EAU-ESMO consensus statements on the management of advanced and variant bladder cancer-an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees†.

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.

ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.

The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

The effect of real-time electronic monitoring of patient-reported symptoms and clinical syndromes in outpatient workflow of medical oncologists: E-MOSAIC, a multicenter cluster-randomized phase III study (SAKK 95/06).

BACKGROUND: Patients with advanced, incurable cancer receiving anticancer treatment often experience multidimensional symptoms. We hypothesize that real-time monitoring of both symptoms and clinical syndromes will improve symptom management by oncologists and patient outcomes. PATIENTS AND METHODS: In this prospective multicenter cluster-randomized phase-III trial, patients with incurable, symptomatic, solid tumors, who received new outpatient chemotherapy with palliative intention, were eligible. Immediately before the weekly oncologists' visit, patients completed the palm-based E-MOSAIC assessment (Edmonton-Symptom-Assessment-Scale, ≤3 additional symptoms, estimated nutritional intake, body weight change, Karnofsky Performance Status, medications for pain, fatigue, nutrition). A cumulative, longitudinal monitoring sheet (LoMoS) was printed immediately. Eligible experienced oncologists were defined as one cluster each and randomized to receive the immediate print-out LoMoS (intervention) or not (control). Primary analysis limited to patients having uninterrupted (>4/6 visits with same oncologist) patient-oncologist sequences was a mixed model for the difference in patients global quality of life (G-QoL; items 29/30 of EORTC-QlQ-c30) between baseline (BL) and week 6. Intention-to-treat (ITT) analysis included all eligible patients. RESULTS: In 8 centers, 82 oncologists treated 264 patients (median 66 years; overall survival intervention 6.3, control 5.4 months) with various tumors. The between-arm difference in G-QoL of 102 uninterrupted patients (intervention: 55; control: 47) was 6.8 (P = 0.11) in favor of the intervention; in a sensitivity analysis (oncologists treating ≥2 patients; 50, 39), it was 9.0 (P = 0.07). ITT analysis revealed improvement in symptoms (difference last study visit-BL: intervention -5.4 versus control 2.1, P = 0.003) and favored the intervention for communication and coping. More patients with high symptom load received immediate symptom management (chart review, nurse-patient interview) by oncologists getting the LoMoS. CONCLUSION: Monitoring of patient symptoms, clinical syndromes and their management clearly reduced patients' symptoms, but not QoL. Our results encourage the implementation of real-time monitoring in the routine workflow of oncologist with a computer solution.

Treatment outcome and patterns of relapse following adjuvant carboplatin for stage I testicular seminomatous germ-cell tumour: results from a 17-year UK experience.

BACKGROUND: Following inguinal orchidectomy, management options for patients with stage I seminoma include initial surveillance or treatment with adjuvant radiotherapy or chemotherapy. The anticipated relapse rate for patients followed by surveillance alone is ∼15%, with adjuvant treatment this risk is reduced to ∼4%-5% at 5 years. After carboplatin treatment, follow-up strategies vary and there are no validated, predictive markers of relapse. PATIENTS AND METHODS: We conducted a retrospective analysis of all patients presenting with stage I seminoma who received a single cycle of adjuvant carboplatin in South Central England between 1996 and 2013. We report on outcome and the results of univariate and multivariate analysis evaluating possible risk factors for post carboplatin relapse. RESULTS: A total of 517 eligible patients were identified. All underwent nuclear medicine estimation of glomerular filtration rate before treatment with carboplatin (dosed at area under the curve × 7). With a median follow-up of 47.2 months (range 0.4-214 months), 21/517 patients have relapsed resulting in a 5-year estimated relapse-free survival of 95.0% (95% confidence interval 92.8% to 97.3%). Median time to relapse was 22.7 months (range 12.5-109.5 months). Relapse beyond 3 years was rare (4/517; 0.8%). Twenty of 21 (95%) relapsed patients had retroperitoneal lymph node metastases. The majority (16/21; 76%) of patients had elevated tumour markers at relapse. Twenty of 517 (3.9%) patients developed a new contralateral testicular germ-cell cancer. There were no seminoma-related deaths. Tumour size was the only variable significantly associated with an increased risk of relapse. CONCLUSIONS: Overall results for this large cohort of patients confirm an excellent prognosis for these patients with outcomes equivalent to those seen in prospective clinical trials. Increasing tumour size alone appears to be associated with an increased risk of post chemotherapy relapse.

Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours.

BACKGROUND: Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221). METHODS: Patients received 28-day cycles of olaparib, continuously (days 1-28) or intermittently (days 1-7), plus PLD (40 mg m(-2), day 1); seven olaparib dose cohorts (50-400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)). RESULTS: Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ≥3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation. CONCLUSIONS: Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m(-2)) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.

Relevant risk of carboplatin underdosing in cancer patients with normal renal function using estimated GFR: lessons from a stage I seminoma cohort.

BACKGROUND: Seminoma stage I is the most frequent testis cancer and single-dose carboplatin (AUC7) is an effective and widely used adjuvant treatment. Underdosing of carboplatin by 10% has been shown to almost double the rate of relapse and hence correct dosing based on accurate GFR measurement is crucial. The gold standard of GFR measurement with a radiolabelled isotope is expensive and not readily available. In many institutions, it is replaced by GFR estimation with the Cockcroft-Gault formula, which might lead to significant carboplatin underdosing and potentially inferior clinical outcome. METHODS: Retrospective analysis of all patients with stage I seminoma treated with adjuvant carboplatin between 1999 and 2012. All patients had serum creatinine measured and underwent GFR measurement with a radioisotope ((51)Cr EDTA or (99m)Tc DTPA), which was compared with seven standard GFR estimation formulae (Cockcroft-Gault, CKD-EPI, Jelliffe, Martin, Mayo, MDRD, Wright) and a flat dosing strategy. Bias, precision, rates of under- and overdosing of GFR estimates were compared with measured GFR. Bland-Altman plots were done. RESULTS: A total of 426 consecutive Caucasian male patients were included: median age 39 years (range 19-60 years), median measured GFR 118 ml/min (51-209), median administered carboplatin dose 1000 mg (532-1638). In comparison to isotopic GFR measurement, a relevant proportion of patients would have received ≤ 90% of carboplatin dose through the use of GFR estimation formulae: 4% using Mayo, 9% Martin, 18% Cockcroft-Gault, 24% Wright, 63% Jelliffe, 49% MDRD and 41% using CKD-EPI. The flat dosing strategy, Wright and Cockcroft-Gault formulae, showed the smallest bias with mean percentage error of +1.9, +0.4 and +2.1, respectively. CONCLUSIONS: Using Cockcroft-Gault or any other formula for GFR estimation leads to underdosing of adjuvant carboplatin in a relevant number of patients with Seminoma stage I and should not be regarded as standard of care.

Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer.

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, ∼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.

[Integration of drug treatment in the management concept of prostate cancer]. / Arzneimittel im Gesamtkonzept der Therapie des Prostatakarzinoms.

The drug treatment of prostate cancer was for many years based on androgen deprivation with luteinizing hormone-releasing hormone (LHRH) analogues.This treatment still represents the standard first line treatment for advanced prostate cancer. In cases of progression to metastatic castration-resistant prostate cancer (mCRPC) further treatment options used to be limited. Only the chemotherapy drug docetaxel could demonstrate a significant overall survival benefit. Within the last few years, however, five new treatments for patients with mCRCP have achieved significant results in large phase III trials. Interestingly they have different mechanisms of action: abiraterone is a testosterone synthesis inhibitor, enzalutamide is a novel antiandrogen, cabazitaxel is a cytotoxic drug, radium-223 is a radionuclide and sipuleucel-T an immunotherapy. Further new drugs are under investigation. The integration of these new treatment options as well as an optimal sequence and combination is the main focus of current research.

First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07).

BACKGROUND: Oral temozolomide has shown similar efficacy to dacarbazine in phase III trials with median progression-free survival (PFS) of 2.1 months. Bevacizumab has an inhibitory effect on the proliferation of melanoma and sprouting endothelial cells. We evaluated the addition of bevacizumab to temozolomide to improve efficacy in stage IV melanoma. PATIENTS AND METHODS: Previously untreated metastatic melanoma patients with Eastern Cooperative Oncology Group performance status of two or more were treated with temozolomide 150 mg/m(2) days 1-7 orally and bevacizumab 10 mg/kg body weight i.v. day 1 every 2 weeks until disease progression or unacceptable toxicity. The primary end point was disease stabilisation rate [complete response (CR), partial response (PR) or stable disease (SD)] at week 12 (DSR12); secondary end points were best overall response, PFS, overall survival (OS) and adverse events. RESULTS: Sixty-two patients (median age 59 years) enrolled at nine Swiss centres. DSR12 was 52% (PR: 10 patients and SD: 22 patients). Confirmed overall response rate was 16.1% (CR: 1 patient and PR: 9 patients). Median PFS and OS were 4.2 and 9.6 months. OS (12.0 versus 9.2 months; P = 0.014) was higher in BRAF V600E wild-type patients. CONCLUSIONS: The primary end point was surpassed showing promising activity of this bevacizumab/temozolomide combination with a favourable toxicity profile. Response and OS were significantly higher in BRAF wild-type patients.

[Advances in the treatment of prostate cancer - dawn of a new era]. / Fortschritte beim Prostatakarzinom - Aufbruch in ein neues Zeitalter.

Over the recent years we have seen a rapid increase in published research both in the preclinical and clinical field regarding the treatment of prostate cancer. Only within the last two years the results of four positive phase III trials, all showing improved survival for patients with metastatic castration resistant prostate cancer (mCRPC), have been presented. In this article the basis of treatment of localized and advanced prostate cancer is discussed with a focus on new treatment options. Due to the rapid evolution of options an interdisciplinary management of patients with prostate cancer has become crucial in order to offer the best treatment to the patients.

Imaging response during therapy with radium-223 for castration-resistant prostate cancer with bone metastases-analysis of an international multicenter database.

BACKGROUND: The imaging response to radium-223 therapy is at present poorly described. We aimed to describe the imaging response to radium-223 treatment. METHODS: We retrospectively evaluated the computed tomography (CT) and bone scintigraphy response of metastatic castration-resistant prostate cancer (CRPC) patients treated with radium-223, in eight centers in three countries. RESULTS: A total of 130 patients were included, the majority (n=84, 65%) received radium-223 post docetaxel. Thirty-four of 99 patients with available data (34%) received concomitant abiraterone or enzalutamide. A total of 54% (n=70) patients completed the planned six injections of radium-223. In patients with available data, a transient increase in bone metastases-related pain was observed in 27% (n=33/124) and an improvement of bone metastases-related pain on treatment with radium-223 was noted in 49% of patients (n=61/124). At 3 and 6 months of treatment with radium-223, bone imaging showed stable disease in 74% (n=84/113) and 94% of patients (n=93/99) with available data, respectively. An increase in the number of bone lesions was documented at 3 months compared with baseline in 26% (n=29/113) and at 6 months compared with 3 months in 6% of patients (n=6/99), respectively. Radiological extraskeletal disease progression occurred in 46% of patients (n=57/124) with available CT data at 3 and/or 6 months. CONCLUSIONS: Progression of bone metastases during radium-223 therapy is uncommon. A bone flare (pain and/or radiological) may be noted during the first 3 months, and should not be confused with progression. Imaging by CT scan should be considered after three and six doses of radium-223 to rule out extraskeletal disease progression.

An unusual differential diagnosis of penile warts: metastases from rectal carcinoma.

Patients with penile lesions, such as virally induced papillomata, frequently present to genitourinary medicine clinics and general practitioners. Their diagnosis is usually based on clinical observation and biopsy is not generally undertaken. Penile lesions may rarely have a more sinister aetiology and represent metastatic spread from solid tumours arising at distant sites. Penile metastases arise most frequently from genitourinary cancers (prostate, bladder and kidney), but may also arise from tumours of the large bowel; other primary sites are extremely uncommon. We report the case of a patient presenting with penile metastases from rectal carcinoma arising during third-line chemotherapy for metastatic disease.

Multidrug and toxin extrusion 1 and human organic cation transporter 1 polymorphisms in patients with castration-resistant prostate cancer receiving metformin (SAKK 08/09).

BACKGROUND: This study was initiated to explore the impact of organic cation transporter 1 (OCT1) and multidrug and toxin extrusion transporter 1 (MATE1) genetic polymorphisms on toxicity, and clinical activity of metformin in patients with castration-resistant prostate cancer (CRPC). METHODS: The SAKK 08/09 trial included 44 patients with CRPC to receive single-agent metformin 1000 mg two times a day until disease progression or unwanted toxicity. Drug pathway-associated gene polymorphisms of OCT1 (rs622342) and MATE1 (rs2289669) were assessed. The primary objective of this study was to define the relationship between mutations in OCT1, MATE1 and progression-free survival (PFS) at 12 weeks absolute PFS and PSA response in consenting patients of SAKK 08/09. The secondary objective of this study was to analyze the association between mutations in OCT1, MATE1, metformin-related toxicity, PSA response at 12 weeks and overall survival. RESULTS: Thirty-six patients were evaluable for pharmacogenetic analysis. Homozygous carriers of the polymorphic OCT1 C-allele had no metformin-related toxicity as compared with 41.9% for any metformin-related toxicity in carriers of at least one wild-type A-allele (P=0.07). Disease progression according to RECIST (Response Evaluation Criteria In Solid Tumors) was significantly more frequent in homozygous carriers of the polymorphic OCT1 C-allele (80%) as compared with carriers of at least one wild-type A-allele (28.6%) (P=0.002). Disease progression according to RECIST was also more frequent in carriers of at least one polymorphic MATE1 A-allele (44%) as compared with homozygous carriers of the wild-type G-allele (12.5%) (P=0.07). OCT1 and MATE1 were not associated with PFS. CONCLUSIONS: The polymorphic OCT1 C-allele has been shown to be associated with less metformin-related toxicity and a higher risk of tumor progression in patients with CRPC receiving metformin as an anticancer treatment. Polymorphisms in metformin drug transporters are attractive molecular markers to serve as potential predictors of efficacy in future clinical studies.

Life-threatening envenoming by the Saharan horned viper (Cerastes cerastes) causing micro-angiopathic haemolysis, coagulopathy and acute renal failure: clinical cases and review.

BACKGROUND: The desert horned vipers (Cerastes cerastes and C. gasperettii) are the most familiar snakes of the great deserts of North Africa and the Middle East, including the plains of Iraq. They are responsible for many human snake bites. In Western countries, they are popular among exotic-snake keepers. AIM: To investigate mechanisms of life-threatening envenoming and treatment. DESIGN: Clinical investigation. METHODS: Clinical and laboratory studies with measurement of serum venom antigen concentrations by enzyme immunoassay. RESULTS: Two men bitten while handling captive Saharan horned vipers (Cerastes cerastes) in Europe developed extensive local swelling and life-threatening systemic envenoming, characterized by coagulopathy, increased fibrinolysis, thrombocytopenia, micro-angiopathic haemolytic anaemia and acute renal failure. The clinical picture is explicable by the presence in C. cerastes venom of several thrombin-like, Factor-X-activating, platelet-aggregating, haemorrhagic and nephrotoxic components. In one case, prophylactic use of subcutaneous epinephrine may have contributed to intracranial haemorrhage. The roles in treatment of heparin (rejected) and specific antivenom (recommended) are discussed. DISCUSSION: Cerastes cerastes is capable of life-threatening envenoming in humans. Optimal treatment of envenoming is by early administration of specific antivenom, and avoidance of ineffective and potentially-dangerous ancillary methods.

Bilocal recurrence of a neuroendocrine carcinoma of the small intestine: A case report.

INTRODUCTION: Neuroendocrine tumors of the small intestine represent about half of all small intestine neoplasms. Recurrence after surgery with curative intention is frequently observed but recurrence rate has not yet been described or analyzed sufficiently. PRESENTATION OF CASE: In this case bilocal recurrence 4 years after curative surgery of an ileocoecal neuroendocrine carcinoma was observed in a 64 year old female. Diagnosis and follow-up was carried out as proposed in current ENETS guidelines using somatostatin receptor scintigraphy for primary diagnosis and Ga-DOTATOC-PET/CT in follow-up. DISCUSSION: We can confirm that PET/CT for somatostatin receptor imaging shows good sensitivity in detecting neuroendocrine neoplasms and should be preferred for diagnostic, if available. For individual adaptation of follow-up procedures, as far as time intervals and preferred imaging methods are concerned, research on recurrence rate and long term outcome after curative surgery should be extended. CONCLUSION: Livelong follow-up after surgical resection of neuroendocrine tumors is necessary and Ga-DOTA/TOC-PET/CT should be the method of choice, if available.