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Antineoplastic Induced Nausea and Vomiting (AINV) Management CAPhO Oncology Fundamentals Day September 28, 2019 Stephanie Lovering BSc(Hon), BScPhm, PharmD, ACPR Clinical Pharmacist, Medical Oncology The Ottawa Hospital

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Antineoplastic Induced Nausea and Vomiting (AINV) Management

CAPhO Oncology Fundamentals Day

September 28, 2019

Stephanie Lovering BSc(Hon), BScPhm, PharmD, ACPR

Clinical Pharmacist, Medical Oncology

The Ottawa Hospital

Disclosures

• No conflicts of interest to declare

Learning Objectives

By the end of this presentation, participants should be able to:

1. Identify risk factors for AINV.

2. Define ‘emetogenic potential’ of antineoplastic agents.

3. Describe the types of AINV with respect to their onset.

4. List antiemetic therapy agents available for the management of AINV.

5. Describe how to assess and select effective pharmacologic strategies for the management of AINV.

Definitions

• Nausea

• “A feeling of sickness with an inclination to vomit”

• Emesis

• “The action or process of vomiting”

• Complete response

• No emesis, no use of rescue medications

Drugs 2013; 73:249-262Oxford Dictionary

Image from: Drugs 2013; 73:249-262

Image from: Drugs 2013; 73:249-262

Impact of AINVIf AINV is not managed effectively, it can lead to:

• Poor adherence to treatment

• Decreased willingness to continue treatment

• Poor quality of life

• Pharmacoeconomic impact• Health care system – MD visits, ED visits, hospitalizations

• Patient – unable to work

Goals of Therapy

• No nausea following antineoplastic therapy

• No vomiting following antineoplastic therapy

• Improve quality of life

• Improve adherence to antineoplastic treatment

• Reduce unnecessary utilization of healthcare system

Complete response

Polling Question #1

ID: 75 year old male with newly diagnosed metastatic NSCLC

HPI: 6 month history of weakness, weight-loss 15lbs over 2 months, dyspnea, hemoptysis

SHx: quit smoking 10 years ago but has a 30 pack-year Hx; drinks ~2 beers/day

ID: 40 year old female with newly diagnosed colorectal cancer

HPI: 4 month history of weakness, fatigue and 20lb unintentional weight loss

SHx: never smoked, does not drink alcohol

Assuming both patients are to start anticancer therapy that have equivalent emetogenicity, which patient is at a higher risk of AINV?

A) Patient 1B) Patient 2C) Not sure!

Patient 1 Patient 2

Risk Factors of AINV

• Age (younger)

• Gender (female)

• History of motion sickness

• Abstinence from alcohol

N Engl J Med 2008; 358:2482-2494

Risk Factors of AINV

• Age (younger)

• Gender (female)

• History of motion sickness

• Abstinence from alcohol

N Engl J Med 2008; 358:2482-2494

Polling Question #1

ID: 75 year old male with newly diagnosed metastatic NSCLC

HPI: 6 month history of weakness, weight-loss 15lbs over 2 months, dyspnea, hemoptysis

SHx: quit smoking 10 years ago but has a 30 pack-year Hx; drinks ~2 beers/day

ID: 40 year old female with newly diagnosed colorectal cancer

HPI: 4 month history of weakness, fatigue and 20lb unintentional weight loss

SHx: never smoked, does not drink alcohol

Assuming both patients are to start anticancer therapy that have equivalent emetogenicity, which patient is at a higher risk of AINV?

A) Patient 1B) Patient 2C) Not sure!

Patient 1 Patient 2

Classes of AINV

• Acute: less than 24 hours after treatment administered

• Delayed: more than 24 hours after treatment administered

• Breakthrough: occurs despite taking prophylactic antiemetics

• Anticipatory: occurs as a conditioned response prior to receiving treatment, often a result of past negative experience with treatment

N Engl J Med 2016; 374:1356-1367

Classification of Emetogenicity

Level of Emetogenicity Emetogenic Potential (% of Patient with Emesis)

High >90%

Moderate 30 – 90%

Low 10 - 30%

Minimal <10%

• Emetogenic potential: likelihood of acute vomiting without antiemetic prophylaxis

N Engl J Med 2016; 374:1356-1367

Emetogenic Potential of IV Antineoplastic Agents

Level Agent

High • Anthracycline/• cyclophosphamide

combination• Carmustine• Cisplatin

• Cyclophosphamide ≥ 1500 mg/m2

• Dacarbazine• Mechlorethamine• Streptozocin

Moderate • Alemtuzumab• Azacitadine

Bendamustine• Busulfan• Carboplatin• Clofarabine

• Cyclophosphamide <1500 mg/m2

• Cytarabine> 1000 mg/m2

• Daunorubicin• Doxorubicin• Epirubicin• Idarubicin• Ifosfamide

• Irinotecan• Irinotecan liposomal

injection• Oxaliplatin• Romidepsin• Thiotepa• Trabectedin

J Clin Oncol 2017; 35:3240-3261

Emetogenic Potential of IV Antineoplastic AgentsLevel Agent

Low • Aflibercept• Atezolizumab• Belinostat• Blinatumomab• Bortezomib• Brentuximab• Cabazitaxel• Carfilzomib• Catumaxumab• Cetuximab• Cytarabine ≤ 1000mg/m2

• Docetaxel• Elotuzumab• Eribulin• Etoposide• Fluorouracil• Gemcitabine• Ipilimumab• Ixabepilone• Methotrexate• Mitomyin• Mitoxantrone• Nab-paclitaxel

• Necitumumab• Paclitaxel• Panitumumab• Pemetrexed• Pegylated liposomal

doxorubicin• Pertuzumab• Temsirolimus• Topotecan• Trastuzumab-emtansine• Vinflunine

Minimal • Bevacizumab• Bleomycin• 2-Chlorodeoxyadenosine• Cladribine• Daratumumab• Fludarabine

• Nivolumab• Obinutuzumab• Ofatumumab• Pembrolizumab• Pixantrone• Pralatrexate

• Ramucirumab• Rituximab• Trastuzumab• Vinblastine• Vincristine• Vinorelbine

J Clin Oncol 2017; 35:3240-3261

Pharmacologic Alternatives

Image from: http://clipartbarn.com/pill-clipart_9734/

Serotonin Receptor Antagonists

(5-HT3 RA)

• Prevention of acute AINV• Lack of evidence to use beyond the first 24 hours

• 1st generation 5-HT3 RA: ondansetron, granisetron

• 2nd generation 5-HT3 RA: palonosetron• Demonstrated activity in both acute and delayed phase

• Stronger receptor binding affinity

• Longer t1/2: palonosetron 40h vs granisetron 6h vs ondansetron 3-6h

• Main adverse effects: headache, constipation, potential for QTc prolongation

Lexi-Drugs: ondansetron, granisetron, palonosetron monographsN Engl J Med 2016; 374: 1356-1367

Neurokinin-1 Receptor Antagonists(NK1 RA)

• Prevention of acute and delayed AINV

• Three NK1 RA available in Canada:• Aprepitant (oral formulation)

• Fosaprepitant (IV formulation)

• NEPA (combination of netupitant-palonosetron in fixed dose capsule; single dose required)

• CYP3A4 inhibitor• Reduced dose of dexamethasone (CYP3A4 substrate) should be administered with NK1 RA

• Main adverse effects: fatigue, dyspepsia

Lexi-Drugs: aprepitant, fosaprepitant, netupitant-palonosetron monographsN Engl J Med 2016; 374: 1356-1367

Corticosteroids

• Prevention of acute and delayed AINV (primarily delayed)

• Mechanism of action is unknown

• Main adverse effects: GI upset, insomnia, hyperglycemia, mood changes

Lexi-Drugs: dexamethasone monographN Engl J Med 2016; 374: 1356-1367

Olanzapine

• Preventing nausea, particularly delayed

• Treating breakthrough AINV

• Atypical antipsychotic, blocks multiple neurotransmitter• Dopamine at D1-4 receptors• Serotonin at 5-HT2a, 5-HT2c, 5-HT3 receptors• Catecholamines at α1 receptors• Acetylcholine at muscarinic receptors• Histamine at H1 receptors

• Main adverse effects: sedation, postural hypotension, dizziness

Lexi-Drugs: olanzapine monographsN Engl J Med 2016; 374: 1356-1367Clinical handbook of psychotropic drugs 20th ed.

• Dopamine antagonists• Frequently used to treat breakthrough AINV• Prochlorperazine – sedation, dry mouth• Metoclopramide – EPS• Haloperidol – sedation

• Antihistamines• Dimenhydrinate - sedation

• Synthetic cannabinoids• Dronabinol, nabilone• Poor tolerability – dysphoria, dry mouth, hypotension, dizziness

• Benzodiazepines• Prevention of anticipatory AINV• Lorazepam most commonly used

Other Agents

Lexi-Drugs: prochlorperazine, metoclopramide, haloperidol, dronabinol, nabilone monographs

Antiemetic Guidelines

• ASCO (2017) – American Society of Clinical Oncology

• NCCN (2019) – National Comprehensive Cancer Network

• ESMO / MASCC (2016; 2019 update) – European Society for Medical Oncology / Multinational Association of Supportive Care in Cancer

• Overall there is a lot of consistency among guidelines with minor differences

• This presentation will focus on recommendations from ASCO

Support Care Cancer 2019; 27:87-95

Polling Question #2

65 year old female with breast cancer comes to the outpatient treatment unit today for her first cycle of antineoplastic therapy. She is planned to receive first cycle of AC (doxorubicin + cyclophosphamide) today.

Drug regimen:Doxorubicin 60 mg/m2 IV Day 1

Cyclophosphamide 600 mg/m2 IV Day 1

Antiemetic guidelines suggest the most appropriate antiemetic regimen for this patient is which of the following:

A) NK1 RA + 5-HT3 RA Day 1 + Dexamethasone x 4 daysB) Palonosetron Day 1 + Dexamethasone Day 1 + Olanzapine x 4 daysC) NK1 RA + 5-HT3 RA Day 1 + Dexamethasone x 4 days + Olanzapine x 4 daysD) NK1 RA + 5-HT3 RA Day 1 + dexamethasone Day 1 + Olanzapine x 4 daysE) Any of the above

Polling Question #2

65 year old female with breast cancer comes to the outpatient treatment unit today for her first cycle of antineoplastic therapy. She is planned to receive first cycle of AC (doxorubicin + cyclophosphamide) today.

Drug regimen:Doxorubicin 60 mg/m2 IV Day 1

Cyclophosphamide 600 mg/m2 IV Day 1

Antiemetic guidelines suggest the most appropriate antiemetic regimen for this patient is which of the following:

A) NK1 RA + 5-HT3 RA Day 1 + Dexamethasone x 4 days NCCNB) Palonosetron Day 1 + Dexamethasone Day 1 + Olanzapine x 4 days NCCNC) NK1 RA + 5-HT3 RA Day 1 + Dexamethasone x 4 days + Olanzapine x 4 days NCCND) NK1 RA + 5-HT3 RA Day 1 + dexamethasone Day 1 + Olanzapine x 4 days ASCOE) Any of the above

ASCO Guideline – High Emetic Risk

• Patients treated with cisplatin and other high-emetic risk single agents should be offered a four-drug combination:

• NK1 receptor antagonist + 5-HT3 antagonist + dexamethasone + olanzapine (dexamethasone and olanzapine should be continued on days 2 – 4)

• Patients treated with an anthracycline combined with cyclophosphamide should be offered a four-drug combination:

• NK1 receptor antagonist + 5-HT3 antagonist + dexamethasone + olanzapine (olanzapine should be continued on days 2 – 4)

J Clin Oncol 2017; 35:3240-3261

STRONG RECOMMENDATION

STRONG RECOMMENDATION

HIGH QUALITY

HIGH QUALITY

HEC Antiemetic Regimen

Dosing on day of antineoplastic treatment Dosing on subsequent days

Choose one NK1 RA-Aprepitant 125 mg PO -Fosaprepitant 150 mg IV-NEPA (netupitant 300 mg + palonosetron 0.5 mg) PO

Aprepitant 80 mg po daily on days 2 – 3 (if used on Day 1)

Choose one 5HT3 RA-Granisetron 2 mg PO-Ondansetron 8 mg PO BID-Palonosetron 0.5 mg PO

No 5HT3 RA recommended after day of antineoplastic treatment

Dexamethasone 12 mg PO Dexamethasone 8 mg po daily days 2 - 4

Olanzapine 10 mg PO Olanzapine 10 mg PO daily on days 2 - 4

Efficacy and Safety of Olanzapine in Patients Receiving HEC

N Engl J Med 2016; 375:134-142

Randomized, multi-centre, double-blind, phase III trial, n = 380

P

≥ 18 yoNo previous chemotherapyECOG 0, 1, 2Receiving HEC:• Receiving cisplatin (≥70 mg/m2) OR• cyclophosphamide (>600 mg/m2) plus doxorubicin (>60 mg/m2)

IOlanzapine 10 mg orally daily on days 1 - 4+NK1 antagonist + 5-HT3 antagonist + dexamethasone

CPlacebo+NK1 antagonist + 5-HT3 antagonist + dexamethasone

Baseline Characteristics

N Engl J Med 2016; 375:134-142

Characteristic Olanzapine(N = 192)

Placebo(N = 188)

Total(N = 380)

Age - Median 58.0 56.0 57.0

Female sex - No. (%) 139 (72.4) 136 (72.3) 275 (72.4)

5-HT3-receptor antagonist - No. (%)

Palonosetron 145 (75.5) 143 (76.1) 288 (75.8)

Ondansetron 46 (24.0) 44 (23.4) 90 (23.7)

Granisetron 1 (0.5) 1 (0.5) 2 (0.5)

Chemotherapy regimen - No. (%)

Cisplatin-containing regimen 71 (37.0) 65 (34.6) 136 (35.8)

Anthracycline + Cyclophosphamide 121 (63.0) 123 (65.4) 244 (64.2)

ECOG performance status - No. (%)

0 149 (77.6) 144 (76.6) 293 (77.1)

1 40 (20.8) 41 (21.8) 81 (21.3)

2 2 (1.0) 3 (1.6) 5 (1.3)

Primary Endpoint – Nausea Prevention

N Engl J Med 2016; 375:134-142

Olanzapine(N = 192)

Placebo(N = 188)

p-Value

0 – 24 hr after chemotherapy

No nausea 74% 45% <0.001

25 – 120 hr after chemotherapy

No nausea 42% 25% 0.001

0 – 120 hr after chemotherapy

No nausea 37% 22% 0.002

Primary Endpoint – Nausea Prevention

N Engl J Med 2016; 375:134-142

Olanzapine(N = 192)

Placebo(N = 188)

p-Value

0 – 24 hr after chemotherapy

No nausea 74% 45% <0.001

25 – 120 hr after chemotherapy

No nausea 42% 25% 0.001

0 – 120 hr after chemotherapy

No nausea 37% 22% 0.002

NNT = 4NNT = 6NNT = 7

Secondary Endpoint – Complete Response

N Engl J Med 2016; 375:134-142

Olanzapine(N = 192)

Placebo(N = 188)

P-Value

0 – 24 hr after chemotherapy

Complete response 86% 65% <0.001

25 – 120 hr after chemotherapy

Complete response 67% 52% 0.007

0 – 120 hr after chemotherapy

Complete response 64% 41% <0.001

Secondary Endpoint – Complete Response

N Engl J Med 2016; 375:134-142

Olanzapine(N = 192)

Placebo(N = 188)

P-Value

0 – 24 hr after chemotherapy

Complete response 86% 65% <0.001

25 – 120 hr after chemotherapy

Complete response 67% 52% 0.007

0 – 120 hr after chemotherapy

Complete response 64% 41% <0.001

NNT = 5

NNT = 7

NNT = 5

Adverse Effect - Sedation

N Engl J Med 2016; 375:134-142

ASCO Guideline – Moderate Emetic Risk

• Patients treated with carboplatin AUC ≥ 4 should be offered a three-drug combination

• NK1 receptor antagonist + 5-HT3 antagonist + dexamethasone

• Patients treated with moderate-emetic risk agents (excluding carboplatin AUC ≥ 4) should be offered a two-drug combination

• 5-HT3 antagonist + dexamethasone

• Patients treated with cyclophosphamide, doxorubicin, oxaliplatin, and other agents known to cause delayed nausea

• Dexamethasone on days 2 – 3 may be offered

J Clin Oncol 2017; 35:3240-3261

STRONG RECOMMENDATION

HIGH QUALITY

STRONG RECOMMENDATION

HIGH QUALITY

MODERATERECOMMENDATION

LOW QUALITY

ASCO Guideline – Low Emetic Risk

• Patients treated with low-emetic risk agents should be offered a single dose of a 5-HT3 antagonist or a single 8-mg dose of dexamethasone

J Clin Oncol 2017; 35:3240-3261

MODERATERECOMMENDATION

LOW QUALITY

ASCO Guideline – Minimal Emetic Risk

• Patients treated with minimal-emetic-risk antineoplastic agents should not be offered routine antiemetic prophylaxis

J Clin Oncol 2017; 35:3240-3261

MODERATERECOMMENDATION

LOW QUALITY

Polling Question #3

JL is a 50 year old female with ovarian cancer who received first cycle of carboplatin AUC 6 and paclitaxel 175 mg/m2 two weeks ago. She received aprepitant, ondansetron and dexamethasone for cycle 1 as recommended by the ASCO Guidelines; however she experienced severe nausea throughout the first 48 hours and had 2 episodes of acute emesis.

What would you give JL for antiemetics in cycle 2?

A) Same as cycle 1, but add olanzapine 10 mg po daily x 4 daysB) Change to a different 5-HT3 RA and NK1 RA since they were ineffective cycle 1C) Same as cycle 1, but extend the 5-HT3 RA for 48 hoursD) Something other than A, B, CE) Not sure!

ASCO Guideline – Breakthrough AINV

• Patients who experience AINV despite optimal prophylaxis, and who did not receive olanzapine prophylactically, should be offered olanzapine in addition to continuing the standard antiemetic regimen

• Patients who experience AINV despite optimal prophylaxis, and who have already received olanzapine, may be offered a drug of a different class in addition to continuing the standard antiemetic regimen

J Clin Oncol 2017; 35:3240-3261

MODERATERECOMMENDATION

INTERMEDIATE QUALITY

MODERATERECOMMENDATION

INTERMEDIATE /LOWQUALITY

Polling Question #3

JL is a 50 year old female with ovarian cancer who received first cycle of carboplatin AUC 6 and paclitaxel 175 mg/m2 two weeks ago. She received aprepitant, ondansetron and dexamethasone as recommended by the ASCO Guidelines. She experienced severe nausea throughout the first 48 hours and had 2 episodes of acute emesis.

What would you give JL for antiemetics in cycle 2?

A) Same as cycle 1, but add olanzapine 5-10 mg po daily x 4 daysB) Change to a different 5-HT3 RA and NK1 RA since they were ineffective cycle 1C) Same as cycle 1, but extend the 5-HT3 RA for 48 hoursD) Something other than A, B, CE) Not sure!

High emetic risk(>90%)

HE chemotherapyOlanzapine

(continue D2-4)NK1

antagonist5-HT3

antagonistDexamethasone(continue D2-4)

Anthracycline + Cyclophosphamide

Olanzapine (continue D2-4)

NK1

antagonist5-HT3

antagonistDexamethasone

(D1 only)

Moderate emetic risk(30-90%)

Carboplatin ≥ AUC4 -NK1

antagonist5-HT3

antagonistDexamethasone

No agents with delayed emesis risk

- -5-HT3

antagonistDexamethasone

(D1 only)

Agents that may cause delayed

emesis**- -

5-HT3

antagonist

Dexamethasone (may be offered

D2-3 also)

Low emetic risk(10-30%)

- -

Single dose 5-HT3

antagonistOR

Single dose dexamethasone

8 mg

Minimal emetic risk(<10%)

- - - -

**drugs such as oxaliplatin, doxorubicin, cyclophosphamideJ Clin Oncol 2017; 35:3240-3261

References• Bezchlibnyk-Butler KZ, Jeffries JJ, Adil V, et al. Clinical handbook of psychotropic drugs 20th rev. Ed. 2014 Hogrefe

Publishing.

• Ettinger DS, Berger MJ, Aston J, et al. NCCN clinical practice guidelines in oncology antiemesis version 1.2019 NatlCompr Cancer Care Netw

• Hesketh PJ. Chemotherapy induced nasea and vomiting. N Engl J Med 2008; 358:2482-2494.

• Hesketh PJ, Kris MG, Basch E et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2017; 35:3240-3261.

• McKenzie E, Ziki P, Raman S, et al. ASCO, NCCN, MASCC/ESMO: a comparison of antiemetic guidelines for the treatment of chemotherapy-induced nausea and vomiting in adult patients. Support Care Cancer 2019; 27:87-95.

• Navari RM and Aapro M. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med 2016; 374:1356-1367.

• Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N EnglJ Med 2016; 375:134-142.

• Navari RM. Management of chemotherapy-induced nausea and vomiting. Drugs 2013; 73:249-262.

• Roila F, Molassiotis A, Herrstedt J, et al. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy-and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol27:V119-v113.