Chemotherapy-Induced Nausea and Vomiting for PEBC exams
Introduction

Effective management of nausea and vomiting in patients undergoing anti-cancer treatment remains a critical challenge, particularly for those preparing for the Pharmacy Examining Board of Canada (PEBC) exams. While substantial data exist on the relative emetogenic potential of many intravenous (IV) chemotherapeutic agents, there is comparatively limited information on oral chemotherapy regimens, immunotherapies, targeted therapies, or the combined effects of chemotherapy and radiation therapy.

This chapter focuses on chemotherapy-induced nausea and vomiting (CINV), a significant complication of cancer therapy that is classified into five types: acute, delayed, anticipatory, refractory, and breakthrough. Each classification is discussed with attention to its clinical presentation, underlying mechanisms, and relevance to real-world scenarios, which are critical for both clinical practice and PEBC exam preparation.

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Acute CINV

Acute CINV manifests within minutes to hours following the administration of anti-cancer agents and typically subsides within 24 hours. This type of nausea and vomiting is highly prevalent, occurring in over 90% of patients treated with highly emetogenic chemotherapy regimens such as cisplatin and cyclophosphamide. Key patient-related risk factors include younger age, female sex, minimal alcohol consumption, a history of poor symptom control in prior chemotherapy cycles, motion sickness, and pregnancy-related nausea.

The primary neurotransmitter implicated in acute CINV is serotonin, which activates 5-HT3 receptors in the gastrointestinal tract. Additionally, dopamine (D2) and neurokinin-1 (NK1) receptors play contributory roles. Chemotherapy and radiation therapy stimulate enterochromaffin cells in the gastrointestinal lining to release large amounts of serotonin, triggering vomiting through 5-HT3 receptor activation and subsequent stimulation of the medulla oblongata’s vomiting center.

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Delayed CINV

Delayed CINV begins at least 24 hours after chemotherapy and can persist for up to 6–7 days. Drugs like cisplatin and cyclophosphamide are commonly implicated, often causing both acute and delayed symptoms with a symptom-free interval between the two phases. The incidence of delayed nausea and vomiting can be as high as 80% for cisplatin.

Unlike acute CINV, delayed nausea and vomiting rely less on serotonin-mediated pathways. Instead, substance P and NK1 receptor-dependent mechanisms play a more significant role, offering a unique pharmacological target for antiemetic therapies.

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Anticipatory CINV

Anticipatory CINV is a conditioned response triggered by previous negative experiences with poorly managed nausea and vomiting. This psychological form of CINV occurs in approximately 25% of patients by the fourth cycle of chemotherapy and may present even before chemotherapy administration begins. Without effective intervention, anticipatory CINV worsens with each cycle, leading to substantial distress. Notably, up to 30% of patients may discontinue chemotherapy due to intolerable nausea and vomiting, underlining the importance of proactive management.

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Refractory CINV

Refractory CINV occurs when antiemetic regimens fail to control symptoms in subsequent cycles of chemotherapy. This type underscores the need for enhanced strategies and individualized treatment approaches to manage persistent symptoms.

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Breakthrough CINV

Breakthrough CINV emerges despite the use of optimal antiemetic prophylaxis and occurs within five days of chemotherapy administration. It necessitates the use of rescue therapy with alternative antiemetic agents to provide symptom relief.

Goals of Therapy

The primary objectives in managing chemotherapy-induced nausea and vomiting (CINV) include:

1. Prevention of Acute and Delayed CINV: Mitigating the occurrence of acute, delayed, anticipatory, and refractory nausea and vomiting to ensure that patients maintain their quality of life. Preventing these side effects improves treatment adherence and reduces delays in scheduled cancer therapies.

2. Symptom Reduction: Decreasing the frequency and intensity of nausea and vomiting to enhance patient comfort. This also minimizes the psychological distress often associated with these symptoms.

3. Complication Prevention: Preventing complications that can arise from severe nausea and vomiting, such as:

   • Esophageal tears
   • Dehydration
   • Anorexia and malnutrition
   • Weight loss
   • Metabolic alkalosis
   • Electrolyte imbalances (e.g., chloride and potassium depletion)
   • Bone fractures from pathological causes

Intravenous Cancer Treatment Agents
High Emetogenic	Anthracycline/cyclophosphamide combination, carmustine, cisplatin, cyclophosphamide, dacarbazine, sacituzumab govitecan, streptozocin
Moderate Emetogenic	Alemtuzumab, azacitidine, bendamustine, busulfan, carboplatin, cyclophosphamide, cytarabine, cytarabine/daunorubicin liposome, daunorubicin, dinutuximab, doxorubicin, epirubicin, idarubicin, ifosfamide
Low Emetogenic	Abemaciclib, alpelisib, axicabtagene ciloleucel, brentuximab, cabazitaxel, carfilzomib, cytarabine, docetaxel, doxorubicin liposomal, enfortumab vedotin, eribulin, etoposide, 5-Fluorouracil, gemcitabine, gemtuzumab ozogamicin, idecabtagene vicleucel, isatuximab, L-asparaginase, lisocabtagene, maraleucel, melphalan, mitomycin, mitoxantrone
Minimal	Alemtuzumab, atezolizumab, avelumab, bevacizumab, bleomycin, bortezomib, busulfan, cetuximab, cladribine, daratumumab, decitabine, dexrazoxane, durvalumab, fludarabine, ipilimumab, nivolumab, obinutuzumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, siltuximab, trastuzumab, vinblastine, vincristine, vindesine, vinorelbine

Oral Cancer Treatment Agents
High Emetogenic	procarbazine
Moderate Emetogenic	Azacitidine, binimetinib, bosutinib, cabozantinib, ceritinib, crizotinib, cyclophosphamide, dabrafenib, encorafenib, etoposide, fedratinib, imatinib, lenvatinib, lomustine, midostaurin, mitotane, niraparib, olaparib, selinexor, temozolomide
Low Emetogenic	Acalabrutinib, afatinib, alectinib, axitinib, brigatinib, bosutinib, capecitabine, dasatinib, everolimus, etoposide, fludarabine, ibrutinib, idelalisib, lapatinib, larotrectinib, lenalidomide, lorlatinib, mercaptopurine, nilotinib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, selpercatinib, sonidegib, sunitinib, tegafur uracil, tepotinib, thalidomide, trametinib, tucatinib, vandetanib, venetoclax, vorinostat, zanubrutinib
Minimal	busulfan, chlorambucil, erlotinib, gefitinib, hydroxyurea, L-phenylalanine mustard, melphalan, methotrexate, pomalidomide, ruxolitinib, 6-thioguanine, sorafenib, vemurafenib, vismodegib

Therapeutic Choices for Managing Nausea and Vomiting, Including Chemotherapy-Induced Nausea and Vomiting (CINV)

Nonpharmacologic Strategies

Dietary Adjustments

Patients experiencing nausea and vomiting can benefit from specific dietary strategies aimed at minimizing discomfort and improving tolerance:

1. Small, Frequent Meals: Consuming light meals in smaller portions multiple times daily can reduce the burden on the digestive system.
2. Avoid High-Fat and Strong-Smelling Foods: Foods rich in fat or with strong aromas can exacerbate nausea and should be minimized.
3. Dry, Starchy Foods: Incorporate easily digestible options like crackers to help settle the stomach.
4. Clear Liquids and Ice Chips: For patients struggling with solid food, sipping small amounts of clear liquids or sucking on ice chips can be helpful.
5. Avoid Food Preparation: The act of cooking, especially smelling food, can worsen nausea and should be delegated if possible.

Behavioral Interventions

Behavioral approaches can complement dietary adjustments to alleviate symptoms:

1. Relaxation Techniques: Engaging in guided relaxation exercises or meditation helps to lower anxiety levels, which can worsen nausea.
2. Exercise Programs: Tailored physical activity regimens can reduce anxiety and improve overall well-being.
3. Systematic Desensitization: This method involves gradually exposing the patient to nausea-inducing stimuli while employing relaxation techniques to replace the nausea response with a sense of calm.

Other Nonpharmacologic Recommendations

1. Minimize Movement: Resting in bed or sitting in a chair can reduce vestibular stimulation, which may trigger nausea.
2. Acupuncture and Acupressure: Evidence supports the use of these techniques to relieve nausea, particularly in chemotherapy settings.
3. Prioritize Sleep: Ensuring adequate sleep can enhance the body’s ability to manage symptoms.

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Pharmacologic Approaches

Nausea and vomiting, particularly related to chemotherapy, involve complex interactions among various receptors, primarily serotonin (5-HT3) and neurokinin-1 (NK-1). Pharmacologic therapy focuses on targeting these pathways and optimizing drug combinations for effective prevention and treatment.

Key Principles of Management

1. Prevent Acute Symptoms: Addressing acute nausea and vomiting during the chemotherapy cycle is critical to preventing delayed and anticipatory symptoms in subsequent cycles.
2. Scheduled Antiemetics: Proactive, regular dosing is significantly more effective than as-needed (PRN) usage.
3. Combination Therapy: Utilizing drugs targeting multiple receptor pathways is essential for moderate to highly emetogenic chemotherapy regimens.

Pharmacologic Classes

1. Serotonin (5-HT3) Antagonists

   • First-Generation Agents: Drugs like granisetron and ondansetron are equally effective for acute CINV prevention. Combining them with olanzapine, dexamethasone, and NK-1 antagonists improves outcomes for highly emetogenic chemotherapy.
   • Second-Generation Agents: Palonosetron offers superior efficacy in both acute and delayed CINV, particularly with moderately and highly emetogenic chemotherapy. A single IV dose of palonosetron before chemotherapy is often preferred due to convenience.
   • Common Side Effects: Headache and constipation.

2. Neurokinin-1 (NK-1) Receptor Antagonists

   • Examples include aprepitant, fosaprepitant, and netupitant. These agents block the action of substance P in the brainstem and GI tract, enhancing the efficacy of antiemetic regimens.
   • Drug Interactions: NK-1 antagonists inhibit CYP3A4, necessitating dose adjustments for corticosteroids like dexamethasone.
   • Side Effects: Fatigue, hiccups (aprepitant), and constipation (netupitant).

3. Corticosteroids

   • Dexamethasone is commonly used for both acute and delayed CINV. It is particularly effective when combined with olanzapine, a 5-HT3 antagonist, and an NK-1 antagonist.
   • For patients intolerant to corticosteroids, dexamethasone can be replaced by olanzapine.

4. Dopamine Antagonists

   • Prochlorperazine and metoclopramide are suitable for low-emetogenic regimens or as rescue agents. Prochlorperazine offers multiple formulations, including oral and suppository, for ease of use.
   • Limitations: These agents can cause extrapyramidal symptoms, limiting their prolonged use.

5. Olanzapine

   • A second-generation antipsychotic, olanzapine effectively targets multiple receptors (dopamine, serotonin, histamine, and acetylcholine-muscarine) involved in nausea. It is effective as part of combination regimens or as monotherapy for breakthrough symptoms.
   • Supported for both acute and delayed nausea prevention.

6. Benzodiazepines

   • Lorazepam and alprazolam are beneficial for anticipatory nausea due to their anxiolytic and sedative effects. They are typically used alongside antiemetics.

7. Cannabinoids

   • Synthetic nabilone is a second-line agent for refractory CINV but has notable side effects such as dizziness, mood alterations, and hypotension. While medical cannabis is sometimes considered for treatment-refractory cases, it is not part of standard guidelines.

8. Antihistamines and Anticholinergics

   • Agents like dimenhydrinate and scopolamine are primarily effective for motion sickness and not recommended for CINV.

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Practical Tips for Antiemetic Therapy

1. Preferred Administration Routes:

   • Oral: Optimal for patients who can tolerate it.
   • Rectal: Useful for vomiting patients in outpatient settings.
   • IV: Recommended for hospitalized patients with severe vomiting.

2. Duration of Therapy:

   • For highly emetogenic chemotherapy (HEC): Dexamethasone and olanzapine should continue for up to two days post-chemotherapy.
   • For moderately emetogenic chemotherapy (MEC): Olanzapine may also be extended for up to two days.

3. Multiday Regimens:

   • Anti-emetics should be administered daily during multiday chemotherapy courses.

Management Algorithm for CINV Based on Risk of Emesis

1. High Emetogenic Risk (>90%)

• Acute Phase:

  • Day 1: NK-1 RA + 5-HT3 RA + Olanzapine + Dexamethasone

• Delayed Phase:

  • Days 2–4: Olanzapine + Dexamethasone
  • If aprepitant was used on Day 1, continue it on Days 2–3.

• Breakthrough Nausea/Vomiting (N/V):

  • Controlled: Continue original antiemetics until the course is completed.
  • Not Controlled: Add one or more agents with different mechanisms of action:
    • Metoclopramide
    • Prochlorperazine
    • Haloperidol
    • Lorazepam or alprazolam (if anxiety is present)
    • Olanzapine
  • If still not controlled, add a cannabinoid (e.g., nabilone).
  • If still not controlled, consider changing the chemotherapy regimen.

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2. Moderate Emetogenic Risk (31–90%)

• Acute Phase:

  • Day 1: 5-HT3 RA + Dexamethasone

• Delayed Phase:

  • Days 2–4: Dexamethasone

• Breakthrough N/V:

  • Controlled: Continue original antiemetics until the course is completed.
  • Not Controlled: Add one or more agents with different mechanisms of action:
    • Metoclopramide
    • Prochlorperazine
    • Haloperidol
    • Lorazepam or alprazolam (if anxiety is present)
    • Olanzapine
  • If still not controlled, add a cannabinoid (e.g., nabilone).
  • If still not controlled, consider changing the chemotherapy regimen.

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3. Low Emetogenic Risk (10–30%)

• Acute Phase:

  • Day 1: 5-HT3 RA, Dexamethasone, Metoclopramide, or Prochlorperazine

• Delayed Phase:

  • No prophylaxis necessary.

• Breakthrough N/V:

  • Controlled: Continue original antiemetics until the course is completed.
  • Not Controlled: Add one or more agents with different mechanisms of action:
    • Metoclopramide
    • Prochlorperazine
    • Haloperidol
    • Lorazepam or alprazolam (if anxiety is present)
    • Olanzapine
  • If still not controlled, add a cannabinoid (e.g., nabilone).
  • If still not controlled, consider changing the chemotherapy regimen.

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4. Minimal Emetogenic Risk (<10%)

• Acute Phase:

  • No prophylaxis necessary.

• Delayed Phase:

  • No prophylaxis necessary.

• Breakthrough N/V:

  • If uncontrolled in the current cycle, administer antiemetics from the next higher emetogenic category for subsequent cycles.
  • Consider lorazepam for anticipatory nausea/vomiting.

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General Notes for Breakthrough N/V

• If controlled, continue the current antiemetic regimen.
• If not controlled, consider escalating therapy:
  • Add antiemetics with differing mechanisms.
  • Use cannabinoids as secondary agents.
  • Alter the chemotherapy protocol as a last resort.