Hypertension in patients receiving sunitinib should be controlled with standard antihypertensive therapies. A temporary interruption in therapy is recommended if severe hypertension develops; treatment can resume when hypertension is controlled.2

Hemorrhage was reported in clinical trials of these kinase inhibitors, including grade 3/4 hemorrhage with imitanib in patients with newly diagnosed chronic myelogenous leukemia (CML) and unresectable or metastatic GIST. However, in a randomized trial comparing imatinib and nilotinib in newly diagnosed Ph+ CML, GI hemorrhage occurred but was not grade 3/4.1


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Regorafenib should be permanently discontinued in patients who develop severe or life-threatening hemorrhage. INR levels should be monitored more frequently in patients receiving warfarin.3

Nosebleeds were the most common form of hemorrhage reported in patients taking sunitinib; less common bleeding events including rectal, gingival, upper gastrointestinal, genital, and wound bleeding. Tumor-related hemorrhage may occur suddenly, with treatment-emergency grade 3 and 4 hemorrhage observed as early as cycle 1 and as late as cycle 6 in patients with GIST. Clinical assessment of tumor-related hemorrhage should include serial complete blood counts and physical examinations.2

OTHER SIGNIFICANT WARNINGS

Imatinib Patients receiving imatinib should be weighed regularly, with careful investigation of any unexpected rapid weight gain.1 Higher dose and age older than 65 years increase the probability of edema. Severe fluid retention should be managed with drug interruption and diuretics.

Patients should be advised to use caution regarding driving or operating machinery, as dizziness, blurred vision, and somnolence have been reported. Other reported adverse events include gastrointestinal perforation; bullous dermatologic reactions such as erythema multiforme and Stevens-Johnson syndrome; and growth retardation in children and preadolescents.1

Regorafenib Adverse reactions involving the skin and subcutaneous tissues occur more often in patients treated with regorafenib, including hand-foot skin reaction (HFSR), grade 3 rash, serious adverse reactions of erythema multiforme, and Stevens-Johnson syndrome.3 Incidence of all grades of HFSR was higher in Asian patients. Recommended management is dose reduction or permanently discontinue therapy on the basis of severity and persistence of dermatologic toxicity.

Although rare, reversible posterior leukoencephalopathy (RPLS), which occurred in 1 of 1200 patients receiving regorafenib in clinical trials, should be suspected in patients presenting with seizures, severe headache, visual disturbances, confusion, or altered mental function. Discontinue treatment for any patient who develops RPLS. Treatment should be discontinued if the patient develops gastrointestinal perforation or fistula, also rare (0.6% of 1200 patients across all clinical trials).

Formal studies of the effect of regorafenib on wound healing have not been conducted; however, vascular endothelial growth factor receptors (VEGFR) can impair wound healing. Therefore, discontinuing treatment at least 2 weeks prior to scheduled surgery is recommended. Resume treatment on the basis of clinical judgment of adequate wound healing; discontinue treatment in patients with wound dehiscence.3

Sunitinib Tumor lysis syndrome (TLS) has been reported, primarily occurring in patients with GIST or renal cell carcinoma.2 Patients at risk for TLS were those with a high tumor burden prior to treatment. Management includes monitoring and treatment as clinically indicated.