Adding an Antipsychotic Agent Reduces Nausea From Chemotherapy

For patients receiving highly emetogenic chemotherapy, adding the antipsychotic agent Zyprexa (olanzapine) was found to demonstrate a significant improvement in the prevention of nausea compared with a standard antiemetic regimen.

Zyprexa blocks multiple neurotransmitters, some of which may be involved in nausea and vomiting. This suggests that it might have clinically significant properties for the prevention of chemotherapy-induced nausea and vomiting (CINV). Known side effects of the agent with short-term use in its approved setting include mild sedation.

“We’ve long known the nausea and vomiting that come along with chemotherapy are a major problem and affect the quality of life of our patients,” said study author Steven Powell, M.D., an oncologist at Sanford Health in Sioux Falls, South Dakota, and a community co-chair of the study, in a statement. “The findings of this study, fortunately, provide physicians with a tool to better address the needs of those they are treating for cancer.”

The phase 3 trial enrolled 380 chemotherapy-naïve patients being treated with highly emetogenic chemotherapy (either cisplatin or cyclophosphamide-doxorubicin). They were randomized to two groups, with 190 patients given 10 mg of Zyprexa orally and 188 a matching placebo on days 1 through 4 of chemotherapy. All patients in both cohorts were treated with an antiemetic regimen of dexamethasone, aprepitant or fosaprepitant and a 5-HT3—receptor antagonist, as well.

The study’s primary endpoint of no nausea was assessed during three time periods: early assessment (0 to 24 hours), later assessment (25 to 120 hours) and overall (0 to 120 hours) after chemotherapy. Researchers were also interested in comparing complete response (no emesis and no use of rescue medication) in the two study arms over the three phases, as well as any toxicities related to Zyprexa.

Patients were asked to record any daily episodes of vomiting or retching, the use of rescue therapy, and daily levels of nausea from the first day of chemotherapy through day 5. A study nurse also contacted each patient on days 2 through 5 to ask about and record any side effects related to the regimen.

In the Zyprexa arm, 73.8 percent of patients experienced no nausea during the early assessment period versus 45.3 percent of patients with placebo. During later assessment, nausea was prevented in 42.4 percent of patients with Zyprexa, versus 25.4 percent in the control arm, and during the overall period, no nausea was reported in 37.3 percent of patients receiving Zyprexa compared with 21.9 percent with placebo.

The complete response rate also was better with Zyprexa compared with placebo during the acute phase (85.7 percent vs 64.6 percent, respectively), the delayed phase (66.9 percent vs 52.4 percent), and over the entire period (63.6 percent vs 40.6 percent).

In keeping with Zyprexa's known side effect profile, drowsiness was significantly increased on day 2 in the experimental arm and was severe in 5 percent of patients, the researchers reported; however, no patients stopped taking Zyprexa as a result, and the study showed that sedation resolved after the first day, even though patients in the Zyprexa arm were still taking the drug on days 3 and 4.

The researchers suggested that lower dosing of Zyprexa (e.g., 5 mg) represents an area for further study, adding that evaluating the agent only at the 10-mg dose is one limitation of this trial. In addition, they reported no significant differences between the two arms on the side effect of undesired increase in appetite on days 2 through 5 after chemotherapy.

Three grade 4 adverse events (AEs) — including two hematologic — were seen in the Zyprexa arm and none in the placebo arm. Two grade 3 adverse events occurred in the experimental arm — hyperglycemia and fatigue; in the placebo arm, two grade 3 adverse events (diarrhea and abdominal pain) were observed. Notably, however, treating clinicians did not attribute any of the grade 3/4 adverse events to the study drug.

Study authors explained that although previous research has shown that NK-1 receptor antagonists (aprepitant, fosaprepitant, netupitant, and rolapitant) provide significant control of early and later emesis in patients receiving highly emetogenic chemotherapy, “they appear to have been less effective in controlling nausea” — an unmet need. Based on the findings of this trial, they wrote, “Patients who received [Zyprexa] were more likely than those who received placebo to be free of nausea and emesis in the early, later, and overall assessment periods.”