Christopher Wallis: Hello, and thank you for joining this first UroToday Journal Club discussion. Today we're talking about a recent publication entitled "The Effect of Robotic Assisted Radical Cystectomy with Intracorporeal Urinary Diversion versus Open Radical Cystectomy on 90-Day Morbidity and Mortality among Patients with bladder cancer: A Randomized Clinical Trial." I'm Chris Walls, an assistant professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, an assistant professor in the Division of Urology at the Medical College of Georgia. This is a citation for the iROC trial recently published in JAMA and led by Dr. Catto.

Patients with aggressive, localized bladder cancer, whether muscle invasive or BCG refractory non-muscle invasive disease are often recommended to undergo radical cystectomy and pelvic lymph node dissection. While the procedure has significant oncologic benefits, morbidity is not uncommon. Most patients have at least one complication, nearly one in five require intervention and 20 to 30% are readmitted in the postoperative period. These events are expensive, delay recovery, and increased both morbidity and mortality. Robotic assisted surgery in many domains has been suggested to improve outcomes for patients undergoing surgery. In particular, patients undergoing radical cystectomy may benefit more from robotic surgery than those undergoing other procedures due to their underlying co-morbidity.

Previous studies have shown that robotic assisted radical cystectomy provides non-inferior cancer control to open surgery at two years. This is based on data from small preliminary trials as well as the larger RAZOR study. Patients undergoing robotic radical cystectomy had lower blood loss, fewer transfusions, longer operative time but shorter possible length of stay. However, to date, these studies have used extracorporeal urinary diversion and reconstruction rather than a fully intracorporeal approach. Thus, the goal of iROC was to compare totally intracorporeal robotic assisted radical cystectomy with open radical cystectomy in patients with non-metastatic bladder cancer. The primary objective was to test the hypothesis that total intracorporeal robotic assisted cystectomy would have faster recovery and fewer days in hospital. To do this, the authors performed an investigator-initiated phase three, multi-center, unblinded, randomized control trial at nine NHS sites in the UK. They included patients undergoing radical cystectomy who are recruited from urology clinics between March of 2017 and March of 2020.

Included patients had to be adults 18 years or older who were suitable for either approach including robotic or open surgery, and to have non-metastatic bladder cancer with no more than N1 disease, be fit for radical cystectomy as well as able and willing to give written informed consent. Patients were excluded if they had prior abdominal or pelvic surgery or radiotherapy, concomitant disease which rendered either robotic or open surgery unsuitable, synchronous upper tract disease or were pregnant or lactating. Patients were randomizing in a one to one fashion using an online system to open a robotic surgery with stratification according to the center as well as the type of planned diversion continent with either a neobladder or continent catheterizable channel or an ileal conduit.

In terms of the treatment, all surgeons who participated required accreditation from the trial management group were mandated to use ERAS and required submission of their outcomes to the public database. In this context, the ERAS included thromboprophylaxis, early postoperative mobilization, the avoidance of bowel preparation and pre-op calorific drinks, while robotic surgeons must have completed at least 30 cases independently prior to the start of the trial. The surgical approach included removal of the prostate and seminal vesicles in men as well as removal of the uterus, fallopian tubes and vaginal wall with or without ovaries in women. Any variation to this approach required approval from the trial management group. Lymphadenectomy was mandated to include the internal and external iliac nodes as well as obturator lymph nodes with proximal dissection up to the level of the ureter crossing over the common iliac vessels. The primary outcome was a number of days alive and out of hospital in the first 90 days after surgery.

This outcome accounts were postoperative length of stay, readmissions and deaths within 90 days of surgery. That also included 20 secondary outcomes, including those related to complications and adverse events, oncologic outcomes, and health related quality of life with metrics as listed below. The sample size calculation assumed a skewed distribution of the number of days alive and out of hospital. Therefore, they plan to use a log transformation. With an assumed difference equivalent to two days, 80% power in alpha of 0.05, 160 patients per group would be required to allow identification of a significant two day difference. Following a planned interim analysis of 30 patients, they increased this to 170 patients per group.

The primary outcome was log transformed and then compared using a mixed model with fixed effects for the randomization group and diversion type and random effects for site. Patients who dropped out prior to 90 days and those who declined radical cystectomy were excluded. Proportional differences in 95% confidence intervals were calculated for surgical complications between the two groups in differences as well as their 95% confidence intervals for quality of life measures were calculated with mixed models. Pre-specified subgroup analyses were performed according to age, performance status and comorbidity, body mass index, tumor stage, and baseline exercise levels. These were assessed by adding the variable as well as an interaction term with the randomization variable into the model followed by testing of the interaction term. A significant effect was seen where the interaction term had a significant P value. Now going to hand us over to Zach to walk us through the results of the iROC trial.

Zachary Klaassen: Thanks so much for that great introduction. This is the participant flow chart in the iROC trial. You can see about halfway down that 338 patients were randomized, including 169 of robotic cystectomy with 156 being included in the primary analysis and 169 randomized to open cystectomy with 149 patients included in the primary analysis. This is the baseline characteristics for this trial because the size of this table have broken this down into two slides, and you can see here that about 80% of patients were male. The majority of these patients, more than 80% had an ECOG performance status of zero. In terms of age at surgery, primarily these patients were 60 to 79 years of age. With regards to body mass index, the most common BMI was 25 to 29.9 for each arm of the trial, and roughly 70% of patients were either current smokers or ex smokers.

Moving down to the bottom here, we see that in terms of neoadjuvant chemotherapy, roughly one third of patients received neoadjuvant chemo. 14% of patients in the robotic arm and 11% in the open arm received immunotherapy. Not surprisingly, predominant histology was urothelial carcinoma at roughly 80% of tumors and roughly three quarters of tumors were grade three poorly differentiated tumors.

This is the second half of this table and we can see that in terms of cystectomy histology and pathological tumor stage, most commonly in both arms was pTis, pTA, or pT1 at 32% in the robotic arm and 36% in the open arm. Positive margins was quite rare at 7% in the robotic arm and 8% in the open arm. Lymph node yield, 16.1 in the robotic arm and 15.1 in the open arm and metastatic lymph nodes were found in roughly 17 to 18% of patients. At the very bottom, you can see the majority of these patients, nearly 90% had an ileal conduit as their choice per urinary diversion.

This is the primary outcome looking at the distribution of days alive and out of the hospital within 90 days of surgery stratified by robotic versus open radical cystectomy. This was statistically significant P value of 0.01 and this was 82 days for robotic cystectomy with a 95% confidence that enrolled 76 to 84 days and for open radical cystectomy was 80 days with a 95% confidence interval, 72 to 83 days.

This looks like the complications recorded within 12 weeks of surgery, stratified by each of these groups, and you can see in this table there was no complications in 39.1% of the robotic cystectomy patients and 33.3% of the open cystectomy patients. When we look at specific type of complications, you can see them here listed on the left, I've used asterisks to highlight the two significant complications that were less in the robotic compared to open cystectomy arm. So 5.6% of patients robotic arm had a wound infection compared to 17.3% in the open arm. In terms of thromboembolic events, 1.9% in the robotic cystectomy arm and 8.3% in the open cystectomy arm. The rest of these complications, including by Clavien-Dindo classification were not different. There was no difference between the two groups.

The next two slides look at several of the secondary outcomes after radical cystectomy. So on the far left, this is EQ-5D-5L, which is an overall quality of life at baseline between the two arms, there was no difference. At five weeks, the open patients had worse quality of life, but then at 12 and 26 weeks there was no difference. In the middle, we have the EORTC QLQ-C30 score, which looks a cancer quality of life at baseline again, no difference. At five and 12 weeks open patients had worse cancer quality of life, and at 26 weeks there was no difference between these groups. The far right looks at the WHODAS 2.0 score, which looks at disability. At baseline, there was no difference, however, at five and 12 weeks, the open patients had worse disability, but again, at 26 weeks there was no difference between these arms.

The second slide, looking at secondary outcomes, looks at mean steps per day and maximum steps per day on the left of the screen and there was no difference between open and robotic cystectomy in terms of mean or maximum steps per day. On the right is the 32nd chair to stand test, which looks at stamina at baseline. There was no difference between this groups. However, at five and 12 weeks, the open patients had less stands. However, again, at 26 weeks there was no difference between robotic and open cystectomy.

This figure looks at the bladder cancer recurrence following radical cystectomy after median follow up of 18.4 months, the recurrence rate for robotic patients was 18% compared to 16% for open patients with a non statistically significant hazard ratio of 0.90 and a 95% confidence intervals 0.53 to 1.54. Similar looking figure for all-cause mortality following cystectomy, again, similar follow up with an all-cause mortality rate for robotic patients at 14.3% and for open patients of 14.7% and a non-significant hazard ratio of 1.06 95% confidence intervals 0.60 to 1.90. So several important discussion points from the iROC trial. This RCT a robotic radical cystectomy with intracorporeal diversion versus open radical cystectomy, the robotic approach led to significantly more days alive and out of the hospital over 90 days since surgery. This is likely to be much of the benefit from robotic operations occurring immediately after surgery, which may be secondary to smaller incisions and less blood loss.

With regards to intracorporeal reconstruction, this may offer further benefits such as a smaller burden of incisions. However, should be known this that this can be technically challenging. Importantly, the secondary endpoints all favored robotic surgery of five weeks with the greatest difference seen in disability scores and stamina tests. But as we also see at 26 weeks, there was no difference between the robotic and open arms.

So in conclusion, among patients with non-metastatic bladder cancer undergoing radical cystectomy treatment with robotic assisted radical cystectomy with intracorporeal urinary diversion versus open radical cystectomy resulted in statistically significant increase in days alive and out of the hospital over 90 days. However, the authors point out that the clinical importance of these findings remains uncertain. We thank you very much for your attention. We hope we enjoyed this UroToday Journal Club discussion of the iROC Trial publishing JAMA.