Help For Chemotherapy-Induced Nausea and Vomiting

Improved emesis prevention and treatment during the past 15 years have made the prospect of antineoplastic chemotherapy less daunting for patients. Although treatment of chemotherapy- induced nausea and vomiting (CINV) is much better than that available in the 1980s?when patients might vomit 10 to 20 times in a 24-hour period after receiving cisplatin?practitioners may be remiss if they believe that it is no longer a problem.

The ideal antiemetic would (1) control acute and delayed nausea and vomiting completely; (2) be without side effects; (3) offer convenient and easy-to-use dosing; and (4) eliminate cost as a barrier to use. All of those ideals have not yet been achieved.

Who Experiences CINV?

Individuals who possess certain risk factors are predisposed to CINV: women, people <50 years of age, those with low or no alcohol intake, and those who previously have experienced emesis from chemotherapy. A history of motion sickness and emesis during past pregnancy also increase the chances of experiencing CINV.¹ Currently, CINV treatment paradigms are not based on risk factors, but doing so remains a goal of therapy for the future.

Generally, CINV is described as one of 3 types:

• Acute nausea and vomiting occurring within 24 hours of chemotherapy, usually peaking within 6 hours
• Delayed nausea and vomiting occurring on or after treatment day 2?a frequent treatment complication following cisplatin, carboplatin, cyclophosphamide, or doxorubicin
• Anticipatory nausea and vomiting?a conditioned response that may follow prior chemotherapy-induced emesis

These clinical trial-based definitions are not rigid. It is sometimes difficult to differentiate between the end of acute emesis and the beginning of delayed emesis.

Peripherally and centrally mediated, vomiting is driven by multiple receptors (5-hydroxytryptamine³ [5HT₃], neurokinin 1 [NK₁; substance P], and dopamine). Good prevention and control require multiple receptor intervention.

What Helps CINV?

The current armamentarium to treat CINV consists of a short list of drug categories:

• The 5HT₃ receptor antagonists (5HT₃RAs)
• Steroids, usually dexamethasone
• Metoclopramide
• Substance P inhibitors
• Other drugs

Until recently, optimal dosing lacked empirical evidence. The Italian Group for Antiemetic Research conducted one of the first multicenter, randomized, double-blind studies to determine the optimal intravenous (IV) dose of dexamethasone. They established its efficacy for highly emetogenic chemotherapy at single doses of 12 to 20 mg when given with a 5HT₃RA. Dexamethasone was well tolerated, and no significant adverse events occurred.² Roila et al examined 585 patients and found that single doses of 8, 12, and 24 mg of dexamethasone are equally effective as combination therapy with moderately emetogenic chemotherapy. Reducing or eliminating the steroid dose, a prudent clinical goal, is thus possible.³

A meta-analysis of studies comparing 5HT₃ antagonists with conventional antiemetics confirmed that 5HT₃ antagonists reduce acute vomiting risk, compared with conventional antiemetics with moderately to highly emetogenic treatments. The investigators also concluded that acute vomiting risk seems to be improved when 5HT₃ antagonists are combined with dexamethasone.⁴

Preclinical trials of selective NK₁ antagonists (of which only aprepitant is FDA-approved) suggested possible activity for these agents in cisplatin-induced delayed emesis. Indeed, the utility of aprepitant has been validated.^5-7 A pharmacokinetic study in healthy subjects found that concurrent administration of aprepitant increased dexamethasone levels approximately 2-fold.8 Consequently, researchers reduced the oral dexamethasone dose by 50% to 12 mg in aprepitant arms of randomized trials.^9,10 The 12-mg oral dose that was tested in 2 phase 3 studies is now recommended.

In the "Other Drugs"category are prochlorperazine and trimethobenzamide and similar traditional agents. Prochlorperazine remains the most commonly prescribed antiemetic in the United States. Randomized controlled trials of platinum-induced emesis, however, demonstrated that it was no better than placebo.¹¹

How Likely Is CINV?

Experts classify antineoplastic chemotherapy as acutely, moderately, or highly emetogenic (Table)?descriptors that do not include information about when to expect CINV. Emesis often is very predictable in terms of likelihood and type following specific drugs. Often, it is biphasic. Cisplatin causes day 1 emesis in almost all patients, and its delayed component appears to peak around day 3 and may last for 7 to 9 days after treatment. It is considered the most emetogenic of antineoplastic chemotherapies, and it is used as a standard in trials testing new agents. On the other hand, emesis from cyclophosphamide may start 10 to 14 hours after administration and persist for 48 hours.

Treatment Considerations

According to antiemetic guidelines developed at the University of Texas12 and augmented with recent consensus guidelines,13 clinicians should consider several facts when prescribing:

• As with most medical problems, prevention is preferable to treatment.
• The 5HT₃RAs are clinically equivalent when administered at appropriate doses. Doses of 100 mg dolesetron IV, 1 mg granisetron IV (1 mg po bid, 2 mg po daily), 8 mg ondasetron IV (8 mg po bid, 24 mg po daily), or 0.25 mg palonosetron IV are considered equivalent.
• Using the lowest effective antiemetic dose reduces the likelihood of side effects and also contains cost. Higher doses or longer exposure will probably not help breakthrough emesis. It probably is mediated by something other than inadequate 5HT₃ receptor blockade.^12,13
• A single daily dose of any 5HT₃RA is as effective as multiple daily doses.^12,13
• Adding a corticosteroid whenever possible will reduce acute CINV^12,13
• Oral and IV regimens of any 5HT₃RA are clinically equivalent.^12,13 The simplicity and lower cost of oral administration make it preferable if the patient's gastrointestinal tract is uncompromised and if the patient is reliably adherent.

When antiemetics, used according to the guidelines, fail to control CINV, there is no standard treatment. Clinicians have reported adjusting doses, switching, and adding drugs. The paucity of data fails to elucidate an appropriate course of action.¹⁴

Is There Room for Improvement?

Around the time that palonosetron and aprepitant were introduced, a group of researchers surveyed physicians, nurses, and patients about CINV. They were interested in perceptions and satisfaction with the existing therapies. Their findings indicate room for improvement:

• Experienced oncologists and nurses overestimate acute CINV control rates for patients receiving moderately emetogenic chemotherapy regimens
• Although 5HT₃ antagonists and steroids are used frequently, fully a third of patients treated with common regimens experience CINV on the first day of treatment
• Particularly for women and younger patients, delayed CINV is more common than previously thought
• Compliance with existing CINV guidelines helps, but delayed CINV still occurs¹⁵

Better drugs are needed for delayed CINV. It will be interesting to see whether the addition of aprepitant?which improves the complete response rate of delayed CINV when used in combination with dexamethasone, compared with dexamethasone alone16?and palonosetron?with its longer duration of action?will prove effective for the prevention of delayed CINV when used extensively outside of clinical trials.

Vomiting Versus Nausea

The current standard of care is based on research findings that available 5HT₃ antagonists address acute vomiting well, but they are not as effective for nausea. In trials in which nausea and vomiting were measured, the response to nausea was typically lower than the response to vomiting control. Additional doses of a 5HT₃RA will not help patients who report nausea or breakthrough vomiting.^17-19

Conclusion

Given a choice, it is safe to assume that anyone would choose to avoid CINV. Fortunately, the newer agents described herein have few side effects and are used for such a short period of time that they rarely become a treatment concern. Until chemotherapy becomes antiquated, emesis prevention and treatment will continue to be highlighted in oncology care.

Dr. Zanni is a psychologist and health-systems consultant based in Alexandria, Va.

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