Guidelines for the control of nausea and vomiting with chemotherapy of low or minimal emetic potential

Abstract

Purpose

The purpose of this study is to update the guidelines for antiemetic therapy to be used with anticancer agents of low to minimal emetic potential.

Methods

Experts from the Multinational Association of Supportive Care in Cancer (MASCC) met in Perugia in 2009 to revise the MASCC antiemetic consensus guidelines. There is an increasing number of anticancer agents which are classified as being associated with a low or minimal risk of nausea and vomiting. However, the emetic potential of such agents and particularly those given as prolonged oral therapy is not well documented, and neither is the optimal antiemetic therapy.

Results

The consensus is that patients receiving anticancer therapy of low emetic potential should receive single-agent antiemetic prophylaxis such as dexamethasone, 5 hydroxytryptamine3 (5HT3) receptor antagonists, or dopamine receptor antagonists. Those receiving anticancer therapy of minimal emetic potential and who have no prior history of nausea and vomiting should not receive antiemetic prophylaxis. Those who experience nausea and vomiting subsequently can receive single-agent dexamethasone, 5HT3 receptor antagonists, or dopamine receptor antagonists.

Conclusions

More data are needed on the emetic potential and the outcome of antiemetic treatment with agents likely to fall into the low or minimal emetic potential category.

The level of risk of a patient experiencing nausea and vomiting after the administration of anticancer therapy is graded from high to minimal depending on the proportion of patients who would experience emesis if no effective antiemetic prophylaxis was given. Low emetic risk is where the frequency of emesis is estimated to be 10% to 30%, while minimal risk is <10% [8]. This will be influenced by the dose of an agent as well as the schedule and route of administration. The list of agents in these categories includes both cytotoxics and newer targeted therapies, by both the intravenous and oral routes [6] (Tables 1 and 2).

Table 1 Emetogenic potential of single oral antineoplastic agents

Table 2 Emetogenic potential of single intravenous antineoplastic agents

There is a lack of clinical data on the emetic potential of some agents, and the emetic potential has not been subdivided into whether the emesis is acute or delayed. The patients’ risk factors for emesis will also need to be taken into account in forming a clinical judgement about the need for prophylactic antiemetics prior to treatment with anticancer agents with low or minimal emetic potential. These include an increased risk by being young, female, not having a high alcohol intake, having experienced emesis during pregnancy or motion sickness, and a past experience of emesis with chemotherapy [18]. Psychosocial factors such as anxiety can also have an impact. Given that the low-risk category covers such a range of frequencies of emesis from 10% to 30%, it can be argued that some patients with no high risk factors may not require prophylactic antiemetics. However, there is no data yet on which to recommend in redefining the boundary between minimal and low risk groups.

A particular issue is the growing number of drugs that are administered in prolonged courses of oral dosing in outpatients. Since emesis may not occur for weeks on such schedules, it is reasonable to observe until the need to treat arises in the absence of data to the contrary. Also, the safety of chronic oral dosing of 5HT3 receptor antagonists has not been defined.

With the increasing number of targeted therapies, more agents of low and minimal emetic potentials are being added to the list. The emetic potential of oral etoposide was studied in 16 patients and found to have been associated with a low risk of emesis [3]. A study of 40 patients demonstrated the feasibility of patient diaries to record the nausea and vomiting of patients receiving oral agents including capecitabine, temozolomide, procarbazine, cyclophosphamide, erlotinib and sunitinib [16].

There are, however, few clinical trials of antiemetic prophylaxis or treatment of emesis associated with these agents. This creates the possibility for overtreatment by antiemetics if regimens which have evidence of efficacy for preventing emesis with anticancer drugs of moderate emetic potential are used. In an Italian Group for Antiemetic Research review of antiemetic prescribed in 4,477 patients, 509 of whom were receiving chemotherapy of low emetic potential, 65.7% were prescribed 5HT3 antagonists inappropriately [20].

In two prior consecutive non-randomised Italian studies where patients were receiving 5-fluorouracil plus folinic acid, half the patients received a 5-HT3 receptor antagonist, and half were observed. There were no differences in emetic control between the two patient groups [11, 12]. A similar finding occurred where 32.2% of patients receiving treatment with agents of low emetic potential received unnecessary prophylaxis for delayed emesis [2].

There is limited information about the antiemetics used successfully with anticancer treatment of low emetic potential. Patients receiving oral etoposide who needed antiemetics were successfully treated with lorazepam, and lorazepam with prochlorperazine [3].

The antiemetic prophylaxis prior to anticancer therapy of high emetic potential is triple therapy with a 5HT3 antagonist, an NK1 antagonist, and dexamethasone [15].

Chemotherapy of low emetic potential does not need to be managed with such an aggressive regimen in order to control the emesis, and single agents are often sufficient. Corticosteroids are used as single agents and in antiemetic combinations of emesis with chemotherapy of severe or moderate emetic potential. Of the corticosteroids, dexamethasone is the most widely used with a meta-analysis of 32 randomised trials showing its efficacy over placebo or no treatment [10]. There is no standard dosing, but trials in combination with 5HT3 antagonists with chemotherapy of moderate emetic potential have shown no advantage to increasing the dose beyond 8 mg/day [13].

There are few trials of which other single agents are best. The 5HT3 receptor antagonists are well tolerated and are candidates to be used in this situation. Older dopamine receptor antagonists are also used.

Prochlorperazine was one of the original agents used for antiemetic prophylaxis prior to chemotherapy and became the control arm for studies of new antiemetic agents [4]. It has been used with chemotherapy of low emetic potential as either prophylaxis or salvage therapy, but has side effects such as sedation, hypotension in high doses and extra pyramidal reactions [9].

Metoclopramide at conventional doses has some limited efficacy in chemotherapy induced emesis including agents of low emetic potential and may be associated with extrapyramidal side effects [5]. It has been shown to have efficacy in delayed emesis. As doses are increased, metoclopramide is a more effective antiemetic probably because at high doses, it inhibits 5HT3 receptors as well as dopamine receptors. In conventional doses, it has been found to be inferior to steroids in alleviating the emesis associated with chemotherapy of moderate emetic potential [19].

Lorazepam is an adjunctive drug to antiemetics, and, when added to agents such as prochlorperazine, improves the control of emesis over prochlorperazine alone for a number of anticancer regimens, including those with low emetic potential, but elderly patients may not tolerate it well [1].

The synthetic cannabinoids, nabilone and dronabinol, have been shown to have antiemetic activity particularly in preventing nausea and vomiting from agents of low to moderate emetic potential [22]. However, the dysphoric side effects, again particularly in the elderly, limit their usefulness.

Olanzapine acts on multiple receptors including dopamine and 5HT receptors, and in antiemetic combinations, has been proven effective against both acute and delayed emesis with anticancer drugs of high or moderate emetic potential. No studies with this agent prior to anticancer therapy of low emetic potential have been reported [17].

There has been a broad consensus between the American Society of Clinical Oncology (ASCO), Multinational Association of Supportive Care in Cancer (MASCC), and the National Cancer Comprehensive Network (NCCN) guidelines over the use of antiemetics with chemotherapy of low and minimal emetic potential [14]. These MASCC guidelines update the previously published version [21].

Low emetic potential

The ASCO guidelines recommend single-agent dexamethasone at 8 mg p.o. or IV daily [15]. The NCCN guidelines recommend single agents, but suggest that they can be dexamethasone 12 mg p.o. or IV daily, or prochlorperazine 10 mg p.o. or IV every 4 or 6 h, metoclopramide 10–40 mg p.o. or IV every 4 or 6 h, and they suggest that these agents may also be administered with or without the adjunctive drug lorazepam 0.5–2 mg p.o. or IV every 4 or 6 h and/or an H2 blocker or proton pump inhibitor [7].

Minimal emetic potential

All guidelines recommend no prophylactic antiemetics prior to administering anticancer agents with minimal emetic potential. If nausea or vomiting occurs, it can be managed with the same regimens as suggested for use with anticancer therapy of low emetic potential.

Guidelines recommendation

Patients with no prior history of nausea and vomiting who receive chemotherapy of low emetic potential in intermittent dosing schedules should be treated with a single antiemetic agent such as dexamethasone, 5HT3 receptor antagonists, or dopamine receptor antagonists as prophylaxis (Table 3). Patients receiving chemotherapy of minimal emetic potential should receive no antiemetic prophylaxis (Table 4). If nausea and vomiting occurs in subsequent cycles, single-agent antiemetics can be used as above.

Table 3 Recommendation for antiemetic prophylaxis for chemotherapy of low emetic risk

Table 4 Recommendation for antiemetic prophylaxis for chemotherapy of minimal emetic risk