Impact of clinical stage on the outcome of laparoscopic radical cystectomy: a prospective cohort study

Some authors recommend not to perform laparoscopic radical cystectomy (LRC) for large bulky bladder cancer (BC) as the laparoscopic manipulation will be difficult. As there were no prospective studies focusing on the effect of the tumor stage of BC on the outcome of LRC, the aim of this prospective cohort study was to evaluate the effect of tumor stage on the outcome of LRC. LRC was completed for 47 patients. All patients were followed for at least 1 year, and there was no recurrence. COPD, DM, hypertension and renal impairment were detected, respectively, in 57.4%, 36.2%, 44.7% and 10.6% of patients. Transitional cell carcinoma and squamous cell carcinoma were found, respectively, in 91.5% and 8.5% of patients. Complications were reported in 29.78% including 29.78% Clavien grade 1, 17.02% grade 2 and 6.38% grade 3. There was no significant difference between cT2 and cT3 in perioperative criteria including demographic features, operative time, estimated blood loss, blood transfusion, pain score, hospital stay and complications. Upon final pathological assessment, 44.68% of patients were upgraded to higher pathological stages. Additional comparison was performed according to pathological stage and revealed no significant difference in the outcome of LRC between pT2 and higher stages except the pain score at first postoperative day which was higher in patients with pT3 stage. LRC is a feasible and safe technique for both T2 and T3 clinical and pathological stages.

Therefore, there has been a widespread shift toward minimally invasive surgery including robotic and laparoscopic RC (LRC) to reduce these complications and to improve the recovery time with comparable oncological outcome to ORC [1,2,8]. However, most LRC series had a selection bias as they favored patients with more localized disease and less comorbid conditions leaving more complicated cases to the open surgery [1,2]. Therefore, the rate of patients with localized disease; pT2 or less, undergoing LRC was reported to be 70% in some studies [8]. Some authors recommend not to perform laparoscopy for large bulky tumors as the laparoscopic manipulation will be difficult due to reduced working space together with the increased incidence for associated nearby organ involvement which may necessitate their resection. They prefer ORC which is more suitable for these complicated circumstances [2]. As there were no prospective studies focusing on the effect of the tumor stage of BC on the outcome of LRC, the aim of this study was to compare the outcome of LRC for patients with cT2 versus cT3.

Study design and inclusion criteria
This is a prospective cohort study that recruited patients with cT2-3 BC amenable for LRC from January 2015 to March 2017. Patients with American Society of Anesthesiologists (ASA) score of > 3, clinically positive lymph nodes (L.N.s), BMI ≥ 35, multiple prior abdominal and pelvic open surgical procedures and/or severe pulmonary restrictive conditions precluding safe pneumoperitoneum were excluded.

Clinical assessment
History taking, clinical examination and basic laboratory tests were performed for all patients to assess their performance status. Additionally, age-adjusted Charlson comorbidity index in addition to ASA score was assessed in each patient. Preoperative staging was performed using CT abdomen and pelvis with IV contrast. CT was replaced by MRI for patients with renal impairment or contrast allergy. CT chest without contrast was also performed. Cystoscopic biopsy/TURBT was performed for all patients. All patients were clinically staged using the 2010 tumor-node-metastases (TNM) staging system from the American Joint Committee on Cancer (AJCC).
The study was approved by the local ethical committee, and an informed written consent was taken from all patients.

Surgical management and postoperative care
Neoadjuvant chemotherapy was used for fit patients whenever possible. All patients underwent preoperative bowel preparation. DVT prophylaxis was performed using prophylactic dose of low molecular weight heparin the night before the procedure and continued for 5 days in addition to wearing above-knee elastic stockings. Prophylactic third-generation cephalosporin and metronidazole were administered 2 h before induction of anesthesia. Patients were placed in the low lithotomy position to facilitate access to the rectum and perineum. Patient's arms were secured to their sides in an adducted position. Pneumoperitoneum was obtained using a veress needle placed at the umbilicus. LRC was performed using 4-5 ports which were placed in a fan-shaped manner across the lower abdomen in addition to 10-mm camera port one finger breadth above the umbilicus (Fig. 1). Patients were then placed in a steep Trendelenburg position. After complete radical dissection of the bladder, the specimen was placed immediately in an impermeable retrieval bag. Obturator, external, internal, common iliac lymph nodes were dissected.
Pfannenstiel or midline incision (7-10 cm) was performed for both retrieval of the specimen and extracorporeal urinary reconstruction. A Studer orthotopic neobladder was reconstructed. Alternatively, ileal conduit was performed if the tumor was involving the prostatic urethra, the patient had renal impairment or poor performance status. The urethro-ileal anastomosis was performed intracorporeally after closure of the Pfannenstiel or midline incision and re-establishing pneumoperitoneum. All ureterointestinal anastomoses were stented with an 8 Fr external feeding tube which was removed 5-9 days postoperatively before discharge. Tube drains were removed after stent removal. Neobladder patients were discharged with a urethral catheter which was removed 2 weeks postoperatively following a pouchogram to rule out leakage. All our patients were ambulant on first day following the surgery.

Data collection and follow-up
Perioperative data were collected. Patients were classified according to tumor stage into T2 or T3 groups. The perioperative data including operative time, estimated blood loss (EBL), blood transfusion, complications, return of bowel activity and hospital stay of these groups were compared.
Complications were reported according to the Clavien-Dindo classification [12]. Additionally, postoperative pain score was calculated according to the numeric rating scale (NRS-11) which is an 11-point scale for patient self-reporting of pain [13].
Follow-up ultrasonography of abdomen and pelvis was performed at the first month then every 3 months during the first year and then biannually together with CT/MRI of abdomen and pelvis every 6 months.

Statistical analysis
Data were coded and entered using the statistical package SPSS (Statistical Package for the Social Sciences) version 24. Comparisons between quantitative variables were done using the parametric Student t test or the nonparametric Mann-Whitney test according to normality of data. For comparing categorical data, Chi-square (χ 2 ) test was performed. Fisher's exact test was used instead when the expected frequency was less than 5. p values less than 0.05 were considered as statistically significant. We calculated the sample size based on assuming that a mean difference of 10 min in cystectomy time between cT2 group and cT3 group will be significant. The minimum sample size was found to be 17 participants in each group to be able to reject the null hypothesis in the presence of an 80% power and a 5% α error level. Calculations were done using PS Power and Sample Size Calculations

Results
LRC was performed in 47 patients. An additional 2 (4.7%) cases were converted to a palliative chemo-radiotherapy due to fixation to the lateral pelvic wall and non-resectability even upon open exploration. They were excluded from the study as they were pT4 masses. All patients were followed for at least 1 year, and there was no recurrence.

Effect of clinical stage on LRC outcome
We compared the effect of clinical stage on LRC outcome and found no significant difference between cT2 and cT3 in perioperative criteria including operative time, estimated blood loss, pain score, hospital stay and complications ( Table 2). Upon final pathological assessment, 21/47 (44.68%) patients were upgraded to higher pathological stages (Table 1). Additional comparison was performed but according to pathological stage. Again, we found no significant difference in the outcome of LRC according to the pathological stage between pT2 and higher stages except the pain score at the first postoperative day which was higher in patients with > pT2 stage (Table 3).

Discussion
The current study may be the first prospective study that focused on the comparison of the effect of clinical stage of BC on the outcome of LRC.
The outcome of LRC in the current study was similar to what previously was reported in a systematic review on LRC [1]. In that meta-analysis, Tang et al. compared LRC versus ORC and analyzed sixteen studies (seven prospective and nine retrospective studies) with 1165 cases (545 LRC and 620 ORC). The LRC group had a lower ASA score and a significantly higher proportion of organ confined ≤ pT2 disease and fewer nodal disease (11%) which lead to lower distant metastasis rate (8.6%) and fewer death (8.4%). However, there was no significant difference in other criteria including age, gender, BMI, history of previous surgery, pathological grade and type of diversion [1]. We had a higher incidence of nodal disease (27.7%), but we had no mortalities which may be due to exclusion of T4 cases and short follow-up in the current study. In their meta-analysis, Tang et al. reported that there were no differences between the LRC and ORC in wound dehiscence, neurologic, renal fistula/ leak, ureteric obstruction, GI fistula/leak or thromboembolic events. However, LRC had a longer operative time (371.5 min) but significantly fewer overall complications (33.5%) including less blood loss (469.15 mL), less infections especially wound infections, shorter time to ambulation and shorter length of hospital stay (15.3 days), less need of blood transfusion (25.7%), less narcotic analgesic requirement, less ileus (11%) and fewer positive surgical margins (3%) [1]. We had a comparable complications rates (29.78%), ileus (10.6%), blood loss (458.9 mL) and blood transfusion (17%). Furthermore, we had a comparable operative time (316.9 min).
In a more recent study, Khan et al. [8] compared the outcomes of ORC, RARC, and LRC in 60 patients. Similar to our study, the urinary diversion was performed extracorporeally. ORC complication rate (70%) was significantly higher than LRC (26%) but no significant difference in major complications [8]. In the LRC arm (19 patients), the mean operative time (301 min), mean EBL (460 mL) and mean hospital stay (9.7 days) were similar to our results.