Adverse Events of Systemic Anti-Cancer Therapies (SACT)
Instructor: Shereen Nabhani-Gebara, PharmD, BCOP, SFHEA, MBOPA
Course: PY6011
Role of the Cancer Pharmacist
Significance: The role of the cancer pharmacist is becoming increasingly important due to several factors:
Increasing number of SACT: There is a growing array of systemic anti-cancer therapies being employed.
Complexity of regimens: Regimens involving SACT are becoming more complicated.
Specialized therapies: New therapies demand more specialized understanding and management.
Improved survival rates: Patients are living longer due to advancements in cancer treatment.
Co-morbidities: With longer patient survival, there is a rise in co-morbid conditions that need to be managed.
Management of toxicities: There is a crucial need for the prevention and management of both short and long-term toxicities associated with cancer treatment.
Pharmacist-led clinics: These clinics are vital for addressing the medication-related needs and complications of patients undergoing SACT.
Blood and Bone Marrow
Components of Bone Marrow
The bone marrow is essential for producing:
Red Blood Cells (RBCs)
White Blood Cells (WBCs)
Platelets
Typical counts include:
Total WBC count: 6300
Breakdown of WBC types:
Lymphocyte, Monocyte, Eosinophil, Basophil, Neutrophil.
Bone Marrow Suppression
Neutropenia
Definition: A condition characterized by a low neutrophil count, leading to a high risk of infection.
Management: Often managed with education about hygiene practices such as:
Handwashing for visitors
Wearing masks in crowded areas
Avoiding contact with sick individuals
Preventing activities that increase infection risk (e.g., changing nappies, swimming, etc).
Anemia
Symptoms of anemia: Includes fatigue, pallor, and shortness of breath.
Transfusions: Might be needed to address severe anemia.
Thrombocytopenia
Risk: Patients are at risk of bleeding.
Management: Transfusions might be necessary for critically low platelet counts.
Erythrocytes (RBCs): Frequently administered to quickly elevate hemoglobin levels.
Nadir
Definition: Refers to the lowest point of blood cell count following chemotherapy, typically occurring 7-14 days post-chemotherapy.
Absolute Neutrophil Count (ANC): Calculated using the formula:
Complications of Neutropenia
Counseling Points
Hygiene and Safety: Recommendations include:
Wash hands regularly
Avoid crowded places and sick individuals
Caution with pets and flowers.
Nausea and Vomiting
Emetogenic Potentials
Classification of drugs by emetogenic potential:
High ( >90%): Cisplatin, Doxorubicin and Cyclophosphamide
Moderate (30-90%): Doxorubicin, Carboplatin
Low (10-30%): Docetaxel
Minimal ( <10%): Bevacizumab, Vincristine
Pathophysiology of Nausea & Vomiting
Involves an interaction among various mediators including:
5-HT3 receptors
Dopamine receptors (D2)
Histamine (H1)
Acetylcholine (ACh)
Substance P
The vomiting center is located in the brain stem and can be triggered by:
Vagal and sympathetic afferents.
Management of Nausea and Vomiting
Prokinetics: Metoclopramide
Antihistamines: Cyclizine, Promethazine
Dopamine antagonists: Haloperidol, Olanzapine
5-HT3 antagonists: Ondansetron
NK1 antagonists: Aprepitant
Types of Nausea/Vomiting
Acute: Managed with prophylactic combinations within 30 minutes before chemotherapy.
Delayed: Managed with dexamethasone in combinations.
Anticipatory: Managed with Lorazepam for anxiety and nausea.
High Emetic Risk Anti-Emetic Regimen Recommendations
Day 1 Options:
Treatment Option A (preferred):
Olanzapine 2.5–10 mg PO once daily
NK1 receptor antagonist
Aprepitant 125 mg PO once
Or its injectable form
5-HT3 receptor antagonist; select one based on specific treatment
Dolasetron 100 mg PO once, or others as specified
Dexamethasone 12 mg PO/IV once
Follow-up Dose Management for Days 2-4:
Continue the use of combinations including Olanzapine and CORTICOSTEROIDS depending on patient needs.
Gastrointestinal Toxicities
Diarrhea
Causes: 5FU (Capecitabine), irinotecan
Treatment: - Loperamide 2 mg every 2 hrs until 12 hrs of being stool-free.
Constipation
Causes: Opioids, Vinca alkaloids (e.g. Vincristine)
Management: Use appropriate laxatives for prophylaxis and treatment.
Mucositis
Causes: 5FU, significant complication observed with combinations
Management: Good oral hygiene, mouthwashes, and ice chips during infusion (particularly with oxaliplatin).
Nephrotoxicity
Overview
Culprit Drug: Cisplatin, noted for having a 25-40% incidence rate of nephrotoxicity.
Mechanism of Action (MOA): Involves inter-strand cross-links with DNA in renal tubular cells altering water and electrolyte handling.
Indicators: Increase in serum creatinine and decrease in urine output, potassium and magnesium levels.
Prevention
Hydration: Strategic hydration protocols to mitigate nephrotoxicity.
Use of Mannitol: To protect kidneys mens synch
e.Required urine output (UOP): Maintain at 100 ml/hr.
Hemorrhagic Cystitis
Associated Drug: Ifosfamide
Mechanism: Bi-product of acrolein is toxic.
Prevention Methods: Using Mesna and ensuring hydration during treatment.
Neurotoxicity
Peripheral Nervous System
Symptoms: Peripheral neuropathy, paresthesia developing slowly.
Notable Drugs: Vinca alkaloids, monitored for cumulative doses (e.g., Cisplatin at 300 mg/m²).
Central Nervous System
Notable Drugs: Cytarabine (ARA-C) can cause cerebellar toxicity at high doses (1-3 g/m²) with symptoms like ataxia.
Intrathecal Methotrexate: Can lead to chemical meningitis characterized by headaches, nausea/vomiting, and stiff neck; requires steroids for management.
Hepatotoxicity
Overview
Mainly asymptomatic but drug dosages require caution due to hepatic metabolism involvement.
Key Drugs: Anthracyclines (e.g., Doxorubicin, Epirubicin, Daunorubicin) necessitate careful monitoring of liver enzymes (e.g. bilirubin).
Dermatological Toxicities
Palmar-Plantar Erythrodysesthia (PPE)
Commonly Associated With: Capecitabine leading to skin conditions and discomfort.
Extravasation
Mechanism
Definition: Leakage of chemotherapeutic agents outside the vessel due to needle dislodgement.
Drugs Involved: Doxorubicin, Vincristine, Taxotere.
Effects:
Irritants: Pain, inflammation
Vesicants: Significant risks include indurations, burning, or necrosis.
Ocular Toxicity
Symptoms
Associated with targeted therapies leading to chemical conjunctivitis, blurred vision, and pain particularly following high doses of Cytarabine.
Management
Preventive measures include using steroid eye drops throughout treatment and 2 days post-therapy.
Otological Toxicity
Symptoms
Cisplatin associated with high frequency hearing loss and coclear damage, irreversible damage without baseline hearing evaluations prior to treatment.
Immune Checkpoint Inhibitors (ICIs)
Overview
Mechanism: Tumors exploit CTLA-4 and PD1/PD-L1 pathways, downregulating T-cell activity; ICIs help prevent this.
Efficacy: ICIs have transformed outcomes for melanoma and NSCLC (Non-Small Cell Lung Cancer).
Prominent Drugs Include:
Atezolizumab (PD-L1 Inhibitor)
Pembrolizumab (PD-1 Inhibitor)
Mechanism of Action Comparison: Chemotherapy vs. Immune Checkpoint Inhibitors
Chemotherapy: Targets rapidly dividing cells indiscriminately, including both cancer and healthy cells.
ICIs: Modulates the immune system by inhibiting checkpoints, preferentially enhancing anti-tumor immune response.
Toxicity Management Differences:
Chemotherapy: Commonly includes nausea, vomiting, anemia, enhanced infection susceptibility. Treatment requires supportive care (antiemetics, antivirals).
ICIs: Immune-related side effects may include skin reactions, colitis, endocrinopathies, etc. Require corticosteroids, monitoring, and potential treatment delays.
Immune-Related Adverse Events (irAEs)
Characteristics
Delayed onset: occur weeks to months post-therapy.
Common Organ Systems Affected:
Skin: Rash, pruritus
Gastrointestinal: Diarrhea, colitis
Endocrine: Hypothyroidism, adrenal insufficiency, diabetes
Lungs: Pneumonitis
Liver: Hepatitis
Kidneys: Nephritis
Cardiac: Myocarditis
Hematologic: Immune thrombocytopenia
Treatment Strategies for irAEs
Management based on Severity:
Mild (Grade 1): Symptomatic care without stopping immunotherapy.
Moderate (Grade 2): May require pausing treatment, starting corticosteroids.
Severe (Grade 3-4): Need high-dose corticosteroids; potential reassessment if rechallenge indicated.
Endocrine Toxicity:
Requires lifelong hormone replacement therapy, treatment does not stop immunotherapy.
Follow-Up and Quality of Life Monitoring
Key Aspects
Long-Term Monitoring: Continuous organ function assessment and blood counts are vital to identify delayed irAEs.
Late-Onset Toxicity: Monitoring extends beyond one year post-treatment is critical.
Quality of Life Assessment: Evaluating physical, emotional, and psychosocial wellness facilitates targeted therapeutic interventions.
Specialized Follow-Up Programs
Clinics that provide lifelong care to manage chronic complications post-immunotherapy.
Reflect and Feedback
Key Reflection Questions
How can equitable cancer care be provided for diverse populations?
What protected characteristics and factors may lead to suboptimal experiences? Examples include age, race/ethnicity, and religion.
Cardio-Oncology
Definition
The rapidly developing field that addresses the cardiovascular care of individuals receiving anti-cancer therapies.
Focuses on prevention, early detection, and management of cardiotoxicities.
Contextual Overview
The rising incidence of cardiovascular disease among cancer patients: aging populations, improving survival rates, and increased prevalence of pre-existing cardiovascular disease.
Monitoring Cardiotoxicity in Cancer Patients
Risk Factors
Pre-existing cardiovascular disease and its risk factors (modifiable).
Cancer Treatments with Risks
Chemotherapy Regimens: Notably anthracyclines and trastuzumab are linked to left ventricular dysfunction.
Regular monitoring recommended for baseline cardiovascular risk factors and with continued assessments.
Cardiotoxicity Management
Commonly Identified Conditions
Heart Failure: Cumulative life-time doses (e.g., doxorubicin at 450 mg/m²) may lead to irreversible conditions unless monitored and treated appropriately.
Hypertension and QTc Prolongation: Assessment tools for cardiovascular management during therapy are essential.
Arrhythmias and Atrial Fibrillation: Early cardio-oncology consultations facilitate proper management of risks, engendering lifestyle adjustments and medication evaluations.
Drug Interactions in Cancer Therapy
Overview
Complex regimens increase the risk of pharmacological interactions impacting both efficacy and toxicity.
Common Interactions
Pharmacokinetic Interactions: Involve multiple liver enzyme pathway interactions including CYP450 enzymes affecting drug metabolism.
Identifying and Managing Cardiotoxicity in Study Cohort
Study Design
A retrospective cohort study approved by The Royal Marsden NHS Foundation Trust with a target period spanning from 2017-2019.
Patient Inclusion
Non-small cell lung cancer (NSCLC) patients who received anti-cancer agents aligning with study constraints.
Conclusion
Summary of Findings
Data detailing distributions of cardiotoxicities, risk factors for developing cardiotoxicities, and therapeutic management will remain the focus of ongoing analysis in future sessions.
Emphasis on Monitoring Practices
Continuous assessment protocols are imperative for successful interventions and patient safety.
Case Study Patient GH
Overview
A cis-gender woman diagnosed with Grade 3 invasive ductal breast cancer undergoing chemotherapy.
Treatment and Monitoring Outcomes
Regular cardiac evaluations post-treatment to measure ejection fraction changes, adapting therapeutic approaches in response to evolving cardiovascular health throughout her treatment informs both oncology and cardiology teams.
Final Thoughts
Collaboration among healthcare professionals, continuous education, and patient engagement are foundational for advancing cancer care and achieving optimal outcomes.