Triggers for Delayed Intervention in Patients with Small Renal Masses Undergoing Active Surveillance: A Systematic Review - Beyond the Abstract

While the incidence of renal cell carcinoma (RCC) has been increasing worldwide, patient survival has not improved as dramatically,1 suggesting potential treatment disconnect inherent to overdiagnosis and overtreatment of indolent and benign tumors.2-4

In this scenario, active surveillance (AS) represents a feasible and acceptable initial strategy for the management of small renal masses (SRMs). It allows indeed to avoid the risks of invasive interventions, preserving maximal renal function, and delaying treatment until it is necessary.5,6 As such, while the selection of those patients who are most likely to benefit from AS remains a nuanced decision-making process,5-8 all major guidelines and opinion-leaders nowadays consider AS an option for patients with SRMs.7-9

Nevertheless, AS remains underutilized.5 The ultimate reasons for such underutilization are likely complex and multifactorial. Yet, one key factor is represented by the current lack of consensus and guidance on the triggers prompting delayed intervention in patients undergoing AS.7-9

To fill this gap, in our study published in Minerva Urologica e Nefrologica,10 we aimed at investigating the actual triggers for delayed intervention in patients followed with AS for SRMs. For this purpose, we conducted a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations using the MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials, and Web of Science (WOS) databases.

A specific PICO framework defined the study eligibility for our review. Studies were included in the qualitative analysis if they included patients with nonmetastatic SRMs (< 4cm) (P), managed with AS (I), with or without a comparative (C) study group, and reporting the actual triggers for delayed intervention (O), defined as the specific patient-, tumor- or physician-related factors ultimately driving the choice to switch from AS to active treatment. Studies that did not report enough data on the selection criteria for AS at patient enrollment, the timing and intensity of the AS protocol, and the oncologic outcomes of patients undergoing delayed intervention, were excluded from the review. 

Our search strategy ended up with the inclusion of 10 prospective studies,11-20 published between 2006 and 2018, including 1870 patients. Most studies were performed in the US or Canada. Of these, five were single-center and five multicenter, of which three prospective AS Registries (RCCCC, DISSRM, TUCAN). Overall, the quality of the evidence according to GRADE was low, and only a minority of studies (10 out of 122 screened for final eligibility) detailed the list of actual triggers for delayed intervention (rather than the potential triggers as per AS protocol). 

Considering the 10 studies included in the review, the overall median (or mean) patient age ranged between 64 and 75 years. Only a few studies provided information on patients’ comorbidity burden and/or performance status at enrollment. The factors driving the decision-making toward AS were generally patient age (or comorbidity burden), tumor size, or patient preference. 

The overall median (or mean) tumor size at diagnosis ranged from 1.7 to 2.3 cm; yet, the range (or IQR) of tumor diameters was highly variable across the included series. The proportion of cystic SRMs ranged from 0 to 30%. No study reported a nephrometry characterization of SRMs using validated tools to assess the tumor’s complexity. Notably, the proportion of patients undergoing RTB before enrollment in the AS protocol was highly variable across the 10 included series, ranging from 7% to 45.2%. Likewise, among patients undergoing RTB, the rate of malignant SRMs was variable (range: 28.5% - 83.3%). 
Despite a variable tumor growth rate across the included series, the overall median (or mean) growth rate of SRMs ranged between 0.10 and 0.27 cm/year.

The proportion of patients with SRMs undergoing delayed intervention after a period of AS among the included series ranged between 7% and 44%, with a median length of AS period ranging between 12 and 27 months. The reasons for this variability across the AS studies are likely the critical differences in patient-, tumor- and/or physician-related factors driving the decision-making toward AS, the use of RTB, and the inherent heterogeneity of SRMs. 

The key finding of our review is that not only tumor-related but also patient-related factors can be important triggers for delayed intervention in patients with SRMs managed with AS. Among tumor-related factors, the most reported included (in order of relevance): a) renal mass growth (increasing mass diameter); b) stage progression (shift from cT1a to >cT1b stage or development of metastatic disease) and c) development of local complications (i.e. renal vein thrombosis or spontaneous retroperitoneal bleeding) or clinical symptoms (gross haematuria). 

On the contrary, the most commonly reported patient-related factors driving the decision of delayed intervention were (in order of relevance): 1) patient preference; 2) “improved medical conditions”; 3) qualification for other surgical procedures; and 4) patient “anxiety”. 

Of note, we found favorable oncologic outcomes in patients receiving delayed intervention after an initial AS period in the series included in our review. Indeed, at a median follow-up of 21.7 – 57.6 months, the proportion of patients experiencing metastatic disease, cancer-specific, and other-cause mortality was 0-3.1%, 0-4%, and 0-45.6%, respectively. 

To date, few registered prospective Registries from both North America and Europe are enrolling patients with SRMs in AS protocols: these cohorts will refine our knowledge on the potential triggers for delayed intervention among patient-, tumor, and physician-related factors. Nonetheless, to minimize the harms of overtreatment of SRMs, further research is needed to improve the current strategies for AS.21,22 This will likely rely on accurate prediction of life expectancy and patient’s frailty, use of nomograms incorporating tissue-based biomarkers and/or new technologies for evaluation of renal core biopsies, and improved understanding of SRM’ inherent heterogeneity. Notably, patient preference and values will likely have an increasingly central role in decision-making in patients with SRMs. 

Written by: Riccardo Campi1,2, Alessandro Berni1, Francesco Esperto3, Francesco Sessa1,2, Umberto Capitanio4, Alessandro Volpe5, Alexander Kutivok6, Phillip M. Pierorazio7, Francesco Porpiglia8, Andrea Minervini1,2 & Sergio Serni1,2

  1. Department of Urology, Careggi Hospital, University of Florence, Florence, Italy; 
  2. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; 
  3. Department of Urology, Campus Bio-Medico University, Rome, Italy;
  4. Division of Experimental Oncology, Unit of Urology, IRCCS San Raffaele Hospital, Milan, Italy; 
  5. Department of Urology, University of Eastern Piedmont, Maggiore della Carità Hospital, Novara, Italy; 
  6. Division of Urology and Urologic Oncology, Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA; 
  7. Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  8. Division of Urology, Department of Oncology, School of Medicine, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.

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