Cochrane metaanalysis 5 year OS Intent to treat

Transcription

1 RADICAL CYSTECTOMY IS THE ONLY EFFECTIVE TREATMENT FOR PATIENTS WITH OPERABLE MUSCLE INVASIVE BLADDER CANCER The Con position Scott Tyldesley Radiation Oncology, Vancouver Centre, BC Cancer Agency Cochrane metaanalysis 5 year OS Intent to treat Odds ratio: 1.85 (CI ) Shelley, Cochrane Reviews Volume 3,

2 An Old debate Old Trials 1) Wallace & Bloom: BJU 1982: 54: RCT: 189 patients with T3 bladder cancer 40 Gy plus early cystectomy vs 40 Gy whole pelvis + 20Gy bladder boost with delayed salvage cystectomy prn 5 yr OS: 38% vs 29% (NS) Accrual 1966 to

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4 What has Changed? Chemotherapy ~ Cisplatin Cochrane 2003 o Metanalysis of RCT of Cisplatin with local Tx of T2-T4a TCC Cisplatinum combination chemotherapy provided OS benefit: o HR 0.86, P=0.003 o 5% Absolute decrease in deaths From 45 to 50% 5 yr survival 4

5 Multicenter Canadian NCIC trial 99 patients < 76 yo good performance status T2-T4 Planned for: preoperative radiation definitive radiation Radiation: 4000/20# to full pelvis 2000/10# bladder boost Chemotherapy 100 mg/m 2, q 2wks for 3 cycles Follow up cystoscopy at 12, 18, and 24 weeks Treatment response: at planned cystectomy, 13/24 in the chemo arm. Coppin et al, 1996 Concurrent Chemo-RT Improved pelvic progression free survival Pelvic recurrence CH + Local Local only 2 yrs 33% 55% 5 yrs 40% 59% P = Coppin et al,

6 Trimodality Protocol Shipley et al, 2004 Survival following Trimodality Tx 190 patients with T2-T4a disease Treated at Mass General from /3 patients retain their own bladder 6

7 QOL after trimodality treatment 221 patients treated with trimodality approach ( ) T2-T4a 71 were alive with native bladder in 2001 med f/u 6.3 years Of these: QOL questionnaire urodynamic studies. Urodynamic study N=32 % Normal bladder function 75% Reduced bladder compliance Bladder hypersensitivity and incontinence 22% 6% Zeitman et al, 2003 QOL after trimodality treatment Distress Sexual Function 54% of men maintained erections Zeitman et al,

8 Function majority of conserved bladders function normally Symptoms: 6% flow problems, 10% frequency, 25% nocturia 5% urinary embarrassment 9% diarrhea, 14% fecal urgency, 2% rectal blood Overall toxicity acceptable Cystectomy for bladder dysfunction rare (<5%) Cystectomy: Neobladder vs Ileal conduit Swedish Registry study 1997 to T2-4 Bladder Ca 1143 Cystectomy 64% Ileal conduit 36% continent diversion 8

9 What bladder: Neobladder vs Ileal conduit vs conservation If ileal conduits work so well, why are there neobladders? If neobladders work so well, why are there so many different types? If neobladders are so great, why do most patients only get ileal conduits? Comparison of Contemporary Results Centre Treatment N 5 Yr DSpS % 5Yr OS MGH RT/CT % 54% Erlangen* RT +/- CT % 45% BCCA RT/CT 26 42% ~ 39% 47% RTOG 8903 RT/CT % U of Cali Cystectomy % MSKCC Cystectomy % ~ 45% Intergroup Cystectomy % * Not all had CT 9

10 Comparison of Results T2 Centre Treatment % 5 yr DSpS % 5Yr OS MGH RT/CT 74% 62% BCCA RT/CT 62% ~ 54% 57% Erlangen RT +/- CT 56% USC* Cystectomy 72% Intergroup Cystectomy 57% ~ 63% MSKCC Cystectomy 59% * pt2 Comparison of Results T3-4 Centre Treatment % 5 yr DSpS % 5Yr OS MGH RT/CT 47% 53% BCCA RT/CT 36% ~ 33% 42% Erlangen RT+/-CT 40% USC cystectomy 42% Intergroup cystectomy ~ 32% 33% MSKCC cystectomy 25% 10

11 Guidelines: NICE- UK SIGN- Scotland NCCN- US NICE Guidelines: UK: Muscle invasive tumours and locally advanced disease: All patients with invasive disease (pt2 and above) should be offered a joint meeting with a surgeon, oncologist, clinical nurse specialist, and palliative care specialist if appropriate, to discuss treatment options. There is no clear-cut evidence for the overall superiority of surgery or radiotherapy 11

12 SIGN Guidelines: Scotland: All new invasive and complicated bladder cancer cases must be discussed by a properly constituted multidisciplinary team. SIGN Guidelines: Scotland: Many UK centres have favoured radiotherapy with salvage cystectomy for treatment failure. There have been no randomised controlled trials comparing radical radiotherapy with radical cystectomy alone. There remains a lack of evidence for the overall superiority of surgery or radiotherapy. 12

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14 Bladder Conservation Now: All BCCA are RTOG members 14

15 Future of Conservation: Ongoing Studies: Targeted Tx Trastuzumab Sunitinib Dasantinib CDX 1307 Bevicizumab OGX Future of Conservation: Ongoing Studies: ChemoTx Gemcitabine Cisplatin and 5FU Taxanes Adjuvant Chemo 15

16 Future of Conservation: Ongoing Studies: RadioTx Altered fractionation IMRT IGRT - On board imaging/ cone beam CT - tomotherapy - fiducial markers Image Guided Radiotherapy (IGRT) CT Plan Cone beam image Fields adjusted daily using on beam CT. 16

17 Image Guided Radiotherapy (IGRT) Daily imaging adjustment using Gold seeds placed at time of cystoscopy BCCA Data: Chemo-RT utilization and outcomes 17

18 2000 to 2006 Incident Cases 6271 Bladder Cancers 3079 Invasive Cancers 529 Referred to Rad Onc within 6 mo Dx 244 Radical RT 192 Known Stage & Radical RT 27 Chemo-Radiotherapy ~1% of invasive cases 165 RT alone BCCA CT/RT Overall Survival T2: 6 cases T3-4: 20 cases 18

19 BCCA CT/RT Disease Specific Survival T2: 6 cases T3-4: 20cases My Cases in 2000 to Invasive TCCa patients: 13: Referred with invasive M0 TCC 6: T2-T3,N0 7: locally advanced (T4, N0) or gross node positive 8: Referred post-cystectomy or metastatic TCC 19

20 6 localized (T2-T3, N0) pts Pt age Comorbidity Operable 1 71 Etohic, Dementia, PUD No 2 85 Class IV CHF and CAD No 3 72 Etohic, Dementia, COPD No 4 78 Class III CHF, CAD No 5 73 CAD,ECOG3,Stroke No 6 76 Arryth, Angina, HTN No *Potentially fit for Chemo-RT Case Ms X, 76 year old woman: Dec 2000, clinical ~ T2 bladder cancer with muscle invasion on TURB with post TURB thickening on CT and EUA Hypotensive and arrythmia during TURB thus sent to RO Treated with max TURB, then concurrent Cisplatinum and RT to 64Gy in Jan

21 Case Urologist s note May 2010 She continues to do very well. She is voiding without difficulty and has had no problems. Cystoscopy: Trigone and orifices are unremarkable. The bladder is clean and tumour free and she continues to do exceptionally well. Conclusions Cystectomy is clearly not the only option for MIBCa Trimodality bladder Conserving therapy: Provides similar survival outcomes Leaves an intact functional bladder in 2/3 rd of patients Should be offered to all patients with MIBCa prior to cystectomy 21

22 7 Advanced pts Pt age Comorbidity Operable *1 50 Fit, preop opinion yes 2 86 Dementia, ECOG4 No 3 51 Quad, CHF,T4b No 4 68 MS,Colitis,ECOG4 No 5 63 Fit,T4, ureter&rectal Obs No 6 68 NS,Colitis,OA,ECOG3 Node Quad,ECOG4 Node + *Potentially fit for a trial 22

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24 Tstage * combined chemo (conc or na CT) Crosstabulation Count Tstage Total combined chemo (conc or na CT) n y Total Future Bladder Conservation Study of EGFR and Her-2 in RTOG Bladder Trials Cell cycle regulators in Bladder Cancer 24

25 Adjuvant Chemotherapy Adjuvant chemotherapy Allows treatment based on pathologic staging Avoids overtreatment Does not delay definitive treatment eg surgery or XRT Initial retrospective papers showed significant improvements in 5 yr OS No clear evidence yet Small series Inconsistent results Some closed prematurely But seems to delay recurrence and prevent recurrence in locally advanced. EORTC study underway: 1300 patients > pt3 or node+ Randomized to: I. Immediate cisplatinum based chemo (MVAC or cis-gem) x 4 cycles. II. Deferred chemotherapy at relapse Radiotherapy Planning Accurate radiotherapy to minimal volumes is difficult due to variations in bladder size, shape, and position Studies of planning volumes: GTV fell outside of PTV at least once in 65% of patients Bladder moved outside the treatment volume in 20% Most bladder movement is superiorly in the A/P direction Potential Solutions Planning Imaging: MRI CT planning IMRT: potentially beneficial to decrease toxicity to surrounding structures U/S: can be used to improve consistency of bladder filling prior to treatment 25

26 Trimodality Approach Shipley et al, MGH 190 patients with T2-T4a disease Treated at Mass General from Tx according to 6 RTOG protocols All patients had concurrent cisplatinum Other chemo varied including MVC, paclitaxel, and gemcitabine 2/3 patients able to maintain their bladder 1/3 (66 patients) had cystectomy 41 for incomplete response 25 for recurrent invasive disease 26

27 Comparison of Results Canadian GU ROC Consensus statement: Consultation with a radiation oncologist early in the postoperative period is advised to discuss benefits and side effects of adjuvant radiotherapy in those with adverse pathological features at prostatectomy blah MGH Trimodality Outcomes 27

28 Results Results 28

29 Results Trimodality Bladder Conservation: Why add Chemotherapy: Is there any evidence that chemotherapy increases Overall survival or tumour control in bladder conservation? 29

30 Concurrent Cisplat/RT Trial 1) BL 3 NCIC: Ph III: RT/CisPlat then phys/pt choice cystectomy or consolidation with CisPlat/RT Eligible: T2-T4b 99 patients 50% had RT, 50% had RT then cystectomy Randomized to +/- concurrent CT 100mg/m2 cisplatinum q 2 weekly Conclusions: Increased pelvic control No difference OS - Coppin et al, JCO 14: 2901, ) BL 3 NCIC/EORTC/MRC: 30

31 1) BL 5 NCIC/EORTC/MRC: 5 yr Overall survival, 55% vs 50% p=0.07 pcr rate 33% Ongoing Trials RT Trials 1) MRC: Phase III in Stage I Grade 3 post TURB: Adj RT vs BCG or Mitomycin vs Observation 2) Mt Vernon: Phase III in Locally advanced TCC RT vs RT with Nicotinamide and Carbogen 3) Birmingham 4 arm Phase III in Stage II/III TCC Whole bladder volume RT +/- 5FU/MMC vs Partial bladder RT +/- 5FU/MMC 4) RTOG 0233 Ph III RCT: TURB then Taxol/CisPt & RT vs 5FU/CisPt & RT then 3 wk gap then cysto If CR consolidate Ct/RT if < Cr cystectomy Then 4 cycles adjuvant Gem/CisPt/Taxol 31

32 All Invasive Bladder Cases 3079 cases 32

33 All Radical RT 2000 to 2006 diagnosis N=192 An Old debate 33

34 Symptoms Distress : 6% flow problems, 10% frequency, 25% nocturia 5% urinary embarrassment 9% diarrhea, 14% fecal urgency, 2% rectal blood Function Post conservative treatment symptom scores, show 75% report good urinary function. Overall 22% had some bowel symptoms with 14% experience distress from bowels 8% of men sexually dissatisfied, 54% had functional erections Good overall quality of life < 1-5% require cystectomy for bladder dysfunction after bladder conservation 34

35 BCCA results: (Radical cases) BCCA year cause specific survival 39% T stage 5 yr Survival MS 1 55% 6.1y 2 45% 4.6y 3a 52% 5.2y 3b 28% 1.3y 4a 17% 2.3y 4b 17% 0.8y BCCA results (Radical cases) 35

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