At the 28th Annual Congress of the Oncology Nursing Society, several presentations focused on the management of chemotherapy induced nausea and vomiting, including evaluating patients' perception of symptoms, efficacy of acupressure, and new approaches with NK-1 antagonists.

Past and Present Strategies

Chemotherapy and radiation therapy may induce emesis by causing enterochromafin cells lining the GI tract to release serotonin. The Antiemetic Unifying Consensus Meeting 2001 developed risk categories of commonly used chemotherapy agents to help guide practioners in their treatment of chemotherapy induced nausea and vomiting (CINV). ¹

*Not Inclusive

Patients receiving combination should receive treatment according to the agent with the maximum risk.

Current classes of antiemtics include benzodiazepines, butyrophenones, phenothiazines, cannabinoids, and most recently serotonin inhibitors – ondansetron, granisetron and dolasetron. Serotonin binds to vagal afferent 5-HT 3 receptors in the GI tract, which in turn send impulses to the vomiting center – physiologic entity that is located in the medulla. Even though the 5-HT c inhibitors drug class shares the same chemical structure, there are pharmacological difference in their selectivity, potency, dose response profiles and half-lives which may affect their activity as antiemetic agents in certain individuals. ² These same differences may assist in differentiating a patient’s individual response to a given antiemetic therapy, resulting in the impact on control of nausea as well as safety of the therapy.

Major differences among the 5-HT 3 antagonists are variations in the metabolism by the cytochrome P450 enzyme, affinities for other receptors involved in potential side effects, dose-response curves, and duration of receptor blockade. ³

Even with the advent of 5HT-3 receptor antagonists in the early 1990’s, now regarded as the gold standard for CINV, some patients still report nausea as being the most distressing side effect of chemotherapy. Adequate control of the acute symptoms of nausea and vomiting seems to correlate well with control of delayed emesis in the same and subsequent cycles. ⁴ The challenge that remains is how we then reduce CINV for the subset of patients who continue to experience emesis undergoing preparative chemotherapy regimens for blood and marrow transplant (BMT) and other intensive chemotherapy regimens.

Prophylactic CINV guidelines have been published by the American Society of Clinical Oncology (ASCO), American Society of Hospital Pharmacists (ASHP), and the National Comprehensive Cancer Network (NCCN). Despite the guidelines, studies indicate that providers are still prescribing incorrectly. Prevention of delayed nausea is being underutilized and mildly emetogenic agents are being over utilized. Temple University is currently conducting a drug utilization evaluation (DUE) based on anecdotal evidence that antiemetics have been prescribed inconsistently for CINV. The goal of the DUE is to apply the findings to clinical practice by educating providers and nurses regarding proper use of antiemetics for CINV. ⁵

In order to plan appropriate symptom management, accurate assessment and documentation of patient’s perception of the symptoms is necessary. Identical surveys were conducted before and after the availability of 5-HT3 antagonist which demonstrated little change in patient perception.⁶

A randomized placebo-controlled clinical trial investigating the effectiveness of acupressure as adjunct to pharmacological control of emesis during the preparative regimen prior to BMT was conducted at Sidney Kimmel Comprehensive Cancer Center (SKCCC). The study purpose was to identify a valid, reliable and clinically useful instrument for the nurse to assess N/V and retching in BMT patients. The validity of the 8-item Modified Rhodes Index of N/V Scale (RINV) was compared to a shortened version of the scale, the Modified Rhodes Index of N/V-Short Version (RINV-SV) developed at SKCCC. The RINV-SV showed an internal consistency reliability of .92. Thus, SKCCC has incorporated the modified instrument in their daily clinical assessment, and symptom management of N/V and retching. ⁷ Patients at risk for developing CINV may be assessed through past medical history, prior chemotherapy experiences and, prescription use for comorbid conditions.

Future Directions

New approaches to the treatment of CINV focus on the recent availability of the neurokinin-1 (NK-1) receptor antagonists (MK-869; aprepitant) for those patients experiencing uncontrolled acute and delayed CINV. Apreitant is a substrate, a moderate inhibitor of the CYP3A4 and CYP2C9 metabolic pathways. The challenges of treating delayed symptoms may be related to neurotransmitters other than serotonin that may be involved. Data suggests that the use of NK-1 antagonist in combination with granisetron and dexamethasone may provide better control of emesis during both the acute and delayed phases of emesis. Patients who were previously incompletely uncontrolled during prior cycles of chemotherapy may be at higher risk, thus suggesting a possible synergism in these classes of agents.

A phase III mutlicenter, randomized, placebo-controlled study of patients who were to receive emetogenic regimens was reported. Groups were stratified by regimens. Aprepitant was compared to standard therapy. Group A (aprepitant) received the following: Day 1 aprepitant 125mg, ondansetron 32mg and dexamethasone 12mg. Days 2-3 dexamethasone 8mg and aprepitant 80mg. Day 4 dexamethasone 8mg. Group B (control) received the following : Day 1 placebo, ondansetron 32mg and dexamethasone 20mg. Days 2-3 dexamethasone 16mg and placebo. Day 4 dexamethasone 16mg. Overall response was defined as no emesis and no rescue required in the 120 hours following chemotherapy in cycle 1. Primary cancer diagnosis was lung, ovarian, head and neck, esophageal and gastric cancer. Overall 60% of the patients in the aprepitant arm maintained a CR in the first 120 hours following chemotherapy versus 20% in the control arm. The incidence of adverse experiences was similar to standard therapy. There were no clinically important differences among patient subgroups (age, gender race, primary cancer diagnosis) and the treatment was well tolerated during multiple cycles of chemotherapy.

In conclusion, NK-1 antagonists are the first new approach to CINV prevention in over a decade. Aprepitant in combination with other antiemtic agents appears to improve the prevention of acute and delayed nausea and vomiting associated with initial and repeat cycles of highly emetogenic chemotherapy, including high dose cisplatin. This agent has a novel mechanism of action, appears effective in both acute and delayed nausea and vomiting, and offers an advantage of maintaining control in subsequent cycles of chemotherapy.

References

1. Antiemetic Unifying Consensus Meeting, April 21-22, 2001, New York, NY.

2. Goodin, S., Cunningham, R. 5-HT(3)-receptor antagonist for the treatment of nausea and vomiting a reappraisal of their side-effect profile. Oncologist. 2002;7:426-436.

3. Blower, P., Aapro, M. Granisetron vs andonsetron: is it a question of duration of 5-HT3 receptor blockade? British Journal Cancer. 2002; 86: 1662-1663.

4. Schnell, F.M. Chemotherapy-induced nausea and vomiting – the importance of acute antiemetic control. Oncologist. 2003; (accepted for publication).

5. Pretchel, E., Walker,S. Improving The Use Of Antiemetics For Prophylaxis Of Chemeotherapy-Induced Nausea And Vomiting In An Outpatient Cancer Center. Oncology Nursing Forum. Vol. 30, No. 2. 2003:127. Abstractde 68.

6. de Boer-Dennet, M., et al. British Journal of Cancer. 1997;76:1057.

7. Saltzman, E., Shivnan, J.C., Tolman-Jager, A., Malik, R., Melvin, M., Roman, J. Measuring Nausea, Vomiting and Retching: The Modified Rhodes Index of Nausea and Vomiting Short Version for Research and Clinical Use. Oncology Nursing Forum. Vol. 30, No. 2. 2003:127. Abstract 68.