What are the common side effects of Paclitaxel (chemotherapy agent)?

Paclitaxel Side Effects

Paclitaxel causes dose-limiting peripheral neuropathy in up to 60% of patients and severe myelosuppression requiring close monitoring, along with hypersensitivity reactions that mandate premedication with corticosteroids, diphenhydramine, and H2 antagonists before every infusion. 1

Hematologic Toxicity

Neutropenia is the primary dose-limiting hematologic toxicity of paclitaxel. 1

• Severe neutropenia (<500/mm³) occurs in 28-74% of patients depending on dose and schedule, with higher rates at 175 mg/m² compared to 135 mg/m². 1
• Grade 3-4 neutropenia occurs in 37-48% of patients according to NCCN guidelines. 2
• Thrombocytopenia is less common, with severe cases (<50,000/mm³) occurring in 2-11% of patients. 1
• Anemia requiring intervention (<8 g/dL) develops in 8-20% of patients. 1
• Frequent peripheral blood cell counts must be performed on all patients receiving paclitaxel to monitor for bone marrow suppression. 1
• Febrile neutropenia occurs in 2-23% of patients, with higher rates when combined with cisplatin. 1

Neurologic Toxicity

Peripheral neuropathy is the most clinically significant non-hematologic toxicity and is clearly dose-dependent. 1, 2

• Peripheral neuropathy occurs in 60% of all patients (3% severe) and 52% of patients without pre-existing neuropathy (2% severe). 1
• The frequency increases with cumulative dose and is observed in 27% after the first course, rising to 34-51% from courses 2-10. 1
• Severe neurosensory symptoms occur in 13% of NSCLC patients receiving paclitaxel 135 mg/m² by 24-hour infusion followed by cisplatin 75 mg/m². 1
• When paclitaxel is combined with cisplatin 75 mg/m², severe neurotoxicity is more common at 175 mg/m² by 3-hour infusion (21%) than at 135 mg/m² by 24-hour infusion (3%). 1
• Patients with pre-existing neuropathy or diabetes are at higher risk for developing peripheral neuropathy. 2
• Risk is particularly high when retreating within 12 months of prior paclitaxel-containing regimen due to cumulative neurotoxicity. 2
• Sensory symptoms typically improve or resolve within several months of discontinuation, though pre-existing neuropathies from prior therapies are not a contraindication. 1
• Peripheral neuropathy causes treatment discontinuation in 1% of all patients. 1
• Rare severe neurologic events (<1%) include grand mal seizures, syncope, ataxia, neuroencephalopathy, and autonomic neuropathy resulting in paralytic ileus. 1
• Optic nerve and visual disturbances (scintillating scotomata) occur particularly at higher doses and are generally reversible, though rare reports of persistent optic nerve damage exist. 1
• Postmarketing reports include ototoxicity (hearing loss and tinnitus), convulsions, dizziness, and headache. 1

Hypersensitivity Reactions

Anaphylaxis and severe hypersensitivity reactions occur in 2-4% of patients despite premedication, with fatal reactions reported. 1

• All patients must be pretreated with corticosteroids, diphenhydramine, and H2 antagonists before every infusion. 1
• Hypersensitivity reactions are characterized by dyspnea, hypotension requiring treatment, angioedema, and generalized urticaria. 1
• Patients experiencing severe hypersensitivity reactions should never receive paclitaxel again. 1, 2
• Infusion reactions are more common with paclitaxel than true allergic reactions (which are more common with platinum agents). 3, 2
• For patients with prior mild allergic reactions, desensitization protocols must be used with each subsequent infusion, potentially in the intensive care unit for safety. 3
• Approximately 90% of patients can be successfully desensitized. 3

Cardiovascular Toxicity

Paclitaxel causes cardiac ischemia and conduction abnormalities, particularly when combined with other cardiotoxic agents. 3

• Myocardial ischemia and infarction occur in 5% of patients, with manifestations including cardiac ischemia documented in retrospective studies. 3
• Reversible sinus bradycardia occurs with an incidence ranging from 0.1% to 31%. 3
• Bradycardia may occur directly through actions on the Purkinje system or indirectly through the formulation vehicle Cremophor EL (polyoxyethylated castor oil). 3
• Baseline ECG evaluation is recommended, with frequent vital sign monitoring during infusion. 3
• Monitoring of BNP and troponin I should be performed in patients with history of cardiac ischemia. 3
• Hypotension occurs in 17% of patients and bradycardia in 3%. 1
• When used in combination, paclitaxel enhances doxorubicin cardiotoxicity by altering doxorubicin pharmacokinetics and increasing myocyte formation of doxorubicinol. 3
• Ischemic ECG changes have been reported in up to 68% of patients, though myocyte damage with cardiac marker elevation is lacking in the majority. 3
• Coronary artery thrombosis, arteritis, and vasospasm secondary to drug exposure are proposed mechanisms. 3

Musculoskeletal Toxicity

Arthralgia and myalgia occur in 60% of all patients, with 8% experiencing severe symptoms. 1

• Symptoms are usually transient, occurring 2-3 days after administration and resolving within a few days. 1
• No consistent relationship exists between dose or schedule and the frequency or severity of arthralgia/myalgia. 1
• The frequency and severity remain unchanged throughout the treatment period. 1
• In adjuvant breast cancer treatment, patients receiving paclitaxel after AC therapy experience more Grade III/IV myalgia/arthralgia compared to AC alone. 1

Gastrointestinal Toxicity

Nausea/vomiting, diarrhea, and mucositis are common but usually mild to moderate. 1

• Nausea/vomiting occurs in 52-69% of patients. 1
• Diarrhea affects 38-79% of patients. 1
• Mucositis occurs in 31% of patients overall and is schedule-dependent, occurring more frequently with 24-hour infusion than 3-hour infusion. 1
• When combined with cisplatin, the incidence of nausea and vomiting is greater compared to single-agent paclitaxel. 1
• Severe gastrointestinal events include intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis, and dehydration. 1

Hepatic and Renal Toxicity

Hepatic enzyme elevations occur but are not consistently related to dose or schedule. 1

• Among patients with normal baseline liver function, 7% had bilirubin elevations, 22% had alkaline phosphatase elevations, and 19% had AST elevations. 1
• Prolonged exposure is not associated with cumulative hepatic toxicity. 1
• Hepatic necrosis and hepatic encephalopathy leading to death have been reported. 1
• Patients with gynecological cancers treated with paclitaxel and cisplatin have increased risk of renal failure compared to cisplatin alone. 1
• Renal insufficiency with reversible creatinine elevations occurs in some patients. 1
• Liver and renal function tests should be assessed regularly. 2

Dermatologic Toxicity

Total alopecia develops in most patients receiving paclitaxel. 1, 4

• Alopecia occurs in 46% of patients during paclitaxel treatment in adjuvant breast cancer studies. 1

Common Pitfalls and Monitoring Recommendations

• Paclitaxel should not be given to patients with solid tumors who have baseline neutrophil counts <1,500 cells/mm³ or to AIDS-related Kaposi's sarcoma patients with baseline neutrophil counts <1,000 cells/mm³. 1
• The 3-hour infusion schedule at 175 mg/m² produces more severe neurotoxicity than the 24-hour infusion at 135 mg/m² when combined with cisplatin. 1
• Adequate diagnostic and treatment facilities must be readily available, as paclitaxel should only be administered under supervision of a physician experienced in cancer chemotherapy. 1
• More severe toxicity occurs with higher doses (250 mg/m² vs 135 mg/m²) across all categories. 1