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Use of Placebos in Delayed-Emesis Studies

MacLean Center for Clinical Medical Ethics, University of Chicago School of Medicine, Chicago, IL

To the Editor: In the January 1999 issue of the Journal of Clinical Oncology, Hesketh et al¹ reported the success of the neurokinin 1 (NK₁) receptor antagonist CJ-11,974 in controlling cisplatin-induced acute and delayed emesis. Simultaneously, L-754,030, another NK₁ receptor antagonist, has been reported to be effective in controlling cisplatin-induced acute and delayed emesis.² These new agents and this drug class obviously have marked potential for improving the chemotherapy-induced acute and delayed emesis experienced by patients.

As noted by Hesketh et al, these results suggest that future studies should not only explore the appropriate doses, schedule, and safety of these agents but also investigate how this new class of agents compares with the use of the 5-hydroxytryptamine-3 (5-HT₃) receptor antagonists and dexamethasone in the control of acute emesis, and of dexamethasone, metoclopramide, and the 5-HT₃ receptor antagonists in the control of delayed emesis in both cisplatin and noncisplatin chemotherapy.

At a recent consensus conference on the prevention of chemotherapy- and radiotherapy-induced emesis, it was suggested that a 5-HT₃ receptor antagonist and dexamethasone was the regimen of choice in the prevention of acute emesis induced by cisplatin or by noncisplatin moderately high emetogenic chemotherapy.³ For the prevention of delayed emesis, a combination of dexamethasone with either metoclopramide or a 5-HT₃ antagonist was recommended for patients receiving cisplatin, and the use of dexamethasone alone or a 5-HT₃ antagonist alone or their combination was recommended for patients receiving moderately high emetogenic chemotherapy.

An issue not discussed by either of the recent reports^1,2 was the use of a placebo in future studies. This issue has been resolved in studies of acute emesis where a placebo group is no longer acceptable because of the significant reduction of emesis from over 90%, to 25% to 30% by the 5-HT₃ receptor antagonists and dexamethasone.^3,4 A placebo group was used in both recent reports in the delayed-emesis portion of the studies in order to permit a direct evaluation of the new agents and because of a lack of consensus on the efficacy and toxicities of agents available for delayed-emesis prophylaxis at the time the studies were planned. Should a placebo group continue to be used in future delayed-emesis studies? Or are there now enough data in the literature to suggest that even though the available agents to prevent delayed emesis are less than optimal,^3,5 patients receiving cisplatin or noncisplatin moderately high emetogenic chemotherapy should receive some form of prophylaxis?

With the use of corticosteroids combined with either metoclopramide or a 5-HT₃ receptor antagonist in patients receiving cisplatin, delayed emesis has been reduced from 90%, to 40% to 50% in some studies.^6-8 In patients receiving moderately high emetogenic chemotherapy, delayed emesis was reduced from 65% to 70%, to 40% to 45% with the use of dexamethasone alone or in combination with a 5-HT₃ antagonist.^9-11 Do these studies demonstrate adequate efficacy to eliminate a placebo group in future delayed-emesis studies?

Are there adequate arguments in favor of continuing placebo-controlled trials in the study of new agents for delayed emesis? Regulatory authorities require data that demonstrate that a new agent be effective and safe in well-controlled studies that usually include a placebo. A study design with a placebo is usually preferred by the United States Food and Drug Administration (FDA) and the industry sponsor in order to demonstrate efficacy. In the area of delayed emesis, the FDA may even point out that there are no medications currently approved for delayed emesis. However, what is ethically acceptable as a control arm to demonstrate efficacy of a new agent may evolve over time to a point where placebos may no longer be acceptable, and alternative study designs may be what is appropriately used by regulatory agencies and industry.

One of the assumptions used to justify the use of a placebo in a clinical trial is that of equipoise. Equipoise exists when the outcome of the study is unknown, and the probability of the risk and benefit to patients is similar in the treatment and placebo groups. Equipoise does not exist when a treatment is available that is known to be at least partially effective, which is most likely the situation at this time for delayed-emesis prophylaxis.

Although at this time relatively few patients have been reported to receive the NK1 receptor antagonists for cisplatin-induced delayed emesis,¹,²,¹²,¹³ and larger trials are necessary to demonstrate the effectiveness of these agents, the use of placebo groups in future studies may be unjustified. A discussion of this issue is warranted at this time.

REFERENCES

1. 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[Abstract/Free Full Text]

2. 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[Abstract/Free Full Text]

3. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer: Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the Perugia consensus conference. Ann Oncol 9:811-819, 1998[Abstract/Free Full Text]

4. Kris MG, Cubeddu LX, Gralla RJ, et al: Are more antiemetic trials with a placebo necessary? Report of patient data from randomized trials of placebo antiemetics with cisplatin. Cancer 78:2193-2198, 1996[Medline]

5. Tavorath R, Hesketh PJ: Drug treatment of chemotherapy induced delayed emesis. Drugs 52:639-648, 1996[Medline]

6. Kris MG, Gralla RJ, Tyson LB, et al: Controlling delayed vomiting: Double blind, randomized trial comparing placebo, dexamethasone alone, and metoclopramide plus dexamethasone in patients receiving cisplatin. J Clin Oncol 7:108-114, 1989[Abstract]

7. Italian Group for Antiemetic Research: Ondansetron versus metoclopramide, both combined with dexamethasone, in the prevention of cisplatin induced delayed emesis. J Clin Oncol 15:124-130, 1997[Abstract/Free Full Text]

8. Gebbia V, Testa A, Valenza R, et al: Oral granisetron with or without methylprednisolone versus metoclopramide plus methylprednisolone in the management of delayed nausea and vomiting induced by cisplatin-based chemotherapy. Cancer 76:1821-1828, 1995[Medline]

9. Pater JL, Lofters WS, Zee B, et al: The role of the 5 HT3 antagonists ondansetron and dolasetron in the control of delayed onset nausea and vomiting in patients receiving moderately emetogenic chemotherapy. Ann Oncol 8:181-185, 1997[Abstract/Free Full Text]

10. Koo WH, Ang PT: Role of maintenance oral dexamethasone in prophylaxis of delayed emesis caused by moderately emetogenic chemotherapy. Ann Oncol 7:71-74, 1996[Abstract/Free Full Text]

11. Kaizer L, Warr D, Hoskins P, et al: Effect of schedule and maintenance on the antiemetic efficacy of ondansetron combined with dexamethasone in acute and delayed nausea and emesis in patients receiving moderately emetogenic chemotherapy: A phase III trial by the National Cancer Institute of Canada Trials Group. J Clin Oncol 12:1050-1057, 1994[Abstract/Free Full Text]

12. Kris MG, Radford JE, Pizzo BA, et al: Use of a NK1 receptor antagonist to prevent delayed emesis after cisplatin. J Natl Cancer Inst 89:817-818, 1997[Free Full Text]

13. VanBelle S, Cocquyt V, Desmer M, et al: Comparison of a neurokinin-1 antagonist, L-758,298, to ondansetron in the prevention of cisplatin-induced emesis. Proc Am Soc Clin Oncol 17:51a, 1998 (abstr 198)

St Elizabeth's Medical Center, Boston, MA

In Reply: Dr Navari raises an important issue for antiemetic trial design in the evaluation of new agents for chemotherapy-induced delayed emesis, the use of placebo treatment arms. In two recent reports evaluating a promising new class of antiemetics, the neurokinin 1 receptor antagonists, a placebo arm was included during the delayed-emesis portion of the studies.^1,2 As Navari correctly points out, there has been broad consensus for a number of years that a placebo group is no longer acceptable in the evaluation of acute chemotherapy-induced emesis, given the high degree of effectiveness of standard antiemetic therapy in patients receiving moderate to highly emetogenic chemotherapy.

This issue, until recently, has been less well defined for emesis occurring more than 24 hours after chemotherapy, so-called delayed emesis. The highest risk for delayed emesis is seen in patients receiving cisplatin, where the risk approaches 90% with cisplatin doses of 100 mg/m².³ Current options for preventing cisplatin-induced delayed emesis are suboptimal. In addition, the standard of care in many clinical settings in the United States is to use antiemetics only on an as-needed basis. The best results are obtained with the prophylactic administration of dexamethasone combined with either metoclopramide or a 5-HT₃ receptor antagonist over a 3- to 4-day period after cisplatin. Delayed emesis will be completely prevented in approximately 50% of patients with such regimens.^4,5 This therapeutic approach was recently endorsed by an international antiemetic consensus conference, which also concluded that placebos should no longer be used in trials evaluating delayed emesis after high-dose cisplatin ( 100 mg/m²).^6,7 Should these conclusions guide current clinical practice and future antiemetic trial design? In my opinion, the answer is yes to both of these questions.

As standard antiemetic therapy options become increasingly more effective, it becomes a progressively greater challenge to design acceptable trials to evaluate promising new therapeutic approaches. Nevertheless, innovative trial designs should be sought to continue such evaluations. It is also critically important that regulatory authorities recognize the inappropriateness of placebo arms in this setting and demonstrate a willingness to accept alternative study designs.

Another important issue relates to the status of ongoing clinical trials with the NK₁ receptor antagonists that may be nearing completion but still include a placebo arm during the delayed portion of the study. These trials typically were designed up to 3 years ago, before the current consensus on delayed therapy was reached. These trials have collected clinical data that may provide valuable insights into the usefulness of these new agents, but they must reach their accrual goals for the information to become fully interpretable. Should these trials continue to completion? The answer, in my opinion, is a qualified yes, provided two conditions are met: (1) there is a need for patients participating on such trials to render a truly informed consent. They need to be fully aware that one of the treatment arms has a placebo during the delayed phase and that a number of conventional antiemetics are available that might prove useful in this setting and would be used if the patients elected not to participate in the study. (2) Patients should be provided with rescue antiemetics at the commencement of the study and fully instructed in their appropriate use. At the first instance of nausea or emesis, the patient should be directed to take the rescue medications.

A cardinal principal of acute antiemetic management is to use antiemetics prophylactically, recognizing the effectiveness of such treatment and the negative impact of inadequately controlled emesis on outcome with subsequent chemotherapy cycles. It is much less clear whether a single, transient episode of delayed nausea or emesis immediately treated with rescue medications will have any adverse effect on future antiemetic outcomes.

In summary, I would agree that the recently released international antiemetic consensus guidelines recommending prophylactic therapy for delayed emesis should be widely promulgated and become the standard of care. In addition, there is now a broad consensus that future antiemetic trials evaluating new antiemetic approaches should not include placebo arms for acute emesis or in situations where there is a significant risk of delayed emesis.

REFERENCES

1. 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

2. 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

3. 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[Abstract/Free Full Text]

4. Kris MG, Gralla RJ, Tyson LB, et al: Controlling delayed vomiting: Double-blind, randomized trial comparing placebo, dexamethasone alone, and metoclopramide plus dexamethasone in patients receiving cisplatin. J Clin Oncol 7:108-114, 1989

5. Italian Group for Antiemetic Research: Ondansetron versus metoclopramide, both combined with dexamethasone, in the prevention of cisplatin-induced delayed emesis. J Clin Oncol 15:124-130, 1997

6. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer: Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the Perugia consensus conference. Ann Oncol 9:811-819, 1998

7. Hesketh PJ, Gralla RJ, du Bois A, et al: Methodology of antiemetic trials: Response assessment, evaluation of new agents and definition of chemotherapy emetogenicity. Support Care Cancer 6:221-227, 1998[Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Navari, R. M. Articles by Hesketh, P. J. Search for Related Content PubMed PubMed Citation Articles by Navari, R. M. Articles by Hesketh, P. J. Social Bookmarking                            What's this?