Minimal Invasive Approach ro radical cystectomy: Results of the European multicentric study

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1 Minimal Invasive Approach ro radical cystectomy: Results of the European multicentric study Dr Alexandre Peltier Institut Jules Bordet, Bruxelles (BE) The 9 th Congress of the Lebanese Urology Society 1 October 2016, Beirut

2 Background Laparoscopic Radical Cystectomy is feasible Gill, J Urol 2002 Cathelineau, Eur Urol 2005 Huang, Eur Urol 2010 Indeed valid laparoscopic skill are needed (Challacombe Eur Urol 2011) Extracorporeal urinary diversion greatly simplifies the job and reduces the need for complex lap reconstructive surgery

3 Background Current controversies: Mainly single-center/single-surgeon series have been published Paucity of systematic complication reporting Absence of strong, long-term oncologic follow-up data Role of extended lymphadenectomy Controversies on effect of pneumoperitoneum of cancer spreading

4 Background To date, the largest cohort published on complications is the International Robotic Cystectomy Cohort (IRCC) >900 patients Multicenter Mainly USA centers All robotic assisted procedures Largest cohort on LRC with intermediate/long term oncologic FU comes from China 171 patients Single center Median FU: 37mo

5 Our answer.. The ESUT study group on LRC OBJECTIVES: Build a large multicentric prospective European database Only laparoscopic cases Explore long-term oncologic results Evaluate complications systematically Define the future of LRC in Europe

6 Materials and Methods Currently 10 European centers Starting from 2000 >700 patients enrolled All laparoscopic procedures, no robotic assistance In some centers, multiple surgeons perform LRC Non-standardized surgical procedure, each surgeon follows his technique

7 Materials and Methods Inclusion/exclusion criteria For muscle invasive and high-risk non-muscle invasive bladder cancer No formal contrindications to LRC Even locally advanced disease (pt4a), especially in the beginning ( the exploratory years ) Also patients with prior history of major abdominal surgery Neoadjuvant chemiotherapy administered according to multidisciplinary decision (center-specific protocol)

8 Materials and Methods Different bowel preparation techniques, according to center: No prep Enema on -1 day PEG + low-fiber diet + enema Lymphadenectomy: currently mainly extended, including common iliac nodes Urinary diversion principally via extracorporeal approach (95%) Adapted from Abol-Enein J Urol 2004

9 RESULTS Baseline cohort after exclusion of patients with incomplete complication or FU data 548 patients Sex ration: 4:1 ASA score 1: 19% 2: 45% 3: 18% 4: 1% Neoadjuvant: 10% Number of patients 548 Age (years) median (IQR) Sex M F 68 (62-74) 452 (82%) 96 (18%) BMI (kg/m 2 ) median (IQR) 26 ( ) Smoker ASA CIS No Yes Unknown Unknown No Yes Unknown Neoadjuvant treatment No Chemiotherapy 99 (18%) 223 (41%) 226 (41%) 106 (19%) 245 (45%) 98 (18%) 4 (1%) 95 (17%) 377 (69%) 79 (14%) 92 (17%) 494 (90%) 54 (10%)

10 RESULTS Pathologic features Cancer Histology pt Urothelial Cell Carcinoma Squamous Cell carcinoma Adenocarcinoma pt0 pt1 pt2 pt3 pt4 540 (98%) 5 (1%) 3 (1%) 62 (11%) 90 (16%) 155 (28%) 184 (34%) 57 (10%) Elevated percentage of patients with locally advanced disease ( pt3) 24% of node-positive disease Comparable to large ORC series (Stein JCO 2001) pn Total LN retrived Surgical margins pn0 pn1 pn2 pn3 median (IQR) mean±sd Negative Positive 416 (76%) 59 (11%) 67 (12%) 6 (1%) 13 (9-17) 14±7 514 (94.2%) 34 (5.8%) LN retrieval in line with current recommendations (>10-14 nodes) (Herr J Urol 2004) LN yield has grown over time Limited % of PSM (recommended <10%)

11 RESULTS Perioperative outcomes Total OR time (mins) median (IQR) 318 ( ) EBL (ml) median (IQR) 450 ( ) OR time is probably longer compared to open RC, consistent with literature 1,2 Urinary Diversion Bricker Orthotopic neobladder Ureterocutanostomy Mainz II Continent pouch (Kock, Indiana) 372 (68%) 144 (26%) 13 (2%) 15 (3%) 4 (1%) LOS (days) median (IQR) 14 (11-20) EBL is significantly lower in LRC compared to ORC (Pneumoperitoneum!) Albisinni World J Urol 2013 Patients leave the clinic only when all drains and catheters are out 1 Nix Eur Urol Styn Urology 2012

12 RESULTS - Complications Number of patients with 1 complications: 1 complication 2 complications 3 complications 258 (47%) Radical cystectomy is a morbid procedure!!! Grade of worst complication n (% of total population) - Clavien I - Clavien II - Clavien III - Clavien IV - Clavien V (death) IIIa IIIb IVa IVb 39 (11%) 120 (22%) 22 (4%) 58 (11%) 7 (1%) 2 (0.5%) 10 (2%) The vast majority of complications are minor complications Nonetheless, reoperation rates and mortality is non-negligeable (3% mortality in ORC trials) Albisinni et al, J Urol, under revision

13 RESULTS - Complications Complications by organ system Infective > GI > GU Infective Gastro-Intestinal Genito-Urinary Hemato/Bleeding Vascular Abdominal wall Cardiac Pulmonary Electrolyte disturbance Neurologic Drain extraction under anesthesia Unknown 71 (28%) 45 (18%) 29 (11%) 14 (5%) 13 (5%) 12 (5%) 10 (4%) 5 (2%) 4 (2%) 3 (1%) 1 (0.5%) 50 (19%) Clavien IIIb complications (11%) Reoperation n Digestive leak 18 Wound revision 10 Urinary leak 8 Obstructive ileus 3 Hemorrhage 3 Drainage of infected collection 3 Fasciotomy 3 Ureteral reimplantation 2 Drainage of infected lymphocele 1 Rectovaginal fistula 1 Endarterectomy 1 Circumcision (prepuce necrosis) 1 Unknown 11

14 RESULTS - Complications Exploring risk factors On multivariate logistic regression, BMI (0.02), neoadjuvant chemiotherapy (0.01) and EBL (0.02) were indipendent, significant predictors of overall risk of complications (minor and major) Regarding major complications, only ASA score was significantly predictive of the outcome (0.003), as expected 1 àthe impact of neoadjuvant chemotherapy on complications deserves further investigation 1 Boström BJU Int 2009

15 COMPLICATIONS In conclusion: Laparoscopic Radical cystectomy is feasible and SAFE, with acceptable post-operative complications LRC remains a morbid procedure, though the majority of complications are minor (Clavien I-II), mostly infective In this cohort 11% of patients underwent surgical re-operation BMI, neoadjuvant chemiotherapy and EBL may be associated to increased overall complications Can LRC yield valid oncologic results on the long-term?

16 RESULTS Oncologic FU

17 RESULTS Oncologic FU Slightly smaller cohort (503 patients, one center missing) Median follow-up was 50 months (mean 60, IQR 19-90). 134 recurrences detected: 118 (23%) metastasis, 14 (3%) local recurrences and 2 (0.5%) urethral. Currently: 343 (68%) patients are alive with no evidence of disease (NED) 108 died of bladder cancer 52 died of non-cancer specific causes

18 Oncologic FU - RFS Recurrence Free Survival (RFS) RFS 2-yrs 5-yrs 10-yrs pt0-1 91% 87% 85% pt2 82% 71% 67% pt3 60% 51% 45% pt4 34% 34% --- Cox HR %CI p < pn0 82% 75% 71% pn1-3 46% 36% 30% Cox HR %CI p < PSM - 77% 68% 64% PSM + 27% 27% ---- Cox HR 95%CI p Overall 74% 66% 62% pt, pn and PSM are the most important predictors of RFS In ORC trials on >1500 pts: 68-62% at 5years 1, % at 10years 1,2 1 Stein JCO Maderbacher JCO 2003

19 Oncologic FU - RFS 66% 62% From Albisinni et al, BJU 2014

20 Oncologic FU - RFS Recurrence Free Survival (RFS) Similar results in other LRC and RARC trials: RFS of 72.6% at 5yrs (Huang Eur Urol 2010) (171 chinese patients undergoing LRC) No port site metastases in the present study Howeverer..1 early vaginal recurrence: transvaginal specimen extraction without (!!!) Endocatch bag. Principles of oncologic surgery MUST be respected! Tissue manipulation Control of the urethra Endocatch bag

21 Oncologic FU Cancer Specific Survival 75% 55% CSS OS 2-yrs 5-yrs 10-yrs 2-yrs 5-yrs 10-yrs Overall 82 % 75% 55% 79% 62% 38% Contemporary ORC trials: 59-66% 37-43%

22 Oncologic FU Overall survival The reported survival rates are comparable to ORC findings and other minimally invasive RC cohorts Snow-Lisy et al (Eur Urol 2014): 121 pts LRC and RARC at Cleveland clinic OS at 5yrs: 48% OS at 10yrs: 35% Raza et al. (International Robotic Cystectomy consortium; Eur Urol 2015) 702 pts RARC pt0-2: 62%; pt3-4: 38% pn0: 79%; pn+: 21% Median FU: 67mo (18-84) Overall recurrence: 29% (of which 11% local) 5year RFS: 67% 5year CSS: 75%

23 ONCOLOGIC FU In conclusion: We reported the largest cohort of LRC to date with long-term follow-up Our results are encouraging and comparable to large, contemporary ORC cohorts pt, pn and PSM remain the most important predictors of recurrence and survival The principles of open oncologic surgery MUST be respected in laparoscopic surgery Failure to do so WILL result in poor oncologic control of the disease

24 ONCOLOGIC FAILURES Laparoscopic Surgery perfomed respecting open surgical principles Open Surgery?!! PNEUMOPERITONEUM!!!! There is raising concern on the impact of the pneumoperitoneum and highflow insufflations on urothelial cell migration Several cases of colorectal, ovarian and urothelial cancers developing local relapses, port-site seeding or early metastases after laparoscopic surgery are reported

25 ONCOLOGIC FAILURES RARC was associated to a higher risk of developing peritoneal carcinosis and distant LN metastasis

26 ONCOLOGIC FAILURES In the ESUT cohort? 311/627 patients had favorable pathologic features ( pt2;n0;r0) 27/311 (4.3% of the entire cohort) experienced a recurrence during the first 2years, albeit pt2;n0;r0 pathology! High-volume metastases, 10/27 presenting disseminated metastatic disease Unusual localisations: axial skeleton, corpora cavernosa, axillary nodes In 1/27 patients a surgical negligence was found (rupture of the endobag during transvaginal extraction à patient had vulvar and peritoneal mets 4mo post-op No apparent cause in the other 26.?????? Albisinni et al, J Urol 2016

27 ONCOLOGIC FAILURES The Venous Plexus of Batson Role in the spread of pelvic malignancies and infections CO 2 insufflation=modification of peritoneal physiologic ph, increase in vascular permeability and modification in adhesion molecules High-flow insufflation and exsufflations (long and bleeding procedure) = squeezing of hollow organs and of bladder pedicle Hypothesis: Pneumoperitoneum and repeated highflow insufflations increase the release of tumor emboli in the Batson s plexus with consequent unexpected metastasis after minimally-invasive RC

28 ONCOLOGIC FAILURES Robotic experience in Institut Jules Bordet: pt pn Margins LVI Adj ttt Type of Rx Recurrence RFS (months) Recurrence localisation 0 0 Neg 0 No No Neg 0 No No Neg 0 No No Neg 0 No Yes 16 Lung 0 2 Neg 1 Yes Gem cis Yes 48 Brain frontal lobe 0 2 Neg 0 Yes carbo-gem Yes 18 Lymph node, Liver 1 0 Neg 0 No No 48 Cis 0 Neg 0 No No Neg 0 No No 48 2b 1 Neg 0 Yes Gem cis No Neg 0 Yes Gemcitabine Yes 24 lymph node 3a 0 Neg 0 No Yes 12 Lung, lymph node, liver, bone 3b 0 Pos 0 No No 12 3b 2 Neg 1 Yes Gem cis Yes 5 Lymph node 3a 2 Neg 1 Yes Gemcitabine Yes 11 Lymph node 3a 2 Neg 1 Yes Yes 24 sternum 3a 2 Pos, urethral 0 Yes gem cis No 36 4a 0 Neg 0 No Yes 2 Peritoneal Carcinosis 4a 2 Neg 0 Yes gem cis No 2 4a 2 Neg 0 Yes Gem cis Yes 2 Bone pelvis

29 ONCOLOGIC FAILURES Solutions? ü Neoadjuvant chemotherapy (NAC) in all patients candidates for MI cystectomy?? Only 1/27 patients in our cohort who experienced unexpected progressions had NAC ü SurgiQuest Airseal?? ü Markers to identify patients at risk?? ü Open cystectomy Effects of RARC such as insufflation, pneumoperitoneum, quality of resection, lymph node dissection, methods for lymph node extraction, and their effect on oncologic efficacy remain unproven. The continued advancement of RARC depends on this. Tim Wilson

30 Thank you for your attention!