UROLOGICAL ONCOLOGY Comparison of Partial and Radical Laparascopic Nephrectomy: Long-Term Outcomes for Clinical T1b Renal Cell Carcinoma Yi Cai, Han-Zhong Li, Yu-Shi Zhang* Purpose: To compare the long-term clinical and oncologic outcomes in patients treated with laparoscopic partial nephrectomy (LPN) and laparoscopic radial nephrectomy (LRN) for clinical T1b renal cell carcinoma. Materials and Methods: We retrospectively reviewed the records of all patients who underwent LPN or LRN for a single clinical T1b tumor between January 2005 and January 2012, an actual follow-up of 2-year or greater was available in 39 and 160 after LPN and LRN, respectively. Survival was calculated using the Kaplan-Meier method. Multivariable Cox regression analysis was done to assess predictors of survival. Results: The two cohorts of patients were similar in age, sex, body-mass index and preoperative eGFR. There were no differences in tumors size (4.97 vs 5.29cm, P = .08), and pathological stage distribution between the two cohorts. The median follow-up after LPN and LRN were 67 (range: 18-118) and 70 (19-120) months, respectively. For LPN versus LRN, 5-years overall and cancer specific survival rates were 93.33% vs 85.69% and 96.00% vs 91.35%, respectively. For LPN versus LRN, 10-years overall and cancer specific survival rates were 85.56% vs 73.41% and 88.00% vs 82.85%, respectively. On multivariate analysis, patients’ age, ASA score and pathological stage were the major factors affecting overall survival, and patients’ age and pathological stage were associated with cancer specific survival. The percent decrease in glomerular filtration rate was significantly lower in the LRN group at early and last followup. Conclusion: LPN is an effective treatment option in appropriately selected patients with cT1b RCC. It provides 5-year, 10-year overall survival and cancer specific survival comparable to those of LRN as well as better preser- vation of renal function than LRN. Overall survival and cancer specific survival are associated with nonmodifiable factors but not by the choice of operative technique. Keywords: renal cell carcinoma; T1b; laparoscopy; partial nephrectomy. INTRODUCTION Partial nephrectomy (PN) is the current standard of care for localized RCC, especially in patients with tumors < 4cm(1,2). The oncological equivalence and better functional outcomes of PN compared to radical nephrectomy (RN) for T1a renal cell carcinoma have been widely reported. Further, PN is associated with improved quality of life, preservation of renal function and potentially improved overall survival. However, up to 25% of RCCs are still detected at a size of 4 ~7cm (T1b), for which RN was the gold standard of treat- ment in the last decades(3). Recent data suggest that PN should be performed if feasible for T1b renal tumors(4,5). With advances in laparoscopic suturing techniques and the availability of hemosealant substances, lapa- roscopic partial nephrectomy (LPN) has also become a well-defined method(6,7). In fact, LPN for T1b renal tumor has been demonstrated to be feasible in expert hands(8,9). There are some studies about the short-term oncological and renal function outcome of LRN or LPN on T1b renal tumors(7). However, the long-term clinical and oncologic outcomes of LRN and LPN remain to be defined. Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. 1 Shuaifuyuan Road, Beijing, China, 100730. *Correspondence: Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medi- cal Sciences and Peking Union Medical College, Beijing 100730, China. Tel: +86 138 1003 3903. Fax: +86 010-8915 2510. E-mail: zhangyushi2014@126.com. Received March 2017 & Accepted In the current study, we reviewed a single-institution database of patients treated with LPN and LRN for clin- ical T1b renal cell carcinoma to assess long-term clini- cal and oncologic outcomes. MATERIALS AND METHODS Study design Institutional review board approval was obtained for this retrospective study. We reviewed the records of all patients who underwent LPN or LRN between January 2005 and January 2012 at Peking Union Medical Col- lege Hospital. All patients were preoperatively evaluat- ed with computed tomography or magnetic resonance imaging. Only those with histologically confirmed RCC, a solitary tumor with a maximum diameter of 4.0 to 7.0 cm (clinical stage T1b) and a minimum 2-year post treatment radiographic follow up were included in anal- ysis. Patients with synchronous bilateral, clinic stage tumor (cT) ≥ 2, benign tumors in pathology specimens and those who underwent open surgery (laparoscopic switch open surgery also was excluded) were excluded from study. In addition, patients with solitary kidneys or end-stage renal disease (ESRD) (stage 5, estimated glo- Urological Oncology 16 merular filtration rate (eGFR) <15mL/minute/1.73m2) were excluded from the study as well. Estimated GFR was calculated using the Modification of Diet in Re- nal Disease equation, eGFR in ml/minute/1.73m2 =186.3×(serum creatinine)-1.154×(age)-0.203 × (0.742 if female)(10). Statistical analysis The SPSS software package (version 17.0) was used for all statistical analysis. Between-group compari- sons were assessed using Student’s t-test, chi-square test, Mann-Whitney test or Fisher exact test. The Kaplan-Meier method was applied to generate survival curves, which were compared using the log rank test. Multivariable Cox regression analysis performed to determine predictors of survival. P value < 0.05 was defined as statistically significant. RESULTS Patient clinical characteristics Between January 2005 and January 2012, a total of the 633 patients underwent LPN or LRN, including 39 and 160 patients treated with LPN and LRN, respectively (Figure 1). Table 1 lists patient demographics and tu- mor characteristics. The mean age in the LPN cohort was 54 (range: 20-79) years and in the LRN cohort was 53 (range: 38-74) years (P = .63). There were no dif- ferences in tumors size (4.97 vs 5.29cm, P = .08), and pathological stage distribution between the two cohorts. The mean follow-up was 67 (range: 18-118) months in the LPN cohort and 70(19-120) months in the LRN cohort (P = .29). No significant differences were observed between the two groups for patients’ sex, body mass index, diabetes mellitus, coronary artery disease, hyper- tension and preoperative eGFR. There was no signifi- cant difference in tumor characteristics between the two cohorts, including the laterality of the affected kidney, histology subtype, Fuhrman nuclear grade, pathologic stage and histology feature (Table 1). Only one patient in the LPN cohort was diagnosed with positive surgi- cal margin, because the tumor was located completely within the renal parenchyma. The patient died from car- diovascular disease 36 months after LPN for a 5.2cm clear renal cell carcinoma, however, the patient did not experience local recurrence or metastasis. Renal function analysis Table 1 displays renal functional outcomes. Preoper- ative GFR was 78.94 ± 18.74 and 85.27 ± 19.87ml/ minute/1.73m2 in the LPN and LRN cohorts (P = .09), and the early GFR (lowest measured value 7 to 180 days postoperatively) was 66.43 ± 23.08 and 59.59 ± 15.42 ml/minute/1.73m2, respectively (P = .04). The latest GFR (value at last followup) was 67.14 ± 17.07 and 52.36 ± 13.21ml/minute/1.73m2, respectively (P < .001). The median percent decrease in GFR was 15.04% and 38.59% after LPN and LRN, respective- ly (P < .001). Renal functional outcomes of LPN were superior to those of LRN both in early and long term follow-up period. Table 1. Baseline demographics and patient characteristics. Characteristics LPN(n=39) LRN(n=160) p-Value Age, median(range) 53 (38-74) 54 (20-79) 0.632 Gender (%) Male(%) 26 (67%) 97(61%) 0.486 Female(%) 13 (33%) 63(39%) BMI(kg/m2), mean±SD 23.55 ± 3.82 23.25 ± 4.19 0.654 ASA score, mean±SD 1.96 ± 0.44 1.95 ± 0.49 0.461 Follow-up(months), median(range) 67 (18-118) 70 (19-120) 0.293 Laterality Right(%) 21 (54%) 68 (43%) 0.201 Left(%) 18 (46%) 92 (57%) No. hypertension (%) 13 (33%) 55 (34%) 0.902 No. diabetes mellitus (%) 4 (10%) 24 (15%) 0.445 No. coronary artery disease (%) 1 (3%) 6 (4%) 0.718 Mean tumor size (cm), mean±SD 4.97 ± 0.75 5.29 ± 0.74 0.082 No. histology (%): Clear cell RCC 28 (72%) 129 (81%) 0.226 Other RCC subtype 11 (28%) 31 (19%) papillary RCC 8 15 chromophobe RCC 3 12 Translocation RCC Xp11.2 - 2 carcinoma of the collecting ducts of Bellini - 2 Histology feature Sarcomatoid-change (%) 1 (3%) 5 (3%) 0.854 Tumor necrosis (%) 3 (8%) 15 (9%) 0.743 No. Fuhrman nuclear grade (%) 1 or 2 30 (77%) 115 (72%) 0.525 3 or 4 9 (23%) 45 (28%) PSM 1(3%) - pT stage, (%) pT1 37 (95%) 145 (91%) 0.394 ≥ pT2 2 (5%) 15 (9%) GFR ml/min/1.73m2 Pretreatment 78.94 ± 18.74 85.27 ± 19.87 0.091 Early 66.43 ± 23.08 59.59 ± 15.42 0.042 Latest 67.14 ± 17.07 52.36 ± 13.21 < 0.001 Median % renal functional decrease 15.04% 38.59% < 0.001 Abbreviations: BMI,body-mass index; LPN,laparoscopic partial nephrectomy; LRN,laparoscopic radical nephrectomy; ASA, American Society of Anesthesiologists; PSM, positive surgical margins; pT stage, pathological tumor stage. Comparison of LPN and LRN Long-Term Outcomes for cT1b RCC-Cai et al. Vol 15 No 02 March-April 2018 17 Overall and cancer specific survival analysis The 5-year and 10-year overall survival (OS) in pa- tients who underwent LPN was 93.33% and 85.56%, respectively, and in the LRN cohort, 85.69% and 73.41%, respectively (log-rank test P = .15) (Figure. 2A). The 5-year and 10-year OS seems to be better in the LPN cohort compared with LRN, however, this difference showed marginally significant. In the LPN cohort, the 5-year cancer specific survival (CSS) was 96.00% and 10-year CSS was 88.00%. In the LRN co- hort, the 5-year CSS was 91.35% and 10-year CSS was 82.85%. The difference was not significant between the two groups for 5 or 10 year CSS (log-rank test P = .39) (Figure 2B). The factors that significantly affected OS were the patients’ age, pT stage and preoperative ASA score. Each year of age increased the risk of death by 1.02-fold. The increase of the ASA class one point in- creased 1.65-fold the risk of death. The increase of the pT stage (pT1 vs. pT2 vs. ≥ pT3) by one unit increased the risk of death by 1.36-fold. OS was not affected by the surgical technique or Fuhrman grade (Table 2). CSS was significantly affected by the patients’ age and pT stage. However, CSS was not affected by the sur- gical technique, preoperative ASA score or Fuhrman grade (Table 2). DISCUSSION The optimal treatment for clinical T1b RCC is contro- versial at present, partial nephrectomy is becoming an alternate standard to radical nephrectomy in the man- agement of T1b tumors. Milonas D et al(11) in their study reported that open partial nephrectomy showed better 12-year OS (55.2% vs 53.7%) and CSS (80.6% vs 69.6%) compared with open radical nephrectomy, although no significant differences were observed be- tween the two groups. Emerging data demonstrate fea- sibility of LPN for increasing the proportion of cT1b tu- mors; however, recent trends analyses demonstrate that the majority of T1b PN are still carried out by open sur- gery, and concerns continue about prolonged ischem- ic times and risk of bleeding(12). LPN appears to have comparable short-term functional and oncologic out- comes relative to LRN. In one of the most recent studies with about 20 months follow-up conducted by Deklaj T.(8), LPN was an approach to NSS that was feasible and associated with preservation of intermediate-term renal function compared with LRN. A prospective, ran- domized EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing sur- gery and radical nephrectomy showed that NSS seems to be significantly less effective than RN in terms of OS, however, the major parts of patients were low-stage renal cell carcinoma (≤ 5 cm)(13). Long-term results of oncologic and functional outcomes comparison of LPN and LRN for clinical T1b renal cell carcinoma remain to be defined. Our study is specific because it report- ed 10-year oncologic and renal functional outcomes of LPN and LRN for cT1b RCC. In our study, the 5-year OS in the LRN group was 93.33% compared with 85.69% in the LRN group; and the 10-year OS was 85.56% and 73.41%, respectively. CSS at 5 years was 91.35% and 96.00% in the LRN and LPN groups, respectively; and at 10 years, 82.85% and 88.00%. Better 10-year OS and CSS in LPN cohort were also observed in the current study, although the difference was not significant. On multivariate anal- ysis, patients’ age, ASA score and pathological stage were the major factors affecting overall survival, and patients’ age and pathological stage was the associated with cancer specific survival. No significant differences in OS or CSS were observed according to surgical ap- proach. There were no local recurrences in LRN group. One patient in the LPN group demonstrated local re- currence and received radical surgery three years after LPN. Then, he got sorafenib treatment and was alive in a recent follow-up. Another one LPN patient was Table 2. Predictors of overall survival and cancer specific survival for patients. OS CSS Variables Univariable Multivariable Univariable Multivariable HR(95% CI) P-value HR(95% CI) P-value HR(95% CI) P-value HR(95% CI) P-value Age 1.45 (1.36-1.54) < 0.001 1.17 (1.10-1.24) < 0.001 1.07 (1.01-1.12) 0.012 1.16 (1.08-1.23) 0.022 ASA score 1.58 (1.39-1.78) < 0.001 1.64 (1.21-2.14) 0.008 1.79 (1.12-2.58) 0.043 1.56 (0.97-2.23) 0.094 pT stage (pT1 vs ≥ pT2) 1.98(1.83-2.17) <0.001 1.39(1.13-1.45) < 0.001 2.13(1.83-2.79) < 0.001 1.62(1.23-2.08) < 0.001 Fuhrman grade (1/2 vs 3/4) 0.47(0.38-0.62) 0.022 0.65(0.19-2.15) 0.482 0.39 (0.22-0.58) 0.031 0.63(0.19-2.12) 0.462 LPN vs LRN 1.45（0.78-3.26（ 0.461 1.37(0.41-4.55) 0.603 1.21(0.56-3.78) 0.553 1.13(0.36-3.47) 0.833 Abbreviations: OS, overall survival; CSS, cancer specific survival; pT stage, pathological tumor stage; ASA, American Society of An- esthesiologists; LPN, laparoscopic partial nephrectomy; LRN, laparoscopic radical nephrectomy. Figure 1. Study population included in analysis. Comparison of LPN and LRN Long-Term Outcomes for cT1b RCC-Cai et al. Urological Oncology 18 found PSM because the tumor was located completely within the renal parenchyma, although we used scissors to remove the tumor with a margin of 0.5cm. The pa- tient died for cardiovascular disease 3 years after LPN, however, the patient did not experience local recurrence or metastasis. Interesting, several studies demonstrated that PSM were not associated with tumor recurrence, which may be explained by ischemic damage to residu- al tumor from hemostatic sutures, or intraoperative ful- guration of the tumor bed(14,15). The most important aims of PN is to preserve renal function. In this study, renal functional outcomes of LPN were superior to those of LRN both in early and long term follow-up period. Chronic renal insufficien- cy is a well-established risk factor for the development of anemia, hypertension, malnutrition, and neuropathy (16,17). It is associated with poorer quality of life, in- creased risk of hospitalization, cardiovascular events, and death(18,19). Better health-related quality of life also represents an advantage of LPN relative to LRN and may cancel out some of the short-term disadvantages of LPN, relative to LRN. Our study has several limitations(1). This was a retro- spective design with obvious selection bias. However, the baseline patients’ characteristics were comparable in the two groups (Table 1)(2). Given the significant number of patients who were lost to followup, survival outcomes in our study may be underestimated or over- estimated(3). Our sample sizes were relatively small. Despite these limitations our results support the clinical usefulness of LPN in approximately selected patients with cT1b RCC. A randomized, controlled trial in larg- er samples could be ideal and may be done in the future to validate our preliminary results. CONCLUSIONS LPN is an effective treatment option in appropriately selected patients with cT1b RCC. It provides 5-year, and 10-year overall survival and cancer specific surviv- al comparable to those of LRN as well as better pres- ervation of renal function than LRN. Overall survival and cancer specific survival are associated with non- modifiable factors but not by the choice of operative technique. ACKNOWLEDGMENTS This research was supported by the National Natural Science Foundation of China (81670611) and PUMCH Youth Scientific Research Fund (IH1028800). Figure 2. Overall survival (A) and Cancer-specific survival (B) according the surgical type (LPN vs LRN). CONFLICT OF INTEREST The other authors declare that they have no competing interests. REFERENCES 1. Ljungberg B, Bensalah K, Canfield S, et al. EAU Guidelines on Renal Cell Carcinoma: 2014 Update. Eur Urol. 2015;67:913-24. 2. Liss MA, Wang S, Palazzi K, et al. 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