Chemotherapy Induced Emetogenecity

Cancer is one of the top three killers today and Emergency Departments are expected to  see more and more Oncological Emergencies in future. CINV i.e. Chemo Induced Nausea and Vomiting is one such complication of chemotherapy. 

Few patients receiving chemotherapy rank CINV as the most severe side effects and in the past, about half of the patients postponed or refused, potentially curative treatments due to the fear of CINV. With the correct use of antiemetics, CINV can be prevented in almost 70% to up to 80% of patients. Though over the past 25 years, steady improvements in the control of chemotherapy-induced nausea and vomiting (CINV) have been achieved but it still remains a significant issue of concern. 

Pathophysiology of CINV

CINV happens due to noxious reactions along the neuronal pathways. Chemoreceptor trigger zone, which is outside the blood-brain barrier senses emetic stimuli through receptors such as 5HT3, NK1, D2 and muscaranic. Chemicals bind to these receptors and initiate a response. Additionally, activation of these receptors may also occur through GI irritation. 

CLASSIFICATION OF CINV

CINV is differentiated into the following categories: 

1. Acute onset: within 24 hours of initial administration of chemotherapy
2. Delayed onset: occurring 24 hours to several days after initial treatment
3. Anticipatory: emetic episodes are triggered by taste, odor sight, thoughts, or anxiety secondary to a history of poor response to antiemetic agents 
4. Breakthrough: occurring despite prophylactic treatment
5. Refractory: occurring during subsequent cycles when antiemetics have failed in earlier cycles

Risk of CINV with Chemotherapy medications 

Patient-related risk factors, including young age, female gender, experience of emesis during pregnancy, impaired quality of life, and previous experience with chemotherapy, are also known to increase the risk for CINV. Conversely, patients with a history of high alcohol consump- tion have a lower risk of chemotherapy-induced nausea and vomiting.

Management

5-HT3RAs (Receptor Antagonists)

• High therapeutic index for prevention of CINV, most effective antiemetics in the prophylaxis of acute CINV. 
• Generally safe, with a favorable side effect profile (low grade headache, malaise, and constipation). High-dose (24-32mg) Ondansetron appears to be more effective  
• Some literature reports suggest a potential link between 5-HT3 receptor antagonists and the serotonin syndrome, QTc prolongation esp with a single IV dose of 32mg

Steroids, Dexamethasone/Methylpresdnisolone 

• Steroids can be effective when administered as a single agent in patients receiving chemotherapy of low emetic potential. Most beneficial, when used in combination with other antiemetic agents.
• When corticosteroids are administered with aprepitant, doses should be reduced by half.

NK1RAs, Aprepitant

• Aprepitant is the first representative of this new group that blocks the NK1 receptor in the brainstem emetic center and gastrointestinal tract
• Aprepitant is a moderate inhibitor of CYP3A4; therefore, the dexamethasone dose has to be reduced if used concomitantly.

Adjunctive therapy 

1. Metoclopramide

• In the past, metoclopramide was used alone or in combination with a corticosteroids
• Now, it is reserved for those who are intolerant to 5-HT3RAs or steroids
• May cause extrapyramidal side effects including acute dystonic reactions, akathisia  

2. Olanzapine  

• An atypical antipsychotic drug with potential antiemetic properties because of its action at multiple receptor sites implicated in the control of nausea and vomiting.

3. Benzodiazepines

• Used in certain circumstances, to cut anxiety and risk of anticipatory CINV or in patients with refractory and breakthrough emesis.

4. Antihistamines

5. Cannabinoids

• Possess beneficial side effects (sedation, euphoria) in addition to weak antiemetic efficacy but usefulness is limited by the high incidence of toxic effects, such as dizziness and hallucinations.
• Advised in patients intolerant or refractory to 5-HT3RAs or steroids and aprepitant. 

Key Points

First Line for CINV - 5HT3 Antagonists, Steroids, NK1RA
Adjuncts - Benzodiazepines, D2 RA, Olanzapine, Anti-Histaminics, Cannabinoids 


References: 

1. Jordan K, Sippel C, Schmoll HJ. Guidelines for antiemetic treatment of chemotherapy-induced nausea and vomiting: past, present, and future recommendations. The oncologist. 2007 Sep 1;12(9):1143-50.
2. WHO Pharmaceuticals newsletter. Ondansetron and serotonin syndrome. 2012; 3:16.
3. Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, Seeman P, Wong DT. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuro psychopharmacology. 1996 Feb 29;14(2):87-96.
4. WarrDG, HeskethPJ, GrallaRJetal. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in pa- tients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 2005;23:2822–2830. 
5. www.uspharmacist.com
6. Hesketh, Paul J. "Chemotherapy-induced nausea and vomiting." New England Journal of Medicine 358.23 (2008): 2482-2494.

Author:

              

     Lakshay Chanana

     @EMDidactic