Publications by authors named "Anja Lorch"

48 Publications

Predicting Outcomes in Men With Metastatic Nonseminomatous Germ Cell Tumors (NSGCT): Results From the IGCCCG Update Consortium.

J Clin Oncol 2021 May 6;39(14):1563-1574. Epub 2021 Apr 6.

St Bartholomew's Hospital, London, United Kingdom.

Purpose: The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990.

Materials And Methods: Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,543 patients with complete information on potentially relevant variables. The results were validated in an independent data set.

Results: Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided (https://www.eortc.org/IGCCCG-Update).

Conclusion: The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.
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http://dx.doi.org/10.1200/JCO.20.03296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099402PMC
May 2021

Renal cell carcinoma pathology in 2021: 'new need for renal cancer immune profiling'.

Curr Opin Urol 2021 May;31(3):228-235

Department of Pathology and Molecular Pathology, University of Zurich and University Hospital Zurich.

Purpose Of Review: The aim of this review is to outline characteristics of the renal cell carcinoma (RCC) tumor immune microenvironment (TIME), the potential impact of tumor intrinsic alterations on the TIME and the value of metastatic tissue assessment in this context.

Recent Findings: According to the latest European Association of Urology, European Society for Medical Oncology and National Comprehensive Cancer Network guidelines immune checkpoint inhibition represents a new core treatment strategy in advanced clear cell RCC (ccRCC). Despite its success, the prognosis of many RCC patients remains unsatisfactory most likely because of resistance mechanisms within the TIME. Moreover, most studies assess the primary tumor even though the advanced metastatic disease is targeted. Overall, metastatic RCC has hardly been investigated. First insights into the complexity of the genomic and immune landscape in RCC were recently provided. The functional impact of tumor intrinsic alterations on the TIME has just been described potentially contributing to therapy response in RCC.

Summary: The complexity of the RCC TIME and its potential interdependence with tumor intrinsic alterations has only just been recognized. A deeper understanding of the TIME may reveal predictive and prognostic biomarkers long-awaited in RCC, improve RCC patient stratification and could possibly be most instructive if assessed in metastatic tissue.
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http://dx.doi.org/10.1097/MOU.0000000000000864DOI Listing
May 2021

Survival and New Prognosticators in Metastatic Seminoma: Results From the IGCCCG-Update Consortium.

J Clin Oncol 2021 May 17;39(14):1553-1562. Epub 2021 Mar 17.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Current affiliation: Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy.

Purpose: The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium.

Materials And Methods: Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients.

Results: Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH.

Conclusion: PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.
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http://dx.doi.org/10.1200/JCO.20.03292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099394PMC
May 2021

The prognostic significance of lactate dehydrogenase levels in seminoma patients with advanced disease: an analysis by the Global Germ Cell Tumor Collaborative Group (G3).

World J Urol 2021 Mar 8. Epub 2021 Mar 8.

SWENOTECA, Trondheim, Norway.

Purpose: The prognostic significance of lactate dehydrogenase (LDH) in patients with metastatic seminoma is not defined. We investigated the prognostic impact of LDH levels prior to first-line systemic treatment and other clinical characteristics in this subset of patients.

Methods: Files from two registry studies and one single-institution database were analyzed retrospectively. Uni- and multivariate analyses were conducted to identify patient characteristics associated with recurrence free survival (RFS), overall survival (OS), and complete response rate (CRR).

Results: The dataset included 351 metastatic seminoma patients with a median follow-up of 5.36 years. Five-year RFS, OS and CRR were 82%, 89% and 52%, respectively. Explorative analysis revealed a cut-off LDH level of < 2.5 upper limit of normal (ULN) (n = 228) vs. ≥ 2.5 ULN (n = 123) to be associated with a significant difference concerning OS associated with 5-years OS rates of 93% vs. 83% (p = 0.001) which was confirmed in multivariate analysis (HR 2.87; p = 0.004). Furthermore, the cut-off LDH < 2.5 ULN vs. ≥ 2.5 ULN correlated with RFS and CRR associated with a 5-years RFS rate and CRR of 76% vs. 86% (p = 0.012) and 32% vs. 59% (p  ≤  0.001), respectively.

Conclusions: LDH levels correlate with treatment response and survival in metastatic seminoma patients and should be considered for their prognostic stratification.
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http://dx.doi.org/10.1007/s00345-021-03635-3DOI Listing
March 2021

Clinicopathological characteristics and outcomes in men with mesothelioma of the tunica vaginalis testis: analysis of published case-series data.

J Cancer Res Clin Oncol 2021 Feb 9. Epub 2021 Feb 9.

Department of Urology, University Hospital Zurich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland.

Purpose: Mesothelioma of the tunica vaginalis testis (MTVT) is a rare tumor, and currently, there are no published treatment recommendations.

Methods: We performed a systematic literature review and synthesized clinical presentation, clinicopathological factors associated with metastatic disease, treatment options, and outcomes in men with MTVT.

Results: We included 170 publications providing data on 275 patients. Metastatic disease occurred in 84/275 (31%) men with malignant MTVT: Most common sites included retroperitoneal lymph nodes (LNs) (40/84, 48%), lungs (30/84, 36%), and inguinal LNs (23/84, 27%). Invasion of the spermatic cord or scrotum was the only risk factor for local recurrence [odds ratio (OR) 3.21, 95% confidence interval (CI) 1.36-7.57]. Metastatic disease was associated with age ≥ 42 years (OR 3.02, 95% CI 1.33-6.86), tumor size ≥ 49 mm (OR 6.17, 95% CI 1.84-20.74), presence of necrosis (OR 8.31, 95% CI 1.58-43.62), high mitotic index (OR 13.36, 95% CI 1.53-116.51) or angiolymphatic invasion (OR 3.75, 95% CI 1.02-13.80), and local recurrence (OR 4.35, 95% CI 2.00-9.44). Complete remission in the metastatic setting was observed in five patients, most of whom were treated with multimodal therapy. Median survival in patients with metastatic disease was 18 months (IQR 7-43).

Conclusion: Malignant MTVT is a rare but aggressive disease. Since local recurrence is a risk factor for metastatic progression, we recommend aggressive local treatment. Survival and response to any treatment in the metastatic setting are limited.
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http://dx.doi.org/10.1007/s00432-021-03533-6DOI Listing
February 2021

Management of Germ Cell Tumours of the Testes in Adult Patients: German Clinical Practice Guideline, PART II - Recommendations for the Treatment of Advanced, Recurrent, and Refractory Disease and Extragonadal and Sex Cord/Stromal Tumours and for the Management of Follow-Up, Toxicity, Quality of Life, Palliative Care, and Supportive Therapy.

Urol Int 2021 22;105(3-4):181-191. Epub 2021 Jan 22.

II. Medical Clinic and Polyclinic, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Objectives: We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult patients. We present the guideline content in 2 separate publications. The present second part summarizes therecommendations for the treatment of advanced disease stages and for the management of follow-up and late effects.

Materials And Methods: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search in March 2018), were provided. Thirty-one experts, who were entitled to vote, rated the final clinical recommendations and statements.

Results: Here we present the treatment recommendations separately for patients with metastatic seminoma and non-seminomatous GCT (stages IIA/B and IIC/III), for restaging and treatment of residual masses, and for relapsed and refractory disease stages. The recommendations also cover extragonadal and sex cord/stromal tumours, the management of follow-up and toxicity, quality-of-life aspects, palliative care, and supportive therapy.

Conclusion: Physicians and other medical service providers who are involved in the diagnostics, treatment, and follow-up of GCT (all stages, outpatient and inpatient care as well as rehabilitation) are the users of the present guideline. The guideline also comprises quality indicators for measuring the implementation of the guideline recommendations in routine clinical care; these data will be presented in a future publication.
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http://dx.doi.org/10.1159/000511245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006578PMC
January 2021

Management of Germ Cell Tumours of the Testis in Adult Patients. German Clinical Practice Guideline Part I: Epidemiology, Classification, Diagnosis, Prognosis, Fertility Preservation, and Treatment Recommendations for Localized Stages.

Urol Int 2021 7;105(3-4):169-180. Epub 2021 Jan 7.

II. Medical Clinic and Polyclinic, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Introduction: This is the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up on germ cell tumours (GCTs) of the testis in adult patients. We present the guideline content in two publications. Part I covers the topic's background, methods, epidemiology, classification systems, diagnostics, prognosis, and treatment recommendations for the localized stages.

Methods: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search was in March 2018) were provided. Thirty-one experts entitled to vote, rated the final clinical recommendations and statements.

Results: We provide 161 clinical recommendations and statements. We present information on the quality of cancer care and epidemiology and give recommendations for staging and classification as well as for diagnostic procedures. The diagnostic recommendations encompass measures for assessing the primary tumour as well as procedures for the detection of metastases. One chapter addresses prognostic factors. In part I, we separately present the treatment recommendations for germ cell neoplasia in situ, and the organ-confined stages (clinical stage I) of both seminoma and nonseminoma.

Conclusion: Although GCT is a rare tumour entity with excellent survival rates for the localized stages, its management requires an interdisciplinary approach, including several clinical experts. Quality of care is highly related to institutional expertise and can be reassured by established online-based second-opinion boards. There are very few studies on diagnostics with good level of evidence. Treatment of metastatic GCTs must be tailored to the risk according to the International Germ Cell Cancer Collaboration Group classification after careful diagnostic evaluation. An interdisciplinary approach as well as the referral of selected patients to centres with proven experience can help achieve favourable clinical outcomes.
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http://dx.doi.org/10.1159/000510407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006579PMC
January 2021

Short-term and long-term outcomes after resection of thoracic growing teratoma syndrome.

World J Urol 2020 Oct 31. Epub 2020 Oct 31.

Department of Thoracic Surgery, Agaplesion Markus Krankenhaus Frankfurt, Wilhelm-Epstein-Str. 4, 60431, Frankfurt, Germany.

Purpose: Thoracic growing teratoma syndrome (TGTS) is a rare disease in patients with germ cell tumors. Other than a few case reports and a limited number of case series, studies of this topic are not available.

Methods: We retrospectively analyzed the data from our patients who received surgery for TGTS between 1999 and 2016. Descriptive statistical analyses were performed to analyze the characteristics of the patients, tumors, and short-term outcomes. Furthermore, the long-term outcomes and survival curves were analyzed using the Kaplan-Meier method.

Results: Twenty-nine patients underwent surgery for TGTS. The median age was 32 years (range: 19-50 years). All patients received cisplatin-based chemotherapy. Many of the patients had multilocalized TGTS (n = 10). The median tumor size was 64.5 mm (range 10-210 mm). In all cases, R0 resection was achieved. The minor morbidity, major morbidity, and mortality rates were 3.4%, 6.9%, and 0%, respectively. Altogether, 28 patients were included in the long-term follow-up analysis, with a median follow-up time of 94 months (13-237 months). The 5-, 10-, and 15-year survival rates were 93%, 93%, and 84%, respectively.

Conclusions: TGTS may occur in multiple localizations and grow to a large tumor size. The resection of TGTS can be performed with low morbidity and mortality rates and is associated with good overall survival after complete resection. Important are an early detection and knowledge of the systemic treatment options by the oncologist and urologist, as well as a thoracic surgeon with a large experience in extended thoracic resections.
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http://dx.doi.org/10.1007/s00345-020-03503-6DOI Listing
October 2020

Risk factors and treatment outcomes of 239 patients with testicular granulosa cell tumors: a systematic review of published case series data.

J Cancer Res Clin Oncol 2020 Nov 27;146(11):2829-2841. Epub 2020 Jul 27.

Department of Urology, University Hospital, University of Zurich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland.

Purpose: Testicular granulosa cell tumors (tGrCT) are rare sex cord-stromal tumors. This review aims to synthesize the available evidence regarding the clinical presentation and clinicopathological characteristics, treatment and outcomes.

Methods: We conducted a systematic literature search using the most important research databases. Whenever feasible, we extracted the data on individual patient level.

Results: From 7863 identified records, we included 88 publications describing 239 patients with tGrCT. The majority of the cases were diagnosed with juvenile tGrCT (166/239, 69%), while 73/239 (31%) patients were diagnosed with adult tGrCT. Mean age at diagnosis was 1.5 years (± 5 SD) for juvenile tGrCT, and 42 years (± 19 SD) for adult tGrCT. Information on primary treatment was available in 231/239 (97%), of which 202/231 (87%) were treated with a radical orchiectomy and 20/231 (9%) received testis sparing surgery (TSS). Local recurrence after TSS was observed in 1/20 (5%) cases. Metastatic disease was never observed in men with juvenile tGrCT but in 7/73 (10%) men with adult tGrCT. In 5/7 men with metastatic tGrCT, metastases were diagnosed at initial staging, while 2/7 patients developed metastases after 72 and 121 months of follow-up, respectively. Primary site of metastasis is represented by the retroperitoneal lymph nodes, but other sites including lungs, liver, bone and inguinal lymph nodes can also be affected. In comparison with non-metastatic adult tGrCT, men with metastatic adult tGrCT had significantly larger primary tumors (70 vs 24 mm, p 0.001), and were more likely to present with angiolymphatic invasion (57% vs 4%, p 0.002) or gynecomastia (29% vs 3%, p 0.019). In five out of seven men with metastatic disease, resection of metastases or platinum-based chemotherapy led to complete remission.

Conclusion: Juvenile tGrCT represent a benign entity whereas adult tGCTs have metastatic potential. Tumor size, presence of angiolymphatic invasion or gynecomastia represent risk factors for metastatic disease. The published literature supports the use of testis sparing surgery but there is only limited experience with adjuvant therapies. In the metastatic setting, the reviewed literature suggests that aggressive surgical and systemic treatment might cure patients.
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http://dx.doi.org/10.1007/s00432-020-03326-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519920PMC
November 2020

European Association of Urology Guidelines on Primary Urethral Carcinoma-2020 Update.

Eur Urol Oncol 2020 08 27;3(4):424-432. Epub 2020 Jun 27.

Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.

Context: Primary urethral carcinoma (PUC) is a rare cancer accounting for <1% of all genitourinary malignancies.

Objective: To provide updated practical recommendations for the diagnosis and management of PUC.

Evidence Acquisition: A systematic search interrogating Ovid (Medline), EMBASE, and the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews was performed.

Evidence Synthesis: Urothelial carcinoma of the urethra is the predominant histological type of PUC (54-65%), followed by squamous cell carcinoma (16-22%) and adenocarcinoma (10-16%). Diagnosis of PUC depends on urethrocystoscopy with biopsy and urinary cytology. Pathological staging and grading are based on the tumour, node, metastasis (TNM) classification and the 2016 World Health Organization grading systems. Local tumour extent and regional lymph nodes are assessed by magnetic resonance imaging, and the presence of distant metastases is assessed by computed tomography of the thorax/abdomen and pelvis. For all patients with localised distal tumours (≤T2N0M0), partial urethrectomy or urethra-sparing surgery is a valid treatment option, provided that negative intraoperative surgical margins can be achieved. Prostatic Ta-Tis-T1 PUC can be treated with repeat transurethral resection of the prostate and bacillus Calmette-Guérin. In prostatic or proximal ≥ T2N0 disease, neoadjuvant cisplatin-based chemotherapy should be considered prior to radical surgery. All patients with locally advanced disease (≥T3N0-2M0) should be discussed within a multidisciplinary team. In men with locally advanced squamous cell carcinoma, curative radiotherapy combined with radiosensitising chemotherapy can be offered for definitive treatment and genital preservation. In patients with local urethral recurrence, salvage surgery or radiotherapy can be offered. For patients with distant metastatic disease, systemic therapy based on tumour characteristics can be evaluated.

Conclusions: These updated European Association of Urology guidelines provide up-to-date guidance for the contemporary diagnosis and management of patients with suspected PUC.

Patient Summary: Primary urethral carcinoma (PUC) is a very rare, but aggressive disease. These updated European Association of Urology guidelines provide evidence-based guidance for clinicians treating patients with PUC.
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http://dx.doi.org/10.1016/j.euo.2020.06.003DOI Listing
August 2020

Human chorionic gonadotropin-positive seminoma patients: A registry compiled by the global germ cell tumor collaborative group (G3).

Eur J Cancer 2020 06 29;132:127-135. Epub 2020 Apr 29.

Department of Oncology, Hematology and Bone Marrow Transplantation with Division of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: The prognostic role of human chorionic gonadotropin (hCG) and lactate dehydrogenase (LDH) serum levels in seminoma patients remains uncertain. This observational study evaluates the prognostic impact of tumour marker levels, and other clinicopathological findings, in hCG-positive seminoma patients.

Methods: Seminoma patients with serum hCG levels above normal at first diagnosis were eligible for recruitment. Statistical analysis, including multivariate regression, was performed to identify risk factors. Primary end-points were overall survival (OS) and recurrence-free survival (RFS).

Results: We recruited 1031 hCG-positive patients (stage I: n = 586; stage II + III: n = 427) diagnosed between 1981 and 2018. In metastatic disease, LDH levels ≥3 above upper normal limit (UNL) pre- (n = 109) or post-orchiectomy (n = 73) and patients aged ≥40 years (n = 187) were associated with poor prognosis: 5-year OS rates of 84% (LDH ≥3 UNL pre-orchiectomy) versus 92% (<3 UNL pre-orchiectomy) (hazard ratio [HR]: 3.155, [95% confidence interval {CI}: 1.28-7.75], P = 0.012), 82% (≥3 UNL post-orchiectomy) versus 92% (<3 UNL post-orchiectomy) (HR: 6.877, [95% CI: 1.61-29.34]; P = 0.009) and 86% (≥40 years) versus 91% (<40 years) (HR: 6.870, [95% CI: 1.45-13.37], P = 0.009), respectively. A subset of patients with hCG levels ≥2000 IU/l pre-orchiectomy (n = 17) exhibited a poor prognosis, with 5-year OS rates of 73% (≥2000 IU/l) versus 94% (<2000 IU/l) (HR: 3.936, [95% CI: 1.02-12.61], P = 0.047).

Conclusions: Age and LDH levels are significantly associated with poor prognosis in hCG-positive seminoma patients. A small number of patients, with levels of hCG ≥2000 IU/l, may represent a separate prognostic subgroup associated with impaired survival rates.
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http://dx.doi.org/10.1016/j.ejca.2020.03.022DOI Listing
June 2020

European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines.

Eur Urol 2021 01 29;79(1):82-104. Epub 2020 Apr 29.

Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Context: This overview presents the updated European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC).

Objective: To provide practical evidence-based recommendations and consensus statements on the clinical management of MMIBC with a focus on diagnosis and treatment.

Evidence Acquisition: A broad and comprehensive scoping exercise covering all areas of the MMIBC guideline has been performed annually since its 2017 publication (based on the 2016 guideline). Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries, resulting in yearly guideline updates. A level of evidence and a grade of recommendation were assigned. Additionally, the results of a collaborative multistakeholder consensus project on advanced bladder cancer (BC) have been incorporated in the 2020 guidelines, addressing those areas where it is unlikely that prospective comparative studies will be conducted.

Evidence Synthesis: Variant histologies are increasingly reported in invasive BC and are relevant for treatment and prognosis. Staging is preferably done with (enhanced) computerised tomography scanning. Treatment decisions are still largely based on clinical factors. Radical cystectomy (RC) with lymph node dissection remains the recommended treatment in highest-risk non-muscle-invasive and muscle-invasive nonmetastatic BC, preceded by cisplatin-based neoadjuvant chemotherapy (NAC) for invasive tumours in "fit" patients. Selected men and women benefit from sexuality sparing RC, although this is not recommended as standard therapy. Open and robotic RC show comparable outcomes, provided the procedure is performed in experienced centres. For open RC 10, the minimum selected case load is 10 procedures per year. If bladder preservation is considered, chemoradiation is an alternative in well-selected patients without carcinoma in situ and after maximal resection. Adjuvant chemotherapy should be considered if no NAC was given. Perioperative immunotherapy can be offered in clinical trial setting. For fit metastatic patients, cisplatin-based chemotherapy remains the first choice. In cisplatin-ineligible patients, immunotherapy in Programmed Death Ligand 1 (PD-L1)-positive patients or carboplatin in PD-L1-negative patients is recommended. For second-line treatment in metastatic disease, pembrolizumab is recommended. Postchemotherapy surgery may prolong survival in responders. Quality of life should be monitored in all phases of treatment and follow-up. The extended version of the guidelines is available at the EAU website: https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/.

Conclusions: This summary of the 2020 EAU MMIBC guideline provides updated information on the diagnosis and treatment of MMIBC for incorporation into clinical practice.

Patient Summary: The European Association of Urology Muscle-invasive and Metastatic Bladder Cancer (MMIBC) Panel has released an updated version of their guideline, which contains information on histology, staging, prognostic factors, and treatment of MMIBC. The recommendations are based on the current literature (until the end of 2019), with emphasis on high-level data from randomised clinical trials and meta-analyses and on the findings of an international consensus meeting. Surgical removal of the bladder and bladder preservation are discussed, as well as the use of chemotherapy and immunotherapy in localised and metastatic disease.
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http://dx.doi.org/10.1016/j.eururo.2020.03.055DOI Listing
January 2021

Non-Coding microRNAs as Novel Potential Tumor Markers in Testicular Cancer.

Cancers (Basel) 2020 Mar 22;12(3). Epub 2020 Mar 22.

Research Unit of Non-Coding RNAs and Genome Editing in Cancers, Medical University of Graz, 8010 Graz, Austria.

Testicular cancer is an important disease with increasing incidence and a high burden of morbidity and mortality in young men worldwide. Histological examination of the testicular tissue after orchiectomy plays an important role alongside patient history, imaging, clinical presentation and laboratory parameters. Surgical procedures and chemotherapeutic treatment provide a high chance of cure in early stages, though some patients in advanced stages belonging to a poor risk group experience cancer-related death. Though conventional serum-based tumor markers, including α-fetoprotein (AFP), the β-subunit of human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH), are useful as prognostic and diagnostic biomarkers, unfortunately, these tumor markers only have a sensitivity of about 60%, and in pure seminoma even lower with about 20%. Therefore, the development of new tumor markers is an important and intensively ongoing issue. The analysis of epigenetic modification and non-coding RNA microRNAs (miRNAs) are carrying most promising potential as tumor markers in future. miRNAs are small RNAs secreted by testicular tumor cells and circulate and be measurable in body fluids. In recent years, miRNAs of the miR-371-373 cluster in particular have been identified as potentially superior tumor markers in testicular cancer patients. Studies showed that miR-371a-3p and miR-302/367 expression significantly differ between testicular tumors and healthy testicular tissue. Several studies including high prospective multi-center trials clearly demonstrated that these miRNAs significantly exceed the sensitivity and specificity of conventional tumor markers and may help to facilitate the diagnosis, follow-up, and early detection of recurrences in testicular cancer patients. In addition, other miRNAs such as miR-223-3p, miR-449, miR-383, miR-514a-3p, miR-199a-3p, and miR-214 will be discussed in this review. However, further studies are needed to identify the value of these novel markers in additional clinical scenarios, including the monitoring in active surveillance or after adjuvant chemotherapy, but also to show the limitations of these tumor markers. The aim of this review is to give an overview on the current knowledge regarding the relevance of non-coding miRNAs as biomarkers in testicular cancer.
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http://dx.doi.org/10.3390/cancers12030749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140096PMC
March 2020

Sertoli Cell Tumors of the Testes: Systematic Literature Review and Meta-Analysis of Outcomes in 435 Patients.

Oncologist 2020 07 11;25(7):585-590. Epub 2020 Feb 11.

Department of Urology, University Hospital, University of Zurich, Zurich, Switzerland.

Background: Sertoli cell tumors (SCTs) of the testes are rare, and the literature provides only weak evidence concerning their clinical course and management. The objective of this study was to summarize evidence on SCTs' clinical presentation, clinicopathological risk factors for malignancy, treatment options, and oncological outcomes.

Materials And Methods: Data sources included Medline, Embase, Scopus, the Cochrane Database of Systematic Reviews, and Web of Science. Published case reports, case series, and cohorts were included. Data on clinicopathological variables, treatment of local or metastatic disease, site of metastasis, or survival were extracted from each study considered in this paper, and associations between clinicopathological variables and metastatic disease were analyzed. Whenever feasible, data on individual patients were collected.

Results: Of the 435 patients included, only one (<1%) showed local recurrence after testis-sparing surgery (TSS). Three patients underwent adjuvant retroperitoneal lymphadenectomy. Fifty patients presented with metastases, located in the retroperitoneal lymph nodes (76%), lungs (36%), and bones (16%); median time to recurrence was 12 months. Risk factors for metastatic disease included age, tumor size, necrosis, tumor extension to the spermatic cord, angiolymphatic invasion, and mitotic index. Patients with metastases had a median life expectancy of 20 months. In six patients, metastasectomy resulted in complete remission.

Conclusion: Our findings suggest that few local recurrences result after TSS, and no adjuvant therapy can be regarded as a standard of care. Several risk factors are predictive of metastatic disease. Surgery leads to remission in metastatic disease, whereas systemic treatment alone does not result in long-term remission.

Implications For Practice: Testicular Sertoli cell tumors usually present without metastatic disease and show low local recurrence rates after testis-sparing surgery; no adjuvant therapy option can be regarded as a standard of care. Patients with risk factors should undergo staging investigations. Those with metastatic disease have poor prognoses, and metastasectomy may be offered in selected cases.
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http://dx.doi.org/10.1634/theoncologist.2019-0692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356704PMC
July 2020

Outcome of Men With Relapses After Adjuvant Bleomycin, Etoposide, and Cisplatin for Clinical Stage I Nonseminoma.

J Clin Oncol 2020 04 26;38(12):1322-1331. Epub 2019 Dec 26.

Cantonal Hospital St Gallen, Department of Medical Oncology and Hematology, St. Gallen, Switzerland.

Purpose: Clinical stage I (CSI) nonseminoma (NS) is a disease limited to the testis without metastases. One treatment strategy after orchiectomy is adjuvant chemotherapy. Little is known about the outcome of patients who experience relapse after such treatment.

Patients And Methods: Data from 51 patients with CSI NS who experienced a relapse after adjuvant bleomycin, etoposide, and cisplatin (BEP) from 18 centers/11 countries were collected and retrospectively analyzed. Primary outcomes were overall and progression-free survivals calculated from day 1 of treatment at first relapse. Secondary outcomes were time to, stage at, and treatment of relapse and rate of subsequent relapses.

Results: Median time to relapse was 13 months, with the earliest relapse 2 months after start of adjuvant treatment and the latest after 25 years. With a median follow-up of 96 months, the 5-year PFS was 67% (95% CI, 54% to 82%) and the 5-year OS was 81% (95% CI, 70% to 94%). Overall, 19 (37%) of 51 relapses occurred later than 2 years. Late relapses were associated with a significantly higher risk of death from NS (hazard ratio, 1.10 per year; = .01). Treatment upon relapse was diverse: the majority of patients received a combination of chemotherapy and surgery. Twenty-nine percent of patients experienced a subsequent relapse. At last follow-up, 41 patients (80%) were alive and disease-free, eight (16%) had died of progressive disease, and one patient (2%) each had died from therapy-related or other causes.

Conclusion: Outcomes of patients with relapse after adjuvant BEP seem better compared with patients who experience relapse after treatment of metastatic disease but worse compared with those who have de-novo metastatic disease. We found a substantial rate of late and subsequent relapses. There seem to be three patterns of relapse with different outcomes: pure teratoma, early viable NS relapse (< 2 years), and late viable NS relapse (> 2 years).
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http://dx.doi.org/10.1200/JCO.19.01876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164488PMC
April 2020

The Importance of Hospital and Surgeon Volume as Major Determinants of Morbidity and Mortality After Radical Cystectomy for Bladder Cancer: A Systematic Review and Recommendations by the European Association of Urology Muscle-invasive and Metastatic Bladder Cancer Guideline Panel.

Eur Urol Oncol 2020 04 19;3(2):131-144. Epub 2019 Dec 19.

Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.

Context: In bladder cancer patients treated with radical cystectomy (RC), controversy exists regarding the impact of the annual hospital volume (HV) and/or surgeon volume (SV) on oncological outcomes and quality of care.

Objective: A systematic review was performed to evaluate the impact of HV and SV on clinical outcomes. Primary outcomes included in-hospital, 30-d, and 90-d mortality. Secondary outcomes included complications, long-term survival, positive surgical margin rate, lymphadenectomy performance, length of hospital stay, neobladder performance, and blood loss/transfusion rate.

Evidence Acquisition: Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched. Comparative studies published after the year of 2000 including patients who underwent RC for bladder cancer were eligible for inclusion. Partial cystectomy was an exclusion criterion. Risk of bias (RoB) assessment was performed according to the ROBINS-1 tool.

Evidence Synthesis: After screening of 1190 abstracts, 39 studies recruiting 549 542 patients were included. All studies were retrospective observation cohort studies (level of evidence 3). Twenty-two studies reported on HV only, six studies on SV only, and 12 on both. Higher HV, specifically an HV of >10, was associated with improved primary and secondary outcomes in most studies. In addition, there is some evidence that an HV of >20 improves outcomes. For SV, limited and conflicting data are reported. Most studies had moderate to high RoB. The results were synthesized narratively.

Conclusions: Acknowledging the lower level of evidence, HV is likely associated with in-hospital, 30- and 90-d mortality, as well as the secondary outcomes assessed. Based on this study, the European Association of Urology Muscle-invasive and Metastatic Bladder Cancer Guideline Panel recommends hospitals to perform at least 10, and preferably >20, RCs annually or refer the patient to a center that reaches this number. For SV, limited and conflicting data are available. The available evidence suggests HV rather than SV to be the main driver of perioperative outcomes.

Patient Summary: Current literature suggests that the number of bladder removal operations per hospital per year is associated with postoperative survival as well as the quality of care provided.
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http://dx.doi.org/10.1016/j.euo.2019.11.005DOI Listing
April 2020

Treatment of refractory germ-cell tumours with single-agent cabazitaxel: a German Testicular Cancer Study Group case series.

J Cancer Res Clin Oncol 2020 Feb 14;146(2):449-455. Epub 2019 Dec 14.

Haematology and Bone Marrow Transplantation with Division of Pneumology, Department of Oncology, University Medical Centre Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Purpose: Outcomes of multiply relapsed, refractory germ-cell tumour (GCT) patients remain poor with an overall survival (OS) of a few months only. Thus, new therapeutic advances are urgently needed. Cabazitaxel has shown preclinical activity in platinum-resistant GCT models. Here, we report the first clinical case series of cabazitaxel treatment for platinum-refractory GCT.

Methods: Data of multiply relapsed GCT patients receiving single-agent cabazitaxel were retrospectively analysed. Endpoints included 12-week progression-free survival (PFS) rate, disease control rate, tumour marker responses, median PFS and OS, and toxicity.

Results: Cabazitaxel showed limited activity in 13 heavily pre-treated GCT patients. After a median follow-up of 23 weeks (IQR 29), 69% of patients were deceased. A median of 2 cycles of cabazitaxel (range 1-7) were applied. The 12-week PFS rate was 31%. Median PFS and OS were 7 and 23 weeks, respectively. Two patients achieved objective responses (15%), three patients (23%) achieved a tumour marker decline ≥ 50%, and the disease control rate was 39%. Cabazitaxel was well tolerated. CTCAE° III-IV haemato-toxicity was most common (54%), and dose reductions were scarce (15%).

Conclusion: In this case series, cabazitaxel showed limited activity in heavily pre-treated GCT patients. Two-phase II studies are underway (NCT02115165, NCT02478502) prospectively assessing cabazitaxel in multiply relapsed GCTs.
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http://dx.doi.org/10.1007/s00432-019-03071-2DOI Listing
February 2020

EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort: Under the Auspices of the EAU-ESMO Guidelines Committees.

Eur Urol 2020 02 19;77(2):223-250. Epub 2019 Nov 19.

Department of Biomedical Sciences, Humanitas University, Milan, Italy; Humanitas Research Hospital, Milan, Italy.

Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.

Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.

Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.

Setting: Online Delphi survey and consensus conference.

Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.

Outcome Measurements And Statistical Analysis: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).

Results And Limitations: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.

Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.

Patient Summary: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.
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http://dx.doi.org/10.1016/j.eururo.2019.09.035DOI Listing
February 2020

Serum Levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell Tumors: Results of a Prospective Multicentric Study.

J Clin Oncol 2019 06 15;37(16):1412-1423. Epub 2019 Mar 15.

27 Kantonsspital Graubünden, Chur, Switzerland.

Purpose: Previous studies suggested that serum levels of microRNA (miR)-371a-3p (so-called M371 test) have a much higher sensitivity and specificity than the classic markers of testicular germ cell tumors (GCTs) and are applicable toward both seminoma and nonseminoma. We sought to confirm the usefulness of this test as a novel biomarker for GCT.

Patients And Methods: In a prospective, multicentric study, serum samples of 616 patients with testicular GCTs and 258 male controls were examined for serum levels of miRNA-371a-3p (miR levels) by quantitative polymerase chain reaction. The GCT population encompassed 359 patients with seminoma and 257 with nonseminoma; 371 had clinical stage I disease, 201 had systemic disease, and 46 had relapses. Paired measurements before and after orchiectomy were performed in 424 patients; 118 with systemic disease had serial measurements during treatment. miR levels were compared with those of β-human chorionic gonadotropin, α-fetoprotein, and lactate dehydrogenase.

Results: For the primary diagnosis of GCT, the M371 test showed a sensitivity of 90.1%, a specificity of 94.0%, an area under the curve of 0.966 upon receiver operating characteristic analysis, and a positive predictive value of 97.2%. α-Fetoprotein, β-human chorionic gonadotropin, and lactate dehydrogenase had sensitivities of less than 50% in seminoma and slightly higher sensitivities in nonseminomas. miR levels were significantly associated with clinical stage, primary tumor size, and response to treatment. Relapses had elevated miR levels that subsequently dropped to normal upon remission. Teratoma did not express miR-371a-3p.

Conclusion: The M371 test outperforms the classic markers of GCT with both a sensitivity and a specificity greater than 90%. All histologic subgroups, except teratoma, express this marker. The test could be considered for clinical implementation after further validation.
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http://dx.doi.org/10.1200/JCO.18.01480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544462PMC
June 2019

Questioning the Value of Fluorodeoxyglucose Positron Emission Tomography for Residual Lesions After Chemotherapy for Metastatic Seminoma: Results of an International Global Germ Cell Cancer Group Registry.

J Clin Oncol 2018 Oct 4:JCO1800210. Epub 2018 Oct 4.

Richard Cathomas, Kantonsspital Graubünden, Chur; Dirk Klingbiel, Swiss Group for Clinical Cancer Research Coordinating Center; Silke Gillessen, University of Bern; Jörg Beyer, Inselspital, Bern University Hospital, University of Bern, Bern; Christian Fankhauser, University of Zürich, Zürich; Silke Gillessen, Kantonsspital St Gallen, St Gallen, Switzerland; Brandon Bernard, Dana-Farber Cancer Institute, Boston, MA; Anja Lorch, University of Düsseldorf, Düsseldorf; Christoph Oing, University Medical Center Hamburg-Eppendorf, Hamburg; Marcus Hentrich, Rotkreuzklinikum München, München, Germany; Xavier Garcia del Muro, Institute Catalan of Oncology, Bellvitge Biomedical Research Institute, University of Barcelona, Barcelona, Spain; Franco Morelli, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo; Ugo De Giorgi, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Istituto di Ricovero e Cura a Carattere Scientifico, Meldola, Italy; Mikhail Fedyanin, N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia; and Hege Sagstuen Haugnes, University Hospital of North Norway and Universitetet i Tromsø-The Arctic University, Tromsø, Norway.

Purpose: Residual lesions after chemotherapy are frequent in metastatic seminoma. Watchful waiting is recommended for lesions < 3 cm as well as for fluorodeoxyglucose (FDG) positron emission tomography (PET)-negative lesions ≥ 3 cm. Information on the optimal management of PET-positive residual lesions ≥ 3 cm is lacking.

Patients And Methods: We retrospectively identified 90 patients with metastatic seminoma with PET-positive residual lesions after chemotherapy. Patients with elevated α-fetoprotein or nonseminomatous histology were excluded. We analyzed the post-PET management and its impact on relapse and survival and calculated the positive predictive value (PPV) for PET.

Results: Median follow-up time was 29 months (interquartile range [IQR], 10 to 62 months). Median diameter of the largest residual mass was 4.9 cm (range, 1.1 to 14 cm), with masses located in the retroperitoneum (77%), pelvis (16%), mediastinum (17%), and/or lung (3%). Median time from the last day of chemotherapy to PET was 6.9 weeks (IQR, 4.4 to 9.9 weeks). Post-PET management included repeated imaging in 51 patients (57%), resection in 26 patients (29%), biopsy in nine patients (10%) and radiotherapy in four patients (4%). Histology of the resected specimen was necrosis in 21 patients (81%) and vital seminoma in five patients (19%). No biopsy revealed vital seminoma. Relapse or progression occurred in 15 patients (17%) after a median of 3.7 months (IQR, 2.5 to 4.9 months) and was found in 11 (22%) of 51 patients on repeated imaging, in two (8%) of 26 patients after resection, and in two (22%) of nine patients after biopsy. All but one patient who experienced relapse were successfully treated with salvage therapy. The PPV for FDG-PET was 23%.

Conclusion: FDG-PET has a low PPV for vital tumor in residual lesions after chemotherapy in patients with metastatic seminoma. This cautions against clinical decisions based on PET positivity alone.
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http://dx.doi.org/10.1200/JCO.18.00210DOI Listing
October 2018

Everolimus in patients with multiply relapsed or cisplatin refractory germ cell tumors: results of a phase II, single-arm, open-label multicenter trial (RADIT) of the German Testicular Cancer Study Group.

J Cancer Res Clin Oncol 2019 Mar 19;145(3):717-723. Epub 2018 Sep 19.

Department of Oncology, Hematology and Bone Marrow Transplantation and Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Treatment options for patients (pts) with multiply relapsed or refractory metastatic germ cell cancer (GCC) are limited. The mTOR inhibitor everolimus has been approved for the treatment of different solid tumors and was assessed in refractory GCC within this phase II RADIT trial of the German Testicular Cancer Study Group.

Methods: GCC pts progressing during cisplatin-based salvage chemotherapy, or relapsing after high-dose chemotherapy, or failing at least two lines of cisplatin-based chemotherapy were eligible. Prior combination chemotherapy with gemcitabine, oxaliplatin and paclitaxel, or a doublet combination of these drugs was mandatory. Primary endpoint was the progression-free survival rate at 12 weeks. Twenty-five evaluable pts were needed, assuming a 20% two-sided type 1 error and 95% power to reject the null hypothesis of 5% of patients being progression-free after 12 weeks. At least one pt among the first 13 pts being progression-free after 6 weeks was mandatory to complete recruitment. Secondary endpoints were objective response rate, disease control rate (SD + PR + CR), median progression-free survival (PFS), median overall survival (OS), and safety. The trial was registered at http://clinicaltrials.gov as NCT01242631.

Results: Twenty-five pts from six German centers were treated with everolimus 10 mg orally once daily until disease progression or unacceptable toxicity between December 2010 and January 2014. 12-week PFS rate was 0%, no objective responses were achieved, and only one pt had stable disease after 6 weeks on treatment as a prerequisite of completing patient accrual accounting for a 6-week disease control rate of 5.4%. Median PFS and OS were estimated at 7.4 weeks and 8.3 weeks, respectively. Toxicity was acceptable, with one treatment discontinuation due to adverse events, and no new safety signals detected.

Conclusions: Targeting the mTOR pathway with single-agent everolimus failed to produce clinically relevant responses in pts with heavily pretreated and/or cisplatin-refractory GCC.
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http://dx.doi.org/10.1007/s00432-018-2752-zDOI Listing
March 2019

Management of Refractory Germ Cell Cancer.

Authors:
Anja Lorch

Am Soc Clin Oncol Educ Book 2018 May;38:324-329

From Genitourinary Medical Oncology, Department of Urology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Over the past 5 decades, the use of well-validated, guideline-based strategies has resulted in high cure rates in newly diagnosed patients with germ cell cancer. However, about 30% of those with metastatic disease at initial presentation will experience refractory disease. Salvage treatment is far more complex and less validated than first-line treatment because it is rare, patient cohorts are more heterogeneous, and prognostic factors seem to have greater impact. Prior to the initiation of any salvage treatment, several considerations must be made, including assessment of known prognostic factors and choice of the optimal salvage strategy. Evaluation of patients according to their disease biology, response to prior treatment, and the extent of their tumor burden at the time of salvage treatment is crucial for establishing the optimal salvage strategy. Patients with metastatic germ cell cancer in whom adequate cisplatin-based first-line chemotherapy fails should be included in the ongoing randomized TIGER trial comparing conventional-dose chemotherapy with high-dose chemotherapy as first salvage treatment. Outside this trial, patients may be treated with conventional or high-dose chemotherapy depending on the presence or absence of adverse prognostic factors, availability of resources, and patient and physician preferences.
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http://dx.doi.org/10.1200/EDBK_201189DOI Listing
May 2018

The Role of Salvage High-Dose Chemotherapy in Relapsed Male Germ Cell Tumors.

Oncol Res Treat 2018 8;41(6):365-369. Epub 2018 May 8.

Germ cell tumors (GCT) are a unique tumor entity with excellent cure rates if guideline-endorsed treatment is thoroughly applied. Even patients with widespread metastatic disease can often be cured with cisplatin-based combination chemotherapy as part of a multimodal treatment approach. However, about 30% of patients with metastatic disease at initial presentation, corresponding to about 5-10% of all GCT patients, relapse or progress despite first-line treatment and therefore require salvage chemotherapy. Salvage systemic treatment either consists of conventional-dose cisplatin-based combination chemotherapy or sequential high-dose treatment with carboplatin and etoposide plus subsequent autologous stem cell support. This review is based on a comprehensive literature search of MEDLINE and conference proceedings of ESMO, ASCO, and EAU meetings until 2018 and provides an overview of current treatment options for germ cell cancer patients relapsing after or progressing during first-line cisplatin-based combination chemotherapy.
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http://dx.doi.org/10.1159/000489135DOI Listing
August 2019

High β-1,4-Galactosyltransferase-I expression in peripheral T-lymphocytes is associated with a low risk of relapse in germ-cell cancer patients receiving high-dose chemotherapy with autologous stem cell reinfusion.

Oncoimmunology 2018;7(5):e1423169. Epub 2018 Feb 16.

Department of Hematology, Oncology and Immunology at the Philipps-University Marburg; Baldinger Strasse, Marburg, Germany.

Survival of patients with germ-cell cancer (GCC) and primary progression or relapse after cisplatin-based first-line chemotherapy is highly heterogeneous, ranging from close to zero to more than 70%. We investigated β-1,4-Galactosyltransferase-I () expression levels in peripheral lymphocytes in a cohort of 46 testicular cancer patients. enhances immune cell crosstalk via glycosylation of surface molecules. A high expression level of in T-lymphocytes, but not in monocytes, was associated with a lower risk of relapse with a hazard ratio (HR) of 0.66 (95% confidence interval (CI) of HR: 0.45-0.97; = 0.02) upon multivariate Cox regression analysis. Correspondingly, interleukin 10 (IL10), a cytokine released by cytotoxic T-cells, was likewise significantly elevated in T-lymphocytes of non-relapse GCC patients (HR: 0.3; 95% CI of HR: 0.14-0.65; = 0.002). Our data indicate that glycosylation and activation of T-lymphocytes may play a pivotal role in disease control in GCC patients with primary progressive or relapsed disease.
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http://dx.doi.org/10.1080/2162402X.2017.1423169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927517PMC
February 2018

How we treat germ cell cancers.

Cancer 2017 06 17;123(12):2190-2192. Epub 2017 May 17.

Department of Oncology, University Hospital Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1002/cncr.30751DOI Listing
June 2017

Outcome of Men With Relapse After Adjuvant Carboplatin for Clinical Stage I Seminoma.

J Clin Oncol 2017 Jan 28;35(2):194-200. Epub 2016 Nov 28.

Stefanie Fischer and Silke Gillessen, Cantonal Hospital St Gallen, St Gallen; Dirk Klingbiel, SAKK Coordinating Center, Bern; Jörg Beyer, Universitätsspital Zürich, Zürich, Switzerland; Torgrim Tandstad, St Olavs University Hospital, Trondheim, Norway; Matthew Wheater, Caroline Chau, and Edurne Arriola, University Hospital Southampton, Southampton; Emilio Porfiri, Kalena Marti, and Paul Hutton, Birmingham University Hospital, Birmingham; Jonathan Shamash, St Bartholomew's Hospital, London, United Kingdom; Aude Fléchon, Centre Léon Bérard, Lyon; Brigitte Laguerre, Centre Eugène Marquis, Rennes, France; Jorge Aparicio, Hospital Universitari i Politècnic La Fe, Valencia; Pablo Maroto, Hospital Sant Pau, Barcelona, Spain; Breda Skrbinc, Institute of Oncology, Ljubljana, Slovenia; Umberto Basso, Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy; Anja Lorch, Universitätsklinikum Düsseldorf, Düsseldorf; Klaus-Peter Dieckmann, Klinik für Urologie, Hamburg, Germany; Gabriella Cohn-Cedermark, Karolinska Institute; Gabriella Cohn-Cedermark, Karolinska University Hospital, Stockholm; and Olof Ståhl, Skane University Hospital, Lund, Sweden.

Purpose Adjuvant carboplatin is one of three management strategies that may follow inguinal orchiectomy in clinical stage I seminoma. However, little is known about the outcome of patients who experience a relapse after such treatment. Patients and Methods Data from 185 patients who relapsed after adjuvant carboplatin between January 1987 and August 2013 at 31 centers/groups from 20 countries were collected and retrospectively analyzed. Primary outcomes were disease-free survival and overall survival. Secondary outcomes were time to, stage at, and treatment of relapse as well as rate of subsequent relapses. Results With a median follow-up of 53 months (95% CI, 48 to 60 months) the 5-year disease-free survival was 82% (95% CI, 77% to 89%), and the 5-year overall survival was 98% (95% CI, 95% to 100%). The median time from orchiectomy to relapse was 19 months (95% CI, 17 to 23 months); 15% (95% CI, 10% to 21%) of relapses occurred > 3 years after treatment. The majority of relapses were detected by computed tomography scan during routine follow-up, 98% in the International Germ Cell Cancer Collaborative Group good prognosis group. Chemotherapy was administered to 92% of patients, mostly as standard first-line treatment corresponding to stage; 8% of patients had additional local treatments. Only 28 patients experienced a second relapse. At last follow-up, 174 (94%) of 185 patients were alive without disease, and four patients with disease. Seven patients died, three of whom due to progressive disease. Conclusion Within the limitations of a retrospective analysis, the results suggest that the majority of patients who experience a relapse after adjuvant carboplatin for clinical stage I seminoma can be successfully treated with a cisplatin-based chemotherapy regimen adequate for stage. Because 15% of the relapses occurred > 3 years after adjuvant treatment, a minimum of 5 years follow-up is recommended.
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http://dx.doi.org/10.1200/JCO.2016.69.0958DOI Listing
January 2017

High-dose chemotherapy as salvage treatment in germ-cell cancer: when, in whom and how.

World J Urol 2017 Aug 27;35(8):1177-1184. Epub 2016 Sep 27.

Department of Oncology, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.

Over the past two decades, the use of well-validated, guideline-based strategies resulted in high cure rates in patients with germ-cell cancer (GCC) often despite widespread metastatic disease at initial presentation. Yet, about 30 % of patients diagnosed with metastatic disease corresponding to about 5-10 % of GCC patients overall will experience disease progression or recurrence at some time point of their disease with the need for salvage treatment. Salvage treatment is more complex and less well validated than first-line treatment: Its rare patient cohorts are more heterogeneous and prognostic factors impact more compared to other treatment scenarios. In patients with metastatic GCC, there are several scenarios in which first-line treatment strategies can fail (Fig. 1). Prior to initiation of any salvage treatment, several considerations have to be made, which will be addressed in this review: verification that first-line treatment has indeed failed, estimation of the adequacy and the effectiveness of first-line treatment, search for metastatic sites and extent of disease recurrence, assessment of known prognostic factors and finally the choice of the optimal salvage strategy taking into account the aforementioned variables. High-dose chemotherapy will be a rational choice for many patients in need of salvage treatment, but careful patient selection will be required to avoid overtreatment and unnecessary long-term toxicity.
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http://dx.doi.org/10.1007/s00345-016-1941-0DOI Listing
August 2017

Efficacy and safety of gemcitabine, oxaliplatin, and paclitaxel in cisplatin-refractory germ cell cancer in routine care--Registry data from an outcomes research project of the German Testicular Cancer Study Group.

Urol Oncol 2016 Apr 11;34(4):167.e21-8. Epub 2015 Dec 11.

Department of Oncology, Hematology and Bone Marrow Transplantation With Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Chemotherapy (CTX) with gemcitabine, oxaliplatin, and paclitaxel (GOP) has demonstrated efficacy with an overall response rate (ORR) of approximately 50% in patients with multiply relapsed or cisplatin-refractory germ cell cancer (GCC) or both within a phase II study. We analyzed the efficacy and safety of GOP in routine clinical practice within a registry of the German Testicular Cancer Study Group.

Methods: Overall, 63 patients with refractory GCC, who received GOP because of progression under cisplatin-based treatment or relapse after high-dose CTX, were included in this database. Patient characteristics, response rate, toxicity, progression-free and overall survival (OS) were analyzed. For further risk stratification, univariate and multivariate analyses were performed.

Results: GOP was applied as second to eighth treatment line (median fourth) after cisplatin-based CTX. The ORR was 44% with complete remissions achieved in 8 patients (4 patients with CTX plus additional residual tumor resections and 4 patients with CTX alone) and partial remissions achieved in 19 of all for best response evaluable patients. The median progression-free survival and OS were 4.0 months (95% CI: 3.08-4.94) and 13.3 months (95% CI: 9.50-17.06), respectively. Long-term OS of>2 years was achieved in 13 (21%), and grade III and IV toxicities, mainly thrombocytopenia and leukopenia, occurred in 29 patients.

Conclusion: Our results were similar compared with the previous results from the phase II study with a distinct activity with an ORR of 44%, and a long-term OS in 21% of the patients. Our data support the recommendation to use GOP ± secondary surgery in patients with multiply refractory metastatic GCC.
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http://dx.doi.org/10.1016/j.urolonc.2015.11.007DOI Listing
April 2016

Brain Metastases in Patients With Germ Cell Tumors: Prognostic Factors and Treatment Options--An Analysis From the Global Germ Cell Cancer Group.

J Clin Oncol 2016 Feb 12;34(4):345-51. Epub 2015 Oct 12.

Darren R. Feldman, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY; Anja Lorch, University Hospital Düsseldorf, Düsseldorf; Carsten Bokemeyer, University Hospital Eppendorf, Hamburg, Germany; Andrew Kramar, Centre Oscar Lambret, Lille; Aude Flechon and Helen Boyle, Centre Léon Bérard, Lyon, France; Costantine Albany and Lawrence H. Einhorn, Indiana University, Bloomington, IN; Patrizia Giannatempo and Andrea Necchi, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milano; Teodoro Sava, Azienda Ospedaliera Universitaria Integrata di Verona, Verona; Ugo De Giorgi, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Istituto di Ricovero e Cura a Carattere Scientifico, Meldola, Italy; Peter Chung, Princess Margaret Cancer Centre, University of Toronto, Toronto; Eric William Winquist, London Health Sciences Center, London, Ontario, Canada; Robert A. Huddart, Royal Marsden Hospital; Thomas Powles, St Bartholomew's Hospital, London, United Kingdom; Alexey Tryakin, Blokhin's Russian Cancer Research Center, Moscow, Russia; Jorge Aparicio, University Hospital Le Fe, Valencia, Spain; Christopher J. Sweeney, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Gabriella Cohn Cedermark, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden; and Jörg Beyer, UniversitätsSpital Zürich, Zürich, Switzerland.

Purpose: To define characteristics, treatment response, and outcomes of men with brain metastases (BM) from germ cell tumors (GCT).

Patients And Methods: Data from 523 men with BM from GCT were collected retrospectively from 46 centers in 13 countries by using standardized questionnaires. Clinical features were correlated with overall survival (OS) as the primary end point.

Results: BM were present at initial diagnosis in 228 men (group A) and at relapse in 295 men (group B). OS at 3 years (3-year OS) was superior in group A versus group B (48% v 27%; P < .001). Multiple BM and the presence of liver or bone metastasis were independent adverse prognostic factors in both groups; primary mediastinal nonseminoma (group A) and elevations of α-fetoprotein of 100 ng/mL or greater or of human chorionic gonadotropin of 5,000 U/L or greater (group B) were additional independent adverse prognostic factors. Depending on these factors, the 3-year OS ranged from 0% to 70% in group A and from 6% to 52% in group B. In group A, 99% of patients received chemotherapy; multimodality treatment or high-dose chemotherapy was not associated with statistically improved survival in multivariable analysis. In group B, only 54% of patients received chemotherapy; multimodality treatment was associated with improved survival compared with single-modality therapy (hazard ratio, 0.51; 95% CI, 0.36 to 0.73; P < .001), as was high-dose compared with conventional-dose chemotherapy (hazard ratio, 0.41; 95% CI, 0.24 to 0.70; P = .001).

Conclusion: Men with BM from GCT have poor OS, particularly if additional risk factors are present. High-dose chemotherapy and multimodality treatment seemed to improve survival probabilities in men with BM at relapse.
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http://dx.doi.org/10.1200/JCO.2015.62.7000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070579PMC
February 2016