Colony-stimulating factors: clinical evidence for treatment and prophylaxis of chemotherapy-induced febrile neutropenia

The hematopoietic growth factors (HGFs) are a family of glycoproteins which plays a major role in the proliferation, differentiation, and survival of primitive hematopoietic stem and progenitor cells, and in the functions of some mature cells. More than 20 different molecules of HGF have been identified. Among them, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been demostrated to be effective in reducing the incidence of febrile neutropenia when administered inmediately after chemotherapy and as supportive therapy in patients undergoing bone marrow transplantation. Chemotherapy used for treatment of cancer often causes neutropenia, which may be profound, requiring hospitalization, and leading to potentially fatal infection. The uses of the recombinant human hematopoietic colony-stimulating factors G-CSF and GM-CSF for treatment and prophylaxis of chemotherapy-induced febrile neutropenia will be reviewed here.     

Acupuncture for chemotherapy-induced leukopenia: exploratory meta-analysis of randomized controlled trials

Chemotherapy-induced leukopenia and neutropenia are common side effects during cancer treatment. Acupuncture has been reported as an adjunct therapy for this complication. The current study reviewed published randomized controlled trials of acupuncture's effect and explored the acupuncture parameters used in these trials. We searched biomedical databases in English and Chinese from 1979 to 2004. The study populations were cancer patients who were undergoing or had just completed chemotherapy or chemoradiotherapy, randomized to either acupuncture therapy or usual care. The methodologic quality of trials was assessed. From 33 reviewed articles, 682 patients from 11 eligible trials were included in analyses. All trials were published in non-PubMed journals from China. The methodologic quality of these trials was considerably poor. The median sample size of each comparison group was 45, and the median trial duration was 21 days. The frequency of acupuncture treatment was once a day, with a median of 16 sessions in each trial. In the seven trials in which white blood cell (WBC) counts were available, acupuncture use was associated with an increase in leukocytes in patients during chemotherapy or chemoradiotherapy, with a weighted mean difference of 1,221 WBC/muL on average (95% confidence interval 636-1,807; p < .0001). Acupuncture for chemotherapy-induced leukopenia is an intriguing clinical question. However, the inferior quality and publication bias present in these studies may lead to a false-positive estimation. Meta-analysis based on these published trials should be treated in an exploratory nature only.     

Interpreting febrile neutropenia rates from randomized,controlled trials for consideration of primary prophylaxis in the real world: a systematic review and meta-analysis

BackgroundGuidelines recommend primary prophylaxis (PP) with granulocyte-colony-stimulating factors (G-CSF) for patients above a febrile neutropenia (FN) risk threshold of 20%. Practitioners often use FN rates of regimens based on data from randomized, controlled trials (RCTs), which are often comprised of highly selected patients. Patients in the community setting may be at higher risk of FN.Materials and methodsA systematic literature search was conducted for full-length articles reporting FN rates for breast cancer-related chemotherapies between January 1996 and February 2014. A regimen was included if there was at least one RCT and one observational study. Meta-regression was used to model the odds of FN.Results130 studies involving 29 regimens and 50 069 patients were identified. Sixty-five observational study (n = 7812) and 110 RCT (n = 42 257) cohorts were included. The unadjusted FN rate was 11.7% in observational and 7.9% in RCT cohorts. The univariable odds ratio (OR) for FN in the observational study compared with RCT cohorts was 1.58 [95% confidence interval (CI) 1.09–2.28; P = 0.017]. The FN rates remained significantly higher in the observational study compared with RCT cohorts (OR = 1.74; 95% CI 1.15–2.62; P = 0.012) after adjusting for age, chemotherapy intent, and regimen; this meant that a 13% (95% CI 8.7% to 17.9%) FN rate in RCT would translate into 20% FN rate in observational study.ConclusionsFN rates in the observational studies are significantly higher than suggested by RCTs. Guidelines should clarify how FN rates from RCTs should be applied in clinical practice. Large population-based studies are needed to confirm FN rates in the real world.     

Prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor decrease febrile neutropenia after chemotherapy in children with cancer: a meta-analysis of randomized controlled trials.

PURPOSE: To determine whether prophylactic hematopoietic colony-stimulating factors (CSFs) used in children with cancer reduce the rate of febrile neutropenia, hospitalization duration, documented infection rate, parenteral antibiotic duration, amphotericin B use, or infection-related mortality. METHODS: We included studies in this meta-analysis if their populations consisted of children, if there was randomization between CSFs and placebo or no therapy, if CSFs were administered prophylactically (before neutropenia or febrile neutropenia), and if chemotherapy treatments preceding CSFs and placebo or no therapy were identical. From 971 reviewed study articles, 16 were included. RESULTS: The mean rate of febrile neutropenia in the control arms was 57% (range, 39% to 100%). Using a random effects model, CSFs were associated with a reduction in febrile neutropenia, with a rate ratio of 0.80 (95% CI, 0.67 to 0.95; P =.01), and a decrease in hospitalization length, with a weighted mean difference of -1.9 days (95% CI, -2.7 to -1.1 days; P <.00001). CSF use was also associated with reduction in documented infections (rate ratio, 0.78; 95% CI, 0.62 to 0.97; P =.02) and reduction in amphotericin B use (rate ratio, 0.50; 95% CI, 0.28 to 0.87; P =.02). There was no difference in duration of parenteral antibiotic therapy (weighted mean difference, -4.3; 95% CI, -10.6 to 2.0 days; P =.2) or infection-related mortality (rate ratio, 1.02; 95% CI, 0.34 to 3.06; P =.97). CONCLUSION: CSFs were associated with a 20% reduction in febrile neutropenia and shorter duration of hospitalization; however, CSFs did not reduce infection-related mortality.     

A new prognostic model for chemotherapy-induced febrile neutropenia

Background

The objective of this study was to develop and validate a new prognostic model for febrile neutropenia (FN).

Methods

This study comprised 1001 episodes of FN: 718 for the derivation set and 283 for the validation set. Multivariate logistic regression analysis was performed with unfavorable outcome as the primary endpoint and bacteremia as the secondary endpoint.

Results

In the derivation set, risk factors for adverse outcomes comprised age ≥60 years (2 points), procalcitonin ≥0.5 ng/mL (5 points), ECOG performance score ≥2 (2 points), oral mucositis grade ≥3 (3 points), systolic blood pressure <90 mmHg (3 points), and respiratory rate ≥24 breaths/min (3 points). The model stratified patients into three severity classes, with adverse event rates of 6.0 % in class I (score ≤2), 27.3 % in class II (score 3–8), and 67.9 % in class III (score ≥9). Bacteremia was present in 1.1, 11.5, and 29.8 % of patients in class I, II, and III, respectively. The outcomes of the validation set were similar in each risk class. When the derivation and validation sets were integrated, unfavorable outcomes occurred in 5.9 % of the low-risk group classified by the new prognostic model and in 12.2 % classified by the Multinational Association for Supportive Care in Cancer (MASCC) risk index.

Conclusions

With the new prognostic model, we can classify patients with FN into three classes of increasing adverse outcomes and bacteremia. Early discharge would be possible for class I patients, short-term observation could safely manage class II patients, and inpatient admission is warranted for class III patients.

     

Granisetron is equivalent to ondansetron for prophylaxis of chemotherapy-induced nausea and vomiting: results of a meta-analysis of randomized controlled trials

BACKGROUND: The introduction of serotonin antagonists as antiemetics for prophylaxis of chemotherapy-induced nausea and vomiting represented a major step toward better patient tolerance and adherence to this type of treatment. Several published trials compared different serotonin antagonists without demonstrating clear superiority of any one of them. Because most of these trials compared ondansetron with granisetron, the authors conducted a meta-analysis to determine if the current data available show any therapeutic difference between them. METHODS: MEDLINE and CANCERLIT databases were searched from 1990 to May 1999, and pertinent article references also were surveyed, without restriction to English language. The authors included all randomized controlled trials (RCTs) that had more than 25 patients per arm and compared ondansetron to granisetron for prophylaxis of acute (A) (< 24 hours) and delayed (D) (> 24 hours) nausea (N) and vomiting (V) induced by highly (H) or moderately (M) emetogenic chemotherapy. Only the first chemotherapy cycle was considered for studies that involved a crossover design. RESULTS: Fourteen studies with 6467 evaluable patients among the 21 studies retrieved were selected for this meta-analysis. In none of the eight scenarios studied (AHV, AHN, AMV, AMN, DHV, DHN, DMV, and DMN) could the authors detect any significant differences in the antiemetic efficacy of any of these medications. CONCLUSIONS: The authors conclude that both granisetron and ondansetron have similar antiemetic efficacy for prophylaxis of chemotherapy-induced nausea and vomiting. Because the number of comparative studies that addressed the delayed nausea and vomiting scenarios is low, further RCTs are still needed to confirm these results.     

Prophylactic colony-stimulating factors in children receiving myelosuppressive chemotherapy: a meta-analysis of randomized controlled trials

BACKGROUND: The colony-stimulating factors (CSFs) are widely utilized to prevent neutropenic complications in both adults and children, but randomized controlled trials in the pediatric setting have reported varied results. A systematic review of the literature and meta-analysis were conducted to definitively assess the impact of prophylactic CSFs on the risk of febrile neutropenia (FN) in pediatric oncology patients. METHODS: MEDLINE was searched and references hand-searched through July 2004 for randomized controlled trials of prophylactic G-CSF or GM-CSF in pediatric oncology patients. Objectives, outcomes, and quality of the 16 included studies were extracted by two reviewers. Weighted summary estimates of relative risks (RR) were calculated for FN and documented infection (DI). Mean differences in hospitalization, antibiotic use, and duration of neutropenia were calculated. RESULTS: FN occurred in 68% of 400 controls and 59% of 404 CSF patients. The estimated RR was 0.88 [0.81-0.97; (P=0.01)] favoring the CSFs for leukemia and high grade lymphoma studies and 0.71 [0.51-0.97; (P=0.03)] for solid tumor studies. DI occurred in 25% of controls and 20% of CSF patients for an estimated RR of 0.80 [0.61-1.06; (P=0.12)]. The mean decrease in duration of neutropenia was 3.5 days [2.2-4.7; (P<0.0001)]. Mean decreases favoring CSF use were also observed for hospital stay of 1.7 days [0.9-2.5 (P<0.01)] and antibiotic use of 2.0 days [0.4-3.6; P=0.02]. CONCLUSIONS: Prophylactic CSFs significantly decrease the incidence of FN and the durations of severe neutropenia, hospitalization, and antibiotic use in pediatric cancer patients, but they do not significantly decrease documented infections.     

Prognostic factors for febrile neutropenia

Cytotoxic chemotherapy suppresses the haematopoietic system, impairing host protective mechanisms and limiting the doses of chemotherapy that can be tolerated. Febrile neutropenia, the most serious haematological toxicity, is associated with the risk of life-threatening infections as well as chemotherapy dose reductions and delays that may compromise treatment outcomes. The recent literature in chemotherapy-induced neutropenia and its complications and impact was provided an update on research, and the implications for improving the management of patients with cancer who are treated with myelosuppressive chemotherapy was discussed. Despite its importance as the primary dose-limiting toxicity of chemotherapy, much concerning neutropenia and its consequences and impact remains unknown. Recent surveys indicate that neutropenia remains a prevalent problem associated with substantial morbidity, mortality, and costs. The colony-stimulating factors (CSFs) have been used effectively in a variety of clinical settings to prevent or treat febrile neutropenia and to assist patients receiving dose-intensive chemotherapy. A meta-analysis of the available randomized controlled trials (RCTs) has confirmed the efficacy of prophylactic CSFs. Much research has sought to identify risk factors that may predispose patients to neutropenic complications, including febrile neutropenia, in an effort to predict better which patients are at risk and to use preventive strategies, such as prophylactic colony-stimulating factors, more cost-effectively. Research in quantifying the risk of neutropenic complications may make it possible in the near future to target patients at greater risk with appropriate preventive strategies, thereby maximizing the benefits and minimizing the costs.     

Bevacizumab in metastatic breast cancer: a meta-analysis of randomized controlled trials

Amplification of the HER2 gene, present in 15–30% of breast carcinomas, correlates with poor outcome and is an indication for treatment with trastuzumab. Standard testing methods for HER2 amplification are fluorescence (FISH) or chromogenic in situ hybridization (CISH). In FISH/CISH scoring, correction for chromosome 17 polysomy is believed to be critical for determination of true HER2 amplification as opposed to increased chromosome 17 copy number. The term “polysomy 17” is widely used and defined as ≥3 copies of the chromosome 17 centromere (probe CEP17, D17Z1). Thus, the centromere is assumed to be representative for the entire chromosome. This study aimed to investigate the frequency of polysomy 17 and its association with HER2 amplification in 111 invasive breast cancer patients by CEP17 CISH and by copy number analysis of a set of 17 genes along chromosome 17 using multiplex ligation-dependent probe amplification (MLPA). Chromosome 17 usually showed a complex pattern of gains and losses by MLPA, unrelated to the copy number status of the centromere. Increase in centromere 17 copy number (denoted “polysomy 17”), as assessed by CEP17 CISH, was found in 19% of the patients. Of these patients, 60% also showed amplification of HER2 measured by MLPA. However, none of the 111 patients showed a true polysomy of chromosome 17 by MLPA. Only two patients (1.8%) had a possible gain of 17q. Amplification of 17p was not found in any of the patients, although a possible loss of 17p was found in one patient. In conclusion, this extensive analysis of amplicons along chromosome 17 shows that true polysomy of chromosome 17, either of the whole chromosome or of the short or the long arm, is very rare in invasive breast cancer. Abnormal CEP17 copy numbers may therefore actually stem from high level gains or amplification of CEP17 regardless of copy number gains of the short and long arms of chromosome 17 and, at least in some cases, correction with CEP17 probes may provide misleading HER2 gene status assessment results.     

化疗后粒细胞缺乏与患者特异性危险因素的相关分析

目的探讨肿瘤患者化疗后粒细胞缺乏与患者特异性危险因素的相关性.方法采用单因素和多因素的分析方法,回顾性分析74例肿瘤患者化疗后粒细胞缺乏的发生情况及其可能的相关因素.结果在74例患者共计145次的化疗中,有55例患者82次出现粒细胞缺乏,发生率为56.6%,其中Ⅰ～Ⅱ度49次(33.8%),Ⅲ～Ⅳ度33次(22.8%).在首次化疗出现粒细胞缺乏的患者在以后的化疗中粒细胞缺乏的发生率高于其他患者(P＜0.05),化疗期间食欲、肿瘤分期、年龄等因素与化疗后粒细胞缺乏明显相关(P＜0.05);多因素回归分析显示食欲下降、肿瘤分期是Ⅲ～Ⅳ度粒细胞缺乏的危险因素,食欲下降是Ⅰ～Ⅱ度粒细胞缺乏的危险因素.结论在肿瘤患者特异性的因素中,食欲下降、肿瘤分期、年龄等因素是肿瘤化疗后粒细胞缺乏的危险因素,尤其应当重视食欲下降对粒细胞缺乏的影响.     

Efficacy of front-line immunochemotherapy for follicular lymphoma: a network meta-analysis of randomized controlled trials

Front-line treatment for follicular lymphoma has evolved with the introduction of maintenance therapy, bendamustine (Benda), obinutuzumab (G), and lenalidomide (Len). We conducted a random-effects Bayesian network meta-analysis (NMA) of phase 3 randomized controlled trials (RCTs) to identify the regimens with superior efficacy. Progression-free survival (PFS) was compared between 11 modern regimens with different immunochemotherapy and maintenance strategies. G-Benda-G resulted in with the best PFS, with an HR of 0.41 compared to R-Benda, a surface under the cumulative ranking curve (SUCRA) of 0.97, a probability of being the best treatment (PbBT) of 72%, and a posterior ranking distribution (PoRa) of 1 (95% BCI 1–3). This was followed by R-Benda-R4 (HR = 0.49, PbBT = 25%, PoRa = 2) and R-Benda-R (HR = 0.60, PbBT = 3%, PoRa = 3). R-CHOP-R (HR = 0.96) and R-Len-R (HR = 0.97) had similar efficacy to R-Benda. Bendamustine was a better chemotherapy backbone than CHOP either with maintenance (R-Benda-R vs R-CHOP-R, HR = 0.62; G-Benda-G vs G-CHOP-G, HR = 0.55) or without maintenance therapy (R-Benda vs R-CHOP, HR = 0.68). Rituximab maintenance improved PFS following R-CHOP (R-CHOP-R vs R-CHOP, HR = 0.65) or R-Benda (R-Benda-R vs R-Benda, HR = 0.60; R-Benda-R4 vs R-Benda, HR = 0.49). In the absence of multi-arm RCTs that include all common regimens, this NMA provides an important and useful guide to inform treatment decisions.Subject terms: B-cell lymphoma, Medical research     

Treatment of community-acquired pneumonia with moxifloxacin: a meta-analysis of randomized controlled trials

Abstract

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality throughout the world. To investigate whether moxifloxacin monotherapy is associated with better clinical outcomes than other antibiotics recommended for CAP among adults with mild-to-moderate or severe CAP, we performed a meta-analysis. MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched for randomized control trials (RCTs). The efficacy and safety of moxifloxacin were compared with other antimicrobial agents used to treat CAP. Fourteen RCTs, consisting of 6923 total patients, were included in the meta-analysis. No difference was found regarding the incidence of adverse events and mortality between moxifloxacin and the compared regimens. We found that moxifloxacin is as effective and well-tolerated as other recommended antibiotics for the treatment of CAP and possesses a better pathogen eradication rate than beta-lactam-based therapy.     

Cetuximab-based therapy versus non-cetuximab therapy for advanced cancer: a meta-analysis of 17 randomized controlled trials

Purpose

To assess the efficacy and safety of cetuximab-based therapy versus non-cetuximab therapy for advanced cancer.

Methods

A total of 7,954 patients from 17 randomized controlled trials are identified, with 3,965 patients in the cetuximab group and 3,989 patients in the non-cetuximab group. The outcome was progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and grade 3/4 advent events.

Results

There was a significant improvement of PFS (HR 0.83, 95%CI 0.78–0.88), OS (HR 0.89, 0.84–0.95), and ORR in the cetuximab group (OR 1.39, 1.22–1.58). In subgroup analysis, in colorectal cancer, there was a significant improvement of PFS (0.72, 0.66–0.78), OS (0.90, 0.81–1.00), and ORR in the cetuximab group (1.36, 1.15–1.60). In head and neck carcinoma, there was a significant improvement of PFS (0.63, 0.54–0.73), OS (0.78, 0.67–0.91), and ORR in the cetuximab group (1.57, 1.15–2.16). In non-small-cell lung cancer, there was a significant improvement of OS (0.86, 0.76–0.96) in the cetuximab group, and no difference on PFS (0.82, 0.64–1.07) and ORR (1.56, 0.85–2.88). In pancreatic cancer, there was no difference on PFS (1.11, 0.97–1.28), OS (1.07, 0.93–1.25), and ORR (0.94, 0.66–1.33). There were higher incidences of grade 3–4 toxicity (OR 1.84), skin-related toxicity (OR 31.80), acneiform rash (OR 30.14), and hypomagnesemia (OR 6.72) in the cetuximab group.

Conclusions

Cetuximab-based therapy improved PFS and OS, and better ORR versus non-cetuximab therapy. The severe adverse events should be predictable and manageable.     

降钙素原在化疗致粒细胞减少伴发热患者中的临床意义

背景与目的：以往研究显示血清降钙素原可用于发热性疾病的诊断及其严重程度的评估。该研究旨在探讨血清降钙素原在化疗致粒细胞减少伴发热患者中的临床意义。方法：回顾性分析2012年1月—2014年12月以化疗致粒细胞减少伴发热收入复旦大学附属肿瘤医院ICU治疗的147例患者的临床资料。根据患者临床症状、体征、病原生物学特征确定患者有无感染,进而分为感染组及发热原因不详组。根据患者感染严重程度又将感染组分为脓毒症组、严重脓毒症组及脓毒性休克组,分析比较各组血清降钙素原的变化。结果：降钙素原大于0.935 ng/mL为临界值诊断粒细胞减少伴感染患者的敏感度为90.5%,特异度为90.0%,曲线下面积为0.905。感染组与发热原因不详组比较,降钙素原显著增高[1.805(1.268~2.523) ng/mLvs 0.555(0.398~0.818) ng/mL,P<0.001]。亚组分析表明,严重脓毒症组与脓毒症组比较,血清降钙素原水平明显增高[13.885(7.600~17.961) ng/mLvs 1.805(1.268-2.563) ng/mL,P<0.001];脓毒性休克组血清降钙素原水平显著高于严重脓毒症组[23.800(20.050~30.478) ng/mLvs 13.885(4.955~19.133) ng/mL,P<0.001]。结论：血清降钙素原检测可用于粒细胞减少伴感染患者的诊断及感染严重程度的判断。     

香菇多糖治疗恶性胸腔积液随机对照试验的Meta分析

目的:运用系统评价Meta分析的方法评价香菇多糖(LNT)单药或联合其他药物治疗恶性胸腔积液(MPE)的临床疗效及安全性。方法:应用Pubmed、Cochrane图书馆、Embase、CBM、CNKI、维普及万方数据库系统,全面收集有关LNT单药或联合其他药物治疗MPE的临床对照研究。结果:本系统评价共纳入17篇随机对照试验,共计978例患者,其中LNT组500例,顺铂组478例。Meta分析结果显示,LNT组临床有效率明显优于顺铂组(OR=3.68,95%CI=2.75～4.94;P<0.000 01);LNT组治疗后Karnofsky评分升高患者例数均显著多于顺铂组患者(OR=3.79,95%CI=2.46～5.84,P<0.000 01),其降低及稳定患者例数明显低于顺铂组患者(OR=0.41,95%CI=0.21～0.78,P=0.007;OR=0.37,95%CI=0.22～0.60,P<0.000 1);LNT组胃肠道反应和血液学毒性发生率较顺铂组明显减少(OR=0.31,95%CI=0.21～0.47,P<0.000 01;OR=0.49,95%CI=0.28～0.84,P=0.01)。结论:现有证据表明,LNT单药或联合其他药物治疗MEP的临床疗效及安全性均优于顺铂单药,可广泛应用于临床治疗晚期肿瘤恶性胸腔积液。     

Breast conservation therapy for stage I or stage II breast cancer: a meta-analysis of randomized controlled trials.

BACKGROUND: We carried out a meta-analysis to determine the effectiveness of breast conservation therapy (BCT) or mastectomy (MT) for stage I or stage II breast cancer. METHODS: A fully recursive literature search was conducted in the Cochrane Controlled Trials Register Databases, Medline, EMBASE and Chinese Biomedical Literature Database in any language. Randomized controlled trials (RCTs) were considered for inclusion. Analyses were carried out using RevMan software. RESULTS: In all, 18 RCTs including a total of 9388 patients were included. The meta-analysis showed that the overall survival in 3, 5, 10, 15 and 20 years and the locoregional recurrence rate in 3, 5, 15 and 20 years were not statistically significantly different between group BCT and group MT, but 10-year locoregional recurrence rate increased in group BCT. The sensitivity analysis indicated that both overall survival and locoregional recurrence rate were not statistically significant difference between group BCT and group MT. In the subgroup analysis, there was no significant difference in OS and locoregional recurrence rate between group BCT and group MT, but 20-year locoregional recurrence rate was statistically significantly higher in group BCT than group MT for women with tumors 2 cm or smaller. CONCLUSION: BCT was better choice than MT for women with stage I or stage II breast cancer.