tibial tuberosity with the Maquet procedure has a proven positive effect on patellofemoral contact forces. This case series studied the effects of a physical therapy management approach that included translating the tibia anteriorly while performing open kinetic chain quadriceps training and manual muscle stretching of the rectus femoris muscle. Outcome measures used included the numeric pain rating scale and goniometric measurement of rectus femoris muscle length in a standardized test position. Anterior tibial translation reduced pain during both interventions and also produced clinically and statistically significant pre- to post-intervention improvements in pain during manual muscle testing and rectus femoris length testing in addition to statistically significant pre- to post-intervention increases in rectus femoris muscle length. The results of this quasi-experimental study indicate the need for future experimental study. Future study should include functional in addition to impairment-based outcome measures, standardization and blinding for the rectus femoris muscle length test (should future researchers chose to again use this outcome measure), a pilot study establishing reliability of outcome measures collected by the therapist, younger subjects, and the collection of longer-term outcome data.