Management of Urinary Bladder

By Dr Parneet Singh

Moderator-Dr Anirudh K. Punnakal

Stage Wise Treatment

Aim of Management of Bladder cancers- Stage wise•Superficial bladder cancer- prevent recc and progression to muscle invasive cancer.•Muscle invasive bladder cancer- patient selection for cystectomy and for bladder preservation protocol and for integrated systemic chemotherapeutic approach.•Metastatic bladder cancer- palliation and quality of life.

Urinary Bladder Cancer

Superficial cancer (75%)

Musc. Invasive cancer(20%) Metastatic cancer

(<5%)

Petrovich JCO 2001

Superficial Bladder cancer

Superficial Bladder Cancer

1. Non-invasive papillary tumor (Ta)

2. Tx invading lamina propria (T1)

3. High grade CIS (Tis)

Risk Stratification on the basis of prognostic factors

1. High grade or P.D tx.2. Co-existant CIS or dysplasia in random mucosal biopsies.3. Multiple or multicentric tumors.4. Rapidly recc. Tumors.5. Lamina propria invasion.6. Ts>3cm. 7. Prostatic urethral involvement.

•Low risk- single, Ta, G1, <3cm in diameter.15% Recurrence Risk(RR)• Intermediate Risk- Ta-1, G1-2, >3cm in dia.RR-38%• High Risk- T1, G3, Multifocal or highly recurrent, CIS.RR-61%

Sylvester 2006 Eur Urol

Treatment Options For Superficial Bladder Cancers

1. TURBT

2. Intravesical Therapy

3. Laser

4. Photodynamic Therapy

5. Cystectomy.

Trans Urethral Resection of Bladder Tumor(TURBT)

• Under GA/Regional Anasthesia

• Remove all visible tumors

• Bimanual examination must before and after

• Ideal Method – 2 specimen to be collected

• First superficial portion of the tumour• Deep portion along with underlying bladder muscle

The base of resection site is fulgrated

TUR of Bladder Tumor (TURBT)

Intravesical Therapy

• Indications:1. Lamina propria invasion.2. High grade Ta disease/Ta>3cm.3. All cases of Carcinoma in situ.4. Extravesical (Prostatic urethra inv)5. Post resection cytology positive.6. Multiple tx rec or rapidly rec.

All cases of superficial bladder cancer except low risk cases and all cases of superficial recurrences.

Increase Recurrence free interval by 38 %

Huncharek M JCE 2000

Perlis M 2013 Eur Urol

Agents Used1. BCG (Most common agent)

2. MMC

3. Doxorubicin/Epirubicin/Valrubicin.

4. Interferon

5. Thiotepa

6. Gemcitabine Can be used Perioperatively or as adjuvant therapy

Administration of BCG• Wait atleast for 10-14 days after invasive procedures.

• Avoid intake 4 hrs before instillation; empty bladder.

• Urethral catheter to drain bladder; abort procedure if traumatic.

• Recon. BCG suspension instilled slowly by gravity –don't force .

• Patient retains suspension upto 2 hrs

• Void in seated position to avoid splashing.

• For 6hrs after, disinfect voided urine with bleach.

• Excessive fluid intake not necessary.

Schedule of BCG admsistration• Usually started 2 weeks after invasive procedure

• Usually 2 inductions given without complete response

• If complete response then continued for 6 weeks

• Some suggest the benefit of maintenance therapy

• Dose reduction advised if local symptoms persist

NCCN 2015

Maintenance Therapy 3 week BCG course at Month

3rd 6th 12th 18th 24th 30th ,36th ,48th ,60th

Toxicities• Bladder irritability(dysuria,cystitis,urgency,frequency)(50-60%)

• Flu like symptoms-maliase,fever chills(45%)

• Hematuria (30-35%)

• Nausea &Anorexia(15-20%)

• Arthritis (20%)

• Headache

• BCG sepsis(1-3%)

• UTI(<5%)

• Contracted bladder(<5%)Rakesh K IJU 2008

LASER• Tumor ablation but no pathological analysis• Hence mostly used for treating recurrences.• Neodymium-Yittrium-Aluminium-Garnet Laser most

commonly used.

• Advantages over TUR:1. Less bleeding

2. Less invasive (can use flexible cystoscope)

3. Less postoperative irritation.

Photodynamic Therapy• Combines non toxic photo sensitivity dyes + Visible light to

destroy cancer cells.

• Indication- CIS, Ta, T 1 tumour

• Photoforphyrin-II – 2 mg/kg body weight is given

• After 48 hrs –bladder illuminated with red light (630 mm)

• Cascade of photo chemical reaction- generate cytotoxic molecular oxygen.

• Not routinely used

Muscle invasive bladder cancer

Modalities

• Surgery

• Radiation

• Chemo-radiation

• Chemotherapy

Management of Muscle Invasive Bladder Cancer

Radical Cystoprostatectomy +/- urethrectomy- MalesAnterior Exenteration –Females+ Bilateral Pelvic nodal dissection

Bladder Preservation Approaches.

Partial Cystectomy• Indications

• Solitary lesion• Bladder dome• Less than 2 cm• Complete excision can be done• Possible with 2 cm margin• Adequate bladder capacity• No CIS• Pt reliable for follow up

• B/L pelvic LN dissection also done till common illiac LN

NCCN 2015

Radical Cystectomy• Radical cystectomy is the gold standard for surgical

management of patients with muscle invasive bladder cancer.

• In males prostate is removed with bladder and is the equivalent of an anterior exenteration with a pelvic lymphadectomy

• In women radical cystectomy for muscle invasive bladder cancer is same as anterior exenteration with pelvic LN dissection.

• It includes removal of the uterus, fallopian tubes, ovaries, bladder, urethra, and a segment of anterior vaginal wall with LN dissection

Urinary diversion: Ileal Conduit• Urine empties

through stoma• No reservoir

therefore incontinent

Urinary diversion: Ileal reservoir

• Kock’s pouch

• Reservoir created from ascending colon and terminal ileus

Urinary Diversion: Ureterostomy

• UreterostomyDivert urine

directly to skin opening

Must wear bag or pouch after surgery

Lymphadenectomy• Pelvic lymphadenectomy done to asses the local extent

of disease.

• Usually pelvic LN-internal illiac,external, illiac,obturaor and common illiac removed

• Extended lymph node dissection should include the distal para-aortic and paracaval lymph nodes as well as the presacral nodes

• Lymph nodes positive disease needs post op RT

• At least 15 nodes should be removedDhar 2008 J Urol

Leissner 2004 J Urol

Bladder Preservation Approaches

1. Radical radiotherapy.

2. Concurrent chemoradiotherapy.( European approach)

3. Induction chemoradiotherapy f/b consolidation chemoradiotherapy.(RTOG/MGH protocol)

4. Neoadjuvant chemotherapy f/b chemoradiotherapy.

5. Chemoradiotherapy f/b adjuvant chemotherapy.

Radiotherapy• Traditionally RT alone was given only for unfit/older pts.

• Definitive radiotherapy gives consistent and reproducible effects.

• It’s a viable option for bladder preservation.

• Results are better in younger, fitter and in those without extravesical disease.

• Poor prognostic factors in Radical cystectomy hold true for radical radiotherapy series also.

Preoperative radiotherapy• Tumor size reduction in locally advanced ,muscle invasive disease

• Downstaging of disease

• Decrease in incidence of local recurrence following radical cystectomy

• Decrease in incidence of distant metastasis

• Improvement of survival

• No increase in incidence of surgical complications.

• Disadvantage : i) Possibility of problems in interpreting pathologic finding in cystectomy

& lymphadenectomyii) Possibility of side effects of operating on previously irradiated tissue

• Dose schedule - 40 - 50 Gy / 4 – 5 wksRodel C JCO 2002

Efstathiou Eur Ural 2012

Post operative radiotherapy• Indications – i) Extravesical disease ii) Positive resection margins iii) Pelvic LN involvement iv) Perinodal extension

• Advantage – Availability of pathologic staging

• Allows administration of adjuvant irradiation to those having high probability of tumor recurrence

• Disadvantage- increased small intestine toxicity

• Dose schedule- 40-50 Gy/ 5-6 weeks @ 1.8-2Gy/ #

MIllikan JCO 2001

Ideal candidate for definitive Radiotherapy

• Disease confined to the bladder

• With good bladder function

• cT2 tumor

• No associated CIS

• Willingness for prolonged course of therapy & regular follow up

Cozzarini IJROBP 1999

Ideal candidate for definitive Radiotherapy

• Disease confined to the bladder

• With good bladder function

• cT2 tumor

• No associated CIS

• Willingness for prolonged course of therapy & regular follow up

Cozzarini IJROBP 1999

Contraindications of pelvic Radiotherapy

• Pt with active inflammatory bowel disease

• Previous pelvic irradiation

• Pts with extensive bladder CIS are at high risk for tumor recurrence after RT so cystectomy should be done

Bladder : EMPTY or FULL • Empty bladder –• More reproducible• More comfortable to patient• Overall irradiated volume is smaller.• • Full bladder – • Displaces small intestine & some part of rectum out of

radiation portals

• AT Max• Urine voiding then treat after 15 min

Conv. Radiation Portals• ANTERIOR- POSTERIOR FIELDS

:

• Superiorly -L5-S1 interface,

• Inferiorly – Lower border of obturator foramen

• Lateraly – 1.5- 2 cm outside the bony pelvic wall

• Anterior field should not include femoral heads & neck.

• Upper corners can be shielded to reduce small bowel volume.

In 4 field Tech. LATERAL FIELDS • Superior and inferior

borders same

• Anterior border- 1.5-2 cm in front of anterior bladder wall as seen on imaging study

• Posterior border – 2.5 cm posterior to the most posterior aspect of the bladder and falls within the rectum

Two phase approach

• Phase I - • The whole pelvis• The pelvic lymph nodes To include• The whole Bladder• Proximal urethra• Any extravesical disease spread• Any region deemed to be at risk of microscopic disease

spread.

Boost fields

• Phase II

• Either The whole bladder or• Only the involved part of bladder with at least 2

cm margin• Techniques 1) 2 lateral fields 2) oblique fields

Dose Fractionation Schedule • 1.8- 2 Gy / #, to a total dose of 45 – 50 Gy to the

whole pelvis

• Followed by a boost to smaller volume to a combined total dose of 60-65 Gy

• In expanding the CTV to the planning target volume (PTV), accepted standard practice is to add isotropic margins of 1.5 to 2 cm uniformly around the bladder or bladder tumor in three dimensions.

• Allow for organ motion and for errors in target delineation and daily treatment set-up.

• ICRU 62 advocates subdivision of treatment margins into

• Internal margins (IM), to account for variations in the size, shape, and position of the organ,

• Set-up margins (SM), to account for uncertainties in patient positioning and beam arrangement

Field at cranial End

Mid Field

Field at caudal End

Palliative radiotherapy

• Rapid resolution of symptoms

• Severe gross hematuria

• Pelvic pain

• Ureteral obstruction.

• Dose schedule – 10 Gy / single fraction to pelvis.

Patient Care During RT• High fluid intake

• Skin care

• Diarrhea – oral medications, suspension of treatment

• Cystitis / urinary frequency- urine for bacteriological examination

Side effects• ACUTE TOXICITY : • Cystitis – frequency, urge incontinence, dysuria.(55-

60%)• Diarrhea(30-40%)• Mild proctitis(25%)

• LATE SEQUELAE:• Teleangiectasia of bladder mucosa• Hematuria• Rectal bleeding• Contraction of bladder• Reduced bladder capacity

NCCN 2015

Comparsion cystectomy & bladderpresevation protocols.

Survival is equivalent

Chemotherapy

Chemotherapy• NEOADJUVANT

• Down staging• Inoperable• Rx of micrometastasis

• CONCURRENT CHEMO

• ADJUVANT

• Some studies showed increased survival.

Chemotherapy FOUR – DRUG COMBINATION M-VAC

• Methotrexate 30 mg/m2 – 1,15 & 22• Vinblastine 3 mg/m2- 2,15 & 22 Q28 days for 6

cycles• Adriamycin 30 mg/m2 on day 2• Cisplatin 70 mg/m2 on day 2•

• Gemcitabine +cisplatin• Gem-1000mg/m2-D1,8,15 Q28 days for 6 cycles• Cisplatin-D1or2

• For concurrent inj Cisplatin 40mg/m2

Chemotherapy for bladder cancer Combination chemotherapy.

RR

MVAC 10-25%

Gem/ Cisplatin 40-50%

Gem/ Carboplatin 65%

Taxol / Carboplatin 40-60%

Von Dar Massse 2000 JCO

Adjuvant Chemotherapy• Local definitive treatment is not delayed.

• Better patient selection on surgical and pathological findings

• 5 RCT addressed this issue of adjuvant chemotherapy after local therapy either after Sx or RT/RTCT

Author N Standard arm Adjuvant arm

results

Skinner et al 91 cystectomy C+CAP Benefit

Stockle et al 49 cystectomy C+MVAC Benefit

Struder et al 77 cystectomy C+CDDP No benefit

Freiha et al 55 cystectomy C+CMV Benefit

Bono et al 83 cystectomy C+CM No benefit

Follow up

NCCN 2015

Thank You

Prognostic Factors• Tumor stage• Tumor morphology• Absence of concomitant Tis• Presence of intravesical Vs extravesical tumor• Completeness of TURB• Solitary Vs multiple bladder tumors• Presence of ureteric obstruction• Presence of complete response after EBRT• Radiation dose