E. Jason Abel

Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy

The benefits of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) should outweigh surgical morbidity. Even when the generally agreed upon selection criteria for CN are met, some patients do poorly after surgery. The objective of this study was to identify preoperative factors that were prognostic of outcome in patients who were being considered for CN.

The Impact of Targeted Molecular Therapies on the Level of Renal Cell Carcinoma Vena Caval Tumor Thrombus

BACKGROUND Targeted molecular therapies (TMTs) previously have demonstrated oncologic activity in renal cell carcinoma (RCC) by reducing the size of primary tumors and metastases. OBJECTIVE To assess the cytoreductive effect of TMTs on inferior vena cava tumor thrombi. DESIGN, SETTING, AND PARTICIPANTS A multi-institutional database of patients treated with TMTs for RCC was reviewed. The subset with in situ level II or higher caval thrombi (above renal vein) was assessed for radiographic response in thrombus size and level. Pre- and posttreatment characteristics of this population were assessed for predictors of response in height, diameter, and level of the tumor thrombi. MEASUREMENTS The main outcome measured was a change in the clinical level of tumor thrombus following TMT. We also measured radiographic responses in thrombus size and location before and after TMT. RESULTS AND LIMITATIONS Twenty-five patients met the inclusion criteria. Before TMT, thrombus level was II in 18 patients (72%), III in 5 patients (20%), and IV in 2 patients (8%). The first-line therapy was sunitinib in 12 cases; alternative TMTs were administered in 13. The median duration of therapy was two cycles (range: one to six cycles). Following TMT, 7 patients (28%) had a measurable increase in thrombus height, 7 (28%) had no change, and 11 (44%) had a decrease. One patient (4%) had an increase in thrombus-level classification, 21 (84%) had stable thrombi, and in 3 (12%) the thrombus level decreased. There was only one case (4%) where the surgical approach was potentially affected by tumor thrombus regression (level IV to III). No statistically significant predictors of tumor thrombus response to TMTs were found. Limitations include the descriptive and retrospective study design. Because TMTs were initiated according to physician and/or patient preferences, and not all patients were treated in anticipation of surgery, no conclusions could be drawn regarding selection and duration of therapy. Thus it may not be appropriate to extrapolate our experience to all patients with locally advanced RCC. Although this is the largest reported experience with in situ caval tumor thrombi treated with TMT, this series lacks sufficient statistical power to assess the usefulness of TMTs adequately in tumor thrombus cytoreduction. CONCLUSIONS TMT had a minimal clinical effect on RCC tumor thrombi. Only patients treated with sunitinib had clinical thrombus regression; however, the clinical magnitude and relevance of this effect is not clear and should be investigated prospectively.

Primary Tumor Response to Targeted Agents in Patients with Metastatic Renal Cell Carcinoma

BACKGROUND The recent development of multiple targeted agents for metastatic renal cell carcinoma (mRCC) has changed the treatment paradigm; hence the benefit and optimal timing of cytoreductive nephrectomy is being reevaluated. OBJECTIVE To determine primary tumor response to treatment with targeted agents in patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS We reviewed the clinical and radiographic data of all mRCC patients seen at our institution between November 2004 and December 2009 without prior systemic treatment who received targeted therapy with their primary tumor in situ. MEASUREMENTS Two independent reviewers measured the diameter of primary and metastatic tumors at baseline and subsequent scans, using Response Evaluation Criteria Solid Tumors (RECIST) v.1.1 to assess disease response. RESULTS AND LIMITATIONS We identified 168 consecutive patients with a median 15 mo of follow-up and a median maximum tumor diameter of 9.6 cm. Median maximum primary tumor response was -7.1% (interquartile range: -14.0 to -0.1). A total of 61 patients had multiple studies available for evaluation. In 43 patients with <10% decrease in primary tumor within in the first 60 d, median maximum response was -7.2% at 154 d versus -24.5% maximum response at 174.5 d for 18 patients with ≥10% decrease in primary tumor during the initial 60 d. CONCLUSIONS Decrease in primary tumor diameter >30% while on targeted therapy for mRCC is rare, with most patients demonstrating minimal or no decrease in primary tumor diameter. Early response predicts a better overall primary tumor response.

Early primary tumor size reduction is an independent predictor of improved overall survival in metastatic renal cell carcinoma patients treated with sunitinib.

BACKGROUND In metastatic renal cell carcinoma (mRCC) patients treated with targeted agents and their primary tumor (PT) in situ, early PT decrease in size correlates with improved overall PT response, but the effect on overall survival (OS) is unknown. OBJECTIVE To evaluate whether early PT size reduction is associated with improved OS in patients with mRCC undergoing treatment with sunitinib. DESIGN, SETTING, AND PARTICIPANTS We reviewed the clinical and radiographic data of all mRCC patients seen at our institution between January 2004 and December 2009 without prior systemic treatment who received sunitinib with their PT in situ. MEASUREMENTS Two independent reviewers measured the diameter of the PT and metastatic disease at baseline and subsequent scans to assess response. Early minor response was defined as ≥10% decrease within 60 d of treatment initiation. Univariate and multivariate analyses were used to calculate a hazard ratio (HR) corresponding to the risk of death based on clinical and pathologic factors as well as PT response. RESULTS AND LIMITATIONS We identified 75 consecutive patients with a median follow-up of 15 mo. All patients were intermediate or poor risk by common risk stratification systems. Median initial PT diameter was 9.7cm. Median maximum PT size reduction was -10.2% overall and -36.4% in patients who had early minor PT response. Median OS for patients without minor PT response, with minor PT response after 60 d, and with early minor PT response was 10.3, 16.5, and 30.2 mo, respectively. On multivariate analysis, early minor response was an independent predictor of improved OS (HR: 0.26; p=0.031). Other significant predictors included venous thrombus, multiple bone metastases, lactate dehydrogenase above the upper limit of normal, symptoms at presentation, and more than two metastatic sites. CONCLUSIONS Early minor PT response is associated with improved OS. Future studies should evaluate this prognostic factor to identify patients with prolonged OS.

Perioperative outcomes following surgical resection of renal cell carcinoma with inferior vena cava thrombus extending above the hepatic veins: a contemporary multicenter experience.

BACKGROUND Surgery for renal cell carcinoma (RCC) patients with inferior vena cava (IVC) thrombus above the hepatic veins is technically complex and associated with an increased risk of perioperative morbidity and mortality. However, minimal data exist that describe contemporary perioperative outcomes at major referral centers or the prognostic factors associated with poor outcomes. OBJECTIVE To determine the preoperative predictors of major complications and 90-d mortality after surgery in RCC patients who have IVC thrombus above the hepatic veins. DESIGN, SETTING, AND PARTICIPANTS We reviewed medical records of all RCC patients who had IVC tumor thrombus above hepatic veins and had had surgery between January 2000 and December 2012 at the Mayo Clinic, M.D. Anderson Cancer Center, University of Texas Southwestern Medical Center, and the University of Wisconsin Hospital. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS Major complications recorded were defined as ≥ 3A according to the Clavien-Dindo system within 90 d of surgery. Univariate and multivariate analyses were used to evaluate associations of preoperative variables with risk of major complications or 90-d mortality. RESULTS AND LIMITATIONS A total of 162 patients were identified for study (level 3, 4 in 69, 93 patients, respectively, according to the Neves classification). Cardiopulmonary bypass was used in 60 of 162 patients (37.5%), and 40 patients (24.7%) had preoperative angioembolization. Major complications were reported in 55 patients (34.0%), with the most common being respiratory, cardiac, and hematologic issues. After multivariate analysis, preoperative systemic symptoms and level 4 thrombus were independently associated with increased risk of major complications. Mortality was reported in 17 patients (10.5%) within 90 d after surgery. After multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status (PS) and low serum albumin were preoperative factors independently associated with increased risk of 90-d mortality. CONCLUSIONS Contemporary perioperative mortality and major complication rates for RCC patients who have upper-level thrombus are 10% and 34%, respectively. Patients who have ECOG PS >1 or low serum albumin have increased risk for perioperative mortality.

Development of accurate models for individualized prediction of survival after cytoreductive nephrectomy for metastatic renal cell carcinoma.

BACKGROUND There is limited evidence to guide patient selection for cytoreductive nephrectomy (CN) following the diagnosis of metastatic renal cell carcinoma (mRCC). OBJECTIVE Given the significant variability in oncologic outcomes following surgery, we sought to develop clinically relevant, individualized, multivariable models for the prediction of cancer-specific survival at 6 and 12 mo after CN. The development of this nomogram will better help clinicians select patients for cytoreductive surgery. DESIGN, SETTING, AND PARTICIPANTS We identified 601 consecutive patients who underwent CN for kidney cancer at a single tertiary cancer center. INTERVENTION CN for mRCC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The development cohort was used to select predictive variables from a large group of candidate predictors. The discrimination, calibration, and decision curves were corrected for overfit using 10-fold crossvalidation that included stepwise variable selection. RESULTS AND LIMITATIONS With a median follow-up of 65 mo (range: 6-199) for the entire cohort, 110 and 215 patients died from kidney cancer at 6 and 12 mo after surgery, respectively. For the preoperative model, serum albumin and serum lactate dehydrogenase were included. Final pathologic primary tumor stage, nodal stage, and receipt of blood transfusion were added to the previously mentioned parameters for the postoperative model. Preoperative and postoperative nomograms demonstrated good discrimination of 0.76 and 0.74, respectively, when applied to the validation data set. Both models demonstrated excellent calibration and a good net benefit over large ranges of threshold probabilities. The retrospective study design is the major limitation of this study. CONCLUSIONS We have developed models for accurate prediction of cancer-specific survival after CN, using either preoperative or postoperative variables. While these tools need validation in independent cohorts, our results suggest that the models are informative and can be used to aid in clinical decision making.

Development and multi‐institutional validation of an upgrading risk tool for Gleason 6 prostate cancer

Many patients with low‐risk prostate cancer (PC) who are diagnosed with Gleason score 6 at biopsy are ultimately found to harbor higher grade PC (Gleason ≥ 7) at radical prostatectomy. This finding increases risk of recurrence and cancer‐specific mortality. Validated clinical tools that are available preoperatively are needed to improve the ability to recognize likelihood of upgrading in patients with low‐risk PC.

Percutaneous Biopsy of Primary Tumor in Metastatic Renal Cell Carcinoma to Predict High Risk Pathological Features: Comparison With Nephrectomy Assessment

PURPOSE As treatment options evolve for metastatic renal cell carcinoma, there is a need for predictive information to help guide therapy. We assessed the accuracy of percutaneous primary tumor biopsy for metastatic renal cell carcinoma by comparing biopsy findings to final nephrectomy pathology in patients undergoing cytoreductive nephrectomy. MATERIALS AND METHODS Using an institutional database we reviewed the records of patients who underwent percutaneous primary tumor biopsy before cytoreductive nephrectomy. In patients who underwent biopsy elsewhere pathology findings were re-reviewed at our institution. Differences in accuracy based on biopsy technique, imaging modality and biopsy period were determined by chi-square analysis. RESULTS We identified 166 patients who underwent percutaneous biopsy of the primary tumor before cytoreductive nephrectomy between 1991 and 2007, and had data available for review. Median pathological tumor size was 9.1 cm (range 3 to 32). Median time from biopsy to surgery was 46 days (range 6 to 717). Of 104 patients in whom biopsy was assigned a Fuhrman nuclear grade 33 (31.7%) had the same grade in the nephrectomy specimen, including 74 of 109 (67.9%) when considering only high or low grade. Grade change by more than 2 points was seen in 18 of 104 patients (17.3%). Sarcomatoid features were present in 34 of 166 nephrectomy specimens (20.5%) but only 4 (11.8%) were identified preoperatively. CONCLUSIONS In patients with metastatic renal cell carcinoma percutaneous renal biopsy has poor accuracy to assess Fuhrman nuclear grade or sarcomatoid features. Physicians should use caution when using biopsy data to guide therapy.

Cytoreductive nephrectomy for metastatic RCC in the era of targeted therapy

Metastatic renal cell carcinoma (RCC) has traditionally been associated with a poor prognosis with few effective treatments. In the multimodal treatment of metastatic RCC, cytoreductive nephrectomy (CN) became the standard of care after two randomized trials demonstrated a benefit in overall survival in patients who received CN prior to treatment with interferon. More recently, several agents (sunitinib, sorafenib, temsirolimus, everolimus and bevacizumab) have been developed that target angiogenesis and the cellular growth pathways involved in metastatic RCC. These targeted agents have demonstrated improved outcomes compared to cytokine therapy, and have transformed metastatic RCC treatment. Targeted agents are being used as a first-line systemic treatment in patients with metastatic RCC with unprecedented success, and many studies are now focusing on the role of CN in combination with these agents for patients with metastatic RCC.

Perioperative Blood Transfusion and Radical Cystectomy: Does Timing of Transfusion Affect Bladder Cancer Mortality?

BACKGROUND While perioperative blood transfusion (BT) has been associated with adverse outcomes in multiple malignancies, the importance of BT timing has not been established. OBJECTIVE The objective of this study was to evaluate whether intraoperative BT is associated with worse cancer outcomes in bladder cancer patients treated with radical cystectomy (RC). DESIGN, SETTING, AND PARTICIPANTS Outcomes from two independent cohorts of consecutive patients with bladder cancer treated with RC were analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Recurrence-free survival, cancer-specific survival (CSS), and overall survival were estimated and multivariate analyses were performed to evaluate the association of BT timing with cancer outcomes. RESULTS AND LIMITATIONS In the primary cohort of 360 patients, 241 (67%) received perioperative BT, including 162 intraoperatively and 79 postoperatively. Five-year CSS was 44% among patients who received an intraoperative BT versus 64% for patients who received postoperative BT (p=0.0005). After multivariate analysis, intraoperative BT was associated with an increased risk of cancer mortality (hazard ratio [HR]: 1.93; p=0.02), while receipt of postoperative BT was not (p=0.60). In the validation cohort of 1770 patients, 1100 (62%) received perioperative BT with a median postoperative follow-up of 11 yr (interquartile range: 8.0-15.7). Five-year RFS (p<0.001) and CSS (p<0.001) were significantly worse among patients who received an intraoperative BT. Intraoperative BT was independently associated with recurrence (HR: 1.45; p=0.001), cancer-specific mortality (HR: 1.55; p=0.0001), and all-cause mortality (HR: 1.40; p<0.0001). Postoperative BT was not associated with risk of disease recurrence or cancer death. CONCLUSIONS Intraoperative BT is associated with increased risk of bladder cancer recurrence and mortality. PATIENT SUMMARY In this study, the effects of blood transfusion on bladder cancer surgery outcomes were evaluated. Intraoperative blood transfusion, but not postoperative transfusion, was associated with higher rates of recurrence and cancer-specific mortality.