Active Surveillance for Small Renal Masses: Lessons Learned over the Past Decade with a Focus on the DISSRM Registry
Keywords: small renal masses (SRM), benign lesion, malignant tumor, DISSRM registry, active surveillance, renal mass biopsy, growth rate, pulmonary imaging.
Corresponding Author: Joseph Cheaib, MD, MPH, Post-Doctoral Research Fellow, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Park 200E, Baltimore, MD 21287; P: 410-972-8080 | Email:email@example.com
Small renal masses (SRM), defined as solid cortical neoplasms of the kidney less than 4 cm, comprise approximately 40% of all newly diagnosed renal tumors and are most-often detected incidentally when working up another medical complaint.1-4 The discovery of a SRM presents a substantial challenge to patients and their health- care providers. Given the biological heterogeneity of SRMs, it is often difficult to determine preoperatively whether a SRM is a benign lesion, an indolent malignant tumor, or, most worrisome, an aggressive malignancy (Figure). Consequently, a significant number of patients with small benign masses undergo unnecessary nephrectomy in the US yearly.5
Active surveillance (AS) with rigorous clinical follow-up and scheduled serial imaging has emerged over the past decade as a safe management strategy in patients with SRMs and particularly those with indolent or low-grade disease. Recent evidence, however, shows that the adoption of AS for SRMs has been outpaced by robotic surgical extirpation and that the diffusion of robotic technology is propagating overtreatment of SRMs.6 To minimize this, better patient selection criteria for guiding the decision to undergo AS versus primary intervention need to be defined, and AS protocols should be optimized. In this review, we will discuss the lessons learned over the past years in AS with particular focus on our experience with the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry.
Rethinking Growth Rates and Progression
Establishing optimal criteria for patient selection for AS and identifying proper triggers for delayed intervention remain a challenge in the management of SRMs. While SRMs generally grow slowly, linear growth rate, which is the change in maximum tumor diameter over time and usually expressed in cm/year, is believed to be an objective parameter for guiding patient treatment and currently serves as the most commonly used metric for recommending intervention in patients managed by AS.7
An up-to-date and robust systematic review showed that linear tumor growth rate varied dramatically among published series on AS for localized renal masses.8 The authors reported a median linear growth rate of 0.37 cm/year (IQR 0.15-0.7) for clinically localized renal masses (cT1-2); in patients with cT1a masses (SRMs), median growth rate was 0.22 cm/year (IQR 0.11-0.27), and in those with cT1b-2 masses, it was 0.45 cm/year (0.34 and 0.57 in 2 series). Recent prospective data from the Fox Chase Cancer Center (FCCC) indicate a median growth rate of 0.19 cm/year for localized renal masses.9 In two major prospective experiences with AS specifically for SRMs, the DISSRM registry10 and the Renal Cell Carcinoma Consortium of Canada (RCCC)11, median linear tumor growth rates appear to be similarly low at 0.09 and 0.12 cm/year, respectively.12,13 It is important to note, however, that a significant proportion of SRM patients on AS have zero or negative growth rates. In fact, contemporary data on growth rate outcomes suggest that most SRMs demonstrate non-linear growth over time, with alternating periods of positive, zero, and negative growth.12 Mir, et al. reported that zero tumor growth ranged from 10% to 44% in currently published series.8 An updated DISSRM analysis of growth kinetics revealed that 41% of masses (n = 114) had a zero or negative growth rate.12 Similarly, 33% and 36% of SRMs in the RCCC and the FCCC experiences were found to have zero or negative growth.9,13
Progression in the prospective DISSRM registry is defined as any of the following: (1) linear growth rate >0.5 cm/year, (2) greatest tumor diameter >4.0 cm, (3) evidence of metastatic disease, or (4) elective crossover (due to change in patient preference or improvement in patient health status)10; all these currently represent indications for delayed intervention in SRM patients managed by AS.
The latest report on intermediate-term outcomes from DISSRM (n = 317 on AS) at median follow-up of 2.9 years (including 203 patients with follow-up of >5 years) indicated that 5-year and 7-year progression-free survival rates were 76% and 48%, respectively.14 Approximately one-third of progressions (n = 20, 30.3%) were elevated linear growth rates in patients who did not undergo intervention. The remaining two-thirds were mostly crossover events from AS to delayed intervention (n = 46, 68.2%); half of those (n = 24, 52.2%) were clinically indicated, while the others (n = 22, 47.8%) were elective and mostly based on patient preference. Almost all the clinically indicated crossover events (n = 23, 96%) were due to growth rate >0.5 cm/year.
Given this impact of elevated growth rate, patients who pursued delayed intervention were expectedly found to have a significantly greater median growth rate compared to those who remained on AS (0.38 vs 0.05 cm/year, p<0.001).15 Similar findings were established in the systematic review by Mir, et al.; relative to overall median linear growth rates, higher rates were reported when only subgroups of patients who underwent delayed intervention were analyzed (0.73 cm/year (IQR 0.25-1.35) versus the previously stated 0.37 cm/year in the cT1-2 cohort and 0.62 cm/year (IQR 0.30-0.88) versus the previously stated 0.22 cm/year in the cT1a cohort).8 In the analysis by McIntosh, et al., patients with an elevated growth rate were significantly more likely to undergo delayed intervention compared to those with a low or zero growth rate, but cancer-specific survival persisted at 99% in both cohorts.9 Therefore, elevated growth rate, as a sole factor, appears to be the most prominent trigger for progression and delayed intervention in AS cohorts but may not indicate true metastatic potential of a SRM.
Oncologic outcomes, namely progression to metastatic disease and cancer-specific death, do not seem to be influenced by tumor growth rate. In a systematic review of SRMs progressing to metastases under AS, the rate of metastatic progression was significantly low at 2%; a pooled analysis of the metastatic renal masses showed that 23% of lesions displayed no evidence of growth.7 Mir, et al. demonstrated in their review that linear growth rate among patients who experienced progression to metastatic disease was similar to the overall growth rate of clinically localized renal masses.
In the DISSRM registry, despite the previously reported high progression rates resulting mainly from tumor growth rate >0.5 cm/year, oncologic outcomes remained excellent; the cancer-specific survival rate at 7 years was still 100%, and none of the patients (0%) experienced metastatic progression.14,15 Similarly, the RCCC prospective experience found no association of SRM growth rate with any predictors of or progression to metastatic disease.13,16 Furthermore, as noted earlier, McIntosh, et al. highlighted that while an elevated growth rate was associated with delayed intervention, it had no impact on oncologic outcomes; the 5-year cancer-specific mortality was 1.2% (95% CI: 0.4-2.8%) without any correlation to growth rate, and only 1 of 99 (1%) patients on AS for longer than 5 years developed metastases.9
In patients who undergo delayed surgical intervention, RCC is identified in the majority (up to 90%) of pathology reports.8,15 Because increased linear growth rate is known to be the major trigger for intervention, a direct correlation between growth rate and malignant biology is assumed. While prior retrospective analyses have demonstrated elevated tumor growth rate as a predictor of adverse pathologic outcomes, these analyses were inherently subject to retrospective biases and lacked the rigorous inclusion criteria and standardized follow-up protocols of AS programs.17-19
Our recent understanding suggests that both benign and malignant lesions can grow at similar rates or not at all, underlining that growth alone is not an indicator of histology.11,20,21 Among AS patients who underwent percutaneous renal biopsy in the DISSRM registry, growth rate was not significantly associated with tumor pathology.12 Moreover, in those who crossed over to receive delayed surgical intervention, no difference in the pro- portion of RCC histology, high-grade disease, or pT3 upstaging based on growth rate has been found upon histopathologic analysis.15 We, therefore, believe that an absolute growth rate threshold might not be a reliable predictor of malignant potential.
The growth rate of SRMs on AS has been shown to be variable. This variability was found to be highest within the first year of follow-up and appeared to dampen with increasing time.12 The high variability did not seem to reflect tumor biology and was likely the result of random measurement error; as there were few available images to use early in AS for assessing tumor size in a short interval, mathematical artifacts would have been introduced from extrapolation to longer times. Most SRMs that demonstrated elevated growth rates in the first 6 months did not do so at future interval follow-up or on repeat imaging.12
It is important to note here, however, that patients who underwent delayed intervention in the DISSRM registry stayed for a median of 12 months (IQR 5.5-23.6) only on AS before crossing over15; in other words, 50% of patients who pursued delayed intervention did so within the first year of follow-up, and while the decision was based on personal preferences for some of them (elective crossovers), a significant proportion of patients actually crossed over due to an elevated growth rate that was interpreted in the period of highest variability. Therefore, when an elevated growth rate is encountered in the first year of AS, we recommend avoiding reflex intervention, given the high tumor growth rate variability and the low metastatic potential of SRMs. We also believe that short interval repeat imaging and/or renal mass biopsy should be considered as they could prove helpful in this scenario.
Given our experience thus far with AS, we feel it is worth rethinking and re-evaluating the importance of SRM linear growth rate in the context of our current definitions of progression and triggers for intervention. As discussed in this review, tumor growth rate predicts intervention but is a poor indicator of malignant biology or metastatic potential. Overall tumor size, on the other hand, has been shown to be the greatest predictor of malignant histology, aggressive pathology, and oncologic outcomes10,22,23; we, thus, recommend intervention based on this metric. Given that most SRMs demonstrate non-linear growth, recent data showed that multiple consecutive positive growth periods were positively associated with unfavorable pathology.24 While these hypothesis-generating data warrant validation, the number of positive growth periods may be a new reasonable parameter for malignant potential in patients undergoing AS for SRMs and could be utilized to initiate delayed intervention. Lastly, it is essential to recognize that the growth rate cutoff of >0.5 cm/year was based on retrospective data; as such, a more relevant biological threshold may exist and differ than this. Alternatively, a growth rate threshold could be used to trigger a biopsy, biomarker, or novel imaging modality parameter, rather than surgical intervention.
Renal Mass Biopsy
The role of percutaneous renal mass biopsy (RMB) in AS patients with SRMs remains debatable. While RMB exhibits excellent positive performance characteristics (sensitivity, specificity, and positive predictive value above 90%)25,26, it is not uniformly performed in patients enrolling in AS programs. Its clinical utility has been limited by concerns about its safety and the lack of perceived impact on clinical management in most cases given its inability to reliably detect high-grade disease due to intra- tumoral grade heterogeneity (40-60%), its significant non-diagnostic rate (14%), and its poor negative predictive value (68.5%).27-29
Despite the general belief in potential morbidity, RMB has been demonstrated to be a safe procedure with exceedingly low risk of serious complications – less than 1% of patients develop serious bleeding requiring blood transfusion and only 5% experience a hematoma. Moreover, tumor seeding does not occur with modern techniques of biopsy.26 RMB has also been shown to alleviate disease-related anxiety and depression in select patients. In a prospective DISSRM analysis of quality of life using the SF12 questionnaire, a significant improvement (p = 0.04) in the mental component score of AS patients was noted after RMB.30 It is important to emphasize, however, that overall quality of life is primarily driven by perceived differences in physical health and not mental health domains30; as such, while RMB can promote the emotional wellbeing of patients with SRMs managed by AS, its impact on overall quality of life is less profound.
RMB is not a requisite for safe AS. Nevertheless, it can provide valuable information for patients and providers when used appropriately. RMB can be offered initially if surveillance strategies will be tailored to tumor histology and perceived biology. Given the uncertainties surrounding a “benign” biopsy and poor grade concordance for high-grade RCC, we follow a similar surveillance strategy regardless of RMB histology and therefore recommend the use of RMB in patients in whom the findings may alter treatment decision. Baseline risk stratification of patients based on clinical predictors of metastatic potential and death of competing causes should ideally dictate if/when RMB is useful. For example, younger and healthier patients who can tolerate a minimally-invasive partial nephrectomy should be alarmed by the significant negative predictive value and still consider surgery even if biopsy shows benign or low-grade tumor due to heterogeneity of SRMs.
On the other hand, elderly patients with multiple comorbidities and limited life expectancy who are poor surgical candidates would preferably be better off if managed with AS regardless of RMB result, especially given the excellent cancer-specific survival of SRMs mentioned earlier. Patients in whom the decision to choose AS or surgery is less clear, or patients in whom the role of nephron-sparing approaches versus radical nephrectomy is uncertain, may benefit from RMB and, thus, are the ones in whom RMB should be performed. Moreover, as reported previously in this review, RMB may be useful in growing SRMs, particularly those demonstrating elevated growth rate within the first year of AS, as a diagnosis of high grade RCC would prompt timely intervention.
The frequency of RMB in the DISSRM registry has increased from being done in approximately 5% of patients per year to 20% in the most recent update.12 As our understanding of the role of RMB in the management of SRMs matures and with increasing follow-up in DISSRM, we expect to see an even greater proportion of patients electing biopsy.
Active Surveillance and Chest Imaging
Lung metastases are common in patients with RCC. Given this metastatic potential, yearly chest imaging is currently widely accepted as standard follow-up for patients managed by AS for SRMs suspicious for clinically localized RCC. However, as noted previously in this review, metastatic progression of SRMs while on AS is significantly rare.8 Moreover, all patients with progression to metastatic RCC in the AS literature either had a baseline tumor diameter of 3 cm or greater, experienced significant growth of their SRM on surveillance and were upstaged to cT1b, and/or were lost to follow-up for a significant period of time.31 As such, routine chest imaging is unlikely to detect pulmonary metastases in patients with SRMs that do not progress by size. Yearly chest imaging can, on the other hand, potentially lead to an increased rate of incidental findings that are unrelated to RCC and result in unnecessary and costly work-up for patients on AS.
An analysis of chest imaging data in the DISSRM registry was recently performed to support these hypotheses; while the actual manuscript including the results of that analysis is currently still under review for publication, a brief summary of the findings is presented here. The DISSRM AS protocol recommends chest imaging – either chest x-ray (CXR) or computed tomography (CT) scan – at enrollment and annually thereafter.10 Available chest imaging reports were examined to identify patients with abnormal findings, and abnormal findings were then determined to be actionable or non-actionable based on receipt of further work-up and/or procedures. Of 268 AS patients included in the analysis, 51 (19%) were found to have abnormal baseline chest images. Of these 51 initially abnormal chest imaging reports, 22 (43%) were or eventually became actionable, and 29 (57%) were non-actionable. Of the 217 patients with normal baseline chest images, 23 (11%) showed abnormal findings on subsequent follow-up chest imaging; abnormal findings were actionable in 10 (43%) of these 23 patients.
Actionable findings included pulmonary nodule ≥5 mm (single or multiple) concerning for lung malignancy or metastasis, anterior mediastinal masses suspicious for potential aortic aneurysms, thyroid nodules, and pulmonary lesions suggestive of benign infectious processes. Patients with such findings accordingly underwent further chest CT imaging, lung biopsies, thyroid ultrasound imaging and/or biopsy, or fungal/bacterial culture testing with antimicrobial treatment. Most importantly, none of the patients (0%) were found to have metastatic RCC after subsequent work-up. Non-actionable findings included small (<5 mm), stable pulmonary nodules, atelectatic changes, chronic scarring and post-inflam- matory changes, signs of pulmonary hypertension, and subcutaneous breast nodules.
Such findings illustrate that standardized annual chest imaging for all patients undergoing AS for SRMs results in random diagnoses and additional testing that could subject the patients to undesired risks and costs, including anxiety, monetary losses, and unnecessary radiation exposure, often with no major changes in their care. Given the low rates of metastatic progression of stable SRMs, we believe that not all patients enrolled in AS programs for SRMs require yearly chest images. However, we recommend yearly chest imaging “for cause” in the following: (1) patients with indeterminate findings at baseline imaging (i.e. subcentimeter pulmonary nodule(s)), (2) patients with growing SRMs, particularly those that exceed 0.5 cm/year or cross size thresholds of 3 cm or 4 cm, due to the small, but increased, risk of pulmonary metastases, and (3) patients electing crossover to surgical intervention for accurate re-staging prior to intervention.
AS is a safe and efficacious initial management strategy for many patients with SRMs. Long-term results from ongoing prospective studies will determine the durability of AS for select patients. Elevated growth rate is associated with delayed intervention but may not indicate biological behavior of a SRM. RMB is informative and safe, and it may reduce anxiety in certain patients. While it is not a requisite for AS, it may be used to guide decision making in patients in whom management is not clear. Pulmonary imaging should be used to initially stage patients presenting with a SRM, but it may be unnecessary on an annual basis without cause.
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