dos Santos, L.V., Souza, F.H., Brunetto, A.T., Sasse, A.D., & da Silveira Nogueira Lima, J.P. (2012). Neurokinin-1 receptor antagonists for chemotherapy-induced nausea and vomiting: A systematic review. Journal of the National Cancer Institute, 104(17), 1280–1292.

To evaluate the overall effectiveness and safety of neurokinin 1 (NK1) receptor antagonists (RAs) in the prevention of chemotherapy-induced nausea and vomiting (CINV) when compared to standard antiemetic regimens including a 5-HT₃ RA plus dexamethasone

Databases searched were MEDLINE, Embase, Cochrane Central Register of Controlled Trials (Central), and Latin American and Carribean Health Sciences Literature (LILACS).

Search keywords were neurokinin, aprepitant, casopitant, ezlopitant, netupitant, vestipitant, chemotherapy-induced nausea and vomiting, nausea in cancer patients, vomiting in cancer patients, and randomized trials.

Studies were included in the review if they

• Were randomized controlled trials (RCTs) that addressed the addition of an NK1 RAs to standard antiemetic therapy (dexamethasone plus 5-HT₃ RA) for the prevention of CINV.
• Provided an adequate description of outcomes that could be pooled in the meta-analysis.
• Used adequate antiemetic therapy in the control arm.

No specific exclusion criteria were identified.

A total of 4,034 references were retrieved.

Two reviewers assessed the quality of each study. Items from Delphi list and Jadad score were utilized for data extraction; however, the authors did not describe if any specific scoring system was used for quality assessment.

• The final number of studies included was 17.
• The sample range across all studies was 36–1,933.
• The total number of patients included in the review was 8,740. Data from 8,173 patients in 13 studies were used for analysis about complete response (CR), which is defined as no vomiting, no retching, and no use of rescue medication. Data from 8,376 patients from 15 studies were used for acute and delayed phase analysis.
• All patients were diagnosed with cancer and receiving either highly or moderately emetogenic chemotherapy.

All patients were in active antitumor treatment.

• The use of an NK1 RA increased the CR rate in the overall phase from 54% to 72% (overall response [OR] = 0.51, 95% confidence interval (CI) = 0.46–0.57, p < 0.001), in the acute phase (OR = 0.56, 95% CI = 0.48–0.65, p < 0.001), and in the delayed phase (OR = 0.48, 95% CI = 0.42–0.56, p < 0.001).
• The addition of an NK1 RA to standard antiemetic therapy improved CR rates in the overall phase for patients who received highly emetegenic chemotherapy (OR = 0.46, 95% CI = 0.40–0.53, p < 0.001) or moderately emetogenic chemotherapy (OR = 0.59, 95% CI = 0.51–0.67, p < 0.001).
• The addition of an NK1 RA increased CR rates in the overall phase independently depending on if ondansetron was used in the control arm beyond day 1 or not (ondansetron: OR = 0.64, 95% CI = 0.54–0.76, p < 0.001; no ondansetron: OR = 0.47, 95% CI = 0.41–0.53, p < 0.001). CR in the acute phase and delayed phase demonstrated a strong correlation (r = 0.91, p < 0.001).
• Three trials (n = 1,480) suggested a statistically significant increase (from 2% to 6%) in the risk of severe infection among patients receiving NK1 RAs (OR = 3.10. 95% CI = 1.69–5.67, p < 0.001).

The addition of an NK1 RA increased CINV control in the acute, delayed, and overall phases.

The use of an NK1 RA may be associated with a statistically significant increase in the risk of severe infection. A more comprehensive evaluation of the safety profile of NK1 RAs and additional appraisal of specific data from RCTs is needed.

• Subgroup analysis requires careful scrutinization. In this review, most patients in the moderately emetogenic chemotherapy group received an AC regimen, which is now considered highly emetogenic chemotherapy.
• Favorable ondansetron use for the delayed phase was suggested after comparing its effect with placebo control. However, current guidelines suggest the use of dexamethasone rather than ondansetron as a combination regimen for delayed CINV control. Comparison should have been between an NK1 RA plus dexamethasone versus NK1 plus ondansetron.
• Toxicity analysis was based on reports  of 3 studies (out of 17 studies included) which reported on the most prevalent adverse events. NK1 RA use did not increase the risk of febrile neutropenia or any other hematologic toxicity. OR findings are not clearly interpretable.

• This systematic review summarized the results from RCTs which investigated the effect of an NK1 RA for CINV control. Overall, the use of an NK1 RA improved the CR in acute, delayed, and overall phases.
• Further studies are warranted to determine whether adding an NK1 RA to standard antiemetics could improve CINV control in non-AC, moderately emetogenic chemotherapy as most NK1 RA RCTs were based on cases receiving highly emetogenic chemotherapy (including an AC regimen).
• Although further study is warranted, occurrence of infection with NK1 use requires special attention.