Case 1 89 year old male with initial occurrence of gross hematuria Office flexible cystoscopy shows two papillary tumors with some surface necrosis Complete TURBT into muscle Florescence cysto shows two suspicious flat lesion remote from the primary tumors that are normal by white light Final path TaG3Tis urothelial cancer
Case 1 Receives induction BCG weekly x 6 without significant toxicity Next step should be: Follow up cysto and cytology in 6 weeks Bladder biopsies and cytology in 6 weeks
Case 1 Patient is taken back to operating room for bladder biopsies 6 weeks after completing BCG What additional imaging should be included in order to accurately stage the response to BCG? BJUI 2010: 105, 789
Case 1 Site directed biopsies of prior areas of CIS were negative/bcg related inflammation and cytology was negative. False positives can occur with PDD after BCG. OCT showed normal urothelium Next step is: Surveillance cysto every 3 months Second induction course of BCG Monthly maintenance BCG 3 weeks of BCG at 3 months
Case 1 Patient receives 3 weeks of BCG at 3 and 6 months, becomes BCG intolerant and maintains a complete response for 2.5 years. He now presents with significant microhematuria and 2 months of dysuria. Urinalysis is otherwise normal. Cysto shows a 2 cm tumor with papillary and sessile features with some surface necrosis Cytology is positive and voided FISH is abnormal
Case 1 Patient has a complete TURBT into muscle and biopsy of prior sites of CIS are positive Path T1G3Tis
Case 1 Next step is: BCG weekly for 6 weeks BCG + Interferon MMC Gem/MMC Re-resection with biopsies of prostatic urethra
Case 1 Patient has re-resection and prostatic urethra biopsies No residual tumor at previous tumor site but there is CIS of the urethra and prostatic ducts Next step is? TURP to determine extent of CIS and open bladder neck for intravesical therapy P ducts Verumontanum CIS
Case 1 Patient would like to avoid cystectomy and his TURP shows residual CIS of the prostatic urethra, ducts and acini Next step should be: Radical cysto prostatectomy BCG weekly for 6 weeks BCG + Interferon MMC Gem/MMC
Case 1 Patient decides on cystectomy Final pathology: 2 focal areas of CIS of the bladder Diffuse CIS of the prostatic ducts and acini with possible focus of stromal invasions
Case 2 62 yo female with T2aTis urothelial cancer with squamous differentiation involving bladder neck and proximal urethra. Fullness at bladder neck but no palpable dimensional mass. She is sexually active and desires to continue. egfr is 50 and she takes Cytoxan for chronic rheumatoid arthritis.
Case 2 Treatment should be: Neoadjuvant cisplatin based chemotherapy Neoadjuvant carboplatin based chemotherapy Radical cystectomy Radiation therapy with radiosensitizing chemotherapy Integrated trimodal therapy with cisplatin based chemotherapy and radiotherapy
Case 2 She elects to go ahead with cystectomy. What are technical considerations with muscle invasive cancer of bladder neck and urethra? Vaginal reconstruction? Diversion type? Radical cystectomy with en bloc inferior pubectomy, bilateral pelvic lymphadenectomy including pre-sacral nodes, Indiana pouch and anterior vaginal wall reconstruction with rectus flap
Case 2 The final path was pt4ag2tisn0 with squamous differentiation. The tumor was involving the anterior vaginal wall, bladder neck and urethra with negative margins. What is her risk of occult metastatic disease and progression? Should she get adjuvant chemothrapy? Pre-op egfr 50 and no change after surgery
Case 2 She was felt to be at high risk for progression based on pt4a stage and was treated with adjuvant chemotherapy with 4 cycles of carboplatin and paclitaxel. She has been continuously free of disease since the surgery for 13 years.
Case 3 - Localized Bladder Cancer 62 y/o healthy male First occurrence ct2 high grade urothelial Single 4 cm tumor, left posterior wall Complete TUR (R0) according to local urologist no mass on EUA no hydronephrosis no adenopathy egfr 74 ml/min (MDRD)
Case 3 ct2nxmx Localized Bladder Cancer
Invasion of muscularis propria TCC with squamous cell features
Case 3 T2 High Grade Mixed Histology What is the appropriate management of this case? 1) Radical TURBT alone 2) Initial cystectomy ± adjuvant chemotherapy 3) Neoadjuvant chemotherapy + cystectomy 4) Bladder sparing chemo/radiation therapy
Case 3 Why Neoadjuvant Chemotherapy? Can we risk stratify when deciding between upfront definitive treatment vs. neoadjuvant chemotherapy? What chemotherapy regimen? Number of cycles? Does mixed histology affect response to neoadjuvant chemotherapy Neoadjuvant vs. adjuvant chemotherapy Why does it matter as long as we give it?
NCCN Guidelines (2010) First Line Chemotherapy Neoadjuvant for T2-4aN0 category 1 recommendation Level 1 evidence; uniform consensus MVAC is the historical standard of care GC de facto standard of care based on treatment of measurable metastatic disease
NCCN Guidelines (2010) First Line Chemotherapy 3 drug regimens (GC + taxane) not superior to GC alone Carboplatin should not be substituted for cisplatin in patients with normal renal function Split does cisplatin may be considered for patients with borderline renal function or minimal dysfunction
Neoadjuvant Selection Criteria Higher risk of relapse: 3-D mass on EUA Prostatic stroma, vaginal wall involvement LVI increased risk of occult nodal involvement Hydronephrosis Increased risk of extra-organ extension thin ureteral wall Upper tract tumor Ureteral or renal pelvis (requires G3 TCC or measurable mass on CT) Micropapillary tumor Small cell tumor (on small cell chemotherapy) Use of these criteria: 80% likelihood of upstaging to >=pt3b or N+ with initial surgery (Millikan et al. JCO 2001) MDACC criteria
Case 3 Why not Bladder Preservation Is patient a candidate for bladder preservation? What strategy?
Case 3 Definitive Loco-Regional Treatment 1) Radical cystectomy and standard pelvic lymphadenectomy 2) Radical cystectomy and extended pelvic lymphadenectomy 3) Laparascopic/Robotic assisted radical cystectomy and standard pelvic lymphadenectomy 4) Laparascopic/Robotic assisted radical cystectomy and extended pelvic lymphadenectomy 5) Bladder preservation with trimodal therapy Complete TURBT, integrated chemoradiation?
Case 3 Treatment and Outcome Neoadjuvant chemotherapy - gemcitabine and cisplatin x4 cycles Open radical cystectomy, BPLND - pt0 bladder specimen - 32 negative nodes Ileal neobladder Incidental adenocarcinoma prostate -pt1c, G6
Case 4 Locally advanced bladder cancer in unfit patient 84 y/o frail female Obese, HTN, CAD (stents x2), COPD (smoking), NIDDM ct3, TCC, mild left hydro No pelvic mass, mobile bladder Visibly complete TUR, deep fat invasion No adenopathy, or mets Severe LUTS, hematuria with clots, incontinence egfr 45 ml/min (MDRD)
Case 4 Questions? What is appropriate treatment for this lady? Is she a candidate for cystectomy? Can she receive chemotherapy? If yes, which regimen? If no, why not? Is chemoradiation an option for cure or palliation? How are unfit patients defined for curative therapy of advanced bladder cancer?
Case 4 Questions? What statement best reflects your view regarding her candidacy for cystectomy? 1) Her age and body habitus rule out surgery. 2) Her cardiopulmonary status (stents x2, COPD) and performance status rule out surgery. 3) She remains a surgical candidate and given her extent of disease and bladder function, I recommend surgery. 4) I don t know how to define unfit for surgery.
Who is Too Sick for Surgery Anyone can undergo surgery if the alternative is dying from their cancer. Poor surgical Candidates: Home oxygen Ejection fraction < 25% PS 2 or greater.
Cardiac Stents Bare metal Dual anti-platelet therapy for 90 days Drug eluting Dual anti-platelet therapy for 365 days. If therapy is stopped in these time periods 10 fold increase in major cardiac event Both require low-dose ASA for life, even during surgery.
Cystectomy alone: ~ 33% survival @ 3 yrs Grossman et al. NEJM 2003
Fig 2. Overall survival of all 140 registered patients by assigned therapy Millikan, R. et al. J Clin Oncol; 19:4005-4013 2001 Copyright American Society of Clinical Oncology
Long-term MGH Experience 1986-2002 Efstathiou et al ASTRO 2009; ASCO GU 2010
Bladder sparing trimodality therapy 74% 67% 63% 53% 49% 49% Efstathiou et al ASTRO 2009; ASCO GU 2010
Case 4 What is appropriate management for this patient? 1) Radical TURBT alone 2) Radical cystectomy ± chemotherapy 3) Trimodality therapy with TUR followed by radiation therapy and concurrent radiosensitizing chemotherapy 4) TUR followed by chemotherapy alone 5) TUR followed by radiation therapy alone
Case 4 Treatment and Outcome Radical cystectomy, BPLND - pt3 bladder (negative margins) - 16 negative lymph nodes No complications (hospital stay, 8 days) egfr 49 ml/min (MDRD) Significant palliation - no pelvic symptoms
Bladder Cancer Case 5 52 yo WM No prior history of urothelial cancer Hematuria Intravenous pyelogram Filling defect bladder Mild right hydronephrosis
Operative Findings Cystoscopy, bimanual exam under anesthesia and transurethral resection of bladder tumor Pathology T1G3Tis minor component Small Cell Small cell carcinoma involving 80-90% of tumor LVI Metastatic work up negative Chromogranin A normal
Synaptophysin
Chromogranin
What is the next step in management? T1G3Tis mixed TCC and predominant small cell carcinoma with LVI 1) Intravesical immunotherapy with BCG 2) Radical cystectomy and bilateral pelvic and iliac lymphadenectomy 3) Systemic chemotherapy 4) Radiation therapy with concurrent chemotherapy
Neoadjuvant chemotherapy recommended. What is the regimen of choice in patients with normal renal function? 1) M-VAC 2) GC 3) Ifosfamide and doxorubicin 4) Etoposide and cisplatin 5) Etoposide and carboplatin
Response to chemotherapy Re-staged Cystoscopy Small lesion consistent with scar Cytology and FISH negative Re-resection bladder biopsies negative Chest x-ray and CT abdomen and pelvis negative
The patient has had a complete clinical response to chemotherapy. What is the next step in management? 1) Close surveillance 2) Cystectomy and pelvic lymphadenectomy 3) Radiation therapy with concurrent chemotherapy
Post Chemotherapy Management Cystectomy with extended pelvic and iliac node dissection (IMA); Neobladder Pathology pt0n0m0 38 nodes all negative Management Adjunctive therapy? Surveillance Status Alive NED 6.5 years months post cystectomy
Case 6-57 year old male with microhematuria History of radical prostatectomy in 3 years prior to presentation pt3an0 Gleason 3 + 4 Current PSA <.003 Cystoscopy shows 2 foci of papillary tumor right posterior wall Total diameter 2cm
Initial Surgery and Staging Compete TURBT T1aG3 micropapillary without CIS (100%) Muscularis propria in specimen CT Abdomen and pelvis negative
Does this patient need re-resection before deciding on therapy? 1) Yes 2) No
What is the next step in management? 1) BCG 2) BCG + Interferon 3) Neoadjuvant chemotherapy 4) Radical Cystectomy and bilateral pelvic and iliac lymphadenectomy 5) Radiation therapy with chemotherapy (bladder preservation)
Case 6 - Follow-up BCG 6 week induction course Follow-up cystoscopy shows a 1cm papillary tumor adjacent to previous resection site TURBT T1aG3 micropapillary
What is the next step in management? 1) Second induction course of BCG 2) BCG plus interferon 3) Intravesical Mitomycin C 4) Experimental Salvage Protocol - Gemcitabine, Eoquin, Abraxane, other? 5) Radical cystectomy and bilateral pelvic and iliac lymphadenectomy
Treatment and Follow up Radical cystectomy and bilateral iliac and pelvic lymphadenectomy pt0n0m0 0/31 nodes Follow-up Alive, NED 7 years post-op