· Chemoreceptor trigger zone: 5 hydroxytryptamine type 2 (5-HT2) or serotonin type 2; D2, neurokinin-1 (NK1), or substance P
· Vomiting center: AChM, H1, 5-HT2, D2, NK1, ([GK mµ] opioid receptors), and cannabinoid (CB) receptors
Each of the aforementioned substances in turn stimulate receptors in the intestinal tract and in the chemoreceptor trigger zone, triggering the vomiting center.1,13,17 Most antiemetic agents block the receptors for one or more of these mediators and are discussed later in more detail. Chemotherapeutic agents specifically cause the release 5-HT and NK1 in the gut, which contains over 90% of the body’s serotonin. This knowledge has led to the development of newer 5-HT3 and NK1 antagonists for CINV. Unlike the other mediators, cannabinoids cause an antiemetic effect when they bind to CB receptors.13,17,19 This finding has led to the development of specific pharmacologic treatment agents.
Etiology and Differential Diagnosis
Perhaps the best way for the emergency physician (EP) to assess the cancer patient with nausea or vomiting is to determine whether the cause is treatment- or nontreatment-related. Treatment-related causes are due to chemotherapy or radiotherapy, and any other causes would be considered nontreatment related. It is, however, wise for the EP to remember that a patient who has had recent chemotherapy can still be at risk for nontreatment etiologies.
Treatment-Related Nausea and Vomiting
Chemotherapy-Induced
Chemotherapy-induced nausea and vomiting has been well-studied in the literature. Chemotherapy is classified as highly, moderately, low, and minimally emetogenic.18,19 Nausea itself is classified as acute (onset within 24 hours), delayed (onset after 24 hours), and anticipatory (prior to the chemotherapy, usually due to anxiety over previous unpleasant experiences). Breakthrough vomiting occurs despite the use of antiemetics and may be acute or delayed up to 5 days.
When evaluating the patient with recent chemotherapy and vomiting, it is prudent to find out if the agent is expected to cause vomiting. For example, a patient on cladribine, which is classified as minimally emetogenic, who experiences significant nausea and vomiting should likely be worked up for another etiology. Even when vomiting is controlled, a significant number of patients still experience nausea without vomiting, which in turn has a negative impact on quality of life.
Even though prophylactic regimens of 5-HT3 and NK1 receptor antagonists have led to improved rates of CINV control,18,19,21 both persistent nausea without vomiting and breakthrough vomiting remain problematic,18 and little scientific work has been done on breakthrough treatment. A small prospective pilot study of the efficacy of prochlorperazine versus serotonin 5-HT3 receptor antagonists for breakthrough vomiting found both medications reduced nausea by 75% at 4 hours.15 In contrast, randomized controlled trials comparing olanzapine to metoclopramide and prochlorperazine for breakthrough vomiting found that at 3 days, olanzapine consistently achieved total relief of vomiting 66% to 70%, while the success rates of the other agents ranged from 20% to 37%.18
Radiotherapy-Induced
Radiotherapy has long been known to adversely affect the gastrointestinal (GI) tract. 5-HT3 (ie, serotonin) is released from the gut enterochromaffin cells, in a manner similar to chemotherapy. A 2015 review on the subject showed that radiotherapy to the upper abdomen is most likely to lead to nausea and vomiting, with 50% to 67% of patients reporting nausea and 21% to 38% reporting vomiting.20 Recommended prophylaxis and treatment regimens are based on consensus expert opinion, highlighting the lack of quality evidence that is seen with CINV. Prophylaxis regimens use 5-HT3 antagonists prior to every session, plus dexamethasone for the first 5 days. Rescue from breakthrough is also treated with 5-HT3 antagonists. The use of daily 5-HT3 antagonists for a long course of radiotherapy, however, can be very expensive and unnecessary.
In addition, there is a delayed nausea and vomiting phenomena that may be due to substances other than serotonin, since 5-HT3 depletes a few days after radiotherapy is begun, and may explain why 5-HT3 antagonists are less effective after the first few days of radiotherapy. Nonpharmacologic treatments such as acupuncture, acupressure, hydrogen therapy, and ginger have been used or proposed as treatments for nausea, with mild benefit and little toxicity, so they should be studied further.20
Nontreatment-Related Nausea or Vomiting
Again, much of what is known about nontreatment cancer-related nausea and/or vomiting comes from the palliative-care literature. It is estimated that 60% of advanced cancer patients experience nontreatment-related nausea, and 30% experience vomiting.1,11 One study of 61 hospice patients showed nausea or vomiting occurred due to the following (listed in order from most to least frequent):
· Impaired gastric emptying due to tumor or hepatomegaly, bowel obstruction, metabolic problems (eg, renal failure, liver failure, hypercalcemia, hyponatremia, ketoacidosis)