Stephen H. Culp

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.

Safety of Presurgical Targeted Therapy in the Setting of Metastatic Renal Cell Carcinoma

BACKGROUND In patients with metastatic renal cell carcinoma (mRCC), the timing of systemic targeted therapy in relation to cytoreductive nephrectomy (CN) is under investigation. OBJECTIVE To evaluate postoperative complications after the use of presurgical targeted therapy prior to CN. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of all patients who underwent a CN at The University of Texas M.D. Anderson Cancer Center from 2004 to 2010 was performed. Inclusion in this study required documented evidence of mRCC, with treatment incorporating CN. INTERVENTIONS Patients receiving presurgical systemic targeted therapy prior to CN were compared to those undergoing immediate CN. MEASUREMENTS Complications were assessed using the modified Clavien system for a period of 12 mo postoperatively. RESULTS AND LIMITATIONS Presurgical therapy was administered to 70 patients prior to CN (presurgical), while 103 patients had an immediate CN (immediate). A total of 232 complications occurred in 57% of patients (99 of 173). Use of presurgical systemic targeted therapy was predictive of having a complication>90 d postoperatively (p=0.002) and having multiple complications (p=0.013), and it was predictive of having a wound complication (p<0.001). Despite these specific complications, presurgical systemic targeted therapy was not associated with an increased overall complication risk on univariable or multivariate analysis (p=0.064 and p=0.237) and was not predictive for severe (Clavien ≥3) complications (p=0.625). This study is limited by its retrospective nature. As is inherent to any retrospective study reporting on complications, we are limited by reporting bias and the potential for misclassification of specific complications. CONCLUSIONS Despite an increased risk for specific wound-related complications, overall surgical complications and the risk of severe complications (Clavien ≥3) are not greater after presurgical targeted therapy in comparison to upfront cytoreductive surgery.

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.

Outcome of patients with metastatic renal cell carcinoma treated with targeted therapy without cytoreductive nephrectomy

BACKGROUND Cytoreductive nephrectomy (CN) became a standard procedure in metastatic renal cell carcinoma (mRCC) in the immunotherapy era. Historically, median overall survival (OS) of patients treated with interferon alpha (IFN-α) without CN was 7.8 months. Median OS in patients treated with targeted therapy (TT) without CN is unknown. PATIENTS AND METHODS We retrospectively reviewed records of patients with mRCC who received TT without CN. Kaplan-Meier methods and Cox regression analysis were used to estimate median OS and identify poor prognostic factors. RESULTS One hundred and eighty-eight patients were identified. Most patients had intermediate-risk (54.8%) or poor-risk (44.1%) disease. Median OS for all patients was 10.4 months [95% confidence interval (CI) 8.1-12.5]. By multivariable analysis, elevated baseline lactate dehydrogenase and corrected calcium, performance status of two or more, retroperitoneal nodal metastasis, thrombocytosis, current smoking, two or more metastatic sites, and lymphopenia were independent risk factors for inferior OS. Patients with four or more factors had increased risk of death (hazard ratio 8.83, 95% CI 5.02-15.5, P < 0.001) and 5.5-month median OS. Nineteen patients (10.0%) survived for 2+ years. CONCLUSIONS These data highlight the improved OS of patients with mRCC treated with TT without CN, compared with historical IFN-α treatment, and may guide the design of trials investigating the role of CN in the TT era.

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.

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.

Development and Characterization of Clinically Relevant Tumor Models From Patients With Renal Cell Carcinoma

BACKGROUND Animal models are instrumental in understanding disease pathophysiology and mechanisms of therapy action and resistance in vivo. OBJECTIVE To establish and characterize a panel of mouse models of renal cell carcinoma (RCC) derived from patients undergoing radical nephrectomy. DESIGN, SETTING, AND PARTICIPANTS In vivo and in vitro animal experiments. MEASUREMENTS Tumor tissues obtained during surgery were implanted into the subcutaneous space of female BALB/c nude mice and serially passaged into new mice. Tumors were characterized by histology, short tandem repeat (STR) fingerprinting, von Hippel-Lindau (VHL) gene sequencing, and single nucleotide polymorphism (SNP) analysis. Tumor-bearing mice were treated with sunitinib or everolimus. Primary cell cultures were derived from patient tumors and transfected with a lentivirus carrying the luciferase gene. Four subcutaneous xenograft mouse models were developed, representing papillary type 1, papillary type 2, clear cell, and clear cell with sarcomatoid features RCC. RESULTS AND LIMITATIONS RCC mouse models were established from four patients with distinct histologies of RCC. Tumor growth was dependent on histologic type, the size of the implanted tumor chip, and the passage number. Mouse tumors accurately represented their respective original patient tumors, as STR fingerprints were matching, histology was comparable, and SNP profiles and VHL mutation status were conserved with multiple passages. Bioluminescence imaging results were commensurate with subcutaneous xenograft growth patterns. Mice treated with sunitinib and everolimus exhibited an initial response, followed by a later stage of resistance to these agents, which mimics the clinical observations in patients with RCC. CONCLUSIONS We developed four mouse xenograft models of RCC with clear-cell and papillary histologies, with stable histologic and molecular characteristics. These models can be used to understand the basic biology of RCC as well as response and resistance to therapy.

Limitations of preoperative biopsy in patients with metastatic renal cell carcinoma: comparison to surgical pathology in 405 cases

Study Type – Diagnostic (cohort)