Breast cancer Can I still keep my breast?

Bladder Cancer Organ-Sparing Approaches SAMO Interdisciplinary Workshop on Urogenital Tumors September 15, 2012 Daniel R. Zwahlen, MD Radiation Oncology

History of breast surgery 1894 Radical mastectomy by William Halsted 1967 Modified radical mastectomy 1981 Breast conservation surgery 87 years

Facts on breast conserving therapy Studies have shown that there is no difference in the outcome in all these three types of surgery However surgery is important to eradicate all obvious gross cancer Research and public awareness

Bladder Cancer Can I still keep my bladder? Are there viable alternatives to surgery? 1.Overview of standard treatments and the role of radiation therapy 2.Optimizing radiation therapy and integrated treatment strategies 3.Organ-sparing approaches: Conclusions

Bladder Cancer 1. Overview of standard treatments and the role of radiation therapy

Standard treatment Non muscle-invasive bladder cancer Superficial low-risk bladder cancer Ta without Tis Single, small T1 G1-2 Treatment Recurrence @ 1 and 5 y Superficial high-risk bladder cancer TaT1 G3 +/- Tis, Tis Multiple T1 G2 Treatment Recurrence @ 1 and 5 y TURB + chemoinstillation No furhter treatment prior to recurrence Follow-up cystoscopy 20%, 35% 1 st TURB + chemoinstillation 2 nd TURB after 4-6 weeks BCG (1 year) Follow-up cystoscopy Early cystectomy (timing) >40%, >60% Babjuk et al. Eur Urol 2011;59:997-1008

Standard treatment Muscle-invasive bladder cancer T2-T4a N0 M0 High risk NMIBC Surgically fit patients pt2n0m0 selected patients Surgically unfit patients Surgically non-curable, T4b Treatment OS @ 5 and 10 y Treatment OS @ 5 Radical cystectomy (+ LN) and urinary diversion High volume center better outcome Preop RT not recommended Neoadjuvant ChT (PS 2) Adjuvant ChT in clinical trials (not routine therapeutic option) pn0 65%, 60% pn+ 25%, 20% Multimodality bladder sparing therapy for selected T2 tumors (TURB + RT/ChT) Palliative treatment RT alone Palliative cystectomy (optional, QoL) 30-65% Stenzl et al. Eur Urol 2011;59:1009-1018

Radiation therapy beyond superficial low risk bladder cancer RT as radical treatment has declined 1. Perception that radical cystectomy is more effective in controlling the disease late 1980s: 10-15% 15% worse outcome with RT 2. Improvements in surgical techniques 3. Alternatives for urinary diversion (neobladder) Milosevic et al. Urology 2007;69 (Suppl 1A):80-92

Radiation therapy beyond superficial low risk bladder cancer Reasons for worse outcomes with RT Selection bias: operable vs. inoperable patients TNM: pt vs. ct Understaging of patients in RT series (pt2 vs. ct2) Incomplete TURB, no RT/ChT, no salvage cystectomy for non-responders after RT/ChT Weiss et al. Aktuel Urol 2008;59:123-129

Role of radiation therapy for high-risk T1 bladder cancer TUR-B + adjuvant intravesical therapy vs. TUR-B + RT or RT/ChT Study N Treatment Time to Recurrence (months) Recurrence (%) Mulders et al. 48 TURB only 11 48 27 EJC 30, 1994 51 TURB + BCG/MMC 19 30 25 (Dutch) 17 TURB + RT 25 18 17 Harland et al. J Urol 178, 2007 (GB, phase III) Shahin et al. J Urol 169, 2003 (CH) Weiss et al. JCO 24, 2006 (D) 64 64 TURB + BCG/MCC TURB + RT 44 44 71 69 92 TURB + BCG 64 70 33 84 TURB + RT/ChT (cystectomy) Recurrence with progression (%) 28 34 63 31 16

Role of radiation therapy for high-risk T1 bladder cancer Early vs. late cystectomy vs. TUR-B + RT/ChT Study N Treatment Time to Recurrence (months) DSS @ 5 y (%) Stöckle et al. 55 Early cystectomy 60 90 Eur Urol 13, 1987 39 Late cystectomy 60 61 Denzinger et al. Eur Urol 53, 2008 54 51 Early cystectomy Late cystectomy 60 60 83 67 Weiss et al. JCO 24, 2006 84 TURB + RT/ChT (cystectomy) 62 82 Selection bias: patients who underwent late cystectomy failed conservative treatment

Role of radiation therapy for high-risk T1 bladder cancer: QoL TRUB + RT/ChT Weiss et al. JCO 2006;24:2318-2324, p.2322

Role of radiation therapy for high-risk T1 bladder cancer Take home messages Treatment of high-risk T1 bladder cancer remains challenging Results of TURB + intravesical therapy are unsatisfying Early cystectomy is associated with morbidity TURB + RT/ChT offers a reasonable alternative in close collaboration with urologist Phase III studies are needed but will it be done? Weiss et al. Strahlenther Onkol 2008;184:443-449

Role of radiation therapy for muscle-invasive bladder cancer No Phase III data comparing organ-sparing approach vs. cystectomy SPARE trial (ISCRCTN: 61126465) [closed due to poor accrual] Huddart et al. BJU Int 2010;106:753-755 Eradicate muscle-invasive bladder Preserve normal bladder function Overall survival is not compromised

Role of radiation therapy for muscle-invasive bladder cancer RT alone vs. cystectomy (Evidence level 2 and 3) Study N Treatment Recurrence @ 5 y (%) Duncan et al. Radiother Oncol 260, 1986 Borgaonkar et al. Clin Oncol 14, 2002 963 RT alone (1971-1982) 163 RT alone (1994-1998) Overall Survival @ 5 y (%) 37 T2: 40; T3: 26; T4:12 50 45 T2: 48; T3: 26 Stein et al. JCO 19, 2001 Grossman et al. NEJM 349, 2003 Shariat et al. J Urol 176, 2006 105 4 Cystectomy + LN (1971-1997) (no other treament: 84%) 307 Cystectomy + LN (n=154) Cystectomy + LN+ neoadj. ChT (n=153) (1987-1998) 888 Cystectomy + LN (1984-2003) (neoadjv. ChT: 5%; adjv. RT: 5%) 30 60-45 58 66 43 57 (p=0.06)

RT alone for muscle-invasive bladder cancer RT alone (historic data) Selection bias: Patients often in poor health condition, unfit for surgery 1. 70% complete regression 2. 30-54% local control @ 5 years James et al. NEJM 2012;366:1477-14881488 3. >50% developed distant metastasis 4. Salvage cystectomy <30% Milosevic et al. Urology 2007;69 (Suppl 1A):80-92

Role of radiation therapy for muscle-invasive bladder cancer Preoperative RT + cystectomy vs. RT alone Preoperative RT + cystectomy vs. cystectomy (Evidence level 1 and 2) Study N Stage Experimental Arm Control Arm Overall Survival @ 5 y (%) Bloom et al. 18 T3 Preop RT (40 Gy) RT alone (60 Gy) 38 vs. 29 Br J Urol 54, 1982 9 + cystectomy + salvage cystectomy (n.s.) Sell et al. Scand J Urol Nephrol 138, 1991 18 3 T2-T4a Preop RT (40 Gy) + cystectomy RT alone (60 Gy) + salvage cystectomy 20 vs. 20 (n.s.) Miller et al. Cancer 39, 1977 68 T2-T3 Preop RT (50 Gy) + cystectomy RT alone (70 Gy) + salvage cystectomy 46 vs 16 (p<0.01) Anderstrom et al. Eur Urol 9, 1983 44 T1-T3 Preop RT (5 x 4 Gy) + cystectomy Cystectomy alone 75 vs. 61 (n.s.)

Role of radiation therapy for muscle-invasive bladder cancer RT and ChT (neoadjuvant, concomitant, adjuvant) (Evidence level 1 and 2) Before 2012 Study N Stage Experimental Arm Control Arm Overall Survival @ 5 y (%) Richards et al. 12 T3 RT + adj ChT RT alone 35 vs. 37 Br J Urol 55, 1982 9 (Doxo + 5-FU x 4) (n.s) Shearer et al. Br J Urol 62, 1986 42 3 T3 Neoadj + RT + adj ChT (MTX) RT alone (64 Gy) or Preop RT 44 Gy + cystectomy 39 vs. 37 (n.s.) Shipley et al. JCO 16, 1998 (RTOG 89-03) 12 3 T2- T4 Neoadj ChT (MCV) + TURB + 39.6 Gy (Pelvis) + RT/ChT (25.2 Gy/Cis) when CR otherwise cystectomy TURB + 39.6 Gy (Pelvis) + RT/ChT (25.2 Gy/Cis) when CR otherwise cystectomy 48 vs. 49 (n.s.) No difference in CR International collaboration Lancet 354, 1999 97 6 T2- T4 Neoadj ChT (CMV) + RT or cystectomy RT or cystectomy 55 vs. 50 pcr = 32.5%

RT and concomitant ChT (Evidence level 2 and 3) Before 2012 Role of radiation therapy for muscle-invasive bladder cancer Study N Stage RT/ChT pcr (%) RT/ChT Overall Survival (%) Zietman et al. 18 T2- max TURB + 42.5 Gy (bid) 78 when pcr 22.5 Gy @ 3 y: 83 J Urol 160, 1998 (MGH) T4a + conc ChT (Cis + 5-FU) (bid) + conc ChT (Cis + 5-FU) + adj ChT (MCV x 3) with bladder @ 3 y: 78 Kaufmann et al. Oncologist 5, 2000 (RTOG 95-06) 34 T2- T4a max TURB + 24 Gy (bid) + conc ChT (Cis + 5-FU) 67 when pcr 20 Gy (bid) + conc ChT (Cis + 5-FU) @ 3 y: 83 with bladder @ 3 y: 66 Sauer et al. IJROBP 40, 1998 33 3 T1-4 TURB + 50.0-59.4 Gy + conc ChT (Carbo/Cis) 71 - @ 5 y: 58 with bladder @ 5 y: 41 R-Status is prognostic Rödel et al. JCO 14, 2002 41 5 T1-4 TURB + 50.0-59.4 Gy + conc ChT (Carbo/Cis) 72 - @ 5 y: 50 With bladder @ 5 y: 42 R-Status is prognostic

Role of radiation therapy for muscle-invasive bladder cancer RT and concomitant ChT vs. RT alone (Evidence level 1) 2012 Study N Neoadj ChT Treatment DFS (%) 5 y Overall Survival (%) James et al. 360 31 % TURB + RT (55 Gy/20f or 64 Gy/32) @ 2 y: 67 48 (95 % CI 40-55) NEJM 366, 2012 Median age: 72 y (64-76) M : F = 4 : 1 PS 0: 64 % (2001-2008) 43 centers 34 % + conc ChT (5-FU + MTX) (n=173, 56 % R0) vs. TURB + RT (55 Gy/20f or 64 Gy/32) (n=173, 53 % R0) HR: 0.66 @ 2 y: 54 vs. 35 (95 % CI 28-43) @ 2 y: n.s. Cystectomy @ 2 y (secondary endpoint) RT/ChT: 11.4 % vs. RT alone: 16.8% (p=0.07) Effecitve radiosensitization without the need of cisplatin

Role of radiation therapy for muscle-invasive bladder cancer RT and concomitant ChT vs. RT alone (Evidence level 1) 2012 Study N Neoadj ChT Treatment Toxicity RTOG G 3-4 Toxicity LENT/SOM G 3-4 James et al. 360 31 % TURB + RT (55 Gy/20f or 64 Gy/32) 8 54 NEJM 366, 2012 Median age: 72 y (64-76) M : F = 4 : 1 PS 0: 64 % (2001-2008) 43 centers 34 % + conc ChT (5-FU + MTX) (n=173, 56 % R0) vs. TURB + RT (55 Gy/20f or 64 Gy/32) (n=173, 53 % R0) vs. 16 (n.s.) vs. 51 (n.s.) RT volume and fractionation had no impact on toxicity Whole bladder RT did not impair post-treatment treatment bladder function or bladder filling capacity

Role of radiation therapy for muscle-invasive bladder cancer Take home messages No Phase III data comparing organ-sparing approach vs. cystectomy RT/ChT is effective treatment that produces Better results than RT alone Complete eradication of tumour (60-85 %) Sustained local control (80 % bladder preservation) Prolonged survival in selected patients (40-60 %) QoL after bladder preservation remains intact

Bladder Cancer 2. Optimizing radiation therapy and integrated treatment strategies

Optimizing radiation therapy for bladder cancer Bladder cancer is radiosensitive! 55 Gy: 50 % CR for macroscopic tumours RT should start 4 weeks after max TURB Elective LN-irradiation is recommended (45 Gy) Tumour-Boost (3DCRT or IMRT/VMAT) ( 60-70 Gy) Minimal dose for adjuvant setting is 50 Gy Weiss et al. Aktuel Urol 2008;59:123-129 Rödel et al. JCO 2006;24:5536-5544

Optimizing radiation therapy for bladder cancer Beware of organ motion! RT volume should account for daily change in bladder and tumour position as a result of variation of bladder and rectal filling Treatment margins: 1.5-2 cm Impacts on toxicity produced

Transverse, sagittal and coronal CT simulation images of bladder positions from 15 daily cone-beam CT images taken consecutive prior to RT Needs to be addressed using modern RT techniques as IMRT or VMAT Rosewall et al. Radiother Oncol 2010;97:40-47, p.44

Integrated treatment strategies for bladder cancer Rödel et al. JCO 2006;24:5536-5544, p.5537

Integrated treatment strategies Evolutionary process for bladder cancer Constant improvement of results Optimized multidisciplinary teamwork Ott et al. Clinical Oncology 2009;21:557-565, p.561

Bladder Cancer 3.Organ-sparing approaches: Conclusions

Bladder Cancer Can I still keep my bladder? YES BUT

Organ-sparing approaches: Patient selection Only in a multidisciplinary team Small tumour < 5 cm, no associated CIS No lymph nodes or distant metastases Normally functioning bladder Max TURB required Lifelong cystoscopic bladder surveillance Salvage cystoscopy should be possible

Organ-sparing approaches: Conclusions Limited Stage RT/ChT Cystectomy Limited Stage Cystectomy not possible (comorbidities) Advanced Stage Cystectomy not adequate (metastases) RT or RT/ChT for palliation RT/ChT with curative intention Alternative to cystectomy Research and public awareness Ott et al. Clinical Oncology 2009;21:557-565, p.561 Khosravi-Shahi et al. Surg Oncol 2012;21:17-22

Thank you

Appendix

Role of radiation therapy for muscle-invasive bladder cancer James et al. NEJM 2012;366:1477-1488

Role of radiation therapy for muscle-invasive bladder cancer RTOG/EORTC Late Radiation Morbidity Scoring Schema Organ tissue Bladde r 0 1 2 3 4 5 none www.rtog.org Slight epithelial atrophy Minor telangiectasia (microscopic hematuria) Moderate frequency Generalized telangiectasia Intermittent macroscopic hematuria Severe frequency and dysuria Severe generalized telangiectasia (often with petechiae) Frequent hematuria Reduction in bladder capacity (<150 cc) Necrosis/ Contracted bladder (capacity <100 cc) Severe hemorrhagic cystitis Dead

Role of radiation therapy for muscle-invasive bladder cancer

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