FINAL CINV cancer induced nausea vomiting

Cancer induced nausea vomiting

1. CHEMOTHERAPY INDUCED NAUSEA & VOMITING PATHOGENESIS, RECOMMENDATIONS, NEW TRENDS DR BAGHATH SINGH

2. HOW IMPORTANT IS THE TOPIC

3. Patient Perceptions of the Most Severe Side Effects of Cancer Chemotherapy treatment takes an injection Rank 1983 1 1993 2 1995 3 1999 4 1. Vomiting Nausea Nausea Nausea 2. Nausea Constantly tired Loss of hair Loss of hair 3. Loss of hair Loss of hair Vomiting Constantly tired 4. Thought of coming for treatment Effect on family Constantly tired Vomiting 5. Length of time Vomiting Having to have Changes in the way things taste Adapted from: 1 Coates A et al. Eur J Cancer Clin Oncol. 1983;19:203- 8. 2 Griffin AM et al. Ann Oncol. 1996;7:189- 95. 3 De Boer- Dennert M et al. Br J Cancer. 1997;76:1055- 61. 4 Lindley C et al. Cancer Pract 1999;7:59- 65.

4. CONSEQUENCES OF UNRESOLVED CINV D I S C O N T I N U A T I O N O F T H E R A P Y SERIOUS ME TABOL IC DE R ANGE ME NTS NUTRITIONAL DEPLETION AND ANOREXIA ESOPHAGEAL TEARS WOUND DEHISCENCE DETERIORATION OF PATIENTS’ PHYSICAL AND MENTAL STATUS

5. BEFORE WE GET STARTED…

6. IN ADDITION TO ‘CINV’ VOMITING CAN BE CAUSED BY POTENTIALLY DANGEROUS CAUSES WHICH COULD MASQUERADE AS CINV : PARTIAL / COMPLETE BOWE L OBSTR U C T ION U R E M I A B R A I N M E T A S T A S E S E L EC TROLYTE / M E TABOL IC IMBALANCE : – HYPERCALCEMIA, HYPERGLYCEMIA, HYPONATREMIA, CONCOMITANT DRUGS , INCLUDING OPIATES VESTIBULAR DYSFUNCTION I M P O R TA N T TO K N O W

7. History The physical examination should assess for other potential causes of nausea and vomiting, including a fundoscopic examination to look for signs of increased intracranial pressure, any signs of GI system obstruction or ileus , and signs of  dehydration . Laboratory Studies Imaging Studies

8. TODAY’S TOPIC CHEMOTHERAPY INDUCED NAUSEA VOMITING

9. NAUSEA/VOMITING P R O T E C T I V E R E F L E X CNS plays a critical role in physiology of NAUSEA and VOMITING R E C E I V E S & P R O C E S S E S a variety of emetic stimuli  generating efferent signals  these signals sent to a number of organs and tissues  ultimately result in nausea/vomit

10. V O M I T I N G

11. THE CENTRAL PATTERN GENERATOR Locations of neurons in the medulla support the notion that a ' central pattern generator ' coordinates the sequence of behaviours during emesis This 'central pattern generator' receives indirect input from both the area postrema (also called the CHEMORECEPTOR TRIGGER ZONE ) the abdominal vagus by means of the nucleus tractus solitarius NOTE: There is NO PROOF of the existence of an anatomically discrete vomiting centre!

12. HOW CHEMOTHERAPEUTIC AGENTS PRODUCE AN EMETIC RESPONSE In response to the 'toxin = chemotherapy', A P R O T E C T I V E E V O L U T I O N A R Y M E C H A N I S M One of the well described mechanisms  Release of serotonin from the enterochromaffin cells This interacts with 5HT3 receptors on vagal afferents in the bowel wall These vagal afferents project to the dorsal brain stem (primarily nucleus tractus solitarius and area postrema) In this area, receptors for various neurotransmitters such as substance P, serotonin, dopamine, etc are present. Efferent fibers project from here to the 'central pattern generator ' which is present more ventrally in the brain stem.

13. Serotonin and 5- HT 3 Receptor Pathway Primary mechanism of action appears to be peripheral. First recognized with high- dose metoclopramide. Development of 5- HT 3 antagonists has had dramatic impact: Highly effective in acute vomiting, less effective for delayed events. Optimal use is with dexamethasone.

14. Substance P and Neurokinin1 (NK 1 ) Receptor Pathway 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- HT 3 receptor antagonist and corticosteroid.

15. CONCEPTUAL MODEL OF ACUTE & DELAYED CINV Adapted from Andrews & Davis. In: Andrews PLR & Sanger GJ (Eds). Emesis in Anti- Cancer Therapy: Mechanisms and Treatment. London: Arnold; 1993:147. Disrupted gut motility Intensity of emesis 1 2 Time (days) 3 Cell breakdown products 4 5 5HT 5-HT 3 -sensitive phase Prokinetic- sensitive phase NK 1 -sensitive phase Steroid- sensitive phase

16. Definitions A C U T E – within a few minutes to several hours after drug administration and commonly resolves within 24 hours. D E L A Y E D – develops in patients more than 24 hours after chemotherapy administration. May last up to 6 days It commonly occurs with PLATINUMS, cyclophosphamide and/or anthracyclines. A N T I C I P A T O R Y – nausea and/or vomiting before patients receive their chemotherapy, after a prior negative experience with chemotherapy B R E A K T H R O U G H – occurs despite prophylactic treatment and/or requires rescue. R E F R A C T O R Y – nausea and emesis during subsequent cycles when antiemetic prophylaxis and/or rescue have failed in earlier cycles

17. DRUG EMESIS RISK GROUPS

18. A NTIEMETICS 5-HT 3 RAs : Granisetron , Ondansetron , Palonosetron , Tropisetron Steroids, Dexamethasone NK 1 RAs, Aprepitant Metoclopramide Cannabinoids

19. Some special Challenges Multiple- day chemotherapy regimens Breakthrough CINV Anticipatory CINV Delayed CINV

20. Multiple- Day Chemotherapy Regimens Challenge  Patients receiving multi-day chemotherapy are at risk for both acute and delayed nausea and vomiting. It is difficult to recommend appropriate antiemetics for each day since acute and delayed may overlap after the initial day of chemotherapy.

21. BREAKTHROUGH CINV Breakthrough emesis refers to vomiting that occurs despite prophylactic treatment. Refractory emesis refers to emesis that occurs during subsequent treatment cycles when antiemetic prophylaxis and/or rescue have failed in earlier cycles. Challenge – Breakthrough nausea and vomiting represents a difficult situation as ongoing refractory nausea is hard to reverse.

22. Management Strategies Give AROU N D THE C LOC K ADM IN I STR ATION versus prn. Additional agents should be from a different drug class than initial therapy. No one treatment is better than the other. – Possibilities include: dopamine antagonists, metoclopramide, haloperidol, cannabinoids, corticosteroids, or agents such as lorazepam If patient has dyspepsia, consider antacid therapy (H2 blocker or Proton Pump Inhibitor).

23. ANTICIPATORY CINV Anticipatory nausea and/or vomiting is the occurrence of nausea and/or vomiting before patients receive their chemotherapy treatment. Because it is a conditioned response, it can only occur after a negative past experience with chemotherapy. Challenge - Anticipatory nausea and/or vomiting occurs in 18% to 57% of chemotherapy patients. Younger patients may be more susceptible.

24. Either: Alprazolam PO 0.25 to 0.5 mg t.i.d. beginning on the night before treatment OR; Lorazepam 0.5- 2 mg PO on the night before and the morning of treatment. Behavioral therapy Systemic densensitization

25. Why ANTIEMETICS give suboptimal responses in a few? I N T E R - I N D I V I D U A L DIFF ERENCE S I N D R U G R E S P O N S E Genetic polymorphisms in drug metabolizing enzymes and drug transporters may provide substantial knowledge about the mechanisms of inter- individual differences in drug response.

26. P H A R M A C O G E N O M I C S Pharmacogenomics - the study of the relationship between specific DNA sequence variations and the actual effect of a drug. CYP2D6 is involved in the metabolism of all of the most commonly available serotonin antagonists, except granisetron, and their efficacy and side effects may therefore be affected by the CYP2D6 polymorphism. As this enzyme is polymorphic, several different alleles may be present in different individuals.

27. We are better off….

28. T H A N K Y O U