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Bladder cancer
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- 2. Outline • Case • Non-MuscleInvasive Disease • Muscle Invasive Disease Neo-adjuvant & Adjuvant therapy Bladder Preservation • Recurrent Disease • Metastatic Disease
- 3. Case • 57 yearold man – from Arusha; • No history of smoking, no alcohol; • No exposure to chemicals in the past reported;
- 4. Case, cont’d • Intermittentabdominal pain for 1 month – non specific in nature, no history of dysuria/trauma; • Gross hematuria slowly settled within 2 weeks of abdominal pain; • P/E – unremarkable; urine dipstick only positive for blood
- 5. Case, cont’d • 1stultrasound report: echodense lesion at the left side of the bladder wall measuring 21x15x16mm; • Referred to urologist (KCMC): flexible cytoscopy reads: 2 × 2 cm raised lesion and some surrounding erythematous patches nearby;
- 6. Case, cont’d • Scan– mass invading the perivesical tissues, but no evidence of any upper tract abnormality, lymph nodes or metastases; • Rigid cystoscopy was performed for biopsy and attempt of full resection; • Histology revealed high grade transitional cell carcinoma of the bladder
- 7. NON MUSCLE INVASIVEDISEASE
- 8. What is theevidence for and against treatment for NMI?
- 9. Central to allNMI • Transurethral Resection of Bladder Tumor (TURBT) is the mainstay of treatment; • Allow depth + muscularis propria & Areas of CIS, abnormal areas in the urethra; • Conservative therapy – in the measure of the possible - is preferred
- 10. Risk Stratification Risk GroupDetails Recurrence Risk Low Solitary, low-grade Ta primary, <3 cm in diameter, no carcinoma in situ (CIS) 1 year: 15% 5 year: 31% Intermediate All tumors not meeting the criteria for low risk or high risk. 1 year: 38% 5 year: 62% High CIS, high-grade disease, or T1 lesion + multiple, large (>3 cm), and Ta grade 1 or grade 2 1 year: 38% 5 year: 62%
- 11. Re-staging • Incomplete TURor if muscularis propria is not included in specimen – repeat cystoscopy staging; • Added - risks of disease understaging and for the value of providing more tissue for pathologic examination; • To be repeated 2-6 weeks after initial TUR
- 12. Low Risk NMI •M. Craig Hall et al. 2007 (AUA 2007 Guidelines Update): - Established role of single agent Mitomycin C for immediate chemotherapy instillation; - 17% reduction in early recurrence found with single intravesical chemotherapy;
- 13. Intermediate Risk NMI •Intra-vesical therapy recommended after TURBT – options with Bacille Calmette Guerin or Chemotherapy; Given to prevent recurrence & treat residual disease; • If BCG is chosen – to be administered ideally 2-3 weeks post TURBT then maintenance for 1 year
- 14. High Risk NMI •Indicated for intravesical therapy – BCG is preferred, after restaging TURBT; • Maintenance given for at least 36 months; • A few selected cases might undergo cystectomy if high risk to invasive disease, or recurrence of High Risk within 6 months
- 15. What is theexisting value of BCG? Bacille Calmette Guerin Details Nature Live attenuated form of Mycobacterium Bovis Mechanism of Action Triggers local immune responses – correlating with antitumor activity: -Expression of Interferon Gamma; - Induction of CD4 T cells and macrophages - Elevated systemic (urine) cytokines (interleukins and tumor necrosis facor) Indications Alternative for intermediate risk NMI, Preferred for High Risk NMI Dose and Schedule Given 2-6 weeks post TURBT, weekly for 6 weeks; reconstituted BCG – 81mg + 50 mls of NS; Give maintenance weekly for 3 weeks at 3, 6, 12, 18, 24, 30 and 36 months. Limit to 1 year for intermediate disease
- 16. What is theoptimal maintenance duration of BCG? N – 1355 Intermediate & High Risk Disease Follow-up: 7.1 year Full Dose – 1 year (337) 1/3 Dose – 3 years (339) Full Dose- 3 years (338) 1/3 Dose – 1 year (341) Toxicity – No significant difference Intermediate Risk Patients – no benefit of 3 years High Risk patients – 3 years BCG decreases the recurrence Oddens J, 2013
- 17. How does BCGcompare with conventional chemotherapy? Sylvester RJ, 2005
- 18. How does BCGcompare with conventional chemotherapy, cont’d Sylvester RJ, 2005
- 19. What is thesuitable timing for instillation? N= 2844 Arm 1: Immediate instillation LR: 43% Vs 46% (p=0.11) IR: 20% Vs 32% (p = 0.037) Arm 2: Delayed – 2 weeks HR: 28% Vs 35% (p=0.007) Bosschieter J, et al, 2018 Recurrence Risk
- 20. Other chemotherapy alternatives AgentDetails Mitomycin C Established role in intravesical therapy for low risk disease – however, inferior to BCG for higher risk groups Gemcitabine Lower toxicity compared with MMC – however, studies (SWOG 0337) limited use in low grade only Epirubicin Used for low & intermediate risk – given as 50mg weekly for 6 weeks Tiothepa First used agent – associated with low recurrence risk but high toxicity – voiding symptoms
- 21. Recurrent NMI Recurrence Recurrence afterprior adjuvant intra-vesical therapy Recurrence without prior adjuvant intra-vesical therapy LR- Treat as IR IR- Risk Factors: 1/ >2-3 tumors 2/Tumor Size 3/Early Recurrence (<1 year) 4/Frequent Recurrences >1 year No RF: Low Risk 1-2RF: Interm. Risk 3-4 RF: High Risk BCG failure – single BCG without maintenance BCG unresponsive: -Induction w/o maintenance; - initial CR – relapse <6mo; - Relapse >6mo
- 22. Recurrent NMI, cont’d RecurrentW/o prior intravesical therapy All Low Risk No further treatment Intermediate Risk: Adjuvant intra-vesical therapy + 1 year maintenance High Risk: Adjuvant Intravesical therapy + 3 year maintenance TURBT Failure Intermediate Risk: Intravesical BCG/ChT High Risk (HG Ta, Cis): Same as second line (BCG) Very High Risk (T1 HG): Cystectomy
- 23. Recurrent NMI, cont’d Priorintra-vesical therapy Received MaintenanceSingle Dose BCG BCG for all risk groups +/- cystectomy for VHR Cystectomy Relapse < 6months Attempt ChT if prior BCG /Cystectomy for selected cases Relapse > 6 months BCG – if failure - Cystectomy
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- 25. Common Indications, Cystectomy IndicationsDetails Muscle Invasive Disease Common practice is to start off with Neo-adjuvant chemotherapy – if not – high recurrence rate Non-Muscle Invasive Disease Prophylactic cystectomy – T1a, high grade, women with bladder neck ca +/- urethra Tis Locally advanced disease Disease responding after induction cisplatin-based chemotherapy
- 26. Radical Cystectomy Item Details ValueMainstay of treatment and modality by which every other is judged Techniques Males – Bladder + Prostate, seminal vesicles; Females – Bladder + Removal of affected reproductive organs Pelvic LN metastasis & dissection Bilateral pelvic LND; existing evidence advocates for an extended template including pre-sacral and common iliac LN Urinary Diversion Depends much on preference of patient/physician – most commonly used is continent reservoirs (gut) or orthotopic neo-bladder Nerve Sparing procedures Males: Cavernous nerves; Females: Parasympathetic efferent fibers from S2 to 4
- 27. What is thebest valued & studied Neo- adjuvant chemotherapy regimen? N=317 (T2-T4a) N = 154 (Surgery Alone) Median Survival – 46 Vs 77 months* Occurrence of residual disease 38 Vs 15%* N = 153 (MVAC > Surgery)* Higher Toxicity with MVAC (grade 3& 4) Grossman, 2003
- 28. Other alternative chemotherapy regimens& Dose Regimen Details MVAC Methotrexate 30mg/m2 (d1, 15, 22), Vinblastine 3 mg/m2, Doxorubicin 30mg/m2 , Cisplatin 70mg/m2 on D2 – repeat after 28 days – 3 cycles Dose-dense MVAC Same dose as above, add filgastrim – repeat 14 days if toxicity permits GC Gemcitabine 1000mg/m2 d1, 8, 15 + Cisplatin 70mg/m2 on D2, after 28 days – 6 cycles CMV Cisplatin 100mg/m2 , Methotrexate 30mg/m2 , Vinblastine 4mg/m2 q 28 x 3 cycles
- 29. Evidence-based options foradjuvant chemotherapy Details Rationale Given to patients with no prior neo-adjuvant chemotherapy Options Single Agents Platinums (Cisplatin & Carboplatin – if Renal Function is poor – give up to 3 cycles) Combination: MVAC & GC – same doses as prescribed above + given up to 3 cycles
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- 31. A BLADDER WORTHSAVING Patients to be selected Criteria 1. Urothelial histology – for most studied patients; hard to extrapolate the findings 2. Maximal TURBT 3. Clinical T2-T3a – decreased rates of response 4. Good renal function & no tumor-associated hydronephrosis 5. Absence of extensive carcinoma in situ – presence of CIS leads to poor outcomes
- 33. What is theexisting evidence supporting the use of chemoradiation? N=123 Arm 1: 2xMCV + CRT – 39.6Gy/cisplat in OS – 48 Vs 49% DM: 33 Vs 39% Arm 2: CRT – 39.6Gy/cisplatin 5-year survival with functional bladder: 36 Vs 40% Shipley, 1998
- 34. Evidence, cont’d N=468 5-y OS:57% 10-y OS: 36% 5-y DSS: 71% 10-y DSS: 65% 5-y LF: 13% 10-y LF: 14% T2=61%; T3=35% T4=4% Mak R, 2014
- 35. Can Chemotherapy beomitted? N=360 5-FU + MMC + RT 2- Year Local control: 67* Vs 54% 5-y OS: 48* Vs 35% RT Alone Grade 3-4 Adverse Events: 36* Vs 27.5% James ND, 2012
- 36. Chemotherapy options& Relevant studies Chemotherapy Regimens StudyDetails Cisplatin + 5-FU Cisplatin + Paclitaxel (Mitin T, 2013 – phase II, RTOG 02-33): 72% in the paclitaxel group had CR; 62% had CR in the 5-FU group 5-FU +MMC (Rodel C, 2002 – RTOG 0524): combination used in case of renal impairment Low Dose Gemcitabine (Coen J, 2017 - RTOG 0712): alternative to cisplatin/compared with combination 5-FU+ Cisplatin/similar toxicities and local control outcomes
- 37. What is thecurrent evidence supporting the use of neo-adjuvant Chemotherapy? N=123 T2-T4a Arm 1: 2xMCV + CRT – 39.6Gy/cisplat in OS – 48 Vs 49% DM: 33 Vs 39% Arm 2: CRT – 39.6Gy/cisplatin 5-year survival with functional bladder: 36 Vs 40% Shipley, 1998
- 38. General approach forRT in the bladder preserving therapy 40-45 GY/20-25# to entire bladder, prostatic or proximal urethra, and LN Repeat cytoscopy/TURBT + Biopsy CR, Ta, Tis Muscle Invasive Disease Boost – 20- 25Gy in 10-14# Radical Cystectomy
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- 40. PROGNOSTIC FACTORS Prognostic factors Details Clinical FactorsLoehrer PJ, 1992 &Saxman SB, 1997: Non-Transitional Cell Histology, Visceral & Bone metastasis, Poor performance status fare worse Molecular Factors ERCC1 gene ERCC2 gene Low levels confer longer term of survival
- 41. Medical Fitness Criteriato chemotherapy • WHO / ECOG Performance Status ≤2 (KPS ≥ 60-70); • Creatinine Clearance > 60ml/min; • NYHA < Class III; • Less than grade 2 peripheral neuropathy; • Intact hearing function Galsky, Lancet Oncol. 2011,
- 42. Platinum-based regimens Regimens Details MVACMethotrexate 30mg/m2 (d1, 15, 22), Vinblastine 3 mg/m2, Doxorubicin 30mg/m2 , Cisplatin 70mg/m2 on D2 – repeat after 28 days – 3 cycles GC Gemcitabine 1000mg/m2 d1, 8, 15 + Cisplatin 70mg/m2 on D2, after 28 days – 6 cycles PGC Paclitaxel before GC – 80mg/m2 on d1& 8 then GC givn as above MCAVI/Carbo-GC For patients who cannot receive cisplatin – proposed by EORTC
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- 44. Patient Immobilization andData Acquisition • Position – supine, arms folded across the chest; • Immobilization aids – ankle and knee supports; • Bladder& Rectum protocols – both to be emptied before scanning & treatment; • Scan – oral contrast (small bowels)/ starts from lower border of L5 and inferior border of ischial tuberosities
- 45. Volume Definition Volumes Details GTVPrimary bladder tumor + extravesical spread– visible on imaging CTV GTV + Whole bladder PTV 1.5-2cm added to CTV; cranio-caudal &AP movements (1.5cm) expected, randomly; 1.5 cm added around normal bladder tissue; 3cm added for cranial tumors – as they can move away from volume
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- 50. PTV – largefield
- 51. Full Plan withOARs
- 52. Field Planning Fields Details AP-PASuperior: top of sacrum Inferior: below the bladder to at least the bottom of the obturator foramen Lateral: include 2 cm of the pelvic rim Lateral Superior/inferior: as AP/PA fields Anterior: at least 2 cm anterior to the bladder Posterior: at least 2 cm posterior to the bladder Block small bowel superiorly/anteriorly
- 53. BACK TO THECASE
- 54. Management • After attemptedTURBT – patient sent for definitive chemoradiation; • Planned 45Gy + cisplatin; 3/25# now – awaiting repeat cystoscopy to establish further treatment
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Editor's Notes
- #23 G