Antiemetics for adults for prevention of nausea and vomiting caused by moderately or highly emetogenic chemotherapy: a network meta‐analysis

Vanessa Piechotta; Anne Adams; Madhuri Haque; Benjamin Scheckel; Nina Kreuzberger; Ina Monsef; Karin Jordan; Kathrin Kuhr; Nicole Skoetz

doi:10.1002/14651858.CD012775.pub2

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 4

Network graph for the outcome complete control of vomiting in the overall phase (HEC).

A line connects any two treatments when there is at least one study comparing the two treatments. Line width: number of patients.

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 5

League table for the outcome complete control of vomiting in the overall phase (HEC). Network estimates with 95% CIs are given. Descending P score shows ranking of treatment options. Statistically significant results are marked in yellow. Global approach to check inconsistency/heterogeneity: Q‐statistics, I².

No. of studies: 34. No. of treatments: 14. No. of pair‐wise comparisons: 36. No. of designs: 21.

Q_total = 23.95, df = 22, P = 0.35/Q_within = 17.60, df = 13, P = 0.17/Q_between = 6.34, df = 9, P = 0.71; I² = 8.1%, Tau² = 0.0005.
Treatment effects + 95% CIs (risk ratios, random‐effects model).

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 6

Exemplary network meta‐analysis forest plot for the outcome complete control of vomiting during the overall phase (HEC) (random‐effects model).

Aprepitant + granisetron was used as exemplary reference treatment. Ranking of treatments is ordered by P score (descending).

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 7

Comparison of direct and indirect evidence (in closed loops) for the outcome complete control of vomiting in the overall phase (HEC). CI: confidence interval; RR: risk ratio.

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 8

Network graph for the outcome serious adverse events (HEC).

A line connects any 2 treatments when there is at least 1 study comparing the 2 treatments. Line width: number of patients.

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 9

League table for the outcome serious adverse events (HEC). Network estimates with 95% CIs are given. Descending P score shows ranking of treatment options. Statistically significant results are marked in yellow. Global approach to check inconsistency/heterogeneity: Q‐statistics, I².

No. of studies: 20. No. of treatments: 12. No. of pair‐wise comparisons: 22. No. of designs: 13.

Q_total = 20.26, df = 9, P = 0.016/Q_within = 16.39, df = 7, P = 0.022/Q_between = 3.87, df = 2, P = 0.14; I² = 55.6%, Tau² = 0.1057.
Treatment effects + 95% CIs (risk ratios, random‐effects model).

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 10

Exemplary network meta‐analysis forest plot for the outcome serious adverse events (HEC) (random‐effects model).

Aprepitant + granisetron was used as exemplary reference treatment. Ranking of treatments is ordered by P score (descending).

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 11

Comparison of direct and indirect evidence (in closed loops) for the outcome serious adverse events (HEC). CI: confidence interval; RR: risk ratio.

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 12

Exemplary ranking plot representing simultaneously the efficacy (x‐axis, CR during the overall phase) and the acceptability (y‐axis, SAEs) of all antiemetic regimens for patients receiving highly emetogenic chemotherapy.

Only antiemetic regimens for which data for both endpoints (CR during the overall phase and SAEs) were available are represented in the ranking plot.

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 13

League table with network estimates (RR with 95% CIs) of all treatment combinations for efficacy (CR during the overall phase) and acceptability (SAEs) (HEC).

Treatments are presented in alphabetical order. For efficacy, RRs > 1 favour the first treatment in alphabetical order. For safety, RRs < 1 favour the first treatment in alphabetical order.

n.a.: no data were available for this comparison

Statistically significant results are marked bold.

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 14

Network graph for the outcome complete control of vomiting during the overall phase (MEC).

A line connects any 2 treatments when there is at least 1 study comparing the 2 treatments. Line width: number of patients.

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 15

League table for the outcome complete control of vomiting during the overall phase (MEC). Network estimates with 95% CIs are given. Descending P score shows ranking of treatment options. Statistically significant results are marked in yellow. Global approach to check inconsistency/heterogeneity: Q‐statistics, I².

No. of studies: 22. No. of treatments: 11. No. of pair‐wise comparisons: 22. No. of designs: 11.

Q_total = 13.90, df = 12, P = 0.31/Q_within = 13.80, df = 11, P = 0.24/Q_between = 0.09, df = 1, P = 0.76; I² = 13.7%, Tau² = 0.0018.

Treatment effects + 95% CIs (risk ratios, random‐effects model); RR > 1 favours the upper treatment/treatment on the left.

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 16

Exemplary network meta‐analysis forest plot for the outcome complete control of vomiting during the overall phase (MEC) (random‐effects model).

Granisetron was used as exemplary reference treatment. Ranking of treatments is ordered by P score (descending).

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 17

Comparison of direct and indirect evidence (in closed loops) for the outcome complete control of vomiting during the overall phase (MEC). CI: confidence interval; RR: risk ratio.

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 18

Network graph for the outcome serious adverse events (MEC).

A line connects any 2 treatments when there is at least 1 study comparing the 2 treatments. Line width: number of patients.

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 19

League table for the outcome serious adverse events (MEC). Network estimates with 95% CIs are given. Descending P score shows ranking of treatment options. Statistically significant results are marked in yellow. Global approach to check inconsistency/heterogeneity: Q‐statistics, I².

No. of studies: 4. No. of treatments: 5. No. of pair‐wise comparisons: 4. No. of designs: 4.

Heterogeneity/inconsistency: Q = 0, df = 0, P = not available; I² = not available, Tau² = not available.

Treatment effects + 95% CIs (risk ratios, random‐effects model).

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 20

Exemplary network meta‐analysis forest plot for the outcome serious adverse events (MEC) (random‐effects model).

Ondansetron was used as exemplary reference treatment. Ranking of treatments is ordered by P score (descending).

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 21

Exemplary ranking plot representing simultaneously the efficacy (x‐axis, CR during overall phase) and the acceptability (y‐axis, SAEs) of all antiemetic regimens for patients receiving moderately emetogenic chemotherapy.

Only antiemetic regimens for which data for both endpoints (CR during the overall phase and SAEs) were available are represented in the ranking plot.

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Figure 22

League table with network estimates (RR with 95% CIs) of all treatment combinations for efficacy (CR during the overall phase) and acceptability (SAEs) (MEC).

Treatments are presented in alphabetical order. For efficacy, RRs > 1 favour the first treatment in alphabetical order. For safety, RRs < 1 favour the first treatment in alphabetical order.

n.a.: no data were available for this comparison.

Statistically significant results are marked bold.

A list of treatment abbreviations is provided in Table 1; all treatments included a corticosteroid.

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Summary of findings 1. Summary of findings: complete control of vomiting during the overall phase (HEC) when compared to treatment with aprepitant + granisetron

Efficacy
Antiemetics for adults for prevention of nausea and vomiting caused by highly emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by highly emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: aprepitant (NK₁) combined with granisetron (5‐HT₃) + corticosteroid Outcome: complete control of vomiting during the overall phase (0 to 120 h of treatment with chemotherapy) RR < 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)^a	*Illustrative comparative risks (95% CI)**		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with aprepitant + granisetron	Corresponding risk with the intervention

fosnetupitant + palonosetron	704 of 1000	810 of 1000 (683 to 944)	RR 1.15 (0.97 to 1.37)	21,642 (39)	⊕⊕⊕⊝ moderate^b	Fosnetupitant + palonosetron probably increases complete response in the overall phase when compared with aprepitant + granisetron
aprepitant + palonosetron	704 of 1000	753 of 1000 (690 to 831)	RR 1.07 (0.98 to 1.18)	21,642 (39)	⊕⊕⊝⊝ low^b,c	Aprepitant + palonosetron may result in a slight increase in complete response in the overall phase when compared with aprepitant + granisetron
aprepitant + ramosetron	704 of 1000	753 of 1000 (669 to 852)	RR 1.07 (0.95 to 1.21)	21,642 (39)	⊕⊕⊝⊝ low^b,c	Aprepitant + ramosetron may result in a slight increase in complete response in the overall phase when compared with aprepitant + granisetron
fosaprepitant + palonosetron	704 of 1000	746 of 1000 (676 to 838)	RR 1.06 (0.96 to 1.19)	21,642 (39)	⊕⊕⊝⊝ low^b,c	Fosaprepitant + palonosetron may result in a slight increase in complete response in the overall phase when compared with aprepitant + granisetron
netupitant + palonosetron	704 of 1000	704 of 1000 (655 to 760)	RR 1.00 (0.93 to 1.08)	21,642 (39)	⊕⊕⊕⊕ high	Netupitant + palonosetron has little to no impact on complete response in the overall phase when compared with aprepitant + granisetron
fosaprepitant + granisetron	704 of 1000	697 of 1000 (655 to 746)	RR 0.99 (0.93 to 1.06)	21,642 (39)	⊕⊕⊕⊕ high	Fosaprepitant + granisetron has little to no impact on complete response in the overall phase when compared with aprepitant + granisetron
aprepitant + ondansetron	704 of 1000	676 of 1000 (620 to 739)	RR 0.96 (0.88 to 1.05)	21,642 (39)	⊕⊕⊝⊝ low^b,c	Aprepitant + ondansetron may result in a slight decrease in complete response in the overall phase when compared with aprepitant + granisetron
fosaprepitant + ondansetron	704 of 1000	662 of 1000 (598 to 732)	RR 0.94 (0.85 to 1.04)	21,642 (39)	⊕⊕⊝⊝ low^b,c	Fosaprepitant + ondansetron may result in a slight decrease in complete response in the overall phase when compared with aprepitant + granisetron
casopitant + ondansetron	704 of 1000	634 of 1000 (556 to 725)	RR 0.90 (0.79 to 1.03)	21,642 (39)	⊕⊕⊝⊝ low^b,c	Aprepitant + ondansetron may decrease complete response in the overall phase when compared with aprepitant + granisetron
rolapitant + granisetron	704 of 1000	627 of 1000 (549 to 711)	RR 0.89 (0.78 to 1.01)	21,642 (39)	⊕⊕⊕⊝ moderate^b	Rolapitant + granisetron probably decreases complete response in the overall phase when compared with aprepitant + granisetron
rolapitant + ondansetron	704 of 1000	598 of 1000 (458 to 788)	RR 0.85 (0.65 to 1.12)	21,642 (39)	⊕⊕⊝⊝ low^c,d	Rolapitant + ondansetron may decrease complete response in the overall phase when compared with aprepitant + granisetron
Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 1312 of 1863 (70.4%) participants treated with aprepitant + granisetron achieved complete response during the overall phase (aprepitant + granisetron was used in 7 studies reporting the outcome). The corresponding risk* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aEither dexamethasone or methylprednisolone was used in all treatment regimens. ^bDowngraded once for serious imprecision because 95% CIs cross unity. ^cDowngraded once for serious study limitations due to high risk of bias. ^dDowngraded once for serious imprecision due to wide confidence intervals.

Summary of findings 1. Summary of findings: complete control of vomiting during the overall phase (HEC) when compared to treatment with aprepitant + granisetron

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Summary of findings 2. Summary of findings: serious adverse events (HEC) when compared to treatment with aprepitant + granisetron

Safety
Antiemetics for adults for prevention of nausea and vomiting caused by highly emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by highly emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: aprepitant (NK₁) combined with granisetron (5‐HT₃) + corticosteroid Outcome: serious adverse events RR < 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)^a	*Illustrative comparative risks (95% CI)**		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with aprepitant + granisetron	Corresponding risk with the intervention	Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
aprepitant + ondansetron	35 of 1000	8 of 1000 (1 to 40)	RR 0.22 (0.04 to 1.14)	16,065 (23)	⊕⊝⊝⊝ very low^b,c,d	Evidence is very uncertain about the effect of aprepitant + ondansetron on risk of serious adverse events when compared to aprepitant + granisetron
fosaprepitant + ondansetron	35 of 1000	8 of 1000 (2 to 37)	RR 0.23 (0.05 to 1.07)	16,065 (23)	⊕⊕⊝⊝ low^b,c	Fosaprepitant + ondansetron may decrease the risk of serious adverse events slightly when compared to aprepitant + granisetron
casopitant + ondansetron	35 of 1000	8 of 1000 (1 to 49)	RR 0.24 (0.04 to 1.39)	16,065 (23)	⊕⊕⊝⊝ low^b,c	Casopitant + ondansetron may decrease the risk of serious adverse events slightly when compared to aprepitant + granisetron
netupitant + palonosetron	35 of 1000	9 of 1000 (2 to 55)	RR 0.27 (0.05 to 1.58)	16,065 (23)	⊕⊕⊝⊝ low^b,c	Netupitant + palonosetron may decrease the risk of serious adverse events slightly when compared to aprepitant + granisetron
aprepitant + ramosetron	35 of 1000	11 of 1000 (2 to 67)	RR 0.31 (0.05 to 1.90)	16,065 (23)	⊕⊝⊝⊝ very low^b,c,d	Evidence is very uncertain about the effect of aprepitant plus ramosetron on risk of serious adverse events when compared to aprepitant + granisetron
fosaprepitant + palonosetron	35 of 1000	12 of 1000 (1 to 103)	RR 0.35 (0.04 to 2.95)	16,065 (23)	⊕⊝⊝⊝ very low^b,e	Evidence is very uncertain about the effect of fosaprepitant + palonosetron on risk of serious adverse events when compared to aprepitant + granisetron
fosnetupitant + palonosetron	35 of 1000	13 of 1000 (2 to 76)	RR 0.36 (0.06 to 2.16)	16,065 (23)	⊕⊝⊝⊝ very low^b,e	Evidence is very uncertain about the effect of fosnetupitant + palonosetron on risk of serious adverse events when compared to aprepitant + granisetron
fosaprepitant + granisetron	35 of 1000	13 of 1000 (3 to 53)	RR 0.37 (0.09 to 1.50)	16,065 (23)	⊕⊕⊝⊝ low^b,c	Fosaprepitant + granisetron may decrease the risk of serious adverse events slightly when compared to aprepitant + granisetron
aprepitant + palonosetron	35 of 1000	17 of 1000 (2 to 167)	RR 0.48 (0.05 to 4.78)	16,065 (23)	⊕⊝⊝⊝ very low^b,d,e	Evidence is very uncertain about the effect of aprepitant + palonosetron on risk of serious adverse events when compared to aprepitant + granisetron
rolapitant + granisetron	35 of 1000	20 of 1000 (7 to 60)	RR 0.57 (0.19 to 1.70)	16,065 (23)	⊕⊕⊝⊝ low^b,c	Rolapitant + granisetron may decrease the risk of serious adverse events slightly when compared to aprepitant + granisetron
Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 20 of 573 (3.5%) participants treated with aprepitant + granisetron experienced at least 1 SAE (aprepitant + granisetron was used in 2 studies reporting the outcome, with follow‐up of up to 29 days). The corresponding risk* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aEither dexamethasone or methylprednisolone was used in all treatment regimens. ^bDowngraded once for moderate inconsistency. ^cDowngraded once for serious imprecision because 95% CIs cross unity and confidence intervals are wide. ^dDowngraded once for serious study limitations due to high risk of bias. ^eDowngraded twice for very serious imprecision because 95% CIs cross unity and confidence intervals are very wide, suggesting high possibility of harm.

Summary of findings 2. Summary of findings: serious adverse events (HEC) when compared to treatment with aprepitant + granisetron

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Summary of findings 3. Summary of findings: complete control of vomiting during the overall phase (MEC) when compared to treatment with granisetron

Efficacy
Antiemetics for adults for prevention of nausea and vomiting caused by moderately emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by moderately emetogenic chemotherapy Settings: inpatient and outpatient care Intervention neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid OR 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: granisetron (5‐HT₃) + corticosteroid Outcome: complete control of vomiting during the overall phase (0 to 120 h of treatment with chemotherapy) RR < 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)^a	*Illustrative comparative risks (95% CI)**		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with granisetron	Corresponding risk with the intervention	Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
aprepitant + palonosetron	555 of 1000	716 of 1000 (555 to 921)	RR 1.29 (1.00 to 1.66)	7800 (22)	⊕⊕⊝⊝ low^b,c	Aprepitant + palonosetron may increase complete response in the overall phase when compared to granisetron
netupitant + palonosetron	555 of 1000	694 of 1000 (510 to 944)	RR 1.25 (0.92 to 1.70)	7800 (22)	⊕⊕⊝⊝ low^b,d	Netupitant + palonosetron may increase complete response in the overall phase when compared to granisetron
rolapitant + granisetron	555 of 1000	660 of 1000 (588 to 738)	RR 1.19 (1.06 to 1.33)	7800 (22)	⊕⊕⊕⊕ high	Rolapitant + granisetron results in an increase in complete response in the overall phase when compared to granisetron
palonosetron	555 of 1000	588 of 1000 (472 to 733)	RR 1.06 (0.85 to 1.32)	7800 (22)	⊕⊕⊝⊝ low^b,d	Palonosetron may or may not increase complete response in the overall phase when compared to granisetron
aprepitant + granisetron	555 of 1000	577 of 1000 (483 to 694)	RR 1.06 (0.85 to 1.32)	7800 (22)	⊕⊕⊝⊝ low^b,d	Aprepitant + palonosetron may or may not increase complete response in the overall phase when compared to granisetron
azasetron	555 of 1000	561 of 1000 (422 to 738)	RR 1.01 (0.76 to 1.33)	7800 (22)	⊕⊕⊝⊝ low^b,e	Azasetron may result in little to no difference in complete response in the overall phase when compared to granisetron
fosaprepitant + ondansetron	555 of 1000	500 of 1000 (366 to 677)	RR 0.90 (0.66 to 1.22)	7800 (22)	⊕⊕⊝⊝ low^b,d	Fosaprepitant + ondansetron may decrease complete response in the overall phase when compared to granisetron
aprepitant + ondansetron	555 of 1000	477 of 1000 (355 to 649)	RR 0.86 (0.64 to 1.17)	7800 (22)	⊕⊕⊝⊝ low^b,d	Aprepitant + ondansetron may decrease complete response in the overall phase when compared to granisetron
casopitant + ondansetron	555 of 1000	461 of 1000 (344 to 622)	RR 0.83 (0.62 to 1.12)	7800 (22)	⊕⊕⊝⊝ low^b,d	Casopitant + ondansetron may decrease complete response in the overall phase when compared to granisetron
ondansetron	555 of 1000	433 of 1000 (327 to 577)	RR 0.78 (0.59 to 1.04)	7800 (22)	⊕⊕⊝⊝ low^b,d	Ondansetron may decrease complete response in the overall phase when compared to granisetron
Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 623 of 1123 (55.5%) participants treated with granisetron achieved complete response during the overall phase (granisetron was used in 5 studies reporting the outcome). The corresponding risk* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aEither dexamethasone or methylprednisolone was used in all treatment regimens. ^bDowngraded once for serious study limitations due to high risk of bias. ^cDowngraded once for serious imprecision because 95% CIs included zero effect line. ^dDowngraded once for serious imprecision because 95% CIs cross unity. ^eDowngraded once for serious imprecision due to wide confidence intervals.

Summary of findings 3. Summary of findings: complete control of vomiting during the overall phase (MEC) when compared to treatment with granisetron

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Summary of findings 4. Summary of findings: serious adverse events (MEC) when compared to treatment with granisetron

Safety
Antiemetics for adults for prevention of nausea and vomiting caused by moderately emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by moderately emetogenic chemotherapy Settings: inpatient and outpatient care Intervention neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid OR 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: granisetron (5‐HT₃) + corticosteroid Outcome: serious adverse events RR < 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)^a	*Illustrative comparative risks (95% CI)**		Risk ratio (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk with granisetron	Corresponding risk with the intervention	Risk ratio (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
rolapitant + granisetron	153 of 1000	176 of 1000 (135 to 230)	RR 1.15 (0.88 to 1.50)	1344 (1)	⊕⊕⊝⊝ low^b	Rolapitant + granisetron may increase the risk of serious adverse events slightly when compared to granisetron
Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 103 of 674 (10.3%) participants treated with granisetron experienced at least 1 SAE (granisetron was used in 1 study reporting the outcome; time frame for reporting safety data was not described). The corresponding risk* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aEither dexamethasone or methylprednisolone was used in all treatment regimens. ^bDowngraded twice for very serious imprecision because 95% CIs cross unity, confidence intervals are wide, and information size is small.

Summary of findings 4. Summary of findings: serious adverse events (MEC) when compared to treatment with granisetron

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Table 1. Overview of treatment regimens and treatment abbreviations

Drug combinations	Treatment regimen^a	Abbreviation	Used in HEC^b setting	Used in MEC^c setting
NK₁ receptor antagonists and 5‐HT₃ receptor antagonists + corticosteroid	aprepitant with granisetron	apre_grani	X	X
	aprepitant with ondansetron	apre_ondan	X	X
	aprepitant with palonosetron	apre_palo	X	X
	aprepitant with ramosetron	apre_ramo	X
	aprepitant with tropisetron	apre_tropi	X
	casopitant with ondansetron	caso_ondan	X	X
	fosaprepitant with granisetron	fosa_grani	X	X
	ezlopitant with granisetron	ezlo_grani	X
	fosaprepitant with ondansetron	fosa_ondan	X	X
	fosaprepitant with palonosetron	fosa_palo	X
	fosnetupitant with palonosetron	fosnetu_palo	X
	netupitant with palonosetron	netu_palo	X	X
	rolapitant with granisetron	rola_grani	X	X
	rolapitant with ondansetron	rola_ondan	X
5‐HT₃ receptor antagonists+ corticosteroid	azasetron	aza	X	X
	dolasetron	dola		X
	granisetron	grani	X	X
	ondansetron	ondan	X	X
	palonosetron	palo	X	X
	ramosetron	ramo	X	X
	tropisetron	tropi	X	X
^aAll treatment regimens also include a corticosteroid. ^bHighly emetogenic chemotherapy. ^cModerately emetogenic chemotherapy.

Table 1. Overview of treatment regimens and treatment abbreviations

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Table 2. Overview of outcomes

Outcome	Definition	Unit of outcome measurement	Referred to as/abbreviation	Prioritisation
Complete control of nausea	No nausea and no significant nausea, as defined on a study level^a Assessed for: acute phase: first 24 h of treatment with chemotherapy delayed phase: after 24 to 120 h of treatment with chemotherapy overall: 0 to 120 h of treatment with chemotherapy	Binary; participants with complete control of nausea	No nausea	Overall phase prioritised for GRADE assessment
Complete control of vomiting	No vomiting and no use of rescue medications Assessed for: acute phase: first 24 h of treatment with chemotherapy delayed phase: after 24 to 120 h of treatment with chemotherapy overall: 0 to 120 h of treatment with chemotherapy	Binary; participants with complete control of vomiting	Complete response (CR)	Delayed and overall phases prioritised for GRADE assessment Overall phase chosen as most important efficacy outcome
Quality of life	No impairment in quality of life during active study period	Binary; participants with no impairment in quality of life	QoL	Prioritised for GRADE assessment
On‐study mortality	Deaths occurring from randomisation up to 30 days after the active study period	Binary; participants who died	OSM	Prioritised for GRADE assessment
Adverse events	As defined on a study level; during active study period	Binary; participants with at least 1 event	AEs	‐
Serious adverse events	As defined on a study level; during active study period	Binary; participants with at least 1 event	SAEs	Prioritised for GRADE assessment Chosen as most crucial safety outcome
Neutropenia	As defined on a study level; during active study period	Binary; participants with at least 1 event	‐	‐
Febrile neutropenia	As defined on a study level; during active study period	Binary; participants with at least 1 event	‐	‐
Infection	As defined on a study level; during active study period	Binary; participants with at least 1 event	‐	‐
Local reaction at infusion site	As defined on a study level; during active study period	Binary; participants with at least 1 event	‐	Prioritised for GRADE assessment
Hiccup	As defined on a study level; during active study period	Binary; participants with at least 1 event	‐	‐
^aStandardised tools are typically used to assess degree of nausea and vomiting (Wood 2011). No nausea and no significant nausea were defined on a study level and typically refer to pre‐defined cutoffs, e.g. in Rapoport 2015 (a) or Schwartzberg 2015, nausea was assessed on a visual analogue scale (VAS; 0 to 100 mm; 0 = no nausea, 100 = severe nausea; < 5 mm = no nausea, < 25 mm = no significant nausea). No significant nausea is typically more subjective because of the wider range on the scale and is therefore less objective, especially in an open‐label study design. To increase comparability of studies and minimise biased results, we were therefore interested in patients with no nausea.

Table 2. Overview of outcomes

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Table 3. Summary of findings: complete control of nausea during the overall phase (HEC) when compared to treatment with aprepitant + granisetron

Antiemetics for adults for prevention of nausea and vomiting caused by highly emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by highly emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: aprepitant (NK₁) combined with granisetron (5‐HT₃) + corticosteroid Outcome: complete control of nausea during the overall phase (0 to 120 h of treatment with chemotherapy) RR < 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)^a	*Illustrative comparative risks (95% CI)**		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with aprepitant + granisetron	Corresponding risk with the intervention	Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
fosaprepitant + palonosetron	896 of 1000	NE of 1000 (NE to NE)	RR 1.46 (1.12 to 1.90)	14,588 (22)	⊕⊕⊕⊝ moderate^b	Fosaprepitant + palonosetron probably results in a large increase in complete control of nausea in the overall phase when compared with aprepitant + granisetron
fosnetupitant + palonosetron	896 of 1000	NE of 1000 (851 to NE)	RR 1.21 (0.95 to 1.56)	14,588 (22)	⊕⊕⊕⊝ moderate^c	Fosnetupitant + palonosetron probably increases complete control of nausea in the overall phase when compared with aprepitant + granisetron
ezlopitant + granisetron	896 of 1000	NE of 1000 (554 to NE)	RR 1.31 (0.62 to 2.80)	14,588 (22)	⊕⊕⊝⊝ low^d	Ezlopitant + granisetron may increase complete control of nausea in the overall phase when compared with aprepitant + granisetron
rolapitant + granisetron	896 of 1000	NE of 1000 (860 to NE)	RR 1.12 (0.96 to 1.31)	14,588 (22)	⊕⊕⊕⊝ moderate^c	Rolapitant + granisetron probably increases complete control of nausea in the overall phase when compared with aprepitant + granisetron
fosaprepitant + granisetron	896 of 1000	914 of 1000 (780 to NE)	RR 1.02 (0.87 to 1.20)	14,588 (22)	⊕⊕⊕⊕ high	Fosaprepitant + granisetron has little to no effect on complete control of nausea in the overall phase when compared with aprepitant + granisetron
rolapitant + ondansetron	896 of 1000	860 of 1000 (591 to NE)	RR 0.96 (0.66 to 1.39)	14,588 (22)	⊕⊕⊕⊝ moderate^c	Rolapitant + ondansetron probably decreases complete control of nausea slightly in the overall phase when compared with aprepitant + granisetron
netupitant + palonosetron	896 of 1000	860 of 1000 (753 to 986)	RR 0.96 (0.84 to 1.10)	14,588 (22)	⊕⊕⊕⊕ high	Netupitant + palonosetron has little to no effect on complete control of nausea in the overall phase when compared with aprepitant + granisetron
fosaprepitant + ondansetron	896 of 1000	806 of 1000 (645 to NE)	RR 0.90 (0.72 to 1.13)	14,588 (22)	⊕⊕⊕⊝ moderate^c	Fosaprepitant + ondansetron probably decreases complete control of nausea slightly in the overall phase when compared with aprepitant + granisetron
aprepitant + ondansetron	896 of 1000	780 of 1000 (609 to NE)	RR 0.87 (0.68 to 1.10)	14,588 (22)	⊕⊕⊕⊝ moderate^c	Aprepitant + ondansetron probably decreases complete control of nausea in the overall phase when compared with aprepitant + granisetron
casopitant + ondansetron	896 of 1000	717 of 1000 (538 to 950)	RR 0.80 (0.60 to 1.06)	14,588 (22)	⊕⊕⊕⊝ moderate^c	Casopitant + ondansetron probably decreases complete control of nausea in the overall phase when compared with aprepitant + granisetron
Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 412 of 460 (89.6%) participants treated with aprepitant + granisetron experienced no nausea during the overall phase (aprepitant + granisetron was used in 5 studies reporting the outcome). The corresponding risk* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; NE: not estimable; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aEither dexamethasone or methylprednisolone was used in all treatment regimens. ^bDowngraded once for serious study limitations due to high risk of bias. ^cDowngraded once for serious imprecision because 95% CIs cross unity and confidence intervals are wide. ^dDowngraded twice for very serious imprecision because wide confidence intervals suggest both a potentially substantial harm and benefit for the intervention.

Table 3. Summary of findings: complete control of nausea during the overall phase (HEC) when compared to treatment with aprepitant + granisetron

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Table 4. Summary of findings: complete control of vomiting during the delayed phase (HEC) when compared to treatment with aprepitant + granisetron

Interventions (corticosteroids included in all regimens)^a	*Illustrative comparative risks (95% CI)**		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Antiemetics for adults for prevention of nausea and vomiting caused by highly emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by highly emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: aprepitant (NK₁) combined with granisetron (5‐HT₃) + corticosteroid Outcome: complete control of vomiting during the delayed phase (24 to 120 h of treatment with chemotherapy) RR > 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
	Assumed risk aprepitant + granisetron	Corresponding risk with the intervention	Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
fosnetupitant + palonosetron	694 of 1000	784 of 1000 (632 to 972)	RR 1.13 (0.91 to 1.40)	21,563 (37)	⊕⊕⊝⊝ low^b,c	Fosnetupitant + palonosetron may increase complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
fosaprepitant + palonosetron	694 of 1000	736 of 1000 (632 to 854)	RR 1.06 (0.91 to 1.23)	21,563 (37)	⊕⊝⊝⊝ very low^b,c,d	Evidence is very uncertain about the effect of fosaprepitant + palonosetron on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
aprepitant + palonosetron	694 of 1000	722 of 1000 (652 to 798)	RR 1.04 (0.94 to 1.15)	21,563 (37)	⊕⊝⊝⊝ very low^b,c,d	Evidence is very uncertain about the effect of aprepitant + palonosetron on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
aprepitant + ramosetron	694 of 1000	722 of 1000 (625 to 1.21)	RR 1.04 (0.90 to 1.21)	21,563 (37)	⊕⊝⊝⊝ very low^b,c,d	Evidence is very uncertain about the effect of aprepitant + ramosetron on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
fosaprepitant + granisetron	694 of 1000	701 of 1000 (632 to 770)	RR 1.01 (0.91 to 1.11)	21,563 (37)	⊕⊕⊕⊝ moderate^b	Fosaprepitant + granisetron probably has little to no effect on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
netupitant + palonosetron	694 of 1000	687 of 1000 (618 to 763)	RR 0.99 (0.89 to 1.10)	21,563 (37)	⊕⊕⊕⊝ moderate^b	Netupitant + palonosetron probably has little to no effect on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
aprepitant + ondansetron	694 of 1000	645 of 1000 (576 to 722)	RR 0.93 (0.83 to 1.04)	21,563 (37)	⊕⊝⊝⊝ very low^b,c,d	Evidence is very uncertain about the effect of aprepitant + ondansetron on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
rolapitant + granisetron	694 of 1000	632 of 1000 (541 to 736)	RR 0.91 (0.78 to 1.06)	21,563 (37)	⊕⊕⊝⊝ low^b,c	Rolapitant + granisetron may decrease complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
fosaprepitant + ondansetron	694 of 1000	632 of 1000 (548 to 722)	RR 0.91 (0.79 to 1.04)	21,563 (37)	⊕⊕⊝⊝ low^b,c	Fosaprepitant + ondansetron may decrease complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
casopitant + ondansetron	694 of 1000	618 of 1000 (507 to 756)	RR 0.89 (0.73 to 1.09)	21,563 (37)	⊕⊕⊝⊝ low^b,c	Casopitant + ondansetron may decrease complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
rolapitant + ondansetron	694 of 1000	583 of 1000 (437 to 784)	RR 0.84 (0.63 to 1.13)	21,563 (37)	⊕⊝⊝⊝ very low^b,c,d	Evidence is very uncertain about the effect of rolapitant + ondansetron on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 1537 of 2215 (69.4%) participants treated with aprepitant + granisetron achieved complete response during the delayed phase (aprepitant + granisetron was used in 10 studies reporting the outcome). The corresponding risk* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aEither dexamethasone or methylprednisolone was used in all treatment regimens. ^bDowngraded once for moderate inconsistency. ^cDowngraded once for serious imprecision because 95% CIs cross unity and confidence intervals are wide. ^dDowngraded once for serious study limitations due to high risk of bias.

Table 4. Summary of findings: complete control of vomiting during the delayed phase (HEC) when compared to treatment with aprepitant + granisetron

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Table 5. Summary of findings: quality of life (HEC) when compared to treatment with aprepitant + granisetron

Antiemetics for adults for prevention of nausea and vomiting caused by highly emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by highly emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: aprepitant (NK₁) combined with granisetron (5‐HT₃) + corticosteroid Outcome: no impairment in quality of life RR <1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)^a	*Illustrative comparative risks (95% CI)**		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with aprepitant + granisetron	Corresponding risk with the intervention	Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
rolapitant + ondansetron	714 of 1000	893 of 1000 (486 to 1649)	RR 1.25 (0.68 to 2.31)	7894 (14)	⊕⊝⊝⊝ very low^b,c	Evidence is uncertain about the effect of rolapitant + ondansetron on quality of life when compared to aprepitant + granisetron
netupitant + palonosetron	714 of 1000	764 of 1000 (585 to 1007)	RR 1.07 (0.82 to 1.41)	7894 (14)	⊕⊝⊝⊝ very low^b,d	Evidence is uncertain about the effect of netupitant + palonosetron on quality of life when compared to aprepitant + granisetron
casopitant + ondansetron	714 of 1000	743 of 1000 (421 to 1307)	RR 1.04 (0.59 to 1.83)	7894 (14)	⊕⊝⊝⊝ very low^b,c	Evidence is uncertain about the effect of casopitant + ondansetron on quality of life when compared to aprepitant + granisetron
rolapitant + granisetron	714 of 1000	693 of 1000 (521 to 921)	RR 0.97 (0.73 to 1.29)	7894 (14)	⊕⊝⊝⊝ very low^b,d	Evidence is uncertain about the effect of rolapitant + granisetron on quality of life when compared to aprepitant + granisetron
aprepitant + ondansetron	714 of 1000	657 of 1000 (393 to 1100)	RR 0.92 (0.55 to 1.54)	7894 (14)	⊕⊝⊝⊝ very low^b,c,e	Evidence is uncertain about the effect of aprepitant + ondansetron on quality of life when compared to aprepitant + granisetron
Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 569 of 797 participants treated with aprepitant + granisetron experienced no impact on QoL (aprepitant + granisetron was used in 3 studies reporting the outcome, follow‐up on Day 6). The corresponding risk* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aEither dexamethasone or methylprednisolone was used in all treatment regimens. ^bDowngraded twice for high inconsistency within the network. ^cDowngraded twice for very serious imprecision because 95% CIs cross unity and confidence intervals are very wide, suggesting high benefit for the comparator. ^dDowngraded once for serious imprecision because 95% CIs cross unity and confidence intervals are wide. ^eDowngraded once for serious study limitations due to high risk of bias.

Table 5. Summary of findings: quality of life (HEC) when compared to treatment with aprepitant + granisetron

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Table 6. Summary of findings: on‐study mortality (HEC) when compared to treatment with aprepitant + granisetron

Antiemetics for adults for prevention of nausea and vomiting caused by highly emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by highly emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: aprepitant (NK₁) combined with granisetron (5‐HT₃) + corticosteroid Outcome: on‐study mortality RR < 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)^a	*Illustrative comparative risks (95% CI)**		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with aprepitant + granisetron	Corresponding risk with the intervention	Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
netupitant + palonosetron	8 of 1000	2 of 1000 (0 to 19)	RR 0.29 (0.04 to 2.34)	8030 (16)	⊕⊕⊝⊝ low^b	Netupitant + palonosetron may have little to no effect on on‐study mortality when compared with aprepitant + granisetron
aprepitant + ondansetron	8 of 1000	5 of 1000 (1 to 35)	RR 0.57 (0.07 to 4.39)	8030 (16)	⊕⊕⊝⊝ low^b	Aprepitant + ondansetron may have little to no effect on on‐study mortality when compared with aprepitant + granisetron
casopitant + ondansetron	8 of 1000	5 of 1000 (1 to 44)	RR 0.65 (0.08 to 5.53)	8030 (16)	⊕⊕⊝⊝ low^b	Casopitant + ondansetron may have little to no effect on on‐study mortality when compared with aprepitant + granisetron
rolapitant + granisetron	8 of 1000	5 of 1000 (1 to 33)	RR 0.66 (0.11 to 4.09)	8030 (16)	⊕⊕⊝⊝ low^b	Rolapitant + granisetron may have little to no effect on on‐study mortality when compared with aprepitant + granisetron
rolapitant + ondansetron	8 of 1000	12 of 1000 (1 to 216)	RR 1.56 (0.09 to 26.97)	8030 (16)	⊕⊕⊝⊝ low^b	Rolapitant + ondansetron may have little to no effect on on‐study mortality when compared with aprepitant + granisetron
Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 7 of 844 (0.08%) participants treated with aprepitant + granisetron died during the study (aprepitant + granisetron was used in 4 studies reporting the outcome, with follow‐up of up to 29 days). The corresponding risk* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aEither dexamethasone or methylprednisolone was used in all treatment regimens. ^bDowngraded twice for very serious imprecision due to few events and very wide confidence intervals, suggesting potential benefit and harm for the comparator.

Table 6. Summary of findings: on‐study mortality (HEC) when compared to treatment with aprepitant + granisetron

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Table 7. Summary of findings: complete control of nausea during the overall phase (MEC) when compared to treatment with granisetron

Antiemetics for adults for prevention of nausea and vomiting caused by moderately emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by moderately emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid OR 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: granisetron (5‐HT₃) + corticosteroid Outcome: complete control of nausea during the overall phase (0 to 120 h of treatment with chemotherapy) RR < 1 indicates an advantage for the intervention. Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)^a	*Illustrative comparative risks (95% CI)**		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with granisetron	Corresponding risk with the intervention

aprepitant + granisetron	419 of 1000	570 of 1000 (365 to 897)	RR 1.36 (0.87 to 2.14)	1423 (2)	⊕⊕⊝⊝ low^b	Aprepitant + granisetron may increase complete control of nausea in the overall phase when compared with granisetron
rolapitant + granisetron	419 of 1000	453 of 1000 (402 to 511)	RR 1.08 (0.96 to 1.22)	1423 (2)	⊕⊕⊝⊝ low^c	Rolapitant + granisetron may increase complete control of nausea in the overall phase slightly when compared with granisetron
Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 298 of 712 (41.9%) participants treated with granisetron experienced no nausea during the overall phase (granisetron was used in 2 studies reporting the outcome). The corresponding risk* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aEither dexamethasone or methylprednisolone was used in all treatment regimens. ^bDowngraded twice for very serious imprecision because 95% CIs cross unity, information size is small, and confidence intervals are very wide, suggesting benefit and harm for the comparator. ^cDowngraded twice for very serious imprecision because 95% CIs cross unity, confidence intervals are wide, and information size is small.

Table 7. Summary of findings: complete control of nausea during the overall phase (MEC) when compared to treatment with granisetron

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Table 8. Summary of findings: complete control of vomiting during the delayed phase (MEC) when compared to treatment with granisetron

Interventions (corticosteroids included in all regimens)^a	*Illustrative comparative risks (95% CI)**		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
Antiemetics for adults for prevention of nausea and vomiting caused by moderately emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by moderately emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid OR 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: granisetron (5‐HT₃) + corticosteroid Outcome: complete control of vomiting during the delayed phase (24 to 120 h of treatment with chemotherapy) RR > 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
	Assumed risk with granisetron	Corresponding risk with the intervention

aprepitant + palonosetron	641 of 1000	823 of 1000 (712 to 962)	RR 1.29 (1.11 to 1.50)	8421 (21)	⊕⊕⊕⊝ moderate^b	Aprepitant + palonosetron likely results in a large increase of complete control of vomiting during the delayed phase when compared to granisetron
rolapitant + granisetron	641 of 1000	744 of 1000 (679 to 814)	RR 1.16 (1.06 to 1.27)	8421 (21)	⊕⊕⊕⊕ high	Rolapitant + granisetron increases complete control of vomiting during the delayed phase when compared to granisetron
palonosetron	641 of 1000	679 of 1000 (622 to 750)	RR 1.06 (0.97 to 1.17)	8421 (21)	⊕⊕⊝⊝ low^b,c	Palonosetron may increase complete control of vomiting during the delayed phase slightly when compared to granisetron, but the evidence is uncertain
aprepitant + granisetron	641 of 1000	667 of 1000 (564 to 788)	RR 1.04 (0.88 to 1.23)	8421 (21)	⊕⊕⊝⊝ low^b,c	Palonosetron may or may not increase complete control of vomiting during the delayed phase slightly when compared to granisetron, but the evidence is uncertain
azasetron	641 of 1000	647 of 1000 (494 to 846)	RR 1.01 (0.77 to 1.32)	8421 (21)	⊕⊕⊝⊝ low^b,d	Azasetron may result in little to no difference in complete control of vomiting during the delayed phase slightly when compared to granisetron, but the evidence is uncertain
fosaprepitant + ondansetron	641 of 1000	596 of 1000 (551 to 718)	RR 0.98 (0.86 to 1.12)	8421 (21)	⊕⊕⊕⊝ moderate^b	Fosaprepitant + ondansetron probably results in little to no difference in complete control of vomiting during the delayed phase slightly when compared to granisetron
aprepitant + ondansetron	641 of 1000	596 of 1000 (526 to 679)	RR 0.93 (0.82 to 1.06)	8421 (21)	⊕⊕⊝⊝ low^b,c	Aprepitant + ondansetron may decrease complete control of vomiting during the delayed phase slightly when compared to granisetron, but the evidence is uncertain
casopitant + ondansetron	641 of 1000	570 of 1000 (506 to 647)	RR 0.89 (0.79 to 1.01)	8421 (21)	⊕⊕⊝⊝ low^b,d	Casopitant + ondansetron may decrease complete control of vomiting during the delayed phase when compared to granisetron, but the evidence is uncertain
ondansetron	641 of 1000	551 of 1000 (493 to 609)	RR 0.86 (0.77 to 0.95)	8421 (21)	⊕⊕⊕⊝ moderate^b	Ondansetron probably decreases complete control of vomiting during the delayed phase when compared to granisetron
Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 953 of 1486 (64.1%) participants treated with granisetron achieved complete response during the delayed phase (granisetron was used in 7 studies reporting the outcome). The corresponding risk* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aEither dexamethasone or methylprednisolone was used in all treatment regimens. ^bDowngraded once for serious study limitations due to high risk of bias. ^cDowngraded once for serious imprecision because 95% CIs cross unity and include potential advantages and disadvantages. ^dDowngraded once for serious imprecision due to wide confidence intervals.

Table 8. Summary of findings: complete control of vomiting during the delayed phase (MEC) when compared to treatment with granisetron

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Table 9. Summary of findings: quality of life (MEC) when compared to treatment with granisetron

Antiemetics for adults for prevention of nausea and vomiting caused by moderately emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by moderately emetogenic chemotherapy Settings: inpatient and outpatient care Intervention neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid OR 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: granisetron (5‐HT₃) + corticosteroid Outcome: no impairment in quality of life RR < 1 indicates an advantage for the intervention. Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network.
Interventions (corticosteroids included in all regimens)^a	*Illustrative comparative risks (95% CI)**		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with granisetron	Corresponding risk with the intervention
rolapitant + granisetron	674 of 1000	620 of 1000 (580 to 667)	RR 0.92 (0.86 to 0.99)	1212 (1)	⊕⊕⊕⊝ moderate^b	Rolapitant + granisetron probably decreases quality of life slightly when compared to granisetron
Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 409 of 607 (67.4%) participants treated with granisetron experienced no impact on QoL (granisetron was used in 1 study reporting the outcome, follow‐up on Day 6). The corresponding risk* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aEither dexamethasone or methylprednisolone was used in all treatment regimens. ^bDowngraded once for serious imprecision for the small sample size.

Table 9. Summary of findings: quality of life (MEC) when compared to treatment with granisetron

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Table 10. Summary of findings: on‐study mortality (MEC) when compared to treatment with granisetron

Antiemetics for adults for prevention of nausea and vomiting caused by moderately emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by moderately emetogenic chemotherapy Settings: inpatient and outpatient care Intervention neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid OR 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: granisetron (5‐HT₃) + corticosteroid Outcome: on‐study mortality RR < 1 indicates an advantage for the intervention. Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network.
Interventions (corticosteroids included in all regimens)^a	*Illustrative comparative risks (95% CI)**		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with granisetron	Corresponding risk with the intervention
rolapitant + granisetron	6 of 1000	18 of 1000 (6 to 56)	RR 3.00 (0.97 to 9.27)	1369 (1)	⊕⊕⊝⊝ low^b	Rolapitant + granisetron may make little to no difference in on‐study mortality when compared to granisetron
Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 4 of 685 (0.6%) participants treated with granisetron died during the study (granisetron was used in 1 study reporting the outcome, time frame for reporting safety data was not described). The corresponding risk* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aEither dexamethasone or methylprednisolone was used in all treatment regimens. ^bDowngraded twice for very serious imprecision because 95% CIs cross unity and because of the small information size.

Table 10. Summary of findings: on‐study mortality (MEC) when compared to treatment with granisetron

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