Collection of Recorded Radiotherapy Seminars

Transcription

1 IAEA Human Health Campus Collection of Recorded Radiotherapy Seminars

2 Conservative Treatment of Invasive Bladder Cancer Luis Souhami, MD Professor Department of Radiation Oncology University, Montreal, Canada

3 Bladder Cancer - USA Bladder 17,580

4 Bladder Cancer New Cases (males) - Canada

5 Lifetime Probability of Developing Cancer, by Site, Women, US, Site Risk All sites 1 in 3 Breast 1 in 7 Lung & bronchus 1 in 17 Colon & rectum 1 in 18 Uterine corpus 1 in 38 Non-Hodgkin lymphoma 1 in 57 Ovary 1 in 59 Pancreas 1 in 83 Melanoma 1 in 82 Urinary bladder 1 in 91 Uterine cervix 1 in 128 Source:DevCan: Probability of Developing or Dying of Cancer Software, Version 5.1 Statistical Research and Applications Branch, NCI,

6 2010 Estimated US Cancer Deaths Lung & bronchus 29% Prostate 11% Colon & rectum 9% Pancreas 6% Leukemia 4% Non-Hodgkin 4% lymphoma Esophagus 4% Liver & intrahepatic 4% bile duct Urinary bladder 3% Kidney & renal pelvis 3% All other sites 23% Men 299,200 Women 270,290 26% Lung & bronchus 15% Breast 9% 5% 7% 3% 4% 3% 2% 2% Colon & rectum Ovary Pancreas Leukemia Non-Hodgkin lymphoma Uterine corpus Liver & intrahepatic bile duct Brain/ONS 24% All other sites ONS=Other nervous system. Source: American Cancer Society, 2004.

7 Extent of Primary Bladder Cancer AJCC

8 AJCC Staging Ta non-invasive papillary carcinoma Tis in situ T1 invades subepithelial connective tissue T2 invades muscle pt2a - superficial muscle pt2b - deep muscle T3 invades perivesical tissues pt3a microscopically pt3b macroscopically (extravesical) T4 outside bladder T4a invades prostatic stroma, uterus, vagina T4b invades pelvic wall, abdominal wall

9 AJCC Staging N0 no nodes N1 single node in the true pelvis N2 multiple nodes in the true pelvis N3 nodal metastasis to the common iliac nodes M0 no distant metastasis M1 distant metastasis

10 Bladder Cancer - Facts 70% have localized disease at diagnosis Often multifocal Most are transitional cell carcinomas Hematuria most common sign

11 Bladder Cancer - Facts Radical cystectomy is considered standard therapy for invasive bladder cancer Survival unchanged over last decades Metastatic disease Stein, Skinner BJU 2004

12 Bladder Cancer Pelvic Nodes pt1 5% 5% pt2 30% 18% pt3a - 31% 27% pt3b - 64% 45% pt4-50% 43% Skinner J Urol 1982 Stein, Skinner BJU 2004

13 Combined treatment in modern oncology Major goal is organ preservation Breast cancer Anal cancer Larynx cancer Esophagus cancer Prostate cancer Soft tissue sarcomas Why not bladder cancer?

14 Is there an alternative for a radical cystectomy?

15 Muscle Invasive Disease Surgery is standard treatment Overall Survival Node + Survival Stein, Skinner BJU 2004

16 Invasive Bladder Cancer Cystectomy Bladder preservation Cure the patient Avoid recurrence Keep adequate quality of life

17 How to keep the same control and cure rates? Combined treatment (tri-modality) Maximum transurethral bladder tumor resection (TURBT) Radiation therapy Chemotherapy

18 Pioneering Studies Harvard University MGH Boston University of Erlangen Germany University of Paris France

19 Agent CDDP 15 mg/mg 2 5-FU 400 mg/mg 2 X RT 3.0 Gy BID X Cystoscopy (w/ biopsy ) University of Paris Hypofractionation BID X After maximum TURBT X X X X X X X X X X X X X X CDDP 15 mg/mg 2 5-FU 400 mg/mg 2 RT 2.5 Gy BID X X X X X X X X X X X X X X X X Housset et al J Clin Oncol 1993

20 University of Erlangen Rodel et al J Clin Oncol 2002

21 Harvard University TURBT XRT (40Gy) + Concomitant Chemotherapy Cystoscopic response evaluation CR Consolidation Chemo-radiation (64Gy) +/- adjuvant chemo Non-CR Radical Cystectomy +/- adjuvant chemo Courtesy Dr J. Efastathiou

22 The MGH and Erlangen Treatment Algorithm

23 RTOG and MGH Regimen Shipley et al. Sem Radiat Oncol % 20-30%

24 Bladder Conservation: Evolution of the MGH and RTOG approach Courtesy of Dr J Efstathiou Neoadjuvant chemo Response evaluation Accelerated radiation Adjuvant chemotherapy Enhanced Radiation sensitization Adjuvant chemotherapy MCVx2 RT + C bidrt+c/5fu MCV x 3 bidrt+c/tax G + C x 4

25 Long-term MGH Experience N = 348 Clinical stages T2-T4a Median age 66.3 years (range ) Median FU for those alive 7.7 years

26 Long-term MGH Experience Background Characteristics (n=348) Gender Male 74% Female 26% Clinical Stage T2 54% T3 38% T4a 8% Visibly complete TURBT Yes 65% No 33% Hydronephrosis Yes 17% No 83%

27 Long-term MGH Experience Outcomes CR rate 72% Overall Survival 5 yrs 52% 10 yrs 35% 15 yrs 22% Disease Specific Survival 5 yrs 64% 10 yrs 59% 15 yrs 57% % undergoing Cystectomy* 29% Immediate (non-cr) 17% Salvage 12% *No patient required cystectomy due to treatment-related toxicity

28 Long-term MGH Experience % 43% 41% 27% 28% 16%

29 Long-term MGH Experience % 59% 57% 80% of those alive at 5 years still have native bladder

30 Long-term MGH Experience % 67% 63% 53% 49% 49%

31 Long-term MGH Experience Neoadjuvant chemotherapy

32 Long-term MGH Experience Immediate versus Delayed Cystectomy 1.00 Disease-specific survival Number at risk Immediate Delayed Log-rank test: p = Follow-up time (years) Immediate cystectomy Delayed cystectomy

33 All TURBT TURBT patients complete not complete p value Number CR rate 72% 79% 57% < year outcomes Long-term MGH Experience The value of complete TURBT Overall Survival 52% 57% 43% DSS 64% 68% 56% 0.03 % undergoing cystectomy TOTAL 29% 22% 42% <0.001 Immediate (non-cr) 17% 11% 29% Salvage 12% 11% 13%

34 Bladder Cancer Preservation Contemporary Series Series # Pts 5-yr Surv. Cystectomy (%) 10-yr Surv. (%) USC MSKCC Bladder Preservation Erlangen Harvard RTOG

35 Results: Surgery vs. Trimodality Rene, Cury, Souhami: Current Oncology 2009 * * USC: 39% of patients <pt1 disease

36 MGH Quality of Life Study 221 patients, urodynamics study, QOL questionnaire 78% have compliant bladders with normal capacity and flow parameters 85% have no urgency or occasional urgency 25% have occasional to moderate bowel control symptoms 50% of men have normal erectile function Zietman et al J Urol 2003

37 Late Pelvic Toxicity: RTOG Results 157 patients with bladder preservation who survived 2 to 13 years (median follow-up 5.2 years) 22% Grade 1 10% Grade 2 7% Grade 3 (5.7% GU, 1.9% GI) 0% Grade 4 0% Grade 5 Efstathiou et al J Clin Oncol 2009

38 53 patients Median age: 77 years M/F: 37/16 T2:68%; T3:30%; T4:2% Complete TURBT: 62% 48 pts (90%) completed therapy Complete response: 59%

39 5 year OS T2: 45.2% 5 year OS T3-T4: 28.1% Overall Survival - Subgroup analysis Percent survival T2 T3-T months

40 5 year CSS T2: 59.0% 5 year CSS T3-T4: 33.8% =50.2% Cause-specific Survival - Subgroup analysis Percent survival months T2 T3-T4 Log-rank (Mantel-Cox) Test Chi square df P value P value summary Are the survival curves sig different? ** Yes

41 Acute toxicity Hematological Grade 1-2: 28 patients (52.8%) Grade 4: 2 patients (3.7%) Gastrointestinal Grade 1-2: 26 patients (49.0%) Grade 3: 4 patients (7.5%) Grade 4: 2 patients (3.7%) Genitourinary Grade 1-2: 30 patients (56.6%) Grade 3: 2 patients (3.7%) Grade 4: 1 patient (1.9%)

42 Late toxicity 7 Grade 1 Urinary frequency/dysuria (13.2%) 4 Grade 2 Hematuria (7.6%) intermittent gross hematuria 4 Grade 3 Hematuria (7.6%) persistent gross hematuria or clots 4 Grade 1 diarrhea (7.6%)

43 Bladder Preservation Proper patient selection Complete TURBT Single lesion (< 5 cm) No lymph node disease Absence of Cis No hydronephrosis Adequate renal function Combined treatment modality

44 Bladder Cancer Pelvic Nodes pt1 5% 5% pt2 30% 18% pt3a - 31% 27% pt3b - 64% 45% pt4-50% 43% Skinner J Urol 1982 Stein, Skinner BJU 2004

45 Radiation Therapy Lymphatics

46 Treatment Volume RTOG

47 What Dose? Whole small pelvis Gy Boost primary tumor Gy

48 IMRT in Bladder Cancer

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50 Bowel Rectum Lymph node

51 What Chemotherapy? Period # Pts Regimen CR (%) 5-yr S 5-yr S (Bladder) RT alone RT+Carbo RT+Cis RT+Cis+5FU Rodel C Strahlenther Onkol 2004

52 New chemotherapy agents Taxol Gemcitabine Bi-weekly gemcitabine Hypofx RT + weekly gemcitabine Oh et al Int J Radiat Oncol Biol Phys 2009 Choudhury et al J Clin Oncol (in press)

53 Conclusion Combined treatment with surgery, radiation therapy and chemotherapy (trimodality therapy) provides results similar to radical cystectomy 60-70% of patients preserve the bladder with an adequate urinary function

54 Conclusions Trimodality therapy is a valid alternative for the majority of patients The control of metastatic disease remains a challenge