What are the side effects of Irinotecan (Camptosar) and how are they managed?

Irinotecan Side Effects and Management

Irinotecan causes two distinct patterns of diarrhea (early cholinergic and delayed life-threatening), severe neutropenia, and multiple other toxicities that require specific prophylactic and treatment strategies based on established guidelines. 1

Major Side Effects

Diarrhea (Most Critical Toxicity)

Early-Onset (Acute) Diarrhea:

• Occurs immediately during or shortly after infusion due to acetylcholinesterase inhibition 2
• Accompanied by cholinergic symptoms: abdominal cramping, rhinitis, lacrimation, salivation, diaphoresis, flushing, intestinal hyperperistalsis, and bradycardia 2
• Management: Atropine 0.25-1 mg subcutaneously or intravenously 2
• Prophylaxis: Atropine 0.5 mg subcutaneously before infusion 2
• Mean duration is only 30 minutes 2

Delayed-Onset (Late) Diarrhea:

• Begins 6-14 days after administration 2
• Occurs in 50-80% of patients, with grade 3-4 severity in ≥30% 1
• Potentially life-threatening, especially when combined with neutropenia 1, 3
• Grade 3-4 late diarrhea occurs in up to 40% of patients 2
• Management: Loperamide is the primary treatment 1
• Octreotide and tinctura opii are recommended for refractory cases 1
• Octreotide LAR 30 mg dose is adequate for most patients 4

Hematologic Toxicity

Neutropenia:

• Severe (grade 3-4) neutropenia occurs in 30-40% of patients 1, 5
• Generally short-lived but may be severe when combined with diarrhea 6
• Weekly dosing schedule: Grade 3/4 neutropenia in 54% of patients 3
• Three-weekly dosing: Grade 3/4 leukopenia/neutropenia in 22% of patients 3
• Risk of febrile neutropenia is <20% for irinotecan-based chemotherapy 1

Other Hematologic Effects:

• Anemia: Grade 3/4 in 7% of patients 3
• Thrombocytopenia: Grade 3/4 in 1% of patients 3

Gastrointestinal Toxicity (Beyond Diarrhea)

• Nausea: 70-86% of patients (grade 3-4: 14-17%) 3
• Vomiting: 62-67% of patients (grade 3-4: 14%) 3
• Abdominal cramping/pain: 57% (grade 3-4: 14-16%) 3
• Anorexia: 44-55% (grade 3-4: 5-7%) 3
• Constipation: 30-32% (grade 3-4: 10%) 3
• Mucositis: 2% (grade 3-4: 2%) 3

Antiemetic Prophylaxis:

• For moderate emetogenic chemotherapy (FOLFIRI, FOLFOX): 5-HT3-receptor antagonist (palonosetron preferred) + dexamethasone 8 mg on day 1 1
• Delayed phase (days 2-3): Dexamethasone 8 mg, alternatively 5-HT3-RA 1
• NK-1-receptor antagonist (aprepitant) is not routinely recommended but may benefit selected patients if standard prophylaxis fails 1

Dermatologic Toxicity

• Alopecia: 60-72% of patients 3, 6
• Sweating: 16% 3
• Rash: 13% (grade 3-4: 1%) 3

Constitutional Symptoms

• Asthenia: 76% (grade 3-4: 12-15%) 3
• Fever: 45% (grade 3-4: 1-2%) 3
• Pain: 24% (grade 3-4: 2%) 3
• Headache: 17% (grade 3-4: 1%) 3

Respiratory Effects

• Dyspnea: 22% (grade 3-4: 4%) 3
• Coughing: 17% 3
• Rhinitis: 16% 3

Metabolic and Hepatic Effects

• Dehydration: 15% (grade 3-4: 4%) 3
• Weight loss: 30% (grade 3-4: 1%) 3
• Elevated alkaline phosphatase: 13% (grade 3-4: 4%) 3
• Elevated transaminases (AST/ALT) in absence of progressive liver metastasis 3
• Hyponatremia, mostly with diarrhea and vomiting 3

Cardiovascular Effects

• Vasodilation/flushing: 11% 3
• Myocardial ischemic events have been observed 3
• Thromboembolic events reported 3

Neurologic Effects

• Insomnia: 19% 3
• Dizziness: 15% 3
• Transient dysarthria (attributed to cholinergic syndrome) 3
• Akathisia: 8.5% when prochlorperazine given same day as irinotecan vs 1.3% when given on separate days 3

Rare but Serious Effects

• Symptomatic pancreatitis and asymptomatic pancreatic enzyme elevation 3
• Fungal and viral infections 3
• Interaction with neuromuscular blocking agents: Irinotecan has anticholinesterase activity that may prolong suxamethonium effects and antagonize non-depolarizing drugs 3

Genetic Considerations: UGT1A1 Polymorphisms

Critical Pharmacogenetic Factor:

• Irinotecan is inactivated by UGT1A1 enzyme 1
• UGT1A1*28 homozygotes have 3.5-fold increased risk of severe (grade 3/4) neutropenia 1
• UGT1A1*28 homozygotes have 1.6-fold increased risk of severe diarrhea (not statistically significant) 1
• FDA label warning: Reduced starting dose required for patients homozygous for UGT1A1*28 1

Dosing Based on Genotype:

• Maximum tolerated dose every 3 weeks: 850 mg (*1/*1), 700 mg (*1/*28), 400 mg (*28/*28) 1

Clinical Approach:

• Use irinotecan with caution and decreased dose in Gilbert syndrome or elevated serum bilirubin 1
• UGT1A1 testing in patients who already experienced irinotecan toxicity is NOT recommended—they require dose reduction regardless of test result 1
• Commercial tests available for UGT1A1*28 allele detection 1

Dose-Dependent Toxicity Patterns

Weekly Schedule (125 mg/m²):

• Grade 3/4 diarrhea: 31% (late), 15% (early) 3
• Grade 3/4 neutropenia: 54% 3

Three-Weekly Schedule (350 mg/m²):

• Grade 3/4 diarrhea: 22% 3
• Grade 3/4 leukopenia/neutropenia: 22% 3

Critical Management Pitfalls

Avoid These Errors:

• Never use antimotility agents (loperamide) in bloody diarrhea or suspected STEC infection 7
• Do not routinely use anticholinergics for diarrhea management—they increase risk of severe outcomes from C. difficile and C. perfringens 7
• Prochlorperazine should be given on separate days from irinotecan to reduce akathisia risk from 8.5% to 1.3% 3
• Monitor closely for combined neutropenia and diarrhea—this combination is life-threatening 1, 6

Hepatic Dysfunction Considerations

• Patients with hepatic insufficiency are at greater risk for irinotecan-induced toxicity 4
• Dose adjustment required based on degree of hepatic insufficiency 4
• "Chemo liver" can develop in neoadjuvant colorectal cancer setting 4

Mortality Risk

• 3.5% of patients died within 30 days of treatment in phase 3 studies 3
• 1% of deaths potentially related to irinotecan: neutropenic infection, grade 4 diarrhea, and asthenia 3
• Hospitalizations due to serious adverse events occurred in 60% of patients 3