EUROPEAN UROLOGY 61 (2012)

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1 EUROPEAN UROLOGY 61 (2012) available at journal homepage: Platinum Priority Kidney Cancer Editorial by Alvin C. Goh and Inderbir S. Gill on pp of this issue Radiofrequency Ablation Versus Partial Nephrectomy in Patients with Solitary Clinical T1a Renal Cell Carcinoma: Comparable Oncologic Outcomes at a Minimum of 5 Years of Follow-Up Ephrem O. Olweny a, Samuel K. Park a, Yung K. Tan a, Sara L. Best a, Clayton Trimmer b, Jeffrey A. Cadeddu a, * a Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; b Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA Article info Article history: Accepted January 2, 2012 Published online ahead of print on January 10, 2012 Keywords: Carcinoma renal cell Ablation techniques Treatment outcome Abstract Background: Long-term comparative outcomes for radiofrequency ablation (RFA) versus partial nephrectomy (PN) for the primary treatment of clinical T1a renal cell carcinoma (RCC) have not previously been reported. Objective: Report comparative 5-yr oncologic outcomes for RFA versus PN in patients with clinical T1a RCC. Design, setting, and participants: Observational single-institution cohort study, involving consecutive patients with a solitary histologically confirmed T1a RCC treated by RFA or PN and followed for a minimum of 5 yr. Those presenting with synchronous multiple, metachronous, bilateral, and/or metastatic disease, a history of hereditary RCC syndromes, a family history of RCC, and with post-treatment follow-up <5 yr were excluded from analysis. Measurements: The Kaplan-Meier method was used to determine 5-yr overall survival (OS), cancer-specific survival (CSS), local recurrence-free survival (local RFS), overall disease-free survival (DFS), and metastasis-free survival (MFS) for RFA versus PN. Survival curves were compared using the log-rank test. A p value 0.05 was considered statistically significant. Results and limitations: A total of 37 patients in each group met the selection criteria. The RFA cohort was significantly older and had more advanced comorbidities, but other patient characteristics were similar. For RFA versus PN, median follow-up was 6.5 yr (interquartile range [IQR]: ) versus 6.1 yr (IQR: ) ( p = 0.68), respectively. The 5-yr OS was 97.2% versus 100% ( p = 0.31), CSS was 97.2% versus 100% ( p = 0.31), DFS was 89.2% versus 89.2% ( p = 0.78), local RFS was 91.7% versus 94.6% ( p = 0.96), and MFS was 97.2% versus 91.8% ( p = 0.35), respectively. Study limitations are retrospective data analysis, loss to follow-up, limited statistical power, and limited generalizability of our data. Conclusions: In appropriately selected patients, RFA is an effective minimally invasive therapy for the treatment of ct1a RCC, yielding comparable long-term oncologic outcomes to nephron-sparing surgery. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, J8.106, Dallas, TX , USA. Tel ; Fax: address: Jeffrey.Cadeddu@utsouthwestern.edu (J.A. Cadeddu) /$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 61 (2012) Introduction Current treatment guidelines recommend reserving the use of thermal ablative therapies for the primary treatment of small renal cell carcinomas (RCCs) for older patients, those with significant medical comorbidities who are poor surgical candidates, those with genetic predispositions to recurrent tumor formation, and/or those with imperative indications for nephron-sparing procedures [1,2]. The basis for these recommendations was lack of long-term oncologic efficacy data, unreliability of measures of treatment efficacy, higher rates of local recurrence compared with surgery, and difficulty of surgical salvage in the setting of recurrence [1]. Only a handful of studies have evaluated long-term oncologic outcomes following radiofrequency ablation (RFA) for RCC [3 6]. Limitations of these series were small numbers of patients with follow-up 5 yr and inclusion of patients presenting with synchronous multiple or bilateral tumors, metachronous tumors, and/or hereditary RCC syndromes, factors that are each independently associated with an increased risk of recurrence after definitive therapy for RCC [7 9]. With these limitations, these studies demonstrated combined long-term local recurrence-free survival (RFS) rates of % and estimated metastasisfree survival (MFS) rates of % [3 6]. To our knowledge, only one study to date has evaluated comparative oncologic outcomes for RFA versus partial nephrectomy (PN) for RCC in a direct comparison within homogeneous contemporaneous patient cohorts [10]. Stern et al. reported actuarial 3-yr RFS rates of 91.4% versus 95.2% ( p = 0.58) for RFA versus PN in patients with unilateral spontaneous clinical T1a RCC, lacking confounding factors for post-treatment recurrence [10]. The purpose of the present study was to evaluate oncologic outcomes for RFA versus PN at a significantly longer minimum follow-up of 5 yr. 2. Materials and methods 2.1. Patients Through oncologic databases approved by our institutional review board, we identified 84 consecutive patients who underwent RFA and 56 who underwent PN for solitary ct1a RCC between December 1998 and November Only those with histologic confirmation of RCC and a minimum post-treatment follow-up of 5 yr with imaging were considered. Those presenting with synchronous multiple, metachronous, bilateral, and/or metastatic disease, a history of hereditary RCC syndromes, a family history of RCC, and/or post-treatment follow-up <5 yr were excluded from analysis. However, if a patient with disease progression was identified (metastasis and/or cancer-related death), he or she was included in this analysis regardless of duration of follow-up, given that a primary objective of our study was to estimate progressionfree survival (PFS) accurately Surgical methods RFA approach was percutaneous or laparoscopic, whereas PN approach was open or laparoscopic. Indication for treatment was a solid enhancing renal mass on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) that was worrisome for malignancy. Choice of approach was based on tumor size, location, clinical judgment, and/or patient preference; those with central or endophytic tumors were primarily offered PN or laparoscopic RFA as appropriate. Our surgical techniques for RFA, laparoscopic, and open PN were previously described [10,11]. During laparoscopic RFA or PN, a transperitoneal approach was used. The kidney surface was dissected, exposing the tumor. Laparoscopic ultrasound was used to size the tumor and to guide placement of the radiofrequency probe during RFA and to aid tumor identification and margin delineation during laparoscopic PN. A 14-gauge Starburst XL (RITA Medical Systems, Mountain View, CA, USA) was inserted percutaneously, and the treatment tines deployed to create an ablation zone that encompassed a 0.5- to 1-cm peritumoral margin. Ablation cycles of 5, 7, and 8 min at a target temperature of 105 8C were delivered for tine deployments of <2 cm, 2 4 cm, and 4 cm, respectively, with two cycles delivered per treatment. A 150-W radiofrequency generator (RITA Medical Systems) was used in each case. A 5-mm toothed laparoscopic forceps was then used to obtain a biopsy prior to conclusion of the procedure. Percutaneous RFA was performed using a similar protocol, but CT guidance was used for probe positioning, and a renal biopsy was obtained using a 20-gauge TruCut needle immediately prior to ablation. During PN, after mobilization of the kidney and renal hilum, the hilum was cross-clamped, the tumor excised sharply, and the renal defect repaired over oxidized cellulose bolsters Post-treatment follow-up Patient follow-up after RFA and PN included periodic history and physical, chest radiograph, contrast-enhanced abdominal CT or MRI, serum chemistries, and liver function tests. For RFA, these studies were obtained at 6 wk, 6 mo, 12 mo, and yearly thereafter. Incomplete ablation was defined as persistent enhancement in any portion of the treated lesion on the 6-wk CT or MRI and was managed by observation or repeat ablation. Complete treatment resulted when nonenhancement was achieved. Suspicious enhancement or lesion growth during subsequent follow-up prompted shorter interval imaging and/or renal biopsy prior to intervention. For PN, a similar follow-up protocol was followed but at yearly intervals. The follow-up routine for each patient varied only slightly according to the treating surgeon s preference and imaging findings. When necessary, patients and/or referring physicians were contacted for missing follow-up imaging data. Uncertainty in radiology reports regarding possible recurrences was resolved by consultation with staff having considerable experience in the interpretation of postablation imaging findings Definitions of recurrence We used definitions for survival outcomes similar to those used by the American Urological Association (AUA) small renal mass guideline panel [1], as applied to the study follow-up period. Local RFS referred to the proportion of patients without any disease in the ablation zone, PN defect, or the remainder of the treated kidney. MFS was the proportion of patients without disease anywhere in the body other than the treated kidney. Cancer-specific survival (CSS) was the proportion of patients that did not die from RCC; overall survival (OS) was the proportion of patients that did not die from any cause. Overall disease-free survival (DFS) was the proportion of patients free from total recurrence (local recurrence plus metastatic recurrence). We calculated 95% confidence intervals (CIs) for each survival probability Statistical methods Survival analysis was performed using the Kaplan-Meier method, and survivor curves were compared using the log-rank test. Demographic

3 1158 EUROPEAN UROLOGY 61 (2012) and clinical data were analyzed using the Mann-Whitney U test for continuous and ordinal variables, and the chi-square test for categorical variables. Two-tailed hypothesis tests were used in each case, and a p value 0.05 was considered statistically significant. Univariable and multivariable regression analyses to determine predictors of recurrence were performed. Statistical analyses were performed using Stata v.10 statistical software (StataCorp, College Station, TX, USA). 3. Results A total of 37 patients in each group met the selection criteria (Fig. 1). Table 1 summarizes the patient characteristics. Overall, the RFA cohort was significantly older ( p = ) and had a significantly higher proportion of patients with an American Society of Anesthesiologists (ASA) score 2 ( p = 0.03). All other baseline patient characteristics were similar (Table 1). Median follow-up for RFA versus PN was 6.5 yr (interquartile range [IQR]: ) versus 6.1 yr (IQR: ) ( p = 0.68). The 5-yr OS (95% CI) was 97.2 ( ) versus 100% ( p = 0.31), and CSS was 97.2 ( ) versus 100% ( p = 0.31), respectively (Fig. 2a and 2b). Disease progression occurred in one patient in each group. An RFA patient with a history of prior nephrectomy for oncocytoma initially underwent incomplete ablation for a 3.5-cm clear cell RCC. He was observed given his significant medical comorbidities but developed pulmonary metastases 1.2 yr postablation and died of metastatic disease 5 mo subsequently. A patient who underwent open PN with negative margins for a Fuhrman grade 2 pt1a clear cell RCC developed a biopsy-confirmed [(Fig._1)TD$FIG] Table 1 Demographic and clinical characteristics RFA PN p value n Follow-up, yr, 6.5 ( ) 6.1 ( ) 0.68 median (IQR) Age, yr, median (IQR) 63.8 ( ) 54.8 ( ) Male/female 24/13 20/ Ethnicity, n (%) White 27 (72.9) 29 (80.6) 0.25 African American 6 (16.2) 2 (5.4) 0.13 Hispanic 1 (2.7) 2 (5.4) 0.56 Other 3 (8.1) 3 (8.1) 1.0 ASA score, n 0.03 * Tumor size, cm, 2.1 ( ) 2.5 ( ) 0.44 median (IQR) Surgical approach, n (%) Percutaneous 25 (67.6) Laparoscopic 12 (32.4) 28 y (75.6) Open 9 (24.4) Tumor histology, n (%) Clear cell 25 (67.6) 28 (77.8) 0.34 Papillary 9 (24.3) 3 (8.3) 0.06 Chromophobe 1 (2.7) 3 (8.3) 0.29 Not specified 2 (5.6) 2 (5.6) 1.0 RFA = radiofrequency ablation; PN = partial nephrectomy; IQR = interquartile range; ASA = American Society of Anesthesiology. * The p value is for comparison of ASA categories for RFA versus PN using the chi-square test. y Includes one patient who was converted to open PN. Fig. 1 Flowchart of included patients. NED = no evidence of disease; PN = partial nephrectomy; RCC = renal cell carcinoma; RFA = radiofrequency ablation.

4 [(Fig._2)TD$FIG] EUROPEAN UROLOGY 61 (2012) p = 0.78; 5-yr local RFS was 91.7 ( ) versus 94.6 ( ); p = 0.96); and 5-yr MFS was 97.2 ( ) versus 91.8 ( %); p =0.35). Table 2 presents detailed information on recurrences. Univariable and multivariable analysis revealed that age, tumor size, duration of follow-up, histology (clear cell vs non clear cell), and approach (RFA vs PN) were not significant predictors of any of the oncologic outcomes analyzed. Table 3 shows these outcomes for overall DFS. For RFA, each of the oncologic outcomes was statistically similar for the laparoscopic versus the percutaneous approach. Overall, 2 of 37 patients (5.4%) in the RFA cohort had incomplete ablation. The first was discussed earlier. The second had an incompletely ablated 3.4-cm clear cell RCC that was subsequently successfully reablated, and he remains disease-free 5.3 yr after retreatment. Two additional patients underwent biopsy for suspected recurrence, but histology showed necrotic tissue only with no viable tumor. They remain without evidence of recurrence >5 yr after initial treatment. 4. Discussion Fig. 2 (a) Overall survival and (b) cancer-specific survival for radiofrequency ablation (RFA) versus partial nephrectomy (PN). 1.2 cm local recurrence 26 mo subsequently. He underwent salvage radical nephrectomy, with renal vein involvement identified histologically. After a 31-mo disease-free interval, he then developed retroperitoneal and lung metastases, which progressed while on targeted therapy. He died approximately 4 yr later. Figure 3a 3c shows comparative outcomes for DFS, local RFS, and MFS for RFA versus PN. Respective 5-yr DFS (95% CI) was 89.2 ( ) versus 89.2 ( ); Open PN is currently considered the gold standard treatment for ct1a RCC, and RFA is considered an option for high surgical risk patients [1,2]. One of the major reasons for this guideline recommendation by the AUA and European Association of Urology was lack of long-term oncologic efficacy data for RFA. However, more recent series have reported long-term oncologic outcomes for thermal ablation that mirror those for extirpative surgery [4,5,12]. Only one study, however, has directly compared RFA with PN in homogeneous contemporaneous patient cohorts, reporting intermediate-term outcomes [10]. In the present selective series, 5-yr OS and CSS were statistically similar for RFA and PN, each exceeding 95%. Additionally, 5-yr local RFS, MFS, and overall DFS were statistically similar for the cohorts. By excluding patients with risk factors independently associated with an increased likelihood of recurrence after RCC treatment, we believe that this series more accurately evaluates the long-term oncologic efficacy of RFA, establishing equivalency to that for Table 2 Details on recurrences Recurrence type n Detection and treatment details RFA Local recurrence 3 One underwent Nx at 24 mo with pathology that showed giant cell reaction only; one reablated at 21 mo, now NED; one recurrence identified on CT at 22 mo, proven by biopsy, then underwent radical Nx. Metastatic recurrence 1 Had incomplete ablation; was observed; then developed pulmonary metastases at 14 mo. PN Local recurrence 3 * One detected at 48 mo, being observed; one detected at 60 mo underwent radical Nx; one detected at 26 mo underwent radical Nx but had metastatic progression 31 mo after Nx. Metastatic recurrence 3 * Two developed metachronous recurrence; one detected at 60 mo being observed; the other detected at 25 mo was managed by RFA-assisted PN. One patient (marked by *) developed distant metastases 31 mo after radical Nx for local recurrence (see above), had disease progression over 4 yr while on targeted therapy, and eventually died about 8.5 yr after initial treatment. RFA = radiofrequency ablation; Nx = nephrectomy; NED = no evidence of disease; CT = computed tomography; PN = partial nephrectomy. * One patient initially developed a local recurrence that was treated, after which he developed metastatic disease.

5 1160 [(Fig._3)TD$FIG] EUROPEAN UROLOGY 61 (2012) Fig. 3 Comparative (a) disease-specific survival, (b) local recurrence-free survival, and (c) metastasis-free survival for radiofrequency ablation (RFA) versus partial nephrectomy (PN). nephron-sparing surgery for T1a RCC. As reflected by the median age and ASA score distribution of our RFA cohort, this treatment was initially offered primarily to elderly patients and those with significant medical comorbidities who were poor surgical candidates but yet desired active treatment. The excellent cancer control among those surviving a minimum of 5 yr post-treatment suggests that indication for RFA may be extended to select younger, healthier patients who desire a minimally invasive therapeutic option. However, further prospective studies in additional patient populations will be needed prior to more widespread clinical applicability. Our oncologic outcomes mirror those reported in individual long-term RFA [3,4,6] and PN [13 15] series. However, as previously mentioned, limitations of the RFA series were small numbers of patients with >5 yr of followup and heterogeneous patient populations. Nonetheless, the combined favorable outcomes from this and other series is further supportive evidence of the long-term efficacy of this relatively new technology. Although encouraging, it is worth mentioning that ablative surgery and technical success requires training, experience, and careful patient selection. Additionally, better indications of treatment failure are needed to optimize follow-up because radiologic criteria alone can be inconsistent and variable, prompting additional invasive interventions. In our experience, equivocal radiologic findings resulted in interventions in three patients, including one radical nephrectomy (with final pathology confirming only giant cell reaction) and two renal biopsies where histology revealed giant cell inflammation Table 3 Univariable and multivariable regression analyses evaluating risk factors for overall disease-free survival Covariate Univariable analysis Multivariable analysis OR 95% CI p value OR 95% CI p value Age Tumor size Years of follow-up Histology (clear cell vs non clear cell) ; NA Treatment approach (RFA vs PN) OR = odds ratio; CI = confidence interval; NA = not applicable; RFA = radiofrequency ablation; PN = partial nephrectomy.

6 EUROPEAN UROLOGY 61 (2012) and necrosis only. This occurred early in our experience with RFA and underscores the modest learning curve associated with the procedure. Our study has a few limitations that warrant discussion. First, the data are retrospective, introducing the potential for selection bias and additional confounders. Second, given factors such as referral patterns to our institution and the wide variability of RFA devices among others, our outcomes may not by generalizable to other centers. Third, given the loss to follow-up in a significant number of patients, our progression and recurrence-free outcomes may be underor overestimated. However, we believe that the true values for these outcomes most likely fall within the estimated 95% CIs. Reproducible anatomic tumor characteristics such as RENAL nephrometry or PADUA scores were not reportable, which may limit future comparison across series. Additionally, the modest sample size and low number of events limited the statistical power of our analyses. A retrospective power calculation revealed that our study had 21% power to detect a 10% difference in the primary outcome of MFS, based on the final sample size of 37 patients per group; however, the accuracy of this calculation is limited by small sample size and low event rate. Lastly, despite relatively homogeneous patient cohorts, multiple approaches for RFA and PN were included in our analysis, which could potentially introduce variation in treatment efficacy. Despite these limitations, we believe that our findings importantly highlight excellent and durable 5-yr oncologic outcomes achievable with RFA, which are comparable with those for extirpative surgery in appropriately selected patients. Given the added benefits of decreased morbidity and excellent preservation of renal function as compared with surgical approaches [16], we believe that it is it an attractive addition to the urologist s armamentarium of treatment options for small renal masses. 5. Conclusions In appropriately selected patients, RFA is an effective minimally invasive therapy for the treatment of ct1a RCC, yielding equivalent long-term oncologic outcomes to nephron-sparing surgery. Prospective randomized studies in diverse patient populations will help to further inform on its role as an acceptable treatment alternative to surgery for the definitive management of ct1a RCC. Author contributions: Jeffery A. Cadeddu had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Cadeddu, Olweny. Acquisition of data: Park, Tan, Best. Analysis and interpretation of data: Olweny. Drafting of the manuscript: Olweny. Critical revision of the manuscript for important intellectual content: Cadeddu, Trimmer. Statistical analysis: Olweny. Obtaining funding: None. Administrative, technical, or material support: Cadeddu. Supervision: Cadeddu. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. J Urol 2009;182: [2] Ljungberg B, Cowan NC, Hanbury DC, et al. EAU guidelines on renal cell carcinoma: the 2010 update. 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