Both chemotherapy and radiotherapy are the main treatments for malignant tumors, while nausea and vomiting are among the most common adverse effects of chemotherapy and radiotherapy. Acute and severe nausea and vomiting may lead to dehydration, electrolyte disorders, malnutrition, and in serious cases, bleeding, infection or even death due to damage of the gastrointestinal mucosa. Therefore, how to prevent and treat chemotherapy-induced nausea and vomiting has been one of the important issues faced by clinical oncologists.
Chemotherapy-induced nausea and vomiting
Classification of CINV
Anticipatory CINV Anticipatory chemotherapy-induced nausea and vomiting (CINV) refers to nausea and vomiting that occurs immediately before the start of the next cycle of chemotherapy in patients who have had uncontrollable CINV during previous chemotherapy, and is seen in 18% to 57% of patients who have received chemotherapy.
Psychosomatic factors are the main cause of anticipatory CINV and are associated with poor control of previous CINV. Once it occurs, treatment with existing antiemetic drugs is basically ineffective and can be treated with sedation, behavioral modification, and systemic desensitization.
Acute CINV: Acute CINV usually occurs within 24 hours (h) after the administration of chemotherapeutic agents, peaks at 5-6 h and may last for more than 18 h, after which the vomiting stops or turns chronic. The most severe form of CINV is associated with the release of 5-hydroxytryptamine (5-HT) from intestinal chromophores caused by chemotherapeutic agents. 5-HT3 receptor antagonists combined with glucocorticoids are the usual treatment regimen. Acute symptoms that are not effectively controlled in a timely manner increase the risk of delayed CINV.
Delayed CINV: Delayed CINV usually occurs 24-48 h after chemotherapy and sometimes lasts up to 1 week. It occurs in about 40% to 50% of chemotherapy patients. These reactions occur late, last longer, and have relatively mild symptoms. The mechanism of its occurrence is unknown.
Fulminant CINV: Fulminant CINV is defined as severe nausea and vomiting that occurs despite prophylactic treatment of the patient and requires salvage antiemetic therapy.
Refractory CINV: Refractory CINV is defined as the recurrence of vomiting after failure of previous prophylactic and salvage antiemetic therapy.
Mechanisms of CINV
CINV is currently thought to be caused mainly through the following pathways.
(i) stimulation of the gastrointestinal tract by chemotherapeutic agents, release of neurotransmitters by chromophores, binding of neurotransmitters to the corresponding receptors and transmission from the vagus and sympathetic nerves to the vomiting center resulting in vomiting.
(ii) Chemotherapeutic drugs and their metabolites directly stimulate the chemoreceptor trigger zone (CTZ, located at the base of the 4th ventricle), which in turn transmits to the vomiting center and triggers vomiting.
(iii) Sensory and psychological factors directly stimulate the cortical pathways leading to vomiting, which is mostly seen in anticipatory CINV.
The main neurotransmitters that cause vomiting are dopamine, histamine, 5-HT and substance P. Among them, dopamine, 5-HT and substance P are the three neurotransmitters most relevant to CINV, which bind to the corresponding dopamine receptor 2, 5-HT3 receptor and NK-1 receptor, respectively, and stimulate the CTZ and vomiting center to induce the vomiting response.
Influencing factors of CINV
The influencing factors are divided into two categories: pharmacological and non-pharmacological.
Pharmacological factors: pharmacological factors are related to the strength of the emetogenic effect of chemotherapeutic drugs, single dose of drugs, usage and whether antiemetic drugs were applied reasonably and effectively in previous chemotherapy.
Non-pharmacologic factors: Non-pharmacologic factors include age, gender, tolerance of alcohol intake, degree of vomiting during pregnancy, and degree of nausea and vomiting from previous chemotherapy. Patients who are usually younger, female, poor drinkers, have a heavy reaction to previous pregnancy vomiting, and have poorly controlled previous CINV are at increased risk of nausea and vomiting.
Basic principles of controlling chemotherapy vomiting in cancer patients
Prevention of nausea and vomiting is the fundamental goal.
In patients receiving chemotherapy with moderate or high risk of emesis, nausea and vomiting may persist for 2 and 3 days, respectively, after the end of chemotherapy, and antiemetic therapy must be administered throughout the chemotherapy emesis risk period.
For nausea and vomiting induced by multi-drug combination regimens, the treatment plan should be based on the drug with the highest risk of causing emesis.
In addition, attention must be paid to other potential emesis-causing factors in cancer patients, including intestinal obstruction, vestibular dysfunction, brain metastases, electrolyte disturbances, uremia, use of opioid narcotics, concomitant gastric disorders, and psychosomatic factors.
Prevention and treatment of anticipatory vomiting
Optimal antiemetic treatment regimens during each cycle of chemotherapy are essential to prevent anticipatory vomiting. Behavioral treatments include relaxation therapy, systematic desensitization, hypnosis, reverie, music therapy, acupuncture and acupressure. In terms of pharmacological treatment, oral alprazolam starting 1 night before treatment or oral lorazepam 1 night before and the morning of treatment is currently recommended.
Treatment of fulminant CINV
For fulminant CINV, prevention is more important and easier than treatment.
The general principle of management is to combine other effective antiemetic drugs with different mechanisms of action, including antipsychotics, benzodiazepines, cannabinoids, dopamine receptor antagonists, phenothiazines, 5-HT3 receptor antagonists, and steroids, with no superiority or inferiority among the various types of drugs.
Treatment of fulminant CINV emphasizes on-time dosing rather than on-demand dosing. If nausea and vomiting are controlled, treatment continues with the original regimen, and vice versa with a higher level of antiemetic therapy. If the patient vomits too frequently to take oral medication, rectal or intravenous administration is more appropriate, and adequate fluid intake must be ensured to prevent electrolyte disturbances.
The efficacy of the current antiemetic regimen should be re-evaluated before the next cycle of chemotherapy, and if it is not effective, the antiemetic should be changed. In addition, various non-chemotherapy factors associated with fulminant CINV, such as brain metastasis, electrolyte disturbance, intestinal tumor infiltration or abnormal gastrointestinal function, should be noted.
When antiemetic therapy is ineffective, the following measures are recommended.
① Addition of aripitant for those who have not used it previously.
② Combination with other antiemetic drugs.
③ Adjusting the intensity or frequency of 5-HT3 receptor antagonists or switching to other similar drugs.
④ If the patient is receiving palliative chemotherapy, consider using other chemotherapy regimens with similar efficacy and less risk of emetogenesis.
⑤ Combining anti-anxiety medications with treatment with antiemetics.
Guidelines for prevention and treatment of radiation-induced nausea and vomiting
The prevention of radiation-induced nausea and vomiting (RINV) depends on the site of radiation therapy and whether it is combined with chemotherapy; the guidelines for the prevention and treatment of CINV are available for the combination of radiation and chemotherapy. For those who receive upper abdominal or systemic radiotherapy, daily oral ondansetron or granisetron and, if necessary, oral dexamethasone are recommended; prophylaxis is not recommended for radiotherapy at other sites. For those who develop explosive vomiting, daily oral ondansetron is recommended.
Treatment principles for managing multi-day chemotherapy vomiting
Patients receiving multiple days of chemotherapy are at risk for both acute and delayed emesis, the emesis-causing properties of which are related to the chemotherapeutic agents and their sequence of administration. After the first day of chemotherapy, acute and delayed emesis will overlap, and treatment of delayed emesis must be tailored to the severity of emesis from the previous cycle of chemotherapy. For those receiving chemotherapy with moderate-to-high risk of emesis, a 5-HT3 receptor antagonist is recommended first before each day of chemotherapy and dexamethasone once daily; for those receiving chemotherapy with a higher risk of delayed emesis, dexamethasone should be administered for 2 to 3 days after the end of chemotherapy. If the chemotherapy regimen already contains glucocorticoids, the addition of dexamethasone is not recommended. The use of palonosetron avoids the previous cumbersome use of first-generation 5-HT3 receptor antagonists that had to be administered daily in multi-day chemotherapy. Arepitant is recommended for multi-day chemotherapy with a high risk of emetogenic or delayed vomiting, and may be used in combination with a 5-HT3 receptor antagonist and dexamethasone.