Robotic-Assisted Laparoscopic Nephroureterectomy

Epidemiology

Upper urinary tract urothelial carcinomas (UTUC) are relatively rare tumors that arise from the urothelial lining, from the renal calyces to the distal ureter. UTUC accounts for 5-7% of all renal tumors and 5-10% of all urothelial tumors. ^{[3, 4]}  The incidence of UTUC has been gradually rising over time, probably as a result of increased detection. Since 1973, the mean age at presentation has increased from 68 to 73 years old, with a predilection for men (2:1 male to female ratio) and Whites (88% of newly diagnosed cases in the United States). ^{[5, 6]}

Individuals with a history of bladder cancer are at risk for upper tract recurrence, with a further increase in patients with carcinoma in situ (CIS), a risk not diminished in patients treated with cystectomy for CIS. ^[7]  Although most series report the risk of upper tract recurrence to be 2-4% in patients with a previous history of bladder cancer, ^{[7, 8]} some have reported rates as high as 21% after a median interval of 7.3 years. ^[9] Individuals with a history of bladder cancer have been recommended to undergo rigorous upper tract surveillance for an extended period (>10 years) to rule out upper tract recurrence. ^[8]

Additional environmental risk factors for primary UTUC include tobacco use (strongest for current smokers of > 20 cigarettes per day), a history of Balkan endemic or Chinese herbal nephropathy (via aristolochic acid derivatives), a history of cyclophosphamide therapy (via the metabolite acrolein), long-term hemodialysis, and exposure to polycyclic aromatic hydrocarbons or chlorinated solvents (rare in developed countries). ^{[10, 11, 12]}  A relationship with Lynch syndrome (hereditary non-polyposis coli) has been demonstrated in 10-20% of cases of UTUC. The clinician should suspect possible Lynch syndrome in patients who present with UTUC at younger than 60 years of age and who have a personal history of related cancer (colorectal, gastric, UTUC, and endometrial or ovarian cancer) or a relative with a related Lynch syndrome cancer. If Lynch syndrome is suspected, further genetic testing should be performed. ^[13]

Signs and symptoms

The following are signs and symptoms of UTUC:

• Hematuria (microscopic or gross) occurs in 56-98% of patients. ^{[14, 15, 16]}

• Flank pain occurs in 30% of patients.

• UTUC is an incidental finding in 15% of (asymptomatic) patients.

• Symptoms of advanced disease are abdominal mass, anorexia, weight loss, and bone pain.

Diagnosis

Cross-sectional imaging remains the gold standard for the non-invasive diagnosis of UTUC. Multiphasic computed tomography (CT) has the highest diagnostic accuracy, with a sensitivity of 0.67-1 and a specificity of 0.93-0.99. ^[17]  Magnetic resonance imaging (MRI) may be substituted if CT with contrast is contraindicated.

Both the European Association of Urology and the National Comprehensive Cancer Network (NCCN) recommend further evaluation with cystoscopy, cytology, and ureteroscopy with biopsy or washings when the results will further affect treatment decisions. ^[18]  In addition to primary UTUC, up to 33% of patients may have concomitant urothelial bladder cancer; this possibility makes thorough cystoscopy and bladder tumor resection mandatory prior to planned surgical intervention. ^[19]

Nephroureterectomy

In a large Surveillance, Epidemiology, and End Results (SEER) cohort, UTUC stage and grade migration toward more aggressive disease has been observed over time in patients undergoing nephroureterectomy. ^[20] . Because of the multifocal nature of these tumors and the consequent high risk of ipsilateral recurrence after partial resection, the kidney and the entire ureter, including the intramural portion and the ureteric orifice, should be removed. The risk of tumor recurrence in the remaining ureteral stump is in the range of 33-75%. ^{[21, 22, 23]}  Cancer-specific survival is driven primarily by TNM (tumor, nodes, metastasis) stage, higher grade, tumor size, and certain molecular signatures (well reviewed by Lughezzani et al). ^[24]

Open nephroureterectomy with excision of a bladder cuff is considered the gold standard for the treatment of large, high-grade, or invasive tumors of the renal pelvis or proximal ureter. It is also indicated for large, multifocal or rapidly recurring, low-grade, noninvasive tumors of the renal pelvis or proximal ureter. 

Robot-assisted laparoscopic nephroureterectomy is a relatively new procedure with promising results. Similar to traditional laparoscopy, it is a minimally invasive surgery that minimizes surgical morbidity for the patient. However, unlike traditional laparoscopy, it simplifies excision of the distal ureter and bladder closure, and as such it has the potential for more widespread adoption by urologists.

Oncologic outcomes have been encouraging, and it seems reasonable to expect long-term outcomes as good as those seen with traditional laparoscopy, which in turn have been comparable to the outcomes of open surgery. Whether robotic assistance can improve the performance of lymphadenectomy, which is an essential component of this surgery, remains to be seen.

Main components of nephroureterectomy

The four main components of nephroureterectomy are as follows:

• Patient preparation
• Nephrectomy
• Distal ureterectomy with bladder cuff excision and closure
• Lymphadenectomy

Patient preparation

Patient preparation for nephroureterectomy is key to success. Patients should be counseled about the risks and benefits of surgery. Consideration of neoadjuvant, systemic chemotherapy or counseling regarding adjuvant systemic chemotherapy should be discussed. Retrospective studies regarding neoadjuvant chemotherapy have demonstrated some utility in pathologic downstaging after nephroureterectomy and might assist in making unresectable masses amenable to resection. ^[25]  The use of adjuvant, cisplatin-based chemotherapy is supported by a large meta-analysis and, more recently, level 1 evidence from the Peri-Operative Chemotherapy Versus Surveillance in Upper Tract Urothelial Cancer (POUT) trial, which has led to the consideration of adjuvant chemotherapy in UTUC as the standard of care for patients with pT2-T2, N0-3, M0 disease. ^{[26, 27, 28]}

In addition, cystoscopy and transurethral resection of bladder tumors (TURBT) as indicated should be performed prior to nephroureterectomy. Patients should also be counseled about perioperative instillation of intravesical chemotherapy. A meta-analysis demonstrated that intravesical chemotherapy at the time of nephroureterectomy significantly reduces the risk of bladder cancer. ^[29]  These findings were confirmed in the One Dose Mitomycin C (ODMIT-C) randomized, controlled trial, in which a single, post-operative dose of intravesical mitomycin C reduced the risk of recurrent bladder tumor for patients with UTUC undergoing nephroureterectomy from 27% to 17% over the first 12 months of follow-up. ^[30]

As mitomycin C has generally been replaced by intravesical gemcitabine (1 g per 50 cc or 2 g per 100 cc) at our institution, we prefer to use gemcitabine. We instill the intravesical chemotherapy agent at the start of the procedure, immediately after 3-way catheter placement, and let it dwell for 60 minutes prior to draining. 

Nephrectomy

This is a key component of nephroureterectomy, whether by open or laparoscopic (purely laparoscopic or hand- or robot-assisted) approach. Additionally, surgery may be performed extraperitoneally or transperitoneally, depending upon patient comorbidities, previous abdominal surgeries, and surgeon and patient preferences.

Distal ureter and bladder cuff

During nephroureterectomy, the standard practice is to remove the entire ipsilateral ureter, including the intramural portion and a 1 cm portion of the surrounding bladder (bladder cuff). Ideally, this should be achieved by en bloc, closed-system removal of the specimen without any spillage. Although the open technique has traditionally served as the criterion standard, it is associated with considerable morbidity. Therefore, several less-invasive techniques have evolved to minimize morbidity while attempting to conform to standard oncologic principles.

Phe et al reviewed the various surgical techniques for excision of the distal ureter. ^[31] They reported that open removal of the distal ureter can be performed extravesically or intravesically with an approximately 30% risk of bladder recurrence. The laparoscopic stapling technique maintains a closed system but runs the risk of incomplete excision and potential for stone formation on the staple line in the bladder wall. While transvesical laparoscopic detachment and ligation is oncologically sound, it was found to be technically difficult. The transurethral resection of ureteric orifice (TURUO), or the “pluck” technique, is relatively easy to learn but carries the risks of tumor spillage, incomplete resection, and need for repositioning the patient.

The technique of ureteric intussusception/stripping carries the risk of tumor spillage. The authors noted that the recurrence rates within the bladder after various management techniques of the distal ureter during nephroureterectomy varied considerably, from 6.7% to 50%. Unfortunately, to date, no prospective randomized trials have compared the different approaches. Removal of the entire bladder cuff is given a grade A recommendation by the European Association of Urology. 

Lymphadenectomy

Komatsu et al reported that lymphadenectomy may be useful in determining the accurate stage of UTUC but does not improve prognosis. ^[32] In contrast, Miyake et al reported a survival benefit with lymphadenectomy for aggressive disease. ^[33] Because of the conflicting reports in the literature on the benefit of lymph node dissection, and its clear benefit in lower tract urothelial cell carcinoma (UCC), ^{[34, 35, 36, 37]} this is a topic of intense debate in the management of UTUC. To complicate matters further, a lack of understanding and agreement with regard to what should be considered as regional lymph nodes exists.

Kondo et al examined the primary site of nodal metastasis according to primary tumor location and described regional lymph nodes corresponding to various parts of the upper urinary tract. ^[38] In tumors of the right renal pelvis, the primary metastatic sites were the right renal hilar, paracaval, and retrocaval nodes. Tumors of the upper two-thirds of the right ureter metastasized to inter-aortocaval nodes, in addition to the right renal hilar, paracaval, and retrocaval nodes. Tumors within the left renal pelvis or proximal ureter tended to metastasize to the left renal hilar and para-aortic nodes. Tumors of the lower ureter (on either the right or left) primarily metastasized inferior to the aortic bifurcation. In a subsequent article, these authors observed that the extent of lymphadenectomy significantly influenced survival in patients with T3 or higher upper tract UCC. ^[39]

Additional evaluation of the lymph node (LN) metastasis patterns during nephroureterectomy demonstrated the following landing site involvement for renal pelvis and proximal ureteral tumors:

• On the right side: renal hilum, paracaval, retrocaval, and inter-aortocaval (suggesting right to left spread) regions
• On the left side: renal hilum and paraaortic regions

Proximal tumors demonstrated rare LN involvement distal to the aortic bifurcation. Distal and mid-ureteral tumors were more commonly associated with internal, external, and common iliac LN positivity. ^[40]  In accordance with employing a high LN yield template, oncologic outcomes may be improved with the removal of a greater number of LNs in LN-positive disease and in muscle-invasive disease. ^[41]  

A large systematic review and meta-analysis of 9 studies demonstrated that a template-based or complete lymphadenectomy improved patient survival when compared with performing no lymphadenectomy. ^[42]

Evolution of minimally invasive nephroureterectomy

Laparoscopic nephroureterectomy was first reported in the literature by Clayman et al in 1991. ^[43] Since then, several centers of excellence have adopted the laparoscopic approach. Management of the distal ureter, including excision of the bladder cuff, presents a significant challenge laparoscopically. Multiple techniques have been described to manage the distal ureter, none clearly superior to others. ^{[44, 45, 46, 47, 48, 49]} The challenge has been the development of a technique that is safe, easily reproducible, and oncologically sound.

Robot-assisted nephroureterectomy was first reported by Rose et al in 2006. ^[50] In the 2 cases that they reported, the robot was used for only the nephrectomy portion of the surgery, and an open incision was performed for excision of the distal ureter.

Later in the same year, Nanigian et al reported their series of 10 consecutive patients who underwent laparoscopic nephrectomy followed by robot-assisted transvesical excision of the distal ureter and bladder cuff. ^[51] In their technique, patients were initially placed in the modified flank position for laparoscopic nephrectomy. This was followed by robot-assisted distal ureterectomy for which one additional trocar was placed on the contralateral lower quadrant and the patient was switched to a steep Trendelenburg position. The robot was docked, the bladder was clam-shelled, and a cuff of the bladder was removed en bloc with the specimen.

With robotic assistance, the ureteric orifice defect and bladder wall were closed in 2 layers. This technique was a good adaptation of the open technique of bladder cuff excision; however, concerns existed regarding the spillage of bladder contents when the bladder is bivalved in a patient who is in steep Trendelenburg. At 6-month follow-up, 9 out of 10 patients were tumor-free, while one had a remote recurrence at the bladder neck.

In 2008, Hu et al reported their technique of robot-assisted nephroureterectomy in which the Si robot was utilized in an extravesical excision of the distal ureter and bladder cuff in 9 consecutive patients. ^[52] The first 5 patients were repositioned after laparoscopic nephrectomy from flank to lithotomy position to dock the robot between the legs for excision of the bladder cuff.

In the last 4 patients, the authors modified their approach and kept patients in the flank position throughout the entire procedure, with the robot docked in flank position at an angle of 30° to the foot of the table. This not only shortened operative time by obviating the need to reposition but also improved exposure by allowing gravity to displace bowel away from the distal ureter. With their extravesical approach, as opposed to a transvesical approach, the authors hoped to decrease the risk of tumor spillage, obviate the need for a drain, shorten the duration of bladder catheterization, and minimize hematuria postoperatively.

To minimize operative time lost to repositioning and redocking of the robot, Park et al described their technique of “hybrid” port placement and “telescoping” the 8-mm robotic ports into 12-mm laparoscopic ports. ^[53] The first 6 patients were repositioned after the robotic nephrectomy, from flank to lithotomy position, and the robot was re-docked for excision of the distal ureter and bladder cuff. The next 5 patients underwent the entire surgery without repositioning or redocking, which led to the reduction of operative time by approximately 50 minutes.

Hemal et al described their technique of a rather seamless transition from upper tract to lower tract surgery without the need to reposition the patient, re-dock the robot, or “telescope” a robotic port into a 12-mm laparoscopic port. ^[54] Ports were strategically placed to allow access to the kidney, ureter, and bladder. The bladder cuff was excised extravesically, and the cystotomy was closed in 2 layers in the standard fashion. The authors reported that the “short-term” oncologic outcomes revealed no recurrence in their series of 15 patients.

Most recently, the advent of the DaVinci Xi robot has allowed for greater ease of performing the operation, without the need to undock the robot and place new ports, using an "in-line," camera-hopping technique that will be discussed in the Technique section. ^[55]

Despite the documented benefits of minimally invasive nephroureterectomy in perioperative morbidity and recovery, the oncologic equivalence of this procedure to open nephroureterectomy remains to be established. The bar is set high for this procedure because UTUC is a biologically aggressive disease with a high potential for recurrence and disease progression. For it to be recommended as an alternative to open surgery in formal guidelines, its noninferiority to the open approach in terms of oncologic outcomes has to be proven.

Aboumohamed et al conducted intermediate-term follow-up for the use of robot-assisted laparoscopic nephroureterectomy with bladder cuff excision for the treatment of upper tract urothelial carcinoma. The investigators reported that the procedure offered satisfactory oncologic control. Overall survival at 2 and 5 years was 86.9% and 62.6%, respectively, with cancer-specific survival being 92.9% and 69.5%, respectively, and recurrence-free survival being 65.3% and 57.1%, respectively. On multivariate analysis, an association was found between lymphovascular invasion and reduced cancer-specific survival. ^[56]

Several potential risks exist with laparoscopic nephroureterectomy that might compromise the oncologic efficacy of the procedure. Concerns exist that tumor manipulation during laparoscopic nephroureterectomy may lead to increased gravitational migration of tumor cells and implantation into the bladder leading to future recurrence. Up to 50% of patients with primary upper tract UCC are at risk for secondary bladder recurrence owing to tumor seeding. ^[57]

In addition, the high-pressure pneumoperitoneum required for laparoscopic surgeries could allow tumor cells to spread through pressurized aerosolization. ^[58] Furthermore, port site recurrence has also been reported in conjunction with laparoscopic nephroureterectomy. ^[59] These risks are controversial, though to date there are no clinical outcomes that validate these concerns as true risks.

Within the past decade, several large-scale retrospective studies and one prospective randomized trial have been published comparing the oncologic outcomes of laparoscopic and open nephroureterectomy. In one of the first large multi-institutional series, Manabe et al compared outcomes of 58 patients who underwent laparoscopic nephroureterectomy to 166 patients who underwent an open procedure. ^[60] At a median follow-up of 13.6 months for the laparoscopic group and 28 months for the open group, they found no difference in the frequency of bladder recurrence, local recurrence, and distant metastases.

Two-year disease-free survival rates were similar: 75.6% in the laparoscopic group versus 81.7% in the open. One incidence of port-site metastasis occurred in the laparoscopic group. The authors concluded that laparoscopic nephroureterectomy does not negatively affect long-term oncologic control and can be considered an alternative modality.

In a large multi-institutional study with 1249 patients and a median follow-up of 49 months, Capitanio et al compared the outcomes for open and laparoscopic nephroureterectomy. ^[61] On univariate analysis they found recurrence rates and cancer-specific mortality rates were lower in the laparoscopic group; however, this finding was explained by selection bias, wherein patients with favorable pathologic stage and less lymphovascular invasion were selected for laparoscopic surgery.

After adjustment for these covariates, no difference was found between the groups in terms of recurrence and mortality. Absence of data on local recurrence in the bladder and the fact that a large proportion of patients (50% in the laparoscopic group and 58% in the open group) did not undergo bladder cuff excision were the major criticisms of this study. The authors failed to report the rates of port-site metastasis.

In another single-center study with 140 patients, Greco et al did not find any difference in 5-year disease-free survival (DFS) between the laparoscopic and open groups. ^[62] The 5-year DFS was 75% in the laparoscopic group (100% for pTa, 88% for pT1, 78% for pT2, and 35% for pT3) versus 73% in the open group (100% for pTa, 89% for pT1, 75% for pT2, and 31% for pT3).

More recently, in a single-center study, Favaretto et al reported their experience with 324 consecutive patients. ^[63] At a median follow-up of 23 months, no significant difference in recurrence or disease-specific mortality existed between the open and laparoscopic groups. Of note, the surgical technique was consistent—92% had bladder cuff control by the open technique and most patients underwent lymphadenectomy.

To date, only one randomized prospective study has compared the outcomes of open and laparoscopic nephroureterectomy reported in the literature. ^[64] This study raised some suspicion regarding the efficacy of the laparoscopic approach in the treatment of locally advanced UTUC. Eighty patients with non-metastatic upper tract UCC without a prior history of UCC were randomized equally between the 2 treatment arms. As expected, mean blood loss and mean time to discharge were significantly lower in the laparoscopic group.

At a median follow-up of 44 months, bladder recurrence, metastasis-free survival (MFS), and cancer-specific survival (CSS) were not significantly different between the 2 groups. When matched for pT3 and high-grade tumors, MFS and CSS were significantly lower in the laparoscopic group. The authors concluded that the efficacy of the laparoscopic approach in advanced-stage disease remains to be proven. At the same time, they acknowledged their results to be preliminary because of the small sample size.

In line with the results of Simone et al, Terakawa et al found a slightly lower disease-specific survival rate in a laparoscopic group with grade 3 disease; however, on multivariate analysis, surgical approach was not an independent predictor of survival irrespective of tumor grade. ^[65] To counter this, in another large French multicenter collaborative study with 609 patients, the authors reported no difference in survival between the laparoscopic and open groups. ^[66] The median follow-up in this study was 27 months. More specifically, the cancer-specific survival and recurrence-free survival for cases with advanced disease (pT3/pT4) were similar between the 2 groups.

Stewart et al reported long-term outcomes of open and laparoscopic nephroureterectomy in a comparative study with 62 patients. ^[67] After a median follow-up of 13.6 years, they found no significant difference between the 2 groups in terms of bladder recurrence, overall survival, progression-free survival, or cancer-specific survival. Probability of progression-free survival at 10 years was 79% for open nephroureterectomy and 76% for the laparoscopic group and was unchanged at 15 years.

Overall, numerous retrospective studies have demonstrated oncologic equivalence for laparoscopic and open nephroureterectomies. A large systematic review and a contemporary single center review have both demonstrated the oncologic equivalence of the open, laparoscopic, and robotic approaches to nephroureterectomy. ^{[1, 2]}  It appears the laparoscopic approach is equally efficacious in cancer control in expert hands at large institutions, and certainly for lower grade/stage tumors. The ultimate choice of the surgical approach depends upon careful patient selection and surgeons’ comfort with their abilities to perform an oncologically safe operation via a given approach.