Oncology Pharmacotherapy

Chemotherapy-Induced Nausea and Vomiting: Rationale for Cost-Effective Management

Robert P. Bradbury, RPh, BCPS
Department of Pharmacy, H. Lee Moffitt Cancer Center & Research Institute

Introduction

Chemotherapy-induced nausea and vomiting (CINV) is the symptom that causes the most concern to patients receiving chemotherapy.[1] The symptoms vary from slight nausea to protracted vomiting with dehydration, which can significantly affect a patient's well-being.[2] Prevention of CINV has greatly improved the quality of life of patients who are receiving chemotherapy. While recent progress has been remarkable, chemotherapy-induced emesis is still a significant problem, and it is incorrect to assume that the majority of patients can experience complete control of emesis.[3] Treatment of CINV continues to challenge the oncologist and pharmacotherapist.

Economic issues complicate the evaluation of the effectiveness of antiemetic treatments. While the serotonin antagonists have added an effective tool to the clinician's armamentarium, they also have added financial costs that can impact on a hospital's budget. A justification for high antiemetic drug costs has been the shortened hospital stay that can result when effective agents are used.[4] This discussion reviews the etiology of CINV and provides guidelines for the appropriate use of antiemetic agents in accordance with the emetogenic potential of the chemotherapy agent.

Physiology of Chemotherapy-Induced Nausea and Vomiting

The vomiting center (VC) is the physiologic control center that causes emesis. The VC receives input from several areas including the limbic system, the chemoreceptor trigger zone, the vestibular system, and the gastrointestinal tract. The mechanism for CINV is unclear but appears to be closely associated with the release of serotonin. The physiologic mechanism for CINV has been hypothesized to follow this sequence of events (Figure)[4]:

1. Chemotherapy or radiation irritates enterochromaffin cells in the gut mucosa.
2. Enterochromaffin cells are stimulated to release serotonin.
3. Serotonin activates 5-hydroxytryptamine-3 (5-HT3) receptors that have a neuronal connection with the VC.
4. The 5-HT3 receptors stimulate either vagal afferent nerves or central receptors associated with the VC.
5. The chemoreceptor trigger zone (CTZ) also sends impulses to the VC.
6. When a threshold is reached in the VC, nerve impulses travel by the vagus to stimulate emesis.
   

The release of 5-HT3 from the enterochromaffin cells correlates strongly with the administration of cisplatin.[5] The profound nausea and vomiting associated with cisplatin use, probably due to the release of 5-HT3, had been difficult to prevent, but the discovery of the 5-HT3 mechanism for CINV and the production of agents to block the 5-HT3 receptors enable clinicians to reduce cisplatin-induced nausea. The serotonin antagonists have significant activity in preventing the acute nausea experienced with cisplatin administration.

Stimulation of the CTZ may play a significant role in producing CINV. The CTZ can be stimulated by substances either in the blood or in the cerebrospinal fluid. Input from the CTZ is fed into the VC, thereby causing neuronal activity in the periphery that results in vomiting.[4] Dopamine antagonists such as the phenothiazines and butyrophenones seem to have the greatest activity in preventing CTZ-induced nausea and vomiting.

The role of the cerebral cortex in nausea and vomiting is complex and difficult to predict. Anticipatory nausea is a conditioned response based on treatment-related associations. Previous experience will influence the incidence of this type of nausea and vomiting.[4] Anticipatory nausea can be addressed with behavior modification or with dronabinol (a cannabinoid) or with lorazepam (a benzodiazepine).

Delayed emesis is a phenomenon that occurs more than 24 hours after chemotherapy has been administered. Corticosteroids such as dexamethasone have an unknown mechanism of action but exhibit some efficacy against delayed emesis in combination with either metoclopramide or phenothiazine (Table 1).[4]

Emetogenic Potential of Chemotherapy Agents

The emetogenic potential of the specific chemotherapy being used is considered when prescribing antiemetic drugs for CINV. Emetogenic potential is defined as the intrinsic capacity of a chemotherapy agent to produce an emetic episode in a patient who is receiving the agent. The emetogenic potential of chemotherapy agents vary widely (Table 2).[6] Agents with low emetogenic potential such as paclitaxel, vinorelbine, and vincristine require minimal antiemetic intervention. The use of a phenothiazine such as prochlorperazine should be adequate for prevention of nausea and vomiting. The slightly higher incidence of nausea associated with agents such as idarubicin and mitomycin can be treated in most cases with dexamethasone and a phenothiazine. Chemotherapy agents with a high emetic potential include carmustine, ifosfamide, and high doses of doxorubicin, requiring emetic prophylaxis with appropriate doses of serotonin antagonists. Agents such as high-dose cisplatin and streptozocin have a very high emetogenic potential and require high doses of serotonin antagonist plus dexamethasone.

Combinations of agents with moderate emetogenic potential can produce a higher than expected incidence of nausea and vomiting due to additive effects. Cyclophosphamide, doxorubicin, and fluorouracil have a lower potential for causing emesis as single agents than in combinations.[6] Therefore, more aggressive prophylactic treatment may be needed. In addition, when agents with low or moderate potential are administered in high doses, such as before bone marrow or stem cell transplantation, aggressive antiemetic treatment is often necessary to prevent nausea and vomiting.

Some agents such as cisplatin exhibit a delayed emesis effect with an onset at more than 24 hours after chemotherapy administration. Patients receiving this agent often require antiemetic treatment beyond the first 24 hours to reduce nausea and vomiting.

The evaluation and classification of the emetogenic potential of chemotherapy agents enables the clinician to choose appropriate, cost-effective interventions. A classification system of emetogenic potential provides a tool to predict the incidence of CINV prior to treatment and to prescribe accordingly. The selection of the appropriate antiemetic agent can be based on the classification of the chemotherapy being administered. This methodology provides a cost-effective tool to minimize nausea and vomiting in patients treated with chemotherapy.

Choice of Antiemetic Treatment

Serotonin antagonists have greatly enhanced the clinician's choices for treatment of CINV. Prior to their introduction, high-dose metoclopramide was given in doses ranging from 1 to 2 mg/kg every three hours with a maximum daily dose of 12 mg/kg.[1] Metoclopramide was the mainstay of treatment until ondansetron was produced. Approximately 10% of patients receiving metoclopramide experience central nervous system side effects including dystonic reactions and sedation. Dystonic reactions can occur in up to 25% of younger patients.[7] These adverse effects motivated researchers to find an agent with the same antiemetic properties but without the side effects.

The discovery of ondansetron represented a significant improvement in the management of CINV. This drug provides a more specific blockade of the serotonin receptor sites than metoclopramide[8-11] and has a better side-effect profile. Headache is the major side effect of ondansetron.

Dexamethasone was found to improve efficacy when added to metoclopramide, so researchers tested it in combination with ondansetron. A significant improvement in response is seen when dexamethasone is added to ondansetron.[12] Roila et al[13] revealed that by combining dexamethasone with ondansetron, the antiemetic response was improved by as much as 27%. The increased efficacy of the serotonin antagonists when combined with dexamethasone makes this combination a standard of treatment unless contraindicated. Patients using dexamethasone may experience short-term hyperglycemia, or they may experience perineal burning if intravenous (IV) dexamethasone is given too rapidly. This effect is minimized by administering the 20-mg dose over at least 20 minutes.[7]

Granisetron, a serotonin antagonist used extensively in Europe, was introduced in the United States in 1995. The standard IV dose of granisetron in Europe is 3 mg or 40 µg/kg. In a double-blind, crossover study by Noble et al,[14] IV doses of 3 mg of granisetron once daily were compared with 8 mg of ondansetron three times daily. The investigators found no significant difference in response or failure in patients who underwent five days of chemotherapy consisting of daily doses of 15 mg/m² of cisplatin or 1.2 g/m² of ifosfamide in combination with other agents. Gebbia et al[15] compared 3 mg of IV granisetron and 24 mg of IV ondansetron on day 1 of cisplatin therapy and found no significant difference in response. This study also tested the effects of both agents on delayed effects of cisplatin and showed little benefit against delayed nausea and vomiting. In a study of 496 patients for the prevention of cisplatin-induced CINV, Ruff et al[16] compared 3 mg of IV granisetron with 8 mg and 32 mg of IV ondansetron as single doses. No statistical difference in response was found in the treatment arms. In another study by Jantunen et al,[17] IV doses of 8 mg of ondansetron, 5 mg of tropisetron, and 3 mg of granisetron were compared in 166 patients receiving moderately emetogenic chemotherapy, and significantly fewer failures were seen with the granisetron arm. Granisetron has proven effectiveness in CINV as a once-daily dose. Studies in a ferret model suggest that granisetron has twice the duration of action of ondansetron, possibly due to affinity to bind to 5-HT3 receptor sites.[18] This duration of effect with granisetron allows once-daily dosing to prevent CINV.

Butyrophenones and phenothiazines are useful for chemotherapies with low emetogenic potential and for some with moderate potential. They are not indicated for highly emetogenic chemotherapy except in combination with serotonin antagonists. Their greatest benefit is the prevention of CINV mediated by the CTZ center. The recommended dose of the butyrophenone droperidol is 1.25 to 2.5 mg intravenously every four to six hours. The dose for the phenothiazine prochlorperazine is 10 mg (orally, intramuscularly, or intravenously) every six to eight hours in adults up to 40 mg per day. Prochlorperazine may be given rectally as a 25-mg suppository twice daily in adults.

Delayed Nausea and Vomiting

Delayed nausea and vomiting from chemotherapy is not easily treated. Cisplatin is the drug that most often produces this effect and provides the basis for study of this phenomenon. Studies of oral ondansetron compared with placebo found no advantage for ondansetron.[19,20] Kris et al[20] compared oral administration of placebo, dexamethasone, and a combination of metoclopramide plus dexamethasone. Significantly better control of delayed emesis was seen with the combination of 0.5 mg/kg of metoclopramide four times daily for four days plus 8 mg of dexamethasone twice daily for two days followed by 4 mg twice daily for two days.[21] Thus, the use of oral dexamethasone plus metoclopramide or phenothiazine should be considered to prevent delayed emesis due to cisplatin.

Serotonin antagonists - ondansetron and granisetron - are expensive agents that can have a significant impact on the drug expense for the institution (Table 3). The serotonin antagonists constitute the most significant expenditure, ranging from $55 to $186 per day.

Dosage of Serotonin Antagonists

Determination of the effective dosage of serotonin antagonists for various chemotherapy regimens is an important economic issue. An early study[22] to determine effective dosage compared IV doses of ondansetron ranging from .01 mg/kg to 0.48 mg/kg for patients who were receiving cisplatin. Doses above .36 mg/kg offered no greater efficacy and more headache. In a 70-kg patient, a dose of .36 mg/kg is approximately 25 mg. In a European study[16] of 496 patients comparing 8 mg and 32 mg of IV ondansetron and 3 mg of granisetron, no significant differences were found. This study demonstrated the efficacy of low doses of ondansetron in patients who were receiving chemotherapy.

Some clinicians question the use of 32 mg of ondansetron that is promoted on the package insert. A US study by Beck et al[23] showed that this dosage had a greater effect than either a single dose of 8 mg or three doses of 0.15 mg/kg each. This study did not justify the 32-mg dose of ondansetron over the .36 mg/kg dose suggested in the early studies, but it prompted the use of a single, 32-mg dose of ondansetron in the US market. It appears that the most cost-effective use of ondansetron is between 8 mg and 32 mg as a single dose. Some centers have found that 20 mg of ondansetron is effective when combined with dexamethasone for cisplatin-induced nausea and vomiting,[24] while others are currently gathering data to determine the efficacy of lower doses of ondansetron. In a study by Hesketh et al,[25] dosage of ondansetron was calculated according to the emetogenic potential of the agents prescribed. Patients received 8 mg, 24 mg, or 32 mg of ondansetron depending on whether the emetogenic potential from chemotherapy was moderate, moderately high, or high, respectively. A complete response was seen in 77%, 88%, or 72% in the patients who received doses of 8 mg, 24 mg, or 32 mg, respectively. The study concluded that when combined with a fixed dose of dexamethasone, lower doses of ondansetron are effective for chemotherapy with moderately high emetogenic potential. As an example of the authors' classifications, cisplatin above 70 mg/m² was classified as having a high emetogenic potential and 20 to 70 mg/m² as having a moderately high emetogenic potential. This study proved that antiemetic therapy can be tailored to the intrinsic emetogenicity of the agents administered.

Granisetron shares the same dosing challenge that is seen with ondansetron. When approved for use in Europe, granisetron was given as a single, daily IV dose of 40 µg/kg. This represents an average of 3 mg of granisetron per day. While the approved dose of granisetron in Europe is 40 µg/kg once daily, in the United States the approved IV dose is 10 µg/kg. Studies show no significant difference between doses of 10 µg/kg or 40 µg/kg of granisetron.[26,27] Oral granisetron has been recently promoted in the United States as a cost-effective therapy for CINV. Studies evaluating the efficacy of oral granisetron concluded that 2 mg given as either a single dose or divided into two doses daily is effective for highly emetogenic chemotherapy.[28,29] The use of oral granisetron would reduce the cost of the intravenous use by 30% to 50%.

Practice Guidelines for CINV

Implementing practice guidelines can provide a systematic method to provide cost-effective methodology for the prevention of CINV. Clinical practice guidelines are "systematically developed statements to assist practitioner and patient decisions about appropriate health care for a clinical circumstance." [30] Adhering to practice guidelines results in consistent prescribing, which in turn allows for assessment of the cost-effectiveness of a given treatment.

Cost-effectiveness can be defined by the apparent value or outcome obtained with consideration given to the cost in order to achieve that outcome. If a $2 drug results in the same outcome as a $100 drug, then the less expensive drug is more cost-effective. However, if the $100 drug provides an outcome that is valued at more than $98 greater, then the $100 drug is more cost-effective. Complying with practice guidelines would enhance therapy through continuous assessment and adjustment when variances are seen. The use of guidelines also would prevent the use of the $100 drug when the $2 drug would result in the same effect or outcome.

After implementation of practice guidelines for treatment of CINV, Berard and Mahoney[31] reported savings of 32% to 38% over previous expenses on serotonin antagonists. Tables 4 and 5 present guidelines employed at our institution for the prevention of CINV in the nontransplant population. The projected savings after implementation are 20% to 40% of the approximately $1 million annual expenditure at our center. Table 4 provides recommended treatment guidelines for CINV caused by chemotherapy with high/very high (Level 3), moderate (Level 2), and low (Level 1) emetogenic potential. Table 5 provides guidelines for treating delayed emesis from chemotherapy.

Each institution must tailor its practice guidelines to fit its patients' needs. Some centers use protocols for research that have an unpredictable capacity to produce CINV. This requires individualization of practice guidelines due to variability in emetogenic potential produced by the research protocols. For example, transplant centers may use dosages and combinations of chemotherapy with very high emetogenic potentials that may require innovative treatment schemes to prevent CINV. Several factors are considered in the development of practice guidelines for CINV. (1) The emetogenic potential of the chemotherapy is evaluated and classified by current literature, (2) the serotonin antagonists are designated for those patients with high to moderately high emetogenic chemotherapy in combination with dexamethasone, (3) the chosen dosage and route represent the most cost-effective benefit to the patient, and (4) results of treatment are collected to track variance, treatment failures, or noncompliance so adjustments can be made to improve outcomes. Incorporating these considerations not only will improve the outcome of patients who receive chemotherapy, but also will allow reduction of costs.

Conclusions

Utilizing practice guidelines for CINV offers a tool for cost-effective use of antiemetic agents that should improve the outcome of the patient at the lowest cost to the institution. Consistent application of the guidelines allows institutions to assess effectiveness and to make adjustments to improve outcomes. Patient satisfaction and quality of life should be enhanced when CINV is controlled by methodology of practice guidelines that are based on evidence and are tested over time.

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