The optimal treatment approach for patients with relapsed metastatic non-seminomatous germ-cell tumors (GCT) remains unsettled. Treatment options include high-dose chemotherapy (HDCT) + peripheral-blood stem-cell transplant (PBSCT), standard-dose cisplatin-based combination chemotherapy, or salvage surgery for anatomically localized disease.
For patients with multifocal disease progression, our institutional preference is treatment with HDCT with carboplatin etoposide for 2 tandem cycles (Einhorn et al, NEJM 2007; Adra et al, JCO 2017). Each course consisted of carboplatin 700 mg/m2 body-surface area plus etoposide 750 mg/m2 intravenously on days 5, 4, and 3. Stem-cell infusion was performed on day 0.
Oral etoposide is a topoisomerase II inhibitor and has been shown to induce remissions in a subset of patients with refractory GCTs. From 2001 to 2016, we treated 141 patients with maintenance daily oral etoposide after achieving remission with HDCT. However, during that period, it was difficult to follow up with patients from multiple areas within and outside the United States; thus, we discontinued the practice with the inability to document benefits or assess the harm. The current advances in data retrieval made this analysis reasonable and possible. In this retrospective analysis, we evaluate the role of maintenance oral etoposide in patients with relapsed non-seminomatous GCT who completed HDCT plus PBSCT and achieved complete serologic remission and hematologic recovery compared to observation. Oral etoposide was administered in a dose of 50 mg/m² for 21 consecutive days every 4 weeks for target 3 cycles.
After completion of HDCT+PBSCT x2, 141 patients were treated with maintenance etoposide and 242 were observed. Median follow-up time from the start of HDCT was 3.8 years. 2-year progression-free survival (PFS) in the maintenance etoposide vs observation group was 55% vs. 46% (P=0.028). 2-year overall survival (OS) was 61% in maintenance etoposide group vs 54% in the observation group (P=0.04). A multivariable analysis including high risk features was performed and maintenance etoposide was confirmed as an independent predictor of improved PFS with HR 0.51 [95% CI, 0.37-0.70] (P= 0.001). The improvement in PFS and OS was particularly observed in patients with platinum refractory disease defined as progression within 4 weeks of first-line cisplatin-based chemotherapy: 2-year PFS 44.2% in maintenance etoposide vs. 23.1% in observation (P=.0003); 2-year OS 50.2% in maintenance etoposide vs. 26.1% in observation (P<.0001).
Within the limitations of a retrospective analysis, maintenance daily oral etoposide produced encouraging efficacy results in patients with relapsed non-seminomatous GCT who completed salvage HDCT + PBSCT. These data have led to an ongoing randomized phase II clinical trial (NCT04804007).
Written by: Nabil Adra, MD, MS, Assistant Professor of Clinical Medicine, Assistant Professor of Urology, Program Leader, Genitourinary Oncology, Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN
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