Dr. Daneshmand started with an overview of the National Comprehensive Cancer Network (NCCN) guidelines for nonseminomatous germ cell tumors highlighting that for patients with stage I disease and no risk factors, surveillance is preferred. Similarly, in patients with stage I disease and risk factors (LVI – pT2, invasion into the cord – pT3, or invasion into the scrotum – pT4) surveillance is still an option, as is primary chemotherapy (bleomycin, etoposide and platinum [BEP] 1 cycle) or nerving retroperitoneal lymph node dissection (RPLND). There is a known efficacy for RPLND in treating germ cell tumors, including for patients with stage I non-seminomatous germ cell tumors (NSGCT), stage IIA NSGCT, and for post-chemotherapy NSGCT and seminoma.
High-risk clinical stage I NSGCT is primarily defined as lymphovascular invasion. The tumor size, presence of embryonal cell carcinoma, presence/absence of teratoma, and presence of choriocarcinoma elements and/or yolk sac elements do not add sufficient power to lymphovascular invasion (LVI) to enter into general risk calculations. Regardless of the treatment option for high-risk clinical stage I NSGCT, there is a 99-100% cause-specific survival at five years. Relapses do occur in 50% of patients, with a median time to relapse of four to six months. Almost all patients that relapse have International Germ Cell Consensus Classification (IGCCC) good risk disease and most patients then proceed to receive three cycles of BEP, with about 7% of patients requiring a post-chemotherapy RPLND. Importantly, there are very few second relapses amongst these patients. As follows is a table summarizing the burden of treatment among patients with clinical stage I NSGCT:
Primary nerve-sparing RPLND is well tolerated with minimal short and negligible long-term morbidity. Chemotherapy has significant short-term and long-term morbidity. Importantly, an RPLND avoids chemotherapy in substantial numbers of high-risk stage I NSGCT and may be worth the increase in dual therapy.
For patients with clinical stage IIA germ cell tumors, we know that for NSGCT a RPLND has a 70-80% chance of cure without adjuvant chemotherapy with ample data demonstrating lower morbidity compared with chemotherapy and radiotherapy. Specific to stage IIA seminoma, this includes patients with a <3 cm node in the retroperitoneum or at relapse, with standard treatment being radiotherapy or chemotherapy, which was been this way for decades. RPLND has typically not been thought of as a treatment option for these patients, but there are 15 patients reported in the literature treated with RPLND with a 0% recurrence rate. As such, Dr. Daneshmand is the lead PI on the SEMS (Surgery in Early Metastatic Seminoma) trial, with the objective of evaluating the efficacy of first-line RPLND in retroperitoneal positive (1-3 cm) seminoma. The primary endpoint of this trial is 2-year recurrence-free survival, with the trial having accrued 55 patients (results pending).
There are several important statements regarding RPLND in the recently published American Urological Association (AUA) guidelines for early-stage testicular cancer:1
- RPLND should be performed with curative intent
- A full, bilateral template dissection should be performed if there are suspicious lymph nodes based on CT imaging or intraoperative evaluation and in those with somatic-type malignancy (teratoma with malignant transformation)
- In appropriate patients, nerve-sparing procedures can be performed in the setting of a full, bilateral template with preservation of ejaculatory function in 90% or more of patients
- In patients with clinically negative lymph nodes, a full bilateral template or a modified template dissection may be performed
For right-sided tumors, an acceptable modified template must include the right common iliac, paracaval, precaval, interaortocaval, pre-aortic, and retroaortic lymph nodes, with no consensus regarding para-aortic nodes above the inferior mesenteric artery. For left-sided tumors, an acceptable modified template must include the left common iliac, paraaortic, preaortic, and retroaortic lymph nodes, with no consensus whether the interaortocaval lymph nodes may be safely omitted. In the post-chemotherapy setting, generally, bilateral templates should be performed, although some do advocate for modified templates with small left-sided disease only.
Indications for post-chemotherapy RPLND for patients with NSGCT include those with a residual mass of ≥1 cm on CT following adequate chemotherapy and normal serum tumor markers. Additional indications may include a resectable mass following salvage chemotherapy, and chemotherapy-resistant disease (growing mass on chemotherapy with normal tumor markers, resectable masses with elevated markers, or late recurrences). Preservation of fertility is of significant concern given the patient population, and every attempt should be made to perform a nerve-sparing technique to maintain ejaculatory function without compromising oncologic efficacy. PET scans for post-chemotherapy seminoma can be helpful, as FDG-PET helps determine the viability of residual masses > 3 cm. Importantly, there is no role for FDG-PET imaging in the management of NSGCT.
Indications for post-chemotherapy RPLND in advanced seminoma according to Dr. Daneshmand are as follows:
- Patients with growing residual masses during follow-up after chemotherapy without marker elevation
- Cases with solitary, resectable tissue after salvage chemotherapy (to exclude non-seminoma elements)
However, Dr. Daneshmand cautions that post-chemotherapy RPLND for seminomas typically have an intense desmoplastic reaction that frequently requires vascular reconstruction, with more than 80-90% of masses being necrosis/fibrosis.
There has been increasing interest in robotic RPLND with the goal of minimizing morbidity of this procedure. In a multi-center study of 47 patients undergoing robotic primary RPLND, the median operative time was 235 minutes (IQR 214-258 minutes), estimated blood loss was 50 ml (IQR 50-100 ml), node count was 26 (IQR 18-32), and length of stay was one day. There were two intraoperative complications (4%), four early postoperative complications (9%), no late complications, and the rate of antegrade ejaculation was 100%. The midline extraperitoneal technique has also been advocated by Dr. Daneshmand and his group. In a study from their center among 12 patients, the extraperitoneal technique had a shorter mean operative time of 292 versus 337 minutes (p = 0.02) and lower estimated blood loss of 305 versus 575 mL (p = 0.05) compared to the transperitoneal approach.3 More lymph nodes were retrieved in the extraperitoneal group (44 vs 27 nodes, p = 0.0006), as well as an earlier return of bowel function (1.7 vs 2.9 days, p = 0.0001) and a shorter median length of stay (3.3 vs 5.3 days, p = 0.0001).
Dr. Daneshmand concluded his presentation with the following take-home messages:
- Primary nerve-sparing RPLND is an option for high-risk clinical stage I NSGCT with cure rates of 75%
- Post-chemotherapy PRLND should be performed for any residual NSGCT >1 cm
- Post-chemotherapy RPLND may be performed for select residual tumors of >3 cm for patients with seminoma
- Midline extraperitoneal RPLND decreases morbidity of the procedure and length of hospital stay
Presented by: Sia Daneshmand, MD, Associate Professor of Urology (Clinical Scholar), Director of Clinical Research, Keck School of Medicine, University of Southern California, Los Angeles, California
Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md at the 2020 Société Internationale d'Urologie Virtual Congress (#SIU2020), October 10th - October 11th, 2020
1. Stephenson, Andrew, Scott E. Eggener, Eric B. Bass, David M. Chelnick, Siamak Daneshmand, Darren Feldman, Timothy Gilligan et al. "Diagnosis and treatment of early stage testicular cancer: AUA guideline." The Journal of urology 202, no. 2 (2019): 272-281.
2. Pearce, Shane M., Shay Golan, Michael A. Gorin, Amy N. Luckenbaugh, Stephen B. Williams, John F. Ward, Jeffrey S. Montgomery et al. "Safety and early oncologic effectiveness of primary robotic retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer." European urology 71, no. 3 (2017): 476-482.
3. Kim, Philip, Sumeet Syan-Bhanvadia, Hooman Djaladat, Ken Faber, Nicholas N. Tadros, Craig Nichols, and Siamak Daneshmand. "Midline extraperitoneal approach for retroperitoneal lymph node dissection for testicular germ cell tumor." Urology 80, no. 4 (2012): 941-945.