Doxorubicin/Ifosfamide Combo for Sarcoma Most Effective in Select Population

Robin Young, MBChB, PhD

Chemotherapy with doxorubicin and ifosfamide improved progression-free survival (PFS) and tumor response compared with doxorubicin alone in soft tissue sarcoma, but the combination may be best suited for young, fit patients, according to results published online in Acta Oncologica.

“Single-agent doxorubicin remains standard of care first-line chemotherapy for patients with advanced soft tissue sarcoma,” wrote the study authors, led by Robin Young, MBChB, PhD, Weston Park Hospital, Sheffield, United Kingdom. “However, combination doxorubicin/ifosfamide is indicated for selected patients, and this analysis suggests combination treatment may be most appropriate to consider in patients ≤60 years old, [performance status] of 0 or 1, with poorly differentiated grade 3 tumors, including [undifferentiated pleomorphic sarcoma (UPS)].”

Researchers concluded that UPS, synovial sarcoma and “other” histological subtypes were most likely to respond to treatment with the doxorubicin/ifosfamide combination.

In results from the phase III, multicenter, randomized EORTC 62012 trial (N = 455) published in 2014, researchers found that the combination was associated with a significantly higher tumor response rate (26% vs 14%; P <.0006) and improved PFS (HR, 0.74; 95% CI, 0.60-0.90; P = .003) compared with doxorubicin alone. However, there was no significant difference in overall survival (OS; HR, 0.83; 95% CI 0.67-1.03; P = .076) and the combination was associated with a significant increase in adverse events.

To validate factors prognostic of tumor response to chemotherapy and OS, researchers conducted a subgroup analysis of EORTC 62012. They then analyzed histological subtype and tumor grade as predictive factors to identify patient subgroups more likely to benefit from treatment with combination therapy.

Researchers classified histological subtypes as liposarcoma, leiomyosarcoma, synovial sarcoma, UPS, or “other subgroups. The “other” group was a pooled collection of rarer soft tissue sarcoma subtypes with diverse pathologies that appeared too infrequently to be assessed separately. That subgroup represented a third of all patients included in this analysis.

Gender, age, performance status, time elapsed from initial presentation with sarcoma to starting palliative chemotherapy, tumor grade, histological subgroup, primary tumor site involvement, and site of metastases (liver, lung, bone, and “other”) were also assessed as factors prognostic for tumor response and OS.

After excluding patients who did not meet eligibility criteria, researchers included 310 patients in the subgroup analysis. Young et al observed discordance between local and central pathology assessment of tumor histology in 32% of cases and of tumor grade in 39%.

As in the main study results, the combination was associated with improved tumor response (odds ratio [OR] = 2.44; 95% CI, 1.38-4.31; P = .002), but there was no significant difference in OS (HR, 0.82; 95% CI, 0.64-1.04; P = .105).

In multivariate analysis, liposarcoma histology and “other” metastatic disease sites were prognostic for tumor response to chemotherapy. Patients with liposarcoma had improved tumor response to chemotherapy compared to other histological subgroups (overall P = .014).

A performance status of 1 (HR, 1.39; 95% CI, 1.07-1.80; P = .013), shorter time from initial presentation with sarcoma to starting palliative chemotherapy (HR, 1.43; 95% CI, 1.02-2.00; P = .020), and presence of bone metastases (HR, 1.45; 95% CI, 1.01-2.09; P = .046) were associated with reduced OS. Only bone metastases remained statistically significant in the final reduced model (HR, 1.56; 95% CI, 1.16-2.09; P = 003).

By local pathology assessment of histology, synovial sarcomas had a 43.5% response rate with combination therapy compared with 11.1% with doxorubicin alone (OR, 6.15; 95% CI, 1.43-26.39). For “other” subtypes, the response rate was 29.0% with the combination versus 10.5% for doxorubicin (OR, 3.48; 95% CI, 1.27-9.53). Tumor response rates for liposarcoma, leiomyosarcoma, and UPS subgroups did not differ significantly by treatment arm.

Analysis of OS by local pathology assessment showed no interaction between histological subgroup and treatment arm. As assessed by central pathology review, doxorubicin/ifosfamide was associated with improved OS in patients with UPS compared with single-agent doxorubicin (HR, 0.44; 95% CI, 0.26-0.79).

Grade 3 tumors had an improved response rate with doxorubicin/ifosfamide compared with doxorubicin by both local (OR, 2.93; 95% CI, 1.30-6.61) and central pathology assessment (OR, 3.64; 95% CI; 1.72-7.70).

Response rate in grade 2 tumors did not differ significantly by treatment arm with either local or central pathology assessment, and researchers said no interaction between treatment arm and tumor grade was identified in the OS analysis.

Young RJ, Litière S, Lia M, et al. Predictive and prognostic factors associated with soft tissue sarcoma response to chemotherapy: a subgroup analysis of the European Organization for Research and Treatment of Cancer 62012 study [published online April 21, 2017]. Acta Oncol. doi: 10.1080/0284186X.2017.1315173.

The UPS subgroup had a higher response rate with combination chemotherapy (42.3%) than with doxorubicin (6.9%; OR, 9.90; 95% CI, 1.93-50.7) according to central pathology assessment. Tumor response did not differ significantly between treatment arms for liposarcoma, leiomyosarcoma, synovial sarcoma or “other” subgroups.