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Previous Renal Cell Carcinoma Research: 2002-2006   
The Renal Cell Carcinoma File also contains summaries of past research that has shown promise and may still be standard practice among many physicians. To download earlier research findings on Renal Cell Carcinoma, click HERE.
 

Latest Research on
Renal Cell Carcinoma
     
Genetika. 2008 Feb;44(2):250-6.
[Human chromosome 3P regions of putative tumor-suppressor genes in renal, breast, and ovarian carcinomas]
[Article in Russian]
Loginov VI, Bazov IV, Khodyrev DS, Pronina IV, Kazubskaia TP, Ermilova VD, Gar'kavtseva RF, Zbarovskiĭ ER, Braga EA.

Allelic imbalances (AI) of polymorphic markers at the short arm of chromosome 3 (3p) were mapped using DNA samples of renal cell carcinoma (RCC, 80 cases), breast carcinoma (BC, 95 cases), and epithelial ovarian cancer (EOC, 50 cases) at the same dense panel of markers (up to 24 loci). Six regions with the increased AI frequency (versus the average values determined for all the analyzed 3p markers) at RCC, BC or EOC were found in 3p chromosome. Four 3p regions presumably contain suppressor genes of tumor growth (TSG) observed in the epithelial tumors of various types. Region between D3S2409 and D3S3667 markers in the 3q21.31 region was identified in this study for the first time. The AI peak in D3S2409-D3S3667 region was statistically significant (P < 0.001, according to Fisher) when representative sample of 95 BC patients was analyzed. The data on increased frequency of polymorphic marker allele amplification suggest that the D3S2409-D3S3667 region contains both putative TSG and protooncogenes.

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Lancet. 2008 Jul 12;372(9633):145-54. Epub 2008 Jul 3. Comment in: Lancet. 2008 Jul 12;372(9633):92-3.
An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial.
Wood C, Srivastava P, Bukowski R, Lacombe L, Gorelov AI, Gorelov S, Mulders P, Zielinski H, Hoos A, Teofilovici F, Isakov L, Flanigan R, Figlin R, Gupta R, Escudier B; C-100-12 RCC Study Group.
M D Anderson Cancer Center, Houston, TX, USA. cgwood@mdanderson.org

BACKGROUND: Treatment of localised renal cell carcinoma consists of partial or radical nephrectomy. A substantial proportion of patients are at risk for recurrence because no effective adjuvant therapy exists. We investigated the use of an autologous, tumour-derived heat-shock protein (glycoprotein 96)-peptide complex (HSPPC-96; vitespen) as adjuvant treatment in patients at high risk of recurrence after resection of locally advanced renal cell carcinoma. METHODS: In this open-label trial, patients were randomly assigned to receive either vitespen (n=409) or observation alone (n=409) after nephrectomy. Randomisation was done in a one to one ratio by a computer-generated pseudo-random number generator, with a block size of four, and was stratified by performance score, lymph node status, and nuclear grade. Vitespen was given intradermally once a week for 4 weeks, then every 2 weeks until vaccine depletion. The primary endpoint was recurrence-free survival. The final analysis of recurrence-free survival was planned to take place after 214 or more events of disease recurrence or deaths before recurrence had occurred. Analysis was by intention to treat (ITT). This study is registered with ClinicalTrials.gov, number NCT00033904. FINDINGS: 48 patients in the vitespen group and 42 in the observation group were excluded from the ITT population because they did not meet post-surgery inclusion criteria; the ITT population thus consisted of 361 patients in the vitespen group and 367 in the observation group. Final analysis of recurrence-free survival was triggered in November, 2005. Re-review of all patients in the ITT population by the clinical events committee identified 149 actual recurrences (73 in the vitespen group and 76 in the observation group), nine deaths before recurrence (two in the vitespen group and seven in the observation group), and 124 patients with baseline metastatic or residual disease (61 in the vitespen group and 63 in the observation group). Thus, after a median follow-up of 1.9 years (IQR 0.9-2.5) in the ITT population, recurrence events were reported in 136 (37.7%) patients in the vitespen group and 146 (39.8%) in the observation group (hazard ratio 0.923, 95% CI 0.729-1.169; p=0.506). After continued follow-up until March, 2007, there had been 70 deaths in the vitespen group and 72 in the observation group (p=0.896); however, overall survival data were not mature, and patients continue to be followed up for survival. In predefined exploratory analyses by AJCC stage, recurrence events in patients with stage I or II disease were reported in 19 (15.2%) patients in the vitespen group and 31 (27.0%) in the observation group (hazard ratio 0.576, 95% CI 0.324-1.023; p=0.056). The most commonly reported adverse events in the vitespen group were injection-site erythema (n=158) and injection-site induration (n=153). One serious adverse event-autoimmune thyroiditis of grade 2 severity-was reported in the vitespen group; no treatment-related grade 3 or 4 adverse events were reported. INTERPRETATION: No difference in recurrence-free survival was seen between patients given vitespen and those who received no treatment after nephrectomy for renal cell carcinoma. A possible improvement in recurrence-free survival in patients with early stage disease who received vitespen will require further validation.

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Urol Int. 2008;80(4):372-7. Epub 2008 Jun 27.
Activation of PI3K is associated with reduced survival in renal cell carcinoma.
Merseburger AS, Hennenlotter J, Kuehs U, Simon P, Kruck S, Koch E, Stenzl A, Kuczyk MA.
Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany.

OBJECTIVES: The epidermal growth factor receptor- (EGFR) activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt) pathway is associated with tumorigenesis and progression. The aims of the present study were to determine the expression patterns of Akt pathway parameters PI3K, phosphatase and tensin homolog (PTEN), phosphor-Akt (p-Akt) and their combination, for their possible prognostic value in renal cell carcinoma (RCC). PTEN dephosphorylates the liquid product of PI3K. METHODS: Tumor samples from 176 RCC patients were investigated for PTEN, p-Akt and PI3K expression by immunohistochemistry. Expression levels were correlated to clinical variables and postoperative outcome by uni- and multivariate statistical analysis. RESULTS: The various expression levels within the tumor samples were independent of histological grade and tumor stage, due to different levels of activation of the PI3K/p-Akt pathway. The activation of PI3K protein was found to be significantly associated with reduced survival times (p = 0.0304, multivariate analysis). Analysis of combined biomarker expressions showed that decreased long-term survival was correlated with PTEN low/p-Akt high expression (p < 0.05). CONCLUSIONS: Activation of the PI3K pathway is significantly associated with adverse clinical outcome in RCC. Analysis of biomarker combinations might identify high-risk patients and a subsequent need to adapt treatment modalities. Molecular pathways regulating PI3K activation appear to be promising targets for drug development in the clinical management of RCC patients. 2008 S. Karger AG, Basel.

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Urol Int. 2008;80(4):367-71. Epub 2008 Jun 27.
Cytokine therapy response as a selection criterion for cytoreductive nephrectomy in metastatic renal clear-cell carcinoma of intermediate prognosis. Results and conclusions from a combined analysis.
Bex A, Haanen JB, Vyth-Dreese FA, Horenblas S, de Gast GC.
Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. a.bex@nki.nl

AIMS: To assess the strategy of using an absence of progression at metastatic sites following initial cytokine therapy outcome as a selection criterion for nephrectomy in patients with synchronous metastatic renal carcinoma and an intermediate prognosis according to the Memorial Sloan Kettering prognostic index classification. MATERIALS AND METHODS: A combined retrospective analysis of patients with clear-cell subtype from studies of initial cytokine treatment response to assist with selection of patients for nephrectomy. We analyzed survival times, UCLA integrated staging system scores, number of nephrectomies and risk of progression to unresectability of the primary tumor during treatment. RESULTS: There were 33 patients in total. Nephrectomies were not performed in 10 (30%) patients whose cancers had progressed at metastatic sites. Median survival time was 4 months with none of the patients dying of local tumor progression. The median survival time of the 21 patients with nonprogressive cancer and the primary removed was 17 months. Of those, 8 had a survival time < or =1 year (median 8.5 months) and a progression-free survival time of 4 months and 13 had a survival time >1 year (median 25 months). The median progression-free survival time was 7 months (4-57 months). Four of the 5 objective responses at metastatic sites (5/33, 14%) occurred in those surviving >1 year. CONCLUSIONS: We propose that progression at metastatic sites during initial immunotherapy may be used to identify patients with a short survival time and who are unlikely to benefit from nephrectomy. 2008 S. Karger AG, Basel.

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Praxis (Bern 1994). 2008 Apr 16;97(8):427-30.
[Current aspects in the therapy of renal cell cancer]
[Article in German]
Heynemann H.
Univ.-Klinik und Poliklinik für Urologie, Klinikum Medizinischen Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle. hans.heynemann@medizin.uni-halle.de

The nephron-sparing partial nephrectomy has become the gold standard in the surgical therapy of small renal tumors (4-7 cm). In metastased renal cell cancers it is reasonable to perform a nephrectomy or a partial nephrectomy in combination with cytokine-therapy (clear cell type) and/or a targeted therapy with Angiogenesis-Inhibition, in presence of a Karnofsky-Index > 70%. A surgical standard procedure for organ-confined renal cell cancers and an immunological standard therapy for metastased renal cell cancers are no more proper; in fact nowadays exists a spectrum of different efficient therapies. Surgery in metastased diseases is indicated if it can improve the quality of life of the patient.

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Int J Cancer. 2008 Sep 1;123(5):1080-8.
Global analysis of metastasis-associated gene expression in primary cultures from clinical specimens of clear-cell renal-cell carcinoma.
Tan X, Zhai Y, Chang W, Hou J, He S, Lin L, Yu Y, Xu D, Xiao J, Ma L, Wang G, Cao T, Cao G.
Department of Epidemiology, Second Military Medical University, Shanghai, China.

Metastatic clear-cell renal-cell carcinoma (ccRCC) has a poor prognosis and unpredictable course, and there are no molecular markers that reliably predict ccRCC metastasis. In this study, ccRCC specimens from 84 patients were directly cultured in vitro. Primary cultures from 38 of 94 specimens contained more than 90% tumor cells at the fourth passage. After identification by immunostaining, the primary cultures of metastatic and nonmetastatic ccRCC specimens from the age- and gender-matched patients were subjected to cDNA microarray assays. A total of 842 differentially expressed genes with a FDR (false discovery rate) of 4.79% were identified. Pathway analysis and co-occurrence with "cancer", "metastasis" and "invasion" in the literature annotations functionally enriched the 842 genes and provided an indication of the reliability of our microarray assays. Novel genes associated with metastasis were selected based on protein-protein interactions between 205 differentially expressed genes that co-occurred with "metastasis" and those that did not co-occur with "metastasis" on Medline, and the results of co-expression analysis between the co-occurred genes and unpublished genes. FSTL1, AV722783, SLC15A1, DDX17, ORC2L and PKMYT1 were found to be potential ccRCC metastasis-associated novel genes, according to expression patterns in cultures and tumor tissues. Interestingly, the upregulated genes (CAV1, PKMYT1 and ORC2L) were also upregulated and the downregulated genes (FSTL1, GSTM3, CYR61, SLC15A1 and AV722783) were also downregulated in the primary ccRCC specimens compared with expression in adjacent renal tissues in 37 patients. This study has identified new candidate biomarkers and targets for the early diagnosis and treatment of ccRCC metastasis.

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Int J Cancer. 2008 Sep 1;123(5):1126-32.
A three-gene expression signature model to predict clinical outcome of clear cell renal carcinoma.
Yao M, Huang Y, Shioi K, Hattori K, Murakami T, Sano F, Baba M, Kondo K, Nakaigawa N, Kishida T, Nagashima Y, Yamada-Okabe H, Kubota Y.
Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. masayao@med.yokohama-cu.ac.jp

Renal cell carcinomas (RCCs) are morphologically and genetically heterogeneous tumors and present diverse clinical courses. We developed a scoring system using levels of gene expression to predict the outcome for clear cell RCC patients. We selected differentially expressed genes from the DNA microarray data of 27 clear cell RCCs; 16 were metastasis phenotypes and 11 were not. We compared the selected gene set with previously published data and identified 33 overlapping genes closely associated with patient outcome. We selected the 12 top-ranked genes and confirmed the level of expression using quantitative reverse transcriptase PCR. Multivariate Cox analysis revealed that 3 genes-vascular cell adhesion molecule 1 (VCAM1), endothelin receptor type B (EDNRB), and regulator of G-protein signaling 5 (RGS5)-were the most tightly associated with cancer-specific survival and that higher expression of the 3 genes correlated with better outcome. A formula for an outcome predictor was generated from integration of the measurements of the expression levels of the 3 genes. Multivariate Cox models combined with a split-sample cross-validation method in a cohort of 386 clear cell RCC patients demonstrated that the derived score for outcome prediction was an independent predictor in cancer-specific survival tests. The accuracy of the prediction of cancer death after nephrectomy was improved by the inclusion of this score in receiver operating characteristic analysis from multivariate logistic regression models, suggesting that a scoring system based on the expression levels of these 3 genes is useful in the prediction of survival for patients with clear cell RCC.

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Expert Rev Anticancer Ther. 2008 Jun;8(6):921-7.
Laparoscopic partial nephrectomy in the treatment of renal cell carcinoma: a minimally invasive means to nephron preservation.
Blitstein J, Ghavamian R.
Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA. jbliste@montefiore.org

With the advent of cross-sectional imaging, the incidence of asymptomatic detected small renal masses, 'incidentalomas', has increased in the past 20 years. Recent studies have demonstrated that patients with renal masses have worse renal function at baseline and have more comorbidities than the general population. Nephron-sparing surgery allows for maximal preservation of functioning nephrons with comparable oncologic outcomes. Recently, laparoscopic partial nephrectomy has emerged as a minimally invasive nephron-sparing surgical option for treating the appropriately selected renal mass. While open-partial nephrectomy has undisputedly become standard of care for the management of the small renal mass (<4 cm), laparoscopic partial nephrectomy is becoming the preferred option for select patients in institutions in which advanced laparoscopic experience is available.

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Expert Rev Anticancer Ther. 2008 Jun;8(6):907-19.
Immunotherapy for renal cell cancer in the era of targeted therapy.
Coppin C.
Medical Oncology, University of British Columbia & BC Cancer Agency, Vancouver, Canada. ccoppin@bccancer.bc.ca

Until recently, cytokine therapy has been the only validated option for patients with advanced renal cancer. IFN-alpha is one of very few treatments that have demonstrated improved median survival compared with the appropriate control. In patients with synchronous metastases at diagnosis, debulking nephrectomy prior to interferon, further improves overall survival. High-dose IL-2 appears to be able to cure a small percentage of highly selected patients. There is potential to further improve patient selection for these options. The demonstrated value of cytokines should not be overlooked in the rush to use new drugs. In the adjuvant setting, vaccine therapy has provided the only systemic approach that has any promise. New insights into the complexities of the immune system at the molecular level, as well as the ingenuity and enthusiasm of immunotherapists, will undoubtedly lead to continuing attempts to identify and overcome obstacles to achieve the grail of human tumor rejection in clinical practice. Targets within the immune regulatory system and the use of vaccines as targeting agents may bring together the fields of immunotherapy and targeted therapy in the near future.

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Expert Rev Anticancer Ther. 2008 Jun;8(6):895-905.
Molecular genetics of hereditary renal cancer: new genes and diagnostic and therapeutic opportunities.
Hansel DE, Rini BI.
Department of Anatomic Pathology, Glickman Urological & Kidney Institute and Taussig Cancer Institute, The Cleveland Clinic, 9500 Euclid Avenue, Desk L25, Cleveland, OH 44195, USA. hanseld@ccf.org

Renal cell carcinoma may be sporadic or occur in the setting of an inherited cancer syndrome, such as von Hippel-Lindau or Birt-Hogg-Dube syndrome. Although the clinical spectrum of heritable renal cancer syndromes varies significantly, commonalities include the often young age of presentation, multifocal and bilateral nature of renal lesions, and autosomal dominant pattern of inheritance. Molecular studies have recently begun to elucidate the genetic abnormalities and subsequent alterations in downstream intracellular signaling cascades that underlie the development of these syndromes. This review will highlight the clinicopathologic and molecular features associated with the diverse array of heritable renal cancer syndromes and emphasize the potential cellular pathways that may be utilized to develop novel treatment strategies for patients with these syndromes.

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Expert Rev Anticancer Ther. 2008 Jun;8(6):887-93.
Chemokines as therapeutic targets in renal cell carcinoma.
Reckamp KL, Strieter RM, Figlin RA.
Divisions of Medical Oncology and Therapeutics Research & Hematology, City of Hope and Beckman Research Institute, 1500 E Duarte Road, MOB 1001, Duarte, CA 91010, USA. kreckamp@coh.org

Targeting novel pathways associated with tumor angiogenesis, invasion and immunity, may lead to improvement in patient outcomes for renal cell carcinoma. Chemokines potentiate tumor growth, metastasis, angiogenesis and immune evasion through interactions with stromal cells and neoplastic cells. Further understanding of the mechanisms involved in chemokine-mediated angiogenesis and metastasis may lead to improved therapeutic strategies in this disease. Interactions between chemokine expression and signaling, and the VEGF and hypoxia-inducible factor pathways offer important opportunities to intervene in the process of renal cell carcinoma proliferation, angiogenesis and invasion. Modulation of the CXCR3/CXCR3-ligand or the CXCR4/CXCL12 biologic axis may be potential therapeutic targets for the treatment of renal cell carcinoma. Furthermore, combination treatment with agents targeting chemokine signaling with therapies directed at angiogenesis and tumor immunity may lead to improved outcomes in this disease.

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Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006017.
Targeted therapy for advanced renal cell carcinoma.
Coppin C, Le L, Porzsolt F, Wilt T.

BACKGROUND: Advanced renal cell carcinoma has been resistant to drug therapy of different types and new types of drug therapy are needed. Targeted agents inhibit known molecular pathways involved in cellular proliferation and neoangiogenesis, the induction by the tumour of host microvascular networks. Angiogenesis is of special interest in the clear cell histologic subtype of renal cancer because of its vascularity and constitutively activated hypoxia-inducible path in the majority of tumours. OBJECTIVES: 1) To provide a systematic review of studies testing targeted agents.2) To identify the type and degree of clinical benefit, if any, of targeted agents over the prior standard of care, particularly any impact on overall survival. SEARCH STRATEGY: 1) Electronic search of CENTRAL, MEDLINE and EMBASE databases.2) Hand search of international cancer meeting abstract and other sources specified in the protocol. SELECTION CRITERIA: Randomized controlled studies of targeted agents in patients with advanced renal cell cancer reporting major remission rate or overall survival by allocation. Progression-free survival (PFS) was adopted as an additional outcome because PFS was a commonly chosen primary outcome, and because several pivotal studies allowed crossover from the control to the investigational arm after closure to accrual thereby making overall survival a problematic endpoint. DATA COLLECTION AND ANALYSIS: Nineteen fully eligible studies tested ten different targeted agents (Table 04). One additional study was excluded because no outcome data by allocation have been reported (Hutson 2007). For purposes of comparison, the studies were divided into three groups: Group 1 studies compared different doses of the same agents; Group 2 studies examined the impact of targeted agents in patients who had received prior cytokine or other systemic therapy; and Group 3 studies tested targeted agents in systemically naive patients, either against standard inter
feron-alfa or against another control therapy. Meta-analysis was not utilized because there were very few situations where the same agents had been tested in the same group in more than one study. MAIN RESULTS: In systemically untreated patients in studies using subcutaneous interferon-alfa as control therapy, the major findings were: 1) An improvement in overall survival has been demonstrated only with the use of weekly intravenous temsirolimus in patients with unselected renal cancer histology and adverse prognostic features (median survival 10.9 months versus 7.3 months for temsirolimus or interferon-alfa respectively, HR 0.73, P = 0.008 log rank, Hudes 2007). However, the chance of major remission was low and not improved with temsirolimus. 2) In patients with mostly good or intermediate prognostic risk with clear cell renal cancer, oral sunitinib improves the chance of major remission, the probability of symptomatic improvement, and freedom from disease progression (Motzer 2007); in a similar setting, the addition of biweekly intravenous bevacizumab to interferon-alfa also improved the chance of major remission and prolonged progression-free survival (Escudier 2007b); overall survival had not changed at the time of interim reporting of either study.In patients with clear cell renal cancers who had failed prior cytokine therapy, oral sorafenib gives a better quality of life than placebo as well as improved chance of being free of disease progression; overall survival may have improved but is hard to evaluate because of crossover of placebo-assigned patients after the study closed to accrual (Escudier 2007a). AUTHORS' CONCLUSIONS: Based on less than a decade of experience, some targeted agents with specified molecular targets have demonstrated clinically useful benefits over the previous standard of care for patients with advanced renal cancer. Much more research is required to fully establish the role of targeted agents in this condition.

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Br J Cancer. 2008 Apr 22;98(8):1336-41. Epub 2008 Mar 25.
Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings.
Jonasch E, Wood C, Tamboli P, Pagliaro LC, Tu SM, Kim J, Srivastava P, Perez C, Isakov L, Tannir N.
1Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374, Houston, Texas 77030, USA.

The aim of this study was to evaluate the clinical efficacy as determined by time to progression and response rate (RR) of autologous vitespen (formerly HSPPC-96; Oncophage, Antigenics Inc., New York, NY, USA) with and without interleukin-2 (IL-2; Proleukin: Chiron, Emoryville, CA, USA) in stage IV metastatic renal cell carcinoma (RCC) patients undergoing nephrectomy. Eighty-four patients were enrolled on study, and then underwent nephrectomy and harvest of tumour tissue for use in autologous vaccine manufacture. Initial treatment schedule started approximately 4 weeks after surgery and consisted of six injections: once weekly for 4 weeks, then two injections biweekly (vaccines administered at weeks 1, 2, 3, 4, 6, 8), followed by restaging at or around week 10. Patients who had stable or responsive disease continued to receive vaccine, with four more vaccinations biweekly (at weeks 10, 12, 14, 16). Patients who had progressive disease at week-10 evaluation received four consecutive 5-day-per-week courses of 11 x 10(6) U of IL-2 subcutaneously (weeks 10, 11, 12, 13), with four doses of vitespen at 2-week intervals (at weeks 10, 12, 14, 16). At the next evaluation (week 18), patients with a complete response received two further cycles of vitespen (with IL-2 if also received during prior cycle) or until vaccine supply was exhausted. Patients with stable disease or partial response repeated their prior cycle of therapy. Disease progressors who had not yet received IL-2 began IL-2 treatment, and progressors who had already received IL-2 came off study. Of 60 evaluable patients, 2 demonstrated complete response (CR), 2 showed partial response (PR), 7 showed stable disease, and 33 patients progressed. Sixteen patients had unconfirmed stable disease. Two patients who progressed on vaccine alone experienced disease stabilisation when IL-2 was added. Treatment with vitespen did not result in a discernable benefit in the majority of patients with metastatic RCC treated in this study. Use in combination with immunoregulatory agents may enhance the efficacy of vitespen.British Journal of Cancer (2008) 98, 1336-1341. doi:10.1038/sj.bjc.6604266 www.bjcancer.com Published online 25 March 2008.

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J Clin Oncol. 2008 Apr 20;26(12):2034-9. Epub 2008 Mar 17.
Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma.
Thompson JA, Curti BD, Redman BG, Bhatia S, Weber JS, Agarwala SS, Sievers EL, Hughes SD, DeVries TA, Hausman DF.
Seattle Cancer Care Alliance, 825 Eastlake Ave East, Mailstop G4-830, Seattle, WA 98109-1023, USA. jat@u.washington.edu

PURPOSE: A phase I study of patients with metastatic malignant melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of recombinant human interleukin-21 (rIL-21). PATIENTS AND METHODS: Patients who had one or fewer prior systemic treatments for metastatic MM or RCC were treated with rIL-21 administered for two 5-day cycles on days 1 through 5 and 15 through 19 of a treatment course; rIL-21 was administered by rapid intravenous infusion in an outpatient setting. Cohorts of patients received doses ranging from 3 to 100 microg/kg/dose, and an expanded cohort was treated at the MTD. Patients with stable disease (SD) or better could receive additional treatment cycles. RESULTS: Forty-three patients were treated (24 MM; 19 RCC), including 28 in the expanded cohort. Dose-limiting toxicities consisted primarily of transient grade 3 laboratory abnormalities. The MTD was estimated to be 30 microg/kg. The most common adverse events included flu-like symptoms, pruritus, and rash. Twelve patients received up to five additional two-cycle courses of treatment without cumulative toxicity, except for one patient with reversible grade 4 hepatotoxicity. Serum concentrations of rIL-21 increased in a dose-proportional manner. Dose-dependent increases in soluble CD25 reflected lymphocyte activation. Antitumor activity was observed in both MM (one complete response and 11 SD) and RCC (four partial responses, 13 SD). CONCLUSION: Outpatient therapy with rIL-21 at 30 microg/kg was well tolerated, had dose-dependent pharmacokinetics and pharmacodynamics, and was associated with antitumor activity in patients with MM and RCC.

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J Urol. 2008 Apr 16 [Epub ahead of print]
Waiting Time From Initial Urological Consultation to Nephrectomy for Renal Cell Carcinoma-Does it Affect Survival?
Stec AA, Coons BJ, Chang SS, Cookson MS, Herrell SD, Smith JA Jr, Clark PE.
Department of Urology, Vanderbilt University Medical Center, Nashville, Tennessee.

PURPOSE: We report survival and recurrence outcomes in all patients undergoing radical or partial nephrectomy for renal cell carcinoma, as related to surgical waiting time. MATERIALS AND METHODS: We retrospectively reviewed the records of 722 patients who underwent surgical resection for renal cell carcinoma. Patients were subdivided by waiting time from the initial urology visit until surgery. Surgical waiting time was evaluated as a continuous variable and by monthly subgroups. Univariate and multivariate analyses were performed to evaluate factors associated with overall, disease specific and recurrence-free survival. RESULTS: Mean time from the first visit to surgery was 1.2 months with 64.1% and 94.3% of patients undergoing surgery within 30 days and within 3 months, respectively. Overall and disease specific survival was not affected by surgical waiting time regardless of how time was analyzed. On univariate analysis 5-year recurrence-free survival was poorer in patient
s undergoing surgery within 1 month vs more than 1 month (75.7% vs 88.4%, p = 0.02). On multivariate analysis T stage (p <0.0001), grade (p = 0.009), lymph node involvement (p = 0.0001) and histology (p = 0.006) were independent predictors of recurrence-free survival, while surgical waiting time was not (p = 0.18). Surgical waiting time less than 1 month was associated with higher stage and higher grade tumors (p <0.0001 and 0.0006, respectively). CONCLUSIONS: Surgical waiting time from initial urological consultation to operative intervention does not adversely affect the outcome of renal cell carcinoma within the time frames analyzed in this study, in which 94% of cases occurred within 3 months. Individual urologist judgment remains a critical factor in the appropriate and timely care of the patient with a suspicious renal mass.

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J Urol. 2008 Apr 16 [Epub ahead of print]
Percutaneous Renal Cryoablation: Experience Treating 115 Tumors.
Atwell TD, Farrell MA, Leibovich BC, Callstrom MR, Chow GK, Blute ML, Charboneau JW.
Department of Radiology (TDA, MAF, MRC, JWC), Mayo Clinic, Rochester, Minnesota.

PURPOSE: We determined technical feasibility, safety and short-term outcomes following percutaneous renal cryoablation. MATERIALS AND METHODS: We performed a retrospective review of 115 renal tumors in 110 patients treated with percutaneous cryoablation. Specific attention was directed to tumor characteristics, hospital course, complications, technical success and treatment success based on followup imaging. RESULTS: Mean tumor size was 3.3 cm (range 1.5 to 7.3), including 29 tumors 4.0 cm or larger and 21 tumors in the anterior kidney. Of 90 renal mass biopsies performed 52 (58%) showed renal cell carcinoma. All patients were admitted to the hospital following cryoablation and most (87%) were discharged home the next day (range 1 to 12 days). There were 7 major complications associated with the 113 cryoablation procedures (6%). Technical success was achieved in 112 of the 115 (97%) treated tumors and 3 residual tumors were seen on 3 month followup imaging. In 80 tumors followed 3 months or longer (mean 13.3 months) There has been no local progression of (100% treatment success). CONCLUSIONS: Percutaneous renal cryoablation is technically feasible and relatively safe. With experience many anterior tumors and tumors larger than 4 cm can be successfully treated. Long-term followup remains necessary to prove treatment durability.

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Oncology. 2008 Apr 16;73(3-4):204-209 [Epub ahead of print]
Safety and Activity of Sorafenib in Different Histotypes of Advanced Renal Cell Carcinoma.
Procopio G, Verzoni E, Gevorgyan A, Mancin M, Pusceddu S, Catena L, Platania M, Guadalupi V, Martinetti A, Bajetta E.
Medical Oncology Unit 2, Fondazione IRCCS ‘Istituto Nazionale dei Tumori’, Milano, Italy.

Background: The aim of our study was to evaluate the efficacy and safety in unresectable or advanced renal carcinoma treated with sorafenib, in a situation closely similar to the everyday medical practice. Patients and Methods: One hundred and thirty-six patients have been treated with 400 mg b.i.d. of sorafenib administered orally until disease progression or unacceptable toxicity. They were either previously untreated or relapsed after one or more previous treatments with systemic therapy. Most of them had clear cell renal carcinoma (RCC), but other histological types such as papillary, chromophobe, Bellini ducts, sarcomatoid and mixed forms were also represented. Results: Overall disease control of 70.6% was achieved with 7.9% of partial remissions. Response was observed in the majority of patients with RCC, but also in some patients with non-clear cell RCC. Safety was acceptable, with the most common adverse events consisting of hand-foot skin reaction, cutaneous rash, diarrhoea, fatigue and hypertension. Conclusions: The results confirm previous ones reported in the literature concerning the efficacy and the safety of sorafenib as second-line treatment in patients with RCC. In addition, they disclose the hypothesis that sorafenib could be effective also in patients who underwent multiple previous treatments and in those with histology different from clear cells. Copyright (c) 2008 S. Karger AG, Basel.

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BJU Int. 2008 Apr 10 [Epub ahead of print]
Renal tumour surgery in elderly patients.
Roos FC, Pahernik S, Melchior SW, Thüroff JW.
Department of Urology, Johannes Gutenberg-University, Medical School, Mainz, Germany.

OBJECTIVE To analyse morbidity, renal function and oncological outcome in patients aged >/=80 years who had surgery for renal tumours, as in the elderly such surgery is controversial in relation to life-expectancy and other causes of death. PATIENTS AND METHODS Between 1990 and 2006, in our institution 1625 patients had surgery to treat solid renal tumours suspected to be renal cell carcinoma (RCC); 62 (4%) were aged >/=80 years (mean 82.5), and 73% of these elderly patients had radical nephrectomy (RN) and 27% nephron-sparing surgery (NSS). Results The median (range) follow-up was 3.1 (0.2-14.1) years (89% of the patients). There was no perioperative mortality. There were only minor complications in 47% of patients, most (34%) being temporary increases in serum creatinine level. Histopathologically, 10% of the 62 patients had benign lesions and 90% had RCC. Of the 56 patients with RCC, the stage was pT1a in 34%, pT1b in 25%, pT2 in 5% and pT3 in 36%. For those treated with RN the median (range) serum creatinine level before and after RN was 1.0 (0.7-1.8) and 1.4 (1.0-2.8) mg/dL (P < 0.05), and for those treated with NSS were 1.1 (0.7-4.4) and 1.2 (0.7-4.8) mg/dL (not significant), respectively. The 5-year overall survival was 68% and the cancer-specific survival was 85%. CONCLUSIONS Surgery for renal tumours is safe in elderly patients, with a low perioperative morbidity and a good overall survival rate. Patients should be selected carefully according to comorbidities, biological age and social support.

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BJU Int. 2008 Apr 2 [Epub ahead of print]
Enucleation of renal cell carcinoma with ablation of the tumour base.
Kutikov A, Vanarsdalen KN, Gershman B, Fossett LK, Guzzo TJ, Wein AJ, Malkowicz SB.
Division of Urology, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

OBJECTIVE To retrospectively assess the effectiveness of cancer control with enucleation of renal cell carcinoma (RCC), which is surgically expedient, allows preservation of maximal renal parenchyma, and makes intraoperative renal ischaemia unnecessary, by two surgeons routinely enucleating renal tumours and ablating the tumour bed with argon beam and the Nd-YAG laser. PATIENTS AND METHODS Between 1996 and 2006 at our institution, 97 patients had RCC enucleated, with ablation of the tumour base. Patients with lesions other than RCC and those with von Hippel-Lindau disease or Birt-Hogg-Dube syndrome were excluded from the study. The mean follow-up was 24.9 months. Patients were evaluated for RCC recurrence with cross-sectional imaging at least every 6 months for the first 2 years and then annually thereafter. RESULTS The mean (median, range) tumour size was 2.8 (2.5, 0.8-7.0) cm. Of the 97 patients only one had disease progression after a mean follow-up of 24.9 months. This pa
tient presented with a solitary grade 2 clear cell RCC and had a local recurrence 30 months after original surgery. CONCLUSIONS The present series and other available clinical data suggest that enucleation with cavity ablation is an oncologically sound approach that is simple, versatile and obviates the need for renal ischaemia.

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Expert Rev Anticancer Ther. 2008 Mar;8(3):481-90.
Improving outcomes in patients with advanced renal cell carcinoma.
Sosman JA.
Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, TN 37232, USA. jeff.sosman@vanderbilt.edu

The emergence of targeted therapies for advanced renal cell carcinoma has been a dramatic turning point in improving outcomes for the majority of patients with this disease. In study populations comprising primarily good- and intermediate-risk patients with clear cell renal cell carcinoma and prior nephrectomy, prolonged progression-free survival was demonstrated for three angiogenesis-targeted agents: sunitinib (compared with interferon [IFN]), bevacizumab plus IFN (vs IFN alone) and sorafenib (vs placebo in cytokine-refractory patients). As a first-line treatment for patients with multiple poor-risk factors, temsirolimus, which inhibits mTOR, has improved not only progression-free survival compared with IFN but, more importantly, overall survival. Further studies are needed to determine whether combinations and/or sequencing of these targeted agents can further improve outcomes.

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Urol Oncol. 2008 Jan-Feb;26(1):102.
Intermediate comparison of partial nephrectomy and radiofrequency ablation for clinical T1a renal tumors.
Stern JM, Svatek R, Park S, Hermann M, Lotan Y, Sagalowsky AI, Cadeddu JA, Department of Urology, University of Texas, Southwestern Medical Center, Dallas, TX.Boorjian SA, Blute ML.

OBJECTIVE: To compare the intermediate term outcomes of patients with clinical T1a renal tumors who were treated with nephron-sparing surgery by partial nephrectomy (PN), the preferred approach for small (cT1a) renal tumors, or radiofrequency ablation (RFA), recently offered to selected patients as an alternative, less morbid technique. PATIENTS AND METHODS: We identified patients with stage T1a renal masses who had >/=2 years of follow-up; those with bilateral synchronous or metachronous tumors, metastatic disease at presentation, or a family history of renal cell carcinoma were excluded. From July 1996 to January 2004, 110 PNs were identified in our database; 37 patients who fulfilled the inclusion criteria had either open (30) or laparoscopic PN (7), and 40 had either percutaneous (26) or laparoscopic (14) RFA. RESULTS: The mean (range) follow-up for the RFA and PN groups was 30 (18-42) and 47 (24-93) months, respectively; the respective mean tumor size was 2.41 and 2.43 c
m. There was 1 incomplete ablation and 2 local recurrences in the RFA group, and 2 recurrences in the PN group (1 local and 1 in the contralateral kidney). There were no disease-specific deaths. The overall actuarial disease-free probability for the PN and RFA groups, respectively, was 95.8% and 93.4% (P = 0.67). CONCLUSIONS: This initial 3-year actuarial analysis showed that RFA for cT1a renal tumors has comparable oncological outcomes to PN; however, longer term data are still needed.

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Urol Oncol. 2008 Jan-Feb;26(1):102-3.
Renal cell carcinoma clinically involving adjacent organs: Experience with aggressive surgical management.
Margulis V, Sánchez-Ortiz RF, Tamboli P, Cohen DD, Swanson DA, Wood CG, Department of Urology, University of Texas, M.D. Anderson Cancer Center, Houston, TX.Russo P.

BACKGROUND: Historically, patients with nonmetastatic renal cell carcinoma (RCC) involving adjacent organs have been considered inoperable and incurable. The oncologic efficacy of an aggressive surgical approach was evaluated in a selected subpopulation of RCC patients. Further, an attempt was made to define the clinical and pathologic characteristics predictive of surgical failure. METHODS: With Institutional Review Board approval, the institutional nephrectomy database of 3,470 patients treated at M. D. Anderson Cancer Center from 1990 to 2006 was searched for RCC patients treated with radical nephrectomy and resection of at least 1 adjacent organ thought to be directly involved by RCC. Patients with nonmetastatic RCC and a minimum follow-up of 6 months were included in the analysis. RESULTS: In all, 30 patients with clinical T4NxM0 RCC and median follow-up of 32.3 months (range, 8.5-140.1) met the study inclusion criteria and comprise the dataset for the analysis. On pathologic evaluation 60% of patients were clinically overstaged, as only 12 (40%) of 30 patients demonstrated direct invasion into adjacent organs resected. None of the clinical tumor characteristics predicted a finding of pathologic T4 RCC. Nodal involvement and pathologic T stage were significant independent predictors of disease recurrence (hazard ratio [HR] 3.726, P = 0.043, and HR 2.414, P = 0.045, respectively) and cancer-specific survival (HR 17.145, P = 0.002, and HR 3.791, P = 0.024, respectively). Disease recurred in 11 of 18 (61.1%) of <pT4 patients and in 10 of 12 (83.3%) of pT4 patients at a median 13.3 and 2.3 months, respectively; 13 (73.3%) <pT4 patients and 5 (41.7%) pT4 patients were alive at the time of analysis. CONCLUSIONS: True pathologic involvement of adjacent organs by RCC cannot be predicted from pre- or intraoperative parameters. A significant proportion of patients clinically suspected of having T4 RCC are downstaged, and benefit from aggressive surgical resection with en bloc removal of involved organs.

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Urol Oncol. 2008 Jan-Feb;26(1):101-2.
A prospective randomized EORTC intergroup Phase 3 study comparing the complications of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma.
Van Poppel H, Da Pozzo L, Albrecht W, Matveev V, Bono A, Borkowski A, Marechal JM, Klotz L, Skinner E, Keane T, Claessens I, Sylvester R, European Organization for Research and Treatment of Cancer (EORTC); National Cancer Institute of Canada Clinical Trials Group (NCIC CTG); Southwest Oncology Group (SWOG); Eastern Cooperative Oncology Group (ECOG). Department of Urology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium.Boorjian SA, Blute ML.

OBJECTIVES: This study compared the complications and the cancer control of elective nephron-sparing surgery (NSS) and radical nephrectomy (RN) in patients with a small (</=5 cm), solitary, low-stage N0 M0 tumor suspicious for renal cell carcinoma (RCC), and a normal contralateral kidney. METHODS: Five hundred forty-one patients were randomized in a prospective, multicenter, Phase 3 trial to undergo NSS (n = 268) or RN (n = 273) together with a limited lymph node dissection. RESULTS: This publication reports only on the complications reported for both surgical methods. The rate of perioperative blood loss was slightly higher after RN (96.0% vs. 87.2%) and the rate of severe hemorrhage was slightly higher after NSS (3.1% vs. 1.2%). Ten patients (4.4%), all of whom were treated with NSS, developed urinary fistulas. Pleural damage (11.5% for NSS vs. 9.3% for RN) and spleen damage (0.4% for NSS and 0.4% for RN) were observed with similar rates in both groups. Postoperative computed tomography scanning abnormalities were seen in 5.8% of NSS and 2.0% of RN patients. Reoperation for complications was necessary in 4.4% of NSS and 2.4% of RN patients. CONCLUSIONS: NSS for small, easily resectable, incidentally discovered RCC in the presence of a normal contralateral kidney can be performed safely with slightly higher complication rates than after RN. The oncologic results are eagerly awaited to confirm that NSS is an acceptable approach for small asymptomatic RCC.

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J Clin Oncol. 2008 Jan 1;26(1):127-31.
Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma.
Choueiri TK, Plantade A, Elson P, Negrier S, Ravaud A, Oudard S, Zhou M, Rini BI, Bukowski RM, Escudier B.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Toni_Choueiri@dfci.harvard.edu

PURPOSE: Sunitinib and sorafenib are novel tyrosine kinase inhibitors (TKIs) that have shown significant clinical activity in metastatic clear cell renal cell carcinoma (RCC). The activity of sunitinib and sorafenib in non-clear cell histologies has not been evaluated. PATIENTS AND METHODS: Clinical features at study entry and treatment outcomes were evaluated in patients with metastatic papillary RCC (PRCC) and chromophobe RCC (ChRCC) who received either sunitinib or sorafenib as their initial TKI treatment in five US and French institutions. Response rate and survival were documented. Fisher's exact test was used for categoric variables, and the Kaplan-Meier method was used to estimate survival. RESULTS: Fifty-three patients were included. The number of patients with papillary and chromophobe histologies was 41 (77%) and 12 (23%), respectively. Response rate, progression-free survival (PFS) time, and overall survival time for the entire cohort were 10%, 8.6 months, and 19.6
months, respectively. Three (25%) of 12 ChRCC patients achieved a response (two patients treated with sorafenib and one treated with sunitinib), and PFS was 10.6 months. Two (4.8%) of 41 PRCC patients achieved a response (both patients were treated with sunitinib). PFS for the whole cohort was 7.6 months. Sunitinib-treated PRCC patients had a PFS of 11.9 months compared with 5.1 months for sorafenib-treated patients (P < .001). CONCLUSION: Patients with PRCC and ChRCC may have prolonged PFS from sunitinib and sorafenib, although clinical responses remain overall low in PRCC. Additional prospective trials with these agents in non-clear cell RCC will further clarify their use in the future.

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Lancet. 2007 Dec 22;370(9605):2103-11. Comment in: Lancet. 2007 Dec 22;370(9605):2071-3.
Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial.
Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators.
Department of Medicine, Institut Gustave Roussy, Villejuif, France. escudier@igr.fr

BACKGROUND: Vascular endothelial growth factor (VEGF) inhibition is a valid therapeutic approach in renal cell carcinoma. Therefore, an investigation of the combination treatment of the humanised anti-VEGF monoclonal antibody bevacizumab with interferon alfa was warranted. METHODS: In a multicentre, randomised, double-blind, phase III trial, 649 patients with previously untreated metastatic renal cell carcinoma were randomised to receive interferon alfa-2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n=327) or placebo and interferon alfa-2a (n=322). The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. An interim analysis of overall survival was prespecified after 250 deaths. On the basis of new second-line therapies that became available while the trial was in progress, which could have confounded analyses of overall survival data, we agreed with regulatory agencies that the pre-planned final analysis of progression-free survival would be acceptable for regulatory submission. The protocol was amended to allow the study to be unblinded at this point. The final analysis of progression-free survival is reported here. Efficacy analyses were done by intention to treat. This trial is registered with centerwatch.com, number BO17705E. FINDINGS: 325 patients in the bevacizumab plus interferon alfa group and 316 in the placebo plus interferon alfa group received at least one dose of study treatment. At the time of unblinding, 230 progression events had occurred in the bevacizumab plus interferon alfa group and 275 in the control group; there were 114 deaths in the bevacizumab plus interferon alfa group and 137 in the control group. Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alfa group than it was in the control group (10.2 months vs 5.4 months; HR 0.63, 95% CI 0.52-0.75; p=0.0001). Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received. Deaths due to adverse events were reported in eight (2%) patients who received one or more doses of bevacizumab and seven (2%) of those who did not receive the drug. Only three deaths in the bevacizumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue (40 [12%] patients in the bevacizumab group vs 25 [8%] in the control group) and asthenia (34 [10%] vs 20 [7%]). INTERPRETATION: The combination of bevacizumab with interferon alfa as first-line treatment in patients with metastatic renal cell carcinoma results in a significant improvement in progression-free survival, compared with interferon alfa alone.

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Expert Rev Anticancer Ther. 2007 Dec;7(12):1749-61.
Current status of cytoreductive nephrectomy in metastatic renal cell carcinoma.
Harshman LC, Srinivas S.
Fellow, Medical Oncology, Stanford University School of Medicine, Division of Medical Oncology, 875 Blake Wilbur Drive, Stanford, CA 94305, USA. laurenhs@stanford.edu

The incidence of metastatic renal cell carcinoma (mRCC) continues to rise. While treatment options have increased dramatically in the last few years, few patients achieve a cure. The standard of care for mRCC in cytokine-eligible candidates is nephrectomy followed by high-dose IL-2. High-dose IL-2 can induce durable complete remissions, but only select patients can enjoy its benefits owing to toxicities. While not curative, the newer targeted therapies offer a broader patient population the chance for treatment response and prolonged survival. This review highlights the historical background of cytoreductive nephrectomy in mRCC, discusses the available treatment options and considers alternative treatment paradigms, such as the integration of the targeted agents with nephrectomy and the use of systemic therapy as medical selection for determining appropriate nephrectomy candidates.

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Urology. 2007 Nov;70(5):900-4; discussion 904.
Surgical resection provides excellent outcomes for patients with cystic clear cell renal cell carcinoma.
Webster WS, Thompson RH, Cheville JC, Lohse CM, Blute ML, Leibovich BC.
Department of Urology, Mayo Clinic, Rochester, Minnesota 55905, USA.

OBJECTIVES: Previous observations suggest that cystic clear cell renal cell carcinoma (RCC) is cured with surgical resection. However, long-term outcome data are lacking. We reviewed our experience with RCC and report on pathologic features and patient outcome associated with the cystic variant. METHODS: We identified 2431 patients treated with nephrectomy for unilateral, sporadic clear cell RCC between 1970 and 2002. A single urologic pathologist (J.C.C.) reviewed all of the microscopic slides without knowledge of patient outcome. Cystic clear cell RCC was characterized by numerous confluent cysts lined by clear cells, and containing nests of clear cells within the cyst walls. RESULTS: There were 85 (3.5%) patients with cystic RCC. Among these patients, 22 died during follow-up, although no patient died of RCC. The median follow-up for the remaining 63 patients was 5 years. The estimated cancer-specific survival rate at 5 years after surgery for patients with noncystic clear cell RCC was 70.6% compared with 100% for patients with the cystic variant (P <0.001). This difference persisted even when comparing patients with cystic RCC to the subset with noncystic RCC who had pT1, pNx/pN0, and no clinical evidence of metastases (cM0). No patient with cystic clear cell RCC had extrarenal disease at time of nephrectomy with the exception of 1 patient who had perinephric fat invasion. CONCLUSIONS: Cystic RCC is a distinct pathologic entity and should be assessed routinely during pathologic evaluation. Furthermore, we present data supporting that cystic RCC patients should expect to be cured after surgical extirpation.

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Eur Urol. 2007 Nov 20 [Epub ahead of print]
Nephron-Sparing Surgery versus Radical Nephrectomy in the Treatment of Intracapsular Renal Cell Carcinoma up to 7cm.
Antonelli A, Cozzoli A, Nicolai M, Zani D, Zanotelli T, Perucchini L, Cunico SC, Simeone C.
Department of Urology, University of Brescia, Brescia, Italy.

OBJECTIVE: To compare the oncologic outcomes of nephron-sparing surgery versus radical nephrectomy in intracapsular renal cell carcinoma (RCC) up to 7cm by reviewing surgical experience retrospectively. METHODS: Data from 1290 consecutive patients who had surgery for RCC have been stored in a dedicated database since 1983. We selected and reviewed those related to disease-free patients who had been treated for unilateral pT1a/pT1b pN0/Nx M0 carcinomas up to 7cm and later followed for a minimum of 12 mo. RESULTS: A total of 642 patients with mean follow-up of 72.9 mo were selected; 313 had been treated for tumours <4cm in diameter (176 nephron-sparing surgery, 137 nephrectomy), whereas 329 had been treated for tumours measuring >/=4cm (52 nephron-sparing surgery, 277 nephrectomy). The comparison between tumours <4cm or >/=4cm in diameter showed worse progression and disease-free survival rates for the latter, but the type of surgery (nephron-sparing or radical) seemed to have no significant impact. CONCLUSIONS: Conservative management can be cautiously suggested for RCC up to 7cm because the worsening of prognosis as diameter increases shows no statistical differences for either nephron-sparing or radical surgery. The agreement of our results with those of similar studies available in the literature may suggest designing a prospective study to compare conservative and more radical surgery in the management of RCC up to 7cm.

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Curr Treat Options Oncol. 2007 Aug 22; [Epub ahead of print]
Tyrosine Kinase Inhibitors and Anti-Angiogenic Therapies in Kidney Cancer.
Haas NB, Uzzo RG.
The Department of Medical Oncology, Fox Chase Cancer Center, Temple University School of Medicine, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.

OPINION STATEMENTS: Renal cell carcinoma (RCC) is a heterogeneous disease as reflected in its presentation and clinical course, pathological subtypes, nuclear grades and molecular biology. Emerging data indicate that renal tumors express a variety of molecular tumor markers and unique patterns of gene expression. Clinically the disease behaves quite heterogeneously, with courses ranging from indolent to highly aggressive. Surgical monotherapy or as part of a multimodal approach remains the standard of care for most cases of RCC. Radical or partial nephrectomy is associated with a 5-year cancer specific survival (CSS) of 85-97% for pT1 tumors. Unfortunately, 20% of patients have either locally advanced or node positive (N+) RCC while another 22% have metastatic RCC (mRCC) at presentation. Unlike the outcomes in early localized disease, survival rates for N+ patients are poor and patients with mRCC are rarely cured despite aggressive multimodal therapy. Classic cytotoxic chemo therapy has repeatedly been shown to have little effect and only 5-20% of patients with mRCC respond to immunologic agents such as interferon and/or interleukin. Cytoreductive nephrectomy with systemic immunotherapy is associated with few cures with median survivals of 12-24 months. Recent advances in our understanding of the molecular origins and pathways of RCC have led to the development of more effective targeted therapies. Here we review the molecular pathways that define the pertinent therapeutic targets in RCC and the clinical data for these new and promising agents.

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Nat Clin Pract Oncol. 2007 Aug;4(8):470-9.
Drug insight: advances in renal cell carcinoma and the role of targeted therapies.
Larkin JM, Chowdhury S, Gore ME.
Royal Marsden Hospital, London, UK.

In metastatic renal cell carcinoma (RCC) immunotherapy results in a small but important improvement in overall survival, but a need exists to develop more-effective systemic therapies. Recent developments in our understanding of the molecular biology of RCC have identified several pathways associated with the development of the disease. A number of strategies designed specifically to target these pathways have resulted. Initial studies have shown marked clinical benefits of so-called 'targeted therapies'. Sunitinib, sorafenib and axitinib are kinase inhibitors that inhibit the VEGF, platelet-derived growth factor and c-kit receptor tyrosine kinases. Bevacizumab is a monoclonal antibody that is directed against VEGF. Temsirolimus inhibits the mammalian target of rapamycin. These agents have all shown considerable activity with manageable toxicity in phase II and III studies in both previously treated and untreated patients. In phase III studies, sorafenib and bevacizumab have been associated with prolonged progression-free survival compared with placebo. Phase III data have shown improvements in progression-free and overall survival with sunitinib and temsirolimus, respectively, compared with interferon alfa. Additional studies are needed to determine the optimum utilization of these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit.

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Anticancer Res. 2007 Jul-Aug;27(4C):2985-8.
Efficacy of IL-2 immunotherapy in metastatic renal cell carcinoma in relation to the psychic profile as evaluated using the Rorschach test.
Messina G, Lissoni P, Bartolacelli E, Fumagalli L, Brivio F, Colombo E, Gardani GS.
Division of Radiation Oncology, San Gerardo Hospital, 20052 Monza, Milan, Italy. giusy.messina@libero.it

BACKGROUND: Despite the well-documented importance of the psycho-emotional status in modulating the anticancer immunity, at present no study has been performed to analyse the influence of the psychological condition on the efficacy of IL-2 cancer immunotherapy. Previous clinical studies have already suggested that the evidence of anxiety may negatively affect the therapeutic efficacy of IL-2 immunotherapy of cancer. Moreover, previous psycho-oncological investigations showed that the suppression of sexual pleasure and sexual identity would represent one of the most frequent psychological profiles in cancer patients. On this basis, a study was planned in an attempt to evaluate relations existing between psychological status, analysed using the Rorschach test and efficacy of IL-2 immunotherapy in the treatment of metastatic renal cell cancer patients. PATIENTS AND METHODS: The study included 30 consecutive metastatic RCC patients. IL-2 was injected s.c. at a dose of 3 million IU twice/day 5 days/week for 4 consecutive weeks, corresponding to one complete immunotherapeutic cycle, followed by a second cycle after a 21-day rest period. RESULTS: A complete response (CR) was achieved in only 1/30 (3%) patients; a partial response (PR) was obtained in 6/30 (20%) patients. The tumor response rate (CR +PR) was 7/30 (23%) patients. The performance of a psychological analysis was accepted by 24/30 (80%) patients. A normal sexual identity was present in 7/24 (29%) patients. The tumor response rate achieved in patients with sexual identity was significantly higher compared to these who had no sexual identity or who refused the psychological investigation (p<0.05 and p<0.01, respectively). In the same way, the increase in mean lymphocyte number obtained in patients with sexual identity was significantly higher compared to that found in the other two groups of patients. CONCLUSION: This study demonstrated that the psychological status prior to treatment may be associated with the clinical response to IL-2 cancer immunotherapy.

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J Endourol. 2007 Jul;21(7):709-13.
Nephron-Sparing Surgery and Percutaneous Biopsies in Renal-Cell Carcinoma: A Global Impression among Endourologists.
Kümmerlin IP, Borrego J, Wink MH, Van Dijk MM, Wijkstra H, de la Rosette JJ, Laguna MP.
Department of Urology, Academic Medical Center, University of Amsterdam, The Netherlands.

Background and Purpose: On the one hand, nephron-sparing surgery (NSS) in small renal tumors is a safe and effective alternative to radical nephrectomy. On the other hand, the role of preoperative percutaneous needle biopsies (PNB) remains controversial. The purpose of this study was to evaluate the global current use of NSS in the treatment of renal-cell carcinoma (RCC) and the use of PNB among endourologists. Materials and Methods: One thousand questionnaires were distributed during the 23rd World Congress of Endourology and SWL. Six questions regarding NSS and two questions regarding PNB were presented. Two hundred twenty-two questionnaires were returned. Results: Of the respondents, 86.6% perform NSS for small renal tumors, whereas 13.4% perform only radical nephrectomies; 7.5% will consider NSS only in patients with a solitary kidney, and 0.5% will never consider NSS. The techniques for NSS, in descending order of preference, are partial nephrectomy, enucleation, cryoablation, radiofrequency ablation, and high-intensity focused ultrasound. The mean and maximum diameter of the tumor in patients with a normal contralateral kidney for which the urologists perform NSS is 4.0 cm. For a centrally located tumor, NSS is an option for 27.2% of the respondents. Regarding PNB in patients with suspicion of RCC, 55.9% of respondents never obtain renal biopsies in the preoperative assessment and 41.8% obtain them only in rare cases. The majority (90%) prefer histologic over cytologic biopsies. Conclusions: Nephron-sparing surgery is evolving to a global worldwide standard treatment for small renal tumors. Percutaneous needle biopsy remains a highly debated procedure.

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Urology. 2007 Jul;70(1):43-6.
Laparoscopic radical nephrectomy with hilar lymph node dissection in patients with advanced renal cell carcinoma.
Simmons MN, Kaouk J, Gill IS, Fergany A.
Section of Laparoscopic and Robotic Surgery, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

OBJECTIVES: Lymph node dissection (LND) may improve accuracy of staging, decrease recurrence rates, and improve survival in patients with advanced renal cell carcinoma (RCC). Here we assess the feasibility and safety of laparoscopic LND. METHODS: Data were analyzed for patients who underwent combined laparoscopic radical nephrectomy (LRN) with LND between July 1997 and September 2006. Demographics, operative data, pathologic data, outcomes, and complications were assessed. RESULTS: In a cohort of 700 patients who underwent LRN, 14 (13 male, 1 female) underwent LND. Transperitoneal LRN was conducted in 12 patients (86%). Retroperitoneal LRN and laparoscopic partial nephrectomy were conducted in 1 patient each (7%). Lymph node dissection yielded an average of 2.7 lymph nodes. Median tumor size was 9.5 cm (range, 1.5 to 13 cm), and median node size was 2.3 cm (range, 0.8 to 11 cm). Tumor stage was T2 or higher in 9 cases (64%), and distant metastasis was present in 7 patients (50%). One elective hand-assist and one open conversion were performed. Median estimated blood loss was 250 mL (range, 100 to 2100 mL). Median length of hospital stay was 2.5 days (range, 2 to 5 days). Median operative time was 199 minutes (range, 152 to 260 minutes). There was a single grade 1 complication (7%). CONCLUSIONS: Patients with advanced or metastatic RCC may require cytoreductive nephrectomy for staging and tumor debulking before secondary therapy. Laparoscopic LND is both feasible and safe in select patients. Decreased morbidity associated with the laparoscopic approach is beneficial to patients with advanced disease.

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Proc (Bayl Univ Med Cent). 2007 Jul;20(3):244-8.
Targeted therapy for renal cell carcinoma: a new treatment paradigm.
Hutson TE.
Genitourinary Oncology Program, Department of Oncology, Baylor Charles A. Sammons Cancer Center, Dallas, Texas.

Metastatic clear cell renal cell cancer has traditionally been treated with cytokines (interferon or interleukin-2). Improved understanding of biology has engendered novel targeted therapeutic agents that have altered the natural history of this disease. The vascular endothelial growth factor and its related receptor and the mTOR signal transduction pathway have particularly been exploited. Sunitinib malate, sorafenib tosylate, temsirolimus, and bevacizumab have improved clinical outcomes in randomized trials. Other multitargeted tyrosine kinase inhibitors (lapatinib, axitinib, pazopanib) and antiangiogenic agents (VEGF Trap, lenalidomide) have also demonstrated activity in early studies. Combinations of these agents are being evaluated. The future of the therapy of renal cancer appears promising owing to the efficacy of these novel agents.

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ScientificWorldJournal. 2007 Apr 9;7:837-49.
Cytokine-based immunotherapy for advanced kidney cancer: past results and future perspectives in the era of molecularly targeted agents.
Porta C, Paglino C, Imarisio I, Bonomi L.
Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation, Pavia, Italy. c.porta@smatteo.pv.it

Until recently, immunotherapy has been the only therapeutic option available for patients with advanced kidney cancer, even though different choices were often made on the two sides of the Atlantic Ocean. The absence of alternatives made different immunotherapeutic approaches common practice, even with few adequate randomized studies that addressed key questions, such as the best treatment and schedule, and so on. The recent registration of the first two, molecularly targeted, agents Sorafenib and Sunitinib could (and will) render many therapeutic approaches, e.g., single-agent Interferon, obsolete. In this review, we shall cover the past achievements obtained so far with cytokine-based immunotherapy and discuss the present role of immunotherapy in the era of molecularly targeted agents. In particular, specific indications for immunotherapy are emerging (e.g., the use of Interleukin-2 in patients with high CAIX expression), while new trials are ongoing to test immunotherapy i
n combination with molecularly targeted agents, such as Sorafenib, Sunitinib, or Bevacizumab.

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Urology. 2007 Apr;69(4):642-5; discussion 645-6.
Superselective embolization as first step of laparoscopic partial nephrectomy.
Gallucci M, Guaglianone S, Carpanese L, Papalia R, Simone G, Forestiere E, Leonardo C.
Department of Urology, Regina Elena Cancer Institute, Rome, Italy. gallucci@ifo.it

OBJECTIVES: Laparoscopic partial nephrectomy is currently very hard to perform because of the great difficulty in obtaining renal parenchymal hemostasis during tumor excision and the consequent high risk of bleeding. The aim of this study was to propose a method to decrease the risk of bleeding, consisting of the superselective embolization of tumor vessels before performing the laparoscopic partial nephrectomy. METHODS: Fifty patients with small, solitary, enhancing, predominantly exophytic renal tumors underwent a superselective radiographically guided embolization of tumor vessels. An average of 6 hours after embolization, the patients underwent partial laparoscopic nephrectomy, with transperitoneal access and three trocars placed, under balanced general anesthesia. The mean operative time was measured, as was the mean estimated blood loss. RESULTS: The mean operative time was 90 minutes, the mean estimated blood loss was 200 mL, and the average hospital stay was 6 days. Complications were reported in only 2 patients. The final pathologic evaluation confirmed the diagnosis of renal cell carcinoma in 43 cases. The median follow-up was 11 months and, to date, the examinations have revealed no recurrences in any of the cases. CONCLUSIONS: Superselective embolization is a valid option for laparoscopic partial nephrectomy. The procedure does not require any regional vascular control or clamping, reduces the estimated blood loss, and reduces the operative time.

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Clin Orthop Relat Res. 2007 Apr 12; [Epub ahead of print]
Radiotherapy to Bone Has Utility in Multifocal Metastatic Renal Carcinoma.
Reichel LM, Pohar S, Heiner J, Buzaianu EM, Damron TA.
>From the *Department of Orthopedics and Radiation Oncology, Upstate Medical University, State University of New York, Syracuse, NY; the daggerDepartment of Orthopedics, University of Wisconsin, Madison, WI; and the double daggerDept. of Mathematics and Statistics, University of North Florida, Jacksonville, FL.

Renal cell carcinoma metastases to bone are classically considered radioresistant. We reviewed 28 patients who underwent irradiation for metastatic renal cell carcinomas to bone to test the hypothesis that irradiation of renal metastases to bone provides adequate palliation in carefully selected patients. Metastases were multifocal in all patients. All patients were followed until death. Overall, 36 index radiotherapy treatments were given as palliative initial treatment for 36 osseous metastatic sites. Twenty-five of 36 sites (69.5%) had no subsequent radiotherapy. Eight sites (22.2%) underwent repeat radiotherapy at a mean 28.9 weeks after treatment. Two (5.6%) additional sites underwent surgery at the site at an average 74 weeks later, and a pathologic fracture occurred at one (2.8%) site 3 weeks after irradiation. Overall, 33 of 36 (91.7%) sites had only radiotherapy as their source of palliation. Median times to return to pretreatment pain and functional levels, however, were 2 months and 1 month, respectively. Radiotherapy to osseous sites appears to control pain for the short term and generally prevents fractures and avoids the need for surgery in renal cell carcinoma patients with multiple bone metastases.Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

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Cancer. 2007 Apr 9; [Epub ahead of print]
Renal cell carcinoma clinically involving adjacent organs: experience with aggressive surgical management.
Margulis V, Sanchez-Ortiz RF, Tamboli P, Cohen DD, Swanson DA, Wood CG.
Department of Urology, University of Texas M. D. Anderson Cancer Center, Houston, Texas.

BACKGROUND.: Historically, patients with nonmetastatic renal cell carcinoma (RCC) involving adjacent organs have been considered inoperable and incurable. The oncologic efficacy of an aggressive surgical approach was evaluated in a selected subpopulation of RCC patients. Further, an attempt was made to define the clinical and pathologic characteristics predictive of surgical failure. METHODS.: With Institutional Review Board approval, the institutional nephrectomy database of 3470 patients treated at MD Anderson Cancer Center from 1990 to 2006 was searched for RCC patients treated with radical nephrectomy and resection of at least 1 adjacent organ thought to be directly involved by RCC. Patients with nonmetastatic RCC and a minimum follow-up of 6 months were included in the analysis. RESULTS.: In all, 30 patients with clinical T4NxM0 RCC and median follow-up of 32.3 months (range, 8.5-140.1) met the study inclusion criteria and comprise the dataset for the analysis. On pathologic evaluation 60% of patients were clinically overstaged, as only 12 (40%) of 30 patients demonstrated direct invasion into adjacent organs resected. None of the clinical tumor characteristics predicted a finding of pathologic T4 RCC. Nodal involvement and pathologic T stage were significant independent predictors of disease recurrence (hazard ratio [HR] 3.726, P = .043, and HR 2.414, P = .045, respectively) and cancer-specific survival (HR 17.145, P = .002, and HR 3.791, P = .024, respectively). Disease recurred in 11 of 18 (61.1%) of <pT4 patients and in 10 of 12 (83.3%) of pT4 patients at a median 13.3 and 2.3 months, respectively; 13 (73.3%) <pT4 patients and 5 (41.7%) pT4 patients were alive at the time of analysis. CONCLUSIONS.: True pathologic involvement of adjacent organs by RCC cannot be predicted from pre- or intraoperative parameters. A significant proportion of patients clinically suspected of having T4 RCC are downstaged, and benefit from aggressive surgical resection with en bloc removal of involved organs. Cancer 2007. (c) 2007 American Cancer Society.

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CA Cancer J Clin. 2007 Mar-Apr;57(2):112-25.
Recent progress in the management of advanced renal cell carcinoma.
Garcia JA, Rini BI.
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH.

A better understanding of the molecular biology of renal cell carcinoma (RCC) has led to a dramatic paradigm shift in the treatment of patients with metastatic disease. Historically, a nonspecific immune approach using cytokines was employed, but recently this has transitioned to a molecularly-targeted approach against vascular endothelial growth factor (VEGF) and related pathways. Several anti-VEGF agents, including ligand-binding agents such as bevacizumab and the small molecule inhibitors of VEGF and related receptors such as sunitinib and sorafenib, have demonstrated clinical activity in patients with metastatic RCC. Other agents that inhibit alternative targets such as the mammalian target of rapamycin (mTOR) have also demonstrated activity. This generation of novel molecular targeted therapies continues to show great promise. The purpose of this review is to summarize the current management and to discuss potential future directions in the management of metastatic RCC.

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Invest New Drugs. 2007 Mar 28; [Epub ahead of print]
Phase II study of Triapine(R) in patients with metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC IND.161).
Knox JJ, Hotte SJ, Kollmannsberger C, Winquist E, Fisher B, Eisenhauer EA.
Department of Medical Oncology, University Health Network-OCI/Princess Margaret Hospital, 610 University Avenue, Toronto, ON, M5G 2M9, Canada, jennifer.knox@uhn.on.ca.

Triapine(R) is a novel small molecule ribonucleotide reductase inhibitor that showed activity in renal cell carcinoma (RCC) cell lines. Evaluating new agents with novel mechanisms remains of interest for patients with incurable RCC. This was a single-arm, multicentre phase II trial where Triapine was given at a schedule of 96 mg/m(2) 2-h infusion daily x 4 repeated every 2 weeks in patients with recurrent RCC. A median of four cycles of Triapine was administered to 19 eligible patients. One response was seen (7%.) Median time to progression was 3.6 months. Common adverse events (AEs) were grade 1-2, with fatigue in 74%, nausea in 68% and vomiting in 58%. However grade 3/4 neutropenia was seen in 79% and acute reactions of hypoxia, hypotension, methemoglobinemia were seen. Dose reductions/delays due to AEs were common with only 47% of patients receiving > 90% of planned dose intensity. The study closed, at the end of stage 1 as it did not meet the minimal efficacy criteria to proceed. Further evaluation of Triapine at this dose and schedule in patients with advanced kidney cancer is not recommended.

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Urology. 2007 Mar;69(3):462-4.
Renal cell carcinoma in renal transplant patients.
Ianhez LE, Lucon M, Nahas WC, Sabbaga E, Saldanha LB, Lucon AM, Srougi M.
Department of Urology, Sao Paulo University Medical School, Sao Paulo, Sao Paulo, Brazil.

OBJECTIVES: To report our experience with renal cell carcinoma in patients with end-stage renal failure receiving dialysis at two institutions that perform a large number of transplantations. Renal cell carcinoma is more frequent in patients with end-stage renal failure treated with dialysis and in renal transplant patients than in the population at large. METHODS: We reviewed the case histories of 1375 consecutive patients who had transplanted kidneys functioning for more than 1 year. RESULTS: Eleven renal tumors were found in 10 patients (1.37%); 10 of the tumors (90%) were in the native kidney (9 unilateral and 1 bilateral) and 1 (10%) was in the transplanted kidney. The tumors in the native kidneys were discovered incidentally. Three were in organs removed for treatment of arterial hypertension and the other seven were found by ultrasonography. The tumor in the transplanted kidney was found after nephrectomy for the treatment of hematuria. The tumor types were clear cell in six, papillary in four, and chromophobe in one. Of the 9 patients who were treated with radical nephrectomy, 7 were alive with no evidence of the disease and 2 had died of other causes, also with no evidence of the disease. One patient who already had metastases at the diagnosis did not undergo surgery and died 4 months later. CONCLUSIONS: The native kidneys of renal transplant patients should be examined by ultrasonography annually because they are at greater risk of renal cell carcinoma. Radical nephrectomy cures those cases in which the tumors are clinically localized and 6 cm or less in size.

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Scand J Urol Nephrol. 2007;41(1):10-3.
Nephron-sparing surgery for renal cell carcinoma in the solitary kidney.
Berdjis N, Hakenberg OW, Novotny V, Manseck A, Oehlschlager S, Wirth MP.
Department of Urology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.

OBJECTIVE: Partial nephrectomy in solitary kidneys carries the risk of tumour progression as well as loss of renal function. We evaluated complications and outcome in patients with renal cell cancer in solitary kidneys who were treated by means of nephron-sparing surgery. MATERIAL AND METHODS: Between 1993 and 2003, 38 patients with renal cell carcinoma in a solitary kidney underwent nephron-sparing surgery (partial nephrectomy, n = 37; work-bench resection, n = 1). Of these patients, 21 had asynchronous and eight had synchronous bilateral tumours and underwent contralateral radical nephrectomy. The variables examined were tumour size, disease progression, pre- and postoperative renal function and early (within 30 days of nephron-sparing surgery) and late complications. RESULTS: After a mean follow-up period of 41.7 months (range 8-93 months) the mean serum creatinine level had increased from 1.25 mg/dl preoperatively to 1.62 mg/dl postoperatively. Seventeen patients retained normal renal function and 21 developed some degree of renal insufficiency. New-onset chronic renal insufficiency after nephron-sparing surgery with creatinine levels >2 mg/dl was the only late complication observed, occurring in 10 cases. None of the patients required dialysis. Transient urinary leakage was the most frequent early complication, occurring in four cases. Recurrence and/or progression were seen in six patients: four with local recurrence (three of whom also had distant metastases) and two with pure metastatic progression. Nephron-sparing surgery was repeated for the patient with isolated local tumour recurrence. The mean tumour size was 3.8 cm (range 0.7-9.9 cm). Tumour size was markedly greater in patients who developed disease progression (6.2 vs 3.5 cm) and in those who developed renal insufficiency (5.2 vs 3.3 cm). CONCLUSIONS: Nephron-sparing surgery for renal cell carcinoma involving a solitary kidney provides effective curative treatment for small tumours, with preservation of renal function. However, patients who undergo partial nephrectomy for locally extensive tumours are at high risk of disease progression.

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J Endourol. 2007 Jan;21(1):71-4.
Laparoscopic partial nephrectomy: experience in 60 cases.
Brown GA, Matin SF.
Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

Purpose: To identify the factors associated with better outcomes in patients undergoing laparoscopic partial nephrectomy (LPN). Patients and Methods: We retrospectively analyzed the medical records of 36 men and 24 women aged 31 to 80 years (mean 60 years) in whom LPN was attempted at our institution over a 3.5-year period. Baseline patient characteristics and operative, pathologic, and postoperative outcomes were analyzed. The median duration of follow-up was 14.2 months (range 1-38 months). Results: The median pathologic tumor size was 2.1 cm (range 0.7-6.0 cm). Final pathologic review revealed renal-cell carcinoma in 73% of patients. Six patients (10%) required conversion to either an open partial nephrectomy or a laparoscopic radical nephrectomy. Dense perinephric adipose tissue in the setting of a small renal tumor and unanticipated multifocal disease were factors associated with surgical conversion. The median overall estimated blood loss was 112 mL, and the median warm-ischemia time was 30 minutes. Blood loss was greater in patients who did not undergo hilar clamping (467 v 65 mL; P = 0.008). Conclusion: Factors influencing successful LPN outcomes include selecting a tumor commensurate with the surgeon's laparoscopic experience, performing routine hilar clamping, adjunctive use of hemostatic agents, and renal-parenchymal suture ligation. The presence of thick, fibrotic perinephric fat overlying a small tumor increases the technical difficulty.

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Clin Cancer Res. 2007 Jan 15;13(2):747s-52s.
Sorafenib in renal cell carcinoma.
Flaherty KT.
Author's Affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.

Sorafenib is an orally available inhibitor of vascular endothelial growth factor receptors, platelet-derived growth factor receptor-beta, and RAF kinases. A dose of 400 mg twice daily administered continuously was selected for phase 2 testing, although 600 mg twice daily formally met criteria for a maximum tolerated dose. It is well tolerated compared with cytokine therapy. Antitumor activity was shown clearly in the context of a randomized discontinuation phase 2 trial. In this setting, even disease stabilization was established as a treatment-related phenomenon. A phase 3 trial with sorafenib confirmed a benefit of therapy across the vast majority of patients treated with sorafenib as opposed to placebo. Limited investigations into the mechanism of action of sorafenib in renal cell carcinoma support vascular endothelial growth factor receptor antagonism as the primary mediator of effect. The toxicity profile of sorafenib allows for its use in combination regimens. The focus of efforts to improve on the efficacy of sorafenib is on use with IFN, bevacizumab, or temsirolimus. Preliminary evidence with this approach is promising and will be the subject of the next generation of randomized trials in renal cell carcinoma.

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Clin Cancer Res. 2007 Jan 15;13(2):716s-20s.
Update on the application of interleukin-2 in the treatment of renal cell carcinoma.
McDermott DF.
Author's Affiliation: Beth Israel Deaconess Medical Center and the Dana-Farber/Harvard Cancer Center Renal Cancer Program, Boston, Massachusetts.

High-dose bolus interleukin 2 (IL-2) was granted Food and Drug Administration approval based on its ability to produce durable complete responses in a small number of patients with metastatic renal cell carcinoma. Results from randomized phase 3 trials suggest that regimens involving lower doses of IL-2, either alone or in combination with IFN, produce fewer tumor regressions of less overall quality. Given the toxicity, expense, and limited efficacy of this treatment, recent studies have focused on identifying predictors of response (or resistance) to IL-2 therapy. This year, investigators launched a clinical trial designed to prospectively determine if patients who are more likely to respond to high-dose IL-2 can be identified before starting therapy. As the list of effective therapies for metastatic renal cell carcinoma grows, improvements in patient selection will be necessary to ensure that patients who might attain a durable remission with IL-2 will not miss this opportunity.

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Clin Cancer Res. 2007 Jan 15;13(2):697s-702s.
Multimodal approaches in the management of locally advanced and metastatic renal cell carcinoma: combining surgery and systemic therapies to improve patient outcome.
Wood CG.
Author's Affiliation: The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

Patients with locally advanced renal cell carcinoma are at high risk of metastatic relapse following surgery. Patients with metastatic disease have a poor prognosis and few systemic therapy options. Radiation, chemotherapy, hormonal therapy, vaccines, and immunotherapy have all been tested as adjuvant therapy without benefit. Neoadjuvant therapy in the metastatic setting holds promise as a new treatment paradigm. It can serve as a litmus test to allow proper patient selection for aggressive surgical intervention and may provide limited downstaging of primary tumors in selected cases. It can also provide a histologic assessment of the effect of targeted therapy. Application of this paradigm may have merit in the locally advanced setting as well. Effective adjuvant therapy for renal cell carcinoma remains elusive. The benefit of new targeted therapies has yet to be tested in this setting. Neoadjuvant strategies that integrate aggressive surgical intervention with systemic therapy may hold promise as a treatment paradigm.

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Clin Cancer Res. 2007 Jan 15;13(2):693s-6s.
Cytoreductive nephrectomy for metastatic renal cell carcinoma: is it still imperative in the era of targeted therapy?
Pantuck AJ, Belldegrun AS, Figlin RA.
Authors' Affiliation: Departments of Urology and Medicine, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California.

In the era before cytokine therapy, controversy existed about the need for cytoreductive nephrectomy in treating patients with metastatic renal cell carcinoma. In 1978, Dekernion showed that nephrectomy alone had no effect on survival. During this period, removal of the malignant kidney was confined to palliative therapy in some settings of metastatic RCC, such as pain related to the kidney mass, intractable hematuria, erythrocytosis, uncontrolled hypertension, or poorly controlled hypercalcemia. When interleukin-2 was approved by the Food and Drug Administration in 1992, the role of nephrectomy was reexamined. After a decade of controversy, two randomized controlled studies established that cytoreductive surgery has a role in properly selected patients and offers a survival advantage when done before cytokine therapy. Unfortunately, the mechanisms underlying this benefit remain poorly understood. Immunotherapy may work best when there is a small volume of cancer present, and removing a large primary tumor may prevent the seeding of additional metastases. Data have also suggested that primary tumors were capable of producing immunosuppressive compounds that might decrease the efficacy of immunotherapy. Another hypothesis suggested that removing the kidney altered the acid/base status of the patient to such an extent that the growth of the tumor was hindered. With the emergence in 2006 of two targeted agents for advanced renal cell carcinoma, the role of cytoreductive nephrectomy has reemerged as a source of controversy. Although evidence-based medical practice suggests a role for nephrectomy before the use of targeted agents, the arguments for and against this practice will be weighed.

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Curr Urol Rep. 2007 Jan;8(1):19-30.
Adjuvant therapy for high-risk renal cell carcinoma patients.
Kunkle DA, Haas NB, Uzzo RG.
Department of Urologic Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. R_Uzzo@FCCC.edu

For most cases of renal cell carcinoma (RCC), the standard of care is surgical resection as monotherapy or as part of a multimodal approach. In patients with early localized disease, radical nephrectomy is associated with a favorable prognosis, whereas patients with advanced disease are rarely cured. A significant number of patients undergoing surgery for localized RCC experience recurrence, suggesting that there are some individuals in whom surgical excision is necessary but insufficient. In these patients, the development of effective adjuvant strategies is imperative. In this article, we review the prognostic variables and comprehensive staging algorithms for identifying patients at high risk for disease recurrence. Additionally, we review data from completed adjuvant RCC trials and highlight relevant ongoing trials.

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Oncology (Williston Park). 2006 Dec;20(14):1745-53; discussion 1756.
Novel targets and therapies for metastatic renal cell carcinoma.
Feldman DR, Motzer RJ.
Division of Medical Oncology and Hematology, Department of Internal Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

For the past 20 years, the systemic treatment of metastatic renal cell carcinoma (RCC) has been limited primarily to cytokines, with few patients showing benefit. However, recent advances in understanding the pathobiology of RCC have led to the identification of novel therapeutic targets for this disease. Drugs specifically designed to inhibit these targets have been developed, with several showing superior efficacy over traditional cytokine therapy. Moreover, these agents are well tolerated and have improved the span of progression-free, and in some cases, overall survival. As a result, between December 2005 and January 2006, two of these targeted therapies--sunitinib (Sutent) and sorafenib (Nexavar)--were approved by the U.S. Food and Drug Administration for the treatment of advanced RCC. The authors review the clinical trials that have focused on these two drugs as well as those concentrating on two other promising agents, bevacizumab (Avastin) and temsirolimus. The ways in which these novel drugs are changing the standard of care for metastatic RCC and the future directions of RCC clinical trials are also discussed.

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Clin Genitourin Cancer. 2006 Dec;5 Suppl 1:S24-30.
Improving outcomes with novel therapies for patients with newly diagnosed renal cell carcinoma.
Speca J, Yenser S, Creel P, George D.
Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC.

With the approval of sunitinib and sorafenib, 2 new multitargeted tyrosine kinase inhibitors, for the treatment of advanced renal cell carcinoma (RCC), the natural history and prognosis of patients with this disease has significantly improved. These drugs were approved based upon clinical data demonstrating robust, unprecedented response rates in one case and dramatic prolongation of progression-free survival in the other. In both cases, these results were seen in study patients in whom standard therapy had failed and who, on average, carried substantial disease burden. Important challenges today include integrating these therapies with other standard therapeutic options and into other advanced-stage RCC patient populations. This article addresses current data and practice patterns regarding the clinical use of tyrosine kinase inhibitors in patients with advanced-stage RCC, including dose modifications and alternative dosing, the current role of debulking nephrectomy, and use in patients with indolent disease. Finally, a summary of the more common side effects and management strategies for these is also discussed. Ultimately, more clinical data is needed to address the chronic use of these agents alone, in combination with other agents, with radiation therapy, and in sequence.
  
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