Landmark Trial Puts Robotic Surgery to the Test in Bladder Cancer

Vivek Venkatramani, MD

Visiting Assistant Professor,

Department of Urology

University of Miami Miller

School of Medicine

Miami, Florida

Dipen J. Parekh, MD

Professor and Chair,

Department of Urology

Director, Robotic Surgery

The Victor A. Politano Endowed

Chair in Urology

University of Miami Miller

School of Medicine

Sylvester Comprehensive Cancer Center

Chief Clinical Officer

University of Miami

Health System

Miami, Florida

Robotic surgery using the Intuitive da Vinci Surgical System was introduced nearly 2 decades ago. The platform allows the surgeon an ergonomically comfortable position to perform the operation, a magnified 3-dimensional view, and “wristed” instruments that mimic the movements of the surgeon’s hand, often in tight spaces in the human body. It was expected that this technology would lead to more precise surgery, translating into better patient outcomes, and the robotic platform was adopted rapidly, crossing 5 million total surgeries performed and 4409 robotic systems installed worldwide by the end of 2017.¹

Challenges in Bladder Cancer

One would expect that robotic surgery would have been put through the scientific process of rigorous clinical trials before such widespread adoption. However, this was not the case and no adequately powered, prospective multicenter randomized trials were performed comparing it with the open approach in any surgical specialty. Only a small number of single-center randomized trials were conducted, with endpoints focused on perioperative recovery and not on oncologic outcomes.Surgical techniques are particularly important in bladder cancer, which is among the most common cancers in both men (4th) and women (11th) in the United States, with an estimated 81,190 new patients diagnosed with bladder cancer and 17,240 deaths attributable to it in 2018.² Invasive disease is treated surgically with radical cystectomy and urinary diversion. Traditionally, this has been a formidable procedure, with significant morbidity and even mortality, but it does provide patients with the best oncological survival. A laparoscopic approach to radical cystectomy was attempted in order to improve perioperative outcomes, but it was a very time-consuming procedure with a large learning curve and was never widely adopted.

With the advent of the surgical robot, it was believed that the disadvantages of traditional laparoscopy could be overcome and that a truly minimally invasive alternative to open cystectomy was available. Retrospective studies and case series suggested that the robotic approach was indeed technically feasible and reproducible, and that it had potential perioperative benefits in terms of reduced blood loss, complication rates, and length of hospital stay. Two single-center pilot studies and 1 small singlecenter randomized trial comparing open with robotic cystectomy found no difference between the procedures in oncological surrogates such as positive margins and lymph node yield, with similar complication rates. The study findings also noted better perioperative outcomes, including reduced blood loss and length of hospital stay, in the robotic group.

Rationale for the Razor Trial

However, there were questions regarding the lack of tactile feedback available with the robot, and how that would affect the complete removal of locally advanced tumors. Further concerns were raised after uncommon locations of cancer recurrence, such as peritoneal carcinomatosis, were observed following robotic cystectomy in certain studies. It was believed that these 2 concerns could compromise the oncological efficacy of robotic cystectomy.Given that no prospective randomized study had compared oncological outcomes between robotic and open cystectomy, investigators in the Sylvester Comprehensive Cancer Center’s Department of Urology, at the University of Miami Miller School of Medicine in Florida, led the design of the RAZOR trial. Patients with clinical stage T1-T4, N0-N1, M0 bladder cancer were randomized to receive robotic versus open cystectomy. The noninferiority study had a primary endpoint of 2-year progression- free survival (PFS) after radical cystectomy for invasive bladder cancer (NCT01157676).

The trial was a multicenter phase III randomized study performed across 15 centers in the United States between 2011 and 2017. The trial was funded by a grant from the National Cancer Institute. All participating centers were high-volume academic centers with experienced surgeons performing both robotic and open cystectomy. All patients with invasive bladder cancer who were candidates for radical cystectomy were eligible for inclusion except those who had previous abdominal surgery or comorbid conditions that would make pneumoperitoneum difficult to tolerate.

Relevant intraoperative and perioperative data were collected, and patients were followed with axial imaging at predefined intervals for a minimum of 2 years after surgery to assess disease recurrence. The 2-year interval was chosen because the majority of bladder cancer recurrences appear within this time and this is an excellent marker for 5-year survival. Any recurrence or death within 2 years was considered as progression.

To obtain 80% power at a 1-sided α error of P = .025 and take dropouts into account, a total of 350 patients were randomized between July 1, 2011, and November 18, 2014. Following exclusions and dropouts, a total of 150 patients were available for analysis in the robotic group and 152 in the open group (302 in total). Patients in both groups were well matched for demographic and tumor variables.

In findings reported in Lancet, the 2-year PFS was 72.3% (95% CI, 64.3%-78.8%) in the robotic cystectomy group and 71.6% (95% CI, 63.6%-78.2%) in the open cystectomy group for a difference of 0.7% (95% CI, —9.6% to 10.9%; overall P = .90; P for noninferiority = .001).³ This fell within the predefined 15% margin for noninferiority, thereby proving the noninferiority of robotic cystectomy. This margin was chosen based on the available data at the time regarding alternatives to open cystectomy and the consensus of trial investigators who were all experts in the field of bladder cancer.

Estimated blood loss during robotic cystectomy was less than half that of open cystectomy, with a corresponding significantly lower transfusion rate for robotic surgery. The median length of stay was a day less in patients undergoing robotic surgery (6 days versus 7 days), with 29% of them hospitalized fewer than 5 days compared with only 18% of those undergoing open surgery. There was no significant difference between the 2 groups with respect to overall or major complication rates as measured using the Clavien-Dindo classification system (Table).³

Similarly, the quality-of-life questionnaires showed no difference between the 2 groups. Importantly, the study showed no difference in positive margin rates, lymph node yield, or patterns of recurrence between robotic and open cystectomy, providing further evidence that the robotic approach did not compromise oncological safety.

Table. Comparison of Clinical Outcomes With Surgical Techniques³

Take-Home Messages and Conclusions

Unfortunately, we were not able to obtain reliable cost data from the participating institutions to perform a meaningful comparison between open and robotic cystectomy. Whether the increased equipment, disposable costs, and/ or time costs of robotic surgery will be offset by its improved perioperative recovery remain a matter for debate. In today’s era of ever-burgeoning healthcare costs, this remains a valid potential criticism of robotic surgery and one that needs to be investigated.We believe that this is the first phase III multicenter trial comparing robotassisted technology with open surgery for any surgical site and, as such, marks a notable landmark in the surgical literature. Our data suggest that robotic cystectomy is not inferior to open cystectomy with regard to oncological outcomes. We believe that this trial reinforces the fact that surgical trials are possible and should be attempted across other surgical specialties.

Although it is essential that high-quality trials should be performed prior to adoption of any new surgical technology, Buxton’s law provides an excellent explanation for why this is often not the case. It states that it is always too early for rigorous assessment of a new technique—until it suddenly becomes too late.

The reason, Buxton’s law continues, is that new procedures usually have a learning curve, making surgeons reluctant to participate in trials early on. Later on, the technique becomes widely adopted and trials cannot be done because it is deemed unethical to deny patients what is already perceived as cuttingedge care, and the chance to thoroughly evaluate surgical innovations is missed. The successful completion of this trial should serve an encouragement to surgeon-scientists that such studies can be performed.

These findings finally provide high-level evidence to inform discussion between patients and physicians regarding potential benefits and risks of various approaches for a complex and often morbid surgery, such as radical cystectomy

References

1. Intuitive Surgical hits 2018 priorities. blows past Q1 expectations. Medtech[y] website. medtechy.com/the-ticker/articles/2018/intuitive-surgical-hits-2018-priorities.-blows-past-q1-expectations. Published April 18, 2018. Accessed November 19, 2018.
2. American Cancer Society. Cancer Facts & Figures 2018. Atlanta, GA: American Cancer Society; 2018. cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed November 18, 2018.
3. Parekh DJ, Reis IM, Castle EP, et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3 non-inferiority trial. Lancet. 2018;391(10139):2525-2536. doi: 10.1016/S0140-6736(18)30996-6.