understanding and overcoming barriers to the optimal management of cinv

Understanding and Overcoming Barriers to the Optimal Management of CINV

Mark G. Kris, MDWilliam and Joy Ruane Chair in Thoracic Oncology

Memorial Sloan Kettering Cancer Center

Disclosure of Conflicts of Interest

Dr. Kris discloses the following commercial relationships:

– Advisor/consultant: Genentech/Roche, AstraZeneca, Ariad

Learning Objectives Assess the mechanisms of action of antiemetic

regimens Evaluate the risk for nausea and vomiting in

cancer patients scheduled to receive chemotherapy

Differentiate antiemetic strategies for anticipatory, delayed, breakthrough, and refractory nausea and vomiting

Physiology of CINV

CINV = chemotherapy-induced nausea and vomiting; CTZ = chemoreceptor trigger zone; VC = vomiting center. Wickham, 2012.

Neurotransmitters in Emesis

Hesketh et al, 2003; Wickham, 2012.

Serotonin and the 5-HT3 Receptor Pathway

Pathway first recognized with high-dose metoclopramide

Introduction of 5-hydroxytryptamine (5-HT3) receptor antagonists offered an improved treatment option– Effective in acute vomiting; variable efficacy for delayed

events Primary mechanism of action appears to be

peripheral

Miner & Sanger, 1986; Andrews et al, 1998; Hesketh et al, 2003; Wickham, 2012.

Substance P and the NK-1 Receptor Pathway

Substance P relays noxious sensory information to the brain (ie, modulates nociception)

High density of substance P/neurokinin-1 (NK-1) receptors located in brain regions is implicated in the emetic reflex

Primary mechanism of NK-1 receptor blockade action appears to be central– Effective for both acute and delayed events– Augments antiemetic activity of a 5-HT3 receptor antagonist

and a corticosteroid

DeVane, 2001; Hargreaves, 2002; Hesketh et al, 2003; Hesketh, 2001; Tattersall et al, 1996; Wickham, 2012.

Patient Perspective Nausea and vomiting are among the most

common, feared, and distressing experiences to patients receiving cancer treatment

Good management of CINV often determines overall patient experience and satisfaction with care, and adherence

Quality metrics are in development nationally to assess CINV control based on patient self-reported questionnaires

NCCN, 2015.

Anticipatory Feeling of nausea or vomiting prior to next chemotherapy Conditioned response Occurs in 25–50% of patients

Acute Occurs and resolves within 24 hours of chemotherapy Generally peaks within 5–6 hours

Delayed Occurs 1–6 days after chemotherapy Common with administration of cisplatin, carboplatin,

cyclophosphamide, and doxorubicin

Breakthrough Occurs despite prophylactic treatment Requires rescue therapy Can be acute or delayed

Refractory Occurs during chemotherapy cycle after prophylaxis and/or rescue therapy has failed in earlier cycles

Classification of CINV

NCCN, 2015.

Characterizing Nausea

Less understood at neurochemical level than vomiting

Results of direct treatment not as effective as treating vomiting

Impact of nausea on quality of life (QOL) often overlooked

Grunberg, 2012.

Characterizing Nausea (cont.)

Vomiting is a more “observable” or quantifiable event

Nausea is a subjective symptom Nausea commonly suffered in silence Nausea not as well assessed in clinical trials

as vomiting (most drugs evaluated based on vomiting primarily)

Grunberg, 2012.

Impact of Nausea on QOL

Nausea has more of a deleterious effect on QOL and sense of well-being than emesis

Patients rate severe nausea worse for QOL than vomiting

Börjeson et al, 2002; Bloechl-Daum et al, 2006; Sun et al, 2005; Grunberg, 2012.

The Importance of Treating Nausea

Nausea duration may result in even greater distress and altered QOL than severity of nausea

Reduction of nausea rather than emesis has been shown to guide patient preference in antiemetic treatment

Grunberg, 2012.

CINV Risk Factors

Treatment-related risk factors– High emetogenicity of chemotherapy drugs– High drug dose, # of cycles

Patient-related risk factors– Younger age– Female gender– No/minimal history of alcohol use– Susceptibility to motion sickness– Poor control with prior chemotherapy– Anxiety

NCCN, 2015.

CINV Risk Factors (cont.) Medical procedures such as surgery and radiation Medications such as digitalis derivatives, opioids,

nonsteroidal anti-inflammatory drugs, and antibiotics Uremia Hypercalcemia Hepatic dysfunction Increased intracranial pressure Gastrointestinal abnormalities: obstruction, ascites,

hepatomegaly, paraneoplastic syndrome, gastroparesis, gastric outlet syndrome

NCCN, 2015.

Risk of Emesis Increases With Number of Risk Factors Despite 5-HT3 Antagonist Use

Osoba, Zee, Pater, et al, 1997.

CINV: Predictability and Preventability

CINV is a common, often predictable, and often preventable adverse reaction to chemotherapy

Consider using preventive measures for CINV with cycle 1 of chemotherapy

CINV negatively affects patients’ overall chemotherapy experience

Preventing CINV on first exposure to chemotherapy can reduce the risk for developing anticipatory CINV in subsequent cycles

Lau et al, 2004; Basch et al, 2011; Osoba, Zee, Warr, et al, 1997; Aapro et al, 2005; Fernández-Ortega et al, 2012.

Chemotherapy-Specific Risk Factors

Use of emetogenic regimens such as:– AC (anthracycline + cyclophosphamide)– Carboplatin-based regimens– Cisplatin-based regimens– Cyclophosphamide-based regimens– FOLFOX/FOLFIRI (oxaliplatin + leucovorin +

5-fluorouracil/irinotecan + leucovorin + 5-fluorouracil)– ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine)

Short IV infusion time Repeated cycles of chemotherapy

NCCN, 2015; Basch, 2011.

Cisplatin: Prototypical Highly Emetogenic Chemotherapy

Cisplatin is the cornerstone of therapy for many cancers

Risk of emesis is universal– Agent causes emesis in all patients (there is >99% risk

without antiemetics) Well-characterized emetogenic profile serves as a

model for antiemetic testing– Efficacy shown with cisplatin is predictive of antiemetic

efficacy with other chemotherapy drugs

Basch, 2011.

Maximal emetic intensity seen within 24 hours post dose Distinct second phase occurs during Days 2-5 post chemotherapy

Cisplatin: Biphasic Pattern of CINV

Tavorath & Hesketh, 1996; Wilder-Smith, 1993.

Comparison of Biphasic and Monophasic Patterns of Emesis

Martin, 1996.

Considerations When Selecting the Initial Antiemetic Regimen

Emetogenicity of chemotherapeutic regimen Side-effect profile of antiemetic(s) Other symptoms Cost Ease of administration

Key Clinical Practice Guidelines

American Society of Clinical Oncology (ASCO)– Late 2011 full update– 2015 focused update recommending NEPA

(netupitant/palonosetron combination) National Comprehensive Cancer Network (NCCN)

– 2015 update lists emetogenicity ratings for numerous oral antineoplastic agents

Multinational Association of Supportive Care in Cancer (MASCC)– 2013 update

Basch et al, 2011; Hesketh et al, 2015; NCCN, 2015; MASCC, 2013.

High Emetogenic Potential of Selected Antineoplastic Agents

>90% emetic riska:– Anthracycline + cyclophosphamide combination (defined as

either doxorubicin or epirubicin with cyclophosphamide)– Carmustine ≥250 mg/m2

– Cisplatin– Cyclophosphamide ≥1,500 mg/m2

– Dacarbazine– Doxorubicin ≥60 mg/m2

– Epirubicin >90 mg/m2

– Ifosfamide ≥2 g/m2 per dose– Streptozocin

aSee guidelines for full/updated listsNCCN, 2015; Basch et al, 2011; MASCC, 2013.

Moderate Emetogenic Potential of Selected Antineoplastic Agents

30–90% emetic riska:– Arsenic trioxide – Bendamustine– Oxaliplatin– Carboplatin– Carmustine ≤250 mg/m2

– Cyclophosphamide ≤1,500 mg/m2

– Ifosfamide <2 g/m2 per dose– Irinotecan– Cytarabine >200 mg/m2

– Doxorubicin <60 mg/m2, daunorubicin, idarubicin)– Temozolamide– Methotrexate ≥250 mg/m2

aSee guidelines for full/updated listsNCCN, 2015; Basch et al, 2011; MASCC, 2013.

Low Emetogenic Potential of Selected Antineoplastic Agents

10–30% emetic riska:– 5-Fluorouracil– Ado-trastuzumab emtansine– Cytarabine (low dose)– Docetaxel– Eribulin– Gemcitabine– Topotecan– Paclitaxel– Pemetrexed– Ziv-aflibercept

aSee guidelines for full/updated lists.NCCN, 2015; Basch et al, 2011; MASCC, 2013.

Minimal Emetogenic Potential of Selected Antineoplastic Agents

<10% emetic riska:– Bevacizumab– Bleomycin– Bortezomib– Cetuximab– Fludarabine– Nivolumab, pembrolizumab– Obinutuzumab, ofatumumab– Pertuzumab, trastuzumab– Ramucirumab– Rituximab– Vincristine, vinblastine, vinorelbine

aSee guidelines for full/updated lists.NCCN, 2015; Basch et al, 2011; MASCC, 2013.

Selected Oral Agents With Moderate to High Emetogenic Potential (NCCN)

See guidelines for full/updated lists:– Ceritinib– Crizotinib– Cyclophosphamide ≥100 mg/m2/d– Etoposidea

– Lenvatinib– Olaparib– Panobinostat– Temozolomide >75 mg/m2/d

aClassified as low risk by MASCC.NCCN, 2015; MASCC, 2013.

Antiemetics Used in CINV

Serotonin (5-HT3) antagonists: ondansetron, granisetron, dolasetron mesylate, palonosetron– Most effective for acute, not delayed, emesis– Palonosetron has much higher binding affinity for 5-HT3 receptor

and longer half life (~40 hrs), so is better for preventing delayed emesis

NK-1 antagonists: aprepitant, fosaprepitant, netupitant, rolapitant– Combination NK-1/5-HT3: netupitant/palonosetron

Olanzapine Steroids (dexamethasone)

NCCN, 2015.

Additional Antiemetics Used in CINV

Anticholinergics: scopolamine transdermal patch Antihistamines: diphenhydramine Barbiturates: pentobarbital, secobarbital Benzodiazepines: lorazepam Butyrophenones: droperidol, haloperidol Cannabinoids: dronabinol, nabilone

– Appear to have low efficacy Phenothiazines: prochlorperazine, chlorpromazine,

promethazine Substituted benzamides: metoclopramide

NCCN, 2015.

Potential Side Effects of Antiemetics

5-HT3 antagonists: QTc prolongation (not palonosetron), increased liver function tests, generally mild symptoms (headache, constipation, diarrhea)

NK-1 antagonists: weakness, dizziness, diarrhea, constipation, flatus, abdominal discomfort, reflux symptoms, hiccups, headache

Wickham, 2012.


Anticholinergics: dry mouth, drowsiness, blurred vision, disorientation, restlessness, confusion

Antihistamines: drowsiness, restlessness (eg, restless legs), confusion, dizziness, blurred vision/diplopia, tinnitus, dry mouth/nose/throat, urinary retention, frequency, rash, hypotension, palpitations

Cannabinoids: mood changes; disorientation; dizziness; brief impairment of perception, coordination, and sensory functions; tachycardia; hypotension

Brafford & Glode, 2014; Rao & Faso, 2012.


Barbiturates: drowsiness, lethargy, hangover, respiratory depression, Stevens-Johnson syndrome, angioedema

Benzodiazepines: drowsiness, sedation, disorientation

Butyrophenones: restlessness, sedation, extrapyramidal reactions, respiratory depression, tachycardia, hypotension, prolonged QTc

Brafford & Glode, 2014; Rao & Faso, 2012.

Guidelines for CINV Prevention: Highly Emetogenic IV Chemotherapy

NCCN

5-HT3 + NK-1 + Dexamethasone(schedule varies depending on selected agents)

Or

Olanzapine + Palonesetron +Dexamethazone

Or

Netupitant/Palonosetron Combination + Dexamethasone

Note: ASCO focused update includes netupitant/palonosetron combination

NCCN, 2015; Hesketh et al, 2015.

NK-1 Substantially Improves Delayed Emesis

Hesketh, 2003.

Olanzapine in Acute and Delayed Emesis

Navari, 2011; Navari & Nagy, 2015.

Additional data reported at ASCO 2015 suggests olanzapine has similar vomiting complete response (CR) as fosaprepitant but superior nausea control

NCCN

5-HT3 + Dexamethasone ± NK-1 (Aprepitant, Fosaprepitant, Rolapitant)

Or

Olanzapine + Palonesetron +Dexamethazone

Or

Netupitant/Palonosetron Combination + Dexamethasone

Guidelines for CINV Prevention: Moderately Emetogenic IV Chemotherapy

NCCN, 2015; Hesketh et al, 2015.

NCCN

Start before chemotherapy; repeat daily:

5-HT3 (Dolasetron, Granisetron, Ondansetron)

Guidelines for CINV Prevention: Moderate to High Emetogenic Oral Chemotherapy

NCCN, 2015.

NCCN

Start before chemotherapy; repeat daily:

For IV Chemotherapy: 5-HT3 or Metochlopramide or

Prochlorperazine or Dexamethasone

For Oral Chemotherapy:5-HT3 or Metochlopramide or

Prochlorperazine or Haloperidol

Guidelines for CINV Prevention: Low Emetogenic Chemotherapy

NCCN, 2015.

ASCO: Choosing Wisely

“Do not give patients starting a chemotherapy regimen that has a low or moderate risk of causing nausea or vomiting antiemetic drugs intended for use with a regimen that has a high risk of causing nausea or vomiting.”

– ASCO 2013 Top Five List in Oncology

Schnipper et al, 2013.

Management of Breakthrough Nausea and Vomiting

Around-the-clock (ATC) a better option than as needed (PRN)

Use agent(s) from different class than previously used

NCCN guidelines list specific choices from multiple classes of agents

NCCN, 2015.

Treatment for Breakthrough Nausea and Vomiting

Atypical antipsychotic– Olanzapine– Benzodiazepine– Lorazepam

Cannabinoid– Dronabinol– Nabilone

Other– Haloperidol– Metoclopramide– Scopolamine

NCCN, 2015.

Treatment for Breakthrough Nausea and Vomiting (cont.)

Phenothiazine– Prochlorperazine– Promethazine

Serotonin 5-HT3 antagonists– Dolasetron– Granisetron– Ondansetron

Steroid– Dexamethasone

NCCN, 2015.

Prevention and Treatment of Anticipatory Emesis

Prevention is key Nonpharmacological interventions

– Behavioral therapy– Relaxation/systemic desensitization– Hypnosis/guided imagery– Music therapy– Acupuncture/acupressure

Antianxiety agents: alprazolam or lorazepam

NCCN, 2015.

Compliance With Clinical Practice Guidelines

Historically, prior to about 5-10 years ago, levels of compliance with were low with antiemetic guidelines, about 50% for acute emesis and 20% for delayed

Current compliance is substantially better due to:1. Standardized protocols at cancer centers for antiemetics,

linked to specific treatment regimens2. Use of computer order entry for chemotherapy3. Inclusion of quality metrics evaluating appropriate

antiemetic use These strategies are strongly encouraged

Mertens et al, 2003.

NCCN Guidelines:Principles of CINV Control

Current guidelines include the following principles: – Prevention is the goal– Risk for CINV lasts for at least 3 days with highly emetogenic

chemotherapy and 2 days with moderately emetogenic chemotherapy

– Consider the toxicity of specific antiemetic(s)– Choose antiemetic(s) based on emetogenicity of therapy and

patient factors– Consider other potential causes of emesis in cancer patients (eg,

bowel obstruction, electrolyte imbalance, brain metastases)

NCCN, 2015; Basch, 2011; MASCC, 2013.

CINV: Aim for Prevention Prevention of CINV is the goal

– Patients need protection for the full period of CINV risk

– Assess patient and chemotherapy factors related to CINV risk

– The choice of antiemetic(s) should be based on emetogenicity of therapy and patient risk factors

Provide patient education and counseling tools for both in-office and take-home use– They should be simple and easy to understand

– Consider a visual analog scale for nausea and patient diaries for vomiting

– MASCC Antiemesis Tool is available online at http://www.mascc.org/mat

NCCN, 2015; Basch, 2011; Roila et al, 2010; Boogaerts, 2000; Osoba, Zee, Pater, 1997.

Case Study 1: Delayed CINV Ms. DL is a 49-year-old attorney with node-positive

invasive ductal carcinoma of the breast, estrogen and progesterone receptor positive, and HER2 negative. She undergoes a lumpectomy

Oncologist recommends adjuvant chemotherapy with four cycles of AC chemotherapy: doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV Day 1, every 3 weeks

Patient is anxious and concerned about any side effects that might keep her from working

Case Study 1 (cont.)

Which chemotherapy-induced side effects may be particularly important for this patient?a. Nausea and vomitingb. Alopeciac. Neutropeniad. All of the above


Which patient characteristic can increase the risk for CINV?a. Female sexb. Age <50 years

c. Anxietyd. All of the above


What other risk factors for CINV might be important in this patient?– History of motion sickness– History of morning sickness– History of low alcohol intake (<1.5 oz/d)


What steps can be taken to prevent CINV in this patient?– Make prevention a goal of treatment– Implement optimal prophylaxis to prevent both

acute and delayed CINV– Start antiemetic therapy before chemotherapy

Case Study 2: Breakthrough CINV

Mr. CW is a 72-year-old engineer with stage IIA adenocarcinoma of the lung; status post right-upper lobectomy and mediastinal lymphadenopathy

Oncologist recommends adjuvant chemotherapy with docetaxel 75 mg/m2 IV and cisplatin 75 mg/m2 IV Day 1, every 3 weeks for four cycles


Mr. CW’s regimen is considered highly emetogenic.a. Trueb. False


Oncologist reviews side effects associated with chemotherapy regimen

Informs patient that 75% of patients experience some nausea and vomiting (grades 1 and 2) while approximately 24% experience severe nausea and vomiting (grades 3 and 4)

Patient states he is very anxious about occurrence of nausea and vomiting


Since patient is receiving a regimen considered highly emetogenic, oncologist gives patient the following antiemetic regimen prior to starting chemotherapy:– Olanzapine 10 mg Days 1-4– Palonosetron 0.25 mg IV Day 1– Dexamethasone 20 mg IV Day 1

Patient also given lorazepam 0.5 mg PO every 6 hours Days 1–4


Mr. CW experiences some nausea without vomiting during first 24 hours after chemotherapy

Experiences progressive nausea and vomiting for next 96 hours

Forty-eight hours after he received chemotherapy, patient calls oncology nurse, who recommends additional antiemetics for breakthrough nausea and vomiting


What regimen would you recommend for Mr. CW’s breakthrough nausea and vomiting?– Add one agent from a different class to current

regimen– Consider increasing dose of lorazepam

Case Study 3: Refractory CINV

Ms. WB is a 56-year-old woman with stage IV ovarian carcinoma with bulky abdominal metastases as well as liver metastases– ECOG (Eastern Cooperative Oncology Group)

performance status 2– Complains of abdominal pain for which she is

receiving narcotics Started on paclitaxel 175 mg/m2 IV Day 1 and

carboplatin with area under the curve (AUC) 6 IV Day 1 given every 3 weeks

Case Study 3 (cont.) With the first cycle of chemotherapy, Ms. WB

received palonosetron 0.25 mg IV Day 1 and dexamethasone 12 mg IV Day 1– Developed nausea and vomiting on the evening of Day 1

extending through Day 2 With the second cycle, fosaprepitant 150 mg IV Day

1 was added to the previous antiemetic regimen– Developed more nausea and vomiting that continued for a

week


What is the appropriate management of refractory nausea and vomiting?a. Investigate other causes of nausea and

vomiting (eg, liver metastases, bowel obstruction, electrolyte imbalances)

b. Increase doses of antiemeticsc. Switch antiemetics

d. a and c

Antiemetic Treatment: Current Status and Future Considerations

Marked advances in antiemetic therapy have occurred over past few decades and recently

Best antiemetic control occurs when efficacy from clinical trials is emulated in clinical practice

Advances have had major impact on patient QOL and patterns of treatment (move to ambulatory chemotherapy)

Future studies need to concentrate on mechanisms of resistance and identification of patients at risk

Research is needed on understanding and controlling nausea

New agents are needed

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understanding and overcoming barriers to the optimal management of cinv

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