Introduction

Standard treatment for early metastatic seminoma (Stage IIA–B) includes external beam radiotherapy (XRT) or systemic chemotherapy.¹ Although these treatments are efficacious, they can be associated with significant long-term toxicities, which are often accentuated given the long-life expectancy of testicular cancer survivors.^2–4 Although the current management framework provides long-term disease-free survival in more than 90% of patients presenting with or progressing to Stage II disease, long-term treatment-related patient burden remains a concern. Retroperitoneal lymph node dissection (RPLND) is an established and effective treatment for testicular germ cell tumors. It is recommended for postchemotherapy residual masses and is an option in high-risk stage I, IIA and IIB nonseminomatous germ cell tumors. There is a paucity of data, however, on the efficacy of RPLND as primary treatment for pure seminoma metastatic to the retroperitoneum. Given the biological and clinical rationale for such an approach, we postulated that surgical management of regional seminoma would be at least as curable as in similar stage nonseminoma.

The Surgery in Early Metastatic Seminoma (SEMS) trial was a single-arm prospective phase II clinical trial (NCT02537548) evaluating the efficacy of RPLND as first-line treatment for pure testicular seminoma with isolated retroperitoneal disease (1–3 cm). The lymph node enlargement could be synchronous with primary disease diagnosis (presenting stage IIA/B) or metachronous (stage I with recurrence). Exclusion criteria included history of prior chemotherapy, or serum tumor marker elevation of 1.5× the upper limit of normal. All surgeries were performed via an open approach. The study was initiated at the University of Southern California (USC) and included 11 other institutions throughout the U.S. and Canada: Indiana University, University of British Columbia, Loma Linda University, University of Oklahoma, Emory University, Stanford University, Madigan Army Medical Center, University of Texas Southwestern, Johns Hopkins University, Mayo Clinic and University of Chicago.

Results

The trial consisted of 55 patients who were enrolled by 19 different previously vetted surgeons. Templates of dissection and nerve-sparing approaches were left to surgeon discretion (fig. 1). At USC, a midline extraperitoneal incision was employed with a median hospital stay of 1 day (fig. 2). Pathologic upstaging occurred in 49% of patients, 16% had pN0, 22% had pN1, 56% had pN2, 6% had pN3. The overall recurrence rate was 20% (11/55) with a median time to recurrence of 8 months. The 2-year recurrence free survival was 84% (46/55) and overall survival was 100% (fig. 3). Of those who relapsed 9 were treated with chemotherapy and 2 were treated with additional surgery. There were 7 (13%) patients who experienced short-term complications within 1 year of RPLND (5 grade I–II and 2 grade III Clavien-Dindo complications), with no patients thus far reporting long-term complications. Of the patients who underwent nerve sparing RPLND (48/55), only 4.2% (2/48) developed retrograde ejaculation.

Several features and secondary outcomes of the trial design merit discussion. Our study, in which stage and volume assessments were made by expert high-volume surgeons, demonstrated a 16% rate of false positive rate in small volume marker negative seminoma pathologically determined to be N0 disease. These are the same subset of patients who would have been “cured” with chemotherapy or radiotherapy for disease that was never present. In addition, nearly 50% of patients were found to have more advanced volumes of disease at RPLND. This underscores the modest fidelity of current preoperative clinical assessment in determining pathologic stage in small volume stage II, marker negative germ cell tumors.

Figure 1. Right extended template.

Figure 2. Midline extraperitoneal RPLND.

Figure 3. Survival probability by month after surgery.

While the 2-year followup may be short and additional relapses may be discovered with further followup, patterns and timing of relapse in seminoma are generally limited to the first 2 years and relapse beyond 3 years is extremely rare.

The next planned development of a precision surgical approach is a large multicenter trial of RPLND in limited volume, marker negative stage II seminoma and nonseminoma, guided by plasma miR371 assessment to decrease the current rate of false positive radiographic assessments. Plasma miR371 is being studied across the full spectrum of disease in the North American intergroup trial, S1823 through SWOG and the NCTN. In multiple large studies, miR371 appears to be a remarkably accurate liquid biomarker with positive predictive value approaching 100%.⁵

The SEMS trial represents a substantial opportunity to further reduce use of toxic modalities in early metastatic seminoma improving long-term survivorship. In addition, it further solidifies the current recommendations for surveillance in patients with clinical stage I disease, as we know that the vast majority of those who do relapse will have isolated retroperitoneal disease which in turn can be managed surgically.

In conclusion, primary RPLND for small volume regional seminoma is safe and effective, and represents an excellent opportunity to cure the majority of patients without long term toxicity. Other similar trials are underway (PRIMETEST, P Albers et al in Germany and Minimally Invasive RPLND + adjuvant carbo for Stage IIA Seminoma, D Nichol and R Huddart et al in the UK) and should help further establish the efficacy of RPLND in this setting.

Collaborators on the trial include Clint Cary, Tim Masterson, Lawrence Einhorn, Steve Boorjian, Christian Kollmansberger, Anne Schuckman, Alan So, Peter Black, Aditya Bagrodia, Eila Skinner, Mehrdad Alemozaffar, Timothy Brand, Scott Eggener, Phillip Pierorazio, Kelly Stratton, Lucia Nappi and Craig Nichols.