Usefulness of R.E.N.A.L. Nephrometry Scoring System for Predicting Outcomes and Complications of Percutaneous Ablation of 751 Renal Tumors

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1 Usefulness of R.E.N.A.L. Nephrometry Scoring System for Predicting Outcomes and Complications of Percutaneous Ablation of 751 Renal Tumors Grant D. Schmit,* R. Houston Thompson, Anil N. Kurup, Adam J. Weisbrod, Stephen A. Boorjian, Rickey E. Carter, Jennifer R. Geske, Matthew R. Callstrom and Thomas D. Atwell From the Departments of Radiology (GDS, ANK, AJW, MRC, TDA), Urology (RHT, SAB) and Biostatistics (REC, JRG), Mayo Clinic School of Medicine, Rochester, Minnesota Abbreviations and Acronyms CT computerized tomography egfr estimated glomerular filtration rate MRI magnetic resonance imaging RCC renal cell carcinoma RFA radio frequency ablation Accepted for publication July 17, Study received Mayo Clinic institutional review board approval. * Correspondence: Department of Radiology, Mayo Clinic, 200 1st St. Southwest, Rochester, Minnesota (telephone: ; FAX: ; schmit.grant@mayo.edu). Financial interest and/or other relationship with Endocure and Siemens Medical. For another article on a related topic see page 321. Purpose: We applied the R.E.N.A.L. (radius, exophytic/endophytic, nearness to collecting system or sinus, anterior/posterior and location relative to polar lines) nephrometry scoring system to renal tumors treated with percutaneous ablation to determine whether this score is associated with oncological outcomes and complications. Materials and Methods: A total of 751 renal tumors were treated at 679 percutaneous ablation sessions in 627 patients at our institution between 2000 and Of these renal masses 430 (57%) were treated with cryoablation and the remaining 321 were treated with radio frequency ablation. R.E.N.A.L. tumor scores were analyzed to determine the association of the score with ablation treatment outcomes and complications according to Clavien criteria. Results: The mean SD R.E.N.A.L. nephrometry score of all ablated tumors was Those treated with cryoablation had higher scores than those treated with radio frequency ablation (mean vs , p 0.001). We identified a total of 28 local treatment failures (3.7%) in the 751 tumors during a mean computerized tomography/magnetic resonance imaging followup of months. There was a significant association between R.E.N.A.L. nephrometry score and local treatment failure. Mean nephrometry score was vs for tumors with vs without local treatment failure (p 0.001). Of the 679 ablation treatments 38 (5.6%) major (grade 3 or greater) patient complications occurred. There was a significant association between R.E.N.A.L. nephrometry score and major complications. Patients with vs without a major complication had a mean nephrometry score of vs (p 0.001). Conclusions: The R.E.N.A.L. nephrometry scoring system predicts treatment efficacy and complications following percutaneous renal ablation. Key Words: kidney; carcinoma, renal cell; cryosurgery; catheter ablation; forecasting SURGICAL resection in the form of partial or radical nephrectomy represents the gold standard treatment for patients with clinically localized RCC. It is associated with durable cancer control (88% to 100% 10-year diseasefree survival in patients with renal tumors 7 cm or less). 1 Nevertheless, less invasive treatment options are becoming increasingly popular for managing small renal tumors. This phenomenon is at least partially ex /13/ /0 THE JOURNAL OF UROLOGY Vol. 189, 30-35, January by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. Printed in U.S.A.

2 USEFULNESS OF R.E.N.A.L. SCORE FOR PREDICTING OUTCOMES AND COMPLICATIONS 31 plained by the increasing number of older patients with incidental renal tumors detected as a result of the increasing use of cross-sectional abdominal imaging. These incidental renal tumors are generally smaller and correspondingly more likely to represent benign lesions or more indolent RCC subtypes than the symptomatic renal tumors diagnosed in the past. 2,3 Percutaneous ablation is a minimally invasive treatment option that has proved to be effective and safe for select patients with small renal tumors In fact, the American Urological Association consensus guidelines now include percutaneous ablation as a treatment option for patients at high surgical risk with T1a (4 cm or less) renal tumors. 11 To our knowledge the long-term efficacy of renal ablation has yet to be established. However, as patient interest and physician acceptance continue to grow, indications for percutaneous renal ablation are beginning to expand. With this comes the necessity for urologists and interventional radiologists to develop an understanding of the specific advantages and disadvantages of surgery vs ablation for renal tumors. Comparing outcomes and complications among renal tumor treatments is difficult due to the heterogeneity in small renal tumor complexity, ie different sizes and locations in the kidney. Since 2009, 3 scoring systems have been introduced in the urology literature to quantify the pertinent characteristics of renal tumors as they relate to partial nephrectomy. The 3 systems are the R.E.N.A.L. nephrometry scoring system, 12 the PADUA (preoperative aspects and dimensions used for anatomical) classification system 13 and the centrality index system. 14 The primary goal of these systems is to improve how anatomical renal tumor data are recorded and analyzed for academic purposes. Standardized renal tumor scoring systems are also important because the feasibility of partial nephrectomy was previously based almost exclusively on the subjective surgeon assessment of whether tumor resection and renorrhaphy could be accomplished in an appropriate time. Studies of the R.E.N.A.L. nephrometry system show that tumor scores correlate with surgical outcomes and complications A recent study of 39 patients who underwent laparoscopic and percutaneous thermal ablation suggested that R.E.N.A.L. scores might also be associated with tumor recurrence and periprocedural complications. 21 Since a reproducible, comprehensive standardized system for reporting renal tumor anatomy is critical to compare surgical and percutaneous ablation studies, we evaluated this model in 751 renal tumors treated with percutaneous ablation at our institution to determine the value of this scoring system for predicting ablation outcomes and complications. MATERIALS AND METHODS After receiving approval from the Mayo Clinic institutional review board we identified a total of 751 renal tumors that were percutaneously ablated at 679 separate ablation procedures in 627 patients at our institution between May 2000 and January The R.E.N.A.L. nephrometry scoring system was applied retrospectively to all 751 treated tumors by one of 4 ablation radiologists. The R.E.N.A.L. score includes 5 critical anatomical components of a renal mass, of which 4 are scored on a 1, 2 or 3-point scale with the fifth component indicating an anterior or posterior location of the tumor in the kidney. 12 The score includes (R)adius (maximal tumor diameter) 1 point if 4 cm or less, 2 points if greater than 4 but less than 7 cm and 3 points if 7 cm or greater; tumor (E)xophytic/endophytic properties 1 point if 50% or greater exophytic, 2 points if less than 50% exophytic and 3 points if completely endophytic; (N)earness of the deepest portion to the tumor to the collecting system or sinus 1 point if 7 mm or greater, 2 points if greater than 4 but less than 7 mm and 3 points if 4 mm or less; (A)nterior (a)/posterior (p)/no designation (x) descriptor; and (L)ocation relative to the polar line 1 point if completely above the upper or completely below the lower polar line, 2 points if the lesion crosses the polar line and 3 points if greater than 50% of the mass is between the polar lines or crosses the renal midline. Low, moderate and high complexity renal tumors were considered those with a R.E.N.A.L. score of 4 to 6, 7 to 9 and 10 to 12, respectively. Our percutaneous renal ablation methods and techniques were previously described in detail. 4,7,22 Briefly, all patients were initially seen at the urology department for formal urological consultation. If the patient and urologist determined that percutaneous ablation would be the best treatment option, an ablation radiologist was contacted to confirm that the mass was amenable to ablation. From May 2000 to March 2003 RFA was the only method used for percutaneous renal ablation at our institution. Cryoablation was introduced in our practice in March As our practice has evolved during the years, larger, central renal tumors have been primarily treated with cryoablation, 22 while smaller, peripheral renal tumors are still treated with RFA (table 1). All renal masses were treated at a single cryoablation or RFA session with the patient under general anesthesia. No staged ablation was performed. From 2000 to 2002 renal mass biopsy was rarely done in patients treated with ablation. Since that time, it has been routine to obtain 1 or 2 core biopsies of the tumor at the time of ablation. Abdominal CT or MRI was done in all patients within 24 hours of ablation to determine the technical success of the procedure. As adapted from the International Working Group on Image-Guided Tumor Ablation, 23 the technical success of cryoablation was defined as ice ball extension at least 0.5 cm beyond the tumor margins on monitoring noncontrast CT performed during the procedure. For cryoablation and RFA technical success was defined as extension of the ablation zone beyond the tumor margins on contrast enhanced CT or MRI done within 3 months of ablation. Local tumor recurrence was defined as a hyperenhancing or enlarging soft tissue nodule in or around the

3 32 USEFULNESS OF R.E.N.A.L. SCORE FOR PREDICTING OUTCOMES AND COMPLICATIONS Table 1. Renal tumor characteristics All Ablation Cryoablation RFA No. renal tumors Mean SD max diameter (cm) Mean SD R.E.N.A.L score: Radius Exophytic/endophytic Nearness Location No. R.E.N.A.L. anterior score (%): Anterior 274 (37) 153 (36) 121 (38) Posterior 334 (44) 178 (41) 155 (48) No designation 143 (19) 99 (23) 45 (14) No. R.E.N.A.L. score tumor complexity (%): Low (4 6) 351 (47) 155 (36) 196 (61) Moderate (7 9) 330 (44) 222 (52) 108 (34) High (10 12) 70 (9) 53 (12) 17 (5) No. biopsy (%): 552 (74) 352 (82) 200 (62) No. pathological result (%): RCC 335 (61) 223 (63) 112 (56) Oncocytoma 74 (14) 46 (14) 28 (14) Oncocytic neoplasm 33 (6) 19 (5) 14 (7) Angiomyolipoma 13 (2) 6 (2) 7 (3) Metastasis 6 (1) 1 (less than 1) 5 (3) Lymphoma 1 (less than 1) 1 (less than 1) 0 Nondiagnostic 90 (16) 56 (16) 34 (17) No. RCC subtype (%): Clear cell 215 (64) 154 (69) 61 (54) Papillary 71 (21) 42 (19) 29 (26) Chromophobe 4 (1) 1 (less than 1) 3 (3) Not specified 45 (14) 26 (12) 19 (17) No. RCC grade (%): 1 87 (26) 56 (25) 31 (27) (45) 98 (44) 52 (46) 3 23 (7) 19 (8) 4 (4) 4 2 (less than 1) 2 (1) 0 Low 29 (9) 16 (7) 13 (12) High 4 (1) 4 (2) 0 Not specified 40 (12) 28 (13) 12 (11) ablation zone on CT or MRI performed 3 months or later after ablation. Tumors with technically unsuccessful ablation or evidence of local recurrence on followup imaging were considered local treatment failures. Post-ablation followup imaging was recommended at 3, 6 and 12 months, and yearly thereafter. No routine followup biopsies of the renal ablation zone were performed unless there was imaging evidence of residual/recurrent tumor. Complications were assessed using the revised Clavien-Dindo classification system, 24 which grades surgical complications based on the degree of the necessity for unanticipated intervention during the normal postoperative course. Any grade 3 or greater complication was considered a major complication. Renal function outcomes were based on egfr using serum creatinine and the Modification of Diet in Renal Disease equation. 25 All patients were admitted to the hospital urology service after ablation for overnight observation. Local treatment failure, regarded as a combination of technical failure and local tumor recurrence, was determined on a per tumor basis. Major complications were determined on a per procedure basis. If more than 1 renal tumor was ablated at a single treatment session, the maximal R.E.N.A.L. nephrometry score of the treated tumors was considered the score for that ablation procedure. Logistic regression models were used to test for an association of R.E.N.A.L. scores with major complications. The concordance statistic was used to summarize overall discrimination and the Cochran-Armitage trend test was used to evaluate for a monotonic association of increasing R.E.N.A.L. score category (low, moderate and high tumor complexity) with major complications. The Spearman correlation was used to test for an association of R.E.N.A.L. score with egfr. The log rank test was used to test for a difference in tumor recurrence among R.E.N.A.L. score categories and among location descriptors. A chi-square test was used to test for an association of tumor location descriptor with major complication as well as RENAL score category. One and 2-year tumor recurrence was estimated using the Kaplan-Meier product limit estimator to account for censored observations. Statistical analyses were done using SAS, version All reported p values are unadjusted for multiple comparisons. RESULTS Of the patients 405 (65%) were male and 222 were female. Mean SD patient age at ablation was years. Table 1 lists renal tumor characteristics. Of the 751 renal tumors 430 (57.3%) were treated with cryoablation and 321 were treated with RFA. Mean R.E.N.A.L. nephrometry score of all ablated tumors was Mean nephrometry score for tumors treated with cryoablation was , while the mean score for tumors treated with RFA was (p 0.001). Imaging followup was available for our review greater than 3 months after ablation for 668 tumors (88.9%). Mean imaging followup of all patients after treatment was months. Overall there were 28 local treatment failures (3.7%), including 11 technical failures and 17 local tumor recurrences. Of these local treatment failures 14 occurred in the 335 renal tumors that were biopsy proven to be RCC. A total of 15 local treatment failures (3.5%) occurred with renal cryoablation and 13 occurred (4.0%) with RFA. There was a significant association between the R.E.N.A.L. nephrometry score classification and overall local treatment failure (table 2 and fig. 1). Mean nephrometry score was vs for tumors with vs without local treatment failure (p 0.001). There was no significant association of the anterior/posterior/no designated location descriptor and treatment failure (p 0.701). Mean nephrometry score was 7.6 for tumors with technical failure and those with local recurrence. Major complications (grade 3 or greater) developed after 38 of 679 percutaneous renal ablation

4 USEFULNESS OF R.E.N.A.L. SCORE FOR PREDICTING OUTCOMES AND COMPLICATIONS 33 Table 2. Local treatment failure in 751 tumors R.E.N.A.L. Score Tumor Complexity Low (4 6) Moderate (7 9) High (10 12) No. tumors No. treatment failures (% tumors)* 9 (2.6) 11 (3.3) 8 (11.4) % Estimate (95% CI): Yr 1 1 (0 3) 1 (0 3) 6 (2 17) Yr 2 2 (1 5) 2 (1 5) 10 (3 25) * Log rank p Based on Kaplan-Meier survival curve with 95% CIs based on log-log transformation. procedures (5.6%), including 30 of 387 cryoablations (7.8%) and 8 of 292 RFAs (2.7%). This included 1 death, which occurred 20 days after renal cryoablation. This patient had an indwelling stent placed after ablation due to obstructing hematoma in the renal collecting system. The patient was discharged from the hospital but readmitted with urosepsis and eventually died of septic complications. There was a significant association between the R.E.N.A.L. nephrometry score classification and major patient complications following percutaneous ablation (p 0.001, fig. 2, A). As measured by the concordance statistic, overall discrimination was low at 0.69 (fig. 2, B). Patients in whom major complications did vs did not develop had tumors with a mean nephrometry score of 8.1 2vs (p 0.001). Complication rates by location did not significantly differ by anterior, posterior and no designation tumor location descriptor (5.5%, 4.5% and 9.8%, respectively, p 0.074). The mean egfr of study patients before ablation was ml/minute/1.73 m 2. In 480 patients egfr was available for review within 1 week before and within 1 week after ablation. The mean egfr change in these patients was ml/minute/ 1.73 m 2. No significant correlation was identified between the R.E.N.A.L. nephrometry score and the egfr change ( 0.056, p 0.197). Two patients needed temporary dialysis in the immediate post-ablation period but neither patient required chronic dialysis. Another 7 patients progressed to chronic dialysis at a mean of months following ablation. Mean hospital stay was days. tumors treated were of low or moderate complexity by R.E.N.A.L. score. Of tumor recurrences 83% and 100% of complications developed in patients with moderate complexity tumors. 21 Our study differs in that it validates the usefulness of the R.E.N.A.L. nephrometry tumor score to predict oncological outcomes and complications after percutaneous ablation in a large number of patients. In addition, just as the R.E.N.A.L. nephrometry score can bring objectivity to surgical decision making, 15 our results suggest that it may also provide objectivity for percutaneous ablation planning purposes. For example, given the increased risk of major complications (14.3%) and local treatment failures (11.4%) in patients with high complexity renal masses (R.E.N.A.L. score 10 to 12), it may be prudent to avoid percutaneous ablation in these patients or refer them to a tertiary ablation center if percutaneous ablation remains the best treatment option. Since the R.E.N.A.L. nephrometry system was based on the 5 most reproducible, pertinent anatomical features of a renal mass critical to resectability, 12 score components are less significant for percutaneous renal ablation than for surgery. This is particularly true for tumor location in relationship to the polar lines. A tumor located partially or completely between the renal polar lines is often more accessible for percutaneous ablation than one located in the upper pole. While it is important for percutaneous ablation planning, the relationship of the renal tumor to the ureter and bowel is not considered in the R.E.N.A.L. nephrometry score. Hydrodisplacement of the small bowel or colon and retrograde pyeloperfusion via an externalized ureteral stent to protect the ureter can be performed but there are certainly increased risks for percutaneous ablation of tumors within 1 cm of the bowel or ureter Despite this, the R.E.N.A.L. scoring system provides a standardized method for quantifying the DISCUSSION Prior studies have shown a correlation of R.E.N.A.L. tumor scores with surgical decision making, oncological and functional renal outcomes, complications and even tumor grade A recent study of 39 patients who underwent percutaneous plus laparoscopic thermal ablation demonstrated that 95% of Figure 1. Time to local failure by R.E.N.A.L. score classification, including 4 to 6 (blue curve), 7 to 9 (green curve) and 10 to 12 (red curve).

5 34 USEFULNESS OF R.E.N.A.L. SCORE FOR PREDICTING OUTCOMES AND COMPLICATIONS Figure 2. A, ablation major complication rate by R.E.N.A.L. score or maximum R.E.N.A.L. score in patients with more than 1 tumor treated at single procedure, including 3.4 (10 of 297, 95% CI ), 5.4 (17 of 313, 95% CI ) and 15.9 (11 of 69, 95% CI ) for low, moderate and high scores, respectively (p for trend 0.001). B, probability of major ablation complications by R.E.N.A.L. score. Overall discrimination measured by concordance index was 0.69 (95% CI ). Odds of major procedural complication increased by for each unit increase in R.E.N.A.L. score. complexity of a renal mass. It should be helpful for a comparative analysis of surgery vs renal ablation. There are important limitations to this retrospective study. Comparison between percutaneous renal RFA, and cryoablation complications and outcomes are limited due to the built-in tumor selection bias in our practice. While at first it may appear that the risk of a major complication is significantly higher for renal cryoablation than for RFA (7.9% vs 2.7%), this is likely related to our practice of treating larger, more complex renal masses with cryoablation. Another limitation is the 11.1% of patients without imaging followup greater than 3 months after ablation. Our tertiary care center serves patients from a wide geographical area, of whom many elect to undergo imaging and clinical followup closer to home. We attempt to obtain followup imaging done elsewhere on all patients treated with ablation but are sometimes unsuccessful. Also, the initial description of the R.E.N.A.L. scoring system included an h designation for hilar renal tumors 12 but this was not evaluated in our study. Finally, only 335 treated renal masses (44.6%) were biopsy proven to be RCC, which significantly complicated the evaluation of patient oncological outcomes. CONCLUSIONS The R.E.N.A.L. nephrometry scoring system predicts oncological outcomes and complications following percutaneous renal ablation. As such, this tool may be used to facilitate the standardization of comparisons of treatment efficacy and safety across various approaches to small renal tumors. REFERENCES 1. Crispen PL, Boorjian SA, Lohse CM et al: Outcomes following partial nephrectomy by tumor size. J Urol 2008; 180: Pantuck AJ, Zisman A, Belldegrun AS: The changing natural history of renal cell carcinoma. J Urol 2001; 166: Frank I, Blute ML, Cheville JC et al: Solid renal tumors: an analysis of pathological features related to tumor size. J Urol 2003; 170: Farrell MA, Charboneau WJ, DiMarco SD et al: Imaging-guided radiofrequency ablation of solid renal tumors. AJR Am J Roentgenol 2003; 180: Gervais DA, McGovern FJ, Arellano RS et al: Radiofrequency ablation of renal cell carcinoma. Part 1. Indications, results, and role in patient management over a 6-year period and ablation of 100 tumors. AJR Am J Roentgenol 2005; 185: McDougal WS, Gervais DA, McGovern FJ et al: Long-term followup of patients with renal cell carcinoma treated with radiofrequency ablation. J Urol 2005; 174: Atwell TD, Farrell MA, Leibovich BC et al: Percutaneous renal cryoablation: experience treating 115 tumors. J Urol 2008; 179: Gupta A, Allaf ME, Kavoussi LR et al: Computerized tomography guided percutaneous renal cryo-

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