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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 6  |  Issue : 2  |  Page : 46-51

Addition of metoclopramide to triple antiemetic therapy towards prevention of anthracycline-based chemotherapy-induced nausea and vomiting in breast cancer patients


Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Date of Submission08-Mar-2022
Date of Decision18-Jul-2022
Date of Acceptance15-Aug-2022
Date of Web Publication29-Aug-2022

Correspondence Address:
A H Rudresha
Associate Professor, Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/oji.oji_9_22

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  Abstract 


Objective: The aim of this study was to evaluate if addition of metoclopramide to the triplet antiemetic therapy is superior to the triplet antiemetic therapy for prevention of delayed chemotherapy-induced nausea and vomiting. Materials and Methods: A randomized single-blind trial was performed on 200 chemotherapy-naïve breast cancer patients who have to receive anthracycline-based highly emetogenic chemotherapy (HEC). The patients were randomized to study arm (n = 100) and control arm (n = 100). Triplet antiemetic therapy (fosaprepitant on day 1, 5-HT3 antagonist on day 1, and dexamethasone for days 1–4) was used in both the arms and metoclopramide (day 1–5) was added to the study arm. Response to antiemetic prophylaxis was assessed in terms of “complete response (CR),” “only nausea,” and “both nausea and vomiting.” CR is defined as no nausea, no vomiting, and no rescue medication during the overall phase (days 1–5). Nausea/vomiting was detected by using the Visual Analog Scale and its impact on quality of life was determined by using the Functional Living Index Emesis (FLIE) score. Results: The demographical and clinical features were similar in both the groups. Majority of patients in both the arms presented with Eastern Cooperative Oncology Group PS 0, Stage III, and positive hormone receptor status. CR was observed more in the study arm than that of the control arm (51% vs. 37%; P = 0.046). The mean total FLIE score was 29.23 in the study arm and 31.16 in the control arm (P = 0.036). Conclusion: This study resulted in a significant CR and clinically relevant improvement in FLIE score for addition of metoclopramide to triple antiemetic prophylaxis. Therefore, a quadruple antiemetic combination including metoclopramide might be an antiemetic prophylaxis option for breast cancer patients receiving anthracycline-based HEC for better compliance to treatment.

Keywords: Chemotherapy-induced nausea and vomiting, complete response, Functional Living Index Emesis, highly emetogenic chemotherapy, metoclopramide


How to cite this article:
Rudresha A H, Abhilash G H, Lokanatha D, Babu M C, Lokesh K N, Rajeev L K, Saldanha S, Jacob LA, Pandey A, Dubey P, Babbar P. Addition of metoclopramide to triple antiemetic therapy towards prevention of anthracycline-based chemotherapy-induced nausea and vomiting in breast cancer patients. Oncol J India 2022;6:46-51

How to cite this URL:
Rudresha A H, Abhilash G H, Lokanatha D, Babu M C, Lokesh K N, Rajeev L K, Saldanha S, Jacob LA, Pandey A, Dubey P, Babbar P. Addition of metoclopramide to triple antiemetic therapy towards prevention of anthracycline-based chemotherapy-induced nausea and vomiting in breast cancer patients. Oncol J India [serial online] 2022 [cited 2022 Sep 30];6:46-51. Available from: https://www.ojionline.org/text.asp?2022/6/2/46/354904




  Introduction Top


Nausea and vomiting are among the most distressing side effects of chemotherapy which can cause significant negative impacts on patients' quality of life and their ability to comply with therapy by causing anorexia, decreased performance status, metabolic imbalance, esophageal tears, and nutritional deficiency.[1],[2] Although there is a change in strategies toward the prevention and management of chemotherapy-induced nausea and vomiting (CINV), they remain distressing. Approximately 30%–60% of patients experience either acute or delayed nausea/vomiting after chemotherapy with antiemetic prophylaxis.[3] Emetogenicity refers to an agent's tendency to cause nausea and/or vomiting. The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have divided emetogenicity into four categories such as highly emetogenic, moderately emetogenic, low emetogenic, and minimally emetogenic.[4],[5] Highly emetogenic chemotherapy (HEC) are the drugs with CINV rates >90%, whereas CINV rates among moderately emetogenic, low emetogenic, and minimally emetogenic drugs are >30%–90%, 10%–30%, and <10%, respectively.

CINV are of four major subtypes such as (a) acute onset: observes within the first 24 h after administration of chemotherapy; (b) delayed onset: occurs 24 h or later after administration of chemotherapy (till 120 h); (c) anticipatory type: occurs before chemotherapy administration, an indicator of previous poor control of nausea and vomiting; and (d) breakthrough/refractory: nausea and vomiting occurs despite appropriate prophylaxis, and requires the use of rescue medications. Since there are many independent and variable risk factors that can influence the risk for CINV in any patient, it becomes paramount to individualize the approach to the prevention and treatment of CINV in every case.[4],[5]

Anthracycline-based combination chemotherapy, particularly with cyclophosphamide, has been extensively used in breast cancer patients, which was traditionally classified as moderately emetogenic.[6] However, in ASCO 2011, this chemotherapy combination regimen was considered HEC.[4] The antiemetic regimen of choice in HEC setting is triplet regimen which is a combination of aprepitant, 5HT3 receptor antagonist, and dexamethasone. Clinical data support this combination for patients receiving Adriamycin-based chemotherapy.[7] Metoclopramide as a dopamine 2 (D2)-receptor with prokinetic effects was used only for the treatment of breakthrough emesis and can be useful for improvement in the control of delayed nausea. In general, metoclopramide at high doses can cause unacceptable extrapyramidal symptoms, whereas at lower doses, there is a rare chance of development of such extrapyramidal symptoms.[8],[9] Few trials safely used metoclopramide at lower doses with other antiemetics in different combinations or different dose schedules at low doses for prevention of delayed CINV. A recent randomized Phase III trial by van der Vorst et al.[10] stated that dexamethasone-sparing strategies incorporating palonosetron or multiple-day metoclopramide are safe and at least as effective as multiple-day DEX regimen in preventing delayed CINV, particularly in patients undergoing moderately emetogenic chemotherapy (MEC).

However, the studies on combination use of metoclopramide along with common triplet antiemetic therapy for prevention of delayed CINV, particularly in patients undergoing treatment with HEC, are lacking. In this prospective study, we evaluated the superiority of addition of metoclopramide to triplet antiemetic therapy over triplet antiemetic therapy for prevention of delayed CINV in breast cancer patients. Moreover, studied the impact of CINV on quality of life using the functional living index-emesis (FLIE) scores in both the arms.[11],[12]


  Materials and Methods Top


The present single-blind randomized study was conducted on histologically confirmed breast cancer patients who will receive first cycle of anthracycline-based HEC among chemotherapy-naïve patients in neoadjuvant, adjuvant, or metastatic settings. Outpatients/inpatients of the department of medical oncology of our tertiary care cancer institute were enrolled for a duration of 1 year from September 2020 to September 2021. Antiemetic prophylaxis was added during chemotherapy. The aim was to verify whether adding metoclopramide to the triplet antiemetic therapy is superior to the triplet antiemetic therapy in preventing CINV.

The study was approved by the institutional ethics committee vide letter number--KMIO/MEC/002/August 31, 2020.

Inclusion criteria were as follows:

  • Patients aged more than 18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0–2
  • Histologically confirmed breast carcinoma patients
  • Receiving first cycle of anthracycline-based chemotherapy.


Exclusion criteria were as follows:

  • ECOG PS 3–4
  • Patients with central nervous system (CNS) metastases
  • Patients who had vomiting 24 h before the expected date of chemotherapy
  • Patients taking corticosteroids/opioids for any other cause
  • Patients who had received radiation to abdomen or pelvis in the prior week before the chemotherapy
  • Breast cancer patients who received anthracycline-based chemotherapy previously.


In this study, fluorouracil + epirubicin + cyclophosphamide (FEC), Adriamycin + cyclophosphamide (AC), or epirubicin + cyclophosphamide (EC) chemotherapy regimens were used either in neoadjuvant chemotherapy (NACT), adjuvant, or metastatic settings. FEC regimen consisted of 5-fluorouracil 500 mg/m2 plus epirubicin 100 mg/m2 plus cyclophosphamide 500 mg/m2 given on day 1. AC regimen consisted of Adriamycin 60 mg/m2 plus cyclophosphamide 600 mg/m2 given on day 1. EC regimen consisted of epirubicin 75 mg/m2 plus cyclophosphamide 600 mg/m2 given on day 1.

The patients were randomized to study arm and control arm with 1:1 randomization to analyze the superiority of adding metoclopramide to triplet antiemetic prophylaxis over triplet antiemetic prophylaxis. Triplet antiemetic therapy prophylaxis was used in both the arms and consisted of intravenous administration of fosaprepitant 150, granisetron 1, and dexamethasone 12 mg on day 1 and oral dexamethasone 4 mg twice daily for days 2–4. In the study arm, oral metoclopramide 10 mg twice daily on days 1–5 was added to this triplet antiemetic therapy.

The primary endpoint of the study was to assess the response to antiemetic prophylaxis in terms of “complete response (CR),” “only nausea,” and “both nausea and vomiting.” CR is defined as no nausea, no vomiting, and no rescue medication during the overall phase (days 1–5).

Patients were given a printed visual analog scale (VAS) to detect nausea and vomiting for duration of 5 days after chemotherapy. Patients were also given the modified FLIE questionnaire on day 1 and were explained clearly that they will be required to fill the questionnaire on day 6. VAS was utilized to detect nausea/vomiting, and FLIE was used to determine its impact on the patient's quality of life.

The modified version of FLIE scale is a validated nausea and vomiting-specific patient-reported quality-of-life questionnaire consisting of 18 questions. It is a patient-reported outcome instrument divided into two categories such as nausea and vomiting with nine identical questions in each category. The first question asks the patient to rate how much nausea or vomiting he/she experienced during the past 5 days. The remaining eight questions in the questionnaire assess the impact of nausea/vomiting in terms of ability to enjoy meals/liquids, to prepare meals or to do household tasks, to perform daily functions, to perform usual recreation/leisure activities, willingness to spend time with family and friends, and the extent to which the side-effect has caused personal hardship and hardship on others during the 5-day study period. The response to each question was answered on a 100 mm VAS (1–7 points). The score of the FLIE was calculated by summing the responses to these 18 questions on the 7-point analog scale. Hence, 18–126 is the possible range of total scores. VAS with “1 point” corresponds to “none”/“not at all” and “6–7 points” correspond to “a great deal.” The questionnaire was completed by each patient on day 6 following chemotherapy in order to assess the effect of nausea and emesis on quality of life. Examples of two questions in the scale are shown below.

Example 1: How much nausea have you had in the past 3 days?



Example 2: Has vomiting affected your ability to maintain usual recreation or leisure activities during the past 3 days?



Statistical analysis

SPSS version 22 (IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp) was used to analyze data. Categorical data was represented in the form of frequencies and proportions. Chi-square test or Fisher's exact test was used as a test of significance for qualitative data. Continuous data were represented as mean and standard deviation. Independent t-test was used as a test of significance to identify the mean difference between two quantitative variables. P < 0.05 was considered statistically significant after assuming all the rules of statistical tests.


  Results Top


Two-hundred and nine breast cancer patients who had to receive the first cycle of anthracycline-based chemotherapy were encountered during the study period. Six patients who were receiving corticosteroids (CNS metastasis – 3 and skeletal metastasis – 3) and three patients receiving opioids were excluded from the study analysis. Hence, after inclusion and exclusion criteria, a total of 200 patients were enrolled as a sample size for analysis. The patients were randomized to study arm (n = 100) and control arm (n = 100) according to antiemetic prophylaxis used in both the arms.

The basic clinical characteristics for both the study and control groups are depicted in [Table 1]. The overall median age at presentation was 56 years (range: 30–67 years). The demographical and clinical features were similar in both the groups (P > 0.05). In both the study and control arms, majority of patients presented with ECOG performance status 0 and Stage III. Hormone receptor expression was seen in 73% of patients of the study arm and 69% of the control arm. Majority of patients received FEC chemotherapy regimen in both the study (64%) and control (68%) arms.
Table 1: Baseline characteristics of the patients

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Our study had patients receiving NACT with either FEC or AC regimen in 28 patients in the study arm and 30 patients in the control arm. Adjuvant chemotherapy was given in 56 patients and 51 patients in the study and control arms, respectively. About 16 patients in the study arm and 19 patients in the control arm had metastatic disease, and they were treated with EC regimen.

Response to antiemetic prophylaxis therapy and FILE score are depicted in [Table 2]. CR was found in 51 patients (51%) in the study arm, while it was seen in 37 patients (37%) in the control arm, and the difference was statistically significant (P = 0.046). In the study arm, only nausea was seen in 28 patients, while both nausea and vomiting were observed in 21 patients. The control arm reported only nausea in 27 patients, and both nausea and vomiting were reported in 36 patients. FILE score ranges from 18 to 52 in the study arm and 18–71 in the control arm. The mean total FLIE score was 29.23 ± 6.298 in the study arm, while it was 31.16 ± 6.636 in the control arm, and the difference was statistically significant (P = 0.036). Hence, CR was observed more in the study arm than control arm, and the FILE score was improved in the study arm favoring the metoclopramide arm. The study arm had two patients with Grade 2 involuntary movements of the oral and facial musculature. These patients recovered without sequelae when metoclopramide was stopped.
Table 2: Comparison of responses after antiemetic prophylactics and Functional Living Index Emesis score among cases and controls

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  Discussion Top


The present prospective study demonstrates the efficacy of metoclopramide in addition to triplet antiemetic prophylaxis over triplet prophylaxis for prevention of delayed CINV among breast cancer patients. Efficacy was determined in terms of “CR,” “only nausea,” and “both nausea and vomiting.”

Approximately about 70%–80% of patients receiving chemotherapy experience nausea and/or vomiting. CINV in the delayed phase (24–120 h after chemotherapy) remains one of the most troublesome adverse effects associated with cancer treatment. Clinical studies among patients receiving HEC demonstrate a significantly higher incidence of delayed CINV compared with acute CINV (0–24 h after chemotherapy), with twice as many patients requiring rescue antiemetic therapy during the delayed phase.[13],[14],[15] Hesketh et al. in their study showed that compared to standard dual therapy, triplet therapy was generally well tolerated and provided superior protection against CINV in patients receiving HEC.[7] Anthracycline combination with cyclophosphamide regimens is now considered to be HEC by the NCCN Panel. The NCCN Panel recommends prophylactic fosaprepitant in combination with dexamethasone, a 5-HT3 receptor antagonist for acute and delayed emesis prevention for HEC based on clinical trial data and on the Food and Drug Administration (FDA) approvals.[16],[17]

Receptors other than serotonergic, such as dopaminergic, histaminic, and muscarinic, may be the dominant receptors in the control of nausea. Therefore, D2-receptor antagonists with prokinetic effects such as metoclopramide could be useful in improving delayed nausea control.[8] Metoclopramide as a central D2-receptor antagonist has activity at the chemoreceptor trigger zone and vomiting center. It also induces prokinetic activity by acting on peripheral D2, muscarinic, and 5-HT4 receptors. Metoclopramide at higher doses (2 mg/kg) also has 5-HT3 antagonist activity.[8] Prescribing high doses of metoclopramide such as 200 mg every 4–6 h may develop an increased incidence of unacceptable extrapyramidal symptoms (>30%). However, metoclopramide at a lower dose (25–50 mg/day) has very low incidence rate (<1%) of dyskinetic or extrapyramidal symptoms.[9] The daily dose of metoclopramide prescribed in this study (10 mg twice daily for 5 days) will not result in 5-HT3 antagonist activity. The U. S. FDA issued a black box warning for metoclopramide use beyond 12 weeks due to the high risk of developing tardive dyskinesia.[10],[18],[19] However, such black box warning is not a matter of concern in our study due to the use of short-term course of metoclopramide. We observed that only two patients suffered from Grade 2 involuntary movements of the oral and facial musculature and also these involuntary movements recovered without sequelae when metoclopramide was stopped.

There are only a few comparative studies published to investigate the efficacy of a prophylactic antiemetic regimen including a dopamine receptor antagonist with a 5-HT3 RA plus dexamethasone among cancer patients treated with HEC. A randomized double-blind trial by the Italian Group for Antiemetic Research compared the efficacy of metoclopramide with aprepitant in the prevention of delayed CINV. The study found a numeric advantage of metoclopramide plus dexamethasone over aprepitant and dexamethasone for CR rate. A similar result for FILE score was observed in both the cohorts. They suggested a metoclopramide-based regimen as a preferred choice of antiemetic prophylaxis over aprepitant, especially in economically constrained situations due to similar efficacy between both the regimens but with seven times higher cost of aprepitant than that of metoclopramide.[20]

In our study, we evaluated the efficacy of adding metoclopramide with triplet antiemetics for prevention of delayed CINV among breast cancer patients who received anthracycline-based HEC. We observed a higher CR in the metoclopramide plus triplet antiemetic regimen arm than only triplet antiemetic regimen arm (51% vs. 37%; P = 0.046). Moreover, we observed an improvement in mean FILE score. Our data were supported by previously published similar studies.[21] A randomized trial conducted by Oflazoglu et al. verified the effect of addition of metoclopramide to the standard triple antiemetic prophylactic regimen (dexamethasone and 5HT3RA on day 1 and aprepitant on days 1–3) among breast cancer patients receiving HEC. They also found higher CR in the metoclopramide plus triplet antiemetic arm than only triplet antiemetic arm (45.8% vs. 26.5%; P = 0.038). Moreover, they observed an improvement in mean FILE score in the metoclopramide arm over no metoclopramide arm (31.31 vs. 42.29; P = 0.045).[21]

Our study with metoclopramide in combination with standard drugs optimizes protection against both nausea and vomiting compared to the standard of care and can be considered an alternative therapy for prevention of CINV among patients who are treated with HEC. Its role in improving quality of life is also an important fact that must be clearly underlined with improved mean FLIE scores in the metoclopramide arm with reduced requirement of rescue medications during the delayed period.

Research is still lacking to find out better alternative antiemetics in the prevention of delayed CINV. Due to available published literature showing better or comparable results of alternative regimens with compared to expensive counterparts, we should not hesitate to practice different CINV prevention strategies, especially in resource-limited settings which may help to improve the therapy experience and quality of life for the patients.


  Conclusion Top


In patients receiving anthracycline-based chemotherapy, addition of metoclopramide to triple antiemetic therapy is associated with a significant CR and clinically relevant improvement in FLIE score, compared to triplet antiemetic therapy. Improved outcomes in the study arm also indicate better compliance to treatment and hence with better overall treatment outcomes. Therefore, a quadruple antiemetic combination including metoclopramide might be a treatment option for breast cancer patients receiving anthracycline-based HEC.

Acknowledgment

We would like to thank the residents and faculty of the department of medical oncology for their various inputs toward writing the article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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