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Kinase activity is frequently altered in renal cell carcinoma (RCC), and tyrosine kinase inhibitors (TKIs) are part of the standard treatment strategy in patients with metastatic disease. However, there are still no established biomarkers to predict clinical benefits of a specific TKI. Here, we performed protein tyrosine kinase (PTK) profiling using PamChip® technology. The aim of this study was to identify differences in PTK activity between normal and malignant kidney tissue obtained from the same patient, and to investigate the inhibitory effects of TKIs frequently used in the clinics: sunitinib, pazopanib, cabozantinib and tivozanib. Briefly, our results showed that 36 kinase substrates differs (FDR < 0.05) between normal and cancer kidney tissue, where members of the Src family kinases and the phosphoinositide-3-kinase (PI3K) pathway exhibit high activity in renal cancer. Furthermore, ex vivo treatment of clear cell RCC with TKIs revealed that pathways such as Rap1, Ras and PI3K pathways were strongly inhibited, whereas the neurotrophin pathway had increased activity upon TKI addition. In our assay, tivozanib and cabozantinib exhibited greater inhibitory effects on PTK activity compared to sunitinib and pazopanib, implying they might be better suitable as TKIs for selected RCC patients.

Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. 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 before 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), 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, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements 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 where further evidence is available to guide our approach, The authors would like to thank Peter E. Clark from Atrium Health, Levine Cancer Institute, Charlotte, NC, USA, for his contribution to the Delphi survey. Angela Corstorphine of Kstorfin Medical Communications Ltd provided medical writing support with the preparation of this manuscript; this support was funded jointly by EAU and ESMO.

Background The treatment landscape of metastatic clear cell renal cell carcinoma (mccRCC) has been transformed by targeted therapies with tyrosine kinase inhibitors (TKI) and more recently by the incorporation of immune checkpoint inhibitors (ICI). Today, a spectrum of single agent TKI to TKI/ICI and ICI/ICI combinations can be considered and the choice of the best regimen is complex. Materials and methods We performed an updated decision-making analysis among 11 international kidney cancer experts. Each expert provided their treatment strategy and relevant decision criteria in the first line treatment of mccRCC. After the collection of all input a list of unified decision criteria was determined and compatible decision trees were created. We used a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees, to determine the most common treatment recommendations as well as deviations. Results Diverse parameters were considered relevant for treatment selection, various drugs and drug combinations were recommended by the experts. The parameters, chosen by the experts, were performance status, International Metastatic renal cell carcinoma Database Consortium (IMDC) risk group, PD-L1 status, zugzwang and contraindication to immunotherapy. The systemic therapies selected for first line treatment were sunitinib, pazopanib, tivozanib, cabozantinib, ipilimumab/nivolumab or pembrolizumab/axitinib. Conclusion A wide spectrum of treatment recommendations based on multiple decision criteria was demonstrated. Significant inter-expert variations were observed. This demonstrates how data from randomized trials are implemented differently when transferred into daily practice., Highlights • Treatment options for metastatic clear cell renal cell carcinoma have become diverse. • We performed a decision-making analysis among 11 international kidney cancer experts. • Significant inter-expert variations for systemic first line treatments were observed. • Influencing factors were performance status, IMDC risk group, PD-L1 status, zugzwang and contraindication to immunotherapy. • The treatments selected were: sunitinib, pazopanib, tivozanib, cabozantinib, ipilimumab/nivolumab or pembrolizumab/axitinib.

5021 Background: A baseline prostate-specific antigen (PSA) level in midlife is strongly associated with risk of lethal prostate cancer several decades later. In most prior studies, PSA was measured in archived blood from men participating in cohort studies unrelated to prostate cancer. In clinical practice, however, men commonly obtain a PSA test because of lower urinary tract symptoms. Here, we study the association between PSA values when a first PSA test was obtained as part of clinical care – and subsequent risks of prostate cancer diagnosis and death. Methods: The NPCC database contained laboratory results from 1995-2006 of the first (“baseline”) PSA test below 4.0 ng/mL in 157,836 men aged 40-69 years without prior prostate cancer (PCa) diagnosis. PSA strata were pre-defined: < 1, 1-1.99, 2-2.99, 3-3.99 ng/ml and analyses were split in two age groups based on a prior risk: 40-54 (“younger”) and 55-69 (“older”). Predictive accuracy was assessed with Harrell’s concordance (C) index. The Kaplan-Meier method was used to visualize risk of PCa death as reported on the death certificate by PSA strata for the two age groups. Results: Among 157,836 men with a PSA below 4.0 ng/mL, 83% had < 2.0 ng/mL. Risk of prostate cancer and death from prostate cancer were strongly associated with PSA-levels and age: Harrell’s C-index 0.75 and 0.72 for diagnosis of younger and older group, respectively and 0.72 for PCa death for both age groups. In the younger age group 196 deaths among 75,446 men (0.26%) were registered, in the older 943 deaths among 82,390 men (1.14%). The risk of PCa death in lowest (< 1) and highest (3-3.99) strata were 0.23% and 3.22%, respectively (189 deaths among 81,982 vs. 274 deaths among 8517 men). Conclusions: This population-based NPCC study shows as strong predictive impact of the different strata of the initial PSA measurement in routine clinical care as prior studies based on cryopreserved blood samples. [Table: see text]

Background The coronavirus pandemic has provoked discussions among healthcare providers how to manage cancer patients when faced with the threat of severe acute respiratory syndrome related coronavirus 2 (SARS-CoV-2) infection. Immune checkpoint inhibitor (ICI) containing regimens are standard of care in the majority of metastatic clear cell renal cell carcinoma (mccRCC) patients. It remains unclear whether therapies should be modified in response to the COVID-19 pandemic. Methods We performed an online survey among physicians involved in the treatment of mccRCC, and 41 experts responded. Questions focused on criteria relevant for treatment decision outside the pandemic and the modifications of systemic therapy during COVID-19. Findings For the majority of experts (73%), the combination of International metastatic renal cell carcinoma Database Consortium (IMDC) risk category and patient fitness are two important factors for decision-making. The main treatment choice in fit, favourable risk patients outside the pandemic is pembrolizumab/axitinib for 53%, avelumab/axitinib, sunitinib or pazopanib for 13% of experts each. During the pandemic, ICI-containing regimens are chosen less often in favour of a tyrosine kinase inhibitors (TKI) monotherapy, mainly sunitinib or pazopanib (35%). In fit, intermediate/poor-risk patients outside the pandemic, over 80% of experts choose ipilimumab/nivolumab, in contrast to only 41% of physicians during COVID-19, instead more TKI monotherapies are given. In patients responding to established therapies with ICI/ICI or ICI/TKI combinations, most participants modify treatment regimen by extending cycle length, holding one ICI or even both. Conclusion mccRCC treatment modifications in light of the coronavirus pandemic are variable, with a shift from ICI/ICI to ICI/TKI or TKI monotherapy. CA extern

Background Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression-free survival (PFS) remains modest, potentially explained by tumor molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment selection and prolong PFS. We designed a platform trial to test this hypothesis. Methods The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC. Discussion Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study. Conclusions The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care. Trial registration ClinicalTrials.gov Identifier NCT03903835. Date of registration: April 4, 2019. Status: Recruiting.

The long-term toxicities after cisplatin-based chemotherapy (CBCT) reveal a remarkable inter-individual variation among testicular cancer survivors (TCSs). Therefore, we assessed long-term platinum (Pt) changes and their associations with CBCT-related late effects in TCSs.In 77 TCSs treated with CBCT from 1984 to 1990, blood samples for analyses of Pt and a questionnaire including self-reported neuro- and ototoxicity (NTX) symptoms were collected during two follow-up surveys at median 12 (Survey I; SI) and 20 (Survey II; SII) years after treatment. Information about second cancers after SII was retrieved from the Norwegian Cancer Registry.A larger Pt decline from SI to SII was associated with a decreased risk of a second cancer diagnosis (HR 0.78, 95% CI 0.62-0.99 per 10 ng/L/year), and worsening of paresthesias in hands (OR 1.98, 95% CI 1.09-3.59 per 10 ng/L/year) and tinnitus (OR 1.51, 95% CI 1.01-2.27 per 10 ng/L/year).In summary, we found a significant association between a larger Pt decline and a reduced risk of second cancers and deterioration of paresthesias in hands and tinnitus.

Background: Tyrosine kinase inhibitors (TKIs) constitute the backbone of treatment of metastatic (m) RCC. TKIs show great inter-individual variability of both efficacy and toxicity. The aim of this study was to compare the tyrosine kinase activity in normal and malignant kidney tissue and explore TKI effect on tumor tissue ex vivo. Materials and methods: Human nephrectomy samples (n = 295) consecutively collected at Akershus University Hospital from 2013 to 2019 were available. For this study, 22 samples of patients with mRCC (twenty-one clear cell and one chromophobe histology) and 3 with non-metastatic disease (two clear cell and one papillary histology) were selected. Tumor and normal tissue from each patient were prepared and assessed by an experienced pathologist, and 5µg of protein lysates was extracted. Kinase activity profiling of 144 tyrosine kinase peptides was performed using PamChip Arrays for PAMSTATION12. Protein lysates from tumors were in addition treated with four different TKIs ex vivo, based on IC50; sunitinib (2.5 µM), cabozantinib (2.5 µM), pazopanib (10 µM) and tivozanib (2 µM). All data was processed and analyzed in Bionavigator V.6 (PamGene). Results: The overall tyrosine kinase activity was increased in tumor tissue compared to normal tissue in all samples. The activity of 36 tyrosine kinases differed significantly (FDR < 0.05), with 20 kinases showing higher and 16 showing lower phosphorylation in tumor compared to normal tissue. Furthermore, adding TKIs to tumor samples ex vivo revealed different potencies of the TKIs. Tivozanib and cabozantinib showed higher inhibition potency compared to sunitinib and pazopanib. Two well-defined peptide clusters were especially affected by tivozanib and cabozantinib exposure. Compared to untreated tumor tissue, the activity of 29 kinases including common TKI targets MET, EGFR, PDGFR and FGFR was significantly reduced in cluster 1. However, we also identified reduced activity of several other kinases i.e. RB, CDK2, CLB, CAM, ZAP70 and PDK1 involved in RAS, RAP1, PI3K-AKT and prostate cancer signaling pathways. In cluster 2, 21 kinases showed increased activity upon TKI exposure, amongst them JNK, ERK, erbB1/erbB2, Shp2 and PLCγ involved in MAPK, ERBB and proteoglycans signaling pathways, and possibly accounting for subsequent TKI resistance. Conclusion: Kinase activity differs significantly between malignant and normal kidney tissue. Furthermore, we have demonstrated different inhibitory effects of TKIs ex-vivo and identified two peptide clusters significantly affected by TKI. Further analysis of affected kinases and signaling pathways as well as correlations with clinical data for the same group of patients will be performed. To our knowledge, similar systematic comprehensive analysis of tyrosine kinase activity and correlation to clinical data has not been reported previously. Citation Format: Katarina Puco, Andliena Tahiri, Faris Naji, Daniel Heinrich, Vessela N. Kristenssen, Glenny C. Alfsen, Lorant Farkas, Frode S. Nilsen, Stig Müller, Jan Oldenburg, Jürgen Geisler. Tyrosine kinome profiling of renal cell carcinoma (RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2292.

Background Treatment options in patients with advanced urothelial carcinoma (aUC) have improved significantly in the last decade, highlighting the need for adequate biomarkers. High tumor CGB5 mRNA, encoding Human Chorionic Gonadotrophin β (hCGβ) and elevated serum free hCGβ are related to poorly differentiated UC and correlated to poor prognosis. Hypothetically, hCG could be used as serum tumor marker in aUC patients. Patients and methods From December 2018 to November 2020, serum hCG levels were measured in 62 aUC patients referred to the oncology department, Akershus University Hospital. Median age 68 years, 42 male and 21 female. Total serum hCG (intact hCG + free hCGβ) was measured by electrochemiluminescence immunoassay “ECLIA”. In order to compensate for hypogonadism-related increases, hCG ≥ 50% above upper normal limit was considered as being elevated (hCG+), otherwise it was considered negative (hCG-). Further, hCG levels were defined as increasing (↑) or declining (↓) at treatment evaluation and follow up. Radiologically, patients had newly diagnosed disease (ND), progressive disease (PD) or non-PD (stable disease, partial or complete response) according to RECIST 1.1 at evaluation and follow up. hCG values were correlated with radiological findings at diagnosis, during and after treatment. Statistics by 2 x 2 contingency table and Chi Square (χ2) test. Results At least one hCG+ value was measured in 38 of 62 patients (61%), range 0.8 - 62,700 IU/L, and hCG was elevated in 22 of 43 patients (51%) with available hCG value at diagnosis, mean 15 IU/L (range 0.8 - 58). In total 213 hCG measurements could be correlated with concomitant CT or MR scans. At radiologic evaluation of ND & PD, hCG+/↑ and hCG -/↓ was found in 62 and 50 measurements, respectively. At non-PD, hCG -/↓ and hCG+/↑ was found in 94 and 7 measurements, respectively. For ND & PD versus non-PD, hCG showed a sensitivity and specificity of 55% and 93% respectively (95% CI 46-65% and 86-97%), positive and negative predictive value of 90% and 65% (95% CI 81-95% and 60-70%) and accuracy of 73% (95% CI 66-79%), χ2: p Conclusions Ectopic hCG production was observed in 61% of aUC patients with a strong and meaningful correlation between hCG changes and radiologic evaluation of treatment response. Intriguingly, hCG increase sometimes preceded radiologic PD, thus categorized as “false positive” until subsequent radiologic PD. hCG appears to be a promising tumor marker for biochemical treatment response evaluation in aUC patients. Citation Format: Katarina Puco, Johan Bjerner, Stig Müller, Gunder M. Lilleaasen, Haldor Husby, Mattias Røed-Undlien, Daniel Heinrich, Fredrik A. Dahl, Oluf D. Røe, Jan Oldenburg. Utility of hCG as a biomarker of treatment response in advanced urothelial cancer: A population based series at Akershus University Hospital, Norway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 481.

BackgroundAlthough guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.ObjectiveTo bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.DesignA 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.SettingOnline Delphi survey and consensus conference.ParticipantsThe European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.Outcome measurements and statistical analysisStatements 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 limitationsOverall, 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.ConclusionsThese 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 summaryThis 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.

Objective In this study, we evaluated the toxicity and clinical efficacy of nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, on patients with platinum resistant ovarian cancer. Methods Every second week, 18 patients with platinum resistance ovarian cancer received nivolumab until disease progression occurred. We assessed toxicity, disease control rate, progression free survival (PFS) and overall survival (OS). Radiological response evaluation according to irRECIST was performed every 12th week, while clinical evaluation was done every second week. Results The disease control rate was 44% (95% confidence interval [CI]=19-87) as 8 showed stable disease, 6 showed progressive disease and 4 died before the first radiological response evaluation. The median OS was 30 weeks (95% CI=14-42; range, 3-95), and PFS was 15 weeks (95% CI=13-17). The median follow-up time was 30 weeks (range, 3-123). The rate of grade 2-5 adverse events was 28% (5 out of 18). Two patients (11%) developed grade 2 and 3 adverse events, respectively, while no grade 4 events were observed. One patient died from intestinal perforation, believed to be caused by concomitant bevacizumab rather than nivolumab. Conclusion This study shows few adverse events, and promising clinical efficacy when using nivolumab for ovarian cancer.

Context The centralization of cancer care is associated with better clinical outcomes and may be a method for optimizing value-based health care systems. Objective To systematically review the literature regarding the impact of centralization of care on clinical outcomes for genitourinary malignancies. Evidence acquisition A systematic review was conducted using Ovid and MEDLINE to identify studies between 1970 and 2018 reporting on the centralization of care for genitourinary malignancies. Prospective and retrospective studies were screened. Evidence synthesis There were no published randomized control trials (RCTs) on the centralization of care for genitourinary malignancies. Twenty-two retrospective studies met inclusion criteria. Centralization of radical cystectomy was the most studied. Care for bladder cancer, prostate cancer, penile cancer, testicular cancer, and renal cancer was reportedly associated with better morbidity and survival outcomes for patients treated at high-volume centers. However, evidence of better outcomes for centralization of care remains limited for penile, renal, and testicular cancers owing to the paucity of data and/or the lower incidence of these genitourinary malignancies. Conclusions Care for genitourinary malignancies by high-volume providers was associated with greater utilization of cancer surgery, lower morbidity, and better survival outcomes. Centralization of care was most appropriate for complex procedures such as radical cystectomy when interpreted in the context of survival outcomes. Further research is needed to address the impact of centralizing care for all urologic malignancies with consideration of the associated costs and patient-reported measures, including quality of life and patient experience. Patient summary We explored the evidence for moving major operations into larger centers. We focused on surgery for cancers of the bladder, prostate, testicle, penis, and kidney, and found that larger-volume hospitals had better survival outcomes and fewer complications when compared to smaller hospitals. The difference may be greatest for complex major surgeries such as radical cystectomy.

Testicular cancer (TC) is the most common neoplasm in males aged 15-40 years. The majority of patients have no evidence of metastases at diagnosis and thus have clinical stage I (CSI) disease [Oldenburg J, Fossa SD, Nuver J et al. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6): vi125-vi132; de Wit R, Fizazi K. Controversies in the management of clinical stage I testis cancer. J Clin Oncol 2006; 24: 5482-5492.]. Management of CSI TC is controversial and options include surveillance and active treatment. Different forms of adjuvant therapy exist, including either one or two cycles of carboplatin chemotherapy or radiotherapy for seminoma and either one or two cycles of cisplatin-based chemotherapy or retroperitoneal lymph node dissection for non-seminoma. Long-term disease-specific survival is similar to 99% with any of these approaches, including surveillance. While surveillance allows most patients to avoid additional treatment, adjuvant therapy markedly lowers the relapse rate. Weighing the net benefits of surveillance against those of adjuvant treatment depends on prioritizing competing aims such as avoiding unnecessary treatment, avoiding more burdensome treatment with salvage chemotherapy and minimizing the anxiety, stress and life disruption associated with relapse. Unbiased information about the advantages and disadvantages of surveillance and adjuvant treatment is a prerequisite for informed consent by the patient. In a clinical scenario like CSI TC, where different disease-management options produce indistinguishable long-term survival rates, patient values, priorities and preferences should be taken into account. In this review, we provide an overview about risk factors for relapse, potential benefits and harms of adjuvant chemotherapy and active surveillance and a rationale for involving patients in individualized decision making about their treatment rather than adopting a uniform recommendation for all.

A contralateral tumor occurs in 3.5-5% of men diagnosed with testicular germ cell cancer (TGCC). Biopsy of the contralateral testis may detect intratubular germ cell neoplasia ITGCNU, a precursor of TGCC. Biopsy of the contralateral testis to detect ITGCNU is controversial. If adjuvant chemotherapy (ACT) protects against bilateral cancer is debated.A total of 1003 patients with clinical stage I (CS I) non-seminomatous testicular germ cell cancer (NSGCT) were included in two prospective, population-based protocols. Fifteen patients were excluded. Treatment was either adjuvant chemotherapy (n = 494), or surveillance (n = 494). Contralateral testicular biopsy was recommended for all patients, but was performed only in 282 patients. In case of ITGCNU radiotherapy (RT) to 16 Gy was recommended.During a follow-up of 8.3 years, 31 (3.6%) patients developed contralateral TGCC. ITGCNU was detected in 3.2% (9/282) of biopsied patients. The incidence of bilateral TGCC was similar following ACT, 2.5% (11/494), and surveillance, 3.4% (13/494), p = 0.41. Young age was a risk factor for metachronous TGCC (HR 0.93; 95% CI 0.88-0.99, p = 0.02). In total 2.2% (6/273) of patients without ITGCNU in the biopsy developed contralateral TGCC. One irradiated patient developed contralateral cancer, and one developed contralateral tumor before RT was given.ACT did not reduce the incidence of contralateral TGCC. Young patients had the highest risk of developing contralateral TGCC. The proportion of false negatives biopsies was higher than reported in earlier trials, but this may in part be related to patient selection, single biopsies and lack of mandatory immunohistochemistry.

Context Patients with clinical stage I (CS I) seminoma testis with large primary tumours and/or rete testis invasion (RTI) might have an increased risk of relapse. In recent years, these risk factors have frequently been employed to decide on adjuvant treatment. Objective To systematically review the literature on tumour size and RTI as risk factors for relapse in CS I seminoma testis patients under surveillance. Evidence acquisition Relevant databases including Medline, Embase, and the Cochrane Library were searched up to November 2016. Randomised controlled trials (RCTs) or quasi-RCTs, prospective observational studies with controls, retrospective matched-pair studies, and comparative studies from well-defined registries/databases were included. The primary outcome was the rate of relapse and relapse-free survival (RFS). The risk of bias was assessed by the Quality in Prognosis Studies tool. Evidence synthesis After assessing 3068 abstracts and 80 full-text articles, 20 studies met the inclusion criteria. Although evidence to justify a cut-off of 4cm for size was lacking, it was the most frequently studied. The reported hazard ratio (HR) for the RFS for tumours >4cm was 1.59–2.8. Accordingly, the reported 5-yr RFS ranged from 86.6% to 95.5% and from 73.0% to 82.6% for patients having tumours ≤4 and >4cm, respectively. For tumours with RTI present, the reported HR was 1.4–1.7. The 5-yr RFS ranged from 86.0% to 92.0% and 74.9% to 79.5% for patients without versus those with RTI present, respectively. A meta-analysis was considered inappropriate due to data heterogeneity. Conclusions Primary tumour size and RTI are associated with the risk of relapse in CS I seminoma testis patients during surveillance. However, in the presence of either risk factor, the vast majority of patients are cured by orchiectomy alone and will not relapse. Furthermore, the evidence on the prognostic value of size and RTI has significant limitations, so prudency is warranted on their routine use in clinical practice. Patient summary Primary testicular tumour size and rete testis invasion are considered to be important prognostic factors for the risk of relapse in patients with clinical stage I seminoma testis. We systematically reviewed all the literature on the prognostic value of these two postulated risk factors. The outcome is that the prognostic power of these factors in the published literature is too low to advocate their routine use in clinical practice and to drive the choice on adjuvant treatment in clinical stage I seminoma testis patients.

Christian Beisland,1,2 Tom B Johannesen,3 Olbjorn Klepp,4 Ulrika Axcrona,5 Knut Martin Torgersen,6 Jan Kowalski,7 Oddvar Solli,6 Rickard Sandin,8 Jan Oldenburg9,10 1Department of Urology, Haukeland University Hospital, 2Department of Clinical Medicine, University of Bergen, Bergen, 3Department of Registration, Cancer Registry of Norway, Oslo, 4Department of Oncology, Ålesund Hospital, Ålesund, 5Department of Pathology, Oslo University Hospital, the Norwegian Radium Hospital, Oslo, 6Pfizer AS, Oslo, Norway; 7JK Biostatistics AB, Stockholm, 8Pfizer AB, Sollentuna, Sweden; 9Department of Oncology, Akershus University Hospital, Lørenskog, 10Medical Faculty, University of Oslo, Oslo, Norway Background: This population-wide retrospective, non-interventional registry study assessed changes in overall survival (OS) and factors influencing OS in Norwegian patients with renal cell carcinoma (RCC). Methods: Two population-wide health registries were used to identify all RCC patients with (mRCC) or without metastases diagnosed before (2002–2005) and after (2006–2008 and 2009–2011) introduction of targeted therapies. Median OS was estimated using Kaplan–Meier method. Cox proportional hazards regression modeling was used to identify prognostic factors. Results: Overall, 5,463 patients were diagnosed with RCC during 2002–2005 (n=1,898), 2006–2008 (n=1,631), and 2009–2011 (n=1,934); of these, 1,678 (31%) had mRCC. Patients diagnosed in 2009–2011 and 2006–2008 had significant (P

Purpose To assess longitudinal long-term alterations of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in testicular cancer survivors (TCSs). Patients and Methods In all, 307 TCSs treated from 1980 to 1994 provided blood samples after orchiectomy but before further treatment, at Survey I (SI; 1998-2002), and Survey II (SII; 2007-2008). Levels of sex hormones were categorized according to quartiles and reference range (2.5 and 97.5 percentiles) of 599 controls for each decadal age group. TCSs were categorized according to treatment: surgery, radiotherapy (RT), or chemotherapy (CT). The risk of higher (LH) or lower (testosterone) levels was assessed with χ2 test (FSH) or ordinal logistic regression analysis and expressed as odds ratios (ORs) with 95% CIs. Results Risk of lower testosterone and higher LH and FSH levels was significantly increased for TCSs at all time points after RT or CT. At SII, ORs were 3.3 (95% CI, 2.3 to 4.7) for lower testosterone categories and 5.2 (95% CI, 3.5 to 7.9) for RT and CT. ORs for increased LH and FSH were 4.4 (95% CI, 3.1 to 6.5) and 18.9 (95% CI, 11.0 to 32.6) for RT, respectively, and 3.6 (95% CI, 2.4 to 5.3) and 14.2 (95% CI, 8.3 to 24.4) for CT, respectively. The cumulative platinum dose was significantly associated with risk of higher LH levels at both surveys and higher FSH at SI. In total, half the TCSs had at least one of three sex hormone levels outside the reference range at SII. Conclusion Long-term TCSs are at risk of premature hormonal aging. Our findings may pertain to cancer survivors in general, underlining the importance of extended follow-up.

In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377-1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478-496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497-513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues. The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, similar to 50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.

In the article that accompanies this editorial, Frisina et al report on ototoxicity after cisplatin-based chemotherapy in the Platinum Study. This study comprehensively assesses hearing impairment, both as audiometric and as patient-reported outcome, as well as tinnitus in 488 cisplatin-treated testicular cancer (TC) survivors. One out of five survivors was found to have such severe hearing loss that a hearing aid was recommended. However, only 1.2% of the participants reported actually using such a device. Cisplatin-based chemotherapy was introduced in the late 1970s by Larry Einhorn and cures most patients with metastatic TC. However, long-term complications and late effects after cancer treatment are increasingly recognized as a major contributor to morbidity of survivors, influencing quality of life (QoL) and representing a burden for the growing community of cancer survivors. Similar to the unique position of TC as a model for a curable neoplasm, TC survivors represent a prime cohort for long-term survivorship studies because of their good life expectancy as a result of high cure rates and young age at diagnosis. Although the report by Frisina et al is a valuable contribution to the literature, it would have benefitted from inclusion of additional information, such as pretreatment assessments, the impact of ototoxicity on health-related QoL, details about and adjustment for other ototoxic agents (eg, aminoglycosides), and occupational hearing loss after completion of cisplatin-based chemotherapy. The cohort represents TC survivors receiving standard cisplatin-based chemotherapy for metastatic disease for which we do have some long-term ototoxicity outcomes, whereas high-quality data on ototoxicity after adjuvant chemotherapy with either one or two cycles of bleomycin, etoposide, and cisplatin (BEP) or carboplatin as well as after high-dose chemotherapy are still lacking. In general, long observation periods—a prerequisite for survivorship research—make translation of the impact of former to contemporary treatment challenging. Testicular cancer is an exception. For the last four decades, no alternative regimen was superior to BEP. In accordance with current guidelines, roughly nine out of 10 participants received three or four cycles of BEP or four cycles of etoposide and cisplatin (EP). Normative data from healthy individuals comprising median quartile threshold values for different age groups were applied to categorize decibel thresholds of individual TC survivors in an ordinal fashion up to 8 kHz as adjustment for physiologic age-related hearing decline—an approach similar to the percentiles of pediatric growth curves. Retesting this survivor cohort in some years would yield longitudinal data allowing testing of whether this group is vulnerable to subsequent age-related declines. A hypothesized reduced functional reserve leading to accelerated hormonal ageing could recently be demonstrated in TC survivors with a similar percentile categorization. Except for patients with TC who depend strongly on unimpaired hearing capability (eg, musicians, composers, or ornithologists), the risk of high-frequency hearing impairment should generally play no role in treatment planning of advanced testicular cancer in view of the high curative potential of platinum-based chemotherapy in this setting. In this study, hearing loss according the American SpeechLanguage-Hearing Association criteria was found in 80% of TC survivors, including 18% with a severe (71 to 90 dB) or profound (. 90 dB) hearing loss. On the other hand, one cycle of cisplatin increased the hearing threshold only by 2.5 dB. Thus, cisplatinbased chemotherapy for metastases should not cause more than 10 dB of hearing loss. Age-related hearing decline probably represented much of the observed hearing loss as defined by the American Speech-Language-Hearing Association, which might not be optimal for cross-sectional studies without preceding measurements. Calculation of hearing decline over various frequencies is complex: “For each patient i, the geometric mean Yi was calculated using standard methods by taking the arithmetic mean of the natural log-transformed hearing threshold, di, from n frequencies and then using exponentiation to return the computation to the original decibel scale (ie, log-average).” Understanding this end point, which scores high on specificity and poor on patient relevance (Fig 1), is difficult formost readers who are not familiar with this field. High specificity is needed for disentangling the impact of a single component on a given end point. Chemotherapy-related development of cardiovascular disease (CVD), for example, is complex to assess both due to interaction of different chemotherapy components and further dilution of the cause-effect relationship by multiple genetic and environmental risk factors. Chemotherapyinduced ototoxicity, on the other hand, is almost exclusively linked to cisplatin. Hypertension and hearing loss might be associated independent of cisplatin treatment. However, both symptoms might represent different cisplatin-related long-term toxicities despite adjustment for the cumulative cisplatin dose. Residual serum platinum increases the risk of paresthesia and Raynaud phenomenon more strongly than the applied cumulative cisplatin dose. Residual platinum, however, was not associated with tinnitus or hearing impairment assessed by the Scale for

Cisplatin-based chemotherapy is highly effective in metastasized germ cell tumours (GCT). However, 10-30 % of patients develop resistance to cisplatin, requiring salvage therapy. We investigated the in vitro activity of paclitaxel and the novel taxane cabazitaxel in cisplatin-sensitive and -resistant GCT cell lines.In vitro activity of paclitaxel and cabazitaxel was determined by proliferation assays, and mode of action of cabazitaxel was assessed by western blotting and two screening approaches, i.e. whole proteome analysis and a human apoptosis array.Activity of paclitaxel and cabazitaxel was not affected by cisplatin resistance, suggesting that there is no cross-resistance between these agents in vitro. Cabazitaxel treatment showed a strong inhibitory effect on colony formation capacity. Cabazitaxel induced classical apoptosis in all cell lines, reflected by cleavage of PARP and caspase 3, without inducing specific changes in the cell cycle distribution. Using the proteomic and human apoptosis array screening approaches, differential regulation of several proteins, including members of the bcl-2 family, was found, giving first insights into the mode of action of cabazitaxel in GCT.Cabazitaxel shows promising in vitro activity in GCT cells, independent of levels of cisplatin resistance.

To evaluate the associations between long-term serum levels of platinum (se-Pt) and neurotoxicity and ototoxicity (NTX), endocrine gonadal function (endocrine-GF), and cardiovascular disease (CVD) in testicular cancer survivors.A total of 292 cisplatin-treated testicular cancer survivors (1980-1994) participated in a national follow-up study (2007-2008). Se-Pt was quantified by inductively coupled plasma mass spectrometry, and categorized in quartiles. Symptoms of NTX were assessed with scale for chemotherapy-induced neurotoxicity (SCIN), with each symptom in 4 categories and total SCIN score categorized in quartiles. Endocrine-GF was categorized according to cutoff values for the 25, 50, and 75 percentiles of luteinizing hormone (LH) and testosterone within each decadal age group established from a control group. CVD was defined as ischemic heart disease, stroke, or artery occlusion. Associations between se-Pt levels and NTX, endocrine-GF, or risk for CVD, were analyzed with ordinal logistic regression and Cox regression, respectively.Median follow-up was 19 years (range: 13-28). In ordinal regression analyses, increasing quartiles of se-Pt were significantly associated with increasing quartiles of SCIN (P for trend = 0.05), increased tinnitus (P0.001), and increased hearing impairment (P = 0.04). The association remained significant for tinnitus when adjusting for cisplatin dose. Increasing LH quartiles was associated with increasing se-Pt quartiles (P = 0.04). No association between se-Pt in quartiles and CVD was established.Median 19 years after treatment, increasing quartiles of se-Pt are associated with increasing SCIN score, tinnitus, hearing impairment, and increasing LH levels. However, these associations remained significant only for tinnitus and LH when adjusting for administered cisplatin dose.

Germ cell testicular cancer (TC) represents a malignancy with high cure rates. Since the introduction of cisplatin-based chemotherapy in the late 1970s, the 5-year survival rate has increased considerably, and it is currently above 95%. Because TC is usually diagnosed before the age of 40 years, these men can expect to live for another 40 to 50 years after being successfully treated. This success, however, is hampered by an increased risk of long-term and late effects of treatment. Secondary malignant neoplasms and cardiovascular disease represent the most common potentially life-threatening late effects, typically occurring more than 10 years after treatment. Other long-term effects include pulmonary toxicity, nephrotoxicity, neurotoxicity, decreased fertility, hypogonadism, and psychosocial problems. The incidence and time to onset of these various adverse effects vary according to treatment type and intensity. There is still little knowledge about underlying mechanisms and genetic susceptibility of the various adverse effects. Apart from treatment burden, it is not yet possible to identify patients who are at high risk for certain late effects after TC treatment. In this clinical review, we present the current status regarding different somatic and psychosocial long-term late effects after treatment for TC, based on Medline searches and our own research. Moreover, we postulate recommendations for general medical evaluations that should begin after treatment is completed and continue during follow-up.

Purpose Cisplatin-induced neurotoxicity and ototoxicity (NTX) are important adverse effects after chemotherapy for testicular cancer (TC). Although serum platinum is measurable years after therapy, its impact on NTX has not been evaluated. Patients and Methods In all, 169 cisplatin-treated survivors of TC provided blood samples at Survey I and reported NTX during Survey I (1998-2002) and Survey II (2007-2008). Serum platinum was quantified by inductively coupled plasma mass spectrometry. Patient-reported outcomes were evaluated with the Scale for Chemotherapy-Induced Neurotoxicity (SCIN), regarding the extent of symptom bother as 0, “not at all”; 1, “a little”; 2, “quite a bit”; or 3, “very much.” Summing the six symptom scores yielded a total SCIN score of 0 to 18. Categorizing total SCIN scores into quartiles yielded similar-sized groups with increasing symptoms. Multivariate ordinal logistic regression analyses evaluated associations between NTX and long-term serum platinum levels, adjusting for cisplatin dose, dosing schedule, and age. Results At Survey I, a significant four- to five-fold association with total SCIN score emerged for the highest serum platinum quartile (odds ratio [OR], 4.69; 95% CI, 1.82 to 12.08). Paresthesias and Raynaud's syndrome (hands and feet) showed significant two- to four-fold increased risks with the highest platinum quartile. At Survey II, total SCIN score remained significantly associated with the highest platinum quartile (OR, 4.28; 95% CI, 1.36 to 13.48). Paresthesias (hands and feet) and tinnitus showed significant three- to four-fold increased risks for the highest platinum quartile. Cumulative cisplatin dose was not associated with total SCIN score or individual SCIN symptoms in multivariate analyses. Conclusion Here we document a significant relationship between increasing levels of residual serum platinum and NTX severity after adjusting for initial cisplatin dose.

Background 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) has been recommended in international guidelines in the evaluation of postchemotherapy seminoma residuals. Our trial was designed to validate these recommendations in a larger group of patients. Patients and methods FDG-PET studies in patients with metastatic seminoma and residual masses after platinum-containing chemotherapy were correlated with either the histology of the resected lesion(s) or the clinical outcome. Results One hundred and seventy seven FDG-PET results were contributed. Of 127 eligible PET studies, 69% were true negative, 11% true positive, 6% false negative, and 15% false positive. We compared PET scans carried out before and after a cut-off level of 6 weeks after the end of the last chemotherapy cycle. PET sensitivity, specificity, negative predictive value (NPV), and positive predictive value were 50%, 77%, 91%, and 25%, respectively, before the cut-off and 82%, 90%, 95%, and 69% after the cut-off. PET accuracy significantly improved from 73% before to 88% after the cut-off (P = 0.032). Conclusions Our study confirms the high specificity, sensitivity, and NPV of FDG-PET for evaluating postchemotherapy seminoma residuals. When carried out at an adequate time point, FDG-PET remains a valuable tool for clinical decision-making in this clinical setting and spares patients unnecessary therapy.

Purpose The prognostic significance of age at testicular cancer (TC) diagnosis, socioeconomic status (SES), race, and marital status on TC-specific mortality is not well-characterized. In a cancer that is so curable, it is important to identify any influence that confers an increased risk of TC-specific mortality. Patients and Methods Using multivariate cause-specific Cox regression models that accounted for competing risks, hazard ratios (HRs) were calculated for 10-year TC-specific mortality among 27,948 patients with TC reported to the Surveillance, Epidemiology and End Results program (1978 to 2006). Independent predictors were age at diagnosis, SES, race, marital status, extent of disease (EOD), calendar year of diagnosis, radiotherapy, and retroperitoneal lymph node dissection (RPLND). Results Compared with younger patients, diagnostic age 40+ was associated with increased mortality (seminoma, HR, 2.00, P < .001; nonseminoma, HR, 2.09; P < .001; most evident in metastatic disease, HR, 8.62; P < .001; HR, 6.35; P < .001, respectively). Unmarried men had two-to three-fold excess mortality compared to married men (HR, 2.97; P < .001; HR, 1.54; P < .001, respectively). Among nonseminoma patients, decreasing SES (P trend < .001) and nonwhite race (HR, 2.11; P < .001) increased mortality. Diagnosis after 1987 resulted in reduced mortality compared to earlier calendar years (HR, 0.58; P = .001; HR, 0.74; P = .001, respectively). Lack of RPLND was associated with seven-fold increase in death (P < .001). Conclusion TC-specific mortality is doubled among US patients diagnosed with seminoma or nonseminoma after age 40, even when initial treatment and EOD are taken into account. Among men with nonseminoma, nonwhite race and lower SES also significantly increase TC-specific mortality. Additional research is needed, enabling the development of interventional strategies and preventive approaches, as applicable.

e22067Background: In this longitudinal study, we report long-term change in Pt serum concentration and associations between Pt change and cisplatin-related late effects (second cancers and neurotox...

e17555Background: We evaluated the toxicity and clinical efficacy of a programmed cell death (PD-1) inhibitor on patients with platinum resistant ovarian cancer. Further, we explored whether the du...

Background Sensory neuropathy (paresthesias), tinnitus, hearing impairment, and Raynaud phenomena are side effects of cisplatin-based chemotherapy used to treat testicular cancer patients. We assessed the long-term occurrence of these side effects among testicular cancer survivors according to the treatment they received. Methods A total of 1814 men who were treated for unilateral testicular cancer in Norway during 1980 – 1994 were invited to participate in a national multicenter follow-up survey conducted during 1998 – 2002. The men were allocated to six groups according to the treatment they had received. Self-reported symptoms were assessed by a mailed questionnaire that included the Scale for Chemotherapy-Induced Neurotoxicity. A total of 1409 participants who responded to the questionnaire and/or underwent audiometry were assessable in this study. Respondents to the questionnaire (n = 1402) scored the relevant symptoms according to how troubled they were by each (not at all, a little, quite a bit, or very much). Hearing impairment was objectively assessed by audiometry at 4000 Hz in 755 men (seven of whom did not respond to the questionnaire). Group comparisons of symptom assessments were performed with 2 or Kruskal – Wallis tests. Associations between relevant factors and self-reported symptoms or hearing impairment measured by audiometry were assessed using proportional odds ordinal logistic regression models and linear regression models, respectively. All statistical tests were two-sided. Results The median follow-up for the 1409 assessable men was 10.7 years (range = 4 – 21 years). All chemotherapy groups had statistically significantly higher odds for increasing severity of all assessed symptoms and inferior audiometric results compared with men who did not receive chemotherapy. Among chemotherapytreated men, 39% (95% confidence interval [CI] = 35% to 43%) reported Raynaud-like phenomena (defined as white or cold hands or fingers [or feet or toes] on cold exposure), 29% (95% CI = 25% to 33%) reported paresthesias in the hands or feet, 21% (95% CI = 18% to 25%) reported hearing impairment, and 22% (95% CI = 19% to 26%) reported tinnitus as major symptoms troubling them quite a bit or very much. Hearing impairment (odds ratio [OR] = 5.3, 95% CI = 3.0 to 9.2) and tinnitus (OR = 7.1, 95% CI = 4.1 to 12.4) were particularly common in the dose-intensive chemotherapy group compared with the no chemotherapy group. Men who were treated with radiotherapy had higher odds of self-reported paresthesias in feet compared with those not treated with radiotherapy (OR = 1.5, 95% CI = 1.01 to 2.1, P = .04). Conclusion Long-term survivors of testicular cancer who were treated with cisplatin-based chemotherapy were more often troubled by dose-dependent neurological side effects and Raynaud-like phenomena compared with those who were not treated with chemotherapy. J Natl Cancer Inst 2009;101:1682–1695

BACKGROUND: The purpose of this study was to validate a prognostic index [surgical complete response 1 (sCR1)] in patients with postchemotherapy viable nonseminomatous germ-cell tumors (NSGCT). PATIENTS AND METHODS: Data and specimens from 61 patients with normalized tumor markers and postchemotherapy viable nonteratomatous NSGCT treated in 13 institutions were collected. RESULTS: With a median follow-up of 5.4 years, the 5-year progression-free survival (PFS) rate was 65%; the 5-year overall survival (OS) rate was 72%. Favorable PFS was predicted by a complete resection

Purpose: The purpose of this research is to study the prevalence of posttraumatic stress disorder (PTSD) and variables associated with PTSD in Norwegian long-term testicular cancer survivors (TCSs) both cross-sectionally and longitudinally. Methods: At a mean of 11 years after diagnosis, 1418 TCSs responded to a mailed questionnaire, and at a mean of 19 years after diagnosis, 1046 of them responded again to a modified questionnaire. Posttraumatic symptoms related to testicular cancer were self-rated with the Impact of Event Scale (IES) at the 11-year study only. An IES total score ≥35 defined Full PTSD, and a score 26–34 identified Partial PTSD, and the combination of Full and Partial PTSD defined Probable PTSD. Results: At the 11-year study, 4.5 % had Full PTSD, 6.4 % had Partial PTSD, and 10.9 % Probable had PTSD. At both studies, socio-demographic variables, somatic health, anxiety/depression, chronic fatigue, and neurotoxic adverse effects were significantly associated with Probable PTSD in bivariate analyses. Probable anxiety disorder, poor self-rated health, and neurotoxicity remained significant with Probable PTSD in multivariate analyses at the 11-year study. In bivariate analyses, probable PTSD at that time significantly predicted socio-demographic variables, somatic health, anxiety/depression, chronic fatigue, and neurotoxicity among participants of the 19-year study, but only probable anxiety disorder remained significant in multivariable analysis. Conclusions: In spite of excellent prognosis, 10.9 % of long-term testicular cancer survivors had Probable PTSD at a mean of 11 years after diagnosis. Probable PTSD was significantly associated with a broad range of problems both at that time and was predictive of considerable problems at a mean of 19 year postdiagnosis. Implications for cancer survivors: Among long-term testicular cancer survivors, 10.9 % have Probable PTSD with many associated problems, and therefore health personnel should explore stress symptoms at follow-up since efficient treatments are available. © 2016, Springer Science+Business Media New York.

Background. With the advent of targeted therapies, many treatment options in the first-line setting of metastatic clear cell renal cell carcinoma (mccRCC) have emerged. Guidelines and randomized trial reports usually do not elucidate the decision criteria for the different treatment options. In order to extract the decision criteria for the optimal therapy for patients, we performed an analysis of treatment algorithms from experts in the field. Materials and Methods. Treatment algorithms for the treatment of mccRCC from experts of 11 institutions were obtained, and decision trees were deduced. Treatment options were identified and a list of unified decision criteria determined. The final decision trees were analyzed with a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees. The most common treatment recommendations were determined, and areas of discordance were identified. Results. The analysis revealed heterogeneity in most clinical scenarios. The recommendations selected for first-line treatment of mccRCC included sunitinib, pazopanib, temsirolimus, interferon-α combined with bevacizumab, high-dose interleukin-2, sorafenib, axitinib, everolimus, and best supportive care. The criteria relevant for treatment decisions were performance status, Memorial Sloan Kettering Cancer Center risk group, only or mainly lung metastases, cardiac insufficiency, hepatic insufficiency, age, and “zugzwang” (composite of multiple, related criteria). Conclusion. In the present study, we used diagnostic nodes to compare treatment algorithms in the first-line treatment of mccRCC. The results illustrate the heterogeneity of the decision criteria and treatment strategies for mccRCC and how available data are interpreted and implemented differently among experts. Implications for Practice: The data provided in the present report should not be considered to serve as treatment recommendations for the management of treatment-naïve patients with multiple metastases from metastatic clear cell renal cell carcinoma outside a clinical trial; however, the data highlight the different treatment options and the criteria used to select them. The diversity in decision making and how results from phase III trials can be interpreted and implemented differently in daily practice are demonstrated.

The purpose of this study was to explore the incidence of late relapse in patients with malignant germ cell tumour (MGCT) in a population-based series, with emphasis on the mode of detection, survival, and the relevance of histological findings. The clinical records from a population-based cohort of patients with seminoma (n=1123) or non-seminoma (n=826) were evaluated for late relapses. Twenty-five patients developed a late relapse. The cumulative 10-year incidence rate was 1.3%. All 10 seminoma patients, but only eight of 15 non-seminoma patients relapsed with vital malignant tumour (P=0.02). Teratoma or necrosis was found in seven of nine primarily chemotherapy-treated non-seminoma patients with normal tumour markers at late relapse. Six of nine patients operated with limited retroperitoneal lymph node dissection as part of the primary treatment had relapsed retroperitoneally outside the original operation field. The 10-year cause-specific survival was 68% in all patients, 50% in patients relapsing with vital malignant tumour and 100% in those with teratoma/ necrosis before or after salvage chemotherapy. The 10-year incidence rate of late relapses of 1.3% might reflect the true incidence rate in a population-based cohort of MGCT patients, with cure in at least half of them.

Chronic fatigue (CF) has been reported to be slightly more prevalent in testicular cancer survivors (TCSs) than in the general population. In this study, we wished to explore possible determinants of CF in TCSs median 12 (survey I) and 19 years (survey II) after treatment, in particular the relation to late effects after treatment.Overall, 812 TCSs treated between 1980 and 1994 provided blood samples (testosterone and luteinizing hormone) and completed questionnaires at survey I (1998-2002) and survey II (2007-2008). Hormone levels were categorized according to quartile thresholds for decadal age groups of controls. Associations between CF and possible risk factors, including the Hospital Anxiety and Depression Scale (HADS), treatment, physical activity, hormone levels, neurotoxicity, and comorbidity, were analyzed by logistic regression.Prevalence of CF increased from 15% at survey I to 27% at survey II (P0.001). At survey II, risk for CF was increased three- to four-fold for high levels of neuropathy compared with no neuropathy, and two- to three-fold for high levels of Raynaud-like phenomena, and having testosterone levels in the lowest quartile, while being moderately and highly physically active, had a protective effect. Risk for CF in TCSs with higher levels of HADS-Anxiety and HADS-Depression was increased two- to five-fold, respectively.The increasing prevalence of CF in TCSs is a novel finding. Lifestyle interventions, early detection and treatment of depression and anxiety, and possibly testosterone substitution might reduce the risk of CF. Extended long-term follow-up seems to be important.

Testicular cancer (TC) is the most common solid organ malignancy among young men at their peak of family life, education, and career. The exceptionally high cure rates are hampered by an increased risk of several treatment-related toxicities that may emerge several years after treatment. In this article, we review the current knowledge regarding pulmonary and cardiovascular toxicity in long-term survivors of TC. Bleomycin pulmonary toxicity is associated with the cumulative bleomycin dose, renal function, age and smoking status and can be avoided by a careful patient evaluation before chemotherapy. Lung function assessments are not routinely recommended for detecting bleomycin pulmonary toxicity. Long-term decreased pulmonary function may also be related to other chemotherapy agents such as cisplatin. Cardiovascular disease represents one of the most serious late effects of cytotoxic treatment in TC survivors and typically appears several years to decades after treatment. The increased risk for cardiovascular disease is probably mediated by a direct vascular damage from cytotoxic treatment that may stimulate the endothelium, possibly ultimately inducing the atherosclerotic process, as well as an indirect cytotoxic effect by increasing the levels of cardiovascular risk factors. Follow-up of these cancer survivors should include recommendations for maintaining a healthy lifestyle to reduce the risk of future cardiovascular events and to avoid declining pulmonary function.

Radiotherapy has been applied to for the treatment of testicular cancer for several decades. Due to its exquisite radiation-sensitivity, localized seminoma could efficiently be eradicated by abdominal field radiotherapy. Furthermore, adjuvant abdominal radiotherapy for stage I seminoma has been the standard approach for the last 50 years. However, the risk of long-term toxicities, mainly radiation-.induced second neoplasms, as well as overtreatment of approximately 85 % of these patients, render surveillance or adjuvant carboplatin the new standards of care in Europe and many cancer centers in the U.S. For metastatic seminoma, radiotherapy is currently mostly applied in early stage II, or for brain- and bone metastases as well as part of palliative treatment.

SWENOTECA has since 1998 offered patients with clinical stage I (CS I) nonseminoma, adjuvant chemotherapy with one course of bleomycin, etoposide and cisplatin (BEP). The aim has been to reduce the risk of relapse, sparing patients the need of toxic salvage treatment. Initial results on 312 patients treated with one course of adjuvant BEP, with a median follow-up of 4.5 years, have been previously published. We now report mature and expanded results.In a prospective, binational, population-based risk-adapted treatment protocol, 517 Norwegian and Swedish patients with CS I nonseminoma received one course of adjuvant BEP. Patients with lymphovascular invasion (LVI) in the primary testicular tumor were recommended one course of adjuvant BEP. Patients without LVI could choose between surveillance and one course of adjuvant BEP. Data for patients receiving one course of BEP are presented in this study.At a median follow-up of 7.9 years, 12 relapses have occurred, all with IGCCC good prognosis. The latest relapse occurred 3.3 years after adjuvant treatment. The relapse rate at 5 years was 3.2% for patients with LVI and 1.6% for patients without LVI. Five-year cause-specific survival was 100%.The updated and expanded results confirm a low relapse rate following one course of adjuvant BEP in CS I nonseminoma. One course of adjuvant BEP should be considered a standard treatment in CS I nonseminoma with LVI. For patients with CS I nonseminoma without LVI, one course of adjuvant BEP is also a treatment option.

DOI: 10.1200/JCO.2013.54.2449 “The date of diagnosis? Do you mean a specific day?” The well-mannered older man with advanced lung cancer sighs, pauses, takes off his glasses, strokes through his gray, cared-for beard, and looks at me as if trying to decide whether or not I will be able to follow his thoughts. “Kafkaesque! That’s what it is, Kafkaesque.” He was obviously pleased with his exclamation, which to be honest, did not help me much. Looking in my eyes, he felt my uncertainty, sighed again, not in an unfriendly or arrogant manner, but perhaps with a bit of disappointment that I was unable to share his moment of delight at finding a fitting expression. Few tasks are more challenging than breaking bad news, especially if a patient seems reluctant to engage in conversation. Any question posed by a patient provides an opportunity to get started. What made this situation unusual is that the question referred only to the time of diagnosis. This lovable bibliophilic man introduced me to the particular atmosphere in Kafka’s work: “...instances in which bureaucracies overpower people, often in a surreal, nightmarish milieu which evokes feelings of senselessness, disorientation, and helplessness.” The patient continued, “You understand that the many tests and the elusive information of the recent weeks remind me of Franz Kafka’s words in his famous work Der Prozess, meaning both trial and process.” “The verdict does not come suddenly, proceedings continue until a verdict is reached gradually.” Another way to translate the sentence from German would be: “The verdict does not come suddenly, the process gradually transforms into the verdict.” The patient went on. “First there was this cough, not unusual for me, but a bit more pronounced than in recent months. One day I had to consult my general physician after I had tripped and broken a rib. I think my process/trial started as my first x-ray touched the backlight in my GP’s office. “A ‘shadow’ was visible. A CT scan was ordered the same week. A ‘mass’ is described—in my right lower lung. “My physician advised me not to think too much before cytology results were available; samples would be taken the next day. Of course, I was absorbed by frightening scenarios, including a painful death. How could I avoid these thoughts after losing friends whose processes/trials started with shadows and masses and culminated in the verdict of a death sentence? My trial had begun—consuming my days and my thoughts.” “...without having done anything wrong he was arrested one fine morning.” “Another doctor tried to move my trial along by sampling some of these cells through a tube which he inserted into my airways in order to prove or exclude a neoplasm. I am being taught new technical terms on a daily basis. Two days later I was informed of the results: No malignant cells. “So did my head stop spinning now? Was this trial over? Am I being released? I am not sure that I felt relief. “Somehow, this doctor did not see it end here: ‘Sometimes, cytology is not reliable enough. In order to proceed you need a biopsy.’ This is arranged for me for the next day.” “It is not necessary to accept everything as true, one must only accept it as necessary.” “It was the cancer tissue under the pathologist’s microscope, which irrevocably established my diagnosis, my verdict. Relief—that was my first emotion,” the patient said with watery eyes. “Not that I did not understand the impact of this serious disease, but it was a verdict. Finally! “I was transferred to this hospital and I realize that my process/trial continues here. The hospital’s staff explains that as a patient I am expected to be patient; that several experts are working on my case, ensuring that my process is following its predefined course. “Before retirement I had been smoking for many years, and feelings of guilt surface from time to time. However, I am not thinking clearly and the last week’s ordeal left me an emotional cripple—unable to feel grief or joy. Surely, the doctors here know how to proceed, but like in Kafka’s Trial, nobody addresses me directly.” “‘We’re all human beings here, one like the other.’ “‘That is true,’ said the priest. ‘But that is how the guilty speak.’ “‘Do you presume I’m guilty, too?’ asked K. JOURNAL OF CLINICAL ONCOLOGY A R T O F O N C O L O G Y VOLUME 32 NUMBER 10 APRIL 1 2014

Objective To advise urologists and other clinicians on the appropriate management of low-stage (clinical Stage [CS] I, IS, IIA, and IIB) nonseminomatous germ cell tumors of the testis. Methods A panel was convened of experts from 5 countries. A literature search in MEDLINE was used to identify evidence from relevant studies on the outcome and toxicity of observational, surgical, and chemotherapeutic approaches for low-stage nonseminomatous germ cell tumors to form the basis of the panel's recommendations. Results The panel has recommended the treatment of nonseminomatous germ cell tumors in centers with medical, surgical, and diagnostic expertise in testicular cancer. The cancer-specific survival rate for CS I and CS IIA-IIB should approach 100% and 95%-100%, respectively. Patients with CS I should be made aware of all treatments (ie, surveillance, primary chemotherapy, and retroperitoneal lymph node dissection) and the potential side effects. For patients with CS I at low risk of occult metastasis, surveillance is preferred. For patients at high risk of occult metastasis, all 3 options can be considered. For immediate treatment, the choice between primary chemotherapy and retroperitoneal lymph node dissection should be determined by patient preference and the specific expertise of the treating institution. Patients with increasing postorchiectomy serum α-fetoprotein or human choriogonadotropin levels (CS IS and CS IIA-IIB) should receive induction chemotherapy. Induction chemotherapy or retroperitoneal lymph node dissection can be considered for patients with CS IIA-IIB with normal postorchiectomy α-fetoprotein and human choriogonadotropin levels. Surveillance can be considered for patients with equivocal computed tomography retroperitoneal findings who are otherwise at low risk of metastatic disease. Conclusion These clinical practice guidelines are designed to improve clinical practice from the available evidence and the expert opinion of the panel. As such, deviation from these recommendations should be based on sound clinical judgment, considering the unique situation of the patient and the expertise of the treating physician and institution.

Testicular cancer represents the most curable solid tumor, with a 10-year survival rate of more than 95%. Given the young average age at diagnosis, it is estimated that effective treatment approaches, in particular, platinum-based chemotherapy, have resulted in an average gain of several decades of life. This success, however, is offset by the emergence of considerable long-term morbidity, including second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems. Data on underlying genetic or molecular factors that might identify those patients at highest risk for late sequelae are sparse. Genome-wide association studies and other translational molecular approaches now provide opportunities to identify testicular cancer survivors at greatest risk for therapy-related complications to develop evidence-based long-term follow-up guidelines and interventional strategies. We review research priorities identified during an international workshop devoted to testicular cancer survivors. Recommendations include 1) institution of lifelong follow-up of testicular cancer survivors within a large cohort setting to ascertain risks of emerging toxicities and the evolution of known late sequelae, 2) development of comprehensive risk prediction models that include treatment factors and genetic modifiers of late sequelae, 3) elucidation of the effect(s) of decades-long exposure to low serum levels of platinum, 4) assessment of the overall burden of medical and psychosocial morbidity, and 5) the eventual formulation of evidence-based long-term follow-up guidelines and interventions. Just as testicular cancer once served as the paradigm of a curable malignancy, comprehensive follow-up studies of testicular cancer survivors can pioneer new methodologies in survivorship research for all adult-onset cancer. J Natl Cancer Inst 2010; 102: 1114-1130

Objective: To explore fear of recurrence (FoR) in long-term testicular cancer survivors (TCSs) since FoR hardly has been examined in TCSs. Methods: In a cross-sectional questionnaire study, 1336 TCSs at a mean of 11.4 years (SD 4.2) after diagnosis gave information about their medical and social situation, and completed measures on mental distress, fatigue, quality of life, coping, self-esteem and neuroticism. FoR during the last week was explored with one question, with the response categories rated on a 4-point Likert scale. Nine percent of the TCSs had a structured psychiatric interview. Results: Twenty-four percent of the TCSs reported ‘quite a bit’ FoR and 7% reported ‘very much’ FoR during the last week. The FoR question showed moderate correlations (0.22–0.51) with established psychological measures. The level of FoR was significantly positively correlated with mental distress, fatigue and neuroticism and significantly negatively correlated with quality of life, self-esteem and coping. In univariate analyses, neurotoxic side effects and somatic symptoms, but not treatment modality, were significantly associated with level of FoR. In a multivariate analysis, a medium educational level, increasing levels of traumatic cancer-related stress symptoms and of neuroticism were significantly associated with rising FoR. Among those who had a psychiatric interview, the presence of at least one current mental disorder was significantly associated with FoR. Conclusions: High levels of FoR in long-term TCSs are not uncommon. Levels of mental and somatic problems are associated with the levels of FoR. Clinical consequences of these findings for TCSs are discussed. Copyright © 2008 John Wiley & Sons, Ltd.

443 Background: The Renal Comparison study in Norway (RECON) is a retrospective non-interventional study of OS in all patients diagnosed with RCC and metastatic (m)RCC before and after the introduction of TTs. Methods: Using data from two national health registries, Cancer Registry of Norway (diagnosis and cause of death) and Norwegian Prescription Database (all dispensed drugs), we assessed OS in RCC and mRCC patients diagnosed during two periods after (2009–2011 and 2006–2008) and one period before (2000–2005 [RCC]; 2002–2005 [mRCC]) the introduction of TTs and factors influencing OS in mRCC. Multivariate analysis was performed using a Cox proportional hazards model, including estimation of adjusted HR. The regression model included the covariates age, gender, geographic region, nephrectomy status, diagnostic period and TT prescription. Results: In total, 2,176, 1,887, and 3,233 RCC patients were identified in 2009–2011, 2006–2008 and 2000–2005, respectively, of whom 2,160 (30%) had mRCC. From 2006 to 2011, TT use in mRCC patients significantly increased from 21% to 56% (p