Breast cancer Can I still keep my breast?

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

2 Breast cancer Can I still keep my breast?

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

4 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

5 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

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

7 Standard treatment Non muscle-invasive bladder cancer Superficial low-risk bladder cancer Ta without Tis Single, small T1 G1-2 Treatment 1 and 5 y Superficial high-risk bladder cancer TaT1 G3 +/- Tis, Tis Multiple T1 G2 Treatment 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:

8 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 5 and 10 y Treatment 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:

9 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

10 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:

11 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 EJC 30, TURB + BCG/MMC (Dutch) 17 TURB + RT 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) TURB + BCG/MCC TURB + RT TURB + BCG TURB + RT/ChT (cystectomy) Recurrence with progression (%)

12 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) 5 y (%) Stöckle et al. 55 Early cystectomy Eur Urol 13, Late cystectomy Denzinger et al. Eur Urol 53, Early cystectomy Late cystectomy Weiss et al. JCO 24, TURB + RT/ChT (cystectomy) Selection bias: patients who underwent late cystectomy failed conservative treatment

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

14 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:

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

16 Role of radiation therapy for muscle-invasive bladder cancer RT alone vs. cystectomy (Evidence level 2 and 3) Study N Treatment 5 y (%) Duncan et al. Radiother Oncol 260, 1986 Borgaonkar et al. Clin Oncol 14, RT alone ( ) 163 RT alone ( ) Overall 5 y (%) 37 T2: 40; T3: 26; T4: T2: 48; T3: 26 Stein et al. JCO 19, 2001 Grossman et al. NEJM 349, 2003 Shariat et al. J Urol 176, Cystectomy + LN ( ) (no other treament: 84%) 307 Cystectomy + LN (n=154) Cystectomy + LN+ neoadj. ChT (n=153) ( ) 888 Cystectomy + LN ( ) (neoadjv. ChT: 5%; adjv. RT: 5%) (p=0.06)

17 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 % local 5 years James et al. NEJM 2012;366: >50% developed distant metastasis 4. Salvage cystectomy <30% Milosevic et al. Urology 2007;69 (Suppl 1A):80-92

18 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 5 y (%) Bloom et al. 18 T3 Preop RT (40 Gy) RT alone (60 Gy) 38 vs. 29 Br J Urol 54, cystectomy + salvage cystectomy (n.s.) Sell et al. Scand J Urol Nephrol 138, T2-T4a Preop RT (40 Gy) + cystectomy RT alone (60 Gy) + salvage cystectomy 20 vs. 20 (n.s.) Miller et al. Cancer 39, 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, T1-T3 Preop RT (5 x 4 Gy) + cystectomy Cystectomy alone 75 vs. 61 (n.s.)

19 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 5 y (%) Richards et al. 12 T3 RT + adj ChT RT alone 35 vs. 37 Br J Urol 55, (Doxo + 5-FU x 4) (n.s) Shearer et al. Br J Urol 62, 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 Gy (Pelvis) + RT/ChT (25.2 Gy/Cis) when CR otherwise cystectomy TURB 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, T2- T4 Neoadj ChT (CMV) + RT or cystectomy RT or cystectomy 55 vs. 50 pcr = 32.5%

20 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 Gy (bid) 78 when pcr 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 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 + 3 y: 83 with 3 y: 66 Sauer et al. IJROBP 40, T1-4 TURB Gy + conc ChT (Carbo/Cis) 71 5 y: 58 with 5 y: 41 R-Status is prognostic Rödel et al. JCO 14, T1-4 TURB Gy + conc ChT (Carbo/Cis) 72 5 y: 50 With 5 y: 42 R-Status is prognostic

21 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 % TURB + RT (55 Gy/20f or 64 2 y: (95 % CI 40-55) NEJM 366, 2012 Median age: 72 y (64-76) M : F = 4 : 1 PS 0: 64 % ( ) 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: 2 y: 54 vs. 35 (95 % CI 2 y: n.s. 2 y (secondary endpoint) RT/ChT: 11.4 % vs. RT alone: 16.8% (p=0.07) Effecitve radiosensitization without the need of cisplatin

22 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 % 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 % ( ) 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

23 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

24 Bladder Cancer 2. Optimizing radiation therapy and integrated treatment strategies

25 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) ( Gy) Minimal dose for adjuvant setting is 50 Gy Weiss et al. Aktuel Urol 2008;59: Rödel et al. JCO 2006;24:

26 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: cm Impacts on toxicity produced

consecutive prior to RT Needs to be addressed using modern RT

27 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

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

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

32 Bladder Cancer 3.Organ-sparing approaches: Conclusions

33 Bladder Cancer Can I still keep my bladder? YES BUT

34 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

35 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: , p.561 Khosravi-Shahi et al. Surg Oncol 2012;21:17-22

36 Thank you

37 Appendix

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

39 Role of radiation therapy for muscle-invasive bladder cancer RTOG/EORTC Late Radiation Morbidity Scoring Schema Organ tissue Bladde r none 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

40 Role of radiation therapy for muscle-invasive bladder cancer

41 Role of radiation therapy for muscle-invasive bladder cancer

42 Role of radiation therapy for muscle-invasive bladder cancer

43 Role of radiation therapy for muscle-invasive bladder cancer

49 References European Urology Association 2012: Guidelines on NonNon-invasive Bladder Cancer (TaT1 and CIS) European Urology Association 2012: Guidelines on Bladder Cancer Muscle Muscle--invasive and Metastatic Babjuk M et al. EAU guidelines on non.muscle non.muscle--invasive urothelial carcinoma of the bladder, the 2011 update. European Urology 2011;59: ;59: Borgaonkar S et al. Radical radiotherapy and salvage cystectomy as the primary management of transitional cell carcinoma of the bladder. Results following the introduction of a CT planning technique. Clinical Oncology 2002;14: ;14: Denzinger S et al. Early versus deferred cystectomy for initial high high--risk pt1g3 urothelial carcinoma of the bladder: Do risk factors define feasibility of bladderbladder-sparing approach? European Urology 2008;53: ;53: Efstathiou JA et al. BladderBladder-sparing approaches to invasive disease. World Journal of Urology 2006;24: ;24: International collaboration of trialists. trialists. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle muscle--invasive bladder cancer: a randomised controlled trial. Lancet 1999;354: ;354: Grossman HB et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Eng J Med 2003; 349:59 349: Harland SJ et al. A randomized trial of radical radiotherapy for the management of pt1g3nxm0 transitional cell carcinoma of the bladder. The Journal of Urology 2007;178: ;178: Herr HW et al. Neoadjuvant chemotherapy and bladder bladder--sparing surgery for invasive bladder cancer: Ten Ten--year outcome. J Clin Oncol 1998;16: ;16: Huddart RA et al. Life and death of SPARE (Selective bladder preservation against radical excision): Reflections on why the SPARE trial closed. BJU International 2010;106: ;106:

50 James ND et al. Radiotherapy with or without chemotherapy in muscle muscle--invasive bladder cancer. N Engl J Med 2012;366: ;366: Khosravi Khosravi--Shahi P et al. Selective organ preservation in musclemuscle-invasive bladder cancer: Review of the literature. Surgical Oncology 2012;21:e ;21:e17--e22 Mak RH et al. Bladder preservation: optimizing radiotherapy and integrated treatment strategies. BJU International 2008;102: ;102: Milosevic M et al. Radiotherapy for bladder cancer. Urology 2007;69(Suppl 1A):80 1A): Ott OJ et al. Radiochemotherapy for bladder cancer. Clinical Oncology 2009;21: ;21: Rödel C et al. Trimodality treatment and selective organ preservation for bladder cancer. J Clin Oncol 2006;24: ;24: Rödel C et al. Organ preservation by combined modality treatment in bladder cancer: The European perspective. Semin Radiat Oncol 2004;15: ;15: Rödel C et al. Combined Combined--modality treatment and selective organ preservation in invasive bladder cancer: Long Long-term results. J Clin Oncol 2002;20: ;20: Rosewall T et al. The relationship between external beam radiotherapy dose and chronic urinary dysfunction A methodological approach. Radiotherapy and Oncology 2010;97: ;97: Sauer R et al. Efficacy of radiochemotherapy with platin derivates compared to radiotherapy alone in organ organ-sparing treatment of bladder cancer. Int J Radiation Oncology Biol Phy 1998;40: ;40: Shahin O et al. A retrospective analysis of 153 patients treated with or without intravesical Bacillus CalmetteCalmetteGuerin for primary stage T1 grade 3 bladder cancer: recurrence, progression and survival. The Journal of Urology;169:96 Urology;169: Shariat SF et al. Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: A contemporary series from the bladder cancer research consortium. The Journal of Urology 2006;176: ;176: Shipley WU et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: Initial results of Radiation Oncoology Group J Clin Oncol 1998;16: ;16:

51 Shipley WU et al. Old drugs, new purpose bladder cancer turning a corner. N Engl J Med 2012;366: ;366: Stenzl A et al. Treatment of muscle muscle--invasive and metastatic bladder cancer: Update of the EUA guidelines. European Urology 2011;59: ;59: Weiss C et al. Radiochemotherapy after transurethral resection for high high--risk T1 bladder cancer: An alternative to intravesical therapy for early cystectomy? J Clin Oncol 2006;24: ;24: Weiss C et al. Radiochemotherapeutische Optionen beim Harnblasenkarzinom. Aktuelle Urologie 2008;39: ;39: Weiss et al. Treatment options for high high--risk T1 bladder cancer. Strahlenther Onkol 2008;184: ;184: Zietman AL et al. A phase I/II trial of transurethral surgery combined with concurrent cisplatin, 5 5--Fluorouracil and twice daily radiation followed by selective bladder preservation in operable patients with muscle invading bladder cancer. The Journal of Urology 1998;160: ;160:

Collection of Recorded Radiotherapy Seminars

IAEA Human Health Campus Collection of Recorded Radiotherapy Seminars http://humanhealth.iaea.org Conservative Treatment of Invasive Bladder Cancer Luis Souhami, MD Professor Department of Radiation Oncology