In patients with renal-cell carcinoma at high risk for relapse after nephrectomy, the rate of disease-free survival was significantly higher among those receiving sunitinib than among those receiving ...placebo, at the cost of a higher rate of toxic events.
Each year, approximately 300,000 persons worldwide are diagnosed with renal-cell carcinoma, resulting in 129,000 deaths.
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The prognosis for patients with renal-cell carcinoma is dependent on the stage of disease and other risk factors. The 5-year survival rate is 53% for locoregional (stage III) disease and 8% for metastatic disease.
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Overall, locoregional disease is diagnosed in 16% of patients with renal-cell carcinoma,
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and up to 40% of these patients have a relapse with metastasis after nephrectomy.
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The relapse risk can be assessed with the use of two validated models, the University of California Los Angeles Integrated Staging System (UISS) . . .
In a phase 3 clinical trial involving previously treated patients with advanced renal-cell carcinoma, progression-free survival was significantly longer with the VEGF receptor inhibitor cabozantinib ...than with everolimus (7.4 months vs. 3.8 months).
Renal-cell carcinoma is the most common form of kidney cancer, with more than 330,000 cases diagnosed and more than 140,000 deaths attributed to it worldwide every year.
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Approximately one third of patients present with metastatic disease at diagnosis,
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and in about one third of treated patients with localized disease, the disease will relapse.
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Inactivation of the von Hippel–Lindau (VHL) tumor-suppressor protein characterizes clear-cell tumors, the predominant histologic subtype in patients with renal-cell carcinoma, and results in the up-regulation of vascular endothelial growth factor (VEGF) production.
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Antiangiogenic drugs that target VEGF (bevacizumab) and its receptors (sunitinib, sorafenib, pazopanib, and . . .
Tumor-associated neutrophils (TAN) have been reported in a variety of malignancies. We conducted an up-to-date meta-analysis to evaluate the prognostic role of TAN in cancer.
Pubmed, Embase and web ...of science databases were searched for studies published up to April 2013. Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated. The impact of neutrophils localization and primary antibody were also assessed.
A total of 3946 patients with various solid tumors from 20 studies were included. High density of intratumoral neutrophils were independently associated with unfavorable survival; the pooled HRs were 1.68 (95%CI: 1.36-2.07, I2 = 55.8%, p<0.001) for recurrence-free survival (RFS)/disease-free survival (DFS), 3.36 (95%CI: 2.08-5.42, I2 = 0%, p<0.001) for cancer-specific survival (CSS) and 1.66 (95%CI: 1.37-2.01, I2 = 70.5%, p<0.001) for overall survival (OS). Peritumoral and stromal neutrophils were not statistically significantly associated with survival. When grouped by primary antibody, the pooled HRs were 1.80 (95%CI: 1.47-2.22, I2 = 67.7%, p<0.001) for CD66b, and 1.44 (95%CI: 0.90-2.30, I2 = 45.9%, p = 0.125) for CD15, suggesting that CD66b positive TAN might have a better prognostic value than CD15.
High levels of intratumoral neutrophils are associated with unfavorable recurrence-free, cancer-specific and overall survival.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In a randomized trial involving patients with advanced previously treated renal-cell carcinoma, nivolumab produced higher response rates than everolimus (25% vs. 5%) and median overall survival was ...longer (by 5.4 months), to more than 2 years.
Each year, an estimated 338,000 new cases of renal-cell carcinoma are diagnosed worldwide,
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and approximately 30% of patients present with metastatic disease at the time of diagnosis.
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A number of targeted therapies have been approved for the treatment of advanced or metastatic renal-cell carcinoma. These agents include vascular endothelial growth factor (VEGF) pathway inhibitors and mammalian target of rapamycin (mTOR) inhibitors.
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Everolimus is an mTOR inhibitor that is recommended for the treatment of advanced renal-cell carcinoma after treatment with sorafenib or sunitinib has failed.
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Although everolimus and other agents have changed the therapeutic landscape for this disease, these . . .
Abstract The clinical relevance of the interaction between human cancer and neutrophils has recently begun to emerge. This review will focus on recently published articles regarding immunomonitoring ...of neutrophils in blood and tumor tissue in clinical trials comprising the main human tumor types, with a strong emphasis on independent prognostic relevance assessed by multivariate analyses. The prognostic role of tumor-infiltrating neutrophils, elevated blood neutrophils and elevated blood neutrophil/lymphocyte ratio has been associated with poor clinical outcome in several human cancers, most notably in renal cell carcinoma, melanoma, colorectal cancer, hepatocellular carcinoma, cholangiocarcinoma, glioblastoma, GIST, gastric, esophageal, lung, ovarian and head and neck cancer. A striking finding is the notion that high baseline neutrophil count in either tumor or blood, or both, was identified as strong, independent risk factor for poor outcome in multivariate analyses, and the negative prognostic impact of neutrophils was not eliminated by increasing the dose of cytokines, chemotherapy, or targeted therapy. For several cancers, patients benefit most from therapy if baseline neutrophil was low. Thus, baseline neutrophils over-ride nadir counts in prognostic significance. In summary, a proportion of patients who do not experience benefit from surgery or medical intervention may be associated with a worst prognosis because they are characterized by baseline tumor-related neutrophilia protecting them from benefit from therapy. Further research to unraveling the cancer biology and new treatment options is encouraged.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the ...mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. Methods In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov , number NCT01865747. Findings Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1–21·1) in the cabozantinib group and 18·8 months (16·0–21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7–not estimable) with cabozantinib and 16·5 months (14·7–18·8) with everolimus (hazard ratio HR 0·66 95% CI 0·53–0·83; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 95% CI 0·41–0·62; p<0·0001) and objective response (17% 13–22 with cabozantinib vs 3% 2–6 with everolimus; p<0·0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 15% in the cabozantinib group vs 12 4% in the everolimus group), diarrhoea (43 13% vs 7 2%), fatigue (36 11% vs 24 7%), palmar-plantar erythrodysaesthesia syndrome (27 8% vs 3 1%), anaemia (19 6% vs 53 17%), hyperglycaemia (3 1% vs 16 5%), and hypomagnesaemia (16 5% vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). Interpretation Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. Funding Exelixis Inc.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We have previously demonstrated a significant negative impact of intratumoral neutrophils in metastatic renal cell carcinoma. This study assessed intratumoral neutrophils in localized clear cell ...renal cell carcinoma (RCC).
The study comprised 121 consecutive patients who had a nephrectomy for localized RCC. Biomarkers (intratumoral CD8+, CD57+ immune cells, CD66b+ neutrophils, and carbonic anhydrase IX CA IX) were assessed by immunohistochemistry, and the relationship with clinical and histopathologic features and patient outcome was evaluated.
The intratumoral neutrophils ranged from zero to 289 cells/mm(2) tumor tissue. The presence of intratumoral neutrophils was statistically significantly associated with increasing tumor size, low hemoglobin, high creatinine, and CA IX < or = 85%. In multivariate analysis, the presence of intratumoral neutrophils (hazard ratio HR, 3.0; 95% CI, 1.7 to 5.4; P < .0001), pT stage T3b/T4 (HR, 2.1; 95% CI, 1.2 to 3.6; P = .007), and low hemoglobin (HR, 1.8; 95% CI, 1.0 to 3.1; P = .03) were independent prognostic factors significantly associated with short recurrence-free survival. The presence of intratumoral neutrophils was also an independent prognostic factor for cancer-specific survival (HR, 3.5; 95% CI, 1.9 to 6.4; P < .0001) and overall survival (HR, 3.1; 95% CI, 1.9 to 5.0; P < .0001). Applying the prognostic value of intratumoral neutrophils to the Leibovich low-/intermediate-risk group (n = 78) showed a 5-year recurrence-free survival of 53% (95% CI, 34.6% to 71.8%; presence of intratumoral neutrophils) versus 87% (95% CI, 77.8% to 96.8%; absence of intratumoral neutrophils). The estimated concordance index was 0.74 using the Leibovich risk score and 0.80 when intratumoral neutrophils were added.
The presence of intratumoral neutrophils is a new, strong, independent prognostic factor for short recurrence-free, cancer-specific, and overall survival in localized clear cell RCC.
Abstract Background The randomized, phase 3 CheckMate 025 study of nivolumab ( n = 410) versus everolimus ( n = 411) in previously treated adults (75% male; 88% white) with advanced renal cell ...carcinoma (aRCC) demonstrated significantly improved overall survival (OS) and objective response rate (ORR). Objective To investigate which baseline factors were associated with OS and ORR benefit with nivolumab versus everolimus. Design, setting, and participants Subgroup OS analyses were performed using Kaplan-Meier methodology. Hazard ratios were estimated using the Cox proportional hazards model. Intervention Nivolumab 3 mg/kg every 2 wk or everolimus 10 mg once daily. Results and limitations The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age <65 and ≥65 yr; one and two or more sites of metastases; bone, liver, and lung metastases; number of prior therapies; duration of prior therapy; and prior sunitinib, pazopanib, or interleukin-2 therapy. The benefit with nivolumab versus everolimus was noteworthy for patients with poor MSKCC risk (hazard ratio 0.48, 95% confidence interval 0.32–0.70). The mortality rate at 12 mo for all subgroups was lower with nivolumab compared with everolimus. ORR also favored nivolumab. The incidence of grade 3 or 4 treatment-related adverse events across subgroups was lower with nivolumab. Limitations include the post hoc analysis and differing sample sizes between groups. Conclusion The trend for OS and ORR benefit with nivolumab for multiple subgroups, without notable safety concerns, may help to guide treatment decisions, and further supports nivolumab as the standard of care in previously treated patients with aRCC. Patient summary We investigated the impact of demographic and pretreatment features on survival benefit and tumor response with nivolumab versus everolimus in advanced renal cell carcinoma (aRCC). Survival benefit and response were observed for multiple subgroups, supporting the use of nivolumab as a new standard of care across a broad range of patients with previously treated aRCC. The trial is registered on ClinicalTrials.gov as NCT01668784.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
PurposeTo report updated analyses of the phase III CheckMate 214 trial with extended minimum follow-up assessing long-term outcomes with first-line nivolumab plus ipilimumab (NIVO+IPI) versus (vs) ...sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC).MethodsPatients with aRCC with a clear cell component were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk and randomised to NIVO (3 mg/kg) plus IPI (1 mg/kg) every three weeks ×4 doses, followed by NIVO (3 mg/kg) every two weeks; or SUN (50 mg) once per day ×4 weeks (6-week cycle). Efficacy endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) per independent radiology review committee in patients with intermediate/poor-risk disease (I/P; primary), intent-to-treat patients (ITT; secondary) and in patients with favourable-risk disease (FAV; exploratory).ResultsOverall, 1096 patients were randomised (ITT: NIVO+IPI, n=550, SUN, n=546; I/P: NIVO+IPI, n=425, SUN, n=422; FAV: NIVO+IPI, n=125, SUN, n=124). After 4 years minimum follow-up, OS (HR; 95% CI) remained superior with NIVO+IPI vs SUN in ITT (0.69; 0.59 to 0.81) and I/P patients (0.65; 0.54 to 0.78). Four-year PFS probabilities were 31.0% vs 17.3% (ITT) and 32.7% vs 12.3% (I/P), with NIVO+IPI vs SUN. ORR remained higher with NIVO+IPI vs SUN in ITT (39.1% vs 32.4%) and I/P (41.9% vs 26.8%) patients. In FAV patients, the HRs (95% CI) for OS and PFS were 0.93 (0.62 to 1.40) and 1.84 (1.29 to 2.62); ORR was lower with NIVO+IPI vs SUN. However, more patients in all risk groups achieved complete responses with NIVO+IPI: ITT (10.7% vs 2.6%), I/P (10.4% vs 1.4%) and FAV (12.0% vs 6.5%). Probability (95% CI) of response ≥4 years was higher with NIVO+IPI vs SUN (ITT, 59% (0.51 to 0.66) vs 30% (0.21 to 0.39); I/P, 59% (0.50 to 0.67) vs 24% (0.14 to 0.36); and FAV, 60% (0.41 to 0.75) vs 38% (0.22 to 0.54)) regardless of risk category. Safety remained favourable with NIVO+IPI vs SUN.ConclusionAfter long-term follow-up, NIVO+IPI continues to demonstrate durable efficacy benefits vs SUN, with manageable safety.Trial registration detailsClinicalTrials.gov identifier: NCT02231749.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background The International Metastatic Renal-Cell Carcinoma Database Consortium model offers prognostic information for patients with metastatic renal-cell carcinoma. We tested the accuracy ...of the model in an external population and compared it with other prognostic models. Methods We included patients with metastatic renal-cell carcinoma who were treated with first-line VEGF-targeted treatment at 13 international cancer centres and who were registered in the Consortium's database but had not contributed to the initial development of the Consortium Database model. The primary endpoint was overall survival. We compared the Database Consortium model with the Cleveland Clinic Foundation (CCF) model, the International Kidney Cancer Working Group (IKCWG) model, the French model, and the Memorial Sloan-Kettering Cancer Center (MSKCC) model by concordance indices and other measures of model fit. Findings Overall, 1028 patients were included in this study, of whom 849 had complete data to assess the Database Consortium model. Median overall survival was 18·8 months (95% 17·6–21·4). The predefined Database Consortium risk factors (anaemia, thrombocytosis, neutrophilia, hypercalcaemia, Karnofsky performance status <80%, and <1 year from diagnosis to treatment) were independent predictors of poor overall survival in the external validation set (hazard ratios ranged between 1·27 and 2·08, concordance index 0·71, 95% CI 0·68–0·73). When patients were segregated into three risk categories, median overall survival was 43·2 months (95% CI 31·4–50·1) in the favourable risk group (no risk factors; 157 patients), 22·5 months (18·7–25·1) in the intermediate risk group (one to two risk factors; 440 patients), and 7·8 months (6·5–9·7) in the poor risk group (three or more risk factors; 252 patients; p<0·0001; concordance index 0·664, 95% CI 0·639–0·689). 672 patients had complete data to test all five models. The concordance index of the CCF model was 0·662 (95% CI 0·636–0·687), of the French model 0·640 (0·614–0·665), of the IKCWG model 0·668 (0·645–0·692), and of the MSKCC model 0·657 (0·632–0·682). The reported versus predicted number of deaths at 2 years was most similar in the Database Consortium model compared with the other models. Interpretation The Database Consortium model is now externally validated and can be applied to stratify patients by risk in clinical trials and to counsel patients about prognosis. Funding None.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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