Survival advantage of partial over radical nephrectomy in patients presenting with localized renal cell carcinoma

Complete surgical excision of the tumor still remains the only curative treatment for renal cell carcinoma (RCC) [1]. Preserving renal function by performing partial nephrectomy (PN), was originally reserved for patients with an anatomically or functionally solitary kidney or for those with a functioning contralateral kidney at risk for future functional impairment [2]. However, the use of PN has increased tremendously, even in patients with localized unilateral RCC and a healthy contralateral kidney [3]. Having shown excellent long-term oncological outcomes equivalent to those of radical nephrectomy (RN) [4–7], combined with limited perioperative morbidity [8], PN has become the gold standard for all patients with renal tumors < 4 cm [1, 6, 9, 10]. Some authors recommend PN in all cases where PN is oncologically safe and technically feasible, even for pT ≥ 1b and high-risk tumors [10–13]. This is surely attributable in part to recent studies demonstrating that elective PN (ePN) can be associated with significantly lower long-term mortality than RN [14–17], probably due to the preservation of renal function [18–20] and the lower incidence of subsequent cardiovascular diseases (CVD) [14].

While it is indisputable that PN leads to better preservation of renal function, there is still debate over the extent to which this surgically induced chronic kidney disease does also increase the risk of CVD and non-RCC-related death [21–23]. This observation became a particularly hot issue after van Poppel et al. [24] published the overall survival (OS) results of the EORTC 30904 phase III study. Contrary to expectations, the authors found no OS advantage of ePN over RN.

In view of these contradictory results, this large retrospective multicenter study was performed to comparatively investigate partially and radically nephrectomized patients comprising tumor and patient parameters and to evaluate the influence of the surgical technique on OS of patients with localized RCC.

Our patient population of 2675 (61.8%) men and 1651 (38.2%) women had a mean (median) age of 61.2 (62.0) years (range, 16–92). 3545 (81.9%) had clear cell, 496 (11.5%) papillary, 182 (4.2%) chromophobe, and 103 (2.3%) unclassified RCC. There were 3259 (75.3%) patients with pT1, 530 (12.3%) with pT2, and 537 (12.4%) with pT3a RCC. The mean (median) tumor size was 4.9 (4.3) cm (SD ±2.7 cm).

Association between tumor/patient characteristics, the type of surgery, and overall survival

Using univariate Cox regression analysis we could reveal that in contrast to male sex (HR 1.04, 95% CI 0.92-1.18, p = 0.51) and non-clear cell histology (HR 0.93, 95% CI 0.79-1.10, p = 0.40), the following were significantly associated with reduced OS: age (in years, HR 1.05, 95% CI 1.04-1.06, p < 0.001), tumor stage (p < 0.001), increasing tumor diameter (in cm, HR 1.08, 95% CI 1.06-1.10, p < 0.001), and poor tumor differentiation (HR 2.10, 95% CI 1.76-2.50, p < 0.001). The type of tumor surgery also correlated significantly with OS: unlike iPN (HR 1.12, 95% CI 0.88-1.43, p = 0.35), ePN was associated with a significantly longer OS than RN (HR 0.61, 95% CI 0.51-0.71, p < 0.001). The Kaplan-Meier 5- and 10-year OS rates were 90.0% and 74.6% for ePN, and 81.2% and 64.7% for RN (p < 0.001; log rank; Figure 1).

To further assess the potential advantage of ePN over RN, we separately evaluated patients with tumors ≤ 4 and > 4 cm. In either case ePN was associated with significantly improved OS (HR 0.68, 95% CI 0.55-0.85, p = 0.001 for RCC ≤ 4 cm, and HR 0.69, 95% CI 0.51-0.93, p = 0.02 for RCC > 4 cm; univariate Cox regression).

The impact of age was also taken into consideration. A survival advantage of ePN over RN was found in all four calculated age subgroups (< 55, 55–63, 63–69, and > 69 years): HR 0.52 (95% CI 0.35-0.78), HR 0.70 (95% CI 0.51-0.96), HR 0.58 (95% CI 0.40-0.83), and HR 0.71 (95% CI 0.54-0.94; univariate Cox regression).

Finally, OS was superior with ePN vs. RN in all 5 periods evaluated: < 1990: HR 0.80 (95% CI 0.57-1.12), 1990–1994: HR 0.62 (95% CI 0.46-0.84), 1995–1999: HR 0.51 (95% CI 0.36-0.72), 2000–2004: HR 0.57 (95% CI 0.39-0.84), ≥ 2005: HR 0.56 (95% CI 0.27-1.13).

For many decades, RN was regarded as standard therapy for localized RCC [25]. This dogma has changed dramatically in recent years [1] because a large number of studies have shown that PN for elective or imperative indications is a technically feasible and safe surgical procedure with an only slightly higher complication rate [6, 8, 26]. Moreover, the oncological outcomes appear to be fully comparable in terms of local relapses and tumor-specific survival [4, 6, 24]. The main advantage of PN, however, lies in the markedly lower rate of postoperative renal failure achieved by preserving functional nephrons [18, 19, 21, 24]. Thus, nephron sparing surgery-especially ePN-is now considered the gold standard for treatment of small renal tumors [1, 9].

Several non-randomized studies have recently described a longer OS for PN than for RN in patient populations with mostly small renal tumors [14, 15, 27, 28]. This was attributed to lower rates of surgery-associated chronic renal failure and subsequent CVD. However, these results do not go unchallenged [21], and the studies largely show the same limitations: retrospective and not comprehensive data collection, mostly small patient populations, and possible selection bias. Moreover, it has not yet been fully clarified whether surgically induced renal failure, like the type of chronic renal failure due to various internal disorders, also involves an increased risk of CVD and subsequent mortality [22, 29].

Up to now, there has been only one randomized phase III study (EORTC-GU 30904) comparing the safety and effectiveness of ePN and RN in patients with localized renal tumors [24]. The 541 patients included had renal tumors up to 5 cm in diameter. During a median follow-up of more than 9 years, no survival advantage was found for patients who underwent PN. On the contrary, the intent-to-treat population had a calculated 10-year OS rate of 81.1% for RN and only 75.7% for ePN, and the PN group did not have fewer cardiovascular events (9.3% vs. 7.3%). Tumor-specific survival was nearly equal. Limitations of the study include the involvement of 45 varyingly experienced centers in 17 countries and the failure to recruit the intended sample size (1300 patients). Nevertheless, this randomized investigation was unable to demonstrate a survival advantage for PN. Since these results were generally surprising and did not appear to be scientifically conclusive, we found it expedient to evaluate another very large patient population that was treated at 6 German university medical centers. Unlike the EORTC trial [24], our retrospective study only included patients with histologically verified RCC. Since those who underwent ePN in our patient population had a younger median age as well as smaller and better differentiated tumors, it was not surprising that they had a significantly longer median OS than those submitted to RN. However, subsequent multivariate analysis also showed a significant survival advantage for the ePN group.

Even though we are dealing with a retrospective analysis that does not include comorbidity, this large study shows that OS appears to be better, but by no means worse, for ePN than for RN. Of great interest is also the finding that patients who underwent nephron-sparing surgery for imperative indications did not have a significantly worse prognosis than the RN group, even though they probably tended to have more serious comorbidities.

Therefore, our results are in line with a recent meta-analysis published by Kim et al. [30] who also found that PN lead to a 19% risk reduction in all-cause mortality. However, in contrast to our study evaluating a rather homogeneous patient collective with surgically resected RCC, Kim et al. [30] included patients with benign tumors and patients from observational studies.

Our results also support current recommendations to perform a PN for small renal tumors. However, in line with other recent publications [5, 10–13, 31], we were able to demonstrate in subgroup analyses that PN may also be justified for larger tumors leading to a potentially better prognosis.

Hillyer et al. [32] recently described that even elderly RCC patients do not have a significantly increased perioperative risk if submitted to organ-sparing surgery and benefit accordingly from PN. Smaldone et al. [33] demonstrated a survival advantage of PN over RN for patients up to age 85. Chang et al. [34] examined the secondary economic impact of RN compared to PN on the U.S. health care system. They came to the conclusion that PN is associated with fewer follow-up costs than RN irrespective of age, which also reflects the lower postoperative morbidity rate in patients treated by PN. We divided our patient population into 4 subgroups to assess the influence of age on the prognostic relevance of the surgical procedure. No significant difference was found between the subgroups: ePN was associated with a lower risk of shorter OS irrespective of age.

However, our study also has significant limitations. It is a retrospective non-randomized study in which patients’ comorbidities and general condition could not be taken into account. There was also a lack of detailed information on preoperative renal function. Moreover, there was no stringent standardization of criteria for the selection of the surgical approach and no central pathological review. Thus, a significant selection bias cannot be excluded. Only recently, Shuch et al. [35] published a highly interesting matched cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data base. Elderly patients treated with PN or RN for localized RCC (≤ 4 cm) were compared with two control groups (non–muscle-invasive bladder cancer and noncancer controls). Median overall survival following PN was significantly higher than in controls without cancer or with nonmuscle invasive bladder cancer, while median overall survival after RN was similar among the 3 groups, confirming the hypothesis that selection bias may be present in observational data and that RN may be less harmful than often believed [35, 36].

On the other hand, our study stands out in that we could assess whether PN was performed for elective or imperative indications even though this definition was not based on hard criteria but the individual subjective surgeon’s appraisal (based on the number of kidneys, renal function and comorbidities). Remarkably, the iPN group showed a poorer prognosis than the ePN group, as expected, but not a significantly worse OS than the RN group. At the same time, it can at least be speculated that the patients submitted to iPN probably tended to have the highest comorbidity in our patient population. A last limitation is that a tumor-specific survival analysis could not be performed for lack of reliable cause-of-death information.

Taken together, our results suggest that PN is associated with a potentially better but apparently not worse OS irrespective of center, age, and tumor size. This could of course only be definitively confirmed by an adequately large randomized study that provides detailed assessment of the patients’ general condition, comorbidities including renal function, and tumor-specific characteristics; a valid nephrometry score might also be taken into account [37–39]. However, it seems doubtful at present whether such a study a) would achieve better patient recruitment than the already prematurely terminated EORTC 30904 trial and b) would still be ethically acceptable, at least for patients with small tumors. There is also the question of what could possibly argue against performing a PN, whether for elective or imperative indications, considering that the rate and severity of postinterventional chronic renal failure could be significantly reduced, while perioperative morbidity is not significantly increased, and oncological outcomes are comparable to those of RN. Is this alone not reason enough to favor PN, regardless of whether or not the surgically induced chronic renal failure is directly associated with the occurrence of CVD? In any case, the results of our large multicenter study support the performance of PN in all cases where it appears technically feasible and oncologically safe.

Even allowing for the significant weaknesses and selection bias any retrospective analysis may involve, our results indicate that in patients with localized RCC, PN may be associated with better OS than RN. Patients with RCC > 4 cm as well as elderly patients did also seem to benefit from a nephron-sparing approach.