BLADDER CANCER- Diagnostics Urine cytology is performed to detect cancer and inflammatory diseases of urinary tract with specimen obtained via voiding or from bladder washing. Urine cytology is more superior at detecting higher grade UC due to higher cells shedding. The criteria for positive urine cytology are largely subjective and are dependent on experience of pathologist. Low grade UC does not always exfoliate in aggregates and cell changes might be subtle; hence the sensitivity can be as low as 20%. For primary lesion urine cytology, it has an overall sensitivity 78% with specificity 90% while on detection of residual UC after TURBT, the is sensitivity 75% and specificity 85% and overall diagnostic accuracy of 66% cf to exfoliative cytology (overall accuracy 49%). Due to the low sensitivity (for diagnosis of low grade UC) and non-immediate availability of test result of urine cytology and high propensity for recurrence of UC, urinary biomarkers are being investigated for both diagnostic and prognostic purposes. Biomarkers should be inexpensive, easy to use and interpret, and provide results rapidly. Variety of potential biomarkers includes nuclear matrix protein, bladder tumor antigen, fibrin/fibrinogen product, telomeric repeat amplication protocols (TRAP), tumor associated antigens, hyaluronic acid, and hyaluronidases. Two prospective RCTs showed sensitivity and specificity of cytology; BTA TRAK and NMP 22 were 24% and 97%, 51% and 80%, 78% and 73%. A systemic review by Lotan concluded that all evaluated urinary markers have higher sensitivity than cytology, both overall and after stratification by grade and stage, but specificity if inferior to cytology overall. This is further confirmed by meta-analysis by Glas demonstrated that cytology had the best specificity and telomerase had the best sensitivity. Photodynamic diagnosis (PDD) exploits effect of photosensitizer accumulating preferentially in cancer cells, and fluoresce in visible spectrum when illuminate with light of appropriate wavelength. Endogenous ALA is natural precursor of photoactive intermediate protoporphyrin IX (PpIX); part of the haem biosynthesis pathway. Early studies using ALA in bladder tumors confirmed good demarcation between red fluorescence from malignant tissue and background reflected blue light; correlation between fluorescence and histology findings with sensitivity of 100% and specificity of 69%. 5-aminolevulinic acid (ALA) accumulates at 20:1 ratio compared to normal tissue. Lipophilic derivatives of ALA; hexyl ester of ALA (hexaminolevulinic acid, HAL) gives twice the fluorescence in half the time and 20 times lower concentration. The sensitivity of HAL is 96% compared to 73% for white light cystoscope. Studies on PDD have shown significantly less residual tumor post-resection, higher RFS at 2 year (89% vs 66%), improved treatment in 22% and economic advantage average recurrence of 0.3 in fluorescence group cf to 1 in white-light group. However, false positive could arise due to excitation by a tangential instead of perpendicular beam; preferential accumulation in inflamed and scarred of mucosa and previous PDD instillation within 6 months. When re-resection is performed, PDD has no additional value as it only detects superficial disease. Intravesical Chemotherapy • Indications • Agents Used ( Comparison of risk benefits & outcomes) • Regimens (treatment vs maintenance) Please discuss current worlds best practice Aims • Reduce recurrence • Prevent progression • Treat residual disease after TURBT Indications • Potentially all patients with superficial bladder cancer – one single post operative dose • “High risk” patients (high grade Ta/T1, CIS) – maintenance Agents used • many tried (over 35), a few effective including BCG, mitomycin C, thiotepa, epirubicin, epodyl, doxorubicin, valrubicin, interferon, keyhole-limpet hemocyanin, bropirimine, recently tried gemcitabine and taxanes Studies • individual studies a guide. Differences in patients, drugs, dosages, regimens. • Meta-analysis completed o BCG in Ta and T1 bladder cancer o BCG versus Mitomycin C for Ta and T1 bladder cancer o BCG versus Mitomycin C for superficial bladder cancer: recurrence, toxicity and progression o Combined analysis of EORTC and MRC trials for prophylactic treatment of TaT1 bladder cancer o BCG versus chemotherapy for CIS of the bladder o Single post operative dose of chemotherapy and the risk of recurrence in TaT1 bladder cancer o Intravesical chemotherapy and the recurrence rate in superficial TCC of the bladder (all agents) Agent Used BCG Recurrence (vs TURBT) Progression (vs TURBT) Cochrane Review Ta and T1 585 patients, 6 RCT’s 67% reduction in incidence of recurrences at 12 months Lamm (Uro 2000) 29% vs 67% TURBT=difference 38% 36% vs 48% TURBT=difference 12% Evidence less strong Vs TUR, 26% vs 42% need cystectomy 2 metas positive Sylvester 2.5yr f/u, 9.8% vs 13.8% progress No evidence Mitomycin C 39% vs 51% TURBT=difference 12% No evidence Epirubicin 44% vs 61% TURBT=difference 17% No evidence Thiopeta No evidence Doxorubicin 39% vs 55% TURBT=difference 16% Suggests no significant difference between intravesical chemotherapy options in reducing TCC recurrence Complications -locally occurring – direct effects on bladder -systemic – absorption some factors increase risk – TUR recently, traumatic catheterisation, active UTI Agent Minor Major Frequency/Urgency 71% <5% BCG Cystitis 67% Fever 25% Hematuria 23% Mitomycin Irritative LUTS 3-30% Palmar desquamation (contact dermatitis) Epi/doxorubicin Irritative LUTS 13-56% Thiopeta Irritative LUTS 12-69% Regimens NO STANDARDISED PROTOCOL! Agent MW Peri-op Risk use group Adriamycin 580 Yes Low-int Epirubicin 580 Yes Low-int Thiopeta 189 Yes Low-int Mitomycin 334 Yes Low-int BCG NA No Int-high Interferon 23,000 No Salvage granulomatous prostatitis 1% granulomatous epididymo-orchitis rare granulomatous hepatitis/pneumonitis <1% BCG sepsis 0.4% Allergic reactions (arthritis, athralgia) 0.5% Ureteral obstruction 0.3% Contracted bladder <1% Myelosuppression-rare Contracted bladder Extravasation – peritonitis, pelvic pain, fibrosis, necrosis, ulceration Rare <5% Gastrointestinal upset Fever Hypersensitivity reactions Up to 1/3 of drug absorbed Leukopenia 8–55% Thrombocytopenia 3-31% Dropout Concentration Cost 2-16% 3-6% 2-11% 2-14% 5-10% Rare $36 $595 $80 $130 $150 $6701340 50mg/50ml 50mg/50ml 30mg/30ml 40mg/20-40ml 1 vial/50ml 50100MU/50ml Treatment vs Maintenance doses Chemotherapy agents • Single dose post operative decreases relative recurrence rate 39% (for single tumours, 48.4% in TUR alone, 36.7% in TUR + chemotherapy) • Maintenance doses o In general up to 1 year o Conflicting results o Not routine BCG • Single induction course appears more effective than a similar course of chemotherapy • Maintenance therapy o Controversial o Some trials show no significant benefit but higher toxicity o SWOG trial (Lamm, J Urol 2000) 660 pts, high risk, 6 week induction course • 550 pt randomised to no additional or maintenance BCG (6+3) • median recurrence free survival improved (77 vs 36 months) • 5 year survival no difference • only 16% of patients completed the maintenance course Worlds best practice • weigh up benefits vs risk to individual patients • TUR is important – resect all visible tumour, consider re-resection for high risk large lesions • One dose of intravesical chemotherapy peri-operatively within 6 hours. The agent does not appear to matter • Consider induction therapy o ?only for high risk ?for all o ?which agent – chemotherapy for intermediate risk, BCG for high risk • Maintenance o Appears to be helpful for BCG but appears to have toxicity ?decrease time ?decrease dose o chemotherapy – may be useful • Failure of therapy o Salvage intravesical therapy o Radical cystectomy option Role of chemotherapy (adjuvant and neoadjuvant) and lymphadenectomy in invasive bladder cancer Chemotherapy Neoadjuvant cystectomy is the gold standard Rx localised muscle-invasive bladder TCC When considering neoadjuvant chemo remember up to 40% clinical staging discrepancy Toxicity and mortality associated with neoadjuvantchemo are acceptable, however scant data on QOL available Meta-analysis of cisplatin-containing combination neoadjuvant chemo revealed a modest difference in favor of chemo: 5% survival benefit (ABC collaboration 2003 NEJM) Available data suggests that for ‘average risk’ cancer cT2, benefit of chemo is at best modest. More substantial benefit for high-risk disease eg cT3b Quality of surgery is a confounder Adjuvant Advent of orthotopic bladder and decreased morbidity of cystectomy have increased tendency of Urologists to operate early and then consider adjuvant Advantage local treatment performed immediately and then pathologic result can then be considered Available trials are small and provide insufficient evidence to support routine use of adjuvant chemo Result of larger collaborative international trials will be needed before the true value can be assessed Lymphadenectomy Robust evidence to support the use of lymphadenectomy with radical cystectomy as it increases survival Micrometastatic disease present in between 2-10% in Ta/T1 disease and 25% overall in bladder TCC Herr (Urology 2003) clearly showed significant survival benefit in those who have lymphadenectomy whether node positive or not, particularly if at least 10-14 nodes removed. This has been validated by other Authors including Stein and Leissner (BJU 2000) Konety (JUrol 2003) analysed data from SEER database over 2000 cystectomies and showed 60% reduced chance of death if 10-14 nodes removed Theories are the removal of micrometastases and possibly better technique Standard is to iliac bifurcations, extended up to aorta, at present no clear guidelines to suggest extent. References Campbells 9th Sternberg et al. Chemotherapy for bladder TCC. Urol. 2006 Urinary Diversions The development in urinary diversions has progressed considerably over the last 3 decades. Beginning with Bricker with ileal conduits in the 1950s to cutaneous reservoirs in the 70s and neobladders in the late 80s there has been a paradigm shift in the use of these methods for diversion in cystectomised patients. It has come to a time in the present age where most Urologist should be adept in performing such operations based on sound patient selections. There are four domains that need to be considered before formulating a decision plan for urinary diversion. They include: choice of bowel segment, sound selection criteria, options available for urinary diversion and onco-surgical outcomes. Most common bowel segments used involve either the distal ileum or colon. These have the least effect on metabolic changes. While most metabolic abnormalities are clinically subtle, they may assume significance in younger patients from prolonged exposure and in patients with renal insufficiency. Jejunal segments are rarely used due to significant metabolic derangements and stomach may have a place in patients with preexisting acidotic state. The therapeutic goals are to provide a patient with a diversion that matches their medical, physical and emotional needs. The key to a successful outcome is largely dependent on sound patient selection. The most important aspect is to uphold sound oncological principles with negative surgical margins. Baseline renal and hepatic function needs to be evaluated as continent diversions have long urine contact time and may predispose to metabolic complications. Impaired creatinine >2mg/dL precludes a continent diversion. If the renal function is borderline a creatinine clearance should be > 60ml/min. Normal hepatic function is a prerequisite to deal with the increased ammonia re-absorption. Patients should have good manual hand dexterity before consideration of continent cutaneous diversion or neobladder, as intermittent catherisation is required. Advance age, obesity, associated comordities, bowel disease or previous radiotherapy are less relevant. Three options are available for diversion post-cystectomy: conduit diversions, continent cutaneous diversions (CCD) and orthotopic neobladders. Conduits are the oldest, simplest and most commonly performed and remain the standard to which all other newer diversions are compared. Terminal 15 cm of ileum should be spared to avoid B12 deficiency and bile salt loss. External appliance is required and this may compromise patient’s body image. CCD requires a reservoir from detubularised bowel segments for urinary storage as well as an efferent catherisable aperistaltic limb. Importance of CIC cannot be overemphasized. Orthotopic neobladder requires a formation of spherical pouch based on La Place’s law and a reliance on the external urethral sphincter and pelvic floor for continence. Finally complications are common in the early (within 30 days) and late (>30days) phases of recovery. They can be divided into technical-surgical and metabolic complications. Technicalsurgical complications are further subdivided into stoma, diversion, ureterointestinal anastamosis and bowel related complications. Metabolic complications include electrolyte and acid-base derangements usually in the form of hyperchloraemic metabolic acidosis, sepsis, calculi, renal deterioration, delayed malignancy and osteomalacia. Specific complications for neobladders include daytime and nighttime incontinence and hypercontinence requiring CIC. For CCD, pouch urolithiasis, incontinence and problems with catherization of the stoma are often encountered. Most complications require re-operations to a greater or lesser extent and this must be discussed with the patient in consultation prior to obtaining consent. Case presentation Recurrent T1 G3 TCC Bladder, Dr Adam Davies Background history 52 year old male, Smoke, Otherwise well, Painless gross haematuria 3/52 Investigations MSU – RBC, WBC, nil UTI, Cytology – likely high grade TCC Creatinine – normal, CT Scan – thickening left bladder wall Further investigations Abdominal exam – NAD, CXR – clear, Flexible cystoscopy – tumour left bladder wall Operation 1 Trans urethral resection bladder tumour, Histology – pT1 G3 N0 M0 Operation 2 Repeat cystoscopy at 6/52, Small recurrence posterior wall resected, Histology – pT1 G3 Commenced 6 weeks intra-vesical BCG Operation 3 Check cystoscopy 6/52 post BCG, Erythema left lateral wall, histology – pT1 G3 Probability of progression? pT1 G3 N0 M0, Single tumour > 3 cm, > 1 recurrence in 12 months, Nil CIS, 17% at 1 year, 45% at 5 year Management options BCG Superior to chemotherapy for preventing recurrences, Intermediate and high-risk tumours, Maintenance therapy Salvage combination immunotherapy Only if cystectomy not feasible, Consider in BCG failure, Only for low-risk or intermediate-risk disease recurrence (TaG1, TaG2), Several regimes being trialled Radio-chemotherapy TURBT, radiation therapy , simultaneous chemotherapy, cisplatin, carboplatin and/or 5fluorouracil Radical cystectomy remains gold standard for salvage of failed intravesical therapy a third of patients initially treated by endoscopic and intravesical therapy for high-risk superficial TCC will require cystectomy a third will die of their cancer despite an initial response to BCG therapy, patients with T1 remain at risk for progression and death patients with T1 tumours who fail initial intravesical therapy are at greatest risk for pathologic upstaging at time of cystectomy prognosis is correspondingly poorer Consider as first line treatment for young, otherwise healthy patients with high-grade T1 disease 5-year disease-free survival rate 85% for pathologic node-negative T1 tumors Summary: Radiation Induced Bladder Cancer 1. Radiation treatment for prostate cancer may increase subsequent bladder cancer risk (relative risk 1.5) 2. Radiation induced bladder cancers are usually of higher grade 3. Cystectomy in irradiated pelvis is associated with higher mortality and morbidity 4. Overall survival appears to be similar Summary: Angiosarcoma 1. Radiation induced bladder angiosarcoma is very rare 2. Histological recognition often difficult without specific immunohistochemical staining 3. Associated with very poor prognosis 4. Poorly responsive to chemotherapy 5. Due to previous irradiation, surgery often becomes the only viable treatment options Bladder Angiosarcoma Risk factors Arsenic, thorium dioxide, polyvinyl chloride, radiation, and chemotherapeutic agents Post‐irradiation 22% of reported cases M:F 8:1 Presentation Most presented as large hemorrhagic masses difficult to resect with adequate margins in 7th decades Metastatic sites Lung and liver mets described Surgical options Cystoprostatectomy/cystectomy/partial cystectomy Radiotherapy treatment No accepted protocol, ~60Gy used May be limited by previous local irradiation Chemotherapy treatment Mesna, doxorubicin ifosfamide, and dacarbazine Angiogenesis inhibitor Thalidomide, ?multi‐kinase inhibitors Prepared by Rex Chan for Registrar Training week 2007 Bladder Cancer Case (Scott Leslie) 65 yo ♂ Macroscopic Haematuria B/g: COPD Sx: Smoker Investigations: Hb-123, Cr-89 U/A – blood++ MSU – no growth Urine Cytology – Positive for malignant cells CT IVP - 4cm enhancing mass left wall of bladder - Left hydronephrosis TUR(BT) - Tumour resected down to detrusor - Left ureteric stent inserted (? theoretical risk of upper tract seeding) Complicated post-op by perforation at dome by tip of foley’s catheter (? Conversion of T2 to T3 disease) Histopath - T2G3 Treatment options - Cystectomy - Chemoradiation Treated with chemoradiation: 60Gy RTX and concurrent MVAC chemotherapy 3 month check CE – residual muscle invasive high grade disease + prostatic stromal involvement Treated – Radical cystoprostatectomy + bilateral standard PLND + urethrectomy. Pt still smokes! Bladder Cancer Case Presentation Trainees Week 2007 Mark Louie-Johnsun 75M 3/52 history of macroscopic haematuria Background – IHD: AMI X3 Rx Aspirin No angina 5 yrs – NIDDM – Smokes 15/day – Reasonable exercise tolerance (walk 1km) Investigations 2/3 positive urine cytology MSU neg CT and IVP – filling defect L lateral bladder and L renal pelvis 12/06 Cystoscopy TURBT and L RPG Solid looking lesion around L UO and superficial lesions L lateral L renal washings positive cytology Histo: T1G3 (smooth muscle present) Random biopsies no CIS TREATMENT?? Upper tract TCC and T1G3 (focal) TCC ?Rebiopsy Priorities in Rx – ? Rx upper tract TCC – ? Intravesical BCG – ? Synchronous Rx upper tract TCC / bladder 2/07 Lap L nephroureterectomy – Uncomplicated – Histo HG invasive TCC “Tumour extend into muscle layer renal pelvis” Tumour extend prox ureter and focal infiltration muscle Renal parenchyma normal 5-6/07 6X weekly course BCG No complications 8/07 Cystoscopy – Recurrent TCCs largest around L UO site of previous resection and BN – Rx TURBT to complete clearance – Histo Deep Bx: T1G3 (L UO tumour) Random Bx and prostate urethra Bx NAD No CIS Further Rx?? Options – Further course BCG – Radical cystectomy and diversion Further course BCG given – Completed 4/6 (unable tolerate further due to irritative symptoms) – Due for check cystoscopy this month Case Summary Muscle Invasive Urothelial Ca in Patient Not Fit For Radical Cystectomy Ben Kwok 74M. Presentation with 3/12 haematuria + obstructive LUTS B/G: Heavy smoker, emphysema, poor exercise tolerance, past AMI x2 O/E ‐ Abdo unremarkable ‐ Prostate moderate size, smooth Investigations ‐ Creatinine 90 ‐ PSA 1.3 ‐ Urine m/c/s o Homogenous red cells Imaging ‐ Ultrasound o Left hydronephrosis +several solid mass lesions in bladder ‐ CT o Bilateral hydronephrosis + hydroureter L>R o No mass visible in bladder on CT Cystoscopy ‐ Extensive tumour bladder trigone, bladder neck and proximal prostatic fossa ‐ TURBT/prostate ‐ Unable to identify ureteric orifices to insert stent Histo ‐ High grade muscle invasive Patient declined radical cystectomy due to comorbidities Decision at MDTM to have radiotherapy + chemotherapy ‐ 64Gy in 32 fractions ‐ Cisplatin 40mg/m2 Treatment options for muscle‐invasive urothelial ca ‐ Cystectomy o 5yr survival o Overall 40‐60% o T1‐75% T2‐60% T3‐30% T4‐20% ‐ Radiotherapy o 5yr survival 40‐60% o Cochrane review 2001 suggested cystectomy has overall survival advantage c/w radiotherapy for muscle‐invasive cancer but older studies (1977‐1991) with older surgical + radiotherapy techniques ‐ Radiotherapy + Chemotherapy o 5yr survival 50‐60% ‐ Partial cystectomy +/‐ chemotherapy o T2 5yr survival 30‐80% in very selected patients ANGIOSARCOMA OF BLADDER PRESENTATION: 32 year old fit and well ♀ G2P3 presents 6 months postpartum with • macroscopic haematuria • left flank pain • preceeding irritative voiding symptoms EXAMINATION: Unremarkable INVESTIGATIONS: Blood workup normal MSU: blood, no growth Renal US: Posterior bladder mass with left hydronephrosis and hydroureter down to VUJ MANAGEMENT: Cystoscopy, JJ stent and biopsy shows angiosarcoma Vascular tumour forming solid sheets/nests. Endothelial cells are poorly differentiated with pleomorphic, large hyperchromatic nuclei, prominent nucleoli and frequent mitotic figures Staging PET scan: metastatic involvement of regional LN MRI: involvement of anterior vaginal wall Disease progression 5 months after diagnosis with • Haematuria • Renal Impairment • Bilateral hydronephrosis • Increasing vaginal mass • PV bleeding • Sacral pain Palliative chemotherapy (epirubicin and ifosfamide) and radiotherapy PRIMARY ANGIOSARCOMA OF BLADDER: • 11 cases reported to date • Extremely rare vascular malignancy arising from blood vessel endothelium • Male predominence 8:1 • 5th to 9th decade • Linked to exposure to vinyl chloride, arsenic, therapeutic radiation • Most have metastasized at diagnosis • Very poor prognosis with 50% mortality at 12 months Angiosarcoma of Bladder Tanya Ha