**2.1.1 Positive Surgical Margins (PSM): Incidence, clinical relevance**

NSS aims to preserve renal function without lacking its primary goal: eradicate the tumour. One of the challenges of NSS is to achieve negative surgical margins (NSM). It means that there are no cancer cells seen at the outer edge of the resection piece. This is marked with ink.

In general, the incidence of PSM in T1b tumours is between 0 % (Patel et al., 2009) and 16.7% (Lee et al., 2010). Lee showed that the difference in recurrence rate for patients with PSM compared to NSM was not significant.

Coffin et al (Coffin et al., 2011) found that an imperative indication for NSS had an impact on PSM rates (p=0.03). However, he also noticed that the median tumour size was

The Role of Nephron-Sparing Surgery (NSS) for Renal Tumours >4 cm 331

We reviewed 98 patients operated at our institution between 1997 and 2009 for a renal tumour larger than 4 cm. All patients underwent an open partial nephrectomy. Mean diameter was 5.32 cm. At final histopathology, three quarters of the tumours were malignant and 2.7% were staged pT3a. 53.4% of the renal cell cancers (RCC) showed a low grade (Furhman grade 1-2) versus 46.6% high grade (Furhman grade 3-4). The 5–year OS and CSS rates were 77.9% and 98%, respectively. We observed 5 local reccurences (5.1%) and

Roos and Brenner (Roos et al., 2010) compared 73 patients who had undergone elective NSS for T1b or greater tumours with a pair-matched cohort of 100 radical nephrectomies: the OS rates were comparable for NSS vs. RN. The 5, 10 and 15-year CSS rates after NSS (95%, 91% and 82%, respectively) were comparable with RN (97%, 95 and 88%, respectively).The 5, 10 and 15-year PFS rate after NSS (89%, 85% and 76%, respectively) were similar to RN (92%, 89% and 77%, respectively). In a retrospective study by Antonelli (Antonelli et al., 2008), there was no significant difference in progression and survival rates between NSS and RN both for tumours ≤ 4 cm as for those >4 cm. Interestingly, even when not significant, the group of patients with the larger tumours treated with radical surgery experienced a progression rate which was double compared to those who underwent NSS. In the same study, when operated by NSS, the patients with a T1a tumours had a higher risk of local recurrence in the operated kidney, as well as in the contralateral kidney. T1b tumours showed a higher risk of metastatic and local recurrence. Cytonuclear grading was correlated with higher risk of recurrence in tumours larger than 4 cm. However, even in large tumours with high cytonuclear grade, the type of surgery had no significant influence on oncologic

**2.1.2 Overall survival, cancer-specific survival, progression free survival** 

outcomes: nor on progression rate nor on disease free survival rate at 5 years.

recurrence free survival with 100% for PN vs. 89.3% for RN.

more pT3a in the NSS group compared to the RN group.

a significant prognostic factor for 5- and 10-year Overall Survival.

Nemr (Nemr et al., 2007) described similar oncologic outcomes for NSS and RN in T1b renal tumours: Mean follow up was 45 months and there was no significant difference in

Margulis (Margulis et al., 2007) retrospectively compared RN (576) with NSS (34) for tumours >4 cm: recurrence occurred in 4 patients (12%) who underwent NSS vs. 164 patients (28.9%) who underwent RN at a median follow-up of 24.2 and 13.2 months, respectively. 5-year RFS was higher for NSS but CSS was similar. 27% of NSS were performed for elective indications; the remainders had solitary kidneys (29%) or chronic kidney disease (CKD) (44%). The indication does not seem to impact 5-year RFS and CSS. However, this was a retrospective comparison of a small group of NSS versus a large group of RN cases, with a selection bias resulting in an imbalance for smaller tumour size and

Coffin et al (Coffin et al., 2011) tried to determine the impact of an imperative indication for NSS on the oncologic outcomes. The study counted 155 patients who underwent NSS: 96 elective indications and 59 imperative indications. 62.7% (37 patients) with imperative indications were staged pT1B or higher versus 22% (22 patients) with elective indications. NSS was applied whenever possible: the usual limitations were tumour size and location. Imperative cases were associated with lower 5- and 10-year OS rates. Tumour size was also

7 metastatic recurrences (7.1%). (Joniau et al., 2011)


significantly larger in the imperative indication group, compared to the elective indication group (p=0.03).

\* There were 12/158 Positive frozen section, therefore a RN was performed.

Table 1. PSM rates.

Nevertheless, he noticed that tumour size was not a significant predictor of recurrence, while multifocality was associated with recurrence. These findings demonstrate that the clinical impact of PSM is not as important as previously thought. To evaluate the impact of PSM, Bensalah et al. (Bensalah et al., 2010) collected 111 cases with PSM from an international multicentre database. Tumours were stage T1, T2 or T3 without nodal invasion or distant metastasis. He compared those with a population of 664 patients who had NSM at resection: groups were matched for age, indication, tumour size and grade. With comparable follow up (PSM 37 versus NSM 35.4 months), the recurrence rate was higher in PSM group than NSM group (10.1% versus 2.2%). However, Overall Survival (OS) and cancer specific survival (CSS) were not significantly different. He also compared 101 PSM with 102 NSM matched for surgical indication (elective versus imperative), tumour size and Fuhrman grade and also found a higher rate of tumour recurrence (10.9% vs. 2.9%), however OS and CSS were again similar.

Russo (Russo 2010) commented the study of Bensalah (Bensalah 2010): in his experience he has more PSM for small renal tumours than for larger, particularly when they are endophytic.

Yossepowitch (Yossepowitch et al., 2008) analysed a cohort of 1344 patients who had undergone partial nephrectomy: there were 77 cases of PSM. Surprisingly, the larger the tumour, the lower the incidence of PSM was. He could not show an association between PSM and a higher risk of recurrence or metastatic progression.

These observations suggest that the presence of PSM is a risk factor for recurrence but does not impact on OS and CSS. These facts also argue for a closer follow up in the first postoperative years.

Most patients with PSM will not experience local recurrence (Van Poppel et al., 2007). Positive margins detected at frozen section or at final histology should not be considered an indication for RN.

significantly larger in the imperative indication group, compared to the elective indication

Publication TNM Single vs multi- n= PSM institution %

Roos pT1b (J Urol 2010) pT1b Single 73 7.6 \* Coffin (2011) all sizes Single 155 9.7 Joniau (2008) pT1b Single 67 5.8 Porpiglia (2010) World J Urol pT1b Multi 63 6.5 Porpiglia (2010) BJU pT1b Single 33 0 Patel (2009) pT1b Single 15 0 Coffin (2011) all sizes Single 155 9.7

Nevertheless, he noticed that tumour size was not a significant predictor of recurrence, while multifocality was associated with recurrence. These findings demonstrate that the clinical impact of PSM is not as important as previously thought. To evaluate the impact of PSM, Bensalah et al. (Bensalah et al., 2010) collected 111 cases with PSM from an international multicentre database. Tumours were stage T1, T2 or T3 without nodal invasion or distant metastasis. He compared those with a population of 664 patients who had NSM at resection: groups were matched for age, indication, tumour size and grade. With comparable follow up (PSM 37 versus NSM 35.4 months), the recurrence rate was higher in PSM group than NSM group (10.1% versus 2.2%). However, Overall Survival (OS) and cancer specific survival (CSS) were not significantly different. He also compared 101 PSM with 102 NSM matched for surgical indication (elective versus imperative), tumour size and Fuhrman grade and also found a higher rate of tumour recurrence (10.9% vs. 2.9%),

Russo (Russo 2010) commented the study of Bensalah (Bensalah 2010): in his experience he has more PSM for small renal tumours than for larger, particularly when they are

Yossepowitch (Yossepowitch et al., 2008) analysed a cohort of 1344 patients who had undergone partial nephrectomy: there were 77 cases of PSM. Surprisingly, the larger the tumour, the lower the incidence of PSM was. He could not show an association between

These observations suggest that the presence of PSM is a risk factor for recurrence but does not impact on OS and CSS. These facts also argue for a closer follow up in the first post-

Most patients with PSM will not experience local recurrence (Van Poppel et al., 2007). Positive margins detected at frozen section or at final histology should not be considered an

\* There were 12/158 Positive frozen section, therefore a RN was performed.

group (p=0.03).

Table 1. PSM rates.

endophytic.

operative years.

indication for RN.

however OS and CSS were again similar.

PSM and a higher risk of recurrence or metastatic progression.

### **2.1.2 Overall survival, cancer-specific survival, progression free survival**

We reviewed 98 patients operated at our institution between 1997 and 2009 for a renal tumour larger than 4 cm. All patients underwent an open partial nephrectomy. Mean diameter was 5.32 cm. At final histopathology, three quarters of the tumours were malignant and 2.7% were staged pT3a. 53.4% of the renal cell cancers (RCC) showed a low grade (Furhman grade 1-2) versus 46.6% high grade (Furhman grade 3-4). The 5–year OS and CSS rates were 77.9% and 98%, respectively. We observed 5 local reccurences (5.1%) and 7 metastatic recurrences (7.1%). (Joniau et al., 2011)

Roos and Brenner (Roos et al., 2010) compared 73 patients who had undergone elective NSS for T1b or greater tumours with a pair-matched cohort of 100 radical nephrectomies: the OS rates were comparable for NSS vs. RN. The 5, 10 and 15-year CSS rates after NSS (95%, 91% and 82%, respectively) were comparable with RN (97%, 95 and 88%, respectively).The 5, 10 and 15-year PFS rate after NSS (89%, 85% and 76%, respectively) were similar to RN (92%, 89% and 77%, respectively). In a retrospective study by Antonelli (Antonelli et al., 2008), there was no significant difference in progression and survival rates between NSS and RN both for tumours ≤ 4 cm as for those >4 cm. Interestingly, even when not significant, the group of patients with the larger tumours treated with radical surgery experienced a progression rate which was double compared to those who underwent NSS. In the same study, when operated by NSS, the patients with a T1a tumours had a higher risk of local recurrence in the operated kidney, as well as in the contralateral kidney. T1b tumours showed a higher risk of metastatic and local recurrence. Cytonuclear grading was correlated with higher risk of recurrence in tumours larger than 4 cm. However, even in large tumours with high cytonuclear grade, the type of surgery had no significant influence on oncologic outcomes: nor on progression rate nor on disease free survival rate at 5 years.

Nemr (Nemr et al., 2007) described similar oncologic outcomes for NSS and RN in T1b renal tumours: Mean follow up was 45 months and there was no significant difference in recurrence free survival with 100% for PN vs. 89.3% for RN.

Margulis (Margulis et al., 2007) retrospectively compared RN (576) with NSS (34) for tumours >4 cm: recurrence occurred in 4 patients (12%) who underwent NSS vs. 164 patients (28.9%) who underwent RN at a median follow-up of 24.2 and 13.2 months, respectively. 5-year RFS was higher for NSS but CSS was similar. 27% of NSS were performed for elective indications; the remainders had solitary kidneys (29%) or chronic kidney disease (CKD) (44%). The indication does not seem to impact 5-year RFS and CSS. However, this was a retrospective comparison of a small group of NSS versus a large group of RN cases, with a selection bias resulting in an imbalance for smaller tumour size and more pT3a in the NSS group compared to the RN group.

Coffin et al (Coffin et al., 2011) tried to determine the impact of an imperative indication for NSS on the oncologic outcomes. The study counted 155 patients who underwent NSS: 96 elective indications and 59 imperative indications. 62.7% (37 patients) with imperative indications were staged pT1B or higher versus 22% (22 patients) with elective indications. NSS was applied whenever possible: the usual limitations were tumour size and location. Imperative cases were associated with lower 5- and 10-year OS rates. Tumour size was also a significant prognostic factor for 5- and 10-year Overall Survival.

The Role of Nephron-Sparing Surgery (NSS) for Renal Tumours >4 cm 333

2 were embolized and 2 were treated conservatively. There was one urinary fistula which was successfully managed by placing a double–J stent. Thus, major complication rate

Coffin (Coffin et al., 2011) encountered a higher complication rate in NSS compared to RN. Total complication rate was 37.7% (of 69 patients) versus 24.5%, respectively. Rates of pulmonary complications and delirium were comparable in both techniques (9.4% versus 9.6% and 3.1% versus 1.1%, respectively) while cardiac complications were more frequent after RN (20.2% versus 1.5% after NSS). Urinary fistula rate was 5.8%. Transfusion rate was higher in NSS (23.2%) versus RN (13.8%). Spleen damage was not encountered during NSS but occurred three times during RN. Contrary to most studies, NSS did not require surgical

Publication Approach Single N = C SR RN CR I II IIIa IIIb IV V

NSS has a higher rate of complications, however this remains acceptable. Most complications can be managed in a conservative or minimally invasive fashion and therefore in none of the

Is there an impact of imperative indications for NSS on peri-operative complications? In a study by Cofin, no significant difference was seen between elective and imperative indications regarding operating time, but the elective group had better surgical outcomes: less blood loss and better control of post-operative creatinin level (Coffin 2011). For oncologic outcomes, Antonelli (Antonelli et al., 2008) found a lower recurrence rate and a higher disease free

Being older than 65 years does not seem to be a significant prognostic factor for having surgical as well as medical complications after partial nephrectomy. The difference was

 institution % % % % % % % % % Porpiglia (2010) Lap multi 41 7.3 7.3 2.4 26 4.8 7.3 7.3 7.3 0 \*Porpiglia (2010) Lap one 33 0 6 3 27 9 3 9 6 0 Becker (2006) open one 69 - 13 10 3 0 Patel (2009) Robot one 15 0 6 26.6 0 6.6 13.2 0 6.6 0 Joniau (2011) open one 98 - 3 0 27,5 8.16 11.2 0 5.1 2 1

vs multi-

revision but one patient was re-operated after a RN. (Roos et al., 2010)

I, II, III, IV, V = Complication rate according to the Dindo-Clavien classification

reports, an impact on the length of hospital stay or the hospital costs was found.

survival rate at 5 years in elective indications compared with imperative indications.

statistically significant for cardiac complications only (Roos et al., 2010).

(Dindo score 3) was 9.2%.

C= Conversion SR = Surgical Revision RN = Radical Nephrectomy CR = Complication rate

**2.2.2.2 Elderly** 

Table 3. Complication Rate.

**2.2.2 Risk factors for complications** 

**2.2.2.1 Imperative indications** 

Becker (Becker et al., 2006) evaluated the oncologic outcomes of NSS in tumours larger than 4 cm with mean follow up of 6.2 years. There were 10% of deaths but none was cancer related. The Cancer specific survival was 100% after 5, 10 and 15 years. Of the 69 patients, 5.8% experienced disease recurrence. 5-, 10- and 15-year overall survival rates were 94.9%, 86.7% and 86.7%, respectively.

In carefully selected patients with tumours >4 cm, NSS appears to obtain equivalent oncologic outcomes compared to those achieved with RN. Although higher morbidity rates were seen after NSS, the complication type and severity were acceptable.


Table 2. Oncologic outcomes.
