Doxorubicin is a standard of care in patients with advanced inoperable soft-tissue sarcoma. In the EPAZ study, German researchers tested whether pazopanib showed comparable efficacy to doxorubicin in the first-line treatment of elderly patients with soft-tissue sarcoma. Grünwald et al reported in the Journal of Clinical Oncology that pazopanib demonstrated noninferior efficacy to doxorubicin in first-line treatment of elderly patients with soft-tissue sarcoma, with improvement in treatment-related myelotoxicity.
Approximately 40% of patients with soft-tissue sarcoma are aged 65 or older. A retrospective analysis in elderly patients indicated that being age 80 or older, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, and a large number of metastatic sites were associated with poor median overall survival, and indicated that younger and fitter patients were more likely to receive systemic therapy in clinical practice. Furthermore, a low percentage of patients 65 or older are included in clinical trials.
Treatment with doxorubicin, a drug predominantly used in systemic therapy for advanced or metastatic soft-tissue sarcoma, is associated with adverse events such as neutropenia and febrile neutropenia. Given the vulnerability of geriatric patients, chemotherapy endangers this patient population and, as a consequence, hospitalization is frequently required.
Pazopanib is a tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor. It is associated with limited hematologic toxicity and has a global health status comparable to that of placebo. It is the standard of care in advanced and metastatic soft-tissue sarcoma after failure of treatment with anthracyclines.
EPAZ Trial Design
The study team assumed that the lack of severe hematologic toxicity would make pazopanib a suitable candidate for first-line treatment of elderly patients with soft-tissue sarcoma, thus minimizing the risk of febrile neutropenia. They designed the EPAZ trial to test whether pazopanib was noninferior to doxorubicin in patients with soft-tissue sarcoma aged 60 or older, while offering a better risk-benefit ratio for neutropenia and febrile neutropenia. Treatment-naive patients with an ECOG performance status of 0 to 2 and adequate organ function were included. Treatment consisted of pazopanib at 800 mg once per day or doxorubicin at 75 mg/m2 once every 3 weeks for six cycles after patients were randomly assigned in a 2:1 ratio.
Noninferiority was assumed for progression-free survival, if the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) was less than 1.8. Neutropenia and febrile neutropenia were key secondary endpoints. The European Organisation for Research and Treatment of Cancer (30-item) Quality of Life Questionnaire and geriatric assessment were used to measure patient-reported outcomes.
Pazopanib and doxorubicin were given to 81 and 39 patients, respectively. The median age was 71 years (range = 60–88 years).
Progression free-survival on the pazopanib arm was noninferior (HR = 1.00, 95% CI = 0.65–1.53). The incidence of grade 4 neutropenia and febrile neutropenia favored treatment with pazopanib. The objective response rates for pazopanib and doxorubicin were 12.3% and 15.4%, respectively. Overall survival did not differ significantly between arms.
Geriatric assessment revealed two or more comorbidities in 15.8% of the patients and impairment of activities of daily living in 28.3% of patients. The overall incidence of toxicity remained similar for both treatments, but there were differences between adverse event profiles that may help tailoring treatment to individual needs in this population.
The authors underlined that currently, predominantly fit elderly patients are selected to participate in the clinical trials. Future studies should focus on frail patients determined by geriatric assessment to develop a therapeutic strategy for this vulnerable patient population.
The study authors concluded, “Pazopanib was noninferior to doxorubicin, rendering pazopanib a putative therapeutic option in the first-line treatment of soft-tissue sarcoma in patients age 60 years or older. The distinct adverse event profile may be used to counsel patients and tailor therapy to individual needs.”
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