FLOT (a chemotherapy regimen for gastric/esophagogastric junction cancer): 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.

PURPOSE: The 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. STUDY: Patients 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. RESULTS: A total of 165 chemotherapy-naïve patients (52 FLOT recipients) were eligible to enter the study. At the end of day 5, "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, and 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 with the FOLFOX group, which was insignificant in comparison with the TAC group. CONCLUSION: According to the findings, FLOT has to be considered as a high-emetic-risk regimen; provided that, as recommended by the antiemetic guidelines towards better management of delayed nausea and vomiting induced by highly emetogenic regimens, executing clinical trials concerning the efficacy of continuing dexamethasone on days 2-4 in aprepitant-containing triple antiemetic regimen schedule is required.

Gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the neurokinin-1 receptor antagonist-based antiemetic regimens: a candidate-gene association study in breast cancer patients.

PURPOSE: The current candidate gene association study aims to investigate tag SNPs from the TACR1 gene as pharmacogenetic predictors of response to the antiemetic guidelines-recommended, NK-1 receptor antagonist-based, triple antiemetic regimens. METHODS: A set of eighteen tag SNPs of TACR1 were genotyped in breast cancer patients receiving anthracycline and cyclophosphamide (with/without docetaxel) applying real-time PCR-HRMA. Data analysis for 121 ultimately enrolled patients was initiated by defining haplotype blocks using PHASE v.2.1. The association of each tag SNP and haplotype alleles with failure to achieve the defined antiemetic regimen efficacy endpoints was tested using PLINK (v.1.9 and v.1.07, respectively) based on the logistic regression, adjusting for the previously known chemotherapy-induced nausea and vomiting (CINV) prognostic factors. All reported p-values were corrected using the permutation test (n = 100,000). RESULTS: Four variants of rs881, rs17010730, rs727156, and rs3755462, as well as haplotypes containing the mentioned variants, were significantly associated with failure to achieve at least one of the defined efficacy endpoints. Variant annotation via in-silico studies revealed that the non-seed sequence variant, rs881, is located in the miRNA (hsa-miR-613) binding site. The other three variants or a variant in complete linkage disequilibrium with them overlap a region of high H3K9ac-promoter-like signature or regions of high enhancer-like signature in the brain or gastrointestinal tissue. CONCLUSION: Playing an essential role in regulating TACR1 expression, gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the NK-1 receptor antagonist-based, triple antiemetic regimens. If clinically approved, modifying the NK-1 receptor antagonist dose leads to better management of CINV in risk-allele carriers.

Cytidine deaminase enzyme activity is a predictive biomarker in gemcitabine-treated cancer patients.

BACKGROUND: Gemcitabine is a chemotherapeutic agent, widely used for the treatment of many types of cancer. Cytidine deaminase (CDA) enzyme plays an important role in the metabolism of gemcitabine. This study aimed to assess the power of serum CDA residual activity in predicting drug efficacy and toxicity in gemcitabine-treated cancer patients. METHODS: This prospective observational study enrolled 63 patients with different types of malignancies who received gemcitabine chemotherapy between May 2019 and January 2022. Blood samples were obtained before the initiation of chemotherapy and serum CDA residual activity was determined using a modification of the Berthelot assay. The patients were followed up for at least 12 months up to 41 months. Overall survival was recorded and treatment-related toxicities were documented according to National Cancer Institute Common Terminology Criteria. RESULTS: Kaplan-Meier analysis showed that patients with a lower than median CDA value (≤ 8.06 U/mg protein) had a significantly longer survival compared to patients with higher CDA values (> 8.06 U/mg, P ˂ 0.005). Among several potentially involved factors, a significant association between CDA activity and overall survival was observed in univariate analysis (HR = 4.219, 95% CI 1.40-12.74, P = 0.011). On the other hand, the rate of anemia was significantly higher in low-CDA patients compared to high-CDA individuals (P < 0.05). CONCLUSION: These findings suggest that CDA activity could be a promising biomarker to predict survival and the occurrence of anemia in cancer patients treated with gemcitabine.