1. Management of muscle-invasive bladder cancer Todd M. Morgan Vanderbilt University

2. Case #1  63-year-old male referred with T2 bladder ca. Re-TUR shows small amt of muscle-invasive cancer  Staging work-up negative  Management: 1)Cystectomy? 2)Neoadjuvant chemotherapy + cystectomy? 3)Chemotherapy? 4)Radiation? 5)Cystoscopy in 3 months?

3. Goal Practical information to help guide clinical management of patients with muscle-invasive bladder cancer

4. Outline  Surgical management  Metastatic disease  Neoadjuvant/adjuvant chemotherapy  Bladder preservation

6. Bladder cancer  68,810 new cases/yr in US  14,100 deaths annually  Peak age: 70 yrs  80% initially non-invasive  15-25% will progress  20% initially invasive  ~50% have occult distant metastases

7. Staging  T2a: superficial m. propria  T2b: deep m. propria  T3a: micro extension into fat  T3b: macro extension into fat  T4a: invades pelvic viscera  T4b: extends to abd/pelvic walls

8. Staging  TUR – local staging  CT abd/pelvis – regional/distant staging  Relatively inaccurate for local invasion  Fails to detect nodal mets in 20-60%  MRI no better  CXR (or CT chest)  CBC, complete metabolic panel  Bone scan if elevated alk phos or sx’s

9. Outline  Surgical management  Metastatic disease  Neoadjuvant/adjuvant chemotherapy  Bladder preservation

10. Overall survival after cystectomy Path stageN5-year (%)10-year (%) T0, Ta, Tis N02088567 T1N01947652 T2N0947757 T3N0986444 T4N0794423 N+2463123 Stein 2001 JCO  24% with LN involvement

11. Lymph node involvement varies with tumor stage StageLymph node positive T0, Ta, Tis, T1 5% T2a 18% T2b 27% T3 45% T4 45% Stein 2001 JCO

12. Perioperative complications  MSKCC:  64% complication rate within 90 days  13% grade 3-5 complications  1.5% 30-day mortality  GI > infectious > wound Donat 2009 Eur Urol

13.  Vanderbilt:  45% complication rate within 30 d (7.4% major)  1.7% 30 day mortality Cookson 2008 J Urol Perioperative complications

14. Surgical factors affecting cancer outcomes  Surgical margins  MSKCC: 67/1589 (4.2%) positive margins  21% with local recurrence at 5 yrs (vs. 6%)  Median time to recurrence: 16 mo  HR 1.98 (1.2-2.43) for disease-specific death  Lymph node dissection  Numerous studies showing correlation between node count and survival post-RC  eg. Stein et al (J Urol 2003), Herr et al (J Urol 2002), Leissner et al (BJUI 2000), May (Eur Urol 2011)

15. Rationale for between node count-survival association  More LNs removed/examined = more accurate staging  “Will Rogers” phenomenon  Applicable to node-negative patients  Improved disease control  Removal of LNs with micrometatases  Surrogate marker for quality of care  Observed association may actually be due to confounding by indication

16. Proposed surgical standards  At least 10 yearly cystectomies to maintain proficiency  Positive margin rate <10%  At least 10-14 LNs should be retrieved BCOG 2001 J Urol

17. Case #2  69M with large, muscle-invasive bladder tumor and bulky lymphadenopathy.  Treatment: 1)MVAC? 2)Gemcitabine/cisplatin? 3)High-dose intensity MVAC? 4)Cystectomy?

18. Chemotherapy questions  Best regimen?  Neoadjuvant vs. adjuvant?

19. MVAC  Methotrexate/vinblastine/doxorubicin/cisplatin  Efficacy in phase III trials in advanced bladder ca  3-4% toxic death rate Cisplatin (n=120) % MVAC (n=126) (%)p Thrombocytopenia 260.1 Neutropenia 124<0.0001 Granulocytopenic fever -100.0002 Sepsis 160.04 Renal 370.22 Mucositis 017<0.0001 Hepatic 310.2 Loehrer 1992 JCO Grade 3/4 toxicities

20. MVAC vs. GC  Gemcitabine/cisplatin: better safety profile  Phase III trial: 405 patients with locally advanced or metastatic TCC  GC: Median survival 7.7 mo  MVAC: Median survival 8.3 mo  Log rank p =0.41 von der Maase 2005 JCO

21. In-service break: 2 key prognostic factors in advanced TCC von der Maase 2005 JCO  Visceral metastases  Performance score

22. High-dose intensity MVAC  EORTC 30924: phase III trial  Standard MVAC vs. HD MVAC + GCSF Metastatic or unresectable T3-4 TCC Standard MVAC MTX: 30mg/m 2 d1,d15, d22 VLB: 3mg/m 2 d2,d15,d22 ADM: 30mg/m 2 d2 CDDP: 70mg/m 2 d2 HD MVAC + GCSF MTX: 30mg/m 2 d1 VLB: 3mg/m 2 d2 ADM: 30mg/m 2 d2 CDDP: 70mg/m 2 d2 Sternberg Eur Urol 2006 Q28 days Q15 days

23. HD MVAC toxicity ToxicityGrade MVAC (n=129) (%) HD MVAC (n=134) (%)p Neutropenia 34612<0.001 4168 Neutropenic fever 2610<0.001  1 toxic death in each arm  Less WBC toxicity in HD MVAC likely secondary to GCSF  Toxicities otherwise similar Sternberg Eur Urol 2006

24. MVAC vs. HD MVAC Sternberg Eur Urol 2006  HD MVAC median survival: 9.5 mo  MVAC median survival: 8.0 mo  Log rank p=0.017  HR = 0.73 (9%CI 0.56-0.95) for HD MVAC vs. MVAC

25. Chemotherapy in advanced/metastatic TCC  MVAC ~ GC  HD MVAC > MVAC

26. Case #3  65F with T2 bladder cancer s/p TURBT, (5cm, complete resection) negative staging work-up.  Recommendation: 1)Neoadjuvant chemo + cystectomy? 2)Cystectomy, consider adjuvant chemo? 3)Chemo + RT? 4)Re-TUR?

27. Why neoadjuvant or adjuvant chemotherapy? Path stageN5-year (%)10-year (%) T0, Ta, Tis N02088567 T1N01947652 T2N0947757 T3N0986444 T4N0794423 N+2463123 Stein 2001 JCO

28. Neoadjuvant rationale  Early treatment of microscopic mets  Downstaging of primary tumor  Drug delivery not compromised by previous surgery/radiation  Precise end-point of treatment  Better patient tolerance

29. Phase 3 trials of neoadjuvant chemotherapy Study groupNeoadjuvant armStandard armPatients (n)Survival Australia/United Kingdom DDP/RTRT255No difference Canada/NCIC DDP/RT or preop RT + Cyst RT/preop RT + Cyst99No difference Spain (CUETO)DDP/CystCyst121No difference EORTC/MRCCMV/RT or CystRT or Cyst976 5.5% difference in favor of CMV SWOGM-VAC/CystCyst307 Trend in survival benefit with M-VAC (p=0.06) Italy (GUONE)M-VAC/CystCyst206No difference Italy (GISTV)M-VEC/CystCyst171No difference GenoaDDP/5FU/RT/CystCyst104No difference Nordic 1ADM/DDP/RT/CystRT/Cyst311 No difference, 15% benefit with ADM + DDP in T3-T4a Nordic 2MTX/DDP/CystCyst317No difference Abol-EneinCarboMV/CystCyst194Benefit with CarboMV From Calabro Eur Urol 2009

30. EORTC neoadjuvant trial  Largest trial of neoadjuvant chemoRx  987 pts undergoing RT or cystectomy  Randomized to MVC or no treatment  106 institutions  Powered to detect 10% difference in overall survival  5.5% difference in 3-year survival (p=0.075) EORTC Lancet 1999

31. SWOG 8710  307 pts with locally advanced bladder cancer  Randomized to neoadjuvant MVAC + cystectomy vs. cystectomy alone Grossman 2003 NEJM

32. SWOG 8710  Increased risk of death in cystectomy alone group: HR 1.33 (CI 1.00-1.76)  Disease specific HR 1.66 (CI 1.22-2.45)  Survival benefit linked to downstaging MVAC + cystectomyCystectomyp Median survival 77 mo46 mo0.06 pT0 38%15%<0.001 Grossman 2003 NEJM

33. Neoadjuvant meta-analysis ABC Eur Urol 2005  5% survival benefit in favor of neoadjuvant chemotherapy

34. Critiques  Driven by SWOG and EORTC trials  Majority in these trials were young (63-65 yrs), had excellent performance status, and good renal function  Quality of surgery—confounding factor?  Delay in surgery for non-responders (~40%)  Is 5% benefit sufficient given toxicities?  Minimal benefit for T2  What about gemcitabine/cisplatin?

35. Adjuvant rationale  Selection of patients at highest risk for failure  Avoids over-treating patients likely to have good outcome from surgery alone  Surgery performed without delay

36. Adjuvant chemotherapy trials InvestigatorYearRegimenChemoNo chemoResults Logothetis1988CISCA6271 Benefit but not randomized Skinner1991CAP4744 Benefit few patients received therapy Stockle1992M-VAC/M-VEC2326 Benefit no treatment at relapse Studer1994DDP4037No benefit Bono1995CM4835No benefit for N0 Freiha1996CMV25 Benefit in relapse-free survival Otto2001M-VEC5553No benefit Cognetti2008GC9786No benefit for N0 or N+ From Calabro Eur Urol 2009

37. Is it reasonable to extrapolate neoadjuvant data to adjuvant setting?  140 pts randomized to neoadjuvant (peri-operative) MVAC vs. adjuvant MVAC  Suggests similar survival rates between the two groups Millikan 2001 JCO

38. Problems with this study  At least 2 cycles of chemo received by 97% in neoadj group vs. 77% in adj group  Significant delays in treatment in adjuvant group  Positive surgical margins: 2% in neoadj group vs. 11% in adj group Millikan 2001 JCO

39. Case #1  63-year-old male referred with T2 bladder ca. Re-TUR shows small amt of muscle-invasive cancer  Staging work-up negative  Management: 1)Cystectomy? 2)Neoadjuvant chemotherapy + cystectomy? 3)Chemotherapy? 4)Radiation (+/- chemo)? 5)Cystoscopy in 3 months?

40. Outline  Surgical management  Metastatic disease  Neoadjuvant/adjuvant chemotherapy  Bladder preservation

41. Chemotherapy + radiation  Goal = bladder preservation  “Radiosensitizers” – 5-fluorouracil, cisplatin, gemcitabine, paclitaxil  No randomized trials of chemoradiation vs. surgery

42. Efficacy of chemoradiation  415 pts treated with radiotherapy +/- chemotherapy  Re-TUR 6 wks after treatment  Cystectomy recommended if incomplete response  Median f/u 5 yrs Rodel 2002 JCO

43.  Complete response: 72%  Local control after CR (no muscle invasion) maintained in 64% at 10 yrs  10-year disease-specific survival = 42%  >80% of survivors preserved their bladder  Tumor stage and TUR most important predictors of outcome Efficacy of chemoradiation Rodel 2002 JCO

44. Chemoradiation toxicity Toxicity% Grade 4 Salvage cystectomy due to contracted bladder2 Bowel obstruction requiring surgery1.5 Grade 3 Bladder capacity < 200cc3 Grade 2 Frequency/urgency10 Dysuria8 Diarrhea5 Proctitis2 Rodel 2002 JCO

45. Candidates for chemoradiation  Solitary tumor <5 cm  Clinical stage T2-T3a  No CIS  No hydronephrosis  No evidence of LN or distant mets  Normally functioning bladder

46. Bladder preservation with chemo + TUR only  63 pts with m.-inv ca with CR to neoadj chemo who then refused cystectomy  All underwent re-staging TUR  64% survived  54% with intact bladder  8/14 pts who underwent salvage cystectomy died of bladder cancer  Prognostic factors: single invasive tumor, size <5cm, complete resection Herr 2008 Eur Urol

47. Summary  Surgical management  Margins  LN dissection  Metastatic disease  MVAC, HD MVAC, and GC  Neoadjuvant/adjuvant chemotherapy  Modest benefit  Best regimen?  Bladder preservation  Chemoradiation  Chemotherapy + TUR

48. “Optimal” management  Quality of cystectomy, LN dissection, and peri-operative management critical  Best evidence supports neoadjuvant chemo + cystectomy for pts who will tolerate it  Chemotherapy regimen still under debate – need more trial data  Bladder-sparing approaches may be considered in selected individuals