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BLADDER CANCER: CYSTECTOMY

Radical Cystectomy

• Includes excision of perivesical soft tissue and:

• Males (2):
  1. Prostate
  2. Seminal vesicles
• Females (4)
  1. Ovaries
  2. Fallopian tubes
  3. Uterus with cervix
  4. Anterior vagina
• In male patients, a nerve-sparing procedure can be safely offered to select patients interested in preserving sexual function.
• In female patients, a female organ sparing (i.e. uterus, ovaries and/or vagina) operation can be offered to women interested in preserving sexual and/or reproductive function in situations where the tumour location allows (i.e. anterior tumours)
• Bilateral pelvic lymph node dissection
• Primary lymphatic drainage sites for bladder cancer (4):
  1. Obturator
  2. Internal iliac
  3. External iliac
  4. Presacral lymph nodes
• Secondary lymphatic drainage sites
  1. Common iliac
  2. Para-aortic
  3. Interaortocaval
  4. Paracaval lymph nodes
• CUA: Bilateral pelvic lymph node dissection with removal, at minimum, of the obturator, internal iliac and external iliac lymph nodes should be performed in all patients undergoing radical cystectomy
• Standard template:
• Superiorly by the ureter/bifurcation of the common iliac artery
• Inferiorly by the circumflex iliac vein and Cloquet’s node/Cooper ligament at the femoral canal
• Laterally by the genitofemoral nerve
• Medially by the bladder and internal iliac artery
• Posteriorly by the obturator nerve/fossa
• Many retrospective studies have suggested a survival benefit of extending the cystectomy lymph node dissection boundaries to a level as high as the inferior mesenteric artery. Campbell’s: in cases of advanced disease, an extended dissection inclusive of the entire common iliac lymph node packet and the presacral lymph node packet can be obtained
• LEA AUO AB 25/02
• Population: 401 patients with locally resectable T1G3 or muscle-invasive urothelial BCa (T2-T4aM0)
• Randomized to limited (obturator, and internal and external iliac nodes) vs. extended LND (in addition, deep obturator, common iliac, presacral, paracaval, interaortocaval, and para-aortal nodes up to the inferior mesenteric artery).
• Results:
• The median number of dissected nodes was 19 in the limited and 31 in the extended arm.
• No difference in RFS (5-yr RFS 65% extended vs 59%; p=0.36), CSS (5-yr CSS 76% vs 65%; p=0.10), and OS (5-yr OS 59% vs 50%; p=0.12).
• Clavien grade ≥3 lymphoceles were more frequently reported in the extended LND group within 90d after surgery.
• Gschwend, Jürgen E., et al."Extended versus limited lymph node dissection in bladder cancer patients undergoing radical cystectomy: survival results from a prospective, randomized trial." European urology 75.4 (2019): 604-611.
• ≈25% of patients will have pathologic lymph node metastases at the time of cystectomy, and lymph node status is the most powerful surrogate for long-term recurrence-free and overall survival following radical cystectomy
• Lymph node count
  • The absolute number of nodes removed has been shown to provide important prognostic information and staging accuracy both in lymph node positive and lymph node negative patients
    • Removing > 10 nodes is recommended [AUA MIBC Guidelines say >12] based on observational studies evaluating node count and survival
• Approach
  • Both laparoscopic/robotic and open approaches are acceptable methods to perform radical cystectomy with comparable cancer outcomes.
    • RAZOR trial§
      • Population: 360 patients with T1–T4, N0–N1, M0 bladder cancer or refractory carcinoma in situ
      • Randomized to robotic vs. open radical cystectomy
      • Results:
        • Robotic cystectomy was non-inferior to open on 2-year PFS [similar results at 3 years]
        • Adverse event were not significantly different between groups (67% robotic vs. 69% open)
          • No difference in risk of post-operative ileus (22% robotic vs. 20% open)

Patient preparation

1. Prostate cancer screening (DRE and PSA)
   • If concerned for prostate cancer, attention at the time of cystectomy will be needed for complete oncologic removal of the prostate
2. Marking stoma site
• Careful marking of the ostomy site to avoid interference, both in a standing and in a seated position, is performed to maximize appliance fit and to minimize stomal irritation.
3. Patients with a planned continent diversion should be made aware of the rare possibility of receiving an ileal conduit urinary diversion
4. Bowel preparation
• Based on data from colorectal surgery, routine bowel preparation is not recommended for patients undergoing radical cystectomy with urinary diversion, especially if only ileal segments are to be used
5. Antibiotic prophylaxis:
   • The choice of antibiotic should include both gram-positive coverage (skin flora) and gram-negative aerobes and anaerobes (distal small bowel and large bowel flora)
   • 2019 AUA Best Practice Statement: Urologic Procedures and Antimicrobial Prophylaxis recommends single dose of cefazolin within 1 hour of surgical incision.
6. Thromboembolic prophylaxis
• Patients should undergo both mechanical thromboembolic prophylaxis (stockings and pneumatic compression) and pharmacologic prophylaxis before the induction of general or spinal anesthesia.
7. μ opioid receptor antagonist

• NCT00708201
  • Population: 277 patients undergoing radical cystectomy
  • Randomized to oral alvimopan vs. placebo
  • Primary outcome: two-component end point was time to  (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). 
  • Results:
    • Alvimopan group had:
      • Quicker lower GI recovery
      • Reduced length of stay
      • Fewer episodes of postoperative ileus-related morbidity
• Lee, Cheryl T., et al."Alvimopan accelerates gastrointestinal recovery after radical cystectomy: a multicenter randomized placebo-controlled trial." European urology 66.2 (2014): 265-272.
• Contraindicated for use in patients who have taken therapeutic doses of opioids for more than seven consecutive days immediately before starting alvimopan

Surgical technique

• Position
  • Males: supine with anterior superior iliac spine at or just below the flexion point of the table
  • Females: low lithotomy position with the aid of stirrups or the use of spreader bars provides access to the vagina.
    • In female patients, table flexion is generally not possible.
• Prepartation
  • The abdomen should be prepared from the level of the xiphoid to the upper portion of the thighs. The genital organs, including the vagina in women, and the perineum should be prepared as well
• Incision
  • A lower midline incision is made sharply extending distally from the level of the symphysis pubis to the umbilicus superiorly
• Summary of Steps
  • See BJUI Surgical Atlas for details and figures
  • After the midline is identified, the fascia is divided and the space of Retzius is entered.
    • Upward retraction of the umbilicus (toward the ceiling) aids in the identification of the linea alba.
  • Blunt dissection is performed to mobilize the bladder from the pelvic sidewall attachments anteriorly and bilaterally. This is carried superiorly to the level of the vas deferens in men and the round ligament in women.
  • At this point, a peritonotomy is made lateral to either medial umbilical ligament and the urachus is controlled and divided.
  • The peritoneum is incised lateral to the medial umbilical ligaments bilaterally to the level of the internal inguinal rings at which point the vas deferentia in men and the round ligaments in women will be identified and are divided
  • With the aid of a self-retaining retractor such as a Bookwalter, exposure is maximized and the bowel retracted cephalad. Communication with the anesthesiologist at this point is vital to ensure that inadvertent compression of the vena cava has not resulted. A moistened laparotomy pad or pads should be placed behind retractor blades to protect the abdominal contents.
  • After adequate exposure is achieved, the bilateral ureters are identified and dissected free from their attachments beginning a few cm above where they cross the iliac arteries to the level of the detrusor hiatus. Care should be used to ensure that adequate ureteral adventitia is maintained. The superior vesical artery should be ligated and divided before completing the ureteral dissection as this aids in maximizing ureteral length. The ureter is then controlled with either suture ties or suture ligature and is divided.
    • Although controversial, the distal ureteral margin can be sent for frozen section analysis to evaluate for the presence of urothelial carcinoma. Studies have shown a correlation between findings of carcinoma in the ureteral margin and subsequent upper tract recurrence, however, an impact on survival has not been well established
  • The lateral vascular pedicles are ligated. If sealing instruments are used, the heat they generate can transmit and may injure the rectum if in close proximity. With a gloved finger surgeons should shield the rectum from the tips of such instruments while in use
  • After completely ligating the lateral vascular pedicles, attention is turned to the posterior dissection. The rectal cul-de-sac is identified and the peritoneum is incised where it overlies the seminal vesicles
  • The rectum is dissected free with either blunt dissection or sharp dissection in the midline and is carried to the level of the prostate, at which point Denonvilliers fascia is encountered and incised.
  • At this point, attention can be turned to the anterior dissection in a fashion similar to a radical prostatectomy. The endopelvic fascia overlying the levator muscles is incised sharply, allowing for identification of the confluence between the urethra and the dorsal venous complex. Ligation and division of the dorsal venous complex allows for visualization of the anterior urethra, which is then incised
  • If a continent ileal neobladder urinary diversion is planned, adequate urethral length must be maintained and a frozen section analysis of the urethral margin performed. Orthotopic neobladder is contraindicated patients with a positive urethral margin due to risk of urethral recurrence
  • The role of preservation of the neurovascular bundles, unlike in radical prostatectomy, remains controversial in radical cystectomy. A technique analogous to radical prostatectomy can be used, however, the functional outcomes remain significantly worse than radical prostatectomy.
  • Female cystectomy:
    • The initial steps for bowel mobilization, anterior bladder mobilization, and ureteral dissection are the same in men and in women with the exception of the gonadal vessels. In female patients the ovarian vessels should be identified during the bowel mobilization and ligated with a 2-0 silk suture distally, and both a 2-0 silk suture ligature and a tie proximally, and then divided.
    • Anterior pelvic exenteration begins with identification of the posterior cervical fornix (Fig. 95-14A), and the vaginal cuff is incised at this position (Fig. 95-14B).
    • After gaining entry to the vaginal canal, control the lateral and posterior vascular pedicles to the bladder. According to surgeon preference, vascular staplers, sealing devices, or clips are applied and the specimen can be dissected free inclusive of the uterus, cervix, anterior vaginal cuff, and bladder.
    • The urethral meatus is then incised, either antegrade from the pelvis or externally from the vaginal introitus, and the specimen is removed (Fig. 95-15A and B). Care should be taken to ensure that sufficient vaginal mucosa is maintained above the urethral meatus to allow for closure of the vaginal defect in subsequent steps.
      • Radical cystectomy in the female patient historically included total anterior pelvic exenteration inclusive of the bladder, urethra, anterior vagina, uterus, and cervix. However, in the absence of bladder neck involvement and the presence of low-stage disease (≤cT2), orthotopic neobladder can be considered. This necessitates urethral sparing with adequate length proximal to the striated sphincter and anterior vaginal wall sparing to provide support to the neobladder.
        • Maintaining the integrity of the striated sphincter, the specimen is removed at this level and a frozen section of the urethral margin is sent and managed in the same fashion as in male neobladder candidates. Again, if the urethral margin analysis demonstrated malignancy, orthotopic diversion is contraindicated.
    • Because of the vascular nature of the female pelvis and the sinusoidal nature of the vascular pedicles as they pass over the lateral vaginal wall, care is needed to ensure hemostasis
      • Lateral vascular pedicles are intimate with the lateral wall of the vagina and to control these vessels properly they must be separated from the vagina before ligation. This can be achieved either after removal of the cervix and uterus at the level of the cervical fornix (Fig. 95-16A) or while they are still in place. A vaginal packing during this step can aid in defining the plane of separation between the bladder and the anterior vaginal wall in the midline. After development this space is extended laterally, separating the lateral vascular pedicles from the lateral vaginal wall. To ensure that an adequate bladder margin is maintained, the vessels should not be divided until the midpoint of the lateral vaginal wall, in the anterior posterior plane, has been reached. This dissection is carried to the level of the bladder neck, which can easily be identified by use of the Foley catheter balloon as a guide.
    • To complete the vaginal closure with a 2-0 polyglactin suture, the posterior vaginal wall must be released from the rectum. The posterior vaginal flap is then closed to the corresponding mucosae of the introitus in a clamshell fashion to maintain vaginal girth at the cost of some vaginal length. Bothersome drainage of peritoneal fluid will result if the vaginal closure is not watertight, and an interrupted closure is preferred.
    • A vaginal packing is then placed with the dual purpose of distending the vagina and tamponading any residual vaginal wall hemorrhage (particularly useful if vaginal sparing is performed; discussed later) and aids in the identification of unrecognized defect in the closure. This packing should be removed within two postoperative days.

Intra-operative Decision Making

• Clinically T4b
  • A CT-guided biopsy can be performed to confirm histology. If positive for urothelial carcinoma, chemotherapy should be initiated followed by consideration of RC
• Grossly positive nodes
  • If adenopathy is encountered at the time of cystectomy, a frozen section should be taken to confirm metastasis, and RC with extended lymph node dissection and should be completed when feasible
    • Cystectomy is not performed when
      1. Lymph node metastases are unresectable (because of bulk)
      2. Extensive periureteral disease
      3. Bladder is fixed to the pelvic sidewall
• Intraoperative ureteral tumor
  • The finding of a papillary lesion at the ureteral margin requires on-the-table flexible ureteroscopy to fully ascertain the extent of tumors in the system prior to planning the correct therapy.
    • If only CIS or dysplasia is present, intraoperative endoscopy is not indicated, because visual identification of CIS is unlikely.
    • If on-the-table ureteroscopy shows no additional tumors, resect until negative margins are obtained. Nephroureterectomy and extensive ureteral resection would only be performed if the ureteroscopy demonstrated tumors at more proximal location.
• Intraoperative Frozen Sections of the Ureter
  • The distal ureter is involved with tumour on final pathology ≈6-8% at the time of RC
  • Intraoperative frozen-section analysis of the ureters at the time of cystectomy remains controversial. Patients with ureteral disease at the time of cystectomy experience an increased risk of upper tract recurrence regardless of margin status, but this risk can be partially mitigated by achieving a negative margin
    • Final ureteral margin status has proven to be an independent predictor of upper tract recurrence following cystectomy. However, the overall incidence of upper tract recurrence following cystectomy is a relatively rare event ranging from 2-8%.
      • Risk factors for upper tract recurrence following cystectomy:
        • Bladder CIS
        • Distal ureteral involvement with tumor
        • High-grade pTa-T1 disease.
  • There is no definitive recommendation for the length of the distal ureter that should be removed at the time of surgery
• Urethrectomy
  • Risk of urethral recurrence in men
  • The overall risk of urethral recurrence following cystectomy is ≈7% at 5 years and 9% at 10 years. Recurrences are observed at a median of 2 years after cystectomy (range 0.2-13 years)
  • Involvement of the prostatic urethra is associated with a higher risk of subsequent urethral recurrence (absolute risk increase 6% at 5 years (11% men with any prostate involvement vs. 5% men without any prostate tumour involvement)
  • The extent of prostatic tumor involvement correlates with the risk of subsequent urethral recurrence.
  • 5-year risk of urethral recurrence 18% pT2 (stromal invasion) vs. 12% CIS or pT1 (mucosa and ductal prostatic urethral involvement)
  • Isolated prostatic stromal involvement is unusual in the absence of nodal disease
  • Other risk factors have been evaluated to predict risk of urethral recurrence after cystectomy including presence of papillary tumours, multifocality, trigone or bladder neck involvement and CIS, but these have demonstrated mixed results. The presence of [bladder] CIS or a multifocal tumor should not preclude orthotopic diversion.
  • Some evidence suggests that orthotopic diversion itself may provide some protection against urethral recurrence
  • Patients with documented prostatic mucosal, ductal, or stromal invasion [found at TURBT of the primary tumour] should be counselled about the increased risk of urethral recurrence if the urethra is left in situ to help them weigh that risk against any perceived advantage of an orthotopic diversion. In general, those with prostatic stromal invasion are counseled to undergo neoadjuvant chemotherapy. In those who are not candidates for neoadjuvant chemotherapy or who have persistent prostatic urethral involvement, at surgery a concomitant urethrectomy and cutaneous form of diversion are recommended. Close surveillance of the urethra is mandatory if a neobladder procedure is performed, with periodic urethral wash cytology and urethroscopy as indicated.
  • Risk of urethral recurrence in women
  • Risk factors for urethral involvement:
    1. Tumour involving bladder neck
    • In one study, ≈50% of women with bladder neck tumors had a normal (tumor-free) proximal urethra. No patient with a normal bladder neck demonstrated tumor involvement of the urethra. In all cases, intraoperative frozen-section analysis of the proximal urethra correlated with and was correctly confirmed by final permanent section. These results suggest that one may depend on the intraoperative frozen section to determine the feasibility of orthotopic diversion.
    2. Tumour invading anterior vaginal wall
    • Vaginal wall involvement is best evaluated on bimanual examination under anesthesia at the time of TURBT or cystectomy.
    • Anterior vaginal wall involvement by a posterior-based bladder tumor or bladder neck or urethra involvement is a contraindication to urethra sparing and orthotopic bladder replacement because one cannot get an adequate distal vaginal margin and urethra margin
  • Indications for urethrectomy
    • 2019 CUA MIBC guidelines (4):
      1. Positive urethral margin
      2. Males with:
         1. High grade or invasive urethral disease distal to the prostatic urethra
         2. Suspected prostatic stromal involvement
      3. Females with bladder neck tumours (note CUA does not include tumour invading anterior vaginal wall)
    • Campbell’s
      • Males
        • Absolute (2):
          1. Positive urethral margin
             • If a frozen section of the urethral margin is positive, an orthotopic neobladder is contraindicated
               • When an orthotopic neobladder is to be constructed, frozen sections need to be done at the level of the urethral section margin in males and females. Conversion to a cutaneous diversion with immediate urethrectomy is mandatory if the frozen sections turn out to be positive§
             • While preoperative evaluation of the prostatic urethra via transurethral biopsy can be performed (TUR biopsies of the prostate, preferably at the 5- and 7-o’clock positions lateral to the verumontanum, at the time of TURBT of the primary bladder tumor) to further characterize the risk of urethral recurrence and help dictate intraoperative management of the distal urethra and choice of urinary diversion, the sensitivity and specificity of transurethral biopsy is moderate with a relatively low positive predicate value compared to final cystoprostatectomy specimens.
          2. Presence of CIS or urothelial carcinoma in the prostatic urethra, glands or stroma [different than CUA Guidelines]
        • Relative (1):
          1. Patients that undergo other types of diversions (incontinent, continent cutaneous), even when no poor prognostic factors are present because the risk of urethral recurrence is always present
      • Females
        • Unless indicated, a complete urethrectomy can be omitted at the time of cystectomy allowing for orthotopic bladder substitution in women
        • Absolute (3):
          1. Positive urethral margin
             • Frozen-section analysis of the distal urethra has demonstrated high correlation with final urethral margin and should be performed in all women in which orthotopic bladder substitution is being considered
          2. Tumour involving bladder neck
             • Clinical features associated with an increased risk of distal urethral tumor involvement include primary tumor location at the bladder neck, vaginal involvement, or inguinal lymphadenopathy
               • Although tumor presence at the bladder neck is significantly associated with urethral involvement, ≈60% of patients with tumors in this location will not have a tumor in the urethra on final pathology and therefore controversy exists with regard to an absolute need for complete urethrectomy in this setting
          3. T4 tumors involving the urethra and/or vagina [different than CUA Guidelines]
    • Urethrectomy is ideally done through a prepubic approach
  • Delayed urethrectomy
    • Absolute indications (3):
      1. Urethral cytology washing becomes positive
      2. A patient develops bloody discharge
      3. Local recurrence is clinically obvious in the perineum or penis

Postoperative care

• 0.9% inpatient mortality rate and a 2.7% 90-day mortality rate following radical cystectomy
• Mortality after radical cystectomy is typically < 5%, but may increase substantially in the elderly with 90-day mortality rates over 10% in patients > 75 years of age and almost 20% in octagenarians.
• The incidence of symptomatic venous thromboembolism in short-term follow-up after radical cystectomy is 3-12%, of which > 50% of cases will occur after hospital discharge.
• Meta-analyses of clinical trials in patients undergoing major abdominal oncologic operations suggest a decreased risk of venous thromboembolisms for patients receiving extended (4 weeks) venous thromboembolism prophylaxis.
• Extended prophylaxis should be considered in all radical cystectomy cases. Although the relative risk of bleeding also increases, the overall net benefit of extended prophylaxis clearly favors use for at least 28 days postoperatively.
• Extrarenal eliminated prophylaxis agents are preferred given the risk of renal insufficiency in radical cystectomy cases, with newer oral anticoagulants providing an alternative route of administration.
• Klaassen, Zachary, et al."Extended venous thromboembolism prophylaxis after radical cystectomy: A call for adherence to current guidelines." The Journal of urology 199.4 (2018): 906-914.

Partial cystectomy

• See 2019 CUA MIBC Guidelines
• For those with solitary lesions of small size and who lack concurrent carcinoma in situ (CIS), results from partial cystectomy are similar to those of radical cystectomy
• Patients initially treated with partial cystectomy can be salvaged with radical cystectomy
• Procedure:
• Cystotomy is performed in an area away from the tumor.
• The tumor is then excised including the underlying bladder wall and perivesical fat with a mucosal margin of 1 to 2 cm and confirmation of resection adequacy with frozen section analysis. If necessary, the ureteral orifice or intramural ureter can be excised and a reimplantation performed.
• After excision of the tumor the cystotomy is closed with 2-0 polyglactin suture in 2 or 3 layers, and an instillation of fluid via a Foley catheter is performed to ensure a watertight closure.
• Copious warm water irrigation of the surgical field is performed to minimize the possibility of pelvic seeding.
• A closed suction drain should be placed and the cystotomy closure interrogated with a cystogram on postoperative day 7 before removal of the Foley catheter.
• Although rare, primary adenocarcinoma arising from the urachus requires additional resection. These tumors are most commonly confined to the dome of the bladder although they may grow by direct extension to involve other areas. Complete excision includes the umbilicus, the urachus, and the dome of the bladder with a visual margin free from tumor

Questions

1. What organs are removed at the time of radical cystectomy?
2. What are the primary lymphatic drainage sites in bladder cancer?
3. What are the boundaries of lymph node dissection in bladder cancer?
4. What are the indications for urethrectomy at the time of radical cystectomy?

Answers

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 95