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Owing to the rarity and heterogeneity in biology and presentation, there are multiple areas in the diagnosis, treatment and follow-up of soft tissue sarcoma (STS), with no, low-level or conflicting evidence.During the first Consensus Conference on the State of Science in Sarcoma (CSSS), we used a modified Delphi process to identify areas of controversy in the field of sarcoma, to name topics with limited evidence-based data in which a scientific and knowledge gap may remain and a consensus statement will help to guide patient management. We determined scientific questions which need to be addressed in the future in order to generate evidence and to inform physicians and caregivers in daily clinical practice in order to improve the outcomes of patients with sarcoma. We conducted a vote on STS key questions and controversies prior to the CSSS meeting, which took place in May 2022.Sixty-two European sarcoma experts participated in the survey. Sixteen strong consensus (≥95%) items were identified by the experts, as well as 30 items with a ≥75% consensus on diagnostic and therapeutic questions. Ultimately, many controversy topics remained without consensus.In this manuscript, we summarise the voting results and the discussion during the CSSS meeting. Future scientific questions, priorities for clinical trials, registries, quality assurance, and action by stakeholders are proposed. Platforms and partnerships can support innovative approaches to improve management and clinical research in STS.

NUTM1 gene rearrangements were originally identified in NUT carcinoma. Recently, NUTM1 has been discovered to rearrange with a variety of gene partners in malignancies of diverse location and type. Only one NUTM1-rearranged tumor occurring in the colon has been reported. Herein we report five such tumors. The five tumors occurred in four females and one male, ranging from 38 to 67 years of age (median 51 years). The masses occurred in the colon (cecum, descending, sigmoid) and ileocecal valve region, measuring 2.5-20 cm in size (median 7 cm). Four patients had metastases at presentation (liver, n = 4; lymph nodes, n = 3). Histologically, the lesions arose in the submucosa, infiltrating into the mucosa and muscularis propria, and grew in fibrosarcoma-like fascicles and sheets of epithelioid or rhabdoid cells, with foci of hyalinized to vaguely osteoid-like matrix. The tumors were composed of relatively monomorphic, spindled to epithelioid cells with focal rhabdoid morphology, hyperchromatic nuclei, and small nucleoli. Mitotic activity was usually low (range 1-14/10 HPF; median 5/10 HPF); necrosis was present in two cases. Variable keratin expression and uniform nuclear NUT expression was present; KIT/DOG1 were negative and SMARCB1/SMARCA4 were retained. Next-generation sequencing identified MXD4-NUTM1 rearrangement in all cases (breakpoints: MXD4 exon 5, NUTM1 exons 2 or 3). Follow-up showed one of the four patients who presented with metastases to be dead of disease at 30 months; the other three patients were alive with metastatic disease. The final patient is disease-free, 5 months after diagnosis. NUTM1-rearranged colorectal sarcomas have characteristic morphologic, immunohistochemical, and molecular genetic features, suggesting that they represent a distinct entity within the family of NUTM1-rearranged neoplasia. A NUTM1-rearranged tumor should be considered for any difficult-to-classify submucosal spindle cell neoplasm of the gastrointestinal tract, in particular keratin-positive tumors showing an unusual combination of fibrosarcomatous, epithelioid to rhabdoid and hyalinized morphologies. Recognition of MXD4-NUTM1 rearranged sarcomas may be therapeutically important, even though best treatment is currently elusive/unknown.

SummaryThe standard treatment of high-risk localized extremity and trunk soft-tissue sarcoma is wide local excision and radiation therapy, which can be delivered pre- or postoperatively. Improved care for sarcoma patients at expert centres with multidisciplinary tumour boards, specialized pathologists, surgeons, radio-oncologists, and medical oncologists, according to national or international guidelines, has improved outcomes. Yet, a substantial number of patients will experience disease recurrence with metastatic spread and ultimately die from their disease. In many solid tumours neo/adjuvant chemotherapy has become an accepted standard treatment, whereas in soft-tissue sarcoma discussions on the use of cytotoxic therapy in localized and resectable disease are ongoing. Some centres demonstrated the feasibility and now treat with concomitant neoadjuvant chemoradiotherapy as standard. Others argue that treatments should be given in the order of the accompanying evidence (surgery → radiotherapy → chemotherapy), which does not take biology of the disease into account and probably attempts to simplify complex decision making processes. It is important to enhance our ability to identify patients at highest risk of recurrence, and to generate data and develop tools to predict which patients will benefit from neo/adjuvant systemic therapy most.

To provide recommendations for the follow-up of rare, clinically localised testis tumours, including Leydig, Sertoli or granulosa cell and spermatocytic tumours.Medline and Embase searches to identify published clinical trials, cohort studies, reviews, clinical practise guidelines and meta-analyses to design expert opinion-based follow-up schedules.In four different systematic reviews, we previously identified 1375 men with Leydig, 435 with Sertoli, 239 with granulosa cell lesions and 146 with spermatocytic tumours. Local recurrence after testis-sparing surgery (TSS) was observed in 7%, 1% and 5% of men with Leydig, Sertoli and granulosa cell tumours: no reports were available regarding recurrence after TSS in men with spermatocytic tumours. Distant recurrence was observed in 6%, 4%, 4% and 7% of the first four tumour types, respectively: metastasis was never reported in granulosa cell tumours of juvenile type. For patients with metastatic disease, complete response after surgical resection was reported in 10%, 18%, 43% and 4%. Complete response after chemotherapy was reported in 5%, 0%, 29% and 4%. There was no report of patients responding to radiotherapy alone.We have collated the existing data about local and distant recurrence and response to treatment in men with rare testicular tumours and propose new recommendations for follow-up with cross-sectional imaging, stratified for each histological subtype.

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.

Background Metastatic soft tissue sarcoma (STS) are a heterogeneous group of malignancies which are not curable with chemotherapy alone. Therefore, understanding the molecular mechanisms of sarcomagenesis and therapy resistance remains a critical clinical need. ASPP2 is a tumor suppressor, that functions through both p53-dependent and p53-independent mechanisms. We recently described a dominant-negative ASPP2 isoform (ASPP2κ), that is overexpressed in human leukemias to promote therapy resistance. However, ASPP2κ has never been studied in STS. Materials and methods Expression of ASPP2κ was quantified in human rhabdomyosarcoma tumors using immunohistochemistry and qRT-PCR from formalin-fixed paraffin-embedded (FFPE) and snap-frozen tissue. To study the functional role of ASPP2κ in rhabdomyosarcoma, isogenic cell lines were generated by lentiviral transduction with short RNA hairpins to silence ASPP2κ expression. These engineered cell lines were used to assess the consequences of ASPP2κ silencing on cellular proliferation, migration and sensitivity to damage-induced apoptosis. Statistical analyses were performed using Student’s t-test and 2-way ANOVA. Results We found elevated ASPP2κ mRNA in different soft tissue sarcoma cell lines, representing five different sarcoma sub-entities. We found that ASSP2κ mRNA expression levels were induced in these cell lines by cell-stress. Importantly, we found that the median ASPP2κ expression level was higher in human rhabdomyosarcoma in comparison to a pool of tumor-free tissue. Moreover, ASPP2κ levels were elevated in patient tumor samples versus adjacent tumor-free tissue within individual patients. Using isogenic cell line models with silenced ASPP2κ expression, we found that suppression of ASPP2κ enhanced chemotherapy-induced apoptosis and attenuated cellular proliferation. Conclusion Detection of oncogenic ASPP2κ in human sarcoma provides new insights into sarcoma tumor biology. Our data supports the notion that ASPP2κ promotes sarcomagenesis and resistance to therapy. These observations provide the rationale for further evaluation of ASPP2κ as an oncogenic driver as well as a prognostic tool and potential therapeutic target in STS.

Background Important regional disparities in patterns of care in breast cancer have recently been described. In Switzerland, nationwide data on hospitalisations have been collected since 1998. They have not been used up to now to explore space–time patterns and trends of breast cancer healthcare-related procedures for control and health planning purposes. We aimed to assess geographical and temporal variation of mastectomy rates. Methods Bayesian negative-binomial spatio-temporal models have been applied. Covariates included patient characteristics as provided in the hospital data, data on mammography screening programme duration, and surgeon and gynaecologist density. Results We analyzed more than 70,000 patients. Mastectomy rates declined from 43% to 30% in Switzerland between 2000 and 2012 for patients aged 50–69 and from 61% to 43% for those 70+, and remained stable for those under 50. Important geographical differences in rates were present. Rates were significantly influenced by age [relative rate ratio (RR) 50–69: 0.92, RR 70+: 1.25], differences in co-morbidity (RR one co-morbidity: 1.17, RR more than one: 1.35), higher surgeon or gynaecologist density (RR surgeons: 1.01, RR gynaecologists: 1.06). Regions in the French-speaking part (RR: 0.72) and/or with mammography screening programmes showed significantly lower rates (RR: 0.87). No difference was found for patients in different socio-economic groups or with different insurance types. Conclusion This research unveiled important differences in mastectomy rates in Switzerland. The results play an essential role in the identification of regions where special attention is required, and indications for extensive surgery in breast cancer should be revisited.

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.

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 Research on soft-tissue sarcoma (STS) and bone sarcoma (BS) is increasingly in the focus of physicians and pharmaceutical companies. Expanding knowledge has improved the management of sarcoma and possibly survival. Here we provide the first population-based data on time trends of incidence, mortality, and survival of STS and BS diagnosed in Switzerland between 1996 and 2015. Methods We performed a retrospective registry study with data from the National Institute for Cancer Epidemiology and Registration (NICER) database in Switzerland between 1996 and 2015. Results We identified 5384 STS patients and 940 BS patients. The three most common STS subtypes were undifferentiated/unclassified sarcoma (22.3%), liposarcoma (20.6%) and leiomyosarcoma (20.6%). Chondrosarcoma, osteosarcoma and Ewing sarcoma represented 40.4%, 27.0% and 15.2% of the BS group, respectively. The age-standardized incidence and mortality rates in 2011–2015 were 4.43 and 1.42 per 100,000 person-years for STS, and 0.91 and 0.42 for BS. Age-standardized incidence of STS in males was significantly higher during 1996–2000 than during 2001–2015; however, mortality rates did not change significantly over time. Five-year relative survival (RS) for STS improved significantly from 56.4% (95%CI 52.9–59.7 for 1996–2001) to 61.6% (95%CI 58.6–64.4 for 2011–2015) (p = 0.025). No improvement in 5-year RS for BS could be observed (RS 1996–2000: 69.6%, 95%CI 61.2–76.6; RS 2011–2015: 73.1%, 95%CI 66.6–78.6; p = 0.479). Conclusion Incidence rates of STS and BS have been stable since 2001. The longer RS in STS can be attributed to advances in sarcoma patient management.

Background: Medical decision-making is complex and involves a variety of decision criteria, many of which are universally recognised. However, decision-making analyses have demonstrated that certain decision criteria are not used uniformly among clinicians. Aim: We describe decision criteria, which for various contexts are only used by a minority of decision makers. For these, we introduce and define the term “insular criteria”. Methods: 19 studies analysing clinical decision-making based on decision trees were included in our study. All studies were screened for decision-making criteria that were mentioned by less than three local decision makers in studies involving 8–26 participants. Results: 14 out of the 19 included studies reported insular criteria. We identified 42 individual insular criteria. They could be intuitively allocated to seven major groups, these were: comorbidities, treatment, patients’ characteristics/preferences, caretaker, scores, laboratory and tumour properties/staging. Conclusion: Insular criteria are commonly used in clinical decision-making, yet, the individual decision makers may not be aware of them. With this analysis, we demonstrate the existence of insular criteria and their variety. In daily practice and clinical studies, awareness of insular criteria is important.

Background The management of localized extremity soft tissue sarcomas (STS) is challenging and the role of pre- and postoperative chemotherapy is unclear and debated among experts. Materials and Methods Medical oncology experts of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group were asked to participate in this survey on the use of pre- and postoperative chemotherapy in STS. Experts from 12 centers in Belgium, France, Germany, Great Britain, Italy, Switzerland, and The Netherlands agreed to participate and provided their treatment algorithm. Answers were converted into decision trees based on the objective consensus methodology. The decision trees were used as a basis to identify consensus and discrepancies. Results Several criteria used for decision-making in extremity STS were identified: chemosensitivity, fitness, grading, location, and size. In addition, resectability and resection status were relevant in the pre- and postoperative setting, respectively. Preoperative chemotherapy is considered in most centers for marginally resectable tumors only. Yet, in some centers, neoadjuvant chemotherapy is used routinely and partially combined with hyperthermia. Although most centers do not recommend postoperative chemotherapy, some offer this treatment on a regular basis. Radiotherapy is an undisputed treatment modality in extremity STS. Conclusion Due to lacking evidence on the utility of pre- and postoperative chemotherapy in localized extremity STS, treatment strategies vary considerably among European experts. The majority recommended neoadjuvant chemotherapy for marginally resectable grade 2–3 tumors; the majority did not recommend postoperative chemotherapy in any setting. Implications for Practice The management of localized extremity soft tissue sarcomas (STS) is challenging and the role of pre- and postoperative chemotherapy is unclear and debated among experts. This study analyzed the decision-making process among 12 European experts on systemic therapy for STS. A wide range of recommendations among experts regarding the use of perioperative chemotherapy was discovered. Discrepancies in the use of decision criteria were also uncovered, including the definition of what constitutes high-risk cancer, which is a basis for many to recommend chemotherapy. Before any standardization is possible, a common use of decision criteria is necessary.

Summary Background For many years, first-line treatment for locally advanced or metastatic soft-tissue sarcoma has been doxorubicin. This study compared gemcitabine and docetaxel versus doxorubicin as first-line treatment for advanced or metastatic soft-tissue sarcoma. Methods The GeDDiS trial was a randomised controlled phase 3 trial done in 24 UK hospitals and one Swiss Group for Clinical Cancer Research (SAKK) hospital. Eligible patients had histologically confirmed locally advanced or metastatic soft-tissue sarcoma of Trojani grade 2 or 3, disease progression before enrolment, and no previous chemotherapy for sarcoma or previous doxorubicin for any cancer. Patients were randomly assigned 1:1 to receive six cycles of intravenous doxorubicin 75 mg/m 2 on day 1 every 3 weeks, or intravenous gemcitabine 675 mg/m 2 on days 1 and 8 and intravenous docetaxel 75 mg/m 2 on day 8 every 3 weeks. Treatment was assigned using a minimisation algorithm incorporating a random element. Randomisation was stratified by age (≤18 years vs >18 years) and histological subtype. The primary endpoint was the proportion of patients alive and progression free at 24 weeks in the intention-to-treat population. Adherence to treatment and toxicity were analysed in the safety population, consisting of all patients who received at least one dose of their randomised treatment. The trial was registered with the European Clinical Trials (EudraCT) database (no 2009–014907–29) and with the International Standard Randomised Controlled Trial registry (ISRCTN07742377), and is now closed to patient entry. Findings Between Dec 3, 2010, and Jan 20, 2014, 257 patients were enrolled and randomly assigned to the two treatment groups (129 to doxorubicin and 128 to gemcitabine and docetaxel). Median follow-up was 22 months (IQR 15·7–29·3). The proportion of patients alive and progression free at 24 weeks did not differ between those who received doxorubicin versus those who received gemcitabine and docetaxel (46·3% [95% CI 37·5–54·6] vs 46·4% [37·5–54·8]); median progression-free survival (23·3 weeks [95% CI 19·6–30·4] vs 23·7 weeks [18·1–20·0]; hazard ratio [HR] for progression-free survival 1·28, 95% CI 0·99–1·65, p=0·06). The most common grade 3 and 4 adverse events were neutropenia (32 [25%] of 128 patients who received doxorubicin and 25 [20%] of 126 patients who received gemcitabine and docetaxel), febrile neutropenia (26 [20%] and 15 [12%]), fatigue (eight [6%] and 17 [14%]), oral mucositis (18 [14%] and two [2%]), and pain (ten [8%] and 13 [10%]). The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]). 154 (60%) of 257 patients died in the intention-to-treat population: 74 (57%) of 129 patients in the doxorubicin group and 80 (63%) of 128 in the gemcitabine and docetaxel group. No deaths were related to the treatment, but two deaths were due to a combination of disease progression and treatment. Interpretation Doxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma. Funding Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen.

Zusammenfassung. Wir stellen den Fall einer 52-jährigen Frau vor, die initial mit Husten und leichten Brustschmerzen in der Hausarztpraxis vorstellig wurde. Bei stetiger Progression der Beschwerden wurde eine CT-Thorax durchgeführt, wobei eine ausgedehnte Lungenembolie festgestellt wurde. Nach Beginn einer oralen Antikoagulation zeigte sich keine Besserung der Beschwerden. Durch weiterführende Diagnostik mit MRI und PET-CT wurde schliesslich der Verdacht auf ein Pulmonalissarkom gestellt. Es erfolgte die operative Entfernung mittels pulmonaler Tumor-Endarteriektomie. In der Histologie zeigte sich ein R1-Resektat eines intimalen Sarkoms, weshalb zusätzlich eine additive Chemotherapie durchgeführt wurde. Trotz multimodaler Therapie und anfänglich erfreulichen klinischen Verlaufskontrollen kam es im weiteren Verlauf zur Krankheitsprogredienz, sodass weitere Metastasektomien pulmonal sowie auch im Grosshirn frontal und temporal folgten. Zudem wurde eine Radiotherapie des Ganzhirns durchgeführt. 31 Monate nach Diagnosestellung lebt die Patientin noch.

Background The outcome for patients with unresectable or metastatic soft tissue sarcoma (STS) is poor. Following failure from first-line doxorubicin based chemotherapy no standard therapy has been established. Combination treatment with docetaxel/gemcitabine (gem) has emerged as an effective regimen but administration is limited to fit patients only due to the toxicity profile. Nanoparticle albumin bound paclitaxel (nab-PC) was invented for avoidance of the toxicities related to polyethylated castor oil. In this context, we want to evaluate toxicity and antitumor effect of biweekly nab-PC 150mg/m2 / gem 1000mg/m2 administration in STS patients. Methods We conducted this proof-of-concept phase I trial to assess the safety of biweekly nab-PC/gem administration in the 2nd and 3rd line setting of STS. Results As of 1 April 2019, 6 pts were treated within the phase I. Three pts were male (50%); median age was 67 yrs (range 44 – 72). The current total number of biweekly doses received is 29 (median biweekly doses per patient is 5, range 2 – 7). One dose reduction due to skin toxicity occurred. 3 pts remain on study, 3 stopped treatment due to treatment unrelated reasons (refusal, death unrelated to progression or toxicity and investigator’s decision). The most common treatment-emergent AEs Gr1-2 were fatigue (3 pts), alopecia (3 pts), and neutropenia (2 pts). There were no dose-limiting toxicities or discontinuations due to AEs. We were able to confirm the tolerability of the regimen and are currently accruing patients to a prospective single arm phase II trial. Treatment will be given biweekly until progression, unacceptable toxicity or patient withdrawal. The primary endpoint of the trial is progression-free rate (PFR) at 12 weeks. Secondary endpoints are PFS, overall survival and symptom-specific quality of life. A total of 8 Swiss sites will participate for a total of 37 patients, as required by Simon’s two-stage design. Conclusions These preliminary results indicate that biweekly administration of nab-PC/gem was well tolerated. The phase I established dose and schedule were selected for further evaluation in phase II trial. Clinical trial identification NCT03524898. Editorial acknowledgement Celgene Corporation. Legal entity responsible for the study Swiss Group for Clinical Cancer Research (SAKK). Funding Swiss League Against Cancer, Celgene. Disclosure A. Digklia: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen, PharmaMar, Servier, BMS; Research grant / Funding (self), Research grant / Funding (institution): Research Funding Recipient Institution. C. Britschgi: Advisory / Consultancy: Roche, Pfizer,takeda,AstraZeneca. Y. Metaxas: Advisory / Consultancy: Roche, MSD, Pierre Fabre, Merck-Serono, BMS. F. Krasniqi: Advisory / Consultancy: Roche Pharma (Schweiz) AG, Mundipharma Medical Company (Schweiz), Celgene GmbH. A. Stathis: Travel / Accommodation / Expenses: Abvie, PharmaMar; Research grant / Funding (institution): Amgen, Bayer, Novartis, Roche, MEI-Pharma. T. Rordorf: Advisory / Consultancy: Bristol-Myers Squibb and Merck KGaA. N. Mach: Honoraria (institution), Advisory / Consultancy: Amgen, AstraZeneca, Bristol-Myers Squibb, F. Hoffmann-La Roche, Merck Sharp and Dohme, Merck Serono, Novartis, Pharma Mar, as well as honorarium for talks in a company’s organised public event from Bristol-Myers Squibb and Pharma Mar. C.A. Rothermundt: Advisory / Consultancy: BMS, Astellas Pharma Schweiz, GSK, Novartis, Roche, Pfizer, PharmaMar; Research grant / Funding (institution): Research Funding Recipient Institution. All other authors have declared no conflicts of interest.

Despite several treatment options and an initial high response rate to androgen deprivation therapy, the majority of prostate cancers will eventually become castration-resistant in the metastatic stage (mCRPC). Androgen receptor splice variant 7 (ARV7) is one of the best-characterized androgen receptor (AR) variants whose expression in circulating tumor cells (CTCs) has been associated with enzalutamide resistance. ARV7 expression analysis before and during enzalutamide treatment could identify patients requiring alternative systemic therapies. However, a robust test for the assessment of the ARV7 status in patient samples is still missing. Here, we implemented an RT-qPCR-based assay for detection of AR full length (ARFL)/ARV7 expression in CTCs for clinical use. Additionally, as a proof-of-principle, we validated a cohort of 95 mCRPC patients initiating first line treatment with enzalutamide or enzalutamide/metformin within a clinical trial. A total of 95 mCRPC patients were analyzed at baseline of whom 27.3% (26/95) had ARFL+ARV7+, 23.1% (22/95) had ARFL+ARV7&minus, 23.1% (22/95) had ARFL&minus, ARV7&minus, and 1.1% (1/95) had ARFL&minus, ARV7+ CTCs. In 11.6% (11/95), no CTCs could be isolated. A total of 25/95 patients had another CTC analysis at progressive disease, of whom 48% (12/25) were ARV7+. Of those, 50% (6/12) were ARV7&minus, and 50% (6/12) were ARV7+ at baseline. Our results show that mRNA analysis of isolated CTCs in mCRPC is feasible and allows for longitudinal endocrine agent response monitoring and hence could contribute to treatment optimization in mCRPC.

Background: To provide rapid evaluation of patients with advanced urological malignancies, a joint urological-oncological clinic was initiated at our institution in January 2015. We present the first 3-year evaluation of this joint urological-oncological clinic in Switzerland. Method: We performed a retrospective analysis of the characteristics and treatment of all patients reviewed at the joint clinic between January 2015 and December 2017. Statistical analysis was performed by survival analysis. A patient satisfaction questionnaire was handed out to new patients (from April to September 2017). Results: A total of 135 new patients were counseled in the joint clinic and 563 consultations were performed in the period from January 2015 to December 2017. The majority were men with prostate cancer (85%), followed by bladder cancer (9%), and renal cell carcinoma (4%). Men with newly diagnosed metastatic prostate cancer (n = 69) received ADT alone (57%), ADT with docetaxel or abiraterone (33%), and metastasis-directed therapy (10%). High rates of patient satisfaction were reported based on the questionnaire. Conclusions: The joint clinic model has been successfully implemented at our institution and continues on a weekly basis. The clinic is increasingly used, not only for newly diagnosed metastatic prostate cancer, but also for other complex uro-oncological cases. The clinic allows optimized oncological treatment without delay and with a reduced effort for patients.

Objective Measuring the success of molecularly guided therapies is a major challenge in precision oncology trials. A commonly used endpoint is an intra-patient progression-free survival (PFS) ratio, defined as the PFS interval associated with molecularly guided therapy (PFS2) divided by the PFS interval associated with the last prior systemic therapy (PFS1), above 1.3 or, in some studies, above 1.33 or 1.5. Methods To investigate if the concept of PFS ratios is in agreement with actual response evaluations by physicians, we conducted a survey among members of the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Programme of the German Cancer Consortium who were asked to classify the success of molecularly guided therapies in 194 patients enrolled in the MOSCATO 01 trial based on PFS1 and PFS2 times. Results A comparison of classification profiles revealed three distinct clusters of PFS benefit assessments. Only 29% of assessments were consistent with a PFS ratio threshold of 1.3, whereas the remaining 71% of participants applied a different classification scheme that did not rely on the relation between PFS times alone, but also took into account absolute PFS1 intervals. Based on these community-driven insights, we developed a modified PFS ratio that incorporates the influence of absolute PFS1 intervals on the judgement of clinical benefit by physicians. Application of the modified PFS ratio to outcome data from two recent precision oncology trials, MOSCATO 01 and WINTHER, revealed significantly improved concordance with physician-perceived clinical benefit and identified comparable proportions of patients who benefited from molecularly guided therapies. Conclusions The modified PFS ratio may represent a meaningful clinical endpoint that could aid in the design and interpretation of future precision oncology trials.

Background There is evidence linking metformin to improved prostate cancer–related outcomes. Patients and Methods Twenty-five men with metastatic castration-resistant prostate cancer and prostate-specific antigen (PSA) progression while receiving treatment with abiraterone from 3 Swiss centers were included in this single-arm phase 2 trial between November 2013 and September 2016. Metformin was added to abiraterone continuously at 1000 mg twice daily in uninterrupted 4-week cycles. The primary end point was the absence of disease progression at 12 weeks (PFS12). The Fleming single-stage design was applied. With a 5% significance level and 80% power, 25 patients were required to test PFS12 ≤ 15% (H0) compared to ≥ 35% (H1). Secondary end points included toxicity and safety issues. The study was registered at ClinicalTrials.gov ( NCT01677897 ). Results The primary end point PFS12 was 12% (3 of 25 patients) (95% confidence interval, 3-31). Most patients had PSA progression, almost half had radiographic progression, but only 1 patient had symptomatic progression. Eleven (44%) of 25 patients had grade 1 and 2 patients each grade 2 (8%) or grade 3 (8%) gastrointestinal toxicity (nausea, diarrhea, loss of appetite). One patient discontinued treatment at week 5 because of intolerable grade 3 diarrhea. Conclusion The addition of metformin to abiraterone for patients with metastatic castration-resistant prostate cancer and PSA progression while receiving abiraterone therapy does not affect further progression and has no meaningful clinical benefit. A higher-than-expected gastrointestinal toxicity attributed to metformin was observed.

BACKGROUND We tested whether a switch maintenance treatment with orteronel, an oral inhibitor of androgen biosynthesis, prolongs disease control in men with metastatic castration resistant prostate cancer (mCRPC) after documented disease stabilization with docetaxel. METHODS Men with mCRPC and non-progressive disease after a cumulative dose of ?300mg/m2 docetaxel for first line treatment were randomized 1:1 to receive orteronel 300mg twice daily or placebo. The primary endpoint was event-free survival (EFS) defined as the time from randomization to death or the combination of at least two of radiographic, clinical, or PSA progression. Ninety-six patients per arm were planned to demonstrate an improvement of median EFS from 4 months on placebo to 6.7 months on orteronel (hazard ratio (HR) 0.6; type I error 5% and power 90%). RESULTS Forty-seven patients (23 orteronel, 24 placebo) were randomized before premature closure of the trial because of discontinuation of clinical development of orteronel. Median EFS was 8.5 months with orteronel and 2.9 months with placebo (P¼0.001; HR 0.32; 95%CI 0.15–0.65). Median radiographic progression-free survival (rPFS) was 8.5 and 2.8 months (P¼0.02; HR 0.42; 95%CI 0.20–0.91) in the orteronel and placebo arm, respectively. PSA decline ?50% was seen in 57% on orteronel and 4% on placebo. Toxicity was mainly mild, one patient on orteronel developed transient grade 3 adrenal insufficiency and one grade 4 pneumonitis. CONCLUSIONS Orteronel significantly prolongs EFS in men with mCRPC who achieve disease stabilization with docetaxel. The concept of switch maintenance therapy in mCRPC warrants further research.

An increasing number of older patients are suffering from aggressive lymphoma. Effective and more tolerable treatment regimens are urgently needed for this growing patient population. Patients with aggressive lymphoma not eligible for anthracycline-based first-line therapy or intensive salvage regimens were treated with the rituximab-bendamustine-lenalidomide (R-BL) regimen (rituximab 375 mg/m(2) day 1, bendamustine 70 mg/m(2) d 1, 2, lenalidomide 10 mg d 1-21) for six cycles every 4 weeks. Forty-one patients with a median age of 75 (range 40-94) years were enrolled: 33 patients had substantial co-morbidities. 13 patients were not eligible for anthracycline-based first-line chemotherapy, 28 patients had relapsed/refractory disease. The primary endpoint, overall response, was achieved by 25 (61%) patients (95% confidence interval 45-76%). Grade ≥ 3 toxicity comprised haematological (59%), skin (15%), constitutional (15%) and neurological (12%) events. 9 patients died during trial treatment: 5 from lymphoma progression, 2 from toxicity, 2 with sudden death. After a median follow-up of 25·9 (interquartile range 20·4-31·6) months, 13 patients were still alive. Median overall survival was 14·5 months. In conclusion, R-BL can be considered a treatment option for elderly patients with treatment naïve or relapsed/refractory aggressive lymphoma not eligible for standard aggressive regimens.

Background In the past years, there has been significant progress in anticancer drug development for patients with metastatic castration-resistant prostate cancer (CRPC). However, the current instruments to assess clinical treatment response have limitations and may not sufficiently reflect patient benefit. Our objective was to systematically identify tools to evaluate both patient benefit and clinical anticancer-treatment response as basis for an international consensus process and development of a specific pragmatic instrument for men with CRPC. Methods PubMed, Embase and CINAHL were searched to identify currently available tools to assess anticancer-treatment benefit, other than standard imaging procedures and prostate-specific antigen measurements, namely quality of life (QoL), detailed pain assessment, physical function and objective measures of other complex cancer-related syndromes in patients with CRPC. Additionally, all CRPC phase III trials published in the last 5 years were reviewed as well as studies using physical function tools in a general cancer population. The PRIMSA statement was followed for the systematic review process. Results The search generated 1096 hits, 185 full-text papers were screened and finally 73 publications were included. Additional 89 publications were included by hand-search. We identified a total of 98 tools used in CRPC trials and grouped these into three categories: 22 tools assessing QoL domains and subgroups, 47 tools for pain assessment and 29 tools for objective measures, mainly physical function and assessment of skeletal disease burden. Conclusion A wide variety of assessment tools and also efforts to standardize and harmonize patient-reported outcomes and pain assessment were identified. However, the specific needs of the increasing CRPC population living longer with their incurable cancer are insufficiently captured and objective physical outcome measures are under-represented. In the age of new anticancer drug targets and principles, new methods to monitor patient relevant outcomes of antineoplastic therapy are of utmost importance.

BACKGROUND: The majority of germ cell tumour (GCT) patients can be cured by orchiectomy followed by active surveillance or subsequent systemic and/or local treatments. There are various guidelines for a structured follow-up including radiographic and clinical examinations.OBJECTIVE: The Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS) prospectively evaluates follow-up, indicator of relapse and late toxicities. This is a descriptive analysis; we present baseline characteristics and treatment strategies for the first 299 patients with primary GCT or relapsed GCT after completion of treatment.RESULTS: Of the patients included in this study, 192 (64.2%) had seminoma and 107 (35.8%) non-seminoma. Mean age was 41 years (standard deviation [SD] 11.7) for seminoma and 31 (SD 9.3) years for non-seminoma patients. Median tumour size was 3.5 cm (interquartile range 2.5¬‒5.0 and 2.3‒4.5 in seminoma and non-seminoma, respectively) in both histological groups. Among seminoma patients, 81 (42.2%) had primary tumours >4cm; 154 (80.2%) seminoma patients had stage I, 26 (13.5%) stage II and 12 (6.3%) stage III disease. Fifty-seven (53.3%) non-seminoma tumours were stage I, 29 (27.1%) stage II and 21 (19.6%) stage III. Marker-positive disease was present in 58 (30.2%) seminoma patients and 78 (72.9%) non-seminoma patients. Of 154 stage I seminoma patients, 89 (57.8%) chose active surveillance and 65 (42.2%) adjuvant chemotherapy. Twenty-six (45.6%) stage I non-seminoma patients had high-risk disease; 23 of these were treated with adjuvant chemotherapy and 3 chose active surveillance. Among the 30 (52.6%) low risk stage I patients, all opted for active surveillance. Twelve (46.2%) stage II seminoma patients had radiotherapy, 14 (53.8%) were treated with three to four cycles of chemotherapy. All stage III seminoma patients, and all stage II and III non-seminoma patients were treated with three to four cycles of chemotherapy. Treatment decisions were made at the respective centre. Eleven patients did not receive therapy that conformed with guidelines.CONCLUSION: It is important to enrol GCT patients in prospective studies in general, but also in follow-up studies to assess baseline characteristics, oncological outcome, and long-term toxicity and to validate the performance of follow-up schedules. This is the first time that the distribution of disease, detailed baseline characteristics and the respective treatment of men with GCT is collected in a prospective manner in German speaking countries (Switzerland, Austria and Germany) and therefore patterns of care have been evaluated. SAG TCCS results will inform on future modifications of surveillance schedules and follow-up procedures.TRIAL REGISTRATION NUMBER: NCT02229916 (Clinicaltrials.gov).

IntroductionIn the past decades, mortality due to breast cancer has declined considerably in Switzerland and other developed countries. The reasons for this decline remain controversial as several factors occurred almost simultaneously, including important advances in treatment approaches, breast cancer awareness and the introduction of mammography screening programmes in many European countries. In Switzerland, mammography screening programmes (MSPs) have existed in some regions for over 20 years but do not yet exist in others. This offers the possibility to analyse its effects with modern spatiotemporal methodology. We aimed to assess the spatiotemporal patterns and the effect of MSPs on breast cancer mortality.SettingSwitzerland.ParticipantsThe study covers breast cancer deaths of the female population of Switzerland during the period 1969–2012. We retrieved data from the Swiss Federal Statistical Office aggregated on a small-area level.DesignWe fitted Bayesian hierarchical spatiotemporal models on death rates indirectly standardised by national references. We used linguistic region, degree of urbanisation, duration of population-based screening programmes and socioeconomic index as covariates.ResultsIn Switzerland, breast cancer mortality in women slightly increased until 1989–1992 and declined strongly thereafter. Until 2009–2012, the standardised mortality ratio declined to 57% (95% CI 54% to 60%) of the 1969–1972 value. None of the other coefficients of the spatial regressions had a significant effect on breast cancer mortality. In 2009–2012, no region had significantly elevated or reduced breast cancer mortality at 95% credible interval level compared with the national mean.ConclusionThere has been a strong reduction of breast cancer mortality from the 1990s onwards. No important spatial disparities were observed. The factors studied (urbanisation, language, duration of population-based MSP and socioeconomic characteristics) did not seem to have an influence on them. Low participation rates and opportunistic screening use may have contributed to the low impact of MSPs.