Active surveillance for clinically localized renal tumors: An updated review of current indications and clinical outcomes

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1 bs_bs_banner International Journal of Urology (2015) 22, doi: /iju Review Article Active surveillance for clinically localized renal tumors: An updated review of current indications and clinical outcomes Marco Borghesi, 1,2 Eugenio Brunocilla, 1 Alessandro Volpe, 3 Hussam Dababneh, 1 Cristian Vincenzo Pultrone, 1,2 Valerio Vagnoni, 1 Gaetano La Manna, 2,4 Angelo Porreca, 5 Giuseppe Martorana 1,2 and Riccardo Schiavina 1,2 Department of 1 Urology, 2 Medical and Surgical Sciences and 4 Nephrology, University of Bologna, Bologna, 3 Department of Urology, University of Eastern Piedmont, Maggiore della Carità Hospital, Novara, and 5 Department of Urology, Abano Terme Hospital, Abano Terme, Italy Abbreviations & Acronyms AML = angiomyolipoma AS = active surveillance CCI = Charlson Comorbidity Index RCC = renal cell carcinoma RTB = renal tumor biopsy SRM = small renal masses Correspondence: Riccardo Schiavina M.D., Department of Urology, University of Bologna, S. Orsola-Malpighi Hospital, 9 Palagi, Bologna, Italy. rschiavina@yahoo.it Received 17 November 2014; accepted 16 January Online publication 17 March 2015 Abstract: The widespread use of abdominal imaging has led to an increasing detection of small renal masses, and approximately 20 30% of those tumors will prove to be benign, with low metastatic potential if not immediately treated. In elderly or comorbid patients diagnosed with small renal masses, competing cause mortality seems to exceed cancer-specific mortality at short- and intermediate-term follow up. In these cases, surgery might represent an overtreatment, and an expectant management, such as active surveillance, might be proposed. According to the current available evidence, active surveillance is a safe and reasonable option for patients with renal tumors 4 cm (ct1a) and short life expectancy. A few studies with short-term follow up reported the preliminary results of active surveillance even in ct1b ct2 tumors, with acceptable risk of disease progression and mortality, even if this approach should be considered in this setting only for highly-selected and wellinformed patients. Furthermore, surveillance protocols can be proposed in selected patients with uncomplicated benign tumors, such as angiomyolipomas, in which active surveillance should be considered the initial standard management. At present, reliable clinical predictors of a tumor s growth rate and aggressiveness are not available. Renal tumor biopsy is useful in the clinical work-up of patients who are candidates for active surveillance, in order to improve patient selection based on tumor histological characterization. Despite the proof of safety offered by expectant management for small renal masses in selected patients, further prospective studies with longer follow up are required in order to confirm the indications and long-term oncological outcomes of active surveillance protocols for renal tumors. Key words: active surveillance, clinically localized renal tumors, percutaneous biopsy, renal cell carcinoma, small renal mass. Introduction Based on the GLOBOCAN estimates, over new cases of RCC were diagnosed in 2012, leading to approximately deaths in developed countries. 1 RCC currently accounts for 3 4% of all adult malignant neoplasms, with a growing incidence in the Western population. 2,3 The widespread use of non-invasive abdominal imaging has led to an increasing detection of renal tumors less than 4 cm in size, defined as SRM. 4 Partial nephrectomy is currently considered the standard of care for the management of such small, clinically localized renal tumors whenever technically feasible, because of equivalent oncological outcomes and lower renal function impairment when compared with radical nephrectomy. 5 8 Nevertheless, similar to other surgical procedures in urology, the conservative surgical treatment of every renal tumor, even if small, is not devoid of perioperative complications, which could lead to patient morbidity and impair overall survival outcomes. 9,10 Currently, a non-negligible number of clinically localized renal tumors are frequently diagnosed in patients that are suboptimal surgical candidates, because of older age or relevant comorbidities. 3 Furthermore, approximately 20 30% of SRM will prove to be benign at final histological examination, and will show low metastatic potential if not immediately treated. 11 Considering that the potential benefits of surgical intervention might be outweighed by the competing risks related to medical comorbidities, especially in elderly patients, an AS protocol could be a valid alternative in these selected cases Many studies reporting oncological outcomes of AS protocols have been 432

2 AS for clinically localized renal tumors published in the literature since the early 2000s, showing promising results at intermediate- and long-term follow up in selected patients with SRM, with a low risk of metastatic disease progression (1 2%). 11,15 22 Notably, all these reports are based on clinically localized tumors 4 cm in maximum diameter, and only a few studies showing the intermediate-term outcomes of AS for larger (ct1b ct2) renal tumors have been reported to date. 23 Furthermore, although the radiographic linear and volumetric growth pattern were shown to be useful indicators for aggressive behavior of SRM initially managed with AS, no convincing predictors of tumor growth rate or biological behavior of small renal cortical neoplasms have been yet described Based on these premises, the decision whether or not to carry out active surveillance in selected patients with clinically localized renal tumors can sometimes be challenging for the clinician. Even if the radiological detection of parenchymal kidney tumors is generally easier compared with upper urothelial tract tumors, the current diagnostic methods are not definitely able to accurately identify the malignant potential of all renal tumors. 24,25 In this scenario, a percutaneous renal tumor biopsy might play an important role in the decision-making in each individual patient, allowing to reduce the morbidity of any unnecessary procedure and maximize the effectiveness of treatments, either surgical or ablative. 13,26 Based on these relevant perspectives, we sought to offer a comprehensive and updated review of the current criteria, indications and results of active surveillance in patients with clinically localized renal tumor. Evidence acquisition We carried out a review of the literature using the MEDLINE and Scopus databases, including a free-text protocol using the terms active surveillance, renal cell carcinoma, small renal mass, renal tumors, percutaneous biopsy, and growth kinetics across the title and abstract fields of the records, using these limits: English language; humans; adults. Three authors (MB, EB and RS) separately reviewed all the retrieved abstracts and selected the papers reporting data about active surveillance for renal tumors, including those contributions evaluating the role of percutaneous biopsy of renal masses and studies reporting outcomes of active surveillance for kidney tumors. In a second step analysis, we carefully examined the full-length articles. Any discrepancy was resolved by open discussion. Other significant studies cited in the reference lists of the selected papers were also evaluated, based on the quality and the strength of the manuscript. Globally, at the end of the review process, a total of 61 representative papers were selected and discussed in the present review. Evidence analysis AS for renal tumors 4cm (SRM) It has been largely discussed how the risk of death from competing and non-cancer-related causes could exceed the risk of cancer-specific mortality for a clinically localized RCC in elderly and comorbid patients, especially if the tumor is smaller than 4 cm. 12,27 Furthermore, several previous studies showed that roughly 20% of SRM would behave as potentially aggressive RCC during their natural history, whereas more than half will show indolent biological behavior, and approximately 20% will be benign at definitive histological examination Therefore, in such patients with limited life expectancy and with high perioperative risk of surgical or medical complications, major urological surgery with general anesthesia for a SRM with negligible oncologic potential might not offer significant survival benefits. 31,32 The observation that many patients with a SRM might have a higher chance of dying from other causes rather than renal cancer, together with the awareness of a potential overtreatment, have represented a major input for AS protocols. 27 In this context, before any clinical or surgical management, the differentiation between benign or indolent forms and more aggressive renal tumors would be advisable, in order to select the most appropriate treatment for any individual patient. Percutaneous RTB currently plays an important role in the evaluation of SRM, and its application in clinical practice is progressively increasing, thanks to more convincing proof of safety and accuracy. 33 In the latest series, indeed, RTB morbidity was found to be very low, as well as the incidence of highgrade complications. In a recent review of the literature, Volpe et al. summarized the rationale and outcomes of renal tumor biopsy. 26 Interestingly, the authors showed an overall incidence of clinically relevant complications, requiring active treatment or hospital admission, of 0 2%. 26 The retroperitoneal hematoma, as a result of parenchymal bleeding after RTB, generally represents the most frequent event, but very rarely requires surgical treatment or embolization. 26,33 The fear of malignant cells needle-tract seeding could represent another argument against the use of RTB. Although in the past few cases of cancer dissemination along the percutaneous tract have been reported, in the modern series, with the use of coaxial biopsy techniques, the reports of tumor seeding have been anecdotal. 26 Renal mass biopsy, furthermore, allows in the majority of cases to distinguish benign lesions/indolent RCC, mostly suitable for AS regimens, from high-risk malignant tumors, requiring surgical extirpative or radical surgery. 14,34 Although in most cases a correct histological subtyping can be obtained in a single RTB core, the definition of the correct diagnosis in hybrid tumors (where different histological architectures are simultaneously present within the same mass) could be challenging. 33 Similarly, it might be difficult to distinguish chromophobe RCC from oncocytomas, even with the aid of immunohistochemical markers. 33 Even though the diagnostic accuracy is progressively improving, according to the current recommendations not all patients with SRM are ideal candidates to RTB, but only those patients in which a percutaneous biopsy is going to impact the future clinical management. 14,35 In these different scenarios, RTB could reduce the morbidity of unnecessary procedures and, in contrast, maximize treatment effectiveness. To date, the currently available series underline the feasibility and safety of active surveillance for ct1a RCC, but very little is known about the natural history of such tumors that have remained on AS for a long period. Indeed, outcomes of patients with SRM expectantly managed are based on studies with short- or intermediate-term follow up, on average approximately 3 years. 36 A detailed report of the clinical and oncological outcomes from the most representative AS series for ct1a renal tumors with retrospective or prospective design is shown 433

3 M BORGHESI ET AL. in Table 1. Of these contributions, just four reported a mean follow up longer than 3 years, and, remarkably, just two studies had an observation time higher than 5 years. 15,16,20,37 Among all reports, the mean linear growth rate was low, ranging from 0.1 to 0.4 cm/year, and only a few patients experienced progression to metastases (0 5.7%). Deaths from renal cancer-related causes were uncommon (Table 1), thereby highlighting the safety and feasibility of AS for SRM in selected patients. Similar results have previously been reported in other studies In a comprehensive meta-analysis of 10 studies from nine single-institutional series, Chawla et al. reported outcomes of 234 expectantly managed SRM. 11 The evaluated series included six to 40 patients, with a mean follow up of 34 months (median 32, range 26 39). In all series combined together, the mean tumor size at presentation was 2.6 cm (median 2.48 cm), and the mean linear growth rate was 0.28 cm/year. Remarkably, progression to metastatic disease was described in just three patients, representing approximately 1% of the entire cohort. No significant correlations between lesion size and overall growth rate were found (P = 0.46). 11 To date, only one phase II prospective trial evaluating the role and safety of AS for SRM has been reported. 41 In this relevant contribution, in which 178 patients diagnosed with 209 lesions in eight Canadian institutions were prospectively evaluated, the average growth rate was 0.13 cm/year, and 37% of the SRM showed zero growth. Metastatic tumor progression was recorded in just two patients (1.1%), who experienced cancer-specific mortality during follow up. With the aim to investigate the risk of metastatic progression, a systematic review of all reported cases of SRM progressing to metastases under AS was published by Smaldone et al. 22 Among 880 pooled patients, 18 developed distant metastases after a mean follow up of 40 months. Interestingly, among the 65 masses (23%) that showed zero growth under surveillance, none progressed to metastasis. When analyzing the clinical differences between these two groups, those patients with metastatic disease had larger tumors (4.1 ± 2.1 cm vs 2.3 ± 1.3 cm; P < 0.001) and a faster linear growth rate (0.8 ± 0.7 cm/year vs 0.3 ± 0.4 cm/year; P < 0.001) than those without systemic progression. 22 According to this evidence, and to the low risk of disease dissemination and development of metastases during AS protocols, the use of delayed active treatment appears to be feasible, with no limitations in the spectrum of treatment options offered and without significant risks for patients survival. Crispen et al.examined the kidney cancer database of the Fox Chase Cancer Center, with the aim to assess whether changes in method of treatment and disease recurrence could be observed with delayed management. 42 After retrospective review of the records of 82 patients diagnosed with 87 SRM who underwent AS with delayed treatment at a mean follow up of 14 months, no significant limitations in treatment options or increased disease progression were found. Indeed, 76% of patients were treated with nephron-sparing surgery, and 60% of these patients underwent a minimally invasive treatment, either with a laparoscopic or percutaneous approach. No patient developed metastatic disease before or after intervention, and no cancerrelated deaths were found in this cohort. 42 Based on the aforementioned results, especially those reported in studies with a larger cohort of patients and longer follow up, an initial AS protocol seems to be a safe and reasonable option for patients with small, slowly progressing renal mass, and with short life expectancy and increased perioperative risk. Notably, according to this proven evidence of feasibility and safety, both the European Association of Urology and American Urological Association guidelines recommend AS protocols as a first-line management option in selected patients, who are elderly and have decreased life expectancy or significant medical comorbidities, that would be associated with increased risk if a therapeutic intervention would be undertaken. 43,44 In the context of AS protocols, a RTB could be pursued as a part of the clinical work-up of SRM, and recommended to all patients in whom a histological confirmation would be helpful in choosing the proper management. Table 1 Most representative, non-redundant, retrospective and prospective series reporting data of active surveillance for ct1a renal tumors (SRM) Author Patients/tumors (n) Mean age (years) size (cm) growth rate (cm/year) Tumor biopsies, n (%) Mean follow up (months) Delayed surgery, n (%) Progression to metastases, n (%) Deaths, n (%) Chawla et al (1.6%) (32.8%) 1.6% 0 (0%) Volpe et al / (0%) (27.5%) 0% 2 (6.9%) Abou Youssif et al / (2.8%) (22.9%) 5.7% 9 (25.7%) Mason et al / (8.5%) (14.6%) 1.2% 7 (8.6%) 1 (1.2%) Brunocilla et al / (40.3%) (25.8%) 3.2% 18 (29%) 2 (3.2%) Crispen et al / (39%) 1.3% 0 (0%) Rosales et al / (19%) (5%) 1.9% 14 (6.6%) 1 (0.5%) Abouassaly et al / (5%) 24 4 (3.6%) 0% 34 (31%) Jewett et al / (55.6%) 28 9 (5%) 1.1% 10 (5.6%) 2 (1.1%) Haramis et al / (38.6%) (4.5%) 0% 1 (2.2%) Repetitive cohorts have not been included. Prospective, Phase II study. Non-cancer related deaths. Cancer-related deaths. 434

4 AS for clinically localized renal tumors AS for ct1b ct2 renal tumors To date, most of the published series have reported data of AS protocols only from patients diagnosed with tumors 4 cm. Conversely, the field of active surveillance for larger renal tumors still remains rather unexplored. Indeed, even if more detailed results regarding the feasibility and safety of AS have been reported for the former, the natural history of tumors greater than 4 cm expectantly managed remains poorly characterized. Dealing with a larger renal mass not always reflects a higher risk of metastatic progression or disease-specific mortality, and growth rates could perhaps be comparable with those of smaller tumors. 45 In a selected group of patients, such as elderly and sick patients, the competing risk from medical comorbidities could outweigh the potential benefits of a tumor s surgical extirpation even in this higher-risk population. To date, there has been a paucity of published data on the growth kinetics and clinical outcomes for ct1b or ct2 tumors managed with AS. A brief summary of the most relevant demographic, clinical and pathological data are reported in Table 2. The first report evaluating the natural history of large renal tumors left untreated was published in 2004 by Lamb et al. 46 The authors examined 36 patients diagnosed with kidney cancer, expectantly managed because of advanced age, severe comorbidities or high risk of postoperative dialysis. The mean patient age was 76.1 years, and the median tumor size was 6.0 cm (range cm). The median follow up was 24 months. A total of 13 patients (36.1%) died after a median time of 9 months after diagnosis for, but no cases of cancer-specific deaths were observed. Only one patient developed metastatic disease after 132 months from diagnosis, and was still alive at 136 months. The mean tumor size was roughly unchanged in most patients during the follow-up period. 46 In 2010, Mues et al. reported data on 36 patients diagnosed with 42 renal tumors larger than 4 cm, without detectable lymph node or metastatic involvement, scheduled for AS. 23 The mean patient age was 73.8 years, the mean tumor size was 7.13 cm and the median linear growth rate was 0.57 cm/year. Notably, more than half of the patients (19/36, 52.8%) were significantly comorbid (CCI 3), and just 25% of them were symptomatic at the time of presentation. 23 Percutaneous renal biopsies were carried out in one-third of patient (12 patients), and pathological examination showed 10 clear cell RCC, one chromophobe RCC and one undifferentiated tumor. At a mean follow up of 36 months, just five patients developed disease progression or systemic metastases and, of those patients with a mean growth rate of 2.8 cm/year, three were treated with laparoscopic radical nephrectomy. The final pathological examination showed clear cell RCC in all cases. Among the overall cohort of patients, just two (5.6%) progressed to metastases, and no cancer-related deaths were observed. 23 A more recent report from the Fox Chase Cancer Center with a larger cohort of patients has been published by Mehrazin et al. 47 In that study, 68 patients with 72 enhancing ct1b CT2 renal tumors were expectantly managed with AS for at least 6 months from the time of diagnosis. The mean age was 68.9 ± 12.2 years, the mean tumor size at the time of presentation was 5.3 ± 1.6 cm and the mean linear growth rate was 0.44 ± 0.45 cm/year. Even in that study, the median CCI was 3, with a range of The mean RENAL nephrometry score was 8.7 ± 1.6, thus suggesting anatomically intermediate to complex renal tumors. Renal tumor biopsies were carried out in 21 patients (31%). At a mean follow up of 38.9 ± 25.7 months, 45 patients remained on surveillance, whereas 23 underwent delayed surgical intervention because of a faster tumor growth rate, patient s choice, medical clearance or developing of symptoms related to the kidney tumor. Interestingly, compared with those who underwent delayed surgery, patients who remained on AS were older (77 vs 60 years; P = ) and had slower linear growth rate (0.37 cm/year vs 0.73 cm/year; P = 0.02). Conversely, no significant differences in terms of mean RENAL score or CCI were found among the two groups. 47 The most relevant data coming from the aforementioned studies is relative to the low number of metastatic disease progression, even in larger tumors, when managed with AS; indeed, just 2.7% and 5.9% of patients experienced disease progression in the studies by Lamb and Mues, respectively, and no cases were observed in the more recent report. Furthermore, no cancer-specific deaths were observed in these studies. 23,46,47 Nevertheless, these promising oncological outcomes should be carefully interpreted, mainly because of the intermediate to short-term follow up, approximately 3 years, which is too short to reliably comment on kidney cancer-related mortality. This important consideration, together with the awareness of the low number of patients with large renal tumor managed with AS to date, make these results preliminary. Therefore, at present, an AS protocol for larger T1b T2 renal tumors should be considered only for highly-selected and well-informed patients. AS for benign tumor (angiomyolipoma) Renal AML are benign tumors of the kidney, accounting for approximately 3% of all renal masses. 48 The fatty component of AML is easily identified during computed tomography, and the clinical diagnosis is generally carried out at the time of computed tomography scans or magnetic resonance imaging Table 2 Contemporary series reporting data of active surveillance for ct1b ct2 renal tumors Author Patients/tumors (n) Mean age (years) size (cm) growth rate (cm/year) Tumor biopsies, n (%) Mean follow up (months) Delayed surgery, n, (%) Progression to metastases, n (%) Deaths, n (%) Lamb et al / (0%) 1 (2.7%) 13 Mues et al / (33%) 36 5 (13.8%) 2 (5.6%) 4 Mehrazin et al / (31%) (34%) 0 9 Non-cancer related deaths. 435

5 M BORGHESI ET AL. in most cases. 49,50 The current guidelines on AML suggest a prophylactic treatment in patients with large tumors, women of child-bearing age and patients in whom follow up or access to emergency care might be inadequate, assuming a high probability of complications. 5 Elective active treatments for AML are represented by angioembolization or surgery (partial or radical nephrectomy). 5 To date, whether to carry out a prophylactic intervention in every single case is controversial, and the optimal size threshold for active surgical intervention is still debated. 48 Furthermore, given the paucity of series in the literature reporting outcomes after active treatment or AS, the natural history of such benign tumors is poorly understood, and the risk of a potential surgical overtreatment remains high, even if still undefined. Unlike malignant neoplasms, in which the fear of metastatic progression represents urologists main concern when scheduling a patient on AS, in case of benign tumors this worrisome problem is absent, and surveillance aims exclusively to avoid long-term impairment of renal function and complications that inevitably could threaten the patient s postoperative recovery. However, it is noteworthy that the most important risk when proposing expectant management for AML is bleeding, both retroperitoneal or in the upper urinary tract, which could potentially be life threatening. 51 Therefore, the benefits offered by AS in a patient diagnosed with AML should always be balanced with the risks of spontaneous complications of a fast-growing benign tumor. Currently, a high level of evidence answering the question of whether surgical intervention or angioembolization are superior to AS is lacking. Several retrospective series have shown the feasibility of AS for AML The identification of clinical predictors showing the need for delayed active treatment, thus allowing to minimize the risk of spontaneous complications, would be extremely useful in AS protocols. With the aim to answer this relevant question, Ouzaid et al. reported outcomes from a retrospective cohort of 130 patients diagnosed with AML on computed tomography imaging and managed with AS at the Glickman Urological and Kidney Institute. 56 The mean patient age was 53.3 ± 16.5 years, and the vast majority of enrolled patients were female (77.7%). A total of 70% of tumors were less than 4 cm at the time of diagnosis, and 28 patients (21%) were symptomatic (flank pain and hematuria). After a mean follow up of 49 ± 40 months, 17 patients (13%) underwent delayed surgical intervention, because of increased flank pain, their tumor s fast growth rate, gross hematuria, retroperitoneal hemorrhage or the patient s preference. Interestingly, tumor size >4 cm and symptomatic presentation were found to be clinical predictors of delayed surgical treatment at the multivariate analysis. No significant AS failures or deaths from any cause were reported. 56 These results are comparable with those reported in the smaller series by De Luca et al. 53 Conversely, Mues et al. did not find statistically significant correlations between clinical predictors (such as tumor dimension, growth rate or symptoms) and the need for active treatment. 52 In that study, among 91 patients diagnosed with AML, 48 were placed on AS as primary management. At a median follow up of 54.8 months, AS failed only in three patients because of retroperitoneal bleeding or fast growth rate (0.7 cm/year). In the other group of patients who remained on AS, the mean growth rate was very low (0.09 cm/year), and no relevant complications were found. 52 These studies, even if necessarily biased from a low level of evidence deriving from their retrospective design, currently represent the only available reports showing the feasibility and safety of AS for AML. According to the reported outcomes, active surveillance protocols for such benign lesions with habitual benign behavior can be advisable in selected patients, such as those with tumor size smaller than 4 cm, asymptomatic disease and slow growing tumors, and should be considered the standard for all uncomplicated AML at presentation. Predictive factors of renal tumor aggressiveness and growth rates Despite a great deal of evidence showing slow growth rates and low malignant potential, the natural history of SRM has not been yet clarified. 11,18 20 A better understanding of their growth kinetics and biological behavior would be a significant step forward for the clinician, and an important support when suggesting an AS protocol to the patient as the first-line management for SRM. In the vast majority of the previously published series, the growth patterns among patients initially scheduled for AS and treated with delayed surgical intervention were found to be significantly higher than those who remained on surveillance. 11,17 20,22 Apparently, considering that most patients treated with delayed surgery had been diagnosed with RCC, growth patterns could represent good clinical predictors of aggressive biological behavior of SRM, and can suggest the need for a delayed surgical treatment. Furthermore, even the mode of presentation (symptomatic vs asymptomatic) of a small cortical tumor could reflect its biological aggressiveness and serve as useful indicator when proposing AS. In a recently published study, Schiavina et al. evaluated the clinical predictors of tumor growth rate in a retrospective cohort of 70 patients diagnosed with 72 SRM, and stratified results by dividing the participants into two subgroups (AS vs delayed surgery groups). Interestingly, male sex was found to be a significant predictor of tumor growth rate in both the overall cohort of patients (HR 1.70, P = 0.04) and AS subgroup (HR 1.78, P = 0.03). 57 Similarly, symptomatic tumors at the time of diagnosis showed faster growth rates than the counterparts in the overall patient population (HR 1.85, P = 0.02), in the AS and delayed surgery group (HR 1.92 and 1.82, respectively; P = 0.02). 57 Matsumoto et al., in their retrospective, single-institutional study, showed the results of 47 patients diagnosed with SRM scheduled for AS or surgery, with a median follow up of 24 months. 58 In that report, male sex was not significantly associated with faster tumor growth rates. On the contrary, the RENAL nephrometry score on initial imaging was found to be a significant predictor of growth kinetics at both univariate and multivariate analyses. 58,59 Organ et al., in their multi-institutional, prospective phase II clinical trial from the Renal Cell Carcinoma Consortium of Canada, reported results on 207 SRM initially managed with AS with a median follow up of 603 days. Notably, no significant clinical or radiological predictors of growth kinetics were found. 60 The predictive role of tumor dimension at the time of presentation has been a matter of debate in literature. In the study by Schiavina et al., the size was not a significant predictor of growth kinetics. 57 Similar results have been reported by others. 9,55 57 On the contrary, several studies showed 436

6 AS for clinically localized renal tumors significant correlations between tumor size at the time of diagnosis and its growth rate. Mason et al. showed that larger ( 2.45 cm) renal masses will grow more quickly than smaller (<2.45 cm) ones, with higher risk to develop metastatic disease. 17 Based on these critical considerations, the clinical decision-making for patients with localized renal tumors is complex. A myriad of factors, such as age, competing health risks, tumor anatomy, contralateral renal status and patient s preference generally affect the treatment decision. Recently, Tomaszewski et al. examined the Fox Chase Cancer Center s prospectively maintained database of ct1a ct1b renal tumors, and compared patients who underwent an initial AS with those who proceeded to immediate surgery. 61 The aim of their investigation was to evaluate which tumor s characteristic, beyond tumor size or growth rate, could influence the decision of whether to safely select patients for an AS protocol or not. Interestingly, the authors found that tumor anatomical complexity, expressed by the RENAL nephrometry score, was strongly correlated to the urologist s decision. Indeed, patients scheduled for AS had a lower overall nephrometry score, with smaller tumors, further from the sinus or collecting system, more often polar and less often hilar (P < ) than patients undergoing immediate surgical treatment, maybe because simple renal tumors are deemed less worrisome than the more complex counterpart. 61 Based on these results and on the non-negligible limitations of the aforementioned studies, especially related to the common retrospective design and the low number of patients, convincing proof of correlations between clinical predictive factors, and tumor growth rate and aggressiveness does not yet exist. Nevertheless, we believe that these data could serve as preliminary arguments for more accurate patient enrolment and follow up during AS, as well as for planning more comprehensive and thorough prospective studies. Conclusion Active surveillance seems to be a reasonable alternative to surgery or ablative therapies for patients with incidental ct1a renal tumors who have relevant comorbidities or are unfit for surgery, with low reported risk of metastatic progression and cancer-specific mortality. In the presence of ct1b ct2 renal masses, surveillance protocols are currently not supported by strong evidences or proof of safety, and should be therefore recommended only in highly-selected and wellinformed patients, based on the non-negligible risk of disease progression under surveillance. Furthermore, AS represents a valid first-line management option in patients diagnosed with asymptomatic AML. The oncological outcomes are the most relevant end-points of studies regarding the feasibility and safety of AS protocols, and represent the main concern of every urologist proposing conservative, non-interventional management. The pathological information obtained by percutaneous tumor biopsies at diagnosis, and the identification of clinical predictive factors of tumor aggressiveness and growth rate are useful for a proper patient selection, which is crucial together with proper indications for delayed intervention in order to minimize the risk of disease progression and mortality during AS. Further prospective studies with large cohorts of patients and longterm follow up are required in order to confirm the indications, feasibility and safety of active surveillance protocols for renal tumors. Conflict of interest None declared. References 1 Ferlay J, Soerjomataram I, Ervik M et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. International Agency for Research on Cancer, Lyon, France, Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics. CA Cancer J. Clin. 2014; 64: Ljungberg B, Campbell SC, Choi HY et al. The epidemiology of renal cell carcinoma. Eur. 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