aprepitant and Colorectal-Neoplasms

Delayed chemotherapy-induced nausea and vomiting (CINV) is not well controlled in colorectal cancer (CRC) patients undergoing oxaliplatin (L-OHP)-based chemotherapy. Whether neurokinin-1 receptor antagonist addition to a first-generation 5HT

Topics: Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Colorectal Neoplasms; Dexamethasone; Female; Humans; Incidence; Male; Middle Aged; Nausea; Oxaliplatin; Palonosetron; Serotonin 5-HT3 Receptor Antagonists; Vomiting

Chemotherapy-induced nausea and vomiting (CINV) causes significant morbidity among colorectal cancer patients, receiving fluorouracil, oxaliplatin, and leucovorin (FOLFOX) chemotherapy even with standard antiemetic prophylaxis. The purpose of this study is to determine if the addition of aprepitant to standard antiemetic therapy improves CINV in these patients.. Patients receiving FOLFOX for colorectal cancer were given antiemetic prophylaxis with aprepitant 125 mg orally on day 1 and 80 mg on days 2 and 3. Palonosetron 0.25 mg was given IV push on day 1 only. Dexamethasone 12 mg was administered orally on day 1 and 8 mg each morning on days 2 through 4. Assessments including emetic events, rescue doses, nutritional intake, and appetite were recorded in a patient diary which was returned to study personnel in the following cycle.. Of the 53 patients screened, 50 were evaluable and had a complete dataset for cycle 1. For the first cycle, 74% of patients achieved a complete response (CR), 22% achieved a major response and 4% experienced treatment failure. The percentage of patients achieving a CR remained high throughout each cycle at 83, 83, and 86% for cycles 2, 3, and 4, respectively. Appetite and nutritional status remained largely unchanged throughout treatment. Adverse events occurring in more than 10% of patients included diarrhea (13.6%), fatigue (12.6%), and neutropenia (11%).. Aprepitant added to standard antiemetic therapy appears to be an effective and safe regimen for prevention of CINV in patients receiving FOLFOX.

Topics: Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Colorectal Neoplasms; Dexamethasone; Female; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Male; Middle Aged; Morpholines; Nausea; Organoplatinum Compounds; Palonosetron; Pilot Projects; Vomiting

We previously reported in the SENRI trial on the usefulness of aprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in colorectal cancer patients receiving an oxaliplatin-based regimen which is classified as moderately emetogenic cancer chemotherapy. In the present subgroup analysis of the SENRI trial, we assessed the risk factors for CINV in colorectal cancer patients who received oxaliplatin-based chemotherapy.. Multivariate logistic regression models were used to assess the impact of aprepitant use and patient characteristics on vomiting and nausea. We also assessed the proportion of CINV in patients by gender.. Female gender and aprepitant use were associated with the incidence of vomiting and no significant nausea. Significantly more men achieved no vomiting than women (92.9 vs 84.5 % in men and women, respectively; P = 0.0001). The rate of no nausea, complete response, complete protection, and total control was also higher in men. The rate rescue therapy use was significantly higher in women than men. We compared the rate of CINV between aprepitant and control groups and found a significant difference in male patients who achieved no vomiting and complete protection in the overall phase. In women, the rate of no nausea, no vomiting, and total control was higher in the aprepitant group than in the control group.. Gender and aprepitant use were risk factors for CINV in colorectal patients who received oxaliplatin-based chemotherapy. Aprepitant therapy was more effective for women than for men in the prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen.

Topics: Adult; Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Colorectal Neoplasms; Female; Humans; Logistic Models; Male; Middle Aged; Morpholines; Nausea; Organoplatinum Compounds; Oxaliplatin; Risk Factors; Vomiting

The oral neurokinin-1 antagonist aprepitant is recommended in several guidelines for preventing chemotherapy-induced nausea & vomiting (CINV) due to highly emetogenic cancer chemotherapy. Little is known about the feasibility and safety of aprepitant in patients treated with oxaliplatin.. In this multicentre, open label, randomised, phase 3 trial, we recruited patients with colorectal cancer who underwent an oxaliplatin-based chemotherapy. Patients were centrally randomised in a 1:1 ratio to the control group (5-HT3-receptor antagonist+dexamethasone) or aprepitant group (5-HT3-receptor antagonist+dexamethasone+aprepitant or fosaprepitant) in the first course. All patients were treated with aprepitant/fosaprepitant therapy in the second course. The primary end-point was the proportion of patients with no emesis.. A total of 413 patients entered this clinical trial from 25 centres in Japan. Significantly more patients in the aprepitant group achieved no vomiting overall and delayed phase than those in the control group (95.7% versus 83.6%, and 95.7% versus 84.7%, respectively). The aprepitant group also had statistically significantly higher percentages of no significant nausea, complete response and complete protection than the control group overall. In the control group, the percentages of no vomiting were higher in the second cycle than in the first cycle. The incidence of vomiting occurred day 7 or later was significantly higher in the control group compared with the aprepitant group. Other adverse events were not significant between the groups.. The aprepitant therapy was more effective than the control therapy for prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen.

Topics: Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Morpholines; Nausea; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Vomiting

A standard therapeutic regimen of a 5-HT₃ receptor antagonist antiemetic agent+dexamethasone was administered as antiemetic therapy for 29 patients who received chemotherapy for colorectal cancer in the Department of Surgery at Gunma Saiseikai Maebashi Hospital, from January to March 2010. For 13 patients with delayed nausea, the therapy was changed to an aprepitant regimen (aprepitant+5-HT₃ receptor antagonist antiemetic agent+dexamethasone)to evaluate the preventive effect of aprepitant on acute and delayed nausea and vomiting. This aprepitant regimen produced a significant improvement in the primary endpoint, based on a complete response (CR) of no vomiting and no rescue treatment throughout the administration period, and in the secondary endpoint of CR in the delayed phase, with no delayed nausea. In addition, a tendency for improvement was found in other secondary endpoints: complete protection (CP) based on no vomiting, no rescue treatment, and no significant nausea throughout the observation period; no vomiting; and no significant nausea. These findings suggest that using aprepitant as an antiemetic therapy during chemotherapy for colorectal cancer may be effective for patients with nausea and vomiting that are intractable to standard therapeutic regimens.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Aprepitant; Colorectal Neoplasms; Female; Humans; Male; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Vomiting

The substance P (SP)/neurokinin-1 receptor (NK1R) system, a critical metastatic signaling pathway, can be targeted by substance P antagonists to prevent its cancer-progressive impacts. In the current study, we aimed to investigate the carcinogenic activity of the SP/NK1R system in human SW480 colorectal cancer cells and study the antagonistic impact of aprepitant (AP) by measuring MMP-2 and MMP-9 enzymatic activity.. Different concentrations of SP, alone or mixed by AP, were utilized to treat SW480 cells to investigate the cells' viability and metastasis by applying Resazurin and Gelatin Zymography methods, respectively. The cells' metastatic response was analyzed by measuring the MMP-2 and MMP-9 in transcriptional and translational levels. Finally, the Scratch assay was carried out to evaluate the cells' metastatic response following the SP/AP treatment.. A significant metastatic activity was observed in SW480 cells following incubation with the increasing SP doses by detecting MMP-2/MMP-9 enzyme activity, genes overexpression, and enhanced cell migration. This is while the AP treatment meaningfully diminished all the SP-mediated metastatic effects (p-Value < 0.001).. According to the results, the SP/NKR1 signaling pathway can be considered one of the main metastatic effectors in human colorectal cancer. Therefore, AP might be suggested to be used as the SP antagonist and an efficient anti-metastatic drug.

Topics: Aprepitant; Colorectal Neoplasms; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-1; Signal Transduction; Substance P

The neurokinin-1 receptor (NK-1R) antagonists are approved as treatment for chemotherapy-associated nausea and vomiting in cancer patients. The emerging role of the substance P-NK-1R system in oncogenesis raises the possibility of repurposing well-tolerated NK-1R antagonists for cancer treatment. This study reports that human colorectal cancer (CRC) patients with high NK-1R expression have poor survival, and NK-1R antagonists SR140333 and aprepitant induce apoptotic cell death in CRC cells and inhibit CRC xenograft growth. This cytotoxicity induced by treatment with NK-1R antagonists is mediated by induction of endoplasmic reticulum (ER) stress. ER stress triggers calcium release, resulting in the suppression of prosurvival extracellular signal-regulated kinase (ERK)-c-Myc signaling. Along with ER calcium release, one ER stress pathway mediated by protein kinase RNA-like ER kinase (PERK) is specifically activated, leading to increased expression of proapoptotic C/EBP-homologous protein (CHOP). Moreover, NK-1R antagonists enhance the efficacy of chemotherapy by increasing the sensitivity and overcoming resistance to 5-fluorouracil in CRC cells through the induction of sustained ER stress and the consequent suppression of ERK-c-Myc signaling both in vitro and in vivo. Collectively, the findings provide novel mechanistic insights into the efficacy of NK-1R antagonists either as a single agent or in combination with chemotherapy for cancer treatment.

Topics: Animals; Antineoplastic Agents; Apoptosis; Aprepitant; Cell Line, Tumor; Colorectal Neoplasms; Drug Resistance, Neoplasm; Endoplasmic Reticulum Stress; Extracellular Signal-Regulated MAP Kinases; Humans; Mice; Mice, Nude; Neurokinin-1 Receptor Antagonists; Piperidines; Proto-Oncogene Proteins c-myc; Quinuclidines; Signal Transduction; Survival Rate; Transplantation, Heterologous

For patients undergoing cancer chemotherapy, sufficient supportive antiemetic therapy is important for maintaining the quality of life. Although there are many studies on antiemetic support therapy for high emetic risk regimens, studies on moderately emetic risk regimens are scarce. FOLFOX and FOLFIRI are generic regimens for the treatment of advanced colorectal cancer; evidence for antiemetic supportive therapy at the time of this treatment is scarce. In addition, research on patients over 65 years of age is limited. Among the advanced colorectal cancer patients who received treatment with FOLFOX or FOLFIRI at Koyama Memorial Hospital, patients older than 65 years of age were selected in order to assess the effectiveness of aprepitant as an antiemetic supportive therapy. Aprepitant was used in combination with granisetron and dexamethasone in 14 patients. After 5 days of treatment, complete control rate of emesis was 100%, and complete control rate of nausea was 64.3%. Our results suggest that aprepitant can be used as a safe antiemetic supportive therapy in elderly advanced colorectal cancer patients undergoing FOLFOX and FOLFIRI, as well as granisetron and dexamethasone.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Camptothecin; Colorectal Neoplasms; Dexamethasone; Female; Fluorouracil; Granisetron; Humans; Leucovorin; Male; Morpholines; Organoplatinum Compounds; Vomiting