Surgical Management of Invasive Bladder Cancer Yao Kai

Indications for radical cystectomy Infiltrating muscle-invasive bladder cancer without evidence of metastasis or with low-volume, resectable locoregional metastases (stage T2-T3b) Superficial bladder tumors characterized by any of the following: Refractory to cystoscopic resection and intravesical chemotherapy or immunotherapy Extensive disease not amenable to cystoscopic resection Invasive prostatic urethral involvement Stage-pT1, grade-3 tumors unresponsive to intravesical BCG vaccine therapy CIS refractory to intravesical immunotherapy or chemotherapy Palliation for pain, bleeding, or urinary frequency Primary adenocarcinoma, SCC, or sarcoma

Radical cystectomy: evolution More than removing just the bladder (simple cystectomy) First performed in 1800s for bladder cancer 1948, landmark report showed a 47% incidence of local recurrence within 1 year and 33% mortality after recurrent disease within 1-2 years Overall outcomes of patients undergoing simple cystectomies were poor.

Modern Radical Cystectomy Removal of bladder with surrounding fat Prostate/seminal vesicles (males) Uterus/fallopian tubes/ovaries/cervix (females) + Urethrectomy Pelvic Lymphadenectomy More is better Urinary Diversion Ileal conduit Continent cutaneous reservoir Orthotopic neobladder Surgery for bladder cancer can really be divided into 3 main components: First, the radical cystectomy which is removal of the bladder with its surrounding fat. In males that also routinely includes the prostate and seminal vesicles, and in women, the uterus, cervix, tubes, and ovaries. Depending on the stage of disease, the urethra may also need to be removed. The removal of the pelvic lymph nodes is also a critical component to the completeness of the surgical resection. And finally, the urinary diversion which typically has the most direct impact on the patient’s quality of life.

Radical Cystectomy OUTCOMES 35-40% will develop a recurrence after surgery Most recur within first 3 yrs after surgery Usually at a distant site Almost all will eventually die from their disease Based on one of the largest experiences from the University of Southern California, looking at over 1000 patients, we know that about 35-40% will develop a recurrence of the disease after surgery. Most of these recurrences will become evident within the first 3 yrs after surgery. Usually the cancer shows up at a distant site such as the liver or lungs, and unfortunately, despite our advances in chemotherapy, most of these patients will eventually die from their disease. Stein JP, et al. J Clin Oncol 19:666, 2001

Radical Cystectomy OUTCOMES The most important prognostic factor after surgery is the stage of disease. Those who have a tumor that is confined to the bladder have about an 80% chance of being cured of their disease. When the cancer extends outside of the capsule of the bladder to involve the surrounding fat, that cure rate goes down to about 50%, and when there is spread to the lymph nodes, only about 20% will be cured. Stein JP, et al. J Clin Oncol 19:666, 2001

Impact of Surgical Technique on Outcomes More extended lymph nodes dissection = better outcomes More lymph nodes removed = better outcomes Lower positive margin rate = better outcomes More experienced surgeons = better outcomes

Pelvic Lymphadenectomy Standard LND common iliac vessel bifurcation One of the current controversies in the Urologic community is what is the optimal extent of the lymph node dissection. For a long time, the standard dissection would include only the lower pelvic nodes directly around the bladder. Several studies have recently supported a more extended dissection to include the nodes around the lower portions of the aorta and inferior vena cava. Extended LND

Pelvic Lymphadenectomy ~25% have LN involvement at cystectomy Accurate staging Assessment of prognosis Adjuvant therapies (chemotherapy, clinical trials) Therapeutic benefit Removal of micrometastatic disease Despite our CT scans and MRI’s, still about 25% of patients who go into surgery without any evidence of spread outside of the bladder will be found to have positive lymph nodes once the specimen is analyzed.A properly performed pelvic lymphadenectomy provides accurate staging and therefore a better idea of the prognosis. Those patients with lymph node involvement should be considered for other treatments such as chemotherapy or inclusion in clinical trials.It was once thought that once the tumor had spread to the lymph nodes, that “the cat was out of the bag” so to speak and that there was little benefit to doing a thorough lymph node removal.However, there is now increasing evidence to suggest that there is a therapeutic benefit to removing these nodes and that some patients can be cured of their disease with surgery.

All Patients No. lymph node removed ≥12 n=613 100 All Patients 90 80 No. lymph node removed ≥12 n=613 70 60 Bladder Cancer-specific Survival Probability 50 40 No. lymph node removed <12 n=113 30 20 3 yr. ± SE 7 yr. ± SE 10 yr. ± SE No. LN removed ≥12 78.1 ±1.9% 71.8 ±2.4% 63.6 ±3.6% No. LN removed <12 59.2 ±5.1% 44.9 ±6.3% 44.9 ±6.3% Log rank test P<0.0001 10 4 6 8 10 12 14 16 18 Years after Radical Cystectomy

Number of Nodes Sampled Affects Survival in Both Node Negative and Node Positive Patients Node negative Node Positive This paper from Memorial Sloan Kettering Cancer Center clearly shows how the number of nodes removed affects survival probability in both node negative and node positive patients. In apparently node negative patients, the sensitivity of detecting node metastases will be lowered with a more limited node dissection yielding fewer nodes or the pathologists failure to examine all potential node bearing tissue and the nodes contained in that tissue. In node positive patients the number of positive nods has a significant impact on outcome. Herr Urology 61:105, 2003

All cases were staged N0M0 prior to radical cystectomy Two consecutive series of patients treated with radical cystectomy and limited PLND (336; Cleveland Clinic) and extended PLND (322; University of Bern) were analyzed All cases were staged N0M0 prior to radical cystectomy (without treatment of neoadjuvant therapy) Outcome After Radical Cystectomy With Limited or Extended Pelvic Lymph Node Dissection. J Urol 179, 873-878, March 2008

Using the limited template and with submission as a single packet from each side, a median of 12 nodes were reported per CC patient. Median number of positive nodes was 1 Using the extended template and submission of 6 packets, a median of 22 nodes were reported per Bern patient. Median number of positive nodes was 2 The overall lymph node positive rate was 13% for patients with limited and 26% for those who had extended PLND Outcome After Radical Cystectomy With Limited or Extended Pelvic Lymph Node Dissection. J Urol 179, 873-878, March 2008

Recurrence-free survival After Radical Cystectomy With Limited or Extended PLND for pT2+3pN+ Limited PLND Extended PLND This slide describe the Recurrence-free survival of limited or extended PLND combined with radical cystectomy for pT2+3pN+ urothelial bladder cancer.We can see the Difference in survival is significant. Outcome After Radical Cystectomy With Limited or Extended Pelvic Lymph Node Dissection. J Urol 179, 873-878, March 2008

Recurrence-free survival After Radical Cystectomy With Limited or Extended PLND for pT2+3pN0 Limited PLND Extended PLND This slide describe Recurrence-free survival of limited or extended PLND combined with radical cystectomy for pT2pN0 urothelial bladder cancer.We can see the Difference in survival for pT3pN0 patients is significant Outcome After Radical Cystectomy With Limited or Extended Pelvic Lymph Node Dissection. J Urol 179, 873-878, March 2008

Overall survival After Radical Cystectomy With Limited or Extended PLND for pT2pN0-2 and pT3pN0-2 Limited PLND Extended PLND This slide describe Overall survival of limited or extended PLND combined with radical cystectomy for pT2pN0-2 and pT3pN0-2 urothelial bladder cancer. We can see the Difference in Overall survival for pT3pN0-2 is significant. Outcome After Radical Cystectomy With Limited or Extended Pelvic Lymph Node Dissection. J Urol 179, 873-878, March 2008

Urinary Diversion Use of intestinal segment to bypass/ reconstruct/ replace the normal urinary tract Goals: Storage of urine without absorption Maintain low pressure even at high volumes to allow unobstructed flow of urine from kidneys Prevent reflux of urine back to the kidneys Socially-acceptable continence Empties completely “Ideal” diversion has yet to be discovered Now for the part of the talk that I think most of you are interested in- the urinary diversion.This is basically using a portion of the intestine to bypass, reconstruct, or replace the normal urinary tract.The goals of a urinary diversion are straight forward:To store urine without absorption of the waste products.To store that urine at low pressures so that the urine can continue to drain from the kidneys.To prevent reflux of urine back into the kidneys.To hold on to the urine until it is socially-acceptable to empty, and then to empty completely.If you think about it, this is what our normal bladders do everyday.Having said that, the ideal form of diversion has yet to be discovered.

Types of Urinary Diversion There are 3 main types of diversions practiced at this time.The ileal conduit which is an incontinent diversion to the skin. This is also known as a urostomy in which an external bag collects the urine continuously.Continent reservoir was constructed with an opening to the skin which would then have to be catheterized in order to empty.And it really wasn’t until the 1990’s that the neobladder became popular, which is a continent diversion connected to the native urethra. ILEAL CONDUIT (incontinent diversion to skin) CONTINENT CUTANEOUS RESERVOIR (continent diversion to skin) ORTHOTOPIC NEOBLADDER (continent diversion to urethra)

Ileal Conduit 15-20 cm of small intestine (ileum) is separated from the intestinal tract Intestines are sewn back together (re-establish intestinal continuity) The ileal conduit is created from 15-20 cm of small intestine (ileum). This segment of intestine is separated from the rest of the intestinal tract. The intestines are obviously sewn back together so that one can still have bowel movements.

Ileal Conduit Ureters are attached to one end of the segment of ileum Natural peristalsis of intestine propels urine through the segment Other end is brought out through an opening on the abdomen The ureters that drain the kidneys are then sewn into one end of the ileum. And the other end is brought up to an opening on the abdomen as a stoma. The intestine naturally has a propulsive movement, almost like a snake, that normally would be moving food through the GI tract, but in this instance, is pushing the urine through the segment and out of the body. Ileum ureter ureter

Ileal Conduit ADVANTAGES Simplest to perform Least potential for complications No need for intermittent catheterization Less absorption of urine DISADVANTAGES Need to wear an external collection bag Stoma complications Parastomal hernia Stomal stenosis Long-term sequelae Pyelonephritis Renal deterioration So for each of these diversions, I’m going to give you a breakdown of the advantages and disadvantages.For the conduit, the advantage is that it is simple to perform. Arguably, it has the least potential for complications. There is no need for catheterization, and because of the movement of the intestine, there is less time for absorption of the urine in the intestine. The disadvantages are that you need to wear an external collection bag. There can be problems with the stoma- either a hernia or scarring making it difficult for the urine to pass. Some long-term problems that have been noted include risks of infections and decreased function of the kidneys after many years.

Continent Cutaneous Reservoir Many variations (same theme) Indiana Pouch, Penn Pouch, Kock Pouch… All use various parts of the intestine ileum, right colon most commonly Reservoir “Detubularized” intestine- low pressure storage Continence mechanism Ileocecal valve (Indiana) Flap valve (Penn, Lahey) Intussuscepted nipple valve (Kock) For the continent cutaneous reservoir- These go by many names with slight variations but all with a similar theme. You may hear these referred to as an Indiana pouch, or a Kock pouch.All use various parts of the intestine, most commonly the ileum and right colon.The intestine is detubularized to create a low pressure storage reservoir. The main difference between these pouches are in terms of how they provide continence. The Indiana uses the natural valve between the small and large intestine called the ileocecal valve. This normally prevents the stool in the colon from backing up into the small intestine. A variety of other techniques have been created to also prevent leakage from the reservoir, including flap valves and nipple valves.

Continent Cutaneous Reservoir INDIANA POUCH Appendix removed Right colon and distal ileum isolated Right colon is opened lengthwise and folded down to create a sphere The Indiana Pouch is probably the most commonly used cutaneous reservoir.Here, the right colon and ileum are isolated. The appendix is removed.The right colon is opened lengthwise and folded down to create a sphere.

Continent Cutaneous Reservoir INDIANA POUCH Ureters attached to back of reservoir (not shown) catheter The ureters are attached to the back of the reservoir and the ileum becomes that efferent limb that is brought up to the skin opening. Continence is maintained by this one way ileocecal valve. So that the only way to empty the reservoir is by passing a catheter through the skin opening through the efferent limb (or ileum) and into the pouch.This needs to be done at regular intervals throughout the day, usually every 4-6 hours. EFFERENT LIMB (to skin) RESERVOIR Continence maintained by ileocecal valve

Continent Cutaneous Reservoir INDIANA POUCH

Continent Cutaneous Reservoir ADVANTAGES No external bag Stoma can be covered with bandaid DISADVANTAGES Most complex Need for regular intermittent catheterization Potential complications: Stoma stenosis Stones Urine infections The main advantage of this type of reservoir is that no external bag is needed. The stoma can be covered with a bandaid. The disadvantages can be quite significant. It is much more complex to create than the ileal conduit. It does require regular intermittent catheterization every 4-6 hours. There are potential for complications with scarring at the stoma making it difficult to catheterize. Urine infections and stones can form within the reservoir since the urine is sitting in there for longer periods of time.

Orthotopic Neobladder Currently the diversion of choice Hautmann, Studer, T-Pouch,etc. COMPONENTS: Internal reservoir – detubularized ileum Connect to urethra (“efferent limb”) Urethral sphincter provides continence “Antirefluxing” – ureteral connection Antirefluxing uretero-intestinal anastomosis(Hautmann ) Low pressure isoperistaltic limb (Studer) Just as with the catheterizable cutaneous diversions, there are a number of different type of neobladders, though all are based on the same principles. The internal reservoir is created from detubularized intestine. The continence mechanism here is the body’s own urethral sphincter that we naturally depend upon for our urine control normally. The main differences between the various neobladders is how the ureters are attached to the reservoir.

Orthotopic Neobladder ADVANTAGES No external bag Urinate through urethra May not need catheterization DISADVANTAGES Incontinence (10-30%) Retention (5-20%) Risk of stones, UTI’s Need to “train” neobladder The advantages: no external bag, ability to urinate through the urethra, and you may not need to do any catheterization. There are significant risks of incontinence (10-30%) which would require pads. There is also a risk of retention of urine that might require intermittent catheterization, which appears to be higher in females for whatever reason. Similar to the Indiana Pouch, there is a risk of stone and UTI’s. It does take some effort to train the neobladder. Patients do need to be very motivated to learn to urinate at regular intervals, practice exercises to control the urine, and to basically learn how to empty the neobladder through a combination of pelvic floor relaxation and abdominal straining.

Choice of Urinary Diversion Disease Factors Urethral margin Patient Factors Kidney function / liver function Manual dexterity Preoperative urinary continence/ urethral strictures Motivation Surgeon Factors Familiarity with various types of diversions With all of these options, how does one decide. Well, I think there are really 3 main factors that go into the decision.First is the bladder cancer itself. If the cancer involves the urethra, it does not make sense to create a fancy diversion and connect it to any area where there is cancer. So, if the urethra is involved, the urethra is removed and one of the skin diversions is performed. Secondly, patient factors are clearly important. Due to the potential for absorption of the urine through the intestine, a continent diversion requires normal kidney and liver function to compensate. Good manual dexterity is needed for diversions that may require intermittent catheterization. It’s good to know if there are any preexisting problems with the urethra or urinary sphincter when considering a neobladder. The continent diversions do require a bit of work and patients do need to be motivated to take care of themselves, catheterize when needed, and to be diligent about medical followup to prevent problems down the road.And finally, the surgeon’s familiarity and experience will also play into the choice of diversion.

Urinary Diversions Enterostomal therapist is CRITICAL for success Urinary diversions require lifelong follow-up Imaging (kidneys/ureters/diversion) Labs (electrolytes, acid-base, B12 levels) Cancer follow-up (surveillance imaging, cytology) One of the keys to success is having a dedicated enterostomal therapist or nurse specialist who can work with patients both before and after surgery. All of these urinary diversions require lifelong followup. This includes periodic imaging of the kidneys, ureters, and diversion, regular blood work, as well as the routine follow-up for surveillance of the cancer.

Conclusions Surgery is the cornerstone of treatment for invasive bladder cancer Accurate staging (after surgery) is the most important determinant of prognosis A properly performed lymph node dissection makes a difference Choice of urinary diversion must be individualized for optimal outcomes In conclusion, surgery remains the cornerstone of treatment for invasive bladder cancer. Accurate staging is the most important determinant of prognosis.A properly performed lymph node dissection makes a difference.The choice of urinary diversion must be individualized for optimal outcomes.

Conclusions Limited PLND is associated with suboptimal staging, poorer outcome for patients with node positive and node negative disease with comparable pT stage and a higher rate of LP Extended PLND appears not only to allow for more accurate staging but also for improved survival of patients with organ confined, nonorgan confined and LN positive disease

Thank you