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Morbidity, perioperative outcomes and complications of robot-assisted radical prostatectomy in kidney transplant patients: A French multicentre study
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Urologic Oncology: Seminars and Original Investigations 000 (2020) 1−7
Clinical-Prostate cancer
Morbidity, perioperative outcomes and complications of robot-assisted radical prostatectomy in kidney transplant patients: A French multicentre study Margaux Felber, M.D.a, Sarah J. Drouin, M.D.a, Pietro Grande, M.D.a, Christophe Vaessen, M.D.a, Jerome Parra, M.D.a, Benoit Barrou, M.D., Ph.D.a, Xavier Matillon, M.D.b, Sebastien Crouzet, M.D., Ph.D.b, Quentin Leclerc, M.D.c, Jerome Rigaud, M.D., Ph.D.c, Thomas Prudhomme, M.D.d, Nicolas Doumerc, M.D.d, Sebastien Bergerat, M.D.e, Herve Lang, M.D., Ph.D.e, Charles Laine, M.D.f, Gregoire Robert, M.D., Ph.D.f, Aurelien Gobert, M.D.a, Benjamin Granger, M.D., Ph.D.g, Morgan Roupr^et, M.D., Ph.D.a,* a
Department of Urology, Sorbonne Universit e, GRC n°5, ONCOTYPE-URO, AP-HP, Urology, H^ opital Piti e-Salp^ etri ere, F-75013 Paris, France b Department of Urology, Hospices Civils de Lyon, Lyon, France c Department of Urology, Centre Hospitalier Universitaire de Nantes, Nantes Cedex 01, France d Department of Urology, Andrology and Renal Transplantation, CHU Rangueil, Paul-Sabatier University, Toulouse Cedex, France e Department of Urology, H^ opital Civil, Strasbourg, France f Department of Urology, Andrology and Renal Transplantation, GH Pellegrin Tripod, Bordeaux, France g Department of Biostatistics, Groupe Hospitalo-Universitaire Est, Publique H^ opitaux de Paris, H^ opital Piti e-Salp^ etri ere, Paris, France Received 11 August 2019; received in revised form 25 October 2019; accepted 19 December 2019
Abstract Objective: Evaluate the safety, feasibility and efficiency of robot-assisted radical prostatectomy (RARP) in kidney transplant recipients, performed in high-volume French referral centres, and describe intra- and postoperative, oncological and functional outcomes. Materials and methods: A multicentre study was conducted on prospective RARP databases from 5 centres between 2008 and 2017. We retrospectively identified a first group (G1) of transplant patients. The following data were collected: age, body mass index, prostate-specific antigen, ISUP score, TNM stage, stratification according to d’Amico, renal function, renal disease, time between renal transplant and prostate cancer (PCa), operating time, bleeding, pre- and postoperative complications (according to Clavien). Group 1 data were matched with a second group (G2) of nontransplanted PTRA patients. Results: A total of 321 patients were included (G1 N = 39 and G2 N = 282). The median operating time was 180 minutes (interquartile range 125−227) for G1 and 150 minutes (120−180) in G2 (P = 0.0623) and the median bleeding volume was 150 mL (150−400) and 250 mL (175−400), respectively (P = 0.1826). No grafts were damaged by RARP. Postoperative complication rate was significantly higher in G1: 51.2% vs. G2: 8.2% with a majority of minor complications (41%) according to Clavien Dindo (P < 0.001). Pathological assessment was as follows in G1: T2 = 28 (71.8%), T3 = 11 (28.2%), and G2: T2 = 206 (73.3%), T3 = 75 (26.7%) (P = 0.77). Postoperative ISUP scores were mainly grade 1: G1 = 14 (35.9%) vs. 99 (35.2%) in G2 and grade 2: respectively 18 (46.1%) 94 (33.5%). The rate of positive surgical margins was comparable in both groups: 13.2% for transplant patients vs. 18.1% (P = 0.65). Renal function was not significantly different at one year (P = 0.07). The median follow-up was 47.9 months (42.3; 52.5). Conclusion: RARP is conceivable to treat localized prostate cancer in kidney transplant recipients. This procedure does not appear to have any negative impact on graft renal function and cancer prognosis. Ó 2020 Elsevier Inc. All rights reserved.
Keywords: Prostatic neoplasm; Kidney transplantation; Prostatectomy; Immunosuppresion *Corresponding author. Tel.: 01.42.17.71.39 E-mail address: [email protected] (M. Roupr^et). https://doi.org/10.1016/j.urolonc.2019.12.017 1078-1439/Ó 2020 Elsevier Inc. All rights reserved.
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1. Introduction Renal transplantation is the gold-standard treatment for patients with end-stage renal failure. Compared to dialysis, it provides better results in terms of quality of life and survival [1]. Advancements in immunosuppressive therapy over the past few decades have resulted in a longer and better quality of life for kidney transplant recipients (KTRs). Nonetheless, the increased incidence of cancer in this patient is well established [2,3]. Cancer development has become a major problem in KTRs and is currently one of the primary causes of death in this population [4]. Genitourinary malignancies stand for 34% of the nonskin solid cancer in KTR [5]. Prostate cancer (PCa) incidence remains controversial some studies reported a 2 to 5 times higher incidence in KTR [6,7] but other showed a similar or lower incidence than in the general population [2,8]. As in the general population, localized PCa in KTRs can be treated with the usual options, including surgery, radiotherapy and brachytherapy [9,10]. Due to the possible complications associated with radiotherapy in this group of patients (such as nephritis, ureteral anastomosis strictures, avascular necrosis of the femoral head), radical prostatectomy is the preferred option for this type of tumour. Various prostatectomy techniques have been described in these patients, although the case-series have been small [11−14]. The robotic approach offers a good balance between oncological results and accelerated postoperative recovery compared to open radical prostatectomy. For these reasons, robot-assisted radical prostatectomy (RARP) is becoming the preferred option in KTRs, although few data exist on the functional and oncological results. Our aim was to evaluate the safety, feasibility and efficiency of RARP in KTRs, performed in high-volume French referral centres, and to describe intra- and postoperative outcomes, and oncological and functional outcomes at short- and medium-term follow-up. 2. Materials and methods 2.1. Study design and patients A prospectively maintained French multicentre database of RARP (including data from 5 major uro-oncology and transplantation centres) was investigated retrospectively. Patients who underwent RARP after renal transplantation (RT) between 2008 and 2017 were selected. Clinical data including age at the time of prostatectomy, aetiology of end-stage renal disease, body mass index, interval between renal transplantation and prostatectomy, side of transplantation, Charlson comorbidity index, preoperative serum creatinine, continence and erectile function were recorded prospectively for each patient.
The diagnosis of PCa was established based on digital rectal examination, prostate-specific antigen (PSA) assay, prostate MRI and ultrasound-guided prostate biopsy. The following pre- and intraoperative data were collected for each patient: preoperative ISUP grade, preoperative PSA, intraoperative events, surgery duration, blood loss, any surgical difficulties (tissue adhesions or tissue infiltrates or other) and Clavien-Dindo score [15]. During the follow-up, the following item were collected: PSA, continence and erectile function, serum creatinine. This follow-up was every 6 months for this first year and each year during the following 5 years thereafter. We designed 2 groups: patients who underwent RARP after RT (group 1), and we also included 282 subjects who presented to our hospital for a localized PCa (group2 = control). Controls were matched for age, PSA level and clinical stage. The determination of the sample size in group 2 was based on a noninferiority approach [16]. Considering a significant number of missing data (30% of incomplete observations), the sample size was assessed at 282. All 282 patients without history of transplantation were drawn at random in the database. 2.2. Surgical technique All patients were treated using a previously described transperitoneal approach [17]. Four robotic and 2 assistant trocars were employed. It was possible to use the usual trocars sites in KTR patients, but the lateral trocar was located more towards the flank than in the iliac fossa depending on the position of the graft. Pelvic lymph node dissection was performed in intermediate- and high-risk patients [18] and was always unilateral (contralateral to the graft site) in KTRs in order to prevent any damage to the graft. Abdominal exploration revealed the transplanted kidney in its right or left iliac position, which did not hamper further dissection. Seminal vesicles were first dissected to ligate deferent canals. The Denonvilliers’ fascia was opened and the posterior face of the prostate freed. The bladder was carefully dissected, especially on the right or left lateral face, to preserve the transplanted ureter. The bladder neck was incised until the posterior dissection plane was joined. Prostatic lateral attachments were then dissected. The Santorini plexus was ligated with an overlock V-LOCK 3-0 and the urethra cut. An urethrovesical anastomosis was performed using Vicryl 3.0 stiches. The specimen was extracted through a supraumbilical incision into a laparoscopic bag. Patient discharge was planned on the third or fourth postoperative day according to the usual hospital protocol and bladder catheter removal was planned on postoperative day 7. 2.3. Statistics Quantitative data (i.e., medians [interquartile range]) and qualitative data (i.e., frequency and percentages) were described. Age at onset data was described according
ARTICLE IN PRESS M. Felber et al. / Urologic Oncology: Seminars and Original Investigations 00 (2020) 1−7
the Kaplan-Meier method. Association between variables were assessed by nonparametric test: Mann-Whitney-Wilcoxon rank sum test and Kruskal-Wallis rank sum test to compare rank symmetry between 2 or more sets of quantitative data; Fisher exact test to compare 2 or more proportions. Study of associations with age at onset were done according a 2-step process: first 2 by 2 by log-rank test for qualitative data or univariate cox model for quantitative data; second, significant variables identified by the first step were overall assessed in a multivariate Cox model after applying a correction for multiple comparisons according the Benjamini-Hochberg procedure. A P value <0.05 was considered significant. Statistical analyses were performed (R version 3.5.1). 3. Results 3.1. Study population Three hundred twenty-one patients were included in the final analysis (Group 1, n = 39; Group 2, n = 282). The demographic data are summarized in Table 1. At the time of PCa diagnosis, median (IQR) age was 62 years (58‒67) in the KTRs and 62 years (58‒66) in the control group. Median preoperative PSA was 6.8 ng/ml in KTRs vs. 6.7 ng/ml in controls. Biopsies demonstrated a majority of ISUP grade 1, 2 and 3 in the 2 groups Median time between kidney transplantation and diagnosis of PCa was 58 months (36.9; 117.3). The graft was located in the right iliac fossa in the majority of cases (n = 30; 76.9%) all the renal transplantation were done extraperitoneally according to the protocol of the reference centres. 3.2. Intraoperative data, surgical complications and immediate postoperative data Intraoperative data, surgical complications and immediate postoperative data are shown in Table 2. Median operative time was 180 minutes (125−227) in KTRs vs. 150 minutes (120−180) in controls, and median blood loss was 150 ml (150−400) vs. 250 ml (175−400), respectively. Median surgery time and blood loss did not differ significantly between the 2 groups (P = 0.0623 and P = 0.1826, respectively). Surgical difficulties occurred in 12/39 patients (30.8%) in group 1 and were mostly related to adhesions or tissue infiltrates directly related to the history of kidney transplantation (18%). Immediate postoperative complications occurred in 20/ 39 patients (51.2%), with only 4 (10.2%) classified as Clavien grade ≥3. The occurrence of Clavien grade ≥3 in the control group was 0.8% (n = 2). Although most of these complications were minor grade I-II (n = 16; 41%) (most of them were pyelonephritis treated by antibiotics, hematoma and anaemia) and resolved
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promptly with appropriate therapy, our analysis demonstrates this group of patients has a high risk of complications. Four out of 39 patients suffered more serious complications (IIIb (n = 2; 5.1%) with 2 lymphoceles treated by laparoscopic marsupialisation between 7 and 10 days after the RARP and IVa (n = 2; 5.1%) with 1 postoperative bradycardia episode requiring 48 hours of intensive care and the other patient needing intensive care for ionic disorders. Contralateral lymph node dissection (LND) was performed in 12 KTRs (30.8%); only 1 patient had a bilateral LND (his graft was placed in an orthotopic position). A bilateral nerve-sparing procedure was performed in 11 patients (28.2%), a unilateral procedure was performed in 5 (12.8%) and a non-nerve sparing procedure was performed in 23 KTRs (59.0%). The procedure was completed robotic in all cases and no conversion to open surgery was necessary. The rate of positive surgical margins (PSM) was 13.2% in KTRs vs. 18.1% in control patients. Median length of hospital stay was 4 days (3;5) in group 1 and 3 (3;4) in group 2 (P = 0.0249). 3.3. Oncological functional and graft outcomes At the final pathological analysis, the tumour was stage T2c in most cases (53.9% in KTRs vs. 56.6% in controls). ISUP grade was mostly 1 and 2 in group1 and for group 2 it was more grade 1, 2 and 3 (P = 0.0308). At the 6 months follow-up, median PSA was 0.02 ng/l (0.01‒0.05) in KTRs and 0.01 mg/l (0.01‒0.03) in the control group. After a median follow-up of 47.9 months (42.3‒52.5), there were 3 (7%) biochemical recurrences in the KTR group vs. 24 (8.5%) in the control group. In the KTR group, 66.7% of patients were treated with adjuvant radiotherapy and 33.3% with androgen deprivation therapy (Table 3). Recovery of continence at 6 months occurred in 68.6% of patients in the KTR group vs. 65% in the control group (Table 4). At this time, complete restoration of erectile function was observed in 31.4% of patients in the control group vs. 12.9% in the KTR group (Table 4). Median serum creatinine levels in KTRs preoperatively and at 1 year postsurgery were 134 mmol/l (108−170) and 147 mmol/l (119.5−179.5), respectively (Tables 1 and 4). No patient had a significant preoperative to postoperative change in renal function (P = 0.07). Progression-free survival (PFS) at 4 years was 96.4% in the KTR group vs. 90.6% in the control group (Raw = 0.5399; Fig. 1). 4. Discussion According to the latest European guidelines, radical prostatectomy is the gold-standard treatment for localized prostate cancer in KTRs [10]. The first RARP in KTR was performed in 2006 by Jhaveri et al. [11] and small caseseries have confirmed the feasibility of this approach since
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Table 1 Characteristics of the study population Renal transplant patients (N = 39) Age at time of diagnosis BMI Charlson comorbidity index Aetiology of renal failure Polycystic kidney disease IgA nephropathy Glomerular nephropathy Nephroangiosclerosis Focal segmental glomerulosclerosis Diabetic nephropathy Alport syndrome Interstitial nephropathy Undetermined Location of renal transplant Right iliac fossa Left iliac fossa Time between renal transplant and PCa diagnosis (mo) PSA concentration at diagnosis (ng/ml) Prostate biopsy (ISUP grade) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Clinical stage T1c T2a T2b T2c T3a Unknown Amico score Low Intermediate High Erectile function Normal Medical treatment Implant None Missing data Preoperative continence Acquireda Not acquired Missing data Preoperative serum creatinine (mmol/l)
62 (58−67) 25 (23.5−28) 5 (4−6)
Nontransplant patients (N = 282) 62 (58−66) 25 (24−28) 4 (4−5)
P
0.92 0.87 0.0006
8 (20.5%) 7 (18.0%) 5 (12.8%) 4 (10.3%) 3 (7.7%) 2 (5.1%) 1 (2.6%) 1 (2.6%) 8 (20.5%) 30 (76.9%) 9 (23.1%) 58 (36.9; 117.4) 6.8 (6.0−8.8)
6.7 (5.4−8.8)
19 (48.7%) 16 (41.0%) 1 (2.6%) 2 (5.1%) 1 (2.6%)
172 (61.0%) 58 (20.6%) 35 (12.4%) 9 (3.2%) 8 (2.8%)
26 (66.6%) 7 (18.0%) 3 (7.7%) 2 (5.1%) 1 (2.6%)
185 (66.3%) 51 (18.3%) 18 (6.5%) 17 (6.1%) 8 (2.9%) 3
14 (35.9%) 18 (46.2%) 7 (17.9%)
140 (49.6%) 114 (40.4%) 28 (10%)
6 (37.5%) 3 (18.7%) 1 (6.3%) 6 (37.5%) 23
155 (86.0%) 7 (3.9%) 0 (0%) 18 (10.1%) 102
37 (97.4%) 1 (2.6%) 1 134 (108−170)
229 (97.0%) 7 (3.0%) 46
0.0794
0.99
0.153
<0.0001
1.00
Values shown are median (IQR) or n (%) unless stated otherwise. Bold values mean statistically significant. a Continence was considered acquired in the case where no or 1 protection per day was necessary and not acquired in other cases.
then. To our knowledge, our study represents the biggest series to date (n = 39) in a national multicentre study involving referral centres for both PCa and kidney transplantation. Most studies regarding PCa in KTR are epidemiological and descriptive based on small series [19−22] and only few studies compared KTR to the general population [13,23,24]. Whether or not the incidence of PCa is increased in KTRs when compared to the general population and
associated with worse disease-specific survival remains a topic of debate [2,6−8]. The higher incidence of PCA in KTRs may be due to several factors. Firstly, long-term immunosuppression may favour carcinogenesis and the development of more aggressive forms of cancer [3]. Several studies identified changes in the immune phenotype of KTR with cancer which may explain the development of cancer due to immunosuppressive therapy [25,26].
ARTICLE IN PRESS M. Felber et al. / Urologic Oncology: Seminars and Original Investigations 00 (2020) 1−7 Table 2 Intraoperative and immediate postoperative data
Table 3 Oncological outcomes
Renal transplant Nontransplant P patients (N = 39) patients (N = 282) Operative time (min) Blood loss (ml) Lymphadenectomy No Unilateral Bilateral Nerve sparing No Unilateral Bilateral Surgical difficulties No Yes Tissue adhesions/ infiltrations Other causes Postoperative complicationsa I−II IIIb IVa Hospital stay (d) Duration of urinary catheter Change in immunosuppressive treatment Yes No
180 (125−227) 150 (150−400)
150 (120−180) 250 (175−400)
26 (66.6%) 12 (30.8%) 1 (2.6%)
151 (53.5%) 16 (5.7%) 115 (40.8%)
23 (59.0%) 5 (12.8%) 11 (28.2%)
76 (27.0%) 74 (26.2%) 132 (46.8%)
27 (69.2%) 12 (30.8%) 7 (18.0%)
259 (91.8%) 23 (8.2%) 12 (4.3%)
5 (12.8%)
11 (3.9%)
Renal transplant patients (N = 39)
0.0623 0.1826 <0.0001
0.005
<0.0001
<0.0001 16 (41.0%) 2 (5.1%) 2 (5.1%) 4 (3;5) 7 (7;7)
21 (7.4%) 1 (0.4%) 1 (0.4%) 3 (3;4) 7 (7;7)
5
0.0249 0.5946
8 (20.5%) 31 (79.5%)
Values shown are median (IQR) or n (%). Bold values mean statistically significant. a According to Clavien Dindo classification.
Secondly, the KTR are older and live longer thanks to the surgical and medical progress of transplantation. Thirdly, these patients are monitored more closely than other patients as they are at higher risk of developing cancer and so we can discover cancers earlier, which increases the incidence of cancer. However, this strict monitoring can detect prostate cancer at an early stage with a better prognosis. Up to now without any available and powerful randomized clinical trials assessing PCa screening benefit in KTR, it seems appropriate to continue this close checking of prostate cancer by an annual PSA and DRE in the KTR [27]. In our cohort, the majority of PCa in KTR was diagnosed at an early stage that is why we have less aggressive disease in the pathological analyse than in group 2 (P = 0.0308). From an oncological point of view, surgical margins are considered a guarantee of quality for RARP. In our series, a PSM rate of 13.2% (5 of 39 patients) was obtained. This rate is quite low compared to other studies in the literature: Polacari et al. [20] reported a PSM rate of 28.6%, Le Clerc et al. [19] 50% and Iwamoto et al. [28] 46%. In a recent meta-analysis by Zeng et al. [29], which included a total of 35 RARPs in KTRs, the PSM rate was
Postoperative T-stage T2a T2b T2c T3a T3b Postoperative N-stage N0 N1 Nx Positive surgical margins Anatomopatholgy ISUP grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Missing data 6 months PSA (ng/ml) Recurrence Treatment Radiotherapy Hormone therapy Radio/hormone therapy
Nontransplant patients (N = 282)
P
0.7717 5 (12.8%) 2 (5.1%) 21 (53.9%) 9 (23.1%) 2 (5.1%)
23 (8.2%) 24 (8.5%) 159 (56.6%) 65 (23.1%) 10 (3.6%) 0.4954
18 (46.1%) 1 (2.6%) 20 (51.3%) 5 (13.2%)
146 (52.0%) 4 (1.4%) 131 (46.6%) 51 (18.1%)
0.649 0.0308
14 (35.9%) 18 (46.1%) 4 (10.3%) 0 (0%) 3 (7.7%) 0.02 (0.01−0.05) 3 (7.7%) 2 (66.7%) 1 (33.3%) 0
99 (35.2%) 94 (33.5%) 67 (23.8%) 14 (5.0%) 7 (2.5%) 1 0.01 (0.01−0.03) 24 (8.5%)
0.0393 0.84
13 (54.2%) 3 (12.5%) 8 (33.3%)
Values shown are median (IQR) or n (%). Bold values mean statistically significant.
32.4%. This low PSM rate in our cohort can be explained by several factors. Firstly, surgery was performed only in referral centres [30]. In addition, most of the patients had low-grade preoperative clinical stages (mainly pT1c and pT2a) and a low ISUP grade in biopsies. Table 4 Functional and graft outcomes at 6 months and 1 year Renal transplant patients (N = 39) Erectile function Normal Medical treatment Implant None Missing data Continence Acquired Not acquired Missing data Serum creatinine at 1 year (mmol/l)
Nontransplant patients (N = 282)
P
0.001 4 (12.9%) 10 (32.3%) 1 (3.2%) 16 (51.6%) 8
76 (31.4%) 107 (44.2%) 1 (0.4%) 58 (24.0%) 40 0.7098
24 (68.6%) 11 (31.4%) 4 147 (119.5−179.5)
Values shown are median (IQR) or n (%). Bold values mean statistically significant.
169 (65.0%) 91 (35.0%) 22
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Fig. 1. Progression-free survival in kidney transplant recipients and controls with prostate cancer undergoing robot-assisted radical prostatectomy.
Biochemical recurrence was not significantly different between RTR and control. Our rate of recurrence was also lower when compared to other series; Iwamoto et al. [28] reported 4 biochemical recurrences in 12 patients (33.3%), Le Clerc et al. [19] reported 2 of 12 patients with recurrence (16.7%), and Polcari et al. [20] and Pettenati et al. [24] had a rate close to ours at 7.1%. We had no metastatic evolution disease. Our study confirms the feasibility of RARP, but significantly more surgical difficulties were observed in the KTR group compared to the control group. These were mainly related to adhesions or tissue infiltrates directly related to the history of kidney transplantation. However, no death was reported, the renal grafts did not suffer any damage in any patient and renal function was preserved. Such an outcome may reflect the relatively small sample size and the fact that, due to the prospective collection of the data, all minor changes were reported. Concerning the graft, there were no injuries or graft loss during our procedure and serum creatinine at 1 year did not differ significantly (P = 0.07) from preoperative values. Despite the strengths of our study, our findings should be interpreted with care due to several study limitations. Firstly, despite the collection of data prospectively, our study was retrospective, leading to the risk of selection bias (even if our study population was multicentric). Although this is the largest series reported to date, the number of KTRs was small (n = 39). Secondly, the follow-up period was not long hence it is difficult to interpret the oncological outcomes in such a short follow-up time (i.e., <5 years). Taking these limitations into account, our study suggests
RARP is technically feasible for treating localized PCa in KTRs without graft deterioration, but the oncological outcome remains a major topic requiring further evaluation. In conclusion, the results of our multicentre study suggest that RARP is a safe and feasible approach to treat localized PCa in a select group of KTRs. No major modifications of the surgical approach were necessary, and the intervention appeared to have no negative impact on renal function and prognosis when performed in experienced centres. Conflict of Interest The authors declare that they have no conflict of interest. References [1] Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341:1725–30. [2] Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, Stewart JH, Law M, et al. Cancer incidence before and after kidney transplantation. JAMA 2006;296:2823–31. [3] Au E, Wong G, Chapman JR. Cancer in kidney transplant recipients. Nat Rev Nephrol 2018;14:508–20. [4] Sampaio MS, Cho YW, Qazi Y, Bunnapradist S, Hutchinson IV, Shah T. Posttransplant malignancies in solid organ adult recipients: an analysis of the U.S. National Transplant Database. Transplantation 2012;94:990–8. [5] Konety BR, Tewari A, Howard RJ, Barry JM, Hodge EE, et al. Prostate cancer in the post-transplant population. Urologic Society for Transplantation and Vascular Surgery. Urology 1998;52:428–32.
ARTICLE IN PRESS M. Felber et al. / Urologic Oncology: Seminars and Original Investigations 00 (2020) 1−7 [6] Kasiske BL, Snyder JJ, Gilbertson D T, Wang C. Cancer after kidney transplantation in the United States. Am J Transplant 2004;4: 905–13. [7] Kessler M, Jay N, Molle R, Guillemin F. Excess risk of cancer in renal transplant patients. Transpl Int 2006;19:908–14. [8] Penn I. Occurrence of cancers in immunosuppressed organ transplant recipients. Clin Transpl 1998:147–58. [9] Marra G, Dalmasso E, Agnello M, Munegato S, Bosio A, Sedigh O, et al. Prostate cancer treatment in renal transplant recipients: a systematic review. BJU Int 2018;121:327–44. Fraser-Taylor C, Hassan[10] Hevia V, Boissier R, Rodrıguez-Faba O, Zakri R, Lledo E, et al. Management of localised prostate cancer in kidney transplant patients: a systematic review from the EAU guidelines on renal transplantation panel. Eur Urol Focus 2018;4:153–62. [11] Jhaveri JK, Tan GYM, Scherr DS, Tewari AK. Robot-assisted laparoscopic radical prostatectomy in the renal allograft transplant recipient. J Endourol 2008;22:2475–9. [12] Wagener N, Nyarangi-Dix JN, Teber D, Zeier M, Hohenfellner M. Applicability of robot-assisted laparoscopic radical prostatectomy in renal allograft recipients. Transplant Proc 2012;44:1287–92. [13] Kleinclauss FM, Neuzillet Y, Tillou X, Terrier N, Guichard G, Petit J, et al. Morbidity of retropubic radical prostatectomy for prostate cancer in renal transplant recipients: multicenter study from Renal Transplantation Committee of French Urological Association. Urology 2008;72:1366–70. [14] Maestro MA, G omez AT, Alonso Y, Gregorio S, Ledo JC, de la Pe~na Barthel J, Martınez-Pi~neiro L, et al. Laparoscopic transperitoneal radical prostatectomy in renal transplant recipients: a review of the literature. BJU Int 2010;105:844–8. [15] Dindo D, Demartines N, Clavien P-A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–13. [16] Elie C, De Rycke Y, Jais J-P, Marion-Gallois R, Landais P. Methodological and statistical aspects of equivalence and non inferiority trials. Rev Epidemiol Sante Publique 2008;56:267–77. [17] Drouin SJ, Comperat E, Varinot J, Vaessen C, Bitker MO, ChartierKastler E, et al. The surgical approach can be determined from the pathological specimen obtained after open or robot-assisted laparoscopic radical prostatectomy. World J Urol 2014;32:489–93. [18] Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch MG, De Santis M, et al. EAU-ESTRO-SIOG Guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol 2017;71:618–29.
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[19] Le Clerc QC, Lecornet E, Leon G, Rigaud J, Glemain P, Branchereau J, et al. Technical feasibility of robot-assisted laparoscopic radical prostatectomy in renal transplant recipients: results of a series of 12 consecutive cases. Can Urol Assoc J 2015;9:E490–3. [20] Polcari AJ, Allen JC, Nunez-Nateras R, Mmeje CO, Andrews PE, Milner JE, et al. Multicenter experience with robot-assisted radical prostatectomy in renal transplant recipients. Urology 2012;80: 1267–72. [21] Binsaleh S. Diagnosis and treatment of prostate cancer in renal-transplant recipients. Int Urol Nephrol 2012;44:149–55. [22] Moreno Sierra J, Ciappara Paniagua M, Galante Romo MI, Senovilla Perez JL, Redondo Gonzalez E, Galindo Herrero MI, et al. Robot assisted radical prostatectomy in kidney transplant recipients. Our clinical experience and a systematic review. Urol Int 2016;97:440–4. [23] Hoda MR, Hamza A, Greco F, Wagner S, Reichelt O, Heynemann H, et al. Management of localized prostate cancer by retropubic radical prostatectomy in patients after renal transplantation. Nephrol Dial Transplant 2010;25:3416–20. [24] Pettenati C, Jannot AS, Hurel S, Verkarre V, Kreis H, Housset M, et al. Prostate cancer characteristics and outcome in renal transplant recipients: results from a contemporary single center study. Clin Transplant 2016;30:964–71. [25] Morteau O, Blundell S, Chakera A, Bennett S, Christou CM, Mason PD, et al. Renal transplant immunosuppression impairs natural killer cell function in vitro and in vivo. PLoS One 2010;5:e13294. [26] Peraldi MN, Berrou J, Venot M, Chardiny V, Durrbach A, Vieillard V, et al. Natural killer lymphocytes are dysfunctional in kidney transplant recipients on diagnosis of cancer. Transplantation 2015;99: 2422–30. [27] Wong G, Chapman JR, Craig JC. Cancer screening in renal transplant recipients: what is the evidence? Clin J Am Soc Nephrol 2008;3 (Suppl 2):S87–S100. [28] Iwamoto K, Iizuka J, Hashimoto Y, Kondo T, Takagi T, Hata K, et al. Radical prostatectomy for localized prostate cancer in renal transplant recipients: 13 cases studied at a single center. Transplant Proc 2018;50:2539–44. [29] Zeng J, Christiansen A, Pooli A, Qiu F, LaGrange CA. Safety and clinical outcomes of robot-assisted radical prostatectomy in kidney transplant patients: a systematic review. J Endourol 2018. https://doi. org/10.1089/end.2018.0394. [30] Grande P, Campi R, Roupr^et M. Relationship of surgeon/hospital volume with outcomes in uro-oncology surgery. Curr Opin Urol 2018;28:251–9.
Urologic Oncology: Seminars and Original Investigations 000 (2020) 1−7
Clinical-Prostate cancer
Morbidity, perioperative outcomes and complications of robot-assisted radical prostatectomy in kidney transplant patients: A French multicentre study Margaux Felber, M.D.a, Sarah J. Drouin, M.D.a, Pietro Grande, M.D.a, Christophe Vaessen, M.D.a, Jerome Parra, M.D.a, Benoit Barrou, M.D., Ph.D.a, Xavier Matillon, M.D.b, Sebastien Crouzet, M.D., Ph.D.b, Quentin Leclerc, M.D.c, Jerome Rigaud, M.D., Ph.D.c, Thomas Prudhomme, M.D.d, Nicolas Doumerc, M.D.d, Sebastien Bergerat, M.D.e, Herve Lang, M.D., Ph.D.e, Charles Laine, M.D.f, Gregoire Robert, M.D., Ph.D.f, Aurelien Gobert, M.D.a, Benjamin Granger, M.D., Ph.D.g, Morgan Roupr^et, M.D., Ph.D.a,* a
Department of Urology, Sorbonne Universit e, GRC n°5, ONCOTYPE-URO, AP-HP, Urology, H^ opital Piti e-Salp^ etri ere, F-75013 Paris, France b Department of Urology, Hospices Civils de Lyon, Lyon, France c Department of Urology, Centre Hospitalier Universitaire de Nantes, Nantes Cedex 01, France d Department of Urology, Andrology and Renal Transplantation, CHU Rangueil, Paul-Sabatier University, Toulouse Cedex, France e Department of Urology, H^ opital Civil, Strasbourg, France f Department of Urology, Andrology and Renal Transplantation, GH Pellegrin Tripod, Bordeaux, France g Department of Biostatistics, Groupe Hospitalo-Universitaire Est, Publique H^ opitaux de Paris, H^ opital Piti e-Salp^ etri ere, Paris, France Received 11 August 2019; received in revised form 25 October 2019; accepted 19 December 2019
Abstract Objective: Evaluate the safety, feasibility and efficiency of robot-assisted radical prostatectomy (RARP) in kidney transplant recipients, performed in high-volume French referral centres, and describe intra- and postoperative, oncological and functional outcomes. Materials and methods: A multicentre study was conducted on prospective RARP databases from 5 centres between 2008 and 2017. We retrospectively identified a first group (G1) of transplant patients. The following data were collected: age, body mass index, prostate-specific antigen, ISUP score, TNM stage, stratification according to d’Amico, renal function, renal disease, time between renal transplant and prostate cancer (PCa), operating time, bleeding, pre- and postoperative complications (according to Clavien). Group 1 data were matched with a second group (G2) of nontransplanted PTRA patients. Results: A total of 321 patients were included (G1 N = 39 and G2 N = 282). The median operating time was 180 minutes (interquartile range 125−227) for G1 and 150 minutes (120−180) in G2 (P = 0.0623) and the median bleeding volume was 150 mL (150−400) and 250 mL (175−400), respectively (P = 0.1826). No grafts were damaged by RARP. Postoperative complication rate was significantly higher in G1: 51.2% vs. G2: 8.2% with a majority of minor complications (41%) according to Clavien Dindo (P < 0.001). Pathological assessment was as follows in G1: T2 = 28 (71.8%), T3 = 11 (28.2%), and G2: T2 = 206 (73.3%), T3 = 75 (26.7%) (P = 0.77). Postoperative ISUP scores were mainly grade 1: G1 = 14 (35.9%) vs. 99 (35.2%) in G2 and grade 2: respectively 18 (46.1%) 94 (33.5%). The rate of positive surgical margins was comparable in both groups: 13.2% for transplant patients vs. 18.1% (P = 0.65). Renal function was not significantly different at one year (P = 0.07). The median follow-up was 47.9 months (42.3; 52.5). Conclusion: RARP is conceivable to treat localized prostate cancer in kidney transplant recipients. This procedure does not appear to have any negative impact on graft renal function and cancer prognosis. Ó 2020 Elsevier Inc. All rights reserved.
Keywords: Prostatic neoplasm; Kidney transplantation; Prostatectomy; Immunosuppresion *Corresponding author. Tel.: 01.42.17.71.39 E-mail address: [email protected] (M. Roupr^et). https://doi.org/10.1016/j.urolonc.2019.12.017 1078-1439/Ó 2020 Elsevier Inc. All rights reserved.
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1. Introduction Renal transplantation is the gold-standard treatment for patients with end-stage renal failure. Compared to dialysis, it provides better results in terms of quality of life and survival [1]. Advancements in immunosuppressive therapy over the past few decades have resulted in a longer and better quality of life for kidney transplant recipients (KTRs). Nonetheless, the increased incidence of cancer in this patient is well established [2,3]. Cancer development has become a major problem in KTRs and is currently one of the primary causes of death in this population [4]. Genitourinary malignancies stand for 34% of the nonskin solid cancer in KTR [5]. Prostate cancer (PCa) incidence remains controversial some studies reported a 2 to 5 times higher incidence in KTR [6,7] but other showed a similar or lower incidence than in the general population [2,8]. As in the general population, localized PCa in KTRs can be treated with the usual options, including surgery, radiotherapy and brachytherapy [9,10]. Due to the possible complications associated with radiotherapy in this group of patients (such as nephritis, ureteral anastomosis strictures, avascular necrosis of the femoral head), radical prostatectomy is the preferred option for this type of tumour. Various prostatectomy techniques have been described in these patients, although the case-series have been small [11−14]. The robotic approach offers a good balance between oncological results and accelerated postoperative recovery compared to open radical prostatectomy. For these reasons, robot-assisted radical prostatectomy (RARP) is becoming the preferred option in KTRs, although few data exist on the functional and oncological results. Our aim was to evaluate the safety, feasibility and efficiency of RARP in KTRs, performed in high-volume French referral centres, and to describe intra- and postoperative outcomes, and oncological and functional outcomes at short- and medium-term follow-up. 2. Materials and methods 2.1. Study design and patients A prospectively maintained French multicentre database of RARP (including data from 5 major uro-oncology and transplantation centres) was investigated retrospectively. Patients who underwent RARP after renal transplantation (RT) between 2008 and 2017 were selected. Clinical data including age at the time of prostatectomy, aetiology of end-stage renal disease, body mass index, interval between renal transplantation and prostatectomy, side of transplantation, Charlson comorbidity index, preoperative serum creatinine, continence and erectile function were recorded prospectively for each patient.
The diagnosis of PCa was established based on digital rectal examination, prostate-specific antigen (PSA) assay, prostate MRI and ultrasound-guided prostate biopsy. The following pre- and intraoperative data were collected for each patient: preoperative ISUP grade, preoperative PSA, intraoperative events, surgery duration, blood loss, any surgical difficulties (tissue adhesions or tissue infiltrates or other) and Clavien-Dindo score [15]. During the follow-up, the following item were collected: PSA, continence and erectile function, serum creatinine. This follow-up was every 6 months for this first year and each year during the following 5 years thereafter. We designed 2 groups: patients who underwent RARP after RT (group 1), and we also included 282 subjects who presented to our hospital for a localized PCa (group2 = control). Controls were matched for age, PSA level and clinical stage. The determination of the sample size in group 2 was based on a noninferiority approach [16]. Considering a significant number of missing data (30% of incomplete observations), the sample size was assessed at 282. All 282 patients without history of transplantation were drawn at random in the database. 2.2. Surgical technique All patients were treated using a previously described transperitoneal approach [17]. Four robotic and 2 assistant trocars were employed. It was possible to use the usual trocars sites in KTR patients, but the lateral trocar was located more towards the flank than in the iliac fossa depending on the position of the graft. Pelvic lymph node dissection was performed in intermediate- and high-risk patients [18] and was always unilateral (contralateral to the graft site) in KTRs in order to prevent any damage to the graft. Abdominal exploration revealed the transplanted kidney in its right or left iliac position, which did not hamper further dissection. Seminal vesicles were first dissected to ligate deferent canals. The Denonvilliers’ fascia was opened and the posterior face of the prostate freed. The bladder was carefully dissected, especially on the right or left lateral face, to preserve the transplanted ureter. The bladder neck was incised until the posterior dissection plane was joined. Prostatic lateral attachments were then dissected. The Santorini plexus was ligated with an overlock V-LOCK 3-0 and the urethra cut. An urethrovesical anastomosis was performed using Vicryl 3.0 stiches. The specimen was extracted through a supraumbilical incision into a laparoscopic bag. Patient discharge was planned on the third or fourth postoperative day according to the usual hospital protocol and bladder catheter removal was planned on postoperative day 7. 2.3. Statistics Quantitative data (i.e., medians [interquartile range]) and qualitative data (i.e., frequency and percentages) were described. Age at onset data was described according
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the Kaplan-Meier method. Association between variables were assessed by nonparametric test: Mann-Whitney-Wilcoxon rank sum test and Kruskal-Wallis rank sum test to compare rank symmetry between 2 or more sets of quantitative data; Fisher exact test to compare 2 or more proportions. Study of associations with age at onset were done according a 2-step process: first 2 by 2 by log-rank test for qualitative data or univariate cox model for quantitative data; second, significant variables identified by the first step were overall assessed in a multivariate Cox model after applying a correction for multiple comparisons according the Benjamini-Hochberg procedure. A P value <0.05 was considered significant. Statistical analyses were performed (R version 3.5.1). 3. Results 3.1. Study population Three hundred twenty-one patients were included in the final analysis (Group 1, n = 39; Group 2, n = 282). The demographic data are summarized in Table 1. At the time of PCa diagnosis, median (IQR) age was 62 years (58‒67) in the KTRs and 62 years (58‒66) in the control group. Median preoperative PSA was 6.8 ng/ml in KTRs vs. 6.7 ng/ml in controls. Biopsies demonstrated a majority of ISUP grade 1, 2 and 3 in the 2 groups Median time between kidney transplantation and diagnosis of PCa was 58 months (36.9; 117.3). The graft was located in the right iliac fossa in the majority of cases (n = 30; 76.9%) all the renal transplantation were done extraperitoneally according to the protocol of the reference centres. 3.2. Intraoperative data, surgical complications and immediate postoperative data Intraoperative data, surgical complications and immediate postoperative data are shown in Table 2. Median operative time was 180 minutes (125−227) in KTRs vs. 150 minutes (120−180) in controls, and median blood loss was 150 ml (150−400) vs. 250 ml (175−400), respectively. Median surgery time and blood loss did not differ significantly between the 2 groups (P = 0.0623 and P = 0.1826, respectively). Surgical difficulties occurred in 12/39 patients (30.8%) in group 1 and were mostly related to adhesions or tissue infiltrates directly related to the history of kidney transplantation (18%). Immediate postoperative complications occurred in 20/ 39 patients (51.2%), with only 4 (10.2%) classified as Clavien grade ≥3. The occurrence of Clavien grade ≥3 in the control group was 0.8% (n = 2). Although most of these complications were minor grade I-II (n = 16; 41%) (most of them were pyelonephritis treated by antibiotics, hematoma and anaemia) and resolved
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promptly with appropriate therapy, our analysis demonstrates this group of patients has a high risk of complications. Four out of 39 patients suffered more serious complications (IIIb (n = 2; 5.1%) with 2 lymphoceles treated by laparoscopic marsupialisation between 7 and 10 days after the RARP and IVa (n = 2; 5.1%) with 1 postoperative bradycardia episode requiring 48 hours of intensive care and the other patient needing intensive care for ionic disorders. Contralateral lymph node dissection (LND) was performed in 12 KTRs (30.8%); only 1 patient had a bilateral LND (his graft was placed in an orthotopic position). A bilateral nerve-sparing procedure was performed in 11 patients (28.2%), a unilateral procedure was performed in 5 (12.8%) and a non-nerve sparing procedure was performed in 23 KTRs (59.0%). The procedure was completed robotic in all cases and no conversion to open surgery was necessary. The rate of positive surgical margins (PSM) was 13.2% in KTRs vs. 18.1% in control patients. Median length of hospital stay was 4 days (3;5) in group 1 and 3 (3;4) in group 2 (P = 0.0249). 3.3. Oncological functional and graft outcomes At the final pathological analysis, the tumour was stage T2c in most cases (53.9% in KTRs vs. 56.6% in controls). ISUP grade was mostly 1 and 2 in group1 and for group 2 it was more grade 1, 2 and 3 (P = 0.0308). At the 6 months follow-up, median PSA was 0.02 ng/l (0.01‒0.05) in KTRs and 0.01 mg/l (0.01‒0.03) in the control group. After a median follow-up of 47.9 months (42.3‒52.5), there were 3 (7%) biochemical recurrences in the KTR group vs. 24 (8.5%) in the control group. In the KTR group, 66.7% of patients were treated with adjuvant radiotherapy and 33.3% with androgen deprivation therapy (Table 3). Recovery of continence at 6 months occurred in 68.6% of patients in the KTR group vs. 65% in the control group (Table 4). At this time, complete restoration of erectile function was observed in 31.4% of patients in the control group vs. 12.9% in the KTR group (Table 4). Median serum creatinine levels in KTRs preoperatively and at 1 year postsurgery were 134 mmol/l (108−170) and 147 mmol/l (119.5−179.5), respectively (Tables 1 and 4). No patient had a significant preoperative to postoperative change in renal function (P = 0.07). Progression-free survival (PFS) at 4 years was 96.4% in the KTR group vs. 90.6% in the control group (Raw = 0.5399; Fig. 1). 4. Discussion According to the latest European guidelines, radical prostatectomy is the gold-standard treatment for localized prostate cancer in KTRs [10]. The first RARP in KTR was performed in 2006 by Jhaveri et al. [11] and small caseseries have confirmed the feasibility of this approach since
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Table 1 Characteristics of the study population Renal transplant patients (N = 39) Age at time of diagnosis BMI Charlson comorbidity index Aetiology of renal failure Polycystic kidney disease IgA nephropathy Glomerular nephropathy Nephroangiosclerosis Focal segmental glomerulosclerosis Diabetic nephropathy Alport syndrome Interstitial nephropathy Undetermined Location of renal transplant Right iliac fossa Left iliac fossa Time between renal transplant and PCa diagnosis (mo) PSA concentration at diagnosis (ng/ml) Prostate biopsy (ISUP grade) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Clinical stage T1c T2a T2b T2c T3a Unknown Amico score Low Intermediate High Erectile function Normal Medical treatment Implant None Missing data Preoperative continence Acquireda Not acquired Missing data Preoperative serum creatinine (mmol/l)
62 (58−67) 25 (23.5−28) 5 (4−6)
Nontransplant patients (N = 282) 62 (58−66) 25 (24−28) 4 (4−5)
P
0.92 0.87 0.0006
8 (20.5%) 7 (18.0%) 5 (12.8%) 4 (10.3%) 3 (7.7%) 2 (5.1%) 1 (2.6%) 1 (2.6%) 8 (20.5%) 30 (76.9%) 9 (23.1%) 58 (36.9; 117.4) 6.8 (6.0−8.8)
6.7 (5.4−8.8)
19 (48.7%) 16 (41.0%) 1 (2.6%) 2 (5.1%) 1 (2.6%)
172 (61.0%) 58 (20.6%) 35 (12.4%) 9 (3.2%) 8 (2.8%)
26 (66.6%) 7 (18.0%) 3 (7.7%) 2 (5.1%) 1 (2.6%)
185 (66.3%) 51 (18.3%) 18 (6.5%) 17 (6.1%) 8 (2.9%) 3
14 (35.9%) 18 (46.2%) 7 (17.9%)
140 (49.6%) 114 (40.4%) 28 (10%)
6 (37.5%) 3 (18.7%) 1 (6.3%) 6 (37.5%) 23
155 (86.0%) 7 (3.9%) 0 (0%) 18 (10.1%) 102
37 (97.4%) 1 (2.6%) 1 134 (108−170)
229 (97.0%) 7 (3.0%) 46
0.0794
0.99
0.153
<0.0001
1.00
Values shown are median (IQR) or n (%) unless stated otherwise. Bold values mean statistically significant. a Continence was considered acquired in the case where no or 1 protection per day was necessary and not acquired in other cases.
then. To our knowledge, our study represents the biggest series to date (n = 39) in a national multicentre study involving referral centres for both PCa and kidney transplantation. Most studies regarding PCa in KTR are epidemiological and descriptive based on small series [19−22] and only few studies compared KTR to the general population [13,23,24]. Whether or not the incidence of PCa is increased in KTRs when compared to the general population and
associated with worse disease-specific survival remains a topic of debate [2,6−8]. The higher incidence of PCA in KTRs may be due to several factors. Firstly, long-term immunosuppression may favour carcinogenesis and the development of more aggressive forms of cancer [3]. Several studies identified changes in the immune phenotype of KTR with cancer which may explain the development of cancer due to immunosuppressive therapy [25,26].
ARTICLE IN PRESS M. Felber et al. / Urologic Oncology: Seminars and Original Investigations 00 (2020) 1−7 Table 2 Intraoperative and immediate postoperative data
Table 3 Oncological outcomes
Renal transplant Nontransplant P patients (N = 39) patients (N = 282) Operative time (min) Blood loss (ml) Lymphadenectomy No Unilateral Bilateral Nerve sparing No Unilateral Bilateral Surgical difficulties No Yes Tissue adhesions/ infiltrations Other causes Postoperative complicationsa I−II IIIb IVa Hospital stay (d) Duration of urinary catheter Change in immunosuppressive treatment Yes No
180 (125−227) 150 (150−400)
150 (120−180) 250 (175−400)
26 (66.6%) 12 (30.8%) 1 (2.6%)
151 (53.5%) 16 (5.7%) 115 (40.8%)
23 (59.0%) 5 (12.8%) 11 (28.2%)
76 (27.0%) 74 (26.2%) 132 (46.8%)
27 (69.2%) 12 (30.8%) 7 (18.0%)
259 (91.8%) 23 (8.2%) 12 (4.3%)
5 (12.8%)
11 (3.9%)
Renal transplant patients (N = 39)
0.0623 0.1826 <0.0001
0.005
<0.0001
<0.0001 16 (41.0%) 2 (5.1%) 2 (5.1%) 4 (3;5) 7 (7;7)
21 (7.4%) 1 (0.4%) 1 (0.4%) 3 (3;4) 7 (7;7)
5
0.0249 0.5946
8 (20.5%) 31 (79.5%)
Values shown are median (IQR) or n (%). Bold values mean statistically significant. a According to Clavien Dindo classification.
Secondly, the KTR are older and live longer thanks to the surgical and medical progress of transplantation. Thirdly, these patients are monitored more closely than other patients as they are at higher risk of developing cancer and so we can discover cancers earlier, which increases the incidence of cancer. However, this strict monitoring can detect prostate cancer at an early stage with a better prognosis. Up to now without any available and powerful randomized clinical trials assessing PCa screening benefit in KTR, it seems appropriate to continue this close checking of prostate cancer by an annual PSA and DRE in the KTR [27]. In our cohort, the majority of PCa in KTR was diagnosed at an early stage that is why we have less aggressive disease in the pathological analyse than in group 2 (P = 0.0308). From an oncological point of view, surgical margins are considered a guarantee of quality for RARP. In our series, a PSM rate of 13.2% (5 of 39 patients) was obtained. This rate is quite low compared to other studies in the literature: Polacari et al. [20] reported a PSM rate of 28.6%, Le Clerc et al. [19] 50% and Iwamoto et al. [28] 46%. In a recent meta-analysis by Zeng et al. [29], which included a total of 35 RARPs in KTRs, the PSM rate was
Postoperative T-stage T2a T2b T2c T3a T3b Postoperative N-stage N0 N1 Nx Positive surgical margins Anatomopatholgy ISUP grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Missing data 6 months PSA (ng/ml) Recurrence Treatment Radiotherapy Hormone therapy Radio/hormone therapy
Nontransplant patients (N = 282)
P
0.7717 5 (12.8%) 2 (5.1%) 21 (53.9%) 9 (23.1%) 2 (5.1%)
23 (8.2%) 24 (8.5%) 159 (56.6%) 65 (23.1%) 10 (3.6%) 0.4954
18 (46.1%) 1 (2.6%) 20 (51.3%) 5 (13.2%)
146 (52.0%) 4 (1.4%) 131 (46.6%) 51 (18.1%)
0.649 0.0308
14 (35.9%) 18 (46.1%) 4 (10.3%) 0 (0%) 3 (7.7%) 0.02 (0.01−0.05) 3 (7.7%) 2 (66.7%) 1 (33.3%) 0
99 (35.2%) 94 (33.5%) 67 (23.8%) 14 (5.0%) 7 (2.5%) 1 0.01 (0.01−0.03) 24 (8.5%)
0.0393 0.84
13 (54.2%) 3 (12.5%) 8 (33.3%)
Values shown are median (IQR) or n (%). Bold values mean statistically significant.
32.4%. This low PSM rate in our cohort can be explained by several factors. Firstly, surgery was performed only in referral centres [30]. In addition, most of the patients had low-grade preoperative clinical stages (mainly pT1c and pT2a) and a low ISUP grade in biopsies. Table 4 Functional and graft outcomes at 6 months and 1 year Renal transplant patients (N = 39) Erectile function Normal Medical treatment Implant None Missing data Continence Acquired Not acquired Missing data Serum creatinine at 1 year (mmol/l)
Nontransplant patients (N = 282)
P
0.001 4 (12.9%) 10 (32.3%) 1 (3.2%) 16 (51.6%) 8
76 (31.4%) 107 (44.2%) 1 (0.4%) 58 (24.0%) 40 0.7098
24 (68.6%) 11 (31.4%) 4 147 (119.5−179.5)
Values shown are median (IQR) or n (%). Bold values mean statistically significant.
169 (65.0%) 91 (35.0%) 22
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Fig. 1. Progression-free survival in kidney transplant recipients and controls with prostate cancer undergoing robot-assisted radical prostatectomy.
Biochemical recurrence was not significantly different between RTR and control. Our rate of recurrence was also lower when compared to other series; Iwamoto et al. [28] reported 4 biochemical recurrences in 12 patients (33.3%), Le Clerc et al. [19] reported 2 of 12 patients with recurrence (16.7%), and Polcari et al. [20] and Pettenati et al. [24] had a rate close to ours at 7.1%. We had no metastatic evolution disease. Our study confirms the feasibility of RARP, but significantly more surgical difficulties were observed in the KTR group compared to the control group. These were mainly related to adhesions or tissue infiltrates directly related to the history of kidney transplantation. However, no death was reported, the renal grafts did not suffer any damage in any patient and renal function was preserved. Such an outcome may reflect the relatively small sample size and the fact that, due to the prospective collection of the data, all minor changes were reported. Concerning the graft, there were no injuries or graft loss during our procedure and serum creatinine at 1 year did not differ significantly (P = 0.07) from preoperative values. Despite the strengths of our study, our findings should be interpreted with care due to several study limitations. Firstly, despite the collection of data prospectively, our study was retrospective, leading to the risk of selection bias (even if our study population was multicentric). Although this is the largest series reported to date, the number of KTRs was small (n = 39). Secondly, the follow-up period was not long hence it is difficult to interpret the oncological outcomes in such a short follow-up time (i.e., <5 years). Taking these limitations into account, our study suggests
RARP is technically feasible for treating localized PCa in KTRs without graft deterioration, but the oncological outcome remains a major topic requiring further evaluation. In conclusion, the results of our multicentre study suggest that RARP is a safe and feasible approach to treat localized PCa in a select group of KTRs. No major modifications of the surgical approach were necessary, and the intervention appeared to have no negative impact on renal function and prognosis when performed in experienced centres. Conflict of Interest The authors declare that they have no conflict of interest. References [1] Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341:1725–30. [2] Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, Stewart JH, Law M, et al. Cancer incidence before and after kidney transplantation. JAMA 2006;296:2823–31. [3] Au E, Wong G, Chapman JR. Cancer in kidney transplant recipients. Nat Rev Nephrol 2018;14:508–20. [4] Sampaio MS, Cho YW, Qazi Y, Bunnapradist S, Hutchinson IV, Shah T. Posttransplant malignancies in solid organ adult recipients: an analysis of the U.S. National Transplant Database. Transplantation 2012;94:990–8. [5] Konety BR, Tewari A, Howard RJ, Barry JM, Hodge EE, et al. Prostate cancer in the post-transplant population. Urologic Society for Transplantation and Vascular Surgery. Urology 1998;52:428–32.
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