Can We Preserve The Bladder In Muscle Invasive Bladder Cancer? Dr Manish Patel Urological Cancer Surgeon Westmead Hospital University of Sydney

The Outcomes of Radical Cystectomy Outcomes of RC are very good. Recurrences occur: Median 12 months 86% of recurrences occur in first 3 years. Local only recurrence more likley in OC. Most series- any recurrence= death. Even with LN+ve disease, 30% likelihood of long term survival. Stein et.al. Journal of Clinical Oncology, Vol 19, No 3 (February 1), 2001: pp 666-675

Upstaging is common with Bladder Cancer Based on TURBT, EUA, CT MRI with dynamic contrast enhancement and Fe particles may be better. Ureteric obstruction- 67%-90% >pT2 (Skinner et,al,1998) Muscle invasive bladder cancer (cT2) is upstaged to pT3 in: 52% (Soloway et.al.1994) 78% (Pagano et.al.1991) 41% (Frazier et.al.1992) Most cT2 bladder cancers are pT3 or higher. Occult LN mets increase with increasing P stage P0, Pa, Pis, P1: 5% P2: 18-27% P3-4: 45%

Quality of Life After RC is Good. There are a number of QoL instruments for bladder cancer. Very few reports on QoL after BC treatment. Lack of baseline measurements. Lack of longitudinal measurements. No comparison of RC vs Bladder Preservation. Only on prospective QoL study (SF-36) (Hardt et.al) Physical functioning decreased pre-post-op (80 to 68) Pain, health perception, vitality, social functioning, general well being, satisfaction with life all the same as pre-op at one year.

Options of Bladder Preservation with Muscle Invasive BC TURBT alone Partial Cystectomy alone External Beam Radiation Alone Brachytherapy Neoadjuvant Chemo and TURBT Neoadjuvant Chemo and Partial cystectomy Multimodality therapy

Does a delay in cystectomy Result in lower survival? Randomised studies of immediate cystectomy vs XRT and salvage cystectomy. Study Randomised groups Survival MD Andersen (n=67) Immediate XRT+cystectomy 5yrs: 45% XRT and salvage cystectomy 5yrs: 22% Urologic Co-operative Group UK (n=187) Immediate cystectomy 5 yrs: 39% XRT with salvage surgery 5 yrs: 29% Danish National Bladder Group (n=187) 5 yrs: 23% Possibly: Need low threshold for salvage cystectomy

TURBT Author Protocol Survival Cystectomy rate Barnes (n=85) G1/2 T2 TURBT X1 27% 5 yrs Henry (n=43) Favourable (small T2) TURBT X1 77% 5 yrs 25% Solsona (n=59) Negative cytology and rpt biopsy 83% @4 yrs 19% Herr (n=45) Negative rpt TUR and cytology 82% @ 5 yrs 24% TURBT is feasible for selected T2 bladder tumours. Not for dome or high posterior wall

Partial Cystectomy MSKCC study (contemporary) 85 patients with T2 OS: 69% @ 5yrs 74% alive with bladder intact 67% alive with NED bladder intact 7 pts sup recurrence 15 pts advanced recurrence 75% false negative frozen section margins. 80% of positive margins suffered advanced recurrence. Selection: Dome/post wall/diverticulum

Partial Cystectomy Candidates: CR or PR to Neoadjuvant chemo Solitary lesions in favoyrable locations No CIS Good bladder capacity.

Radiation TURBT and 65 Gy XRT Study Patient no. Survival (5 yr%) T2 T3 Fossa et.al. 308 38 14 Davidson et.al 709 49 28 Gospodarowicz 355 50 32 Goffinet et.al. 384 42 35 TURBT and 65 Gy XRT Tumour debulking (TURBT may be most important) Assessment of response at 40Gy may be useful CR to XRT- will have a good outcome. 60% invasive recurrence rate. Approx 50% cystectomy rate. Co-existant CIS: High recurrence rate in bladder (70%). Squamous differentiation may have poorer outcome

Radiation-Complications Early complications Diarrhea Bladder irritation (particularly if trigonal cancers) Late complications (2-3 years later) Worse if heavily pretreated (TURBTS, BCG etc) Radiation cystitis (heamturia, frequency contracted bladder) Radiation proctitis (persistent diarrhea, rectal bleeding) Sexual dysfunction (60%) Tumour Recurrence Invasive – salvage cystectomy Superficial- as per normal protocols

Neoadjuvant and Partial cystectomy Neoadjuvant chemotherapy (X3-4 cycles) followed by TURBT staging. Then followed by partial cystectomy and pelvic lymph node dissection. Herr et.al (n=26). No Pt was eligible for PC alone. 19 had P0 7 yr median FU: 65% alive 54% with bladder 18% invasive recurrence 26% superficial recurrence PC is a valid option in suitable patients, even with T3 tumours that are small.

Neoadjuvant and TURBT Neoadjuvant chemo (3-4 cycles). Restaging TURBT. Stenberg et.al (n=71). T2-T4a Median 54 months FU: 71% alive 57% bladder intact After chemo: P0 or superficial disease, 5yr survival = 71% Invasive disease 29% MSKCC (n=111) 60(54%) achieved T0 status.- Most preserved bladders 56% recurrence in bladder (30% invasive) 25% of T0 is not P0.

Neoadjuvant chemotherapy and TURBT Srougi et.al. (n=30) TURBT, MVACX3. PR or no response > cystectomy (n=12) CR > all retained their bladder (n=14) 5 yrs, 71% (10) had local recurrences. 8 had radical cystectomy Survival of all CR pts was 79% @ 5yrs. All patients need close observation because of inadequate staging and occurrence of new tumours.

Trimodality Therapy Maximal TURBT XRT Concurrent chemotherapy Rational Cisplatin, 5-FU and paclitaxel sensitise tumour tissues to XRT. Increase cell kill in a synergisitic fashion. Also high (25%-50%) chance of micro-metastatic disease at presentation.

Trimodality Therapy Does the radiation add anything, as XRT outcomes are similar to TURBT outcomes? Series Treatment 5 yr survival 5 yr survival with bladder TURBT, XRT and concurrent Chemotherapy. Dunst (n=79) TURBT, cisplatin, XRT 52% 41% RTOG 1993 (n=42) Cisplatin and XRT 42% Kachnic (n=106) TURBT, MCV and XRT 43% RTOG 1997 (n=123) 49% 38% TURBT and Chemotherapy alone Given (n=93) TURBT and MCV 51% 18% Srougi (n=30) Partial C and MVAC 53% 20% It appears that concurrent chemo/XRT does add something.

Shipley- Massachusetts General Protocol Hydronephrosis, Poor renal function Irritable bladder, Low Capacity T4a/4b, CIS If no, Maximal TURBT If yes, For surgery No Significant Tumour Remaining Bulky Tumour Remaining Chemo/ XRT Protocol-Induction CE 4 weeks after induction Radical Cystectomy CR, consolidation Chemoradiation Residual Cancer

MGH- Chemoradiation Protocol Induction 2 cycles of neoadjuvant MCV Methotrexate, cisplatin, vinblastine Concurrent cisplatin and 40Gy XRT Consolidation chemoradiation Further 24Gy XRT Cisplatin based chemotherapy

MGH- Results Patients selected for Trimodality therapy (n=190) Denominator unknown Induction chemotherapy 29 (15%) had residual disease > RC 40 (21%) unable to tolerate ChemoRad > RC 121 (64%) went on to have consolidation Chemoradiation. After 4 years median FU 86 (45%) alive with NED 110 (58%) still had a bladder. Overall survival @ 5 yrs 54%

RTOG bladder sparing protocols All tumours are small. All tumours are able to be maximally resected. These are not the same tumours in cystectomy series. All patients are healthy with good ECOG status All patients were eligible for cystectomy.

Clinical Preictors of Outcome Stage (cT2=62%, cT3=47%) Hydronephrosis (CR= 37% vs 68%) CR on induction chemoradiation Quality of Life Cystectomy for bladder contracture (2-7%) On going urinary symptoms Women-19% incontinence Reduced urinary compliance in 22% Bowel symptoms- 22% Sexual dysfunction

Concerns with Bladder sparing therapy Need for complete TURBT (visibly clear) CR 77% vs 54% for visble and not visible complete resection. Survival 52% vs 34% @ 5 yrs Urothelial cancer change Those with CR to trimodality will develop 20-30% new or recurrent bladder tumor Occur median of 2.1 years and mainly CIS Ultimately 1/3 of recurrence need late cystectomy. Pelvic recurrence 12% Delay in cystectomy Limited diversion alternatives.

Is Bladder Preservation Equivalent to Radical Cystectomy? No but! Viable alternative for Pts wanting to preserve bladder Only small likely decrease in survival But Not all patients are suitable 50% will ultimately have cystectomy Diversion choices will be limited. Operation more difficult and complications higher. Not evidence that quality of life is actually better. A number of pts will have significant bladder and bowel symptoms.