Emerging Treatment Pathways in the Management of CINV
Lee Schwartzberg MD, FACP
Professor of Medicine
Chief, Division of Hematology/Oncology
University of Tennessee Health Science Center
Why is Preventing CINV Important?
• A major treatment‐related adverse event experienced by 70%‐80% of cancer patient1
• Most patients cite CINV as the most feared side effect associated with chemotherapy2
• Prevention is the key. Controlling nausea or vomiting after
it has occurred is much more difficult.
1. Jenns K. Cancer Nurs. 1994;17:488-493. 2. Hickok JT et al. Cancer. 2003;97:2880-6288.
1
The Clinical Impact of CINV
• Associated with the potential for treatment interruption/
abandonment
Proportions of patients with cancer (N = 298) from a multicenter study reporting “no impact on daily life” (NIDL) for nausea and vomiting domains on day 6 postchemotherapy2
• Negative implications on patient quality of life and ADLs1
• Increased use of
health care resources
1. Wiser W, Berger A. Oncology. 2005;19:637-645. 2.Bloechl-Daum B et al. J Clin Oncol. 2006;24:4472-4478.
The Clinical Impact of CINV (cont’d)
Physiologic manifestations of CINV
• Malnutrition
• Anorexia
• Weight loss
• Dehydration
• Esophageal tears
2
Emetogenicity of IV Chemotherapy
Emetogenic
Classification
Incidence of
Emesis
Index Agent
High
> 90%
Cisplatin
High-moderate
90%
Moderate
30%-90%
Low
10%-30%
5-Fluorouracil
Minimal
< 10%
Vincristine
Cyclophosphamide
/Doxorubicin
Carboplatin,
Oxaliplatin
MASCC/ESMO[2]; Basch E,et al[3]; NCCN.[4]
Emetogenicity of Oral Chemotherapy
Emetogenic
Classification
Incidence of
Emesis
Index Agent
High
> 90%
Procarbazine
Moderate
30%-90%
Temozolomide
Low
10%-30%
Etoposide
Minimal
< 10%
Methotrexate
MASCC/ESMO.[2]
3
Patient‐Related Risk Factors for CINV
1. NCCN antiemetic 2013
Types of Chemotherapy‐induced Nausea and Vomiting
• Acute: occurs in the first 24 hours after chemotherapy
• Delayed: occurs 24‐120 hours after chemotherapy
• Breakthrough: occurs despite appropriate prophylaxis
• Anticipatory: occurs as a learned response based on prior exposure
4
Neurotransmitters Involved in Emesis
Histamine
Dopamine
Endorphins
Serotonin
Emetic Center
Substance P
Cannabinoid
GABA
Major Classes of Antiemetic Agents: Definitions
• 5‐HT3 = 5‐hydroxytryptamine type 3 (serotonin) receptor antagonist, including ondansetron, granisetron, dolasetron, palonosetron
• Corticosteroids = Usually dexamethasone; an alternative may be methyl prednisolone
• NK1 = NK1 (neurokinin type 1 receptor) antagonist, including aprepitant, fosaprepitant
5
Endpoints in Clinical Trials of CINV
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Complete Response (CR)
Delayed (>24 hrs – 120 hrs)*
Acute (0 – 24 hrs)
Overall (0 – 24 hrs)
No emesis and no use of rescue medication
No Emesis
No vomiting, retching or dry heaves
No Significant Nausea
Max. VAS <25 mm (scale of 0 to 100 mm) for the Nausea and Vomiting Subject Diary Question 2
No Nausea
Max. VAS <5 mm (scale of 0 to 100 mm) for the Nausea and Vomiting Subject Diary Question 2
Complete Protection
No emesis, no rescue medication, and max nausea VAS <25 mm (scale of 0 to 100 mm) for the Nausea and Vomiting Subject Diary Question 2
No Impact on Daily Life
Functional Living Index‐Emesis (FLIE) total score >108. Denominator is based on the number of subjects with valid questionnaire
HEC: Guideline Recommendations Acute CINV
Delayed CINV Delayed CINV (d 2‐3)
(d 4)
NCCN
5HT3 + Dex + APR* (Palo preferred)
Or
Olanzapine + Palo + Dex
Dex + APR*
Dex
ASCO
5HT3 + Dex + APR Dex + APR*
Dex
MASCCǂ
5HT3 + Dex + APR Dex +APR*
*If fosaprepitant used, d 1 only; ǂNon‐AC
6
MEC: Guideline Recommendations Acute CINV
Delayed CINV (d 2‐3)
NCCN
Palo + Dex
+/‐ APR* Or
Olanzapine + Palo + Dex
5‐HT3 (if Palo not used d1)
Or
Dex
Or
APR* +/‐ Dex
Or
OlanzapineƗ
ASCO
Palo** + Dex**
Dex
MASCCǂ
Palo + Dex
Dex
*If fosaprepitant used, d 1 only; ƗIf used on d 1; ǂNon‐AC; If APR added, Palo not preferred.
Pharmacokinetic and Physiological Differences Among 5‐HT3 RAs
5‐HT3
Half‐Life t1/2 (h)
Binding Affinity (pKi)
Dolasetron
~7.0
~7.6
Granisetron
~9.0
~8.9
Ondansetron
~4.0
~8.4
Palonosetron
~40.0
~10.5
7
5‐HT3 RAs
• Palonosetron is currently the only 5‐HT3 RA approved in both the acute and delayed settings for patients receiving MEC.
• 3 formulations of granisetron (oral, IV, transdermal patch) are FDA‐approved for the prevention of CINV with initial and repeat courses of chemotherapy.
• A long‐acting subcutaneous formulation of granisetron (APF530) for the prevention of CINV in both acute and delayed settings is in clinical development.a,b
a. Boccia RV, et al. J Clin Oncol. 2013;31: Abstract 9626; b. Arevalo-Araujo R, et al. J
Clin Oncol. 2013;31:Abstract e20569.
8
NK‐1 RAs
Aprepitant
• Only FDA‐approved NK‐1 RA
• Available in oral and IV (fosaprepitant) formulations
• Oral aprepitant is typically administered over at least a 3 day period; IV fosaprepitant is administered on day 1 only
• Aprepitant and fosaprepitant affect CYP3A4 activity; can impact the metabolism of other concomitantly administered medications (eg, oral contraceptives, corticosteroids; warfarin) metabolized through this route
• Multiday administration of oral formulation needed; shorter duration of actiona
Rolapitant
• High binding affinity to NK‐1 receptor and long duration of action observed in certain animal modelsb
• Evidence that rolapitant does not impact the metabolism of concomitantly administered medications that are metabolized by CYP3A4c
Netupitant
• Being developed as a fixed‐dose oral formulation with palonosetron
• No clinically relevant interaction with palonosetron observedd; preclinical evidence of synergistic effect with coadministratione
• Evidence of long‐lasting NK‐1 receptor occupancy in humansf
• Moderate inhibitor of CYP3A4, although no clinically relevant interaction with oral contraceptives has been observedd
•
•
•
a. EMEND PI; b. Duffy RA, et al. Pharm Biochem Behav. 2012;102:95-100; c. Poma A, et al. MASCC Presentation 2013; d. Calcagnile S, et
al. Support Care Cancer. 2013;21:2879-2887; e. Stathis T, et al. Eur J Pharmacol. 2012;689:25-30; f. Spinelli T, et al. Clin Pharmacol. 2013
NEPA: Combination NK‐1/5HT3 RA
NETUPITANT
•Selective neurokinin type 1 receptor
antagonist (NK1 RA)1
•Competitively binds to and blocks activity of
human substance P receptors1
•High binding affinity, long half-life (90 h)1, 2
•High (>90%), long-lasting (>96 h) brain
receptor saturation after single
oral dose1
•Moderate inhibitor of CYP3A43
1Spinelli
et al. J Clin Pharmacol 2014;54(1):97-108
on file
et al. Supp Care Cancer 2013;21(10):2783-2791.
4Rojas et al. J Pharmacol Exp Ther 2010;335(2):362-368
5Basch et al. J Clin Oncol 2011;29:4189-4198
PALONOSETRON
•Higher binding affinity and longer half-life
than other 5-HT3 RAs4
•Exhibits distinctly different receptor binding
(allosteric binding, positive cooperativity)4
•Results in long-lasting inhibition of 5-HT3
receptor function4
•Inhibits cross-talk between the 5-HT3 and
NK1 receptor pathways4
•Antiemetic guideline-recommended
“preferred” 5-HT3 RA5
2Data
3Lanzarotti
9
IV vs. PO Palonosetron
Complete Response
* Non‐inferiority margin set at 15%
Karthaus M et.al. J Thoracic Oncology. 2013;8 (suppl 2):S705.
Data on file. Eisai Inc; Woodcliff Lake, NJ.
1
9
NEPA MEC (AC)
Phase 3 Study
Aapro M, Rugo H, Rossi G, et al. A randomized phase III study evaluating the efficacy and safety of
NEPA,
a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced
nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol. 2014; 25:1328–
1333.
10
NEPA MEC Study: Study Design1,2
•
•
•
Phase 3, multicenter, randomized, parallel, double-blind, active-controlled superiority study
of 1455 patients
Measured efficacy and safety of NEPA compared with oral palonosetron in cancer patients
scheduled to receive the first cycle of an anthracycline and cyclophosphamide regimen for the
treatment of a solid malignant tumor
Primary analysis: 725 patients who received NEPA and 725 patients who received oral
palonosetron
Treatment Regimen
Day 1
Days 2–4
Netupitant 300 mg PO
Palonosetron 0.5 mg PO
No antiemetic treatment
Dexamethasone 12 mg PO
•
After completion of cycle 1, patients had the option to participate in a multiple-cycle extension,
Palonosetron 0.5 mg PO
Palonosetron
antiemeticlimit
treatment
receiving the same treatment as assigned in cycle 1. There was no No
prespecified
to the
Dexamethasone 20 mg PO
number of repeat consecutive cycles for any patient
NEPA
References: 1. AKYNZEO (netupitant/palonosetron) capsules [prescribing information]. Woodcliff Lake, NJ: Eisai Inc; 2014.
2. Data on file. Woodcliff Lake, NJ: Eisai Inc.
21
NEPA MEC Study: Complete Response1
P = .001
P = .047
NEPA (N = 724)
P = .001
PALO (N = 725)
NEPA superior to PALO in acute, delayed, and overall phases
P value from logistic regression.
References: 1. Aapro M et al. Ann Oncol. 2014;25(7):1328-1333.
22
11
NEPA + Dex in MEC
Aapro M, et al. Ann Onc 2014
NEPA in HEC
Gralla R, et al. 2013 ESMO. Abstract 1301.
12
NEPA in HEC
Gralla R, et al. 2013 ESMO. Abstract 1301.
Complete Response in Registration Studies Cycle 1 Overall (0-120 h)
Complete Response
NEPA + DEX
Oral PALO
+ DEX
APR + 5-HT3 RA‡
+ DEX
Phase 2 Dose-ranging
HEC Study
90%*
(N = 136)
77%
(N = 136)
87%
(N = 134)
Phase 3
AC MEC Study†
74%*
(N = 724)
67%
(N = 725)
NA
Phase 3 Multiple Cycle
Non-AC MEC + HEC Study
81%
(N = 309)
NA
76%
(N = 104)
* P < 0.01 vs Oral PALO
† Primary endpoint delayed (25-120h) phase – NEPA 77% vs Oral PALO 70% (P = 0.001)
‡ 5-HT RA = ondansetron in phase 2 and palonosetron in phase 3
3
•
•
•
Complete Response = No emesis and no use of rescue medication
All patients were chemotherapy naïve with solid tumors
No formal (efficacy) comparisons with APR + 5-HT3 RA + DEX; included as
exploratory and to help interpret results
HEC: highly emetogenic chemotherapy; MEC: moderate emetogenic chemotherapy; AC: anthracycline + cyclophosphamide; APR: aprepitant
All 3 studies published in Annals of Oncology July 2014
13
Multiple cycle CINV control and safety of NEPA, a capsule
containing netupitant and palonosetron administered once per
cycle of
moderately emetogenic chemotherapy (MEC)
Matti Aapro1, Meinolf Karthaus2, Lee Schwartzberg3,
Giorgia Rossi4, Giada Rizzi4, Maria Elisa Borroni4,
Marco Palmas4, Hope Rugo5
1Clinique
de Genolier, Genolier, Switzerland; 2Hematology & Oncology, Staedt. Klinikum
Neuperlach and Harlaching, Munich, Germany; 3West Clinic, Memphis, TN; 4Helsinn
Healthcare, SA, Lugano, Switzerland; 5University of California San Francisco
Comprehensive Cancer Center, San Francisco, CA
Methods & Study Design
•
•
•
Phase 3, multinational, randomized, double‐blind study in chemotherapy‐naïve patients undergoing AC chemotherapy Patients randomized to receive one of the following prior to chemotherapy on Day 1
Following completion of cycle 1, patients had the option to enter the multiple‐cycle extension phase, to receive the same treatment as assigned in cycle 1
Randomized
1:1
Oral NEPA + Oral DEX 12 mg
(NEPA = NETU 300 mg + PALO 0.50 mg)
N = 1455
Oral PALO 0.50 mg + Oral DEX 20 mg
• NO antiemetics given after Day 1
• NEPA or PALO: ingested 60 min prior to chemotherapy; DEX: 30 min prior to chemotherapy
14
Overall (0‐120 h) Complete Response
100
80
*74
75
67
70
Patients (%)
** 84
**84
**80
90
67
70
60
50
NEPA + DEX
40
Oral PALO + DEX
30
* P = 0.001
** P < 0.0001
20
10
0
Cycle 1
NEPA + DEX
Oral PALO + DEX
N=
N=
Cycle 2
724
725
Cycle 3
635
651
Cycle 4
598
606
551
560
No Emesis / No Significant Nausea (0‐120 h) No Emesis
No Significant Nausea
(max < 25 mm of 100 mm VAS)
NEPA +
DEX
Oral PALO
+ DEX
p-value
NEPA +
DEX
Oral PALO
+ DEX
p-value
Cycle 1
80%
72%
< 0.001
75%
69%
0.020
Cycle 2
86%
74%
<0.0001
77%
72%
0.018
Cycle 3
88%
77%
<0.0001
78%
73%
0.034
Cycle 4
87%
79%
0.0003
80%
75%
0.042
Based on full analysis set of 1449 patients
Analyses not adjusted for multiplicity
15
Summary of Most Common (≥2%) Treatment‐Related Adverse Events NEPA
(N = 635)
Oral PALO
(N = 651)
Adverse Event
Entire Multiple Cycle Study Period*
Headache
22 (3.5%)
18 (2.8%)
Constipation
13 (2.0%)
14 (2.2%)
*Cycles 2-6
*Cycles 2-6
NEPA (akynzeo):
Approved October 10, 2014 by FDA
Indications and Usage
• AKYNZEO is a fixed combination of netupitant, a
substance P/neurokinin 1 (NK1) receptor antagonist, and
palonosetron, a serotonin-3 (5-HT3) receptor antagonist
indicated for the prevention of acute and delayed nausea
and vomiting associated with initial and repeat courses of
cancer chemotherapy, including, but not limited to, highly
emetogenic chemotherapy. Oral palonosetron prevents
nausea and vomiting during the acute phase and
netupitant prevents nausea and vomiting during both the
acute and delayed phase after cancer chemotherapy.
Reference: AKYNZEO (netupitant/palonosetron) capsules [prescribing information]. Woodcliff Lake, NJ: Eisai Inc; 2014.
Data on file. Eisai Inc., Woodcliff Lake, NJ.
16
Rolapitant is an Novel NK‐1 Receptor Antagonist
• Rolapitant is a potent, selective, long‐acting NK‐1 receptor antagonist
– Long T1/2 (~180 hrs) suggests a single dose may be sufficient to prevent CINV during the entire 5‐day (0–120 hrs) at risk period – 200 mg dose achieved >90% NK‐1 receptor occupancy in the brain and maintained this clinically significant level for up to 5 days post a single dose
– Reduced risk of drug interaction; not an inducer or inhibitor of CYP3A4
• Demonstrated safety and efficacy of a single oral dose in large global randomized, controlled, double blind Phase 2 study in subjects receiving cisplatin based highly emetogenic chemotherapy (HEC)
– Primary endpoint, CR in the overall phase, was achieved with 200 mg dose of rolapitant compared to active‐control (ondansetron + dexamethasone)
• Overall (0–120 hrs) phase (62.5% vs. 46.7%; p=0.032)
• Acute (0–24 hrs) phase (87.6% vs. 66.7%; p=0.001 )
• Delayed (>24–120 hrs) phase (63.6% vs. 48.9%; p=0.045)
– Safe and well tolerated when administered as a single dose
for up to 6 cycles
F 3C
O
N
H
N
H
CF3
O
.
HCl . H2O
Phase 2 Trial: Rolapitant (oral) + Ondansetron + Dex (HEC)
CR 200 mg group
Placebo group
P value
Overall (0‐120 h)
62.5%
46.7%
0.032
Acute (0‐≤24 h)
87.6%
66.7%
0.001
Delayed (>24‐120 h)
63.6%
48.9%
0.045
Treatment-related AEs were mild including
constipation, headache, fatigue, dizziness.
Phase III trials of rolapitant (oral and IV) in are
ongoing.
Fein LE, et al. J Clin Oncol. 2012;30(suppl): Abstract 9077.
17
Phase 3 Trial Results for Rolapitant, a Novel NK‐1 Receptor Antagonist, in the Prevention of Chemotherapy‐Induced Nausea and Vomiting (CINV) in Subjects Receiving Moderately Emetogenic Chemotherapy (MEC)
Lee Schwartzberg, I. Schnadig, M. Modiano, A. Poma, M.L. Hedley, R. Martell, MASCC/ISOO 2014
Phase 3 Large, Double‐Dummy, Double‐
Blind, Global MEC Study • Key Inclusions criteria included:
Study Flow Diagram
N=1369
1:1 Randomization
– Subject was 18 years of age or older,
of either gender, and of any race
– Subject was naive to moderately or highly emetogenic chemotherapy
– MEC included one or more of the following agents: cyclophosphamide IV (<1500 mg/m2), doxorubicin, epirubicin, carboplatin, idarubicin, ifosfamide, irinotecan, daunorubicin, cytarabine IV (>1 g/m2)
– The length of each chemotherapy cycle should be ≥2 weeks
Day 1
-2 to -1 hrs
-30 min
0
Rolapitant 200mg PO
or Placebo PO
Granisetron 2mg PO
Dexamethasone 20mg PO
MEC1
Up to 5
Additional
Cycles
Days 2–3
Granisetron 2 mg PO
• Key Exclusion criteria included: – Subject was scheduled to receive any other chemotherapeutic agent with an emetogenicity level of ≥3 (Hesketh Scale) from Day –2 through Day 6
Events of Emesis and Use of Rescue
Medication Were Recorded for 5 Days
1MEC: cyclophosphamide IV (<1500 mg/m2), doxorubicin, epirubicin, carboplatin, idarubicin, ifosfamide, irinotecan, daunorubicin, cytarabine IV (>1 g/m2)
18
Rolapitant Achieved Primary Endpoint
•
Rolapitant group achieved statistically significant higher CR rates in the primary endpoint of delayed phase (>24–120 hrs) compared to the control group
Complete Response Rate
mITT Population
p = 0.143
p < 0.001
80.3%
p < 0.001*
71.3%
83.5%
68.6%
61.6%
57.8%
Delayed Phase
(>24–120 hr) Overall Phase
(0–120 hr) Control
(N=666)
Acute Phase
(0–24 hr)
Rolapitant 200mg
(N=666)
*Unadjusted p value.
Rolapitant Protection Initiates in the Acute Phase and is Maintained in the “Late” Delayed Phase Patients without Emesis or Use of Rescue Medication (mITT)
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
p <0.001 for the
between-treatment
group comparison
0
24
48
72
96
120
Time (Hours) to First Emesis or
Use of Rescue Medication
Rolapitant
Control
19
Additional CINV Assessment Supportive for Rolapitant
p = <0.001
p = <0.001
80.5%
78.7%
Complete Protection*
p = 0.085
84.5%
87.8%
Complete Response Rate
Complete Response Rate
No Emesis*
69.8%
65.3%
p = 0.006
p = 0.001
64.3%
62.0%
56.9%
53.2%
Delayed Phase
(>24–120 hr)
Control
Overall Phase
Acute Phase (0–120 hr)
(0–24 hr)
Rolapitant 200mg
(N=666)
Delayed Phase
(>24–120 hr) Control
(N=666)
* No Emesis: No vomiting, retching or dry heaves (incl. subj who receive rescue meds)
** Complete Protection: No emesis, No rescue medication and maximum nausea score of <25mm on the VAS.
(N=666)
Overall Phase
(0–120 hr) Rolapitant 200mg
(N=666)
All p values are unadjusted.
Phase 3 Trial Results for Rolapitant, a Novel NK‐1 Receptor Antagonist,
for the Prevention of Chemotherapy‐Induced Nausea and Vomiting
(CINV) in Subjects Receiving Cisplatin‐based, Highly Emetogenic Chemotherapy (HEC)
Bernardo Rapoport, MD
A. Poma, M.L. Hedley, R. Martell, R. Navari
MASCC/ISOO 2014
20
Phase 3, Double‐Blind, Double‐Dummy, Double‐Blind, Global HEC Studies •
•
Study Flow Diagram
Study design and endpoints were identical in both HEC studies
Key Inclusions criteria included:
HEC1: N=532; HEC2: N=555
1:1 Randomization
– Subject was 18 years of age or older,
of either gender, and of any race
– Subject was naive to cisplatin‐therapy
– Cisplatin‐based chemotherapy
defined as ≥60 mg/m2
•
Day 1
Rolapitant 200mg PO
or Placebo PO
-2 to -1 hrs
Granisetron 10 μg/kg IV
Dexamethasone 20mg PO
-30 min
Key Exclusion criteria included: – Subject was scheduled to receive any other chemotherapeutic agent with an emetogenicity level of ≥4 (Hesketh
Scale) from Day –2 through Day 6
0
HEC1
Up to 5
Additional
Cycles
Days 2–4
Dexamethasone 8 mg BID PO
Events of Emesis and Use of Rescue
Medication Were Recorded for 5 Days
1HEC: cisplatin
≥60mg/m2
Rolapitant Achieved Primary Endpoint in Both HEC Studies
CR rate is superior in rolapitant vs the control arm in the delayed phase
CR rate is superior in rolapitant vs the control arm in the acute and overall phases
HEC1 (mITT Population)
Complete Response Rate
HEC1
p = 0.005
p <0.001
73.7%
70.1%
58.4%
56.5%
Acute Phase
(0–24 hr) Control
Overall Phase
(0–120 hr)
Rolapitant 200mg
HEC2 (mITT Population)
Complete Response Rate
HEC2
CR rate is numerically greater in rolapitant vs the control arm in the acute and overall phases
p = 0.001
83.7%
72.7%
Delayed Phase
(>24–120 hr) CR rate is superior in rolapitant vs the control arm in the delayed phase
p = 0.005
p = 0.043
p = 0.233
p = 0.084
83.4%
79.5%
70.1%
67.5%
61.9%
Delayed Phase
(>24–120 hr) 60.4%
Acute Phase
(0–24 hr) Control
Overall Phase
(0–120 hr)
Rolapitant 200mg
42
21
Rolapitant Protection Initiates in the Acute Phase and is Maintained in the “Late” Delayed Phase For Both HEC Studies:
Time to first emesis or use of rescue medication was longer in rolapitant vs control group
Treatment effect initiated in the acute phase at ~8–10 hrs following administration of chemotherapy
By days 2–3 the rolapitant curve begins to plateau, indicating these subjects are protected for the remaining CINV at risk period for up to 5 days
In contrast, patients in the control group continue to experience late events of emesis and use of rescue medication
HEC2 Figure 3: Kaplan-Meier Plot of Proportions of Subjects
Without Emesis or Use of Rescue Medication (mITT Population)
Proportion of Patients Without Event
Proportion of Patients Without Event
HEC1 Figure 2: Kaplan-Meier Plot of Proportions of Subjects
Without Emesis or Use of Rescue Medication (mITT Population)
Time (Hours) to First Emesis or Use of Rescue Medication
Time (Hours) to First Emesis or Use of Rescue Medication
OTHER EMERGING CINV PRINCIPLES
22
Olanzapine + Palonosetron + Dexamethasone vs
Aprepitant + Palonosetron + Dexamethasone:
Study Design
• Multicenter, phase 3, open-label study of 257
chemotherapy-naïve patients receiving highly
emetogenic chemotherapy
Day 1
Day 2
Day 3
Day 4
Olanzapine
Olan + palo + dex
Olan
Olan
Olan
Aprepitant
Apr + palo + dex
Apr + dex
Apr + dex
Dex
• End points: Complete response (no emesis, no
rescue), no nausea (score = 0, MD Anderson
Symptom Inventory 0–10 scale)
Navari RM, et al. J Support Oncol. 2011;9:188‐195.
Olanzapine + Palonosetron + Dexamethasone
vs Aprepitant + Palonosetron +
Dexamethasone: Complete Response
Patients with Complete Response, %
100
Complete Response OPD (n=121)
97
Complete Response APD (n=120)
87
77
80
73
77
73
60
40
20
0
Acute (0‐24 h)
Delayed (24‐120 h) Overall (0‐120 h)
Navari RM, et al. J Support Oncol. 2011;9:188-195.
23
Olanzapine + Palonosetron +
Dexamethasone vs Aprepitant +
Palonosetron + Dexamethasone: No Nausea
100
No Nausea OPD (n=121)
Patients with No Nausea, %
87
87
No Nausea APD (n=120)
80
69
69
60
38
40
38
20
0
Acute (0‐24 h)
Delayed (24‐120 h) Overall (0‐120 h)
Navari RM, et al. J Support Oncol. 2011;9:188-195.
Assessing the Efficacy of Single‐Dose Dexamethasone
Complete Response Rate
5‐HT3 + 5‐HT3 on Day 1 + Dexamethasone on Dexamethasone on Day 1
Days 1‐3
Acute phase (0‐24 h)
69.5%
68.5%
Delayed phase (24‐120 h)
62.3%
65.8%
Overall (0‐120 h)
53.6%
53.7%
Aapro MS, et al. Ann Oncol. 2010;21:1083-1088.
24
Palo + Dex (d1) vs Palo + Dex (d1‐3)
Sasaki K, et al. ESMO 2013. Abstract 1303.
Palo + Dex (d1) vs Palo + Dex (d1‐3_
Sasaki K, et al. ESMO 2013. Abstract 1303.
25
CINV Guideline Adherence Rates
• Population‐based study of patients in the Texas Cancer Registry‐Medicare‐linked database (2001‐2007)
• Overall adherence rate to NCCN recommendations: – Cisplatin‐based (High)
• 5HT3: 78% adherence
• Dexamethasone: 65% adherence
• Aprepitant: too low to count (n < 11)
– Carboplatin‐based (Moderate)
• 5HT3: 83% adherence
• Dexamethasone: 66% adherence
• Aprepitant: too low to count (n < 11)
Gomez DR, et al. Cancer. 2013; 119(7):1428-36.
Outcome based on Guideline Adherence
• Prospective, observational, multicenter study in patients with solid tumors receiving HEC or MEC
• Two cohorts:
– Guideline‐consistent (GC), n = 287
– Guideline‐inconsistent (GI), n = 704
• GC had higher rates of:
–
–
–
–
Complete response: 60% vs. 51%; p = 0.008
No emesis: 63% vs. 59% (NS)
No nausea: 48% vs. 41% (NS)
No CINV: 43% vs. 34%; p = 0.016
Aapro M, et al. Ann Oncol. 2012;23(8):1986-92.
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Antiemetic Prescribing Practices Using a Computerized Physician Order Entry System
• Review of electronic medical records of 100 consecutive adult patients at a single tertiary care institution
• Institutional guideline‐directed antiemetic order sets automatically provided
– Option to deviate from guideline‐based recommendations per clinician discretion
• High degree of compliance to institutional GLs in delayed period (97%)
• 100% compliance for patients receiving MEC or minimally emetogenic
chemotherapy
• Patients receiving AC were less likely to be treated according to institutional GLs compared with pts receiving other types of chemotherapy. (OR=0.24; P=.05)
Kadakia KC, etal. Support Care Cancer. 2014;22:217-223.
The Oncology Team and CINV Prevention
Step‐by‐Step Guide to Preventing Relevant Oncology Team Members
CINV
 Assess for treatment and patient risk factors for CINV
Physician, nurse
 Have established antiemetic protocols within the clinic
Physician, pharmacists
 Communicate emetic risk and Physician, nurse, educator
recommended preventive plan with patient
 Initiate antiemetics prior to chemotherapy
Physician, nurse
 Monitor the patient during and after cycles of anticancer therapy
Physician, nurse, navigator
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Educating the Patient on CINV
 Take patient concerns and fears about CINV seriously
 Inform patients about emetic risk of various chemotherapy agents
 Explain the various stages of CINV
 Discuss/explain your institutions antiemetic protocols
 Review some of the potential side effects of antiemetics
 Headache, constipation
 Encourage patients to report symptoms/side effects promptly to the nurse or other oncology team members
Summary:
• Improved adherence to CINV guidelines and improved patient‐clinician communication have the potential to decrease CINV rates
• Nevertheless, CINV rates are still too high and new approaches are needed to prevent CINV
• Palo/dex/APR vs Palo/dex/olanzapine in HEC:
• Palo + dex (d1) vs palo + dex (d1‐3) in MEC:
• Emerging therapies:
• 5HT3 RAs
• Newer formulations of approved 5HT3 RAs (ie, long‐acting subcutaneous formulation of granisetron)
• NK‐1 RAs:
• Rolapitant + 5HT3 RA + Dex in MEC:
• Fixed dose netupitant/palo + Dex in MEC and HEC:
• Fixed dose netupitant/palo + Dex in multi‐day HEC:
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