Overview
Although marked progress in controlling chemotherapy-induced emesis has occurred over the past 25 years, nausea and vomiting remain among the most distressing side effects of cancer chemotherapy. With the increased use of chemotherapy in primary and adjuvant treatment settings, the need for improved control of emesis remains an important consideration in both medical oncology and supportive care.
Several major oncology groups have published consensus reports or guidelines on the prevention of chemotherapy-induced emesis. However, the introduction of new agents may change these paradigms. In addition, an understanding of the neuropharmacology of this problem is valuable in planning patient care.
Pathophysiology of Emesis
Stimulation of Neurotransmitter Receptors
The emetic reflex arc is activated by stimulation of receptors in the central nervous system (CNS) and/or gastrointestinal (GI) tract. These receptor areas relay information to the vomiting center in the medulla, which then coordinates the act of vomiting. The chemoreceptor trigger zone, also located in the medulla, serves as a "chemosensor" and is exposed to blood and cerebrospinal fluid. These areas are rich in a variety of neurotransmitter receptors.
Dopamine
For many years, the dopamine(Drug information on dopamine) receptors were the main focus of interest in antiemetic research. Available antiemetics, such as phenothiazines (chlorpromazine and prochlorperazine(Drug information on prochlorperazine)) and substituted benzamides (metoclopramide), were known to affect these receptors, as were butyrophenones (haloperidol and droperidol(Drug information on droperidol)).
Serotonin
The role of the neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) has also been elucidated. The improved antiemetic activity of higher doses of metoclopramide(Drug information on metoclopramide) was not explained by its dopamine-binding properties but by the fact that it also affects serotonin receptors. This finding led to the development of several highly specific compounds that interact solely with serotonin receptors, specifically the type 3, or 5-HT3, receptor subtype. Several compounds (ondansetron, granisetron(Drug information on granisetron), palonosetron(Drug information on palonosetron)) from this family are currently available in the United States. The 5-HT3 receptor, which is found in both the GI tract and CNS, is an important mediator of the emetic reflex arc. Molecular studies have suggested that mutation of the 5-HT3B receptor subunit may affect antiemetic efficacy.
Substance P
Tachykinins, such as substance P, play an important role in emesis, as well as in pain and a variety of inflammatory conditions. These neurotransmitters are 11–amino acid molecules that bind to specific receptors. Substance P binds to the neurokinin type 1, or NK1, receptor.
Several NK1 receptor antagonists have been synthesized and used both preclinically and in clinical trials in patients receiving cancer chemotherapy. Results indicate that these agents are effective against a broad range of causes of emesis, particularly delayed emesis. The oral agent aprepitant and its intravenous prodrug fosaprepitant have been approved for clinical use. Clinical trials of netupitant and rolapitant are also in progress.
Emetic Problems
Emesis Related to Chemotherapy
Both nausea and vomiting are seen in patients receiving cancer chemotherapy. Nausea occurs at a higher frequency than vomiting and is more difficult to control. The control of vomiting is strongly correlated with the control of nausea, although some patients experience nausea without vomiting.
The three most common emetic patterns in patients receiving chemotherapy are outlined below.
Acute chemotherapy-induced emesis
Acute chemotherapy-induced emesis is defined as nausea or vomiting that occurs within the initial 24 hours of chemotherapy administration. The time of greatest risk is from 1 to 6 hours after chemotherapy with most agents.
Delayed emesis
Delayed emesis is emesis that begins 24 hours or more after chemotherapy administration. Delayed emesis is particularly likely to occur in patients who have received cisplatin(Drug information on cisplatin), carboplatin(Drug information on carboplatin), or cyclophosphamide(Drug information on cyclophosphamide). However, this problem may begin somewhat earlier than 24 hours in some patients.
Anticipatory emesis
Anticipatory emesis is defined as a conditioned vomiting response following inadequate antiemetic protection with prior courses of chemotherapy.
Emesis Unrelated to Chemotherapy
Patients receiving anticancer drugs may also develop emesis for other reasons. Emesis can be induced by concomitant medications (such as analgesics, anti-infectives, or bronchodilators) or by tumor-related complications (such as intestinal obstruction or brain metastases). In these instances, adjustment of medication or treatment of tumor-related complications is more important than selecting an antiemetic agent.
Patient Characteristics and Emesis
History of Poor Emetic Control
Poor control of emesis with past courses of chemotherapy predisposes a patient to unsatisfactory antiemetic results with any subsequent treatment, regardless of the emetic stimulus or antiemetic employed. Both delayed and conditioned anticipatory emesis are more likely to occur in such patients, and there is likely to be greater difficulty in controlling acute emesis.
History of Alcohol(Drug information on alcohol) Intake
Emesis is easier to control in patients with a history of chronic, high alcohol intake (> 100 g/d of alcohol [approximately five alcohol units, or drinks]). In a prospective evaluation of 52 patients receiving high-dose cisplatin and an effective combination antiemetic regimen, 93% of those with a history of high alcohol intake had no emesis, as opposed to 61% of those without such a history. This difference in emesis control is independent of the patient's current alcohol intake.
Age
Most trials have found that it is easier to control emesis in older patients than in younger ones. Younger patients have a predilection for developing acute dystonic reactions when dopamine-blocking antiemetics are administered (see section on "Antiemetic agents for high–emetic-risk chemotherapy"). Younger patients also have a greater tendency to develop anticipatory emesis than do older patients.
Gender
It is more difficult to control emesis in women than in men given the same chemotherapy and antiemetic regimen.
Motion Sickness/Morning Sickness
Patients with a history of motion sickness or morning sickness are more likely to develop chemotherapy-induced nausea and vomiting than are those without such a history.
The above predisposing factors appear to be additive. One can identify patients at particularly high risk for emesis, such as younger women without a history of high alcohol intake. Awareness of these factors is helpful in monitoring individual patients and interpreting the results of clinical trials.
