哪种药物组合最适合预防由癌症成年人化学疗法引起的恶心和呕吐?

由化学疗法引起的恶心和呕吐的负担,什么有助于预防?

In about 70% to 80% of adults with cancer, chemotherapy induces nausea and vomiting (CINV). Depending on the type of chemotherapy, treatment can cause strong or moderate sickness (hereafter referred to as HEC (highly emetogenic chemotherapy) and MEC (moderately emetogenic chemotherapy)). Multiple drug combinations have showed high benefit for CINV among adults receiving HEC or MEC.

What was the aim of our review?

使用网络荟萃分析,我们旨在比较the benefits and harms of different drug combinations for prevention of CINV among people receiving HEC or MEC, and to identify treatment ranking. A network meta-analysis is a technique used to compare different treatments described in already published trials, even when the original individual trial does not describe such comparisons.

我们看了什么研究?

We searched selected medical databases and trial registries until April 2019. We included studies comparing multiple drug combinations for prevention of CINV among adults with any type of cancer receiving HEC or MEC that is commonly used in clinical practice. In particular, we looked at drugs inhibiting two specific biochemical receptors (neurokinin receptor and serotonin receptor) that trigger nausea and vomiting after chemotherapy. We looked at the preventative effects of these treatments over five days. This is the period during which the maximum intensity of CINV and further peaks of intensity are expected, after the start of chemotherapy.

我们的关键结果...

...for people receiving HEC

我们发现73项研究报告了25,275名参与者的经验,并比较了我们感兴趣的14个治疗组合。

Benefits.Over five days, investigated treatments helped to prevent any vomiting in 60% to 81% of people on average. Those individuals also had no need for rescue medicines, which are used in case nausea and vomiting occur even though prophylactic treatment has been given. The results of our analysis suggest some differences in effectiveness of different treatments, but overall we had little confidence that those differences would be reflected in real-world observations.

危害。我们估计1%到4%的人ple experience serious side effects. The differences between treatments were small.

...for people receiving MEC

我们发现38项研究报告了12,038名参与者的经验,并比较了我们感兴趣的15个治疗组合。

Benefits.Over five days, investigated treatments helped prevent any vomiting in 43% to 72% of people on average. Those individuals also had no need for rescue medicines. The results of our analysis suggest some differences in the effectiveness of different treatments, but overall, we had little confidence that those differences would be reflected in real-world observations.

危害。Few studies reported serious side effects. The ones that did suggest that on average 15% to 18% of people experience such events. Differences between treatments were small. However, we think that future research is needed to rule out potential differences between treatments.

Our confidence in the findings

We assessed how confident we were that there are differences between compared treatments. We had low or very low confidence that one treatment is better or worse than another in preventing CINV. Our confidence in differences between statistical results was mainly limited because measures of variation were wide apart and included both potential advantages and disadvantages, although measures of precision showed no or little effect. We also identified limitations in some of the included studies, which further limited our confidence in the effects. This was mainly the case when study personnel and participants knew which treatments were given and therefore may not adhere to the planned intervention, or may perceive or report effects differently.

Our conclusions

我们的分析结果表明,对于接受HEC或MEC的人来说,没有用于预防CINV的卓越组合。然而,结果表明,靶向5-羟色胺受体的药物的选择可能会影响有效性,而与靶向神经蛋白受体的药物有或没有药物。但是,在解释这些结果时,重要的是,读者必须了解,这些多种多种比较分析不能代替头对头比较,并且结果不一定排除可能在临床上与之相关的差异一些人。

How up-to-date is this evidence?

Evidence is up-to-date to 2 February 2021.

Authors' conclusions:

This field of supportive cancer care is very well researched. However, new drugs or drug combinations are continuously emerging and need to be systematically researched and assessed.

对于接受HEC的人来说,合成的证据并不建议一种用于预防和控制化疗引起的恶心和呕吐的卓越治疗方法。

For people receiving MEC, synthesised evidence does not suggest superiority for treatments including both NK₁ and 5-HT₃ inhibitors when compared to treatments including 5-HT₃ inhibitors only. Rather, the results of our NMA suggest that the choice of 5-HT₃ inhibitor may have an impact on treatment efficacy in preventing CINV.

When interpreting the results of this systematic review, it is important for the reader to understand that NMAs are no substitute for direct head-to-head comparisons, and that results of our NMA do not necessarily rule out differences that could be clinically relevant for some individuals.

Read the full abstract...
背景:

About 70% to 80% of adults with cancer experience chemotherapy-induced nausea and vomiting (CINV). CINV remains one of the most distressing symptoms associated with cancer therapy and is associated with decreased adherence to chemotherapy. Combining 5-hydroxytryptamine-3 (5-HT₃) receptor antagonists with corticosteroids or additionally with neurokinin-1 (NK₁) receptor antagonists is effective in preventing CINV among adults receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). Various treatment options are available, but direct head-to-head comparisons do not allow comparison of all treatments versus another.

Objectives:

In adults with solid cancer or haematological malignancy receiving HEC

- 比较包括NK₁受体拮抗剂,5-HT₃受体拮抗剂和皮质类固醇包括预防急性相(第1天),延迟相(第2至5天)和整体化学疗法(第1至5天的化学疗法)的抗激发治疗组合的影响- 在网络荟萃分析(NMA)中引起恶心和呕吐

- 根据治疗安全和功效产生临床意义的治疗排名

在患有固体癌症或血液学恶性肿瘤的成年人中接受MEC

- To compare whether antiemetic treatment combinations including NK₁ receptor antagonists, 5-HT₃ receptor antagonists, and corticosteroids are superior for prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy-induced nausea and vomiting to treatment combinations including 5-HT₃ receptor antagonists and corticosteroids solely, in network meta-analysis

- 根据治疗安全和功效产生临床意义的治疗排名

Search strategy:

我们从1988年至2021年2月搜索了中央,MEDLINE,EMBASE,会议记录和研究注册表,以进行随机对照试验(RCT)。

选择标准:

We included RCTs including adults with any cancer receiving HEC or MEC (according to the latest definition) and comparing combination therapies of NK₁ and 5-HT₃ inhibitors and corticosteroids for prevention of CINV.

Data collection and analysis:

We used standard methodological procedures expected by Cochrane.

We expressed treatment effects as risk ratios (RRs). Prioritised outcomes were complete control of vomiting during delayed and overall phases, complete control of nausea during the overall phase, quality of life, serious adverse events (SAEs), and on-study mortality. We assessed GRADE and developed 12 'Summary of findings' tables. We report results of most crucial outcomes in the abstract, that is, complete control of vomiting during the overall phase and SAEs. For a comprehensive illustration of results, we randomly chose aprepitant plus granisetron as exemplary reference treatment for HEC, and granisetron as exemplary reference treatment for MEC.

Main results:

Highly emetogenic chemotherapy(HEC)

We included 73 studies reporting on 25,275 participants and comparing 14 treatment combinations with NK₁ and 5-HT₃ inhibitors. All treatment combinations included corticosteroids.

在整个阶段完全控制呕吐

我们估计,用Aprepitant + Granisetron处理,在1000名参与者中,有704名在整个治疗阶段(一到五天)完全控制了呕吐。NMA(39 RCT,21,642名参与者;与NK₁和5-HT₃抑制剂的12种治疗组合)的证据表明,以下药物组合比Aprepitant + Granisetron更有效,可以完全控制整体治疗阶段(1至五天)(1至五天):fosnetupitant + palonosetron (810 of 1000; RR 1.15, 95% confidence interval (CI) 0.97 to 1.37; moderate certainty), aprepitant + palonosetron (753 of 1000; RR 1.07, 95% CI 1.98 to 1.18; low-certainty), aprepitant+ RamoSetron(1000中的753; RR 1.07,95%CI 0.95至1.21;低确定性)和Fosaprepitant + Palonosetron(1000 of 1000; RR 1.06,95%CI 0.96至1.19;低确定性)。

Netupitant + Palonosetron(1000 of 1000; RR 1.00,95%CI 0.93至1.08;高确定性)和Fosaprepitant + Granisetron(1000中的697; RR 0.99,95%CI 0.93至1.06;高确定性)几乎没有影响)在整体治疗阶段(一到五天)中完全控制呕吐后,与植物 +花岗岩分别相比。

Evidence further suggests that the following drug combinations are less efficacious than aprepitant + granisetron in completely controlling vomiting during the overall treatment phase (one to five days) (ordered by decreasing efficacy): aprepitant + ondansetron (676 of 1000; RR 0.96, 95% CI 0.88 to 1.05; low certainty), fosaprepitant + ondansetron (662 of 1000; RR 0.94, 95% CI 0.85 to 1.04; low certainty), casopitant + ondansetron (634 of 1000; RR 0.90, 95% CI 0.79 to 1.03; low certainty), rolapitant + granisetron (627 of 1000; RR 0.89, 95% CI 0.78 to 1.01; moderate certainty), and rolapitant + ondansetron (598 of 1000; RR 0.85, 95% CI 0.65 to 1.12; low certainty).

由于缺少直接比较,我们无法在NMA中包括两个治疗组合(Ezlopitant + Granisetron,Aprepitant + Tropisetron)。

Serious adverse events

We estimated that 35 of 1000 participants experience any SAEs when treated with aprepitant + granisetron. Evidence from NMA (23 RCTs, 16,065 participants; 11 treatment combinations) suggests that fewer participants may experience SAEs when treated with the following drug combinations than with aprepitant + granisetron: fosaprepitant + ondansetron (8 of 1000; RR 0.23, 95% CI 0.05 to 1.07; low certainty), casopitant + ondansetron (8 of 1000; RR 0.24, 95% CI 0.04 to 1.39; low certainty), netupitant + palonosetron (9 of 1000; RR 0.27, 95% CI 0.05 to 1.58; low certainty), fosaprepitant + granisetron (13 of 1000; RR 0.37, 95% CI 0.09 to 1.50; low certainty), and rolapitant + granisetron (20 of 1000; RR 0.57, 95% CI 0.19 to 1.70; low certainty).

Evidence is very uncertain about the effects of aprepitant + ondansetron (8 of 1000; RR 0.22, 95% CI 0.04 to 1.14; very low certainty), aprepitant + ramosetron (11 of 1000; RR 0.31, 95% CI 0.05 to 1.90; very low certainty), fosaprepitant + palonosetron (12 of 1000; RR 0.35, 95% CI 0.04 to 2.95; very low certainty), fosnetupitant + palonosetron (13 of 1000; RR 0.36, 95% CI 0.06 to 2.16; very low certainty), and aprepitant + palonosetron (17 of 1000; RR 0.48, 95% CI 0.05 to 4.78; very low certainty) on the risk of SAEs when compared to aprepitant + granisetron, respectively.

We could not include three treatment combinations (ezlopitant + granisetron, aprepitant + tropisetron, rolapitant + ondansetron) in NMA for this outcome because of missing direct comparisons.

Moderately emetogenic chemotherapy (MEC)

我们包括了38项有关12,038名参与者的研究,并将15种治疗组合与NK₁和5-HT₃抑制剂或仅5-HT₃抑制剂进行了比较。所有治疗组合包括皮质类固醇。

在整个阶段完全控制呕吐

We estimated that 555 of 1000 participants achieve complete control of vomiting in the overall treatment phase (one to five days) when treated with granisetron. Evidence from NMA (22 RCTs, 7800 participants; 11 treatment combinations) suggests that the following drug combinations are more efficacious than granisetron in completely controlling vomiting during the overall treatment phase (one to five days): aprepitant + palonosetron (716 of 1000; RR 1.29, 95% CI 1.00 to 1.66; low certainty), netupitant + palonosetron (694 of 1000; RR 1.25, 95% CI 0.92 to 1.70; low certainty), and rolapitant + granisetron (660 of 1000; RR 1.19, 95% CI 1.06 to 1.33; high certainty).

Palonosetron (588 1000;相对危险度1.06,95%可信区间0.85到1.32; low certainty) and aprepitant + granisetron (577 of 1000; RR 1.06, 95% CI 0.85 to 1.32; low certainty) may or may not increase complete response in the overall treatment phase (one to five days) when compared to granisetron, respectively. Azasetron (560 of 1000; RR 1.01, 95% CI 0.76 to 1.34; low certainty) may result in little to no difference in complete response in the overall treatment phase (one to five days) when compared to granisetron.

Evidence further suggests that the following drug combinations are less efficacious than granisetron in completely controlling vomiting during the overall treatment phase (one to five days) (ordered by decreasing efficacy): fosaprepitant + ondansetron (500 of 100; RR 0.90, 95% CI 0.66 to 1.22; low certainty), aprepitant + ondansetron (477 of 1000; RR 0.86, 95% CI 0.64 to 1.17; low certainty), casopitant + ondansetron (461 of 1000; RR 0.83, 95% CI 0.62 to 1.12; low certainty), and ondansetron (433 of 1000; RR 0.78, 95% CI 0.59 to 1.04; low certainty).

We could not include five treatment combinations (fosaprepitant + granisetron, azasetron, dolasetron, ramosetron, tropisetron) in NMA for this outcome because of missing direct comparisons.

Serious adverse events

We estimated that 153 of 1000 participants experience any SAEs when treated with granisetron. Evidence from pair-wise comparison (1 RCT, 1344 participants) suggests that more participants may experience SAEs when treated with rolapitant + granisetron (176 of 1000; RR 1.15, 95% CI 0.88 to 1.50; low certainty). NMA was not feasible for this outcome because of missing direct comparisons.

Certainty of evidence

我们降级的主要原因是严重或非常严重的不精确(例如,由于95%CIS越过或包括统一性,很少有导致95%CI的事件或小型信息大小)。降级一些比较或整个网络的其他原因是由于网络内部偏见或中度不一致的高风险而导致的严重研究局限性。