David Y.T. Chen

The natural history of observed enhancing renal masses : meta-analysis and review of the world literature

PURPOSE Standard therapy for an enhancing renal mass is surgical. However, operative treatment may not be plausible in all clinical circumstances. Data on the natural history of untreated enhancing renal lesions is limited but could serve as a decision making resource for patients and physicians. We examined available data on the natural history of observed solid renal masses. MATERIALS AND METHODS A Medline review of the literature was performed from 1966 to the present regarding untreated, observed, localized solid renal masses. To these data we added our institutional experience with a total of 61 lesions observed in 49 patients for a minimum of 1 year. Variables examined were initial lesion size at presentation, growth rate, duration of followup, pathological findings and progression to metastatic disease. Overall weighted mean estimates were calculated for lesion size at presentation, growth rate and followup based upon combining single institutional series with complete information. RESULTS We identified 10 reports from 9 single institutional series in the world literature regarding the natural history of untreated solid localized renal lesions. The series included 6 to 40 patients (mean 25) with a mean followup of 30 months (range 25 to 39). When combined with our institutional data, a total of 286 lesions were analyzed, of which 234 could be included in the meta-analysis. Mean lesion size at presentation was 2.60 cm (median 2.48, range 1.73 to 4.08). Meta-analysis revealed a mean growth rate of 0.28 cm yearly (median 0.28, range 0.09 to 0.86) at a mean followup of 34 months (median 32, range 26 to 39) in all series combined. Pathological confirmation was available in 46% of the cases (131 of 286) and it confirmed 92% (120 of 131) as RCC variants. Evaluable data in this subset of confirmed RCC demonstrated a mean growth rate of 0.40 cm yearly (median 0.35, range 0.42 to 1.6). Lesion size at presentation did not predict the overall growth rate (p = 0.46). Progression to metastatic disease was identified in only 1% of lesions (3 of 286) during followup. CONCLUSIONS The majority of small enhancing renal masses grow at a slow rate when observed. Although metastatic and cancer specific death are low, serial radiographic data alone are insufficient to predict the true natural history of these lesions. Therefore, physicians and patients assume a calculated risk when following these tumors. Basic biological data are needed to assess the natural history of untreated renal masses.

Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis.

The authors systematically reviewed the literature and conducted a pooled analysis of studies on small renal masses who underwent active surveillance to identify the risk progression and the characteristics associated with metastases.

Objective Measures of Renal Mass Anatomic Complexity Predict Rates of Major Complications Following Partial Nephrectomy

BACKGROUND The association between tumor complexity and postoperative complications after partial nephrectomy (PN) has not been well characterized. OBJECTIVE We evaluated whether increasing renal tumor complexity, quantitated by nephrometry score (NS), is associated with increased complication rates following PN using the Clavien-Dindo classification system (CCS). DESIGN, SETTING, AND PARTICIPANTS We queried our prospectively maintained kidney cancer database for patients undergoing PN from 2007 to 2010 for whom NS was available. INTERVENTIONS All patients underwent PN. MEASUREMENTS Tumors were categorized into low- (NS: 4-6), moderate- (NS: 7-9), and high-complexity (NS: 10-12) lesions. Complication rates within 30 d were graded (CCS: I-5), stratified as minor (CCS: I or 2) or major (CCS: 3-5), and compared between groups. RESULTS AND LIMITATIONS A total of 390 patients (mean age: 58.0 ± 11.9 yr; 66.9% male) undergoing PN (44.6% open, 55.4% robotic) for low- (28%), moderate- (55.6%), and high-complexity (16.4%) tumors (mean tumor size: 3.74 ± 2.4 cm; median: 3.2 cm) from 2007 to 2010 were identified. Tumor size, estimated blood loss, and ischemia time all significantly differed (p<0.0001) between groups; patient age, body mass index (BMI), and operative time were comparable. When stratified by CCS, minor and major complication rates for all patients were 26.7% and 11.5%, respectively. Minor complication rates were comparable (26.6 vs. 24.9 vs 32.8%; p=0.45), whereas major complication rates differed (6.4 vs. 11.1 vs. 21.9%; p=0.009) among tumor complexity groups. Controlling for age, gender, BMI, type of surgical approach, operative duration, and tumor complexity, prolonged operative time (odds ratio [OR]: 1.01; confidence interval [CI], 1.0-1.02) and high tumor complexity (OR: 5.4; CI, 1.2-24.2) were associated with the postoperative development of a major complication. Lack of external validation is a limitation of this study. CONCLUSIONS Increasing tumor complexity is associated with the development of major complications after PN. This association should be validated externally and integrated into the decision-making process when counseling patients with complex renal tumors.

Anatomic Features of Enhancing Renal Masses Predict Malignant and High-Grade Pathology: A Preoperative Nomogram Using the RENAL Nephrometry Score

BACKGROUND Counseling patients with enhancing renal mass currently occurs in the context of significant uncertainty regarding tumor pathology. OBJECTIVE We evaluated whether radiographic features of renal masses could predict tumor pathology and developed a comprehensive nomogram to quantitate the likelihood of malignancy and high-grade pathology based on these features. DESIGN, SETTING, AND PARTICIPANTS We retrospectively queried Fox Chase Cancer Centers prospectively maintained database for consecutive renal masses where a Nephrometry score was available. INTERVENTION All patients in the cohort underwent either partial or radical nephrectomy. MEASUREMENTS The individual components of Nephrometry were compared with histology and grade of resected tumors. We used multiple logistic regression to develop nomograms predicting the malignancy of tumors and likelihood of high-grade disease among malignant tumors. RESULTS AND LIMITATIONS Nephrometry score was available for 525 of 1750 renal masses. Nephrometry score correlated with both tumor grade (p < 0.0001) and histology (p < 0.0001), such that small endophytic nonhilar tumors were more likely to represent benign pathology. Conversely, large interpolar and hilar tumors more often represented high-grade cancers. The resulting nomogram from these data offers a useful tool for the preoperative prediction of tumor histology (area under the curve [AUC]: 0.76) and grade (AUC: 0.73). The model was subjected to out-of-sample cross-validation; however, lack of external validation is a limitation of the study. CONCLUSIONS The current study is the first to objectify the relationship between tumor anatomy and pathology. Using the Nephrometry score, we developed a tool to quantitate the preoperative likelihood of malignant and high-grade pathology of an enhancing renal mass.

Natural history, growth kinetics, and outcomes of untreated clinically localized renal tumors under active surveillance

The growth kinetics of untreated solid organ malignancies are not defined. Radiographic active surveillance (AS) of renal tumors in patients unfit or unwilling to undergo intervention provides an opportunity to quantify the natural history of untreated localized tumors. The authors report the radiographic growth kinetics of renal neoplasms during a period of surveillance.

Robot-assisted partial nephrectomy: a large single-institutional experience.

OBJECTIVES To report experience with 100 robot-assisted partial nephrectomy (RAPN) operations performed at our institution. Nephron-sparing surgery is an established treatment for patients with small renal masses. The laparoscopic approach has emerged as an alternative to open nephron-sparing surgery, but it is recognized to be technically challenging. The robotic surgical system may enable faster and greater technical proficiency, facilitating a minimally invasive approach to more difficult lesions while reducing ischemia time. METHODS A total of 100 RAPN operations were performed for suspicious solid renal lesions during a 21-month period. Clinicopathologic variables, nephrometry scores, operative parameters, and renal functional outcomes were prospectively recorded and analyzed. RESULTS Median tumor size was 2.8 cm (range, 1.0-8). Nephrometry scores of resected lesions were low in 47.9% of patients, medium in 45.7%, and high in 6.4% of patients. Forty-seven percent of patients had tumors>50% intraparenchymal, and 61.7% had tumors located less than 7 mm away from the renal sinus or collecting system. In 17% of patients, the tumors were touching a first-order vessel in the renal hilum. Mean warm ischemia time was 25.5 minutes (range, 0-53). Mean change in postoperative glomerular filtration rate improved 6.32 mL/min/1.73 m2 (range, -41.9 to 68.9). Histology was renal cell carcinoma in 81% (87/107) of tumors. There were 5 microscopically positive margins on final pathology (5.7%). Major and minor complication rates were 6% and 5%, respectively. There were 2 conversions to open surgery. CONCLUSIONS RAPN seems to be a safe and technically feasible minimally invasive approach to nephron-sparing surgery even in more complex cases, with acceptable pathologic and renal function outcomes.

Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer

BACKGROUND Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25-50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking. OBJECTIVE To discover and validate biomarkers predictive of response to NAC for MIBC. DESIGN, SETTING, AND PARTICIPANTS Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments-certified laboratory. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. RESULTS AND LIMITATIONS Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p=0.024) and validation (p=0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p<0.001; 87% sensitivity, 100% specificity) and better overall survival (p=0.007). This test remained predictive for pathologic response in the validation set (p=0.033), with a trend towards better overall survival (p=0.055). These results require further validation in additional sample sets. CONCLUSIONS Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. PATIENT SUMMARY Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.

Delayed intervention of sporadic renal masses undergoing active surveillance

Prompt surgical management remains the standard of care for renal cell carcinoma (RCC). Occasionally, it is necessary to postpone or delay surgical treatment. The authors of this report assessed whether delayed intervention following a period of active surveillance altered minimally invasive or nephron‐sparing treatment plans, increased the risk of stage progression, and/or decreased recurrence‐free survival rates.

Positron Emission Tomography/Computed Tomography Identification of Clear Cell Renal Cell Carcinoma: Results From the REDECT Trial

PURPOSE A clinical study to characterize renal masses with positron emission tomography/computed tomography (PET/CT) was undertaken. PATIENTS AND METHODS This was an open-label multicenter study of iodine-124 ((124)I) -girentuximab PET/CT in patients with renal masses who were scheduled for resection. PET/CT and contrast-enhanced CT (CECT) of the abdomen were performed 2 to 6 days after intravenous (124)I-girentuximab administration and before resection of the renal mass(es). Images were interpreted centrally by three blinded readers for each imaging modality. Tumor histology was determined by a blinded central pathologist. The primary end points-average sensitivity and specificity for clear cell renal cell carcinoma (ccRCC)-were compared between the two modalities. Agreement between and within readers was assessed. RESULTS (124)I-girentuximab was well tolerated. In all, 195 patients had complete data sets (histopathologic diagnosis and PET/CT and CECT results) available. The average sensitivity was 86.2% (95% CI, 75.3% to 97.1%) for PET/CT and 75.5% (95% CI, 62.6% to 88.4%) for CECT (P = .023). The average specificity was 85.9% (95% CI, 69.4% to 99.9%) for PET/CT and 46.8% (95% CI, 18.8% to 74.7%) for CECT (P = .005). Inter-reader agreement was high (κ range, 0.87 to 0.92 for PET/CT; 0.67 to 0.76 for CECT), as was intrareader agreement (range, 87% to 100% for PET/CT; 73.7% to 91.3% for CECT). CONCLUSION This study represents (to the best of our knowledge) the first clinical validation of a molecular imaging biomarker for malignancy. (124)I-girentuximab PET/CT can accurately and noninvasively identify ccRCC, with potential utility for designing best management approaches for patients with renal masses.

Randomized Phase II Study of Erlotinib in Combination With Placebo or R1507, a Monoclonal Antibody to Insulin-Like Growth Factor-1 Receptor, for Advanced-Stage Non–Small-Cell Lung Cancer

PURPOSE R1507 is a selective, fully human, recombinant monoclonal antibody (immunoglobulin G1 subclass) against insulin-like growth factor-1 receptor (IGF-1R). The strong preclinical evidence supporting coinhibition of IGF-1R and epidermal growth factor receptor (EGFR) as anticancer therapy prompted this study. PATIENTS AND METHODS Patients with advanced-stage non-small-cell lung cancer (NSCLC) with progression following one or two prior regimens, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, and measurable disease were eligible. Patients were randomly assigned to receive erlotinib (150 mg orally once a day) in combination with either placebo, R1507 9 mg/kg weekly, or R1507 16 mg/kg intravenously once every 3 weeks. Treatment cycles were repeated every 3 weeks. The primary end point was comparison of the 12-week progression-free survival (PFS) rate. RESULTS In all, 172 patients were enrolled: median age, 61 years; female, 33%; never-smokers, 12%; and performance status 0 or 1, 88%. The median number of R1507 doses was six for the weekly arm and 3.5 for the every-3-weeks arm. Grades 3 to 4 adverse events occurred in 37%, 44%, and 48% of patients with placebo, R1507 weekly, and R1507 every 3 weeks, respectively. The 12-week PFS rates were 39%, 37%, and 44%, and the median overall survival was 8.1, 8.1, and 12.1 months for the three groups, respectively, with statistically nonsignificant hazard ratios. The 12-week PFS rate in patients with KRAS mutation was 36% with R1507 compared with 0% with placebo. CONCLUSION The combination of R1507 with erlotinib did not provide PFS or survival advantage over erlotinib alone in an unselected group of patients with advanced NSCLC. Predictive biomarkers are essential for further development of combined inhibition of IGF-1R and EGFR.