UICC World Cancer Congress 2006

Objective:  See below Methods:  See below Results:  See below  

Many societies and organizations including the American Society for Clinical Oncology (ASCO) [1], the European Society for Medical Oncology (ESMO) [2], the National Comprehensive Cancer Network (NCCN) [3], the American Society of Health-System Pharmacists (ASHP) [4] and The Canadian Consensus Group [5] have developed clinical guidelines for antiemesis. The Multinational Association of Supportive Care in Cancer (MASCC) developed their first set of evidence-based clinical guidelines for chemotherapy- and radiotherapy-induced nausea and vomiting in 1997 [6]. An update of these guidelines took place in March 2004 and was published in 10 review papers in the Supportive Care of Cancer in February 2005. The latest update was published recently in the Annals of Oncology [7]. This presentation will briefly discuss data from 1997-2004, that constituted the basis for updating the MASCC 1997 consensus guidelines, and the recent studies included in the latest update [7]. A summary of the MASCC recommendations will follow, addressing chemotherapy-induced nausea and vomiting only.

The review will be divided into:

• The emetogenicity of cytotoxic agents

·        Prophylaxis of acute emesis induced by highly emetogenic chemotherapy (HEC).

·        Prophylaxis of acute emesis induced by moderately emetogenic chemotherapy (MEC)

·        Prophylaxis of delayed emesis induced by HEC or MEC.

·        Prophylaxis of acute and delayed emesis induced by low and minimal emetogenic chemotherapy.

The emetogenicity of cytotoxic agents

Several publications, including the Hesketh classification [8], have classified the emetogenic potential of cytotoxic agents. The MASCC 2004 recommendations were based on this classification [8], but divided chemotherapy agents into four (instead of five) emetogenic groups: high, moderate, low, and minimal. The oral agents are often given daily for several days or weeks, and the emetogenicity can only be judged for the entire period without a distinction between acute and delayed emesis. Antiemetic regimens will therefore differ from those recommended for single dose intravenous chemotherapeutic agents [7].

Prophylaxis of acute emesis induced by HEC

Three kinds of studies were of particular interest between 1997 and 2004. These included the investigation of the neurokinin (NK)₁-receptor antagonist, aprepitant, a comparative trial between ondansetron and the new serotonin (5-HT)₃-receptor antagonist, palonosetron, and a study defining the optimum dose of dexamethasone.

Five phase II studies all investigated aprepitant in patients receiving cisplatin-based chemotherapy. These studies defined the optimum dose of aprepitant, demonstrated potential interaction risks between aprepitant and a number of drugs at the CYP450 enzyme system, and indicated that aprepitant has significant effect against both acute and delayed emesis.

Two phase III studies including 569 [9] and 530 [10] patients, respectively, used an identical design and both compared a single dose of ondansetron plus dexamethasone days 1-4 with or without the addition of aprepitant 120 mg day 1 plus 80 mg days 2 and 3. The effect of standard antiemetic therapy day 1 was significantly improved by the addition of aprepitant in both studies (82.8% versus 68.4% [9] and 89.2% versus 78.1% [10] complete response (no emesis and no rescue antiemetics), P < 0.001 both studies). A major problem has been the difficulty in maintaining antiemetic effect during multiple cycles of chemotherapy. A pooled analysis from the two phase III trials showed, that the addition of the NK₁ receptor antagonist, aprepitant to the combination of ondansetron plus dexamethasone was consistently better in each cycle, and able to maintain antiemetic effect through six cycles [11].

Palonosetron was investigated in a phase III study comparing the effect with ondansetron in patients receiving HEC. The study was designed as a non-inferiority study and showed that palonosetron was at least as effective as ondansetron [12].

The optimum dose of dexamethasone was defined in a trial in which patients treated with cisplatin-based chemotherapy were randomized to ondansetron plus one of four different doses of dexamethasone. A single dose of 20 mg was recommended [13].  The MASCC guidelines for prophylaxis of acute emesis in, patients treated with HEC [7, 14], are given in the Table.

Prophylaxis of acute emesis induced by moderately emetogenic chemotherapy (MEC)

Since the publication of the first Perugia Consensus guidelines [6], the optimum dose of dexamethasone, in the prophylaxis of acute emesis, has been verified as a single 8 mg dose [15]. Two randomized, double-blind studies have compared the effect of a single dose of palonosetron, with dolasetron and ondansetron, respectively [16, 17]. Both studies were designed as non-inferiority studies and showed that palonosetron was at least as effective as ondansetron and dolasetron. Although a number of parameters significantly favoured palonosetron, due to the design of the studies, the consensus group was unable to make a decision about possible differences between these 5-HT₃-receptor antagonists [18].

At the time of the consensus meeting in 2004, no published studies had investigated the use of adding an NK₁ receptor antagonist to the combination of a 5-HT₃ receptor antagonist plus dexamethasone in patients treated with MEC. In 2005, data from a large phase III study in 857 patients, of whom 99% received the combination of cyclophosphamide and an anthracycline, was published. These results were available at the time of the latest update of the MASCC guidelines [7]. Warr and co-workers compared ondansetron plus dexamethasone (plus placebo) versus the same antiemetic therapy plus aprepitant as antiemetic prophylaxis day 1, followed by either aprepitant or ondansetron days 2-3 [19]. A 9% statistically significant increase in complete response days 1-5 was seen in the aprepitant-based arm, and a 7% increase in complete response was observed in the first 24 hours after chemotherapy (76% vs 69%, P = 0.034). As regards the number of patients without emesis, the difference was 17% days 1-5 and 11% day 1 (88% in the aprepitant-based arm vs 77%, P < 0.001). No significant difference in the number of patients with nausea was found. Patients were followed during a maximum of four cycles, and the number of patients, who sustained a complete response, was greater with the aprepitant regimen, than with ondansetron plus dexamethasone alone [20]. The MASCC recommendations for patients receiving MEC are summarised in the Table.

Prophylaxis of delayed emesis induced by HEC or MEC

The primary endpoint in all three phase III studies including aprepitant was complete response day 1-5 (no emesis, no rescue medication). Furthermore, the studies were not designed to investigate delayed emesis, because patients received different antiemetics during day 1 [9, 10, 19]. Nevertheless, significantly higher complete protection rates were obtained in the delayed phase (days 2-5), in patients who received aprepitant in addition to dexamethasone. Taking into account the weakness of the design, addition of aprepitant increased efficacy (complete response) with approximately 20% in the delayed phase in the HEC studies and with 6% in the MEC study. The recommendation of aprepitant in this setting is therefore of lower scientific confidence, than the recommendation of aprepitant for acute emesis (Table).

The two palonosetron phase III studies in MEC indicated a superiority of palonosetron as compared to dolasetron [16] and ondansetron [17] in the delayed phase. Again, the consensus group concluded, that due to the study design, no decision about possible differences between palonosetron and the other 5-HT₃-receptor antagonists could be made [21]. 

Prophylaxis of acute and delayed emesis induced by low and minimal emetogenic chemotherapy

Very few studies have investigated patients receiving chemotherapy of low or minimal emetic risk [22]. A scientific confidence was therefore not possible (Table).

Conclusion

Guidelines are only of value if updated on a regular basis. The MASCC guidelines are updated every 6 month, if any new data are available. Updated guidelines are published on www.mascc.org.

Another prerequisite for the use of guidelines is that implementation is ensured. To facilitate this process, the MASCC guidelines have been translated into several languages.

References 1.                                      Gralla RJ, Osoba D, Kris MG et al. Recommendations for the use of antiemetics: evidence-based clinical practice guidelines. J Clin Oncol 1999;17:2971-94.

2.                                       Herrstedt J, Aapro MS, Roila F, Kataja VV. ESMO minimum clinical recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (NV). Ann Oncol 2005;16(suppl 1):i77-i79.

3.                                      Antiemesis. Clinical Practice Guidelines in Oncology – v.1. 2006. National Comprehensive Cancer Network. www.nccn.com/physician_gls/f_guidelines.

4.                                      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 1999;56:729-64.

5.                                      Osoba D, Warr D, Fitch MI, Nakashima L, Warren B. Guidelines for the optimal management of chemotherapy-induced nausea and vomiting: A consensus. Can J Oncol 1995;5:381-400.

6.                                      The Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC). Prevention of chemotherapy- and radiotherapy-induced emesis: results of the Perugia Consensus Conference. Ann Oncol 1998;9:811-19.

7.                                      The Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC). Prevention of chemotherapy– and radiotherapy-induced emesis: results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Oncol 2006;17:20-28.

8.                                      Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy.  J Clin Oncol 1997; 15:103-109.

9.                                      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 2003;97:3090-3098.

10.                                  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 052 study group. J Clin Oncol 2003;21:4112-4119.

11.                                  De Wit R, Herrstedt J, Rapoport B et al. The oral NK1 antagonist APR given with standard antiemetics provided protection against nausea and vomiting over multiple cycles of cisplatin-based chemotherapy: a combined analysis of 2 randomized, placebo controlled phase III trials. Eur J Cancer 2004;40:403-10.

12.                                  Aapro MS, Bertoli L, Lordick F et al. Palonosetron is effective in preventing acute and delayed chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer 2003;11(6):A-17.

13.                                  Italian Group for Antiemetic Research. Double-blind, dose-finding study of four intravenous doses of dexamethasone in the prevention of cisplatin-induced acute emesis. J Clin Oncol 1998;16:2937-42.

14.                                  Kris MG, Hesketh PJ, Herrstedt J et al. Consensus proposals for the prevention of acute and delayed vomiting and nausea following high emetic risk chemotherapy. Support Care Cancer 2005;13:85-96.

15.                                  Italian Group for Antiemetic Research. Randomized, double-blind, dose-finding study of dexamethasone in preventing acute emesis induced by anthracyclines, carboplatin or cyclophosphamide. J Clin Oncol 2004;22:725-29.

16.                                  Eisenberg P, Figueroa-Vadillo J, Zamora R et al: Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT₃ receptor antagonist. Cancer 2003;98:2473-82.

17.                                  Gralla RJ, Lichinitser M, van der Vegt S et al: Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol 2003;14:1570-77.

18.                                  J Herrstedt, JM Koeller, F Roila, D Warr, PJ Hesketh, C Rittenberg, M Dicato. Acute emesis: moderately emetogenic chemotherapy. Support Care Cancer 2005;13:97-103.

19.                                  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 2005;23:2822-30.

20.                                  Herrstedt J, Muss HB, Warr DG et al. Efficacy and tolerability of APR for the prevention of chemotherapy-induced nausea and vomiting over multiple cycles of moderately emetogenic chemotherapy. Cancer 2005;104:1548-55.

21.                                  F Roila, D Warr, RA Clark-Snow et al. Delayed emesis: moderately emetogenic chemotherapy. Support Care Cancer 2005;13:104-8.

22.                                  Tonato M, Clark-Snow RA, Osoba D et al. Emesis induced by low or minimal emetic risk chemotherapy. Support care Cancer 2005;13:109-11.

            MASCC recommendations for prophylaxis of chemotherapy-induced nausea and vomiting

Acute nausea and vomiting1
Emetogenic potential	Antiemetics	Levels of confidence/consensus
High	Serotonin antagonist + dexamethasone                 + aprepitant	High                              /  High
Anthracycline (A) + Cyclophosphamide (C)	Serotonin antagonist + dexamethasone             + aprepitant	Moderate                       /  High
Moderate (other than AC)	Serotonin antagonist + dexamethasone	High                              /  High
Low	A single agent such as dexamethasone	No confidence possible/  Moderate
Minimal	No routine prophylaxis	No confidence possible/  High

 

Delayed nausea and vomiting2
Emetogenic potential	Antiemetics	Levels of confidence/consensus
High	Dexamethasone + aprepitant	Moderate                       /  High
Anthracycline (A) + Cyclophosphamide (C)	Dexamathasone or aprepitant	Moderate                       /  High
Moderate (other than AC)	Dexamethasone. Serotonin antagonist is an alternative	High                              /  High Moderate                       /  Moderate
Low	No routine prophylaxis	No confidence possible/   Moderate
Minimal	No routine prophylaxis	No confidence possible/   High

1. The oral agents are those with the lowest emetic risk. A single antiemetic is often sufficient as prophylaxis.

2. The oral agents rarely induce delayed nausea and vomiting. No routine prophylaxis after day one is recommended.