Scolaris Content Display Scolaris Content Display

Cochrane Database of Systematic Reviews Protocol - Intervention

Neurokinin‐1 receptor antagonists for prevention of chemotherapy‐related nausea and vomiting in adults

This is not the most recent version

Collapse all Expand all

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

  • To assess the effectiveness of NK1 receptor antagonists in controlling acute and delayed nausea and vomiting in participants on moderate and highly emetogenic chemotherapy.

  • To determine the adverse events associated with NK1 receptor antagonists in participants receiving these drugs.

  • To assess the effect that NK1 receptor antagonists have had on the quality of life of participants treated with moderate and highly emetogenic chemotherapy.

Background

Nausea and vomiting are distressing adverse effects of chemotherapy drugs used to treat cancer, and rank as the two most disturbing side effects for many patients (Coates 1983; Herrstedt 2002; Hickok 2003; Bloechl‐Daum 2006), despite the advances in prevention, treatment, and the availability of evidence‐based guidelines which are periodically revised and updated (Gralla 1999; Kris 2005; Kris 2006). An incomplete understanding of the vomiting reflex, the subjective perception of nausea, the influence of anticipatory nausea, and other factors account for the partial symptom control that results in failure to prevent these adverse effects.

It is convenient to define several concepts related to chemotherapy‐induced nausea and vomiting to better understand this systematic review. Firstly, chemotherapy drugs differ in their ability to trigger nausea and vomiting. This property is known as 'emetogenic potential' or 'emetogenicity', and chemotherapy drugs can have a low, moderate, or high emetogenic potential (see Additional Table 1). Cisplatin is the best known example of a highly emetogenic drug, causing nausea and vomiting in more than 90% of patients receiving cisplatin doses greater than 50 mg/m2 of body surface area. Secondly, treatment with chemotherapy causes nausea and vomiting at two distinct phases, classically described in (or in the setting of) one‐day chemotherapy cycles. Acute nausea and vomiting is the onset of these symptoms which happens within 24 hours after chemotherapy. Delayed nausea and vomiting by convention occurs after 24 hours of chemotherapy, and may last for up to five days. The drugs we use to treat or prevent nausea and vomiting are called antiemetics. Thirdly, age, gender, and alcohol intake are also predictors of nausea and vomiting, so a good antiemetic trial has to take these confounders into account (Gralla 1999). Fourthly, with the methodology of antiemetic clinical trials evolving as a discipline of its own (Aapro 1993; Hesketh 1998), the expected standards of antiemetic trials include a randomized, controlled, blinded, parallel design, and the complete control of acute and delayed nausea and vomiting as separate outcomes (Morrow 1998).

Open in table viewer
Table 1. Emetogenic potential of chemotherapy drugs (Modified from Kris 2006)

Emetogenicity

Drug

HIGH (> 90%)

Cisplatin

Dacarbazine

Mechloretamine

Streptozocin

Cyclophosphamide (> 1500 mg/m2)

Actinomycin‐D

Carmustine

MODERATE (30 to 90%)

Carboplatin

Oxaliplatin

Cyclophosphamide (<1500 mg/m2)

Lomustine (CCNU)

Daunorubicin

Doxorubicin

Epirubicin

Idarubicin

ARA‐C (Arabinoside cytosine)

Ifosfamide

Irinotecan

LOW (10 to 30%)

Paclitaxel

Docetaxel

Mitoxantrone

Topotecan

Etoposide

Pemetrexed

Methotrexate

Mitomycin

Gemcitabine

Cytarabine (< 1000 mg/m2)

Fluorouracil

Bortezomib

Cetuximab

Trastuzumab

Rituximab

Bevacizumab

Busulfan

2‐chlorodeoxyadenosine

Fludarabine

Vinblastine

Vincristine

Vinorelbine

Bleomycin

Corticosteroids (notably dexamethasone) and drugs that block the 5‐hydroxytriptamine type 3 receptor (5‐HT3 receptor antagonists: ondansetron, granisetron, palonosetron and others), have been indicated for the treatment and prevention of both acute and delayed nausea and vomiting caused by chemotherapy drugs. The 5‐HT3 receptor antagonists work well during the first day of chemotherapy administration, but are less effective at protecting patients after 24 hours. This finding suggests that delayed nausea and vomiting has different reflex pathways and mediators. Research has identified substance P is one of these mediators. Substance P is a small peptide that functions as a neurotransmitter in the central nervous system, eliciting a potent emetic response when it binds the neurokinin‐1 (NK1) receptors in areas that control nausea and vomiting: the area postrema, the nucleus tractus solitarius, and the dorsal motor nucleus of the tenth cranial nerve (vagus nerve), located in the medulla oblongata (Saito 2003). Drugs that compete against substance P for the NK1 receptor are known as NK1 receptor antagonists (Bleiberg 2000), and several prototypes entered clinical trials in the mid‐nineties (Kris 1997). The addition of one of these NK1 receptor antagonists to a 5‐HT3 receptor antagonist and a steroid increases the control over the acute and delayed nausea and vomiting caused by cisplatin (Navari 2004). These findings prompted the revision and update of guidelines for the prevention of chemotherapy‐induced nausea and vomiting.

This quantitative systematic review intends to examine the contribution of the NK1 receptor antagonists in preventing both acute and delayed nausea and vomiting from highly and moderately emetogenic chemotherapy.

Objectives

  • To assess the effectiveness of NK1 receptor antagonists in controlling acute and delayed nausea and vomiting in participants on moderate and highly emetogenic chemotherapy.

  • To determine the adverse events associated with NK1 receptor antagonists in participants receiving these drugs.

  • To assess the effect that NK1 receptor antagonists have had on the quality of life of participants treated with moderate and highly emetogenic chemotherapy.

Methods

Criteria for considering studies for this review

Types of studies

Randomized, controlled trials (RCTs) with placebo or active control interventions using a double‐blinded method and a parallel design.

Types of participants

Participants older than 16 years with a diagnosis of cancer, who received at least one moderately or highly emetogenic chemotherapy drug, as listed in Additional Table 1. The design of these trials was such that participants allocated to the treatment or control interventions had a good performance status.

Types of interventions

The treatment intervention will be the NK1 receptor antagonist combined with the standard antiemetic treatment, as defined elsewhere (Gralla 1999) for acute and delayed nausea and vomiting at the time when the clinical trial was conducted. The control intervention is the standard antiemetic therapy at the time the clinical trial was planned. All of these trials contemplated the use of other antiemetics to rescue participants receiving the treatment or control intervention who had breakthrough nausea and vomiting.

Types of outcome measures

  • Complete control of nausea (no nausea and no use of rescue medications) in the acute (first 24 hours of treatment with chemotherapy), and delayed (after 24 hours of treatment with chemotherapy) phases of nausea and vomiting for the treatment and control interventions.

  • Complete control of vomiting (no vomiting and no use of rescue medications) in acute and delayed nausea and vomiting for the treatment and control interventions.

  • Adverse effects as defined by each trial that is found to be eligible for this review.

Search methods for identification of studies

This list of relevant words will be used as free text, titles, and MeSH terms to search CENTRAL (current issue); EMBASE (January 1980 to present); Ovid MEDLINE (January 1966 to present); CancerLit (from 1980 to present for abstracts), and the Literatura Latinoamericana e do Caribe em Ciências da Saúde (LILACS) databases. We also plan to do a handsearch of all relevant papers (original articles and reviews) on NK‐1 receptor antagonists in specialty Journals and Conference Proceedings. There will be no language restriction for the search. If necessary, we will contact investigators in the field by e‐mail, conventional mail, or telephone, inquiring about past, ongoing unpublished trials, or to request additional information on published trials. The search strategy based on MEDLINE which will be adapted for searching the other databases can be found in Appendix 1.

Data collection and analysis

Identification of studies and data collection

Two review authors will independently screen all titles and abstracts identified in the literature search. We will also collect and tabulate the data, resolving any disagreement after discussion with a third review author. There will be no blinding to the author names, affiliated institutions, journal of publication, or study results. We plan to assess the methodological quality of each study by checking randomization and description of method of random allocation; blinding and methods to ensure appropriate masking; description of sample size; response analysis based on the intention‐to‐treat principle; and description of adverse effects, toxicity and study withdrawals. Instead of applying a quality scoring system, we plan to rate the validity of each study using a simplified rating system to assess the risk of bias (Higgins 2006).

Data collection and analysis

We will collect data on participants, methods, interventions, and the outcome measurements of interest from the original articles onto a spreadsheet. The outcome measurements will be recorded as binary data (number of participants with total control of nausea and vomiting during the study period relative to the total number of participants evaluable for treatment). If statistically appropriate, we will combine the aggregate data to obtain a pooled effect size.

Synthesis and presentation of data

We will perform a data analysis with the analysis module for RevMan 4.2.10 using the risk ratio (RR) with 95% confidence intervals (95% CI), the absolute risk reduction (ARR), the number need to treat to benefit (NNT), or the number needed to treat to harm (NNH) for five separate outcomes:

  • The complete control of nausea at 24 hours of chemotherapy treatment (acute nausea).

  • The complete control of nausea after 24 hours of chemotherapy treatment (delayed nausea).

  • The complete control of vomiting at 24 hours of chemotherapy treatment (acute vomiting).

  • The complete control of vomiting after 24 hours of chemotherapy treatment (delayed vomiting).

  • The adverse event rate.

We will explore heterogeneity using Cochran Q and I2 statistics, and graphical displays (funnel plots) to explore publication bias. For the sensitivity analyses we will include the comparison between random and fixed effects models, and if appropriate, stratification analysis.

Table 1. Emetogenic potential of chemotherapy drugs (Modified from Kris 2006)

Emetogenicity

Drug

HIGH (> 90%)

Cisplatin

Dacarbazine

Mechloretamine

Streptozocin

Cyclophosphamide (> 1500 mg/m2)

Actinomycin‐D

Carmustine

MODERATE (30 to 90%)

Carboplatin

Oxaliplatin

Cyclophosphamide (<1500 mg/m2)

Lomustine (CCNU)

Daunorubicin

Doxorubicin

Epirubicin

Idarubicin

ARA‐C (Arabinoside cytosine)

Ifosfamide

Irinotecan

LOW (10 to 30%)

Paclitaxel

Docetaxel

Mitoxantrone

Topotecan

Etoposide

Pemetrexed

Methotrexate

Mitomycin

Gemcitabine

Cytarabine (< 1000 mg/m2)

Fluorouracil

Bortezomib

Cetuximab

Trastuzumab

Rituximab

Bevacizumab

Busulfan

2‐chlorodeoxyadenosine

Fludarabine

Vinblastine

Vincristine

Vinorelbine

Bleomycin

Figures and Tables -
Table 1. Emetogenic potential of chemotherapy drugs (Modified from Kris 2006)