The role of primary retroperitoneal lymph node dissection in the treatment of stage II seminoma

Abstract

Purpose of review 

Stage II seminoma is responsive to chemo- or radiotherapy with a progression-free survival of 87–95% at 5 years but at the cost of short- and long-term toxicity. After evidence about these long-term morbidities emerged, four surgical cohorts investigating the role of retroperitoneal lymph node dissection (RPLND) as a treatment option for stage II disease were initiated.

Recent findings 

Currently, two RPLND series have been published as a complete report, while data from other series have only been published as congress abstracts. In series without adjuvant chemotherapy, recurrence rates ranged from 13% to 30% after follow-ups of 21–32 months. In those receiving RPLND and adjuvant chemotherapy, the recurrence rate was 6% after a mean follow-up of 51 months. Across all trials, recurrent disease was treated with systemic chemotherapy (22/25), surgery (2/25), and radiotherapy (1/25). The rate of pN0 disease after RPLND varied between 4% and 19%. Postoperative complications were reported in 2–12%, while antegrade ejaculation was maintained in 88–95% of patients. Median length of stay ranged from 1 to 6 days.

Summary 

In men with clinical stage II seminoma, RPLND is a safe and promising treatment option. Further research is needed to determine the risk of relapse and to personalize treatment options based on patient-specific risk factors.

INTRODUCTION

Seminoma is the most prevalent type of germ cell tumor and approximately 20% of men are diagnosed with clinical stage II disease, which is characterized by enlarged retroperitoneal lymph nodes between 1 and 5 cm in size and the absence of further metastasis ^[1]. The implementation of miR-371a-3p as a diagnostic marker is expected to lead to earlier detection of metachronous stage II disease and the decreasing use of adjuvant carboplatin is expected to increase the number of men with disease recurrence in stage II. The current standard of care for treatment involves either chemotherapy or radiotherapy. The recommended chemotherapy consists of either three cycles of bleomycin, etoposide, and cisplatin (BEP) or four cycles of etoposide and cisplatin (EP). Radiotherapy, consisting of 30–36 Gy delivered to para-aortic and high ipsilateral iliac lymph nodes, is primarily recommended for older patients or those who are unable to tolerate chemotherapy. 

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Both treatments have a high progression-free survival rate of 87–95% at 5 years, however, they are associated with side effects. Short-term adverse effects of cisplatin-based chemotherapy include nausea, fatigue, cytopenia, and hair loss ^[2], while long-term side effects include pulmonary toxicity, nephrotoxicity, neurotoxicity, decreased fertility, hypogonadism, and psychosocial problems ^[3]. Large-volume radiotherapy is associated with fatigue, nausea, and vomiting during treatment and both radiotherapy and chemotherapy increase the risk of secondary malignancies and cardiovascular disease ^[4].

In light of these long-term morbidities, several groups have investigated de-escalation strategies, such as reducing the dose and/or type and number of chemotherapy cycles and radiotherapy. The SAKK 01/10 trial used a reduced chemotherapy regimen of one cycle of carboplatin followed by involved-node radiotherapy with 30–36 Gy and demonstrated a favorable 3-year progression-free survival rate of 94% ^[5▪]. The follow-up trial, SAKK 01/18, employs a one-cycle of carboplatin AUC7 followed by involved-node radiotherapy of 24 Gy for stage IIa patients and one cycle of etoposide and cisplatin followed by a reduced radiotherapy dose of 30 Gy to involved nodes for stage IIb patients.

In an effort to avoid the adverse effects of radio/chemotherapy, several surgical cohorts have been initiated to investigate the role of retroperitoneal lymph node dissection (RPLND) as a treatment option for stage II seminoma (Table 1). Currently, RPLND is mainly utilized for nonseminoma with marker-negative retroperitoneal residual disease after first-line chemotherapy, late recurrence, marker-negative stage II disease or as an adjuvant procedure for stage I. The main disadvantage of RPLND is its potential intra- and postoperative complications ^[6], however, modifications such as extraperitoneal access ^[7] or minimally invasive techniques have been developed to reduce these risks ^[8]. To minimize the risk of retrograde ejaculation, modified bilateral templates and/or nerve-sparing techniques have been developed ^[9–11]. Given those improving functional outcomes and lower complication rates after RPLND, ongoing research is being conducted to determine if RPLND can provide comparable oncological results compared to radio-/chemotherapy in stage II seminoma patients.

Table 1 - Comparison of prospective surgical trials investigating the role of primary RPLND in clinical stage 2 seminoma

Study	PRIMETEST (Primary Retroperitoneal Lymph-Node Dissection in Patients with Seminomatous Testicular Germ Cell Tumors with Clinical Stage IIA/B)	SEMS (Surgery in Early Metastatic Seminoma)	COTRIMS (Cologne Trial of Retroperitoneal lymphadenectomy In Metastatic Seminoma)	Royal Marsden
Country	Germany	USA/Canada	Germany	United Kingdom
Study ID	NCT02797626	NCT02537548	DRKS00025384	NA
Year of accrural	2016–2021	2015–2020	2016–today	2014–2022
Sample size	33	55	16	54
Selection criteria Size Marker Stage	Unilateral Seminoma CS IIA/B HCG <5 mU/ml Synchronous or metachronous after surveillance or adjuvant carboplatin for CS I.	Seminoma with retroperitoneal LN metastasis 1–3 cm (max. 2 LN) LDH max. 1.5 x upper limit, other tumor markers within normal limits Synchronous or metachronous within 3 years after orchiectomy. No previous adjuvant chemotherapy.	Seminoma CS IIA/B HCG <5 mU/ml Synchronous or metachronous after surveillance. No previous adjuvant chemotherapy.	Seminoma CS IIA/B Not stated Synchronous or metachronous after surveillance. No previous adjuvant chemotherapy.
Treatment	RPLND	RPLND	RPLND	RPLND + 1–2 cycles of carboplatin
Surgical approach	Open: 14 (42%) Robotic: 19 (58%)	Open 100% Transperitoneal 40 (73%) Extraperitoneal 15 (27%)	Open: 14 (88%) Robotic: 2 (12%)	Open: 2 (4%) Robotic: 52 (96%)
Surgical template and nerve sparing	Nerve sparing yes Unilateral modified template	Nerve sparing 47 (87%) Unilateral modified template (65%) or bilateral (35%)	Nerve sparing yes Unilateral modified template	Nerve sparing yes Unilateral modified template
Included patients Size Onset of disease	Seminoma CS IIA: 13 (39%) Seminoma CS IIB: 20 (61%) Synchronous 9 (27%) Metachronous after surveillance: 19 (58%) Metachronous after carboplatin: 5 (15%)	Seminoma CS IIA: 44 (80%) Seminoma CS IIB: 11 (20%) Synchronous: 19 (35%) Metachronous after surveillance 36 (65%)	Seminoma CS IIA/IIB: 16 (100%) Synchronous: 9 (56%) Metachronous after surveillance 7 (44%)	Seminoma CS IIA (43, 80%) Seminoma CS IIB (11, 20%) Synchronous: 21 (39%) Metachronous after surveillance: 33 (61%)
Pathological stage	pN0: 3 (9%)	pN0: 9 (16%) Seminoma: 45 (82%) Mixed GCT: 1 (2%)	pN0: 3 (19%) Seminoma: 12 (75%) Embryonal carcinoma: 1 (6%)	pN0: 2 (4%) Seminoma: 51 (94%) Mixed GCT: 1 (2%)
Follow-up	Median: 32 months (IQR 23–46)	Median: 33 months (IQR: 12–62)	Mean: 21 months (Range: 1–36 months)	Mean: 51 months (Range: 6–105 months)
Progression free survival at reported follow-up	70%	78%	87%	94%
Time to recurrence	6 months (median), (IQR: 4–12, Range: 3–36)	10 months (IQR: 7–32 months)	Mean: 5 months (IQR: 4–6 months, range 4–6 months)	Median: 14 months, (IQR or Range not available)
Treatment of recurrence	9/10 3xBEP, 1/10 1xBEP and 2xPEI	6/12 3XBEP, 2/12 4XEP, 1/12 4XBEP 1/12 3XBEP followed by 2x Carboplatin/etoposide at second recurrence 2/12 additional surgery	2/2 4xBEP	2/3 Chemotherapy 1/3 Radiotherapy
Intraoperative complications	2 (6%) - 1 bleeding from renal vein - 1 conversion to open surgery	0	Not reported	Not reported
Postoperative complications	Clavien Dindo III: 4 (12%) (postoperative ileus requiring revision surgery, 2 pulmonary embolism, and 1 lymphocele requiring drainage)	Clavien Dindo I-II: 5 (9%) Clavien Dindo III: 2 (4%) (Incision ulceration, 2 Ileus, Pulmonary embolism, Chylous ascites, Incision hernia)	Clavien Dindo >IIIa: 0	3 patients (6%) with complications, no Clavien Dindo classification provided

BEP, bleomycin etoposide cisplatin; CS, clinical stage; GCT, germ cell tumor; HCG, human chorionic gonadotropin; HDCT, high dose chemotherapy; IQR, interquartile range; LN, lymph node; PEI, cisplatin etoposide ifosfamide; RPLND, retroperitoneal lymph node dissection.

MATERIALS AND METHODS

We conducted a literature search using the Medline database. For this search, we used combinations, synonyms and related search terms to “stage II” or “metastatic” and “seminoma” and “RPLND” or “retroperitoneal lymph node dissection” and selected the time period from 01 January 2020 to 29 January 2023. The following search term was used: ((((((Stage II[Title/Abstract]))AND (Seminoma[Title/Abstract])) AND ((RPLND [Title/Abstract])) OR (retroperitoneal lymph node dissection[Title/Abstract]))) AND ((“2020/01/01”[Date - Publication]: “2023/01/29”[Date - Publication])). The reference lists of the identified publications were screened for further relevant literature. Case-reports, non-English literature, animal studies and letters were excluded.

RETROSPECTIVE DATA

Three surgical series of a total of 26 clinical stage II seminoma treated with RPLND were identified. The first trial consisted of 63 patients (45 stage I and 18 stage II) treated with open RPLND, with recurrence in 0/7 patients with stage IIA seminoma, but in 6/11 (59%) patients with stage IIB/C during the median follow-up of 79 months. Infield retroperitoneal relapses in stage I-II patients occurred in 6/63 patients (10%), outfield recurrence in 3/63 patients (5%) ^[12]. In two other retrospective series of four patients each, no disease recurrence was observed after a mean follow-up period of 56 and 25 months ^[13,14].

PROSPECTIVE COHORTS

Out of four prospective RPLND cohorts, two have been published as original articles. The first published series represents the German PRIMETEST study ^[15▪▪], which included men with unilateral clinical stage IIA/B seminoma. The trial was terminated early as during several interim analyses the lower 95% confidence interval boundary of 73.5% was crossed. At this stage, the authors included 33 men, 9 with synchronous, 19 with metachronous stage II after active surveillance and 5 with retroperitoneal recurrence after 1 cycle of carboplatin. Men with human chorionic gonadotropin (HCG) levels >5 mU/ml, abnormal alpha-fetoprotein, previous scrotal or retroperitoneal surgery and other chemotherapy than carboplatin were excluded.

Robotic surgery was performed in 58% and a modified template was performed in all patients. The left template was defined as a resection limited to renal vein cranially, the common iliac artery caudally, the ureter laterally, the interaortocaval space medially and the psoas muscle dorsally. The right modified template limits included the right renal vein superiorly, the common iliac vessels inferiorly, the ureter laterally, the interaortocaval space between the left renal vein and the superior mesenteric artery, inferior vena cava medially and the psoas muscle posteriorly. No cancer (pN0) was found in 3/33 patients (9%). Intraoperative complications were reported in 6% of the patients, 12% had postoperative a Clavien-Dindo complication ≥IIIa and 94% reported to have antegrade ejaculation. The median hospital stay was 6 days. After a median follow-up of 32 months, 30% of patients had a recurrent disease, with 4 having contralateral recurrence and 3 having ipsilateral retroperitoneal recurrence.

The SEMS trial, a multicenter study in the United States and Canada, had just recently been published ^[16▪]. The study enrolled 55 patients with clinical stage II seminoma and a maximum of two lymph nodes <3 cm in diameter, the strictest inclusion criteria among the four prospective RPLND series. Synchronous and metachronous disease were present in 65% and 35% and either a bilateral (35%) or unilateral modified (65%) template was performed based on the surgeon's preferences. Transperitoneal and extraperitoneal access was chosen in 73% and 27%, respectively. Pathological results showed 9 patients (16%) with pN0 disease. The median hospital stay was 3 (1–7) days. Clavien-Dindo complication ≥IIIa were reported in one patient (2%), and retrograde ejaculation was present in three men (5%). One patient (2%) received one cycle of adjuvant carboplatin, the other patients underwent surveillance. The 2-year recurrence-free-survival was 81%, and after a median follow-up of 33 months the overall recurrence rate was 22%. An in-field recurrence was found in 5/12 patients. The 12 patients (22%) with recurrence were either treated with chemotherapy (83%) or additional surgery (17%).

The interim results of the Cologne Trial of Retroperitoneal Lymphadenectomy In Metastatic Seminoma (COTRIMS) have been presented at the 2022 American Society of Clinical Oncology Symposium ^[17▪]. Data of the first 16 patients including 9 with stage IIA and 7 with stage IIB treated with open RPLND in 88% of participants were presented. A total of 3 patients (19%) had pN0 disease and 1 patient (6%) embryonal carcinoma. No Clavien-Dindo complication >IIIa was reported, and 88% of the patients preserved an antegrade ejaculation. A recurrent disease was diagnoses in 2/16 patients. The mean follow-up was 21 months.

In contrast to the previous RPLND series, the team at the Royal Marsden study presented their data of men with stage IIA/B seminoma treated with RPLND followed by 1–2 cycles of carboplatin at the EAU 2023 annual meeting in Milan ^[18▪]. Robotic RPLND with a unilateral modified template was performed in 52 (96%) out of the total 54 patients. Histopathological evaluation revealed that 4% (two patients) showed pN0 disease and one patient (2%) seminoma with embryonal carcinoma. Complications were reported in 6% and the median length of stay was 1 day. After a mean follow-up of 51 months, three patients had a recurrence, resulting in a progression-free survival of 94%.

DISCUSSION

While we are expecting the original publication of the COTRIMS and the Royal Marsden data during 2023 we would like to review the currently available data and provide and outlook of current research niches in stage II seminoma.

The treatment of clinical stage II seminoma in men presents a challenge in balancing oncological efficacy and short- and long-term health which also depends on access to affordable high-quality specialized care. Certainly, any treatment strategies result in significant short-term toxicities. Primary Chemotherapy is associated with short-term toxicity in 80–95% of men and includes peripheral neuropathy, ototoxicity, hematologic, renal and pulmonary toxicity, alopecia as well as nausea and vomiting ^[19,20]. Radiotherapy can lead to nausea and vomiting, diarrhea, gastrointestinal and dermatological side effect ^[21,22]. RPLND has the risk of intra- and postoperative complications including hemorrhage, lymphoceles, ileus, thromboembolic events, wound healing problems ^[6].

Similarly, any treatment option has treatment specific long-term toxicities ^[23]. Chemotherapy increases the risk of metabolic syndrome, hypogonadism and cardiovascular risks, whereas radiotherapy is associated with secondary malignancy and late bowel toxicity ^[24,25]. For RPLND retrograde ejaculation represents the most important long-term toxicity if surgical complications led to disabilities ^[23].

No head to head comparisons regarding oncological long-term outcomes of the three treatment options have been performed. The most recently published data for primary RPLND suggests a recurrence rate of 13–30% with short follow-up periods of 21–51 months. Of note are the retroperitoneal recurrences which represent two thirds of all recurrences after primary RPLND, suggesting that either a bilateral template and/or adjuvant carboplatin should be studied to minimize the risk of retroperitoneal recurrence. To our knowledge, the Memorial Sloan Kettering cancer center will soon publish a report of their experience using a bilateral template in all patients which may partially answer the question regarding the ideal surgical template. With longer follow-up, not only the risk of retroperitoneal but also systemic relapse can be defined more precisely which will allow to explore potential risk factors for systemic relapse and allow to personalize which patients may benefit from adjuvant chemotherapy. The proportion of pN0 disease varies among trials from 0–20% but the use of miR-371a-3p as a serum biomarker may help to decrease overtreatment in future trials ^[26,27].

Functional outcomes such as postoperative complications, length of stay, and antegrade ejaculation rates were favorable in all trials with complication rates of 4–12%, antegrade ejaculation rates of 88–95%, and a short median length of stay of 1–6 days. These results were achieved by experienced high-volume surgeons, and it is important to note that if RPLND becomes a more widely recommended alternative treatment, the functional outcomes may not be as favorable with less experienced surgeons. Although financial costs should not be the primary focus of treatment decisions, it is important to note that the implementation of chemotherapy results in a significant loss of working hours for several months, making RPLND a more attractive option from an economic perspective. However, further studies are needed to fully assess the financial implications of the different treatment options.

CONCLUSION

For men with stage II seminoma, RPLND is an emerging treatment option with reduced long-term toxicity compared to radio- and/or chemotherapy. However, longer follow-up is required to determine the risk of retroperitoneal or systemic relapse and to identify risk factors to personalize treatment plans. As a further step, decision analyses will help determine whether adjuvant chemotherapy after RPLND may decrease the overall treatment burden.

Acknowledgements

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Conflicts of interest

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