Nausea and Vomiting After Chemotherapy: Prevention and Recommendations

Nausea and vomiting caused by anticancer therapy are among the most unpleasant side effects, reducing quality of life and leading to dehydration, missed doses, and premature treatment discontinuations. Modern strategies are based on the principle of "prevention, not cure": if proper prophylaxis is given before the first course, the likelihood of severe nausea and vomiting drops sharply in all subsequent cycles. This is confirmed by large meta-analyses and consensus reports from specialized societies. [1]

Today, five clinical forms of CINV are distinguished: acute (within the first 24 hours), delayed (24 to 120 hours), anticipatory (a conditioned reflex before the next cycle), breakthrough (against the background of prophylaxis, requiring "rescue"), and refractory (despite multiple preventive attempts). Each form has its own pathophysiological "drivers," so regimens are selected with an eye toward preventing both acute and delayed episodes. Particular attention is paid to delayed nausea, which is the type that most often disrupts the patient's daily routine. [2]

The risk of CINV depends on two major factors: "which drug to treat" (the emetogenic potential of the regimen) and "who to treat" (individual factors). Drugs are divided into four risk categories for intravenous administration: minimal, low, moderate, and high; for oral chemotherapy, the system was simplified in 2023-2024 to two categories: "minimal-low" and "moderate-high." This helps standardize prophylaxis choices and reduce interclinical variability. [3]

Current guidelines agree on the key point: highly emetogenic chemotherapy requires triple or quadruple prophylaxis (5-hydroxytryptamine type 3 serotonin receptor antagonist, neurokinin-1 receptor antagonist, dexamethasone, ± olanzapine), while moderately emetogenic chemotherapy requires at least double prophylaxis (5-hydroxytryptamine type 3 + dexamethasone), with expansion to triple prophylaxis for individual drugs, primarily carboplatin with an area under the curve ≥4 and anthracycline-cyclophosphamide-containing regimens. [4]

How risk is assessed: drugs, regimens, and the patient – together

The first thing they look at is the "emetogenicity level" of a specific antitumor agent and regimen. Platinum (especially cisplatin) is considered high-risk; carboplatin, with an area under the curve ≥4, is now considered highly emetogenic in most guidelines; combination regimens with an anthracycline and cyclophosphamide are also considered high-risk. This automatically "raises the bar" for prophylaxis to 3-4 drugs in most patients. [5]

Second, individual factors. The risk is higher in women, in people under 50, with low usual alcohol consumption, a history of motion sickness, severe anxiety, and a history of nausea in previous cycles. These factors add to the "table" risk of the scheme and often prompt the physician to recommend enhanced prophylaxis during the first cycle. This is especially important because a "bad first experience" can be reinforced in the form of anticipatory nausea. [6]

Third, the form of administration. For oral chemotherapy (e.g., capecitabine, trudelvy-sakituzumab govitecan, etc.), the classification was simplified in 2023-2024 to "minimally low" and "moderately high" risk, making the choice of prophylaxis clearer: either no routine prophylaxis is needed at all (but can be prescribed "on demand"), or regular administration of an antiemetic is required on days when the cytostatic is taken. [7]

Finally, the duration and type of antitumor therapy are taken into account. With multi-day courses (for example, high-dose chemotherapy, to which stem cell transplantation is added), prophylaxis regimens are expanded and "stretched" over the entire course, sometimes adding olanzapine; with checkpoint monoimmunotherapy, routine prophylaxis is usually not necessary, but with combinations with chemotherapy, the "chemotherapy rule" applies. [8]

Table 1. Classification of emetogenic risk and practical examples (abridged)

Category (in/in)	Examples	Basic level of prevention
High	Cisplatin; carboplatin AUC ≥4; anthracycline + cyclophosphamide; some antibody conjugates	3-4 drugs (neurokinin-1 receptor antagonist + 5-hydroxytryptamine type 3 + dexamethasone ± olanzapine)
Moderate	Oxaliplatin, doxorubicin <60 mg/m², low-dose ifosfamide, etc.	2-3 drugs (5-hydroxytryptamine type 3 + dexamethasone; consider adding a neurokinin-1 receptor antagonist to carboplatin, AUC 4-5)
Low	Paclitaxel, etoposide, etc.	1 drug before administration (usually dexamethasone or 5-hydroxytryptamine type 3)
Minimum	Vincristine/vinblastine, etc.	No prophylaxis required; medications are available on an as-needed basis.

First-line prevention drugs: who, when, and why

The basis is made up of 3 classes: 5-hydroxytryptamine type 3 receptor antagonists (ondansetron, granisetron, palonosetron), neurokinin-1 receptor antagonists (aprepitant, fosaprepitant, netupitant/fosnetupitant in fixed combination with palonosetron, rolacitant) and dexamethasone. Palonosetron (IV or as part of a fixed combination of netupitant-palonosetron) is particularly effective against the delayed phase, therefore it is often preferred in moderately and highly emetogenic regimens. [9]

Olanzapine has established a strong position in prophylaxis: adding 5-10 mg daily for 3-4 days to the standard triple regimen improves nausea and vomiting control during highly emetogenic chemotherapy. ASCO guidelines now allow a 5 mg dose in adults (with less drowsiness), which is important for the elderly and those who lead an active lifestyle. For moderately emetogenic courses, olanzapine is added on a case-by-case basis if control was poor in the previous cycle. [10]

Neurokinin-1 receptor antagonists differ in their pharmacokinetics and interactions. Aprepitant/fosaprepitant and netupitant/fosnetupitant are moderate inhibitors of cytochrome P450 3A4, so the dexamethasone dose is typically reduced (e.g., by half) when used with them. Rolacitant does not require dexamethasone adjustments, but may interact with cytochrome P450 2D6 and the BCRP transporter; this should be taken into account during concomitant therapy. [11]

Important special cases: carboplatin with an AUC ≥4 - add a neurokinin-1 receptor antagonist already in the first cycle; anthracycline + cyclophosphamide - manage as "high risk" with triple prophylaxis (± olanzapine). Oral chemotherapy of "moderate-high" risk will require daily prophylactic administration of an antiemetic (often 5-hydroxytryptamine type 3), "minimal-low" - an "on-demand" regimen. [12]

Table 2. Standard primary prevention regimens by risk level (adults)

Risk of the scheme	Recommended prevention (day 1)	Next (days 2-4)
High	Neurokinin-1 receptor antagonist + palonosetron/granisetron/ondansetron + dexamethasone ± olanzapine 5-10 mg	Dexamethasone ± neurokinin-1 receptor antagonist ± olanzapine (guidelines)
Moderate	Palonosetron/other 5-hydroxytryptamine type 3 + dexamethasone (if carboplatin AUC ≥4, add neurokinin-1 receptor antagonist)	Dexamethasone or palonosetron/neurokinin-1 antagonist as indicated
Short	One drug 30-60 minutes before infusion (usually dexamethasone or 5-hydroxytryptamine type 3)	Nothing or "on demand"
Minimum	Not required	"On demand"

Step-by-step algorithm: how the team and the patient operate

Step 1: Before the first course, the doctor records the risk based on the regimen and patient factors, selects the initial prophylaxis, and explains which pills to take and when over the next 3-4 days. This is critical: missed "home" doses are the main cause of delayed nausea. The patient receives a written plan with appointment times. [13]

Step 2: At each cycle, a symptom diary is collected: the number of vomiting episodes, the severity of nausea on a 10-point scale, and the use of rescue medications. If nausea persists, prophylaxis is strengthened for the next cycle (for example, olanzapine is added, 5-hydroxytryptamine type 3 is replaced with palonosetron, a neurokinin-1 receptor antagonist is added, or its form is changed to a fixed-dose combination). [14]

Step 3 – in case of a breakthrough, the patient has a "rescue kit": a prouretic (e.g., prochlorperazine), metoclopramide, and sometimes olanzapine for 2-3 days in small doses. If anticipatory nausea recurrs, behavioral techniques and a short course of an anxiolytic are added. The goal is to regain control in the current cycle and prevent the negative reflex from becoming entrenched. [15]

Step 4: "fine-tuning" with consideration of drug interactions. With aprepitant/netupitant, the dexamethasone dose is reduced; when taking antidepressants or antipsychotics, the risk of drowsiness associated with olanzapine is carefully assessed (selecting a dose of 5 mg instead of 10 mg in sensitive patients). During opioid therapy, anticonstipation measures are increased to avoid confusion with symptoms of gastrointestinal toxicity. [16]

Table 3. "If... then..." - quick solutions for complex situations

Situation	What to add/change
Carboplatin AUC ≥4 (from the 1st cycle)	Add a neurokinin-1 receptor antagonist to 5-hydroxytryptamine type 3 + dexamethasone
Delayed nausea persists	Switch to palonosetron; add olanzapine for 3-4 days
Breakthrough nausea in the first day	“Rescue”: prochlorperazine or metoclopramide ± olanzapine
Drowsiness on olanzapine 10 mg	Reduce to 5 mg; move the dose to the evening
Multi-day courses/high-dose therapy	"Stretch" prophylaxis over all days of the course; consider olanzapine

Special populations and scenarios: children, elderly, oral therapy, radiotherapy

For children, the approach depends on age, regimen, and experience. Fosaprepitant is approved for use in young children; palonosetron has a convenient long-acting effect; dexamethasone remains the mainstay of regimens. A balance between efficacy and drowsiness is important, so olanzapine is used selectively and under supervision. Parents are given a clear written home care plan—adherence to the regimen is critical. [17]

Elderly patients are at higher risk of drug interactions, postural hypotension, and daytime sleepiness. Palonosetron and careful use of olanzapine at a dose of 5 mg in the evening are particularly appropriate. Glucose levels should be monitored while taking dexamethasone and the risk of constipation should be monitored when combined with opioids. Reducing the pill load helps with adherence. [18]

For oral chemotherapy, according to the MASCC/ESMO updates, two risk categories and corresponding strategies are sufficient: for "minimal-low" risk, medications "on demand," and for "moderate-high" risk, daily administration of 5-hydroxytryptamine type 3 (or an alternative) on days when the cytostatic is taken. This is a simple and effective algorithm that improves adherence. [19]

During radiation therapy, nausea is provoked by irradiation of the upper abdominal cavity and the whole body; prophylaxis is usually based on 5-hydroxytryptamine type 3 ± dexamethasone on the days of irradiation, and with the combination of chemotherapy and radiation, the rule of the more emetogenic component applies. In patients after stem cell transplantation, quadruple-component regimens are included in certain protocols, but caution is exercised with steroids during cell therapies. [20]

Side effects and pitfalls: how to avoid harm while preventing CINV

Olanzapine may cause drowsiness, dry mouth, and increased appetite; in susceptible patients, a dose of 5 mg at night is selected instead of 10 mg, as recommended in the ASCO/MASCC guidelines. With long-term use of steroids, there is a risk of insomnia, hyperglycemia, and dyspepsia; therefore, short courses are used in prophylactic regimens and doses are reduced when used in combination with aprepitant/netupitant (cytochrome P450 3A4 inhibitors). [21]

Aprepitant and netupitant interact with a number of drugs via cytochrome P450 3A4 (e.g., some cancer drugs, anticoagulants, and antifungals). Rolacitant does not require a reduction in dexamethasone dosage, but it affects cytochrome P450 2D6 and transporters—this is important when taking antidepressants, antipsychotics, and some targeted agents concomitantly. Patients should be aware of these nuances in advance. [22]

Cannabinoids are among the "gray areas." Guidelines reserve them as a "last-line" treatment for refractory nausea when standard approaches have been exhausted. This is based on limited evidence and side effects (sedation, cognitive impairment, dry mouth). Therefore, they are not recommended as prophylaxis. (Consensus position of guidelines.)

Finally, behavioral and non-pharmacological measures such as frequent meals, avoiding strong odors, ginger, and relaxation techniques can add some control, but do not replace pharmacoprophylaxis for moderately and highly emetogenic regimens. Their strength lies precisely in their complementarity with a proper regimen. (Review materials and clinical practice.)

Table 4. Important interactions and dose adjustments

Preparation	What does it affect?	What to do
Aprepitant/fosaprepitant	Cytochrome P450 3A4 inhibitors	Reduce dexamethasone dose; check concomitant medications
Netupitant/fosnetupitant (in combination with palonosetron)	Cytochrome P450 3A4 inhibitors	Reduce dexamethasone dose; consider interactions
Rolacitant	Cytochrome P450 2D6/BCRP inhibitor	Do not reduce dexamethasone; check antidepressants/targeted agents
Olanzapine	Sedation, appetite enhancement	5 mg at night for sensitive individuals; warn of drowsiness

What's new and where is the consensus of societies?

In 2023-2024, MASCC/ESMO updated the classification for oral agents (2 risk categories) and confirmed the role of olanzapine in the prophylaxis of highly emetogenic regimens, including the 5-10 mg dose option. ASCO added a 5 mg dose option in adults back in 2020 and supported the use of intravenous aprepitant and the fixed-dose combination of netupitant-palonosetron (including the intravenous one). These changes have already been integrated into the practices of many centers. [23]

The NCCN and national/regional guidelines have aligned their position on carboplatin: at AUC ≥4, it is recommended to add a neurokinin-1 receptor antagonist from the first cycle. This has significantly increased the proportion of patients receiving adequate prophylaxis in carboplatin regimens, which were previously often limited to dual regimens. [24]

For breakthrough nausea, the consensus remains: "switching the mechanism" (adding or replacing olanzapine, using prochlorperazine/metoclopramide), rather than simply increasing the dose of previous medications. In practice, this offers the best chance of "intercepting" symptoms already in the current cycle. [25]

Finally, a number of reviews emphasize that fixed-dose combinations (e.g., netupitant-palonosetron) are convenient and reduce "adherence errors" at home, as well as simplifying the 3-4-day regimen for the patient. The choice between free-form and fixed-dose combinations is a question of availability and interactions. [26]

Table 5. "Consensus minimum" 2023-2025 for everyday practice

Paragraph	The essence of the update/unified position
Carboplatin AUC ≥4	Maintain as "high risk", add neurokinin-1 receptor antagonist from the 1st cycle
Olanzapine	5-10 mg may be used; preferred for high risk and poor nausea control
Oral chemotherapy	2 risk categories: "minimally low" and "moderately high"
Fixed combinations	Convenient, increases adherence, reduces errors on home days

Frequently Asked Questions (FAQ)

Should I take prophylaxis with every cycle if I didn't experience nausea in the first one?
Yes. The absence of symptoms is due to the prophylaxis. Stopping it without good reason is not recommended: the risk of "rolling back" control is high. Doses and composition can be adjusted based on tolerability. [27]

What's best for severe drowsiness from olanzapine?
Move the dose to the evening and reduce the dose to 5 mg—this option is included in the ASCO/MASCC/ESMO updates and often maintains efficacy with better tolerability. [28]

Why "switch to palonosetron" if another 5-hydroxytryptamine type 3 antagonist has already been used?
Palonosetron is longer-acting and more effective in the delayed phase, so if nausea recurs within 24-120 hours, switching is justified. [29]

Is it true that oral agents are now easier to classify?
Yes. MASCC/ESMO in 2023-2024 simplified the categories to two: "minimally low" and "moderately high" risk, making it easier to choose prophylaxis. [30]

Is prophylaxis necessary with immunotherapy?
If the immunotherapy drug is used alone, usually not. If it is combined with chemotherapy, prophylaxis follows the same guidelines as for chemotherapy drugs. [31]