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Over the last several decades, the incidence of RCC has increased steadily . This trend is probably attributable to biological factors, such as the obesity epidemic and tobacco exposure  as well as increased detection with more frequent use of abdominal imaging . Radical nephrectomy has traditionally been the standard of care in the management of RCC; however, growing evidence regarding the long-term detrimental effects of renal insufficiency and increased mortality [4,5], combined with demonstrated oncological efficacy of nephron-sparing surgery (NSS) , has resulted in greater interest in renal preservation and alternative treatment methods.
The spectrum of minimally invasive methods for the management of renal tumours includes extirpative procedures, such as laparoscopic and robot-assisted NSS, as well as thermal ablative techniques, including radiofrequency and cryotherapy. In single-centre series, ablation appears to be effective in the short and intermediate term . In addition, two series have reported cryoablation outcomes beyond 5 years [8,9]. A review for the AUA guidelines  and a recently published large systematic review  both reported a significant increase in local progression with ablation. However, there remains no adequately controlled study comparing survival in patients undergoing ablation or NSS. It is unclear, therefore, whether increased local progression translates into lower cancer-specific or overall survival over time.
We sought to address this issue using a population-based registry, comparing the long-term oncological outcomes in patients undergoing either NSS or ablation for clinical T1a renal masses.
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Between 1998 and 2007, a total of 8818 incident cases of RCC were treated with either NSS (7704) or ablation (1114). Among those undergoing ablation, 662 (59%) had cryoablation, 239 (21%) had ablation NOS and 213 (19%) had radiofrequency ablation. Compared with patients who underwent NSS, those who underwent ablation were older and were less likely to be married (Table 1). Although the difference in tumour size was statistically significant, it did not appear clinically significant.
Table 1. Comparison of baseline demographic, clinical and pathological characteristics according to treatment group
|Characteristic||NSS, n= 7704||Ablation, n= 1114|| P |
|Diagnosis year: median (IQR)||2004 (2002–2006)||2006 (2004–2007)||<0.001|
|Mean (sd) age, years||59 (13)||68 (12)||<0.001|
|Male, n (%)||4770 (62)||687 (62)||0.87|
|Ethnicity, n (%)|| || ||0.77|
| White||5816 (76)||858 (77)|| |
| Black||696 (9)||98 (9)|| |
| Hispanic||730 (10)||103 (9)|| |
| Asian||386 (5)||49 (4)|| |
|Married, n (%)||577 (67)||683 (61)||<0.001|
|Urban area, n (%)||6904 (90)||995 (90)||0.63|
|Median (IQR) % poverty level||9 (6–13)||9 (6–13)||0.62|
|Mean (sd) tumour size, cm||2.4 (0.8)||2.6 (0.8)||<0.001|
|Histology*, n (%)|| || ||0.38|
| Clear-cell||3794 (71)||421 (72)|| |
| Papillary||1141 (21)||124 (21)|| |
| Chromophobe||419 (8)||36 (6)|| |
| Sarcomatoid||25 (0.5)||1 (0.2)|| |
|Grade*, n (%)|| || ||<0.001|
| 1||1540 (25)||171 (33)|| |
| 2||3568 (58)||292 (57)|| |
| 3||908 (15)||46 (9)|| |
| 4||81 (1)||1 (0.2)|| |
The median (interquartile range [IQR]) follow-up was 2.8 (1.2–4.7) years in the NSS group and 1.6 (0.7–2.9) years in the ablation group, although 10% of each cohort had follow-up beyond 5 years. A total of 716 (8.1%) patients died during follow-up, of whom 110 (15%) died from RCC: 91 (1.2%) in the NSS group and 19 (1.7%) in the ablation group. Based on Kaplan–Meier analysis (Fig. 1) and the log-rank test, a significant difference in actuarial survival was observed. At 5 years, DSS survival was high after both NSS (98.2%) and ablation (94.4%). This difference appears to increase over time, although the number at risk becomes small with very long follow-up.
Figure 1. Kaplan–Meier estimates of DSS stratified by procedure type. The 5- and 10-year survival rates were 98% and 94% in those undergoing NSS, and 96% and 82% in those undergoing ablation.
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Univariable Cox regression analysis was performed to examine factors associated with DSS in the study cohort (Table 2). A significant difference in survival was observed in those who underwent ablation compared with NSS (hazard ratio [HR] 2.6, 95% CI 1.6–4.2, P < 0.001). After multivariable adjustment (Table 2), there was little change in the risk of kidney cancer death associated with most factors. However, a clinically significant decrease in the association of treatment type with survival was observed (HR 1.9, 95% CI 1.1–3.3, P= 0.02); this difference occurred primarily after adjustment for age.
Table 2. Cox regression analyses of factors associated with DSS
|Covariate||Univariable analysis||Multivariable analysis|
|HR(95% CI)|| P ||HR(95% CI)|| P |
|Diagnosis year, per year increase||0.9 (0.8–1.0)||0.14||0.9 (0.8–1.0)||0.09|
|Age per decade increase||1.6 (1.3–1.9)||<0.001||1.5 (1.3–1.8)||<0.001|
|Male vs female||1.6 (1.1–2.5)||0.03||1.9 (1.2–2.9)||0.006|
|Ethnicity vs white|| ||0.84|| ||0.75|
| Black||1.1 (0.6–2.1)||0.75||0.9 (0.4–2.0)||0.78|
| Hispanic||1.3 (0.7–2.4)||0.38||1.3 (0.6–2.9)||0.48|
| Asian||1.2 (0.5–2.6)||0.74||1.2 (0.5–2.9)||0.63|
|Married vs other||0.6 (0.4-–0.9)||0.007||0.6 (0.4–0.8)||0.005|
|Urban vs rural area||0.8 (0.5–1.5)||0.57||0.9 (0.5–1.7)||0.76|
|Poverty level, per 10% increase||1.2 (1.0–1.6)||0.08||1.2 (0.8–1.8)||0.35|
|Tumour size, per 1-cm increase||1.5 (1.2–1.9)||<0.001||1.4 (1.1–1.8)||0.006|
|Ablation vs NSS||2.6 (1.6–4.2)||<0.001||1.9 (1.1–3.3)||0.02|
Adjusted survival curves were plotted stratified by treatment type. The 5-year predicted probability of survival in a 59.9-year-old, married man with a 2.2-cm RCC undergoing NSS was 98.3%, while in the same person undergoing ablation it was 96.6%.
A difference was observed in the risk of death based upon type of ablation performed. Ablation NOS was associated with a significant increase in mortality compared with NSS (HR 2.5, 95% CI 1.2–5.2, P= 0.01). The best estimate of the risk of death in those treated with cryoablation (HR 1.5, 95% CI 0.7–3.2, P= 0.31) and radiofrequency ablation (HR 2.2, 95% CI 0.7–7.1, P= 0.21) were in a similar direction but did not reach significance.
There was suggestion of an interaction between treatment type and year of diagnosis (P= 0.10). For those treated in 1998, a much stronger difference in survival was observed in those undergoing surgery vs ablation (HR 3.4, 95% CI 1.5–7.5), while for those undergoing treatment in 2007, there was no difference between treatment arms (P= 0.56). This trended with an increase in the proportion of ablated patients undergoing cryoablation and a decrease in those coded as ablation NOS.
By contrast, there was no evidence of an interaction between treatment type and tumour size (P= 0.93). Thus, over the range of tumours studied (<4 cm), the improved survival in those undergoing NSS vs ablation was similar.
Significantly more patients who underwent ablation than patients who underwent NSS did not have pathological confirmation of RCC available (34% vs. 7%, P < 0.001). Although the test of interaction was not significant (P= 0.38), a clinically relevant difference in survival was seen when comparing those in whom a specific grade and histology were known (HR 2.2, 95% CI 1.2–4.0, P < 0.001) with those in whom the diagnosis was RCC NOS (HR 1.3, 95% CI 0.4–3.7, P= 0.68).
As grade appeared systematically lower in those undergoing ablation, adjustment for grade led to worsened relative survival with ablation (HR 3.2, 95% CI 1.6–6.6, P= 0.001). By contrast, because histologies were similar between treatment types, adjustment did not change relative survival (HR 1.9, 95% CI 0.9–4.0, P= 0.09).
Restricting the analysis to only those patients who had >5 years of follow-up increased the survival advantage seen with NSS over ablation (HR 3.0, 95% CI 0.7–13.2, P= 0.15), although given the smaller sample size this did not reach significance.
A competing risk model was created to determine if non-kidney-cancer-related deaths could affect the results. No change in the association between ablation and increased kidney cancer-specific mortality was observed (HR 1.9, 95% CI 1.1–3.3, P= 0.02).
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The contemporary management of small renal masses is a challenging problem given the multiple options available including surveillance, surgical extirpation and thermal ablation . Recent data have helped clarify several issues, such as the comparable oncological efficacy of radical nephrectomy and NSS , as well as the importance of preserving as much renal function as possible. Although active surveillance remains an attractive choice for older patients and those with significant comorbid diseases , there is a small but real risk of disease progression and many patients receive treatment during follow-up despite initial observation . Thus, much of the current debate centres around the relative oncological benefits of NSS vs ablation, and the purported decreased morbidity of ablation vs NSS.
While the kind of question posed in the present study is best addressed with a randomized controlled trial in order to limit bias and confounding, ablation has been taken up rapidly without such investigation. In the absence of a randomized trial, observational studies play an important role in providing a best estimate as to the comparative effectiveness of two treatments. Our findings indicate that in a population-based cohort with cT1a renal masses, those who undergo ablation suffer at least a two-fold worse DSS than those who undergo NSS. DSS in all treated patients was high and in the typical patient presenting with a cT1a renal mass – a 60-year-old married man with a 2.2-cm mass – 5-year survival was improved by 1.7% with NSS vs ablation. Therefore, in patients who are surgical candidates, NSS should remain the standard of care.
Adjustment for multiple potential confounders, in particular age, did not eliminate the significant difference between treatments (univariable HR 2.6, multivariable HR 1.9). Furthermore, a competing risks regression analysis, taking into account differences between groups in non-RCC causes of mortality, yielded identical results (multivariable HR 1.9). These models account for all known potential confounders except the presence of benign histology, which may be present in 20% of cT1a renal masses . Because far more patients in the ablation group lacked pathological confirmation, it is highly likely that these patients more often had benign disease. However, this would bias the results toward the null, and therefore the benefit of NSS is probably larger than that observed. In fact, a sub-group analysis in only those with pathological confirmation showed a further increase in the risk of death with ablation (HR 2.2), though because of small sample size the test of interaction was not significant.
Other factors which are strong determinants of DSS such as grade  or histology , cannot confound the association between treatment type and outcome since they were unknown at time of treatment in the majority of patients . The observation that grade was lower in patients undergoing ablation than NSS is probably attributable to measurement error, as there is evidence that grade determined by biopsy rather than pathology is systematically lower [21,22]. Although it is predictable that adjustment for grade would worsen relative outcomes for ablated patients (HR 3.2), this is probably biased by measurement error of grade.
Our analyses also provide evidence that the specific technique of thermal ablation is important and may result in variable outcomes. Ablation of unspecified type had the greatest risk of death compared with NSS (HR 2.5), while cryoablation had the lowest relative risk of death (HR 1.5), with radiofrequency ablation inbetween (HR 2.2). A meta-analysis of ablative techniques showed improved efficacy with cryoablation vs radiofrequency ablation for both retreatment (1% vs. 8%) and local disease progression (5% vs. 13%) . The proportion of patients undergoing cryoablation increased significantly over time. If cryoablation is the most effective form of ablation, this may explain the observation that the difference in DSS between ablation and NSS decreased over time. It is also possible that increased experience and technical improvements [24–26] over time have minimized the difference in survival between those undergoing ablation and NSS. Further comparative studies are necessary to elucidate the optimum technology in specific situations, as well as details of the best method of delivering thermal ablation.
The present study is the first well-powered study to compare the effectiveness of NSS and ablation. Two previous studies, which attempted to compare oncological outcomes between treatments, had <40 patients in the ablation arms [7,27]. Two studies have reported single-institution outcomes of ablation and concluded they were similar to outcomes in the literature of patients undergoing NSS [8,28]. A radiofrequency ablation cohort (N= 208) had reported 5-year DSS of 99%; however, recurrence-free survival was only 90% in those with biopsy-proven RCC and metastasis-free survival was 95%, suggesting that DSS will decrease significantly over time. A cryoablation cohort (N= 80) had reported 5-year and 10-year DSS of 92% and 83%, respectively. In contrast with the authors' conclusion, these results do not appear similar to the literature on NSS outcomes for cT1a RCC . However, this may be attributable to selection bias within the cryoablation cohort, particularly because a significant number of patients had previous RCC.
Limitations of the present study include the relatively short follow-up in the ablation group; however, in the more than 100 patients in the ablation group who had >5-years of follow-up, kidney cancer mortality appeared to increase relative to NSS (HR 3.0). A cohort effect cannot be excluded, as those with longest follow-up were also treated earliest. Using a cancer registry, we were unable to retrospectively determine unmeasured factors which might be of interest, such as the reason that surgery or ablation was performed, or the Padua classification. Another limitation of SEER is the absence of details regarding ablative techniques: cryoablation or radiofrequency ablation, percutaneous or laparoscopic approach, and specific device and type and number of probes. Performance status or comorbidity data are not available in SEER and could not be adjusted for individually, although competing risks regression did not change the findings. Finally, SEER relies on death certificate reporting, which is imperfect, although in patients with malignancy accuracy may be increased .