Lauren C. Harshman

External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study

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 Consortiums 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.

The Frequency and Severity of Cardiovascular Toxicity From Targeted Therapy in Advanced Renal Cell Carcinoma Patients

OBJECTIVES The purpose of this study was to document the incidence and extent of cardiovascular toxicity among advanced renal cell carcinoma patients treated with newer targeted cancer agents. BACKGROUND The potential for targeted cancer agents to induce cardiovascular toxicity has been increasingly recognized, but the overall incidence and extent of toxicity have not been well characterized. Early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality. METHODS The incidence of hypertension, left ventricular dysfunction, and heart failure was assessed for all advanced renal cell carcinoma patients treated with targeted therapies at our institution between 2004 and 2011. Grading was performed according to the Common Terminology Criteria for Adverse Events version 4.0. RESULTS Cardiovascular toxicity developed in 116 of 159 patients (73%), including 52 of 159 patients (33%) when hypertension was excluded. Toxicity varied from occurrences of asymptomatic drops in left ventricular ejection fraction to rises in N-terminal-pro-B-type natriuretic peptide to severe heart failure. The tyrosine kinase inhibitor sunitinib was the agent most frequently used, with 66 of 101 sunitinib-treated patients (65%) developing a form of cardiovascular toxicity, including 32 of 101 patients (32%), excluding hypertension. Other VEGF inhibitors such as bevacizumab, sorafenib, and pazopanib also elicited significant cardiovascular toxicity with incidences ranging from 51% to 68%. CONCLUSIONS The frequency and severity of cardiovascular toxicity in advanced renal cell carcinoma patients treated with targeted cancer therapies are high.

Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a population-based study

BACKGROUND The advent of targeted therapies in the past 7 years has extended median survival for metastatic renal-cell carcinoma. This improvement in clinical outcome has created a need for new, more accurate prognostic measures. We assessed the use of conditional survival--a measure that accounts for elapsed time since treatment initiation--for prognostication in patients with metastatic renal-cell carcinoma treated with first-line VEGF-targeted therapies. METHODS We obtained data for patients with metastatic renal-cell carcinoma who were treated with a first-line VEGF-targeted therapy between April 7, 2003, and Oct 12, 2010, from our large multi-institutional International mRCC Database Consortium (centres in Canada, the USA, Singapore, Denmark, and South Korea). All histologies, performance statuses, and prognostic risk groups were included. The primary outcome was 2-year conditional survival, defined as the probability of surviving an additional 2 years from a given timepoint since the start of targeted therapy. Secondary analyses included 1-year and 3-year conditional survival, along with stratification of patients by Heng prognostic risk criteria and Karnofsky performance score, and conditional survival based on length of time on therapy. We used the Kaplan-Meier method and a landmark analysis to calculate conditional survival. FINDINGS In the 1673 patients analysed, median follow-up for alive patients was 20·1 months (IQR 9·0-34·4). We recorded an increase in the 2-year conditional survival probability from 44% (95% CI 41-47) at 0 months to 51% (46-55) at 18 months since beginning targeted therapy. When stratified by the Heng prognostic risk criteria defined at therapy initiation, 2-year conditional survival changed little in the favourable and intermediate groups, but in the poor-risk group, 2-year conditional survival improved from 11% (8-15) at 0 months to 33% (18-48) after 18 months. When conditioned on time on targeted therapy from 0 months to 18 months, 2-year conditional survival improved from 44% (41-47) to 68% (60-75) in the overall population and from 74% (68-79) to 90% (77-96) in the favourable group, 49% (45-53) to 57% (45-67) in the intermediate group, and 11% (8-15) to 73% (43-89) in the poor risk group. INTERPRETATION Conditional survival is a clinically useful prediction measure that adjusts prognosis of patients with metastatic renal-cell carcinoma on the basis of survival since treatment initiation or therapy duration. Conditional survival might be especially relevant to adjust prognosis for poor-risk patients. FUNDING The Trust Family Fund for Kidney Cancer Research.

Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle‐invasive bladder cancer

Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle‐invasive bladder cancer despite the lack of Level I evidence in this setting.

Cost-Effectiveness Analysis of Nephron Sparing Options for the Management of Small Renal Masses

PURPOSE A recent increase in the detection of contrast enhancing renal masses 4 cm or smaller suspicious for malignancy has led to the widespread use of nephron sparing options. Limited data exist to help clinicians decide which of these competing nephron sparing therapies is most appropriate. We performed a cost-effectiveness analysis to evaluate the relative clinical and economic merits of commonly available nephron sparing strategies for small renal masses. MATERIALS AND METHODS We developed a decision analytic Markov model estimating the costs and health outcomes of treating a healthy 65-year-old patient with an asymptomatic unilateral small renal mass using competing nephron sparing options of immediate intervention (ie open and laparoscopic partial nephrectomy as well as laparoscopic and percutaneous ablation), active surveillance with possible delayed intervention and nonsurgical management with observation. Benefits were measured in quality adjusted life-years. We used a societal perspective, lifetime horizon and willingness to pay threshold of

First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC.

50,000 per quality adjusted life-year gained. Model results were assessed with sensitivity analyses. RESULTS In the base case scenario the least costly option was observation and the optimal option was immediate laparoscopic partial nephrectomy, which had an incremental cost-effectiveness ratio of

Surgical outcomes and complications associated with presurgical tyrosine kinase inhibition for advanced renal cell carcinoma (RCC)

36,645 per quality adjusted life-year gained compared to surveillance with possible delayed percutaneous ablation. Results were sensitive to age at diagnosis, health status and tumor size. CONCLUSIONS Immediate laparoscopic partial nephrectomy is the preferred nephron sparing option for healthy patients younger than 74 years old with a small renal mass. Surveillance with possible delayed percutaneous ablation is a cost-effective alternative for patients with advanced age or significant comorbidities. Observation maximizes quality adjusted life-years in patients who are poor surgical candidates or with limited life expectancy (less than 3 years).

Elevated IL-8, TNF-α, and MCP-1 in men with metastatic prostate cancer starting androgen-deprivation therapy (ADT) are associated with shorter time to castration-resistance and overall survival.

Background:Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design.Methods:Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria.Results:In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months.Conclusions:Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.

Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma.

BACKGROUND Tyrosine kinase inhibitors (TKI) have dramatically changed the management paradigm of advanced renal cell carcinoma (RCC) and are increasingly being used preoperatively to achieve cytoreduction. OBJECTIVE To review our case series of post-TKI surgical procedures to add to the current perioperative efficacy and complication profile. MATERIALS AND METHODS Between October 2006 and February 2010, 14 cytoreductive nephrectomies, radical nephrectomies, and metastectomies were performed after neoadjuvant sunitinib or sorafenib for advanced RCC. During the same time frame, a control group of 73 consecutive patients underwent radical nephrectomy, cytoreductive nephrectomy, or metastectomy in the absence of prior systemic therapy. We compared the incidence of perioperative complications and outcomes after surgical procedures between the two cohorts. RESULTS Median preoperative renal mass size was 11 cm (6.7-24.2 cm). Primary tumor shrinkage was seen in 57%; median shrinkage was 18% (8%-25%). The median treatment period was 17 weeks, and the median time from TKI discontinuation was 2 weeks. Compared with a control group and after adjusting for confounding covariates, presurgical TKI use was not associated with a significant increase in perioperative complications (50% vs. 40%, P = 0.25) or perioperative bleeding (36% vs. 34%, P = 0.97) but was associated with increased incidence and grade of intraoperative adhesions (86% vs. 58%, P = 0.001; grade 3 vs. 1, P = 0.002). CONCLUSIONS Compared with the published reports, we observed less hemorrhagic and wound healing issues but a significant increase in incidence and severity of intraoperative adhesions, which can present a formidable technical challenge. Potential reasons for our lower complication rate could be increased time from TKI discontinuation to surgery, longer time to postoperative TKI re-initiation, increased use of preoperative angioembolization, and the lack of preoperative bevacizumab administration. Presurgical TKI therapy can permit effective surgical cytoreduction with a safety and complication profile equivalent to that of non-TKI-nephrectomy; however safety data continue to evolve, and preoperative TKI use requires further prospective investigation.

Laparoscopic radical nephrectomy after shrinkage of a caval tumor thrombus with sunitinib

Chemokines and cytokines have been implicated in progression to castration‐resistant prostate cancer (CRPC).