sign in sign up
<<
Home , Dolasetron, Palonosetron, Retching

Update on - Induced and (CINV): An Interprofessional

Approach

Stephanie Sutphin, PharmD, BCOP Hematology/Oncology Clinical Specialist University of Kentucky HealthCare Assistant Professor, Adjunct University of Kentucky College of Pharmacy Learning Objectives

Evaluate a patient’s chemotherapy regimen to determine the NCCN risk category for chemotherapy-induced nausea and vomiting (CINV) Develop a treatment plan for a patient receiving moderately emetogenic chemotherapy Discuss how multiple health care professionals can contribute to the care of a patient receiving chemotherapy in order to prevent and/or treat CINV

CINV Rates Cycle 1 N = 322 Pts assessed

245 (76%) 96 (30%) Nausea (N) Vomiting (V)

139 (43%) 234 (73%) 36 (11%) 81 (25%) Acute N Delayed N Acute V Delayed V

126 (39%) Acute & 21 (7%) Acute & Delayed N Delayed V

Hickok, J.T., et al. Cancer 2003;97:2880-6

Palonosetron Trial HEC 100

90 0.25 mg (n=223) 80 Palonosetron 0.75 mg (n=223) 70 32 mg (n=221) 60 50 40 30

20 P=NS for palonosetron 0.25 mg or 0.75 mg vs ondansetron. 10

0 0 24 48 72 96 120 Time (h) Time to Treatment Failure = time to 1st emetic episode or use of rescue medication.

PALO-99-05 HEC

Palonosetron Trial MEC 100

90 Palonosetron 0.25 mg (n=189) 80 Palonosetron 0.75 mg (n=189) 70 100 mg (n=191) 60

50 † * 40

30 20 *P=0.017 for palonosetron 0.25 mg vs dolasetron. 10 †P=0.025 for palonosetron 0.75 mg vs dolasetron.

0 0 24 48 72 96 120 Time (h)

Time to Treatment Failure = time to 1st emetic episode or use of rescue medication. PALO-99-04 MEC Is CINV still a problem? Nausea

. Unpleasant sensation, inclination to vomit (subjective) . loss of gastric () tone & motility . duodenal contractions . reflux of intestinal contents into stomach . cold sweat, salivation, tachycardia . patient-scored (0-10) or visual analogue scale (VAS) Vomiting (Emesis)

Rapid, forceful evacuation of stomach contents out of mouth (involuntary) Abdominal/chest wall muscle contraction Objective quantification: how many episodes in 24 hours Often responds to medication emesis=retching + vomiting Incidence of CINV

One of most common toxicities of chemotherapy >75 % of patients receiving combination therapy ↑ frequency & severity w/repetition Significant impact on quality of life (QOL) 15% will still have severe acute CINV despite optimal treatment Delayed CINV still poorly controlled

Abeloff 2004 Implications of CINV

Quality of life – Fatigue, depression, anxiety – Degeneration of functional ability and self care – Decline in performance status and mental status Compliance Nutritional status Dehydration Electrolyte imbalances Anorexia, weight loss Esophageal tears, fractures Other Causes of Emesis in Cancer Patients Bowel obstruction Vestibular dysfunction Brain mets Electrolytes: ↑Ca, ↑Glu, ↓Na Uremia Drugs Gastroparesis (drug or tumor) or other causes (diabetes) Psychophysiologic (anxiety or anticipatory) Radiation Treatment Emetic Syndromes

Anticipatory Acute Delayed Breakthrough Refractory

Types of Nausea and Vomiting

Anticipatory Acute Delayed

Chemo 24 hours

Time Goals of Therapy

Achieve complete control in all settings Maximum convenience to patient and staff Eliminate side effects Minimize the cost of treatment

DeVita 2005 Risk Factors

Chemotherapy drugs used – Emetogenic potential, dose, schedule Patient Characteristics – Age (<50 years), gender (female), alcohol use (chronic alcoholism decreases risk), prior control, motion sickness, pregnancy-induced nausea – Dose, schedule, combination Anticipatory Emesis

Triggers: sights, smells, sounds, memory, fear, anticipation Cause: inadequate control in past (cortex) Conditioned behavior Incidence: 18-57% Risks: treatment>6month and/or history anxiety/depression Variable response to therapy

Anticipatory

Treatment – Best therapy is prevention of emesis during chemotherapy – Relaxation techniques shown to be effective – Acupunture/Acupressure – Benzodiazepines or alprazolam usually beginning prior to chemotherapy or triggering event. Emetogenic Risk of Chemotherapy Based on % of patients that will get sick if given placebo

Minimal Risk < 10% Low Risk 10 - 30% Moderate Risk 30 - 90% High Risk > 90% High Emetic Risk (>90%)

AC (doxorubicin or epirubicin + cyclophosphamide) Carmustine > 250 mg/m2 Cisplatin Cyclophosphamide > 1,500 mg/m2 Dacarbazine Doxorubicin > 60mg/m2 Epirubicin > 90mg/m2 Ifosfamide > 2gm/m2 Mechlorethamine Streptozocin

NCCN @www.nccn.org v.1.2013 Moderate Emetic Risk (30-90%)

Aldesleukin >12-15 mu/m2 Dactinomycin Amifostine > 500 mg/m2 Daunorubicin Arsenic trioxide Doxorubicin < 60mg/m2 Azacitadine Epirubicin < 90mg/m2 Bendamustine Idarubicin Busulfan Ifosfamide < 2gm/m2 Carboplatin Interferon alfa >10,000/m2 Carmustine ≤ 250 mg/m2 Irinotecan Clofarabine Melphalan Cyclophosphamide <1500 Methotrexate > 250mg/m2 mg/m2 Oxaliplatin Cytarabine > 200mg/m2 Temozolomide

NCCN @www.nccn.org v.1.2013

Moderate Risk

Day 1 Days 2-3 (delayed)

12mg dexamethasone 8mg qday + 5-HT3 RA or 5HT3 RA ± NK1 RA * ± lorazepam 0.5-2mg or oral NK1 RA if used on Day 1 ± H-2 blocker or proton pump inhibitor ± lorazepam *consider for patients receiving ± H-2 blocker or proton pump carboplatin, inhibitor cyclophosphamide, doxorubicin, epirubicin, ifosfamide, ironotecan, methotrexate

NCCN @www.nccn.org v.1.2013 Sites of Action Blood born Local irritants: emetics: cytotoxic, Peripheral GI Cytotoxic, radiation opioids, 5-HT3, NK-1 Acute N/V: type 3 In GI tract Vagal afferent or blood

CTZ Nucleus Tractis Solitarius Vomiting Center 5-HT3,D2,M,H1, 5-HT3, D2, M, H1, NK1 (Medulla) NK1 5-HT3 antagonist Abdominal muscles Diaphragm antagonist Stomach NK-1 antagonist

5HT3 Receptor Antagonists Prototypes: Ondansetron, , Dolasetron, Palonosetron MOA: Inhibition of 5-HT3 receptors on vagal afferent neurons in GI and in CTZ. Effective against Acute N/V At equipotent doses=efficacy & safety Efficacy improved when used with a steroid (e.g., dexamethasone), all except palonosetron Well tolerated, minimal side effects – headache, constipation, <1% EKG changes Expensive to very expensive Serotonin and Chemotherapy

16 14 12 10 8 6 4

2 0

Urinary 5HIAA (note estimated estimated (note 5HIAA Urinary values) 0 5 10 15 20 25 30 Hours after cisplatin administration

Cubeddu, L.X. Oncology 1996;53(suppl 1):18-25 Recommended Doses of 5-HT3 RAs AGENT ROUTE DOSE IV 8-16mg (max 16mg) Ondansetron Oral 16-24mg IV 10 mcg/kg (max 1mg) Granisetron Oral 2 mg or 1 mg BID Transdermal 3.1mg/24hr patch Dolasetron Oral 100 mg Palonosetron IV 0.25mg x1 Neurokinin-1 Receptor Antagonists

NK-1 receptor mediates effects of substance P Substance P: tachykinin (or neurokinin) – emesis – depression – pain after inflammation – inflammatory/immune response in asthma

Micromedex 2013

Oral capsule 125mg, 80mg Combination w/ 5-HT3 RA & corticosteroid Renal/hepatic dysfunction- no change in dose Absorption not affected by food Side effects: somnolence ( w/↑ dose), fatigue, diarrhea, hiccups CYP3A4 (major) & CYP1A2 (minor)drug interactions NK-1 RA Summary Monotherapy not as effective as 5HT3 receptor antagonists to prevent acute CINV Additive to 5HT3 receptor antagonists and dexamethasone to prevent acute CINV Superior to dexamethasone at preventing delayed CINV Aprepitant: 125mg PO day1, 80 mg PO days 2- 3 : 150mg IV on Day 1 only Corticosteroids

Dexamethasone – High emetic risk: 12mg – Moderate emetic risk: 8-12mg – Not as a single agent for high or moderate risk Synergistic with 5-HT RAs and (↑efficacy by 20%) Mechanism of action: Unknown

Steroid Side Effects

Side effects from single and short course therapy are infrequent Mood changes (euphoria, anxiety) Increased appetite Hyperglycemia Mild fluid retention Intense, transient perineal, vaginal or anal burning with rapid IV administration

MOA: blocks dopamine receptors Examples: , ADRs: sedation, hypotension, akathisia (lorazepam 1-2mg) & dystonia (diphen or benztropine) Effective w/moderately & mildly emetogenic Promethazine not as potent in cancer pts Metoclopramide

1981: high dose metoclopramide ↓ emesis by 90% MOA – dopamine receptor blockade (low dose) – 5-HT3 receptor blockade (high dose) – Stimulates cholinergic activity in gut ↑ motility 1-2 mg/kg prior to chemo, then q4-6h; or 3mg/kg q2h x2 doses Side effects of high dose: dystonia or trismus (34%) – 25-50mg or benztropine 1-2 mg Miscellaneous Antiemetics

Butyrophenones ( & ) – Block dopamine receptors Benzodiazepines (lorazepam) – Little to no antiemetic activity alone – Anticipatory N/V (antegrade amnesia) & ↓ anxiety (, ) – Target receptors in central & peripheral CNS, synthetic form of THC, side effects Belladonna alkaloid ( patch) – Block acetylcholine receptors in vestibular apparatus – Useful when N&V positional or due to motion Breakthrough and Refractory

Breakthrough – Occurs despite prophylactic treatment and/or – Requires rescue with antiemetics Refractory – Occurs during subsequent treatment cycles when prophylaxis and/or rescue have failed in previous cycles Breakthrough

Give additional agent from a different class

– Prochlorperazine 10mg q6h or Promethazine 12.5-25mg q4h – Dexamethasone 12mg daily – Metoclopramide 10-40 q4-6h ± diphenhydramine – Lorazepam 0.5-2mg q4-6h – Ondansetron 16mg PO or IV – Granisetron 1-2mg PO or 0.01mg/kg IV (max 1mg) – Dolasetron 100mg daily – Haloperidol 0.5-2 mg q4-6h – Dronabinol 5-10mg q3-6h or Nabilone 1-2mg bid – 10 mg daily for 3 days (use with caution in elderly dementia patients: death, DM, hyperglycemia – Scopolamine patch every 72 hours

NCCN @www.nccn.org v.1.2013

Assessing Response

Primary Endpoint: – Complete Response = no emesis and no rescue medication Secondary Endpoints: – Frequency of vomiting episodes – Use of rescue therapy – Nausea – Quality of life Patient Counseling Important to inform patients regarding their chemotherapy regimens Discuss options Lifestyle measures (may need dietary consult) – Small, frequent meals – Control amount consumed – Eat food at room temp Best treatment is prevention Last Thoughts…

>1.6 million people in US diagnosed w/cancer in 2012 – KY: >25,000 >1 million people received chemotherapy Risks for N&V are both chemotherapy & patient specific Quality of life!