Pathophysiology of Chemotherapy-Induced Nausea and Vomiting
Chemotherapy works by killing rapidly dividing cancer cells but can also damage normal cells with high turnover rates, such as those in the gastrointestinal tract, hair follicles, and bone marrow. The gastrointestinal tract is particularly sensitive to the toxic effects of chemotherapy. Various chemotherapeutic agents can stimulate the chemoreceptor trigger zone (CTZ), a vomiting center located in the area postrema of the brain stem. The CTZ is normally protected by the blood-brain barrier but chemotherapy can cause it to become exposed and stimulated. Stimulation of the CTZ leads to activation of the vomiting reflex pathway and nausea/vomiting as a result.
Dopamine, serotonin, and substance P are important neurotransmitters involved in the vomiting reflex pathway. Chemotherapy drugs such as cisplatin are potent stimulators of dopamine and serotonin receptors in the CTZ and other brain regions implicated in nausea and vomiting. Substance P facilitates communication between the Cancer Chemotherapy Associated Nausea And Vomiting Therapeutics and vomiting center in the brain stem. Understanding the molecular mechanisms and signaling pathways involved in chemotherapy-induced nausea and vomiting has led to development of improved antiemetic therapies targeting these neurotransmitters.
First Generation Anti-Emetics: Limited Efficacy Against Highly Emetogenic Chemo
The first generation of antiemetic drugs developed in the 1970s-80s provided only limited protection against nausea and vomiting caused by highly emetogenic chemotherapy (HEC) regimens containing cisplatin or other platinum agents. These first generation anti-emetics included:
– Antihistamines such as diphenhydramine and hydroxyzine, which block histamine H1 receptors peripherally and centrally. However, histamine plays only a minor role in chemotherapy-induced nausea and vomiting.
– Phenothiazines like prochlorperazine and potassium permanganate, which are dopamine D2 receptor antagonists. Though dopamine receptor antagonism improved control of vomiting versus antihistamines alone, many patients still experienced nausea.
– Benzodiazepines like lorazepam, which have antiemetic effects by augmenting gamma-aminobutyric acid (GABA) activity in the CTZ. However, benzodiazepines showed limited benefit against HEC-induced vomiting and no effect on nausea.
The major limitation of first generation anti-emetics was their inability to control both acute and delayed nausea and vomiting in the majority of patients receiving HEC regimens. This led to development of more effective medications targeting additional neurotransmitter pathways.
Second Generation Anti-Emetics: Multitargeted Approach Improves Outcomes
In the late 1980s and 1990s, second generation 5-HT3 receptor antagonists such as ondansetron, granisetron, and dolasetron were introduced. 5-HT3 receptors contribute significantly to chemotherapy-induced vomiting and these agents demonstrated superior efficacy versus first generation anti-emetics alone in trials of HEC regimens containing cisplatin. Around 60-70% of HEC patients achieved complete response (no vomiting, mild nausea) with 5-HT3 antagonists.
Subsequent introduction of the neurokinin-1 (NK1) receptor antagonist aprepitant in 2003 further improved efficacy. Aprepitant and other NK1 antagonists actcentrally to block binding of substance P to NK1 receptors in trigger zones like the CTZ. Combination therapy with a 5-HT3 antagonist plus aprepitant has become the gold standard for preventing acute and delayed nausea and vomiting caused by HEC, achieving complete response rates of 80-90% in clinical studies.
Corticosteroids such as dexamethasone are frequently included in combination regimens as well. Corticosteroids reduce inflammation in brain areas involved in nausea/vomiting and may also impact neurotransmitter pathways. They provide additional efficacy against delayed nausea and vomiting when combined with 5-HT3 antagonists and NK1 antagonists.
These second generation anti-emetics work through a multitargeted approach, simultaneously blocking pathways mediated by dopamine, serotonin, substance P, and other probable factors. Their superior multi-route efficacy represents a major step forward versus first generation anti-emetics alone.
Current Standards and New Developments
The American Society of Clinical Oncology’s antiemetic guideline recommends palonosetron plus dexamethasone as the preferred dual therapy for acute nausea/vomiting prevention in patients receiving MEC, and a 5-HT3 antagonist plus dexamethasone plus aprepitant as standard therapy for patients receiving HEC. For delayed nausea/vomiting prevention with HEC, extended NK1 antagonist therapy beyond the first day is recommended.
New agents are currently under investigation to provide even better control of chemotherapy-induced nausea and vomiting. These include:
– NK3 receptor antagonists such as serlopitant – NK3 receptors may facilitate emesis through downstream signaling effects on 5-HT3 and NK1 receptors.
– Cannabinoid receptor 1 (CB1) agonists like dronabinol – CB1 agonism shows potential synergistic antiemetic activity with 5-HT3 and NK1 antagonism in preclinical studies.
Various classes of antiemetic medications continue to improve management of CINV as a debilitating chemotherapy side effect. Treatment guidelines recommend optimizing antiemetic prophylaxis based on chemotherapy emetogenicity. Newer agents are further enhancing control of nausea and vomiting for cancer patients undergoing chemotherapy. With the availability of well-studied and effective antiemetic options, CINV need no longer be the dose-limiting factor for administering chemotherapy.
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it.
