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Concept: Renal cell carcinoma

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BACKGROUND: To evaluated the prognostic significance of the pre-operative C-reactive protein (CRP) serum level in patients with renal cell cancer (RCC). METHODS: We evaluated 1,161 RCC patients with complete patient and tumour specific characteristics as well as information about their pre-operative CRP-level, who had undergone either radical nephrectomy or nephron-sparing surgery at two German high-volume centres (University Hospitals of Hannover and Ulm). The mean follow-up was 54 months. RESULTS: The CRP-level, stratified to three subgroups (CRP <= 4, 4--10, and >10 mg/l), correlated significantly with tumour stage (p < 0.001), the risk of presenting nodal disease (2.1, 3.1, and 16.4%) and distant metastasis (2.9, 8.6, and 30.0%; p < 0.001). The Kaplan-Meier 5-year cancer specific survival (CSS) rates were 89.4, 77.9, and 49.5%, respectively (p < 0.001). Multivariate analysis identified CRP as an independent prognosticator for CSS as well as overall survival (p < 0.001). Patients with a CRP of 4--10 and >10 mg/l had a 1.67 and 2.48 fold higher risk of dying due to their RCC compared to those with a pre-operative CRP <=4 mg/l, respectively. CONCLUSIONS: A high preoperative serum CRP level is an independent predictor of poor survival in patients with RCC. Its routine use could allow better risk stratification and risk-adjusted follow-up of RCC patients.

Concepts: Cancer, Lung cancer, Cancer staging, C-reactive protein, Renin, Renal cell carcinoma, Nephrectomy, Kidney cancer

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OBJECTIVE: To clearly define the proportions of benign vs malignant histologic findings in resected renal masses through an in-depth review of the contemporary medical data to assist in preoperative risk assessment. MATERIALS AND METHODS: PubMed and select oncology congresses were searched for publications that identify the histologic classification of resected renal masses in a representative sample from the contemporary data: [search] incidence AND (renal cell carcinoma AND benign); incidence AND (renal tumor AND benign); percentage AND (renal cell carcinoma AND benign); limit 2003-2011. RESULTS: We identified 26 representative studies meeting the inclusion criteria and incorporating 27,272 patients. The frequency of benign tumors ranged from 7% to 33%, with most studies within a few percentage points of the mean (14.5% ± 5.2%, median 13.9%). Clear cell renal cell carcinoma occurred in 46% to 83% of patients, with a mean of 68.3% (median 61.3; SD = 11.9%). An inverse relationship between tumor size and benign pathologic features was identified in 14 of 19 (74%) studies that examined an association between tumor size and pathologic characteristics. A statistically significant correlation between clear cell renal cell carcinoma and tumor size was identified in 13 of 19 studies (63%). The accuracy of preoperative cross-sectional imaging was low in the 2 studies examining computed tomography (17%). CONCLUSION: Benign renal tumors represent ∼15% of detected surgically resected renal masses and are more prevalent among small clinical T1a lesions. Noninvasive preoperative differentiation between more and less aggressive renal masses would be an important clinical advance that could allow clinicians greater diagnostic confidence and guide patient management through improved risk stratification.

Concepts: Cancer, Oncology, Statistics, Anatomical pathology, Benign tumor, Tumor, Standard deviation, Renal cell carcinoma

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Background Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. Methods A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. Results The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%). Conclusions Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784 .).

Concepts: Clinical trial, Cancer, Clopidogrel, Odds ratio, Normal distribution, Renal cell carcinoma, Paclitaxel, Bristol-Myers Squibb

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Immunotherapy has produced durable clinical benefit in patients with metastatic renal cell cancer (RCC). In the past, patients treated with interferon-alpha (IFN) and interleukin-2 (IL-2) have achieved complete responses, many of which have lasted for multiple decades. More recently, a large number of new agents have been approved for RCC, several of which attack tumor angiogenesis by inhibiting vascular endothelial growth factors (VEGF) and VEGF receptors (VEGFR), as well as tumor metabolism, inhibiting the mammalian target of rapamycin (mTOR). Additionally, a new class of immunotherapy agents, immune checkpoint inhibitors, is emerging and will play a significant role in the treatment of patients with RCC. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a Task Force, which met to consider the current role of approved immunotherapy agents in RCC, to provide guidance to practicing clinicians by developing consensus recommendations and to set the stage for future immunotherapeutic developments in RCC.

Concepts: Immune system, Cancer, Angiogenesis, Vascular endothelial growth factor, Interferon, VEGF receptors, Renal cell carcinoma, Immunotherapy

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Background Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. Methods We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate. Results Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus. Conclusions Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747 .).

Concepts: Clinical trial, Cancer, Signal transduction, Angiogenesis, Growth factor, Vascular endothelial growth factor, Protein kinase, Renal cell carcinoma

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Background Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. Methods In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. Results The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects. Conclusions Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).

Concepts: Clinical trial, Cancer, Disease, Chemotherapy, Vascular endothelial growth factor, Normal distribution, Toxicity, Renal cell carcinoma

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Introduction The analysis of predictive factors of response may aid in predicting which patients with advanced renal cell carcinoma (RCC) would be good candidates for systemic treatments. Materials and methods The expression of several biomarkers was retrospectively analyzed using immunohistochemistry (IHC), as well as 2 analytical variables in 135 patients with advanced RCC treated with cytokines (CK) and/or new targeted drugs (NTD). Results 67 patients were treated solely with NTD and 68 with CK (23 also received NTD). Univariate analysis: HIF1α did not correlate significantly with response to these drugs. Overexpression of CAIX was associated with more responses (%) to NTD (64.7 vs. 21.1; p = 0.004) and CK (22.6 vs. 0; p = 0.038). PTEN demonstrated predictive value of response to sunitinib (70.8 vs. 34.1; p = 0.005). p21 was associated with a lower response to sunitinib (35.9 vs. 65.4; p = 0.025). Thrombocytosis was not significantly associated with response to NTD, although it was with CK (0 vs. 20; p = 0.017). Neutrophilia correlated with a lower response to NTD (29.6 vs. 57.5; p = 0.045), although not with CK. Multivariate analysis: Overexpression of CAIX was an independent predictor of significantly higher response to NTD and CK; OR = 8.773 (p < 0.001). Conclusions Our findings highlight the usefulness of CAIX in selecting patients with advanced RCC as candidates for systemic treatment. PTEN and p21 may be important in predicting response to sunitinib. Thrombocytosis and neutrophilia correlate well with response to CK and NTD, respectively.

Concepts: Scientific method, Multivariate statistics, Univariate, Renal cell carcinoma

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The historical treatment paradigm for metastatic renal cell carcinoma has focused on immunomodulatory agents, such as IFN-α and IL-2, which provide good clinical outcomes in only a subset of patients. The development of therapies that target the VEGF and mTOR pathways have significantly altered the treatment landscape for this disease, with novel inhibitors providing substantial improvements in progression-free and overall survival over previous standards of care. Despite these advances, toxicity from targeted therapy and the development of resistance results in disease progression. By contrast, vaccine-based immunotherapy represents a promising new approach for the treatment of patients with metastatic renal cell carcinoma; however, tumor-induced immunosuppression has limited the clinical efficacy of this modality until recently. Some evidence suggests that certain targeted therapies, such as sunitinib, may reduce this immunosuppression and enhance the tumor microenvironment to promote synergy with autologous dendritic cell vaccines.

Concepts: Immune system, Medicine, Cancer, Oncology, Chemotherapy, Immunology, Renal cell carcinoma, Sunitinib

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Background:Currently, sunitinib represents one of the therapeutic strongholds for renal cell carcinoma, but the criteria for treatment selection are lacking. We assessed the role of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) polymorphisms in the prediction of the clinical outcome in metastatic renal cell carcinoma (mRCC) patients.Methods:A total of 84 tumour samples from mRCC patients receiving first-line sunitinib were tested for VEGF and VEGFR single-nucleotide polymorphisms (SNPs). The SNP results were correlated with progression-free survival (PFS) and overall survival (OS).Results:Median PFS was 8.22 months, although whereas median OS was 32.13 months. The VEGF A rs833061 resulted significant in PFS (17 vs 4 months; P<0.0001) and OS (38 vs 10 months; P<0.0001). The VEGF A rs699947 was significant for PFS (18 vs 4 months; P=0.0001) and OS (37 vs 16 months; P<0.0001). The VEGF A rs2010963 was significant in PFS (18 vs 8 vs 2 months; P=0.0001) and OS (31 vs 36 vs 9 months; P=0.0045). The VEGR3 rs6877011 was significant in PFS (12 vs 4 months; P=0.0075) and OS (36 vs 17 months; P=0.0001). At multivariate analysis, rs833061, rs2010963 and rs68877011 were significant in PFS, and rs833061 and rs68877011 were independent factors in OS.Conclusions:In our analysis, patients with TT polymorphism of rs833061, CC polymorphism of rs699947, CC polymorphism of rs2010963 and CG polymorphism of rs6877011 seem to have a worse PFS and OS when receiving first-line sunitinib.

Concepts: Cancer, Angiogenesis, Vascular endothelial growth factor, Single-nucleotide polymorphism, VEGF receptors, Renal cell carcinoma, Single-base extension, Sunitinib

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PURPOSE: The Surveillance, Epidemiology, and End Results (SEER) program is an important epidemiologic research tool to study cancer. No information is available on its pathologic accuracy for renal cell carcinoma (RCC). METHODS: Central pathology review was analyzed as a part of the United States Kidney Cancer Study. Cases previously identified through the Detroit SEER registry were reviewed. The sensitivity and specificity, and positive and negative predictive values were calculated for each SEER-assigned subtype, with the central review assignments used as the reference. RESULTS: Of the 498 cases included in this study, 490 (98.5%) were confirmed to be RCC. The overall agreement for histology was 78.2% (κ = 0.55); however, individual cases were frequently reclassified. The sensitivity and specificity for SEER-assigned clear cell RCC were 79.1% and 88.1%, respectively, when based solely on the ICD-O-3 morphology code 8310 (n = 310), and 99.2% and 80.5% when 8312 (RCC not otherwise specified; n = 41) was also assumed to be clear cell. Although RCC not otherwise specified is frequently grouped with clear cell, only 78.1% had this histology. Assignments of papillary and chromophobe RCC had comparable sensitivities (73.5% and 72.4%, respectively) and specificities (97.5% and 97.6%). Positive predictive values for clear cell (excluding/including 8312), papillary, and chromophobe RCC were 95.5%/93.5%, 85.9%, and 65.6%, respectively. CONCLUSIONS: Our findings confirm that nearly all RCC cases are correctly classified in SEER. The positive predictive value was higher for clear cell RCC than for papillary or chromophobe RCC, suggesting that pathologic confirmation may be warranted for studies of non-clear cell tumors.

Concepts: Cancer, Positive predictive value, Negative predictive value, Sensitivity and specificity, Biostatistics, Renal cell carcinoma