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ANTIEMETICS: NEW DEVELOPMENTS

ANTIEMETICS OF CHOICE. Cisplatin - acute emesis NK1 5-HT3 DEX - delayed emesis NK1 DEX or DEX MTC or DEX 5-HT3Moderately emetogenic chemotherapy - acute emesis

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ANTIEMETICS: NEW DEVELOPMENTS

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    1. ANTIEMETICS: NEW DEVELOPMENTS Fausto Roila Medical Oncology Division, Perugia, Italy

    2. ANTIEMETICS OF CHOICE Cisplatin - acute emesis NK1 + 5-HT3 + DEX - delayed emesis NK1 + DEX or DEX + MTC or DEX + 5-HT3 Moderately emetogenic chemotherapy - acute emesis 5-HT3 + DEX ?NK1 - delayed emesis NK1 or DEX

    3. Complete protection from vomiting with antiemetic prophylaxis

    4. NEW ANTIEMETICS PALONOSETRON CASOPITANT OLANZAPINE MIDAZOLAM GABAPENTIN GHRELIN

    5. PALONOSETRON

    6. PALONOSETRON Potent and selective 5-HT3 antagonist with a high affinity for 5-HT3 receptors. Mean plasma elimination T of ~ 40 h T of other 5-HT3 antagonists is 4-8 h.

    7. PALONOSETRON Metabolized primarily by CYP2D6 and to a lesser extent by CYP3A and CYP1A2. No difference in metabolism between poor and extensive metabolisers of CYP2D6 substrates. Age, hepatic dysfunction or mild-to-moderate renal impairment have no clinically significant effect on the pharmacokinetics of palonosetron.

    8. PALONOSETRON IN CISPLATIN-TREATED PATIENTS

    12. Complete Response Acute and Delayed Emesis Slide 66 Although not statistically significant, a greater proportion of patients treated with palonosetron 0.25 mg or 0.75 mg achieved a CR compared with those treated with ondansetron during all time intervals of the study (with the exception of palonosetron 0.25 mg in the acute phase, which showed results similar to ondansetron).Slide 66 Although not statistically significant, a greater proportion of patients treated with palonosetron 0.25 mg or 0.75 mg achieved a CR compared with those treated with ondansetron during all time intervals of the study (with the exception of palonosetron 0.25 mg in the acute phase, which showed results similar to ondansetron).

    13. PALONOSETRON IN PATIENTS SUBMITTED TO MODERATELY EMETOGENIC CHEMOTHERAPY

    16. Complete Response Acute and Delayed Emesis Slide 36 During the acute, delayed, and overall time intervals, significantly more patients treated with palonosetron 0.25 mg achieved a CR compared with those treated with ondansetron (P<0.025; 97.5% CI of the difference does not include zero). During these time intervals, CR rates were numerically higher, but not statistically superior, for palonosetron 0.75 mg compared with ondansetron. Slide 36 During the acute, delayed, and overall time intervals, significantly more patients treated with palonosetron 0.25 mg achieved a CR compared with those treated with ondansetron (P<0.025; 97.5% CI of the difference does not include zero). During these time intervals, CR rates were numerically higher, but not statistically superior, for palonosetron 0.75 mg compared with ondansetron.

    17. Complete Response Acute and Delayed Emesis Slide 36 During the acute, delayed, and overall time intervals, significantly more patients treated with palonosetron 0.25 mg achieved a CR compared with those treated with ondansetron (P<0.025; 97.5% CI of the difference does not include zero). During these time intervals, CR rates were numerically higher, but not statistically superior, for palonosetron 0.75 mg compared with ondansetron. Slide 36 During the acute, delayed, and overall time intervals, significantly more patients treated with palonosetron 0.25 mg achieved a CR compared with those treated with ondansetron (P<0.025; 97.5% CI of the difference does not include zero). During these time intervals, CR rates were numerically higher, but not statistically superior, for palonosetron 0.75 mg compared with ondansetron.

    18. SHORTCOMINGS OF THE STUDIES DEX was given to 0%, 5% and 67% only 30-60% of pts pretreated No prophylaxis for delayed emesis Can we conclude that PALO is superior when a non-inferiority design was used?

    19. TOLERABILITY Palonosetron is well tolerated Adverse events are similar to other 5-HT3 antagonists

    20. CONCLUSIONS Palonosetron in three well conducted double-blind studies demonstrated similar efficacy as ondansetron in cisplatin-treated patients and was superior to ondansetron and dolasetron in patients submitted to moderately emetogenic chemotherapy. Palonosetron should be evaluated with respect to the other 5-HT3 antagonists when combined with dexamethasone (and aprepitant).

    22. Palonosetron + Aprepitant + Dexamethasone Complete Response (N=58) The percent of patients (N=39) with no emetic episodes was 97% during each of the acute, delayed, and overall time periods. 1. Grote T et al. Palonosetron (PALO) plus aprepitant (APREP) and dexamethasone (DEX) for the prevention of chemotherapy-induced nausea and vomiting (CINV) after emetogenic chemotherapy (CT). Proc Am Soc Clin Oncol. 2004;23:790. Abstract 8262. The percent of patients (N=39) with no emetic episodes was 97% during each of the acute, delayed, and overall time periods. 1. Grote T et al. Palonosetron (PALO) plus aprepitant (APREP) and dexamethasone (DEX) for the prevention of chemotherapy-induced nausea and vomiting (CINV) after emetogenic chemotherapy (CT). Proc Am Soc Clin Oncol. 2004;23:790. Abstract 8262.

    24. Chemotherapy = doxorubicin + cyclophosphamide Antiemetics: palonosetron 0.25 mg iv aprepitant 285 mg po dexamethasone 20 mg po Day 1 Days 2-5 Complete response: 80% 47% No emesis : 100% 100%

    25. CASOPITANT

    26. CASOPITANT It is a potent and selective oral NK1 receptor antagonist which has shown activity in preventing chemotherapy-induced nausea and vomiting in preclinical studies Based on phase I positron emission tomography studies, casopitant doses from 50 - 150 mg result in 70 - 95% saturation of NK1 receptors

    28. ANTIEMETICS: OND 8 mg x 2 day 1-3 + Dex 8 mg x 1 day 1 : CR (%) - placebo 70 - casopitant 50 mg po day 1-3 81 - casopitant 100 mg po day 1-3 79 - casopitant 150 mg po day 1-3 85 - casopitant 150 mg day 1 80 Ond 16 mg po day 1-3 + Dex 8 mg iv day 1 + 84 casopitant 150 mg po day 1-3

    30. ANTIEMETICS: OND 32 mg x 1 day 1 + Dex 8 mg x 1 day 1-4 : CR (%) - placebo 60 - casopitant 50 mg po day 1-3 76 - casopitant 100 mg po day 1-3 86 - casopitant 150 mg po day 1-3 77 - casopitant 150 mg day 1 75 - aprepitant 125 mg po day 1 and 80 mg day 2-3 72 p=0.0036

    31. OLANZAPINE

    32. OLANZAPINE It is an antipsychotic drug that blocks multiple neurotransmitters: - dopamine at D1, D2, D3 and D4 brain receptors, - serotonin at 5-HT2a, 5-HT2c, 5-HT3 and 5-HT6 receptors, - catecholamines at alpha 1 adrenergic receptors - histamine at H1 receptors

    33. OLANZAPINE - Case reports on the use of olanzapine as an antiemetic for chronic nausea in advanced cancer patients and for opioid-induced nausea - In a retrospective chart review of 28 patients who received olanzapine on an as-needed basis following moderately to highly emetogenic chemotherapy, data suggested that olanzapine may decrease delayed emesis (Passik SD et al. J Pain Symptom Manage 2003;25:485-89)

    35. Phase II trial of olanzapine Treatment

    36. Phase II trial of olanzapine Complete Response Slide 36 During the acute, delayed, and overall time intervals, significantly more patients treated with palonosetron 0.25 mg achieved a CR compared with those treated with ondansetron (P<0.025; 97.5% CI of the difference does not include zero). During these time intervals, CR rates were numerically higher, but not statistically superior, for palonosetron 0.75 mg compared with ondansetron. Slide 36 During the acute, delayed, and overall time intervals, significantly more patients treated with palonosetron 0.25 mg achieved a CR compared with those treated with ondansetron (P<0.025; 97.5% CI of the difference does not include zero). During these time intervals, CR rates were numerically higher, but not statistically superior, for palonosetron 0.75 mg compared with ondansetron.

    37. Phase II trial of olanzapine No nausea Slide 36 During the acute, delayed, and overall time intervals, significantly more patients treated with palonosetron 0.25 mg achieved a CR compared with those treated with ondansetron (P<0.025; 97.5% CI of the difference does not include zero). During these time intervals, CR rates were numerically higher, but not statistically superior, for palonosetron 0.75 mg compared with ondansetron. Slide 36 During the acute, delayed, and overall time intervals, significantly more patients treated with palonosetron 0.25 mg achieved a CR compared with those treated with ondansetron (P<0.025; 97.5% CI of the difference does not include zero). During these time intervals, CR rates were numerically higher, but not statistically superior, for palonosetron 0.75 mg compared with ondansetron.

    38. CONCLUSIONS - In this study it seems that olanzapine is safe (no grade 3 or 4 toxicities) and effective in controlling acute and delayed chemotherapy-induced nausea and vomiting in patients receiving highly and moderately emetogenic chemotherapy - Limitations of the study: small number of patients and lack of a control arm and, therefore, RCT are necessary to define its role

    39. MIDAZOLAM

    40. MIDAZOLAM Short-acting benzodiazepine with a rapid onset of action which has been demonstrated efficacious as antiemetic in postoperative emesis resistant to the usual treatments Midazolam decreases dopamine input at the CTZ or dopaminergic neuronal activity and 5-HT release by binding to the GABA benzodiazepine complex In a phase I study in patients submitted to chemotherapy the dose for phase II studies was defined as 0.04 mg/kg (Potanovich LM. J Pain Symptom Manage 1991;8:519-24)

    42. Cisplatin-induced acute emesis refractory to granisetron and dexamethasone Antiemetics: Gran 3 mg iv + Dex 20 mg iv + Midazolam 0.04 mg/kg 4-hour c.i. during chemotherapy Results: 73% of pts had a reduction of at least one grade (NCI common toxicity criteria) in nausea and vomiting intensity in the subsequent courses. 6 pts (23%) had no acute emesis during the second course

    43. GABAPENTIN

    44. GABAPENTIN It is a ?-aminobutyric acid analogue approved in 1994 as an anticonvulsant In an anedoctal report, complete resolution of chemotherapy-induced nausea was seen in a patient with breast cancer, after she was placed on gabapentin for the treatment of hot flushes

    46. Patients with moderate nausea after the 1st course of adjuvant doxorubicin and cyclophosphamide Antiemetics: Ond 16-24 mg iv + Dex 20 mg iv ? lorazepam 0.5-1 mg iv before chemotherapy On course 2nd and 4th gabapentin was added Results: 3 pts had complete resolution of nausea during gabapentin and 6/9 had at least a 3-point reduction (8-point nausea scale) in delayed nausea

    47. GHRELIN

    49. Is ghrelin involved in antiemesis? Ghrelin Stimulates gastric motility Protects gastric mucosa Increases appetite Ghrelin receptor mRNA (rats) Expression increased in the stomac and hypothalamus after cisplatin

    51. NEW ANTIEMETICS PALONOSETRON CASOPITANT OLANZAPINE MIDAZOLAM GABAPENTIN GHRELIN

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