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  • 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 (<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).

t 2006 t 2006 Presentation Transcript

  • 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
  • Chemotherapy-Induced Nausea Vomiting: The Challenge of Management
    • Patient Case:
    • LT is 46 y/o women diagnosed with sarcoma
    • admitted to the hospital for treatment with 3 rd cycle of doxorubicin and ifosfamide
    • 1st cycle: complicated with severe acute and delayed CINV
    • 2 nd cycle: complicated with severe acute and delayed CINV
    • During admission evaluation today, LT told her nurse that if she experiences CINV she will not receive any more chemotherapy.
  • Chemotherapy-Induced Nausea Vomiting: The Challenge of Management
    • Patient Case:
    • LT is 46 y/o women diagnosed with sarcoma admitted to the hospital for treatment with her 3 rd cycle of doxorubicin and ifosfamide
    • 1st cycle of chemotherapy:
      • Prevention: 5HT 3 antagonist + dexamethasone
      • Treatment: dopamine antagonist
    • 2 nd cycle of chemotherapy:
      • Prevention: 5HT 3 antagonist + dexamethasone + lorazepam
      • Treatment: dopamine antagonist
  • Chemotherapy-Induced Nausea Vomiting: The Challenge of Management
    • CINV is a broad term for a range of symptoms associated with chemotherapy:
      • pathophysiology
      • manifestation
        • nausea and/or vomiting
        • timing (e.g. onset, duration)
        • intensity
      • impact of symptom
  • Chemotherapy-Induced Nausea Vomiting: The Challenge of Management
    • CINV is a broad term for a range of symptoms associated with chemotherapy
    • Chemotherapy is a broad category of medications:
      • classical chemotherapy
      • biotherapy
      • oral versus parenteral chemotherapy
      • combination of medications
      • impact of dose of chemotherapy
  • Patterns of Acute Emesis % of pts w/ vomiting Time (hours) Martin M. Oncology 1996;53(suppl 1):26-31
  • New Treatment Strategies for Chemotherapy-Induced Nausea and Vomiting
    • discuss new treatment strategies based on current understanding of pathophysiology of CINV
    • list published guidelines for management of CINV
    • discuss strategies for individualization of treatment strategies for CINV
  • Pathophysiology of Chemotherapy-Induced Emesis
  • 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
  • Chemotherapy Induced Nausea and Vomiting Emetic Center Cortical GI vestibular Nausea / Vomiting CTZ Neurokinins: Substance P DA 5HT
  • Chemotherapy Induced Nausea / Vomiting Emetic Center Cortical GI vestibular Nausea / Vomiting CTZ Neurokinins DA 5HT 3
  • Neurotransmitter Crosstalk in CINV
    • Animal data demonstrate:
    • modulation of the 5HT 3 receptor can directly effect NK receptors signaling
    • modulation of NK receptors can influence 5HT 3 receptor
    • substance P has shown to potentiate 5HT 3 receptor mediated inward current in rat trigeminal ganglion neuron
      • Hu WP, et al. Neuroscie Letter 2004:365:147
    • serotonin unmasks substance P inducible depolarization of NK receptors in nodose ganglion neurons
      • Moore KA, et al. J Appl Physiol 2002:92:2529
      • Minami M, et al. Eur J Pharmacol 2001:428:215
  • Rubenstein ED, et al Cancer J 2006
    • Neuroanatomical
    • Centers:
    • Emetic center
    • Chemoreceptor trigger zone
    • Vagal afferents of GI
    • Neurotransmitters:
    • Dopamine (DA)
    • Serotonin (5HT)
    • Substance P
    • GABA
    • Cannabinoid I
    • Acetylcholine
    • Endorphins
    Emetic Center CTZ
  • CINV: Classification Anticipatory Acute Delayed Chemo 16 - 24 hours
  • Serotonin and Chemotherapy Urinary 5HIAA Hours after chemotherapy administration Cubeddu, L.X. Oncology 1996;53(suppl 1):18-25
  • Serotonin and Chemotherapy Urinary 5HIAA Hours after chemotherapy administration Cubeddu, L.X. Oncology 1996;53(suppl 1):18-25
  • Perception vs Reality: Emetogenic Chemotherapy Grunberg S. Cancer . 2004;100:2261-2268. Highly Emetogenic Chemotherapy Moderately Emetogenic Chemotherapy
  • Chemotherapy-Induced Nausea / Vomiting N = 322 76% Nausea 43% Acute 39% Acute & Delayed 73% Delayed 30% Vomiting 11% Acute 7% Acute & Delayed 25% Delayed Hickok, JT, et al. Cancer 2003;97:2880-6
  • Acute CINV  Delayed CINV No Acute CINV No Delayed 76% Delayed 24% Yes Acute CINV No Delayed 20% Delayed 80%
  • CINV: A Broad Definition Anticipatory acute delayed …. chemotherapy administration
  • CINV: Current Problem
    • CINV is still a clinical problem
    • do not fully understand the pathophysiology of CINV (e.g. acute, delayed)
    • “ traditional” definition of acute and delayed CINV does not match the physiology
    • Appears that:
      • acute CINV impacts delayed CINV
      • prevention of acute CINV may help management of delayed CINV
  • New Treatment Strategies for Chemotherapy-Induced Nausea and Vomiting
    • discuss new treatment strategies based on current understanding of pathophysiology of CINV
      • aprepitant
      • palonosetron
  • CINV Emetic Center Cortical GI vestibular Nausea / Vomiting CTZ Neurokinins: Substance P
  • Substance P
    • prototypic neuropeptide of the 50 known neuroactive molecules
      • now recognized as a member of the tachykinin family of neurotransmitters
      • neurokinins are tachykinins found in mammals (substance P, NKA, NKB)
      • 3 categories of NK receptors
      • NK1 - affinity for substance P
      • NK2 - affinity for NKA
      • NK3 - affinity for NKB
    • currently considered a modulator of nociception, stress, anxiety, nausea / vomiting
    DeVane CL. Pharmacotherapy 2001:21:1061-9
  • CINV: Aprepitant (Emend  )
    • aprepitant (Emend  , Merck & Co., Inc.) approved in the US in 2003
    • Mechanism of action:
      • selective, high affinity antagonist of human substance P at neurokinin 1 (NK 1 ) receptors  interferes with the substance P pathway that produces N/V
      • no affinity for serotonin (5HT 3 ), dopamine and corticosteroid receptors
    • Indication:
      • combination with other antiemetics
      • indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy
  • Neurokinin-1 Antagonist: Role in CINV
    • Purpose:
    • neurokinin-1 antagonist (NK-1a) vs . ondansetron
    • Study design:
    • dbl-blind randomized, parallel study in cisplatin naive pts
      • group I (n = 61)
      • acute: NK-1a x 1 dose + dexamethasone 20 mg IV x 1
      • delayed: NK-1a po q d x 4 days
      • group II (n = 58)
      • acute: NK-1a IV x 1 dose + dexamethasone 20 mg IV x 1
      • delayed: placebo x 4 days
      • group III (n = 57)
      • acute: ondansetron 32 mg IV x 1
      • delayed: placebo x 4 days
    Van Belle S, et al. ASCO 1999. Abstract 2281
  • Neurokinin-1 Antagonist: Role in CINV
      • group I : NK-1a + dexamethasone  NK-1a
      • group II: NK-1a + dexamethasone  placebo
      • group III: ondansetron  placebo
    • Results (% patients without emesis):
    • Acute Emesis
      • group I - 50% group II - 47% group III - 84%
    • Delayed Emesis
      • group I - 68% group II - 63% group III - 41%
    Van Belle S, et al. ASCO 1999. Abstract 2281
  • Neurokinin-1 Antagonist: Role in CINV
      • group I : NK-1a + dexamethasone  NK-1a
      • group II: NK-1a + dexamethasone  placebo
      • group III: ondansetron  placebo
    • Results (% patients without emesis):
    • Acute Emesis
      • group I - 50% group II - 47% group III - 84%
    • Delayed Emesis
      • group I - 68% group II - 63% group III - 41%
    Van Belle S, et al. ASCO 1999. Abstract 2281
  • Neurokinin-1 Antagonist: Role in CINV
    • Multicenter, dbl blind, parallel-group trial in CDDP naive patients (n=351)
    • Groups:
      • acute delayed
      • I gran + dex placebo
      • II gran + NK-1a + dex NK-1a
      • III NK-1a + dex NK-1a
      • IV NK-1a + dex NK-1a
    Campos-D, et al. JCO 2001
  • Neurokinin-1 Antagonist: Role in CINV
    • Group I: granisetron + dexamethasone  placebo
    • Group II: granisetron + NK-1a + dexamethasone  NK-1a
    • Group III: NK-1a + dexamethasone  NK-1a
    • Group IV: NK-1a + dexamethasone  NK-1a
    • Percentage of patients without emesis:
    • acute delayed
    • I 57 % 29 %
    • II 80 % 63 %
    • III 46 % 51 %
    • IV 43 % 57 %
    Campos-D, et al. JCO 2001
  • Neurokinin-1 Antagonist: Role in CINV
    • Group I: granisetron + dexamethasone  placebo
    • Group II: granisetron + NK-1a + dexamethasone  NK-1a
    • Group III: NK-1a + dexamethasone  NK-1a
    • Group IV: NK-1a + dexamethasone  NK-1a
    • Percentage of patients without emesis:
    • acute delayed
    • I 57 % 29 %
    • II 80 % 63 %
    • III 46 % 51 %
    • IV 43 % 57 %
    Campos-D, et al. JCO 2001
  • Neurokinin-1 Antagonist: Role in CINV
    • Purpose: evaluation of time course of emesis for antiemetic strategies
    • Patients: CDDP naïve  CDDP  70 mg/m2
      • acute (day 1) delayed (day 2-5)
    • group I: gran + dex placebo
    • group II: gran + NK-1a + dex NK-1a
    • group III: NK-1a * + dex NK-1a
    • group IV: NK-1a + dex NK-1a
    • * higher dose
    • granisetron = gran
    • dexamethasone = dex
    Hesketh PJ, et al. ASCO 2002 (abst 1476)
  • Neurokinin-1 Antagonist: Role in CINV
      • group I: gran + dex  placebo
    • group II: gran + NK1a + dex  NK1a
    • group III: NK1a* + dex  NK1a
    • group IV: NK1a + dex  NK1a
    • Results: % of patients without emesis
    • group 0 - 8 hrs 0 - 16 hrs 0 - 24 hrs 0 - 120 hrs
    • I 92 % 81 % 57 % 23 %
    • II 88 % 86 % 80 % 57 %
    • III 49 % 47 % 46 % 35 %
    • IV 45 % 44 % 43 % 37 %
    Hesketh PJ, et al. ASCO 2002 (abst 1476)
  • CINV: A Broad Definition Anticipatory Early acute Chemo Late acute Delayed 16 hours 24 hours
  • CINV: Aprepitant (Emend  )
    • aprepitant (Emend  , Merck & Co., Inc.) approved in the US in 2003
    • Mechanism of action:
      • selective, high affinity antagonist of human substance P at neurokinin 1 (NK 1 ) receptors  interferes with the substance P pathway that produces N/V
      • no affinity for serotonin (5HT 3 ), dopamine and corticosteroid receptors
    • Indication:
      • combination with other antiemetics
      • indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy
  • Aprepitant Administration
    • Given for three days as part of a regimen that includes a 5-HT 3 antagonist and a corticosteroid
    • Recommended dose
      • 125 mg po 1 hour prior to chemotherapy
      • 80 mg daily in the morning on days 2 and 3
    • Supplied in 125- and 80-mg capsules
  • Aprepitant Metabolism
    • metabolized in the liver through the P450 enzyme system
    • primarily metabolized by the CYP3A4 isozyme
    • Some drug-drug interactions may be more significant for oral medications (first pass effect)
  • Aprepitant: Drug Interactions
    • CYP3A4 Inducers:
    • Rifampin
    • Carbamazepine
    • Phenytoin
    •  aprepitant level
    • CYP3A4 Inhibitors:
    • Ketoconazole
    • Itraconazole
    • Nefazodone
    • Troleandomycin
    • Clarithromycin
    • Ritonavir
    • Nelfinavir
    •  aprepitant level
  • Effect of Other Drugs on Aprepitant
  • Aprepitant: Impact on CYP450
    • Aprepitant is primarily metabolized by the CYP3A4 isoenzyme
    • Aprepitant inhibits CYP3A4 (as early as 1 hr after first dose)
    • Induces its own metabolism upon dosing for 2 weeks (autoinduction) via CYP 3A4
    • Aprepitant induces CYP2C9
            • Shadle CR, et al. J Clin Pharmacol 2004
  • Aprepitant: Drug Interactions
      • paclitaxel
      • etoposide
      • vinorelbine
      • docetaxel
      • irinotecan
      • ifosfamide
      • imatinib
      • vinblastine
      • vincristine
    Antineoplastic agents commonly metabolized through CYP3A4:
  • 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)
  • Aprepitant Does Not Affect Docetaxel Pharmacokinetics
    • Plasma Concentration Profiles of Docetaxel
    Docetaxel AUC of individual patients Docetaxel Plasma Concentration (mcg/mL)
  • Aprepitant: Challenges for Care
    • Potential drug interactions with anticancer medication
    • Evaluation of drug interactions should look at impact beyond 24 hours
    • Potential drug interactions with other medications (e.g. chronic)
  • The Complexity of Pharmacotherapy in the Patient with Cancer Drug A - chronic Drug B - chronic Drug C - chronic
  • The Complexity of Pharmacotherapy in the Patient with Cancer Jan Feb March April Drug A - chronic Drug B - chronic Drug C - chronic
  • The Complexity of Pharmacotherapy in the Patient with Cancer Jan Feb March April Drug A - chronic Drug B - chronic Drug B - chronic Chemotherapy
  • 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…..
  • 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
  • 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
  • CINV: Triple Upfront Therapy 5HT3 Antagonist + NK1 Antagonist + Dexamethasone
    • Clinical Trials:
    • Phase III for highly emetogenic chemotherapy: Cisplatin
    • Pooled analysis:
      • Overall vomiting prevention with triple drug approach by 20%
      • Improvement in acute nausea and vomiting by 13%
      • Improvement in delayed nausea and vomiting by 21%
      • No differences in treatment-related adverse effect comparison
        • Warr et al. Eur J Cancer 2005
  • CINV: Triple Upfront Therapy Rationale: Clinical Guidelines
    • Guidelines include triple upfront therapy for highly emetogenic regimens:
      • MASCC
      • NCCN 2007
      • ASCO 2006
      • Kris MG, et al. JCO 2006:24:2932
  • 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
  • CINV: Triple Upfront Therapy MEC Breast Cancer Regimens
    • Overall CR favored triple drug therapy
      • 51% vs 42%
    • Acute CR favored triple drug therapy
      • 76% vs 69%
    • Delayed CR favored triple drug therapy
      • 55% vs 49%
    • Patients experiencing no vomiting higher in the triple drug therapy group
      • 76 % vs 59%
    • Increased QOL (measured by FLIE) in patients receiving triple drug therapy
      • 85% vs 71%
    Warr, D.G., et al. J Clin Oncol 2005;23:2822-30
  • CINV: Triple Upfront Therapy Moderately Emetogenic Therapy Complete Response (%) Warr, DG, et al. J Clin Oncol 2005;23:2822-30
  • CINV Emetic Center Cortical GI vestibular Nausea / Vomiting CTZ Neurokinins: Substance P DA 5HT
  • 5HT3 Receptor Antagonists
    • Prototypes:
      • Ondansetron
      • Granisetron
      • Dolasetron
      • Palonosetron
    • MOA: Inhibition of 5-HT3 receptors on vagal afferent neurons in GI and in CTZ
    • Efficacy improved when used with a steroid
    • Well tolerated, minimal side effects
      • headache
      • constipation
      • bradycardia
  • 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
  • Palonosetron: Metabolism and Excretion
    • Approximately equal contribution of renal and hepatic routes of elimination
      • ~40% renally cleared unchanged
      • ~50% of administered dose metabolized
    • Total body clearance is not significantly affected by gender, age, hepatic impairment, renal impairment
    • Plasma protein binding of ~60%
    • Does not inhibit or induce cytochrome P450 isozymes at clinically relevant concentrations.
  • Palonosetron vs Ondansetron: CINV
    • Study Design:
    • Phase III randomized, multicenter, double-blind, active-controlled, stratified, parallel-arm trial
    • Moderately emetogenic chemotherapy (single dose)
    • Active comparator trial (n = 563)
      • Day 1:
      • Palonosetron 0.25 mg IV
      • Palonosetron 0.75 mg IV
      • Ondansetron 32 mg IV
    • No corticosteroid administered prophylactically
    • Patients were followed for 14 days for evaluation
    Gralla R et al. Ann Oncol . 2003;14:1570-1577.
  • 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)
  • 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, % †‡
  • 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
  • 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)
  • 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) *
  • 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
  • Palonosetron: What is the role?
    • 5HT 3 antagonist with a long half life (40 hr)
    • Appears to have activity in both acute and delayed CINV
    • Initial studies done with single day chemotherapy  how does this apply to multiple day therapy?
    • How does this agent impact decision for use of aprepitant?
  • Neurotransmitter Crosstalk in CINV
    • Animal data demonstrate:
    • modulation of the 5HT 3 receptor can directly effect NK receptors signaling
    • modulation of NK receptors can influence 5HT 3 receptor
    • substance P has shown to potentiate 5HT 3 receptor mediated inward current in rat trigeminal ganglion neuron
      • Hu WP, et al. Neuroscie Letter 2004:365:147
    • serotonin unmasks substance P inducible depolarization of NK receptors in nodose ganglion neurons
      • Moore KA, et al. J Appl Physiol 2002:92:2529
      • Minami M, et al. Eur J Pharmacol 2001:428:215
  • CINV: Upfront Therapy
    • Selection of the patient / patient groups
    • Current:
      • emetogenicity potential of regimen
      • prior history of CINV
    • Future:
      • identify and utilize patient specific factor (e.g. pharmacogenomics)
  • Chemotherapy-Induced Nausea Vomiting: The Challenge of Management
    • Patient Case:
    • LT is 46 y/o women diagnosed with sarcoma
    • admitted to the hospital for treatment with 3 rd cycle of doxorubicin and ifosfamide
    • 1st cycle: complicated with severe acute and delayed CINV
    • 2 nd cycle: complicated with severe acute and delayed CINV
    • During admission evaluation today, LT told her nurse that if she experiences CINV she will not receive any more chemotherapy.
  • Chemotherapy-Induced Nausea Vomiting: The Challenge of Management
    • Patient Case:
    • LT is 46 y/o women diagnosed with sarcoma
    • admitted to the hospital for treatment with 3 rd cycle of doxorubicin and ifosfamide
    • 1st cycle: complicated with severe acute and delayed CINV
      • 5HT 3 antagonist
      • corticosteroid
      • ? Aprepitant
      • prn dopamine antagonist
    • 2 nd cycle: complicated with severe acute and delayed CINV
    • During admission evaluation today, LT told her nurse that if she experiences CINV she will not receive any more chemotherapy.
  • Chemotherapy-Induced Nausea Vomiting: The Challenge of Management
    • Patient Case:
    • LT is 46 y/o women diagnosed with sarcoma
    • admitted to the hospital for treatment with 3 rd cycle of doxorubicin and ifosfamide
    • 1st cycle: complicated with severe acute and delayed CINV
      • 5HT 3 antagonist
      • corticosteroid
      • ? Aprepitant
      • prn dopamine antagonist
    • 2 nd cycle: complicated with severe acute and delayed CINV
      • evaluation of acute and delayed CINV from first cycle
      • evaluation of contibutory factors for CINV
  • Etiology of Nausea and Vomiting in Patients with Cancer
    • Direct Treatment Related:
    • chemotherapy
      • - acute
      • - delayed
      • - anticipatory
      • - breakthrough N/V
      • - refractory N/V
    • radiation therapy
    • prophylactic antibiotics
    • Indirect Treatment Related:
    • mucositis
    • opiates
    • anti-infectives
    • gastroparesis
    • infection
    • hyperacidity
    • anorexia
    • diarrhea
    • pain
    • anxiety
  • Chemotherapy-Induced Nausea Vomiting: The Challenge of Management
    • Patient Case:
    • LT is 46 y/o women diagnosed with sarcoma
    • admitted to the hospital for treatment with 3 rd cycle of doxorubicin and ifosfamide
    • 1st cycle: complicated with severe acute and delayed CINV
    • 2 nd cycle: complicated with severe acute and delayed CINV
      • evaluation of acute and delayed CINV from first cycle
      • evaluation of contibutory factors for CINV
      • scheduled:
        • 5HT3 antagonist
        • Corticosteroid
        • Dopamine antagonist
        • Benzodiazepine
        • antihistamine