ICUD 2011 Recommendations. Bladder Cancer

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Denis Long
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2 ICUD 2011 Recommendations Bladder Cancer

3 ICUD Bladder Cancer 2011 Chair Mark Soloway Co chair Henk van der Poel

4 Committee Chairs A. Kamat/P. Hegarty M. Amin/V. Reuter P. Karakiewicz/S. Shariat B. Konety/W. Oosterlinck F. Witjes/M. Burger A. Stenzyl/S. Lerner/W. Shipley/D. Quinn/J. Bellmunt

5 ICUD Guidelines on Bladder Cancer: Diagnosis and Evaluation Ashish M. Kamat (MD Anderson Cancer Center, Houston, TX) Paul K. Hegarty (Guy s Hospital, London, UK)

6 Cytology In follow-up of patients with BC, cytology is most useful for diagnosis of high-grade tumor Atypia diagnosis does not help the clinician

7 Eliminate The Term Superficial Bladder Cancer As used it includes: Ta, low grade Ta, high grade CIS T1

8 Superficial Bladder Cancer Implies good prognosis May suggest low grade Patient friendly (as opposed to invasive) To most implies no invasion Perpetuates concept that lamina propria invasion is not a relatively aggressive cancer

9 Cancer Staging The purpose of staging cancer is to communicate the prognosis of a given tumor Superficial adds no information regarding a tumors prognosis Pathologists do not use the term superficial BC

10 Superficial Lying on, not penetrating below, or affecting only the surface. A tumor which invades the lamina propria should not be termed superficial since it is not confined to the surface Merriam-Webster's Collegiate Dictionary, 10th Edition, 1999.

11 Endoscopy/TUR BT Skill Required Teaching

13 My Perception Little Data Wide variability in skill of this common operation Little emphasis on technique Consider the number of articles on RP, lap nephrectomy, vs. TUR of bladder tumor Lack of guidelines on what constitutes adequate resection

15 TUR BT Are They Complete Retrospective review of UM referrals (MSS) All to OR within 4 wks of TURBT for Ta T1 33/47 (70%) had incomplete resection 10 macroscopic at main site 23 tumor at another location

19 TUR BT Complete tumor resection should be attempted except in patients with diffuse CIS Look for CIS

21 Technique A second TURBT should be performed in all patients with high-grade T1 and select HG Ta The optimal timing of repeat TURBT is 4-6 weeks after the first resection

22 Prostatic Urethra Biopsies Routine prostate bxs not recommended Helpful if multifocal urothelial carcinoma of the bladder, CIS, and visible abnormalities of the prostatic urothelium Use loop resection, veru

23 Pathology Mahul Amin (Chair) USA Victor Reuter (Co chair) USA

24 Pathology Should we abandon the term transitional cell carcinoma? Yes Urothelial carcinoma Optimal grading LG/HG or 1 3? LG/HG

26 Minimal (micro) invasion

27 Extensive invasion

30 ICUD-EAU 2011 Recommendations of committee on LG Ta disease Badrinath Konety (USA), Willem Oosterlinck (Belgium), Paul Sved (Aus), Raj Pruthi (USA), Sam Chang (USA), Eduardo Solsona (Spain), Sigurdur Gudjonsson (Sweden), Mark Soloway (USA)

31 Low Grade Ta Cystoscopy is accurate Biopsy needed if: > 0.5 cm, positive cytology, first presentation, > 5 lesions Upper tract evaluation not needed unless symptoms or positive cytology Mucosal biopsies only if positive cytology ( biopsies may enhance implantation)

32 Low Grade Ta Single intravesical MMC or epirubicin post resection. Recurrence rate decreased by 40%. More effective if given same day as resection Additional doses if multiple tumors

33 Low Grade Ta BCG reserved as second line Office fulguration is OK after first TUR if small and appear low grade Formal TUR if cytology positive Cytology not required for follow up

34 Three Confirmatory Studies

35 MSS Do no harm Can monitor small LG Ta tumors Office cautery +/- chemotherapy If TUR BT not deep resection

36 High grade Ta, T1 and CIS ICUD update session prof. Fred Witjes, Nijmegen March 21, 2011 Department of Urology Radboud University Nijmegen Medical Centre The Netherlands

37 High Grade Ta and CIS High risk since 20% risk of progression After TUR of apparent HG Ta instill single MMC or epi Second TUR 2 4 weeks If HG Ta 6 week BCG and 1 3 years of maintenance

38 High Grade Ta and CIS If recurrence or new occurrence of high grade T1 or CIS during BCG consider cystectomy For Ta new tumor resect and continue BCG Early failure on BCG consider RC Late failure consider TUR + intravesical therapy

39 CIS Flourescence endoscopy Do not overdistend bladder Biopsy prostatic urethra if positive cytology and no bladder tumor BCG probably most effective If incomplete response at 3 month can consider another 6 weeks since some patients will still respond; timing of RC is unknown

40 CIS Cystectomy at diagnosis of CIS is overtreatment in 50%

41 T1 Second TUR One to four weeks after first TUR Two options: cystectomy or BCG Maintenance BCG Monitor upper tract

43 High risk superficial bladder cancer Recommendation of primary RC in T1 G3 Associated with CIS > 3 cm (endoscopically difficult) Lymphovascular invasion T1b Within bladder diverticulum Multifocal Prostatic tumor involvement Hautmann

44 Risk Categories of T1 Tumors Low-risk T1 Unifocal disease No associated carcinoma in situ Tumors in an accessible part of the bladder Residual disease less than T1 on restaging TURBT High-risk T1 Multifocal disease Associated carcinoma in situ Tumors located in dome and anterior wall of bladder Residual disease T1 on restaging TURBT

45 Radical cystectomy for BCG failure: has the timing improved? Prof. Mark S Soloway University of Miami Miller School of Medicine

46 Introduction Intravesical BCG : for high-grade Ta, T1 and CIS bladder cancer. BCG is not uniformly effective. More than 30% of them progress requiring radical cystectomy.

47 Introduction Survival following RC is directly related to the pathologic stage. If cystectomy is performed before progression to muscle invasion (<pt2), as is the case when BCG is first initiated, the cancer specific survival is over 90 %.

48 Methods RC from (group 1) RC from (group 2) Pathologic stage and survival were compared.

49 Results 1993 to 2007: 445 patients underwent RC by a single surgical team. 168 (38%) had BCG prior to RC. 152 met the inclusion criteria. (75 group 1 & 77 group 2).

50 Both groups were similar in Results Baseline demographics T-stage prior to BCG initiation BCG cycles received Time interval from initiation to RC.

51 Results There was no change in the proportion of patients undergoing RC with <T2 BC in recent years. 52% in groups 1 and 43% in group 2 had progressed to muscle invasive BC (p=0.5)

52 Results Comparison of Pathologic stage at RC and survival. Characteristic Group 1(%) Group 2(%) P <T2 36(48) 44(57) 0.5 T2 15(20) 13(17) >T2 24(32) 20(26) N+ 12(16%) 8(11%) yr Overall Survival 68±8 60±6 (Events) (Log rank)

53 Results Disease specific survival by group (log rank p=0.2)

54 Results Disease specific survival by final pathologic stage

55 Conclusions A high percentage of patients who undergo radical cystectomy for Ta, T1, and/or CIS after receiving BCG have pt2 or higher BC.

56 Conclusions Over the past 15 years, we did not find a trend towards early surgery at a lower pathologic stage in patients undergoing RC after BCG. Intense monitoring of the BCG patients and optimal timing of RC is essential to improve survival.

57 MIBC Arnulf Stenzl (Chair) Germany Seth Lerner (Co chair) USA Arthur Sagalowsky USA Axel Heidenreich Germany

58 So what s the alternative to cystectomy? Trimodality therapy Maximal TURBT Radiation therapy Chemotherapy

59 Bladder Conservation: Evolution of the MGH and RTOG approach 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

60 Cystectomy gold standard of treatment for localized muscle-invasive bladder cancer Grade B recommendation FOR The quality of the surgery is a confounding factor in interpreting studies of perioperative chemotherapy Grade B recommendation FOR A discrepancy between clinical/cystoscopic & pathologic staging can be anticipated after neoadjuvant chemotherapy & therefore cystectomy is not obviated by response, Grade B recommendation FOR Available data suggest that for average-risk cancer patients with ct2, the benefit of adding chemotherapy to local therapy is modest. In distinction, available studies show a much more substantial benefit for patients with high-risk disease, such as ct3+ and/or LN + cancers Grade B recommendation FOR

61 Meta-Analysis of 10 Randomized Neo-adjuvant Chemotherapy Trials (n=2,687) Survival HR (95% CI) p value Absolute benefit (5 yrs) All patients 0.92 ( ).088 No difference Cisplatin 1.15 ( ).246 No difference Cisplatin Combination Therapy 0.87 ( ).017 5% (1% -7%) 45% 50% Vale CL, Lancet 361: , 2003

62 Neoadjuvant MVAC chemotherapy supported by: A phase III randomised clinical trials (Level 1 evidence) Neoadjuvant cisplatin combination chemotherapy supported by: Two meta-analyses of randomized trials (Level 1 evidence). MVAC chemotherapy in the neoadjuvant setting: Grade A recommendation FOR Cisplatin-based combination therapy in the adjuvant setting: Grade B recommendation FOR Non-Cisplatin-based combination therapy in the neoadjuvant setting: Grade A recommendation AGAINST For patients who are not candidates for cisplatin-based combinations, a clinical trial remains the best choice for patients with locally advanced bladder cancer.

63 The quality of the surgery is a confounding factor in interpreting studies of perioperative chemotherapy A discrepancy between clinical/cystoscopic & pathologic staging can be anticipated after neoadjuvant chemotherapy & therefore cystectomy is not obviated by response, For average-risk cancer patients with ct2, the benefit of adding chemotherapy to local therapy is modest. In distinction, available studies show a much more substantial benefit for patients with high-risk disease, such as ct3+ and/or LN + cancers Grade B recommendation FOR MIBC: Neoadjuvant chemotherapy: Summary 2#

64 Surviv al Adjuvant [Post-Operative] Chemotherapy in Invasive Bladder Cancer Meta-analysis Survival % absolute benefit 25% relative reduction in death HR: 0.75 (p=.019) Events Total 0.1 Adj CT Control Patients at risk Years Adj Chemotherapy Control Eur Urol Aug;48(2):

65 MIBC: Adjuvant chemotherapy: Summary Adjuvant cisplatin-based regimens supported by: a recent large cohort analysis (Level 2A evidence); several relatively small randomised clinical trials (Level 1B evidence) a meta-analysis and composite analysis or randomized trials (Level 1A evidence). Cisplatin-based combination therapy in the adjuvant setting: Grade B recommendation FOR pt3/4 and/or lymph node positive cancer at cystectomy whom has not had neoadjuvant chemotherapy and medically fit the consensus in the writing group is that the trials used in metaanalyses were flawed so as to make definitive conclusions difficult Non-Cisplatin-based combination therapy in the adjuvant setting: Grade A recommendation AGAINST

66 Why Adjuvant Not Delivered Perioperative complications; wound, ileus, SBO, leak, cardiac event Patient not up to it. Ave age 70. Many 80. Patient refuses or delays

67 ICUD EAU GUIDELINES ON BLADDER CANCER Committee 7: Urinary diversion Richard E. Hautmann, Thomas Davidsson, Stefan H. Hautmann Cheryl T. Lee Stephan Madersbacher Murugesan Manoharan David F. Penson Raimund Stein Joachim W. Thuerof Bjoern G. Volkmer Hassan Abol-Enein, S. Gudjonsson Henriette V. Holm Fredrik Liedberg Wiking Mansson Robert D. Mills Eila C. Skinner Urs E. Studer William H. Turner

regionalization High volume surgeons / hospitals

71 ICUD-EAU GUIDELINES ON BLADDER CANCER COMMITTEE 7 FINAL RECOMMENDATION FOR RCX AND UD Centralisation / regionalization High volume surgeons / hospitals Annual case load of 25 procedures Not more than 2 surgeons

Small Cell Carcinoma Rare tumor (neuroendocrine tumor in the lungs) +/- 300 cases reported 0.4 0.

72 Small Cell Carcinoma Rare tumor (neuroendocrine tumor in the lungs) +/- 300 cases reported % of all bladder tumors Age above 60, 80% are males Pathological diagnosis is difficult Usual appearance at stage T2 Metastatic disease in 67% (LN, liver, bone, lung and brain). (Sved et al.,2004))

73 Bladder Tumors Lack of Awareness The cancer no one speaks about No poster person Lack of media attention Similarities to head and neck cancer (smoking, elderly, not sexy)

74 Prostate or Bladder Cancer?

75 Prostate Bladder

76 Typical Scenario Prostate 55 year old man Healthy Medium Build Diagnosed by PSA (DRE) Usually localized Bladder 75 year old man CoPD, CAD Overweight Hematuria Often locally advanced

77 Contrast BC and PC Pts diagnosed with low stage PC > BC Public awareness PC >>BC Available and used marker PC >>>BC Patients seek testing PC >>>BC

GUIDELINES ON NON-MUSCLE- INVASIVE BLADDER CANCER

GUIDELINES ON NON-MUSCLE- INVASIVE BLADDER CANCER (Limited text update December 21) M. Babjuk, W. Oosterlinck, R. Sylvester, E. Kaasinen, A. Böhle, J. Palou, M. Rouprêt Eur Urol 211 Apr;59(4):584-94 Introduction