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Chemotherapy Induced Nausea and Vomiting (CINV ) Causes, Challenges, Evaluation and Optimizing Clinical Management

Innovation ● Investigation ● Application. Chemotherapy Induced Nausea and Vomiting (CINV ) Causes, Challenges, Evaluation and Optimizing Clinical Management . Program Co-Chairman Lee S. Schwartzberg, MD, FACP Medical Director, The West Clinic Supportive Oncology Services

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Chemotherapy Induced Nausea and Vomiting (CINV ) Causes, Challenges, Evaluation and Optimizing Clinical Management

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  1. Innovation ● Investigation ● Application Chemotherapy Induced Nausea and Vomiting (CINV)Causes, Challenges, Evaluation and Optimizing Clinical Management Program Co-Chairman Lee S. Schwartzberg, MD, FACP Medical Director, The West Clinic Supportive Oncology Services President, Accelerated Community Oncology Research Network Memphis, TN

  2. Chemotherapy Experienced Patients Rank Severe CINV Near Death Moderate Delayed Nausea Poorly Controlled Acute & Delayed CINV Median VAS Scores Complete Control Death Mucositis Remission Perfect Health Thrombocytopenia CINV 1 Current Health Alopecia Taste Change Depression Ototoxicity Weight Gain Sexual Dysfunction Memory loss Constipation Leg pain Fatigue Flu Peripheral Neuropathy CINV 2 Febrile Neutropenia Diarrhea Mucositis Dysuria CINV 3 CINV 4 CINV 6 CINV 5 Death Sun C et al. Support Care Cancer. 2005

  3. Emetogenic Potential of Single Antineoplastic Agents

  4. Age <50 years Women > men History of light alcohol use History of vomiting with prior exposure to chemotherapeutic agents Other risks History of motion sickness History of nausea or vomiting during pregnancy History of anxiety Patient-Specific Risk Factors for CINV ASHP. Am J Health Syst Pharm. 1999:56:729-764; Balfour and Goa. Drugs. 1997:54:273-298.

  5. Acute (post-treatment) Occurs within first 24 hours after administration of cancer chemotherapy Delayed CINV that begins after first 24 hours May last for 120 hours Anticipatory Learned or conditioned response from poorly controlled nausea and vomiting associated with previous chemotherapy Breakthrough CINV that occurs despite prophylaxis and requires rescue Refractory Occurs during subsequent treatment cycles when prophylaxis and/or rescue has failed in previous cycles Types of CINV: Definitions

  6. Pathophysiology of Chemotherapy-Induced Emesis

  7. Chemotherapy-Induced Emesis: Key Treatment Milestones Aprepitant, March 2003 Palonosetron July, 2003

  8. Corticosteroids Dopamine antagonists Serotonin (5-HT3) antagonists NK-1 receptor antagonists Cannabinoids Pharmacologic Agents

  9. Pts receiving MEC* (N=1,085) 1st Generation 5HT3 RAs Are Therapeutically Equivalent • Highest Level Evidence & • Not Debated • MASCC 2004 • NCCN 2009 • ASCO 2006 • 1st Generation Agents are • Therapeutically Equivalent • Dolasetron • Ondansetron • Granisetron • 1st Generation oral and IV • doses equally effective Oral granisetron 2 mg IV ondansetron 32 mg 72.0 71.0 60.0 59.0 58.0 58.0 Complete Control (%) Emesis Total Nausea 80% of pts received prophylactic steroids *Cyclophosphamide 500 - 1200 mg/m2, carboplatin ≥300 mg/m2 Perez et al. J ClinOncol 1998;16:754

  10. Second generation 5-HT3 antagonist Pharmacologic differences from older 5-HT3 antagonists prolonged half-life (~40 hours) enhanced receptor binding affinity (30-fold) FDA approved IV formulation July 25, 2003 Oral formulation August 22, 2008 Regimens IV 0.25 mg pre chemotherapy acute/delayed HEC/MEC PO 0.50 mg pre chemotherapy acute MEC Palonosetron

  11. Palonosetron vs. 1st gen HT-3RA:Complete Response on Day of Chemo & Beyond Palonosetron 0.25 mg (n=378) Ondansetron/Dolasetron 32/100 mg (n=376) 100 * 80 72.0 * * 64.0 60.6 57.7 60 Complete Response (CR) (% of Patients) 46.8 42.0 40 20 0 Acute: 0-24 (Day 1) Delayed: 24-120 (Days 2-5) Overall: 0-120 (Days 1-5) Time (hr) CR = no emetic episodes or use of rescue medications *p<0.025 for pairwise difference (2-sided Fisher’s exact test) between palonosetron and ondansetron/dolasetron. Gralla R et al. Ann Oncol. 2003; Eisenberg P et al. Cancer. 2003. Rubenstein EB et al. Proc Am Soc Clin Oncol. 2003. Abstract 2932.

  12. PalonosetronvsOndansetronHigh Emetic Risk Chemotherapy Patients Also Receiving Dexamethasone N=447 (67%) * * p < 0.05 Aapro M Support Care Cancer 2003:11:391

  13. 1114 patients Cisplatin (57%) or anthracycline/cyclophosphamide (43%) Single 0.75 mg dose of palo vs. single 40 μg/kg dose of granisetron Dexamethasone 16 mg d1; 4mg/d d 2-3 (AC/EC); 8mg/d d 2-3 CDDP Objective: demonstrate non-inferiority d1 and superiority d 2-5 of palo Primary endpoint complete response (no emesis/no rescue) Phase III Trial of IV Palonosetron vs. IV Granisetron with Cisplatin or AC-Based Chemotherapy Saito M et al. Lancet Oncol. 2009;10(2):115-24

  14. Phase III Trial Palonosetron vs. Granisetron both with Dexamethasonein HEC Saito M et al. Lancet Oncol. 2009;10(2):115-24

  15. Palonosetron is a 5-HT3 antagonist with strong receptor binding affinity and an extended half-life In 2 MEC trials, IV palonosetron (single dose) was superior to dolasetron and ondansetron (single dose) in the prevention of acute and delayed emesis in a post-hoc analysis In 1 HEC trial, emetic control was comparable between IV palonosetron and ondansetron; better control with palonosetron in the subset receiving dexamethasone In large phase III trial with cisplatin or AC, palonosetron was equivalent to granisetron in acute control and superior during the delayed phase Comparable tolerability Ease of use and trends towards superiority favor palonosetron as the preferred 5-HT3 antagonist Definitive proof of superiority to first generation 5-HT3 antagonists would require trials with control arms utilizing corticosteroids, NK1 antagonists and repetitive dosing of the first generation agents Palonosetron: 5-HT3 Antagonist of Choice?

  16. Selective antagonist of the binding of Substance P to the neurokinin 1 (NK1) receptor FDA approved Oral formulation: March 26, 2003 IV formulation (fosaprepitant): January 31, 2008 Regimen 125 mg PO day 1, 80 mg PO days 2-3 acute/delayed HEC/MEC 115 mg IV day 1, 80 mg PO days 2-3 acute/delayed HEC/MEC Aprepitant

  17. Aprepitant Randomized Trial: Patients Receiving AC O D A 0 A 8 mg BID 12 mg 125 mg P 80 mg 8 mg BID 20 mg P 8 mg BID P O = ondansetron PO A = aprepitant PO D = dexamethasone PO P = placebo PO Warr DG et al. J Clin Oncol 2005; 23:2822-2830

  18. Aprepitant in Anthracycline/Cyclophosphamide Chemotherapy: Complete Response (N=857) Aprepitant (n=433) 100 Standard (n=424) * 76 80 69 * 55 60 51 49 Complete Response (CR) (% of Patients) 42 40 20 0 Delayed: 24-120 (Days 2-5) Acute: 0-24 (Day 1) Overall: 0-120 (Days 1-5) Time (hr) *p<0.05 Complete response (CR): no emesis and no rescue medication. Warr DG et al. J ClinOncol 2005; 23:2822-2830

  19. Aprepitant (n=433) * 100 * Standard (n=424) 88 * 81 77 76 80 69 59 60 Emesis-Free (% of Patients) 40 20 0 Acute: 0-24 (Day 1) Delayed: 24-120 (Days 2-5) Overall: 0-120 (Days 1-5) Aprepitant in Moderately Emetogenic Chemotherapy: Percent of Patients with No Emesis Time (hr) *p<0.001 Warr DG et al. J ClinOncol 2005; 23:2822-2830

  20. Aprepitant in Moderately Emetogenic Chemotherapy: Percent of Patients with No Nausea Aprepitant (n=430) 100 Standard (n=424) 80 61 59 60 Nausea-Free (% of Patients) 37 36 40 33 33 20 0 Delayed: 24-120 (Days 2-5) Overall: 0-120 (Days 1-5) Acute: 0-24 (Day 1) Time (hr) No nausea: score <5 mm on 0-100 mm VAS. Warr DG et al. J ClinOncol 2005; 23:2822-2830; Warr DG et al. Support Care Cancer. 2004. Abstract A027.

  21. Phase III Aprepitant Study (801):Multiple-day Ondansetron • Initial cycle cisplatin> 70 mg/m2 • 445 patients Group Day 1 Days 2-3 Day 4 O D A O D A O D 32 12 125 P 8 80 P 8 Aprepitant 32 20 P 16 16 P 16 16 Control O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo Schmoll et al: Ann Oncol 17:1000-6, 2006

  22. Identical design to Protocols 052 and 054 except ondansetron dosed days 1-4 Primary endpoint: complete response on days 1 - 5 after cisplatin Aprepitant regimen superior to control regimen of protracted ondansetron and dexamethasone dosing, CR 72% vs. 61% respectively Phase III Aprepitant Study (801):Multiple-day Ondansetron Schmoll et al: Ann Oncol 17:1000-6, 2006

  23. Palonosetron + Aprepitant + DexamethasonePhase II Study Design • Multicenter, phase II, open-label study • Naïve and non-naïve patients receiving moderately to moderately-highly emetogenic chemotherapy • Treatment: PALO D A D A 0.25 mg 12 mg 125 mg 8 mg 80 mg PALO = palonosetron IV A = aprepitant PO D = dexamethasone PO Grote T et al. Proc Am Soc Clin Oncol. 2004. Abstract 8262.

  24. Palonosetron + Aprepitant + Dexamethasone Complete Response (ITT, N=58) 100 87.9 77.6 77.6 80 60 Complete Response (CR) (% of Patients) 40 20 0 Acute: 0-24 (Day 1) Delayed: 24-120 (Days 2-5) Overall: 0-120 (Days 1-5) Time (hr) Grote T et al. Proc ASCO 2004. Abstract 8262

  25. Perception vs Reality: Emetogenic Chemotherapy Highly Emetogenic Chemotherapy Moderately Emetogenic Chemotherapy Grunberg S. Cancer. 2004;100:2261-2268.

  26. Despite Compliance w/ Guidelines Problems Remain: Better Antiemetics Needed 100 After Adjustment For Prognostic Factors For Delayed CINV 90 80 • Age • Gender • Emetogenic Potential • Presence of Acute CINV 70 60 50 % of Pts w/ Delayed CINV 40 30 20 10 0 Compliance w/ Guidelines Noncompliance w/ Guidelines Even when physicians follow guidelines (using 1st generation 5HT3 RAs), 50% of pts experience delayed CINV DeMoor C et al. Proc Am Soc ClinOncol. 2003. Abstract 2924.

  27. Is acute CINV a strong predictive factor for delayed CINV in patients receiving moderately emetogenic chemotherapy? Is prevention of delayed CINV a carryover effect from prevention of acute CINV or a true pharmacologic effect during the delayed phase? What is the difference in the treatment effect of the first-generation 5-HT3 receptor antagonists vs palonosetron in preventing delayed CINV after accounting for known prognostic factors, including the carryover effect? Relationship Between Acute CINV and Delayed CINV: Questions Grunberg SM et al. Proc Am Soc ClinOncol. 2004. Abstract 8051.

  28. 75 80 70 60 50 No Delayed CINV(% of Patients) 40 30 17 20 10 0 With Acute CINV (n=254) Without Acute CINV (n=500) Protection From Delayed CINV:All Patients Grunberg SM et al. Proc Am Soc Clin Oncol. 2004. Abstract 8051.

  29. Protection From Acute and Delayed CINV:PalonosetronvsOndansetron/Dolasetron *p=0.005 for palonosetron vs ondansetron/dolasetron.†p=0.027 for palonosetron vs ondansetron/dolasetron. Grunberg SM et al. Proc Am Soc Clin Oncol. 2004. Abstract 8051.

  30. 671 pts receiving doxorubicin-based chemotherapy all treated w/ 1st generation5HT3 + Dex on Day 1 of CT Pts then randomized for days 2 and 3: Arm 1: Prochlorperazine 10 mg p.o. three times daily (q 8 h) Arm 2: Any oral 5-HT3 antiemetic, using standard dosing regimens Arm 3: Prochlorperazine 10 mg p.o. as needed for nausea Rescue medications for control of symptoms were allowed Are Oral Followup 5-HT3 RAs Really Effective for Delayed CINV? Hickock et al ASCO 2005 Final Results URCC-CCOP

  31. 100 Prochlorperazineq 8h* 87 83 90 5HT3* 75 80 ProchlorperazinePRN* 70 60 % Patients with Delayed Nausea 50 40 30 20 10 1st Generation Oral 5HT3 RAs:Majority of Patients Experience Nausea * p = 0.002 (overall comparison); p = 0.06 (Prochlorperazineq 8 h vs 5-HT3 ); p = NS (Prochlorperazineprnvs 5-HT3 ) • Patients randomized for days 2 and 3; rescue medications allowed • Hickock et al ASCO 2005 Final Results URCC-CCOP

  32. Vomiting Significantly more patients vomited at least once during the delayed period (34%) than on the day of treatment (19%) p <0.01 Nausea Nausea severity was significantly greater during the delayed period than on the day of treatment p < 0.01 More patients getting oral 5HT3 RAs required rescue medications (45%) than patients getting Compazine®(27-30%)p=0.002 1st Generation Oral 5HT3 RAs Not Effective for Delayed CINV Hickock et al ASCO 2005 Final Results URCC-CCOP

  33. Reviewed 5 studies, 1,716 pts comparing 5-HT3 RA to placebo, 5 studies, 2,240 pts comparing 5-HT3 RA + dexamethasone to dexamethasone alone 5-HT3 RA as monotherapy Absolute RR (95% CI) 8.2% (3.0-13.4) NNT 12.2 Number of doses per protected pt: 74.4 5-HT3 RA as adjunct to dexamethasone Absolute RR (95% CI) 2.6% (-0.6-5.8) NNT 38.8 Number of doses per protected pt: 423 Meta-Analysis of Efficacy of 5-HT3RA in Prevention of Delayed Emesis from Chemotherapy Geling and Eichler, JCO 23:1289-1294

  34. ASCO 2006/NCCN 2009 Recommendations by Risk Category

  35. Value = Quality How Can We Improve the Value of Care in CINV? • Direct • Indirect  Cost  CR  Nausea or Emesis  Functioning  Side Effects  Compliance or  Patient Inconvenience  Access to Care

  36. 1st generation 5HT3 RA’s therapeutically equivalent & major advance in supportive care for control of acute emesis No major progress in CINV for ~ 10+ yrs until aprepitant & palonosetron Treatment guidelines have changed Degree of nausea incurred has been refined for many agents Delayed CINV recommendations are updated Prevention of CINV has improved, but challenges remain Improving detection of CINV, especially after 24 hours Educating patients and oncology healthcare givers The development and evaluation of clinically useful assessment tools Further development of regimens to treat delayed CINV Summary

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