(P 41) THE IMPACT OF PAZOPANIB AND EXTREMITY RADIOTHERAPY ON TRANSAMINASES

Objective: Transaminase elevations are common adverse effects of pazopanib. In the PASART trials, approximately one-third of patients receiving concurrent pazopanib and radiotherapy experienced grade ≥3 transaminase elevations, substantially higher than expected. No clear explanation was identified. Although, alanine transaminases (ALT) and aspartate transaminase (AST) primarily originate from the liver, both are also present in muscle tissue. In patients with 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.

Methods: A prospective cohort of patients treated with extremity radiotherapy alone was combined with retrospective cohorts treated with pazopanib or both (PASART). Patient characteristics, radiation and pazopanib details, and laboratory values (liver enzymes and muscle injury biomarkers) were collected. Descriptive analyses and logistic regression were conducted to evaluate the effect of radiotherapy and pazopanib on the incidence of grade ≥3 ALT/AST elevations. Binomial probability analysis assessed the likelihood of the observed events in PASART.

Results: Among 146 patients (10 radiotherapy, 100 pazopanib, 36 PASART), none of the radiotherapy group experienced grade ≥3 ALT/AST elevations. Post-irradiation ALT/AST, creatine kinase and myoglobin elevations were minimal. Grade ≥3 ALT/AST elevations occurred in 6% of pazopanib and 36% of PASART patients. ALT/AST typically normalized after discontinuing pazopanib. Grade ≥3 ALT/AST elevations were significantly associated with pazopanib use, but not with radiotherapy or pazopanib Ctrough levels. The probability of ≥13 events (36%) in 36 patients, assuming a true event rate of 6% is < 1 in 13 million, indicating the PASART incidence exceeds the expected variability.

Conclusion: Extremity radiotherapy does not meaningfully contribute to transaminase elevations. The higher observed incidence in PASART is unlikely due to chance or radiation-induced muscle damage. The cause of transaminase elevations in PASART remains unclear.