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
Preliminary preference (utility) data from nausea and vomiting health states from 3 studies involving ovarian cancer patients, clinicians, and healthy female controls were evaluated.
Preferences were assessed using the visual analog scale (VAS), with scores ranging from 0.0 (worst) to 1.0 (best).
Definitions of CINV were:
CINV 1 - Days 1-5 = little to no nausea or vomiting.
CINV 2 - Day 1 = complete control; Days 2-5 = moderate nausea, no vomiting.
CINV 3 - Day 1 = complete control; Days 2-5 = moderate nausea, severe vomiting.
CINV 4 - Day 1 = nausea and vomiting; Days 2-5 = moderate nausea.
CINV 5 - Day 1 = nausea and vomiting; Days 2-5 = moderate nausea, severe vomiting.
CINV 6 - Day 1 = complete control; Days 2-5 = severe nausea.
Patients rated significant CINV (CINV 3-6) comparable to the score for death.
1. Sun C, Bodurka D, Donato M et al. Nausea and vomiting side-effects of cancer therapies: preference assessments from patients, health care providers and healthy women. Support Care Cancer. 2002:10:378. Abstract #93.
Perfect Health
Remission
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
Thrombocytopenia
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
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
Emetogenic Potential of Single Antineoplastic Agents
Shown are agents of moderate to high emetic risk. Low emetic risk (Level 2; 10-30% frequency of emesis) and minimal emetic risk (Level 1; <10% frequency of emesis) agents are also detailed in NCCN guidelines v but not shown here.
Frequency of emesis shown are proportions of patients who experience emesis in the absence of effective antiemetic prophylaxis.
1NCCN guidelines v Available at

6. Patient-Specific Risk Factors for CINV
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
Individuals bring to chemotherapy a unique set of characteristics that moderate their responses—positive and negative—to treatment.
Patient risk factors that increase the likelihood of developing CINV are listed on the slide.
Age <50 years
Women more likely than men to develop CINV
History of light alcohol use; people who drink more heavily are less likely to develop CINV
History of nausea or vomiting associated with pregnancy or motion sickness
History of CINV associated with prior exposure to chemotherapeutic agents
Patients who have a tendency to be anxious are at increased risk
ASHP. Am J Health Syst Pharm. 1999:56: ; Balfour and Goa. Drugs. 1997:54:
American Society of Health-System Pharmacists. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm. 1999;56:
Balfour JA, Goa KL. Dolasetron: a review of its pharmacology and therapeutic potential in the management of nausea and vomiting induced by chemotherapy, radiotherapy or surgery. Drugs. 1997;54:

7. Types of CINV: Definitions
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
Chemotherapy-induced nausea and vomiting (CINV) falls into 3 distinct phases. Familiarity with these is useful for planning prophylactic treatment.
Acute CINV is defined as nausea and/or vomiting that occurs within 24 hours of the administration of cancer chemotherapy.
Delayed CINV is defined as nausea and vomiting that occurs after the first 24 hours. It may last for as long as 120 hours after administration of cancer chemotherapy.
Anticipatory CINV is nausea and vomiting that occurs as a learned response or conditioning. It generally occurs during subsequent cycles of chemotherapeutic treatment when CINV has been poorly managed following previous cycles of chemotherapy. Anticipatory CINV occurs before, during, or after chemotherapy, but usually earlier than an episode of acute CINV would be expected to occur.
Anticipatory CINV does not respond to antiemetic agents or other pharmacologic interventions, but has been shown to respond to behavioral modifications or nonpharmacologic approaches. It is preferable to preempt anticipatory CINV by ensuring adequate control of CINV with the first course of emesis-producing chemotherapy.
American Society of Health-System Pharmacists. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm. 1999;56:

8. Pathophysiology of Chemotherapy-Induced Emesis
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-HT3 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-HT3 receptors signal the chemoreceptor trigger zone via pathways that may include the afferent fibers of the vagus nerve. Serotonin also may bind with 5-HT3 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:

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

10. Serotonin (5-HT3) antagonists NK-1 receptor antagonists Cannabinoids
Pharmacologic Agents
Corticosteroids
Dopamine antagonists
Serotonin (5-HT3) antagonists
NK-1 receptor antagonists
Cannabinoids
Four classes of drugs are commonly used to treat CINV: corticosteroids, dopamine antagonists, serotonin antagonists, and NK-1 receptor antagonists.
Corticosteroids and 5-HT3 receptor antagonists, alone or in combination, are recommended for treatment of acute CINV.
The newest class of drugs approved to treat CINV is the NK-1 receptor antagonist.
American Society of Health-System Pharmacists. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm. 1999;56:
Hesketh PJ, Van Belle S, Aapro M, et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer. 2003;39:

11. 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
Pts receiving MEC* (N=1,085)
Oral granisetron 2 mg
IV ondansetron 32 mg
71.0
72.0
59.0
58.0
60.0
58.0
Complete Control (%)
Total
Nausea
Emesis
80% of pts received prophylactic steroids
*Cyclophosphamide mg/m2, carboplatin ≥300 mg/m2
Perez et al. J Clin Oncol 1998;16:754

12. Palonosetron 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 mg pre chemotherapy acute/delayed HEC/MEC
PO 0.50 mg pre chemotherapy
acute MEC

13. Complete Response (CR)
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
Pooled results from studies and (see individual study results) show that during the acute, delayed, and overall time intervals significantly more patients treated with palonosetron 0.25 mg had a CR compared with those treated with either ondansetron or dolasetron (p<0.025).
Trials included palonosetron 0.25 mg and 0.75 mg dose (N=378) groups; shown are data for only the approved 0.25 mg dose.
Rubenstein EB et al. Palonosetron (PALO) compared with ondansetron (OND) or dolasetron (DOL) for prevention of acute & delayed chemotherapy-induced nausea and vomiting (CINV): combined results of two phase III trials. Proc Am Soc Clin Oncol. 2003;22:729. Abstract 2932.
2. 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:
3. Eisenberg P et al. Improved prevention of moderate CINV with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial vs dolasetron.
Cancer. 2003;98:
Acute: 0-24
(Day 1)
Delayed:
(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
Rubenstein EB et al. Proc Am Soc Clin Oncol Abstract 2932.

14. Palonosetron vs Ondansetron High Emetic Risk Chemotherapy Patients Also Receiving Dexamethasone
(67%) * *
Among the subset of patients receiving dexamethasone, the unadjusted response rates, not controlling for other risk factors, were higher for each dose regimen of palonosetron compared with ondansetron for both acute and delayed phases, and for the overall evaluation period from 0 to 120 hours after administration of highly emetic chemotherapy.
Reference
Aapro M, Bertoli L, Lordick P, et al. Palonosetron (PALO) is effective in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC): results of a phase III trial [abstract A-17]. Support Care Cancer. 2003:11:391.
p < Aapro M Support Care Cancer 2003:11:391

15. Cisplatin (57%) or anthracycline/cyclophosphamide (43%)
Phase III Trial of IV Palonosetron vs. IV Granisetron with Cisplatin or AC-Based Chemotherapy
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)
Saito M et al. Lancet Oncol. 2009;10(2):115-24

16. Complete Response, Acute (0-24h)
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)
73.7
72.1 ND
CR, Delayed (24-120h)
53.0
42.4
0.0003
CR, Overall (0-120h)
47.9
38.1
0.0007
No Nausea:
0-120 hours 32 25
0.01
No Emesis: 58 49
0.006
Saito M et al. Lancet Oncol. 2009;10(2):115-24

17. Palonosetron: 5-HT3 Antagonist of Choice?
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
Slide 39
Compared with other 5-HT3 receptor antagonists, palonosetron demonstrates a strong receptor binding affinity and an extended half-life.
Compared with dolasetron, palonosetron achieved a better CR rate in preventing acute emesis induced by moderately emetogenic chemotherapy.
Efficacy of palonosetron persists throughout the period of major risk for delayed emesis, without repeated dosing.

18. Aprepitant
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

19. Aprepitant Randomized Trial: Patients Receiving AC
Group
Day 1
Days 2-3
Aprepitant
(n = 438)
Standard
(n = 428) O D A A
8 mg BID
12 mg
125 mg P
80 mg
8 mg BID
20 mg P
8 mg BID P
Aprepitant in Moderately Emetogenic Chemotherapy
Aprepitant added to standard therapy was compared with standard therapy alone in a phase III, worldwide, randomized, double-blind study in patients receiving moderately emetogenic chemotherapy. Patients were naïve to emetogenic chemotherapy and treated with cyclophosphamide (C) +/- doxorubicin or epirubicin (A). Of 866 patients randomized, 857 were evaluable (99%), and 99% received A+C.
On day 1, aprepitant patients received 125 mg of oral aprepitant plus 8 mg of oral ondansetron and 12 mg of oral dexamethasone prior to chemotherapy, plus 8 mg oral ondansetron 8 hours later. The standard group received 8 mg of oral ondansetron and 20 mg of oral dexamethasone prior to chemotherapy. On days 2 and 3, the aprepitant group doses were decreased to 80 mg, given once in the morning. Patients in the standard group received oral ondansetron 8 mg twice daily (morning and evening) plus placebo. Of note, dexamethasone was not used on days 2-3 in either group.
1. Warr D, Eisenberg PJ, Hesketh PJ, et al. Effect of aprepitant for the prevention of nausea and vomiting after one cycle of moderately emetogenic chemotherapy: A randomized, double-blind, trial in 866 patients. Proc Am Soc Clin Oncol. 2004;23(July 15 suppl):19. Abstract 8007 and oral presentation.
2. Warr DG, Eisenberg PD, Hesketh PJ, Raftopolous H, Gralla RJ, Muss HB. Phase III, double-blind study to assess an aprepitant-containing regimen for the prevention of nausea and vomiting due to moderately emetogenic chemotherapy. Support Care Cancer 2004;12:374. Abstract A027 and poster.
O = ondansetron PO A = aprepitant PO
D = dexamethasone PO P = placebo PO
Warr DG et al. J Clin Oncol 2005; 23:

20. Complete Response (CR)
Aprepitant in Anthracycline/Cyclophosphamide Chemotherapy: Complete Response (N=857)
Aprepitant (n=433)
100
Standard (n=424) * 76 80 69 * 55 60 51
Complete Response (CR)
(% of Patients) 49 42 40 20
Aprepitant in MEC – Response Rates
In this study of patients receiving moderately emetogenic chemotherapy (99% A+C), the primary analysis was CR overall (0-120 hours), which was achieved by 51% of patients in the aprepitant group and 42% of patients in the standard group (p=0.015). In the acute interval, CR rates were 76% for the aprepitant group vs 69% for the standard group (p=0.034). Delayed CR rates were not statistically significantly different between groups, with 55% for aprepitant vs 49% for the standard group (NS, p=0.064).
No vomiting and no nausea rates were also assessed.
1. Warr D, Eisenberg PJ, Hesketh PJ, et al. Effect of aprepitant for the prevention of nausea and vomiting after one cycle of moderately emetogenic chemotherapy: A randomized, double-blind, trial in 866 patients. Proc Am Soc Clin Oncol. 2004;23(July 15 suppl):19. Abstract 8007 and oral presentation.
2. Warr DG, Eisenberg PD, Hesketh PJ, Raftopolous H, Gralla RJ, Muss HB. Phase III, double-blind study to assess an aprepitant-containing regimen for the prevention of nausea and vomiting due to moderately emetogenic chemotherapy. Support Care Cancer 2004;12:374. Abstract A027 and poster.
Acute: 0-24
(Day 1)
Delayed:
(Days 2-5)
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 Clin Oncol 2005; 23:

21. Aprepitant in Moderately Emetogenic Chemotherapy: Percent of Patients with No Emesis* 88 81 76 77 69 59 20 40 60 80
100
Acute: 0-24
(Day 1)
Delayed:
(Days 2-5)
Overall: 0-120
(Days 1-5)
Emesis-Free
(% of Patients)
Aprepitant (n=433)
Standard (n=424)
No Emesis Rates with Aprepitant in MEC
No vomiting was achieved in 63% of the aprepitant treatment group compared with 43% of the standard group (p<0.001) during the overall period. In the acute phase, no vomiting rates were 88% for aprepitant and 77% for standard therapy (p<0.001). In the delayed phase, no vomiting rates were 81% for aprepitant and 69% for standard therapy (p<0.001).
1. Warr D et al. Effect of aprepitant for the prevention of nausea and vomiting after one cycle of moderately emetogenic chemotherapy: A randomized, double-blind, trial in 866 patients. Proc Am Soc Clin Oncol. 2004;23(July 15 suppl):19. Abstract 8007 and oral presentation.
2. Warr DG et al. Phase III, double-blind study to assess an aprepitant-containing regimen for the prevention of nausea and vomiting due to moderately emetogenic chemotherapy. Support Care Cancer 2004;12:374. Abstract A027 and poster.
Time (hr)
*p<0.001
Warr DG et al. J Clin Oncol 2005; 23:

22. Aprepitant in Moderately Emetogenic Chemotherapy: Percent of Patients with No Nausea
Aprepitant (n=430)
100
Standard (n=424) 80 61 59 60
(% of Patients)
Nausea-Free 37 36 40 33 33 20
No Nausea Rates with Aprepitant in MEC
Nausea was not statistically significantly different between the two groups. In the overall period, 33% of patients in both groups experienced no nausea (peak VAS on 0-100mm scale <5 mm). In the acute phase, no nausea rates were 61% for aprepitant and 59% for standard therapy. In the delayed phase, no nausea rates were 37% for aprepitant and 36% for standard therapy.
1. Warr D et al. Effect of aprepitant for the prevention of nausea and vomiting after one cycle of moderately emetogenic chemotherapy: A randomized, double-blind, trial in 866 patients. Proc Am Soc Clin Oncol. 2004;23(July 15 suppl):19. Abstract 8007 and oral presentation.
2. Warr DG et al. Phase III, double-blind study to assess an aprepitant-containing regimen for the prevention of nausea and vomiting due to moderately emetogenic chemotherapy. Support Care Cancer 2004;12:374. Abstract A027 and poster. .
Acute: 0-24
(Day 1)
Delayed:
(Days 2-5)
Overall: 0-120
(Days 1-5)
Time (hr)
No nausea: score <5 mm on mm VAS.
Warr DG et al. J Clin Oncol 2005; 23: ; Warr DG et al. Support Care Cancer Abstract A027.

23. 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

24. Phase III Aprepitant Study (801): Multiple-day Ondansetron
Identical design to Protocols 052 and 054 except ondansetron dosed days 1-4
Primary endpoint: complete response on days after cisplatin
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
Multicenter, phase II, open-label study
Naïve and non-naïve patients receiving moderately to moderately-highly emetogenic chemotherapy
Treatment:
Day 1
Days 2-3
PALO D A D A
0.25 mg
12 mg
125 mg
8 mg
80 mg
Aprepitant in Moderately Emetogenic Chemotherapy
This was a multicenter, phase II, open-label study of patients receiving moderately to moderately-highly emetogenic chemotherapy (one or more moderately emetogenic agents).
On Day 1, patients received aprepitant 125 mg orally 1 hour before chemotherapy, dexamethasone 12 mg orally and palonosetron 0.25 mg IV 30 minutes before chemotherapy; on Days 2-3, patients received aprepitant 80 mg orally and dexamethasone 8 mg orally.
The primary endpoint was the proportion of patients with CR during the first 24 hours following chemotherapy; a secondary endpoint was the percent of patients with no emetic episodes during the acute, delayed, and overall time periods.
1. Grote T, Hajdenberg J, Cartmell A, et al. Palonosetron (PALO) plus aprepitant (APREP) and dexamethasone (DEX) for the prevention of chemotherapy-induced nausea and vomiting (CINV) after emetogenic chemotherapy (CT). Proc Am Soc Clin Oncol. 2004;23:790. Abstract 8262.
PALO = palonosetron IV A = aprepitant PO
D = dexamethasone PO
Grote T et al. Proc Am Soc Clin Oncol Abstract

26. Complete Response (CR)
Palonosetron + Aprepitant + Dexamethasone Complete Response (ITT, N=58)
100
87.9
77.6
77.6 80 60
Complete Response (CR)
(% of Patients) 40 20
The percent of patients (N=39) with no emetic episodes was 97% during each of the acute, delayed, and overall time periods.
1. Grote T et al. Palonosetron (PALO) plus aprepitant (APREP) and dexamethasone (DEX) for the prevention of chemotherapy-induced nausea and vomiting (CINV) after emetogenic chemotherapy (CT). Proc Am Soc Clin Oncol. 2004;23:790. Abstract 8262.
Acute: 0-24
(Day 1)
Delayed:
(Days 2-5)
Overall: 0-120
(Days 1-5)
Time (hr)
Grote T et al. Proc ASCO Abstract 8262

27. Perception vs Reality: Emetogenic Chemotherapy
Highly Emetogenic Chemotherapy
Moderately Emetogenic Chemotherapy
In an international prospective observational study of 298 patients from 14 oncology practices performed in , 97% of patients received a 5-HT3 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:
Grunberg S. Cancer. 2004;100:

28. 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
Noncompliance w/ Guidelines
Compliance 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 Clin Oncol Abstract 2924.

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 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?
Grunberg SM et al. Proc Am Soc Clin Oncol Abstract 8051.

30. Protection From Delayed CINV: All Patients17 75 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 Abstract 8051.

31. Protection From Delayed CINV
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% †
(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 Abstract 8051.

32. Are Oral Followup 5-HT3 RAs Really Effective for Delayed CINV?
671 pts receiving doxorubicin-based chemotherapy
all treated w/ 1st generation 5HT3 + 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
Hickock et al ASCO 2005 Final Results URCC-CCOP

33. 1st Generation Oral 5HT3 RAs: Majority of Patients Experience Nausea10 20 30 40 50 60 70 80 90
100
Prochlorperazine q 8h*
5HT3*
Prochlorperazine PRN*
% Patients with Delayed Nausea 75 83 87
* p = (overall comparison); p = 0.06 (Prochlorperazine q 8 h vs 5-HT3 );
p = NS (Prochlorperazine prn vs 5-HT3 )
Patients randomized for days 2 and 3; rescue medications allowed
Hickock et al ASCO 2005 Final Results URCC-CCOP

34. 1st Generation Oral 5HT3 RAs Not Effective for Delayed CINV
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
Hickock et al ASCO 2005 Final Results URCC-CCOP

35. Meta-Analysis of Efficacy of 5-HT3RA in Prevention of Delayed Emesis from Chemotherapy
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) % ( )
NNT Number of doses per protected pt: 74.4
5-HT3 RA as adjunct to dexamethasone
Absolute RR (95% CI) 2.6% ( )
NNT Number of doses per protected pt: 423
Geling and Eichler, JCO 23:

36. ASCO 2006/NCCN 2009 Recommendations by Risk Category
High (>90% emetic risk)
Including AC containing regimens
Three-drug combination of a HT3 serotonin receptor antagonist, (palonosetron preferred-NCCN) dexamethasone, and aprepitant
Moderate (>30% to 90% emetic risk)
Two-drug combination of a HT3 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
Direct
Indirect
 CR
 Nausea or Emesis  Functioning
 Side Effects
 Compliance or  Patient Inconvenience
 Access to Care
Chemotherapy-induced nausea and vomiting may be classified as acute (beginning within the first 24 hours after chemotherapy), delayed (beginning more than 24 hours after chemotherapy), or anticipatory (beginning before acute chemotherapy-related symptoms would be expected to occur).
Some data suggest the delayed phase may begin as early as 16 hours.
Although mild nausea and vomiting may be discomforting, more severe cases of nausea and vomiting may result in dehydration, malnutrition, and electrolyte imbalance. These conditions can affect quality of life, the desire to continue with antitumor therapy, and survival.1,2 Studies have demonstrated that nausea and vomiting secondary to chemotherapy impair a patient’s ability to complete household tasks, enjoy meals, and maintain activities of daily living and recreation.3,4
1. ASHP Commission on Therapeutics. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm. 1999;56:
2. Hesketh PJ. Comparative review of 5-HT3 receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting. Cancer Invest. 2000;18:
3. Lindley CM, Hirsch JD, O’Neill CV et al. Quality of life consequences of chemotherapy-induced emesis. Qual Life Res. 1992;1:
4. O’Brien BJ, Rusthoven J, Rocchi A et al. Impact of chemotherapy-associated nausea and vomiting on patients’ functional status and on costs: survey of five Canadian centres. Can Med Assoc J. 1993;149:
5. Grunberg SM, Ehler E, McDermed JE et al. Oral metoclopramide with or without diphenhydramine: potential for prevention of late nausea and vomiting induced by cisplatin. J Natl Cancer Inst. 1988;80:

38. Summary
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