Nexavar scientific update |
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Lung Cancer. 2010 Jun 24. [Epub ahead of print]
Davies JM, Dhruva NS, Walko CM, Socinski MA, Bernard S, Hayes DN, Kim WY, Ivanova A, Keller K, Hilbun LR, Chiu M, Dees EC, Stinchcombe TE.
Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hil, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, USA.
A phase I trial of sorafenib combined with cisplatin/etoposide or carboplatin/pemetrexed in refractory solid tumor patients.
INTRODUCTION: Sorafenib has demonstrated single agent activity in non-small cell (NSCLC) and small cell lung cancer (SCLC). Carboplatin/pemetrexed (CbP) and cisplatin/etoposide (PE) are commonly used in the treatment of these diseases. METHODS: A phase I trial escalating doses of sorafenib in combination with fixed doses of PE (Arm A) or CbP (Arm B) was performed using a 3-patient cohort design to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT); DLT were assessed in the first cycle. The trial was subsequently amended with closure of Arm B and to include Arm C with a reduced dose of carboplatin. RESULTS: Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 42-73), male/female ratio 12/8, PS 0/1 ratio 6/14, and median number of prior therapies 2 (range 1-4). The most common tumor types were NSCLC and SCLC. On Arm A at dose level 0 (sorafenib 200mg BID), 2 of 4 patients experienced DLT; 2 patients were enrolled at dose level -1 (sorafenib 200mg QD) without DLT, but this arm was closed due to slow accrual. On Arm B, 2 of 3 patients experienced DLT at dose level 0 (sorafenib 200mg BID). On Arm C at dose level 0 (sorafenib 200mg BID), 1 of 6 patients experienced DLT, and at dose level +1 (sorafenib 400mg BID) 2 of 5 patients experienced a DLT. CONCLUSIONS: The MTD of sorafenib was 200mg BID continuously in combination with carboplatin (AUC of 5) and pemetrexed 500mg/m(2) every 3 weeks. However, only 6 patients were treated at this dose level, and the results should be interpreted cautiously.
Hepatology. 2010 Mar 1;52(1):360-369. [Epub ahead of print]
Siegel AB, Olsen SK, Magun A, Brown RS Jr.
Departments of Medicine and Surgery, Columbia University College of Physicians and Surgeons, New York, NY.
Sorafenib: Where do we go from here?
The approval of sorafenib as the first effective drug for the treatment of hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. A better understanding of HCC pathogenesis has led to the development of several novel targeted treatments. HCC is treated in a uniquely multidisciplinary way requiring surgeons, hepatologists, interventional radiologists, and oncologists. This review describes the molecular pathogenesis of HCC, explores current and future treatments based on these pathways, and describes how these new therapies may augment existing approaches to HCC treatment.
Hepatocellular carcinoma (HCC) remains a highly complex disease resistant to commonly used chemotherapy and radiotherapy. As the sixth most common cancer worldwide with the third highest mortality rate and very poorly understood molecular pathways dr
Rimassa L, Santoro A.
Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
The present and the future landscape of treatment of advanced hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a highly lethal disease that is resistant to conventional cytotoxic drugs. Historically, effective systemic treatment options have not been available for patients with unresectable advanced disease. However, an improved understanding of the molecular mechanisms that regulate tumor initiation and progression over the past few years has led to the development of novel molecularly-targeted therapies that specifically block the different cellular signaling pathways involved. Recently, the antiangiogenesis and Raf kinase inhibitor, sorafenib showed a survival advantage in advanced stage HCC in two randomized, double-blind, controlled trials. These positive results were the first to demonstrate the efficacy of molecularly-targeted therapies in advanced HCC. Moreover, results from phase I and II trials evaluating other agents in this disease are promising and are under active clinical development. In the near future, we expect to have more data, knowledge, and evidence regarding the use of molecularly-targeted therapies in advanced HCC, both as single agents and in combination regimens. In this review, we will summarize the data concerning the present standard treatment for advanced HCC and discuss the newest, most promising clinical research that may affect the future treatment of this disease.
Dig Liver Dis. 2010 Jul;42 Suppl 3:S264-72.
Lachenmayer A, Alsinet C, Chang CY, Llovet JM.
Liver Cancer Program, Division of Liver Diseases, Mount Sinai School of Medicine, New York, USA.
Molecular approaches to treatment of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) remains a highly complex disease resistant to commonly used chemotherapy and radiotherapy. As the sixth most common cancer worldwide with the third highest mortality rate and very poorly understood molecular pathways driving hepatocarcinogenesis, new treatment strategies are urgently needed for this devastating disease. The multikinase inhibitor sorafenib was the first molecular targeted drug in HCC that led to significant survival benefit in patients with advanced tumors. It is the first drug to be considered standard of care for advanced HCC and supports the importance of molecular therapies in the treatment of this cancer. Analyses of genetic and epigenetic alterations as well as different molecular pathways involved in the development of HCC help to identify potential new druggable targets. A variety of novel compounds are already under preclinical or clinical investigation, and accumulating evidence suggests that combination therapy targeting different pathways will potentiate anti-tumoral effects and will become the future therapeutic approach. In addition the establishment of a robust molecular classification will pave the way for a more personalized treatment scheme in HCC. In this article we review the current knowledge of the molecular pathogenesis of HCC and provide an overview of molecular targeted therapies in the management of HCC
Methods Find Exp Clin Pharmacol. 2009 Dec;31(10):661-700.
Tomillero A, Moral MA.
Gateways to clinical trials.
[Methoxy-(11)C]PD-153035, 2-Methoxyestradiol; Adalimumab, Adecatumumab, Adefovir dipivoxil, ADH-1, ADX-10059, Aflibercept, AIR-human growth hormone, Aliskiren fumarate, AMG-221, Amlodipine besylate/olmesartan medoxomil, Aprepitant; Bavituximab, Bevacizumab, Bexarotene, BIBW-2992, BMS-690514, Bortezomib, Bosentan, Briakinumab; Capecitabine, Certolizumab pegol, Cetuximab, Cholecalciferol, Choline fenofibrate, Chorionic gonadotropin (human), Cixutumumab, Clopidogrel, CP-690550 citrate; Dabigatran, Dacetuzumab, Daclizumab, Dapagliflozin, Darbepoetin alfa, Dasatinib, Denosumab; Efavirenz, Elisidepsin, Enoxaparin, Enzastaurin hydrochloride, Eribulin mesilate, Erlotinib hydrochloride, Everolimus, Exenatide; Fenobam, Figitumumab, Filibuvir, Fondaparinux sodium, Fresolimumab; Gefitinib, Golimumab, Golnerminogene pradenovec; Ifosfamide, Imatinib mesylate, Ipilimumab, Ivabradine hydrochloride, Ixabepilone; Lapatinib ditosylate, Lenalidomide, Levocetirizine dihydrochloride, Liposomal vincristine, Liraglutide; M-118, Masitinib mesylate, Metformin hydrochloride, Micafungin sodium, Moxifloxacin hydrochloride; Neratinib; Oblimersen sodium, Ofatumumab, Olmesartan medoxomil; Paclitaxel nanoparticles, Palifosfamide lysine, Panobacumab, Panobinostat, Patupilone, Peginterferon alfa-2a, Pegylated arginine deiminase 20000, Piclozotan hydrochloride hydrate, Pixantrone maleate, Prasterone, Prasugrel, Prednisone, Progesterone, Prucalopride, pVGI.1 (VEGF-2); Retigabine, rhFSH, Rituximab, Rivaroxaban, Rosuvastatin calcium; Salinosporamide A, Selumetinib, Sipuleucel-T, Somatropin, Sorafenib, SSR-244738, Sunitinib malate; Tamoxifen citrate, Teduglutide, Telavancin hydrochloride, Telmisartan, Telmisartan/amlodipine, Telmisartan/hydrochlorothiazide, Temsirolimus, Tenofovir disoproxil fumarate, Tipifarnib, Tolvaptan, Trastuzumab, Trastuzumab-MCC-DM1, Travoprost, Tremelimumab; Valsartan/amlodipine besylate, Valsartan/amlodipine besylate/hydrochlorothiazide, Valsartan/hydrochlorothiazide, Vandetanib, Vorinostat.
Cases J. 2009 Dec 2;2:9133.
Valsuani C, Siclari O, Camerini A, Canale ML, Rondini M, Donati S, Puccinelli P, Tartarelli G, Puccetti C, Amoroso D.
Medical Oncology Division, Versilia Hospital, via Aurelia 335, 55041 Lido di Camaiore (LU), Italy.
Sorafenib in a patient with advanced hepatocellular carcinoma and serious impairment of left ventricular function: a case report.
INTRODUCTION: sorafenib, a tyrosine-kinase inhibitor, is widely used in the treatment of advanced hepatocellular carcinoma. Drug-related toxicities are generally mild but sorafenib, as other similar agents, may induce elevation of systemic arterial blood pressure levels in relation to an interaction with cardiovascular system probably mediated by HIF pathway. This side effect may be particularly critical for patients with underlying serious heart disease as it can induce acute heart failure, a life-threatening condition, and usually such patients are excluded from active treatment with tyrosine-kinase inhibitors. We report the case of a patient affected by advanced hepatocellular carcinoma and serious impairment of cardiac function treated with sorafenib without any worsening of heart function. To our knowledge this is the first report of this kind in the literature. CASE PRESENTATION: We report the case of a 74-year-old patient affected by advanced multifocal HCV-cirrhosis related hepatocellular carcinoma and severe post-ischemic fall of left-ventricular function with serious risk of cardiac functional impairment. The patient presented with an ECOG performance status of 0. Blood chemistry tests showed a substantial elevation of alpha-fetoprotein values and slight increases of bilirubin, of gamma-GT and of GOT; the absence of encephalopathy and ascites and the normality of coagulation parameters and of albumin led to classify the patient into the functional class Child-Pugh A. The patients was successfully treated with sorafenib at the reduced daily dose of 400 mg for long-time without any worsening of heart function. CONCLUSION: The presented case can offer to oncologists a clinical support to take into consideration when deciding to treat with sorafenib advanced hepatocellular carcinoma patients presenting with serious impairment of cardiac function that are usually excluded from an active treatment.
Rozhl Chir. 2009 Aug;88(8):434-8.
Varga M, Valsamis A, Matia I, Peregrin J, Honsová E, Safanda M, Oliverius M.
Klinika transplantacní chirurgie IKEM. mavg@medicon.cz
[Transarterial chemoembolization in hepatocellular carcinoma] [Article in Czech]
INTRODUCTION: Hepatocelullar carcinoma (HCC) is the fifth most common cancer in the world. It mostly occurs in patients with cirrhosis. In the Czech Republic, about 250 new cases are reported per year. Surgery, i.e. liver resection or transplantation, as the only potentially curable method is possible in 15-20% of them. For the rest, palliative treatment is indicated. This includes ablative methods (radiofrequency ablation, alcoholization), transarterial chemoembolization (TACE), systemic chemotherapy or biological treatment by sorafenib. TACE is method of choice in patients unsuitable for surgery and ablative treatment. Another indication is embolization of HCC before liver transplantation to prevent tumour progression. In combination with other methods, down staging of the tumour and curable treatment afterward is possible. AIMS: To assess the outcome of transarterial chemoembolisation in patients with hepatocellular carcinoma. METHODS: Between 2004-2008 we performed 30 TACE. Of that number, 28 TACE were performed in 20 patients with HCC. We super selectively catheterized the tumour via arteria femoralis and used Doxorubicin with Lipiodol as embolic material. In follow up, we carried out laboratory studies and CT. RESULTS: We have not noticed any major complications. Post-embolization syndrome with fever, nausea and right upper quadrant pain occurred after 10 TACE (33%). One-, two- and three years survival of the patients was 53%, 40% a 20%. CONCLUSION: TACE is safe method prolonging patients' survival with unresectable HCC. For the correct treatment of HCC, its concentration to cancer centres and the cooperation between multiple specialists is necessary.
BJU Int. 2009 Dec;104(11):1585-9.
Mulders P.
Radboud University Medical Centre, Nijmegan, the Netherlands. p.mulders@uro.umcn.nl
Vascular endothelial growth factor and mTOR pathways in renal cell carcinoma: differences and synergies of two targeted mechanisms.
Renal cell carcinoma (RCC) is among the most resistant tumours to chemotherapy, radiotherapy and hormonal therapy. Cytokine therapy is effective in a small subset of patients, but it is associated with substantial toxicity and rarely benefits patients with extensive tumour burdens or adverse prognostic factors. Since 2005, clinical trials have shown significant clinical benefits for five molecularly targeted therapies in patients with advanced RCC. These agents constitute two mechanistic classes: (i) angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) ligand (bevacizumab, in combination with interferon-a) or VEGF receptors (sunitinib, sorafenib); and (ii) inhibitors of the mammalian target of rapamycin (mTOR) signalling (temsirolimus, everolimus). This review assesses the mechanistic distinctions and functional overlaps of these classes of agents, and discusses key characteristics of their respective clinical efficacy and side-effect profiles in patients with RCC, some of which might affect patient selection and treatment strategies. Current research is designed to optimize the use of these agents, as well as the development of new investigational therapies within these mechanistic classes. The differences and synergies are particularly important for understanding the best ways to integrate VEGF/VEGF receptor inhibitors and mTOR inhibitors for combination or sequential treatment of patients with advanced RCC.
Clin Genitourin Cancer. 2008 Dec;6 Suppl 1:S22-8.
Chung EK, Stadler WM.
Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medical Center, IL 60637-1479, USA.
Vascular endothelial growth factor pathway-targeted therapy as initial systemic treatment of patients with renal cancer.
Advanced renal cancer is known to be largely refractory to traditional DNA- and DNA repair-targeted chemotherapy. Until recently, immunotherapy had been the mainstay for the treatment; however, it is effective in only a small proportion of patients. Advances in the understanding of the association between the von Hippel-Lindau pathway and angiogenesis and their role in the development of renal cancer has led to the development of highly effective vascular endothelial growth factor (VEGF) pathway-targeted inhibitors. Several such novel agents have demonstrated increased clinical benefit, progression-free survival, and superior quality of life in large, randomized phase III clinical trials, and additional VEGF pathway inhibitors are currently being studied. This review will summarize the major clinical trials and practical recommendations for the most studied VEGF inhibitors, including sunitinib, sorafenib, and bevacizumab; introduce novel VEGF inhibitor agents; outline side effects and toxicities; and discuss sequential and combination therapy with these agents.
Clin Genitourin Cancer. 2008 Dec;6 Suppl 1:S14-21.
Bukowski RM.
Cleveland Clinic Taussig Cancer Center, CCF Lerner College of Medicine of Case Western Reserve University, Ohio, USA. bukow464@sbcglobal.net
What role do combinations of interferon and targeted agents play in the first-line therapy of metastatic renal cell carcinoma?
Interferons (IFNs) are a class of cytokines with pleotropic actions that regulate a variety of cellular activities. Clinical trials with recombinant IFNs (IFN-alpha2a and IFN-alpha2b) have demonstrated clinical activity in patients with advanced renal cell carcinoma (RCC). Their efficacy is characterized by a low overall tumor regression rate of < 15%, progression-free survival of 4-5 months, and overall median survival of 10-18 months. This cytokine became the standard of care for patients with metastatic RCC and was then used as the comparator arm in a series of phase II and III clinical trials that have defined a new treatment paradigm for patients with advanced RCC. This paradigm uses the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib, the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, and the vascular endothelial growth factor monoclonal antibody bevacizumab. These 3 categories of agents were then investigated in combination with IFN-alpha in a series of preclinical and clinical studies. The collective data from these reports suggest the combination of IFN-alpha and bevacizumab is active and has a role in RCC therapy, whereas combinations with the TKIs or mTOR inhibitors have limited efficacy and/or excessive toxicity. The clinical and preclinical studies leading to these conclusions are reviewed herein.
Clin Genitourin Cancer. 2008 Dec;6 Suppl 1:S7-13.
Molina AM, Motzer RJ.
Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Current algorithms and prognostic factors in the treatment of metastatic renal cell carcinoma.
Metastatic renal cell carcinoma (RCC) is highly resistant to chemotherapy but responds modestly to cytokine therapy. The prognosis for long-term survival is poor. Approximately 10% of patients who present with metastatic disease or relapse after nephrectomy are alive at 5 years. Identification of prognostic or predictive factors for individual patient outcomes is necessary in order to develop tailored treatments that reduce the risk of relapse and enhance the chance of successful management. The relationship between pretreatment clinical features and survival has been evaluated in studies leading to the creation of a Memorial Sloan-Kettering Cancer Center (MSKCC) risk model. Additionally, the cloning of the von Hippel-Lindau tumor suppressor gene, and the elucidation of its role in upregulating growth factors associated with angiogenesis, has provided insight into RCC biology and defined a series of targets for novel therapeutic agents. These targeted agents, including sunitinib, sorafenib, temsirolimus, everolimus, and bevacizumab plus interferon-alpha, have shown benefit in phase III trials in first- and second-line therapy. Analysis of the data from these trials and use of prognostic models have resulted in a new paradigm for the treatment of metastatic RCC. Herein, we review these targeted agents, the MSKCC risk model, and the new paradigm for treatment of metastatic RCC.
Biologics. 2008 Dec;2(4):779-88.
Furuse J.
Department of Internal Medicine, Medical Oncology, School of Medicine, Kyorin University.
Sorafenib for the treatment of unresectable hepatocellular carcinoma.
Raf kinases and vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases are potential molecular targets for obtaining both anti-tumor cell progression and anti-angiogenesis effects in cancers, including hepatocellular carcinoma (HCC). Sorafenib is an oral multi-kinase inhibitor that mainly targets Raf kinases and receptor tyrosine kinases associated with angiogenesis (VEGFR-2/-3, PDGFR-beta). A global randomized controlled trial (RCT) of sorafenib versus placebo conducted in patients with advanced HCC demonstrated the beneficial effects of the drug on the time-to-progression and overall survival. Furthermore, a RCT with a similar design to that of the global trial conducted in the Asia-Pacific region also demonstrated the efficacy of the drug. The most common treatment-related adverse events of sorafenib were found to be diarrhea, fatigue, and skin toxicity, namely, hand-foot syndromes and rash. Based on the results of the RCTs, sorafenib has been established as a standard agent for systemic chemotherapy in HCC patients with metastatic disease or transcatheter arterial chemoembolization (TACE)-refractory disease who are not suitable candidates for local treatments. The efficacy and safety of sorafenib in patients with moderate liver dysfunction have not been confirmed to date and more data are needed. Development of new therapeutic methods is needed for the treatment of advanced HCC in the future; clinical trials of sorafenib-based combination therapy, second-line therapy after sorafenib failure, and adjuvant therapy after local treatments are warranted in HCC patients.
Curr Opin Support Palliat Care. 2007 Oct;1(3):174-9.
Patard JJ, Pouessel D, Culine S.
Department of Urology, Rennes University Hospital, Rennes, France. jean-jacques.patard@univ-rennes1.fr
New therapies in renal cell carcinoma.
PURPOSE OF REVIEW: We present an update on the dramatic changes that have occurred over the past year in the management of patients with metastatic renal cell carcinoma. RECENT FINDINGS: Although it was demonstrated that benefit from immunotherapy is restricted to a minority of patients, a better understanding of the molecular mechanisms involved in the pathogenesis of clear cell carcinoma has led to development of multiple targeted therapies, with significant clinical benefits. Two compounds that predominantly inhibit the tyrosine kinase activity of vascular endothelial growth factor receptor have been demonstrated to improve the progression-free survival of patients as first-line (sunitinib versus interferon-alpha) or second-line (sorafenib versus placebo) treatment. Temsirolimus, which inhibits the serine-threonine kinase activity of the mammalian target of rapamycin, offers better overall survival than interferon in patients with poor risk characteristics. Finally, bevacizumab combined with interferon is yielding substantial response rates and increased progression-free survival compared with interferon alone. SUMMARY: Four major drugs or regimens with proven efficacy are now available for first-line and second-line therapy in metastatic renal cell carcinoma. Further studies are needed to determine the optimal combinations of these agents in metastatic disease and to assess their impact in the adjuvant setting.
Can Urol Assoc J. 2007 Jun;1(2 Suppl):S34-40.
Hotte SJ, Kapoor AK.
Department of Oncology, Juravinski Cancer Centre.
Systemic therapy for patients with advanced, unresectable ormetastatic renal cell carcinoma: moving to guidelines.
Until recently, patients with advanced, unresectable or metastatic renal cell cancer (RCC) had very few therapeutic options. Cytokine therapy, consisting mainly of interferon-alpha and interleukin-2, was considered the mainstay of therapy. A better understanding of the biology of RCC has led to the development of novel therapeutic agents that target angiogenesis. Inactivation of the von Hippel-Lindau tumour-suppressor gene VHL, which is present in the vast majority of clear-cell RCC tumours, leads to overexpression of the vascular endothelial growth factor, which in turn promotes angiogenesis. Recent observations from a number of positive studies with agents such as sunitinib malate, sorafenib, temsirolimus and bevacizumab have led to a rapid and exciting change in the standard of care for patients with advanced renal cell carcinoma. This article reviews these agents in the context of their use in clinical practice and provides suggestions about the appropriateness of various agents in specific clinical situations.
Rev Recent Clin Trials. 2007 May;2(2):121-34.
Pratilas CA, Solit DB.
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Therapeutic strategies for targeting BRAF in human cancer.
Constitutive ERK activation is a common finding in human cancer and is often the result of activating mutations of BRAF and RAS. BRAF missense mutations occur in approximately 8% of human tumors, most frequently in melanoma, papillary thyroid cancer and colon cancer. Mutations in BRAF have been found predominantly in tumors in which RAS is commonly mutated but concurrent mutations of both BRAF and RAS are extremely rare. Though over 40 different kinase domain mutations in BRAF have been identified, a single base-pair substitution in exon 15 at codon 600 (V600E) is found in over 80% of cases. These mutations cluster in the glycine-rich loop and activation segments of the kinase and are predicted to induce kinase activation by disrupting the inhibitory glycine-rich loop/activation segment interaction which characterizes the inactive conformation. The majority of mutations identified cause constitutive kinase activation with the V600E mutation demonstrating approximately 500-fold greater kinase activity than wild-type BRAF. Supporting its classification as an oncogene, V600E BRAF stimulates ERK signaling, induces proliferation and is capable in model systems of promoting transformation. However, BRAF mutations are common in nevi and colon polyps suggesting that BRAF mutation alone is insufficient for tumorigenesis and additional mutations are required for cancer development. Though such data suggest that BRAF mutation is likely an early initiating event in tumors such as melanoma and colon cancer, preclinical studies suggest that tumors with V600E BRAF mutation remain dependent upon BRAF for proliferation and survival. Given its frequent occurrence in human cancer and the continued requirement for BRAF activity in tumors with BRAF mutation, efforts are underway to develop targeted inhibitors of BRAF and its downstream effectors. The first generation of RAF inhibitors, including sorafenib, were notable for their lack of specificity and potency for RAF and these agents have shown limited efficacy in tumors with a high incidence of BRAF mutation such as melanoma. Novel inhibitors of the pathway with greater selectivity for BRAF and MEK are now in Phase 1 and 2 clinical trials with promising early results. To maximize the likelihood of success with these agents, clinical trials enriched with patients whose tumors possess BRAF and RAS mutations have been proposed.
Khirurgiia (Sofiia). 2007;(3):54-9.
Chakŭrov S.
Department of Urology University Hospital St. Ana.
[Current progress and problems in oncourology] [Article in Bulgarian]
One of the most serious problems of urology as specialized surgery is the oncological diseases. A large part of the scientific research is dedicated to their basic research, diagnostics and treatment as the results are then presented at the big international forums each year. The new achievements in the investigations of urological diseases excite special interest and mark the stages of the actual progress of the respective science. The overview is a panorama of the newest and at the same time most significant achievements of the science of urology in this field in 2006 presented at the biggest international congresses - the Congress of the European Association of Urology, the Annual Meeting of the American urologists and the Congress of the American Society of Clinical Oncology - ASCO. What is typical is the existence of the large number of researches of the carcinoma of the prostate - an issue on which the urological society focuses its attention quite often. Without any revolutionary breakthroughs being made new scientific proof has been added which considerably enriches our knowledge about this disease and places special focus on the real value and interpretation of the levels of the Prostate Specific Antigen (PSA). What is especially impressive in bladder cancer research is the discovery of a protein element called "survivin", which is of the family of the inhibitors of apoptosis and its level is connected with qualities of the tumors like aggressiveness, recurrence and progression of the disease and mortality rate. The weight of the scientific research in the field of kidney tumors is placed on the basic research of their oncogenesis. After quite a few years of standstill in the area of chemotherapy new drugs like Sunitinib, Sorafenib and Temserolimus are being introduced, some of which even have independent antitumor effect. As far as the testicle tumors are concerned, the necessity of an extensive lymphadenectomy is confirmed. The increased possibilities of conservative treatment of the lymph node metastases are stressed though radiation therapy and chemotherapy, especially in the cases of seminoma tumors. In the case of penis cancer the weight is placed on the timely diagnostics and treatment allowing organ-preserving operations. The summarized messages of the achievements that are part of the development of the oncourology have also been pointed out.
Invest New Drugs. 2009 Sep 24. [Epub ahead of print]
Roy Choudhury S, Karmakar S, Banik NL, Ray SK.
Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Building 2, Room C11, 6439 Garners Ferry Road, Columbia, SC, 29209, USA.
Synergistic efficacy of sorafenib and genistein in growth inhibition by down regulating angiogenic and survival factors and increasing apoptosis through upregulation of p53 and p21 in malignant neuroblastoma cells having N-Myc amplification or non-am
Neuroblastoma is an extracranial, solid, and heterogeneous malignancy in children. The conventional therapeutic modalities are mostly ineffective and thus new therapeutic strategies for malignant neuroblastoma are urgently warranted. We examined the synergistic efficacy of combination of sorafenib (SF) and genistein (GST) in human malignant neuroblastoma SK-N-DZ (N-Myc amplified) and SH-SY5Y (N-Myc non-amplified) cell lines. MTT assay showed dose-dependent decrease in cell viability and the combination therapy more prominently inhibited the cell proliferation in both cell lines than either treatment alone. Apoptosis was confirmed morphologically by Wright staining. Flow cytometric analysis of cell cycle phase distribution and Annexin V-FITC/PI staining showed increase in subG1 DNA content and early apoptosis, respectively, after treatment with the combination of drugs. Apoptosis was further confirmed by scanning electron microscopy. Combination therapy showed activation of caspase-8, cleavage of Bid to tBid, increase in p53 and p21 expression, down regulation of anti-apoptotic Mcl-1, and increase in Bax:Bcl-2 ratio to trigger apoptosis. Down regulation of MDR, hTERT, N-Myc, VEGF, FGF-2, NF-kappaB, p-Akt, and c-IAP2 indicated suppression of angiogenic and survival pathways. Mitochondrial release of cytochrome c and Smac into cytosol indicated involvement of mitochondia in apoptosis. Increases in proteolytic activities of calpain and caspase-3 were also confirmed. Our results suggested that combination of SF and GST inhibited angiogenic and survival factors and increased apoptosis via receptor and mitochondria mediated pathways in both neuroblastoma SK-N-DZ and SH-SY5Y cell lines. Thus, this combination of drugs could be a potential therapeutic strategy against human malignant neuroblastoma cells having N-Myc amplification or non-amplification.
Expert Rev Anticancer Ther. 2009 Oct;9(10):1429-34.
Merseburger AS, Simon A, Waalkes S, Kuczyk MA.
Department of Urology and Urologic Oncology Hannover Medical School (MHH) Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
Sorafenib reveals efficacy in sequential treatment of metastatic renal cell cancer.
Metastatic renal cell carcinoma (mRCC) is a highly vascularized tumor with a generally poor prognosis. It is largely resistant to conventional cancer treatment, including most schemes of hormonal and cytokine therapy as well as to modern chemotherapy. Although IFN-alpha has been the first choice in mRCC treatment strategies for more than a decade, recent recommendations of the European Association of Urology focus on so-called molecular-targeted therapies, with multikinase inhibitors, such as sorafenib and sunitinib, blocking the progression of cell proliferation and tumor angiogenesis, as preferential therapy. Sorafenib targets the VEGF receptor, the PDGF receptor beta and, finally, Raf kinase, and is approved for patients who have either received cytokines or are unsuitable for such a therapy. Although targeted therapies reveal superior efficacy compared with previous cytokine-based approaches, they do not cure patients with metastatic disease. Therefore, following tumor progression, most patients require a second-line or sequential therapy during the further progress of the disease. Owing to the fact that optimal sequencing of these new agents has not been fully elucidated, some recent mainly retrospective studies compared the sequence of sorafenib and sunitinib in order to assess the best clinical benefit in mRCC patients. Apparently, no cross-resistance could be observed in any trial, and most results demonstrated a superior efficacy of a sequence strategy when sorafenib was applied as first-line treatment. Regarding current investigations, the aim of the present article is to address and critically discuss the clinical data concerning the efficacy of sorafenib as part of a sequential treatment of mRCC.
Int J Clin Oncol. 2009 Oct;14(5):465-7. Epub 2009 Oct 25.
Hasegawa Y, Mita K, Matsubara A, Ohdan H.
Department of Urology, Hiroshima University Graduate School of Biomedical Sciences, Minami-ku, Hiroshima, Japan.
Multidisciplinary treatment including sorafenib stabilized the bone metastases of renal cell carcinoma in an immunosuppressed renal transplant recipient.
We report a case of metastatic renal cell carcinoma in the native kidney of a renal transplant recipient. The patient was a 57-year-old man in whom a tumor in the native kidney and bone metastasis were found incidentally on imaging, 10 years after cadaveric renal transplantation. Interferon-alpha was administered after nephrectomy and following palliative irradiation of the metastasis, but could not be continued because of allograft dysfunction. Subsequent administration of zoledronic acid and sorafenib stabilized the disease for 18 months after nephrectomy. This is the first reported case of sorafenib administration to a renal transplant recipient with metastatic renal cell carcinoma.
Tumori. 2009 Jul-Aug;95(4):542-4.
Ferraris E, Di Cesare P, Lasagna A, Paglino C, Imarisio I, Porta C.
Oncologia Medica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Use of sorafenib in two metastatic renal cell cancer patients with end-stage renal impairment undergoing replacement hemodialysis.
Patients with renal cell carcinoma (RCC) may exhibit renal impairment as a more or less direct consequence of their primary disease. Renal impairment may become a severe complication and alter the normal pharmacokinetic and pharmacodynamic behavior of treatment drugs, thus increasing the risk of side effects. We will discuss the cases of two advanced RCC patients with end-stage renal impairment submitted to dialysis who were treated with sorafenib tosylate in our center. Our experience confirms the scarce literature data available so far that indicate that sorafenib can be used in patients undergoing dialysis. Dialysis cannot be considered per se a contraindication to sorafenib therapy, which can be effective. However, patients must be carefully selected and monitored, since sorafenib administration unquestionably increases the risk of side effects in patients affected by several conditions.
Cancer. 2009 Oct 27. [Epub ahead of print]
Jonasch E, Corn P, Pagliaro LC, Warneke CL, Johnson MM, Tamboli P, Ng C, Aparicio A, Ashe RG, Wright JJ, Tannir NM.
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Upfront, randomized, phase 2 trial of sorafenib versus sorafenib and low-dose interferon alfa in patients with advanced renal cell carcinoma: clinical and biomarker analysis.
BACKGROUND:: The objective of this study was to independently evaluate the objective response rate of sorafenib and sorafenib plus low-dose interferon-alfa 2b (IFN) as frontline therapy in patients with metastatic renal cell carcinoma (mRCC). METHODS:: Untreated patients with clear cell mRCC were randomized to receive sorafenib 400 mg orally twice daily or sorafenib 400 mg orally twice daily plus subcutaneous IFN 0.5 million U (MU) twice daily. Primary endpoints included the objective response rate (ORR) and safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory endpoints included the predictive value of tumor tissue biomarkers. RESULTS:: Eighty patients were enrolled. The median follow-up was 19.7 months (range, 0-34.2 months). The ORR was 30% (95% confidence interval [CI], 16.6%-46.5%) in the sorafenib arm and 25% (95% CI, 12.7%-41.2%) in the combination arm. The median PFS was 7.39 months in the sorafenib-alone arm (95% CI, 5.52-9.20 months) and 7.56 months in the sorafenib plus IFN arm (95% CI, 5.19-11.07 months). The median OS was 27.04 months in the combination arm (95% CI, from 22.31 to not attained) and was not reached in the sorafenib arm. Toxicities were comparable in both arms. In a multivariate model, increased phosphorylated protein kinase B (pAKT) levels were associated with poorer PFS (hazard ratio, 1.04; 95% CI, 1.00-1.08; P = .0411) and OS (hazard ratio, 1.15; 95% CI, 1.02-1.29; P = .0173). CONCLUSIONS:: The addition of low-dose IFN to sorafenib resulted in efficacy outcomes that were comparable to those achieved with sorafenib monotherapy. The current results indicated that pAKT levels may predict for clinical outcome, but further mechanistic study is required. Cancer 2009. (c) 2009 American Cancer Society.
Hepatology. 2009 Aug 31. [Epub ahead of print]
Vitale A, Volk ML, Pastorelli D, Lonardi S, Farinati F, Burra P, Angeli P, Cillo U.
Unità di Chirurgia Oncologica, Istituto Oncologico Veneto, IRCCS, Padova, Italy.
Use of sorafenib in patients with hepatocellular carcinoma before liver transplantation: A cost-benefit analysis while awaiting data on sorafenib safety.
The role of bridging therapies for patients with hepatocellular carcinoma (HCC) on the waiting list for liver transplantation (LT) remains controversial. There is strong evidence to support the effectiveness of sorafenib in extending the time to progression of HCC. Using a Markov model, we compared two strategies: one using sorafenib as neoadjuvant therapy before LT (Strategy A), and the other using no bridging therapy in the first 6 months (Strategy B). Reference case: T2 HCC patient with compensated cirrhosis. The benefit of sorafenib in delaying time to HCC progression was expressed as the hazard ratio (HR) and taken from recently published randomized trials. The endpoints considered were: survival benefit measured in quality-adjusted life days (QALDs), transplant probability, costs (C) in euro, willingness to pay (WTP), and net health benefit (NHB), where NHB = survival benefit - C/WTP. The calculated WTP of sorafenib in Italy was 346 euro per QALD. Probabilistic sensitivity analysis showed a median survival benefit of 94 QALDs (10% percentile = 38, 90% percentile = 210). In the base-case scenario (HR = 0.47, monthly dropout probability = 5%, median time to LT = 3 months), the gain in LT probability due to sorafenib was 5% and it increased proportionally with increasing median times to LT and decreasing HR. In the cost-benefit analysis, the incremental NHB of Strategy A versus Strategy B was 37 QALDs; it increased as sorafenib HR decreased and when median times to LT were shorter than 6 months, whereas for longer times it gradually dropped, particularly when Strategy B included effective locoregional treatments. Conclusion: Sorafenib neoadjuvant therapy is cost-effective by comparison with no therapy for T2-HCC patients waiting for LT, particularly for median times to LT under 6 months. (HEPATOLOGY 2009.).
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