Chirurgie conservatrice du rein dans les tumeurs de plus de 7 cm

25 mai 2018

Auteurs : N. de Saint Aubert, F. Audenet, F. Mccaig, C. Delavaud, V. Verkarre, T. Le Guilchet, C. Dariane, C. Pettenati, H. Slaoui, A. Mejean, M.O. Timsit
Référence : Prog Urol, 2018, 6, 28, 336-343




 




Introduction


Partial nephrectomy (PN) in the treatment of renal cell carcinoma has a triple objective: to achieve equivalent oncological results when compared with radical nephrectomy (RN), while preserving renal function, and preventing cardiovascular events and mortality associated with chronic kidney disease.


PN is the gold standard treatment of renal carcinomas under 4cm (cT1a), and it is now preferred where technically possible for tumours up to 7cm (cT1b) [1].


PN is generally not recommended for patients with limited life expectancy or poor performance status due to an increased rate for complications as compared to RN.


For tumours greater than 7cm (cT2), PN is recommended in imperative indications: solitary kidneys, bilateral tumours, reduced renal function of contralateral kidney or advanced chronic kidney disease. However, current guidelines remain unclear regarding the relative indications for PN in cT2 [1].


In clinical practice, PN is relatively offered to cT2 patients on an individual approach, based on patients characteristics, tumour complexity (as assessed using predicitive score such as RENAL or C Index) as well as surgical expertise [2]. Few retrospective series report satisfying oncological and functional outcome of PN in cT2; nevertheless, due to the larger tumor burden, it remains unclear whether remaining renal parenchyma is always significant. In addition, PN for such large tumours has been associated with an increased risk for surgical complications that challenges the theoretical reduction of risk for cardiovascular mortality [3, 4, 5, 6, 7].


The aim of the present study is to assess the outcome of PN in cT2 tumours treated at our institution.


Methods


This was a retrospective single center study.


Study population


Between January 2000 and December 2013, all patients presenting with a renal mass classified as cT2N0M0 (TNM 2009 classification) were included.


Inclusion criteria were: tumour size greater than 7cm, no lymphadenopathy or visible metastasis on preoperative imaging (CT or MRI). Patients with personal or family history of kidney cancer (or hereditary associated syndrome) were excluded.


Indication for PN and surgical approach were depending on surgeon's appreciation. Indication was considered relative when normal renal function and a healthy contralateral kidney. Patients were included in group 1 for underdoing PN and group 2 for underdoing RN.


After surgery, patients were followed clinically and radiologically, according to guidelines, first one month after surgery and thereafter every 6 months until one year and annually for 5 years [1]. After this time, patients were followed up annually for a further 5 years. In the high-risk renal cell carcinoma (ISUP grade 4 or sarcomatoid component) as well as in non-type I papillary sub-types, patients were monitored at 3 months postoperatively with imaging, either CT or MRI.


Data collection


The following patient characteristics were collected retrospectively, including:

past medical and surgical history with the calculation of Charlson score, Bosniak classification of cystic renal masses;
histopathology;
postoperative complications were classified according to classification of Clavien-Dindo;
evaluation of renal function at specific time points: preoperative, early (day 5) and late (last recorded values at follow up);
oncological data: positive surgical margins were defined by tumoral effraction more than 1mm on the histologic examination into renal parenchyma for PN or into fat invasion for both group. Overall, disease-specific and recurrence-free survivals were measured;
the trifecta was defined and considered as accomplished when the 3 following criteria were met:
∘
no positive margins,
∘
no complication≥Clavien III,
∘
no reduction of renal function:
-
no patients developed CKD≥stage 3,
-
for those patients who had CKD≥3 preoperative, there were no upstaging in CKD stage observed.




Statistical analyses


Statistical analyses were performed using the &khgr;2 test for qualitative variables and the Mann-Whitney test for quantitative variables.


Survival was calculated using the Kaplan-Meier method and the curves were compared according to the log rank test. Multivariate analysis was performed using the Cox Proportional Hazard model.


All the statistical analyses were performed using the ADDINSOFT® XLSTAT version 2015.2.01.16714 software.


Results


Patients


During the study period, 130 patients met inclusion criteria. Characteristics of the patients are shown in Table 1.


Surgical approach for RN was laparoscopic in 53% of cases (43/81), and for PN open in 98% of cases (48/49).


Indication for PN was relative in 84% of cases (41/49) and imperative in 16% (8/49). Median follow-up was 42 months (IQR 19-69).


Pathology


Renal masses were malignant in 78% (102/130) of cases. Most of them were clear cell carcinomas (59%, 60/102) with unequal distribution between PN and RN: 39% and 66% respectively (P =0.014). In total, 36% of cT2 tumours were upgraded following histological examination to pT3a. There was an unequal distribution between the group 1 (14%) and group 2 (43%), P =0.006).


There were benignant in 22% (28/130). Most of them were cystic tumours classified Bosniak≥3 (57%, 16/28), there were 8 oncocytomas and 4 angiomyolipomas.


Histological findings are reported in Table 2.


Morbidity


PN was significantly associated with higher rates of complications as compared with RN (37% and 14%, respectively, OR=3.7, 95% CI: 1.58-8.62, P =0.002) but independently of the indication (relative vs. imperative: 36.6% vs. 37.5, respectively, OR=1.02, 95% CI: 0.24-4.57, P =0.961).


Comparison of the Clavien-Dindo severity classification showed no significant difference for grades≥3 (16% vs. 6%, P =0.06).


Details of the complications by group are presented in Table 3.


Postoperative renal function


Renal function data were available for 90 patients, 35 in group 1 and 55 in group 2. Variations of median postoperative eGFR was significantly higher for RN compared with PN (−20.0 [−30; −12] vs. −8.0 [−16; +2], P =0.0001). One patient developed late and severe renal failure in group 1 and 3 in group 2. This difference was not statistically significant.


Table 4 shows the renal function outcomes in both groups.


Trifecta


There were 69 malignant tumours whereby the trifecta was calculated. There were no significant differences between the two groups (P =0.49):

PN 63% (12/19);
RN 54% (27/50).


Percentage of each criterion is presented in Figure 1.


Figure 1
Figure 1. 

Trifecta function of surgical type.




Oncological outcomes


Among 102 patients with malignant tumours, 28 patients (27%) underwent PN and 74 (73%) RN.


The median follow-up was 44.8 months [20-67] with no significant difference: 38.3 months [11.8-65.0] in group 1 vs. 45.05 [20.4-71.4] in group 2 (P =0.35).


In the group 1 (PN), 4 deaths (14.3%) were observed at the end of follow-up. They occurred after 18, 31,42 and 74 months. All deaths were cancer specific, in patients with high-grade clear cell carcinoma and tumour size<10cm. Overall and specific 5-year survival rates were 89%. At the end of follow-up, 5 patients (18%) presented disease recurrence: 3 with lung metastases, 1 with cerebral metastasis and one local recurrence. All occurred within 5 years and for patients who had a tumour with high RENAL score (≥10). Disease-free survival at 5 and 10 years were 82%.


For survival, there were no significant differences between the two groups (P =0.36, P =0.17, P =0.39; overall, specific and disease-free survival, respectively).


In the PN group 10.7% of patients had positive tumour margins versus 2.7% in the RN group. These differences were not statistically significant (P =0.09).


Univariate analyses of several variables are presented in Table 5.


The multivariate analysis was not significant for any criteria.


Discussion


Since the landmark publication from Huang et al. that showed radical nephrectomy was associated with a significant increased risk for developing chronic kidney disease, RN was no longer regarded as the gold standard treatment for small, renal cortical tumours [8]. The rationale to offer PN in the treatment of larger tumours relies not only on the feasibility of the procedure but also on the reported increased mortality after RN in the treatment of T1 tumours as compared with PN. Thus, Weight et al. indicated that loss of renal function after RN surgery for tumours between 4 and 7cm (T1b) was associated with an increased mortality of 17% (95% CI: 12-27) and an increased cardiac-specific mortality of 25% (95% CI: 3-73) [9].


In our study, we report a further deterioration of CKD stage in 38% of patients who underwent PN, compared with a deterioration of 65% in those who underwent RN (P =0.038) supporting that the remaining renal parenchyma, after excision of a T2 mass, has a significant functional value. However, due to the paucity of event, our data failed to demonstrate a significant protective effect of PN for the onset of end-stage renal disease. Indeed, ESRD occurred in 1 of 35 patients after PN vs. 3 on 55 after RN (P =0.85). Nevertheless, a larger cohort of 256 patients with overall increased rates of ESRD already reported the protective effect of PN reducing the risk for ESRD from 22.4% after RN to 11.6% [RR=3.97; 95% CI: 1.2-11.2; (P =0.01)] [10].


Considering the association between chronic renal failure and mortality, including cardiovascular mortality, our findings, together with previously published retrospective series, suggest that PN should be offered in the treatment of renal cell carcinoma in larger tumours such as T2.


However, it has been shown in an extensive report of 2675 renal tumours that each additional centimeter in tumour diameter increased the risk of high-grade Fuhrman (OR: 1.25, 95% CI: 1.21-1.30, P <0.001). The authors revealed an increasing occurrence of high-grade tumours from 0% for the masses≤1cm and up to 59% for tumours≥7cm [11]. Our findings are consistent with these dates, since we observed 81% of high-grade tumours, highlighting a particular aggressiveness of tumours≥7cm and pledging for careful oncological consideration before performing PN on cT2 tumours.


Thus, the risk of chronic kidney disease and associated morbidity induced by surgery needs to be balanced with the risk for oncological failure, especially since grade and pathological stage cannot be accurately predicted on preoperative imaging and core biopsy whereas PN for pT3a tumours has been reported to be associated with reduced disease-free survival [12].


In our study, 43% of cT2 tumours in RN group were upgraded to pT3a on definite pathological result versus 14% in the PN group (P =0.006). This difference might be explained by the retrospective design of the study since patients with well limited peripheral T2 tumours were more likely to undergo PN conversely to patients with gross hilar invasion. In addition, the fewer peri-tumoural veins and fat obtained on PN specimen as compared with RN might also lead to a less accurate T3a staging. Despite significant, the observed T3a upgrading in our study did not impact the overall survival. The proportion of cT2 upgraded to pT3a tumours postoperatively varies in the literature from 6.9 to 41% [3, 5, 7, 13, 14, 15, 16, 17, 18]. Compared with the same work, cT1b tumours were upgraded to pT3a less often [13, 15]. Highlighting the difficulties to draw oncological conclusion from retrospective studies in that matter.


Our two groups presented with significant differences in patients' and tumors' characteristics such as age, tumour size, mode of presentation, proportion of pT3a tumours and RENAL score. This selection bias might explain the failure of multivariate analysis to identify predictive factors since heterogeneity of the two populations reduces the strength of the statistical comparison. However, we were able to show that RENAL score>10 was statistically associated with postoperative recurrence and reduced overall survival, P =0.011, similarly to Nagahara et al. who showed a significant association between RENAL nephrometry score≥10 and postoperative recurrence for localized renal cell carcinomas treated by radical nephrectomy [19].


Another limitation to the extension of indication for PN in cT2 tumours is the postoperative morbidity. Our work has highlighted an increased total morbidity associated with PN as compared with RN (respectively 37% vs. 14%, OR=3.7, 95% CI: 1.58-8.62, P =0.002).


Although the severe complication rate (Clavien-Dindo≥3) between PN and RN did not show a statistically significant difference (6% for PN versus 16% RN, P =0.06), this may be a result of the small number of patients included in the analysis (n =130).


Postoperative morbidity did not have a statistically significant impact on length of stay: mean length of stay was 6.3 versus 6.5 days and median length of stay was 6 versus 5 days for PN and RN respectively.


Morbidity following both PN and RN has been recorded using different parameters in the literature, specifically the Clavien-Dindo sub-classifications are rarely documented. This results in difficulty comparing studies accurately.


PN was associated with higher rates of complications in most published series. Breau et al. described 39% of complications after PN vs. 15% in the RN group. Kopp et al. published similar results (respectively 37.5% vs. 24.6% for total complications and 17.5% vs. 2.5% for severe complications in PN vs. RN). Becker et al. described 29.6% for total complications and 10.9% for severe ones in their cohort, which included only PN [3, 6, 7].


The difference of morbidity between PN and RN can be explained in different ways: both of them were associated with typical surgical complications: hemorrhage, infection and embolic events. PN is associated with specific complications including urinary fistulae. Breau et al., Long et al., Karellas et al., Kopp et al. and Becker et al. described 17.5%, 12%, 11%, 10% and 3.2% urinary fistulas respectively [3, 4, 5, 7, 17]. These fistulae strongly impacted morbidity even though they did not always require specific intervention. This complication is difficult to compare between studies due to the differences in diagnostic tools as well as management. For example, inserting a ureteric stent versus conservative treatment for a urinary fistula impacts the reported complication grade and could significantly bias any interpretation of the results. In addition, the surgical approach for PN also impacts the incidence of urinary complications since robotic assisted PN has been associated with a significant reduction in the risk for urinary complication [20].


Bigot et al., in a multivariate analysis, demonstrated that absolute indication was a risk factor for major postoperative complications (HR=2.7; P =0.0019). There were 65.7% complications in the absolute indication group and 29.3% in the relative indication group. We did not find comparable rates with 37.5% and 36.6% respectively (P =0.961). This can be explained by exclusion of hereditary kidney cancers [16].


Our work highlights that PN may be offered as a treatment option in cT2 renal tumours, providing comparable oncological outcome but significant benefits regarding preservation of renal function as compared with RN. Because of PN associated morbidity, patients should be highly selected with attentive considerations for their comorbidities and optimal assessment of competitive mortality. However, recent data tend to show that development of minimally-invasive techniques along with the diffusion of conservative renal surgery contributes to the reduction of PN related overall morbidity [20, 21].


Concerns about adverse pathological findings and upstaging on definite pathology highlights the need for predictive tools that might accurately help clinicians to increase oncological safety when providing patients with this challenging conservative surgery.


Contributions


N. de Saint Aubert: data collection, data analysis, manuscript writing. F. Audenet: data analysis. F. Mccaig: translation helper. C. Delavaud: data collection (radiologist). V. Verkarre: data collection (pathologist). T. Le Guilchet: data collection (urologist). C. Dariane: data collection (urologist). C. Pettenati: data collection (urologist). H. Slaoui: data collection (urologist). A. Mejean: project development. M.O. Timsit: project development.


Disclosure of interest


The authors have not supplied their declaration of competing interest.




Table 1 - Clinical variables (n =130).
  PN (n =49)  RN (n =81)  P  
Mean (SD)       
Age, years  60.8 (14.3)  56.4 (12.9)  0.08 
BMI, kg/m2  25.1 (3.6)  26.0 (4.6)  0.51 
Tumor size from CT, cm  8.6 (1.3)  10.1 (3.6)  0.007 
Preoperative eGFR  76.9 (21.2)  80.8 (20.3)  0.32 
n (%)       
Gender      0.47 
Male  29 (59)  53 (65)   
Female  20 (41)  28 (35)   
Charlson comorbidity index      0.51 
≤ 2  21 (43)  30 (37)   
> 28 (57)  51 (63)   
Mode of presentation      0.002 
Symptomatic  11 (22)  40 (49)   
Incidental  38 (78)  41 (51)   
Clinical T stage      0.002 
cT2a  44 (90)  53 (65)   
cT2b  5 (10)  28 (35)   
RENAL score      0.006 
<10  23 (47)  19 (23)   
≥ 10  26 (53)  62 (77)   
Histology      <0.001 
Renal cell carcinoma  28 (57)  74 (91)   
Benign tumours  21 (43)  7 (9)   
Median [IQR] follow-up, month  31 [11-65]  45 [20-73]  0.14 



Légende :
SD: standard deviation; BMI: body mass index; CT: computerized tomography; eGFR: estimated glomerular filtration rate; IQR: interquartile range.



Table 2 - Pathological variables of malignant tumours (n =102).
  PN (n =28)  RN (n =74)  P  
Pathology, n (%)      0.014 
Clear cell carcinomas  11 (39)  49 (66)   
Non clear cell carcinomas  17 (61)  25 (34)   
Pathological T stage, n (%)      0.006 
pT2  24 (86)  42 (57)   
pT3a  4 (14)  32 (43)   
Fuhrman Grade, when recorded, n (%)      0.24 
Low grade  (I and II)  6 (27)  10 (16) 
High grade  (III and IV)  16 (73)  53 (84) 





Table 3 - Postoperative data (n =130).
  PN (n =49)  RN (n =81)  P  
Total complication, n (%)  18 (37)  11 (14)  0.002 
Clavien Dindo≥3 complications, n (%)  8 (16)  5 (6)  0.06 
3a Haemorrhage requiring embolisation   
Pancreatic fistula   
Pleural effusion   
Abscess   
3b Retroperitonal urinoma   
Parietal hématoma   
Peritonitis   
4a Acute respiratory failure   
Length of hospital stay       
Mean (SD)  6.3 (4.2)  6.5 (6.0)  0.124 
Median [IQR]  6 [4-7]  5 [4-6]  0.961 



Légende :
SD: standard deviation; IQR: interquartile range.



Table 4 - Renal function outcomes (n =90).
  PN (n =35)  RN (n =55)  P  
Mean preoperative eGFR (SD)  76.9±21.2  80.9±20.3  0.32 
Mean early postoperative eGFR (SD)  64.5±22.4  59.5±16.2  0.16 
Median variation of early postoperative eGFR [IQR]  −8.5 [−28; +0.5]  −20.0 [−29; −10]  0.033 
Mean last recorded eGFR, (SD)  68.9±17.3  59.4±16.4  0.003 
Median variation of last recorded eGFR [IQR]  −8.0 [−16; +2]  −20.0 [−30; −12]  0.0001 
Reduction of renal functiona (%)  8 (38)  33 (65)  0.038 
Late severe chronic renal failureb (%)  1 (5)  3 (6)  0.85 



Légende :
eGFR: estimated glomerular filtration rate; SD: standard deviation; IQR: interquartile range.

[a] 
Change of chronic kidney disease stage.
[b] 
CKD stages 4 and 5.


Table 5 - Univariate analysis of survival factors (n =85).
Variable  Overall survival
P  
Disease free survival
P  
Specific survival
P  
Charlson comorbidity index (≤2 vs.>2)  0.41  0.34  0.19 
Tumour size (≤10 vs.>10cm)  0.16  0.84  0.64 
RENAL score (≤10 vs.>10)  0.011  0.20  0.020 
Surgical option (radical vs. partial nephrectomy)  0.36  0.39  0.17 
Pathology (non clear cell vs. clear cell)  0.048  0.17  0.09 
Pathological T stage (pT2 vs. pT3a)  0.80  0.81  0.51 
Fuhrman grade (low grade vs. high grade)  0.07  0.031  0.10 




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© 2018 
Publié par Elsevier Masson SAS.