|Ahead of print publication
Active surveillance in renal tumors: Clinical and oncological outcomes
Alfredo Aguilera Bazan1, Diego M Carrion2, Juan Gomez Rivas1, Jose Quesada-Olarte2, Luis M Quintana2, Mario Alvarez-Maestro1, Luis Martínez-Piñeiro1
1 Department of Urology, La Paz University Hospital; Universidad Autonoma de Madrid; La Paz University Hospital Institute for Health Research (IdiPAZ), Madrid, Spain
2 Department of Urology, La Paz University Hospital; Universidad Autonoma de Madrid, Madrid, Spain
Diego M Carrion,
Department of Urology, La Paz University Hospital, Paseo de la Castellana 261, Madrid 28046
Source of Support: None, Conflict of Interest: None
Context: Some patients diagnosed with small renal solid masses or complex cystic lesions may benefit from active surveillance (AS) instead of immediate treatment.
Aims: Report our series of patients undergoing AS for small renal solid and complex cystic lesions, and compare growth rates and outcomes between both types of lesions.
Materials and Methods: A retrospective review AS database for renal lesions was conducted. From 1995 to 2017, a total of 82 patients with 89 renal lesions were included. We describe our AS protocol, patient and tumor characteristics, comparisons between solid and cystic lesions, and final outcome of patients who underwent delayed intervention (DI).
Statistical Analysis Used: Categorical and continuous data were analyzed by the Chi-square and the Student's t-test, respectively. The Wilcoxon/Kruskal–Wallis test was used for growth rate comparisons of solid and complex cystic lesions.
Results: Median age of patients at the beginning of AS was 77-year-old, median size for solid and cystic lesions was 2.3 cm (0.08–3.8) and 2.6 cm (1.2–4.0), respectively. No differences in annual growth rate between solid and complex cystic lesions (0.04 cm [0.00–1.5] and 0.05 cm [0.01–1.7]) were observed at a similar median follow-up of 61 months for both groups (range: 15–182, and 14–254). Five patients with solid lesions underwent DI, 3 for rapid growth (>0.5 cm/year), 1 demanded treatment, and 1 due to hematuria. Adherence to AS protocol was high (94%). No cancer-related deaths or metastatic progression was observed, six patients died of another medical condition, being cardiovascular disease the most frequent cause.
Conclusions: AS is a reasonable and safe option for the management of small renal masses. No difference was observed in the growth rate between solid and complex cystic lesions during AS. Centers offering AS should present a standardized protocol and give exhaustive information to patients regarding benefits and risks.
Keywords: Active surveillance, comorbidity, delayed intervention, kidney cancer, renal cell carcinoma
|How to cite this URL:|
Bazan AA, Carrion DM, Rivas JG, Quesada-Olarte J, Quintana LM, Alvarez-Maestro M, Martínez-Piñeiro L. Active surveillance in renal tumors: Clinical and oncological outcomes. J Can Res Ther [Epub ahead of print] [cited 2020 Sep 18]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=264701
| > Introduction|| |
Renal cell carcinoma (RCC) represents 2%–3% of all cancers, with the highest incidence in Western countries. The increase in life expectancy and the wide use of diagnostic imaging methods such as ultrasound and computerized tomography (CT), has increased the diagnosis of solid and cystic renal lesions in the general population.
Elderly patients with high comorbidities and findings in imaging tests of incidental small renal masses have a low specific mortality.,, Due to the excellent oncological results, active surveillance (AS) and other therapeutic approaches alternatives to surgery have been incorporated into recent urological guidelines.,, AS is defined as the initial monitoring of lesion size by serial abdominal imaging with delayed intervention (DI) reserved for tumors showing clinical progression during the follow-up.,
One of the largest reported series, at more than 5 years of follow-up, showed that AS with or without delayed DI was a successful strategy in carefully managed patients. DI occurred during the first 2–3 years, becoming less likely over time, this study found rare metastasis and low cancer-specific mortality (CSM) rates in the intermediate to long-term follow-up.
We believe AS is a reasonable and safe option for the management of small renal masses. The primary outcome of the present study is to present our results of AS of renal solid and complex cystic lesions at our center. As a secondary outcome, we sought differences in outcomes and growth rate between solid and complex cystic lesions over time.
| > Materials and Methods|| |
We performed a retrospective review of our Institutional Board approved database for renal tumors and retrieved patients with renal solid and complex cystic lesions managed with AS from January 1995 to January 2017.
Inclusion criteria for AS were as follows: Patients ≥18 years of age with a localized, solid, contrast-enhancing (>20 HU) renal mass ≤4 cm (cT1aN0M0) on axial imaging (CT-scan), or complex renal cysts (Bosniak IIF-IV). Patients with a history of a hereditary RCC syndrome or with suspicion of metastatic disease to the kidney were excluded from the study.
All patients who met inclusion criteria met with their primary urologist and were counseled regarding AS and primary intervention. After discussing the risks and benefits, patients were offered enrollment in our AS protocol. Characteristics such as lesion metrics, and individual patient factors, including age, cardiovascular comorbidities, Charlson comorbidity index (CCI), co-existing diagnosis of any cancer, and patient willingness to undergo surgery were taken in count for the decision to proceed with AS. All patients underwent a complete history, physical examination, complete blood analysis, and baseline chest imaging to rule out metastatic disease. The beginning of AS for every patient was defined as the date of diagnosis of the renal mass with the initial axial image where metrics have been taken.
Follow-up during AS was performed in a standardized manner, by 2 consultants in our department, every visit included a complete physical examination, blood and urine analyses, and abdominal and thoracic imaging studies. Serial abdominal images were performed with CT and magnetic resonance imaging (MRI) at months 3 and 6, then every 6 6 months during the first 2 years. After the 2nd year and thereafter, if the mass remained stable, imaging studies were done every 6–12 months. Measurements were made at consistent anatomical levels in the kidney in a two-dimensional manner using a standardized desktop ruler on digital radiology view-box software. All CT Scans and MRIs were performed in the same hospital and dictated by the same team of abdominal radiologists. At any time during follow-up, if the patient decided to stop AS and receive DI, or a rapid growth pattern (≥0.5 cm/year) was detected on imaging, we proposed treatment with nephron-sparing surgery (NSS) or percutaneous radiofrequency ablation (RFA) whenever possible.
For the purpose of analysis, the study population was divided into patients who presented solid lesions and those who presented cystic lesions. Statistical analysis was performed using Statistical Package for the Social Sciences 20.0 software (SPSS Inc., Chicago, IL, USA). Quantitative variables were described with mean values and standard deviations or median values with range, qualitative variables were expressed with absolute frequencies and relative frequencies were expressed in percentages. Categorical and continuous data were evaluated by the Chi-square and the Student's t-test, respectively. The Wilcoxon/Kruskal–Wallis test was used for growth rate comparison between cystic and solid lesions.
| > Results|| |
Eighty-two patients with a total of 89 renal lesions met inclusion criteria and were consecutively enrolled in our database between 1995 and 2017. The median age of the entire cohort at the beginning of AS was 77-year-old (range 47–93), median CCI was 2 (range 0–7), 50 patients (61%) were male, and mean follow-up was 55 months (median: 61 months, range 14–254 months). About 35% of the patients who were initially enrolled presented complex cystic lesions, from which Bosniak cysts IIF were the most common (55%). Complete demographics are depicted in [Table 1].
|Table 1: Demographics of 82 patients who underwent active surveillance for small renal tumors|
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Differences among patients with solid and cystic lesions can be found in [Table 2]; no statistical significance was found when analyzing age, CCI, DI, death from other causes, and follow-up time. On the other hand, we performed an analysis stratifying solid and cystic lesions separately, without finding differences regarding lesion localization, initial and final lesion size, and annual growth rate [Table 3].
|Table 2: Characteristics of 82 patients stratified according to lesion type|
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|Table 3: Characteristics and growth rates of 89 renal lesions followed in our series|
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No growth was observed in 12 patients with cystic lesions, and in 17 patients with solid lesions during a median follow-up of 38 (14–114) and 62 (12–136) months, respectively. Overall 6 patients (7%) developed symptoms during follow-up. Four out of five patients with solid lesions presented microscopic hematuria, and the fifth presented macroscopic hematuria, whereas only one patient in the cystic lesion group presented related symptoms (intermittent flank pain that was treated with nonsteroidal anti-inflammatory drugs).
A total of five patients (6%), all with solid lesions, underwent DI [Figure 1], in 3 cases due to rapid growth (≥0.5 cm/year), 1 case due to incoercible hematuria, and 1 because the patient demanded treatment. Two patients underwent surgery with radical nephrectomy (maximal diameter of solid lesions was 4.8 cm and 5.6 cm, respectively) with a final histopathological diagnosis of RCC (clear cell carcinoma, pT3, Fuhrman II) in the first case and oncocytoma in the second. Three patients were treated with successful RFA (prior biopsy showed clear cell carcinoma in all three cases) for lesions measuring at maximum diameter 2.4 cm in two cases, and 2.6 cm in the last. We did not observe any progression to metastatic disease or CSM during the follow-up. All-cause mortality was 7% (six cases): two patients died due to cerebrovascular disease, one case of an acute coronary syndrome, one after aspiration pneumonia, one case of breast cancer metastatic progression, and one patient of infectious cholangitis.
|Figure 1: Patients who received delayed intervention for their renal masses under active surveillance. DI = Delayed intervention, RN = Radical nephrectomy, RFA = Radiofrequency ablation, RCC = Renal cell carcinoma, CCRC = Clear-cell renal carcinoma|
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| > Discussion|| |
Nowadays, the word “Cancer” comprises a group of malignancies with completely different natural history. Recently, overdiagnosis and overtreatment have been recognized phenomena in incidentally detected cancers., Our series reports that AS for renal masses is a safe alternative to primary intervention in patients, and may propose a even higher benefit in elderly patients (median age 77 years) with a high load of comorbidities (median CCI: 2). There was no progression to metastatic disease or death associated with RCC during the time of follow-up.
Literature shows that up to 20% to 30% of renal masses <4 cm are of benign nature, and those which are malignant, tend to have a low degree of aggressiveness and metastatic capacity., The presence of small renal masses, especially in elderly patients with significant comorbidities brings the possibility of adopting a conservative attitude with other therapeutic approaches alternative to surgery. In our series, 40% of the patients studied were ≥80-year-old (24 solid and 9 cystic lesions), with 35% of the cases presenting a CCI ≥3 (21 solid and 8 cystic lesions).
Although it was described two decades ago, the CCI is still widely used to assess the status of patients, helping healthcare professionals in the decision-making process. In the original research, Charlson et al. highlighted a 10-year mortality rate of 59% for the group of patients with an index ≥3. In our series, overall mortality is 7%, with cardiovascular events being the main cause of death. In the selection of patients, although there is a standardized protocol, each patient is evaluated individually, and the psychological burden of patients is assessed, to foresee the acceptance and adherence of joining an AS protocol.
Even though the literature shows a high diagnostic sensitivity and specificity for the biopsy of the lesion previous to initiate AS;,, in our study, it has not been the usual practice for various reasons: (1) the efficacy for diagnosis of tumor subtypes that seems to have biopsies, was not evidenced in the early analysis of our series, (2) due to the advanced age and comorbidities of a large number of patients, it is likely that the biopsy result would not change the decision to continuing with the AS protocol, and (3) in our series, 35% of the lesions were complex cysts (Bosniak IIF-IV), in which the performance of the biopsy is clearly inferior.
The median size of the lesions in our study at enrollment (2.3 cm for solid and 2.6 for cystic lesions) is similar to other series, being an incidental finding in 93% of the cases., In some circumstances, masses >4 cm have been monitored due to the patient's age, the presence of important comorbidities or by the expressed consent of the patient to be in an AS protocol instead of receiving active treatment.
The median annual growth rate recorded in our series is low (0.04 cm/year for solid and 0.05 cm/year for cystic lesions), with no significant relationship with the initial lesion diameter and no difference regarding if the lesion was solid or cystic in nature. A scheme showing annual axial imaging of a 72-year-old patient who was initially enrolled in our AS protocol in 2012 for a left renal solid lesion is shown in [Figure 2]. There are some publications trying to find a correlation between the speed of growth with tumor aggressiveness, not finding any clear results. What does seem evident is that lesions <4 cm, rarely metastasize or present a high aggressiveness.,, Crispen et al., described in their work that the smallest lesions had the fastest growing rates. This situation is not reflected in our series, where the greatest growth is found in larger cystic lesions, although without being statistically significant when compared to solid lesions.
|Figure 2: Annual follow-up in 74-year-old patient who begun active surveillance for a clinically localized computed tomography 1a upper pole peripheral tumor in 2012. (a): 2012 computed tomography-scan 2.0 cm × 1.9 cm; (b): 2013 computed tomography-scan 2.2 cm × 2.3 cm; (c): 2014 2.2 cm × 2.5 cm, (d): 2015 computed tomography-scan 2.5 cm × 2.6 cm; (e): Magnetic resonance imaging 2.5 cm × 2.6 cm; (f): 2017 computed tomography-scan 2.5 cm × 2.7 cm|
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Regarding tumor progression, none of the cases has developed metastases until the time of the analysis, and none of the patients has died due to RCC within a median follow-up of 61 months for all lesions (no difference was found in median follow-up between solid and cystic lesions). As a general rule, the rate of systemic dissemination of the disease is usually low in the cases of small renal lesions. Pierorazio et al., found no disease dissemination in a multi-institutional study of 223 lesions under AS with a short follow-up (2.1 years). In a prospective multicenter study, Jewett et al. showed 1.3% of metastases in 151 tumors with a follow-up of 28 months. Brunocilla et al., with a larger follow-up (88.5 months), found 2 deaths from RCC in 60 patients (3.4%), reaching the conclusion that those with a fast tumor growth index have a greater risk of disease dissemination. In our series, we found an interesting case; an 81-year-old patient who, after 68 months of follow-up of a right peri-hilar solid mass (annual growth rate of 0.21 cm/year) underwent a laparoscopic radical nephrectomy due to several episodes of incoercible hematuria. Pathology results showed a high-grade RCC (pT3) with local invasion of perinephric fat. Surprisingly, after almost 7 years of postoperative follow-up, this patient did not develop distant metastases.
The most frequent causes of death among elderly patients diagnosed with renal masses are not related to RCC. In our series, we recorded 7% of deaths, all of them not related to RCC. Berger et al. analyzed in 697 patients the impact of age and comorbidities on the mortality of those undergoing nephrectomy for RCC, concluding that comorbidity is an independent prognostic factor for overall survival, reducing the beneficial effect of surgery.
Adherence to AS protocol was high (94%) in our series. Most of the literature demonstrates a 35% to 40% change in attitude (ending AS protocol and turning into active treatment/DI), most of them by the decision of the patient. We believe that the high adherence of patients to our protocol is due to a careful case selection, the slow average growth observed, and the implementation of a specialized consultation under our RCC-unit with two dedicated faculty members.
Whenever possible, small renal masses should undergo treatment with a curative intention with NSS approaches,, unfortunately, this was not possible in the two patients surgically treated in our cohort, due to lesion size and location. In the past years, several studies have addressed the benefits of preserving renal parenchyma and diminishing ischemia time as much as possible. Along from the options of minimally invasive NSS, the retroperitoneal laparoscopic approach allows an early identification of the renal artery for its control, while tumor enucleation offers the advantage of no warm ischemia with maximum preservation of healthy tissue. If arterial clamping is necessary, one innovative approach we believe it is worth mentioning is the use of local hypotension on demand during laparoscopic tumor enucleation.,
The percutaneous management of small renal masses (RFA, microwave ablation, or cryotherapy) facilitates the therapeutic approach in case of rapid growth or change in the patient's decision. Literature is growing in this sense and shows good oncological outcomes in short to medium term. Wagstaff et al. stated indications for the patients that would benefit from percutaneous approaches. The conclusions of the findings were that in the absence of randomized and prospective studies, percutaneous approaches provide good oncological control with a low rate of residual disease. In our series, three patients underwent treatment by RFA for biopsy-proven RCC, being successful in all cases, with no need for re-treatment.
Our study is not off limitations; one of them is the retrospective nature of the study with its intrinsic drawbacks. In some cases, the patient age and comorbidities could have influenced the acceptance of AS and the strong adherence to protocol. In addition, the absence of biopsy of the masses, although it probably would not have changed our attitude in a high percentage of patients, it is true that it would provide us much more information about the RCC subtype. Although most of the available data on AS protocols lack predefined eligibility criteria or rigorously defined follow-up schedules, in our department we have a defined inclusion/exclusion criteria with a clear follow-up schedule, making our protocol one of the highest in adherence in the current literature, giving to the data presented an added value.
| > Conclusions|| |
As our results show, AS is a reasonable and safe option for the management of small renal masses as long as there is adherence to the protocol.
There were no differences observed in the growth rate between renal solid and cystic lesions.
The information given to the patient must be exhaustive and presented in a protocol, implicating the patient actively in the decision-making process.
The rapid linear growth of the lesion, the psychological burden, or symptoms related may change our attitude regarding intervention.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Patard JJ, Rodriguez A, Rioux-Leclercq N, Guillé F, Lobel B. Prognostic significance of the mode of detection in renal tumours. BJU Int 2002;90:358-63.
Celtik KE, Shah PH, Patel VR, Moreira DM, George AK, Iacovelli V, et al.
Active surveillance for incidental renal mass in the octogenarian. World J Urol 2017;35:1089-94.
Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK. Five-year survival after surgical treatment for kidney cancer: A population-based competing risk analysis. Cancer 2007;109:1763-8.
Volpe A, Panzarella T, Rendon RA, Haider MA, Kondylis FI, Jewett MA. The natural history of incidentally detected small renal masses. Cancer 2004;100:738-45.
Finelli A, Ismaila N, Bro B, Durack J, Eggener S, Evans A, et al.
Management of small renal masses: American society of clinical oncology clinical practice guideline. J Clin Oncol 2017;35:668-80.
Ljungberg B, Albiges L, Bensalah K, Bex A, Gilles RH, Hora M, et al
. EAU guidelines on renal cell carcinoma. Presented at the EAU Annual Congress Copenhagen 2018. Arnhem, The Netherlands: EAU Guidelines Office; 2018.
Campbell S, Uzzo RG, Allaf ME, Bass EB, Cadeddu JA, Chang A, et al.
Renal mass and localized renal cancer: AUA guideline. J Urol 2017;198:520-9.
McIntosh AG, Ristau BT, Ruth K, Jennings R, Ross E, Smaldone MC, et al.
Active surveillance for localized renal masses: Tumor growth, delayed intervention rates, and >5-yr clinical outcomes. Eur Urol 2018;74:157-64.
Esserman LJ, Thompson IM, Reid B, Nelson P, Ransohoff DF, Welch HG, et al.
Addressing overdiagnosis and overtreatment in cancer: A prescription for change. Lancet Oncol 2014;15:e234-42.
Warren KS, McFarlane J. The Bosniak classification of renal cystic masses. BJU Int 2005;95:939-42.
Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. Solid renal tumors: An analysis of pathological features related to tumor size. J Urol 2003;170:2217-20.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 1987;40:373-83.
Marconi L, Dabestani S, Lam TB, Hofmann F, Stewart F, Norrie J, et al.
Systematic review and meta-analysis of diagnostic accuracy of percutaneous renal tumour biopsy. Eur Urol 2016;69:660-73.
Capitanio U, Volpe A. Renal tumor biopsy: More dogma belied. Eur Urol 2015;68:1014-5.
Richard PO, Jewett MA, Bhatt JR, Kachura JR, Evans AJ, Zlotta AR, et al.
Renal tumor biopsy for small renal masses: A single-center 13-year experience. Eur Urol 2015;68:1007-13.
Perez Gonzalez S, Aguilera Bazán A, Polo Lopez CA, Bañuelos Marco B, Diaz J, De la Peña Barthel J, et al.
Evolution of the clinical presentation of renal cancer. Fifteen years experience. Arch Esp Urol 2013;66:558-67.
Leveridge MJ, Finelli A, Kachura JR, Evans A, Chung H, Shiff DA, et al.
Outcomes of small renal mass needle core biopsy, nondiagnostic percutaneous biopsy, and the role of repeat biopsy. Eur Urol 2011;60:578-84.
Pierorazio PM, Johnson MH, Ball MW, Gorin MA, Trock BJ, Chang P, et al.
Five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: The DISSRM registry. Eur Urol 2015;68:408-15.
Sunela KL, Kataja MJ, Kellokumpu-Lehtinen PL. Changes in symptoms of renal cell carcinoma over four decades. BJU Int 2010;106:649-53.
Lughezzani G, Jeldres C, Isbarn H, Perrotte P, Shariat SF, Sun M, et al.
Tumor size is a determinant of the rate of stage T1 renal cell cancer synchronous metastasis. J Urol 2009;182:1287-93.
Smaldone MC, Kutikov A, Egleston BL, Canter DJ, Viterbo R, Chen DY, et al.
Small renal masses progressing to metastases under active surveillance: A systematic review and pooled analysis. Cancer 2012;118:997-1006.
Jewett MA, Mattar K, Basiuk J, Morash CG, Pautler SE, Siemens DR, et al.
Active surveillance of small renal masses: Progression patterns of early stage kidney cancer. Eur Urol 2011;60:39-44.
Crispen PL, Viterbo R, Boorjian SA, Greenberg RE, Chen DY, Uzzo RG. Natural history, growth kinetics, and outcomes of untreated clinically localized renal tumors under active surveillance. Cancer 2009;115:2844-52.
Brunocilla E, Borghesi M, Schiavina R, Palmieri F, Pernetti R, Monti C, et al.
Active surveillance for small renal masses diagnosed in elderly or comorbid patients: Looking for the best treatment strategy. Actas Urol Esp 2014;38:1-6.
Berger DA, Megwalu II, Vlahiotis A, Radwan MH, Serrano MF, Humphrey PA, et al.
Impact of comorbidity on overall survival in patients surgically treated for renal cell carcinoma. Urology 2008;72:359-63.
Ficarra V, Galfano A, Cavalleri S. Is simple enucleation a minimal partial nephrectomy responding to the EAU guidelines' recommendations? Eur Urol 2009;55:1315-8.
Pansadoro A, Cochetti G, D'amico F, Barillaro F, Del Zingaro M, Mearini E, et al.
Retroperitoneal laparoscopic renal tumour enucleation with local hypotension on demand. World J Urol 2015;33:427-32.
Cochetti G, Puxeddu E, Zingaro MD, D'Amico F, Cottini E, Barillaro F, et al.
Laparoscopic partial nephrectomy of thyroid cancer metastasis: Case report and review of the literature. Onco Targets Ther 2013;6:355-60.
Wagstaff P, Ingels A, Zondervan P, de la Rosette JJ, Laguna MP. Thermal ablation in renal cell carcinoma management: A comprehensive review. Curr Opin Urol 2014;24:474-82.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]