FLOT; To Be Treated as a Highly Emetogenic Regimen or a Moderately Emetogenic One? Comparison of the Emetogenic Potential of FLOT versus FOLFOX and TAC Regimens

PurposeThe current study aimed at investigating the efficacy of aprepitant-containing triple antiemetic regimen in FLOT (Fluorouracil+Leucovorin+Oxaliplatin+Docetaxel) recipients as well as the emetogenic potential of FLOT regimen, through comparison of nausea and vomiting rates in a moderately emetogenic chemotherapy, FLOT, and a highly emetogenic chemotherapy recipients.StudyPatients planned to receive one of FLOT, FOLFOX (Fluorouracil+Leucovorin+ Oxaliplatin/moderate-emetic-risk), or TAC (Docetaxel+Doxorubicin+Cyclophosphamide/high-emetic-risk) regimens were recruited. All patients were treated with the same triple antiemetic regimen containing aprepitant.ResultsA total of 165 chemotherapy-naïve patients (52 FLOT recipients) were eligible to enter the study. At the end of day five, “complete response” (primary efficacy endpoint) was achieved by 84.6%, 63.5%, and 61.5% of the FLOT-receiving patients in acute, delayed, and overall phases, respectively. A significant difference was seen among the odds of FLOT recipients and FOLFOX recipients concerning “complete response” achievement in delayed (p=0.014) and overall (p=0.017) phases, “no emesis” in delayed (p=0.018) and overall (p=0.010) phases, also “complete protection” in acute (p=0.023), delayed (p=0.009) and overall (p=0.006) phases; however, the difference between the odds of FLOT recipients and TAC recipients, in relation to achieving these endpoints was insignificant. FLOT group showed significantly faster time-to-antiemetic regimen failure and time-to-first emetic episode in comparison to the FOLFOX group, which was insignificant in comparison to the TAC group.ConclusionAccording to the findings, FLOT has to be considered as a high-emetic-risk regimen. To better management of highly emetogenic regimens, antiemetic guidelines recommend adding olanzapine to aprepitant-containing triple antiemetic regimen besides continuing dexamethasone and olanzapine administration on days 2-4.

Randomized, Double-Blind, Phase III Study of Fosnetupitant Versus Fosaprepitant for Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: CONSOLE

PURPOSE We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone. PATIENTS AND METHODS Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, –10% for the difference in the overall CR rate). RESULTS Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392] v FosAPR [N = 393]) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, –2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% ( P < .001) and 0.3% versus 3.6% ( P < .001), respectively. CONCLUSION FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting.

Use of Low Dose Olanzapine for the Control of Nausea and Vomiting in Patients Receiving Highly Emetogenic Chemotherapy in a Rural Medical College in Etawah District, Uttar Pradesh, India

BACKGROUND Chemotherapy-induced nausea and vomiting (CINV) is a frequent and feared adverse effect of cancer chemotherapy. International guidelines recommend combinations of 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, dexamethasone, and/or neurokinin-1 (NK1) receptor antagonists for the control of CINV in patients receiving highly emetogenic chemotherapy (HEC) as a part of their treatment. Even though, nausea in delayed period is less controlled and poses a major concern for these patients. METHODS This open label, prospective study was conducted in a rural medical college in Etawah District in Uttar Pradesh, India from November 2017 to November 2018 over a period of 1 year to observe the efficacy of low dose (5 mg OD) olanzapine in combination with standard anti-emetic regimen for the prevention of CINV. Olanzapine is a food and drug administration (FDA) approved antipsychotic drug that has anti-emetic activity and has shown to improve CINV. Low dose olanzapine along with a standard combination of ondansetron, dexamethasone and aprepitant was given to patients receiving highly emetogenic chemotherapy (Cisplatin >70 mg/m2 or doxorubicin-cyclophosphamide combination). CINV was assessed using common toxicity criteria of adverse events (CTCAE) version 5.0. RESULTS Complete response to nausea was observed in 90.90 %, 60.60 % and 54.54 % in acute, delayed and overall period respectively. Complete response to vomiting was observed in 96.96 %, 69.69 % and 66.66 % in acute, delayed and overall period respectively. Complete response to Grade-2 (or above) nausea was observed in 96.96 %, 93.93 % and 90.90 % in acute, delayed and overall period, respectively. Daytime Grade -3 somnolence which was seen in 2/33 patients (6.06 %) was attributable to olanzapine. Patients receiving olanzapine were more likely to have complete response of nausea and emesis in the early, late, and overall assessment periods especially of higher grade (G2 and G3). CONCLUSIONS The authors concluded that low dose olanzapine 5 mg OD combined with an NK1- receptor antagonist, a 5-HT3–receptor antagonist, and dexamethasone is safe and efficacious in the prevention of CINV in patients receiving HEC. KEYWORDS Olanzapine, Low Dose, CINV, HEC

Efficacy of Granisetron in the Prevention of Nausea and Vomiting among Paediatric Oncology Patients Receiving Moderate to Highly Emetogenic Chemotherapy: A Single-Blinded, Non-Inferiority Trial

This single-blinded, non-inferiority trial was conducted over an 8-month period to examine the efficacy of intravenous granisetron at two differing doses in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV)among paediatric patients receiving moderate to highly emetogenic chemotherapy. Seventeen patients (9 males and 8 females) were recruited and randomly assigned to receive alternating granisetron dosages of 0.01 mg/kg and 0.04 mg/kg during each chemotherapy cycle. The severity of CINV during and three days post-completion of chemotherapy, as well as common side effects of granisetron were recorded. A total of 78 cycles of chemotherapy (38 cycles of 0.01 mg/kg and 40 cycles of 0.04 mg/kg) were evaluated. The median age of the study population was 5.2 years (interquartile range 25th, 3.8; 75th, 8.7). Patients’ diagnoses comprised of haematological malignancy, bone tumour and cerebral neoplasm. From this study, we demonstrated that intravenous (IV) granisetron 0.01 mg/kg was non-inferior to 0.04 mg/kg in terms of achieving a complete response for acute CINV. However, a similar observation was not seen in the post-treatment period analysis (delayed CINV). In conclusion, IV granisetron at 0.04 mg/kg/dose provides effective protection and prophylaxis of both acute and delayed CINV. Further study with a larger sample size may be required before a definite conclusion can be made with regards to efficacy of 0.01 mg/kg dose.

A phase III, randomized, double-blind, multicenter, active control study of fosnetupitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving cisplatin-based highly emetogenic chemotherapy (HEC): CONSOLE.

12099 Background: Fosnetupitant (FN) is a phosphorylated pro-drug of netupitant that has high binding affinity for the neurokinin-1 (NK-1) receptor and a long half-life of 70 h. This phase 3 study is the first head-to-head study to compare two NK-1 receptor antagonists, FN and fosaprepitant (FA), in combination with palonosetron and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (JapicCTI-194611). Methods: Patients scheduled to receive cisplatin (≥70 mg/m2) -based chemotherapy were randomly assigned 1:1 to receive FN 235 mg or FA 150 mg, in combination with palonosetron 0.75 mg and dexamethasone (9.9 mg on day 1, 6.6 mg on days 2-4). The stratification factors were sex, age category (<55 vs. ≥55 years), and site. The primary endpoint was the complete response (CR; no emetic events and no rescue medication) rate, stratified by sex and age category, during the overall phase (0-120 h) to show the non-inferiority (margin, -10%) of FN to FA. The secondary endpoints were: CR rate, complete protection rate, total control rate, no nausea rate, no emetic events rate in each period [i.e., acute (0-24 h), delayed (24-120 h), overall, 0-168 h and 120-168 h], time to treatment failure, and safety, including injection site reactions (ISRs). Assessment of efficacy was continued until 168 h after the initiation of cisplatin. Some eligible patients were evaluated for safety and efficacy of FN for up to four cycles. Results: Between February 2019 and March 2020, total 795 patients were enrolled in the study. The study drug was administered to 785 patients (n=392 in FN vs. n=393 in FA), and all of them were evaluated for efficacy and safety. Baseline characteristics were generally balanced between the two groups. The adjusted overall CR rate was 75.2% in FN vs. 71.0% in FA [MH common risk difference, 4.1%; 95% CI, -2.1% to 10.3%), thus demonstrating non-inferiority of FN to FA. Regarding the other secondary endpoints of efficacy until 168 h, FN was favorable against FA, especially the CR rate during 0-168 h (73.2% in FN vs. 66.9% in FA) (Table). The incidence rates of treatment-related adverse events were 22.2% in FN vs. 25.4% in FA, whereas those of ISRs with any cause or with treatment-related were 11.0% or 0.3% in FN vs 20.6% or 3.6% in FA, respectively ( p<0.001). Conclusions: FN demonstrated non-inferiority to FA, with a favorable safety profile and lower risk for ISRs. For the period beyond 120 h after initiation of chemotherapy, FN may have the potential to improve the prevention of “beyond delayed” CINV. Clinical trial information: JapicCTI-194611. [Table: see text]