Questions and Concerns of Robotic Approaches to Bladder Cancer Surgery


References

Number of patients (RC vs. OC)

Mean nodes RC (range)

Mean nodes OC (range)

Complications from ePLND

Abraham et al. [81]

10

22.3 (13–42)
 
NR

Wang et al. [43]

33

17 (6–32)
 
0

Woods et al. [26]

27

12.3 (7–20)
 
0

Guru et al. [34]

100

21
 
0

Gamboa et al. [58]

41

25 (4–68)
 
3

Guru et al. [49]

26

25.5 (13–56)
 
1

Lavery et al. [82]

15

41.8 (18–67)
 
0

Pruthi et al. [41]

100

19 (8–40)
 
NR

Nix et al. [32]

41 (21 vs. 20)

19 (12–30)

18 (8–30)

NR

Richards et al. [33]

70 (35 vs. 35)

16 (11–24)

15 (11–22)

NR

Kauffman et al. [83]

85

19 (0–56)
 
NR

Khan et al. [59]

50

17 (9–28)
 
1

Schumacher et al. [36]

14

32 (19–52)
 
5

Davis et al. [30]

11

43 (19–63)

4 (0–8)a

NR


Results from various trials reporting lymph node yields from extended pelvic lymph node dissection from robot-assisted radical cystectomy alone or comparison to open cystectomy

There were no statistically significant differences for lymph node yields in the studies that directly compared OC versus RC

aNodes removed during second-look open LND following robotic extended LND

RC robot-assisted radical cystectomy, OC open cystectomy



An additional small, but provocative study by Davis et al. [30] looked directly at the number of lymph nodes leftover by robot-assisted “extended” LND through the use of a second look open LND. A total of 11 patients underwent robot-assisted LND by a single surgeon, and each robotic LND was immediately followed by a second-look open LND by a different team of surgeons to extract any leftover nodal tissue. The mean lymph node yield was 43 (range 19–63) with a median of 93 % of all lymph nodes retrieved removed by the robotic technique. Interestingly, the newer da Vinci S system allowed for even higher retrieval rates with a range of 83–100 % of all lymph nodes removed robotically compared to 70 and 75 % in each of the two procedures using the older da Vinci machine.

Surgeon learning and experience with the robotic platform may also be an important factor affecting lymph node yield. Of concern, Guru et al. [34] found a significant increase in lymph node yield over time which plateaued at the 30th case. Similarly, Hayn et al. [35] found that lymph node yield increased 73 % when surgeons had performed >50 RARC’s compared to those who had performed <30 cases. On the other hand, several other studies found no change in lymph node yields with increasing experience/volume [27, 36, 37]. Therefore, available data on the effects of early experiences with RARC on lymph node yield remains controversial.

Given the abundance of reports including two small randomized trials, it appears that robot-assisted extended lymphadenectomy up to the aortic bifurcation is technically feasible and safe, yielding lymph node counts on par with open surgery. With the varied initial results, further evaluation of the surgical learning curve is needed to determine whether early experience with RARC sacrifices acceptable lymph node yields. However, it appears that, when using lymph node counts as a surrogate for the extent of lymph node dissection (LND), robot-assisted lymphadenectomy does not represent an inferior surgical intervention compared to open lymphadenectomy, and, all other factors being equal, we would expect similar long-term oncologic outcomes.



Positive Margin Rate: Can the Robot-Assisted Approach Match or Improve on the Open Approach?


Whereas there exists some controversy on lymph node yield as a surrogate for adequate surgical resection, it is well established that the completeness of the primary resection plays a critical role in oncologic outcomes following treatment for bladder cancer. A positive surgical margin at time of radical cystectomy has been shown to be an independent predictor of disease recurrence, metastatic progression, and cancer-specific mortality [19, 3840]. The overall positive margin rates in large series of open radical cystectomy have ranged from 4 to 9 %, with slightly higher rates in advanced disease [19, 3840]. As a result of such studies and the importance of surgical margins in patient survival, Herr et al. [19] recommended a surgical benchmark of less than 10 % positive surgical margin rate for all cystectomies and less than 15 % positive margin rate for advanced (≥pT3) disease.

Though the use of the surgical robot can improve visualization with the 3D, 10× magnifications available with the stereoscopic laparoscope, questions arise as to whether visual cues alone are sufficient for determining the extent of surgical resection. Some argue that the lack of tactile sensation may compromise the ability to assess the level of tumor extension, particularly with pT3/pT4 disease, thus leading to a higher rate of positive margins. Are surgical margin rates similar between robotic versus open cystectomies? Does the stage of the tumor have an effect?

Table 18.2 shows a list of the robot-assisted cystectomy studies and their rates of positive surgical margins. The overall incidence of positive surgical margins at the time of robot-assisted radical cystectomy has ranged from 0 to 7.2 %, with most of the studies showing an overall positive surgical margin rate <10 %, which meets the standard set by series of open radical cystectomy. However, the data raises concern for the rates of positive surgical margins in more advanced disease. There also exists the potential for significant unaccounted for selection bias in many of these retrospective and/or nonrandomized reports. Early studies that reported 0 % positive margins often did not report the breakdown of organ confined versus more advanced disease and, these being early experiences, may have bias toward selecting patients with less aggressive disease for RARC. More recently, however, there have been reports which include significant numbers of patients with pT3/pT4 disease. In one of the larger multi-institutional trials, Hellenthal et al. [40] used the IRCC database to show an overall positive margin rate of 6.8 % in 513 patients undergoing robot-assisted radical cystectomy. However, the positive margin rate increased to 16.6 % when considering pathologic stage ≥pT3; a rate slightly above the standard suggested by Herr et al. [19]. Patients in this study with pT4 disease were found to have a positive margin rate of 39 %. Another larger retrospective study by Guru et al. [34] showed an overall positive surgical margin rate of 7 % for 100 patients undergoing RARC, with the positive margin rate increasing to 13 % in the patients with advanced disease. Pruthi et al. [41] found no positive margins in a cohort of 100 patients undergoing RARC. However, when looking at the patient population included in the trial, most of the patients (87 %) had pathologic stage ≤pT2.


Table 18.2
Rates of positive surgical margins from trials of robotic and open cystectomy


































































































































References

Number of patients (RC vs. OC)

Total PSM RC: n (%)

Total PSM OC: n (%)

PSM in pT3/T4 RC: n (%)

PSM in pT3/pT4 OC: n (%)

Beecken et al. [10]

1

0
     

Menon et al. [11]

17

0
     

Hemal et al. [78]

24

0
     

Rhee et al. [70]

30 (7 vs. 23)

0

0

0

0

Galich et al. [42]

37 (13 vs. 24)

0

3 (12.5)

0

3 (20)

Wang et al. [43]

54 (33 vs. 21)

2 (6)

3 (14)

2 (22)

3 (25)

Guru et al. [34]

100

7 (7)
 
7 (13)
 

Richards et al. [33]

70 (35 vs. 35)

1 (3)

3 (9)

1 (7)

2 (13.3)

Ng et al. [44]

187 (83 vs. 104)

6 (7.2)

9 (8.7)

6 (19)

9 (20.5)

Nix et al. [32]

41 (21 vs. 20)

0

0

0

0

Hellenthal et al. [40]

513

35 (6.8)
 
31 (17)
 

Pruthi et al. [41]

100

0
 
0
 

Khan et al. [59]

50

1 (2)
 
1 (7)
 

Schumacher et al. [36]

45

1 (2.2)
 
1 (10)
 

Nepple et al. [45]

65 (36 vs. 29)

2 (6)

2 (7)

2 (12)

2 (17)

Davis et al. [30]

11

0
 
0
 


The total number of positive margins is shown followed by the rate of positive surgical margins in patients with non-organ-confined disease (pT3/pT4)

n number of patients, PSM positive surgical margins, RC radical cystectomy, OC open cystectomy

Several nonrandomized comparisons have been performed comparing open and RARC but these are generally single-institution case series with surgeon preference governing which patients received an open vs. robot-assisted approach [33, 4245]. As seen from the data in Table 18.2, overall positive margin rates were actually slightly higher in the open group, though in most studies this did not reach statistical significance [33, 4245]. This trend persists when only pT3/pT4 patients were analyzed. However, these differences again did not reach statistical significance and the studies were not powered to detect these differences [33, 42, 44, 45]. Though some series had similar stage breakdown between cohorts [42, 44, 45], they may have suffered from other unaccounted selection bias. Others clearly were early robot experiences with a significant bias toward more difficult cases being performed open [43]. The only published prospective randomized trial comparing open and robotic was reported by Nix et al. [32]. The patient populations did not differ with respect to pathologic stage, and there were no patients in either cohort that had positive surgical margins. Though the absolute number of patients was relatively low and there were a disproportionate number of patients with ≤pT2, this last study would suggest non-inferiority of robot-assisted radical cystectomy compared to open surgery in pT2 or lower disease when possible bias is controlled for by randomization. However this study was not powered to detect difference in positive margin rates between groups and hence additional studies with that specific endpoint in mind are required to truly answer that question.

While a direct comparison of positive margins to open cystectomy is important, there is also the need to assess changes in positive margin rates over time as surgeons are progressing on their learning curves. Similar to lymph node yields, if there were a significant increase in positive margins during early robotic experiences, it may be irresponsible to implement use of the robot since positive margins result in substantial consequences to oncologic outcomes [19, 3840]. While Guru et al. [34] found a significant decrease in positive margin rate from their first to fourth cohort, other studies found no change in positive margin rate with increasing surgeon experience/volume [27, 36, 37]. Therefore, the available data on the effect of RARC on positive margins (both compared to open and along surgeons’ learning curves) is controversial. All training surgeons must remember the oncologic principles of radical cystectomy and prioritize their operation to maximize patient outcomes.

It is important to remember that measures of positive margins, in addition to lymph node yields, are only surrogates for oncologic outcomes. The true measure of oncologic efficacy of a procedure is the effect on overall and disease-free survival. Unfortunately, there is limited long-term follow-up among patients undergoing RARC so discussion is therefore limited to short and medium-term follow-up. Table 18.3 shows results from a few studies reporting oncologic outcomes following RARC. However, the follow-up time across studies ranged from 1 to 3 years. While the overall survival, disease-specific survival, recurrence-free survival rates are promising and deemed comparable to results from an open series by Stein et al. [5], they do not allow for adequate comparison due to limited follow-up periods and bias toward performing RARC on patients with less aggressive disease.


Table 18.3
Medium-length follow-up reports of oncologic outcomes following robot-assisted radical cystectomy





















































References

Number of patients

Mean follow-up

Overall survival (%)

Recurrence-free survival (%)

Disease-specific survival (%)

Dasgupta et al. [57]

20

23 mo

95

90

95

Pruthi et al. [41]

100

21 mo

91

85

94

Kauffman et al. [83]

85

18 mo

79

71

85

Nepple et al. [45]

36

12 mo

68

72

75

Martin et al. [84]

59

36 mo

69

71

72

Currently, we are left with comparisons to historical controls, case series, one small randomized trial, and studies with limited follow up to assess (1) the ability to obtain an adequate resection with the surgical robot and (2) the long-term oncologic efficacy of this approach. From the data available for stage T2 or lower disease, it appears that a number of groups have shown the ability to match or even improve on historically acceptable positive margin and lymph node yield rates. For more advanced disease, the data are not as clear since many of the cohorts had positive margin rates greater than 15 %. There is currently an ongoing large multicenter randomized trial which should be able to more definitively assess this concern. Until then, and until more studies report on the long-term follow-up after RARC, patient selection for robot-assisted radical cystectomy should be made carefully, and one should abide by the surgical benchmarks from studies of ORC [19] that serve as surrogates for optimizing long term oncologic outcomes.


Should Urinary Diversions Be Performed Intracorporeally for Robot-Assisted Cystectomy?


Surgeons employing a pure laparoscopic approach to radical cystectomy have demonstrated the feasibility of intracorporeal (IC) urinary diversion, but this was never widely adopted due to the technical challenges. In fact, purely laparoscopic intracorporeal urinary diversion was associated with significantly more complications along with higher blood loss, longer operative times, and increased time to ambulation and oral intake when compared to extracorporeal (EC) urinary diversion [46]. Despite these short comings, the smaller incisions, decreased bowel exposure, and reduced tissue manipulation creates the potential for decreased pain, decreased fluid imbalances with perhaps subsequent advantages in time to bowel function return and overall recovery. Does the use of the surgical robot improve results of intracorporeal diversion compared to a pure laparoscopic approach? Have the theoretical advantages been demonstrated?

The first robot-assisted radical cystectomy (RARC) involved an intracorporeal urinary diversion [10]. The total operating time was 8.5 h, but the blood loss was only 200 ml and the reservoir was considered functionally and oncologically excellent at 5 months follow-up. Another early attempt at RARC with IC diversion by Balaji et al. [47] included three patients all of whom had operative times greater than 10 h, but similarly had nominal mean blood loss of 250 ml and good postoperative functional outcomes at 2 months.

Since these early attempts, there has been continued interest with reports of additional small series showing promising results. Pruthi et al. [48] compared the perioperative outcomes among 12 patients undergoing RARC and IC to 20 patients receiving RARC and EC diversion during the same period. The overall operative time was significantly longer in patients who underwent the IC diversion; 5.3 h versus 4.2 h in the EC cohort, but not as substantial as that seen in the earliest reports. There was, however, no difference in mean blood loss, time to return of bowel function, time to discharge, or the number of complications. A benefit of the IC method was evidenced by a significantly decreased narcotic requirement in the group receiving an IC diversion.

Recently, Guru and colleagues [49] published data on their initial experience with IC conduit diversion in which they found no difference in operative times compared to EC diversion. A total of 26 patients underwent RARC; the first 13 patients received an EC diversion and the last 13 an IC conduit diversion. There was no difference in overall operative time. The difference in diversion times alone trended toward but did not reach significance (159 min for IC versus 120 min EC, P = 0.058). The groups did not differ in number of complications or other perioperative parameters (mean blood loss, lymph node yield, time to oral feeds, and length of hospital stay), and the mean time for IC diversion decreased over sequential case number which suggests a rapid learning curve. Lastly, Smith et al. [50] reported on a multi-institution, multi-surgeon experience with RARC with regard to operative outcomes. There were 227 patients in the study with a mixture of EC and IC diversions performed. The 30-day complication rate was 30 % with 7 % major complications. Multivariate analysis showed that the type of diversion was not associated with postoperative complications.

Unfortunately, there is a lack of evidence comparing IC versus EC while subdividing for type of urinary diversion. This is an important consideration because different types of urinary diversion represent different levels of difficulty and pose a risk for different associated complication rates and operative times when performed intracorporeally. Lee et al. [51] compared RARC with EC versus ORC and found significantly longer operative times in RARC with EC for ileal conduit and orthotopic neobladders, but not for continent cutaneous diversions. This study supports the variability in operative time as a function of diversion type during RARC. Additional studies are needed to determine which (if any) diversion types confer an unsuitable risk to patient outcome if performed intracorporeally.

Current assessment suggests that in experienced hands there is a place for intracorporeal urinary diversion in the armamentarium of urologists, with some evidence for improvement in pain and non-inferiority across other measures. However, inferences should be made with caution as these studies were not randomized trials and therefore were subject to selection bias that accompanies early attempts with new procedures; patients tended to be younger with fewer comorbidities or a lower stage disease in order to optimize tolerability to a potentially prolonged procedure. We currently believe that the potential advantages of the intracorporeal method have not been fully demonstrated and thus, except in the most expert hands, do not outweigh the associated disadvantages or potential complications. Furthermore, longer studies and follow-up are required to confirm that other complications such as stricture rate are not adversely affected.


Does Restriction of Movement in an Enclosed Pelvis During Robot-Assisted Radical Cystectomy Result in Increased Ureteral Skeletonization and Stricture Formation?


Proponents of minimally invasive surgery cite that one of the advantages over open surgery is that there are fewer surgical-related complications [52]. However, a theoretical concern exists that robot-assisted radical cystectomy (RARC), with its lack of tactile feedback and limited workspace, may lead to excessive tissue skeletonization and devascularization resulting in an increased frequency of delayed complications, specifically ureteral–intestinal anastomic strictures. Anastomotic strictures are a well-known occurrence in open radical cystectomy with urinary diversion with an overall incidence ranging from 2 to 4 % [5356], but have been reported as high as 10 % [4, 53]. While it is not fully known why ureteral anastomotic strictures develop, there are number of factors thought to play a role: tissue ischemia, tissue tension, inflammation from urinary leak, and/or suturing errors. While studies have sought to determine risk factors for stricture formation [53, 55, 56], the results remain inconclusive and/or controversial over the extent any of these play in stricture formation.

With RARC in addition to the potential issues related to ureteral skeletalization, there exists particular concern on the ability to fully mobilize the left ureter allowing for a tension free anastomosis. The rate of ureteral anastomotic stricture formation reported among the various RARC series has ranged from 1.5 to 10 % [44, 5759]. This is similar to the reports from large series of open radical cystectomy. Thus, early data may suggest that RARC has similar stricture rates as ORC.

However, the emerging use of intracorporal urinary diversion (a diversion limited to minimally invasive surgery) could theoretically play a role in decreasing the relative risk of stricture formation in RARC compared to ORC. It has been proposed [36] that urinary diversion performed extracorporally may be a risk factor in stricture formation due to increased mobilization required for the appropriate tissue exposure required for suturing. With this in mind, perhaps employment of more intracorporeal diversions will decrease tissue mobilization and subsequently the incidence of ureteral strictures associated with urinary diversion. Evidence to support this theory comes from studies performing RARC with extracorporeal diversions that reported stricture rates from 8 to 10 % [49, 57, 59] which are at the high end of the range for ORC. Further, Guru et al. [49] compared the two types of diversion in their series and found a 7.9 % stricture rate in the extracorporeal group and 0 % in their intracorporeal group. However, a stricture rate of 7.3 % was reported in a group of patients undergoing intracorporeal diversion which may argue against this theory [58]. However, this study did not perform a comparison to patients undergoing open surgery, so it is hard to assess the relative difference in stricture rates between open and robotic approaches. Overall, definitive conclusions are limited because of the small sample sizes, few direct comparisons, and highly variable stricture rates regardless of the diversion type reported in different studies.

Perhaps the greatest hindrance to full realization of the risk of stricture formation in RARC is the lack of long-term follow-up. To date, many of the studies of RARC have either been (1) feasibility studies or (2) reports on the perioperative and short-term outcomes following the procedure. Thus, many of the current studies likely did not follow patients long enough to report on stricture formation since studies of ORC have shown stricture formation can occur at a time point ranging from 8.8 months [54] to 1 year [4]. This is an area that will need close monitoring and more studies employing long-term follow-up to determine whether this technology confers increased or unique complications or whether perhaps provides an opportunity to reduce the complication risks associated with ORC. As of this time it does not appear that there is a significant increase risk of stricture formation with RARC compared to open cystectomy, though availability of additional data in the future may shed more light on this issue.

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Mar 29, 2017 | Posted by in UROLOGY | Comments Off on Questions and Concerns of Robotic Approaches to Bladder Cancer Surgery

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