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1. New Treatment Strategies for Chemotherapy-Induced Nausea and Vomiting Rowena N. Schwartz, Pharm.D., BCOP Director of Oncology Pharmacy The Johns Hopkins Hospital Adjunct Associate Professor of Pharmacy Therapeutics University of Pittsburgh School of Pharmacy
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6. Patterns of Acute Emesis % of pts w/ vomiting Time (hours) Martin M. Oncology 1996;53(suppl 1):26-31
9. Rubenstein ED, et al Cancer J 2006 Neuroanatomical Centers: Emetic center Chemoreceptor trigger zone Vagal afferents of GI tract Neurotransmitters: Dopamine (DA) Serotonin (5HT) Substance P Emetic Center CTZ
10. Chemotherapy Induced Nausea and Vomiting Emetic Center Cortical GI vestibular Nausea / Vomiting CTZ Neurokinins: Substance P DA 5HT
11. Chemotherapy Induced Nausea / Vomiting Emetic Center Cortical GI vestibular Nausea / Vomiting CTZ Neurokinins DA 5HT 3
42. Aprepitant’s effect on Plasma Concentrations of Dexamethasone N=12 per treatment Dexamethasone: 20 mg P.O. Day 1, 8 mg/d P.O. Days 2-5 Aprepitant: 125 mg Day 1, 80 mg/d Days 2-5 Dexamethasone Plasma Concentration (ng/mL)
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45. The Complexity of Pharmacotherapy in the Patient with Cancer Drug A - chronic Drug B - chronic Drug C - chronic
46. The Complexity of Pharmacotherapy in the Patient with Cancer Jan Feb March April Drug A - chronic Drug B - chronic Drug C - chronic
47. The Complexity of Pharmacotherapy in the Patient with Cancer Jan Feb March April Drug A - chronic Drug B - chronic Drug B - chronic Chemotherapy
48. The Complexity of Pharmacotherapy in the Patient with Cancer Jan Feb March April Drug A - chronic Drug B - chronic Drug B - chronic Chemotherapy Antiemetic(s) Antibiotic Pain Medication And so the complexity continues…..
49. The Complexity of Pharmacotherapy in the Patient with Cancer Jan Feb March April Drug A - chronic Drug B - chronic Drug C - chronic Chemotherapy Antiemetic(s) Antibiotic Pain Medication
50. The Complexity of Pharmacotherapy in the Patient with Cancer Jan Feb March April Drug A - chronic Drug B - chronic Drug C- chronic Chemotherapy Antiemetic(s) Antibiotic Pain Medication
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53. CINV: Triple Upfront Therapy Aprepitant for Moderately Emetogenic Chemotherapy (Breast Cancer Regimens) Aprepitant Control Group Day 1 12 125 20 Days 2-3 80 16 O D A O A O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo P P P 16 16 Warr, D.G., et al. J Clin Oncol 2005;23:2822-30 N = 866
56. CINV Emetic Center Cortical GI vestibular Nausea / Vomiting CTZ Neurokinins: Substance P DA 5HT
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58. Half-Life and Binding Affinities of 5-HT 3 Receptor Antagonists * Log-scale. † In vitro data; clinical significance has not been established. 5-HT 3 Antagonist Half-Life (h) Binding Affinity (pKi)* † Palonosetron (Aloxi ® ) 40.0 10.45 Ondansetron (Zofran ® ) 4.0 8.39 Dolasetron (Anzemet ® ) 7.3 7.60 Granisetron (Kytril ® ) 9.0 8.91
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61. Palonosetron vs Ondansetron: CINV Demographics (ITT population) Gralla R et al. Ann Oncol . 2003;14:1570-1577. 57.8 57.7 59.8 Non-naïve 42.2 42.3 40.2 Naïve Chemotherapeutic history, % Gender, % 1.1 0.5 1.6 Other 98.9 99.5 98.4 White Ethnic group, % 71.9 73.0 71.4 Female 28.1 27.0 28.6 Male 55.3 54.8 56.1 Age, mean yrs Ondansetron 32 mg (n=185) Palonosetron 0.75 mg (n=189) Palonosetron 0.25 mg (n=189)
62. Palonosetron vs Ondansetron: CINV Chemotherapy Agents and Tumor Types † R eported for the most common categories. ‡ Multiple agents were possible. Gralla R et al. Ann Oncol . 2003;14:1570-1577. Tumor Type, % † 3.2 3.2 3.2 Gastric 1.6 5.8 5.8 Colon 6.5 6.3 2.6 Bladder 11.3 10.6 11.1 Lung 56.8 54.5 60.3 Breast 13.5 13.2 7.9 Carboplatin 19.5 16.9 12.2 Methotrexate (>250 mg/m 2 ) 16.8 17.5 19.0 Cisplatin ( 50 mg/m 2 ) 47.0 46.0 51.3 Doxorubicin (>25 mg/m 2 ) 63.3 63.5 63.0 Cyclophosphamide (<1500 mg/m 2 ) Ondansetron 32 mg (n=185) Palonosetron 0.75 mg (n=189) Palonosetron 0.25 mg (n=189) Chemotherapy, % †‡
63. Palonosetron vs Ondansetron: CINV Complete Response: Acute and Delayed Emesis Palonosetron 0.25 mg (n=189) Palonosetron 0.75 mg (n=189) Ondansetron 32 mg (n=185) *97.5% CIs and 2-sided Fisher’s exact test (significance level = 0.025) indicate a difference between palonosetron and ondansetron. Complete response (CR): no emesis, no rescue medication. Gralla R et al. Ann Oncol . 2003;14:1570-1577. Time (hr) 0 20 40 60 80 100 Acute: 0-24 (Day 1) Delayed: 24-120 (Days 2-5) Overall: 0-120 (Days 1-5) Complete Response (% of Patients) * 81.0 73.5 68.6 * 74.1 64.6 55.1 * 69.3 58.7 50.3
64. Palonosetron vs Ondansetron: CINV Complete Control: Acute and Delayed Emesis Time (hr) Palonosetron 0.25 mg (n=189) Palonosetron 0.75 mg (n=189) Ondansetron 32 mg (n=185) * p 0.05 for palonosetron vs ondansetron (Chi-Square test). Complete control (CC): no emesis, no rescue medication, no more than mild nausea. Gralla R et al. Ann Oncol . 2003;14:1570-1577. 76.2 * 66.7 * 63.0 70.9 58.7 53.4 65.4 50.3 44.9 0 20 40 60 80 100 Acute: 0-24 (Day 1) Delayed: 24-120 (Days 2-5) Overall: 0-120 (Days 1-5) Complete Control (% of Patients)
65. Palonosetron vs Ondansetron: CINV Patients With No Emetic Episodes: Acute and Delayed * p 0.05 for palonosetron vs ondansetron (Chi-Square test). Gralla R et al. Ann Oncol . 2003;14:1570-1577. Palonosetron 0.25 mg (n=189) Palonosetron 0.75 mg (n=189) Ondansetron 32 mg (n=185) Time (hr) * 85.2 * 80.4 75.1 77.8 * 72.0 * 65.1 71.4 61.6 55.1 0 20 40 60 80 100 Acute: 0-24 (Day 1) Delayed: 24-120 (Days 2-5) Overall: 0-120 (Days 1-5) Emesis-Free (% of Patients) *
66. Phase III: Palonasetron vs Ondansetron Highly Emetogenic Chemotherapy Time (h) 10 20 0 30 40 50 60 70 80 90 100 0 24 48 72 96 120 Percent of Patients Palonosetron 0.25 mg (n=223) Palonosetron 0.75 mg (n=223) Ondansetron 32 mg (n=221) P =NS for palonosetron 0.25 mg or 0.75 mg vs ondansetron. Time to Treatment Failure = time to 1 st emetic episode or use of rescue medication. PALO-99-05 HEC
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Notes de l'éditeur
Two sites in the brainstem—the vomiting center and the chemoreceptor trigger zone—are important to emesis control. The vomiting center consists of an intertwined neural network in the nucleus tractus solitarius that controls patterns of motor activity. The chemoreceptor trigger zone, located in the area postrema, is the entry point for emetogenic stimuli. Enterochromaffin cells in the gastrointestinal tract respond to chemotherapy by releasing serotonin. Serotonin binds to 5-HT 3 receptors, which are located not only in the gastrointestinal tract, but also on vagal afferent neurons and in the nucleus tractus solitarius and the area postrema. The activated 5-HT 3 receptors signal the chemoreceptor trigger zone via pathways that may include the afferent fibers of the vagus nerve. Serotonin also may bind with 5-HT 3 receptors in the brainstem. Other neurotransmitters, including dopamine and substance P, also influence the chemoreceptor trigger zone. Afferent impulses from the chemoreceptor trigger zone stimulate the vomiting center, which initiates emesis. 1 1. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med . 1993;329: 1790-1796.
In an international prospective observational study of 298 patients from 14 oncology practices performed in 2001-2002, 97% of patients received a 5-HT 3 receptor antagonist, with 78% receiving a corticosteroid prior to receipt of moderately or highly emetogenic chemotherapy (78% received moderately emetogenic regimens). Physicians and nurses overestimated the efficacy of antiemetic treatment for the majority of patients. The greatest discrepancy between predicted and actual nausea and emesis occurred for the delayed period, with physicians and nurses underestimating the incidence of nausea/vomiting by nearly 30%. Of interest, even with treatment with antiemetics, 35% of patients experienced acute nausea and over 50% experienced delayed nausea. 1 1. Grunberg SM, Hansen M, Deuson RR, Mavros P et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer. 2004;100:2261-2268.
Rochester – Wilmot cancer center Data compiled from 2 randomized clinical trials. 73% female – 44% breast, 22% lung 52% dox, 33% carbo, 15% CDDP Stratified between CDDP > or < 60 mg/m2 Acute ond 24 po or 20 IV + dex 12 mg PO or 10 IV Delayed according to current standard
Palonosetron demonstrates key pharmacologic differences compared with previously approved 5-HT 3 receptor antagonists, including an extended plasma elimination half-life (approximately 40 hours) compared with other agents. 1-4 Another pharmacologic difference between palonosetron and other 5-HT 3 receptor antagonists is the 30-fold+ higher binding affinity for the 5-HT 3 receptor of palonosetron compared with other agents in the class. 5,6 The extended plasma half-life of palonosetron, combined with its high binding affinity, may contribute to its prolonged effect. 1. Aloxi ® [package insert]. Bloomington, MN, USA: MGI PHARMA, INC.; 2004. 2. Zofran ® [package insert]. Research Triangle Park, NC, USA: GlaxoSmithKline; 2001. 3. Anzemet ® [package insert]. Bridgewater, NJ, USA: Aventis Pharmaceuticals; 2000. 4. Kytril ® [package insert]. Nutley, NJ, USA: Roche Laboratories Inc.; 2000. 5. Wong EHF, Clark R, Leung E et al. The interaction of RS 25259-197, a potent and selective antagonist, with 5-HT 3 receptors in vitro . Br J Pharmacol . 1995;114:851-859. 6. Miller RC, Galvan M, Gittos MW et al. Pharmacological properties of dolasetron, a potent and selective antagonist at 5-HT 3 receptors. Drug Dev Res . 1993;28:87-93.
This slide summarizes the metabolism and excretion of palonosetron. 1 Palonosetron does not inhibit or induce cytochrome P450 isozymes. 1 Palonosetron is widely distributed throughout the body. Of note, total body clearance of palonosetron is not significantly affected by gender, age, hepatic impairment, renal impairment, or comedications. 1 Therefore, no dose adjustment is necessary in these populations. 1. Aloxi ® [package insert]. Bloomington, MN, USA: MGI PHARMA, INC.; 2004.
This was a phase III, randomized, double-blind, double-dummy, multicenter comparator trial of 563 patients with confirmed malignant disease scheduled to receive a single dose of a moderately emetogenic chemotherapeutic agent. Patients with cardiac, renal, or hepatic disease could be included at the investigator’s discretion. On Day 1, patients were randomized to receive a single fixed IV dose of palonosetron 0.25 mg, palonosetron 0.75 mg, or ondansetron 32 mg, administered 30 minutes prior to moderately emetogenic chemotherapy. Patients were followed for 14 days following study drug administration to evaluate safety. Prophylactic use of corticosteroids was not permitted. 1. Gralla R 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;14:1570-1577.
Of the 570 patients initially randomized, 563 patients received treatment and were evaluated for efficacy (intent-to-treat) and 562 were evaluated for safety. This table displays the demographic data for the intent-to-treat cohort. The distribution of all patients by factors that could influence results, including gender and chemotherapeutic history, were similar across all treatment groups. Approximately 72% of patients were female—not surprising, as moderately emetogenic regimens are often used to treat breast cancer. In addition (data not shown), there were no relevant differences between groups with respect to numbers of patients with renal, hepatic, or cardiovascular dysfunction. Approximately 40% of patients in each of the 3 treatment arms were chemotherapy-naïve. As this study included patients previously exposed to chemotherapy, as well as those who were naïve, it is very relevant as the studied population is similar to that of clinical practice. This population was challenging due to the following demographics (significant risk factors): Mostly female Non-alcohol users/non-smokers Inclusion of patients who were non-naïve to chemotherapy. 1. Gralla R 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;14:1570-1577.
The most common chemotherapeutic agents administered on Day 1 (received by >10% of patients) were cyclophosphamide (63.3%), doxorubicin (48.1%), cisplatin (17.8%), methotrexate (16.2%), and carboplatin (11.5%). Others (<10%) included epirubicin, irinotecan, ifosfamide, mitoxantrone, and idarubicin. The most common cancer type was breast cancer (57.2% of patients), followed by lung cancer (11.0%), bladder cancer (5.1%), colon cancer (4.4%), and gastric cancer (3.2%). Others (<5%) included rectal, prostate, Hodgkin’s disease, ovarian, and bile duct cancers. 1. Gralla R 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;14:1570-1577.
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 different, for palonosetron 0.75 mg compared with ondansetron. 1. Gralla R 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;14:1570-1577.
The CC rate for palonosetron 0.25 mg during the acute interval was numerically higher, but not statistically different, to ondansetron. During the delayed and overall time intervals, significantly more patients treated with palonosetron 0.25 mg achieved CC compared with those treated with ondansetron ( p =0.001). During all 3 time intervals, CC rates were numerically higher, but not statistically different, for palonosetron 0.75 mg compared with ondansetron. 1. Gralla R 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;14:1570-1577.
During the acute, delayed, and overall time intervals, significantly more patients (14%-20% more) treated with palonosetron 0.25 mg had no emetic episodes compared with those treated with ondansetron ( p 0.05). During the delayed and overall time intervals, significantly more patients treated with palonosetron 0.75 mg had no emetic episodes compared with those treated with ondansetron ( p 0.05). 1. Gralla R 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;14:1570-1577.
~50% male, ~60% white, Ovarian, Lung, Hodgkin’s most common, 60% naïve, 2/3 rd steroid, 80+% high dose CDDP. Time to treatment failure was numerically higher in the palonosetron 0.25-mg and 0.75-mg group (median = 45.3 and 45.6 hours, respectively) compared with the ondansetron group (median = 34.2 hours; P =not significant).
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