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Optimizing CINV management: applying evidence in clinical practice

Petra Tesařová Charles University Hospital

Prague, Czech Republic

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Disclosures

• Speakers bureau

– Angelini Pharma

– Novartis

– Pfizer

• Consultant/advisor

– Pfizer

“…Cancer patients are living longer and better lives,

thanks to better symptom control, more effective therapies,

and a deeper understanding of cancer…”

− Dr Harold Varmus

Director NCI, PBS NewsHour, September 24, 2012

NCI, National Cancer Institute; PBS, Public Broadcasting Service.

At the beginning

of the 1990s,

we did not have

effective prevention

and treatment of

CINV

My reminiscence…

CINV, chemotherapy-induced nausea and vomiting. Image available from: https://www.medicalnewstoday.com/articles/321083.php.

Nausea and vomiting significantly decreased the

quality of life…

What are the current treatment options?

a NEPA, fixed combination of netupitant (300 mg) and palonosetron (0.50 mg).

5-HT3, 5-hydroxytryptamine type 3; DEX, dexamethasone;

ESMO, European Society for Medical Oncology;

MASCC, Multinational Association of Supportive Care in Cancer;

NCCN, National Comprehensive Cancer Network; NK1, neurokinin 1;

RA, receptor antagonist.

1. MASCC/ESMO Antiemetic guideline, version 2016 V.1.2.

Available from: http://www.mascc.org/assets/Guidelines-

Tools/mascc_antiemetic_guidelines_english_v.1.2.1.pdf. Accessed June 2018.

2. Hesketh PJ, et al. J Clin Oncol. 2017;35:3240-61.

3. NCCN Clinical Practice Guidelines Oncology. Antiemesis Version 3, 2018.

Available from: https://www.nccn.org. Accessed June 2018.

4. Hesketh PJ, et al. Eur J Cancer. 2003;39:1074-80.

5-HT3 RA

Ondansetron

Granisetron

Dolasetron

Palonosetron

Corticosteroids Dexamethasone

NK1 RA

Aprepitant

Fosaprepitant

Netupitant (NEPAa)

Rolapitant

Multi-receptor Olanzapine

DEX 5-HT3 RA

NK1 RA

NK1 RAs used in combination with

5-HT3 RAs can better control acute

and delayed CINV4

Guideline-recommended

triplet antiemetic combination1–3

…but how many situations are really standard?

Image available from: https://www.alamy.com.

Question 1

Have you ever met a patient who is experiencing vomiting

after chemotherapy even though a standard preventive

treatment had been given?

1) Yes

2) No

3) Not applicable

Evidence from the “real world” clinical setting

Number of CT cycles = 4,197.

Missing data: acute vomiting 3.6%; acute nausea 3.2%;

delayed vomiting 4.2%; delayed nausea 4.2%.

h, hours. Dranitsaris G, et al. Ann Oncol. 2017;28:1260-7.

80

0

10

20

30

40

50

60

70

Acute (0–24 h) Delayed (25–120 h) Overall (0–120 h)

Cycle

s (

%)

Any vomiting

Any nausea

Any nausea or vomiting

≥ Grade 2 CINV

23

47

25

68

61

42

Patient case: RL

• RL is a 60-year-old female with a new diagnosis of metastatic NSCLC

• She is a smoker and drinks 1-2 alcoholic drinks/week

• RL has had three pregnancies involving hospitalization for morning sickness

• She also has a significant medical history of depression, hypothyroidism, anxiety, impaired glucose tolerance, and GERD

• She will receive her 1st cycle of chemotherapy: – Cisplatin 75 mg/m2 i.v. on Day 1

– Etoposide 100 mg/m2 i.v. on Days 1–3

• This regimen will be given every 28 days for 4–6 cycles

GERD, gastroesophageal reflux disease;

NSCLC, non-small-cell lung cancer.

Image available from:

https://www.memorangapp.com/flashcards/68829/Lung+Cancer+Pathology.

Question 2

What is the optimal tailoring approach to preventing CINV?

1) According to the patient's wishes

2) Provide treatment based on patient-related and

regimen-based risk factors

3) Utilize standardized institution-specific antiemetic

guidelines

4) Postpone treatment until symptoms occur

CINV risk assessment tool for establishing

overall emetic risk

Overall

emetic

risk

Patient

risk

factors

Regimen

risk

factors

Level Frequency of emesis (%) Agent a

High

(i.v. agents) > 90

• AC combination defined as any

chemotherapy regimen that contains an

anthracycline and cyclophosphamine

• Carboplatin AUC ≥ 4

• Carmustine ˃ 250 mg/m2

• Cisplatin

• Cyclophosphamide >1,500 mg/m2

• Dacarbazine

• Doxorubicin ≥ 60 mg/m2

• Epirubicin > 90 mg/m2

• Ifosfamide ≥ 2 g/m2/dose

• Mechlorethamine

• Streptozocin

Moderate

(i.v. agents) 30–90

• Bendamustine

• Carboplatin AUC < 4

• Carmustine ≤ 250 mg/m2

• Cyclophosphamide ≤ 1,500 mg/m2

• Cytarabine > 200 mg/m2

• Daunorubicin

• Doxorubicin < 60 mg/m2

• Epirubicin ≤ 90 mg/m2

• Ifosfamide < 2 g/m2/dose

• Irinotecan

• Melphalan

• Methotrexate ≥ 250 mg/m2

• Oxaliplatin

• Temozolamide

Low

(i.v. agents) 10–30

• 5-fluorouracil (5-FU)

• Ado-trastuzumab emtansine

• Cytarabine 100–200 mg/m2

• Docetaxel

• Doxorubicin (liposomal)

• Eribulin

• Gemcitabine

• Paclitaxel

• Pemetrexed

• Topotecan

• Ziv-aflibercept

Oral agents

with

moderate to high

≥ 30

• Altretamine

• Busulfan ≥ 4 mg/d

• Ceritinib

• Crizotinib

• Cyclophosphamide ≥ 100 mg/m2/d

• Estramustine

• Etoposide

• Lenvatinib

• Lomustine (single day)

• Mitotane

• Olaparib

• Panobinostat

• Procarbazine

• Rucaparib

• Temozolomide > 75 mg/m2/d

a See guidelines for complete updated lists of emetic risk categories,

including minimal level (< 10% frequency of emesis).

AUC, area under the curve; i.v., intravenous.

Based on NCCN Clinical Practice Guidelines Oncology. Antiemesis Version 3, 2018.

Available from: https://www.nccn.org. Accessed June 2018.

Regimen-specific risk factors: emetogenic

potential of anticancer agents

Predictive factors for optimizing selection of

prophylactic antiemetics

• 8 risk factors identified:

1) Patient age < 60 years

2) The first 2 cycles of chemotherapy

3) Anticipatory nausea and vomiting

4) History of morning sickness

5) Hours of sleep the night before chemotherapy

6) CINV in the prior cycle

7) Patient self-medication with non-prescribed treatments

8) Use of platinum or AC-based regimens

Dranitsaris G, et al. Ann Oncol. 2017;28:1260-7.

Patient case: RL

• RL is a 60-year-old female with a new diagnosis of metastatic NSCLC

• She is a smoker and drinks ~1-2 alcoholic drinks/week

• RL has had three pregnancies involving hospitalization for morning sickness

• She also has a significant medical history of depression, hypothyroidism, anxiety, impaired glucose tolerance, and GERD

• She will receive her 1st cycle of chemotherapy: – Cisplatin 75 mg/m2 i.v. on Day 1

– Etoposide 100 mg/m2 i.v. on Days 1–3

• This regimen will be given every 28 days for 4–6 cycles

Image available from:

https://www.memorangapp.com/flashcards/68829/Lung+Cancer+Pathology.

Question 3

What kind of antiemetic regimen would you choose for RL?

1) 5-HT3 RA + DEX + metoclopramide

2) 5-HT3 RA + NK1 RA + DEX + lorazepam

3) NK1 RA + DEX + metoclopramide

Recommended antiemetic assessment

and treatment plan for RL: HEC

For acute CINV:

• NK1 RA

• 5-HT3 RA

• DEX

For delayed CINV:

• DEX on Days 2−4

• APR Days 2, 3

(if given on Day 1)

• Patient-specific

assessment due to

diabetes risk

and corticoids

APR, aprepitant; HEC, highly emetic chemotherapy.

MASCC/ESMO Antiemetic guideline, version 2016 v.1.2.

Available from: http://www.mascc.org/assets/Guidelines-Tools/mascc_antiemetic_guidelines_english_v.1.2.1.pdf.

Accessed June 2018.

Patient case: AS

• AS is a 42-year-old female • She is a teacher at a local elementary school • She presents with 3-month history of fatigue and a

> 4 kg unintentional weight loss • Never smoked, does not drink alcohol • Three children, history of significant

morning sickness with 3rd child • Colonoscopy revealed 8 cm caecal tumour • Biopsy confirmed diagnosis of colorectal

adenocarcinoma with KRAS mutation

• Treatment: m-FOLFOX6 + bevacizumab – AS will receive this regimen q2w for 6 cycles – FOLFOX: oxaliplatin + folinic acid + 5-fluorouracil

M-FOLFOX6, modified FOLFOX6; q2w, every 2 weeks. Courtesy of Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.

Question 4

Based on the guidelines, which antiemetic regimen is

recommended for AS?

1) 5-HT3 RA + DEX

2) NK1 RA + PPI + H1 antagonist

3) Institution-based protocol

4) None of the above

PPI, proton pump inhibitor.

Recommended antiemetic assessment

and treatment plan for AS: MEC

For acute CINV:

• 5-HT3 RA + DEX

For delayed CINV:

• DEX on Days 2, 3

• No treatment in patients

with low risk of CINV

DOL, dolasetron; GRAN, granisetron;

MEC, moderately emetogenic chemotherapy;

PALO, palonosetron; OND, ondansetron.

1. NCCN Clinical Practice Guidelines Oncology. Antiemesis Version 3, 2018.

2. Schwartzberg L, et al. Support Cancer Care. 2014;22:469-77.

3. Aloxi SmPC. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-

_Product_Information/human/000563/WC500024259.pdf. Accessed June 2018.

5-HT3 RAs • DOL, GRAN, OND, PALO

− PALO and GRAN extended-release injection are preferred in

NCCN1

− PALO has longer half-life vs other 5-HT3 RAs2

− PALO is specifically approved for the prevention of nausea and

vomiting3

Patient case: AS (cont.)

• During cycle 1, AS continues to experience nausea and

vomiting in the days following chemotherapy

• She reports developing additional symptoms

– Weight loss of 3 kg

– Depression

– Fatigue

Question 5

Which is considered a risk factor for developing CINV?

1) Age < 60 years

2) Anticipatory nausea and vomiting

3) CINV in the previous cycle

4) History of morning sickness

5) All of the above

How would you modify her antiemetic regimen?

• What further recommendations would you make?

– Addition of NK1 RA to 5-HT3 RA + DEX

– In consideration of busy schedule with 3 small children and

teaching responsibilities, NEPA single-dose for convenience

NCCN Clinical Practice Guidelines Oncology. Antiemesis Version 3, 2018.

Available from: https://www.nccn.org. Accessed June 2018.

Image available from: https://topnews.in.

How can adherence to antiemetic guidelines be

improved in your practice?

• Suggested approaches from ONS survey

– Education of providers

• Physicians

• Nurses

• Pharmacists

– Use standardized protocols and orders

– Improve patient teaching

– Follow-up

ONS, Oncology Nursing Society.

Clark-Snow R, et al. Support Care Cancer. 2018;26:557-64.

Image available from: https://www.careerguide.com/blog/the-importance-of-education.

Message for clinical practice

• Prevention of CINV is better than symptomatic treatment

• Follow the guidelines for prevention of CINV, based on

the emetogenicity of chemotherapy regimens

• Additionally, take each patient’s individual risk factors

and comorbidities into account

• New therapeutic options offer the opportunity to improve

guideline adherence and ensure a better quality of life

– NK1 RAs and fixed-combination (NEPA)

• Applying effective therapeutic strategies as indicated for

nausea and vomiting will result in improved adherence to

cancer treatment

The way is tailoring…

Images available from:

https://www.leaf.tv/articles/how-much-does-suit-tailoring-cost/. https://www.dreamstime.com/stock-illustration-closeup-portrait-sick-

young-woman-to-throw-up-vomit-white-background-image73632909.