Partial nephrectomy for T3aN0M0 renal cell carcinoma: shall we step forward?

ABSTRACT Objectives: To evaluate the prognosis of non-metastatic T3a renal cell carcinoma (RCC) with partial nephrectomy (PN). Patients and Methods: We retrospectively evaluated 125 patients with non-metastatic T3a RCC. Patients undergoing PN and radical nephrectomy (RN) were strictly matched by clinic-pathologic characteristics. Log-rank test and Cox regression model were used for univariate and multivariate analysis. Results: 18 pair patients were matched and the median follow-up was 35.5 (10-86) months. PN patients had a higher postoperative eGFR than RN patients (P=0.034). Cancer-specific survival (CSS) and recurrence-free survival (RFS) did not differ between two groups (P=0.305 and P=0.524). On multivariate analysis, CSS decreased with positive surgical margin and anemia (both P <0.01) and RFS decreased with Furhman grade, positive surgical margin, and anemia (all P<0.01). Conclusions: For patients with non-metastatic pT3a RCC, PN may be a possible option for similar oncology outcomes and better renal function.


INTRODUCTION
Radical nephrectomy (RN) used to be the standard therapeutic option for localized and locally advanced renal cell carcinoma (RCC) (1). In recent years, the oncology outcomes with partial nephrectomy (PN) were found not worse than those of RN (2). Moreover, PN may improve overall survival by preventing cardiovascular events caused by chronic kidney disease (CKD) for that the incidence of CKD was lower with PN than RN (3)(4)(5).
PN was recommended by the European Association of Urology and National Comprehensive Cancer Network guidelines as the preferred option for tumor type 1a-b (T1a-b) RCC 2 (1,6). In recent years, several studies expanded the application further to T2 RCC patients (7). However, whether PN is a possible option for non-metastatic T3a RCC is unknown. Actually, some non-metastatic patients with pT3a RCC (perinephric and renal sinus fat invasion) have undergone PN for various reasons.
The aim of this study was to analyze the prognostic differences in T3a RCC patients who underwent PN or RN with a strictly case-matched design.

PATIENTS AND METHODS
We searched the renal cancer database in Peking University First Hospital for cases occurring from 2007 to 2012 and retrospectively identified 2651 RCC patients who underwent nephrectomy, including PN and RN. The study received institutional review board approval. According to the 2010 American Joint Committee on Cancer (AJCC) TNM staging, the patients included 125 with non-metastatic pathological T3a (pT3a) RCC; 18 underwent PN. Patients who underwent PN and RN were exactly matched by gender, age, tumor size, American Society of Anesthesiologists (ASA) score, pathological subtype, surgical margin status, tumor invasion status and Fuhrman grade (Table-1). When more than one RN patient with criteria identified was matched, we chose patients with a smaller difference in tumor size with PN patients.
Complete preoperative examinations included chest X-ray, abdominal ultrasonography, abdominal CT, laboratory examinations and other necessary exams for preoperative evaluation. Pathological specimens were assessed by at least two experienced pathologists to confirm the pathologic subtype, surgical margin status, tumor invasion status and lymph-node metastasis status. Histological subtype and Fuhrman grade were stratified according to the 2004 WHO classification system and 1997 WHO recommended standards, respectively. According to 2010 AJCC TNM staging system, T3a staging was diagnosed when the tumor grossly extended into the renal vein or its segmented (muscle-containing) branches or invaded the perirenal and/or renal sinus fat but not beyond Gerota's fascia.
Patients were followed up by the standard strategy for outpatients in our institution, every 3 months post-operatively for the first 2 years and every 6 months for the next 3 years. From the fifth year and thereafter, patients were followed up annually. The general follow-up included imaging examinations (chest X-ray, abdominal ultrasonography or CT) and laboratory examinations (blood, urine and biochemistry). The outcomes investigated during follow-up included cancer--specific survival (CSS) and recurrence-free survival (RFS). The period from the surgery date to the date of recurrence, death or last follow-up was calculated as the follow-up time.
Statistics analysis involved use of SPSS 22.0 (SPSS Inc., Chicago, IL). Student t test was used to compare continuous variables and chi-square test to compare categorical variables. Survival was estimated by Kaplan-Meier method and log-rank test was used for survival difference analysis and univariate analysis. Variables with significant differences on univariate analysis for all T3aN0M0 patients were included in Cox multivariate regression analysis. All comparisons involved two-tailed tests and P<0.05 was considered statistically significant.

RESULTS
A total of 18 patients with non-metastatic pT 3a renal cell carcinoma underwent PN in our institution. The reasons were solitary kidney (n=3), renal insufficiency (n=3) and preoperative diagnosis of clinical T1 or T2 (cT1 or cT2). From the matching variables, 18 patients who underwent RN were chosen as the control group. For the 36 patients, the median age was 68.5 years (range 36-85); 28 (77.8%) were male and median followup was 35.5 months (10-86). The two groups did not differ in baseline characteristics (P >0.05) or some post-operative features such as blood loss (P=0.845), operative time (P=0.110), drainage-tube indwelling time (P=0.778) and post-operative stay (P=0.540). The preoperative eGFR in both groups is not significant different (P=0.357) and the postoperative eGFR in PN group is higher than RN At the end of follow-up, 4 (22.2%) and 2 (11.1%) patients in the PN and RN groups died due to the disease and 5 (27.8%) and 4 (22.2%) showed recurrence, respectively. The patients who died in the PN group were 1 with renal insufficiency, 3 up-graded after operation and the patients with recurrence in PN group were 1 for renal insufficiency, 1 with solitary kidney and 3 up-graded after operation. The estimated 5-year CSS for the PN and RN patients was 80.5% and 85.9%, and the estimated 5-year RFS was 76% and 80.8%. CSS (P=0.305) and RFS (P=0.524) did not differ between the two groups on log-rank testing ( Figure-1).
Univariate analysis revealed that tumor invasion status, Fuhrman grade, positive surgical margin, hypoalbuminaemia and anemia were

DISCUSSION
From our institution's data on 125 patients with non-metastatic pT3a RCC, 18 patients with PN and 18 with RN were matched. We compared the outcomes of patients with localized RCC undergoing PN and other patients undergoing routine RN treatment to evaluate the outcomes and effectiveness of PN for non-metastatic T3a RCC. The postoperative eGFR in PN group is higher than RN group. CSS and RFS did not differ between the groups. In the multivariate analysis, positive surgical margin and anemia were independent risk factors for CSS and high Furhman grade, positive surgical margin, and anemia were risk factors for RSS.
A number of studies have shown no significant differences between PN and RN in survival with localized RCC (2,8,9). Moreover, several studies suggested that PN could reduce the incidence of CKD and prevent the associated cardiovascular events and improve survival quality (2,10). However, the therapeutic recommendation is still RN for T3aN0M0 RCC (1,6). Nevertheless, some T3a RCC patients undergo PN for various reasons such as solitary kidney and renal insufficiency. As well, a few patients were preoperatively diagnosed with cT1-2 cancer and treated with PN, which was pathologically upstaged to pT3a cancer.
In a study by Lee et al. (11), 43 (3.2%) of 1367 patients with small RCC (≤4cm) had pT3a lesions. Gorin et al. (12) retrospectively analyzed 1.096 cT1 patients after PN and found 41 (4.8%) tumors upstaged to pT3a; the 2-year RFS with pT3a tumors was 91.8%, which was lower than   Table 3 (14,15). Therefore, strict matching should be conducted to mitigate potential selection bias caused by these features. Lee et al. (11) found no significant differences between T1a and T3a patients in overall survival (P=0.521), CSS (P=0.651) and RFS (P=0.250). However, several variables such as age (P=0.015), tumor size (P <0.001), subtype (P=0.020), and Fuhrman grade (P=0.021) differed between the 2 cohorts. Jeldres et al. (16) matched pT3a RCC by age, gender, tumor size, Fuhrman grade and histopathologic subtype to create a cohort of PN patients (n=30) and RN patients (n=63) and demonstrated no significant difference between the groups in CSS (P=0.9). The authors also included all unmatched 72PN patients and 789RN patients in the multivariate analysis and found PN not associated with worse CSS as compared with RN (HR=0.62, P=0.11). In our study, the matching criteria (gender, age, tumor size, ASA score, pathological subtype, surgical margin status, tumor invasion status and Fuhrman grade) were more stringent than that used by Jeldres et al., and we found no significant differences between the PN and RN groups in CSS Renal insufficiency has an independent and graded association with risk of death and cardiovascular events (17,18). RCC patients have about a 25% rate of CKD, which can lead to a series of metabolic disorders and cardiovascular events (19). PN was suggested to benefit renal function as compared with RN (20,21 Positive surgical margin was previously found significantly associated with tumor recurrence, although the development of metastases and CSS were comparable with positive and negative surgical margins (25)(26)(27). Borghesi et al. (28) reported that the overall incidence of recurrence after negative surgical margins ranged from 0% to 7%. In our study, 2 of 125 patients (1.6%) with T3aN0M0 RCC showed positive surgical margins and the variable was associated with CSS (P=0.000) and RFS (P=0.000) on Cox multiple regression analysis. However, because of the low rate of positive surgical margins in singlecenter T3aN0M0 RCC patients, the association with oncological outcomes demands larger cohort studies.

-Univariate analysis of clinicopathological variables associated with cancer-specific survival (CSS) and recurrencefree survival (RFS) at 5 years for all T 3a N 0 M 0 patients (n=125).
This study has several strengths. The experienced surgeons in a single center ensured that every patient received similar and standard treatment. Furthermore, the sequential and uniform follow-up provided high-quality data for analysis. Moreover, the characteristics of patients in the PN and RN groups were comparable with the strict case matching.
However, this study still presents several limitations. First, it was retrospective and cannot avoid the inevitable disadvantages of a retrospective study. Second, this is a small sample and single-center study, for a low ratio of T3a RCC patients undergoing PN and this cannot avoid the type 1 or 2 error. Third, the median follow-up time was short. Prospective, large-sample and multi-institutional studies are required to further test the use of PN and discover risk factors for non-metastatic T3a RCC patients.
In conclusion, this case-matched analysis demonstrates that for non-metastatic T3a RCC patients, PN may be is a possible option for similar oncology outcomes and better renal function.