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Muscle invasive tumorMuscle invasive tumor

Edmond

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Case• M/64y• Chronic smoker, HT, DM, IHD• C/o painless gross haematuria x 1y• FC: one 5cm sessile growth over right lateral

wall• IVU: upper tract normal• TURBT: Muscle involved, G3• CT + CXR: Extravesical extension, enlarged

pelvic LN, no liver/lung/bone metastasis

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What are the options of What are the options of treatmenttreatment？？

• Radical cystectomy

• Radiotherapy

• Chemotherapy

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Radical cystectomyRadical cystectomy

• Indication: – Muscle invasive or locally advanced disease T2-T4a

N0-Nx, M0– BCG-resistant Cis, T1G3– High risk recurrent superficial tumors– Extensive papillary tumors not controlled by TUR

• Standard RC:– Male: Prostate + bladder + macroscopic visible &

resectable tumor extension, adjacent distal ureter + LN

– Female: Anterior pelvic exenteration include bladder, entire urethra, upper 1/3 vagina , uterus , distal ureters and LN

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• Complications– Re-operation (10%) – Bleeding (10%)– Sepsis and wound infection (10%)– Intestinal obstruction or prolong ileus (10%)– Cradio-pulmonary morbidity– Rectal injury (4%)– Cx of urinary diversion– Peri-operative mortality : 3%– Early complications (within 3 months of surgery) in 28% ( Stein JP, Skinner DG.

Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World J Urol 2006 )

• Result: – Pathological upstaging (40%) – LN metastasis : T1 (10%) , T3-4 (33%)

• Survival– 10 years recurrence free survival: 60%, overall survival 50% (Stein series)– 5 years recurrence free survival (Studer series): overall 70%

• 90% in pT1/CIS• 74% in pT2, • 52% in pT3, and • 36% in pT4

– 5 yr OS: 60%– Long term survival in LN +ve: 20% - 30%

• Nomogram to predict survival following RC have been develop but cannot be recommended

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How to perform radical How to perform radical cystectomy in male?cystectomy in male?

• Fr 18 Foley• Midline incision• Develop space of Retzius• Mobilize bladder from pelvic side wall• Divide the urachus remnant• Divide vas• Divide posterior peritoneum to expose ureters• Mobilize ureter proximally to preserve the periureteral blood supply • Pelvic lymphadenectomy• Divide endopelvic fascia• Divide lateral vascular bladder pedicles• Establish plane between rectum and posterior bladder wall• Ligate dorsal vein• Dissect neurovascular bundles off prostate bilaterally• Incise urethra• Divide posterior bladder pedicle

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How to perform radical cystectomy in female (anterior pelvic How to perform radical cystectomy in female (anterior pelvic exenteration)?exenteration)?

• Mobilization of bladder from pelvic side wall

• Divide urachus

• Ligate infundibulopelvic ligaments (ovarian artery) and round ligaments (vas)

• Incise broad ligament to expose ureters and moblize

• Pelvic lymphadenectomy

• Circumferencially incise on cervix

• Close vaginal defect

• Dissection of place bt anterior vaginal wall and posterior surface of bladder

• Divide urethra

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Technique to improve QOLTechnique to improve QOLLevel of preservation: • Anterior & membranous urethra + external sphincter

– For orthotopic neobladder• Part of prostate and seminal vesicle

– Fertility , potency and continence• Autonomic & sensory nerve (NVB)

– soft tissue adjacent to the tips of the seminal vesicles. • Uterus & part of vagina ;

– Improve antomical support for neobladder & autonomic nerves

Disadv: – Residual Ca prostate (30%) 10% clinically significant– Increase oncologica risk need long term data

Adv: • Improve potency rate after nerve sparing cystectomy (Walsh J Urol 1996)

– 20y – 29y: 100%, 70y – 79y: 20% – Overall 48%, depends on age of patient– vs < 30% in non NS cystectomy

• Allow formation of neobladder and more natural voiding

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Other technical consideration

• Distal ureteral segment– Length to be removed not defined– FZ –ve give overall accuracy of > 98%

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Is radical cystectomy contraindicated in pt >80yo?

• Cystectomy is associated with greatest risk reduction in disease-related and non-disease related death in patient > 80yo

• Pt older than 80 year of age have increase post-operative morbidity but not increased mortality

Hollenbeck Urology 2004

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What are methods of urinary What are methods of urinary diversion ?diversion ?

• To skin: – Ureterocutaneostomy– Ileal conduit– Continent cutaneous urinary diversion

• To bowel: Ureterocolic diversion• To urethra:

– Orthotopic neobladder

• Renal deterioration is not more frequent in refluxing than non-refluxing ureteric implant

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How to perform ileal conduit ?How to perform ileal conduit ?• 15cm segment with major arch, 15cm from ileocecal valve • Ileoileostomy• Closure of mesenteric window• Flush conduit with copious saline• Ureteroileal anastomosis

– Bricker– Wallace – lowest complication like stricture and leakage, not recommended

extensive CIS (difficult mx in recurrence + bil obstruction) – Absorbable suture, spatulation, water-tight mucosa to mucosa apposition over

stent (bilateral separate stent) • Abdominal stoma (everting, tension free, ant abd fascia not too tight) • Complications

– Fewer than the other 2 urinary diversion method– Early: pyelonephritis, uertero-ileal leakage, stenosis– Late: stoma complications (24%), upper tract changes (30%), urolithiasis– Higher chance or urethral recurrence than neobladder (

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Continent cutaneous urinaryContinent cutaneous urinary diversion diversion

• Suitable candidate: self care ability, renal (CrCl 60ml/min) and liver function, colonoscopy

• 4 types of continent mechanism– Appendiceal tunneling– Terminal ileum and ileocecal valve– Intussuscepted nipple valve– Hydraulic valve, as in Benchekroun nipple

• Common reservoirs– Indiana pouch, Mainz pouch, double T-pouch

• Contraindication: same as neobladder – Severe neurological & psychiatric illness– Limited life expectancy– Impaired LRFT– +ve urethral margin or other surgical margin

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Orthotopic Urinary diversionOrthotopic Urinary diversion• Assessment: self cath ability, renal function 60ml/min, life expectancy

(<75), no liver failure• Relative contraindication specific to orthotopic bladder :

– Pre-operative RT– Complex urethral stricture– Severe urethral sphincter related incontinence

• Contraindication: – Severe neurological & psychiatric illness– Limited life expectancy– Impaired LRFT– +ve urethral margin or other surgical margin

• Overall risk of urethral recurrence 10%• Terminal ileum most often used for bladder substitution• Long term complications:

– urinary retention – diurnal/nocturnal incontinence – ureterointestinal stenosis– metabolic disorders (hyperCl metabolic acidosis) – Vit B12 deficiency

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How to perform Studer pouchHow to perform Studer pouch

• 60cm terminal ileum• 25cm from ileocecal valve• Distal 40cm placed in U shape, opened along

antimesenteric border• Ureters anastomosed end-to side fashion to afferent limb• Closure of anterior and posterior wall of U-shaped ileum• Cut a hole in dependent portion of ileum• Uretheroenteric anastomosis

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What is partial cystectomy?

• Ideal candidate: only 20%– solitary lesion at dome allowing 2cm margin

– Tumour in diverticulum

• Need cystoscopy every 3 month for at least 2 years

• T3-4 tumors have the highest risk of developing metastases (70%) but also have the lowest rate (10-20%) of successful control of local disease with bladder preservation – Many of these patients will be curable with PLND

• 5-year survival from 50% to 70%

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What is the situation cystectomy is prefer as opposed to RT?

• CIS (RT does not treat CIS)

• Upper tract obstruction

• Inflammatory bowel disease

• Severe irritative LUTS

• Previous RT

But if significant comorbidity or preserve sexual function > RT

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Neoadjuvant chemotherapyNeoadjuvant chemotherapy

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• Advantage: – At the earliest time point, when the burden of micrometastatic disease is

expected to be low– In vivo chemosensitivity is tested– The tolerability of chemotherapy is expected to be better before than after

cystectomy– Potentially downstaging the tumor– Did not affect the percentage of cystectomy performable [Nordic Trail 1+2]

• Disadvantage: – 50% without micrometastasis will be overtreated– Staging error may lead to overtreatment– Delay in cystectomy may compromise outcome– Chemo therapy may have SE that affect outcome of surgery– Although overall morbidity is similar ,more anemia & neuropathy

• Regimen: MVAC (SWOG 2003), CMV (EORTC)o GC less toxic with similar efficacy (Dash et al 2003)

Neo-Adj Chemo

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• Indication : – Stage II-III and selected T4bN0 or N1 disease– Good PS (0-1)– Adequate renal function

• CMV Q3W for 3 cycles

• Advanced Bladder Cancer (ABC) Meta-analysis. [Lancet 2003]– Analysis of 11 trial– Cisplatin-containing chemotherapy :

• 5% (45% > 50%) absolute improvement 5yr overall survival• 9% improvement in 5yr DFS • 13% reduction in risk of death

– Combination is better than single agent– Complete tumor response in 30% – Update in 2005 [EU 2005]

• Absolute overall survival benefit of 5% (95% CI 1-9%, from 45-50%)• Significant disease-free survival benefit (HR 0.78, 95% CI 0.71-0.86,

p<0.0001) with 9% improvement in 5 years• Platinum combination significantly better than platinum single agent

– GC: Phase III metastatic trial: similar efficacy with CMV/M-VAC but less toxic• EAU

– Neoadjuvant cisplatin-containing combination chemotherapy should be considered in muscle invasive bladder cancer, irrespective of definitive treatment

• Contraindication: PS ≥ 2 and impaired renal function - <50-60 mL/minute

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What is SPARE trial?

• Cancer research UK

• Randomised trial of muscle invasive tumor

• RT VS cystectomy after neoadjavant chemotherapy

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Delay cystectomyDelay cystectomy

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What is the problem of delay cystectomy?

• Delay of treatment beyond 90 days of primary diagnosis caused a significant increase in extravesical disease (81 vs. 52%), decrease in overall survival, recurrence-free survival, cause-specific survival– Chang SS, et al. Delaying radical cystectomy for muscle invasive bladder

cancer results in worse pathological stage. J Urol 2003;170(4 Pt 1):1085-7.

• Also affect the options of urinary diversion– Hautmann RE, et al. Does the option of the ileal neobladder stimulate

patient and physician decision toward earlier cystectomy?. J Urol 1998;159(6):1845-50.

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LymphadenectomyLymphadenectomy

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Why PLND?Why PLND?

• Chance of LN metChance of LN met• From Stein series

– Overall estimate ~ 25% patient undergo cystectomy have LN met

– Superficial disease (P0, Pis, Pa, P1): 5%– pT2 : 15– pT3 : 40%– pT4 : 50%

• EAU - In retrospective studies extended lymphadenectomy has been reported to improve survival in patients with muscle-invasive bladder cancer.

• The curative value of lymph node dissection, however, is still unknown and a standardised lymph node dissection has yet to be defined

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Standard PLND

• Proximal: Bifurcation of common iliac artery

• Lateral :Gentitofemoral nerve

• Medial: Bladder wall

• Distal: Circumflex iliac vein

• Pelvic floor and hypogastric vessel

Anything less = limited

Anything more = extended

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Extended PLNDExtended PLNDIn the boundaries of:• Aortic bifurcation and common iliac vessel• Genitofemoral nerve• Circumflex iliac vein and node of Cloquet• Hypogastic vessels

Including:• obturator, internal, external, common iliac and presacral nodes as well as

nodes at the aortic bifurcation May also Extend to IMA• Rationale of extended lymphadenectomy

– Early lymph node metastasis can occur in pT1 (5%) and pT2 (18-27%) diseases

– Long term survival is possible in patients with lymph node metastasis– 20-30% of metastatic lymph nodes outside the field of “standard” LND

J Stein, D Skinner, 2006 BUJI

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Key Concepts of LN Metastasis

• Number of lymph nodes removed

• Number of lymph node metastasis

• Lymph node density

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Number of Lymph Nodes

• The number of lymph nodes assessed pathologically depends,– Boundaries of the LND

– Pathologist’s diligence in searching and preparing the lymph nodes

– How the specimen is actually submitted for pathological evaluation

– Patient’s variation

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Benefits of Extended LND

• Survival benefit in organ-confined node-positive bladder cancer patients (TxN+)-> Some evidence

• Survival benefit in organ-confined node-negative bladder cancer patients (TxN0)-> Strong evidence

• Overall 5yRFS – pT1 76%, pT2 74%, pT3 52%, pT4 36%

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Benefit of Extended LND• Patients with TxN+ disease

– Leissner et al. evaluated 79 patients with < 5 positive lymph nodes, and demonstrated improved survival when >16 lymph nodes were removed, although a multivariate analysis was not reported. [Leissner, BJU Int 2000]

– Herr et al. reviewed a lymph node-positive cystectomy series of 162 patients and observed that the removal of >13 total lymph nodes was not a significant predictor of survival on multivariate analysis (P = 0.56). [Herr, J Urol 2003]

– Stein et al. described the largest lymph node-positive series with 244 patients and observed no recurrence-free survival advantage with the removal of ≥15 lymph nodes (P = 0.21). [Stein, J Urol 2003]

• However:– Based on the 1260 patients from SEER database, removal of >10 lymph

nodes was associated with increased overall survival (hazard ratio, 0.52; 95% confidence interval , 0.43 - 0.64). [Wright, Cancer 2009]

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Leissner, BJUI 2000;85;817-823Leissner, BJUI 2000;85;817-823

5yRFS >=16 <=15

Tis or 1or 2, pN0

85% 63%

T3 55% 40%

pLN+ 1-5i.e. density

53% 25%

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Benefits of Extended LND

• In patients with TxN0 disease– Better and more accurate staging by sampling

more lymph nodes– Removal of micro-metastasis– 33% of patients had unexpected microscopic

nodal metastasis to common iliac lymph nodes

Bochner, J Urol. 2004

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Survival in patients with N0 disease

Herr, Urol 2003

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Recommendation

• The Bladder Cancer Collaborative Group recommends 10-14 lymph nodes should be removed at time cystectomy

Herr, J Urol 2004

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Technical Considerations

• Operation technique– Standardized procedure– Cystectomy-first or LND-first approach– Extra operation time (63 minutes)

• Open versus laparoscopic– Technically demanding in laparoscopic procedure– No difference in term of lymph node yield and

complication rate– Increased operation time but blood loss reduced

Finelli, J Urol. 2004. Porpiglia, J Endourol. 2007

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Why need extended LN?

• 90% of bladder draining LN distal and caudal to where ureter cross common iliac arteries [Studer EU2010]

• Limited LND likely understage LN status [Studer JU2008]– Cleveland clinic vs University of Bern– 1) overall pLN +ve rate lower– 2) more recurrence despite same pT2 / pT3 /

pLN+

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Where are the regional lymph nodes of the bladder ?

11%

20%

18% 7%

20%5%

4%4%11%

B. Roth et al., Eur Urol 57:205-211, 2010

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LIMITED PLND: CC EXTENDED PLND: Bern

Boundaries of Dissection

{median 12 nodes: range 2-31} {median 22 nodes: range 10-43}

Dhar N., Studer U.E. et al., J. Urol 179: 873-878, 2008

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Patients with pT2 and pT3 N0 Patients with pT2 and pT3 N0 bladder cancerbladder cancer

Institution Stage # of Patients # with pN+

CC

Limited

pT2 pN0-2 200 15/200 (7.5%)

Bern

Extended

pT2 pN0-2 150 24/150 (16%)

CC

Limited

pT3 pN0-2 136 29/136 (21%)

Bern

Extended

pT3 pN0-2 172 59/172 (34%)

Dhar N., Studer U.E. et al., J. Urol 179: 873-878, 2008

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Recurrenc free survival pT2Recurrenc free survival pT2 pNpN0-2 0-2 & pT3& pT3 pNpN0-2 0-2

p< 0.001p< 0.001

Limited PLND Extended PLND

0

.2

.4

.6

.8

1

0 12 24 36 48 60

CC Patients

RF

S

M onths

19%

pT 2a + b, pN 0-2 (n=200)

pT 3a + b, pN 0-2 (n=136)

p<0.0001

63%

0

.2

.4

.6

.8

1

0 12 24 36 48 60

CC Patients

RF

S

M onths

19%

pT 2a + b, pN 0-2 (n=200)

pT 3a + b, pN 0-2 (n=136)

p<0.0001

63%

B ern P a tien ts

0

.2

.4

.6

.8

1

0 12 24 36 48 60

pT2 a + b, pN 0-2 (n=150)

pT3 a + b, pN 0-2 (n=172)

RF

S

M on ths

p<0 .0001

49%

71%

B ern P a tien ts

0

.2

.4

.6

.8

1

0 12 24 36 48 60

pT2 a + b, pN 0-2 (n=150)

pT3 a + b, pN 0-2 (n=172)

RF

S

M on ths

p<0 .0001

49%

71%

Dhar N., Studer U.E. et al., J. Urol 179: 873-878, 2008

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limited extendedOverall pLN +ve 13% 26%

LN+ 5y RFS 7% 35%

pT2N0 67% 77%

pT3N0 23% 57%

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Also affect survivalAlso affect survival

• LN density

• Extracapsular extension of LN met

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Can we just perform the PLND only on Can we just perform the PLND only on the side of tumor?the side of tumor?

• Bilateral nodal involvement is common even if tumor is limited in the left or right hemisphere of bladder. Bilateral PLND should be performed– Mapping study by Leissner

• In some series, up to 40% of positive nodes were found in the contralateral side

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What are the advantages of doing extended LN dissection?

• Extended PLND increased the total number of LN removed (from 14 to 25) Prospective multicentre study by Leissner

• Extended PLND although takes longer time to perform, it makes subsequent cystectomy more straightforward because of a better delineated vascular anatomy

• Cohort data from Bladder cancer collaborative group extended PLND apparently reduce the incidence of positive surgical margins

• By increase the number of LN removed, it is associated with better recurrence free survival in patients with organ confined disease, extravesical disease and patients with nodal disease. (as shown in multiple series, Stein/Leissner/Herr’s series)

• Although increased operating time, no evidence that extended PLND would lead to increased morbidity, such as lymphocele, DVT, bleeding (Stein & Leissner’s series)

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What are the morbidity and mortality of PLND?

• According to Stein & Skinner’s series, the perioperative mortality was 3% with early complication of 28%. But there were no perioperative deaths or early complications related directly to PLND

• Patients who had high dose of irradiation before operation are at risk of vascular and associated injury. They are not good candidates for extended PLND

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What is the concept of lymph node density?

• From Stein’s series, LN density was shown to be an independent significant prognostic factor

• LN density of <=20%: 40% 10 year recurrence free survival

• LN density of > 20%: 20% 10 year recurrence free survival

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Urethrectomy

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• What is the urethral recurrence rate after cystectomy?– Overall incidence of urethral recurrence in retained

male urethra: 7.9% • Skinner series

• What is the median time to recurrence?– Median time to recurrence is 1.5 yrs with most

recurrence occurring before 5 years– Some cases are reported up to 20 years after

cystectomy– That is why life long follow up is required

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What are the reasons for urethral recurrence after radical cystectomy?

1. Unrecognised TCC in the urethra at the time of cystectomy (synchronus TCC)

2. Growth of TCC from a positive margin of cystectomy

3. Recurrence owing to tumor spillage / implantation

4. De novo TCC occurrence due to field change (metachronus)

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What are the Risk factors for urethral recurrence?

• Prostate involvement

– Most consistent risk factor (confirmed by multiple cystectomy series)

– Risks associated with depth of prostate involvement (Freeman’s series)

• Prostate stromal involvement: 20%

• Superficial prostate involvement: 15%– Some study showed no increased risk if tumor is limited

to mucosa

• No prostate involvement: 6%

– Overall 5 year survival for patient with prostatic stromal invasion is 35%. (according to Skinner’s series)

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What are the Risk factors for urethral Recurrence?

• Type of urinary diversion (From Skinner/Freeman series)– Lower in orthotopic diversion

• Cutaneous diversion 11.1%• Orthotopic diversion: 2.9%• Even in patients with prostate involvement

– Orthotopic diversion: 5%– Cutaneous diversion: 24%

• Possible reasons– Possible excretion of protective substance by ileum– Protective effect is present when there is continued exposure of urethra to urine– Some systemic effect of orthopic neobladder construction

• Carcinoma in situ• Involvement of bladder neck

– Most consistent association in women

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What are the indications of urethrectomy?

• Positive margins at the level of urethral dissection (FZ) • If the primary tumour is located at the bladder neck or

in the urethra (in women - Universally accepted that en-bloc urethrectomy should be done if not for orthotopic neobladder because this adds minimal time and morbidity to the overall procedure), or if tumour infiltrates the prostate stroma

• +ve resection margin anywhere in the bladder• Tumor infiltrate into the prostate • CIS

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Laparoscopic/robotic-Laparoscopic/robotic-assisted laparoscopic assisted laparoscopic

cystectomycystectomy

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What is the role of laparoscopic/robotic-assisted laparoscopic cystectomy?

• Maintain oncology efficacy of ORC, ↓morbidity, ↑recovery, ↑QoL

• Most authors have favoured an extracorporeal approach based on currently available technology and using intestinal segments for the urinary diversion

• Open versus laparoscopic– Technically demanding in laparoscopic procedure– Urinary diversion is usually performed extracorporeally– No difference in term of lymph node yield and complication rate– Increased operation time but blood loss reduced– No consensus on oncology outcome

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Urinary diversionUrinary diversion

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Now

• Preferably: – Continent reservoir connected to urethra– Ileal segments (lower pressure peaks and

ease of surgical handling)

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Classification of Diversion

• Orthotopic• Heterotopic

– Continent cutaneous• Kock pouch – small bowel > complication – secretory diarrhea

• Mainz I pouch - Ileocecal reservoir with appendix catherterizable pouch

• Mainz II pouch – ureterosigmoidostomy

• Mainz III - Transverse colon• Indiana pouch - the ascending colon and a portion of the ileum

– Non-continent Cutaneous

– Diversion to GIT

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3 Principles for lower urinary tract reconstruction

• A reservoir in which to store urine in low pressure

• A conduit through which the urine is conducted to the surface

• A continence mechanism

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Bladder reservoir must have:

• Able to retent 500-1000ml of fluid

• Maintenance of low pressure after filling

• Elimination of intermittency pressure spikes

• True continence

• Ease of catheterization and emptying

• Prevention of reflux

• Skinner

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Factors influencing complication• Patient Factors

1. Performance Status/ Co-morbidities2. Patient /Caretaker compliance to CISC

Mobility3. Previous RT4. Renal function5. Liver function6. Body Habitus/BMI

• Bowel Factors1. Type of intestinal segment used2. Length of intestinal segment3. Continent vs Continuously draining4. Method/ extent of detubularization5. Capacity6. Compliance7. Reflux or non-refluxing uretero-intestinal anastomosis8. Type of diversion chosen

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Which Gastrointestinal segments?

• Stomach

• Ileum

• Colon– Colonic conduit is not preferred to ileal

conduit in renal impairment– Colonic conduit have less risk of intestinal

obstruction compared to ileal conduit

• Appendix

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1. Stomach

• Advantage: – Less hyperchloremic acidosis– Reduced mucus production + UTI

• Disadvantage: – Hematuria-dysuria syndrome (overcome with composite

urinary reservoir)– Hyper-gastinemia– hypochloremic Hypokalemic metabolic alkalosis • Reduced intrinsic factor, possibly leading to vitamin B12

deficiency• Gastric pouch ulceration• Theoretical risk of bone demineralization• Higher risk of malignancy

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Complication

• Gastric retention due to atony of the stomach or edema of the anastomosis

• Hemorrhage (anastomotic site)

• Hiccups (gastric distention)

• Pancreatitis (intraoperative injury)

• Duodenal leakage• Dumping syndrome Steatorrhea, small stomach

syndrome• Hypoproteinemia• Bowel obstruction (10%)

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2. Ileum2. Ileum

• Advantage: – Can be reconfigured as low-pressure reservoir

• Disadvantage: – Impaired Vit B12 and Bile acid absorption (if >60cm

resected)– Increased oxalate absorption stone formation– HypoK, Hyperchloraemic acidosis (secrete Na HCO3)– Osteoporosis and osteomalacia

66

2.1 Ileocoecal valve2.1 Ileocoecal valve

• Controlled transport of ileal content into colon• Rapid bowel propulsion soft stools, diarrhoea,

malabsorption• If the ileocecal valve be used, diarrhea, excessive

bacterial colonization of the ileum with malabsorption, and fluid and bicarbonate loss may occur

• Decrease Vit B (32%)• Decrease folic acid (11%)• Metabolic acidosis (30%)• Increase risk of renal and gall bladder stones

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3. Colon3. Colon

• Advantage: – mobile sigmoid (easy to brought down) – Larger diameter– Less Vit B12 and bile salt absorption problem– results in fewer nutritional problems – incidence of postoperative bowel obstruction with colon is 4%,

less than that occurring with ileum– An antireflux ureterointestinal anastomosis by the submucosal

tunnel technique is easier to perform with use of colon• Disadvantage:

– Hyperchloremic hypokalemic Metabolic acidosis– Frequent night time voiding (enhance peristalsis + higher

pressure)– Increased UTI and malignancy (nitrosamine)

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JejunumJejunum

• Not usually employed due to severe electrolyte imbalance

• Hyponatremia

• Hyperkalemic Hypochloremia metabolic acidosis

• Severe dehydration

69

4. Appendix

• Useful for catheterizable nipple for continuent cutaneous diversion

• If appendix not available Monti pouch with ileal segments

70

Summary

• 1. Jejunum• Salt loss syndrome (dehydration, hyponatraemia,

hypochloraemia, hyperkalaemia, metabolic acidosis).

• 2. lleum• Salt loss syndrome• Hyperchloraemic acidosis

• 3. Colon• Hyperchloraemic acidosis

• 4. Bone disease• Demineralization (long-term)• Reduced growth (young patients)• Increased fracture rate• Pain in weight-bearing joints

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Preparation of ureter

• Preserve blood supply: periureteral adventitial tissue (reduce ischemia and stricture

• Left ureter moved across retroperitoneum above level of IMA

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(Transuretero-) Ureterocutaneostomy

• Indications: – After palliative cystectomy in elderly frail pt– Temporary diversion when GI tract not possible– Diversion for fistula or hemorrhage

• Procedure: – Ureter mobolized to bladder ligated and divided– V or U shaped skin incision – Track throught abd wall in most direct line– Ureter with largest diameter pulled thru track (spatulated)– Apex of skin flap to ureteral apex (4-5/0)– The other ureter End-to-side to complete TUU– Oemntal flap to secure anastomosis and abdominal tunnel

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Ileal conduit

• Ileal Conduit still the standard for urinary diversions

• Wide facial opening (x-type incision) • Ileum in isoperistaltic fashion• Stoma site

– Above or below the waist band– Not close to umbilicus , through the belly of

rectus , bony prominence or scar– Be test with patient and marked pre-op

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Submucosal tunneling

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Ureteric implantation

• Bricker and Nesbit: o Both ureter implant individually in an end-to-side

• Wallace 66: o Paralllel orientated ureter o Spatualted at distal endo Posterior plate suture o Side-to-end fashion to ileal stump

• Wallace 69: o End to end oriented uretero Spatulated and sutureo Side-to-end fashion to ileal stump

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Bricker

77

Wallace

78

Pros and Cons

• Advantage: o Short segment use limited metabolic changeo Suitable in renal or hepatic insufficencyo Use when post-op radiation necessary

• Contraindications: o Short bowel syndromeo Radiation to terminal ileumo Ascites

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Complications of ileal or colon urinary diversion

• Early – Anastomotic leak, enteric fistula, bowel obstruction, ileus, conduit

necrosis, urinary leakage• Late

– Stomal prolapse, retraction, parastomal hernia, conduit stenosis-ileal conduit only

– uretero-ileal stenosis – UTI (colonization of ileal conduit) – 25% Upper tract deterioration (reflux, chronic bacteriuria)– Upper tract calculi– Entero-conduit fistulae– Metabolic ↑Cl metabolic acidosis, B12, bile acids

• HyperChloremic Metabolic Acidosis (10%)• Secondary to RTA with derange RFT• Txn: Oral sodium bicarbonate• Cx: Bone demineralization

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Continent urinary diversion

• Good Reservoir– Good capacity– Lower pressure storage– Low metabolic issue

• Spherical reservoir: low end-filling pressure with maximum radius

• M/ W/ U folded reservoir

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Continent catheterizable reservior

• Indication: – External urethral sphincter sparing surgery

impossibile– Urethral malformations– Spinal injury or complex neurological defects

• Patient compliance is of utmost importance

• Risk of perforation or bladder rupture

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• Continence mechanism: – Appendix (Mitrofanoff)– Tapered ileum (Monti) – Intussucepted ileal nippples

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Complications

• Re-operation rate: 22-49%

• Stomal stenosis: 4-15%

• Incontinence rate: 3.2%

• Ureteral stenosis : 8%

• Metabolic (if IC valve & terminal ileum): diarrhoea, hyperchloraemic acidosis, malabsorbtion

84

Orthotopic neobladder

• EUS must be intact

• To rule out cancer infiltration: – Pre-op cystoscopy+ bx of BN/ Prostatic

urethra– Intra-op FS of resected margin

• Advantage: – Good QOL (physical integrity)– Near normal voiding and continence

85

CI to neobladder

86

Neobladder construction

87

Afferent anastomosis

• Reflux prevention: – Camey-Le Duc– Intussuceptive ileal nipple (Hemi-Kock)– Abol-Enein, Stein : Serosa-lined extramural

tunnel implantation– Isoperistaltic tubular limb

88

Efferent anastomosis

• Day time continence: 87-98%

• Night time continence: 72-95%

• Need of CISC: M 4%, F 15%

• Precise preparation of urethra is essential

• Avoid Corner of pouch to urethra anastomosis kinking and difficulties with voiding

89

Uretero (ileo-)Sigmoidostomy

• Largely replace by conduits

• Main Disadvantages: – Metabolic acidosis– Renal failure– Tumourigenesis (adenoCa) at site of

anastomosis– Bacterial reflux (Pyelonephritis and ureteric

stenosis)

90

What are the advantages and disadvantages of end and loop ileal

conduit stomas?

• Advantage of loop ileal conduit– Ease of obtaining everted bud above skin

level

• Disvantage of end ileal conduit– More prone of ischemic complication

91

What is the effort of emptying bladder after neobladder?

• Abdominal straining, intestinal peristalsis and sphincter relaxation

92

Prognosis after Prognosis after cystectomycystectomy

93

What are the prognostic factors What are the prognostic factors of survival post cystectomy?of survival post cystectomy?

• Age• Pathological stage• Positive margins• LN status

– Herr, et al

– Single node involvement have similar survival to node negative patients

• Molecular markers– P53 nuclear accumulation

– Loss of p21 expression

94

What is the recurrence-free What is the recurrence-free survival rate after cystectomy?survival rate after cystectomy?

5 year 10 yearP0 N0 92% 86%Pis N0 91% 89%Pa N0 79% 74%P1 N0 83% 78%P2/3aN0 78-89% 76-87%P3b N0 62% 61%P4 N0 50% 45%LN+ 35% 34%• 10 years recurrence free survival: 60%, overall survival 40%

• Stein + Skinners group USC 2001 1054 patients J Clin Oncol. 2001 Feb 1;19(3):666-75

95

T2 T3 T4

5yr OS for radical cystectomy

60-80% 30-60% >20%

5yr OS for radiotherapy

40% 30% 10%

96

• What are the other results drawn from Skinner’s series?

• Overall ~30% of cancers recurred• 22% distant and 7% local recurrence• Median time to recurrence = 12 months

• A large series of cystectomies from Johns Hopkins has recently reported a 7% incidence of pT0

J Clin Oncol. 2001 Feb 1;19(3):666-75

97

Palliative cystectomy for muscle-invasive bladder

carcinoma

98

What is the indication of palliative cystectomy for muscle-invasive

bladder carcinoma?• Primary radical cystectomy in T4b bladder

cancer is not a curative option• If there are symptoms, radical cystectomy

may be a therapeutic/palliative option• Intestinal or non-intestinal forms of urinary

diversion can be used with or without palliative cystectomy

• Morbidity of surgery and quality of life should be weighed against other options

99

Neoadjuvant RT

100

What is the role of neoadjuvant RT?

• No role in improving survive

• Improved local control in T3b(10%)

• Tumour downstaging after 4-6 weeks (50%)

• Preoperative radiotherapy cannot reduce local recurrence after radical cystectomy

101

What are the means of Bladder preserving strategies

• Definitive RT

• Definitive Chemo

• Radical TURBT + systemic chemo– Little data, not mainstream

• Palliative TURBT +/- RT : for elderly unfit

• Partial cystectomy +/- neo-adj chemo

• TURBT + definitive RT

102

What is the role of TUR alone for muscle invasive tumor?

• TUR alone is not a curative treatment option in most patients

• If tumour growth is limited to the superficial muscle layer and if restaging biopsies are negative for residual tumour, without hydronephrosis or CIS

• Therapeutic option, when the patient is unfit for cystectomy or refuses open surgery

103

What is the role of EBRT?• Cochrane analysis - cystectomy has an overall survival benefit compared to radiotherapy• Target field: bladder only with 2cm margin• Dose: 60-66Gy• Indication:

– Should only be considered as sole txn when the patient is unfit for cystectomy or a multimodality bladder-preserving approach

– Can stop bleeding from the tumour when local control cannot be achieved by transurethral manipulation because of extensive local tumour growth

– For metastasis bone pain (30Gy) or palliative RT (40Gy)– SCC and adenocarcinoma do not respond to RT

• Result: – 3y local control rate: 50%– Overall 5-year survival rates : 30%- 60% (inferior to RC) – 5 yr Cancer-specific survival rate of 20% - 50%, with or without a complete response following

radiotherapy, respectively (EAU)– Preserve bladder function in 50% of cases, esp in low volume/minimal residual disease

• Complication: – 3-5% required cystectomy for complication– 50% ED– <5% major long term GU, GI morbidity

• Important prognostic factors – Age, tumour size/stage, hydronephrosis and the completeness of the initial TURBT

• Previously RT patient undergoing RC later have a higher risk of early complication

104

Definitive Chemo

• Chemotherapy alone rarely produce durable complete response of the primary tumor

• Radical TURBT + Chemo may allow long term survival with intact bladder

• EAU 2011: cannot be recommended for routine use

105

Bladder sparing treatmentBladder sparing treatment• Bladder preservation protocol

– A comparable long-term cancer specific survival rate of 50-60% at 5 years’ follow-up is reported by both multimodality bladder-preserving trials with negative tumor bed and cystectomy series.

– However, both therapeutic approaches have never been directly compared and patients in multimodality series are highly selected.

– A bladder-preserving multimodality strategy requires very close multidisciplinary co-operation and a high level of patient compliance.

– Even if a patient has shown a complete response to a multimodality bladder-preserving strategy, the bladder remains a potential source of recurrence

– Rodel et al (the largest series)• 415 patients, TURBT + Chemo + XRT• 40% 5 years overall survival

106

What is the role of Multimodality treatment?

• Methrotrexate, cisplatin and vinblastine (MCV) aims at the eradication of micrometastasis in combination with radiotherapy, following TURBT, results in a complete response rate of two-third

• Salvage rates of one-third

• Delay in surgical therapy can compromise survival rates

107

Adjuvant chemotherapy

108

What is benefit of adjuvant chemotherapy?

• After accurate pathological staging

• Overtreatment is avoided

• No delay in definitive surgery

109

What is the disadvantage of adjuvant chemotherapy?

• Assessment of in-vivo chemosensitivity is not possible• Delay of chemotherapy, due to post-operative morbidity• Adjuvant chemotherapy is under debate• Neither randomized trials nor a meta-analysis supported

adjuvant chemotherapy– No benefit for N0M0 patients– Patients with lymph node metastasis or T3/4 disease appear

to benefit most– Adjuvant chemo MAY delay progression

– No difference in overall survival at 5 years• Adjuvant chemotherapy is advised within clinical trials, but

not for routine use because it has not been studied sufficiently

110

ChemotherapyChemotherapy

• Accelerated MVAC – 2 weekly regimen for 3 cycles (overnight as using diuretics to increase U/O so as to reduce the toxicity

111

Metastatic Ca BladderMetastatic Ca Bladder• Advance CaB is a chemosensitive tumor• 10-15% metastatic disease• Metastatic disease died in 3-4 months without

treatment• Treatment depends on Prognostic factors:

– 2 most important :KPS (Karnofsky PS) + visceral metastasis i.e. Bajorin prognostic factor

– Age – RFT (obstruting disease or chronic upper tract

inflammation) – Metabolic change post urinary diversion– Comorbidity

112

Chemo for fit pt

• Prolong survival : MVAC 14.8mon vs GC 13.8mon• GC : Gemcitabine + cisplatin• M-VAC: Methrotrexate, vinblastine, adriamycin + cisplatin• Response rate up to 70%• GC less toxic (regimen of choice), or use HD-MVAC + GCSF

– Less neutropenic fever– Less mucositis– Less fatique– More anaemia– More thrombocytopenia

• 5y survival: – LN only disease 20%– Visceral metastasis 7 %

• Conclusion: 1st line txn for fit patient cisplatin containing combination (GC or M-VAC) preferably with GCSF (granulocyte-stimulating colony factor

113

Cisplatin• Alkylating agent• Form reactive molecular species that alkylate

nucleophilic groups on DNA bases, particularly the N-7 position of guanine

• This lead to cross-linking of base, abnormal base sparing and DNA strand breakage

• Impaired DNA synthesis, interfering mitosis, cause cell death/apoptosis

• SE: nephrotoxicity, neurotoxicity, ototoxicity, N/V, e- disturbance: hypomagnesaemia, hypokalaemia and hypocalcaemia

11401/07/11

Gemicitabine

• Nucleoside analog • Triphosphate analogue of gemcitabine replaces one of

the building blocks of nucleic acids(cytidine), during DNA replication. The process arrests tumor growth, as only one additional nucleoside can be attached to the "faulty" nucleoside, resulting in apoptosis.

• Another target of gemcitabine: ribonucleotide reductase (RNR). The diphosphate analogue binds to RNR active site and inactivates the enzyme irreversibly. Once RNR is inhibited, the cell cannot produce the deoxyribonucleotides required for DNA replication and repair, and cell apoptosis is induced

115

• Chemotx for unfit pt– 50% pt unfit due to poor PS, impaired RFT, co-morbidity forbids

high volume hydration– Carboplatin combination (Carbo +Gemzar) or M-CAVI – M-CAVI: Methrotrexate, Caboplatin + vinblastine– Carbo/Gem : less toxic (13% vs 23%) , more response (42% vs

30%)• Second line agent

– Vinflunine: 3rd generation vinca alkaloid, highest level of evidence ever reported (Gr A recommendation in EAU guideline)

– Overall response rate 8% but significant survival benefit – Others treatment should take plase in clinical trial:

• Bone metastasis– In 30-40% pt– Zoledronic acid: the only bisphosphonate approved for

metastatic bone disease– Reduce and delay skeletal related events, improve QoL and 1y

OS

116

Palliative chemotherapyPalliative chemotherapy

• First-line treatment–CMV RR 56%; median OS 8 months

(JCO 1985)

–M-VAC RR 72%, CR 18%; median OS 13 months (JCO 1997)

–Gemcitabine, cisplatin (c/w M-VAC) RR 46% (49%); median OS 13.8 months (14.8 months) (JCO 2006)

117

Palliative chemotherapyPalliative chemotherapy

• First-line treatment– Paclitaxel, gemcitabine, cisplatin (c/w GC) ORR

57.1% vs 46.4% (p=0.02); median OS 2.9 months longer (ASCO 2007)

– Can carboplatin replace cisplatin?• Carboplatin-based regimens in patients with normal RFT

have ORRs in the range of 30-40%• But CR rates are lower• Shorter median OS of 8-10 months• Only be used when RFT not fit for cisplain

118

Palliative chemotherapyPalliative chemotherapy

• Second-line treatment–Ifosfamide ORR 20% (CR 9%, PR 11%)

(JCO 1997)–Paclitaxel, weekly ORR 10% (PR 10%); MS

7.2m (JCO 2002)–Docetaxel ORR 13% (PR 13%); MS 9m

(BJC 1998)–Pemetrexed ORR 28% (CR 6%, PR 21%);

MS 9.6m (JCO 2006)

119

Palliative chemotherapyPalliative chemotherapy

• Novel agents– Trastuzumab + paclitaxel, carboplatin and

gemcitabine (ASCO 2005)• Phase II trial of 32 HER2-positive patients• RR 73%• But survival similar to combination without Trastuzumab

– Bevacizumab + GC (ASCO 2009)• Phase II trial• ORR 58% (CR 14%, PR 44%)• Stable disease 30%• DVT/PE 21 %, 42% stopped chemotherapy due to

toxicities

120

What is QOL for different forms of treatment for invasive bladder tumor?

• No randomized prospective HRQL study

• The overall HRQL after cystectomy remains good in most patients, whichever type of urinary diversion is used

• Some data suggests that continent diversions produce a better HRQL – Body image, social, sexual and physical

function

121

What is the evidence of urethral surveillance after cystectomy?

• Urethral washes and cytology are not recommended– MSKCC– They review 24 patients who had urethral

recurrence • followed by routine urethral wash cytology • those not followed by urethral wash cytology and

presented with bleeding or urethral discharge• No significant survival difference in patients

followed and not followed with urethral washing

122

What is the treatment of urethral occurrence?

• Standard treatment remains total urethrectomy• Subtotal urethrectomy sparing the meatus

– Has been abandoned• 27% of glanular urethra involvement rate in total

urethrectomy series• Documented reports of late recurrence at urethral meatus

• In patients with orthotopic diversion– Can attempt endoscopic management +/-intravesical therapy– Or neobladder has been reconstructed

• CIS in the urethra > BCG instillations have shown success rates of 80%

• In distant disease > systemic chemotherapy

123

What is the Survival data regarding patients with urethral recurrence?

• Survival after urethral recurrence has generally been disappointing

• Median survival : 28 months

• Invasive disease and symptomatic presentation may carry a worse prognosis

124

Upper tract recurrenceUpper tract recurrence

125

What is the incidence of upper tract involvement?

• <5% of patients with bladder ca• 1-2% may be bilateral • Following radical cystectomy UUT occur typically

after 3 years • Majority of UUT occur in patients who have been

treated with radical cystectomy for organ confined disease – This may purely reflect the poorer outcome of patients

with extravesical involvement who therefore do not survive long enough to develop UUT

• Risk factors - intramural ureteric involvement and CIS