Primary RPLND Versus Systemic Chemotherapy in Good-prognosis Metastatic Testicular Cancer

The current SWENOTECA guidelines from 2020 state that patients with seminoma stage IIA-IIB with <3 lymph nodes <30 mm in any dimension should be recommended a primary RPLND rather than the previously considered standard treatment, chemotherapy. The rationale behind this change is to reduce the number of patients at risk of acute and long-term side effects from chemotherapy. We aim to perform a quality-of-life assessment to determine whether the change from chemotherapy to surgery is justified regarding short- and long-term (2 years) quality-of-life.

Two study groups are formed:

1. Surgery group consisting of patients scheduled for a primary RPLND due to a CS IIa/b seminoma (maximum 2 nodes, maximum 30 mm in any diameter)
2. Chemotherapy group (control group) of patients receiving 3 doses of BEP due to a good prognosis seminoma or nonseminoma.

Patients will be recrutied at eight study centers in Sweden and Norway. Since RPLND is centralized in Sweden and Norway, the study will be population-based.

Primary outcome is:

1. Changes across study-groups in global HRQOL after treatment as measured by the EORTC QLQ-C30 with the testicular cancer-specific supplement EORTC QLQ-TC26.

Secondary outcomes are:
2. Differences in fatigue across study-groups as measured by the Fatigue Questionnaire (FQ).
3. Differences across study-groups in patient-reported prevalence of retrograde ejaculation as assessed by supplementary questions.
4. Rate of doctor-reported complications related to treatment in the study-groups.
5. Differences in quality-adjusted life years across study-groups as measured by the EQ-5D-5L tool
6. PFS in both study-groups (longer follow-up than 2 years permitted)

Data will be assessed at baseline, at 3 months after start of treatment, at 6 months, 1 year and 2 years.

• primary RPLND for low-stage metasatatic seminoma (Procedure): surgical lymph node dissection
• 3 courses of chemotherapy; Blemocin, Etoposide and Platinum (BEP) (Drug), also known as Systemic chemotherapy, Bleomycin, Etoposide, Platinum: systemic tretament for good prognosis metastastic testicular cancer

Primary outcomes

• HRQOL after treatment as measured by the EORTC QLQ-C30 with the testicular cancer-specific supplement EORTC QLQ-TC26 [2 years]: Changes across study-groups in global HRQOL after treatment as measured by the EORTC QLQ-C30 with the testicular cancer-specific supplement EORTC QLQ-TC26 The QLQ-C30 comprises both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.

Secondary outcomes

• Fatigue after RPLND vs. chemotherapy [2 years]: Differences in fatigue across study-groups as measured by the Fatigue Questionnaire (FQ). The FQ is an established, self-report fatigue questionnaire comprising 14 items that assess the intensity of fatigue-related symptoms. Each item was rated on a 4-point Likert scale (0 'better than usual', 1 'no more than usual', 2 'worse than usual', 3 'much worse than usual'). The FQ score is the sum of all items' scores (range 0-42).
• Ejaculation problems [2 years]: Differences across study-groups in patient-reported prevalence of retrograde ejaculation as assessed by two "supplementary" questions. These questions concern difficulties achieving ejaculation following sexual stimulation and whether the amount of semen is considered a problem. Answers are given on 4-point scales (no sexual stimulation has occurred, big difficulties (achieving ejaculation), small difficulties, no difficulties, and no sexual stimulation has occurred, large problem (amount of semen), small problem, no problem, respectively).
• Treatment related complications [2 years]: Rate of doctor-reported complications related to treatment in the study-groups. Journals are reviewed to gather information regarding the time and type of complication. Surgery group: Surgical complications are classified according to the Clavien-Dindo (CD) system, a standardised, 5-grade system used to grade surgical complications based on the level of therapeutic intervention required to manage them. Chemotherapy group: Complications following chemotherapy are classified according to the Common Terminology Criteria for Adverse Events, using a 1-5 scale to grade the severity of the event.
• Healt economy [2 years]: Differences in quality-adjusted life years across study groups as measured by the EQ-5D-5L tool, consisting of an index varying from 1 (full health) to 0 (dead), with scores below 0 indicating states worse than being dead. The index is evaluated at baseline (before start of treatment) and at 3, 6, 12 and 24 months thereafter.
• PFS [10 years]: Progression-free survival (PFS) are evaluated in both study groups. Medical records and national registers are used to identify recurrences of testicular cancer. Patients who do not have elevated markers or radiological evidence of disease recurrence or progression are considered free of recurrence or progression. The outcome will be dated and dicomotized (progression: yes/no).

Sex: Male, ages: 18 Years to any

Inclusion Criteria:

* Patients ≥18 years undergoing an open or minimally invasive primary retroperitoneal lymph node dissection (RPLND) due to seminoma stage II A/B (maximum 2 nodes, <30 mm in any dimension)
* Patients undergoing an open or minimally invasive primary RPLND due to a retroperitoneal relapse of seminoma (maximum 2 nodes, <30 mm in any dimension)
* Patients ≥18 years scheduled for 3-4 courses of chemotherapy due to a newly diagnosed good-prognosis metastatic germ cell tumor (nonseminoma or seminoma)

Exclusion Criteria:

* Previous chemotherapy (including adjuvant chemotherapy at diagnosis)
* Previous RPLND
* Practical considerations, such as not being able to read and sign informed consent or understand the questionnaires

• Thor A, Negaard HFS, Grenabo Bergdahl A, Almas B, Melsen Larsen S, Lundgren PO, Gerdtsson A, Halvorsen D, Johannsdottir B, Jansson AK, Hellstrom M, Wahlqvist R, Langberg CW, Hedlund A, Akre O, Glimelius I, Stahl O, Haugnes HS, Cohn-Cedermark G, Kjellman A, Tandstad T. Primary Retroperitoneal Lymph Node Dissection as Treatment for Low-volume Metastatic Seminoma in a Population-based Cohort: The Swedish Norwegian Testicular Cancer Group Experience. Eur Urol Open Sci. 2024 Jun 11;65:13-19. doi: 10.1016/j.euros.2024.05.006. eCollection 2024 Jul. PMID 38966804
• Hiester A, Che Y, Lusch A, Kuss O, Niegisch G, Lorch A, Arsov C, Albers P. Phase 2 Single-arm Trial of Primary Retroperitoneal Lymph Node Dissection in Patients with Seminomatous Testicular Germ Cell Tumors with Clinical Stage IIA/B (PRIMETEST). Eur Urol. 2023 Jul;84(1):25-31. doi: 10.1016/j.eururo.2022.10.021. Epub 2022 Nov 10. PMID 36372627
• Matulewicz RS, Benfante N, Funt SA, Feldman DR, Carver B, Doudt A, Knezevic A, Sheinfeld J. Primary Retroperitoneal Lymph Node Dissection for Seminoma Metastatic to the Retroperitoneum. J Urol. 2024 Jan;211(1):80-89. doi: 10.1097/JU.0000000000003697. Epub 2023 Sep 6. PMID 37672753
• Heidenreich A, Paffenholz P, Hartmann F, Seelemeyer F, Pfister D. Retroperitoneal Lymph Node Dissection in Clinical Stage IIA/B Metastatic Seminoma: Results of the COlogne Trial of Retroperitoneal Lymphadenectomy In Metastatic Seminoma (COTRIMS). Eur Urol Oncol. 2024 Feb;7(1):122-127. doi: 10.1016/j.euo.2023.06.004. Epub 2023 Jul 10. PMID 37438222
• Grenabo Bergdahl A, Mansson M, Holmberg G, Fovaeus M. Robotic retroperitoneal lymph node dissection for testicular cancer at a national referral centre. BJUI Compass. 2022 Mar 31;3(5):363-370. doi: 10.1002/bco2.149. eCollection 2022 Sep. PMID 35950045
• Daneshmand S, Cary C, Masterson T, Einhorn L, Adra N, Boorjian SA, Kollmannsberger C, Schuckman A, So A, Black P, Bagrodia A, Skinner E, Alemozaffar M, Brand T, Eggener S, Pierorazio P, Stratton K, Nappi L, Nichols C, Luo C, Li M, Hu B. Surgery in Early Metastatic Seminoma: A Phase II Trial of Retroperitoneal Lymph Node Dissection for Testicular Seminoma With Limited Retroperitoneal Lymphadenopathy. J Clin Oncol. 2023 Jun 1;41(16):3009-3018. doi: 10.1200/JCO.22.00624. Epub 2023 Mar 13. PMID 36913642
• Hellesnes R, Myklebust TA, Fossa SD, Bremnes RM, Karlsdottir A, Kvammen O, Tandstad T, Wilsgaard T, Negaard HFS, Haugnes HS. Testicular Cancer in the Cisplatin Era: Causes of Death and Mortality Rates in a Population-Based Cohort. J Clin Oncol. 2021 Nov 10;39(32):3561-3573. doi: 10.1200/JCO.21.00637. Epub 2021 Aug 13. PMID 34388002