Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting
Three distinct types of CINV have been defined, with important implications for both prevention and management:
- Acute emesis, which most commonly begins within one to two hours of chemotherapy and usually peaks in four to six hours
- Delayed emesis, occurring more than 24 hours after chemotherapy
- Anticipatory emesis, occurring prior to treatment as a conditioned response in patients who have developed significant nausea and vomiting during previous cycles of chemotherapy
OVERVIEW OF THE APPROACH TO PROPHYLAXIS
- Estimating the risk of nausea and vomiting — The most important factor determining the likelihood of acute or delayed emesis developing during chemotherapy is the intrinsic emetogenicity of the particular agent.
- other factors
- patient age,
- sex, and
- history of alcohol consumption,
Chemotherapy agents were divided into four categories based upon the risk of emesis in the absence of antiemetic prophylaxis:
●Highly emetic – >90 percent risk of emesis Anthracycline/cyclophosphamide for breast cancer
(Carmustine, Cisplatin, Cyclophosphamide ≥1500 mg/m2, Dacarbazine, Mechlorethamine, Streptozocin)
●Moderately emetic – >30 to 90 percent risk of emesis
●Low emetogenicity – 10 to 30 percent risk of emesis
●Minimally emetic – <10 percent risk of emesis
For combination regimens, the emetic level is determined by identifying the most emetic agent in the combination and then assessing the relative contribution of the other agents.
As an example, cyclophosphamide and doxorubicin are both moderately emetogenic agents, but when given together, the regimen is highly emetic.
Choosing the prophylactic strategy —
The three categories of drugs with the highest therapeutic index for the management of CINV are
- (5-HT3) receptor antagonists,
- the neurokinin-1 receptor (NK1R) antagonists,
- and glucocorticoids (especially dexamethasone).
- antipsychotic medication olanzapine.
An important point is that virtually all of the clinical trials evaluating CINV have focused on intravenously delivered chemotherapy.
Therefore, evidence-based guidelines for antiemetic prophylaxis with oral chemotherapy agents are not currently possible.
Highly emetogenic chemotherapy
Cisplatin and other highly emetogenic single agents
●Day 1 – a combination of an NK1R antagonist, a 5-HT3 receptor antagonist, dexamethasone, and olanzapine.
●Days 2 to 4 – continuing dexamethasone (days 2 to 4) and continuing olanzapine (days 2 to 4).
If aprepitant is used on day 1, we recommend continuing aprepitant on days 2 and 3.
All other NK1R antagonists (i.e., fosaprepitant, rolapitant, netupitant) are administered on day 1 only.
Moderately emetogenic chemotherapy
●Day 1 – a combination of an NK1R antagonist, a 5-HT3 receptor antagonist, and dexamethasone on day 1.
●No additional prophylaxis beyond day 1 for delayed emesis is recommended.
●Day 1 – a combination of a 5-HT3 receptor antagonist plus dexamethasone on day 1.
●Days 2 to 3 – To prevent delayed emesis if the regimen contains agents with known potential to induce delayed emesis (eg, oxaliplatin), we suggest single-agent treatment with dexamethasone on days 2 and 3.
If a first-generation 5-HT3 receptor antagonist is used rather than palonosetron on day 1, then treatment with a first-generation 5-HT3 receptor antagonist alone on days 2 and 3 is a reasonable alternative.
Low emetogenic chemotherapy
● dexamethasone (4 to 8 mg) as a single agent.
glucocorticoid use is contraindicated à a single dose of a drug such as prochlorperazine or a 5-HT3 receptor antagonist.
This patient population generally does not require prophylaxis against delayed emesis.
Minimally emetogenic chemotherapy
● antiemetic therapy not be routinely administered
Prophylactic antiemetics (dexamethasone 4 to 8 mg, prochlorperazine, or metoclopramide) may be administered to patients who have had emesis with prior low-risk regimens, or on an “as needed” basis.
●The primary approach to the prevention of anticipatory emesis is the prevention of CINV beginning with the initial cycles of chemotherapy.
behavioral therapy and/or benzodiazepines.
Poor emesis control/rescue therapy
●For patients who do not achieve adequate control of CINV with their initial antiemetic regimen, the patient’s management à
Olanzapine 5 or 10 mg daily for three days can be considered as rescue therapy for patients with breakthrough nausea and vomiting who did not receive olanzapine initially.
For patients already receiving olanzapine, à agent from a different class than was used for initial prophylaxis (eg, prochlorperazine).
●The modest antiemetic activity of cannabinoids and their unfavorable side effect profile, especially in older patients, limit the clinical utility of this class of agents for the treatment of refractory CINV.
Nevertheless, guidelines from NCCN and ASCO state that cannabinoids can be considered for refractory nausea and vomiting, and as a rescue antiemetic.
ANTIEMETIC EFFICACY OF INDIVIDUAL AGENTS —
- 5-HT3 receptor antagonists —
- has a high therapeutic index for the prevention of CINV.
- more effective than less-specific agents such as high-dose metoclopramide and as effective as the combination of high-dose metoclopramide and dexamethasone.
- When are used in combination with dexamethasone, they are more effective than high-dose metoclopramide plus dexamethasone.
first-generation 5-HT3 receptor antagonists
- ramosetron, and
- An orally disintegrating formulation of ondansetron also is available,àformulation may be particularly useful for patients with dysphagia or anorexia.
- A granisetron transdermal system à extended-release subcutaneous formulation à approved by the US FDA in August 2016 à for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, or combination anthracycline and cyclophosphamide chemotherapy regimens.
● first-generation 5-HT3 receptor antagonists all appear equally effective
●There is a plateau in therapeutic efficacy at a definable dose level for each drug, and further dose escalation does not improve outcomes.
●A single dose of a 5-HT3 receptor antagonist prior to chemotherapy is therapeutically equivalent to a multiple-dose schedule.
●The efficacy of 5-HT3 receptor antagonists is significantly improved when they are combined with glucocorticoids.
●Oral formulations of these agents are as effective as IV formulations.
Electrocardiogram (ECG) interval changes are a class effect of the first-generation 5-HT3 antagonists and are not been reported with transdermal granisetron or extended-release subcutaneous granisetron
ECG interval changes appear to be most prominent one to two hours after a dose of these agents, are mostly small and clinically insignificant, and return to baseline within 24 hours.
potentially fatal cardiac arrhythmias, including torsade de pointes (TdP),
warnings/precautions regarding cardiotoxicity of these agents from the FDA.
Dolasetron — Due to the risk of QTc prolongation from increased drug exposure, the injection form of dolasetron is contraindicated for prophylaxis of CINV in both children and adults.
Ondansetron — The FDA has issued a warning about QTc prolongation and potentially fatal cardiac arrhythmias in patients treated with ondansetron. at a single IV dose of 32 mg
Revised labeling in the United States includes a recommendation to limit single IV doses to no more than 16 mg,
Canadian guidelines that took effect in June 2014 place additional dosing restrictions on IV ondansetron to mitigate the risk of QT prolongation in older adults:
●All IV doses must be infused over no less than 15 minutes.
30- to 100-fold higher affinity for the 5-HT3 receptor and a significantly longer half-life (40 hours) compared with first-generation 5-HT3 receptor antagonists
In contrast to first-generation 5-HT3 antagonists, QTc prolongation has not been described with palonosetron
more effective than ondansetron or dolasetron at preventing emesis due to chemotherapy agents of varying emetogenicity
clinical trial à The dose of 0.75 mg was not significantly superior compared with 0.25 mg.
Netupitant and Palonosetron Combination.
A combination of NK1 receptor antagonist plus 5HT3 receptor antagonist à was recently approved in 2016.
orally about 1 h prior to chemotherapy (together with dexamethasone, at doses varying according to the type of chemotherapy).
When used in combination with glucocorticoids, palonosetron provides superior control of delayed emesis compared with first-generation 5-HT3 receptor antagonists combined with glucocorticoids.
Updated antiemetic guidelines from the National Comprehensive Cancer Network (NCCN) recommend palonosetron as the preferred 5-HT3 antagonist for patients who receive moderately emetogenic chemotherapy.
In contrast, updated guidelines from the Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) do not specify a preferred 5-HT3 antagonist for patients receiving moderately emetogenic chemotherapy.
Neurokinin-1 receptor antagonists —
- aprepitant and fosaprepitant à prevent both acute and delayed CINV in patients receiving highly emetic, IV-administered chemotherapy
longer plasma half-life (approximately seven days) than aprepitant.
NEPA à oral fixed-dose combination containing 300 mg of netupitant (a highly selective NK1R antagonist) and 0.5 mg of the 5-HT3 receptor antagonist palonosetron.
Although few studies have directly compared these agents head to head, the available evidence suggests that they have similar efficacy for control of acute and delayed emesis, at least in the setting of highly emetogenic chemotherapy
An IV equivalent (IV NEPA) consisting of 235 mg of fosnetupitant, a prodrug of netupitant, plus 0.25 mg of palonosetron is also approved in the United States for prevention of CINV in patients receiving highly emetogenic chemotherapy, largely based upon a phase III safety study comparing oral versus IV NEPA.
Like aprepitant and fosaprepitant, netupitant is also an inhibitor of CYP3A4, and a reduced dose of concurrently administered glucocorticoids is needed.
- Short courses of glucocorticoids are widely used both as single agents for regimens with low risk of causing CINV and in combination with 5-HT3 receptor inhibitors and/or NK1R antagonists for more emetic chemotherapy regimens.
- When used in this fashion, glucocorticoids have a high therapeutic index.
Although the various glucocorticoids are probably equally effective when used at an appropriate dose, dexamethasone has been the most extensively evaluated and is the most widely used.
Combination with a 5-HT3 antagonist —
Glucocorticoids alone represent insufficient first-line therapy for patients receiving either moderate or highly emetic chemotherapy agents. However, the antiemetic efficacy of the 5-HT3 receptor antagonists is significantly enhanced by the addition of a glucocorticoid.
single 8 mg IV dose prior to chemotherapy represented the appropriate dexamethasone regimen.
the dose of dexamethasone is reduced when it is in combination with an NK1R antagonist.
- second-generation antipsychotic
- blocks serotonin 5-hydroxytryptamine (5-HT2) receptors and dopamine D2 receptors, maybe a particularly useful agent for the prevention of both acute and delayed nausea and vomiting.