Management of muscle-invasive bladder cancer

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: • Cystectomy? • Neoadjuvant chemotherapy + cystectomy? • Chemotherapy? • Radiation? • 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 • 24% with LN involvement Stein 2001 JCO

11. Lymph node involvement varies with tumor stage 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. Perioperative complications • Vanderbilt: • 45% complication rate within 30 d (7.4% major) • 1.7% 30 day mortality Cookson 2008 J Urol

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: • MVAC? • Gemcitabine/cisplatin? • High-dose intensity MVAC? • Cystectomy?

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

19. MVAC Grade 3/4 toxicities • Methotrexate/vinblastine/doxorubicin/cisplatin • Efficacy in phase III trials in advanced bladder ca • 3-4% toxic death rate Loehrer 1992 JCO

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 Visceral metastases Performance score von der Maase 2005 JCO

22. High-dose intensity MVAC Q28 days Q15 days • EORTC 30924: phase III trial • Standard MVAC vs. HD MVAC + GCSF Sternberg Eur Urol 2006

23. HD MVAC toxicity • 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 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 Sternberg Eur Urol 2006

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: • Neoadjuvant chemo + cystectomy? • Cystectomy, consider adjuvant chemo? • Chemo + RT? • Re-TUR?

27. Why neoadjuvant or adjuvant chemotherapy? 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 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 Grossman 2003 NEJM

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

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 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: • Cystectomy? • Neoadjuvant chemotherapy + cystectomy? • Chemotherapy? • Radiation (+/- chemo)? • 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. Efficacy of chemoradiation 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 Rodel 2002 JCO

44. Chemoradiation toxicity 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