The new generation of drugs that have emerged as part of antiemetic cocktails have demonstrated greater success in preventing and controlling CINV but the symptoms—particularly nausea—still present significant obstacles in anticancer therapy, and the ultimate goal of prevention in all patients has yet to be attained.
Major Categories of CINV
Based on differences in the timing of onset, CINV has been classified into five main categories: acute, occurring within 24 hours of the start of chemotherapy; delayed, occurring 24 hours to several days postchemotherapy; anticipatory, occurring before a subsequent cycle of chemotherapy (this is a learned response often triggered by a fear of CINV or previous experience); and breakthrough and refractory, both occurring despite preventive treatment.
CINV occurs following treatment with many different kinds of chemotherapeutic agent, but it was the introduction of cisplatin-based therapy in the late 1970s that dramatically increased the incidence of this toxicity and thrust it into the spotlight. Clinicians have since developed guidelines for the management of CINV, which introduced a classification system for cytotoxic drugs based on their emetogenic potential.
During the past 25 years, an improved understanding of the molecular pathways involved in the pathophysiology of chemotherapy-induced nausea and vomiting (CINV) has translated into major advancements in preventive treatment including FDA approval of two new drugs in the past 18 months. Nevertheless, it has become clear that these pathways are highly complex, involving a myriad of different neurotransmitters and receptors located centrally in the brain and peripherally in a number of tissues and organs.
Cisplatin falls into the category of highly emetogenic. The percentage of patients with acute emesis caused by single-agent cisplatin in the absence of preventive therapy is more than 90%. Chemotherapy drugs can also be classed as having moderate (>30%-90%), low (10%-30%), or minimal (0-<10%) emetogenic potential.
The emetogenic potential varies not only according to the type of drug but also in response to other factors, such as the dose administered and the intravenous infusion rate. What’s more, drugs that are only moderately emetogenic when administered as a single agent may become highly emetogenic when used in combination, with a prime example being the combination of epirubicin and cyclophosphamide.
Nausea and vomiting are not restricted to chemotherapy and can be caused by other types of anticancer drugs; however, until recently this was largely overlooked. Numerous anticancer agents including targeted therapies and immunotherapies are now being assessed for their emetogenic potential.
Unraveling Pathways of Emesis
Two pathways have been pinpointed as particularly important in CINV: the peripheral pathway in the gastrointestinal (GI) tract and the central pathway involving the chemoreceptor trigger zone (CTZ) in the brain. Both pathways lead to the vomiting center, a network of neurons located in the region of the brain known as the nucleus tractus solitarius (NTS), which ultimately coordinates the physical manifestation of vomiting.
Chemotherapy is toxic to the enterochromaffin cells that are found throughout the GI tract and causes them to release increased amounts of the neurotransmitter serotonin. This binds to serotonin receptors located on structures in the GI tract and the brain and on the vagal afferent nerves that transmit signals between the two. This then either stimulates nausea and vomiting directly (acute CINV) or initiates the central pathway, resulting predominantly in delayed CINV.
Chemotherapy also stimulates the release of another neurotransmitter, substance P, which activates the central pathway by binding to neurokinin 1 (NK1) receptors, primarily in the NTS in the brain. The signal is then transmitted to the CTZ and then on to the rest of the vomiting center.
A number of other receptors and neurotransmitters including the dopamine, cannabinoid, his tamine, and acetylcholine receptors are thought to be involved in CINV; however, substantially less is known about their precise mechanism of action. It is also likely that there is significant crosstalk between the serotonin and NK1 receptor pathways and potentially other as yet unidentified pathways of nausea and vomiting.
Advances in Preventive Therapy
Initially, corticosteroids such as dexamethasone and dopamine receptor antagonists including metoclopramide and haloperidol formed the basis of preventive therapy for CINV, but these proved to have limited effectiveness in the setting of more highly emetogenic chemotherapy (HEC). With the introduction and widespread adoption of cisplatin-based chemotherapy, this became an increasingly important unmet need.