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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 We included full‐text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available.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.

In our present summary of key features of recent RCTs, we focus on chronic lymphatic leukemia. Four recently published trials in patients with chronic lymphocytic leukemia (CLL) are presented in detail: three examine different therapeutic options for first-line therapy for CLL and one addresses the role of oblimersen sodium (Bcl-2 antisense) as an addition to cyclophosphamide and fludarabine. In lesser detail, we present the results of three other interesting trials published during the 9-month period. After a short overview of the clinical relevance and the selection of patients for these trials, we discuss important methodologic aspects of each trial, eg, randomization, loss to follow-up, dropout rate, and statistical analysis. We also discuss the results of the primary efficacy endpoints and the methods used to report health-related quality of life. The main objective of this summary report is to provide the knowledge in a way that busy practitioners can easily interpret it. Published Trials in Patients With CLL CLL is a chronic disease of the B-cell lineage that is characterized by an accumulation of ineffective lymphocytes. Because early treatment is not associated with increased length of survival, treatment is reserved for patients with clinical symptoms or rapidly progressing disease. CLL is staged according to the Binet criteria or Rai’s criteria, both of which are based on the number of lymphatic sites or organs (liver, spleen) affected as

BACKGROUND: The prevalence and incidence of pain and skeletal complications of metastatic bone disease such as pathologic fractures, spinal cord compression and hypercalcemia is high and an important contributor to morbidity, poor performance status and decreased quality of life. Moreover, pathologic fractures are associated with increased risk of death in people with disseminated malignancies. Therefore, prevention of pain and fractures are important goals in men with prostate cancer at risk for skeletal complications. OBJECTIVES: To assess the effects of bisphosphonates in men with bone metastases from prostate cancer. SEARCH METHODS: We identified studies by electronic search of bibliographic databases including the Cochrane Controlled Trials Register and MEDLINE on 13 July 2017 and trial registries. We handsearched the Proceedings of American Society of Clinical Oncology (to July 2017) and reference lists of all eligible trials identified. This is an update of a review last published in 2006. SELECTION CRITERIA: We included randomized controlled studies comparing the effectiveness of bisphosphonates in men with bone metastases from prostate cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of trials. We defined the proportion of participants with pain response as the primary end point; secondary outcomes were skeletal‐related events, mortality, quality of life, adverse events, analgesic consumption and disease progression. We assessed the quality of the evidence for the main outcomes using the GRADE approach. MAIN RESULTS: We included 18 trials reporting on 4843 participants comparing the effect of bisphosphonate administration to control regimens. Primary outcome: there was no clear difference in the proportion of participants with pain response (RR 1.15, 95% CI 0.93 to 1.43; P = 0.20; I(2) = 0%; 3 trials; 876 participants; low quality evidence). In absolute terms, bisphosphonates resulted in a pain response in 40 more participants per 1000 (19 fewer to 114 more). Secondary outcomes: bisphosphonates probably reduced the incidence of skeletal‐related events in participants with prostate cancer metastatic to bone (RR 0.87, 95% CI 0.81 to 0.94; P = 0.27; I(2) = 19%; 9 trials; 3153 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 58 fewer SREs per 1000 (85 fewer to 27 fewer). We found no clinically relevant differences in mortality (RR 0.97, 95% CI 0.91 to 1.04; P = 0.43; I(2) = 1%; 9 trials; 2450 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 16 fewer deaths per 1000 (47 fewer to 21 more). Outcome definition of quality of life and the measurement tools varied greatly across trials and we were unable to extract any quantitative data for meta‐analysis. Bisphosphonates probably increased the number of participants affected by nausea (RR 1.19, 95% CI 1.00 to 1.41; P = 0.05; I(2) = 0%; 9 trials; 3008 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in seven more cases of nausea per 1000 (0 fewer to 14 more). Bisphosphonates probably increased the number of renal adverse events (RR 1.65, 95% CI 1.11 to 2.46; P = 0.01; I(2) = 0%; 7 trials; 1794 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 22 more renal adverse events per 1000 (4 more to 50 more). We found no clear difference in the number of participants with osteonecrosis of the jaw between groups (RR 1.92, 95% CI 0.75 to 4.90; P = 0.17; I(2) = 0%; 5 trials; 1626 participants; very low quality evidence). In absolute terms, bisphosphonates resulted in seven more cases with osteonecrosis of the jaw per 1000 (2 fewer to 29 more). We observed no clinically relevant difference in the proportion of participants with decreased analgesic consumption (RR 1.19, 95% CI 0.87 to 1.63; P = 0.28; I(2) = 37%; 4 trials; 416 participants). Statistical analysis revealed that bisphosphonates probably reduced the number of participants with disease progression (RR 0.94, 95% CI 0.90 to 0.98; P = 0.006; I(2) = 0%; 7 trials; 2115 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 36 fewer cases of disease progression per 1000 (71 fewer to 7 fewer). Findings of our predefined subgroup and sensitivity analyses were no different from those of the primary analyses. AUTHORS' CONCLUSIONS: Based on low quality evidence, there may be no clinically relevant difference in the proportion of men with pain response between bisphosphonates and control regimens in men with bone metastases from prostate cancer. Bisphosphonates probably decrease the number of skeletal‐related events and disease progression. These benefits need to be weighed against the increased risk of renal impairment and nausea in men receiving bisphosphonates. Future studies should explicitly evaluate patient important outcomes such as quality of life and pain by using standardized and comparable assessment tools.

Abstract 4632 Introduction: Chronic lymphocytic leukemia (CLL) accounts for 25% of all leukemias and remains incurable with conventional chemotherapy (CX). Rituximab (R) may be an effective treatment option for CLL patients with the potential to improve overall survival (OS) when given in combination with CX but there is also a risk of more side effects such as infections. This review aims to summarize the evidence for this new treatment option by evaluating the effects on OS, progression-free survival (PFS) and side effects. Methods: MEDLINE and CENTRAL were systematically searched for randomized controlled trials up to April 2010. Trials of patients with CLL comparing CX including R and treatment with CX alone (CX identical in both groups) were included. Clinical trials with previously untreated and pre-treated patients were explored in the main meta-analyses. Trial selection, quality assessment and data extraction were done independently by two review authors. Dichotomous data were analyzed as relative effect measures (i.e. relative risk, RR) with 95% confidence intervals (CI). Time-to-event outcomes were analyzed with hazard ratios (HR) and 95% CI in a random effects model. Results: A total of 992 records were screened. Two eligible trials with 921 untreated (GCLLSG CLL 8 trial (CLL8) and CALGB 9712 trial (CALGB 9712)) and two eligible trials with 604 pre-treated patients (REACH trial (REACH) and NCRI CLL 201 trial) that were fitting the inclusion criteria were identified. The NCLRI CLL 201 trial provided response data only. CALGB 9721 did not report HRs or P-values on OS or PFS and the survival curves for PFS and OS were of low quality, so the provided data were not included in the meta-analysis. Both, CLL8 and REACH examined patients receiving fludarabine (F) and cyclophosphamide (C) with or without R and were meta-analyzed with regard to PFS and OS. PFS (1342 patients) was significantly longer for FCR (HR 0.65, 95% CI [0.48, 0.88]). Analysis of OS (1368 patients) also showed a significantly longer survival for FCR (HR 0.73 (95% CI [0.58, 0.93]). CLL8 provided HRs for the different disease stages and showed significantly improved OS after FCR for Binet B patients only [Binet A: HR 0,19, 95% CI [0.23, 1.613]; Binet B: HR 0.45, 95% CI [0.295, 0.689]; Binet C: HR 1.4, 95% CI [0.843, 2.620]). REACH had not been significant regarding OS (HR 0.83, 95% CI [0.59, 1.17]). With regard to severe hematologic toxicity, meta-analysis of CLL8, REACH and CALGB 9721 showed a significantly higher risk of neutropenia (RR 1.46, CI 95% [1.03, 2.08]) for regimens including R, but there was no statistical difference for thrombocytopenia (RR 1.06, CI 95% [0.60, 1.87]), anemia (RR 0.89 [0.63, 1.26]) or the incidence of severe infections (RR 1.08 CI 95% [0.86, 1.35]). REACH reported a higher rate of secondary malignancies in the FCR-arm (FCR (7%), FC (5%)). Conclusions: This systematic review demonstrates significantly longer OS for CLL patients that received FCR compared to FC (HR 0.65, 95% CI [0.48, 0.88]) and confirms better PFS for patients receiving FCR (HR 0.73 (95% CI [0.58, 0.93]). Adverse events (particularly neutropenia) occurred more often when patients were treated with CX plus R but did not result in an increased infection rate. However, data of CLL8 were only available from the abstract and need to be subsequently confirmed. Disclosures: Hallek: Roche: Consultancy, Honoraria, Research Funding.

Abstract 3705 Poster Board III-641 Introduction The main challenge in treating Hodgkin lymphoma (HL) is to find the optimal treatment with the best efficacy and least toxicity. So far there are two different international standards for the treatment of intermediate and advanced stage HL: chemotherapy with ABVD regime and chemotherapy with escalated BEACOPP regime. This review aims to clarify advantages and disadvantages of both treatments. Methods MEDLINE, CENTRAL and EMBASE were systematically searched for randomised controlled trials from 1985 to 2008. Trials comparing treatment with at least 2 cycles escalated BEACOPP versus chemotherapy with at least 4 cycles of ABVD within patients in intermediate or advanced stages HL were included. Trials without any published results will be excluded from the meta-analysis. Trial selection, quality assessment and data extraction were done independently by two review authors. Time-to-event outcome were analyzed with hazard ratios (HR) and 95% confidence interval (CI) in a fixed effects model. Results A total of 683 references were screened. Four eligible trials with 1970 patients were identified and included in the main analysis: the HD9 and HD14 trials from Germany, the HD2000 and GSM-HD trials from Italy. The escalated BEACOPP regime was more toxic during treatment than ABVD. Progression free survival (PFS) was statistically significantly longer for escalated BEACOPP: HR was 0.53 (95% CI [0.42, 0.67], I2=0%). In the main analysis of overall survival (OS), escalated BEACOPP was statistically significantly better than ABVD: HR was 0.70 (95% CI [0.50, 0.98], I2=0%). However, this result is not robust. In the OS-analysis restricted to advanced stage trials, the HR was 0.93 (95% CI [0.52, 1.04], I2=0%). Due to the high weight of the HD9 trial (57%), the OS-results are strongly influenced by this trial. In a sensitivity OS analysis without the HD9 trial the HR was 0.83 (95% CI [0.50, 1.38]). Only one trial (HD9) had a follow-up of over 5 years; the median of the other trials was approx. 3 years. Conclusions This meta-analysis showed a better PFS and suggests a benefit in OS for escalated BEACOPP in comparison to ABVD-like regimen. However, many trials had a short follow-up. Longer follow-up and the inclusion of the ongoing EORTC 20012 trial should allow a more definitive answer concerning OS. Disclosures: No relevant conflicts of interest to declare.

Background Combined modality treatment (CMT) consisting of chemotherapy followed by localised radiotherapy is 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 We performed a systematic review with meta-analysis of randomised controlled trials (RCTs) comparing chemotherapy alone with CMT in patients with early stage Hodgkin lymphoma with respect to response rate, progression-free survival (alternatively tumour control) and overall survival (OS). Search methods We searched MEDLINE, EMBASE and CENTRAL as well as conference proceedings from January 1980 to November 2010 for randomised controlled trials comparing chemotherapy alone to the same chemotherapy regimen plus radiotherapy. Selection criteria Randomised controlled trials comparing chemotherapy alone with CMT in patients with early stage HL. Trials in which the chemotherapy differed between treatment arms were excluded. Trials with more than 20% of patients in advanced stage were also excluded. Data collection and analysis Effect measures used were hazard ratios (HR) for tumour control and OS as well as relative risks for response rates. Two review authors independently extracted data and assessed quality of trials. We contacted study authors to obtain missing information. Since none of the trials reported progression-free survival according to our definitions, all similar outcomes were evaluated as tumour control. Main results Five RCTs involving 1245 patients were included. The HR was 0.41 (95% confidence interval (CI) 0.25 to 0.66) for tumour control and 0.40 (95% CI 0.27 to 0.61) for OS for patients receiving CMT compared to chemotherapy alone. Complete response rates were similar between treatment groups. In sensitivity analyses another six trials were included that did not fulfil the inclusion criteria of our protocol but were considered relevant to the topic. These trials underlined the results of the main analysis. Authors' conclusions Adding radiotherapy to chemotherapy improves tumour control and overall survival in patients with early stage Hodgkin lymphoma.