Bohlius J, Tonia T, Nüesch E, Jüni P, Fey M F, Egger M, Bernhard J
Institute of Social and Preventive Medicine (ISPM), University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland.
1] Institute of Social and Preventive Medicine (ISPM), University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland [2] Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
Br J Cancer. 2014 Jul 8;111(1):33-45. doi: 10.1038/bjc.2014.171. Epub 2014 Apr 17.
Erythropoiesis-stimulating agents (ESAs) reduce the need for red blood cell transfusions; however, they increase the risk of thromboembolic events and mortality. The impact of ESAs on quality of life (QoL) is controversial and led to different recommendations of medical societies and authorities in the USA and Europe. We aimed to critically evaluate and quantify the effects of ESAs on QoL in cancer patients.
We included data from randomised controlled trials (RCTs) on the effects of ESAs on QoL in cancer patients. Randomised controlled trials were identified by searching electronic data bases and other sources up to January 2011. To reduce publication and outcome reporting biases, we included unreported results from clinical study reports. We conducted meta-analyses on fatigue- and anaemia-related symptoms measured with the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) and FACT-Anaemia (FACT-An) subscales (primary outcomes) or other validated instruments.
We identified 58 eligible RCTs. Clinical study reports were available for 27% (4 out of 15) of the investigator-initiated trials and 95% (41 out of 43) of the industry-initiated trials. We excluded 21 RTCs as we could not use their QoL data for meta-analyses, either because of incomplete reporting (17 RCTs) or because of premature closure of the trial (4 RCTs). We included 37 RCTs with 10581 patients; 21 RCTs were placebo controlled. Chemotherapy was given in 27 of the 37 RCTs. The median baseline haemoglobin (Hb) level was 10.1 g dl(-1); in 8 studies ESAs were stopped at Hb levels below 13 g dl(-1) and in 27 above 13 g dl(-1). For FACT-F, the mean difference (MD) was 2.41 (95% confidence interval (95% CI) 1.39-3.43; P<0.0001; 23 studies, n=6108) in all cancer patients and 2.81 (95% CI 1.73-3.90; P<0.0001; 19 RCTs, n=4697) in patients receiving chemotherapy, which was below the threshold (≥ 3) for a clinically important difference (CID). Erythropoiesis-stimulating agents had a positive effect on anaemia-related symptoms (MD 4.09; 95% CI 2.37-5.80; P=0.001; 14 studies, n=2765) in all cancer patients and 4.50 (95% CI 2.55-6.45; P<0.0001; 11 RCTs, n=2436) in patients receiving chemotherapy, which was above the threshold (≥ 4) for a CID. Of note, this effect persisted when we restricted the analysis to placebo-controlled RCTs in patients receiving chemotherapy. There was some evidence that the MDs for FACT-F were above the threshold for a CID in RCTs including cancer patients receiving chemotherapy with Hb levels below 12 g dl(-1) at baseline and in RCTs stopping ESAs at Hb levels above 13 g dl(-1). However, these findings for FACT-F were not confirmed when we restricted the analysis to placebo-controlled RCTs in patients receiving chemotherapy.
In cancer patients, particularly those receiving chemotherapy, we found that ESAs provide a small but clinically important improvement in anaemia-related symptoms (FACT-An). For fatigue-related symptoms (FACT-F), the overall effect did not reach the threshold for a CID.
促红细胞生成素（ESAs）可减少红细胞输血需求；然而，它们会增加血栓栓塞事件和死亡风险。ESAs对生活质量（QoL）的影响存在争议，导致美国和欧洲的医学协会及当局提出了不同建议。我们旨在严格评估并量化ESAs对癌症患者生活质量的影响。
我们纳入了关于ESAs对癌症患者生活质量影响的随机对照试验（RCTs）数据。通过检索电子数据库和其他来源，截至2011年1月确定了随机对照试验。为减少发表和结果报告偏倚，我们纳入了临床研究报告中的未报告结果。我们对使用癌症治疗功能评估-疲劳（FACT-F）和FACT-贫血（FACT-An）子量表（主要结局）或其他有效工具测量的与疲劳和贫血相关的症状进行了荟萃分析。
我们确定了58项符合条件的RCTs。27%（15项中的4项）研究者发起的试验和95%（43项中的41项）行业发起的试验有临床研究报告。我们排除了21项RTCs，因为我们无法将其生活质量数据用于荟萃分析，要么是因为报告不完整（17项RCTs），要么是因为试验提前结束（4项RCTs）。我们纳入了37项RCTs，共10581例患者；21项RCTs为安慰剂对照。37项RCTs中有27项给予了化疗。基线血红蛋白（Hb）水平中位数为10.1 g·dl⁻¹；在8项研究中，ESAs在Hb水平低于13 g·dl⁻¹时停用，在27项研究中高于13 g·dl⁻¹时停用。对于FACT-F，所有癌症患者的平均差异（MD）为2.41（95%置信区间（95%CI）1.39 - 3.43；P<0.0001；23项研究，n = 6108），接受化疗的患者为2.81（95%CI 1.73 - 3.90；P<0.0001；19项RCTs，n = 4697），低于临床重要差异（CID）的阈值（≥3）。促红细胞生成素对所有癌症患者与贫血相关的症状有积极影响（MD 4.09；95%CI 2.37 - 5.80；P = 0.001；14项研究，n = 2765），接受化疗的患者为4.50（95%CI 2.55 - 6.45；P<0.0001；11项RCTs，n = 2436），高于CID的阈值（≥4）。值得注意的是，当我们将分析限制在接受化疗患者的安慰剂对照RCTs时，这种效果仍然存在。有一些证据表明，在基线Hb水平低于12 g·dl⁻¹的接受化疗的癌症患者的RCTs中以及在Hb水平高于13 g·dl⁻¹时停用ESAs的RCTs中，FACT-F的MD高于CID的阈值。然而，当我们将分析限制在接受化疗患者的安慰剂对照RCTs时，FACT-F的这些发现未得到证实。
在癌症患者中，尤其是接受化疗的患者，我们发现ESAs在与贫血相关的症状（FACT-An）方面有微小但具有临床意义的改善。对于与疲劳相关的症状（FACT-F），总体效果未达到CID的阈值。
