epidemiology, staging, management of bladder cancer including intravesical chemotherapy, chemoRT and surgery

1. BLADDER CANCER
Dr. Amina Abdul Rahman
Junior Resident
Dept of Radiotherapy
Medical College, Calicut

2. EPIDEMIOLOGY

3. 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

4. ETIOLOGY

5. Etiology
• Cigarette Smoking
• Industrial Chemicals :
Dye workers, Dry Cleaners, Hair Dyes
o-aminophenol is the carcinogen
Slow acetylators have more risk
• Schistosoma hematobium
• Chronic Bladder infection

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

7. ANATOMY

11. PATHOLOGY

12. Pathology
• Most Common Type is Transitional Cell
Carcinoma 93%
Papillary Flat
Benign Dyspalsia
Malignant Cis
Invasive Cancer

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

14. STAGING

18. Nodal Staging
N1 : single first echelon lymph node
N2 : multiple first echelon lymph nodes
N3 : second echelon lymph nodes

20. MOLECULAR GENETICS

21. 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

22. MULTIFOCAL TUMORS

23. Metachronous / Synchronous Disease
Field Cancerisation
Whole urothelium exposed to carcinogen
Transforms independent separate groups of cells
Multiple tumors which are genetically unrelated

24. 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

25. CLINICAL FEATURES

26. Clinical Features
• Painless gross hematuria 75%
• Symptoms of Bladder irritation
• Advanced disease : pelvic pain, ureteral
obstruction, HUN, Rectal obstruction

27. INVESTIGATIONS

28. 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

29. 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

30. TURBT

31. TURBT
• Bimanual examination under anesthesia before
and after
If mass palpable : invasive
Mobile mass : T3
Fixed 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

39. TURBT
Pathologist should comment on:
1. If muscle is present in the sample or not
2. If muscle is invaded or not
3. If CIS is present
4. If LVI is present

40. CLASSIFICATION

41. Classification
• NMIBC : Ta, Tis, T1
• MIBC : T2 onwards, any N
• Metastatic disease : M1

44. NON MUSCLE INVASIVE
BLADDER CANCER

45. 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

46. Ta
• High grade
Intravesical induction therapy with BCG 1-2
weeks after resection (upto 2 inductions)
Cystoscopy at 3 monthly intervals
Maintainence therapy is recommended 3 weekly
instillations for a year

47. T1
• After T1 disease is diagnosed from a TURBT, a
second TURBT is strongly recommended
• But if the following factors are present:
1. Multifocal lesions
2. LVI
3. Recurring after BCG
Directly do cystectomy and not repeat TURBT

48. T1
Second TURBT
residual disease no residual disease
Intravesical BCG Intravesical BCG
or or
Cystectomy Mitomycin

49. Tis
• Considered high grade with high risk for
progression
• Treated with intravesical BCG

50. INTRAVESICAL
CHEMO/IMMUNOTHERAPY

51. 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, hematuria
Arthralgia, rash, fever
Pneumonitis, hepatitis, prostatitis, sepsis

53. 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

55. 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

56. Intravesical chemotherapy
• CI : bladder perforation, myelosuppression
• S/E : skin rash, irritative bladder symptoms,
myelosuppression

57. 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

58. PROGNOSIS

62. SURVEILLANCE

63. 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

64. MUSCLE INVASIVE
BLADDER CANCER

65. MIBC
• Start treatment after full metastatic work up
• Treatment options:
Radical Cystectomy
Partial Cystectomy
Neoadjuvant/Adjuvant Chemotherapy
Definitive ChemoRT

66. RADICAL CYSTECTOMY

67. Radical Cystectomy
Cystoprostatectomy + Urinary diversion
procedure + Pelvic Lymph Node Dissection
Advocates of Surgery argue that:
1. There is good long term survival rates
2. Morbidity and mortality due to surgery have
now decreased
3. Provides for accurate pathological T and N
staging

68. 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

69. Urinary Diversion
• Incontinent :
Ileal conduit : 15 cm of distal ileum to which
both ureters are anastomosed, stoma is
attached to the ant abd wall

70. Ileal Conduit

71. Incontinent urinary diversion

72. Urinary Diversion
• Continent :
1. Stomal reservoir that require intermittent
catheterisation
Indiana pouch
Koch pouch
2. Orthotopic Neobladder
Anastomosed to remaining distal urethra

73. Indiana Pouch

74. Orthotopic Neobladder

75. 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

77. Complications of Surgery
Early
• Urinary Leakage
• Lymphatic Leakage
Late
• Recurrent UTI
• Stomal infarction/strictures/retraction
• Parastomal Hernia
• Ureteric ischemic stricture

78. Metabolic problems of Urinary
Diversion
• Hyperchloremic Metabolic Acidosis
• Hypokalemia
• Hypocalcemia
• Hypomagnesemia
• Abnormal Drug Kinetics

79. 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

80. NEOADJUVANT CHEMO

81. Neoadjuvant Chemotherapy
Advantages :
1. Invivo drug sensitivity testing
2. Shrinks down tumor for easier surgery
3. Delivers full dose of systemic chemotherapy
upfront thus addressing micrometastatic
disease early

82. 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

83. SWOG MVAC Trial
• Chemo regimen
Methotrexate 30mg/m2 D1, D15, D22
Vinblastine 3mg/m2 D2, D15, D22
Doxorubicin 30mg/m2 D2
Cisplatin 70mg/m2 D2
• Median survival 77 months in the chemo arm
vs 46 months in the surgery alone arm
• 38% had complete pathologic response

84. 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

85. BA06 30894 CMV Trial
• Chemo Regimen
Methotrexate 30mg/m2 iv bolus D1, D8
Vinblastine 4mg/m2 D1 D8
Cisplatin 100mg/m2 D2
• Statistically significant 16% reduction in risk of
death

86. MVAC Vs DD- MVAC
• DD-MVAC Q14days
Methotrexate 30mg/m2 iv push over 2-3 min D1
Vinblastine 3mg/m2 slow iv push D1
Doxorubicin 30mg/m2 slow iv push over 15min
D1
Cisplatin 70mg/m2 inf over 4 hrs D1
Pegfilgrastim 24-48 hrs later
• Grade 3 or 4 toxicity in only 11%
• Complete response of 43%

87. ADJUVANT CHEMOTHERAPY

88. 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 more
2. Node positive
3. LVI present
4. >20% cells are positive for p53

89. Adjuvant RT
• No strong evidence supporting RT in the adj
setting
• Maybe given in cases of high risk for
locoregional relapse :
1. Positive surgical margins
2. Tumor spillage
• 40-45 Gy ± Cisplatin , if no NAC was given

90. DEFINITIVE CHEMO RT

91. Definitive ChemoRT
Rationale:
1. Micrometastases is common early in the
disease history
2. 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 radiosensitisers
5. Post op patients may not tolerate CCRT due
to surgical morbidity

92. Ideal Candidates for CCRT
1. T2 to T3a
2. Node negative
3. No HUN/ disease at or near ureteric orifice
4. No trigone involvement
5. Unifocal dis
6. No extensive CIS
7. Complete TURBT
8. Good bladder function

93. 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

94. 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%

95. 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

96. RTOG 05-24
• Ongoing Study
• Continuous – course chemoradiation instead
of split course RT
• Rationale : to prevent time gap for tumor cells
to repopulate

97. 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

98. Radiation Fields
• 4 field technique
• AP-PA field:
Superior border : L5-S1
Inferior border : bottom of obturator foramina
Lateral border : 1.5 – 2 cm lateral to bony pelvis

99. AP - PA

100. Radiation fields
• Lateral fields
Anterior border : anterior bladder with a margin
with 1.5 – 2cm
Posterior border : 2-3 cm posterior to bladder

101. Lateral Fields

102. 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

103. Boost Field

104. Radiation Toxicity
• Acute effects:
Dysuria
Urgency
Frequency
Diarrhoea

105. Radiation toxicity
• Late effects:
Chronic irritative cystitis
Hemorrhagic cystitis
Bladder contracture
Rectal stricture
Small bowel obstruction
79% of patients had normal bladder fn at 10 yrs

106. PALLIATIVE CHEMOTHERAPY

107. Palliative Chemotherapy
• Benefits only those with good PS, no visceral
mets
• 2 commonly used regimens are
1. DD-MVAC
2. GC
• GC is not inferior to MVAC, with more toxic
deaths in MVAC

108. PALLIATIVE RT

109. 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

110. Summary
• NMIBC (Ta, Tis, T1)
TURBT
Intravesical therapy
Close follow up
Cystectomy in selected cases

111. Summary
MIBC
T2, 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

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

113. THE END