Vanessa Piechotta1, Anne Adams2, Madhuri Haque1, Benjamin Scheckel1,3, Nina Kreuzberger1, Ina Monsef1, Karin Jordan4, Kathrin Kuhr2, Nicole Skoetz5. 1. Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. 2. Institute of Medical Statistics and Computational Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. 3. Institute of Health Economics and Clinical Epidemiology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. 4. Department of Medicine V, University of Heidelberg, Heidelberg, Germany. 5. Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Abstract
BACKGROUND: 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 - To compare the effects of antiemetic treatment combinations including NK₁ receptor antagonists, 5-HT₃ receptor antagonists, and corticosteroids on prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy-induced nausea and vomiting in network meta-analysis (NMA) - To generate a clinically meaningful treatment ranking according to treatment safety and efficacy • In adults with solid cancer or haematological malignancy receiving 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 - To generate a clinically meaningful treatment ranking according to treatment safety and efficacy SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings, and study registries from 1988 to February 2021 for randomised controlled trials (RCTs). SELECTION CRITERIA: 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. Complete control of vomiting during the overall phase We estimated that 704 of 1000 participants achieve complete control of vomiting in the overall treatment phase (one to five days) when treated with aprepitant + granisetron. Evidence from NMA (39 RCTs, 21,642 participants; 12 treatment combinations with NK₁ and 5-HT₃ inhibitors) suggests that the following drug combinations are more efficacious than aprepitant + granisetron for completely controlling vomiting during the overall treatment phase (one to five days): 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 (753 of 1000; RR 1.07, 95% CI 0.95 to 1.21; low certainty), and fosaprepitant + palonosetron (746 of 1000; RR 1.06, 95% CI 0.96 to 1.19; low certainty). Netupitant + palonosetron (704 of 1000; RR 1.00, 95% CI 0.93 to 1.08; high-certainty) and fosaprepitant + granisetron (697 of 1000; RR 0.99, 95% CI 0.93 to 1.06; high-certainty) have little to no impact on complete control of vomiting during the overall treatment phase (one to five days) when compared to aprepitant + granisetron, respectively. 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). We could not include two treatment combinations (ezlopitant + granisetron, aprepitant + tropisetron) in NMA for this outcome because of missing direct comparisons. 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) We included 38 studies reporting on 12,038 participants and comparing 15 treatment combinations with NK₁ and 5-HT₃ inhibitors, or 5-HT₃ inhibitors solely. All treatment combinations included corticosteroids. Complete control of vomiting during the overall phase 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 of 1000; RR 1.06, 95% CI 0.85 to 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 Our main reason for downgrading was serious or very serious imprecision (e.g. due to wide 95% CIs crossing or including unity, few events leading to wide 95% CIs, or small information size). Additional reasons for downgrading some comparisons or whole networks were serious study limitations due to high risk of bias or moderate inconsistency within networks. 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. For people receiving HEC, synthesised evidence does not suggest one superior treatment for prevention and control of chemotherapy-induced nausea and vomiting. 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.
BACKGROUND: 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 - To compare the effects of antiemetic treatment combinations including NK₁ receptor antagonists, 5-HT₃ receptor antagonists, and corticosteroids on prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy-induced nausea and vomiting in network meta-analysis (NMA) - To generate a clinically meaningful treatment ranking according to treatment safety and efficacy • In adults with solid cancer or haematological malignancy receiving 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 - To generate a clinically meaningful treatment ranking according to treatment safety and efficacy SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings, and study registries from 1988 to February 2021 for randomised controlled trials (RCTs). SELECTION CRITERIA: 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. Complete control of vomiting during the overall phase We estimated that 704 of 1000 participants achieve complete control of vomiting in the overall treatment phase (one to five days) when treated with aprepitant + granisetron. Evidence from NMA (39 RCTs, 21,642 participants; 12 treatment combinations with NK₁ and 5-HT₃ inhibitors) suggests that the following drug combinations are more efficacious than aprepitant + granisetron for completely controlling vomiting during the overall treatment phase (one to five days): 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 (753 of 1000; RR 1.07, 95% CI 0.95 to 1.21; low certainty), and fosaprepitant + palonosetron (746 of 1000; RR 1.06, 95% CI 0.96 to 1.19; low certainty). Netupitant + palonosetron (704 of 1000; RR 1.00, 95% CI 0.93 to 1.08; high-certainty) and fosaprepitant + granisetron (697 of 1000; RR 0.99, 95% CI 0.93 to 1.06; high-certainty) have little to no impact on complete control of vomiting during the overall treatment phase (one to five days) when compared to aprepitant + granisetron, respectively. 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). We could not include two treatment combinations (ezlopitant + granisetron, aprepitant + tropisetron) in NMA for this outcome because of missing direct comparisons. 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) We included 38 studies reporting on 12,038 participants and comparing 15 treatment combinations with NK₁ and 5-HT₃ inhibitors, or 5-HT₃ inhibitors solely. All treatment combinations included corticosteroids. Complete control of vomiting during the overall phase 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 of 1000; RR 1.06, 95% CI 0.85 to 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 Our main reason for downgrading was serious or very serious imprecision (e.g. due to wide 95% CIs crossing or including unity, few events leading to wide 95% CIs, or small information size). Additional reasons for downgrading some comparisons or whole networks were serious study limitations due to high risk of bias or moderate inconsistency within networks. 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. For people receiving HEC, synthesised evidence does not suggest one superior treatment for prevention and control of chemotherapy-induced nausea and vomiting. 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.
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