Viktor Grünwald

Publications of Viktor Grünwald

• Progression free survival of first line vascular endothelial growth factor-targeted therapy is an important prognostic parameter in patients with metastatic renal cell carcinoma.

  Authors: Christoph Seidel, Jonas Busch, Steffen Weikert, Sandra Steffens, Martin Fenner, Arnold Ganser, Viktor Grünwald

  European journal of cancer (Oxford, England : 1990). 03/2012;

  PURPOSE: Intrinsic resistance in metastatic renal cell carcinoma (mRCC) was recently associated with poor overall survival (OS), suggesting that VEGF inhibitor sensitivity may represent a valuablePURPOSE: Intrinsic resistance in metastatic renal cell carcinoma (mRCC) was recently associated with poor overall survival (OS), suggesting that VEGF inhibitor sensitivity may represent a valuable prognostic marker. We explored the duration of progression free survival (PFS) in first-line treatment and other variables as prognostic markers in mRCC. METHODS: Medical records from 119 mRCC patients receiving first line treatment with tyrosine kinase inhibitors (TKI) were retrieved retrospectively. Kaplan-Meier and log-rank analyses were employed on PFS and OS and multivariate Cox proportional hazard model analysed clinical parameters for their prognostic relevance. RESULTS: The median PFS of first line treatment was 8.4months (95% confidence interval 5.8-11) associated with a median OS of 28.2months (95% CI 20.9-35.4). Second line therapy with another TKI or mTOR-inhibitor was applied to 81 patients (68%). PFS of any second line therapy was 5.1 and 3.7months in first line treatment responders and non-responders (p=0.3), respectively. Univariate analyses revealed bone metastases, prior cytokine treatment, Memorial Sloan Kettering cancer centre (MSKCC) score, objective response rate, Eastern Cooperative Oncology Group (ECOG) performance status, first line PFS with 6months taken as cut-off parameter and second line treatment as prognostic variables. Multivariate analyses proved first line PFS above 6months (95% CI 0.154-0.641; HR 0.314), second line treatment (95% CI 0.162-0.657; HR 0.326), MSKCC score (95% CI 1.07-3.392; HR 1.905) and objective response rate (95% CI 0.358-0.989; HR 0.595) to be independent prognostic markers. CONCLUSIONS: The duration of first line PFS is an independent prognostic variable but not predictive for subsequent therapy.

• A phase I dose-escalating study of ES-285, a marine sphingolipid-derived compound, with repeat dose administration in patients with advanced solid tumors.

  Authors: Eduardo Vilar, Viktor Grünwald, Patrick Schöffski, Harald Singer, Ramon Salazar, Jose Luis Iglesias, Esther Casado, Martin Cullell-Young, Jose Baselga, Josep Tabernero

  Investigational new drugs. 02/2012; 30(1):299-305.

  ES-285 (Spisulosine) is a novel marine compound with antitumor activity in preclinical studies. A phase I study was performed in patients with advanced solid tumors to determine the maximum toleratedES-285 (Spisulosine) is a novel marine compound with antitumor activity in preclinical studies. A phase I study was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), establish a safety profile, and to evaluate pharmacokinetics and efficacy of the drug. Thirty patients from two centers were treated with a three-hour ES-285 intravenous infusion for five consecutive days, every 3 weeks. Eleven dose levels were explored. No dose-limiting toxicity (DLT) occurred from 2 to 81 mg/m²/day. Three patients had DLT, one each at dose levels 160, 120 and 100 mg/m²/day; all had grade 4 transaminase increases, one of whom (160 mg/m²/day) had concomitant grade 4 hepatitis and grade 3 bilirubin elevation. The MTD of this regimen was not reached due to early termination of the ES-285 phase I program, but was considered to be 80 to 100 mg/m²/day. Other toxicities included mild to moderate asthenia, nausea, vomiting, anemia, lymphopenia, and injection site reaction. Pharmacokinetic analyses showed dose proportionality on Days 1 and 5, a wide distribution and a long half-life. Seven patients (five with colorectal cancer) had stable disease (1.2-4.1 months), lasting for more than 3 months in three patients. Liver enzyme elevations were dose limiting for ES-285 in this administration schedule. Low antitumor activity was observed.

• Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes.

  Authors: Patrick Schöffski, Isabelle Laure Ray-Coquard, Angela Cioffi, Nguyen Bin Bui, Sebastian Bauer, Joerg Thomas Hartmann, Anders Krarup-Hansen, Viktor Grünwald, Raf Sciot, Herlinde Dumez, Jean-Yves Blay, Axel Le Cesne, Jantien Wanders, Carolyn Hayward, Sandrine Marreaud, Monia Ouali, Peter Hohenberger

  The lancet oncology. 09/2011; 12(11):1045-52.

  Eribulin inhibits microtubule dynamics via a mechanism distinct from that of other tubulin-targeting drugs, inducing cell-cycle arrest and tumour regression in preclinical models. We assessed theEribulin inhibits microtubule dynamics via a mechanism distinct from that of other tubulin-targeting drugs, inducing cell-cycle arrest and tumour regression in preclinical models. We assessed the activity and safety of eribulin in four strata of patients with different types of soft-tissue sarcoma. In this non-randomised multicentre phase 2 study, patients were included if they had progressive or high-grade soft-tissue sarcoma and had received no more than one previous combination chemotherapy or up to two single drugs for advanced disease. They were stratified by the type of soft-tissue sarcoma they had. Eribulin was given intravenously at a concentration of 1·4 mg/m(2) over 2-5 min at days 1 and 8 every 3 weeks to primarily assess progression-free survival at 12 weeks (RECIST 1.0), which we evaluated in all patients who started treatment. Safety analyses were done in all patients who started treatment. This trial is registered at ClinicalTrials.gov, number NCT00413192. Of 128 patients included, 37 had adipocytic sarcoma, 40 had leiomyosarcoma, 19 had synovial sarcoma, and 32 had other sarcomas. 12 (31·6%) of 38 patients with leiomyosarcoma evaluable for the primary endpoint, 15 (46·9%) of 32 patients with adipocytic sarcoma, four (21·1%) of 19 with synovial sarcoma, and five (19·2%) of 26 in other sarcomas were progression-free at 12 weeks. The most common grade 3-4 adverse events were neutropenia (66 [52%] of 127 patients evaluable for safety), leucopenia (44 [35%]), anaemia (nine [7%]), fatigue (nine [7%]), febrile neutropenia (eight [6%]), abnormal alanine aminotransferase concentrations (six [5%]), mucositis (four [3%]), and sensory neuropathy (four [3%]). Eribulin deserves further study in this setting, based on progression-free survival at 12 weeks in leiomyosarcoma and adipocytic sarcoma. Eisai Limited, Hatfield, UK.

• An international expanded-access programme of everolimus: addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy.

  Authors: Viktor Grünwald, Pierre I Karakiewicz, Sevil E Bavbek, Kurt Miller, Jean-Pascal Machiels, Se-Hoon Lee, James Larkin, Petri Bono, Sun Young Rha, Daniel Castellano, Christian U Blank, Jennifer J Knox, Robert Hawkins, Oezlem Anak, Marianne Rosamilia, Jocelyn Booth, Nicoletta Pirotta, István Bodrogi

  European journal of cancer (Oxford, England : 1990). 07/2011; 48(3):324-32.

  The RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosineThe RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to address an unmet medical need by providing everolimus prior to commercial availability, and also to further assess the safety and efficacy of everolimus in patients with VEGFr-TKI-refractory mRCC. REACT (Clinicaltrials.gov: NCT00655252) was a global, open-label, expanded-access programme in patients with mRCC who were intolerant of, or who had progressed on or after stopping treatment with, any available VEGFr-TKI therapy. Patients received everolimus 10mg once daily, with dose and schedule modifications allowed for toxicity. Patients were closely monitored for the development of serious and grades 3/4 adverse events (AEs). Response was assessed by RECIST every 3months for the first year and every 6months thereafter. A total of 1367 patients were enroled. Safety findings and tumour responses were consistent with those observed in RECORD-1, with no new safety issues identified. The most commonly reported serious AEs were dyspnoea (5.0%), pneumonia (4.7%) and anaemia (4.1%), and the most commonly reported grades 3/4 AEs were anaemia (13.4%), fatigue (6.7%) and dyspnoea (6.5%). Best overall response was stable disease in 51.6% and partial response in 1.7% of patients. Median everolimus treatment duration was 14weeks. Everolimus is well tolerated in patients with mRCC and demonstrates a favourable risk-benefit ratio.

• Sequence therapy in patients with metastatic renal cell carcinoma: comparison of common targeted treatment options following failure of receptor tyrosine kinase inhibitors.

  Authors: Jonas Busch, Christoph Seidel, Carsten Kempkensteffen, Manfred Johannsen, Ingmar Wolff, Stefan Hinz, Ahmed Magheli, Kurt Miller, Viktor Grünwald, Steffen Weikert

  European urology. 07/2011; 60(6):1163-70.

  The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined. To describe the efficacy and toxicity of sequential everolimus (EV)The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined. To describe the efficacy and toxicity of sequential everolimus (EV) versus receptor tyrosine kinase inhibitor (rTKI) following failure of first rTKI treatment. Retrospective study of 108 patients receiving rTKI or EV after progression on rTKI therapy at two German academic centres. Sequence of systemic targeted treatment with sunitinib (n=85) or sorafenib (n=23) followed by EV (n=62) or another rTKI (n=46; sorafenib, n=35; sunitinib, n=11). We measured response rate (Response Evaluation Criteria in Solid Tumours 1.0) and toxicity. Survival analysis (Kaplan-Meier method and Cox regression) was conducted for progression-free survival (PFS) and overall survival (OS). Main patient characteristics did not significantly differ by sequence of treatment groups (rTKI-rTKI vs rTKI-EV). Response rate following first rTKI failure was not significantly different between sequential therapies with a disease control rate of 51.6% (EV) and 43.5% (rTKI). The corresponding median PFS was 3.6 mo (95% confidence interval [CI], 1.8-5.4) for EV and 4.0 mo (3.2-4.9) for rTKI treatment. The estimated OS was longer for the rTKI-EV group (43 mo; 95% CI, 33.9-52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6-39.5; p=0.03), but this difference lost statistical significance in multivariable-adjusted analyses. Intrinsic rTKI resistance was independently associated with inferior subsequent PFS (hazard ratio [HR]: 1.79; 95% CI, 1.15-3.62; p=0.015) and OS (HR: 6.54; 95% CI, 3.01-14.20; p<0.001). Limitations are the retrospective design, limited numbers of cases, and residual confounding factors. The sequence therapies rTKI-EV and rTKI-rTKI may be equally efficacious in terms of PFS and response rate, whereas a tendency towards superior survival was observed for the rTKI-EV sequence. These data, particularly the potential benefit of an early change of mode of action, need confirmation in randomised comparative trials.

• The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication.

  Authors: Anja Puklowski, Yahya Homsi, Debora Keller, Martin May, Sangeeta Chauhan, Uta Kossatz, Viktor Grünwald, Stefan Kubicka, Andreas Pich, Michael P Manns, Ingrid Hoffmann, Pierre Gönczy, Nisar P Malek

  Nature cell biology. 07/2011; 13(8):1004-9.

  Deregulated centrosome duplication can result in genetic instability and contribute to tumorigenesis. Here, we show that centrosome duplication is regulated by the activity of an E3-ubiquitin ligaseDeregulated centrosome duplication can result in genetic instability and contribute to tumorigenesis. Here, we show that centrosome duplication is regulated by the activity of an E3-ubiquitin ligase that employs the F-box protein FBXW5 (ref. 3) as its targeting subunit. Depletion of endogenous FBXW5 or overexpression of an F-box-deleted mutant version results in centrosome overduplication and formation of multipolar spindles. We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6. FBXW5 is a cell-cycle-regulated protein with expression levels peaking at the G1/S transition. We show that FBXW5 levels are controlled by the anaphase-promoting (APC/C) complex, which targets FBXW5 for degradation during mitosis and G1, thereby helping to reset the centrosome duplication machinery. In summary, we show that a cell-cycle-regulated SCF complex is regulated by the kinase PLK4, and that this in turn restricts centrosome re-duplication through degradation of the centriolar protein HsSAS-6.

• Sequential mTOR inhibitor treatment with temsirolimus in metastatic renal cell carcinoma following failure of VEGF receptor tyrosine kinase inhibitors.

  Authors: Steffen Weikert, Carsten Kempkensteffen, Jonas Busch, Manfred Johannsen, Viktor Grünwald, Kaja Zimmermann, Anne Flörcken, Jörg Westermann, Lisa Weinkauf, Kurt Miller, Ulrich Keilholz

  World journal of urology. 04/2011;

  PURPOSE: Agents targeting the mammalian target of rapamycin (mTOR) pathway, e. g. everolimus, can provide clinical benefit in pretreated patients with metastatic renal cell carcinoma (mRCC), but dataPURPOSE: Agents targeting the mammalian target of rapamycin (mTOR) pathway, e. g. everolimus, can provide clinical benefit in pretreated patients with metastatic renal cell carcinoma (mRCC), but data from randomized trials on the sequential use of temsirolimus are lacking. We retrospectively studied the efficacy and safety of temsirolimus therapy following failure of rTKI therapy. METHODS: Twenty-nine patients treated with temsirolimus (25 mg/week) following progression on rTKI therapy were studied at four institutions. All patients had failed at least one prior rTKI therapy (sunitinib, n = 6; sorafenib, n = 1; both, n = 22). Over 80% had two or more prior therapies. Data on efficacy (response assessment, progression-free survival [PFS], overall survival [OS]) and safety (NCI-CTC) were analyzed. RESULTS: Adverse events occurred in 90% of patients with the majority being grade 1 (n = 4, 14%) or grade 2 (n = 12, 41%). Most grade 3/4 toxicities (n = 10, 34%) were manageable and included anemia (n = 4, 14%), leukopenia/neutropenia (n = 2, 7%), hyperglycemia (n = 1, 3%), acidosis/alkalosis (n = 2, 7%), and infection (n = 1, 3%). One patient discontinued temsirolimus for grade 3 pneumonitis. Median (range) PFS and OS were 5.1 months (1-10.4) and 18.0 months (12.6-23.3), respectively. Best response included partial response (n = 1) and stable disease (n = 15) for a disease control rate of 55%, and disease progression of 45% (n = 13). CONCLUSIONS: Temsirolimus after rTKI failure appears to provide promising safety and efficacy comparable to other treatment options in pretreated patients with mRCC.

• [Use of mTOR-inhibitors in solid tumors].

  Authors: Christoph Seidel, Viktor Grünwald

  Medizinische Monatsschrift für Pharmazeuten. 04/2011; 34(4):116-26; quiz 127-8.

  mTOR-inhibitors are part of targeted agents and are already in use in the clinic, especially for treatment of metastatic renal cell carcinoma. Distinct from conventional chemotherapeutics, targetedmTOR-inhibitors are part of targeted agents and are already in use in the clinic, especially for treatment of metastatic renal cell carcinoma. Distinct from conventional chemotherapeutics, targeted agents imply chronic treatment, which has changed our perspective on the commerce of adverse events (AE). In principle, mTOR-inhibitors are associated with a broad number of AEs. The occurrence of stomatitis, infection, pneumonitis, hyperlipidemia and hyperglycemia are considered major class effects of mTOR-inhibitors. However, severe adverse events remain scarce among mTOR-inhibitors and support chronic use of these agents. Based on their good clinical tolerability mTOR-inhibitors are prone to be developed in combinational therapies. However, the hepatic metabolism of these agents may limit their use to partners with a distinct metabolism in order to avoid drug interaction. Meanwhile about 40 different trials use mTOR-inhibitors in different tumor entities. The use of mTOR-inhibitors in neuroendocine tumors of the intestine, mantle cell lymphoma and sarcomas has hereby shown to be very promising. The mainstay of therapy already incorporates the use of everolimus in second line and temsirolimus in first line treatment in patients with metastatic renal cell carcinoma.

• A phase I study of recombinant human interleukin-21 (rIL-21) in combination with sunitinib in patients with metastatic renal cell carcinoma (RCC).

  Authors: Viktor Grünwald, Ingrid M E Desar, John Haanen, Walter Fiedler, Ulrik Mouritzen, M W Brændholt Olsen, Carla M L van Herpen

  Acta oncologica (Stockholm, Sweden). 01/2011; 50(1):121-6.

  sunitinib induces partial responses in 47% of patients with metastatic renal cell carcinoma (mRCC). However, the achievement of complete responses remains scarce and all patients will eventuallysunitinib induces partial responses in 47% of patients with metastatic renal cell carcinoma (mRCC). However, the achievement of complete responses remains scarce and all patients will eventually develop progressive disease. Recombinant interleukin-21 (rIL-21) is a novel cytokine, which is believed to deliver sustained cellular anti-tumor response and the combination of both agents may work synergistically. from July 2007 to July 2008 in this phase I trial nine therapy-naive patients with metastatic RCC in five European centers were enrolled. Patients with either good or intermediate risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) were eligible without restrictions to histology subtype nor measurable disease. Patients were treated with increasing doses of rIL-21 administered subcutaneously (s.c.) in combination with sunitinib 50 mg once daily (OD) orally at the '4 weeks on/2 weeks off' schedule. Dose-escalation was applied by a conventional '3+3 design'. Planned dose levels (DL) for rIL-21 were 3, 10, 30 and 100 microg/kg s.c. The primary endpoint was to determine the maximum tolerated dose (MTD) and recommended dose (rd). secondary objectives included pharmacokinetics of sunitinib and ril-21, and the induction of ril-21 antibodies. at 10 microg/kg two dose-limiting toxicities (DLT) occurred in four patients, consisting of grade 4 neutropenia and grade 3 thrombocytopenia. The MTD was 3 microg/kg rIL-21 combined with sunitinib 50 mg OD at the '4 weeks on/2 weeks off' schedule. Frequent occurring adverse events were injection site reaction, stomatitis, fatigue and dysgeusia. the combination of sunitinib 50 mg at the '4 weeks on/2 weeks off' schedule and 10 microg/kg IL-21 was not tolerated due to hematological DLTs. The dose level of 3 microg/kg rIL-21 was considered too low to be therapeutically relevant for further evaluation and therefore the study was discontinued.

• Retrospective analyses of patient characteristics having predictive impact on survival under everolimus.

  Authors: Christoph Seidel, Martin Fenner, Christoph Reuter, Axel S Merseburger, Arnold Ganser, Viktor Grünwald

  Onkologie. 01/2011; 34(3):111-4.

  Everolimus is the standard second-line therapy for patients with metastatic renal cell carcinoma (mRCC). We evaluated whether the response to first-line therapy with a tyrosine kinase inhibitor (TKI)Everolimus is the standard second-line therapy for patients with metastatic renal cell carcinoma (mRCC). We evaluated whether the response to first-line therapy with a tyrosine kinase inhibitor (TKI) has predictive impact on the progression-free survival (PFS) and overall survival (OS) under everolimus. In addition, patient characteristics were evaluated for their predictive impact on the response under everolimus. 42 patients with mRCC treated with everolimus (RAD001) within a clinical trial were analyzed. Prior to everolimus, every patient had received at least 1 TKI therapy. Another TKI for second line was given to 15 patients. PFS and OS were estimated according to the Kaplan-Meier method and compared with the log-rank test. Median PFS during everolimus therapy was 5.2 months (range 1.3-17.8). 27 patients (64%) achieved stable disease (SD) or partial remission (PR). Patients with a beneficial PFS under first-line TKI achieved a better OS after start of everolimus treatment (p = 0.05) and so did TKI responders (p = 0.04). A reduced OS was associated with liver metastases (p = 0.04) and high tumor burden (p = 0.01). A beneficial outcome under prior TKI therapy is predictive for a superior survival in patients treated with everolimus, while high tumor burden and liver metastases impair the OS.

• Does obesity influence the prognosis of metastatic renal cell carcinoma in patients treated with vascular endothelial growth factor-targeted therapy?

  Authors: Sandra Steffens, Viktor Grünwald, Kristina I Ringe, Christoph Seidel, Hendrik Eggers, Mark Schrader, Frank Wacker, Markus A Kuczyk, Andres J Schrader

  The oncologist. 01/2011; 16(11):1565-71.

  Obesity increases the risk for renal cell carcinoma (RCC). However, it has only recently been identified as an independent positive prognostic factor for localized RCC. To determine whether obesityObesity increases the risk for renal cell carcinoma (RCC). However, it has only recently been identified as an independent positive prognostic factor for localized RCC. To determine whether obesity influences long-term prognosis in metastatic RCC patients receiving vascular endothelial growth factor-targeted therapy. In 116 patients with metastatic RCC who received antiangiogenic agents (sunitinib, sorafenib, axitinib, bevacizumab) in 2005-2010, we evaluated whether body mass index (BMI), a body surface area (BSA) above the European average, the visceral fat area (VFA), or s.c. fat area (SFA) were of predictive relevance. BMI was categorized based on current World Health Organization definitions. BSA was stratified according to the European average for men (1.98 m(2)) and women (1.74 m(2)). VFA and SFA were dichotomized using the median of the observed distribution as the cutoff. The primary endpoints of this study were time to progression and overall survival time. The whole population had median progression-free and overall survival times of 8.3 months and 20.5 months, respectively. In contrast to BMI and BSA, higher than average VFA and SFA levels were significant predictors of longer progression-free and overall survival times. The major limitations of this study are its retrospective design and its heterogeneous patient population. This is the first study to identify high VFA and SFA levels as positive predictive biomarkers for patients who receive first-line antiangiogenic agents for metastatic RCC.

• Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma.

  Authors: Jonas Busch, Christoph Seidel, Steffen Weikert, Ingmar Wolff, Carsten Kempkensteffen, Lisa Weinkauf, Stefan Hinz, Ahmed Magheli, Kurt Miller, Viktor Grünwald

  BMC cancer. 01/2011; 11:295.

  Data on sequential therapy in patients with metastatic renal cell carcinoma (mRCC) and intrinsic resistance to receptor tyrosine kinase inhibitor (rTKI) treatment remains vague. We retrospectivelyData on sequential therapy in patients with metastatic renal cell carcinoma (mRCC) and intrinsic resistance to receptor tyrosine kinase inhibitor (rTKI) treatment remains vague. We retrospectively studied treatment characteristics and outcome of mRCC patients refractory to first rTKI therapy. Thirty-five mRCC patients (male, 18; female, 11) with primary resistance to first rTKI therapy (sunitinib, n = 28; sorafenib, n = 7) and a median treatment interval of 2.4 months (1 - 4.6) were identified. In 22 patients, progressive disease (PD) was determined by a new metastatic lesion. Of these, 16 patients received subsequent therapy with 12 patients remaining refractory and 4 patients achieving disease stabilization. In 13 patients continuous growth of existing metastatic lesions determined PD. Of these, 9 received sequential therapy with 6 achieving disease stabilization. Altogether, 25 patients were treated sequentially (rTKI: n = 15; mTOR-inhibitor: n = 10) and achieved a median PFS of 3.2 months (range, 1-16.6). Fifteen patients failed to respond to either line of therapy. Disease control was not associated with type of subsequent therapy. Median OS was 14.9 months (CI: 5.5-24.4). Intrinsic resistance to rTKI is associated with a low chance of response to sequential therapy and a poor prognosis in mRCC patients.

• Efficacy of sunitinib re-exposure after failure of an mTOR inhibitor in patients with metastatic RCC.

  Authors: Viktor Grünwald, Steffen Weikert, Christoph Seidel, Jonas Busch, Antje Johannsen, Martin Fenner, Christoph Reuter, Arnold Ganser, Manfred Johannsen

  Onkologie. 01/2011; 34(6):310-4.

  The sequential use of tyrosine kinase inhibitors (TKI) followed by mTOR inhibitors (mTORi) has been recently established for the systemic treatment of metastatic renal cell carcinoma (mRCC). However,The sequential use of tyrosine kinase inhibitors (TKI) followed by mTOR inhibitors (mTORi) has been recently established for the systemic treatment of metastatic renal cell carcinoma (mRCC). However, subsequent treatment in mTORi-refractory disease remains undetermined. We analyzed the efficacy of sunitinib re-challenge after failure of an mTORi at 2 German centers. Thirteen patients who failed both sunitinib and an mTORi were analyzed, and all patients were re-exposed to sunitinib. Tumor assessment was performed every 2nd cycle of sunitinib or every 3 months. Tumor response was assessed according to RECIST criteria. Initial treatment with sunitinib was associated with a median progression free survival (PFS) of 21 months. Objective response consisted of 2 (15%) complete remissions and 7 (54%) partial remissions (PR) as best response. At the time of re-exposure, 12 of 13 (92%) patients again showed clinical benefit which was associated with a median PFS of 6.9 months and consisted of 2 (15%) PR and 10 (77%) disease stabilizations. In sunitinib-responsive patients, re-challenge with sunitinib has been successfully introduced after mTORi-refractory disease, underscoring the at least partially transient nature of TKI resistance in mRCC.

• Treatment with tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma is associated with drug-induced hyperparathyroidism: a single center experience in 59 patients.

  Authors: Philipp Ivanyi, Thomas Winkler, Anika Grosshennig, Christoph Reuter, Axel S Merseburger, Arnold Ganser, Viktor Grünwald

  World journal of urology. 06/2010; 28(3):311-7.

  Multi-targeted tyrosine kinase inhibitors (MTKIs) are the standard in the treatment of metastatic renal cell carcinoma (mRCC). In spite their clinical activity, interaction with physiologicalMulti-targeted tyrosine kinase inhibitors (MTKIs) are the standard in the treatment of metastatic renal cell carcinoma (mRCC). In spite their clinical activity, interaction with physiological functions has been shown. Here, we report on alterations of the bone mineral metabolism in patients with mRCC treated with MTKIs. Fifty-nine patients with mRCC treated during April 2005 and September 2009 at our center were evaluated. Demographics, chemistry, parathyroid and renal function, bone metastasis and clinics were assessed, retrospectively. Parathyroid hormone (PTH), calcium and phosphate were either determined prior to, during or after cessation of MTKI therapy. From evaluable patients, 90% (N = 53) received at least one MTKI treatment, 10% (N = 8) had evaluations without MTKI exposure. The mean PTH value prior to MTKI treatment was 49.4 (range (r):2.5-115), increased during the therapy to 121.2 (r:5-302) (P = 0.003) and returned to its basic values after MTKI cessation. In parallel, mean phosphate significantly decreased during the treatment from 1.10 (r = 0.66-1.59) to 0.87 (r = 0.48-1.45) (P < 0.001) and calcium showed a slight decrease (P = 0.039). PTH alterations were associated with clinical signs in some patients but not with bone metastasis or renal function. Univariate logistic regression analysis of pathologically elevated PTH levels revealed an association with MTKI treatment duration. Even though the mechanism of bone mineral alteration remains elusive, the MTKI treatment is associated with a dysregulated parathyroid axis, which may have clinical implications in a number of patients. Furthermore, prospective trials are mandatory, and PTH monitoring should be considered in selected patients during MTKI treatment.

• Management of sunitinib-related adverse events: an evidence- and expert-based consensus approach.

  Authors: Viktor Grünwald, Daniel Kalanovic, Axel S Merseburger

  World journal of urology. 06/2010; 28(3):343-51.

  The advance of medical treatment in renal cell carcinoma (RCC) has fostered the development of diverse continuous oral therapies with tyrosine kinase inhibitors (TKI), among these sunitinib remainsThe advance of medical treatment in renal cell carcinoma (RCC) has fostered the development of diverse continuous oral therapies with tyrosine kinase inhibitors (TKI), among these sunitinib remains the mainstay of therapy for most of the patients. Based on its clinical activity, disease control over a period of 11 months can be expected with sunitinib treatment. Given this prolonged period of exposure to sunitinib, adverse events tend to reoccur and can possibly decrease the quality of life in our patients. Hence, development of modalities to detect, treat and cope with such adverse events has become a major focus for physicians and patients. Today, numerous publications address these questions and offer advice from experienced centers. However, these reviews summarize single or oligo-center experiences. Our approach is based (1) on an extensive review and analysis of available evidence from literature and (2) a structured consensus survey among 12 German experts in the field who treated at least 30 patients each with a TKI. Derived from this process, this paper gives an overview on Sunitinib therapy management recommendations deducted from published evidence and consensus agreement among experts.

• Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer.

  Authors: Christoph W M Reuter, Michael A Morgan, Philipp Ivanyi, Martin Fenner, Arnold Ganser, Viktor Grünwald

  World journal of urology. 03/2010; 28(3):391-8.

  There is no proven, effective, standard second-line chemotherapy for castration- and docetaxel-resistant prostate cancer (DRPC). Recent data suggest that carboplatin may be effective in combinationThere is no proven, effective, standard second-line chemotherapy for castration- and docetaxel-resistant prostate cancer (DRPC). Recent data suggest that carboplatin may be effective in combination with docetaxel in this setting; however, the optimal docetaxel/carboplatin-based regimen is still unclear. We identified 43 consecutive patients with DRPC treated with carboplatin (AUC5 d1) and docetaxel (35 mg/m(2) d1, 8, 15 q4w i.v.) as a second-line or subsequent salvage chemotherapy until discontinuation of therapy due to disease progression or unacceptable toxicity. Decreased prostate-specific antigen (> or =50% PSA) was observed in 22/43 (51.2%, 95% CI, 35.5, 66.7%) patients, with > or =90% reduction in 12/43 patients (27.9%). At the time of analysis, the median follow-up time for all patients was 10.4 months. Median progression-free survival (PFS) for all patients was 6.5 months (95% CI 4.1, 8.9), and median overall survival (OS) was 15.8 months (95% CI 12.1, 18.5). In PSA responders, PFS was 9.5 (95% CI 8.2, 19.0) months versus 3.3 (95% CI 2.6, 4.0) months in PSA non-responders (P < 0.0001; hazard ratio (HR) 0.108) and OS was 24.4 months (95% CI 19.5, 29.4) versus 7.8 (95% CI 5.2, 10.3) months (P = 0.001; HR 0.232). Established prognostic factors were associated with survival. This regimen was reasonably well tolerated, with leukopenia/neutropenia as the most common reversible grade 3/4 toxicity (41.9/39.5%). These data suggest that weekly docetaxel plus carboplatin may be an important therapeutic second-line treatment option for patients with DRPC.

• Molecular targeted therapies for solid tumors: management of side effects.

  Authors: Viktor Grünwald, Jens Soltau, Philipp Ivanyi, Jochen Rentschler, Christoph Reuter, Joachim Drevs

  Onkologie. 04/2009; 32(3):129-38.

  This review will provide physicians and oncologists with an overview of side effects related to targeted agents that inhibit vascular endothelial growth factor (VEGF), epidermal growth factor (EGF)This review will provide physicians and oncologists with an overview of side effects related to targeted agents that inhibit vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and mammalian target of rapamycin (mTOR) signaling in the treatment of solid tumors. Such targeted agents can be divided into monoclonal antibodies, tyrosine kinase inhibitors, multitargeted tyrosine kinase inhibitors and serine/threonine kinase inhibitors. Molecular targeted therapies are generally well tolerated, but inhibitory effects on the biological function of the targets in healthy tissue can result in specific treatment-related side effects, particularly with multitargeted agents. We offer some guidance on how to manage adverse events in cancer patients based on the range of options currently available.

• Can Tyrosine Kinase Inhibitors be Discontinued in Patients with Metastatic Renal Cell Carcinoma and a Complete Response to Treatment? A Multicentre, Retrospective Analysis.

  Authors: Manfred Johannsen, Anne Flörcken, Axel Bex, Jan Roigas, Marco Cosentino, Vincenzo Ficarra, Christian Kloeters, Matthias Rief, Patrik Rogalla, Kurt Miller, Viktor Grünwald

  European urology. 11/2008;

  BACKGROUND: Discontinuation of treatment with tyrosine kinase inhibitors (TKIs) and readministration in case of recurrence could improve quality of life (QoL) and reduce treatment costs for patientsBACKGROUND: Discontinuation of treatment with tyrosine kinase inhibitors (TKIs) and readministration in case of recurrence could improve quality of life (QoL) and reduce treatment costs for patients with metastatic renal cell carcinoma (mRCC) in which a complete remission (CR) is achieved by medical treatment alone or with additional resection of residual metastases. OBJECTIVE: To evaluate whether TKIs can be discontinued in these selected patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of medical records and imaging studies was performed on all patients with mRCC treated with TKIs (n=266) in five institutions. Patients with a CR under TKI treatment alone or with additional metastasectomy of residual disease following a partial response (PR), in which TKIs were discontinued, were included in the analysis. Outcome criteria analysed were time to recurrence of previous metastases, occurrence of new metastases, symptomatic progression, improvement of adverse events, and response to reexposure to TKIs. INTERVENTIONS: Sunitinib 50mg/day for 4 wk on and 2 wk off, sorafenib 800mg/day. MEASUREMENTS: Response according to Response Evaluation Criteria in Solid Tumours (RECIST). RESULTS AND LIMITATIONS: We identified 12 cases: 5 CRs with sunitinib, 1 CR with sorafenib, and 6 surgical CRs with sunitinib followed by residual metastasectomy. Side-effects subsided in all patients off treatment. At a median follow-up of 8.5 mo (range: 4-25) from TKI discontinuation, 7 of 12 patients remained without recurrence and 5 had recurrent disease, with new metastases in 3 cases. Median time to progression was 6 mo (range: 3-8). Readministration of TKI was effective in all cases. The study is limited by small numbers and retrospective design. CONCLUSIONS: Discontinuation of TKI in patients with mRCC and CR carries the risk of progression with new metastases and potential complications. Further investigation in a larger cohort of patients is warranted before such an approach can be regarded as safe.

• Targeted therapies for patients with germ cell tumors.

  Authors: Martin H Fenner, Gernot Beutel, Viktor Grünwald

  Expert opinion on investigational drugs. 05/2008; 17(4):511-22.

  BACKGROUND: Patients with advanced germ cell tumors can be cured with cisplatin-based chemotherapy but the outcome remains unsatisfactory for patients with relapsed disease. Targeted therapies haveBACKGROUND: Patients with advanced germ cell tumors can be cured with cisplatin-based chemotherapy but the outcome remains unsatisfactory for patients with relapsed disease. Targeted therapies have changed the standard of care for many advanced solid tumors. OBJECTIVE: To identify clinically available drugs that have the potential as targeted therapies in germ cell tumors. METHODS: A literature search was carried out for expression and mutation status of receptor tyrosine kinases in germ cell tumors, also a literature and clinical trial database search for completed and ongoing clinical trials with targeted therapies in germ cell tumors. RESULTS/CONCLUSIONS: c-KIT is mutated in some seminomas and bilateral germ cell tumors. Several case reports and small clinical trials with trastuzumab, thalidomide and imatinib were identified and clinical trials with sunitinib and bevacizumab are ongoing. We expect an increased use of targeted therapies in advanced germ cell tumors in the next few years.

• Novel therapies in advanced renal cell carcinoma: management of adverse events from sorafenib and sunitinib.

  Authors: Philipp Ivanyi, Thomas Winkler, Arnold Ganser, Christoph Reuter, Viktor Grünwald

  Deutsches Ärzteblatt international. 04/2008; 105(13):232-7.

  INTRODUCTION: Sorafenib and Sunitinib are the first tyrosine kinase inhibitors licensed for the treatment of advanced renal cell carcinoma. In contrast to conventional chemotherapy, targetedINTRODUCTION: Sorafenib and Sunitinib are the first tyrosine kinase inhibitors licensed for the treatment of advanced renal cell carcinoma. In contrast to conventional chemotherapy, targeted therapies have distinct and specific side effects. METHODS: Selective review in Medline and the data base of the American Society of Clinical Oncology on the treatment and side effects of tyrosine kinase inhibitors in renal cell carcinoma, drawing on the authors' own experience. RESULTS AND DISCUSSION: Tyrosine kinase inhibitors are characterized by a variety of uncommon side effects, such as lassitude, mucosal inflammation and skin changes. The detection and treatment of adverse events are critical for interdisciplinary cancer treatment in order to ensure patients' safety. This article offers an overview of the unwanted effects of drug therapy in the management of renal cell carcinoma.