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Chemotherapy Induced Nausea and Vomiting (CINV) Causes, Challenges, Evaluation and Optimizing Clinical Management Innovation Investigation Application.

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Presentation on theme: "Chemotherapy Induced Nausea and Vomiting (CINV) Causes, Challenges, Evaluation and Optimizing Clinical Management Innovation Investigation Application."— Presentation transcript:

1 Chemotherapy Induced Nausea and Vomiting (CINV) Causes, Challenges, Evaluation and Optimizing Clinical Management Innovation Investigation Application 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 Taste Change Chemotherapy Experienced Patients Rank Severe CINV Near Death Sun C et al. Support Care Cancer. 2005 Thrombocytopenia Median VAS Scores Remission CINV 1 Current Health AlopeciaDepressionOtotoxicity Weight Gain Sexual Dysfunction Memory loss Constipation Leg pain FatigueFlu Peripheral Neuropathy DiarrheaDysuria CINV 4 CINV 6 CINV 5 Death Perfect Health CINV 2 Mucositis CINV 3 Febrile Neutropenia Complete Control Mucositis Death Moderate Delayed Nausea Poorly Controlled Acute & Delayed CINV

3 Emetogenic Potential of Single Antineoplastic Agents HIGH Risk in nearly all patients (> 90%) MODERATE Risk in 30% to 90% of patients LOW Risk in 10% to 30% of patients MINIMAL Fewer than 10% at risk

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

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

8 Pathophysiology of Chemotherapy-Induced Emesis

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

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

11 1 st Generation 5HT 3 RAs Are Therapeutically Equivalent Pts receiving MEC* (N=1,085) 80% of pts received prophylactic steroids *Cyclophosphamide 500 - 1200 mg/m 2, carboplatin 300 mg/m 2 59.0 60.0 71.0 58.0 72.0 TotalNausea Emesis Oral granisetron 2 mg IV ondansetron 32 mg Complete Control (%) Highest Level Evidence &Highest Level Evidence & Not Debated MASCC 2004MASCC 2004 NCCN 2009NCCN 2009 ASCO 2006ASCO 2006 1 st Generation Agents are1 st Generation Agents are Therapeutically Equivalent DolasetronDolasetron OndansetronOndansetron GranisetronGranisetron 1 st Generation oral and IV1 st Generation oral and IV doses equally effective Perez et al. J Clin Oncol 1998;16:754

12 Palonosetron Second generation 5-HT 3 antagonist Second generation 5-HT 3 antagonist Pharmacologic differences from older 5-HT 3 antagonists Pharmacologic differences from older 5-HT 3 antagonists prolonged half-life (~40 hours) prolonged half-life (~40 hours) enhanced receptor binding affinity (30-fold) enhanced receptor binding affinity (30-fold) FDA approved FDA approved IV formulation July 25, 2003 IV formulation July 25, 2003 Oral formulation August 22, 2008 Oral formulation August 22, 2008 Regimens Regimens IV 0.25 mg pre chemotherapy acute/delayed HEC/MEC IV 0.25 mg pre chemotherapy acute/delayed HEC/MEC PO 0.50 mg pre chemotherapy PO 0.50 mg pre chemotherapy acute MEC acute MEC

13 Palonosetron vs. 1 st gen HT-3RA: Complete Response on Day of Chemo & Beyond Palonosetron 0.25 mg (n=378) Ondansetron/Dolasetron 32/100 mg (n=376) 46.8 42.0 * 57.7 * 64.0 * 72.0 60.6 0 20 40 60 80 100 Time (hr) Acute: 0-24 (Day 1) Delayed: 24-120 (Days 2-5) Overall: 0-120 (Days 1-5) Complete Response (CR) (% of Patients) *p<0.025 for pairwise difference (2-sided Fishers 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. CR = no emetic episodes or use of rescue medications

14 p < 0.05 Aapro M Support Care Cancer 2003:11:391 Palonosetron vs Ondansetron High Emetic Risk Chemotherapy Patients Also Receiving Dexamethasone Palonosetron vs Ondansetron High Emetic Risk Chemotherapy Patients Also Receiving Dexamethasone * * N=447 (67%)

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

16 Phase III Trial Palonosetron vs. Granisetron both with Dexamethasone in HEC Palo+ Dex (n=555) % Grani+ Dex (n=558) % P Complete Response, Acute (0-24h) 73.772.1ND CR, Delayed (24-120h)53.042.40.0003 CR, Overall (0-120h)47.938.10.0007 No Nausea: 0-120 hours 32250.01 No Emesis: 0-120 hours 58490.006 Saito M et al. Lancet Oncol. 2009;10(2):115-24

17 Palonosetron: 5-HT 3 Antagonist of Choice? Palonosetron is a 5-HT 3 antagonist with strong receptor binding affinity and an extended half-life Palonosetron is a 5-HT 3 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 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 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 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 Comparable tolerability Ease of use and trends towards superiority favor palonosetron as the preferred 5-HT 3 antagonist Ease of use and trends towards superiority favor palonosetron as the preferred 5-HT 3 antagonist Definitive proof of superiority to first generation 5-HT 3 antagonists would require trials with control arms utilizing corticosteroids, NK 1 antagonists and repetitive dosing of the first generation agents Definitive proof of superiority to first generation 5-HT 3 antagonists would require trials with control arms utilizing corticosteroids, NK 1 antagonists and repetitive dosing of the first generation agents

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

19 Aprepitant Randomized Trial: Patients Receiving AC Group Day 1 Days 2-3 Aprepitant (n = 438) Standard (n = 428) ODA0A 8 mg BID 12 mg 125 mg 8 mg BID 20 mg P 80 mg 8 mg BID P Warr DG et al. J Clin Oncol 2005; 23:2822-2830 O = ondansetron PO A = aprepitant PO D = dexamethasone PO P = placebo PO P

20 Aprepitant in Anthracycline/Cyclophosphamide Chemotherapy: Complete Response (N=857) *p<0.05 Complete response (CR): no emesis and no rescue medication. Warr DG et al. J Clin Oncol 2005; 23:2822-2830 * * 76 55 51 69 49 42 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 (CR) (% of Patients) Aprepitant (n=433) Standard (n=424) Time (hr)

21 Aprepitant in Moderately Emetogenic Chemotherapy: Percent of Patients with No Emesis Warr DG et al. J Clin Oncol 2005; 23:2822-2830 *p<0.001 * * * 88 81 76 77 69 59 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) Aprepitant (n=433) Standard (n=424) Time (hr)

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

23 Phase III Aprepitant Study (801): Multiple-day Ondansetron Aprepitant Control Group Day 4 16 8 Day 1 3212125 3220 Days 2-3 808 16 ODADDA O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo PP P 16 P 16 OO Schmoll et al: Ann Oncol 17:1000-6, 2006 Initial cycle cisplatin > 70 mg/m2Initial cycle cisplatin > 70 mg/m2 445 patients445 patients

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

25 Palonosetron + Aprepitant + Dexamethasone Phase II Study Design Day 1 Days 2-3 PALODADA 0.25 mg12 mg125 mg80 mg Grote T et al. Proc Am Soc Clin Oncol. 2004. Abstract 8262. PALO = palonosetron IV A = aprepitant PO D = dexamethasone PO 8 mg Multicenter, phase II, open-label studyMulticenter, phase II, open-label study Naïve and non-naïve patients receiving moderately to moderately- highly emetogenic chemotherapyNaïve and non-naïve patients receiving moderately to moderately- highly emetogenic chemotherapy Treatment:Treatment:

26 Grote T et al. Proc ASCO 2004. Abstract 8262 Palonosetron + Aprepitant + Dexamethasone Complete Response (ITT, N=58) 87.9 77.6 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 (CR) (% of Patients) Time (hr)

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

28 Despite Compliance w/ Guidelines Problems Remain: Better Antiemetics Needed DeMoor C et al. Proc Am Soc Clin Oncol. 2003. Abstract 2924. 20 30 40 50 60 70 80 % of Pts w/ Delayed CINV Noncompliance w/ Guidelines 0 10 100 90 Compliance w/ Guidelines Even when physicians follow guidelines (using 1 st generation 5HT 3 RAs), 50% of pts experience delayed CINV AgeAge GenderGender Emetogenic PotentialEmetogenic Potential Presence of Acute CINVPresence of Acute CINV After Adjustment For Prognostic Factors For Delayed CINV

29 Relationship Between Acute CINV and Delayed CINV: Questions Is acute CINV a strong predictive factor for delayed CINV in patients receiving moderately emetogenic chemotherapy? 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? 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-HT 3 receptor antagonists vs palonosetron in preventing delayed CINV after accounting for known prognostic factors, including the carryover effect? What is the difference in the treatment effect of the first-generation 5-HT 3 receptor antagonists vs palonosetron in preventing delayed CINV after accounting for known prognostic factors, including the carryover effect? Grunberg SM et al. Proc Am Soc Clin Oncol. 2004. Abstract 8051.

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

31 Protection From Acute and Delayed CINV: Palonosetron vs Ondansetron/Dolasetron Protection From Delayed CINV (n/n with No Acute CINV) Protection From Acute CINV PALO 0.25 mg OND 32 mg/ DOL 100 mg Yes(218/272) 80% * (158/228)69% No(24/106) 23% 23% (18/148)12% *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.

32 671 pts receiving doxorubicin-based chemotherapy 671 pts receiving doxorubicin-based chemotherapy all treated w/ 1 st generation 5HT 3 + Dex on Day 1 of CT all treated w/ 1 st generation 5HT 3 + Dex on Day 1 of CT Pts then randomized for days 2 and 3: Pts then randomized for days 2 and 3: Arm 1: Prochlorperazine 10 mg p.o. three times daily (q 8 h) Arm 1: Prochlorperazine 10 mg p.o. three times daily (q 8 h) Arm 2: Any oral 5-HT 3 antiemetic, using standard dosing regimens Arm 2: Any oral 5-HT 3 antiemetic, using standard dosing regimens Arm 3: Prochlorperazine 10 mg p.o. as needed for nausea Arm 3: Prochlorperazine 10 mg p.o. as needed for nausea Rescue medications for control of symptoms were allowed Rescue medications for control of symptoms were allowed Are Oral Followup 5-HT 3 RAs Really Effective for Delayed CINV? Hickock et al ASCO 2005 Final Results URCC-CCOP

33 1 st Generation Oral 5HT 3 RAs: Majority of Patients Experience Nausea Patients randomized for days 2 and 3; rescue medications allowedPatients randomized for days 2 and 3; rescue medications allowed Hickock et al ASCO 2005 Final Results URCC-CCOPHickock et al ASCO 2005 Final Results URCC-CCOP * p = 0.002 (overall comparison); p = 0.06 (q 8 h vs 5-HT 3 ); * p = 0.002 (overall comparison); p = 0.06 (Prochlorperazine q 8 h vs 5-HT 3 ); p = NS (prn vs 5-HT 3 ) p = NS (Prochlorperazine prn vs 5-HT 3 ) 10 20 30 40 50 60 70 80 90 100 Prochlorperazine q 8h* 3 * 5HT 3 * Prochlorperazine PRN* % Patients with Delayed Nausea 75 83 87

34 1 st Generation Oral 5HT 3 RAs Not Effective for Delayed CINV Vomiting Vomiting Significantly more patients vomited at least once during the delayed period (34%) than on the day of treatment (19%) p <0.01 Significantly more patients vomited at least once during the delayed period (34%) than on the day of treatment (19%) p <0.01 Nausea Nausea Nausea severity was significantly greater during the delayed period than on the day of treatment p < 0.01 Nausea severity was significantly greater during the delayed period than on the day of treatment p < 0.01 More patients getting oral 5HT 3 RAs required rescue medications (45%) than patients getting Compazine ® (27-30%) p=0.002 More patients getting oral 5HT 3 RAs required rescue medications (45%) than patients getting Compazine ® (27-30%) p=0.002 Hickock et al ASCO 2005 Final Results URCC-CCOP

35 Meta-Analysis of Efficacy of 5-HT 3 RA in Prevention of Delayed Emesis from Chemotherapy Reviewed 5 studies, 1,716 pts comparing 5-HT 3 RA to placebo, 5 studies, 2,240 pts comparing 5-HT 3 RA + dexamethasone to dexamethasone alone 5-HT 3 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-HT 3 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 Geling and Eichler, JCO 23:1289-1294

36 ASCO 2006/NCCN 2009 Recommendations by Risk Category High (>90% emetic risk) Including AC containing regimens Three-drug combination of a HT 3 serotonin receptor antagonist, (palonosetron preferred-NCCN) dexamethasone, and aprepitant Moderate (>30% to 90% emetic risk) Two-drug combination of a HT 3 serotonin receptor antagonist and dexamethasone (+/-aprepitant for selected patients) Low (10% to 30% emetic risk) Dexamethasone 8-12 mg Minimal (<10% emetic risk No antiemetic routinely

37 How Can We Improve the Value of Care in CINV? Value = Quality Cost Cost CR CR Nausea or Emesis Functioning Nausea or Emesis Functioning Side Effects Side Effects Compliance or Patient Inconvenience Compliance or Patient Inconvenience Access to Care Access to Care DirectDirect IndirectIndirect

38 Summary 1 st generation 5HT 3 RAs therapeutically equivalent & major advance in supportive care for control of acute emesis 1 st generation 5HT 3 RAs therapeutically equivalent & major advance in supportive care for control of acute emesis No major progress in CINV for ~ 10+ yrs until aprepitant & palonosetron No major progress in CINV for ~ 10+ yrs until aprepitant & palonosetron Treatment guidelines have changed Treatment guidelines have changed Degree of nausea incurred has been refined for many agents Degree of nausea incurred has been refined for many agents Delayed CINV recommendations are updated Delayed CINV recommendations are updated Prevention of CINV has improved, but challenges remain Prevention of CINV has improved, but challenges remain Improving detection of CINV, especially after 24 hours Improving detection of CINV, especially after 24 hours Educating patients and oncology healthcare givers Educating patients and oncology healthcare givers The development and evaluation of clinically useful assessment tools The development and evaluation of clinically useful assessment tools Further development of regimens to treat delayed CINV Further development of regimens to treat delayed CINV


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