The antiemetic presentations at the Annual Meeting of the Multinational Association of Supportive Care in Cancer, held in Toronto June 22-25, 2006, reflected a consolidation of advances in the field that have appeared over the last several years with more consideration being given as to how this developing body of knowledge can best be put into effect. Palonosetron and aprepitant were again the two agents most commonly studied in abstracts that were presented at the meeting.

Roila et al., noting that corticosteroids are commonly given in most antiemetic combinations, confirmed that palonosetron and dexamethasone are compatible when admixed without either significantly affecting the pharmacokinetics of the other and also demonstrated a high level of activity, with 91%/81% of patients having no emesis in the acute/delayed period and 88%/approximately 90% having no more than mild nausea during those periods.[1]

Brames examined use of these two agents in the challenging setting of 5-day fractionated cisplatin chemotherapy with a regimen consisting of palonosetron on days 1, 3, and 5, and dexamethasone on days 1-2, 6-8.[2] Protection from emesis in over 70% of patients without major toxicity was seen.

Palonosetron and Aprepitant Schedules

Several abstracts examined new schedules or new uses for palonosetron and aprepitant. Grunberg administered single doses of palonosetron, dexamethasone, and aprepitant on day 1 only.[3] Escalated doses were calculated—based on the pharmacokinetic properties of these agents—that would provide sufficient drug exposure to achieve acute and delayed antiemetic protection for patients receiving moderately emetogenic chemotherapy (cyclophosphamide and/or doxorubicin). Using a single dose of palonosetron 0.25 mg IV, dexamethasone 20 mg PO, and aprepitant 285 mg PO, complete response rates during the acute/delayed periods for the 15 patients reported were 80%/47% while no emesis rates were 100%/100%. No significant nausea was experienced by 100%/53% and only four patients had more than one day of significant nausea. This study continues to accrue patients.

Sanjay reported a Phase II study to determine whether aprepitant could be used successfully as a salvage antiemetic for patients receiving moderately emetogenic chemotherapy (cyclophosphamide and doxorubicin).[4] Thirty-six patients who failed to achieve complete control (no emesis, nausea, or rescue antiemetics) with a serotonin antagonist plus dexamethasone received the same antiemetic regimen with the addition of aprepitant on the next cycle of chemotherapy. The proportion of patients achieving complete control, overall complete response, and complete response for the acute and delayed periods each increased by approximately 30 percentage points with the addition of aprepitant to the salvage antiemetic regimen.

Two abstracts presented in the oral session of the meeting described results of randomized Phase II studies of casopitant, a new NK-1 antagonist.[5],[6] In both of these studies, casopitant was combined with ondansetron and dexamethasone. Doses of casopitant ranged from 50 mg to 150 mg PO Days 1-3. A single dose of casopitant 150 mg was also tested in an exploratory study arm. All casopitant-containing arms demonstrated similar efficacy and improvement as compared to the control regimen without casopitant. For moderately emetogenic chemotherapy, the 0-120 hour complete response rate increased from 70% to about 80%, and for highly emetogenic chemotherapy, the 0-120 hour complete response rate increased from 60% to about 80%, with most of the improvement seen during the delayed period.

In the highly emetogenic setting, efficacy with casopitant was similar to efficacy with aprepitant. Of interest, the single day 150 mg dose of casopitant appeared to be equally efficacious to the 3-day dosing scheme. Single day and multiple day casopitant regimens with a serotonin antagonist and dexamethasone will be tested in planned Phase III studies.

Mechanisms and Pathways of Emesis

Several studies looked at potential new mechanisms and pathways of emesis. Yamamoto investigated the effect of hypothalamic glutamatergic pathways on radiation-induced emesis in the rat both through direct measurement of hypothalamic glutamic acid and through observation of emesis-equivalent behavior (pica).[7] Hypothalamice glutamic acid was shown to increase after total body irradiation. The increase in glutamate and the development of pica could be prevented through the use of granisetron. However, other glutamate receptor inhibitors also caused a decrease in pica, suggesting that this is indeed a relevant pathway. Menendez-Leal added gabapentin to the antiemetic regimen of 24 patients who had had nausea and vomiting during a previous chemotherapy cycle, in spite of use of a serotonin antagonist and dexamethasone.[8] Nausea and vomiting was prevented in a majority of patients with the three-drug combination, suggesting either a new neural pathway for emesis or protection through modulation of previously appreciated neural pathways.

Patterns of Prescription and Adherence to Guidelines

Patterns of prescription, adherence to antiemetic guidelines, and prediction of emesis were explored by several groups. Chen reviewed antiemetic management of 616 patients through two cycles of chemotherapy.[9] Although 80% of these patients had nausea and vomiting during the first cycle of treatment, only 20% had their antiemetic regimen changed before the second cycle of chemotherapy. An effect of reported patient experience on future antiemetic prescriptions was therefore demonstrated for only 20% of patients. The question of why failed antiemetics were maintained without change for the second cycle in 80% of patients remains unanswered.

The value of a computerized physician order entry (CPOE) system with antiemetic regimens linked to chemotherapeutic regimens was investigated by Cassells during 1082 chemotherapy cycles. Use of this system resulted in a significant decrease in the number of cycles “missing” an indicated antiemetic.[10]

As an aid to prescription of appropriate antiemetics, Petrella et al. developed and validated an algorithm for prediction of severe nausea and vomiting using the experience of 346 patients.[11] Commonly appreciated factors, such as age, alcohol history, chemotherapy regimen, use of non-prescription antiemetics, and previous nausea/vomiting were confirmed as being predictive of chemotherapeutic emetogenicity.

Roila provided further insights into antiemetic guideline adherence and physician behavior in a review of the Italian experience.[12] Several factors that would prevent adoption of guidelines were identified, including lack of appreciation of the incidence and severity of emesis, lack of total effectiveness of currently available agents, and reluctance of physicians to change current prescribing habits. Numerous possible strategies to increase compliance, including passive diffusion of information, local consensus conferences, audit of patient experience, and opinion leader educational outreach were reviewed. A trend over the last decade toward increased compliance with guidelines was noted. Passive diffusion of information was found to have only a limited role while educational outreach was favored as a strategy to encourage change. A role for direct patient feedback as part of an overall strategy was also seen. However a combination of strategies tailored to the needs of the particular institution rather than a single strategy for all settings was determined to be most effective.

Conclusion

The field of antiemetics has therefore advanced through more sophisticated use of currently available agents and the development of new agents from both old and new pharmacologic families. Further investigations in the field of health services research will aid in more effective dissemination of knowledge gained and may result in improved antiemetic protection in general oncologic practice.

References