BLADDER CANCER

Dr. Amina Abdul RahmanJunior Resident

Dept of RadiotherapyMedical College, Calicut

EPIDEMIOLOGY

EPIDEMIOLOGY

• Disease affecting the elderly• Median age of Diagnosis is 70 yrs• Male : Female ratio is 3:1• More for whites than Africans or Hispanics

ETIOLOGY

Etiology

• Cigarette Smoking• Industrial Chemicals :Dye workers, Dry Cleaners, Hair Dyeso-aminophenol is the carcinogenSlow acetylators have more risk• Schistosoma hematobium• Chronic Bladder infection

Etiology

• Bladder calculi• Long term indwelling catheter• Past history of upper urothelial cancers• Chlorinated municipal water• Radiation Exposure• Use of Cyclophosphamide

ANATOMY

PATHOLOGY

Pathology

• Most Common Type is Transitional Cell Carcinoma 93%

Papillary Flat Benign Dyspalsia Malignant Cis Invasive Cancer

Pathology

• Squamous Cell Carcinoma• Adenocarcinoma• Small Cell Cancer• Rhabdomyosarcoma• Lymphoma• Melanoma• Secondaries frm other sites• Primary UB Pheochromocytoma

STAGING

Nodal Staging

N1 : single first echelon lymph node

N2 : multiple first echelon lymph nodes

N3 : second echelon lymph nodes

MOLECULAR GENETICS

Molecular Genetics

• LOH of TS on Ch 9 - earliest• The loss of TS gene p53 on Ch 17 for NIBC to

MIBC• P53 accumulation in nucleus is an

independent bad prognostic factor• Aneuploid DNA content in NIBC, more risk for

progression• IHC for microvessel density, marker for Tr

angiogenesis

MULTIFOCAL TUMORS

Metachronous / Synchronous Disease

Field Cancerisation

Whole urothelium exposed to carcinogen

Transforms independent separate groups of cells

Multiple tumors which are genetically unrelated

Metachronous / Synchronous Disease

Clonality

Single carcinogenic insult to a single cell

Clones from this cell spread thro out the UB

Topographically distinct lesions but genetically related

CLINICAL FEATURES

Clinical Features

• Painless gross hematuria 75%

• Symptoms of Bladder irritation

• Advanced disease : pelvic pain, ureteral obstruction, HUN, Rectal obstruction

INVESTIGATIONS

Investigations

• Urine cytology • Cystoscopy and TURBT

• If sessile lesion , perform further imaging of the pelvis as lesion likely invasive

• If papillary, go ahead with resection

Imaging of the pelvis

• To assess extravesical spread and pelvic LN• MRI is better than CT• Imaging of the upper pelvis : CT urogram for

ruling out synchronous lesions• Chest Xray/ CT Thorax to rule out mets• Bone scan if symptomatic or raised ALP• FDG PET for LN mets or Distant mets

TURBT

TURBT

• Bimanual examination under anesthesia before and after

If mass palpable : invasiveMobile mass : T3Fixed mass : T4• Sample muscle within the area of tumor to assess

invasion• Sample biopsies from multiple sites and prostatic

urethra to r/o CIS only if high grade/sessile/in bladder neck

TURBT

Pathologist should comment on:1. If muscle is present in the sample or not2. If muscle is invaded or not3. If CIS is present4. If LVI is present

CLASSIFICATION

Classification

• NMIBC : Ta, Tis, T1

• MIBC : T2 onwards, any N

• Metastatic disease : M1

NON MUSCLE INVASIVE BLADDER CANCER

Ta

Low grade• 15% risk of recurrence and 0.2% risk of

progression• TURBT f/b immediate single intravesical

instillation of mitomycin within 24 hrs• Repeat at 6 weeks if high risk for recurrence• Cystoscopy 3 monthly

Ta

• High gradeIntravesical induction therapy with BCG 1-2 weeks after resection (upto 2 inductions)Cystoscopy at 3 monthly intervalsMaintainence therapy is recommended 3 weekly instillations for a year

T1

• After T1 disease is diagnosed from a TURBT, a second TURBT is strongly recommended

• But if the following factors are present:1. Multifocal lesions2. LVI3. Recurring after BCG Directly do cystectomy and not repeat TURBT

T1

Second TURBT

residual disease no residual disease

Intravesical BCG Intravesical BCG or or Cystectomy Mitomycin

Tis

• Considered high grade with high risk for progression

• Treated with intravesical BCG

INTRAVESICAL CHEMO/IMMUNOTHERAPY

Immunotherapy

• Bacillus Calmette Guerin, attenuated form of M. bovis

• Acts as immune stimulant• stimulates cellular response releasing

cytokines IL-1,2,6,8,TNF and IFN gamma• S/E : Urinary frequency ,dysuria, hematuriaArthralgia, rash, feverPneumonitis, hepatitis, prostatitis, sepsis

Intravesical BCG

• Given 1-2 weeks after resection• Patient is dehydrated over night• Urine is voided completely • 50 mg of TICE in 50cc of 0.9% NS is instilled via

catheter• Patient is asked to void urine after 2 hours• Weekly for 6 weekly• Maintenance is 3 weekly for a year for high risk

and CIS

Intravesical chemotherapy

• Mitomycin is the recommended chemo agent• Dose is 40mg in 20cc sterile water• Given immediately after resection and then 6

weeks later• Other agents : doxorubicin, epirubicin,

valrubicin, thiotepa• Interferon Alfa2b

Intravesical chemotherapy

• CI : bladder perforation, myelosuppression

• S/E : skin rash, irritative bladder symptoms, myelosuppression

Intravesical therapy CHEMOTHERAPY IMMUNOTHERAPY

Directly kills tumor cells Stimulates patient’s immune response to fight the tumor

Increasing dose increases cell killing

Increasing dose will only suppress patient’s immune response

Penetrates bladder by diffusion

Attaches by receptors

When given within 6 hours of resection prevents tumor seeding

Immediate immunotherapy is very toxic

Low grade tumor more responsive to chemo

High grade tumors are more responsive

PROGNOSIS

SURVEILLANCE

Surveillance

• Use cystoscopy and urine cytology• Low grade Ta Cystoscopy at 9 months, then annually thereafter• High grade Ta and T1:Cystoscopy at 3-6 monthly intervals for 2 years, then at increasing intervals

MUSCLE INVASIVE BLADDER CANCER

MIBC

• Start treatment after full metastatic work up• Treatment options:Radical CystectomyPartial CystectomyNeoadjuvant/Adjuvant ChemotherapyDefinitive ChemoRT

RADICAL CYSTECTOMY

Radical Cystectomy

Cystoprostatectomy + Urinary diversion procedure + Pelvic Lymph Node DissectionAdvocates of Surgery argue that:1. There is good long term survival rates2. Morbidity and mortality due to surgery have

now decreased3. Provides for accurate pathological T and N

staging

Radical Cystectomy

• Males :Urinary Bladder, Prostate, Seminal Vesicles, Visceral peritoneum, perivesical adipose tissue and lower ureter• Females:Bladder, uterus, cervix, vaginal cuff, FT, ovaries, anterior peritoneum Followed by a Urinary diversion procedure

Urinary Diversion

• Incontinent :

Ileal conduit : 15 cm of distal ileum to which both ureters are anastomosed, stoma is attached to the ant abd wall

Ileal Conduit

Incontinent urinary diversion

Urinary Diversion

• Continent :1. Stomal reservoir that require intermittent

catheterisationIndiana pouchKoch pouch2. Orthotopic NeobladderAnastomosed to remaining distal urethra

Indiana Pouch

Orthotopic Neobladder

Pelvic LN Dissection

• Extended pelvic LN dissection is beneficial• Remove all first echelon nodes the

hypogastric, obturator, int and ext iliac, pre sciatic and presacral LN

• Also extended to incl common iliac, lower para aortic, paracaval, intr aortic LN

Complications of Surgery

Early• Urinary Leakage• Lymphatic LeakageLate• Recurrent UTI• Stomal infarction/strictures/retraction• Parastomal Hernia• Ureteric ischemic stricture

Metabolic problems of Urinary Diversion

• Hyperchloremic Metabolic Acidosis• Hypokalemia• Hypocalcemia• Hypomagnesemia • Abnormal Drug Kinetics

Partial Cystectomy

• Done when invasive tumor can be removed with a 2 cm margin of normal mucosa without compromising continenence or capacity

• MC site where it can be done is Dome• CI at neck and trigone• LN dissection should also be done

NEOADJUVANT CHEMO

Neoadjuvant Chemotherapy

Advantages :1. Invivo drug sensitivity testing2. Shrinks down tumor for easier surgery3. Delivers full dose of systemic chemotherapy

upfront thus addressing micrometastatic disease early

Neoadjuvant Chemotherapy

• Supported by Two large RCTs• Grossman et al studied 317 pts with T2 to T4a

disease

Surgery alone MVAC x 3 cycles

Surgery• Duration of Follow Up : 11 years

SWOG MVAC Trial

• Chemo regimenMethotrexate 30mg/m2 D1, D15, D22Vinblastine 3mg/m2 D2, D15, D22Doxorubicin 30mg/m2 D2Cisplatin 70mg/m2 D2• Median survival 77 months in the chemo arm

vs 46 months in the surgery alone arm• 38% had complete pathologic response

BA06 30894 CMV Trial

976 patients with T2-T4a disease

CMV x 3 cycles Surgery or ChemoRT

Surgery or ChemoRT• Duration of follow up : 8 years

BA06 30894 CMV Trial

• Chemo RegimenMethotrexate 30mg/m2 iv bolus D1, D8Vinblastine 4mg/m2 D1 D8Cisplatin 100mg/m2 D2• Statistically significant 16% reduction in risk of

death

MVAC Vs DD- MVAC

• DD-MVAC Q14daysMethotrexate 30mg/m2 iv push over 2-3 min D1Vinblastine 3mg/m2 slow iv push D1Doxorubicin 30mg/m2 slow iv push over 15min D1Cisplatin 70mg/m2 inf over 4 hrs D1Pegfilgrastim 24-48 hrs later• Grade 3 or 4 toxicity in only 11%• Complete response of 43%

ADJUVANT CHEMOTHERAPY

Adjuvant Chemotherapy

• Not enough evidence supporting adj chemo in UB cancer

• It is justified in patients with high risk for relapse, if neoadj chemo was not given

1. T3 or more2. Node positive3. LVI present4. >20% cells are positive for p53

Adjuvant RT

• No strong evidence supporting RT in the adj setting

• Maybe given in cases of high risk for locoregional relapse :

1. Positive surgical margins2. Tumor spillage• 40-45 Gy ± Cisplatin , if no NAC was given

DEFINITIVE CHEMO RT

Definitive ChemoRTRationale:1. Micrometastases is common early in the

disease history2. This is the optimal time to treat potential

micromets during RT, before gross mets appear

3. RT induces vascular sclerosis decreasing access of chemo to tumor later

4. CCRT acts as radiosensitisers5. Post op patients may not tolerate CCRT due to

surgical morbidity

Ideal Candidates for CCRT

1. T2 to T3a2. Node negative3. No HUN/ disease at or near ureteric orifice4. No trigone involvement5. Unifocal dis6. No extensive CIS7. Complete TURBT8. Good bladder function

Definitive CCRT

Complete TURBT

40 Gy CCRT with 2 cycles Cisplatin Q3wkly

Cystoscopy ( 3wks later)

Disease No Disease

Cystectomy 25 Gy with 1 cycle Cisplatin

RTOG 89-03 Shipley et al

• 123 pts with cT2 to T4a MIBC• 3 cycles MCV f/b definitive CCRT Vs definitive CCRT alone• OS was similar in both arms 49%• CR of 77%

Analysis of Definitive CCRT Trials

• 4 major RTOG trials• Complete response rate ranging from 59% to

81%• 80% of long term survival maintained intact

bladder• Low rates of grade 3 toxicity, no late grade 4

toxicity

RTOG 05-24

• Ongoing Study• Continuous – course chemoradiation instead

of split course RT • Rationale : to prevent time gap for tumor cells

to repopulate

Simulation

• Patient supine with bladder empty• Foley’s catheter is inserted and 30 ml of

contrast injected• Rectum should be empty, Rectal tube with

barium to visualize the rectum• 2 phases used, first whole pelvis with nodes

f/b boost to tumor

Radiation Fields

• 4 field technique

• AP-PA field:Superior border : L5-S1Inferior border : bottom of obturator foraminaLateral border : 1.5 – 2 cm lateral to bony pelvis

AP - PA

Radiation fields

• Lateral fieldsAnterior border : anterior bladder with a margin with 1.5 – 2cmPosterior border : 2-3 cm posterior to bladder

Lateral Fields

Boost Fields

• For treating the tumor site alone• Exact location of tumor should be obtained

from Pre TURBT imaging• Full bladder is preferred to min dose to bowel

and remaining bladder

Boost Field

Radiation Toxicity

• Acute effects:DysuriaUrgencyFrequency Diarrhoea

Radiation toxicity

• Late effects:Chronic irritative cystitisHemorrhagic cystitisBladder contractureRectal strictureSmall bowel obstruction

79% of patients had normal bladder fn at 10 yrs

PALLIATIVE CHEMOTHERAPY

Palliative Chemotherapy

• Benefits only those with good PS, no visceral mets

• 2 commonly used regimens are 1. DD-MVAC2. GC• GC is not inferior to MVAC, with more toxic

deaths in MVAC

PALLIATIVE RT

Palliative RT

• Beneficial for pain or hematuria• Short high dose per fraction schedules for ill

patients with large disease burden• For better GC patients, longer schedules

concurrent with chemotherapy maybe tried

Summary

• NMIBC (Ta, Tis, T1)TURBTIntravesical therapyClose follow upCystectomy in selected cases

Summary

MIBCT2, T3, T4a :• Neoadj chemo f/b cystectomy• Adj chemo/RT in selected cases if no NAC was

given• Definitive ChemoRT• Patients with poor PS : TURBT alone,

ChemoRT, chemo alone

Summary

• T4b or Node positive Neoadj Chemo, assess for response, then give further chemo or RT/ cystectomy

THE END