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Localized renal cell carcinoma (RCC) has an associated risk of recurrence after nephrectomy. Several clinical risk models attempt to predict oncologic outcomes based on clinical and pathologic features. In addition, novel gene signatures have been developed to refine risk prediction based on tumor biology. Systemic therapies targeting angiogenic pathways that are effective in metastatic RCC failed to show an improvement in overall survival in the adjuvant setting. Immune checkpoint inhibitors have shown significant antitumor activity with prolonged and durable responses in metastatic RCC, which led to an interest in evaluating these agents in the adjuvant setting. In this review, clinical risk-predictive models, novel gene signatures, major clinical trials completed in the adjuvant setting, ongoing immune checkpoint inhibitor trials, and the perspective of adjuvant treatment in RCC are discussed.

BACKGROUND To the authors' knowledge, outcomes and prognostic tools have yet to be clearly defined in patients with metastatic renal cell carcinoma (mRCC) who are treated with immuno-oncology (IO) checkpoint inhibitors (programmed death-ligand 1 [PD-L1] inhibitors). In the current study, the authors aimed to establish IO efficacy benchmarks in patients with mRCC and update patient outcomes in each International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic class. METHODS A retrospective analysis was performed using the IMDC database with data from 38 centers. It included patients with mRCC who were treated with ≥1 line of IO. Overall response rates (ORRs), duration of treatment (DOT), and overall survival (OS) were calculated. Patients were stratified using IMDC prognostic factors. RESULTS A total of 687 patients (90% with clear cell and 10% with non-clear cell) were included. The ORR was 27% in evaluable patients (461 patients). In patients treated with first-line nivolumab and ipilimumab (49 patients), the combination of PD-L1 inhibitor and vascular endothelial growth factor inhibitor (72 patients), and PD-L1 inhibitor (51 patients), the ORR was 31%, 39%, and 40%, respectively, and the median DOT was 8.3 months, 14.7 months, and 8.3 months, respectively. The ORR for second-line, third-line, and fourth-line nivolumab was 22%, 24%, and 26%, respectively. The median DOT was 5.7 months, 6.2 months, and 8.3 months, respectively, in the second-line, third-line, and fourth-line settings. When segregated into IMDC favorable-risk, intermediate-risk, and poor-risk groups, the median OS rates for the first-line, second-line, third-line, and fourth-line treatment settings were not reached (NR), NR, and NR, respectively (P = .163); NR, 26.7 months, and 7.4 months, respectively (P

To the authors' knowledge, outcomes and prognostic tools have yet to be clearly defined in patients with metastatic renal cell carcinoma (mRCC) who are treated with immuno-oncology (IO) checkpoint inhibitors (programmed death-ligand 1 [PD-L1] inhibitors). In the current study, the authors aimed to establish IO efficacy benchmarks in patients with mRCC and update patient outcomes in each International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic class.A retrospective analysis was performed using the IMDC database with data from 38 centers. It included patients with mRCC who were treated with ≥1 line of IO. Overall response rates (ORRs), duration of treatment (DOT), and overall survival (OS) were calculated. Patients were stratified using IMDC prognostic factors.A total of 687 patients (90% with clear cell and 10% with non-clear cell) were included. The ORR was 27% in evaluable patients (461 patients). In patients treated with first-line nivolumab and ipilimumab (49 patients), the combination of PD-L1 inhibitor and vascular endothelial growth factor inhibitor (72 patients), and PD-L1 inhibitor (51 patients), the ORR was 31%, 39%, and 40%, respectively, and the median DOT was 8.3 months, 14.7 months, and 8.3 months, respectively. The ORR for second-line, third-line, and fourth-line nivolumab was 22%, 24%, and 26%, respectively. The median DOT was 5.7 months, 6.2 months, and 8.3 months, respectively, in the second-line, third-line, and fourth-line settings. When segregated into IMDC favorable-risk, intermediate-risk, and poor-risk groups, the median OS rates for the first-line, second-line, third-line, and fourth-line treatment settings were not reached (NR), NR, and NR, respectively (P = .163); NR, 26.7 months, and 7.4 months, respectively (P 0. 0001); 36.1 months, 28.2 months, and 11.1 months, respectively (P = .016); and NR, NR, and 6.7 months, respectively (P = .047).The ORR was not found to deteriorate from the first-line to the fourth-line of IO therapy. In the second line through fourth line, the IMDC criteria appropriately stratified patients into favorable-risk, intermediate-risk, and poor-risk groups for OS.

Purpose To investigate the dependence between PFS and OS in mRCC patients and to explore whether PFS can be used as an intermediate endpoint of OS in this patient population.

Background This study aims to apply the International mRCC Database Consortium (IMDC) Prognostic Model in metastatic non clear cell renal cell carcinoma (nccRCC). Additionally, the survival outcome of metastatic nccRCC patients was characterized.

BACKGROUND. The objective of this study was to evaluate the effect of pericyte coverage (PC) of differentiated tumor microvessels on the prognosis of patients with clear cell renal cell carcinoma (CCRCC). METHODS. Samples from 2 cohorts of patients with CCRCC (101 Asian patients and 524 US patients) were prepared using 2 different histologic approaches: routine sectioning versus tissue microarray. Then, the samples were immunohistochemically doubled-stained for a pericyte marker (alpha smooth muscle actin [α-SMA]) and a differentiated vessel marker (cluster of differentiation 34 [CD34]), followed by multispectral image capturing and computerized image analyses to quantify the microvessel density (MVD) and the PC of differentiated vessels. The correlations of PC and the MVD:PC ratio with clinicopathologic characteristics were analyzed. RESULTS. There was an inverse correlation between differentiated MVD and PC. Higher PC correlated with more aggressive clinicopathologic characteristics of CCRCC in both cohorts, including more advanced T-classification, higher pathologic grades, and the occurrence of tumor necrosis. The MVD:PC ratio was an independent favorable prognostic factor for overall and recurrence-free survival in the Asian cohort and for recurrence-free survival in the US cohort. PC also was an independent prognostic factor, with higher PC predicting a poorer outcome. The combination of PC and MVD was better at distinguishing the outcome of patients with CCRCC. PC combined with differentiated MVD or with the MVD:PC ratio provided additional, independent prognostic information to the Leibovich risk model, and that information was used to generate improved risk models. CONCLUSIONS. The authors consistently observed that higher PC was correlated with more aggressive clinicopathologic characteristics. PC was an independent unfavorable prognostic factor. The authors concluded that pericytes should be considered for therapeutic targeting. Cancer 2013. © 2012 American Cancer Society.

Upregulation of proangiogenic factors in response to inactivation of the von Hippel-Lindau (VHL) gene is a critical component in the development and progression of clear cell renal cell carcinoma (RCC).1 Several inhibitors of the vascular endothelial growth factor (VEGF) signaling pathway have been shown to improve outcomes in patients with metastatic RCC (mRCC).1 However, because almost all patients ultimately develop resistance to therapy, combination treatment strategies that may result in more complete angiogenesis inhibition are of interest.2 The angiopoietin-1/angiopoietin-2 and Tie2 (tyrosine kinase with immunoglobulin-like and EGF-like domains 2) receptor axis may be a legitimate target for inhibiting angiogenesis in mRCC. Preclinical studies have demonstrated that its components are regulated by VHL and are dysregulated in RCC cell lines.3 Plasma angiopoietin-2 concentrations are significantly elevated in patients with mRCC (compared with localized disease or healthy controls), and increase at the time of disease progression.4 Concurrent blockade of the angiopoietin and VEGF pathways augments inhibition of angiogenesis and tumor growth in tumor xenograft models.5 Hence, combinations of angiopoietin/Tie2 inhibitors and VEGF inhibitors might induce clinically meaningful activity. AMG 386 is an investigational recombinant peptide-Fc fusion protein that neutralizes the receptor-ligand interaction between Tie2 and angiopoietin-1/2.5 In Colo205 xenograft models, simultaneous antagonism of angiopoietin-1/2 with AMG 386 suppressed tumor growth more effectively than did selective inhibition of angiopoietin-1 or angiopoietin-2 alone.5 Interim results of a phase 1b study suggested that treatment of patients who have mRCC with sorafenib or sunitinib plus AMG 386 had an acceptable toxicity profile, distinct from that of VEGF inhibitors, and may have antitumor activity.6 We evaluated in a phase 2 study the tolerability and anti-tumor activity of AMG 386 plus sorafenib in previously untreated patients who have clear cell mRCC.

BACKGROUND: The current treatment of metastatic renal cell carcinoma (mRCC) with vascular endothelial growth factor (VEGF)-targeted agents is continuous therapy until progression of disease (PD) or unacceptable toxicity. Chronic mild to moderate toxicity and risk of long-term toxicity ensue for some patients. It is hypothesized that patients with an initial response to treatment can maintain disease control off all therapy for a period of time. METHODS: A retrospective study of patients with mRCC who initiated VEGF-targeted therapy between January 2004 and December 2009 at The Cleveland Clinic Foundation, Cleveland, Ohio, or Institut Gustave-Roussy, Villejuif, France, was conducted. Patients had achieved RECIST (Response Evaluation Criteria in Solid Tumors)-defined stable disease or better on therapy, and were then taken off all therapy for reasons not including disease progression. Patient, disease, and therapy characteristics were recorded. The primary objective was progression-free survival (PFS), measured as the time from discontinuation of therapy to RECIST-defined PD. RESULTS: Forty patients were identified. After a median follow-up of 29.7 months (range, 4.2 to 84.7 months), 25 patients (63%) had PD off therapy (median PFS, 10.0 months; range, 1.4-27.2 months). Among these patients, 8 (32%) had progression in sites that were not previously involved with disease. Heng risk group (hazard ratio, 2.49; 95% confidence interval, 1.19-5.22; P = .011) and achievement of a complete response prior to discontinuing therapy (hazard ratio, 0.20; 95% confidence interval, 0.04-0.86; P = .025) were independent predictors of PFS in a multivariable Cox proportional hazards model. CONCLUSIONS: A select subset of mRCC patients achieving stable disease or better on VEGF-targeted therapy can be observed off all therapy. Further prospective investigation is warranted. Cancer 2011. © 2011 American Cancer Society.

Although the long natural history of prostate cancer presents challenges in the development of novel therapeutics, major contributions have been observed recently. A better understanding of the long-term complications of androgen deprivation has changed the initial approach to most patients with advanced disease. Specifically, recognition of the limitations of prostate-specific antigen has driven the pursuit of new tools capable of becoming true surrogates for disease outcome. Understanding the molecular biology of castration-resistant prostate cancer (CRPC) has led to a dramatic paradigm shift in the treatment of patients with metastatic disease where the androgen receptor becomes a central therapeutic target. Specific adrenal inhibitors and engineered super androgen receptor inhibitors have become the most promising agents in the disease. Novel immune therapies have been shown to improve survival in selected patients with castration-resistant disease despite the inability to impact traditional markers of response. Similarly, agents such as cabazitaxel and abiraterone acetate have demonstrated clinical benefit are now a standard of care in docetaxel-refractory metastatic CRPC patients. All these changes have occurred in a relatively short period and are likely to change the prostate cancer treatment paradigm. This review summarizes the current management of CRPC and discusses potential future directions.

BACKGROUND: A study was undertaken to investigate the effect of baseline renal function on treatment outcome in patients treated with vascular endothelial growth factor (VEGF)-targeted therapy for metastatic renal cell carcinoma (mRCC). METHODS: Retrospective data from 6 North American cancer centers (3 US and 3 Canadian) were pooled to identify patients with mRCC treated with VEGF-targeted therapy. Patient characteristics, response rate, time to treatment failure, and overall survival were collected. The Modification of Diet in Renal Disease formula was used at therapy initiation for calculation of glomerular filtration rate (GFR). RESULTS: Five hundred twenty-nine patients with mRCC who received sunitinib (n = 323), sorafenib (n = 165), or bevacizumab (n = 41) were included in this analysis. Patient characteristics included: 74% male, median age 61 years, and median GFR 60.1 mL/min/1.73 m2 (range, 6.5-174.2). On univariate analysis, patients with a GFR

BACKGROUND: Bevacizumab and sunitinib are standard initial therapy in metastatic renal cell carcinoma (mRCC). Despite common use, the safety and activity of sorafenib in bevacizumab- or sunitinib-refractory mRCC have not been prospectively investigated. METHODS: Metastatic RCC patients with Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease progression (PD) after treatment with either bevacizumab or sunitinib received twice daily 400 mg of sorafenib in a multicenter, prospective phase 2 study. Dose escalation was permitted in the absence of significant toxicity. The primary endpoint was tumor burden reduction rate, defined as the proportion of patients with ≥5% reduction in the sum of RECIST-defined target lesions without other PD. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival, and safety. A 2-stage accrual design was used to test the alternative hypothesis that the tumor burden reduction rate was >20% versus

BACKGROUND. The majority of metastatic renal cell carcinoma (mRCC) clinical trials that examined targeted agents used progression-free survival (PFS) as the primary endpoint. Whether PFS can be used as a predictor of overall survival (OS) is unknown. METHODS. Patients from 12 cancer centers who received targeted therapy for mRCC were identified. Landmark analyses for progression at 3 months and 6 months after drug initiation were performed to minimize lead-time bias. A proportional hazards model was used to assess the utility of PFS for predicting OS. RESULTS. In total, 1158 patients were included. The median follow-up was 30.6 months, the median age was 60 years, and the median Karnofsky performance status was 80%. For the entire cohort, the median PFS was 7.6 months, and the median OS was 19.7 months. In the landmark analysis, the median OS for patients who progressed at 3 months was 7.8 months compared with 23.6 months for patients who did not progress (log-rank test; P < .0001). Similarly, for patients who progressed at 6 months, the median OS was 8.6 months compared with 26 months for patients who did not progress (P < .0001). Compared with those who did not progress, for the patients who progressed at 3 months and at 6 months, the hazard ratios for death adjusted for adverse prognostic factors were 3.05 (95% confidence interval, 2.42-3.84) and 2.96 (95% confidence interval, 2.39-3.67), respectively. Similar results were demonstrated with landmark analyses at 9 months and at 12 months and in the bootstrap validation. Kendall tau rank correlation and a Fleischer model demonstrated a statistically significant dependent correlation. CONCLUSIONS. PFS at 3 months and at 6 months predicted OS, and the current results indicated that PFS may be a meaningful intermediate endpoint for OS in patients with mRCC who receive treatment with novel agents. Cancer 2011;. © 2010 American Cancer Society.

BACKGROUND: On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP-675206; an antibody against cytotoxic T-lymphocyte–associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated. METHODS: Adult patients with mRCC who had received ≤1 previous systemic treatment received tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to assess antitumor activity, safety, and pharmacokinetics. RESULTS: Twenty-eight patients were enrolled. Two of 5 patients who received 50 mg sunitinib plus tremelimumab 6 mg/kg experienced dose-limiting toxicities (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of 7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib experienced DLTs. An expansion cohort (n = 7) was enrolled at tremelimumab 10 mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs. Overall, rapid-onset renal failure was the most common DLT. Nine of 21 patients who were evaluable for response achieved partial responses (43%; 95% confidence interval, 22%-66%), and 4 of those responses were ongoing at the time of the current report. CONCLUSIONS: In this study of tremelimumab plus sunitinib, rapid-onset acute renal failure was observed unexpectedly, and further investigation of tremelimumab doses >6 mg/kg plus sunitinib 37.5 mg daily is not recommended. Preclinical investigation may be warranted to understand the mechanism of renal toxicity. Cancer 2011. © 2010 American Cancer Society.

Inactivation of the von Hippel-Lindau tumor suppressor gene in most sporadic renal cell carcinoma (RCC) tumors leads to a fundamental reliance on elements of this pathway, namely, the potent proangiogenic factor, vascular endothelial growth factor (VEGF). Thus, VEGF-targeted therapeutics have undergone extensive clinical testing in RCC. Approaches to bind circulating VEGF protein (eg, bevacizumab) and small molecule inhibitors of the receptor on which the VEGF ligand binds (eg, sunitinib, sorafenib, axitinib, and pazopanib) have been tested. Robust clinical effects have been observed, including high objective response rates, prolonged progression-free survival, and evidence of long overall survival for patients with metastatic RCC patients who are treated with these agents. Future directions include investigation of combination and sequenced therapy, elucidation of mechanisms of response and resistance, and exploration of the effect of these agents in other disease settings.

The Third Cambridge Conference on Innovations and Challenges in Renal Cancer, a symposium held in Cambridge, Massachusetts, June 27-28, 2008, and chaired by Michael B. Atkins, was convened to discuss the current state of knowledge in the field, critique new data, stimulate communication among those involved in basic and clinical research, and offer recommendations for further study. Four main topics were discussed: genetics and molecular biology of renal cell cancer, staging and prognosis, systemic therapy, and correlative science and biomarkers in stage IV disease. The conference format combined brief presentations with extended periods of discussion. The conclusions and recommendations are summarized in this paper and presented in more detail in the individual papers that follow.

BACKGROUND Cyclooxygenase-2 (COX-2) plays a major role in the development of cancer through numerous mechanisms. COX-2 is expressed in the majority of renal cell carcinoma (RCC) tumors and correlates with stage, grade, and microvessel density. Based on potential additive or synergistic antitumor effects, interferon-alpha (IFNα) and celecoxib, an oral COX-2 inhibitor, were given to metastatic RCC patients in a Phase II trial. METHODS Patients with untreated, metastatic RCC received IFNα 3 million units (MU) daily and celecoxib 400 mg orally (p.o.) twice daily continuously until disease progression or unacceptable toxicity. Pretreatment, paraffin-embedded RCC tumor samples were immunohistochemically stained for COX-2 expression and plasma basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) levels were assayed to determine predictive or prognostic potential. RESULTS There were three partial responses among 25 patients treated (objective response rate, 12%; 95% confidence interval [CI], 3–31%). The observed median time to disease progression (TTP) for the entire cohort was 3.3 months. A significant association between maximal COX-2 staining and clinical response was observed: all patients who experienced an objective response demonstrated 3+ COX-2 tumor immunostaining (trend test: P = 0.03). Therapy was well tolerated without cardiac or other notable toxicity. CONCLUSIONS The addition of celecoxib to IFNα did not increase the objective response rate or TTP of this unselected cohort. Maximal COX-2 tumor immunostaining may identify RCC patents more likely to achieve clinical benefit with COX-2 inhibition in combination with IFNα. Further investigation of this combination in 3+ COX-2-overexpressing RCC tumors is warranted. Cancer 2006. © 2005 American Cancer Society.

BACKGROUND The objective of this study was to verify previous reports of activity with gemcitabine plus a fluoropyrimidine in patients with metastatic renal cell cancer in a multiinstitutional setting. METHODS Eligibility included a Zubrod performance status from 0 to 2, no prior gemcitabine or fluoropyrimidine therapy, and normal organ function. Patients received gemcitabine at a dose of 1000 mg/m2 on Days 1, 8, and 15 and capecitabine at a dose of 830 mg/m2 twice daily on Days 1 through 21 on a 28-day cycle with specified dose reductions for baseline renal insufficiency. The primary endpoint was the response rate, which was assessed every 8 weeks. The statistical plan tested the hypothesis that the response rate was 5% versus an alternative of 15%. RESULTS Sixty patients were enrolled, and 4 of those patients never started treatment. Of the 56 evaluable patients, 79% of patients underwent prior nephrectomy, 75% of patients received prior systemic therapy, and 75% of patients had clear cell histology. Risk stratification revealed that 34%, 43%, and 16% of patients were in Risk Groups 1, 2, and 3, respectively. Toxicity (graded according to the National Cancer Institute's Common Toxicity Criteria [version 2.0]) included Grade 3 or 4 neutropenia in 45% of patients, Grade 2 or greater fatigue in 32% of patients, Grade 2 or greater nausea in 29% of patients, Grade 2 or greater hand-foot reaction in 39% of patients, and Grade 2 or greater diarrhea in 22% of patients. Six patients responded (11%; 95% confidence interval, 4–22%), and the overall median survival was 14.5 months. CONCLUSIONS Gemcitabine plus capecitabine had modest activity in patients with metastatic renal cancer, although the degree of activity and its associated toxicity would not support further evaluation in a Phase III trial of unselected patients. More focused investigations to identify patients most likely to benefit or to enhance activity with additional agents would be reasonable. Cancer 2006. © 2006 American Cancer Society.

BACKGROUND APC8015 (sipuleucel-T) is a cellular prostate cancer vaccine containing autologous antigen-presenting cells (APC) loaded with PA2024, a recombinant prostatic acid phosphatase/granulocyte-macrophage–colony-stimulating factor fusion protein, as the immunogen. Bevacizumab is a recombinant antibody against vascular endothelial growth factor, a proangiogenic protein with inhibitory effects on APC. A clinical trial was conducted to determine the prostate-specific antigen (PSA) and immunomodulatory effects of this combination immunotherapy. METHODS Patients with androgen-dependent prostate cancer who had received prior definitive therapy with nonmetastatic, recurrent disease as manifested by a rising PSA of between 0.4 ng/mL and 6.0 ng/mL were enrolled. APC8015 was given intravenously(i.v.) on Weeks 0, 2, and 4. Bevacizumab was given at a dose of 10 mg/kg i.v. on Weeks 0, 2, 4, and every 2 weeks thereafter until toxicity or disease progression. PSA changes were recorded and the PSA doubling time (PSADT) was calculated. Immune response versus PA2024 was measured at baseline and after treatment by T-cell proliferation and interferon-γ enzyme-linked immunospot (ELISPOT) assays. RESULTS Twenty-two patients were treated. One patient achieved a ≥50% decrease in PSA. Nine patients exhibited some decrease in PSA from baseline, ranging from 6% to 72%, with the PSA of 3 patients decreasing at least 25%. The median pretreatment PSADT for the 20 evaluable patients was 6.9 months and the median posttreatment PSADT was 12.7 months (P = .01). All patients demonstrated induction of an immune response against PA2024. CONCLUSIONS The combination of APC8015 and bevacizumab induces an immune response and modulates PSA in patients with biochemically recurrent prostate cancer. Cancer 2006. © 2006 American Cancer Society.

BACKGROUND Metastatic renal cell carcinoma (RCC) has modest response rates to chemotherapy with gemcitabine and 5-fluorouracil (5-FU). Fixed dose rate gemcitabine infusion leads to enhanced intracellular accumulation of drug and possible augmented clinical effect. To determine the toxicity of this combination therapy in metastatic RCC, a Phase I trial was conducted. METHODS Patients with metastatic RCC were enrolled in a Phase I dose escalation trial. Patients received fixed dose rate gemcitabine on Days 1, 8, and 15 in combination with capecitabine, an oral 5-FU analog, given on Days 1–21 of a 28-day cycle. RESULTS Nine patients were enrolled at one of two dose levels. The initial dose level produced dose-limiting toxicity (DLT), including prominent palmar-plantar erythrodysesthesia (hand-foot syndrome). A modified second dose level also resulted in DLT, precluding further study. No central nervous system (CNS) toxicity was observed in three patients with CNS metastases. Two patients demonstrated an objective partial response. CONCLUSIONS Fixed dose rate gemcitabine in combination with capecitabine produced unacceptable toxicity in patients with advanced RCC. Further development of this schedule in RCC cannot be recommended. Cancer 2005. © 2004 American Cancer Society.

This study aimed to apply the International mRCC Database Consortium (IMDC) prognostic model in metastatic non-clear cell renal cell carcinoma (nccRCC). In addition, the survival outcome of metastatic nccRCC patients was characterized.Data on 2215 patients (1963 with clear-cell RCC [ccRCC] and 252 with nccRCC) treated with first-line VEGF- and mTOR-targeted therapies were collected from the IMDC. Time to treatment failure (TTF) and overall survival (OS) were compared in groups with favorable, intermediate, and poor prognoses according to IMDC prognostic criteriaThe median OS of the entire cohort was 20.9 months. nccRCC patients were younger (P .0001) and more often presented with low hemoglobin (P = .014) and elevated neutrophils (P = .0001), but otherwise had clinicopathological features similar to those of ccRCC patients. OS (12.8 vs 22.3 months; P .0001) and TTF (4.2 vs 7.8 months; P .0001) were worse in nccRCC patients compared with ccRCC patients. The hazard ratio for death and TTF when adjusted for the prognostic factors was 1.41 (95% CI, 1.19-1.67; P .0001) and 1.54 (95% CI, 1.33-1.79; P .0001), respectively. The IMDC prognostic model reliably discriminated 3 risk groups to predict OS and TTF in nccRCC; the median OS of the favorable, intermediate, and poor prognosis groups was 31.4, 16.1, and 5.1 months, respectively (P .0001), and the median TTF was 9.6, 4.9, and 2.1 months, respectively (P .0001).Although targeted agents have significantly improved the outcome of patients with nccRCC, for the majority survival is still inferior compared with patients with ccRCC. The IMDC prognostic model reliably predicts OS and TTF in nccRCC and ccRCC patients.

Although the long natural history of prostate cancer presents challenges in the development of novel therapeutics, major contributions have been observed recently. A better understanding of the long-term complications of androgen deprivation has changed the initial approach to most patients with advanced disease. Specifically, recognition of the limitations of prostate-specific antigen has driven the pursuit of new tools capable of becoming true surrogates for disease outcome. Understanding the molecular biology of castration-resistant prostate cancer (CRPC) has led to a dramatic paradigm shift in the treatment of patients with metastatic disease where the androgen receptor becomes a central therapeutic target. Specific adrenal inhibitors and engineered super androgen receptor inhibitors have become the most promising agents in the disease. Novel immune therapies have been shown to improve survival in selected patients with castration-resistant disease despite the inability to impact traditional markers of response. Similarly, agents such as cabazitaxel and abiraterone acetate have demonstrated clinical benefit are now a standard of care in docetaxel-refractory metastatic CRPC patients. All these changes have occurred in a relatively short period and are likely to change the prostate cancer treatment paradigm. This review summarizes the current management of CRPC and discusses potential future directions.

A study was undertaken to investigate the effect of baseline renal function on treatment outcome in patients treated with vascular endothelial growth factor (VEGF)-targeted therapy for metastatic renal cell carcinoma (mRCC).Retrospective data from 6 North American cancer centers (3 US and 3 Canadian) were pooled to identify patients with mRCC treated with VEGF-targeted therapy. Patient characteristics, response rate, time to treatment failure, and overall survival were collected. The Modification of Diet in Renal Disease formula was used at therapy initiation for calculation of glomerular filtration rate (GFR).Five hundred twenty-nine patients with mRCC who received sunitinib (n = 323), sorafenib (n = 165), or bevacizumab (n = 41) were included in this analysis. Patient characteristics included: 74% male, median age 61 years, and median GFR 60.1 mL/min/1.73 m(2) (range, 6.5-174.2). On univariate analysis, patients with a GFR60 (n = 262) were more likely to have had a previous nephrectomy (P.0001) and to be older (P.0001), but were less likely to have poor prognostic features such as anemia (P = .041), hypercalcemia (P = .008), neutrophilia (P = .039), thrombocytosis (P.0001), short diagnosis to treatment interval (P = .007), and low Karnofsky performance status (P = .051). GFR60, when adjusted for poor risk factors, did not have an impact on type of objective response (odds ratio, 1.31; 95% confidence interval [CI], 0.74-2.32; P = .359), time to treatment failure (hazard ratio [HR], 0.97; 95% CI, 0.79-1.19; P = .772), or overall survival (HR, 0.90; 95% CI, 0.69-1.17; P = .439).Renal function at therapy initiation does not adversely affect the efficacy of VEGF-targeted therapy in mRCC. Clinicians should not avoid treating patients with impaired baseline renal function.

An important goal of noncurative therapy for metastatic renal cell carcinoma (mRCC) is tumor burden (TB) control. However, to the authors' knowledge, the impact of TB characteristics on clinical outcome has not been studied in patients with mRCC who were treated with vascular endothelial growth factor-targeted therapy.Patients with clear cell mRCC who were treated with sunitinib between June 2004 and October 2007 were retrospectively identified. Computed tomography scans were re-reviewed from baseline, at the time of maximal TB shrinkage (TS) while receiving sunitinib, and at the time of progressive disease (PD). Measurements were recorded as per Response Evaluation Criteria In Solid Tumors (RECIST).A total of 69 patients were identified. The majority (54%) were classified as being of favorable risk using Cleveland Clinic Foundation Tyrosine Kinase Inhibitor (CCF TKI) risk group criteria. All patients underwent prior nephrectomy and 77% received prior systemic therapy. There were a median of 8 metastatic deposits across all organs (range, 1-27 deposits). The median TB at the initiation of therapy was 14.0 cm (range, 3.0 cm-42.2 cm). On multivariable analysis, baseline characteristics of disease confined to above the diaphragm (P = .03) and a total TB13 cm (P = .09) were found to be independent positive predictors of progression-free survival. A+ baseline, total number of metastases10 (P.001) and TB above the diaphragm6.5 cm (P = .05) were found to be independent positive predictors of overall survival (OS). Increased TS while receiving sunitinib was found to be significantly associated with OS (P.001). At the time of PD, tumor location and pattern of disease progression were not found to be associated with survival as measured from the date of PD. However, total TB (P = .003) and total number of metastatic deposits (≤12 vs12; P.001) were found to be significant predictors of survival after PD.The results of the current study indicate that TB characteristics are associated with clinical outcome in patients with mRCC who are treated with sunitinib.

BACKGROUND: Sunitinib was a standard initial therapy in metastatic renal cell carcinoma (mRCC). Given the fact that many patients progressed through many available therapies and antitumor activity had been demonstrated with sequential vascular endothelial growth factor-targeting approaches, a retrospective review was performed of the experience of rechallenge with sunitinib in sunitinib-refractory mRCC. METHODS: mRCC patients who received sunitinib therapy after disease progression on prior sunitinib and other therapy were retrospectively identified. Patient characteristics, toxicity, clinical outcome, Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate, and progression-free survival (PFS) were recorded. RESULTS: Twenty-three mRCC patients who were rechallenged with sunitinib were identified. Upon rechallenge, 5 patients (22%) achieved an objective partial response. The median PFS with initial treatment was 13.7 months and 7.2 months with rechallenge. Patients with >6-month interval between sunitinib treatments had a longer PFS with rechallenge than patients who started the rechallenge within 6 months (median PFS, 16.5 vs 6.0 months; P = .03). There was no significant difference in outcome to sunitinib rechallenge based on number or mechanism of intervening treatments. Substantial new toxicity or significantly increased severity of prior toxicity was not seen during rechallenge in this cohort. CONCLUSIONS: Sunitinib rechallenge had potential benefits and was tolerated in select metastatic RCC patients. Additional prospective investigation was warranted. Cancer 2010. © 2010 American Cancer Society.

BACKGROUND: Sunitinib has replaced interferon (IFN) as a first-line standard of care in the treatment of metastatic renal cell carcinoma (RCC). This study aimed to determine overall survival and to confirm effectiveness in a population that includes poor prognosis patients. METHODS: Data were collected on all patients identified by the BC Cancer Registry with metastatic RCC who were treated with IFN or sunitinib. The IFN group consisted of patients who received IFN between January 2000 and October 2005, and the sunitinib group included patients treated with first-line sunitinib from October 2005 to September 2007. RESULTS: There were 131 and 69 patients in the IFN and sunitinib groups, respectively. The median follow-up of those still alive was 12.6 months. The median age (62 vs 63 years; P = .41), Memorial Sloan Kettering Cancer Center (MSKCC) prognostic criteria (poor in 19% vs 30%; P = .41), and proportion with >1 metastasis (53% vs 62%; P = .21) were similar between the IFN and sunitinib groups, respectively. The median survival of the IFN and sunitinib groups was 8.7 and 17.3 months, respectively (log-rank P = .004). The median survival of patients with favorable, intermediate, and poor MSKCC prognostic profiles in the IFN group was 22.9, 8.7, and 4.1 months, respectively (P < .001), whereas in the sunitinib group it was not reached, 16.8, and 10.7 months, respectively (P = .006). The hazard ratio of death after adjusting for MSKCC criteria was 0.49 (95% confidence interval, 0.31-0.76; P = .001). CONCLUSIONS: The introduction of first-line sunitinib was associated with a doubling of overall survival compared with patients treated with IFN alone. This benefit extended to patients with poor MSKCC prognostic profiles. Cancer 2009. © 2009 American Cancer Society.

BACKGROUND. Caveolin-1 is a major component of membrane caveolae, which are specialized lipid raft microdomains on cell membrane that are implicated in molecular transport, cell adhesion, and signal transduction. The overexpression of caveolin-1 recently was associated with a poor outcome in patients with clear-cell renal cell carcinoma (CCRCC) and was proposed as a useful diagnostic marker. In the current study, the authors used immunohistochemistry to investigate the membranous and cytoplasmic expression of caveolin-1 and its correlation with other pathologic parameters in different subtypes of renal neoplasms. METHODS. A tissue microarray (TMA) was constructed from 60 normal kidneys, 22 CCRCCs, 20 papillary renal cell carcinomas (PRCCs), 16 chromophobe renal cell carcinomas (ChRCCs), and 19 oncocytomas (ONCs). The TMA was immunostained for caveolin-1 protein. Both membranous and cytoplasmic caveolin-1 expression levels were measured and were correlated with tumor size, Fuhrman nuclear grade, and pathologic stage. RESULTS. Caveolin-1 was expressed normally in distal convoluted tubules, collecting ducts, parietal cells of Bowman capsule, smooth muscle, and vascular endothelial cells. Membranous caveolin-1 expression was detected in 19 of 22 CCRCCs (86.4%), which was significantly higher than the membranous caveolin-1 expression detected in PRCCs (1 of 20 tumors; 5%), ChRCCs (0 of 16 tumors; 0%), and ONCs (1 of 19 tumors; 5.3%). Cytoplasmic caveolin-1 expression was detected in 16 of 22 CCRCCs (72.7%), in 13 of 20 PRCCs (65%), in 8 of 16 ChRCCs, (50%), and in 13 of 19 ONCs (68.4%). The percentage of tumors that expressed cytoplasmic caveolin-1 did not differ significantly among the different types of renal tumors (P = .1). Only membranous caveolin-1 expression was correlated with tumor size (Pearson correlation = 0.266; P = .043). There was no correlation between membranous or cytoplasmic caveolin-1 expression and other pathologic parameters, including Fuhrman nuclear grade and staging according to the American Joint Committee on Cancer tumor, lymph node, metastasis classification system. CONCLUSIONS. Caveolin-1 expression has 2 distinctive patterns in renal neoplasms: membranous and cytoplasmic. In the current study, membranous caveolin-1 expression was detected predominantly in CCRCCs and only rarely in other subtypes of renal neoplasms. Thus, the current results indicated that caveolin-1 expression may have potential both as a diagnostic marker in the differential diagnosis of renal tumors and as a therapeutic target, especially for CCRCC. Cancer 2007. © 2007 American Cancer Society.

BACKGROUND. Therapy targeted against the vascular endothelial growth factor (VEGF) pathway is a standard of care for patients with metastatic renal cell carcinoma (RCC). The identification of patients who are more likely to benefit from these agents is warranted. METHODS. In total, 120 patients with metastatic clear-cell RCC received bevacizumab, sorafenib, sunitinib, or axitinib on 1 of 9 prospective clinical trials at the Cleveland Clinic. Clinical features associated with outcome were identified by univariate analysis; then, a stepwise modeling approach based on Cox proportional hazards regression was used to identify independent prognostic factors and to form a model for progression-free survival (PFS). A bootstrap algorithm was used to provide internal validation. RESULTS. The overall median PFS was 13.8 months, and the objective response according to the Response Criteria in Solid Tumors was 34%. Multivariate analysis identified time from diagnosis to current treatment \2 years; baseline platelet and neutrophil counts [300 K/lL and [4.5 K/lL, respectively; baseline corrected serum calcium \8.5 mg/dL or [10 mg/dL; and initial Eastern Cooperative Oncology Group performance status [0 as independent, adverse prognostic factors (PF) for PFS. Three prognostic subgroups were formed based on the number of adverse prognostic factors present. The median PFS in patients with 0 or 1 adverse prognostic factor was 20.1 months compared with 13 months in patients with 2 adverse prognostic factors and 3.9 months in patients with [2 adverse prognostic factors. CONCLUSIONS. Five independent prognostic factors for predicting PFS were identified and were used to categorize patients with metastatic RCC who received VEGF-targeted therapies into 3 risk groups. These prognostic factors can be incorporated into patient care and clinical trials that use such novel, VEGF-targeted agents. Cancer 2007;110:543–50. � 2007 American Cancer Society.

BACKGROUND. Lenalidomide (LEN) is a structural and functional analogue of thalidomide that has demonstrated enhanced immunomodulatory properties and a more favorable toxicity profile. A Phase II, open-label study of LEN in patients with metastatic renal cell carcinoma (RCC) was conducted to determine its safety and clinical activity. METHODS. Patients with metastatic RCC received LEN orally at a dose of 25 mg daily for the first 21 days of a 28-day cycle. The primary endpoint was the objective response rate. Time to treatment failure, safety, and survival were secondary endpoints. RESULTS. In total, 28 patients participated in the trial and were included in the current analysis. Three of 28 patients (11%) demonstrated partial responses and continued to be progression-free for >15 months. Eleven patients (39%) had stable disease that lasted >3 months, including 8 patients who had tumor shrinkage. In total, 6 patients (21%) remained on the trial, and 5 additional patients continued to be followed for survival. The median follow-up for those 11 patients was 13.5 months (range, 8.3–17.0 months). The median survival had not been reached at the time of the current report. Serious adverse events included fatigue (11%), skin toxicity (11%), and neutropenia (36%). CONCLUSIONS. LEN demonstrated an antitumor effect in metastatic RCC, as evidenced by durable partial responses. LEN toxicities were manageable. Further studies will be required to assess the overall activity of LEN in patients with metastatic RCC. Cancer 2006. © 2006 American Cancer Society.

BACKGROUND Renal cell carcinoma (RCC) is characterized by von Hippel-Lindau gene inactivation and vascular endothelial growth factor (VEGF) overproduction. The mechanism of VEGF overproduction may involve protein kinase C (PKC) delta and zeta isoforms. UCN-01 (7-hydroxystaurosporine) is a selective inhibitor of PKC. Given the historically low objective response rate in RCC, time to disease progression (TTP) as an alternative endpoint was employed to evaluate the antitumor activity of UCN-01 in RCC. METHODS Patients with progressive, metastatic RCC received UCN-01 intravenously on Day 1 of each 21-day cycle. The initial dose was 90 mg/m2 and all subsequent doses were 45 mg/m2 unless modified for toxicity. TTP was the primary endpoint, defined as the period from the first day of treatment until disease progression. Detection of circulating EpCAM-positive renal carcinoma cells was undertaken for predictive or prognostic potential. RESULTS Twenty-one patients were enrolled in this Phase II study. Accrual was halted after failure to reach a predetermined efficacy requirement with 7 patients remaining disease progression free after 4 months (6 cycles). The median TTP for all patients was 2.67 months (range, 0.4–7.6 months). There were no objective responses. Therapy was generally well tolerated. Thirteen patients had < 0.6 EpCAM-positive cells/mL (considered negative) at all time points measured. Two patients had detectable EpCAM-positive cells at a single time point with other measurements being negative. CONCLUSIONS TTP is a novel endpoint for the evaluation of agents in RCC. UCN-01 did not demonstrate significant antitumor activity. No evidence for significant circulating EpCAM-positive cells was found in this study cohort. Cancer 2004. © 2004 American Cancer Society.