What are the toxicities of Sunitinib (Sunitinib malate)?

From the Guidelines

Sunitinib toxicity should be managed with dose interruptions or reductions, and close monitoring for hypertension, left ventricular ejection fraction, and other common toxicities is essential to minimize morbidity and mortality. The management of sunitinib-related toxicities is crucial to improve the quality of life of patients receiving this treatment. According to the study published in the Journal of the National Comprehensive Cancer Network 1, common toxicities include fatigue, nausea, vomiting, hematologic toxicities, diarrhea, abdominal pain, mucositis, anorexia, and skin discoloration. Some key points to consider in the management of sunitinib toxicity include:

• Close monitoring for hypertension and left ventricular ejection fraction is essential, especially in patients with a history of heart disease or cardiac risk 1.
• Hand-foot skin reaction (HFSR) can be prevented with routine application of emollient lotions, and dose reduction should be considered if severe 1.
• Laboratory monitoring should include complete blood counts, liver function tests, and thyroid function tests before treatment and regularly thereafter.
• Cardiac toxicity requires baseline ECG and periodic cardiac evaluation.
• Dose reductions to 37.5mg or 25mg may be necessary based on toxicity. It is also important to note that sunitinib is associated with a significant risk for developing cardiotoxicity and hypothyroidism, and the risk for hypothyroidism increases with the duration of therapy 1. Overall, the management of sunitinib toxicity requires a comprehensive approach that includes close monitoring, dose adjustments, and prompt treatment of side effects to minimize morbidity and mortality, and improve the quality of life of patients receiving this treatment.

From the FDA Drug Label

In nonclinical studies, mortality was observed following as few as 5 daily doses of 500 mg/kg (3000 mg/m 2) in rats At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection, and gastrointestinal distress. Bone abnormalities consisted of thickening of the epiphyseal cartilage of the femur and an increase of fracture of the tibia at doses ≥ 5 mg/kg (approximately 10 times the combined AUC in patients administered the RDD of 50 mg).

Toxicity of Sunitinib:

• The drug can cause mortality in rats at high doses (500 mg/kg).
• Bone abnormalities such as thickening of the epiphyseal cartilage of the femur and increase of fracture of the tibia can occur at doses ≥ 5 mg/kg.
• Signs of toxicity include impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection, and gastrointestinal distress.
• The incidence and severity of physeal dysplasia were dose-related and reversible upon cessation of treatment. 2

From the Research

Sunitinib Toxicity

• Sunitinib, a vascular endothelial growth factor receptor inhibitor, has a distinct pattern of novel side effects that require monitoring and management 3.
• The most clinically relevant toxicities of sunitinib include:
  • Fatigue
  • Diarrhea
  • Anorexia
  • Oral changes
  • Skin toxicity
  • Hypertension
• These side effects can be managed with proactive assessment and consistent treatment, allowing for optimal benefit from sunitinib therapy 3, 4.

Management of Sunitinib-Related Side Effects

• Fatigue may be partly related to the development of hypothyroidism during sunitinib therapy, and patients should be observed and treated if necessary 3.
• Hypertension can be treated with standard antihypertensive therapy and rarely requires treatment discontinuation 3.
• Neutropenia and thrombocytopenia usually do not require intervention, and no episodes of neutropenic fever have been reported to date 3.
• A decrease in left ventricular ejection fraction is a rare but potentially life-threatening side effect 3.

Individualized Sunitinib Therapy

• Individualized sunitinib therapy, based on toxicity-driven dose and schedule changes, can optimize drug exposure and outcome for each patient 5.
• This approach can lead to fewer dose reductions and discontinuations due to toxicity, and can result in improved efficacy and safety 5.

Relationship Between Sunitinib Exposure and Toxicity

• There is a established exposure-toxicity relationship for sunitinib, with higher exposure levels associated with increased toxicity 6.
• Therapeutic drug monitoring (TDM) can help optimize sunitinib exposure and minimize toxicity 6.
• Cutaneous side effects, such as genital lesions, cutaneous eruption, and hand-foot syndrome, can occur with sunitinib treatment and may require dose adjustment or discontinuation 7.