management of bladder cancer

1. Bladder Cancer
Dr Ali Azher, MD (Radiation Oncology)
The Gujarat Cancer & Research Institute, BJ Medical College,
Ahmedabad, Gujarat
aliazhermuhammed@gmail.com

2. Introduction
• Three major categories
• Non muscle invasive bladder cancer (NMIBC) 75%
• Not penetrated epithelial basement membrane
• Ta to T1
• Muscle invasive bladder cancer (MIBC) 25%
• T2 or higher
• Poor prognosis
• Metastatic cancers

3. Quick review
• Risk factors- smoking, aromatic amines, nitrites/nitrates,
Cytoxan exposure, aniline dyes, Schistosoma haematobium
infection, chronic indwelling catheter (e.g. in patients with
spinal cord injury)
• Transitional Cell Carcinoma –93%
• Squamous Cell Carcinoma 5%
• Most common sites of the tumor are trigone, lateral and
posterior walls, an bladder neck
• Presentation: hematuria, irritative voiding, pelvic pain,
obstructive uropathy, hydronephrosis
• Lymphatic Drainage: hypogastric, obturator, internal and
external iliac, perivesical, sacral, presacral

4. Mutational Landscape
• FGFR 3
• ≥ 70% of Ta
• 10-45% T1 NMIBC
• 15% MIBC
• PI3K
• Low grade Ta 40-50%
• T1 NMIBC & MIBC 20%
• TERT
• Most common genomic alteration
• 60-80% all stages all grades
• Tumor suppressor genes
• TP53, RB1 and CDKN2A
• MIBC

5. • P53 most commonly mutated in MIBC 50%
• Very infrequent in low grade Ta – 1%
• Higher frequency in T1 – 35%
• Small association between P53 positivity & poor prognosis
• Both loss of expression & high level expression of P16 → RB
pathway down regulation
• Adverse prognostic biomarker
• Found in > 50% of MIBC

6. Molecular subtypes
• Similar to Breast Cancer
• Express markers of urothelial differentiation & normal basal
cells of urothelium (luminal & basal)
• Basal tumors – high levels of KRT5, KRT6, KRT14 & CD44
• Luminal – FGFR3, uroplakins

7. • Luminal papillary
• Papillary architecture with lower stage
• FGFR overexpresssion
• Luminal
• Uroplakins UPKs
• Luminal infiltrated
• Lymphocytic inflitration
• High levels of myofibroblast markers
• Chemoresistance
• Basal squamous
• KRT5, KRT6,KRT14, CD44
• Squamous markers TGM1
• Neuro
• Neuroendocrine markers
• TP53, RB1 mutation
• Poorest survival

8. Risk factors
• Gene abnormalities
• Chemical exposure
• Tobacco
• cyclophosphamide
• Chronic irritation
• Indwelling catheter, R/C UTI → SCC
• Schistosoma Hematobium → SCC & UCC
• Pelvic irradiation

9. Field cancer & Multiclonality
• Monoclonality
• Transformed cell gives rise to daughter cells
• Exhibit same genetic changes
• Field cancer
• Urothelium is exposed to same urinary carcinogens →
transformation of many independent urothelial cells
• Multiple tumors, independent multiple sites

10. Management
• NIMBC
• MIBC
• Metastatic Bladder Cancer

12. Jewett-Marshall
Staging(Clinical)
• Stage A: Submucosal invasion but no muscle invasion
• Stage B Bladder wall or muscle invasion
• B1 Superficial
• B2 Deep
• Stage C Extension through serosa into perivesical fat
• Stage D Lymph nodes and other distant metastasis
• D1 regional nodes
• D2 distant nodes and other distant mets
• AJCC T1 TO T4 = JEWETT A TO D
• N AND M PART OF STAGE D

14. NMIBC
• 80% not involve muscularis propria
• Tis, Ta & T1
• 15-20% progress to T2 or greater
• < 5% NMIBC – Mets
• TURBT – Gold Standard
G/T Recurrence rate Progression rate
G1/G2/Ta 50% 5%
G3/T1/CIS/Multifocal 70% 30-50%

15.  Number of tumors
 Tumor size
 Prior recurrence rate
 Presence of CIS
 T stage
 Tumor grade
TURBT specimen
Risk stratification

16. AUA risk stratification
Risk group Features
Low risk  Solitary low grade tumors ≤ 3cm
 Ta G1
Intermediate  Solitary low grade tumors >3cm
 Solitary high gradeTa G2 G3
 Multi focal low grade
 Low grade recurrence within 1 year
 Low grade T1
High risk  High grade T1
 Recurrent high grade Ta
 High grade Ta>3cm
 Multifocal
 Any CIS
 LVI
 High grade prostatic urethral involvement
 Any variant histology
 BCG failure

18. Risk group Recurrence rate % Progression risk %
Low risk
<3cm, Ta, G1, No CIS
15 0.2
Intermediate 38 5
High risk 61 17

19. Low risk
• TURBT
• Flexible Cystoscopy @ 3months of resection
• Negative
• Flexible Cystoscopy 9 months later
• Annually thereafter

20. Adjuvant Intravesical Drug
Therapy
• Lessen the rate of recurrence
• Following TURBT
• Multifocal CIS
• CIS + Ta or T1
• Any grade 3
• Multifocal tumors
• Rapidly recurring after TURBT

21. Drugs
• BCG
• Live attenuated form of mycobacterium bovis
• Triggers an immune response cascade
• Direct tumor cell suppression
• thioTEPA
• Mitomycin-C
• Doxorubicin
• Gemcitabine

22. Schedule
• Once a week for 6 weeks
• Followed by subsequent 3 weeks as induction
• No cystoscopic evidence of recurrence
• Ongoing maintenance BCG 6 week courses every 3-6 months
• Regular cystoscopic suveillance
• 32% reduction in risk of recurrence
• Optimal timing within 6hrs of TURBT

23. Adverse effects
• Frequency
• Dysuria
• Irritating voiding symptoms
• Bladder contracture (long term)
• BCG – fever, joint pain, granulomatous prostatitis, sinus
formation, Disseminated TB, Death
• thioTEPA – myelosuppression
• Mito C skin desquamation/rash
• Doxo GI upset

24. BCG failure
• BCG unresponsive
• Recurrence within 6 months
• BCG refractory
• HG non-muscle-invasive papillary tumor is present at 3 month
• CIS is present at both 3 and 6 months
• HG tumor appears during BCG therapy
• Intolerant
• Severe side effects
• Relapsing
• Recurrence of HG/grade 3 tumor after completion of BCG
maintenance, despite an initial response (1-2years)
BCG+IFNα or GEM or Docetaxel

25. • BCG refractory T1/BCG unresponsive
• Cystectomy
• Preemptive cystectomy
• High grade T1
• >3cm
• Concomitant CIS
• Deep lamina propria invasion
• LVI
• Micropapillary variant histology

26. MIBC
• 20-40%
• 85% of patients will die within 2 years if untreated
• Two school of thoughts
• US model
• UK model

27. Surgery
• Radical cystectomy
• Good long term survival rates
• Lowest local recurrences
• Accurate pathological staging & nodal status
• Timing – delay > 3 months after TURBT undermines patient
survival
• PLND
• Urinary diversions

28. Radical cystectomy
• En bloc removal of pelvic organs anterior to rectum
• Men – bladder, urachus, prostate, seminal vesicles & visceral
peritoneum
• Women - bladder, urachus, ovaries, fallopian tubes, uterus,
cervix, vaginal cuff & anterior pelvic peritoneum
• Lymphadenectomy
• Extended lymphadenectomy is beneficial
• Bilaterally all obsturator, hypogastric, presciatic & presacral LN
• >15 LNs sufficient

29. • Urinary diversions
• Incontinent – standard
• Continent
• Incontinent
• Conduit derived from distal ileum → Ureter anastomosed →
Anterior abdominal wall stoma
• Continent
• To retain continence
• Abdominal – stomal reservoir
• Orthotopic neobladders anastomosed to remaing distal urethra

30. Survival after RC
P Stage Disease Specific Survival
%
OS %
pTa, Tis, T1 82
pT2, pN0
Organ cofined
73 49
pT3-pT4a or pN1-pN2
Non Organ cofined
33 23
LN positive 28 21

31. Complication
• Metabolic complications
• Acidosis
• Vit B12 malabsorption (loss of distal ileum)
• Neuromechanical
• Urinary retention – atonic segment
• Surgical
• Urine leak
• Fecal leak
• Pyelonephritis
• Renal failure

32. Recurrence following RC
• Pelvic
• Within the soft tissue field of exenteration
• 6-9%
• Distant
• Outside the pelvis
• 20-35%
• Urethral recurrence
• New primary tumor occurring in the retained urethra

33. North America model
• Trimodality therapy
• Maximal TURBT
• Chemotherapy
• Radiotherapy
• Split course RT
• 40Gy with synchronous CT → interval cystoscopy → total dose of
64-68Gy
• Selective bladder preservation
• Exit to surgery

35. Contraindications to Bladder
Preservation
• Hydronephrosis
• Multifocal CIS
• Incomplete TURBT
• Non-TCC histology
• Poor bladder capacity/function
• Inability to tolerate chemotherapy

36. Evolution
• RTOG Trials

37. • Bladder preservation is reserved for those with cCR to CRT
• Predictors of successful outcome
• Solitary T2 or T3
• < 6cm
• No hydronephrosis
• Visibly complete TURBT
• No Extensive CIS
• UC histology

38. UK model
• RT single course
• Radical RT after TURBT
• 64Gy in 32# → cystoscopy
• Younger/more fit – surgery
• Older/less fit – RT
Higher rate of bladder preservation
full dose radical RT + synchronous chemotherapy

40. Definitive RT
• Radical RT
• Node negative MIBC
• T2 to T4aN0M0

41. External beam radiotherapy
• 2D conventional
• 3D conformal
• IGRT

42. 2D Conventional
• Phase I
• Phase II

43. Simulation
• Give oral contrast 1 hr before
• Ask patient to voiding urine
• Foley’s catheter inserted immediately after voiding urine
• 7CC Hypaque solution to inflate balloon and pull down at
base of bladder
• This volume is replaced by an equal volume of hypaque
solution plus an additional 25 ml and 10-15 ml of air then
clamp the catheter.
• Hypaque solution- Urographin :NS = 1: 3
• Air will rise to the top & define the anterior extension of
bladder.

44. • Simulator couch & positioned.
• pelvis is straight, relative to the axes of treatment couch.
• Following simulation & radiographic exposure of anterior
fields, rectal contrast may be given & lateral simulation is
exposed.

45. • Empty bladder :
• More reproducible
• More comfortable to patient
• Keep the Overall irradiated volume as small as possible.
• Minimize the risk of geographical miss
• Full bladder:
• Displaces small intestine & some part of rectum out of radiation
portals

46. • Phase I:
• The whole pelvis, encompassing the pelvic lymph nodes,
bladder, and proximal urethra
• Elective irradiation of the pelvic lymph nodes

47. 2D portals
• AP-PA
• Superior :at the L5-S1 disc space
• Inferior : below obturator foramen.
• Laterally:1.5-2 cm to the bony pelvis at its widest section

48. • Lateral field
• Superior & Inferior border same as in AP-PA portal
• Anterior : anterior to bladder with a margin with 1.5 – 2cm
• Posterior : 2-3 cm posterior to bladder

49. Phase II Boost
• PORTALS :
• Anterior –Bladder with a margin of 1-1.5cm
• Lateral – Bladder with a margin of 1-1.5cm
• Oblique– Selected at an angle which spares the rectum
completely and encompasses the bladder with 1.5 cm margin
• FIELDS : 3 fields
• 2 laterals and one anterior
• 2 obliques and one anterior

50. 3D – RT planning
• PLANNING CT
• Supine, arms on chest
• Knee and Ankle immobilization
• Empty Rectum (flatus & feces) – daily microenema
• Empty Bladder 15 minutes before
• Scan is performed with 3 mm slices from the bottom of L5
(above the dome of the bladder) to the bottom of the ischial
tuberosities.
• Radio opaque markers

51. OARs
• Femoral head
• Rectum
• Bowel bag

52. Contouring Vessels
• From L5 Lower border – femoral Head upper border
• CTV Nodal
• Vessels + 0.7mm margin
• Presacral 10mm brush
• Obturator 18mm
• CTV Nodal+CTV Primary = CTV Combined
• CTV Combined + 1cm = PTV

55. Target volumes
• GTV = macroscopic tumor visible on CT/MRI/cystoscopy
• CTV Tumour –Whole bladder and any extra-vesical extension
• Men : entire prostate & Seminal Vesicles
• Women : Proximal 2 cm of urethra is also considered as part of
the target field
• CTV Nodal
• CTV Total = CTV Tumour+ CTV Nodal
• PTV 1= 1.5-2cm around CTV
• PTV Boost= CTV Tumour+ 1cm

57. Nodal irradiation
• BC2001 Trial
• Nodal relapse rate
• 3% in CRT
• 6% in RT

58. Radiation Dose
• Phase I : 40 to 46 Gy at 1.8 – 2Gy per fraction.
• Phase II (Boost): 14-20 Gy at 1.8-2 Gy per fraction
• Total Dose : 60-66 Gy

59. • Perez
• CRT full dose RT
• Higher rates of bladder preservation
• Korpic et al
• <50Gy & 50-55Gy worse OS
• <60Gy worse OS
• >66Gy no survival advantage
• 63-66Gy optimal dose

60. OAR dose constraints
• Small Bowel V45 <195cc
• Femoral head Dmax <45Gy
• Rectum V40 <40%

61. Acute toxicity
• Dysuria
• Urgency
• Frequency
• Diarrhoea

62. Late toxicity
• Chronic irritative cystitis
• Hemorrhagic cystitis
• Bladder contracture
• Rectal stricture
• Small bowel obstruction

63. IGRT – rationale
• Organ motion
• Delineation errors
• Set up errors
• Treatment verification
• Reproducibility of bladder volume

64. Goals
• Accurate dose delivery to targeted areas
• Avoidance of normal structures by reducing the margins
around the CTV.
• Patient-specific variations assessed at treatment console with
volumetric 3D imaging modalities fitted to treatment
machines, such as kilovoltage CBCT.

65. Preoperative RT
• Waned
• Chemosensitivity of bladder cancer
• Subsequent improvements in radiation & surgical techniques
• Old, non randomised comparisons
• 40Gy

66. Postoperative RT
• Based on the grounds of positive margins & tumor spillage
• Anticipation of recurrences

67. Intraoperative RT
• Electrons

68. Proton
• MIBC
• Proton boost
• 36.3Gy/11#
Late toxicities
Urinary hemorrage
Urethral stricture
Ureter stricture
OS Local control Bladder preservation
71.4 83.4 86.3
Recurrence 25%

69. Brachytherapy
• Indications
• Solitary T1 T2, 5mm or less diameter
• Contra indications
• Tumor invasion of bladder neck
• T3
• Multifocal
• LN (+)
• TURBT → EBRT 40Gy (Bladder+LN) → HDR BT within 1 week
• 2.5 Gy x 10#, 3# per day
• Conservation of bladder function

70. NACT
• To down size & down stage the tumors
• Occult micro mets in muscularis propria
• Standard of care in T3/T4 or node positive disease
• MVAC
• CMV
• dd MVAC (dense dose)
• Accelerated MVAC/high dose MVAC
• Compressed schedule over 14 days
• NCCN 2018
• Category 1 recommendation
• T2 – T4a
• dd MVAC
• CMV
• GC

71. Adjuvant CT
• More accurate selection of patients (p stage)
• Two settings
• Following bladder sparing chemoradiation
• Following radical cystectomy
• Regimens
• MCV
• GC
• Paclitaxel
• Standard recommendation
• Positive nodes
• High p Stage T3 T4
• LVI

72. Metastatic Bladder Cancer
• MVAC
• 28 day cycles
• Mtx 30mg/m2 Days 1, 15, 22
• Vinblastine 3mg/m2 Days 2, 15, 22
• Doxorubin 30mg/m2 Day 2
• Cisplatin 70mg/m2 Day 2
• CMV
• Omits Doxorubicin
• GC
• Gemcitabine 1000mg/m2 Days 1, 8, 15
• Cisplatin 70mg/m2 Day 2
• Less toxic, improved tolerability

73. Toxic effects of MVAC
• Neutropenia
• Anemia
• Thrombocytopenia
• Stomatitis

75. Palliative RT
• 35Gy/10# - 71% symptomatic improvement
• 21Gy/3# - 64%