optimal management of chemotherapy-induced nausea and ... cinv.pdf · –no/minimal prior history...

Udomsak Bunworasate Chulalongkorn University

Optimal Management of

Chemotherapy-induced

Nausea and Vomiting (CINV)

Scope of the Problem

Classification of CINV • Acute

– Occurring within the first 24 hrs. after initiation of chemo; generally peaks after 5 to 6 hrs.

• Delayed – Occurring from 24 hrs. to several days (days 2 to 5) after chemo

(commonly seen with cisplatin, carboplatin, cyclophosphamide, ifosfamide, doxorubicin)

• Anticipatory – Occurring before a treatment as a conditioned response to the

occurrence of CINV in previous cycles

• Breakthrough – Occurring despite appropriate prophylactic treatment

• Refractory – Recurring in subsequent cycles of therapy,

excluding anticipatory CINV

R.M.Navari, M Aapro. NEJM 2016

Patterns of CINV

Martin M. Oncology. 1996;53(suppl 1): 26–31.

0 1 2 3 4 5

Days

Cisplatin

Cyclophosphamide/Carboplatin

Inte

nsit

y o

f em

esis

34

17 24

15

35

13

52

28

0

20

40

60

80

100

Acute

Nausea

Acute

Vomiting

Delayed

Nausea

Delayed

Vomiting

Per

cen

t o

f P

atie

nts

MD/RN prediction

Patient experience

Physicians and nurses from 14 oncology practices in 6 countries

Patients: 75% women; 78% Mod emetic chemo; 50% breast cancer; 18% lung cancer

Grunberg et al. (2004). Cancer, 100, 261-268.

PERCEPTIONS versus EVIDENCE - Underestimation of Emesis with Chemotherapy -

CINV prevention from the start • Uncontrolled CINV in the previous cycle is the key factor for

CINV in the subsequent cycle, increasing the likelihood of CINV by 6.5 times in Cycle 2 and 14 times in Cycle 3.

• Patients at high risk of CINV need effective prevention from the start.

Molassiotis A, et al. J Pain Symptom Manage. 2016 Feb 16.

Risk Factors of CINV

• Patient-related risk factors:1

– Younger age (<60 years)

– Female gender

– No/minimal prior history of alcohol and tobacco use

– Susceptibility to motion sickness

– Prior CINV*

– Anxiety

• Treatment-related risk factors:1,2

– Moderate-to-high emetogenicity of chemotherapy agents or regimens

– Use of moderate-to-high drug dose and multiple agents

1. Gregory RE, et al. Drugs. 1998;55:173–189. 2. Hesketh PJ, et al. J Clin Oncol. 1997;15:103–109.

Physiology of CINV

Grunberg SM, et al. N Engl J Med.1993;329:1790–1796.

• Adapted from: Navari RM. Drugs. 2013;73:249–262. • Frame DG. J Support Oncol. 2010 Mar-Apr;8(2 Suppl 1):5-9. • Lorusso V et al. Future Oncol. 2014 Oct 31:1-13. DA: dopamine; GABA: gamma-aminobutyric acid; NK1: neurokinin-1 RAs: receptor antagonists; 5-HT3:

5-hydroxytryptamine3.

Neurotransmitters involved in the Emetic Reflex

Emetic Reflex

Histamine

Endorphins

Acetylcholine Dopamine

Substance P

GABA

Cannabinoids

Serotonin

NK1 RAs 5-HT3 RAs

DA RAs

Antiemetics Available for CINV • Most commonly used classes of antiemetics

– 5-HT3 Receptor Antagonists (ondansetron, dolasetron, granisetron, palonosetron)

• Inhibit serotonin, 5-HT3, mediated activation of the vagal afferent fibres in the stomach and the central CTZ and vomiting centres through the 5-HT3 receptor

– Corticosteroids (dexamethasone)

• Unknown mechanism but increase the 5-HT3 RA antiemetic efficacy

– NK1 Receptor Antagonists (aprepitant, fosaprepitant)

• Inhibition of the substance P-mediated activation of the vomiting centre

– Other agents

Other Neurotransmitters, Receptors, and Drugs

Antiemetic Risk Groups

Antiemetic Risk

Groups

Percentage of Patients (%)

High 90% or more of patients experience acute emesis

Moderate 30% to 90% of patients experience acute emesis

Low 10% to 30% of patients experience acute emesis

Minimal < 10% of patients experience acute emesis

Specific antiemetic regimen recommended for each antiemetic risk group

Aapro M, Gralla RJ, Herrstedt J, et al. MASCC/ESMO antiemetic guideline 2016. Multinational Association of Supportive Care in Cancer. 2016. Available at http://www.mascc.org/assets/Guidelines-Tools/mascc_antiemetic_guidelines_english_2016_v.1.2.pdf. Accessed on April 6, 2016.

Emetic Risk Categories (examples) • High

– Cyclophosphamide/doxorubicin combination – Cisplatin, carboplatin AUC ≥ 4 – Dacarbazine – High doses chemotherapy agents (HDCy, HDIfos, Transplant)

• Moderate – IV Alkylaing agents – Anthracyclines (< 60 mg/m2) – Azacitidine, bendamustine – ARA-C > 200 mg/m2, MTX ≥ 250 mg/m2

• Low – Antimetabolites

• Minimal – Monoclonal antibodies, vinca alkaloids, bortezomib, -nibs

Grunberg SM, et al. Support Care Cancer. 2011;19 (Suppl 1):S43-7.

Prophylaxis for CINV: General Principles

• Acute – Typically administered IV in the infusion center

• Delayed – Some IV drugs will cover delayed (eg. Palonosetron) – May receive prescription to take as scheduled

• Breakthrough – Should always receive a prescription that is PRN – Use a different MOA than for prophylaxis

• Anticipatory – Lorazepam if fearful or poor control after previous

cycle

Grunberg SM, et al. Support Care Cancer. 2011;19 (Suppl 1):S43-7.

Emetic risk groups Antiemetics

High (non-AC)

High: anthracycline +

cyclophosphamide (AC)a

Carboplatinb

Moderatec

Low

Overview of NCCN / ASCO / MASCC-ESMO guidelines for Acute nausea and vomiting

* The addition of OLA is recommended in HEC by ASCO, is one possible option in HEC and MEC by NCCN and only when nausea is an issue by MASCC/ESMO a If an NK1 RA is not available for AC chemotherapy, palonosetron is the preferred 5-HT3 RA for MASCC/ESMO. b Carboplatin is considered as “high-MEC” by ASCO (here only AUC > 4) and MASCC/ESMO, and reclassified as HEC by NCCN (when AUC >4): an NK1 RA

should be added in all cases. c An NK1 RA is recommended as option in MEC for selected patients with additional risk factors or who have failed previous therapy with 5-HT3 antagonist plus

steroid by NCCN. d Palonosetron and granisetron extended-release injection formulation are the preferred 5-HT3 RAs in MEC regimens without an NK1 RA by NCCN. e Not for ASCO.

5-HT3 RA =

serotonin receptor

antagonist

DEX =

dexamethasone

NK1 RA= neurokinin 1

receptor antagonist

PALO =

palonosetron

DRA =

dopamine receptor

antagonist

5-HT3 RA DEX NK1 RA

5-HT3 RA DEX NK1 RA

DEX

DEX 5-HT3 RA DRAe

+ +

OR

+

+

OR

+

+

+ OLA*

OLA*

5-HT3 RA DEX NK1 RA + +

OLA =

Olanzapina

5-HT3 RAd

1. Roila F. et al. Ann Oncol. 2016 Sep;27(suppl 5):v119-v133. MASCC/ESMO Antiemetic Guideline 2016 V.1.2. Available at: http://www.mascc.org/; 2. NCCN: National Comprehensive Cancer Network; NCCN Clinical Practice Guidelines in Oncology; Version 2.2018. Available at: www.nccn.org ; 3. Hesketh P. J. et al. J Clin Oncol. 2017 Oct 1;35(28):3240-3261. doi: 10.1200/JCO.2017.74.4789. Epub 2017 Jul 31.

http://www.mascc.org/

http://www.nccn.org/

Overview of NCCN / ASCO / MASCC-ESMO guidelines for Delayed nausea and vomiting

Emetic risk groups Antiemetics

High (non-AC)

High: anthracycline +

cyclophosphamide (AC)

Carboplatinb

Moderatec

Low -

DEX

DEX**

+ OLA*

+ OLA*

a NK1 RA (aprepitant 80 mg) only if aprepitant 125 mg was used on Day 1. Other NK1 RAs, netupitant, rolapitant, aprepitant 165 mg or fosaprepitant 150 mg do not

need repeat doses.

* The addition of OLA is recommended in HEC by ASCO, is one possible option in HEC and MEC by NCCN and only when nausea is an issue by MASCC/ESMO.

** DEX is recommended in AC by NCCN and, If APR on D1, APR or DEX by MASCC/ESMO. b Carboplatin: DEX is recommended only by NCCN over AUC >4

c Only for regimens with known delayed CINV potential by MASCC/ESMO and ASCO.

NK1 RAa

NK1 RAa +

NK1 RAa +

OLA ?* +

DEX

1. Roila F. et al. Ann Oncol. 2016 Sep;27(suppl 5):v119-v133. MASCC/ESMO Antiemetic Guideline 2016 V.1.2. Available at: http://www.mascc.org/; 2. NCCN: National Comprehensive Cancer Network; NCCN Clinical Practice Guidelines in Oncology; Version 1.2018. Available at: www.nccn.org ; 3. Hesketh P. J. et al. J Clin Oncol. 2017 Oct 1;35(28):3240-3261. doi: 10.1200/JCO.2017.74.4789. Epub 2017 Jul 31.

http://www.mascc.org/

http://www.nccn.org/

Guideline Recommendations: Low and Minimal

Guideline Recommendations: Moderate Emetogenicity, Acute

Yes Yes

Guideline Recommendations: Moderate Emetogenicity, Delayed

No No 5HT3 RA

Guideline Recommendations: High Emetogenicity, Acute

Add Olanzapine

Guideline Recommendations: High Emetogenicity, Delayed

Add Olanzapine

+/-

Breakthrough CINV

NCCN ver.2, 2017

5-HT3: 5-hydroxytryptamine 3; RA: receptor antagonist; PALO: palonosetron; PK: pharmacokinetics 1. Rojas C et Slusher BS. Eur J Pharmacol. 2012 Jun 5;684(1-3):1-7. 2. Wong EHF et al. Br J Pharmacol. 1995;114:851-859.

[(3aS)-2-[(S)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-

hexahydro-1-oxo-1H-benzo[de]isoquinoline-hydrochloride]2

N H

O

O C H 3 N

N C H 3

N

N H

O C H 3 N

N C H 3

O

N N

N H

O

O N

O N H

H O N H 2

Ondansetron

Tropisetron Granisetron

Dolasetron

N

O

H

N PALO

Chemical structures of serotonin and 5-HT3 RAs: Most 5-HT3 RAs are based on a 3-substituted indole structure that resembles serotonin, PALO's structure has

a tricyclic ring system attached to a quinuclidine moiety 1

Serotonin

Antiemetics Available for CINV Prevention Palonosetron and other 5-HT3 RAs: Chemical Structure

The 5-HT3 RA can displace serotonin-inhibiting signal transduction

Cell membrane

Competitive binding

Rojas C et Slusher BS. Eur J Pharmacol. 2012 Jun 5;684(1-3):1-7.

PALO: Palonosetron; 5-HT3: 5-hydroxytryptamine 3; RA: receptor antagonist.

5-HT3 receptor serotonin 5-HT3 RAs Signal transduction

5-HT3 RA administration

5-HT3 RA and Serotonin Receptor Binding Characteristics Competitive binding

Serotonin can displace the 5-HT3 RA and reactivate signal transduction

Cell membrane


PALO: Palonosetron; 5-HT3: 5-hydroxytryptamine 3; RA: receptor antagonist.

5-HT3 receptor serotonin Signal transduction

Competitive binding

Serotonin and the 5-HT3 RA compete for the same binding site.

5-HT3 RAs

5-HT3 RA and Serotonin Receptor Binding Characteristics Competitive binding

PALO binding to the allosteric site causes a conformational change that increases the affinity for

a second molecule of PALO to bind

Cell membrane


PALO: Palonosetron; 5-HT3: 5-hydroxytryptamine 3.

Allosteric binding and positive cooperativity

PALO can displace serotonin and has a stronger binding affinity compared to other

setrons such as ondansetron and granisetron

5-HT3 receptor serotonin Signal transduction PALO

PALO and Serotonin Receptor Binding Characteristics Allosteric binding and positive cooperativity

+ PALO + Granisetron + Ondansetron

5-HT3 receptor is still on the cell membrane after ondansetron and granisetron treatment

(orange/yellow zones)

5-HT3 receptor is no longer present on the cell membrane after PALO treatment

(no or limited orange/yellow zones)

Evidence of 5-HT3 Receptor Internalization:

Confocal fluorescence microscopy of cells after treatment with 5-HT3 RAs

Rojas C et al. Eur J Pharmacol. 2010 Jan 25;626(2-3):193-9. PALO: Palonosetron; 5-HT3: 5-hydroxytryptamine 3; RA: receptor antagonist.

PALO Impact on 5-HT3 Receptor Function 5-HT3 Receptor Internalization

HEK-293 cells transfected with fluorescent 5-HT3 receptor (GREEN)

Cell membrane counterstained with wheat germ agglutinin, Alexa Fluor 594 (RED)

Receptor overlapping on the cell membrane (ORANGE / YELLOW)

All 5-HT3 RAs structures resemble serotonin...

Parameter Palonosetron Ondansetron Granisetron

Half Life (hrs)1 40 4 9

Binding Affinity1 10.45 8.39 8.91

Positive Cooperativity2 YES NO NO

Inhibition of Receptor Function2 Long Lasting Short Lasting Short Lasting

Receptor Internalization3 YES NO NO

Inhibition of 5-HT3/NK1 receptor cross-talk4 YES NO NO

... except palonosetron

5HT3 RAs

N H

H O N H 2

S e r o t o n i n

N

O

H

N

1. Constenla, M., 2004 Ann Pharmacother . 38, 1683-1691. 2. Wong E.H. et al. Br J Pharmacol. 1995;114:851-859. 3.Rojas C et al. Anesth Analg.

2008 Aug;107(2):469-78. 4. Rojas C et al. Eur J Pharmacol. 2010 Jan 25;626(2-3):193-9. 5. Rojas C et al. J Pharmacol Exp Ther. 2010

Nov;335(2):362-8. 6.Saito M et al. Lancet Oncol. 2009 Feb;10(2):115-24. 7.Janelsins MC et al. Expert Opin Pharmacother. 2013 April ; 14(6): 757–

766.

Annals of Oncology 14: 1570–1577, 2003

Palonosetron vs Ondansetron Moderately emetogenic chemotherapy

• Multicenter, phase III, randomized, controlled, double-blind, non-inferiority study

• Primary Endpoints : % patients achieving CR in acute phase

• Schedule to receive moderately emetogenic chemotherapy (MEC)

• The most common cancer type was breast cancer (57% of patients)

• The most common chemotherapeutic agents administered on day 1 (received by

>10% of patients) were Cyclophosphamide (63%) and Doxorubicin (48%)

Chemotherapy Dose

Carboplatin, Epirubicin, Idarubicin,

Ifosfamide, Irinotecan or Mitoxantrone

Any dose

Methotrexate >250 mg/m2

Cyclophosphamide <1500 mg/m2

Doxorubicin >25 mg/m2

Cisplatin <50 mg/m2 (infused over 1–4 h)


Gralla R, et al. Ann Oncol. 2003;14:1570–1577 .

Complete Response

81* 74.1*

69.3* 68.6

55.1 50.3

0

20

40

60

80

100

Acute: 0–24 (Day 1)

Delayed: 24–120 (Days 2–5)

Overall: 0–120 (Days 1–5)

Co

mp

lete

Resp

on

se

(N

o E

mesis

, N

o R

esc

ue)

(% o

f P

ati

en

ts)

Time (h)

Palonosetron 0.25 mg I.V. (n=189)

Ondansetron 32 mg I.V. (n=185)

*p<0.025 (Fisher’s exact test)


Gralla R, et al. Ann Oncol. 2003;14:1570–1577 .

• 72% female; mean age 56 years; 41% chemotherapy-naïve

• Majority receiving cyclophosphamide and/or doxorubicin combination MEC for breast cancer

• No concomitant dexamethasone pretreatment

Support Care Cancer (2009) 17:205–209

Day 1 Days 1-5 Breakthrough treatment

after 72/120 hours

Treatment

A

Palo 0.25 + Dex 8 mg iv

Dex 8 mg (4 mg BID) iv

Palo 0.25 mg

Treatment

B

Ond 8 mg iv + Dex 8 mg iv

Dex 8 mg (4 mg BID) iv

Metoclopramide

(20 mg iv every 6 or 12 h)

• Single centre, prospective, observational study

• 46 patients undergoing multiple-day CT for hematologic malignancies were

treated with palonosetron and retrospectively compared with patients treated

with ondansetron

Treatment scheme:

Study Design

Note: Palonosetron should be used only before chemotherapy administration. Palonosetron should not be used to prevent

nausea and vomiting in the days following chemotherapy if not associated with another chemotherapy administration

Palonosetron in Haematological Malignancies

Characteristic Palonosetron (n=46) Ondansetron (n=45)

Median age, years (range) 51 (15-80) 50 (20-77)

Gender, male/female (number) 29/17 27/18

Haematological malignancy (%)

Non-Hodgkin lymphoma 50 48

Hodgkin disease 18 24

Acute myeloid leukemia 30 28

Solid tumor 2 0

Chemotherapy regimen (%) (number of cycles)

DHAP 24 (22) 24 (24)

Hyper-CVAD 9 (16) 7 (12)

FluCy 17 (52) 13 (48)

HD-Mtx-AraC 4 (6) 2 (4)

BEACOPP 9 (28) 9 (36)

IGEV 9 (18) 11 (24)

ICE 22 (18) 18 (16)

FLANG 6 (6) 2 (4)

HD-AraC 17 (7) 18 (5)

Other 2 (7) 0

Total number of cycles 180 173

Patient Characteristics


Overall Incidence of CINV

Musso M, et al. Support Care Cancer 2009;17:205-9

80

60

0

10

20

30

40

50

60

70

80

90

100

Palonosetron Ondansetron

CINV 3

CINV 2

CINV 1

CINV 0

*

p<0.05

% o

f P

atients


No C

INV

(%

of P

atients

)

Efficacy of Rescue Therapy


Note: Palonosetron should be used only before chemotherapy administration. Palonosetron should not be used to prevent

nausea and vomiting in the days following chemotherapy if not associated with another chemotherapy administration

67

22

0

10

20

30

40

50

60

70

80

Second dose of Palonosetron Multiple dose Metoclopramide

*

p=0.039


• The most common adverse events were headache (17.1%) and constipation

(9.8%)

• No changes in electrocardiogram intervals or cardiac rhythm were seen after

either single or multiple administrations of Palonosetron

Tolerability


• This trial demonstrates the clinically relevant efficacy of Palonosetron in the

control of CINV in multi-day chemo and in rescuing patients experiencing

breakthrough emesis

Conclusion


5-HT3 RAs : systematic review and meta-analysis

Support Care Cancer (2014) 22:1685-1697

44

• Odds ratios demonstrated statistical superiority of Palonosetron in complete

response of acute phase.

Efficacy – CR in acute phase

Popovic, M et. al. Support Care Cancer (2014) 22:1685–1697


45

Efficacy – CR in delayed phase

• Odds ratios demonstrated statistical superiority of Palonosetron in complete

response in delayed phase.

Popovic, M et. al. Support Care Cancer (2014) 22:1685–1697


• Superior efficacy (especially in the delayed phase where CINV

control is more difficult).

• Similar safety profile.

• Not associated to a significant increase of QTc.

• Possibility to reduce dexamethasone dose without impacting

significantly on the antiemetic regimen efficacy.

• Possibility to reduce polypharmacy also in multiple day

chemotherapy.

• Associated with a lower impact on chemotherapy compliance

• Preferred 5-HT3 RA in the NCCN guideline.

Palonosetron vs 1st Generation 5-HT3 RAs

1. Gralla R, et al. Ann Oncol. 2003;14:1570-1577

2. Morganroth J, et al. Support Care Cancer. 2015 Jun 26

3. Gonullu G, et al. Support Care Cancer. 2012;20(7):1435-1439.

4. Yavas et al. Support Care Cancer. 2012; 20(10):2343-7.

5. Dogan U, et al. Eur Rev Med Pharmacol Sci. 2012;16(4):462-468.

6. Antiemesis. Version1. National comprehensive cancer network. 2017.

7. Hesketh PJ, Bohlke K, Lyman GH, et al. Antiemetics: American society of clinical oncology focused guideline update. J Clin Oncol. 2016;34(4):381-6.

8. MASCC/ESMO antiemetic guideline 2016.

NEPA: Combination of NK1 and 5-HT3 RAs

• 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

1. Spinelli et al. J Clin Pharmacol. 2014;54(1):97-108;

2. Data on file;

3. Lanzarotti et al. Supp Care Cancer. 2013;21(10):2783-2791;

4. Rojas et al. J Pharmacol Exp Ther. 2010;335(2):362-368;

5. Basch et al. J Clin Oncol. 2011;29:4189-4198.

Oral Netupitant

• 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

Oral Palonosetron

NEPA Phase III study: multi cycles

• Phase III study1: multinational, double-blind, randomized, parallel groups • Non-AC MEC or HEC over multiple cycles • No pre-specified limit to the number of consecutive chemotherapy cycles

NEPA, PALO, APR, and DEX were all orally administered On Day 1, NEPA, PALO and APR were taken 60 minutes, and DEX 30 minutes, prior to chemotherapy

Group Day 1 Days 2 and 3

NEPA (N = 309)

APR + PALO

(N = 104)

Day 4

NEPA + DEX 12 mg (HEC & MEC)

HEC: DEX 8 mg MEC: none


APR 125 mg + oral PALO 0.50 mg + DEX 12 mg

(HEC & MEC)

HEC: APR 80 mg + DEX 8 mg

MEC: APR 80 mg


Randomize 3:1

76%/24% MEC/HEC

N = 413

AC: anthracycline-cyclophosphamide; APR: aprepitant; DEX: dexamethasone; HEC: highly emetogenic chemotherapy; MEC: moderately emetogenic chemotherapy; NEPA: oral fixed combination of netupitant (300 mg) and palonosetron (0.50 mg); PALO: palonosetron 1. Gralla RJ, et al. Ann Oncol 2014;25:1333–9. 2. Jordan K, et al. Support Care Cancer (2016) 24:4617–4625

Carboplatin subset: CR rates (0-120 hrs)

80.0

90.6 92.2 93.4

82.4 87.5 87.5 90

0

10

20

30

40

50

60

70

80

90

100

Cycle 1 Cycle 2 Cycle 3 Cycle 4

Pat

ien

ts (

%)

NEPA + DEX

APR + PALO + DEX

128 145 106 116 NEPA + DEX: N = 48 51 40 48 APR + PALO + DEX: N =

APR: aprepitant; CR: complete response (no emesis, no rescue medication); DEX: dexamethasone; NEPA: oral fixed combination of netupitant (300 mg) + palonosetron (0.50 mg); PALO: palonosetron

Overall (0-120hrs) CR rates with NEPA were high and maintained across 4 cycles of chemotherapy

Jordan K, et al. Support Care Cancer (2016) 24:4617–4625

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Source: BETADINE® Gargle Product Monograph

optimal management of chemotherapy-induced nausea and ... cinv.pdf · –no/minimal prior history...

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