Chemotherapy-Induced Nausea and Vomiting (CINV) Treatment Protocol

Objective:
To outline first- and second-line treatments for CINV, including manufacturer dosing instructions and recommendations based on clinical guidelines.

1. First-Line Treatments for CINV

1. Ondansetron (Zofran)

   • Class: 5-HT3 receptor antagonist

   • Indication: Prevention and treatment of acute CINV

   • Dosage:

     • Prevention: 8-16 mg orally, 30 minutes before chemotherapy.

     • IV dose: 8 mg, given 30 minutes prior to chemotherapy, can be repeated after 4 hours.

   • Manufacturer Instructions: Administer IV over at least 15 minutes. Maximum recommended oral dose is 24 mg/day.

   • Mechanism: Blocks serotonin receptors (5-HT3) in the central nervous system and gastrointestinal tract to prevent nausea and vomiting.

   • Notes: Generally well-tolerated, though some patients may experience constipation or headaches.

2. Aprepitant (Emend)

   • Class: NK1 receptor antagonist

   • Indication: Prevention of acute and delayed CINV in combination with 5-HT3 antagonists and corticosteroids

   • Dosage:

     • Prevention: 125 mg orally 1 hour before chemotherapy on day 1, followed by 80 mg orally on days 2 and 3.

   • Manufacturer Instructions: Administer the oral capsule with or without food.

   • Mechanism: Blocks substance P from binding to NK1 receptors in the brain, reducing vomiting signals.

   • Notes: Often used in combination with other agents like ondansetron and dexamethasone for high emetic-risk chemotherapy regimens.

3. Dexamethasone (Decadron)

   • Class: Corticosteroid

   • Indication: Prevention of both acute and delayed CINV, often used in combination with 5-HT3 antagonists and NK1 antagonists

   • Dosage:

     • Prevention: 12 mg orally or IV on day 1 of chemotherapy, followed by 8 mg on days 2-4 (for highly emetogenic chemotherapy).

   • Manufacturer Instructions: Administer IV over 1-4 minutes or orally with or without food.

   • Mechanism: Suppresses inflammation and reduces prostaglandin synthesis, which may reduce nausea. Enhances efficacy of other antiemetic drugs.

   • Notes: Side effects may include hyperglycemia, especially in patients with diabetes, and mood disturbances.

2. Second-Line Treatments for CINV

1. Metoclopramide (Reglan)

   • Class: Dopamine (D2) receptor antagonist and prokinetic agent

   • Indication: Treatment of breakthrough or delayed CINV

   • Dosage:

     • Prevention: 10-20 mg orally or IV, administered before chemotherapy.

     • Treatment: 10-20 mg IV every 6 hours for breakthrough CINV.

   • Manufacturer Instructions: Administer IV slowly over 1-2 minutes to avoid adverse reactions like restlessness or dystonia.

   • Mechanism: Inhibits dopamine receptors in the chemoreceptor trigger zone, while enhancing gastric motility to prevent nausea.

   • Notes: Extrapyramidal symptoms are common, particularly at higher doses or in younger patients.

2. Prochlorperazine (Compazine)

   • Class: Dopamine (D2) receptor antagonist

   • Indication: Treatment of breakthrough CINV when first-line therapies fail

   • Dosage:

     • Treatment: 5-10 mg orally every 6-8 hours as needed or 5-10 mg IV/IM every 3-4 hours as needed.

   • Manufacturer Instructions: Administer IV slowly to reduce the risk of hypotension.

   • Mechanism: Blocks dopamine receptors in the chemoreceptor trigger zone to reduce nausea and vomiting.

   • Notes: Sedation and extrapyramidal symptoms are common, especially in elderly patients. Use with caution in those prone to falls.

3. Olanzapine (Zyprexa)

   • Class: Atypical antipsychotic (off-label for CINV)

   • Indication: Treatment of breakthrough and delayed CINV

   • Dosage:

     • Prevention: 5-10 mg orally on days 1-4, starting on the day of chemotherapy.

     • Treatment: 5-10 mg orally as needed for breakthrough CINV.

   • Manufacturer Instructions: Can be taken with or without food.

   • Mechanism: Blocks multiple neurotransmitters, including dopamine and serotonin, involved in the vomiting reflex.

   • Notes: Sedation is a common side effect, so it’s often given at bedtime. Avoid in patients with known metabolic syndrome or diabetes.

3. Combination Therapy

• For Highly Emetogenic Chemotherapy (e.g., cisplatin, AC regimen):

  • Combine ondansetron (5-HT3 antagonist) + aprepitant (NK1 antagonist) + dexamethasone for maximal control of acute and delayed CINV.

• For Moderately Emetogenic Chemotherapy (e.g., carboplatin):

  • Combine ondansetron with dexamethasone as the first-line option. Add aprepitant for patients at higher risk of nausea or vomiting.

4. Monitoring and Follow-Up

• Acute CINV: Monitor for symptom relief within 30 minutes to 4 hours after chemotherapy.

• Delayed CINV: Assess for nausea or vomiting occurring more than 24 hours post-chemotherapy, often requiring additional dosing of NK1 receptor antagonists or corticosteroids.

• Breakthrough CINV: Treat promptly with second-line agents like prochlorperazine, metoclopramide, or olanzapine if first-line treatments fail.

5. Patient Education

• Instruct patients on the importance of adhering to scheduled doses, especially for delayed CINV prevention.

• Warn about potential side effects such as constipation (with 5-HT3 antagonists) or sedation (with dopamine antagonists or olanzapine).

• Encourage patients to report any breakthrough nausea promptly to adjust treatment.

6. Considerations for Treatment Choice

• Risk Factors: Tailor treatment to patient-specific factors, such as history of CINV, age, and concurrent use of emetogenic drugs (e.g., opioids).

• Combination Therapy: Combining antiemetics from different classes (e.g., 5-HT3 antagonists, NK1 antagonists, and corticosteroids) increases efficacy in high-risk patients.

Tumor markers are molecules produced by cancer cells or by normal cells in response to the presence of cancer. They can be detected in blood, urine, or tissues and are crucial for diagnosing, monitoring, and prognosticating various cancers. At the PhD/MD level, understanding tumor markers requires in-depth knowledge of the molecular pathways, protein-molecule interactions, and signal transduction mechanisms involved in their production and regulation.

For example:

1. Prostate-Specific Antigen (PSA)
   PSA is produced by prostate epithelial cells. Increased PSA in the blood is a marker for prostate cancer or benign prostatic hyperplasia (BPH). PSA gene expression --> PSA protein synthesis (via mRNA translation) --> PSA secretion into bloodstream ↑ in malignancy due to disrupted prostate gland architecture.

2. Alpha-Fetoprotein (AFP)
   AFP is normally produced during fetal development but becomes a marker in hepatocellular carcinoma. AFP gene transcription ↑ due to oncogenic mutations --> ↑ AFP translation and secretion --> AFP binding to receptors on liver cells --> downstream signaling pathways like PI3K/AKT and MAPK --> cell proliferation and survival ↑. AFP ↔ Albumin (structural similarity) may affect interactions with albumin-binding proteins.

3. Carcinoembryonic Antigen (CEA)
   CEA is associated with colorectal cancer. Oncogene mutations (e.g., KRAS, BRAF) --> transcriptional activation ↑ of CEA --> CEA protein synthesis --> CEA cell-surface expression --> ↑ cell adhesion, contributing to metastasis. CEA ↔ E-Cadherin modulates epithelial-mesenchymal transition (EMT), influencing cell invasiveness.

4. CA-125
   CA-125 is commonly used in monitoring ovarian cancer. Mutations in TP53 ↔ BRCA --> CA-125 gene upregulation ↑ --> increased production and release of CA-125 --> binds to mesothelin on mesothelial cells --> mesothelial-ovarian tumor interactions → promotes metastasis and peritoneal dissemination.

5. Human Chorionic Gonadotropin (hCG)
   Elevated hCG is a marker for trophoblastic diseases and some testicular cancers. Syncytiotrophoblast cells ↑ hCG production --> hCG release into circulation --> hCG binds to LH/hCG receptors on reproductive cells --> downstream activation of cyclic AMP (cAMP) pathways --> increased cell proliferation and resistance to apoptosis. hCG ↔ FSH (homology in structure) impacts receptor binding and signaling specificity.

6. Cancer Antigen 19-9 (CA 19-9)
   CA 19-9 is elevated in pancreatic cancer. KRAS mutations → PI3K/AKT and MAPK signaling ↑ --> increased synthesis of CA 19-9 glycoprotein --> secretion and circulation ↑ --> CA 19-9 ↔ Sialyl-Lewis A antigen interaction modulates immune evasion by tumor cells.

7. Lactate Dehydrogenase (LDH)
   LDH is a marker for several malignancies, including lymphoma and testicular cancer. Tumor cells ↑ anaerobic glycolysis (Warburg effect) --> ↑ LDH activity converting pyruvate ↔ lactate (equilibrium) --> lactate accumulation → promotes angiogenesis and immune escape in the tumor microenvironment. LDH-5 isoform ↑ correlates with aggressive cancer phenotypes.

Each marker is reflective of dynamic changes in cellular metabolism, gene expression, and molecular pathways, often involving complex feedback loops where ↑ tumor cell proliferation or ↓ apoptosis drives cancer progression. Monitoring these markers in the blood provides insights into tumor burden, therapeutic response, and metastatic potential.

Protocol: Medical Cannabis for Chemotherapy-Induced Symptom Management

Objective:
To provide a standardized approach for utilizing medical cannabis to manage chemotherapy-induced nausea and vomiting (CINV), pain, and sleep disturbances in patients who do not achieve adequate symptom relief with standard medications.

1. Indications for Medical Cannabis Use
Medical cannabis should be considered for:

• Chemotherapy-induced nausea and vomiting (CINV) when standard treatments (e.g., ondansetron, Marinol) are ineffective.

• Chemotherapy-related pain, especially when opioids are insufficient or poorly tolerated.

• Sleep disturbances due to chemotherapy or associated stress.

2. Treatment Goals

• Reduction of nausea and vomiting by 60-70%

• Improvement in sleep onset and duration

• Daytime anxiety and pain management without sedation or cognitive impairment

3. Dosing and Formulations

Nausea/Vomiting (CINV)

• Formulation: THC-dominant or THC
  sublingual or vaporized products.

• Initial Dose: 2.5-5 mg THC for cannabis-naive patients (sublingual or vaporized).

• Titration: Increase gradually based on symptom relief and tolerance. Monitor closely for side effects.

• Efficacy Goal: Achieve a 60-70% reduction in nausea.

Pain Management

• Formulation: THC
  (balanced 1:1 ratio) product, with a focus on beta-myrcene (higher concentrations).

• Initial Dose: 2.5-5 mg THC, adjusted based on patient’s experience with cannabis and pain severity.

• Titration: Adjust dose upwards by 2.5 mg as tolerated, aiming for pain relief without excessive sedation.

Sleep Disturbances

• Formulation: THC
  (1:1 ratio) with high beta-myrcene content to aid sleep onset and duration.

• Initial Dose: 2.5-5 mg THC/CBD taken 1 hour before bedtime.

• Efficacy Goal: Promote quicker sleep onset and longer duration of restful sleep.

• Considerations: Monitor for adverse effects like dizziness, psychoactivity, or next-day fatigue.

Daytime Anxiety/Pain (Functional Use)

• Formulation: High-CBD product (20:1 CBD
  ratio) with calming terpenes (limonene, linalool, beta-myrcene in low concentration).

• Initial Dose: 10-20 mg CBD, with minimal THC content to avoid euphoria or sedation.

• Titration: Adjust CBD dosage based on daytime symptom control without impairing daily function.

4. Patient Assessment and Monitoring

• Pre-Treatment Assessment: Evaluate patient’s goals, medical history, current medications, allergies, and previous experience with cannabis.

• Contraindications: Review for any drug interactions or contraindications based on current chemotherapy regimen.

• Monitoring: Assess patient regularly for symptom relief, adverse reactions (e.g., sedation, psychoactivity), and overall well-being. Adjust dose/formulation as necessary.

5. Education and Counseling

• Educate the patient on starting with low doses and slowly titrating up to minimize adverse effects.

• Discuss the entourage effect of cannabis (synergistic interaction between cannabinoids and terpenes) to explain why cannabis may be more effective than isolated THC (Marinol).

• Review the importance of choosing appropriate formulations for specific symptoms (e.g., sublingual or vaporized for rapid relief, oral for prolonged effects).

6. Communication

• Regular communication between the patient and healthcare provider is essential to optimize treatment.

• Encourage the patient to report any side effects or concerns promptly.

Contact Information
For further support or to schedule a consultation, contact:
Dr. Terel Newton
Email: Terel.Newton@Trulieve.com | DrTerelNewton@gmail.com