Markus A. Kuczyk

EAU Guidelines on Renal Cell Carcinoma: 2014 Update.

CONTEXT The European Association of Urology Guideline Panel for Renal Cell Carcinoma (RCC) has prepared evidence-based guidelines and recommendations for RCC management. OBJECTIVES To provide an update of the 2010 RCC guideline based on a standardised methodology that is robust, transparent, reproducible, and reliable. EVIDENCE ACQUISITION For the 2014 update, the panel prioritised the following topics: percutaneous biopsy of renal masses, treatment of localised RCC (including surgical and nonsurgical management), lymph node dissection, management of venous thrombus, systemic therapy, and local treatment of metastases, for which evidence synthesis was undertaken based on systematic reviews adhering to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Relevant databases (Medline, Cochrane Library, trial registries, conference proceedings) were searched (January 2000 to November 2013) including randomised controlled trials (RCTs) and retrospective or controlled studies with a comparator arm. Risk of bias (RoB) assessment and qualitative and quantitative synthesis of the evidence were performed. The remaining sections of the document were updated following a structured literature assessment. EVIDENCE SYNTHESIS All chapters of the RCC guideline were updated. For the various systematic reviews, the search identified a total of 10,862 articles. A total of 151 studies reporting on 78,792 patients were eligible for inclusion; where applicable, data from RCTs were included and meta-analyses were performed. For RCTs, there was low RoB across studies; however, clinical and methodological heterogeneity prevented data pooling for most studies. The majority of studies included were retrospective with matched or unmatched cohorts based on single or multi-institutional data or national registries. The exception was for systemic treatment of metastatic RCC, in which several RCTs have been performed, resulting in recommendations based on higher levels of evidence. CONCLUSIONS The 2014 guideline has been updated by a multidisciplinary panel using the highest methodological standards, and provides the best and most reliable contemporary evidence base for RCC management. PATIENT SUMMARY The European Association of Urology Guideline Panel for Renal Cell Carcinoma has thoroughly evaluated available research data on kidney cancer to establish international standards for the care of kidney cancer patients.

GuidelinesEAU Guidelines on Renal Cell Carcinoma: The 2010 Update

CONTEXT AND OBJECTIVES The European Association of Urology Guideline Group for renal cell carcinoma (RCC) has prepared these guidelines to help clinicians assess the current evidence-based management of RCC and to incorporate the present recommendations into daily clinical practice. EVIDENCE ACQUISITION The recommendations provided in the current updated guidelines are based on a thorough review of available RCC guidelines and review articles combined with a systematic literature search using Medline and the Cochrane Central Register of Controlled Trials. EVIDENCE SYNTHESIS A number of recent prospective randomised studies concerning RCC are now available with a high level of evidence, whereas earlier publications were based on retrospective analyses, including some larger multicentre validation studies, meta-analyses, and well-designed controlled studies. CONCLUSIONS These guidelines contain information for the treatment of an individual patient according to a current standardised general approach. Updated recommendations concerning diagnosis, treatment, and follow-up can improve the clinical handling of patients with RCC.

Treatment of Muscle-Invasive and Metastatic Bladder Cancer: Update of the EAU Guidelines.

CONTEXT New data regarding treatment of muscle-invasive and metastatic bladder cancer (MiM-BC) has emerged and led to an update of the European Association of Urology (EAU) guidelines for MiM-BC. OBJECTIVE To review the new EAU guidelines for MiM-BC with a specific focus on treatment. EVIDENCE ACQUISITION New literature published since the last update of the EAU guidelines in 2008 was obtained from Medline, the Cochrane Database of Systematic Reviews, and reference lists in publications and review articles and comprehensively screened by a group of urologists, oncologists, and a radiologist appointed by the EAU Guidelines Office. Previous recommendations based on the older literature on this subject were also taken into account. Levels of evidence (LEs) and grades of recommendations (GRs) were added based on a system modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence. EVIDENCE SYNTHESIS Current data demonstrate that neoadjuvant chemotherapy in conjunction with radical cystectomy (RC) is recommended in certain constellations of MiM-BC. RC remains the basic treatment of choice in localised invasive disease for both sexes. An attempt has been made to define the extent of surgery under standard conditions in both sexes. An orthotopic bladder substitute should be offered to both male and female patients lacking any contraindications, such as no tumour at the level of urethral dissection. In contrast to neoadjuvant chemotherapy, current advice recommends the use of adjuvant chemotherapy only within clinical trials. Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected, well-informed, and compliant patients for whom cystectomy is not considered for medical or personal reasons. In metastatic disease, the first-line treatment for patients fit enough to sustain cisplatin remains cisplatin-containing combination chemotherapy. With the advent of vinflunine, second-line chemotherapy has become available. CONCLUSIONS In the treatment of localised invasive bladder cancer (BCa), the standard treatment remains radical surgical removal of the bladder within standard limits, including as-yet-unspecified regional lymph nodes. However, the addition of neoadjuvant chemotherapy must be considered for certain specific patient groups. A new drug for second-line chemotherapy (vinflunine) in metastatic disease has been approved and is recommended.

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

OBJECTIVES The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands. METHODS Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma. CONCLUSIONS Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

Evaluation of long-term toxicity after chemotherapy for testicular cancer.

PURPOSE The current study evaluates the extent and reversibility of late sequelae after chemotherapy in longterm survivors of testicular cancer. The influence of therapy and patient characteristics and the relationship between different toxicities are assessed. PATIENTS AND METHODS Ninety patients with a median age of 28 years (range, 19 to 53) and a median followup time of 58 months (range, 15 to 159) participated in the clinical examinations, a personal interview, and technical investigations. Overall health and the impact of late toxicity were assessed by the patients. All patients were in complete remission (CR) for at least 1 year. Chemotherapy had consisted of cisplatin (P), bleomycin (B), and vinblastine (V) in 30 patients (33%); P, B, and etoposide (E) in 26 patients (29%); P, B, E, and a vinca alkaloid in 22 patients (24%); and other P-based combination regimens in 12 patients (13%). RESULTS Alterations of gonadotropin levels (follicle-stimulating hormone [FSH] luteinizing hormone [LH]) in up to 68% of patients and Leydig cell insufficiency in one third of patients were the most frequently detected abnormalities. Approximately 20% of patients had low serum magnesium [Mg] or phosphate levels, or elevated creatinine levels. Cardiovascular risk factors were identified in one third of patients with elevated serum cholesterol levels with or without obesity; 15% had developed arterial hypertension after chemotherapy. The most frequent symptomatic toxicities were Raynauds phenomenon (RP) in 30% of patients, ototoxicity in 21%, and peripheral neuropathy in 17%. Major risk factors for the development of toxicity were cumulative dose of P (P < .0001 for ototoxicity and neurotoxicity; P < .01 for overall toxicity, gonadal toxicity, and dehydroepiandrosteron elevation; P < .05 for hypertension and Mg depletion) and type of chemotherapy (57% of PVB-treated patients v25% of PEB +/- vincristine-treated patients with RP; P < .01). CONCLUSION The cumulative dose of P was a major predictor for toxicity. Patients and treatment characteristics such as noise exposure, age, history of smoking, and mode of B application were less important. Further clinical trials should evaluate the sequelae of chemotherapy treatment for testicular cancer prospectively.

Secondary leukemia following high cumulative doses of etoposide in patients treated for advanced germ cell tumors.

PURPOSE High cumulative epipodophyllotoxin dosages are reported to be associated with an elevated risk for secondary acute myeloid leukemia (s-AML). This study examined the risk of s-AML following cumulative etoposide doses greater than 2 g/m2 in patients with metastatic germ cell tumors (GCT). PATIENTS AND METHODS The incidence of s-AML was retrospectively assessed in patients treated within clinical trials between January 1986 and February 1996 at four university centers. All patients received high-dose chemotherapy (HDCT) plus autologous stem-cell support for metastatic GCT, including high cumulative etoposide doses (> 2 g/m2). Minimum patient follow-up was 12 months. Standardized morbidity ratio (SMR) was calculated to estimate the risk associated with high cumulative etoposide doses, as compared with the general population. RESULTS A total of 302 patients with a median age of 29 years (range, 15 to 55) received a median cumulative etoposide dose of 5 g/m2 (range, 2.4 to 14 g/m2). Four cases of s-AML were observed, which resulted in a cumulative incidence of 1.3% (95% confidence interval [CI], 0.38% to 3.59%) at 52 months of median follow-up (range, 12 to 198). Two cases of secondary myelodysplasia (s-MDS) developed in patients with primary mediastinal GCT. Based on the observed four cases of AML, which are most likely etoposide-related, the risk for developing s-AML (SMR, 160 [95% CI, 43.7 to 411.2]) is significantly increased in comparison to the age-matched general population. CONCLUSION Due to the low incidence of AML in the general population, the significantly elevated risk for developing s-AML affects only 1.3% of all patients who receive etoposide doses greater than 2 g/m2. HDCT, including etoposide doses greater than 2 g/m2, is associated with an acceptably low incidence of s-AML in patients with advanced GCT.

Long-term effects on sexual function and fertility after treatment of testicular cancer.

SummaryThis retrospective study evaluates the types and incidences of sexual disturbances and fertility distress in patients cured from testicular cancer and examines whether there is an effect resulting from different treatment modalities. A self-reported questionnaire was sent to 124 randomly selected patients who were treated at Hanover University Medical School between 1970 and 1993. Ninety-eight patients were included in the study, representing a response rate of 78%. All patients had been in complete remission (CR) for at least 24 months. The median age at diagnosis was 28 years (range 17–44). The median follow-up at the time of study was 12.0 years (range 2.8–25.6). Twenty patients (20%) had been treated for seminomatous and 78 patients (80%) for non-seminomatous germ cell tumours. Treatment included surveillance (7%), primary retroperitoneal lymph node dissection (RPLND) (13%), chemotherapy (CT) (33%), CT + secondary resection of residual retroperitoneal tumour mass (SRRTM) (43%) and infradiaphragmatic radiotherapy (4%). Patients receiving two treatment modalities (CT+SRRTM) reported more frequent an unfulfilled wish for children. Inability of ejaculation was clearly associated with RPLND and SRRTM. Subjective aspects of sexuality, like loss of sexual drive and reduced erectile potential, occurred only in a minority of patients after treatment. No abnormalities were observed concerning the course of pregnancies of partners. In conclusion, sexual dysfunction and infertility are common long-lasting sequelae in testicular cancer survivors affecting approximately 20% of patients. The relative risk for infertility appeared to be elevated for patients treated with the combination of CT+SRRTM. Twenty-one of 40 patients were able to fulfil their wish for children, and no congenital abnormalities were observed in these children.

Expression of stem-cell factor and its receptor c-kit protein in normal testicular tissue and malignant germ-cell tumours

The proto-oncogene c-kit and its ligand stemcell factor (SCF) may play an important role in the development of normal and malignant testicular tissue. This study investigates the presence of SCF and c-kit protein in 32 orchiectomy specimens of patients with testicular cancer, in 5 specimens of normal testicular tissue and in three established non-seminomatous germ-cell cancer cell lines (H12.1, H32, 577ML) by an immunohistochemical approach. Out of 9 testicular cancer specimens classified as pure seminomas, 7 (78%) showed a strong immunohistochemical reaction for both SCF and c-kit protein on the surface of the tumour cells. Fourteen non-seminomatous germ-cell tumours composed of embryonal carcinoma were completely negative for both SCF and c-kit protein and only faint positivity was found in 6 tumours (26%). Differentiated teratomatous structures within the specimens of nonseminomatous tumours showed a strong immunohistochemical reaction for SCF and c-kit protein in 8 of 11 (73%) cases. All three testicular cancer cell lines showed only faint staining reactions for c-kit protein and none for SCF. No secretion of SCF by the three lines in vitro was detected. The addition of high concentrations of SCF (100 ng/ml) to the testicular cancer cell lines in culture conditions without fetal calf serum resulted in a 1.4 to 3-fold growth stimulation compared to cell growth in serum-free medium alone. This effect was not detectable when the cells were cultured in serum-containing media. In the normal testicular tissue the germ-cells displayed a strong immunohistochemical reaction for c-kit protein while SCF positivity was found at the tubular membrane and on the surface of Sertoli cells. The SCF/c-kit system may possess a regulatory function in normal testicular tissue by possibly providing the microenvironment necessary for spermatogenesis. With the development of testicular cancer, this regulatory system seems to be lost, particularly in non-seminomatous germ-cell tumours. A growthstimulatory effect of high concentrations of SCF on nonseminomatous testicular cancer cell lines can be detected only in culture conditions with serum-free media. The effects achievable by the combination of SCF with other growth factors need to be further studied, as well as the role of the c-kit/SCF regulatory system for normal spermatogenesis and its possible implications for the understanding and treatment of male infertility.

Systematic Review and Meta-analysis of Diagnostic Accuracy of Percutaneous Renal Tumour Biopsy

CONTEXT The role of percutaneous renal tumour biopsy (RTB) remains controversial due to uncertainties regarding its diagnostic accuracy and safety. OBJECTIVE We performed a systematic review and meta-analysis to determine the safety and accuracy of percutaneous RTB for the diagnosis of malignancy, histologic tumour subtype, and grade. EVIDENCE ACQUISITION Medline, Embase, and Cochrane Library were searched for studies providing data on diagnostic accuracy and complications of percutaneous core biopsy (CB) or fine-needle aspiration (FNA) of renal tumours. A meta-analysis was performed to obtain pooled estimates of sensitivity and specificity for diagnosis of malignancy. The Cohen kappa coefficient (κ) was estimated for the analysis of histotype/grade concordance between diagnosis on RTB and surgical specimen. Risk of bias assessment was performed (QUADAS-2). EVIDENCE SYNTHESIS A total of 57 studies recruiting 5228 patients were included. The overall median diagnostic rate of RTB was 92%. The sensitivity and specificity of diagnostic CBs and FNAs were 99.1% and 99.7%, and 93.2% and 89.8%, respectively. A good (κ = 0.683) and a fair (κ = 0.34) agreement were observed between histologic subtype and Fuhrman grade on RTB and surgical specimen, respectively. A very low rate of Clavien ≥ 2 complications was reported. Study limitations included selection and differential-verification bias. CONCLUSIONS RTB is safe and has a high diagnostic yield in experienced centres. Both CB and FNA have good accuracy for the diagnosis of malignancy and histologic subtype, with better performance for CB. The accuracy for Fuhrman grade is fair. Overall, the quality of the evidence was moderate. Prospective cohort studies recruiting consecutive patients and using homogeneous reference standards are required. PATIENT SUMMARY We systematically reviewed the literature to assess the safety and diagnostic performance of renal tumour biopsy (RTB). The results suggest that RTB has good accuracy in diagnosing renal cancer and its subtypes, and it appears to be safe. However, the quality of evidence was moderate, and better quality studies are required to provide a more definitive answer.

Activity of Oxaliplatin in Patients With Relapsed or Cisplatin-Refractory Germ Cell Cancer: A Study of the German Testicular Cancer Study Group

PURPOSE To investigate the efficacy and toxicity of oxaliplatin, a diaminocyclohaxane platinum derivative with incomplete cross-resistance to cisplatin in patients with relapsed or cisplatin-refractory germ cell cancer. PATIENTS AND METHODS Thirty-two patients with nonseminomatous cisplatin-refractory germ cell cancer or relapsed disease after high-dose chemotherapy (HDCT) plus autologous stem-cell support were treated with single-agent oxaliplatin 60 mg/m(2) on days 1, 8, and 15 repeated every 4 weeks (group 1; n = 16) or oxaliplatin 130 mg/m(2) given on days 1 and 15 of a 4-week cycle (group 2; n = 16). Patients were pretreated with a median of seven (range, three to 13) cisplatin-containing treatment cycles; 78% had received carboplatin/etoposide-based HDCT before oxaliplatin therapy. Twenty-seven patients (84%) were considered refractory (n = 20; 63%) or absolutely refractory (n = 7; 22%) to cisplatin therapy. RESULTS Overall, four patients achieved a partial remission (13%; 95% confidence interval, 1% to 24%). Two additional patients achieved disease stabilization. All responses were observed in cisplatin-refractory patients, including three who had not responded to previous HDCT. Patients received a median two cycles of oxaliplatin with a median cumulative dose of 350 mg/m(2). Hematologic toxicity was generally mild, with five patients developing grade 3/4 thrombocytopenia. Nonhematologic side effects consisted mainly of nausea/vomiting. One patient developed grade 3 neurotoxicity. CONCLUSION Considering the particularly unfavorable prognostic characteristics of this patient population compared with patients from previous trials for new drugs in germ cell cancer, eg, paclitaxel and gemcitabine, a 13% overall response rate and a 19% response rate in the group treated with oxaliplatin 130 mg/m(2) seems to be of interest. Oxaliplatin may be a palliative treatment option for this patient population, and evaluation in combination regimens is warranted.