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Originally published as JCO Early Release 10.1200/JCO.2003.07.968 on October 14 2003 © 2003 American Society for Clinical Oncology
Why Do We Need Another Antiemetic? Just Ask.Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer and Weill Medical College of Cornell University, New York, NY VOMITING AND nausea are always unpleasant and are, at times, downright awful. Even a single episode of vomiting or wave of nausea can ruin a day and leave a lasting mark on one’s memory. For persons with cancer, who struggle to maintain their physical health, vomiting and nausea are devastating consequences of cancer therapy. Patients surveyed named nausea and vomiting as the most feared effects of chemotherapy.1 When these symptoms occur with repeated cycles of treatment, some persons become conditioned to vomit or develop nausea even before the treatment is given. The mere sight of the clinic building, chemotherapy nurse, or physician can trigger the emetic reflex.2 You don’t need a visit to the library or the Internet to confirm these facts. Just go into a waiting room or chemotherapy suite and ask any patient. The discoveries of metoclopramide,3 dexamethasone,4 and the specific serotonin receptor antagonists ondansetron,5 granisetron,6 and dolasetron7 have all helped prevent, or at least lessen, these symptoms. Giving both dexamethasone and a specific serotonin receptor antagonist works even better.8–10 Evidence-based guidelines have standardized treatments and have fostered their routine implementation.11–15 None of these drugs or regimens, however, prevent symptoms in all patients; nor do they treat vomiting or nausea once they occur. Although physicians—me included—maintain we have made "dramatic improvements in the control and prevention of chemotherapy-induced vomiting"16 during the last two decades, a large proportion of the people we care for disagree. Physicians and nurses must face the fact: nausea and vomiting still occur. Our declared success in controlling emesis provides no comfort to the person who cannot work or attend his or her grandchild’s soccer game because of nausea after chemotherapy or radiation. Follow-up surveys taken long after effective antiemetics were generally available show that nausea and vomiting have not been removed from the top of the lists of patient fears from chemotherapy.17,18 And with good reason. For patients receiving cisplatin, 55% experience nausea or vomiting.19 For individuals with breast cancer receiving so-called moderately emetogenic drugs, such as doxorubicin and cyclophosphamide, 41% to 43% have nausea or vomiting.19,20 Two other disturbing trends emerge in these reports. First, the guidelines designed to define optimal care in this area are not followed. In one series, 57% of patients given cisplatin and 36% given doxorubicin or cyclophosphamide were not treated according to any guideline.19 Second, physicians and nurses underestimate the incidence of nausea and emesis experienced by patients. In one group of women with breast cancer, doctors and nurses predicted that emesis 24 or more hours after chemotherapy would occur in 8% of patients. Patient records showed that 41% of patients vomited.20 We can do more to ensure that antiemetic guidelines are followed in every patient, each time the patient receives chemotherapy or radiation. When this occurs, control improves.21 This effort alone, however, will not be enough to prevent symptoms for everyone. We need better ways to do the job. In this issue of the Journal of Clinical Oncology, two papers present clinical trial results using aprepitant (EmendTM; Merck, Whitehouse Station, NJ), an antagonist of substance P that blocks NK1 receptors in the brainstem emetic center. Aprepitant is the first of a new class of drugs. The NK1 receptor antagonists have been tested for nearly a decade in patients receiving cisplatin with amazingly consistent results.22–24 In all studies, these unique drugs improve emesis prevention both on the day chemotherapy is given (acute emesis) and during the 3 or 4 days that follow (delayed emesis).25 This latter attribute is particularly relevant because most patients who experience nausea and emesis do so not on the day they receive chemotherapy but one or several days later.26 Equally important, NK1 receptor antagonists augment the benefits of dexamethasone and serotonin receptor antagonists given before chemotherapy. This is great news for patients receiving chemotherapy. To the researcher, it suggests that the NK1 receptor provides a unique target for antiemetic drugs and adds one more piece to the puzzle of cancer-treatment-related emesis. In the study by Hesketh et al,27 all patients received ondansetron plus dexamethasone on the day of chemotherapy, and then dexamethasone alone for 3 days to treat delayed emesis. Additionally, patients were randomly assigned to receive either aprepitant or a placebo. Adding aprepitant decreased the incidence of vomiting by 20% for the overall 5-day period, by 20% on the day of cisplatin compared with the standard two-drug antiemetic regimen, and by 15% during the delayed phase, compared with dexamethasone alone. A second trial of similar size and design reached exactly the same conclusions.28 The authors should be commended for defining emesis prevention over the entire 5-day period after treatment as "success" and the primary end point of the trial. This definition reflects the views of patients who fear any emesis or nausea anytime after treatment. It should set a new standard when designing future antiemetic trials. These two placebo-controlled, randomized trials provide sufficient data to make the addition of aprepitant to current antiemetic regimens a standard of care for individuals receiving cisplatin, and they formed the basis for the approval of aprepitant by the United States Food and Drug Administration in March 2003. Through the indication for the addition of aprepitant to ondansetron and dexamethasone in patients given cisplatin is clear, its use with other chemotherapy agents remains largely untested. Relatively few people receive cisplatin. Most are given moderately emetogenic chemotherapies incorporating drugs such as cyclophosphamide, doxorubicin, epirubicin, and carboplatin. Even though the incidence and severity of emesis may be less in these patients, they represent the largest group who experience vomiting and nausea today. Historically, cisplatin has been used as the emetic stimulus in clinical trials because of the severity and predictability of emesis following treatment. Decades of research have proven that if an antiemetic drug prevents cisplatin-induced emesis, it will also block emesis caused by other agents as well. If this principle holds true, aprepitant will prevent emesis caused by less emetogenic drugs. Because the incidence of emesis is inherently lower with moderately emetogenic chemotherapy agents, the differences between aprepitant and standard regimens will be smaller. This will make it harder for physicians to observe the beneficial effects and will necessitate even larger clinical trials to show smaller but clinically important differences in outcome. To further complicate the recommendations for the management of these patients, in July 2003 palonosetron (Aloxi; MGI Pharma Inc, Bloomington, MN) was approved by the US Food and Drug Administration for the prevention of acute and delayed emesis following moderately emetogenic chemotherapy.29 That approval and the clinical investigations behind it make palonosetron a standard of care for those receiving moderately emetogenic chemotherapy. The available data support the use of the combination of aprepitant, palonosetron, and dexamethasone in patients receiving moderately emetogenic chemotherapy. However, in the era of evidence-based medicine, a clinical trial of this three-drug regimen will be required before modification of guidelines to permit the routine addition of aprepitant for the prevention of emesis following regimens containing doxorubicin, cyclophosphamide, and carboplatin. Although the trial proved that aprepitant is a safe and effective antiemetic, its design left open many questions that impact on the daily care of patients. First, for the delayed emesis phase, all treatment guidelines now recommend both dexamethasone plus either metoclopramide or a specific serotonin receptor antagonist. Aprepitant regimens have not been compared with this standard, making it more difficult to change the evidence-based guidelines. Second, the doses of dexamethasone in the aprepitant regimen are not standard. For convenience, clarity, and perhaps efficacy, it would have been helpful to have aprepitant studied with standard doses of dexamethasone. The definitions of secondary end points in this trial are confusing. Even the authors seemed to have difficulty reporting "complete response" in the abstract and "complete protection" in Table 2, in Hesketh et al,27 for what appears to be the same end point—no emetic episodes and no use of rescue therapy. Reporting a visual analog scale score for nausea of less than 25 mm as "No Significant Nausea" neither serves to guide the clinician nor is meaningful to the patient. Toxicity reporting is equally murky and not coordinated with efficacy results. For example, although "no nausea" was reported to occur in 3% more patients receiving the aprepitant regimen in the efficacy results (Table 2, Hesketh et al27), "nausea" as an "adverse event" was 3% more common with aprepitant (Table 3, Hesketh et al27). My patients tell me that any nausea is unpleasant, no matter what causes it or when it occurs. These contrived definitions confuse rather than clarify. Future trials should simply state the most important results (no vomiting, no nausea) and avoid adjectives. This will also make data collection, analysis, and reporting easier. de Wit et al30 authored the second paper that discusses aprepitant in this issue. This study attempted to demonstrate that the benefit of adding aprepitant to ondansetron (32 mg) and dexamethasone (20 mg dose pretreatment) is maintained when used with subsequent cycles of cisplatin. These data must be interpreted with caution. Only 17 of the 184 patients enrolled on the trial—a mere 10%—were still receiving chemotherapy (and aprepitant) by the end of the study. The conclusions drawn of this type of analysis will be much stronger when repeated with the data set of more than 1,000 patients from the Hesketh and Poli-Bigelli trials.27,28 The de Wit et al30 study raises several new issues in the Hesketh et al27 trial. Intriguingly, de Wit et al reports slightly higher rates of "complete response" using higher doses of aprepitant: 70% of patients receiving aprepitant 375 mg on day 1 and 250 mg on days 2–5 versus 64% given aprepitant 125 mg on day 1 and 80 mg on days 2–5. No justification of the dose selection is provided in the Hesketh et al study. With no apparent increase in adverse events reported, would higher aprepitant doses provide better prevention? Why did de Wit et al use a 20 mg dose of dexamethasone on the day of cisplatin administration, whereas Hesketh et al used 12 mg? Most guidelines recommend 20 mg. There appears to be no safety benefit using lower doses in the aprepitant trials, and The Italian Group has shown both better control and comparable toxicity with 20 mg doses of dexamethasone in its elegant study.10 What lessons can we learn from aprepitant’s development? It is disheartening to realize just how long it took to get aprepitant into the pharmacy and how much longer it will take to get the data needed to alter our evidence-based guidelines to include aprepitant in regimens to prevent emesis caused by moderately emetogenic chemotherapies. The scientific underpinnings for the development of NK1 antagonists as antiemetics and the fact that they were safe and likely effective in persons with cancer were known by the mid 1990s.22 Initial randomized trials with NK1 receptor antagonists were published both in this journal23 and the New England Journal of Medicine in 1999.31 Despite this, no practitioner in the United States could prescribe aprepitant until April 2003. Physicians everywhere else are still waiting. In comparison, ondansetron, another so-called first-in-class antiemetic drug, went from synthesis to the pharmacy in 8 years.32 One cause for this delay was the low priority given to develop NK1 receptor antagonists as antiemetics. Aprepitant’s antiemetic development nearly ground to a halt while it was being tested as an antidepressant.33 The sponsor’s prioritization was buttressed by the waning interest to test antiemetics for the space program and the misconception held by many in the oncology community that the problem of chemotherapy-induced emesis had been solved. Preventing emesis caused by cancer therapy is a high priority for our patients and should be an equally high priority for researchers and sponsors as well. One trip to the oncology clinic is usually all it takes to demonstrate the urgent need to eliminate nausea and vomiting for all persons fighting cancer. We need to focus our efforts to hasten drug development, especially for unique agents like aprepitant. Aprepitant should be added to the antiemetic regimens of all patients receiving highly emetogenic chemotherapy. Even with the admittedly scant data in hand, I would encourage using aprepitant with palonosetron and dexamethasone in persons receiving moderately emetogenic chemotherapies, such as doxorubicin, cyclophosphamide, and carboplatin. We should carefully review the experience gained in aprepitant’s approval to identify ways to improve the development process. We need to apply these lessons quickly as we seek to discover better ways to prevent treatment-related nausea and to stop both emesis and nausea if they occur. Why do we need another antiemetic? Just ask a person about to receive chemotherapy. Preventing all vomiting and nausea is a tough but important goal. Aprepitant is an incremental step, providing both new information and developmental experience to more rapidly achieve the ultimate objective: to eliminate nausea and emesis associated with cancer. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Mark G. Kris, Aventis Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Merck and Company, MGI Pharma Inc, Pfizer Inc. Received more than $2,000 a year from a company for either of the last 2 years: Mark G. Kris, Aventis Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Merck and Company, MGI Pharma Inc, Pfizer Inc. REFERENCES 1. Coates A, Abraham S, Kaye SB, et al: On the receiving end: Patient perception of the side effects of cancer chemotherapy. Eur J Cancer Clin Oncol 19:203–208, 1983[CrossRef][Medline] 2. Morrow GR, Morrell C: Behavioral treatment for the anticipatory nausea and vomiting induced by cancer chemotherapy. N Engl J Med 307:1476–1480, 1982[Abstract] 3. Gralla RJ, Braun TJ, Squillante A, et al: Metoclopramide: initial clinical studies of high dose regimens in cisplatin-induced emesis, in Poster D (ed): The Treatment Of Nausea And Vomiting Induced By Cancer Chemotherapy. New York, NY, Masson, 1981, pp 167–176
4. Ioannidis JP, Hesketh PJ, Lau J: Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: A meta-analysis of randomized evidence. J Clin Oncol 18:3409–3422, 2000 5. Kris MG, Gralla RJ, Clark RA, et al: Dose-ranging evaluation of the serotonin antagonist GR-C507/75 (GR38032F) when used as an antiemetic in patients receiving anticancer chemotherapy. J Clin Oncol 6:659–662, 1988[Abstract]
6. Navari RM, Kaplan HG, Gralla RJ, et al: Efficacy and safety of granisetron, a selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of nausea and vomiting induced by high-dose cisplatin. J Clin Oncol 12:2204–2210, 1994 7. Hesketh P, Navari R, Grote T, et al: Double-blind, randomized comparison of the antiemetic efficacy of intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced emesis in patients with cancer. J Clin Oncol 14:2242–2249, 1996[Abstract] 8. Kris MG, Gralla RJ, Tyson LB, et al: Improved control of cisplatin-induced emesis with high-dose metoclopramide and with combinations of metoclopramide, dexamethasone, and diphenhydramine: Results of consecutive trials in 255 patients. Cancer 55:527–534, 1985[CrossRef][Medline] 9. Roila F, Tonato M, Cognetti F, et al: Prevention of cisplatin-induced emesis: a double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol 9:675–678, 1991[Abstract]
10. Double-blind, dose-finding study of four intravenous doses of dexamethasone in the prevention of cisplatin-induced acute emesis: Italian Group for Antiemetic Research. J Clin Oncol 16:2937–2942, 1998
11. Gralla RJ, Osoba D, Kris MG, et al: Clinical practice guidelines for the use of antiemetics: Evidence-based report by the American Society of Clinical Oncology. J Clin Oncol 17:2971–2994, 1999 12. Osoba D, Warr D, Fitch M, et al: Guidelines for the optimal management of chemotherapy-induced nausea and vomiting: A consensus. Can J Oncol 5:381–400, 1995[Medline] 13. Ettinger DS, Huber S, Kris MG, et al: NCCN antiemesis practice guidelines. Oncology 11:11A, 1997
14. American Society of Health-System Pharmacists: ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm 56:729–764, 1999
15. Roila F, Del Favero A, Gralla RJ, et al: Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the Perugia Consensus Conference. Ann Oncol 9:811–819, 1998 16. Kris MG: Preventing vomiting after anticancer therapy: The road taken, in Von Roenn JH (ed): Classic Papers and Current Comments: Highlights of Supportive Care. Chestnut Hill, MD, Lippincott Williams & Wilkins, 1999, pp 480–482
17. Griffin AM, Butow PN, Coates AS, et al: On the receiving end. V: Patient perceptions of the side effects of cancer chemotherapy in 1993. Ann Oncol 7:189–195, 1996 18. de Boer-Dennert M, de Wit, R, Schmitz, Pl: Patient perceptions of the side effects of chemotherapy: The influence of 5 HT3 antagonists. Br J Cancer 76:1055–1061, 1997[Medline] 19. Fabi A, Barduagni M, Lauro S, et al: Is delayed chemotherapy-induced emesis well managed in oncological clinical practice? An observational study. Support Care Cancer 11:156–161, 2003[Medline] 20. Grunberg SM, Hansen M, Deuson R, et al: Incidence and impact of nausea/vomiting with modern antiemetic: Perception vs. reality. Proc Am Soc Clin Oncol 21:250a, 2002 (abstr 996)
21. Mertens WC, Higby DJ, Brown D, et al: Improving the care of patients with regard to chemotherapy-induced nausea and emesis: The effect of feedback to clinicians on adherence to antiemetic prescribing guidelines. J Clin Oncol 21:1373–1378, 2003 22. Kris MG, Radford JE, Pizzo BA, et al: Use of a NK-1 receptor antagonist to prevent delayed emesis following cisplatin. J Natl Cancer Inst 89:53–54, 1997
23. Hesketh PJ, Gralla RJ, Webb RT, et al: Randomized phase II study of the neurokinin 1 receptor antagonist CJ-11,974 in the control of cisplatin-induced emesis. J Clin Oncol 17:338–343, 1999
24. Navari RM, Reinhardt RR, Gralla RJ, et al: Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. N Engl J Med 340:190–195, 1999
25. Kris MG, Gralla RJ, Clark RA, et al: Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol 3:1379–1384, 1985 26. Hickok JT, Roscoe JA, Morrow GR, et al: Nausea and emesis remain significant problems of chemotherapy despite prophylaxis with 5-Hydroxytryptamine-3 Antiemetrics. Cancer 97:2880–2886, 2003[CrossRef][Medline]
27. Hesketh PJ, Grunberg SM, Gralla RJ, et al: The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: A multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—The Aprepitant Protocol 052 Study Group. J Clin Oncol 21:4112–4119, 2003 28. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al: Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer 97:3090–3098, 2003[CrossRef][Medline] 29. Aapro E, Selak M, Lichinitser D, et al: Palonosetron (PALO) is more effective than ondansetron (OND) in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC): Results of a Phase III trial. Proc Am Soc Clin Oncol 22:726, 2003
30. de Wit R, Herrstedt J, Rapoport B, et al: Addition of the oral NK1 antangonist aprepitant to standard antiemetics provides protection aganist nausea and vomiting during multiple cycles of cisplatin-based chemotherapy. J Clin Oncol 21:4105–4111, 2003 31. Navari RM, Reinhardt RR, Gralla RJ, et al: Prevention of cisplatin-induced emesis by a neurokinin-1-receptor antagonist [letter]. N Engl J Med 340:1927–1928, 1999 32. Kris MG: Ondansetron: A specific serotonin antagonist for the prevention of chemotherapy-induced vomiting, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Important Advances in Oncology. Philadelphia, PA, J.B. Lippincott Co, 1994, pp 165–177
33. Enserink M: Can the placebo be the cure? Science 284:238–240, 1999
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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