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LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
LCT10001280
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LCT10001280
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LCT10001280

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    • 1. NEW ANTIEMETIC TREATMENTS Fausto Roila Medical Oncology Division, Perugia, Italy
    • 2. ANTIEMETICS OF CHOICE <ul><li>Cisplatin </li></ul><ul><li>- acute emesis NK1 + 5-HT 3 + DEX </li></ul><ul><li>- delayed emesis NK1 + DEX or </li></ul><ul><li>DEX + MTC or </li></ul><ul><li>DEX + 5-HT 3 </li></ul><ul><li>Moderately emetogenic chemotherapy </li></ul><ul><li>- acute emesis 5-HT 3 + DEX  NK1 </li></ul><ul><li>- delayed emesis NK1 or DEX </li></ul>
    • 3. A RANDOMIZED, DOUBLE-BLINDED, PILOT TRIAL OF APREPITANT ADDED TO STANDARD ANTIEMETICS DURING CONDITIONING THERAPY FOR HEMATOPOIETIC STEM CELL TRANSPLANT Bubalo JS, et al. Proc. ASCO 2007; 25: 520s (abst. 9112)
    • 4. Patients submitted to high dose chemotherapy  TBI Antiemetics: ondansetron + dexamethasone + - aprepitant 125 mg po on day 1 and 80 mg on subsequent days (begun on day - 7 through day + 4; alone on days + 1 through + 4) - placebo RESULTS (n = 30)
    • 5. O+D+A O+D Complete + major response 14/15 (93%) 7/15 (47%) No emesis 10/15 (67%) 5/15 (33%) Complete response = no emesis, mild-moderate nausea Major response = 1- 2 emesis in only 1 day with any level nausea or no emesis with severe nausea RESULTS
    • 6. “ NEW” ANTIEMETICS <ul><li>PALONOSETRON </li></ul><ul><li>CASOPITANT </li></ul><ul><li>OLANZAPINE </li></ul><ul><li>MIDAZOLAM </li></ul><ul><li>GABAPENTIN </li></ul><ul><li>GHRELIN </li></ul>
    • 7. PALONOSETRON
    • 8. PALONOSETRON - Potent and selective 5-HT3 antagonist with a high affinity for 5-HT3 receptors - Mean plasma elimination half-life of ~ 40 hours substantially longer than that of ondansetron (4-6 h), granisetron (5-8 h), tropisetron (7 h) and dolasetron (7 h)
    • 9. PALONOSETRON - Metabolized primarily by CYP2D6 and to a lesser extent by CYP3A and CYP1A2 - No difference in the drug’s 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
    • 10. PALONOSETRON IN CISPLATIN-TREATED PATIENTS
    • 11. EFFICACY, SAFETY AND PHARMACOKINETICS OF PALONOSETRON IN PATIENTS RECEIVING HIGHLY EMETOGENIC CISPLATIN-BASED CHEMOTHERAPY: A DOSE-RANGING CLINICAL STUDY Eisenberg P, et al Ann Oncol 2004; 15: 330-337
    • 12. Dose (  g/kg) 0.3 1 3 10 30 90 No. pts 29 24 25 24 46 Complete response* 24 46 40 50 46 * No vomiting and no rescue therapy on day 1 1/3 of pts treated with 3-10  g/kg presented a complete response on the 7 days after chemotherapy RESULTS
    • 13. A PHASE III, DOUBLE-BLIND, RANDOMIZED TRIAL OF PALONOSETRON COMPARED WITH ONDANSETRON IN PREVENTING CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING FOLLOWING HIGHLY EMETOGENIC CHEMOTHERAPY Aapro MS, et al. Ann Oncol 2006; 17:1441-449
    • 14. PAL PAL OND p Dose (mg) 0.25 0.75 32 No. of pts 225 225 223 C.R. day 1 59.2 65.5 57.0 n.s. C.R. day 2-5 45.3 48.0 38.9 n.s. C.R. day 1-5 40.8 42.2 33.0 n.s. 67% of pts received dexamethasone on day 1 RESULTS
    • 15. PALONOSETRON IN PATIENTS SUBMITTED TO MODERATELY EMETOGENIC CHEMOTHERAPY
    • 16. 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 Gralla RJ, et al. Ann Oncol 2003; 14:1570-77
    • 17. IMPROVED PREVENTION OF MODERATE CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING WITH PALONOSETRON, A PHARMACOLOGICALLY NOVEL 5-HT3 RECEPTOR ANTAGONIST: RESULTS OF A PHASE III SINGLE-DOSE TRIAL VERSUS DOLASETRON Eisemberg P, et al. Cancer 2003; 98: 2473-82
    • 18. PAL PAL OND PAL PAL DOL Dose (mg) 0.25 0.75 32 0.25 0.75 100 No. pts 189 189 185 189 189 185 C.R. day 1 81.0* 73.5 68.6 63.0 57.1 52.9 C.R. day 2-5 74.1* 64.6 55.1 54.0* 56.6* 38.7 C.R. day 1-5 69.3* 58.7 50.3 46.0* 47.1* 34.0 * Statistically significant RESULTS
    • 19. SHORTCOMINGS OF THE STUDIES - Less than 5% and 67% of pts, respectively submitted to MEC and HEC, received dexamethasone on day 1 - 30-60% of pts pretreated - No prophylaxis for delayed emesis - Can we conclude that PALO is superior being the studies planned as non-inferiority trials?
    • 20. TOLERABILITY - Palonosetron is well tolerated - Adverse events are similar to the other 5-HT3 antagonists; in particular palonosetron induces headache in about 10% and constipation in about 5% of patients
    • 21. CONCLUSIONS - Palonosetron in three well conducted double-blind studies demonstrated similar efficacy than ondansetron in cisplatin-treated patients and superior efficacy than ondansetron and dolasetron in patients submitted to moderately emetogenic chemotherapy. - It remains to evaluate palonosetron with respect to the other 5-HT3 antagonists when combined with dexamethasone (and aprepitant) on day 1 and on day 2-5
    • 22. COMBINATION THERAPY FOR CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING IN PATIENTS RECEIVING MODERATELY EMETOGENIC CHEMOTHERAPY:PALONOSETRON, DEXAMETHASONE, AND APREPITANT Grote T, et al. J Support Oncol 2006; 4:403-8
    • 23. Palonosetron + Aprepitant + Dexamethasone Complete Response (N=58) 88% 78% 78% 0 20 40 60 80 100 Acute: 0-24 Delayed: 24-120 Overall: 0-120 (% of Patients) Time (hr)
    • 24. PREVENTION OF MODERATELY EMETOGENIC CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING WITH A 1-DAY 3-DRUG ANTIEMETIC REGIMEN – PRELIMINARY REPORT Grunberg S, et al. Support Care Cancer 2006; 14:596-7
    • 25. 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% RESULTS (n = 15)
    • 26. EFFICACY OF A 1-DAY 3-DRUG ANTIEMETIC REGIMEN FOR PREVENTION OF ACUTE AND DELAYED NAUSEA AND VOMITING INDUCED BY MODERATELY EMETOGENIC CHEMOTHERAPY Grunberg SM, et al. Proc. ASCO 2007; 25: 520s (abstr 9111)
    • 27. CASOPITANT
    • 28. CASOPITANT - 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 study, casopitant doses from 50 - 150 mg result in 70 - 95% saturation of NK1 receptors
    • 29. MULTICENTER, RANDOMIZED, DOUBLE-BLIND, ONDANSETRON-CONTROLLED, DOSE-RANGING, PARALLEL GROUP TRIAL OF THE NEUROKININ-1 RECEPTOR ANTAGONIST CASOPITANT MESYLATE FOR CHEMOTHERAPY-INDUCED NAUSEA / VOMITING IN PATIENTS RECEIVING MODERATELY EMETOGENIC CHEMOTHERAPY Arpornwirat W, et al. Proc. ASCO 2006; 24:471s (ab.8512)
    • 30. 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 RESULTS (n = 719) p=0.0124
    • 31. RANDOMIZED PHASE II TRIAL OF THE NEUROKININ-1 RECEPTOR ANTAGONIST CASOPITANT MESYLATE WITH ONDANSETRON / DEXAMETHASONE FOR CHEMOTHERAPY-INDUCED NAUSEA / VOMITING IN PATIENTS RECEIVING HIGHLY EMETOGENIC CHEMOTHERAPY Rolski J, et al. Proc. ASCO 2006; 24:471s (ab.8513)
    • 32. 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 RESULTS (n = 493)
    • 33. OLANZAPINE
    • 34. OLANZAPINE 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
    • 35. 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)
    • 36. A PHASE I TRIAL OF OLANZAPINE (ZYPREXA) FOR THE PREVENTION OF DELAYED EMESIS IN CANCER PATIENTS: A HOOSIER ONCOLOGY GROUP STUDY Passik SD, et al. Cancer Invest 2004; 22:383-8
    • 37. Four-cohort dose escalation of 3-6 pts per cohort Antiemetics: standard premedication + olanzapine on day -2 and -1 prior chemotherapy and for 8 days after Dose: the maximum tolerated dose was 5 mg for day -2 and -1 and 10 mg for day 0 - 7 Results: no vomiting observed in 4/6 pts treated with cisplatin and 9/9 with moderately emetogenic chemotherapy RESULTS (n = 15)
    • 38. A PHASE II TRIAL OF OLANZAPINE FOR THE PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING: A HOOSIER ONCOLOGY GROUP STUDY Navari RM, et al. Support Care Cancer 2005; 13:529-34
    • 39. Phase II trial of olanzapine Treatment Day 1 Days 2-4 G D O D O G=granisetron; D=dexamethasone; O=olanzapine Days -2-1 O Navari RM et al. Support Care Cancer 2005;13:529-534.
    • 40. Phase II trial of olanzapine Complete Response Complete Response (CR) = no emesis, no rescue medication. Navari RM et al. Support Care Cancer 2005;13:529-534. 85% 80% Overall (0-120 h) 85% 80% Delayed (24-120 h) 100% 100% Acute (0-24 h) Moderately emetogenic (n=20) Highly emetogenic (n=10)
    • 41. Phase II trial of olanzapine No nausea Navari RM et al. Support Care Cancer 2005;13:529-534. 65% 100% Overall (0-120 h) 65% 100% Delayed (24-120 h) 85% 100% Acute (0-24 h) Moderately emetogenic (n=20) Highly emetogenic (n=10)
    • 42. 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
    • 43. MIDAZOLAM
    • 44. 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 imput at the CTZ or dopaminergic neuronal activity and 5-HT release by binding to the GABA benzodiazepine complex - In a phase I study in outpatients submitted to chemotherapy the dose for phase II studies was 0.04 mg/kg (Potanovich LM. J Pain Symptom Manage 1991; 8: 519-524)
    • 45. MIDAZOLAM FOR ACUTE EMESIS REFRACTORY TO DEXAMETHASONE AND GRANISETRON AFTER HIGHLY EMETOGENIC CHEMOTHERAPY Mandalà M, et al. Support Care Cancer 2005; 13:375-80
    • 46. 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 RESULTS (n = 30)
    • 47. GABAPENTIN
    • 48. GABAPENTIN - 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 - The mitigation of tachykinin neurotransmitter activity useful to control both hot flushes and emesis has been suggested as possible mechanism of action
    • 49. EFFECT OF GABAPENTIN ON NAUSEA INDUCED BY CHEMOTHERAPY IN PATIENTS WITH BREAST CANCER Guttuso T, et al. Lancet 2003; 361:1703-05
    • 50. 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 RESULTS (n = 9)
    • 51. GHRELIN
    • 52. Rudd JA et al. Neuroscience Letters 2006;392:79-85.
    • 53. Is ghrelin involved in antiemesis? <ul><li>Ghrelin </li></ul><ul><li>Stimulates gastric motility </li></ul><ul><li>Protects gastric mucosa </li></ul><ul><li>Increases appetite </li></ul><ul><li>Ghrelin receptor mRNA (rats) </li></ul><ul><li>Expression increased in the stomach and hypothalamus after cisplatin </li></ul>Rudd JA et al. Neuroscience Letters 2006;392:79-85.
    • 54. Ghrelin and cisplatin-induced emesis Rudd JA et al. Neuroscience Letters 2006;392:79-85.

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