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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
- 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
- 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%