[Classical chemotherapy, immunotherapy, or adjuvant radiotherapy-how to improve the oncologic outcome of radical cystectomy?] / Klassische Chemotherapie, Immuntherapie oder adjuvante Strahlentherapie ­ Wie können wir die onkologischen Ergebnisse der radikalen Zystektomie verbessern?

According to current guidelines, patients with muscle-invasive urothelial carcinoma (pT2-pt4a pN0) should be offered neoadjuvant cisplatin-containing chemotherapy before radical cystectomy. If not used neoadjuvantly, chemotherapy can be administered in the adjuvant setting (for > pT3 or pN+ disease). Both neoadjuvant and adjuvant therapy lead to improved overall survival. In the adjuvant setting, the checkpoint inhibitor nivolumab has also been approved for treatment of PD-L1-positive tumors (tumor proportion score [TPS] ≥ 1%). On the one hand, real-world evidence shows that cisplatin-fit patients often do not receive chemotherapy and, on the other hand, that a relevant proportion of patients are also not suitable for cisplatin-based chemotherapy. Further multimodal therapeutic strategies are hence urgently needed to improve the prognosis of affected patients. In particular, the use of antibody-drug conjugates and combination strategies involving checkpoint inhibitors are currently being intensively researched.

Cabozantinib Plus Nivolumab in Adult Patients with Advanced or Metastatic Renal Cell Carcinoma: A Retrospective, Non-Interventional Study in a Real-World Cohort/GUARDIANS Project.

INTRODUCTION: Combinations of immune-checkpoint inhibitors (ICIs) are the standard of care (SOC) for treatment-naive metastatic renal cell carcinoma (mRCC) patients. In this multicenter study, we evaluated the RW safety and efficacy of cabozantinib plus nivolumab in mRCC patients. METHODS: Data were retrospectively collected from twelve cancer centers in Germany, Switzerland, and Austria. Patients with advanced or mRCC were eligible. The investigator-based objective response rate (ORR) and progression free survival (PFS) were calculated from the start of the treatment to progression or death. Descriptive statistics and Kaplan-Meier (KM) plots were utilized where appropriate. RESULTS: In total, 96 eligible patients (66.6% male) with a median age of 66.0 years were included. The most common histology was clear-cell RCC (ccRCC) in 63.4% (n = 61). A prior nephrectomy was performed in 60.4% (n = 58). ECOG 0-1 was 68.8% (n = 66). A partial response was documented in 43.8% of patients (n = 42), a stable disease in 32.3% (n = 31), and a progressive disease in 8.3% (n = 8) as the best overall response. Response data were not evaluable in 13.5% (n = 13). The median follow-up time was 12.7 months (95% CI, 10.0-15.3). The PFS rate at 6 months was 89.8% in the overall population (86.8% for ccRCC; 90.0% for non-ccRCC). Adverse events (AEs) were reported in 82.3% (n = 79) for all grades and 41.7% (n = 40) for grades 3-5. Elevated liver enzymes (34.4%), diarrhea (31.3%), and hand-foot syndrome (29.2%) were the three most frequent AEs of any grade and causality. DISCUSSION/CONCLUSIONS: In this real-world cohort of mRCC patients, the application of cabozantinib plus nivolumab was shown to be safe and feasible. Our data support the use of cabozantinib plus nivolumab as a first-line standard therapy in mRCC patients. Major limitations were the retrospective data capture and short follow-up time of our study.

[Primary retroperitoneal lymph node dissection in testicular germ cell cancer in clinical stage IIA/B-renaissance of an established treatment?] / Die primäre retroperitoneale Lymphadenektomie beim testikulären Keimzelltumor im klinischen Stadium IIA/B ­ Renaissance einer etablierten Therapie?

BACKGROUND: The guideline-recommended treatment of choice for clinical stage IIA/B testicular germ cell tumors is chemotherapy with three cycles of PEB/four cycles of PE or, alternatively, radiation for seminomas. Despite their high curative efficacy, both options are associated with significant long-term toxicities. We evaluated the functional and oncological outcomes of primary retroperitoneal lymph node dissection (RPLND) as a therapeutic alternative. PATIENTS AND METHODS: Between 2018 and 2022, 76 patients (n = 34 seminomas, n = 42 nonseminomas) underwent primary RPLND for marker-negative clinical stage IIA/B testicular germ cell cancer. All patients underwent nerve-sparing RPLND with a unilateral or bilateral template dissection and had a follow-up ≥ 3 months. None of the patients received adjuvant chemotherapy. In 24 patients, the serum concentration of miR371a-3p was evaluated preoperatively. Follow-up was performed according to EAU guidelines. RESULTS: Median age and median follow-up were 30.1 (17-62) years and 29.3 (3-72) months, respectively. Mean operation time, blood loss, and duration of hospitalization were 131 (105-195) min, < 150 ml, and 4.5 (3-9) days, respectively. A Clavien-Dindo IIIa complication was experienced by 8 (10.9%) patients. Antegrade ejaculation was preserved in 90.8%. A mean number of 19 (7-68) lymph nodes were dissected. The mean number of positive lymph nodes was 1.1 (1-5), and the mean diameter of positive lymph nodes was 2.4 (0.8-4.6) cm. Eleven (14.5%) patients had stage pN0 (3/34 seminomas, 8/42 nonseminomas). In 24/27 patients (88.9%) miR371 was positive, and it was negative in 4/4 with pN0 and 3/3 (100%) with teratoma. An outfield relapse was experienced by 7 patients (9.2%), who then received salvage chemotherapy. CONCLUSION: Primary RPLND for marker-negative clinical stage IIA/B germ cell tumors results in high cure rates without adjuvant chemotherapy and is associated with a low rate of complications if performed in experienced hands. Therefore, primary RPLND should be included in the management of these patients.

Contralateral Testicular Biopsy in Men with Testicular Cancer.

Testicular germ cell tumors (TGCTs) are an uncommon disease accounting for roughly 1% of newly diagnosed cancers in men worldwide. Incidence rates vary from 7 to 10 per 100000 males in Europe and North America. Approximately 2-5% of patients with unilateral TGCT will also harbor germ cell neoplasia in situ (GCNIS) in the contralateral testicle, which may progress to cancer in at least 50% of individuals. The question of whether routine contralateral testicular biopsy should be performed in patients with testicular cancer to detect the presence of GCNIS remains controversial. Screening and treatment of GCNIS are warranted only if the patient's outcome will be improved and there will be little impact on testicular function. In this review, we evaluate current guideline recommendations and the issues concerning contralateral testicular biopsy. PATIENT SUMMARY: Among men with cancer in one testicle, about 2-5% will also have cells with cancerous potential, called germ cell neoplasia in situ (GCNIS), in the other testicle. This mini-review discusses issues related to routine biopsy of the other testicle and the risk factors and treatment options for GCNIS in men with testicular cancer.

Retroperitoneal Lymph Node Dissection in Patients with Stage II Seminomatous Germ Cell Tumour.

Treatment de-escalation strategies in patients with seminoma with retroperitoneal metastases are being investigated in ongoing clinical trials. Primary retroperitoneal lymph node dissection conducted by expert surgeons may avoid any cytotoxic treatment and related long-term side effects in ≥70% of patients with clinical stage IIA/B seminoma.

Regionalization of Testis Cancer Care-Is It Necessary?

Testicular germ cell tumors are rare genitourinary malignancies, but they represent the most common malignancies in men aged 15 to 30 years. Whereas the initial steps of management such as staging imaging studies, inguinal orchiectomy, and tumor marker can be performed elsewhere, the surgical and cytotoxic therapy needs to be done at reference centers. Regionalization of testis care has been shown to result in superior oncological outcome.

Serum Levels of MicroRNA-371a-3p for Predicting the Histology of Postchemotherapy Residual Masses of Germ Cell Tumours.

BACKGROUND AND OBJECTIVE: Serum levels of microRNA-371a-3p (M371) represent a novel and sensitive biomarker of germ cell tumours (GCTs). This study analysed the utility of M371 to identify viable cancer (VC) in postchemotherapy (pc) residual masses with the underlying goal of avoiding overtreatment. METHODS: A multicentric, prospective diagnostic study was conducted in 180 GCT patients undergoing pc resection of residual masses. A correlation of M371 measurement results with the histological presence of VC in masses was found. A receiver operating characteristic analysis was performed for exploring the performance characteristics of the test. KEY FINDINGS AND LIMITATIONS: The sensitivity was found to be 68.9%, specificity 99.3%, area under the curve 0.813, positive predictive value 0.969, and negative predictive value 0.905; sensitivity is significantly associated with the percentage of VC in the mass. In specimens with ≤10% VC, there were 33.3% elevated M371 levels as opposed to 85.7% in specimens with >50% VC. Teratoma and somatic-type malignancy do not express M371. A lack of a central pathological review is a limitation. CONCLUSIONS AND CLINICAL IMPLICATIONS: The M371 test can identify 68.9% of patients with VC in pc masses. However, cases with <10% VC in the mass may escape detection. Teratoma does not express M371. The test alone cannot correctly identify patients requiring pc surgery, but it may be a tool for scheduling the extent of surgery. PATIENT SUMMARY: The microRNA-371a-3p (M371) test can identify about two-thirds of patients with viable cancer in residual metastatic masses following chemotherapy for germ cell tumours. Only masses with high percentages of viable cancer cells can be identified, and the histological subtype teratoma remains undetected with the test.

Medical care services provision and stress experience in urologists during all waves of the COVID-19 pandemic in Germany.

Purpose: Urologists' practices reported decreasing medical care provision and increasing stress experience in the first wave of the COVID-19 pandemic. However, long-term effects of the pandemic are unknown. Methods: Medical record data of n = 127 urologists were used to assess changes in healthcare provision, comparing the pandemic with the pre-pandemic period. An online survey among n = 101 urologists was conducted to assess the physicians' perceptions of the identified healthcare provision and organizational changes and experiences of anxiety, stress, and support needs during the pandemic waves. Urologists consultations, specialists' referrals, hospital admissions, documented cancer diagnoses, urologists' perceptions of causes for these changes and experienced stress, anxiety and support needs. Results were demonstrated using descriptive statistics. Results: Over the first two years of the pandemic, there was a slight decline in consultations (-0,94%), but more intensive reduction in hospital admissions (-13,6%) and identified cancer diagnoses (-6,2%). Although patients' behavior was seen as the main reason for the changes, 71 and 61% of consultations of high-risk patients or urgent surgeries were canceled. Telemedical approaches were implemented by 58% of urologists, and 88% stated that the reduced cancer detection rate would negatively affect patients' outcomes. Urologists reported higher anxiety, stress, and need for support during all waves of the pandemic than other disciplines, especially females. Conclusion: The pandemic tremendously affects urologists' health care provision and stress experience, possibly causing long-term consequences for patients and physicians.

Assessing the risk to develop a growing teratoma syndrome based on molecular and epigenetic subtyping as well as novel secreted biomarkers.

In germ cell tumors (GCT), a growing teratoma during chemotherapy with decreasing tumor markers was defined as 'growing teratoma syndrome' (GTS) by Logothetis et al. in 1982. So far, its pathogenesis and specific treatment options remain elusive. We aimed at updating the GTS definition based on molecular and epigenetic features as well as identifying circulating biomarkers. We selected 50 GTS patients for clinical characterization and subsequently 12 samples were molecularly analyzed. We further included 7 longitudinal samples of 2 GTS patients. Teratomas (TER) showing no features of GTS served as controls. GTS were stratified based on growth rates into a slow (<0.5 cm/month), medium (0.5-1.5) and rapid (>1.5) group. By analyzing DNA methylation, microRNA expression and the secretome, we identified putative epigenetic and secreted biomarkers for the GTS subgroups. We found that proteins enriched in the GTS groups compared to TER were involved in proliferation, DNA replication and the cell cycle, while proteins interacting with the immune system were depleted. Additionally, GTSrapid seem to interact more strongly with the surrounding microenvironment than GTSslow. Expression of pluripotency- and yolk-sac tumor-associated genes in GTS and formation of a yolk-sac tumor or somatic-type malignancy in the longitudinal GTS samples, pointed at an additional occult non-seminomatous component after chemotherapy. Thus, updating the Logothetis GTS definition is necessary, which we propose as follows: The GTS describes a continuously growing teratoma that might harbor occult non-seminomatous components considerably reduced during therapy but outgrowing over time again.

[Systemic therapy for mHSPC: doublet or triplet therapy - who, when and how?] / Medikamentöse Tumortherapie des mHSPC: Double- oder Tripletherapie: wer, wann und wie?

At present, androgen deprivation therapy (ADT) as monotherapy for metastatic hormone-sensitive prostate cancer (mHSPC) should be an exception. The new standard of care is a doublet combination consisting of ADT + a new hormonal agent (NHA) or ADT + chemotherapy. Contemporary investigations even recommend a triplet therapy consisting of ADT + NHA + chemotherapy for selected mHSPC patients. The current evolution of mHSPC therapy demands a pretherapeutic classification of mHSPC: "low" vs. "high risk", "low" vs. "high volume" and synchronous vs. metachronous mHSPC. Additionally, attention should be paid to the drug specific side effects and especially whether the patient is fit for chemotherapy. This article gives a concise overview of the key clinical trials, current guideline recommendations and drug approvals for Germany.

Detection of Recurrence through microRNA-371a-3p Serum Levels in a Follow-up of Stage I Testicular Germ Cell Tumors in the DRKS-00019223 Study.

PURPOSE: Surveillance of clinical stage I (CSI) testicular germ cell tumors (GCT) is hampered by low sensitivity and specificity of current biomarkers for detecting relapses. This study evaluated if serum levels of microRNA371a-3p (M371 test) can: (i) Accurately detect relapses, (ii) detect relapses earlier than conventional technology, and (iii) if elevated postoperative M371 levels may predict relapse. EXPERIMENTAL DESIGN: In a multicentric setting, 258 patients with testicular CSI GCT were prospectively followed by surveillance for a median time of 18 months with serial measurements of serum M371 levels, in addition to standard diagnostic techniques. Diagnostic characteristics of M371 for detecting relapses were calculated using ROC curve analysis. RESULTS: Thirty-nine patients recurred (15.1%), all with elevated M371 levels; eight without relapse had elevations, too. The test revealed the following characteristics: area under the ROC curve of 0.993, sensitivity 100%, specificity 96.3%, positive predictive value 83%, negative predictive value 100%. Earlier relapse detection with the test was found in 28%, with non-significant median time gain to diagnosis. Postoperative M371 levels did not predict future relapse. CONCLUSIONS: The sensitivity and specificity of the M371 test for detecting relapses in CSI GCTs are much superior to those of conventional diagnostics. However, post-orchiectomy M371 levels are not predictive of relapse, and there is no significant earlier relapse detection with the test. In all, there is clear evidence for the utility of the M371 test for relapse detection suggesting it may soon be ready for implementation into routine follow-up schedules for patients with testicular GCT.

Adjunctive Surgery Is Often Without Oncological Benefit at Time of Postchemotherapy Retroperitoneal Lymph Node Dissection.

PURPOSE: Postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for advanced nonseminomatous germ cell tumors (GCTs) aims to resect all remaining metastatic tissue. Resection of adjacent visceral or vascular organs is commonly performed for complete resection. Resection of organs harboring only necrosis results in relevant overtreatment. The study aimed to describe the frequency of metastatic involvement of resected organs with teratoma or viable cancer and to analyze perioperative complications and relapse-free survival. MATERIALS AND METHODS: In a 2-center study, we reviewed a cohort of 1204 patients who underwent PC-RPLND between 2008 and 2021 and identified 242 (20%) cases of adjunctive surgery during PC-RPLND. We analyzed the removed adjacent structures and the pathohistological presence of GCT elements in the resected organs: viable GCT, teratoma, or necrosis/fibrosis. Surgery-associated complications were reported according to the Clavien-Dindo classification. RESULTS: Viable GCT, teratoma, and necrosis were present in 54 (22%), 94 (39%), and 94 (39%), respectively, of all patients with adjunctive resection of adjacent organs. Vascular resections or reconstructions (n = 112; viable: 23%, teratoma: 41%, necrosis: 36%) were performed most frequently, followed by nephrectomies (n = 77; viable: 29%, teratoma: 39%, necrosis: 33%). Perioperative complications of grade ≥ IIIa occurred in 6.6% of all patients, with no difference between the viable GCT and teratoma/necrosis groups (P = .1). A total of 76 patients have been followed without a relapse for at least 36 months. Median follow-up of the whole cohort was 22 months (quartile 7 and 48). Patients with viable GCT/teratoma in the resected specimens had a significantly increased risk of recurrence by 5 years compared to patients with only necrosis (19% vs 59% vs 81%, P < .001). CONCLUSIONS: This study shows that 33% to 40% of all resections of adjacent organs do not harbor teratoma or viable GCT. This highlights the need for better patient selection for these complex patients.

Retroperitoneal Lymph Node Dissection in Clinical Stage IIA/B Metastatic Seminoma: Results of the COlogne Trial of Retroperitoneal Lymphadenectomy In Metastatic Seminoma (COTRIMS).

BACKGROUND: Radiation therapy and systemic chemotherapy are recommended treatment options in marker-negative clinical stage (CS) IIA/B seminoma. Despite high cure rates of 82-94%, both therapeutic options are associated with significant long-term toxicities. OBJECTIVE: To evaluate the feasibility, oncological efficacy, and treatment-associated morbidity of primary nerve-sparing retroperitoneal lymph node dissection (nsRPLND) in CS IIA/B seminoma. DESIGN, SETTING, AND PARTICIPANTS: A prospective, single-arm, clinical phase 2 trial including CS IIA/B seminoma patients was conducted. INTERVENTION: Primary nerve-sparing retroperitoneal lymphadenectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relapse-free and overall survival, surgery-associated complications according to the Clavien-Dindo classification, and Kaplan-Meier methods for survival calculation were assessed. RESULTS AND LIMITATIONS: Thirty patients at a mean age of 39.1 (34-52) yr with marker-negative CS IIA and IIB seminomas were recruited. The median follow-up was 22 (8-30) mo. Nineteen (63%) and 11 (36%) patients were diagnosed with stages IIA and B, respectively, at the time of primary diagnosis. Fourteen (47%) and 16 (53%) patients were diagnosed with CS IIA and IIB, respectively, at the time of nsRPLND. Twenty-seven and three patients underwent open and robot-assisted nsRPLND, respectively. The median operating room time was 125 (115-145) min, median blood loss was <150 ml, and median time of hospitalization was 4.5 (3-9) d. Four (13%) patients experienced Clavien-Dindo grade 3a complications. Lymph node histology revealed seminoma in 25 (80%) patients; two and three patients demonstrated embryonal carcinoma and benign disease, respectively. Sixteen patients underwent a serum analysis of miR371 preoperatively, which predicted metastatic disease in 12/13 and benign histology in 3/3 patients. Three of 30 (10%) patients developed an outfield relapse 4, 6, and 9 mo postoperatively and were salvaged by systemic chemotherapy. Limitations are the low patient number and length of follow-up. CONCLUSIONS: The nsRPLND approach results in a high cure rate at midterm follow-up and is associated with a low frequency of treatment-associated morbidities, making this approach a feasible alternative to radiation therapy or systemic chemotherapy. PATIENT SUMMARY: The standard treatment of clinical stage IIA/B seminomas is radiation therapy or chemotherapy, which results in a significantly increased frequency of long-term toxicity and secondary neoplasms. In this trial, we demonstrate that nerve-sparing retroperitoneal lymph node dissection is a feasible therapeutic approach with low morbidity and high oncological efficacy.

[Venous thromboembolism: risk factors and prophylaxis]. / Thrombembolie-Risikofaktoren und Prophylaxe.

Venous thromboembolism is an important complication in tumour patients as it occurs frequently in these patients and causes relevant morbidity. The risk of thromboembolic complications in tumour patients is 3-9 times higher than in non-tumour patients and is the second most common cause of death in tumour patients. The risk of thrombosis depends on tumour-induced coagulopathy and on individual factors, type and stage of cancer, time since cancer diagnosis as well as type of systemic cancer therapy. Thromboprophylaxis in tumour patients is effective but can be associated with increased bleeding. Even though there are currently no dedicated recommendations for individual tumour entities, international guidelines recommend prophylactic measures in high-risk patients. A thrombosis risk of >8-10% can be considered an indication for thromboprophylaxis, which is indicated by a Khorana score ≥2, and should be calculated individually using nomograms. In particular, patients with a low risk of bleeding should receive thromboprophylaxis. Risk factors and symptoms of a thromboembolic event should also be intensively discussed with the patient and materials for patient information should be handed out.

Molecular and histopathological characterization of seminoma patients with highly elevated human chorionic gonadotropin levels in the serum.

Approximately 30% of seminoma (SEM) patients present with moderately elevated human chorionic gonadotropin (hCG) levels at first diagnosis. In case of high hCG serum levels, the presence of a non-SEM component, i.e. choriocarcinoma (CC), may be assumed. To characterize cases described as pure seminoma with high serum hCG levels, tissue samples and DNA were analyzed. Patient files from an international registry were screened for patients with SEM and extraordinarily high hCG serum levels. IHC and qRT-PCR analysis was performed for markers of SEM, embryonal carcinoma (EC) and CC/trophoblast cells. The cell lines TCam-2 (SEM), 2102EP, NCCIT, NT2/D1 (EC) and JAR, JEG3 and BeWo (CC) were included for comparison. Of 1031 SEM patients screened, 39 patients (3.7%) showed hCG serum levels > 1000 U/l. Of these, tumor material for IHC and RNA for qRT-PCR was available from n = 7 patients and n = 3 patients, respectively. Median pre-orchiectomy serum hCG level was 5356 U/l (range: 1224-40909 U/L). Histopathologically, all investigated samples were classified as SEM with syncytiotrophoblast sub-populations. SEM cells were SALL4+ / OCT3/4+ / D2-40+, while syncytiotrophoblast cells were hCG+ / GATA3+ / p63+ and SOX2-/CDX2-. qRT-PCR analysis detected trophoblast stem cell markers CDX2, EOMES and TFAP2C as well as the trophectoderm-specifier TEAD4, but not GATA3. Additionally, SOX17 and PRAME, but not SOX2, were detected, confirming the pure SEM-like gene expression signature of the analyzed samples. In conclusion, excessively increased hCG serum levels can appear in patients with pure SEM. To explain detectable hCG serum levels, it is important to diagnose the subtype of a SEM with syncytiotrophoblasts.

Evaluation of a miRNA-371a-3p Assay for Predicting Final Histopathology in Patients Undergoing Primary Nerve-sparing Retroperitoneal Lymphadenectomy for Stage IIA/B Seminoma or Nonseminoma.

Patients with marker-negative clinical stage IIA/B seminoma or nonseminoma represent a therapeutic challenge, as 20-30% might harbor nonmalignant histologies. MicroRNA 371a-3p (miR371) may represent a biomarker with diagnostic and predictive properties in testicular germ cell tumors (TGCTs). We evaluated the predictive accuracy of this biomarker in identifying the presence or absence of lymph node metastases (LNMs) in clinical stage IIA/B TGCT. In a cohort of 24 consecutive patients with marker-negative clinical stage IIA/B TGCT (n = 15 seminoma, n = 9 nonseminoma) serum miR371 was assessed 1 d before nerve-sparing retroperitoneal lymphadenectomy. Histology revealed metastatic TGCT in 22/24 patients (91.7%), with positive miR371a findings for 20 of these 22 patients with metastases (90.9%). Histology revealed no malignancy in one patient and lymphoma in another, both of whom had negative miR371a findings. One additional patient with pure teratoma and one with a microscopic seminomatous LNM had false-negative miR371a findings. The miR371 assay had sensitivity of 90.9% and specificity of 50%. The positive predictive value was 100.0% and the negative predictive value was 75.0%. According to the data available, miR371a represents a highly reliable, personalized tumor marker for predicting the presence of low-volume retroperitoneal LNMs in marker-negative TGCT. miR371 has potential for inclusion in the diagnostic armamentarium for men with equivocal lymph nodes to facilitate avoidance of unnecessary treatment and the associated toxicity. PATIENT SUMMARY: Our study demonstrates that blood tests for the biomarker miR371 are highly reliable in predicting the presence of lymph node metastases in patients with stage IIA/B testicular cancer. For patients with equivocal findings, use of this test may help in avoiding unnecessary treatment.

Risk Factors for Relapse in Nonseminomatous Testicular Cancer After Postchemotherapy Retroperitoneal Lymph Node Dissection With Viable Residual Cancer.

PURPOSE: No consensus exists on the management of men with nonseminoma and viable nonteratomatous germ cell tumor in the postchemotherapy retroperitoneal lymph node dissection (pcRPLND) specimen after first-line chemotherapy. We analyzed surveillance versus different adjuvant chemotherapy regimens and the influence of time to pcRPLND on oncologic outcomes. METHODS: Data on 117 men treated with cisplatin-based first-line chemotherapy between 1990 and 2018 were collected from 13 institutions. All patients had viable nonteratomatous germ cell tumor in the pcRPLND specimen. Surgery was performed after a median of 57 days, followed by either surveillance (n = 64) or adjuvant chemotherapy (n = 53). Primary end points were progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: After controlling for International Germ Cell Cancer Cooperative Group risk group and percent of viable malignant cells found at RPLND, no difference was observed between men managed with surveillance or adjuvant chemotherapy regarding PFS (hazard ratio [HR], 0.72 [95% CI, 0.32 to 1.6]; P = .4), CSS (HR, 0.69; 95% CI, 0.20 to 2.39; P = .6), and OS (HR, 0.78 [95% CI, 0.25 to 2.44]; P = .7). No statistically significant differences for PFS, CSS, or OS were observed on the basis of chemotherapy regimen or in men treated with pcRPLND ≤57 versus >57 days after first-line chemotherapy. Residual disease with <10% versus ≥10% viable cancer cells were associated with a longer PFS (HR, 3.22 [95% CI, 1.29 to 8]; P = .012). Relapse in the retroperitoneum was observed in 34 (29%) men. CONCLUSION: Men with a complete resection at pcRPLND and <10% viable cells have favorable outcomes without further treatment. Complete retroperitoneal resection seems more important than early pcRPLND.

Real-world Outcomes and Predictive Biomarkers for 177Lutetium Prostate-specific Membrane Antigen Ligand Treatment in Metastatic Castration-resistant Prostate Cancer: A European Association of Urology Young Academic Urologists Prostate Cancer Working Group Multi-institutional Observational Study.

BACKGROUND: The European Association of Urology guidelines include the lutetium-177 (177Lu) PSMA-617 prostate-specific membrane antigen (PSMA) ligand as a therapy option for metastatic castration-resistant prostate cancer (mCRPC). A major challenge in clinical practice is to pursue a personalized treatment approach based on robust predictive biomarkers. OBJECTIVE: To assess the performance of 177Lu PSMA in real-world practice and to elaborate clinical biomarkers for evaluating treatment responses. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective observational study including 233 patients with mCRPC treated with 177Lu PSMA in eight high-volume European centers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline characteristics and clinical parameters during and after 177Lu PSMA treatment were documented. Correlations to treatment response were analyzed using χ2 and log-rank tests, with differences between groups with and without disease progression calculated using a Mann-Whitney U test. Univariate and multivariate-adjusted hazard ratios (HRs) were measured using Cox proportional hazards models. RESULTS AND LIMITATIONS: A prostate-specific antigen (PSA) decrease of ≥30% was observed in 41.7%, 63.5%, and 77.8% of patients after the first, second, and third treatment cycle, respectively. Restaging performed via PSMA positron emission tomography-computed tomography revealed that 33.7% of patients had an imaging-based response, including two patients with a complete response, while 13.4% had stable disease. The median time to progression was 5 mo and the median time until the start of a consecutive antineoplastic therapy was 8.5 mo. Of importance, a PSA decrease ≥30% after the first two cycles of 177Lu PSMA (1 cycle: p = 0.0003; 2 cycles: p = 0.004), absolute PSA after the first three cycles (1 cycle: p = 0.011; 2 cycles: p = 0.0005; 3 cycles: p = 0.002), and a PSA doubling time >6 mo (p = 0.009) were significantly correlated to treatment response. Furthermore, gamma-glutamyl transferase ≤31 U/L at the start of 177Lu PSMA therapy was correlated with 1.5 times higher risk of progression for patients without but not with visceral metastases (p = 0.046). CONCLUSIONS: 177Lu PSMA is an effective treatment option in mCRPC in the real-world setting. A PSA decrease ≥30% after the first two cycles is an early marker of response that can be easily implemented in clinical practice. PATIENT SUMMARY: 177Lu PSMA is a radioactive agent approved for treatment of advanced prostate cancer. We reviewed its use outside of clinical trials for patients treated at eight European centers. We found that 177Lu PSMA is an effective treatment option in real-world practice. A PSA (prostate-specific antigen) decrease of ≥30% after the first two therapy cycles is an early indicator of response to treatment and can be used in personalizing treatments for patients.