Anthracycline, Gemcitabine, and Pazopanib in Epithelioid Sarcoma: A Multi-institutional Case Series.

Importance: Epithelioid sarcoma (ES) is an exceedingly rare malignant neoplasm with distinctive pathologic, molecular, and clinical features as well as the potential to respond to new targeted drugs. Little is known on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in this disease. Objective: To report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with advanced ES. Design, Setting, and Participants: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis of patients with locally advanced/metastatic ES diagnosed between 1990 and 2016. Local pathological review was performed in all cases to confirm diagnosis according to most recent criteria. Exposures: All patients included in the study received anthracycline-based regimens, gemcitabine-based regimens, or pazopanib. Main Outcome and Measures: Response was assessed by RECIST. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Classic and proximal subtypes were defined based on morphology (according to 2013 World Health Organization guidelines). Results: Overall, 115 patients were included, 80 (70%) were men and 35 (30%) were women, with a median age of 32 years (range, 15-77 years). Of the 115 patients with ES, 85 were treated with anthracycline-based regimens, 41 with gemcitabine-based regimens, and 18 with pazopanib. Twenty-four received more than 1 treatment. Median follow-up was 34 months. Response rate for anthracycline-based regimens was 22%, with a median PFS of 6 months. One complete response (CR) was reported. A trend toward a higher response rate was noticed in morphological proximal type (26%) vs classic type (19%) and in proximal vs distal primary site (26% vs 18%). The response rate for gemcitabine-based regimens was 27%, with 2 CR and a median PFS of 4 months. In this group, a trend toward a higher response rate was reported in classic vs proximal morphological type (30% vs 22%) and in distal vs proximal primary site (40% vs 14%). In the pazopanib group, no objective responses were seen, and median PFS was 3 months. Conclusions and Relevance: This is the largest retrospective series of systemic therapy in ES. We confirm a moderate activity of anthracycline-based and gemcitabine-based regimens in ES, with a similar response rate and PFS in both groups. The value of pazopanib was low. These data may serve as a benchmark for trials of novel agents in ES.

Topoisomerase II-alpha protein expression and histological response following doxorubicin-based induction chemotherapy predict survival of locally advanced soft tissues sarcomas.

PURPOSE: Neoadjuvant chemotherapy for locally advanced soft tissue sarcomas (LASTS), although not standard, represents a promising option for resectable tumours. Current lack of biological predictors of chemotherapy response led us to establish a relationship between Topoisomerase II-alpha (Topo2A), HER2, excision repair cross-complementing group 1 (ERCC1) protein expression, histological response and clinical outcomes of LASTS patients. PATIENTS AND METHODS: A retrospective study based on clinical data and archival paraffin-embedded tumour tissue at diagnosis from 78 consecutive LASTS patients treated with neo-adjuvant chemotherapy in our institution enabled analysis of ERCC1, HER2 and Topo2A protein expression by immuno-histochemistry. RESULTS: Disease free survival (DFS) and overall survival (OS) were 48% and 64%, respectively. The annual risk of relapse increased with a higher percentage of residual identifiable cells (RIC). A higher Topo2A protein was associated with an improved rate of good HR (r=0.416) and with a decreased risk of relapse. Median DFS decreased with low Topo2A (p⩽0.042). The ERCC1 status had no impact on histological response while ERCC1 positive tumours correlated with a favourable OS (p ≤ 0.058). Patients with LASTS co-expressing Topo2A and ERCC1 had a significant better outcome (p=0.018). Topo2A was the only independent variable linked to a good HR (p ≤ 0.017); histological grade 3 was the only independent adverse prognostic variable linked to both DFS (p ≤ 0.04) and OS (p ≤ 0.004). CONCLUSIONS: While histological response predicts better DFS, Topo2A protein expression correlates with histological response and better DFS. The combination of an early predictive factor for chemosensitivity (Topo2A) and for survival (ERCC1) highlights the possibility to develop individualised therapeutic approaches (CONTICANET program).