Introduction

At the 2004 annual meeting of the Oncology Nursing Society, several aspects of the management of chemotherapy-induced nausea and vomiting (CINV) were addressed. CINV remains one of the most common and distressing side effects of cancer treatment. Although management of CINV has improved over time, both nausea and vomiting remain high on the list of the most severe and upsetting of chemotherapy-induced side effects experienced by patients.^1-4 Acute CINV significantly reduces quality of life during treatment, and delayed CINV continues to be an issue after patients return home following their treatment, affecting their ability to perform daily activities.⁵ Furthermore, metabolic disturbances, such as electrolyte imbalances and/or dehydration may occur due to CINV, as well as tearing of the esophageal mucosa, re-hospitalization, increased medical costs and increased time commitments by healthcare providers for the management of sequelae caused by CINV.^6,7 However, one of the most disconcerting consequences of CINV is the tendency of patients to refuse subsequent treatment for their disease because of the distress and/or significant reduction in quality of life caused by CINV, ultimately resulting in suboptimal delivery of treatment for their cancer.⁷

Although practice guidelines for the prevention and treatment of CINV have improved over time, actual clinical practice in this regard lags behind.⁸ Improvement in risk assessment and stricter adherence to guidelines for the prevention and management of both acute and delayed CINV, particularly for initial courses of treatment, may ultimately lead patients to an improved quality of life during therapy, a reduction in time spent by healthcare providers addressing CINV, and ultimately, a higher compliance rate by patients to optimal therapeutic doses for the management of their disease. Newer anti-emetic agents, such as Aloxi™ (palonosetron HCL) and Emend® (aprepitant), which have achieved improved effectiveness coupled with ease of administration, may help to launch a new phase in properly addressing, preventing and managing CINV. Both of these agents were discussed in-depth at this year's ONS meeting.

CINV Physiology

CINV is classified into three separate phases: acute, delayed and anticipatory. Acute CINV is defined as nausea and/or vomiting that occurs within 24 hours of treatment; delayed CINV is defined as nausea and/or vomiting that occurs after the first 24 hours of treatment and up to 120 hours following treatment; and anticipatory CINV is defined as nausea and/or vomiting that occurs prior to the delivery of subsequent courses of therapy.⁹ Breakthrough emesis refers to vomiting that occurs despite optimal prophylactic anti-emetic therapy; however, breakthrough emesis is difficult to assess, as no substantial studies have gathered information to differentiate between true breakthrough emesis and inadequate prophylactic anti-emetic therapy.¹⁰

The physiology behind CINV remains complex, with many biological pathways contributing to its development, several of which are currently under investigation. It is important to recognize that nausea and vomiting are two distinct entities. Nausea is a feeling characterized by the urge to vomit. It is characteristically reported as an extremely unpleasant and uncomfortable sensation, often accompanied by tachycardia, sweating, flushing, and/or restlessness. Vomiting is the actual propulsion of stomach contents through the esophagus and out of the mouth.⁹

CINV is triggered through complex interactions between neurotransmitters and receptors located in both the peripheral and central nervous systems. Vomiting is triggered by a center in the brain located in the lateral reticular formation of the medulla, referred to as the vomiting center. The vomiting center receives afferent signals from the chemoreceptor trigger zone (CTZ), gastrointestinal tract, cerebral cortex, and vestibular apparatus. Several different neurotransmitters are involved in CINV, including serotonin, dopamine, acetylcholine, histamine, and substance P to name a few. One common way in which chemotherapy is believed to induce emesis is by stimulating the release of serotonin by enterochromaffin cells of the mucosal lining of the small intestine. The release of serotonin by enterochromaffin cells is believed to be caused, at least in part, by free radical formation by the chemotherapy agent or other emesis-inducing agent. Serotonin binds to 5-HT3 receptors, which in turn activates vagal afferent nerves that deliver the message to the CTZ. The CTZ stimulates the vomiting center and emesis occurs.^11,12

There are several different types of anti-emetics, including 5-HT3 receptor antagonists, corticosteroids, D2 receptor antagonists, and NK-1 receptor antagonists, with newer and more effective agents continuing to emerge. Perhaps the greatest breakthrough in anti-emesis was the development of 5-HT3 inhibitors, which block the 5-HT3 receptors at both peripheral and central sites from binding of neurotransmitters.¹³ Although it was previously thought that 5-HT3 inhibitors were only useful in the management of acute CINV, the 5-HT3 inhibitor Aloxi™ has demonstrated significant effectiveness in the management of delayed CINV and is the only FDA approved agent in this class for management of both acute and delayed CINV.¹⁴ Other effective 5-HT3 inhibitors include Dolasetron (Anzemet®), granisetron (Kytril®), and ondansetron (Zofran®).

Incidence Discrepancy

One of the major reasons that CINV may be so under-treated in the clinical setting is that healthcare providers perceive the incidence of CINV to be much lower than the actual incidence in patients undergoing chemotherapy or radiation for their cancer. This is particularly true with delayed CINV. The significant discrepancy between the perceived incidence versus the actual incidence of delayed CINV may be partly due to the fact that patients often experience delayed CINV while at home and may not report the side effect to their healthcare provider. A 2002 trial by Grunberg et al. surveyed physicians, nurses and patients from 6 oncology practices regarding the incidence of CINV following moderately emetogenic chemotherapy. The healthcare staff estimated that only 31% of patients would experience acute nausea and 17% would experience acute vomiting following treatment, while patients reported a 47% actual incidence of acute nausea and a 28% actual incidence of acute vomiting. Furthermore, the staff reported an estimated 24% rate of delayed nausea and a 9% rate of delayed vomiting following treatment, while patients reported a rate of 57% for delayed nausea and 41% for delayed vomiting. These results indicate that there is a significant discrepancy between the perceived incidence versus the actual incidence of delayed CINV.¹⁴

Delayed CINV

In 1999, the American Society of Health-System Pharmacists (ASHP) published results from a series of studies evaluating delayed CINV that included placebo-controlled arms. The overall results from these studies indicated that 61% of patients treated with cisplatin-based chemotherapy experienced delayed CINV. Furthermore, according to the patient reports, the most severe nausea and vomiting occurred 48 to 72 hours following therapy.¹⁵ However, prophylaxis against delayed CINV appears to be underutilized according to recommended guidelines, perhaps partly due to the discrepancies between the perceptions of healthcare providers in regards to the incidence of delayed CINV and the actual incidence. In fact, clinical management of the prevention of delayed CINV has not changed substantially since 1985.^15,16 De Angelis et al. conducted a study in 2003 to evaluate the clinical practice of prophylactic anti-emetic use following the publication of recommended guidelines. Records from nearly 2,400 patients treated with chemotherapy – ranging from highly emetogenic to low emetogenic chemotherapy – were reviewed. Less than half (47%) of patients treated with cisplatin-based chemotherapy, and only 20% of patients treated with other highly or moderately emetogenic chemotherapy agents were treated with prophylactic anti-emetics for delayed CINV according to published guidelines.⁸

The prophylaxis of delayed CINV is extremely important in maintaining a patient’s quality of life. For example, Lindley et al. reported that CINV during the 3-day period following chemotherapy (often while a patient is at home) prevented or reduced a patient’s ability to prepare and eat meals, take medications, perform household tasks, run errands, visit with friends, work, or care for others. In addition, quality-of-life assessments have associated uncontrolled CINV with a reduction in scores in cognitive function, insomnia, anorexia, fatigue, dyspnea, and overall quality of life.⁵ Furthermore, oncology nurses report spending an average of approximately 1.5 hours per week on the telephone with their patients at home assessing CINV, indicating that prevention of delayed CINV may allow nurses to have more time to tend to other patients or medical tasks.¹⁷

Prevention is the Key

The optimal strategy is to attempt to prevent both acute and delayed CINV in the initial course of treatment, rather than treating the problem once it has occurred. First, quality of life and patient compliance to further treatment may be maintained if CINV prevention occurs in the initial courses of therapy. In addition, preventing CINV can help to reduce medical cost and the burden of managing CINV. Furthermore, prevention of CINV in the initial course of therapy may lead to reduced CINV in subsequent courses of therapy as experience of CINV with initial courses of chemotherapy is considered to be a risk factor for the development of CINV in subsequent cycles. According to a study published by Montgomery et al., women being treated for breast cancer who experienced nausea following initial treatment had a higher rate of nausea on subsequent courses of therapy compared to those who did not experience nausea during their initial course of therapy.¹⁸ In addition, Gregory et al. and Morrow et al. reported that prior CINV is a significant risk factor for the development of subsequent chemotherapy-induced emesis during treatment with chemotherapy.^19,20

The prevention of CINV may be achieved with the use of risk assessments and models, created from a compilation of data from clinical studies. Risk assessments help to determine which patients are at a higher risk of developing CINV according to patient and treatment characteristics. High-risk patients that are identified through the risk assessment models may be strictly managed for the prevention of CINV according to specified guidelines. Patients identified at moderate-risk for developing CINV may also be treated for the prevention of CINV, while low-risk patients may be spared unnecessary therapy.

Known risk factors for developing chemotherapy-induced emesis include:^20,21,22

• Highly emetogenic chemotherapy agents used in treatment
• High drug doses
• Prior CINV
• Female patients
• Younger patients
• Low alcohol intake
• Anxiety
• Combination chemotherapy
• Higher tumor burden
• Combined modality therapy
• Performance status
• History of morning sickness or motion sickness
• Rapid rate of infusion
• Repetitive daily doses
• Concomitant use of specific other drugs

Emetogenic potential of oncologic agents is classified into 5 levels according to the frequency of emesis without anti-emetic prophylaxis. The moderately and highly-emetogenic agents listed below are from the National Comprehensive Cancer Network (NCCN) guidelines.²³ Some chemotherapy agents are considered moderately emetogenic at lower doses, and highly emetogenic at higher doses.

• Level 1: < 10% frequency of emesis
• Level 2: 10% to 30% frequency of emesis
• Level 3: 30% to 60% frequency of emesis (amifostine, arsenic trioxide, cyclophosphamide, doxorubicin, epirubicin, hexamethylmelamine, idarubicin, ifosfamide, IL-2, irinotecan, lomustine, methotrexate, mitoxantrone, oxaliplatin)
• Level 4: >60% to 90% frequency of emesis (amifostine, busulfan, carboplatin, carmustine, cisplatin, cyclophosphamide, cytarabine, dactinomycin, doxorubicin, epirubicin, melphalan, methotrexate, procarbazine)
• Level 5: >90% frequency of emesis (carmustine, cisplatin, cyclophosphamide, dacarbazine, mechlorethamine, streptozocin)

If combination chemotherapy is being utilized as treatment, the most highly emetogenic agent should be considered as the base level or “score”, with the addition of other agents as follows:^21,22

• Adding a level 1 emetogenic agent does not affect the emetogenic “score” of the combination
• Adding a level 2 emetogenic agent(s) increases the emetogenic “score” by one greater than the most emetogenic agent
• Adding a level 3 or 4 agent increases the emetogenic “score” by one (for each additional agent) greater than the most emetogenic agent

It is important for healthcare providers to properly assess their patients and intended treatment protocols in order to determine the risk of their patient in developing CINV. Once a patient’s risk is determined, healthcare providers should implement prevention protocols according to established guidelines.

New Agents

Aloxi™

5-HT3 inhibitors are among the most widely used and effective anti-emetic agents for CINV. 5-HT3 inhibitors are highly effective in prevention or management of acute CINV, particularly in highly or moderately emetogenic chemotherapy agents. However, the 5-HT3 receptor antagonist Aloxi™ is distinct from other agents in its class in that it has been approved for the treatment of both acute and delayed CINV for initial and repeat doses of chemotherapy. Aloxi™ has 30 times the binding affinity for 5-HT3 receptors than other 5-HT3 receptor antagonists, as well as a significantly longer plasma half-life than other 5-HT3 receptor antagonists (Table 1). The extended plasma half-life of Aloxi™ does not increase the duration of side effects caused by anti-emetic therapy, and its specificity of receptor binding reduces its binding to other untargeted receptors. The most commonly experienced side effects with Aloxi™ are headache, constipation, diarrhea and dizziness, all of which occur in less than 10% of patients.

Table 1.

Aloxi™ is recommended as a single dose given intravenously over 30 seconds and is administered approximately 30 minutes prior to chemotherapy. Results from several phase III clinical trials directly comparing Aloxi™ to other 5-HT3 inhibitors for CINV have been recently published, indicating superiority of Aloxi™ in terms of response rates and duration of response. Furthermore, Aloxi™ has the added convenience of a one-time, short-duration administration coupled with few adverse effects.¹⁴

Phase III trial results

A phase III trial by Gralla et al. directly compared Aloxi™ (.25 mg) to Zofran® following moderately emetogenic chemotherapy in 563 patients.²⁴ Treatment groups were comparable in terms of chemotherapy regimens used, with the majority of primary chemotherapy agents being cyclophosphamide, doxorubicin or cisplatin. Complete responses (including the acute phase, delayed phase and overall), the percentage of patients with no emetic episodes and no nausea, as well as duration of protection against CINV all significantly favored Aloxi™ compared to Zofran® (Table 2).

Table 2. (moderately emetogenic chemotherapy)

  
A second phase III trial by Eisenberg et al. directly compared Aloxi™ to Anzemet® following moderately emetogenic chemotherapy.²⁵ This trial included 569 patients, with the majority of primary chemotherapy agents being cyclophosphamide, doxorubicin and epirubicin. Complete response rates, the percentage of patients with no emetic episodes and no nausea, as well as duration of protection against CINV all significantly favored Aloxi™ compared to Anzemet® (Table 3).

Table 3. (moderately emetogenic chemotherapy)

  

Aapro et al. demonstrated the superiority of Aloxi™ to Zofran® following highly emetogenic chemotherapy.²⁶ This phase III trial included 667 patients whose primary chemotherapy consisted of cisplatin, cyclophosphamide or dacarbazine. All endpoints, including complete response rates, percentage of patients with no emesis, and time to first emetic episode, favored Aloxi™ over Zofran® (Table 4).

Table 4 (highly emetogenic chemotherapy)

  

A trial by Carnmell et al. demonstrated that Aloxi™ (.75 mg) was effective in maintaining high rates of complete responses over repeated cycles of chemotherapy.²⁷ This trial included 875 patients who were treated with a total of 1,167 chemotherapy cycles, the majority of which were rated moderately emetogenic. Prophylactic dexamethasone was utilized primarily only in patients receiving highly emetogenic chemotherapy. In addition to high response rates over the course of several chemotherapy cycles, over 50% of patients (up to approximately 78%) did not experience any emetic episodes (either acute or delayed) during 4 cycles of chemotherapy when treated with Aloxi™ for prevention of CINV.

Aloxi™ was approved in July 2003 with the specific indication of the prevention of acute CINV associated with initial and repeat courses of moderately or highly emetogenic chemotherapy, and for the prevention of delayed CINV associated with initial and repeat courses of moderately emetogenic chemotherapy. Aloxi™ has been incorporated into the 2004 NCCN guidelines as the “preferred” agent to be used for the prevention of acute CINV with moderately emetogenic chemotherapy.²³

Emend®

Emend®, a substance P/neurokinin 1-receptor antagonist (NK1 receptor antagonist), represents a new class of anti-emetic agents.²⁸ Emend® was approved in 2004 to be used in combination with other anti-emetic agents for the prevention of acute and delayed CINV in initial and repeat courses of highly emetogenic chemotherapy, including high-dose cisplatin.²⁹ Substance P is a peptide that is present in the brain and gastrointestinal tract, and is believed to play a role in signal transmission that induces emesis. The signals of substance P are mediated through the neurokinin 1 receptor, classified as a G-protein that is coupled to the inositol phosphate signal transduction pathway. Emend® is an antagonist of the NK 1 receptor, disabling or reducing the emesis signal pathway initiated by substance P.²⁹

Two randomized clinical trials evaluating Emend® that prompted FDA approval were recently published.³⁰ The two trials evaluated the addition of Emend® to a standard anti-emetic regimen (ondansetron plus dexamethasone) to the standard regimen alone. The trials included 1,105 patients, all of whom were treated with cisplatin and 90% of whom also received an additional chemotherapy agent. Outcomes for patients who received Emend® as a component of their anti-emetic regimen were significantly improved over those who received just Zofran® plus dexamethasone.

Study 1

Study 2

  
    
In addition, analyses of these trials demonstrated that female patients achieved the same level of protection against CINV as their male counterparts when treated with Emend®. This finding is notable as female patients tend to have a higher overall incidence of CINV. The recommended dosing regimen is Emend® 125 mg orally one hour prior to chemotherapy treatment (day 1) and 80 mg once daily in the morning on days 2 and 3. The most common side effects of Emend® are fatigue, constipation, diarrhea, and hiccups, all of which are generally mild to moderate.³⁰

Conclusion

The identification of patients who are at risk for developing CINV by healthcare providers through risk assessment models and subsequent aggressive therapy to prevent CINV may ultimately change the course of one of the most dreaded side effects by cancer patients. Through prevention of CINV by diligent management and forethought on the part of the oncology team, patients may enjoy a significantly improved quality of life in several aspects during treatment and following treatment, as well as comply with subsequent treatment choices, ultimately providing the patient with optimal long-term outcomes. In addition, time and resources of healthcare providers and facilities may be utilized more effectively, as costly and timely management of CINV may be dramatically reduced or prevented altogether. Furthermore, newer agents such as Aloxi™ and Emend® that are on the market represent great strides in the improvement of management of CINV. Aloxi™ allows one-time dosing that is effective in preventing both acute and delayed CINV and is associated with minimal side effects, which will provide further convenience in the management of CINV. Emend® helps improve prevention of CINV in both genders of patients undergoing highly emetogenic chemotherapy, including cisplatin.

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