Chemotherapy-Induced Nausea and Vomiting: Great Achievements but Room for Improvement

Clinicians should be aware that the control of emesis has the greatest impact on quality of life during chemotherapy. With the correct use of antiemetics, chemotherapy-induced nausea and vomiting can be prevented in 70% to 80% of patients. Twenty years ago, nausea and vomiting were common adverse events associated with certain types of chemotherapy, forcing up to 20% of patients to postpone or refuse potentially curative treatment. Clinical and basic research over the past 25 years has led to steady improvements in the control of chemotherapy-induced nausea and vomiting.

The development of the 5-hydroxytryptamine (HT)3 receptor antagonists in the early 1990s was one of the most significant advances in chemotherapy of cancer patients. Another group of antiemetics, the neurokinin-1-receptor antagonists, has recently been developed, and the first drug in this class, aprepitant (Emend), has been incorporated in updated antiemetic guidelines. In 1998, the first international antiemetic guidelines from the Multinational Association for Supportive Care in Cancer (MASCC), based on the results of the Perugia consensus conference, were published. These were followed by the American Society for Clinical Oncology (ASCO) guidelines in 1999. Last year, these two sets of guidelines, as well as those from the National Comprehensive Cancer Network (NCCN), were updated.[1-3]

 Noteworthy Study

In this issue of ONCOLOGY, Schwartzberg has reviewed the latest findings in the field of antiemesis as well as the updated antiemesis guidelines. In particular, the author summarizes the results of a recently published study by Grote et al,[4] which deserves closer attention. In this small phase II study, patients with moderately to highly emetogenic chemotherapy received a combination of palonosetron (Aloxi), dexamethasone, and aprepitant on day 1 followed by aprepitant and dexamethasone on days 2 and 3. The intent-to-treat analysis demonstrated an overall response rate of 78% in the delayed phase. These very promising results raised two questions.

First, could the combination of dexamethasone and aprepitant in the delayed phase be responsible for the good response rate achieved in this study? In the updated guidelines, only aprepitant monotherapy is recommended in the delayed phase for patients receiving moderately emetogenic chemotherapy (doxorubicin/cyclophosphamide [AC]-based regimens), when aprepitant was part of the antiemesis prophylaxis in the acute phase. In the study by Warr et al, which formed the basis for the updated guidelines in this setting, patients with moderately/highly emetogenic chemotherapy (AC) received prophylaxis with aprepitant monotherapy alone in the delayed phase. Dexamethasone was used for the prevention of acute, but not for delayed, prophylaxis. In this study, a complete response rate of 55% in the delayed phase was achieved.[5] It might be asserted that the combination of dexamethasone and aprepitant in the delayed phase would have enhanced the antiemetic efficacy rate.

Second, what impact does palonosetron-the so-called second-generation 5-HT3 receptor antagonist-have in the delayed phase? Without doubt, 5-HT3 receptor antagonists are the most important agents in the prevention of chemotherapy-induced nausea and vomiting. Whereas they have excellent activity in the acute phase, they show little activity in the delayed phase. In a recently published meta-analysis, it was demonstrated that the addition of a 5-HT3 receptor antagonist did not significantly improve control of delayed emesis, as compared with dexamethasone monotherapy.[6] However, a patient might benefit from the additional use of 5-HT3 receptor antagonists in the delayed setting.

Indeed, palonosetron demonstrated antiemetic activity in the delayed period, as shown in several studies. However, no steroids were permitted in one study, and in another, only 5% of patients received a steroid as a late treatment modification. Thus, further investigation with different study designs will be necessary to explore the actual role of palonosetron in this setting. Although the results from the phase II study by Grote et al are promising, the use of palonosetron, aprepitant, and dexamethasone should be validated in a large randomized trial.

Metoclopramide

Before the introduction of 5-HT3 receptor antagonists, metoclopramide-usually at high doses and in combination with a steroid-played a primary role in the management of nausea and vomiting. Although not discussed in detail in the review by Schwartzberg (probably because this agent is no longer recommended as a primary drug choice in the management of chemotherapy-induced nausea and vomiting), metoclopramide still deserves attention.

Metoclopramide was included in previous MASCC and ASCO guidelines and was suggested for the prevention of delayed emesis. Although metoclopramide has proven as effective as 5-HT3 receptor antagonists when combined with steroids in the prevention of delayed emesis in some studies, it is, again, not recommended in newer guidelines. Instead, the guidelines suggest that metoclopramide should be reserved for special circumstances, including known intolerance to 5-HT3 receptor antagonists or steroids.

However, given that 5-HT3 receptor antagonists are recommended as an alternative to dexamethasone in the delayed phase with moderately emetogenic chemotherapy, metoclopramide might also be an adequate alternative. In daily practice, metoclopramide is still widely used for the prevention of delayed emesis, possibly due to lower costs and "good experience." A meta-analysis comparing the 5-HT3 receptor antagonists vs metoclopramide in the delayed phase after moderately emetogenic chemotherapy would be beneficial.

Olanzapine

Schwartzberg briefly discusses the antiemetic potential of the atypical antipsychotic agent olanzapine (Zyprexa). Olanzapine's antiemetic properties are the result of its action at multiple receptor sites implicated in the control of nausea and vomiting.[7] The drug has been found to be efficacious and well tolerated in the treatment of chronic nausea related to opioids prescribed for pain in advanced cancer patients.[8] Future studies of olanzapine may not only provide additional options for the control of nausea and emesis due to chemotherapy but may also reveal new information on the pathophysiology of nausea and vomiting due to chemotherapy. The latest phase II study by Navari et al showed exceptionally high rates of complete protection from both acute and delayed nausea and vomiting using a combination of palonosetron (day 1), dexamethasone (day 1), and olanzapine (days 1-4) in patients receiving highly or moderately emetogenic chemotherapy.[9]

Regardless of the major improvements made in controlling chemotherapy-induced nausea and vomiting, the effectiveness of available antiemetic prophylaxis for nausea remains limited. More studies are required to define the optimal treatment of chemotherapy-induced nausea.

-Karin Jordan, MD

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References:

1. Kris MG, Hesketh PJ, Somerfield MR, et al: American Society of Clinical Oncology guideline for antiemetics in oncology: Update 2006. J Clin Oncol 24:2932-2947, 2006.

2. Roila F, Hesketh PJ, Herrstedt J: Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Oncol 17:20-28, 2006.

3. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Antiemesis v.1.2007. Available at www.nccn.org. Accessed June 25, 2007.

4. Grote T, Hajdenberg J, Cartmell A, et al: Combination therapy for chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy: Palonosetron, dexamethasone, and aprepitant. J Support Oncol 4:403-408, 2006.

5. Warr DG, Hesketh PJ, Gralla RJ, et al: Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 23:2822-2830, 2005.

6. Geling O, Eichler HG: Should 5-hydroxytryptamine-3 receptor antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systematic re-evaluation of clinical evidence and drug cost implications. J Clin Oncol 23:1289-1294, 2005.

7. Bymaster FP, Calligaro DO, Falcone JF, et al: Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14:87-96, 1996.

8. Passik SD, Lundberg J, Kirsh KL, et al: A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. J Pain Symptom Manage 23:526-532, 2002.

9. Navari RM, Einhorn LH, Loehrer PJ Sr, et al: A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: A Hoosier Oncology Group study. Support Care Cancer March 21, 2007 (epub ahead of print).