The impact of pazopanib and extremity radiotherapy on transaminase elevations in soft tissue sarcoma

BACKGROUND AND PURPOSE: Unexpected high rates of grade ≥ 3 transaminase elevations were observed in patients receiving pazopanib and extremity radiotherapy. Although alanine transaminase (ALT) and aspartate transaminase (AST) primarily originate from the liver, both are also present in muscle tissue. In extremity soft tissue sarcomas (STS), where large muscle volumes are within the radiation field, radiation-induced muscle damage may contribute to these elevations. This study evaluated the impact of extremity radiotherapy, pazopanib, and their combination on the incidence and degree of ALT/AST elevations in STS patients. PATIENTS AND METHODS: A prospective cohort treated with extremity radiotherapy alone was combined with a retrospective cohort treated with pazopanib alone or in combination. Patient characteristics, treatment details, and laboratory values (liver enzymes and muscle injury biomarkers) were collected. Descriptive analyses and logistic regression were conducted to evaluate the association with grade ≥ 3 ALT/AST elevations. RESULTS: Among 154 patients (10 radiotherapy, 108 pazopanib, 36 radiotherapy plus pazopanib), none of the radiotherapy-only patients experienced grade ≥ 3 elevations. Post-irradiation ALT/AST, creatine kinase and myoglobin elevations were minimal. Grade ≥ 3 elevations occurred in 6% of patients receiving pazopanib and 36% of those receiving both radiotherapy and pazopanib. All elevations typically resolved after pazopanib discontinuation. Grade ≥ 3 elevations were significantly associated with pazopanib, and modestly associated with pazopanib trough levels (odds ratio [OR]: 1.43 per 10 mg/L, 95% confidence interval [CI]: 1.12-1.90), but not with radiotherapy. INTERPRETATION: Adding pazopanib to radiotherapy in localised extremity sarcoma significantly increases the rate of AST/ALT elevations. Extremity radiotherapy alone does not induce clinically relevant transaminase elevations. Grade ≥ 3 elevations were associated with pazopanib treatment. The mechanism underlying the substantially higher incidence of transaminase elevations with combined pazopanib and radiotherapy, compared with pazopanib alone, remains unknown.