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Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m 2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; pinteraction=0·71) or between-trial heterogeneity (I 2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (

Purpose: There is ongoing controversy about the recommended dose of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods: This multicenter phase II open-label, randomized, parallel-group study compared 3-weekly cabazitaxel at 25 mg/m2 (conventional arm A) with cabazitaxel therapeutic drug monitoring (experimental arm B) in mCRPC. The primary objective was to improve the clinical feasibility rate (CFR), defined as the absence of grade 4 neutropenia or thrombocytopenia, any thrombocytopenia with bleeding, febrile neutropenia, severe nonhematologic toxicity, withdrawal for cabazitaxel-related toxicity, or death. A total of 60 patients had to be randomized to detect a difference in CFR of 35% (power 80%, two-sided alpha 10%). Results: A total of 40 patients were randomized to arm A and 33 patients to arm B. CFR was 69.4% in arm A and 64.3% in arm B (P = 0.79). Week-12 PSA response was 38.5% in both arms. A radiological response by RECIST v.1.1 was seen in 3 (9.7%) patients in arm A versus 6 (23.1%) patients in arm B (P = 0.28), disease progression was higher in arm A compared with arm B (61.3% vs. 30.8%, P = 0.05). Median progression-free survival was longer in arm B compared with arm A (9.5 vs. 4.4 months; HR = 0.46; P = 0.005). Median overall survival was higher in arm B compared with arm A (16.2 vs. 7.3 months; HR = 0.33; P < 0.0001). Conclusions: Pharmacokinetic-guided dosing of cabazitaxel in patients with mCRPC is feasible and improves clinical outcome due to individual dose escalations in 55% of patients.

Representativeness of Study Participants

CONSORT Diagram

Per-patient ADA responses

Summary of mean (%CV) PK parameters of Total ADC and Active ADC after a single IV infusion of MEDI3726

CTC while on treatment (patients with at least one CTC measurement >50)

Mutation profiles in ctDNA: truncating and/or pathogenic mutations in DDR or DDR-related pathway

Purpose:There is ongoing controversy about the recommended dose of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC).Patients and Methods:This multicenter phase II open-label, randomized, parallel-group study compared 3-weekly cabazitaxel at 25 mg/m2 (conventional arm A) with cabazitaxel therapeutic drug monitoring (experimental arm B) in mCRPC. The primary objective was to improve the clinical feasibility rate (CFR), defined as the absence of grade 4 neutropenia or thrombocytopenia, any thrombocytopenia with bleeding, febrile neutropenia, severe nonhematologic toxicity, withdrawal for cabazitaxel-related toxicity, or death. A total of 60 patients had to be randomized to detect a difference in CFR of 35% (power 80%, two-sided alpha 10%).Results:A total of 40 patients were randomized to arm A and 33 patients to arm B. CFR was 69.4% in arm A and 64.3% in arm B (P = 0.79). Week-12 PSA response was 38.5% in both arms. A radiological response by RECIST v.1.1 was seen in 3 (9.7%) patients in arm A versus 6 (23.1%) patients in arm B (P = 0.28), disease progression was higher in arm A compared with arm B (61.3% vs. 30.8%, P = 0.05). Median progression-free survival was longer in arm B compared with arm A (9.5 vs. 4.4 months; HR = 0.46; P = 0.005). Median overall survival was higher in arm B compared with arm A (16.2 vs. 7.3 months; HR = 0.33; P < 0.0001).Conclusions:Pharmacokinetic-guided dosing of cabazitaxel in patients with mCRPC is feasible and improves clinical outcome due to individual dose escalations in 55% of patients.

Purpose:MEDI3726 is an antibody–drug conjugate targeting the prostate-specific membrane antigen and carrying a pyrrolobenzodiazepine warhead. This phase I study evaluated MEDI3726 monotherapy in patients with metastatic castration-resistant prostate cancer after disease progression on abiraterone and/or enzalutamide and taxane-based chemotherapy.Patients and Methods:MEDI3726 was administered at 0.015–0.3 mg/kg intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary objective was to assess safety, dose-limiting toxicities (DLT), and MTD/maximum administered dose (MAD). Secondary objectives included assessment of antitumor activity, pharmacokinetics, and immunogenicity. The main efficacy endpoint was composite response, defined as confirmed response by RECIST v1.1, and/or PSA decrease of ≥50% after ≥12 weeks, and/or decrease from ≥5 to Results:Between February 1, 2017 and November 13, 2019, 33 patients received MEDI3726. By the data cutoff (January 17, 2020), treatment-related adverse events (TRAE) occurred in 30 patients (90.9%), primarily skin toxicities and effusions. Grade 3/4 TRAEs occurred in 15 patients (45.5%). Eleven patients (33.3%) discontinued because of TRAEs. There were no treatment-related deaths. One patient receiving 0.3 mg/kg had a DLT of grade 3 thrombocytopenia. The MTD was not identified; the MAD was 0.3 mg/kg. The composite response rate was 4/33 (12.1%). MEDI3726 had nonlinear pharmacokinetics with a short half-life (0.3–1.8 days). The prevalence of antidrug antibodies was 3/32 (9.4%), and the incidence was 13/32 (40.6%).Conclusions:Following dose escalation, no MTD was identified. Clinical responses occurred at higher doses, but were not durable as patients had to discontinue treatment due to TRAEs.

Background Patients with advanced prostate cancer have a poor prognosis, and well-tolerated new treatment strategies are required to improve survival outcomes. Apalutamide is a novel androgen signalling inhibitor developed to be used in combination with continuous androgen deprivation therapy (ADT) for the treatment of patients with advanced prostate cancer. Based on evidence from two phase 3 pivotal clinical trials in non-metastatic castration-resistant (nmCRPC; SPARTAN) and metastatic hormone-sensitive prostate cancer (mHSPC; TITAN), ADT plus apalutamide significantly extends overall survival compared with the standard of care. Aims To provide practical recommendations to guide optimal use in the real-world setting as the use of apalutamide in clinical practice increases. Methods Expert opinion from a group of European physicians is presented here to educate on the use of apalutamide in combination with ADT in patients with mHSPC and patients with nmCRPC who are at risk of developing metastatic disease, focusing on practical considerations such as patient selection, monitoring, and management of side effects. Results In clinical practice, apalutamide in combination with ADT can be used in a broad patient population including patients with high and low volume/risk mHSPC, patients with de novo metastatic disease or metastases following treatment for localised disease, as well as older patients. Apalutamide in combination with ADT is well tolerated, with manageable side effects which do not impact health-related quality of life compared to ADT alone. Conclusions Real-world experience with apalutamide supports the efficacy and safety findings reported by the SPARTAN and TITAN clinical trials.

Contains fulltext : 248305.pdf (Publisher’s version ) (Closed access) CONTEXT: Treatment of metastatic urothelial carcinoma is currently undergoing a rapid evolution. OBJECTIVE: This overview presents the updated European Association of Urology (EAU) guidelines for metastatic urothelial carcinoma. EVIDENCE ACQUISITION: A comprehensive scoping exercise covering the topic of metastatic urothelial carcinoma is performed annually by the Guidelines Panel. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries, resulting in yearly guideline updates. EVIDENCE SYNTHESIS: Platinum-based chemotherapy is the recommended first-line standard therapy for all patients fit to receive either cisplatin or carboplatin. Patients positive for programmed death ligand 1 (PD-L1) and ineligible for cisplatin may receive immunotherapy (atezolizumab or pembrolizumab). In case of nonprogressive disease on platinum-based chemotherapy, subsequent maintenance immunotherapy (avelumab) is recommended. For patients without maintenance therapy, the recommended second-line regimen is immunotherapy (pembrolizumab). Later-line treatment has undergone recent advances: the antibody-drug conjugate enfortumab vedotin demonstrated improved overall survival and the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib appears active in case of FGFR3 alterations. CONCLUSIONS: This 2021 update of the EAU guideline provides detailed and contemporary information on the treatment of metastatic urothelial carcinoma for incorporation into clinical practice. PATIENT SUMMARY: In recent years, several new treatment options have been introduced for patients with metastatic urothelial cancer (including bladder cancer and cancer of the upper urinary tract and urethra). These include immunotherapy and targeted treatments. This updated guideline informs clinicians and patients about optimal tailoring of treatment of affected patients.

PURPOSE To assess the efficacy and safety of darolutamide maintenance after successful taxane chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS Swiss Group for Clinical Cancer Research (SAKK) 08/16 is a randomized phase II study. Patients with mCRPC who received prior androgen-receptor pathway inhibitors (ARPIs) and subsequently had nonprogressive disease on a taxane were randomly assigned to darolutamide 600 mg twice a day or placebo twice a day. The primary end point was radiographic progression-free survival (rPFS) at 12 weeks. Secondary end points were rPFS, event-free survival, overall survival (OS), prostate-specific antigen (PSA) 50% response rate, and adverse events. RESULTS Overall, 92 patients were recruited by 26 centers. Prior taxane was docetaxel in 93% and cabazitaxel in 7%. Prior ARPI was abiraterone in 60%, enzalutamide in 31%, and both in 9%. rPFS at 12 weeks was significantly improved with darolutamide (64.7% v 52.2%; P = .127). Median rPFS on darolutamide was 5.5 versus 4.5 months on placebo (hazard ratio [HR], 0.54; 95% CI, 0.32 to 0.91; P = .017), and median event-free survival was 5.4 versus 2.9 months (HR, 0.46; 95% CI, 0.29 to 0.73; P = .001). PSA 50% response rate was improved (22% v 4%; P = .014). Median OS for darolutamide was 24 versus 21.3 months for placebo (HR, 0.62; 95% CI, 0.3 to 1.26; P = .181). Treatment-related adverse events were similar in both arms. CONCLUSION SAKK 08/16 met its primary end point, showing that switch maintenance with darolutamide after prior taxane chemotherapy and at least one ARPI resulted in a statistically significant but clinically modest rPFS prolongation with good tolerability. The median OS with darolutamide maintenance appears promising. Should these findings be confirmed in a larger trial, maintenance treatment could be a novel strategy in managing patients with mCRPC, especially those who responded well to prior ARPI.

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 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 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.

4515 Background: SAKK 06/17 investigated the addition of perioperative immunotherapy with the anti-PD-L1 antibody durvalumab (Durva) in the multimodality treatment of resectable MIUC. While most similar trials had a primary endpoint of pathological complete remission rate, this study evaluated the clinically more relevant primary endpoint of event-free survival (EFS) at 2 years (yrs). Methods: SAKK 06/17 was an open-label, single-arm phase II study including 61 cisplatin-fit patients (pts) with stage cT2-T4a cN0-1 operable MIUC. Pts received four cycles of neoadjuvant Cis/Gem q3w in combination with 4 cycles Durva 1500mg q3w followed by complete resection. Adjuvant Durva 1500mg q4w was given for 10 cycles or a maximum of 40 weeks. The primary endpoint was EFS at 2 yrs after neoadjuvant trial treatment (NAT) start. An event was defined as progression during NAT, appearance of metastases, locoregional recurrence after surgery or death from any cause. 58 pts were needed based on one-sided type I error 10% and power 80% for H1 EFS at 2 yrs ≥ 65% compared to H0 EFS at 2 yrs ≤ 50%. Secondary endpoints included pathological response, recurrence free survival after R0 resection (RFS), overall survival (OS) and safety. We report the primary analysis of the full analysis set (FAS, received at least one dose of Durva). Results: 61 pts were included between July 2018 and September 2019 at 12 sites. Median follow up is 28.1 months (95%CI 27.8-28.4). FAS consisted of 58 pts (79% male, median age 68 yrs) with bladder cancer (95%) or upper urinary tract/urethral cancer (5%). Clinical T2, T3, T4 stage was present at diagnosis in 69%, 21%, 10%, respectively, and 17% had cN1. Resection was performed in 53 pts (91%; 4 refused, 1 unresectable) with R0 resection in 52 pts (98%). 48 (91%) of resected pts started adjuvant Durva and 32 (67%) completed it. Pathological response < ypT2 ypN0 was achieved in 32 pts (18 pts ypT0 and 14 pts ypT1/a/is), corresponding to 60% of resected pts and 55% of the FAS. EFS at 2 yrs was overall 76.1% (one-sided 90% CI (lower bound): 67.6%; 95% CI 62.3% - 85.3%), for ypT1/a/is 92.9% and for ypT0 100%. RFS at 2 yrs after R0 resection (N=52) was 83.5% (95% CI 69.6% - 91.4%) and OS at 2 yrs for the FAS population was 87.3% (95% CI 73.8% - 94.1%). Grade 1, 2, 3, 4 adverse events attributed to Durva during overall treatment were 14%, 35%, 19%, 7%, respectively. Conclusions: The addition of perioperative Durvalumab to the standard of care for pts with resectable MIUC results in a high EFS, RFS and OS at 2 yrs, especially for pts with downstaging to

Metastatic castration resistant prostate cancer (CRPC) is an inevitably fatal disease. However, in recent years, several treatments have been shown to improve the outcome of CRPC patients both in the non-metastatic (nmCRPC) as well as the metastatic setting (mCRPC). In nmCRPC patients with a PSA doubling time10 months, the addition of enzalutamide, apalutamide and darolutamide to androgen deprivation therapy (ADT) compared to ADT alone resulted in improved metastases free (MFS) and overall survival (OS). For mCRPC patients, several treatment options have been shown to be effective: two taxane based chemotherapies (docetaxel and cabazitaxel), two androgen-receptor pathway inhibitors (ARPI) (abiraterone and enzalutamide), two radiopharmaceutical agents (radium 223 and 177Lutetium-PSMA-617), one immunotherapy treatment (sipuleucel-T) and two poly ADP-ribose polymerase (PARP) inhibitors (olaparib and rucaparib). Pembrolizumab is US Food and Drug Administration (FDA) approved in all MSI high solid tumors, although a very small proportion of prostate cancer patients harboring this characteristic will benefit. Despite having a broad variety of treatments available, there are still several unmet clinical needs for CRPC. The objective of this review was to describe the therapeutic landscape in CRPC patients, to identify criteria for selecting patients for specific treatments currently available, and to address the current challenges in this setting.

Background: With the expanding indications and thus broader use of immune checkpoint inhibitors, clinicians are faced with a new kind of immune-related adverse events. Because of their immune modulating effects, immune checkpoint inhibitors have the potential to worsen autoimmunity in general. Paraneoplastic syndromes can be caused by tumor-induced autoimmune mechanisms. The use of immune-activating substances such as checkpoint inhibitors might lead to exacerbation of paraneoplastic syndromes causing premature discontinuation of the immunotherapy. Case presentation: We report on a 64-year-old patient with metastasized renal cell carcinoma who developed acute kidney failure after cytoreductive nephrectomy. Work-up revealed a paraneoplastic syndrome that caused tubulointerstitial nephritis (TIN). Glucocorticoid therapy successfully reversed the acute kidney injury. However, adjuvant therapy with Nivolumab provoked a flare-up of the paraneoplastic syndrome on two occasions, eventually leading to a treatment discontinuation. Conclusions: Many cases of Nivolumab-induced TIN have been described lately. However, our case demonstrates therapy failure due to a flare-up of a pre-existing paraneoplastic syndrome of the renal cancer. Against this background, it can only be speculated that some of the TIN cases discussed in prior literature might also have been flare-ups of subclinical autoimmunity.

BACKGROUND MiR-371a-3p predicts the presence of a macroscopic non-teratomatous germ cell tumour (GCT). We hypothesised that miR-371a-3p can also detect recurrence during active surveillance (AS) of stage I GCT. METHODS We prospectively collected serum samples of 33 men. Relative expression of serum miR-371a-3p levels was determined at each follow-up visit using real-time quantitative reverse transcription-polymerase chain reaction. RESULTS Recurrence was detected using standard follow-up investigations in 10/33 patients (30%) after a median of 7 months. Directly after orchiectomy, miR-371a-3p levels were not elevated in any of the 15 patients with available post-orchiectomy samples. However, all ten recurring patients exhibited increasing miR-371a-3p levels during follow-up, while miR-371a-3p levels remained non-elevated in all but one patient without recurrence. MiR-371a-3p detected recurrences at a median of 2 months (range 0-5) earlier than standard follow-up investigations. CONCLUSIONS MiR-371a-3p levels immediately post orchiectomy are not predictive for recurrences and unfortunately cannot support decision-making for AS vs. adjuvant treatment. However, miR-371a-3p detects recurrences reliably and earlier than standard follow-up investigations. If this can be confirmed in larger cohorts, monitoring miR-371a-3p could replace surveillance imaging in seminomatous GCT and reduce the amount of imaging in non-seminomatous GCT. Earlier detection of disease recurrence may also reduce the overall treatment burden.

Approximately 420 men are diagnosed with germ-cell cancer (GCC) in Switzerland each year. Recent international guidelines outline management issues, but many aspects remain controversial in an area of highly individualised treatments. Even more than in other tumour types, in GCC the challenge is to choose exactly the correct treatment for an individual patient. Overtreatment in patients likely to be cured must be avoided to reduce long-term toxicities. On the other hand, treatment intensification is required in patients presenting with adverse prognostic factors. Therefore, referral to expert centres or consultations with an expert for a second opinion is strongly recommended. In 2020, Swiss experts discussed their strategies in a consensus meeting during the virtual Swiss Oncology and Haematology Congress (SOHC) in order to harmonise their concepts and to suggest optimal strategies for the management of GCC patients in Switzerland. Votes on controversial issues were obtained and are presented in this review wherever applicable.

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 Results from large randomised controlled trials have shown that adding docetaxel to the standard of care (SOC) for men initiating hormone therapy for prostate cancer (PC) prolongs survival for those with metastatic disease and prolongs failure-free survival for those without. To date there has been no formal assessment of whether funding docetaxel in this setting represents an appropriate use of UK National Health Service (NHS) resources. Objective To assess whether administering docetaxel to men with PC starting long-term hormone therapy is cost-effective in a UK setting. Design, setting, and participants We modelled health outcomes and costs in the UK NHS using data collected within the STAMPEDE trial, which enrolled men with high-risk, locally advanced metastatic or recurrent PC starting first-line hormone therapy. Intervention SOC was hormone therapy for ≥2 yr and radiotherapy in some patients. Docetaxel (75 mg/m2) was administered alongside SOC for six three-weekly cycles. Outcome measurements and statistical analysis The model generated lifetime predictions of costs, changes in survival duration, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Results and limitations The model predicted that docetaxel would extend survival (discounted quality-adjusted survival) by 0.89 yr (0.51) for metastatic PC and 0.78 yr (0.39) for nonmetastatic PC, and would be cost-effective in metastatic PC (ICER £5514/QALY vs SOC) and nonmetastatic PC (higher QALYs, lower costs vs SOC). Docetaxel remained cost-effective in nonmetastatic PC when the assumption of no survival advantage was modelled. Conclusions Docetaxel is cost-effective among patients with nonmetastatic and metastatic PC in a UK setting. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in patients with nonmetastatic PC, as the opportunity to offer docetaxel at hormone therapy initiation will be missed for some patients by the time more mature survival data are available. Patient summary Starting docetaxel chemotherapy alongside hormone therapy represents a good use of UK National Health Service resources for patients with prostate cancer that is high risk or has spread to other parts of the body., Take Home Message Docetaxel is a cost-effective intervention in patients with metastatic and nonmetastatic prostate cancer starting hormone therapy. Clinicians and National Health Service funding bodies should consider whether the evidence is now sufficiently compelling to support initiating docetaxel in patients with nonmetastatic disease.

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.

BACKGROUND International guidelines state that bone-targeted agents such as denosumab or zoledronic acid at doses used for bone metastasis are not indicated for patients with metastatic castration-sensitive prostate cancer (mCSPC) with bone metastases. Whereas denosumab has never been studied in this patient population, zoledronic acid has been shown to be ineffective in decreasing the risk for skeletal-related events. This study estimates the prevalence and economic consequences of real-world use of bone-targeted agents for mCSPC patients in Switzerland. METHODS To estimate the frequency of bone-targeted agent administration and skeletal-related events, data from a non-interventional, cross-sectional survey involving oncologists across Switzerland (SAKK 95/16) was combined with data from the Swiss National Institute for Cancer Epidemiology and Registration (NICER). Economic parameters were calculated from the perspective of the healthcare system over the median time to prostate-specific antigen (PSA) progression for the extrapolated patient group, using data from NICER. The cost calculation covered costs for bone-targeted agents, their administration and skeletal-related events. The time to PSA progression (33.2 months), as well as the probability and cost of skeletal-related events were derived from the literature. RESULTS The survey was answered by 86 physicians treating 417 patients, of whom 106 (25.4%) had prostate cancer, with 36 (34.0%) of these mCSPC. The majority of mCSPC patients (52.8%, n = 19) received bone-targeted agents monthly. Denosumab was the treatment of choice in 84.2% of patients (n = 16). Extrapolation using data from NICER indicated that 568 mCSPC patients may be treated with bone-targeted agents at doses used for bone metastasis every year in Switzerland, leading to estimated total costs of more than CHF 8.3 million over 33.2 months. Because of its more frequent prescription and higher price, it appears that almost 93% of the total costs can be attributed to denosumab. For both denosumab and zoledronic acid, the most expensive components were the cost of administration and the drug cost, making up more than 90% of the total costs, with the rest being costs of skeletal-related events. CONCLUSIONS This study found that the administration of bone-targeted agents in doses used for bone-metastatic diseases to prevent skeletal-related events is frequent in the setting of mCSPC and results in significant costs for the healthcare system.

Bone-modifying agent (BMA) therapy is recommended for metastatic castration-resistant prostate cancer but not metastatic castration-sensitive prostate cancer (mCSPC). BMA treatment in mCSPC may therefore constitute overuse.In this retrospective cohort study using linked Surveillance, Epidemiology, and End Results-Medicare data, we included patients diagnosed with stage IV prostate adenocarcinoma from 2007 to 2015 who were 66 years of age or older at diagnosis and had received androgen-deprivation or antiandrogen therapy. We excluded patients who had previously received BMAs or had existing osteoporosis, osteopenia, hypercalcemia, or prior bone fracture. The primary outcome was receipt of BMA (zoledronic acid or denosumab) within 180 days of diagnosis (emergence of CRPC within this time frame is unlikely). The secondary outcome was receipt of a BMA within 90 days. Exposures of interest included practice location (physician office vs hospital outpatient) and the specialty (medical oncologist vs urologist) of the treating physician.Our sample included 2627 patients, of whom 52.9% were treated by medical oncologists and 47.1% by urologists; 77.7% and 22.3% received care in physician office and hospital outpatient locations, respectively. Overall, 23.6% received a BMA within 180 days; 18.4% did within 90 days. BMA therapy was more common among patients treated by oncologists (odds ratio = 8.23, 95% confidence interval = 6.41 to 10.57) and in physician office locations (odds ratio = 1.33, 95% confidence interval = 1.06 to 1.69). Utilization has increased: 17.3% of patients received BMAs from 2007 to 2009 (17.3% zoledronic acid, 0% denosumab) and 28.1% from 2012 to 2015 (8.4% zoledronic acid, 20.3% denosumab).Among patients with mCSPC who had no evidence of high osteoporotic fracture risk, more than one-quarter have received BMAs in recent years. This overuse may lead to excess costs and toxicity.

Background Bone-targeted agents (BTAs) are widely used in the management of patients with bone metastases from solid tumors. Knowledge of the impact of their routine care use on patient-reported pain and bone pain-related quality of life (QoL) is limited. Methods This real world, cross-sectional study enrolled patients over a 3-month period through oncologists across Switzerland. Patients were ≥ 18 years, had solid tumors and at least one bone metastasis, and received routine care for bone metastases. Physicians provided data on BTA-related practices, risk of bone complications and BTA regimen. Patients completed questionnaires about pain (BPI-SF), general and bone pain-related QoL (FACT-G, FACT-BP) and treatment satisfaction (FACIT-TS-G). Results Eighteen sites recruited 417 patients. Based on the FACT-BP, 42% of the patients indicated not having bone pain. According to the BPI-SF, 28% reported no, 43% mild, 14% moderate, and 15% severe pain, respectively. Patients not treated with a BTA had better overall QoL (FACT-G: p = 0.031) and bone pain-related QoL (FACT-BP, p = 0.007) than those treated with a BTA. All pain and other QoL scales did not differ between groups. Patients perceived at ‘low risk of bone complications’ by their physician not receiving a BTA reported less pain and better QoL than those considered at ‘low risk’ but receiving BTA treatment or those considered at ‘high risk’ regardless of BTA treatment. Overall satisfaction with the treatment was good; almost 50% of patients reporting that they were completely satisfied. Conclusions Overall, pain and QoL did not differ according to BTA treatment or physicians’ risk perception. Patient with low risks not receiving BTA treatment reported least pain and highest QoL scores. These results may suggest that treating physicians assess bone complication risk appropriately and treat patients accordingly, but they need to be confirmed by objective determination of longitudinal skeletal complication risk.

Introduction: Primary breast malignancy in adolescent women is very rare and differs in several aspects from findings in adult women. Case Presentation: A young woman aged 16 years presented with a locally aggressive breast tumor. The patient received cisplatin-based chemotherapy followed by tumor resection assuming a diagnosis of germ cell tumor. Four months later, she developed locally recurrent disease and underwent a mastectomy. No definite diagnosis was agreed upon despite intensive pathological workup. Subsequent management consisted of follow-up only and the patient remains in complete remission 9 years later. Conclusion: This case demonstrates the difficulty of diagnosis and management of rare malignancies in adolescents, and highlights the importance of international and interdisciplinary collaboration in diagnosis and clinical decision-making.

Die vorliegenden interdisziplinaren schweizerischen Konsensempfehlungen konnen als Grundlage fur eine gemeinsame Entscheidungsfindung an interdisziplinaren Tumorboards und im Gesprach mit Patienten behilflich sein.