Treatment of elderly patients with soft tissue sarcoma (STS) is challenging with a need to take into account comorbidities and vulnerability to medical treatments. Doxorubicin is a standard of care in patients with advanced, inoperable STS. In the EPAZ study, the German researchers tested whether pazopanib has comparable efficacy in first-line treatment of elderly patients with STS and offers better tolerability to doxorubicin. Viktor Grünwald of the Medical School Hannover and University Hospital Essen and colleagues reported on 24 August 2020 in the Journal of Clinical Oncology that pazopanib demonstrated non-inferior efficacy to doxorubicin in first-line treatment of fit elderly patients with STS with improvement in treatment-related myelotoxicity. It also had advantage in adverse events (AEs) profile, such as alopecia, stomatitis, and mucosal inflammation.
Approximately 40% of patients with STS are age 65 years or older. A retrospective analysis in elderly patients indicated that age 80 years or older, ECOG performance status of 2 or higher, and a large number of metastatic sites were associated with poor median overall survival (OS) and indicated that younger and fitter patients were more likely to receive systemic therapy in clinical practice. Furthermore, only low percentage of patients age 65 years or older are included in clinical trials.
Treatment with doxorubicin, drug predominantly used in systemic therapy for advanced or metastatic STS is associated with AEs such as neutropenia and febrile neutropenia. Given the vulnerability of geriatric patients, chemotherapy endangers this patient population and, as a consequence, hospitalisation is frequently required. Pazopanib is a tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor. It is associated with limited haematologic toxicity and has a global health status comparable to that of placebo. It is the standard of care in advanced and metastatic STS after failure of treatment with anthracyclines.
The study team assumed that the lack of severe haematologic toxicity renders pazopanib a suitable candidate for first-line treatment in elderly patients with STS, thus minimising the risk of febrile neutropenia. They designed the EPAZ trial to test whether pazopanib is not inferior to doxorubicin in patients with STS who are age 60 years or older, while offering a better risk-benefit ratio for neutropenia and febrile neutropenia. Treatment naïve patients with ECOG performance status of 0 to 2 and adequate organ function were included. Treatment consisted of pazopanib 800 mg once per day or doxorubicin 75 mg/m2 once every 3 weeks for 6 cycles after being randomly assigned in a 2:1 ratio.
Non-inferiority was assumed for progression-free survival (PFS), 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). The PFS was not inferior (HR, 1.00; 95% CI, 0.65 to 1.53). The incidence of grade 4 neutropenia and febrile neutropenia favoured pazopanib. Objective response rates for pazopanib and doxorubicin were 12.3% and 15.4%, respectively. The OS did not differ significantly between arms.
Geriatric assessment revealed 2 or more comorbidities in 15.8% of the patients and impairment of activities of daily living in 28.3% of patients.
The authors concluded that pazopanib is not inferior in terms of efficacy compared with doxorubicin, rendering pazopanib a putative therapeutic option in the first-line treatment of STS in patients age 60 years or older. There was superiority with pazopanib in terms of neutropenia and febrile neutropenia in elderly patients with STS. Overall incidence of toxicity remained similar for both treatments, but there were differences in the AE profiles that may help tailoring treatment to individual needs in this population.
The authors underlined that the 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.
Reference
Grünwald V, Karch A, Schuler M, et al. Randomized Comparison of Pazopanib and Doxorubicin as First-Line Treatment in Patients With Metastatic Soft Tissue Sarcoma Age 60 Years or Older: Results of a German Intergroup Study. JCO; Published online 24 August 2020. DOI: http://ascopubs.org/doi/full/10.1200/JCO.20.00714